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Autophagy-related 4B (ATG4B) is a protease required for core machinery of autophagy. Phosphorylation of ATG4B promotes autophagy and is correlated with poor outcome of cancer. However, little is known about the upstream kinases for ATG4B phosphorylation and their association with clinical outcomes of cancer patients. Through siRNA library screening, MAP3K11 was identified as a potential kinase that phosphorylates ATG4B and increases its proteolytic activity. Ablation of MAP3K11 attenuated pS383/392-ATG4B protein levels and autophagic flux in oral cancer cells. Moreover, loss of MAP3K11 inhibited oral cancer cell growth, migration/invasion, and synergized starvation-reduced cell viability. MAP3K11 knock-out cancer cells also showed growth inhibition in vivo. Furthermore, the protein level of MAP3K11 was higher in tumor tissues than that in adjacent normal tissues in patients with oral squamous cell carcinoma (OSCC), comprising 179 buccal mucosa squamous cell carcinoma (BMSCC) and 249 tongue squamous cell carcinoma (TSCC). MAP3K11 protein levels were positively correlated with ATG4B and pS383/392-ATG4B levels in patients with OSCC, particularly in TSCC. In addition, high coexpression of MAP3K11 and ATG4B was associated with poor disease-specific survival in BMSCC and TSCC, while high coexpression of MAP3K11 and pS383/392-ATG4B was associated with unfavorable disease-free survival in BMSCC and TSCC. Taken together, our results indicated that MAP3K11 stimulated activity of ATG4B and autophagy, which may confer to malignancy of cancer cells. The expression of MAP3K11 and ATG4B was further associated with poor survival of OSCC, suggesting MAP3K11 could serve as a theranostic target of patients with OSCC.

Kawasaki disease (KD) typically occurs in children aged under 5 years and can cause coronary artery lesions (CALs). Early diagnosis and treatment with intravenous immunoglobulin can reduce the occurrence of CALs, therefore, identifying a good biomarker for diagnosing KD is essential. Here, using next-generation sequencing in patients with recurrent KD, those with viral infection, and healthy controls, we identified dysregulated circulating microRNAs as diagnostic biomarkers for KD. Pathway enrichment analysis illustrated the putative role of these miRNAs in KD progression. Their expression levels were validated using real-time polymerase chain reaction (qPCR). Fifteen dysregulated circulating miRNAs (fold changes &gt, 2 and &lt, 0.5) were differentially expressed in the recurrent KD group compared with the viral infection and control groups. These miRNAs were significantly involved in the transforming growth factor-β, epithelial–mesenchymal transition, and cell apoptosis signaling pathways. Notably, their expression levels were frequently restored after intravenous immunoglobulin treatment. Among the candidates, miR-24-3p expression level was significantly higher in patients with recurrent KD compared with healthy controls or viral infection controls (p &lt, 0.001). Receiver operating characteristic analysis revealed that high miR-24-3p expression levels may be a potential biomarker for KD diagnosis. In conclusion, we identified miR-24-3p significantly higher in KD patients, which may be a potential diagnostic biomarker for KD.

Aims/Hypothesis: Large-scale prediabetes screening is still a challenge since fasting blood glucose and HbA1c as the long-standing, recommended analytes have only moderate diagnostic sensitivity, and the practicability of the oral glucose tolerance test for population-based strategies is limited. To tackle this issue and to identify reliable diagnostic patterns, we developed an innovative metabolomics-based strategy deviating from common concepts by employing urine instead of blood samples, searching for sex-specific biomarkers, and focusing on modified metabolites. Methods: Non-targeted, modification group-assisted metabolomics by liquid chromatography–mass spectrometry (LC-MS) was applied to second morning urine samples of 340 individuals from a prediabetes cohort. Normal (n = 208) and impaired glucose-tolerant (IGT; n = 132) individuals, matched for age and BMI, were randomly divided in discovery and validation cohorts. ReliefF, a feature selection algorithm, was used to extract sex-specific diagnostic patterns of modified metabolites for the detection of IGT. The diagnostic performance was compared with conventional screening parameters fasting plasma glucose (FPG), HbA1c, and fasting insulin. Results: Female- and male-specific diagnostic patterns were identified in urine. Only three biomarkers were identical in both. The patterns showed better AUC and diagnostic sensitivity for prediabetes screening of IGT than FPG, HbA1c, insulin, or a combination of FPG and HbA1c. The AUC of the male-specific pattern in the validation cohort was 0.889 with a diagnostic sensitivity of 92.6% and increased to an AUC of 0.977 in combination with HbA1c. In comparison, the AUCs of FPG, HbA1c, and insulin alone reached 0.573, 0.668, and 0.571, respectively. Validation of the diagnostic pattern of female subjects showed an AUC of 0.722, which still exceeded the AUCs of FPG, HbA1c, and insulin (0.595, 0.604, and 0.634, respectively). Modified metabolites in the urinary patterns include advanced glycation end products (pentosidine-glucuronide and glutamyl-lysine-sulfate) and microbiota-associated compounds (indoxyl sulfate and dihydroxyphenyl-gamma-valerolactone-glucuronide). Conclusions/Interpretation: Our results demonstrate that the sex-specific search for diagnostic metabolite biomarkers can be superior to common metabolomics strategies. The diagnostic performance for IGT detection was significantly better than routinely applied blood parameters. Together with recently developed fully automatic LC-MS systems, this opens up future perspectives for the application of sex-specific diagnostic patterns for prediabetes screening in urine.

BACKGROUND Prescribing opioids for patients with chronic noncancer pain (CNCP) remains controversial. This study surveyed Taiwanese physicians who were clinically treating CNCP outpatients with long-term opioids. METHODS Anonymous questionnaires investigating the clinical practices, opioid knowledge, attitude, and barriers regarding the prescription of long-term opioids were delivered to 66 physicians treating CNCP outpatients who were officially registered and monitored by the Taiwan Food and Drug Administration in 2011. RESULTS All 66 (100%) physicians responded to the survey, comprising 41 (62%) board-certified pain specialists and 25 (38%) nonpain board-certified physicians. Pain specialists treated a greater number of CNCP outpatients and attended more CNCP training courses than nonpain board-certified physicians (97.6% vs. 56.0%, p < 0.001). Most of pain specialists stated that they were familiar with the Taiwan's narcotic regulations for CNCP patients (92.7% vs. 68.0%, p = 0.015). In addition, pain specialists were less likely to skip or reduce the dosage and duration of opioid prescriptions (22.0% vs. 36.0%, p < 0.001). By contrast, nonpain board-certified physicians had significantly less knowledge and a more negative attitude toward opioid prescription. The major perceived barriers were physician's reluctance to prescribe opioids (78% vs. 92%) and an inadequate knowledge of pain management (73% vs. 84%) among all physicians. CONCLUSION Among the Taiwanese physicians treating the officially registered CNCP patients, nonpain board-certified physicians had fewer patients, less knowledge, and an increased negative attitude toward long-term opioid prescriptions. Better education on chronic pain management is needed for improvement of clinical practice.

Brian metastasis, which is diagnosed in 30% of triple-negative breast cancer (TNBC) patients with metastasis, causes poor survival outcomes. Growing evidence has characterized miRNAs involving in breast cancer brain metastasis; however, currently, there is a lack of prognostic plasma-based indicator for brain metastasis. In this study, high level of miR-211 can act as brain metastatic prognostic marker in vivo. High miR-211 drives early and specific brain colonization through enhancing trans-blood–brain barrier (BBB) migration, BBB adherence, and stemness properties of tumor cells and causes poor survival in vivo. SOX11 and NGN2 are the downstream targets of miR-211 and negatively regulate miR-211-mediated TNBC brain metastasis in vitro and in vivo. Most importantly, high miR-211 is correlated with poor survival and brain metastasis in TNBC patients. Our findings suggest that miR-211 may be used as an indicator for TNBC brain metastasis.

Lupus nephritis (LN) is a significant cause of various acute and chronic renal diseases, which can eventually lead to end-stage renal disease. The pathogenic mechanisms of LN are characterized by abnormal activation of the immune responses, increased cytokine production, and dysregulation of inflammatory signaling pathways. LN treatment is an important issue in the prevention and treatment of systemic lupus erythematosus. Mesenchymal stem cells (MSCs) have the advantages of immunomodulation, anti-inflammation, and anti-proliferation. These unique properties make MSCs a strong candidate for cell therapy of autoimmune diseases. MSCs can suppress the proliferation of innate and adaptive immune cells, such as natural killer cells (NKs), dendritic cells (DCs), T cells, and B cells. Furthermore, MSCs suppress the functions of various immune cells, such as the cytotoxicity of T cells and NKs, maturation and antibody secretion of B cells, maturation and antigen presentation of DCs, and inhibition of cytokine secretion, such as interleukins (ILs), tumor necrosis factor (TNF), and interferons (IFNs) by a variety of immune cells. MSCs can exert immunomodulatory effects in LN through these immune functions to suppress autoimmunity, improve renal pathology, and restore kidney function in lupus mice and LN patients. Herein, we review the role of immune cells and cytokines in the pathogenesis of LN and the mechanisms involved, as well as the progress of research on the immunomodulatory role of MSCs in LN.

BACKGROUND Buccal mucosal squamous cell carcinoma (BMSCC) is an aggressive oral cancer. Moreover, reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a well-known tumor suppressor in many cancers. Our aim was to investigate the association of RECK expression with prognosis in BMSCC patients with different clinicopathological features. MATERIALS AND METHODS The expression level of RECK was determined by immunohistochemistry using tissue microarrays containing specimens from 193 BMSCC patients. The association of RECK expression with outcomes in BMSCC patients stratified by different clinicopathological features was analyzed by Cox proportional hazards models. RESULTS The low expression level of RECK was associated with shorter disease-specific survival, especially in patients with age >40 years, moderate or poor cell differentiation, advanced pathological stage, and history of postoperative radiotherapy. However, the low expression level of RECK was not associated with poor disease-free survival, except in BMSCC patients with age ≦40 years, advanced pathological stage and lymph node metastasis. Furthermore, RECK-knockdowned cells showed higher cell viability and abilities of invasion/migration, indicating that RECK might be a tumor suppressor for tumor progression in oral cancer. CONCLUSION The low expression of RECK might be a potential prognostic biomarker for pathological outcome-dependent BMSCC patients.

Guanylate-binding protein 6 (GBP6) is a member of the guanylate-binding protein family, and its role in cancer has not yet been reported. We aimed to investigate the clinical significance of GBP6 in oral squamous cell carcinoma (OSCC). Next-generation sequencing was applied for analyzing differential gene expression profiling between corresponding tumor adjacent normal (CTAN) and tumor tissue from two paired OSCC patients. Real-time PCRs (RT-PCRs) were used to investigate the gene expression level of GBP6 of CTAN and tumor tissue samples from 14 TSCC patients. Immunohistochemistry was used to investigate the protein expression level of GBP6 in tumor tissues and paired CTAN tissues from 488 OSCC patients, including 183 buccal mucosa squamous cell carcinoma (BMSCC), 245 tongue squamous cell carcinoma (TSCC), and 60 lip squamous cell carcinoma (LSCC) patients. Compared with CTAN tissues of OSCC patients, GBP6 is identified as a downregulated gene using the NGS platform, which was confirmed in 14 OSCC patients by RT-PCR. Moreover, protein expression level of GBP6 in tumor tissues was lower than that in CTAN tissues and the low GBP6 expression was correlated with poor cell differentiation/lymph node metastasis in TSCC patients. In addition, TSCC patients with low expression levels of GBP6 had poor disease-specific survival rate. The low expression of GBP6 was associated with tumorigenesis and poor prognosis in OSCC patients, especially in TSCC patients. GBP6 may serve as a novel favorable diagnostic and prognostic biomarker in TSCC patients.

Oral squamous cell carcinoma (OSCC) is one of the most common types of malignant tumor. Sequestosome 1 (SQSTM1) serves as an adaptor of autophagy for degrading protein aggregates. The regulation of autophagy by EGFR and its clinical impacts are indicated in various types of cancer. However, the association of EGFR and SQSTM1 in OSCC is still unknown. Our results show that the expression levels of SQSTM1 and EGFR proteins are higher in tumor tissues than in the corresponding tumor-adjacent (CTAN) tissues of OSCC patients. The expression levels of SQSTM1 were positively associated with the EGFR expression level. High co-expression of SQSTM1 and EGFR is associated with poor prognosis in OSCC patients. Moreover, SQSTM1 expression is decreased in EGFR-knockdown cells. Cell growth and invasion/migration are also decreased in cells with single/combined knockdowns of EGFR and SQSTM1 or in SQSTM1-knockdown cells without EGFR kinase inhibitor Lapatinib treatment compared to that in scrambled cells. However, cell growth and invasion/metastasis were not significantly different between the scrambled cells and SQSTM1-knockdown cells in the presence of Lapatinib. This study is the first to indicate the biological roles and clinical significance of SQSTM1 regulation by EGFR in OSCC.

Buccal mucosa squamous cell carcinoma (BMSCC) is one of major subsites of oral cancer and is associated with a high rate of metastasis and poor prognosis. Heat shock proteins (HSPs) act as potential prognostic biomarkers in many cancer types. However, the role of HSPD1 in oral cancer, especially in BMSCC, is still unknown. Through data analysis with The Cancer Genome Atlas (TCGA), we found the association of HSPD1 gene expression with tumorigenesis and poor prognosis in oral cancer patients. Our cohort study showed that higher HSPD1 protein level was associated with tumorigenesis and poor prognosis in BMSCC patients with lymph node invasion, suggesting that HSPD1 may be involved in tumor metastasis. Moreover, knockdown of HSPD1 induced E-cadherin expression and decreased the migration and invasion of BMSCC cells. In contrast, ectopic expression of HSPD1 diminished E-cadherin expression and promoted the migration/invasion of BMSCC cells. Further, HSPD1 regulated RelA activation to repress E-cadherin expression, enhancing the migration and invasion of BMSCC cells. Furthermore, HSPD1 protein level was inversely correlated with E-cadherin protein level in tumor tissues and co-expression of high HSPD1/low E-cadherin showed a significant association with poor prognosis in BMSCC patients. Taken together, HSPD1 might repress E-cadherin expression and promote metastatic characters of BMSCC cells for poor prognosis of BMSCC patients.

BACKGROUND Type V collagen (COL5), in the functional heterotrimer [α1(V)2 α2(V)] isoform, participates in the malignancies of various cancers. However, its role in tongue squamous cell carcinoma (TSCC) remains unclear. MATERIALS AND METHODS The expression levels of COL5A1 and COL5A2 polypeptide chains were examined using the tissue microarray from 245 TSCC patients with immunohistochemistry. Paired t test and Wilcoxon signed-rank test were performed for comparisons among the groups. Survival rates were estimated by using the Kaplan-Meier method and compared with log-rank tests. A Cox proportional hazards model was used to evaluate the impact of protein expression level on survival rate. RESULTS Expression level of COL5A1 was significantly increased in tumor tissues (P

C6orf141 (Chromosome 6 open reading frame 141) is a novel gene, and its role in oral cancer progression remains unclear. C6orf141 expression in oral squamous cell carcinoma (OSCC) and adjacent normal tissues from 428 patients was examined through immunohistochemistry (IHC). Our results revealed that C6orf141 expression was significantly reduced in OSCC compared with adjacent normal tissues. Low C6orf141 expression was significantly associated with a poor American Joint Committee on Cancer pathological stage (P P = 0.002), and pN stage (P = 0.032). Kaplan–Meier curves revealed that low C6orf141 expression was significantly associated with shorter disease-specific survival (DSS) in patients with OSCC (log-rank P = 0.007). Multivariate analysis indicated that low C6orf141 expression was an independent prognostic biomarker for DSS (adjusted hazard ratio = 1.34; 95% confidence interval = 1.10–1.81; P = 0.05). Additionally, ectopic C6orf141 expression could significantly suppress oral cancer cell proliferation, colony formation, and migratory and invasive abilities. Xenograft tumor growth assay revealed that C6orf141 could significantly suppress oral tumor growth in vivo. Our results suggest that C6orf141 plays a novel tumor-suppressive role in oral cancer cell growth and motility. Furthermore, C6orf141 dysfunction could be a potential prognostic biomarker for OSCC and provide new therapeutic strategies in the future.

The interleukin-(IL)-1 subfamily consists of IL-1α, IL-1β, IL-1 receptor antagonist IL-1Ra and IL-33. These cytokines are the main members of the IL-1 family and have been widely recognized as having significant roles in pro-inflammatory and immunomodulatory actions. Mounting evidence has revealed that these cytokines also play key roles in the regulation of glycolysis, which is an important metabolic pathway in most organisms that provides energy. Dysregulation of glycolysis is associated with various diseases, including type 2 diabetes, rheumatoid arthritis (RA) and cancer. We reviewed studies addressing the important roles of IL-1 subfamily cytokines, with particular focus on their ability to regulate glycolysis in disease states. In this review, we summarize the potential roles of IL-1 subfamily members in glycolysis in disease states and address the underlying mechanisms. Furthermore, we discuss the potential of these cytokines as therapeutic targets in clinical applications to provide insight into possible therapeutic strategies for treatment, especially for cancers.

Background Elucidation of the molecular mechanisms involved in the pathogenesis of coronavirus disease (COVID-19) may help to discover therapeutic targets. Methods To determine the metabolomic profile of circulating plasma from COVID-19 survivors with pulmonary sequelae 3 months after discharge, a random, outcome-stratified case-control sample was analyzed. We enrolled 103 recovered COVID-19 patients as well as 27 healthy donors, and performed pulmonary function tests, computerized tomography (CT) scans, laboratory examinations, and liquid chromatography-mass spectrometry. Results Plasma metabolite profiles of COVID-19 survivors with abnormal pulmonary function were evidently different from those of healthy donors or subjects with normal pulmonary function. These alterations were associated with disease severity and mainly involved amino acid, and glycerophospholipid metabolic pathways. Furthermore, increased levels of triacylglycerols, phosphatidylcholines, prostaglandin E2, arginine, and decreased levels of betain and adenosine were associated with pulmonary CO diffusing capacity and total lung capacity. The global plasma metabolomic profile differed between subjects with abnormal and normal pulmonary function. Conclusions Further metabolite-based analysis may help to identify the mechanisms underlying pulmonary dysfunction in COVID-19 survivors, and provide potential therapeutic targets in the future.

BACKGROUND/AIM Breast cancer is a common type of cancer in women, and metastasis frequently leads to therapy failure. Using next-generation sequencing (NGS), we aspired to identify the optimal differentially expressed genes (DEGs) for use as prognostic biomarkers for breast cancer. MATERIALS AND METHODS NGS was used to determine transcriptome profiles in breast cancer tissues and their corresponding adjacent normal tissues from three patients with breast cancer. RESULTS Herein, 15 DEGs (fold change >4 and

Background High Snail expression is known as a poor prognostic factor in breast cancer. However, its prognostic impact for breast cancer with different molecular subtypes is still controversial. Methods Snail expression was examined by immunohistochemistry in tissue microarray slides of 85 corresponding tumor-adjacent normal (CTAN) and 247 breast invasive ductal carcinoma (IDC) tissues. Multivariable Cox regression analysis was used to assess the impact of Snail expression on survival rate by different molecular subtypes of breast IDC patients. Results The level of Snail expression in IDC tumor tissues was significantly higher than that in CTAN tissues. Moreover, high Snail expression had direct impacts on poor disease specific survival (DSS) and disease-free survival (DFS) in breast IDC patients with human epidermal growth factor receptor 2 (HER2)-positive and human epidermal growth factor receptor (EGFR)-positive statuses as well as the HER2 intrinsic subtype. Additionally, breast IDC patients with a combination of three prognostic factors, including high Snail expression and HER2-positive and EGFR-positive statuses, had much poor DSS and DFS with a statistically significant linear trend. Conclusion High Snail expression could predict a poor prognosis for breast IDC patients with HER2/EGFR-positive subtypes.

The aim of this study was to investigate the associations among the immunoexpression levels of manganese superoxide dismutase (Mn-SOD), glutathione peroxidase (GPx), and myeloperoxidase (MPO) in lip squamous cell carcinoma (LSCC) tissues and the clinicopathological characteristics, and prognostic factors in patients with LSCC. The immunoexpression levels of Mn-SOD, GPx, and MPO were examined in 76 LSCC tissue samples using immunohistochemical staining on tissue microarray slides, and compared to those in normal lip mucosa adjacent to venous lakes (normal controls), normal tissue adjacent to corresponding tumors (NTACT), and recurrent tumors. Associations between immunoexpression levels and clinicopathological characteristics were analyzed using the Student's t-test. The prognostic factors were analyzed using Cox regression. The immunoexpression levels of Mn-SOD, GPx, and MPO were significantly different among the normal controls, NTACTs, tumors, and recurrent tumors (Mn-SOD: p = 0.001, GPx: p

Background The isocitrate dehydrogenase (IDH) gene family expresses key functional metabolic enzymes in the Krebs cycle and mediates the epigenetic reprogramming, which serves as an important biomarker of breast cancer. However, the expression levels of the IDH protein and their biological function in human breast cancer remain largely unknown. Methods In this study, the clinical impact of IDH1 expression on the progression and prognosis of breast cancer was evaluated using immunohistochemistry assay (IHC) of the corresponding tumor-adjacent normal, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) tissues from 309 patients with breast ductal carcinoma. The relationship between microRNA (miRNA) and IDH1 were examined by a bioinformatics approach, western blot and reporter assay. The biological functions of IDH1 were examined in breast cancer cells with IDH1 knockdown, including proliferation, migration and invasion. Results The present findings revealed that the mRNA and protein expression levels of IDH1 were both significantly lower in breast cancer tissues than in adjacent normal tissues. A low expression level of IDH1 in breast cancer significantly correlated with advanced stage (p = 0.012), lymph node metastasis (p = 0.018), and poor disease-specific survival (DSS) (adjusted hazard ratio (AHR), 1.57, 95% confidence interval (CI), 1.08–2.30; p = 0.02). Furthermore, oncogenic miR-32 and miR-92b were identified to suppress IDH1 expression, leading to the inhibition of cell migration and invasion. We further explored whether reduced expression of IDH1 significantly increases snail expression by activating HIFα (hypoxia-inducible factor-1 alpha) and NFκB (nuclear factor kappa B) signaling. Multivariate Cox regression analysis revealed that the combination of low IDH1 and high snail expression could be an independent risk factor for shorter DSS (AHR, 2.34; 95% CI, 1.32–4.16; p = 0.004) and shorter disease-free survival (AHR, 2.50; 95% CI, 1.39–4.50; p = 0.002) in patients with breast cancer. Conclusion Our findings revealed that a IDH1low/Snailhigh molecular signature could serve as an independent biomarker for poor prognosis in breast cancer Electronic supplementary material The online version of this article (10.1186/s13058-018-0953-7) contains supplementary material, which is available to authorized users.

Background/purpose Prescribing opioids for chronic noncancer pain has been strictly regulated for two decades in Taiwan. The aim of this study was to survey the patients' perspectives and potential drawbacks following long-term use of opioids. Methods An observational cross-sectional survey using the Taiwanese version of Brief Pain Inventory was conducted among outpatients with chronic noncancer pain registered by the Taiwan Food and Drug Administration. Patients were also asked about their sexual behavior, depression, opioid misuse behaviors, and use of complementary and alternative medicine. Results For 210 of 328 outpatients (64.0%), the median pain duration was 96 months and opioid treatment duration was 57 months. The median morphine equivalent dose was 150 mg/d, with 30.5% of patients exceeding the daily watchful dose, defined as 200 mg of morphine equivalent dose. Pain reduction after taking opioids was ∼50% in the past week. The top three diagnoses were chronic pancreatitis, spinal cord injury, and neuralgia. The leading side effects were constipation (46.7%), and decreased sexual desire (69.5%) and satisfaction (57.9%). Depression was currently diagnosed in 55.2% of patients. Twenty patients (9.5%) displayed at least one aberrant behavior in the past month. Only 76 (36.2%) patients had ever received nerve block procedures, and 118 (56.2%) tried complementary and alternative medicine. Conclusion This nationwide survey described the concurrent pain intensity, daily function, and various adverse effects by long-term opioids among 210 monitored outpatients with chronic noncancer pain in Taiwan. More efforts are suggested to reduce opioid prescriptions in the 30% of patients exceeding daily watchful dose.

Dysfunctional microRNAs (miRNAs) play a crucial role in oral squamous cell carcinoma (OSCC) progression. In the present study, we performed next-generation sequencing for miRNA profiling of the OSCC tissues and corresponding adjacent normal tissues in two patients with OSCC. We observed that 45 miRNAs were substantially up-regulated and 17 miRNAs were down-regulated in OSCC tissues. Since information on the biological role of miR-21-3p (passenger strand) in OSCC is limited, the expression levels of miR-21-3p were further evaluated in 95 OSCC tissue samples by a stem-loop real-time polymerase chain reaction. Our results revealed that miR-21-3p is significantly overexpressed in the OSCC tissues compared with the corresponding adjacent normal tissues (p

Objective To investigate the relationships between two single-nucleotide polymorphisms at miR-146a C > G (rs2910164) and miR-1269b G > C (rs7210937) and the risk of developing oral premalignant lesions (OPLs), oral squamous cell carcinoma (OSCC), pharyngeal SCC (PSCC), and oral and pharyngeal SCC (OPSCC). Design Genotyping of miR-146a C > G and miR-1269b G > C was performed in two case-control studies using the TaqMan assay. A total of 197 healthy control subjects, 241 OPLs patients, and 188 OPSCC patients who habitually chewed betel quid (BQ) were recruited into one case-control study. Additionally, 668 cancer-free control subjects and 658 OPSCC patients were recruited into the other case-control study. Results The G/G genotype at miR-146a C > G was associated with the decreased risk of OSCC [adjusted odds ratio (AOR) = 0.66, P = 0.040], PSCC (AOR = 0.42, P = 0.013), and OPSCC (AOR = 0.63, P = 0.020). Additionally, the C allelic type and C/C genotype at miR-1269b G > C decreased the risk of BQ-related oral leukoplakia (C vs. G: AOR = 0.68, P = 0.012; C/C vs. G/G: AOR = 0.43, P = 0.009), BQ-related OPLs (C vs. G: AOR = 0.69, P = 0.008; C/C vs. G/G: AOR = 0.44, P = 0.005), and BQ-related OPSCC (C vs. G: AOR = 0.65, P = 0.003; C/C vs. G/G: AOR = 0.47, P = 0.011). In OPSCC patients, the G/G genotype of miR-146a was correlated with well-differentiated cells (P = 0.041), and the G/C and C/C genotypes of miR-1269b were correlated with the absence of lymph node involvement (P = 0.031), especially in OSCC patients (P = 0.038 and P = 0.007, respectively). Conclusion The genetic variants of miR-146a and miR-1269b are biomarkers against the development of OPLs and OPSCC.

// Ting-Ying Fu 1, 2, * , Chao-Nan Wu 3, 4, * , Huei-Cin Sie 1 , Jiin-Tsuey Cheng 5 , Yaoh-Shiang Lin 6 , Huei-Han Liou 7 , Yu-Kai Tseng 8, 9 , Chih-Wen Shu 7 , Kuo-Wang Tsai 7, 10 , Leing-Ming Yen 1 , Hui-Wen Tseng 11, 12 , Ching-Jiunn Tseng 7, 13, 14, 15 , Luo-Ping Ger 7, 16 , Pei-Feng Liu 7, 17 1 Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 2 Department of Optometry, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan 3 Department of Stomatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 4 Department of Dental Technology, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan 5 Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan 6 Department of Otorhinolaryngology-Head & Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 7 Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 8 Department of Orthopedics, Show Chwan Memorial Hospital, Changhua, Taiwan 9 Department of Orthopedics, National Cheng Kung University Hospital, Tainan, Taiwan 10 Department of Chemical Biology, National Pingtung University of Education, Pingtung, Taiwan 11 Department of Dermatology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan 12 Department of Nursing, Meiho University, Pingtung, Taiwan 13 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 14 Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan 15 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan 16 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan 17 Department of Biotechnology, Fooyin University, Kaohsiung, Taiwan * These authors have contributed equally to this work Correspondence to: Luo-Ping Ger, email: lpger@vghks.gov.tw Pei-Feng Liu, email: pfliu@vghks.gov.tw Keywords: DDX60, oral cancer, subsite-specific, tumorigenesis, prognosis Received: April 14, 2016 Accepted: October 28, 2016 Published: November 08, 2016 ABSTRACT The clinical significance and biological function of DEXD/H box helicase 60 (DDX60) in oral cancer remains unknown. Herein, we evaluated the association of DDX60 expression with tumorigenesis and the prognosis of oral squamous cell carcinoma (OSCC). DDX60 expression was examined by immunohistochemistry on tissue microarray slides of 494 OSCC patients, including 180 buccal mucosal SCC (BMSCC), 241 tongue SCC (TSCC), and 73 lip SCC (LSCC) patients. DDX60 expression was significantly increased in all three subsites of OSCC compared to its expression in tumor adjacent normal tissues. However, its association with tumorigenesis was specific to the oral cavity subsite after the stratification of betel quid chewing, smoking, and drinking. Among OSCC patients, higher levels of DDX60 expression were associated with the male gender, a well-differentiated tumor, advanced stage of disease, and a large tumor size with subsite specific features. LSCC patients with high DDX60 expression levels showed shorter disease-specific survival, particularly those with moderately or poorly differentiated tumors. Additionally, TSCC or OSCC patients with high DDX60 expression showed a poor disease-free survival (DFS), particularly those with moderately or poorly differentiated tumors. Therefore, DDX60 is a novel and unfavorable biomarker for tumorigenesis and prognosis of OSCC in a subsite-specific manner.

Long-term exposure to betel quid (BQ)-, cigarette-, and alcohol-induced chronic inflammation is a crucial risk factor for oral and pharyngeal squamous cell carcinoma (OPSCC) progression. We analyzed the genotypes of stromal-cell-derived factor-1 (SDF-1) and CXC-chemokine receptor-4 (CXCR4) and determined the association between their polymorphisms and the risk of OPSCC.This study consisted of 452 patients with pathologically proved OPSCC and 424 sex- and age-matched cancer-free controls. The genotypes of SDF-1 and CXCR4 were detected through the TaqMan real-time polymerase chain reaction (PCR) method.Our data indicated that the C allele and C/C genotypes of CXCR4 were significantly associated with OPSCC [adjusted odds ratio (AOR)=1.41, 95% confidence interval (CI):1.02-1.96, p=0.037 and AOR=1.51, 95% CI:1.05-2.17, p=0.028, respectively] and OSCC (AOR=1.41, 95%CI:1.00-2.00, p=0.049 and AOR=1.49, 95%CI:1.01-2.20, p=0.044, respectively) risk. Patients with genetic polymorphisms of the genotype combination SDF-1/CXCR4 had a higher risk of OSCC (p trend=0.033). We analyzed the effects of CXCR4 genetic variants on susceptibility to OPSCC in patients with different risk habits of BQ chewing, tobacco smoking and alcohol consumption, and revealed that C/T+T/T genotypes exerted an increased risk only in patients with one (AOR=2.68, p=0.036) or two risk habits (AOR=2.02, p=0.027) compared to patients with the C/C genotype.We concluded that CXCR4 CT can be used as a genetic marker of susceptibility to OPSCC, particularly in OPSCC patients with one or two types of risk habits with a synergistic effect.

Supplemental Digital Content is available in the text, Background: The comparative efficacy and safety of PCSK9 inhibitors, statins, and ezetimibe to lower lipid levels in patients with hypercholesterolemia remain unknown. We aimed to investigate the benefits and harms of the lipid-lowering agents in these patients. Methods: PubMed, Embase, and the Cochrane Library were searched from January 1, 2000 to June 1, 2018 for relevant randomized controlled trials (RCTs). Frequentist network meta-analysis was used to pool all estimates. Ranking probabilities were used to rank the comparative effects of all drugs against placebo. Results: Eighty-four RCTs enrolled 246,706 patients were included. Most of the included were assessed as low risk of bias. The probabilities of PCSK9 inhibitors that ranked first in improving lipid outcomes were all 100%. The probability of statins that ranked first in reducing the risk of cardiovascular (CV) events was 60.6%, and the probability of PCSK9 inhibitor was 37.1%, while no significant difference of efficacy in reducing CV events was observed between the 2 agents (odds ratios [OR] 0.98, 95% CI 0.87–1.11). Statin ranked first in reducing all-cause and CV death. Compared with placebo, statins were associated with reduced risks of all-cause (OR 0.90, 95% CI 0.85–0.96) and CV death (OR 0.83, 95% CI 0.75–0.91) while PCSK9 inhibitors and ezetimibe were not. No agents caused adverse events (including neurocognitive events), except that statins therapy significantly increases the levels of alanine aminotransferase (ALT) (OR 1.89, 95% CI 1.42–2.51) and creatine kinase (CK) (OR 1.45, 95% CI 1.09–1.93) and the incidence of diabetes (OR 1.13, 95% CI 1.02–1.26). Conclusions: PCSK9 inhibitors were the most effective lipid-lowering agents in improving lipid levels. Furthermore, PCSK9 inhibitors achieved similar CV benefits like statins, while PCSK9 inhibitors were not associated with any increased risk of statin-related side-effects. Thus, PCSK9 inhibitors may also be recommended as promisingly first-line lipid-lowering treatment for patients with hypercholesterolemia, especially for these with statins intolerance or resistance.

Purpose Cisplatin resistance is still a serious problem in the clinic. However, the underlying mechanism remains unknown. In our study, we investigated cisplatin resistance by using the cisplatin-resistant cell line HCT116R. Methods The HCT116 cell line, a colon cancer cell line, was purchased. Cell viability was determined using CCK-8 Assay Kit. The gene expression levels of MIR4435-2HG, Nrf2, and HO-1, and caspase activity were determined using qRT-PCR and Caspase 3 Assay Kit, respectively. Results In this study, we found that the levels of the lncRNA MIR4435-2HG were dramatically increased in the cisplatin-resistant cell line HCT116R. Knockdown of MIR4435-2HG in HCT116R cells significantly restored the sensitivity to cisplatin, inhibited cell proliferation and promoted cell apoptosis. Furthermore, Nrf2 and HO-1 mRNA levels, as critical molecules in the oxidative stress pathway, were inhibited by siRNAs targeting MIR4435-2HG, suggesting that MIR4435-2HG-mediated cisplatin resistance occurs through the Nrf2/HO-1 pathway. Conclusion Our findings demonstrate that the lncRNA MIR4435-2HG is a main factor driving the cisplatin resistance of HCT116 cells.

Background Uncoordinated 51-like kinase 1 (ULK1) plays a vital role in autophagy. ULK1 dysregulation has recently been found in several human cancers. Methods mRNA expression levels of ULK1 and clinical information were analysed from The Cancer Genome Atlas data. ULK1 expression levels were verified in 36 paired fresh ccRCC tissue specimens by western blot analysis. Expression of ULK1 was knockdown by shRNA lentivirus. ULK1 activity was inhibited by SBI-0206965. The effect of inhibition of ULK1 was measured by detecting the apoptotic rate, autophagy, and the ratio of ROS and NADPH. The efficacy of SBI-0206965 in vivo was assessed by the murine xenograft model. Findings ULK1 mRNA expression was significantly upregulated in clear cell renal cell carcinoma (ccRCC) and overexpression of ULK1 correlated with poor outcomes. We found that ULK1 was highly expressed in 66.7% of ccRCC tumours (p

Background The ageing population and the expected increase in the number of elderly patients make an evidence-based assessment of Extracorporeal Membrane Oxygenation (ECMO) therapy in old patients progressively more important. Veno-arterial (VA) ECMO results for patient aged

Background Triple negative breast cancer (TNBC) lacks both early detection biomarkers and viable targeted therapeutics. Moreover, chemotherapy only produces 20–30% pathologic complete response. Because miRNAs are frequently dysregulated in breast cancer and have broad tissue effects, individual or combinations of circulating miRNAs may serve as ideal diagnostic, predictive or prognostic biomarkers, as well as therapeutic targets. Understanding the role and mechanism of dysregulated miRNAs in TNBC may help to develop novel diagnostic and prognostic strategy for TNBC patients. Methods The miRNA array profiles of 1299 breast cancer patients were collected from the Metabric database and subjected to analysis of the altered miRNAs between TNBC and non-TNBC. In Student’s t-test and Kaplan-Meier analysis, four upregulated miRNAs correlated with poor survival in TNBC but not in non-TNBC. Four miRNAs were manipulated in multiple cell lines to investigate their functional role in carcinogenesis. From these results, we studied miR-105 and miR-93-3p in greater detail. The level of miR-105 and miR-93-3p were evaluated in 25 breast cancer tumor tissues. In addition, the diagnostic utility of circulating miR-105 and miR-93-3p were examined in 12 normal and 118 breast cancer plasma samples by ROC curve construction. Results miR-105 and miR-93-3p were upregulated and correlated with poor survival in TNBC patients. Both miR-105 and miR-93-3p were found to activate Wnt/β-catenin signaling by downregulation of SFPR1. By this action, stemness, chemoresistance, and metastasis were promoted. Importantly, the combination of circulating miR-105/93-3p may serve as a powerful biomarker for TNBC, even in early-stage disease. Conclusions miR-105/93-3p activates Wnt/β-catenin signaling by downregulating SFRP1 and thereby promotes stemness, chemoresistance, and metastasis in TNBC cells. Most importantly, combined circulating miR-105/93-3p levels represent a prime candidate for development into a diagnostic biomarker for both early- and late-stage TNBC. Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0918-2) contains supplementary material, which is available to authorized users.

DNA methylation at the 5 position of cytosine (5 mC) is an epigenetic hallmark in cancer. The 5 mC can be converted to 5-hydroxymethylcytosine (5 hmC) through a ten-eleven-translocation (TET). We investigated the impact of 5 mC, 5 hmC, TET1, and TET2 on tumorigenesis and prognosis of breast cancer. Immunohistochemistry was used to assess the levels of 5 mC, 5 hmC, TET1, and TET2 in the corresponding tumor adjacent normal (n = 309), ductal carcinoma in situ (DCIS, n = 120), and invasive ductal carcinoma (IDC, n = 309) tissues for 309 breast ductal carcinoma patients. 5 mC, 5 hmC, TET1-n, and TET2-n were significantly decreased during DCIS and IDC progression. In IDC, the decrease of 5 hmC was correlated with the cytoplasmic mislocalization of TET1 (p < 0.001) as well as poor disease-specific survival (DSS) (adjusted hazard ratio [AHR] 1.95, p = 0.003) and disease-free survival (DFS) (AHR 1.91, p = 0.006). The combined decrease of 5 mC and 5 hmC was correlated with worse DSS (AHR 2.19, p = 0.008) and DFS (AHR 1.99, p = 0.036). Stratification analysis revealed that the low level of 5 mC was associated with poor DSS (AHR 1.89, p = 0.044) and DFS (AHR 2.02, p = 0.035) for the ER/PR-positive subtype. Conversely, the low level of 5 hmC was associated with worse DSS (AHR 2.77, p = 0.002) and DFS (AHR 2.69, p = 0.006) for the ER/PR-negative subtype. The decreases of 5 mC, 5 hmC, TET1-n, and TET2-n were biomarkers of tumor development. The global reduction of 5 hmC was a poor prognostic factor for IDC, especially for ER/PR-negative subtype.

Background OCT4, SOX2, and NANOG are major transcription factors related to stem cell self-renewal and differentiation. The aim of this study was to examine the association of OCT4, SOX2, and NANOG expression levels with the development and prognosis of patients with oral squamous cell carcinoma (OSCC). Materials and Methods Expression levels of OCT4, SOX2, and NANOG were evaluated by immunohistochemistry with tissue microarray slides of 436 OSCC, 362 corresponding tumor-adjacent normal (CTAN) tissues, and 71 normal uvula epithelium tissues. The clinicopathologic and follow-up data of the OSCC patients were recorded. Results OCT4 expression was significantly higher in normal and CTAN tissues than in tumor tissue (both P

To evaluate the clinicopathological characteristics, high-risk lifestyle factors (HRLF: chronic exposure to sun, betel quid, alcohol, and tobacco), and prognostic factors of lip cancer. The hospital records of patients with pathologically confirmed lip squamous cell carcinoma (LSCC, n = 112) and lip basal cell carcinoma (LBCC, n = 21) were reviewed. Differences in clinicopathological characteristics between LSCC and LBCC, upper and lower lip, and status of second primary tumors were compared by chi-square test and logistic regression. The prognostic factors for LSCC were analyzed by Cox regression. Compared with LBCC patients, LSCC patients were men-predominant (p 0.001), had younger ages at onset (p 0.001), and higher rates of lower lips involvement (p 0.001) and HRLFs. Patients with second primary tumors were highly associated with lower lip cancer involvement (adjusted odds ratio = 2.91, p = 0.03). Patients with lower lip cancer had more HRLFs with an increasing linear trend (p = 0.004). The poorer prognostic factors of LSCC for disease-specific survival were advanced stage III/IV [crude hazard ratio (CHR) = 11.16, p 0.001], tumor dimension 4 cm (CHR = 8.19, p = 0.006), lymph node involvement (CHR = 11.48, p 0.001), and recurrence (CHR = 3.96, p = 0.01); whereas for disease-free survival were moderately to poorly differentiated LSCC (CHR = 4.97, p = 0.002) and alcohol consumption (CHR = 3.13, p = 0.04). LSCC and lower lip cancer were highly associated with HRLFs.

We aimed to investigate the association of the expression levels of five epithelial–mesenchymal transition (EMT)-related proteins (Snail, Twist, E-cadherin, N-cadherin, and Vimentin) with tumorigenesis, pathologic parameters and prognosis in tongue squamous cell carcinoma (TSCC) patients by immunohistochemistry of tissue microarray. The expression levels of Snail, E-cadherin, N-cadherin and Vimentin were significantly different between the tumor adjacent normal and tumor tissues. In tumor tissues, lower E-cadherin and higher N-cadherin levels were associated with a higher grade of cell differentiation, advanced stage of disease, and lymph node metastasis. However, higher Vimentin expression was associated with poor cell differentiation and lymph node metastasis. Patients with low E-cadherin expression had poor disease-specific survival (DSS). Conversely, positive N-cadherin and higher Vimentin expression levels were associated with poor DSS and disease-free survival. Notably, our multivariate Cox regression model indicated that high Vimentin expression was an adverse prognostic factor for DSS in TSCC patients, even after the adjustment for cell differentiation, pathological stage, and expression levels of Snail, Twist, E-cadherin, and N-cadherin. Snail, E-cadherin, N-cadherin, and Vimentin were associated with tumorigenesis and pathological outcomes. Among the five EMT-related proteins, Vimentin was a potential prognostic factor for TSCC patients.

Apoptosis plays a dual role in cancer development and malignancy. The role of apoptosis-related caspases in cancer remains controversial, particularly in oral tongue squamous cell carcinoma (OTSCC). In this study, we examined the protein levels of cleaved caspase-3, caspase-3, caspase-8, and caspase-9 on tissue microarrays consisting of samples from 246 OTSCC patients by immunohistochemistry. Wilcoxon signed-rank test indicated that the protein levels of cleaved caspase-3, caspase-3, caspase-8, and caspase-9 in tumor tissues were significantly higher compared to those in adjacent normal tissues (all p

Backgrounds Diabetes mellitus (DM) is a common endocrine disorder and an increasing epidemic worldwide. Proportional diabetic patients eventually develop cutaneous diseases. Objectives This study determined the statistical association of cutaneous manifestations and DM as well as the DM-associated cutaneous manifestations in elderly male residents. Methods A cross-sectional study was conducted in a Veterans Home in Taiwan. The cutaneous manifestations and major systemic diseases of the residents were recorded separately. Univariate logistic regression and multivariate analysis after adjustment for age, body mass index and significant major systemic diseases provided odds ratios and P values for the statistical association. Results A total of 313 male residents (age ≥65 years) were recruited, including 70 (22.4%) with DM. Their most common cutaneous manifestations included fungal infection (77%) and brown spots on the legs (38.3%). Chronic ulcers adjusted odds ratios (AOR 4.90, 95%CI: 1.82–13.19; P = 0.002), brown spots on the legs (AOR 6.82, 95%CI: 3.60–12.89; P

Objective To investigate the association of miR-499a genetic polymorphism with the risk of oral leukoplakia, oral submucous fibrosis (OSF), oral squamous cell carcinoma (OSCC), and clinicopathological outcomes of OSCC. Methods The genotyping of miR-499a T>C (rs3746444) using TagMan assay was conducted in two case-control studies of 1549 subjects. miR-499a-5p and miR-499a-3p were assayed using stem-loop RT-PCR for 63 paired OSCC and adjacent normal tissues. Results T/C+C/C genotypes [adjusted odds ratio (AOR) 1.84, P = 0.032] and C allelic type (AOR 1.91, P = 0.007) at miR-499a T>C were associated with an increased risk of BQ-related OSF as compared to those with T/T genotype or T allelic type, respectively. Conversely, T/C+C/C genotypes and C allelic type decreased the risk of OSCC, especially for non-BQ-related OSCC (for genotype: AOR 0.49, P = 0.010; for allelic type: AOR 0.50, P = 0.007). Additionally, downregulation of miR-499a-5p was found in OSCC tissues (P = 0.001) and correlated with the TT genotype (P = 0.001). Conclusion The T/C+C/C genotypes of MiR-499a may contribute to an increased risk of BQ-related OSF, but a decreased risk of OSCC. miR-499a T>C influences the expression levels of miR-499a-5p during the tumorigenesis of OSCC.

Interleukin (IL)-4 is a key cytokine in humoral and adaptive immunity. This study aimed to evaluate the association of IL-4 genetic variants (-590CT and VNTR in intron 3) with the risk and prognosis of oral and pharyngeal squamous cell carcinoma (OPSCC).A total of 1215 subjects, which included 623 healthy controls and 592 OPSCC cases (463 oral squamous cell carcinoma (OSCC) and 129 pharyngeal squamous cell carcinoma (PSCC) cases), were recruited. The genotypes were determined by TaqMan real-time assay and PCR-based assay.The IL-4 genotypes at locus -590CT and intron 3 VNTR were not correlated with increased risk of OSCC, PSCC, and OPSCC, with the exception of early-stage OPSCC (at -590CT: T/T vs. C/C+C/T, adjusted odds ratio (AOR)=1.42, 95% CI: 1.02-1.98; at intron 3 VNTR: RP1/RP1 vs. RP2/RP2+RP2/RP1, AOR=1.46, 95% CI: 1.05-2.04). Compared with other IL-4 diplotypes, the T,RP1/T,RP1 diplotype was associated with an increased risk of OPSCC (AOR=1.37, 95% CI: 1.03-1.81), particularly early-stage OSCC (AOR=1.43, 95% CI: 1.02-2.00), PSCC (AOR=2.35, 95% CI: 1.06-5.19), and OPSCC (AOR=1.52, 95% CI: 1.10-2.11). Interactions between the IL-4 diplotype and the alcohol drinking status were found to contribute to the risk of early-stage OPSCC (p=0.024). In addition, the T,RP1/T,RP1 diplotype was correlated with better disease-specific survival (T,RP1/T,RP1 vs. other diplotypes, adjusted hazard ratio=0.70, 95% CI: 0.50-0.97).The T, RP1/T, RP1 diplotype of IL-4 was associated with an increased risk but favourable prognosis of OPSCC.

Background The effect of maternal exposure to essential minerals and heavy metals on fetus is an important issue, which affects women around the world. Few data are available on the concentration of both essential minerals and heavy metals in maternal/fetal medicine. The aims of this study were to (1) assess the correlation of mercury (Hg), manganese (Mn), iron (Fe), and copper (Cu) in paired maternal/fetal blood samples, and (2) study potential confounding factors during pregnancy. Methods Our study recruited 145 healthy pregnant women with a mean age of 28.06 years, gathering information by collecting interviewer-administered questionnaires. Paired maternal/fetal blood samples were collected by delivery. Results There was a positive correlation of Hg ( r = 0.78, p r = 0.31, p r = 0.17, p = 0.038), and Cu ( r = 0.21, p = 0.010) in paired maternal/fetal samples. Prenatal vitamin use (>3 times/wk) was significantly associated with lower maternal Hg (adjusted odds ratio 0.272, p = 0.005) and lower maternal Cu (adjusted odds ratio 0.267, p = 0.004) levels. Median fetal Hg, Mn, and Fe levels were higher than corresponding maternal levels, while median fetal Cu level was lower than maternal Cu level. Conclusion There was a positive correlation of Hg, Fe, Cu, and Mn in paired maternal/fetal samples in this series. Our findings have raised the possibility of reducing maternal Hg and Cu by way of prenatal vitamin supplementation.

Background Long noncoding RNAs (lncRNAs) are more than 200 nucleotides in length and lack transcriptional ability. The biological function of lncRNAs in oral squamous cell carcinoma (OSCC) remains unclear. The aim of this study was to identify the dysfunction of lncRNA in OSCC. Results We analyzed the transcriptome profiles of human OSCC tissues and paired adjacent normal tissues from two patients through a next-generation sequencing approach. A total of 14 lncRNAs were upregulated (fold change ≥3) and 13 were downregulated (fold change ≤−3) in OSCC tissues compared with the adjacent normal tissues. SOX21-AS1 was subjected to further analysis, revealing that the expression levels of SOX21-AS1 significantly decreased in OSCC compared with the adjacent normal tissue. The promoter activity of SOX21-AS1 was obviously suppressed by in vitro methylation. The DNA methylation status of the SOX21-AS1 promoter was analyzed using combined bisulfite restriction analysis, revealing that the aberrant promoter hypermethylation of SOX21-AS1 was observed frequently in OSCC tissues. The effects of SOX21-AS1 on cell proliferation and invasion were examined through transient transfection. Our data showed that SOX21-AS1 could significantly suppress oral cancer cell growth and invasion. Furthermore, the low expression level of SOX21-AS1 was significantly correlated with an advanced stage (P = 0.047), large tumor size (P = 0.033), and poor disease-specific survival in OSCC patients (P = 0.002). Conclusions SOX21-AS1 was identified as susceptible dysfunction correlated with promoter hypermethylation in OSCC. Low SOX21-AS1 expression may be an adverse prognostic biomarker for OSCC. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0291-5) contains supplementary material, which is available to authorized users.

Objectives This case-control study evaluated the association of the single nucleotide polymorphism rs7372209 (T>C) in pri-mir-26a-1 with the risk and progression of betel quid (BQ)–related oral premalignant lesions (OPLs) and oral squamous cell carcinoma (OSCC). Study Design In total, 597 BQ chewers were recruited: 196 healthy controls, 241 patients with OPLs, and 160 patients with OSCC. Genotypes were determined using the TaqMan real-time assay. Results The C/T + T/T genotypes and T allele in pri-mir-26a-1 were correlated with a decreased risk of BQ-related OPLs (P = .038 and .005, respectively), oral leukoplakia (P = .01 and .001, respectively), and advanced-stage OSCC (P = .021 and .004, respectively). The effects of the C/T + T/T genotypes and T allele on the decreased risk of OPLs were potent in the older age group (both Pinteraction Conclusions BQ chewers carrying the T allele or C/T + T/T genotypes in pri-mir-26a-1 may have a decreased risk of oral leukoplakia, OPLs, and advanced-stage OSCC.

Akt activation has been implicated broadly in tumorigenesis, but the basis for its dysregulation in cancer cells is incompletely understood. In this study, we sought to clarify a regulatory role for the Akt-binding carboxy-terminal modulator protein (CTMP), which has been controversial. In evaluating CTMP expression in paired normal–tumor specimens of 198 patients with breast cancer, we found that CTMP was upregulated in breast tumors, where it was associated with poor patient survival. Notably, CTMP expression also correlated positively with Akt phosphorylation in breast cancer clinical specimens and cell lines. Furthermore, ectopic expression of CTMP promoted cell proliferation and enhanced the tumorigenic properties of estrogen-dependent breast cancer cells. This effect was correlated with increased sensitivity to insulin-induced Akt phosphorylation, which is mediated primarily by the phosphoinositide 3-kinase–Akt pathway. In contrast, short hairpin RNA-mediated silencing of endogenous CTMP decreased the proliferation of estrogen-dependent or estrogen-independent breast cancer cells. Mechanistic investigations defined the N-terminal domain of CTMP at amino acids 1 to 64 as responsible for Akt binding. Taken together, our results firmly corroborate the concept that CTMP promotes Akt phosphorylation and functions as an oncogenic molecule in breast cancer. Cancer Res; 73(20); 6194–205. ©2013 AACR.

Objective The present study investigated the relationship between the expression of manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase (GPx), and myeloperoxidase (MPO) in buccal mucosal squamous cell carcinoma (SCC), and the risk of second primary tumors (SPTs). Study design Immunohistochemistry was performed to examine the expression of MnSOD, GPx, catalase, and MPO in tissue microarray slides of 173 male patients with buccal mucosal SCC who had undergone potentially curative resections. Results Forty-five (26.01%) patients developed SPTs. The prevalent subsites of SPTs were buccal mucosa (48.89%), tongue (13.33%), and lip (11.11%). High expression level of MPO was correlated with an increased risk of SPTs, even after adjustment for development of clinicopathologic parameters (high vs. low expression, adjusted hazard ratio = 3.89; 95% confidence interval, 1.33-11.41; P = .013). Conclusions SPTs are common in male buccal mucosal SCC patients. Higher MPO expression in buccal mucosal SCC is a risk factor for SPTs.

Background Interleukin-18 (IL-18) plays an important role in mediating cytokine cascade leading to coronary artery lesions (CALs) in Kawasaki disease (KD). However, our research suggested that the literature regarding IL-18 and KD is limited. Consequently, this study aimed to evaluate the correlation between IL-18 and CALs in patients with KD. Methods In this prospective study of 14 children with KD (seven without and seven with CALs in the acute phase), we obtained patient measurements of a series of serum IL-18 levels in the acute, subacute, and convalescent phases. Serum IL-18 levels were measured with a Bio-Plex cytokine assay. Control samples were obtained from 18 febrile children with viral infection. Results Compared with febrile controls, patients with acute-stage CALs [postintravenous immunoglobulin (post-IVIG) period] had a significantly higher IL-18 level (88.4 ± 20.7 vs 56.0 ± 35.0 pg/mL, p = 0.006). However, those without acute-stage CALs (post-IVIG period) lacked similarly elevated IL-18 level readings (62.0 ± 40.6 vs 56.0 ± 35.0 pg/mL, p = 0.762). The IL-18 level of patients with acute-stage CALs did not decrease significantly until the convalescent phase (97.4 ± 55.8 vs 38.7 ± 22.6 pg/mL, p = 0.018), but for those without CALs, it decreased significantly in the subacute phase (60.2 ± 37.4 vs 23.6 ± 13.8 pg/mL, p = 0.018). In the subacute stage, there was a significant difference of IL-18 level between patients with and without acute-stage CALs ( p = 0.048). Conclusion Our data show that IL-18 levels were elevated in the acute phase of KD and might be related to the formation of CALs.

Background Prescribing opioids for chronic noncancer pain (CNCP) has been strictly regulated in Taiwan. This study was undertaken to survey pain and non-pain related physicians’ knowledge, attitudes, and practices regarding prescribing opioids for CNCP. Methods A questionnaire survey was conducted in this comparison study. All 66 physicians who were treating officially registered CNCP outpatients were visited and completed anonymous questionnaires. The other physicians (anesthesiologists, oncologists, and non-pain physicians) were surveyed by a mailed questionnaire. Results A total of 266 (75%) questionnaires were received from 355 board-certified physicians. More CNCP physicians (81.8%) and anesthesiologists (69.7%) had received prior CNCP-related training courses than had oncologists (21.2%) and non-pain physicians (10.3%). Varied proportions of physicians by type were unfamiliar with the Taiwan opioid regulations (16.7–86.8%) and would accordingly skip or reduce dosage of opioid prescriptions (27.3–73.5%). In addition, non-pain physicians had a significantly lower knowledge level, more negative attitudes, and greater hesitation about prescribing opioids compared to the pain-related physicians (P Conclusion There are substantial knowledge gaps, negative attitudes, and hesitation toward prescribing long-term opioids for CNCP patients by physicians in Taiwan, suggesting that efforts are needed to improve postgraduate education regarding adequate opioid management for CNCP.

Background: The purpose of this study was to examine the influence of maternal seafood consumption and vitamin supplementation during pregnancy on maternal and umbilical cord blood mercury (Hg) concentration. Methods: In this study of 145 healthy pregnant women (mean age 28.1±5.2 years), we administered questionnaires, collected paired maternal/umbilical cord blood samples, and measured the anthropometrics of newborns. Blood Hg concentration was assayed by inductively coupled plasma-mass spectrometry. Results: Sixty-one of these women (42.1%) used vitamins >3 times/wk prenatally. Seventy-eight of our study participants (61.9%) reported eating higher amounts of seafood during pregnancy. We found a strong correlation (r=0.76, p5.8 μg/L). However, mothers whose prenatal vitamin intake was >3 times/wk were found to have low Hg levels (≤5.8 μg/L) (adjusted odds ratio 0.06, 95% confidence interval: 0.01–049, p=0.008). Conclusion: High seafood consumption was an independent risk factor for high maternal Hg level, while vitamin supplementation was a protective factor. Further study is needed to investigate the specific effect of vitamins on Hg level.

Background Verrucous carcinoma is a non-metastasizing variant of welldifferentiated squamous cell carcinoma, which has been associated with reactive oxygen species generated by betel quid chewing. Salivary antioxidant systems have been suggested to play a protective role in reducing the oxidative damage. Herein, we investigated the difference of the enzymatic antioxidant system expressions in oral verrucous carcinoma and oral squamous cell carcinoma. Methods The enzymatic antioxidant system expressions, including manganese superoxide dismutase, glutathione peroxidase, and catalase were evaluated by immunohistochemistry in a series of 202 surgically resected oral squamous cell carcinoma and 20 oral verrucous carcinoma specimens, using tissue microarray slides. Results The immuno-staining intensities of superoxide dismutase and glutathione peroxidase were strongest in the oral squamous cell carcinoma group than in verrucous carcinoma. The catalase expression showed no difference between different pathological groups. Conclusions The different degrees of superoxide dismutase and glutathione expressions in verrucous carcinoma and squamous cell carcinoma may be helpful for pathologists to differentiate these two entities, especially between oral verrucous carcinoma and well differentiated oral squamous cell carcinoma.

Nucleolar protein interacting with the FHA domain of pKi-67 (NIFK) is a Ki-67-interacting protein. However, its precise function in cancer remains largely uninvestigated. Here we show the clinical significance and metastatic mechanism of NIFK in lung cancer. NIFK expression is clinically associated with poor prognosis and metastasis. Furthermore, NIFK enhances Ki-67-dependent proliferation, and promotes migration, invasion in vitro and metastasis in vivo via downregulation of casein kinase 1α (CK1α), a suppressor of pro-metastatic TCF4/β-catenin signaling. Inversely, CK1α is upregulated upon NIFK knockdown. The silencing of CK1α expression in NIFK-silenced cells restores TCF4/β-catenin transcriptional activity, cell migration, and metastasis. Furthermore, RUNX1 is identified as a transcription factor of CSNK1A1 (CK1α) that is negatively regulated by NIFK. Our results demonstrate the prognostic value of NIFK, and suggest that NIFK is required for lung cancer progression via the RUNX1-dependent CK1α repression, which activates TCF4/β-catenin signaling in metastasis and the Ki-67-dependent regulation in cell proliferation. DOI: http://dx.doi.org/10.7554/eLife.11288.001, eLife digest Cancer cells can rapidly divide to form a tumor. Small groups of cells can leave the tumor to migrate to other sites in the body, and it is these “secondary” tumors that are often responsible for the death of cancer patients. Many proteins influence how and when cells divide and migrate. One such protein called Ki67 is only produced when cells are dividing and it is often used in the clinic as a marker to indicate whether cells have become cancerous. However, it is not clear how Ki67 regulates the progression of cancer. Ki67 interacts with another protein called NIFK, and Lin, Su et al. have now investigated the role of NIFK in cancer. First, publicly available data on the levels of proteins in tumor samples from cancer patients were analyzed. This revealed that, in several different types of cancer, tumors that produced more NIFK were more likely to spread to other parts of the body than tumors that produced smaller amounts of NIFK. Next, Lin, Su et al carried out experiments using human lung cancer cells. This revealed that cells that produced larger amounts of NIFK were more likely to migrate, while cells with lower levels of NIFK divided and migrated less often. Further experiments showed that NIFK increases the activity of genes that are involved in cell migration. NIFK achieves this by reducing the production of a protein that inhibits the activity of another protein called β-catenin. Lin, Su et al.’s findings reveal a new role for NIFK in promoting the development of cancer. A future challenge is to find out whether chemicals that inhibit NIFK could be used in the treatment of lung cancer. DOI: http://dx.doi.org/10.7554/eLife.11288.002

Background The aim of this study was to investigate whether mutation in AMP-activated protein kinase (AMPK) subunit genes (PRKAG3-230) is associated with sporadic, isolated Wolff–Parkinson–White (WPW) syndrome. Methods This study consisted of 87 patients with symptomatic WPW syndrome and 93 healthy controls. PRKAG3-230 genotypes were determined using real-time polymerase chain reaction assay. Genotype and allele frequencies of PRKAG3-230 between patients with WPW syndrome and healthy controls were ascertained using chi-square test or Fisher exact test when appropriate. Results PRKAG3-230 were genotyped in 87 patients (53 men and 34 women; age=24.4±18.0 years) with WPW syndrome and 93 healthy controls (57 men and 36 women; age=16.8±4.2 years). There were no significant differences between the two groups in terms of age and sex. The patients with CG and CG+CC genotypes had a significantly increased risk of WPW syndrome compared with those with GG genotype [odds ratio (OR)=1.99, 95% confidence interval (CI)=1.01–3.89, p =0.045; OR=1.99, 95% CI=1.04–3.78, p =0.037, respectively]. The allelic types were not associated with the risk of WPW syndrome. The patients with manifest type with CG and CG+CC genotypes had a significantly increased risk of WPW syndrome compared with those with GG genotype (OR=2.86, 95% CI=1.16–7.05, p =0.022; OR=2.84, 95% CI=1.19–6.80, p =0.019, respectively). The patients with right-side accessory pathways with CG and CG+CC genotypes had a significantly increased risk of WPW syndrome compared with those with GG genotype (OR=3.07, 95% CI=1.25–7.51, p =0.014; OR=2.84, 95% CI=1.19–6.80, p =0.019, respectively). The allelic types were not associated with the risk of WPW types and locations. Conclusion This study shows that PRKAG3-230 may be associated with sporadic WPW syndrome among a Taiwanese population. Further studies are warranted to elucidate the role of mutations in AMPK subunit genes other than PRKAG3-230 in sporadic WPW syndrome.

MicroRNAs (miRNAs) are short noncoding RNAs derived from the 3′ and 5′ ends of the same precursor. However, the biological function and mechanism of miRNA arm expression preference remain unclear in breast cancer. We found significant decreases in the expression levels of miR-193a-5p but no significant differences in those of miR-193a-3p in breast cancer. MiR-193a-3p suppressed breast cancer cell growth and migration and invasion abilities, whereas miR-193a-5p suppressed cell growth but did not influence cell motility. Furthermore, NLN and CCND1, PLAU, and SEPN1 were directly targeted by miR-193a-5p and miR-193a-3p, respectively, in breast cancer cells. The endogenous levels of miR-193a-5p and miR-193a-3p were significantly increased by transfecting breast cancer cells with the 3′UTR of their direct targets. Comprehensive analysis of The Cancer Genome Atlas database revealed significant differences in the arm expression preferences of several miRNAs between breast cancer and adjacent normal tissues. Our results collectively indicate that the arm expression preference phenomenon may be attributable to the target gene amount during breast cancer progression. The miRNA arm expression preference may be a means of modulating miRNA function, further complicating the mRNA regulatory network. Our findings provide a new insight into miRNA regulation and an application for breast cancer therapy.