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Software-defined network (SDN) allows traffic engineering and flow management by decoupling the control and data planes. SDN has attracted a lot of attention recently because of its centralized control, flow programmability and flexible resource management. However, to support centralized control, flow programmability and flexible resource management, most of the advanced SDN designs require per-flow management, which would easily make the flow table of a software switch overflow and incur undesired processing overhead when a network scales up. To overcome such huge traffic demands, we propose a cluster-based macro-flow management framework to balance the trade-off between customized services and management costs. The key idea of our design is to group similar flows into a cluster and replace per-flow management with per-cluster management. To achieve this goal, we cluster flows with consideration of the similarity of their traffic patterns. To adapt to varying traffic load, we further propose a hierarchical cluster merging scheme to dynamically merge clusters and make the best tradeoff between flow entry saving and routing performance guarantee. Our evaluation demonstrates that the proposed cluster-based flow management framework can significantly reduce the flow table usage, while producing minimum negative impact on routing performance.

Mei-Hsuen Huang,1 Yu-Fan Liu,2,3 Oswald Ndi Nfor,4 Shu-Yi Hsu,4 Wei-Yong Lin,5– 7 Yuan-Shiun Chang,1 Yung-Po Liaw4,8 1Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan; 2Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan; 3Division of Allergy, Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan; 4Department of Public Health and Institute of Public Health, Chung Shan Medical University, Taichung, 40201, Taiwan; 5Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan; 6Department of Medical Research, China Medical University Hospital, Taichung, 40447, Taiwan; 7Brain Diseases Research Center, China Medical University, Taichung, 40402, Taiwan; 8Department of Medical Imaging, Chung Shan Medical University Hospital, Taichung City, 40201, TaiwanCorrespondence: Yung-Po LiawDepartment of Public Health and Institute of Public Health, Chung Shan Medical University, No. 110, Sec. 1 Jianguo N. Road, Taichung City, 40201, TaiwanTel +886-4-24730022 ext.11838Fax +886-4-23248179Email Liawyp@csmu.edu.twYuan-Shiun ChangDepartment of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung, 40402, TaiwanTel +886-4-22053366 ext. 5502Fax +886-4-22083362Email yschang@mail.cmu.edu.twPurpose: We investigated the interactive effect of rs10506151 polymorphism of the Leucine-rich repeat kinase 2 (LRRK2) gene and type 2 diabetes (T2D) on neurodegenerative disease (ND) risk.Materials and Methods: Data of 17, 927 participants in the Taiwan Biobank (TWB) assessed between 2008 and 2015 were linked to healthcare records in the National Health Insurance Research Database (NHIRD). The odd ratios (ORs) and 95% confidence intervals (CIs) for NDs were determined using logistic regression analysis.Results: There were 145 cases with NDs, and 28.28% (n = 41) of these individuals had T2D. Associations of neurodegenerative disorders with LRRK2 rs10506151 variant and T2D were not significant. The corresponding ORs (95% CI) for NDs were 1.06 (0.75– 1.49) in CA/AA compared to CC individuals and 0.93 (0.63– 1.39) in those with T2D compared to non-diabetic participants. However, we found evidence of a significant interaction between rs10506151 and T2D (p = 0.0073). After stratification by genotypes of rs10506151, the OR for NDs was 0.37 (CI, 0.17– 0.82) in CA/AA individuals with T2D and 1.41 (0.88– 2.27) in their CC counterparts. When CA/AA individuals with T2D represented the reference group, the OR (95% CI) was 1.74 (0.81– 3.73) in CC individuals with no T2D, 2.47 (CI, 1.14– 5.38) in CA/AA individuals with no T2D, and 2.34 (CI, 1.07– 5.11) in CC individuals with T2D.Conclusion: Our data indicated that the risk of NDs was significantly lower among diabetic individuals with combined CA/AA of the LRRK2 rs10506151 variant in Taiwan.Keywords: polymorphism, neurodegenerative disorders, diabetes, variation

Lung cancer is the leading cause of cancer-related deaths worldwide. Identifying genetic risk factors and understanding their mechanisms will help reduce lung cancer incidence. The p53 apoptosis effect is related to PMP-22 (PERP), a tetraspan membrane protein, and an apoptotic effector protein downstream of p53. Although historically considered a tumor suppressor, PERP is highly expressed in lung cancers. Stable knockdown of PERP expression induces CL1-5 and A549 lung cancer cell death, but transient knockdown has no effect. Interestingly, relative to the PERP-428GG genotype, PERP-428CC was associated with the highest lung cancer risk (OR = 5.38; 95% CI = 2.12-13.65, p 0.001), followed by the PERP-428CG genotype (OR = 2.34; 95% CI = 1.55-3.55, p 0.001). Ectopic expression of PERP-428G, but not PERP-428C, protects lung cancer cells against ROS-induced DNA damage. Mechanistically, PERP-428 SNPs differentially regulate p53 protein stability. p53 negatively regulates the expression of the antioxidant enzymes catalase (CAT) and glutathione reductase (GR), thereby modulating redox status. p53 protein stability is higher in PERP-428C-expressing cells than in PERP-428G-expressing cells because MDM2 expression is decreased and p53 Ser20 phosphorylation is enhanced in PERP-428C-expressing cells. The MDM2 mRNA level is decreased in PERP-428C-expressing cells via PTEN-mediated downregulation of the MDM2 constitutive p1 promoter. This study reveals that in individuals with PERP-428CC, CAT/GR expression is decreased via the PTEN/MDM2/p53 pathway. These individuals have an increased lung cancer risk. Preventive antioxidants and avoidance of ROS stressors are recommended to prevent lung cancer or other ROS-related chronic diseases.

Background Allergic asthma, a chronic airway inflammatory disease, is a critical public health problem. Indoor house dust mites (HDMs) could cause allergic asthma. The prevalence of sensitization to Dermatophagoides microceras (Der m) was approximately 80% and is related to the immunoglobulin E crossing-reactivity of mites belonging to the same genus, Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farina (Der f). However, studies on Der m are scant. Methods We used integrated OMICs approaches to identify and characterize the group 2 mite allergen-like protein in Der m (Der m 2). We established a Der m 2-induced allergic asthma mouse model and treated the mice with a fungal immunomodulatory protein (FIP-fve) isolated from Flammulina veluptipes to evaluate the allergenicity of Der m 2 and the immunomodulatory effects of FIP-fve. Results By performing de novo draft genome assembly and comparative genome analysis, we identified the putative 144-amino acid Der m 2 in silico and further confirmed its existence through liquid chromatography–tandem mass spectrometry. Der m 2 is a lipopolysaccharides (LPS)-binding protein. Thus, we examined the LPS-binding activity of recombinant Der m 2 by performing molecular docking analysis, co-immunoprecipitation (Co-IP), and a pull-down assay. Der m 2 elicited the production of pro-inflammatory cytokines, interleukin (IL)-6, and IL-8 in BEAS-2B cells, a human bronchial epithelial cell line, and induced airway hyperresponsiveness in mice. Furthermore, in mice sensitized with Der m 2, the administration of FIP-fve in either the earlier stage or the late stage, FIP-fve alleviated allergic asthma by moderating airway inflammation and remodeling. Conclusions Der m 2 induced inflammatory responses in cell and mouse models. FIP-fve alleviated inflammation in Der m 2-induced asthma in mice by exerting an immunomodulatory effect.

Distributed permutation flowshop group scheduling problem (DPFGSP) is studied in this paper. This problem can be regarded as a combination of the distributed flowshop scheduling and group scheduling. An improved iterated local search (dILS) algorithm is proposed to minimize the total flowtime. First of all, we use a simple heuristic algorithm based on the famous NEH heuristics to generate an initial solution. Next, we use the solutions obtained from two different neighborhoods to perform an iterated local search. The acceptance criterion is the simulated-annealing type with a constant temperature. Finally, the propo dILS algorithm is compared with the existing VND algorithm based on the 810 benchmark instances. The experimental results show that the proposed dILS algorithm has significant advantages in solving the DPFGSP under consideration.

In recent years, the distributed permutation flowshop scheduling problem (DPFSP) has become a hotspot in research. In this paper, we change several heuristics for a single factory to the heuristics for a multi-factory environment to solve the DPFSP with total completion time (TCT) criterion. Further, these distributed heuristics are improved to deal with the minimization of the TCT for the DPFSP with release dates by modifying the initialization procedure and local search methods. Finally, we calculate 720 instances and compare our proposed heuristics and those from the recent literature. Computational results indicate the superiority of the presented heuristics for the problem considered.

Due to the extensive applications of the flowshop sequence-dependent group scheduling problem(FSDGSP), especially in the manufacturing industry, there has been a growing interest in the research of it. In this paper, a constructive heuristic called JPALRx is proposed for solving FSDGSP with total flow time criterion. In the JPALRx, a sequence of part families is determined by a jigsaw puzzle inspired algorithm considering major family setup times. Afterwards, a job sequence within each part family is obtained by using a heuristic algorithm called LRx. Furthermore, an insert operator based on family is used to further improve the quality of the solution obtained. The experimental results demonstrate the effectiveness and efficiency of JPALRx.

Midazolam (MDZ) could affect lymphocyte immune functions. However, the influence of MDZ on cell’s K+ currents has never been investigated. Thus, in the present study, the effects of MDZ on Jurkat T lymphocytes were studied using the patch-clamp technique. Results showed that MDZ suppressed the amplitude of delayed-rectifier K+ current (IK(DR)) in concentration-, time-, and state-dependent manners. The IC50 for MDZ-mediated reduction of IK(DR) density was 5.87 μM. Increasing MDZ concentration raised the rate of current-density inactivation and its inhibitory action on IK(DR) density was estimated with a dissociation constant of 5.14 μM. In addition, the inactivation curve of IK(DR) associated with MDZ was shifted to a hyperpolarized potential with no change on the slope factor. MDZ-induced inhibition of IK(DR) was not reversed by flumazenil. In addition, the activity of intermediate-conductance Ca2+-activated K+ (IKCa) channels was suppressed by MDZ. Furthermore, inhibition by MDZ on both IK(DR) and IKCa-channel activity appeared to be independent from GABAA receptors and affected immune-regulating cytokine expression in LPS/PMA-treated human T lymphocytes. In conclusion, MDZ suppressed current density of IK(DR) in concentration-, time-, and state-dependent manners in Jurkat T-lymphocytes and affected immune-regulating cytokine expression in LPS/PMA-treated human T lymphocytes.

The Mass Rapid Transit (MRT) project is a massive, large-scale construction venture with a complex interface. In order to reduce the risk of disasters and industrial accidents in the project and to save costs, a simple and flexible risk management system is necessary for projects such as MRT. A set of risk management processes was identified through a literature review and data collection, and the Integration Definition for Function Modeling (IDEF0) process was used for logical analysis. The IDEF0 diagram clearly depicts the items to be delivered at each interface, and risk is reduced by facilitating the flow of data on various risk items. The results of this research will be applied to other practical projects, with special emphasis on the project planning and design stages. Future work will verify whether the implementation of the proposed risk management process does indeed effectively reduce risks in the completed project.

Oral squamous cell carcinoma (OSCC) is a multifactorial malignancy, and its high incidence and mortality rate remain a global public health burden. Polymorphisms in the long intergenic noncoding RNA 673 (LINC00673) have been currently connected to the predisposition to various cancer types. The present study attempted to explore the impact of LINC00673 gene polymorphisms on the risk and progression of OSCC. Three LINC00673 single-nucleotide polymorphisms (SNPs), including rs11655237, rs9914618, and rs6501551, were evaluated in 1231 OSCCC cases and 1194 cancer-free controls. We did not observe any significant association of three individual SNPs with the risk of OSCC between the case and control group. However, while assessing the clinicopathological parameters, patients carrying at least one minor allele of rs9914618 (GA and AA, OR, 1.286, 95% CI, 1.008–1.642, p = 0.043) were found to develop lymph node metastasis more often compared to those who are homozygous for the major allele. Further stratification analyses revealed that this genetic correlation with increased risk of lymphatic spread was further fortified in habitual betel quid chewers (OR, 1.534, 95% CI, 1.160–2.028, p = 0.003) or smokers (OR, 1.320, 95% CI, 1.013–1.721, p = 0.040). Moreover, through analyzing the dataset from The Cancer Genome Atlas (TCGA), we found that elevated LINC00673 levels were associated with the development of large tumors in patients with head and neck squamous cell carcinoma and the risk of lymphatic spread in smokers. These data demonstrate a joint effect of LINC00673 rs9914618 with betel nut chewing or smoking on the progression of oral cancer.

A disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) family are widely implicated in tissue remodeling events manifested in cancer development. ADAMTS1, the most fully characterized ADAMTS, plays conflicting roles in different cancer types; however, the role of ADAMTS1 in renal cell carcinoma (RCC) remains unclear. Herein, we found that ADAMTS1 is highly expressed in RCC tissues compared to normal renal tissues, and its expression was correlated with an advanced stage and a poor prognosis of RCC patients. In vitro, we observed higher expression of ADAMTS1 in metastatic (m)RCC cells compared to primary cells, and manipulation of ADAMTS1 expression affected cell invasion and clonogenicity. Results from protease array showed that ADAMTS1 is modulated by melatonin through mechanisms independent of the MT1 receptor in mRCC cells, and overexpression of ADAMTS1 relieved the invasion/clonogenicity and growth/metastasis inhibition imposed by melatonin treatment in vitro and in an orthotopic xenograft model. The human microRNA (miR) OneArray showed that miR-181d and miR-let-7f were induced by melatonin and, respectively, targeted the 3'-UTR and non-3'-UTR of ADAMTS1 to suppress its expression and mRCC invasive ability. Clinically, RCC patients with high levels of miR-181d or miR-let-7f and a low level of ADAMTS1 had the most favorable prognoses. In addition, ubiquitin/proteasome-mediated degradation of ADAMTS1 can also be triggered by melatonin. Together, our study indicates that ADAMTS1 may be a useful biomarker for predicting RCC progression. The novel convergence between melatonin and ADAMTS1 post-transcriptional and post-translational regulation provides new insights into the role of melatonin-induced molecular regulation in suppressing RCC progression.

High-efficiently conductive networks have been well demonstrated to improve electrical properties of conductive polymer composites (CPCs). Here, a facile approach was introduced to control distribution of multi-walled carbon nanotubes (MWCNTs) in isotactic polypropylene/poly(ethylene-co-1-octene) blends (iPP/POE). The POE first melt-crosslinked by the addition of dicumyl peroxide, pulverized into small particles (40–60 meshes), then coated with iPP/MWCNTs composites, and finally compression molded to achieve the segregated iPP/POE/MWCNTs composites with MWCNTs confinedly dispersing in continuous iPP phase. This segregated structure could easily construct high-efficiently conductive networks, resulting in a low percolation threshold of 0.24 vol.%, high-performance electrical conductivity, and electromagnetic interference shielding effectiveness (EMI SE). For example, the EMI SE of ∼25 dB could be achieved in the segregated nanocomposites with 3.0 vol.% MWCNTs (thickness 1.2 mm) which reached the commercial requirement. Furthermore, the segregated samples also exhibited a relatively linear negative temperature coefficient (NTC) effect through wide temperature ranges of 45–120 °C and 150–190 °C because of anisotropic volume expansion effect caused by the segregated structure.

Genetic and acquired factors are thought to be interrelated and imperative to estimate the risk and prognosis of oral squamous cell carcinoma (OSCC). HOX transcript antisense intergenic RNA ( HOTAIR) plays crucial roles in gene regulation and is regulated in a variety of cancers. Polymorphisms in HOTAIR have been recently linked to the predisposition to diverse malignancies. In the present study, we aimed to evaluate the influences of HOTAIR gene polymorphisms, combined with environmental triggers, on the susceptibility to oral tumorigenesis. Four single-nucleotide polymorphisms of the HOTAIR gene— rs920778, rs1899663, rs4759314, and rs12427129—were tested in 1,200 control participants and 907 patients with OSCC. We detected a significant association of rs1899663 with the risk of OSCC (adjusted odds ratio, 2.227; 95% confidence interval [95% CI], 1.197 to 4.146; P = 0.012) after adjustment for 3 potential confounders: smoking, betel quid chewing, and alcohol consumption. In further analyses where habitual exposure to each of 3 environmental factors was excluded, we found that, in addition to rs1899663, non–betel quid users who carried the polymorphic allele of rs920778 were more prone to develop OSCC than were those homozygous for wild-type allele (TC: odds ratio [OR], 1.472; 95% CI, 1.069 to 2.029; P = 0.018; TC+CC: OR, 1.448; 95% CI, 1.060 to 1.977; P = 0.020). Moreover, in exploring the relationship between HOTAIR gene polymorphisms and the clinical status of only patients with OSCC who were non–betel quid chewers (excluding the advanced clinical stage), we found that rs920778 and rs4759314 were correlated with the development of large-size tumors (OR, 1.891; 95% CI, 1.027 to 3.484; P = 0.04) and increased lymph node metastasis (OR, 4.140; 95% CI, 1.785 to 9.602; P = 0.001), respectively. Further functional assessments link rs920778 to the regulation of HOTAIR expression and epigenetic status. Our results reveal an interactive effect of HOTAIR gene polymorphisms and betel quid chewing on the development and progression of oral cancer.

This is the first study to investigate the relationships among fibroblast growth factor receptor 4 (FGFR4) genetic polymorphisms, development of uterine cervical cancer, clinicopathological variables, and patient prognosis in Taiwanese women. Real-time polymerase chain reaction and genotyping were used to detect the genotype frequencies of 4 FGFR4 single-nucleotide polymorphisms (SNPs), rs351855 (C/T, Gly388Arg), rs2011077 (G/A), rs7708357 (G/A), and rs1966265 (Ile10Val), in 138 patients with invasive cancer, 89 with precancerous lesions of uterine cervix, and 335 normal controls. The results showed that there is no significant difference in the frequencies of FGFR4 SNPs rs351855, rs2011077, rs7708357, and 1966265 between women with cervical invasive cancer and normal controls even after controlling for age. However, significant differences existed in the distributions of the FGFR4 genetic polymorphism rs2011077, when mutant homozygotes (AA) were compared using other genotypes (GG/GA) as a reference, as well as rs1966265, when mutant homozygotes (AA) were compared using GG/GA as a reference, between women with cervical precancerous lesions and normal women even after controlling for age. In multivariate analysis, lymph node metastasis was associated with cancer recurrence, and lymph node metastasis and FGFR4 rs351855 were associated with patient survival. In conclusion, our study demonstrated that FGFR4 rs2011077 and rs1966265 are associated with the progression of cervical normal tissues to precancerous lesions in Taiwanese women. Moreover, rs351855 (Gly388Arg) is the only FGFR4 genetic polymorphism that is associated with patient survival.

This study aimed to explore the involvement of carbonic anhydrase 9 (CA9) single nucleotide polymorphisms (SNPs) in the development of invasive cancer of uterine cervix for Taiwanese women. Ninety-seven patients with cervical invasive squamous cell carcinoma and 88 with preinvasive squamous cell lesions as well as 324 control women were recruited. Two CA9 SNPs in exons, including rs2071676 (+201, G/A) in exon 1 and rs3829078 (+1081, A/G) in exon 7, rs1048638 (+1584, C/A) in 3'-untranslated region of exon 11, as well as an 18-base pair deletion/insertion (376deltion393) in exon 1 were selected and their genotypic distributions were determined by real-time polymerase chain reaction. Haplotype was then constructed with rs2071676, 376del393, rs3829078 and rs1048638 in order. The results revealed that Taiwanese women with genotypes CA or CA/AA in CA9 SNP rs1048638 displayed a more risk in developing cervical invasive cancer, assigning wild genotype CC as a reference. AA in SNP rs2071676 tended to increase the risk of developing cervical invasive cancer, using GG/GA as a reference. When women had the diplotypes, carrying at least one haplotype A1AA (one mutant allele A in rs2071676, no deletion in 376del393, no mutant allele A in rs3829078 and one mutant allele A in rs1048638), they were significantly susceptible to cervical invasive cancer. In conclusion, CA9 SNP rs1048638 and haplotype A1AA are associated with the susceptibility of cervical invasive squamous cell carcinoma for Taiwanese women.

// Shun-Fa Yang 1, 2 , Yu-Fan Liu 3 , Chao-Wen Cheng 4 , Wei-En Yang 1, 2 , Wea-Lung Lin 5, 6 , Jiunn-Liang Ko 1, 2 and Po-Hui Wang 1, 5, 7 1 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan 2 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan 3 Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan 4 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 5 School of Medicine, Chung Shan Medical University, Taichung, Taiwan 6 Department of Pathology, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, Taiwan 7 Department of Obstetrics and Gynecology, Chung Shan Medical University Hospital, Taichung, Taiwan Correspondence to: Po-Hui Wang, email: ginhow84921344@yahoo.com.tw Keywords: carbonic anhydrase, single nucleotide polymorphisms, miR-34a, migration, tissue microarray Received: April 18, 2017 Accepted: August 17, 2017 Published: September 12, 2017 ABSTRACT The purposes of this study were to associate the genetic polymorphisms in carbonic anhydrase (CA) 9 with uterine cervical cancer and identify the clinical implications. Three single-nucleotide polymorphisms (SNPs), rs2071676 (+201, G/A), rs3829078 (+1081, A/G), and rs1048638 (+1584, C/A), and an 18-base-pair deletion/insertion (376del393) in CA9 were examined. We used the Boyden chamber assay to evaluate the influence of CA9 on the migration of cervical cancers. Tissue microarrays were used to evaluate CAIX immunoreactivity and determine its clinical significance. The results revealed that the CA9 SNP rs1048638 is the only significant polymorphism that increases the risk of cervical cancer in Taiwanese women. We discovered that the CA9 SNP rs1048638 influences the expression of CA9 through the interaction between the 3′-untranslated region (UTR) of exon 11, where the SNP is located, and miR-34a, and influences the migration of cervical cancer cells. Moreover, we demonstrated that CAIX immunoreactivity is related to the occurrence of cervical cancer, and elevated CAIX immunoreactivity is associated with a more advanced stage. In conclusion, the finding that the CA9 SNP rs1048638 exerts its action through duplexes of the miR-34a and CA9 3′-UTRs and plays a vital role in cervical cancer in Taiwanese women may be applicable to translational medicine.

// Shih-Chi Su 1, 2 , Yung-Chuan Ho 3 , Yu-Fan Liu 4 , Russel J. Reiter 5 , Chia-Hsuan Chou 6 , Chia-Ming Yeh 6 , Hsiang-Lin Lee 6, 7 , Wen-Hung Chung 1, 2, 8 , Ming-Ju Hsieh 6, 9, 10 and Shun-Fa Yang 6, 11 1 Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan 2 Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linkou and Keelung, Taiwan 3 School of Medical Applied Chemistry, Chung Shan Medical University, Taichung, Taiwan 4 Department of Biomedical Sciences, College of Medicine Sciences and Technology, Chung Shan Medical University, Taichung, Taiwan 5 Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, TX, USA 6 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan 7 Deptartment of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan 8 College of Medicine, Chang Gung University, Taoyuan, Taiwan 9 Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan 10 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan 11 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan Correspondence to: Shun-Fa Yang, email: ysf@csmu.edu.tw Ming-Ju Hsieh, email: 170780@cch.org.tw Keywords: melatonin receptor, polymorphism, hepatocellular carcinoma, metastasis Received: August 12, 2017 Accepted: September 04, 2017 Published: September 20, 2017 ABSTRACT Hepatocellular carcinoma (HCC) is a prevalent primary neoplasm of the liver, whose heterogeneous global incidence suggests the likely impact of genetic variations among individuals on the susceptibility to this disease. Increasing evidence indicates that melatonin exhibits oncostatic properties in many cancer types at least in part mediated by its membrane-bound receptors, melatonin receptor 1A (encoded by MTNR1A ) and 1B ( MTNR1B ). In this study, the effect of melatonin receptor gene polymorphisms on the risk and progression of hepatic tumors was evaluated between 335 HCC patients and 1196 cancer-free subjects. We detected a significant association of MTNR1A single nucleotide polymorphism (SNP), rs6553010, with the elevated risk of HCC (AOR, 1.587; 95% CI, 1.053–2.389; p = 0.027) after being adjusted for two potential confounders, age and alcohol use. In addition, patients who carry at least one polymorphic allele (heterozygote or homozygote) of MTNR1A rs2119882 or rs2375801 were more prone to develop distant metastasis (OR, 5.202; 95% CI, 1.163–23.270; p = 0.031, and OR, 7.782; 95% CI, 1.015–59.663; p = 0.048, for rs2119882 and rs2375801, respectively). Further analyses revealed that rs2119882 is located on the consensus binding site of GATA2 transcription factor within the promoter region of MTNR1A gene, and that a correlation between the levels of GATA2 and melatonin receptor 1A was observed in the TCGA (The Cancer Genome Atlas) dataset. Moreover, individuals bearing a specific haplotype of four MTNR1B SNPs were more prone to develop HCC. In conclusion, our data suggest an association of melatonin receptor gene polymorphisms with the risk of HCC and hepatic cancer metastasis.

Background Acetic acid is a predominant by-product of lignocellulosic biofuel process, which inhibits microbial biocatalysts. Development of bacterial strains that are tolerant to acetic acid is challenging due to poor understanding of the underlying molecular mechanisms. Results In this study, we generated and characterized two acetic acid-tolerant strains of Zymomonas mobilis using N-methyl-N′-nitro-N-nitrosoguanidine (NTG)-acetate adaptive breeding. Two mutants, ZMA-142 and ZMA-167, were obtained, showing a significant growth rate at a concentration of 244 mM sodium acetate, while the growth of Z. mobilis ATCC 31823 were completely inhibited in presence of 195 mM sodium acetate. Our data showed that acetate-tolerance of ZMA-167 was attributed to a co-transcription of nhaA from ZMO0117, whereas the co-transcription was absent in ATCC 31823 and ZMA-142. Moreover, ZMA-142 and ZMA-167 exhibited a converstion rate (practical ethanol yield to theorical ethanol yield) of 90.16% and 86% at 195 mM acetate-pH 5 stress condition, respectively. We showed that acid adaptation of ZMA-142 and ZMA-167 to 146 mM acetate increased ZMA-142 and ZMA-167 resulted in an increase in ethanol yield by 32.21% and 21.16% under 195 mM acetate-pH 5 stress condition, respectively. Conclusion The results indicate the acetate-adaptive seed culture of acetate-tolerant strains, ZMA-142 and ZMA-167, could enhance the ethanol production during fermentation.

Carbonic anhydrase IX (CA9) expression level has been considered as a poor prognostic factor in hepatocellular carcinoma (HCC) patients. However, the judging criteria of CA9 level is hard to define for potential clinical applications. Unlike CA9 expression level, CA9 polymorphism is poorly documented in HCC. Here, we found that people carry A allele at CA9 rs1048638, a 3′UTR SNP, has higher risk of HCC. rs1048638-CA correlates with advanced stages, larger tumor sizes, more vascular invasion, and shorter survival of HCC patients. A allele at CA9 rs1048638 impairs miR-34a, a tumor suppressor miRNA in HCC, binding to CA9 3′UTR and desensitizes CA9 mRNA to miR-34a-dependent RNA degradation. CA9 expression levels were also correlated with miR-34a levels and rs1048638 genotypes in HCC patients. rs1048638 influences HCC risk and progression through effects on miR-34a-targeted CA9 expression in HCC. In conclusion, genetic variations of the CA9 3′UTR play important roles in regulating CA9 expression and cancer progression, which is a novel determinant and target for HCC metastasis and prognosis.

Brain glycogen stored in astrocytes provides lactate as an energy source to neurons through monocarboxylate transporters (MCTs) to maintain neuronal functions such as hippocampus-regulated memory formation. Although prolonged exhaustive exercise decreases brain glycogen, the role of this decrease and lactate transport in the exercising brain remains less clear. Because muscle glycogen fuels exercising muscles, we hypothesized that astrocytic glycogen plays an energetic role in the prolonged-exercising brain to maintain endurance capacity through lactate transport. To test this hypothesis, we used a rat model of exhaustive exercise and capillary electrophoresis-mass spectrometry-based metabolomics to observe comprehensive energetics of the brain (cortex and hippocampus) and muscle (plantaris). At exhaustion, muscle glycogen was depleted but brain glycogen was only decreased. The levels of MCT2, which takes up lactate in neurons, increased in the brain, as did muscle MCTs. Metabolomics revealed that brain, but not muscle, ATP was maintained with lactate and other glycogenolytic/glycolytic sources. Intracerebroventricular injection of the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol did not affect peripheral glycemic conditions but suppressed brain lactate production and decreased hippocampal ATP levels at exhaustion. An MCT2 inhibitor, α-cyano-4-hydroxy-cinnamate, triggered a similar response that resulted in lower endurance capacity. These findings provide direct evidence for the energetic role of astrocytic glycogen-derived lactate in the exhaustive-exercising brain, implicating the significance of brain glycogen level in endurance capacity. Glycogen-maintained ATP in the brain is a possible defense mechanism for neurons in the exhausted brain.

// Chiao-Wen Lin 1, 2 , Ying-Erh Chou 3, 4 , Chia-Ming Yeh 4, 5 , Shun-Fa Yang 4, 5 , Chun-Yi Chuang 3, 6 and Yu-Fan Liu 7, 8 1 Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan 2 Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan 3 School of Medicine, Chung Shan Medical University, Taichung, Taiwan 4 Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan 5 Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan 6 Department of Otolaryngology, Chung Shan Medical University Hospital, Taichung, Taiwan 7 Department of Biomedical Sciences, College of Medicine Sciences and Technology, Chung Shan Medical University, Taichung, Taiwan 8 Division of Allergy, Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan Correspondence to: Yu-Fan Liu, email: yfliu@csmu.edu.tw Keywords: HMGB1, polymorphism, OSCC, bioinformatics analysis, haplotypes Received: January 04, 2017 Accepted: February 15, 2017 Published: March 11, 2017 ABSTRACT Oral squamous cell carcinoma (OSCC) is a common malignancy that has been causally associated with both hereditary and acquired factors. The high mobility group box 1 ( HMGB1 ) gene plays an important role as a DNA chaperone to help maintain nuclear homeostasis. Altered expression of HMGB1 has been implicated in a wide range of pathological processes, including inflammation and cancer. The present study explores the impact of HMGB1 gene polymorphisms, combined with environmental risks regarding susceptibility to oral tumorigenesis. Four single-nucleotide polymorphisms (SNPs) of the HMGB1 gene, rs1412125, rs2249825, rs1045411, and rs1360485, were evaluated in 1,200 normal controls and 772 patients with OSCC. We found an association between the wild-type allele of rs1045411 and genotypes CT and CT/TT (AOR=0.754, 95% CI=0.582-0.978 and AOR=0.778, 95% CI=0.609-0.995, respectively). Additionally, bioinformatics analysis was used to characterize the functional relevance of these variants for the miRNA-505-5p binding site and transcriptional regulation by the HMGB1 3’-UTR and promoter regions. Moreover, in considering behavioral exposure to environmental carcinogens, the presence of the four HMGB1 SNPs, combined with/without betel quid chewing and smoking showed, profoundly synergistic effects on the risk of OSCC. In conclusion, we present a potential clinical relevance for HMGB1 variants in OSCC, as well as associations between HMGB1 polymorphisms, haplotypes and environmental risk factors. The finding may help in development of optimal therapeutic approaches for OSCC patients.

Oral squamous cell carcinoma (OSCC), an epithelial malignancy affecting a variety of subsites in the oral cavity, is prevalent in Asia. The survival rate of OSCC patients has not improved over the past decades due to its heterogeneous etiology, genetic aberrations, and treatment outcomes. Improvement in therapeutic strategies and tailored treatment options is an unmet need. To unveil the mutational spectrum, whole-exome sequencing of 120 OSCC from male individuals in Taiwan was conducted. Analyzing the contributions of the five mutational signatures extracted from the dataset of somatic variations identified four groups of tumors that were significantly associated with demographic and clinical features. In addition, known (TP53, FAT1, EPHA2, CDKN2A, NOTCH1, CASP8, HRAS, RASA1, and PIK3CA) and novel (CHUK and ELAVL1) genes that were significantly and frequently mutated in OSCC were discovered. Further analyses of gene alteration status with clinical parameters revealed that the tumors of the tongue were enriched with copy-number alterations in several gene clusters containing CCND1 and MAP4K2. Through defining the catalog of targetable genomic alterations, 58% of the tumors were found to carry at least one aberrant event potentially targeted by US Food and Drug Administration (FDA)-approved agents. Strikingly, if targeting the p53-cell cycle pathway (TP53 and CCND1) by the drugs studied in phase I-III clinical trials, those possibly actionable tumors are predominantly located in the tongue, suggesting a better prediction of sensitivity to current targeted therapies. Our work revealed molecular OSCC subgroups that reflect etiological and prognostic correlation as well as defined the landscape of major altered events in the coding regions of OSCC genomes. These findings provide clues for the design of clinical trials for targeted therapies and stratification of OSCC patients with differential therapeutic efficacy.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, whose diversified occurrence worldwide indicates a connection between genetic variations among individuals and the predisposition to such neoplasms. Mounting evidence has demonstrated that long non-coding RNA (lncRNA) H19 can have both promotive and inhibitory effects on cancer development, revealing a dual role in tumorigenesis. In this study, the link of H19 gene polymorphisms to hepatocarcinogenesis was assessed between 359 HCC patients and 1190 cancer-free subjects. We found that heterozygotes for the minor allele of H19 rs2839698 (T) and rs3741219 (G) were more inclined to develop HCC (OR, 1.291, 95% CI, 1.003&ndash, 1.661, p = 0.047, and OR, 1.361, 95% CI, 1.054&ndash, 1.758, p = 0.018, respectively), whereas homozygotes for the polymorphic allele of rs2107425 (TT) were correlated with a decreased risk of HCC (OR, 0.606, 95% CI, 0.410&ndash, 0.895, p = 0.012). Moreover, patients who bear at least one variant allele (heterozygote or homozygote) of rs3024270 were less prone to develop late-stage tumors (for stage III/IV, OR, 0.566, 95% CI, 0.342&ndash, 0.937, p = 0.027). In addition, carriers of a particular haplotype of three H19 SNPs tested were more susceptible to HCC. In conclusion, our results indicate an association between H19 gene polymorphisms and the incidence and progression of liver cancer.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, whose diversified occurrence worldwide indicates a connection between genetic variations among individuals and the predisposition to such neoplasms. Mounting evidence has demonstrated that long non-coding RNA (lncRNA) H19 can have both promotive and inhibitory effects on cancer development, revealing a dual role in tumorigenesis. In this study, the link of H19 gene polymorphisms to hepatocarcinogenesis was assessed between 359 HCC patients and 1190 cancer-free subjects. We found that heterozygotes for the minor allele of H19 rs2839698 (T) and rs3741219 (G) were more inclined to develop HCC (OR, 1.291; 95% CI, 1.003–1.661; p = 0.047, and OR, 1.361; 95% CI, 1.054–1.758; p = 0.018, respectively), whereas homozygotes for the polymorphic allele of rs2107425 (TT) were correlated with a decreased risk of HCC (OR, 0.606; 95% CI, 0.410–0.895; p = 0.012). Moreover, patients who bear at least one variant allele (heterozygote or homozygote) of rs3024270 were less prone to develop late-stage tumors (for stage III/IV; OR, 0.566; 95% CI, 0.342–0.937; p = 0.027). In addition, carriers of a particular haplotype of three H19 SNPs tested were more susceptible to HCC. In conclusion, our results indicate an association between H19 gene polymorphisms and the incidence and progression of liver cancer.

Aflatoxins are carcinogenic secondary metabolites of fungi that contaminate many staple crops and foods. Aflatoxin contamination is a worldwide problem, especially in developing countries, posing health hazards, e.g., causing aflatoxicosis and hepatocellular carcinoma, and even death. Biological solutions for aflatoxin detoxification are environmentally friendly and a cheaper alternative than chemical methods. The aims of the current study were to investigate: (1) the ability of MSMEG_5998, an aflatoxin-degrading F420H2-dependent reductase from Mycobacterium smegmatis, to degrade aflatoxin B1 (AFB1) and reduce AFB1-caused damage in HepG2 cell culture model, and (2) whether a thioredoxin (Trx) linkage of MSMEG_5998 enhanced the enzyme activity. We show that Trx-linked MSMEG_5998 degraded 63% AFB1 and native MSMEG_5998 degraded 31% after 4 h at 22 &deg, C, indicating that the Trx-linked enzyme had a better AFB1-degrading ability. In a HepG2 cell culture model, Trx-linked MSMEG_5998 reduced DNA damage and p53-mediated apoptosis caused by AFB1 to a greater extent than the native enzyme. These findings suggest that Trx-linked MSMEG_5998 could potentially be developed to protect the liver from AFB1 damage, or as a candidate protein to reduce AFB1-related toxicity in animals.