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No comparative study with a long-term follow-up period has evaluated the survival outcomes of preoperative 18-fluorodeoxyglucose positron emission tomography/computed tomography ((18)FDG PET/CT) in patients with p16-negative OPSCC. We included patients with stage I-IVB p16-negative OPSCC undergoing surgery and categorized them into two groups based on whether they underwent preoperative (18)FDG PET/CT and compared their outcomes: the case group comprised patients who did not undergo preoperative (18)FDG PET/CT, whereas the control group comprised patients who underwent preoperative (18)FDG PET/CT. The findings of the multivariable Cox regression analysis revealed no association between preoperative (18)FDG PET/CT and overall survival (OS) in the case and control groups in the patients with stage I-III p16-negative OPSCC undergoing surgery (after multivariable adjustment, the hazard ratio [HR] was 1.12; 95% confidence interval [CI] = 0.86-1.48: P = 0.4028). However, we noted an association between preoperative (18)FDG PET/CT and OS in the case and control groups in the patients with stage IVA and IVB p16-negative OPSCC undergoing surgery (after multivariable adjustment, the HR of all-cause mortality for nonpreoperative PET/CT was 1.82 compared with preoperative PET/CT; 95% CI = 1.47-2.26; P < 0.0001). Preoperative (18)FDG PET/CT use was associated with a lower risk of mortality in the patients with stage IVA and IVB p16-negative OPSCC without metastasis.

Arginine synthesis deficiency due to the suppressed expression of ASS1 (argininosuccinate synthetase 1) represents one of the most frequently occurring metabolic defects of tumor cells. Arginine-deprivation therapy has gained increasing attention in recent years. One challenge of ADI-PEG20 (pegylated ADI) therapy is the development of drug resistance caused by restoration of ASS1 expression and other factors. The goal of this work is to identify novel factors conferring therapy resistance. Methods: Multiple, independently derived ADI-resistant clones including derivatives of breast (MDA-MB-231 and BT-549) and prostate (PC3, CWR22Rv1, and DU145) cancer cells were developed. RNA-seq and RT-PCR were used to identify genes upregulated in the resistant clones. Unbiased genome-wide CRISPR/Cas9 knockout screening was used to identify genes whose absence confers sensitivity to these cells. shRNA and CRISPR/Cas9 knockout as well as overexpression approaches were used to validate the functions of the resistant genes both in vitro and in xenograft models. The signal pathways were verified by western blotting and cytokine release. Results: Based on unbiased CRISPR/Cas9 knockout screening and RNA-seq analyses of independently derived ADI-resistant (ADIR) clones, aberrant activation of the TREM1/CCL2 axis in addition to ASS1 expression was consistently identified as the resistant factors. Unlike ADIR, MDA-MB-231 overexpressing ASS1 cells achieved only moderate ADI resistance both in vitro and in vivo, and overexpression of ASS1 alone does not activate the TREM1/CCL2 axis. These data suggested that upregulation of TREM1 is an independent factor in the development of strong resistance, which is accompanied by activation of the AKT/mTOR/STAT3/CCL2 pathway and contributes to cell survival and overcoming the tumor suppressive effects of ASS1 overexpression. Importantly, knockdown of TREM1 or CCL2 significantly sensitized ADIR toward ADI. Similar results were obtained in BT-549 breast cancer cell line as well as castration-resistant prostate cancer cells. The present study sheds light on the detailed mechanisms of resistance to arginine-deprivation therapy and uncovers novel targets to overcome resistance. Conclusion: We uncovered TREM1/CCL2 activation, in addition to restored ASS1 expression, as a key pathway involved in full ADI-resistance in breast and prostate cancer models.

Fibroblast growth factor 9 (FGF9) is an autocrine/paracrine growth factor that plays critical roles in embryonic and organ developments and is involved in diverse physiological events. Loss of function of FGF9 exhibits male-to-female sex reversal in the transgenic mouse model and gain of FGF9 copy number was found in human 46, XX sex reversal patient with disorders of sex development. These results suggested that FGF9 plays a vital role in male sex development. Nevertheless, how FGF9/Fgf9 expression is regulated during testis determination remains unclear. In this study, we demonstrated that human and mouse SRY bind to −833 to −821 of human FGF9 and −1010 to −998 of mouse Fgf9, respectively, and control FGF9/Fgf9 mRNA expression. Interestingly, we showed that mouse SRY cooperates with SF1 to regulate Fgf9 expression, whereas human SRY-mediated FGF9 expression is SF1 independent. Furthermore, using an ex vivo gonadal culture system, we showed that FGF9 expression is sufficient to switch cell fate from female to male sex development in 12–16 tail somite XX mouse gonads. Taken together, our findings provide evidence to support the SRY-dependent, fate-determining role of FGF9 in male sex development.

PurposeThe study discovers a crisis of authority and administration in Catholic mission of Taiwan during 1910 and 1920s. It aims to discover the reasons and the significance of the problem.Design/methodology/approachThe author works on the reports and correspondence of Jean de Guébriant, apostolic visitor of China missions in 1919–1920. He received some reports from the Dominican Prefect Apostolic of Formosa, Clemente Fernandez.FindingsThe author discovers a severe problem of authority brought about some conflicts between the Prefect Apostolic Clemente Fernandez, o.p. and some Dominican missionaries in the mission, conflicts reflecting ambiguous status of this prefecture apostolic with regard to not only the Dominican Provincia del Santo Rosario, headquarters of Dominican missions in East Asia, but also the Dominican apostolic vicariate of Southern Fujian in China, and even the Japanese Catholic church, because Taiwan had been conceded to the Japanese empire since 1895 until 1945.Research limitations/implicationsThe author has not yet consulted the archives in Propaganda Fide in Vatican circle and in Dominican archives. Still, some questions remain unanswered for lack of related archives. This study calls for further works in the future.Originality/valueVery few relevant studies are found on the Dominican mission in Taiwan during 1860–1949. This study reveals a serious problem on the structure of Catholic mission due to an unclear status of Taiwan. It reflects, in fact, the delicate situation in ecclesial and political aspects between China, Japan and Spanish missions in Manila, Philippines.

Head and neck squamous cell carcinoma (HNSCC) is a major contributor to cancer incidence globally and is currently managed by surgical resection followed by adjuvant chemoradiotherapy. However, local recurrence is the major cause of mortality, indicating the emergence of drug-tolerant persister cells. A specific histone demethylase, namely lysine-specific demethylase 5D (KDM5D), is overexpressed in diverse types of cancers and involved in cancer cell cycle regulation. However, the role of KDM5D in the development of cisplatin-tolerant persister cells remains unexplored. Here, we demonstrated that KDM5D contributes to the development of persister cells. Aurora Kinase B (AURKB) disruption affected the vulnerability of persister cells in a mitotic catastrophe–dependent manner. Comprehensive in silico, in vitro, and in vivo experiments were performed. KDM5D expression was upregulated in HNSCC tumor cells, cancer stem cells, and cisplatin-resistant cells with biologically distinct signaling alterations. In an HNSCC cohort, high KDM5D expression was associated with a poor response to platinum treatment and early disease recurrence. KDM5D knockdown reduced the tolerance of persister cells to platinum agents and caused marked cell cycle deregulation, including the loss of DNA damage prevention, and abnormal mitosis-enhanced cell cycle arrest. By modulating mRNA levels of AURKB, KDM5D promoted the generation of platinum-tolerant persister cells in vitro, leading to the identification of the KDM5D/AURKB axis, which regulates cancer stemness and drug tolerance of HNSCC. Treatment with an AURKB inhibitor, namely barasertib, resulted in a lethal consequence of mitotic catastrophe in HNSCC persister cells. The cotreatment of cisplatin and barasertib suppressed tumor growth in the tumor mouse model. Thus, KDM5D might be involved in the development of persister cells, and AURKB disruption can overcome tolerance to platinum treatment in HNSCC.

The exact mechanisms of Head and neck squamous carcinoma (HNSCC) chemoresistance and metastatic transformation remain unclear. In recent decades, members of the transient receptor potential (TRP) channel family have been proposed as potential biomarkers and/or drug targets in cancer treatment. First, in a TCGA cohort of HNSCC, TRPM7 is highly expressed in cancer tissues, especially the expression in invasive cancer tissues is statistically significant (p0.001). In GEO and TCGA cohort, patients with high expression of TRPM7 and NFATC2 have poor overall survival rates. The expression of TRPM7 and NFATC2 showed a positive correlation. Compared to human normal oral keratinocytes (hNOK), TRPM7 is overexpressed in FaDU, SAS, and TW2.6 cell lines. Similarly, patients with HNSCC exhibited higher TRPM7 expression than non-HNSCC subjects, and this high TRPM7 expression was associated with worse 5-year overall survival. Furthermore, TRPM7 inversely correlated with E-cadherin, but positively correlated with Vimentin, NANOG, and BMI-1 mRNA levels. Consistent with this, we demonstrated the overexpression of TRPM7 in cisplatin-resistant subjects, compared to the cisplatin-sensitive counterparts. Moreover, shRNA-mediated silencing of TRPM7 significantly suppressed the migration, invasion, colony formation, and tumorsphere formation of SAS cells, with associated downregulation of Snail, c-Myc, cyclin D1, SOX2, OCT4, and NANOG proteins expression. Finally, compared with the untreated wild-type SAS cells or cisplatin-treated cells, shTRPM7 alone or in combination with cisplatin significantly inhibited tumorsphere and colony formation. These findings serving as the basis for development of novel therapeutic strategies against metastasis and chemoresistance, while providing new insights into TRPM7 biology and activity in HNSCC.

We sought to compare the clinical outcomes of Taiwanese patients with resected oral cavity squamous cell carcinoma (OCSCC) who underwent reconstruction with free versus local flaps.From 2011 to 2017, we examined 8646 patients with first primary OCSCC who received surgery either with or without adjuvant therapy. Of these patients, 7297 and 1349 received free and local flap reconstruction, respectively. Two propensity score-matched groups of patients who underwent free versus local flap (n = 1268 each) reconstructions were examined. Margin status was not included as a propensity score-matched variable.Compared with local flaps, patients who received free flaps had a higher prevalence of the following variables: male sex, age 65 years, pT3-4, pN1-3, p-Stage III-IV, depth ≥ 10 mm, margin 4 mm, extranodal extension (ENE), and adjuvant therapy (all p 0.0001). Multivariable analysis identified the reconstruction method (local vs. free flaps, only overall survival [OS]), age ≥ 65 years, pT3-4, pN1-3, p-Stage III-IV, depth ≥ 10 mm (only OS), margins ≤ 4 mm, and ENE as independent adverse prognosticators for disease-specific survival (DSS) and OS. The results of propensity score-matched analyses revealed that, compared with free flaps, patients who underwent local flap reconstruction showed less favorable 5-year DSS (hazard ratio [HR] 1.26, 82%/77%; p = 0.0100) and OS (HR 1.21, 73%/68%; p = 0.0079).After adjusting for covariates using multivariate models, and also by propensity score modeling, OCSCC patients who underwent free flap reconstruction showed a higher frequency of clear margins and a significant survival advantage compared with those who received local flaps.

There is currently no system to predict 90-day morality among patients with locally advanced head and neck squamous cell carcinoma (HNSCC) after the completion of concurrent chemoradiotherapy (CCRT).To validate the accuracy of a predictive scoring system for 90-day mortality among patients with locally advanced HNSCC who have completed CCRT.This prognostic study included 16 029 patients with HNSCC who completed CCRT between January 2006 and December 2015. Data were extracted from the Taiwan Cancer Registry Database. A risk scoring system was developed based on significant risk factors and corresponding risk coefficients. Data analysis was conducted from June 2018 to February 2019.Mortality within 90 days of completion of definitive CCRT.The 90-day mortality rate after completion of CCRT and the accuracy of the scoring system, based on a comparison of mortality rates between training and test data sets.Among 16 029 patients with locally advanced HNSCC, 1068 (6.66%; 1016 [95.1%] men; mean [SD] age, 55.11 [11.45] years) died before reaching the 90-day threshold, and 14 961 (93.4%; 14 080 [94.1%] men; mean [SD] age, 52.07 [9.99] years) survived. Multivariable analysis revealed that being aged 50 years or older (adjusted hazard ratio [aHR], 1.263; 95% CI, 1.104-1.445; P .001), being aged 70 years or older (aHR, 2.183; 95% CI, 1.801-2.645; P .001), having pneumonia (aHR, 1.946; 95% CI, 1.636-2.314; P .001), having sepsis (aHR, 3.005; 95% CI, 2.503-3.607; P .001), having hemiplegia (aHR, 1.430; 95% CI, 1.085-1.884; P = .01), having moderate or severe renal disease (aHR, 2.054; 95% CI, 1.643-2.568; P .001), having leukemia (aHR, 4.541; 95% CI, 1.132-8.207; P = .03), and having non-HNSCC metastatic solid cancers (aHR, 1.457; 95% CI, 1.292-1.644; P .001) were significant risk factors for 90-day mortality. Risk scores were categorized as very low risk (score of 0), low risk (score 1-3), moderate risk (score 4-6), and high risk (score ≥7), with 90-day mortality rates of 3.37%, 5.00% to 10.98%, 16.15% to 29.13%, and 33.93% to 37.50%, respectively. Mortality rates for patients with the same risk score in the training and test data sets were similar (score of 0, 3.27% vs 3.66%; score of 6, 27.42% vs 25.00%).In this prognostic study, a 90-day mortality scoring system accurately predicted 90-day mortality among patients with locally advanced HNSCC who completed CCRT.

Focal adhesion kinase (FAK) mediates vital cellular pathways during development. Despite its necessity, how FAK regulates and integrates with other signals during early embryogenesis remains poorly understood. We found that the loss of Fak1a impaired epiboly, convergent extension and hypoblast cell migration in zebrafish embryos. We also observed a clear disturbance in cortical actin at the blastoderm margin and distribution of yolk syncytial nuclei. In addition, we investigated a possible link between Fak1a and a well-known gastrulation regulator, Wnt5b, and revealed that the overexpression of fak1a or wnt5b could cross-rescue convergence defects induced by a wnt5b or fak1a antisense morpholino (MO), respectively. Wnt5b and Fak1a were shown to converge in regulating Rac1 and Cdc42, which could synergistically rescue wnt5b and fak1a morphant phenotypes. Furthermore, we generated several alleles of fak1a mutants using CRISPR/Cas9, but those mutants only revealed mild gastrulation defects. However, injection of a subthreshold level of the wnt5b MO induced severe gastrulation defects in fak1a mutants, which suggested that the upregulated expression of wnt5b might complement the loss of Fak1a. Collectively, we demonstrated that a functional interaction between Wnt and FAK signalling mediates gastrulation cell movements via the possible regulation of Rac1 and Cdc42 and subsequent actin dynamics.

Background No large-scale, head-to-head, phase III, randomized, controlled trial with an adequate sample size has investigated the effect of concurrent low-dose (LD) or high-dose (HD) cisplatin with radiotherapy on nasopharyngeal cancer (NPC). Thus, we conducted a propensity-score-matched, nationwide, population-based cohort study in Taiwan to investigate the outcomes of LD-concurrent chemoradiotherapy (CCRT) or HD-CCRT with intensity-modulated radiotherapy (IMRT) in patients with advanced NPC. Methods In this study, patients were categorized into 2 groups according to their chemotherapy regimen: HD-CCRT and LD-CCRT groups. Results We enrolled 1968 patients (328 and 1640 in the LD-CCRT and HD-CCRT groups, respectively) who had received CCRT with IMRT. According to both univariate and multivariate Cox regression analyses, a hazard ratio (95% confidence interval) of 0.75 (0.54–1.06, P = .103) was derived for the HD-CCRT group. Conclusion LD-CCRT or HD-CCRT with IMRT can be a standard treatment that can prolong the survival of patients with advanced NPC.

Background Recurrent aphthous stomatitis (RAS) is considered a prophase symptom in patients with specific cancers. This study assessed the association between RAS and subsequent onset of cancer based on a nationwide population‐based database in Taiwan. Materials and Methods We selected study participants from the National Health Insurance Research Database from January 2000 to December 2008. Patients in the non‐RAS cohort were matched to case study patients at a 1:1 ratio through frequency matching. All participants were followed up for at least 5 years, and those who received cancer diagnoses during follow‐up were identified. Results Among 52 307 patients with and 52 304 patients without RAS, the combined hazard ratio (HR) of all subsequent cancer cases was 1.3 (95% confidence interval [CI]: 1.25‐1.35, P = 0). RAS diagnosis was associated with risk for cancers of the head and neck (aHR = 2, 95% CI: 1.8‐2.3), colon (aHR = 1.2, 95% CI: 1.1‐1.4), liver (aHR = 1.1, 95% CI: 1‐1.3), pancreas (aHR = 1.4, 95% CI: 1.1‐1.7), skin (aHR = 1.4, 95% CI: 1.2‐1.7), breast (aHR = 1.2, 95% CI: 1.1‐1.4), and prostate (aHR = 1.5, 95% CI: 1.3‐1.8), as well as hematologic cancers (aHR = 1.6, 95% CI: 1.3‐1.9). A higher risk was observed for male patients (aHR = 1.35, 95% CI: 1.28‐1.42) than for female patients (aHR = 1.25, 95% CI: 1.18‐1.31) with RAS. Conclusions RAS was associated with specific cancers. Susceptible RAS patients should be screened for specific cancers.

The aim of this study was to examine the effect of dumping harbor dredged sediments into the ocean on the phthalate esters distribution in the sediments of Kaohsiung Ocean Dredged Material Disposal Site (KODMDS). Compared with the sediments outside the disposal site (Area R), the particle size distribution of sediment in disposal site has no significant difference, because the pattern of particle size distribution in the dredged sediments is similar to that in the sediments of KODMDS. Results indicated that the mean phthalate ester content in the centres of the four disposal areas (Area I) were significantly (p

Background Emergency complications of colon cancer include perforation and obstruction which were recognized as poor prognostic factors. Few studies have directly compared the outcomes of these two groups. In this study, we evaluated mortality and morbidity in patients with colon cancer initially presenting as perforation and obstruction. Methods Newly diagnosed colon cancer cases initially presenting with perforation or obstruction at Tzu Chi General Hospital, Hualien, Taiwan, between 2009 and 2015 were included. Cases of iatrogenic perforation or perforation sites far away from the tumor sites and rectal (

Although patients with buccal squamous cell carcinoma (SCC) usually show acceptable outcomes, local control and survival rates are generally lower than those observed for tongue SCC. This study was designed to compare the clinical outcomes of Taiwanese patients with these two common oral cavity malignancies.Patients with first primary buccal or tongue SCC who were included in the Taiwanese Cancer Registry Database between 2004 and 2012 were eligible. The study sample consisted of 16,379 patients (7870 buccal SCC and 8509 tongue SCC) who received surgery with or without adjuvant therapy. The 5-year disease-specific survival (DSS) and overall survival (OS) rates served as the outcome measures.Compared with tongue SCC, patients with buccal SCC had a higher prevalence of males (95.7% vs. 86.4%, p0.0001), pT4 disease (21.4% vs. 12.7%, p0.0001), and p-Stage IV (30.4% vs. 24.8%, p0.0001) but a lower frequency of pN2 disease (15.2% vs. 18.5%, p0.0001). The 5-year DSS and OS rates of buccal SCC patients were slightly higher than those of tongue SCC (78% vs. 77%, p=0.0297; and 71% vs. 69%, p=0.0231, respectively). Multivariate analysis identified tumor site (tongue vs. buccal SCC), sex (male vs. female), age (≥65 vs.65years), pT classification (T4/T3/T2 vs. T1), and pN classification (N3/N2/N1vs. N0) as independent prognostic factors in the entire study cohort.The survival advantage of buccal SCC over tongue SCC appears significant in large clinical samples, despite a higher prevalence of p-Stage IV disease in the former.

Canine parvovirus type 2 (CPV-2) is a severe enteric pathogen mainly affecting dogs. CPV-2 contains three antigenic variants (2a, 2b, and 2c) that are distributed internationally. Detection and characterization of the currently circulating CPV-2 strains are vital for the understanding of viral evolution, transmission, and the development of methods to control its spreading. Herein, we analyzed the strains in central Taiwan to provide information of local viral evolution, diversity, and epidemiology. Stool and blood samples from 24 dogs and 2 cats were genotyped by PCR amplification of strain-specific VP2 sequence collected during 2011–2013. 60% (16/26) of them were positive and 100% (16/16) of these positive samples were type 2b. Then, the full length VP2 gene was sequenced in 6 CPV-positive samples and a maximum-likelihood phylogenetic tree was constructed using both Taiwan and other strains worldwide. Surprisingly, all Taiwan CPVs showed high relatedness to type 2a. Recombination analysis revealed a recombination of VP2 gene between type 2a and 2b. This study demonstrates a recombination between CPV-2a and 2b in nature that contributes to the genetic diversity and evolution of CPV-2.

Focal adhesion kinase (FAK) mediates vital cellular pathways during development. Despite its necessity, how FAK regulates and integrates with other signals during early embryogenesis remains poorly understood. We found that the loss of Fak1a impaired epiboly, convergent extension and hypoblast cell migration in zebrafish embryos. We also observed a clear disturbance in cortical actin at the blastoderm margin and distribution of yolk syncytial nuclei. In addition, we investigated a possible link between Fak1a and a well-known gastrulation regulator, Wnt5b, and revealed that the overexpression of fak1a or wnt5b could cross-rescue convergence defects induced by a wnt5b or fak1a antisense morpholino (MO), respectively. Wnt5b and Fak1a were shown to converge in regulating Rac1 and Cdc42, which could synergistically rescue wnt5b and fak1a morphant phenotypes. Furthermore, we generated several alleles of fak1a mutants using CRISPR/Cas9, but those mutants only revealed mild gastrulation defects. However, injection of a subthreshold level of the wnt5b MO induced severe gastrulation defects in fak1a mutants, which suggested that the upregulated expression of wnt5b might complement the loss of Fak1a. Collectively, we demonstrated that a functional interaction between Wnt and FAK signalling mediates gastrulation cell movements via the possible regulation of Rac1 and Cdc42 and subsequent actin dynamics.

Osteoarthritis (OA) is a degenerative joint disorder and is the leading cause of disability of people, which negatively impact people's physical and mental health. Although OA causes great socioeconomic burden and individual suffering, no effective treatment options are provided so far. This is partially resulted from poor regenerative activity of articular cartilage and our incomplete understanding of the underlying mechanism of OA. Traditional drug therapies such as acetaminophen and opioids are effective in relieving pain but do not reverse cartilage damage and are often associated with adverse events. Therefore, it is necessary to find effective OA drugs. In recent years, novel regenerative therapies have received much attention because they can effectively promote tissue repair and regeneration. The fibroblast growth factor (FGF) signaling has been suggested to involve in cartilage homeostasis for decades. The current research shows that sprifermin/recombinant FGF18 significantly reduces the loss of cartilage thickness and volume without serious side effects, thus warrants a continued research for potential new medications of OA. This review mainly highlights the current research progress on FGFs and FGF receptors as a potential therapeutic target for OA.

We examined the overall survival rates of a national cohort to determine optimal treatments and prognostic factors for patients with metachronous second primary head and neck squamous cell carcinomas (mspHNSCCs) at different stages and sites. We analyzed data of mspHNSCC patients collected from the Taiwan Cancer Registry database. The patients were categorized into four groups based on the treatment modality: Group 1 (control arm; chemotherapy [CT] alone), Group 2 (reirradiation [re‐RT] alone with intensity‐modulated radiotherapy [IMRT]), Group 3 (concurrent chemoradiotherapy alone [irradiation with IMRT]), and Group 4 (salvage surgery with or without RT or CT). We enrolled 1741 mspHNSCC patients without distant metastasis. Multivariate Cox regression analyses revealed that Charlson comorbidity index (CCI) ≥6, stage of second HNSCC, stage of first HNSCC, and duration from first primary HNSCC of

Oral antiviral therapy may reduce the disease progression of chronic hepatitis B (CHB) patients. We aimed to further investigate the efficacy of long-term entecavir therapy in reduction of the risk of hepatocellular carcinoma (HCC), cirrhotic events and mortality in a large group of CHB-related cirrhosis patients.The C-TEAM (Cirrhosis-Taiwanese EntecAvir Multicenter) study was a nationwide, multicenter, retrospective-prospective cohort study in Taiwan. We enrolled treatment-naïve patients with CHB-related cirrhosis and baseline HBV-DNA≥2000 IU/mL receiving long-term entecavir therapy and compared the development of HCC, cirrhotic events and mortality with that of a historical untreated cohort.In total, 1315 entecavir-treated and 503 untreated patients with cirrhosis were enrolled, with median treatment and follow-up durations of 4 and 6 years respectively. Compared with the untreated cohort, entecavir therapy was associated with a 60% HCC risk reduction [hazard ratio (HR): 0.40, 95% confidence interval (CI): 0.28-0.57]. Additionally, an older age, the male gender, HBeAg positivity, alpha-fetoprotein (AFP)≥7 ng/mL before therapy were independent predictors of HCC development. Further analysis showed that entecavir therapy significantly reduced risks of variceal bleeding, spontaneous bacterial peritonitis, and liver-related and all-cause mortality. These findings were confirmed by propensity score-matched cohorts in sensitivity analysis. In patients under entecavir therapy, an older age, the male gender, HBeAg positivity, AFP level ≥7 ng/mL before therapy, and 1-year virological response were predictive of HCC development.Four-year entecavir therapy significantly reduces the risk of HCC, cirrhotic events and mortality in patients with CHB-related cirrhosis.

// Wei-Chien Huang 1, 2, 3, 4 , Chao-Ming Hung 5, 6 , Ching-Ting Wei 5, 6, * , Tsung-Ming Chen 7, * , Pei-Hsuan Chien 8 , Hsiao-Lin Pan 5 , Yueh-Ming Lin 9 , Yun-Ju Chen 5, 8, 10 1 The Ph.D. program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 404, Taiwan 2 Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan 3 Center for Molecular Medicine, China Medical University and Hospital, Taichung 404, Taiwan 4 Department of Biotechnology, Asia University, Taichung 413, Taiwan 5 School of Medicine for International Students, I-Shou University, Kaohsiung 824, Taiwan 6 Department of General Surgery, E-Da Hospital, Kaohsiung 824, Taiwan 7 Department and Graduate Institute of Aquaculture, National Kaohsiung Marine University, Kaohsiung 811, Taiwan 8 Department of Medical Research, E-Da Hospital, Kaohsiung 824, Taiwan 9 Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan 10 Department of Biological Science & Technology, I-Shou University, Kaohsiung 824, Taiwan * These authors have contributed equally to this work Correspondence to: Yun-Ju Chen, email: yjchen0326@isu.edu.tw Keywords: lapatinib, interleukin-6, HER2, resistance, breast cancer Received: February 10, 2016 Accepted: August 09, 2016 Published: August 22, 2016 ABSTRACT Lapatinib is an inhibitor of human epidermal growth factor receptor 2 (HER2), which is overexpressed in 20-25% of breast cancers. Clinically, lapatinib has shown promising benefits for HER2-positive breast cancer patients; however, patients eventually acquire resistance, limiting its long-term use. In a previous study, we found that interleukin-6 (IL-6) production was increased in acquired lapatinib-resistant HER2-positive breast cancer cells. In the present study, we confirmed that lapatinib-resistant cells had elevated IL-6 expression and also maintained both stemness population and property. The increase in IL-6 was required for stemness property maintenance, which was mediated primarily through the activation of signal transducer and activator of transcription 3 (STAT3). Blocking IL-6 activity reduced spheroid formation, cell viability and subsequently overcame lapatinib resistance, whereas stimulation of IL-6 rendered parental cells more resistant to lapatinib-induced cytotoxicity. These results point to a novel mechanism underlying lapatinib resistance and provide a potential strategy to overcome resistance via IL-6 inhibition.

Lei Qin,1,* Yi-Wei Kao,2,* Yueh-Lung Lin,3 Bou-Yue Peng,4 Win-Ping Deng,5 Tsung-Ming Chen,6 Kuan-Chou Lin,7 Kevin Sheng-Po Yuan,8 Alexander TH Wu,9 Ben-Chang Shia,10 Szu-Yuan Wu11–14 1School of Statistics, University of International Business and Economics, Beijing, China; 2Graduate Institute of Business Administration, Fu Jen Catholic University, Taipei, Taiwan; 3School of Mathematical Sciences, University of Nottingham, Ningbo, China; 4Department of Dentistry, Taipei Medical University Hospital, Taipei, Taiwan; 5Graduate Institute of Biomedical Materials and Engineering, Taipei Medical University, Taipei, Taiwan; 6Department of Otorhinolaryngology, Shuang-Ho Hospital, Taipei Medical University, Taipei, Taiwan; 7Department of Oral and Maxillofacial Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 8Department of Otorhinolaryngology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 9PhD Program for Translational Medicine, Taipei Medical University, Taipei, Taiwan; 10College of Management, Taipei Medical University, Taipei, Taiwan; 11Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China; 12Department of Radiation Oncology, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan; 13Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 14Epidemiology and Bioinformatics Center, Wanfang Hospital, Taipei Medical University, Taipei, Taiwan *These authors contributed equally to this work Background: Few studies have evaluated the risk of oral cavity cancer (OC) in patients with recurrent oral aphthae (ROA) and dry eye syndrome (DES). This study assessed the risk of OC in patients who had received diagnoses of ROA and DES in Taiwan.Methods: A population-based frequency-matched case–control study was conducted in which data were analyzed from the National Health Insurance Research Database of Taiwan. Patients with ROA and DES were identified as the case cohort. Patients and controls without ROA and DES were frequency matched (1:4) on the basis of age, sex, monthly income, geographical location, and urbanization level. Chi-squared tests were conducted to compare demographic factor distributions between the patients and controls. Cox proportional hazards models were used to calculate the adjusted hazard ratios (aHRs) and 95% CI of OC diagnoses among the patients and controls. Risk consistency between the two cohorts was determined using subgroup analysis.Results: A total of 7,110 patients with ROA and DES and 28,388 controls were identified. The OC risk was significantly higher for female patients than controls (aHR=3.41, 95%CI=1.69–6.86). Furthermore, women aged 50–69 years exhibited a higher risk of OC than those in the other age groups. Female patients aged 50–59 years exhibited the highest aHR for OC (aHR=5.56, 95%CI=1.70–18.25), followed by those aged 60–69 years (aHR=4.34, 95%CI=1.26–15.99).Conclusion: ROA and DES may be associated with a high risk of OC in elderly women. Keywords: risk factor, oral cavity cancer, recurrent oral aphthae, dry eye syndrome, women

Background Hypoxia suppresses global protein production, yet certain essential proteins are translated through alternative pathways to survive under hypoxic stress. Translation via the internal ribosome entry site (IRES) is a means to produce proteins under stress conditions such as hypoxia; however, the underlying mechanism remains largely uncharacterized. Methods Proteomic and bioinformatic analyses were employed to identify hnRNPM as an IRES interacting factor. Clinical specimens and mouse model of tumorigenesis were used for determining the expression and correlation of hnRNPM and its target gene. Transcriptomic and translatomic analyses were performed to profile target genes regulated by hnRNPM. Findings Hypoxia increases cytosolic hnRNPM binding onto its target mRNAs and promotes translation initiation. Clinical colon cancer specimens and mouse carcinogenesis model showed that hnRNPM is elevated during the development of colorectal cancer, and is associated with poor prognosis. Genome-wide transcriptomics and translatomics analyses revealed a unique set of hnRNPM-targeted genes involved in metabolic processes and cancer neoplasia are selectively translated under hypoxia. Interpretation These data highlight the critical role of hnRNPM-IRES-mediated translation in transforming hypoxia-induced proteome toward malignancy. Fund This work was supported by the Ministry of Science and Technology, Taiwan (MOST 104–2320-B-006-042 to HSS and MOST 105–2628-B-001-MY3 to TMC).

Chondrosarcoma is a malignant and common bone tumor that is highly resistant to radiation and chemotherapy. At this moment, amputation surgery is the only option which unfortunately has serious impact to daily lives of the patients. Thus, there is an urgent need to understand causative molecular mechanisms underlying the disease for more accurate prognosis and more effective targeted treatment. In the current study, we identify the transcription factor FOXA1 through cDNA microarray screening comparing normal versus chondrosarcoma cells and investigate the mechanisms underlying its function in chondrosarcoma development. We show that FOXA1 enhances expression of the cyclin B1 gene, which in turn drives cell cycle progression through G2-M transition thus promotes cell cycle progression of chondrosarcoma cells.

Background Hepatitis B virus (HBV) relapse is a practical issue after nucleos(t)ide analogue (NA) therapy discontinuation in chronic hepatitis B (CHB). However a prospective multi-centre study remains lacking. The aim of this study was to prospectively investigate virological and clinical outcomes after NA therapy. Methods CHB patients, who discontinued tenofovir disoproxil fumarate (TDF) or entecavir (ETV) therapy based on the NA stopping guidelines, were prospectively recruited from January 2015 to January 2018. Patients with liver cirrhosis, active malignancies, hepatitis C virus, hepatitis D virus or human immunodeficiency virus coinfection, liver transplantation history, immune disorders, a history of NA therapy other than TDF or ETV, or a follow-up period of fewer than 4 weeks were excluded. Serum HBV DNA and quantitative hepatitis B surface antigen (qHBsAg) levels were measured every 3 months. Both cumulative incidences of and hazard ratios (HRs) for the predictors of HBV relapse were analysed. Results Totally, 178 patients (40 HBeAg-positive and 138 HBeAg-negative prior to NA therapy) were enrolled for this analysis (98 TDF and 80 ETV users), and the median follow-up period was 10.6 (interquartile range [IQR]: 5.6–7.2) months. The cumulative incidences of virological (VR) and clinical relapse (CR) in 2 years were 59.5% (95% confidence interval [CI]: 50.6%–68.3%) and 49.0% (95% CI: 34.0%–65.0%), respectively. Moreover, the cumulative incidences of severe hepatitis flare (ALT >500 IU/L) and liver decompensation were 11.8% (95% CI: 3.4%–19.6%) and 1.4% (95% CI: 0%–3.3%), respectively. No patient died of liver disease. In multivariable analysis, qHBsAg >100 IU/mL at the end of therapy was an independent risk factor of VR (HR 2.47, 95% CI: 1.30–4.70) and of CR (HR 3.16, 95% CI: 1.25–7.89), respectively. TDF users initially demonstrated a faster pattern of HBV relapse when compared to ETV users, but the relapse rates were not significantly different in 2 years. Conclusions In this study for non-cirrhotic patients, HBV relapse was common after cessation of NA therapy, and serum qHBsAg can be used as a predicting marker. A longer study period is essential for investigating long-term outcomes.

Bladder cancer is one of the major cancer types and both environmental factors and genetic background play important roles in its pathology. Kaohsiung is a high industrialized city in Taiwan, and here we focused on this region to evaluate the genetic effects on bladder cancer. Muscarinic acetylcholine receptor M3 (CHRM3) was reported as a key receptor in different cancer types.CHRM3is located at 1q42-43 which was reported to associate with bladder cancer. Our study attempted to delineate whether genetic variants ofCHRM3contribute to bladder cancer in Chinese Han population in south Taiwan. Five selected SNPs (rs2165870, rs10802789, rs685550, rs7520974, and rs3738435) were genotyped for 30 bladder cancer patients and 60 control individuals and genetic association studies were performed. Five haplotypes (GTTAT, ATTGT, GCTAC, ACTAC, and ACCAC) were found significantly associated with lowCHRM3mRNA level and contributed to increased susceptibility of bladder cancer in Kaohsiung city after rigid 10000 consecutive permutation tests. To our knowledge, this is the first genetic association study that reveals the genetic contribution ofCHRM3gene in bladder cancer etiology.

A subgroup analysis of a GLOBE study identified subgroups of chronic hepatitis B (CHB) patients with excellent outcomes to telbivudine (LdT) treatment. The aim of this study was to validate this concept using a real-world clinical population. This prospective, retrospective, and multicenter study examined both HBeAg-positive and HBeAg-negative CHB patients treated with LdT for 2 years. A total of 116 CHB patients were recruited. Of the 64 HBeAg-positive patients, 35 had favorable baseline characteristics [hepatitis B virus (HBV) DNA ≤ 9 log10 copies/mL and alanine aminotransferase ≥ 2× the upper limit of normal (ULN)], but only 40 % (14/35) achieved polymerase chain reaction (PCR) negativity at week 24. Among the 14 patients with favorable baseline characteristics and on-treatment response, the rates of virologic, biochemical, and serologic response and genotypic resistance were 78.6 % (11/14), 64.3 % (9/14), 50 % (7/14), and 7.1 % (1/14), respectively, at week 104 of therapy. Of the 52 HBeAg-negative patients, 34 met the criteria of a baseline serum HBV-DNA level less than 7 log10 copies/mL, and 29 (85.3 %) achieved PCR negativity at week 24. Among the 29 patients with favorable baseline characteristics and on-treatment response, the rates of virologic and biochemical response and genotypic resistance were 96.6 % (28/29), 72.4 % (21/29), and 6.9 % (2/29), respectively. In addition, the PCR negativity at week 24 was the only factor associated with the virologic response and genotypic resistance to LdT treatment. The efficacy and resistance to LdT treatment in CHB patients with favorable predictors were comparable between a real-world clinical population and the GLOBE study. In addition, PCR negativity at week 24 could predict virologic response and genotypic resistance to LdT treatment.

Detailed scanning tunneling microscopy and spectroscopy (STM and STS) studies for the effects of thermal migration and electromigration on the growth of gadolinium–silicide nanomeshes on double-domain Si(1 1 0)-16 × 2 surfaces are presented to identify the driving force for the self-organization of a perfectly ordered silicide nanomesh on Si(1 1 0). STM results clearly show that the anisotropic electromigration effect is crucial for the control of the spatial uniformity of a self-ordered silicide nanomesh on Si(1 1 0). This two-dimensional self-ordering driven by the anisotropic-electromigration-induced growth allows the sizes and positions of crossed nanowires to be precisely controlled within a variation of ±0.2 nm over a mesoscopic area, and it can be straightforwardly applied to other metals (e.g., Au and Ce) to grow a variety of highly regular silicide nanomeshes for the applications as nanoscale interconnects. Moreover, the STS results show that the anisotropic electromigration-induced growth causes the metallic horizontal nanowires to cross over the semiconducting oblique nanowires, which opens the possibility for the atomically precise bottom-up fabrication of well-defined crossbar nanoarchitectures.

Mesenchymal stem cells (MSCs) have a high self-renewal potential and can differentiate into various types of cells, including adipocytes, osteoblasts, and chondrocytes. Previously, we reported that the enhancer of zeste homolog 2 (EZH2), the catalytic component of the Polycomb-repressive complex 2, and HDAC9c mediate the osteogenesis and adipogenesis of MSCs. In the current study, we identify the role of p38 in osteogenic differentiation from a MAPK antibody array screen and investigate the mechanisms underlying its transcriptional regulation. Our data show that YY1, a ubiquitously expressed transcription factor, and HDAC9c coordinate p38 transcriptional activity to promote its expression to facilitate the osteogenic potential of MSCs. Our results show that p38 mediates osteogenic differentiation, and this has significant implications in bone-related diseases, bone tissue engineering, and regenerative medicine.

Background Treatment for metastatic nasopharyngeal carcinoma (NPC) is challenging. Till now, a truly effective chemotherapy regimen for NPC has not yet been identified. These clinical observations prompted us to investigate a potential drug as alternative option for treating. Purpose This study evaluated the inhibitory effects of Ovatodiolide (Ova), on tumorigenic and cancer stem cell characteristics of NPC cells. Methods Two NPC cell lines (NPC-BM1 and NPC-BM2) were used to examine the anticancer effects of Ova and the molecular mechanism underlying these activities by using sulforhodamine B cytotoxicity assay, western blot, immunofluorescence, migration, colony and tumorsphere formation assays. Results Ova significantly inhibited the viability of BM1 and BM2 cells, downregulated Bcl-xL and Puma, and upregulated Bax/Bad expression levels. Ova dose-dependent suppressed migratory/invasive potential of NPC cells, and reduced ability to form colonies. Ova-induced apoptosis correlated with increased Bax/Bcl-xL ratio while NPC motility and colony formation inhibition were associated with reduced expression of p-FAK, p-PXN, F-actin, and Slug proteins and increased E-cadherin. Furthermore, ova inhibited NPC tumorsphere formation, associated with decreased SOX2, OCT4 and JAK-STAT signaling pathway. Ova also attenuated NPC stem cell tumorigenicity, inhibited tumor growth, and enhanced the sensitivity of NPC cells to cisplatin treatment, in vivo. Conclusions Our results demonstrated the anticancer efficacy of Ova in NPC and its potential as a putative inhibitor of JAK2 and STAT3, which are essential in tumorigenesis of NPC. Further development of Ova is encouraged.

Chondrosarcoma is the second most common primary malignancy form of bone cancer, exhibiting resistance to chemotherapy and radiation therapy as well as developing high metastasis ability in late-stage tumors. Thus, understanding the metastatic processes of chondrosarcoma is considered a strategy for the treatment of this disease. Sphingosine 1-phosphate (S1P), a bioactive sphingolipid, is produced intracellularly by sphingosine kinase (SphK) and is regarded as a second signaling molecule that regulates inflammation, proliferation, angiogenesis, and metastasis. However, the effect of S1P on chondrosarcoma remains uncertain. As demonstrated by the transwell, immunoblotting, and real-time PCR analyses, we found that S1P inhibited cell migration and MMP-2 expression through the upregulation of the tissue inhibitor of metalloproteinase-3 (TIMP-3) expression in human chondrosarcoma cells. Additionally, we also showed that microRNA (miRNA)-101, which targets the 3' untranslated region (3'UTR) of TIMP-3, decreased significantly following S1P treatment. After transfection with miR-101 mimics, the S1P-regulated cell migration and TIMP-3 expression were both reversed. Furthermore, we also showed that the S1P-inhibited cell migration is mediated through the c-Src/MEK/ERK signaling axis. Meanwhile, the in vivo study indicated that overexpression of SphK1 decreases chondrosarcoma metastasis to the lungs. Our results illustrate the clinical significance between SphK1, TIMP-3, and miR-101 in human chondrosarcoma patients. Taken together, our results suggest that S1P and miR-101 may prove to be potential therapeutic targets for future chondrosarcoma treatment.

In recent years, the explosive growth of handheld smart devices has demanded increasing network capacity and higher data-rate. With around 1GHz bandwidth in the 5GHz UNII frequency band, 802.11ac offers great flexibility in utilizing a wider signal bandwidth and more complex modulation scheme to achieve the PHY rate up to 1.733Gb/s with VHT160 2×2 MIMO. The increased signal bandwidth from 80MHz (Stage1) to 160MHz (Stage2) poses stringent design challenges for radio transceivers, such as tighter frequency synthesizer phase-noise requirement for better EVM floor, techniques of using integrated high-power PAs for achieving 160MHz operation, and overcoming the effect of LPF 3dB-corner-mismatch-induced Frequency-Dependent IQ imbalance (FD-IQ) [1] due to finite OP-Amp Gain-BW product and submicron process gradient effect. This paper describes a monolithic MIMO 802.11ac Stage-2 Wi-Fi SoC chip with integrated dual-band PA's, LNA's, and T/R switches.