Publications by authors named "Jia-Ming Chang"

83 Publications

9-O-Terpenyl-Substituted Berberrubine Derivatives Suppress Tumor Migration and Increase Anti-Human Non-Small-Cell Lung Cancer Activity.

Int J Mol Sci 2021 Sep 13;22(18). Epub 2021 Sep 13.

Department of Microbiology and Immunology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.

Lung cancer is one of the most common cancers and the leading cause of death in humans worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and is often diagnosed at a late stage. Among patients with NSCLC, 50% die within 1 year after diagnosis. Even with clinical intervention, the 5-year survival rate is only approximately 20%. Therefore, the development of an advanced therapeutic strategy or novel agent is urgently required for treating NSCLC. Berberine exerts therapeutic activity toward NSCLC; therefore, its activity as an antitumor agent needs to be explored further. In this study, three terpenylated-bromide derivatives of berberrubine were synthesized and their anti-NSCLC activities were evaluated. Each derivative had higher anti-NSCLCs activity than berberrubine and berberine. Among them, 9-O-gernylberberrubine bromide (B4) and 9-O-farnesylberberrubine bromide (B5) showed greater growth inhibition, cell-cycle regulation, in vitro tumorigenesis suppression, and tumor migration reduction. In addition, some degree of apoptosis and autophagic flux blocking was noted in the cells under B4 and B5 treatments. Our study demonstrates that the berberrubine derivatives, B4 and B5, exhibit impressive anti-NSCLC activities and have potential for use as chemotherapeutic agents against NSCLC.
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http://dx.doi.org/10.3390/ijms22189864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469690PMC
September 2021

Autophagy drives plasticity and functional polarization of tumor-associated macrophages.

IUBMB Life 2021 Aug 31. Epub 2021 Aug 31.

The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and are key cells in regulating tumor development, metastasis, immune responses, inflammation, and chemoresistance. In response to TME stimulation, circulating monocytes are recruited and differentiated as TAMs. Most TAMs are defined as alternatively activated (M2) phenotype to create immunosuppressive TME and support tumor progression. In contrast, classically activated (M1) TAMs can produce pro-inflammatory cytokines and enhance immune responses against tumor development. Autophagy is a conserved catabolic process to control cellular homeostasis and biological function. Emerging evidence reveals crucial contribution of autophagy in modulating TAM plasticity and functional polarization in TME. In this review, we introduce the current understanding of autophagy-regulated TAM function in development of cancer. We focus on how autophagy modulates antigen presentation, LC3-associated phagocytosis, cytokine secretion, inflammasome regulation, recruitment, differentiation, and polarization of TAMs and suggest strategies for potential therapeutics by targeting autophagy in TAMs. We expect this review can provide a new notion of future cancer immunotherapy.
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http://dx.doi.org/10.1002/iub.2543DOI Listing
August 2021

GODoc: high-throughput protein function prediction using novel k-nearest-neighbor and voting algorithms.

BMC Bioinformatics 2020 Nov 18;21(Suppl 6):276. Epub 2020 Nov 18.

Department of Computer Science, National Chengchi University, 11605, Taipei, Taiwan.

Background: Biological data has grown explosively with the advance of next-generation sequencing. However, annotating protein function with wet lab experiments is time-consuming. Fortunately, computational function prediction can help wet labs formulate biological hypotheses and prioritize experiments. Gene Ontology (GO) is a framework for unifying the representation of protein function in a hierarchical tree composed of GO terms.

Results: We propose GODoc, a general protein GO prediction framework based on sequence information which combines feature engineering, feature reduction, and a novel ​k​-nearest-neighbor algorithm to resolve the multiple GO prediction problem. Comprehensive evaluation on CAFA2 shows that GODoc performs better than two baseline models. In the CAFA3 competition (68 teams), GODoc ranks 10th in Cellular Component Ontology. Regarding the species-specific task, the proposed method ranks 10th and 8th in the eukaryotic Cellular Component Ontology and the prokaryotic Molecular Function Ontology, respectively. In the term-centric task, GODoc performs third and is tied for first for the biofilm formation of Pseudomonas aeruginosa and the long-term memory of Drosophila melanogaster, respectively.

Conclusions: We have developed a novel and effective strategy to incorporate a training procedure into the k-nearest neighbor algorithm (instance-based learning) which is capable of solving the Gene Ontology multiple-label prediction problem, which is especially notable given the thousands of Gene Ontology terms.
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http://dx.doi.org/10.1186/s12859-020-03556-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672824PMC
November 2020

Prognostic Factor of Completely Resected and Pathologic T3 N0 M0 Thymic Epithelial Tumor.

Ann Thorac Surg 2021 04 2;111(4):1164-1173. Epub 2020 Sep 2.

Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: A multiinstitutional study was conducted to analyze prognosticators of completely resected and pathologic T3 N0 M0 (pT3 N0 M0) stage thymic epithelial tumors.

Methods: A total of 607 patients with surgically treated thymic epithelial tumors between June 1988 and December 2017 were enrolled. A Cox proportional hazards model and an inverse probability of treatment weighting-adjusted analysis using the propensity score were performed.

Results: A total of 394 patients with thymoma and 130 patients with thymic carcinoma underwent complete tumor resections. Forty-one thymomas and 49 thymic carcinomas were confirmed as pT3 N0 M0 stage tumors. Postoperative adjuvant radiotherapy was associated with improved disease-free and overall survival in patients with thymoma (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.23 to 0.69; and HR, 0.24; 95% CI, 0.11 to 0.52, respectively) and in patients with thymic carcinoma (HR, 0.15; 95% CI, 0.07 to 0.33; and HR, 0.12; 95% CI, 0.05 to 0.31, respectively). Although lung invasion was associated with poor disease-free survival (HR, 3.28; 95% CI, 1.90 to 5.89) and overall survival (HR, 2.60; 95% CI, 1.21 to 6.07), male sex (HR, 1.88; 95% CI, 1.10 to 3.18), older age (HR, 2.77; 95% CI, 1.29 to 5.70), and advanced histologic features (HR, 3.84; 95% CI, 1.42 to 14.51) were associated with poor overall survival in patients with pT3 N0 M0 thymoma. Adjuvant chemotherapy was associated with improved disease-free survival (HR, 0.11; 95% CI, 0.03 to 0.41) and overall survival (HR, 0.11; 95% CI, 0.06 to 0.20) in patients with pT3 N0 M0 thymic carcinoma with superior vena cava or innominate vein invasion.

Conclusions: Postoperative radiotherapy was associated with improved survival in patients with pT3 N0 M0 thymic epithelial tumors. Lung invasion was associated with poor survival in patients with pT3 N0 M0 thymoma. Adjuvant chemotherapy was associated with improved survival in patients with pT3 N0 M0 thymic carcinoma with superior vena cava or innominate vein invasion.
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http://dx.doi.org/10.1016/j.athoracsur.2020.06.078DOI Listing
April 2021

Berberine Derivatives Suppress Cellular Proliferation and Tumorigenesis In Vitro in Human Non-Small-Cell Lung Cancer Cells.

Int J Mol Sci 2020 Jun 13;21(12). Epub 2020 Jun 13.

Department of Medical Research, Ditmanson Medical Foundation Chiayi Christian Hospital, Chiayi City 60002, Taiwan.

Lung cancer is the leading cause of death in the world, and the most common type of lung cancer is non-small-cell lung cancer (NSCLC), accounting for 85% of lung cancer. Patients with NSCLC, when detected, are mostly in a metastatic stage, and over half of patients diagnosed with NSCLC die within one year after diagnosis; the 5-year survival rate is 24%. However, in patients with metastatic NSCLC, the 5-year survival rate is 6%. Therefore, development of a new therapeutic agent or strategy is urgent for NSCLCs. Berberine has been illustrated to be a therapeutic agent of NSCLC. In the present study, we synthesized six derivatives of berberine, and the anti-NSCLC activity of these agents was examined. Some of them exert increasing proliferation inhibition comparing with berberine. Further studies demonstrated that two of the most effective agents, 9--decylberberrubine bromide (B6) and 9--dodecylberberrubine bromide (B7), performed cell cycle regulation, in-vitro tumorigenesis inhibition and autophagic flux blocking, but not induction of cellular apoptosis in NSCLC cells. Moreover, B6 and B7 were determined to be green fluorescent and could be penetrated and localized in cellular mitochondria. Herein, B6 and B7, the berberine derivatives we synthesized, revealed better anti-NSCLC activity with berberine and may be used as therapeutic candidates for the treatment of NSCLCs.
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http://dx.doi.org/10.3390/ijms21124218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352437PMC
June 2020

Discovery of T-1101 tosylate as a first-in-class clinical candidate for Hec1/Nek2 inhibition in cancer therapy.

Eur J Med Chem 2020 Apr 7;191:112118. Epub 2020 Feb 7.

Taivex Therapeutics Corporation, 2nd Floor, Dongxing Rd., Songshan Dist., Taipei City, 10511, Taiwan.

Highly expressed in cancer 1 (Hec1) plays an essential role in mitosis and is correlated with cancer formation, progression, and survival. Phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function, thus any disruption of Hec1/Nek2 protein-protein interaction has potential for cancer therapy. We have developed T-1101 tosylate (9j tosylate, 9j formerly known as TAI-95), optimized from 4-aryl-N-pyridinylcarbonyl-2-aminothiazole of scaffold 9 by introducing various C-4' substituents to enhance potency and water solubility, as a first-in-class oral clinical candidate for Hec1 inhibition with potential for cancer therapy. T-1101 has good oral absorption, along with potent in vitro antiproliferative activity (IC: 14.8-21.5 nM). It can achieve high concentrations in Huh-7 and MDA-MB-231 tumor tissues, and showed promise in antitumor activity in mice bearing human tumor xenografts of liver cancer (Huh-7), as well as of breast cancer (BT474, MDA-MB-231, and MCF7) with oral administration. Oral co-administration of T-1101 halved the dose of sorafenib (25 mg/kg to 12.5 mg/kg) required to exhibit comparable in vivo activity towards Huh-7 xenografts. Cellular events resulting from Hec1/Nek2 inhibition with T-1101 treatment include Nek2 degradation, chromosomal misalignment, and apoptotic cell death. A combination of T-1101 with either of doxorubicin, paclitaxel, and topotecan in select cancer cells also resulted in synergistic effects. Inactivity of T-1101 on non-cancerous cells, a panel of kinases, and hERG demonstrates cancer specificity, target specificity, and cardiac safety, respectively. Subsequent salt screening showed that T-1101 tosylate has good oral AUC (62.5 μM·h), bioavailability (F = 77.4%), and thermal stability. T-1101 tosylate is currently in phase I clinical trials as an orally administered drug for cancer therapy.
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http://dx.doi.org/10.1016/j.ejmech.2020.112118DOI Listing
April 2020

MS2CNN: predicting MS/MS spectrum based on protein sequence using deep convolutional neural networks.

BMC Genomics 2019 Dec 24;20(Suppl 9):906. Epub 2019 Dec 24.

Department of Computer Science, National Chengchi University, 11605, Taipei City, Taiwan.

Background: Tandem mass spectrometry allows biologists to identify and quantify protein samples in the form of digested peptide sequences. When performing peptide identification, spectral library search is more sensitive than traditional database search but is limited to peptides that have been previously identified. An accurate tandem mass spectrum prediction tool is thus crucial in expanding the peptide space and increasing the coverage of spectral library search.

Results: We propose MSCNN, a non-linear regression model based on deep convolutional neural networks, a deep learning algorithm. The features for our model are amino acid composition, predicted secondary structure, and physical-chemical features such as isoelectric point, aromaticity, helicity, hydrophobicity, and basicity. MSCNN was trained with five-fold cross validation on a three-way data split on the large-scale human HCD MS dataset of Orbitrap LC-MS/MS downloaded from the National Institute of Standards and Technology. It was then evaluated on a publicly available independent test dataset of human HeLa cell lysate from LC-MS experiments. On average, our model shows better cosine similarity and Pearson correlation coefficient (0.690 and 0.632) than MSPIP (0.647 and 0.601) and is comparable with pDeep (0.692 and 0.642). Notably, for the more complex MS spectra of 3+ peptides, MSPIP is significantly better than both MSPIP and pDeep.

Conclusions: We showed that MSCNN outperforms MSPIP for 2+ and 3+ peptides and pDeep for 3+ peptides. This implies that MSCNN, the proposed convolutional neural network model, generates highly accurate MS spectra for LC-MS/MS experiments using Orbitrap machines, which can be of great help in protein and peptide identifications. The results suggest that incorporating more data for deep learning model may improve performance.
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http://dx.doi.org/10.1186/s12864-019-6297-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929458PMC
December 2019

The Alteration of CTNNBIP1 in Lung Cancer.

Int J Mol Sci 2019 Nov 13;20(22). Epub 2019 Nov 13.

Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 97004, Taiwan.

β-catenin is a major component of the Wnt/β-catenin signaling pathway, and is known to play a role in lung tumorigenesis. β-catenin-interacting protein 1 (CTNNBIP1) is a known repressor of β-catenin transactivation. However, little is known about the role of CTNNBIP1 in lung cancer. The aim of this study was to carry out a molecular analysis of CTNNBIP1 and its effect on β-catenin signaling, using samples from lung cancer patients and various lung cancer cell lines. Our results indicate a significant inverse correlation between the CTNNBIP1 mRNA expression levels and the CTNNBIP1 promoter hypermethylation, which suggests that the promoter hypermethylation is responsible for the low levels of CTNNBIP1 present in many lung cancer patient samples. The ectopic expression of CTNNBIP1 is able to reduce the β-catenin transactivation; this then brings about a decrease in the expression of β-catenin-targeted genes, such as matrix metalloproteinase 7 (MMP7). Conversely, CTNNBIP1 knockdown is able to increase β-catenin transactivation and the expression of MMP7. In agreement with these findings, a low level of CTNNBIP1 was found to be correlated with a high level of MMP7 when a publicly available microarray dataset for lung cancer was analyzed. Also, in agreement with the above, the ectopic expression of CTNNBIP1 inhibits the migration of lung cancer cells, whereas the CTNNBIP1 knockdown increases cancer cell migration. Our findings suggest that CTNNBIP1 is a suppressor of cancer migration, thus making it a potential prognostic predictor for lung cancer.
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http://dx.doi.org/10.3390/ijms20225684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888110PMC
November 2019

The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens.

Genome Biol 2019 11 19;20(1):244. Epub 2019 Nov 19.

Departments of Bioengineering and Mechanical Engineering, Berkeley, CA, USA.

Background: The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function.

Results: Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory.

Conclusion: We conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.
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http://dx.doi.org/10.1186/s13059-019-1835-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864930PMC
November 2019

Incorporating alignment uncertainty into Felsenstein's phylogenetic bootstrap to improve its reliability.

Bioinformatics 2019 Feb 6. Epub 2019 Feb 6.

Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.

Motivation: Most evolutionary analyses are based on pre-estimated multiple sequence alignment. Wong et al. established the existence of an uncertainty induced by multiple sequence alignment when reconstructing phylogenies. They were able to show that in many cases different aligners produce different phylogenies, with no simple objective criterion sufficient to distinguish among these alternatives.

Results: We demonstrate that incorporating MSA induced uncertainty into bootstrap sampling can significantly increase correlation between clade correctness and its corresponding bootstrap value. Our procedure involves concatenating several alternative multiple sequence alignments of the same sequences, produced using different commonly used aligners. We then draw bootstrap replicates while favoring columns of the more unique aligner among the concatenated aligners. We named this concatenation and bootstrapping method, Weighted Partial Super Bootstrap (wpSBOOT). We show on three simulated datasets of 16, 32 and 64 tips that our method improves the predictive power of bootstrap values. We also used as a benchmark an empirical collection of 853 1-to-1 orthologous genes from seven yeast species and found wpSBOOT to significantly improve discrimination capacity between topologically correct and incorrect trees. Bootstrap values of wpSBOOT are comparable to similar readouts estimated using a single method. However, for reduced trees by 50% and 95% bootstrap thresholds, wpSBOOT comes out the lowest Type I error (less FP).

Availability: The automated generation of replicates has been implemented in the T-Coffee package, which is available as open source freeware available from www.tcoffee.org.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275982PMC
February 2019

Recurrent tertiary hyperparathyroidism due to supernumerary parathyroid glands in a patient receiving long-term hemodialysis: a case report.

BMC Endocr Disord 2019 Jan 28;19(1):16. Epub 2019 Jan 28.

Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, 539 Chung Hsiao Rd, Chiayi, 600, Taiwan.

Background: Renal hyperparathyroidism is a common complication of chronic kidney disease (CKD) or end-stage renal disease (ESRD) characterized by elevated parathyroid hormone levels secondary to derangements in the homeostasis of calcium, phosphate, and vitamin D. Rapid correction of severe and prolonged hyperparathyroidism by surgical parathyroidectomy in long-term hemodialysis patients occasionally causes hungry bone syndrome. These patients then exhibit severe and long-lasting secondary or tertiary hyperparathyroidism with high bone turnover.

Case Presentation: We report a case of recurrent tertiary hyperparathyroidism after total parathyroidectomy due to supernumerary parathyroid gland in a patient with long-term hemodialysis. Supplementation with intravenous calcium, oral calcium, and vitamin D immediately after patient surgery helps to prevent and treat hungry bone syndrome.

Conclusions: We should prompt a search for the supernumerary parathyroid glands in ESRD patients, who have recurrent or persistent hyperparathyroidism after total parathyroidectomy. ESRD patients are more likely to develop hungry bone syndrome after parathyroidectomy. Prevention and treatment of hungry bone syndrome may be required after ectopic parathyroidectomy in clinical practice.
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http://dx.doi.org/10.1186/s12902-019-0346-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350335PMC
January 2019

Pharmacological inhibition of bacterial β-glucuronidase prevents irinotecan-induced diarrhea without impairing its antitumor efficacy in vivo.

Pharmacol Res 2019 01 1;139:41-49. Epub 2018 Nov 1.

Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Biomedical and Environmental Biology, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. Electronic address:

Irinotecan (CPT-11), a first-line chemotherapy for advanced colorectal cancer, causes serious diarrhea in patients receiving treatment. The underlying mechanism has been shown that the active metabolite of CPT-11, SN-38, is metabolized to the inactive metabolite SN-38 glucuronide (SN-38 G) during hepatic glucuronidation, and subsequently is exported into the intestine, where SN-38 G is hydrolyzed by bacterial β-glucuronidase (βG) to be SN-38, thus leading to intestinal toxicity. Thus, inhibition of the intestinal bacterial βG activity is expected to prevent CPT-11-induced diarrhea. However, the effects of such inhibition on serum pharmacokinetics of SN-38, the key determinant of CPT-11 treatment, are uncertain. Here, we determined the effects of a potent E. coli βG (eβG)-specific inhibitor pyrazolo[4,3-c]quinoline derivative (TCH-3562) for the potential use in preventing CPT-11-induced diarrhea. TCH-3562 exhibited efficacious inhibitory potency of endogenous βG activity in two anaerobes, Eubacteriumsp. and Peptostreptococcus anaerobius. Oral administration of TCH-3562 also effectively reduced the bacterial βG activity in mice intestine. Moreover, pharmacokinetic analysis of TCH-3562 revealed a relatively low amount of TCH-3562 was detected in the plasma whereas the majority of TCH-3562 was found in the feces. Importantly, co-treatment of CPT-11 and TCH-3562 did not decrease active SN-38 level in mice plasma. Finally, we established that TCH-3562 as an adjuvant treatment showed protective effects on CPT-11-induced diarrhea and had no negative effects on the therapeutic efficacy of CPT-11 in tumor-bearing mice. Therefore, inhibition of the intestinal bacterial βG activity by the specific inhibitor, TCH-3562, is promising to prevent CPT-11-induced diarrhea while maintaining its anti-tumor efficacy that may have clinical potentials for the treatment with CPT-11.
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http://dx.doi.org/10.1016/j.phrs.2018.10.029DOI Listing
January 2019

Polycomb-Dependent Chromatin Looping Contributes to Gene Silencing during Drosophila Development.

Mol Cell 2018 07 28;71(1):73-88.e5. Epub 2018 Jun 28.

Institute of Human Genetics, UMR9002 CNRS and University of Montpellier, 141 Rue de la Cardonille, 34396 Montpellier Cedex 5, France. Electronic address:

Interphase chromatin is organized into topologically associating domains (TADs). Within TADs, chromatin looping interactions are formed between DNA regulatory elements, but their functional importance for the establishment of the 3D genome organization and gene regulation during development is unclear. Using high-resolution Hi-C experiments, we analyze higher order 3D chromatin organization during Drosophila embryogenesis and identify active and repressive chromatin loops that are established with different kinetics and depend on distinct factors: Zelda-dependent active loops are formed before the midblastula transition between transcribed genes over long distances. Repressive loops within polycomb domains are formed after the midblastula transition between polycomb response elements by the action of GAGA factor and polycomb proteins. Perturbation of PRE function by CRISPR/Cas9 genome engineering affects polycomb domain formation and destabilizes polycomb-mediated silencing. Preventing loop formation without removal of polycomb components also decreases silencing efficiency, suggesting that chromatin architecture can play instructive roles in gene regulation during development. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.molcel.2018.05.032DOI Listing
July 2018

From one incision to one port: The surgical technique and the evolution of segmentectomy in patients with pulmonary tuberculosis.

PLoS One 2018 15;13(5):e0197283. Epub 2018 May 15.

Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medical College, National Cheng Kung University, Tainan, Taiwan.

Objectives: We retrospectively reviewed the evolution of segmentectomy for pulmonary tuberculosis (TB) and the feasibility of multi- and single-incision video-assisted thoracoscopic segmentectomy.

Methods: Of 348 patients undergoing surgery for TB, the medical records of 121 patients undergoing segmentectomy between January 1996 and November 2015 were reviewed. Clinical information and computed tomography (CT) image characteristics were investigated and analyzed.

Results: Eighteen patients underwent direct or intended thoracotomy. Sixty-four underwent video-assisted thoracoscopic segmentectomy (VATS), including 53 multi-incision thoracoscopic segmentectomy (MITS), and 11 single-incision thoracoscopic segmentectomy (SITS). Thirty-nine were converted to thoracotomy. The intended thoracotomy group had more operative blood loss (p = 0.005) and hospital stay (p = 0.001) than the VATS group although the VATS group had higher grade of cavity (p = 0.007). The intended thoracotomy group did not differ from converted thoracotomy in operative time, blood loss, or hospital stay, and the grade of pleural thickening was higher in the converted thoracotomy group (p = 0.001). The converted thoracotomy group had more operative blood loss, hospital stay, and complication rate than the MITS group (p = 0.001, p<0.001, and p = 0.009, respectively). The MITS group had lower pleural thickening, peribronchial lymph node calcification, cavity, and tuberculoma grading than the converted thoracotomy group (p<0.001, p = 0.001, 0.001, and 0.017, respectively). The SITS group had lower grading in pleural thickening, peribronchial lymph node calcification, and aspergilloma grading than the converted thoracotomy group (p = 0.002, 0.010, and 0.031, respectively). Four patients in the intended thoracotomy group and seven in the converted thoracotomy group had complications compared with three patients in the MITS and two in the SITS group. Risk factors of conversion were pleural thickening and peribronchial lymph node calcification.

Conclusion: Although segmentectomy is technically challenging in patients with pulmonary TB, it could be safely performed using MITS or SITS and should be attempted in selected patients. Its efficacy for medical treatment failure needs investigation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0197283PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953493PMC
November 2018

TADs are 3D structural units of higher-order chromosome organization in .

Sci Adv 2018 02 28;4(2):eaar8082. Epub 2018 Feb 28.

Institute of Human Genetics, CNRS, Univ Montpellier, Montpellier, France.

Deciphering the rules of genome folding in the cell nucleus is essential to understand its functions. Recent chromosome conformation capture (Hi-C) studies have revealed that the genome is partitioned into topologically associating domains (TADs), which demarcate functional epigenetic domains defined by combinations of specific chromatin marks. However, whether TADs are true physical units in each cell nucleus or whether they reflect statistical frequencies of measured interactions within cell populations is unclear. Using a combination of Hi-C, three-dimensional (3D) fluorescent in situ hybridization, super-resolution microscopy, and polymer modeling, we provide an integrative view of chromatin folding in . We observed that repressed TADs form a succession of discrete nanocompartments, interspersed by less condensed active regions. Single-cell analysis revealed a consistent TAD-based physical compartmentalization of the chromatin fiber, with some degree of heterogeneity in intra-TAD conformations and in cis and trans inter-TAD contact events. These results indicate that TADs are fundamental 3D genome units that engage in dynamic higher-order inter-TAD connections. This domain-based architecture is likely to play a major role in regulatory transactions during DNA-dependent processes.
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http://dx.doi.org/10.1126/sciadv.aar8082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829972PMC
February 2018

Single-cell absolute contact probability detection reveals chromosomes are organized by multiple low-frequency yet specific interactions.

Nat Commun 2017 11 24;8(1):1753. Epub 2017 Nov 24.

Centre de Biochimie Structurale, CNRS UMR5048, INSERM U1054, Université de Montpellier, 29 rue de Navacelles, 34090, Montpellier, France.

At the kilo- to megabase pair scales, eukaryotic genomes are partitioned into self-interacting modules or topologically associated domains (TADs) that associate to form nuclear compartments. Here, we combine high-content super-resolution microscopies with state-of-the-art DNA-labeling methods to reveal the variability in the multiscale organization of the Drosophila genome. We find that association frequencies within TADs and between TAD borders are below ~10%, independently of TAD size, epigenetic state, or cell type. Critically, despite this large heterogeneity, we are able to visualize nanometer-sized epigenetic domains at the single-cell level. In addition, absolute contact frequencies within and between TADs are to a large extent defined by genomic distance, higher-order chromosome architecture, and epigenetic identity. We propose that TADs and compartments are organized by multiple, small-frequency, yet specific interactions that are regulated by epigenetics and transcriptional state.
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http://dx.doi.org/10.1038/s41467-017-01962-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700980PMC
November 2017

MicroRNA-200c inhibits epithelial-mesenchymal transition, invasion, and migration of lung cancer by targeting HMGB1.

PLoS One 2017 20;12(7):e0180844. Epub 2017 Jul 20.

Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

MicroRNAs (miRs) play critical roles in cancer development, proliferation, epithelial-mesenchymal transition (EMT), invasion, and migration through regulating the expression of oncogenes and tumour suppressor genes. Previous studies have indicated that miR-200c acts as a tumour suppressor in various cancers by downregulating high-mobility group box 1 (HMGB1) and thereby suppressing EMT and metastasis. In addition, miR-200c was reported to be downregulated and correlated with poor outcomes in non-small cell lung cancer (NSCLC). However, its functional role in HMGB1 regulation in NSCLC is still unclear. This study aimed to clarify whether miR-200c acts as a tumour suppressor in NSCLC by downregulating HMGB1, which is associated with EMT, invasion, cytoskeleton rearrangement, and migration in vitro and in vivo. In order to demonstrate HMGB1 downregulation by miR-200c, the NSCLC cell line A549 was transfected with miR-200c mimic or inhibitor. The mimic significantly reduced HMGB1 expression and suppressed EMT, invasion, and migration, while the inhibitor generated the opposite effects. Additionally, using xenograft mouse models, we confirmed that HMGB1 overexpression increased tumour EMT. In summary, our results demonstrated that miR-200c could suppress EMT, invasion, and migration of NSCLC cells by downregulating HMGB1.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180844PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519074PMC
September 2017

Pull method percutaneous endoscopic gastrostomy using transnasal ultrathin endoscopy in head and neck cancer.

Endoscopy 2017 08 14;49(8):E188-E189. Epub 2017 Jun 14.

Division of Thoracic Surgery, Department of Surgery, Chia-Yi Christian Hospital, Chia-Yi, Taiwan.

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http://dx.doi.org/10.1055/s-0043-111709DOI Listing
August 2017

Curcumin Inhibits LIN-28A through the Activation of miRNA-98 in the Lung Cancer Cell Line A549.

Molecules 2017 Jun 3;22(6). Epub 2017 Jun 3.

Department of Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung 80756, Taiwan.

Metastasis is common in lung cancer and is associated with poor clinical outcomes and increased mortality. Curcumin is a natural anti-cancer agent that inhibits the metastasis of various cancers by modulating the expression of micro (mi) RNAs such as miR-98, which acts as a tumor suppressor. This study investigated the effect of curcumin on miR-98 expression and in vitro cell line growth and invasiveness in lung cancer. Curcumin treatment enhanced the expression of miR-98 and reduced that of the miR-98 target gene as well as () and in vitro and in vivo. MiR-98 overexpression suppressed lung cancer cell migration and invasion by inhibiting LIN28A-induced MMP2 and MMP9 expression. Meanwhile, level was downregulated by overexpression of miR-98 mimic. Induction of miR-98 by curcumin treatment suppressed MMP2 and MMP9 by targeting LIN28A. These findings provide insight into the mechanisms by which curcumin suppresses lung cancer cell line growth in vitro and in vivo and invasiveness in vitro.
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http://dx.doi.org/10.3390/molecules22060929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152786PMC
June 2017

Pleural tenting as an effective adjunct in patients with pneumothorax secondary to emphysema evaluated with computed tomography scan.

J Thorac Dis 2016 Oct;8(Suppl 9):S652-S658

Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medical College, National Cheng Kung University, Tainan, Taiwan.

Background: The efficacy of thoracoscopic blebectomy and pleurodesis for secondary spontaneous pneumothorax (SSP) is often attenuated by diffuse emphysematous parenchyma. In this study, we reviewed our surgical results of pleural tenting and its association with preoperative chest computed tomography (CT) in patients with SSP.

Methods: From September 2005 to December 2014, there were 96 surgeries on 84 patients with SSP due to pulmonary emphysema. The data was collected on age, sex, smoking status, preoperative chest CT scan image, surgical procedure, blood loss, operative time, duration of tube thoracostomy, and hospital stay. We used Goddard score, a visual scoring system, to evaluate the severity of emphysema. Multivariable regression and logistic regression were performed to identify the factors associated with outcomes.

Results: The patients were separated according to the Goddard score, where patients with Goddard score ≤2 were in group 1 and those with Goddard score >2 in group 2. Goddard score and pleural tenting both significantly influenced the duration of tube thoracostomy in group 2 (P=0.026 and 0.003) but not in group 1. The Goddard score had significant impact on recurrence (P=0.019, OR =2.525), the risk of secondary procedure (P=0.033, OR =4.754), and complication (P=0.002, OR =2.913). Pleural tenting was found to decrease the risk of secondary procedure (P=0.034, OR =0.059). For complication and mortality rate, age was an important risk factor (P<0.001, OR =1.110 and P=0.028, OR =1.146).

Conclusions: In patients with moderate and severe emphysema, pleural tenting significantly reduced the duration of tube thoracostomy and the risk of secondary procedure.
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http://dx.doi.org/10.21037/jtd.2016.09.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179346PMC
October 2016

7-Dehydrocholesterol (7-DHC), But Not Cholesterol, Causes Suppression of Canonical TGF-β Signaling and Is Likely Involved in the Development of Atherosclerotic Cardiovascular Disease (ASCVD).

J Cell Biochem 2017 06 13;118(6):1387-1400. Epub 2016 Dec 13.

Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Doisy Research Center, 1100 S. Grand Blvd., St. Louis, Missouri 63104.

For several decades, cholesterol has been thought to cause ASCVD. Limiting dietary cholesterol intake has been recommended to reduce the risk of the disease. However, several recent epidemiological studies do not support a relationship between dietary cholesterol and/or blood cholesterol and ASCVD. Consequently, the role of cholesterol in atherogenesis is now uncertain. Much evidence indicates that TGF-β, an anti-inflammatory cytokine, protects against ASCVD and that suppression of canonical TGF-β signaling (Smad2-dependent) is involved in atherogenesis. We had hypothesized that cholesterol causes ASCVD by suppressing canonical TGF-β signaling in vascular endothelium. To test this hypothesis, we determine the effects of cholesterol, 7-dehydrocholesterol (7-DHC; the biosynthetic precursor of cholesterol), and other sterols on canonical TGF-β signaling. We use Mv1Lu cells (a model cell system for studying TGF-β activity) stably expressing the Smad2-dependent luciferase reporter gene. We demonstrate that 7-DHC (but not cholesterol or other sterols) effectively suppresses the TGF-β-stimulated luciferase activity. We also demonstrate that 7-DHC suppresses TGF-β-stimulated luciferase activity by promoting lipid raft/caveolae formation and subsequently recruiting cell-surface TGF-β receptors from non-lipid raft microdomains to lipid rafts/caveolae where TGF-β receptors become inactive in transducing canonical signaling and undergo rapid degradation upon TGF-β binding. We determine this by cell-surface I-TGF-β-cross-linking and sucrose density gradient ultracentrifugation. We further demonstrate that methyl-β-cyclodextrin (MβCD), a sterol-chelating agent, reverses 7-DHC-induced suppression of TGF-β-stimulated luciferase activity by extrusion of 7-DHC from resident lipid rafts/caveolae. These results suggest that 7-DHC, but not cholesterol, promotes lipid raft/caveolae formation, leading to suppression of canonical TGF-β signaling and atherogenesis. J. Cell. Biochem. 118: 1387-1400, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcb.25797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123222PMC
June 2017

From biportal to uniportal video-assisted thoracoscopic anatomical lung resection: A single-institute experience.

Medicine (Baltimore) 2016 Oct;95(40):e5097

Division of Thoracic Surgery, Department of Surgery, Chia-Yi Christian Hospital, Chia-Yi, Taiwan Graduate Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan Graduate Institute of Medical Sciences, College of Health Science, Chang Jung Christian University, Tainan, Taiwan Division of Thoracic Surgery, Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan Division of Pulmonary and Critical Care Medicine, Chia-Yi Christian Hospital, and Department of Respiratory Therapy, China Medical University Division of Thoracic Surgery, Department of Surgery, Tainan Municipal Hospital, Tainan, Taiwan Department of Thoracic Surgery, Coruna University Hospital and Minimally Invasive Thoracic Surgery Unit, Coruna, Spain.

Our study sought to review our experience from biportal to uniportal video-assisted thoracoscopic surgery (VATS) major lung resection. Lessons we learned from the evolution regarding technical aspects were also discussed.We retrospectively reviewed patients who underwent VATS lobectomy or segmentectomies in Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan, during January 2012 and December 2014. Patient clinical profiles, surgical indications and procedures, postoperative course, and oncological parameters were analyzed and compared between the biportal and uniportal groups.A total of 121 patients were enrolled in this study with median follow-up of 19.5 ± 11.6 months for all patients and 22.5 ± 11.5 months for primary lung cancer patients. Operation time (146.1 ± 31.9-158.7 ± 40.5 minutes; P = 0.077), chest drainage time (3.8 ± 3.3-4.4 ± 2.4 days; P = 0.309), conversion to thoracotomy rate (2.2%-2.6%; P = 0.889), and complication rate (15.6%-19.7%; P = 0.564) were equal between the groups, whereas blood loss (96.7 ± 193.2-263.6 ± 367; P = 0.006) was lower in the uniportal group. For lung cancer cases, there were no statistical differences in the histology, cancer staging, mediastinal lymph node dissection stations, numbers of dissected N1, N2, and overall lymph nodes between uniportal and biportal groups.Our preliminary data showed that uniportal VATS anatomical lung resection is as feasible, equally safe, and of comparative oncological clearance efficacy to biportal VATS.
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http://dx.doi.org/10.1097/MD.0000000000005097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5059092PMC
October 2016

The Role of Video-Assisted Thoracoscopic Therapeutic Resection for Medically Failed Pulmonary Tuberculosis.

Medicine (Baltimore) 2016 May;95(18):e3511

From the Department of Surgery, Division of Thoracic Surgery, National Cheng Kung University Hospital, College of Medical College, National Cheng Kung University, Tainan (Y-LT, Y-YC, Y-TY); Department of Surgery, Division of Thoracic Surgery, Chia-Yi Christian Hospital, Chia-Yi (J-MC); Graduate Institute of Medical Sciences, Collage of Health Science, Chang Jung Christian University, Tainan (J-MC); Department of Diagnostic Radiology, National Cheng Kung University Hospital, College of Medical College, National Cheng Kung University (Y-SL, LC); Department of Surgery, Division of Thoracic Surgery, Tainan Municipal Hospital (M-HW); Center for Infection Control, National Cheng Kung University Hospital (C-LL); and Institute of Clinical Medicine, College of Medical College (J-MC, Y-TY), National Cheng Kung University, Tainan, Taiwan.

There are few reports regarding video-assisted thoracoscopic therapeutic resection for medically failed pulmonary tuberculosis (TB). We reviewed our surgical results of video-assisted thoracoscopic surgery (VATS) therapeutic resection for pulmonary TB with medical failure, and its correlation with image characteristics on chest computed tomography (CT) scan.Between January 2007 and December 2012, among the 203 patients who had surgery for TB, the medical records of 89 patients undergoing therapeutic resection for medically failed pulmonary TB were reviewed. Clinical information and the image characteristics of CT scan were investigated and analyzed.Forty-six of the 89 patients undergoing successful VATS therapeutic resection had significantly lower grading in pleural thickening (P < 0.001), peribronchial lymph node calcification (P < 0.001), tuberculoma (P = 0.015), cavity (P = 0.006), and aspergilloma (P = 0.038); they had less operative blood loss (171.0 ± 218.7 vs 542.8 ± 622.8 mL; P < 0.001) and shorter hospital stay (5.2 ± 2.2 vs 15.6 ± 15.6 days; P < 0.001). They also had a lower percentage of anatomic resection (73.9% vs 93.0%; P = 0.016), a higher percentage of sublobar resection (56.5% vs 32.6%; P = 0.023), and a lower disease relapse rate (4.3% vs 23.3%; P = 0.009). Eighteen of the 38 patients with multi-drug resistant pulmonary tuberculosis (MDRTB) who successfully underwent VATS had significantly lower grading in pleural thickening (P = 0.001), peribronchial lymph node calcification (P = 0.019), and cavity (P = 0.017). They were preoperatively medicated for a shorter period of time (221.6 ± 90.8 vs 596.1 ± 432.5 days; P = 0.001), and had more sublobar resection (44.4% vs 10%), less blood loss (165.3 ± 148.3 vs 468.0 ± 439.9 mL; P = 0.009), and shorter hospital stay (5.4 ± 2.6 vs 11.8 ± 6.9 days; P = 0.001).Without multiple cavities, peribronchial lymph node calcification, and extensive pleural thickening, VATS therapeutic resection could be safely performed in selected patients with medically failed pulmonary TB as an effective adjunct with satisfactory results.
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http://dx.doi.org/10.1097/MD.0000000000003511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863768PMC
May 2016

PSI/TM-Coffee: a web server for fast and accurate multiple sequence alignments of regular and transmembrane proteins using homology extension on reduced databases.

Nucleic Acids Res 2016 07 22;44(W1):W339-43. Epub 2016 Apr 22.

Department of Computer Science, National Chengchi University, Taipei 11605, Taiwan

The PSI/TM-Coffee web server performs multiple sequence alignment (MSA) of proteins by combining homology extension with a consistency based alignment approach. Homology extension is performed with Position Specific Iterative (PSI) BLAST searches against a choice of redundant and non-redundant databases. The main novelty of this server is to allow databases of reduced complexity to rapidly perform homology extension. This server also gives the possibility to use transmembrane proteins (TMPs) reference databases to allow even faster homology extension on this important category of proteins. Aside from an MSA, the server also outputs topological prediction of TMPs using the HMMTOP algorithm. Previous benchmarking of the method has shown this approach outperforms the most accurate alignment methods such as MSAProbs, Kalign, PROMALS, MAFFT, ProbCons and PRALINE™. The web server is available at http://tcoffee.crg.cat/tmcoffee.
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http://dx.doi.org/10.1093/nar/gkw300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987888PMC
July 2016

Behind and Beyond the Masaoka Staging: A 25-Year Follow-up Study of Tumor Recurrence in Completely Resected Thymic Epithelial Tumors in a Single Institution.

Medicine (Baltimore) 2015 Dec;94(52):e2278

From the Division of Thoracic Surgery (Y-LT, W-WL, Y-TY), Department of Surgery, National Cheng Kung University Hospital, College of Medical College, National Cheng Kung University, Tainan; Division of Thoracic Surgery (J-MC), Department of Surgery, Chia-Yi Christian Hospital, Chia-Yi; Department of Pathology (K-CC), National Cheng Kung University Hospital, College of Medical College, National Cheng Kung University; Biostatistics Consulting Center (S-CL), National Cheng Kung University Hospital, College of Medical College, National Cheng Kung University; and Institute of Clinical Medicine (S-HL, Y-TY), National Cheng Kung University, Tainan, Taiwan.

We analyzed prognosticators for recurrence and post-recurrence survival in completely resected thymic epithelial tumors for the past 25 years in a single institution.Between June 1988 and December 2013, 238 patients undergoing intent-to-treat surgery for thymic epithelial tumors were reviewed. Sex, age, myasthenia gravis (MG), tumor histology, Masaoka staging, characteristic of locoregional invasion and recurrence, and the treatment for recurrence were collected. Comparison between groups was conducted using the Student t test and χ test. Survival analysis was performed using the Kaplan-Meier method and log-rank test. The Cox proportional hazards model was used for univariate and multivariate analyses of prognostic factors.One hundred sixteen of 135 patients with completely resected thymoma and 35 of 56 patients with thymic carcinoma remained free of recurrence. In patients with completely resected thymoma, Masaoka staging, MG, tumor invasion into the lung, pericardium, and innominate vein or superior vena cava (SVC) invasion were associated with recurrence-free survival in univariate analysis (P = 0.004, 0.003, 0.001, 0.007, and 0.039, respectively). In multivariate analysis, MG was the positive independent prognosticator (P = 0.039). In patients with completely resected thymic carcinoma, Masaoka staging and innominate vein or SVC invasion were associated with recurrence-free survival in univariate analysis (P = 0.045 and 0.005, respectively), whereas innominate vein or SVC invasion was the negative independent prognosticator (P = 0.012). In patients with recurrent thymoma, those treated with surgery followed by chemotherapy had a significantly better post-recurrence survival than those undergoing chemoradiotherapy (P = 0.029) and those without treatment (P = 0.007). Patients with recurrent thymic carcinoma undergoing surgery followed by chemotherapy had a significantly better post-recurrence survival than those without treatment (P = 0.004), but not significantly better than those undergoing chemoradiotherapy (P = 0.252).In patients with completely resected thymoma, MG was the positive independent prognosticators of recurrence-free survival. Surgery should be attempted for recurrent disease for better post-recurrence survival. In patients with completely resected thymic carcinoma, innominate vein or SVC invasion was the negative independent prognosticator. Surgery for recurrence could be considered since it provided benefit for post-recurrence survival as chemoradiotherapy did.
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http://dx.doi.org/10.1097/MD.0000000000002278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5291605PMC
December 2015

Multiple sequence alignment modeling: methods and applications.

Brief Bioinform 2016 11 27;17(6):1009-1023. Epub 2015 Nov 27.

This review provides an overview on the development of Multiple sequence alignment (MSA) methods and their main applications. It is focused on progress made over the past decade. The three first sections review recent algorithmic developments for protein, RNA/DNA and genomic alignments. The fourth section deals with benchmarks and explores the relationship between empirical and simulated data, along with the impact on method developments. The last part of the review gives an overview on available MSA local reliability estimators and their dependence on various algorithmic properties of available methods.
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http://dx.doi.org/10.1093/bib/bbv099DOI Listing
November 2016

Expression Divergence of Chemosensory Genes between Drosophila sechellia and Its Sibling Species and Its Implications for Host Shift.

Genome Biol Evol 2015 Oct 1;7(10):2843-58. Epub 2015 Oct 1.

Biodiversity Research Center, Academia Sinica, Taipei, Taiwan Department of Ecology and Evolution, University of Chicago

Drosophila sechellia relies exclusively on the fruits of Morinda citrifolia, which are toxic to most insects, including its sibling species Drosophila melanogaster and Drosophila simulans. Although several odorant binding protein (Obp) genes and olfactory receptor (Or) genes have been suggested to be associated with the D. sechellia host shift, a broad view of how chemosensory genes have contributed to this shift is still lacking. We therefore studied the transcriptomes of antennae, the main organ responsible for detecting food resource and oviposition, of D. sechellia and its two sibling species. We wanted to know whether gene expression, particularly chemosensory genes, has diverged between D. sechellia and its two sibling species. Using a very stringent definition of differential gene expression, we found a higher percentage of chemosensory genes differentially expressed in the D. sechellia lineage (7.8%) than in the D. simulans lineage (5.4%); for upregulated chemosensory genes, the percentages were 8.8% in D. sechellia and 5.2% in D. simulans. Interestingly, Obp50a exhibited the highest upregulation, an approximately 100-fold increase, and Or85c--previously reported to be a larva-specific gene--showed approximately 20-fold upregulation in D. sechellia. Furthermore, Ir84a (ionotropic receptor 84a), which has been proposed to be associated with male courtship behavior, was significantly upregulated in D. sechellia. We also found expression divergence in most of the chemosensory gene families between D. sechellia and the two sibling species. Our observations suggest that the host shift of D. sechellia was associated with the enrichment of differentially expressed, particularly upregulated, chemosensory genes.
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http://dx.doi.org/10.1093/gbe/evv183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684695PMC
October 2015

Apex-to-Cupola Distance Following VATS Predicts Recurrence in Patients With Primary Spontaneous Pneumothorax.

Medicine (Baltimore) 2015 Sep;94(37):e1509

From the Department of Surgery, Division of Thoracic Surgery, Chia-Yi Christian Hospital, Chia-Yi; (JMC); Department of Surgery, Division of Thoracic Surgery, National Cheng Kung University Hospital, Tainan; (WWL, YTY, YLT, YYC); Department of Surgery, Division of Thoracic Surgery, Tainan Municipal Hospital, Tainan; (MHW); Division of Pulmonary and Critical Care Medicine, Chiayi Christian Hospital, and Department of Respiratory Therapy, China Medical University, Taiwan; (WC); and Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN (RWL).

Our study sought to determine whether the size of the residual apical pleural space in young patients with primary spontaneous pneumothorax (PSP) following video-assisted thoracoscopic surgery is associated with the risk of recurrence. We retrospectively reviewed patients (≤30 years' old) with primary spontaneous pneumothorax following thoracoscopic surgery (2002-2010) in a university-affiliated hospital. The size of residual apical pleural space was estimated by measuring the apex-to-cupola distance on a postoperative chest radiograph at 2 time windows: first between postoperative day (POD) 0 and 3, and second between POD 4 and 14. A total of 149 patients were enrolled with a median follow-up of 11.2 months (interquartile range, 0.95-29.5 months), of whom 141 (94.6%) were male with a mean age of 20 years. The postoperative recurrence rate was 11.4%. Comparing the characteristics between the patients with and without recurrent pneumothorax, the patients with recurrence were younger (18.2 + 2.4 vs 20.7 + 3.7 years, P = 0.008), with a lower rate of pleurodesis (35% vs1 69%, P = 0.037), longer apex-to-cupola distance at POD 0 to 3 (22.41 ± 19.56 vs 10.07 ± 10.83 mm, P < 0.001) and POD 4 to 14 (11.82 ± 9.75 vs 5.54 ± 8.38 mm, P = 0.005) than the patients without recurrence. In a multivariate logistic regression model for recurrent pneumothorax, age <18 years (P = 0.026, odds ratio [OR]: 4.694), apex-to-cupola distance at POD 0 to 3 >10 mm (P = 0.027, OR: 5.319), and no pleurodesis during VATS (P = 0.022, OR: 5.042) were independent risk factors for recurrent pneumothorax. The recurrence rate was not low (11.4%) in young patients with PSP following VATS. Residual apical pleural space with apex-to-cupola distance of 10 mm or greater at POD 0 to 3, younger age, and no pleurodesis would increase postoperative recurrence of primary spontaneous pneumothorax.
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http://dx.doi.org/10.1097/MD.0000000000001509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635810PMC
September 2015

TCS: a web server for multiple sequence alignment evaluation and phylogenetic reconstruction.

Nucleic Acids Res 2015 Jul 8;43(W1):W3-6. Epub 2015 Apr 8.

Comparative Bioinformatics, Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Dr Aiguader 88, 08003 Barcelona, Spain Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain

This article introduces the Transitive Consistency Score (TCS) web server; a service making it possible to estimate the local reliability of protein multiple sequence alignments (MSAs) using the TCS index. The evaluation can be used to identify the aligned positions most likely to contain structurally analogous residues and also most likely to support an accurate phylogenetic reconstruction. The TCS scoring scheme has been shown to be accurate predictor of structural alignment correctness among commonly used methods. It has also been shown to outperform common filtering schemes like Gblocks or trimAl when doing MSA post-processing prior to phylogenetic tree reconstruction. The web server is available from http://tcoffee.crg.cat/tcs.
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http://dx.doi.org/10.1093/nar/gkv310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489230PMC
July 2015

Deregulation of SLIT2-mediated Cdc42 activity is associated with esophageal cancer metastasis and poor prognosis.

J Thorac Oncol 2015 Jan;10(1):189-98

*Department of Molecular Biology and Human Genetics, College of Life Science, Tzu Chi University, Hualien, Taiwan; †Department of Surgery, Chia-Yi Christian Hospital, Chiayi, Taiwan; ‡Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; §Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; ‖Department of Biomedical Engineering, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan; ¶Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; #Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; and **Department of Surgery, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Introduction: SLIT2, a secreted protein, has been found to inactivate Cdc42 GTPase to modulate neural cell migration. However, alteration of SLIT2-mediated Cdc42 in terms of migration regulation remains undefined in esophageal squamous cell carcinoma (ESCC).

Methods: We report here in ESCC cell, animal, and clinical models that SLIT2 acts as a migration suppressor and serves as a prognostic biomarker.

Results: The immunohistochemistry data indicated that 31.8% (49 of 154) of tumors from ESCC patients showed low expression of SLIT2 protein which correlated with poor overall survival and disease-free survival. DNA methylation analysis suggested that promoter hypermethylation is responsible for low expression of SLIT2 in ESCC. Knockdown of SLIT2 increased ESCC cell migration, while SLIT2 stable overexpression reduced cell migration. ESCC cells treated with conditioned media from cells overexpressing SLIT2 also suppressed cell migration. Importantly, silencing of SLIT2 decreased the complex formation, and thus induced Cdc42 activity and promoted membrane localization of focal adhesion kinase and Paxillin. Anti-metastatic effect of SLIT2 was confirmed in an experimental metastasis model of SLIT2 knockdown ESCC cells.

Conclusion: Our results provide novel evidence that low expression of SLIT2 correlates with poor prognosis and promotes metastasis in ESCC, which may be regulated by the Cdc42-mediated pathways.
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http://dx.doi.org/10.1097/JTO.0000000000000369DOI Listing
January 2015
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