Publications by authors named "Hung-Chih Chen"

53 Publications

Perturbation of PI3K/Akt signaling affected autophagy modulation in dystrophin-deficient myoblasts.

Cell Commun Signal 2021 10 27;19(1):105. Epub 2021 Oct 27.

School of Biosciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.

Background: The absence of dystrophin has gave a massive impact on myotube development in Muscular Dystrophy pathogenesis. One of the conserved signaling pathways involved in skeletal muscle differentiation is the PI3K/Akt/mTOR pathway that plays a vital role in autophagy regulation. To further understand and establish targeted therapy in dystrophin-deficient myoblasts, protein expression profiling has been determined which provides information on perturbed autophagy modulation and activation.

Methods: In this study, a dystrophin-deficient myoblast cell line established from the skeletal muscle of a dystrophic (mdx) mouse was used as a model. The dfd13 (dystrophin-deficient) and C2C12 (non-dystrophic) myoblasts were cultured in low mitogen conditions for 10 days to induce differentiation. The cells were subjected to total protein extraction prior to Western blotting assay technique. Protein sub-fractionation has been conducted to determine protein localization. The live-cell analysis of autophagy assay was done using a flow cytometer.

Results: In our culture system, the dfd13 myoblasts did not achieve terminal differentiation. PTEN expression was profoundly increased in dfd13 myoblasts throughout the differentiation day subsequently indicates perturbation of PI3K/Akt/mTOR regulation. In addition, rictor-mTORC2 was also found inactivated in this event. This occurrence has caused FoxO3 misregulation leads to higher activation of autophagy-related genes in dfd13 myoblasts. Autophagosome formation was increased as LC3B-I/II showed accumulation upon differentiation. However, the ratio of LC3B lipidation and autophagic flux were shown decreased which exhibited dystrophic features.

Conclusion: Perturbation of the PTEN-PI3K/Akt pathway triggers excessive autophagosome formation and subsequently reduced autophagic flux within dystrophin-deficient myoblasts where these findings are of importance to understand Duchenne Muscular Dystrophy (DMD) patients. We believe that some manipulation within its regulatory signaling reported in this study could help restore muscle homeostasis and attenuate disease progression. Video Abstract.
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http://dx.doi.org/10.1186/s12964-021-00785-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554905PMC
October 2021

Generation of induced pluripotent stem cells from a Bardet-Biedl syndrome patient carrying a homologous BBS2 c.534 + 1G > T mutation.

Stem Cell Res 2021 08 30;55:102480. Epub 2021 Jul 30.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Bardet-Biedl syndrome is a autosomal recessive hereditary disorder characterized by polydactyly, multiple renal cysts, retinal cone-rod dystrophy, obesity, and variable neural development or cognitive impairment. We reported the generation and characterization of an iPS cell line, IBMS-iPSC-063-06, from a patient carrying the BBS2 homologous c534 + 1G > T mutation. The generated iPS cell line retains the mutation and exhibits pluripotency and differentiation ability both in vivo and in vitro condition.
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http://dx.doi.org/10.1016/j.scr.2021.102480DOI Listing
August 2021

Relationship of Hydroxychloroquine and Ophthalmic Complications in Patients with Type 2 Diabetes in Taiwan.

Int J Environ Res Public Health 2021 08 1;18(15). Epub 2021 Aug 1.

Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.

The purpose of this study is to evaluate the relationship between hydroxychloroquine (HCQ) and diabetic retinopathy (DR) via the national health insurance research database (NHIRD) of Taiwan. All patients with newly diagnosed type 2 diabetes ( = 47,353) in the NHIRD (2000-2012) were enrolled in the study. The case group consists of participants with diabetic ophthalmic complications; 1:1 matching by age (±1 year old), sex, and diagnosis year of diabetes was used to provide an index date for the control group that corresponded to the case group ( = 5550). Chi-square test for categorical variables and Student's t-test for continuous variables were used. Conditional logistic regression was performed to estimate the adjusted odds ratio (aOR) of DR. The total number of HCQ user was 99 patients (1.8%) in the case group and 93 patients (1.7%) in the control group. Patients with hypertension (aOR = 1.21, 95% CI = 1.11-1.31) and hyperlipidemia (aOR = 1.65, 95% CI = 1.52-1.79) significantly increased the risk of diabetic ophthalmic complications ( < 0.001). Conversely, the use of HCQ and the presence of rheumatoid diseases did not show any significance in increased risk of DR. HCQ prescription can improve systemic glycemic profile, but it does not decrease the risk of diabetic ophthalmic complications.
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http://dx.doi.org/10.3390/ijerph18158154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345959PMC
August 2021

Immune cell shuttle for precise delivery of nanotherapeutics for heart disease and cancer.

Sci Adv 2021 Apr 23;7(17). Epub 2021 Apr 23.

Ph.D. Program in Translational Medicine, National Taiwan University and Academia Sinica, Taipei, Taiwan.

The delivery of therapeutics through the circulatory system is one of the least arduous and less invasive interventions; however, this approach is hampered by low vascular density or permeability. In this study, by exploiting the ability of monocytes to actively penetrate into diseased sites, we designed aptamer-based lipid nanovectors that actively bind onto the surface of monocytes and are released upon reaching the diseased sites. Our method was thoroughly assessed through treating two of the top causes of death in the world, cardiac ischemia-reperfusion injury and pancreatic ductal adenocarcinoma with or without liver metastasis, and showed a significant increase in survival and healing with no toxicity to the liver and kidneys in either case, indicating the success and ubiquity of our platform. We believe that this system provides a new therapeutic method, which can potentially be adapted to treat a myriad of diseases that involve monocyte recruitment in their pathophysiology.
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http://dx.doi.org/10.1126/sciadv.abf2400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064633PMC
April 2021

Repeated centrifuging and washing concentrates bacterial samples in peritoneal dialysis for optimal culture: an original article.

BMC Microbiol 2020 11 27;20(1):365. Epub 2020 Nov 27.

Department of Bioinformatics and Medical Engineering Asia University, Taichung, 41354, Taiwan.

Background: Bacterial cultures allow the identification of infectious disease pathogens. However, obtaining the results of conventional culture methods is time-consuming, taking at least two days. A more efficient alternative is the use of concentrated bacterial samples to accelerate culture growth. Our study focuses on the development of a high-yield sample concentrating technique.

Results: A total of 71 paired samples were obtained from patients on peritoneal dialysis (PD). The peritoneal dialysates were repeat-centrifuged and then washed with saline, namely the centrifuging and washing method (C&W method). The concentrated samples were Gram-stained and inoculated into culture plates. The equivalent unprocessed dialysates were cultured as the reference method. The times until culture results for the two methods were compared. The reference method yielded no positive Gram stain results, but the C&W method immediately gave positive Gram stain results for 28 samples (p < 0.001). The culture-negative rate was lower in the C&W method (5/71) than in the reference method (13/71) (p = 0.044). The average time for bacterial identification achieved with the C&W method (22.0 h) was shorter compared to using the reference method (72.5 h) (p < 0.001).

Conclusions: The C&W method successfully concentrated bacterial samples and superseded blood culture bottles for developing adequate bacterial cultures. The C&W method may decrease the culture report time, thus improving the treatment of infectious diseases.
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http://dx.doi.org/10.1186/s12866-020-02044-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694434PMC
November 2020

Swaying leukocyte traffic from the bone marrow.

Nat Biomed Eng 2020 11;4(11):1026-1027

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

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http://dx.doi.org/10.1038/s41551-020-00647-zDOI Listing
November 2020

Association of diabetes, education level, and care dependency with use of temporary vascular access in patients with chronic kidney disease.

Semin Dial 2021 03 26;34(2):130-136. Epub 2020 Oct 26.

Division of Nephrology, Asia University Hospital, Taichung, Taiwan.

Objective: Temporary vascular access (TVA) is frequently used during the first dialysis in patients with chronic kidney disease (CKD), and it is associated with an increased risk of infection, central vein stenosis, and mortality. Here, factors associated with TVA in patients with CKD were explored.

Methods: This study included patients in a single-center CKD care program who initiated long-term renal replacement therapy. The primary outcome was TVA use at first dialysis. Factors possibly associated with TVA use were analyzed using Cox regression.

Results: Temporary vascular access was used in 53.2% of the patients at first dialysis. In total, 73.2% (n = 865) and 26.8% (n = 317) of the patients were on hemodialysis and peritoneal dialysis, respectively. Multivariate Cox regression analysis showed that TVA use in patients with CKD was associated with diabetes (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.28-1.81, p < 0.001), lower albumin (HR 0.82, 95% CI 0.75-0.91, p < 0.001), lower education level (HR 0.75, 95% CI 0.56-1.00, p = 0.055), and total care dependency (HR 1.92, CI 1.44-3.43, p = 0.003).

Conclusion: Diabetes, education level, and care dependency are associated with TVA at dialysis initiation in patients with CKD.
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http://dx.doi.org/10.1111/sdi.12930DOI Listing
March 2021

s-Ethyl cysteine, an amino acid derivative, attenuated cisplatin induced nephrotoxicity.

Amino Acids 2020 Aug 13;52(8):1181-1190. Epub 2020 Aug 13.

Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan.

Renal protection from s-ethyl cysteine (SEC) against cisplatin (CP)-induced inflammatory and oxidative injury was examined. Mice were divided into five groups: normal group, 0.25% SEC group, CP group, 0.125% SEC + CP group, 0.25% SEC + CP group. After 2 weeks supplementation, mice of CP and SEC + CP groups received CP treatment. H&E stain showed that CP caused infiltration of inflammatory cells and necrosis of tubular cells. SEC pre-treatments attenuated CP-induced inflammatory injury and degeneration. SEC pre-treatments limited CP-stimulated release of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha and prostaglandin E in kidney. CP raised the renal activity and mRNA expression of cyclooxygenase-2 and nuclear factor kappa B. SEC pre-treatments reversed these alterations. CP increased the production of reactive oxygen species and nitric oxide, and lowered glutathione content, glutathione peroxidase and glutathione reductase activities in kidney. SEC pre-treatments reversed these changes. CP up-regulated renal inducible nitric oxide synthase (iNOS) mRNA expression, and down-regulated nuclear factor E2-related factor (Nrf)-2 and heme oxygenase (HO)-1 mRNA expression. SEC pre-treatments suppressed iNOS mRNA expression; and enhanced renal Nrf2 and HO-1 mRNA expression. These novel findings suggest that dietary SEC via exerting its multiple bio-functions could be considered as a protective agent for kidney against CP.
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http://dx.doi.org/10.1007/s00726-020-02882-9DOI Listing
August 2020

The Development of Dry Eye Disease After Surgery-Indicated Chronic Rhinosinusitis: A Population-Based Cohort Study.

Int J Environ Res Public Health 2020 05 28;17(11). Epub 2020 May 28.

Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.

We aim to evaluate the risk of dry eye disease (DED) occurrence in patients with surgery-indicated chronic rhinosinusitis (CRS) via the national health insurance research database in Taiwan. After exclusion, patients with a diagnostic code of CRS and had received functional endoscopic sinus surgery (FESS) were regarded as having surgery-indicated CRS and enrolled in the study group, then each patient in the study group was age- and gender-matched to four non-CRS patients that served as the control group. The outcome was considered as the development of DED and Cox proportional hazard regression was used for the statistical analysis, which involved multiple potential risk factors of DED. A total of 6076 patients with surgery-indicated CRS that received FESS and another 24,304 non-CRS individuals were enrolled after exclusion. There were 317 and 770 DED events in the study group and the control group during the 16-year follow-up interval, and the study group demonstrated a significantly higher adjusted hazard ratio (1490, 95% confidence intervals (CI): 1.303-1.702) of DED development compared to the control group in the multivariable analysis. In addition, the cumulative probability analysis illustrated a positive correlation of DED occurrence and the disease period of surgery-indicated CRS ( < 0.0001). In the subgroup analysis, both genders revealed a higher but not significant incidence of developing DED in the study group. In conclusion, the existence of surgery-indicated CRS will increase the risk of developing DED, which correlated to the disease interval.
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http://dx.doi.org/10.3390/ijerph17113829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312531PMC
May 2020

Generation of a gene corrected human isogenic IBMS-iPSC-014-C from polycystic-kidney-disease induced pluripotent stem cell line using CRISPR/Cas9.

Stem Cell Res 2020 05 20;45:101784. Epub 2020 Apr 20.

Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

We report the engendering an isogenic iPSC line from the IBMS-iPSC-014-05 with homozygous correction of the R803X, Chr4: 88989098C > T in PKD2, using CRISPR/Cas9 technology. The results from the isogenic control, IBMS-iPSC-014-05C, showed that mutation had been corrected, while maintaining normal morphology, pluripotency, and differentiation capacity into three germ layers.
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http://dx.doi.org/10.1016/j.scr.2020.101784DOI Listing
May 2020

Association of ATG4B and Phosphorylated ATG4B Proteins with Tumorigenesis and Prognosis in Oral Squamous Cell Carcinoma.

Cancers (Basel) 2019 Nov 23;11(12). Epub 2019 Nov 23.

Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan.

Oral squamous cell carcinoma (OSCC) is one of the major leading causes of cancer death worldwide due to the limited availability of biomarkers and therapeutic targets. Autophagy related protease 4B (ATG4B) is an essential protease for the autophagy machinery, and ATG4B phosphorylation at Ser383/392 increases its proteolytic activity. ATG4B expression and activation are crucial for cancer cell proliferation and invasion. However, the clinical relevance of ATG4B and phospho-Ser383/392-ATG4B for OSCC remains unknown, particularly in buccal mucosal SCC (BMSCC) and tongue SCC (TSCC). With a tissue microarray comprising specimens from 498 OSCC patients, including 179 BMSCC and 249 TSCC patients, we found that the protein levels of ATG4B and phospho-Ser383/392-ATG4B were elevated in the tumor tissues of BMSCC and TSCC compared with those in adjacent normal tissues. High protein levels of ATG4B were significantly associated with worse disease-specific survival (DSS) in OSCC patients, particularly in patients with tumors at advanced stages. In contrast, phospho-Ser383/392-ATG4B expression was correlated with poor disease-free survival (DFS) in TSCC patients. Moreover, ATG4B protein expression was positively correlated with phospho-Ser383/392-ATG4B expression in both BMSCC and TSCC. However, high coexpression levels of ATG4B and phospho-Ser383/392-ATG4B were associated with poor DFS only in TSCC patients, whereas they had no significant association with DSS in BMSCC and TSCC patients. In addition, silencing ATG4B with an antisense oligonucleotide (ASO) or small interfering RNA (siRNA) diminished cell proliferation of TW2.6 and SAS oral cancer cells. Further, knockdown of ATG4B reduced cell migration and invasion of oral cancer cells. Taken together, these findings suggest that ATG4B might be a biomarker for diagnosis/prognosis of OSCC and a potential therapeutic target for OSCC patients.
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http://dx.doi.org/10.3390/cancers11121854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966594PMC
November 2019

Guanylate-binding protein 6 is a novel biomarker for tumorigenesis and prognosis in tongue squamous cell carcinoma.

Clin Oral Investig 2020 Aug 9;24(8):2673-2682. Epub 2019 Nov 9.

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Objectives: Guanylate-binding protein 6 (GBP6) is a member of the guanylate-binding protein family, and its role in cancer has not yet been reported. We aimed to investigate the clinical significance of GBP6 in oral squamous cell carcinoma (OSCC).

Materials And Methods: Next-generation sequencing was applied for analyzing differential gene expression profiling between corresponding tumor adjacent normal (CTAN) and tumor tissue from two paired OSCC patients. Real-time PCRs (RT-PCRs) were used to investigate the gene expression level of GBP6 of CTAN and tumor tissue samples from 14 TSCC patients. Immunohistochemistry was used to investigate the protein expression level of GBP6 in tumor tissues and paired CTAN tissues from 488 OSCC patients, including 183 buccal mucosa squamous cell carcinoma (BMSCC), 245 tongue squamous cell carcinoma (TSCC), and 60 lip squamous cell carcinoma (LSCC) patients.

Results: Compared with CTAN tissues of OSCC patients, GBP6 is identified as a downregulated gene using the NGS platform, which was confirmed in 14 OSCC patients by RT-PCR. Moreover, protein expression level of GBP6 in tumor tissues was lower than that in CTAN tissues and the low GBP6 expression was correlated with poor cell differentiation/lymph node metastasis in TSCC patients. In addition, TSCC patients with low expression levels of GBP6 had poor disease-specific survival rate.

Conclusion: The low expression of GBP6 was associated with tumorigenesis and poor prognosis in OSCC patients, especially in TSCC patients.

Clinical Relevance: GBP6 may serve as a novel favorable diagnostic and prognostic biomarker in TSCC patients.
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http://dx.doi.org/10.1007/s00784-019-03129-yDOI Listing
August 2020

Prognostic role of RECK in pathological outcome-dependent buccal mucosa squamous cell carcinoma.

Oral Dis 2020 Jan 15;26(1):62-71. Epub 2019 Nov 15.

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Background: Buccal mucosal squamous cell carcinoma (BMSCC) is an aggressive oral cancer. Moreover, reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a well-known tumor suppressor in many cancers. Our aim was to investigate the association of RECK expression with prognosis in BMSCC patients with different clinicopathological features.

Materials And Methods: The expression level of RECK was determined by immunohistochemistry using tissue microarrays containing specimens from 193 BMSCC patients. The association of RECK expression with outcomes in BMSCC patients stratified by different clinicopathological features was analyzed by Cox proportional hazards models.

Results: The low expression level of RECK was associated with shorter disease-specific survival, especially in patients with age >40 years, moderate or poor cell differentiation, advanced pathological stage, and history of postoperative radiotherapy. However, the low expression level of RECK was not associated with poor disease-free survival, except in BMSCC patients with age ≦40 years, advanced pathological stage and lymph node metastasis. Furthermore, RECK-knockdowned cells showed higher cell viability and abilities of invasion/migration, indicating that RECK might be a tumor suppressor for tumor progression in oral cancer.

Conclusion: The low expression of RECK might be a potential prognostic biomarker for pathological outcome-dependent BMSCC patients.
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http://dx.doi.org/10.1111/odi.13214DOI Listing
January 2020

Kinome-Wide Screening with Small Interfering RNA Identified Polo-like Kinase 1 as a Key Regulator of Proliferation in Oral Cancer Cells.

Cancers (Basel) 2019 Aug 5;11(8). Epub 2019 Aug 5.

School of Medicine for International Students, I-Shou University, Kaohsiung 82445, Taiwan.

Oral squamous cell carcinoma (OSCC) is one of the major leading causes of cancer-related death worldwide, with limited effective markers for diagnosis and therapy, which has caused a low overall survival rate in the past decades. Kinases play important roles in tumor development and malignancy in various types of cancer. However, little is known about the role of kinases in OSCC cells. In this study, an arrayed kinome small interfering RNA (siRNA) library was used to screen oral cancer cell lines and counter assayed with normal fibroblast cells to identify the genes required for cancer cell proliferation. We found that polo-like kinase 1 (PLK1) was one of the most potent genes required for OSCC cell proliferation. The knockdown of PLK1 with a siRNA or antisense oligonucleotide (ASO) consistently diminished cyclin-B1 (CCNB1) expression/phosphorylation and the G-M phase transition. Similar effects were observed in cells treated with the PLK1 kinase inhibitor BI6727. Besides, The Cancer Genome Atlas (TCGA) analysis revealed that PLK1 was elevated in tumor tissues and associated with short survival in patients with OSCC. We also found that PLK1 expression was highly correlated with the expression of its downstream effector, CCNB1, in patients with OSCC. Coexpression of the two genes resulted in a poor prognosis of OSCC patients, particularly those in the advanced stages of OSCC. Taken together, our results suggest that might be a diagnostic or therapeutic marker for OSCC.
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http://dx.doi.org/10.3390/cancers11081117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721596PMC
August 2019

Nanotechnology Approaches in Tackling Cardiovascular Diseases.

Molecules 2019 May 27;24(10). Epub 2019 May 27.

Institute of Biomedical Sciences, Academia Sinica, 128 Section 2 Academia Road, Nangang District, Taipei 115, Taiwan.

Cardiovascular diseases have continued to remain a leading cause of mortality and morbidity worldwide. Poor proliferation capability of adult cardiomyocytes disables the heart from regenerating new myocardium after a myocardial ischaemia event and therefore weakens the heart in the long term, which may result in heart failure and death. Delivery of cardioprotective therapeutics soon after the event can help to protect the heart from further cell death and improve cardiac function, but delivery methods and potential side effects of these therapeutics may be an issue. Advances in nanotechnology, particularly nanoparticles for drug delivery, have enabled researchers to obtain better drug targeting capability, thus increasing the therapeutic outcome. Detailed study of nanoparticles in vivo is useful as it can provide insight for future treatments. Nanogel can help to create a more favourable environment, not only for a sustained delivery of therapeutics, but also for a better navigation of the therapeutics to the targeted sites. Finally, if the damage to the myocardium is too severe for drug treatment, nanopatch can help to improve cardiac function and healing by becoming a platform for pluripotent stem cell-derived cardiomyocytes to grow for the purpose of cell-based regenerative therapy.
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http://dx.doi.org/10.3390/molecules24102017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572019PMC
May 2019

Differential clinical significance of COL5A1 and COL5A2 in tongue squamous cell carcinoma.

J Oral Pathol Med 2019 Jul 29;48(6):468-476. Epub 2019 Apr 29.

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Background: Type V collagen (COL5), in the functional heterotrimer [α1(V) α2(V)] isoform, participates in the malignancies of various cancers. However, its role in tongue squamous cell carcinoma (TSCC) remains unclear.

Materials And Methods: The expression levels of COL5A1 and COL5A2 polypeptide chains were examined using the tissue microarray from 245 TSCC patients with immunohistochemistry. Paired t test and Wilcoxon signed-rank test were performed for comparisons among the groups. Survival rates were estimated by using the Kaplan-Meier method and compared with log-rank tests. A Cox proportional hazards model was used to evaluate the impact of protein expression level on survival rate.

Results: Expression level of COL5A1 was significantly increased in tumor tissues (P < 0.001) compared to that in corresponding adjacent normal tissues. High expression level of COL5A1 was associated with advanced pathological stage (III, IV, P = 0.015) and lymph node metastasis (P = 0.005) of TSCC patients. High expression level of COL5A1 was also correlated with poor disease-specific survival (DSS, P = 0.001) and disease-free survival (DFS, P = 0.003) in TSCC patients. However, high expression level of COL5A2 was correlated with better DFS in TSCC patients (P = 0.043). Moreover, co-expression level of high (COL5A1) /low (COL5A2) heterotrimer was correlated with worse DSS (P = 0.004) and DFS (P = 0.004).

Conclusion: COL5A1 is an unfavorable factor for tumorigenesis, clinicopathological outcomes, and prognosis, whereas COL5A2 is only a favorable factor for prognosis in TSCC. The co-expression of high (COL5A1)2/low (COL5A2) heterotrimer is a more potential unfavorable factor for prognosis in TSCC.
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http://dx.doi.org/10.1111/jop.12861DOI Listing
July 2019

Factors pertaining to long-term mortality following emergency visits for head and neck cancer.

J Dent Sci 2018 Sep 31;13(3):234-241. Epub 2018 May 31.

Research Center of Medical Informatics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC.

Background/purpose: Avoiding mortality has been the ultimate goal in the management of head and neck cancer (HNC) patients with emergency department (ED) visits, however, risk factors and causes of mortality are not well studied. The objective of the present study is to verify the factors associated with long-term mortality of patients with HNC who visited ED.

Materials And Methods: We retrospectively collected data of 1660 HNC patients who made ED visits from the Longitudinal Health Insurance Database 2000 during 2000-2012 in Taiwan. The multivariate Cox proportional hazard model was used to measure the mortality-associated risk factors in HNC patients who made ED visits.

Results: The prognostic factors associated with mortality risk were age (≥65 vs. < 65 y; HR = 1.58, p < 0.0001), geographic region (central vs. northern; HR = 1.20, p = 0.0384; southern vs. northern; HR = 1.38, p = 0.0001), surgery (yes vs. no; HR = 0.61, p < 0.0001), radiotherapy (yes vs. no; HR = 1.80, p < 0.0001), chemotherapy (yes vs. no; HR = 1.68, p < 0.0001), acute myocardial infarction (yes vs. no; HR = 2.01, p = 0.0303), diabetes mellitus (yes vs. no; HR = 1.60, p < 0.0001), chronic obstructive pulmonary (yes vs. no; HR = 1.51, p = 0.0002), number of ED visits (≥4 vs. 1; HR = 0.69, p = 0.0003), and number of admissions (1 vs. 0; HR = 1.54, p < 0.0001; ≥2 vs. 0; HR = 1.48, p = 0.0002).

Conclusion: Higher mortality was associated with older age, living in southern Taiwan, not having undergone surgery, having received radiotherapy and chemotherapy, comorbidities, and more hospital admissions. A coordinated and extended multidisciplinary approach including ED care is required to improve the long-term survival and further decrease the economic burden of HNC treatment.
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http://dx.doi.org/10.1016/j.jds.2018.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388814PMC
September 2018

Low C6orf141 Expression is Significantly Associated with a Poor Prognosis in Patients with Oral Cancer.

Sci Rep 2019 03 14;9(1):4520. Epub 2019 Mar 14.

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

C6orf141 (Chromosome 6 open reading frame 141) is a novel gene, and its role in oral cancer progression remains unclear. C6orf141 expression in oral squamous cell carcinoma (OSCC) and adjacent normal tissues from 428 patients was examined through immunohistochemistry (IHC). Our results revealed that C6orf141 expression was significantly reduced in OSCC compared with adjacent normal tissues. Low C6orf141 expression was significantly associated with a poor American Joint Committee on Cancer pathological stage (P < 0.001), T classification (P = 0.002), and pN stage (P = 0.032). Kaplan-Meier curves revealed that low C6orf141 expression was significantly associated with shorter disease-specific survival (DSS) in patients with OSCC (log-rank P = 0.007). Multivariate analysis indicated that low C6orf141 expression was an independent prognostic biomarker for DSS (adjusted hazard ratio = 1.34; 95% confidence interval = 1.10-1.81; P = 0.05). Additionally, ectopic C6orf141 expression could significantly suppress oral cancer cell proliferation, colony formation, and migratory and invasive abilities. Xenograft tumor growth assay revealed that C6orf141 could significantly suppress oral tumor growth in vivo. Our results suggest that C6orf141 plays a novel tumor-suppressive role in oral cancer cell growth and motility. Furthermore, C6orf141 dysfunction could be a potential prognostic biomarker for OSCC and provide new therapeutic strategies in the future.
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http://dx.doi.org/10.1038/s41598-019-41194-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418188PMC
March 2019

Maximum Glomerular Filtration Decline Rate is Associated with Mortality and Poor Renal Outcome in Chronic Kidney Disease Patients.

Blood Purif 2019 1;48(2):131-137. Epub 2019 Feb 1.

Division of Nephrology, Asia University Hospital, Taichung, Taiwan,

Background: Glomerular filtrate rate (GFR) decline is associated with increased risk of dialysis in patients with chronic kidney disease (CKD). It is unclear whether the maximum, the minimum, or the average of GFR decline rate is associated with the risk of mortality and the initiation of renal replacement therapy (RRT). We investigated prognostic role of the maximum, the minimum, and the average of GFR decline rate in patients with CKD not yet on dialysis.

Methods: Patients, enrolled in the CKD program of China Medical University Hospital between July 2004 and Aug 2013, with CKD stages 3-5 (estimated GFR [eGFR] < 60 mL/min/1.73 m2) not yet on dialysis were analyzed. Primary outcome was a composite of mortality and RRT. The association between 3 readings of GFR decline rate and primary outcome was analyzed using Cox proportional hazard regression.

Results: We analyzed 815 patients aged 75 (interquartile range [IQR] 65-82) years with a median follow-up of 5.2 years (IQR 3.9-6.9). The maximum of eGFR decline rate was associated with the primary outcome (hazard ratio 2.19, 95% CI 1.16-4.12, p = 0.015), independent of age, gender, diabetes, cerebrovascular accident, smoking, baseline eGFR, serum albumin, calcium, urine protein/creatinine ratio, usage of renin-angiotensin system blockade. The minimum and the average of eGFR decline rate were not associated with the primary outcome.

Conclusions: The maximum of GFR decline rate was associated with mortality and poor renal outcome in CKD patients, independent of other contributive confounders.
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http://dx.doi.org/10.1159/000496082DOI Listing
January 2020

Loss of Gut Microbiota Alters Immune System Composition and Cripples Postinfarction Cardiac Repair.

Circulation 2019 01;139(5):647-659

Program in Molecular Medicine, National Yang Ming University and Academia Sinica, Taipei, Taiwan (T.W.H.T., P.C.C.H.).

Background: The impact of gut microbiota on the regulation of host physiology has recently garnered considerable attention, particularly in key areas such as the immune system and metabolism. These areas are also crucial for the pathophysiology of and repair after myocardial infarction (MI). However, the role of the gut microbiota in the context of MI remains to be fully elucidated.

Methods: To investigate the effects of gut microbiota on cardiac repair after MI, C57BL/6J mice were treated with antibiotics 7 days before MI to deplete mouse gut microbiota. Flow cytometry was applied to examine the changes in immune cell composition in the heart. 16S rDNA sequencing was conducted as a readout for changes in gut microbial composition. Short-chain fatty acid (SCFA) species altered after antibiotic treatment were identified by high-performance liquid chromatography. Fecal reconstitution, transplantation of monocytes, or dietary SCFA or Lactobacillus probiotic supplementation was conducted to evaluate the cardioprotective effects of microbiota on the mice after MI.

Results: Antibiotic-treated mice displayed drastic, dose-dependent mortality after MI. We observed an association between the gut microbiota depletion and significant reductions in the proportion of myeloid cells and SCFAs, more specifically acetate, butyrate, and propionate. Infiltration of CX3CR1+ monocytes to the peri-infarct zone after MI was also reduced, suggesting impairment of repair after MI. Accordingly, the physiological status and survival of mice were significantly improved after fecal reconstitution, transplantation of monocytes, or dietary SCFA supplementation. MI was associated with a reorganization of the gut microbial community such as a reduction in Lactobacillus. Supplementing antibiotic-treated mice with a Lactobacillus probiotic before MI restored myeloid cell proportions, yielded cardioprotective effects, and shifted the balance of SCFAs toward propionate.

Conclusions: Gut microbiota-derived SCFAs play an important role in maintaining host immune composition and repair capacity after MI. This suggests that manipulation of these elements may provide opportunities to modulate pathological outcome after MI and indeed human health and disease as a whole.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.035235DOI Listing
January 2019

Diagnosis of Bacterial Pathogens in the Urine of Urinary-Tract-Infection Patients Using Surface-Enhanced Raman Spectroscopy.

Molecules 2018 Dec 19;23(12). Epub 2018 Dec 19.

College of Medicine, China Medical University, Taiwan, No. 49, Hsueh-Shih Rd, North District, Taichung 40402, Taiwan.

(1) Background: surface-enhanced Raman spectroscopy (SERS) is a novel method for bacteria identification. However, reported applications of SERS in clinical diagnosis are limited. In this study, we used cylindrical SERS chips to detect urine pathogens in urinary tract infection (UTI) patients. (2) Methods: Urine samples were retrieved from 108 UTI patients. A 10 mL urine sample was sent to conventional bacterial culture as a reference. Another 10 mL urine sample was loaded on a SERS chip for bacteria identification and antibiotic susceptibility. We concentrated the urine specimen if the intensity of the Raman spectrum required enhancement. The resulting Raman spectrum was analyzed by a recognition software to compare with spectrum-form reference bacteria and was further confirmed by principal component analysis (PCA). (3) Results: There were 97 samples with single bacteria species identified by conventional urine culture and, among them, 93 can be successfully identified by using SERS without sample concentration. There were four samples that needed concentration for bacteria identification. Antibiotic susceptibility can also be found by SERS. There were seven mixed flora infections found by conventional culture, which can only be identified by the PCA method. (4) Conclusions: SERS can be used in the diagnosis of urinary tract infection with the aid of the recognition software and PCA.
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http://dx.doi.org/10.3390/molecules23123374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321215PMC
December 2018

Abdominal aortic calcification score can predict future coronary artery disease in hemodialysis patients: a 5-year prospective cohort study.

BMC Nephrol 2018 11 8;19(1):313. Epub 2018 Nov 8.

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

Background: Abdominal aortic calcification (AAC) has been known to be associated with cardiovascular mortality in hemodialysis. However, the association between AAC and future coronary artery disease (CAD) occurrence is not clear. We aimed to clarify the association of AAC severity and the occurrence of future CAD events in hemodialysis patients.

Methods: Hemodialysis (HD) patients were recruited in this prospective cohort study. AAC severity was quantified by AAC score, which was measured by lateral lumbar radiography. We used receiver operation curve (ROC) analysis to find the cutoff AAC value for CAD prediction. CAD-free survival was analyzed by Kaplan-Meier study.

Results: There were 303 patients recruited for study with a median (interquartile range) follow-up of 95 (65-146) months. The AAC score in patients with occurrence of new CAD [9 (3-15.25), n = 114] was higher than in patients without new CAD occurrence [5 (1-9) n = 189], p < 0.001. Multivariate hazard ratio of AAC score for CAD was 1.039 (p = 0.016). ROC study showed that an AAC score of 5.5 had a sensitivity of 0.658 and a specificity of 0.587 in the prediction of new CAD occurrence. Patients with AAC score above 5.5 had significantly higher cumulative incidence of CAD than patients with AAC score below 5.5. Age, diabetes, prior history of CAD, and longer dialysis vintage were major factors associated with higher AAC score.

Conclusions: AAC score can predict the occurrence of future CAD events in HD patients. The best cut-off value of AAC score is 5.5. AAC score greater than 5.5 is a reliable abdominal aortic calcification marker, and can predict future CAD in ESRD patients. Major contributive factors for higher AAC score were age, presence of diabetes, prior history of CAD, and longer dialysis vintage.
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http://dx.doi.org/10.1186/s12882-018-1124-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225627PMC
November 2018

Vegetarian diet may ameliorate uremic pruritus in hemodialysis patients.

Ren Fail 2018 Nov;40(1):514-519

g Division of Nephrology , Asia University Hospital , Taichung , Taiwan.

Objectives: Systemic inflammation has been reported to be associated with uremic pruritus (UP). Although a vegetarian diet can reduce systemic inflammation in hemodialysis patients, the effect of vegetarian diet on UP is not clear. The purpose of the study was to know the possible effects of vegetarian diet on UP.

Methods: A cross-sectional study was done to compare the severity of UP and blood levels of systemic inflammatory markers between vegetarian and non-vegetarian hemodialysis patients. Six non-vegetarian patients with uremic pruritus changed their non-vegetarian diet to vegetarian diet for 2 months. Visual Analogue Scale (VAS) and pruritus score (PS) were used to measure the UP severity. The serum high-sensitivity C-reactive protein (hs-CRP), and interleukin-2 (IL-2) were used as markers of inflammation.

Results: Both the median VAS scores (p = .043) and the median PS scores (p < .001) were lower in the Vegetarian than in the non-vegetarian group. The median values of hs-CRP in Vegetarian were lower than that for the non-vegetarian (p = .020). The median value of IL-2 was also lower in Vegetarian than that of the non-vegetarian (p = .016). There were 6 non-vegetarian patients shift to vegetarian for 2 months. The pruritus score improved and IL-2 level decreased after change to vegetarian diet.

Conclusion: We concluded that vegetarian diet might be associated with the amelioration of the uremic pruritus severity in hemodialysis patients.
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http://dx.doi.org/10.1080/0886022X.2018.1512871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012008PMC
November 2018

Abdominal aortic calcification score predicts the occurrence of coronary artery disease in middle-aged peritoneal dialysis patients.

Nephrology (Carlton) 2019 Mar;24(3):336-340

Division of Nephrology, China Medical University Hospital, Taichung, Taiwan.

Aim: Abdominal aortic calcification (AAC) score in dialysis patients was associated with coronary artery disease (CAD) in cross-sectional study, but the use of AAC score in the CAD prediction was not clear. We aimed to use AAC score in the estimation of CAD occurrence in middle-aged peritoneal dialysis (PD) patients.

Methods: Middle-aged (45-65 years old) PD patients were recruited and followed up until CAD occurrence, patient mortality, or PD failure. We quantified AAC score by lateral lumbar radiography, and used receiver operation curve (ROC) analysis to find the cut-off value for CAD prediction.

Results: There were 187 patients recruited for study with a mean follow-up of 1027 ± 427 days. AAC score in patients with CAD during follow-up period (9.7 ± 7.6, n = 41) was higher than in patients without CAD occurrence (5.5 ± 6.1, n = 146) (P < 0.001). Multivariate hazard ratio of AAC score for CAD was 1.07 (P = 0.044). ROC showed that AAC score of 5.5 had a sensitivity of 0.667 and a specificity of 0.581 in the prediction of CAD occurrence. Patients with AAC score above 5.5 had significantly higher cumulative incidence of CAD than patients with AAC score below 5.5 (Log-rank test, P = 0.003). Age (P = 0.002), diabetes (P = 0.002), hypertension (P = 0.032), longer dialysis vintage (P < 0.001) and lower serum potassium (P = 0.012) were parameters significantly associated with higher AAC score.

Conclusion: AAC score can predict CAD occurrence in PD patients. Age, diabetes, hypertension, dialysis vintage and serum potassium level are factors associated with higher AAC score.
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http://dx.doi.org/10.1111/nep.13231DOI Listing
March 2019

Risk of new-onset diabetes in end-stage renal disease patients undergoing dialysis: analysis from registry data of Taiwan.

Nephrol Dial Transplant 2018 04;33(4):670-675

Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan.

Background: This study compared the risk of developing new-onset diabetes between hemodialysis (HD) and peritoneal dialysis (PD) patients. We further investigated the effectiveness of icodextrin in reducing the risk of new-onset diabetes in PD patients.

Methods: From the Taiwan health insurance database, 36 879 incident HD patients and 6382 incident PD patients from 2000 to 2010 were identified as study cohorts. We further selected an additional HD cohort matched by propensity scores (PSs) of PD patients. Incidence rates and hazard ratios (HRs) of new-onset diabetes were assessed among cohorts and between icodextrin users and nonusers by the end of 2011.

Results: For the unmatched cohorts, the incidence of new-onset diabetes was higher in PD patients than in HD patients (9.16 versus 8.18 per 1000 person-years), with an adjusted HR of 1.51 (95% CI 1.30-1.75) for PD patients. For the PS-matched cohorts, the corresponding incidence rates were 9.43 and 5.90 per 1000 person-years, respectively, with an adjusted HR of 1.61 (95% CI 1.32-1.97). Among PD patients, the incidence was lower in icodextrin users than in nonusers (6.22 versus 12.1 per 1000 person-years), with an adjusted HR of 0.66 (95% CI 0.50-0.88) for users.

Conclusions: Our study suggests that PD patients are at a higher risk of developing new-onset diabetes than HD patients. Icodextrin is recommended for PD patients to reduce the risk of new-onset diabetes.
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http://dx.doi.org/10.1093/ndt/gfx250DOI Listing
April 2018

Utrophin Compensates dystrophin Loss during Mouse Spermatogenesis.

Sci Rep 2017 08 7;7(1):7372. Epub 2017 Aug 7.

Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder resulting from mutations in the dystrophin gene. The mdx/utrn mouse, lacking in both dystrophin and its autosomal homologue utrophin, is commonly used to model the clinical symptoms of DMD. Interestingly, these mice are infertile but the mechanisms underlying this phenomenon remain unclear. Using dystrophin deficient mdx mouse and utrophin haplodeficient mdx/utrn mouse models, we demonstrate the contribution of Dp427 (full-length dystrophin) and utrophin to testis and epididymis development, as well as spermatogenesis. We show that Dp427 deficiency disturbed the balance between proliferation and apoptosis of germ cells during spermatogenesis, which was further disrupted with utrophin haplodeficiency, deciphering a compensatory role of utrophin for dystrophin in the male reproductive system. In the spermatozoa, we have found a compensatory response of utrophin to dystrophin deficiency - namely the upregulation and relocation of utrophin to the flagellar midpiece. This study demonstrates the contribution of Dp427 and utrophin in male fertility, suggesting a potential pathology in DMD patients.
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http://dx.doi.org/10.1038/s41598-017-05993-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547154PMC
August 2017

An Analysis of Emergency Department Visits and the Survival Rate for Colorectal Cancer Patients: A Nationwide Population-based Study.

Intern Med 2017 Aug 1;56(16):2125-2132. Epub 2017 Aug 1.

Radiation Oncology Department, Kaohsiung Veterans General Hospital, Taiwan.

Objective We examined the general characteristics, survival rate, and most common reasons for visiting the emergency department (ED) among colorectal cancer patients in Taiwan. We performed a population-based retrospective study and used data sourced from the National Health Insurance Research Database (NHIRD). Methods The colorectal cancer patient population, their diagnosis, and their medical management at the ED were identified using the Longitudinal Health Insurance Database 2000 (HV) codes and International Classification of Diseases, Ninth Revision, Clinical Modification system. We investigated their reasons for visiting the ED and the medications used there, analyzed their cumulative survival curves using the Kaplan-Meier method, and compared the survival curves with other colorectal cancer patients who had never visited the ED. Results Between 2000 and 2012, there were 6,532 ED visits by 3,347 colorectal patients, and the number per year increased gradually. The top three most common reasons for visiting ED were ill-defined conditions, abdominal pain, and intestinal obstruction. The overall survival rates of colorectal patients in the ED visit group at 3, 5, and 10 years, were 0.65, 0.56, and 0.47, respectively, without significant differences from the rates among colorectal cancer patients who did not visit the ED (p=0.2072). Conclusion We described the circumstances of ED visitation by colorectal cancer patients in Taiwan. Health care providers and researchers should pay more attention to improve medical care quality and investigate more details to predict the outcome among colorectal cancer patients.
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http://dx.doi.org/10.2169/internalmedicine.7629-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596271PMC
August 2017

The variant of pri-mir-26a-1 polymorphism is associated with decreased risk of betel quid-related oral premalignant lesions and oral squamous cell carcinoma.

Oral Surg Oral Med Oral Pathol Oral Radiol 2017 Oct 8;124(4):378-389.e1. Epub 2017 Jun 8.

Investigator, Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Professor, Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan. Electronic address:

Objectives: This case-control study evaluated the association of the single nucleotide polymorphism rs7372209 (T>C) in pri-mir-26a-1 with the risk and progression of betel quid (BQ)-related oral premalignant lesions (OPLs) and oral squamous cell carcinoma (OSCC).

Study Design: In total, 597 BQ chewers were recruited: 196 healthy controls, 241 patients with OPLs, and 160 patients with OSCC. Genotypes were determined using the TaqMan real-time assay.

Results: The C/T + T/T genotypes and T allele in pri-mir-26a-1 were correlated with a decreased risk of BQ-related OPLs (P = .038 and .005, respectively), oral leukoplakia (P = .01 and .001, respectively), and advanced-stage OSCC (P = .021 and .004, respectively). The effects of the C/T + T/T genotypes and T allele on the decreased risk of OPLs were potent in the older age group (both P < .001), heavy smokers (P ≤ .003 and .006, respectively) and alcohol drinkers (P ≤ .004 and .001, respectively). Furthermore, among patients with OSCC, the C/T + T/T genotypes and T allele were associated with a decreased risk of advanced pathologic stage (P = .032) and lymph node involvement (P = .017).

Conclusions: BQ chewers carrying the T allele or C/T + T/T genotypes in pri-mir-26a-1 may have a decreased risk of oral leukoplakia, OPLs, and advanced-stage OSCC.
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http://dx.doi.org/10.1016/j.oooo.2017.05.515DOI Listing
October 2017

Next-generation Sequencing for microRNA Profiling: MicroRNA-21-3p Promotes Oral Cancer Metastasis.

Anticancer Res 2017 03;37(3):1059-1066

Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, R.O.C.

Dysfunctional microRNAs (miRNAs) play a crucial role in oral squamous cell carcinoma (OSCC) progression. In the present study, we performed next-generation sequencing for miRNA profiling of the OSCC tissues and corresponding adjacent normal tissues in two patients with OSCC. We observed that 45 miRNAs were substantially up-regulated and 17 miRNAs were down-regulated in OSCC tissues. Since information on the biological role of miR-21-3p (passenger strand) in OSCC is limited, the expression levels of miR-21-3p were further evaluated in 95 OSCC tissue samples by a stem-loop real-time polymerase chain reaction. Our results revealed that miR-21-3p is significantly overexpressed in the OSCC tissues compared with the corresponding adjacent normal tissues (p<0.001). High miR-21-3p expression levels were significantly correlated with N classification (p=0.042). After transfection with a miR-21-3p inhibitor (antagomir), the invasive ability of the OSCC cells was significantly abrogated. Altogether, our findings indicated that miR-21-3p plays a crucial oncogenic role in cell metastasis during OSCC progression.
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http://dx.doi.org/10.21873/anticanres.11417DOI Listing
March 2017
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