Publications by authors named "Chia-Hao Chan"

18 Publications

  • Page 1 of 1

The Effect of Far-Infrared Therapy on the Peritoneal Expression of Glucose Degradation Products in Diabetic Patients on Peritoneal Dialysis.

Int J Mol Sci 2021 Apr 2;22(7). Epub 2021 Apr 2.

Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan.

Peritoneal dialysis (PD) is a treatment modality for end-stage renal disease (ESRD) patients. Dextrose is a common osmotic agent used in PD solutions and its absorption may exacerbate diabetes mellitus, a common complication of ESRD. PD solutions also contain glucose degradation products (GDPs) that may lead to encapsulating peritoneal sclerosis (EPS), a severe complication of PD. A previous study showed that far-infrared (FIR) therapy improved a patient's gastrointestinal symptoms due to EPS. Due to limited literature on the matter, this study aims to investigate dialysate GDPs and peritoneal function in diabetic patients on PD. Thirty-one PD patients were enrolled and underwent 40 min of FIR therapy twice daily for six months. We demonstrated the effect of FIR therapy on the following: (1) decrease of methylglyoxal = 0.02), furfural ( = 0.005), and 5-hydroxymethylfurfural ( = 0.03), (2) increase of D/D0 glucose ratio ( = 0.03), and (3) decrease of potassium levels ( = 0.008) in both DM and non-DM patients, as well as (4) maintenance and increase of peritoneal Kt/V in DM and non-DM patients, respectively ( = 0.03). FIR therapy is a non-invasive intervention that can decrease dialysate GDPs in PD patients by improving peritoneal transport rate and solute removal clearance, while also maintaining dialysis adequacy.
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http://dx.doi.org/10.3390/ijms22073732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038268PMC
April 2021

Prenatal diagnosis and molecular cytogenetic characterization of a small supernumerary marker chromosome derived from chromosome 15 in a pregnancy associated with recurrent Down syndrome.

Taiwan J Obstet Gynecol 2021 Jan;60(1):152-156

Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.

Objective: We present prenatal diagnosis and molecular cytogenetic characterization of a small supernumerary marker chromosome (sSMC) derived from chromosome 15 in a pregnancy associated with recurrent Down syndrome.

Case Report: A 33-year-old, gravida 4, para 2, woman underwent amniocentesis at 16 weeks of gestation because of a previous child with Down syndrome and a karyotype of 46,XY,der(14;21)(q10; q10),+21. In this pregnancy, amniocentesis revealed a karyotype of 47,XX,+21[12]/48,XX,+21,+mar[3]. The parental karyotypes were normal. The pregnancy was terminated, and a malformed fetus was delivered with characteristic craniofacial appearance of Down syndrome and hypoplastic middle phalanx of the fifth fingers. The placenta had a karyotype of 47,XX,+21[37]/48,XX,+21,+mar[3]. The umbilical cord had a karyotype of 47,XX,+21[38]/48,XX,+21,+mar[2]. In addition to trisomy 21, array comparative genomic hybridization (aCGH) on the DNA extracted from umbilical cord revealed 40∼50% mosaicism for a 2.604-Mb duplication of 15q25.2-q25.3, or arr 15q25.2q25.3 (83,229,665-85,834,131) × 2.4 [GRCh37 (hg19)] encompassing 19 Online Mendelian Inheritance in Man (OMIM) genes. Quantitative fluorescent polymerase chain reaction (QF-PCR) using the DNAs extracted from cultured amniocytes and parental bloods revealed maternal origin of the sSMC(15) and the extra chromosome 21.

Conclusion: aCGH is useful for identification of the nature of sSMC, and QF-PCR is useful for determination of the parental origin of the aberrant chromosomes.
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http://dx.doi.org/10.1016/j.tjog.2020.11.023DOI Listing
January 2021

Prognosis of Vascular Access in Haemodialysis Patients with Autosomal Dominant Polycystic Kidney Disease.

Sci Rep 2020 02 6;10(1):1985. Epub 2020 Feb 6.

School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Vascular diseases are commonly observed in patients with autosomal dominant polycystic kidney disease (ADPKD). We aim to investigate the differences in the risk for arteriovenous fistula or graft (AVF/AVG) dysfunction in haemodialysis (HD) patients with and without ADPKD. 557 ADPKD and 1671 non-ADPKD patients were enrolled in the study after propensity score matching. The primary outcome measure is the incidence rate of AVF/AVG dysfunction. The incidence rates and risks of AVF/AVG dysfunction (per 100 person-years) for ADPKD and non-ADPKD patients were (1) 38.83 and 48.99 [SHR = 0.79, P = 0.137], respectively, for within 90 days, (2) 45.85 and 51.31 [SHR = 0.90, P = 0.300], respectively, for within 180 days, (3) 44.42 and 41.40 [SHR = 1.08, P = 0.361], respectively, for within the first year, (4) 27.38 and 24.69 [SHR = 1.09, P = 0.168], respectively, for within 5 years, (5) 17.35 and 13.80 [SHR = 1.19, P = 0.045], respectively, for between the 1st and 10th year, and (6) 25.40 and 21.22 [SHR = 1.14, P = 0.031], respectively, for all periods. ADPKD patients had lower incidence rates of AVF/AVG dysfunction within the first 180 days than non-ADPKD patients, but presented a higher incidence rate after 1 year of AVF/AVG creation and onwards.
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http://dx.doi.org/10.1038/s41598-020-58441-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004976PMC
February 2020

Role of PGRMC1 in cell physiology of cervical cancer.

Life Sci 2019 Aug 16;231:116541. Epub 2019 Jun 16.

Dept. of Medical Sciences & Inst. of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan. Electronic address:

Aims: The most frequent cancers among women worldwide. The mortality of cervical cancer has declined significantly primarily due to the widespread use of Pap smear tests as a screening test and therapeutic vaccination. However, cervical cancer still remains a severe disease among the female population, as the prognosis of metastatic cervical cancer is very poor.

Key Methods: In this study, we performed 2D-DIGE and MALDI-TOF/TOF MS to analyze differentially expressed proteins between HeLa and invasive HeLa-I5 cells..

Key Findings: According to our proteomics data, 68 differentially expressed proteins between the HeLa and HeLa-I5 cells were identified. One of these differentially expressed proteins, Progesterone receptor membrane component 1 (PGRMC1), was selected as a candidate for further studies. To correlate the role of PGRMC1 with cellular migration and cancer progression, small interfering RNA (siRNA) was used to knockdown the expression of PGRMC1. Similar function of PGRMC1 was also observed in two other cervical cancer lines, CaSki and ME-180.

Significance: PGRMC1 plays an essential role in regulating cancer progression and metastasis of cervical cancer cells, thus serving as a potential therapeutic target for cervical cancer.
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http://dx.doi.org/10.1016/j.lfs.2019.06.016DOI Listing
August 2019

Remote Magnetic Control of Autophagy in Mouse B-Lymphoma Cells with Iron Oxide Nanoparticles.

Nanomaterials (Basel) 2019 Apr 4;9(4). Epub 2019 Apr 4.

Institute of Biomedical Engineering, College of Electrical and Computer Engineering, National Chiao Tung University, Hsinchu 30010, Taiwan.

Autophagy is the spontaneous degradation of intracellular proteins and organelles in response to nutrient deprivation. The phagocytosis of iron oxide nanoparticles (IONPs) results in intracellular degradation that can be exploited for use in cancer treatment. Non-invasive magnetic control has emerged as an important technology, with breakthroughs achieved in areas such as magneto-thermal therapy and drug delivery. This study aimed to regulate autophagy in mouse B-lymphoma cells (A20) through the incorporation of IONPs-quantum dots (QDs). We hypothesized that with the application of an external magnetic field after phagocytosis of IONPs-QDs, autophagy of intracellular IONPs-QDs could be regulated in a non-invasive manner and subsequently modulate the regulation of inflammatory responses. The potential of this approach as a cancer treatment method was explored. The application of IONPs and an external magnetic force enabled the non-invasive regulation of cell autophagy and modulation of the self-regulatory function of cells. The combination of non-invasive magnetic fields and nanotechnology could provide a new approach to cancer treatment.
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http://dx.doi.org/10.3390/nano9040551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524120PMC
April 2019

Current status of dialysis and vascular access in Taiwan.

J Vasc Access 2019 Jul 25;20(4):368-373. Epub 2018 Oct 25.

1 School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Due to the implementation of the National Health Insurance system in 1995, the number of patients receiving maintenance dialysis has increased rapidly. This contributed to Taiwan to be in an unfortunate position of possessing the highest prevalence of end-stage renal disease globally. Although the age-standardized incidence of end-stage renal disease gradually decreased to -1.1% in 2014, the huge economic burden that comes with dialysis is detrimental to the quality of dialysis treatment. To achieve a balance between economy and quality of care requires multidisciplinary cooperation. Through a variety of chronic kidney disease-related care projects, we have gradually reversed this situation and achieved good results. Further promotion of kidney transplantation and hospice care for terminal patients will improve the situation. With respect to vascular access, the "fistula first" policy is carried out and percutaneous transluminal angioplasty is the mainstay of treatment to resolve vascular access dysfunction. The medical expenses for dialysis and vascular access management are both fully paid for by the National Health Insurance, and patients do not have to worry about the medical expenses. However, the statistics and vascular access monitoring are relatively insufficient in the past. The comprehensive integration of vascular access management into public policy related to kidney disease will complete the missing piece of the puzzle of overall care.
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http://dx.doi.org/10.1177/1129729818807336DOI Listing
July 2019

Far-infrared therapy improves ankle brachial index in hemodialysis patients with peripheral artery disease.

Heart Vessels 2019 Mar 18;34(3):435-441. Epub 2018 Sep 18.

School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Ankle brachial index (ABI) is a diagnostic tool for peripheral artery disease (PAD), which is an important issue in hemodialysis (HD) patients. We enrolled 198 maintenance HD patients in this study. PAD is defined as ABI ≤ 0.90. Only PAD patients received far-infrared (FIR) therapy using the WS TY101 FIR emitter for 40 min during each HD session, three times weekly for 6 months. The ABI was measured at the bilateral lower extremities for 4 times [pre-dialytic timing (0 min) and 40 min after the initiation of HD session at both day 0 and 6 months after the FIR therapy]. The primary outcome is the change in ABI. There were 51 out of 198 patients with PAD. In comparison with the period without FIR therapy in the 51 PAD patients, 6 months of FIR therapy significantly improved the ABI of the right/left side for 0 min (from 0.77 ± 0.19 to 0.81 ± 0.20, p = 0.027/0.79 ± 0.20 to 0.81 ± 0.17, p = 0.049), 40 min during HD (from 0.73 ± 0.23 to 0.83 ± 0.19, p < 0.001/from 0.77 ± 0.21 to 0.83 ± 0.18, p < 0.001), and the incremental change between 0 and 40 min (from - 0.04 ± 0.14 to 0.05 ± 0.13, p = 0.007/from - 0.05 ± 0.13 to 0.03 ± 0.11, p = 0.012), respectively. In conclusion, the application of FIR therapy for 40 min, three times weekly for 6 months, has improved the ABI of both lower extremities, thus providing a new strategy of PAD treatment in HD patients.
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http://dx.doi.org/10.1007/s00380-018-1259-5DOI Listing
March 2019

Proteomic investigating the cooperative lethal effect of EGFR and MDM2 inhibitors on ovarian carcinoma.

Arch Biochem Biophys 2018 Jun 12;647:10-32. Epub 2018 Apr 12.

Institute of Bioinformatics and Structural Biology and Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan. Electronic address:

With the concept of precision medicine, combining multiple molecular-targeting therapies has brought new approaches to current cancer treatments. Malfunction of the tumor suppressor protein, p53 is a universal hallmark in human cancers. Under normal conditions, p53 is degraded through an ubiquitin-proteosome pathway regulated by its negative regulator, MDM2. In contrast, cellular stress such as DNA damage will activate p53 to carry out DNA repair, cell cycle arrest, and apoptosis. In this study, we focused on ovarian carcinoma with high EGFR and MDM2 overexpression rate. We assessed the effects of combined inhibition by MDM2 (JNJ-26854165) and EGFR (gefitinib) inhibitors on various ovarian cell lines to determine the importance of these two molecular targets on cell proliferation. We then used a proteomic strategy to investigate the relationship between MDM2 and EGFR inhibition to explore the underlying mechanisms of how their combined signaling blockades work together to exert cooperative inhibition. Our results demonstrated that all four cell lines were sensitive to both individual and combined, MDM2 and EGFR inhibition. The proteomic analysis also showed that gefitinib/JNJ-treated CAOV3 cells exhibited downregulation of proteins involved in nucleotide biosynthesis such as nucleoside diphosphate kinase B (NME2). In conclusion, our study showed that the combined treatment with JNJ and gefitinib exerted synergistic inhibition on cell proliferation, thereby suggesting the potential application of combining MDM2 inhibitors with EGFR inhibitors for enhancing efficacy in ovarian cancer treatment.
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http://dx.doi.org/10.1016/j.abb.2018.04.004DOI Listing
June 2018

YM500v3: a database for small RNA sequencing in human cancer research.

Nucleic Acids Res 2017 01 29;45(D1):D925-D931. Epub 2016 Nov 29.

Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 40402, Taiwan

We previously presented the YM500 database, which contains >8000 small RNA sequencing (smRNA-seq) data sets and integrated analysis results for various cancer miRNome studies. In the updated YM500v3 database (http://ngs.ym.edu.tw/ym500/) presented herein, we not only focus on miRNAs but also on other functional small non-coding RNAs (sncRNAs), such as PIWI-interacting RNAs (piRNAs), tRNA-derived fragments (tRFs), small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs). There is growing knowledge of the role of sncRNAs in gene regulation and tumorigenesis. We have also incorporated >10 000 cancer-related RNA-seq and >3000 more smRNA-seq data sets into the YM500v3 database. Furthermore, there are two main new sections, 'Survival' and 'Cancer', in this updated version. The 'Survival' section provides the survival analysis results in all cancer types or in a user-defined group of samples for a specific sncRNA. The 'Cancer' section provides the results of differential expression analyses, miRNA-gene interactions and cancer miRNA-related pathways. In the 'Expression' section, sncRNA expression profiles across cancer and sample types are newly provided. Cancer-related sncRNAs hold potential for both biotech applications and basic research.
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http://dx.doi.org/10.1093/nar/gkw1084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210564PMC
January 2017

Association of Genetic Polymorphisms of Renin-Angiotensin-Aldosterone System-Related Genes with Arterio-Venous Fistula Malfunction in Hemodialysis Patients.

Int J Mol Sci 2016 May 27;17(6). Epub 2016 May 27.

Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan.

Hemodialysis (HD) is the most commonly-used renal replacement therapy for patients with end-stage renal disease worldwide. Arterio-venous fistula (AVF) is the vascular access of choice for HD patients with lowest risk of infection and thrombosis. In addition to environmental factors, genetic factors may also contribute to malfunction of AVF. Previous studies have demonstrated the effect of genotype polymorphisms of angiotensin converting enzyme on vascular access malfunction. We conducted a multicenter, cross-sectional study to evaluate the association between genetic polymorphisms of renin-angiotensin-aldosterone system and AVF malfunction. Totally, 577 patients were enrolled. Their mean age was 60 years old and 53% were male. HD patients with AVF malfunction had longer duration of HD (92.5 ± 68.1 vs. 61.2 ± 51.9 months, p < 0.001), lower prevalence of hypertension (44.8% vs. 55.3%, p = 0.025), right-sided (31.8% vs. 18.4%, p = 0.002) and upper arm AVF (26.6% vs. 9.7%, p < 0.001), and higher mean dynamic venous pressure (DVP) (147.8 ± 28.3 vs. 139.8 ± 30.0, p = 0.021). In subgroup analysis of different genders, location of AVF and DVP remained significant clinical risk factors of AVF malfunction in univariate and multivariate binary logistic regression in female HD patients. Among male HD patients, univariate binary logistic regression analysis revealed that right-side AVF and upper arm location are two important clinical risk factors. In addition, two single nucleotide polymorphisms (SNPs), rs275653 (Odds ratio 1.90, p = 0.038) and rs1492099 (Odds ratio 2.29, p = 0.017) of angiotensin II receptor 1 (AGTR1), were associated with increased risk of AVF malfunction. After adjustment for age and other clinical factors, minor allele-containing genotype polymorphisms (AA and CA) of rs1492099 still remained to be a significant risk factor of AVF malfunction (Odds ratio 3.63, p = 0.005). In conclusion, we demonstrated that rs1492099, a SNP of AGTR1 gene, could be a potential genetic risk factor of AVF malfunction in male HD patients.
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http://dx.doi.org/10.3390/ijms17060833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926367PMC
May 2016

Small RNA and RNA-IP Sequencing Identifies and Validates Novel MicroRNAs in Human Mesenchymal Stem Cells.

OMICS 2016 Mar 24;20(3):191-8. Epub 2016 Feb 24.

1 Department of Obstetrics and Gynecology, Hsinchu Mackay Memorial Hospital , Hsinchu, Taiwan .

Organ regeneration therapies using multipotent mesenchymal stem cells (MSCs) are currently being investigated for a variety of common complex diseases. Understanding the molecular regulation of MSC biology will benefit regenerative medicine. MicroRNAs (miRNAs) act as regulators in MSC stemness. There are approximately 2500 currently known human miRNAs that have been recorded in the miRBase v21 database. In the present study, we identified novel microRNAs involved in MSC stemness and differentiation by obtaining the global microRNA expression profiles (miRNomes) of MSCs from two anatomical locations bone marrow (BM-MSCs) and umbilical cord Wharton's jelly (WJ-MSCs) and from osteogenically and adipogenically differentiated progenies of BM-MSCs. Small RNA sequencing (smRNA-seq) and bioinformatics analyses predicted that 49 uncharacterized miRNA candidates had high cellular expression values in MSCs. Another independent batch of Ago1/2-based RNA immunoprecipitation (RNA-IP) sequencing datasets validated the existence of 40 unreported miRNAs in cells and their associations with the RNA-induced silencing complex (RISC). Nine of these 40 new miRNAs were universally overexpressed in both MSC types; nine others were overexpressed in differentiated cells. A novel miRNA (UNI-118-3p) was specifically expressed in BM-MSCs, as verified using RT-qPCR. Taken together, this report offers comprehensive miRNome profiles for two MSC types, as well as cells differentiated from BM-MSCs. MSC transplantation has the potential to ameliorate degenerative disorders and repair damaged tissues. Interventions involving the above 40 new microRNA members in transplanted MSCs may potentially guide future clinical applications.
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http://dx.doi.org/10.1089/omi.2015.0136DOI Listing
March 2016

Genetic polymorphisms of the human cytomegalovirus UL144 gene in colorectal cancer and its association with clinical outcome.

J Gen Virol 2015 Dec;96(12):3613-3623

Institute of Public Health, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Human cytomegalovirus (HCMV) has been increasingly detected in colorectal cancer (CRC), and genetic polymorphisms in HCMV affect its pathogenesis. This study aimed to investigate HCMV genetic polymorphisms in CRC and its correlation with the clinical outcomes. We performed PCR and sequencing of a viral immunomodulatory gene, UL144, in clinical isolates and CRC specimens. The nucleotide and amino acid sequences were aligned, and a phylogenetic tree was constructed. The clinical, pathological and survival data were compared among tumours with different UL144 genotypes. HCMV was detected in 49 (47.8 %) of the tumour specimens. Genotype A predominated in 43 samples (22/43; 51.2 %) with successful sequencing, followed by genotype B (13/43; 30.2 %) and genotype C (8/43; 18.6 %). The genotypic distribution was similar to that of the clinical isolates and those reported in other Asian populations. The amino acid sequence of genotype B was the most conserved. For stage II and III CRC patients with HCMV-positive tumours, disease-free survival (DFS) varied among the three major genotypes (P50.0046). The presence of genotype B virus in the tumours was associated with a shorter DFS and independently predicted tumour recurrence in a multivariate Cox proportional hazards model (hazard ratio, 5.79; 95 % confidence interval, 1.30–25.81; P50.021). By reverse transcription PCR, tumour samples with genotype B viruses had the highest rate of UL144 expression. Our results suggest that genetic polymorphisms of HCMV UL144 are associated with clinical outcome in CRC and that HCMV may play an immunomodulatory role in the tumour microenvironment of CRC.
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http://dx.doi.org/10.1099/jgv.0.000308DOI Listing
December 2015

Identification of protein expression alterations in gefitinib-resistant human lung adenocarcinoma: PCNT and mPR play key roles in the development of gefitinib-associated resistance.

Toxicol Appl Pharmacol 2015 Nov 20;288(3):359-73. Epub 2015 Aug 20.

Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan. Electronic address:

Gefitinib is the first-line chemotherapeutic drug for treating non-small cell lung cancer (NSCLC), which comprises nearly 85% of all lung cancer cases worldwide. However, most patients eventually develop drug resistance after 12-18 months of treatment. Hence, investigating the drug resistance mechanism and resistance-associated biomarkers is necessary. Two lung adenocarcinoma cell lines, PC9 and gefitinib-resistant PC9/Gef, were established for examining resistance mechanisms and identifying potential therapeutic targets. Two-dimensional differential gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used for examining global protein expression changes between PC9 and PC9/Gef. The results revealed that 164 identified proteins were associated with the formation of gefitinib resistance in PC9 cells. Additional studies using RNA interference showed that progesterone receptor membrane component 1 and pericentrin proteins have major roles in gefitinib resistance. In conclusion, the proteomic approach enabled identifying of numerous proteins involved in gefitinib resistance. The results provide useful diagnostic markers and therapeutic candidates for treating gefitinib-resistant NSCLC.
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http://dx.doi.org/10.1016/j.taap.2015.08.008DOI Listing
November 2015

Mitochondrial proteomics with siRNA knockdown to reveal ACAT1 and MDH2 in the development of doxorubicin-resistant uterine cancer.

J Cell Mol Med 2015 Apr 30;19(4):744-59. Epub 2015 Jan 30.

Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan.

Mitochondria are key organelles in mammary cells in responsible for a number of cellular functions including cell survival and energy metabolism. Moreover, mitochondria are one of the major targets under doxorubicin treatment. In this study, low-abundant mitochondrial proteins were enriched for proteomic analysis with the state-of-the-art two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assistant laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) strategy to compare and identify the mitochondrial protein profiling changes in response to the development of doxorubicin resistance in human uterine cancer cells. The mitochondrial proteomic results demonstrate more than fifteen hundred protein features were resolved from the equal amount pooled of three purified mitochondrial proteins and 101 differentially expressed spots were identified. In which, 39 out of these 101 identified proteins belong to mitochondrial proteins. Mitochondrial proteins such as acetyl-CoA acetyltransferase (ACAT1) and malate dehydrogenase (MDH2) have not been reported with the roles on the formation of doxorubicin resistance in our knowledge. Further studies have used RNA interference and cell viability analysis to evidence the essential roles of ACAT1 and MDH2 on their potency in the formation of doxorubicin resistance through increased cell viability and decreased cell apoptosis during doxorubicin treatment. To sum up, our current mitochondrial proteomic approaches allowed us to identify numerous proteins, including ACAT1 and MDH2, involved in various drug-resistance-forming mechanisms. Our results provide potential diagnostic markers and therapeutic candidates for the treatment of doxorubicin-resistant uterine cancer.
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http://dx.doi.org/10.1111/jcmm.12388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395189PMC
April 2015

miRNome traits analysis on endothelial lineage cells discloses biomarker potential circulating microRNAs which affect progenitor activities.

BMC Genomics 2014 Sep 18;15:802. Epub 2014 Sep 18.

Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Background: Endothelial progenitor cells (EPCs) play a fundamental role in not only blood vessel development but also post-natal vascular repair. Currently EPCs are defined as early and late EPCs based on their biological properties and their time of appearance during in vitro culture. Both EPC types assist angiogenesis and have been linked to ischemia-related disorders, including coronary artery disease (CAD).

Results: We found late EPCs are more mobile than early EPCs and matured endothelial cells (ECs). To pinpoint the mechanism, microRNA profiles of early EPCs late EPCs, and ECs were deciphered by small RNA sequencing. Obtained signatures made up of both novel and known microRNAs, in which anti-angiogenic microRNAs such as miR-221 and miR-222 are more abundant in matured ECs than in late EPCs. Overexpression of miR-221 and miR-222 resulted in the reduction of genes involved in hypoxia response, metabolism, TGF-beta signalling, and cell motion. Not only hamper late EPC activities in vitro, both microRNAs (especially miR-222) also hindered in vivo vasculogenesis in a zebrafish model. Reporter assays showed that miR-222, but not miR-221, targets the angiogenic factor ETS1. In contrast, PIK3R1 is the target of miR-221, but not miR-222 in late EPCs. Clinically, both miR-221-PIK3R1 and miR-222-ETS1 pairs are deregulated in late EPCs of CAD patients.

Conclusions: Our results illustrate EPCs and ECs exploit unique miRNA modalities to regulate angiogenic features, and explain why late EPC levels and activities are reduced in CAD patients. These data will further help to develop new plasma biomarkers and therapeutic approaches for ischemia-related diseases or tumor angiogenesis.
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http://dx.doi.org/10.1186/1471-2164-15-802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176563PMC
September 2014

Deficiency of the microRNA-31-microRNA-720 pathway in the plasma and endothelial progenitor cells from patients with coronary artery disease.

Arterioscler Thromb Vasc Biol 2014 Apr 20;34(4):857-69. Epub 2014 Feb 20.

From the Institute of Microbiology and Immunology, School of Life Science (H.-W.W., T.-S.H., H.-H.L., K.-H.L., C.-F.T., Y.-C.C., Y.-L.C.), Cancer Research Center & Genome Research Center (H.-W.W.), School of Medicine (P.-H.H., C.-C.L.), and Cardiovascular Research Center (P.-H.H.), National Yang-Ming University, Taipei, Taiwan; Division of Cardiology, Department of Medicine (P.-H.H.) and Division of Nephrology, Department of Medicine (C.-C.L.), Taipei Veterans General Hospital, Taipei, Taiwan ; Department of Education and Research, Taipei City Hospital, Taipei, Taiwan (H.-W.W.); Department of Obstetrics and Gynecology, Hsin-Chu Mackay Memorial Hospital, Hsin Chu, Taiwan (S.-J.C., C.-H.T., C.-H.C.); and Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (T.-N.T., C.-C.C., S.-M.C.).

Objective: Defects in angiogenesis/vasculogenesis or vessel repair are major complications of coronary artery disease (CAD). Endothelial progenitor cells (EPCs) play a fundamental role in postnatal vascular repair and CAD. The role of microRNAs in CAD pathogenesis and their potential as biomarkers remain to be elucidated.

Approach And Results: MicroRNA-31 (miR-31) level in both the plasma and EPCs of patients with CAD is found lower. miR-31 regulates EPC activities by targeting FAT atypical cadherin 4 and thromboxane A2 receptor, which show increased expression in CAD EPCs. Overexpressing miR-31 in CAD EPCs rescued their angiogenic and vasculogenic abilities both in vitro and in vivo. When exploring approaches to restore endogenous miR-31, we found that far-infrared treatment enhanced the expression of not only miR-31, but also miR-720 in CAD EPCs. miR-720, which was also decreased in EPCs and the plasma of patients with CAD, stimulated EPC activity by targeting vasohibin 1. The miR720-vasohibin 1 pair was shown to be downstream of FAT atypical cadherin 4, but not of thromboxane A2 receptor. FAT atypical cadherin 4 inhibited miR-720 expression via repression of the planar cell polarity signaling gene four-jointed box 1 (FJX1), which was required for miR-720 expression through a hypoxia-inducible factor 1, α subunit-dependent mechanism. Restoring miR-720 level strengthened activity of CAD EPCs. The miR-31-miR-720 pathway is shown critical to EPC activation and that downregulation of this pathway contributes to CAD pathogenesis. Circulating levels of miR-31, miR-720, and vasohibin 1 have the potential to allow early diagnosis of CAD and to act as prognosis biomarkers for CAD and other EPC-related diseases.

Conclusions: Manipulating the expression of the miR-31-miR-720 pathway in malfunction EPCs should help develop novel therapeutic modalities.
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http://dx.doi.org/10.1161/ATVBAHA.113.303001DOI Listing
April 2014

Interleukin-27 and interleukin-12 augment activation of distinct cord blood natural killer cells responses via STAT3 pathways.

J Formos Med Assoc 2012 May 10;111(5):275-83. Epub 2012 Mar 10.

Department of Medical Research, Tao-Yuan General Hospital, Taoyuan, Taiwan.

Background/purpose: Umbilical cord blood is rich in primitive natural killer (NK) cells, which are activated by interleukin (IL)-12. It was previously reported that a novel IL-12 family cytokine, IL-27 comprised of EBI3 and p28, was elevated in maternal serum during normal pregnancy. Thus, we compared the immune regulatory functions of IL-27 and IL-12 on mononuclear cells derived from cord blood and adult peripheral blood.

Methods: After stimulation with IL-27, IL-12, and IL-27 combined with IL-12, the cytotoxicity against BJAB lymphoma cells by blood mononuclear cells was performed. Then immunofluorescence staining, reverse transcriptase-polymerase chain reaction and Western blotting were used to detect the effects of IL-27 and IL-12 in isolated NK cells.

Results: IL-27, IL-12, and IL-27 combined with IL-12 enhanced the cytotoxicity of adult peripheral blood cells and cord blood cells, but the proliferation of distinct subpopulations of cells was not evident. Similar results were also obtained with purified cord blood NK cells. Interestingly, distinct from IL-12, IL-27 could induce aggregation and morphological changes of umbilical cord blood cells. Finally, IL-27 combined with IL-12 could stimulate increased IL-27 receptor (gp130 and WSX-1) transcripts in purified cord blood NK cells. However, the activation of signal transducer and activator of transcription 3 (STAT3) in NK cells was only detected in the presence of IL-27, but not IL-12 alone.

Conclusion: From previous results, we summarize our current understanding of the augmentation of distinct regulation of NK cells by IL-27 and IL-12.
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http://dx.doi.org/10.1016/j.jfma.2010.10.002DOI Listing
May 2012

Human cytomegalovirus preferentially infects the neoplastic epithelium of colorectal cancer: a quantitative and histological analysis.

J Clin Virol 2012 Jul 15;54(3):240-4. Epub 2012 May 15.

Department of Medicine, National Yang-Ming University Hospital, Yilan, Taiwan.

Background: It has long been suggested that human cytomegalovirus (HCMV) might be involved in human oncogenesis. However, whether HCMV was associated with colorectal cancer (CRC) was still controversial.

Objective: To clarify whether HCMV specifically infects the tumorous tissue of CRC.

Study Design: Paired tumor and adjacent non-neoplastic CRC specimens were collected from 163 patients. HCMV DNA was detected and quantified through PCR and quantitative real-time PCR. Virus location was determined by in situ hybridization (ISH) of formalin-fixed paraffin-embedded tissue sections with an HCMV-specific probe.

Results: By PCR, HCMV DNA was detected in 42.3% (69/163) of the tumor specimens, while only 5.6%(14/163) samples of adjacent non-neoplastic tissue were positive for HCMV (p<0.0001). Quantitative real-time PCR in 54 sample pairs revealed significantly higher viral copies in the tumor specimens than the adjacent non-neoplastic tissue specimens (p<0.001). By ISH, the nucleic acids of HCMV were detected in the cytoplasm of neoplastic epithelium. No hybridization was detected in the inflammatory infiltrates, submucosa, or other stromal tissues.

Conclusions: HCMV preferentially infects the tumor epithelium of CRC. How the virus subsists in and interacts with the microenvironment of tumor epithelium of CRC should be studied.
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http://dx.doi.org/10.1016/j.jcv.2012.04.007DOI Listing
July 2012