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693
result(s) for
"Cheng, Wei-Chung"
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Picky comprehensively detects high-resolution structural variants in nanopore long reads
Acquired genomic structural variants (SVs) are major hallmarks of cancer genomes, but they are challenging to reconstruct from short-read sequencing data. Here we exploited the long reads of the nanopore platform using our customized pipeline, Picky (https://github.com/TheJacksonLaboratory/Picky), to reveal SVs of diverse architecture in a breast cancer model. We identified the full spectrum of SVs with superior specificity and sensitivity relative to short-read analyses, and uncovered repetitive DNA as the major source of variation. Examination of genome-wide breakpoints at nucleotide resolution uncovered micro-insertions as the common structural features associated with SVs. Breakpoint density across the genome is associated with the propensity for interchromosomal connectivity and was found to be enriched in promoters and transcribed regions of the genome. Furthermore, we observed an over-representation of reciprocal translocations from chromosomal double-crossovers through phased SVs. We demonstrate that Picky analysis is an effective tool for comprehensive detection of SVs in cancer genomes from long-read data.
Journal Article
Ultrafast laser ablation of copper by GHz bursts
The ablation of copper, using a 10 GHz burst ultrafast laser with a wavelength of 1030 nm, a pulse duration of 1 ps, a variable total laser fluence, and a number of sub-pulses per burst, is investigated theoretically. A two-temperature model with an extended Lorentz–Drude model for dynamic optical properties is used to simulate the melting and ablation process. Due to the heat accumulation from the preceding pulses, multipulse laser ablation could be advantageous over a single pulse. Moreover, the ablation performance can be maximized by properly selecting the pulse number, separation time, and energy in a laser burst. The numerical result shows that the present prediction is in fairly agreement with existing experimental result. Under the same total laser fluence of 32 J/cm
2
, a 10 GHz burst laser with an optimized 128 sub-pulse can significantly enhance the ablation depth, 4.2 times that a single pulse does. It is found that the optimized ablation depth is a linear function of the total fluence of ultrafast laser bursts.
Journal Article
The prevalence and incidence of systemic lupus erythematosus in Taiwan: a nationwide population-based study
To estimate the prevalence and incidence rate of systemic lupus erythematosus (SLE) in Taiwan by using a population-based longitudinal database from 2001 to 2011. We conducted a longitudinal Health Insurance Database (LHID) containing 1,000,000 beneficiaries’ records for calculation of prevalence and incidence rate of SLE from 2001–2011. The overall prevalence of SLE in Taiwan in 2011 is 8.11 per 10,000 people with 14.3 per 10,000 people in female and 1.62 per 10,000 people in male. The overall incidence rate of SLE is 0.74–1 per 10,000 person-years with 1.09–1.76 per 10,000 person-years in female and 0.12–0.25 per 10,000 person-years in male. The highest prevalence rate was observed at 40–49 age group in females. There were no significant differences in the overall prevalence among the urban, suburban and rural area in Taiwan while the relative risk is higher in male population living in rural area (RR 1.36, 95% C.I. 1.03–1.79,
p
= 0.0303). The highest income group has a lower relative risk for the prevalence of SLE (RR 0.83, 95% C.I. 0.71–0.97,
p
= 0.0197). The incidence rate of SLE in male in the rural area is also higher than the urban area (RR 2.34, 95% C.I. 1.3–4.22,
p
= 0.0046). Our study covers the longest period among the nation-wide population studies of SLE in Taiwan. The prevalence was increasing especially in the elderly.
Journal Article
Corylin protects LPS-induced sepsis and attenuates LPS-induced inflammatory response
Corylin is a main compound isolated from
Psoralea corylifolia
L. (Fabaceae). A variety of pharmacological effects such as antioxidant, anti-proliferation, and anti-inflammatory properties of corylin have been reported. Nevertheless, the effect of corylin in microbial infection and sepsis remains unclear. In the present study, we investigated the anti-inflammatory effects of corylin. Our experimental results demonstrated that corylin inhibited the production of TNF-α, IL-6 and NO by both LPS-activated RAW 264.7 cells and LPS-activated murine peritoneal macrophages. Moreover, corylin suppressed the expression levels of iNOS and COX-2, reduced the production of PGE
2
and HMGB1, blocked the translocation of HMGB1 from the nucleus to cytosol, and decreased the phosphorylation of MAPKs in LPS-activated RAW 264.7 cells as well as suppressed the activity of NF-κB in LPS-activated J-Blue cells. In addition, the administration of corylin reduced the production of NO and TNF-α, decreased LPS-induced liver damage markers (AST and ALT) and kidney damage markers (BUN and CRE), attenuated infiltration of inflammatory cells and tissue damage of lung, liver and kidney, and enhanced the survival rate of LPS-challenged mice. Taken together, these results show the anti-inflammatory properties of corylin on LPS-induced inflammation and sepsis. Corylin could potentially be a novel anti-inflammatory and immunosuppressive drug candidate in the treatment of sepsis and septic shock.
Journal Article
Efficacy and safety of brodalumab, an anti-IL17RA monoclonal antibody, in patients with axial spondyloarthritis: 16-week results from a randomised, placebo-controlled, phase 3 trial
ObjectiveTo investigate the efficacy and safety of brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, in patients with axial spondyloarthritis (axSpA).MethodsIn a multicentre, placebo-controlled phase 3 study (NCT02985983) conducted at 48 sites across Japan, Korea and Taiwan, patients with axSpA were randomised 1:1 to receive subcutaneous brodalumab 210 mg (n=80) or placebo (n=79) at baseline, weeks 1 and 2 and every 2 weeks thereafter, during the 16-week double-blind period. The primary endpoint was the proportion of patients with Assessment of SpondyloArthritis International Society (ASAS) 40 response at week 16. Secondary endpoints included the proportion of patients with ASAS 20 response and change in Ankylosing Spondylitis Disease Activity Score using C-reactive protein (ASDAS-CRP) at week 16 and safety.ResultsASAS 40 response rate (n/N; 95% CI) was 43.8% (35/80; 32.7, 55.3) with brodalumab vs 24.1% (19/79; 15.1, 35.0) with placebo (rate difference, 19.7% (5.3, 34.1); p=0.018 by stratified Cochran-Mantel-Haenszel test). ASAS 20 response rate (n/N; 95% CI) was 67.5% (54/80; 56.1, 77.6) vs 41.8% (33/79; 30.8, 53.4) and least squares mean change (95% CI) from baseline (brodalumab, 2.660; placebo, 2.716) in ASDAS-CRP was –1.127 (–1.322, –0.931) with brodalumab vs –0.672 (–0.872, –0.473) with placebo at week 16. Treatment-emergent adverse events were reported in 44 (55%) and 45 (57%) patients in the brodalumab and placebo groups, respectively.ConclusionBrodalumab demonstrated a significant improvement at week 16 in patients with active axSpA. Safety of brodalumab was consistent with that reported in previous global/Japanese psoriasis studies.
Journal Article
AICAR Induces Apoptosis and Inhibits Migration and Invasion in Prostate Cancer Cells Through an AMPK/mTOR-Dependent Pathway
Current clinical challenges of prostate cancer management are to restrict tumor growth and prohibit metastasis. AICAR (5-aminoimidazole-4-carbox-amide-1-β-d-ribofuranoside), an AMP-activated protein kinase (AMPK) agonist, has demonstrated antitumor activities for several types of cancers. However, the activity of AICAR on the cell growth and metastasis of prostate cancer has not been extensively studied. Herein we examine the effects of AICAR on the cell growth and metastasis of prostate cancer cells. Cell growth was performed by MTT assay and soft agar assay; cell apoptosis was examined by Annexin V/propidium iodide (PI) staining and poly ADP ribose polymerase (PARP) cleavage western blot, while cell migration and invasion were evaluated by wound-healing assay and transwell assay respectively. Epithelial–mesenchymal transition (EMT)-related protein expression and AMPK/mTOR-dependent signaling axis were analyzed by western blot. In addition, we also tested the effect of AICAR on the chemosensitivity to docetaxel using MTT assay. Our results indicated that AICAR inhibits cell growth in prostate cancer cells, but not in non-cancerous prostate cells. In addition, our results demonstrated that AICAR induces apoptosis, attenuates transforming growth factor (TGF)-β-induced cell migration, invasion and EMT-related protein expression, and enhances the chemosensitivity to docetaxel in prostate cancer cells through regulating the AMPK/mTOR-dependent pathway. These findings support AICAR as a potential therapeutic agent for the treatment of prostate cancer.
Journal Article
Metformin use and the risk of bacterial pneumonia in patients with type 2 diabetes
Persons with type 2 diabetes (T2D) have neutrophil dysfunction with a higher risk of infection than those without diabetes. We conducted this study aiming to compare the risk of pneumonia between metformin use and nonuse in persons with T2D. We identified 49,012 propensity score-matched metformin users and nonusers from Taiwan’s National Health Insurance Research Database between January 1, 2000, and December 31, 2017. We used the Cox proportional hazards model to compare the risks of pneumonia and respiratory death. The mean (SD) age of the participants was 57.46 (12.88) years, and the mean follow-up time for metformin users and nonusers was 5.47 (3.71) years and 5.15 (3.87) years, respectively. Compared with the nonuse of metformin, the adjusted hazard ratios (95% CI) for metformin use in bacterial pneumonia, invasive mechanical ventilation, and respiratory cause of death were 0.89 (0.84–0.94), 0.77 (0.73–0.82), and 0.64 (0.56–0.74), respectively. A longer cumulative duration of metformin use had further lower adjusted hazard ratios in these risks compared with nonuse. In patients with T2D, metformin use was associated with significantly lower risks of bacterial pneumonia, invasive mechanical ventilation, and respiratory cause of death; moreover, longer metformin use duration was associated with lower hazard ratios of these risks.
Journal Article
Your height affects your health: genetic determinants and health-related outcomes in Taiwan
Background
Height is an important anthropometric measurement and is associated with many health-related outcomes. Genome-wide association studies (GWASs) have identified hundreds of genetic loci associated with height, mainly in individuals of European ancestry.
Methods
We performed genome-wide association analyses and replicated previously reported GWAS-determined single nucleotide polymorphisms (SNPs) in the Taiwanese Han population (Taiwan Biobank;
n
= 67,452). A genetic instrument composed of 251 SNPs was selected from our GWAS, based on height and replication results as the best-fit polygenic risk score (PRS), in accordance with the clumping and
p
-value threshold method. We also examined the association between genetically determined height (PRS
251
) and measured height (phenotype). We performed observational (phenotype) and genetic PRS
251
association analyses of height and health-related outcomes.
Results
GWAS identified 6843 SNPs in 89 genomic regions with genome-wide significance, including 18 novel loci. These were the most strongly associated genetic loci (
EFEMP1
,
DIS3L2
,
ZBTB38
,
LCORL
,
HMGA1
,
CS
, and
GDF5
) previously reported to play a role in height. There was a positive association between PRS
251
and measured height (
p
< 0.001). Of the 14 traits and 49 diseases analyzed, we observed significant associations of measured and genetically determined height with only eight traits (
p
< 0.05/[14 + 49]). Height was positively associated with body weight, waist circumference, and hip circumference but negatively associated with body mass index, waist-hip ratio, body fat, total cholesterol, and low-density lipoprotein cholesterol (
p
< 0.05/[14 + 49]).
Conclusions
This study contributes to the understanding of the genetic features of height and health-related outcomes in individuals of Han Chinese ancestry in Taiwan.
Journal Article
Preclinical evaluation of exemestane as a novel chemotherapy for gastric cancer
CYP19A1/aromatase (Ar) is a prognostic biomarker of gastric cancer (GCa). Ar is a critical enzyme for converting androstenedione to oestradiol in the steroidogenesis cascade. For decades, Ar has been targeted with Ar inhibitors (ARIs) in gynaecologic malignancies; however, it is unexplored in GCa. A single‐cohort tissue microarray examination was conducted to study the association between Ar expression and disease outcome in Asian patients with GCa. The results revealed that Ar was a prognostic promoter. Bioinformatics analyses conducted on a Caucasian‐based cDNA microarray databank showed Ar to be positively associated with GCa prognosis for multiple clinical modalities, including surgery, 5‐Fluorouracil (5‐FU) for adjuvant chemotherapy, or HER2 positivity. These findings imply that targeting Ar expression exhibits a potential for fulfilling unmet medical needs. Hence, Ar‐targeting compounds were tested, and the results showed that exemestane exhibited superior cancer‐suppressing efficacy to other ARIs. In addition, exemestane down‐regulated Ar expression. Ablating Ar abundance with short hairpin (sh)Ar could also suppress GCa cell growth, and adding 5‐FU could facilitate this effect. Notably, adding oestradiol could not prevent exemestane or shAr effects, implicating a nonenzymatic mechanism of Ar in cancer growth. Regarding translational research, treatment with exemestane alone exhibited tumour suppression efficacy in a dose‐dependent manner. Combining subminimal doses of 5‐FU and exemestane exerted an excellent tumour suppression effect without influencing bodyweight. This study validated the therapeutic potentials of exemestane in GCa. Combination of metronomic 5‐FU and exemestane for GCa therapy is recommended.
Journal Article