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1.
Molecular heterogeneity unravelled by single-cell transcriptomics in patients with essential thrombocythaemia.
Hsu, CC, Chen, YJ, Huang, CE, Wu, YY, Wang, MC, Pei, SN, Liao, CK, Lu, CH, Chen, PT, Tsou, HY, et al
British journal of haematology. 2020;(5):707-722
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Abstract
Significant phenotypic heterogeneity exists in patients with all subtypes of myeloproliferative neoplasms (MPN), including essential thrombocythaemia (ET). Single-cell RNA sequencing (scRNA-Seq) holds the promise of unravelling the biology of MPN at an unprecedented level of resolution. Herein we employed this approach to dissect the transcriptomes in the CD34+ cells from the peripheral blood of seven previously untreated ET patients and one healthy adult. The mutational profiles in these patients were as follows: JAK2 V617F in two, CALR in three (one type I and two type II) and triple-negative (TN) in two. Our results reveal substantial heterogeneity within this enrolled cohort of patients. Activation of JAK/STAT signalling was recognized in discrepant progenitor lineages among different samples. Significantly disparate molecular profiling was identified in the comparison between ET patients and the control, between patients with different driver mutations (JAK2 V617F and CALR exon 9 indel), and even between patients harbouring the same driver. Intra-individual clonal diversity was also found in the CD34+ progenitor population of a patient, possibly indicating the presence of multiple clones in this case. Estimation of subpopulation size based on cellular immunophenotyping suggested differentiation bias in all analysed samples. Furthermore, combining the transcriptomic information with data from targeted sequencing enabled us to unravel key somatic mutations that are molecularly relevant. To conclude, we demonstrated that scRNA-Seq extended our knowledge of clonal diversity and inter-individual heterogeneity in patients with ET. The obtained information could potentially leapfrog our efforts in the elucidation of the pathogenesis of the disease.
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2.
Independent association between subjective cognitive decline and frailty in the elderly.
Hsieh, TJ, Chang, HY, Wu, IC, Chen, CC, Tsai, HJ, Chiu, YF, Chuang, SC, Hsiung, CA, Hsu, CC
PloS one. 2018;(8):e0201351
Abstract
BACKGROUND The relationship between subjective cognitive decline and frailty, two components of the so-called reversible cognitive frailty, in the elderly remains unclear. This study aims to elucidate whether this association exists, independent of confounding factors such as nutritional status, kidney function, inflammation, and insulin resistance. METHODS 2386 participants (≥ 65 years of age) selected from the Healthy Aging Longitudinal Study in Taiwan (HALST) study. Fried frailty phenotype was adopted to quantify frailty status. We classified cognitive status into two categories-subjective cognitive decline (SCD), and normal cognition-and used polytomous logistic regressions to investigate the associations between SCD and frailty. RESULTS There were 188 (7.88%), 1228 (51.47%), and 970 (40.65%) participants with frailty, pre-frailty, and robustness, respectively. Compared to those with normal cognition, elders with SCD were more likely to have pre-frailty (odds ratio [OR]: 1.36, 95% confidence interval [CI]: 1.10-1.67, p = 0.004) or frailty (OR: 1.78, 95% CI: 1.23-2.58, p = 0.002) after adjusting for age, gender, education level, comorbidity, nutritional status, kidney function, and biochemical-related factors. CONCLUSIONS A significant association between subjective cognitive decline and frailty was revealed in this study. Subjective cognitive decline was positively associated with pre-frailty or frailty even after adjusting for potential confounding factors. Our results can provide useful references in understanding mechanisms and developing suitable preventive strategies for the elderly with reversible cognitive frailty.
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Intake of Phthalate-tainted Foods and Serum Thyroid Hormones in Taiwanese Children and Adolescents.
Tsai, HJ, Wu, CF, Tsai, YC, Huang, PC, Chen, ML, Wang, SL, Chen, BH, Chen, CC, Wu, WC, Hsu, PS, et al
Scientific reports. 2016;:30589
Abstract
On April-May, 2011, phthalates, mainly Di-(2-ethylhexyl) phthalate (DEHP), were deliberately added to a variety of foodstuff as a substitute emulsifier in Taiwan. This study investigated the relationship between DEHP-tainted foodstuffs exposure and thyroid function in possibly affected children and adolescents. Two hundred fifty participants <18 years possibly exposed to DEHP were enrolled in this study between August 2012 and January 2013. Questionnaires were used to collect details on their past exposure to DEHP-tainted food items. Blood and urine samples were collected for biochemical workups to measure current exposure derived from three urinary DEHP metabolites using a creatinine excretion-based model. More than half of 250 participants were estimated to be exposed to DEHP-tainted foods found to exceed the recommend tolerable daily intake of DEHP established by the European Food Safety Authority (<50 μg/kg/day). The median daily DEHP intake (DDI) among those 250 participants was 46.52 μg/kg/day after multiple imputation. This value was ~10-fold higher than the current median DEHP intake (4.46 μg/kg/day, n = 240). Neither past nor current DEHP exposure intensity was significantly associated with serum thyroid profiles. Future studies may want to follow the long-term health effects of this food scandal in affected children and adolescents.
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Serum free indoxyl sulfate associated with in-stent restenosis after coronary artery stentings.
Tsai, ML, Hsieh, IC, Hung, CC, Chen, CC
Cardiovascular toxicology. 2015;(1):52-60
Abstract
Uremic toxins, including P-cresyl sulfate (PCS) and indoxyl sulfate (IS), have been found to participate in the process of atherosclerosis and patient mortality. We aim to discover if uremic toxins are related to in-stent restenosis in patients with coronary artery disease after stent implantation. We enrolled 214 patients who received coronary angioplasty with stenting and follow-up angiography between November 1995 and June 2011 with a total of 293 lesions divided into bare metal stent (BMS) or drug-eluting stent (DES) groups. Patients' basic information and total and free form IS and PCS were used to correlate with the late loss (LL) and loss index (LI). Significantly higher LL and LI in the BMS group compared with the DES group (1.10 vs. 0.45 mm, p < 0.001, and 0.46 vs. 0.19, p < 0.001, respectively). The unadjusted correlation revealed a positive relationship between log-normalized free IS and LL, LI in the DES group (p = 0.001). After adjustment for multiple variables, the log-normalized free IS still presented as an independent predictor for the LL and LI (p = 0.012 and p = 0.031). Free IS is an independent predictor for coronary restenosis in patients receiving DES implantations. However, among patients undergoing BMS stentings, uremic toxin is not a predictor of the intracoronary restenosis.
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A putative novel protein, DEPDC1B, is overexpressed in oral cancer patients, and enhanced anchorage-independent growth in oral cancer cells that is mediated by Rac1 and ERK.
Su, YF, Liang, CY, Huang, CY, Peng, CY, Chen, CC, Lin, MC, Lin, RK, Lin, WW, Chou, MY, Liao, PH, et al
Journal of biomedical science. 2014;(1):67
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Abstract
BACKGROUND The DEP domain is a globular domain containing approximately 90 amino acids, which was first discovered in 3 proteins: Drosophila disheveled, Caenorhabditis elegans EGL-10, and mammalian Pleckstrin; hence the term, DEP. DEPDC1B is categorized as a potential Rho GTPase-activating protein. The function of the DEP domain in signal transduction pathways is not fully understood. The DEPDC1B protein exhibits the characteristic features of a signaling protein, and contains 2 conserved domains (DEP and RhoGAP) that are involved in Rho GTPase signaling. Small GTPases, such as Rac, CDC42, and Rho, regulate a multitude of cell events, including cell motility, growth, differentiation, cytoskeletal reorganization and cell cycle progression. RESULTS In this study, we found that it was a guanine nucleotide exchange factor and induced both cell migration in a cultured embryonic fibroblast cell line and cell invasion in cancer cell lines; moreover, it was observed to promote anchorage-independent growth in oral cancer cells. We also demonstrated that DEPDC1B plays a role in regulating Rac1 translocated onto cell membranes, suggesting that DEPDC1B exerts a biological function by regulating Rac1. We examined oral cancer tissue; 6 out of 7 oral cancer tissue test samples overexpressed DEPDC1B proteins, compared with normal adjacent tissue. CONCLUSIONS DEPDC1B was a guanine nucleotide exchange factor and induced both cell migration in a cultured embryonic fibroblast cell line and cell invasion in cancer cell lines; moreover, it was observed to promote anchorage-independent growth in oral cancer cells. We also demonstrated that DEPDC1B exerts a biological function by regulating Rac1. We found that oral cancer samples overexpressed DEPDC1B proteins, compared with normal adjacent tissue. Suggest that DEPDC1B plays a role in the development of oral cancer. We revealed that proliferation was linked to a novel DEPDC1B-Rac1-ERK1/2 signaling axis in oral cancer cell lines.
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Translational predictive biomarker analysis of the phase 1b sorafenib and bevacizumab study expansion cohort.
Azad, N, Yu, M, Davidson, B, Choyke, P, Chen, CC, Wood, BJ, Venkatesan, A, Henning, R, Calvo, K, Minasian, L, et al
Molecular & cellular proteomics : MCP. 2013;(6):1621-31
Abstract
Predictive biomarkers are needed to triage patients to the best therapy. We prospectively planned examination of sequential blood, biopsy, and functional imaging with which to confirm the mechanism and to identify potential predictive biomarkers in a phase Ib clinical trial expansion of patients with solid tumors receiving sorafenib/bevacizumab. The maximally tolerated doses of sorafenib at 200 mg twice daily with bevacizumab at 5 mg/kg every other week were given to biopsiable patients. Patients were randomized to receive either sorafenib or bevacizumab monotherapy for the first 28-day cycle with the second drug added with cycle 2. Biopsies, dynamic contrast-enhanced MRI, and fluorodeoxyglucose-proton emission tomography were done pre-therapy and at 2 and 6 weeks (2 weeks into combination therapy). Tumor and serum proteomics, Ras/Raf mutational analysis, and functional imaging results were examined individually and across the dataset to identify potential changes predictive of response to therapy and those that confirm the biochemical drug mechanism(s). Therapy with sorafenib/bevacizumab resulted in clinical benefit in 45% of this mixed solid tumor group. ERK activation and microvessel density were decreased with monotherapy treatment with sorafenib or bevacizumab, respectively; whereas a decreased signal over the group of total AKT, phospho(p)-VEGF receptor2, p-endothelial nitric-oxide synthase, b-RAF, and cleaved poly(ADP-ribose) polymerase was associated with earlier progression of disease. Tumor metabolic activity decreased in those patients with clinical benefits lasting longer than 4 months, and activity increased with progression of disease. Cleavage of caspase 3 and poly(ADP-ribose) polymerase was increased, and Ki67 expression decreased in patients with prolonged clinical benefits, consistent with decreased proliferation and increased apoptosis. The conglomerate analysis, incorporating pharmacodynamic and tumor biochemistry, demonstrated sorafenib/bevacizumab-targeted vascular activity in the tumor. Results suggest potential biomarkers for which changes, as a group, during early therapeutic exposure may predict clinical benefit.
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Cerebrolysin enhances cognitive recovery of mild traumatic brain injury patients: double-blind, placebo-controlled, randomized study.
Chen, CC, Wei, ST, Tsaia, SC, Chen, XX, Cho, DY
British journal of neurosurgery. 2013;(6):803-7
Abstract
In adults, mild traumatic brain injury (MTBI) frequently results in impairments of cognitive functions which would lead to psychological consequences in the future. Cerebrolysin is a nootropic drug, and can significantly improve cognitive function in patients with Alzheimer's disease and stroke. The purpose of this study was to investigate how Cerebrolysin therapy enhances cognitive recovery for mild traumatic brain injury patients using a double-blinded, placebo-controlled, randomized phase II pilot study. Patients having head injury within 24 h sent to our hospital were screened and recruited if patients were alert and conscious, and had intracranial contusion haemorrhage. From July 2009 to June 2010, totally, thirty-two patients were recruited in the double-blinded, placebo-controlled, and randomized study. Patients were randomized to receive Cerebrolysin (Group A, once daily intravenous infusion of 30 mL Cerebrolysin over a 60-min period for 5 days) or placebo (Group B, same dosage and administration of normal saline as Group A). The primary outcome measures were differences of cognitive function including Mini-Mental Status Examination (MMSE), and Cognitive Abilities Screening Instrument (CASI) scores between baseline and week 1, between baseline and week 4, and between baseline and week 12. Thirty-two patients completed the trial. For Group A, the CASI score difference between baseline and week 12 was 21.0 ± 20.4, a significantly greater change than that of Group B (7.6 ± 12.1) (p = 0.0461). Besides, drawing function (one of the domains of CASI; p = 0.0066) on week 4 and both drawing function (p = 0.0472) and long-term memory (one of the domains of CASI; p = 0.0256) on week 12 were also found to be significantly improved in the patients receiving Cerebrolysin treatment. Our results suggest that Cerebrolysin improves the cognitive function of the MTBI in patients at 3rd month after injury, especially for long-term memory and drawing function.
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Decreased blood lead levels after calcitriol treatment in hemodialysis patients with secondary hyperparathyroidism.
Lu, KC, Wu, CC, Ma, WY, Chen, CC, Wu, HC, Chu, P
Bone. 2011;(6):1306-10
Abstract
OBJECTIVE Secondary hyperparathyroidism (SHP) is characterized by high bone turnover, which may, in turn, result in increased release of lead from bone stores. This study investigated the effects of intravenous calcitriol on blood lead (BL) levels in patients with SHP. METHODS Intravenous calcitriol therapy was administered for 16 wk to 28 patients who were on maintenance hemodialysis (HD) and had intact parathyroid hormone (iPTH) plasma levels of >300 pg/mL. Blood was drawn at baseline and every 4 wk for 16 wk to determine the levels of iPTH; bone remodeling markers, including bone-specific alkaline phosphatase (bAP) and type 5b tartrate-resistant acid phosphatase (TRAP); and BL. RESULTS Of the 28 patients, 25 responded to calcitriol therapy; they exhibited significant decrements in serum iPTH levels by the end of 4 wk of therapy and thereafter. After 16 wk of therapy, these patients had significant reductions in serum iPTH levels (p<0.01) and significant and parallel decreases in the levels of bAP (p<0.01), TRAP (p<0.01), and BL (p<0.01). Further analysis showed a significant positive correlation between the levels of BL and serum iPTH (r=0.34, p<0.01) and BL and serum TRAP (r=0.22, p<0.05). However, there was no significant correlation between the levels of BL and serum bAP. CONCLUSION Elevated levels of BL and serum bone remodeling markers, which are common features of SHP, can be effectively suppressed by calcitriol therapy. This indicates that hyperparathyroidism not only accelerates bone remodeling but may also enhance bone lead mobilization in patients on maintenance HD.
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Final analysis of a phase II trial using sorafenib for metastatic castration-resistant prostate cancer.
Aragon-Ching, JB, Jain, L, Gulley, JL, Arlen, PM, Wright, JJ, Steinberg, SM, Draper, D, Venitz, J, Jones, E, Chen, CC, et al
BJU international. 2009;(12):1636-40
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Abstract
OBJECTIVE To determine if sorafenib is associated with an improved 4-month probability of progression-free survival, using radiographic and clinical criteria alone, in patients with metastatic castration-resistant prostate cancer. Secondary endpoints included pharmacokinetics, toxicity analysis and overall survival. PATIENTS AND METHODS The study was an open-label, phase II, two-stage design, focusing on the results from the second stage, as criteria for progression were modified after completing the first stage. Sorafenib was given at a dose of 400 mg orally twice daily in 28-day cycles. Clinical and laboratory assessments were done every 4 weeks, and radiographic scans were obtained every 8 weeks. RESULTS Twenty-four patients were accrued in the second stage; the median (range) age was 66 (49-85) years, the on-study prostate-specific antigen level was 68.45 (5.8-995) ng/mL, the Gleason score 8 (6-9) and Eastern Cooperative Oncology Group status 1 (in 17 patients). Of the 24 patients, 21 had previous chemotherapy with docetaxel. All patients had bony metastases, either alone (in 11) or with soft-tissue disease (in 13). One patient had a partial response; 10 patients had stable disease (median duration 18 weeks, range 15-48). At a median potential follow-up of 27.2 months, the median progression-free survival was 3.7 months and the median overall survival was 18.0 months. For the whole trial of 46 patients the median survival was 18.3 months. Most frequent toxicities included hand-foot skin reaction (grade 2 in nine patients, grade 3 in three), rash, abnormalities in liver function tests, and fatigue. CONCLUSIONS Sorafenib has moderate activity as a second-line treatment for metastatic castration-resistant prostate cancer.
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Montelukast as monotherapy in children with mild persistent asthma.
Wu, WF, Wu, JR, Dai, ZK, Tsai, CW, Tsai, TC, Chen, CC, Yang, CY
Asian Pacific journal of allergy and immunology. 2009;(4):173-80
Abstract
The cysteinyl leukotrienes cause bronchoconstriction, increased mucus production and airway inflammation, three major features of asthma. Several randomized controlled trials have shown the efficacy of leukotriene receptor antagonists for improving asthma outcomes. The drug is favored for treating childhood asthma, where poor compliance with inhalation therapy is a therapeutic challenge. To assess the effectiveness of Montelukast in asthmatic children under real-life conditions, a prospective, single-arm, multicenter, open-label observational study was performed on asthmatic children 2- to 14-years-old with a history of physician-diagnosed mild persistent asthma. Montelukast was given once daily for 12 consecutive weeks. By the end a significant improvement of the daytime asthma symptom score, nighttime asthma score, peak expiratory flow rate (PEFR) and mean score of the investigators' global evaluation was noted (p < 0.05). These results suggest that montelukast is an effective monotherapy controller in children with mild persistent asthma.