Graduate Institute of Clinical Medicine

Medicine, Taiwan

Graduate Institute of Clinical Medicine

Medicine, Taiwan
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Lee W.-H.,Taipei Medical University | Liu H.E.,Graduate Institute of Clinical Medicine | Chang J.-Y.,National Health Research Institute | Liou J.-P.,Taipei Medical University | Huang H.-M.,Taipei Medical University
Pharmacology | Year: 2013

The polymerization of tubulin molecules forms microtubules which are considered an attractive target for cancer treatment. Herein, we synthesized a new tubulin inhibitor, MPT0B169 (2-dimethylamino-N-[1-(4-methoxy- benzenesulfonyl)-2, 3-dihydro-1H-indol-7-yl]-acetamide) and demonstrated its action in leukemia cell lines HL60 and NB4 and lymphoma cell line U937. We found that MPT0B169 prevented tubulin assembly by binding the colchicine-binding site of tubulin in vitro. MPT0B169 also induced tubulin depolymerization in vivo. MPT0B169 inhibited the growth of HL60, NB4, and U937 cells in dose- and time-dependent manners. It also inhibited the growth of paclitaxel-resistant cancer cells. In addition, MPT0B169 caused G2/M cell cycle arrest in nonresistant and paclitaxel-resistant cancer cells, with a concomitant increase in cyclin B1 levels and cyclin-dependent kinase 1 (CDK1) phosphorylation. These results suggest that MPT0B169, a tubulin inhibitor, inhibits cell growth and induces G2/M cell cycle arrest of cancer cells through the disruption of tubulin polymerization. Copyright © 2013 S. Karger AG, Basel.


Chen C.-Y.,University of California at San Francisco | Chen C.-Y.,National Taiwan University Hospital | Chen C.-Y.,National Taiwan University | Chen C.-Y.,Graduate Institute of Clinical Medicine | And 4 more authors.
Developmental Neuroscience | Year: 2013

Traumatic brain injury in children commonly involves the frontal lobes and is associated with distinct structural and behavioral changes. Despite the clinical significance of injuries localized to this region during brain development, the mechanisms underlying secondary damage and long-term recovery are poorly understood. Here, we have characterized the first model of unilateral focal traumatic injury to the developing frontal lobe. Male C57Bl/6J mice at postnatal day (p)21, an age approximating a toddler-aged child, received a controlled cortical impact or sham surgery to the left frontal lobe and were euthanized 1 or 7 days later. A necrotic cavity and local inflammatory response were largely confined to the unilateral frontal lobe, dorsal corpus callosum and striatum anterior to the bregma. While cell death and accumulated β-amyloid precursor protein were characteristic features of the pericontusional motor cortex, corpus callosum, cingulum and dorsal striatum, underlying structures including the hippocampus showed no overt pathology. To determine the long-term functional consequences of injury at p21, two additional cohorts were subjected to a battery of behavioral tests in adolescence (p35-45) or adulthood (p70-80). In both cohorts, brain-injured mice showed normal levels of anxiety, sociability, spatial learning and memory. The signature phenotypic features were deficits in motor function and motor learning, coincident with a reduction in ipsilateral cortical brain volumes. Together, these findings demonstrate classic morphological features of a focal traumatic injury, including early cell death and axonal injury, and long-term volumetric loss of cortical volumes. The presence of deficits in sensorimotor function and coordination in the absence of abnormal findings related to anxiety, sociability and memory likely reflects several variables, including the unique location of the injury and the emergence of favorable compensatory mechanisms during subsequent brain development. © 2013 S. Karger AG, Basel.


Lin C.-L.,Taipei City Hospital | Lin C.-L.,National Chengchi University | Kao J.-H.,National Taiwan University Hospital | Kao J.-H.,Graduate Institute of Clinical Medicine
Journal of Gastroenterology and Hepatology (Australia) | Year: 2011

Outcomes of chronic hepatitis B virus (HBV) infection are heterogeneous. Estimates of annual incidence of cirrhosis and hepatocellular carcinoma (HCC) are 2-10% and 1-3%, respectively. Several viral factors, including HBV genotype, viral load and specific viral mutations, have been associated with disease progression. Among these, HBV genotype is not only predictive of clinical outcomes but has also been associated with response to interferon treatment. Currently, at least 10 HBV genotypes and several subtypes have been identified; they have distinct geographic distribution. Acute infection with genotypes A and D results in higher rates of chronicity than genotypes B and C. Compared to genotype A and B cases, patients with genotypes C and D have lower rates of spontaneous hepatitis B e antigen (HBeAg) seroconversion; when this occurs, it tends to be delayed. HBV genotype C has a higher frequency of basal core promoter (BCP) A1762T/G1764A mutation, pre-S deletion and is associated with higher viral load than genotype B. Similarly, genotype D has a higher prevalence of BCP A1762T/G1764A mutation than genotype A. These observations suggest important pathogenic differences between HBV genotypes. These may contribute to more severe liver disease, including cirrhosis and HCC with genotypes C and D HBV infection. In addition, genotype A and B patients have better responses to interferon-based therapy than genotypes C and D, but there are few consistent differences for direct HBV antivirals. In conclusion, genotyping of chronic HBV infections can help practicing physicians identify those at risk of disease progression and determine optimal anti-viral therapy. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.


Yeh Y.-C.,National Taiwan University Hospital | Ko W.-J.,Graduate Institute of Clinical Medicine | Chan W.-S.,National Taiwan University | Tsai J.-C.,Far Eastern Memorial Hospital | Lin T.-Y.,Far Eastern Memorial Hospital
Anesthesia and Analgesia | Year: 2012

BACKGROUND:: Anesthesia can become inadequate inadvertently or by misjudgment during surgery or emergence, and the surgical stress and pain stimulation will increase without adequate treatment. Overt stimulation may activate the sympathetic nervous system, increase the blood level of catecholamines, and lead to splanchnic arterial vasoconstriction. METHODS:: We divided 30 male Wistar rats into the following 3 groups: control, surgical stress and pain (SSP), and surgical stress and pain + dexmedetomidine (SSP + Dex). The rats received midline laparotomy to exteriorize a segment of terminal ileum for microcirculation examination by a full-field laser perfusion imager and sidestream dark-field video microscope on mucosa, muscle, and Peyer patch. The inspired concentration of isoflurane was decreased from 1.2% to 0.7% in SSP and SSP + Dex groups. In the SSP + Dex group, the rats received an initial loading dose of dexmedetomidine (0.5 μg/kg) and a maintenance infusion (0.5 μg • kg • h). RESULTS:: Dexmedetomidine prevented surgical stress and pain-related tachycardia and hypertension, and it attenuated the reduction of the microcirculatory blood flow intensity in intestinal mucosa (1100 ± 185 perfusion units [PU] vs 800 ± 105 PU, P = 0.001) and muscle (993 ± 208 PU vs 713 ± 92 PU, P < 0.001). Dexmedetomidine restored perfused small vessel density in intestinal mucosa and muscle. CONCLUSIONS:: We established a promising rat model to investigate the effect of surgical stress and pain stimulation on the intestinal microcirculation during light anesthesia. Using this rat model, we found that dexmedetomidine can normalize global hemodynamics and prevent the alteration of intestinal microcirculation. Copyright © 2012 International Anesthesia Research Society.


Kao J.-H.,Graduate Institute of Clinical Medicine | Kao J.-H.,National Taiwan University Hospital
Korean Journal of Internal Medicine | Year: 2011

Although safe and effective vaccines for hepatitis B virus (HBV) have been available for nearly three decades, this virus kills at least 600,000 people annually worldwide and remains the leading global cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Because the HBV reverse transcriptase lacks a proofreading function, many HBV genotypes, subgenotypes, mutants, and recombinants exist. At least 10 HBV genotypes (HBV-A through J) with distinct geographic distributions have been identified; by definition, their complete genomic sequences diverge by more than 8%. HBV genotype is increasingly becoming recognized as an important factor in the progression and clinical outcome of HBV- induced disease. Infections by HBV-C or -D are significantly more likely to lead to cirrhosis and hepatocellular carcinoma than are infections by HBV-A or -B. Additionally, the hepatitis B e antigen seroconversion response to standard or pegylated interferon is more favorable in patients with HBV-A or -B than in those with HBV-C or -D. However, therapeutic responses to nucleos(t)ide analogues are generally comparable among HBV genotypes. In conclusion, genotyping of HBV is useful in identifying chronic hepatitis B patients who are at increased risk of disease progression, thereby enabling physicians to optimize antiviral therapy for these patients. © 2011 The Korean Association of Internal Medicine.


Hung M.-H.,Graduate Institute of Clinical Medicine | Chen J.-S.,National Taiwan University Hospital
Journal of Thoracic Disease | Year: 2014

In the recent decade, nonintubated-intubated video-assisted thoracoscopic surgery (VATS) has been extensively performed and evaluated. The indicated surgical procedures and suitable patient groups are steadily increasing. Perioperative anesthetic management presents itself as a fresh issue for the iatrogenic open pneumothorax, which is intended for unilateral lung collapse to create a steady surgical field, and the ensuing physiologic derangement involving ventilatory and hemodynamic perspectives. With appropriate monitoring, meticulous employment of regional anesthesia, sedation, vagal block, and ventilatory support, nonintubated VATS is proved to be a safe alternative to the conventional intubated general anesthesia. © Pioneer Bioscience Publishing Company.


Chi N.-F.,Taipei Medical University | Chi N.-F.,Graduate Institute of Clinical Medicine | Chien L.-N.,Taipei Medical University | Ku H.-L.,Taipei Medical University | And 4 more authors.
Neurology | Year: 2013

Objective: To investigate the risk of stroke in patients clinically diagnosed with Alzheimer disease (AD) compared with non-AD patients with similar vascular risk factors. Methods: Using data obtained from Taiwan's National Health Insurance Research Database, we evaluated the risk of ischemic stroke (IS) and intracerebral hemorrhage (ICH) in patients with AD (n = 980) who had no history of stroke, vascular dementia, or other cerebral degenerative diseases. Our evaluation period spanned from 2000 to 2010. We performed a 1:5 case-control matched analysis, in which cases were matched to controls according to their estimated propensity scores, which were based on demographics and existing vascular risk factors. This approach reduced selection bias. Cox proportional hazards regression analysis was then used to estimate the risk of IS and ICH in AD, conditional for matched pairs. Results: Overall, patients with AD had a higher risk of IS and ICH than those without AD. The incidence of IS in AD cases and non-AD controls was 37.8 and 23.2 per 1,000 person-years, with an adjusted hazard ratio of 1.66 (95% confidence interval, 1.37-2.01, p < 0.001). The incidence of ICH in AD cases and non-AD controls was 5.2 and 3.0 per 1,000 person-years, with an adjusted hazard ratio of 1.70 (95% confidence interval, 1.03-2.79, p = 0.037). Conclusion: Clinical diagnosis of AD is associated with considerably increased risk of stroke development. © 2013 American Academy of Neurology.


Gau S.S.-F.,National Taiwan University Hospital | Gau S.S.-F.,Graduate Institute of Clinical Medicine | Gau S.S.-F.,National Taiwan University | Huang W.-L.,National Taiwan University Hospital
Psychological Medicine | Year: 2014

Background. Deficits in sustained attention and reaction time are core features of attention deficit hyperactivity disorder (ADHD). However, little is known about attention performance in unaffected siblings. Hence, we examined sustained attention and reaction time in youths with ADHD, unaffected siblings and controls to test whether impaired performance in attention tasks can be a potential endophenotype of ADHD. Method. We recruited 438 probands with clinical diagnosis of ADHD according to DSM-IV criteria, 180 unaffected siblings, and 173 healthy controls without lifetime ADHD. They were assessed using psychiatric interviews, Conners' Continuous Performance Test, and the tasks involving attention performance of the Cambridge Neuropsychological Test Automated Battery (CANTAB): Rapid Visual Information Processing (RVP), Reaction Time (RTI) and Match to Sample Visual Search (MTS). Multi-level models were used for data analysis. Results. Compared with the controls, probands with ADHD and unaffected siblings had significantly higher total misses, lower probability of hits in the RVP task and probands with ADHD performed worse in the RTI and MTS tasks after controlling for sex, age, co-morbidity, parental educational levels and IQ. The duration of methylphenidate use and IQ but not psychiatric co-morbidity or current use of methylphenidate were associated with deficits in sustained attention in probands with ADHD. Conclusions. Our findings suggest that attention performance assessed by the RVP task, but not the RTI or MTS tasks, of the CANTAB may be a useful cognitive endophenotype for ADHD genetic studies. Copyright © Cambridge University Press 2013.


Liu Y.-P.,National Cheng Kung University | Liu Y.-P.,Academia Sinica, Taiwan | Yang C.-J.,Kaohsiung Medical University | Huang M.-S.,Kaohsiung Medical University | And 13 more authors.
Cancer Research | Year: 2013

Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer, but recurrence occurs in most patients. Recent evidence suggests that CD133+ cells are the cause of drug resistance and tumor recurrence. However, the correlation between chemotherapy and regulation of CD133+ cells has not been investigated methodically. In this study, we revealed that CD133+ lung cancer cells labeled by a human CD133 promoter-driven GFP reporter exhibited drug resistance and stem cell characteristics. Treatment of H460 and H661 cell lines with low-dose cisplatin (IC20) was sufficient to enrich CD133+ cells, to induce DNA damage responses, and to upregulate ABCG2 and ABCB1 expression, which therefore increased the cross-resistance to doxorubicin and paclitaxel. This cisplatin-induced enrichment of CD133+ cells was mediated through Notch signaling as judged by increased levels of cleaved Notch1 (NICD1). Pretreatment with the g-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-1- alanyl]-S-phenylglycine t-butyl ester (DAPT), or Notch1 short hairpin RNAs (shRNA) remarkably reduced the cisplatin-induced enrichment of CD133+ cells and increased the sensitivity to doxorubicin and paclitaxel. Ectopic expression of NICD1 reversed the action of DAPT on drug sensitivity. Immunohistochemistry showed that CD133+ cells were significantly increased in the relapsed tumors in three of six patients with lung cancer who have received cisplatin treatment. A similar effect was observed in animal experiments as cisplatin treatment increased Notch1 cleavage and the ratio of CD133+ cells in engrafted tumors. Intratumoral injection of DAPT with cisplatin treatment significantly reduced CD133+ cell number. Together, our results showed that cisplatin induces the enrichment of CD133 + cells, leading to multidrug resistance by the activation of Notch signaling. ©2012 AACR.


Chen C.-L.,Graduate Institute of Clinical Medicine | Chiou H.-Y.,Taipei Medical University Hospital | Hsu L.-I.,Academia Sinica, Taiwan | Hsueh Y.-M.,Taipei Medical University Hospital | And 4 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2010

The evidence linking arsenic in drinking water with increased urinary cancer risk comes from populations in relatively high exposure areas (>100 μg/L), whereas studies from lower exposure areas (<100 μg/L) reported inconsistent results. A previous study conducted in northeastern Taiwan, where residents were exposed to relatively lower concentrations, reported increased risk of urinary cancer in a dose-response way. Using the same cohort with longer follow-up, we conducted analysis to elucidate the relationship between ingested arsenic and urinary cancer in lower exposure groups and assessed the influence of duration, recency, and latency of drinking arsenic-containing well water. A total of 8,086 residents from northeastern Taiwan were followed for 12 years. Incident urinary cancer was ascertained through linkage with the national cancer registry. All analysis was done by Cox proportional hazards regression models. There were 45 incidences of urinary cancer and a monotonic increased risk of urinary cancer was found with increasing arsenic concentration (P < 0.001). For the highly exposed (>100 μg/L), the relative risks (RR) were >5-fold, whereas the risk was elevated but not significant for low exposure (<100 μg/L). Relative to the arsenic concentration <10 μg/L, those who drank well water with higher concentration from birth [RR, 3.69; 95% confidence interval (95% CI), 1.31-10.4], still drank at enrollment (RR, 3.50; 95% CI, 1.33-9.22), and drank for >50 years (RR, 4.12; 95% CI, 1.48-11.5) had a significantly increased risk of urinary cancer. When restricted to urothelial carcinoma, all risk estimates including concentration and characteristics of well water consumption were higher. ©2010 AACR.

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