Showing papers by "Taipei Veterans General Hospital published in 2008"

Direct regulation of TWIST by HIF-1alpha promotes metastasis.

Abstract: Stabilization of the hypoxia-inducible factor-1alpha (HIF-1alpha) transcription complex, caused by intratumoural hypoxia, promotes tumour progression and metastasis, leading to treatment failure and mortality in different types of human cancers. The transcription factor TWIST is a master regulator of gastrulation and mesoderm-specification and was implicated recently as an essential mediator of cancer metastasis. Notably, HIF-1alpha- and TWIST-null mice show similarities in their phenotypes. Here, we have shown that hypoxia or overexpression of HIF-1alpha promotes epithelial-mesenchymal transition (EMT) and metastastic phenotypes. We also found that HIF-1 regulates the expression of TWIST by binding directly to the hypoxia-response element (HRE) in the TWIST proximal promoter. However, siRNA-mediated repression of TWIST in HIF-1alpha-overexpressing or hypoxic cells reversed EMT and metastastic phenotypes. Co-expression of HIF-1alpha, TWIST and Snail in primary tumours of patients with head and neck cancers correlated with metastasis and the worst prognosis. These results provide evidence of a key signalling pathway involving HIF-1alpha and TWIST that promotes metastasis in response to intratumoural hypoxia.

Coordinated Changes of Mitochondrial Biogenesis and Antioxidant Enzymes During Osteogenic Differentiation of Human Mesenchymal Stem Cells

Abstract: The multidifferentiation ability of mesenchymal stem cells holds great promise for cell therapy. Numerous studies have focused on the establishment of differentiation protocols, whereas little attention has been paid to the metabolic changes during the differentiation process. Mitochondria, the powerhouse of mammalian cells, vary in their number and function in different cell types with different energy demands, but how these variations are associated with cell differentiation remains elusive. In this study, we investigated the changes of mitochondrial biogenesis and bioenergetic function using human mesenchymal stem cells (hMSCs) because of their well-defined differentiation potentials. Upon osteogenic induction, the copy number of mitochondrial DNA, protein subunits of the respiratory enzymes, oxygen consumption rate, and intracellular ATP content were increased, indicating the upregulation of aerobic mitochondrial metabolism. On the other hand, undifferentiated hMSCs showed higher levels of glycolytic enzymes and lactate production rate, suggesting that hMSCs rely more on glycolysis for energy supply in comparison with hMSC-differentiated osteoblasts. In addition, we observed a dramatic decrease of intracellular reactive oxygen species (ROS) as a consequence of upregulation of two antioxidant enzymes, manganese-dependent superoxide dismutase and catalase. Finally, we found that exogenous H(2)O(2) and mitochondrial inhibitors could retard the osteogenic differentiation. These findings suggested an energy production transition from glycolysis to oxidative phosphorylation in hMSCs upon osteogenic induction. Meanwhile, antioxidant enzymes were concurrently upregulated to prevent the accumulation of intracellular ROS. Together, our findings suggest that coordinated regulation of mitochondrial biogenesis and antioxidant enzymes occurs synergistically during osteogenic differentiation of hMSCs.

Oct-4 Expression Maintained Cancer Stem-Like Properties in Lung Cancer-Derived CD133-Positive Cells

Abstract: CD133 (prominin-1), a 5-transmembrane glycoprotein, has recently been considered to be an important marker that represents the subset population of cancer stem-like cells. Herein we report the isolation of CD133-positive cells (LC-CD133+) and CD133-negative cells (LC-CD133−) from tissue samples of ten patients with non-small cell lung cancer (LC) and five LC cell lines. LC-CD133+ displayed higher Oct-4 expressions with the ability to self-renew and may represent a reservoir with proliferative potential for generating lung cancer cells. Furthermore, LC-CD133+, unlike LC-CD133−, highly co-expressed the multiple drug-resistant marker ABCG2 and showed significant resistance to chemotherapy agents (i.e., cisplatin, etoposide, doxorubicin, and paclitaxel) and radiotherapy. The treatment of Oct-4 siRNA with lentiviral vector can specifically block the capability of LC-CD133+ to form spheres and can further facilitate LC-CD133+ to differentiate into LC-CD133−. In addition, knock-down of Oct-4 expression in LC-CD133+ can significantly inhibit the abilities of tumor invasion and colony formation, and increase apoptotic activities of caspase 3 and poly (ADP-ribose) polymerase (PARP). Finally, in vitro and in vivo studies further confirm that the treatment effect of chemoradiotherapy for LC-CD133+ can be improved by the treatment of Oct-4 siRNA. In conclusion, we demonstrated that Oct-4 expression plays a crucial role in maintaining the self-renewing, cancer stem-like, and chemoradioresistant properties of LC-CD133+. Future research is warranted regarding the up-regulated expression of Oct-4 in LC-CD133+ and malignant lung cancer.

CLEC5A is critical for dengue-virus-induced lethal disease.

Abstract: Dengue haemorrhagic fever and dengue shock syndrome, the most severe responses to dengue virus (DV) infection, are characterized by plasma leakage (due to increased vascular permeability) and low platelet counts. CLEC5A (C-type lectin domain family 5, member A; also known as myeloid DAP12-associating lectin (MDL-1)) contains a C-type lectin-like fold similar to the natural-killer T-cell C-type lectin domains and associates with a 12-kDa DNAX-activating protein (DAP12) on myeloid cells. Here we show that CLEC5A interacts with the dengue virion directly and thereby brings about DAP12 phosphorylation. The CLEC5A-DV interaction does not result in viral entry but stimulates the release of proinflammatory cytokines. Blockade of CLEC5A-DV interaction suppresses the secretion of proinflammatory cytokines without affecting the release of interferon-alpha, supporting the notion that CLEC5A acts as a signalling receptor for proinflammatory cytokine release. Moreover, anti-CLEC5A monoclonal antibodies inhibit DV-induced plasma leakage, as well as subcutaneous and vital-organ haemorrhaging, and reduce the mortality of DV infection by about 50% in STAT1-deficient mice. Our observation that blockade of CLEC5A-mediated signalling attenuates the production of proinflammatory cytokines by macrophages infected with DV (either alone or complexed with an enhancing antibody) offers a promising strategy for alleviating tissue damage and increasing the survival of patients suffering from dengue haemorrhagic fever and dengue shock syndrome, and possibly even other virus-induced inflammatory diseases.

Hepatitis B virus/hepatitis C virus coinfection: Epidemiology, clinical features, viral interactions and treatment

Abstract: Because of the shared modes of transmission, hepatitis B virus (HBV)/hepatitis C virus (HCV) coinfection is not uncommon in highly endemic areas and among subjects with a high risk of parenteral infections. The worldwide prevalence of HBV/HCV coinfection is unknown and might be underestimated with the phenomenon of silent (occult) HBV infection. HCV superinfection in patients with chronic HBV infection was the most common clinical features of coinfection in Asia-Pacific countries. Further, most, but not all, clinical observations suggested that interference between the two viruses was more frequently characterized by an inhibition of HBV replication exerted by HCV. However, longitudinal follow-up studies have demonstrated that the virological patterns in coinfection cases are widely divergent and have dynamic profiles over time. As compared with monoinfected patients, HBV/HCV coinfected persons tend to have more severe liver injury, a higher probability of liver cirrhosis and hepatic decompensation, and a higher incidence of hepatocellular carcinoma. Detailed serological and virological evaluations are required for coinfected patients before initiation of antiviral therapy. Previous studies demonstrated that HBV/HCV coinfected patients responded poorly to interferon (IFN) monotherapy. Currently, for patients with dominant HCV infection and low level HBV viremia (<10(4) IU/mL), IFN or pegylated IFN plus ribavirin can achieve comparable sustained virus response as expected with HCV monoinfection. However, phenomenon of reciprocal viral interference can happen, and resultant "flare" of hepatitis activity may cause liver function deterioration. For coinfected patients with dually-active HBV/HCV, the optimal regimen for therapy remains unclear although adding oral nucleos(t)ide analogs to pegylated IFN and ribavirin seems a reasonable empiric option.

Transplantation of Human Umbilical Mesenchymal Stem Cells from Wharton's Jelly after Complete Transection of the Rat Spinal Cord

Abstract: Background Human umbilical mesenchymal stem cells (HUMSCs) isolated from Wharton's jelly of the umbilical cord can be easily obtained and processed compared with embryonic or bone marrow stem cells. These cells may be a valuable source in the repair of spinal cord injury.

Incidence, prevalence and mortality trends of dialysis end-stage renal disease in Taiwan from 1990 to 2001: the impact of national health insurance

Abstract: Background Incident and prevalent (I&P) rates in dialysis end-stage renal disease (ESRD) patients in Taiwan increased rapidly following the launch of National Health Insurance (NHI) in 1995. Our aim was to explore the impact of NHI on the status and trends of ESRD epidemiology in Taiwan. Methods This study was conducted using retrospective cohort analysis of data collected from the Taiwan national dialysis registry. Results From 1990 to 2001, I&P rates of ESRD patients increased 2.6 times from 126 to 331 per million populations (pmp) and 3.46 times from 382 to 1322 pmp, respectively. Increasing ESRD was seen in patients who were middle-aged, elderly and who had diabetic nephropathy as their primary renal disease. The mean age of I&P patients increased by 7.2 years and 7.1 years, respectively. All of these parameters increased markedly in 1995, the year of NHI implementation. First-year mortality decreased to 7.8 per 1000 patient-months in 1994, and then increased to 18.0 in 2001. The cumulative survival rate of the elderly subgroup (age >65) in the incident 1990-1994 cohort was greater than in the 1995-1999 cohort. These data indicated that NHI implementation significantly influenced the inflow and the mortality of ESRD patients. Conclusion In addition to presenting ESRD epidemiology in Taiwan, this study demonstrated that NHI implementation stimulated the growth of treated ESRD populations. Preventive plans mounted against chronic kidney diseases will be essential to reduce the growth of ESRD patient numbers and consequent economic burdens.

Identification of SOX4 target genes using phylogenetic footprinting-based prediction from expression microarrays suggests that overexpression of SOX4 potentiates metastasis in hepatocellular carcinoma.

Abstract: A comprehensive microarray analysis of hepatocellular carcinoma (HCC) revealed distinct synexpression patterns during intrahepatic metastasis. Recent evidence has demonstrated that synexpression group member genes are likely to be regulated by master control gene(s). Here we investigate the functions and gene regulation of the transcription factor SOX4 in intrahepatic metastatic HCC. SOX4 is important in tumor metastasis as RNAi knockdown reduces tumor cell migration, invasion, in vivo tumorigenesis and metastasis. A multifaceted approach integrating gene profiling, binding site computation and empirical verification by chromatin immunoprecipitation and gene ablation refined the consensus SOX4 binding motif and identified 32 binding loci in 31 genes with high confidence. RNAi knockdown of two SOX4 target genes, neuropilin 1 and semaphorin 3C, drastically reduced cell migration activity in HCC cell lines suggesting that SOX4 exerts some of its action via regulation of these two downstream targets. The discovery of 31 previously unidentified targets expands our knowledge of how SOX4 modulates HCC progression and implies a range of novel SOX4 functions. This integrated approach sets a paradigm whereby a subset of member genes from a synexpression group can be regulated by one master control gene and this is exemplified by SOX4 and advanced HCC.

Transcranial color doppler study for reversible cerebral vasoconstriction syndromes

Abstract: Objective Reversible cerebral vasoconstriction syndromes (RCVS) are characterized by thunderclap headaches and reversible cerebral vasoconstrictions. No systematic studies on cerebral hemodynamics have been published. Methods Patients with RCVS were consecutively recruited. Sequential transcranial color-coded sonography studies were performed on the middle cerebral artery (MCA) for 3 months. Mean flow velocities (VMCA) and Lindegaard Index (LI) were recorded and compared with those of controls. Results Thirty-two patients (all female; average age, 49.7 ± 6.8 years) were enrolled. Four developed of reversible posterior leukoencephalopathy syndrome, and two of them, ischemic strokes. One hundred and twenty-six sonography studies were performed on 57 eligible MCAs. The mean maximum VMCA (109.5 ± 30.8cm/sec) and LI (2.2 ± 0.7) of RCVS patients exceeded those of controls (VMCA: 66.3 ± 9.5cm/sec, p < 0.001; LI: 1.4 ± 0.3, p < 0.001). The VMCA and LI levels were still at their plateau at the mean time (day 22 after headache onset) of headache resolution. Fifteen (46.9%) patients had VMCA exceeding 120cm/sec, and 5 (16%) had LI exceeding 3. Patients fulfilling the criteria of subarachnoid hemorrhage mild vasospasm (n = 4; 13%), that is, both VMCA greater than 120cm/sec and LI greater than 3, had a greater risk of posterior leukoencephalopathy (75 vs 4%; p = 0.003) and ischemic strokes (50 vs 0%; p = 0.01) than those without. Interpretation Patients with RCVS experienced prolonged vasoconstriction, making the risk for posterior leukoencephalopathy and ischemic strokes outlast headache resolution. Patients fulfilling mild vasospasm criteria for subarachnoid hemorrhage carry a high risk. Ann Neurol 2008

Constant allelic alteration on chromosome 16p (TSC2 gene) in perivascular epithelioid cell tumour (PEComa): genetic evidence for the relationship of PEComa with angiomyolipoma.

Abstract: Perivascular epithelioid cell tumours (PEComas) are a family of tumours including classic angiomyolipoma, lymphangioleiomyomatosis, and clear epithelioid cell tumours reported under a variety of names such as epithelioid angiomyolipoma, pulmonary and extrapulmonary clear cell sugar tumour, and PEComa. Our previous comparative genomic hybridization study of PEComas demonstrated recurrent chromosomal aberrations including deletions on chromosome 16p, where the TSC2 gene is located. In this study, we focused on the alteration of chromosome 16p, including TSC2. We collected ten sporadic and two tuberous sclerosis complex-associated PEComas, as well as 14 sporadic classic hepatic and renal angiomyolipomas (AMLs) as controls. We used 16 microsatellite markers distributed along chromosome 16p to test for allelic imbalances on chromosome 16p and at TSC2, and two markers for TSC1. Furthermore, we carried out immunohistochemical staining for phospho-p706K, phospho-AKT, and phospho-S6 to evaluate the effect of TSC2 alterations on the mTOR signalling pathway. Loss of heterozygosity (LOH) was found in 11 PEComas and involved the region of the TSC2 locus in seven. Six classic angiomyolipomas had allelic changes at chromosome 16p. Microsatellite instability was detected in two PEComas. The incidence of genetic aberrations was significantly higher in the PEComa group. Only one PEComa showed LOH at the TSC1 locus. Eleven PEComas and 13 AMLs revealed elevated phospho-p70S6K accompanied by reduced phospho-AKT. Five PEComas and eight classic angiomyolipomas were positive for phospho-S6. The phosphorylation profile indicates functional activation of the mTOR pathway through a disrupted TSC1/2 complex. Our observations of frequent deletion of TSC2 and the mTOR signalling pathway provide evidence that the oncogenetic lineage of PEComa, as a distinct TSC2-linked neoplasm, is similar to that of angiomyolipoma.

Biochemical predictors for absence of common bile duct stones in patients undergoing laparoscopic cholecystectomy

Abstract: Background To provide optimal selection of patients for preoperative endoscopic retrograde cholangiopancreatography or intraoperative cholangiography, we evaluated simple, noninvasive biochemical parameters as screening tests to predict the absence of common bile duct stones prior to laparoscopic cholecystectomy.

Diffusion-weighted single-shot echo-planar imaging with parallel technique in assessment of endometrial cancer.

Abstract: OBJECTIVE. The purposes of this study were to determine the feasibility of diffusion-weighted imaging (DWI) with a single-shot echo-planar sequence and parallel technique for depicting endometrial cancer and to examine the role of this technique in preoperative assessment.SUBJECTS AND METHODS. A total of 31 patients were recruited for MRI evaluation of suspicious endometrial lesions found on transvaginal sonography. Twenty-four of the patients were proved to have endometrial cancer (patient group), and seven to have benign diseases (control group). The MRI examinations included diffusion-weighted single-shot echoplanar sequences and contrast-enhanced T1-weighted 3D fat-suppressed spoiled gradient-echo sequences. The apparent diffusion coefficient of endometrial cancer in the patient group and of normal endometrium in the control group were measured on the apparent diffusion coefficient map of each diffusion-weighted image and compared for the two groups. In the patient group, myometrial invasion was evalu...

Brachial-ankle vs carotid-femoral pulse wave velocity as a determinant of cardiovascular structure and function.

Abstract: Carotid-femoral pulse wave velocity (cf-PWV) is a validated marker of arterial stiffening over the central arteries. Brachial-ankle pulse wave velocity (ba-PWV) integrates the mechanical properties from both the central and peripheral arteries and may be more representative than cf-PWV as arterial load for left ventricle (LV). We compared ba-PWV with cf-PWV for the association of cardiovascular structure and function in 320 subjects with various degrees of abnormality in cardiac structure and function. ba-PWV (by oscillometric technique) and cf-PWV (by tonometric technique) were measured simultaneously, and were highly correlated (r=0.79, P<0.001). Both ba-PWV and cf-PWV were significantly correlated with LV mass, but the correlation was better with ba-PWV (r=0.29 vs r=0.22, P=0.0219). While ba-PWV and cf-PWV were similarly significantly correlated with LV end-systolic elastance and mitral E/A ratio, ba-PWV had better correlation with isovolumic relaxation constant (r=0.34 vs r=0.27, P=0.0202) than cf-PWV. In addition, the correlation was also significantly stronger with ba-PWV than with cf-PWV for other indices of arterial stiffness, including carotid incremental modulus (r=0.59 vs 0.50, P=0.0013), effective arterial elastance (r=0.41 vs r=0.33, P=0.0081) and carotid augmentation index (r=0.38 vs r=0.32, P=0.0368). In conclusion, ba-PWV correlates better with LV mass and diastolic function and other indices of arterial function than cf-PWV, probably because ba-PWV encompasses a greater territory of arterial tree than cf-PWV.

Beneficial Effects of Insulin on Glycemic Control and β-Cell Function in Newly Diagnosed Type 2 Diabetes With Severe Hyperglycemia After Short-Term Intensive Insulin Therapy

Abstract: OBJECTIVE—To evaluate whether treatment with insulin is advantageous compared with oral antidiabetes agents in newly diagnosed type 2 diabetes with severe hyperglycemia after short-term intensive insulin therapy. RESEARCH DESIGN AND METHODS—Newly diagnosed type 2 diabetic patients with severe hyperglycemia were hospitalized and treated with intensive insulin injections for 10–14 days. The oral glucose tolerance test (OGTT) was performed after intensive insulin treatment. After discharge, the patients were randomized to receive either insulin injections or oral antidiabetes drugs (OADs) for further management. The OGTT was repeated 6 months later, and β-cell function and insulin sensitivity were evaluated again. These subjects were continually followed up for another 6 months to evaluate their long-term glycemic control. RESULTS—At the 6th month of the study, the A1C level was significantly lower in the insulin group than in the OAD group (6.33 ± 0.70% vs. 7.50 ± 1.50%; P = 0.002). During the follow-up visit, the A1C level was still better in the insulin group (6.78 ± 1.21% vs. 7.84 ± 1.74%; P = 0.009). All parameters regarding β-cell function measured in the OGTT were improved significantly in both groups after 6 months of treatment. Compared with the OAD group, the homeostasis model assessment of β-cell function index, insulin area under the curve, and insulinogenic index were better in the insulin group. CONCLUSIONS—A 6-month course of insulin therapy, compared with OAD treatment, could more effectively achieve adequate glycemic control and significant improvement of β-cell function in new-onset type 2 diabetic patients with severe hyperglycemia.

Polymethylmethacrylate augmentation of pedicle screw for osteoporotic spinal surgery: A novel technique

Abstract: STUDY DESIGN A retrospective study to evaluate the clinical results of patients with osteoporosis and various spinal diseases treated surgically with polymethylmethacrylate (PMMA) augmented pedicle screw. OBJECTIVE To report a novel technique using PMMA for pedicle screw augmentation in osteoporotic spinal surgery. SUMMARY OF BACKGROUND DATA Many studies have proved that the stiffness and strength of pedicle screw fixation can be significantly increased when the pedicle screw is augmented with various cements. However, most of those studies were experimental. Clinical reports using those materials for pedicle screw augmentation are rare and a practical and reliable technique for primary pedicle screw augmentation with cement has not yet been established. METHODS Forty-one patients [23 female, 18 male, mean age 75.1 (50-90) years] with osteoporosis and various spinal diseases underwent spinal decompression and instrumentation with PMMA augmentation of pedicle screw. Pre-and postoperative scores for visual analogue scale for pain and Oswestry disability index questionnaire were analyzed. The screw migration, which is the distance from the screw tip to the anterior cortex and upper endplate of vertebra, was also evaluated immediately after the operation and at the mean 22.3 months final follow-up. RESULTS.: Totally 291 of 300 screws were augmented with PMMA. There was neither neurologic deterioration nor symptomatic cement leakage after surgery. The mean visual analogue scale pain score of these patients improved from 9.2 to 1.5 (P 0.01). CONCLUSION The presented technique of PMMA for augmentation of pedicle screw is a safe, reliable, and practical technique for osteoporotic patients who also had various spinal diseases and need spinal instrumentation.

Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes.

Abstract: p olymorphisms in C yp 2C9 and VK or C1 have been shown to be associated with warfarin dose requirements and could be used to predict warfarin dose. We conducted a prospective study in which warfarin dose was prescribed based on C yp2C9 and VK or C1 polymorphisms in 108 han-Chinese patients without prior warfarin treatments. u sing the genotype-based dosing, 83% of patients reached stable, therapeutic international normalized ratio ( inr ) within 2 weeks of treatment initiation and none of the patients developed clinical bleeding or thromboembolic event. Ten percent (11) of patients with inr >4 and no clinical bleeding were detected during this study. at 12 weeks, 69% of the patients’ maintenance doses matched the prediction. Dosing algorithms incorporating genetic factors, age, and body surface area were developed, which could explain up to 62% of the total variation (R 2 of 0.62). This study demonstrated that pharmacogenetics-based dosing could improve time to stable, therapeutic inr , reduce adverse events, and achieve high sensitivity.

Gait Training—Induced Change in Corticomotor Excitability in Patients With Chronic Stroke

Abstract: Background. Numerous studies have reported the effects of gait training on motor performance after stroke. However, there is limited information on treatment-induced changes in corticomotor excitability. Objectives. The purpose of the study was to investigate the effects of additional gait training on motor performance and corticomotor excitability and to demonstrate the relationship between motor improvement and corticomotor excitability change in patients with chronic stroke. Methods. Fourteen patients were randomly assigned to the experimental or control group. Participants in both groups participated in general physical therapy. Those in the experimental group received additional body weight− supported treadmill training for 4 weeks. All participants received baseline and posttreatment assessments. The outcome measures included assessment of the Berg Balance Scale (BBS) and gait parameters. Focal transcranial magnetic stimulation was used to measure the motor threshold, map size, and location of the amplitude-weighted center of gravity of the motor map for the tibialis anterior (TA) and abductor hallucis (AH) muscles. Results. After general physical therapy, we noted that the patients showed an improvement only in walking speed and cadence, and there were no significant changes in corticomotor excitability. After additional gait training, participants improved significantly on BBS score, walking speed, and step length. Moreover, the motor threshold for TA decreased significantly in the unaffected hemisphere. The map size for TA was increased in both hemispheres, whereas that for AH was increased only in the affected hemisphere. There were significant differences between the change scores of the groups in terms of walking speed, step length, and motor threshold for TA in the unaffected hemisphere and map size for AH in the affected hemisphere. Additionally, the changes in corticomotor excitability correlated with functional improvement. Conclusions. Additional gait training may improve balance and gait performance and may induce changes in corticomotor excitability.

Prevalence and associated risk factors of age-related macular degeneration in an elderly Chinese population in Taiwan: the Shihpai Eye Study.

Abstract: Purpose To assess the prevalence and associated risk factors of age-related macular degeneration (AMD) in an elderly Chinese population in Taiwan. Methods The Shihpai Eye Study was a survey of vision and ocular disease in an elderly Chinese population 65 years of age or older residing in Shihpai, Taipei, Taiwan. Of 2045 elderly residents randomly sampled from the household registration databank, 1361 (66.6%) underwent a detailed ophthalmic examination that included fundus color slides by fundus camera after pupil dilatation. Photographs were graded according to the Wisconsin Age-Related Maculopathy Grading System. Results Fundus photographs were available for 1105 (54.0% in the eligible, 81.2% in the ocular examined) participants. The 47 (4.3%) participants who had ungradable fundus images were older and had more lens opacity. Of the 1058 gradable photographs, the prevalence of early AMD was 9.2% (95% confidence interval [CI], 7.8-10.8); of late AMD, 1.9% (95% CI, 1.3-2.7); of soft drusen, 42.2% (95% CI, 39.7-44.8); of soft indistinct drusen, 4.1% (95% CI, 3.1-5.2); and of any pigmentary change, 8.6% (95% CI, 7.2-10.2). Age was the most significant factor associated with both early and late AMD. The prevalence of early AMD rose from 5.0% in the 65- to 69-year age group to 24.4% in those 80 years of age and older; and for late AMD, from 1.0% to 9.0%. Those who currently drank alcohol had a lower rate of early AMD than did the nondrinker (adjusted odd ratio 0.32, 95% CI: 0.11-0.93, P = 0.037). Conclusions AMD is a common eye disease in the elderly Chinese people in Taiwan. The adjusted prevalence rate of exudative AMD is comparable to that in the Chinese people in the Multiethnic Study of Atherosclerosis (MESA) in the United States but is higher than in the Chinese people in the Beijing study in China. Further studies are needed to clarify the incidence and associated risk factors.

Identification of CD133-Positive Radioresistant Cells in Atypical Teratoid/ Rhabdoid Tumor

Abstract: Atypical teratoid/rhabdoid tumor (AT/RT) is an extremely malignant neoplasm in the central nervous system (CNS) which occurs in infancy and childhood. Recent studies suggested that CD133 could be considered a marker for brain cancer stem-like cells (CSCs). However, the role of CD133 in AT/RT has never been investigated. Herein we report the isolation of CD133-positive cells (CD133+), found to have the potential to differentiate into three germ layer tissues, from tissues of nine AT/RT patients. The migration/invasion/malignancy and radioresistant capabilities of CD133+ were significantly augmented when compared to CD133−. The clinical data showed that the amount of CD133+ in AT/RTs correlated positively with the degree of resistance to radiation therapy. Using cDNA microarray analysis, the genotoxic–response profiles of CD133+ and CD133− irradiated with 10 Gy ionizing radiation (IR) were analyzed 0.5, 2, 6, 12 and 24 h post-IR. We then validated these microarray data and showed increased phosphorylation after IR of p-ATM, p-RAD17, and p-CHX2 as well as increased expression of BCL-2 protein in CD133+ compared to CD133−. Furthermore, we found that CD133+ can effectively resist IR with cisplatin- and/or TRAIL-induced apoptosis. Immunohistochemical analysis confirmed the up-regulated expression of p-ATM and BCL-2 proteins in IR-treated CD133+ xenotransgrafts in SCID mice but not in IR-treated CD133−. Importantly, the effect of IR in CD133+ transplanted mice can be significantly improved by a combination of BCL-2 siRNA with debromohymenialdisine, an inhibitor of checkpoint kinases. In sum, this is the first report indicating that CD133+ AT/RT cells demonstrate the characteristics of CSCs. The IR-resistant and anti-apoptotic properties in CD133+ may reflect the clinical refractory malignancy of AT/RTs and thus the activated p-ATM pathway and BCL-2 expression in CD133+ could be possible targets to improve future treatment of deadly diseases like AT/RT.

UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities without affecting treatment outcome and survival in patients with metastatic colorectal carcinoma.

Abstract: BACKGROUND It is known that the uridine-diphosphoglucuronosyl transferase 1A1 (UGT1A1)*28 polymorphism reduces UGT1A1 enzyme activity, which may lead to severe toxicities in patients who receive irinotecan. This study was conducted to assess the influence of this polymorphism on the efficacy and toxicity of irinotecan treatment in Chinese patients with metastatic colorectal carcinoma (CRC). METHODS In total, 128 patients with metastatic CRC who had received previous treatment with irinotecan plus 5-fluorouracil/leucovorin were analyzed retrospectively. Genomic DNA samples were obtained from patients' leukocytes, and genotypes were determined by analyzing the sequence of TATA boxes in the UGT1A1 gene. The influence of the UGT1A1*28 polymorphism on toxicity and treatment outcome was analyzed. RESULTS Approximately 20% of patients were identified with the UGT1A1*28 polymorphism, including 15.6% (n = 20 patients) with the thymine-adenine (TA)6/TA7 genotype and 4.7% (n = 6 patients) with the TA7/TA7 genotype. The remaining 79.7% of patients (n = 102) had wild type TA6/TA6. Marked increases in grade 3 or 4 neutropenia (53.8% vs 4.9%; P < .01), neutropenic fever (38.5% vs 3.9%; P < .01), diarrhea (26.9% vs 5.9%; P < .01), and pretreatment bilirubin level (23.1% vs 8.8%; P = .04) were observed in patients who had the TA6/TA7 or TA7/TA7 genotypes. Patients' pretreatment bilirubin levels correlated well with irinotecan-induced neutropenia (P < .01). It was noted that, although the requirement for irinotecan dose reduction was significantly greater in patients who had this genetic variant (42.3% vs 12.7%; P < .01), it did not affect the response rate to irinotecan-based chemotherapy (42.3% vs 45.1%; P = .80), and it did not significantly affect progression-free survival (10 months vs 11 months; P = .94) or overall survival (19 months vs 18 months; P = .84). CONCLUSIONS The current data suggested that the UGT1A1*28 polymorphism may be a key determinant for predicting irinotecan-induced severe toxicities without affecting treatment outcome for patients with metastatic CRC. Further prospective studies are warranted for using this polymorphism to optimize irinotecan-based chemotherapy. Cancer 2008. © 2008 American Cancer Society.

Low copy number and low oxidative damage of mitochondrial DNA are associated with tumor progression in lung cancer tissues after neoadjuvant chemotherapy.

Abstract: The decrease in the copy number of mitochondrial DNA (mtDNA) in cancer tissues might be associated with a decrease in oxidative mtDNA damage to achieve cancer immortalization and progression. Lung cancer specimens were collected from 29 patients with stage III non-small cell lung cancer (NSCLC) after neoadjuvant chemotherapy followed by surgical resection. The relative mtDNA copy number and the oxidative mtDNA damage (formation of 8-OHdG in mtDNA) of each cancer tissue were measured by quantitative real-time PCR. Seven female and 22 male lung cancer patients, with a mean age of 63.5 years were evaluated. Tumors of five patients became progressive, 13 stable, and 11 partially responsive after preoperative chemotherapy. Low mtDNA copy number (P=0.089) and low degree of oxidative mtDNA damage (P=0.036) were found to associate with tumor progression. Moreover, mtDNA copy number was significantly related to the degree of oxidative mtDNA damage (P=0.031). The mtDNA copy number and oxidative mtDNA damage were lower in advanced NSCLC after chemotherapy. This finding suggests that a decrease in the content of mtDNA may result in a decrease of mitochondrial density in cancer cells, which leads to a decrease of endogenous ROS production and reduction of ROS-triggered DNA damage to achieve immortalization.