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1.  Longitudinal Changes in Clock Drawing Test (CDT) Performance before and after Cognitive Decline 
PLoS ONE  2014;9(5):e97873.
Many scoring systems exist for clock drawing task variants. However, none of them are reliable in evaluating longitudinal changes of cognitive function. The purpose of this study is to create a simple yet optimal scoring procedure to evaluate cognitive decline using a clinic-based sample.
Clock-drawings from 121 participants (76 individuals with no dementia and later did not develop dementia after a mean 41.2-month follow-up, 45 individuals with no dementia became demented after a mean 42.3-month follow-up) were analyzed using t-test to determine a new and simplified CDT scoring system. The new scoring method was then compared with other commonly used systems.
In the converters, there were only 7 items that are significantly different between the initial visits and the second visits. We propose a new scoring system that includes the seven critical items: numbers are equally spaced (12–3–6–9) (p = 0.031), the other eight numbers are marked (p = 0.022), numbers are clockwise (p = 0.002), all numbers are correct (p = 0.030), distance between numbers is constant (p = 0.016), clock has two hands (p = 0.000), arrows are drawn (p = 0.003). Compared with other traditionally used scoring methods, this based change clock drawing test (BCCDT) has one of the most balanced sensitivities/specificities with a clinic-based sample.
The new CDT scoring system provides further evidence in support of a simple and reliable clock-drawing scoring system in follow-up studies to evaluate cognitive decline, which can be used in assessing the efficacy of medicine.
PMCID: PMC4038629  PMID: 24874454
2.  Ethanol extract of Cirsium japonicum attenuates hepatic lipid accumulation via AMPK activation in human HepG2 cells 
One of the most common causes of chronic liver disease, nonalcoholic fatty liver disease (NAFLD), is strongly associated with obesity and dysregulated insulin action in the liver. However, there are no pharmacological agents currently established for the treatment of NAFLD. A flowering plant in the Asteraceae family, Cirsium japonicum (CJ), exhibits a variety of pharmacological and antioxidative properties that promote hepatoprotection. In the present study, CJ ethanol extract was shown to reduce hepatic triglyceride (TG) and cholesterol accumulation. CJ significantly increased AMP-activated protein kinase (AMPK) phosphorylation in HepG2 hepatocytes and downregulated the level of the target genes, acetyl-CoA carboxylase and fatty acid synthase. In addition, CJ upregulated the expression of carnitine palmitoyltransferase-1, which is involved in fatty acid oxidation. The results of the present study indicated that the positive effects of CJ extract on high-fat diet-induced hepatic TG accumulation were mediated via the AMPK signaling pathway, indicating a potential target for the preventative treatment of NAFLD.
PMCID: PMC4061235  PMID: 24944601
Cirsium japonicum; nonalcoholic fatty liver disease; AMP-activated protein kinase; fatty acid oxidation
3.  Cognitive Decline in Patients with Alzheimer’s Disease and Its Related Factors in a Memory Clinic Setting, Shanghai, China 
PLoS ONE  2014;9(4):e95755.
Progressive cognitive decline is a characteristic hallmark of AD. It is important to identify prognostic markers to improve patient care and long-term planning. We aimed to identify the characteristics of disease progression in AD patients, focusing on cognitive decline and its related factors.
Clinically diagnosed AD patients in a memory clinic were followed. The mini–mental state examination (MMSE) and a battery of other neuropsychological tests were performed to assess the rate of cognitive decline and to analyze the related factors.
A total of 165 AD patients were analyzed for cognitive changes. The MMSE scores declined at a rate of 1.52 points per year. Most neuropsychological test scores deteriorated significantly over time. Younger and early-onset AD patients deteriorated more rapidly than older and late-onset patients in global cognition and executive function. Men declined faster in memory but slower in attention than women. Higher education was associated with more rapid deterioration in visuo-spatial ability. Family history, hypertension and cerebral vascular disease were also associated with disease progression.
Attention, executive and visuo-spatial functions deteriorate at faster rates than other cognitive functions in AD patients. Age and age at onset were the main factors that associated with deterioration.
PMCID: PMC3994158  PMID: 24752600
4.  Accuracy of 16/18G core needle biopsy for ultrasound-visible breast lesions 
To assess the accuracy of ultrasound-guided 16G or 18G core needle biopsy (CNB) for ultrasound-visible breast lesions, and to analyze the effects of lesion features.
Between July 2005 and July 2012, 4,453 ultrasound-detected breast lesions underwent ultrasound-guided CNB and were retrospectively reviewed. Surgical excision was performed for 955 lesions (566 with 16G CNB and 389 with 18G CNB) which constitute the basis of the study. Histological findings were compared between the ultrasound-guided CNB and the surgical excision to determine sensitivity, false-negative rate, agreement rate, and underestimation rate, according to different lesion features.
Final pathological results were malignant in 84.1% (invasive carcinoma, ductal carcinoma in situ, lymphoma, and metastases), high-risk in 8.4% (atypical lesions, papillary lesions, and phyllodes tumors), and benign in 7.5%. False-negative rates were 1.4% for 16G and 18G CNB. Agreement rates between histological findings of CNB and surgery were 92.4% for 16G and 92.8% for 18G CNB. Overall underestimate rates (high-risk CNB becoming malignant on surgery and ductal carcinoma in situ becoming invasive carcinoma) were 47.4% for 16G and 48.9% for 18G CNB. Agreements were better for mass lesions (16G: 92.7%; 18G: 93.7%) than for non-mass lesions (16G, 85.7%; 18G, 78.3%) (P <0.01). For mass lesions with a diameter ≤10 mm, the agreement rates (16G, 83.3%; 18G, 86.7%) were lower (P <0.01).
Ultrasound-guided 16G and 18G CNB are accurate for evaluating ultrasound-visible breast mass lesions with a diameter >10 mm.
PMCID: PMC3895748  PMID: 24400744
Breast; Beast cancer; Core needle biopsy; Surgical excision; Ultrasound
5.  Prevalence and Risk Factors of Poor Sleep Quality among Chinese Elderly in an Urban Community: Results from the Shanghai Aging Study 
PLoS ONE  2013;8(11):e81261.
Sleep disorders causes a significant negative effect on mental and physical health, particularly among the elderly. The disease burden and risk factors of poor sleep quality of the elderly need to be verified using a validated form of measurement in urban mainland China.
This study included 1086 community residents aged ≥60 years who completed the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI). Poor sleeper was defined by a CPSQI global score of >5. Subjects also accepted the neurological and neuropsychological assessments, including the Mini-Mental State Examination, Center for Epidemiological Studies Depression Scale, and Zung Self-Rating Anxiety Scale (ZSAS). A history of chronic diseases was confirmed by the medical records of each participant.
The prevalence of poor sleep quality in this population was 41.5% (95% confidence interval (CI) = 38.6–44.5%), with a higher rate observed in elderly females (45.8% [95% CI = 41.9–49.7%]) than that in elderly males (35.8% [95% CI = 31.4–40.1%]). The prevalence rate increased with age, from 32.1% (95% CI = 27.8–36.4%) in those aged 60–69 years to 52.5% (95% CI = 45.9–59.1%) in those aged ≥80 years (p value for trend<0.001). Multivariate logistic regression analysis indicated that age (OR = 1.03[95% CI = 1.01–1.05], p<0.001), less education duration (OR = 1.04 [95% CI = 1.01–1.08, p = 0.014), living alone (OR = 1.62 [95% CI = 1.02–2.58], p = 0.04), anxiety (ZSAS score: OR = 1.09 [95% CI = 1.05–1.12], p<0.001), number of chronic disease (OR = 1.18 [95% CI = 1.07–1.30], p = 0.14) and arthritis (OR = 1.45[95% CI = 1.05–2.01], p = 0.025) were risk factors of poor sleep quality.
Poor sleep quality is highly prevalent among elderly Chinese residents in urban Shanghai. Growing attention and comprehensive countermeasures involving psycho-social and personal activities might alleviate the sleep problem in the elderly.
PMCID: PMC3839883  PMID: 24282576
6.  Aurora kinase inhibitor VE 465 synergistically enhances cytotoxicity of carboplatin in ovarian cancer cells through induction of apoptosis and downregulation of histone 3 
Cancer Biology & Therapy  2012;13(11):1034-1041.
Aurora kinases are essential for regulation of chromosome segregation and cytokinesis during mitosis and play a role in growth and progression of human tumors, including ovarian cancer. Aurora A and Aurora B are frequently overexpressed in high-grade and low-grade ovarian cancers. Targeting Aurora kinases has great potential for improving the efficacy of chemotherapies of ovarian cancer. In this study, we investigated whether the Aurora kinase inhibitor, VE 465, can enhance the anti-tumor activity of carboplatin in human ovarian cancer cells. The antitumor activity of VE 465 was tested by MTT proliferative assay in multiple established human epithelial ovarian cancer cell lines of varying p53 status. VE 465 and carboplatin had a synergistic effect on cell viability in both platinum-sensitive and -resistant ovarian cancers. The growth-inhibitory effect was accompanied by reduction in expression of histone 3 and an increase in apoptosis. We conclude that VE 465 enhances the efficacy of carboplatin agents in ovarian carcinoma.
PMCID: PMC3461810  PMID: 22895067
ovarian cancer; Aurora kinases; Aurora kinase inhibitors; chemosensitization
7.  Development of a porcine skin injury model and characterization of the dose-dependent response to high-dose radiation 
Journal of Radiation Research  2013;54(5):823-831.
A porcine skin model was developed to characterize the dose-dependent response to high-dose radiation. The dorsal skin of a mini pig was divided into four paraspinal sections, with 11 small irradiation fields (2 cm × 2 cm) in each section, and a single fraction of 15, 30, 50 or 75 Gy was delivered to each section using a 6 MeV electron beam. A spectrophotometer measured gross skin changes, and a biopsy for each radiation dose was performed in the 1st, 2nd, 4th, 6th and 9th weeks for histology, immunostaining with anti-CD31, and western blotting with IL-6 and TGF-β1 to determine the degree of skin damage. After a 4-week latency period, erythema and dry desquamation, moist desquamation, and ulceration appeared at 4, 6 and 9 weeks, respectively. Gross skin toxicity was more pronounced, occurred early and continued to progress with irradiation >50 Gy, whereas complete healing was observed 12 weeks after 15 Gy. Spectrophotometry showed erythema indices rapidly increased during the first 4 weeks after irradiation. The number of eosinophils began rising sharply at 4 weeks and normalized after reaching peaks at 7–8 weeks. Microvessel density showed a biphasic pattern with a transient peak at 1 week, a nadir at 4–6 weeks, and maximum recovery at 9 weeks. Increase in the levels of IL-6 and TGF-β1 was detected soon after irradiation. Most of these parameters indicated complete healing of the skin 12 weeks after 15 Gy. Our porcine skin model provides an effective platform for studying high-dose radiation-induced skin injury, in particular histologic and molecular changes, during the early latency period.
PMCID: PMC3766288  PMID: 23449639
radiation skin injury; porcine skin model; high-dose radiation
8.  The Shape Trail Test: Application of a New Variant of the Trail Making Test 
PLoS ONE  2013;8(2):e57333.
The Trail making test (TMT) is culture-loaded because of reliance on the Latin alphabet, limiting its application in Eastern populations. The Shape Trail Test (STT) has been developed as a new variant. This study is to examine the applicability of the STT in a senile Chinese population and to evaluate its potential advantages and disadvantages.
A total of 2470 participants were recruited, including 1151 cognitively normal control (NC), 898 amnestic mild cognitive impairment (aMCI), and 421 mild Alzheimer disease (AD) patients. Besides the STT, the Mini mental state examination and a comprehensive neuropsychological battery involving memory, language, attention, executive function and visuospatial ability were administered to all the participants. In a subgroup of 100 NC and 50 AD patients, both the STT and the Color Trail Test (CTT) were performed.
In NC, the time consumed for Part A and B (STT-A and STT-B) significantly correlated with age and negatively correlated with education (p<0.01). STT-A and B significantly differed among the AD, aMCI and NC. The number that successfully connected within one minute in Part B (STT-B-1 min) correlated well with STT-B (r = 0.71, p<0.01) and distinguished well among NC, aMCI and AD. In the receiver operating characteristic curve analysis, the AUCs (area under the curve) for STT-A, STT-B, and STT-B-1min in identifying AD were 0.698, 0.694 and 0.709, respectively. The STT correlated with the CTT, but the time for completion was longer.
The TMT is a sensitive test of visual search and sequencing. The STT is a meaningful attempt to develop a “culture-fair” variant of the TMT in addition to the CTT.
PMCID: PMC3577727  PMID: 23437370
9.  Therapeutic Effects of Water Soluble Danshen Extracts on Atherosclerosis 
Danshen is a traditional Chinese medicine with many beneficial effects on cardiovascular diseases. The aim of this study was to evaluate the mechanisms responsible for the antiatherogenic effect of water soluble Danshen extracts (DEs). Rat vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs) were treated with DE. To evaluate the effects of DE in vivo, carotid balloon injury and tail vein thrombosis were induced in Sprague-Dawley (SD) rats and iliac artery stent was induced in New Zealand white rabbits. The inhibitory action of DE on platelet aggregation was confirmed with an impedance aggregometer. DE inhibited the production of reactive oxygen species, and the migration and proliferation of platelet-derived growth factor-BB stimulated VSMCs. Furthermore, DE prevented inflammation and apoptosis in HUVECs. Both effects of DE were reconfirmed in both rat models. DE treatment attenuated platelet aggregation in both in vivo and ex vivo conditions. Pretreatment with DE prevented tail vein thrombosis, which is normally induced by κ-carrageenan injection. Lastly, DE-treated rabbits showed decreased in-stent restenosis of stented iliac arteries. These results suggest that water soluble DE modulates key atherogenic events in VSMCs, endothelial cells, and platelets in both in vitro and in vivo conditions.
PMCID: PMC3562667  PMID: 23401716
10.  Cultivating stem cells for treating amyotrophic lateral sclerosis 
World Journal of Stem Cells  2012;4(12):117-119.
This editorial addresses the current challenges and future directions in the use of stem cells as an approach for treating amyotrophic lateral sclerosis. A wide variety of literature has been reviewed to enlighten the reader on the many facets of stem cell research that are important to consider before using them for a cell based therapy.
PMCID: PMC3600561  PMID: 23516096
Stem cell therapy; Amyotrophic lateral sclerosis
11.  Short-Term Delayed Recall of Auditory Verbal Learning Test Is Equivalent to Long-Term Delayed Recall for Identifying Amnestic Mild Cognitive Impairment 
PLoS ONE  2012;7(12):e51157.
Delayed recall of words in a verbal learning test is a sensitive measure for the diagnosis of amnestic mild cognitive impairment (aMCI) and early Alzheimer’s disease (AD). The relative validity of different retention intervals of delayed recall has not been well characterized. Using the Auditory Verbal Learning Test–Huashan version, we compared the differentiating value of short-term delayed recall (AVL-SR, that is, a 3- to 5-minute delay time) and long-term delayed recall (AVL-LR, that is, a 20-minute delay time) in distinguishing patients with aMCI (n = 897) and mild AD (n = 530) from the healthy elderly (n = 1215). In patients with aMCI, the correlation between AVL-SR and AVL-LR was very high (r = 0.94), and the difference between the two indicators was less than 0.5 points. There was no difference between AVL-SR and AVL-LR in the frequency of zero scores. In the receiver operating characteristic curves analysis, although the area under the curve (AUC) of AVL-SR and AVL-LR for diagnosing aMCI was significantly different, the cut-off scores of the two indicators were identical. In the subgroup of ages 80 to 89, the AUC of the two indicators showed no significant difference. Therefore, we concluded that AVL-SR could substitute for AVL-LR in identifying aMCI, especially for the oldest patients.
PMCID: PMC3517417  PMID: 23236445
12.  Paragonimiasis in Chinese Children: 58 Cases Analysis 
Iranian Journal of Pediatrics  2012;22(4):505-511.
To analyze the clinical and radiological features of paragonimiasis in children and raise the awareness of this disease.
A total of 58 paragonimiasis patients were reviewed. They were 42 boys and 16 girls aged 2.0 to 15.3 years.
Among these patients, 20 were diagnosed in the recent 5 years, 46 with a history of raw water or food ingestion. Except 2 patients without any complaint, the most common features involved the systemic (41, 70.7%) and respiratory systems (43, 74.1%), followed by abdominal, cardiac and nervous systems, with rash and mass. Eosinophilia was noted in 46 (79.3%) patients, granulocytosis in 45 (77.6%), anemia in 14 (24.1%), and thrombocytopenia in 3. Imageology showed pneumonia in 26 (44.8%) patients, pleurisy in 28 (48.3%), hydropericardium in 17 (29.3%), ascites in 16 (27.6%), and celiac lymphadenitis in 13 (22.4%). Besides hepatomegaly and splenomegaly, calcification and multiple lamellar low echogenic areas in the liver were noted, each in one patient. Abnormal brain imaging was noted in 4 of 10 patients. Karyocyte hyperplasia with eosinophilia was noted in all the 19 patients who received bone marrow puncture.
Paragonimiasis should be considered in the differential diagnosis of patients with multiple organs or system lesions, especially those with eosinophilia, serous cavity effusion, respiratory, cardiac, digestive system, nervous system abnormality, and/or mass. Healthy eating habit is helpful for paragonimiasis prevention.
PMCID: PMC3533152  PMID: 23430310
Paragonimiasis; Paragonimus; Metacercariae; Eosinophilia; China
13.  PINCH Expression and Its Clinicopathological Significance in Gastric Adenocarcinoma 
Disease markers  2012;33(4):171-178.
Objective: Particularly interesting new cysteine-histidine rich protein (PINCH) is an important component of the local adhesion complexes and upregulated in several types of malignancies, and involved in the incidence and development of tumours. PINCH expression is also independently correlated with poorer survival in patients with colorectal cancer. However, there is no study of PINCH in gastric cancer, therefore, the aim of this project was to investigate PINCH expression and its clinicopathological significance in gastric adenocarcinoma.
Patients and methods: PINCH expression was immunohistochemically examined in normal gastric mucous (n = 30) and gastric adenocarcinoma (n = 73), from gastric cancer patients.
Results: PINCH expression in the associated-stroma of gastric cancers was heterogeneous, and its positive rate (75%) was higher than that of normal gastric mucosa (43%, X2 = 9.711, p = 0.002). The stronger staining was observed at the invasive edge of tumour when compared to the inner area of tumour. The rate of positive PINCH (88%) in the cases with lymph node metastasis was higher than that (52%) in the cases without metastasis (X2 = 11.151, p = 0.001). PINCH expression was not correlated with patients’ gender, age, tumour size, differentiation and invasion depth (p > 0.05).
Comclusion: PINCH protein might play an important role in the tumourigenesis and metastasis of gastric adenocarcinoma.
PMCID: PMC3810708  PMID: 22976000
PINCH; gastric adenocarcinoma; metastasis; immunohistochemistry
14.  Microanatomy of the spermatic cords during microsurgical inguinal varicocelectomy: initial experience in Asian men 
Asian Journal of Andrology  2012;14(6):897-899.
The microanatomy of the inguinal spermatic cords has never been reported in Asia. The purpose of this study was to describe the number and relationship of the veins, arteries and lymphatics in the spermatic cord and to clarify the location of the vas deferens in Asian men. Fifty-one patients receiving 79 primary microsurgical varicocelectomies performed by a single surgeon from April 2011 to July 2012 were studied. The number of internal and external spermatic veins, testicular arteries and lymphatic channels preserved during the inguinal microsurgical varicocelectomy were recorded. The relationship between the right and left vascular anatomy during bilateral varicocelectomies was evaluated. The data showed that mean numbers of 1.5±0.9 arteries, 5.6±2.2 spermatic veins and 3.6±1.9 lymphatics were identified during the repairs. The internal spermatic arteries were surrounded by a dense complex of adherent veins in 81.2% of the cases. The external spermatic vein or veins were found in 60.8% of the cases. The vas deferens may be contained within the internal spermatic fascia. The results suggest that the number of veins may be highly variable and less than those reported in the English literature, but there is some similarity in the inguinal microanatomy of the right and left spermatic cords. Further research is warranted to clarify our results.
PMCID: PMC3720110  PMID: 23064683
infertility; spermatic cord; varicocele
15.  Cytoplasmic expression of p33ING1b is correlated with tumorigenesis and progression of human esophageal squamous cell carcinoma 
Oncology Letters  2012;5(1):161-166.
p33ING1b, a newly discovered candidate tumor suppressor gene and a nuclear protein, belongs to the inhibitor of growth gene family. Previous studies have shown that p33ING1b is involved in the restriction of cell growth and proliferation, apoptosis, tumor anchorage-independent growth, cellular senescence, maintenance of genomic stability and modulation of cell cycle checkpoints. Loss of nuclear p33ING1b has been observed in melanoma, seminoma, papillary thyroid carcinoma, oral squamous cell carcinoma, breast ductal cancer and acute lymphoblastic leukemia. Inactivation and/or decreased expression of p33ING1b have been reported in various types of cancer, including head and neck squamous cell, breast, lung, stomach, blood and brain malignancies. Since little is known about the clinicopathological significance of p33ING1b in esophageal squamous cell carcinoma (ESCC), this study aimed to investigate the association of p33ING1b expression with clinicopathological variables and particularly interesting new cysteine-histidine rich protein (PINCH) in patients with ESCC. p33ING1b expression was examined by immunohistochemistry in 20 normal esophageal mucosa and in 64 ESCC specimens. The results revealed that the positive expression of p33ING1b protein in normal squamous cells was localized in the nucleus alone and the positive rate was 95%, while in ESCCs, the positive expression was mainly in the cytoplasm, together with nuclear expression, and the positive rate was 36% (P<0.0001). Furthermore, the cases with lymph node metastasis showed a higher frequency of positive cytoplasmic expression than those without metastasis (P=0.001). The cytoplasmic expression of p33ING1b was positively related to PINCH expression (P<0.0001) in ESCC, and the cases positive for both proteins had a high lymph node metastasis rate (P=0.001). In conclusion, p33ING1b cellular compartmental shift from the nucleus to the cytoplasm may cause loss of normal cellular function and play a central role in the tumorigenesis and metastasis of ESCC.
PMCID: PMC3525348  PMID: 23255913
immunohistochemistry; p33ING1b; PINCH; esophageal squamous cell carcinoma; metastasis
16.  Memory and Executive Screening (MES): a brief cognitive test for detecting mild cognitive impairment 
BMC Neurology  2012;12:119.
Mild cognitive impairment (MCI), defined as a transitional zone between normal cognition and dementia, requires a battery of formal neuropsychological tests administered by a trained rater for its diagnosis. The objective of this study was to develop a screening tool for MCI.
One hundred ninety seven cognitively normal controls (NC), one hundred sixteen patients with amnestic MCI –single domain (aMCI-sd), one hundred ninety five patients with amnestic MCI-multiple domain (aMCI-md), and two hundred twenty eight patients with mild Alzheimer’s disease (AD) were evaluated by comprehensive neuropsychological tests and by the Memory and Executive Screening (MES).
Correlation analysis showed that the three indicators of the MES were significantly negatively related with age (P<0.05), yet not related with education (P>0.05). There was no ceiling or floor effect. Test completion averaged seven minutes (421.14±168.31 seconds). The receiver operating characteristics (ROC) analyses performed on the aMCI-sd group yielded 0.89 for the area under the curve (AUC) (95% CI, 0.85–0.92) for the MES-total score, with sensitivity of 0.795 and specificity of 0.828. There was 81% correct classification rate when the cut-off was set at less than 75. Meanwhile, the aMCI-md group yielded 0.95 for the AUC (95% CI, 0.93–0.97) for the MES-total score, with sensitivity of 0.87 and specificity of 0.91, and 90% correct classification rate when the cut-off was set at less than 72.
The MES, minimally time-consuming, may be a valid and easily administered cognitive screening tool with high sensitivity and specificity for aMCI, with single or multiple domain impairment.
PMCID: PMC3492138  PMID: 23050770
Mild cognitive impairment (MCI); Amnestic MCI-single domain (aMCI-sd); Amnestic MCI-multiple domain (aMCI-md); Alzheimer’s disease (AD); Memory and Executive Screening (MES); Mini-Mental State Examination (MMSE)
17.  Cancer stem cells from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall 
The cancer stem cell (CSC) hypothesis posits that deregulated neural stem cells (NSCs) form the basis of brain tumors such as glioblastoma multiforme (GBM). GBM, however, usually forms in the cerebral white matter while normal NSCs reside in subventricular and hippocampal regions. We attempted to characterize CSCs from a rare form of glioblastoma multiforme involving the neurogenic ventricular wall.
We described isolating CSCs from a GBM involving the lateral ventricles and characterized these cells with in vitro molecular biomarker profiling, cellular behavior, ex vivo and in vivo techniques.
The patient’s MRI revealed a heterogeneous mass with associated edema, involving the left subventricular zone. Histological examination of the tumor established it as being a high-grade glial neoplasm, characterized by polygonal and fusiform cells with marked nuclear atypia, amphophilic cytoplasm, prominent nucleoli, frequent mitotic figures, irregular zones of necrosis and vascular hyperplasia. Recurrence of the tumor occurred shortly after the surgical resection. CD133-positive cells, isolated from the tumor, expressed stem cell markers including nestin, CD133, Ki67, Sox2, EFNB1, EFNB2, EFNB3, Cav-1, Musashi, Nucleostemin, Notch 2, Notch 4, and Pax6. Biomarkers expressed in differentiated cells included Cathepsin L, Cathepsin B, Mucin18, Mucin24, c-Myc, NSE, and TIMP1. Expression of unique cancer-related transcripts in these CD133-positive cells, such as caveolin-1 and −2, do not appear to have been previously reported in the literature. Ex vivo organotypic brain slice co-culture showed that the CD133+ cells behaved like tumor cells. The CD133-positive cells also induced tumor formation when they were stereotactically transplanted into the brains of the immune-deficient NOD/SCID mice.
This brain tumor involving the neurogenic lateral ventricular wall was comprised of tumor-forming, CD133-positive cancer stem cells, which are likely the driving force for the rapid recurrence of the tumor in the patient.
PMCID: PMC3546918  PMID: 22995409
Glioblastoma multiforme; Primary tumors; Brain tumor stem cells; Cancer stem cells; Organotypic brain slice culture
18.  The microRNA miR-181c controls microglia-mediated neuronal apoptosis by suppressing tumor necrosis factor 
Post-ischemic microglial activation may contribute to neuronal damage through the release of large amounts of pro-inflammatory cytokines and neurotoxic factors. The involvement of microRNAs (miRNAs) in the pathogenesis of disorders related to the brain and central nervous system has been previously studied, but it remains unknown whether the production of pro-inflammatory cytokines is regulated by miRNAs.
BV-2 and primary rat microglial cells were activated by exposure to oxygen-glucose deprivation (OGD). Global cerebral ischemia was induced using the four-vessel occlusion (4-VO) model in rats. Induction of pro-inflammatory and neurotoxic factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and nitric oxide (NO), were assessed by ELISA, immunofluorescence, and the Griess assay, respectively. The miRNA expression profiles of OGD-activated BV-2 cells were subsequently compared with the profiles of resting cells in a miRNA microarray. BV-2 and primary rat microglial cells were transfected with miR-181c to evaluate its effects on TNF-α production after OGD. In addition, a luciferase reporter assay was conducted to confirm whether TNF-α is a direct target of miR-181c.
OGD induced BV-2 microglial activation in vitro, as indicated by the overproduction of TNF-α, IL-1β, and NO. Global cerebral ischemia/reperfusion injury induced microglial activation and the release of pro-inflammatory cytokines in the hippocampus. OGD also downregulated miR-181c expression and upregulated TNF-α expression. Overproduction of TNF-α after OGD-induced microglial activation provoked neuronal apoptosis, whereas the ectopic expression of miR-181c partially protected neurons from cell death caused by OGD-activated microglia. RNAinterference-mediated knockdown of TNF-α phenocopied the effect of miR-181c-mediated neuronal protection, whereas overexpression of TNF-α blocked the miR-181c-dependent suppression of apoptosis. Further studies showed that miR-181c could directly target the 3′-untranslated region of TNF-α mRNA, suppressing its mRNA and protein expression.
Our data suggest a potential role for miR-181c in the regulation of TNF-α expression after ischemia/hypoxia and microglia-mediated neuronal injury.
PMCID: PMC3488569  PMID: 22950459
Microglial activation; Hypoxia; Neuronal apoptosis; miR-181c; TNF-α
19.  Targeted therapy for glioma using cyclic RGD-entrapped polyionic complex nanomicelles 
The purpose of this study was to test the efficacy of cyclic Arg-Gly-Asp (RGD) peptide conjugated with polyionic complex nanomicelles as targeted therapy for glioma.
A stable cyclic RGD polyionic complex nanostructure, ie, a c(RGDfC) polyionic complex micelle, was synthesized and its biocompatibility with cultured neurons was assessed using a cell viability assay. Targeted binding to cultured glioma cells was evaluated by the CdTe quantum dot marking technique and a cell viability assay. The inhibitory effect of the nanomicelles against glioma cells was also evaluated, and their targeted migration into rat brain glioma cells and apoptotic effects were traced by the CdTe quantum dot marking and immunohistochemical staining.
c(RGDfC) polyionic complex micelles did not affect the growth of neurons but bonded selectively to and inhibited proliferation of glioma cells in vitro. When tested in vivo, the micelles migrated into glioma cells, inducing apoptosis in the rat brain.
The c(RGDfC) polyionic complex micelle is an effective targeted therapy against glioma.
PMCID: PMC3383325  PMID: 22745548
Arg-Gly-Asp; RGD; polyion complex; micelle; glioma; target therapy
20.  1,1′-(Butane-1,4-di­yl)bis­[2-(pyridin-2-yl)-1H-benzimidazole] 
The complete mol­ecule of the title compound, C28H24N6, is generated by inversion symmetry with the inversion centre located at the mid-point of the central C–C bond of the butanediyl unit. The benzimidazole and pyridine rings are almost coplanar, the dihedral angle between their mean planes being 6.86 (11)°.
PMCID: PMC3344554  PMID: 22590316
21.  ZP123 Reduces Energy Required for Defibrillation by Preventing Connexin43 Remodeling during Prolonged Ventricular Fibrillation in Swine 
Texas Heart Institute Journal  2012;39(6):784-791.
In ventricular fibrillation, the uncoupling of gap junctions slows conduction velocity and increases action-potential dispersion, which slows and diminishes defibrillation. We studied how the peptide ZP123, a gap-junction enhancer, might lower defibrillation-energy requirements during ventricular fibrillation in live pigs.
We randomly assigned 33 pigs into 3 groups: ZP123 (receiving a 1-µg/kg bolus and 10 µg/kg/hr of ZP123), control (receiving saline solution), and sham (undergoing a sham operation). After a 30-min administration of agents, ventricular fibrillation was induced and left untreated for 8 min. Biphasic defibrillation of 50 J was increased by 50-J increments as necessary. Defibrillation-energy requirements were defined as the lowest energy required to achieve defibrillation. Electrocardiographic values were obtained before and after the administration of agents. Western blot and immunofluorescence analyses were performed on ventricular myocardial samples.
All but one pig survived. The ZP123 treatment did not alter electrocardiographic variables. In the ZP123 group, the average required defibrillation energy was lower than that in the control group (327.28 ± 269.6 vs 610 ± 192.64 J; P=0.015), and the cumulative percentage of successful defibrillation at upper energy levels was higher (P <0.05). Supraventricular rhythm occurred more often in the ZP123 group than in the control group (72.7% vs 50%, P=0.042). Western-blot and immunofluorescence results showed that ZP123 did not alter the total amount of connexin43 but did prevent its dephosphorylation. We conclude that ZP123 can reduce defibrillation-energy requirements by preventing connexin43 remodeling during prolonged ventricular fibrillation.
PMCID: PMC3528250  PMID: 23304014
Anti-arrhythmia agents/administration & dosage/therapeutic use; arrhythmias, cardiac/prevention & control; connexin 43/analysis/metabolism; gap junctions/drug effects/metabolism/physiology; models, cardiovascular; phosphorylation/drug effects; swine; treatment outcome; ventricular fibrillation/therapy
22.  Brain Morphology and Cerebrovascular Risk in Mild Cognitive Impairment and Dementia: SCOBHI-P study 
Archives of neurology  2010;67(10):1231-1237.
To investigate associations between MRI brain morphology, cerebrovascular risk (VR), clinical diagnosis and cognition among elders living in urban Shanghai.
Cross-sectional study.
Memory Disorders Clinic and community normal control (NC) subject recruitment.
Ninety-six older subjects, 32 with normal cognition, 30 with amnestic MCI (aMCI) and 34 with dementia.
Main outcome measures
Each subject received medical history, neurological/physical exams, neuropsychological evaluations, brain MRI and apolipoprotein E-ε4 (APOE -ε4) genotype test. MRI volumes were assessed using a semi-automatic method.
Brain volume (BV) was significantly smaller in the demented compared with NC (p < 0.001) or aMCI (p = 0.043). Hippocampal volume (HV) was lower, and white matter hyperintensity volume (WMH) was higher, in aMCI (HV: p = 0.028; WMH: p = 0.041) and dementia (HV: p < 0.001; WMH: p = 0.002) compared with NC. APOE -ε4 presence was significantly associated with reduced HV (p = 0.02). Systolic blood pressure was positively associated with VR score (p = 0.037); diastolic blood pressure (p = 0.021) and VR score (p = 0.036) were both positively associated with WMH. WMH (p = 0.029) and VR (p = 0.031) were both higher among the demented than NC.
MRI brain morphology changes were significantly associated clinical diagnosis, in addition, blood pressure was highly associated with VR score and WMH. These results suggest that MRI is a valuable measure of brain injury in a Chinese cohort and can serve to assess the effects of various degenerative and cerebrovascular pathologies.
PMCID: PMC3051396  PMID: 20937951
Dementia; Mild Cognitive Impairment; Magnetic Resonance Imaging; white matter hyperintensities; hippocampal volume; cerebrovascular risk; apolipoprotein E genotype; cognition
23.  Timing Is Critical for an Effective Anti-Metastatic Immunotherapy: The Decisive Role of IFNγ/STAT1-Mediated Activation of Autophagy 
PLoS ONE  2011;6(9):e24705.
Immunotherapy is often recommended as an adjuvant treatment to reduce the chance of cancer recurrence or metastasis. Interestingly, timing is very important for a successful immunotherapy against metastasis, although the precise mechanism is still unknown.
Methods and Findings
Using a mouse model of melanoma metastasis induced by intravenous injection of B16-F10 cells, we investigated the mechanism responsible for the diverse efficacy of the prophylactic or therapeutic TLR4 and TLR9 agonist complex against metastasis. We found that the activation of TLR4 and TLR9 prevented, but did not reverse, metastasis because the potency of this combination was neither sufficient to overcome the tumor cell-educated immune tolerance nor to induce efficacious autophagy in tumor cells. The prophylactic application of the complex promoted antimetastatic immunity, leading to the autophagy-associated death of melanoma cells via IFNγ/STAT1 activation and attenuated tumor metastasis. IFNγ neutralization reversed the prophylactic benefit induced by the complex by suppressing STAT1 activation and attenuating autophagy in mice. However, the therapeutic application of the complex did not suppress metastasis because the complex could not reverse tumor cell-induced STAT3 activation and neither activate IFNγ/STAT1 signaling and autophagy. Suppressing STAT3 activation with the JAK/STAT antagonist AG490 restored the antimetastatic effect of the TLR4/9 agonist complex. Activation of autophagy after tumor inoculation by using rapamycin, with or without the TLR4/9 agonist complex, could suppress metastasis.
Conclusion and Significance
Our studies suggest that activation of IFNγ/STAT1 signaling and induction of autophagy are critical for an efficacious anti-metastatic immunotherapy and that autophagy activators may overcome the timing barrier for immunotherapy against metastasis.
PMCID: PMC3172290  PMID: 21931823
24.  Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson disease 
Neuroscience letters  2010;480(1):78-82.
DJ-1 and α-synuclein are leading biomarkers for Parkinson disease diagnosis and/or monitoring disease progression. A few recent investigations have determined DJ-1 and α-synuclein levels in plasma or serum, a more convenient sample source than cerebrospinal fluid; but the results were variable or even contradictory. Besides limitations in detection technology and limited number of cases in some studies, inadequate control of several important confounders likely has contributed to these inconsistent results. In this study, the relative contribution of each blood component to blood DJ-1 and α-synuclein was evaluated, followed by quantification of plasma levels of both markers in a larger cohort of patients/subjects (~300 cases) whose cerebrospinal fluid DJ-1 and α-synuclein levels have been determined recently. The results demonstrated that the DJ-1 and α-synuclein in blood resided predominantly in red blood cells (>95%), followed by platelets (1-4%), white blood cells and plasma (≤1%), indicating that variations in hemolysis and/or platelet contamination could have a significant effect on plasma/serum DJ-1 and α-synuclein levels. Nonetheless, after adjusting for the age, although there was a trend of decrease in DJ-1 and α-synuclein in patients with Parkinson or Alzheimer disease compared with healthy controls, no statistical difference was observed in this cohort between any groups, even when the extent of hemolysis and platelet contamination were controlled for. Additionally, no correlation between DJ-1 or α-synuclein and Parkinson disease severity was identified. In conclusion, unlike in cerebrospinal fluid, total DJ-1 or α-synuclein in plasma alone is not useful as biomarkers for Parkinson disease diagnosis or progression/severity.
PMCID: PMC2943649  PMID: 20540987
Biomarker; DJ-1; α-synuclein; plasma; Parkinson disease; Alzheimer disease
25.  Comparison of interface contact profiles of a new minimum contact locking compression plate and the limited contact dynamic compression plate 
International Orthopaedics  2009;34(5):715-718.
In this study, we investigated whether or not a new minimum contact locking compression plate (MC-LCP) can provide advantages over the limited contact dynamic compression plate (LC-DCP) in the context of interface contact area and force. Six matched pairs of cadaveric bones were used for each of three bone types of the humerus, radius and ulna. For each bone type, one of two bone plates was fixed to either of two matched cadaveric bones at the middle of the diaphysis. The interface contact area and force of the plate fixed to three types of human cadaveric bones were evaluated using Fuji prescale pressure sensitive film. Data were quantitated using computer-assisted image analysis. Results showed that the average force between the MC-LCP and humerus or radius was about half of that of the LC-DCP. And the average force between the MC-LCP and ulna was one third less than that of the LC-DCP. Meanwhile, the interface contact area between the MC-LCP and humerus or radius was also about half of that of the LC-DCP, and the interface contact area between the MC-LCP and ulna was less than one third of that of the LC-DCP. These results indicate that the MC-LCP has lower interface contact area and lower average force than that of the LC-DCP. Thus, the MC-LCP system may be a good alternate to treat forearm diaphyseal fractures.
PMCID: PMC2903173  PMID: 19603166

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