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1.  Highly Constrained Backprojection for Time-Resolved MRI 
Recent work in k-t BLAST and undersampled projection angiography has emphasized the value of using training data sets obtained during the acquisition of a series of images. These techniques have used iterative algorithms guided by the training set information to reconstruct time frames sampled at well below the Nyquist limit. We present here a simple non-iterative unfiltered backprojection algorithm that incorporates the idea of a composite image consisting of portions or all of the acquired data to constrain the backprojection process. This significantly reduces streak artifacts and increases the overall SNR, permitting decreased numbers of projections to be used when acquiring each image in the image time series. For undersampled 2D projection imaging applications, such as cine phase contrast (PC) angiography, our results suggest that the angular undersampling factor, relative to Nyquist requirements, can be increased from the present factor of 4 to about 100 while increasing SNR per individual time frame. Results are presented for a contrast-enhanced PR HYPR TRICKS acquisition in a volunteer using an angular undersampling factor of 75 and a TRICKS temporal undersampling factor of 3 for an overall undersampling factor of 225.
doi:10.1002/mrm.20772
PMCID: PMC2366054  PMID: 16342275
time resolved MRI; constrained backprojection; undersampled data; ultra-fast imaging; acceleration factors
2.  Incidence Rates of Dementia, Alzheimer’s disease and Vascular Dementia in the Japanese American Population in Seattle, WA: The Kame Project 
There are few dementia incidence studies in representative minority populations in the U.S., and no population-based studies of Japanese American women. We identified 3,045 individuals aged 65+ with at least 1 parent of Japanese descent living in King County, WA in 1992–4, of which 1,836 were dementia-free and were examined every two years (1994–2001) to identify incident cases of all dementias, Alzheimer’s disease (AD), vascular dementia (VaD) and other dementias. Cox regression was used to examine associations with age, sex, years of education and Apolipoprotein (APOE)-ε4. Among 173 incident cases of dementia, the overall rate was 14.4/1,000/yr, with rates being slightly higher among women (15.9/1,000) than men (12.5/1,000). Rates roughly doubled every 5 years for dementia and AD; the age trend for VaD and other dementias was less consistent. Sex was not significantly related to incidence of dementia or its subtypes in adjusted models. There was a trend for an inverse association with increasing years of education. APOE-ε4 was a strong risk factor for all dementias (HR=2.89, 95% CI 1.88–4.46), AD (HR=3.27, 95% CI 2.03–5.28) and VaD (HR=3.33, 95% CI 1.34–8.27). This study is the first to report population-based incidence rates for both Japanese American men and women.
doi:10.1097/WAD.0b013e3182a2e32f
PMCID: PMC4036673  PMID: 24045327
Incidence rates; population-based cohort studies; risk factors; Alzheimer’s disease; vascular dementia; dementias
3.  Analyzing the influence of BDNF heterozygosity on spatial memory response to 17β-estradiol 
Translational Psychiatry  2015;5(1):e498-.
The recent use of estrogen-based therapies as adjunctive treatments for the cognitive impairments of schizophrenia has produced promising results; however the mechanism behind estrogen-based cognitive enhancement is relatively unknown. Brain-derived neurotrophic factor (BDNF) regulates learning and memory and its expression is highly responsive to estradiol. We recently found that estradiol modulates the expression of hippocampal parvalbumin-positive GABAergic interneurons, known to regulate neuronal synchrony and cognitive function. What is unknown is whether disruptions to the aforementioned estradiol–parvalbumin pathway alter learning and memory, and whether BDNF may mediate these events. Wild-type (WT) and BDNF heterozygous (+/−) mice were ovariectomized (OVX) at 5 weeks of age and simultaneously received empty, estradiol- or progesterone-filled implants for 7 weeks. At young adulthood, mice were tested for spatial and recognition memory in the Y-maze and novel-object recognition test, respectively. Hippocampal protein expression of BDNF and GABAergic interneuron markers, including parvalbumin, were assessed. WT OVX mice show impaired performance on Y-maze and novel-object recognition test. Estradiol replacement in OVX mice prevented the Y-maze impairment, a Behavioral abnormality of dorsal hippocampal origin. BDNF and parvalbumin protein expression in the dorsal hippocampus and parvalbumin-positive cell number in the dorsal CA1 were significantly reduced by OVX in WT mice, while E2 replacement prevented these deficits. In contrast, BDNF+/− mice showed either no response or an opposite response to hormone manipulation in both behavioral and molecular indices. Our data suggest that BDNF status is an important biomarker for predicting responsiveness to estrogenic compounds which have emerged as promising adjunctive therapeutics for schizophrenia patients.
doi:10.1038/tp.2014.143
PMCID: PMC4312832  PMID: 25603414
4.  Comparisons of vaginal and abdominal radical trachelectomy for early-stage cervical cancer: preliminary results of a multi-center research in China 
British Journal of Cancer  2013;109(11):2778-2782.
Background:
There are limited data comparing the prognosis and fertility outcomes of the patients with early cervical cancer treated by trans-vaginal radical trachelectomy (VRT) or abdominal radical trachelectomy (ART).The objective of this study was to compare the surgical and pathologic characteristics, the prognosis and fertility outcomes of the patients treated by VRT or ART.
Methods:
Matched-case study based on a prospectively maintained database of patients underwent radical trachelectomy in 10 centres of China was designed to compare the prognosis and fertility outcomes of the patients treated by VRT or ART.
Results:
Totally 150 cases, 77 in the VRT and 73 in the ART group, were included. VRT and ART provide similar surgical and pathological outcomes except larger specimens obtained by ART. In the ART group, no patient developed recurrent diseases, but, in the VRT group, 7 (9.8%) patients developed recurrent diseases and 2 (1.6%) patients died of the tumours (P=0.035). The rate of pregnancy in the VRT group was significantly higher than those of ART (39.5% vs 8.8% P=0.003). The patients with tumour size >2 cm showed significant higher recurrent rate (11.6% vs 2.4%, P<0.05) and lower pregnant rate (12.5% vs 32.1%, P=0.094) compared with the patients with tumour size <2 cm.
Conclusion:
Patients treated by ART obtained better oncology results, but their fertility outcomes were unfavourable compared with VRT. Tumour size <2 cm should be emphasised as an indication for radical trachelectomy for improving the outcome of fertility and prognosis.
doi:10.1038/bjc.2013.656
PMCID: PMC3844910  PMID: 24169350
radical trachelectomy; cervical cancer; fertility; prognosis
5.  Clinical-guide risk prediction of hepatocellular carcinoma development in chronic hepatitis C patients after interferon-based therapy 
British Journal of Cancer  2013;109(9):2481-2488.
Background:
Interferon (IFN)-based therapies could eradicate hepatitis C (HCV) and reduce the risk of hepatocellular carcinoma (HCC). However, HCC could still happen after sustained virological response (SVR). We aimed to develop a simple scoring system to predict the risk of HCC development among HCV patients after antiviral therapies.
Methods:
From 1999 to 2009, 1879 patients with biopsy-proven HCV infection treated with IFN-based therapies were analyzed.
Results:
Multivariable analysis showed old age (adjusted HR (aHR)=1.73, 95% CI=1.13–2.65 for aged 60–69 and aHR=2.20, 95% CI=1.43–3.37 for aged ⩾70), Male gender (aHR=1.74, 95% CI=1.26–2.41), platelet count <150 × 109/l (HR=1.91, 95% CI=1.27–2.86), α-fetoprotein ⩾20 ng ml−1 (HR=2.23, 95% CI=1.58–3.14), high fibrotic stage (HR=3.32, 95% CI=2.10–5.22), HCV genotype 1b (HR=1.53, 95% CI=1.10–2.14), and non SVR (HR=2.40, 95% CI=1.70–3.38) were independent risk factors for HCC. Regression coefficients were used to build up a risk score and the accuracy was evaluated by using the area under the receiver operating characteristic curve (AUC). Three groups as low-, intermediate-, and high-risk are classified based on the risk scores. One hundred sixty patients (12.78%) in the derivation and 82 patients (13.08%) in the validation cohort developed HCC with AUC of 79.4%, sensitivity of 84.38%, and specificity of 60.66%. In the validation cohort, the 5-year HCC incidence was 1.81%, 12.92%, and 29.95% in low-, intermediate-, and high-risk groups, with hazard ratios 4.49 in intermediate- and 16.14 in high-risk group respectively. The risk reduction of HCC is greatest in patients with SVR, with a 5-year and 10-year risk reduction of 28.91% and 27.99% respectively.
Conclusion:
The risk scoring system is accurate in predicting HCC development for HCV patients after antiviral therapies.
doi:10.1038/bjc.2013.564
PMCID: PMC3817320  PMID: 24084770
risk score; hepatitis C virus; interferon; hepatocellular carcinoma
6.  Expression of BCR/ABL p210 from a Knockin Allele Enhances Bone Marrow Engraftment Without Inducing Neoplasia 
Cell reports  2013;5(1):10.1016/j.celrep.2013.08.037.
Chronic myeloid leukemia (CML) and some acute lymphoblastic leukemias are characterized by the t(9;22) that encodes the BCR/ABL oncogene. Multiple mouse models of CML express BCR/ABL at high levels from non-Bcr promoters, resulting in the development of leukemias. In contrast, a significant fraction of healthy humans have been found to have BCR/ABL positive hematopoietic cells. To bridge the gap between the information derived from current mouse models and the non-leukemic humans with the BCR/ABL oncogene, we generated a knockin model with BCR/ABL p210 expressed from the Bcr locus. Unlike previous models, expression of BCR/ABL from the knockin allele did not induce leukemia. BCR/ABL mutant cells did exhibit favorable bone marrow engraftment compared to wild-type cells. These data suggest BCR/ABL expression alone is insufficient to induce disease. This new model allows for inducible spatial and temporal control of BCR/ABL expression for analysis of early steps in the pathogenesis of BCR/ABL-expressing leukemias.
doi:10.1016/j.celrep.2013.08.037
PMCID: PMC3832111  PMID: 24095735
7.  Prognostic value of the trichorhinophalangeal syndrome-1 (TRPS-1), a GATA family transcription factor, in early-stage breast cancer 
Annals of Oncology  2013;24(10):2534-2542.
Background
TRPS-1 is a new GATA transcription factor that is differentially expressed in breast cancer (BC) where it been found recently to regulate epithelial-to-mesenchymal transition (EMT).
Patients and methods
We carried out a quantitative immunohistochemistry (qIHC) analysis of TRPS-1 expression in 341 primary-stage I–III BC samples in relation to patient clinical characteristics as well as its prognostic value, especially in an estrogen receptor-positive (ER+) subgroup.
Results
Higher TRPS-1 expression was significantly associated with a number of clinical and pathological characteristics as well as with improved overall survival (OS) and disease-free survival (DFS). Among stage I/II ER+ BC patients who received endocrine therapy alone, those with high TRPS-1 expression had significantly longer OS and DFS. There was also a strong association between TRPS-1 levels and the EMT marker E-cadherin in the ER+ invasive ductal carcinoma cases. Analysis of gene expression data on a panel of BC lines found that TRPS-1 expression was low or absent in BC lines having enriched mesenchymal features.
Conclusions
Our data indicated that TRPS-1 is an independent prognostic marker in early-stage BC and a new EMT marker that can distinguish patients with ER+ BC who will respond longer to adjuvant endocrine therapy.
doi:10.1093/annonc/mdt190
PMCID: PMC3784330  PMID: 23729783
breast cancer; immunohistochemistry; prognostic marker; TRPS-1
8.  A stem cell-like gene expression signature associates with inferior outcomes and a distinct microRNA expression profile in adults with primary cytogenetically normal acute myeloid leukemia 
Leukemia  2013;27(10):2023-2031.
Acute myeloid leukemia (AML) is hypothesized to be sustained by self-renewing leukemia stem cells (LSCs). Recently, gene expression signatures (GES) from functionally defined AML LSC populations were reported, and expression of a ‘core enriched’ (CE) GES, representing 44 genes activated in LCSs, conferred shorter survival in cytogenetically normal (CN) AML. The prognostic impact of the CE GES in the context of other molecular markers, including gene mutations and microRNA (miR) expression alterations, is unknown and its clinical utility is unclear. We studied associations of the CE GES with known molecular prognosticators, miR expression profiles, and outcomes in 364 well-characterized CN-AML patients. A high CE score (CEhigh) associated with FLT3-internal tandem duplication, WT1 and RUNX1 mutations, wild-type CEBPA and TET2, and high ERG, BAALC and miR-155 expression. CEhigh patients had a lower complete remission (CR) rate (P=0.003) and shorter disease-free (DFS, P<0.001) and overall survival (OS, P<0.001) than CElow patients. These associations persisted in multivariable analyses adjusting for other prognosticators (CR, P=0.02; DFS, P<0.001; and OS, P<0.001). CEhigh status was accompanied by a characteristic miR expression signature. Fifteen miRs were upregulated in both younger and older CEhigh patients, including miRs relevant for stem cell function. Our results support the clinical relevance of LSCs and improve risk stratification in AML.
doi:10.1038/leu.2013.181
PMCID: PMC3890747  PMID: 23765227
acute myeloid leukemia; leukemic stem cells; gene expression profiling; prognostication; gene mutations
9.  Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction 
Molecular psychiatry  2013;18(10):1077-1089.
Autism spectrum disorders (ASDs) have been suggested to arise from abnormalities in the canonical and non-canonical Wnt signaling pathways. However, a direct connection between a human variant in a Wnt pathway gene and ASD-relevant brain pathology has not been established. Prickle2 (Pk2) is a post-synaptic non-canonical Wnt signaling protein shown to interact with post synaptic density 95 (PSD-95). Here we show that mice with disruption in Prickle2 display behavioral abnormalities including altered social interaction, learning abnormalities, and behavioral inflexibility. Prickle2 disruption in mouse hippocampal neurons led to reductions in dendrite branching, synapse number, and post-synaptic density size. Consistent with these findings, Prickle2 null neurons show decreased frequency and size of spontaneous miniature synaptic currents. These behavioral and physiological abnormalities in Prickle2 disrupted mice are consistent with ASD-like phenotypes present in other mouse models of ASDs. In 384 individuals with autism, we identified two with distinct, heterozygous, rare, non-synonymous PRICKLE2 variants (p.E8Q and p.V153I) that were shared by their affected siblings and inherited paternally. Unlike wild-type PRICKLE2, the PRICKLE2 variants found in ASD patients exhibit deficits in morphological and electrophysiological assays. These data suggest that these PRICKLE2 variants cause a critical loss of PRICKLE2 function. The data presented here provide new insight into the biological roles of Prickle2, its behavioral importance, and suggest disruptions in non-canonical Wnt genes such as PRICKLE2 may contribute to synaptic abnormalities underlying ASDs.
doi:10.1038/mp.2013.71
PMCID: PMC4163749  PMID: 23711981
Autism; planar cell polarity; learning; memory; Wnt
10.  Deficiency of osteoblastic Arl6ip5 impaired osteoblast differentiation and enhanced osteoclastogenesis via disturbance of ER calcium homeostasis and induction of ER stress-mediated apoptosis 
Wu, Y | Yang, M | Fan, J | Peng, Y | Deng, L | Ding, Y | Yang, R | Zhou, J | Miao, D | Fu, Q
Cell Death & Disease  2014;5(10):e1464-.
ADP-ribosylation-like factor 6 interacting protein 5 (Arl6ip5), which belongs to the prenylated rab-acceptor-family, has an important role in exocytic protein trafficking, glutathione metabolism and involves in cancer progression. However, its expression pattern and functional role in bone are unknown. Here we demonstrate that Arl6ip5 knock-out mice (Arl6ip5 Δ2/Δ2) show marked decrease of bone mineral density, trabecular bone volume and trabecular thickness. Histomorphometric studies reveal that bone formation parameters are decreased but bone resorption parameters and mRNA level of osteoclast-specific markers are increased in Arl6ip5Δ2/Δ2 mice. In osteoblast, we demonstrate that Arl6ip5 abundantly expresses in osteoblastic cells and is regulated by bone metabolism-related hormones and growth factors. In vitro analysis reveals that osteoblast proliferation and differentiation are impaired in Arl6ip5 knocked-down and deficient primary osteoblast. Arl6ip5 is also found to function as an ER calcium regulator and control calmodulin signaling for osteoblast proliferation. Moreover, Arl6ip5 insufficiency in osteoblast induces ER stress and enhances ER stress-mediated apoptosis. CCAAT/enhancer-binding protein homologous protein (Chop) is involved in the regulation of apoptosis and differentiation in Arl6ip5 knocked-down osteoblasts. For osteoclastogenesis, Arl6ip5 insufficiency in osteoclast precursors has no effect on osteoclast formation. However, knocked-down osteoblastic Arl6ip5 induces receptor activator of nuclear factor-κB ligand (RANKL) expression and enhances osteoclastogenesis. In addition, ER stress and Chop are involved in the RANKL expression in Arl6ip5 knocked-down osteoblasts. In conclusion, we demonstrate that Arl6ip5 is a novel regulator of bone formation in osteoblasts.
doi:10.1038/cddis.2014.427
PMCID: PMC4237252  PMID: 25321471
11.  Effects of Aspergillus Oryzae Culture and 2-Hydroxy-4-(Methylthio)-Butanoic Acid on In vitro Rumen Fermentation and Microbial Populations between Different Roughage Sources 
An in vitro experiment was conducted to evaluate the effects of Aspergillus oryzae culture (AOC) and 2-hydroxy-4-(methylthio)-butanoic acid (HMB) on rumen fermentation and microbial populations between different roughage sources. Two roughage sources (Chinese wild rye [CWR] vs corn silage [CS]) were assigned in a 2×3 factorial arrangement with HMB (0 or 15 mg) and AOC (0, 3, or 6 mg). Gas production (GP), microbial protein (MCP) and total volatile fatty acid (VFA) were increased in response to addition of HMB and AOC (p<0.01) for the two roughages. The HMB and AOC showed inconsistent effects on ammonia-N with different substrates. For CWR, neither HMB nor AOC had significant effect on molar proportion of individual VFA. For CS, acetate was increased (p = 0.02) and butyrate was decreased (p<0.01) by adding HMB and AOC. Increase of propionate was only occurred with AOC (p<0.01). Populations of protozoa (p≤0.03) and fungi (p≤0.02) of CWR were differently influenced by HMB and AOC. Percentages of F. succinogenes, R. albus, and R. flavefaciens (p<0.01) increased when AOC was added to CWR. For CS, HMB decreased the protozoa population (p = 0.01) and increased the populations of F. succinogenes and R. albus (p≤0.03). Populations of fungi, F. succinogenes (p = 0.02) and R. flavefacien (p = 0.03) were increased by adding AOC. The HMB×AOC interactions were noted in MCP, fungi and R. flavefacien for CWR and GP, ammonia-N, MCP, total VFA, propionate, acetate/propionate (A/P) and R. albus for CS. It is inferred that addition of HMB and AOC could influence rumen fermentation of forages by increasing the number of rumen microbes.
doi:10.5713/ajas.2013.13742
PMCID: PMC4150195  PMID: 25178372
Aspergillus Oryzae; 2-Hydroxy-4-(Methylthio)-Butanoic Acid; Chinese Wild Rye; Corn Silage; In vitro Rumen Fermentation; Microbial Population
12.  Reducing dietary loading decreases mouse temporomandibular joint degradation induced by anterior crossbite prosthesis 
Objective
Dietary loading has been reported to have an effect on temporomandibular joint (TMJ) remodeling via periodontal-muscular reflex. We therefore examined whether reducing dietary loading decreased TMJ degradation induced by the unilateral anterior crossbite prosthesis as we recently reported.
Methods
Forty 6-week-old female C57BL/6J mice were randomly divided into two experimental and two control groups. One experimental and one control group received small-size diet and the other two groups received large-size diet. Unilateral anterior crossbite prosthesis was created in the two experimental groups. The TMJ samples were collected 3 weeks after experimental operation. Histological changes in condylar cartilage and subchondral bone were assessed by Hematoxylin & Eosin, toluidine blue, Safranin O and tartrate-resistant acid phosphatase staining. Real-time polymerase chain reaction (PCR) and/or immunohistochemistry were performed to evaluate the expression levels of Collagen II, Aggrecan, a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) and RANKL/RANK/OPG in TMJ condylar cartilage and/or subchondral bone.
Results
Thinner and degraded cartilage, reduced cartilage cellular density, decreased expression levels of Collagen II and Aggrecan, loss of subchondral bone and enhanced osteoclast activity were observed in TMJs of both experimental groups. However, the cartilage degradation phenotype was less severe and cartilage ADAMTS-5 mRNA was lower while OPG/RANKL ratio in cartilage and subchondral bone was higher in the small-size than large-size diet experimental group. No differences of histomorphology and the tested molecules were found between the two control groups.
Conclusions
The current findings suggest that a lower level of functional loading by providing small-size diet could reduce TMJ degradation induced by the biomechanical stimulation from abnormal occlusion.
doi:10.1016/j.joca.2013.11.014
PMCID: PMC4111231  PMID: 24316289
Temporomandibular joint; Dental occlusion; Dietary loading; Osteoarthritis; Cartilage; Subchondral bone
13.  Acetaminophen Enhances Cisplatin- and Paclitaxel-mediated Cytotoxicity to SKOV3 Human Ovarian Carcinoma 
Anticancer research  2013;33(6):2391-2400.
Background
Ovarian cancer is commonly treated with cisplatin/paclitaxel but many tumors become resistant. Acetaminophen reduced glutathione and enhanced chemotherapy efficacy in treating hepatic cancer. The objective of this study was to examine if acetaminophen enhances the cytotoxicity of cisplatin/paclitaxel in ovarian cancer.
Materials and Methods
SKOV3 human ovarian carcinoma cells in vitro and a subcutaneous tumor nude rat model were used and treated with cisplatin/paclitaxel with or without acetaminophen.
Results
In vitro, acetaminophen enhanced apoptosis induced by cisplatin and paclitaxel with similar effects on glutathione, reactive oxygen species and mitochondrial membrane potential but different effects on nuclear factor erythroid 2-related factor 2 (NRF2) translocation. In vivo, acetaminophen was uniformly distributed in tissue and significantly reduced hepatic glutathione. Acetaminophen enhanced cisplatin chemotherapeutic effect by reducing tumor recurrence
Conclusion
Our results suggest that acetaminophen as a chemoenhancing adjuvant could improve the efficacy of cisplatin and paclitaxel in treating patients with ovarian carcinoma and other tumor types.
PMCID: PMC3709593  PMID: 23749887
Acetaminophen; glutathione; chemo-enhancement; cisplatin; ovarian cancer
15.  Draft Genome Sequence of Clostridium sp. Strain Ade.TY, a New Biohydrogen- and Biochemical-Producing Bacterium Isolated from Landfill Leachate Sludge 
Genome Announcements  2014;2(2):e00078-14.
Clostridium sp. strain Ade.TY is potentially a new biohydrogen-producing species isolated from landfill leachate sludge. Here we present the assembly and annotation of its genome, which may provide further insights into its gene interactions for efficient biohydrogen production.
doi:10.1128/genomeA.00078-14
PMCID: PMC3945496  PMID: 24604640
16.  Helicobacter pylori sensitizes TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human gastric epithelial cells through regulation of FLIP 
Cell Death & Disease  2014;5(3):e1109-.
Helicobacter pylori (H. pylori) infection is associated with chronic gastritis, peptic ulcer and gastric cancer. Apoptosis induced by microbial infections is implicated in the pathogenesis of H. pylori infection. Here we show that human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis via modulation of death receptor signaling. Human gastric epithelial cells are intrinsically resistant to TRAIL-mediated apoptosis. The induction of TRAIL sensitivity by H. pylori is dependent on the activation of caspase-8 and its downstream pathway. H. pylori induces caspase-8 activation via enhanced assembly of the TRAIL death-inducing signaling complex (DISC) through downregulation of cellular FLICE-inhibitory protein (FLIP). Overexpression of FLIP abolished the H. pylori-induced TRAIL sensitivity in human gastric epithelial cells. Our study thus demonstrates that H. pylori induces sensitivity to TRAIL apoptosis by regulation of FLIP and assembly of DISC, which initiates caspase activation, resulting in the breakdown of resistance to apoptosis, and provides insight into the pathogenesis of gastric damage in Helicobacter infection. Modulation of host apoptosis signaling by bacterial interaction adds a new dimension to the pathogenesis of Helicobacter.
doi:10.1038/cddis.2014.81
PMCID: PMC3973194  PMID: 24603337
apoptosis signaling; DISC; FLIP; Helicobacter pylori; TRAIL
17.  Inhibiting αv Integrins Decreases the Malignant Characteristics of Medulloblastoma 
Object
Hypoxia induces an aggressive phenotype in some brain tumors in part due to hypoxia inducible factor 1α (HIF-1α) and integrin expression. The importance of hypoxia in medulloblastoma is unclear and the interaction of HIF-1α and c-Myc in medulloblastoma has not been explored. The objective of this project was to determine if hypoxia induces an aggressive phenotype in human medulloblastoma cells that constitutively express high (D283 Med) or low (DAOY) levels of c-Myc and to determine if blocking αv integrins with the monoclonal antibody, intetumumab, inhibits hypoxia-induced cellular stress responses.
Methods
Cells were grown at 21% and 1% O2 and in the presence or absence of intetumumab. Measures of malignancy evaluated included cell proliferation, cell migration, and expression of vascular endothelial growth factor (VEGF), αv integrins, HIF-1α, and c-Myc.
Results
Both cell lines robustly expressed αv integrins. Hypoxic DAOY cells had significantly increased proliferation compared to normoxic controls (P < 0.05) whereas D283 Med cells did not. Both cell lines exhibited a dose-dependent decrease in proliferation when treated with intetumumab, (P < 0.05). Hypoxia did not increase DAOY migration. Regardless, intetumumab significantly inhibited migration at both oxygen conditions (P < 0.05). Intetumumab significantly decreased VEGF levels in DAOY cells at both oxygen conditions (P < 0.05) and in normoxic D283 cells (P < 0.01). Neither cell line had increased HIF-1α expression in response to hypoxia. However, hypoxic D283 Med cells grown in the presence of intetumumab demonstrated significantly decreased c-Myc expression (P < 0.05).
Conclusions
Hypoxia did not clearly induce a more aggressive phenotype in medulloblastoma cells. Despite this, intetumumab decreased medulloblastoma cell proliferation and migration and variably decreased VEGF and c-Myc expression in hypoxic conditions. Targeting αv integrins represents a promising potential adjuvant modality in the treatment of medulloblastoma, particularly subtypes that metastasize and overexpress VEGF and c-Myc.
doi:10.3171/2012.9.PEDS12268
PMCID: PMC3709582  PMID: 23082872
medulloblastoma; intetumumab; αv integrin; hypoxia; c-Myc; HIF-1α
18.  Strategy to Control Type I Error Increases Power to Identify Genetic Variation Using the Full Biological Trajectory 
Genetic epidemiology  2013;37(5):10.1002/gepi.21733.
Genome-wide association studies have been successful in identifying loci that underlie continuous traits measured at a single time point. To additionally consider continuous traits longitudinally, it is desirable to look at SNP effects at baseline and over time using linear-mixed effects models. Estimation and interpretation of two coefficients in the same model raises concern regarding the optimal control of type I error. To investigate this issue, we calculate type I error and power under an alternative for joint tests, including the two degree of freedom likelihood ratio test, and compare this to single degree of freedom tests for each effect separately at varying alpha levels. We show which joint tests are the optimal way to control the type I error and also illustrate that information can be gained by joint testing in situations where either or both SNP effects are underpowered. We also show that closed form power calculations can approximate simulated power for the case of balanced data, provide reasonable approximations for imbalanced data, but overestimate power for complicated residual error structures. We conclude that a two degree of freedom test is an attractive strategy in a hypothesis-free genome-wide setting and recommend its use for genome-wide studies employing linear-mixed effects models.
doi:10.1002/gepi.21733
PMCID: PMC3877575  PMID: 23633177
linear-mixed effects model; genome-wide association study; longitudinal data; power and type I error calculations
19.  miR-1207-5p and miR-1266 suppress gastric cancer growth and invasion by targeting telomerase reverse transcriptase 
Cell Death & Disease  2014;5(1):e1034-.
hTERT is the catalytic subunit of the telomerase complex. Elevated expression of hTERT is associated with the expansion and metastasis of gastric tumor. In this study, we aimed to identify novel tumor suppressor miRNAs that restrain hTERT expression. We began our screen for hTERT-targeting miRNAs with a miRNA microarray. miRNA candidates were further filtered by bioinformatic analysis, general expression pattern in different cell lines, gain-of-function effects on hTERT protein and the potential of these effects to suppress hTERT 3′ untranslated region (3′UTR) luciferase activity. The clinical relevance of two miRNAs (miR-1207-5p and miR-1266) was evaluated by real-time RT-PCR. The effects of these miRNAs on cell growth, cell cycle and invasion of gastric cancer cells were measured with CCK-8, flow cytometry and transwell assays. Finally, the ability of these miRNAs to suppress the transplanted tumors was also investigated. Fourteen miRNAs were identified using a combination of bioinformatics and miRNA microarray analysis. Of these fourteen miRNAs, nine were expressed at significantly lower levels in hTERT-positive cell lines compared with hTERT-negative cell lines and five could downregulate hTERT protein expression. Only miR-1207-5p and miR-1266 interacted with the 3′ UTR of hTERT and the expression levels of these two miRNAs were significantly decreased in gastric cancer tissues. These two miRNAs also inhibited gastric tumor growth in vitro and in vivo. Altogether, miR-1207-5p and miR-1266 were determined to be hTERT suppressors in gastric cancer, and the delivery of these two miRNAs represents a novel therapeutic strategy for gastric cancer treatment.
doi:10.1038/cddis.2013.553
PMCID: PMC4040688  PMID: 24481448
tumor-suppressor miRNA; hTERT; gastric cancer
20.  Contralateral De Novo Intraosseous Arteriovenous Malformation in a Child with Arteriovenous Malformation of Mandible Treated by Endovascular Embolotherapy 
Interventional Neuroradiology  2012;18(4):484-489.
Summary
We describe our experience of the development of contralateral de novo intraosseous AVMs in a ten-year-old girl with AVMs of the mandible who underwent endovascular embolotherapy. She initially presented with intermittent oral bleeding. Computed tomography and digital subtraction angiography demonstrated intraosseous AVMs within the right mandible. The AVMs were treated by transosseous direct-puncture and transarterial embolization with Guglielmi detachable coils and n-butyl cyanoacrylate glue. However, de novo intraosseous AVMs developed within the previously healthy contralateral mandible and resulted in dangerous oral bleeding. Therefore, we suggest regular follow-up and prompt retreatment of any residual mandibular AVMs in patients undergoing endovascular or surgical treatment to prevent subsequent development of “secondary” AVMs and life-threatening oral bleeding.
PMCID: PMC3520563  PMID: 23217644
mandible, arteriovenous malformation, transarterial embolization, transosseous embolization
21.  Designing novel bulk metallic glass composites with a high aluminum content 
Scientific Reports  2013;3:3353.
The long-standing challenge for forming Al-based BMGs and their matrix composites with a critical size larger than 1 mm have not been answered over the past three decades. In this paper, we reported formation of a series of BMG matrix composites which contain a high Al content up to 55 at.%. These composites can be cast at extraordinarily low cooling rates, compatible with maximum rod diameters of over a centimetre in copper mold casting. Our results indicate that proper additions of transition element Fe which have a positive heat of mixing with the main constituents La and Ce can appreciably improve the formability of the BMG matrix composites by suppressing the precipitation of Al(La,Ce) phase resulted from occurrence of the phase separation. However, the optimum content of Fe addition is strongly dependant on the total amount of the Al content in the Al-(CoCu)-(La,Ce) alloys.
doi:10.1038/srep03353
PMCID: PMC3842084  PMID: 24284800
22.  Using Multidimensional Mutual Information to Prioritize Mammographic Features for Breast Cancer Diagnosis 
AMIA Annual Symposium Proceedings  2013;2013:1534-1543.
The goal of this study was to demonstrate that information theory could be used to prioritize mammographic features to efficiently stratify the risk of breast cancer. We compared two approaches, Single-dimensional Mutual Information (SMI), which ranks features based on mutual information of features with outcomes without considering dependency of other features, and Multidimensional Mutual Information (MMI), which ranks features by considering dependency. To evaluate these approaches, we calculated area under the ROC curve for Bayesian networks trained and tested on features ranked by each approach. We found that both approaches were able to stratify mammograms by risk, but MMI required fewer features (ten vs. thirteen). MMI-based rankings may have greater clinical utility; a smaller set of features allows radiologists to focus on those findings with the highest yield and in the future may help improve mammography workflow.
PMCID: PMC3900164  PMID: 24551425
23.  Targeting αV-integrins decreased metastasis and increased survival in a nude rat breast cancer brain metastasis model 
Journal of neuro-oncology  2012;110(1):27-36.
Brain metastases commonly occur in patients with breast, lung and melanoma systemic cancers. The anti-αV integrin monoclonal antibody intetumumab binds cell surface proteins important for adhesion, invasion and angiogenesis in the metastatic cascade. The objective of this study was to investigate the anti-metastatic effect of intetumumab in a hematogenous breast cancer brain metastasis model. Female nude rats received intra-carotid infusion of human brain-seeking metastatic breast cancer cells (231BR-HER2) and were randomly assigned into 4 groups: 1) control; 2) intetumumab mixed with cells in vitro 5 min before infusion without further treatment; 3) intetumumab intravenously 4 h before and weekly after cell infusion; 4) intetumumab intravenously weekly starting 7 d after cell infusion. Brain metastases were detected by magnetic resonance imaging (MRI) and immunohistochemistry. Comparisons were made using the Kruskal-Wallis test and Dunnett’s test. Survival times were estimated using Kaplan-Meier analysis. All control rats with brain tissue available for histology (9 of 11 rats) developed multiple brain metastases (median=14). Intetumumab treatment either in vitro prior to cell infusion or intravenous before or after cell infusion prevented metastasis formation on MRI and decreased the number of metastases on histology (median=2, p=0.0055), including 30% of animals without detectable tumors at the end of the study. The overall survival was improved by intetumumab compared to controls (median 77+ versus 52 d, p=0.0277). Our results suggest that breast cancer patients at risk of metastases might benefit from early intetumumab treatment.
doi:10.1007/s11060-012-0942-0
PMCID: PMC3726254  PMID: 22842979
integrin; intetumumab; breast cancer; brain metastasis; MRI
24.  Loss of TAK1 increases cell traction force in a ROS-dependent manner to drive epithelial–mesenchymal transition of cancer cells 
Cell Death & Disease  2013;4(10):e848-.
Epithelial–mesenchymal transition (EMT) is a crucial step in tumor progression, and the TGFβ–SMAD signaling pathway as an inductor of EMT in many tumor types is well recognized. However, the role of non-canonical TGFβ–TAK1 signaling in EMT remains unclear. Herein, we show that TAK1 deficiency drives metastatic skin squamous cell carcinoma earlier into EMT that is conditional on the elevated cellular ROS level. The expression of TAK1 is consistently reduced in invasive squamous cell carcinoma biopsies. Tumors derived from TAK1-deficient cells also exhibited pronounced invasive morphology. TAK1-deficient cancer cells adopt a more mesenchymal morphology characterized by higher number of focal adhesions, increase surface expression of integrin α5β1 and active Rac1. Notably, these mutant cells exert an increased cell traction force, an early cellular response during TGFβ1-induced EMT. The mRNA level of ZEB1 and SNAIL, transcription factors associated with mesenchymal phenotype is also upregulated in TAK1-deficient cancer cells compared with control cancer cells. We further show that TAK1 modulates Rac1 and RhoA GTPases activities via a redox-dependent downregulation of RhoA by Rac1, which involves the oxidative modification of low-molecular weight protein tyrosine phosphatase. Importantly, the treatment of TAK1-deficient cancer cells with Y27632, a selective inhibitor of Rho-associated protein kinase and antioxidant N-acetylcysteine augment and hinders EMT, respectively. Our findings suggest that a dysregulated balance in the activation of TGFβ–TAK1 and TGFβ–SMAD pathways is pivotal for TGFβ1-induced EMT. Thus, TAK1 deficiency in metastatic cancer cells increases integrin:Rac-induced ROS, which negatively regulated Rho by LMW-PTP to accelerate EMT.
doi:10.1038/cddis.2013.339
PMCID: PMC3824649  PMID: 24113182
reactive oxygen species; cell traction force; epithelial–mesenchymal transition
25.  Quercetin postconditioning attenuates myocardial ischemia/reperfusion injury in rats through the PI3K/Akt pathway 
Quercetin (Que), a plant-derived flavonoid, has multiple benefical actions on the cardiovascular system. The current study investigated whether Que postconditioning has any protective effects on myocardial ischemia/reperfusion (I/R) injury in vivo and its potential cardioprotective mechanisms. Male Sprague-Dawley rats were randomly allocated to 5 groups (20 animals/group): sham, I/R, Que postconditioning, Que+LY294002 [a phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway inhibitor], and LY294002+I/R. I/R was produced by 30-min coronary occlusion followed by 2-h reperfusion. At the end of reperfusion, myocardial infarct size and biochemical changes were compared. Apoptosis was evaluated by both TUNEL staining and measurement of activated caspase-3 immunoreactivity. The phosphorylation of Akt and protein expression of Bcl-2 and Bax were determined by Western blotting. Que postconditioning significantly reduced infarct size and serum levels of creatine kinase and lactate dehydrogenase compared with the I/R group (all P<0.05). Apoptotic cardiomyocytes and caspase-3 immunoreactivity were also suppressed in the Que postconditioning group compared with the I/R group (both P<0.05). Akt phosphorylation and Bcl-2 expression increased after Que postconditioning, but Bax expression decreased. These effects were inhibited by LY294002. The data indicate that Que postconditioning can induce cardioprotection by activating the PI3K/Akt signaling pathway and modulating the expression of Bcl-2 and Bax proteins.
doi:10.1590/1414-431X20133036
PMCID: PMC3854307  PMID: 24068165
Ischemia and reperfusion; Quercetin; Postconditioning; PI3K/Akt

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