bluuebunny/crossref_metadata_2025 huggingface dataset:
EachWiki
Authors: Wang Haofen , Fu Linyun , Jin Wei , Yu Yong
Published: October 2012

Wikipedia, one of the best-known wikis and the world’s largest free online encyclopedia, has embraced the power of collaborative editing to harness collective intelligence. However, using such a wiki to create high-quality articles is not as easy as people imagine, given for instance the difficulty of reusing knowledge already available in Wikipedia. As a result, the heavy burden of upbuilding and maintaining the ever-growing online encyclopedia still rests on a small group of people. In this article, we aim at facilitating wiki authoring by providing annotation recommendations, thus lightening the burden of both contributors and administrators. We leverage the collective wisdom of the users by exploiting Semantic Web technologies with Wikipedia data and adopt a unified algorithm to support link, category, and semantic relation recommendation. A prototype system named EachWiki is proposed and evaluated. The experimental results show that it has achieved considerable improvements in terms of effectiveness, efficiency and usability. The proposed approach can also be applied to other wiki-based collaborative editing systems.
An Ensemble Architecture for Learning Complex Problem-Solving Techniques from Demonstration
Authors: Zhang Xiaoqin Shelley , Shrestha Bhavesh , Yoon Sungwook , Kambhampati Subbarao , DiBona Phillip , Guo Jinhong K. , McFarlane Daniel , Hofmann Martin O. , Whitebread Kenneth , Appling Darren Scott , Whitaker Elizabeth T. , Trewhitt Ethan B. , Ding Li , Michaelis James R. , McGuinness Deborah L. , Hendler James A. , Doppa Janardhan Rao , Parker Charles , Dietterich Thomas G. , Tadepalli Prasad , Wong Weng-Keen , Green Derek , Rebguns Anton , Spears Diana , Kuter Ugur , Levine Geoff , DeJong Gerald , MacTavish Reid L. , Ontañón Santiago , Radhakrishnan Jainarayan , Ram Ashwin , Mostafa Hala , Zafar Huzaifa , Zhang Chongjie , Corkill Daniel , Lesser Victor , Song Zhexuan
Published: October 2012

We present a novel ensemble architecture for learning problem-solving techniques from a very small number of expert solutions and demonstrate its effectiveness in a complex real-world domain. The key feature of our “Generalized Integrated Learning Architecture” (GILA) is a set of heterogeneous independent learning and reasoning (ILR) components, coordinated by a central meta-reasoning executive (MRE). The ILRs are
weakly coupled
in the sense that all coordination during learning and performance happens through the MRE. Each ILR learns independently from a small number of expert demonstrations of a complex task. During performance, each ILR proposes partial solutions to subproblems posed by the MRE, which are then selected from and pieced together by the MRE to produce a complete solution. The heterogeneity of the learner-reasoners allows both learning and problem solving to be more effective because their abilities and biases are complementary and synergistic. We describe the application of this novel learning and problem solving architecture to the domain of airspace management, where multiple requests for the use of airspaces need to be deconflicted, reconciled, and managed automatically. Formal evaluations show that our system performs as well as or better than humans after learning from the same training data. Furthermore, GILA outperforms any individual ILR run in isolation, thus demonstrating the power of the ensemble architecture for learning and problem solving.
Learning Causal Relations in Multivariate Time Series Data
Authors: Wang Zhenxing , Chan Laiwan
Published: October 2012

Many applications naturally involve time series data and the vector autoregression (VAR), and the structural VAR (SVAR) are dominant tools to investigate relations between variables in time series. In the first part of this work, we show that the SVAR method is incapable of identifying contemporaneous causal relations for Gaussian process. In addition, least squares estimators become unreliable when the scales of the problems are large and observations are limited. In the remaining part, we propose an approach to apply Bayesian network learning algorithms to identify SVARs from time series data in order to capture both temporal and contemporaneous causal relations, and avoid high-order statistical tests. The difficulty of applying Bayesian network learning algorithms to time series is that the sizes of the networks corresponding to time series tend to be large, and high-order statistical tests are required by Bayesian network learning algorithms in this case. To overcome the difficulty, we show that the search space of conditioning sets d-separating two vertices should be a subset of the Markov blankets. Based on this fact, we propose an algorithm enabling us to learn Bayesian networks locally, and make the largest order of statistical tests independent of the scales of the problems. Empirical results show that our algorithm outperforms existing methods in terms of both efficiency and accuracy.
Impairment of endoplasmic reticulum in liver as an early consequence of the systemic inflammatory response in rats
Authors: Nürnberger Sylvia , Miller Ingrid , Duvigneau J. Catharina , Kavanagh Edel T. , Gupta Sanjeev , Hartl Romana T. , Hori Osamu , Gesslbauer Bernd , Samali Afshin , Kungl Andreas , Redl Heinz , Kozlov Andrey V.
Published: October 2012

It is well known that systemic inflammatory response (SIR) often causes liver dysfunction. The aim of this study was to identify the intracellular compartment in the liver most susceptible to SIR. We analyzed morphology, ultrastructure, proteome, and expression of relevant genes in livers of rats subjected to endotoxic shock. Histological examination revealed that focal necrosis in liver was insignificant to explain liver dysfunction. Electron microscopy revealed no morphological changes in the mitochondrial structure and in the cytosol, but dilated endoplasmic reticulum (ER) cisterns were frequently observed. Apoptosis was found in white blood cells within liver tissue but not in hepatocytes. Mitochondrial, ER, and cytosolic fractions were subjected to proteome analysis by difference gel electrophoresis, and the protein spots with the highest degree of differential regulation were identified with mass spectrometry. The most pronounced proteome changes appeared in the ER, manifested as a remarkable downregulation of several proteins essential for ER functions, such as protein synthesis and transport, whereas the changes in mitochondrial and cytosolic fractions suggested a compensatory response. ER stress, as an underlying mechanism for ER impairment, was confirmed by analysis of upstream (splicing X-box-binding protein 1 mRNA) and downstream (e.g., 78-kDa glucose-regulated protein mRNA) markers, suggesting ongoing unresolved ER stress as a cause for ER dilation. Because ER is the intracellular compartment responsible for the major liver functions, our data suggest that inflammatory mediators induce unresolved ER stress, resulting in the biochemical, functional, and morphological impairment of ER that in turn causes liver dysfunction. The pathway activating ER stress in response to SIR is not known yet.
Role of the BK channel (KCa1.1) during activation of electrogenic K+ secretion in guinea pig distal colon
Authors: Zhang Jin , Halm Susan T. , Halm Dan R.
Published: October 2012

Secretagogues acting at a variety of receptor types activate electrogenic K+ secretion in guinea pig distal colon, often accompanied by Cl− secretion. Distinct blockers of KCa1.1 (BK, Kcnma1), iberiotoxin (IbTx), and paxilline inhibited the negative short-circuit current ( Isc) associated with K+ secretion. Mucosal addition of IbTx inhibited epinephrine-activated Isc (epi Isc) and transepithelial conductance (epi Gt) consistent with K+ secretion occurring via apical membrane KCa1.1. The concentration dependence of IbTx inhibition of epi Isc yielded an IC50 of 193 nM, with a maximal inhibition of 51%. Similarly, IbTx inhibited epi Gt with an IC50 of 220 nM and maximal inhibition of 48%. Mucosally added paxilline (10 μM) inhibited epi Isc and epi Gt by ∼50%. IbTx and paxilline also inhibited Isc activated by mucosal ATP, supporting apical KCa1.1 as a requirement for this K+ secretagogue. Responses to IbTx and paxilline indicated that a component of K+ secretion occurred during activation of Cl− secretion by prostaglandin-E2 and cholinergic stimulation. Analysis of KCa1.1α mRNA expression in distal colonic epithelial cells indicated the presence of the ZERO splice variant and three splice variants for the COOH terminus. The presence of the regulatory β-subunits KCaβ1 and KCaβ4 also was demonstrated. Immunolocalization supported the presence of KCa1.1α in apical and basolateral membranes of surface and crypt cells. Together these results support a cellular mechanism for electrogenic K+ secretion involving apical membrane KCa1.1 during activation by several secretagogue types, but the observed K+ secretion likely required the activity of additional K+ channel types in the apical membrane.
Induction of epithelial-mesenchymal transition by flagellin in cultured lung epithelial cells
Authors: Kondo Yutaka , Higa-Nakamine Sayomi , Noguchi Nobuhiro , Maeda Noriko , Toku Seikichi , Isohama Yoichiro , Sugahara Kazuhiro , Kukita Ichiro , Yamamoto Hideyuki
Published: October 2012

Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and activates host inflammatory responses, mainly through activation of the NF-κB pathway. Although pulmonary fibrosis occurs in some cases of lung infection by flagellated bacteria, the pathological roles of TLR5 stimulation in pulmonary fibrosis have yet to be elucidated. In the present study, we first confirmed that flagellin activated the NF-κB pathway in cultured A549 alveolar epithelial cells. Next, we examined the types of genes whose expression was modulated by flagellin in the cells. Microarray analysis of gene expression indicated that flagellin induced a change in gene expression that had a similar trend to transforming growth factor-β1 (TGF-β1), a key factor in the induction of epithelial-mesenchymal transition (EMT). Biochemical analysis revealed that TGF-β1and flagellin increased the level of fibronectin protein, while they reduced the level of E-cadherin protein after 30 h of treatment. Interestingly, simultaneous treatment with TGF-β1and flagellin significantly augmented these EMT-related changes. Flagellin strongly activated p38 MAP kinase, and the activation was sustained for longer than 30 h. SB203580, an inhibitor of p38 MAP kinase, inhibited the upregulation of fibronectin by both flagellin and TGF-β1. Simultaneous treatment with TGF-β1and flagellin augmented the activation of p38 MAP kinase by TGF-β1or flagellin alone. These results strongly suggest that flagellin cooperates with TGF-β1in the induction of EMT in alveolar epithelial cells.
Short-term cigarette smoke exposure induces reversible changes in energy metabolism and cellular redox status independent of inflammatory responses in mouse lungs
Authors: Agarwal Amit R. , Zhao Liqin , Sancheti Harsh , Sundar Isaac K. , Rahman Irfan , Cadenas Enrique
Published: October 2012

Cigarette smoking leads to alteration in cellular redox status, a hallmark in the pathogenesis of chronic obstructive pulmonary disease. This study examines the role of cigarette smoke (CS) exposure in the impairment of energy metabolism and, consequently, mitochondrial dysfunction. Male A/J mice were exposed to CS generated by a smoking machine for 4 or 8 wk. A recovery group was exposed to CS for 8 wk and allowed to recover for 2 wk. Acute CS exposure altered lung glucose metabolism, entailing a decrease in the rate of glycolysis and an increase in the pentose phosphate pathway, as evidenced by altered expression and activity of GAPDH and glucose-6-phosphate dehydrogenase, respectively. Impairment of GAPDH was found to be due to glutathionylation of its catalytic site cysteines. Metabolic changes were associated with changes in cellular and mitochondrial redox status, assessed in terms of pyridine nucleotides and glutathione. CS exposure elicited an upregulation of the expression of complexes II, III, IV, and V and of the activity of complexes II, IV, and V. Microarray analysis of gene expression in mouse lungs after exposure to CS for 8 wk revealed upregulation of a group of genes involved in metabolism, electron transfer chain, oxidative phosphorylation, mitochondrial transport and dynamics, and redox regulation. These changes occurred independently of inflammatory responses. These findings have implications for the early onset of alterations in energy and redox metabolism upon acute lung exposure to CS.
Contribution of the TRPV1 channel to salt taste quality in mice as assessed by conditioned taste aversion generalization and chorda tympani nerve responses
Authors: Smith Kimberly R. , Treesukosol Yada , Paedae A. Brennan , Contreras Robert J. , Spector Alan C.
Published: October 2012

In rodents, at least two transduction mechanisms are involved in salt taste: 1) the sodium-selective epithelial sodium channel, blocked by topical amiloride administration, and 2) one or more amiloride-insensitive cation-nonselective pathways. Whereas electrophysiological evidence from the chorda tympani nerve (CT) has implicated the transient receptor potential vanilloid-1 (TRPV1) channel as a major component of amiloride-insensitive salt taste transduction, behavioral results have provided only equivocal support. Using a brief-access taste test, we examined generalization profiles of water-deprived C57BL/6J (WT) and TRPV1 knockout (KO) mice conditioned (via LiCl injection) to avoid 100 μM amiloride-prepared 0.25 M NaCl and tested with 0.25 M NaCl, sodium gluconate, KCl, NH4Cl, 6.625 mM citric acid, 0.15 mM quinine, and 0.5 M sucrose. Both LiCl-injected WT and TRPV1 KO groups learned to avoid NaCl+amiloride relative to controls, but their generalization profiles did not differ; LiCl-injected mice avoided the nonsodium salts and quinine suggesting that a TRPV1-independent pathway contributes to the taste quality of the amiloride-insensitive portion of the NaCl signal. Repeating the experiment but doubling all stimulus concentrations revealed a difference in generalization profiles between genotypes. While both LiCl-injected groups avoided the nonsodium salts and quinine, only WT mice avoided the sodium salts and citric acid. CT responses to these stimuli and a concentration series of NaCl and KCl with and without amiloride did not differ between genotypes. Thus, in our study, TRPV1 did not appear to contribute to sodium salt perception based on gustatory signals, at least in the CT, but may have contributed to the oral somatosensory features of sodium.
Recruitment pattern of sympathetic muscle neurons during premature ventricular contractions in heart failure patients and controls
Authors: Maslov Petra Zubin , Breskovic Toni , Brewer Danielle N. , Shoemaker J. Kevin , Dujic Zeljko
Published: October 2012

Premature ventricular contractions (PVC) elicit larger bursts of multiunit muscle sympathetic nerve activity (MSNA), reflecting the ability to increase postganglionic axonal recruitment. We tested the hypothesis that chronic heart failure (CHF) limits the ability to recruit postganglionic sympathetic neurons as a response to PVC due to the excessive sympathetic activation in these patients. Sympathetic neurograms of sufficient signal-to-noise ratio were obtained from six CHF patients and from six similarly aged control individuals. Action potentials (APs) were extracted from the multiunit sympathetic neurograms during sinus rhythm bursts and during the post-PVC bursts. These APs were classified on the basis of the frequency per second, the content per burst, and the peak-to-peak amplitude, which formed the basis of binning the APs into active clusters. Compared with controls, CHF had higher APs per burst and higher number of active clusters per sinus rhythm burst ( P < 0.05). Compared with sinus rhythm bursts, both groups increased AP frequency and the number of active clusters in the post-PVC burst ( P < 0 .05). However, compared with controls, the increase in burst integral, AP frequency, and APs per burst during the post-PVC burst was less in CHF patients. Nonetheless, the PVC-induced increase in active clusters per burst was similar between the groups. Thus, these CHF patients retained the ability to recruit larger APs but had a diminished ability to increase overall AP content.
Disease-causing R1185C mutation of WNK4 disrupts a regulatory mechanism involving calmodulin binding and SGK1 phosphorylation sites
Authors: Na Tao , Wu Guojin , Zhang Wei , Dong Wen-Ji , Peng Ji-Bin
Published: October 2012

The R1185C mutation in WNK4 is associated with pseudohypoaldosteronism type II (PHAII). Unlike other PHAII-causing mutations in the acidic motif, the R1185C mutation is located in the COOH-terminal region of WNK4. The goal of the study is to determine what properties of WNK4 are disrupted by the R1185C mutation. We found that the R1185C mutation is situated in the middle of a calmodulin (CaM) binding site and the mutation reduces the binding of WNK4 to Ca2+/CaM. The R1185C mutation is also close to serum- and glucocorticoid-induced protein kinase (SGK1) phosphorylation sites S1190 and S1217. In addition, we identified a novel SGK1 phosphorylation site (S1201) in WNK4, and phosphorylation at this site is reduced by Ca2+/CaM. In the wild-type WNK4, the level of phosphorylation at S1190 is the lowest and that at S1217 is the highest. In the R1185C mutant, phosphorylation at S1190 is eliminated and that at S1201 becomes the strongest. The R1185C mutation enhances the positive effect of WNK4 on the Na+-K+-2Cl−cotransporter 2 (NKCC2) as tested in Xenopus laevis oocytes. Deletion of the CaM binding site or phospho-mimicking at two or three of the SGK1 sites enhances the WNK4 effects on NKCC2. These results indicate that the R1185C mutation disrupts an inhibitory domain as part of the suppression mechanism of WNK4, leading to an elevated WNK4 activity at baseline. The presence of CaM binding and SGK1 phosphorylation sites in or close to the inhibitory domain suggests that WNK4 activity is subject to the regulation by intracellular Ca2+and phosphorylation.
Proximal tubule Na+/H+ exchanger activity in adult NHE8−/−, NHE3−/−, and NHE3−/−/NHE8−/− mice
Authors: Baum Michel , Twombley Katherine , Gattineni Jyothsna , Joseph Catherine , Wang Lin , Zhang Qiuyu , Dwarakanath Vangipuram , Moe Orson W.
Published: October 2012

NHE3 is the predominant Na+/H+ exchanger on the brush-border membrane (BBM) of the proximal tubule in adults. However, NHE3 null mice still have significant renal BBM Na+/H+ activity. NHE8 has been localized to the BBM of proximal tubules and is more highly expressed in neonates than adult animals. The relative role of NHE8 in adult renal H+ transport is unclear. This study examined whether there was compensation by NHE8 in NHE3−/− mice and by NHE3 in NHE8−/− mice. NHE3−/− mice had significant metabolic acidosis, and renal BBM NHE8 protein abundance was greater in NHE3−/− mice than control mice, indicating that there may be compensation by NHE8 in NHE3−/− mice. NHE8−/− mice had serum bicarbonate levels and pH that were not different from controls. NHE3 protein expression on the BBM was greater in NHE8−/− mice than in wild-type mice, indicating that there may be compensation by NHE3 in NHE8−/− mice. Both BBM NHE3 and NHE8 protein abundance increased in response to acidosis. Blood pressure and Na+/H+ exchanger activity were comparable in NHE8−/− mice to that of controls, but both were significantly lower in NHE3−/− mice compared with control mice. Compared with NHE3−/− mice, NHE3−/−/NHE8−/− mice had lower blood pressures. While serum bicarbonate was comparable in NHE3−/− mice and NHE3−/−/NHE8−/− mice, proximal tubule Na+/H+ exchange activity was less in NHE3−/−/NHE8−/− mice compared with NHE3−/− mice. In conclusion, NHE3 is the predominant Na+/H+ exchanger in adult mice. NHE8 may play a compensatory role in renal acidification and blood pressure regulation in NHE3−/− mice.
Hypoxic ventilatory response in Tac1−/− neonatal mice following exposure to opioids
Authors: Berner J. , Shvarev Y. , Zimmer A. , Wickstrom R.
Published: October 2012

Morphine is the dominating analgetic drug used in neonates, but opioid-induced respiratory depression limits its therapeutic use. In this study, we examined acute morphine effects on respiration during intermittent hypoxia in newborn Tac1 gene knockout mice (Tac1−/−) lacking substance P and neurokinin A. In vivo, plethysmography revealed a blunted hypoxic ventilatory response (HVR) in Tac1−/− mice. Morphine (10 mg/kg) depressed the HVR in wild-type animals through an effect on respiratory frequency, whereas it increased tidal volumes in Tac1−/− during hypoxia, resulting in increased minute ventilation. Apneas were reduced during the first hypoxic episode in both morphine-exposed groups, but were restored subsequently in Tac1−/− mice. Morphine did not affect ventilation or apnea prevalence during baseline conditions. In vitro, morphine (50 nM) had no impact on anoxic response of brain stem preparations of either strain. In contrast, it suppressed the inspiratory rhythm during normoxia and potentiated development of posthypoxic neuronal arrest, especially in Tac1−/−. Thus this phenotype has a higher sensitivity to the depressive effects of morphine on inspiratory rhythm generation, but morphine does not modify the reactivity to oxygen deprivation. In conclusion, although Tac1−/− mice are similar to wild-type animals during normoxia, they differed by displaying a reversed pattern with an improved HVR during intermittent hypoxia both in vivo and in vitro. These data suggest that opioids and the substance P-ergic system interact in the HVR, and that reducing the activity in the tachykinin system may alter the respiratory effects of opioid treatment in newborns.
Identification of KIF5B-RET and GOPC-ROS1 Fusions in Lung Adenocarcinomas through a Comprehensive mRNA-Based Screen for Tyrosine Kinase Fusions
Authors: Suehara Yoshiyuki , Arcila Maria , Wang Lu , Hasanovic Adnan , Ang Daphne , Ito Tatsuo , Kimura Yuki , Drilon Alexander , Guha Udayan , Rusch Valerie , Kris Mark G. , Zakowski Maureen F. , Rizvi Naiyer , Khanin Raya , Ladanyi Marc
Published: October 2012

Background: The mutually exclusive pattern of the major driver oncogenes in lung cancer suggests that other mutually exclusive oncogenes exist. We conducted a systematic search for tyrosine kinase fusions by screening all tyrosine kinases for aberrantly high RNA expression levels of the 3′ kinase domain (KD) exons relative to more 5′ exons.

Methods: We studied 69 patients (including five never smokers and 64 current or former smokers) with lung adenocarcinoma negative for all major mutations in KRAS, EGFR, BRAF, MEK1, HER2, and for ALK fusions (termed “pan-negative”). A NanoString-based assay was designed to query the transcripts of 90 tyrosine kinases at two points: 5′ to the KD and within the KD or 3′ to it. Tumor RNAs were hybridized to the NanoString probes and analyzed for outlier 3′ to 5′ expression ratios. Presumed novel fusion events were studied by rapid amplification of cDNA ends (RACE) and confirmatory reverse transcriptase PCR (RT-PCR) and FISH.

Results: We identified one case each of aberrant 3′ to 5′ ratios in ROS1 and RET. RACE isolated a GOPC-ROS1 (FIG-ROS1) fusion in the former and a KIF5B-RET fusion in the latter, both confirmed by RT-PCR. The RET rearrangement was also confirmed by FISH. The KIF5B-RET patient was one of only five never smokers in this cohort.

Conclusion: The KIF5B-RET fusion defines an additional subset of lung cancer with a potentially targetable driver oncogene enriched in never smokers with “pan-negative” lung adenocarcinomas. We also report in lung cancer the GOPC-ROS1 fusion originally discovered and characterized in a glioma cell line. Clin Cancer Res; 18(24); 6599–608. ©2012 AACR.
miR-187 Is an Independent Prognostic Factor in Breast Cancer and Confers Increased Invasive PotentialIn Vitro
Authors: Mulrane Laoighse , Madden Stephen F. , Brennan Donal J. , Gremel Gabriela , McGee Sharon F. , McNally Sara , Martin Finian , Crown John P. , Jirström Karin , Higgins Desmond G. , Gallagher William M. , O'Connor Darran P.
Published: October 2012

Purpose: Here, we describe an integrated bioinformatics, functional analysis, and translational pathology approach to identify novel miRNAs involved in breast cancer progression.

Experimental Design: Coinertia analysis (CIA) was used to combine a database of predicted miRNA target sites and gene expression data. Using two independent breast cancer cohorts, CIA was combined with correspondence analysis and between group analysis to produce a ranked list of miRNAs associated with disease progression. Ectopic expression studies were carried out in MCF7 cells and miRNA expression evaluated in two additional cohorts of patients with breast cancer by in situ hybridization on tissue microarrays.

Results: CIA identified miR-187 as a key miRNA associated with poor outcome in breast cancer. Ectopic expression of miR-187 in breast cancer cells resulted in a more aggressive phenotype. In a test cohort (n = 117), high expression of miR-187 was associated with a trend toward reduced breast cancer–specific survival (BCSS; P = 0.058), and a significant association with reduced BCSS in lymph node–positive patients (P = 0.036). In a validation cohort (n = 470), high miR-187 was significantly associated with reduced BCSS in the entire cohort (P = 0.021) and in lymph node–positive patients (P = 0.012). Multivariate Cox regression analysis revealed that miR-187 is an independent prognostic factor in both cohorts [cohort 1: HR, 7.37; 95% confidence interval (CI), 2.05–26.51; P = 0.002; cohort 2: HR, 2.80; 95% CI, 1.52–5.16; P = 0.001] and in lymph node–positive patients in both cohorts (cohort 1: HR, 13.74; 95% CI, 2.62–72.03; P = 0.002; cohort 2: HR, 2.77; 95% CI, 1.32–5.81; P = 0.007).

Conclusions: miR-187 expression in breast cancer leads to a more aggressive, invasive phenotype and acts as an independent predictor of outcome. Clin Cancer Res; 18(24); 6702–13. ©2012 AACR.
Highly Specific Targeting of the TMPRSS2/ERG Fusion Gene Using Liposomal Nanovectors
Authors: Shao Longjiang , Tekedereli Ibrahim , Wang Jianghua , Yuca Erkan , Tsang Susan , Sood Anil , Lopez-Berestein Gabriel , Ozpolat Bulent , Ittmann Michael
Published: October 2012

Purpose: The TMPRSS2/ERG (T/E) fusion gene is present in half of all prostate cancer tumors. Fusion of the oncogenic ERG gene with the androgen-regulated TMPRSS2 gene promoter results in expression of fusion mRNAs in prostate cancer cells. The junction of theTMPRSS2- and ERG-derived portions of the fusion mRNA constitutes a cancer-specific target in cells containing the T/E fusion gene. Targeting the most common alternatively spliced fusion gene mRNA junctional isoforms in vivo using siRNAs in liposomal nanovectors may potentially be a novel, low-toxicity treatment for prostate cancer.

Experimental Design: We designed and optimized siRNAs targeting the two most common T/E fusion gene mRNA junctional isoforms (type III or type VI). Specificity of siRNAs was assessed by transient co-transfection in vitro. To test their ability to inhibit growth of prostate cancer cells expressing these fusion gene isoforms in vivo, specific siRNAs in liposomal nanovectors were used to treat mice bearing orthotopic or subcutaneous xenograft tumors expressing the targeted fusion isoforms.

Results: The targeting siRNAs were both potent and highly specific in vitro. In vivo they significantly inhibited tumor growth. The degree of growth inhibition was variable and was correlated with the extent of fusion gene knockdown. The growth inhibition was associated with marked inhibition of angiogenesis and, to a lesser degree, proliferation and a marked increase in apoptosis of tumor cells. No toxicity was observed.

Conclusions: Targeting the T/E fusion junction in vivo with specific siRNAs delivered via liposomal nanovectors is a promising therapy for men with prostate cancer. Clin Cancer Res; 18(24); 6648–57. ©2012 AACR.
Improving Publication Rates of Biomarker Results from Cancer Trials
Authors: Iannone Robert
Published: October 2012

Mandatory nondiagnostic biopsies for biomarker research pose risk and inconvenience to patients with cancer that should be justified by the knowledge gained. This commentary reflects on the publication by Freeman and Kimmelman, which points to a potentially low publication rate of biomarker results from cancer clinical trials requiring nondiagnostic biopsies. Clin Cancer Res; 18(23); 6398–9. ©2012 AACR.
Assessing Iron Overload: Are We There Yet?
Authors: Kruger Paul C. , Leahy Michael F. , Olynyk John K.
Published: October 2012

Iron overload occurs in many hematologic disorders and causes significant morbidity. The advantages of MRI in quantifying liver iron concentration continue to mount, and the association between iron overload and increased mortality after allogeneic stem cell transplant needs further attention. Clin Cancer Res; 18(23); 6395–7. ©2012 AACR.
Baseline Mammographic Breast Density and the Risk of Invasive Breast Cancer in Postmenopausal Women Participating in the NSABP Study of Tamoxifen and Raloxifene (STAR)
Authors: Cecchini Reena S. , Costantino Joseph P. , Cauley Jane A. , Cronin Walter M. , Wickerham D. Lawrence , Bandos Hanna , Weissfeld Joel L. , Wolmark Norman
Published: October 2012

Mammographic breast density is an established risk factor for breast cancer. However, results are inconclusive regarding its use in risk prediction models. The current study evaluated 13,409 postmenopausal participants in the NSABP Study of Tamoxifen and Raloxifene. A measure of breast density as reported on the entry mammogram report was extracted and categorized according to The American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) classifications. An increased risk of invasive breast cancer was associated with higher mammographic breast density (P < 0.001). The association remained significant after adjusting for age, treatment, and smoking history [HR 1.35, 95% confidence interval (CI): 1.16–1.58], as well as when added to a model including the Gail score (HR 1.33, 95% CI: 1.14–1.55). At five years after random assignment, time-dependent area under the curve (AUC) improved from 0.63 for a model with Gail score alone to 0.64 when considering breast density and Gail score. Breast density was also significant when added to an abbreviated model tailored for estrogen receptor-positive breast cancers (P = 0.02). In this study, high BI-RADS breast density was significantly associated with increased breast cancer risk when considered in conjunction with Gail score but provided only slight improvement to the Gail score for predicting the incidence of invasive breast cancer. The BI-RADS breast composition classification system is a quick and readily available method for assessing breast density for risk prediction evaluations; however, its addition to the Gail model does not seem to provide substantial predictability improvements in this population of postmenopausal healthy women at increased risk for breast cancer. Cancer Prev Res; 5(11); 1321–9. ©2012 AACR.
Lipoprotein(a) and Risk of Coronary, Cerebrovascular, and Peripheral Artery Disease
Authors: Gurdasani Deepti , Sjouke Barbara , Tsimikas Sotirios , Hovingh G. Kees , Luben Robert N. , Wainwright Nicholas W. J. , Pomilla Cristina , Wareham Nicholas J. , Khaw Kay-Tee , Boekholdt S. Matthijs , Sandhu Manjinder S.
Published: October 2012

Objective—

Although the association between circulating levels of lipoprotein(a) [Lp(a)] and risk of coronary artery disease (CAD) and stroke is well established, its role in risk of peripheral arterial disease (PAD) remains unclear. Here, we examine the association between Lp(a) levels and PAD in a large prospective cohort. To contextualize these findings, we also examined the association between Lp(a) levels and risk of stroke and CAD and studied the role of low-density lipoprotein as an effect modifier of Lp(a)-associated cardiovascular risk.

Methods and Results—

Lp(a) levels were measured in apparently healthy participants in the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort. Cox regression was used to quantify the association between Lp(a) levels and risk of PAD, stroke, and CAD outcomes. During 212 981 person-years at risk, a total of 2365 CAD, 284 ischemic stroke, and 596 PAD events occurred in 18 720 participants. Lp(a) was associated with PAD and CAD outcomes but not with ischemic stroke (hazard ratio per 2.7-fold increase in Lp(a) of 1.37, 95% CI 1.25–1.50, 1.13, 95% CI 1.04–1.22 and 0.91, 95% CI 0.79–1.03, respectively). Low-density lipoprotein cholesterol levels did not modify these associations.

Conclusion—

Lp(a) levels were associated with future PAD and CAD events. The association between Lp(a) and cardiovascular disease was not modified by low-density lipoprotein cholesterol levels.
Diagnostic Accuracy of Cardiac Positron Emission Tomography Versus Single Photon Emission Computed Tomography for Coronary Artery Disease
Authors: Parker Matthew W. , Iskandar Aline , Limone Brendan , Perugini Andrew , Kim Hyejin , Jones Charles , Calamari Brian , Coleman Craig I. , Heller Gary V.
Published: October 2012

Background—

Positron emission tomography (PET) myocardial perfusion imaging (MPI) offers technical benefits compared with single photon emission computed tomography (SPECT) MPI, but there has been no systematic comparison of their diagnostic accuracy for coronary artery disease. We performed a bivariate meta-analysis of the published literature to compare the sensitivity and specificity of PET versus SPECT stress MPI for ≥50% stenosis of any epicardial coronary artery in patients with known or suspected coronary artery disease.

Methods and Results—

We searched MEDLINE and EMBASE from inception through January 2012 and the references of identified studies for prospective, English language studies that evaluated the sensitivity and specificity of PET and/or SPECT MPI with coronary angiography as the reference standard and reported sufficient data to calculate patient-level true and false positives and negatives. Two investigators independently extracted patient and study characteristics; a third investigator resolved any disagreements. We identified 117 studies, including 108 evaluating SPECT MPI, 4 evaluating PET MPI, and 5 evaluating both modalities. Bivariate meta-analysis demonstrated a significantly higher pooled mean sensitivity with PET (92.6% [95% Confidence Interval, 88.3% to 95.5%]) compared with SPECT (88.3% [95% confidence interval, 86.4% to 90.0%]) (
P
=0.035). No significant difference in specificity was observed between PET (81.3% [95% confidence interval, 66.6% to 90.4%]) and SPECT (75.8% [95% confidence interval, 72.1% to 79.1%]) (
P
=0.39). Few studies investigated coronary angiography with PET. Only 5 studies directly compared SPECT and PET.

Conclusions—

In a meta-analysis of 11,862 patients, PET MPI demonstrated a higher sensitivity for coronary artery disease than SPECT MPI. No difference in specificity was detected in the pooled analysis of PET and SPECT MPI.
Apolipoprotein B Synthesis Inhibition With Mipomersen in Heterozygous Familial Hypercholesterolemia
Authors: Stein Evan A. , Dufour Robert , Gagne Claude , Gaudet Daniel , East Cara , Donovan Joanne M. , Chin Wai , Tribble Diane L. , McGowan Mary
Published: October 2012

Background—

Heterozygous familial hypercholesterolemia (HeFH) is a common genetic disorder leading to premature coronary artery disease. Despite statins and additional lipid-lowering therapies, many HeFH patients fail to achieve low-density lipoprotein cholesterol (LDL-C) goals. We evaluated mipomersen, an apolipoprotein B synthesis inhibitor, to further lower LDL-C in HeFH patients with coronary artery disease.

Methods and Results—

This double-blind, placebo-controlled, phase 3 trial randomized patients with HeFH and coronary artery disease on maximally tolerated statin and LDL-C ≥2.6 mmol/L (≥100 mg/dL) to weekly subcutaneous mipomersen 200 mg or placebo (2:1) for 26 weeks. The primary end point was percent change in LDL-C from baseline at week 28. Safety assessments included adverse events, laboratory tests, and magnetic resonance imaging assessment of hepatic fat. Of 124 randomized patients (41 placebo, 83 mipomersen), 114 (41 placebo, 73 mipomersen) completed treatment. Mean (95% confidence interval) LDL-C decreased significantly with mipomersen (−28.0% [−34.0% to −22.1%] compared with 5.2% [−0.5% to 10.9%] increase with placebo;
P
<0.001). Mipomersen significantly reduced apolipoprotein B (−26.3%), total cholesterol (−19.4%), and lipoprotein(a) (−21.1%) compared with placebo (all
P
<0.001). No significant change occurred in high-density lipoprotein cholesterol. Adverse events included injection site reactions and influenza-like symptoms. Five mipomersen patients (6%) had 2 consecutive alanine aminotransferase values ≥3 times the upper limit of normal at least 7 days apart; none were associated with significant bilirubin increases. Hepatic fat content increased a median of 4.9% with mipomersen versus 0.4% with placebo (
P
<0.001).

Conclusions—

Mipomersen is an effective therapy to further reduce apolipoprotein B–containing lipoproteins, including LDL and lipoprotein(a), in HeFH patients with coronary artery disease on statins and other lipid-lowering therapy. The significance of hepatic fat and transaminase increases remains uncertain at this time.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00706849.
Revolutionizing Climate Modeling with Project Athena: A Multi-Institutional, International Collaboration
Authors: Kinter J. L. , Cash B. , Achuthavarier D. , Adams J. , Altshuler E. , Dirmeyer P. , Doty B. , Huang B. , Jin E. K. , Marx L. , Manganello J. , Stan C. , Wakefield T. , Palmer T. , Hamrud M. , Jung T. , Miller M. , Towers P. , Wedi N. , Satoh M. , Tomita H. , Kodama C. , Nasuno T. , Oouchi K. , Yamada Y. , Taniguchi H. , Andrews P. , Baer T. , Ezell M. , Halloy C. , John D. , Loftis B. , Mohr R. , Wong K.
Published: October 2012

The importance of using dedicated high-end computing resources to enable high spatial resolution in global climate models and advance knowledge of the climate system has been evaluated in an international collaboration called Project Athena. Inspired by the World Modeling Summit of 2008 and made possible by the availability of dedicated high-end computing resources provided by the National Science Foundation from October 2009 through March 2010, Project Athena demonstrated the sensitivity of climate simulations to spatial resolution and to the representation of subgrid-scale processes with horizontal resolutions up to 10 times higher than contemporary climate models. While many aspects of the mean climate were found to be reassuringly similar, beyond a suggested minimum resolution, the magnitudes and structure of regional effects can differ substantially. Project Athena served as a pilot project to demonstrate that an effective international collaboration can be formed to efficiently exploit dedicated supercomputing resources. The outcomes to date suggest that, in addition to substantial and dedicated computing resources, future climate modeling and prediction require a substantial research effort to efficiently explore the fidelity of climate models when explicitly resolving important atmospheric and oceanic processes.
Sensitivity to Glacial Forcing in the CCSM4
Authors: Brady Esther C. , Otto-Bliesner Bette L. , Kay Jennifer E. , Rosenbloom Nan
Published: October 2012

Results are presented from the Community Climate System Model, version 4 (CCSM4), simulation of the Last Glacial Maximum (LGM) from phase 5 of the Coupled Model Intercomparison Project (CMIP5) at the standard 1° resolution, the same resolution as the majority of the CCSM4 CMIP5 long-term simulations for the historical and future projection scenarios. The forcings and boundary conditions for this simulation follow the protocols of the Paleoclimate Modeling Intercomparison Project, version 3 (PMIP3). Two additional CCSM4 CO2 sensitivity simulations, in which the concentrations are abruptly changed at the start of the simulation to the low 185 ppm LGM concentrations (LGMCO2) and to a quadrupling of the preindustrial concentration (4×CO2), are also analyzed. For the full LGM simulation, the estimated equilibrium cooling of the global mean annual surface temperature is 5.5°C with an estimated radiative forcing of −6.2 W m−2. The radiative forcing includes the effects of the reduced LGM greenhouse gases, ice sheets, continental distribution with sea level lowered by approximately 120 m from the present, and orbital parameters, but not changes to atmospheric aerosols or vegetation biogeography. The LGM simulation has an equilibrium climate sensitivity (ECS) of 3.1(±0.3)°C, comparable to the CCSM4 4×CO2 result. The LGMCO2 simulation shows a greater ECS of 4.2°C. Other responses found at the LGM in CCSM4 include a global precipitation rate decrease at a rate of ~2% °C−1, similar to climate change simulations in the Intergovernmental Panel on Climate Change Fourth Assessment Report (IPCC AR4); a strengthening of the Atlantic meridional overturning circulation (AMOC) with a shoaling of North Atlantic Deep Water and a filling of the deep basin up to sill depth with Antarctic Bottom Water; and an enhanced seasonal cycle accompanied by reduced ENSO variability in the eastern Pacific Ocean’s SSTs.
North Atlantic Climate Response to Lake Agassiz Drainage at Coarse and Ocean Eddy-Permitting Resolutions
Authors: Spence Paul , Saenko Oleg A. , Sijp Willem , England Matthew H.
Published: October 2012

The North Atlantic climate response to the catastrophic drainage of proglacial Lake Agassiz into the Labrador Sea is analyzed with coarse and ocean eddy-permitting versions of a global coupled climate model. The North Atlantic climate response is qualitatively consistent in that a large-scale cooling is simulated regardless of the model resolution or region of freshwater discharge. However, the magnitude and duration of the North Atlantic climate response is found to be sensitive to model resolution and the location of freshwater forcing. In particular, the long-term entrainment of freshwater along the boundary at higher resolution and its gradual, partially eddy-driven escape into the interior leads to low-salinity anomalies persisting in the subpolar Atlantic for decades longer. As a result, the maximum decline of the Atlantic meridional overturning circulation (AMOC) and the ocean meridional heat transport (MHT) is amplified by about a factor of 2 at ocean eddy-permitting resolution, and the recovery is delayed relative to the coarse grid model. This, in turn, increases the long-term cooling in the high-resolution simulations. A decomposition of the MHT response reveals an increased role for transients and the horizontal mean component of MHT at higher resolution. With fixed wind stress curl, it is a stronger response of bottom pressure torque to the freshwater forcing at higher resolution that leads to a larger anomaly of the depth-integrated circulation.
Can a Regional Ocean–Atmosphere Coupled Model Improve the Simulation of the Interannual Variability of the Western North Pacific Summer Monsoon?
Authors: Zou Liwei , Zhou Tianjun
Published: October 2012

A flexible regional ocean–atmosphere–land system coupled model [Flexible Regional Ocean Atmosphere Land System (FROALS)] was developed through the Ocean Atmosphere Sea Ice Soil, version 3 (OASIS3), coupler to improve the simulation of the interannual variability of the western North Pacific summer monsoon (WNPSM). The regionally coupled model consists of a regional atmospheric model, the Regional Climate Model, version 3 (RegCM3), and a global climate ocean model, the National Key Laboratory of Numerical Modeling for Atmospheric Sciences and Geophysical Fluid Dynamics (LASG)/Institute of Atmospheric Physics (IAP) Climate Ocean Model (LICOM). The impacts of local air–sea interaction on the simulation of the interannual variability of the WNPSM are investigated through regionally ocean–atmosphere coupled and uncoupled simulations, with a focus on El Niño’s decaying summer. Compared with the uncoupled simulation, the regionally coupled simulation exhibits improvements in both the climatology and the interannual variability of rainfall over the WNP. In El Niño’s decaying summer, the WNP is dominated by an anomalous anticyclone, less rainfall, and enhanced subsidence, which lead to increases in the downward shortwave radiation flux, thereby warming sea surface temperature (SST) anomalies. Thus, the ocean appears as a slave to atmospheric forcing. In the uncoupled simulation, however, the atmosphere is a slave to oceanic SST forcing, with the warm SST anomalies located east of the Philippines unrealistically producing excessive rainfall. In the regionally coupled run, the unrealistic positive rainfall anomalies and the associated atmospheric circulations east of the Philippines are significantly improved, highlighting the importance of air–sea coupling in the simulation of the interannual variability of the WNPSM. One limitation of the model is that the anomalous anticyclone over the WNP is weaker than the observations in both the regionally coupled and the uncoupled simulations. This results from the weaker simulated climatological summer rainfall intensity over the monsoon trough.
Dynamical Structure of Extreme Floods in the U.S. Midwest and the United Kingdom
Authors: Nakamura Jennifer , Lall Upmanu , Kushnir Yochanan , Robertson Andrew W. , Seager Richard
Published: October 2012

Twenty extreme spring floods that occurred in the Ohio basin between 1901 and 2008, identified from daily river discharge data, are investigated and compared to the April 2011 Ohio River flood event. Composites of synoptic fields for the flood events show that all of these floods are associated with a similar pattern of sustained advection of low-level moisture and warm air from the tropical Atlantic Ocean and the Gulf of Mexico. The typical flow conditions are governed by an anomalous semistationary ridge, situated east of the U.S. East Coast, that steers the moisture and converges it into the Ohio River valley. Significantly, the moisture path common to all of the 20 cases studied here as well as the case of April 2011 is distinctly different from the normal path of Atlantic moisture during spring, which occurs farther west. It is shown further that the Ohio basin moisture convergence responsible for the floods is caused primarily by the atmospheric circulation anomaly advecting the climatological mean moisture field. Transport and related convergence due to the covariance between moisture anomalies and circulation anomalies are of secondary but nonnegligible importance. The importance of atmospheric circulation anomalies to floods is confirmed by conducting a similar analysis for a series of winter floods on the river Eden in northwest England.