bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complete Genomic Sequence of a Novel Reassortant H11N3 Influenza Virus Isolated from Domestic Ducks in Jiangsu, China
Authors: Chen Chaoyang , Zhao Guo , Gu Xiaobing , Gu Min , Hu Jiao , Li Qunhui , Zhao Qingqing , Wang Xiaoquan , Liu Xiaowen , Liu Xiufan 
Published: October 2012

ABSTRACT
For the first time we report the complete genomic sequence of an H11N3 influenza virus from domestic ducks in China. Phylogenetic analysis showed that the H11N3 virus was a novel reassortant with its genes from different subtypes of domestic duck-origin avian influenza viruses, which further underlined that domestic ducks play a key role in the genetic reassortment and evolution of influenza viruses in China.
Complete Genome Sequences of a Novel Reassortant H4N2 Avian Influenza Virus Isolated from a Live Poultry Market in Eastern China
Authors: Teng Qiaoyang , Ji Xiwen , Li Guoxin , Li Xuesong , Li Zejun 
Published: October 2012

ABSTRACT
A/duck/Shanghai/28-1/2009(H4N2) (DK28) was isolated from a live poultry market in Shanghai, China. Using PCR and sequencing analysis, we obtained the complete genome sequences of the DK28 virus. The sequence analysis demonstrated that this H4N2 virus was a novel multiple-gene reassortant avian influenza virus (AIV) whose genes originated from H1N1, H1N3, H3N3, H4N2, and H4N6. Knowledge regarding the complete genome sequences of the DK28 virus will be useful for epidemiological surveillance.
Benchmarking and modeling disk-based storage tiers for practical storage design
Authors: Lee DongJin , O'Sullivan Michael , Walker Cameron 
Published: October 2012

This paper investigates benchmarking and modeling for a disk-based storage system in order to design and build a practical storage tier. As a practical case study, we focus on the design of an archival storage tier. The archival tiers play a critical role in data preservation as almost all current data will eventually be archived and the demands placed on archival tiers are growing because of large regularly-scheduled back-ups. Archival tiers usually consist of tape-based devices with a large storage capacity, but limited I/O performance for retrieving data, especially when multiple retrieval requests are made simultaneously. As the cost of disk-based devices continues to decrease while the capacity of individual disks increases, disk-based systems are becoming a more realistic option for both enterprise and commodity archival storage tiers.
We utilize archival workloads developed from an analysis of historical data in order to provide accurate and robust benchmarks of system performance as an archive. We then embed our practical measurements in a measurementdriven optimization approach to design an archival system. Our approach produces a low cost design for a commodity disk-based archival storage system. Using our measurementdriven model, ideal storage building blocks are identified for a real-world archival tier design.
Cyclin D1 Activity Regulates Autophagy and Senescence in the Mammary Epithelium
Authors: Brown Nelson E. , Jeselsohn Rinath , Bihani Teeru , Hu Miaofen G. , Foltopoulou Parthena , Kuperwasser Charlotte , Hinds Philip W. 
Published: October 2012

Abstract
Overexpression of cyclin D1 is believed to endow mammary epithelial cells (MEC) with a proliferative advantage by virtue of its contribution to pRB inactivation. Accordingly, abrogation of the kinase-dependent function of cyclin D1 is sufficient to render mice resistant to breast cancer initiated by ErbB2. Here, we report that mouse cyclin D1KE/KE MECs (deficient in cyclin D1 activity) upregulate an autophagy-like process but fail to implement ErbB2-induced senescence in vivo. In addition, immortalized cyclin D1KE/KE MECs retain high rates of autophagy and reduced ErbB2-mediated transformation in vitro. However, highlighting its dual role during tumorigenesis, downregulation of autophagy led to an increase in senescence in cyclin D1KE/KE MECs. Autophagy upregulation was also confirmed in human mammary epithelial cells (HMEC) subjected to genetic and pharmacologic inhibition of cyclin D1 activity and, similar to our murine system, simultaneous inhibition of Cdk4/6 and autophagy in HMECs enhanced the senescence response. Collectively, our findings suggest a previously unrecognized function of cyclin D1 in suppressing autophagy in the mammary epithelium. Cancer Res; 72(24); 6477–89. ©2012 AACR.
Oxidative Stress-Regulated Lentiviral TK/GCV Gene Therapy for Lung Cancer Treatment
Authors: Leinonen Hanna M. , Ruotsalainen Anna-Kaisa , Määttä Ann-Marie , Laitinen Heidi M. , Kuosmanen Suvi M. , Kansanen Emilia , Pikkarainen Jere T. , Lappalainen Jari P. , Samaranayake Haritha , Lesch Hanna P. , Kaikkonen Minna U. , Ylä-Herttuala Seppo , Levonen Anna-Liisa 
Published: October 2012

Abstract
Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that regulates protection against a wide variety of toxic insults to cells, including cytotoxic cancer chemotherapeutic drugs. Many lung cancer cells harbor a mutation in either Nrf2 or its inhibitor Keap1 resulting in permanent activation of Nrf2 and chemoresistance. In this study, we sought to examine whether this attribute could be exploited in cancer suicide gene therapy by using a lentiviral (LV) vector expressing herpes simplex virus thymidine kinase (HSV-TK/GCV) under the regulation of antioxidant response element (ARE), a cis-acting enhancer sequence that binds Nrf2. In human lung adenocarcinoma cells in which Nrf2 is constitutively overexpressed, ARE activity was found to be high under basal conditions. In this setting, ARE-HSV-TK was more effective than a vector in which HSV-TK expression was driven by a constitutively active promoter. In a mouse xenograft model of lung cancer, suicide gene therapy with LV-ARE-TK/GCV was effective compared with LV-PGK-TK/GCV in reducing tumor size. We conclude that ARE-regulated HSV-TK/GCV therapy offers a promising approach for suicide cancer gene therapy in cells with high constitutive ARE activity, permitting a greater degree of therapeutic targeting to those cells. Cancer Res; 72(23); 6227–35. ©2012 AACR.
Regression of Human Prostate Cancer Xenografts in Mice by AMG 212/BAY2010112, a Novel PSMA/CD3-Bispecific BiTE Antibody Cross-Reactive with Non-Human Primate Antigens
Authors: Friedrich Matthias , Raum Tobias , Lutterbuese Ralf , Voelkel Markus , Deegen Petra , Rau Doris , Kischel Roman , Hoffmann Patrick , Brandl Christian , Schuhmacher Joachim , Mueller Peter , Finnern Ricarda , Fuergut Melanie , Zopf Dieter , Slootstra Jerry W. , Baeuerle Patrick A. , Rattel Benno , Kufer Peter 
Published: October 2012

Abstract
For treatment of patients with prostate cancer (PCa), we developed a novel T cell-engaging (BiTE) antibody designated AMG 212 or BAY2010112 that is bispecific for prostate-specific membrane antigen (PSMA) and the CD3 epsilon subunit of the T cell receptor complex. AMG 212/BAY2010112 induced target cell-dependent activation and cytokine release of T cells, and efficiently redirected T cells for lysis of target cells. In addition to Chinese hamster ovary cells stably expressing human or cynomolgus monkey PSMA, T cells redirected by AMG 212/BAY2010112 also lysed human PCa cell lines VCaP, 22Rv1, MDA PCa 2b, C4-2, PC-3-huPSMA, and LnCaP at half maximal BiTE concentrations between 0.1 and 4 ng/mL (1.8–72 pmol/L). No lysis of PSMA-negative human PCa cell lines PC-3 and DU145 was observed. The subcutaneous (s.c.) formation of tumors from PC-3-huPSMA cells in NOD/SCID mice was significantly prevented by once daily intravenous (i.v.) injection of AMG 212/BAY2010112 at a dose level as low as 0.005 mg/kg/d. Rapid tumor shrinkage with complete remissions were observed in NOD/SCID mice bearing established s.c. 22Rv1 xenografts after repeated daily treatment with AMG 212/BAY2010112 by either the i.v. or s.c. route. Of note, 22Rv1 tumors were grown in the absence of human T cells followed by intraperitoneal injection of T cells 3 days before BiTE treatment. No effects on tumor growth were observed in the absence of human T cells or AMG 212/BAY2010112. On the basis of these preclinical results, AMG 212/BAY2010112 appears as a promising new BiTE antibody for the treatment of patients with PSMA-expressing PCa. Mol Cancer Ther; 11(12); 2664–73. ©2012 AACR.
Sorafenib-Mediated Targeting of the AAA+ ATPase p97/VCP Leads to Disruption of the Secretory Pathway, Endoplasmic Reticulum Stress, and Hepatocellular Cancer Cell Death
Authors: Yi Ping , Higa Arisa , Taouji Said , Bexiga Mariana G. , Marza Esther , Arma Daniela , Castain Claire , Le Bail Brigitte , Simpson Jeremy C. , Rosenbaum Jean , Balabaud Charles , Bioulac-Sage Paulette , Blanc Jean-Frédéric , Chevet Eric 
Published: October 2012

Abstract
The molecular mechanisms and cellular targets of sorafenib, a multikinase inhibitor used for the treatment of hepatocellular carcinoma (HCC), remain to be fully characterized. Recent studies have shown that sorafenib induces tumor cell death through the activation of endoplasmic reticulum stress signaling and/or autophagy in various cellular models. Using liver cancer–derived cell lines, we specifically show that the IRE1 and phosphorylated extracellular signal–regulated kinase arms of the unfolded protein response (UPR) become activated upon sorafenib treatment, whereas the ATF6 arm is inhibited. Our results also reveal that sorafenib treatment causes disruption to the secretory pathway, as witnessed by the fragmentation of the Golgi apparatus and the induction of autophagy. On the basis of these observations, we tested the relevance of the AAA+ ATPase p97/VCP as a potential functional target of sorafenib. Our results show that p97/VCP tyrosine phosphorylation is prevented upon sorafenib treatment, and that this can be correlated with enhanced membrane association. Moreover, we show that DBeQ, a recently discovered inhibitor of p97/VCP, enhances sorafenib-mediated toxicity in cultured cells. Our data show a novel mechanism for sorafenib-mediated cell death in HCC, which depends on the integrity of the secretory pathway; and we identify p97/VCP phosphorylation as a potential target for improved sorafenib treatment efficacy in patients. Mol Cancer Ther; 11(12); 2610–20. ©2012 AACR.
The Role of Bcl-xL in Synergistic Induction of Apoptosis by Mapatumumab and Oxaliplatin in Combination with Hyperthermia on Human Colon Cancer
Authors: Song Xinxin , Kim Seog-Young , Lee Yong J. 
Published: October 2012

AbstractColorectal cancer is the third leading cause of cancer-related mortality in the world. The main cause of death because of colorectal cancer is hepatic metastases, which can be treated using isolated hepatic perfusion (IHP), allowing treatment of colorectal metastasis with various methods. In this study, we present a novel potent multimodality strategy comprising humanized death receptor 4 (DR4) antibody mapatumumab in combination with oxaliplatin and hyperthermia to treat human colon cancer cells. Oxaliplatin and hyperthermia sensitized colon cancer cells to mapatumumab in the mitochondrial-dependent apoptotic pathway and increased reactive oxygen species (ROS) production, leading to Bcl-xL phosphorylation at serine 62 in a c-jun-NH2-kinase (JNK)-dependent manner. Overexpression of Bcl-xL reduced the efficacy of the multimodality treatment, whereas phosphorylation of Bcl-xL decreased its antiapoptotic activity. The multimodality treatment dissociated Bcl-xL from Bax, allowing Bax oligomerization to induce cytochrome c release from mitochondria. In addition, the multimodality treatment significantly inhibited colorectal cancer xenografts' tumor growth. The successful outcome of this study will support the application of multimodality strategy to colorectal hepatic metastases. Mol Cancer Res; 10(12); 1567–79. ©2012 AACR.
Measuring Oncogenic Signaling Pathways in Cancer with PET: An Emerging Paradigm from Studies in Castration-Resistant Prostate Cancer
Authors: Evans Michael J. 
Published: October 2012

AbstractAs parallel advances in cancer biology and drug development continue to elevate the role of targeted therapies in oncology, the need for imaging biomarkers that systematically measure the biology associated with therapeutic intervention has become more urgent. Although the molecular imaging community has a commitment to develop technologies to this end, few investigational radiotracers directly measure the biology of common oncogenic signaling pathways often addressed by targeted therapies. Visible progress has been achieved with a handful of radiotracers rationally designed to intercalate the pathobiology of prostate cancer, a molecularly heterogeneous disease nevertheless broadly defined by a fairly small repertoire of recurrent oncogenic lesions.Significance: That variable treatment responses or emergent resistance phenotypes are often documented in humans argues strongly for diagnostic technologies that can be realistically applied posttherapy to capture the dynamic patterns of disease response. The purpose of this review is to describe a collection of radiotracers developed to measure the pathobiology of prostate cancer for improved treatment monitoring, placing particular emphasis on the biologic rationale for their preparation. A chronologic description of radiotracer development programs is outlined, primarily to stress how an ongoing dialectic between earlier and more contemporary imaging technologies has accelerated discovery. Cancer Discov; 2(11); 985–94. ©2012 AACR.
Fatty Acids Regulate Endothelial Lipase and Inflammatory Markers in Macrophages and in Mouse Aorta
Authors: Jung Un Ju , Torrejon Claudia , Chang Chuchun L. , Hamai Hiroko , Worgall Tilla S. , Deckelbaum Richard J. 
Published: October 2012

Objective—
Macrophage endothelial lipase (EL) is associated with increased atherosclerosis and inflammation. Because of their anti-inflammatory properties we hypothesized that n-3 fatty acids, in contrast to saturated fatty acids, would lower macrophages and arterial EL and inflammatory markers.

Methods and Results—
Murine J774 and peritoneal macrophages were incubated with eicosapentaenoic acid or palmitic acid in the presence or absence of lipopolysaccaride (LPS). LPS increased EL mRNA and protein. Palmitic acid alone or with LPS dose-dependently increased EL mRNA and protein. In contrast, eicosapentaenoic acid dose-dependently abrogated effects of LPS or palmitic acid on increasing EL expression. EL expression closely linked to peroxisome proliferator activated receptor (PPAR)γ expression. Eicosapentaenoic acid blocked rosiglitazone (a PPARγ agonist)-mediated EL activation and GW9662 (a PPARγ antagonist)-blocked palmitic acid-mediated EL stimulation. Eicosapentaenoic acid alone or with LPS blunted LPS-mediated stimulation of macrophage proinflammatory interleukin-6, interleukin-12p40, and toll-like receptor-4 mRNA and increased anti-inflammatory interleukin-10 and mannose receptor mRNA. In vivo studies in low density lipoprotein receptor knockout mice showed that high saturated fat rich diets, but not n-3 diets, increased arterial EL, PPARγ, and proinflammatory cytokine mRNA.

Conclusion—
n-3 fatty acids, in contrast to saturated fatty acids, decrease EL in parallel with modulating pro- and anti-inflammatory markers, and these effects on EL link to PPARγ.
Microvascular Dysfunction Is Associated With a Higher Incidence of Type 2 Diabetes Mellitus
Authors: Muris Dennis M.J. , Houben Alfons J.H.M. , Schram Miranda T. , Stehouwer Coen D.A. 
Published: October 2012

Objective—
Recent data support the hypothesis that microvascular dysfunction may be a potential mechanism in the development of insulin resistance. We examined the association of microvascular dysfunction with incident type 2 diabetes mellitus (T2DM) and impaired glucose metabolism by reviewing the literature and conducting a meta-analysis of longitudinal studies on this topic.

Methods and Results—
We searched Medline and Embase for articles published up to October 2011. Prospective cohort studies that focused on microvascular measurements in participants free of T2DM at baseline were included. Pooled relative risks were calculated using random effects models. Thirteen studies met the inclusion criteria for this meta-analysis. These studies focused on T2DM or impaired fasting glucose, not on impaired glucose tolerance. The pooled relative risks for incident T2DM (3846 cases) was 1.25 (95% confidence interval, 1.15; 1.36) per 1 SD greater microvascular dysfunction when all estimates of microvascular dysfunction were combined. In analyses of single estimates of microvascular dysfunction, the pooled relative risks for incident T2DM was 1.49 (1.36; 1.64) per 1 SD higher plasma soluble E-selectin levels; 1.21(1.11; 1.31) per 1 SD higher plasma soluble intercellular adhesion molecule-1 levels; 1.48 (1.03; 2.12) per 1 SD lower response to acetylcholine-mediated peripheral vascular reactivity; 1.18 (1.08; 1.29) per 1 SD lower retinal arteriole-to-venule ratio; and 1.43 (1.33; 1.54) per 1 logarithmically transformed unit higher albumin-to-creatinine ratio. In addition, the pooled relative risks for incident impaired fasting glucose (409 cases) was 1.15 (1.01–1.31) per 1 SD greater retinal venular diameters.

Conclusion—
These data indicate that various estimates of microvascular dysfunction were associated with incident T2DM and, possibly, impaired fasting glucose, suggesting a role for the microcirculation in the pathogenesis of T2DM.
Krüppel-Like Factor-11, a Transcription Factor Involved in Diabetes Mellitus, Suppresses Endothelial Cell Activation via the Nuclear Factor-κB Signaling Pathway
Authors: Fan Yanbo , Guo Yanhong , Zhang Jifeng , Subramaniam Malayannan , Song Chao-Zhong , Urrutia Raul , Chen Y. Eugene 
Published: October 2012

Objective—

Endothelial cell (EC) inflammatory status is critical to many vascular diseases. Emerging data demonstrate that mutations of Krüppel-like factor-11 (KLF11), a gene coding maturity-onset diabetes mellitus of the young type 7 (
MODY7
), contribute to the development of neonatal diabetes mellitus. However, the function of KLF11 in the cardiovascular system still remains to be uncovered. In this study, we aimed to investigate the role of KLF11 in vascular endothelial inflammation.

Methods and Results—

KLF11 is highly expressed in vascular ECs and induced by proinflammatory stimuli. Adenovirus-mediated KLF11 overexpression inhibits expression of tumor necrosis factors-α–induced adhesion molecules. Moreover, small interfering RNA–mediated KLF11 knockdown augments the proinflammatory status in ECs. KLF11 inhibits promoter activity of adhesion molecules induced by tumor necrosis factor-α and nuclear factor-κB p65 overexpression. Mechanistically, KLF11 potently inhibits nuclear factor-κB signaling pathway via physical interaction with p65. Furthermore, KLF11 knockdown results in increased binding of p65 to vascular cell adhesion molecule-1 and E-selectin promoters. At the whole organism level,
KLF11
−/−
mice exhibit a significant increase in leukocyte recruitment to ECs after lipopolysaccharide administration.

Conclusion—
Taken together, our data demonstrate for the first time that KLF11 is a suppressor of EC inflammatory activation, suggesting that KLF11 constitutes a novel potential molecular target for inhibition of vascular inflammatory diseases.
Cholesterol Accumulation Regulates Expression of Macrophage Proteins Implicated in Proteolysis and Complement Activation
Authors: Suzuki Masashi , Becker Lev , Pritchard David K. , Gharib Sina A. , Wijsman Ellen M. , Bammler Theo K. , Beyer Richard P. , Vaisar Tomas , Oram John F. , Heinecke Jay W. 
Published: October 2012

Objective—
Cholesterol accumulation by macrophages plays a key role in atherogenesis. To begin to develop a global picture of this process, we used proteomics and transcriptomics to analyze foam cells generated with acetyl-low-density lipoprotein, a classic ligand for scavenger receptors.

Methods and Results—
Tandem mass spectrometry and stringent statistical analysis revealed that foam cells differentially expressed 15 of 542 proteins (2.8%) detected in macrophage-conditioned medium. Apolipoprotein E was one of the most upregulated proteins, confirming that proteins involved in lipid metabolism are important targets for regulation by sterol accumulation. However, levels of proteins linked to complement activation and lysosomal proteolysis also changed markedly. Transcriptional analysis demonstrated that 698 of 19 700 genes (3.5%) were regulated in foam cells, including many genes important in sterol metabolism. We also found that cholesterol accumulation regulated genes implicated in complement activation but failed to affect genes linked to proteolysis and macrophage polarization. Changes in protein levels in macrophage-conditioned medium were largely independent of changes in mRNA levels.

Conclusion—
Loading sterol into macrophages regulates levels of complement proteins and lysosomal proteases—key players in the immune system and plaque rupture. Posttranscriptional mechanisms are likely important for controlling levels of most of the proteins detected in macrophage medium.
Plasma CXCL12 Levels as a Predictor of Future Stroke
Authors: Schutt Robert C. , Burdick Marie D. , Strieter Robert M. , Mehrad Borna , Keeley Ellen C. 
Published: October 2012

Background and Purpose—
The chemokine ligand CXCL12 is constitutively expressed in the bone marrow and other tissues including the brain endothelium and is responsible for regulating the trafficking of bone marrow progenitor cells. CXCL12 has been shown to play a significant role in animal models of ischemic stroke but its role in human stroke is unclear. The aim of this study was to test the hypothesis that elevated circulating baseline CXCL12 levels are associated with subsequent stroke.

Methods—
We prospectively collected demographic and angiographic data from consecutive patients referred for elective coronary angiography. Before coronary angiography a peripheral blood sample was collected for subsequent measurement of CXCL12. One-year stroke risk was calculated using the Framingham Risk Profile. Clinical follow-up was performed at 6 months and 1 year.

Results—

Of 206 subjects enrolled, 10 (4.9%) sustained an ischemic stroke over the 1year follow-up. There were no significant differences in baseline clinical characteristics or angiographic findings. However, median CXCL12 levels were significantly higher in those who sustained an ischemic stroke compared with those who did not (10 856 pg/mL versus 2241 pg/mL,
P
=0.007). The time to stroke distribution between subjects with baseline CXCL12 levels ≥10 421 pg/mL and those with baseline CXCL12 levels <10 421 pg/mL was significantly different (log rank
P
<0.001). The weighted Cox proportional hazard model demonstrated that baseline CXCL12 levels ≥10 421 pg/mL were significantly associated with ischemic stroke at follow-up (hazard ratio, 15.29; 95% CI, 3.05–76.71).

Conclusions—
Plasma CXCL12 levels may represent a novel biomarker of future ischemic stroke.