bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluating the effectiveness of the response to equine influenza in the Australian outbreak and the potential role of early vaccination
Authors: Garner MG , Cowled B , East IJ , Moloney BJ , Kung N 
Published: June 2011

Objective  To use modelling and epidemiological analyses to assess the effectiveness of control strategies employed during the equine influenza outbreak and determine if early vaccination might have had a beneficial effect.Methods  Transmission of infection was modelled using stochastic, spatial simulation, based on data from 16 regions in New South Wales and Queensland over the first month of the outbreak.Results  The model accurately represented the spread of infection in both space and time and showed that vaccination strategies would have reduced new infections by ∼60% and reduced the size of the infected area by 8–9%, compared to the non‐vaccination baseline.Conclusion  When used in conjunction with biosecurity measures and movement controls, early vaccination could play an important role in the containment and eradication of equine influenza.
Iron chelator deferasirox rescued mice from Fas‐induced fulminant hepatitis
Authors: Sato Tsutomu , Kobune Masayoshi , Murase Kazuyuki , Kado Yukari , Okamoto Tetsuro , Tanaka Shingo , Kikuchi Shohei , Nagashima Hiroyuki , Kawano Yutaka , Takada Kohichi , Iyama Satoshi , Miyanishi Koji , Sato Yasushi , Takimoto Rishu , Kato Junji 
Published: June 2011

Aim:  Fulminant hepatitis is a disease characterized by development of hepatic failure due to severe liver cell injury. Orthotopic liver transplantation is the therapy proven to improve patient survival; however, less burdensome and safer strategies are required. In a previous study, we showed that iron was intimately involved in hepatocyte apoptosis by demonstrating that spontaneous development of fulminant hepatitis in Long–Evans cinnamon rats was prevented by feeding an iron‐deficient diet. Recently, a new iron chelator, deferasirox, has become widely available for the treatment of transfusional hemosiderosis. Deferasirox demonstrated good efficacy and improved compliance due to convenient, once‐daily p.o. administration. Our aim was to investigate the efficacy of deferasirox as a therapeutic drug against fulminant hepatitis.Methods:  Human primary hepatocytes undergoing Fas‐stimulated apoptosis were challenged with deferoxamine (DFO) in vitro. In further in vivo experiments, we tested DFO in a mice model of fulminant hepatitis induced by Fas‐stimulation.Results:  The apoptosis‐inducing activity of anti‐Fas antibody on human primary hepatocytes was inhibited by the chelation of iron with DFO. DFO suppressed the Fas‐induced production of reactive oxygen species (ROS) and the activation of caspase‐3, both of which were also suppressed by antioxidant, N‐acetyl‐L‐cystein. In the in vivo experiments, deferasirox effectively reduced hepatic iron concentrations and rescued mice from Fas‐induced fulminant hepatitis.Conclusion:  These findings indicated that the iron chelation exerted a hepatoprotective effect by scavenging ROS upstream of caspase‐3 and that iron chelation with deferasirox is a potential treatment for patients with fulminant hepatitis.
Lymph-node metastases in invasive lobular carcinoma are different from those in ductal carcinoma of the breast
Authors: Fernández Beatriz , Paish E Claire , Green Andrew R , Lee Andrew H S , Macmillan R Douglas , Ellis Ian O , Rakha Emad A 
Published: June 2011

AimInvasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) of the breast are distinct morphological entities with different biological features and clinical behaviour. In the present study, the authors compare the axillary-lymph-node (ALN) status of patients with grade-matched ILC (no=426) and IDC (no=820). The pattern of nodal metastatic deposits (nodular, sinusoidal and diffuse) and the proportion of involved nodes were also analysed in a selected group of 246 tumours, which were associated with a single positive ALN.ResultsCompared with grade-matched IDC, ILC was associated with a higher nodal stage (13.1% vs 4.5% of ILC and IDC were stage 3), higher absolute number of positive nodes and higher ratio of positive nodes (0.46±0.30 and 0.33±0.23 in ILC and IDC respectively). These differences were maintained in the different size subgroups. The most common metastatic morphological pattern was nodular in both types of carcinomas. A sinusoidal pattern was more frequent in IDC, and the diffuse pattern was more frequent in ILC. Despite these differences, ILC and grade-matched IDC exhibited similar rates of regional recurrences (RR) and breast-cancer survival.ConclusionThis study provides clinical evidence which further demonstrates that ILC and IDC are biologically distinct entities with different lymph-node involvement patterns and ILC having a tendency to metastasise to more nodes than IDC. However, this difference was not associated with a significant impact on patient outcome.
The assessment of tobacco dependence in young users of smokeless tobacco
Authors: DiFranza Joseph R , Sweet Michael , Savageau Judith A , Ursprung W W Sanouri 
Published: June 2011

IntroductionAs all published measures of dependence for users of smokeless tobacco (dippers) have poor reliability, in the present work the Hooked on Nicotine Checklist (HONC) and the Autonomy Over Smoking Scale (AUTOS) were evaluated for use with this population. Dippers and smokers were also compared in relation to dependence, the pleasure derived from using tobacco and the latency to the onset of withdrawal.MethodsIn 2010, an anonymous self-completed paper survey was administered to 1541 students of mixed race and ethnicity in grades 9–12 (mean age 15.9 years) in a Florida high school where students used cigarettes and smokeless tobacco.ResultsThe reliability (Cronbach's α) for the HONC was 0.90 for smokers (n=139) and 0.91 for dippers (n=85), and for the AUTOS was 0.94 for smokers and dippers. Dippers and smokers did not differ significantly in relation to scores on the HONC, AUTOS, latency to withdrawal onset or pleasure derived from smoking. One or more symptoms on the HONC were reported by 56% of dippers and 57% of smokers with <100 lifetime uses of their favoured tobacco product, and by 91% of dippers and 91% of smokers with ≥100 lifetime uses (not significant). Greater lifetime use was associated with a significantly shorter latency to withdrawal for smokers and dippers.ConclusionsThe HONC and AUTOS are highly reliable measures of dependence for adolescent users of cigarettes and smokeless tobacco. Using these measures and other indicators, no meaningful differences in dependence were found between dippers and smokers at comparable levels of lifetime use.
HIF Induces Human Embryonic Stem Cell Markers in Cancer Cells
Authors: Mathieu Julie , Zhang Zhan , Zhou Wenyu , Wang Amy J. , Heddleston John M. , Pinna Claudia M.A. , Hubaud Alexis , Stadler Bradford , Choi Michael , Bar Merav , Tewari Muneesh , Liu Alvin , Vessella Robert , Rostomily Robert , Born Donald , Horwitz Marshall , Ware Carol , Blau C. Anthony , Cleary Michele A. , Rich Jeremy N. , Ruohola-Baker Hannele 
Published: June 2011

Abstract
Low oxygen levels have been shown to promote self-renewal in many stem cells. In tumors, hypoxia is associated with aggressive disease course and poor clinical outcomes. Furthermore, many aggressive tumors have been shown to display gene expression signatures characteristic of human embryonic stem cells (hESC). We now tested whether hypoxia might be responsible for the hESC signature observed in aggressive tumors. We show that hypoxia, through hypoxia-inducible factor (HIF), can induce an hESC-like transcriptional program, including the induced pluripotent stem cell (iPSC) inducers, OCT4, NANOG, SOX2, KLF4, cMYC, and microRNA-302 in 11 cancer cell lines (from prostate, brain, kidney, cervix, lung, colon, liver, and breast tumors). Furthermore, nondegradable forms of HIFα, combined with the traditional iPSC inducers, are highly efficient in generating A549 iPSC-like colonies that have high tumorigenic capacity. To test potential correlation between iPSC inducers and HIF expression in primary tumors, we analyzed primary prostate tumors and found a significant correlation between NANOG-, OCT4-, and HIF1α-positive regions. Furthermore, NANOG and OCT4 expressions positively correlated with increased prostate tumor Gleason score. In primary glioma-derived CD133 negative cells, hypoxia was able to induce neurospheres and hESC markers. Together, these findings suggest that HIF targets may act as key inducers of a dynamic state of stemness in pathologic conditions. Cancer Res; 71(13); 4640–52. ©2011 AACR.
FoxM1: A Master Regulator of Tumor Metastasis
Authors: Raychaudhuri Pradip , Park Hyun Jung 
Published: June 2011

Abstract
The FoxM1 transcription factor gene is overexpressed in cancer. Its expression is stimulated by oncogenic signaling pathways and reactive oxygen species. It is also a target of regulation by the tumor suppressor genes. The transcriptional activity of FoxM1 depends upon activation by cyclin and cyclin-dependent kinases as well as Plk1. FoxM1 stimulates expression of several genes involved in the cell cycle progression. Moreover, it supports proliferation of tumor cells by stimulating expression of the antioxidant genes and reducing oxidative stress. A new study provides evidence that FoxM1, in the absence of its inhibitor, the tumor suppressor Arf, drives metastasis of hepatocellular carcinoma (HCC). It induces an epithelial–mesenchymal–like transition phenotype in HCC cells, increases cell migration, and induces premetastatic niche at the distal organ of metastasis. FoxM1 directly activates genes involved in multiple steps of metastasis. In this review, we discuss the evidence for a master regulatory role of FoxM1 in tumor metastasis. Cancer Res; 71(13); 4329–33. ©2011 AACR.
Treatment-Induced Oxidative Stress and Cellular Antioxidant Capacity Determine Response to Bortezomib in Mantle Cell Lymphoma
Authors: Weniger Marc A. , Rizzatti Edgar G. , Pérez-Galán Patricia , Liu Delong , Wang Qiuyan , Munson Peter J. , Raghavachari Nalini , White Therese , Tweito Megan M. , Dunleavy Kieron , Ye Yihong , Wilson Wyndham H. , Wiestner Adrian 
Published: June 2011

Abstract
Purpose: Proteasome inhibition disrupts protein homeostasis and induces apoptosis. Up to 50% of patients with relapsed mantle cell lymphoma (MCL) respond to bortezomib. We used gene expression profiling to investigate the connection between proteasome inhibition, cellular response, and clinical efficacy.
Experimental Design: We assessed transcriptional changes in primary tumor cells from five patients during treatment with bortezomib in vivo, and in 10 MCL cell lines exposed to bortezomib in vitro, on Affymetrix microarrays. Key findings were confirmed by western blotting.
Results: MCL cell lines exposed to bortezomib in vitro showed upregulation of endoplasmic reticulum and oxidative stress response pathways. Gene expression changes were strongest in bortezomib-sensitive cells and these cells were also more sensitive to oxidative stress induced by H2O2. Purified tumor cells obtained at several timepoints during bortezomib treatment in 5 previously untreated patients with leukemic MCL showed strong activation of the antioxidant response controlled by NRF2. Unexpectedly, activation of this homeostatic program was significantly stronger in tumors with the best clinical response. Consistent with its proapoptotic function, we found upregulation of NOXA in circulating tumor cells of responding patients. In resistant cells, gene expression changes in response to bortezomib were limited and upregulation of NOXA was absent. Interestingly, at baseline, bortezomib-resistant cells displayed a relatively higher expression of the NRF2 gene-expression signature than sensitive cells (P &lt; 0.001).
Conclusion: Bortezomib triggers an oxidative stress response in vitro and in vivo. High cellular antioxidant capacity contributes to bortezomib resistance. Clin Cancer Res; 17(15); 5101–12. ©2011 AACR.
Cancer Patients Treated with Sunitinib or Sorafenib Have Sufficient Antibody and Cellular Immune Responses to Warrant Influenza Vaccination
Authors: Mulder Sasja F. , Jacobs Joannes F.M. , Olde Nordkamp Michel A.M. , Galama Joep M.D. , Desar Ingrid M.E. , Torensma Ruurd , Teerenstra Steven , Mulders Peter F.A. , Vissers Kris C.P. , Punt Cornelis J.A. , de Vries I. Jolanda M. , van Herpen Carla M.L. 
Published: June 2011

Abstract
Purpose: The tyrosine kinase inhibitors sorafenib and sunitinib have efficacy in several types of cancer. Recent studies indicate that these agents affect the immune system. The way it affects the immune response to influenza vaccination is unknown. The aim of this study was to elucidate the specific immune response to seasonal flu vaccination in cancer patients treated with sunitinib or sorafenib.
Patients and Methods: Sunitinib- or sorafenib-treated cancer patients were vaccinated against seasonal influenza with an inactivated vaccine. Healthy controls and patients with metastatic renal cell cancer (mRCC) without systemic treatment (nontreated mRCC controls) were included for comparison. Antibody responses were measured at baseline, day 8, and day 22 by a standard hemagglutination inhibition assay and cellular T-cell responses at baseline and day 8 by proliferation assay and secretion of cytokines.
Results: Forty subjects were enrolled: 16 patients treated with sunitinib, 6 patients with sorafenib, 7 nontreated mRCC controls, and 11 healthy controls. All patients treated with sunitinib and sorafenib developed seroprotection rates comparable with controls. Functional T-cell reactivity was observed in all groups, except for patients treated with sorafenib who showed a decreased proliferation rate and IFN-γ/IL-2 production and increased IL-10 compared with healthy controls.
Conclusion: We conclude that influenza vaccination should be recommended to cancer patients treated with sunitinib or sorafenib. Clin Cancer Res; 17(13); 4541–9. ©2011 AACR.
Liposomal Delivery of MicroRNA-7–Expressing Plasmid Overcomes Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-Resistance in Lung Cancer Cells
Authors: Rai Kammei , Takigawa Nagio , Ito Sachio , Kashihara Hiromi , Ichihara Eiki , Yasuda Tatsuji , Shimizu Kenji , Tanimoto Mitsune , Kiura Katsuyuki 
Published: June 2011

Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been strikingly effective in lung cancers harboring activating EGFR mutations. Unfortunately, the cancer cells eventually acquire resistance to EGFR-TKI. Approximately 50% of the acquired resistance involves a secondary T790M mutation. To overcome the resistance, we focused on EGFR suppression using microRNA-7 (miR-7), targeting multiple sites in the 3′-untranslated region of EGFR mRNA. Two EGFR-TKI–sensitive cell lines (PC-9 and H3255) and two EGFR-TKI–resistant cell lines harboring T790M (RPC-9 and H1975) were used. We constructed miR-7-2 containing miR-7–expressing plasmid. After transfection of the miR-7–expressing plasmid, using cationic liposomes, a quantitative PCR and dual luciferase assay were conducted to examine the efficacy. The antiproliferative effect was evaluated using a cell count assay and xenograft model. Protein expression was examined by Western blotting. The miR-7 expression level of the transfectants was approximately 30-fold higher, and the luciferase activity was ablated by 92%. miR-7 significantly inhibited cell growth not only in PC-9 and H3255 but also in RPC-9 and H1975. Expression of insulin receptor substrate-1 (IRS-1), RAF-1, and EGFR was suppressed in the four cell lines. Injection of the miR-7–expressing plasmid revealed marked tumor regression in a mouse xenograft model using RPC-9 and H1975. EGFR, RAF-1, and IRS-1 were suppressed in the residual tumors. These findings indicate promising therapeutic applications of miR-7–expressing plasmids against EGFR oncogene–addicted lung cancers including T790M resistance by liposomal delivery. Mol Cancer Ther; 10(9); 1720–7. ©2011 AACR.
Involvement of microparticles in diabetic vascular complications
Authors: Tsimerman Gala , Roguin Ariel , Bachar Anat , Melamed Eyal , Brenner Benjamin , Aharon Anat 
Published: June 2011

SummaryType 2 diabetes mellitus (T2DM) is associated with increased coagulability and vascular complications. Circulating microparticles (MPs) are involved in thrombosis, inflammation, and angiogenesis. However, the role of MPs in T2DM vascular complications is unclear. We characterised the cell origin and pro-coagulant profiles of MPs obtained from 41 healthy controls and 123 T2DM patients with coronary artery disease, retinopathy and foot ulcers. The effects of MPs on endothelial cell coagulability and tube formation were evaluated. Patients with severe diabetic foot ulcers expressed the highest levels of MPs originated from platelet and endothelial cells and negatively-charged phospholipidbearing MPs. MP coagulability, calculated from MP tissue factor (TF) and TF pathway inhibitor (TFPI) ratio, was low in healthy controls and in diabetic retinopathy patients (<0.7) but high in patients with coronary artery disease and foot ulcers (>1.8, p≥0.002). MPs of all T2DM patients induced a more than two-fold increase in endothelial cell TF (antigen and gene expression) but did not affect TFPI levels. Tube networks were longest and most stable in endothelial cells that were incubated with MPs of healthy controls, whereas no tube formation occurred in MPs of diabetic patients with coronary artery disease. MPs of diabetic retinopathy and diabetic foot ulcer patients induced branched tube networks that were unstable and collapsed over time. This study demonstrates that MP characteristics are related to the specific type of vascular complications and may serve as a bio-marker for the procoagulant state and vascular pathology in patients with T2DM.
The effect of decitabine on megakaryocyte maturation and platelet release
Authors: Wang Jianhui , Yi Zanhua , Wang Shiyang , Li Zongdong 
Published: June 2011

SummaryThrombocytopenia is a common feature of myelodysplastic syndromes (MDS). 5-aza-2’-deoxycytidine (decitabine) has been used to treat MDS with an approximately 20% response rate in thrombocytopenia. However, the mechanism of how decitabine increases platelet count is not clear. In this study, we investigated the effect of decitabine on megakaryocyte maturation and platelet release in the mouse. The effect of decitabine on megakaryocyte maturation was studied in an in vitro megakaryocyte differentiation model utilising mouse bone marrow cells and mouse megakaryoblastic cell line L8057. Decitabine (2.5 μM) is able to induce L8057 cells to differentiate into a megakaryocyte-like polyploidy cells with positive markers of acetylcholinesterase and αIIb integrin (CD41). Higher expression of αIIb integrin was also found in primary mouse bone marrow cells and human cord blood CD34+ cells cultured with both thrombopoietin and decitabine as compared to thrombopoietin alone. In addition, we noted a 30% platelet count increase in Balb/c mice 12 hours after the injection of decitabine at a clinically relevant dose (15 mg/m2), suggesting a rapid platelet release from the spleen or bone marrow. Our data suggest that decitabine increases platelet counts by enhancing platelet release and megakaryocyte maturation.
The inhibition effect of anti-GPIIIa49–66 antibody on megakaryocyte differentiation
Authors: Nardi Michael , Pan Ruimin , Wang Jianhui , Li Zongdong 
Published: June 2011

SummaryWe previously reported that patients with early-onset HIV-1 ITP developed a unique anti-platelet integrin GPIIIa antibody against the GPIIIa49–66 epitope. Anti-GPIIIa49–66 antibody-induced platelet fragmentation requires sequential activation of the platelet 12-lipoxygenase (12-LO) and NADPH oxidase to release reactive oxygen species (ROS). 12-LO is upstream of the NADPH oxidase pathway and 12(S)- HETE, the product of 12-LO, induces the same oxidative platelet fragmentation as anti-GPIIIa49–66. Since the megakaryocyte (MK) is the progenitor cell for platelets, we have investigated the effect of anti- GPIIIa49–66 on MK differentiation and, in particular, the potential role of anti-GPIIIa49–66 induced ROS in this process. We first show that polyclonal anti-GPIIIa49–66 antibody isolated from HIV-1 ITP patients inhibits MK proliferation 2.5-fold in in vitro culture of human cord blood CD34+ cells driven by thrombopoietin (TPO). We also observe a three-fold decrease in the number of MK colony-forming units in the presence of a human monoclonal anti-GPIIIa49–66 antibody. However, we could not detect ROS release in DCFH-loaded mouse megakaryoblastic cells L8057 treated with anti-GPIIIa49–66 antibody. In addition, 12(S)-HETE does not inhibit the in vitro differentiation of L8057 cells induced by TPO. In fact, we found a dose dependent increase in the percentage of CD41 positive cells (from 17.1% to 48.7%) in in vitro culture of L8057 cells treated with various concentrations of H2O2 (from 5 to 20 μM). We therefore conclude that the anti-GPIIIa49–66 antibody inhibits MK differentiation through β3 integrin signalling independent of ROS release.
Potent Long-Term Cardioprotective Effects of Single Low-Dose Insulin-Like Growth Factor-1 Treatment Postmyocardial Infarction
Authors: O'Sullivan John F. , Leblond Anne-Laure , Kelly Geraldine , Kumar Arun H.S. , Metharom Pat , Büneker Chirlei K. , Alizadeh-Vikali Niki , Hristova Ivalina , Hynes Brian G. , O'Connor Rosemary , Caplice Noel M. 
Published: June 2011

Background—
Insulin-like growth factor-1 (IGF-1) is recognized as an important regulator of cardiac structure and cardiomyocyte homeostasis. The prosurvival and antiapoptotic effects of IGF-1 have been investigated in vitro and in rodent models of myocardial infarction (MI). However, the clinical application of IGF-1 has been hampered by dose-dependent side effects both acutely and during chronic administration. We hypothesized that single, low-dose IGF-1 (LD-IGF-1) administered locally and early in the reperfusion phase after acute MI in a large animal model would avoid significant side effects but would have prosurvival effects that would manifest in long-term structural and functional improvement after MI treatment.

Methods and Results—
Forty-four female Landrace pigs underwent intracoronary administration of LD-IGF-1 or saline 2 hours into the reperfusion phase of acute left anterior descending artery occlusion MI. In the area of infarction, IGF-1 receptor and signaling responses were activated at 30 minutes and cardiomyocyte cell death attenuated at 24 hours after LD-IGF-1 but not saline treatment. Hemodynamic and structural studies using pressure-volume loop, CT, and triphenyltetrazolium chloride analysis 2 months post-MI confirmed a marked reduction in infarct size, attenuation of wall thinning, and augmentation of wall motion in the LD-IGF-1-treated but not in the saline-treated animals. These regional structural benefits were associated with global reductions in left ventricular volumes and significant improvement in left ventricular systolic and diastolic function.

Conclusions—
One-time LD-IGF-1 effects potent acute myocardial salvage in a preclinical model of left anterior descending artery occlusive MI, extending to long-term benefits in MI size, wall structure, and function and underscoring its potential as an adjunctive therapeutic agent.