bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alcohol in fatal crashes involving Mexican and Canadian drivers in the USA
Authors: Baker Susan P , Brady Joanne E , Rebok George W , Li Guohua 
Published: March 2011

ObjectiveTo determine the prevalence of alcohol involvement and impairment in fatal crashes in the USA involving Mexican and Canadian drivers.MethodsDrivers in fatal crashes in the USA were identified during 1998 to 2008 from the Fatality Analysis Reporting System, and the prevalence of alcohol involvement and impairment (defined as blood alcohol concentrations ≥0.01 g/dl and ≥0.08 g/dl, respectively) was compared among drivers licensed in Mexico (n=687), Canada (n=598), and the USA (n=561 908).ResultsThe prevalence of alcohol involvement was 27% for US drivers, 27% for Mexican drivers, and 11% for Canadian drivers. Alcohol impairment was found in 23% of US drivers, 23% of Mexican drivers, and 8% of Canadian drivers. With adjustment for driver demographic characteristics and survival status and for crash circumstances, the prevalence of alcohol involvement was significantly lower for Canadian drivers (adjusted prevalence ratio (PR) 0.63, 95% CI 0.49 to 0.80) than for US drivers, and was similar between Mexican and US drivers (adjusted PR 0.91, 95% CI 0.81 to 1.02).ConclusionsAlcohol involvement in fatal motor vehicle crashes in the USA is similarly prevalent in US and Mexican drivers, but is substantially less common in Canadian drivers.
National five-year examination of inequalities and trends in emergency hospital admission for violence across England
Authors: Bellis Mark A , Hughes Karen , Wood Sara , Wyke Sacha , Perkins Clare 
Published: March 2011

ObjectivesTo examine relationships between violence, age (0–74 years), and deprivation, and to explore in which communities, age groups, and gender the potential for transmission of violent tendencies between individuals is greatest.MethodsFive year (2004/2005 to 2008/2009) ecological study of emergency admissions resulting from violence (n=170 074) into all English hospitals using trend and logistic regression analyses.ResultsHospital admissions for violence peak as individuals achieve legal adulthood (18 years). Risks of admission increase exponentially with increasing quintile of deprivation of residence, with odds overall being 5.5 times higher in the poorest quintile compared with the richest. The greatest absolute difference in violence admissions by deprivation quintile is seen in males aged 18 (218/100 000, richest; 698/100 000, poorest). However, the highest deprivation rate ratios (quintile 5:1) are seen at ages 0–10 years in both sexes and at all ages after 40 years in males (40–58 years, females). In males aged 17–19 years, violence accounts for 20% of the entire gap between wealthiest and poorest quintiles in all cause emergency hospital admissions.ConclusionsAnalyses identify four lifetime periods for violence: up to 10 years (prepubescent), 11–20 years (adolescence), 21–45 years (younger adults), and over 45 years (older adults). While violence is most common in adolescence, its concentration in poorer areas during prepubescence and in younger adulthood (parenting age) suggests that poorer children are exposed to much more aggressive communities. This is likely to contribute to the disproportionate escalation in violence they experience during adolescence. Effective interventions to prevent such escalations are available and need to be implemented particularly in poor communities.
How is informed consent related to emotions and empathy? An exploratory neuroethical investigation
Authors: Supady Alexander , Voelkel Antonie , Witzel Joachim , Gubka Udo , Northoff Georg 
Published: March 2011

ContextInformed consent is crucial in daily clinical practice and research in medicine and psychiatry. A recent neuroethical investigation explored the psychological factors that are crucial in determining whether or not subjects give consent. While cognitive functions have been shown to play a central role, the impact of empathy and emotions on subjects' decisions in informed consent remains unclear.ObjectiveTo evaluate the impact of empathy and emotions on subjects' decision in informed consent in an exploratory study.DesignDecisional capacity and informed consent to a subsequent imaging study were evaluated with the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR). Empathy and emotion recognition were measured with the Multifaceted Empathy Test (MET) and the Florida Affect Battery (FAB).SettingPsychiatric subjects were recruited from a general psychiatric hospital and a forensic state hospital.PatientsA mixed group of 98 healthy men and forensic and non-forensic psychiatric subjects were investigated.ResultsBoth empathy (MET) and emotion recognition (FAB) correlated with MacCAT-CR scores. Higher cognitive empathy and good emotion recognition (compared with low empathy and emotion recognition) were associated with increased decisional capacity and higher rates of refusal to give informed consent.ConclusionsThis study shows an empirical relationship between decision-making and informed consent, on the one hand, and emotions and empathy on the other. While this study is exploratory and preliminary, the findings of a relationship between informed consent, emotions and empathy raise important neuroethical questions with regard to an emotional-social concept of informed consent and potential clinical implications for testing informed consent.
MicroRNA-301 Mediates Proliferation and Invasion in Human Breast Cancer
Authors: Shi Wei , Gerster Kate , Alajez Nehad M. , Tsang Jasmine , Waldron Levi , Pintilie Melania , Hui Angela B. , Sykes Jenna , P'ng Christine , Miller Naomi , McCready David , Fyles Anthony , Liu Fei-Fei 
Published: March 2011

Abstract
Several microRNAs have been implicated in human breast cancer but none to date have been validated or utilized consistently in clinical management. MicroRNA-301 (miR-301) overexpression has been implicated as a negative prognostic indicator in lymph node negative (LNN) invasive ductal breast cancer, but its potential functional impact has not been determined. Here we report that in breast cancer cells, miR-301 attenuation decreased cell proliferation, clonogenicity, migration, invasion, tamoxifen resistance, tumor growth, and microvessel density, establishing an important oncogenic role for this gene. Algorithm-based and experimental strategies identified FOXF2, BBC3, PTEN, and COL2A1 as candidate miR-301 targets, all of which were verified as direct targets through luciferase reporter assays. We noted that miR-301 is located in an intron of the SKA2 gene which is responsible for kinetochore assembly, and both genes were found to be coexpressed in primary breast cancer samples. In summary, our findings define miR-301 as a crucial oncogene in human breast cancer that acts through multiple pathways and mechanisms to promote nodal or distant relapses. Cancer Res; 71(8); 2926–37. ©2011 AACR.
Human CD271-Positive Melanoma Stem Cells Associated with Metastasis Establish Tumor Heterogeneity and Long-term Growth
Authors: Civenni Gianluca , Walter Anne , Kobert Nikita , Mihic-Probst Daniela , Zipser Marie , Belloni Benedetta , Seifert Burkhardt , Moch Holger , Dummer Reinhard , van den Broek Maries , Sommer Lukas 
Published: March 2011

Abstract
Human melanoma is composed of distinct cell types reminiscent of neural crest derivatives and contains multipotent cells that express the neural crest stem cell markers CD271(p75NTR) and Sox10. When isolated from solid tumors by using a method that leaves intact cell surface epitopes, CD271-positive, but not CD271-negative, cells formed tumors on transplantation into nude or nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. These tumors fully mirrored the heterogeneity of the parental melanoma and could be passaged more than 5 times. In contrast, in more immunocompromised NOD/SCID/IL2rγnull mice, or in natural killer cell–depleted nude or NOD/SCID mice, both CD271-positive and CD271-negative tumor cell fractions established tumors. However, tumors resulting from either fraction did not phenocopy the parental tumors, and tumors derived from the CD271-negative cell fraction could not be passaged multiple times. Together, our findings identify CD271-positive cells as melanoma stem cells. Our observation that a relatively high frequency of CD271/Sox10-positive cells correlates with higher metastatic potential and worse prognosis further supports that CD271-positive cells within human melanoma represent genuine cancer stem cells. Cancer Res; 71(8); 3098–109. ©2011 AACR.
Bortezomib Sensitizes HCC Cells to CS-1008, an Antihuman Death Receptor 5 Antibody, through the Inhibition of CIP2A
Authors: Chen Kuen-Feng , Yu Hui-Chuan , Liu Chun-Yu , Chen Hui-Ju , Chen Yi-Ching , Hou Duen-Ren , Chen Pei-Jer , Cheng Ann-Lii 
Published: March 2011

Abstract
Previously, we have shown that bortezomib overcame TRAIL resistance in hepatocellular carcinoma (HCC) cells via the inhibition of Akt. Here, we report that bortezomib sensitizes these TRAIL-resistant cells, including Huh-7, Hep3B, and Sk-Hep1, to CS-1008, a humanized agonistic antihuman death receptor 5 antibody. Cancerous inhibitor of protein phosphatase 2A (CIP2A) mediated the sensitizing effect of bortezomib to CS-1008 through inhibiting protein phosphatase 2A (PP2A) activity. Combination treatment of bortezomib and CS-1008 downregulated CIP2A in a concentration- and time-dependent manner, and increased PP2A activity in HCC cells. Importantly, ectopic expression of CIP2A decreased Akt-related PP2A activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells. Moreover, silencing CIP2A by short interfering RNA enhanced CS-1008–induced apoptosis in HCC cells and ectopic expression of CIP2A in HCC cells abolished CS-1008–induced apoptosis, indicating that CIP2A plays an important role in the sensitizing effect of bortezomib to CS-1008. Finally, our in vivo data showed that CS-1008 and bortezomib combination treatment decreased tumor growth significantly. In conclusion, bortezomib sensitized HCC cells to CS-1008 through the inhibition of CIP2A. Mol Cancer Ther; 10(5); 892–901. ©2011 AACR.
Targeted Delivery of an Antibody–Mutant Human Endostatin Fusion Protein Results in Enhanced Antitumor Efficacy
Authors: Shin Seung-Uon , Cho Hyun-Mi , Merchan Jaime , Zhang Jin , Kovacs Krisztina , Jing Yawu , Ramakrishnan Sundaram , Rosenblatt Joseph D. 
Published: March 2011

AbstractThe antiangiogenic protein endostatin showed considerable preclinical antitumor activity, but limited efficacy in phase I/II trials. Prior studies using an anti-HER2 antibody–murine endostatin fusion showed enhanced antitumor activity compared to anti-HER2 antibody or endostatin given alone, or in combination. We have generated two anti-HER2 human endostatin fusion proteins by fusing either wild-type or a mutant human endostatin (huEndo-P125A) to the 3′ end of a humanized anti-HER2 IgG3 antibody. Antitumor efficacy was examined in murine and human breast tumor models. HuEndo-P125A antibody fusion protein (αHER2-huEndo-P125A) inhibited VEGF and bFGF induced endothelial cell proliferation, and tube formation in vitro, more efficiently than endostatin alone, wild-type endostatin fusion protein (αHER2-huEndo), or parental anti-HER2 antibody (αHER2 IgG3). Wild-type and mutant human endostatin was rapidly cleared from serum in mice (T½2 = 2.0–2.1 hours), whereas αHER2-huEndo fusion proteins had a significantly prolonged half-life (T½2 = 40.7–57.5 hours). Treatment of SK-BR-3 breast cancer xenografts with anti-HER2 IgG3-huEndo-P125A fusion resulted in greater inhibition of tumor growth and improved survival, compared to treatment with either αHER2 IgG3 (P = 0.025), human endostatin (P = 0.034), or anti-HER2 IgG3-huEndo (P = 0.016). αHER2-huEndo-P125A specifically inhibited tumors expressing HER2 in mice simultaneously implanted with murine mammary tumor EMT6 cells and with EMT6 engineered to express HER2 antigen (EMT6-HER2). Targeting of endostatin using antibody fusion proteins could improve antitumor activity of either anti-HER2 antibody and/or endostatin and provides a versatile approach that could be applied to other tumor targets with alternative antibody specificities. Mol Cancer Ther; 10(4); 603–14. ©2011 AACR.
CCN1, a Candidate Target for Zoledronic Acid Treatment in Breast Cancer
Authors: Espinoza Ingrid , Liu Hong , Busby Robert , Lupu Ruth 
Published: March 2011

Abstract
CCN1, also known as CYR61, is a survival and proangiogenic factor overexpressed in about 30% of invasive breast carcinomas, and particularly in triple-negative breast carcinomas (TNBC). CCN1 expression in breast cancer promotes tumorigenicity, metastasis, antihormone, and chemoresistance. TNBCs often develop bone metastasis, thus the vast majority of patients receive bisphosphonate treatment as a companion to chemotherapy. Zoledronic acid (ZOL), a bisphosphonate currently in use, inhibits bone resorption, prevents development of new osteolytic lesions induced by tumor metastasis, and has a direct antitumor activity in breast cancer cells and tumors. We have shown that ZOL inhibits anchorage independent growth as well as branching and morphogenesis in CCN1 overexpressing cells. However, the mechanism is not yet well understood. In this study, we investigate the effect of ZOL in breast cancer cells with high and undetectable CCN1 expression levels. We show that CCN1-expressing cells are more sensitive to ZOL, that ZOL induces downregulation of the CCN1 promoter activity and CCN1 protein expression in a dose-dependent manner, and that ZOL is associated with a decrease in phosphorylated Akt and translocation of FOXO3a, a negative regulator of CCN1 expression, to the nucleus. Deletion of the FOXO3a binding site in the CCN1 promoter prevents ZOL inhibition of the CCN1 promoter activity showing that FOXO3a transcriptional activation is necessary for ZOL to induce CCN1 inhibition. This study provides evidence that ZOL targets the proangiogenic factor (CCN1) through FOXO3a and reveals a new mechanism of ZOL action in breast cancer cells. Mol Cancer Ther; 10(5); 732–41. ©2011 AACR.
Modulation of Protein Phosphatase 2A Activity Alters Androgen-Independent Growth of Prostate Cancer Cells: Therapeutic Implications
Authors: Bhardwaj Arun , Singh Seema , Srivastava Sanjeev K. , Honkanen Richard E. , Reed Eddie , Singh Ajay P. 
Published: March 2011

Abstract
Earlier we identified PPP2CA, which encodes for the α-isoform of protein phosphatase 2A (PP2A) catalytic subunit, as one of the downregulated genes in androgen-independent prostate cancer. PP2A is a serine/threonine phosphatase and a potent tumor suppressor involved in broad cellular functions; however, its role in prostate cancer has not yet been determined. Here, we have investigated the effect of PP2A activity modulation on the androgen-independent growth of prostate cancer cells. Our data show that the PPP2CA expression and PP2A activity is downregulated in androgen-independent (C4-2) prostate cancer cells as compared with androgen-dependent (LNCaP) cells. Downregulation of PP2A activity by pharmacologic inhibition or short interfering RNA-mediated PPP2CA silencing sustains the growth of LNCaP cells under an androgen-deprived condition by relieving the androgen deprivation–induced cell-cycle arrest and preventing apoptosis. Immunoblot analyses reveal enhanced phosphorylation of Akt, extracellular signal–regulated kinase (ERK), BAD, increased expression of cyclins (A1/D1), and decreased expression of cyclin inhibitor (p27) on PP2A downregulation. Furthermore, our data show that androgen receptor (AR) signaling is partially maintained in PP2A-inhibited cells through increased AR expression and ligand-independent phosphorylation. Pharmacologic inhibition of Akt, ERK, and AR suggest a role of these signaling pathways in facilitating the androgen-independent growth of LNCaP cells. These observations are supported by the effect of ceramide, a PP2A activator, on androgen-independent C4-2 cells. Ceramide inhibited the growth of C4-2 cells on androgen deprivation, an effect that could be abrogated by PP2A downregulation. Altogether, our findings suggest that modulation of PP2A activity may represent an alternative therapeutic approach for the treatment of advanced androgen-independent prostate cancer. Mol Cancer Ther; 10(5); 720–31. ©2011 AACR.
Stromal Vascular Fraction From Adipose Tissue Forms Profound Vascular Network Through the Dynamic Reassembly of Blood Endothelial Cells
Authors: Koh Young Jun , Koh Bong Ihn , Kim Honsoul , Joo Hyung Joon , Jin Ho Kyoung , Jeon Jongwook , Choi Chulhee , Lee Dong Hun , Chung Jin Ho , Cho Chung-Hyun , Park Won Seok , Ryu Ji-Kan , Suh Jun Kyu , Koh Gou Young 
Published: March 2011

Objective—
Tremendous efforts have been made to establish effective therapeutic neovascularization using adipose tissue-derived stromal vascular fraction (SVF), but the efficiency is low, and underlying mechanisms and their interaction with the host in a new microenvironment are poorly understood.

Methods and Results—
Here we demonstrate that direct implantation of SVF derived from donor adipose tissue can create a profound vascular network through the disassembly and reassembly of blood endothelial cells at the site of implantation. This neovasculature successfully established connection with recipient blood vessels to form a functionally perfused circuit. Addition of vascular growth factors to the SVF implant improved the efficiency of functional neovasculature formation. In contrast, spheroid culture of SVF before implantation reduced the capacity of vasculature formation, possibly because of cellular alteration. Implanting SVF into the mouse ischemic hindlimb induced the robust formation of a local neovascular network and salvaged the limb. Moreover, the coimplantation of SVF prevented fat absorption in the subcutaneous adipose tissue graft model.

Conclusion—
Freshly isolated SVF can effectively induce new vessel formation through the dynamic reassembly of blood endothelial cells and could be applied to achieve therapeutic neovascularization for relieving ischemia and preventing fat absorption in an autologous manner.
Pyripyropene A, an Acyl–Coenzyme A:Cholesterol Acyltransferase 2–Selective Inhibitor, Attenuates Hypercholesterolemia and Atherosclerosis in Murine Models of Hyperlipidemia
Authors: Ohshiro Taichi , Matsuda Daisuke , Sakai Kent , Degirolamo Chiara , Yagyu Hiroaki , Rudel Lawrence L. , Ōmura Satoshi , Ishibashi Shun , Tomoda Hiroshi 
Published: March 2011

Objective—
Pyripyropene A (PPPA) of fungal origin is the first compound that has been found to strongly and selectively inhibit acyl–coenzyme A:cholesterol acyltransferase 2 (ACAT2) isozyme activity in vitro. The purpose of the present study was to investigate in vivo efficacy of the ACAT2-selective inhibitor in atherosclerosis.

Methods and Results—
PPPA treatment (10 to 100 mg/kg) caused 30.5±4.7% to 55.8±3.3% inhibition of the cholesterol absorption from the mouse intestine. When PPPA (10 to 50 mg/kg per day) was orally administered to apolipoprotein E–knockout mice for 12 weeks, the levels of plasma cholesterol, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) and hepatic cholesterol content were lowered. Furthermore, the ratio of cholesteryl oleate (exclusively synthesized in hepatic ACAT2) to cholesteryl linoleate in VLDL- and LDL-derived cholesteryl ester decreased, indicating that hepatic ACAT2 activity was inhibited by PPPA. PPPA-treated mice had reduced atherogenic lesion areas that were lowered by 26.2±3.7% to 46±3.8% in the aortae and by 18.9±3.6% to 37.6±6.0% in the hearts.

Conclusion—
Our findings indicate that ACAT2-selective inhibition in the intestine and the liver can be effective against atherosclerosis and that PPPA appears to be a potential antiatherogenic lead compound. This study is the first demonstration of the in vivo efficacy of PPPA, an ACAT2-selective inhibitor, in atherosclerosis. PPPA-treated atherogenic mice showed a decrease in intestinal cholesterol absorption and cholesterol and cholesteryl oleate levels in both LDL and VLDL, resulting in protection of atherosclerosis development.
Evidence of How rs7575840 Influences Apolipoprotein B–Containing Lipid Particles
Authors: Haas Blake E. , Weissglas-Volkov Daphna , Aguilar-Salinas Carlos A. , Nikkola Elina , Vergnes Laurent , Cruz-Bautista Ivette , Riba Laura , Stancakova Alena , Kuusisto Johanna , Soininen Pasi , Kangas Antti J. , Ala-Korpela Mika , Tusie-Luna Teresa , Laakso Markku , Pajukanta Päivi 
Published: March 2011

Objective—
Recent genome-wide association studies identified a variant rs7575840 in the apolipoprotein B (APOB) gene region as associated with low-density lipoprotein (LDL) cholesterol. However, the underlying functional mechanism of this variant, which resides 6.5 kb upstream of APOB, has remained unknown. Our objective was to investigate rs7575840 for association with refined apoB-containing lipid particles, for replication in a Mexican population, and for its underlying functional mechanism.

Methods and Results—

Our data show that rs7575840 is associated with serum apoB levels (
P
=4.85×10
−10
) and apoB-containing lipid particles, very small very-low-density lipoprotein, intermediate lipoprotein, and LDL particles (
P
=2×10
−5
to 9×10
−7
) in the Finnish Metabolic Syndrome in Men study sample (n=7710). Fine mapping of the APOB region using 43 single-nucleotide polymorphisms replicated the association of rs7575840 with apoB in a Mexican study sample (n=2666,
P
=3.33×10
−5
). Furthermore, our transcript analyses of adipose RNA samples from 175 subjects in the Finnish Metabolic Syndrome in Men study indicate that rs7575840 alters expression of APOB (
P
=1.13×10
−10
) and a regional noncoding RNA (BU630349) (
P
=7.86×10
−6
) in adipose tissue.

Conclusion—
It has been difficult to convert genome-wide association study associations into mechanistic insights. Our data show that rs7575840 is associated with serum apoB levels and apoB-containing lipid particles, as well as influencing expression of APOB and a regional transcript BU630349 in adipose tissue. We thus provide evidence how a common genome-wide significant single-nucleotide polymorphism, rs7575840, may affect serum apoB, LDL cholesterol, and total cholesterol levels.
Impairment of the Programmed Cell Death-1 Pathway Increases Atherosclerotic Lesion Development and Inflammation
Authors: Bu De-xiu , Tarrio Margarite , Maganto-Garcia Elena , Stavrakis George , Tajima Goro , Lederer James , Jarolim Petr , Freeman Gordon J. , Sharpe Arlene H. , Lichtman Andrew H. 
Published: March 2011

Objective—
Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals on interaction with its 2 ligands, PD-L1 and PD-L2. We studied the contribution of the PD-1 pathway to regulation of T cells that promote atherosclerotic lesion formation and inflammation.

Methods and Results—

We show that compared with
Ldlr
−/−
control mice,
Pd1
−/−
Ldlr
−/−
mice developed larger lesions with more abundant CD4
+
and CD8
+
T cells and macrophages, accompanied by higher levels of serum tumor necrosis factor-α. Iliac lymph node T cells from
Pd1
−/−
Ldlr
−/−
mice proliferated more to αCD3 or oxidized low-density lipoprotein stimulation compared with controls. CD8
+
T cells from
Pd1
−/−
Ldlr
−/−
mice displayed more cytotoxic activity compared with controls in vivo and in vitro. Administration of a blocking anti-PD-1 antibody increased lesional inflammation in hypercholesterolemic
Ldlr
−/−
mice with more lesional T cells and more activated T cells in paraaortic lymph nodes. The changes in lesional T-cell content when PD-1 was absent or blocked were also observed in bone marrow chimeric
Ldlr
−/−
mice lacking PD-L1 and PD-L2 on hematopoietic cells.

Conclusion—
PD-1 has an important role in downregulating proatherogenic T-cell responses, and blockade of this molecule for treatment of viral infections or cancer may increase risk of cardiovascular complications.