bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Anti-VEGF on Pharmacokinetics, Biodistribution, and Tumor Penetration of Trastuzumab in a Preclinical Breast Cancer Model
Authors: Pastuskovas Cinthia V. , Mundo Eduardo E. , Williams Simon P. , Nayak Tapan K. , Ho Jason , Ulufatu Sheila , Clark Suzanna , Ross Sarajane , Cheng Eric , Parsons-Reponte Kathryn , Cain Gary , Van Hoy Marjie , Majidy Nicholas , Bheddah Sheila , dela Cruz Chuh Josefa , Kozak Katherine R. , Lewin-Koh Nicholas , Nauka Peter , Bumbaca Daniela , Sliwkowski Mark , Tibbitts Jay , Theil Frank-Peter , Fielder Paul J. , Khawli Leslie A. , Boswell C. Andrew 
Published: January 2012

AbstractBoth human epidermal growth factor receptor 2 (HER-2/neu) and VEGF overexpression correlate with aggressive phenotypes and decreased survival among breast cancer patients. Concordantly, the combination of trastuzumab (anti-HER2) with bevacizumab (anti-VEGF) has shown promising results in preclinical xenograft studies and in clinical trials. However, despite the known antiangiogenic mechanism of anti-VEGF antibodies, relatively little is known about their effects on the pharmacokinetics and tissue distribution of other antibodies. This study aimed to measure the disposition properties, with a particular emphasis on tumor uptake, of trastuzumab in the presence or absence of anti-VEGF. Radiolabeled trastuzumab was administered alone or in combination with an anti-VEGF antibody to mice bearing HER2-expressing KPL-4 breast cancer xenografts. Biodistribution, autoradiography, and single-photon emission computed tomography–X-ray computed tomography imaging all showed that anti-VEGF administration reduced accumulation of trastuzumab in tumors despite comparable blood exposures and similar distributions in most other tissues. A similar trend was also observed for an isotype-matched IgG with no affinity for HER2, showing reduced vascular permeability to macromolecules. Reduced tumor blood flow (P &lt; 0.05) was observed following anti-VEGF treatment, with no significant differences in the other physiologic parameters measured despite immunohistochemical evidence of reduced vascular density. In conclusion, anti-VEGF preadministration decreased tumor uptake of trastuzumab, and this phenomenon was mechanistically attributed to reduced vascular permeability and blood perfusion. These findings may ultimately help inform dosing strategies to achieve improved clinical outcomes. Mol Cancer Ther; 11(3); 752–62. ©2012 AACR.
MYC Is Activated by USP2a-Mediated Modulation of MicroRNAs in Prostate Cancer
Authors: Benassi Barbara , Flavin Richard , Marchionni Luigi , Zanata Silvio , Pan Yunfeng , Chowdhury Dipanjan , Marani Marina , Strano Sabrina , Muti Paola , Blandino Giovanni , Loda Massimo 
Published: January 2012

Abstract
Ubiquitin-specific protease 2a (USP2a) is overexpressed in almost half of human prostate cancers and c-Myc is amplified in one third of these tumor types. Transgenic MYC expression drives invasive adenocarcinomas in the murine prostate. We show that overexpression of USP2a downregulates a set of microRNAs that collectively increase MYC levels by MDM2 deubiquitination and subsequent p53 inactivation. By establishing MYC as a target of miR-34b/c, we demonstrate that this cluster functions as a tumor suppressor in prostate cancer cells. We identify a distinct mRNA signature that is enriched for MYC-regulated transcripts and transcription factor binding sites in USP2a overexpressing prostate cancer cells. We demonstrate that these genes are associated with an invasive phenotype in human prostate cancer and that the proliferative and invasive properties of USP2a overexpressing cells are MYC-dependent. These results highlight an unrecognized mechanism of MYC regulation in prostate cancer and suggest alternative therapeutic strategies in targeting MYC.
Significance: The deubiquitinating enzyme USP2a has previously been shown to be oncogenic, overexpressed in almost half of human prostate adenocarcinomas, and prolongs the half-life of targets such as fatty acid synthase, MDM2, and cyclin D1. Here, we highlight a new mechanism by which USP2a enhances MYC levels through the modulation of specific subsets of microRNAs in prostate cancer, suggesting alternative therapeutic strategies for targeting MYC. Cancer Discovery; 2(3); 236–47. ©2012 AACR.
Read the Commentary on this article by Nelson et al., p. 206
This article is highlighted in the In This Issue feature, p. 193
Socioeconomic Status, Cardiovascular Risk Factors, and Subclinical Atherosclerosis in Young Adults
Authors: Kestilä Paula , Magnussen Costan G. , Viikari Jorma S.A. , Kähönen Mika , Hutri-Kähönen Nina , Taittonen Leena , Jula Antti , Loo Britt-Marie , Pietikäinen Matti , Jokinen Eero , Lehtimäki Terho , Kivimäki Mika , Juonala Markus , Raitakari Olli T. 
Published: January 2012

Objective—
The goal of this study was to investigate the extent to which socioeconomic status (SES) in young adults is associated with cardiovascular risk factor levels and carotid intima-media thickness (IMT) and their changes over a 6-year follow-up period.

Methods and Results—

The study population included 1813 subjects participating in the 21- and 27-year follow-ups of the Cardiovascular Risk in Young Finns Study (baseline age 24–39 years in 2001). At baseline, SES (indexed with education) was inversely associated with body mass index (
P
=0.0002), waist circumference (
P
<0.0001), glucose (
P
=0.01), and insulin (
P
=0.0009) concentrations; inversely associated with alcohol consumption (
P
=0.02) and cigarette smoking (
P
<0.0001); and directly associated with high-density lipoprotein cholesterol levels (
P
=0.05) and physical activity (
P
=0.006). Higher SES was associated with a smaller 6-year increase in body mass index (
P
=0.001). Education level and IMT were not associated (
P
=0.58) at baseline, but an inverse association was observed at follow-up among men (
P
=0.004). This became nonsignificant after adjustment with conventional risk factors (
P
=0.11). In all subjects, higher education was associated with a smaller increase in IMT during the follow-up (
P
=0.002), and this association remained after adjustments for conventional risk factors (
P
=0.04).

Conclusion—
This study shows that high education in young adults is associated with favorable cardiovascular risk factor profile and 6-year change of risk factors. Most importantly, the progression of carotid atherosclerosis was slower among individuals with higher educational level.
Regulatory T-Cell Response to Apolipoprotein B100–Derived Peptides Reduces the Development and Progression of Atherosclerosis in Mice
Authors: Herbin Olivier , Ait-Oufella Hafid , Yu Wang , Fredrikson Gunilla Nordin , Aubier Benjamin , Perez Nicolas , Barateau Véronique , Nilsson Jan , Tedgui Alain , Mallat Ziad 
Published: January 2012

Objective—
The immunoinflammatory response plays a critical role in the development and progression of atherosclerosis. Recent studies suggested an important role for regulatory T (Treg) cells in the inhibition of disease-related vascular inflammation. We hypothesized that induction of a specific Treg cell response to atherosclerosis-relevant antigens would be an attractive strategy to limit the development and progression of atherosclerosis through the promotion of immune tolerance.

Methods and Results—

Young or old
Apoe
−/−
mice were subcutaneously infused for 2 weeks with either a control ovalbumin (OVA) peptide or with apolipoprotein B100 (ApoB100)–derived peptides without adjuvant. Atherosclerosis development, progression and immunologic status were assessed at 8 weeks after the end of the infusion. Treatment with ApoB100 peptides led to significant reduction of lesion development in young
Apoe
−/−
mice (
P
=0.001 versus OVA group) and abrogated atherosclerosis progression in old
Apoe
−/−
mice with already established lesions (0% progression in ApoB100 versus 17% in OVA group,
P
<0.005). Limitation of plaque progression was associated with reduced vascular inflammation and increased collagen content, indicative of plaque stabilization. Infusion of ApoB100 peptides did not alter antibody production but promoted a specific Treg cell response, which was associated with a reduction of both T helper type 1–related and T helper type 2–related cytokines. Interestingly, depletion of CD4
+
CD25
+
Treg cells abrogated ApoB100 peptides-dependent immune modulation and atheroprotection.

Conclusion—

Subcutaneous infusion of adjuvant-free ApoB100-derived peptides to
Apoe
−/−
mice reduces atherosclerosis through the induction of a specific Treg cell response.
Tissue Factor Pathway Inhibitor Blocks Angiogenesis via Its Carboxyl Terminus
Authors: Holroyd Eric W. , Delacroix Sinny , Larsen Katarina , Harbuzariu Adriana , Psaltis Peter J. , Wang Ling , Pan Shuchong , White Thomas A. , Witt Tyra A. , Kleppe Laurel S. , Mueske Cheryl S. , Mukhopadhyay Debabrata , Simari Robert D. 
Published: January 2012

Objective—
Tissue factor pathway inhibitor (TFPI) is the primary regulator of the tissue factor (TF) coagulation pathway. As such, TFPI may regulate the proangiogenic effects of TF. TFPI may also affect angiogenesis independently of TF, through sequences within its polybasic carboxyl terminus (TFPI C terminus [TFPIct]). We aimed to determine the effects of TFPI on angiogenesis and the role of TFPIct.

Methods and Results—
Transgenic overexpression of TFPI attenuated angiogenesis in the murine hindlimb ischemia model and an aortic sprout assay. In vitro, TFPI inhibited endothelial cell migration. Peptides within the human TFPIct inhibited endothelial cell cord formation and migration in response to vascular endothelial growth factor (VEGF) 165 but not VEGF121. Furthermore, exposure to human TFPIct inhibited the phosphorylation of VEGF receptor 2 at residue Lys951, a residue known to be critical for endothelial cell migration. Finally, systemic delivery of a murine TFPIct peptide inhibited angiogenesis in the hindlimb model.

Conclusion—
These data demonstrate an inhibitory role for TFPI in angiogenesis that is, in part, mediated through peptides within its carboxyl terminus. In addition to its known role as a TF antagonist, TFPI, via its carboxyl terminus, may regulate angiogenesis by directly blocking VEGF receptor 2 activation and attenuating the migratory capacity of endothelial cells.
Hyponatremia, Hypernatremia, and Mortality in Patients With Chronic Kidney Disease With and Without Congestive Heart Failure
Authors: Kovesdy Csaba P. , Lott Evan H. , Lu Jun Ling , Malakauskas Sandra M. , Ma Jennie Z. , Molnar Miklos Z. , Kalantar-Zadeh Kamyar 
Published: January 2012

Background—
Hyponatremia is common in patients with conditions such as congestive heart failure and is associated with increased mortality in hospitalized patients. Congestive heart failure is common in patients with chronic kidney disease, but the association of serum sodium concentration with mortality in such patients is not well characterized.

Methods and Results—

We examined the association of serum sodium concentration with all-cause mortality in a nationally representative cohort of 655 493 US veterans with non–dialysis-dependent chronic kidney disease (95 961 [15%] of them with congestive heart failure). Associations were examined in time-dependent Cox models with adjustment for potential confounders. During a median follow-up of 5.5 years, a total of 193 956 patients died (mortality rate, 62.5/1000 patient-years; 95% confidence interval, 62.2–62.8). The association of serum sodium level with mortality was U-shaped, with the lowest mortality seen in patients with sodium level of 140 mEq/L and with both lower and higher levels showing significant associations with increased mortality. Patients with serum sodium levels of <130, 130 to 135.9, 145.1 to 150, and ≥150 mEq/L compared with 136 to 145 mEq/L had multivariable-adjusted mortality hazard ratios (95% confidence interval) of 1.93 (1.83–2.03), 1.28 (1.26–1.30), 1.33 (1.28–1.38), and 1.56 (1.33–1.83) (
P
<0.001 for all). The associations remained consistent in subgroups of patients with and without congestive heart failure.

Conclusions—
Both lower and higher serum sodium levels are independently associated with higher mortality in patients with non–dialysis-dependent chronic kidney disease, irrespective of the presence or absence of congestive heart failure.
Baroreflex Sensitivity to Predict Malignant Middle Cerebral Artery Infarction
Authors: Sykora Marek , Steiner Thorsten , Rocco Andrea , Turcani Peter , Hacke Werner , Diedler Jennifer 
Published: January 2012

Background and Purpose—
Hemicraniectomy has been shown to be an effective treatment of life-threatening edema (LTE) in malignant middle cerebral artery infarction when performed early. Identifying patients who will develop LTE is therefore imperative. We hypothesize that autonomic shift toward sympathetic dominance may relate to LTE formation. We aimed to investigate the predictive potential of baroreflex sensitivity (BRS) as a marker of autonomic balance for calculating the course of large middle cerebral artery infarction.

Methods—
Patients with middle cerebral artery infarction >2/3 of the territory and BRS measurement at admission were analyzed. BRS was estimated using the cross-correlational method. Demographic, clinical, and radiological data including stroke severity, infarct size, and basal ganglia involvement were recorded. Malignant course with LTE was defined as clinical deterioration and midline shift ≥5 mm in the first 48 hours.

Results—

Eighteen (62.8%) patients developed LTE. Patients with LTE had lower BRS (2.3 versus 4.4 mm Hg/ms,
P
=0.007), larger infarcts (214 versus 144 mL,
P
=0.03), more frequent involvement of the basal ganglia (14 versus 4,
P
=0.03), and more often underwent thrombolysis combined with endovascular intervention (6 versus 0,
P
=0.04). In a multivariate model, BRS (OR, 0.36; CI, 0.14–0.93;
P
=0.03) and basal ganglia involvement (OR, 11.53; CI, 1.15–115.9;
P
=0.04) were independent predictors for LTE. This model correctly classified 86.2% of the malignant cases.

Conclusions—
Decreased BRS, mirroring sympathetic activation, and basal ganglia involvement were associated with development of malignant course with LTE in large middle cerebral artery infarction. The predictive relevance of our findings needs to be confirmed in further studies.
Variable Presentations of Postpartum Angiopathy
Authors: Fugate Jennifer E. , Ameriso Sebastián F. , Ortiz Gustavo , Schottlaender Lucia V. , Wijdicks Eelco F.M. , Flemming Kelly D. , Rabinstein Alejandro A. 
Published: January 2012

Background and Purpose—
Postpartum angiopathy (PPA), a rare cause of stroke in the puerperium, is heralded by severe headaches within 1–2 weeks after delivery. Angiography demonstrates segmental vasoconstriction that often resolves spontaneously. PPA is generally regarded as benign. We aimed to define clinical presentations, radiological findings, and outcomes of patients with PPA.

Methods—
We retrospectively reviewed patients from 3 centers with acute neurological symptoms and angiography showing vasoconstriction in the postpartum period. Patients without neuroimaging and with diagnoses of cerebral venous sinus thrombosis and aneurysmal hemorrhage were excluded. Patient characteristics, clinical symptoms, neuroimaging findings, and clinical condition at hospital discharge were collected.

Results—
Eighteen patients (mean age, 31 years; range, 15–41) were identified. Median gestation was 38 weeks. Twelve (67%) had a history of prior uneventful pregnancy. Neurological symptoms began on median day 5 postpartum and included headache (n=16, 89%), focal deficit (n=9, 50%), visual disturbance (n=8, 44%), encephalopathy (n=6, 33%), and seizure (n=5, 28%), often in combination. Brain imaging was abnormal in most (n=13, 72%). The most common abnormalities were intracranial hemorrhage (n=7, 39%), vasogenic edema (n=6, 35%), and infarction (n=6, 35%). Clinical outcomes were markedly variable with full recovery seen in 9 (50%), death after a fulminant course in 4 (22%), and residual deficits in 5 (28%).

Conclusions—
In contrast to prior reports, this group of patients with PPA had a higher proportion of nonbenign outcomes. Most patients who undergo neuroimaging have parenchymal abnormalities, which are most often stroke (hemorrhagic or ischemic) or reversible vasogenic edema.
The Flight of Pudicitia: Juvenal’s Vision of the Past and the Programmatic Function of the Prologue in the Sixth Satire
Authors: Watson Patricia 
Published: January 2012

AbstractIn the prologue toSatire6, Juvenal depicts the primitive woman of the Golden Age as an idealmatrona, only to undercut humorously the paradigmatic value of this picture. The poet’s intentions in so doing have been variously explained; this article views the parodic tone of the passage in terms of its programmatic function. A detailed discussion is offered of Juvenal’s depiction of the cavewife and it is demonstrated how this foreshadows the speaker’s unfavourable treatment of all women, even paradigms such as Cornelia. In short, the prologue establishes the speaker ofSatire6 as a misogynist whose views are so extreme that they cannot be taken seriously.
All’s Well that Ends Well: Storytelling, Predictive Signs, and the Voice of the Author in Chariton’s Callirhoe
Authors: Doulamis Konstantin 
Published: January 2012

AbstractThis article takes a new approach to the study of narrative technique in Chariton’sCallirhoe. Following Chariton’s self-identification at the start of the novel, considerable emphasis is placed upon the narrator, who makes his presence felt throughout the narrative and whose role is further underscored by self-reflexive comments about storytelling made by various characters. This, combined with the fact that the novelist appears to have delegated all responsibility for the shaping of the plot to personified deities, allows the author to remain ‘concealed’ for most of the narrative, thus giving him a voice independent from that of the narrator. With assistance from divine agents, author and narrator operate a suspense-generating system of forewarnings, false predictive signs, and intervention, which enhances the anticipation of the expected happy ending. In the last Book, with the finale drawing near, the narrator hints at the authorial presence behind the novel, but it is only in the last sentence and after the story has reached its dénouement that theauctor’s voice can be heard loud and clear in an undisputed authorial statement.
The Amazonian toad Rhaebo guttatus is able to voluntarily squirt poison from the paratoid macroglands
Authors: Felipe Toledo Luís , Trefaut Rodrigues Miguel , Jared Carlos , Kruth Verdade Vanessa , Maria Antoniazzi Marta 
Published: January 2012

AbstractAmphibian defence mechanisms commonly rely on cutaneous toxins produced in either isolated or clustered glands, such as toad parotoid macroglands. In contrast to the passive mechanism of poison liberation in other amphibians, we discovered that the Amazonian toad Rhaebo guttatus is unique because it can voluntarily squirt jets of poison from its parotoids.
To What Ends EU Foreign Policy? Contending Approaches to the Union’s Diplomatic Objectives and Representation
Authors: Thomas Daniel C. , Tonra Ben 
Published: January 2012

Summary
The strengthened Office of the High Representative for Foreign Affairs and Security Policy and the new European External Action Service (EEAS) presuppose a set of interests and/or values that the European Union (EU) wishes to pursue on the world stage. But what are those interests and/or values and how does the EU reach agreement on them? Rather than simply ‘cutting and pasting’ from EU treaties and strategy papers, this article identifies seven distinct theoretical models of how the EU and its member states arrive collectively at a definition of their diplomatic objectives. The seven models include intergovernmentalist models of veto threats and log-rolling, normative institutionalist models of cooperative bargaining and entrapment, and constructivist and sociological institutionalist models of elite socialization, Europeanization and collective identity formation. The article identifies the logics of each model and notes their implications for the role of the EU’s new foreign policy institutions.
Connecting Subseasonal Movements of the Winter Mean Ridge in Western North America to Inversion Climatology in Cache Valley, Utah
Authors: Wang Shih-Yu , Gillies Robert R. , Martin Randy , Davies Robert E. , Booth Marty R. 
Published: January 2012

AbstractA 10-yr record of PM2.5 (particulate matter of aerodynamic diameter ≤ 2.5 μm), collected in Cache Valley near downtown Logan, Utah, reveals a strong peak in the PM2.5 concentration climatology that is tightly localized in mid-January. The cause of this subseasonal variation in the PM2.5 climatology is investigated through dynamical downscaling and large-scale diagnostics. Climatological analysis of the U.S. winter mean ridge reveals a mid-January subseasonal shift in the zonal direction, likely in response to variations in the Rossby wave source over the central North Pacific Ocean. This displacement of the winter mean ridge, in turn, has an impact on regional-scale atmospheric conditions—specifically, subsidence with local leeside enhancements and midlevel warming over Cache Valley. The analyses of this study indicate that the subseasonal peak of long-term mean PM2.5 concentrations in Cache Valley is linked to the large-scale circulations’ subseasonal evolution, which involves remote forcing in the circumpolar circulations as well as possible tropical–midlatitude interactions. This subseasonal evolution of the winter mean circulation also affects precipitation along the West Coast.
Estimating the Urban Heat Island in Residential Areas in the Netherlands Using Observations by Weather Amateurs
Authors: Wolters Dirk , Brandsma Theo 
Published: January 2012

AbstractA better quantification of the urban heat islands (UHIs) in the Netherlands is urgently needed given the heat stress–related problems in the recent past combined with the expected temperature rise for the coming decades. Professional temperature observations in Dutch urban areas are scarce, however. Therefore, this research explores the use of observations from weather stations that were installed and maintained by weather amateurs. From a set of over 200 stations, suitable and representative data have been selected from 20 stations, using a set of objective selection criteria that are based on metadata. One year of data (January–December 2010) was considered. From these data, estimates have been obtained of the magnitude of the UHI in Dutch low-rise residential areas. A positive relation (linear model with r2 ≈ 0.7) was derived between the summer-averaged UHI and the (neighborhood scale) population density around the observational sites. It was found that the UHI in summer is strongest in nighttime conditions and that it increases with decreasing wind speed, decreasing cloud cover, and increasing sea level air pressure. The summer-averaged UHI was ~0.9°C. During nighttime in a relatively warm 1-month subperiod of the summer, the average UHI was ~1.4°C. During spring and autumn, the UHI was lower than in summer; during winter, no significant UHI was observed. The agreement in results among the different stations and the accordance of the magnitude and variation of the observed UHI with those described in the literature show that automatic observations from weather amateurs can be of sufficient quality for atmospheric research, provided that detailed metadata are available.