bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small Molecule MYC Inhibitor Conjugated to Integrin-Targeted Nanoparticles Extends Survival in a Mouse Model of Disseminated Multiple Myeloma
Authors: Soodgupta Deepti , Pan Dipanjan , Cui Grace , Senpan Angana , Yang Xiaoxia , Lu Lan , Weilbaecher Katherine N. , Prochownik Edward V. , Lanza Gregory M. , Tomasson Michael H. 
Published: April 2015

Abstract
Multiple myeloma pathogenesis is driven by the MYC oncoprotein, its dimerization with MAX, and the binding of this heterodimer to E-Boxes in the vicinity of target genes. The systemic utility of potent small molecule inhibitors of MYC-MAX dimerization was limited by poor bioavailability, rapid metabolism, and inadequate target site penetration. We hypothesized that new lipid-based MYC-MAX dimerization inhibitor prodrugs delivered via integrin-targeted nanoparticles (NP) would overcome prior shortcomings of MYC inhibitor approaches and prolong survival in a mouse model of cancer. An Sn 2 lipase-labile prodrug inhibitor of MYC-MAX dimerization (MI1-PD) was developed which decreased cell proliferation and induced apoptosis in cultured multiple myeloma cell lines alone (P &lt; 0.05) and when incorporated into integrin-targeted lipid-encapsulated NPs (P &lt; 0.05). Binding and efficacy of NPs closely correlated with integrin expression of the target multiple myeloma cells. Using a KaLwRij metastatic multiple myeloma mouse model, VLA-4–targeted NPs (20 nm and 200 nm) incorporating MI1-PD (D) NPs conferred significant survival benefits compared with respective NP controls, targeted (T) no-drug (ND), and untargeted (NT) control NPs (T/D 200: 46 days vs. NT/ND: 28 days, P &lt; 0.05 and T/D 20: 52 days vs. NT/ND: 29 days, P = 0.001). The smaller particles performed better of the two sizes. Neither MI1 nor MI1-PD provided survival benefit when administered systemically as free compounds. These results demonstrate for the first time that a small molecule inhibitor of the MYC transcription factor can be an effective anticancer agent when delivered using a targeted nanotherapy approach. Mol Cancer Ther; 14(6); 1286–94. ©2015 AACR.
PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer
Authors: Thanapprapasr Duangmani , Previs Rebecca A. , Hu Wei , Ivan Cristina , Armaiz-Pena Guillermo N. , Dorniak Piotr L. , Hansen Jean M. , Rupaimoole Rajesha , Huang Jie , Dalton Heather J. , Ali-Fehmi Rouba , Coleman Robert L. , Sood Anil K. 
Published: April 2015

Abstract
PTEN is known to be frequently mutated in uterine cancer and also dephosphorylates FAK. Here, we examined the impact of PTEN alterations on the response to treatment with a FAK inhibitor (GSK2256098). In vitro and in vivo therapeutic experiments were carried out using PTEN-mutated and PTEN-wild-type models of uterine cancer alone and in combination with chemotherapy. Treatment with GSK2256098 resulted in greater inhibition of pFAKY397 in PTEN-mutated (Ishikawa) than in PTEN-wild-type (Hec1A) cells. Ishikawa cells were more sensitive to GSK2256098 than the treated Hec1A cells. Ishikawa cells were transfected with a wild-type PTEN construct and pFAKY397 expression was unchanged after treatment with GSK2256098. Decreased cell viability and enhanced sensitivity to chemotherapy (paclitaxel and topotecan) in combination with GSK2256098 was observed in Ishikawa cells as compared with Hec1a cells. In the Ishikawa orthoptopic murine model, treatment with GSK2256098 resulted in lower tumor weights and fewer metastases than mice inoculated with Hec1A cells. Tumors treated with GSK2256098 had lower microvessel density (CD31), less cellular proliferation (Ki67), and higher apoptosis (TUNEL) rates in the Ishikawa model when compared with the Hec1a model. From a large cohort of evaluable patients, increased FAK and pFAKY397 expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAKY397 expression. These preclinical data demonstrate that PTEN-mutated uterine cancer responds better to FAK inhibition than does PTEN wild-type cancer. Therefore, PTEN could be a biomarker for predicting response to FAK-targeted therapy during clinical development. Mol Cancer Ther; 14(6); 1466–75. ©2015 AACR.
Reversal of anticoagulants: an overview of current developments
Authors: Thiele Thomas , Selleng Kathleen , Greinacher Andreas 
Published: April 2015

SummarySeveral new anticoagulants have entered the clinical arena or are under clinical development. These drugs include indirect (fondaparinux) and direct oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban), and the direct thrombin inhibitor dabigatran. Especially the oral direct FXa and FIIa inhibitors overcome many of the shortcomings of heparins and vitamin K antagonists (VKAs). They are administered orally at a fixed dose; regular monitoring is not necessary; interaction with other drugs or nutrition occur less than with VKAs and they are at least as effective as VKAs for most indications tested. They are associated with about 50 % less intracranial bleeding than VKAs. Nevertheless, they are still associated with bleeding complications. Bleeding can occur spontaneously or as a result of trauma or urgent surgery. In such situations rapid reversal of the anticoagulant effect is highly desirable. For unfractionated heparin protamine, and for VKAs prothrombin complex concentrates are available as specific antidotes. Under clinical development are: for the direct and indirect FXa inhibitors a modified recombinant FXa (andexanet alpha), which lacks enzymatic activity; and for dabigatran a Fab fragment of a monoclonal antibody (idarucizumab). In addition a small molecule (aripazine) has entered phase I clinical trials, which seems to inhibit nearly all anticoagulants but VKAs and argatroban. This review summarises the current options and strategies in development to antagonise anticoagulants with a focus on the status of the development of antidotes for the oral direct FXa and FIIa inhibitors.
Moderate oral supplementation with docosahexaenoic acid improves platelet function and oxidative stress in type 2 diabetic patients
Authors: Colas Romain , Calzada Catherine , Lê Quang Huy , Feugier Nathalie , Cugnet Christine , Vidal Hubert , Laville Martine , Moulin Philippe , Lagarde Michel , Véricel Evelyne 
Published: April 2015

SummaryPlatelets from patients with type 2 diabetes are characterised by hyperactivation and high level of oxidative stress. Docosahexaenoic acid (DHA) may have beneficial effects on platelet reactivity and redox status. We investigated whether moderate DHA supplementation, given as a triglyceride form, may correct platelet dysfunction and redox imbalance in patients with type 2 diabetes. We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (n=11 post-menopausal women with type 2 diabetes) to test the effects of 400 mg/day of DHA intake for two weeks on platelet aggregation, markers of arachidonic acid metabolism, lipid peroxidation status, and lipid composition. Each two week-period was separated from the other by a six-week washout. Daily moderate dose DHA supplementation resulted in reduced platelet aggregation induced by collagen (-46.5 %, p< 0.001), and decreased platelet thromboxane B2 (-35 %, p< 0.001), urinary 11-dehydro-thromboxane B2 (-13.2 %, p< 0.001) and F2-isoprostane levels (-19.6 %, p< 0.001) associated with a significant increase of plasma and platelet vitamin E concentrations (+20 % and +11.8 %, respectively, p< 0.001). The proportions of DHA increased both in plasma lipids and in platelet phospholipids. After placebo treatment, there was no effect on any parameters tested. Our findings support a significant beneficial effect of low intake of DHA on platelet function and a favourable role in reducing oxidative stress associated with diabetes.
Care in the Last Year of Life for Community Patients With Heart Failure
Authors: Dunlay Shannon M. , Redfield Margaret M. , Jiang Ruoxiang , Weston Susan A. , Roger Véronique L. 
Published: April 2015

Background—
Healthcare utilization peaks at the end of life (EOL) in patients with heart failure. However, it is unclear what factors affect end of life utilization in patients with heart failure and if utilization has changed over time.

Methods and Results—
Southeastern Minnesota residents with heart failure were prospectively enrolled into a longitudinal cohort study from 2003 to 2011. Patients who died before December 31, 2012, were included in the analysis. Information on hospitalizations and outpatient visits in the last year of life was obtained using administrative sources. Negative binomial regression was used to assess the association between patient characteristics and utilization. The 698 decedents (47.3% men; 53.4% preserved ejection fraction) experienced 1528 hospitalizations (median 2 per person; range, 0–12; 37.6% because of cardiovascular causes) and 12 927 outpatient visits (median 14 per person; range, 0–119) in their last year of life. Most patients (81.5%) were hospitalized at least once and 28.4% died in the hospital. Patients who were older and those with dementia had lower utilization. Patients who were married, resided in a skilled nursing facility, and had more comorbidities had higher utilization. Patients with preserved ejection fraction had higher rates of noncardiovascular hospitalizations although other utilization was similar. Over time, rates of hospitalizations and outpatient visits decreased, whereas palliative care consults and enrollment in hospice increased.

Conclusions—
Although patient factors remain associated with differential healthcare utilization at the end of life, utilization declined over time and use of palliative care services increased. These results are encouraging given the high resource use in patients with heart failure.
Augmentation of Limb Perfusion and Reversal of Tissue Ischemia Produced by Ultrasound-Mediated Microbubble Cavitation
Authors: Belcik J. Todd , Mott Brian H. , Xie Aris , Zhao Yan , Kim Sajeevani , Lindner Nathan J. , Ammi Azzdine , Linden Joel M. , Lindner Jonathan R. 
Published: April 2015

Background—
Ultrasound can increase tissue blood flow, in part, through the intravascular shear produced by oscillatory pressure fluctuations. We hypothesized that ultrasound-mediated increases in perfusion can be augmented by microbubble contrast agents that undergo ultrasound-mediated cavitation and sought to characterize the biological mediators.

Methods and Results—

Contrast ultrasound perfusion imaging of hindlimb skeletal muscle and femoral artery diameter measurement were performed in nonischemic mice after unilateral 10-minute exposure to intermittent ultrasound alone (mechanical index, 0.6 or 1.3) or ultrasound with lipid microbubbles (2×10
8
IV). Studies were also performed after inhibiting shear- or pressure-dependent vasodilator pathways, and in mice with hindlimb ischemia. Ultrasound alone produced a 2-fold increase (
P
<0.05) in muscle perfusion regardless of ultrasound power. Ultrasound-mediated augmentation in flow was greater with microbubbles (3- and 10-fold higher than control for mechanical index 0.6 and 1.3, respectively;
P
<0.05), as was femoral artery dilation. Inhibition of endothelial nitric oxide synthase attenuated flow augmentation produced by ultrasound and microbubbles by 70% (
P
<0.01), whereas inhibition of adenosine-A
2a
receptors and epoxyeicosatrienoic acids had minimal effect. Limb nitric oxide production and muscle phospho-endothelial nitric oxide synthase increased in a stepwise fashion by ultrasound and ultrasound with microbubbles. In mice with unilateral hindlimb ischemia (40%–50% reduction in flow), ultrasound (mechanical index, 1.3) with microbubbles increased perfusion by 2-fold to a degree that was greater than the control nonischemic limb.

Conclusions—
Increases in muscle blood flow during high-power ultrasound are markedly amplified by the intravascular presence of microbubbles and can reverse tissue ischemia. These effects are most likely mediated by cavitation-related increases in shear and activation of endothelial nitric oxide synthase.
Characterisation of a topotype and other populations of Hemicriconemoides strictathecatus Esser, 1960 (Nematoda: Criconematidae) from Florida with description of H. phoenicis sp. n. from the USA
Authors: Van den Berg Esther , Tiedt Louwrens R. , Inserra Renato N. , Stanley Jason D. , Vovlas Nicola , Palomares-Rius Juan E. , Castillo Pablo , Subbotin Sergei A. 
Published: April 2015

The results of morphological and molecular analyses of a Florida topotype and other populations of Hemicriconemoides strictathecatus showed that this sheathoid nematode consists of two morphotypes, both with an average stylet length of more than 70 μm, but having different tail termini, bluntly pointed or rounded. These findings confirmed the morphological similarity of H. strictathecatus with H. mangiferae, which was considered a junior synonym of this species as previously proposed by Decraemer & Geraert (1992, 1996). Populations of a sheathoid nematode with a stylet length ranging from 62.5 to 72.0 μm from Taiwan, China, South Africa and Venezuela and identified in previous studies as H. strictathecatus were found to be morphologically and molecularly different from this species and are now considered as representatives of H. litchi. Another sheathoid nematode population from Florida, considered to be H. mangiferae by McSorley et al. (1980), was also found to be morphologically and molecularly congruous with H. litchi. During nematological surveys in Florida, a new sheathoid nematode was detected on date palms imported from California into Florida and is described herein as H. phoenicis sp. n. This new species is related morphologically to the H. strictathecatus morphotype with pointed tail terminus. Both have a stylet longer than 70 μm. The new species is phylogenetically related to H. strictathecatus and H. litchi. It differs morphologically from other Hemicriconemoides species by the cuticular ornamentation of the annuli, which are marked by coarse longitudinal ridges, grooves and thick margins. Morphological and molecular characterisations of H. cocophillus from Mozambique and Florida, USA are also elucidated in this study. New phylogenies of the genus Hemicriconemoides as inferred from the analyses of the ITS rRNA, D2-D3 of 28S rRNA and partial coxI gene sequences are provided.
Soil and litter nematode diversity of Mount Hamiguitan, the Philippines, with description of Bicirronema hamiguitanense n. sp. (Rhabditida: Bicirronematidae)
Authors: Qing Xue , Bert Wim , Steel Hanne , Quisado Joeseph , Tandingan De Ley Irma 
Published: April 2015

The nematode diversity in soil and litter was investigated on Mount Hamiguitan, the Philippines, along four eco-habitats from elevations of 75-1600 m a.s.l. A total of 155 and 467 nematodes were identified to 39 and 62 genera from litter and soil, respectively. The nematode assemblages and diversity did not show any relation to eco-habitat or elevation. Bacterivorous nematodes were the most common group (37.5%). Acrobeloides was most abundant from the soil and Aphelenchoides from the litter. Bicirronema hamiguitanense n. sp. is herein described based on morphology, morphometrics and molecular data. The new species has the following diagnostic features: a wide lateral field one-fifth of its body diam. with four incisures forming two ornamented ridges; gubernaculum with proximal thickening; spicules (35-38 μm) and gubernaculum (18-20 μm) longer than B. caledoniense; and with 37 molecular autapomorphies supporting its new species status. The phylogenetic position of the new species within Cephalobomorpha is discussed.
Non-Governmental Organisations and the un Convention on the Rights of the Child
Authors: Polonko Karen A. , Lombardo Lucien X. 
Published: April 2015

This study seeks to contribute to knowledge of the implementation of the U.N Convention on the Rights of the Child (crc). Focus was restricted to one of eight General Measures of Implementation – involvement of civil society, in particular, non-government organisations (ngos), in the implementation and monitoring of the crc. The study had three aims: (1) to develop initial indicators of ngo involvement; (2) to explore level of ngo activity; and (3) to explore which aspects of ngo involvement might have an effect on extending human rights to children in the most fundamental area of protection from violence.
Results indicate that most State Parties (sps) have at least one ngo member and 50 per cent had a National Coalition member in the Child Rights Information Network (crin). Regarding activity, at least one alternative ngo report was submitted to the crc Committee for most sps. Analyses of Concluding Observations indicate that the Committee on the Rights of the Child expressed concerns about most sp’s involvement with ngos and found very few governments encouraging ngos to take a child-rights focus. Overall, few indicators of ngo involvement were related to lower rates of child physical abuse – what appeared most important was having a government that encourages ngos to have a child-rights focus. Reasons for these findings and directions for future research are discussed.
Francesco Boldizzoni: A Critical Comment
Authors: Klamer Arjo 
Published: April 2015

In this comment on Boldizzoni (2013), I outline that his argumentation is problematic and his historical point unclear. He claims that a historical perspective exposes the ‘pseudo’-dimension in science and history. From the case of Chili, he concludes that Chicago-economics is a pseudo-science. This accusation backfires when his own argument is problematic from a scientific and historical perspective. However, I can broadly agree with what is written about the history of economics as a discipline.
I am sympathetic towards Boldizzoni’s observation about the relevance of history. I agree that we should go beyond the assumption of rational decision making, and propose a value-based approach to economics, where behaviour is seen as the realization of values, of which some values have a history. Hence, our understanding of history play a large role in understanding everyday behaviour. I argue that people need history as a source for meaningful life and action.
Structure and Variability of Internal Tides in Luzon Strait
Authors: Pickering Andy , Alford Matthew , Nash Jonathan , Rainville Luc , Buijsman Maarten , Ko Dong Shan , Lim Byungho 
Published: April 2015

AbstractThe Luzon Strait is the generation region for strong internal tides that radiate westward into the South China Sea and eastward into the western Pacific. Intrusions of the Kuroshio and strong mesoscale variability in the Luzon Strait can influence their generation and propagation. Here, the authors use eight moorings and two numerical models to investigate these relationships by quantifying the coherence of the diurnal and semidiurnal internal tides in the Luzon Strait. This study finds that the level of coherence of internal tide generation, energy, and energy flux is quite variable, depending on the specific location within the Luzon Strait. Large-scale spatial patterns in internal tide pressure and velocity exist across the region, shaped by the bathymetry, mean flow, and stratification. Internal tide coherence is lower (<30%) near large gradients in this pattern (predominantly along the eastern ridge), which are shifted by the variable Kuroshio and mesoscale fields. At other locations within the Luzon Strait, the internal tide is largely coherent (>80%), and simple calculations suggest that remote sources of internal tides could account for these small decreases in coherence. To the west of the Luzon Strait (away from the primary generation regions), the model suggests that diurnal internal tide energy is more coherent than semidiurnal.
Intercomparison of Independent Calibration Techniques Applied to the Visible Channel of the ISCCP B1 Data
Authors: Inamdar Anand K. , Knapp Kenneth R. 
Published: April 2015

AbstractThe International Satellite Cloud Climatology Project (ISCCP) B1 data, which were recently rescued at the National Oceanic and Atmospheric Administration’s National Climatic Data Center (NOAA/NCDC), are a resource for the study of the earth’s climate. The ISCCP B1 data represent geostationary satellite imagery for all channels, including the infrared (IR), visible, and IR water vapor sensors. These are global 3-hourly snapshots from satellites around the world, covering the time period from 1979 to present at approximately 10-km spatial resolution. ISCCP B1 data will be used in the reprocessing of the cloud products, resulting in a higher-resolution ISCCP cloud climatology, surface radiation budget (SRB), etc. To realize the promise of a higher-resolution cloud climatology from the B1 data, an independent assessment of the calibration of the visible band was performed. The present study aims to accomplish this by cross-calibrating with the intercalibrated Advanced Very High Resolution Radiometer (AVHRR) reflectance data from the AVHRR Pathfinder Atmospheres–Extended (PATMOS-x) dataset. Since the reflectance calibration approach followed in the PATMOS-x dataset is radiometrically tied to the absolute calibration of the National Aeronautics and Space Administration’s (NASA) Moderate Resolution Imaging Spectroradiometer (MODIS) imager instrument, the present intercalibration scheme yields calibration coefficients consistent with MODIS. Results from this study show that the two independent sets (this study and the ISCCP) of results agree to within their mutual uncertainties. An independent approach to calibration based on multiyear observations over spatially and temporally invariant desert sites has also been used for validation. Results reveal that for most of the geostationary satellites, the mean difference with ISCCP calibration is less than 3% with the random errors under 2%. Another result is that this extends the intercalibrated record to beyond what ISCCP provides (prior to 1983 and beyond 2009).
Improving the Utility of Laryngeal Adductor Reflex Testing
Authors: Shock Leslie A. , Gallemore Brandon C. , Hinkel Cameron J. , Szewczyk Marlena M. , Hopewell Bridget L. , Allen Mitchell J. , Thombs Lori A. , Lever Teresa E. 
Published: April 2015

ObjectivesEvaluation of the laryngeal adductor reflex (LAR) entails delivering air through an endoscope positioned 1 to 2 mm from the arytenoid mucosa to elicit bilateral vocal fold (VF) closure. This short working distance limits visualization to only the ipsilateral arytenoid and results in quantification of a single LAR metric: threshold pressure that evokes the LAR. Our goal was to evolve the LAR procedure to optimize its utility in clinical practice and translational research.Study DesignProspective translational experiment.SettingAcademic institution.SubjectsYoung healthy human adults (n = 13) and 3 groups of mice: healthy, primary aging mice (n = 5), a transgenic mouse model of amyotrophic lateral sclerosis (ALS; n = 4), and young healthy controls (n = 10).MethodsThe VFs were visualized bilaterally during supramaximal air stimulation through an endoscope. Responses were analyzed to quantify 4 novel metrics: VF adduction phase duration, complete glottic closure duration, VF abduction phase duration, and total LAR duration.ResultsThe 4 LAR metrics are remarkably similar between healthy young humans and mice. Compared to control mice, aging mice have shorter glottic closure durations, whereas ALS‐affected mice have shorter VF abduction phase durations.ConclusionsWe have established a new LAR protocol that permits quantification of novel LAR metrics that are translatable between mice and humans. Using this protocol, we showed that VF adduction is impaired in primary aging mice, whereas VF abduction is impaired in ALS‐affected mice. These preliminary findings highlight the enhanced diagnostic potential of LAR testing.