bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrinβ6-Targeted Immunoliposomes Mediate Tumor-Specific Drug Delivery and Enhance Therapeutic Efficacy in Colon Carcinoma
Authors: Liang Benjia , Shahbaz Muhammad , Wang Yang , Gao Huijie , Fang Ruliang , Niu Zhengchuan , Liu Song , Wang Ben , Sun Qi , Niu Weibo , Liu Enyu , Wang Jiayong , Niu Jun 
Published: December 2014

Abstract
Purpose: Adjuvant chemotherapy is one of the significant treatments for colon cancer in clinic. However, it does not achieve the desired therapeutic efficacy, largely due to chemotherapeutic resistance. Integrinβ6 (ITGB6) is expressed in malignant colonic epithelia, but not in normal epithelia, and is associated with the progression, metastasis, and chemotherapeutic resistance of colon cancer. Accordingly, it is necessary to design therapeutic approaches for efficient and targeted drug delivery into ITGB6-positive cancer cells to improve chemotherapeutic efficacy in colon cancer.
Experimental Design: PEGylated liposomes were employed to design ITGB6-targeted immunoliposomes, which have ITGB6 monoclonal antibodies (mAbs) conjugated. We evaluated the ITGB6-targeted immunoliposomes internalization into colon cancer cells and examined 5-fluorouracil (5-FU)–induced cellular apoptosis produced by ITGB6-targeted immunoliposomes+5-FU. In addition, the biodistribution and antitumor efficiency of ITGB6-targeted immunoliposomes were observed in vivo.
Results: ITGB6-targeted immunoliposomes enhanced cellular internalization in ITGB6-positive colon cancer cells compared with liposomes. Furthermore, the ITGB6-targeted immunoliposome internalization was dependent on the ITGB6 expression level on cellular surface. ITGB6-targeted immunoliposomes decreased the 5-FU IC50 more than 90% in HT-29 and SW480β6 cells relative to liposomes. Moreover, when loaded with 5-FU, ITGB6-targeted immunoliposomes produced an approximately 1.5-fold higher 5-FU–induced cellular apoptosis rate than liposomes. In vivo, the therapeutic activity of ITGB6-targeted immunoliposomes+5-FU was significantly superior, resulting in 25% to 35% reduction of tumor weight compared with 5-FU or liposomes+5-FU.
Conclusions: ITGB6-targeted immunoliposomes provide a highly efficient approach for targeted drug delivery in colon cancer and thus offer the potential of a novel and promising anticancer strategy for clinical therapy. Clin Cancer Res; 21(5); 1183–95. ©2014 AACR.
Redifferentiation of Iodine-Refractory BRAF V600E-Mutant Metastatic Papillary Thyroid Cancer with Dabrafenib
Authors: Rothenberg S. Michael , McFadden David G. , Palmer Edwin L. , Daniels Gilbert H. , Wirth Lori J. 
Published: December 2014

Abstract
Purpose: To determine whether the selective BRAF inhibitor, dabrafenib, can stimulate radioiodine uptake in BRAF V600E-mutated unresectable or metastatic iodine-refractory papillary thyroid cancer (PTC).
Experimental Design: Ten patients with BRAF V600E-mutant iodine-refractory PTC were enrolled. Absence of radioiodine uptake on iodine-131 whole body scan obtained within 14 months of study entry was required. Each patient received dabrafenib (150 mg twice daily) for 25 days before thyrotropin α-stimulated iodine-131 whole body scan (4 mCi/148 MBq). Patients whose scan showed new sites of radioiodine uptake remained on dabrafenib for 17 more days, and then were treated with 150 mCi (5.5 GBq) iodine-131. The primary endpoint of the study was the percentage of patients with new radioiodine uptake after treatment with dabrafenib.
Results: Six of 10 patients (60%) demonstrated new radioiodine uptake on whole body scan after treatment with dabrafenib. All 6 were treated with 5.5 GBq iodine-131. Two patients had partial responses and 4 patients had stable disease on standard radiographic restaging at 3 months. Thyroglobulin decreased in 4 of 6 treated patients. One patient developed squamous cell carcinoma of the skin. There were no other significant adverse events attributed to dabrafenib.
Conclusions: Dabrafenib can stimulate radioiodine uptake in patients with metastatic BRAF V600E-mutant iodine-refractory PTC, representing a potential new therapeutic approach for these patients. Clin Cancer Res; 21(5); 1028–35. ©2014 AACR.
Critical Role of Platelet Glycoprotein Ibα in Arterial Remodeling
Authors: Chandraratne Sue , von Bruehl Marie-Luise , Pagel Judith-Irina , Stark Konstantin , Kleinert Eike , Konrad Ildiko , Farschtschi Said , Coletti Raffaele , Gärtner Florian , Chillo Omari , Legate Kyle R. , Lorenz Michael , Rutkowski Simon , Caballero-Martinez Amelia , Starke Richard , Tirniceriu Anca , Pauleikhoff Laurenz , Fischer Silvia , Assmann Gerald , Mueller-Hoecker Josef , Ware Jerry , Nieswandt Bernhard , Schaper Wolfgang , Schulz Christian , Deindl Elisabeth , Massberg Steffen 
Published: December 2014

Objective—
Arteriogenesis is strongly dependent on the recruitment of leukocytes, especially monocytes, into the perivascular space of growing collateral vessels. On the basis of previous findings that platelets are central players in inflammatory processes and mediate the recruitment of leukocytes, the aim of this study was to assess the role of platelets in a model of arterial remodeling.

Approach and Results—

C57Bl6 wild-type mice,
IL4-R/Iba
mice lacking the extracellular domain of the glycoprotein Ibα (GPIbα) receptor, and mice treated with antibodies to block GPIbα or deplete circulating platelets were studied in peripheral arteriogenesis. Using a novel model of intravital 2-photon and epifluorescence imaging, we visualized and quantified the interaction of platelets with leukocytes and the vascular endothelium in vivo. We found that transient platelet adhesion to the endothelium of collateral vessels was a major event during arteriogenesis and depended on GPIbα. Furthermore, leukocyte recruitment was obviously affected in animals with defective platelet GPIbα function. In
IL4-R/Iba
mice, transient and firm leukocyte adhesion to the endothelium of collateral vessels, as well as leukocyte accumulation in the perivascular space, were significantly reduced. Furthermore, we detected platelet–leukocyte aggregates within the circulation, which were significantly reduced in
IL4-R/Iba
animals. Finally, platelet depletion and loss of GPIbα function resulted in poor reperfusion recovery as determined by laser Doppler imaging.

Conclusions—
Thus, GPIbα-mediated interactions between platelets and endothelial cells, as well as leukocytes, support innate immune cell recruitment and promote arteriogenesis-establishing platelets as critical players in this process.
Imaging Vessel Wall Biology to Predict Outcome in Abdominal Aortic Aneurysm
Authors: Golestani Reza , Razavian Mahmoud , Nie Lei , Zhang Jiasheng , Jung Jae-Joon , Ye Yunpeng , de Roo Michelle , Hilgerink Koen , Liu Chi , Robinson Simon P. , Sadeghi Mehran M. 
Published: December 2014

Background—
Abdominal aortic aneurysm (AAA) rupture risk is currently determined based on size and symptoms. This approach does not address the rupture risk associated with small aneurysms. Given the role of matrix metalloproteinases (MMPs) in AAA weakening and rupture, we investigated the potential of MMP-targeted imaging for detection of aneurysm biology and prediction of outcome in a mouse model of AAA with spontaneous rupture.

Methods and Results—
Fifteen-week-old mice (n=66) were infused with angiotensin II for 4 weeks to induce AAA. Saline-infused mice (n=16) served as control. The surviving animals underwent in vivo MMP-targeted micro–single photon emission computed tomographic/computed tomographic imaging, using RP805, a technetium-99m–labeled MMP-specific tracer, followed by ex vivo planar imaging, morphometry, and gene expression analysis. RP805 uptake in suprarenal aorta on micro–single photon emission computed tomographic images was significantly higher in animals with AAA when compared with angiotensin II–infused animals without AAA or control animals. CD68 expression and MMP activity were increased in AAA, and significant correlations were noted between RP805 uptake and CD68 expression or MMP activity but not aortic diameter. A group of angiotensin II–infused animals (n=24) were imaged at 1 week and were followed up for additional 3 weeks. RP805 uptake in suprarenal aorta at 1 week was significantly higher in mice that later developed rupture or AAA. Furthermore, tracer uptake at 1 week correlated with aortic diameter at 4 weeks.

Conclusions—
MMP-targeted imaging reflects vessel wall inflammation and can predict future aortic expansion or rupture in murine AAA. If confirmed in humans, this may provide a new paradigm for AAA risk stratification.
Sex Differences in Short-Term Outcomes After Acute Ischemic Stroke
Authors: Irie Fumi , Kamouchi Masahiro , Hata Jun , Matsuo Ryu , Wakisaka Yoshinobu , Kuroda Junya , Ago Tetsuro , Kitazono Takanari , Ishitsuka Takao , Fujimoto Shigeru , Ibayashi Setsuro , Kusuda Kenji , Arakawa Shuji , Tamaki Kinya , Sadoshima Seizo , Irie Katsumi , Fujii Kenichiro , Okada Yasushi , Yasaka Masahiro , Nagao Tetsuhiko , Ooboshi Hiroaki , Omae Tsuyoshi , Toyoda Kazunori , Nakane Hiroshi , Sugimori Hiroshi , Fukuda Kenji , Fukushima Yoshihisa 
Published: December 2014

Background and Purpose—
Variable sex differences in clinical outcomes after stroke have been reported worldwide. This study aimed to elucidate whether sex is an independent risk factor of poor functional outcome after acute ischemic stroke.

Methods—
Using the database of patients with acute stroke registered in the Fukuoka Stroke Registry in Japan from 1999 to 2013, 6236 previously independent patients with first-ever ischemic stroke who were admitted within 24 hours of onset were included in this study. Baseline characteristics were assessed on admission. Study outcomes included neurological improvement, neurological deterioration, and poor functional outcome (modified Rankin Scale score, 3–6 at discharge). Logistic regression analyses were performed to evaluate the association between sex and clinical outcomes.

Results—
Overall, 2398 patients (38.5%) were women. Severe stroke (National Institutes of Health Stroke Scale score, ≥8) on admission was more prevalent in women than in men. The frequency of neurological improvement or deterioration during hospitalization was not different between the sexes. After adjusting for possible confounders, including age, stroke subtype and severity, risk factors, and poststroke treatments, it was found that female sex was independently associated with poor functional outcome at discharge (odds ratio, 1.30; 95% confidence interval, 1.08–1.57). There was heterogeneity of the association between sex and poor outcome according to age: women had higher risk of poor outcome than men among patients aged ≥70 years, but no clear sex difference was found in patients aged <70 years.

Conclusions—
Female sex was associated with the risk of poor functional outcome at discharge after acute ischemic stroke.
Delayed Pituitary Adenylate Cyclase–Activating Polypeptide Delivery After Brain Stroke Improves Functional Recovery by Inducing M2 Microglia/Macrophage Polarization
Authors: Brifault Coralie , Gras Marjorie , Liot Donovan , May Victor , Vaudry David , Wurtz Olivier 
Published: December 2014

Background and Purpose—
Until now, except thrombolysis, the therapeutical strategies targeting the acute phase of cerebral ischemia have been proven ineffective, and no approach is available to attenuate the delayed cell death mechanisms and the resulting functional deficits in the late phase. Then, we investigated whether a targeted and delayed delivery of pituitary adenylate cyclase–activating polypeptide (PACAP), a peptide known to exert neuroprotective activities, may dampen delayed pathophysiological processes improving functional recovery.

Methods—
Three days after permanent focal ischemia, PACAP-producing stem cells were transplanted intracerebro ventricularly in nonimmunosuppressed mice. At 7 and 14 days post ischemia, the effects of this stem cell–based targeted delivery of PACAP on functional recovery, volume lesions, and inflammatory processes were analyzed.

Results—

The delivery of PACAP in the vicinity of the infarct zone 3 days post stroke promotes fast, stable, and efficient functional recovery. This was correlated with a modulation of the postischemic inflammatory response. Transcriptomic and Ingenuity Pathway Analysis–based bioinformatic analyses identified several gene networks, functions, and key transcriptional factors, such as nuclear factor-κB, C/EBP-β, and Notch/RBP-J as PACAP’s potential targets. Such PACAP-dependent immunomodulation was further confirmed by morphometric and phenotypic analyses of microglial cells showing increased number of Arginase-1
+
cells in mice treated with PACAP-expressing cells specifically, demonstrating the redirection of the microglial response toward a neuroprotective M2 phenotype.

Conclusions—
Our results demonstrated that immunomodulatory strategies capable of redirecting the microglial response toward a neuroprotective M2 phenotype in the late phase of brain ischemia could represent attractive options for stroke treatment in a new and unexploited therapeutical window.
New Grading System Based on Magnetic Resonance Imaging in a Mouse Model of Subarachnoid Hemorrhage
Authors: Egashira Yusuke , Shishido Hajime , Hua Ya , Keep Richard F. , Xi Guohua 
Published: December 2014

Background and Purpose—
A grading system for experimental subarachnoid hemorrhage (SAH) that does not require animal euthanasia is currently unavailable. We proposed a new grading system based on MRI and evaluated the feasibility of this method in a mouse model of SAH.

Methods—
SAH was induced by endovascular perforation in adult male C57BL/6 mice. Mice underwent MRI 24 hours after SAH and were categorized into the following 5 grades based on T2*-weighted imaging: Grade 0, no visible SAH or intraventricular hemorrhage (IVH); Grade 1, minimal/localized SAH without IVH; Grade 2, minimal/localized SAH with IVH; Grade 3, thick/diffuse SAH without IVH; and Grade 4, thick/diffuse SAH with IVH. Neurological deficits were then assessed and the mice euthanized for conventional SAH grading.

Results—

Among a total of 47 mice, 4% were scored as grade 0, 30% as grade 1, 11% as grade 2, 30% as grade 3, and 26% as grade 4. This MRI grading had excellent interobserver reliability (weighted
κ
value =0.94), and there were strong correlations between the MRI grading and the conventional grading (
r
=0.85;
P
<0.001) or between MRI grade and neurological scores (
r
=−0.46;
P
<0.01).

Conclusions—
The new MRI grading correlated well with conventional grading and enabled in vivo evaluation of SAH severity. This grading system may offer advantages in future studies of experimental SAH.
Using Land Cover, Population, and Night Light Data for Assessing Local Temperature Differences in Mainz, Germany
Authors: Lindén Jenny , Esper Jan , Holmer Björn 
Published: December 2014

AbstractUrban areas are believed to affect temperature readings, thereby biasing the estimation of twentieth-century warming at regional to global scales. The precise effect of changes in the surroundings of meteorological stations, particularly gradual changes due to urban growth, is difficult to determine. In this paper, data from 10 temperature stations within 15 km of the city of Mainz (Germany) over a period of 842 days are examined to assess the connection between temperature and the properties of the station surroundings, considering (i) built/paved area surface coverage, (ii) population, and (iii) night light intensity. These properties were examined in circles with increasing radii from the stations to identify the most influential source areas. Daily maximum temperatures Tmax, as well as daily average temperatures, are shown to be significantly influenced by elevation and were adjusted before the analysis of anthropogenic surroundings, whereas daily minimum temperatures Tmin were not. Significant correlations (p < 0.1) between temperature and all examined properties of station surroundings up to 1000 m are found, but the effects are diminished at larger distance. Other factors, such as slope and topographic position (e.g., hollows), were important, especially to Tmin. Therefore, properties of station surroundings up to 1000 m from the stations are most suitable for the assessment of potential urban influence on Tmax and Tmin in the temperate zone of central Europe.
The Potential of Deriving Tree-Ring-Based Field Reconstructions of Droughts and Pluvials over Fennoscandia*,+
Authors: Seftigen Kristina , Cook Edward R. , Linderholm Hans W. , Fuentes Mauricio , Björklund Jesper 
Published: December 2014

Abstract
Moisture availability has been identified as one of the most important factors in the context of future climate change. This paper explores the potential of applying a multiproxy approach to dendroclimatology to infer the twentieth-century moisture variability over Fennoscandia. Fields of the warm-season (June–August) standardized precipitation evapotranspiration index (SPEI) were developed from a dense network of precipitation-sensitive annually resolved tree-ring width (TRW), maximum density (MXD), and stable carbon (δ13C) and oxygen (δ18O) isotope chronologies using a point-by-point local regression technique (PPR). Two different approaches were tested for selecting candidate tree-ring predictors of SPEI for each gridpoint reconstruction: a search radius method and a search spatial correlation contour method. As confirmed by a range of metrics of reconstruction fidelity, both methods produced reconstructions showing a remarkably high accuracy in a temporal sense, but with some minor regional differences. As a whole, the spatial skill of the reconstructed fields was generally quite good, showing the greatest performance in the central and southern parts of the target region. Lower reconstruction skills were observed in northern part of the study domain. Regional-scale moisture anomalies were best captured by the reconstructions, while local-scale features were not as well represented. The authors speculate that a spatially and temporally varying tree-ring proxy response to temperature and precipitation in the region may cause some uncertainties in a Fennoscandian hydroclimatic reconstruction; this needs further investigation. Overall, this study shows a great potential for making long-term spatiotemporal reconstructions of moisture variability for the Fennoscandian region using tree-ring data.
Analyzing the Inundation Pattern of the Poyang Lake Floodplain by Passive Microwave Data
Authors: Shang Haolu , Jia Li , Menenti Massimo 
Published: December 2014

AbstractThe soil wetness condition is a useful indicator of inundation hazard in floodplains, such as the Poyang Lake floodplain. Special Sensor Microwave Imager (SSM/I) passive microwave data were used to monitor water-saturated soil and open water areas of the Poyang Lake floodplain from 2001 to 2008, capturing the inundation patterns of this area in space and time. The polarization difference brightness temperature (PDBT) at 37 GHz is sensitive to the water extension even under dense vegetation. The zero-order radiative transfer model was simplified to retrieve the vertical–horizontal (V–H)-polarized effective emissivity difference from the PDBT at 37 GHz. Vegetation fractional area and vegetation transmission function were derived from NDVI to represent the vegetation attenuation. This effective emissivity difference has a quasi-linear relationship with the fractional area of water-saturated soil and standing water, no matter the frequency. Using the multifrequency-polarization surface emission (Qp) model and the Dobson model of the soil–water mixture, the two segments of this relationship were combined into a quasi-linear model. Comparing the retrieved water-saturated soil and standing water area of Poyang Lake with the lake area obtained from the MODIS and synthetic aperture radar (SAR) image at higher spatial resolution, the calculations show a good fit with the MODIS and SAR data, with R2 = 0.7664 and relative RMSE = 17.74%. The cross-correlation analysis shows that the Poyang Lake extension fluctuates with a 5-day time lag with the upstream land area of water-saturated soil and standing water. Since the closure of the Three Gorges Dam, this relationship is more evident.
Effects of Hydrologic Model Choice and Calibration on the Portrayal of Climate Change Impacts
Authors: Mendoza Pablo A. , Clark Martyn P. , Mizukami Naoki , Newman Andrew J. , Barlage Michael , Gutmann Ethan D. , Rasmussen Roy M. , Rajagopalan Balaji , Brekke Levi D. , Arnold Jeffrey R. 
Published: December 2014

Abstract
The assessment of climate change impacts on water resources involves several methodological decisions, including choices of global climate models (GCMs), emission scenarios, downscaling techniques, and hydrologic modeling approaches. Among these, hydrologic model structure selection and parameter calibration are particularly relevant and usually have a strong subjective component. The goal of this research is to improve understanding of the role of these decisions on the assessment of the effects of climate change on hydrologic processes. The study is conducted in three basins located in the Colorado headwaters region, using four different hydrologic model structures [PRMS, VIC, Noah LSM, and Noah LSM with multiparameterization options (Noah-MP)]. To better understand the role of parameter estimation, model performance and projected hydrologic changes (i.e., changes in the hydrology obtained from hydrologic models due to climate change) are compared before and after calibration with the University of Arizona shuffled complex evolution (SCE-UA) algorithm. Hydrologic changes are examined via a climate change scenario where the Community Climate System Model (CCSM) change signal is used to perturb the boundary conditions of the Weather Research and Forecasting (WRF) Model configured at 4-km resolution. Substantial intermodel differences (i.e., discrepancies between hydrologic models) in the portrayal of climate change impacts on water resources are demonstrated. Specifically, intermodel differences are larger than the mean signal from the CCSM–WRF climate scenario examined, even after the calibration process. Importantly, traditional single-objective calibration techniques aimed to reduce errors in runoff simulations do not necessarily improve intermodel agreement (i.e., same outputs from different hydrologic models) in projected changes of some hydrological processes such as evapotranspiration or snowpack.