bluuebunny/crossref_metadata_2025_split huggingface dataset:
Imaging the Norepinephrine Transporter in Neuroblastoma: A Comparison of [18F]-MFBG and 123I-MIBG
Authors: Zhang Hanwen , Huang Ruimin , Cheung Nai-Kong V. , Guo Hongfen , Zanzonico Pat B. , Thaler Howard T. , Lewis Jason S. , Blasberg Ronald G. 
Published: February 2014

Abstract
Purpose: The norepinephrine transporter (NET) is a critical regulator of catecholamine uptake in normal physiology and is expressed in neuroendocrine tumors like neuroblastoma. Although the norepinephrine analog, meta-iodobenzylguanidine (MIBG), is an established substrate for NET, 123I/131I-MIBG has several clinical limitations for diagnostic imaging. In the current studies, we evaluated meta-[18F]-fluorobenzylguanidine ([18F]-MFBG) and compared it with 123I-MIBG for imaging NET-expressing neuroblastomas.
Experimental Design: NET expression levels in neuroblastoma cell lines were determined by Western blot and 123I-MIBG uptake assays. Five neuroblastoma cell lines and two xenografts (SK-N-BE(2)C and LAN1) expressing different levels of NET were used for comparative in vitro and in vivo uptake studies.
Results: The uptake of [18F]-MFBG in cells was specific and proportional to the expression level of NET. Although [18F]-MFBG had a 3-fold lower affinity for NET and an approximately 2-fold lower cell uptake in vitro compared with that of 123I-MIBG, the in vivo imaging and tissue radioactivity concentration measurements demonstrated higher [18F]-MFBG xenograft uptake and tumor-to-normal organ ratios at 1 and 4 hours after injection. A comparison of 4 hours [18F]-MFBG PET (positron emission tomography) imaging with 24 hours 123I-MIBG SPECT (single-photon emission computed tomography) imaging showed an approximately 3-fold higher tumor uptake of [18F]-MFBG, but slightly lower tumor-to-background ratios in mice.
Conclusions: [18F]-MFBG is a promising radiopharmaceutical for specifically imaging NET-expressing neuroblastomas, with fast pharmacokinetics and whole-body clearance. [18F]-MFBG PET imaging shows higher sensitivity, better detection of small lesions with low NET expression, allows same day scintigraphy with a shorter image acquisition time, and has the potential for lower patient radiation exposure compared with 131I/123I-MIBG. Clin Cancer Res; 20(8); 2182–91. ©2014 AACR.
U.S. Food and Drug Administration Approval: Crizotinib for Treatment of Advanced or Metastatic Non–Small Cell Lung Cancer That Is Anaplastic Lymphoma Kinase Positive
Authors: Malik Shakun M. , Maher Virginia Ellen , Bijwaard Karen E. , Becker Robert L. , Zhang Lijun , Tang Shenghui W. , Song Pengfei , Liu Qi , Marathe Anshu , Gehrke Brenda , Helms Whitney , Hanner Diane , Justice Robert , Pazdur Richard 
Published: February 2014

Abstract
On August 26, 2011, the U.S. Food and Drug Administration (FDA) approved crizotinib (XALKORI Capsules, Pfizer Inc.) for treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive as detected by an FDA-approved test. The Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) was approved concurrently. In two multicenter, single-arm trials, patients with locally advanced or metastatic ALK-positive NSCLC previously treated with one or more systemic therapies received crizotinib orally at a dose of 250 mg twice daily. In 119 patients with ALK-positive NSCLC by local trial assay, the objective response rate (ORR) was 61% [95% confidence intervals (CI), 52%–70%] with a median response duration of 48 weeks. In 136 patients with ALK-positive NSCLC by the to-be-marketed test, the ORR was 50% (95% CI, 42%–59%) with a median response duration of 42 weeks. The most common adverse reactions (≥25%) were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Accelerated approval was granted on the basis of the high ORRs and durable responses. On November 20, 2013, crizotinib received full approval based on an improvement in progression-free survival in patients with metastatic ALK-positive NSCLC previously treated with one platinum-based chemotherapy regimen. Clin Cancer Res; 20(8); 2029–34. ©2014 AACR.
Ultra Low-Dose IL-2 for GVHD Prophylaxis after Allogeneic Hematopoietic Stem Cell Transplantation Mediates Expansion of Regulatory T Cells without Diminishing Antiviral and Antileukemic Activity
Authors: Kennedy-Nasser Alana A. , Ku Stephanie , Castillo-Caro Paul , Hazrat Yasmin , Wu Meng-Fen , Liu Hao , Melenhorst Jos , Barrett A. John , Ito Sawa , Foster Aaron , Savoldo Barbara , Yvon Eric , Carrum George , Ramos Carlos A. , Krance Robert A. , Leung Kathryn , Heslop Helen E. , Brenner Malcolm K. , Bollard Catherine M. 
Published: February 2014

Abstract
Purpose: GVHD after allogeneic hematopoietic stem cell transplantation (alloSCT) has been associated with low numbers of circulating CD4+CD25+FoxP3+ regulatory T cells (Tregs). Because Tregs express high levels of the interleukin (IL)-2 receptor, they may selectively expand in vivo in response to doses of IL-2 insufficient to stimulate T effector T-cell populations, thereby preventing GVHD.
Experimental Design: We prospectively evaluated the effects of ultra low-dose (ULD) IL-2 injections on Treg recovery in pediatric patients after alloSCT and compared this recovery with Treg reconstitution post alloSCT in patients without IL-2. Sixteen recipients of related (n = 12) or unrelated (n = 4) donor grafts received ULD IL-2 post hematopoietic stem cell transplantation (HSCT; 100,000–200,000 IU/m2 ×3 per week), starting &lt;day 30 and continuing for 6 to 12 weeks.
Results: No grade 3/4 toxicities were associated with ULD IL-2. CD4+CD25+FoxP3+ Tregs increased from a mean of 4.8% (range, 0%–11.0%) pre IL-2 to 11.1% (range, 1.2%–31.1%) following therapy, with the greatest change occurring in the recipients of matched related donor (MRD) transplants. No IL-2 patients developed grade 2–4 acute GVHD (aGVHD), compared with 4 of 33 (12%) of the comparator group who did not receive IL-2. IL-2 recipients retained T cells reactive to viral and leukemia antigens, and in the MRD recipients, only 2 of 13 (15%) of the IL-2 patients developed viral infections versus 63% of the comparator group (P = 0.022).
Conclusions: Hence, ULD IL-2 is well tolerated, expands a Treg population in vivo, and may be associated with a lower incidence of viral infections and GVHD. Clin Cancer Res; 20(8); 2215–25. ©2014 AACR.
The various states of von Willebrand factor and their function in physiology and pathophysiology
Authors: Huck Volker , Gorzelanny Christian , Schneider Matthias F. , Schneider Stefan W. 
Published: February 2014

SummaryThe specific interactions of von Willebrand factor (VWF) with the vessel wall, platelets or other interfaces strongly depend on (a shearinduced) VWF activation. Shear flow has been shown to induce a conformational transition of VWF, but is modulated by its thermodynamic state (state-function relationship). The state in turn is determined by physical (e.g. vessel geometry), physico-chemical (e.g. pH) and molecular-biological (e.g. mutants, binding) factors. Combining established results with recent insights, we reconstruct VWF biology and its statefunction relationship from endothelial cell release to final degradation in the human vasculature. After VWF secretion, endothelial-anchored and shear activated VWF multimers can rapidly interact with surrounding colloids, typically with platelets. Simultaneously, this VWF activation enables ADAMTS13 to cleave VWF multimers thereby limiting VWF binding capacity. The subsequent cell-surface dissociation leads to a VWF recoiling to a globular conformation, shielding from further degradation by ADAMTS13. High local concentrations of these soluble VWF multimers, transported to the downstream vasculature, are capable for an immediate reactivation and re-polymerisation initiating colloid-binding or VWF-colloid aggregation at the site of inflamed endothelium, vessel injuries or pathological high-shear areas. Focusing on these functional steps in the lifecycle of VWF, its qualitative and quantitative deficiencies in the different VWD types will facilitate more precise diagnostics and reliable risk stratification for prophylactic therapies. The underlying biophysical principles are of general character, which broadens prospective studies on the physiological and pathophysiological impact of VWF and VWF-associated diseases and beares hope for a more universal understanding of an entire class of phenomena.
New players in haemostasis and thrombosis
Authors: Geddings Julia E. , Mackman Nigel 
Published: February 2014

SummaryThe blood coagulation cascade is essential for haemostasis, but excessive activation can cause thrombosis. Importantly, recent studies have identified factors that contribute to thrombosis but not haemostasis. These include factor XII (FXII), tissue factor-positive microparticles (MPs) and neutrophil extracellular traps (NETs). Studies have shown that FXII plays a role in thrombosis but not haemostasis. FXII is activated in vivo by a variety of negatively-charged polyphosphates, which include extracellular RNA, DNA and inorganic polyphosphate (PolyP) that are released during cell damage and infection. These findings have led to the development of nucleic acid-binding polymers as a new class of anticoagulant drug. Other studies have analysed the role of MPs in experimental thrombosis. MPs are small membrane vesicles released from activated or apoptotic cells. We and others have found that tissue factor-positive MPs enhance thrombosis in mouse models and are elevated in the plasma of pancreatic cancer patients. Finally, NETs have been shown to contribute to experimental venous thrombosis in mouse models and are present in human thrombi. NETs are composed of chromatin fibers that are released from neutrophils undergoing cell death. NETs can capture platelets and increase fibrin deposition. The recent advances in our understanding of the factors contributing to thrombosis in animal models provide new opportunities for the development of safer anticoagulant drugs.
Adherence to lifestyle modifications after a cardiac rehabilitation program and endothelial progenitor cells
Authors: Marcucci Rossella , Gori Anna Maria , Burgisser Costanza , Francini Sara , Roberts Anna Teresa , Sofi Francesco , Gensini Gian Franco , Abbate Rosanna , Fattirolli Francesco , Cesari Francesca 
Published: February 2014

SummaryAn increase of endothelial progenitor cells (EPCs) among acute myo-cardial infarction (AMI) patients participating in a cardiac rehabilitation (CR) program has been reported, but no data on the impact of adherence to lifestyle recommendations provided during a CR program on EPCs are available. It was our aim to investigate the effect of adherence to lifestyle recommendations on EPCs, inflammatory and functional parameters after six months of a CR program in AMI patients. In 110 AMI patients (90 male/20 female; mean age 57.9 ± 9.4 years) EPCs, high sensitivity C-reactive protein (hsCRP), N-terminal pro-brain natriuretic peptide (NT-ProBNP) levels, and cardiopulmonary testings were determined at the end of the CR (T1) and at a six-month follow-up (T2). At T2 we administered a questionnaire assessing dietary habits and physical activity. At T2, we observed a decrease of EPCs (p<0.05), of hsCRP (p=0.009) and of NT-ProBNP (p<0.0001). Patient population was divided into three categories by Healthy Lifestyle (HL) score (none/low, moderate and high adherence to lifestyle recommendations). We observed a significant association between adherence to lifestyle recommendations, increase in EPCs and exercise capacity between T1 and T2 (Δ EPCs p for trend <0.05; ΔWatt max p for trend=0.004). In a multivariate logistic regression analyses, being in the highest tertile of HL score affected the likelihood of an increase of EPC levels at T2 [OR (95% confidence interval): 3.36 (1.0–10.72) p=0.04]. In conclusion, adherence to lifestyle recommendations provided during a CR program positively influences EPC levels and exercise capacity.
Only high levels of dabigatran attenuate catheter thrombosis in vitro and in rabbits
Authors: Yau Jonathan W. , Liao Peng , Fredenburgh James C. , Roberts Robin S. , Weitz Jeffrey I. 
Published: February 2014

SummaryIn patients with mechanical heart valves, thromboembolic events were more frequent with dabigatran, an oral thrombin inhibitor, than with warfarin. This observation raises the possibility that dabigatran may be less effective than conventional anticoagulants in patients with other blood-contacting devices, such as catheters. To address this, we compared the capacity of dabigatran and/or heparin to inhibit catheter-induced thrombin generation in vitro and to attenuate catheter occlusion in rabbits. Using a catheter-induced thrombin generation assay, concentrations of dabigatran over 100 ng/ml prolonged the lag time and time to peak thrombin, and reduced the peak thrombin concentration and endogenous thrombin potential in a concentration-dependent fashion. Compared with saline in a rabbit model of catheter thrombosis, dabigatran prolonged the mean time to catheter occlusion by 2.9– and 1.9-fold when plasma levels were 173 and 140 ng/ml, respectively; values comparable to median peak levels in humans given dabigatran 150 mg twice daily. In contrast, low-dose dabigatran, which produced a level of 60 ng/ml; a value comparable to the trough level of dabigatran in humans, did not prolong the time to occlusion. Whereas a 70 U/kg bolus of heparin prolonged the mean time to occlusion by 3.4-fold, a 15 U/kg bolus had no effect. When low-dose dabigatran was given in combination with 15 U/kg heparin, the mean time to occlusion was prolonged by 2.7-fold. These findings suggest that only peak levels of dabigatran are sufficient to prevent catheter-induced clotting unless supplemented heparin is given.
Brugada Syndrome Disease Phenotype Explained in Apparently Benign Sodium Channel Mutations
Authors: Hoshi Malcolm , Du Xi X. , Shinlapawittayatorn Krekwit , Liu Haiyan , Chai Sam , Wan Xiaoping , Ficker Eckhard , Deschênes Isabelle 
Published: February 2014

Background—
Brugada syndrome (BrS) is an arrhythmogenic disorder that has been linked to mutations in SCN5A, the gene encoding for the pore-forming α-subunit of the cardiac sodium channel. Typically, BrS mutations in SCN5A result in a reduction of sodium current with some mutations even exhibiting a dominant-negative effect on wild-type (WT) channels, thus leading to an even more prominent decrease in current amplitudes. However, there is also a category of apparently benign (atypical) BrS SCN5A mutations that in vitro demonstrates only minor biophysical defects. It is therefore not clear how these mutations produce a BrS phenotype. We hypothesized that similar to dominant-negative mutations, atypical mutations could lead to a reduction in sodium currents when coexpressed with WT to mimic the heterozygous patient genotype.

Methods and Results—
WT and atypical BrS mutations were coexpressed in Human Embryonic Kidney-293 cells, showing a reduction in sodium current densities similar to typical BrS mutations. Importantly, this reduction in sodium current was also seen when the atypical mutations were expressed in rat or human cardiomyocytes. This decrease in current density was the result of reduced surface expression of both mutant and WT channels.

Conclusions—
Taken together, we have shown how apparently benign SCN5A BrS mutations can lead to the ECG abnormalities seen in patients with BrS through an induced defect that is only present when the mutations are coexpressed with WT channels. Our work has implications for risk management and stratification for some SCN5A-implicated BrS patients.
Consumption of Less Than 10% of Total Energy From Added Sugars is Associated With Increasing HDL in Females During Adolescence: A Longitudinal Analysis
Authors: Lee Alexandra K. , Binongo José Nilo G. , Chowdhury Ritam , Stein Aryeh D. , Gazmararian Julie A. , Vos Miriam B. , Welsh Jean A. 
Published: February 2014

Background

Atherosclerotic changes associated with dyslipidemia and increased cardiovascular disease risk are believed to begin in childhood. While previous studies have linked added sugars consumption to low high‐density lipoprotein (
HDL)
, little is known about the long‐term impact of this consumption. This study aims to assess the association between added sugars intake and HDL cholesterol levels during adolescence, and whether this association is modified by obesity.

Methods and Results

We used data from the National Heart Lung and Blood Institute's Growth and Health Study, a 10‐year cohort study of non‐Hispanic Caucasian and African‐American girls (N=2379) aged 9 and 10 years at baseline recruited from 3 sites in 1987‐1988 with biennial plasma lipid measurement and annual assessment of diet using a 3‐day food record. Added sugars consumption was dichotomized into low (0% to <10% of total energy) and high (≥10% of total energy). In a mixed model controlling for obesity, race, physical activity, smoking, maturation stage, age, and nutritional factors, low compared with high added sugar consumption was associated with a 0.26 mg/dL greater annual increase in
HDL
levels (95%
CI
0.48 to 0.04;
P
=0.02). Over the 10‐year study period, the model predicted a mean increase of 2.2 mg/dL (95%
CI
0.09 to 4.32;
P
=0.04) among low consumers, and a 0.4 mg/dL decrease (95%
CI
−1.32 to 0.52;
P
=0.4) among high consumers. Weight category did not modify this association (
P
=0.45).

Conclusion

Low added sugars consumption is associated with increasing
HDL
cholesterol levels throughout adolescence.
The Politics of Negotiating EU Readmission Agreements: Insights from Morocco and Turkey
Authors: Wolff Sarah 
Published: February 2014

Abstract
The subject of this article is the politics of instrumentation of eu Readmission Agreement (eura) negotiations with Morocco and Turkey. Refusing to sign an eura for more than ten years, they share a similar position of ‘hard bargainers’. Recently though a ‘negotiation turn’ took place, Turkey initialling an eura in June 2012 and Morocco committing to sign an eura within the framework of a Mobility Partnership (mp) in June 2013. Unpacking the role of eu incentives and third countries’ preferences, this article reveals that beyond the function of this instrument to co-opt third countries in eu’s fight against irregular migration, a series of obstacles forced the eu to revise the design of eura and to take into account domestic and regional factors. This article engages with the meanings and representations carried by euras in third countries and implications for the logic of consequences and appropriateness within the framework of EU external migration policy.
The Use of the Expressions ‘Prophetic Spirit’ and ‘Holy Spirit’ in the Targum and the Dating of the Targums
Authors: Casanellas Pere 
Published: February 2014

‭Among different expressions used by the targums to translate the Hebrew word meaning ‘spirit’, the terms ‘prophetic spirit’ and ‘Holy Spirit’ stand out. I will try to demonstrate (contra P. Schäfer, ‘Die Termini “Heiliger Geist” und “Geist der Prophetie” in den Targumim und das Verhältnis der Targumim zueinander’, VT 20 (1970), pp. 304–314) that both terms often have a basis in the Hebrew text (namely, the word ‮‮רוח‬‬), that both can have a similar relationship to prophecy and that the expression ‘Holy Spirit’ is as old as ‘prophetic spirit’ or even older. I will also outline the semantic contexts that underlie the use of one or other expression, which has nothing to do with the antiquity of either term.‬
Overcoming Emotions, Conquering Fate: Reflections on Descartes’ Ethics
Authors: Amatayakul Supakwadee 
Published: February 2014

AbstractThis paper offers a reconstruction of Descartes's theory of the emotions, with special focus on the virtue “generosity” (générosité) which he proposed as the master virtue to help humans manage and control their desires so that they can achieve the highest level of happiness which transcends the unpredictability and arbitrariness of fate. It first provides an analysis of Descartes's notion of “divine providence,” “vain desires,” and “regret;” then proceeds to offer an investigation of “générosité” both as an emotion and as a virtue; and concludes with an examination of “générosité” as a tool to master and control the emotions.
Comparative genomics of type VI secretion systems in strains of Pantoea ananatisfrom different environments
Authors: Shyntum Divine Yufetar , Venter Stephanus Nicolaas , Moleleki Lucy Novungayo , Toth Ian , Coutinho Teresa Ann 
Published: February 2014

Abstract

Background
The Type VI secretion system (T6SS) has been identified in several different bacteria, including the plant pathogenPantoea ananatis. Previous in silico analyses described three different T6SS loci present in the pathogenic strain of P. ananatis LMG 20103. This initial investigation has been extended to include an additional seven sequenced strains of P. ananatis together with 39 strains from different ecological niches. Comparative and phylogenetic analyses were used to investigate the distribution, evolution, intra-strain variability and operon structure of the T6SS in the sequenced strains.

Results
Three different T6SS loci were identified in P. ananatis strain LMG 20103 and designated PA T6SS 1-3. PA T6SS-1 was present in all sequenced strains of P. ananatis and in all 39 additional strains examined in this study. In addition, PA T6SS-1 included all 13 core T6SS genes required for synthesis of a functional T6SS. The plasmid-borne PA T6SS-2 also included all 13 core T6SS genes but was restricted to only 33% (15/46) of the strains examined. In addition, PA T6SS-2 was restricted to strains of P. ananatis isolated from symptomatic plant material. This finding raises the possibility of an association between PA T6SS-2 and either pathogenicity or host specificity. The third cluster PA T6SS-3 was present in all strains analyzed in this study but lacked 11 of the 13 core T6SS genes suggesting it may not encoded a functional T6SS. Inter-strain variability was also associated with hcp and vgrG islands, which are associated with the T6SS and encode a variable number of proteins usually of unknown function. These proteins may play a role in the fitness of different strains in a variety of ecological niches or as candidate T6SS effectors. Phylogenetic analysis indicated that PA T6SS-1 and PA T6SS-2 are evolutionarily distinct.

Conclusion
Our analysis indicates that the three T6SSs of P. ananatis appear to have been independently acquired and may play different roles relating to pathogenicity, host range determination and/or niche adaptation. Future work will be directed toward understanding the roles that these T6SSs play in the biology of P. ananatis.
A large esophageal gastrointestinal stromal tumor that was successfully resected after neoadjuvant imatinib treatment: case report
Authors: Yanagawa Senichiro , Tanabe Kazuaki , Suzuki Takahisa , Tokumoto Noriaki , Arihiro Koji , Ohdan Hideki 
Published: February 2014

Abstract
A 49-year-old man was admitted to our hospital with a 1-month history of dysphagia. An upper endoscopy revealed a lower esophageal submucosal tumor. Immunohistochemical staining of the biopsy specimen revealed KIT positivity. Thus, the tumor was diagnosed as a gastrointestinal stromal tumor (GIST). After 6 months of imatinib treatment, the tumor decreased from 92 mm × 55 mm × 80 mm to 65 mm × 35 mm × 55 mm in diameter, and surgery was performed. The tumor was completely resected without rupture, by partial esophagogastric resection through a thoracotomy incision, using an abdominal laparoscopic approach. Immunohistochemical staining revealed that the tumor was negative for c-kit but positive for CD34. Genetic examination showed that the tumor had a mutation in exon 11. The patient experienced minor leakage but recovered conservatively. Adjuvant imatinib was initiated 64 days after surgery. We report this rare case to show the potential of preoperative imatinib treatment in patients with large esophageal GISTs, to achieve complete resection without rupture.