bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the Neurokinin-1 Receptor Compromises Canonical Wnt Signaling in Hepatoblastoma
Authors: Ilmer Matthias , Garnier Agnès , Vykoukal Jody , Alt Eckhard , von Schweinitz Dietrich , Kappler Roland , Berger Michael 
Published: October 2015

Abstract
The substance P (SP)/NK-1 receptor (NK1R) complex represents an intriguing anticancer target for a variety of tumors, including hepatoblastoma (HB). Therefore, NK1R antagonists, such as the clinical drug aprepitant, recently have been proposed as potent anticancer agents. However, very little is known regarding the molecular basis of NK1R inhibition in cancer. Using reverse phase protein array, Western blot, Super TOP/FOP, confocal microscopy, and sphere formation ability (SFA) assays, we identified the AKT and Wnt signaling pathways as the key targets of aprepitant in three human HB cell lines (HepT1, HepG2, and HuH6). Following NK1R blockage, we observed decreased phosphorylation of p70S6K and 4E-BP1/2 and inhibition of the canonical Wnt pathway with subsequent decrease of HB cell growth. This effect was dependent of high baseline Wnt activity either by mutational status of β-catenin or extrinsic Wnt activation. Wnt inhibition seemed to be strengthened by disruption of the FOXM1–β-catenin complex. Furthermore, treatment of HB cells with aprepitant led to reduced expression of (liver) stemness markers (AFP, CD13, SOX2, NANOG, and OCT4) and SFA when grown under cancer stem cell conditions. Taken together, we show for the first time that targeting the SP/NK1R signaling cascade inhibits canonical Wnt signaling in HB cells. These findings reveal important insight into the molecular mechanisms of the SP/NK1R complex as a critical component in a model of pediatric liver cancer and may support the development of novel therapeutic interventions for HB and other Wnt-activated cancers. Mol Cancer Ther; 14(12); 2712–21. ©2015 AACR.
Dual Agonist Surrobody Simultaneously Activates Death Receptors DR4 and DR5 to Induce Cancer Cell Death
Authors: Milutinovic Snezana , Kashyap Arun K. , Yanagi Teruki , Wimer Carina , Zhou Sihong , O'Neil Ryann , Kurtzman Aaron L. , Faynboym Alexsandr , Xu Li , Hannum Charles H. , Diaz Paul W. , Matsuzawa Shu-ichi , Horowitz Michael , Horowitz Lawrence , Bhatt Ramesh R. , Reed John C. 
Published: October 2015

Abstract
Death receptors of the TNF family are found on the surface of most cancer cells and their activation typically kills cancer cells through the stimulation of the extrinsic apoptotic pathway. The endogenous ligand for death receptors 4 and 5 (DR4 and DR5) is TNF-related apoptosis-inducing ligand, TRAIL (Apo2L). As most untransformed cells are not susceptible to TRAIL-induced apoptosis, death receptor activators have emerged as promising cancer therapeutic agents. One strategy to stimulate death receptors in cancer patients is to use soluble human recombinant TRAIL protein, but this agent has limitations of a short half-life and decoy receptor sequestration. Another strategy that attempted to evade decoy receptor sequestration and to provide improved pharmacokinetic properties was to generate DR4 or DR5 agonist antibodies. The resulting monoclonal agonist antibodies overcame the limitations of short half-life and avoided decoy receptor sequestration, but are limited by activating only one of the two death receptors. Here, we describe a DR4 and DR5 dual agonist produced using Surrobody technology that activates both DR4 and DR5 to induce apoptotic death of cancer cells in vitro and in vivo and also avoids decoy receptor sequestration. This fully human anti-DR4/DR5 Surrobody displays superior potency to DR4- and DR5-specific antibodies, even when combined with TRAIL-sensitizing proapoptotic agents. Moreover, cancer cells were less likely to acquire resistance to Surrobody than either anti-DR4 or anti-DR5 monospecific antibodies. Taken together, Surrobody shows promising preclinical proapoptotic activity against cancer cells, meriting further exploration of its potential as a novel cancer therapeutic agent. Mol Cancer Ther; 15(1); 114–24. ©2015 AACR.
Convergence of Acquired Mutations and Alternative Splicing of CD19 Enables Resistance to CART-19 Immunotherapy
Authors: Sotillo Elena , Barrett David M. , Black Kathryn L. , Bagashev Asen , Oldridge Derek , Wu Glendon , Sussman Robyn , Lanauze Claudia , Ruella Marco , Gazzara Matthew R. , Martinez Nicole M. , Harrington Colleen T. , Chung Elaine Y. , Perazzelli Jessica , Hofmann Ted J. , Maude Shannon L. , Raman Pichai , Barrera Alejandro , Gill Saar , Lacey Simon F. , Melenhorst Jan J. , Allman David , Jacoby Elad , Fry Terry , Mackall Crystal , Barash Yoseph , Lynch Kristen W. , Maris John M. , Grupp Stephan A. , Thomas-Tikhonenko Andrei 
Published: October 2015

Abstract
The CD19 antigen, expressed on most B-cell acute lymphoblastic leukemias (B-ALL), can be targeted with chimeric antigen receptor–armed T cells (CART-19), but relapses with epitope loss occur in 10% to 20% of pediatric responders. We detected hemizygous deletions spanning the CD19 locus and de novo frameshift and missense mutations in exon 2 of CD19 in some relapse samples. However, we also discovered alternatively spliced CD19 mRNA species, including one lacking exon 2. Pull-down/siRNA experiments identified SRSF3 as a splicing factor involved in exon 2 retention, and its levels were lower in relapsed B-ALL. Using genome editing, we demonstrated that exon 2 skipping bypasses exon 2 mutations in B-ALL cells and allows expression of the N-terminally truncated CD19 variant, which fails to trigger killing by CART-19 but partly rescues defects associated with CD19 loss. Thus, this mechanism of resistance is based on a combination of deleterious mutations and ensuing selection for alternatively spliced RNA isoforms.
Significance: CART-19 yield 70% response rates in patients with B-ALL, but also produce escape variants. We discovered that the underlying mechanism is the selection for preexisting alternatively spliced CD19 isoforms with the compromised CART-19 epitope. This mechanism suggests a possibility of targeting alternative CD19 ectodomains, which could improve survival of patients with B-cell neoplasms. Cancer Discov; 5(12); 1282–95. ©2015 AACR.
See related commentary by Jackson and Brentjens, p. 1238.
This article is highlighted in the In This Issue feature, p. 1225
IL-37 Is a Novel Proangiogenic Factor of Developmental and Pathological Angiogenesis
Authors: Yang Tianshu , Lin Qing , Zhao Mengmeng , Hu Yongguang , Yu Ying , Jin Jiayi , Zhou Hongyan , Hu Xiao , Wei Rongbin , Zhang Xuetao , Yang Xiaoping , Liu Gaoqin , Lu Peirong , Xu Guotong , Yang Jianhua , Corry David B. , Su Shao Bo , Liu Shangfeng , Liu Xialin 
Published: October 2015

Objective—
Angiogenesis is tightly controlled by growth factors and cytokines in pathophysiological settings. Interleukin 37 (IL-37) is a newly identified cytokine of the IL-1 family, some members of which are important in inflammation and angiogenesis. However, the function of IL-37 in angiogenesis remains unknown. We aimed to explore the regulatory role of IL-37 in pathological and physiological angiogenesis.

Approach and Results—
We found that IL-37 was expressed and secreted in endothelial cells and upregulated under hypoxic conditions. IL-37 enhanced endothelial cell proliferation, capillary formation, migration, and vessel sprouting from aortic rings with potency comparable with that of vascular endothelial growth factor. IL-37 activates survival signals including extracellular signal-regulated kinase 1/2 and AKT in endothelial cells. IL-37 promoted vessel growth in implanted Matrigel plug in vivo in a dose-dependent manner with potency comparable with that of basic fibroblast growth factor. In the mouse model of retinal vascular development, neonatal mice administrated with IL-37 displayed increased neovascularization. We demonstrated further that IL-37 promoted pathological angiogenesis in the mouse model of oxygen-induced retinopathy.

Conclusions—
Our findings suggest that IL-37 is a novel and potent proangiogenic cytokine with essential role in pathophy siological settings.
Right Atrial Function in Pulmonary Arterial Hypertension
Authors: Querejeta Roca Gabriela , Campbell Patricia , Claggett Brian , Solomon Scott D. , Shah Amil M. 
Published: October 2015

Background—
Elevated right atrial (RA) pressure is an established prognostic measure in pulmonary arterial hypertension (PAH). However, little is known about perturbations in RA function in PAH.

Methods and Results—

Reservoir (RA longitudinal strain [RA LS]), conduit (RA early LS rate), and active (RA late LS rate) phases were assessed by 2D speckle tracking in 65 patients with PAH, 6-minute walk distance ≤450 m, and a pulmonary vascular resistance >800 dynes·s/cm
5
, despite therapy with at least 2 PAH-specific medications enrolled in the Imatinib in Pulmonary Arterial Hypertension, a Randomized Efficacy Study (IMPRES) trial and were compared with 30 healthy controls of similar age and sex. We studied the association of RA functional measures with invasive pulmonary hemodynamics, cardiac structure and function, and N-terminal pro brain natriuretic peptide. RA LS and early LS rate were reduced in PAH patients compared with controls (27.1±11.6 versus 56.9±12.7, adjusted
P
<0.001 and −0.6±0.5 versus −1.5±0.5, adjusted
P
<0.001, respectively) even after adjusting for RA area and invasive RA pressure, whereas RA late LS rate was similar between groups (−1.4±0.7 versus −1.5±0.4,
P
=0.42). Among PAH patients, worse RA LS correlated with greater RA size (
r
=−0.50,
P
<0.0001) and pressure (
r
=−0.37,
P
=0.002), but not pulmonary artery pressure (
r
=−0.07,
P
=0.58). Worse RA LS was also associated with right ventricular enlargement and dysfunction and higher N-terminal pro brain natriuretic peptide independent of RA size and pressure.

Conclusions—
RA reservoir and passive conduit functions are impaired in PAH, independent of RA size and pressure, and likely reflect right ventricular failure and overload.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00902174.
Coronary and Basilar Artery Ectasia Are Associated
Authors: Pico Fernando , Labreuche Julien , Hauw Jean-Jacques , Seilhean Danielle , Duyckaerts Charles , Amarenco Pierre 
Published: October 2015

Background and Purpose—
Intracranial artery dolichoectasia (IADE) and coronary artery ectasia have been associated with stroke and myocardial infarction, respectively. Only rarely have cases of coexisting IADE and coronary artery ectasia been reported. We investigated this association in a large consecutive autopsy series.

Methods—
Sixteen stroke patients with IADE were identified among 381 stroke patients and were matched with 16 stroke patients without IADE. The heart and coronary arteries from all patients were examined after a prespecified protocol.

Results—

Coronary artery ectasia was observed in 8 of the stroke patients with IADE, and in none of the stroke patients without IADE (
P
=0.008). The diameters of basilar and right coronary arteries were positively correlated (IADE patients,
r
=0.51;
P
=0.003 and coronary artery ectasia patients,
P
=0.006).

Conclusions—
This autopsy study examining the association of coronary artery ectasia and IADE in stroke patients suggests a common pathogenesis.
Coagulation and Fibrinolytic Activity of Tenecteplase and Alteplase in Acute Ischemic Stroke
Authors: Huang Xuya , Moreton Fiona Catherine , Kalladka Dheeraj , Cheripelli Bharath Kumar , MacIsaac Rachael , Tait R. Campbell , Muir Keith W. 
Published: October 2015

Background and Purpose—
We compared the fibrinolytic activity of tenecteplase and alteplase in patients with acute ischemic stroke, and explored the association between hypofibrinogenaemia and intracerebral hemorrhage.

Methods—

Venous blood samples from a subgroup of participants in the Alteplase–Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST) study were obtained at pretreatment, 3 to 12 hours, and 24±3 hours post-intravenous thrombolysis for analyses of plasminogen, plasminogen activator inhibitor-1,
d
-dimer, factor V, fibrinogen, and fibrin(ogen) degradation products, in addition to routine coagulation assays. Related sample Wilcoxon signed-rank tests were used to test the within-group changes, and independent Mann–Whitney tests for between-group differences.

Results—

Thirty patients were included (alteplase=14 and tenecteplase=16) with similar baseline demographics. Compared with baseline, alteplase caused significant hypofibrinogenaemia (
P
=0.002), prolonged prothrombin time (
P
=0.011), hypoplasminogenaemia (
P
=0.001), and lower factor V (
P
=0.002) at 3 to 12 hours after administration with persistent hypofibrinogenaemia at 24 hours (
P
=0.011), whereas only minor hypoplasminogenaemia (
P
=0.029) was seen in the tenecteplase group. Tenecteplase consumed less plasminogen (
P
<0.001) and fibrinogen (
P
=0.002) compared with alteplase.

Conclusions—
In patients with acute ischemic stroke, alteplase 0.9 mg/kg caused significant disruption of the fibrinolytic system, whereas tenecteplase 0.25 mg/kg did not, consistent with the trend toward lower intracerebral hemorrhage incidence with tenecteplase in the ATTEST study.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01472926.
Expansion of a Holepunch Cloud by a Gravity Wave Front
Authors: Muraki David J. , Rotunno Richard , Morrison Hugh 
Published: October 2015

Abstract
A holepunch cloud is a curious phenomenon where a disturbance in a thin cloud layer initiates an expanding circular hole of clear air. Usually triggered by the passage of aircraft, observations of these holes in clouds date back to the earliest days of aviation, but only recently has a holepunch cloud been simulated within a full-physics numerical model. These computations confirm that ice crystal growth through the Wegener–Bergeron–Findeisen process creates a small cloud-free region whose subsequent outward spread defines the holepunch. The mechanics behind this continued expansion, however, has yet to be definitively identified. In this article, the motion of the cloud edge is explained as a propagating gravity wave front. To support this idea, a hierarchy of three idealizations is analyzed: a full-physics numerical model, a fluid mechanical model with simplified moisture effects, and a conservation law analysis for front motion. The essence of the holepunch cloud is established to be a moist air layer that is unsaturated (clear) and weakly stratified within the hole but saturated (cloudy) and moist neutral outside of it. The cloud edge thus represents a barrier to the outward propagation of gravity waves within the clear air—the result of this collision is a wave front whose velocity determines the growth rate of the hole.
High serum sodium level in affective episode associated with coronary heart disease in old adults with bipolar disorder
Authors: Chen Pao-Huan , Gildengers Ariel G , Lee Chao-Hsien , Chen Meng-Ling , Kuo Chian-Jue , Tsai Shang-Ying 
Published: October 2015

Objective Coronary heart disease (CHD) remains the principal cause of excessive natural deaths in bipolar patients; however, electrocardiogram analyses and clinical features predicting CHDs in elderly bipolar patients remain limited. We sought to examine the relationship between CHDs, as determined by electrocardiogram, and clinical characteristics. Methods We recruited bipolar I outpatients Diagnostic Statistical Manual of Mental Health (DSM-IV) who were more than 60 years old and had at least one psychiatric admission. Subjects were divided into two groups based on the presence or absence of CHD diagnosed by electrocardiogram analysis at entry of study. Clinical data were obtained by a combination of interviewing patients and family members and retrospectively reviewing medical records of the most recent acute psychiatric hospitalization. Results Eighty patients with bipolar disorder were enrolled. A total of 20 (25%) in the study had CHDs. The mean age at the time of entry into study was 67.6 ± 5.5 years old in group with CHD and 66.8 ± 6.8 years old in that without CHD. Among the clinical characteristics examined, higher mean levels of serum sodium and thyroxine during the acute affective phase as well as more first-degree family history with bipolar disorder were related to having CHD, particularly the serum sodium level. Conclusions About one fourth of old bipolar patients have CHDs in both Asian and Western populations. Aging patients with bipolar disorder may have unique clinical factors (e.g., hypernatremia or elevated thyroxine) related CHDs that could warrant special attention in their psychiatric and medical care to minimize cardiovascular disease and mortality.
Defining postoperative stability in children with radial polydactyly
Authors: Engelhardt T. O. , Djedovic G. , Pedross F. , Piza-Katzer H. 
Published: October 2015

There is little fundamental data on paediatric metacarpophalangeal joint instability in radial polydactyly following surgical reconstruction. We evaluated 27 thumbs in a healthy paediatric population (Group A: eight girls and 19 boys with a mean age of 9.7 years (range 2.7–14.2)) and 12 thumbs following Wassel-IV reconstruction (Group B: eight girls and four boys with a mean age at follow-up of 10.6 years (range 2.7–13.2)). Metacarpophalangeal joint radial deviation, ulnar deviation on stress testing, interphalangeal joint and metacarpophalangeal joint alignment on posterior-anterior radiographs were measured and scored according to parameters defining joint instability. The aim of our study was to provide fundamental data on thumb metacarpophalangeal joint mobility patterns and alignment for further postoperative evaluations in children. The average ulnar deviation and radial deviation on stress testing of the healthy (Group A) metacarpophalangeal joints was 25° (10°–45°) and 30° (10°–55°), respectively. In the operated (Group B) thumbs, the ulnar deviation and radial deviation was greater at 35° (10°–55°) and 30° (10°–70°). Ulnar deviation (UD) of the proximal phalanx at the metacarpophalangeal joint on posterior-anterior radiographs was a mean of 10° (range −10°–30°) in Group B; this was significantly greater than in Group A at a mean of 5° (range −5–20°) ( p = 0.029). The mean radial alignment of the interphalangeal joint (distal phalanx relative to the proximal phalanx) was significantly higher in Group B (15°) than Group A (0°) ( p = 0.221). In the literature on radial polydactyly, cut off values defining metacarpophalangeal joint instability in children range from 5° to 20°. According to our results, high but physiological metacarpophalangeal joint mobility of the thumb needs to be taken into consideration when evaluating children following reconstruction. Ulnar or radial deviation greater than 30°, in combination with the lack of a definite end point on metacarpophalangeal joint stress testing, may be regarded as unstable. Based on our study on healthy paediatric and reconstructed thumbs, comparison of joint stability with the healthy contralateral hand is recommended in order to define pathological instability. Level of Evidence: II.
Accuracy of CT angiography in detection of blood supply dominance of posterior cerebral artery in patients with posterior communicating artery aneurysm
Authors: Ahmed Osama , Kalakoti Piyush , Menger Richard , Brown Benjamin , Zhang Shihao , Guthikonda Bharat , Cuellar Hugo 
Published: October 2015

Background and purpose The use of computed tomography angiography (CTA) as the sole vascular imaging study for preoperative planning for clipping of aneurysms is well described in the literature. CTA is widely available, provides quick acquisition, has low morbidity, and low cost. In this study, we describe the accuracy of CTA in determining the blood supply dominance in comparison to standard digital subtraction angiography. Materials and methods Sixty-six patients, with both CTAs and angiograms, were reviewed by two independent neuroradiologists. The posterior cerebral artery was determined to have dominant supply from the posterior communicating artery if it was of similar size to the P2 segment and the P1 segment was smaller by approximately 50%. If the posterior communicating artery and P1 segment were the same size, it was considered to have a dual supply. If P1 and P2 segments were the same caliber and the posterior communicating artery was smaller by 50%, it was deemed to have posterior circulation dominance. Results Based on the findings of our reviewers, CTA had a sensitivity and specificity of 69% and 96%, respectively, in predicting the presence of a fetal PCA. The positive predictive value was found to be 82% while a negative predictive value was estimated as 93%. A small-caliber P1 segment and large-caliber posterior communicating artery led to inaccurate interpretations of the CTAs. Conclusion This study shows that one cannot accurately predict blood supply dominance of the posterior cerebral artery. Knowledge of the blood flow dominance is essential when clipping a posterior communicating artery aneurysm to avoid compromise in posterior circulation.
Design, synthesis, and anti-HIV-1 activity of 1-substituted 3-(3,5-dimethylbenzyl)triazine derivatives
Authors: Sakakibara Norikazu , Balboni Gianfranco , Congiu Cenzo , Onnis Valentina , Demizu Yosuke , Misawa Takashi , Kurihara Masaaki , Kato Yoshihisa , Maruyama Tokumi , Toyama Masaaki , Okamoto Mika , Baba Masanori 
Published: October 2015

Background The reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) is an attractive target for the development of drugs used in the treatment of HIV-1 infection and acquired immune deficiency syndrome (AIDS). We have continued the search for novel anti-HIV-1 agents using the structure–activity relationships of the successful 1,3-disubstituted and 1,3,6-trisubstituted uracil-type HIV-1 RT inhibitors. Methods A series of new triazine analogs were synthesized using an established method. The anti-HIV-1 activities of these compounds were determined based on the inhibition of virus-induced cytopathogenicity in MT-4 cells. The cytotoxicity of the compounds was evaluated by assessing the viability of mock-infected cells. Results Some of the compounds showed good-to-moderate activities against HIV-1, with half-maximal effective concentrations (EC50) in the submicromolar range. In particular, a dihydro-1-(4-aminobenzyl)triazine analog showed satisfactory anti-HIV-1 activity with an EC50 of 0.110 µM and a selectivity index (SI) of 909. Furthermore, molecular modeling analyses were performed to explore the major interactions between HIV-1 RT and potent inhibitors. These results may be important for further development of this class of compounds as anti-HIV-1 agents. Conclusion The satisfactory anti-HIV-1 activity of triazine analogs may serve as the basis for further investigations of the behavior of this class of compounds against drug-resistant mutants.
Anti–miR-148a regulates platelet FcγRIIA signaling and decreases thrombosis in vivo in mice
Authors: Zhou Yuhang , Abraham Shaji , Andre Pierrette , Edelstein Leonard C. , Shaw Chad A. , Dangelmaier Carol A. , Tsygankov Alexander Y. , Kunapuli Satya P. , Bray Paul F. , McKenzie Steven E. 
Published: October 2015

Key PointsTULA-2 negatively regulates platelet FcγRIIA signaling by dephosphorylating Syk. miR-148a targets TULA-2 and inhibition of miR-148a decreases FcγRIIA-mediated platelet activation and thrombosis in vivo.