bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative Expression Analysis Reveals Lineage Relationships between Human and Murine Gliomas and a Dominance of Glial Signatures during Tumor PropagationIn Vitro
Authors: Henriquez Nico V. , Forshew Tim , Tatevossian Ruth , Ellis Matthew , Richard-Loendt Angela , Rogers Hazel , Jacques Thomas S. , Reitboeck Pablo Garcia , Pearce Kerra , Sheer Denise , Grundy Richard G. , Brandner Sebastian 
Published: July 2013

AbstractBrain tumors are thought to originate from stem/progenitor cell populations that acquire specific genetic mutations. Although current preclinical models have relevance to human pathogenesis, most do not recapitulate the histogenesis of the human disease. Recently, a large series of human gliomas and medulloblastomas were analyzed for genetic signatures of prognosis and therapeutic response. Using a mouse model system that generates three distinct types of intrinsic brain tumors, we correlated RNA and protein expression levels with human brain tumors. A combination of genetic mutations and cellular environment during tumor propagation defined the incidence and phenotype of intrinsic murine tumors. Importantly, in vitro passage of cancer stem cells uniformly promoted a glial expression profile in culture and in brain tumors. Gene expression profiling revealed that experimental gliomas corresponded to distinct subclasses of human glioblastoma, whereas experimental supratentorial primitive neuroectodermal tumors (sPNET) correspond to atypical teratoid/rhabdoid tumor (AT/RT), a rare childhood tumor. Cancer Res; 73(18); 5834–44. ©2013 AACR.
KIT Signaling Governs Differential Sensitivity of Mature and Primitive CML Progenitors to Tyrosine Kinase Inhibitors
Authors: Corbin Amie S. , O'Hare Thomas , Gu Zhimin , Kraft Ira L. , Eiring Anna M. , Khorashad Jamshid S. , Pomicter Anthony D. , Zhang Tian Y. , Eide Christopher A. , Manley Paul W. , Cortes Jorge E. , Druker Brian J. , Deininger Michael W. 
Published: July 2013

AbstractImatinib and other BCR-ABL1 inhibitors are effective therapies for chronic myelogenous leukemia (CML), but these inhibitors target additional kinases including KIT, raising the question of whether off-target effects contribute to clinical efficacy. On the basis of its involvement in CML pathogenesis, we hypothesized that KIT may govern responses of CML cells to imatinib. To test this, we assessed the growth of primary CML progenitor cells under conditions of sole BCR-ABL1, sole KIT, and dual BCR-ABL1/KIT inhibition. Sole BCR-ABL1 inhibition suppressed mature CML progenitor cells, but these effects were largely abolished by stem cell factor (SCF) and maximal suppression required dual BCR-ABL1/KIT inhibition. In contrast, KIT inhibition did not add to the effects of BCR-ABL1 inhibition in primitive progenitors, represented by CD34+38− cells. Long-term culture-initiating cell assays on murine stroma revealed profound depletion of primitive CML cells by sole BCR-ABL1 inhibition despite the presence of SCF, suggesting that primitive CML cells are unable to use SCF as a survival factor upon BCR-ABL1 inhibition. In CD34+38+ cells, SCF strongly induced pAKTS473 in a phosphoinositide 3-kinase (PI3K)–dependent manner, which was further enhanced by inhibition of BCR-ABL1 and associated with increased colony survival. In contrast, pAKTS473 levels remained low in CD34+38− cells cultured under the same conditions. Consistent with reduced response to SCF, KIT surface expression was significantly lower on CD34+38− compared with CD34+38+ CML cells, suggesting a possible mechanism for the differential effects of SCF on mature and primitive CML progenitor cells. Cancer Res; 73(18); 5775–86. ©2013 AACR.
Dacarbazine in Solitary Fibrous Tumor: A Case Series Analysis and Preclinical Evidence vis-à-vis Temozolomide and Antiangiogenics
Authors: Stacchiotti S. , Tortoreto M. , Bozzi F. , Tamborini E. , Morosi C. , Messina A. , Libertini M. , Palassini E. , Cominetti D. , Negri T. , Gronchi A. , Pilotti S. , Zaffaroni N. , Casali P.G. 
Published: July 2013

Abstract
Purpose: To explore the value of triazines in solitary fibrous tumor (SFT).
Experimental Design: We retrospectively reviewed 8 cases of patients with SFT treated with dacarbazine (1,200 mg/m2 every 3 weeks) as from January 2012. Then, we studied a dedifferentiated-SFT subcutaneously xenotransplanted into severe combined immunodeficient (SCID) mice. Dacarbazine, temozolomide, sunitinib, bevacizumab, and pazopanib were administered at their reported optimal doses for the mouse model when mean tumor volume (TV) was about 80 mm3; each experimental groups included 6 mice. Drug activity was assessed as tumor volume inhibition percentage (TVI%). Dacarbazine was tested according to two different schedules of administration. One hunded twenty days after treatment interruption, mouse tumor samples were analyzed.
Results: Among the eight patients treated with dacarbazine, best response evaluation criteria in solid tumors responses (RECIST) were three partial responses, 4 stable disease, 1 progression. Two responsive patients had paraneoplastic hypoglycemia that disappeared after 10 days from starting dacarbazine. In the dedifferentiated-SFT xenograft model, dacarbazine and temozolomide showed the highest antitumor activity (about 95% TVI), confirmed pathologically. Sunitinib and pazopanib were only marginally active (52% and 41% TVI, respectively), whereas bevacizumab caused a 78% TVI. No tumor regrowth was observed up to 100 days from end of treatment with temozolomide and dacarbazine, whereas secondary progression followed sunitinib, pazopanib, and bevacizumab interruption.
Conclusions: Dacarbazine as single agent has antitumor activity in SFT. Our preclinical results suggest a cytotoxic effect of temozolomide and dacarbazine, as compared with a cytostatic role for sunitinib, pazopanib, and bevacizumab. A phase II study on dacarbazine in advanced SFT is planned. Clin Cancer Res; 19(18); 5192–201. ©2013 AACR.
PIK3CA and AKT1 Mutations Have Distinct Effects on Sensitivity to Targeted Pathway Inhibitors in an Isogenic Luminal Breast Cancer Model System
Authors: Beaver Julia A. , Gustin John P. , Yi Kyung H. , Rajpurohit Anandita , Thomas Matthew , Gilbert Samuel F. , Rosen D. Marc , Ho Park Ben , Lauring Josh 
Published: July 2013

Abstract
Purpose: Activating mutations in the phosphoinositide-3-kinase (PI3K)/AKT/mTOR pathway are present in the majority of breast cancers and therefore are a major focus of drug development and clinical trials. Pathway mutations have been proposed as predictive biomarkers for efficacy of PI3K-targeted therapies. However, the precise contribution of distinct PI3K pathway mutations to drug sensitivity is unknown.
Experimental Design: We describe the creation of a physiologic human luminal breast cancer cell line model to study the phenotype of these mutations using the MCF-7 cell line. We used somatic cell gene targeting to “correct” PIK3CA E545K-mutant alleles in MCF-7 cells to wild-type sequence. The AKT1 E17K hotspot mutation was knocked in on this wild-type background.
Results: Loss of mutant PIK3CA dramatically reduced phosphorylation of AKT proteins and several known AKT targets, but other AKT target proteins and downstream effectors of mTOR were not affected. PIK3CA wild-type cells exhibited reduced proliferation in vitro and in vivo. Knockin of the AKT1 E17K hotspot mutation on this PIK3CA wild-type background restored pathway signaling, proliferation, and tumor growth in vivo. PIK3CA, but not AKT1 mutation, increased sensitivity to the PI3K inhibitor GDC-0941 and the allosteric AKT inhibitor MK-2206.
Conclusions: AKT1 E17K is a bona fide oncogene in a human luminal breast cancer context. Distinct PI3K pathway mutations confer differential sensitivity to drugs targeting the pathway at different points and by distinct mechanisms. These findings have implications for the use of tumor genome sequencing to assign patients to targeted therapies. Clin Cancer Res; 19(19); 5413–22. ©2013 AACR.
Ligand-Dependent Activation of EGFR in Follicular Dendritic Cells Sarcoma is Sustained by Local Production of Cognate Ligands
Authors: Vermi William , Giurisato Emanuele , Lonardi Silvia , Balzarini Piera , Rossi Elisa , Medicina Daniela , Bosisio Daniela , Sozzani Silvano , Pellegrini Wilma , Doglioni Claudio , Marchetti Antonio , Rossi Giulio , Pileri Stefano , Facchetti Fabio 
Published: July 2013

Abstract
Purpose: The aim of this study was to investigate the biological and clinical significance of epidermal growth factor receptor (EGFR) signaling pathway in follicular dendritic cell sarcoma (FDC-S).
Experimental Design: Expression of EGFR and cognate ligands as well as activation of EGFR signaling components was assessed in clinical samples and in a primary FDC-S short-term culture (referred as FDC-AM09). Biological effects of the EGFR antagonists cetuximab and panitumumab and the MEK inhibitor UO126 on FDC-S cells were determined in vitro on FDC-AM09. Direct sequencing of KRAS, BRAF, and PI3KCA was conducted on tumor DNA.
Results: We found a strong EGFR expression on dysplastic and neoplastic FDCs. On FDC-AM09, we could show that engagement of surface EGFR by cognate ligands drives the survival and proliferation of FDC-S cells, by signaling to the nucleus mainly via MAPK and STAT pathways. Among EGFR ligands, heparin-binding EGF-like growth factor, TGF-α and Betacellulin (BTC) are produced in the tumor microenvironment of FDC-S at RNA level. By extending this finding at protein level we found that BTC is abundantly produced by FDC-S cells and surrounding stromal cells. Finally, direct sequencing of tumor-derived genomic DNA showed that mutations in KRAS, NRAS, BRAF, and PI3KCA, which predicts resistance to anti-EGFR MoAb in other cancer models, are not observed in FDC-S.
Conclusion: Activation of EGFR by cognate ligands produced in the tumor microenvironment sustain viability and proliferation of FDC-S indicating that the receptor blockade might be clinically relevant in this neoplasm. Clin Cancer Res; 19(18); 5027–38. ©2013 AACR.
β1-Integrin Is Essential for Vasoregulation and Smooth Muscle Survival In Vivo
Authors: Turlo Kirsten A. , Scapa Jason , Bagher Pooneh , Jones Allan W. , Feil Robert , Korthuis Ronald J. , Segal Steven S. , Iruela-Arispe M. Luisa 
Published: July 2013

Objective—
Integrins contribute to vascular morphogenesis through regulation of adhesion and assembly of the extracellular matrix. However, the role of β1-integrin in the mature vascular wall is less clear.

Approach and Results—
We sought to determine the function of β1-integrin in mature smooth muscle cells in vivo using a loss of function approach by crossing a tamoxifen-inducible sm22αCre line to a floxed β1-integrin transgenic line. Adult mice lacking smooth muscle β1-integrin survived only 10 weeks post induction. The deletion of β1-integrin resulted in profound loss of vasomotor control. Histological analysis revealed progressive fibrosis in arteries with associated apoptosis of smooth muscle cells, which was not rescued by adventitial stem cells. Smooth muscle cell apoptosis was detected in arteries with dead cells replaced primarily by collagen. Despite the catastrophic effects on vascular smooth muscle, the deleted visceral smooth muscle remained viable with the exception of a short portion of the colon, indicating that vascular but not visceral smooth muscle is particularly sensitive to changes in β1-integrin.

Conclusions—
This study reveals an essential function of β1-integrin in the maintenance of vasomotor control and highlights a critical role for β1-integrin in vascular, but not visceral, smooth muscle survival.
Pharmacological Inhibition of the Chemokine Receptor, CX3CR1, Reduces Atherosclerosis in Mice
Authors: Poupel Lucie , Boissonnas Alexandre , Hermand Patricia , Dorgham Karim , Guyon Elodie , Auvynet Constance , Charles Flora Saint , Lesnik Philippe , Deterre Philippe , Combadiere Christophe 
Published: July 2013

Objective—
Alterations of the chemokine receptor CX3CR1 gene were associated with a reduced risk of myocardial infarction in human and limited atherosclerosis in mice. In this study, we addressed whether CX3CR1 antagonists are potential therapeutic tools to limit acute and chronic inflammatory processes in atherosclerosis.

Approach and Results—

Treatment with F1, an amino terminus–modified CX3CR1 ligand endowed with CX3CR1 antagonist activity, reduced the extent of atherosclerotic lesions in both
Apoe
−/−
and
Ldlr
−/−
proatherogenic mouse models. Macrophage accumulation in the aortic sinus was reduced in F1-treated
Apoe
−/−
mice but the macrophage density of the lesions was similar in F1-treated and control mice. Both in vitro and in vivo F1 treatment reduced CX3CR1-dependent inflammatory monocyte adhesion, potentially limiting their recruitment. In addition, F1-treated
Apoe
−/−
mice displayed reduced numbers of blood inflammatory monocytes, whereas resident monocyte numbers remained unchanged. Both in vitro and in vivo F1 treatment reduced CX3CR1-dependent inflammatory monocyte survival. Finally, F1 treatment of
Apoe
−/−
mice with advanced atherosclerosis led to smaller lesions than untreated mice but without reverting to the initial phenotype.

Conclusions—
The CX3CR1 antagonist F1 is a potent inhibitor of the progression of atherosclerotic lesions by means of its selective impact on inflammatory monocyte functions. Controlling monocyte trafficking and survival may be an alternative or complementary therapy to lipid-lowering drugs classically used in the treatment of atherosclerosis.
Sirolimus-FKBP12.6 Impairs Endothelial Barrier Function Through Protein Kinase C-α Activation and Disruption of the p120–Vascular Endothelial Cadherin Interaction
Authors: Habib Anwer , Karmali Vinit , Polavarapu Rohini , Akahori Hirokuni , Cheng Qi , Pachura Kim , Kolodgie Frank D. , Finn Aloke V. 
Published: July 2013

Objective—
Sirolimus (SRL) is an immunosuppressant drug used to prevent rejection in organ transplantation and neointimal hyperplasia when delivered from drug-eluting stents. Major side effects of SRL include edema and local collection of intimal lipid deposits at drug-eluting stent sites, suggesting that SRL impairs endothelial barrier function (EBF). The aim of this study was to address the role of SRL on impaired EBF and the potential mechanisms involved.

Approach and Results—
Cultured human aortic endothelial cells (HAECs) and intact human and mouse endothelium was examined to determine the effect of SRL, which binds FKBP12.6 to inhibit the mammalian target of rapamycin, on EBF. EBF, measured by transendothelial electrical resistance, was impaired in HAECs when treated with SRL or small interfering RNA for FKBP12.6 and reversed when pretreated with ryanodine, a stabilizer of ryanodine receptor 2 intracellular calcium release channels. Intracellular calcium increased in HAECs treated with SRL and normalized with ryanodine pretreatment. SRL-treated HAECs demonstrated increases in protein kinase C-α phosphorylation, a calcium sensitive serine/threonine kinase important in vascular endothelial (VE) cadherin barrier function through its interaction with p120-catenin (p120). Immunostaining of HAECs, human coronary and mouse aortic endothelium treated with SRL showed disruption of p120–VE cadherin interaction treated with SRL. SRL impairment of HAEC EBF was reduced with protein kinase C-α small interfering RNA. Mice treated with SRL demonstrated increased vascular permeability by Evans blue albumin extravasation in the lungs, heart, and aorta.

Conclusions—
SRL-FKBP12.6 impairs EBF by activation of protein kinase C-α and downstream disruption of the p120–VE cadherin interaction in vascular endothelium. These data suggest this mechanism may be an important contributor of SRL side effects related to impaired EBF.
Improving Survival Rates of Patients With Idiopathic Dilated Cardiomyopathy in Tuscany Over 3 Decades
Authors: Castelli Gabriele , Fornaro Alessandra , Ciaccheri Mauro , Dolara Alberto , Troiani Vito , Tomberli Benedetta , Olivotto Iacopo , Gensini Gian Franco 
Published: July 2013

Background—
Contemporary therapeutic options have led to substantial improvement in survival of patients with heart failure. However, limited evidence is available specifically on idiopathic dilated cardiomyopathy. We thus examined changes in prognosis of a large idiopathic dilated cardiomyopathy cohort systematically followed during the past 30 years.

Methods and Results—

From 1977 to 2011, 603 consecutive patients (age, 53±12 years; 73% men; left ventricular ejection fraction, 32±10%) fulfilling World Health Organization criteria for idiopathic dilated cardiomyopathy, including negative coronary angiography, were followed up for 8.8±6.3 years. Patients were subdivided in 4 enrollment periods on the basis of heart failure treatment eras: (1) 1977–1984 (n=66); (2) 1985–1990 (n=102); (3) 1991–2000 (n=197); (4) 2001–2011 (n=238). Rates of patients receiving angiotensin-converting enzyme inhibitors/angiotensin receptors blockers, β-blockers, and devices at final evaluation increased from 56%, 12%, 8% (period 1) to 97%, 86%, 17% (period 4), respectively (
P
<0.05). There was a trend toward enrollment of older patients with less severe left ventricular dilatation and dysfunction during the years. During follow-up, 271 patients (45%) reached a combined end point including death (heart failure related, n=142; sudden death, n=71; and noncardiac, n=22) or cardiac transplant (n=36). A more recent enrollment period represented the most powerful independent predictor of favorable outcome {period 2 versus 1 (hazard ratio [HR], 0.64;
P
=0.04), period 3 versus 1 (HR, 0.35;
P
<0.001), period 4 versus 1 (HR, 0.14;
P
<001)}. Each period was associated with a 42% risk reduction versus the previous one (HR, 0.58; 95% confidence interval, 0.50–0.67;
P
<0.001), reflecting marked decreases in heart failure–related mortality and sudden death (period 4 versus 1: HR, 0.10;
P
<001 and HR, 0.13;
P
<0.0001, respectively).

Conclusions—
Evidence-based treatment has led to dramatic improvement in the prognosis of idiopathic dilated cardiomyopathy during the past 3 decades. The benefits of controlled randomized trials can be replicated in the real world, emphasizing the importance of tailored follow-up and long-term continuity of care.
Relationship Between Onset-to-Door Time and Door-to-Thrombolysis Time
Authors: Strbian Daniel , Michel Patrik , Ringleb Peter , Numminen Heikki , Breuer Lorenz , Bodenant Marie , Seiffge David J. , Jung Simon , Obach Victor , Weder Bruno , Tiainen Marjaana , Eskandari Ashraf , Gumbinger Christoph , Gensicke Henrik , Chamorro Angel , Mattle Heinrich P. , Engelter Stefan T. , Leys Didier , Köhrmann Martin , Parkkila Anna-Kaisa , Hacke Werner , Tatlisumak Turgut 
Published: July 2013

Background and Purpose—
Inverse relationship between onset-to-door time (ODT) and door-to-needle time (DNT) in stroke thrombolysis was reported from various registries. We analyzed this relationship and other determinants of DNT in dedicated stroke centers.

Methods—
Prospectively collected data of consecutive ischemic stroke patients from 10 centers who received IV thrombolysis within 4.5 hours from symptom onset were merged (n=7106). DNT was analyzed as a function of demographic and prehospital variables using regression analyses, and change over time was considered.

Results—

In 6348 eligible patients with known treatment delays, median DNT was 42 minutes and kept decreasing steeply every year (
P
<0.001). Median DNT of 55 minutes was observed in patients with ODT ≤30 minutes, whereas it declined for patients presenting within the last 30 minutes of the 3-hour time window (median, 33 minutes) and of the 4.5-hour time window (20 minutes). For ODT within the first 30 minutes of the extended time window (181–210 minutes), DNT increased to 42 minutes. DNT was stable for ODT for 30 to 150 minutes (40–45 minutes). We found a weak inverse overall correlation between ODT and DNT (
R
2
=−0.12;
P
<0.001), but it was strong in patients treated between 3 and 4.5 hours (
R
2
=−0.75;
P
<0.001). ODT was independently inversely associated with DNT (
P
<0.001) in regression analysis. Octogenarians and women tended to have longer DNT.

Conclusions—
DNT was decreasing steeply over the last years in dedicated stroke centers; however, significant oscillations of in-hospital treatment delays occurred at both ends of the time window. This suggests that further improvements can be achieved, particularly in the elderly.
Prognostic Evaluation Based on Cortical Vein Score Difference in Stroke
Authors: Parthasarathy Rajsrinivas , Kate Mahesh , Rempel Jeremy L. , Liebeskind David S. , Jeerakathil Thomas , Butcher Kenneth S. , Shuaib Ashfaq 
Published: July 2013

Background and Purpose—
Multimodal imaging in acute ischemic stroke defines the extent of arterial collaterals, resultant penumbra, and associated infarct core, yet limitations abound. We identified superficial and deep venous drainage patterns that predict outcomes in patients with a proximal arterial occlusion of the anterior circulation.

Methods—
An observational study that used computed tomography (CT) angiography to detail venous drainage in a consecutive series of patients with a proximal anterior circulation arterial occlusion. The principal veins that drain the cortex (superficial middle cerebral, vein of Trolard, vein of Labbé, and basal vein of Rosenthal) and deep structures were scored with a categorical scale on the basis of degree of contrast enhancement. The Prognostic Evaluation based on Cortical vein score difference In Stroke score encompassing the interhemispheric difference of the composite scores of the veins draining the cortices (superficial middle cerebral+vein of Trolard+vein of Labbé+basal vein of Rosenthal) was analyzed with respect to 90-day modified Rankin Scale outcomes.

Results—

Thirty-nine patients were included in the study. A Prognostic Evaluation based on Cortical vein score difference In Stroke score of 4 to 8 accurately predicted poor outcomes (modified Rankin Scale, 3–6; odds ratio, 20.53;
P
<0.001). On stepwise logistic regression analyses adjusted for CT Alberta stroke program early CT score, CT angiography collateral grading and National Institutes of Health Stroke Scale score, a Prognostic Evaluation based on Cortical vein score difference In Stroke score of 4 to 8 (odds ratio, 23.598;
P
=0.009) and an elevated admission National Institutes of Health Stroke Scale (odds ratio, 1.423;
P
=0.023) were independent predictors of poor outcome.

Conclusions—
The Prognostic Evaluation based on Cortical vein score difference In Stroke score, a novel measure of venous enhancement on CT angiography, accurately predicts clinical outcomes. Venous features on computed tomography angiography provide additional characterization of collateral perfusion and prognostication in acute ischemic stroke.