bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clonal Relationship of Classical Hodgkin Lymphoma and Its Recurrences
Authors: Obermann Ellen C. , Mueller Nadine , Rufle Alexander , Menter Thomas , Mueller-Garamvoelgyi Esther , Cathomas Gieri , Dirnhofer Stephan , Tzankov Alexandar 
Published: July 2011

Abstract
Purpose: We investigated whether the first and all subsequent manifestations of Hodgkin lymphoma (HL) in a patient are clonally related.
Experimental Design: We identified a collective of 20 patients with sometimes multiple HL recurrences. Relapses were classified as early, that is, within twelve months (eight events in seven patients) or as late, that is, later than one year after the previous neoplasm (24 events in 17 patients). Hodgkin and Reed–Sternberg cells were microdissected after CD30 staining using laser capture technique. Immunoglobulin heavy chain (IgH) gene fragment lengths were analyzed after DNA preamplification, applying consensus FR3 and J primers by ABI 310 Genetic Analyzer. Sequencing of the amplified IgH products was carried out by ABI 3130 and 3730XL Genetic Analyzer. Epstein-Barr virus (EBV) association was assessed by EBV early RNA and LMP1.
Results: Three cases with early relapses after a first HL diagnosis were clonally related to the initial tumor, whereas three of four patients with early relapses after a first or second relapse were not, which was accompanied by change of EBV association in one case. Six patients presenting with late relapses were clonally unrelated, which was accompanied by change of phenotype in two cases and change of EBV association in one case. Two samples from recurrent tumors of the same patient could be successfully sequenced. These two late relapses were clonally unrelated by IgH fragment length and sequencing analysis.
Conclusions: Recurrent HL, especially those accompanied by an EBV-association switch or after a relapse, can represent an unrelated novel neoplasm. Our finding might play a role in clinical decision making. Clin Cancer Res; 17(16); 5268–74. ©2011 AACR.
XPF Expression Correlates with Clinical Outcome in Squamous Cell Carcinoma of the Head and Neck
Authors: Vaezi Alec , Wang XiaoZhe , Buch Shama , Gooding William , Wang Lin , Seethala Raja R. , Weaver David T. , D'Andrea Alan D. , Argiris Athanassios , Romkes Marjorie , Niedernhofer Laura J. , Grandis Jennifer R. 
Published: July 2011

Abstract
Purpose: Tumor-specific biomarkers that predict resistance to DNA damaging agents may improve therapeutic outcomes by guiding the selection of effective therapies and limiting morbidity related to ineffective approaches. XPF (ERCC4) is an essential component of several DNA repair pathways and XPF-deficient cells are exquisitely sensitive to DNA damaging agents. The purpose of this study was to determine whether XPF expression levels predict clinical response to DNA damaging agents in head and neck squamous cell carcinoma (HNSCC).
Experimental Design: Quantitative immunohistochemistry was used to measure XPF expression in tumors from a cohort of 80 patients with newly diagnosed HNSCC treated with radiation therapy with or without platinum-based chemotherapy; samples were collected prospectively. Genomic DNA isolated from blood samples was analyzed for nine single nucleotide polymorphisms (SNP) in the XPF gene by using a custom array. The primary endpoint was progression-free survival (PFS).
Results: XPF expression was higher in tumors from the oral cavity than from the other sites (P &lt; 0.01). High XPF expression correlated with early time to progression both by univariate (HR = 1.87, P = 0.03) and multivariate analysis (HR = 1.83, P = 0.05). The one year PFS for high expressers was 47% (95% CI = 31–62) compared with 72% (95% CI = 55–83) for low expressers. In addition, we identified four XPF SNPs that showed marginal association with treatment failure.
Conclusions: Expression level of XPF in HNSCC tumors correlates with clinical response to DNA damaging agents. XPF has potential to guide next generation personalized cancer therapy. Clin Cancer Res; 17(16); 5513–22. ©2011 AACR.
Determinants of Successful CD8+ T-Cell Adoptive Immunotherapy for Large Established Tumors in Mice
Authors: Klebanoff Christopher A. , Gattinoni Luca , Palmer Douglas C. , Muranski Pawel , Ji Yun , Hinrichs Christian S. , Borman Zachary A. , Kerkar Sid P. , Scott Christopher D. , Finkelstein Steven E. , Rosenberg Steven A. , Restifo Nicholas P. 
Published: July 2011

Abstract
Purpose: Adoptive cell transfer (ACT) of tumor infiltrating or genetically engineered T cells can cause durable responses in patients with metastatic cancer. Multiple clinically modifiable parameters can comprise this therapy, including cell dose and phenotype, in vivo antigen restimulation, and common gamma-chain (γc) cytokine support. However, the relative contributions of each these individual components to the magnitude of the antitumor response have yet to be quantified.
Experimental Design: To systematically and quantitatively appraise each of these variables, we employed the Pmel-1 mouse model treating large, established B16 melanoma tumors. In addition to cell dose and magnitude of in vivo antigen restimulation, we also evaluated the relative efficacy of central memory (TCM), effector memory (TEM), and stem cell memory (TSCM) subsets on the strength of tumor regression as well as the dose and type of clinically available γc cytokines, including IL-2, IL-7, IL-15, and IL-21.
Results: We found that cell dose, T-cell differentiation status, and viral vaccine titer each were correlated strongly and significantly with the magnitude of tumor regression. Surprisingly, although the total number of IL-2 doses was correlated with tumor regression, no significant benefit to prolonged (≥6 doses) administration was observed. Moreover, the specific type and dose of γc cytokine only moderately correlated with response.
Conclusion: Collectively, these findings elucidate some of the key determinants of successful ACT immunotherapy for the treatment of cancer in mice and further show that γc cytokines offer a similar ability to effectively drive antitumor T-cell function in vivo. Clin Cancer Res; 17(16); 5343–52. ©2011 AACR.
The Novel HSP90 Inhibitor, IPI-493, Is Highly Effective in Human Gastrostrointestinal Stromal Tumor Xenografts Carrying Heterogeneous KIT Mutations
Authors: Floris Giuseppe , Sciot Raf , Wozniak Agnieszka , Van Looy Thomas , Wellens Jasmien , Faa Gavino , Normant Emmanuel , Debiec-Rychter Maria , Schöffski Patrick 
Published: July 2011

Abstract
Purpose: KIT activity is crucial for gastrointestinal stromal tumors (GIST). Imatinib (IMA) and sunitinib (SUN) are very effective KIT-inhibitors in patients with advanced GIST but have no curative potential. We evaluated the efficacy of the novel HSP90 inhibitor IPI-493 alone, or in combination with IMA or SUN in GIST xenografts with KIT mutations.
Experimental Design: Nude mice (n = 98) were grafted bilaterally with human GIST carrying KIT exon 11 (GIST-PSW), KIT exon 9 (GIST-BOE), or double, KIT imatinib-sensitive exon 11 and imatinib-resistant exon 17 mutations (GIST-48). Mice were divided into six treatment groups and dosed orally for 15 days as follows: (i) control group, sterile water; (ii) IMA alone; (iii) SUN alone; (iv) IPI-493 alone; (v) IPI-493+IMA; and (vi) IPI-493+SUN.
Results: Treatment with IPI-493 resulted in tumor growth stabilization, variable proliferation arrest, induction of apoptosis and necrosis, and downregulation of KIT and its signaling cascade, especially in the GIST-BOE model. Significant reduction of vessel density was observed with IPI-493 treatment, and was equal to SUN treatment in GIST-PSW and GIST-BOE xenografts. IPI-493 treatment effects were enhanced in combination with TKIs, especially with IPI-493+SUN. In our hands, IPI-493 showed dose-dependent liver damages.
Conclusions: When administered as a single agent in a xenograft model, the HSP90 inhibitor IPI-493 has consistent antitumor activity and induces KIT downregulation in GISTs with heterogeneous KIT mutations. IPI-493 synergizes with TKIs that are commonly used for the treatment of advanced or IMA-resistant GIST. The antitumor response of IPI-493 is particularly enhanced in combination with SUN. Clin Cancer Res; 17(17); 5604–14. ©2011 AACR.
Anti-VEGF Treatment–Resistant Pancreatic Cancers Secrete Proinflammatory Factors That Contribute to Malignant Progression by Inducing an EMT Cell Phenotype
Authors: Carbone Carmine , Moccia Tania , Zhu Cihui , Paradiso Genni , Budillon Alfredo , Chiao Paul J. , Abbruzzese James L. , Melisi Davide 
Published: July 2011

Abstract
Purpose: The resistance of tumors to antiangiogenic therapies is becoming increasingly relevant. There are currently no validated predictive biomarkers for selecting which cancer patients will benefit from antiangiogenic therapy. Also lacking are resistance biomarkers that can identify which escape pathways should be targeted after tumors develop resistance to VEGF treatment. Recent studies showed that anti-VEGF treatment can make tumor cells more aggressive and metastatic. However, the mechanisms and mediators of this are unidentified. Therefore, we aimed this study at directly identifying the tumor cell–initiated mechanisms responsible for the resistance of pancreatic cancer to anti-VEGF treatment.
Experimental Design: We established and validated two murine models of human pancreatic cancer resistant to the VEGF-specific antibody bevacizumab in vivo. We used a genome-wide analysis to directly identify which tumor-secreted factors were overexpressed by pancreatic cancer cells that were resistant to anti-VEGF treatment.
Results: Rather than direct proangiogenic factors, we identified several proinflammatory factors that were expressed at higher levels in cells resistant to anti-VEGF treatment than in treatment-sensitive control cells. These proinflammatory factors acted in a paracrine manner to stimulate the recruitment of CD11b+ proangiogenic myeloid cells. Also, we found that secreted factors overexpressed by anti-VEGF treatment-resistant pancreatic cancer cells acted in an autocrine manner to induce epithelial-to-mesenchymal transition (EMT) and were thus responsible for increased aggressiveness of bevacizumab-resistant pancreatic tumors.
Conclusions: Our results identified proinflammatory factors and EMT markers as potential biomarkers for selecting patients with pancreatic cancer for antiangiogenic therapy. Clin Cancer Res; 17(17); 5822–32. ©2011 AACR.
Lytic Resistance of Fibrin Containing Red Blood Cells
Authors: Wohner Nikolett , Sótonyi Péter , Machovich Raymund , Szabó László , Tenekedjiev Kiril , Silva Marta M.C.G. , Longstaff Colin , Kolev Krasimir 
Published: July 2011

Objective—
Arterial thrombi contain variable amounts of red blood cells (RBCs), which interact with fibrinogen through an eptifibatide-sensitive receptor and modify the structure of fibrin. In this study, we evaluated the modulator role of RBCs in the lytic susceptibility of fibrin.

Methods and Results—
If fibrin is formed at increasing RBC counts, scanning electron microscopy evidenced a decrease in fiber diameter from 150 to 96 nm at 40% (v/v) RBCs, an effect susceptible to eptifibatide inhibition (restoring 140 nm diameter). RBCs prolonged the lysis time in a homogeneous-phase fibrinolytic assay with tissue plasminogen activator (tPA) by up to 22.7±1.6%, but not in the presence of eptifibatide. Confocal laser microscopy using green fluorescent protein–labeled tPA and orange fluorescent fibrin showed that 20% to 40% (v/v) RBCs significantly slowed down the dissolution of the clots. The fluorescent tPA variant did not accumulate on the surface of fibrin containing RBCs at any cell count above 10%. The presence of RBCs in the clot suppressed the tPA-induced plasminogen activation, resulting in 45% less plasmin generated after 30 minutes of activation at 40% (v/v) RBCs.

Conclusion—
RBCs confer lytic resistance to fibrin resulting from modified fibrin structure and impaired plasminogen activation through a mechanism that involves eptifibatide-sensitive fibrinogen-RBC interactions.
Bone Morphogenetic Protein Endothelial Cell Precursor–Derived Regulator Regulates Retinal Angiogenesis In Vivo in a Mouse Model of Oxygen-Induced Retinopathy
Authors: Moreno-Miralles Isabel , Ren Rongqin , Moser Martin , Hartnett Mary Elizabeth , Patterson Cam 
Published: July 2011

Objective—
Bone morphogenetic proteins (BMPs) are potently proangiogenic; however, the mechanisms underlying the regulation of vessel development by BMPs are not fully understood. To assess the significance of BMP endothelial cell precursor-derived regulator (BMPER) in blood vessel formation in vivo, we investigated its role in retinal angiogenesis.

Methods and Results—

In a model of oxygen-induced retinopathy,
Bmper
mRNA expression and protein levels are downregulated, correlating with the initiation of Sma and Mad related protein phosphorylation in endothelial cells. Moreover,
Bmper
haploinsufficiency results in an increased rate of retinal revascularization, with retinas from
Bmper
+/− mice displaying increased numbers of branching points and angiogenic sprouts at the leading edge of the newly formed vasculature. Furthermore, although
Bmper
haploinsufficiency does not alter
Bmp
expression, it does lead to an increase in BMP signaling, as evidenced by increased phosphorylated Sma and Mad related protein levels in endothelial cells and increased expression of known BMP target genes.

Conclusion—
These observations provide compelling evidence that BMPER is important in the regulation of BMP signaling and revascularization in the hypoxic retina. These bring forth the possibility of novel therapeutic approaches for pathological angiogenesis based on manipulation of BMP signaling.
Pericyte-Derived MFG-E8 Regulates Pathologic Angiogenesis
Authors: Motegi Sei-ichiro , Leitner Wolfgang W. , Lu Michael , Tada Yayoi , Sárdy Miklós , Wu Chuanjin , Chavakis Triantafyllos , Udey Mark C. 
Published: July 2011

Objective—
MFG-E8 (also called lactadherin and SED1) is a secreted glycoprotein that has been previously implicated in enhancement of vascular endothelial growth factor–dependent angiogenesis. Major sources of MFG-E8 in vivo and precise mechanisms of MFG-E8 action remain undetermined. The objective of this study was to identify important sources of MFG-E8 in vivo and further elucidate the role(s) of MFG-E8 in the regulation of angiogenesis.

Methods and Results—
We used knockout mice and anti-MFG-E8 antibodies to study MFG-E8 function in vivo. In melanomas and in retinas of mice with oxygen-induced retinopathy, MFG-E8 colocalized with pericytes rather than endothelial cells, and platelet-derived growth factor receptor β+ pericytes/pericyte precursors purified from tumors contained large amounts of MFG-E8 mRNA. Tumor- and retinopathy-associated angiogenesis was diminished in MFG-E8 knockout mice, and pericyte coverage of neovessels was reduced. Inhibition of MFG-E8 production by 10T1/2 cells (surrogate pericyte/pericyte precursors) using small interfering RNAs and short hairpin RNAs, or inhibition of MFG-E8 action with some anti-MFG-E8 antibodies, selectively attenuated migration in vitro. Significantly, the anti-MFG-E8 antibodies that inhibited 10T1/2 cell migration in vitro also inhibited pathological angiogenesis in vivo.

Conclusion—
These studies strongly implicate MFG-E8 in pericyte/pericyte precursor function and indicate that MFG-E8-directed therapeutics may merit further development.
Induction of Smooth Muscle Cell Migration During Arteriogenesis Is Mediated by Rap2
Authors: Pöling Jochen , Szibor Marten , Schimanski Silvia , Ingelmann Marie-Elisabeth , Rees Wolfgang , Gajawada Praveen , Kochfar Zaber , Lörchner Holger , Salwig Isabelle , Shin Jae-Young , Wiebe Karsten , Kubin Thomas , Warnecke Henning , Braun Thomas 
Published: July 2011

Objective—
Collateral artery growth or arteriogenesis is the primary means of the circulatory system to maintain blood flow in the face of major arterial occlusions. Arteriogenesis depends on activation of fibroblast growth factor (FGF) receptors, but relatively little is known about downstream mediators of FGF signaling.

Methods and Results—
We screened for signaling components that are activated in response to administration of FGF-2 to cultured vascular smooth muscle cells (VSMCs) and detected a significant increase of Rap2 but not of other Ras family members, which corresponded to a strong upregulation of Rap2 and C-Raf in growing collaterals from rabbits with femoral artery occlusion. Small interfering RNAs directed against Rap2 did not affect FGF-2 induced proliferation of VSMC but strongly inhibited their migration. Inhibition of FGF receptor-1 (FGFR1) signaling by infusion of a sulfonic acid polymer or infection with a dominant-negative FGFR1 adenovirus inhibited Rap2 upregulation and collateral vessel growth. Similarly, expression of dominant-negative Rap2 blocked arteriogenesis, whereas constitutive active Rap2 enhanced collateral vessel growth.

Conclusion—
Rap2 is part of the arteriogenic program and acts downstream of the FGFR1 to stimulate VSMC migration. Specific modulation of Rap2 might be an attractive target to manipulate VSMC migration, which plays a role in numerous pathological processes.
Intravenous Thrombolysis of Basilar Artery Occlusion
Authors: Sairanen Tiina , Strbian Daniel , Soinne Lauri , Silvennoinen Heli , Salonen Oili , Artto Ville , Koskela Ilkka , Häppölä Olli , Kaste Markku , Lindsberg Perttu J. ,   for the Helsinki Stroke Thrombolysis Registry (HSTR) Group
Published: July 2011

Background and Purpose—
Basilar artery occlusion has a high mortality rate (85% to 95%) if untreated. We describe a large single-center cohort treated mostly with intravenous alteplase and heparin.

Methods—
The cohort included 116 patients with angiography-verified basilar artery occlusion. We studied baseline characteristics, frequencies of recanalization and symptomatic intracranial hemorrhage, and 3-month outcome (modified Rankin Scale [mRS]).

Results—

Thirty patients (25.9%) had mRS 0 to 2, 42 patients (36.2%) had moderate outcome (mRS, 0–3), 26 patients (22.4%) required daily help (mRS, 4–5), and 48 patients (41.4%) died. Eighteen patients (15.7%) developed symptomatic intracranial hemorrhage. In patients with post-treatment angiogram available (n=91), 59 patients (64.8%) had a complete or partial recanalization. Radiological location of basilar artery occlusion was known in 55 of 91 instances, and recanalization was associated directly with clot location at the top-of-basilar (odds ratio, 4.8 [1.1–22];
P
=0.048). Independent outcome (mRS 0-2) was associated with lower age and National Institutes of Health Stroke Scale (NIHSS) score at baseline. Age, nil or minimal recanalization, and symptomatic intracranial hemorrhage were independently associated with fatal outcome. Sixteen of 71 patients (22.5%) who presented with coma eventually reached moderate outcome, and additional 8 patients (11.3%) progressed to mRS 4.

Conclusions—
Whereas recanalization after intravenous thrombolysis strongly predicts survival and moderate outcome, therapeutic techniques should concentrate on clot location. Although most adverse baseline variables, age, symptom severity, but also coma are beyond control, it should not preclude thrombolysis, which may permit independent survival.
Programmed Death-1 Pathway Limits Central Nervous System Inflammation and Neurologic Deficits in Murine Experimental Stroke
Authors: Ren Xuefang , Akiyoshi Kozaburo , Vandenbark Arthur A. , Hurn Patricia D. , Offner Halina 
Published: July 2011

Background and Purpose—
Evaluation of infarct volumes and infiltrating immune cell populations in mice after middle cerebral artery occlusion strongly implicates a mixture of both pathogenic and regulatory immune cell subsets that affect stroke outcome. Our goal was to evaluate the contribution of the well-described coinhibitory pathway, programmed death (PD)-1, to the development of middle cerebral artery occlusion.

Methods—
Infarct volumes, functional outcomes, and effects on infiltrating immune cell populations were compared in wild-type C57BL/6 versus PD-1-deficient mice after 60 minutes middle cerebral artery occlusion and 96 hours reperfusion.

Results—

The results clearly demonstrate a previously unrecognized activity of the PD-1 pathway to limit infarct volume, recruitment of inflammatory cells from the periphery, activation of macrophages and central nervous system microglia, and functional neurological deficits. These regulatory functions were associated with increased percentages of circulating PD-ligand-1 and PD-ligand-2 expressing CD19
+
B-cells in blood, the spleen, and central nervous system with the capacity to inhibit activation of inflammatory T-cells and central nervous system macrophages and microglial cells through upregulated PD-1.

Conclusions—
Our novel observations are the first to implicate PD-1 signaling as a major protective pathway for limiting central nervous system inflammation in middle cerebral artery occlusion. This inhibitory circuit would likely be pivotal in reducing stroke-associated Toll-like receptor-2- and Toll like receptor-4-mediated release of neurotoxic factors by activated central nervous system microglia.
Notch Activation Enhances the Microglia-Mediated Inflammatory Response Associated With Focal Cerebral Ischemia
Authors: Wei Zelan , Chigurupati Srinivasulu , Arumugam Thiruma V. , Jo Dong-Gyu , Li He , Chan Sic L. 
Published: July 2011

Background and Purpose—
Activation of Notch worsens ischemic brain damage as antisense knockdown or pharmacological inhibition of the Notch pathway reduces the infarct size and improves the functional outcome in a mouse model of stroke. We sought to determine whether Notch activation contributes to postischemic inflammation by directly modulating the microglial innate response.

Methods—
The microglial response and the attendant inflammatory reaction were evaluated in Notch1 antisense transgenic (Tg) and in nontransgenic (non-Tg) mice subjected to middle cerebral artery occlusion with or without treatment with a γ-secretase inhibitor (GSI). To investigate the impact of Notch on microglial effector functions, primary mouse microglia and murine BV-2 microglial cell line were exposed to oxygen glucose deprivation or lipopolysaccharide in the presence or absence of GSI. Immunofluorescence labeling, Western blotting, and reverse-transcription polymerase chain reaction were performed to measure microglial activation and production of inflammatory cytokines. The nuclear translocation of nuclear factor-κB in microglia was assessed by immunohistochemistry. The neurotoxic potential of microglia was determined in cocultures.

Results—
Notch1 antisense mice exhibit significantly lower numbers of activated microglia and reduced proinflammatory cytokine expression in the ipsilateral ischemic cortices compared to non-Tg mice. Microglial activation also was attenuated in Notch1 antisense cultures and in non-Tg cultures treated with GSI. GSI significantly reduced nuclear factor-κB activation and expression of proinflammatory mediators and markedly attenuated the neurotoxic activity of microglia in cocultures.

Conclusions—
These findings establish a role for Notch signaling in modulating the microglia innate response and suggest that inhibition of Notch might represent a complementary therapeutic approach to prevent reactive gliosis in stroke and neuroinflammation-related degenerative disorders.