bluuebunny/crossref_metadata_2025_split huggingface dataset:
A New Approach to Simultaneously Quantify Both TCR α- and β-Chain Diversity after Adoptive Immunotherapy
Authors: Zhang Minying , Maiti Sourindra , Bernatchez Chantale , Huls Helen , Rabinovich Brian , Champlin Richard E. , Vence Luis M. , Hwu Patrick , Radvanyi Laszlo , Cooper Laurence J.N. 
Published: July 2012

AbstractPurpose: T-cell receptor (TCR) variable Vα and Vβ gene diversity is a surrogate biomarker for the therapeutic potential of adoptive immunotherapy and cellular immunity. Therefore, creating a straightforward, rapid, sensitive, and reliable method to view the global changes of both TCRVα and Vβ transcripts in heterogeneous populations of T cells is appealing.Experimental Design: We designed a “direct TCR expression assay” (DTEA) using a panel of customized bar-coded probes that simultaneously detects and quantifies 45 Vα and 46 Vβ transcripts in a nonenzymatic digital multiplexed assay from a small number of cells (104 cells) or as little as 100 ng of total RNA.Results: We evaluated DTEA on total RNA samples of tumor-infiltrating lymphocytes and peripheral blood obtained from patients with melanoma after adoptive T-cell therapy. DTEA detected a similar spectrum of the dominant patterns of TCRVβ gene usage as sequencing cloned TCRVβ CDR3 regions. However, DTEA was rapid, achieved a level of sensitivity to identify rare T-cell populations, and simultaneously tracked the full array of Vα and Vβ transcripts.Conclusions: DTEA can rapidly and sensitively track changes in TCRVα and Vβ gene usages in T-cell pools following immune interventions, such as adoptive T-cell transfer, and may also be used to assess impact of vaccination or reconstitution of T-cell compartment after hematopoietic stem cell transplantation. Clin Cancer Res; 18(17); 4733–42. ©2012 AACR.
Attenuation of the Retinoblastoma Pathway in Pancreatic Neuroendocrine Tumors Due to Increased Cdk4/Cdk6
Authors: Tang Laura H. , Contractor Tanupriya , Clausen Richard , Klimstra David S. , Du Yi-Chieh Nancy , Allen Peter J. , Brennan Murray F. , Levine Arnold J. , Harris Chris R. 
Published: July 2012

Abstract
Purpose: In mice, genetic changes that inactivate the retinoblastoma tumor suppressor pathway often result in pancreatic neuroendocrine tumors (Pan-NETs). Conversely, in humans with this disease, mutations in genes of the retinoblastoma pathway have rarely been detected, even in genome-wide sequencing studies. In this study, we took a closer look at the role of the retinoblastoma pathway in human Pan-NETs.
Experimental Design: Pan-NET tumors from 92 patients were subjected to immunohistochemical staining for markers of the retinoblastoma pathway. To search for amplifications of retinoblastoma pathway genes, genomic DNAs from 26 tumors were subjected to copy number analysis. Finally, a small-molecule activator of the retinoblastoma pathway was tested for effects on the growth of two Pan-NET cell lines.
Results: A majority of tumors expressed high amounts of Cdk4 or its partner protein cyclin D1. High amounts of phosphorylated Rb1 were present in tumors that expressed high levels of Cdk4 or cyclin D1. The copy numbers of Cdk4 or the analogous kinase gene Cdk6 were increased in 19% of the tumors. Growth of the human Pan-NET cell line QGP1 was inhibited in a xenograft mouse model by the Cdk4/6 inhibitor, PD 0332991, which reactivates the retinoblastoma pathway.
Conclusions: Inactivation of the retinoblastoma pathway was indicated for most Pan-NETs. Gene amplification and overexpression of Cdk4 and Cdk6 suggests that patients with Pan-NETs may respond strongly to Cdk4/6 inhibitors that are entering clinical trials. Clin Cancer Res; 18(17); 4612–20. ©2012 AACR.
A Tumor Growth Inhibition Model for Low-Grade Glioma Treated with Chemotherapy or Radiotherapy
Authors: Ribba Benjamin , Kaloshi Gentian , Peyre Mathieu , Ricard Damien , Calvez Vincent , Tod Michel , Čajavec-Bernard Branka , Idbaih Ahmed , Psimaras Dimitri , Dainese Linda , Pallud Johan , Cartalat-Carel Stéphanie , Delattre Jean-Yves , Honnorat Jérôme , Grenier Emmanuel , Ducray François 
Published: July 2012

Abstract
Purpose: To develop a tumor growth inhibition model for adult diffuse low-grade gliomas (LGG) able to describe tumor size evolution in patients treated with chemotherapy or radiotherapy.
Experimental Design: Using longitudinal mean tumor diameter (MTD) data from 21 patients treated with first-line procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine (PCV) chemotherapy, we formulated a model consisting of a system of differential equations, incorporating tumor-specific and treatment-related parameters that reflect the response of proliferative and quiescent tumor tissue to treatment. The model was then applied to the analysis of longitudinal tumor size data in 24 patients treated with first-line temozolomide (TMZ) chemotherapy and in 25 patients treated with first-line radiotherapy.
Results: The model successfully described the MTD dynamics of LGG before, during, and after PCV chemotherapy. Using the same model structure, we were also able to successfully describe the MTD dynamics in LGG patients treated with TMZ chemotherapy or radiotherapy. Tumor-specific parameters were found to be consistent across the three treatment modalities. The model is robust to sensitivity analysis, and preliminary results suggest that it can predict treatment response on the basis of pretreatment tumor size data.
Conclusions: Using MTD data, we propose a tumor growth inhibition model able to describe LGG tumor size evolution in patients treated with chemotherapy or radiotherapy. In the future, this model might be used to predict treatment efficacy in LGG patients and could constitute a rational tool to conceive more effective chemotherapy schedules. Clin Cancer Res; 18(18); 5071–80. ©2012 AACR.
Cytolytic Virus Activation Therapy for Epstein-Barr Virus–Driven Tumors
Authors: Wildeman Maarten A. , Novalić Zlata , Verkuijlen Sandra A.W.M. , Juwana Hedy , Huitema Alwin D.R. , Tan I. Bing , Middeldorp Jaap M. , de Boer Jan Paul , Greijer Astrid E. 
Published: July 2012

Abstract
Purpose: Nasopharyngeal carcinoma (NPC) is causally linked to Epstein–Barr virus (EBV) infection. Because all tumor cells carry EBV, the virus itself is a potential target for therapy. In these tumor cells, EBV hides in a latent state and expresses only a few non-immunogenic proteins for EBV maintenance and contributes to tumor growth. We developed a cytolytic virus activation (CLVA) therapy for NPC treatment, reactivating latent EBV, triggering immune recognition, and inducing susceptibility to antiviral therapy.
Experimental Design: CLVA therapy combines gemcitabine (GCb) and valproic acid (VPA) for virus activation and tumor clearance with (val)ganciclovir (GCV) as the antiviral drug to block virus replication and kill proliferating virus-infected cells. CLVA treatment was optimized and validated in NPC cell lines and subsequently tested in 3 Dutch patients with NPC that was refractory to conventional treatment.
Results: In NPC cell lines, both GCb and VPA can induce the lytic cycle of EBV. Their combination resulted in a strong synergistic effect. The addition of GCV resulted in higher cytotoxicity compared with chemotherapy alone, which was not observed in EBV-negative cells. CLVA therapy was analyzed in 3 patients with end-stage NPC. Patients developed increased levels of viral DNA in the circulation originating from apoptotic tumor cells, had disease stabilization, and experienced improved quality of life.
Conclusions: Our results in the initial CLVA-treated patients indicate that the therapy had a biological effect and was well tolerated with only moderate transient toxicity. This new virus-specific therapy could open a generic approach for treatment of multiple EBV-associated malignancies. Clin Cancer Res; 18(18); 5061–70. ©2012 AACR.
First-in-Human, Phase I Dose-Escalation Study of the Safety, Pharmacokinetics, and Pharmacodynamics of RO5126766, a First-in-Class Dual MEK/RAF Inhibitor in Patients with Solid Tumors
Authors: Martinez-Garcia Maria , Banerji Udai , Albanell Joan , Bahleda Rastilav , Dolly Saoirse , Kraeber-Bodéré Françoise , Rojo Federico , Routier Emilie , Guarin Ernesto , Xu Zhi-Xin , Rueger Ruediger , Tessier Jean J. L. , Shochat Eliezer , Blotner Steve , Naegelen Valerie Meresse , Soria Jean-Charles 
Published: July 2012

Abstract
Purpose: This phase I study assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics, and clinical activity of the first-in-class dual MEK/RAF inhibitor, RO5126766.
Experimental Design: Initial dose-escalation was conducted using once daily dosing over 28 consecutive days in 4-week cycles. Further escalation was completed using 2 intermittent dosing schedules [7 days on treatment followed by 7 days off (7on/7off); 4 days on treatment followed by 3 days off (4on/3off)].
Results: Fifty-two patients received RO5126766 at doses of 0.1 to 2.7 mg once daily, 2.7 to 4.0 mg (4 on/3 off), or 2.7 to 5.0 mg (7 on/7 off). The most common DLTs were elevated creatine phosphokinase (CPK) and blurred vision. The MTD for each dosing schedule was 2.25 mg once daily, 4.0 mg (4 on/3 off), and 2.7 mg (7 on/7 off). The dose/schedule recommended for phase II (RP2D) investigation was 2.7 mg (4 on/3 off). Frequent adverse events included rash-related disorders (94.2%), elevated CPK (55.8%), and diarrhea (51.9%). Cmax occurred 1 to 2 hours after dosing and mean terminal half-life was approximately 60 hours. Pharmacodynamic changes included reduced ERK phosphorylation, an increase in apoptosis in tumor tissue, and a reduction in fluorodeoxyglucose (FDG) uptake after 15 days of dosing. Three partial responses were seen: two in BRAF-mutant melanoma tumors and one in an NRAS-mutant melanoma.
Conclusion: This first-in-human study shows that oral RO5126766 has manageable toxicity, a favorable pharmacokinetic/pharmacodynamic profile, and encouraging preliminary antitumor activity in this population of heavily pretreated patients, achieving tumor shrinkage in around 40% of patients across all dose levels and all tumor types. Clin Cancer Res; 18(17); 4806–19. ©2012 AACR.
Prevalence, Clinicopathologic Associations, and Molecular Spectrum of ERBB2 (HER2) Tyrosine Kinase Mutations in Lung Adenocarcinomas
Authors: Arcila Maria E. , Chaft Jamie E. , Nafa Khedoudja , Roy-Chowdhuri Sinchita , Lau Christopher , Zaidinski Michael , Paik Paul K. , Zakowski Maureen F. , Kris Mark G. , Ladanyi Marc 
Published: July 2012

Abstract
Purpose: Activating mutations in the tyrosine kinase domain of HER2 (ERBB2) have been described in a subset of lung adenocarcinomas (ADCs) and are mutually exclusive with EGFR and KRAS mutations. The prevalence, clinicopathologic characteristics, prognostic implications, and molecular heterogeneity of HER2-mutated lung ADCs are not well established in U.S. patients.
Experimental Design: Lung ADC samples (N = 1,478) were first screened for mutations in EGFR (exons 19 and 21) and KRAS (exon 2), and negative cases were then assessed for HER2 mutations (exons 19–20) using a sizing assay and mass spectrometry. Testing for additional recurrent point mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1, and AKT was conducted by mass spectrometry. ALK rearrangements and HER2 amplification were assessed by FISH.
Results: We identified 25 cases with HER2 mutations, representing 6% of EGFR/KRAS/ALK-negative specimens. Small insertions in exon 20 accounted for 96% (24/25) of the cases. Compared with insertions in EGFR exon 20, there was less variability, with 83% (20/24) being a 12 bp insertion causing duplication of amino acids YVMA at codon 775. Morphologically, 92% (23/25) were moderately or poorly differentiated ADC. HER2 mutation was not associated with concurrent HER2 amplification in 11 cases tested for both. HER2 mutations were more frequent among never-smokers (P &lt; 0.0001) but there were no associations with sex, race, or stage.
Conclusions: HER2 mutations identify a distinct subset of lung ADCs. Given the high prevalence of lung cancer worldwide and the availability of standard and investigational therapies targeting HER2, routine clinical genotyping of lung ADC should include HER2. Clin Cancer Res; 18(18); 4910–8. ©2012 AACR.
Optimizing Cancer Treatments to Induce an Acute Immune Response: Radiation Abscopal Effects, PAMPs, and DAMPs
Authors: Ludgate Charles M. 
Published: July 2012

AbstractClinical results indicate improved survival in poorly differentiated prostate cancer patients following a treatment schedule that maximizes hormone therapy prior to radiation. This may be because of a systemic immune response, called an abscopal effect. A literature review showed an association between acute infection and abscopal cancer remission. This led to the theory that, in the presence of endogenous cancer-specific antigens exposed by cancer necrosis, an innate immune response can adapt to respond to those antigens via a cross-talk mechanism. This theory was validated in an animal model. An acute innate immune T-cell response was stimulated using cluster vaccination with Poly(I:C). In the presence of exogenous cancer-specific antigens, this immune response became adaptive, creating an abscopal effect that resulted in cancer resolution. These concepts may be of clinical value, improving outcomes by inducing systemic abscopal effects. Clin Cancer Res; 18(17); 4522–5. ©2012 AACR.
Dacomitinib (PF-00299804), an Irreversible Pan-HER Inhibitor, Inhibits Proliferation of HER2-Amplified Breast Cancer Cell Lines Resistant to Trastuzumab and Lapatinib
Authors: Kalous Ondrej , Conklin Dylan , Desai Amrita J. , O'Brien Neil A. , Ginther Charles , Anderson Lee , Cohen David J. , Britten Carolyn D. , Taylor Ian , Christensen James G. , Slamon Dennis J. , Finn Richard S. 
Published: July 2012

AbstractThe human EGF (HER) family of receptors has been pursued as therapeutic targets in breast cancer and other malignancies. Trastuzumab and lapatinib are standard treatments for HER2-amplified breast cancer, but a significant number of patients do not respond or develop resistance to these drugs. Here we evaluate the in vitro activity of dacomitinib (PF-00299804), an irreversible small molecule pan-HER inhibitor, in a large panel of human breast cancer cell lines with variable expression of the HER family receptors and ligands, and with variable sensitivity to trastuzumab and lapatinib. Forty-seven human breast cancer and immortalized breast epithelial lines representing the known molecular subgroups of breast cancer were treated with dacomitinib to determine IC50 values. HER2-amplified lines were far more likely to respond to dacomitinib than nonamplified lines (RR, 3.39; P &lt; 0.0001). Furthermore, HER2 mRNA and protein expression were quantitatively associated with response. Dacomitinib reduced the phosphorylation of HER2, EGFR, HER4, AKT, and ERK in the majority of sensitive lines. Dacomitinib exerted its antiproliferative effect through a combined G0–G1 arrest and an induction of apoptosis. Dacomitinib inhibited growth in several HER2-amplified lines with de novo and acquired resistance to trastuzumab. Dacomitinib maintained a high activity in lines with acquired resistance to lapatinib. This study identifies HER2-amplified breast cancer lines as most sensitive to the antiproliferative effect of dacomitinib and provides a strong rationale for its clinical testing in HER2-amplified breast cancers resistant to trastuzumab and lapatinib. Mol Cancer Ther; 11(9); 1978–87. ©2012 AACR.
Cancer-Stimulated Mesenchymal Stem Cells Create a Carcinoma Stem Cell Niche via Prostaglandin E2 Signaling
Authors: Li Hua-Jung , Reinhardt Ferenc , Herschman Harvey R. , Weinberg Robert A. 
Published: July 2012

Abstract
Mesenchymal cells of the tumor-associated stroma are critical determinants of carcinoma cell behavior. We focus here on interactions of carcinoma cells with mesenchymal stem cells (MSC), which are recruited to the tumor stroma and, once present, are able to influence the phenotype of the carcinoma cells. We find that carcinoma cell–derived interleukin-1 (IL-1) induces prostaglandin E2 (PGE2) secretion by MSCs. The resulting PGE2 operates in an autocrine manner, cooperating with ongoing paracrine IL-1 signaling, to induce expression of a group of cytokines by the MSCs. The PGE2 and cytokines then proceed to act in a paracrine fashion on the carcinoma cells to induce activation of β-catenin signaling and formation of cancer stem cells. These observations indicate that MSCs and derived cell types create a cancer stem cell niche to enable tumor progression via release of PGE2 and cytokines.
Significance: Although PGE2 has been implicated time and again in fostering tumorigenesis, its effects on carcinoma cells that contribute specifically to tumor formation are poorly understood. Here we show that tumor cells are able to elicit a strong induction of the COX-2/microsomal prostaglandin-E synthase-1 (mPGES-1)/PGE2 axis in MSCs recruited to the tumor-associated stroma by releasing IL-1, which in turn elicits a mesenchymal/stem cell–like phenotype in the carcinoma cells. Cancer Discov; 2(9); 840–55. ©2012 AACR.
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Impact of Parallel Micro-Engineered Stent Grooves on Endothelial Cell Migration, Proliferation, and Function
Authors: Sprague Eugene A. , Tio Fermin , Ahmed S. Hinan , Granada Juan F. , Bailey Steven R. 
Published: July 2012

Background—
Stent luminal surface characteristics influence surface endothelialization. We hypothesize that luminal stent microgrooves created in the direction of coronary flow accelerate endothelial cell migration, resulting in lower levels of neointimal formation.

Methods and Results—

Surface coverage efficiency was evaluated in vitro by allowing human aortic endothelial cells (HAEC) to migrate onto microgrooved (G) or smooth (NG) surfaces. HAEC functionality was assessed by proliferation rate, apoptosis rate, nitric oxide production, and inflammatory markers TNF-α and VCAM-1 expression. Early endothelialization and restenosis studies were performed using the porcine coronary injury model. Stainless steel stents of identical design with (GS) and without (NGS) luminal microgrooves were used. The commercially available Multi-Link Vision (MLVS) stent of identical design was used as a control. The degree of GS and NGS surface endothelialization was compared at 3 days. Biocompatibility and tissue response outcomes were evaluated at 28 days. The in vitro study demonstrated that at 7 days the presence of surface microgrooves increased HAEC migration distance >2-fold. Cell proliferation rate and nitric oxide production were increased and apoptosis rate was decreased. There was no difference in inflammatory marker expression. At 3 days, coronary artery stent endothelialization was significantly increased in GS compared with NGS (81.3% versus 67.5%,
P
=0.0002). At 28 days, GS exhibited lower neointimal thickness compared with either NGS (21.1%,
P
=0.011) or MLVS (40.8%,
P
=0.014).

Conclusion—
Parallel microgrooves on coronary stent luminal surfaces promote endothelial cell migration and positively influence endothelial cell function, resulting in decreased neointimal formation in the porcine coronary injury model.
Visit-to-Visit Blood Pressure Variability, Carotid Atherosclerosis, and Cardiovascular Events in the European Lacidipine Study on Atherosclerosis
Authors: Mancia Giuseppe , Facchetti Rita , Parati Gianfranco , Zanchetti Alberto 
Published: July 2012

Background—
In high-cardiovascular-risk treated hypertensive patients, the incidence of cardiovascular events has been reported to relate to visit-to-visit blood pressure (BP) variability. We investigated whether visit-to-visit BP variability is prognostically important in treated mildly to moderately hypertensive patients in whom treatment aims at avoiding events but also at preventing or delaying progression of organ damage.

Methods and Results—

We analyzed the pooled data from the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind 4-year trial of the effect of lacidipine or atenolol on echographic carotid intima-media thickness. Visit-to-visit BP variability was assessed by the coefficient of variation or the SD of the mean on-treatment systolic BP (SBP) obtained at 6- (clinic BP) and 12- (24 hours BP) month intervals, respectively (1521 and 1264 patients, respectively). In a multivariable linear regression model, mean on-treatment clinic or 24-hour SBP, but not SBP coefficient of variation or SD, was associated with end-of-treatment carotid intima-media thickness. Intima-media thickness increased progressively from the lowest to highest quartile of mean on-treatment clinic or 24-hour SBP (adjusted
P
for trend=0.046 and 0.048) but not along similar quartiles of SBP coefficient of variation or SD. In a multivariable logistic regression model, mean BP, but not variability, was associated with cardiovascular outcomes.

Conclusions—
In mildly to moderately hypertensive patients, carotid intima-media thickness and cardiovascular outcomes were related to the mean clinic or ambulatory SBP achieved by treatment but not to on-treatment visit-to-visit clinic or 24-hour BP variability. Thus, when BP is modestly elevated, inconsistency of BP control between visits plays a less important prognostic role than long-term average BP levels.
Image-Guided Method in the Rat for Inducing Cortical or Striatal Infarction and for Controlling Cerebral Blood Flow Under MRI
Authors: Arnberg Fabian , Lundberg Johan , Söderman Michael , Damberg Peter , Holmin Staffan 
Published: July 2012

Background and Purpose—
Experimental models are essential for research on ischemic stroke, the second most common cause of death worldwide. The failure of clinical trials on neuroprotective treatment may be due in part to poor animal models. To push the translation of new therapies, we describe a new rat model that captures key elements of human brain ischemia. The model includes imaging and neurointerventional tools that represent the near future of clinical diagnosis and treatment of stroke.

Methods—
Using Sprague-Dawley rats (n=26), we navigated a microwire with fluoroscopy and MRI guidance from the ventral tail artery to 2 different positions in the middle cerebral artery to establish local occlusion. Animals were scanned with 9.4-T MRI before occlusion, during ischemia, and after reperfusion.

Results—

We detected stroke lesions, corresponding to the level of occlusion, in all animals by diffusion-weighted and T2 images. We measured lesion volume (mm
3
±SD) on T2 scans at 24 hours to be 23.2±29.8 in the somatosensory cortex group and 107.9±80 in the striatum group.

Conclusion—
We present a new rat model for focal stroke with the possibility to cause lesions in different regions of the brain under fluoroscopic and MRI control. The model will be highly useful for extended studies on the ischemic penumbra, alterations in neural connectivity, and for investigating neurotransmitter-mediated events and biochemical changes in the hyperacute phase of brain ischemia. Also, the model uses clinical routine microcatheters facilitating superselective administration of therapeutics directly to the cerebral circulation.