bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Safety, Pharmacokinetic and Pharmacodynamic Evaluation of the Vascular Disrupting Agent Ombrabulin (AVE8062) in Patients with Advanced Solid Tumors
Authors: Sessa Cristiana , Lorusso Patricia , Tolcher Anthony , Farace Françoise , Lassau Nathalie , Delmonte Angelo , Braghetti Antonio , Bahleda Rastislav , Cohen Patrick , Hospitel Marie , Veyrat-Follet Christine , Soria Jean-Charles 
Published: July 2013

Abstract
Purpose: The vascular disrupting agent ombrabulin rapidly reduces tumor blood flow and causes necrosis in vivo. A phase I dose-escalation study was designed to determine the recommended phase II dose (RP2D) of single-agent ombrabulin administered once every three weeks in patients with advanced solid malignancies.
Experimental Design: Ombrabulin (30-minute infusion) was escalated from 6 to 60 mg/m2, with RP2D cohort expansion. Safety, tumor response, pharmacokinetics, and pharmacodynamic biomarkers were evaluated.
Results: Eleven dose levels were evaluated in 105 patients. Two patients had dose-limiting toxicities in cycle 1 during escalation: grade 3 abdominal pain at 50 mg/m2, grade 3 tumor pain/grade 3 hypertension at 60 mg/m2, and the RP2D was 50 mg/m2 (39 patients). Common toxicities were headache, asthenia, abdominal pain, nausea, diarrhea, transient hypertension, anemia, and lymphopenia. No clinically significant QTc prolongations or left ventricular ejection fraction (LVEF) decreases occurred. Ombrabulin was rapidly converted to its active metabolite RPR258063 (half-life 17 minutes and 8.7 hours, respectively), both having dose-proportional exposure. Weak inhibition of CYP2C19-mediated metabolism occurred at the clinical doses used and there was no effect on CYP1A2 and CYP3A4. A patient with rectal cancer had a partial response and eight patients had stable disease lasting four months or more. Circulating endothelial cells (CEC), VEGF, and matrix metalloproteinase (MMP)-9 levels increased significantly six to 10 hours postinfusion in a subset of patients.
Conclusions: The recommended schedule for single-agent ombrabulin is 50 mg/m2 every 3 weeks. CECs, VEGF, and MMP-9 are potential biomarkers of ombrabulin activity. Clin Cancer Res; 19(17); 4832–42. ©2013 AACR.
Detection of Mutant Free Circulating Tumor DNA in the Plasma of Patients with Gastrointestinal Stromal Tumor Harboring Activating Mutations of CKIT or PDGFRA
Authors: Maier Jacqueline , Lange Thoralf , Kerle Irina , Specht Katja , Bruegel Melanie , Wickenhauser Claudia , Jost Philipp , Niederwieser Dietger , Peschel Christian , Duyster Justus , von Bubnoff Nikolas 
Published: July 2013

Abstract
Purpose: In gastrointestinal stromal tumor (GIST), there is no biomarker available that indicates success or failure of therapy. We hypothesized that tumor-specific v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (CKIT)- or platelet-derived growth factor receptor-α (PDGFRA)–mutant DNA fragments can be detected and quantified in plasma samples of patients with GIST.
Experimental Design: We prospectively collected 291 plasma samples from 38 subjects with GIST harboring activating mutations of CKIT or PDGFRA detected in tumor tissue, irrespective of current disease status or treatment. We used allele-specific ligation PCR to detect mutant free circulating DNA (fcDNA).
Results: We were able to detect fcDNA harboring the tumor mutation in 15 of 38 patients. Patients with active disease displayed significantly higher amounts of mutant fcDNA compared with patients in complete remission (CR). The amount of mutant fcDNA correlated with disease course. We observed repeated positive test results or an increase of mutant fcDNA in five patients with progressive disease or relapse. A decline of tumor fcDNA or conversion from positive to negative was seen in five patients responding to treatment. A negative to positive conversion was seen in two patients with relapse and one patient with progression. In two cases, we aimed to identify additional mutations and found four additional exchanges, including mutations not known from sequentially conducted tumor biopsies.
Conclusions: Our results indicate that fcDNA harboring tumor-specific mutations in the plasma of patients with GIST can be used as tumor-specific biomarker. The detection of resistance mutations in plasma samples might allow earlier treatment changes and obviates the need for repeated tumor biopsies. Clin Cancer Res; 19(17); 4854–67. ©2013 AACR.
Tumor Genetic Analyses of Patients with Metastatic Melanoma Treated with the BRAF Inhibitor Dabrafenib (GSK2118436)
Authors: Nathanson Katherine L. , Martin Anne-Marie , Wubbenhorst Bradley , Greshock Joel , Letrero Richard , D'Andrea Kurt , O'Day Steven , Infante Jeffrey R. , Falchook Gerald S. , Arkenau Hendrik-Tobias , Millward Michael , Brown Michael P. , Pavlick Anna , Davies Michael A. , Ma Bo , Gagnon Robert , Curtis Martin , Lebowitz Peter F. , Kefford Richard , Long Georgina V. 
Published: July 2013

Abstract
Purpose: Dabrafenib is a selective inhibitor of V600-mutant BRAF kinase, which recently showed improved progression-free survival (PFS) as compared with dacarbazine, in metastatic melanoma patients. This study examined potential genetic markers associated with response and PFS in the phase I study of dabrafenib.
Experimental Design: Baseline (pretreatment or archival) melanoma samples were evaluated in 41 patients using a custom genotyping melanoma-specific assay, sequencing of PTEN, and copy number analysis using multiplex ligation amplification and array-based comparative genomic hybridization. Nine patients had on-treatment and/or progression samples available.
Results: All baseline patient samples had BRAFV600E/K confirmed. Baseline PTEN loss/mutation was not associated with best overall response to dabrafenib, but it showed a trend for shorter median PFS [18.3 (95% confidence interval, CI, 9.1–24.3) vs. 32.1 weeks (95% CI, 24.1–33), P = 0.059]. Higher copy number of CCND1 (P = 0.009) and lower copy number of CDKN2A (P = 0.012) at baseline were significantly associated with decreased PFS. Although no melanomas had high-level amplification of BRAF, the two patients with progressive disease as their best response had BRAF copy gain in their tumors.
Conclusions: Copy number changes in CDKN2A, CCND1, and mutation/copy number changes in PTEN correlated with the duration of PFS in patients treated with dabrafenib. The results suggest that these markers should be considered in the design and interpretation of future trials with selective BRAF inhibitors in advanced melanoma patients. Clin Cancer Res; 19(17); 4868–78. ©2013 AACR.
A Dendritic Cell Vaccine Pulsed with Autologous Hypochlorous Acid-Oxidized Ovarian Cancer Lysate Primes Effective Broad Antitumor Immunity: From Bench to Bedside
Authors: Chiang Cheryl Lai-Lai , Kandalaft Lana E. , Tanyi Janos , Hagemann Andrea R. , Motz Gregory T. , Svoronos Nikolaos , Montone Kathleen , Mantia-Smaldone Gina M. , Smith Lori , Nisenbaum Harvey L. , Levine Bruce L. , Kalos Michael , Czerniecki Brian J. , Torigian Drew A. , Powell Daniel J. , Mick Rosemarie , Coukos George 
Published: July 2013

Abstract
Purpose: Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells.
Experimental Design: We compared the ability of DCs to engulf three different tumor lysate preparations, produce T-helper 1 (TH1)-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo.
Results: We showed that DCs engulfed HOCl-oxidized lysate most efficiently stimulated robust MLRs, and elicited strong tumor-specific IFN-γ secretions in autologous T cells. These DCs produced the highest levels of TH1-priming cytokines and chemokines, including interleukin (IL)-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate–pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy, and progression-free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating regulatory T cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of 24 months or more after OCDC.
Conclusions: This is the first study showing the potential efficacy of a DC vaccine pulsed with HOCl-oxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers. Clin Cancer Res; 19(17); 4801–15. ©2013 AACR.
DEAR1 Is a Chromosome 1p35 Tumor Suppressor and Master Regulator of TGF-β–Driven Epithelial–Mesenchymal Transition
Authors: Chen Nanyue , Balasenthil Seetharaman , Reuther Jacquelyn , Frayna Aileen , Wang Ying , Chandler Dawn S. , Abruzzo Lynne V. , Rashid Asif , Rodriguez Jaime , Lozano Guillermina , Cao Yu , Lokken Erica , Chen Jinyun , Frazier Marsha L. , Sahin Aysegul A. , Wistuba Ignacio I. , Sen Subrata , Lott Steven T. , Killary Ann McNeill 
Published: July 2013

Abstract
Deletion of chromosome 1p35 is a common event in epithelial malignancies. We report that DEAR1 (annotated as TRIM62) is a chromosome 1p35 tumor suppressor that undergoes mutation, copy number variation, and loss of expression in human tumors. Targeted disruption in the mouse recapitulates this human tumor spectrum, with both Dear1−/− and Dear1+/− mice developing primarily epithelial adenocarcinomas and lymphoma with evidence of metastasis in a subset of mice. DEAR1 loss of function in the presence of TGF-β results in failure of acinar morphogenesis, upregulation of epithelial–mesenchymal transition (EMT) markers, anoikis resistance, migration, and invasion. Furthermore, DEAR1 blocks TGF-β–SMAD3 signaling, resulting in decreased nuclear phosphorylated SMAD3 by binding to and promoting the ubiquitination of SMAD3, the major effector of TGF-β–induced EMT. Moreover, DEAR1 loss increases levels of SMAD3 downstream effectors SNAIL1 and SNAIL2, with genetic alteration of DEAR1/SNAIL2 serving as prognostic markers of overall poor survival in a cohort of 889 cases of invasive breast cancer.
Significance: Cumulative results provide compelling evidence that DEAR1 is a critical tumor suppressor involved in multiple human cancers and provide a novel paradigm for regulation of TGF-β–induced EMT through DEAR1′s regulation of SMAD3 protein levels. DEAR1 loss of function has important therapeutic implications for targeted therapies aimed at the TGF-β–SMAD3 pathway. Cancer Discov; 3(10); 1172–89. ©2013 AACR.
This article is highlighted in the In This Issue feature, p. 1083
Human Regulatory T Cells Kill Tumor Cells through Granzyme-Dependent Cytotoxicity upon Retargeting with a Bispecific Antibody
Authors: Choi Bryan D. , Gedeon Patrick C. , Herndon James E. , Archer Gary E. , Reap Elizabeth A. , Sanchez-Perez Luis , Mitchell Duane A. , Bigner Darell D. , Sampson John H. 
Published: July 2013

Abstract
A major mechanism by which human regulatory T cells (Treg) have been shown to suppress and kill autologous immune cells is through the granzyme-perforin pathway. However, it is unknown whether Tregs also possess the capacity to kill tumor cells using similar mechanisms. Bispecific antibodies (bscAb) have emerged as a promising class of therapeutics that activate T cells against tumor antigens without the need for classical MHC-restricted T-cell receptor (TCR) recognition. Here, we show that a bscAb targeting the tumor-specific mutation of the EGF receptor, EGFRvIII, redirects human CD4+CD25+FoxP3+ Tregs to kill glioblastoma cells. This activity was significantly abrogated by inhibitors of the granzyme-perforin pathway. Notably, analyses of human primary glioblastoma also displayed diffused infiltration of granzyme-expressing FoxP3+ T cells. Together, these data suggest that despite their known suppressive functions, tumor-infiltrating Tregs possess potent cytotoxic mechanisms that can be co-opted for efficient tumor cell lysis. Cancer Immunol Res; 1(3); 163–7. ©2013 AACR.
Additive Value of Magnetic Resonance Coronary Angiography in a Comprehensive Cardiac Magnetic Resonance Stress-Rest Protocol for Detection of Functionally Significant Coronary Artery Disease
Authors: Bettencourt Nuno , Ferreira Nuno , Chiribiri Amedeo , Schuster Andreas , Sampaio Francisco , Santos Lino , Melica Bruno , Rodrigues Alberto , Braga Pedro , Teixeira Madalena , Leite-Moreira Adelino , Silva-Cardoso José , Portugal Pedro , Gama Vasco , Nagel Eike 
Published: July 2013

Background—
Cardiovascular magnetic resonance (CMR) myocardial perfusion imaging (MPI) is a state-of-the-art noninvasive modality for detection of myocardial ischemia and coronary artery disease. Magnetic resonance coronary angiography (MRCA) allows visualization of the coronary tree, but its incremental value as part of a CMR protocol including MPI and late gadolinium enhancement (LGE) is not well established. We aimed to evaluate the additive diagnostic value of a 3-dimensional whole-heart MRCA integration into a 1.5T CMR-MPI/LGE protocol for the detection of functionally significant coronary artery disease.

Methods and Results—
Forty-three symptomatic patients (61±8.3 years; 65% men) with suspected coronary artery disease and intermediate/high-pretest probability underwent CMR (including CMR-MPI, MRCA, and LGE) and x-ray invasive coronary angiography (XA) with fractional flow reserve evaluation. Diagnostic performances of MRCA, CMR-MPI/LGE, and MRCA+CMR-MPI/LGE integration were determined having XA+fractional flow reserve as standard for coronary artery disease (≥90% stenosis/occlusion or fractional flow reserve≤0.80 in vessels>2 mm). MRCA inclusion into the CMR protocol was associated with a mean increase of 7.9±4.69 (0–17.7) minutes in total examination duration (14%). On patient-based analysis, MRCA had 96% sensitivity, 68% specificity, positive predictive value of 79%, and negative predictive value of 93%. CMR-MPI/LGE had 79% sensitivity, 95% specificity, positive predictive value of 95%, and negative predictive value of 78%. Integration of MRCA with CMR-MPI/LGE further improved CMR performance to 96% sensitivity, 89% specificity, positive predictive value of 92%, and negative predictive value of 94%, with a global accuracy of 93%.

Conclusions—
In this intermediate/high-pretest population, integration of noncontrast-enhanced whole-heart MRCA nonsignificantly improved per-patient diagnostic accuracy of a comprehensive 1.5-T stress-rest CMR-MPI/LGE protocol at a cost of longer scanning times.
Focal Arterial Inflammation Precedes Subsequent Calcification in the Same Location
Authors: Abdelbaky Amr , Corsini Erin , Figueroa Amparo L. , Fontanez Sara , Subramanian Sharath , Ferencik Maros , Brady Thomas J. , Hoffmann Udo , Tawakol Ahmed 
Published: July 2013

Background—
Arterial calcium (Ca) deposition has been identified as an active inflammatory process. We sought to test the hypothesis that local vascular inflammation predisposes to subsequent arterial calcium deposition in humans.

Methods and Results—

From a hospital database, we identified 137 patients (age, 61±13 years; 48.1% men) who underwent serial positron-emission tomography/computed tomography (1–5 years apart). Focal arterial inflammation was prospectively determined by measuring 18F-flourodeoxyglucose uptake (using baseline positron-emission tomography) within predetermined locations of the thoracic aortic wall and was reported as a standardized uptake value. A separate, blinded investigator evaluated calcium deposition (on the baseline and follow-up computed tomographic scans) along the same standardized sections of the aorta. New calcification was prospectively defined using square root–transformed difference of calcium volume score, with a cutoff value of 2.5. Accordingly, vascular segment was classified as either with or without subsequent calcification. Overall, 67 (9%) of aortic segments demonstrated subsequent calcification. Baseline median (interquartile range) standardized uptake value was higher in segments with versus without subsequent calcification (2.09 [1.84–2.44] versus 1.92 [1.72–2.20],
P
=0.002). This was also true in the subset of segments with Ca present at baseline (2.08 [1.81–2.40] versus 1.86 [1.66–2.09],
P
=0.02), as well as those without (2.17 [1.87–2.51] versus 1.93 [1.73–2.20],
P
=0.04). Furthermore, across all patients, subsequent Ca deposition was associated with the underlying 18F-flourodeoxyglucose uptake (inflammatory signal), measured as standardized uptake value (odds ratio [95% confidence interval]=2.94 [1.27–6.89],
P
=0.01) or target-to-background ratio (2.59 [1.18–5.70],
P
=0.02), after adjusting for traditional cardiovascular risk factors.

Conclusions—
Here, we provide first-in-man evidence that arterial inflammation precedes subsequent Ca deposition, a marker of plaque progression, within the underlying location in the artery wall.
Sterol Regulatory Element Binding Protein 2 Activation of NLRP3 Inflammasome in Endothelium Mediates Hemodynamic-Induced Atherosclerosis Susceptibility
Authors: Xiao Han , Lu Min , Lin Ting Yang , Chen Zhen , Chen Gang , Wang Wei-Chi , Marin Traci , Shentu Tzu-pin , Wen Liang , Gongol Brendan , Sun Wei , Liang Xiao , Chen Ju , Huang Hsien-Da , Pedra Joao H.F. , Johnson David A. , Shyy John Y-J. 
Published: July 2013

Background—
The molecular basis for the focal nature of atherosclerotic lesions is poorly understood. Here, we explored whether disturbed flow patterns activate an innate immune response to form the NLRP3 inflammasome scaffold in vascular endothelial cells via sterol regulatory element binding protein 2 (SREBP2).

Methods and Results—
Oscillatory flow activates SREBP2 and induces NLRP3 inflammasome in endothelial cells. The underlying mechanisms involve SREBP2 transactivating NADPH oxidase 2 and NLRP3. Consistently, SREBP2, NADPH oxidase 2, and NLRP3 levels were elevated in atheroprone areas of mouse aortas, suggesting that the SREBP2-activated NLRP3 inflammasome causes functionally disturbed endothelium with increased inflammation. Mimicking the effect of atheroprone flow, endothelial cell–specific overexpression of the activated form of SREBP2 synergized with hyperlipidemia to increase atherosclerosis in the atheroresistant areas of mouse aortas.

Conclusions—
Atheroprone flow induces NLRP3 inflammasome in endothelium through SREBP2 activation. This increased innate immunity in endothelium synergizes with hyperlipidemia to cause topographical distribution of atherosclerotic lesions.
A Lost Maqāma of Badīʿ al-Zamān al-Hamad̠ānī?
Authors: Orfali Bilal W. , Pomerantz Maurice A. 
Published: July 2013

Abstract
This article provides the editio princeps of a previously unknown maqāma attributed to Badīʿ al-Zamān al-Hamad̠ānī (d. 398/1008). It begins with a review of the scholarship on the manuscripts of Hamad̠ānī’s Maqāmāt and discusses how the text of this lost maqāma was uniquely preserved in one manuscript, Yale University, Beinecke Library, Salisbury collection no. 63. This manuscript, copied in 603/1206, was well-known to European scholarship, having been in the possession of Everard Scheidius (1742-1794), Silvestre de Sacy (1775-1838), and Edward Eldridge Salisbury (1814-1901). The maqāma, preserved therein, describes a fraudulent doctor’s sale of medicinal compounds allegedly composed of rare materia medica. The text of this maqāma, which the editors have entitled al-Maqāma l-Ṭibbiyya, is then provided in facsimile, a critical edition, and a fully-annotated English translation. A detailed analysis of the maqāma follows, in which the form, subject matter, language, and style of this maqāma are discussed in relation to the known corpus of Hamad̠ānī’s other maqāmāt. The article concludes with several hypotheses about the possible authenticity of this lost work.
Spider Systematics: Past and Future
Authors: PLATNICK NORMAN I. , RAVEN ROBERT J. 
Published: July 2013

Spider systematics has a history that reaches back over 250 years, to the publication of Carl Clerck’s Svenska Spindlar (Clerck, 1757). Linnaeus (1758), in the famous 10th edition of his Systema Naturae that was published the following year (and which serves as the starting point for the rest of zoological nomenclature), recognized only 39 species of spiders, worldwide, even though he knew (and cited) Clerck’s book. Clerck had already recognized more species than that from Sweden alone, and (unlike Linnaeus) provided good, color illustrations of them, often including even drawings of the male palps. So it is not surprising that arachnologists take Clerck, rather than Linnaeus, as their starting point.
A Test of Recent Inferences of Net Polar Ice Mass Balance based on Long-Wavelength Gravity
Authors: Morrow E. , Mitrovica J. X. , Sterenborg M. G. , Harig C. 
Published: July 2013

Abstract
A comprehensive analysis of satellite datasets has estimated that the ice sheets of Greenland, West Antarctica, the Antarctic Peninsula, and East Antarctica experienced a net mass loss of −100 ± 92 Gt yr−1 over the period 1992–2000 and −298 ± 58 Gt yr−1 over the period 2000–11, representing an increase of −198 ± 109 Gt yr−1 between the two epochs. The authors demonstrate that the time rate of change of the degree-four zonal harmonic of Earth's gravitational potential provides an independent check on these mass balances that is less sensitive to uncertainties that have contaminated previous analyses of the degree-2 zonal harmonic [e.g., due to ongoing glacial isostatic adjustment (GIA), solid Earth body tides, and core–mantle coupling]. For the period 2000–11, the signal implied by the ice sheet mass flux cited above is (3.8 ± 0.6) × 10−11 yr−1, whereas the change in the harmonic across the two epochs is (2.3 ± 1.1) × 10−11 yr−1. In comparison, using satellite laser ranging (SLR) data, the authors estimate a GIA-corrected value of (3.8 ± 0.6) × 10−11 yr−1 for the epoch 2000–11 and a change across the two epochs of (5.3 ± 1.6) × 10−11 yr−1. The authors conclude that the former supports recent estimates of melting over the last decade, whereas the latter suggests either that estimated melt rates for the earlier epoch were too high or that the uncertainty associated with the SLR-based inference of during the earlier epoch is underestimated.