bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes from sudden cardiac arrest in US high schools: a 2-year prospective study from the National Registry for AED Use in Sports
Authors: Drezner Jonathan A , Toresdahl Brett G , Rao Ashwin L , Huszti Ella , Harmon Kimberly G 
Published: October 2013

BackgroundSudden cardiac arrest (SCA) is the leading cause of death in athletes during exercise. The effectiveness of school-based automated external defibrillator (AED) programmes has not been established through a prospective study.MethodsA total of 2149 high schools participated in a prospective observational study beginning 1 August 2009, through 31 July 2011. Schools were contacted quarterly and reported all cases of SCA. Of these 95% of schools confirmed their participation for the entire 2-year study period. Cases of SCA were reviewed to confirm the details of the resuscitation. The primary outcome was survival to hospital discharge.ResultsSchool-based AED programmes were present in 87% of participating schools and in all but one of the schools reporting a case of SCA. Fifty nine cases of SCA were confirmed during the study period including 26 (44%) cases in students and 33 (56%) in adults; 39 (66%) cases occurred at an athletic facility during training or competition; 55 (93%) cases were witnessed and 54 (92%) received prompt cardiopulmonary resuscitation. A defibrillator was applied in 50 (85%) cases and a shock delivered onsite in 39 (66%). Overall, 42 of 59 (71%) SCA victims survived to hospital discharge, including 22 of 26 (85%) students and 20 of 33 (61%) adults. Of 18 student-athletes 16 (89%) and 8 of 9 (89%) adults who arrested during physical activity survived to hospital discharge.ConclusionsHigh school AED programmes demonstrate a high survival rate for students and adults who suffer SCA on school campus. School-based AED programmes are strongly encouraged.
Admission neutrophil–lymphocyte ratio predicts 90 day outcome after endovascular stroke therapy
Authors: Brooks Steven D , Spears Chauncey , Cummings Christopher , VanGilder Reyna L , Stinehart Kyle R , Gutmann Laurie , Domico Jennifer , Culp Stacey , Carpenter Jeffrey , Rai Ansaar , Barr Taura L 
Published: October 2013

ObjectiveImmune dysregulation influences outcome following acute ischemic stroke (AIS). Admission white blood cell (WBC) counts are routinely obtained, making the neutrophil–lymphocyte ratio (NLR) a readily available biomarker of the immune response to stroke. This study sought to identify the relationship between NLR and 90 day AIS outcome.MethodsA retrospective analysis was performed on patients who underwent endovascular therapy for AIS at West Virginia University Hospitals, Morgantown, West Virginia. Admission WBC differentials were analyzed as the NLR. Stroke severity was measured by the National Institutes of Health Stroke Scale (NIHSS) score and outcome by the modified Rankin Scale (mRS) score at 90 days. Univariate relationships between NLR, age, NIHSS, and mRS were established by correlation coefficients; the t test was used to compare NLR with recanalization and stroke location (anterior vs posterior). Logistic regression models were developed to identify the ability of NLR to predict mRS when controlling for age, recanalization, and treatment with IV tissue plasminogen activator (tPA).Results116 patients were reviewed from 2008 to 2011. Mean age of the sample was 67 years, and 54% were women. Mean baseline NIHSS score was 17 and 90 day mRS score was 4. There was a significant relationship between NLR and mRS (p=0.02) that remained when controlling for age, treatment with IV tPA, and recanalization. NLR ≥5.9 predicted poor outcome and death at 90 days.ConclusionsThis study shows that the NLR, a readily available biomarker, may be a clinically useful tool for risk stratification when evaluating AIS patients as candidates for endovascular therapies.
Sequential Application of a Cytotoxic Nanoparticle and a PI3K Inhibitor Enhances Antitumor Efficacy
Authors: Pandey Ambarish , Kulkarni Ashish , Roy Bhaskar , Goldman Aaron , Sarangi Sasmit , Sengupta Poulomi , Phipps Colin , Kopparam Jawahar , Oh Michael , Basu Sudipta , Kohandel Mohammad , Sengupta Shiladitya 
Published: October 2013

Abstract
Nanomedicines that preferentially deploy cytotoxic agents to tumors and molecular targeted therapeutics that inhibit specific aberrant oncogenic drivers are emerging as the new paradigm for the management of cancer. While combination therapies are a mainstay of cancer chemotherapy, few studies have addressed the combination of nanomedicines and molecular targeted therapeutics. Furthermore, limited knowledge exists on the impact of sequencing of such therapeutics and nanomedicines on the antitumor outcome. Here, we engineered a supramolecular cis-platinum nanoparticle, which induced apoptosis in breast cancer cells but also elicited prosurvival signaling via an EGF receptor/phosphoinositide 3-kinase (PI3K) pathway. A combination of mathematical modeling and in vitro and in vivo validation using a pharmacologic inhibitor of PI3K, PI828, demonstrate that administration of PI828 following treatment with the supramolecular cis-platinum nanoparticle results in enhanced antitumor efficacy in breast cancer as compared with when the sequence is reversed or when the two treatments are administered simultaneously. This study addresses, for the first time, the impact of drug sequencing in the case of a combination of a nanomedicine and a targeted therapeutic. Furthermore, our results indicate that a rational combination of cis-platinum nanoparticles and a PI3K-targeted therapeutic can emerge as a potential therapy for breast cancer. Cancer Res; 74(3); 675–85. ©2013 AACR.
Supramolecular Nanoparticles That Target Phosphoinositide-3-Kinase Overcome Insulin Resistance and Exert Pronounced Antitumor Efficacy
Authors: Kulkarni Ashish A. , Roy Bhaskar , Rao Poornima S. , Wyant Gregory A. , Mahmoud Ayaat , Ramachandran Madhumitha , Sengupta Poulomi , Goldman Aaron , Kotamraju Venkata Ramana , Basu Sudipta , Mashelkar Raghunath A. , Ruoslahti Erkki , Dinulescu Daniela M. , Sengupta Shiladitya 
Published: October 2013

AbstractThe centrality of phosphoinositide-3-kinase (PI3K) in cancer etiology is well established, but clinical translation of PI3K inhibitors has been limited by feedback signaling, suboptimal intratumoral concentration, and an insulin resistance “class effect.” This study was designed to explore the use of supramolecular nanochemistry for targeting PI3K to enhance antitumor efficacy and potentially overcome these limitations. PI3K inhibitor structures were rationally modified using a cholesterol-based derivative, facilitating supramolecular nanoassembly with L-α-phosphatidylcholine and DSPE-PEG [1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polythylene glycol)]. The supramolecular nanoparticles (SNP) that were assembled were physicochemically characterized and functionally evaluated in vitro. Antitumor efficacy was quantified in vivo using 4T1 breast cancer and K-RasLSL/+/Ptenfl/fl ovarian cancer models, with effects on glucose homeostasis evaluated using an insulin sensitivity test. The use of PI103 and PI828 as surrogate molecules to engineer the SNPs highlighted the need to keep design principles in perspective; specifically, potency of the active molecule and the linker chemistry were critical principles for efficacy, similar to antibody–drug conjugates. We found that the SNPs exerted a temporally sustained inhibition of phosphorylation of Akt, mTOR, S6K, and 4EBP in vivo. These effects were associated with increased antitumor efficacy and survival as compared with PI103 and PI828. Efficacy was further increased by decorating the nanoparticle surface with tumor-homing peptides. Notably, the use of SNPs abrogated the insulin resistance that has been associated widely with other PI3K inhibitors. This study provides a preclinical foundation for the use of supramolecular nanochemistry to overcome current challenges associated with PI3K inhibitors, offering a paradigm for extension to other molecularly targeted therapeutics being explored for cancer treatment. Cancer Res; 73(23); 6987–97. ©2013 AACR.
Antitumor Activity of the Selective Pan-RAF Inhibitor TAK-632 in BRAF Inhibitor-Resistant Melanoma
Authors: Nakamura Akito , Arita Takeo , Tsuchiya Shuntarou , Donelan Jill , Chouitar Jouhara , Carideo Elizabeth , Galvin Katherine , Okaniwa Masanori , Ishikawa Tomoyasu , Yoshida Sei 
Published: October 2013

Abstract
The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of melanoma cells. Somatic mutations in BRAF and NRAS are frequently observed in melanoma. Recently, the BRAF inhibitors vemurafenib and dabrafenib have emerged as promising agents for the treatment of melanoma patients with BRAF-activating mutations. However, as BRAF inhibitors induce RAF paradoxical activation via RAF dimerization in BRAF wild-type cells, rapid emergence of acquired resistance and secondary skin tumors as well as presence of few effective treatment options for melanoma bearing wild-type BRAF (including NRAS-mutant melanoma) are clinical concerns. Here, we demonstrate that the selective pan-RAF inhibitor TAK-632 suppresses RAF activity in BRAF wild-type cells with minimal RAF paradoxical activation. Our analysis using RNAi and TAK-632 in preclinical models reveals that the MAPK pathway of NRAS-mutated melanoma cells is highly dependent on RAF. We also show that TAK-632 induces RAF dimerization but inhibits the kinase activity of the RAF dimer, probably because of its slow dissociation from RAF. As a result, TAK-632 demonstrates potent antiproliferative effects both on NRAS-mutated melanoma cells and BRAF-mutated melanoma cells with acquired resistance to BRAF inhibitors through NRAS mutation or BRAF truncation. Furthermore, we demonstrate that the combination of TAK-632 and the MAPK kinase (MEK) inhibitor TAK-733 exhibits synergistic antiproliferative effects on these cells. Our findings characterize the unique features of TAK-632 as a pan-RAF inhibitor and provide rationale for its further investigation in NRAS-mutated melanoma and a subset of BRAF-mutated melanomas refractory to BRAF inhibitors. Cancer Res; 73(23); 7043–55. ©2013 AACR.
Increased TGF-α as a Mechanism of Acquired Resistance to the Anti-EGFR Inhibitor Cetuximab through EGFR–MET Interaction and Activation of MET Signaling in Colon Cancer Cells
Authors: Troiani Teresa , Martinelli Erika , Napolitano Stefania , Vitagliano Donata , Ciuffreda Loreta Pia , Costantino Sara , Morgillo Floriana , Capasso Anna , Sforza Vincenzo , Nappi Anna , De Palma Raffaele , D'Aiuto Elena , Berrino Liberato , Bianco Roberto , Ciardiello Fortunato 
Published: October 2013

Abstract
Purpose: Although cetuximab, an anti-EGF receptor (EGFR) monoclonal antibody, is an effective treatment for patients with KRAS wild-type metastatic colorectal cancer (mCRC), its clinical use is limited by onset of resistance.
Experimental Design: We characterized two colorectal cancer models to study the mechanisms of acquired resistance to cetuximab.
Results: Following chronic treatment of nude mice bearing cetuximab-sensitive human GEO colon xenografts, cetuximab-resistant GEO (GEO-CR) cells were obtained. In GEO-CR cells, proliferation and survival signals were constitutively active despite EGFR inhibition by cetuximab treatment. Whole gene expression profiling identified a series of genes involved in the hepatocyte growth factor (HGF)-MET–dependent pathways, which were upregulated in GEO-CR cells. Furthermore, activated, phosphorylated MET was detected in GEO-CR cells. A second colorectal cancer cell line with acquired resistance to cetuximab was obtained (SW48-CR). Inhibition of MET expression by siRNA restored cetuximab sensitivity in GEO-CR and SW48-CR cells, whereas exogenous activation of MET by HGF stimulation in cetuximab-sensitive GEO and SW48 cells induced resistance to cetuximab. Treatment of GEO-CR and SW48-CR cells with PHA665752, a selective MET inhibitor, inhibited cell growth, proliferation, and survival signals and impaired cancer cell migration. Overexpression of TGF-α, a specific EGFR ligand, was involved in the acquisition of cetuximab resistance in GEO-CR and SW48-CR cells. In fact, TGF-α overexpression induced the EGFR–MET interaction, with subsequent MET phosphorylation and activation of MET downstream effectors in GEO-CR and SW48-CR cells.
Conclusions: These results suggest that overexpression of TGF-α through induction of EGFR–MET interaction contributes to cetuximab resistance in colorectal cancer cells. The combined inhibition of EGFR and MET receptor could represent a strategy for preventing and/or overcoming cetuximab resistance in patients with colorectal cancer. Clin Cancer Res; 19(24); 6751–65. ©2013 AACR.
ECOG Phase II Trial of Graded-Dose Peginterferon α-2b in Patients with Metastatic Melanoma Overexpressing Basic Fibroblast Growth Factor (E2602)
Authors: Go Ronald S. , Lee Sandra J. , Shin Donghoon , Callister Steven M. , Jobe Dean A. , Conry Robert M. , Tarhini Ahmad A. , Kirkwood John M. 
Published: October 2013

Abstract
Purpose: We investigated the use of graded-dose peginterferon α-2b (Peg-IFN) in patients with stage IV melanoma overexpressing basic fibroblast growth factor (FGF-2). The primary objective was suppression of plasma FGF-2 to within reference range (≤7.5 pg/mL).
Experimental Design: Plasma FGF-2 was measured at baseline (step 1), and patients with concentrations of 15 pg/mL or more were eligible for study treatment (step 2). Peg-IFN was given weekly at a starting dose of 0.5 μg/kg/wk with increment every 3 weeks based on serial FGF-2 concentrations.
Results: Two hundred seven patients entered step 1; 45 (22%) overexpressed FGF-2 (median = 22 pg/dL). Twenty-nine eligible patients entered step 2 and received treatment. Patients' median age was 64 years (range, 29–84 years). Most had more than two prior therapies. FGF-2 decreased in 28 (97%) patients, with suppression to reference range in 10 (35%). Median time to FGF-2 suppression was 30 days. The best clinical responses were partial response (7%) and stable disease (17%). Median progression-free survival (PFS) and overall survival (OS) were 2.0 and 9.7 months, respectively. Patients who achieved FGF-2 suppression were more likely than those who did not to have a response or stable disease (P = 0.03). VEGF concentrations decreased in 27 patients (93%) during treatment and paralleled those of FGF-2 over time. We found no compensatory increase in VEGF among those with FGF-2 suppression.
Conclusions: Graded-dose Peg-IFN suppresses FGF-2 in patients with metastatic melanoma who overexpress FGF-2. Over one third of patients had complete suppression of plasma FGF-2, which correlated with clinical response to this therapy. Clin Cancer Res; 19(23); 6597–604. ©2013 AACR.
Poor Concordance among Nine Immunohistochemistry Classifiers of Cell-of-Origin for Diffuse Large B-Cell Lymphoma: Implications for Therapeutic Strategies
Authors: Coutinho Rita , Clear Andrew James , Owen Andrew , Wilson Andrew , Matthews Janet , Lee Abigail , Alvarez Rute , da Silva Maria Gomes , Cabeçadas José , Calaminici Maria , Gribben John G. 
Published: October 2013

Abstract
Purpose: The opportunity to improve therapeutic choices on the basis of molecular features of the tumor cells is on the horizon in diffuse large B-cell lymphoma (DLBCL). Agents such as bortezomib exhibit selective activity against the poor outcome activated B-cell type (ABC) DLBCL. In order for targeted therapies to succeed in this disease, robust strategies that segregate patients into molecular groups with high reliability are needed. Although molecular studies are considered gold standard, several immunohistochemistry (IHC) algorithms have been published that claim to be able to stratify patients according to their cell-of-origin and to be relevant for patient outcome. However, results are poorly reproducible by independent groups.
Experimental Design: We investigated nine IHC algorithms for molecular classification in a dataset of DLBCL diagnostic biopsies, incorporating immunostaining for CD10, BCL6, BCL2, MUM1, FOXP1, GCET1, and LMO2. IHC profiles were assessed and agreed among three expert observers. A consensus matrix based on all scoring combinations and the number of subjects for each combination allowed us to assess reliability. The survival impact of individual markers and classifiers was evaluated using Kaplan–Meier curves and the log-rank test.
Results: The concordance in patient's classification across the different algorithms was low. Only 4% of the tumors have been classified as germinal center B-cell type (GCB) and 21% as ABC/non-GCB by all methods. None of the algorithms provided prognostic information in the R-CHOP (rituximab plus cyclophosphamide–adriamycin–vincristine–prednisone)–treated cohort.
Conclusion: Further work is required to standardize IHC algorithms for DLBCL cell-of-origin classification for these to be considered reliable alternatives to molecular-based methods to be used for clinical decisions. Clin Cancer Res; 19(24); 6686–95. ©2013 AACR.
Inhibition of Wee1 Sensitizes Cancer Cells to Antimetabolite Chemotherapeutics In Vitro and In Vivo, Independent of p53 Functionality
Authors: Van Linden Annemie A. , Baturin Dmitry , Ford James B. , Fosmire Susan P. , Gardner Lori , Korch Christopher , Reigan Philip , Porter Christopher C. 
Published: October 2013

Abstract
Inhibition of Wee1 is emerging as a novel therapeutic strategy for cancer, and some data suggest that cells with dysfunctional p53 are more sensitive to Wee1 inhibition combined with conventional chemotherapy than those with functional p53. We and others found that Wee1 inhibition sensitizes leukemia cells to cytarabine. Thus, we sought to determine whether chemosensitization by Wee1 inhibition is dependent on p53 dysfunction and whether combining Wee1 inhibition is tolerable and effective in vivo. Synergistic inhibition of proliferation with a Wee1 inhibitor in clinical development, MK1775, and cytarabine was observed in all acute myelogenous leukemia (AML) cell lines tested, regardless of p53 functionality. Mechanistic studies indicate that inhibition of Wee1 abrogates the S-phase checkpoint and augments apoptosis induced by cytarabine. In AML and lung cancer cell lines, genetic disruption of p53 did not alter the cells' enhanced sensitivity to antimetabolites with Wee1 inhibition. Finally, mice with AML were treated with cytarabine and/or MK1775. The combination of MK1775 and cytarabine was well tolerated in mice and enhanced the antileukemia effects of cytarabine, including survival. Thus, inhibition of Wee1 sensitizes hematologic and solid tumor cell lines to antimetabolite chemotherapeutics, whether p53 is functional or not, suggesting that the use of p53 mutation as a predictive biomarker for response to Wee1 inhibition may be restricted to certain cancers and/or chemotherapeutics. These data provide preclinical justification for testing MK1775 and cytarabine in patients with leukemia. Mol Cancer Ther; 12(12); 2675–84. ©2013 AACR.
Zoroastrian and Hindu Connections in the Priestly Strata of the Pentateuch: The Case of Numbers 31:19-24
Authors: Kiel Yishai 
Published: October 2013

Abstract
Previous studies have traced important parallels between biblical and Iranian and Indic traditions. As opposed to the meticulous philological work invested in the field of ancient near eastern parallels, however, the Indic and Iranian parallels to the Bible were often invoked in a very general manner and no attempt was made to locate these parallels textually through careful philological investigation.
The article demonstrates that, later additions to the priestly strata of the Pentateuch can be significantly illuminated by exploring Indic and Zoroastrian parallels. Through a close examination of Numbers 31:19-24 and its parallels from the Indic and Iranian literatures, the study surmises that particularly the late additions in the biblical text bear resemblance and are connected to the Indic and Iranian traditions. Following an internal analysis of the biblical text, which presents exegetic difficulties that indicate the existence of later interpolations in the text, the study examines Zoroastrian and Hindu parallels relevant to the biblical passage. The light shed by these parallels greatly aids in solving the difficulties and discrepancies inherent in the biblical text.
A Muslim Turned Jesuit: Baldassarre Loyola Mandes (1631-1667)
Authors: Colombo Emanuele 
Published: October 2013

Abstract
The goal of this article is to show, through a case study of a convert from Islam to Catholicism in the seventeenth century, how multi-faceted and complex the phenomenon of conversion is, where political, social, and religious factors are intertwined. The article recounts the conversion story of Mohammed el-Attaz, later known as Baldassarre Loyola (1631-1667). Son of the king of Fez (Morocco) of the Saʿadian dynasty, Mohammed was captured on his way to Mecca by the Knights of Malta; he converted to Christianity, went to Italy, became a Jesuit, and spent some years of his life converting Muslims in Italian port cities. The story of Baldassarre Loyola is unique for many reasons. First, this is the only known case of a Muslim prince joining the Society of Jesus. Second, we have an extraordinary range of sources: more than 200 letters written by Baldassarre, Christian and Muslim first-hand sources, an unpublished Autobiography, and a 600-page unpublished Life written by Baldassarre’s spiritual director, the Jesuit Domenico Brunacci. Additionally, a sacred drama on Baldassarre’s story (El gran principe de Fez) was composed by Calderón de la Barca and performed in Jesuit colleges in Europe as well as overseas. This case study of a man between two worlds—struggling for a new identity but always linked to his ancient roots—illuminates, through the phenomenon of conversion, the tormented, rich, and fascinating relationship between Islam and Christianity on the eve of modernity.
Picturing Global Conversion: Art and Diplomacy at the Court of Paul V (1605-1621)
Authors: Mansour Opher 
Published: October 2013

Abstract
This article examines the progress of a series of ambassadorial visits to Rome by emissaries from the Kongo, Japan, and Safavid Persia as they unfolded over the reign of Pope Paul V. Close attention is paid to the visual representation of the ambassadors, and of their actions, in engravings and in the decoration of the Quirinal Palace. The author argues that the public aspects of diplomacy, and of the visual representations based on it, played a significant role in articulating the Papacy’s missionary ambitions and sense of its global position. Furthermore, it is argued that the diplomatic and courtly practices of the papal court played a significant role in mediating the representation of “other” cultures in early modern Europe.