bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of age and body mass on the response of adolescent male pigs to anaesthesia
Authors: Reed F. C. , Shaw D. J. , McLean K. A. , Clutton R. E. 
Published: May 2015

Age and body mass affect a human's response to drugs, including anaesthetics. In pigs, such effects, if they occur, are likely to be pronounced: commercial breeds have been selected for rapid growth, meaning rapid body composition and mass change with age. Thirty‐six male pigs were anaesthetised for CT scanning on three occasions (S1–3) when aged 105, 137 and 166 days and when mean (±sd) masses were 57.2±4.4, 88.4±6.2 and 114.7±7.6 kg, respectively. Medetomidine (5 μg/kg), azaperone (1 mg/kg), ketamine (5 mg/kg) and midazolam (0.25 mg/kg) were combined and injected intramuscularly. The times when pigs became recumbent (R1) and remained so (RP) were recorded. If venous cannulation was not possible five minutes after recumbency, 2–3 per cent isoflurane in a 1:2 O2 /N2 O mixture was delivered by mask until cannulation was possible and then discontinued. If anaesthetic depth was inadequate for CT scanning, a full dose (midazolam 0.25 mg/kg, ketamine 2 mg/kg) or half dose of induction agents was administered intravenously. During recovery from anaesthesia, the times at first movement (M1), first standing attempt (S1) and successful sustained standing (SP) were recorded. The relationship between mass and time (minutes) from injection to each end point was assessed using regression analysis and linear mixed‐effect models (LMEM); LMEM were used to assess isoflurane and intravenous anaesthetic effects. Analysis using LMEM showed no significant relationships between mass and the times from injection to the five end points. Isoflurane reduced the time to M1, S1 and SP (P<0.037); intravenous agents had no effect on S1 or SP (P>0.585) but increased the time from injection to M1 (P<0.001). In conclusion, age and mass do not influence the response of commercially bred pigs to the intravenous anaesthetic combination described.
First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors
Authors: Starodub Alexander N. , Ocean Allyson J. , Shah Manish A. , Guarino Michael J. , Picozzi Vincent J. , Vahdat Linda T. , Thomas Sajeve S. , Govindan Serengulam V. , Maliakal Pius P. , Wegener William A. , Hamburger Steven A. , Sharkey Robert M. , Goldenberg David M. 
Published: May 2015

Abstract
Purpose: Sacituzumab govitecan (IMMU-132) is an antibody–drug conjugate (ADC) targeting Trop-2, a surface glycoprotein expressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. This phase I trial evaluated this ADC as a potential therapeutic for pretreated patients with a variety of metastatic solid cancers.
Experimental Design: Sacituzumab govitecan was administered on days 1 and 8 of 21-day cycles, with cycles repeated until dose-limiting toxicity or progression. Dose escalation followed a standard 3 + 3 scheme with 4 planned dose levels and dose delay or reduction allowed.
Results: Twenty-five patients (52–60 years old, 3 median prior chemotherapy regimens) were treated at dose levels of 8 (n = 7), 10 (n = 6), 12 (n = 9), and 18 (n = 3) mg/kg. Neutropenia was dose limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (n = 3), neutropenia (n = 2), diarrhea (n = 1), and leukopenia (n = 1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16 to 36 weeks; 6 survived 15 to 20+ months. No preselection of patients based on tumor Trop-2 expression was done.
Conclusions: Sacituzumab govitecan had acceptable toxicity and encouraging therapeutic activity in patients with difficult-to-treat cancers. The 8 and 10 mg/kg doses were selected for phase II studies. Clin Cancer Res; 21(17); 3870–8. ©2015 AACR.
Preclinical Evaluation of a Novel RXR Agonist for the Treatment of Neuroblastoma
Authors: Waters Alicia M. , Stewart Jerry E. , Atigadda Venkatram R. , Mroczek-Musulman Elizabeth , Muccio Donald D. , Grubbs Clinton J. , Beierle Elizabeth A. 
Published: May 2015

Abstract
Neuroblastoma remains a common cause of pediatric cancer deaths, especially for children who present with advanced stage or recurrent disease. Currently, retinoic acid therapy is used as maintenance treatment to induce differentiation and reduce tumor recurrence following induction therapy for neuroblastoma, but unavoidable side effects are seen. A novel retinoid, UAB30, has been shown to generate negligible toxicities. In the current study, we hypothesized that UAB30 would have a significant impact on multiple neuroblastoma cell lines in vitro and in vivo. Cellular survival, cell-cycle analysis, migration, and invasion were studied using AlamarBlue assays, FACS, and Transwell assays, respectively, in multiple cell lines following treatment with UAB30. In addition, an in vivo murine model of human neuroblastoma was utilized to study the effects of UAB30 upon tumor xenograft growth and animal survival. We successfully demonstrated decreased cellular survival, invasion, and migration, cell-cycle arrest, and increased apoptosis after treatment with UAB30. Furthermore, inhibition of tumor growth and increased survival was observed in a murine neuroblastoma xenograft model. The results of these in vitro and in vivo studies suggest a potential therapeutic role for the low toxicity synthetic retinoid X receptor selective agonist, UAB30, in neuroblastoma treatment. Mol Cancer Ther; 14(7); 1559–69. ©2015 AACR.
BRAF Inhibition Decreases Cellular Glucose Uptake in Melanoma in Association with Reduction in Cell Volume
Authors: Theodosakis Nicholas , Held Matthew A. , Marzuka-Alcala Alexander , Meeth Katrina M. , Micevic Goran , Long Georgina V. , Scolyer Richard A. , Stern David F. , Bosenberg Marcus W. 
Published: May 2015

Abstract
BRAF kinase inhibitors have dramatically affected treatment of BRAFV600E/K-driven metastatic melanoma. Early responses assessed using [18F]fluorodeoxyglucose uptake-positron emission tomography (FDG-PET) have shown dramatic reduction of radiotracer signal within 2 weeks of treatment. Despite high response rates, relapse occurs in nearly all cases, frequently at sites of treated metastatic disease. It remains unclear whether initial loss of 18FDG uptake is due to tumor cell death or other reasons. Here, we provide evidence of melanoma cell volume reduction in a patient cohort treated with BRAF inhibitors. We present data demonstrating that BRAF inhibition reduces melanoma glucose uptake per cell, but that this change is no longer significant following normalization for cell volume changes. We also demonstrate that volume normalization greatly reduces differences in transmembrane glucose transport and hexokinase-mediated phosphorylation. Mechanistic studies suggest that this loss of cell volume is due in large part to decreases in new protein translation as a consequence of vemurafenib treatment. Ultimately, our findings suggest that cell volume regulation constitutes an important physiologic parameter that may significantly contribute to radiographic changes observed in clinic. Mol Cancer Ther; 14(7); 1680–92. ©2015 AACR.
Identification and Characterization of MEDI4736, an Antagonistic Anti–PD-L1 Monoclonal Antibody
Authors: Stewart Ross , Morrow Michelle , Hammond Scott A. , Mulgrew Kathy , Marcus Danielle , Poon Edmund , Watkins Amanda , Mullins Stefanie , Chodorge Matthieu , Andrews John , Bannister David , Dick Emily , Crawford Nicola , Parmentier Julie , Alimzhanov Marat , Babcook John S. , Foltz Ian N. , Buchanan Andrew , Bedian Vahe , Wilkinson Robert W. , McCourt Matthew 
Published: May 2015

AbstractProgrammed cell-death 1 ligand 1 (PD-L1) is a member of the B7/CD28 family of proteins that control T-cell activation. Many tumors can upregulate expression of PD-L1, inhibiting antitumor T-cell responses and avoiding immune surveillance and elimination. We have identified and characterized MEDI4736, a human IgG1 monoclonal antibody that binds with high affinity and specificity to PD-L1 and is uniquely engineered to prevent antibody-dependent cell-mediated cytotoxicity. In vitro assays demonstrate that MEDI4736 is a potent antagonist of PD-L1 function, blocking interaction with PD-1 and CD80 to overcome inhibition of primary human T-cell activation. In vivo MEDI4736 significantly inhibits the growth of human tumors in a novel xenograft model containing coimplanted human T cells. This activity is entirely dependent on the presence of transplanted T cells, supporting the immunological mechanism of action for MEDI4736. To further determine the utility of PD-L1 blockade, an anti-mouse PD-L1 antibody was investigated in immunocompetent mice. Here, anti-mouse PD-L1 significantly improved survival of mice implanted with CT26 colorectal cancer cells. The antitumor activity of anti–PD-L1 was enhanced by combination with oxaliplatin, which resulted in increased release of HMGB1 within CT26 tumors. Taken together, our results demonstrate that inhibition of PD-L1 function can have potent antitumor activity when used as monotherapy or in combination in preclinical models, and suggest it may be a promising therapeutic approach for the treatment of cancer. MEDI4736 is currently in several clinical trials both alone and in combination with other agents, including anti–CTLA-4, anti–PD-1, and inhibitors of IDO, MEK, BRAF, and EGFR. Cancer Immunol Res; 3(9); 1052–62. ©2015 AACR.
Single Institution Experience of Ipilimumab 3 mg/kg with Sargramostim (GM-CSF) in Metastatic Melanoma
Authors: Luke Jason J. , Donahue Hilary , Nishino Mizuki , Giobbie-Hurder Anita , Davis Meredith , Bailey Nancy , Ott Patrick A. , Hodi F. Stephen 
Published: May 2015

AbstractIpilimumab, 10 mg/kg with sargramostim (GM-CSF; GM), improved overall survival (OS) and safety of patients with advanced melanoma over ipilimumab in a randomized phase II trial. The FDA-approved dose of ipilimumab of 3 mg/kg has not been assessed with GM (IPI-GM). Consecutive patients treated with IPI-GM at a single institution were reviewed. Treatment included ipilimumab every 3 weeks × 4 and GM, 250-μg s.c. injection days 1 to 14 of each ipilimumab cycle. Efficacy, clinical characteristics, toxicities, and blinded radiology review of tumor burden were evaluated. Thirty-two patients were identified with 25 (78%) having immune-related response criteria (irRC) measurable disease and 41% with central nervous system metastases. A total of 88.6% of GM doses were administered. Response rate by irRC and disease control rate at 12 weeks were 20% and 44%, respectively (median follow-up 37 weeks). Immune-related adverse events (irAE) were observed in 10 (31.3%) patients, with 3 (9.4%) grade 3 events. Patients with grade 3 irAEs had prior autoimmunity, advanced age, and poor performance status. The median OS from first dose of ipilimumab was 41 weeks. Ipi-GM treatment is feasible and in this poor-risk advanced melanoma population, efficacy appeared similar but safety appeared improved relative to historical ipilimumab alone. Cancer Immunol Res; 3(9); 986–91. ©2015 AACR.
Cross talk between serine/threonine and tyrosine kinases regulates ADP-induced thromboxane generation in platelets
Authors: Bhavanasi Dheeraj , Badolia Rachit , Manne Bhanu Kanth , Janapati Sumalaxmi , Dangelmaier Carol , Mazharian Alexandra , Jin Jianguo , Kim Soochong , Zhang Xiaoying , Chen Xiongwen , Senis Yotis , Kunapuli Satya 
Published: May 2015

SummaryADP-induced thromboxane generation depends on Src family kinases (SFKs) and is enhanced with pan-protein kinase C (PKC) inhibitors, but it is not clear how these two events are linked. The aim of the current study is to investigate the role of Y311 phosphorylated PKCδ in regulating ADP-induced platelet activation. In the current study, we employed various inhibitors and murine platelets from mice deficient in specific molecules to evaluate the role of PKCδ in ADP-induced platelet responses. We show that, upon stimulation of platelets with 2MeSADP, Y311 on PKCδ is phosphorylated in a P2Y1/Gq and Lyn-dependent manner. By using PKCδ and Lyn knockout murine platelets, we also show that tyrosine phosphorylated PKCδ plays a functional role in mediating 2MeSADP-induced thromboxane generation. 2MeSADP-induced PKCδ Y311 phosphorylation and thromboxane generation were potentiated in human platelets pre-treated with either a pan-PKC inhibitor, GF109203X or a PKC α/β inhibitor and in PKC α or β knockout murine platelets compared to controls. Furthermore, we show that PKC α/β inhibition potentiates the activity of SFK, which further hyper-phosphorylates PKCδ and potentiates thromboxane generation. These results show for the first time that tyrosine phosphorylated PKCδ regulates ADP-induced thromboxane generation independent of its catalytic activity and that classical PKC isoforms α/β regulate the tyrosine phosphorylation on PKCδ and subsequent thromboxane generation through tyrosine kinase, Lyn, in platelets.
Danger signal-dependent activation of human dendritic cells by plasma-derived factor VIII products
Authors: Miller Lilija , Weissmüller Sabrina , Ringler Eva , Crauwels Peter , van Zandbergen Ger , Seitz Rainer , Waibler Zoe ,   the ABIRISK consortium
Published: May 2015

SummaryTreatment of haemophilia A by infusions of the clotting factor VIII (FVIII) results in the development of inhibitors/anti-drug antibodies in up to 25 % of patients. Mechanisms leading to immunogenicity of FVIII products are not yet fully understood. Amongst other factors, danger signals as elicited upon infection or surgery have been proposed to play a role. In the present study, we focused on effects of danger signals on maturation and activation of dendritic cells (DC) in the context of FVIII application. Human monocyte-derived DC were treated with FVIII alone, with a danger signal alone or a combination of both. By testing more than 60 different healthy donors, we show that FVIII and the bacterial danger signal lipopolysaccharide synergise in increasing DC activation, as characterised by increased expression of co-stimulatory molecules and secretion of pro-inflammatory cytokines. The degree and frequency of this synergistic activation correlate with CD86 expression levels on immature DC prior to stimulation. In our assay system, plasma-derived but not recombinant FVIII products activate human DC in a danger signal-dependent manner. Further tested danger signals, such as R848 also induced DC activation in combination with FVIII, albeit not in every tested donor. In our hands, human DC but not human B cells or macrophages could be activated by FVIII in a danger signal-dependent manner. Our results suggest that immunogenicity of FVIII is a result of multiple factors including the presence of danger, predisposition of the patient, and the choice of a FVIII product for treatment.
Prognostic Implications of Level-of-Care at Tertiary Heart Centers Compared With Other Hospitals After Resuscitation From Out-of-Hospital Cardiac Arrest
Authors: Søholm Helle , Kjaergaard Jesper , Bro-Jeppesen John , Hartvig-Thomsen Jakob , Lippert Freddy , Køber Lars , Nielsen Niklas , Engsig Magaly , Steensen Morten , Wanscher Michael , Karlsen Finn Michael , Hassager Christian 
Published: May 2015

Background—
Studies have found higher survival rates after out-of-hospital cardiac arrest and admission to tertiary heart centers. The aim was to examine the level-of-care at tertiary centers compared with nontertiary hospitals and the association with outcome after out-of-hospital cardiac arrest.

Methods and Results—

Consecutive out-of-hospital cardiac arrest patients (n=1078) without ST-segment–elevation myocardial infarction admitted to tertiary centers (54%) and nontertiary hospitals (46%) were included (2002–2011). Patient charts were reviewed focusing on level-of-care and comorbidity. Survival to discharge differed significantly with 45% versus 24% of patients discharged alive (
P
<0.001), and after adjustment for prognostic factors admissions to tertiary centers were still associated with lower 30-day mortality (hazard ratio, 0.78 [0.64–0.96;
P
=0.02]), independent of comorbidity. The adjusted odds of predefined markers of level-of-care were higher in tertiary centers: admission to intensive care unit (odds ratio [OR], 1.8 [95% confidence interval, 1.2–2.5]), temporary pacemaker (OR, 6.4 [2.2–19]), vasoactive agents (OR, 1.5 [1.1–2.1]), acute (<24 hours) and late coronary angiography (OR, 10 [5.3–22] and 3.8 [2.5–5.7]), neurophysiological examination (OR, 1.8 [1.3–2.6]), and brain computed tomography (OR, 1.9 [1.4–2.6]), whereas no difference in therapeutic hypothermia was noted. Patients at tertiary centers were more often consulted by a cardiologist (OR, 8.6 [5.0–15]), had an echocardiography (OR, 2.8 [2.1–3.7]), and survivors more often had implantable cardioverter defibrillator’s implanted (OR, 2.1 [1.2–3.6]).

Conclusions—
Admissions to tertiary centers were associated with significantly higher survival after out-of-hospital cardiac arrest in patients without ST-segment–elevation myocardial infarction in the Copenhagen area even after adjustment for prognostic factors including comorbidity. Level-of-care seems higher in tertiary centers both in the early phase, during the intensive care unit admission, and in the workup before discharge. The varying level-of-care may contribute to the survival difference; however, differences in comorbidity do not seem to matter significantly.
Optimal Cutoff Levels of More Sensitive Cardiac Troponin Assays for the Early Diagnosis of Myocardial Infarction in Patients With Renal Dysfunction
Authors: Twerenbold Raphael , Wildi Karin , Jaeger Cedric , Gimenez Maria Rubini , Reiter Miriam , Reichlin Tobias , Walukiewicz Astrid , Gugala Mathias , Krivoshei Lian , Marti Nadine , Moreno Weidmann Zoraida , Hillinger Petra , Puelacher Christian , Rentsch Katharina , Honegger Ursina , Schumacher Carmela , Zurbriggen Felicitas , Freese Michael , Stelzig Claudia , Campodarve Isabel , Bassetti Stefano , Osswald Stefan , Mueller Christian 
Published: May 2015

Background—
It is unknown whether more sensitive cardiac troponin (cTn) assays maintain their clinical utility in patients with renal dysfunction. Moreover, their optimal cutoff levels in this vulnerable patient population have not previously been defined.

Methods and Results—

In this multicenter study, we examined the clinical utility of 7 more sensitive cTn assays (3 sensitive and 4 high-sensitivity cTn assays) in patients presenting with symptoms suggestive of acute myocardial infarction. Among 2813 unselected patients, 447 (16%) had renal dysfunction (defined as Modification of Diet in Renal Disease–estimated glomerular filtration rate <60 mL·min
−1
·1.73 m
−2
). The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including coronary angiography and serial levels of high-sensitivity cTnT. Acute myocardial infarction was the final diagnosis in 36% of all patients with renal dysfunction. Among patients with renal dysfunction and elevated baseline cTn levels (≥99th percentile), acute myocardial infarction was the most common diagnosis for all assays (range, 45%–80%). In patients with renal dysfunction, diagnostic accuracy at presentation, quantified by the area under the receiver-operator characteristic curve, was 0.87 to 0.89 with no significant differences between the 7 more sensitive cTn assays and further increased to 0.91 to 0.95 at 3 hours. Overall, the area under the receiver-operator characteristic curve in patients with renal dysfunction was only slightly lower than in patients with normal renal function. The optimal receiver-operator characteristic curve–derived cTn cutoff levels in patients with renal dysfunction were significantly higher compared with those in patients with normal renal function (factor, 1.9–3.4).

Conclusions—
More sensitive cTn assays maintain high diagnostic accuracy in patients with renal dysfunction. To ensure the best possible clinical use, assay-specific optimal cutoff levels, which are higher in patients with renal dysfunction, should be considered.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00470587.
Muscovite Ritual in the Context of Jerusalem Old and New
Authors: Flier Michael S. 
Published: May 2015

The reign of Grand Prince Ivan III (1462–1505) represented a period of wide-ranging consolidation of Rusian lands under the aegis of Moscow at the very time that elites were concerned about the Orthodox Christian prediction of an imminent Apocalypse in 1492. The semiotics of Muscovite rulership incorporated references to Jerusalem and the End Times long after the predicted date had passed. The present study analyzes the elements and relationships employed in iconography, architecture, and ritual to reevaluate the capital in light of Jerusalem old and new.
Attributions to Andrei Kurbskii and Inferential (Bayesian) Probability
Authors: Ostrowski Donald 
Published: May 2015

Attributions of original works, letters, and translations to Prince Andrei Mikhailovich Kurbskii (d. 1583) have been contested for almost 45 years. This article proposes that Bayesian or inferential probability be applied to a number of the main points of contention. Of central importance to the attribution question are the so-called Kurbskii miscellanies (sborniki Kurbskogo), which date no earlier than the mid-1670s. Among the works in the Kurbskii miscellanies are the History of the Grand Prince of Moscow, letters addressed to Tsar Ivan IV, the “Lithuanian” letters, and the History of the Eighth Council. Proponents of attributing these works to Kurbskii tend to weight the evidence differently from the way the skeptics of those attributions do, and both camps find explanations favorable to their respective positions for unexpected oddities in the evidence. No one issue has been defined conclusively in the favor of one side or the other, but placing the differences in the context of inferential probability may allow us to continue to discuss the contentious issues of the attributions in a productive manner.
Origin of Russian Absolutism
Authors: Nefedov S.A. 
Published: May 2015

Although Nicolas Henshall declared “absolutism” to be a myth, the author of this article supports the view held by Brian Downing who argues that, in some cases, military-bureaucratic absolutism developed from the early modern military (or gunpowder) revolution. The author assumes that such cases are relatively rare and happen only when a military revolution causes bitter conflict between a monarchy and elite nobility. In addition to Scandinavian countries, it occurred in Russia under Peter the Great. Upon returning home from his European tour in 1698, Peter I faced the serious problem of finding the financial resourses needed to organize a new regular army; his revenue enhancement efforts provoked a conflict between the Tsar and his boyars. Eventually, Peter the Great staged a military takeover, dissolving the Boyar Duma to become an absolute monarch.