bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk stratification with exercise N13-ammonia PET in adults with anomalous right coronary arteries
Authors: Cremer Paul C , Mentias Amgad , Koneru Srikanth , Schoenhagen Paul , Majdalany David , Lorber Richard , Flamm Scott D , Hobbs Robert E , Pettersson Gosta , Jaber Wael A 
Published: August 2016

ObjectiveIn adults with an interarterial and intramural course of an anomalous right coronary artery from the left sinus (AAORCA), surgical unroofing is recommended in the setting of myocardial ischaemia. However, data regarding functional testing are limited, and the management of adults without ischaemia is unclear. To evaluate these patients, we employed an exercise N13-ammonia positron emission tomography (PET) protocol. We hypothesised that patients with typical angina and exertional dyspnoea would be more likely to have ischaemia and that patients without ischaemia could be managed conservatively.MethodsBetween July 2008 and December 2014, we retrospectively identified 27 consecutive patients >18 years old with an interarterial and intramural course of an AAORCA who had exercise N13-ammonia PET.ResultsThe majority of patients had anatomic delineation with cardiac CT (25, 93%), and most patients had chest pain (24, 89%). Myocardial ischaemia with PET was common (13, 48%), and ischaemia was more likely in patients with typical angina and exertional dyspnoea (p<0.05). Surgery was performed in 12 patients including 11 patients with ischaemia. At a median follow-up of 245 days, there were no deaths in patients with surgery or in patients managed conservatively.ConclusionsIn patients with an interarterial and intramural course of an AAORCA, typical angina and exertional dyspnoea are associated with ischaemia on exercise N13-ammonia PET. Referral for surgical unroofing in symptomatic patients with ischaemia on exercise N13-ammonia PET and initial conservative management in patients without ischaemia seems appropriate, though larger studies with long-term follow-up are needed.
Antitumor Properties of an IgG2-Enhanced Next-Generation MET Monoclonal Antibody That Degrades Wild-Type and Mutant MET Receptors
Authors: Yang Yan , Mandiyan Sreekala , Robinson Brett S. , McMahon Gerald 
Published: August 2016

Abstract
A sound rationale exists for antibody targeting of the MET receptor tyrosine kinase, but therapeutic agents that can broadly block HGF ligand binding and exon 14–mutated or amplified MET to induce receptor degradation have yet to be reported. Here we report the identification of several MET monoclonal antibodies (mAb) that block MET-dependent signaling and tumor growth. In particular, the MET mAb KTN0073 and KTN0074 bind the Sema/PSI domain, at overlapping but distinct epitopes, preventing HGF interaction with MET and triggering receptor ubiquitination and degradation. Notably, both mAbs also triggered degradation of oncogenic MET exon 14 mutants, which propagate more durable MET signals due to a defect in receptor degradation. Mechanistic investigations showed that both mAbs engaged a pathway distinct from HGF-induced receptor degradation and protease-mediated shedding, independently of signaling driven by the exon 14–encoded sequences in the intracellular juxtamembrane region of the MET receptor. Grafting the mAb variable regions onto the IgG2 constant region dramatically enhanced the tumor inhibitory activities of KTN0073 but not KTN0074, suggesting a specific influence of antibody isotype of the epitopes for these two MET mAbs. Overall, our results highlight KTN0073 as a novel IgG2-based MET mAb that acts through exon 14–independent mechanisms to degrade the MET receptor, potentially offering a therapeutic tool to treat a broader range of human tumors where MET is exon 14 mutated or amplified. Cancer Res; 76(19); 5788–97. ©2016 AACR.
Abscopal Effects of Radiotherapy Are Enhanced by Combined Immunostimulatory mAbs and Are Dependent on CD8 T Cells and Crosspriming
Authors: Rodriguez-Ruiz María E. , Rodriguez Inmaculada , Garasa Saray , Barbes Benigno , Solorzano Jose Luis , Perez-Gracia Jose Luis , Labiano Sara , Sanmamed Miguel F. , Azpilikueta Arantza , Bolaños Elixabet , Sanchez-Paulete Alfonso R. , Aznar M. Angela , Rouzaut Ana , Schalper Kurt A. , Jure-Kunkel Maria , Melero Ignacio 
Published: August 2016

Abstract
Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory mAbs to act both on irradiated tumor lesions and on distant, nonirradiated tumor sites. The combination of radiotherapy with immunostimulatory anti-PD1 and anti-CD137 mAbs was conducive to favorable effects on distant nonirradiated tumor lesions as observed in transplanted MC38 (colorectal cancer), B16OVA (melanoma), and 4T1 (breast cancer) models. The therapeutic activity was crucially performed by CD8 T cells, as found in selective depletion experiments. Moreover, the integrities of BATF-3–dependent dendritic cells specialized in crosspresentation/crosspriming of antigens to CD8+ T cells and of the type I IFN system were absolute requirements for the antitumor effects to occur. The irradiation regimen induced immune infiltrate changes in the irradiated and nonirradiated lesions featured by reductions in the total content of effector T cells, Tregs, and myeloid-derived suppressor cells, while effector T cells expressed more intracellular IFNγ in both the irradiated and contralateral tumors. Importantly, 48 hours after irradiation, CD8+ TILs showed brighter expression of CD137 and PD1, thereby displaying more target molecules for the corresponding mAbs. Likewise, PD1 and CD137 were induced on tumor-infiltrating lymphocytes from surgically excised human carcinomas that were irradiated ex vivo. These mechanisms involving crosspriming and CD8 T cells advocate clinical development of immunotherapy combinations with anti-PD1 plus anti-CD137 mAbs that can be synergistically accompanied by radiotherapy strategies, even if the disease is left outside the field of irradiation. Cancer Res; 76(20); 5994–6005. ©2016 AACR.
The Greater Genomic Landscape: The Heterogeneous Evolution of Cancer
Authors: Almassalha Luay M. , Bauer Greta M. , Chandler John E. , Gladstein Scott , Szleifer Igal , Roy Hemant K. , Backman Vadim 
Published: August 2016

Abstract
Results have historically shown a broad plasticity in the origin of tumors and their functions, with significant heterogeneity observed in both morphologies and functional capabilities. Largely unknown, however, are the mechanisms by which these variations occur and how these events influence tumor formation and behavior. Contemporary views on the origin of tumors focus mainly on the role of particular sets of driver transformations, mutational or epigenetic, with the occurrence of the observed heterogeneity as an accidental byproduct of oncogenesis. As such, we present a hypothesis that tumors form due to heterogeneous adaptive selection in response to environmental stress through intrinsic genomic sampling mechanisms. Specifically, we propose that eukaryotic cells intrinsically explore their available genomic information, the greater genomic landscape (GGL), in response to stress under normal conditions, long before the formation of a cancerous lesion. Finally, considering the influence of chromatin heterogeneity on the GGL, we propose a new class of compounds, chromatin-protective therapies (CPT), which target the physical variations in chromatin topology. In this approach, CPTs reduce the overall information space available to limit the formation of tumors or the development of drug-resistant phenotypes. Cancer Res; 76(19); 5605–9. ©2016 AACR.
Found in Translation: Maximizing the Clinical Relevance of Nonclinical Oncology Studies
Authors: Spilker Mary E. , Chen Xiaoying , Visswanathan Ravi , Vage Chandra , Yamazaki Shinji , Li Gang , Lucas Judy , Bradshaw-Pierce Erica L. , Vicini Paolo 
Published: August 2016

Abstract
Purpose: The translation of nonclinical oncology studies is a subject of continuous debate. We propose that translational oncology studies need to optimize both pharmacokinetic (drug exposure) and pharmacodynamic (xenograft model) aspects. While improvements in pharmacodynamic translatability can be obtained by choosing cell lines or patient-derived xenograft models closer to the clinical indication, significant ambiguity and variability exists when optimizing the pharmacokinetic translation of small molecule and biotherapeutic agents.
Experimental Design and Results: In this work, we propose a pharmacokinetic-based strategy to select nonclinical doses for approved drug molecules. We define a clinically relevant dose (CRD) as the dosing regimen in mice that most closely approximates the relevant pharmacokinetic metric in humans. Such metrics include area under the time–concentration curve and maximal or minimal concentrations within the dosing interval. The methodology is applied to six drugs, including targeted agents and chemotherapeutics, small and large molecules (erlotinib, dasatinib, vismodegib, trastuzumab, irinotecan, and capecitabine). The resulting efficacy response at the CRD is compared with clinical responses.
Conclusions: We conclude that nonclinical studies designed with the appropriate CRDs of approved drug molecules will maximize the translatability of efficacy results, which is critical when testing approved and investigational agents in combination. Clin Cancer Res; 23(4); 1080–90. ©2016 AACR.
Higher Order Chromatin Modulator Cohesin SA1 Is an Early Biomarker for Colon Carcinogenesis: Race-Specific Implications
Authors: Wali Ramesh K. , Momi Navneet , Dela Cruz Mart , Calderwood Audrey H. , Stypula-Cyrus Yolanda , Almassalha Luay , Chhaparia Anuj , Weber Christopher R. , Radosevich Andrew , Tiwari Ashish K. , Latif Bilal , Backman Vadim , Roy Hemant K. 
Published: August 2016

Abstract
Alterations in high order chromatin, with concomitant modulation in gene expression, are one of the earliest events in the development of colorectal cancer. Cohesins are a family of proteins that modulate high-order chromatin, although the role in colorectal cancer remains incompletely understood. We, therefore, assessed the role of cohesin SA1 in colorectal cancer biology and as a biomarker focusing in particular on the increased incidence/mortality of colorectal cancer among African-Americans. Immunohistochemistry on tissue arrays revealed dramatically decreased SA1 expression in both adenomas (62%; P = 0.001) and adenocarcinomas (75%; P = 0.0001). RT-PCR performed in endoscopically normal rectal biopsies (n = 78) revealed a profound decrease in SA1 expression in adenoma-harboring patients (field carcinogenesis) compared with those who were neoplasia-free (47%; P = 0.03). From a racial perspective, colorectal cancer tissues from Caucasians had 56% higher SA1 expression than in African-Americans. This was mirrored in field carcinogenesis where healthy Caucasians expressed more SA1 at baseline compared with matched African-American subjects (73%; P = 0.003). However, as a biomarker for colorectal cancer risk, the diagnostic performance as assessed by area under ROC curve was greater in African-Americans (AUROC = 0.724) than in Caucasians (AUROC = 0.585). From a biologic perspective, SA1 modulation of high-order chromatin was demonstrated with both biophotonic (nanocytology) and chromatin accessibility [micrococcal nuclease (MNase)] assays in SA1-knockdown HT29 colorectal cancer cells. The functional consequences were underscored by increased proliferation (WST-1; P = 0.0002, colony formation; P = 0.001) in the SA1-knockdown HT29 cells. These results provide the first evidence indicating a tumor suppressor role of SA1 in early colon carcinogenesis and as a risk stratification biomarker giving potential insights into biologic basis of racial disparities in colorectal cancer. Cancer Prev Res; 9(11); 844–54. ©2016 AACR.
Reduction of MDSCs with All-trans Retinoic Acid Improves CAR Therapy Efficacy for Sarcomas
Authors: Long Adrienne H. , Highfill Steven L. , Cui Yongzhi , Smith Jillian P. , Walker Alec J. , Ramakrishna Sneha , El-Etriby Rana , Galli Susana , Tsokos Maria G. , Orentas Rimas J. , Mackall Crystal L. 
Published: August 2016

Abstract
Genetically engineered T cells expressing CD19-specific chimeric antigen receptors (CAR) have shown impressive activity against B-cell malignancies, and preliminary results suggest that T cells expressing a first-generation disialoganglioside (GD2)-specific CAR can also provide clinical benefit in patients with neuroblastoma. We sought to assess the potential of GD2-CAR therapies to treat pediatric sarcomas. We observed that 18 of 18 (100%) of osteosarcomas, 2 of 15 (13%) of rhabdomyosarcomas, and 7 of 35 (20%) of Ewing sarcomas expressed GD2. T cells engineered to express a third-generation GD2-CAR incorporating the 14g2a-scFv with the CD28, OX40, and CD3ζ signaling domains (14g2a.CD28.OX40.ζ) mediated efficient and comparable lysis of both GD2+ sarcoma and neuroblastoma cell lines in vitro. However, in xenograft models, GD2-CAR T cells had no antitumor effect against GD2+ sarcoma, despite effectively controlling GD2+ neuroblastoma. We observed that pediatric sarcoma xenografts, but not neuroblastoma xenografts, induced large populations of monocytic and granulocytic murine myeloid-derived suppressor cells (MDSC) that inhibited human CAR T-cell responses in vitro. Treatment of sarcoma-bearing mice with all-trans retinoic acid (ATRA) largely eradicated monocytic MDSCs and diminished the suppressive capacity of granulocytic MDSCs. Combined therapy using GD2-CAR T cells plus ATRA significantly improved antitumor efficacy against sarcoma xenografts. We conclude that retinoids provide a clinically accessible class of agents capable of diminishing the suppressive effects of MDSCs, and that co-administration of retinoids may enhance the efficacy of CAR therapies targeting solid tumors. Cancer Immunol Res; 4(10); 869–80. ©2016 AACR.
Why Do Global Reanalyses and Land Data Assimilation Products Underestimate Snow Water Equivalent?
Authors: Broxton Patrick D. , Zeng Xubin , Dawson Nicholas 
Published: August 2016

Abstract
There is a large uncertainty of snow water equivalent (SWE) in reanalyses and the Global Land Data Assimilation System (GLDAS), but the primary reason for this uncertainty remains unclear. Here several reanalysis products and GLDAS with different land models are evaluated and the primary reason for their deficiencies are identified using two high-resolution SWE datasets, including the Snow Data Assimilation System product and a new dataset for SWE and snowfall for the conterminous United States (CONUS) that is based on PRISM precipitation and temperature data and constrained with thousands of point snow observations of snowfall and snow thickness. The reanalyses and GLDAS products substantially underestimate SWE in the CONUS compared to the high-resolution SWE data. This occurs irrespective of biases in atmospheric forcing information or differences in model resolution. Furthermore, reanalysis and GLDAS products that predict more snow ablation at near-freezing temperatures have larger underestimates of SWE. Since many of the products do not assimilate information about SWE and snow thickness, this indicates a problem with the implementation of land models and pinpoints the need to improve the treatment of snow ablation in these systems, especially at near-freezing temperatures.
Differences in Multitask Resource Reallocation After Change in Task Values
Authors: Matton Nadine , Paubel Pierre , Cegarra Julien , Raufaste Eric 
Published: August 2016

Objective The objective was to characterize multitask resource reallocation strategies when managing subtasks with various assigned values. Background When solving a resource conflict in multitasking, Salvucci and Taatgen predict a globally rational strategy will be followed that favors the most urgent subtask and optimizes global performance. However, Katidioti and Taatgen identified a locally rational strategy that optimizes only a subcomponent of the whole task, leading to detrimental consequences on global performance. Moreover, the question remains open whether expertise would have an impact on the choice of the strategy. Method We adopted a multitask environment used for pilot selection with a change in emphasis on two out of four subtasks while all subtasks had to be maintained over a minimum performance. A laboratory eye-tracking study contrasted 20 recently selected pilot students considered as experienced with this task and 15 university students considered as novices. Results When two subtasks were emphasized, novices focused their resources particularly on one high-value subtask and failed to prevent both low-value subtasks falling below minimum performance. On the contrary, experienced people delayed the processing of one low-value subtask but managed to optimize global performance. Conclusion In a multitasking environment where some subtasks are emphasized, novices follow a locally rational strategy whereas experienced participants follow a globally rational strategy. Application During complex training, trainees are only able to adjust their resource allocation strategy to subtask emphasis changes once they are familiar with the multitasking environment.
Changes in Characteristics and Practice Patterns of Ontario Psychiatrists
Authors: Kurdyak Paul , Zaheer Juveria , Cheng Joyce , Rudoler David , Mulsant Benoit H. 
Published: August 2016

Objective: The objective of this study was to evaluate the changes in demographic, geographic, and practice characteristics of all Ontario psychiatrists between 2003 and 2013 and their implication for access to psychiatrists. Methods: We included all psychiatrists who were clinically active in Ontario in any year from 2003 to 2013. For each psychiatrist, we reported age, sex, years since medical school graduation, geographic practice region, and practice characteristics such as total number of inpatients, outpatients, and outpatient visit frequencies. Results: In 2013, there were 2070 psychiatrists, with nearly half (47%) more than 30 years since medical school graduation. Female psychiatrists comprised 41% of all psychiatrists in 2013 but 56% of all psychiatrists within 15 years of medical school graduation. Between 2003 and 2013, there was a 17% increase in the total number of psychiatrists, with the largest growth in psychiatrists occurring in the group more than 30 years from medical school graduation. Over these 11 years, the mean (SD) number of unique outpatients seen by a psychiatrist annually increased from 208 (228) to 249 (275) (19.5%; P = 0.001), with male psychiatrists, on average, seeing more outpatients annually than female psychiatrists. Conclusion: The number of outpatients seen by psychiatrists is slowly increasing. However, the large proportion of aging psychiatrists, the high concentration of psychiatrists in urban settings, and the increase in the number of female psychiatrists with smaller practices suggest that without radical changes to the way psychiatrists practice, access to psychiatrists will remain a challenge in Ontario.
Factors Associated with Infant Feeding Choices in the Adolescent Population
Authors: Godbout Jennifer M. , Goldsberry Whitney N. , Franklin Tanya E. 
Published: August 2016

Background: Strong recommendations have been made for exclusive breastfeeding of infants for the first 6 months of life, with continuation throughout the first year. In an attempt to optimize support for breastfeeding, particular barriers in populations with decreased rates need to be analyzed. Objective: This study aimed to determine if participation in the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) food voucher program, involvement of the infant’s father, involvement of the adolescent mother’s parents or other caregivers, and participation in early skin-to-skin contact after birth are associated with the decision to breastfeed or bottle feed among this adolescent population. Methods: A retrospective chart review of 457 adolescent patients who delivered January 2010 through May 2013 at the University of Louisville Hospital was conducted. Nursing documentation was used to determine the patient’s intention to breastfeed or bottle feed, participation in WIC, involvement of the infant’s father, involvement of the patient’s parents, and participation in early skin-to-skin contact after delivery. These factors were compared using Fisher exact test. Results: Three hundred one adolescents reported a plan to breastfeed (65.9%) and 156 reported a plan to bottle feed (34.1%) when questioned pre-delivery. There was no significant difference between the groups with respect to WIC participation or involvement of the infant’s father. The bottle-feeding group had a significantly higher percentage who reported parental involvement (80.1% vs 67.8%, P = .0059). The breastfeeding group had a significantly higher percentage who participated in early skin-to-skin contact after birth (74.5% vs 58.1%, P = .0064). Conclusion: Involvement of the adolescent mothers’ parents or caregivers was associated with the decision to bottle feed. Participation in early skin-to-skin contact after birth was associated with the decision to breastfeed.
Middle ear polyps: results of traction avulsion after a lateral approach to the ear canal in 62 cats (2004–2014)
Authors: Janssens Sara DS , Haagsman Annika N , Ter Haar Gert 
Published: August 2016

Objectives The objective of this study was to report the surgical outcome and complication rate of deep traction avulsion (TA) of feline aural inflammatory polyps after a lateral approach (LA) to the ear canal. Methods This was a retrospective analysis of data retrieved from an electronic database of 62 cats treated with TA after an LA (TALA) for removal of ear canal polyps. Long-term outcome was assessed via a telephone questionnaire survey with the owners. Results Domestic shorthair cats (48%) and Maine Coons (37%) were over-represented. The most common presenting clinical signs were otorrhoea, ear scratching and head shaking. Video-otoscopic examination confirmed a polypous mass in the ear canal in all patients. All 62 cats underwent TALA, with a mean surgical time of 33 mins for experienced surgeons (n = 4) and 48 mins (n = 12) for less experienced surgeons. The recurrence rate of polyp regrowth for experienced surgeons was 14.3% vs 35% for the less experienced surgeons. Postoperative complications included Horner’s syndrome (11.5%) and facial nerve paralysis (3%). Otitis interna was not observed. Conclusions and relevance A lateral approach to the ear canal in combination with deep TA of an aural inflammatory polyp is an effective first-line technique that results in a low recurrence and complication rate.