bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA12: Combating antigen escape with CD19/CD20 bispecific CAR-T cell therapy
Authors: Zah Eugenia , Lin Meng-Yin , Jensen Michael C. , Silva-Benedict Anne , Chen Yvonne Y. 
Published: March 2017

Abstract
T cells expressing chimeric antigen receptors (CARs) specific for the B-cell marker CD19 have shown impressive results in the treatment of B-cell malignancies. However, multiple clinical trials have also demonstrated the vulnerability of single-input CD19 CAR-T cell therapy to antigen escape, in which patients relapse with the emergence of CD19 tumor cells. Here, we report on the rational design and systematic optimization of bispecific CAR-T cells that trigger robust cytotoxicity against target cells expressing either CD19 or CD20. We demonstrate that optimized bi-specific CARs can rapidly eliminate large, engrafted tumors in vivo. We further demonstrate the bi-specific CAR-T cells ability to prevent tumor escape while single-input CD19 CAR-T cells succumb to the selective expansion of CD19 mutant cells, which are shown to arise spontaneously in engrafted mice. The CD19-OR-CD20 CAR is fully compatible with existing T-cell manufacturing procedures and implementable by current clinical protocols. These results present an effective solution to the challenge of antigen escape in CD19 CAR T-cell therapy, and they highlight the utility of structure-based rational design in the development of receptors with higher-level complexity.
Citation Format: Eugenia Zah, Meng-Yin Lin, Michael C. Jensen, Anne Silva-Benedict, Yvonne Y. Chen. Combating antigen escape with CD19/CD20 bispecific CAR-T cell therapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr IA12.
Abstract PR06: A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models
Authors: Everett Katy , Kraman Matthew , Kmiecik Katarzyna , Allen Natalie , Faroudi Mustapha , Zimarino Carlo , Wydro Mateusz , Doody Jacqueline 
Published: March 2017

Abstract
Combining immunotherapeutic antibodies for treatment of cancer patients has shown benefits over single agent treatment. For example, the addition of anti-PD-1 antibodies to anti-CTLA-4 treatment in advanced melanoma patients has increased objective response rates from 19% to 57.6% (Larkin,J et al. 2015. NEJM 373:23-34). An alternative to combining two antibodies is the development of bispecific antibodies that not only bring two biologies together but may result in novel mechanisms of action that are impossible to attain with combinations.
Lymphocyte Activation Gene-3 (LAG-3) is a member of the Ig superfamily expressed on activated T cells, NK cells, pDCs, B cells, γδ T cells and participates in immune suppression, particularly through persistent strong expression in a percentage of regulatory T cells (Tregs). Programmed Cell Death receptor (PD-1) binds to its ligand PD-L1, expressed not only on activated immune cells to inhibit cellular immune responses but also on tumour cells. Expression of LAG-3 and PD-1 leads to T cell exhaustion, allowing tumour escape from immune surveillance. Combining inhibitory antibodies to PD-1 and LAG-3 reactivates T cells leading to efficacy in murine models over single treatment (Woo,S-R et al. 2012. Cancer Res. 15: 917-27) which prompted interest in the development of a LAG-3 and PD-L1 bispecific antibody for inhibiting tumour growth.
A murine-specific anti-LAG-3 and PD-L1 mAb²TM (bispecific antibody) was engineered which binds both antigens simultaneously and with nanomolar affinities. The anti-LAG-3/PD-L1 mAb² inhibits LAG-3 binding to MHCII and PD-L1 binding to PD-1 and CD80, resulting in T cell activation in an in vitro assay. This potency translates into in vivo efficacy, where the anti-LAG-3/PD-L1 mAb² decreased tumour burden in the MC38 colon carcinoma tumour model, both in early-established or well-established tumours. At the end of the study tumour-free animals were more numerous in the LAG-3/PD-L1 bispecific group than in the group given a combination of individual anti-LAG-3 and PD-L1 antibodies. The results were recapitulated in the CT26 murine colon cancer model, where the LAG-3/PD-L1 mAb² showed an increase of anti-tumour activity as compared to the combination of anti-LAG-3 and anti-PD-L1 antibodies. Thus, the preclinical data supports developing an anti-human LAG-3/PD-L1 mAb² for the treatment of cancer patients.
This abstract is also being presented as Poster A27.
Citation Format: Katy Everett, Matthew Kraman, Katarzyna Kmiecik, Natalie Allen, Mustapha Faroudi, Carlo Zimarino, Mateusz Wydro, Jacqueline Doody. A LAG-3/PD-L1 bispecific antibody inhibits tumour growth in two syngeneic colon carcinoma models. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr PR06.
Contested Foreignness: Indian Migrants and the Politics of Exclusion in Early Colonial Zimbabwe, 1890 to 1923
Authors: Musoni Francis 
Published: March 2017

Abstract
The British South Africa Company’s conquest of Zimbabwe in the 1890s opened the country to settlement by immigrants from Europe, South Africa, India and other regions. Using their position as benefactors of the emerging colony, the British-born settlers deployed various notions of foreignness to marginalize the indigenous populations and other groups. Focusing on thirty-three years of company rule in Zimbabwe, this article examines how Indian immigrants contested the British attempts to foreignize them in the emerging colony. Rather than presenting Indian migrants as passive victims of discrimination and marginalization, the study emphasizes their creativity and determination to establish their own destiny, against all odds. It also shows that foreignness in colonial Zimbabwe was a key factor in the politics of power, identity formation and nation-state building. In that respect, the article explores the constructed-ness as well as the malleability of foreignness in processes of nation-state formation in Africa.
Changes in North American Atmospheric Circulation and Extreme Weather: Influence of Arctic Amplification and Northern Hemisphere Snow Cover
Authors: Vavrus Stephen J. , Wang Fuyao , Martin Jonathan E. , Francis Jennifer A. , Peings Yannick , Cattiaux Julien 
Published: March 2017

Abstract
This study tests the hypothesis that Arctic amplification (AA) of global warming remotely affects midlatitudes by promoting a weaker, wavier atmospheric circulation conducive to extreme weather. The investigation is based on the late twenty-first century over greater North America (20°–90°N, 50°–160°W) using 40 simulations from the Community Earth System Model Large Ensemble, spanning 1920–2100. AA is found to promote regionally varying ridging aloft (500 hPa) with strong seasonal differences reflecting the location of the strongest surface thermal forcing. During winter, maximum increases in future geopotential heights are centered over the Arctic Ocean, in conjunction with sea ice loss, but minimum height increases (troughing) occur to the south, over the continental United States. During summer the location of maximum height inflation shifts equatorward, forming an annular band across mid-to-high latitudes of the entire Northern Hemisphere. This band spans the continents, whose enhanced surface heating is aided by antecedent snow-cover loss and reduced terrestrial heat capacity. Through the thermal wind relationship, midtropospheric winds weaken on the equatorward flank of both seasonal ridging anomalies—mainly over Canada during winter and even more over the continental United States during summer—but strengthen elsewhere to form a dipole anomaly pattern in each season. Changes in circulation waviness, expressed as sinuosity, are inversely correlated with changes in zonal wind speed at nearly all latitudes, both in the projections and as observed during recent decades. Over the central United States during summer, the weaker and wavier flow promotes drying and enhanced heating, thus favoring more intense summer weather.
Evaluation Criteria on the Design for Assimilating Remote Sensing Data Using Variational Approaches
Authors: Lu Sha , Heemink Arnold , Lin Hai Xiang , Segers Arjo , Fu Guangliang 
Published: March 2017

Abstract
Remote sensing, as a powerful tool for monitoring atmospheric phenomena, has been playing an increasingly important role in inverse modeling. Remote sensing instruments measure quantities that often combine several state variables as one. This creates very strong correlations between the state variables that share the same observation variable. This may cause numerical problems resulting in a low convergence rate or inaccurate estimates in gradient-based variational assimilation if improper error statistics are used. In this paper, two criteria or scoring rules are proposed to quantify the numerical robustness of assimilating a specific set of remote sensing observations and to quantify the reliability of the estimates of the parameters. The criteria are derived by analyzing how the correlations are created via shared observation data and how they may influence the process of variational data assimilation. Experimental tests are conducted and show a good level of agreement with theory. The results illustrate the capability of the criteria to indicate the reliability of the assimilation process. Both criteria can be used with observing system simulation experiments (OSSEs) and in combination with other verification scores.
Positive Affect Is Associated With Reduced Fixation in a Realistic Medical Simulation
Authors: Crane Monique F. , Brouwers Sue , Forrest Kirsty , Tan Suyin , Loveday Thomas , Wiggins Mark W. , Munday Chris , David Leila 
Published: March 2017

Objective: This study extends previous research by exploring the association between mood states (i.e., positive and negative affect) and fixation in practicing anesthetists using a realistic medical simulation. Background: The impact of practitioner emotional states on fixation is a neglected area of research. Emerging evidence is demonstrating the role of positive affect in facilitating problem solving and innovation, with demonstrated implications for practitioner fixation. Method: Twelve practicing anesthetists (4 females; Mage= 39 years; SD = 6.71) were involved in a medical simulation. Prior to the simulation, practitioners rated the frequency they had experienced various positive and negative emotions in the previous three days. During the simulation, the patient deteriorated rapidly, and anesthetists were observed for their degree of fixation. After the simulation, practitioners indicated the frequency of these same emotions during the simulation. Results: Nonparametric correlations were used to explore the independent relationships between positive and negative affect and the behavioral measures. Only positive affect impacted the likelihood of fixation. Anesthetists who reported more frequent recent positive affect in the three days prior to the simulation and during the simulation tended to be less fixated as judged by independent raters, identified a decline in patient oxygen saturation more quickly, and more rapidly implemented the necessary intervention (surgical cricothyroidotomy). Conclusion: These findings have some real-world implications for positive affect in patient safety. Application: This research has broad implications for professions where fixation may impair practice. This research suggests that professional training should teach practitioners to identify their emotions and understand the role of these emotions in fixation.
Social network factors as mediators of mental health and psychological distress
Authors: Levula Andrew , Harré Michael , Wilson Andrew 
Published: March 2017

Background: Although mental health (MH) is overall strongly associated with psychological distress (PD), this association is very weak for the sample with high PD. This relationship remains understudied. Aim: This study examines the association between MH and PD and whether this association is mediated by social network (SN) factors for individuals with high PD. Method: Data were taken from the Household Income and Labour Dynamics in Australia study ( N = 756). MH was measured using the MH sub-scale of the general health survey (Short Form (SF)-36) and PD was measured using the Kessler Psychological Distress Scale (K10). The SN measures were derived from the self-completion questionnaire. Using bootstrap mediation analysis, we tested whether the association between MH and PD is mediated by SN factors. Result: The correlation between MH and PD was r = −.410 ( p < .001). The mediational analysis results show that social isolation mediates the association between MH and PD with an indirect effect of β = −0.0070 (confidence interval (CI) = −0.0133 to −0.0023). Moreover, social connections also mediated the association between MH and PD with an indirect effect of β = −0.0073 (CI = −0.0141 to −0.0028). Conclusion: This study has practical implications for the design of social policies that attempt to reduce social isolation and enhance social connectedness to protect MH.
Effect of exclusion of frequently consumed dietary triggers in a cohort of children with chronic primary headache
Authors: Taheri Sepideh 
Published: March 2017

Background: Although dietary factors are known to trigger headaches, the relationship between food and headache in children remains unclear. This prospective, observational case series aimed to evaluate the effect of exclusion of frequently-consumed foods in a cohort of children with headache. Methods: One hundred and fifteen children aged 3–15 (mean 10.5) years with primary headache were followed in a paediatric outpatient clinic. Patients who frequently consumed foods or food additives known to trigger headaches were advised to exclude them for six weeks and to return for follow-up with headache and food diary. Results: One hundred patients attended follow-up. Of these 13 (13%) did not respond to dietary exclusion; 87 (87%) achieved complete resolution of headaches by exclusion of 1–3 of the identified food(s). Caffeine was the most common implicated trigger (28), followed by monosodium glutamate (25), cocoa (22), aspartame (13), cheese (13), citrus (10) and nitrites (six). One patient was sensitive to tomatoes. Conclusions: This study demonstrates the potential scale and significance of seven frequently consumed foods or food additives as triggers for primary headache in children. Also this is the first study to show that headaches can be triggered by the cumulative effect of a food that is frequently consumed, rather than by single time ingestion.
Do virtual reality games improve mobility skills and balance measurements in community-dwelling older adults? Systematic review and meta-analysis
Authors: Neri Silvia GR , Cardoso Jefferson R , Cruz Lorena , Lima Ricardo M , de Oliveira Ricardo J , Iversen Maura D , Carregaro Rodrigo L 
Published: March 2017

Objective:To summarize evidence on the effectiveness of virtual reality games and conventional therapy or no-intervention for fall prevention in the elderly.Data sources:An electronic data search (last searched December 2016) was performed on 10 databases (Web of Science, EMBASE, PUBMED, CINAHL, LILACS, SPORTDiscus, Cochrane Library, Scopus, SciELO, PEDro) and retained only randomized controlled trials.Review method:Sample characteristics and intervention parameters were compared, focusing on clinical homogeneity of demographic characteristics, type/duration of interventions, outcomes (balance, reaction time, mobility, lower limb strength and fear of falling) and low risk of bias. Based on homogeneity, a meta-analysis was considered. Two independent reviewers assessed the risk of bias.Results:A total of 28 studies met the inclusion criteria and were appraised ( n: 1121 elderly participants). We found that virtual reality games presented positive effects on balance and fear of falling compared with no-intervention. Virtual reality games were also superior to conventional interventions for balance improvements and fear of falling. The six studies included in the meta-analysis demonstrated that virtual reality games significantly improved mobility and balance after 3–6 and 8–12 weeks of intervention when compared with no-intervention. The risk of bias revealed that less than one-third of the studies correctly described the random sequence generation and allocation concealment procedures.Conclusion:Our review suggests positive clinical effects of virtual reality games for balance and mobility improvements compared with no-treatment and conventional interventions. However, owing to the high risk of bias and large variability of intervention protocols, the evidence remains inconclusive and further research is warranted.
A randomized controlled feasibility trial exploring partnered ballroom dancing for people with Parkinson’s disease
Authors: Kunkel D , Fitton C , Roberts L , Pickering RM , Roberts HC , Wiles R , Hulbert S , Robison J , Ashburn A 
Published: March 2017

Objective: To determine the feasibility of a Dance Centre delivering a programme of mixed dances to people with Parkinson’s and identify suitable outcomes for a future definitive trial. Design: A two-group randomized controlled feasibility trial. Methods: People with Parkinson’s were randomized to a control or experimental group (ratio 15:35), alongside usual care. In addition, participants in the experimental group danced with a partner for one hour, twice-a-week for 10 weeks; professional dance teachers led the classes and field-notes were kept. Control-group participants were given dance class vouchers at the end of the study. Blinded assessments of balance, mobility and function were completed in the home. Qualitative interviews were conducted with a subsample to explore the acceptability of dance. Results: A total of 51 people with Parkinson’s (25 male) with Hoehn and Yahr scores of 1–3 and mean age of 71 years (range 49–85 years), were recruited to the study. Dance partners were of similar age (mean 68, range 56–91 years). Feasibility findings focused on recruitment (target achieved); retention (five people dropped out of dancing); outcome measures (three measures were considered feasible, changes were recommended). Proposed sample size for a Phase III trial, based on the 6-minute walk test at six months was 220. Participants described dance as extremely enjoyable and the instructors were skilled in instilling confidence and motivation. The main organizational challenges for a future trial were transport and identifying suitable dance partners. Conclusion: We have demonstrated the feasibility of conducting the study through a Dance Centre and recommend a Phase III trial.
Traumatic Patellar Dislocation and Cartilage Injury: A Follow-up Study of Long-Term Cartilage Deterioration
Authors: Salonen Essi E. , Magga Teemu , Sillanpää Petri J. , Kiekara Tommi , Mäenpää Heikki , Mattila Ville M. 
Published: March 2017

Background:Patellofemoral cartilage deterioration and osteoarthritis are reported to be associated with recurrent patellar dislocation. However, the association between first-time traumatic patellar dislocation and cartilage deterioration is unknown.Purpose:The aim of this study was to assess long-term cartilage deterioration in the patellofemoral and tibiofemoral joint after conservatively treated traumatic lateral patellar dislocation.Study Design:Case series; Level of evidence, 4.Methods:Twenty patients (mean age, 25 years) who sustained first-time traumatic lateral patellar dislocation with no previous patellofemoral instability symptoms were initially scanned with 1.5-T magnetic resonance imaging (MRI). A follow-up 3-T MRI was conducted, on average, 8 years after first-time lateral patellar dislocation. Subjective instability symptoms and Knee injury and Osteoarthritis Outcome Score were also assessed.Results:In the primary MRI, patellofemoral cartilage injury was seen in 14 of 20 patients (70%). Most (14/15) of the injuries were seen in the patellar cartilage, especially at the medial facet. On the follow-up MRI, patellofemoral cartilage deterioration was visible for all patients. The central patella ( P = .005) seemed especially prone to cartilage deterioration during the follow-up. Half of the patients (10/20) had grade 3-4 cartilage lesions in the patellofemoral joint in the follow-up MRI. In the primary MRI, only 1 patient exhibited tibiofemoral joint cartilage lesions, whereas at the time of follow-up, 10 of 20 patients exhibited tibiofemoral cartilage lesions. The majority of these lesions were considered clinically nonsignificant (International Cartilage Repair Society = 1) and were seen in the lateral compartment (6/10, 60%). Of the 14 patients (36%) with injury to the patellar cartilage, 5 reported subsequent instability of the patellofemoral joint, but this was not associated with more significant cartilage deterioration in the follow-up MRI compared with patients without redislocation.Conclusion:While recurrent lateral patellar dislocation is known to lead to degenerative process, a single first-time or infrequently recurring traumatic lateral patellar dislocation also seems to be associated with gradual cartilage deterioration. Traumatic lateral patellar dislocation might initiate gradual degeneration of the cartilage in the patellofemoral joint and can lead to the development of generalized knee osteoarthritis. Instability symptoms of the patellofemoral joint, however, were not related to the severity of the deterioration.