bluuebunny/crossref_metadata_2025_split huggingface dataset:
HER2 CAR-T Cells Eradicate Uveal Melanoma and T-cell Therapy–Resistant Human Melanoma in IL2 Transgenic NOD/SCID IL2 Receptor Knockout Mice
Authors: Forsberg Elin M.V. , Lindberg Mattias F. , Jespersen Henrik , Alsén Samuel , Bagge Roger Olofsson , Donia Marco , Svane Inge Marie , Nilsson Ola , Ny Lars , Nilsson Lisa M. , Nilsson Jonas A. 
Published: January 2019

Abstract

Chimeric antigen receptors (CAR) can transmit signals akin to those from activated T-cell receptors when bound to a cell surface target. CAR-expressing T cells against CD19 can cause curative effects in leukemia and lymphoma and is approved for clinical use. However, no CAR-T therapy is currently approved for use in solid tumors. We hypothesize that the resistance of solid tumors to CAR-T can be overcome by similar means as those used to reactivate tumor-infiltrating T lymphocytes (TIL), for example, by cytokines or immune checkpoint blockade. Here we demonstrate that CAR-T cells directed against HER2 can kill uveal and cutaneous melanoma cells in vitro and in vivo. Curative effects in vivo were only observed in xenografts grown in a NOD/SCID IL2 receptor gamma (NOG) knockout mouse strain transgenic for human IL2. The effect was target-specific, as CRISPR/Cas9-mediated disruption of HER2 in the melanoma cells abrogated the killing effect of the CAR-T cells. The CAR–T cells were also able to kill melanoma cells from patients resistant to adoptive T-cell transfer (ACT) of autologous TILs. Thus, CAR-T therapy represents an option for patients that do not respond to immunotherapy with ACT of TIL or immune checkpoint blockade. In addition, our data highlight the use of IL2 transgenic NOG mice as models to prove efficacy of CAR-T-cell products, possibly even in a personalized manner.

Significance:
These findings demonstrate that a novel humanized mouse model can help clinical translation of CAR-T cells against uveal and cutaneous melanoma that do not respond to TIL therapy or immune checkpoint blockade.
Developing Allogeneic Double-Negative T Cells as a Novel Off-the-Shelf Adoptive Cellular Therapy for Cancer
Authors: Lee Jong Bok , Kang Hyeonjeong , Fang Linan , D'Souza Cheryl , Adeyi Oyedele , Zhang Li 
Published: January 2019

Abstract

Purpose:
To expand clinical-grade healthy donor-derived double-negative T cells (DNT) to a therapeutically relevant number and characterize their potential to be used as an “off-the-shelf” adoptive cellular therapy (ACT) against cancers.

Experimental Design:
We developed methods to expand DNTs under GMP conditions and characterized their surface molecule expression pattern using flow cytometry–based high-throughput screening. We investigated the off-the-shelf potential of clinical-grade DNTs by assessing their cytotoxicity against various cancer types and their off-tumor toxicity in vitro and in xenograft models and determining the effect of cryopreservation under GMP conditions on cell viability and cytotoxicity. Further, we determined the susceptibility of DNTs to conventional allogeneic T cells in vitro and in vivo.

Results:
Clinical-grade DNTs expanded 1,558 ± 795.5-fold in 17 days with &gt;90% purity. Expanded DNTs showed potent in vitro cytotoxic activity against various cancer types in a donor-unrestricted manner. DNTs enhanced the survival of mice infused with a lethal dose of EBV-LCL and significantly reduced leukemia engraftment in xenograft models. Expanded DNTs cryopreserved using GMP-compliant reagents maintained viability and anticancer functions for at least 600 days. Live allogeneic DNTs did not induce cytotoxicity of alloreactive CD8+ T cells in vitro, and coinfusion of DNTs with peripheral blood mononuclear cells (PBMC) from a different donor into mice resulted in coengraftment of DNTs and PBMC-derived allogeneic conventional T cells in the absence of cytotoxicity toward DNTs, suggesting the lack of host-versus-graft reaction.

Conclusions:
We have established a method to generate therapeutic numbers of clinical-grade DNTs that fulfill the requirements of an off-the-shelf ACT.
Brentuximab Vedotin plus Chemotherapy in North American Subjects with Newly Diagnosed Stage III or IV Hodgkin Lymphoma
Authors: Ramchandren Radhakrishnan , Advani Ranjana H. , Ansell Stephen M. , Bartlett Nancy L. , Chen Robert , Connors Joseph M. , Feldman Tatyana , Forero-Torres Andres , Friedberg Jonathan W. , Gopal Ajay K. , Gordon Leo I. , Kuruvilla John , Savage Kerry J. , Younes Anas , Engley Gerald , Manley Thomas J. , Fenton Keenan , Straus David J. 
Published: January 2019

Abstract

Purpose:
To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study treated in North America (NA).

Patients and Methods:
ECHELON-1 is a global, open-label, randomized phase III study comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD + bleomycin) as first-line therapy in subjects with stage III or IV classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive A+AVD or ABVD intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles.

Results:
The NA subgroup consisted of 497 subjects in the A+AVD (n = 250) and ABVD (n = 247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary endpoint [modified progression-free survival (PFS) per independent review] demonstrated an improvement among subjects who received A+AVD compared with ABVD (HR = 0.60; P = 0.012). For PFS, the risk of progression or death was also reduced (HR = 0.50; P = 0.002). Subsequent anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as compared with ABVD. Noted differences between arms included higher rates of febrile neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD.

Conclusions:
The efficacy benefit and manageable toxicity profile observed in the NA subgroup of ECHELON-1 support A+AVD as a frontline treatment option for patients with stage III or IV cHL.
Multiplex Quantitative Analysis of Tumor-Infiltrating Lymphocytes and Immunotherapy Outcome in Metastatic Melanoma
Authors: Wong Pok Fai , Wei Wei , Smithy James W. , Acs Balazs , Toki Maria I. , Blenman Kim R.M. , Zelterman Daniel , Kluger Harriet M. , Rimm David L. 
Published: January 2019

Abstract

Purpose:
Because durable response to programmed cell death 1 (PD-1) inhibition is limited to a subset of melanoma patients, new predictive biomarkers could have clinical utility. We hypothesize that pretreatment tumor-infiltrating lymphocyte (TIL) profiles could be associated with response.

Experimental Design:
Pretreatment whole tissue sections from 94 melanoma patients treated with anti–PD-1 therapy were profiled by multiplex immunofluorescence to perform TIL quantification (CD4, CD8, CD20) and assess TIL activation (CD3, GZMB, Ki67). Two independent image analysis technologies were used: inForm (PerkinElmer) to determine cell counts, and AQUA to measure protein by quantitative immunofluorescence (QIF). TIL parameters by both methodologies were correlated with objective response or disease control rate (ORR/DCR) by RECIST 1.1 and survival outcome.

Results:
Pretreatment lymphocytic infiltration, by cell counts or QIF, was significantly higher in complete or partial response than in stable or progressive disease, particularly for CD8 (P &lt; 0.0001). Neither TIL activation nor dormancy was associated with outcome. CD8 associations with progression-free survival (HR &gt; 3) were independently significant in multivariable analyses and accounted for similar CD3 associations in anti–PD-1-treated patients. CD8 was not associated with melanoma prognosis in the absence of immunotherapy. Predictive performance of CD8 cell count (and QIF) had an area under the ROC curve above 0.75 (ORR/DCR), which reached 0.83 for ipilimumab plus nivolumab.

Conclusions:
Pretreatment lymphocytic infiltration is associated with anti–PD-1 response in metastatic melanoma. Quantitative TIL analysis has potential for application in digital precision immuno-oncology as an “indicative” companion diagnostic.
Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes
Authors: Binzer-Panchal Amrei , Hardell Elin , Viklund Björn , Ghaderi Mehran , Bosse Tjalling , Nucci Marisa R. , Lee Cheng-Han , Hollfelder Nina , Corcoran Pádraic , Gonzalez-Molina Jordi , Moyano-Galceran Lidia , Bell Debra A. , Schoolmeester John K. , Måsbäck Anna , Kristensen Gunnar B. , Davidson Ben , Lehti Kaisa , Isaksson Anders , Carlson Joseph W. 
Published: January 2019

AbstractPurpose:Undifferentiated uterine sarcomas (UUS) are rare, extremely deadly, sarcomas with no effective treatment. The goal of this study was to identify novel intrinsic molecular UUS subtypes using integrated clinical, histopathologic, and molecular evaluation of a large, fully annotated, patient cohort.Experimental Design:Fifty cases of UUS with full clinicopathologic annotation were analyzed for gene expression (n = 50), copy-number variation (CNV, n = 40), cell morphometry (n = 39), and protein expression (n = 22). Gene ontology and network enrichment analysis were used to relate over- and underexpressed genes to pathways and further to clinicopathologic and phenotypic findings.Results:Gene expression identified four distinct groups of tumors, which varied in their clinicopathologic parameters. Gene ontology analysis revealed differential activation of pathways related to genital tract development, extracellular matrix (ECM), muscle function, and proliferation. A multivariable, adjusted Cox proportional hazard model demonstrated that RNA group, mitotic index, and hormone receptor expression influence patient overall survival (OS). CNV arrays revealed characteristic chromosomal changes for each group. Morphometry demonstrated that the ECM group, the most aggressive, exhibited a decreased cell density and increased nuclear area. A cell density cutoff of 4,300 tumor cells per mm2 could separate ECM tumors from the remaining cases with a sensitivity of 83% and a specificity of 94%. IHC staining of MMP-14, Collagens 1 and 6, and Fibronectin proteins revealed differential expression of these ECM-related proteins, identifying potential new biomarkers for this aggressive sarcoma subgroup.Conclusions:Molecular evaluation of UUS provides novel insights into the biology, prognosis, phenotype, and possible treatment of these tumors.
Reserve of Right Ventricular-Arterial Coupling in the Setting of Chronic Overload
Authors: Tello Khodr , Dalmer Antonia , Axmann Jens , Vanderpool Rebecca , Ghofrani Hossein A. , Naeije Robert , Roller Fritz , Seeger Werner , Sommer Natascha , Wilhelm Jochen , Gall Henning , Richter Manuel J. 
Published: January 2019

Background:
Right ventricular (RV) maladaptation and failure determine outcome in pulmonary hypertension. The adaptation of RV function to loading (RV-pulmonary arterial coupling) is defined by a ratio of end-systolic to arterial elastances (Ees/Ea). How RV-pulmonary arterial coupling relates to pulmonary hypertension severity and onset of RV failure (defined by excessive volume increase and ejection fraction [EF] decrease) is not exactly known.

Methods and Results:

We performed cardiac magnetic resonance (CMR) imaging within 24 hours of a diagnostic right heart catheterization and invasive measurement of RV pressure-volume loops in 42 patients with pulmonary hypertension. Median (interquartile range) Ees and Ea were 0.49 (0.35–0.74) and 0.74 (0.45–1.04) mm Hg/mL, respectively; Ees/Ea was 0.73 (0.47–1.07). End-diastolic elastance (Eed) was 0.14 (0.06–0.24) mm Hg/mL. RV EF was 39±13%. End-systolic volume and end-diastolic volume/body surface area (BSA) were 62 (45–101) and 104 (83–143) mL/m
2
, respectively. Ees/Ea decreased with increasing RV end-diastolic volume/BSA, mass/BSA, and pulmonary arterial stiffness, and with decreasing EF, from 0.89 to 1.09 in the least impaired tertiles to 0.55 to 0.61 in the most impaired tertiles. Eed increased with increasing RV mass/BSA, end-diastolic volume/BSA, and T1 mapping and with decreasing EF. Receiver operating characteristic analysis identified an Ees/Ea cutoff of 0.805 associated with onset of RV failure defined by increased RV volumes with EF <35%.

Conclusions:
RV-pulmonary arterial coupling (Ees/Ea) has considerable reserve, from normal values of 1.5–2 to <0.8, and has the ability to detect pending RV failure in patients with pulmonary hypertension.

Clinical Trial Registration

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT03403868.
Human-in-the-loop energy flexibility integration on a neighbourhood level: Small and Big Data management
Authors: Zeiler Wim , Labeodan Timi 
Published: January 2019

Modern buildings provide an enormous amount of data available from various sources ranging from modular wireless sensors to smart meters. As well as enhancing energy management and building performance, the analysis of these datasets can enhance the management of decentralized energy systems (electrical storage, PV generation, heat storage, etc.). To optimize the interaction between the building and the grid, it is essential to determine the total energy flexibility of the user and the building. A building has different possibilities for demand side management, energy storage and energy exchange for which a functional-layered approach is proposed from the user up to building and its interaction with the energy infrastructure. Central is the principle of the human-in-the-loop, where a bottom-up approach places the human needs as a central starting point for the energy interaction optimisation. The combination of Big Data with deep learning techniques offers new possibilities in the prediction of energy use and decentralized renewable energy production (e.g. from local weather data taking into account local phenomena such as urban heat islands). This combined with a more bottom-up approach of multi-agent systems with a gossip-based cooperative approach using Small Data offers decentralized control and monitoring autonomy to reduce the complexity of the energy system integration and transition. This makes it possible to relate the outcomes of the urban energy system integration on a neighbourhood level. The approach is being applied to a typically medium-sized office building. A first application of the human-in-the-loop controlling the lighting systems in the open-plan workplace of the test-bed office building showed some estimated annual energy saving of around 24%. Practical application: Analysis of a large database containing so called Big Data of clusters of buildings seems promising. Therefor there is the need to study the potential impact of utilization of big building operational data in building services industry. Besides this there is also a need for a data mining-based method for analyzing massive building operational data of a specific building, Small Data. This work sets out a general framework and method for doing both and to combine the strength of both approaches. The presented combined approach and results will be of interest to engineers and facility managers wondering what the key constraints to optimal use data to optimize low energy/carbon control strategies might have within their work.
Characteristics of Early Work Experiences and Their Association with Future Employment
Authors: McDonnall Michele Capella , O'Mally Jamie 
Published: January 2019

Introduction Early work experiences are a key predictor of future employment for transition-age youths with visual impairments. We investigated how specific characteristics of early work experiences influence future employment and whether the receipt of Supplemental Security Income (SSI) benefits is associated with early work experiences among this population. Method Secondary data analyses were conducted using four waves of data from the second National Longitudinal Transition Study, which included a nationally representative sample of high school students with visual impairments who were receiving special education services. Results Future employment outcomes were positively associated with the characteristics of early work experiences, including finding a job independently, holding multiple jobs, and holding jobs for longer periods of time. Participating in school-sponsored work was not associated with future employment. Youths who received SSI benefits were significantly less likely to engage in productive activities, including employment, in Wave 3 than were those who did not receive benefits; however, this was not the case for youths who received SSI benefits in Wave 2. Discussion Not all early work experiences were found to be equally predictive of future employment for youths with visual impairments. The results indicate that it may not be sufficient for youths simply to be employed during high school without consideration of the types of work, how the jobs were obtained, or how long the jobs lasted. These characteristics of early work experiences are important to future employment and should be considered when helping youths prepare for the transition from school to work. Implications for Practitioners Professionals and parents should emphasize the benefits of early employment to youths with visual impairments. Youths should be encouraged to obtain multiple work experiences during high school while keeping in mind that longer job tenure is also positively associated with future employment. Professionals should particularly encourage youths who receive SSI benefits to obtain early work experiences and should inform them and their families about incentives that allow them to retain benefits while working.
LiveDescribe: Can Amateur Describers Create High-Quality Audio Description?
Authors: Branje Carmen J. , Fels Deborah I. 
Published: January 2019

Introduction The study presented here evaluated the usability of the audio description software LiveDescribe and explored the acceptance rates of audio description created by amateur describers who used LiveDescribe to facilitate the creation of their descriptions. Methods Twelve amateur describers with little or no previous experience with audio description used the software LiveDescribe to describe a single episode of a 20-minute comedy show. Seventy-five reviewers who were blind, had low vision, or were sighted then rated the descriptions using a number of criteria, including overall quality and entertainment value. Results LiveDescribe was found to be easy to use and useful. Three of the 12 describers produced descriptions that were rated as of good overall quality, 6 produced descriptions that were rated as of medium quality, and 3 produced descriptions that were rated as of poor quality. Discussion These findings indicate that amateur description is feasible even with minimal training in either description itself or LiveDescribe. Audiences’ preferences for description seem to be based on various characteristics of describers, such as the describers’ vernacular and tone of voice and the length and timing of the descriptions. Implications for practitioners If amateur description is indeed feasible, the quantity of audio descriptions that are available to the general public could be increased significantly. A great deal of informal description is already created by families and friends of individuals who are visually impaired through the “whisper method.” If this description process could be captured and formalized through a tool such as LiveDescribe and shared through the Internet, many more descriptions could be made available.
The use of Spatialized Speech in Auditory Interfaces for Computer users who are Visually Impaired
Authors: Sodnik Jaka , Jakus Grega , Tomažič Sašo 
Published: January 2019

Introduction This article reports on a study that explored the benefits and drawbacks of using spatially positioned synthesized speech in auditory interfaces for computer users who are visually impaired (that is, are blind or have low vision). The study was a practical application of such systems—an enhanced word processing application compared to conventional screen-reading software with a braille display. Methods Two types of user interfaces were compared in two experimental conditions: a JAWS screen reader equipped with an ALVA 544 Satellite braille display and a custom auditory interface based on spatialized speech. Twelve participants were asked to read and process three different text files with each interface and to collect the information about their form and structure. Task-completion times and the correctness of the perceived information on text decorations, text alignment, and table structures were measured. Results The spatial auditory interface proved to be significantly faster (3 minutes, 12 seconds) than the JAWS screen reader with ALVA braille display (8 minutes, 38 seconds), F(1,70) = 391.523, p < .001, and 15% more accurate when gathering information on text alignment, F(1,70) = 28.220, p < .001. No significant difference between the interfaces could be established when comparing questions on text decorations, F(1,70) = 0.912, p = .343, or table structures, F(1,70) = 1.045, p = .310). Discussion The findings show that the auditory interface with spatialized speech is more than 160% faster than the tactile interface while remaining equally accurate and effective for gathering information on various properties of text and tables. Implications for practitioners The spatial location of synthesized speech can be used for the fast presentation of the physical position of texts in a file, their alignment, the dimensions of tables, and the position of specific texts within tables. The quality of spatial sound reproduction can play an important role in the overall performance of such systems.
Perceptions of Teachers of Students with Visual Impairments regarding Assistive Technology: A Follow-up Study to a University Course
Authors: Kamei-Hannan Cheryl , Howe Jon , Herrera Robyn Rene , Erin Jane N. 
Published: January 2019

Introduction The study presented here examined the learning outcomes of graduate students in visual impairment who were enrolled in an assistive technology course in three university programs. Methods The students’ perceptions of learning were evaluated using pre-and posttests administered during the course. A follow-up questionnaire was e-mailed to the participants in 2011. Information gathered in the questionnaire included the participants’ demographic characteristics, perceived level of skill, training since completion of the course, frequency of use of the devices with students, and perceptions of the importance of specific devices. Variables were coded using a Likert scale, and correlations were coded using Spearman's correlation for nonparametric data. Results Pre–posttest data (n = 97) showed the participants’ improvement in the use of devices introduced during the class, with a greater increase in devices specific to visual impairment. Data from the follow-up questionnaires (n = 60) revealed a relationship between the perceived importance of the devices, frequency of use, and the participants’ skills. The participants were more likely to seek additional training if they perceived that a technology was frequently used and important. Discussion The results suggest that a formal assistive technology course can contribute to the development of skills and that the participants’ initiatives in setting priorities and seeking additional training were important for their continued acquisition of technology skills. Implications for practice Teachers can benefit from university-based training in the use of assistive technology. Also, continued development of such skills is necessary to allow the teachers to gain expertise in the use of frequently used devices and in devices that they perceive as important in educational settings.