bluuebunny/crossref_metadata_2025_split huggingface dataset:
FS118, a Bispecific Antibody Targeting LAG-3 and PD-L1, Enhances T-Cell Activation Resulting in Potent Antitumor Activity
Authors: Kraman Matthew , Faroudi Mustapha , Allen Natalie L. , Kmiecik Katarzyna , Gliddon Daniel , Seal Claire , Koers Alexander , Wydro Mateusz M. , Batey Sarah , Winnewisser Julia , Young Lesley , Tuna Mihriban , Doody Jacqueline , Morrow Michelle , Brewis Neil 
Published: April 2020

AbstractPurpose:Although programmed death-ligand 1 (PD-L1) antibody–based therapy has improved the outcome of patients with cancer, acquired resistance to these treatments limits their clinical efficacy. FS118 is a novel bispecific, tetravalent antibody (mAb2) against human lymphocyte activation gene-3 (LAG-3) and PD-L1 with the potential to reinvigorate exhausted immune cells and overcome resistance mechanisms to PD-L1 blockade. Here, using FS118 and a murine surrogate, we characterized the activity and report a novel mechanism of action of this bispecific antibody.Experimental Design:This study characterizes the binding activity and immune function of FS118 in cell lines and human peripheral blood mononuclear cells and further investigates its antitumor activity and mechanism of action using a surrogate murine bispecific antibody (mLAG-3/PD-L1 mAb2).Results:FS118 demonstrated simultaneous binding to LAG-3 and PD-L1 with high affinity and comparable or better activity than the combination of the single component parts of the mAb2 in blocking LAG-3- and PD-L1–mediated immune suppression and enhancing T-cell activity. In syngeneic tumor mouse models, mLAG-3/PD-L1 mAb2 significantly suppressed tumor growth. Mechanistic studies revealed decreased LAG-3 expression on T cells following treatment with the mouse surrogate mLAG-3/PD-L1 mAb2, whereas LAG-3 expression increased upon treatment with the combination of mAbs targeting LAG-3 and PD-L1. Moreover, following binding of mLAG-3/PD-L1 mAb2 to target-expressing cells, mouse LAG-3 is rapidly shed into the blood.Conclusions:This study demonstrates a novel benefit of the bispecific approach over a combination of mAbs and supports the further development of FS118 for the treatment of patients with cancer.
SHP-2 and PD-L1 Inhibition Combined with Radiotherapy Enhances Systemic Antitumor Effects in an Anti–PD-1–Resistant Model of Non–Small Cell Lung Cancer
Authors: Chen Dawei , Barsoumian Hampartsoum B. , Yang Liangpeng , Younes Ahmed I. , Verma Vivek , Hu Yun , Menon Hari , Wasley Mark , Masropour Fatemeh , Mosaffa Sara , Ozgen Tugce , Klein Katherine , Cortez Maria Angelica , Welsh James W. 
Published: April 2020

Abstract
Immune checkpoint inhibitors, such as anti–PD-1/PD-L1, have emerged as promising therapies for advanced non–small cell lung cancer (NSCLC). However, approximately 80% of patients do not respond to immunotherapy given alone because of intrinsic or acquired resistance. Radiotherapy (XRT) can overcome PD-1 resistance and improve treatment outcomes, but its efficacy remains suboptimal. The tyrosine phosphatase SHP-2, expressed in some cancers and in immune cells, has been shown to negatively affect antitumor immunity. Our hypothesis was that SHP-2 inhibition in combination with anti–PD-L1 would enhance immune-mediated responses to XRT and synergistically boost antitumor effects in an anti–PD-1–resistant mouse model. We treated 129Sv/Ev mice with anti–PD-1–resistant 344SQ NSCLC adenocarcinoma with oral SHP099 (a SHP-2 inhibitor) combined with XRT and intraperitoneal anti–PD-L1. Primary tumors were treated with XRT (three fractions of 12 Gy each), whereas abscopal (out-of-field) tumors were observed but not treated. XRT in combination with SHP099 and anti–PD-L1 promoted local and abscopal responses, reduced lung metastases, and improved mouse survival. XRT also increased SHP-2+ M1 tumor-associated macrophages in abscopal tumors (P = 0.019). The addition of SHP099 also associated with a higher M1/M2 ratio, greater numbers of CD8+ T cells, and fewer regulatory T cells. This triple-combination therapy had strong antitumor effects in a mouse model of anti–PD-1–resistant NSCLC and may be a novel therapeutic approach for anti–PD-1–resistant NSCLC in patients.
Marked Arterial Functional Changes in Patients With Arterial Vascular Events Across the Early Adult Lifespan
Authors: Motau Tshegofatso H. , Norton Gavin R. , Sadiq Eitzaz , Manyatsi Nomvuyo , Kolkenbeck-Ruh Andrea , Robinson Chanel , Tade Grace , Mabena Philanathi , Monareng Taalib , Naran Ravi , Peters Ferande , Peterson Vernice , Abdool-Carrim Talib , Veller Martin , Majane Olebogeng H.I. , Sareli Pinhas , Cassimjee Ismail , Modi Girish , Woodiwiss Angela J. 
Published: April 2020

Objective:
The age at which arteriosclerosis begins to contribute to events is uncertain. We determined, across the adult lifespan, the extent to which arteriosclerosis-related changes in arterial function occur in those with precipitous arterial events (stroke and critical limb ischemia).

Approaches and Results:

In 1082 black South Africans (356 with either critical limb ischemia [n=238] or stroke [n=118; 35.4% premature], and 726 age, sex, and ethnicity-matched randomly selected controls), arterial function was evaluated from applanation tonometry and velocity and diameter measurements in the outflow tract. Compared with age- and sex-matched controls, over 10-year increments in age from 20 to 60years, multivariate-adjusted (including steady-state pressures) aortic pulse wave velocity, characteristic impedance (Zc), forward wave pressures (Pf), and early systolic pulse pressure amplification were consistently altered in those with arterial events. Increases in Zc were accounted for by aortic stiffness (no differences in aortic diameter) and Pf by changes in Zc and not aortic flow or wave re-reflection. Multivariate-adjusted pulse wave velocity (7.48±0.30 versus 5.82±0.15 m/s,
P
<0.0001), Zc (
P
<0.0005), and Pf (
P
<0.0001) were higher and early systolic pulse pressure amplification lower (
P
<0.0001) in those with precipitous events than in controls. In comparison to age- and sex-matched controls, independent of risk factors, pulse wave velocity, and Zc (
P
<0.005 and <0.05) were more closely associated with premature events than events in older persons and Pf and early systolic pulse pressure amplification were at least as closely associated with premature events as events in older persons.

Conclusions:
Arteriosclerosis-related changes in arterial function are consistently associated with arterial events beyond risk factors from as early as 20 years of age.
Coronary Endothelial Dysfunction Is Associated With Increased Risk of Incident Atrial Fibrillation
Authors: Corban Michel T. , Godo Shigeo , Burczak Daniel R. , Noseworthy Peter A. , Toya Takumi , Lewis Bradley R. , Lerman Lilach O. , Gulati Rajiv , Lerman Amir 
Published: April 2020

Background

Coronary artery disease risk factors are associated with atrial fibrillation (
AF
) and coronary endothelial dysfunction (
CED
). We hypothesized that
CED
is associated with increased risk of incident
AF
among patients with chest pain and nonobstructive coronary artery disease.

Methods and Results

Three hundred patients with chest pain, nonobstructive coronary artery disease, and no history of
AF
underwent intracoronary acetylcholine infusion for evaluation of baseline epicardial (decrease in mid–left anterior descending coronary artery diameter in response to acetylcholine) and microvascular (<50% increase in coronary blood flow in response to acetylcholine)
CED
. Primary outcome was incident
AF
over a mean follow‐up period of 10.5±5.5 years. Mean age was 53.3±10.8 years, and 70% were women. Baseline clinical and echocardiographic characteristics were similar between patients with
CED
(n=256) and those with normal endothelial function (n=44). Overall, 35 of 300 (12%) patients developed
AF
, among whom 34 of 35 (97%) had
CED
at baseline. Compared with normal endothelial function, the presence of
CED
was associated with 11% increased absolute risk and 5.8‐fold increased relative risk of incident
AF
. Moreover,
CED
(
odds ratio
, 3.87; 95%
CI
, 1.27–47.0) and increased (>34 mL/m
2
) left atrial volume index (odds ratio, 3.87; 95%
CI
, 1.60–9.11) were independent predictors of incident
AF
.

Conclusions

Patients with normal coronary endothelial function, as compared with those with
CED
and similar
AF
risk factors, have significantly lower incidence of
AF
on long‐term follow‐up. The potential mechanistic link between vascular dysfunction and
AF
development warrants further investigation.
Outcomes and Care Quality Metrics for Women of Reproductive Age Living With Rheumatic Heart Disease in Uganda
Authors: Chang Andrew Y. , Nabbaale Juliet , Okello Emmy , Ssinabulya Isaac , Barry Michele , Beaton Andrea Z. , Webel Allison R. , Longenecker Chris T. 
Published: April 2020

Background
Rheumatic heart disease disproportionately affects women of reproductive age, as it increases the risk of cardiovascular complications and death during pregnancy and childbirth. In sub‐Saharan Africa, clinical outcomes and adherence to guideline‐based therapies are not well characterized for this population.

Methods and Results

In a retrospective cohort study of the Uganda rheumatic heart disease registry between June 2009 and May 2018, we used multivariable regression and Cox proportional hazards models to compare comorbidities, mortality, anticoagulation use, and treatment cascade metrics among women versus men aged 15 to 44 with clinical rheumatic heart disease. We included 575 women and 252 men with a median age of 27 years. Twenty percent had New York Heart Association Class
III
‐
IV
heart failure. Among patients who had an indication for anticoagulation, women were less likely than men to receive a prescription of warfarin (66% versus 81%; adjusted odds ratio, 0.37; 95%
CI
, 0.14–0.96). Retention in care (defined as a clinic visit within the preceding year) was poor among both sexes in this age group (27% for men, 24% for women), but penicillin adherence rates were high among those retained (89% for men, 92% for women). Mortality was higher in men than women (26% versus 19% over a median follow‐up of 2.7 years; adjusted hazard ratio, 1.66; 95%
CI,
1.18–2.33).

Conclusions
Compared with men, women of reproductive age with rheumatic heart disease in Uganda have lower rates of appropriate anticoagulant prescription but also lower mortality rates. Retention in care is poor among both men and women in this age range, representing a key target for improvement.
Mobile Stroke Unit Computed Tomography Angiography Substantially Shortens Door-to-Puncture Time
Authors: Czap Alexandra L. , Singh Noopur , Bowry Ritvij , Jagolino-Cole Amanda , Parker Stephanie A. , Phan Kenny , Wang Mengxi , Sheth Sunil A. , Rajan Suja S. , Yamal Jose-Miguel , Grotta James C. 
Published: April 2020

Background and Purpose—
Endovascular thrombectomy (ET) door-to-puncture time (DTPT) is a modifiable metric. One of the most important, yet time-consuming steps, is documentation of large vessel occlusion by computed tomography angiography (CTA). We hypothesized that obtaining CTA on board a Mobile Stroke Unit and direct alert of the ET team shortens DTPT by over 30 minutes.

Methods—
We compared DTPT between patients having CTA onboard the Mobile Stroke Unit then subsequent ET from September 2018 to November 2019 and patients in Mobile Stroke Unit from August 2014 to August 2018, when onboard CTA was not yet being used. We also correlated DTPT with change in National Institutes of Health Stroke Scale between baseline and 24 hours.

Results—

Median DTPT was 53.5 (95% CI, 35–67) minutes shorter with onboard CTA and direct ET team notification: 41 minutes (interquartile range, 30.0–63.5) versus 94.5 minutes (interquartile range, 69.8–117.3;
P
<0.001). Median on-scene time was 31.5 minutes (interquartile range, 28.8–35.5) versus 27.0 minutes (interquartile range, 23.0–31.0) (
P
<0.001). Shorter DTPT correlated with greater improvement of National Institutes of Health Stroke Scale (correlation=−0.2,
P
=0.07).

Conclusions—
Prehospital Mobile Stroke Unit management including on-board CTA and ET team alert substantially shortens DTPT.

Registration—

URL:
https://clinicaltrials.gov
; Unique identifier: NCT02190500.
Applicability of the UNIDROIT Principles as the Law Governing the Merits of Arbitration in the Gulf Cooperation Council Countries
Authors: Dawwas Amin , Kameel Tareq 
Published: April 2020

Abstract
According to the principle of party autonomy, the disputant parties may choose the law applicable to the merits of international commercial arbitration. In the absence of the parties’ choice, the arbitral tribunal shall determine this law. This article discusses the applicability of ‘rules of law’, namely the UNIDROIT Principles of International Commercial Contracts (UNIDROIT Principles) to the merits of the dispute. It shows whether the UNIDROIT Principles can be selected by the disputant parties or the arbitral tribunal to govern the subject of the dispute under the Arbitration Laws of the Gulf Cooperation Council (GCC) Countries as well as the Constitution and the Arbitral Rules of Procedure of the GCC Commercial Arbitration Center (GCCCAC).
Stabreimende Wortpaare in Wolframs “Willehalm”, “Titurel” und in seiner Lyrik
Authors: Jeep John M. 
Published: April 2020

Abstract
This study presents a first-time complete accounting and analysis of the alliterating word-pairs in Wolfram’s “Willehalm,” “Titurel,” and his poetry, representing the completion of a project to survey Wolframs’ complete oeuvre. Each pair is described philologically within the work in which it appears, relevant earlier or parallel occurrences are noted, and on occasion the further life of the pair is discussed. A complete listing integrates the 98 pairs from “Parzival.” This rounds out studies of the major Middle High German classical works of courtly literature, cataloguing Wolfram’s use of the rhetorical device following similar studies of Hartmann von Aue and Gottfried von Strassburg.
The impact of socioeconomic deprivation on the uptake of colorectal cancer screening in London
Authors: Lal Nikhil , Singh Harpreet KSI , Majeed Azeem , Pawa Nikhil 
Published: April 2020

Objective Screening programmes based on the faecal occult blood test (FOBT) can reduce mortality from colorectal cancer (CRC). However, a significant variation exists in uptake of the test within the UK. Disproportionate uptake risks increasing inequity during staging at diagnosis and survival from CRC. This study aims to evaluate the impact of socioeconomic deprivation on the uptake of CRC screening (FOBT) in London. Methods A retrospective review of the “Vanguard RM Informatics” database was performed to identify eligible individuals for CRC screening across all general practices across London over 30 months (2014–2017). The postcodes of the general practices were used to obtain the deprivation data via the “Indices of Deprivation” database. A Spearman’s rho correlation was performed to quantify the impact of the deprivation variables on FOBT uptake. Results Overall, 697,402 individuals were eligible for screening across 1359 London general practices, within 5 Clinical Commissioning Groups (CCGs); 48.4% (range: 13%–74%) participated in CRC screening with the lowest participation rates in North West (46%) and North East (47%) London CCGs. All indices of deprivation had a significant correlation with the uptake of FOBT ( p < 0.01). Conclusion This is the largest study across London to date demonstrating a significant positive correlation between deprivation indices and FOBT uptake, highlighting areas of particular risk. Further studies are imperative to quantify the impact of deprivation on CRC morbidity and mortality, together with focused strategies to reduce socioeconomic inequalities in screening in these high risk areas.
Machine Learning-Based Adherence Detection of Type 2 Diabetes Patients on Once-Daily Basal Insulin Injections
Authors: Thyde Daniel N. , Mohebbi Ali , Bengtsson Henrik , Jensen Morten Lind , Mørup Morten 
Published: April 2020

Background: Lack of treatment adherence can lead to life-threatening health complications for people with type 2 diabetes (T2D). Recent improvements and availability in continuous glucose monitoring (CGM) technology have enabled various possibilities to monitor diabetes treatment. Detection of missed once-daily basal insulin injections can be used to provide feedback to patients, thus improving their diabetes management. In this study, we explore how machine learning (ML) based on CGM data can be used for detecting adherence to once-daily basal insulin injections. Methods: In-silico CGM data were generated to simulate a cohort of T2D patients on once-daily insulin injection (Tresiba®). Deep learning methods within ML based on automatic feature extraction including convolutional neural networks were explored and compared with simple feature-engineered ML classification models for adherence detection. It was further investigated whether fused expert-dependent and automatically learned features could improve performance, resulting in a comparison of six different detection models. Adherence was detected throughout each day with an increasing amount of CGM data available. Results: The adherence detection accuracy improved as more CGM data became available on the day of classification. The three classification models based on expert-engineered features obtained mean accuracies of 78.6%, 78.2%, and 78.3%. The classification model based purely on learned features obtained a mean accuracy of 79.7%. The two classification models fusing expert-engineered and learned features obtained mean accuracies of 79.7% and 79.8%. All the mentioned results were obtained 16 hours after time of injection. Conclusion: The results suggest that adherence detection based on CGM data is feasible. Even though our study based on in-silico data indicates only slightly improved performance of more complex models, the question remains whether advanced models would outperform the simple in a real-world setting. Thus, future studies on adherence monitoring using real CGM data are relevant.
Biological and clinical significance of dysplastic hematopoiesis in patients with newly diagnosed multiple myeloma
Authors: Maia Catarina , Puig Noemi , Cedena Maria-Teresa , Goicoechea Ibai , Valdes-Mas Rafael , Vazquez Iria , Chillon Maria-Carmen , Aguirre Paula , Sarvide Sarai , Gracia-Aznárez Francisco Javier , Alkorta Gorka , Calasanz Maria-Jose , Garcia-Sanz Ramon , Gonzalez Marcos , Gutierrez Norma C. , Martinez-Lopez Joaquin , Perez José J. , Merino Juana , Moreno Cristina , Burgos Leire , Alignani Diego , Botta Cirino , Prosper Felipe , Matarraz Sergio , Orfao Alberto , Oriol Albert , Teruel Ana-Isabel , de Paz Raquel , de Arriba Felipe , Hernandez Miguel T. , Palomera Luis , Martinez Rafael , Rosiñol Laura , Mateos Maria-Victoria , Lahuerta Juan-Jose , Blade Joan , San Miguel Jesus F. , Paiva Bruno 
Published: April 2020

AbstractRisk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell–targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the most frequently mutated genes. Dynamics of MDS-PA at diagnosis and after autologous transplant were evaluated in 86 of 285 patients and showed that in most cases (69 of 86 [80%]), MDS-PA either persisted or remained absent in patients with or without MDS-PA at diagnosis, respectively. Noteworthy, MDS-associated mutations infrequently emerged after high-dose therapy. Based on MFC profiling, patients with MDS-PA have altered hematopoiesis and T regulatory cell distribution in the tumor microenvironment. Importantly, the presence of monocytic MDS-PA at diagnosis anticipated greater risk of hematologic toxicity and was independently associated with inferior progression-free survival (hazard ratio, 1.5; P = .02) and overall survival (hazard ratio, 1.7; P = .01). This study reveals the biological and clinical significance of dysplastic hematopoiesis in newly diagnosed MM, which can be screened with moderate sensitivity using cost-effective MFC.
Operon-based approach for the inference of rRNA and tRNA evolutionary histories in bacteria
Authors: Pawliszak Tomasz , Chua Meghan , Leung Carson K. , Tremblay-Savard Olivier 
Published: April 2020

Abstract
Background
In bacterial genomes, rRNA and tRNA genes are often organized into operons, i.e. segments of closely located genes that share a single promoter and are transcribed as a single unit. Analyzing how these genes and operons evolve can help us understand what are the most common evolutionary events affecting them and give us a better picture of ancestral codon usage and protein synthesis.

Results
We introduce , a new approach for the inference of evolutionary histories of rRNA and tRNA genes in bacteria, which is based on the identification of orthologous operons. Since operons can move around in the genome but are rarely transformed (e.g. rarely broken into different parts), this approach allows for a better inference of orthologous genes in genomes that have been affected by many rearrangements, which in turn helps with the inference of more realistic evolutionary scenarios and ancestors.

Conclusions
From our comparisons of with other gene order alignment programs using simulated data, we have found that infers evolutionary events and ancestral gene orders more accurately than other methods based on alignments. An analysis of 12 Bacillus genomes also showed that performs just as well as other programs at building ancestral histories in a minimal amount of events.
Modern human changes in regulatory regions implicated in cortical development
Authors: Moriano Juan , Boeckx Cedric 
Published: April 2020

Abstract
Background
Recent paleogenomic studies have highlighted a very small set of proteins carrying modern human-specific missense changes in comparison to our closest extinct relatives. Despite being frequently alluded to as highly relevant, species-specific differences in regulatory regions remain understudied. Here, we integrate data from paleogenomics, chromatin modification and physical interaction, and single-cell gene expression of neural progenitor cells to identify derived regulatory changes in the modern human lineage in comparison to Neanderthals/Denisovans. We report a set of genes whose enhancers and/or promoters harbor modern human single nucleotide changes and are active at early stages of cortical development.

Results
We identified 212 genes controlled by regulatory regions harboring modern human changes where Neanderthals/Denisovans carry the ancestral allele. These regulatory regions significantly overlap with putative modern human positively-selected regions and schizophrenia-related genetic loci. Among the 212 genes, we identified a substantial proportion of genes related to transcriptional regulation and, specifically, an enrichment for the SETD1A histone methyltransferase complex, known to regulate WNT signaling for the generation and proliferation of intermediate progenitor cells.

Conclusions
This study complements previous research focused on protein-coding changes distinguishing our species from Neanderthals/Denisovans and highlights chromatin regulation as a functional category so far overlooked in modern human evolution studies. We present a set of candidates that will help to illuminate the investigation of modern human-specific ontogenetic trajectories.