bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer cell-intrinsic resistance to BiTE therapy is mediated by loss of CD58 costimulation and modulation of the extrinsic apoptotic pathway
Authors: Shen Ye , Eng Jason S , Fajardo Flordeliza , Liang Lingming , Li Cong , Collins Patrick , Tedesco Donato , Nolan-Stevaux Olivier 
Published: March 2022

BackgroundBispecific T-cell engager (BiTE) molecules induce redirected lysis of cancer cells by T cells and are an emerging modality for solid tumor immunotherapy. While signs of clinical activity have been demonstrated, efficacy of T-cell engagers (TCEs) in solid tumors settings, molecular determinants of response, and underlying mechanisms of resistance to BiTE therapy require more investigation.MethodsTo uncover cancer cell-intrinsic genetic modifiers of TCE-mediated cytotoxicity, we performed genome-wide CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loss-of-function and CRISPRa (CRISPR activation) gain-of-function screens using TCEs against two distinct tumor-associated antigens (TAAs). By using in vitro T-cell cytotoxicity assays and in vivo efficacy studies, we validated the roles of two common pathways identified in our screen, T-cell costimulation pathway and apoptosis pathway, as key modifiers of BiTE activity.ResultsOur genetic screens uncovered TAAs-independent cancer cell-intrinsic genes with functions in autophagy, T-cell costimulation, the apoptosis pathway, chromatin remodeling, and cytokine signaling that altered responsiveness to BiTE-mediated killing. Notably, loss of CD58 (the ligand of the CD2 T-cell costimulatory receptor), a gene frequently altered in cancer, led to decreased TCE-mediated cytotoxicity, T-cell activation and antitumor efficacy in vitro and in vivo. Moreover, the effects of CD58 loss were synergistically compounded by concurrent loss of CD80/CD86 (ligands for the CD28 T-cell costimulatory receptor), whereas joint CD2 and CD28 costimulation additively enhanced TCE-mediated killing, indicating non-redundant costimulatory mechanisms between the two pathways. Additionally, loss ofCFLAR(Caspase-8 and FADD Like Apoptosis Regulator),BCL2L1, andBID(BH3 Interacting Domain Death Agonist) induced profound changes in sensitivity to TCEs, indicating that key regulators of apoptosis, which are frequently altered in cancer, impact tumor responsiveness to BiTE therapy.ConclusionsThis study demonstrates that genetic alterations central to carcinogenesis and commonly detected in cancer samples lead to significant modulation of BiTE antitumor activity in vitro and in vivo, findings with relevance for a better understanding of patient responses to BiTE therapy and novel combinations that enhance TCE efficacy.
Decolonising ‘man’, resituating pandemic: an intervention in the pathogenesis of colonial capitalism
Authors: Jolly Rosemary J 
Published: March 2022

This paper brings together fifth-wave public health theory and a decolonised approach to the human informed by the Caribbean thinker, Sylvia Wynter, and the primary exponent of African Humanism, Es’kia Mpahlele. Sub-Saharan indigenous ways of thinking the human as co-constitutive in a subject we might call human-animal-‘environment’, in conjunction with the subcontinent’s experiences of colonial damage in disease ‘prevention’ and ‘treatment’, demonstrate the lack of genuine engagement with Indigenous wisdom in Western medical practice.The paper offers a decolonial reading of pandemic history, focused primarily on the human immunodefiency virus (HIV), the severe acute respiratory syndrome of 2003 caused by the SARS Covid 1 virus (SARS-CoV1) and COVID-19, caused by the SARS COVID 2 virus (SARS-CoV2) to demonstrate the importance of the co-constitutive subject in understanding the genesis of these pandemics as driven by colonial-capitalism. I emphasise that prevention will indeed take the kinds of massive changes proposed by fifth-wave public health theory. However, I differ from the proponents of that theory in an insistence that the new kind of thinking of the human Hanlonet alcall for, has already been conceived: just not within the confines of the normative human of Western culture.I illustrate that Western Global Health approaches remain constitutionally ‘deaf’ to approaches that, although the West may not understand this to be the case, arise from fundamentally different—and extra-anthropocentric—notions of the human. In this context, Man as Wynter names Him is a subject ripe for decolonisation, rather than a premier site of capitalist development, including that of healthcare provision.Recognising that most of us are not individually able to change the structural violence of the colonial capitalist system in which Global Health practices are embedded, I conclude with implications drawn from my argument for quotidian practices that enable healthcare providers see their actions within a harm reduction paradigm, in the context of communities experiencing intergenerational impoverishment consequent on colonial violence.
Association between time to treatment and clinical outcomes in endovascular thrombectomy beyond 6 hours without advanced imaging selection
Authors: Dhillon Permesh Singh , Butt Waleed , Podlasek Anna , McConachie Norman , Lenthall Robert , Nair Sujit , Malik Luqman , Bhogal Pervinder , Makalanda Hegoda Levansri Dilrukshan , Spooner Oliver , Krishnan Kailash , Sprigg Nikola , Mortimer Alex , Booth Thomas Calvert , Lobotesis Kyriakos , White Philip , James Martin A , Bath Philip , Dineen Robert A , England Timothy J 
Published: March 2022

BackgroundThe effectiveness and safety of endovascular thrombectomy (EVT) in the late window (6–24 hours) for acute ischemic stroke (AIS) patients selected without advanced imaging is undetermined. We aimed to assess clinical outcomes and the relationship with time-to-EVT treatment beyond 6 hours of stroke onset without advanced neuroimaging.MethodsPatients who underwent EVT selected with non-contrast CT/CT angiography (without CT perfusion or MR imaging), between October 2015 and March 2020, were included from a national stroke registry. Functional and safety outcomes were assessed in both early (<6 hours) and late windows with time analyzed as a continuous variable.ResultsAmong 3278 patients, 2610 (79.6%) and 668 (20.4%) patients were included in the early and late windows, respectively. In the late window, for every hour delay, there was no significant association with shift towards poorer functional outcome (modified Rankin Scale (mRS)) at discharge (adjusted common OR 0.98, 95% CI 0.94 to 1.01, p=0.27) or change in predicted functional independence (mRS ≤2) (24.5% to 23.3% from 6 to 24 hours; aOR 0.99, 95% CI0.94 to 1.04, p=0.85). In contrast, predicted functional independence was time sensitive in the early window: 5.2% reduction per-hour delay (49.4% to 23.5% from 1 to 6 hours, p=0.0001). There were similar rates of symptomatic intracranial hemorrhage (sICH) (3.4% vs 4.6%, p=0.54) and in-hospital mortality (12.9% vs 14.6%, p=0.33) in the early and late windows, respectively, without a significant association with time.ConclusionIn this real-world study, there was minimal change in functional disability, sICH and in-hospital mortality within and across the late window. While confirmatory randomized trials are needed, these findings suggest that EVT remains feasible and safe when performed in AIS patients selected without advanced neuroimaging between 6–24 hours from stroke onset.
Efficacy of three heat-stable microbial phytases on growth performance and bone development and strength of broilers fed diets deficient in available phosphorus
Authors: Solomon H.S. , Adejoro F.A. , Nkukwana T.T. 
Published: March 2022

A total of 2340 as-hatched Cobb500 chicks were allocated to 9 treatments, each with 13 replicate pens to evaluate the effects of either three phytase enzymes in a P-deficient diet. Starter and finisher diets consisted of a positive control (PC) and negative control 1 and 2 (NC1 and NC2, respectively). The PC, NC1, and NC2 diets had Ca:avP (available phosphorus) ratios of 0.50, 0.33, and 0.43 in the starter feed, and 0.46, 0.22, and 0.35 in the finisher feed, respectively; NC1 diets were then supplemented with Phytaverse, Quantum Blue, and Axtra-PHY at 500 and 1000 FTU/kg. Enzyme type had significant effects on body weight gain, feed conversion ratio, and production efficiency factor during the 0–7-day period. Interactions between enzyme type and inclusion levels had a significant effect on feed intake (FI) at 1–21-day ( P = 0.02) and 1–35-day ( P = 0.031) age. While FI decreased as Axtra-PHY inclusion levels increased from 500 to 1000 FTU/kg feed, FI increased in birds supplemented with Quantum Blue, but with no effects on Phytaverse-supplemented birds. Increasing the enzyme dose to 1000 FTU/kg feed improved bone-breaking strength but did not affect growth performance, tibia ash, Ca, or P concentration of the birds.
Displaced Higgs production in Type-III seesaw at the LHC/FCC, MATHUSLA and muon collider
Authors: Sen Chandrima , Bandyopadhyay Priyotosh , Dutta Saunak , KT Aleesha 
Published: March 2022

AbstractIn this article, we explore the possibility of displaced Higgs production from the decays of the heavy fermions in the Type-III seesaw extension of the Standard Model at the LHC/FCC and the muon collider. The displaced heavy fermions and the Higgs boson can be traced back by measuring the displaced charged tracks of the charged leptons along with the b-jets. A very small Yukawa coupling can lead to two successive displaced decays which makes the phenomenology even more interesting. The prospects of the transverse and longitudinal displaced decay lengths are extensively studied in the context of the boost at the LHC/FCC. Due to the parton distribution function, the longitudinal boosts leads to larger displacement compared to the transverse one, which can reach MATHUSLA and beyond. The longitudinal measurements are indeed possible by the visible part of the finalstate, which captures the complete information about the longitudinal momenta. The comparative studies are made at the LHC/FCC with the centre of mass energies of 14, 27 and 100 TeV, respectively. A futuristic study of the muon collider where the collision happen in the centre of mass frame is analysed for centre of mass energies of 3.5, 14 and 30 TeV. Contrary to LHC/FCC, here the transverse momentum diverges, however, the maximum reach in both the direction are identical due to the constant total momentum in each collision. The reach of the Yukawa couplings and fermion masses are appraised for both the colliders. FCC at 100 TeV can probe a mass of 4.25 TeV and a lowest Yukawa coupling of $${\mathcal {O}}(5 \times 10^{-11})$$

O
(
5
×

10

-
11

)

.
Model Transformation Testing and Debugging: A Survey
Authors: Troya Javier , Segura Sergio , Burgueño Lola , Wimmer Manuel 
Published: March 2022

Model transformations are the key technique in Model-Driven Engineering (MDE) to manipulate and construct models. As a consequence, the correctness of software systems built with MDE approaches relies mainly on the correctness of model transformations, and thus, detecting and locating bugs in model transformations have been popular research topics in recent years. This surge of work has led to a vast literature on model transformation testing and debugging, which makes it challenging to gain a comprehensive view of the current state-of-the-art. This is an obstacle for newcomers to this topic and MDE practitioners to apply these approaches. This article presents a survey on testing and debugging model transformations based on the analysis of 140 papers on the topics. We explore the trends, advances, and evolution over the years, bringing together previously disparate streams of work and providing a comprehensive view of these thriving areas. In addition, we present a conceptual framework to understand and categorize the different proposals. Finally, we identify several open research challenges and propose specific action points for the model transformation community.
Preclinical Development and Evaluation of Allogeneic CAR T Cells Targeting CD70 for the Treatment of Renal Cell Carcinoma
Authors: Panowski Siler H. , Srinivasan Surabhi , Tan Nguyen , Tacheva-Grigorova Silvia K. , Smith Bryan , Mak Yvonne S.L. , Ning Hongxiu , Villanueva Jonathan , Wijewarnasuriya Dinali , Lang Shanshan , Melton Zea , Ghosh Adit , Dusseaux Mathilde , Galetto Roman , Heyen Jonathan R. , Sai Tao , Van Blarcom Thomas , Chaparro-Riggers Javier , Sasu Barbra J. 
Published: March 2022

Abstract

CD70 is highly expressed in renal cell carcinoma (RCC), with limited expression in normal tissue, making it an attractive CAR T target for an immunogenic solid tumor indication. Here we generated and characterized a panel of anti-CD70 single-chain fragment variable (scFv)–based CAR T cells. Despite the expression of CD70 on T cells, production of CAR T cells from a subset of scFvs with potent in vitro activity was achieved. Expression of CD70 CARs masked CD70 detection in cis and provided protection from CD70 CAR T cell–mediated fratricide. Two distinct classes of CAR T cells were identified with differing memory phenotype, activation status, and cytotoxic activity. Epitope mapping revealed that the two classes of CARs bind unique regions of CD70. CD70 CAR T cells displayed robust antitumor activity against RCC cell lines and patient-derived xenograft mouse models. Tissue cross-reactivity studies identified membrane staining in lymphocytes, thus matching the known expression pattern of CD70. In a cynomolgus monkey CD3-CD70 bispecific toxicity study, expected findings related to T-cell activation and elimination of CD70-expressing cells were observed, including cytokine release and loss of cellularity in lymphoid tissues. Finally, highly functional CD70 allogeneic CAR T cells were produced at large scale through elimination of the T-cell receptor by TALEN-based gene editing. Taken together, these efficacy and safety data support the evaluation of CD70 CAR T cells for the treatment of RCC and has led to the advancement of an allogeneic CD70 CAR T-cell candidate into phase I clinical trials.

Significance:
These findings demonstrate the efficacy and safety of fratricide-resistant, allogeneic anti-CD70 CAR T cells targeting renal cell carcinoma and the impact of CAR epitope on functional activity.
See related commentary by Adotévi and Galaine, p. 2517
Targeting Stearoyl-CoA Desaturase in Solid Tumors
Authors: Kubota Casie S. , Espenshade Peter J. 
Published: March 2022

AbstractCancer cells are demarcated from normal cells by distinct biological hallmarks, including the reprogramming of metabolic processes. One of the key players involved in metabolic reprogramming is stearoyl-CoA desaturase (SCD), which converts saturated fatty acids to monounsaturated fatty acids in an oxygen-dependent reaction that is crucial for maintaining fatty acid homeostasis. As such, SCD has been identified as a potential therapeutic target in numerous types of cancers, and its inhibition suppresses cancer cell growth in vitro and in vivo. This review summarizes the evidence implicating SCD in cancer progression and proposes novel therapeutic strategies for targeting SCD in solid tumors.
Three-Year Follow-Up and Response–Survival Relationship of Nivolumab in Previously Treated Patients with Advanced Esophageal Squamous Cell Carcinoma (ATTRACTION-3)
Authors: Okada Morihito , Kato Ken , Cho Byoung Chul , Takahashi Masanobu , Lin Chen-Yuan , Chin Keisho , Kadowaki Shigenori , Ahn Myung-Ju , Hamamoto Yasuo , Doki Yuichiro , Yen Chueh-Chuan , Kubota Yutaro , Kim Sung-Bae , Hsu Chih-Hung , Holtved Eva , Xynos Ioannis , Matsumura Yasuhiro , Takazawa Akira , Kitagawa Yuko 
Published: March 2022

Abstract

Purpose:
Limited long-term data are available on immune checkpoint inhibitor use in patients with advanced esophageal squamous cell carcinoma (ESCC). We report 3-year follow-up data from our study of nivolumab versus chemotherapy (paclitaxel or docetaxel) in patients with previously treated ESCC.

Patients and Methods:
ATTRACTION-3 was a randomized, multicenter, open-label, phase III trial. Overall survival (OS), time from randomization to death from any cause, was the primary endpoint. An exploratory subanalysis assessed OS according to the best overall response (BOR) with and without landmark at 4 months.

Results:
Of the enrolled patients, 210 received nivolumab and 209 received chemotherapy. With a minimum follow-up of 36.0 months, OS was longer in the nivolumab versus the chemotherapy group (median, 10.9 vs. 8.5 months; HR, 0.79; P = 0.0264), with 3-year OS rates of 15.3% and 8.7%, respectively. The median OS was longer with nivolumab versus chemotherapy irrespective of the BOR (complete response/partial response: 19.9 vs. 15.4 months; stable disease: 17.4 vs. 8.8 months; and progressive disease: 7.6 vs. 4.2 months). Grade 3 or higher treatment-related adverse events were reported in 40 patients (19.1%) in the nivolumab group and 133 patients (63.9%) in the chemotherapy group.

Conclusions:
Nivolumab as second-line therapy demonstrated clinically meaningful long-term improvement in OS compared with chemotherapy in previously treated patients with advanced ESCC. The OS was consistently improved in the nivolumab group compared with the chemotherapy group regardless of BOR. Nivolumab was well tolerated over the 3-year follow-up.
See related commentary by Yoon et al., p. 3173
Cerebrovascular Variants and the Role of the Selfish Brain in Young-Onset Hypertension
Authors: Manghat Nathan E. , Robinson Elizabeth , Mitrousi Konstantina , Rodrigues Jonathan C.L. , Hinton Thomas , Paton Julian F.R. , Wise Richard G. , Nightingale Angus K. , Hart Emma C. 
Published: March 2022

Background:
Variants in the posterior anatomy of the cerebral circulation are associated with hypertension and lower cerebral blood flow in midlife (age ≈55 years); however, whether these variants are a result of aging or long-term exposure to high blood pressure is unclear. Additionally, the role these variants play in early onset of hypertension (<40 years) and poor cerebral perfusion in this population is unknown.

Methods:
We retrospectively examined whether specific cerebrovascular variants (vertebral artery hypoplasia and absent/hypoplastic posterior communicating arteries (an incomplete posterior circle of Willis) measured via magnetic resonance angiography) were associated with a diagnosis of hypertension in 220 young adults (<40 years; n=164 primary hypertensive [mean age±SD, 32±6 years] and n=56 [30±6 years] normotensive adults). Whether cerebrovascular variants were associated with lower cerebral blood flow (phase-contrast angiography) was measured in the hypertensive group only (n=146).

Results:

Binary logistic regression (adjusted for age, sex, and body mass index) showed that vertebral artery hypoplasia with an incomplete posterior circle of Willis was associated with hypertension diagnosis (
P
<0.001, odds ratio; 11.79 [95% CI, 3.34–41.58]). Vertebral artery hypoplasia plus an incomplete circle of Willis was associated with lower cerebral blood flow in young adults with hypertension (
P
=0.0172).

Conclusions:
Vertebral artery hypoplasia plus an incomplete posterior circle of Willis independently predicts hypertension in young adults suggesting that this variant is not acquired with aging into midlife. Importantly this variant combination was associated with lower cerebral perfusion, which may have long-term consequences on cerebrovascular health in young adults with hypertension.
Streamlining Acute Stroke Care by Introducing National Institutes of Health Stroke Scale in the Emergency Medical Services: A Prospective Cohort Study
Authors: Larsen Karianne , Jæger Henriette S. , Hov Maren R. , Thorsen Kjetil , Solyga Volker , Lund Christian G. , Bache Kristi G. 
Published: March 2022

Background:
National Institutes of Health Stroke Scale (NIHSS) is the most validated clinical scale for stroke recognition, severity grading, and symptom monitoring in acute care and hospital settings. Numerous modified prehospital stroke scales exist, but these scales contain less clinical information and lack compatibility with in-hospital stroke scales. In this real-life study, we aimed to investigate if NIHSS conducted by paramedics in the field is a feasible and accurate prehospital diagnostic tool.

Methods:
This prospective cohort study is part of Treat-NASPP (Treat-Norwegian Acute Stroke Prehospital Project) conducted at a single medical center in Østfold, Norway. Sixty-three paramedics were trained and certified in NIHSS, and the prehospital NIHSS scores were compared with the scores obtained by in-hospital stroke physicians. Interrater agreement was assessed using a Bland-Altman plot with 95% limits of agreement. In secondary analysis, Cohen κ was used for the clinical categories NIHSS score of 0 to 5 and ≥6. As a safety measure, prehospital time was compared between paramedics conducting NIHSS and conventional paramedics.

Results:

We included 274 patients. The mean difference in NIHSS scores between the paramedics and the stroke physicians was 0.92 with limits of agreement from −5.74 to 7.59. Interrater agreement for the 2 clinical categories was moderate with a κ of 0.58. The prehospital NIHSS scoring was performed mean (SD) 42 (14) minutes earlier than the in-hospital scoring. Prehospital time was not significantly increased in the NIHSS-trained paramedic group compared with conventional paramedics (median [interquartile range] on-scene-time 18 [13–25] minutes versus 16 [11–23] minutes,
P
=0.064 and onset-to-hospital time 86 [65–128] minutes versus 84 [56–140] minutes,
P
=0.535).

Conclusions:
Paramedics can use NIHSS as an accurate and time efficient prehospital stroke severity quantification tool. Introducing NIHSS in the emergency medical services will enable prehospital evaluation of stroke progression and provide a common language for stroke assessment between paramedics and stroke physicians.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03158259.
Experimental Philosophy of Mind: Free Will and a Scientific Conception of the World
Authors: Izadifar Morteza 
Published: March 2022

Abstract
Experimental philosophy has been engaged in many fields of philosophy and has tried to challenge philosophy from a new horizon. In this article, I have tried to examine what the role of sciences are (especially neuroscience) in altering people’s intuition about free will. Could science educate people’s philosophical intuitions? If yes, should we still rely on their intuition as a rational instrument for our philosophical questions? Do science plus cultural and social differences effect on folks’ view? In this cross-cultural research, the emphasis is mostly on recent breakthroughs on neuroscience and its impact on people’s perspective to free will. I have asked some questions about free will and determinism from two groups of Iranian and European participants. The results of this study revealed an interesting amount of cross-cultural similarities. The findings showed that people have a relatively independent view to free will and determinism. It seems that manipulating laymen’s opinion by either the idea of scientific determinism or living under pressure and challenging social conditions cannot touch their perspective. I tried to indicate that the techniques of experimental philosophy and the data offered might help us to learn more and more about the psychological processes, in the mind of the folks, that engender philosophical problems.
Cultural Metaphors in Hungarian Folk Songs as Repositories of Folk Cultural Cognition
Authors: Kóczy Judit Baranyiné 
Published: March 2022

Abstract
The paper explores the status of NATURE metaphors in Hungarian folk songs with respect to their representation and transmission of folk culture and worldview. Employing a Cultural Linguistic analysis, metaphors are observed from three perspectives: in relation to cultural schemas, generic-level conceptual metaphors, and experiential motivation. NATURE metaphors are to a large extent framed by cultural experience regarding their experiential basis, conceptual structure and relation with other cultural conceptualizations.