bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I first-in-human study of HLX07, a novel and improved recombinant anti-EGFR humanized monoclonal antibody, in patients with advanced solid cancers
Authors: Hou Ming-Mo , Ho Ching-Liang , Lin Hsuan-Yu , Zhu Yunting , Zhang Xiaodi 
Published: March 2021

SummaryPurpose This study aimed to evaluate the safety and pharmacokinetic (PK) profiles of HLX07, a novel, recombinant, humanized anti-epidermal growth factor receptor (EGFR) antibody, in patients with advanced solid cancers who had failed standard therapy or for whom no standard therapy was available. Methods In this prospective, open-label, Phase I dose escalation study, patients aged ≥18 years (≥20 years for patients in Taiwan) with histologically-confirmed metastatic or recurrent epithelial carcinoma that had no K-RAS or B-RAF mutations were enrolled in a ‘3 + 3’ escalation design. HLX07 was administered weekly by 2-h intravenous infusion at doses ranging from 50 to 800 mg. The primary endpoint was summary listing of participants reporting treatment-emergent adverse events (TEAEs). Secondary endpoints included PK analysis, serum anti-HLX07 antibody assessments and efficacy. Results In total, 19 patients were enrolled between 1 October 2016 and 16 July 2019 to receive HLX07 at doses of 50 (n = 3), 100 (n = 3), 200 (n = 3), 400 (n = 3), 600 (n = 3) and 800 (n = 4) mg per week. All patients experienced at least one TEAE, most commonly fatigue (68.4%), nausea (47.4%), paronychia (31.6%) and vomiting (31.6%). Serious TEAEs were reported in 11 patients but only one serious TEAE (dyspnea in 600 mg cohort) was regarded as possibly related to study treatment. No dose limiting toxicity (DLT) was reported. Systemic exposure to HLX07 increased proportionally with dose. Anti-HLX07 antibodies were not detected in any patients. Conclusion HLX07 was well tolerated (at dose levels up to 800 mg/week) and promising in patients with advanced solid cancers.Clinical Trial Registration: The study was registered at ClinicalTrials.gov: NCT02648490 (Jan 7, 2016).
Yes Children Need to Learn Their GPCs but There Really Is Little or No Evidence that Systematic or Explicit Phonics Is Effective: a response to Fletcher, Savage, and Sharon (2020)
Authors: Bowers Jeffrey S. 
Published: March 2021

AbstractFletcher, Savage, and Sharon (Educational Psychology Review, 2020) have raised a number of conceptual and empirical challenges to my claim that there is little or no evidence for systematic phonics (Bowers, Educational Psychology Review, 32, 681–705, 2020). But there are many mistakes, mischaracterizations, and omissions in the Fletcher et al. response that not only obscure the important similarities and differences in our views but also perpetuate common mischaracterizations of the evidence. In this response, I attempt to clarify a number of conceptual confusions, perhaps most importantly, the conflation of phonics with teaching GPCs. I do agree that children need to learn their GPCs, but that does not entail a commitment to systematic or any other form of phonics. With regard to the evidence, I respond to Fletcher et al.’s analysis of 12 meta-analyses and briefly review the reading outcomes in England following over a decade of legally mandated phonics. I detail why their response does not identify any flaws in my critique nor alter my conclusion that there is little or no support for the claim that phonics by itself or in a richer literacy curriculum is effective. We both agree that future research needs to explore how to combine various forms of instruction most effectively, including an earlier emphasis of morphological instruction, but we disagree that phonics must be part of the mix. I illustrate this by describing an alternative approach that rejects phonics, namely, Structured Word Inquiry.
Compatibility of intravitreally applied epidermal growth factor and amphiregulin
Authors: Bikbov Mukharram M. , Khalimov Timur A. , Cerrada-Gimenez Marc , Ragauskas Symantas , Kalesnykas Giedrius , Jonas Jost B. 
Published: March 2021

Abstract
Introduction
To examine the compatibility of intravitreally injected epidermal growth factor (EGF) and amphiregulin as EGF family member.

Methods
Four rabbits (age: 4 months; body weight: 2.5 kg) received three intravitreal injections of EGF (100 ng) uniocularly in monthly intervals and underwent ocular photography, tonometry, biometry, and optical coherence tomography. After sacrificing the rabbits, the globes were histomorphometrically examined. In a second study part, eyes of 22 guinea pigs (age: 2–3 weeks) received two intravitreal administrations of amphiregulin (10 ng) or phosphate buffered solution (PBS) in 10-day interval, or were left untouched. Ten days after the second injection, the guinea pigs were sacrificed, the enucleated eyes underwent histological and immune-histological examinations.

Results
The rabbit eyes with EGF injections versus the contralateral untouched eyes did not show significant differences in intraocular pressure (7.5 ± 2.4 mmHg vs. 6.8 ± 2.2 mmHg; P = 0.66), retinal thickness (158 ± 5 µm vs. 158 ± 3 µm; P = 1.0), cell counts in the retinal ganglion cell layer (3.3 ± 1.7 cells/150 µm vs. 3.0 ± 1.4 cells/150 µm; P = 0.83), inner nuclear layer (46.4 ± 23.2 cells/150 µm vs. 39.6 ± 6.4 cells/150 µm; P = 0.61), and outer nuclear layer (215 ± 108 cells/150 µm vs. 202 ± 47 cells/150 µm; P = 0.83), or any apoptotic retinal cells. The guinea pig eyes injected with amphiregulin versus eyes with PBS injections did not differ (P = 0.72) in the degree of microglial activation, and both groups did not differ from untouched eyes in number of apoptotic retinal cells and retinal gliosis.

Conclusions
Intravitreal applications of EGF (100 ng) in rabbits nor intravitreal applications of amphiregulin (10 ng) in guinea pigs led to intraocular specific inflammation or any observed intraocular destructive effect. The findings support the notion of a compatibility of intraocular applied EGF and amphiregulin.
Adapting the DeepSARM approach for dual-target ligand design
Authors: Yoshimori Atsushi , Hu Huabin , Bajorath Jürgen 
Published: March 2021

AbstractThe structure–activity relationship (SAR) matrix (SARM) methodology and data structure was originally developed to extract structurally related compound series from data sets of any composition, organize these series in matrices reminiscent of R-group tables, and visualize SAR patterns. The SARM approach combines the identification of structural relationships between series of active compounds with analog design, which is facilitated by systematically exploring combinations of core structures and substituents that have not been synthesized. The SARM methodology was extended through the introduction of DeepSARM, which added deep learning and generative modeling to target-based analog design by taking compound information from related targets into account to further increase structural novelty. Herein, we present the foundations of the SARM methodology and discuss how DeepSARM modeling can be adapted for the design of compounds with dual-target activity. Generating dual-target compounds represents an equally attractive and challenging task for polypharmacology-oriented drug discovery. The DeepSARM-based approach is illustrated using a computational proof-of-concept application focusing on the design of candidate inhibitors for two prominent anti-cancer targets.
Trichoderma harzianum Strain T22 Modulates Direct Defense of Tomato Plants in Response to Nezara viridula Feeding Activity
Authors: Alınç Tuğcan , Cusumano Antonino , Peri Ezio , Torta Livio , Colazza Stefano 
Published: March 2021

AbstractPlant growth-promoting fungi belonging to genus Trichoderma are known to help plants when dealing with biotic stressors by enhancing plant defenses. While beneficial effects of Trichoderma spp. against plant pathogens have long been documented, fewer studies have investigated their effect on insect pests. Here, we studied the impact of Trichoderma root colonization on the plant defense responses against stink bug feeding attack. For this purpose, a model system consisting of tomato plant, Solanum lycopersicum cv Dwarf San Marzano, Trichoderma harzianum strain T22 and the southern green stink bug, Nezara viridula, was used. We firstly determined stink bug performance in terms of relative growth rate and survival on tomato plants inoculated by T. harzianum T22. Then, we evaluated relative expression of plant defense-related genes on inoculated plants induced by stink bug feeding. We found evidence that T. harzianum T22 affects tomato defense responses against N. viridula nymphs leading to reduction of growth rate. Our results also showed that T. harzianum T22 enhances plant direct defenses by an early increase of transcript levels of jasmonic acid marker genes. Yet this effect was time-dependent and only detected 8 h after herbivore induction. Taken together, our findings provide better understanding on the mechanisms underlying tomato induced resistance against herbivorous stink bugs.
Which graphs are rigid in $$\ell _p^d$$?
Authors: Dewar Sean , Kitson Derek , Nixon Anthony 
Published: March 2021

AbstractWe present three results which support the conjecture that a graph is minimally rigid in d-dimensional $$\ell _p$$

ℓ
p

-space, where $$p\in (1,\infty )$$

p
∈
(
1
,
∞
)

and $$p\not =2$$

p
≠
2

, if and only if it is (d, d)-tight. Firstly, we introduce a graph bracing operation which preserves independence in the generic rigidity matroid when passing from $$\ell _p^d$$

ℓ
p
d

to $$\ell _p^{d+1}$$

ℓ
p

d
+
1

. We then prove that every (d, d)-sparse graph with minimum degree at most $$d+1$$

d
+
1

and maximum degree at most $$d+2$$

d
+
2

is independent in $$\ell _p^d$$

ℓ
p
d

. Finally, we prove that every triangulation of the projective plane is minimally rigid in $$\ell _p^3$$

ℓ
p
3

. A catalogue of rigidity preserving graph moves is also provided for the more general class of strictly convex and smooth normed spaces and we show that every triangulation of the sphere is independent for 3-dimensional spaces in this class.
A novel kind of room temperature self-healing poly(urethane-urea) with robust mechanical strength based on aromatic disulfide
Authors: He Jin , Song Fangfang , Li Xiong , Chen Liyi , Gong Xingyu , Tu Weiping 
Published: March 2021

AbstractAn innovative poly(urethane-urea) elastomer, which exhibited excellent stretchability, thermal stability and autonomous self-healing abilities, was synthesized from the commercially available poly(propylene glycol) (PPG), isophorone diisocyanate (IPDI), 2,4 / 2,6-toluene diisocyanate (80: 20, w / w) (TDI-80) and bis (2-aminophenyl) disulfide (DSDA). This aromatic disulfide containing poly(urethane-urea) (ss-PUs) achieved both rapid room temperature self-healing abilities and robust mechanical strength (the ultimate tensile strength was up to 4.20 ± 0.10 MPa and elongation at break was up to 954 ± 35.6%), through facile metathesis of the aromatic disulfides which embedded in hard segments. After the ss-PUs was cut into two-halves and reconnected, the mechanical properties could recover to ~ 90% of those of the original samples within 12 h at room temperature without extra self-healing agents or any change of environmental conditions.
Towards a pragmatist dealing with algorithmic bias in medical machine learning
Authors: Starke Georg , De Clercq Eva , Elger Bernice S. 
Published: March 2021

AbstractMachine Learning (ML) is on the rise in medicine, promising improved diagnostic, therapeutic and prognostic clinical tools. While these technological innovations are bound to transform health care, they also bring new ethical concerns to the forefront. One particularly elusive challenge regards discriminatory algorithmic judgements based on biases inherent in the training data. A common line of reasoning distinguishes between justified differential treatments that mirror true disparities between socially salient groups, and unjustified biases which do not, leading to misdiagnosis and erroneous treatment. In the curation of training data this strategy runs into severe problems though, since distinguishing between the two can be next to impossible. We thus plead for a pragmatist dealing with algorithmic bias in healthcare environments. By recurring to a recent reformulation of William James’s pragmatist understanding of truth, we recommend that, instead of aiming at a supposedly objective truth, outcome-based therapeutic usefulness should serve as the guiding principle for assessing ML applications in medicine.
Efficient iterative solutions to complex-valued nonlinear least-squares problems with mixed linear and antilinear operators
Authors: Kim Tae Hyung , Haldar Justin P. 
Published: March 2021

AbstractWe consider a setting in which it is desired to find an optimal complex vector $${\mathbf {x}}\in {\mathbb {C}}^N$$

x
∈

C

N

that satisfies $${\mathcal {A}}({\mathbf {x}}) \approx {\mathbf {b}}$$

A
(
x
)
≈
b

in a least-squares sense, where $${\mathbf {b}} \in {\mathbb {C}}^M$$

b
∈

C

M

is a data vector (possibly noise-corrupted), and $${\mathcal {A}}(\cdot ): {\mathbb {C}}^N \rightarrow {\mathbb {C}}^M$$

A

(
·
)

:

C

N

→

C

M

is a measurement operator. If $${\mathcal {A}}(\cdot )$$

A
(
·
)

were linear, this reduces to the classical linear least-squares problem, which has a well-known analytic solution as well as powerful iterative solution algorithms. However, instead of linear least-squares, this work considers the more complicated scenario where $${\mathcal {A}}(\cdot )$$

A
(
·
)

is nonlinear, but can be represented as the summation and/or composition of some operators that are linear and some operators that are antilinear. Some common nonlinear operations that have this structure include complex conjugation or taking the real-part or imaginary-part of a complex vector. Previous literature has shown that this kind of mixed linear/antilinear least-squares problem can be mapped into a linear least-squares problem by considering $${\mathbf {x}}$$
x
as a vector in $${\mathbb {R}}^{2N}$$

R

2
N

instead of $${\mathbb {C}}^N$$

C

N

. While this approach is valid, the replacement of the original complex-valued optimization problem with a real-valued optimization problem can be complicated to implement, and can also be associated with increased computational complexity. In this work, we describe theory and computational methods that enable mixed linear/antilinear least-squares problems to be solved iteratively using standard linear least-squares tools, while retaining all of the complex-valued structure of the original inverse problem. An illustration is provided to demonstrate that this approach can simplify the implementation and reduce the computational complexity of iterative solution algorithms.
Network design for line-based autonomous bus services
Authors: Hatzenbühler Jonas , Cats Oded , Jenelius Erik 
Published: March 2021

AbstractThe maturing of autonomous driving technology in recent years has led to several pilot projects and the initial integration of autonomous pods and buses into the public transport (PT) system. An emerging field of interest is the design of public transport networks operating autonomous buses and the potential to attract higher levels of travel demand. In this work a multi-objective optimization and multi-agent simulation framework is developed to study potential changes in the network design and frequency settings compared to conventional PT systems when autonomous vehicles (AV) systems are deployed on fixed-route networks. During the optimization process multiple deployment scenarios (network configurations and service frequency) are evaluated and optimized considering the operator cost, user cost and infrastructure preparation costs of the system. User-focused network design and operator-focused network design are studied for a real-world urban area in Sweden. The results provide insights into the network design and level of service implications brought about by the deployment of autonomous bus (AB) when those are integrated in route-based PT systems. We show that the deployment of autonomous buses result with a network design that increases service ridership. In the context of our case study this increase is likely to primarily substitute walking.
A multiplicative version of the Lindley recursion
Authors: Boxma Onno , Löpker Andreas , Mandjes Michel , Palmowski Zbigniew 
Published: March 2021

AbstractThis paper presents an analysis of the stochastic recursion $$W_{i+1} = [V_iW_i+Y_i]^+$$

W

i
+
1

=

[

V
i

W
i

+

Y
i

]

+

that can be interpreted as an autoregressive process of order 1, reflected at 0. We start our exposition by a discussion of the model’s stability condition. Writing $$Y_i=B_i-A_i$$

Y
i

=

B
i

-

A
i

, for independent sequences of nonnegative i.i.d. random variables $$\{A_i\}_{i\in {\mathbb N}_0}$$

{

A
i

}

i
∈

N
0

and $$\{B_i\}_{i\in {\mathbb N}_0}$$

{

B
i

}

i
∈

N
0

, and assuming $$\{V_i\}_{i\in {\mathbb N}_0}$$

{

V
i

}

i
∈

N
0

is an i.i.d. sequence as well (independent of $$\{A_i\}_{i\in {\mathbb N}_0}$$

{

A
i

}

i
∈

N
0

and $$\{B_i\}_{i\in {\mathbb N}_0}$$

{

B
i

}

i
∈

N
0

), we then consider three special cases (i) $$V_i$$

V
i

equals a positive value a with certain probability $$p\in (0,1)$$

p
∈
(
0
,
1
)

and is negative otherwise, and both $$A_i$$

A
i

and $$B_i$$

B
i

have a rational LST, (ii) $$V_i$$

V
i

attains negative values only and $$B_i$$

B
i

has a rational LST, (iii) $$V_i$$

V
i

is uniformly distributed on [0, 1], and $$A_i$$

A
i

is exponentially distributed. In all three cases, we derive transient and stationary results, where the transient results are in terms of the transform at a geometrically distributed epoch.
Health-related quality of life in refugee youth and the mediating role of mental distress and post-migration stressors
Authors: Dangmann Cecilie , Solberg Øivind , Andersen Per Normann 
Published: March 2021

Abstract
Purpose
The aim of this study is to explore how potentially traumatic events (PTEs) from war and flight influence health-related quality of life (HRQoL) in young refugees after recent resettlement. In a model based on earlier theory, we tested if post-migration stressors and mental distress mediated the effect of PTEs on HRQoL, individually and in serial. We also explored how different types of post-migration stressors influenced different dimensions of HRQoL.

Methods
This study used a cross-sectional design where 160 Syrian youth recently resettled in Norway completed questionnaires at school between May and December 2018. Correlations between types of post-migration stressors and dimensions of HRQoL were explored and a serial multiple mediator model was tested. Models were adjusted for age and gender, using two types of mental distress; post-traumatic stress disorder (PTSD) and general mental distress.

Results
Higher levels of PTEs reduced experienced HRQoL, but this direct effect was mediated by post-migration stressors alone and in serial with mental distress. Despite high levels of mental distress, this did not affect HRQoL independently, only in serial mediation with increased post-migration stressors. Economic concerns and discrimination were types of post-migration stressors affecting several dimensions of HRQoL.

Conclusion
Quality of life in refugee is affected by past events from war, stressors in current resettlement and elevated mental distress through complex interrelations. The study reiterates the importance of considering structural and everyday post-migration stressors in policy and intervention to improve the health and wellbeing of refugee youth.
A Community-Structure-Based Method for Estimating the Fractal Dimension, and its Application to Water Networks for the Assessment of Vulnerability to Disasters
Authors: Giudicianni C. , Di Nardo A. , Greco R. , Scala A. 
Published: March 2021

AbstractMost real-world networks, from the World-Wide-Web to biological systems, are known to have common structural properties. A remarkable point is fractality, which suggests the self-similarity across scales of the network structure of these complex systems. Managing the computational complexity for detecting the self-similarity of big-sized systems represents a crucial problem. In this paper, a novel algorithm for revealing the fractality, that exploits the community structure principle, is proposed and then applied to several water distribution systems (WDSs) of different size, unveiling a self-similar feature of their layouts. A scaling-law relationship, linking the number of clusters necessary for covering the network and their average size is defined, the exponent of which represents the fractal dimension. The self-similarity is then investigated as a proxy of recurrent and specific response to multiple random pipe failures – like during natural disasters – pointing out a specific global vulnerability for each WDS. A novel vulnerability index, called Cut-Vulnerability is introduced as the ratio between the fractal dimension and the average node degree, and its relationships with the number of randomly removed pipes necessary to disconnect the network and with some topological metrics are investigated. The analysis shows the effectiveness of the novel index in describing the global vulnerability of WDSs.
XChange: A Universal Mechanism for Asset Exchange between Permissioned Blockchains
Authors: de Vos Martijn , Ileri Can Umut , Pouwelse Johan 
Published: March 2021

AbstractPermissioned blockchains are increasingly being used as a solution to record transactions between companies. Several use cases that leverage permissioned blockchains focus on the representation and management of real-world assets. Since the number of incompatible blockchains is quickly growing, there is an increasing need for a universal mechanism to exchange, or trade, digital assets between these isolated platforms. There currently is no universal mechanism for inter-blockchain asset exchange without a requirement for trusted authorities that coordinate the trade. We address this shortcoming and present XChange, a universal mechanism for asset exchange between permissioned blockchains. To achieve universality and to avoid trusted authorities that coordinate a trade, XChange does not provide atomic guarantees but leverages risk mitigation strategies to reduce value at stake. Our mechanism records the specifications and progression of each trade within records on a distributed log. XChange reduces the economic gains of adversaries by bounding the total amount of fraud they can commit at any time. After having committed fraud, an adversary is forced to finish its ongoing trades before it can engage in new trades. We first present a four-phased protocol that coordinates an asset exchange between two traders. We then outline how trade records can be stored on TrustChain, which is a lightweight distributed ledger specifically built for the tamper-proof storage of data elements. We implement XChange and conduct experiments. Our experiments demonstrate that XChange is capable of reducing the economic gains of adversaries by more than 99.9% when replaying a real-world trading dataset. A deployment on low-resource devices reveals that the latency added to a trade by XChange is only 493 milliseconds. Finally, our scalability evaluation shows that XChange achieves over 1’000 trades per second and that its throughput, in terms of trades per second, scales linearly with the system load.