bluuebunny/crossref_metadata_2025 huggingface dataset:
Synergistic Effect of Ferroptosis‐Inducing Nanoparticles and X‐Ray Irradiation Combination Therapy
Authors: Bae Chaewon , Hernández Millares Rodrigo , Ryu Suhyun , Moon Hyowon , Kim Dongwoo , Lee Gyubok , Jiang Zhuomin , Park Min Hee , Kim Kyung Hwan , Koom Woong Sub , Ye Sung‐Joon , Lee Kangwon
Published: January 2024

Ferroptosis, characterized by the induction of cell death via lipid peroxidation, has been actively studied over the last few years and has shown the potential to improve the efficacy of cancer nanomedicine in an iron‐dependent manner. Radiation therapy, a common treatment method, has limitations as a stand‐alone treatment due to radiation resistance and safety as it affects even normal tissues. Although ferroptosis‐inducing drugs help alleviate radiation resistance, there are no safe ferroptosis‐inducing drugs that can be considered for clinical application and are still in the research stage. Here, the effectiveness of combined treatment with radiotherapy with Fe and hyaluronic acid‐based nanoparticles (FHA‐NPs) to directly induce ferroptosis, considering the clinical applications is reported. Through the induction of ferroptosis by FHA‐NPs and apoptosis by X‐ray irradiation, the therapeutic efficiency of cancer is greatly improved both in vitro and in vivo. In addition, Monte Carlo simulations are performed to assess the physical interactions of the X‐rays with the iron‐oxide nanoparticle. The study provides a deeper understanding of the synergistic effect of ferroptosis and X‐ray irradiation combination therapy. Furthermore, the study can serve as a valuable reference for elucidating the role and mechanisms of ferroptosis in radiation therapy.
In‐Situ Derived Defective Ru Particles Anchored on Ru–Ni Layered Double Hydroxides for Enhanced Alkaline Hydrogen Evolution
Authors: Shi Ningning , Ma Ruijie , Lin Linghui , Xie Wangjing , Liu Panpan , Li Peng , Fan Hua , Tang Yu , Wang Yuanqing , Lin Sen , Huang Xing
Published: January 2024

Developing active, stable, and cost‐efficient electrocatalysts to replace platinum for the alkaline hydrogen evolution reaction (HER) is highly desirable yet represents a great challenge. Here, it is reported on a facile one‐pot synthesis of RuxNi layered double hydroxides (RuxNi‐LDHs) that exhibit remarkable HER activity and stability after an in‐situ activation treatment, surpassing most state‐of‐the‐art Ru‐based catalysts as well as commercial Ru/C and Pt/C catalysts. The structural and chemical changes triggered by in‐situ activation are systematically investigated, and the results clearly show that the pristine, less‐active RuxNi‐LDHs are transformed into a highly active catalyst characterized by raft‐like, defect‐rich Ru° particles decorated on the surface of RuxNi‐LDHs. Density functional theory (DFT) calculations reveal that the defective Ru sites can effectively optimize the reaction pathway and lower the free energies of the elemental steps involved, leading to enhanced intrinsic activity. This work highlights the importance of the currently understudied strategy of defect engineering in boosting the HER activity of Ru‐based catalysts and offers an effective approach involving in‐situ electrochemical activation for the development of high‐performance alkaline HER catalysts.
High Polymer Molecular Weight Yields Solar Cells with Simultaneously Improved Performance and Thermal Stability
Authors: Riera‐Galindo Sergi , Sanz‐Lleó Marta , Gutiérrez‐Fernández Edgar , Ramos Nicolás , Mas‐Torrent Marta , Martín Jaime , López‐Mir Laura , Campoy‐Quiles Mariano
Published: January 2024

Simple synthetic routes, high active layer thickness tolerance as well as stable organic solar cells are relentlessly pursued as key enabling traits for the upscaling of organic photovoltaics. Here, the potential to address these issues by tuning donor polymer molecular weight is investigated. Specifically, the focus is on PTQ10, a polymer with low synthetic complexity, with number average molecular weights of 2.4, 6.2, 16.8, 52.9, and 54.4 kDa, in combination with three different non‐fullerene acceptors, namely Y6, Y12, and IDIC. Molecular weight, indeed, unlocks a threefold increase in power conversion efficiency for these blends. Importantly, efficiencies above 10% for blade coated devices with thicknesses between 200 and 350 nm for blends incorporating high molecular weight donor are shown. Spectroscopic, GIWAXS and charge carrier mobility data suggest that the strong photocurrent improvement with molecular weight is related to both, improved electronic transport and polymer contribution to exciton generation. Moreover, it is demonstrated that solar cells based on high molecular weight PTQ10 are more thermally stable due to a higher glass transition temperature, thus also improving device stability.
Combined Fabrication and Performance Evaluation of TOPCon Back‐Contact Solar Cells with Lateral Power Metal‐Oxide‐Semiconductor Field‐Effect Transistors on a Single Substrate
Authors: van Nijen David A. , Stevens Tristan , Mercimek Yavuzhan , Yang Guangtao , van Swaaij René A.C.M.M. , Zeman Miro , Isabella Olindo , Manganiello Patrizio
Published: January 2024

Nowadays, an increasing share of photovoltaic (PV) systems makes use of module‐ or submodule‐level power electronics (PE). Furthermore, PE is used in stand‐alone devices powered by PV‐storage solutions. One way to facilitate further implementation of PE in PV applications is to integrate PE components into crystalline silicon PV cells. Herein, the COSMOS device is introduced, denoting COmbined Solar cell and metal‐oxide‐semiconductor field‐effect transistor (MOSFET). Specifically, the combined manufacturing of lateral power MOSFETs and interdigitated back contact solar cells with tunnel‐oxide passivated contacts (TOPCon) on a single wafer is reported. Many steps of the proposed process flow are used for the fabrication of both devices, enabling cost‐effective integration of the MOSFET. Both n‐type solar cells with integrated p‐channel MOSFETs (PMOS) and p‐type solar cells with integrated n‐channel MOSFETs (NMOS) are successfully manufactured. NMOS devices perform better in achieving low on‐resistance, while PMOS devices exhibit lower leakage currents. Furthermore, the study reveals integration challenges where off‐state leakage currents of the MOSFET can increase due to illumination and specific configurations of monolithic interconnections between the MOSFET and the solar cell. Nevertheless, for both n‐type and p‐type solar cells, efficiencies exceeding 20% are achieved, highlighting the potential of the proposed process for COSMOS devices.
Enhanced Yield Strength and Total Elongation of an Ultrahigh Strength Hot‐Stamped Steel via Tempering Treatment
Authors: Chen Wei Jian , Zhang Shun Hu , Tian Wen Hao , Li Yan
Published: January 2024

A 2460 MPa ultimate tensile strength (UTS) has been achieved in this experimental steel, which was processed by a conventional hot stamping process with water quenching to room temperature. Additionally, comparing the microstructure evolution and strengthening mechanism before and after tempering, the microstructure has changed from fresh martensite transformed into tempered martensite with acicular carbides, and the fracture mode has also changed from brittle fracture transformed into ductile fracture mainly. Meanwhile, the main strengthening mechanism has changed from dislocation strengthening to precipitation and dislocation strengthening. Overall, the tempering process reduces dislocation density and produces acicular carbides, which decrease UTS. However, the tempering process reduces the quenching residual stress and changes the morphology of twin martensite, resulting in an increase in ductility. Meanwhile, it enhances the effect of carbide pinning dislocations, significantly enhances precipitation strengthening, and improves yield strength.
Optimization of Process Parameters for 40Cr Steel Continuous Casting Round Bloom with Pulsed Magneto‐Oscillation Treatment
Authors: Yang Yang , Chen Yongfeng , Zhang Hongbiao , Yin Zihao , Liu Haining , Li Renxing , Li Lijuan , Xu Zhishuai , Zhong Honggang , Zhai Qijie
Published: January 2024

To reduce the solidification structure defects and the macrosegregation of the Φ300 mm continuous casting round bloom, the pulsed magneto‐oscillation (PMO) treatment is added at the secondary cooling zone. A numerical model for calculating the pulsed electromagnetic field, flow field, and temperature field in continuous casting is established, and the coupling simulations of multiphysical fields under different casting parameters and PMO parameters are performed. Their influence on solidification process and the appropriate parameters are discussed. The industrial experiments conducted under the recommended parameters yield good results. Industrial experiments show that when the peak current is increased from 1350 to 1550 KIA and the casting speed is increased from 0.75 to 0.90 m min−1, PMO can increase the equiaxed grain zone and reduce the carbon macrosegregation of the bloom. Moreover, at high casting speed, PMO treatment can significantly promote columnar‐to‐equiaxed transition and increase the width of mixed grain zone.
Biodegradation of 17β‐estradiol by drug‐resistant Stenotrophomonas maltophilia MN08 and Pseudomonas aeruginosa KL10 isolated from the sediment sample
Authors: Farraj Dunia A. Al , Gawwad Mohamed Ragab Abdel , Elshikh Mohamed S. , Arokiyaraj Selvaraj , Vijayaraghavan Ponnuswamy
Published: January 2024

17 β‐Estradiol is produced by animals, and humans and excreted through excreta, and has endocrine‐disrupting activity. Bacterial degradation is one of the suitable methods used for the removal of 17 β‐estradiol (E2) from the natural environment. In this study, E2‐degrading bacteria were screened from the enriched sediment sample from the wastewater environment. Two bacterial strains of E2‐degrading bacteria (Stenotrophomonas maltophilia MN08 and Pseudomonas aeruginosa KL10) were determined and >70% of E2‐degradation was achieved. The strain MN08 could rapidly remove approximately 86.5% ± 1.3% of E2 within 7 days of treatment. In addition, the strain KL10 removed 79.5% ± 1% of E2 within the same period. Optimized culture temperature and pH of the medium could improve E2‐degradation. The results demonstrated that the strain MN08 exhibited maximum E2‐degradation activity at 35°C, and pH 8.0. The optimal pH for strain KL10 to degrade E2 ranged from 7.0 to 9.0. The E2‐degradation level for the mixture culture systems can exhibit synergistic E2‐degradation activity. The degradation of the MN08 and KL10 individual strains was 87.3% ± 1.2% and 81.4% ± 1.5%, respectively. The E2‐degradation potential for the mixed culture system was 91.3% ± 2.9% under optimized conditions in which 100 mg/L of E2 served as the sole source of carbon and energy. The present finding demonstrates that the co‐culture of S. maltophilia MN08 and P. aeruginosa KL10 may provide a promising bio‐treatment strategy for the removal of steroids from wastewater.
Baricitinib and tofacitinib off‐target profile, with a focus on Alzheimer's disease
Authors: Faquetti Maria L. , Slappendel Laura , Bigonne Hélène , Grisoni Francesca , Schneider Petra , Aichinger Georg , Schneider Gisbert , Sturla Shana J. , Burden Andrea M.
Published: January 2024

INTRODUCTION

Janus kinase (JAK) inhibitors were recently identified as promising drug candidates for repurposing in Alzheimer's disease (AD) due to their capacity to suppress inflammation via modulation of JAK/STAT signaling pathways. Besides interaction with primary therapeutic targets, JAK inhibitor drugs frequently interact with unintended, often unknown, biological off‐targets, leading to associated effects. Nevertheless, the relevance of JAK inhibitors’ off‐target interactions in the context of AD remains unclear.

METHODS

Putative off‐targets of baricitinib and tofacitinib were predicted using a machine learning (ML) approach. After screening scientific literature, off‐targets were filtered based on their relevance to AD. Targets that had not been previously identified as off‐targets of baricitinib or tofacitinib were subsequently tested using biochemical or cell‐based assays. From those, active concentrations were compared to bioavailable concentrations in the brain predicted by physiologically based pharmacokinetic (PBPK) modeling.

RESULTS

With the aid of ML and in vitro activity assays, we identified two enzymes previously unknown to be inhibited by baricitinib, namely casein kinase 2 subunit alpha 2 (CK2‐α2) and dual leucine zipper kinase (MAP3K12), both with binding constant (Kd) values of 5.8 μM. Predicted maximum concentrations of baricitinib in brain tissue using PBPK modeling range from 1.3 to 23 nM, which is two to three orders of magnitude below the corresponding binding constant.

CONCLUSION

In this study, we extended the list of baricitinib off‐targets that are potentially relevant for AD progression and predicted drug distribution in the brain. The results suggest a low likelihood of successful repurposing in AD due to low brain permeability, even at the maximum recommended daily dose. While additional research is needed to evaluate the potential impact of the off‐target interaction on AD, the combined approach of ML‐based target prediction, in vitro confirmation, and PBPK modeling may help prioritize drugs with a high likelihood of being effectively repurposed for AD.

Highlights

This study explored JAK inhibitors' off‐targets in AD using a multidisciplinary approach.

We combined machine learning, in vitro tests, and PBPK modelling to predict and validate new off‐target interactions of tofacitinib and baricitinib in AD.

Previously unknown inhibition of two enzymes (CK2‐a2 and MAP3K12) by baricitinib were confirmed using in vitro experiments.

Our PBPK model indicates that baricitinib low brain permeability limits AD repurposing.

The proposed multidisciplinary approach optimizes drug repurposing efforts in AD research.
Safety of methotrexate administration in women with pregnancy of unknown location at high risk of ectopic pregnancy
Authors: Jin C. S. , Uzuner C. , Condous G.
Published: January 2024

Objectives

To evaluate the safety of current guidelines on methotrexate (MTX) administration in women with pregnancy of unknown location (PUL) who are considered to have a high risk of underlying ectopic pregnancy (EP), and to investigate whether implementation of these guidelines would result in inadvertent exposure to MTX of viable intrauterine pregnancies (IUPs).

Methods

This was a retrospective observational study of consecutive clinically stable women who were classified with PUL at the early pregnancy unit of Nepean Hospital, Sydney, Australia, between 2007 and 2021. PUL was defined as a positive pregnancy test in the absence of signs of IUP or EP on transvaginal ultrasound. Patients with a PUL that behaved biochemically like an EP, but for which the location of pregnancy was not confirmed on ultrasound, were eligible for MTX to minimize the risk of subsequent tubal rupture. Criteria discussed in the guidelines of the American College of Obstetricians and Gynecologists (ACOG), American Society for Reproductive Medicine (ASRM), Royal College of Obstetricians and Gynaecologists (RCOG) and National Institute for Health and Care Excellence (NICE) were applied to the PUL database. The number of patients eligible to receive MTX and the number with an underlying viable IUP who would be inadvertently prescribed MTX were calculated.

Results

A total of 816 women with PUL were reviewed, of whom 724 had complete data and were included in the final analysis. Six patients had persistent PUL and the remaining 718 had a diagnosis of viable IUP, non‐viable IUP, EP or failed PUL. According to the ACOG, ASRM, RCOG and NICE guidelines, the rate of MTX administration among patients with PUL would have been 2.76%, 4.56%, 0.41% and 35.36%, respectively. However, no persistent PUL would have received MTX according to the ACOG, ASRM and RCOG protocols (the NICE protocol identified patients with persistent PUL with a sensitivity of 100%), and the majority of MTX treatments were unnecessary because those patients were later classified as having non‐viable IUP or failed PUL. Application of ACOG and ASRM guidance could result theoretically in inadvertent MTX administration to women with an underlying viable IUP at a rate of 4.1/1000 (3/724).

Conclusions

Current guidelines used to predict high risk of EP in the PUL population lead to inadvertent MTX administration to women with an underlying viable IUP. These guidelines should be used wisely to ensure that no wanted pregnancy is exposed to MTX. Women with PUL should be monitored carefully, and MTX should be used judiciously when the location of pregnancy is yet to be confirmed. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Synthesis of (Arylimido)niobium(V) Bis(diethylamide) Complexes Containing Phenoxide Ligands
Authors: Nakashima Nonoka , Paosopa Sirichok , Nomura Kotohiro
Published: January 2024

Reaction of (arylimido)niobium(V) tris(diethylamide) complexes, Nb(NAr)(NEt2)3, prepared by treating Nb(NAr)Cl3(dme) (dme=1,2‐dimethoxyethane) with 3.0 equiv. of LiNEt2, with 1.0 equiv. of phenol afforded the corresponding phenoxide complexes, Nb(NAr)(NEt2)2(O‐2,6‐R2C6H3) [1 a–c, 2 a–c; Ar=2,6‐Me2C6H3 (1) 2,6‐iPr2C6H3 (2); R=tBu (a), iPr (b), Me (c)], which were identified by NMR spectroscopy, elemental analysis and the structures for 2 b, c were determined by X‐ray crystallographic analysis.
On quantum Poisson-Lie T-duality of WZNW models
Authors: Sakatani Yuho , Satoh Yuji
Published: January 2024

Abstract

We study Poisson-Lie T-duality of the Wess-Zumino-Novikov-Witten (WZNW) models which are obtained from a class of Drinfel’d doubles and its generalization. In this case, the resultant WZNW models are known to be classically self-dual under Poisson-Lie T-duality. We describe an explicit construction of the associated currents, and discuss the conformal invariance under this duality. In a concrete example of the SU(2) WZNW model, we find that the self-duality is represented as a chiral automorphism of the $$ \hat{\mathfrak{su}} $$

su
̂

(2) affine Lie algebra, though the transformation of the currents is non-local and non-linear. This classical automorphism can be promoted to the quantum one through the parafermionic formulation of $$ \hat{\mathfrak{su}} $$

su
̂

(2), which in turn induces an isomorphism of the WZNW model. We thus find a full quantum equivalence of the dual pair under Poisson-Lie T-duality. The isomorphism is represented by a sign-change of a chiral boson or the order-disorder duality of the parafermionic conformal field theory as in Abelian T-duality on tori or in the mirror symmetry of the Gepner model.
Probing new physics with charge asymmetries in 2 same-sign leptons plus jets final states at the LHC
Authors: Arganda Ernesto , Da Rold Leandro , Juste Aurelio , Medina Anibal D. , Sandá Seoane Rosa M.
Published: January 2024

Abstract

We study the impact of new physics models in the charge asymmetry defined for LHC final states consisting of two same-sign leptons (2SSl, with l = e, μ) plus jets (Njets ≥ 2), with a center-of-mass energy of $$ \sqrt{s} $$

s

= 13 TeV, where the main SM contribution is $$ t\overline{t}W $$
t

t
¯

W
production. Concretely, we consider three different new physics sources for the charge asymmetries: a heavy neutral scalar/pseudoscalar arising from the general two Higgs doublet model, an effective theory with dimension-6 four-quark operators, and a simplified R-parity-violating supersymmetric model with electroweakino production (higgsino-like or wino-like). We propose measuring the charge asymmetries differentially with respect to several kinematic observables, and inclusively/exclusively with the number of b-tagged jets in the final state (Nb ≥ {1, 2, 3}). Results are compared with the SM prediction using the χ2 criteria, expressing sensitivity in terms of the normal Gaussian significance. We show that some of the proposed new physics scenarios can be probed at the LHC even for the already recorded integrated luminosity of 139 fb−1. Finally, we also estimate the prospects for the potential LHC sensitivity to the considered new physics models in its high-luminosity phase.
Forward dijet production at the LHC within an impact parameter dependent TMD approach
Authors: Deganutti Federico , Royon Christophe , Schlichting Soeren
Published: January 2024

Abstract

We investigate possible signatures of gluon saturation using forward p + A → j + j + X di-jet production processes at the Large Hadron Collider. In the forward rapidity region, this is a highly asymmetric process where partons with large longitudinal momentum fraction x in the dilute projectile are used as a probe to resolve the small x partonic content of the dense target. Such dilute-dense processes can be described in the factorization framework of Improved Transverse Momentum Distributions (ITMDs). We present a new model for ITMDs where we explicitly introduce the impact parameter (b) dependence in the ITMDs, to properly account for the nuclear enhancement of gluon saturation effects, and discuss the phenomenological consequences for p − Pb, p − Xe and p − O collisions at the LHC. While the case of p − p and e − p collisions is used to fix the model parameters, we find that, on average, the nuclear enhancement of the saturation scale is noticeably weaker than expected from naive scaling with a simple dependence on the atomic number. Since our model explicitly accounts for event-by-event fluctuations of the nuclear geometry, it can also be applied to study forward central correlations in p − A collisions.
Low-energy radiative backgrounds in CCD-based dark-matter detectors
Authors: Du Peizhi , Egaña-Ugrinovic Daniel , Essig Rouven , Sholapurkar Mukul
Published: January 2024

Abstract

The reach of sub-GeV dark-matter detectors is at present severely affected by low-energy events from various origins. We present the theoretical methods to compute the single- and few-electron events that arise from secondary radiation emitted by high-energy particles as they pass through detector materials and perform a detailed simulation to quantify them at (Skipper) CCD-based experiments, focusing on the SENSEI data collected at Fermilab near the MINOS cavern. The simulations account for the generation of secondaries from Cherenkov and luminescent recombination radiation; photo-absorption in the bulk, backside layer, pitch adapter, and epoxy; the photon reflection and refraction at interfaces; thin-film interference; the roughness of the interfaces; the dynamics of charges produced in the highly doped CCD-backside-layers; and the partial charge collection on the CCD backside. We consider several systematic uncertainties, notably those stemming from the backside modeling, which we estimate with a “fiducial” and an “extreme” charge-diffusion model, with the former model being preferred due to better agreement with partial-charge collection data. We find that Cherenkov photons constitute about 30% of the observed single-electron events for both diffusion models; radiative recombination contributes negligibly to the event rate for the fiducial model, although it can dominate over Cherenkov for the extreme model. We also estimate the fraction of 2-electron events that arise from 1-electron event coincidences in the same pixel, finding that the entire 2-electron rate can be explained by coincidences of radiative events and spurious charge. Accounting for both radiative and non-radiative backgrounds, we project the sensitivity of future Skipper-CCD-based experiments to different dark-matter models. For light-mediator models with dark-matter masses of 1, 5, and 10 MeV, we find that future experiments with 10-kg-year exposures and successful background mitigation could have a sensitivity that is larger by 9, 3, and 2 orders of magnitude, respectively, when compared to an experiment without background improvements.
APC mutations disrupt β-catenin destruction complex condensates organized by Axin phase separation
Authors: Zhang Dan , Ni Qi-Qi , Wang Shu-Yang , He Wen-Feng , Hong Ze-Xuan , Liu Hui-Ye , Chen Xiao-Hong , Chen Li-Jie , Han Fang-Yi , Zhang Ling-Jie , Li Xiao-ming , Ding Yan-qing , Jiao Hong-li , Ye Ya-ping
Published: January 2024

The Wnt/β-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid–liquid-phase separation (LLPS) of Axin organized the β-catenin destruction complex condensates in a normal cellular state. Mutations inactivating the APC gene are found in approximately 80% of all human colorectal cancer (CRC). However, the molecular mechanism of the formation of β-catenin destruction complex condensates organized by Axin phase separation and how APC mutations impact the condensates are still unclear. Here, we report that the β-catenin destruction complex, which is constructed by Axin, was assembled condensates via a phase separation process in CRC cells. The key role of wild-type APC is to stabilize destruction complex condensates. Surprisingly, truncated APC did not affect the formation of condensates, and GSK 3β and CK1α were unsuccessfully recruited, preventing β-catenin phosphorylation and resulting in accumulation in the cytoplasm of CRCs. Besides, we propose that the phase separation ability of Axin participates in the nucleus translocation of β-catenin and be incorporated and concentrated into transcriptional condensates, affecting the transcriptional activity of Wnt signaling pathway.
Vascular injury activates the ELK1/SND1/SRF pathway to promote vascular smooth muscle cell proliferative phenotype and neointimal hyperplasia
Authors: Su Chao , Liu Mingxia , Yao Xuyang , Hao Wei , Ma Jinzheng , Ren Yuanyuan , Gao Xingjie , Xin Lingbiao , Ge Lin , Yu Ying , Wei Minxin , Yang Jie
Published: January 2024

Background

Vascular smooth muscle cell (VSMC) proliferation is the leading cause of vascular stenosis or restenosis. Therefore, investigating the molecular mechanisms and pivotal regulators of the proliferative VSMC phenotype is imperative for precisely preventing neointimal hyperplasia in vascular disease.

Methods

Wire-induced vascular injury and aortic culture models were used to detect the expression of staphylococcal nuclease domain-containing protein 1 (SND1). SMC-specific Snd1 knockout mice were used to assess the potential roles of SND1 after vascular injury. Primary VSMCs were cultured to evaluate SND1 function on VSMC phenotype switching, as well as to investigate the mechanism by which SND1 regulates the VSMC proliferative phenotype.

Results

Phenotype-switched proliferative VSMCs exhibited higher SND1 protein expression compared to the differentiated VSMCs. This result was replicated in primary VSMCs treated with platelet-derived growth factor (PDGF). In the injury model, specific knockout of Snd1 in mouse VSMCs reduced neointimal hyperplasia. We then revealed that ETS transcription factor ELK1 (ELK1) exhibited upregulation and activation in proliferative VSMCs, and acted as a novel transcription factor to induce the gene transcriptional activation of Snd1. Subsequently, the upregulated SND1 is associated with serum response factor (SRF) by competing with myocardin (MYOCD). As a co-activator of SRF, SND1 recruited the lysine acetyltransferase 2B (KAT2B) to the promoter regions leading to the histone acetylation, consequently promoted SRF to recognize the specific CArG motif, and enhanced the proliferation- and migration-related gene transcriptional activation.

Conclusions

The present study identifies ELK1/SND1/SRF as a novel pathway in promoting the proliferative VSMC phenotype and neointimal hyperplasia in vascular injury, predisposing the vessels to pathological remodeling. This provides a potential therapeutic target for vascular stenosis.

Graphical abstract
q-Painlevé equations on cluster Poisson varieties via toric geometry
Authors: Mizuno Yuma
Published: January 2024

We provide a relation between the geometric framework for q-Painlevé equations and cluster Poisson varieties by using toric models of rational surfaces associated with q-Painlevé equations. We introduce the notion of seeds of q-Painlevé type by the negative semi-definiteness of symmetric bilinear forms associated with seeds, and classify the mutation equivalence classes of these seeds. This classification coincides with the classification of q-Painlevé equations given by Sakai. We realize q-Painlevé systems as automorphisms on cluster Poisson varieties associated with seeds of q-Painlevé type.
A uniqueness criterion and a counterexample to regularity in an incompressible variational problem
Authors: Dengler M. , Bevan J. J.
Published: January 2024

In this paper we consider the problem of minimizing functionals of the form $$E(u)=\int _B f(x,\nabla u) \,dx$$

E

(
u
)

=

∫
B

f

(
x
,
∇
u
)

d
x

in a suitably prepared class of incompressible, planar maps $$u: B \rightarrow \mathbb {R}^2$$

u
:
B
→

R

2

. Here, B is the unit disk and $$f(x,\xi )$$

f
(
x
,
ξ
)

is quadratic and convex in $$\xi $$
ξ
. It is shown that if u is a stationary point of E in a sense that is made clear in the paper, then u is a unique global minimizer of E(u) provided the gradient of the corresponding pressure satisfies a suitable smallness condition. We apply this result to construct a non-autonomous, uniformly convex functional $$f(x,\xi )$$

f
(
x
,
ξ
)

, depending smoothly on $$\xi $$
ξ
but discontinuously on x, whose unique global minimizer is the so-called $$N-$$

N
-

covering map, which is Lipschitz but not $$C^1$$

C
1

.
Regression discontinuity design with principal stratification in the mixed proportional hazard model: an application to the long-run impact of education on longevity
Authors: Bijwaard Govert E. , Jones Andrew M.
Published: January 2024

We investigate the long-run impact of education on longevity using data for England and Wales from the Health and Lifestyle Survey. Longevity is modelled by survival analysis using a mixed proportional hazard model. For identification we propose a Regression Discontinuity Design implied by an increase in the minimum school leaving age in 1947 (from 14 to 15) combined with a principal stratification method for estimation of the mortality hazard rate. This method allows us to derive the causal effect of extended education on longevity. In line with earlier studies we do not find credible evidence of a causal impact of the additional years of schooling that were induced by the reform on longevity.
Experimental demonstration on detonation initiation by laser ignition and shock focusing in elliptical cavity
Authors: Sato T. , Matsuoka K. , Kawasaki A. , Itouyama N. , Watanabe H. , Kasahara J.
Published: January 2024

As a method of initiating detonation in a short distance with a small amount of energy, the combination of laser ignition and shock focusing in an elliptical cavity was proposed and experimentally demonstrated with a $$\hbox {C}_{2}\hbox {H}_{4}{-}\hbox {O}_{2}$$

C
2

H
4

-

O
2

mixture at 100 kPa and 297 K. In the experiment, an elliptical cavity and single rectangular cavities of different heights were used, and their flow-field patterns were visualized using high-speed schlieren imaging. Detonation initiation was achieved in the case of the elliptical cavity, and based on the Mach number change of the leading shock wave, two propagation phases were verified: the deceleration and acceleration phases. The deceleration phase was driven merely by the gasdynamic effect, wherein the initial shock wave (ISW) expanded spherically, and the acceleration phase began when the ISW shifted to planar propagation. In the acceleration phase, although gradual acceleration was observed in rectangular cavities, rapid acceleration occurred in the elliptical cavity. From the schlieren images, the second acceleration was caused not only by the concave reflected shock wave’s catching up with the ISW, but also by the fast-flames that were generated along the cavity corners and engulfed the ISW in the converging section of the elliptical cavity.
Improved sensitivity and automation of a multi-step upconversion lateral flow immunoassay using a 3D-printed actuation mechanism
Authors: Raiko Kirsti , Nääjärvi Oskari , Ekman Miikka , Koskela Sonja , Soukka Tero , Martiskainen Iida , Salminen Teppo
Published: January 2024

The development of sensitive point-of-care (POC) assay platforms is of interest for reducing the cost and time of diagnostics. Lateral flow assays (LFAs) are the gold standard for POC systems, but their sensitivity as such is inadequate, for example, in the case of cardiac diagnostics. The performance can be improved by incorporating different steps, such as pre-incubation to prolong the interaction time between sample and reporter for immunocomplex formation, and washing steps for background reduction. However, for POC assays, manual steps by the assay conductor are not desired. In this research, upconverting nanoparticles (UCNPs) were coated with poly(acrylic acid) (PAA) and conjugated to anti-cTnI antibodies, yielding non-clustering particles with low non-specific binding. The performance of cTnI-LFA in the PAA-anti-cTnI-UCNPs was compared to the same UCNPs with a commercial carboxyl surface. A kitchen-timer mechanism was embedded in a 3D-printed housing to produce a low-cost actuator facilitating a timed pre-incubation step for reporter and sample, and a washing step, to enable a multi-step cTnI-LFA with minimized manual labour. PAA-UCNPs showed improved mobility on nitrocellulose compared to those with a commercial surface. The mechanical actuator system was shown to improve sensitivity compared to a labour-intensive multi-step dipstick method, despite pre-incubation occurring during shaking and heating in the dipstick method. The limit of detection decreased from 7.6 to 1.5 ng/L cTnI in human plasma. The presented actuator can be easily modified for sensitivity improvement in the LFA for different analytes via pre-incubation and washing steps.

Graphical abstract
Unraveling T cell exhaustion in the immune microenvironment of osteosarcoma via single-cell RNA transcriptome
Authors: Cheng Debin , Zhang Zhao , Liu Dong , Mi Zhenzhou , Tao Weidong , Fu Jun , Fan Hongbin
Published: January 2024

Osteosarcoma (OS) represents a profoundly invasive malignancy of the skeletal system. T cell exhaustion (Tex) is known to facilitate immunosuppression and tumor progression, but its role in OS remains unclear. In this study, single-cell RNA sequencing data was employed to identify exhausted T cells within the tumor immune microenvironment (TIME) of OS. We found that exhausted T cells exhibited substantial infiltration in OS samples. Pseudotime trajectory analysis revealed a progressive increase in the expression of various Tex marker genes, including PDCD1, CTLA4, LAG3, ENTPD1, and HAVCR2 in OS. GSVA showed that apoptosis, fatty acid metabolism, xenobiotic metabolism, and the interferon pathway were significantly activated in exhausted T cells in OS. Subsequently, a prognostic model was constructed using two Tex-specific genes, MYC and FCGR2B, which exhibited exceptional prognostic accuracy in two independent cohorts. Drug sensitivity analysis revealed that OS patients with a low Tex risk were responsive to Dasatinib and Pazopanib. Finally, immunohistochemistry verified that MYC and FCGR2B were significantly upregulated in OS tissues compared with adjacent tissues. This study investigates the role of Tex within the TIME of OS, and offers novel insights into the mechanisms underlying disease progression as well as the potential treatment strategies for OS.

Graphic Abstract
Personalized neoantigen vaccine enhances the therapeutic efficacy of bevacizumab and anti-PD-1 antibody in advanced non-small cell lung cancer
Authors: Lin Xiuhua , Tang Shichuan , Guo Yutong , Tang Ruijing , Li Zhenli , Pan Xinting , Chen Geng , Qiu Liman , Dong Xiuqing , Zhang Ling , Liu Xiaolong , Cai Zhixiong , Xie Baosong
Published: January 2024

Clinically, a considerable number of non-small cell lung cancer (NSCLC) patients are unable to receive or resist chemotherapy, and the efficacy of non-chemotherapy treatment strategies based on anti-angiogenic agents combined with immune checkpoint blockade is still unsatisfactory. Neoantigen vaccine, based on personalized tumor DNA mutations, could elicit tumor specific T cell infiltration into the tumor site, exerting potent anti-tumor efficacy. Here, we evaluated the feasibility and safety of a new antitumor strategy by adding neoantigen vaccine to the regimen of bevacizumab and anti-PD-1 antibody. Firstly, 7 novel immunogenic neoantigen peptides were identified and developed for neoantigen vaccine (LLCvac), which can elicit strong antitumor immune response in vivo. Then, in orthotopic lung cancer model, LLCvac further combining with bevacizumab and anti-PD-1 antibody exerted a stronger antitumor effect, exhibiting significant decrease of tumor volume without obvious toxicity. Furthermore, tumor immune microenvironment assessment also showed that the proportion of neoantigen-specific T cells in blood could be induced dramatically by the combined therapy. And a large amount of neoantigen-specific Ki67-positive CD8+ T cells were found in tumor tissues, which infiltrated tumor tissues effectively to kill tumor cells expressing identified neoantigens. Overall, these results suggested that this combined therapy could safely induce robust antitumor efficacy, serving as an effective chemotherapy-free strategy for NSCLC treatment.
New CEACAM-targeting 2A3 single-domain antibody-based chimeric antigen receptor T-cells produce anticancer effects in vitro and in vivo
Authors: Jancewicz Iga , Śmiech Magdalena , Winiarska Magdalena , Zagozdzon Radoslaw , Wisniewski Pawel
Published: January 2024

Recently, a breakthrough immunotherapeutic strategy of chimeric antigen receptor (CAR) T-cells has been introduced to hematooncology. However, to apply this novel treatment in solid cancers, one must identify suitable molecular targets in the tumors of choice. CEACAM family proteins are involved in the progression of a range of malignancies, including pancreatic and breast cancers, and pose attractive targets for anticancer therapies. In this work, we used a new CEACAM-targeted 2A3 single-domain antibody-based chimeric antigen receptor T-cells to evaluate their antitumor properties in vitro and in animal models. Originally, 2A3 antibody was reported to target CEACAM6 molecule; however, our in vitro co-incubation experiments showed activation and high cytotoxicity of 2A3-CAR T-cells against CEACAM5 and/or CEACAM6 high human cell lines, suggesting cross-reactivity of this antibody. Moreover, 2A3-CAR T-cells tested in vivo in the BxPC-3 xenograft model demonstrated high efficacy against pancreatic cancer xenografts in both early and late intervention treatment regimens. Our results for the first time show an enhanced targeting toward CEACAM5 and CEACAM6 molecules by the new 2A3 sdAb-based CAR T-cells. The results strongly support the further development of 2A3-CAR T-cells as a potential treatment strategy against CEACAM5/6-overexpressing cancers.
An analysis pipeline for understanding 6-thioguanine effects on a mouse tumour genome
Authors: Yankilevich Patricio , Nazerai Loulieta , Willis Shona Caroline , Schmiegelow Kjeld , De Zio Daniela , Nielsen Morten
Published: January 2024

Mouse tumour models are extensively used as a pre-clinical research tool in the field of oncology, playing an important role in anticancer drugs discovery. Accordingly, in cancer genomics research, the demand for next-generation sequencing (NGS) is increasing, and consequently, the need for data analysis pipelines is likewise growing. Most NGS data analysis solutions to date do not support mouse data or require highly specific configuration for their use. Here, we present a genome analysis pipeline for mouse tumour NGS data including the whole-genome sequence (WGS) data analysis flow for somatic variant discovery, and the RNA-seq data flow for differential expression, functional analysis and neoantigen prediction. The pipeline is based on standards and best practices and integrates mouse genome references and annotations. In a recent study, the pipeline was applied to demonstrate the efficacy of low dose 6-thioguanine (6TG) treatment on low-mutation melanoma in a pre-clinical mouse model. Here, we further this study and describe in detail the pipeline and the results obtained in terms of tumour mutational burden (TMB) and number of predicted neoantigens, and correlate these with 6TG effects on tumour volume. Our pipeline was expanded to include a neoantigen analysis, resulting in neopeptide prediction and MHC class I antigen presentation evaluation. We observed that the number of predicted neoepitopes were more accurate indicators of tumour immune control than TMB. In conclusion, this study demonstrates the usability of the proposed pipeline, and suggests it could be an essential robust genome analysis platform for future mouse genomic analysis.
Characterization of T cell receptor repertoire in penile cancer
Authors: Zhang Junying , Wang Yapeng , Huang Yiqiang , Tan Xintao , Xu Jing , Yan Qian , Tan Jiao , Zhang Yao , Zhang Jun , Ma Qiang , Zhu Hailin , Ye Jin , Zhu Zhaojing , Lan Weihua
Published: January 2024

Tumor-infiltrating lymphocytes (TILs) play a key role in regulating the host immune response and shaping tumor microenvironment. It has been previously shown that T cell infiltration in penile tumors was associated with clinical outcomes. However, few studies have reported the T cell receptor (TCR) repertoire in patients with penile cancer. In the present study, we evaluated the TCR repertoires in tumor and adjacent normal tissues from 22 patients with penile squamous cell carcinoma (PSCC). Analysis of the T cell receptor beta-variable (TRBV) and joining (TRBJ) genes usage and analysis of complementarity determining region 3 (CDR3) length distribution did not show significant differences between tumor and matched normal tissues. Moreover, analysis of the median Jaccard index indicated a limited overlap of TCR repertoire between these groups. Compared with normal tissues, a significantly lower diversity and higher clonality of TCR repertoire was observed in tumor samples, which was associated with clinical characteristics. Further analysis of transcriptional profiles demonstrated that tumor samples with high clonality showed increased expression of genes associated with CD8 + T cells. In addition, we analyzed the TCR repertoire of CD4 + T cells and CD8 + T cells isolated from tumor tissues. We identified that expanded clonotypes were predominantly in the CD8 + T cell compartment, which presented with an exhausted phenotype. Overall, we comprehensively compared TCR repertoire between penile tumor and normal tissues and demonstrated the presence of distinct T cell immune microenvironments in patients with PSCC.
The complex role of IL-10 in malignant ascites: a review
Authors: Huang Yue , Zou Kangni , Jiang Heng , Li Zhengyu
Published: January 2024

The emergence of malignant ascites (MA) indicates poor prognoses in patients with ovarian, gastrointestinal, breast, and pancreatic cancer. Interleukin-10 (IL-10) is a pleiotropic cytokine with immunoregulatory effects in tumor microenvironment. The level of IL-10 in MA varied across cancer types and patients, influencing cancer progression and outcomes. Originating from various immune and cancer cells, IL-10 contributes to complex signaling pathways in MA. Systemic IL-10 administration, although the evidence of its efficacy on MA is limited, still emerges as a promising therapeutic strategy because it can increase CD8+ T cells cytotoxicity and invigorate exhausted CD8+ tumor infiltration lymphocytes (TILs) directly. IL-10 signaling blockade also demonstrates great potential when combined with other immunotherapies in MA treatment. We reviewed the levels, origins, and functions of IL-10 in malignant ascites and overviewed the current IL-10 signaling targeting therapies, aiming to provide insights for MA treatment.
Presence of Epstein–Barr virus (EBV) antigens detected by sensitive methods has no influence on local immune environment in diffuse large B cell lymphoma
Authors: Mangiaterra T. , Alonso-Alonso R. , Rabinovich A. , De Dios Soler M. , Galluzzo L. , Soria M. , Colli S. , De Matteo E. , Rodriguez Pinilla S. M. , Chabay P.
Published: January 2024

EBV+ diffuse large B cell lymphoma (DLBCL) not otherwise specified (NOS) is a new entity confirmed by the World Health Organization (WHO) in 2017. In this new entity, the virus may contribute to a tolerogenic microenvironment. Traces of the virus have been described in DLBCL with more sensitive methods, in cases that were originally diagnosed as negative. The aim of this study was to analyze the expression of immune response genes in the tumor microenvironment to disclose the role of the virus and its traces in DLBCL. In 48 DLBCL cases, the expression of immune response genes and the presence of molecules that induce tolerance, such as TIM3, LAG3 and PDL1 by immunohistochemistry (IHC), were studied. To broaden the study of the microenvironment, tumor-associated macrophages (TMAs) were also explored. No significant differences were observed in the expression of immune response genes in the EBV+ DLBCL and those cases that were EBV− DLBCL but that exhibited viral traces, assessed by ViewRNA assay. Only the EBV+ DLBCL cases displayed a significantly higher increase in the expression of CD8 and cytotoxic T cells detected by gene expression analysis, and of PDL1 in tumor cells and in the expression of CD68 in the tumor microenvironment detected by IHC, not observed in those cases with viral traces. The increase in CD8 and cytotoxic T cells, PDL1 and CD68 markers only in EBV+ DLBCL may indicate that traces of viral infection might not have influence in immune response markers.
A CAR-T response prediction model for r/r B-NHL patients based on a T cell subset nomogram
Authors: Zhang Xiaomei , Sun Rui , Zhang Meng , Zhao Yifan , Cao Xinping , Guo Ruiting , Zhang Yi , Liu Xingzhong , Lyu Cuicui , Zhao Mingfeng
Published: January 2024

Background

Chimeric antigen receptor (CAR) T cells for refractory or relapsed (r/r) B cell no-Hodgkin lymphoma (NHL) patients have shown promising clinical effectiveness. However, the factors impacting the clinical response of CAR-T therapy have not been fully elucidated. We here investigate the independent influencing factors of the efficacy of CD19 CAR-T cell infusion in the treatment of r/r B-NHL and to establish an early prediction model.

Methods

A total of 43 r/r B-NHL patients were enrolled in this retrospective study. The patients’ general data were recorded, and the primary endpoint is the patients’ treatment response. The independent factors of complete remission (CR) and partial remission (PR) were investigated by univariate and binary logistic regression analysis, and the prediction model of the probability of CR was constructed according to the determined independent factors. Receiver operating characteristic (ROC) and calibration plot were used to assess the discrimination and calibration of the established model. Furthermore, we collected 15 participators to validate the model.

Results

Univariate analysis and binary logistic regression analysis of 43 patients showed that the ratio of central memory T cell (Tcm) and naïve T cell (Tn) in cytotoxic T cells (Tc) was an independent risk factor for response to CD19 CAR-T cell therapy in r/r B-NHL. On this basis, the area under the curve (AUC) of Tcm in the Tc and Tn in the Tc nomogram model was 0.914 (95%CI 0.832–0.996), the sensitivity was 83%, and the specificity was 74.2%, which had excellent predictive value. We did not found the difference of the progression-free survival (PFS).

Conclusions

The ratio of Tcm and Tn in Tc was found to be able to predict the treatment response of CD19 CAR-T cells in r/r B-NHL. We have established a nomogram model for the assessment of the CD19 CAR-T therapy response presented high specificity and sensitivity.