bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors
Authors: Demerlé Clémence , Gorvel Laurent , Mello Marielle , Pastor Sonia , Degos Clara , Zarubica Ana , Angelis Fabien , Fiore Frédéric , Nunes Jacques A , Malissen Bernard , Greillier Laurent , Guittard Geoffrey , Luche Hervé , Barlesi Fabrice , Olive Daniel
Published: May 2023

Background

Tumor necrosis factor superfamily member 14 (TNFRSF14)/herpes virus entry mediator (HVEM) is the ligand for B and T lymphocyte attenuator (BTLA) and CD160-negative immune co-signaling molecules as well as viral proteins. Its expression is dysregulated with an overexpression in tumors and a connection with tumors of adverse prognosis.

Methods

We developed C57BL/6 mouse models co-expressing human (hu)BTLA and huHVEM as well as antagonistic monoclonal antibodies (mAbs) that completely prevent the interactions of HVEM with its ligands.

Results

Here, we show that the anti-HVEM18-10 mAb increases primary human αβ-T cells activity alone (CIS-activity) or in the presence of HVEM-expressing lung or colorectal cancer cells in vitro (TRANS-activity). Anti-HVEM18-10 synergizes with antiprogrammed death-ligand 1 (anti-PD-L1) mAb to activate T cells in the presence of PD-L1-positive tumors, but is sufficient to trigger T cell activation in the presence of PD-L1-negative cells. In order to better understand HVEM18-10 effects in vivo and especially disentangle its CIS and TRANS effects, we developed a knockin (KI) mouse model expressing human BTLA (huBTLA+/+) and a KI mouse model expressing both huBTLA+/+/huHVEM+/+(double KI (DKI)). In vivo preclinical experiments performed in both mouse models showed that HVEM18-10 treatment was efficient to decrease human HVEM+tumor growth. In the DKI model, anti-HVEM18-10 treatment induces a decrease of exhausted CD8+T cells and regulatory T cells and an increase of effector memory CD4+T cells within the tumor. Interestingly, mice which completely rejected tumors (±20%) did not develop tumors on rechallenge in both settings, therefore showing a marked T cell-memory phenotype effect.

Conclusions

Altogether, our preclinical models validate anti-HVEM18-10 as a promising therapeutic antibody to use in clinics as a monotherapy or in combination with existing immunotherapies (antiprogrammed cell death protein 1/anti-PD-L1/anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4)).
Patient data for commercial companies? An ethical framework for sharing patients’ data with for-profit companies for research
Authors: Winkler Eva C , Jungkunz Martin , Thorogood Adrian , Lotz Vincent , Schickhardt Christoph
Published: May 2023

Background

Research using data from medical care promises to advance medical science and improve healthcare. Academia is not the only sector that expects such research to be of great benefit. The research-based health industry is also interested in so-called ‘real-world’ health data to develop new drugs, medical technologies or data-based health applications. While access to medical data is handled very differently in different countries, and some empirical data suggest people are uncomfortable with the idea of companies accessing health information, this paper aims to advance the ethical debate about secondary use of medical data generated in the public healthcare sector by for-profit companies for medical research (ReuseForPro).

Methods

We first clarify some basic concepts and our ethical-normative approach, then discuss and ethically evaluate potential claims and interests of relevant stakeholders: patients as data subjects in the public healthcare system, for-profit companies, the public, and physicians and their healthcare institutions. Finally, we address the tensions between legitimate claims of different stakeholders in order to suggest conditions that might ensure ethically sound ReuseForPro.

Results

We conclude that there are good reasons to grant for-profit companies access to medical data if they meet certain conditions: among others they need to respect patients’ informational rights and their actions need to be compatible with the public’s interest in health benefit from ReuseForPro.
Evaluation of predictive models of aneurysm focal growth and bleb development using machine learning techniques
Authors: Hadad Sara , Mut Fernando , Slawski Martin , Robertson Anne M , Cebral Juan R
Published: May 2023

Background

The presence of blebs increases the rupture risk of intracranial aneurysms (IAs).

Objective

To evaluate whether cross-sectional bleb formation models can identify aneurysms with focalized enlargement in longitudinal series.

Methods

Hemodynamic, geometric, and anatomical variables derived from computational fluid dynamics models of 2265 IAs from a cross-sectional dataset were used to train machine learning (ML) models for bleb development. ML algorithms, including logistic regression, random forest, bagging method, support vector machine, and K-nearest neighbors, were validated using an independent cross-sectional dataset of 266 IAs. The models' ability to identify aneurysms with focalized enlargement was evaluated using a separate longitudinal dataset of 174 IAs. Model performance was quantified by the area under the receiving operating characteristic curve (AUC), the sensitivity and specificity, positive predictive value, negative predictive value, F1 score, balanced accuracy, and misclassification error.

Results

The final model, with three hemodynamic and four geometrical variables, along with aneurysm location and morphology, identified strong inflow jets, non-uniform wall shear stress with high peaks, larger sizes, and elongated shapes as indicators of a higher risk of focal growth over time. The logistic regression model demonstrated the best performance on the longitudinal series, achieving an AUC of 0.9, sensitivity of 85%, specificity of 75%, balanced accuracy of 80%, and a misclassification error of 21%.

Conclusions

Models trained with cross-sectional data can identify aneurysms prone to future focalized growth with good accuracy. These models could potentially be used as early indicators of future risk in clinical practice.
Canadian Nutrition Society Dialogue on disease-related malnutrition: a commentary from the 2022 Food For Health Workshop
Authors: Gramlich Leah , Cardenas Diana , Correia Maria Isabel Toulson Davisson , Keller Heather , Basualdo-Hammond Carlota , Bauer Judy , Jensen Gordon , Nasser Roseann , Tarasuk Valerie , Reynolds Jennifer
Published: May 2023

This commentary represents a dialogue on key aspects of disease-related malnutrition (DRM) from leaders and experts from academia, health across disciplines, and several countries across the world. The dialogue illuminates the problem of DRM, what impact it has on outcomes, nutrition care as a human right, and practice, implementation, and policy approaches to address DRM. The dialogue allowed the germination of an idea to register a commitment through the Canadian Nutrition Society and the Canadian Malnutrition Task Force in the UN/WHO Decade of Action on Nutrition to advance policy-based approaches for DRM. This commitment was successfully registered in October 2022 and is entitled CAN DReaM (Creating Alliances Nationally for Policy in Disease-Related Malnutrition). This commitment details five goals that will be pursued in the Decade of Action on Nutrition. The intent of this commentary is to record the proceedings of the workshop as a stepping stone to establishing a policy-based approach to DRM that is relevant in Canada and abroad.
Respiratory plasticity during acclimation to hypoxia and following a recovery in normoxia
Authors: Zhang Yangfan , Mauduit Florian , Pettinau Luca , Ollivier Helene , Lancien Frédéric , Anttila Katja , Farrell Anthony P. , Claireaux Guy
Published: May 2023

Phenotypic plasticity manifested after acclimatization is a very important source of biological variability among fish species. We hypothesized that hypoxic acclimation, besides potentially generating a temporary hypoxic respiratory phenotype, would also manifest as a continued benefit after reacclimation to normoxia. Hence, we holistically characterized the respiratory phenotype of European sea bass ( Dicentrarchus labrax (Linnaeus, 1758)) acclimated to normoxia with or without prior acclimation to hypoxia. Compared with the original normoxic phenotype, prior acclimation to hypoxia and return to normoxia produced a 27% higher absolute aerobic scope (AAS), a 24% higher citrate synthase activity in red muscle, and a 28% lower excess post exercise O2 consumption. Additional testing of hypoxia-acclimated fish under normoxia explored the specific effects of hypoxic acclimation. The hypoxic phenotype, when compared with the original normoxic phenotype, had a lower standard metabolic rate, a better hypoxia performance, and a lower minimum PO2 for supporting 50% AAS. Thus, respiratory plasticity allows sea bass to improve its maximum aerobic capacity after returning to normoxia from hypoxic acclimation, a potential benefit from exploiting a hypoxic habitat. Given this respiratory malleability, general predictions for marine fish exploiting a more hypoxic future should better consider respiratory plasticity and prolonged effects of hypoxic exposures.
Electromagnetic absorption enhancement of concrete using metamaterials
Authors: Wu Hongya , Zhang Yafan , Dong Han , Zhou Danni , Fang Hao , Qin Guoqiang , Qin Shengjian , Zhang Guanglei
Published: May 2023

Electromagnetic wave (EMW) pollution adversely affects information, facilities safety, and human health, leading to the development of EMW absorbing materials, especially absorbing concrete. Here, the influence of arrangement ways of concrete iron on microwave reflectivity was analyzed, and a split ring resonator (SRR) was designed and introduced to steel-reinforced concrete to improve the EMW absorbing performance of the concrete. The simulation results show that by tuning the diameter and arrangement ways of concrete iron and introducing SRR structure, an EMW absorption concrete which can display 0.3% reflection loss ([Formula: see text]% absorption) at 2.34[Formula: see text]GHz was designed and realized. The reflectivity of concrete iron and EMW absorption capacity of concrete were investigated by a vector network analyzer, and the experimental results almost agree with the simulation results. The reflection and absorption of EMW are caused by magnetic resonance and conductive loss, magnetic loss, respectively.
Investigation of the nanocrystalline nature of silicon carbide (3C–SiC) nanoparticles by XRD and TEM methods
Authors: Huseynov Elchin M. , Naghiyev Tural G.
Published: May 2023

FE-SEM and TEM images were used to identify the size of 3C–SiC nanoparticles. Simultaneously, HRTEM and Selected Area Electron Diffraction (SAED) analyses were conducted in order to determine the crystalline nature of the nanoparticles. Moreover, lattice parameters of 3C–SiC nanoparticles have been studied by SAED and XRD analyses. The possible existence of other modified polytypes of silicon carbide was investigated in the experimental sample. The 2[Formula: see text] angles were determined according to the lattice parameters. Lattice constants and lattice angles for nanocrystalline 3C–SiC particles were defined from the experiments.
A Wavelet Basis ANN and 5-Class Decision Factor AI Algorithm
Authors: Liu Xuepeng , Zhao Dongmei , Peng Yihang , Li Jianping
Published: May 2023

The accuracy and reliability of continuous space curve estimation is the key to global exploration. An improved artificial intelligence algorithm is proposed for continuous space analysis. First, a wavelet basis ANN algorithm is proposed to determine the discretization strategy in continuous space. The hidden layer node transfer function in a BP neural network is replaced by a wavelet basis function, and the modified BP neural network is composed of a wavelet neural network. Second, an improved wolf algorithm is established. The core wolf system ensures the precision of the whole exploration task. Finally, main and auxiliary double cores and a five-class decision factor are used to establish a population classification model to solve the convergence of the algorithm.
Risk Avoidance and Deterrence: Duality of the US Policy toward China
Authors: Xiao He
Published: May 2023

The Biden administration has demonstrated high emphasis on economic competition among major powers. Although it has stated multiple times that the US does not seek confrontation with China, the Biden administration’s security policy toward China, compared with that of the Trump administration, is more confrontational, which is underscored by its constant pushing of China’s red line in the Taiwan issue. Strategic competition against China is clearly regarded as the pivot of the foreign policy by the Biden administration, which has lowered expectation of China and has changed the mentality of striving for “big deals” to “no deal” in its China policy. The Biden administration believes that the US has a long-term advantage, and has developed a composite strategy comprised of two tactics based on its perception of the strategic positioning and the competitive status of China and the US. The first is a dominant strategy of (to gain advantages by risk avoiding), namely to cut off China’s access to external technological innovation resources and maintain the long-term advantage of the US while avoiding bilateral interactions of high costs, risks, and uncertainties, in order to ensure a lasting and secure victory as much as possible. The second is a supporting strategy of (to prevent wars by enhancing commitment), which aims to prevent China from taking high-risk actions or launching military challenges against the US on key issues when perceiving disadvantage. and focus, respectively, on economic and security policies, which together constitute the logic for the US strategic competition against China. To this end, the US has strengthened its strategic deterrence against China by reinforcing its key foreign commitments and mobilizing its allies.
Application of Psychological Effects in Intelligent Digital English Teaching Based on Multimodal Low Resource Language Information Processing from a Psychological Perspective
Authors: Yang Lili , Zhang Yue
Published: May 2023

With the development of information technology, intelligent digital education is gradually emerging. At the same time, with the closer economic and trade relations between regions, the demand for English talents is becoming more and more urgent. Applying the concept and method of intelligent digital education to English Teaching (ET) is of great significance for improving students’ learning efficiency and academic level, and enhancing students’ English application ability and cross-cultural communication ability. However, due to the limitations of the traditional teaching model, such as the single and outdated model, the low interest of students in learning, and the lack of emphasis on cultivating students’ English practical ability, it cannot effectively meet the requirements of improving students’ learning effect. Therefore, this article studies the intelligent digital ET mode based on multimodal low-resource language information processing, proposes the construction method of intelligent digital ET mode, and conducts experimental research on it. The research showed that the positive emotional input level index of Group X students was 8.47% higher than that of Group T students; the efficiency index of Group X students was 5.02% higher than that of Group T students; the autonomous learning ability and English learning level of Group X students were higher than those of Group T; the students in Group X had higher recognition of ET mode than those in Group T. The intelligent digital ET mode can effectively improve the learning effect.
Heat Generation Mechanism and Parameter Sensitivity Analysis of NCA-Graphite Battery Based on Electrochemical-Thermal Coupling Model
Authors: Yu Shuyang , Xu Chao , Mao Ya , Lu Taolin , Xie Jingying
Published: May 2023

This paper presents an electrochemical-thermal coupling model of 5Ah NCA-graphite pouch battery to analyze the heat generation mechanism. The simulation result indicates that the total heat generation increases with current and the polarization heat is dominant. The total heat generation of negative electrode is higher than that of positive electrode, the electrochemical reaction heat and ohmic heat of positive electrode are higher than those of negative electrode. Then four design parameters were selected, their effects on electrochemical-thermal characteristics and the heat generation from different heat sources were analyzed in detail. The results indicate that the increase of capacity and decrease of discharge temperature can be achieved by decreasing the radius of positive/negative particles (R

p
/R

n
) and increasing the initial electrolyte concentration (c

l,0) in a reasonable range. R

p
and R

n
are proportional to polarization heat and ohmic heat, R

p
is proportional to electrochemical reaction heat and R

n
is inversely proportional. c

l,0 does not affect on electrochemical reaction heat, it is proportional to ohmic heat and inversely proportional to polarization heat. The sensitivity order of the design parameters is as follows: R

p
> R

n
> c

l,0 > SEI film resistance (R

sei
).
Understanding the Self-Discharge Redox Shuttle Mechanism of Dimethyl Terephthalate in Lithium-Ion Batteries
Authors: Boetticher Tom , Adamson Anu , Buechele Sebastian , Alter Ethan D. , Metzger Michael
Published: May 2023

Dimethyl terephthalate (DMT) is a redox shuttle molecule that leads to unwanted self-discharge of lithium-ion cells. It can be created in situ as a breakdown product of polyethylene terephthalate (PET), which is a surprisingly common polymer for the adhesive tapes found in commercial cells. This study investigates the shuttling mechanism and electrochemical stability of DMT, as well as its impact on the performance of LFP/graphite pouch cells with LiFSI and LiPF6 conducting salts. Cyclic voltammetry shows that DMT has a redox potential of 1.5 V vs Li+/Li and is redox active in the full voltage range of LFP/graphite cells. Ultra-high precision coulometry and open-circuit storage experiments show that DMT lowers the coulombic efficiency, increases the charge endpoint capacity slippage, and dramatically accelerates the reversible self-discharge of LFP/graphite pouch cells. Gas chromatography-mass spectrometry shows that DMT is stable over weeks in cells with LiPF6, but only for several days in cells with LiFSI. A well-insulating solid-electrolyte interphase layer derived from vinylene carbonate can prevent DMT from shuttling. However, VC can be consumed, and passivation layers can deteriorate in aged cells, so the best way to prevent DMT-induced self-discharge of lithium-ion batteries is to eliminate PET components.
Quantifying Degradation Mechanisms in a High-Performance Parallel Hybrid Lithium-Ion Supercapacitor Induced by Long Term Cycling at High Current Rates
Authors: Vanpeene V. , Martens I. , Mirolo M. , Benayad A. , Daniel L. , Geniès S. , Maletin Y. , Stryzhakova N. , Zelinskyi S. , Chernukhin S. , Drnec J. , Villanova J.
Published: May 2023

Understanding the degradation pathways of electrode materials is a key to develop more reliable Li-ion technologies along with an increased energy density and power rate. This study aims to demonstrate the benefits of the combined use of X-ray based characterization techniques and electrochemical assessment for thorough multi-scale analysis to elucidate the aging mechanisms of a Li4Ti5O12/AC//LiMn2O4/AC parallel hybrid lithium-ion supercapacitor. Analyses performed on samples extracted from full stack representative of industrial battery application, show that irreversible modifications are observed at all length scales on both electrodes. At the negative, the disaggregation and corrosion of the LTO active material, as well as AC particle cracking and electrode film delamination have been observed. In the meantime, drastic cracking of the AC and LMO active material along with important micro-strain increase at the crystallite level for LMO as well as Mn3+ dissolution are reported at the positive. The formation of a cathode electrolyte interface (CEI) is also reported. These structural and chemical changes have been identified as precursors to important polarization increase, Li inventory loss and furthermore capacity fading leading thus to device failure.
Unpacking the “movement of substances” core concept of physiology by an Australian team
Authors: Brown Daniel , Uebergang Tanya , Masters Nicole , Towstoless Michelle , Hayes Alan , Hryciw Deanne H. , Lexis Louise , Tangalakis Kathy ,   and Task Force
Published: May 2023

This article unpacks the core concept of the “movement of substances” within the body, with the aim to produce a resource that will help guide the teaching of physiology at tertiary education institutes in Australia. The concept introduces fundamental knowledge of the factors that drive substance movement and then applies them in physiological contexts.
Anticipatory central command on standing decreases cerebral blood velocity causing hypocapnia in hyperpneic postural tachycardia syndrome
Authors: Stewart Julian M. , Medow Marvin S.
Published: May 2023

Dyspnea is frequent in postural tachycardia syndrome (POTS) and is associated with upright hyperpnea and hypocapnia that drives sinus tachycardia. It is initiated by an exaggerated reduction in cerebral conductance and decreased cerebral blood flow (CBF) that precedes the act of standing. This is a form of autonomically mediated “central command.” Cerebral blood flow is further reduced by initial orthostatic hypotension common in POTS. Hypocapnia is maintained during the standing response and might account for persistent postural tachycardia.
A Predictive Model and Survival Analysis for Tube Feeding in ALS Patients: A Prospective Cohort Study in a Chinese ALS Clinic
Authors: Chen Xi , Xu Jiawen , Guo Jingyan , Ye Ting , Zhao Baocheng , Fang Shiming , Chen Yan , Dong Yi
Published: May 2023

Objectives. Tube feeding is an effective way to provide nutritional support for amyotrophic lateral sclerosis (ALS) patients with severe dysphagia. Currently, the predictors of tube feeding and the survival affected by tube feeding were poorly studied in Chinese ALS patients. Therefore, we aimed to explore predictive factors and establish a prediction model to quantitatively predict the risk of tube feeding. Furthermore, we explored the survival benefit provided by tube feeding. Methods. In this longitudinal, prospective cohort study, we included patients diagnosed with ALS using the Awaji criteria at the ALS clinic in Huashan Hospital. Follow-up was conducted by telephone interview from January 1, 2019, to December 30, 2021, or until death. All statistical analyses were performed using R software. Results. Overall, 218 patients were recruited for the study. The multivariate Cox regression analysis showed a high ALSFRS-R slope (adjusted hazard ratio

aHR

=
4.94

(95% confidence interval (95% CI: 2.26-10.81),

p
<
0.001

), low bulbar score (

aHR
=
0.81

(95% CI: 0.69-0.96),

p
=
0.01

), history of ischemic stroke (

aHR
=
5.69

(95% CI: 1.3-24.82),

p
=
0.02

), and bulbar involvement (

aHR
=
11.87

(95% CI: 1.42-99.31),

p
=
0.02

) as independent risk factors of tube feeding. The nomogram model was established with moderate discrimination and calibration. Among 71 ALS patients with tube feeding indication, 33.8% accepted gastrostomy suggestion and 14.1% had nasogastric tube (NGT) insertion. However, gastrostomy and NGT did not accelerate disease progression (

aHR
=
0.57

(95% CI: 0.20-1.67),

p
=
0.31

and

aHR
=
1.72

(95% CI: 0.43-6.88),

p
=
0.43

, respectively). Conclusions. We developed a nomogram that could be a prediction tool to predict individual timing of tube feeding for ALS patients. In addition, we found that gastrostomy and NGT did not affect ALS patients’ survival.
Carbon Dots for the Treatment of Inflammatory Diseases: An Appraisal of In Vitro and In Vivo Studies
Authors: Sharma Anshul , Choi Hyo-Kyoung , Lee Hae-Jeung
Published: May 2023

In recent decades, several studies demonstrating various applications of carbon dots (C-dots), including metal sensing, bioimaging, pH sensing, and antimicrobial activities, have been published. Recent developments have shifted this trend toward biomedical applications that target various biomarkers relevant to chronic diseases. However, relevant developments and research results regarding the anti-inflammatory properties of C-dots against inflammation-associated diseases have not been systematically reviewed. Hence, this review discusses the anti-inflammatory effects of C-dots in in vivo and in vitro models of LPS-induced inflammation, gout, cartilage tissue engineering, drug-induced inflammation, spinal cord injury, wound healing, liver diseases, stomach cancer, gastric ulcers, acute kidney and lung injury, psoriasis, fever or hypothermia, and bone tissue regeneration. The compiled studies demonstrate the promising potential of C-dots as anti-inflammatory agents for the development of new drugs.
Three-Dimensional Structural Modelling and Characterization of Sodalite Material Network concerning the Irregularity Topological Indices
Authors: Zaman Shahid , Salman Muhammad , Ullah Asad , Ahmad Shahzad , Abdelgader Abas Mohammed Salaheldeen
Published: May 2023

Topological characterization of 3D molecular structures is an emerging study area in theoretical and computational chemistry. These structural descriptors are used in a variety of domains, including chemical graph theory, drug delivery, and nanomaterial characterization. Quantitative structural descriptors can be used to characterize the chemical and physical properties of a given compound. Topological indices of molecular graphs are numerical quantities that allow us to collect information about the chemical structure and reveal its hidden qualities without performing experiments. Due to the low cost of implementation, zeolite networks are considered popular chemical networks. Zeolites are widely used networks with applications in chemistry, medicine, and commercial production owing to their excellent chemical features. The sodalite network is composed of a very unique type of zeolite framework called sodalite. It is a three-dimensional network of interconnected cages and tunnels that provide an ideal environment for a wide range of chemical and physical processes. This paper deals with the sodalite material network’s degree-based and reverse degree-based irregularity indices. These indices provide a quantitative measure of the irregular behaviour of the sodalite material network. It can be used to identify areas of the network where irregular behaviour is occurring and to compare different networks to determine which is more irregular. Additionally, these indices can be used to monitor changes in irregularity over time, allowing us to measure the impact of any interventions that are implemented.
Dynamic Implied Risk Aversion Term Structure: An Empirical Analysis Based on Shanghai Stock Exchange 50 ETF Option
Authors: Jiang Lili , Niu Huawei , Wang Hui , Wang Yifeng , Tong Aihua
Published: May 2023

Risk preference has constantly been one of the vital issues in economics and finance. In this study, the time series and term structure of Chinese investors’ implicit risk aversion are investigated using the implicit risk aversion extraction method, and the dynamic term structure of Chinese investors’ implicit risk aversion is modeled using the Vasicek model. In the empirical process, the SSE 50 ETF option data from March 2015 to July 2018 are adopted to extract model‐free risk‐neutral skewness. The standard deviation, skewness, and kurtosis of reality measure are extracted using the Shanghai 50 ETF data, and then the monthly implied risk aversion time series and term structure of Chinese investors are obtained. As indicated by the results of this study, the risk preference of Chinese investors exhibits significant time series characteristics, and it will show risk‐loving and risk‐averse phenomena at certain times. Moreover, for different periods in the future, differences are generated in investors’ risk preferences, suggesting an aversion to short‐term risk and a certain tolerance for long‐term risk, i.e., there are significant characteristics of the term structure. Besides, the term structure of implied risk aversion of Chinese investors is dynamically modeled using the Vasicek model. To be specific, its first principal component can account for 90% of the change in the term structure. The “level factor” refers to the critical factor load, and the level of long‐term implied risk aversion reaches 0.658. Furthermore, the term structure of implied risk aversion exhibits the characteristics of mean regression. Next, more effective research results on investors’ risk preference are achieved, and the time‐varying characteristics and term structure characteristics of investors’ risk preference are investigated. The result suggests that the long‐term risk preference of Chinese investors approaches 1, and there is a significant feature of “mean regression,” i.e., a vital finding of this study.
Supplementary Table S1 from Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial
Authors: Abel Melissa L. , Takahashi Nobuyuki , Peer Cody , Redon Christophe E. , Nichols Samantha , Vilimas Rasa , Lee Min-Jung , Lee Sunmin , Shelat Meenakshi , Kattappuram Robbie , Sciuto Linda , Pinkiert Danielle , Graham Chante , Butcher Donna , Karim Baktiar , Sharma Ajit Kumar , Malin Justin , Kumar Rajesh , Schultz Christopher W. , Goyal Shubhank , del Rivero Jaydira , Krishnamurthy Manan , Upadhyay Deep , Schroeder Brett , Sissung Tristan , Tyagi Manoj , Kim Jung , Pommier Yves , Aladjem Mirit , Raffeld Mark , Figg William Douglas , Trepel Jane , Xi Liqiang , Desai Parth , Thomas Anish
Published: May 2023

Whole exome sequencing results
Supplementary Table S1 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: May 2023

Supplementary Table S1. Baseline characteristics of acalabrutinib treated patients
Supplementary Figure S4 from CD49d Expression Identifies a Biologically Distinct Subtype of Chronic Lymphocytic Leukemia with Inferior Progression-Free Survival on BTK Inhibitor Therapy
Authors: Alsadhan Anfal , Chen Jonathan , Gaglione Erika M. , Underbayev Chingiz , Tuma Pamela L. , Tian Xin , Freeman Lita A. , Baskar Sivasubramanian , Nierman Pia , Soto Susan , Itsara Andy , Ahn Inhye E. , Sun Clare , Bibikova Elena , Hartmann Tanja Nicole , Mhibik Maissa , Wiestner Adrian
Published: May 2023

Supplementary Figure S4. Clinical impact of CD49d bimodal expression on durability of BTKi therapy.
Supplementary Fig. 3 from Intravenous N-Acetylcysteine to Prevent Cisplatin-Induced Hearing Loss in Children: A Nonrandomized Controlled Phase I Trial
Authors: Orgel Etan , Knight Kristin R. , Chi Yueh-Yun , Malvar Jemily , Rushing Teresa , Mena Victoria , Eisenberg Laurie S. , Rassekh Shahrad R. , Ross Colin J.D. , Scott Erika N. , Neely Michael , Neuwelt Edward A. , Muldoon Leslie L. , Freyer David R.
Published: May 2023

Supplementary Fig. 3 Change in serum glutathione concentrations following NAC infusion
Data from Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial
Authors: Abel Melissa L. , Takahashi Nobuyuki , Peer Cody , Redon Christophe E. , Nichols Samantha , Vilimas Rasa , Lee Min-Jung , Lee Sunmin , Shelat Meenakshi , Kattapuram Robbie , Sciuto Linda , Pinkiert Danielle , Graham Chante , Butcher Donna , Karim Baktiar , Sharma Ajit Kumar. , Malin Justin , Kumar Rajesh , Schultz Christopher W. , Goyal Shubhank , Del Rivero Jaydira , Krishnamurthy Manan , Upadhyay Deep , Schroeder Brett , Sissung Tristan , Tyagi Manoj , Kim Jung , Pommier Yves , Aladjem Mirit , Raffeld Mark , Figg William Douglas. , Trepel Jane , Xi Liqiang , Desai Parth , Thomas Anish
Published: May 2023

Abstract
Purpose: Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations. Patients and Methods: In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels. Results: Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥ grade 4 adverse events occurred. Tumor regressions were observed in two patients with neuroendocrine prostate cancer and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer. Conclusions: ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors.
Data from Intravenous N-Acetylcysteine to Prevent Cisplatin-Induced Hearing Loss in Children: A Nonrandomized Controlled Phase I Trial
Authors: Orgel Etan , Knight Kristin R. , Chi Yueh-Yun , Malvar Jemily , Rushing Teresa , Mena Victoria , Eisenberg Laurie S. , Rassekh Shahrad R. , Ross Colin J.D. , Scott Erika N. , Neely Michael , Neuwelt Edward A. , Muldoon Leslie L. , Freyer David R.
Published: May 2023

AbstractPurpose:
Cisplatin-induced hearing loss (CIHL) is common and permanent. As compared with earlier otoprotectants, we hypothesized N-acetylcysteine (NAC) offers potential for stronger otoprotection through stimulation of glutathione (GSH) production. This study tested the optimal dose, safety, and efficacy of NAC to prevent CIHL.
Patients and Methods:
In this nonrandomized, controlled phase Ia/Ib trial, children and adolescents newly diagnosed with nonmetastatic, cisplatin-treated tumors received NAC intravenously 4 hours post-cisplatin. The trial performed dose-escalation across three dose levels to establish a safe dose that exceeded the targeted peak serum NAC concentration of 1.5 mmol/L (as identified from preclinical models). Patients with metastatic disease or who were otherwise ineligible were enrolled in an observation-only/control arm. To evaluate efficacy, serial age-appropriate audiology assessments were performed. Integrated biology examined genes involved in GSH metabolism and post-NAC GSH concentrations.
Results:
Of 52 patients enrolled, 24 received NAC and 28 were in the control arm. The maximum tolerated dose was not reached; analysis of peak NAC concentration identified 450 mg/kg as the recommended phase II dose (RP2D). Infusion-related reactions were common. No severe adverse events occurred. Compared with the control arm, NAC decreased likelihood of CIHL at the end of cisplatin therapy [OR, 0.13; 95% confidence interval (CI), 0.021–0.847; P = 0.033] and recommendations for hearing intervention at end of study (OR, 0.082; 95% CI, 0.011–0.60; P = 0.014). NAC increased GSH; GSTP1 influenced risk for CIHL and NAC otoprotection.
Conclusions:
NAC was safe at the RP2D, with strong evidence for efficacy to prevent CIHL, warranting further development as a next-generation otoprotectant.
Data from Phase I study of SYNB1891, an engineered E coli Nissle strain expressing STING agonist, with and without atezolizumab in advanced malignancies
Authors: Luke Jason J. , Piha-Paul Sarina A. , Medina Theresa , Verschraegen Claire F. , Varterasian Mary , Brennan Aoife M. , Riese Richard J. , Sokolovska Anna , Strauss James F. , Hava David L. , Janku Filip
Published: May 2023

Abstract
Purpose: SYNB1891 is a live, modified strain of the probiotic E. coli Nissle 1917 (EcN) engineered to produce cyclic dinucleotides under hypoxia leading to stimulator of interferon genes (STING)-activation in phagocytic antigen-presenting cells in tumors and activating complementary innate immune pathways. Patients and Methods: This first-in-human study (NCT04167137) enrolled participants with refractory advanced cancers to receive repeat intratumoral (IT) injections of SYNB1891 either alone or in combination atezolizumab, with the primary objective of evaluating the safety and tolerability of both regimens. Results: Twenty-four participants received monotherapy across 6 cohorts, and 8 participants received combination therapy in 2 cohorts. Five cytokine release syndrome events occurred with monotherapy, including one that met the criteria for dose-limiting toxicity at the highest dose; no other SYNB1891-related serious adverse events occurred, and no SYNB1891-related infections were observed. SYNB1891 was not detected in the blood at 6 or 24h after the first IT dose or in tumor tissue 7 days following the first dose. Treatment with SYNB1891 resulted in activation of the STING pathway and target engagement as assessed by upregulation of interferon-stimulated genes, chemokines/cytokines, and T-cell response genes in core biopsies obtained pre-dose and 7 days following the third weekly dose. In addition, a dose‑related increase in serum cytokines was observed, as well as stable disease in 4 participants refractory to prior PD-1/L1 antibodies. Conclusions: Repeat IT injection of SYNB1891 as monotherapy and in combination atezolizumab was safe and well tolerated and evidence of STING pathway target engagement was observed.
Systemic Alterations in Type-2 Conventional Dendritic Cells Lead to Impaired Tumor Immunity in Pancreatic Cancer
Authors: James C. Alston , Baer John M. , Zou Chong , Panni Usman Y. , Knolhoff Brett L. , Hogg Graham D. , Kingston Natalie L. , Kang Liang-I. , Lander Varintra E. , Luo Jingqin , Tao Yu , Watson Mark A. , Aft Rebecca , Fields Ryan C. , Hawkins William G. , DeNardo David G.
Published: May 2023

Intratumoral T-cell dysfunction is a hallmark of pancreatic tumors, and efforts to improve dendritic cell (DC)–mediated T-cell activation may be critical in treating these immune therapy unresponsive tumors. Recent evidence indicates that mechanisms that induce dysfunction of type 1 conventional DCs (cDC1) in pancreatic adenocarcinomas (PDAC) are drivers of the lack of responsiveness to checkpoint immunotherapy. However, the impact of PDAC on systemic type 2 cDC2 development and function has not been well studied. Herein, we report the analysis of 3 cohorts, totaling 106 samples, of human blood and bone marrow (BM) from patients with PDAC for changes in cDCs. We found that circulating cDC2s and their progenitors were significantly decreased in the blood of patients with PDAC, and repressed numbers of cDC2s were associated with poor prognosis. Serum cytokine analyses identified IL6 as significantly elevated in patients with PDAC and negatively correlated with cDC numbers. In vitro, IL6 impaired the differentiation of cDC1s and cDC2s from BM progenitors. Single-cell RNA sequencing analysis of human cDC progenitors in the BM and blood of patients with PDAC showed an upregulation of the IL6/STAT3 pathway and a corresponding impairment of antigen processing and presentation. These results suggested that cDC2s were systemically suppressed by inflammatory cytokines, which was linked to impaired antitumor immunity.
FIGURE 4 from Reprogramming of Tumor-reactive Tumor-infiltrating Lymphocytes to Human-induced Pluripotent Stem Cells
Authors: Islam S.M. Rafiqul , Maeda Takuya , Tamaoki Naritaka , Good Meghan L. , Kishton Rigel J. , Paria Biman C. , Yu Zhiya , Bosch-Marce Marta , Bedanova Nicole M. , Liu Chengyu , Kruhlak Michael J. , Restifo Nicholas P. , Vizcardo Raul
Published: May 2023

TIL stimulated with autologous tumor cell line generated antigen specific iPSC whereas αCD3/28 beads mediated stimulation did not. A, Summary of three candidate TCR pairs identified in TIL-iPSC lines established by different stimulation methods. Bead Stim TCR: The most dominant clone in the TIL-iPSCs established by αCD3/28 beads stimulation, Tumor Stim TCR: The TCR identified in the TIL-iPSC clones established by coculture with autologous tumor cells (TCR 4 in Fig. 3B), and PIR-TCR III: preidentified reactive TCR clone detected in the TIL-iPSC clones established by coculture with autologous tumor cells. The table includes TCR type, CDR3β amino acid sequences, Vβ family, CDR3α amino acid sequences, Vα family are described. B and C, CD137 (4-1BB) upregulation assay of T cells transduced with candidate TCRα and TCRβ pairs identified from TIL-iPSCs (Fig. 4A). T cells were cocultured with autologous or allogeneic tumor cell lines. B shows the representative FACS plots and C shows the percentage of 4-1BB+ cells in each condition. N = 3 for each condition. Representative data of four independent experiments. Mock: empty vector transduced PBL as a negative control, PIR-TCR III as a positive control. D, A bar graph showing the results of ELISA IFNγ production assay of T cells transduced with candidate TCRα and TCRβ pairs identified from TIL-iPSCs (Fig. 4A). T cells were cocultured with autologous or allogeneic tumor cell lines for 16 hours and culture soup were analyzed for IFNγ by ELISA. N = 3 for each condition. Representative data of four independent experiments. E, A graph showing the real-time cell growth monitoring (cell count/image) of RFP-overexpressed tumor cells from pt. 1913 cocultured with different TCRs (listed in Fig. 4A), analyzed by the Incucyte live imaging and analysis system at effector-to-target ratio of 2:1. Mock indicates empty vector transduced T cells used as a negative control. The results are shown as the mean ± SD of N = 4 each condition. A representative data of four independent experiments.
Data from Reprogramming of Tumor-reactive Tumor-infiltrating Lymphocytes to Human-induced Pluripotent Stem Cells
Authors: Islam S.M. Rafiqul , Maeda Takuya , Tamaoki Naritaka , Good Meghan L. , Kishton Rigel J. , Paria Biman C. , Yu Zhiya , Bosch-Marce Marta , Bedanova Nicole M. , Liu Chengyu , Kruhlak Michael J. , Restifo Nicholas P. , Vizcardo Raul
Published: May 2023

Tumor-infiltrating lymphocytes (TIL) that can recognize and kill tumor cells have curative potential in subsets of patients treated with adoptive cell transfer (ACT). However, lack of TIL therapeutic efficacy in many patients may be due in large part to a paucity of tumor-reactive T cells in TIL and the exhausted and terminally differentiated status of those tumor-reactive T cells. We sought to reprogram exhausted TIL that possess T-cell receptors (TCR) specific for tumor antigens into induced pluripotent stem cells (iPSC) to rejuvenate them for more potent ACT. We first attempted to reprogram tumor neoantigen-specific TIL by αCD3 Ab prestimulation which resulted in failure of establishing tumor-reactive TIL-iPSCs, instead, T cell–derived iPSCs from bystander T cells were established. To selectively activate and enrich tumor-reactive T cells from the heterogenous TIL population, CD8+ PD-1+ 4-1BB+ TIL population were isolated after coculture with autologous tumor cells, followed by direct reprogramming into iPSCs. TCR sequencing analysis of the resulting iPSC clones revealed that reprogrammed TIL-iPSCs encoded TCRs that were identical to the pre-identified tumor-reactive TCRs found in minimally cultured TIL. Moreover, reprogrammed TIL-iPSCs contained rare tumor antigen-specific TCRs, which were not detectable by TCR sequencing of the starting cell population. Thus, reprogramming of PD-1+ 4-1BB+ TIL after coculture with autologous tumor cells selectively generates tumor antigen-specific TIL-iPSCs, and is a distinctive method to enrich and identify tumor antigen-specific TCRs of low frequency from TIL.
Significance:
Reprogramming of TIL into iPSC holds great promise for the future treatment of cancer due to their rejuvenated nature and the retention of tumor-specific TCRs. One limitation is the lack of selective and efficient methods for reprogramming tumor-specific T cells from polyclonal TIL. Here we addressed this limitation and present a method to efficiently reprogram TIL into iPSC colonies carrying diverse tumor antigen reactive TCR recombination.
Data from Mitochondria Transfer from Mesenchymal Stem Cells Confers Chemoresistance to Glioblastoma Stem Cells through Metabolic Rewiring
Authors: Nakhle Jean , Khattar Khattar , Özkan Tülin , Boughlita Adel , Abba Moussa Daouda , Darlix Amélie , Lorcy Frédérique , Rigau Valérie , Bauchet Luc , Gerbal-Chaloin Sabine , Daujat-Chavanieu Martine , Bellvert Floriant , Turchi Laurent , Virolle Thierry , Hugnot Jean-Philippe , Buisine Nicolas , Galloni Mireille , Dardalhon Valérie , Rodriguez Anne-Marie , Vignais Marie-Luce
Published: May 2023

Glioblastomas (GBM) are heterogeneous tumors with high metabolic plasticity. Their poor prognosis is linked to the presence of glioblastoma stem cells (GSC), which support resistance to therapy, notably to temozolomide (TMZ). Mesenchymal stem cells (MSC) recruitment to GBM contributes to GSC chemoresistance, by mechanisms still poorly understood. Here, we provide evidence that MSCs transfer mitochondria to GSCs through tunneling nanotubes, which enhances GSCs resistance to TMZ. More precisely, our metabolomics analyses reveal that MSC mitochondria induce GSCs metabolic reprograming, with a nutrient shift from glucose to glutamine, a rewiring of the tricarboxylic acid cycle from glutaminolysis to reductive carboxylation and increase in orotate turnover as well as in pyrimidine and purine synthesis. Metabolomics analysis of GBM patient tissues at relapse after TMZ treatment documents increased concentrations of AMP, CMP, GMP, and UMP nucleotides and thus corroborate our in vitro analyses. Finally, we provide a mechanism whereby mitochondrial transfer from MSCs to GSCs contributes to GBM resistance to TMZ therapy, by demonstrating that inhibition of orotate production by Brequinar (BRQ) restores TMZ sensitivity in GSCs with acquired mitochondria. Altogether, these results identify a mechanism for GBM resistance to TMZ and reveal a metabolic dependency of chemoresistant GBM following the acquisition of exogenous mitochondria, which opens therapeutic perspectives based on synthetic lethality between TMZ and BRQ.
Significance:
Mitochondria acquired from MSCs enhance the chemoresistance of GBMs. The discovery that they also generate metabolic vulnerability in GSCs paves the way for novel therapeutic approaches.