bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding the language barriers to translating informed consent documents for maternal health trials in Zambia: a qualitative study
Authors: Beardmore-Gray Alice , Simwinga Musonda , Vwalika Bellington , Chinkoyo Sebastian , Chappell Lucy , Sandall Jane , Shennan Andrew
Published: April 2024

Objective

Providing comprehensible information is essential to the process of valid informed consent. Recruitment materials designed by sponsoring institutions in English-speaking, high-income countries are commonly translated for use in global health studies in other countries; however, key concepts are often missed, misunderstood or ‘lost in translation’. The aim of this study was to explore the language barriers to informed consent, focusing on the challenges of translating recruitment materials for maternal health studies into Zambian languages.

Design

We used a qualitative approach, which incorporated a multistakeholder workshop (11 participants), in-depth interviews with researchers and translators (8 participants) and two community-based focus groups with volunteers from community advisory boards (20 participants). Content analysis was used to identify terms commonly occurring in recruitment materials prior to the workshop. The framework analysis approach was used to analyse interview data, and a simple inductive thematic analysis approach was used to analyse focus group data.

Setting

The study was based in Lusaka, Zambia.

Results

The workshop highlighted difficulties in translating research terms and pregnancy-specific terms, as well as widespread concern that current templates are too long, use overly formal language and are designed with little input from local teams. Framework analysis of in-depth interviews identified barriers to participant understanding relating to design and development of recruitment materials, language, local context and communication styles. Focus group participants confirmed these findings and suggested potential solutions to ensure the language and content of recruitment materials can be better understood.

Conclusion

Our findings demonstrate that the way in which recruitment materials are currently designed, translated and disseminated may not enable potential trial participants to fully understand the information provided. Instead of using overly complex institutional templates, recruitment materials should be created through an iterative and interactive process that provides truly comprehensible information in a format appropriate for its intended participants.
Chronic loneliness and chronic social isolation among older adults: a study protocol for a systematic review, meta-analysis and meta-regression
Authors: Hajek André , Posi Giuliana , König Hans-Helmut
Published: April 2024

Introduction

There are around 20 studies identifying the prevalence of chronic loneliness and chronic social isolation in older adults. However, there is an absence of a systematic review, meta-analysis and meta-regression that consolidates the available observational studies. Therefore, our objective was to address this knowledge gap. Here, we present the study protocol for this upcoming work. Such knowledge can help in addressing older individuals at risk for chronic loneliness and chronic social isolation.

Methods and analysis

Established electronic databases will be searched. Observational studies reporting the prevalence of chronic loneliness and chronic social isolation among individuals aged 60 years and over will be included. Disease-specific samples will be excluded. The focus of data extraction will be on methods, sample characteristics and key findings. The Joanna Briggs Institute (JBI) standardised critical appraisal instrument for prevalence studies will be used for assessing the quality of the studies. Two reviewers will be responsible for carrying out the study selection, data extraction and assessment of study quality. The results will be presented through the use of figures, tables, narrative summaries and a meta-analysis and meta-regression.

Ethics and dissemination

No primary data will be collected. Thus, there is no need for approval from an ethics committee. We intend to share our results through publication in a peer-reviewed journal.
Predictive value of anthropometric and biochemical indices in non-alcoholic fatty pancreas disease: a cross-sectional study
Authors: Xiao Yang , Wang Han , Han Lina , Huang Zhibin , Lyu Guorong , Li Shilin
Published: April 2024

Objectives

Triglyceride (TG), triglyceride-glucose index (TyG), body mass index (BMI), TyG-BMI and triglyceride to high-density lipoprotein ratio (TG/HDL) have been reported to be reliable predictors of non-alcoholic fatty liver disease. However, there are few studies on potential predictors of non-alcoholic fatty pancreas disease (NAFPD). Our aim was to evaluate these and other parameters for predicting NAFPD.

Design

Cross-sectional study design.

Setting

Physical examination centre of a tertiary hospital in China.

Participants

This study involved 1774 subjects who underwent physical examinations from January 2016 to September 2016.

Primary and secondary outcome measures

From each subject, data were collected for 13 basic physical examination and blood biochemical parameters: age, weight, height, BMI, TyG, TyG-BMI, high-density lipoprotein (HDL), low-density lipoprotein, total cholesterol, TG, fasting plasma glucose, TG/HDL and uric acid. NAFPD was diagnosed by abdominal ultrasonography. A logistic regression model with a restricted cubic spline was used to evaluate the relationship between each parameter and NAFPD. The receiver operating characteristic (ROC) curve was used to calculate the area under the curve for each parameter.

Results

HDL was negatively correlated with NAFPD, height was almost uncorrelated with NAFPD and the remaining 11 parameters were positively correlated with NAFPD. ROC curve showed that weight-related parameters (weight, BMI and TyG-BMI) and TG-related parameters (TyG, TG and TG/HDL) had high predictive values for the identification of NAFPD. The combinations of multiple parameters had a better prediction effect than a single parameter. All the predictive effects did not differ by sex.

Conclusions

Weight-related and TG-related parameters are good predictors of NAFPD in all populations. BMI showed the greatest predictive potential. Multiparameter combinations appear to be a good way to predict NAFPD.
Salt intake across the hypertension care cascade in the Bangladeshi adult population: a nationally representative cross-sectional study
Authors: Monower Md Mostafa , Abid Shehab Uddin Al , Abrar Ahmad Khairul , Choudhury Sohel Reza
Published: April 2024

Objectives

This study aimed to examine the distribution of daily salt intake across the hypertension care cascade and assess the proportional distribution of these care cascade categories across various salt consumption level.

Design

A population-based national cross-sectional study.

Settings

Data from the Bangladesh STEPS 2018 survey were used, encompassing both urban and rural strata within all eight divisions. National estimates were generated from weighted data.

Participants

A diverse population of 6754 men and women aged 18–69 years was included in the study.

Outcome measures

Daily salt consumption was estimated using the spot urine sodium concentration following Tanaka equation. Distribution of salt intake among different categories of hypertension care cascade, including hypertensives, aware of hypertension status, on treatment and under control, was assessed.

Results

Individuals with hypertension consume more salt on average (9.18 g/day, 95% CI 9.02 to 9.33) than those without hypertension (8.95 g/day, 95% CI 8.84 to 9.05) (p<0.02). No significant differences were found in salt intake when comparing aware versus unaware, treated versus untreated and controlled versus uncontrolled hypertension. In the overall population, 2.7% (95% CI 2.1% to 3.6%) of individuals without hypertension adhered to the recommended salt intake (<5 g/day) while 1.6% (95% CI 1.0% to 2.4%) with hypertension did so (p<0.03). Among individuals with hypertension, 2.4% (95% CI 1.4% to 4.0%) of those aware followed the guideline while only 0.8% (95% CI 0.4% to 1.9%) of those unaware adhered (p<0.03). Additionally, no significant differences were observed in adherence between the treated versus untreated and controlled versus uncontrolled hypertension.

Conclusions

Individuals with hypertension consume significantly more salt than those without, with no significant variations in salt intake based on aware, treated and controlled hypertension. Adhering to WHO salt intake guidelines aids better blood pressure management. By addressing salt consumption across hypertension care cascade, substantial progress can be made in better blood pressure control.
Protocol for evaluating the effects of the Reducing Cardiometabolic Diseases Risk dietary pattern in the Chinese population with dyslipidaemia: a single-centre, open-label, dietary intervention study
Authors: Wu Qi , Zhang Liyang , Cheng Cheng , Chen Xukun , Bian Shanshan , Huang Li , Li Tongtong , Li Zhenshu , Liu Huan , Yan Jing , Du Yue , Chen Yongjie , Zhang Meilin , Cao Lichun , Li Wen , Ma Fei , Huang Guowei
Published: April 2024

Introduction

Cardiometabolic disease (CMD) is the leading cause of mortality in China. A healthy diet plays an essential role in the occurrence and development of CMD. Although the Chinese heart-healthy diet is the first diet with cardiovascular benefits, a healthy dietary pattern that fits Chinese food culture that can effectively reduce the risk of CMD has not been found.

Methods/design

The study is a single-centre, open-label, randomised controlled trial aimed at evaluating the effect of the Reducing Cardiometabolic Diseases Risk (RCMDR) dietary pattern in reducing the risk of CMDs in people with dyslipidaemia and providing a reference basis for constructing a dietary pattern suitable for the prevention of CMDs in the Chinese population. Participants are men and women aged 35–45 years with dyslipidaemia in Tianjin. The target sample size is 100. After the run-in period, the participants will be randomised to the RCMDR dietary pattern intervention group or the general health education control group with a 1:1 ratio. The intervention phases will last 12 weeks, with a dietary intervention of 5 working days per week for participants in the intervention group. The primary outcome variable is the cardiometabolic risk score. The secondary outcome variables are blood lipid, blood pressure, blood glucose, body composition indices, insulin resistance and 10-year risk of cardiovascular diseases.

Ethics and dissemination

The study complies with the Measures for Ethical Review of Life Sciences and Medical Research Involving Human Beings and the Declaration of Helsinki. Signed informed consent will be obtained from all participants. The study has been approved by the Medical Ethics Committee of the Second Hospital of Tianjin Medical University (approval number: KY2023020). The results from the study will be disseminated through publications in a peer-reviewed journal.

Trial registration number

Chinese Clinical Trial Registry (ChiCTR2300072472).
Pyroptosis activates conventional type I dendritic cells to mediate the priming of highly functional anticancer T cells
Authors: Inkol Jordon M , Westerveld Michael J , Verburg Shayla G , Walsh Scott R , Morrison Jodi , Mossman Karen L , Worfolk Sarah M , Kallio Kaslyn LF , Phippen Noah J , Burchett Rebecca , Wan Yonghong , Bramson Jonathan , Workenhe Samuel T
Published: April 2024

Background

Initiation of antitumor immunity is reliant on the stimulation of dendritic cells (DCs) to present tumor antigens to naïve T cells and generate effector T cells that can kill cancer cells. Induction of immunogenic cell death after certain types of cytotoxic anticancer therapies can stimulate T cell-mediated immunity. However, cytotoxic therapies simultaneously activate multiple types of cellular stress and programmed cell death; hence, it remains unknown what types of cancer cell death confer superior antitumor immunity.

Methods

Murine cancer cells were engineered to activate apoptotic or pyroptotic cell death after Dox-induced expression of procell death proteins. Cell-free supernatants were collected to measure secreted danger signals, cytokines, and chemokines. Tumors were formed by transplanting engineered tumor cells to specifically activate apoptosis or pyroptosis in established tumors and the magnitude of immune response measured by flow cytometry. Tumor growth was measured using calipers to estimate end point tumor volumes for Kaplan-Meier survival analysis.

Results

We demonstrated that, unlike apoptosis, pyroptosis induces an immunostimulatory secretome signature. In established tumors pyroptosis preferentially activated CD103+and XCR1+type I conventional DCs (cDC1) along with a higher magnitude and functionality of tumor-specific CD8+T cells and reduced number of regulatory T cells within the tumor. Depletion of cDC1 or CD4+and CD8+T cells ablated the antitumor response leaving mice susceptible to a tumor rechallenge.

Conclusion

Our study highlights that distinct types of cell death yield varying immunotherapeutic effect and selective activation of pyroptosis can be used to potentiate multiple aspects of the anticancer immunity cycle.
Combining CRISPR-Cas9 and TCR exchange to generate a safe and efficient cord blood-derived T cell product for pediatric relapsed AML
Authors: Lo Presti Vania , Meringa Angelo , Dunnebach Ester , van Velzen Alice , Moreira Aida Valera , Stam Ronald W , Kotecha Rishi S , Krippner-Heidenreich Anja , Heidenreich Olaf T , Plantinga Maud , Cornel Annelisa , Sebestyen Zsolt , Kuball Jurgen , van Til Niek P , Nierkens S
Published: April 2024

Background

Hematopoietic cell transplantation (HCT) is an effective treatment for pediatric patients with high-risk, refractory, or relapsed acute myeloid leukemia (AML). However, a large proportion of transplanted patients eventually die due to relapse. To improve overall survival, we propose a combined strategy based on cord blood (CB)-HCT with the application of AML-specific T cell receptor (TCR)-engineered T cell therapy derived from the same CB graft.

Methods

We produced CB-CD8+T cells expressing a recombinant TCR (rTCR) against Wilms tumor 1 (WT1) while lacking endogenous TCR (eTCR) expression to avoid mispairing and competition. CRISPR-Cas9 multiplexing was used to target the constant region of the endogenous TCRα (TRAC) and TCRβ (TRBC) chains. Next, an optimized method for lentiviral transduction was used to introduce recombinant WT1-TCR. The cytotoxic and migration capacity of the product was evaluated in coculture assays for both cell lines and primary pediatric AML blasts.

Results

The gene editing and transduction procedures achieved high efficiency, with up to 95% of cells lacking eTCR and over 70% of T cells expressing rWT1-TCR. WT1-TCR-engineered T cells lacking the expression of their eTCR (eTCR−/−WT1-TCR) showed increased cell surface expression of the rTCR and production of cytotoxic cytokines, such as granzyme A and B, perforin, interferon-γ (IFNγ), and tumor necrosis factor-α (TNFα), on antigen recognition when compared with WT1-TCR-engineered T cells still expressing their eTCR (eTCR+/+WT1-TCR). CRISPR-Cas9 editing did not affect immunophenotypic characteristics or T cell activation and did not induce increased expression of inhibitory molecules. eTCR−/−WT1-TCR CD8+CB-T cells showed effective migratory and killing capacity in cocultures with neoplastic cell lines and primary AML blasts, but did not show toxicity toward healthy cells.

Conclusions

In summary, we show the feasibility of developing a potent CB-derived CD8+T cell product targeting WT1, providing an option for post-transplant allogeneic immune cell therapy or as an off-the-shelf product, to prevent relapse and improve the clinical outcome of children with AML.
Bohr–Sommerfeld quantization condition for self-adjoint Dirac operators
Authors: Yoshida Naoya
Published: April 2024

We study the eigenvalue problem for a self-adjoint 1D Dirac operator. It is known that, near an energy level where the square of the potential makes a simple well, the eigenvalues are approximated by a Bohr–Sommerfeld type quantization rule. A remarkable difference from the Schrödinger case appears in the Maslov correction term. This fact was recently found by Hirota [Real eigenvalues of a non-self-adjoint perturbation of the self-adjoint Zakharov–Shabat operator, J. Math. Phys. 58 (2017) 102–108] under the analyticity condition of the potential using a complex WKB method. In this paper, we approach this problem with a microlocal technique focusing on the asymptotic behavior of the eigenfunction along the characteristic set to generalize the result to [Formula: see text] potentials.
Sparse Spiking Neural-Like Membrane Systems on Graphics Processing Units
Authors: Hernández-Tello Javier , Martínez-del-Amor Miguel Á. , Orellana-Martín David , Cabarle Francis George C.
Published: April 2024

The parallel simulation of Spiking Neural P systems is mainly based on a matrix representation, where the graph inherent to the neural model is encoded in an adjacency matrix. The simulation algorithm is based on a matrix-vector multiplication, which is an operation efficiently implemented on parallel devices. However, when the graph of a Spiking Neural P system is not fully connected, the adjacency matrix is sparse and hence, lots of computing resources are wasted in both time and memory domains. For this reason, two compression methods for the matrix representation were proposed in a previous work, but they were not implemented nor parallelized on a simulator. In this paper, they are implemented and parallelized on GPUs as part of a new Spiking Neural P system with delays simulator. Extensive experiments are conducted on high-end GPUs (RTX2080 and A100 80GB), and it is concluded that they outperform other solutions based on state-of-the-art GPU libraries when simulating Spiking Neural P systems.
Effect of the arrangement of the injectors on the flow quantities in water injection into the hot supersonic crossflow inside the cylinder
Authors: Kamali Hossein Ali , Pasandidehfard Mahmoud , Rashidi Mohmmad Mehdi
Published: April 2024

In this study, the effect of different arrangements of injectors on the injection of liquid water into the hot supersonic crossflow of cylindrical geometry on the performance and the rate of evaporation has been studied using a numerical method. The crossflow has a Mach of about 2 and a total temperature of 800[Formula: see text]K. At first, the penetration height and droplets produced by atomization in the supersonic flow are validated using the Lagrangian technique, and the results have been compared with the experiments. The usage of heat transfer equations and the evaporation model for the spray evaporation of droplets in the hot flow is also performed in the validation process, and the results are compared with the experimental results. Then, the injection into the examined geometry with four, six and eight injectors in three different arrangements was evaluated. The results indicate that employing an arrangement of eight injectors leads to the most significant reduction in total temperature, with average total temperatures decreasing to below 550[Formula: see text]K. The results demonstrate a 40% decrease in total pressure, with a decrease in Mach number to about 1 at the end of the cylinder. Additionally, the evaporation rate shows higher evaporation of water in the eight-injector arrangement compared to other arrangements.
A Dynamic and Stochastic Cumulative Capacitated Vehicle Routing Problem
Authors: Wu Yu
Published: April 2024

The cumulative capacitated vehicle routing problem (CCVRP) is a variant of the classical capacitated vehicle routing problem in which the objective is the minimization of customers’ total waiting time prior to service. Inspired by the first-mile pick-up service within 3rd-Party Logistics operations, we study a dynamic and stochastic variant of the CCVRP. In this variant, a capacitated vehicle undertakes a single tour to collect customers’ parcels, taking into account stochastic service requests, stochastic service cancellations, and stochastic demand (i.e., changes in parcel size) simultaneously. Conditional on maximizing the usage of the vehicle’s capacity, we minimize the total waiting time of both customers who are served and those who request services but are not served due to cancellation or capacity violation. We formulate this problem as a Markov decision process and solve it using a hybrid approach that combines approximate dynamic programming and rollout algorithm. Our main contributions include ([Formula: see text]) the construction of the [Formula: see text] [Formula: see text] that leverages a property of the Poisson process, and ([Formula: see text]) consideration of service fairness-based acceptance/rejection rule in response to excessive stochastic service requests. In the numerical study, our approach is examined to outperform an 2-Opt-based re-optimization policy in terms of both customers’ waiting time and service-request satisfying rate. More importantly, computational results heuristically show that there is no cost to adopting the service fairness-based rule, which is obviously a valuable managerial insight.
Heavy quarkonium production and electromagnetic fragmentation in exclusive rare W-boson decays
Authors: Gao Dao-Neng
Published: April 2024

We have updated theoretical studies of heavy vector quarkonium production, including [Formula: see text], [Formula: see text] and [Formula: see text], in the exclusive W-boson decays. Particularly, in the standard model the branching fraction of [Formula: see text] ([Formula: see text] or [Formula: see text]) has been predicted to be about [Formula: see text], which is substantially larger than those of two-body hadronic radiative W decays. Thus in the future high-luminosity experimental facilities, this rare channel could be very useful to search for the exclusive W-boson decays containing the hadronic final state. Furthermore, the surprisingly large decay rate can be explained by an electromagnetic fragmentation formalism. We have analyzed the lepton fragmentation and the photon fragmentation processes, and calculated their contributions to the differential decay rate of [Formula: see text] in the fragmentation limit. It is found that the fragmentation contribution agrees well with the result from the full calculation.
Skew inverse Laurent series rings with bounded annihilators
Authors: Hajaliakbari A. , Moussavi A.
Published: April 2024

According to Jacobson, a right ideal of a ring [Formula: see text] is bounded if it contains a nonzero ideal of [Formula: see text]. Faith called a ring strongly right bounded if every nonzero right ideal is bounded. We examine some annihilator conditions for skew inverse Laurent series ring [Formula: see text], accomplished with relationships among certain classical sorts of rings such as rings with bounded annihilators and rings with property ([Formula: see text]).
Giant Humanoid Mobility Robot Suit-Method II and Research Challenges
Authors: Park Ill-Woo , Han Jeong-Hye
Published: April 2024

Robot suits can amplify human power, mobility, and height. A giant humanoid mobility robot-Method II was designed using the concept of battle robot suit, AMP in the movie Avatar. The operator aboard Method II is a giant robot that can expand its movement to five times the human muscle strength and 2.5 times the height. The robot suit-type controller can move in synchronization with the movement of both arms and control fingers to collaborate with various tasks. However, there are critical challenges, such as battery weight and duration inefficiency, control complexity, network stability, and difficulties in failure or repair work. This study develops and operates the world’s largest humanoid mobility robot without support fixture up to now, and presents its five future research challenges.
High energy storage properties of (Nb0.5La0.5)4+ complex-ion modified (Ba0.85Ca0.15)(Zr0.10Ti0.90)O3 ceramics
Authors: Sun Yaqiong , Dang Santan , Peng Zhanhui , Chen Bi , Zhang Yibing , Wu Di , Liang Pengfei , Wei Lingling , Chao Xiaolian , Yang Zupei
Published: April 2024

In this work, a traditional solid-state method was adopted to prepare dense Ba[Formula: see text]Ca[Formula: see text][(Zr[Formula: see text]Ti[Formula: see text])[Formula: see text]–(Nb[Formula: see text]La[Formula: see text])x]O3(BCZT–xNL) lead-free relaxation ferroelectrics with excellent energy storage performance (ESP). Remarkably, a large breakdown field strength of BDS ([Formula: see text][Formula: see text]kV/cm) resulting from decreased grain size by double ions doping at the B-site was achieved in BCZT–xNL ceramics. Especially, the BCZT–0.12NL ceramic displays a good recoverable energy density ([Formula: see text]) of 3.1[Formula: see text]J/cm3, a high efficiency of 86.7% ([Formula: see text]) and a superior fatigue resistance, as well as a superior charge–discharge performance ([Formula: see text][Formula: see text]A/cm2, [Formula: see text][Formula: see text]MW/cm3, [Formula: see text][Formula: see text]J/cm3, [Formula: see text][Formula: see text]ns) and good thermal stability. Besides, upon NL doping, the FE to RFE phase transition results in a dielectric behavior traversing the relaxation phase ([Formula: see text]) accompanied by frequency dispersion, which is beneficial to improve ESP. The superior ESP in this work indicates that BCZT–0.12[Formula: see text]NL ceramics are a promising candidate used in energy storage capacitors.
HydraGAN: A Cooperative Agent Model for Multi-Objective Data Generation
Authors: DeSmet Chance , Cook Diane
Published: April 2024

Generative adversarial networks have become a
de facto
approach to generate synthetic data points that resemble their real counterparts. We tackle the situation where the realism of individual samples is not the sole criterion for synthetic data generation. Additional constraints such as privacy preservation, distribution realism, and diversity promotion may also be essential to optimize. To address this challenge, we introduce
HydraGAN
, a multi-agent network that performs multi-objective synthetic data generation. We theoretically verify that training the HydraGAN system, containing a single generator and an arbitrary number of discriminators, leads to a Nash equilibrium. Experimental results for six datasets indicate that HydraGAN consistently outperforms prior methods in maximizing the Area under the Radar Chart, balancing a combination of cooperative or competitive data generation goals.
The Effect of Differentiation of Human Dental Pulp Stem Cells to Glial Cells on the Sensory Nerves of the Dental Pulp
Authors: Liu Yan , Zou Yuxi , Liu Xinxin , Wang Yushan , Sun Jing , Yuan Changyong , Wang Penglai
Published: April 2024

Regeneration of sensory nerves is challenging in dental pulp regeneration. Schwann cells (SCs) are essential glial cells conducive to regenerating sensory nerve, but their source is scarce. The aim of the protocol was to investigate the regenerative potential of Schwann‐like cells derived from dental pulp stem cells (SC‐DPSCs) for sensory nerve regrowth. SC‐DPSCs were generated from dental pulp stem cells using a three‐step protocol. The expression of key markers, including myelin basic protein, S‐100, and p75 neurotrophin receptor, was analyzed. Primary trigeminal neurons were cultured, and the expression of neurofilament 200, β‐tubulin III, and microtubule‐associated protein 2 was assessed. Simultaneous culture experiments were conducted to evaluate trigeminal neuron growth in the presence of SC‐DPSCs. In addition, mRNA sequencing was performed to identify key genes involved in the differentiation process, highlighting prostaglandin‐endoperoxide synthase 2 (PTGS2) as a potential candidate. The results demonstrated that SC‐DPSCs expressed characteristic SCs markers and facilitated axonal growth in rat trigeminal nerves. Differentiated SC‐DPSCs secreted elevated levels of nerve growth factors, including brain‐derived neurotrophic factor and neurotrophin‐3, promoting the growth of trigeminal nerve axons. These findings suggest the regenerative potential of SC‐DPSCs in dentin–dental pulp complex; PTGS2 is considered a crucial gene in this differentiation process.
Research on the Application of Variational Mode Decomposition Optimized by Snake Optimization Algorithm in Rolling Bearing Fault Diagnosis
Authors: Ji Houxin , Huang Ke , Mo Chaoquan
Published: April 2024

The rolling bearing is one of the commonly used mechanical components in rotating machinery, and its health directly affects the normal operation of equipment. However, the fault signal of rolling bearing is susceptible to noise interference, which makes it difficult to extract the fault characteristics of the rolling bearing and thus affects the accuracy of the diagnosis results. To address this problem, this paper proposes a method by using a snake optimization algorithm to optimize variational mode decomposition (SOA‐VMD) and applies it to the extraction of the fault feature of rolling bearing. First, the minimum Shannon entropy to kurtosis ratio (EKR) is used as the fitness function of SOA to search for the best parameter combination of VMD. Second, the optimized VMD is used to decompose the vibration signal of rolling bearing to obtain K intrinsic mode functions (IMFs). Then, the IMF with the most fault information is selected for reconstruction through EKR. The Teager–Kaiser energy operator (TKEO) spectrum analysis is performed on the reconstructed signal. Finally, this method is used to analyze the simulation signal and rolling bearing vibration signal and compared with empirical mode decomposition (EMD), ensemble empirical mode decomposition (EEMD), and complete ensemble empirical mode decomposition adaptive noise (CEEMDAN) algorithms to verify the feasibility and effectiveness of the SOA‐VMD method.
Novel Phytosomal Formulation of Emblica officinalis Extracts with Its In Vivo Nootropic Potential in Rats: Optimization and Development by Box-Behnken Design
Authors: Mane Varsha , Killedar Suresh , More Harinath , Nadaf Sameer , Salunkhe Sachin , Tare Harshal
Published: April 2024

Purpose. The present study aimed to improve the aqueous solubility, permeability, bioavailability, and nootropic potential of standardized Emblica officinalis extract (EOE) by developing a novel phytosomal formulation. Method. Emblica officinalis extract-loaded phytosomes (EOPs) were prepared using solvent evaporation. The EOP was prepared at different molar ratios of extract and phospholipid. Herein, the effects of phospholipid extract ratio (A), temperature (B), and reaction time (C) were systematically investigated on entrapment efficiency using Box-Behnken design. In vitro and in vivo characterizations of the optimized formulation were performed. Results. Optimized EOP formulation (89.90 ± 0.24 μg/ml) exhibited improved aqueous solubility than plain EOE (11.85 ± 0.25 μg/ml). The optimized formulation’s particle size and Zeta potential were 198.4 ± 0.20 nm and −39.0 ± 0.40 mv. DSC and XRD studies confirmed the partial amorphization of EOE in phytosomes. Optimized formulation exhibited 69.82 ± 0.17% of EOE release at 12 h and followed zero-order release kinetics. Moreover, the phytosomal formulation of EOE exhibited its rationality with an improvement of bioavailability by 2.7 folds compared with pure EOE. Compared to EOE, EOP showed significantly (p<0.05 lower escape and transfer latencies on both days in MWMT and EPMT, indicating more effective memory-enhancing activity. Furthermore, EOP-treated rats exhibited improved acetylcholine (Ach) levels than EOE. Brain tissue concentrations measured following EOP oral administration (1.06 ± 0.04 μg/ml) were substantially greater (p<0.05) than those following EOE (0.32 ± 0.07 μg/ml). The brain dopamine and serotonin concentration were found to be higher (16.27 ± 1.209 and 43.28 ± 1.550 ng/ml) in the EOP-treated group as compared to the pure extract-treated group (10.40 ± 1.185 and 32.79 ± 1.738 ng/ml). Conclusion. Improvement of aqueous solubility, permeability, dissolution, bioavailability, and narrower particle size distribution could facilitate enhancement in the nootropic potential of EOE phytosomal formulation.
Sleep Disturbance and Related Factors in the Patients with Relapsing‐Remitting Multiple Sclerosis
Authors: Sempik Izabela , Dziadkowiak Edyta , Wieczorek Małgorzata , Pokryszko–Dragan Anna
Published: April 2024

Background. Sleep disturbances are commonly reported, although underestimated complaints from people with multiple sclerosis (MS). The aim of the study was to analyze the frequency and type of sleep disturbances in MS patients and to evaluate their relationships with demographics and clinical data. Methods. The study group consisted of 178 patients with relapsing‐remitting MS: 130 females and 48 males. Clinical measures (disease duration, disability level in Expanded Disability Status Scale (EDSS), and treatment) were acquired from medical records. The questionnaire was applied, containing questions about sleep disturbances, somatic complaints, perception of fatigue, depression, anxiety, and problems at work and in social/family life. Athens Insomnia Scale (AIS) and Karolinska Sleepiness Scale (KSS) were performed to quantify sleep problems and Hamilton Depression Rating Scale (HDRS) and Addenbrooke’s Cognitive Examination (Mini‐ACE) to assess level of depression and cognitive performance. Electroencephalography was recorded to identify electrophysiological indices of sleep. Results. 109 patients (61%) reported sleep disturbances, most frequently insomnia, snoring, and parasomnias. This subgroup had significantly higher scores in AIS (p < 0.0001) and KSS (p = 0.010) and slightly higher EDSS score (p = 0.048) and more often complained of fatigue (71% vs. 53%, p = 0.0148), involuntary limb movement (42% vs. 25, p = 0.0170), and breathing disturbances (10% vs. 0%). There was a significant correlation between the results of AIS and HDRS (Rs = 0.715, p < 0.05). Conclusion. Sleep disturbances, predominantly insomnia, are reported by more than a half of the patients with relapsing‐remitting MS. Significant associations were found between sleep problems and MS‐related clinical symptoms and psychosocial issues.
Abstract CT079: The Pseudovax trial: A novel peptide vaccine targeting mutated GNAS for pseudomyxoma peritonei
Authors: Flatmark Kjersti , Torgunrud Annette , Karianne Fleten G. , Davidson Ben , Juel Hedvig V. , Mensali Nadia , Andersen Christin Lund , Inderberg Else Marit
Published: April 2024

Background: Pseudomyxoma peritonei (PMP) is a rare cancer originating from appendiceal mucinous tumors, which may spread to encompass the entire peritoneal cavity. Complete surgical removal and hyperthermic intraperitoneal chemotherapy cures approximately half of the patients, but patients with recurrent or non-resectable disease have no efficacious treatment options. These patients have a high unmet need for novel treatment options, and in the Pseudovax trial we will explore a novel therapeutic concept. A main molecular driver of PMP (in up to 90% of cases) is otherwise rare mutations in the GNAS oncogene, coding for the Gsα protein. We hypothesized that mutated Gsα would be a tumor neoantigen, and in T cells isolated from peripheral blood of PMP patients, a strong T cell proliferative response was observed. In the corresponding tumors, T cells with up-regulated immune checkpoint molecules PD-1 and TIGIT were detected.

Study hypotheses: Patients with GNAS-mutated PMP has a preexisting, attenuated immune response directed against mutated Gsα protein. Vaccination with mutated Gsα peptides can be combined with immune checkpoint inhibition (ICI) with acceptable toxicity. The vaccine will reactivate the immune response and ICI will restore measurable anticancer immunity in patients.

Study design: The Pseudovax trial is a small (10 patients) first-in-human, proof-of-concept, prospective, open label, phase I trial. Patients with recurrent or non-resectable PMP are eligible for inclusion. During a treatment period of 12 months, a mutated Gsα peptide vaccine + adjuvant (GM-CSF) will be administered as intradermal injections. After 12 weeks, treatment with ICI will be initiated. The primary endpoints are toxicity and circulating immune response against the vaccine, measured as increase in interferon-gamma production or proliferation of circulating vaccine-specific T cells compared to pre-vaccination baseline. Secondary endpoints are progression-free survival (abdominopelvic CT scans, blood levels of carcinoembryonic antigen (CEA) and/or detection of GNAS mutation by ctDNA analysis).

Citation Format: Kjersti Flatmark, Annette Torgunrud, Fleten G. Karianne, Ben Davidson, Hedvig V. Juel, Nadia Mensali, Christin Lund Andersen, Else Marit Inderberg. The Pseudovax trial: A novel peptide vaccine targeting mutated GNAS for pseudomyxoma peritonei [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT079.
Abstract CT083: A first-in-human phase 1/2a study of a novel anti-PAUF monoclonal antibody PBP1510 in patients with advanced/metastatic pancreatic cancer
Authors: Batlle Jaime Feliu , King Daniel A. , Kim Jamie , Pradhan Sumita , Park Yun-Yong , Mandakhalikar Kedar Diwakar , Loh Wei Qi
Published: April 2024

Background Pancreatic Adenocarcinoma Up-regulated Factor (PAUF) is a protein overexpressed in pancreatic cancer but not in non-cancerous tissues and plays an important role in carcinogenesis and metastasis. PBP1510 is a first-in-class, anti-PAUF humanized immunoglobulin G1 monoclonal antibody developed for treatment of pancreatic cancer. PBP1510 demonstrated promising pancreatic cancer growth inhibition efficacies in in vivo patient-derived xenograft studies and is being evaluated in humans for the first time in the ongoing PAUF-I study.

Methods PAUF-I (NCT05141149) is an open-label, multi-center, Phase 1/2a study in advanced/metastatic pancreatic cancer patients. Eligible patients must have a tumor that has progressed on standard chemotherapy, with at least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status score of 0 or 1, a life expectancy of ≥ 3 months, and adequate baseline organ function to enroll. PBP1510 is administered as a 90-minute intravenous infusion in 28-day cycles and tumor assessments are performed every 8 weeks from the first dose.

Phase 1 uses a 3 + 3 dose-escalation design to assess the safety, tolerability, pharmacokinetics (PK), and immunogenicity of ascending doses of PBP1510 as a single agent or in combination with gemcitabine (Table 1). The observation period for dose-limiting toxicities (DLT) is 28 days. ORR and pre- and post-treatment PAUF levels in tumor tissue will be explored in the analyses. A recommended phase 2 dose (RP2D) will be selected based on PK, safety, and efficacy data from Phase 1. Phase 2a is the dose expansion phase which aims to evaluate the safety, tolerability, PK, immunogenicity, and efficacy of PBP1510 administered at RP2D in combination with gemcitabine.

As of January 2024, 6 patients have been enrolled. The 1M cohort (1 mg/kg) was completed without any report of DLT. Dose escalation is in progress and DLT evaluation is ongoing for the 2nd and 3rd patients in the 2M cohort.

TABLE 1: NAND Dose escalation and cohorts (Phase 1) Monotherapy Combination Cohort PBP1510 Dose (mg/kg) Gemcitabine Dose (mg/m2) Cohort PBP1510 Dose (mg/kg) Gemcitabine Dose (mg/m2) 1M 1 - 1C 1 1000 2M 3 - 2C 3 1000 3M 6 - 3C 6 1000 4M 10 - 4C 10 1000 5M 15 - 5C 15 1000

Citation Format: Jaime Feliu Batlle, Daniel A. King, Jamie Kim, Sumita Pradhan, Yun-Yong Park, Kedar Diwakar Mandakhalikar, Wei Qi Loh. A first-in-human phase 1/2a study of a novel anti-PAUF monoclonal antibody PBP1510 in patients with advanced/metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT083.
Abstract CT221: Belzutifan, a hypoxia-inducible factor-2α (HIF-2α) inhibitor, for von Hippel-Lindau (VHL) disease-associated neoplasms: Long-term results of the phase 2 LITESPARK-004 study
Authors: Srinivasan Ramaprasad , Iliopoulos Othon , Beckermann Kathryn E. , Narayan Vivek , Maughan Benjamin L. , Oudard Stephane , Else Tobias , Maranchie Jodi K. , Iversen Ane B. , Cornell Jerry , Perini Rodolfo F. , Liu Yanfang , Linehan W. Marston , Jonasch Eric
Published: April 2024

Introduction: Belzutifan is a first-in-class HIF-2α inhibitor approved for patients (pts) with VHL disease-associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas (HB), or pancreatic neuroendocrine tumors (pNET) not requiring immediate surgery based on initial results from the phase 2 LITESPARK-004 study (NCT03401788). We present results from pts with more than 4 years of follow-up from LITESPARK-004.

Methods: Adults with germline VHL alteration, ≥1 measurable nonmetastatic RCC tumor, no RCC tumor >3 cm requiring immediate surgery, and no prior systemic anticancer therapy received oral belzutifan 120 mg once daily until disease progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate (ORR) in VHL-associated RCC per RECIST v1.1 by independent review. Secondary end points included ORR in CNS HB and pNET; duration of response (DOR), time to response (TTR), progression-free survival (PFS), and time to surgery (TTS) in RCC, CNS HB, and pNET; and safety.

Results: As of April 3, 2023, 36 of 61 pts (59%) were continuing treatment. Median follow-up was 49.9 mo (range, 48.2-58.1). Efficacy data are shown in the table. In the 4 years preceding belzutifan treatment, 46 pts (75%) underwent a total of 86 VHL-related tumor reduction procedures (surgery or radiation therapy). Since starting belzutifan, 16 pts (26%) underwent 18 tumor reduction procedures (RCC, n = 13; CNS HB, n = 3; retinal HB, n = 2). Safety profile remained unchanged with long-term follow-up.

Conclusions: With a median follow-up of more than 4 years, belzutifan continues to demonstrate clinically meaningful ORR and durable responses in VHL-associated RCC, CNS HBs, and pNET. Fewer tumor reduction procedures were observed after pts started belzutifan treatment. These results support belzutifan as a standard of care for this pt population.

Citation Format: Ramaprasad Srinivasan, Othon Iliopoulos, Kathryn E. Beckermann, Vivek Narayan, Benjamin L. Maughan, Stephane Oudard, Tobias Else, Jodi K. Maranchie, Ane B. Iversen, Jerry Cornell, Rodolfo F. Perini, Yanfang Liu, W. Marston Linehan, Eric Jonasch. Belzutifan, a hypoxia-inducible factor-2α (HIF-2α) inhibitor, for von Hippel-Lindau (VHL) disease-associated neoplasms: Long-term results of the phase 2 LITESPARK-004 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT221.
Abstract CT266: Initial efficacy of surufatinib plus sintilimab and IBI310 for patients with high-grade advanced-neuroendocrine neoplasm: A multicenter, single arm phase 2 stud
Authors: Zhang Panpan , Wang Yakun , Li Jie , Shen Lin , Lu Ming
Published: April 2024

Background: High-grade advanced-neuroendocrine neoplasm (HG-NEN) are more aggressive and have worse prognosis. Surufatinib (SUR, a selective VEGFRs; FGFR1; and CSF-1R inhibitor). Ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) has been recommended for extrapulmonary and non-pancreatic NEC if the disease progresses following chemotherapy by the NCCN guidelines for neuroendocrine tumors. Preclinical and clinical studies have shown that SUR is a good partner of immune checkpoint inhibitors (ICIs). In this study, we present findings of SUR combined with Sintilimab (SIN, anti-PD-1) and IBI310 (IBI, anti-CTLA-4) for HG-NEN patients (pts). Methods: Pts with histologically confirmed HG-NENs who resistant or intolerant to standard treatment were included in the study. Enrolled pts received SUR (250 mg, qd, po, q3w) combined with SIN (200 mg, d1, i.v.gtt, q3w) and IBI (1 mg/kg, d1, i.v.gtt, q6w). The primary endpoint was ORR per RECIST 1.1. The second endpoints were PFS, DCR, safety and OS. Results: By Dec 29, 2023, 14 pts were enrolled and available for efficacy assessment. Median age, 53 yrs (range 22- 66); male, 71.4%; ECOG PS 1, 50%; GEP-NEN, 57.1%; NEC, 71.4%; Median ki-67 index, 65% (range 25%-90%); liver metastases, 57.1%. 85.7% pts received prior systemic therapy (50% 1L and 35.7% ≥2L). Confirmed ORR was 28.6% and DCR 76.8%. Median PFS was 4.15 months. Among 9 pts with ≤1 prior systemic regimens, confirmed ORR and DCR were 44.4% and 88.9%, respectively, with a median PFS of 4.5 months. Out of 14 pts, all experienced some form of treatment- emergent events (TEAEs), with only 3 participants (21.4%) reporting grade 3 TEAEs. These included manageable events like increased bilirubin, immune pancreatitis, gastric retention, and increased amylase, each with a 7.1% incidence. No grade 4 TEAEs or new safety signals occurred. Conclusion: Surufatinib combined with Sintilimab and IBI310 showed a potential antitumor activity and a tolerable safety profile, providing an additional treatment option for pts with high-grade NEN.

Citation Format: Panpan Zhang, Yakun Wang, Jie Li, Lin Shen, Ming Lu. Initial efficacy of surufatinib plus sintilimab and IBI310 for patients with high-grade advanced-neuroendocrine neoplasm: A multicenter, single arm phase 2 stud [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT266.
Abstract LB044: Selective therapeutic antibodies against oncogenic mutations of the HER2 extracellular region
Authors: Bang Injin , Hattori Takamitsu , Leloup Nadia , Corrado Alexis , Nyamaa Atekana , Koide Akiko , Geles Ken , Buck Elizabeth , Koide Shohei
Published: April 2024

Oncogenic mutations of HER2 have been identified in HER2-low tumors. Such mutations in the extracellular region could serve as tumor-specific antigens that are accessible to antibody therapeutics. Although multiple antibody therapeutics have been successfully developed against cancers that overexpress wild-type HER2, none is specifically applicable to treating tumors driven by HER2 mutants expressed at a low level. Here, we developed antibodies exquisitely selective to HER2 S310F and S310Y, two most common oncogenic mutations in the HER2 extracellular region. Cryo-EM structures of the homodimer of HER2 S310F and an antibody bound to HER2 S310F revealed that these antibodies recognize the mutations in a manner that mimic the dimerization arm of HER and inhibit HER2 dimerization. These antibodies as T-cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro and in a mouse xenograft model. These results validate HER2 extracellular region mutations as actionable therapeutic targets and offer promising candidates toward clinical development. More generally, they suggest that point mutations in the extracellular region of cell-surface receptors as actionable targets for anti-cancer therapy.

Citation Format: Injin Bang, Takamitsu Hattori, Nadia Leloup, Alexis Corrado, Atekana Nyamaa, Akiko Koide, Ken Geles, Elizabeth Buck, Shohei Koide. Selective therapeutic antibodies against oncogenic mutations of the HER2 extracellular region [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB044.