bluuebunny/crossref_metadata_2025 huggingface dataset:
Validation of a questionnaire to measure the attitude of the Peruvian population regarding brain donation for the purpose of investigation
Authors: Bulgarelli Lucia , Benavidez‐Carbajal Ernesto , Canevaro‐Sesarego Fiorella , Rodriguez‐Lopez Ethel , Cruzalegui‐Bazán Claudia , Mejia‐Rojas Claudia , Campos Marzhio , Cruz Eddy De La , Mejia‐Rojas Koni
Published: January 2025

Background

Research into human brain tissue is important for medical scientific advancement. Brain Banks worldwide allow the receipt of brains for such purposes through voluntary donation. Attitude towards organ donation can be influenced by cultural, ethical and social factors. The lack of a validated questionnaire to evaluate it in the Peruvian population highlights the need for this study in the context of the creation of the First Brain Bank in Peru.

Method

An observational, descriptive cross‐sectional study was carried out.

The questionnaire was applied to 52 Peruvians over 18 years of age, selected by convenience in different areas of Peru, who agreed to participate voluntarily.

The questionnaire developed took as reference the “Health Street” questionnaire, created by the University of Florida. Then adapted taking into consideration the Peruvian context, according to the comments of experts on the subject. It resulted in 43 items with responses via Likert scale, 1 dichotomous, 10 polytomous and 3 open.

The questionnaire was applied to the participants through an in‐person and/or virtual interview. Likewise, after signing the informed consent, in some cases the administration was guided by the researcher, and in others it was self‐administered.

Finally, the internal consistency of the instrument was evaluated using Cronbach’s Alpha coefficient.

Result

The questionnaire was applied to 52 Peruvians with different socioeconomic and clinical conditions (tab.1 and tab.2), recollected from different parts of the country and whose average age was 38.61 years.

The Cronbach’s alpha coefficient calculation was 0.97.

Conclusion

The evaluation of the questionnaire by the experts was adequate: there were 5 experts, as recommended in the literature.

This questionnaire demonstrated good reliability in relation to the questions (Cronbach’s alpha was 0.97) so there is a good acceptability of the instrument.
Beyond urate lowering: neuroprotective potential of Allopurinol
Authors: Balendra Vyshnavy
Published: January 2025

Background

Oxidative stress is formed by a perturbation of redox homeostasis and linked to the development of Alzheimer’s disease (AD) [1]. This imbalance results in an abundance of free radicals that exceeds the antioxidant capacity. Xanthine oxidase (XO) is an enzyme responsible for producing uric acid through the metabolism of purine nucleotides, specifically hypoxanthine and xanthine to uric acid [2]. XO has shown to be upregulated in inflammatory conditions such as AD promoting the generation of free radicals. Thus, allopurinol, an anti‐gout medication, which works to inhibit XO, has a neuroprotective effect and therapeutic potential in delaying neurodegeneration.

Method

A literature search was conducted across scientific, international databases for English, peer‐reviewed articles and reviews published in the last decade using the following terms: allopurinol, xanthine oxidase and Alzheimer’s disease. Focus was placed on animal‐ or human‐based studies. Case reports were excluded.

Result

In‐ vitro studies revealed that elevated XO was associated with increased glial cell proliferation and reduced neuronal survival [3]. Other experimental studies showed XO overexpression in transgenic mice enhanced oxidative stress with increased secretion of pro‐inflammatory cytokines [4]. Allopurinol, an XO inhibitor, has shown to delay neurodegeneration in animal models with AD. Biochemical results in rodents showed decreased oxidative stress (myeloperoxidase levels), mild degenerative impairments in multipolar and bipolar neurons, and decreased apoptotic changes in glial cells after allopurinol treatment [5]. Inhibition of inflammatory molecules reduced vascular damages to the brain and GFAP immunoreactivity in the hippocampus [6]. The drug attenuated microglia infiltration, reduced astrocytes reactivation and prevented axonal loss and demyelination in mouse models [7,8]. Clinically, in population‐based, case‐control studies, allopurinol was associated with a 13‐34% lower risk of AD, lowered cognitive decline, and decreased behavioral symptoms [9,10].

Conclusion

Evidence ‐ based studies reveal allopurinol, a xanthine oxidase inhibitor, to have a neuroprotective potential against Alzheimer’s disease. Based on the current perspective, further research needs to be conducted in a clinical setting.
AD genes and microglia phenotypes: does microglia phenotypic heterogeneity matter?
Authors: Olah Marta
Published: January 2025

The view of microglial role in the pathogenesis of Alzheimer’s disease (AD) has been shaped by two major breakthroughs in the past decade: the discovery that many of the AD susceptibility genes are preferentially expressed in microglia, and the finding that microglia exist in a variety of previously not described functional phenotypes in the aged human central nervous system. As much as these discoveries brought paradigm shifts to the field, they also revealed major gaps in our understanding of the functional consequences of both the expression of AD susceptibility genes and microglia phenotypic heterogeneity. While there is progress being made in understanding the role of individual AD susceptibility genes in microglia function and what role the different microglia phenotypes might play in disease pathogenesis in AD, the connection between these two determining factors has not been established yet. In order to explore the relationship between the expression of AD susceptibility genes and the different microglia phenotypes that have been described in the aged and AD human brain, we explored the protein expression levels of AD relevant markers in a microglia subset specific way. Our findings highlight the importance of considering the phenotypic heterogeneity of microglia in the course of functional genomic studies and for any future disease modifying therapies targeting AD susceptibility genes in microglia.
Microglial and neuronal subpopulations associated with cognitive resilience to amyloid deposition in genetically diverse mice
Authors: Uyar Asli , Heuer Sarah E , Skelly Daniel A , Carter Gregory W , Bloss Erik B , Howell Gareth R
Published: January 2025

Background

Data from human and model organism studies suggest that genetic background influences susceptibility and resilience to Alzheimer’s Disease (AD) neuropathology. We previously showed that, wild‐derived PWK/PhJ (PWK) mice carrying the APP/PS1 transgene (PWK.APP/PS1) exhibit cognitive and synaptic resilience compared to traditionally‐studied B6.APP/PS1 inbred mice in presence of amyloid beta (Aβ) plaque deposition. PWK.APP/PS1 mice also contain different proportions of transcriptionally‐defined microglia compared to B6.APP/PS1. The precise molecular mechanisms underlying these differences between strains remain unknown. In this study, we aim to identify and characterize cell populations in the hippocampi of genetically distinct B6 and PWK mouse strains, and investigate cell‐type specific gene expression patterns associated with cognitive resilience in presence of amyloid deposition.

Method

We generated cohorts of B6.APP/PS1 and PWK.APP/PS1 transgenic female mice and wild‐type (WT) littermates as controls (n = 4 per strain/genotype group). At 8 months of age mice were euthanized, hippocampi collected, and single nuclear RNA sequencing (snRNAseq) was performed using 10x Genomics Chromium platform. Seurat R package (version 5.0.1) was used for major data analysis.

Result

We identified subpopulations of microglial cells characterized by varying expression patterns of a set of genes including Hk2, Itgam and Dock8. Neuronal subtypes were clustered by top marker genes Plk5 and Adarb2. Oligodendrocytes, oligodendrocyte progenitor cells, and endothelial cells were marked by expression of Mog, Neu4 and Abcc9, respectively. Differential expression and pathway enrichment analysis revealed strain‐specific immune and cell signaling pathways altered in distinct cell populations in response to amyloid pathogenesis. Cross‐species mapping of these transcriptomic signatures with human hippocampal gene modules identified AD‐relevant molecular mechanisms observed in mouse models of AD at the cell‐type level.

Conclusion

This study suggests that cell‐type specific transcriptomic response to amyloid is modulated by genetic background and our findings re‐iterate the importance of incorporating genetic diversity to model phenotypic and molecular heterogeneity in AD. Since the nuclei enriched in this dataset are enriched for neurons, future interrogations will provide evidence for specific neuronal populations and molecular mechanisms that differentiate cognitively resilient PWK from susceptible B6 mice, providing insights into mechanisms that can be leveraged to promote AD resilience.
Evaluating ambroxol as an agent to boost lysosomal function and reduce beta amyloid in 3xTg mice
Authors: Tsang Adrianna R , Wang Lynn , Gajavelli Sairam , Pasternak Stephen H
Published: January 2025

Background

Ambroxol is an expectorant under study as a treatment for synucleinopathies, such as Parkinson’s disease. It is a pharmacological chaperone of the lysosomal enzyme β‐glucocerebrosidase (GCase), increasing this enzyme and subsequently reducing accumulation of alpha‐synuclein. Although the mechanism of enhanced clearance is not fully understood, ambroxol stimulates lysosomal function through activation of transcription factor EB (TFEB), which drives hundreds of lysosomal genes. This project aims to investigate the usefulness of ambroxol as a disease‐modifying treatment for Alzheimer’s disease (AD). We hypothesize that ambroxol will enhance expression of lysosomal proteins and increase clearance of beta‐amyloid (Aβ) in the 3xTg mouse model of AD.

Methods

Wild‐type (B6;129) or 3xTg mice (APP/PS1/MAPT) mice were used. A ‘prevention’ group was treated at 6 months of age for 2 months, during initial Aβ deposition. A second ‘treatment group’ was fed ambroxol from 8 to 10 months of age, after Aβ deposits had developed. Mice received either 1) normal mouse chow, 2) low dose (1200 mg/kg) chow, or 3) or high dose (2400 mg/kg) chow. Brains were collected for immunohistochemistry, western blotting and ELISAs.

Results

By immunostaining, mean expression of ambroxol treated animals demonstrated increased GCase and LAMP1 staining, as predicted. This was accompanied by a significant dose dependant reduction of Aβ in aged 3xTg mice.

Conclusions

Our findings demonstrate that ambroxol is able to reduce intracellular accumulation of Aβ by upregulating lysosomal activity, and therefore may be a promising treatment for AD.
A digital brain sampling protocol atlas to simplify and accelerate biorepository tissue requests
Authors: Webster Jason , Shojaie Ali , Shen Yiqin Alicia , Le Tung , MacDonald Christine , Latimer Caitlin S , Keene C Dirk , Grabowski Thomas J
Published: January 2025

Background

The structural, cellular, and biomolecular research necessary for a mechanistic understanding of Alzheimer’s Disease (AD) relies on brain tissue collected according to a brain sampling protocol (BSP) and preserved in biorepositories. Such research involves discipline‐specific terminology such as cytoarchitectonic domains, brain network nodes, etc. This specificity can result in iterative, time‐consuming, and error‐prone request processes. The digital BSP atlas will streamline this process and offer resources for reference, visualization, training, and refinement of BSPs.

Method

Virtual Neuropathology was performed by a neuropathology technician and Board‐certified neuropathologist in Figma, a collaborative cloud‐based platform with an intuitive dynamic interface, in which metric properties of the brain slices and samples from the University of Washington BioRepository and Integrated Neuropathology (BRaIN) Laboratory BSP were precisely replicated. Virtual brain slices were taken every 4mm from the Montreal Neurological Institute and International Consortium on Brain Mapping 2009b Nonlinear Asymmetric Brain Template, which has 8x higher resolution than typical brain templates. Data were exported in Scalable Vector Graphics and processed in python.

Results

The Digital BSP Atlas contains volumetric labels in MNI 2009b space for the routinely collected samples in the BRaIN lab BSP and is stored using standard neuroinformatics conventions for use with freely available software such as FMRIB’s Software Library (FSL) and FreeSurfer.

For each sample, volume of brain regions defined by anatomical regions, brain areas, white matter pathways, subcortical structure, cytoarchitectonic domains, functional regions, or functional connectivity network nodes was calculated as the overlap with labels from a range of digital atlases which registered to MNI 2009b space.

Conclusion

The digital BSP atlas provides a quantitative representation of the BSP in a standard space which will accelerating the process of requesting brain tissue, allows for the refinement of protocols, and the coordination of neuroimaging information with neuropathology sample. Future directions of this work include customizable visualizations, training software, and website backend to identify corresponding samples from free‐form text with arbitrary neuroscience terms. This research is part of a pipeline to facilitate mechanistic understanding of AD by enhancing the precision and accuracy of neuropathology sampling and robust registration to premortem neuroimaging data even for late‐stage AD participants.
Phase‐Separated Spiropyran Coacervates as Dual‐Wavelength‐Switchable Reactive Oxygen Generators
Authors: Kong Hao , Xie Xian , Bao Yishu , Zhang Fang , Bian Liming , Cheng Kai , Zhao Yuan‐Di , Xia Jiang
Published: January 2025

Low‐molecular‐weight compounds of certain structural features may form coacervates through liquid‐liquid phase separation (LLPS). These coacervates can enter mammalian cells and affect cellular physiology. Controlling the properties of the coacervates inside cells, however, is a challenge. Here, we report photochemical reactions of spiropyran (SP)‐based coacervates with two wavelengths of light, in vitro, in the cell, and in animals, generating reactive oxygen species (ROS) for photo‐controlled cell killing. We identify an SP‐containing compound, SP‐PEG8‐SP, that forms coacervates (SP‐C) in the aqueous solution. Photo illumination by a UV light triggers the isomerization of SP to merocyanine (MC), switching SP‐C to the fluorescent coacervates MC‐C. A visible light converts MC‐C back to SP‐C and induces ROS generation. Notably, coacervate formation increases the compound's ROS generation efficiency. The SP‐C/MC‐C coacervate system (collectively called spiropyran coacervates) can spontaneously enter cells, and a dual‐wavelength‐controlled reversible on/off switch and spatiotemporal‐resolved ROS production is realized within the cytoplasm. Light‐induced ROS generation leads to cytotoxicity to cancer cells, tumor organoids, and tumors in vivo, supporting spiropyran coacervates’ potential use as coacervate photosensitizers in photodynamic therapies.
P‐Dopant with Spherical Anion for Stable n‐i‐p Perovskite Solar Cells
Authors: Shao Guang , Zhou Zu‐Kun , Wang Dian , Xiao Jing , Yang Shang‐Gen , Yu Hui‐Juan , Qu Jun‐Feng , Wu Zhi‐Zheng , Zhang Jun‐Jie , Peng Lifen , Ain Qurat Ul , Khan Ammar Ahmed , Chen Yu , Yang Hua , Qiu Zeliang , Hu Ruiyuan , Li Xingao , Alamry Khalid A. , Xia Jianxing , Zhang Yi , Nazeeruddin Mohammad Khaja
Published: January 2025

Li‐TFSI/t‐BP is the most widely utilized p‐dopant for hole‐transporting materials (HTMs) in state‐of‐the‐art perovskite solar cells (PSCs). However, its nonuniformity of doping, along with the hygroscopicity and migration of dopants, results in the devices exhibiting limited stability and performance. This study reports on the utilization of a spherical anion derived from the p‐dopant, regulated by its radius and shape, as an alternative to the linear TFSI− anion. The theoretical and experimental results reveal that the spherical anion significantly increases the doping effect of HTMs due to an enhanced electron transfer from larger dipole moments. The enhanced transfer leads to a shift in the Pb‐6p defect orbitals, resulting in shallower trap states. Moreover, compared to the linear structure of the TFSI− anion, the anion of sodium tetrakis[3,5‐bis(trifluoro methyl)phenyl]borate (Na‐TFPB) with a larger van der Waals radius and spherical shape offers increased hydrophobicity and migration barriers, which can protect the perovskite crystal and facilitate stable p‐doping of HTMs. The use of Na‐TFPB results in enhanced thermal and ambient stability of PSCs. The devices fabricated with the shape‐ and radius‐regulated p‐dopant achieve remarkable efficiencies of 24.49 % and 24.31 % for CJ‐01 and spiro‐OMeTAD, respectively, representing the highest efficiency values for organic dopants to date. This study underscores the ingenious design of spherical anions of p‐dopants in contrast to the conventional linear anions.
Evaluation of the Impact of HIFU on Peptide Bond Formation: A Study Using SPE‐LC‐MS/MS Methodology
Authors: Liu Jiale , Yuan Rongfei , Wang Qi , Qiao Hai , Yang Yuling , Yang Siyu , Zhang Hua , Chen Chang
Published: January 2025

High‐intensity focused ultrasound (HIFU) is a noninvasive soft tissue ablation technique, which utilizes ultrasound energy to induce thermal coagulation necrosis in targeted tissues. Whether this high energy causes side effects in vivo, such as the formation of peptide bonds, has not been fully investigated. Glycylglycine is the simplest dipeptide and hence is often used as a model compound for peptide studies. In this study, we developed and validated a sensitive quantification method based on ion‐exchange solid‐phase extraction, liquid chromatography, and tandem mass spectrometry (SPE‐LC‐MS/MS) for the analysis of glycylglycine without derivatization, and then used it to evaluate whether HIFU promoted peptide bond formation in aqueous solution (without enzymes) and plasma (with enzymes). The results showed that strong cation exchange SPE significantly reduced the matrix effect and improved the sensitivity of the LC‐MS/MS method. No formation of glycylglycine in the aqueous solution or plasma was observed following HIFU irradiation.
Liquid Chromatography Combined With Tandem Mass Spectrometry for the Pharmacokinetic and Metabolism Studies of PROTAC ARV‐471 in Rats
Authors: Huang Wenbin , Zhang Hongjian , Zhou Yayun , Liu Xuechao , Zhang Qilei , Ma Xiaopeng
Published: January 2025

Proteolysis targeting chimera (PROTAC) is emerging as a promising medicinal modality, which has aroused widespread interest among the field of pharmaceutical manufacturing in the recent years. ARV‐471 is an orally active PROTAC estrogen receptor degrader against breast cancer, which leads to the ubiquitylation and subsequent degradation of estrogen receptors via the proteasome. In this study, we developed a highly sensitive liquid chromatography tandem mass spectrometry method (LLOQ = 0.5 ng/mL) for the measurement of ARV‐471 in rat plasma. The acetonitrile precipitated sample was separated on ACQUITY BEH C18 column using acetonitrile‐0.1% formic acid as mobile phased with gradient elution. Multiple reactions monitoring in positive ESI mode was employed for the quantification of ARV‐471 (m/z 724.4 → 396.2). The assay showed good linearity over the concentration range of 0.5–1000 ng/mL with correlation coefficient > 0.996. The assay was validated according to FDA guidance, and all the validation parameters were within the predefined acceptance criteria. After validation, the assay was applied to the pharmacokinetic study of ARV‐471 in rats. Additionally, the metabolites in rat plasma were identified using liquid chromatography–high resolution mass spectrometry. Four metabolites were identified and characterized. Hydrolysis, glucuronidation and deamination were the main metabolic pathways of ARV‐471 in rats.
Validated LC–MS/MS Method for the Determination of Paxalisib on Mouse Dried Blood Spots: An Application to Pharmacokinetic Study in Mice
Authors: Zakkula Ashok , Haque M. Akiful
Published: January 2025

Paxalisib is a dual PI3K/mTOR inhibitor, being used in advanced cancer treatment. In this research, we report a validated LC–MS/MS method for quantifying paxalisib from mouse dried blood spot (DBS). We validated the method in‐line with the FDA guidelines. Liquid–liquid extraction technique was used to extract paxalisib from the DBS discs. We used a Chromolith RP‐18 end cap (100 × 4.6 mm) column and isocratic mobile phase for the chromatographic separation of paxalisib and the internal standard (IS, dasatinib). The flow was 0.80 mL/min. In the optimized chromatographic conditions, the retention of paxalisib and the IS was ~2.13 and 2.06 min, respectively. Each injection total run time was 2.50 min. The MS/MS ion transitions monitored were m/z 383.2 → 309.1 and 488.1 → 410.1 for paxalisib and the IS, respectively. We have used a broad calibration range (1.24–3762 ng/mL) with a determination coefficient (r2) of 0.995. All the validation parameters assessed met the acceptance criteria, and hematocrit had no effect on DBS Paxalisib concentrations. We have used the validated method to derive the intravenous and oral pharmacokinetic parameters by quantifying paxalisib in mouse blood and correlated with mice pharmacokinetic data.
Acute Transverse Myelitis as an Uncommon Presentation of Neurobrucellosis: A Case Report
Authors: Karaja Saja , Kazkz Waddah
Published: January 2025

Brucellosis mainly affects the musculoskeletal system with neurological manifestations observed in < 5% of all cases. This report outlines a unique case of neurobrucellosis that resulted in acute transverse myelitis (TM) with absent deep reflexes and negative Wright's reaction. In endemic regions, neurobrocellosis should be considered as a potential etiology of acute TM. Timely initiation of treatment is essential for optimizing clinical outcomes.
Effect of sodium content on the electrochemical performance of P2‐Na2Ni2TeO6 layered oxide cathode for sodium‐ion batteries
Authors: Moeez Iqra , Bhatti Ali Hussain Umar , Cho Min‐Kyung , Susanto Dieky , Akbar Muhammad , Ali Ghulam , Chung Kyung Yoon
Published: January 2025

Sodium‐ion batteries (SIBs) employ P2‐type layered transition metal oxides as promising cathode materials, primarily due to their abundant natural reserves and environmentally friendly characteristics. However, structural instability and complex phase transitions during electrochemical cycling pose significant challenges to their practical applications. Employing cation substitution serves as a straightforward yet effective strategy for stabilizing the structure and improving the kinetics of the active material. In this study, we introduce a Ni‐rich honeycomb‐layered Na2+xNi2TeO6 (NNTO) cathode material with variable sodium content (x = 0, 0.03, 0.05, 0.10). Physicochemical characterizations reveal that excess sodium content at the atomic scale modifies the surface and suppresses phase transitions, while preserving the crystal structure. This results in enhanced cyclic performance and improved electrochemical kinetics at room temperature. Furthermore, we investigate the performance of the NNTO cathode material containing 10% excess sodium at a relatively high temperature of 60°C, where it exhibits 71.6% capacity retention compared to 60% for the pristine. Overall, our results confirm that a preconstructed surface layer (induced by excess sodium) effectively safeguards the Ni‐based cathode material from surface degradation and phase transitions during the electrochemical processes, thus exhibiting superior capacity retention relative to the pristine NNTO cathode. This study of the correlation between structure and performance can potentially be applied to the commercialization of SIBs.
Asymmetric charge distribution boosts hydrogen evolution performance in two‐dimensional MoO2/MoS2 step heterostructure
Authors: Kang Mengke , Zhang Xiang , Wang Jingyi , Li Wen , Xue Tianyu , Zhai Kun , Xiang Jianyong , Nie Anmin , Cheng Yingchun , Liu Zhongyuan
Published: January 2025

Step heterostructures are predicted to hold a profound catalytic performance because of the rearranged electronic structure at their interface. However, limitations in the morphology of heterostructures prepared by hydrothermal reactions or molten salt‐assisted strategies make it challenging to directly assess charge distribution and evaluate a single interface's hydrogen evolution reaction (HER) performance. Here, we prepared two‐dimensional MoO2/MoS2 step heterostructures with a large specific surface area by the chemical vapor deposition method. Surface Kelvin probe force microscopy and electrical transport measurement verified the asymmetric charge distribution at a single interface. By fabricating a series of micro on‐chip electrocatalytic devices, we investigate the HER performance for a single interface and confirm that the interface is essential for superior catalytic performance. We experimentally confirmed that the enhancement of the HER performance of step heterostructure is attributed to the asymmetric charge distribution at the interface. This work lays a foundation for designing highly efficient catalytic systems based on step heterostructures.
Stereoselective Synthesis of 2‐Deoxy Glycosides via a Novel 2‐O‐Resided (o‐Alkynyl)benzoate‐Initiated 1,2‐Sulfur Migration/Glycosylation and Desulfurization Protocol as well as Mechanism Elucidation
Authors: Liao Jin‐Xi , Li Zhen‐Qiang , Qiu Yanli , Gao Xiang‐Yang , Lv Xin , Liu Hui , Tu Yuan‐Hong , Sun Jian‐Song
Published: January 2025

Comprehensive Summary

Stereoselective construction of 2‐deoxy‐glycosidic linkages has been achieved by the 1,2‐sulfur migration/glycosylation and desulfurization strategy; however, current protocols suffer from harsh reaction conditions and unsatisfactory stereoselectivity, particularly during the 1,2‐S‐migration/glycosylation step. With 2‐O‐resided (o‐alkynyl)benzoate and anomeric p‐methoxyphenylsulfenyl groups as the initiating and migrating groups, respectively, a novel protocol for the efficient synthesis of 2‐deoxy‐glycosides via the 1,2‐sulfur migration/glycosylation‐desulfurization strategy has been established, which is featured by the mild and catalytic reaction conditions, expanded substrate scope, as well as good to excellent diastereoselectivity. Mechanism studies determined hyperconjugation‐stabilized oxocarbenium ion as the key intermediate, achieving high 1,2‐trans stereocontrol through thermodynamic, steric, as well as electrostatic effects. This provides the fresh insight for the operative mechanism of the 1,2‐sulfur migration/glycosylation and desulfurization strategy, further corroborated by the elaborately designed testing reactions and DFT calculations. Moreover, the synthetic potential of the newly established protocol was examined by the practical synthesis of natural product, culminating in the acquisition of digoxin from acetylated digoxigenin in 25% overall yield through an 8‐step longest linear sequence.
Potential new treatment for cancer‐related cachexia
Authors: Nierengarten Mary Beth
Published: January 2025

This news section offers Cancer readers timely information on events, public policy analysis, topical issues, and personalities. In this issue, patients with cancer‐related cachexia who were treated with ponsegromab had a significant increase in weight gain from the baseline in comparison with patients treated with a placebo. Also, a new first‐line treatment improves progression‐free survival for select men with bone mCRPC, and the addition of an immune checkpoint inhibitor reduces the risk of disease progression for select patients with anal cancer.
No news, bad news: When the result of a clinical biomarker is “no result available”
Authors: Romero Ignacio
Published: January 2025

This study from a tertiary center focuses on how timing, sample selection, and preparation contribute to "no result available” in biomarker analysis. It emphasizes the need to analyze and report the preanalytical, analytical, bioinformatics, and clinical factors underlying these results in future research.
Zanubrutinib plus R‐CHOP for the treatment of newly diagnosed double‐expressor lymphoma: A phase 2 clinical study
Authors: Yin Xia , He Qiang , Liu Dan , Xie Linna , Wang Hui , Chen Chunyan , Zhao Chuanli , Shan Ningning , Shi Shanshan , Wei Haichen , Ma Ji , Lu Ke , Wang Liang , Wang Yan , Xing Lijie , Li Zengjun
Published: January 2025

Background

Double‐expressor lymphoma (DEL) has a poorer prognosis than other subtypes of diffuse large B‐cell lymphoma (DLBCL). This study is a multicenter, prospective, single‐arm, phase 2 clinical study initiated by investigators to evaluate the efficacy and safety of combined zanubrutinib with R‐CHOP, which includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for patients with DEL (stage II or more), as well as to explore factors related to efficacy preliminarily.

Methods

From November 2020 to July 2022, 48 newly diagnosed patients were enrolled. All patients received twice‐daily oral zanubrutinib (160 mg) for 6 months and standardized R‐CHOP regimen for six to eight cycles.

Results

The objective response rate (ORR) was 89.6%, with a complete response rate (CRR) of 83.3%. The median follow‐up was 29.3 months. The median progression‐free survival (PFS) and overall survival (OS) were not reached. The PFS and OS were 81.25% and 93.75% at 2 years, respectively. Grade ≥3 adverse events (AEs) were reported in 23 of 48 (47.9%) patients. Next‐generation sequencing (NGS) results of 33 patients showed that TP53, MYD88, and PIM1 were the most common mutated gene. Multivariate analysis revealed that BCL‐6 gene rearrangement was an adverse prognostic factor for both PFS (hazard ratio [HR], 0.247; 95% confidence article [CI], 0.068–0.9; p = .034) and OS (HR, 0.057; 95% CI, 0.006–0.591; p = .016), whereas the number of extranodal involvements also significantly influenced OS (HR, 15.12; 95% CI, 1.07–213.65; p = .044).

Conclusions

Zanubrutinib in combination with R‐CHOP is an effective option for DEL patients, and the toxicity of zanubrutinib is entirely acceptable for patients.
Cover Image
Authors: Nematimoez Mehdi , Haddas Ram , Breen Alexander
Published: January 2025

The cover image is based on the Article Effect of asymptomatic intervertebral flexion patterns on lumbar disc pressure: A finite element analysis study by Mehdi Nematimoez et al., https://doi.org/10.1002/cnm.3866.

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Clinical Pharmacology and Approach to Dose Selection of Emestedastat, a Novel Tissue Cortisol Synthesis Inhibitor for the Treatment of Central Nervous System Disease
Authors: Rolan Paul , Seckl Jonathan , Taylor Jack , Harrison John , Maruff Paul , Woodward Michael , Mills Richard , Jaros Mark , Hilt Dana
Published: January 2025

This review demonstrates the value of central pharmacodynamics (PD), including positron emission tomography (PET) and computerized cognitive testing, to supplement pharmacokinetic (PK) and peripheral PD for determining the target dose range for clinical efficacy testing of emestedastat, an 11β‐hydroxysteroid dehydrogenase 1 (11β‐HSD1) inhibitor. Combined data from 6 clinical trials in cognitively normal volunteers and patients with Alzheimer disease included a population PK model, endocrine PD, a human PET trial (11β‐HSD1 brain imaging), and computerized cognitive testing. PK and PET findings were similar in volunteers and patients with Alzheimer disease. PK modeling suggested that 20 mg daily would be optimal to maintain cerebrospinal fluid concentrations above the brain half maximal inhibitory concentration. However, subsequent PET scanning suggested that emestedastat doses of 10 or even 5 mg daily may be sufficient to adequately inhibit 11β‐HSD1. With once‐daily doses of 5‐20 mg in cognitively normal, older volunteers, a consistent pattern of pro‐cognitive benefit, without dose‐response, was seen as improvement in attention and working memory but not episodic memory. Thus, emestedastat therapeutic activity might be attained at doses lower than those predicted from cerebrospinal fluid drug levels. Doses as low as 5 mg daily may be efficacious and were studied in subsequent trials.
Ethical Considerations for Conducting Community‐Engaged Research with Women Experiencing Homelessness and Incarcerated Women
Authors: Dickins Kirsten
Published: January 2025

Since 1979, The Belmont Report has served as a guidebook for ensuring that basic standards for ethical research are upheld. The Belmont Report calls for special protections of vulnerable research participants, such as people who are incarcerated and economically and educationally disadvantaged individuals who are deemed susceptible to exploitation. With a growing focus on health equity and community‐engaged approaches in health equity research, efforts to involve vulnerable participants are increasing. Yet there is little understanding of what matters most to vulnerable populations. This study sought to understand, from participant perspectives, ethical considerations when conducting research with two vulnerable populations: women experiencing homelessness and women who are incarcerated. Health care professionals and staff that work closely with homeless and incarcerated populations were also interviewed. The findings from semistructured interviews with these populations underscore the sustained importance of respect for persons, beneficence, and justice, and further highlight the need for self‐determination; privacy/confidentiality; continuous consent; fair treatment; benefit‐burden balance; nonauthoritarian relationships; and fair access to research participation. Although The Belmont Report durably serves to ethically guide standard conventional research, the Report's original concepts should be extended to include specific considerations when vulnerable populations are involved in community‐engaged research.
Investigating Moral Distress in Clinical Research Professionals—A Deep Dive into Troubled Waters
Authors: Bosack Elena , Bourne Dawn , Epstein Elizabeth , Marshall Mary Faith , Chen Donna T.
Published: January 2025

Moral distress occurs when professionals are constrained from taking what they believe to be ethically appropriate actions or are forced to take actions they believe are ethically inappropriate, challenging their professional identities and representing systems‐level issues within organizations. Moral distress has been recognized in a variety of health care‐related fields; however, the phenomenon is still comparatively unexplored among clinical research professionals (CRPs). In this qualitative study, we interviewed ten CRPs to unearth root causes of moral distress in this ethically unique profession. Four themes emerged from the data as contributors to moral distress: commodification of research; concern for research participants; compromised science; and structures of hierarchy. The experience of racism as a source of moral distress is also explored. The findings of this study indicate that the existence of moral distress in clinical research is troubling not only for the welfare of CRPs but also for the greater clinical research enterprise.
Healthcare Data Security and Privacy Protection Framework Based on Dual Channel Blockchain
Authors: Kaur Jasleen , Rani Rinkle , Kalra Nidhi
Published: January 2025

The integration of blockchain technology with healthcare digitalization has the potential to improve data management, reduce administrative costs, increase data security and privacy, and enhance querying capabilities. However, in the traditional blockchain model, all data and transactions are processed and stored in a single, unified ledger, and all participants have access to the same data, which raises privacy concerns and poses congestion issues with an increased number of transactions. It becomes even more problematic in healthcare, where data confidentiality is essential. In literature, centralized storage utilizing cloud‐based solutions is employed to manage large volumes of data, restricting information sharing beyond the institution. Additionally, the direct storage of massive data on the blockchain impacts the performance and scalability of the system. In this paper, to address these issues and ensure the security and rapid retrieval of healthcare information, a framework is proposed, which involves the implementation of a dual‐channel blockchain architecture combined with two robust cryptographic algorithms, i.e., Rivest‐Shamir‐Adleman (RSA) and Advanced Encryption Standard (AES). These encryption techniques deliver safe data transmission via RSA and efficient data storage via AES, offering a secure mechanism to prevent unauthorized access and data breaches. In addition, private data collection is incorporated to securely store confidential patient information, guaranteeing privacy, security, and limited access. Also, an Access Control List (ACL) is defined for different users to implement access permissions, i.e., grant and revoke access to viewers while sharing information. Moreover, an off‐chain storage InterPlanetary File System (IPFS) is used to improve scalability. The performance evaluation is performed by conducting experimental simulations, where critical performance indicators such as throughput and latency are measured across different transaction rates, channels, and rate controllers. Moreover, the proposed framework classifies smart contract functions into query and invoke/write transactions, enhancing the efficiency of data retrieval. Further, the functionality and security analysis of the proposed framework is discussed. The results demonstrate that the proposed approach is highly capable of preserving security and privacy standards while also assuring efficient management and accessibility of data in healthcare applications.
High‐Order Alternative Formulation of Weighted Essentially Non‐Oscillatory Scheme With Minimized Dispersion and Controllable Dissipation for Compressible Flows
Authors: Zeng Wei‐Gang , Liu Lu , Zeng Li‐Jin , Pan Jian‐Hua , Yin Jun‐Ping , Ren Yu‐Xin
Published: January 2025

Following the proposition of the original AWENO (Alternative Formulation of Weighted Essentially Non‐Oscillatory) FD (Finite Difference) scheme, we construct the new AMDCD FD scheme, an Alternative formulation of the linear FD scheme with Minimized Dispersion and Controllable Dissipation, in this article. Spectral analysis shows that the proposed AMDCD FD scheme can be more efficient in resolving smooth solutions due to the flexibility in controlling dissipation. To efficiently solve compressible flows with discontinuities, we further combined the proposed AMDCD FD scheme with the original AWENO FD scheme using a hybrid interpolation scheme, in which the optimized linear MDCD (Minimized Dispersion and Controllable Dissipation) interpolation scheme would be switched to the nonlinear WENO (Weighted Essentially Non‐Oscillatory) type interpolation scheme gradually as the flow structures are in transition from smooth region towards the vicinity of discontinuities. Therefore, the resulting hybrid AWENO‐AMDCD FD scheme is suitable for solving compressible flows with broad‐scale flow structures and/or shock waves. A series of one‐, two‐, and three‐dimensional compressible flow problems are numerically tested to demonstrate the accuracy, superior resolution, as well as the robustness of the proposed hybrid AWENO‐AMDCD FD scheme.
Glial Biologist's Guide to Mass Spectrometry‐Based Lipidomics: A Tutorial From Sample Preparation to Data Analysis
Authors: Randolph Caitlin E. , Walker Katherine A. , Yu Ruilin , Beveridge Connor , Manchanda Palak , Chopra Gaurav
Published: January 2025

Neurological diseases are associated with disruptions in the brain lipidome that are becoming central to disease pathogenesis. Traditionally perceived as static structural support in membranes, lipids are now known to be actively involved in cellular signaling, energy metabolism, and other cellular activities involving membrane curvature, fluidity, fusion or fission. Glia are critical in the development, health, and function of the brain, and glial regulation plays a major role in disease. The major pathways of glial dysregulation related to function are associated with downstream products of metabolism including lipids. Taking advantage of significant innovations and technical advancements in instrumentation, lipidomics has emerged as a popular omics discipline, serving as the prevailing approach to comprehensively define metabolic alterations associated with organismal development, damage or disease. A key technological platform for lipidomics studies is mass spectrometry (MS), as it affords large‐scale profiling of complex biological samples. However, as MS‐based techniques are often refined and advanced, the relative comfort level among biologists with this instrumentation has not followed suit. In this review, we aim to highlight the importance of the study of glial lipids and to provide a concise record of best practices and steps for MS‐based lipidomics. Specifically, we outline procedures for glia lipidomics workflows ranging from sample collection and extraction to mass spectrometric analysis to data interpretation. To ensure these approaches are more accessible, this tutorial aims to familiarize glia biologists with sample handling and analysis techniques for MS‐based lipidomics, and to guide non‐experts toward generating high quality lipidomics data.
The Future Hospital in Global Health Systems: The Future Hospital as an Entity
Authors: Sebire N. J. , Adams A. , Arpiainen L. , Celi L. , Charlesworth A. , Gorgens M. , Gorsky M. , Magrabi F. , Nagasawa Y. , Onoka C. , McKee M.
Published: January 2025

Health care is changing rapidly. Hospitals are, and will remain, an essential setting to deliver it. We discuss how to maximise the benefits of hospitals in the future in different geographic and health system settings, highlighting a series of cross‐cutting issues. We do this by exploring the evolving roles of hospitals and the main factors that we must consider as they adapt. These include changing population and disease profiles, the impact of evolving technology, and new concepts in hospital design and planning.

Our focus is on delivering high‐quality, patient‐centred care while ensuring equitable access, even if strategic decisions require compromise across these functions. The COVID‐19 pandemic has shown the importance of hospitals in societies while also revealing the limitations of current structures and the potential of technology to transform hospital services within the broader healthcare system.

The aim of this multidisciplinary perspective is to provide an overview of pertinent issues whilst highlighting the challenges and opportunities in optimising future hospital planning, construction, design, and development in high‐income (HIC) and low —and medium‐income country (LMIC) settings.
Neo‐enhancers in T‐cell acute lymphoblastic Leukaemia (T‐ALL) and beyond
Authors: Smith Charlotte , Asnafi Vahid , Touzart Aurore
Published: January 2025

T‐cell acute lymphoblastic leukaemia (T‐ALL) is a rare aggressive haematological malignancy characterised by the clonal expansion of immature T‐cell precursors. It accounts for 15% of paediatric and 25% of adult ALL. T‐ALL is associated with the overexpression of major transcription factors (TLX1/3, TAL1, HOXA) that drive specific transcriptional programmes and constitute the molecular classifying subgroups of T‐ALL. Although the dysregulation of transcription factor oncogenes is frequently associated with chromosomal translocations in T‐ALL, epigenetic dysregulation resulting in changes to post‐translational modifications of histones has also been reported. This includes non‐coding intergenic mutations that form oncogenic neo‐enhancers. This review will focus on the known epigenetically activating intergenic mutations reported in T‐ALL, and will discuss the wider implications of neo‐enhancer mutations in cancer.
A case of laparoscopically assisted vulvar reconstruction using the gluteal fold flap for anterior enterocele after robot‐assisted radical cystectomy in a woman
Authors: Sasaki Yutaro , Yamamoto Yasuyo , Mizuguchi Makoto , Kobayashi Saki , Nagasaka Shinji , Tokunaga Takuya , Furukawa Junya
Published: January 2025

Introduction

Vaginal complications following radical cystectomy may require surgical treatment. We herein report a case of successful laparoscopically assisted vulvar reconstruction using the gluteal fold flap for anterior enterocele following robot‐assisted radical cystectomy.

Case presentation

A 71‐year‐old Japanese woman underwent robot‐assisted radical cystectomy for bladder cancer (ypT1ypN1M0). The bladder, urethra, bilateral ovaries, and anterior vaginal wall were removed together transvaginally. The Mercedes‐Benz closure technique was performed for vaginal reconstruction using the posterior vaginal wall. Seventeen months after surgery, she complained of a vulvar bulge, and physical examination confirmed a tennis ball‐sized anterior enterocele. Therefore, she underwent laparoscopically assisted vulvar reconstruction using the gluteal fold flap. No recurrence had developed at 6 months postoperatively.

Conclusion

The combination with laparoscopy allows vulvar reconstruction to be performed safely and efficiently.
Paranoia, Functioning, and the Moderating Effect of Well‐Being in a Community Sample of Adolescents
Authors: Thompson Elizabeth , Kingston Jessica , Ellett Lyn , Krkovic Katarina , Velotta Sydney , Rabasco Ana , Gaudiano Brandon A.
Published: January 2025

Introduction

Paranoid ideation is a relatively common experience in adolescence, yet it has not been well‐explored in relation to psychological well‐being and functioning in general population samples of youth. The current study aimed to investigate the relations between paranoia (operationalized as “persecutory ideation”), well‐being, and two domains of functioning, social (e.g., interpersonal relationships) and role (e.g., school and home responsibilities), in adolescence.

Methods

This nonclinical sample of adolescents (n = 462, aged 14–17 years, 50% male, 50% female) was recruited from the United Kingdom and the United States via an online survey in 2022.

Results

Correlations indicated significant associations between persecutory ideation, in the negative direction, and well‐being, in the positive direction, with both social and role functioning. With respect to social, but not role, functioning, these associations remained significant in linear regression analyses controlling for the effects of depression, past‐year bullying/victimization, and past‐year adverse life events. A subsequent analysis indicated that the association between persecutory ideation and social functioning was moderated by well‐being. Persecutory ideation was significantly associated with social functioning at the lowest level of well‐being (1 SD below the mean), but not at moderate (mean) or high (1 SD above the mean) levels of well‐being.

Conclusions

Results suggest that among adolescents, persecutory ideation is negatively associated with functioning. Furthermore, novel findings suggest that well‐being may buffer the association between persecutory ideation and social functioning. Therapeutic interventions targeting well‐being may be helpful for youth experiencing paranoia, especially with respect to maintaining relationships and social connectedness.