bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prompts to Table: Specification and Iterative Refinement for Clinical Information Extraction with Large Language Models
Authors: Hein David , Christie Alana , Holcomb Michael , Xie Bingqing , Jain AJ , Vento Joseph , Rakheja Neil , Hamza Shakur Ameer , Christley Scott , Cowell Lindsay G. , Brugarolas James , Jamieson Andrew , Kapur Payal 
Published: February 2025

AbstractBackgroundExtracting structured data from free-text medical records is laborious and error-prone. Traditional rule-based and early neural network methods often struggle with domain complexity and require extensive tuning. Large language models (LLMs) offer a promising solution but must be tailored to nuanced clinical knowledge and complex, multipart entities.MethodsWe developed a flexible, end-to-end LLM pipeline to extract diagnoses, per-specimen anatomical-sites, procedures, histology, and detailed immunohistochemistry results from pathology reports. A human-in-the-loop process to create validated reference annotations for a development set of 152 kidney tumor reports guided iterative pipeline refinement. To drive nuanced assessment of performance we developed a comprehensive error ontology— categorizing by clinical significance (major vs. minor), source (LLM, manual annotation, or insufficient instructions), and contextual origin. The finalized pipeline was applied to 3,520 internal reports (of which 2,297 had pre-existing templated data available for cross referencing) and evaluated for adaptability using 53 publicly available breast cancer pathology reports.ResultsAfter six iterations, major LLM errors on the development set decreased to 0.99% (14/1413 entities). We identified 11 key contexts from which complications arose-including medical history integration, entity linking, and specification granularity-which provided valuable insight in understanding our research goals. Using the available templated data as a cross reference, we achieved a macro-averaged F1 score of 0.99 for identifying six kidney tumor subtypes and 0.97 for detecting metastasis. When adapted to the breast dataset, three iterations were required to align with domain-specific instructions, attaining 89% agreement with curated data.ConclusionThis work illustrates that LLM-based extraction pipelines can achieve near expert-level accuracy with carefully constructed instructions and specific aims. Beyond raw performance metrics, the iterative process itself—balancing specificity and clinical relevance—proved essential. This approach offers a transferable blueprint for applying emerging LLM capabilities to other complex clinical information extraction tasks.
Phosphoproteomics Uncovers Tumor Heterogeneity and Therapeutic Opportunities in Early-Stage Hepatocellular Carcinoma
Authors: Ren Liangliang , Jiang Jiahan , Lin Weiran , Qi Lihui , Li Chaoying , Jiang Ying 
Published: February 2025

AbstractHepatocellular carcinoma (HCC) is the third deadliest cancer in the world, however, the mechanisms of genesis, development and recurrence of HCC are not fully clarified yet. Previous studies on phosphoproteome in large-scale of HCC merely investigated the specific regulation on protein phosphorylation levels and identified subgroups consistent with proteomic subgroups. Here, we systematically interrogated the phosphoproteome of early-stage HCC and uncovered the dysregulated signaling pathways and kinases. Unlike previous studies on mRNA and protein levels, we observed a significant decline in phosphorylation regulation of EGFR-mediated canonical ERK/MAPK signaling alongside elevation of atypical MAPK signaling. Classification based on the heterogeneity of the phosphoproteome in tumor identified three phosphoproteomic subtypes, each characterized by distinct phosphorylation signatures, clinical characteristics, cellular signaling pathways and kinase activities. Further validation revealed hyperphosphorylation of SRSF3, one signature in the most malignant subtype, promote proliferation and metastasis of HCC cells. The mechanism of which was further demonstrated to be coordinated by activation of SRPK1/CLKs and potential suppression of PP1 phosphatase via phosphorylation of PPP1R7. Furthermore, inhibitors targeting SRPK1 or CLKs effectively suppressed hyperphosphorylation of SRSF3 mediated migration and invasion in HCC. Our study uncover the dysregulated phosphorylation signatures, offer new insights into the tumor heterogeneity, and identify phosphorylation regulating mechanism and corresponding key kinases with therapeutic value in early-stage HCC, which also spotlight the importance of protein phosphorylation in cancer progression.
Crystal Structure and Catalytic Mechanism of Drimenol Synthase, a Bifunctional Terpene Cyclase-Phosphatase
Authors: Osika Kristin R. , Gaynes Matthew N. , Christianson David W. 
Published: February 2025

AbstractDrimenol synthase fromAquimarina spongiae(AsDMS) is a highly unusual bifunctional sesquiterpene synthase that integrates two distinct, sequential isoprenoid processing activities within a single polypeptide chain. AsDMS catalyzes the class II cyclization of farnesyl diphosphate (FPP) to form drimenyl diphosphate, which then undergoes enzyme-catalyzed hydrolysis to yield drimenol, a bioactive sesquiterpene alcohol with antifungal and anticancer properties. Here, we report the X-ray crystal structures of AsDMS and its complex with a sesquiterpene thiol, which are the first of a terpene cyclase-phosphatase. The AsDMS structure exhibits a two-domain architecture consisting of a terpene cyclase β domain and a haloacid dehalogenase (HAD)-like phosphatase domain, with two distinct active sites located on opposite sides of the protein. Mechanistic studies show that dephosphorylation of the drimenyl diphosphate intermediate proceeds through stepwise hydrolysis, such that two equivalents of inorganic phosphate rather than inorganic pyrophosphate are co-products of the reaction sequence. When the AsDMS reaction is performed in H₂18O,18O is not incorporated into drimenol, indicating that the hydroxyl oxygen of drimenol originates from the prenyl oxygen of FPP rather than bulk water. These results correct a mechanistic proposal previously advanced by another group. Surprisingly, AsDMS exhibits unprecedented substrate promiscuity, catalyzing the conversion of substrate mimic farnesyl-S-thiolodiphosphate into cyclic and linear sesquiterpene products. Structural and mechanistic insights gained from AsDMS expand the functional diversity of terpene biosynthetic enzymes and provide a foundation for engineering “designer cyclases” capable of generating new terpenoid products.
Using Artificial Intelligence to Personalize Caring Contact Messages for Recently Discharged Patients: Protocol for a Mixed-Methods Feasibility Study
Authors: Steinberg Rosalie , Amini Jasmine , Wiliszewski Abigail , Chan Prudence Po Ming , Khan Zardar , Martel Anne L. , Starritt Kaleigh , Sinyor Mark , Schaffer Ayal 
Published: February 2025

AbstractSuicide risk is substantially elevated following discharge from a psychiatric hospitalization. Caring Contact (CC) messages are brief messages of hope, support and information sent post-discharge that can improve mental health outcomes, including suicidal ideation and behaviours. Patients who received CCs in previous studies indicated a desire for increased personalization. To support personalization in an efficient and scalable manner, we will pilot the training of a Large Language Model (LLM) that constructs tailored CCs using information extracted from patients’ electronic health records (EHRs) created during the index psychiatric hospitalization. This is a three-phase, mixed-methods study. In phase 1, psychiatric inpatient clinical staff members will be recruited to generate personalized CC messages from representative, de-identified samples of EHRs. This will be considered the control CCs. Clinical staff focus groups will then identify key components of a successful CC message. In phase 2, the control CCs and focus group feedback will be used to train an LLM on a large number of EHRs to produce personalized CC messages. The LLM will be given the same EHRs used in phase 1 to produce CC messages. In phase 3, we will recruit 30 patients with lived experiences (PWLE) of psychiatric hospitalization to evaluate and compare the control CCs with the LLM-generated messages to determine the acceptability of AI-generated CC messages. We hypothesize that LLM-generated CC messages will achieve acceptability ratings at least as positive as the control CC messages. Since CC messages are modifiable and can be altered to suit the needs of various clinical settings, the findings of this study can potentially be broadly generalizable.
Totipotency and high plasticity in an embryo with a stereotyped, invariant cleavage program
Authors: Rock Amber Q. , Srivastava Mansi 
Published: February 2025

AbstractAnimal embryos begin as totipotent zygotes, which undergo cell divisions and produce progeny with restricted fate potentials over time. However, the timing of when totipotency is lost and the processes through which embryonic cells acquire fates vary across species. Embryos with invariant cleavage programs,e.g.of nematodes and spiralians, tend to show early restriction of blastomere potency and limited robustness to perturbation, particularly after asymmetric cleavages have occurred. In contrast, embryos with variant cleavage programs,e.g.of vertebrates, tend to specify fates later in development and correspondingly show higher plasticity at early stages. Here, we investigate the embryos of the acoelHofstenia miamia, which represents an understudied phylum (Xenacoelomorpha) that is distantly related to well-studied developmental systems. Given the invariant ‘duet’ cleavage program observed inH. miamiaembryos, we found unexpected robustness in this species. Isolated 4-cell stage macromeres, the products of an asymmetric, fate specifying cleavage, were totipotent, forming whole organisms upon isolation. Notably, these isolated macromeres produced pharyngeal and neuronal tissues, which they do not produce during normal development. This assay is highly reproducible and can be done at high throughput inH. miamia, making this species an ideal system to investigate the causes of totipotency after specification. Photoconversion-based lineage tracing revealed that rescued cell types are not merely replaced by neoblasts, the adult pluripotent stem cells inH. miamia, suggesting that the macromere’s totipotency is the result of changes in the fate potentials of early embryonic cells. Remarkably, all blastomeres at the 8-cell stage were capable of reprogramming their fates in embryo reconstitution assays. By assembling different subsets of 8-cell stage blastomeres, none of which are totipotent on their own, we determined that a minimal unit of two blastomeres, one macromere that produces gut and neoblasts and one micromere that is specified to produce muscle and epidermis, was sufficient to develop into a hatchling worm. Future studies of this system could identify the precise mechanisms that can enable tremendous plasticity, including post-zygotic totipotency, in an embryo with well-defined cellular lineages.
A Novel Mouse Model of Parkinson’s Disease for Investigating Progressive Pathology and Neuroprotection
Authors: Subramanya Santhosh Kumar , Shekhar Shreshth , Kumar Devu B , Senthil Sathyapriya , Allimuthu Dharmaraja , Luk Kelvin C , Thakur Poonam 
Published: February 2025

AbstractDeveloping animal models that successfully recapitulate the features of progressive Parkinson’s disease (PD) is crucial for understanding disease progression mechanisms and creating effective therapeutic interventions. In this study, we created a mouse model of PD by overexpressing α-synuclein through a combined injection of AAV6-α-synuclein and preformed fibrils (PFFs) into the medial and lateral substantia nigra (SN). We also demonstrated that chronic administration of the c-Abl inhibitor PD180970 provides neuroprotection in this model.Mice injected with the AAV6-α-synuclein and PFF combination showed a progressive loss of dopaminergic (DA) neurons in the SN and their projections in the striatum over 24 weeks. This neuronal loss coincided with a time-dependent accumulation of phosphorylated α-synuclein (p-syn) in the SN. The p-syn aggregates spread to synaptically connected DARPP-32-positive neurons in the striatum and further extended to the cortex. We also observed a contralateral spread of p-syn aggregates. Additionally, α-synuclein overexpression led to a significant increase in activated microglia and astrocytes at all timepoints, with the strongest activation occurring early and gradually diminishing over time.Daily administration of PD180970 significantly reduced the loss of DA neurons caused by α-synuclein injection and decreased the accumulation of p-syn in the SN. PD180970 treatment also reduced the neuroinflammation significantly.Overall, the combined injection of AAV6-α-synuclein and preformed fibrils into the mouse brain establishes a robust PD model, enabling detailed mechanistic studies of the disease. We further demonstrate the model’s utility for chronic neuroprotection studies using the potential drug PD180970, highlighting its broad applicability.Significance StatementThis study establishes a robust mouse model of Parkinson’s disease (PD) by combining AAV6-mediated α-synuclein overexpression and preformed fibrils (PFFs) to replicate key features of PD, such as progressive dopaminergic neuron loss, phosphorylated α-synuclein accumulation, and neuroinflammation. The model captures the spread of pathological aggregates to synaptically connected brain regions, closely mimicking the human disease. By testing the c-Abl inhibitor PD180970, we demonstrate its neuroprotective effects, including reduced neuronal loss, decreased α-synuclein accumulation, and neuroinflammation highlighting its therapeutic potential. This model offers a valuable platform for investigating PD mechanisms and evaluating novel interventions, bridging the gap between preclinical and clinical applications.
An empirical approach for ESG strategies: policy guidelines for entrepreneurs
Authors: Kim Iksuk , Mollah Muhammad , Lee Freddy , Ardon Jessica 
Published: February 2025

PurposeThis study aims to investigate the strategic priorities of environmental, social and governance (ESG) factors in the contexts of the United States, Korea and Bangladesh. Specifically, it examines how entrepreneurs can integrate these priorities into business operations to drive long-term success, including sustainable revenue growth and enhanced brand perception.Design/methodology/approachUsing a ranked-order approach, this study analyzed a sample of 512 responses from the United States (n = 107), Korea (n = 292) and Bangladesh (n = 113) to prioritize ESG factors for each country. We also conducted a one-way ANOVA to measure how individuals ranked ESG by level of importance in three countries.FindingsThe findings of this study reveal that ESG should be tailored to specific business contexts within each country rather than treated as a universal global standard. More specifically, in the United States, entrepreneurs place significant emphasis on all three ESG dimensions – environmental, social and governance. In contrast, entrepreneurs in Korea prioritize governance factors over social and environmental considerations. Meanwhile, in Bangladesh, the focus is primarily on environmental factors.Originality/valueThis study serves as an eye-opener for entrepreneurs in the United States, Korea and Bangladesh, highlighting where they should focus their efforts when considering ESG factors. It is also the first comparative analysis of ESG priorities across developed and developing countries.
A Multi‐Center Real‐World Study of Clinicopathologic Characteristics and Efficacy of the Malignant Mesothelioma in Chinese Population
Authors: Sun Chenrui , Yang Xue , Chen Lan , Bie Zhixin , Kang Runting , Ai Bin , Ma Junling , Zheng Zitong , Liu Haolan , Liu Juanjuan , Zhong Jia , Yu Jiangyong 
Published: February 2025

ABSTRACTObjectiveMalignant mesothelioma (MM) is a rare malignant tumor. To explore the clinicopathological characteristics and efficacy of Chinese population with MM in the real‐world.MethodsTwo hundred and forty‐eight patients diagnosed with MM between September 2007 and August 2024 from three large medical centers (Beijing Hospital, Peking University Cancer Hospital, and Chinese Academy of Medical Sciences Cancer Hospital) were retrospectively analyzed. Kaplan–Meier and Cox regression were performed. Breast cancer gene 1‐associated protein 1 (BAP1) status was evaluated.ResultsChinese population with MM had a lower diagnostic age, higher proportion of youth and female, more advanced stage and lower expression of characteristic markers. The median progression‐free survival (mPFS) and median overall survival (mOS) were 8.90 and 25.60 months for the first‐line treatment, and 3.28 and 19.50 months for the second‐line. The first‐line immunotherapy provided a relatively higher objective response rate (33.3% vs. 20.5%, p = 0.402) and a trend to prolong mPFS (12.10 vs. 9.20 months, p = 0.345) and mOS (NA vs. 23.90, p = 0.185) compared with chemotherapy. Bevacizumab combined with chemotherapy relatively prolonged mPFS (10.47 vs. 7.93 months, p = 0.074) and mOS (31.30 vs. 23.20 months, p = 0.673) than chemotherapy alone. Carboplatin relatively improved mPFS than cisplatin (10.87 vs. 8.87 months, p = 0.185). Age and histologic type were predictors for PFS, and gender, histologic subtype, and CK5/6 were prognosis factors for OS. Briefly, 17.78% patients existed BAP1 deletions and correlated with OS benefit.ConclusionChinese population with MM present unique clinicopathologic characteristics and could benefit from the first‐line immunotherapy and bevacizumab combined with chemotherapy. Gender, histologic subtype, and CK5/6 are prognosis factors for OS. BAP1 deletions correlate with OS benefit.
Negative Effect of Gst‐35 on the Health Span of Caenorhabditis elegans Through Lysosomal Dysfunction via the Pmk‐1 and Skr Genes
Authors: Gao Yehui , Zhang Xinyun , Wei Congmin , Lin Hongru , Wu Mengchen , Ma Botian , Jiang Jinyun , Li Shan , Wang Hongbing 
Published: February 2025

ABSTRACTAs global life expectancy increases, the focus has shifted from merely extending lifespan to promoting healthy aging. GSTA1, GSTA2, and GSTA3 (GSTA1‐3), members of the alpha class of glutathione S‐transferases, are involved in diverse biological processes, including metabolism and immune regulation, highlighting their potential influence on human health span and lifespan. In this study, we employed Caenorhabditis elegans as a model organism to investigate the role of gst‐35, an ortholog of mammalian GSTA1‐3, in healthy aging. Our results demonstrated that gst‐35 overexpression has detrimental effects on multiple physiological functions in nematodes. Specifically, gst‐35 overexpression significantly reduced lifespan, impaired development and growth, and substantially diminished reproductive capacity, physical fitness, and stress resistance. In contrast, gst‐35 knockout partially enhanced physical fitness and stress resistance. Comprehensive RNA‐sequencing transcriptome analysis revealed that gst‐35 overexpression disrupted metabolic homeostasis and induced lysosomal dysfunction. These effects were mediated through the activation of the pmk‐1 signaling pathway and suppression of skr genes, which collectively impaired healthy aging processes. These findings illuminate the complex role of gst‐35 in aging and provide valuable insights into the molecular mechanisms underlying healthy aging, offering potential targets for interventions aimed at promoting health span.
Gallbladder cholangiocyte organoids
Authors: Dutta Ankita , Chowdhury Nandita , Chandra Shinjini , Guha Payel , Saha Vaskar , GuhaSarkar Dwijit 
Published: February 2025

AbstractOrganoids are miniature three‐dimensional (3D) organ‐like structures developed from primary cells that closely mimic the key histological, functional, and molecular characteristics of their parent organs. These structures self‐organize through cell‐cell and cell‐matrix interaction in culture. In the last decade, organoids and allied 3D culture technologies have catalyzed studies involving developmental biology, disease biology, high‐throughput drug screening, personalized medicine, biomarker discovery, tissue engineering, and regenerative medicine. Many organoid systems have been generated from the gastrointestinal system, for example, intestine, stomach, liver, pancreas, or colon. Gallbladder cancer (GBC) is the most common and highly aggressive form of biliary tract cancer. GBC is rare in the west but has a high incidence in South America and India. Prolonged chronic inflammation is implicated in the pathogenesis of GBC but the driving molecular pathways leading to neoplasia are not well understood. Gallbladder cholangiocyte organoids (GCO) will facilitate the understanding of the evolution of the disease and novel therapeutic strategies. In this review, we have discussed alternative methodologies and culture conditions developed to generate GCO models, applications that these models have been subjected to and the current limitations for the use of GCOs in addressing the challenges in GBC research.
Evaluation of the Photobiomodulation Treatment With the TINI Laser Device for Managing Chronic High‐Frequency Tinnitus: A Randomised Controlled Trial
Authors: Choi Ji Eun , Lee Min Young , Jung Jae Yun 
Published: February 2025

ABSTRACTIntroductionTo evaluate the efficacy of the TINI laser device, a photobiomodulation (PBM) therapy, for managing chronic high‐frequency tinnitus in patients with unilateral or bilateral tinnitus.MethodsA randomised, single‐blind, placebo‐controlled clinical trial was conducted with 38 participants. Subjects were divided into three groups: The TINI 1 group received eight active laser treatments over 4 weeks, the TINI 2 group received four active treatments followed by four sham treatments, and the control group received only sham treatments. The Tinnitus Handicap Inventory (THI), Tinnitus Functional Index (TFI) and Tinnitus Magnitude Index (TMI) were used to assess tinnitus‐related outcomes. Psychological assessments were also conducted to measure levels of depression, stress and anxiety.ResultsSignificant improvements were observed in the emotional subscale of the THI, and in the loudness and perception scores of the TMI in the TINI 1 group. The TINI 2 group showed significant reductions in TFI and TMI scores following active treatments, although these effects diminished after sham treatments. No placebo effects were observed except for TFI scores in the control group.ConclusionThe study indicates that intermittent PBM therapy using the TINI laser may be effective in managing chronic tinnitus. Further research is necessary to explore long‐term efficacy and safety.Trial Registration: cris.nih.go.kr identifier: PRE20240926‐004