bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lenvatinib activates anti-tumor immunity by suppressing immunoinhibitory infiltrates in the tumor microenvironment of advanced hepatocellular carcinoma
Authors: Yamauchi Masami , Ono Atsushi , Amioka Kei , Fujii Yasutoshi , Nakahara Hikaru , Teraoka Yuji , Uchikawa Shinsuke , Fujino Hatsue , Nakahara Takashi , Murakami Eisuke , Okamoto Wataru , Miki Daiki , Kawaoka Tomokazu , Tsuge Masataka , Imamura Michio , Hayes Nelson , Ohishi Waka , Kishi Takeshi , Kimura Mizuki , Suzuki Natsumi , Arihiro Koji , Aikata Hiroshi , Chayama Kazuaki , Oka Shiro 
Published: March 2023

Abstract
Lenvatinib has been expected as an immunomodulator based on its marked anti-angiogenic property in immunotherapy for solid cancers. However, the mechanism by which the tumor immune microenvironment is edited in human cancer tissues remains to be elucidated. Here, we analyzed the multi-omics of serial tumor and blood samples during lenvatinib monotherapy in 51 patients with advanced hepatocellular carcinoma. Lenvatinib yielded survival benefits regardless of baseline immune subtypes as determined by expression of the extracted RNAs. While immune signatures associated with T-cell functions and interferon responses were enriched in the early phase of treatment, signatures associated with immunoinhibitory cells were downregulated along with efficient vascular endothelial growth factor receptor and fibroblast growth factor receptor blockades. These findings were consistently supported by imaging mass cytometry, T-cell receptor repertoire analysis and kinetics of circulating proteins. Our study also identified interleukin-8 and angiopoietin-2 as possible targets of intervention to overcome resistance to existing immunotherapies.
K-means clustering of outpatient prescription claims for health insured in Iran
Authors: Monahhed Shekoofeh , Sefiddashti Sara Emamgholipour , Minaei Behrouz , Shahali Zahra 
Published: March 2023

Abstract
Objective The segmentation of consumers based on their behavior and needs is the most crucial action of the health insurance organization. This study's objective is to cluster Iranian health insureds according to their demographics and data on outpatient prescriptions.
Setting The population in this study corresponded to the research sample. The Health Insurance Organization's outpatient claims were registered consecutively in 2016, 2017, 2018, and 2019 were clustered.
Design The k-means clustering algorithm was used to cross-sectionally and retrospectively analyze secondary data from outpatient prescription claims for secondary care using Python 3.10.
Participants The current analysis transformed 21 776 350 outpatient prescription claims from health insured into 193 552 insureds.
Results Insureds using IQR were split into three classes low, middle, and high risk. Based on the silhouette coefficient the insureds of all classes were divided into three clusters. all data for a period of four years, the first through third clusters, there were 21 799, 7170, and 19 419 insureds in the low risk class. Middle risk class had 48 348,23 321, 25 107 insureds and 14 037, 28 504, 5847 insured in the high risk class were included. For the first cluster of low-risk insureds: the total average cost of prescriptions paid by the insurance for the insureds was 211$, the average age was 26 years, the average franchise 88.5US$, the average number of medications and prescriptions was 409 and 62, the total average costs of prescriptions Outpatient was 302.5 US$, the total average number of medications for acute and chronic disease was 178 and 215 respectively. The majority of insureds were men and those who were part of the householder's family.
Conclusions By segmenting insurance customers insurers can set insurance premium rates, controlling the risk of loss which improves their capacity to compete in the insurance market.
Developing emotional preparedness and mental resilience through high-fidelity simulation: A ‘Bridge Too Far’ for institutions teaching major trauma management and mass-casualty medicine?
Authors: Newton Jon , Smith Andrew 
Published: March 2023

Abstract
Clinical acumen represents only part of being adequately equipped to attend a major incident. The emotive sights, sounds and smells inherent of these dynamic environments are all-encompassing experiences and thus responders must also be armed with the emotional preparedness to perform their clinical or managerial duties effectively; as well as the mental resilience to facilitate professional continuance. Despite this, limited training and a sparsity of evidence exists to guide developments within this domain.
Background: Historically, major incident training has focused on clinical principles; but irrespective of how comprehensive this teaching might be, or how fortuitously the learning materials meet national guidelines, they are of little consequence if tandem steps to cultivate mental resilience and emotional preparedness are absent. Effectively dovetailing these three elements is essential if teaching institutions are to properly prepare students for real-world practice. High-Fidelity Simulation (HFS) has a growing reputation as an effective means of bridging important gaps between theory and practice; and to help identify if this modality could cultivate these advancements, we exposed studentsto a large-scale HFS and conducted an evaluation-based study to better understand their lived experience. The primary aim was to ascertain the impact on clinical acumen, emotional preparedness and mental resilience; to help develop teaching and learning practices
Methods: Quantitative data was obtained from a sample of 108 students undertaking paramedic science, physician associate studies and adult nursing. Self-completed questionnaires incorporating a 7-point Likert scale were utilised; and each student’s strength of agreement was rated against a series of statements surrounding acquisition of clinical acumen, emotional preparedness and mental resilience. Ethical approval was granted and SPSS v28 employed to analyse the data.
Results: 91% of students agreed the combination of theoretical training and HFS provided made them feel clinically prepared to attend a real major incident; 86% agreed this experience had developed their mental resilience and 90% agreed that they felt emotionally prepared to attend a major incident.
Conclusion: HFS is a practicable teaching and learning tool; and effective in developing clinical acumen, mental resilience and emotional preparedness in learners training to work in disaster environments or emergency medicine settings.
GREB1 isoform 4 is specifically transcribed by MITF and required for melanoma proliferation
Authors: Kikuchi Akira , Shinzawa Koei , Matsumoto Shinji , Sada Ryota , Harada Akikazu , Saitoh Kaori , Kato Keiko , Ikeda Satsuki , Hirayama Akiyoshi , Yokoi Kazunori , Tanemura Atsushi , Nimura Keisuke , Ikawa Masahito , Soga Tomoyoshi 
Published: March 2023

Abstract
Growth regulation by estrogen in breast cancer 1 (GREB1) is involved in hormone-dependent and -independent tumor development (e.g., hepatoblastoma). In this study, we found that a GREB1 splicing variant, isoform 4 (Is4), which encodes C-terminal half of full-length GREB1, is specifically expressed via microphthalmia-associated transcription factor (MITF) in melanocytic melanoma, and that two MITF-binding E-box CANNTG motifs at the 5’-upstream region of GREB1 exon 19 are necessary for GREB1 Is4 transcription. MITF and GREB1 Is4 were strongly co-expressed in approximately 20% of the melanoma specimens evaluated (17/89 cases) and their expression was associated with tumor thickness. GREB1 Is4 silencing reduced melanoma cell proliferation in association with altered expression of cell proliferation-related genes in vitro. In addition, GREB1 Is4 targeting by antisense oligonucleotide (ASO) decreased melanoma xenograft tumor formation and GREB1 Is4 expression in a BRAFV600E; PTENflox melanoma mouse model promoted melanoma formation, demonstrating the crucial role of GREB1 Is4 for melanoma proliferation in vivo. GREB1 Is4 bound to CAD, the rate-limiting enzyme of pyrimidine metabolism, and metabolic flux analysis revealed that GREBI Is4 is necessary for pyrimidine synthesis. These results suggest that MITF-dependent GREB1 Is4 expression leads to melanoma proliferation and GREB1 Is4 represents a new molecular target in melanoma.
Energy Band Structure of Relativistic Quantum Plasmon Excitation
Authors: Akbari-Moghanjoughi Massoud 
Published: March 2023

Abstract
In this paper, we use the effective Schrodinger-Poisson and square-root Klein-Gordon-Poisson models to study the quantum and relativistic quantum energy band structure of finite temperature electron gas in a neutralizing charge background. Based on the plasmon band gap appearing above the Fermi level, new definitions on plasmonic excitations and plasma parameters in a wide electron temperature-density regime is suggested. The new equation of state (EoS) for excited electrons to the plasmon band leads to novel aspects of relativistic collective quantum excitations such as the plasmon black-out and quantum pressure collapse, which are studied using both non-relativistic and relativistic quantum models. The plasmon black-out effect may be used to explain why metallic elements do not show collective behavior at low temperatures. The model can be used to predict phases of matter in which the plasmonic activities are shut down, hence, it may behave like a mysterious dark matter. On the other hand, the energy band structure model predicts the plasmon pressure collapse in temperature-density coordinates matching that of a white dwarf star. The prediction of energy band structure of collective quantum excitations may have direct implications for the inertial confinement fusion (ICF), the EoS of warm dense matter (WDM) and evolution of stellar and other unknown cosmological structures. It is found that predictions of non-relativistic and relativistic quantum excitation models closely match up to temperature-density of degenerate stars, which confirms the relevance of non-relativistic plasmon models used in the warm and dense matter regime. The effect of positron on band structure of collective quantum excitations is also studied.
Resolving Quantum Interference Black-Box through Attosecond Photoionization Spectroscopy
Authors: Gong Xiaochun , Jiang Wenyu , Armstrong Gregory , Han Lulu , Xu Yidan , Zuo Zitan , Tong Jihong , Lu Peifen , Dahlström Jan Marcus , Ueda Kiyoshi , Brown Andrew , Hart Hugo van der , Wu Jian 
Published: March 2023

Abstract
Multiphoton light-matter interactions invoke a so-called ‘Black Box’ in which the experimental observations contain the quantum interference between multiple pathways (1–3). Here, we employ attosecond coincidence metrology (4, 5) with a partial wave polarization manipulator to deduce the pathway interference within this quantum ‘Black Box’ (6) for two-photon ionization of neon and argon. The angle-dependent and attosecond time-resolved photoelectron spectra are measured across a broad energy range. Two-photon phase shifts for each partial wave are reconstructed through the comprehensive analysis of these photoelectron spectra. We resolve the quantum interference between the p → d → p and p → s → p ionization pathways, in agreement with our theoretical simulations. Our approach thus provides a microscope to look inside the ‘black box’ of pathway interference in ultrafast dynamics of atoms, molecules, and condensed matter.
Water Restriction Alters the Expression of Calcium Transporters in Eucalypt Roots
Authors: Barros Patricia , Valadares Samuel Vasconcelos , de Barros Nairam Félix , de Oliveira Hellen Oliveira , Araújo Wagner L. , Pita-Barbosa Alice 
Published: March 2023

Abstract
Background and Aims
Calcium (Ca) plays an important role to increase drought tolerance in plants. We evaluated the effect of water restriction and Ca supply on the expression of Ca transporters, on Ca acquisition, allocation and its effects in eucalypt responses to drought.
Methods
Drought-tolerant eucalyptus plants (Eucalyptus urophylla x Eucalyptus camaldulensis - clone VM01) were grown in a hydroponic system in the presence or absence of Ca and subjected or not to water restriction using polyethylene glycol. Ca concentration by plants, gas exchange, plant growth, and the expression of the ACA11 and MCA1 Ca transporters were evaluated.
Results
Water restriction increased the expression of ACA11 (vacuole Ca transporter) and decreased the expression of MCA1(endodermal Ca transporter), in eucalypt roots. Water restriction increased Ca content in plant roots and Ca supply ameliorated the negative effects of water stress.
Conclusion
Water restriction alters the expression of Ca transporters in eucalypt roots altering the Ca allocation pattern and improving root growth and water status. Although caution must be taken, our findings bring novel evidence of an important mechanism that favors survival of drought-tolerant woody plants under water deficit.
Perioperative and frailty outcomes after total knee arthroplasty, an observational study
Authors: Tan Boon Hian , Stacey Simon , Poon Kein Boon 
Published: March 2023

Abstract
Background
Total knee arthroplasty is a common procedure with an increasing demand and there is an increasing proportion of aged people who go through total knee arthroplasty. Frailty is associated with adverse perioperative outcomes in the aged. This report seeks to understand the associations of preoperative frailty status and comorbid conditions in relation to their clinical and healthcare outcomes after total knee arthroplasty. It also examines if frailty can be improved after surgical treatment of osteoarthritis.
Methods
Retrospective cohort study, outcomes assessed over 2 years. Frailty defined by the Clinical Frailty Score.
Results
96 patient records were assessed, of which 13 (13.5%) patients were robust and 83 (86.5%) patients were pre-frail or frail. 2 years after total knee replacement, the number of robust patients increased to 58 (61.1%) patients showing a reversal of frailty in 47.6% of patients.
Conclusions
We report that total knee arthroplasty in prefrail and frail patients is a safe procedure that leads to improvement with subsequent reversal of frailty in 47.6% of patients two years after operation.
Neoadjuvant Chemotherapy or Combined Chemo-Radiation Therapy of Pancreatic Ductal Adenocarcinoma Differentially Shift Immune Activation, ECM Composition, Energy Metabolism, and Ribosomal Proteins of the Residual Tumor Mass
Authors: Stillger Maren Nicole , Bronsert Peter , Brombacher Eva , Kreutz Clemens , Werner Martin , Tang Laura , Timme-Bronsert Sylvia , Schilling Oliver 
Published: March 2023

AbstractBackground: Pancreatic ductal adenocarcinoma (PDAC) belongs to the deadliest malignancies worldwide. Curative therapeutic options are limited as the majority of patients are diagnosed at advanced stages that disqualify them for surgical resection. Currently, neoadjuvant therapy regimens are being discussed as they may offer improved tumor resectability. Although features of the tumor biology (e.g. molecular markers) may potentially guide adjuvant therapy, little is known about the biological tumor alterations after neoadjuvant therapy. Methods: We performed mass spectrometry-based proteomics to characterize the proteomes of 67 PDAC resection specimens of patients who received either neoadjuvant chemo or chemo-radiation therapy. We employed data-independent acquisition (DIA), yielding a proteome coverage in excess of 3,500 proteins. Further, we combined our dataset with the proteomic PDAC CPTAC dataset to compare treatment-naïve and neoadjuvant treated residual PDAC. Results: The two neoadjuvant therapies yielded highly distinguishable proteome profiles of the residual tumor mass. Components of the immune system (e.g., complement cascade and immunoglobulins) and the extracellular matrix are increased in the chemo-radiation group, ribosomal proteins, the protein biosynthesis, degradation via the proteasome, and metabolic turnover in the chemotherapy group. Further analyses on the correlation of protein expressions and patient overall survival identified several proteins of the immune system as potential prognostic candidate biomarkers in both groups. The comparison of treatment-naïve and neoadjuvant treated tumors revealed an increase of ribosomal translation and the aldehyde dehydrogenase family. Conclusion: We present the first proteomic characterization of the residual PDAC tumor mass after neoadjuvant chemo and combined chemo-radiation therapy as well as potential candidates of protein markers associated with survival. We conclude that residual PDAC exhibits fundamentally different proteome profiles between both neoadjuvant therapies with immune system components correlating with overall survival. Notably, ribosomal translation and aldehyde dehydrogenases are suggested to be activated upon neoadjuvant treatment.
Assessing efficiency of fine-mapping obesity associated variants through leveraging ancestry architecture and functional annotation using PAGE and UKBB Cohorts
Authors: Anwar Mohammad Yaser , Graff Mariaelisa , Highland Heather M. , Smit Roelof , Wang Zhe , Buchanan Victoria L. , Young Kristina L. , Kenny Eimear E. , Fernandez-Rhodes Lindsay , Liu Simin , Assimes Themistocles , Garcia David O. , Daeeun Kim , Gignoux Christopher R. , Justice Anne E. , Haiman Christopher A. , Buyske Steve , Peters Ulrike , Loos Ruth , Kooperberg Charles , North Kari E. 
Published: March 2023

Abstract
Inadequate representation of non-European ancestry populations in genome-wide association studies (GWAS) has limited opportunities to isolate functional variants. Fine-mapping in multi-ancestry populations should improve the efficiency of prioritizing variants for functional interrogation. To evaluate this hypothesis, we leveraged ancestry architecture to perform comparative GWAS and fine-mapping of obesity related phenotypes in European ancestry populations from the UK Biobank (UKBB) and multi-ancestry samples from the Population Architecture for Genetic Epidemiology (PAGE) consortium with comparable sample sizes. In 10 of the investigated regions with genome wide significant associations for obesity related traits, fine-mapping in our ancestrally diverse sample led to 95% and 99% credible sets (CS) with fewer variants than in the European ancestry sample. Lead fine-mapped variants in PAGE regions had higher average coding scores, and higher average posterior probabilities for causality compared to UKBB. Importantly, 99% CS in PAGE loci contained strong expression quantitative trait loci (eQTLs) in adipose tissues or harbored more variants in tighter linkage disequilibrium (LD) with eQTLs. Results also suggested three novel candidates for functional effect on waist-to-hip ratio adjusted for BMI (WHRBMI-adj) (rs5781117 near gene RP11-392O17.1, rs10187501 in gene COBLL1, and rs1964599 near gene CCDC92), all within the 99% CS. Leveraging ancestrally diverse populations with heterogeneous ancestry architectures, coupled with functional annotation, increased fine mapping efficiency and performance, and reduced the set of candidate variants for consideration for future functional studies. Significant overlap in genetic causal variants across populations suggest generalizability of genetic mechanisms underpinning obesity related traits across populations.
Deep venous thrombosis and hyponatremia associated with citalopram use for behavioral symptoms in Parkinson’s disease: A case report
Authors: Albalawi Afaf 
Published: March 2023

Abstract
Background:
Evidence is limited regarding the optimal therapeutic approach for neuropsychiatric symptoms associated with Parkinson’s disease dementia (PDD). Selective serotonin reuptake inhibitors (SSRIs) are widely used for mood disorders and behavioral symptoms in older adults with cognitive impairment, but they have limited efficacy in patients with PDD. The effect of SSRIs on hemostasis is also unclear. This report describes a patient with PDD who developed deep venous thrombosis (DVT) and hyponatremia after initiating citalopram (an SSRI) treatment.
Case Presentation:
An 86-year-old woman with PDD presented to our emergency department with altered mental status, generalized weakness, and left lower leg swelling. Citalopram was begun 4 weeks previously for behavioral changes and was discontinued 2 days before presentation because of excessive fatigue. At presentation, her plasma sodium level was 123 mg/dL. Brain computed tomography showed age-related changes. Doppler ultrasound revealed a DVT in the left lower leg. The patient was treated with hypertonic saline and intravenous heparin. After normalization of her sodium, she was discharged on donepezil and apixaban. At follow-up, her sodium remained normal, and her cognition and behavior were noticeably improved.
Conclusion:
Older adults with Parkinson’s disease are sensitive to adverse effects of psychotropic agents, especially SSRIs, which are not recommended first-line agents for behavioral symptoms in PDD. Upon initiating SSRIs in older patients with functional decline and multiple comorbidities, physicians should consider VTE prophylaxis, tailored to the patient’s needs and risk factors of bleeding or thrombosis. Physical activities should also be maintained as much as possible.
The metazoan parasite communities of flounders as indicators of chemical pollution in the southern Gulf of Mexico: taxonomic and trait-based approaches
Authors: Martinez Victor , Ocaña Frank A , Soler-Jimenez Lilia C , May-Tec Ana L , Centeno-Chale Oscar A , Aguirre-Macedo M. Leopoldina 
Published: March 2023

Abstract

Metazoan parasite species composition changes with an increase in geographical distance, but not their functional traits. We compared the performance of the taxonomy and functional traits of metazoan parasites as bioindicators of chemical pollution along the continental shelf of the South Gulf of Mexico (sGOM). Parasites were obtained from Syacium gunteri and Syacium papillosum, together with hydrocarbons, heavy metals and physicochemical variables from water and sediments during 12 oceanographic cruises. We compared regions without oil extraction: Veracruz-Tamaulipas (VT) and Yucatan shelf (YS) and one with it, north-western end of YS to Coatzacoalcos, Veracruz (NYV). In addition to taxonomy, the trait-based approach community-weighted means (CWM) was performed. Species richness was compared between regions using rarefaction curves, and the taxonomic and trait composition between regions were compared using multivariate analyses. The relationships between taxonomy, traits and environmental variables were tested using BIOENV. We identified 57 species and body tegument, transmission, feeding mode, life stage and attachment organs as informative traits. By rarefaction, VT and YS had higher species richness than NYV for both hosts, but there were questionable values due to the small fish sample size. Except for YS, significant parasite community variability was detected by PERMANOVA using taxonomy and CWM for all regions, hosts and interactions. The same group of larval species was detected by SIMPER for regions and hosts, suggesting low functional turnover. BIOENV showed that polyaromatic hydrocarbons explained most of the variability. Taxonomy and functional traits produced similar explained variance, but the latter saved time analysis and financial resources.