bluuebunny/crossref_metadata_2025_split huggingface dataset:
Celastrol promotes DNA damage and apoptosis in uterine corpus endometrial carcinoma via promotion of KAT2B-mediated RBPJ acetylation and repression of MCM4 transcription
Authors: Pei Lipeng , Zhu Yan , Li Wenpeng , Xu Bin , Sun Jingli 
Published: February 2025

Abstract

Background
Uterine corpus endometrial carcinoma (UCEC) is one of the most frequent female genital malignant tumors. Targeting DNA damage and cell apoptosis are regarded as effective ways for UCEC therapy. Celastrol is a natural anti-cancer product from the Celastraceae plant family, while its role in UCEC has not been investigated.

Methods
UCEC cell lines Ishikawa and HEC-1-A were applied and treated with different concentrations of Celastrol. The appropriate and nontoxic concentrations were used for the subsequent experiments. Functional experiments analyzed the cell viability, cell cycle distribution, DNA damage, apoptosis and the expression of related proteins. We determined tumor growth in xenograft nude mice. Bioinformatic analysis, protein coimmunoprecipitation (Co-IP), luciferase assay, cell experiments were performed to reveal the relationship of Celastrol/KAT2B/RBPJ/MCM4 in UCEC.

Results
Treatment of Celastrol inhibited cell viability in a dose-dependent manner, and caused cell cycle arrest, accompanied by the downregulation of CDK2 and cyclin E expression and the upregulation of p21. Celastrol treatment resulted DNA damage and apoptosis in cultured cells, as demonstrated by increased number of TUNEL-positive cells, activity of caspase-3 and expression of cleaved-caspase-9, cleaved PARP1 and γ-H2AX. In xenograft nude mice, Celastrol also repressed tumor growth. Furthermore, lysine acetyltransferase KAT2B was a putative target of Celastrol, and its expression was upregulated by Celastrol in vitro and in vivo. Overexpression of KAT2B in UCEC inhibited cell proliferation and increased DNA damage and apoptosis. KAT2B knockdown overcame the anti-proliferative and pro-apoptotic roles of Celastrol. Moreover, Co-IP demonstrated that KAT2B bound to RBPJ, a transcriptional repressor, and increased the acetylation of RBPJ. RBPJ could bind to the MCM4 promoter to suppress the luciferase activity. Further functional analysis revealed that the functions of KAT2B in UCEC cell proliferation, DNA damage and apoptosis were mediated by MCM4, and Celastrol enhanced RBPJ acetylation and reduced MCM4 expression.

Conclusions
These results underscore that Celastrol is a promising anti-cancer agent in UCEC with preferential anti-proliferative, pro-apoptotic and DNA damage effects through the KAT2B/RBPJ/MCM4 axis, and KAT2B is a promising therapeutic target for UCEC.

Graphical abstract
Exploring proteomic immunoprofiles: common neurological and immunological pathways in multiple sclerosis and type 1 diabetes mellitus
Authors: Cano-Cano Fátima , Lara-Barea Almudena , Cruz-Gómez Álvaro Javier , Martín-Loro Francisco , Gómez-Jaramillo Laura , González-Montelongo María Carmen , Roca-Rodríguez María Mar , Beltrán-Camacho Lucía , Forero Lucía , González-Rosa Javier J. , Durán-Ruiz Mª Carmen , Arroba Ana I. , Aguilar-Diosdado Manuel 
Published: February 2025

Abstract

Background
Interest in the study of type 1 diabetes mellitus (T1DM) and multiple sclerosis (MS) has increased because of their significant negative impact on the patient quality of life and the profound implications for the health care system. Although the clinical symptoms of T1DM differ from those of MS, such as pancreatic β-cell failure in T1DM and demyelination in the central nervous system (CNS) in MS, both pathologies are considered as autoimmune-related diseases with shared pathogenic pathways, which include autophagy, inflammation and degeneration, among others. Considering the challenges in obtaining pancreatic β-cells and CNS tissue from patients with T1DM and MS, respectively, it is fundamental to explore alternative methods for evaluating disease status. Proteomic analysis of peripheral blood mononuclear cells (PBMCs) is an ideal approach for identifying novel and potential biomarkers for both autoimmune diseases.

Methods
We conducted a proteomic analysis of PBMCs from patients with T1DM and relapsing remitting Multiple Sclerosis (herein forth MS) patients (n = 9 per condition), using a label-free quantitative proteomics approach. The patients were diagnosed following the American Diabetes Association (ADA) criteria for T1DM and McDonald criteria for MS respectively, and were aged over 18 years and more than 2 years from the onset respectively.

Results
A total of 2476 proteins were differentially expressed in PBMCs from patients with T1DM and MS patients compared with those form healthy controls (H). Predictive analysis highlighted 15 common proteins, up- or downregulated in PBMCs from patients with T1DM and MS patients vs. healthy controls, involved in the immune system activity (BTF3, TTR, CD59, CSTB), diseases of the neuronal system (TTR), signal transduction (STMN1, LAMTOR5), metabolism of nucleotides (RPS21), proteins (TTR, ENAM, CD59, RPS21, SRP9) and RNA (SRSF10, RPS21). In addition, this study revealed both shared and distinct molecular patterns between the two conditions.

Conclusions
Compared with H, patients with T1DM and MS presented a specific expression pattern of common proteins has been identified. This pattern underscores the shared mechanisms involved in their immune responses and neurological complications, alongside dysregulation of the autophagy pathway. Notably, CSTB has emerged as a differential biomarker, distinguishing between these two autoimmune diseases.
Exploring the association between statins use or HMG-CoA reductase inhibition and migraine: a systematic review and meta-analysis
Authors: Makhlouf Hamdy A. , Hassan Amr K. , Almosilhy Nereen A. , Osman Ahmed S.A. , Ramadan Shrouk , Abouelmagd Moaz Elsayed 
Published: February 2025

Abstract

Background
Statins or 3‑hydroxy‑3‑methyl‑glutarylcoenzyme A (HMG‑CoA) reductase inhibitors are medications that act by reducing the cholesterol content of liver cells Moreover, statins have been found to improve endothelial function and reduce vascular wall inflammation. A growing body of research suggests that statins are associated with less risk of migraine, and they can be used to treat symptoms. However, the evidence has been inconclusive, so we aim to investigate the nature and strength of the effect of statins on the prevention and prophylaxis of migraines.

Methods
We conducted a comprehensive systematic search across multiple electronic databases, including PubMed, Scopus, Web of Science, and the Cochrane Library, from inception until October 2024, to include studies on the association between statins use and migraine. The outcomes of interest involved the association of the HMG-CoA reductase gene with the risk of migraine, as well as the association and efficacy of statins in migraine patients.

Results
Thirteen studies were included in our systematic review. Mendelian Randomization (MR) studies revealed that expression of HMGCR was associated with an increased risk of migraine with odds ratio (OR) ranging from 1.38 to 1.55 (P < 0.001). Three observational studies investigating the relationship between statins and migraine risk demonstrated a protective effect, with odds ratios ranging from 0.73 to 0.94 (P < 0.001). The findings suggest a significant reduction in overall migraine risk, particularly for migraines with aura and in patients with higher vitamin D levels. Meta-analysis of randomized controlled trials (RCTs) showed that statins significantly reduced monthly migraine frequency (MD= -3.16, 95%CI= [-5.79, -0.53]; p = 0.02, I2 = 79%; P = 0.03). RCTs supported the efficacy of statins in reducing migraine frequency, days, and intensity compared to placebo.

Conclusions
Statins, already well-established for cardiovascular benefits, emerge as a promising dual-purpose therapy for many neurological disorders. The association between the HMGCR gene and increased migraine risk, coupled with the possible efficacy of statins in reducing migraine frequency, may open new avenues for migraine prophylaxis. However, the variability in study design hinders definitive conclusions, so larger studies with longer follow-ups are required to ascertain both findings.
Safety and accuracy of digitally supported primary and secondary urgent care telephone triage in England: an observational study using routine data
Authors: Sexton Vanashree , Grimley Catherine , Dale Jeremy , Atherton Helen , Abel Gary 
Published: February 2025

Abstract

Background
England’s urgent care telephone triage system comprises non-clinician-led primary triage (NHS111) assessment followed, for approximately 50% patients, by clinician-led secondary triage. Digital decision support is utilised by both. We explore the system’s safety and accuracy relative to patients’ use of emergency departments (EDs) and in-patient care in the subsequent 24 h.

Methods
Descriptive analyses were used to investigate outcomes of 98,946 calls that underwent primary and secondary triage. We investigated sensitivity (safety) and specificity (efficiency/accuracy) in relation to subsequent ED attendance and in-patient hospital admission. Mixed effects regression models were used to explore potential under-estimation of clinical risk (under-triage).

Results
Sensitivity was greater in primary triage, whilst specificity was greater in secondary triage. The positive predictive value for attending ED after being assigned a triage urgency level of within 2 h was 46.0% for secondary triage compared to 20.7% for primary triage; for inpatient admission it was 18.0% and 9.2% respectively. 1.5% (n = 1468) patients triaged to same-day or less urgent care at secondary triage were subsequently admitted for in-patient care. In relation to in-patient admission within 24 h, there were greater odds of potential under-triage for calls made between midnight and 6am, and for shorter duration calls, respectively OR = 1.71; CI:1.32–2.21 and OR: 1.66, CI: 1.30–2.11. The service provider (e.g., service provider 2, OR = 5.61; CI:3.36–9.36) and individual clinician (OR covering the 95% midrange = 16.15) conducting triage were the characteristics most greatly associated with this potential under-triage; p < 0.001 for all.

Conclusions
Clinician-led urgent care triage is more accurate in identifying the likelihood of a need for ED or in-patient care than non-clinician triage. Non-clinician primary triage is risk averse, reflected in its high sensitivity but low specificity. Service and clinician characteristics associated with potential under-triage need further investigation to inform ways of improving the safety and effectiveness of urgent care telephone triage.

Clinical trial number
Not applicable.
“It was simply disturbing“ - evaluation of the stress factors of nursing staff on special COVID-19 wards during the pandemic: a qualitative study
Authors: Kiefer Lea , Volberg Christian , Graw Jan Adriaan , Bösner Stefan 
Published: February 2025

Abstract

Background
The COVID-19 pandemic has posed enormous challenges for healthcare systems worldwide. The strain on nursing staff working in special COVID-19 wards during the pandemic increased dramatically. To support nursing staff more effectively in similar situations in the future, it is important to identify specific stress factors to design effective support measures.

Objective
To collect the experiences and lessons learned from nursing staff who have been affected by COVID-19 pandemic on a special COVID-19 ward that were perceived as stressful. The findings should contribute to the development of specific support measures for healthcare professionals.

Design
Qualitative interview study.

Setting
We interviewed 14 members of nursing staff who worked on COVID-19 wards at two University Hospitals about their working experiences during the pandemic.

Results
We were able to identify 10 key stress factors. These included an increased workload, communication deficits, a difficult personnel situation, subjective pressure, the establishment of a new ward, a shortage of material resources, inadequate hygiene conditions, a lack of opportunities to cope with the situation, the absence of relatives and decision making.

Conclusion
The identification of various stress factors highlights the urgent need for comprehensive support measures. These measures could include concepts for dealing with physical and psychosocial stress, the provision of resources and sufficient personnel support. It remains crucial to proactively take preventive and supportive measures to reduce the burden and moral distress of nursing staff and protect their health in the long term. Despite the pandemic, the implications of our findings remain relevant for the future.
Hospitalization outcomes in people living with HIV on Dolutegravir-based regimen in Mwanza, Tanzania: a comparative cohort
Authors: Kisigo Godfrey A. , Barongo Eric , Issarow Benson , Cichowitz Cody , Wajanga Bahati , Kalluvya Samuel , Peck Robert N. 
Published: February 2025

Abstract

Introduction
Hospitalized people living with HIV (PLWH) experienced extremely high mortality rates in the first year after an index hospitalization in the pre-Dolutegravir (DTG) era. We conducted a multi-center study in Mwanza, Tanzania to (1) describe causes of hospitalization for PLWH on DTG; (2) determine in-hospital and 3-month post-hospital mortality; (3) examine factors associated with overall mortality; and (4) determine changes in trends and predictors of mortality pre- and post-DTG era.

Methods
Between August 2020 and February 2021, hospitalized PLWH on dolutegravir-based antiretroviral therapy were enrolled and followed for three months after hospitalization. The primary outcome was mortality within 3-months of hospitalization. Cox regression analysis was used to calculate hazard ratios to identify predictors of mortality.

Results
Of the 154 enrolled patients, the median [interquartile range] age was 42 [33–50] years and 57% were female. Suspected immune reconstitution inflammatory syndrome (IRIS) and antiretroviral therapy (ART) non-adherence leading to an HIV-associated admission were common. The overall all-cause mortality was 42%. Male sex, using DTG-based regimen for < 3 months, diagnosis of suspected IRIS, diagnosis of ART side effect, advanced WHO clinical stage, CD4 count < 200 cells/mm3, hemoglobin level 7–11.9 gm/dl and hemoglobin level < 7 gm/dl were all independent risk factors for death.

Conclusion
In conclusion, the mortality rate of hospitalized PLWH in Africa remains high in the DTG era. Clinical trials are urgently needed to test novel interventions for improving survival in this high-risk group. In the meantime, hospital clinicians should be aware of the very high mortality among PLWH with IRIS and those with ART side effect to ensure that all possible diagnostic and therapeutic options are explored.
Point-of-care tests in the emergency medical services: a scoping review
Authors: Moore T. H. M. , Dawson S. , Kirby K. , Body R. , Thompson A. , Adepoju Y. O. , Perry R. , Nicholson H. , Dinnes J. , Mitchell K. , Savović J. , Voss S. , Benger J. R. 
Published: February 2025

Abstract

Background
This scoping review aimed to summarize existing research on point-of-care tests (POCTs) within emergency medical services (EMS). There is a lack of comprehensive reviews covering the breadth and scope of application of POCTs in EMS despite growing interest and potential benefits in this setting. A review of the research will inform how we target future research efforts to support effective implementation and avoid duplication.

Methods
We searched three databases to April 2023 using comprehensive terms for POCTs. One author screened titles and abstracts, full-text papers and extracted data with a second author checking the data. A scoping review framework was used to categorise studies according to demographics, study design, medical conditions, biomarkers and test devices.

Results
We found 141 papers that included 158 reports of 9 study designs, 155 reports of 40 combinations of biomarker and condition and 161 reports of 41 test-devices. The majority of research was done in the UK (19%), US (17%), and the Netherlands (16%), mostly in land-based EMS (82%). Most frequently assessed were troponin for acute coronary syndromes (26%), lactate for sepsis (14%) or lactate for trauma/critical illness (13%). The majority of research designs investigated the accuracy of the tests (43%). Few studies were of a design to inform guidelines to change patient pathways and the associated outcomes, including, randomised controlled trials (RCTs) (4%), non-randomised studies able to assess causality (6%), economic analyses (1%) or qualitative work on acceptability (3%). In those few cases where RCTs were done there were long delays between initial test-accuracy research and publication of the first RCT, for example 11 years delay for troponin for acute coronary syndromes.

Conclusions
We identified a thriving base of research on POCT in the EMS, however most studies established the diagnostic accuracy of the tests with few RCTs, economic analyses or qualitative research on acceptability. The time-lag from diagnostic accuracy to developing an RCT is considerable. Investment in funding and infrastructure is needed to support the research pathway for potential POCTs beyond diagnostic accuracy to designs able to assess clinical effectiveness, acceptability and economic effectiveness.
Long-term outcome of a treat-to-target strategy in late-onset rheumatoid arthritis with chronic lung disease: 5-year results of a prospective observational study
Authors: Nomura Manami , Sugihara Takahiko , Baba Hiroyuki , Hosoya Tadashi , Kamiya Mari , Ishizaki Tatsuro , Matsumoto Takumi , Kubo Kanae , Hirano Fumio , Kojima Masayo , Miyasaka Nobuyuki , Yasuda Shinsuke , Harigai Masayoshi 
Published: February 2025

Abstract

Background
Controlling disease activity and improving physical function would be more difficult in patients with late-onset rheumatoid arthritis (LORA) who have chronic lung disease (CLD) at baseline. Our aim was to evaluate 5-year outcomes of following a treat-to-target (T2T) strategy targeting low disease activity (LDA) in LORA with CLD.

Methods
Data from 197 methotrexate (MTX)-naïve LORA patients (mean age 74.4 years) from a prospective, monocentric registry were analyzed. Patients were treated with MTX if they had one or more poor prognostic features. If they had interstitial lung disease (ILD), tacrolimus could be administered instead of MTX at the discretion of the attending physician. If patients exhibited no response according to the European League Against Rheumatism criteria at week 12 or had not achieved LDA by week 24, biological disease-modifying antirheumatic drugs (bDMARDs) were started targeting LDA. The primary outcomes were the 5-year simplified disease activity index (SDAI) remission and Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ 0.5 by non-responder imputation analysis. Secondary outcomes were serious adverse events (SAEs).

Results
Of the 197 LORA patients, 47 had CLD at baseline. The proportion of patients using MTX at baseline was significantly lower in those with than without CLD. Tacrolimus was initiated in 25.5% of the CLD group. The proportion of patients on bDMARDs was higher in those with CLD at year 5. Achievement of SDAI remission at year 5 was 29.8% in patients with CLD and 44.0% in those without CLD (p = 0.555). Achievement of HAQ-DI ≤ 0.5 at year 5 was 36.2% and 45.3% in patients with and without CLD, respectively (p = 0.939). Non-adherence to T2T due to comorbidities or adverse events was observed in 34.0% and 18.7% of the patients with and without CLD, respectively (p = 0.027). Infections requiring hospitalization, deterioration of extra-articular manifestations and fractures were more frequently reported as SAEs in patients with CLD, and multivariable analysis showed that patients with CLD had a higher risk of developing these SAEs (adjusted hazard ratio:2.53, 95% CI 1.60–4.00, p < 0.001).

Conclusion
For LORA patients with CLD, the T2T strategy is effective, but comorbidities and SAEs make the implementation of the T2T more difficult.
Technology license agreements as public–private partnerships for economic development: evaluations using surveys, input–output modeling, and regression analysis
Authors: Raile Eric D. , Austin Eric K. , Wallner Michael P. , Peterson Jeffrey , Lewandowski Brian , Kapps Derek , Sellegren Bridger , Hutton Joe 
Published: February 2025

Abstract
We evaluate license agreements as a form of technology transfer that constitutes a public–private partnership (PPP) with the primary goal of economic development. These license agreements permit entrepreneurs and other businesses to turn government innovations into earnings. We constructed a complete database of all license agreements between the U.S. Department of Defense and private industry from 2000 to 2021. We first surveyed the companies involved, achieving a 96% response rate. The subsequently anonymized responses allowed us to generate sales numbers and to model a variety of other national economic impacts. We tallied approximately $32 billion in direct sales across 590 license agreements. While the majority of license agreements with sales belong to smaller companies (which often attract additional investment), some large companies generate higher revenues. Further statistical modeling with the heavily anonymized data identifies features of license agreement situations that influence economic outcomes. Technology license agreements are a form of PPP that performs well against its goal of economic development without the downsides of some PPPs. Importantly, entrepreneurs can use this form of PPP to attract investment and to generate jobs and other societal benefits.
Phantom-based investigation of block sequential regularised expectation maximisation (BSREM) reconstruction for zirconium-89 PET-CT for varied count levels
Authors: Bonney Lara M. , Walker Matthew D. , McGowan Daniel R. 
Published: February 2025

Abstract

Background
Zirconium-89 (Zr-89) PET tracers have become increasingly significant in the field of nuclear medicine due to their 3-day physical half-life, allowing for the study of dynamic biological processes over relatively long timeframes. To date there has been limited publication of studies focused on optimisation of acquisition parameters for Zr-89 PET. This paper outlines a short phantom study investigating the optimal beta regularization parameter for quantitation and noise in block sequential regularised expectation maximisation (BSREM) also known as Bayesian penalized likelihood (BPL) reconstruction, for varying image noise characteristics (acquisition duration).

Results
The choice of the beta regularisation parameter substantially impacts image quality and quantitation. For larger volumes, BSREM reconstruction enhanced image quality (lower noise) and maintained quantitation, whereas for smaller volumes quantitation worsened as compared to OSEM for high regularisation parameters.

Conclusion
Where BSREM reconstruction is used for Zr-89 images, careful attention must be paid to the choice of weighting factor, especially for quantitative clinical studies. The effect of varying beta on several measures of image quality was characterised for the case of a phantom, with the results indicating that the value of beta for optimal Zr-89 quantitation is lower than what is generally used for optimal visualisation. This work demonstrates the need for careful attention to the reconstruction methods used for quantitative imaging studies, such as those required for theragnostic imaging.