bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibiting NR5A2 targets stemness in pancreatic cancer by disrupting SOX2/MYC signaling and restoring chemosensitivity
Authors: Zheng Quan , Tang Jiajia , Aicher Alexandra , Bou Kheir Tony , Sabanovic Berina , Ananthanarayanan Preeta , Reina Chiara , Chen Minchun , Gu Jian-Min , He Bin , Alcala Sonia , Behrens Diana , Lawlo Rita T. , Scarpa Aldo , Hidalgo Manuel , Sainz Bruno , Sancho Patricia , Heeschen Christopher 
Published: November 2023

Abstract
Background
Pancreatic ductal adenocarcinoma (PDAC) is a profoundly aggressive and fatal cancer. One of the key factors defining its aggressiveness and resilience against chemotherapy is the existence of cancer stem cells (CSCs). The important task of discovering upstream regulators of stemness that are amenable for targeting in PDAC is essential for the advancement of more potent therapeutic approaches. In this study, we sought to elucidate the function of the nuclear receptor subfamily 5, group A, member 2 (NR5A2) in the context of pancreatic CSCs.

Methods
We modeled human PDAC using primary PDAC cells and CSC-enriched sphere cultures. NR5A2 was genetically silenced or inhibited with Cpd3. Assays included RNA-seq, sphere/colony formation, cell viability/toxicity, real-time PCR, western blot, immunofluorescence, ChIP, CUT&Tag, XF Analysis, lactate production, and in vivo tumorigenicity assays. PDAC models from 18 patients were treated with Cpd3-loaded nanocarriers.

Results
Our findings demonstrate that NR5A2 plays a dual role in PDAC. In differentiated cancer cells, NR5A2 promotes cell proliferation by inhibiting CDKN1A. On the other hand, in the CSC population, NR5A2 enhances stemness by upregulating SOX2 through direct binding to its promotor/enhancer region. Additionally, NR5A2 suppresses MYC, leading to the activation of the mitochondrial biogenesis factor PPARGC1A and a shift in metabolism towards oxidative phosphorylation, which is a crucial feature of stemness in PDAC. Importantly, our study shows that the specific NR5A2 inhibitor, Cpd3, sensitizes a significant fraction of PDAC models derived from 18 patients to standard chemotherapy. This treatment approach results in durable remissions and long-term survival. Furthermore, we demonstrate that the expression levels of NR5A2/SOX2 can predict the response to treatment.

Conclusions
The findings of our study highlight the cell context-dependent effects of NR5A2 in PDAC. We have identified a novel pharmacological strategy to modulate SOX2 and MYC levels, which disrupts stemness and prevents relapse in this deadly disease. These insights provide valuable information for the development of targeted therapies for PDAC, offering new hope for improved patient outcomes.

Graphical Abstract
A Schematic illustration of the role of NR5A2 in cancer stem cells versus differentiated cancer cells, along with the action of the NR5A2 inhibitor Cpd3. B Overall survival of tumor-bearing mice following allocated treatment. A total of 18 PDX models were treated using a 2 x 1 x 1 approach (two animals per model per treatment); n=36 per group (illustration created with biorender.com).
Ginseng-derived nanoparticles reprogram macrophages to regulate arginase-1 release for ameliorating T cell exhaustion in tumor microenvironment
Authors: Lv Yan , Li Mengyuan , Weng Ling , Huang Haoying , Mao Yujie , Yang Danchen Aaron , Wei Qingyun , Zhao Mengmeng , Wei Qin , Rui Ke , Han Xuan , Fan Weiwei , Cai Xueting , Cao Peng , Cao Meng 
Published: November 2023

Abstract
Background
Lines of evidence indicated that, immune checkpoints (ICs) inhibitors enhanced T cell immune response to exert anti-tumor effects. However, T cell exhaustion has been so far a major obstacle to antitumor immunotherapy in colorectal cancer patients. Our previous studies showed that ginseng-derived nanoparticles (GDNPs) inhibited the growth of various tumors by reprograming tumor-associated macrophages (TAMs) and downregulated the ICs expression on T cells in tumor microenvironment (TME), but the underlying effector mechanisms remained unclear.

Methods
The correlation between arginase-1 (ARG1) and T cells was computed based on the colorectal cancer patients in TCGA database. In vitro, we observed that GDNPs reprogrammed TAMs inhibited ARG1 release and ultimately ameliorated T cell exhaustion according to several techniques including WB, PCR, ELISA and flow cytometry. We also used an in vivo MC38 tumor-bearing model and administered GDNPs to assess their anti-tumor effects through multiple indices. The mechanism that GDNPs improved T cell exhaustion was further clarified using the bioinformatics tools and flow cytometry.

Results
GDNPs reprogramed TAMs via reducing ARG1 production. Moreover, normalized arginine metabolism ameliorated T cell exhaustion through mTOR-T-bet axis, resulting in reduced ICs expression and enhanced CD8+ T cells expansion.

Conclusions
By regulating the mTOR-T-bet axis, GDNPs reprogramed macrophages to regulate ARG1 release, which further ameliorated T cell exhaustion in TME. These findings provided new insights into comprehending the mechanisms underlying the mitigation of T cell exhaustion, which may facilitate the development of innovative therapeutic strategies in the field of cancer treatment.
BRCA1 and BRCA2 deficient tumour models generate distinct ovarian tumour microenvironments and differential responses to therapy
Authors: Farokhi Boroujeni Salar , Rodriguez Galaxia , Galpin Kristianne , Yakubovich Edward , Murshed Humaira , Ibrahim Dalia , Asif Sara , Vanderhyden Barbara C. 
Published: November 2023

AbstractClinical trials are currently exploring combinations of PARP inhibitors and immunotherapies for the treatment of ovarian cancer, but their effects on the ovarian tumour microenvironment (TME) remain unclear. Here, we investigate how olaparib, PD-L1 monoclonal antibodies, and their combination can influence TME composition and survival of tumour-bearing mice. We further explored how BRCA deficiencies can influence the response to therapy. Olaparib and combination therapies similarly improved the median survival of Brca1- and Brca2-deficient tumour-bearing mice. Anti-PD-L1 monotherapy improved the survival of mice with Brca1-null tumours, but not Brca2-null tumours. A detailed analysis of the TME revealed that olaparib monotherapy resulted in a large number of immunosuppressive and immunomodulatory effects in the more inflamed Brca1-deficient TME but not Brca2-deficient tumours. Anti-PD-L1 treatment was mostly immunosuppressive, resulting in a systemic reduction of cytokines and a compensatory increase in PD-L1 expression. The results of the combination therapy generally resembled the effects of one or both of the monotherapies, along with unique changes observed in certain immune populations. In-silico analysis of RNA-seq data also revealed numerous differences between Brca-deficient tumour models, such as the expression of genes involved in inflammation, angiogenesis and PD-L1 expression. In summary, these findings shed light on the influence of novel therapeutics and BRCA mutations on the ovarian TME.
The implication of a translational triage tool in mass casualty incidents: part three: a multinational study, using validated patient cards
Authors: Khorram-Manesh Amir , Carlström Eric , Burkle Frederick M. , Goniewicz Krzysztof , Gray Lesley , Ratnayake Amila , Faccincani Roberto , Bagaria Dinesh , Phattharapornjaroen Phatthranit , Sultan Mohammed A. S. , Montán Carl , Nordling Johan , Gupta Shailly , Magnusson Carl 
Published: November 2023

Abstract
Background
Mass casualty incidents (MCI) pose significant challenges to existing resources, entailing multiagency collaboration. Triage is a critical component in the management of MCIs, but the lack of a universally accepted triage system can hinder collaboration and lead to preventable loss of life. This multinational study uses validated patient cards (cases) based on real MCIs to evaluate the feasibility and effectiveness of a novel Translational Triage Tool (TTT) in primary triage assessment of mass casualty victims.

Methods
Using established triage systems versus TTT, 163 participants (1575 times) triaged five patient cases. The outcomes were statistically compared.

Results
TTT demonstrated similar sensitivity to the Sieve primary triage method and higher sensitivity than the START primary triage system. However, the TTT algorithm had a lower specificity compared to Sieve and higher over-triage rates. Nevertheless, the TTT algorithm demonstrated several advantages due to its straightforward design, such as rapid assessment, without the need for additional instrumental interventions, enabling the engagement of non-medical personnel.

Conclusions
The TTT algorithm is a promising and feasible primary triage tool for MCIs. The high number of over-triages potentially impacts resource allocation, but the absence of under-triages eliminates preventable deaths and enables the use of other personal resources. Further research involving larger participant samples, time efficiency assessments, and real-world scenarios is needed to fully assess the TTT algorithm's practicality and effectiveness in diverse multiagency and multinational contexts.
The effects of Olmesartan/amlodipine administered in the Morning or At Night on nocturnal blood pressure reduction in Chinese patients with mild-moderate essential hypertension (OMAN Trial): study protocol for a prospective, multicenter, randomized, open-label clinical trial {1}
Authors: Xu Mengzhuo , Zhang Xin , Ye Runyu , Liu Xueting , Sun Lirong , Jia Shanshan , Zhang Zhipeng , Li Xinran , Wang Ziqiong , Liao Hang , Shi Rufeng , Liu Kai , Wang Si , Meng Qingtao , Chen Xiaoping 
Published: November 2023

Abstract
Introduction
Hypertension increases the risk of cardiovascular disease. Uncontrolled nocturnal blood pressure is prevalent in patients taking antihypertensive medication, with an incidence rate of 30–60%. Although chronotherapy with antihypertensive agents may provide a new direction for effective control of nocturnal blood pressure, the clinical evidence base remains controversial. This research is presently underway to compare the effects of morning and bedtime administration of antihypertensive medication on nocturnal reduction and circadian rhythm of blood pressure in patients with hypertension.

Methods and analysis
This study is being performed as a randomized, multicenter, open-label, parallel-group, clinical trial in which 720 participants are to undergo 24-h ambulatory blood pressure measurement (ABPM) and office blood pressure measurement (OBPM) at baseline before being randomly assigned to a morning (6–10 am) or a bedtime (6–10 pm) administration group. Each participant receives one 20/5-mg tablet of olmesartan/amlodipine (OA) daily for 4 weeks and is then followed up at 4-week intervals for a total of 12 weeks. During follow-up, the OA dosage is adjusted according to the ABPM and OBPM results. Patients with uncontrolled hypertension at the first follow-up visit will receive an increase in OA dosage to 1.5 tablets/day. For patients with blood pressure that is still uncontrolled after a further 4 weeks, the dosage of OA can be increased to 2 tablets/day. The primary objective is the reduction in mean nocturnal systolic blood pressure between baseline and week 12. The secondary objectives are the reduction in ambulatory blood pressure at weeks 4 and 12 and the blood pressure control rate at weeks 4, 8, and 12.

Discussion
Antihypertensive chronotherapy remains controversial. A superiority test hypothesis design has been adopted for this trial, in which all participants will be taking the same antihypertensive medication. We anticipate that our findings will determine if nocturnal blood pressure control in Chinese patients with essential hypertension varies according to whether antihypertensive medication is taken in the morning or at bedtime. This study may provide scientific evidence for the application of chronotherapy in clinical practice.

Trial registration
ChiCTR2200059719. Registered on 10 May 2022
(http://www.chictr.org.cn/edit.aspx?pid=169782&htm=4) {2a,2b}
Hearing intervention for decreasing risk of developing dementia in elders with mild cognitive impairment: study protocol of a multicenter randomized controlled trial for Chinese Hearing Solution for Improvement of Cognition in Elders (CHOICE)
Authors: Chen Ying , Guan Lei , Chen Jie , Han Kun , Yu Qiongfei , Zhou Jin , Wang Xue , Ma Yunqian , Ji Xiangyu , Zhao Zhonglu , Shen Qiyue , Wang Anxian , Wang Mengping , Li Jin , Yu Jiali , Zhang Yiwen , Xu Sijia , Liu Jie , Lu Wen , Ye Bin , Fang Yuan , Hu Haixia , Shi Haibo , Xiang Mingliang , Li Xia , Li Yun , Wu Hao 
Published: November 2023

Abstract
Background
Age-related hearing loss (ARHL) signifies the bilateral, symmetrical, sensorineural hearing loss that commonly occurs in elderly individuals. Several studies have suggested a higher risk of dementia among patients diagnosed with ARHL. Although the precise causal association between ARHL and cognitive decline remains unclear, ARHL has been recognized as one of the most significant factors that can be modified to reduce the risk of developing dementia potentially. Mild cognitive impairment (MCI) typically serves as the initial stage in the transition from normal cognitive function to dementia. Consequently, the objective of our randomized controlled trial (RCT) is to further investigate whether the use of hearing aids can enhance cognitive function in older adults diagnosed with ARHL and MCI.

Methods and design
This study is a parallel-arm, randomized controlled trial conducted at multiple centers in Shanghai, China. We aim to enlist a total of 688 older adults (age ≥ 60) diagnosed with moderate-to-severe ARHL and MCI from our four research centers. Participants will be assigned randomly to either the hearing aid fitting group or the health education group using block randomization with varying block sizes. Audiometry, cognitive function assessments, and other relevant data will be collected at baseline, as well as at 6, 12, and 24 months post-intervention by audiologists and trained researchers. The primary outcome of our study is the rate of progression to dementia among the two groups of participants. Additionally, various evaluations will be conducted to measure hearing improvement and changes in cognitive function. Apart from the final study results, we also plan to conduct an interim analysis using data from 12-month follow-up.

Discussion
In recent years, there has been a notable lack of randomized controlled trials (RCTs) investigating the possible causal relationship between hearing fitting and the improvement of cognitive function. Our findings may demonstrate that hearing rehabilitation can be a valuable tool in managing ARHL and preventing cognitive decline, which will contribute to the development of a comprehensive framework for the prevention and control of cognitive decline.

Trial registration
Chinese Clinical Trial Registry chictr.org.cn ChiCTR2000036139. Registered on 21 August 2020.
Interaction of sulfasalazine with outer surface of boron-nitride nanotube as a drug carrier in aqueous solution: insights from quantum mechanics and Monte Carlo simulation
Authors: Ketabi Sepideh , Shalmashi Saba , Hallajian Sara 
Published: November 2023

AbstractThe improvement of the solubility of sulfasalazine in physiological media was the major aim of this study. Accordingly, BNNT inspected as a notable candidate for the carriage of this drug in aqueous media. For this purpose, four possible interactions of two tautomer of sulfasalazine with (9,0) boron-nitride nanotube were considered in aqueous media. The compounds were optimized in gas phase using density functional calculations. Solvation free energies and association free energies of the optimized structures were then studied by Monte Carlo simulation and perturbation method in water environment. Outcomes of quantum mechanical calculations presented that interaction of keto form of sulfasalazine produce the most stable complexes with boron-nitride nanotube in gas phase. Simulation results revealed that electrostatic interactions play a vital role in the intermolecular interaction energies after binding of drug and nanotube in aqueous solution. Results of association free energy calculations indicated that complexes of both two sulfasalazine tautomers (keto and enol) and nanotube were stable in solution. Computed solvation free energies in water showed that the interaction with boron-nitride nanotube significantly improved the solubility of sulfasalazine, which could improve its in vivo bioavailability.
Determination of cut-off points for the Move4 accelerometer in children aged 8–13 years
Authors: Beck Franziska , Marzi Isabel , Eisenreich Alina , Seemüller Selina , Tristram Clara , Reimers Anne K. 
Published: November 2023

Abstract
Background
To assess physical activity (PA) there is a need of objective, valid and reliable measurement methods like accelerometers. Before these devices can be used for research, they need to be calibrated and validated for specific age groups as the locomotion differs between children and adults, for instance. Therefore, the aim of the present study was the calibration and validation of the Move4 accelerometer for children aged 8–13 years.

Methods
53 normal weighted children (52% boys, 48%girls) aged 8–13 years (mean age = 10.69 ± 1.46, mean BMI = 17.93 kg/m− 2, 60th percentile), wore the Move4 sensor at four different body positions (thigh, hip, wrist and the Move4ecg including heart rate measurement at the chest). They completed nine activities that considered the four activity levels (sedentary behavior (SB), light PA (LPA), moderate PA (MPA) and vigorous PA (VPA)) within a test-retest design. Intensity values were determined using the mean amplitude deviation (MAD) as well as the movement acceleration intensity (MAI) metrics. Determination of activities and energy expenditure was validated using heart rate. After that, cut-off points were determined in Matlab by using the Classification and Regression Trees (CART) method. The agreement for the cut-off points between T1 and T2 was analyzed.

Results
MAD and MAI accelerometer values were lowest when children were lying on the floor and highest when running or doing jumping jacks. The mean correlation coefficient between acceleration values and heart rate was 0.595 (p = 0.01) for MAD metric and 0.611 (p = 0.01) for MAI metric, indicating strong correlations. Further, the MAD cut-off points for SB-LPA are 52.9 mg (hip), 62.4 mg (thigh), 86.4 mg (wrist) and 45.9 mg (chest), for LPA-MPA they are 173.3 mg (hip), 260.7 mg (thigh), 194.4 mg (wrist) and 155.7 mg (chest) and for MPA-VPA the cut-off points are 543.6 mg (hip), 674.5 mg (thigh), 623.4 mg (wrist) and 545.5 mg (chest). Test-retest comparison indicated good values (mean differences = 9.8%).

Conclusion
This is the first study investigating cut-off points for children for four different sensor positions using raw accelerometer metrics (MAD/MAI). Sensitivity and specificity revealed good values for all positions. Nevertheless, depending on the sensor position, metric values differ according to the different involvement of the body in various activities. Thus, the sensor position should be carefully chosen depending on the research question of the study.
How healthy participants value additional diagnostic testing with amyloid-PET in patients diagnosed with mild cognitive impairment — a bidding game experiment
Authors: van Maurik I. S. , Bakker E. D. , van Unnik A. A. J. M. , Broulikova H. M. , Zwan M. D. , van de Giessen E. , Berkhof J. , Bouwman F. H. , Bosmans J. E. , van der Flier W. M. 
Published: November 2023

Abstract
Background
To estimate the perceived value of additional testing with amyloid-PET in Euros in healthy participants acting as analogue patients with mild cognitive impairment (MCI).

Methods
One thousand four hundred thirty-one healthy participants acting as analogue MCI patients (mean age 65 ± 8, 929 (75%) female) were recruited via the Dutch Brain Research Registry. Participants were asked to identify with a presented case (video vignette) of an MCI patient and asked whether they would prefer additional diagnostic testing with amyloid PET in this situation. If yes, respondents were asked how much they would be willing to pay for additional diagnostic testing. Monetary value was elicited via a bidding game in which participants were randomized over three conditions: (A) additional testing results in better patient management, (B) Same as condition A and a delay in institutionalization of 3 months, and (C) same as A and a delay in institutionalization of 6 months. Participants who were not willing to take a test were compared with participants who were willing to take a test using logit models. The highest monetary value per condition was analyzed using random-parameter mixed models.

Results
The vast majority of participants acting as analogue MCI patients (87% (n = 1238)) preferred additional testing with amyloid PET. Participants who were not interested were more often female (OR = 1.61 95% CI [1.09–2.40]) and expressed fewer worries to get AD (OR = 0.64 [0.47–0.87]). The median “a priori” (i.e., before randomization) monetary value of additional diagnostic testing was €1500 (IQR 500–1500). If an additional amyloid PET resulted in better patient management (not further specified; condition A), participants were willing to pay a median price of €2000 (IQR = 1000–3500). Participants were willing to pay significantly more than condition A (better patient management) if amyloid-PET testing additionally resulted in a delay in institutionalization of 3 months (€530 [255–805] on top of €2000, condition B) or 6 months (€596 [187–1005] on top of €2000, condition C).

Conclusions
Members of the general population acting as MCI patients are willing to pay a substantial amount of money for amyloid-PET and this increases when diagnostic testing leads to better patient management and the prospect to live longer at home.