bluuebunny/crossref_metadata_2025_split huggingface dataset:
Darifenacin: a promising chitinase 3-like 1 inhibitor to tackle drug resistance in pancreatic ductal adenocarcinoma
Authors: Sousa Sofia M. , Branco Helena , Avan Amir , Palmeira Andreia , Morelli Luca , Santos Lúcio L. , Giovannetti Elisa , Vasconcelos M. Helena , Xavier Cristina P. R. 
Published: September 2024

Abstract
Purpose
Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive malignancies. Our previous work revealed Chitinase 3-like 1 (CHI3L1) involvement in PDAC resistance to gemcitabine, identifying it as a promising therapeutic target. Here, we aimed to identify putative CHI3L1 inhibitors and to investigate their chemosensitizing potential in PDAC.

Methods
Docking analysis for CHI3L1 identified promising CHI3L1 inhibitors, including darifenacin (muscarinic receptor antagonist). PDAC cell lines (BxPC-3, PANC-1) and primary PDAC cells were used to evaluate darifenacin’s effects on cell growth (Sulforhodamine B, SRB), alone or in combination with gemcitabine or gemcitabine plus paclitaxel. Cytotoxicity against normal immortalized pancreatic ductal cells (HPNE) was assessed. Recombinant protein was used to confirm the impact of darifenacin on CHI3L1-induced PDAC cellular resistance to therapy (SRB assay). Darifenacin’s effect on Akt activation was analysed by ELISA. The association between cholinergic receptor muscarinic 3 (CHRM3) expression and therapeutic response was evaluated by immunohistochemistry of paraffin-embedded tissues from surgical resections of a 68 patients’ cohort.

Results
In silico screening revealed the ability of darifenacin to target CHI3L1 with high efficiency. Darifenacin inhibited PDAC cell growth, with a GI50 of 26 and 13.6 µM in BxPC-3 and PANC-1 cells, respectively. These results were confirmed in primary PDAC-3 cells, while darifenacin showed no cytotoxicity against HPNE cells. Importantly, darifenacin sensitized PDAC cells to standard chemotherapies, reverted CHI3L1-induced PDAC cellular resistance to therapy, and decreased Akt phosphorylation. Additionally, high CHMR3 expression was associated with low therapeutic response to gemcitabine.

Conclusion
This work highlights the potential of darifenacin as a chemosensitizer for PDAC treatment.
Accelerated wound healing and reduced scar formation induced by D-mannose: a possible role of mannose binding lectin
Authors: Ciucanu Cristian Ionuț , Rațiu Sonia , Crîșmariu Gianina Elena , Olariu Sorin , Ciucanu Ionel 
Published: September 2024

AbstractWounds are most commonly caused by accidents, surgery and burns, and can be internal or external. Naturally, the wound healing process can take a long time and lead to scarring. In this study we present a technique to shorten wound healing time and prevent or mitigate scarring using D-mannose that is applied directly on the wound. The results showed that the healing time is almost halved compared to treatment with povidone-iodine solution which is an antiseptic widely used in surgery. D-Mannose is neither an antisepsis nor an antibiotic. We propose a posssible mechanism by which D-mannose binds to D-mannose binding lectin and immediately activates the innate immune system that ultimately phagocytizes pathogens and clears the wound of degraded cells and materials, which reduces inflammation and implicitly wound healing time. D-Mannose also intervenes in the coagulation process by binding to fibrinogen, generating a finer and denser fibrin, which visibly reduces collagen scars. Our findings show that applying D-mannose directly on the wound as a powder shortens wound healing time and visibly attenuates scarring. Apart from the unaesthetic appearance, these scars can also cause a certain tissue dysfunction, regardless of the affected organ.
Graphical abstract
Assessment of the reliability, responsiveness, and meaningfulness of the scale for the assessment and rating of ataxia (SARA) for lysosomal storage disorders
Authors: Park Julien , Bremova-Ertl Tatiana , Brands Marion , Foltan Tomas , Gautschi Matthias , Gissen Paul , Hahn Andreas , Jones Simon , Arash-Kaps Laila , Kolnikova Miriam , Patterson Marc , Perlman Susan , Ramaswami Uma , Reichmannová Stella , Rohrbach Marianne , Schneider Susanne A. , Shaikh Aasef , Sivananthan Siyamini , Synofzik Matthis , Walterfarng Mark , Wibawa Pierre , Martakis Kyriakos , Manto Mario 
Published: September 2024

Abstract
Objective
To evaluate the reliability, responsiveness, and validity of the Scale for the Assessment and Rating of Ataxia (SARA) in patients with lysosomal storage disorders (LSDs) who present with neurological symptoms, and quantify the threshold for a clinically meaningful change.

Methods
We analyzed data from three clinical trial cohorts (IB1001-201, IB1001-202, and IB1001-301) of patients with Niemann–Pick disease type C (NPC) and GM2 Gangliosidoses (Tay–Sachs and Sandhoff disease) comprising 122 patients and 703 visits. Reproducibility was described as re-test reliability between repeat baseline visits or baseline and post-treatment washout visits. Responsiveness was determined in relation to the Investigator’s, Caregiver’s, and Patient’s Clinical Global Impression of Improvement (CGI-I). The CGI-I data was also used to quantify a threshold for a clinically meaningful improvement on the SARA scale. Using a qualitative methods approach, patient/caregiver interviews from the IB1001-301 trial were further used to assess a threshold of meaningful change as well as the breadth of neurological signs and symptoms captured and evaluated by the SARA scale.

Results
The Inter-Class Correlation (ICC) was 0.95 or greater for all three trials, indicating a high internal consistency/reliability. The mean change in SARA between repeat baseline and post-treatment washout visit assessments in all trials was −0.05, SD 1.98, i.e., minimal, indicating no significant differences, learning effects or other systematic biases. For the CGI-I responses and change in SARA scores, Area Under the Curve (AUC) values were 0.82, 0.71, and 0.77 for the Investigator’s, Caregiver’s, and Patient’s CGI-I respectively, indicating strong agreement. Further qualitative analyses of the patient/caregiver interviews demonstrated a 1-point or greater change on SARA to be a clinically meaningful improvement which is directly relevant to the patient’s everyday functioning and quality of life. Changes captured by the SARA were also paralleled by improvement in a broad range of neurological signs and symptoms and beyond cerebellar ataxia.

Conclusion
Qualitative and quantitative data demonstrate the reliability and responsiveness of the SARA score as a valid measure of neurological signs and symptoms in LSDs with CNS involvement, such as NPC and GM2 Gangliosidoses. A 1-point change represents a clinically meaningful transition reflecting the gain or loss of complex function.
Metabolomic profile of cerebrospinal fluid from patients with diffuse gliomas
Authors: Möhn Nora , Hounchonou Harold F. , Nay Sandra , Schwenkenbecher Philipp , Grote-Levi Lea , Al-Tarawni Fadi , Esmaeilzadeh Majid , Schuchardt Sven , Schwabe Kerstin , Hildebrandt Herbert , Thiesler Hauke , Feuerhake Friedrich , Hartmann Christian , Skripuletz Thomas , Krauss Joachim K. 
Published: September 2024

Abstract
Background
Diffuse gliomas are among the most common brain tumors in adults and are associated with a dismal prognosis, especially in patients with glioblastoma. To date, tumor tissue acquisition is mandatory for conclusive diagnosis and therapeutic decision-making. In this study, we aimed to identify possible diagnostic and prognostic biomarkers in cerebrospinal fluid (CSF) and blood.

Methods
During glioma surgery at our institution, CSF and blood samples were collected from patients. Subsequently, targeted metabolomics analysis was used to detect and quantify circulating metabolites. The metabolome profiles of glioma patients were compared with those of patients in a control group who had undergone neurosurgery for other entities, such as nonglial tumors or hydrocephalus, and were correlated with established glioma diagnostic molecular markers.

Results
In this study, a total of 30 glioma patients were included, along with a control group of 21 patients without glioma. Serum metabolomic analysis did not detect any significant differences between the groups, whereas CSF-metabolome analysis revealed increased levels of six metabolites in glioma patients. Among these, the most pronounced differences were found for the biogenic amine putrescine (p = 0.00005). p-Cresol sulfate was identified as a potential CSF marker for determining isocitrate dehydrogenase (IDH) status in glioma patients (p = 0.0037).

Conclusion
CSF-metabolome profiling, unlike blood profiling, shows promise as a diagnostic tool for glioma patients with the potential to assign molecular subtypes. The next step will involve a larger multicenter study to validate these findings, with the ultimate objective of integrating CSF metabolomics analysis into clinical practice.
Assessing the effects of spontaneous intracranial hypotension on quality of life, work ability and disability
Authors: Kapan Ali , Waldhör Thomas , Wöber Christian 
Published: September 2024

Summary
Background
Spontaneous intracranial hypotension (SIH), characterized by headaches due to cerebrospinal fluid leaks or low pressure, is a challenging condition to diagnose and treat and affects the quality of life.

Methods
An 8‑week online survey was conducted to assess the impact of SIH on symptoms, sociodemographics and quality of life. The cohort was comprised of patients who had a self-reported diagnosis of SIH and were divided into two groups: those with radiological evidence of SIH and those with clinical suspicion but no radiological evidence. Mental health and disability were evaluated using the Depression, Anxiety and Stress Scale-21 (DASS-21) and the Henry Ford Hospital Headache Disability Inventory (HDI).

Results
A total of 86 participants were included in the study, 59 with radiological evidence and 27 without. Most participants were female (84.9%) with a mean age of 44.8 years. Orthostatic headache was more common in participants without radiological evidence (74.1% vs. 42.4%). The severity in those with radiological evidence was 27.1% mild, 27.1% moderate, 30.5% severe and 15.3% extremely severe, while those without had 7.4% mild, 18.5% moderate, 63.0% severe and 11.1% extremely severe headaches. Mental health assessment using the DASS-21 scale showed that 77.9% of all participants reported signs of depression, 96.5% reported anxiety and 89.5% reported stress. The HDI showed 2.3% total disability, 40.7% severe, 19.8% moderate and 37.2% mild. The impact on employment was significant: 15.1% were able to work full-time, 48.8% part-time, 30.2% were unable to work and 5.8% retired early due to SIH.

Conclusion
The study demonstrates the broad impact of SIH affecting physical health, mental well-being, and socioeconomic status, and calls for multifaceted and robust management approaches to address its complex effects on patients.
Therapeutic drug monitoring in Parkinson’s disease
Authors: Müller Thomas , Gerlach Manfred , Hefner Gudrun , Hiemke Christoph , Jost Wolfgang H. , Riederer Peter 
Published: September 2024

AbstractA patient-tailored therapy of the heterogeneous, neuropsychiatric disorder of Parkinson’s disease (PD) aims to improve dopamine sensitive motor symptoms and associated non-motor features. A repeated, individual adaptation of dopamine substituting compounds is required throughout the disease course due to the progress of neurodegeneration. Therapeutic drug monitoring of dopamine substituting drugs may be an essential tool to optimize drug applications. We suggest plasma determination of levodopa as an initial step. The complex pharmacology of levodopa is influenced by its short elimination half-life and the gastric emptying velocity. Both considerably contribute to the observed variability of plasma concentrations of levodopa and its metabolite 3-O-methyldopa. These amino acids compete with other aromatic amino acids as well as branched chain amino acids on the limited transport capacity in the gastrointestinal tract and the blood brain barrier. However, not much is known about plasma concentrations of levodopa and other drugs/drug combinations in PD. Some examples may illustrate this lack of knowledge: Levodopa measurements may allow further insights in the phenomenon of inappropriate levodopa response. They may result from missing compliance, interactions e.g. with treatments for other mainly age-related disorders, like hypertension, diabetes, hyperlipidaemia, rheumatism or by patients themselves independently taken herbal medicines. Indeed, uncontrolled combination of compounds for accompanying disorders as given above with PD drugs might increase the risk of side effects. Determination of other drugs used to treat PD in plasma such as dopamine receptor agonists, amantadine and inhibitors of catechol-O-methyltransferase or monoamine oxidase B may refine and improve the value of calculations of levodopa equivalents. How COMT-Is change levodopa plasma concentrations? How other dopaminergic and non-dopaminergic drugs influence levodopa levels? Also, delivery of drugs as well as single and repeated dosing and continuous levodopa administrations with a possible accumulation of levodopa, pharmacokinetic behaviour of generic and branded compounds appear to have a marked influence on efficacy of drug treatment and side effect profile. Their increase over time may reflect progression of PD to a certain degree. Therapeutic drug monitoring in PD is considered to improve the therapeutic efficacy in the course of this devastating neurologic disorder and therefore is able to contribute to the patients’ precision medicine. State-of-the-art clinical studies are urgently needed to demonstrate the usefulness of TDM for optimizing the treatment of PD.
Towards an EPR on a Chip Spectrometer for Monitoring Radiation Damage During X-ray Absorption Spectroscopy
Authors: Shabratova Ekaterina , Lotfi Hadi , Sakr Ayman , Hassan Mohamed Atef , Kern Michal , Neeb Matthias , Grüneberger René , Klemke Bastian , Marcozzi Gianluca , Kiefer Klaus , Tsarapkin Aleksei , Höflich Katja , Dittwald Alina , Denker Andrea , Anders Jens , McPeak Joseph E. , Lips Klaus 
Published: September 2024

Abstract
Electron paramagnetic resonance (EPR) spectroscopy is an essential tool to investigate the effects of ionizing radiation, which is routinely administered for reducing contaminations and waste in food products and cosmetics as well as for sterilization in industry and medicine. In materials research, EPR methods are not only employed as a spectroscopic method of structural investigations, but also have been employed for detection of changes in electronic structure due to radiation damage from high energy X-rays, for example, to monitor radical formation inside biomolecules caused by X-ray irradiation at carbon, nitrogen, and oxygen K-edges at synchrotron facilities. Here a compact EPR spectrometer, based on EPR-on-a-chip (EPRoC) sensor and a portable electromagnet, has been developed as a solution for monitoring radiation damage of samples during their investigation by X-ray absorption spectroscopy (XAS) at synchrotron facilities. A portable electromagnet with a soft iron core and forced air temperature stabilization was constructed as the source of the external magnetic field. The sweep range of magnetic field inside the most homogeneous region of the portable electromagnet is 12–290 mT. The compact spectrometer performance was evaluated by placing the EPRoC sensor inside either a commercial electromagnet or the portable electromagnet to record the EPR spectrum of tempol, irradiated alanine, and dilithium phthalocyanine (Li2Pc). The potential performance of the portable spectrometer for the detection of radiation damage in organic compounds and transition metal-containing catalysts during XAS measurements in both fluorescence and transmission modes was calculated with promising implications for measurements after implementation in a synchrotron-based XAS spectrometer.
Genomic profiling of pan-drug resistant proteus mirabilis Isolates reveals antimicrobial resistance and virulence gene landscape
Authors: Soliman Sarah , Abdalla Salah , Zedan Amal , Enany Shymaa 
Published: September 2024

AbstractProteus mirabilis is a gram-negative pathogen that caused significant opportunistic infections. In this study we aimed to identify antimicrobial resistance (AMR) genes and virulence determinants in two pan-drug resistant isolate “Bacteria_11” and “Bacteria_27” using whole genome sequencing. Proteus mirabilis “Bacteria_11” and “Bacteria_27” were isolated from two different hospitalized patients in Egypt. Antimicrobial susceptibility determined using Vitek 2 system, then whole genome sequencing (WGS) using MinION nanopore sequencing was done. Antimicrobial resistant genes and virulence determinants were identified using ResFinder, CADR AMR database, Abricate tool and VF analyzer were used respectively. Multiple sequence alignment was performed using MAFFT and FastTree, respectively. All genes were present within bacterial chromosome and no plasmid was detected. “Bacteria_11” and “Bacteria_27” had sizes of approximately 4,128,657 bp and 4,120,646 bp respectively, with GC content of 39.15% and 39.09%. “Bacteria_11” and “Bacteria_27” harbored 43 and 42 antimicrobial resistance genes respectively with different resistance mechanisms, and up to 55 and 59 virulence genes respectively. Different resistance mechanisms were identified: antibiotic inactivation, antibiotic efflux, antibiotic target replacement, and antibiotic target change. We identified several genes associated with aminoglycoside resistance, sulfonamide resistance. trimethoprim resistance tetracycline resistance proteins. Also, those responsible for chloramphenicol resistance. For beta-lactam resistance, only blaVEB and blaCMY-2 genes were detected. Genome analysis revealed several virulence factors contribution in isolates pathogenicity and bacterial adaptation. As well as numerous typical secretion systems (TSSs) were present in the two isolates, including T6SS and T3SS. Whole genome sequencing of both isolates identify their genetic context of antimicrobial resistant genes and virulence determinants. This genomic analysis offers detailed representation of resistant mechanisms. Also, it clarifies P. mirabilis ability to acquire resistance and highlights the emergence of extensive drug resistant (XDR) and pan-drug resistant (PDR) strains. This may help in choosing the most appropriate antibiotic treatment and limiting broad spectrum antibiotic use.
Valuation of the EQ-5D-3L in Jordan
Authors: Al Rabayah Abeer , Roudijk Bram , Purba Fredrick Dermawan , Rencz Fanni , Jaddoua Saad , Siebert Uwe 
Published: September 2024

Abstract
Background
In Jordan, no national value set is available for any preference-accompanied health utility measure.

Objective
This study aims to develop a value set for EQ-5D-3L based on the preferences of the Jordanian general population.

Methods
A representative sample of the Jordanian general population was obtained through quota sampling involving age, gender, and region. Participants aged above 18 years were interviewed via videoconferencing using the EuroQol Valuation Technology 2.1 protocol. Participants completed ten composite time trade-offs (cTTO) and ten discrete choice experiments (DCE) tasks. cTTO and DCE data were analyzed using linear and logistic regression models, respectively, and hybrid models were applied to the combined DCE and cTTO data.

Results
A total of 301 participants with complete data were included in the analysis. The sample was representative of the general population regarding region, age, and gender. All model types applied, that is, random intercept model, random intercept Tobit, linear model with correction for heteroskedasticity, Tobit with correction for heteroskedasticity, and all hybrid models, were statistically significant. They showed logical consistency in terms of higher utility decrements with more severe levels. The hybrid model corrected for heteroskedasticity was selected to construct the Jordanian EQ-5D-3L value set as it showed the best fit and lowest mean absolute error. The predicted value for the most severe health state (33333) was − 0.563. Utility decrements due to mobility had the largest weight, followed by anxiety/depression, while usual activities had the smallest weight.

Conclusion
This study provides the first EQ-5D-3L value set in the Middle East. The Jordanian EQ-5D-3L value set can now be used in health technology assessments for health policy planning by the Jordanian health sector’s decision-makers.
Multiscale spatial analysis of two plant–insect interactions: effects of landscape, resource distribution, and other insects
Authors: Pocull Guillem , Baskett Carina , Barton Nicholas H. 
Published: September 2024

Abstract
Context
Biotic resource exploitation is a critical determinant of species’ distributions. However, quantifying resource exploitation patterns through space and time can be difficult, complicating their incorporation in spatial ecology studies. Therefore, understanding the local drivers of spatial patterns of resource exploitation may contribute to better large-scale species distribution models.

Objectives
We investigated (1) how the resource exploitation patterns of two trophic interactions (plant–insect) are explained by insect behaviour, resource aggregation, and potential insect-insect interactions. We also analyzed how (2) resource patch size and (3) resource accessibility in a heterogeneous landscape affected host exploitation patterns.

Methods
We quantified nectar robbing by insects in the genus Bombus (bumblebees) and seed predation by Brachypterolus vestitus larvae (Antirrhinum beetle) on Antirrhinum majus L. (wild snapdragons) in the Pyrenees Mountains, Catalonia, Spain. We tested hypotheses about resource exploitation by integrating spatial analyses at multiple scales.

Results
Both trophic interactions were aggregated, explained by the aggregation of their resource. At some scales, nectar robbing is more aggregated than the resource. Trophic interaction abundance is proportional to resource patch size, following the ideal free distribution model. Landscape features do not explain the locations exploited. Nectar robbing and seed predation occur together more often than expected.

Conclusions
Our findings suggest that multiple biotic and ecological spatial factors may simultaneously affect resource exploitation at a local scale. These findings should be considered when developing agricultural projects, management plans and conservation policies.