bluuebunny/crossref_metadata_2025_split huggingface dataset:
miR-21 and cathepsin B in familial Mediterranean fever: novel findings regarding their impact on disease severity
Authors: Durmus Sinem , Gelisgen Remise , Hajiyeva Ramila , Adrovic Amra , Yildiz Mehmet , Yucesan Emrah , Barut Kenan , Kasapcopur Ozgur , Uzun Hafize 
Published: January 2025

ObjectiveThe limited predictive effect of genotype on familial Mediterranean fever (FMF) phenotype suggests that epigenetic factors and alternative mechanisms that may cause IL-1β release could contribute to phenotypic heterogeneity. The objective of this study was to examine the role of IL-1β levels and miR-21-5p, cathepsin B and pyrin levels, which were identified as potential factors causing IL-1β release through the use of bioinformatics tools, in the pathogenesis of FMF and their relationship with disease severity.Materials and methods50 paediatric patients with FMF and 40 healthy children were enrolled in this study. Patients were divided into subgroups according to Pras disease severity score. Serum miR-21-5p expression levels were assessed by qRT-PCR, while serum pyrin, IL-1β and cathepsin B levels were determined by ELISA.ResultsSerum miR-21-5p was significantly downregulated in FMF patients compared with the control group (p<0.001), while serum pyrin, IL-1β and cathepsin B levels were markedly elevated (p<0.001 for each). Only miR-21-5p was negatively correlated with IL-1β (r=−0.855; p<0.001). In moderately severe FMF patients, miR-21-5p exhibited a statistically significant downregulation (p<0.001), whereas IL-1β and cathepsin B showed a statistically significant increase (p<0.001 and p<0.05, respectively). Furthermore, the Pras score showed a strong negative correlation (r=−0.738; p<0.001) with miR-21-5p levels. Multivariate logistic regression showed that in FMF, a one-unit decrease in miR-21 increased disease severity risk 6.76-fold, while a one-unit increase in cathepsin B raised it 1.71-fold.ConclusionThis might be considered one of the mechanisms for subclinical inflammation in paediatric FMF patients through increased activation of cytokines via the downregulation of miR-21-5p. Our findings suggest that miR-21-5p and IL-1β play key roles in subclinical inflammation, and these molecules might be a potential therapeutic target.
Society for Immunotherapy of Cancer: updates and best practices for multiplex immunohistochemistry (IHC) and immunofluorescence (IF) image analysis and data sharing
Authors: Taube Janis M , Sunshine Joel C , Angelo Michael , Akturk Guray , Eminizer Margaret , Engle Logan L , Ferreira Cláudia S , Gnjatic Sacha , Green Benjamin , Greenbaum Shirley , Greenwald Noah F , Hedvat Cyrus V , Hollmann Travis J , Jiménez-Sánchez Daniel , Korski Konstanty , Lako Ana , Parra Edwin R , Rebelatto Marlon C , Rimm David L , Rodig Scott J , Rodriguez-Canales Jamie , Roskes Jeffrey S , Schalper Kurt A , Schenck Emanuel , Steele Keith E , Surace Michael J , Szalay Alexander S , Tetzlaff Michael T , Wistuba Ignacio I , Yearley Jennifer H , Bifulco Carlo B 
Published: January 2025

Objectives
Multiplex immunohistochemistry and immunofluorescence (mIHC/IF) are emerging technologies that can be used to help define complex immunophenotypes in tissue, quantify immune cell subsets, and assess the spatial arrangement of marker expression. mIHC/IF assays require concerted efforts to optimize and validate the multiplex staining protocols prior to their application on slides. The best practice guidelines for staining and validation of mIHC/IF assays across platforms were previously published by this task force. The current effort represents a complementary manuscript for mIHC/IF analysis focused on the associated image analysis and data management.

Methods
The Society for Immunotherapy of Cancer convened a task force of pathologists and laboratory leaders from academic centers as well as experts from pharmaceutical and diagnostic companies to develop best practice guidelines for the quantitative image analysis of mIHC/IF output and data management considerations.

Results
Best-practice approaches for image acquisition, color deconvolution and spectral unmixing, tissue and cell segmentation, phenotyping, and algorithm verification are reviewed. Additional quality control (QC) measures such as batch-to-batch correction and QC for assembled images are also discussed. Recommendations for sharing raw outputs, processed results, key analysis programs and source code, and representative photomicrographs from mIHC/IF assays are included. Lastly, multi-institutional harmonization efforts are described.

Conclusions
mIHC/IF technologies are maturing and are routinely included in research studies and moving towards clinical use. Guidelines for how to perform and standardize image analysis on mIHC/IF-stained slides will likely contribute to more comparable results across laboratories and pave the way for clinical implementation. A checklist encompassing these two-part guidelines for the generation of robust data from quantitative mIHC/IF assays will be provided in a third publication from this task force. While the current effort is mainly focused on best practices for characterizing the tumor microenvironment, these principles are broadly applicable to any mIHC/IF assay and associated image analysis.
Prospective association of tobacco retailer density and neighbourhood walkability with youth vaping initiation in California, USA
Authors: Harlow Alyssa F , Thompson Laura K , Eckel Sandrah P , Leventhal Adam M , Haley Danielle F , Roberts Megan E , Cockburn Myles G , Barrington-Trimis Jessica L 
Published: January 2025

BackgroundTobacco retailer density might influence youth e-cigarette use due to increased access and exposure to point-of-sale marketing. There is a need for longitudinal investigations on the association of tobacco retailer density with youth e-cigarette use, with consideration of contextual factors such as neighbourhood walkability that could enhance retailer exposure.MethodsFive semi-annual waves (Fall 2021-Fall 2023) of a Southern California school-based cohort of youth who never vaped at baseline (n=3401; mean baseline age=15 years [range=12–17]) were merged with spatial data on tobacco retailers corresponding to each school year. Time-varying measures of retailer exposures included count of retailers within circular home buffers (800 m/1600 m buffers) and retailer density/km2within home census tracts. Discrete-time survival analyses estimated associations of time-lagged and time-varying retailer exposures with vaping initiation at each 6-month follow-up, adjusting for race/ethnicity, parental education, neighbourhood walkability and an Area Deprivation Index. Secondary analyses examined moderation by neighbourhood walkability based on a National Walkability Index.ResultsThe incident rate of vaping initiation was 3.8% per 6-month follow-up. After covariate adjustment, only associations with census tract retail density were statistically significant (risk ratio (RR) highest vs lowest quartile=1.36, 95% CI=1.01 to 1.84). In moderation analyses, count of retailers within 800 m home buffers was positively associated with vaping initiation for youth who lived in the most walkable neighbourhoods (RR=1.08, 95% CI: 1.01 to 1.16), with no association for youth in less walkable neighbourhoods (RR=1.00, 95% CI:0.95 to 1.05; interaction p-value=0.0238).ConclusionFindings highlight the potential role of restricting retailer density in preventing youth vaping, particularly in areas characterised by both greater walkability and tobacco retailer density.
Balancing specialization and adaptation in a transforming scientific landscape
Authors: Gautheron Lucas 
Published: January 2025

AbstractHow do scientists navigate between the need to capitalize on their prior knowledge through specialization, and the urge to adapt to evolving research opportunities? Drawing from diverse perspectives on adaptation, this paper proposes an unsupervised Bayesian approach motivated by Optimal Transport of the evolution of scientists’ research portfolios in response to transformations in their field. The model relies on $186{,}162$
186
,
162
scientific abstracts and authorship data to evaluate the influence of intellectual, social, and institutional resources on scientists’ trajectories within a cohort of 2108 high-energy physicists between 2000 and 2019. Using Inverse Optimal Transport, the reallocation of research efforts is shown to be shaped by learning costs, thus enhancing the utility of the scientific capital disseminated among scientists. Two dimensions of social capital, namely “diversity” and “power”, have opposite associations with the magnitude of change in scientists’ research interests: while “diversity” is associated with greater change and expansion of research portfolios, “power” is associated with more stable research agendas. Social capital plays a more crucial role in shifts between cognitively distant research areas. More generally, this work suggests new approaches for understanding, measuring and modeling collective adaptation using Optimal Transport.
Nerve Capping Using Renerve® Synthetic Collagen Conduits for Hand Amputation Neuroma Pain
Authors: TAKEDA Shinsuke , KURIMOTO Shigeru , SHIBATA Ryutaro , MITSUYA So , OKAMOTO Hideki , MURAKAMI Hideki 
Published: January 2025

Background: Amputated neuromas, a common consequence of peripheral nerve injury, can cause significant pain and may impair daily life. Herein, we conducted a retrospective study on patients who underwent a nerve-capping technique using the bioabsorbable nerve conduit Renerve®, with a minimum follow-up period of 6 months. Methods: We conducted a retrospective study to assess patients with amputation neuromas of the finger or palm who underwent surgical treatment using the capping technique with the Renerve® conduit between October 2018 and September 2022. The data on demographics, operative details, pre- and postoperative evaluations (visual analogue scale [VAS] pain scores and Tinel sign) and complications were analysed. Results: Seven patients (seven nerves) with a median age of 51 years (three men and four women) were assessed. The median follow-up duration was 15 months. Renerve® conduits of varying sizes (1.0–2.3 mm) and lengths (15–25 mm) were used. The median duration until surgery was 195 days. After the procedure, VAS pain scores significantly decreased from a baseline of 53.1 mm to 5.7 mm at the 6-month follow-up. Tinel sign persisted in four patients, and no postoperative complications occurred. Conclusions: Our study demonstrates the clinical usefulness of the Renerve® conduit as a nerve-capping technique for amputation neuroma. Considering the limited availability of real-world data on Renerve® conduits for nerve capping, our findings provide valuable insights for clinical practitioners. Level of Evidence: Level IV (Therapeutic)
The Higher Positive Amyloid Deposition in Electrophysiologically Proven Idiopathic Carpal Tunnel Syndrome Patients
Authors: MAEHARA Haruka , TADOKORO Nobuaki , UEBA Hiroaki , IKEUCHI Masahiko 
Published: January 2025

Background: Carpal tunnel syndrome (CTS) due to amyloid deposition was reported to precede fatal cardiac amyloidosis by several years. Although nerve conduction study (NCS) supports CTS diagnosis, the incidence of positive amyloid deposition in electrophysiologically proven CTS is unclear. Methods: We retrospectively analysed the demographic data including age, gender, bilateral hand involvement, amyloid deposition and NCS results, of 111 consecutive CTS patients with postoperative symptom improvement (mean 71.1 years old, male/female ratio: 44/67) who simultaneously underwent carpal tunnel release (CTR) and biopsy for amyloid deposition. Results: Electrophysiologically proven CTS patients were 102 (91.9%) out of 111 patients. Amyloid deposition was detected in 62 hands (55.9%), of which 51 were transthyretin amyloid. The NCS severity was associated with a higher prevalence of positive amyloid deposition (p < 0.01). The NCS severity also showed an increased trend between reported risk factors for positive amyloid deposition such as older age, male gender and bilateral hand symptoms (p < 0.01). Conclusions: The prevalence of positive amyloid deposition was higher than previous reports in this study. Abnormal NCS findings in CTS, such as an increased distal motor latency (DML) of abductor pollicis brevis compound muscle action potentials (APB-CMAP) or absent APB-CMAP, may help to increase the pre-test probability of amyloid deposition in tenosynovial biopsy. Level of Evidence: Level IV (Diagnostic Study)
Effectiveness of Nerve Wrapping and Capping with a Nerve Conduit and Blocking Splint Therapy for a Painful Neuroma at the Metacarpophalangeal Joint
Authors: SHINTANI Kosuke , KUBOTA Yutaka , MATSUDA Daisaku 
Published: January 2025

A 42-year-old man suffered an avulsion amputation of his right middle finger. He had undergone several surgeries since the age of 24, including amputation plasty and implantation of the injured nerve into fat and bone, but had difficulty returning to work due to persistent severe pain. He underwent nerve capping with an artificial nerve conduit at a university hospital, and his symptoms improved slightly, but immediately flared up again. Therefore, he was referred to our hospital and was treated with a blocking splint in addition to resection of the traumatic neuroma, covering with an artificial nerve conduit and wrapping with an adiposal flap. The lumen of the conduit was observed without collapse until it was resorbed, and he returned to work without pain 10 months after surgery. The blocking splint to an angle that preserves the lumen of the conduit was useful for artificial nerve surgery near the joint. Level of Evidence: Level V (Therapeutic)
Somatosensory‐Evoked Potentials and Clinical Assessments of Sensory Function Over Time in Patients With Subacute Stroke
Authors: Fuseya Hiroshi , Tashiro Syoichi , Takahashi Osamu , Kobayashi Yukiko , Tsuji Tetsuya , Mizuno Katsuhiro 
Published: January 2025

Objective: To demonstrate the utility of somatosensory evoked potentials (SEPs) following median nerve stimulation for chronological assessment of sensory function in patients with subacute stroke during rehabilitation.Design: Retrospective study.Patients: Forty‐seven patients with hemiparesis due to stroke during the subacute phase.Methods: We screened 363 patients who underwent SEP measurements at a rehabilitation hospital. Among them, 47 who underwent SEP measurements within 1 week after admission and at least 2 weeks after the initial assessment were included in this study. Sensorimotor assessments, including the Semmes−Weinstein monofilament test (SWMT), pain sensation, position sensation, two‐point discrimination, and Stroke Impairment Assessment Set (SIAS) motor tests simultaneously with SEP measurements were available for 20 of the 47 patients. The relationship between the SEP peak count and each sensorimotor assessment was examined.Results: SEP amplitudes and latencies showed no significant differences between the initial and second assessments (paired t‐test, p  > 0.05). However, the counts of SEP peaks after NI (N20) increased (Wilcoxon signed‐rank test, p  < 0.05), indicating changes in the SEP waveform. Furthermore, strong correlations were observed between SEP peak counts, stage, and all functional assessments (counts and SWMT, RS = −0.77, p < 0.001; counts and pain sensation, RS = −0.71, p < 0.001; counts and position sensation, RS = 0.75, p < 0.001; counts and two‐point discrimination, RS = −0.74, p < 0.001; stage and SWMT, RS = −0.74, p < 0.001; stage and pain sensation, RS = −0.69, p < 0.001; stage and position sensation, RS = 0.74, p < 0.001; and stage and two‐point discrimination, RS = −0.75, p < 0.001; all Spearman’s rank correlation coefficients).Conclusion: Despite the limitations of the retrospective study design, our study highlights the utility of SEPs for evaluating sensory function in patients with subacute stroke, setting the foundation for further investigations on the use of SEPs to assess functional changes in patients with subacute stroke undergoing rehabilitation.
Oxidative Phosphorylation is a Metabolic Vulnerability of Endocrine Therapy-Tolerant Persister Cells in ER+ Breast Cancer
Authors: Tau Steven , Chamberlin Mary D. , Yang Huijuan , Marotti Jonathan D. , Muskus Patricia C. , Roberts Alyssa M. , Carmichael Melissa M. , Cressey Lauren , Dragnev Christo Philip C. , Demidenko Eugene , Hampsch Riley A. , Soucy Shannon M. , Kolling Fred W. , Samkoe Kimberley S. , Alvarez James V. , Kettenbach Arminja N. , Miller Todd W. 
Published: January 2025

Abstract
Despite adjuvant treatment with endocrine therapies, estrogen receptor-positive (ER+) breast cancers recur in a significant proportion of patients. Recurrences are attributable to clinically undetectable endocrine-tolerant persister cancer cells that retain tumor-forming potential. Therefore, strategies targeting such persister cells may prevent recurrent disease. Using CRISPR-Cas9 genome-wide knockout screening in ER+ breast cancer cells, we identified a survival mechanism involving metabolic reprogramming with reliance upon mitochondrial respiration in endocrine-tolerant persister cells. Quantitative proteomic profiling showed reduced levels of glycolytic proteins in persisters. Metabolic tracing of glucose revealed an energy-depleted state in persisters where oxidative phosphorylation was required to generate ATP. A phase II clinical trial was conducted to evaluate changes in mitochondrial markers in primary ER+/HER2- breast tumors induced by neoadjuvant endocrine therapy (NCT04568616). In an analysis of tumor specimens from 32 patients, tumors exhibiting residual cell proliferation after aromatase inhibitor-induced estrogen deprivation with letrozole showed increased mitochondrial content. Genetic profiling and barcode lineage tracing showed that endocrine-tolerant persistence occurred stochastically without genetic predisposition. Pharmacological inhibition of mitochondrial complex I suppressed the tumor-forming potential of persisters in mice and synergized with the anti-estrogen fulvestrant to induce regression of patient-derived xenografts. These findings indicate that mitochondrial metabolism is essential in endocrine-tolerant persister ER+ breast cancer cells and warrant the development of treatment strategies to leverage this vulnerability for treating breast cancer.
Usefulness of Aortic Valve Calcification in Patients With Low-Flow Aortic Stenosis
Authors: Mogensen Nils Sofus Borg , Sanchez Dahl Jordi , Ali Mulham , Annabi Mohamed-Salah , Haujir Amal , Powers Andréanne , Carter-Storch Rasmus , Grenier-Delaney Jasmine , Møller Jacob Eifer , Øvrehus Kristian Altern , Pibarot Philippe , Clavel Marie-Annick 
Published: January 2025

BACKGROUND:
Aortic valve calcification (AVC) has been shown to be a powerful assessment of aortic stenosis (AS) severity and a predictor of adverse outcomes. However, its accuracy in patients with low-flow AS has not yet been proven. The objective of the study was to assess the predictive value of AVC in patients with classical low-flow (CLF, that is, low-flow reduced left ventricular ejection fraction) or paradoxical low-flow (PLF, that is, low-flow preserved left ventricular ejection fraction) AS.

METHODS:
We prospectively included 641 patients, 319 (49.8%) with CLF-AS and 322 (50.2%) with PLF-AS, who underwent Doppler echocardiography and multidetector computed tomography. AVC ratio (AVCratio) was calculated as AVC divided by the sex-specific AVC threshold for AS severity; AVC score ≥2000 Agatston units in male patients and ≥1200 Agatston units in female patients. The primary end point of the study was all-cause mortality regardless of treatment.

RESULTS:

Sex-specific AVC thresholds identified AS severity correctly in 137 (87%) of the patients. During a median follow-up of 4.9 (4.3–5.9) years, there were 265 deaths. After comprehensive adjustment, AVCratio was associated with all-cause mortality in patients with CLF-AS (adjusted hazard ratio, 1.25 [95% CI, 1.01–1.56];
P
=0.046) and PLF-AS (adjusted hazard ratio, 1.51 [95% CI, 1.14–2.00];
P
=0.004). There was an interaction (
P
=0.001) between AVC and AS flow patterns (ie, CLF versus PLF) with regard to the prediction of mortality. The best AVCratio threshold to predict mortality was different in patients with CLF-AS (AVCratio ≥0.7) and PLF-AS (AVCratio ≥1). After a comprehensive analysis, AVCratio as a dichotomic variable was associated with all-cause mortality in all groups (
P
≤0.001). The addition of AVCratio to the models improved all models’ predictive value (all net reclassification index >18%; all
P
≤0.05).

CONCLUSIONS:
In patients with CLF-AS or PLF-AS, AVC is a major predictor of mortality. Thus, AVC should be used in low-flow patients to assess AS severity and stratify risk. Importantly, in patients with reduced left ventricular ejection fraction, a nonsevere AS (ie, AVC 70% of severe) could be associated with reduced survival.
NPA7: A Dual Receptor Activating Peptide That Inhibits Cardiac Oxidative Stress
Authors: Ma Xiaoyu , Malsawmzuali Joute Chawngvawr , Moroni Dante G. , Ma Xiao , Zheng Ye , Pan Shuchong , Wang Ying , Sangaralingham S. Jeson , Burnett John C. 
Published: January 2025

BACKGROUND:
Cardiomyocyte oxidative stress significantly contributes to the progression of hypertension-induced heart failure, highlighting the need for targeted therapies. We developed a novel peptide, NPA7, that coactivates the GC-A (guanylyl cyclase A)/cGMP and MasR (Mas receptor)/cAMP pathway. This study aimed to test NPA7’s ability to inhibit oxidative stress by modulating the p62 (Sequestosome 1)-KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (nuclear factor erythroid 2-related factor 2) pathway in human cardiomyocytes (HCMs) and a rat model of hypertension.

METHODS:

Oxidative stress was induced in HCMs using H
2
O
2
with phosphate-buffered saline or NPA7 treatment. Intracellular reactive oxygen species levels were assessed via dihydroethidium staining. Western blotting analysis measured p62, KEAP1, and NRF2 protein levels, while GSH/GSSG (glutathione/glutathione disulfide) ratios and antioxidant gene expression were analyzed. HCMs were transfected with small interfering RNA targeting GC-A, MasR, or p62 before NPA7 and H
2
O
2
treatment. In vivo, spontaneously hypertensive rats received saline or NPA7, with normotensive Wistar Kyoto rats as control and cardiac oxidative stress, KEAP1 protein levels, NOX2 (NADPH oxidase 2), and p67 (NADPH oxidase subunit p67-phox) mRNA levels were measured.

RESULTS:

NPA7 reduced H
2
O
2
-induced reactive oxygen species levels and increased GSH/GSSG ratio in HCMs. Silencing GC-A (guanylyl cyclase A receptor) and MasR (Mas receptor) reversed NPA7’s effects. NPA7 activated the KEAP1-NRF2 pathway, enhancing NRF2’s antioxidant target gene expression. In p62 knockdown HCMs, NPA7-induced KEAP1 degradation and NRF2 activation were diminished. Reactive oxygen species levels were elevated in spontaneously hypertensive rat versusWistar Kyoto rats’ hearts, however, NPA7 treatment reduced myocardial reactive oxygen species, suppressed KEAP1 protein, and decreased NOX2 and p67 mRNA levels.

CONCLUSIONS:
NPA7 exhibits antioxidant properties in HCMs and spontaneously hypertensive rat hearts by targeting GC-A and MasR through the p62-KEAP1-NRF2 pathway, supporting a novel therapeutic approach against cardiovascular disease–related oxidative stress.