bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differentiation status determines the effects of IFNγ on the expression of PD-L1 and immunomodulatory genes in melanoma
Authors: Sævarsson Teitur , de Lomana Adrián López García , Sánchez Ólafur , van Esch Veerle , Ragnarsson Gunnar Bjarni , Brynjólfsson Siggeir Fannar , Steingrímsson Eiríkur , Einarsdóttir Berglind Ósk 
Published: December 2024

Abstract
Background
Melanoma cells frequently dedifferentiate in response to inflammation which can increase responses to certain cytokines. Interferon-γ (IFNγ) is an integral part of the anti-tumor immune response and can directly induce both differentiational changes and expression of immunosuppressive proteins in melanoma cells. How the differentiation status of melanoma cells affects IFNγ responses remains unclear.

Methods
Dedifferentiation of melanoma cells was induced via either siRNA or shRNA mediated MITF knockdown and the cells were subsequently treated with IFNγ. Effects of MITF knockdown and IFNγ treatment on gene expression were evaluated via qPCR and RNA sequencing. A Luminex assay was used to analyze the effects of dedifferentiation and IFNγ treatment on cytokine secretion. Effects on PD-L1 protein expression were analyzed via flow cytometry and western blotting. Inhibition of the JAK kinases, NF-κB and STAT3 with small molecule inhibitors, and siRNA mediated knockdown of STAT1 and IRF1 was applied to investigate the molecular mechanism behind IFNγ induced PD-L1 expression in dedifferentiated melanoma cells. The effects of inhibitor treatments and siRNA mediated knockdowns were evaluated via qPCR and western blotting. Bioinformatic analysis of publicly available RNA sequencing data, consisting of 45 patient derived melanoma cell lines, with or without IFNγ treatment, was conducted to assess the generalizability of the in vitro results.

Results
Dedifferentiation renders 624Mel melanoma cells hypersensitive to IFNγ stimulation in a context-dependent manner, resulting in non-additive upregulation of IFNγ-induced genes, increased PD-L1 protein expression and amplified secretion of CCL2, CXCL10 and IL-10. Furthermore, the intensified PD-L1 protein expression occurs through the JAK-STAT1-IRF1 axis. Lastly, dedifferentiated patient derived melanoma cell lines showed enhanced inflammatory signaling in response to IFNγ compared to differentiated cells, and tended to have higher PD-L1 expression, associated with increased IRF1 expression and activity.

Conclusions
Together, these findings indicate the existence of a molecular context linking dedifferentiation and IFNγ signaling in melanoma which may lead to immune evasion. Additionally, the variability in PD-L1 expression among MITFlow and MITFhigh cells suggests that high IFNγ-induced PD-L1 expression associates with enhanced inflammatory gene expression. These results imply that modulating melanoma differentiation may help shape IFNγ responsiveness.

Graphical Abstract
Supporting teams with designing for dissemination and sustainability: the design, development, and usability of a digital interactive platform
Authors: Kepper Maura M. , L’Hotta Allison J. , Shato Thembekile , Kwan Bethany M. , Glasgow Russell E. , Luke Douglas , Graham Andrea K. , Baumann Ana A. , Brownson Ross C. , Morse Brad 
Published: December 2024

Abstract
Background
Designing for Dissemination and Sustainability (D4DS) principles and methods can support the development of research products (interventions, tools, findings) that match well with the needs and context of the intended audience and setting. D4DS principles and methods are not well-known or used during clinical and public health research; research teams would benefit from applying D4DS. This paper presents the development of a new digital platform for research teams to learn and apply a D4DS process to their work.

Methods
A user-centered design (UCD) approach engaged users (n = 14) and an expert panel (n = 6) in an iterative design process from discovery to prototyping and testing. We led five design sessions using Zoom and Figma software over a 5-month period. Users (71% academics; 29% practitioners) participated in at least 2 sessions. Following design sessions, feedback from users was summarized and discussed to generate design decisions. A prototype was then built and heuristically tested with 11 users who were asked to complete multiple tasks within the platform while verbalizing their decision-making using the ‘think aloud’ procedure. The System Usability Scale (SUS) was administered at the end of each testing session. After refinements to the platform were made, usability was reassessed with 7 of 11 same users to examine changes.

Results
The interactive digital platform (the D4DS Planner) has two main components: 1) the Education Hub (e.g., searchable platform with literature, videos, websites) and 2) the Action Planner. The Action Planner includes 7 interactive steps that walk users through a set of activities to generate a downloadable D4DS action plan for their project. Participants reported that the prototype tool was moderately usable (SUS = 66) but improved following refinements (SUS = 71).

Conclusions
This is a first of its kind tool that supports research teams in learning about and explicitly applying D4DS to their work. The use of this publicly available tool may increase the adoption, impact, and sustainment of a wide range of research products. The use of UCD yielded a tool that is easy to use. This tool's future use and impact will be evaluated with a broader sample of community partners and projects and the tool will continue to be refined and improved.
Daidzein improves muscle atrophy caused by lovastatin by regulating the AMPK/FOXO3a axis
Authors: Wang Keke , Zeng Hao , Yang Hua 
Published: December 2024

Abstract
Background
Lovastatin, the main lipid-lowering component in red yeast rice, is a golden anti-lipid drug, but its long-term application is continuously challenged by potential skeletal muscle atrophy. Daidzein, an isoflavone derived from soybeans and many Chinese medicines, shows therapeutic potential in treating muscle-related diseases and metabolic disorders. However, whether daidzein can improve lovastatin-induced muscle atrophy and the specific mechanism needs to further study.

Methods
Lovastatin-induced mice and zebrafish muscle atrophy models were used to validate the protective effect of daidzein in vivo. And the lovastatin-induced C2C12 myotube atrophy model was employed to validate the therapeutic efficacy and investigate the specific mechanism of daidzein in vitro. We combined specific siRNA targeting FOXO3a and AMPK-selective inhibitor, agonist to elucidate AMPK/FOXO3a-dependent muscle-protective mechanism of daidzein. The anti-atrophy effects of daidzein through blockage of abnormal activation of AMPK/FOXO3a was presented in Immunofluorescence, H&E staining, Western blot, qRT-PCR. Serum creatine kinase level was detected by ELISA and we used mouse muscle grip instrument to detect the strength of mouse muscles.

Results
In this study, we demonstrated that daidzein could dose-dependently alleviate lovastatin-induced mice skeletal muscle atrophy, reduce serum creatine kinase, and improve muscle grip strength in mice. Mechanistically, daidzein inhibited lovastatin-induced FOXO3a phosphorylation caused by AMPK activation, thereby inhibiting FOXO3a nuclear translocation to restrain the expression of muscle-related proteins Atrogin-1 and MuRF-1. In C2C12 myotube, administration of AMPK-selective inhibitor Compound C recapitulated the therapeutic effects of daidzein against lovastatin-induced myotubes atrophy, while the anti-atrophy effects of daidzein were lost in the presence of AMPK-selective agonist MK-3903. In lovastatin-induced mice muscle atrophy models, Compound C elicited similar anti-atrophy effects as daidzein, but this effect was not potentiated when it was applied in combination with daidzein, suggesting that daidzein exerted therapeutic efficacy dependent on blockage of AMPK activity.

Conclusions
Our study identified daidzein as an effective component that ameliorated lovastatin-induced skeletal muscle atrophy through blockage of abnormal activation of AMPK/FOXO3a and transcriptional activation of genes encoding downstream muscle-related proteins. Our results also highlighted the therapeutic potential by regulating the AMPK/FOXO3a axis in management of statin-induced myotoxicity.
A case of subcutaneous metastatic malignant melanoma of the left medial ankle: a case report and review of literature
Authors: Workman Lauren , Fang Lauren , Blazevic Martina , Chen Joanna , Simman Richard 
Published: December 2024

Abstract
Background
Although rare, melanoma confined to the dermis or subcutaneous tissue without evidence of a primary cutaneous site should provoke consideration of melanoma of unknown primary. This diagnosis carries a favorable prognosis when compared with cutaneous metastatic melanoma. Several hypotheses have been proposed for how melanoma of unknown primary develops, two of which were considered in our patient case: (1) spontaneous regression of the primary tumor following metastasis or (2) the traumatic implantation of ectopic melanocytic cells in other tissues, such as the subcutaneous tissue. Although not a true example of melanoma of unknown primary, our case is still noteworthy as it represents a unique instance of melanoma presenting subcutaneously from trauma to a preexisting epidermal nevus.

Case presentation
We present the case of a 66-year-old non-Hispanic Caucasian male who initially sought evaluation for a nontender lump of the left groin. Ultrasound-guided needle biopsy demonstrated stage III malignant melanoma. Upon further history taking, it was discovered that he had a nevus of the left medial ankle that was subjected to traumatic removal. He later developed a subcutaneous nodule at the same site. Positron emission tomography scan results supported the histopathologic findings which demonstrated invasive melanoma centered in the subcutaneous tissue without an epidermal component. Following left inguinal lymph node dissection, the patient received adjuvant immunotherapy and radiation to the left inguinal area. At 6 months following completion of therapy, metastases were identified in the lungs, vertebra, ribs, and liver. The patient is currently receiving immunotherapy with ipilimumab-nivolumab.

Conclusion
As our patient did not have a readily apparent primary epidermal melanoma site at presentation, consideration was given as to whether this case may represent a melanoma of unknown primary, as originally defined by Das Gupta. This case does not meet the proposed criteria, however, as the patient reported a preexisting nevus in the area that was subjected to traumatic removal. Instead, we postulate that this trauma allowed for implantation of melanocytes into the subcutaneous tissue that later resulted in a malignant melanoma.
PATL2 mutations affect human oocyte maternal mRNA homeostasis and protein interactions in cell cycle regulation
Authors: Zhang Yin-Li , Hu Zhanhong , Jiang Huifang , Jin Jiamin , Zhou Yan , Lai Mengru , Ren Peipei , Liu Siya , Zhang Ying-Yi , Rong Yan , Zheng Wei , Zhang Shen , Tong Xiaomei , Zhang Songying 
Published: December 2024

Abstract
Background
Oocyte maturation defect (OMD) and early embryonic arrest result in female infertility. Previous studies have linked biallelic mutations in the PATL2 gene to OMD, yet the underlying mechanism remains largely unknown.

Results
This study uncovers three novel mutations (c.1201G > T, c.1284delA and c.1613 + 2_1613 + 3insGT) and three reported mutations (c.1204 C > T, c.1271T > C, c.223 − 14_223-2delCCCTCCTGTTCCA) in the PATL2 gene across five unrelated individuals exhibiting OMD, oocyte death, and early embryonic arrest. RNA sequencing revealed that PATL2 mutations decreased mRNA storage in human germinal vesicle (GV) oocytes and impeded mRNA decay during maturation and in early embryos. We demonstrate that PATL2 interacts with CPEB1 and TUT7 in human oocytes to maintain mRNA homeostasis. Additionally, we observed a reduction in CCNB1 and CCNE1 mRNA levels in PATL2-mutant GV oocytes, which may be linked to GV arrest. Employing both wild-type and mutated PATL2V401F/R402W variants, we characterized the protein interactome of PATL2, identifying disruptions of PATL2V401F/R402W variants predominantly affecting cell cycle-related proteins, including CDC23, APC1 and MAD2L1. PATL2’s interaction with and stabilization of CDC23 in oocytes may elucidate the mechanisms behind the mutation-induced MI arrest. PALT2 is required for the efficient mRNA translation and it maintains the protein level of CDC23, APC1 and MAD2L1 in mouse GV oocyte.

Conclusion
PATL2 plays a critical role in regulating mRNA accumulation and decay in human oocytes, potentially through interactions with CPEB1 and TUT7, respectively. Mutations in PATL2 lead to oocyte meiosis defects by affecting the mRNA accumulation, mRNA translation, and direct binding to and stabilizing proteins related to cell cycle regulation, such as CCNB1 and CDC23. This study expands the mutational spectrum of PATL2 and provides new insights into the molecular mechanisms underlying PATL2 mutation-associated oocyte maturation disorders.
Association of continuous renal replacement therapy downtime with fluid balance gap and clinical outcomes: a retrospective cohort analysis utilizing EHR and machine data
Authors: Braun Chloe , Takeuchi Tomonori , Lambert Josh , Liu Lucas , Roberts Sarah , Carter Stuart , Beaubien-Souligny William , Tolwani Ashita , Neyra Javier A. 
Published: December 2024

Abstract
Background
Fluid balance gap (FBgap—prescribed vs. achieved) is associated with hospital mortality. Downtime is an important quality indicator for the delivery of continuous renal replacement therapy (CRRT). We examined the association of CRRT downtime with FBgap and clinical outcomes including mortality.

Methods
This is a retrospective cohort study of critically ill adults receiving CRRT utilizing both electronic health records (EHR) and CRRT machine data. FBgap was calculated as achieved minus prescribed fluid balance. Downtime, or percent treatment time loss (%TTL), was defined as CRRT downtime in relation to the total CRRT time. Data collection stopped upon transition to intermittent hemodialysis when applicable. Linear and logistic regression models were used to analyze the association of %TTL with FBgap and hospital mortality, respectively. Covariates included demographics, Sequential Organ Failure Assessment (SOFA) score at CRRT initiation, use of organ support devices, and the interaction between %TTL and machine alarms.

Results
We included 3630 CRRT patient-days from 500 patients with a median age of 59.5 years (IQR 50–67). Patients had a median SOFA score at CRRT initiation of 13 (IQR 10–16). Median %TTL was 8.1% (IQR 4.3–12.5) and median FBgap was 17.4 mL/kg/day (IQR 8.2–30.4). In adjusted models, there was a significant positive relationship between FBgap and %TTL only in the subgroup with higher alarm frequency (6 + alarms per CRRT-day) (β = 0.87 per 1% increase, 95%CI 0.48–1.26). No association was found in the subgroups with lower alarm frequency (0–2 and 3–5 alarms). There was no statistical evidence for an association between %TTL and hospital mortality in the adjusted model with the interaction term of alarm frequency.

Conclusions
In critically ill adult patients undergoing CRRT, %TTL was associated with FBgap only in the subgroup with higher alarm frequency, but not in the other subgroups with lower alarms. No association between %TTL and mortality was observed. More frequent alarms, possibly indicating unexpected downtime, may suggest compromised CRRT delivery and could negatively impact FBgap.
Prediction of Ki-67 expression in gastric gastrointestinal stromal tumors using histogram analysis of monochromatic and iodine images derived from spectral CT
Authors: Liu Xianwang , Han Tao , Wang Yuzhu , Liu Hong , Deng Juan , Xue Caiqiang , Li Shenglin , Zhou Junlin 
Published: December 2024

Abstract
Purpose
To assess and compare the diagnostic efficiency of histogram analysis of monochromatic and iodine images derived from spectral CT in predicting Ki-67 expression in gastric gastrointestinal stromal tumors (gGIST).

Methods
Sixty-five patients with gGIST who underwent spectral CT were divided into a low-level Ki-67 expression group (LEG, Ki-67 < 10%, n = 33) and a high-level Ki-67 expression group (HEG, Ki-67 ≥ 10%, n = 32). Conventional CT features were extracted and compared. Histogram parameters were extracted from monochromatic and iodine images, respectively. The diagnostic efficiency of the histogram parameters from monochromatic and iodine images was assessed and compared between the two groups. Spearman’s correlation analysis was used to correlate histogram parameters with Ki-67 expression.

Results
The HEG was more likely to present with an irregular shape and a larger size than the LEG (all p < 0.05). Regarding histogram parameters, the HEG showed higher maximum, mean, Perc.10, Perc.25, Perc.50, Perc.75, Perc.90, Perc.99, SD, variance, and CV of monochromatic images; higher maximum, Perc.99, and entropy of iodine images, compared with the LEG (all p < 0.003125). ROC analysis showed that significant histogram parameters of monochromatic and iodine images allowed for effective differentiation between LEG and HEG. DeLong’s test showed that the diagnostic efficiency of histogram parameters in monochromatic images (Perc.90) was superior to that of iodine images (maximum) (p = 0.010). A positive correlation was observed between the significant histogram parameters and Ki-67 expression (all p < 0.05).

Conclusion
Both histogram analysis of monochromatic and iodine images derived from spectral CT can predict Ki-67 expression in gGIST, and the diagnostic efficacy of monochromatic images is superior to iodine images.
Facilitators’ experiences with virtual simulation and their impact on learning
Authors: Verkuyl Margaret , Violato Efrem , Southam Theresa , Lavoie-Tremblay Mélanie , Goldsworthy Sandra , MacEachern Diane , Atack Lynda 
Published: December 2024

Abstract
Background
Increasingly, virtual simulations are being integrated into higher education. A successful experience goes far beyond simply offering learners access to a virtual simulation; it requires a facilitator who understands the learners’ needs and course objectives, choses the right virtual simulation for the learner, creates a welcoming space that promotes learning, and evaluates the experience.

Methods
Facilitators from three different healthcare programs and six educational institutions and students from two different healthcare programs were included in this exploratory qualitative research study. Interviews and focus groups and thematic analysis were conducted to understand the role of the facilitator when using virtual simulations and their impact on student learning.

Results
The facilitator themes were supported by the student focus groups. The first theme, the facilitator experience, included sub-themes of simulation pedagogy and debriefing with a practice partner. The second theme was virtual simulation: impact on learning and included sub-themes on student outcomes, technology and design, and repetitive play.

Conclusion
Effective facilitation skills are integral to quality virtual simulation experiences. Trained facilitators help students achieve virtual simulation learning outcomes and prepare for clinical practice.
The study on multi-defect detection for leather using object detection techniques
Authors: Ataç Hasan Onur , Kayabaşı Ahmet , Aslan M. Fatih 
Published: December 2024

AbstractLeather has played a very important role in human life for thousands of years. Ensuring the quality of leather and addressing surface defects poses significant challenges. Traditionally, human inspectors are responsible for detecting surface defects in tanneries, but this approach is labor-intensive and susceptible to human error. As a result, there is a growing demand for automated systems to detect the defects. Herein, artificial intelligence (AI) was developed to detect the defects on leather surfaces. Six targeted defect types, denoted as insect bites, scratches, holes, stitch marks, diseased and ruptures, were specifically addressed to enhance the overall quality assessment process. AI-based vision techniques were used to detect flaws on the leather on photographs taken with a high-resolution camera. Deep learning algorithms Mask R-CNN, YOLOv8 and within the framework of Detectron2, RetinaNet R101 3x, Faster R-CNN R101-FPN 3x models were performed and a comparison was made between these algorithms. By using the slicing aided hyper-inference (SAHI) algorithm in coordination with these algorithms, the detection rates of small defects on the images were increased. The highest accuracy rate was achieved when the YOLOv8 algorithm had 75 epoch values for training, and the SAHI algorithm had slice height-width values of 256 × 256 pixels.
Graphical Abstract
Reoperation for chronological complete dislodgement of the bioprosthetic aortic valve into the left ventricle due to Takayasu arteritis
Authors: Matsunaga Shogo , Sonoda Hiromichi , Ushijima Tomoki , Kan-o Meikun , Kimura Satoshi , Shiose Akira 
Published: December 2024

Abstract
Background
Takayasu arteritis is a large-vessel vasculitis, in addition to giant cell arteritis. Various post-operative complications associated with the cardiac macrovasculature have been reported. Detachment of the prosthetic valve, pseudoaneurysm formation, and dilatation of the aortic root are well-known post-operative complications associated with vasculitis syndromes, including Takayasu arteritis. Here, we report a rare complication involving aortic bioprosthetic valve dislodgement in the left ventricular outflow tract due to Takayasu arteritis.

Case presentation
A 76-year-old female underwent aortic valve replacement with a 21-mm Carpentier–Edwards Perimount valve for severe aortic regurgitation and a coronary artery bypass graft from the left internal thoracic artery to the left anterior descending artery for ischemic heart disease. Fourteen years after the initial surgery, echocardiography revealed severe aortic valve sclerosis due to structural valve deterioration of the bioprosthesis. Upon scrutiny, the bioprosthetic aortic valve was found to have dislodged into the left ventricular outflow tract. We performed re-implantation of the bioprosthetic aortic valve and replacement of the ascending aorta.

Conclusions
Although dislodgement of the bioprosthetic aortic valve is an extremely rare complication associated with Takayasu arteritis, the possibility that it could occur should be considered when treating the post-operative patients.