bluuebunny/crossref_metadata_2025_split huggingface dataset:
A millifluidic bioreactor allows the long term culture of primary lymphocytes or CD34+ hematopoietic cells while allowing the detection of tumorigenic expansion
Authors: Ritter Paolo , Oliveto Stefania , Cordiglieri Chiara , Fasciani Alessandra , Di Buduo Christian Andrea , della Volpe Lucrezia , Bocconi Alberto , Conci Claudio , Miguel Carolina Paula , Di Micco Raffaella , Balduini Alessandra , Raimondi Manuela Teresa , Biffo Stefano 
Published: October 2024

Long-term culture of primary lymphocytes and hematopoietic stem and progenitor cells (HSPCs) is pivotal to their expansion and study. Furthermore, genetic engineering of the above-mentioned primary human cells has several safety needs, including the requirement of efficient in vitro assays for unwanted tumorigenic events. In this work, we tested and optimized the Miniaturized Optically Accessible Bioreactor (MOAB) platform. The MOAB consists of a millifluidic cell culture device with three optically-accessible culture chambers. Inside the MOAB, we inserted a silk-based framework that resembles some properties of the bone marrow environment and cultivated in this device either CD4+ T lymphocytes isolated from healthy donor buffy coat or cord blood-derived hematopoietic CD34+ cells. A fraction of these cells is viable for up to 3 months. Next, we tested the capability of the MOAB to detect tumorigenic events. Serial dilutions of engineered fluorescent tumor cells were mixed with either CD4+ or CD34+ primary cells, and their growth was followed. By this approach, we successfully detected as little as 100 tumorigenic cells mixed with 100,000 primary cells. We found that non-tumorigenic primary cells colonized the silk environment, whereas tumor cells, after an adaptation phase, expanded and entered the circulation. We conclude that the millifluidic platform allows the detection of rare tumorigenic events in the long-term culture of human cells.
TCRcost: a deep learning model utilizing TCR 3D structure for enhanced of TCR–peptide binding
Authors: Li Fan , Qian Xinyang , Zhu Xiaoyan , Lai Xin , Zhang Xuanping , Wang Jiayin 
Published: October 2024

IntroductionPredicting TCR–peptide binding is a complex and significant computational problem in systems immunology. During the past decade, a series of computational methods have been developed for better predicting TCR–peptide binding from amino acid sequences. However, the performance of sequence-based methods appears to have hit a bottleneck. Considering the 3D structures of TCR–peptide complexes, which provide much more information, could potentially lead to better prediction outcomes.MethodsIn this study, we developed TCRcost, a deep learning method, to predict TCR–peptide binding by incorporating 3D structures. TCRcost overcomes two significant challenges: acquiring a sufficient number of high-quality TCR–peptide structures and effectively extracting information from these structures for binding prediction. TCRcost corrects TCR 3D structures generated by protein structure tools, significantly extending the available datasets. The main and side chains of a TCR structure are separately corrected using a long short-term memory (LSTM) model. This approach prevents interference between the chains and accurately extracts interactions among both adjacent and global atoms. A 3D convolutional neural network (CNN) is designed to extract the atomic features relevant to TCR–peptide binding. The spatial features extracted by the 3DCNN are then processed through a fully connected layer to estimate the probability of TCR–peptide binding.ResultsTest results demonstrated that predicting TCR–peptide binding from 3D TCR structures is both efficient and highly accurate with an average accuracy of 0.974 on precise structures. Furthermore, the average accuracy on corrected structures was 0.762, significantly higher than the average accuracy of 0.375 on uncorrected original structures. Additionally, the average root mean square distance (RMSD) to precise structures was significantly reduced from 12.753 Å for predicted structures to 8.785 Å for corrected structures.DiscussionThus, utilizing structural information of TCR–peptide complexes is a promising approach to improve the accuracy of binding predictions.
SARS-CoV-2 induced vitamin D deficiency and psychological stress: a manifestation of autoimmune disease onset
Authors: Alobaid Meshal A. , Alqabandi Bshaier S. 
Published: October 2024

IntroductionThe global SARS-CoV-2 pandemic significantly altered lifestyles, access to healthcare, and social interactions, introducing unprecedented physical and psychological stress all over the world. This study explores the relationship between psychological stress, vitamin D (Vit-D) levels, and autoimmune connective tissue diseases, including systemic lupus erythematosus, systemic sclerosis, polymyositis, dermatomyositis, and rheumatoid arthritis.MethodsThe analysis was based on over one million patient data points derived from anti-nuclear antibody (ANA) testing conducted both before and during the COVID-19 pandemic 2017-2021. In a subset of patients, longitudinal data were collected bi-yearly to yearly over 5-8 years using the same three-month criteria. The dataset was analyzed using GraphPad Prism9 using paired t-tests or ordinary one-way ANOVA with a significance threshold of p &lt; 0.05 to ensure robust correlations between the variables.ResultsData indicated that Vit-D levels peaked between 2017 and 2019 before declining, while ANA data demonstrated a rise in autoimmune connective tissue disease cases during the pandemic, reaching a peak in 2021. A clear correlation was observed, with autoimmune disease incidence increasing as Vit-D levels decreased. In-depth case analysis revealed that declining Vit-D levels preceded higher ANA titers and increased autoimmune disease severity, whereas improvements in Vit-D levels were associated with reduced ANA titers and less severe disease manifestations.ConclusionsThe findings suggest that maintaining mental health and ensuring adequate Vit-D supplementation could be essential strategies for mitigating autoimmune disease risks and maintaining immune stability, particularly in pandemic scenarios. Clinically, these results underscore the need for early interventions targeting both psychological well-being and Vit-D levels to reduce the burden of autoimmune diseases.
M protein ectodomain-specific immunity restrains SARS-CoV-2 variants replication
Authors: Tang Yibo , Tang Kaiming , Hu Yunqi , Ye Zi-Wei , Luo Wanyu , Luo Cuiting , Cao Hehe , Wang Ran , Yue Xinyu , Liu Dejian , Liu Cuicui , Ge Xingyi , Liu Tianlong , Chen Yaoqing , Yuan Shuofeng , Deng Lei 
Published: October 2024

IntroductionThe frequent occurrence of mutations in the SARS-CoV-2 Spike (S) protein, with up to dozens of mutations, poses a severe threat to the current efficacy of authorized COVID-19 vaccines. Membrane (M) protein, which is the most abundant viral structural protein, exhibits a high level of amino acid sequence conservation. M protein ectodomain could be recognized by specific antibodies; however, the extent to which it is immunogenic and provides protection remains unclear.MethodsWe designed and synthesized multiple peptides derived from coronavirus M protein ectodomains, and determined the secondary structure of specific peptides using circular dichroism (CD) spectroscopy. Enzyme-linked immunosorbent assay (ELISA) was utilized to detect IgG responses against the synthesized peptides in clinical samples. To evaluate the immunogenicity of peptide vaccines, BALB/c mice were intraperitoneally immunized with peptide-keyhole limpet hemocyanin (KLH) conjugates adjuvanted with incomplete Freund’s adjuvant (IFA). The humoral and T-cell immune responses induced by peptide-KLH conjugates were assessed using ELISA and ELISpot assays, respectively. The efficacy of the S2M2-30-KLH vaccine against SARS-CoV-2 variants was evaluated in vivo using the K18-hACE2 transgenic mouse model. The inhibitory effect of mouse immune serum on SARS-CoV-2 virus replication in vitro was evaluated using microneutralization assays. The subcellular localization of the M protein was evaluated using an immunofluorescent staining method, and the Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) activity of the S2M2-30-specific monoclonal antibody (mAb) was measured using an ADCC reporter assay.ResultsSeroconversion rates for ectodomain-specific IgG were observed to be high in both SARS-CoV-2 convalescent patients and individuals immunized with inactivated vaccines. To assess the protective efficacy of the M protein ectodomain-based vaccine, we initially identified a highly immunogenic peptide derived from this ectodomain, named S2M2-30. The mouse serum specific to S2M2-30 showed inhibitory effects on the replication of SARS-CoV-2 variants in vitro. Immunizations of K18-hACE2-transgenic mice with the S2M2-30-keyhole limpet hemocyanin (KLH) vaccine significantly reduced the lung viral load caused by B.1.1.7/Alpha (UK) infection. Further mechanism investigations reveal that serum neutralizing activity, specific T-cell response and Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) correlate with the specific immuno-protection conferred by S2M2-30.DiscussionThe findings of this study suggest that the antibody responses against M protein ectodomain in the population most likely exert a beneficial effect on preventing various SARS-CoV-2 infections.
Long-term efficacy of mepolizumab in patients with eosinophilic granulomatosis with polyangiitis: a propensity score matching analysis in the multicenter REVEAL cohort study
Authors: Shiomi Mayu , Watanabe Ryu , Matsuda Shogo , Kotani Takuya , Okazaki Ayana , Masuda Yuichi , Yoshida Tsuneyasu , Shoji Mikihito , Tsuge Ryosuke , Kadoba Keiichiro , Hiwa Ryosuke , Yamamoto Wataru , Takeda Akitoshi , Itoh Yoshiaki , Hashimoto Motomu 
Published: October 2024

BackgroundMepolizumab (MPZ) has demonstrated efficacy in clinical trials for eosinophilic granulomatosis with polyangiitis (EGPA); however, few studies compare the disease course between patients treated with MPZ (MPZ group) and those who were not treated with MPZ (non-MPZ group) in real-world settings.ObjectivesThis study aimed to compare the disease course and outcomes between the two groups and assess the long-term efficacy of MPZ in a multicenter cohort in Japan. Methods: We enrolled 113 EGPA patients registered in the cohort until June 2023. Data on clinical characteristics, disease activity, organ damage, treatments, and outcomes were retrospectively collected. To minimize potential confounding factors, we conducted propensity score matching (PSM).ResultsAfter PSM, 37 pairs of matched patients were identified. Clinical characteristics, including age at disease onset, sex, disease duration at last observation, antineutrophil cytoplasmic antibody positivity at disease onset, Birmingham Vasculitis Activity Score (BVAS) at disease onset, and Five-factor score at disease onset, were comparable between the groups. The median BVAS at the last observation was 0 in both groups; however, more cases in the non-MPZ group exhibited elevated BVAS, resulting in a significantly higher BVAS in the non-MPZ group at the last observation (median; MPZ group: 0, non-MPZ group: 0, p=0.028). The MPZ group had significantly lower glucocorticoid (GC) doses at the last observation (median; MPZ group: 4 mg/day, non-MPZ group: 5 mg/day, p=0.011), with a higher proportion achieving a GC dose ≤ 4 mg/day at the last observation (MPZ group: 51.4%, non-MPZ group: 24.2%, p=0.027). Three models of multivariable logistic regression analyses were performed to identify factors associated with GC doses ≤ 4 mg/day at the last observation. In all models, achieving a GC dose ≤ 4 mg/day was positively associated with MPZ administration and inversely associated with asthma at disease onset. Finally, we evaluated the survival rates between the groups, and the 5-year survival rates were significantly higher in the MPZ group compared to the non-MPZ group (MPZ group: 100%, non-MPZ group: 81.3%, p=0.012).ConclusionMepolizumab not only contributes to disease activity control but also reduces the GC dose, which may lead to improved survival in EGPA patients.
Identification of PPREs and PPRE associated genes in the human genome: insights into related kinases and disease implications
Authors: Saha Pritha , Talwar Priti 
Published: October 2024

Introduction“Peroxisome Proliferator-Activated Receptors” (PPARs) belong to the class of transcription factors (TF) identified as Nuclear Receptors (NR). Upon activation by peroxisome proliferators (PPs), PPARs modulate a diverse range of genes, consequently regulating intra-cellular lipid metabolism, glucose uptake, apoptosis, and cell proliferation. Subsequent to the heterodimerization of Retinoid X Receptors (RXR) with PPARs induced by the binding of activators to PPARs, facilitates the binding of the resulting complex to Peroxisome Proliferator-Activated Receptors Response Elements (PPRE), with a consensus sequence 5’AGGTCANAGGTCA-3’, and regulate the transcription of the targeted genes.MethodsA comprehensive screening of PPRE within the whole human genome was performed using the Genome Workbench and UCSC Genome Browser to find the associated genes. Subsequently, the kinase subset was isolated from the extracted list of PPRE-related genes. Functional enrichment of the kinases was performed using FunRich, ToppGene, and ShinyGO. Network analysis and enrichment studies were then further performed using NDEx to elucidate these identified kinases' connections and significance. Additionally, the disease association of the PPRE kinases was analyzed using DisGeNET data in R studio and the COSMIC dataset.ResultsA comprehensive analysis of 1002 PPRE sequences within the human genome (T2T), yielded the identification of 660 associated genes, including 29 kinases. The engagement of these kinases in various biological pathways, such as apoptosis, platelet activation, and cytokine pathways, revealed from the functional enrichment analysis, illuminates the multifaceted role of PPAR in the regulation of cellular homeostasis and biological processes. Network analysis reveals the kinases interact with approximately 5.56% of the Human Integrated Protein-Protein Interaction rEference (HIPPIE) network. Disease association analysis using DisGeNET and COSMIC datasets revealed the significant roles of these kinases in cellular processes and disease modulation.DiscussionThis study elucidates the regulatory role of PPAR-associated genes and their association with numerous biological pathways. The involvement of the kinases with disease-related pathways highlights new potential for the development of therapeutic strategies designed for disease management and intervention.
IgG reactivity to different desmoglein-3 ectodomains in pemphigus vulgaris: novel panels for assessing disease severity
Authors: Tavakolpour Soheil , Noormohammadi Zahra , Daneshpazhooh Maryam , Gholami Alireza , Mahmoudi Hamidreza 
Published: October 2024

IntroductionPemphigus vulgaris (PV) is an autoimmune disease characterized by IgG autoantibodies targeting desmoglein-3 (Dsg3), leading to blistering of mucous membranes and skin. Although commercial ELISA kits effectively diagnose PV, correlation with clinical phenotype remains unclear. This study assesses multiple panels for monitoring disease severity and activity by profiling IgG autoantibodies against Dsg3’s various extracellular ectodomains.MethodWe designed and expressed different extracellular domains of Dsg3 in HEK293T cell line and developed 15 different ELISA panels, each using a single or multi ectodomains encompassing the entire extracellular region of Dsg3 to detect specific autoantibodies against the particular part of Dsg3.ResultsTo validate our approach, we compared our ELISA panel for the full Dsg3 (EC1-5) against a commercial kit using 154 random serum samples from PV patients, demonstrating a strong correlation. For evaluation of IgG autoantibody profiles in our panels, 59 PV patients were included, along with 11 bullous pemphigoid patients, and 49 healthy controls. For all the included subjects, 15 predefined ELISA panels were tested. The IgG autoantibodies against EC1 were detected in 86% of patients with a positive full Dsg3 ectodomain (EC1-5) ELISA, with 26% against EC2, 14% for EC3, 29% for EC4, and 23% for EC5. Among the panels with multiple Dsg3 ectodomains, EC1-3 and EC1-4 were representative of the entire Dsg3 ectodomain in terms of ELISA positivity across all included patients. A significant correlation (P&lt;0.05) was observed between ELISA optical density (OD) and Pemphigus Disease Area Index (PDAI) scores in five panels, EC1, EC2-3, EC2-5, and EC3-4 in addition to the full ectodomain. It suggests an association with disease severity. Interestingly, while the ELISA panel for the entire Dsg3 extracellular ectodomains did not differentiate disease phases, in three of our panels, including EC1, EC3-5, and EC2-5, ANOVA analysis showed a statistically significant difference between the groups of patients in remission, partial remission or persistent lesions, and those with active disease (new cases or relapse). Among these three panels, EC1 was the only one that showed a significant difference in the multiple comparisons analysis; patients in the active phase had higher levels of autoantibodies than those in ‘partial remission or persistent lesions’ and ‘complete remission’ groups.ConclusionThe level of autoantibodies against EC1 was not only correlated with the full ectodomain but also associated with higher disease severity and active disease phase. This study indicates that a detailed autoantibody profile against Dsg3 ectodomains could serve as a marker for PV severity and activity which may potentially enhance early treatment initiation.
A novel metastatic tumor segmentation method with a new evaluation metric in clinic study
Authors: Li Bin , Sun Qiushi , Fang Xianjin , Yang Yang , Li Xiang 
Published: October 2024

BackgroundBrain metastases are the most common brain malignancies. Automatic detection and segmentation of brain metastases provide significant assistance for radiologists in discovering the location of the lesion and making accurate clinical decisions on brain tumor type for precise treatment.ObjectivesHowever, due to the small size of the brain metastases, existing brain metastases segmentation produces unsatisfactory results and has not been evaluated on clinic datasets.MethodologyIn this work, we propose a new metastasis segmentation method DRAU-Net, which integrates a new attention mechanism multi-branch weighted attention module and DResConv module, making the extraction of tumor boundaries more complete. To enhance the evaluation of both the segmentation quality and the number of targets, we propose a novel medical image segmentation evaluation metric: multi-objective segmentation integrity metric, which effectively improves the evaluation results on multiple brain metastases with small size.ResultsExperimental results evaluated on the BraTS2023 dataset and collected clinical data show that the proposed method has achieved excellent performance with an average dice coefficient of 0.6858 and multi-objective segmentation integrity metric of 0.5582.ConclusionCompared with other methods, our proposed method achieved the best performance in the task of segmenting metastatic tumors.
Case report: A case of proliferative glomerulonephritis with monoclonal kappa-light chain deposits treated with daratumumab combination therapy
Authors: Wang Jue , Lv Jun-Ting , Xiao Dan , Liu Jia , Du Jun , Zhong Lu 
Published: October 2024

IntroductionProliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a chronic glomerular disease caused by monoclonal gammopathy. IgG (mainly IgG3) is the most commonly involved isotype of PGNMID. Here we illustrated a novel medication regimen for the rare variant of PGNMID with deposition of monoclonal immunoglobulin light chain only (PGNMID-LC). Daratumumab has been proved effective in the treatment of plasma cell myeloma while its effect for PGNMID-LC has rarely been reported.MethodsA daratumumab combination therapy (D-VCd regimen, specifically are daratumumab + dexamethasone + bortezomib + cyclophosphamide) was adopted to treat a patient diagnosed with PGNMID-LC.ResultsThe utility of D-VCd regimen showed a favorable effect in this patient. After the fixed course, his clinical symptom, laboratory parameters, neoplastic plasma cells clonity all restored to normal range, and no obvious disease progression was observed throughout the treatment. After a follow up of 14 months, no significant renal or hematological disease progression has been observed.ConclusionThis case underscores the utility of D-VCd regimen in treatment of PGNMID-LC, and it’s inferred that daratumumab regimen has clinical effects in the disease primarily through targeting tumor clonity. However, data on the use of daratumumab (either in monotherapy or in combination) in clinical trials of PGNMID-LC is currently so limited that that more experiments are needed to support the inference.
Incidental findings on MRI for the evaluation of endometriosis: prevalence and clinical significance
Authors: Harth Sebastian , Roller Fritz Christian , Brose Alexander , Kaya Hasan Emin , Zeppernick Felix , Meinhold-Heerlein Ivo , Krombach Gabriele Anja 
Published: October 2024

ObjectivesThis study aimed to analyze the prevalence and clinical significance of incidental findings on MRI for endometriosis. Differences between patients with and without evidence of deep infiltrating endometriosis on MRI were to be examined.MethodsThis was a retrospective, descriptive cross-sectional single-center study. All patients who received a pelvic MRI for endometriosis between April 2021 and February 2023 were included. The presence and frequency of incidental findings were noted after review of all MR images and radiology reports. The potential clinical significance of the findings was analyzed. Differences in the frequency of incidental findings between patients with and without evidence of deep infiltrating endometriosis on MRI were evaluated, utilizing the Chi-square test, Fisher's exact test and Mann–Whitney U-test.Results303 consecutive patients (mean age, 33.4 years ± 8.3) were evaluated. Incidental findings were noted in 299/303 (98.7%) patients. Most frequently, ossification of the hip acetabular rim and degenerative changes of the lumbar spine were noted. In 25/303 (8.3%) patients, incidental findings had high clinical significance. For specific incidental findings, significantly higher prevalences were found in patients with than in patients without evidence of deep infiltrating endometriosis on MRI (hip acetabular rim ossification, p = 0.041; annulus fibrosus fissures, p = 0.006; gallstones, p = 0.042).ConclusionsIncidental findings are very common on pelvic MRI for endometriosis. The detection of incidental findings can lead to the diagnosis of relevant diseases and thus enable early treatment. On the other hand, many incidental findings have no, only minor, or uncertain consequences.
Advancing healthcare through data: the BETTER project's vision for distributed analytics
Authors: Bregonzio Matteo , Bernasconi Anna , Pinoli Pietro 
Published: October 2024

IntroductionData-driven medicine is essential for enhancing the accessibility and quality of the healthcare system. The availability of data plays a crucial role in achieving this goal.MethodsWe propose implementing a robust data infrastructure of FAIRification and data fusion for clinical, genomic, and imaging data. This will be embedded within the framework of a distributed analytics platform for healthcare data analysis, utilizing the Personal Health Train paradigm.ResultsThis infrastructure will ensure the findability, accessibility, interoperability, and reusability of data, metadata, and results among multiple medical centers participating in the BETTER Horizon Europe project. The project focuses on studying rare diseases, such as intellectual disability and inherited retinal dystrophies.ConclusionThe anticipated impacts will benefit a wide range of healthcare practitioners and potentially influence health policymakers.