bluuebunny/crossref_metadata_2025_split huggingface dataset:
An optimized method for IgE-mediated degranulation of human lung mast cells
Authors: Gong Yitao , Johnsson Anna-Karin , Säfholm Jesper , Al-Ameri Mamdoh , Sachs Erik , Vali Kasra , Nilsson Gunnar , Rönnberg Elin 
Published: May 2024

BackgroundMast cells are critically involved in IgE-mediated diseases, e.g., allergies and asthma. Human mast cells are heterogeneous, and mast cells from different anatomical sites have been shown to respond differently to certain stimuli and drugs. The origin of the mast cells is therefore of importance when setting up a model system, and human lung mast cells are highly relevant cells to study in the context of asthma. We therefore set out to optimize a protocol of IgE-mediated activation of human lung mast cells.MethodsHuman lung mast cells were extracted from lung tissue obtained from patients undergoing pulmonary resection by enzyme digestion and mechanical disruption followed by CD117 magnetic-activated cell sorting (MACS) enrichment. Different culturing media and conditions for the IgE-mediated degranulation were tested to obtain an optimized method.ResultsIgE crosslinking of human lung mast cells cultured in serum-free media gave a stronger response compared to cells cultured with 10% serum. The addition of stem cell factor (SCF) did not enhance the degranulation. However, when the cells were put in fresh serum-free media 30 minutes prior to the addition of anti-IgE antibodies, the cells responded more vigorously. Maximum degranulation was reached 10 minutes after the addition of anti-IgE. Both CD63 and CD164 were identified as stable markers for the detection of degranulated mast cells over time, while the staining with anti-CD107a and avidin started to decline 10 minutes after activation. The levels of CD203c and CD13 did not change in activated cells and therefore cannot be used as degranulation markers of human lung mast cells.ConclusionsFor an optimal degranulation response, human lung mast cells should be cultured and activated in serum-free media. With this method, a very strong and consistent degranulation response with a low donor-to-donor variation is obtained. Therefore, this model is useful for further investigations of IgE-mediated mast cell activation and exploring drugs that target human lung mast cells, for instance, in the context of asthma.
International regulatory and publicly-funded initiatives to advance drug repurposing
Authors: Spin Eva Louise , Mantel-Teeuwisse Aukje K. , Pasmooij Anna Maria Gerdina 
Published: May 2024

IntroductionAlthough drug repurposing holds great potential in addressing unmet needs, successful practical implementation is challenging and has been less widespread than anticipated. Regulators may play a critical role in addressing this, and recent years have seen the conception of regulator-initiated and publicly-funded repurposing initiatives, with significant regulator involvement.MethodsInternational regulators and public funders (n = 8) were interviewed to obtain insight in how repurposing can be advanced from a regulatory perspective. Transcripts were thematically analyzed.ResultsMost initiatives employed a broad concept of repurposing. While patient access was the main focus, label extension remained the gold standard. Commonly perceived barriers were a lack of regulatory expertise, limited downstream drug development, insufficient financial incentives, inadequate awareness of challenges, and poor collaboration. Ways for regulators to facilitate repurposing include early and accessible involvement fostering education, collaboration, and awareness. Increased stakeholder engagement, including internationally, was recommended. Legislative changes may enable the current repurposing ecosystem to evolve.DiscussionRegulators may play a central role in advancing repurposing by reconsidering their responsibilities within the current regulatory framework, both in mitigating repurposing pitfalls and actively encouraging repurposing initiatives by industry and non-traditional drug developers.
Most accurate mutations in SARS-CoV-2 genomes identified in Uzbek patients show novel amino acid changes
Authors: Ayubov Mirzakamol S. , Mirzakhmedov Mukhammadjon K. , Yusupov Abdurakhmon N. , Asrorov Akmal M. , Nosirov Bakhtiyor V. , Usmanov Dilshod E. , Shermatov Shukhrat E. , Ubaydullaeva Khurshida A. , Abdukarimov Abdusattor , Buriev Zabardast T. , Abdurakhmonov Ibrokhim Y. 
Published: May 2024

PurposeThe rapid changes in the coronavirus genomes created new strains after the first variation was found in Wuhan in 2019. SARS-CoV-2 genotypes should periodically undergo whole genome sequencing to control it because it has been extremely helpful in combating the virus. Many diagnoses, treatments, and vaccinations have been developed against it based on genome sequencing. With its practical implications, this study aimed to determine changes in the delta variant of SARS-CoV-2 widespread in Uzbekistan during the pandemic by genome sequencing, thereby providing crucial insights for developing effective control strategies that can be directly applied in the field.DesignWe meticulously generated 17 high-quality whole-genome sequence data from 48 SARS-CoV-2 genotypes of COVID-19 patients who tested positive by PCR in Tashkent, Uzbekistan. Our rigorous approach, which includes stringent quality control measures and multiple rounds of verification, ensures the accuracy and reliability of our findings.MethodsOur study employed a unique combination of genome sequencing and bioinformatics web tools to analyze amino acid (AA) changes in the virus genomes. This approach allowed us to understand the genetic changes in the delta variant of SARS-CoV-2 widespread in Uzbekistan during the pandemic.ResultsOur study revealed significant nucleotide polymorphisms, including non-synonymous (missense) and synonymous mutations in the coding regions of the sequenced sample genomes. These findings, categorized by phylogenetic analysis into the G clade (or GK sub-clade), contribute to our understanding of the delta variant of SARS-CoV-2 widespread in Uzbekistan during the pandemic. A total of 134 mutations were identified, consisting of 65 shared and 69 unique mutations. These nucleotide changes, including one frameshift mutation, one conservative and disruptive insertion-deletion, four upstream region mutations, four downstream region mutations, 39 synonymous mutations, and 84 missense mutations, are crucial in the ongoing battle against the virus.ConclusionThe comprehensive whole-genome sequencing data presented in this study aids in tracing the origins and sources of circulating SARS-CoV-2 variants and analyzing emerging variations within Uzbekistan and globally. The genome sequencing of SARS-CoV-2 from samples collected in Uzbekistan in late 2021, during the peak of the pandemic’s second wave nationwide, is detailed here. Following acquiring these sequences, research efforts have focused on developing DNA and plant-based edible vaccines utilizing prevalent SARS-CoV-2 strains in Uzbekistan, which are currently undergoing clinical trials.
Gut microbiota and functional dyspepsia: a two-sample Mendelian randomization study
Authors: Xv Yichuan , Chen Jiaxu , Lin Jiang 
Published: May 2024

BackgroundNumerous studies have established that alterations in the gut microbiota (GM) constitute an embedded mechanism in functional dyspepsia (FD). However, the specific GM taxa implicated in the pathological process of FD have remained unclear.MethodsA two-sample Mendelian randomization analysis was initially conducted to examine the causal relationships between GM and FD, utilizing GWAS data from the MiBioGen Consortium (18,340 cases) and FinnGenn (8,875 cases vs. 320,387 controls). The MR study primarily employed the inverse-variance weighted (IVW) method. Sensitivity analyses were performed to test for heterogeneity and pleiotropy. Single-nucleotide polymorphisms of causal GM taxa were mapped to genes, which were subsequently assessed for causal relationships with FD employing the same methodology.ResultsIVW results revealed that the genus Clostridium innocuum group (OR: 1.12, 95% CI: 1.02–1.24, P = 0.020) and genus Ruminiclostridium 9 were positively associated with FD risk (OR: 1.27, 95% CI: 1.03–1.57, P = 0.028), while the genus Lachnospiraceae FCS020 group tended to exert a negative effect on FD risk (OR = 0.84, 95% CI: 0.73–0.98, P = 0.023). Among GM-related genes, a notable association was observed between RSRC1 and increased FD risk (OR = 1.13, 95% CI: 1.07–1.20, P &lt; 0.001). In sensitivity analyses, no significant pleiotropy or heterogeneity of the results was found.ConclusionsThis study furnished evidence for distinct effects of specific GM taxa on FD risk and hinted at a potential biological mechanism, thereby offering theoretical underpinning for future microbiotherapy of FD.
Dissecting and tracing the gut microbiota of infants with botulism: a cross sectional and longitudinal study
Authors: Wang Dai , Li Kexin , Wang Lijuan , Teng Zhongqiu , Luo Xia , Sun Hui , Huang Ying , Hu Songnian , Xu Xuefang , He Zilong 
Published: May 2024

BackgroundInfant botulism is caused by botulinum neurotoxin (BoNT), which is mainly produced by Clostridium botulinum. However, there is a lack of longitudinal cohort studies on infant botulism. Herein, we have constructed a cross-sectional and longitudinal cohort of infants infected with C. botulinum. Our goal was to reveal the differences in the intestinal microbiota of botulism-infected and healthy infants as well as the dynamic changes over time through multi-omics analysis.MethodsWe performed 16S rRNA sequencing of 20 infants’ stools over a period of 3 months and conducted whole genome sequencing of isolated C. botulinum strains from these laboratory-confirmed cases of infant botulism. Through bioinformatics analysis, we focused on the changes in the infants’ intestinal microbiota as well as function over time series.ResultsWe found that Enterococcus was significantly enriched in the infected group and declined over time, whereas Bifidobacterium was significantly enriched in the healthy group and gradually increased over time. 18/20 isolates carried the type B 2 botulinum toxin gene with identical sequences. In silico Multilocus sequence typing found that 20\u00B0C. botulinum isolates from the patients were typed into ST31 and ST32.ConclusionDifferences in intestinal microbiota and functions in infants were found with botulism through cross-sectional and longitudinal studies and Bifidobacterium may play a role in the recovery of infected infants.
Bioinformatics gene analysis for potential biomarkers and therapeutic targets of Parkinson’s disease based on neutrophil extracellular traps
Authors: Wang Qiang , Gu Youquan , Chen Jun , Liu Xiaoyan , Xie Chen , Wang Xueping 
Published: May 2024

IntroductionNeutrophil extracellular traps (NETs) provide key innate immune mechanisms, and studies have shown innate immunity and adaptive immunity are directly linked to Parkinson’s disease (PD) pathology. However, limited research has been conducted on NETs in the context of PD.MethodsA differential analysis was implemented to acquire differentially expressed genes (DEGs) between PD and control as well as between high- and low-score groups determined by a gene set variation analysis (GSVA). Then, the genes within the critical module, obtained through a weighted gene co-expression network analysis (WGCNA), were intersected with the DEGs to identify the overlapping genes. Then, five kinds of algorithms in the protein–protein interaction (PPI) were performed to identify potential biomarkers. Subsequently, a nomogram for forecasting PD probability was created. An enrichment analysis and an immune infiltration analysis were performed on the identified biomarkers. qRT-PCR was performed to validate the expression trends of three biomarkers.ResultsWe revealed 798 DEGs between PD and control groups as well as 168 DEGs between high- and low-score groups obtained by differential analyses. The pink module containing 926 genes was identified as the critical module. According to the intersection of these gene sets, a total of 43 overlapping genes were screened out. Furthermore, GPR78, CADM3, and CACNA1E were confirmed as biomarkers. Moreover, we found that biomarkers mainly participated in pathways, such as the ‘hydrogen peroxide catabolic process’, and ‘cell cycle’; five kinds of differential immune cells between PD and control groups were identified. Finally, the qRT-PCR analysis demonstrated the up-regulation of GPR78, CADM3, and CACNA1E in the PD group.DiscussionOur study authenticated GPR78, CADM3, and CACNA1E as the biomarkers associated with PD. These findings provide an original reference for the diagnosis and treatment of PD.
Vascular architecture characters and risk factors analysis of unstable moyamoya disease
Authors: Zhao Liming , Wu Ruiyu , Xue Bingqian , Gao Tao , Liu Yang , Sun Yuxue , Guo Gaochao , Li Tianxiao , Li Chaoyue 
Published: May 2024

BackgroundIn some MMD patients, the digital subtraction angiography (DSA) examination found, occlusion in the ipsilateral internal carotid artery or middle cerebral artery, accompanied by the formation of numerous moyamoya vessels. Conversely, the contralateral internal carotid artery or middle cerebral artery shows signs of stenosis without the presence of moyamoya vessels. Notably, cerebral perfusion studies reveal a similar or even more severe reduction in perfusion on the occluded side compared to the stenotic side. Importantly, clinical symptoms in these patients are typically attributed to ischemia caused by the stenotic side. This condition is referred to as unstable moyamoya disease (uMMD).ObjectiveThis clinical research focuses on evaluating risk factors related to MMD and developing strategies to minimize postoperative complications. The study aims to analyze vascular characteristics and identify potential risk factors in patients with uMMD.MethodsThe authors reviewed consecutive cases with complete clinical and radiological documentation of patients who underwent surgery between January 2018 and June 2023. Univariate analysis and multivariate logistic regression analysis were employed to understand the risk factors and prognosis of postoperative complications in uMMD.ResultsPostoperative complications were retrospectively analyzed in 1481 patients (aged 14 to 65). Among them, 1,429 patients were assigned to the conventional treatment group, while 52 were in the unstable moyamoya disease group. The uMMD treatment group showed a significantly higher incidence of early postoperative complications such as RIND, cerebral infarction, and cerebral hemorrhage (p &lt; 0.05). Univariate and multivariate logistic regression analyses were conducted on the postoperative complications of 52 uMMD patients. Initial symptoms of stenosis ≤50% (univariate: p = 0.008, multivariate: p = 0.015; OR [95% CI] =23.149 [1.853–289.217]) and choosing occluded side surgery (univariate: p = 0.043, multivariate: p = 0.018; OR [95% CI] =0.059 [0.006–0.617]) were identified as significant risk factors for postoperative neurological complications.ConclusionCompared to the conventional treatment group, uMMD has higher complication rates, with vascular stenosis degree and surgical side selection identified as significant risk factors. A comprehensive understanding of preoperative clinical symptoms and vascular characteristics in moyamoya disease patients, coupled with the formulation of rational surgical plans, contributes positively to decreasing postoperative mortality and disability rates in uMMD.
Clinical value of auditory nerve enhancement in idiopathic sudden sensorineural hearing loss: a retrospective study
Authors: Sun Xiao , Chen Lei , Hu Na , Xiong Wenping , Wang Yingjun , Lu Kunpeng , Duan Fujia , Wang Haibo , Wang Mingming 
Published: May 2024

BackgroundThe pathogenesis of idiopathic sudden sensorineural hearing loss remains unclear, and no substantial breakthroughs have been achieved in its treatment. Therefore, we conducted this study with the aim to investigate the clinical features and prognostic factors of patients with idiopathic sudden sensorineural hearing loss and auditory nerve enhancement by using three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) magnetic resonance imaging (MRI) of the inner ear.MethodsWe retrospectively analyzed the clinical data of adult patients, who experienced sudden unilateral deafness and were admitted to the Department of Otolaryngology, Shandong Provincial ENT Hospital, between December 2020 and July 2021. Patients were divided into an auditory nerve enhancement group and a normal inner ear group, according to 3D-FLAIR MRI findings. Differences in sex, age, side, disease course, underlying diseases, dizziness/vertigo, vestibular function, degree of deafness, hearing classification, and treatment efficacy were analyzed.ResultsOf the 112 cases of sudden idiopathic deafness, 16.07% exhibited enhancement of the auditory nerve on inner-ear 3D-FLAIR MRI. Statistically significant differences in the degree and type of hearing loss were detected between the two groups (p &lt; 0.05). The rates of abnormal results in the caloric, vestibular-evoked myogenic potential, and video head impulse tests were higher in the auditory nerve enhancement group. The cure rate (11.1%) in patients with auditory nerve enhancement was lower than that in patients with normal inner ear MRI findings (28.7%); however, the difference was not statistically significant.ConclusionFindings from 3D-FLAIR MRI scans of the inner ear indicated that patients with sudden deafness and auditory nerve enhancement experienced severe hearing loss, aggravated vestibular function injury, and a significantly decreased cure rate. Prompt treatment, ideally within 2 weeks of disease onset, can facilitate hearing recovery.
MR histology reveals tissue features beneath heterogeneous MRI signal in genetically engineered mouse models of sarcoma
Authors: Blocker Stephanie J. , Mowery Yvonne M. , Everitt Jeffrey I. , Cook James , Cofer Gary Price , Qi Yi , Bassil Alex M. , Xu Eric S. , Kirsch David G. , Badea Cristian T. , Johnson G. Allan 
Published: May 2024

PurposeTo identify significant relationships between quantitative cytometric tissue features and quantitative MR (qMRI) intratumorally in preclinical undifferentiated pleomorphic sarcomas (UPS).Materials and methodsIn a prospective study of genetically engineered mouse models of UPS, we registered imaging libraries consisting of matched multi-contrast in vivo MRI, three-dimensional (3D) multi-contrast high-resolution ex vivo MR histology (MRH), and two-dimensional (2D) tissue slides. From digitized histology we generated quantitative cytometric feature maps from whole-slide automated nuclear segmentation. We automatically segmented intratumoral regions of distinct qMRI values and measured corresponding cytometric features. Linear regression analysis was performed to compare intratumoral qMRI and tissue cytometric features, and results were corrected for multiple comparisons. Linear correlations between qMRI and cytometric features with p values of &lt;0.05 after correction for multiple comparisons were considered significant.ResultsThree features correlated with ex vivo apparent diffusion coefficient (ADC), and no features correlated with in vivo ADC. Six features demonstrated significant linear relationships with ex vivo T2*, and fifteen features correlated significantly with in vivo T2*. In both cases, nuclear Haralick texture features were the most prevalent type of feature correlated with T2*. A small group of nuclear topology features also correlated with one or both T2* contrasts, and positive trends were seen between T2* and nuclear size metrics.ConclusionRegistered multi-parametric imaging datasets can identify quantitative tissue features which contribute to UPS MR signal. T2* may provide quantitative information about nuclear morphology and pleomorphism, adding histological insights to radiological interpretation of UPS.
Imaging response to immune checkpoint inhibitors in patients with advanced melanoma: a retrospective observational cohort study
Authors: Gupta Mehul , Stukalin Igor , Meyers Daniel E. , Heng Daniel Y. C. , Monzon Jose , Cheng Tina , Navani Vishal 
Published: May 2024

BackgroundThe association between objective imaging response and first line immune checkpoint inhibitor (ICI) therapy regimes in advanced melanoma remains uncharacterized in routine practice.MethodsWe conducted a multi-center retrospective cohort analysis of advanced melanoma patients receiving first line ICI therapy from August 2013-May 2020 in Alberta, Canada. The primary outcome was likelihood of RECIST v1.1 assessed objective imaging response between patients receiving anti-programmed cell death protein 1 (anti-PD1) monotherapy and those receiving combination ipilimumab-nivolumab. Secondary outcomes were identification of baseline characteristics associated with non-response and the association of imaging response with overall survival (OS) and time to next treatment (TTNT).Results198 patients were included, 41/198 (20.7%) had complete response, 86/198 (43.4%) had partial response, 23/198 (11.6%) had stable disease, and 48/198 (24.2%) had progressive disease. Median OS was not reached (NR) (95% CI 49.0-NR) months for complete responders, NR (95%CI 52.9-NR) months for partial responders, 33.7 (95%CI 15.8-NR) months for stable disease, and 6.4 (95%CI 5.2–10.1) months for progressive disease (log-rank p&lt;0.001). Likelihood of objective imaging response remained similar between anti-PD1 monotherapy and ipilimumab-nivolumab groups (OR 1.95 95%CI 0.85–4.63, p=0.121). Elevated LDH level (OR 0.46; 95%CI 0.21–0.98, p=0.043), mucosal primary site (OR 0.14; 95%CI 0.03–0.48, p=0.003), and BRAF V600E mutation status (OR 0.31; 95%CI 0.13–0.72, p=0.007) were associated with decreased likelihood of response.ConclusionNo significant difference in likelihood of imaging response between anti-PD1 monotherapy and combination ipilimumab-nivolumab was observed. Elevated LDH level, mucosal primary site, and BRAF V600E mutation status were associated with decreased likelihood of response. Given that pivotal clinical trials of ipilimumab-nivolumab did not formally compare ipilimumab-nivolumab with nivolumab monotherapy, this work adds context to differences in outcomes when these agents are used. These results may inform treatment selection, and aid in counseling of patients treated with first-line ICI therapy in routine clinical practice settings.
A life-threatening, massive subcutaneous hematoma caused by trauma in a patient with neurofibromatosis type 1: a case report and literature review
Authors: Zhang Lu , Wang Xingtong , Yin Huinan , Chu Wanli , Zhang Ming , Zhu Minhui , Shi Zhiyuan , Chen Zequn , Zhao Fan 
Published: May 2024

BackgroundNeurofibromatosis type 1 (NF1) is an autosomal dominant disease that can give rise to the formation of vascular lesions in affected individuals. These lesions, whether occurring spontaneously or as a result of trauma, have the potential to cause severe and even fatal hemorrhage.Case descriptionWe presented a case demonstrating the most extensive hematoma ever documented in a patient with NF1, resulting from a minor trauma. He experienced hemodynamic instability due to severe anemia. Arteriography revealed a rupture in the intercostal artery, which was successfully treated through interventional embolization to stop the hemorrhage. Additionally, we implemented a refined surgical approach, beginning with suturing, followed by the meticulous resection of necrotic and aberrant tissues, thereby markedly diminishing bleeding.ConclusionMinor trauma may cause severe bleeding in patients with NF1, which can be life-threatening. Timely diagnosis of NF1 and effective hemostatic techniques are key to successful treatment.