bluuebunny/crossref_metadata_2025_split huggingface dataset:
miRNA signatures underlie chemoresistance in the gemcitabine-resistant pancreatic ductal adenocarcinoma cell line MIA PaCa-2 GR
Authors: Fuller Ryan N. , Vallejos Paul A. , Kabagwira Janviere , Liu Tiantian , Wang Charles , Wall Nathan R. 
Published: June 2024

Introduction: Chemotherapy resistance remains a significant challenge in the treatment of pancreatic adenocarcinoma (PDAC), particularly in relation to gemcitabine (Gem), a commonly used chemotherapeutic agent. MicroRNAs (miRNAs) are known to influence cancer progression and chemoresistance. This study investigates the association between miRNA expression profiles and gemcitabine resistance in PDAC.Methods: The miRNA expression profiles of a gemcitabine-sensitive (GS) PDAC cell line, MIA PaCa-2, and its gemcitabine-resistant (GR) progeny, MIA PaCa-2 GR, were analyzed. miRNA sequencing (miRNA-seq) was employed to identify miRNAs expressed in these cell lines. Differential expression analysis was performed, and Ingenuity Pathway Analysis (IPA) was utilized to elucidate the biological functions of the differentially expressed miRNAs.Results: A total of 1867 miRNAs were detected across both cell lines. Among these, 97 (5.2%) miRNAs showed significant differential expression between the GR and GS cell lines, with 65 (3.5%) miRNAs upregulated and 32 (1.7%) miRNAs downregulated in the GR line. The most notably altered miRNAs were implicated in key biological processes such as cell proliferation, migration, invasion, chemosensitization, alternative splicing, apoptosis, and angiogenesis. A subset of these miRNAs was further analyzed in patient samples to identify potential markers for recurrent tumors.Discussion: The differential miRNA expression profiles identified in this study highlight the complex regulatory roles of miRNAs in gemcitabine resistance in PDAC. These findings suggest potential targets for improving prognosis and tailoring treatment strategies in PDAC patients, particularly those showing resistance to gemcitabine. Future research should focus on validating these miRNAs as biomarkers for resistance and exploring their therapeutic potential in overcoming chemoresistance.
Uncovering periodontitis-associated markers through the aggregation of transcriptomics information from diverse sources
Authors: Peng Chujun , Huang Jinhang , Li Mingyue , Liu Guanru , Liu Lingxian , Lin Jiechun , Sun Weijun , Liu Hongtao , Huang Yonghui , Chen Xin 
Published: June 2024

IntroductionPeriodontitis, a common chronic inflammatory disease, significantly impacted oral health. To provide novel biological indicators for the diagnosis and treatment of periodontitis, we analyzed public microarray datasets to identify biomarkers associated with periodontitis.MethodThe Gene Expression Omnibus (GEO) datasets GSE16134 and GSE106090 were downloaded. We performed differential analysis and robust rank aggregation (RRA) to obtain a list of differential genes. To obtain the core modules and core genes related to periodontitis, we evaluated differential genes through enrichment analysis, correlation analysis, protein-protein interaction (PPI) network and competing endogenous RNA (ceRNA) network analysis. Potential biomarkers for periodontitis were identified through comparative analysis of dual networks (PPI network and ceRNA network). PPI network analysis was performed in STRING. The ceRNA network consisted of RRA differentially expressed messenger RNAs (RRA_DEmRNAs) and RRA differentially expressed long non-coding RNAs (RRA_DElncRNAs), which regulated each other’s expression by sharing microRNA (miRNA) target sites.ResultsRRA_DEmRNAs were significantly enriched in inflammation-related biological processes, osteoblast differentiation, inflammatory response pathways and immunomodulatory pathways. Comparing the core ceRNA module and the core PPI module, C1QA, CENPK, CENPU and BST2 were found to be the common genes of the two core modules, and C1QA was highly correlated with inflammatory functionality. C1QA and BST2 were significantly enriched in immune-regulatory pathways. Meanwhile, LINC01133 played a significant role in regulating the expression of the core genes during the pathogenesis of periodontitis.ConclusionThe identified biomarkers C1QA, CENPK, CENPU, BST2 and LINC01133 provided valuable insight into periodontitis pathology.
Long-term outcomes and predictive factors of achieving low disease activity status in childhood systemic lupus erythematosus: a Chinese bicentric retrospective registered study
Authors: Yu Xi Xi , Deng Jia , Chen Qiu Xia , Qiu Shi Yuan , Jiang Chao Hui , Wu Yi Qian , Yang Qin , Zhang Gao Fu , Yang Hai Ping , Zhao Fei , Li Qiu , Zhang Ai Hua , Wang Mo 
Published: June 2024

BackgroundThis study aims to explore the clinical value of low disease activity state (LDAS) in the treat-to-target strategy of pediatric systemic lupus erythematosus (pSLE) and find the risk factors for never reaching LDAS.MethodsA total of 272 children with SLE who were diagnosed and followed up in two tertiary hospitals in China during the period from January 2012 to December 2019 were involved in this study, and the clinical presentation, pathology, and treatment were retrospectively studied.ResultsThe male-to-female ratio was 1:5.2, the age at diagnosis was 11.1 years (IQR, 9.8–13.1 years), the disease duration was 1.0 month (IQR, 0.5–2.0 months), and follow-up was 36.5 months (IQR, 25.7–50.9 months). During follow-up, 230 children achieved LDAS, and 42 were never been in. Male (P = 0.018), mucosal ulcer (P = 0.048), liver function damage (P = 0.026), cardiac effusion (P = 0.034), anemia (P = 0.048), urine red blood cells (P = 0.017), urinary leukocytes (P = 0.032), and endothelial cell proliferation in renal biopsy (P = 0.004)—these indexes have statistical differences between the two groups in the baseline. At baseline, endothelial cell proliferation (P = 0.02) is an independent risk factor for never achieving LDAS by multivariate logistic analysis. During follow-up, non-compliance was a risk factor for never achieving LDAS by comparing between groups. Children with biologics achieved LDAS at a higher rate than children without biologics (P = 0.038). The proportion of organ damage in patients never been in LDAS was significantly higher than that in patients who achieved LDAS (P &lt; 0.001).ConclusionEndothelial cell proliferation in renal biopsy and non-compliance during follow-up were independent risk factors for never achieving LDAS. At the end of the follow-up, the organ damage in the remission group was similar to that in the LDAS group, indicating that LDAS can be used as a target for pSLE treatment.
NLRP3 promotes allergic responses to birch pollen extract in a model of intranasal sensitization
Authors: Bauer Renate , Dang Hieu-Hoa , Neureiter Daniel , Unger Michael Stefan , Neuper Theresa , Jensen Melanie , Taliento Alice Emma , Strandt Helen , Gratz Iris , Weiss Richard , Sales Angelika , Horejs-Hoeck Jutta 
Published: June 2024

Introduction &amp; ObjectiveAllergic sensitization is an essential step in the development of allergic airway inflammation to birch pollen (BP); however, this process remains to be fully elucidated. Recent scientific advances have highlighted the importance of the allergen context. In this regard, microbial patterns (PAMPs) present on BP have attracted increasing interest. As these PAMPs are recognized by specialized pattern recognition receptors (PRRs), this study aims at investigating the roles of intracellular PRRs and the inflammasome regulator NLRP3.MethodsWe established a physiologically relevant intranasal and adjuvant-free sensitization procedure to study BP-induced systemic and local lung inflammation.ResultsStrikingly, BP-sensitized Nlrp3-deficient mice showed significantly lower IgE levels, Th2-associated cytokines, cell infiltration into the lung, mucin production and epithelial thickening than their wild-type counterparts, which appears to be independent of inflammasome formation. Intriguingly, bone-marrow chimera revealed that expression of NLRP3 in the hematopoietic system is required to trigger an allergic response.ConclusionOverall, this study identifies NLRP3 as an important driver of BP-induced allergic immune responses.
Expansion of effector memory Vδ2neg γδ T cells associates with cytomegalovirus reactivation in allogeneic stem cell transplant recipients
Authors: Huang Yiwen , Jiang Cen , Zhu Jiacheng , Lin Lin , Mao Minjing , Yin Tong , Cai Gang 
Published: June 2024

BackgroundCytomegalovirus (CMV) reactivation is a significant concern following allogeneic stem cell transplantation. While previous research has highlighted the anti-CMV reactivation effect of γδ T cells in immunocompromised transplant patients, their characterization in recipients at high risk of CMV reactivation remains limited.MethodsThis study focused on D+/R+ recipients (where both donor and recipient are CMV seropositive) at high risk of CMV reactivation. We analyzed 28 patients who experienced CMV recurrence within 100 days post-allogeneic hematopoietic stem cell transplantation, along with 36 matched recipients who did not experience CMV recurrence. Clinical data from both groups were compared, and risk factors for CMV reactivation were identified. Additionally, CMV viral load was measured, and flow cytometric analysis was conducted to assess changes in peripheral blood γδ T cell proportions, subpopulation distribution, and differentiation status. We also analyzed the CDR3 repertoire of the TCR δ chain in different γδ T cell subsets. Functional analysis was performed by measuring the lysis of CMV-infected cells upon stimulation.ResultsCMV reactivation post-transplantation was associated with acute graft-versus-host disease (aGvHD) and reactivation of non-CMV herpesviruses. Notably, CMV reactivation led to sustained expansion of γδ T cells, primarily within the Vδ2neg γδ T cell subpopulation, with a trend toward differentiation from Naive to effector memory cells. Analysis of the δ chain CDR3 repertoire revealed a delay in the reconstitution of clonal diversity in Vδ2neg γδ T cells following CMV reactivation, while Vδ2pos T cells remained unaffected. Upon stimulation with CMV-infected MRC5 cells, the Vδ2neg γδ T cell subpopulation emerged as the primary effector cell group producing IFN-γ and capable of lysing CMV-infected cells. Moreover, our findings suggest that NKG2D is not necessary involved in Vδ2neg γδ T cell-mediated anti-CMV cytotoxicity.ConclusionThis study provides novel insights into the role of γδ T cells in the immune response to CMV reactivation in transplantation recipients at high risk of CMV infection. Specifically, the Vδ2neg γδ T cell subpopulation appears to be closely associated with CMV reactivation, underscoring their potential role in controlling infection and reflecting CMV reactivation in HSCT patients.
Whole-blood culture-derived cytokine combinations for the diagnosis of tuberculosis
Authors: Østergaard Anne Ahrens , Feddersen Søren , Barnkob Mike B. , Lynggaard Rasmus Bank , Karstoft Amanda Cecilie Annie , Borup Maria , Titlestad Ingrid Louise , Jensen Torben Tranborg , Hilberg Ole , Wejse Christian , Bjerrum Stephanie , Blaabjerg Morten , Assing Kristian , Johansen Isik Somuncu 
Published: June 2024

IntroductionThe diagnosis of tuberculosis (TB) disease and TB infection (TBI) remains a challenge, and there is a need for non-invasive and blood-based methods to differentiate TB from conditions mimicking TB (CMTB), TBI, and healthy controls (HC). We aimed to determine whether combination of cytokines and established biomarkers could discriminate between 1) TB and CMTB 2) TB and TBI 3) TBI and HC. MethodsWe used hemoglobin, total white blood cell count, neutrophils, monocytes, C-reactive protein, and ten Meso Scale Discovery analyzed cytokines (interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon (IFN)-ɣ, and tumor necrosis factor (TNF)-α) in TruCulture whole blood tubes stimulated by lipopolysaccharides (LPS), zymosan (ZYM), anti-CD3/28 (CD3), and unstimulated (Null) to develop three index tests able to differentiate TB from CMTB and TBI, and TBI from HC. ResultsIn 52 persons with CMTB (n=9), TB (n=23), TBI (n=10), and HC (n=10), a combination of cytokines (LPS-IFN-ɣ, ZYM-IFN-ɣ, ZYM-TNF-α, ZYM-IL-1β, LPS-IL-4, and ZYM-IL-6) and neutrophil count could differentiate TB from CMTB with a sensitivity of 52.2% (95% CI: 30.9%–73.4%) and a specificity of 100 % (66.4%-100%). Null- IFN-ɣ, Null-IL-8, CD3-IL-6, CD3-IL-8, CD3-IL-13, and ZYM IL-1b discriminated TB from TBI with a sensitivity of 73.9% (56.5% - 91.3%) and a specificity of 100% (69.2-100). Cytokines and established biomarkers failed to differentiate TBI from HC with ≥ 98% specificity.DiscussionSelected cytokines may serve as blood-based add-on tests to detect TB in a low-endemic setting, although these results need to be validated.
Profibrogenic role of IL-15 through IL-15 receptor alpha-mediated trans-presentation in the carbon tetrachloride-induced liver fibrosis model
Authors: Cloutier Maryse , Variya Bhavesh , Akbari Sara Ali , Rexhepi Fjolla , Ilangumaran Subburaj , Ramanathan Sheela 
Published: June 2024

BackgroundInflammatory cytokines play key pathogenic roles in liver fibrosis. IL-15 is a proinflammatory cytokine produced by myeloid cells. IL-15 promotes pathogenesis of several chronic inflammatory diseases. However, increased liver fibrosis has been reported in mice lacking IL-15 receptor alpha chain (IL-15Rα), suggesting an anti-fibrogenic role for IL-15. As myeloid cells are key players in liver fibrosis and IL-15 signaling can occur independently of IL-15Rα, we investigated the requirement of IL-15 and IL-15Rα in liver fibrosis.MethodsWe induced liver fibrosis in Il15–/–, Il15ra–/– and wildtype C57BL/6 mice by the administration of carbon tetrachloride (CCl4). Liver fibrosis was evaluated by Sirius red and Mason’s trichrome staining and α-smooth muscle acting immunostaining of myofibroblasts. Gene expression of collagens, matrix modifying enzymes, cytokines and chemokines was quantified by RT-qPCR. The phenotype and the numbers of intrahepatic lymphoid and myeloid cell subsets were evaluated by flow cytometry.ResultsBoth Il15–/– and Il15ra–/– mice developed markedly reduced liver fibrosis compared to wildtype control mice, as revealed by reduced collagen deposition and myofibroblast content. Il15ra–/– mice showed further reduction in collagen deposition compared to Il15–/– mice. However, Col1a1 and Col1a3 genes were similarly induced in the fibrotic livers of wildtype, Il15–/– and Il15ra–/– mice, although notable variations were observed in the expression of matrix remodeling enzymes and chemokines. As expected, Il15–/– and Il15ra–/– mice showed markedly reduced numbers of NK cells compared to wildtype mice. They also showed markedly less staining of CD45+ immune cells and CD68+ macrophages, and significantly reduced inflammatory cell infiltration into the liver, with fewer pro-inflammatory and anti-inflammatory monocyte subsets compared to wildtype mice.ConclusionOur findings indicate that IL-15 exerts its profibrogenic role in the liver by promoting macrophage activation and that this requires trans-presentation of IL-15 by IL-15Rα.
NOD2 activation enhances macrophage Fcγ receptor function and may increase the efficacy of antibody therapy
Authors: Merchand-Reyes Giovanna , Bull Mikayla F. , Santhanam Ramasamy , Valencia-Pena Maria L. , Murugesan Rakesh A. , Chordia Aadesh , Mo Xiaokui-Molly , Robledo-Avila Frank H. , Ruiz-Rosado Juan De Dios , Carson William Edgar , Byrd John C. , Woyach Jennifer A. , Tridandapani Susheela , Butchar Jonathan P. 
Published: June 2024

IntroductionTherapeutic antibodies have become a major strategy to treat oncologic diseases. For chronic lymphocytic leukemia, antibodies against CD20 are used to target and elicit cytotoxic responses against malignant B cells. However, efficacy is often compromised due to a suppressive microenvironment that interferes with cellular immune responses. To overcome this suppression, agonists of pattern recognition receptors have been studied which promote direct cytotoxicity or elicit anti-tumoral immune responses. NOD2 is an intracellular pattern recognition receptor that participates in the detection of peptidoglycan, a key component of bacterial cell walls. This detection then mediates the activation of multiple signaling pathways in myeloid cells. Although several NOD2 agonists are being used worldwide, the potential benefit of these agents in the context of antibody therapy has not been explored.MethodsPrimary cells from healthy-donor volunteers (PBMCs, monocytes) or CLL patients (monocytes) were treated with versus without the NOD2 agonist L18-MDP, then antibody-mediated responses were assessed. In vivo, the Eµ-TCL1 mouse model of CLL was used to test the effects of L18-MDP treatment alone and in combination with anti-CD20 antibody.ResultsTreatment of peripheral blood mononuclear cells with L18-MDP led to activation of monocytes from both healthy donors and CLL patients. In addition, there was an upregulation of activating FcγR in monocytes and a subsequent increase in antibody-mediated phagocytosis. This effect required the NF-κB and p38 signaling pathways. Treatment with L18-MDP plus anti-CD20 antibody in the Eµ-TCL model of CLL led to a significant reduction of CLL load, as well as to phenotypic changes in splenic monocytes and macrophages.ConclusionsTaken together, these results suggest that NOD2 agonists help overturn the suppression of myeloid cells, and may improve the efficacy of antibody therapy for CLL.
Impact of assimilating satellite surface velocity observations in the Mercator Ocean International analysis and forecasting global 1/4° system
Authors: Mirouze Isabelle , Rémy Elisabeth , Lellouche Jean-Michel , Martin Matthew J. , Donlon Craig J. 
Published: June 2024

Representing and forecasting global ocean velocities is challenging. Velocity observations are scarce and sparse, and are rarely assimilated in a global ocean configuration. Recently, different satellite mission candidates have been proposed to provide surface velocity measurements. To assess the impact of assimilating such data, Observing System Simulation Experiments (OSSEs) have been run in the Mercator Ocean International analysis and forecasting global 1/4° system. Results show that assimilating simulated satellite surface velocities in addition to classical observations has a positive impact on the predicted currents at the surface and below to some extent. Compared to an experiment that assimilates only the classical observations, the surface velocity root-mean-squared error (RMSE) is reduced, especially in the Tropics. From a certain depth depending on the region (e.g. 200 m in the Tropics) however, slight degradations can be spotted. Temperature and salinity RMSEs are generally slightly degraded except in the Tropics where there is a small improvement at the surface and sub-surface. Sea surface height results are mixed, with some areas having reduced RMSE and some increased. The OSSEs reported here constitute a first study and aim to provide first insights on the features that improve by assimilating surface velocity data, and those which need to be worked on.
Predicting COPD exacerbations based on quantitative CT analysis: an external validation study
Authors: Wu Ji , Lu Yao , Dong Sunbin , Wu Luyang , Shen Xiping 
Published: June 2024

PurposeQuantitative computed tomography (CT) analysis is an important method for diagnosis and severity evaluation of lung diseases. However, the association between CT-derived biomarkers and chronic obstructive pulmonary disease (COPD) exacerbations remains unclear. We aimed to investigate its potential in predicting COPD exacerbations.MethodsPatients with COPD were consecutively enrolled, and their data were analyzed in this retrospective study. Body composition and thoracic abnormalities were analyzed from chest CT scans. Logistic regression analysis was performed to identify independent risk factors of exacerbation. Based on 2-year follow-up data, the deep learning system (DLS) was developed to predict future exacerbations. Receiver operating characteristic (ROC) curve analysis was conducted to assess the diagnostic performance. Finally, the survival analysis was performed to further evaluate the potential of the DLS in risk stratification.ResultsA total of 1,150 eligible patients were included and followed up for 2 years. Multivariate analysis revealed that CT-derived high affected lung volume/total lung capacity (ALV/TLC) ratio, high visceral adipose tissue area (VAT), and low pectoralis muscle cross-sectional area (CSA) were independent risk factors causing COPD exacerbations. The DLS outperformed exacerbation history and the BMI, airflow obstruction, dyspnea, and exercise capacity (BODE) index, with an area under the ROC (AUC) value of 0.88 (95%CI, 0.82–0.92) in the internal cohort and 0.86 (95%CI, 0.81–0.89) in the external cohort. The DeLong test revealed significance between this system and conventional scores in the test cohorts (p &lt; 0.05). In the survival analysis, patients with higher risk were susceptible to exacerbation events.ConclusionThe DLS could allow accurate prediction of COPD exacerbations. The newly identified CT biomarkers (ALV/TLC ratio, VAT, and pectoralis muscle CSA) could potentially enable investigation into underlying mechanisms responsible for exacerbations.
Optimizing sedation in gastroscopy: a study on the etomidate/propofol mixture ratio
Authors: Tang Shuyi , Zheng Yuling , Li Xiaoli , Zhang Yiwen , Zhang Zhongqi 
Published: June 2024

ObjectivePropofol and etomidate are the most commonly used sedative agents in procedural sedation, each with its own advantages and disadvantages. However, there remains considerable controversy regarding the optimal ratio for the mixture of these two drugs, warranting further investigation. Therefore, this study aims to investigate the optimal ratio for combining propofol and etomidate during gastroscopy.MethodsThis study is a prospective, double-blinded, randomized controlled clinical trial. One hundred and sixty-two patients from July 2019 to December 2022 were evenly classified into three groups using a random number table as follows: (1) P group (propofol); (2) EP1 group (5 mL etomidate +10 mL propofol); (3) EP2 group (10 mL etomidate +10 mL), 54 patients per group. The medications, including a pre-sedation dose of 50 μg/kg dezocine followed by sedatives, ceasing when the patient’s eyelash reflex vanished, indicating adequate sedation. Mean arterial pressure (MAP), heart rate (HR), and peripheral oxygen saturation (SpO2) measurements taken before anesthesia (T1), immediately after the administration of sedatives (T2), immediately gastroscopic insertion (T3) and immediately recovery (T4) were determined. Additional, perioperative related outcomes and adverse events were also recorded.ResultsThe EP2 group exhibited a higher MAP at T2 compared to the P and EP1 groups (p &lt; 0.05). Calculated decreases in MAP revealed values of 19.1, 18.8, and 13.8% for the P, EP1, and EP2 groups at T2, respectively. Adverse events: Group EP2 exhibited a significantly lower hypotension incidence (11.1%) compared to the Propofol group (50%) and EP1 (31.5%). Concerning injection pain, Group EP2 also showing a significant decrease in comparison to P and EP1 groups (p &lt; 0.05).ConclusionThe use of a mixture of 10 mL etomidate and 10 mL propofol (at a 1:1 ratio) combined with dezocine for painless gastroscopy demonstrates hemodynamic stability, a low incidence of adverse reactions.Clinical Trial Registrationhttps://www.chictr.org.cn/showproj.html?proj=39874