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Neoplasma Apr 2024It has been demonstrated that calreticulin (CALR) is expressed abnormally in various tumors and is involved in the occurrence and development of tumors. In this study,...
It has been demonstrated that calreticulin (CALR) is expressed abnormally in various tumors and is involved in the occurrence and development of tumors. In this study, CALR and EIF2AK2 expression was measured in the clinical specimens of 39 patients with melanoma. Then, we constructed knockdown and overexpression cell models of CALR and EIF2AK2 and used wound healing and Transwell assays to observe cell migration and invasion. Apoptosis, EDU, and ROS assays were used to measure cell apoptosis and proliferation, as well as ROS levels. The effect of CALR on endoplasmic reticulum stress was detected using endoplasmic reticulum fluorescent probes. Western blotting was used to detect protein levels of CALR, EIF2AK2, ADAR1, and MMP14. The results indicated that CALR and EIF2AK2 expression levels were significantly higher in human melanoma tissues than in adjacent non-tumor tissue. In addition, we found a correlation between CALR and the expression of EIF2AK2 and MMP14, and the experimental results indicated that overexpression of CALR significantly upregulated the expression of EIF2AK2, MMP14, and ADAR1, while knockdown of CALR inhibited their expression. Notably, the knockdown of EIF2AK2 in the CALR overexpression group blocked the upregulation of MMP14 and ADAR1 expression by CALR, and the knockdown of both CALR and EIF2AK2 significantly inhibited MMP14 and ADAR1 expression. In conclusion, CALR and EIF2AK2 play a promoting role in melanoma progression, and knockdown of CALR and EIF2AK2 may be an effective anti-tumor target, and its mechanism may be through MMP14, ADAR1 signaling.
Topics: Humans; Adenosine Deaminase; Melanoma; eIF-2 Kinase; RNA-Binding Proteins; Calreticulin; Cell Proliferation; Signal Transduction; Cell Line, Tumor; Matrix Metalloproteinase 14; Cell Movement; Apoptosis; Endoplasmic Reticulum Stress; Female; Disease Progression; Male; Gene Expression Regulation, Neoplastic; Middle Aged
PubMed: 38766853
DOI: 10.4149/neo_2024_240116N24 -
Communications Biology May 2024Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA...
Non-alcoholic fatty liver disease (NAFLD) is a chronic disease caused by hepatic steatosis. Adenosine deaminases acting on RNA (ADARs) catalyze adenosine to inosine RNA editing. However, the functional role of ADAR2 in NAFLD is unclear. ADAR2/GluR-B mice (wild type, WT) and ADAR2/GluR-B mice (ADAR2 KO) mice are fed with standard chow or high-fat diet (HFD) for 12 weeks. ADAR2 KO mice exhibit protection against HFD-induced glucose intolerance, insulin resistance, and dyslipidemia. Moreover, ADAR2 KO mice display reduced liver lipid droplets in concert with decreased hepatic TG content, improved hepatic insulin signaling, better pyruvate tolerance, and increased glycogen synthesis. Mechanistically, ADAR2 KO effectively mitigates excessive lipid production via AMPK/Sirt1 pathway. ADAR2 KO inhibits hepatic gluconeogenesis via the AMPK/CREB pathway and promotes glycogen synthesis by activating the AMPK/GSK3β pathway. These results provide evidence that ADAR2 KO protects against NAFLD progression through the activation of AMPK signaling pathways.
Topics: Animals; Adenosine Deaminase; RNA-Binding Proteins; Signal Transduction; Mice; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Diet, High-Fat; Male; AMP-Activated Protein Kinases; Insulin Resistance; Mice, Obese; Obesity; Mice, Inbred C57BL; Liver
PubMed: 38760406
DOI: 10.1038/s42003-024-06215-4 -
Journal of Clinical Immunology May 2024Deficiency of Adenosine Deaminase 2 (DADA2) patients presenting with primary immunodeficiency are at risk of uncontrolled EBV infection and secondary malignancies...
Deficiency of Adenosine Deaminase 2 (DADA2) patients presenting with primary immunodeficiency are at risk of uncontrolled EBV infection and secondary malignancies including EBV-related lymphoproliferative disorders (LPD). This paper describes the first case of EBV related diffuse large B-cell lymphoma in a patient with DADA2 and uncontrolled EBV infection. Consideration should be given to monitoring for EBV viraemia and to preventative EBV specific therapy in DADA2 and patients with at risk primary immunodeficiencies. A type I interferon (IFN) gene signature is associated with DADA2 though its association with immune dysregulation is unclear.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Epstein-Barr Virus Infections; Adenosine Deaminase; Herpesvirus 4, Human; Intercellular Signaling Peptides and Proteins; Male; Female; Hereditary Autoinflammatory Diseases
PubMed: 38758417
DOI: 10.1007/s10875-024-01712-x -
International Journal of Clinical... May 2024Venlafaxine is frequently prescribed for patients with depression. To control the concentration of venlafaxine within the therapeutic window for the best treatment...
BACKGROUND
Venlafaxine is frequently prescribed for patients with depression. To control the concentration of venlafaxine within the therapeutic window for the best treatment effect, a model to predict venlafaxine concentration is necessary.
AIM
Our objective was to develop a prediction model for venlafaxine concentration using real-world evidence based on machine learning and deep learning techniques.
METHOD
Patients who underwent venlafaxine treatment between November 2019 and August 2022 were included in the study. Important variables affecting venlafaxine concentration were identified using a combination of univariate analysis, sequential forward selection, and machine learning techniques. Predictive performance of nine machine learning and deep learning algorithms were assessed, and the one with the optimal performance was selected for modeling. The final model was interpreted using SHapley Additive exPlanations.
RESULTS
A total of 330 eligible patients were included. Five influential variables that affect venlafaxine concentration were venlafaxine daily dose, sex, age, hyperlipidemia, and adenosine deaminase. The venlafaxine concentration prediction model was developed using the eXtreme Gradient Boosting algorithm (R = 0.65, mean absolute error = 77.92, root mean square error = 93.58). In the testing cohort, the accuracy of the predicted concentration within ± 30% of the actual concentration was 73.49%. In the subgroup analysis, the prediction accuracy was 69.39% within the recommended therapeutic range of venlafaxine concentration within ± 30% of the actual value.
CONCLUSION
The XGBoost model for predicting blood concentration of venlafaxine using real-world evidence was developed, guiding the adjustment of regimen in clinical practice.
PubMed: 38753076
DOI: 10.1007/s11096-024-01724-y -
BMC Pulmonary Medicine May 2024Pleural fluid is one of the common complications of thoracic diseases, and tuberculous pleural effusion (TPE) is the most common cause of pleural effusion in TB-endemic...
BACKGROUND
Pleural fluid is one of the common complications of thoracic diseases, and tuberculous pleural effusion (TPE) is the most common cause of pleural effusion in TB-endemic areas and the most common type of exudative pleural effusion in China. In clinical practice, distinguishing TPE from pleural effusion caused by other reasons remains a relatively challenging issue. The objective of present study was to explore the clinical significance of the pleural fluid lactate dehydrogenase/adenosine deaminase ratio (pfLDH/pfADA) in the diagnosis of TPE.
METHODS
The clinical data of 618 patients with pleural effusion were retrospectively collected, and the patients were divided into 3 groups: the TPE group (412 patients), the parapneumonic pleural effusion (PPE) group (106 patients), and the malignant pleural effusion (MPE) group (100 patients). The differences in the ratios of pleural effusion-related and serology-related indicators were compared among the three groups, and receiver operating characteristic curves were drawn to analyze the sensitivity and specificity of the parameter ratios of different indicators for the diagnosis of TPE.
RESULTS
The median serum ADA level was higher in the TPE group (13 U/L) than in the PPE group (10 U/L, P < 0.01) and MPE group (10 U/L, P < 0.001). The median pfADA level in the TPE group was 41 (32, 52) U/L; it was lowest in the MPE group at 9 (7, 12) U/L and highest in the PPE group at 43 (23, 145) U/L. The pfLDH level in the PPE group was 2542 (1109, 6219) U/L, which was significantly higher than that in the TPE group 449 (293, 664) U/L. In the differential diagnosis between TPE and non-TPE, the AUC of pfLDH/pfADA for diagnosing TPE was the highest at 0.946 (0.925, 0.966), with an optimal cutoff value of 23.20, sensitivity of 93.9%, specificity of 87.0%, and Youden index of 0.809. In the differential diagnosis of TPE and PPE, the AUC of pfLDH/pfADA was the highest at 0.964 (0.939, 0.989), with an optimal cutoff value of 24.32, sensitivity of 94.6%, and specificity of 94.4%; this indicated significantly better diagnostic efficacy than that of the single index of pfLDH. In the differential diagnosis between TPE and MPE, the AUC of pfLDH/pfADA was 0.926 (0.896, 0.956), with a sensitivity of 93.4% and specificity of 80.0%; this was not significantly different from the diagnostic efficacy of pfADA.
CONCLUSIONS
Compared with single biomarkers, pfLDH/pfADA has higher diagnostic value for TPE and can identify patients with TPE early, easily, and economically.
Topics: Humans; Adenosine Deaminase; Male; Female; Retrospective Studies; Middle Aged; Pleural Effusion; L-Lactate Dehydrogenase; Tuberculosis, Pleural; Adult; Aged; Sensitivity and Specificity; ROC Curve; China; Diagnosis, Differential; Pleural Effusion, Malignant; Biomarkers; Clinical Relevance
PubMed: 38750432
DOI: 10.1186/s12890-024-03055-0 -
Artificial Intelligence in Medicine Jul 2024Tuberculous pleural effusion poses a significant threat to human health due to its potential for severe disease and mortality. Without timely treatment, it may lead to...
Tuberculous pleural effusion poses a significant threat to human health due to its potential for severe disease and mortality. Without timely treatment, it may lead to fatal consequences. Therefore, early identification and prompt treatment are crucial for preventing problems such as chronic lung disease, respiratory failure, and death. This study proposes an enhanced differential evolution algorithm based on colony predation and dispersed foraging strategies. A series of experiments conducted on the IEEE CEC 2017 competition dataset validated the global optimization capability of the method. Additionally, a binary version of the algorithm is introduced to assess the algorithm's ability to address feature selection problems. Comprehensive comparisons of the effectiveness of the proposed algorithm with 8 similar algorithms were conducted using public datasets with feature sizes ranging from 10 to 10,000. Experimental results demonstrate that the proposed method is an effective feature selection approach. Furthermore, a predictive model for tuberculous pleural effusion is established by integrating the proposed algorithm with support vector machines. The performance of the proposed model is validated using clinical records collected from 140 tuberculous pleural effusion patients, totaling 10,780 instances. Experimental results indicate that the proposed model can identify key correlated indicators such as pleural effusion adenosine deaminase, temperature, white blood cell count, and pleural effusion color, aiding in the clinical feature analysis of tuberculous pleural effusion and providing early warning for its treatment and prediction.
Topics: Humans; Pleural Effusion; Support Vector Machine; Algorithms; Tuberculosis, Pleural; Adenosine Deaminase; Leukocyte Count
PubMed: 38749310
DOI: 10.1016/j.artmed.2024.102886 -
Research Square Apr 2024There is currently no prophylactic vaccine available for human immunodeficiency virus (HIV). Research efforts have resulted in improved immunogens that mimic the native...
There is currently no prophylactic vaccine available for human immunodeficiency virus (HIV). Research efforts have resulted in improved immunogens that mimic the native envelope (Env) glycoprotein structure. Recently, a novel triple tandem trimer (TTT) platform has been used to generate a plasmid encoding Env immunogen (pBG505-TTT) that expresses only as trimers, making it more suitable for nucleic acid vaccines. We have previously demonstrated that adenosine deaminase-1 (ADA-1) is critical to the T follicular helper (TFH) function and improves vaccine immune responses . In this study, we demonstrate that co-delivery of plasmid-encoded adenosine deaminase 1 (pADA) with pBG505-TTT enhances the magnitude, durability, isotype switching and functionality of HIV-specific antibodies in a dose-sparing manner. Co-delivery of the molecular immune modulator ADA-1 also enhances HIV-specific T cell polyfunctionality, activation, and degranulation as well as memory B cell responses. These data demonstrate that pADA enhances HIV-specific cellular and humoral immunity, making ADA-1 a promising immune modulator for HIV-targeting vaccines.
PubMed: 38746176
DOI: 10.21203/rs.3.rs-4139764/v1 -
Frontiers in Immunology 2024Tuberculous pleural effusion (TPE) stands as one of the primary forms of extrapulmonary tuberculosis (TB) and frequently manifests in regions with a high prevalence of...
INTRODUCTION
Tuberculous pleural effusion (TPE) stands as one of the primary forms of extrapulmonary tuberculosis (TB) and frequently manifests in regions with a high prevalence of TB, consequently being a notable cause of pleural effusion in such areas. However, the differentiation between TPE and parapneumonic pleural effusion (PPE) presents diagnostic complexities. This study aimed to evaluate the potential of myeloid-derived suppressor cells (MDSCs) in the pleural fluid as a potential diagnostic marker for distinguishing between TPE and PPE.
METHODS
Adult patients, aged 18 years or older, who presented to the emergency room of a tertiary referral hospital and received a first-time diagnosis of pleural effusion, were prospectively enrolled in the study. Various immune cell populations, including T cells, B cells, natural killer (NK) cells, and MDSCs, were analyzed in both pleural fluid and peripheral blood samples.
RESULTS
In pleural fluid, the frequency of lymphocytes, including T, B, and NK cells, was notably higher in TPE compared to PPE. Conversely, the frequency of polymorphonuclear (PMN)-MDSCs was significantly higher in PPE. Notably, compared to traditional markers such as the neutrophil-to-lymphocyte ratio and adenosine deaminase level, the frequency of PMN-MDSCs emerged as a more effective discriminator between PPE and TPE. PMN-MDSCs demonstrated superior positive and negative predictive values and exhibited a higher area under the curve in the receiver operating characteristic curve analysis. PMN-MDSCs in pleural effusion increased the levels of reactive oxygen species and suppressed the production of interferon-gamma from T cells following nonspecific stimulation. These findings suggest that MDSC-mediated immune suppression may contribute to the pathology of both TPE and PPE.
DISCUSSION
The frequency of PMN-MDSCs in pleural fluid is a clinically useful indicator for distinguishing between TPE and PPE.
Topics: Humans; Myeloid-Derived Suppressor Cells; Male; Female; Pleural Effusion; Middle Aged; Diagnosis, Differential; Adult; Biomarkers; Tuberculosis, Pulmonary; Aged; Pneumonia; Prospective Studies; Tuberculosis, Pleural
PubMed: 38742106
DOI: 10.3389/fimmu.2024.1390327 -
Toxicology Reports Jun 2024Liver diseases have gained increasing attention due to their substantial impact on health, independently as well as in association with cardio-metabolic disorders....
Liver diseases have gained increasing attention due to their substantial impact on health, independently as well as in association with cardio-metabolic disorders. Studies have suggested that glutathione and adenosine assist in providing protection against oxidative stress and inflammation while glucocorticoid (GC) therapy has been associated with chronic inflammatory disorders, even in pregnancy. The implications of Glucocorticoid exposure on maternal health and fetal growth is a concern, however, the possible role of glutathione and adenosine has not been thoroughly investigated. The study therefore hypothesize that exposure to glucocorticoids leads to depletion of hepatic glutathione and adenosine levels, contributing to oxidative stress and tissue injury. Additionally, we aim to investigate whether the effects of glucocorticoids on hepatic health are pregnancy dependent in female rats. Twelve Pregnant and twelve age-matched non-pregnant rats were used for this study; an exogenous administration of glucocorticoid (Dex: 0.2 mg/kg) or vehicle () was administered to six pregnant and six non-pregnant rats from gestational day 14 to 19 or for a period of 6 days respectively. Data obtained showed that GC exposure led to a decrease in hepatic glucose-6-phosphate dehydrogenase, glutathione peroxidase, GSH/GSSG ratio and adenosine content in both pregnant and non-pregnant rats. In addition, increased activities of adenosine deaminase and xanthine oxidase, along with increased production of uric acid and increased levels of lactate dehydrogenase, aspartate aminotransferase, alanine transferase, alkaline phosphatase and gamma-glutamyl transferase were observed. In summary, the study indicates that GC-induced liver damage is underlined by depleted hepatic adenosine and glutathione levels as well as elevated markers of tissue inflammation and/or injury. Furthermore, the findings suggest that the effects of GC exposure on hepatic health are pregnancy independent.
PubMed: 38741615
DOI: 10.1016/j.toxrep.2024.04.011 -
Fish & Shellfish Immunology Jul 2024Adenosine deaminases acting on RNA 1 (ADAR1) is a dsRNA adenosine (A)-to-inosine (I) editing enzyme that regulates the innate immune response against virus invasion. In...
Adenosine deaminases acting on RNA 1 (ADAR1) is a dsRNA adenosine (A)-to-inosine (I) editing enzyme that regulates the innate immune response against virus invasion. In the present study, a novel CgADAR1 was identified from the oyster Crassostrea gigas. The open reading frame (ORF) of CgADAR1 was of 3444 bp encoding a peptide of 1147 amino acid residues with two Zα domains, one dsRNA binding motif (DSRM) and one RNA adenosine deaminase domain (ADEAMc). The mRNA transcripts of CgADAR1 were detected in all the examined tissues, with higher expression levels in mantle and gill, which were 7.11-fold and 4.90-fold (p < 0.05) of that in labial palp, respectively. The mRNA transcripts of CgADAR1 in haemocytes were significantly induced at 24 h and 36 h after Poly (A: U) stimulation, which were 6.03-fold (p < 0.01) and 1.37-fold (p < 0.001) of that in control group, respectively. At 48 h after Poly (A:U) stimulation, the mRNA expression of CgRIG-Ⅰ, CgIRF8 and CgIFNLP significantly increased, which were 4.36-fold (p < 0.001), 1.82-fold (p < 0.05) and 1.92-fold (p < 0.05) of that in control group. After CgADAR1 expression was inhibited by RNA interference (RNAi), the mRNA expression levels of CgMDA5, CgRIG-Ⅰ, CgTBK1, CgIRF8 and CgIFNLP were significantly increased, which were 11.88-fold, 11.51-fold, 2.22-fold, 2.85-fold and 2.52-fold of that in control group (p < 0.001), and the phosphorylation level of CgTBK1 was also significantly increased. These results suggested that CgADAR1 played a regulation role in the early stages of viral infection by inhibiting the synthesis of interferon-like protein.
Topics: Animals; Crassostrea; Immunity, Innate; Gene Expression Regulation; Interferons; Amino Acid Sequence; Adenosine Deaminase; Phylogeny; Gene Expression Profiling; Sequence Alignment; Base Sequence
PubMed: 38740229
DOI: 10.1016/j.fsi.2024.109620