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BACKGROUND: Despite increasing studies confirming the efficacy of vedolizumab in Crohn's disease (CD), improving the responses to this biologic agent remains challenging in clinical practice. Here, we investigated the efficacy of combined treatment of vedolizumab and 16-week exclusive enteral nutrition (EEN) in moderately to severely active CD. METHODS: From October 2020 to October 2023, 81 patients with moderately to severely active CD treated with vedolizumab from three IBD centers were retrospectively selected. Forty-one patients received treatment of vedolizumab with concomitant 16-week EEN (vedolizumab, VDZ+EEN cohort) and 40 patients received vedolizumab treatment alone (VDZ cohort). Clinical and biological outcomes were evaluated. Endoscopic response and mucosal healing were assessed by colonoscopy at week 16 and 52. RESULTS: There was no statistically significant difference between two groups at baseline for demographic and clinical characteristics. Compared to patients treated with vedolizumab alone, patients in the VDZ+EEN cohort achieved higher rates of clinical response (84.2% vs. 40.0%), clinical remission (81.6% vs. 30.0%), endoscopic response (91.4 % vs. 34.6%) including mucosal healing (85.7% vs. 26.9%) at week 16. The superiority of VDZ+EEN treatment sustained in maintenance, with 76.7% (vs. 33.3%) clinical response, 70.0% (vs. 26.7%) clinical remission, 76.9% (vs. 33.3%) endoscopic response, and 61.5% (vs. 26.7%) mucosal healing at week 52. None of patients experienced severe adverse events. CONCLUSION: Vedolizumab with concomitant 16-week EEN might be an effective and optimized approach with solid efficacy in the induction and maintenance treatment of active CD.
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Objective: To estimate decadal trends in the prevalence of metabolic syndrome (MetS) in economically developed regions in China and its association with city economic levels. Methods: Using a comprehensive Chinese healthcare database, repeated cross-sectional studies were conducted on adults who had annual health check-ups from 2012 to 2021 in 4 economically developed cities. MetS was defined by the criteria of the Chinese Diabetes Society in 2013. The crude prevalence of MetS adjusted for sex and age was reported. The association between prevalence, calendar year, and city gross domestic product (GDP) per capita was analyzed by regression model. Results: 158 274 participants aged 18 years and older were included. The unadjusted prevalence of MetS increased from 15.5% (95% CI: 14.2%-16.8%) to 20.0% (95% CI: 19.5%-20.5%) from 2012 to 2021. The adjusted overall prevalence has increased steadily from 12.8% to 20.8% after controlling age and sex (P < .001). Male and older age groups had a higher MetS prevalence. In the regression model of the association between the MetS prevalence, calendar year, and city GDP per capita, calendar year had a positive association with the prevalence (P < .001, 95% CI: 0.648-1.954) and city GDP per capita had a negative association (P = .030, 95% CI: -0.136 to -0.007). Conclusion: The MetS prevalence increased steadily in the economically developed regions in China among the health check-up population during 2012-2021. The MetS prevalence is shown to be negatively associated with GDP per capita in the study population.
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INTRODUCTION: Peripheral nerve block, a common technique for managing postoperative pain and providing intraoperative analgesia, often includes adjuncts like dexmedetomidine (DEX) to enhance the effectiveness of local anesthetics. DEX, known for its α2-adrenoceptor agonist properties, extends sensory blockade and improves postoperative analgesia while offering sedative benefits. The objective of this study is to rigorously assess the effectiveness and safety of perineural DEX injection in orthopedic nerve block procedures, focusing on orthopedic surgeries to minimize heterogeneity and provide clearer insights for clinical practice. EVIDENCE ACQUISITION: This meta-analysis, registered on PROSPERO, involved a comprehensive literature search across multiple databases, focusing on RCTs comparing DEX with local anesthetics for peripheral nerve blocks in orthopedic surgery patients. The eligibility criteria included adult participants and various nerve block methods in orthopedic surgeries. Studies were rigorously appraised for methodological quality using Cochrane Handbook guidelines. GRADE profiler 3.6 was used for evidence grading. EVIDENCE SYNTHESIS: Among 1391 documents, 21 studies were included, focusing on DEX with local anesthetics in orthopedic nerve blocks. Findings showed significant improvements in analgesia duration, sensory and motor block duration, and reduced postoperative opioid consumption, with an increased risk of bradycardia. Quality assessments indicated moderate bias risk. CONCLUSIONS: DEX with local anesthetics significantly enhances nerve block effectiveness, extending analgesia and block durations while reducing opioid need. However, it requires careful monitoring due to increased bradycardia risk. These findings highlight the need for cautious use in clinical practice, considering both potential benefits and adverse effects.
Subject(s)
Anesthetics, Local , Dexmedetomidine , Nerve Block , Orthopedic Procedures , Dexmedetomidine/therapeutic use , Humans , Nerve Block/methods , Anesthetics, Local/therapeutic use , Analgesics, Non-Narcotic/therapeutic use , Pain, Postoperative/drug therapy , Treatment OutcomeABSTRACT
Recent studies have shown that cellular senescence is involved in the pathogenesis of severe asthma (SA). The objective of this study was to investigate the role of cellular senescence-related genes (CSGs) in the pathogenesis of SA. Here, 54 differentially expressed CSGs were identified in SA patients compared to healthy control individuals. Among the 54 differentially expressed CSGs, 3 CSGs (ETS2, ETS1 and AURKA) were screened using the LASSO regression analysis and logistic regression analysis to establish the CSG-based prediction model to predict severe asthma. Moreover, we found that the protein expression levels of ETS2, ETS1 and AURKA were increased in the severe asthma mouse model. Then, two distinct senescence subtypes of SA with distinct immune microenvironments and molecular biological characteristics were identified. Cluster 1 was characterized by increased infiltration of immature dendritic cells, regulatory T cells, and other cells. Cluster 2 was characterized by increased infiltration levels of eosinophils, neutrophils, and other cells. The molecular biological characteristics of Cluster 1 included aerobic respiration and oxidative phosphorylation, whereas the molecular biological characteristics of Cluster 2 included activation of the immune response and immune receptor activity. Then, we established an Random Forest model to predict the senescence subtypes of SA to guide treatment. Finally, potential drugs were searched for each senescence subgroup of SA patients via the Connectivity Map database. A peroxisome proliferator-activated receptor agonist may be a potential therapeutic drug for patients in Cluster 1, whereas a tachykinin antagonist may be a potential therapeutic drug for patients in Cluster 2. In summary, CSGs are likely involved in the pathogenesis of SA, which may lead to new therapeutic options for SA patients.
Subject(s)
Asthma , Cellular Senescence , Asthma/genetics , Asthma/immunology , Cellular Senescence/genetics , Humans , Mice , Animals , Male , Proto-Oncogene Protein c-ets-1/genetics , Proto-Oncogene Protein c-ets-1/metabolism , Female , Disease Models, Animal , AdultABSTRACT
BACKGROUND & AIMS: Although biologics were prescribed to achieve and maintain clinical remission of active Crohn's disease (CD), almost half of patients experienced a loss of response or intolerance. Here, we investigated the efficacy of combined treatment of biologics and 16-weeks exclusive enteral nutrition (EEN) in moderate-to-severe CD patients with small intestine lesions. METHODS: This was a real-world, multicenter retrospective study, from October 2016 to March 2023, medical records of patients registered at three IBD centers were reviewed for patients with ileal or ileocolonic CD in moderate-to-severe activity. All patients received treatment of biologics with concomitant 16-week EEN (BioEEN) or biologics alone (Bio). The clinical outcomes and endoscopic outcomes were assessed at week 16 and 52. RESULTS: There was no statistically significant difference between Bio (97 patients) and BioEEN group (100 patients) at baseline for demographic and clinical characteristics. Compared to treatment with biologics alone, patients with BioEEN treatment achieved higher rates of clinical response (95.0% vs. 66.0%), clinical remission (87.0% vs. 52.6%), endoscopic response (91.4% vs. 47.4%) including mucosal healing (85.7% vs. 23.7%) at week 16. The superiority of BioEEN sustained in maintenance, with 84.7% (vs. 49.1%) clinical response, 77.8% (vs. 38.6%) clinical remission, 69.2% (vs. 32.6%) endoscopic response and 51.9% (vs. 18.6%) mucosal healing at week 52. CONCLUSIONS: Combined treatment of biologics and 16-week EEN was an efficient therapeutic strategy with affirmative effectiveness for small intestine diseases of active CD.
Subject(s)
Biological Products , Crohn Disease , Enteral Nutrition , Humans , Crohn Disease/therapy , Enteral Nutrition/methods , Male , Female , Retrospective Studies , Adult , Biological Products/administration & dosage , Biological Products/therapeutic use , Treatment Outcome , Middle Aged , Combined Modality Therapy/methods , Ileum , Young Adult , Remission Induction/methodsABSTRACT
Our previous studies have showed that sulfatide-reactive type II NKT (i.e. variant NKT, vNKT) cells inhibit the immunogenic maturation during the development of mature lung dendritic cells (LDCs), leading todeclined allergic airway inflammation in asthma. Nonetheless, the specific immunoregulatory roles of vNKT cells in LDC-mediated Th2 cell responses remain incompletely understood. Herein, we found that administration of sulfatide facilitated the generation of CD4+FoxP3+ regulatory T (Treg) cells in the lungs of wild-type mice, but not in CD1d-/- and Jα18-/- mice, after ovalbumin or house dust mite exposure. This finding implies that the enhancement of lung Treg cells by sulfatide requires vNKT cells, which dependent on invariant NKT (iNKT) cells. Furthermore, the CD4+FoxP3+ Treg cells induced by sulfatide-reactive vNKT cells were found to be associated with PD-L1 molecules expressed on LDCs, and this association was dependent on iNKT cells. Collectively, our findings suggest that in asthma-mimicking murine models, sulfatide-reactive vNKT cells facilitate the generation of lung Treg cells through inducing tolerogenic properties in LDCs, and this process is dependent on the presence of lung iNKT cells. These results may provide a potential therapeutic approach to treat allergic asthma.
Subject(s)
Asthma , T-Lymphocytes, Regulatory , Mice , Animals , Sulfoglycosphingolipids/pharmacology , Sulfoglycosphingolipids/metabolism , Sulfoglycosphingolipids/therapeutic use , Mice, Inbred BALB C , Lung , Asthma/drug therapy , Inflammation/metabolism , Dendritic Cells , Forkhead Transcription Factors/metabolism , Disease Models, AnimalABSTRACT
BACKGROUND: B cells were believed to act as antigen-presenting cells (APCs) to promote T helper type 2 (Th2) cell responses. However, the role of lung B cells and its subpopulations in Th2 cell responses in asthma remains unclear. OBJECTIVE: We leveraged an anti-CD20 monoclonal antibody (mAb) treatment that has been shown to selectively deplete B cells in mice and investigated whether this treatment modulates Th2 cell responses and this modulation is related to lung follicular mature (FM) B cells in a murine model of asthma. METHODS AND RESULTS: We used a house dust mite (HDM)-induced asthma mouse model and found that anti-CD20 mAb treatment attenuates Th2 cell responses. Meanwhile, anti-CD20 mAb treatment did dramatically reduce the number of B cells, especially FM B cells in the lungs, but did not impact the frequency of other immune cell types, including lung T cells, dendritic cells, natural killer cells, and regulatory T cells in wild-type mice. Moreover, we found that the suppressive effect of anti-CD20 mAb treatment on Th2 cell responses could be reversed upon adoptive transfer of lung FM B cells, but not lung CD19+ B cells without FM B cells in asthmatic mice. CONCLUSIONS: These findings reveal that anti-CD20 mAb treatment alleviates Th2 cell responses, possibly by depleting lung FM B cells in a Th2-driven asthma model. This implies a potential therapeutic approach for asthma treatment through the targeting of lung FM B cells.
Subject(s)
Asthma , Th2 Cells , Mice , Animals , Asthma/drug therapy , Lung , B-Lymphocytes , Pyroglyphidae , Dendritic Cells , Disease Models, AnimalABSTRACT
In March 2022, a 58-year-old man was admitted to the local hospital for nausea and vomiting. His blood routine indicated that he had leukocytosis and anemia. The patient was diagnosed with acute myeloid leukemia (AML)-M5b accompanied by DNMT3A, FLT3-TKD, and IDH2 mutations, chest CT revealed pulmonary tuberculosis (TB). Acid-fast bacillus (AFB) was detected in sputum. The patient then received anti-TB treatment with isoniazid + rifampicin + pyrazinamide + ethambutol. On April 8, he was transferred to our hospital's Hematology Department after three consecutive negative sputum smears. He was administered the VA (Venetoclax + Azacytidine) regimen of anti-leukemia treatment and also received levofloxacin + isohydrazide + pyrazinamide + ethambutol anti-TB treatment. After one course of VA therapy, there was no remission in the bone marrow. Therefore, the patient received the HVA (Homeharringtonine + Venetoclax + Azacytidine) regimen of anti-leukemia treatment. On May 25, the bone marrow smear revealed that the original mononuclear cells were 1%. Moreover, bone marrow flow cytometry revealed the absence of any abnormal cells. mNGS showed DNMT3A (mutation rate 44.7%), but no mutations were detected in FLT3-TKD and IDH2. The patient then received the HVA regimen three consecutive times, resulting in complete remission. Repeated chest CT examinations revealed progressive regression of pulmonary TB foci, no AFB was detected in the sputum. This AML patient with DNMT3A, FLT3-TKD, and IDH2 mutations and active TB is difficult to treat. It is very necessary for him to administer prompt anti-leukemia treatment under the premise of active anti-TB treatment. The HVA regimen is effective for this patient.
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Introduction: No study has comprehensively quantified the individual and collective contributions of various risk factors to the growing burden of diabetes in the United States. Methods: This study aimed to determine the extent to which an increase in the prevalence of diabetes was related to concurrent changes in the distribution of diabetes-related risk factors among US adults (aged 20 years or above and not pregnant). Seven cycles of series of cross-sectional National Health and Nutrition Examination Survey data between 2005-2006 and 2017-2018 were included. The exposures were survey cycles and seven domains of risk factors, including genetic, demographic, social determinants of health, lifestyle, obesity, biological, and psychosocial domains. Using Poisson regressions, percent reduction in the ß coefficient (the logarithm used to calculate the prevalence ratio for prevalence of diabetes in 2017-2018 vs. 2005-2006) was computed to assess the individual and collective contribution of the 31 prespecified risk factors and seven domains to the growing burden of diabetes. Results: Of the 16,091 participants included, the unadjusted prevalence of diabetes increased from 12.2% in 2005-2006 to 17.1% in 2017-2018 [prevalence ratio: 1.40 (95% CI, 1.14-1.72)]. Individually, genetic domain [17.3% (95% CI, 5.4%-40.8%)], demographic domain [41.5% (95% CI, 24.4%-76.8%)], obesity domain [35.3% (95% CI, 15.8%-70.2%)], biological domain [46.2% (95% CI, 21.6%-79.1%)], and psychosocial domain [21.3% (95% CI, 9.5%-40.1%)] were significantly associated with a different percent reduction in ß. After adjusting for all seven domains, the percent reduction in ß was 97.3% (95% CI, 62.7%-164.8%). Conclusion: The concurrently changing risk factors accounted for the increasing diabetes prevalence. However, the contribution of each risk factor domain varied. Findings may inform planning cost-effective and targeted public health programs for diabetes prevention.
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Diabetes Mellitus , Adult , Humans , Pregnancy , United States/epidemiology , Female , Nutrition Surveys , Prevalence , Cross-Sectional Studies , Diabetes Mellitus/epidemiology , Risk Factors , Obesity/epidemiologyABSTRACT
Gene-environment (G-E) interactions have important implications for cancer outcomes and phenotypes beyond the main G and E effects. Compared to main-effect-only analysis, G-E interaction analysis more seriously suffers from a lack of information caused by higher dimensionality, weaker signals, and other factors. It is also uniquely challenged by the "main effects, interactions" variable selection hierarchy. Effort has been made to bring in additional information to assist cancer G-E interaction analysis. In this study, we take a strategy different from the existing literature and borrow information from pathological imaging data. Such data are a "byproduct" of biopsy, enjoys broad availability and low cost, and has been shown as informative for modeling prognosis and other cancer outcomes/phenotypes in recent studies. Building on penalization, we develop an assisted estimation and variable selection approach for G-E interaction analysis. The approach is intuitive, can be effectively realized, and has competitive performance in simulation. We further analyze The Cancer Genome Atlas (TCGA) data on lung adenocarcinoma (LUAD). The outcome of interest is overall survival, and for G variables, we analyze gene expressions. Assisted by pathological imaging data, our G-E interaction analysis leads to different findings with competitive prediction performance and stability.
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Gene-Environment Interaction , Neoplasms , Humans , Neoplasms/genetics , Computer Simulation , Phenotype , Models, GeneticABSTRACT
OBJECTIVE: This study was designed to produce a new parent-report measure, the Diagnostic Receptive Expressive Assessment of Mandarin-Infant Toddler Assessment of Communication and Language (DREAM-IT) in order to provide norms for the developmental skills of children aged 0-36 months in four areas: expressive language, receptive language, cognitive play and social skills. METHODOLOGY: The scale was designed to be both broader and deeper than existing instruments that neglect one or more of these significant domains involved in early language. Items were chosen by a group of specialists with clinical experience working with the age group and with attention to the developmental literature. Caregivers were tested individually by a trained person who asked the questions and provided examples. In addition to an extensive health questionnaire, caregivers answered questions in Mandarin about their child's behaviour using a scale of 'not yet', 'sometimes' or 'always' or listing out words and/or sounds understood or said by the child. The 476 participating caregivers were recruited at maternal and child healthcare clinics centred in Chengdu, China, 191 of whom were tested a second time seven months later. The children were sampled in three-month age-bands from 0 to 36 months. The sample was balanced for child gender by age band, and parental education was balanced. Caregivers of 0-24-month-old children and caregivers of 12-36 months were each asked a different set of questions, to determine the appropriate age range and cutoff points for each question, requiring the sample size to be doubled for children aged 12-24 months. RESULTS: The results were subject to item-response theory analysis to remove outlying items, and the resulting internal reliability was high for each domain (average Cronbach's alpha=0.87). The final instrument (between 67 and 113 questions in total) was refined to include the least redundant questions that had the highest intercorrelations, with attention paid to coverage of all domains across the age range. Two scales were developed: one for children 0-18 months, the second for children aged 18-36 months. The longitudinal design permitted the creation of growth curves and norms for each domain for six-month intervals from 0 to 36 months. A small sample of 32 parents of children with Down syndrome aged 18-36 months provided validation that the scales are highly sensitive to developmental delay. CONCLUSION: The instrument shows considerable promise for detecting early communication problems in children in China. WHAT THIS PAPER ADDS: What is already known on the subject In China, efforts were made in recent years to develop language assessments for infants and toddlers, but limitations existed with the domains included and number of items included per age group. Many clinical practitioners also continued to rely on language subtests of general developmental scales, which were limited in depth and breadth of language skills tested and were never intended for diagnosis of language delay. What this paper adds to existing knowledge This paper discusses the development of a valid caregiver report instrument for early communication and language skills of infants and toddlers in mainland China. The Diagnostic Receptive Expressive Assessment of Mandarin-Infant Toddler (DREAM-IT) includes foundational domains necessary for language and communication development in young children (receptive language, expressive language, cognitive play and social communication domains). The results show strong internal reliability (Cronbach's alpha) for each domain on a sample of 716 children sampled in three-month age bands from 0 to 36 months. The external validity proved strong when tested on a group of 32 young children with Down syndrome. What are the potential or actual clinical implications of this work? Besides helping to inform the diagnosis of language delays in infants and toddlers in China, the caregiver report instrument has special features to support clinical practitioners in a field that is just emerging in China. The unique support features include the automatic generation of a profile of relative strengths and weaknesses of the child on the report and the recommendation of child-specific caregiver coaching videos on a companion app.
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Down Syndrome , Humans , Infant , Child, Preschool , Infant, Newborn , Reproducibility of Results , Communication , Language , Cognition , Language DevelopmentABSTRACT
INTRODUCTION: To estimate the up-to-date prevalence of chronic kidney disease among the health check-up population in economically developed areas of China using estimated glomerular filtration rate, urinary albumin creatinine ratio, and kidney ultrasound. METHODS: Healthcare data from 38,093 subjects in 10 megalopolises of China who had an annual health check-up in 2021 were used. The overall and stratified prevalence of chronic kidney disease by sex, age, region and comorbidity group was reported. The association between chronic kidney disease and covariates of demographics, and comorbidities were analyzed in the multivariable-adjusted logistic regression model. RESULTS: A total of 3837 CKD cases were detected meeting any of the three CKD diagnostic criteria, with a crude prevalence of 10.1% in the study population. Using one criterion of decreased glomerular filtration rate, albuminuria and kidney structural abnormalities alone detected 204 (5.3%), 3289 (85.7%) and 563 (14.7%) cases, respectively. The addition of kidney ultrasound detected 427 (11.1%) structural abnormality cases without decreased GFR and albuminuria. The most common abnormalities were renal masses, hydronephrosis due to obstruction and congenital anomalies of kidney and urinary tract. Female, older age, low city-tier, hypertension, diabetes, obesity, hypertriglyceridemia as well as early disease stages such as pre-hypertension, impaired fasting glucose and overweight were significantly associated with chronic kidney disease. CONCLUSION: Kidney ultrasound helps to amplify the detection of CKD patients, which is a supplement to kidney function and urine protein.
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Albuminuria , Renal Insufficiency, Chronic , Humans , Female , Cross-Sectional Studies , Albuminuria/epidemiology , Prevalence , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/etiology , Risk Factors , Kidney , China/epidemiologyABSTRACT
Gene-environment (G-E) interaction analysis plays an important role in studying complex diseases. Extensive methodological research has been conducted on G-E interaction analysis, and the existing methods are mostly based on regression techniques. In many fields including biomedicine and omics, it has been increasingly recognized that deep learning may outperform regression with its unique flexibility (e.g., in accommodating unspecified nonlinear effects) and superior prediction performance. However, there has been a lack of development in deep learning for G-E interaction analysis. In this article, we fill this important knowledge gap and develop a new analysis approach based on deep neural network in conjunction with penalization. The proposed approach can simultaneously conduct model estimation and selection (of important main G effects and G-E interactions), while uniquely respecting the "main effects, interactions" variable selection hierarchy. Simulation shows that it has superior prediction and feature selection performance. The analysis of data on lung adenocarcinoma and skin cutaneous melanoma overall survival further establishes its practical utility. Overall, this study can advance G-E interaction analysis by delivering a powerful new analysis approach based on modern deep learning.
Subject(s)
Deep Learning , Melanoma , Skin Neoplasms , Humans , Gene-Environment Interaction , Models, Genetic , Melanoma, Cutaneous MalignantABSTRACT
BACKGROUND: CDGSH iron sulfur domain 2 (CISD2) is an iron-sulfur protein with a [2Fe-2S] cluster, which is critical for cell proliferation and iron homeostasis. It has been demonstrated that aberrant expression of CISD2 is associated with the progression of multiple cancers. However, the underlying mechanism of CISD2 in regulating tumorigenesis remains obscure. METHODS: Bioinformatics strategies were used to investigate the protein interaction network and functional annotation of CISD2. In the functional experiment, cell viability was measured by CCK-8 kit. The levels of cellular reactive oxygen species (ROS), intracellular free iron, lipid peroxides, and lysosomal activity were determined by DCF-DA, RPA, C11-BODIPY, and cathepsin B staining, respectively. The glutathione (GSH) content was determined using a GSH assay kit. RESULTS: We showed that knockdown of CISD2 significantly accelerated the Erastin-induced ferroptotic cell death with excess lipid peroxidation, GSH exhaustion, and iron accumulation, while overexpression of CISD2 hindered the sensitivity to Erastin. Further assays via confocal microscopy and western blot exhibited that CISD2 knockdown markedly enhanced the lysosomal activity, and activated ferritinophagy under the exposure of Erastin. Pharmacological inhibition of lysosomal function could inhibit the degradation of ferritin heavy chain (FTH), and attenuate the phenotypes of ferroptosis, such as accelerated iron accumulation and lipid peroxidation. Notably, we found that Erastin-induced compensatory elevation of nuclear factor erythroid 2-related factor 2 (NRF2) could be eliminated in CISD2 depletion cells. Mechanically, CISD2 knockdown promoted the degradation of autophagy adaptor p62 and resulted in an increased binding affinity of Keap1 with NRF2, thus leading to the increased ubiquitination and subsequent degradation of NRF2. Enforced expression of NRF2 reversed the sensitivity of shCISD2 cells to ferroptosis both in vitro and in vivo. Conversely, enforced expression of Keap1 exacerbated the degradation of NRF2, reduced the transcriptional expression of FTH and heme oxygenase 1 (HO-1), increased the oxidative damage, and thus further facilitated ferroptosis. CONCLUSION: Taken together, our current results illustrated two parallel mechanisms involved in the shCISD2-mediated ferroptosis. One was that shCISD2 enhanced the accumulation of free iron via ferritinophagy-dependent ferritin turnover; the other was that CISD2 depletion induced the inhibition of the p62-Keap1-NRF2 pathway, which resulted in oxidative stress and ferroptosis.
Subject(s)
Ferroptosis , Iron-Sulfur Proteins , Apoferritins , Cathepsin B/metabolism , Ferritins/genetics , Glutathione/metabolism , Heme Oxygenase-1/metabolism , Iron/metabolism , Kelch-Like ECH-Associated Protein 1/genetics , Kelch-Like ECH-Associated Protein 1/metabolism , Lipid Peroxides/metabolism , NF-E2-Related Factor 2/metabolism , Reactive Oxygen Species/metabolism , Sincalide/metabolism , Sulfur/metabolismABSTRACT
Background: Clostridioides difficile infection (CDI) has been primarily associated with the toxin B (TcdB), one of the three known protein toxins secreted by C. difficile, which can activate the intestinal immune system and lead to pathological damage. Even though the biological functions of intestine epithelial cell-derived extracellular vesicles (I-Evs) have been well documented, the role of I-Evs in the process of CDI is still unknown. Objectives: The protective effect of I-Evs against C. difficile TcdB was investigated both in cultured murine colon carcinoma MC38 cells and a mouse model used in this study. Results: Mouse I-Evs with mean diameter ranging from 100 to 200 nm and a density of 1.09-1.17 g/mL were obtained and confirmed containing the Ev-associated specific surface markers CD63 and TSG101 as well as high level of TGF-ß1. In MC38 cells, I-Evs were able to decrease the gene expression of IL-6, TNF-α, IL-1ß, and IL-22 induced by C. difficile TcdB, but to increase both the gene expression and protein levels of TGF-ß1. I-Evs treatment via intraperitoneal administration alleviates C. difficile TcdB-induced local colon inflammation in mice and increased their survival rate from 50% up to 80%. Furthermore, I-Evs induced an increase in the proportion of CD4+Foxp3+Tregs in vitro and in vivo through a TGF-ß1-dependent mechanism by activating the TGF-ß1 pathway and prompting phosphorylation of the downstream proteins Smad 2/3. Conclusion: For the first time, our study demonstrated that I-Evs originated from intestine epithelial cells can alleviate inflammation induced by C. difficile TcdB both in vitro and in vivo. Therefore, I-Evs might be potentially a novel endogenous candidate for effective treatment of CDI.
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Multiple types of molecular (genetic, genomic, epigenetic, etc.) measurements, environmental risk factors, and their interactions have been found to contribute to the outcomes and phenotypes of complex diseases. In each of the previous studies, only the interactions between one type of molecular measurement and environmental risk factors have been analyzed. In recent biomedical studies, multidimensional profiling, in which data from multiple types of molecular measurements are collected from the same subjects, is becoming popular. A myriad of recent studies have shown that collectively analyzing multiple types of molecular measurements is not only biologically sensible but also leads to improved estimation and prediction. In this study, we conduct an M-E interaction analysis, with M standing for multidimensional molecular measurements and E standing for environmental risk factors. This can accommodate multiple types of molecular measurements and sufficiently account for their overlapping as well as independent information. Extensive simulation shows that it outperforms several closely related alternatives. In the analysis of TCGA (The Cancer Genome Atlas) data on lung adenocarcinoma and cutaneous melanoma, we make some stable biological findings and achieve stable prediction.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Melanoma/genetics , Skin Neoplasms/genetics , Gene-Environment Interaction , Genomics , Computer SimulationABSTRACT
Three human adenovirus (HAdV) genotypes, HAdV-7, HAdV-14, and HAdV-55, emerged as the most prevalent variants in China over the past decade and caused both sporadic, fatal cases and frequent, large outbreaks. Early diagnosis is essential to control infections and endemics. Here, we established a loop-mediated isothermal amplification (LAMP) assay coupled with an instrument-free nucleic acid extraction device recently developed by our group; the assay could detect all the 3 prevalent HAdV genotypes. Specificity analysis showed no cross-reactivity with other common respiratory pathogens and the analytical sensitivity was as low as 10 copies/µL. All detection steps could be completed within 1 hour. The assay's performance was evaluated using clinical samples and compared with the gold standard RT-PCR method, showing highly consistent results. The LAMP assay developed here could be readily used in basic laboratory facilities and with minimal DNA extraction equipment, and as a reliable screening test in a resource-limited setting.
Subject(s)
Adenovirus Infections, Human/diagnosis , Adenoviruses, Human/isolation & purification , Molecular Diagnostic Techniques/methods , Nucleic Acid Amplification Techniques , Respiratory Tract Infections/diagnosis , Adenovirus Infections, Human/epidemiology , Adenoviruses, Human/genetics , Capsid Proteins/genetics , China/epidemiology , DNA, Viral/genetics , Genotype , Humans , Mass Screening , Molecular Diagnostic Techniques/standards , Respiratory Tract Infections/epidemiology , Sensitivity and SpecificityABSTRACT
Abdominal aortic aneurysm (AAA) is a localized enlargement of the abdominal aorta. Once ruptured AAA (rAAA) happens, repairing procedures need to be applied immediately, for which there are two main options: open aortic repair (OAR) and endovascular aortic repair (EVAR). It is of great clinical significance to objectively compare the survival outcomes of OAR versus EVAR using randomized clinical trials; however, this has serious feasibility issues. In this study, with the Medicare data, we conduct an emulation analysis and explicitly "assemble" a clinical trial with rigorously defined inclusion/exclusion criteria. A total of 7826 patients are "recruited", with 3866 and 3960 in the OAR and EVAR arms, respectively. Mimicking but significantly advancing from the regression-based literature, we adopt a deep learning-based analysis strategy, which consists of a propensity score step, a weighted survival analysis step, and a bootstrap step. The key finding is that for both short- and long-term mortality, EVAR has survival advantages. This study delivers a new big data strategy for addressing critical clinical problems and provides valuable insights into treating rAAA using OAR and EVAR.