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Frontiers in Endocrinology 2024The concept of the gut-retinal axis proposed by previous scholars primarily focused on the relationship between intestinal microbiota and retinal diseases, and few...
Mendelian randomization study and mediation analysis about the relation of inflammatory bowel disease and diabetic retinopathy: the further exploration of gut-retina axis.
BACKGROUND
The concept of the gut-retinal axis proposed by previous scholars primarily focused on the relationship between intestinal microbiota and retinal diseases, and few further expanded the relationship between intestinal diseases and retinal diseases. To further substantiate the concept of the gut-retinal axis, we analyzed inflammatory bowel disease (IBD) and diabetic retinopathy (DR) using Mendelian randomization (MR), and use mediation analysis to further explore the potential substances that influence this causal relationship.
METHODS
The genome-wide association study's (GWAS) summary statistics for genetic variations were utilized in a Mendelian randomization (MR) investigation. GWAS data on IBD (including ulcerative colitis (UC), Crohn's disease (CD), and IBD) for non-Finnish Europeans (NFE) were sourced from published articles. In contrast, data on DR (including DR and diabetic maculopathy (DMP)) were obtained from FinnGen R9. The causal relationship has been investigated using inverse variance weighted (IVW), MR-Egger, and weighted median and sensitivity analysis was applied to verify the stability of the results. In addition, we applied mediation analysis to investigate whether circulating inflammatory proteins and plasma lipids played a mediating role, and calculated its effect ratio.
RESULTS
The causal relationship between IBD and DR was discovered by employing the inverse variance weighted (IVW) method and weighted median method. In forward MR, UC was significantly associated with lower risk of DR (IVW: OR=0.874; 95%CI= 0.835-0.916; P value= 1.28E-08) (Weighted median: OR=0.893; 95%CI= 0.837-0.954; P value= 7.40E-04). In reverse MR, it was shown that DR (IVW: OR=0.870; 95%CI= 0.828-0.914; P value= 2.79E-08)(Weighted median: OR=0.857; 95%CI= 0.801-0.916; P value= 6.40E-06) and DMP (IVW: OR=0.900; 95%CI= 0.865-0.937; P value= 3.34E-07)(Weighted median: OR=0.882; 95%CI= 0.841-0.924; P value= 1.82E-07) could reduce the risk of CD. What's more, DR is associated with a lower risk of IBD according to genetic prediction (IVW: OR=0.922; 95%CI= 0.873-0.972; P value= 0.002) (Weighted median: OR=0.924; 95%CI= 0.861-0.992; P value= 0.029). Fibroblast growth factor 21 (FGF21), phosphatidylcholine (PC), and triacylglycerol (TG) serve as mediators in these relationships.
CONCLUSIONS
Our research offers novel insights and sources for investigating the gut-retina axis in the genetic relationship between IBD and DR. We discover four mediators and more about the association between the intestine and retinal disorders and provide more evidence for the gut-retinal axis theory.
Topics: Humans; Mendelian Randomization Analysis; Diabetic Retinopathy; Genome-Wide Association Study; Inflammatory Bowel Diseases; Mediation Analysis; Retina; Polymorphism, Single Nucleotide; Gastrointestinal Microbiome
PubMed: 38948518
DOI: 10.3389/fendo.2024.1382777 -
Frontiers in Endocrinology 2024Lu-oxodotreotide peptide receptor therapy (LuPRRT) is an efficient treatment for midgut neuroendocrine tumors (NETs) of variable radiological response. Several clinical,...
BACKGROUND
Lu-oxodotreotide peptide receptor therapy (LuPRRT) is an efficient treatment for midgut neuroendocrine tumors (NETs) of variable radiological response. Several clinical, biological, and imaging parameters may be used to establish a relative disease prognosis but none is able to predict early efficacy or toxicities. We investigated expression levels for mRNA and miRNA involved in radiosensitivity and tumor progression searching for correlations related to patient outcome during LuPRRT therapy.
METHODS
Thirty-five patients received LuPRRT for G1/G2 midgut NETs between May 2019 and September 2021. Peripheral blood samples were collected prior to irradiation, before and 48 h after the second and the fourth LuPRRT, and at 6-month follow-up. Multiple regression analyses and Pearson correlations were performed to identify the miRNA/mRNA signature that will best predict response to LuPRRT.
RESULTS
Focusing on four mRNAs and three miRNAs, we identified a miRNA/mRNA signature enabling the early identification of responders to LuPRRT with significant reduced miRNA/mRNA expression after the first LuPRRT administration for patients with progressive disease at 1 year ( < 0.001). The relevance of this signature was reinforced by studying its evolution up to 6 months post-LuPRRT. Moreover, nadir absolute lymphocyte count within the first 2 months after the first LuPRRT administration was significantly related to low miRNA/mRNA expression level ( < 0.05) for patients with progressive disease.
CONCLUSION
We present a pilot study exploring a miRNA/mRNA signature that correlates with early hematologic toxicity and therapeutic response 12 months following LuPRRT. This signature will be tested prospectively in a larger series of patients.
Topics: Humans; Neuroendocrine Tumors; Male; Female; MicroRNAs; Middle Aged; Intestinal Neoplasms; RNA, Messenger; Aged; Follow-Up Studies; Adult; Prognosis; Biomarkers, Tumor; Somatostatin; Receptors, Peptide; Radiopharmaceuticals; Lutetium; Radioisotopes
PubMed: 38948517
DOI: 10.3389/fendo.2024.1385079 -
PeerJ 2024This study aimed to assess the accuracy of Mac-2 binding protein glycosylation isomer (M2BPGi) in predicting the stage of liver fibrosis. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
This study aimed to assess the accuracy of Mac-2 binding protein glycosylation isomer (M2BPGi) in predicting the stage of liver fibrosis.
METHODS
Articles published until October 10, 2023, were searched in the PubMed, Embase, Web of Science, and Cochrane Library databases. Pooled sensitivity, specificity, diagnostic odds ratio (DOR), summary receiver-operator curves (SROC), and Spearman's rank correlation coefficient were used to examine the accuracy of M2BPGi in predicting the stage of liver fibrosis. A 95% confidence interval (CI) was provided for each estimate.
RESULTS
Twenty-four studies were included in this meta-analysis, including 3,839 patients with liver fibrosis, 409 of whom progressed to stage 4 or above. The pooled sensitivity, specificity, and area under the ROC (AUC) for M2BPGi predicting liver fibrosis ≥F3 were 0.74 (95% CI [0.65-0.82]), 0.84 (95% CI [0.76-0.89]), and 14.99 (95% CI [9.28-24.21]), respectively. The pooled sensitivity, specificity, and AUC for ≥F4 were 0.80 (95% CI [0.70-0.88]), 0.80 (95% CI [0.73-0.86]), and 16.43 (95% CI [0.84-0.90]), respectively.
CONCLUSION
Among different sample partitions, M2BPGi has the best diagnostic performance for liver fibrosis stage ≥4. Furthermore, the cutoff of 1-2 is more accurate than that of 0-1 or 2-3 for fibrosis ≥ F3 and ≥ F4.
REGISTRATION
CRD42023483260.
Topics: Humans; Liver Cirrhosis; Biomarkers; Glycosylation; Antigens, Neoplasm; ROC Curve; Sensitivity and Specificity; Membrane Glycoproteins
PubMed: 38948207
DOI: 10.7717/peerj.17611 -
PeerJ 2024Gastric cancer (GC), one of the highest venous thromboembolism (VTE) incidence rates in cancer, contributes to considerable morbidity, mortality, and, prominently, extra...
OBJECTIVE
Gastric cancer (GC), one of the highest venous thromboembolism (VTE) incidence rates in cancer, contributes to considerable morbidity, mortality, and, prominently, extra cost. However, up to now, there is not a high-quality VTE model to steadily predict the risk for VTE in China. Consequently, setting up a prediction model to predict the VTE risk is imperative.
METHODS
Data from 3,092 patients from December 15, 2017, to December 31, 2022, were retrospectively analyzed. Multiple logistic regression analysis was performed to assess risk factors for GC, and a nomogram was constructed based on screened risk factors. A receiver operating curve (ROC) and calibration plot was created to evaluate the accuracy of the nomogram.
RESULTS
The risk factors of suffering from VTE were older age (OR = 1.02, 95% CI [1.00-1.04]), Karnofsky Performance Status (KPS) ≥ 70 (OR = 0.45, 95% CI [0.25-0.83]), Blood transfusion (OR = 2.37, 95% CI [1.47-3.84]), advanced clinical stage (OR = 3.98, 95% CI [1.59-9.99]), central venous catheterization (CVC) (OR = 4.27, 95% CI [2.03-8.99]), operation (OR = 2.72, 95% CI [1.55-4.77]), fibrinogen degradation product (FDP) >5 µg/mL (OR = 1.92, 95% CI [1.13-3.25]), and D-dimer > 0.5 mg/L (OR = 2.50, 95% CI [1.19-5.28]). The area under the ROC curve (AUC) was 0.82 in the training set and 0.85 in the validation set.
CONCLUSION
Our prediction model can accurately predict the risk of the appearance of VTE in gastric cancer patients and can be used as a robust and efficient tool for evaluating the possibility of VTE.
Topics: Humans; Nomograms; Venous Thromboembolism; Stomach Neoplasms; Retrospective Studies; Male; Female; Middle Aged; Risk Factors; Aged; China; Risk Assessment; ROC Curve; Fibrin Fibrinogen Degradation Products; Adult
PubMed: 38948205
DOI: 10.7717/peerj.17527 -
Theranostics 2024Immunotherapy has demonstrated its potential to improve the prognosis of patients with hepatocellular carcinoma (HCC); however, patients' responses to immunotherapy...
Immunotherapy has demonstrated its potential to improve the prognosis of patients with hepatocellular carcinoma (HCC); however, patients' responses to immunotherapy vary a lot. A comparative analysis of the tumor microenvironment (TME) in responders and non-responders is expected to unveil the mechanisms responsible for the immunotherapy resistance and provide potential treatment targets. We performed sequencing analyses using 10x Genomics technology on six HCC patients who responded to anti-PD-1 therapy and one HCC patient who did not respond. Additionally, we obtained single cell data from untreated, responsive, and nonresponsive HCC patients from public databases, and used part of the datasets as a validation cohort. These data were integrated using algorithms such as Harmony. An independent validation cohort was established. Furthermore, we performed spatial transcriptomic sequencing on the tumor adjacent tissues of three HCC responsive patients using 10x Genomics spatial transcriptomic technology. Additionally, we analyzed data about three HCC patients obtained from public databases. Finally, we validated our conclusions using immunofluorescence, flow cytometry, and experiments. Our findings confirmed the presence of "immune barrier" partially accounting for the limited efficacy of immunotherapy. Our analysis revealed a significant increase in TREM2 Macrophages among non-responsive patients expressing multiple immunosuppressive signals. anti-Csf1r monoclonal antibodies effectively eliminated these macrophages and augmented the therapeutic effects of anti-PD-1 therapy. TCR Macrophages possessed direct tumor-killing capabilities. IL1B cDC2 was the primary functional subtype of cDC2 cells. Absence of THEMIS CD8 T subtypes might diminish immunotherapeutic effects. Furthermore, CD8 T cells entered a state of stress after anti-PD-1 treatment, which might be associated with CD8 T cell exhaustion and senescence. The profiles of immune TMEs showed differences in HCC patients responsive, non-responsive and untreated. These differences might explain the discounted efficacy of immunotherapy in some HCC patients. The cells and molecules, which we found to carry unique capabilities, may be targeted to enhance immunotherapeutic outcomes in patients with HCC.
Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Single-Cell Analysis; Tumor Microenvironment; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; Immunotherapy; Animals; Male; Mice; Female; Middle Aged
PubMed: 38948071
DOI: 10.7150/thno.95971 -
Theranostics 2024Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), but acquired resistance during the treatment greatly limits its clinical efficiency....
Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), but acquired resistance during the treatment greatly limits its clinical efficiency. Lipid metabolic disorder plays an important role in hepatocarcinogenesis. However, whether and how lipid metabolic reprogramming regulates sorafenib resistance of HCC cells remains vague. Sorafenib resistant HCC cells were established by continuous induction. UHPLC-MS/MS, proteomics, and flow cytometry were used to assess the lipid metabolism. ChIP and western blot were used to reflect the interaction of signal transducer and activator of transcription 3 (STAT3) with glycerol-3-phosphate acyltransferase 3 (GPAT3). Gain- and loss-of function studies were applied to explore the mechanism driving sorafenib resistance of HCC. Flow cytometry and CCK8 in and tumor size in were used to evaluate the sorafenib sensitivity of HCC cells. Our metabolome data revealed a significant enrichment of triglycerides in sorafenib-resistant HCC cells. Further analysis using proteomics and genomics techniques demonstrated a significant increase in the expression of GPAT3 in the sorafenib-resistant groups, which was found to be dependent on the activation of STAT3. The restoration of GPAT3 resensitized HCC cells to sorafenib, while overexpression of GPAT3 led to insensitivity to sorafenib. Mechanistically, GPAT3 upregulation increased triglyceride synthesis, which in turn stimulated the NF-κB/Bcl2 signaling pathway, resulting in apoptosis tolerance upon sorafenib treatment. Furthermore, our and studies revealed that pan-GPAT inhibitors effectively reversed sorafenib resistance in HCC cells. Our data demonstrate that GPAT3 elevation in HCC cells reprograms triglyceride metabolism which contributes to acquired resistance to sorafenib, which suggests GPAT3 as a potential target for enhancing the sensitivity of HCC to sorafenib.
Topics: Sorafenib; Carcinoma, Hepatocellular; Liver Neoplasms; Humans; Drug Resistance, Neoplasm; Cell Line, Tumor; Animals; STAT3 Transcription Factor; Mice; Antineoplastic Agents; Mice, Nude; Xenograft Model Antitumor Assays; Lipid Metabolism; Apoptosis; Gene Expression Regulation, Neoplastic; Signal Transduction
PubMed: 38948063
DOI: 10.7150/thno.92646 -
Canadian Journal of Gastroenterology &... 2024To use hepatic uptake index (HUI) of liver lobes on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI)...
Lobe-Based Hepatic Uptake Index of Gd-EOB-DTPA on Contrast-Enhanced MRI to Quantitatively Discriminate between Compensated and Decompensated Hepatitis B-Related Cirrhosis.
PURPOSE
To use hepatic uptake index (HUI) of liver lobes on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) to discriminate between patients with hepatitis B-related cirrhosis in compensated and decompensated statuses.
METHODS
Forty-four consecutive patients with hepatitis B-related cirrhosis who underwent Gd-EOB-DTPA-enhanced MRI were divided into compensated and decompensated statuses based on clinical evaluation. Volume and signal intensity of individual lobes were retrospectively measured to calculate HUI of the right liver lobe (RHUI), medial (MHUI) and lateral (LHUI) left liver lobes, and caudate lobe (CHUI). Spearman's rank correlation analyses were performed to evaluate relationships of lobe-based HUI with Child-Pugh and model for end-stage liver disease (MELD) scoring system scores in compensated and decompensated statuses. The Mann-Whitney U-test was used to compare the lobe-based HUI between compensated and decompensated statuses. The performance of lobe-based HUI in distinguishing cirrhosis was evaluated using receiver operating characteristic (ROC) analysis, and the area under the ROC curve (AUC) was calculated as a measure of accuracy. Delong's method was used for statistical analysis to elucidate which HUI is optimal.
RESULTS
Compensated and decompensated liver cirrhosis were confirmed in 25 (56.82%) and 19 (43.18%) patients, respectively. According to Spearman's rank correlation analysis, RHUI, MHUI, LHUI, and CHUI were all significantly associated with Child-Pugh and MELD scores (all values <0.05). Receiver operating characteristic analysis demonstrated that among all lobe-based HUI parameters, RHUI could best perform the previous discrimination with a cut-off of 485.73 and obtain an AUC of 0.867. The AUC of RHUI improved and was significantly different from that of MHUI, LHUI, and CHUI ( = 0.03, = 0.007, and < 0.001, respectively, Delong's test).
CONCLUSIONS
The RHUI could help quantitatively discriminate hepatitis B-related cirrhosis between compensated and decompensated statuses.
Topics: Humans; Gadolinium DTPA; Liver Cirrhosis; Female; Male; Contrast Media; Middle Aged; Magnetic Resonance Imaging; Retrospective Studies; Liver; Adult; ROC Curve; Aged; Severity of Illness Index; Hepatitis B
PubMed: 38947874
DOI: 10.1155/2024/6623848 -
Frontiers in Immunology 2024Patients with resectable esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunotherapy (NIT) display variable treatment responses. The purpose of this...
BACKGROUND
Patients with resectable esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunotherapy (NIT) display variable treatment responses. The purpose of this study is to establish and validate a radiomics based on enhanced computed tomography (CT) and combined with clinical data to predict the major pathological response to NIT in ESCC patients.
METHODS
This retrospective study included 82 ESCC patients who were randomly divided into the training group (n = 57) and the validation group (n = 25). Radiomic features were derived from the tumor region in enhanced CT images obtained before treatment. After feature reduction and screening, radiomics was established. Logistic regression analysis was conducted to select clinical variables. The predictive model integrating radiomics and clinical data was constructed and presented as a nomogram. Area under curve (AUC) was applied to evaluate the predictive ability of the models, and decision curve analysis (DCA) and calibration curves were performed to test the application of the models.
RESULTS
One clinical data (radiotherapy) and 10 radiomic features were identified and applied for the predictive model. The radiomics integrated with clinical data could achieve excellent predictive performance, with AUC values of 0.93 (95% CI 0.87-0.99) and 0.85 (95% CI 0.69-1.00) in the training group and the validation group, respectively. DCA and calibration curves demonstrated a good clinical feasibility and utility of this model.
CONCLUSION
Enhanced CT image-based radiomics could predict the response of ESCC patients to NIT with high accuracy and robustness. The developed predictive model offers a valuable tool for assessing treatment efficacy prior to initiating therapy, thus providing individualized treatment regimens for patients.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Male; Female; Neoadjuvant Therapy; Tomography, X-Ray Computed; Esophageal Neoplasms; Middle Aged; Machine Learning; Retrospective Studies; Aged; Immunotherapy; Nomograms; Treatment Outcome; Adult; Radiomics
PubMed: 38947338
DOI: 10.3389/fimmu.2024.1405146 -
Frontiers in Immunology 2024Interleukin-17 (IL-17) family cytokines promote protective inflammation for pathogen resistance, but also facilitate autoimmunity and tumor development. A direct signal...
BACKGROUND
Interleukin-17 (IL-17) family cytokines promote protective inflammation for pathogen resistance, but also facilitate autoimmunity and tumor development. A direct signal of IL-17 to regulatory T cells (Tregs) has not been reported and may help explain these dichotomous responses.
METHODS
We generated a conditional knockout of in Tregs by crossing mice to mice ( mice). Subsequently, we adoptively transferred bone marrow cells from mice to a mouse model of sporadic colorectal cancer ( / ), to selectively ablate IL-17 direct signaling on Tregs in colorectal cancer. Single cell RNA sequencing and bulk RNA sequencing were performed on purified Tregs from mouse colorectal tumors, and compared to those of human tumor infiltrating Treg cells.
RESULTS
IL-17 Receptor A (IL-17RA) is expressed in Tregs that reside in mouse mesenteric lymph nodes and colon tumors. Ablation of IL-17RA, specifically in Tregs, resulted in increased Th17 cells, and exacerbated tumor development. Mechanistically, tumor-infiltrating Tregs exhibit a unique gene signature that is linked to their activation, maturation, and suppression function, and this signature is in part supported by the direct signaling of IL-17 to Tregs. To study pathways of Treg programming, we found that loss of IL-17RA in tumor Tregs resulted in reduced RNA splicing, and downregulation of several RNA binding proteins that are known to regulate alternative splicing and promote Treg function.
CONCLUSION
IL-17 directly signals to Tregs and promotes their maturation and function. This signaling pathway constitutes a negative feedback loop that controls cancer-promoting inflammation in CRC.
Topics: Animals; T-Lymphocytes, Regulatory; Interleukin-17; Mice; Mice, Knockout; Humans; Receptors, Interleukin-17; Colorectal Neoplasms; Lymphocytes, Tumor-Infiltrating; Th17 Cells; Mice, Inbred C57BL; Signal Transduction; Disease Models, Animal
PubMed: 38947320
DOI: 10.3389/fimmu.2024.1408710 -
Frontiers in Immunology 2024Follicular helper T cells are essential for helping in the maturation of B cells and the production of neutralizing antibodies (NAbs) during primary viral infections....
INTRODUCTION
Follicular helper T cells are essential for helping in the maturation of B cells and the production of neutralizing antibodies (NAbs) during primary viral infections. However, their role during recall responses is unclear. Here, we used hepatitis C virus (HCV) reinfection in humans as a model to study the recall collaborative interaction between circulating CD4 T follicular helper cells (cTfh) and memory B cells (MBCs) leading to the generation of NAbs.
METHODS
We evaluated this interaction longitudinally in subjects who have spontaneously resolved primary HCV infection during a subsequent reinfection episode that resulted in either another spontaneous resolution (SR/SR, = 14) or chronic infection (SR/CI, = 8).
RESULTS
Both groups exhibited virus-specific memory T cells that expanded upon reinfection. However, early expansion of activated cTfh (CD4CXCR5PD-1ICOSFoxP3) occurred in SR/SR only. The frequency of activated cTfh negatively correlated with time post-infection. Concomitantly, NAbs and HCV-specific MBCs (CD19CD27IgME2-Tet) peaked during the early acute phase in SR/SR but not in SR/CI. Finally, the frequency of the activated cTfh1 (CXCR3CCR6) subset correlated with the neutralization breadth and potency of NAbs.
CONCLUSION
These results underscore a key role for early activation of cTfh1 cells in helping antigen-specific B cells to produce NAbs that mediate the clearance of HCV reinfection.
Topics: Humans; Hepacivirus; T Follicular Helper Cells; Male; Female; Hepatitis C; Memory B Cells; Adult; Middle Aged; Reinfection; Antibodies, Neutralizing; Immunologic Memory; Hepatitis C Antibodies; Hepatitis C, Chronic; Lymphocyte Activation
PubMed: 38947319
DOI: 10.3389/fimmu.2024.1403769