Dual-mode nanoprobe strategy integrating ultrasound and near-infrared light for targeted and synergistic arterial thrombolysis.

Efficient thrombolysis in time is crucial for prognostic improvement of patients with acute arterial thromboembolic disease, while limitations and complications still exist in conventional thrombolytic treatment methods. Herein, our study sought to investigate a novel dual-mode strategy that integrated ultrasound (US) and near-infrared light (NIR) with establishment of hollow mesoporous silica nanoprobe (HMSN) which contains Arginine-glycine-aspartate (RGD) peptide (thrombus targeting), perfluoropentane (PFP) (thrombolysis with phase-change and stable cavitation) and indocyanine green (ICG) (thrombolysis with photothermal conversion). HMSN is used as the carrier, the surface is coupled with targeted RGD to achieve high targeting and permeability of thrombus, PFP and ICG are loaded to achieve the collaborative diagnosis and treatment of thrombus by US and NIR, so as to provide a new strategy for the integration of diagnosis and treatment of arterial thrombus. From the in vitro and in vivo evaluation, RGD/ICG/PFP@HMSN can aggregate and penetrate at the site of thrombus, and finally establish the dual-mode directional development and thrombolytic treatment under the synergistic effect of US and NIR, providing strong technical support for the accurate diagnosis and treatment of arterial thrombosis.

Efficacy and safety of anti-PD-1/PD-L1-based dual immunotherapies versus PD-1/PD-L1 inhibitor alone in patients with advanced solid tumor: a systematic review and meta-analysis.

INTRODUCTION: Numerous randomized controlled trials (RCTs) have investigated PD-1/PD-L1 inhibitor-based combination therapies. The debate surrounding the potential additive clinical benefits of combination of two immune-oncology (IO) therapies for cancer patients persists. METHODS: Both published and grey sources of randomized clinical trials that compared anti-PD-1/PD-L1-based immunotherapy combinations with monotherapy in patients with advanced or metastatic solid tumors were encompassed. The primary outcome was progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs). RESULTS: Our analysis encompassed 31 studies comprising 10,341 patients, which covered 12 distinct immune-oncology combination regimens. Across all patients, the immunotherapy combinations exhibited the capability to enhance the ORR (OR = 1.23 [95% CI 1.13-1.34]) and extend PFS (HR = 0.91 [95% CI 0.87-0.95]). However, the observed enhancement in OS (HR = 0.96 [95% CI 0.91-1.01]) was of no significance. Greater benefits in terms of PFS (HR = 0.82 [95% CI 0.72 to 0.93]) and OS (HR = 0.85 [95% CI 0.73 to 0.99]) may be particularly pronounced in cases where PD-L1 expression is negative. Notably, despite a heightened risk of any-grade TRAEs (OR = 1.72 [95% CI 1.40-2.11]) and grade greater than or equal to 3 TRAEs (OR = 2.01 [95% CI 1.67-2.43]), toxicity was generally manageable. CONCLUSIONS: This study suggests that incorporating an additional immunotherapy agent with PD-1/PD-L1 inhibitors can elevate the response rate and reduce the risk of disease progression, all while maintaining manageable toxicity. However, there remains a challenge in translating these primary clinical benefits into extended overall survival.

Targeted Ultrasound Nanobubbles Therapy for Prostate Cancer via Immuno-Sonodynamic Effect.

Background: Prostate cancer (PCa) poses a significant global health threaten. Immunotherapy has emerged as a novel strategy to augment the inhibition of tumor proliferation. However, the sole use of anti-PD-L1 Ab for PCa has not yielded improvements, mirroring outcomes observed in other tumor types. Methods: This study employed the thin film hydration method to develop lipid nanobubbles (NBs) encapsulating chlorin e6 (Ce6) and anti-PD-L1 Ab (Ce6@aPD-L1 NBs). Our experimental approach included cellular assays and mouse immunization, providing a comprehensive evaluation of Ce6@aPD-L1 NBs' impact. Results: The Ce6@aPD-L1 NBs effectively induced reactive oxygen species generation, leading to tumor cells death. In mice, they demonstrated a remarkable enhancement of immune responses compared to control groups. These immune responses encompassed immunogenic cell death induced by sonodynamic therapy and PD-1/PD-L1 blockade, activating dendritic cells maturation and effectively stimulating CD8+T cells. Conclusion: Ce6@aPD-L1 NBs facilitate tumor-targeted delivery, activating anti-tumor effects through direct sonodynamic therapy action and immune system reactivation in the tumor microenvironment. Ce6@aPD-L1 NBs exhibit substantial potential for achieving synergistic anti-cancer effects in PCa.

Macrophage-targeted ultrasound nanobubbles for highly efficient sonodynamic therapy of atherosclerotic plaques by modulating M1-to-M2 polarization.

BACKGROUND AND AIMS: Sonodynamic therapy (SDT) is a new approach for the treatment of atherosclerosis (AS), yet the poor targeting ability of sonosensitizers limits its therapeutic efficacy. Herein, we reported a plaque-targeted nanoplatform modified with macrophage type A scavenger receptor (SR-A)-targeted peptide (designated as SR-A-Ce6NB) to augment the efficacy of low-intensity pulsed ultrasound (LIPUS)-mediated SDT of atherosclerotic plaque. METHODS: SR-A-Ce6NB was fabricated by thin hydration method and biotin-avidin system, and its physicochemical properties, biocompatibility and plaque-targeting ability were investigated. RAW 264.7 cells were used for in vitro experimental studies. Male 6-week-old apolipoprotein E-deficient mice were fed a high-fat diet for 16 weeks to induce aortic atherosclerotic plaques. Plaque-bearing mice were randomly allocated into five groups (n = 6): control group, Ce6 + LIPUS group, Ce6NB + LIPUS group, SR-A-Ce6NB + LIPUS group and atorvastatin group. After treatment in each group, the aortic artery was harvested for Oil red O, H&E, Masson's trichrome staining, immunohistochemical and immunofluorescent staining. RESULTS: SR-A-Ce6NB with high stability and excellent biocompatibility was successfully fabricated. SR-A-Ce6NB could actively target activated macrophages and selectively accumulate in the plaque. SR-A-Ce6NB could be triggered by LIPUS and had a more potent sonodynamic effect than free Ce6 to potentiate SDT. SR-A-Ce6NB-mediated SDT enhanced the anti-atherogenic effect via modulating M1-to-M2 macrophage polarization and had an earlier onset of action on plaque than the statin-mediated effect. No apparent side effect was observed after intravenous SR-A-Ce6NB injection and LIPUS exposure. CONCLUSIONS: Macrophage-targeted nanoplatform SR-A-Ce6NB-mediated SDT provides a safe, effective and preferable anti-atherogenic therapy by mediating M1-to-M2 macrophage polarization.

COVID-19 vaccine-related misinformation identification among Chinese residents during a regional outbreak.

Objectives: Misinformation about the COVID vaccines poses a significant challenge to vaccination efforts in many countries. This study examined Chinese citizens' ability to correctly identify COVID-19 vaccine misinformation in geographic areas with and without a regional outbreak. We also investigated the associations between misinformation identification and information source usage, source trust, perceived information quality, and demographic characteristics. Setting: The online survey was conducted in four cities from June 8th to 15th, 2021 in Guangdong Province, two of which were experiencing a regional surge of COVID-19 delta variant infections, and four cities in Hunan Province, a neighboring province largely unaffected. Participants: A total of 4,479 individuals aged 18 and above completed the online questionnaire. Given survey length, those who finished the study under 5 min were excluded, resulting in a final sample of 3,800. Outcome measurements: Misinformation identification, source exposure, source trust, and perceived information quality. Results: Results showed slightly higher levels of correct misinformation identification in surge vs. non-surge areas. Trust in official information sources was positively associated with correct misinformation identification in full sample analysis, while trust in informal sources was negatively associated with the same outcome. Perceived information quality was positively associated with correct misinformation identification in the full sample. Conclusion: Information providers in China should enhance the quality of the vaccine information they provide, and the Chinese public should balance their usage of different sources of information to acquire vaccine knowledge.

Spatiotemporal dynamics and influencing factors of carbon productivity in counties of Shandong Province, China.

In the context of the increasing global greenhouse effect, the Chinese government has proposed a "dual carbon" target. As a major carbon-emitting province in China, Shandong Province needs to improve its carbon productivity to coordinate carbon emission reductions and sustainable economic growth. This study analyzes the spatial and temporal evolution of carbon productivity at the county scale and the factors influencing it in Shandong Province from 2000 to 2017. The study uses the Dagum Gini coefficient, kernel density analysis, spatial autocorrelation model, and geographically and temporally weighted regression model. The results indicate that the carbon productivity in Shandong Province nearly doubled during the study period, revealing a spatial distribution characteristic of "high in the east and low in the west," together with a significant positive spatial autocorrelation. Intra-regional differences, the most important source of development differences among the three economic circles, rose to 32.11% during the study period, whereas inter-regional differences declined to 26.6%. Gross domestic product per capita and population density play a significant positive role in the development of carbon productivity. The balance of deposits in financial institutions at the end of the year has a weak positive effect, and the local average public finance expenditure and secondary industry structure on carbon productivity are negative in general. Shandong Province should identify specific regions with weak carbon productivity levels and understand the key factors to improve carbon productivity to promote the achievement of the "dual carbon" goal.

[Evolution of Research Related to Macrophage Polarization in Atherosclerosis:A Visualization Analysis].

Objective To explore the research status,hotspots,and development tendency of macrophage polarization (MP) in atherosclerosis (AS) by systematically reviewing and visually analyzing the articles published recently in this field,so as to provide new ideas for the basic research and translational research on MP in the prevention and treatment of AS.Methods SCI-Expanded was used as the data source for the retrieval of the articles involving MP in AS from 2012 to 2022.CiteSpace 6.1.R3 was employed to visualize the node information of the publishing country/region,institutions,authors,keywords,and citations.Results A total of 381 papers were included.The number of publications in the world showed an increasing trend year by year.China and the United States were leading this field in the number and centrality of publications,and Shandong University in China contributed the largest number of publications.The analysis of the key words and citations showed that the hotspots and frontiers in this field mainly included the pathogenesis of AS,MP markers,macrophage plasticity regulation,and potential therapeutic targets for AS.Conclusions The research on MP in AS was booming during 2012-2022.The differential gene expression and the molecular mechanism of targeted therapy of MP in AS are the research trends in this field,which will provide new measures for the prevention and treatment of AS.

Industrial eco-efficiency of resource-based cities in China: spatial-temporal dynamics and associated factors.

Promoting the greening of industry is the key to achieving high-quality and sustainable development of the urban economy. It is particularly important for resource-based cities (RBCs) that exploit natural resources as the leading industries. In this paper, the Windows-Bootstrap-DEA model was used to calculate the industrial eco-efficiency (IEE) of 114 RBCs in China from 2003 to 2016, and the regional differences and dynamic evolution characteristics of the IEE were analyzed. The panel Tobit model was used to explore the factors associated with IEE in RBCs. The results showed that the IEE of RBCs in China was at a low level during the study period, and the resource utilization process had not reached an optimal state. There were large regional differences in IEE, and there was a significant degree of spatial agglomeration. The results of conditional probability density estimation showed that the distribution of IEE had strong internal stability on the whole, and the distributions of IEE of RBCs in different regions, different resource types, and different development stages showed significant differences. The results of the panel Tobit model showed that per capita GDP, ownership structure, science and technology input, and industrial agglomeration had significant positive effects on IEE, while industrial structure and employment structure showed significant negative effects. The conclusions of this paper can provide a scientific decision-making basis for industrial transformation planning of RBCs.

Ultrasound-controlled nano oxygen carriers enhancing cell viability in 3D GelMA hydrogel for the treatment of myocardial infarction.

Heart failure is a critical and ultimate phase of cardiovascular ailment that leads to a considerable incidence of disability and mortality. Among various factors contributing to heart failure, myocardial infarction is one of the most frequent and significant causes, which is still difficult to manage effectively. An innovative therapeutic strategy, namely a 3D bio-printed cardiac patch, has recently emerged as a promising approach to substitute damaged cardiomyocytes in a localized infarct region. Nevertheless, the efficacy of this treatment primarily relies on the long-term viability of the transplanted cells. In this study, we aimed to construct acoustically sensitive nano oxygen carriers to improve cell survival inside the bio-3D printed patch. In this study, we initially created nanodroplets capable of phase transition triggered by ultrasound and integrated them into GelMA (Gelatin Methacryloyl) hydrogels, which were then employed for 3D bioprinting. After adding nanodroplets and ultrasonic irradiation, numerous pores appeared inside the hydrogel with improved permeability. We further encapsulated hemoglobin into nanodroplets (ND-Hb) to construct oxygen carriers. Results of in vitro experiments showed the highest cell survival within the patch of ND-Hb irradiated by the low-intensity pulsed ultrasound (LIPUS) group. The genomic analysis discovered that the increased survival of seeded cells within the patch might be related to the protection of mitochondrial function owing to the improved hypoxic state. Eventually, in vivo studies revealed that the LIPUS+ND-Hb group had improved cardiac function and increased revascularization after myocardial infarction. To summarize, our study successfully improved the permeability of the hydrogel in a non-invasive and efficient manner, facilitating the exchange of substances in the cardiac patch. Moreover, ultrasound-controlled oxygen release augmented the viability of the transplanted cells and expedited the repair of infarcted tissues.

Molecular imaging research in atherosclerosis: A 23-year scientometric and visual analysis.

Background: Cardiovascular and cerebrovascular diseases are major global health problems, and the main cause is atherosclerosis. Recently, molecular imaging has been widely employed in the diagnosis and therapeutic applications of a variety of diseases, including atherosclerosis. Substantive facts have announced that molecular imaging has broad prospects in the early diagnosis and targeted treatment of atherosclerosis. Objective: We conducted a scientometric analysis of the scientific publications over the past 23 years on molecular imaging research in atherosclerosis, so as to identify the key progress, hotspots, and emerging trends. Methods: Original research and reviews regarding molecular imaging in atherosclerosis were retrieved from the Web of Science Core Collection database. Microsoft Excel 2021 was used to analyze the main findings. CiteSpace, VOSviewer, and a scientometric online platform were used to perform visualization analysis of the co-citation of journals and references, co-occurrence of keywords, and collaboration between countries/regions, institutions, and authors. Results: A total of 1755 publications were finally included, which were published by 795 authors in 443 institutions from 59 countries/regions. The United States was the top country in terms of the number and centrality of publications in this domain, with 810 papers and a centrality of 0.38, and Harvard University published the largest number of articles (182). Fayad, ZA was the most productive author, with 73 papers, while LIBBY P had the most co-citations (493). CIRCULATION was the top co-cited journal with a frequency of 1,411, followed by ARTERIOSCL THROM VAS (1,128). The co-citation references analysis identified eight clusters with a well-structured network (Q = 0.6439) and highly convincing clustering (S = 0.8865). All the studies calculated by keyword co-occurrence were divided into five clusters: "nanoparticle," "magnetic resonance imaging," "inflammation," "positron emission tomography," and "ultrasonography". Hot topics mainly focused on cardiovascular disease, contrast media, macrophage, vulnerable plaque, and microbubbles. Sodium fluoride ⁃PET, targeted drug delivery, OCT, photoacoustic imaging, ROS, and oxidative stress were identified as the potential trends. Conclusion: Molecular imaging research in atherosclerosis has attracted extensive attention in academia, while the challenges of clinical transformation faced in this field have been described in this review. The findings of the present research can inform funding agencies and researchers toward future directions.

Bacterium-enabled transient gene activation by artificial transcription factors for resolving gene regulation in maize.

Understanding gene regulatory networks is essential to elucidate developmental processes and environmental responses. Here, we studied regulation of a maize (Zea mays) transcription factor gene using designer transcription activator-like effectors (dTALes), which are synthetic Type III TALes of the bacterial genus Xanthomonas and serve as inducers of disease susceptibility gene transcription in host cells. The maize pathogen Xanthomonas vasicola pv. vasculorum was used to introduce 2 independent dTALes into maize cells to induced expression of the gene glossy3 (gl3), which encodes a MYB transcription factor involved in biosynthesis of cuticular wax. RNA-seq analysis of leaf samples identified, in addition to gl3, 146 genes altered in expression by the 2 dTALes. Nine of the 10 genes known to be involved in cuticular wax biosynthesis were upregulated by at least 1 of the 2 dTALes. A gene previously unknown to be associated with gl3, Zm00001d017418, which encodes aldehyde dehydrogenase, was also expressed in a dTALe-dependent manner. A chemically induced mutant and a CRISPR-Cas9 mutant of Zm00001d017418 both exhibited glossy leaf phenotypes, indicating that Zm00001d017418 is involved in biosynthesis of cuticular waxes. Bacterial protein delivery of dTALes proved to be a straightforward and practical approach for the analysis and discovery of pathway-specific genes in maize.

Core indicators of an evaluation and guidance system for quality of care in inflammatory bowel disease centers: A critical review.

The mission of the IBD Quality Care Evaluation Center (IBDQCC) is to establish indicators of quality of care (QoC), certify IBD units to generate a network of IBD quality care, and eventually improve the national level of IBD healthcare. The final list of 28 core and 13 secondary IBD QoC indicators suitable for the healthcare system in China were selected using a Delphi consensus methodology. Units that met all core indicators were qualified as "regional"; units that met all core indicators together with more than 50% of the secondary indicators received a rating of "excellence." Using the selected QoC core indicators for certifying IBD units, a network of IBD quality care units covering the majority of IBD patients in China was established. Funding: This work was financially supported by Cultivation Funding for Clinical Scientific Research Innovation, Renji Hospital, School of Medicine, Shanghai Jiaotong University (RJPY-LX-004), National Natural Science Foundation of China (No. 81,770,545), Shanghai Science and Technology Innovation Initiative (21SQBS02302), and Cultivated Funding for Clinical Research Innovation, Renji Hospital, School of Medicine, Shanghai Jiaotong University (RJPY-LX-004).

Expression and Significance of Programmed Death-1 and Its Ligands in the Accelerated Formation of Atherosclerosis in an Induced Murine Lupus Model.

Atherosclerosis (AS) is a chronic inflammatory disease that occurs in artery walls, which seriously affects the survival and prognosis of patients with systemic lupus erythematosus (SLE). Immune and inflammatory responses have notable effects on all stages of AS. In this study, we modeled SLE combined with AS in vivo via intraperitoneal injection of pristane (2,6,10,14-tetramethylpentadecane) into apolipoprotein E-knockout (ApoE-/- ) mice that had accelerated atherosclerotic lesions compared with wild-type (WT) ApoE-/- mice. In pristane-induced ApoE-/- mice, expression of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in peripheral blood and on the surfaces of atherosclerotic lesions significantly increased, and levels of proinflammatory cytokines, namely, interferon-gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) in peripheral blood were elevated. We did not detect expression of programmed death-ligand 2 (PD-L2) in the arterial plaques of either pristane-induced or WT ApoE-/- mice, nor did we observe any significant difference in PD-L2 expression in peripheral blood between the two groups. Taken together, these results suggested that PD-1/PD-L1 signaling pathway might play an important regulatory role in the progression of AS in an induced murine lupus model which implies a potential target for treatment of AS in SLE.

Novel Gene Signatures Predicting Primary Non-response to Infliximab in Ulcerative Colitis: Development and Validation Combining Random Forest With Artificial Neural Network.

Background: While infliximab has revolutionized the treatment of ulcerative colitis, primary non-response is difficult to predict, which limits effective disease management. The study aimed to establish a novel genetic model to predict primary non-response to infliximab in patients with ulcerative colitis. Methods: Publicly available mucosal expression profiles of infliximab-treated ulcerative colitis patients (GSE16879, GSE12251) were utilized to identify potential predictive gene panels. The random forest algorithm and artificial neural network were applied to further screen for predictive signatures and establish a model to predict primary non-response to infliximab. Results: A total of 28 downregulated and 2 upregulated differentially expressed genes were identified as predictors. The novel model was successfully established on the basis of the molecular prognostic score system, with a significantly predictive value (AUC = 0.93), and was validated with an independent dataset GSE23597 (AUC = 0.81). Conclusion: Machine learning was used to construct a predictive model based on the molecular prognostic score system. The novel model can predict primary non-response to infliximab in patients with ulcerative colitis, which aids in clinical-decision making.

Discovery of new long noncoding RNAs associated with ulcerative colitis with a novel general microarray expression data.

UC is a chronic, nonspecific disease and characterized by a chronic relapsing intestinal inflammation, which puts a person at a higher risk of developing bowel cancer, while the causes of UC are unknown. Recently, with the development of microarray technology, more and more studies are focusing on the potential roles of long noncoding RNAs (lncRNAs) in the pathogenesis of diseases. The purpose of this study is to devise a method, based on cDNA microarray probe genomics data, to computationally determine the potential function of evolutionary conserved lncRNAs in ulcerative colitis (UC). We analysed a total of 12,593 microarray probes present in the Ensembl, OMIM, UniGene, and Gene Ontology databases. We found that lncRNA n385775 was significantly higher (P < 0.001) in patients with active UC, while n336281 (P = 0.017), n341081 (P = 0.041), and n387236 (P = 0.006) were significantly lower. Then, we validated our findings by measuring the expression of lncRNAs in colon tissue samples from patients affected by UC. Moreover, we validated the expression pattern of the lncRNAs in two cell lines, Caco2/bbe and T84, treated with TNF-α. In Caco2/bbe cells, lncRNA n385775 was significantly upregulated after TNF-α treatment (P = 0.002). This study reports a novel method to re- annotate the transcriptome expression profile from existing cDNA microarray data as a potential approach to investigate the function of lncRNAs in UC.

Expanding the range of editable targets in the wheat genome using the variants of the Cas12a and Cas9 nucleases.

The development of CRISPR-based editors recognizing distinct protospacer-adjacent motifs (PAMs), or having different spacer length/structure requirements broadens the range of possible genomic applications. We evaluated the natural and engineered variants of Cas12a (FnCas12a and LbCas12a) and Cas9 for their ability to induce mutations in endogenous genes controlling important agronomic traits in wheat. Unlike FnCas12a, LbCas12a-induced mutations in the wheat genome, even though with a lower rate than that reported for SpCas9. The eight-fold improvement in the gene editing efficiency was achieved for LbCas12a by using the guides flanked by ribozymes and driven by the RNA polymerase II promoter from switchgrass. The efficiency of multiplexed genome editing (MGE) using LbCas12a was mostly similar to that obtained using the simplex RNA guides and showed substantial increase after subjecting transgenic plants to high-temperature treatment. We successfully applied LbCas12a-MGE for generating heritable mutations in a gene controlling grain size and weight in wheat. We showed that the range of editable loci in the wheat genome could be further expanded by using the engineered variants of Cas12a (LbCas12a-RVR) and Cas9 (Cas9-NG and xCas9) that recognize the TATV and NG PAMs, respectively, with the Cas9-NG showing higher editing efficiency on the targets with atypical PAMs compared to xCas9. In conclusion, our study reports a set of validated natural and engineered variants of Cas12a and Cas9 editors for targeting loci in the wheat genome not amenable to modification using the original SpCas9 nuclease.

A Novel Radiomics Nomogram for the Prediction of Secondary Loss of Response to Infliximab in Crohn's Disease.

PURPOSE: The prediction of the loss of response (LOR) to infliximab (IFX) is crucial for optimizing treatment strategies and shifting biologics. However, a secondary LOR is difficult to predict by endoscopy due to the intestinal stricture, perforation, and fistulas. This study aimed to develop and validate a radiomic nomogram for the prediction of secondary LOR to IFX in patients with Crohn's disease (CD). PATIENTS AND METHODS: A total of 186 biologic-naive patients diagnosed with CD between September 2016 and June 2019 were enrolled. Secondary LOR was determined during week 54. Computed tomography enterography (CTE) texture analysis (TA) features were extracted from lesions and analyzed using LIFEx software. Feature selection was performed by least absolute shrinkage and selection operator (LASSO) and ten-fold cross validation. A nomogram was constructed using multivariable logistic regression, and the internal validation was approached by ten-fold cross validation. RESULTS: Predictors contained in the radiomics nomogram included three first-order and five second-order signatures. The prediction model presented significant discrimination (AUC, 0.880; 95% CI, 0.816-0.944) and high calibration (mean absolute error of = 0.028). Decision curve analysis (DCA) indicated that the nomogram provided clinical net benefit. Ten-fold cross validation assessed the stability of the nomogram with an AUC of 0.817 and an accuracy of 0.819. CONCLUSION: This novel radiomics nomogram provides a predictive tool to assess secondary LOR to IFX in patients with Crohn's disease. This tool will help physicians decide when to switch therapy.

Development and Validation of an Interleukin-6 Nomogram to Predict Primary Non-response to Infliximab in Crohn's Disease Patients.

Background: The primary non-response (PNR) rate of infliximab (IFX) varies from 20 to 46% for the treatment of Crohn's disease (CD). Detected PNR reduces the improper use of specific treatments. To date, there is hardly any knowledge regarding early markers of PNR. The aim of this study was to evaluate the role of Interleukin-6 (IL-6) as an early predictor of PNR of IFX for the treatment of CD. Methods: We enrolled 322 bio-naïve patients diagnosed with CD from January 2016 to May 2020. Primary response was determined at week 14. Multivariable logistic regression was used to construct prediction models. Area under the curve (AUC), calibration and decision curve analyses (DCA) were assessed in the validation cohort. GEO data were analyzed to identify potential mechanisms of IL-6 in IFX therapy for CD. Results: PNR occurred in 31.06% (100 of 322) patients who were assessable at week 14. IL-6 levels significantly decreased after IFX therapy (p < 0.001). The validation model containing IL-6 presented enhanced discrimination with an AUC of 0.908 and high calibration. Decision curve analysis (DCA) indicated that the model added extra predictive value. GEO data confirmed the IL-6 levels were increased in the PNR group and IL-6-related differentially expressed genes (DEGs) were enriched in the inflammatory response. Conclusions: We concluded that IL-6 may be used as a predictive factor to assess the risk of PNR to IFX therapy.

Mucosal immunity and tRNA, tRF, and tiRNA.

Mucosal immunity has crucial roles in human diseases such as respiratory tract infection, inflammatory bowel diseases (IBD), and colorectal cancer (CRC). Recent studies suggest that the mononuclear phagocyte system, cancer cells, bacteria, and viruses induce the mucosal immune reaction by various pathways, and can be major factors in the pathogenesis of these diseases. Transfer RNA (tRNA) and its fragments, including tRNA-derived RNA fragments (tRFs) and tRNA-derived stress-induced RNAs (tiRNAs), have emerged as a hot topic in recent years. They not only are verified as essential for transcription and translation but also play roles in cellular homeostasis and functions, such as cell metastasis, proliferation, and apoptosis. However, the specific relationship between their biological regulation and mucosal immunity remains unclear to date. In the present review, we carry out a comprehensive discussion on the specific roles of tRNA, tRFs, and tiRNAs relevant to mucosal immunity and related diseases.