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Abstract Background Intestinal necrosis in uremic patients has been reported but is rare. Case presentation A 56-year-old male patient who underwent long-term regular haemodialysis was admitted to the hospital due to involuntary shaking of the limbs and nonsense speech. The patient’s symptoms improved after continuous blood purification under heparin anticoagulation, rehydration, sedation, and correction of electrolyte disturbances. However, the patient experienced a sudden onset of abdominal pain and a rapid decrease in blood pressure; high-dose norepinephrine were required to maintain his blood pressure. A plain abdominal radiograph performed at bedside showed intestinal dilation. Colonoscopy revealed inflammation and oedema of the entire colon, with purulent secretions and multiple areas of patchy necrosis. The cause of intestinal ischaemia was not clear. Conclusions Although rare, previous causes of uremic colitis have been reported. As the patient developed abdominal pain before the onset of shock and the necrosis was seen on colonoscopy, we suspect that this is a case of fulminant uremic colitis.

Abstract Aims/Introduction Machine learning algorithms based on the artificial neural network (ANN), support vector machine, naive Bayesian or logistic regression model are commonly used to identify diabetes. This study investigated which approach performed the best and whether muscle strength provided any incremental benefit in identifying undiagnosed diabetes in Chinese adults. Methods This cross‐sectional study enrolled 4,482 eligible participants from eight provinces in China, who were randomly divided into the training dataset (n = 3,586) and the testing dataset (n = 896). Muscle strength was assessed by handgrip strength and the number of chair stands in the 30‐s chair stand test. An oral glucose tolerance test was used to ascertain undiagnosed diabetes. The areas under the curve (AUCs) were calculated accordingly and compared with each other. Results Of the included participants, 233 had newly diagnosed diabetes. All the four machine learning algorithms, which were developed based on nonlaboratory parameters, showed acceptable discriminative ability in identifying undiagnosed diabetes (all AUCs >0.70), with the ANN approach performing the best (AUC 0.806). Adding handgrip strength or the 30‐s chair stand test to this approach did not increase the AUC further (P = 0.39 and 0.26, respectively). Furthermore, compared with the New Chinese Diabetes Risk Score, the ANN approach showed a larger AUC in identifying undiagnosed diabetes (Pcomparison

Abstract Background Dysregulation of iron metabolism has been shown to have significant implications for cancer development. We aimed to investigate the prognostic and immunological significance of iron metabolism-related genes (IMRGs) in nasopharyngeal carcinoma (NPC). Methods Multiple Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets were analyzed to identify key IMRGs associated with prognosis. Additionally, the immunological significance of IMRGs was explored. Results A novel risk model was established using the LASSO regression algorithm, incorporating three genes (TFRC, SLC39A14, and ATP6V0D1).This model categorized patients into low and high-risk groups, and Kaplan–Meier analysis revealed significantly shorter progression-free survival for the high-risk group (P

Abstract Background Oral microbiome dysbacteriosis has been reported to be associated with the pathogenesis of advanced esophageal cancer. However, few studies investigated the potential role of oral and gastric microbiota in early-stage intramucosal esophageal squamous carcinoma (EIESC). Method A total of 104 samples were collected from 31 patients with EIESC and 21 healthy controls. The compositions of oral and gastric microbiota were analyzed using 16 S rRNA V3-V4 amplicon sequencing. Linear discriminant analysis effect size (LEfSe) analysis was performed to assess taxonomic differences between groups. The correlation between oral microbiota and clinicopathological factors was evaluated using Spearman correlation analysis. Additionally, co-occurrence networks were established and random forest models were utilized to identify significant microbial biomarkers for distinguishing between the EIESC and control groups. Results A total of 292 oral genera and 223 species were identified in both EIESC and healthy controls. Six oral genera were remarkably enriched in EIESC groups, including the genera Porphyromonas, Shigella, Subdoligranulum, Leptotrichia, Paludibacter, and Odoribacter. LEfSe analysis identified genera Porphyromonas and Leptotrichia with LDA scores > 3. In the random forest model, Porphyromonas endodontalis ranked the top microbial biomarker to differentiate EIESC from controls. The elimination rate of Porphyromonas endodontalis from the oral cavity to the stomach was also dramatically decreased in the EIESC group than controls. In the microbial co-occurrence network, Porphyromonas endodontalis was positively correlated with Prevotella tannerae and Prevotella intermedia and was negatively correlated with Veillonella dispar. Conclusion Our study potentially indicates that the dysbacteriosis of both the oral and gastric microbiome was associated with EIESC. Larger scale studies and experimental animal models are urgently needed to confirm the possible role of microbial dysbacteriosis in the pathogenesis of EIESC. (Chinese Clinical Trial Registry Center, ChiCTR2200063464, Registered 07 September 2022, https://www.chictr.org.cn/showproj.html?proj=178563)

Background: Several studies have identified an association between the gut microbiome and post-stroke depression(PSD), and Helicobacter pylori(H. pylori) infection cause significant alterations in the composition of the gastrointestinal microbiome. However, evidence regarding the role of the H. pylori infection in promoting PSD is still lacking. Here, we conducted a retrospective study to explore risk factors associated with PSD.Methods: Patients with cerebral infarction were consecutively enrolled from December 2021 to October 2022. The diagnosis of PSD is based on the DSM-V criteria, and the Hamilton Depression Rating Scale(HAMD) was used to identify patients with PSD. White matter lesions were evaluated using magnetic resonance imaging(MRI) and H. pylori infection was detected by 13C-urea breath test. Further, 16S rRNA gene sequencing was used to evaluate the changes in gut microbiota composition of fecal samples from PSD patients. The concentration of short-chain fatty acids(SCFAs) was determined by gas chromatography–mass spectrometry(GC–MS).Results: Multivariate regression analysis showed that deep white matter lesions(DWMLs) [odds ratio(OR) 3.382, 95% confidence interval(CI) 1.756–6.512; P = 0.001] and H. pylori infection(OR 2.186, 95% CI 1.149–4.159; P = 0.017) were the independent risk factors for PSD. Patients with H. pylori infection had more severe depressive symptoms than patients without infection. Intestinal microbiota was significantly different between H. pylori-positive PSD[H. pylori(+)] patients and H. pylori-negative PSD[H. pylori (−)] patients. Fecal SCFAs concentrations were significantly reduced in the H. pylori(+) group compared to the negative ones.Conclusion: DWMLs and H. pylori infection may play important roles in the development of PSD. H. pylori infection is likely to be involved in the pathogenesis of PSD by altering the intestinal flora.

ObjectiveThis study aimed to establish an effective prognostic model based on triglyceride and inflammatory markers, including neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR), to predict overall survival (OS) in patients with nasopharyngeal carcinoma (NPC). Additionally, we aimed to explore the interaction and mediation between these biomarkers in their association with OS.MethodsA retrospective review was conducted on 259 NPC patients who had blood lipid markers, including triglyceride and total cholesterol, as well as parameters of peripheral blood cells measured before treatment. These patients were followed up for over 5 years, and randomly divided into a training set (n=155) and a validation set (n=104). The triglyceride-inflammation (TI) score was developed using the random survival forest (RSF) algorithm. Subsequently, a nomogram was created. The performance of the prognostic model was measured by the concordance index (C-index), time-dependent receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). The interaction and mediation between the biomarkers were further analyzed. Bioinformatics analysis based on the GEO dataset was used to investigate the association between triglyceride metabolism and immune cell infiltration.ResultsThe C-index of the TI score was 0.806 in the training set, 0.759 in the validation set, and 0.808 in the entire set. The area under the curve of time-dependent ROC of TI score in predicting survival at 1, 3, and 5 years were 0.741, 0.847, and 0.871 respectively in the training set, and 0.811, 0.837, and 0.758 in the validation set, then 0.771, 0.848, and 0.862 in the entire set, suggesting that TI score had excellent performance in predicting OS in NPC patients. Patients with stage T1-T2 or M0 had significantly lower TI scores, NLR, and PLR, and higher LMR compared to those with stage T3-T3 or M1, respectively. The nomogram, which integrated age, sex, clinical stage, and TI score, demonstrated good clinical usefulness and predictive ability, as evaluated by the DCA. Significant interactions were found between triglyceride and NLR and platelet, but triglyceride did not exhibit any medicating effects in the inflammatory markers. Additionally, NPC tissues with active triglyceride synthesis exhibited high immune cell infiltration.ConclusionThe TI score based on RSF represents a potential prognostic factor for NPC patients, offering convenience and economic advantages. The interaction between triglyceride and NLR may be attributed to the effect of triglyceride metabolism on immune response.

Abstract Background It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity. Methods Two-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCKS9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes. The inverse-variance weighting method was applied as the main approach. Sensitivity tests were conducted to evaluate the robustness, heterogeneity, and pleiotropy of the results. Causal effects were further validated using expression quantitative trait locus (eQTL) data. Results Genetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan. Conclusion This study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies.

BackgroundHuman milk contains a complex mixture of triacylglycerols (TAG), making it challenging to recreate using common ingredients.ObjectiveThe study aimed to develop an innovative fermentation technique to produce essential human milk TAG, effectively tackling a significant hurdle in infant nutrition.MethodAn in-depth analysis of the literature has been conducted to identify the specific TAG to be targeted. We used a microalgal oil production platform and a two-step procedure to modify its fatty acid and TAG composition. The palmitic acid (16:0) content has been increased by classical strain improvement techniques, followed by a step involving the expression of a lysophosphatidic acid acyltransferase (LPAAT) sequence capable of esterifying 16:0 specifically at the internal position (sn-2 palmitate) of TAG. Once the strain was stabilized, the fermentation was scaled up in a 50-L reactor to yield several kilograms of biomass. Subsequently, the oil was extracted and refined using standard oil processing conditions. Liquid chromatography-mass spectrometry was employed to monitor the TAG profile and the region specificity of 16:0 at the internal position (sn-2 palmitate) of TAG.ResultsThe initial strain had a 16:0 level of 25% of total fatty acids, which was increased to 30% by classical strain improvement. Simultaneously, the oleic acid level decreased from 61% to 57% of total fatty acids. Upon expression of an exogenous LPAAT gene, the level of the 16:0 esterified in the internal position of the TAG (sn-2 palmitate) increased by a factor of 10, to reach 73% of total palmitic acid. Consequently, the concentration of oleic acid in the internal position decreased from 81% to 22% of total fatty acids, with TAG analysis confirming that the primary TAG species in the oil was 1,3-dioleoyl-2-palmitoyl-glycerol (OPO). The 50-L-scale fermentation trial confirmed the strain's ability to produce oil with a yield of >150 g of oil per liter of fermentation broth in a timeframe of 5 days, rendering the process scalable for larger-scale industrialization.ConclusionWe have demonstrated the feasibility of producing a suitable TAG composition that can be effectively integrated into the formulations of infant nutrition in combination with other fats and oils to meet the infant feeding requirements.

Understanding antigen-specific T-cell responses, for example, following virus infections or allergen exposure, is of high relevance for the development of vaccines and therapeutics. We aimed on optimizing immunophenotyping of T cells after antigen stimulation by improving staining procedures for flow and mass cytometry. Our method can be used for primary cells of both mouse and human origin for the detection of low-frequency T-cell response using a dual-barcoding system for individual samples and conditions. First, live-cell barcoding was performed using anti-CD45 antibodies prior to an in vitro T-cell stimulation assay. Second, to discriminate between stimulation conditions and prevent cell loss, sample barcoding was combined with a commercial barcoding solution. This dual-barcoding approach is cell sparing and, therefore, particularly relevant for samples with low cell numbers. To further reduce cell loss and to increase debarcoding efficiency of multiplexed samples, we combined our dual-barcoding approach with a new centrifugation-free washing system by laminar flow (Curiox™). Finally, to demonstrate the benefits of our established protocol, we assayed virus-specific T-cell response in SARS-CoV-2–vaccinated and SARS-CoV-2–infected patients and compared with healthy non-exposed individuals by a high-parameter CyTOF analysis. We could reveal a heterogeneity of phenotypes among responding CD4, CD8, and gd-T cells following antigen-specific stimulations. Our protocol allows to assay antigen-specific responses of minute populations of T cells to virus-derived peptides, allergens, or other antigens from the same donor sample, in order to investigate qualitative and quantitative differences.

Abstract In the Neurospora circadian system, the White Collar Complex (WCC) drives expression of the principal circadian negative arm component frequency (frq). FRQ interacts with FRH (FRQ-interacting RNA helicase) and CKI, forming a stable complex that represses its own expression by inhibiting WCC. In this study, a genetic screen identified a gene, designated as brd-8, that encodes a conserved auxiliary subunit of the NuA4 histone acetylation complex. Loss of brd-8 reduces H4 acetylation and RNA polymerase (Pol) II occupancy at frq and other known circadian genes, and leads to a long circadian period, delayed phase, and defective overt circadian output at some temperatures. In addition to strongly associating with the NuA4 histone acetyltransferase complex, BRD-8 is also found complexed with the transcription elongation regulator BYE-1. Expression of brd-8, bye-1, histone h2a.z, and several NuA4 subunits is controlled by the circadian clock, indicating that the molecular clock both regulates the basic chromatin status and is regulated by changes in chromatin. Taken together, our data identify auxiliary elements of the fungal NuA4 complex having homology to mammalian components, which along with conventional NuA4 subunits, are required for timely and dynamic frq expression and thereby a normal and persistent circadian rhythm.

AbstractIt is well known, that the inflammatory process that characterizes acute pancreatitis (AP) can lead to both pancreatic damage and systemic inflammatory response syndrome (SIRS). During the last 20 years, there has been a growing incidence of episodes of acute pancreatitis associated with hypertriglyceridaemia (HTAP). This review provides an overview of triglyceride metabolism and the potential mechanisms that may contribute to developing or exacerbating HTAP. The article comprehensively discusses the various pathological roles of free fatty acid, inflammatory response mechanisms, the involvement of microcirculation, serum calcium overload, oxidative stress and the endoplasmic reticulum, genetic polymorphism, and gut microbiota, which are known to trigger or escalate this condition. Future perspectives on HTAP appear promising, with ongoing research focused on developing more specific and effective treatment strategies.

Lipid metabolism reprogramming is one of the most prominent metabolic anomalies in cancer, wherein cancer cells undergo dysregulation of lipid metabolism to acquire adequate energy, cell membrane building blocks, as well as signaling molecules essential for cell proliferation, survival, invasion, and metastasis. These adaptations enable cancer cells to effectively respond to challenges posed by the tumor microenvironment, leading to cancer therapy resistance and poor cancer prognosis. Head and neck cancer, ranking as the seventh most prevalent cancer, exhibits numerous abnormalities in lipid metabolism. Nevertheless, the precise role of lipid metabolic rewiring in head and neck cancer remains unclear. In line with the LIPID MAPS Lipid Classification System and cancer risk factors, the present review delves into the dysregulated molecules and pathways participating in the process of lipid uptake, biosynthesis, transportation, and catabolism. We also present an overview of the latest advancements in understanding alterations in lipid metabolism and how they intersect with the carcinogenesis, development, treatment, and prognosis of head and neck cancer. By shedding light on the significance of metabolic therapy, we aspire to improve the overall prognosis and treatment outcomes of head and neck cancer patients.

Loss of cell–cell adhesions is the indispensable first step for cancer cells to depart from the primary tumor mass to metastasize. Metastasis suppressor 1 (MTSS1) is frequently lost in metastatic tissues, correlating to advanced tumor stages and poor prognosis across a variety of cancers. Here we explore the anti-metastatic mechanisms of MTSS1, which have not been well understood. We found that MTSS1 is downregulated in NPC tissues. Lower levels of MTSS1 expression correlate to worse prognosis. We show that MTSS1 suppresses NPC cell migration and invasion in vitro through cytoskeletal remodeling at cell–cell borders and assembly of E-cadherin/β-catenin/F-actin in adherens junctions. The I-BAR domain of MTSS1 was both necessary and sufficient to restore this formation of E-cadherin/β-catenin/F-actin–mediated cell adherens junctions.

Abstract Nanosized drug delivery systems have rapidly emerged as a promising approach to tumor therapy, which still have many challenges in clinical application. In this study, doxorubicin-loaded O-carboxymethyl chitosan/perfluorohexane nanodroplets (O-CS-DOX NDs) were synthesized and functionally tested as an effective drug delivery system in vitro and in vivo. O-CS-DOX NDs with small size (159.6 nm) and good doxorubicin encapsuling ability showed pH- and ultrasound-dependent drug release profile and satisfying ultrasound imaging performance. With high biocompatibility and biosafety, these nanodroplets could accumulate in the tumor sites and exhibit high efficiency in inhibiting tumor growth with ultrasound irradiation. These stable, safe and smart O-CS-DOX NDs showed promising potential as a smart dual-responsive bomb for tumor ultrasonic imaging and treatment.

Abstract Background The efficacy of bariatric surgery in moderate and severe obesity patients to reach diabetes remission is clear, but for mild obesity patients, the choice of surgical and non-surgical treatment is still unclear. This study we aim to compare the effect of surgical and nonsurgical treatment on patients BMI

Abstract Background Gut dysbacteriosis has been reported as one of the etiologies for irritable bowel syndrome (IBS). However, the association between gut microbiota and IBS is still inconclusive. Method A paired-sample study was designed by retrieving original multicenter 16 s-rRNA data of IBS patients and healthy controls from the GMrepo database. The propensity score matching (PSM) algorithm was applied to reduce confounding bias. The differential analysis of microbiota composition was performed at different taxonomic levels. The co-occurrence network was established. Subgroup analysis was performed to identify specific microbial compositions in different IBS subtypes. Results A total of 1522 amplicon samples were initially enrolled. After PSM, 708 individuals (354 IBS and 354 healthy controls) were eligible for further analysis. A total of 1,160 genera were identified. We identified significantly changed taxa in IBS groups (IBS-enriched: the families Enterobacteriaceae, Moraxellaceae and Sphingobacteriaceae; the genera Streptococcus, Bacillus, Enterocloster, Sphingobacterium, Holdemania and Acinetobacter. IBS-depleted: the phyla Firmicutes, Euryarchaeota, Cyanobacteria, Acidobacteria and Lentisphaerae; the families Bifidobacteriaceae, Ruminococcaceae, Methanobacteriaceae and the other 25 families; the genera Faecalibacterium, Bifidobacterium and other 68 genera). The co-occurrence network identified three hub genera and six hub species (including Faecalibacterium prausnitzii) that may be involved in IBS pathophysiology. Strong positive interactions were identified among the Bifidobacterium longum, Bifidobacterium breve and Bifidobacterium adolescentis in the Bifidobacterium community. Conclusion This study provides quantitative analysis and visualization of the interaction between the gut microbiota and IBS. The identification of key species should be further validated to evaluate their causal relationships with the pathogenesis of IBS.

Abstract Currently the clinical efficacy of colorectal cancer (CRC) which is the most common malignant tumors over the world has not reached an ideal level. Cetuximab, the monoclonal antibody targeting the extracellular domain of EGFR, has shown its great efficacy in the promotion of apoptosis and the inhibition of tumor cells-like characteristics in numerous cancers. However certain KRAS wild-type CRC patients unexpectedly show cetuximab resistance and the specific mechanism remains unclear. Circular RNAs (circRNAs) as the promising novel type of biomarkers in the cancer diagnosis and therapy, have been reported to be related with the drug resistance. In this study, with wondering the mechanism of cetuximab resistance in KRAS wild-type CRC patients, we evaluate the impact of circIFNGR2 on CRC and detect the association among circIFNGR2, miR-30b and KRAS via various experiments such as RT-qPCR, immunohistochemistry, luciferase assays, cell functional experiments and xenograft model. We conclude that circIFNGR2 induces cetuximab resistance in colorectal cancer cells by indirectly regulating target gene KRAS by sponging miR-30b at the post-transcriptional level. It is thus suggested that inhibition of circIFNGR2 can be a promising therapeutic strategy for malignant CRC patients with cetuximab resistance.

Reducing chemical exposure is a crucial principle in alternatives assessment (AA) frameworks. Since the release of the report, A Framework to Guide Selection of Chemical Alternatives by the National Research Council in 2014, comparative exposure assessment (CEA) has been increasingly viewed as an essential part of selecting safer alternatives to chemicals of concern in consumer products. However, CEA has not been fully integrated into existing AA frameworks. CEA remains merely a technical step, disconnected from other AA components. This paper advocates for the integration of CEA as an essential part of AA, providing a holistic approach to identifying safer alternatives. The paper aims to illustrate the connection between CEA and other AA components, such as problem formulation, hazard assessment, life cycle assessment, economic assessment, and decision-making. It suggests systematic integration of CEA with cross-cutting AA considerations, including transparency, uncertainty, chemical mixtures, and sensitive receptors. This integration will enable the selection of a fit-for-purpose CEA approach based on the decision context and foster a more comprehensive approach to identifying safer alternatives. While the examples provided are not exhaustive, they aim to encourage further discussion on the integration of CEA into AA.

Dietary fibers (DFs) and their metabolites attract significant attention in research on health and disease, attributing to their effects on regulating metabolism, proliferation, inflammation, and immunity. When fermented by gut microbiota, DFs mainly produce short-chain fatty acids (SCFAs), such as acetic acid, propionic acid, and butyric acid. As the essential nutrients for intestinal epithelial cells, SCFAs maintain intestinal homeostasis and play essential roles in a wide range of biological functions. SCFAs have been found to inhibit histone deacetylase, activate G protein-coupled receptors, and modulate the immune response, which impacts cancer and anti-cancer treatment. Notably, while extensive studies have illuminated the roles of SCFAs in colorectal cancer development, progression, and treatment outcomes, limited evidence is available for other types of cancers. This restricts our understanding of the complex mechanisms and clinical applications of SCFAs in tumors outside the intestinal tract. In this study, we provide a comprehensive summary of the latest evidence on the roles and mechanisms of SCFAs, with a focus on butyric acid and propionic acid, derived from microbial fermentation of DFs in cancer. Additionally, we recapitulate the clinical applications of SCFAs in cancer treatments and offer our perspectives on the challenges, limitations, and prospects of utilizing SCFAs in cancer research and therapy.

Background Although colonoscopy is considered the most effective tool for reducing colorectal cancer-related morbidity, the age at which average-risk individuals begin colonoscopic screening is undetermined. This study aimed to compare the adenoma and advanced adenoma detection rates according to age and sex in a large average-risk population in the rural areas of Eastern China. Methods This observational, single-center, retrospective study included patients with average colorectal cancer risk and examined the adenoma and advanced adenoma detection rates using age intervals of 5 years. We also compared the size and age of patients with and without advanced adenoma. Results We included 18 928 patients with a median age of 54 years (range 15–90 years), including 10 143 men and 8785 women. The adenoma and advanced adenoma detection rates were 17.08% and 5.24%, respectively, and increased with age in the whole population. The adenoma detection rates increased from 8.97% (aged 40–44) to 14.98% (aged 45–49) and 6.24% (aged 45–49) to 11.00% (aged 50–54) in men and women (both P < .001), respectively. The advanced adenoma detection rates increased from 2.19% (aged 40–44) to 4.76% (aged 45–49) and 1.89% (aged 45–49) to 3.13% (aged 50–54) in men ( P = .002) and women ( P = .056), respectively. Patients with advanced adenomas were significantly older than those with non-advanced adenomas ( P < .001). The tumors in the advanced adenoma group were significantly larger than those in the non-advanced adenoma group ( P < .001). Conclusion The adenoma and advanced adenoma detection rates increased significantly in average-risk population aged 45 years and older, especially in men.

Abstract Background Previous evidence has shown that the gut microbiota plays a role in the development and progression of colorectal cancer (CRC). This study aimed to provide quantitative analysis and visualization of the interaction between the gut microbiota and CRC in order to establish a more precise microbiota panel for CRC diagnosis. Method A paired-sample study was designed by retrieving original metagenomic data from the GMrepo database. The differences in the distribution of the gut microbiota between CRCs and controls were analysed at the species level. A co-occurrence network was established, and the microbial interactions with environmental factors were assessed. Random forest models were used to determine significant biomarkers for differentiating CRC and control samples. Results A total of 709 metagenomic samples from 6 projects were identified. After matching, 86 CRC patients and 86 matched healthy controls from six countries were enrolled. A total of 484 microbial species and 166 related genera were analysed. In addition to previously recognized associations between Fusobacterium nucleatum and species belonging to the genera Peptostreptococcus, Porphyromonas, and Prevotella and CRC, we found new associations with the novel species of Parvimonas micra and Collinsella tanakaei. In CRC patients, Bacteroides uniformis and Collinsella tanakaei were positively correlated with age, whereas Dorea longicatena, Adlercreutzia equolifaciens, and Eubacterium hallii had positive associations with body mass index (BMI). Finally, a random forest model was established by integrating different numbers of species with the highest model-building importance and lowest inner subcategory bias. The median value of the area under the receiver operating characteristic curve (AUC) was 0.812 in the training cohort and 0.790 in the validation set. Conclusions Our study provides a novel bioinformatics approach for investigating the interaction between the gut microbiota and CRC using an online free database. The identification of key species and their associated genes should be further emphasized to determine the relative causality of microbial organisms in the development of CRC.

The construction of multifunctional oncotherapy nanoplatforms that combine diagnosis and treatment remains challenging. Nanodroplets (NDs), which simultaneously enhance ultrasound imaging and therapeutic effects, are a potential strategy for non-invasive drug delivery. To achieve the goals of precise medicine, novel SP94 peptide-modified and doxorubicin-loaded ultrasonic NDs (SP94-DOX-NDs) for castration-resistant prostate cancer (CRPC) targeting and treatment were constructed in this study. The characteristics, contrast-enhanced ultrasound imaging (CEUI), targeting ability to glucose-regulated protein 78 (GRP78)-overexpressing CRPC and anticancer effect of the SP94-DOX-NDs were assessed. The desired SP94-NDs were successfully prepared using the nanoemulsification method using a certain proportion of SP94-PEG-chitosan, perfluoropentane (PFP), Tween 20, and lecithin. SP94-NDs with a size of ∼300 nm showed great biocompatibility and CEUI ability. Compared with blank NDs, SP94-NDs exhibited higher tumor-specific targeting ability due to conjugation between the SP94 peptide and GRP78-overexpressing 22RV1 cells. Most importantly, in vitro and in vivo investigations showed that SP94-DOX-NDs combined with ultrasound could specifically deliver DOX into 22RV1 cells and thereby demonstrated a stronger anticancer effect than DOX-NDs and DOX. Thus, SP94-DOX-NDs may provide an efficient approach for the real-time imaging of tumors and triggered, accurate drug delivery to tumors.

Ultrasound nanodroplets (NDs) have been reported as a promising nanocarrier for siRNA delivery depending on its unique strengths of sonoporation. Presently, common means for NDs-mediated siRNA delivery is through electrostatic interaction, but challenges like cationic toxicity still exist. In this study, we demonstrated a novel strategy to construct negatively charged and ultrasound (US)-responsive O-carboxymethyl chitosan (O-CMS) NDs as a siRNA targeted delivery system through three-way junction of bacteriophage phi29 DNA packaging motor (3WJ-pRNA) nanotechnology. 39nt A10-3.2 aptamer targeting prostate specific membrane antigen (PSMA) and 21nt siRNA against cationic amino acid transporter 1 (siCAT-1) were annealed to 3WJ-pRNA scaffold via complementation with an extended sequence. The cholesterol molecule attached to one branch facilitates the 3WJ-pRNA nanoparticles anchoring onto NDs. The desired O-CMS NDs with siRNA-loading and RNA-aptamer modification (A10-3.2/siCAT-1/3WJ-NDs) were successfully prepared, which were with spherical shapes, core–shell structures and uniform in sizes (198 nm with PDI 0.3). As a main proportion of shell, O-CMC showed a certain anti-tumor effects. In vitro studies demonstrated that A10-3.2/siCAT-1/3WJ-NDs exhibited good contrast-enhanced US imaging, buffering capacity and high bio-safety, were able to deliver siCAT-1 to PSMA-overexpressed prostate cancer cells under US irradiation, thus silence the CAT-1 expression, and consequently suppressing 22RV1 cell proliferation and migration. Taken overall, our findings provide a promising strategy to develop negatively charged and US-responsive NDs for tumor-targeted siRNA delivery.

Epstein-Barr virus (human herpesvirus 4, EBV) is a linear double-stranded DNA virus that infects over 90% of the population worldwide. However, our understanding of EBV’s contribution to tumorigenesis of EBV-associated GC (EBVaGC) remains incomplete. Recent advancements in EBVaGC research have highlighted that EBV-encoded microRNAs (miRNAs) play prominent roles in critical cellular processes such as migration, cell cycle, apoptosis, cell proliferation, immune response, and autophagy. Notably, the largest group of EBV-encoded miRNAs, known as BamHI-A rightward transcripts (BARTs), exhibit bidirectional effects in EBVaGC. For instance, they present both anti-apoptotic and pro-apoptotic functions and enhance chemosensitivity while also conferring resistance to 5-fluorouracil. Despite these findings, the comprehensive mechanisms through which miRNAs contribute to EBVaGC are yet to be fully elucidated. In this work, we summarize the current evidence of the roles of miRNA in EBVaGC, particularly with the application of multi-omic techniques. Additionally, we discuss the application of miRNA in EBVaGC in retrospective analyses and provide novel perspectives on the use of miRNA in EBVaGC in translational medicine.

Substantial improvement in prognosis among metastatic renal cell carcinoma (mRCC) patients has been achieved, owing to the rapid development and utilization of immunotherapy. In particular, immune checkpoint inhibitors (ICIs) have been considered the backbone of systemic therapy for patients with mRCC alongside multi-targeted tyrosine kinase inhibitors (TKIs) in the latest clinical practice guidelines. However, controversies and challenges in optimal individualized treatment regarding immunotherapy remains still About 2/3 of the patients presented non-response or acquired resistance to ICIs. Besides, immune-related toxicities, namely immune-related adverse events, are still elusive and life-threatening. Thus, reliable biomarkers to predict immunotherapeutic outcomes for mRCC patients are needed urgently. Tumor microenvironment (TME), consisting of immune cells, vasculature, signaling molecules, and extracellular matrix and regulates tumor immune surveillance and immunological evasion through complex interplay, plays a critical role in tumor immune escape and consequently manipulates the efficacy of immunotherapy. Various studied have identified the different TME components are significantly associated with the outcome of mRCC patients receiving immunotherapy, making them potential valuable biomarkers in therapeutic guidance. The present review aims to summarize the latest evidence on the associations between the components of TME including immune cells, cytokines and extracellular matrix, and the therapeutic responses among mRCC patients with ICI-based treatment. We further discuss the feasibility and limitation of these components as biomarkers.

In recent years, there has been a growing emphasis on combining intelligent prospecting algorithms, such as random forest, with extensive geological and mineral data for the purpose of quantitatively predicting exploration geochemistry. This approach holds significant importance for enhancing the accuracy of target delineation. The central Kunlun area in Xinjiang possesses highly favorable ore-forming geological conditions, offering excellent prospects for mineral exploration. However, the depletion of shallow deposits coupled with a decade-long gap in geological exploration have presented increasing challenges in the quest to discover substantial metal resources. Consequently, there is now a severe shortage of reserve assets in the region, prompting an urgent need for the implementation of new theories, methods, and technologies in mineral resource investigation and evaluation efforts. The researchers used geological and regional geochemical data to construct a random forest metallogenic discriminant model for predicting the mineralization of gold polymetallic minerals in the central Kunlun area of Xinjiang and delineating the metallogenic target area. Two different sampling methods were compared to quantitatively predict gold polymetallic mineral resources. The results indicate that the selected training samples offer higher prediction accuracy and reliability by fully capturing the complex information of the original data. The random forest model using select training samples has valuable applications in metallogenic prospect prediction and potential division due to its ability to consider the actual exploration cost and identify small areas with high potential and a high proportion of ore. This study significantly improves prediction accuracy, reduces exploration risk, and expands the use of machine learning algorithms in mathematical geology in the central Kunlun area of Xinjiang.

Patients with type 2 diabetes (T2D) are at an increased risk of morbidity and mortality of coronavirus disease 2019 (COVID-19). Data on the antibody response to COVID-19 vaccines in T2D patients are less studied. This study aimed to evaluate IgG antibody response to inactivated COVID-19 vaccines in hospitalized T2D patients. Hospitalized patients with no history of COVID-19 and received two doses of inactivated COVID-19 vaccines (Sinopharm or CoronaVac) were included in this study from March to October 2021. SARS-CoV-2 specific IgG antibodies were measured 14–60 days after the second vaccine dose. A total of 209 participants, 96 with T2D and 113 non-diabetes patients, were included. The positive rate and median titer of IgG antibody against receptor-binding domain (anti-RBD) of spike (S) protein of SARS-CoV-2 in T2D group were lower than in control group (67.7% vs 83.2%, p = .009; 12.93 vs 17.42 AU/ml, p = .014) respectively. Similarly, seropositivity and median titers of IgG antibody against the nucleocapsid (N) and S proteins of SARS-CoV-2 (anti-N/S) in T2D group were lower than in control group (68.8% vs 83.2%, p = .032; 18.81 vs 29.57 AU/mL, p = .012) respectively. After adjustment for age, sex, BMI, vaccine type, days after the second vaccine dose, hypertension, kidney disease, and heart disease, T2D was identified as an independent risk factor for negative anti-RBD and anti-N/S seropositivity, odd ratio 0.42 (95% confidence interval 0.19, 0.89) and 0.42 (95% CI 0.20, 0.91), respectively. T2D is associated with impaired antibody response to inactivated COVID-19 vaccine.

Direct numerical simulation of pore-scale flow in porous media at pore scale is a fast developing technique to investigate pore-scale flow behaviors. However, with the decrease of the spatial scale, the interfacial tension of the two-phase interface will have an important impact on the two-phase flow processes. As a result, spurious currents near the interface with this method have an important impact on the numerical accuracy and computational efficiency, seriously affecting the numerical prediction of pore-scale fluid flow. Ghost cell method can greatly reduce the spurious currents near the interface, but it needs to locate the phase interface accurately. In this work, a new method using constant velocity spiral to approximate the two-phase interface is proposed. The method not only considers the curvature of the phase interface but also considers the influence of the curvature change on the phase interface, which greatly improves the ability of the phase interface position. The new method can improve the accuracy of interfacial tension treatment and then improve the prediction ability of volume of fluid in high interfacial tension driven flow. Numerical simulations of capillary rising, droplet spreading on a plane, and bubble rising show that the method is accurate and has a strong engineering application prospect.

Due to the particularity of biomedical industry, it has become necessary for biomedical enterprises to seek innovative research and development (R&D) cooperation to maintain advanced technologies and products in multiple fields. Under such circumstance, the biomedical industry has gradually formed a certain cluster to promote the development of the industry. So far, the biomedical industry cluster has formed in China, mainly within the Yangtze River Delta, Pearl River Delta, and Beijing-Tianjin-Hebei three urban agglomerations. Within the industrial clusters, the frequency of innovation cooperation among enterprises, universities, research institutions, and other relevant organizations in the biomedical area is high, and the capacity for innovation cooperation is strong as well. This paper used the representative cross-section data of cooperative patents from the medical science and technology patent database of China National Knowledge Infrastructure (CNKI), researching the R&D cooperation within the three major urban agglomerations in China from 2008 to 2016 (Yangtze River Delta Urban Agglomeration, Pearl River Delta Urban Agglomeration, Beijing-Tianjin-Hebei Urban Agglomeration) on total 36 cities' spatial pattern characteristics of biomedical cooperation and the influencing factors. The spatial interaction model was used to study the spatial, economic, political, and R&D influencing factors of cross-city cooperation. The degree of aggregation showed that cross-city R&D cooperation mainly occurred in well-developed and central cities of urban agglomerations. Econometric results revealed that spatial, economic, political, and R&D bias factors did have a significant impact on the frequency of biomedical R&D cooperation across cities.

Objective We compared the long-term prognosis of surgery and endoscopic treatment (ET) in patients diagnosed with Siewert Type II pT1N0M0 adenocarcinoma of the esophagogastric junction (AEG). Methods Using the Surveillance, Epidemiology, and End Results (SEER) database, we performed a real-world retrospective cohort study and enrolled patients with Siewert Type II pT1N0M0 AEG who underwent surgery or endoscopic treatment (ET) from 2010 to 2018. Matched cohorts were generated using propensity score matching Competing-risk analysis was applied. The cumulative incidence function was used to calculate cancer-specific death and other causes of death (OCD) at different time points. Univariate and multivariate analyses were performed to identify significant prognostic factors by using the subdistribution hazard ratio Results We enrolled 725 patients: 462 underwent surgery and 263 received ET. The 5 year cumulative CSD incidence significantly differed between surgery and ET cohorts (16.87% vs 11.08%, P = .01). Following PSM, 2 balanced groups (n = 219 patients each) were analyzed. No significant difference in the 5 year cumulative incidences of CSD was noted between cohorts (17.61% vs. 12.16%, P = .14 ). In multivariable analysis, the CSD incidence was high among patients with aged ≥65 (SHR 2.29, 95%CI 0.99-5.33, P = .05 ) and T1b-stage (SHR 1.92, 95%CI 1.03-3.57, P = .04 ); treatment (surgery or ET) was not significantly associated with cancer survival (SHR 1.51, 95% CI 0.81-2.81, P = .20 ). Conclusion Long-term survival did not significantly differ among patients with Siewert Type II pT1N0M0 AEG adenocarcinoma undergoing surgery or ET. ET may be considered in patients >65 years old or those with submucosal (T1b-stage) cancer of AEG.

BackgroundAlthough the gut microbiota may be involved in obesity onset and progression, the exact association of the gut microbiota in metabolically healthy obesity (MHO) remains largely unknown.MethodsAn integrated paired-sample metagenomic analysis was conducted to investigate the gut microbial network and biomarkers of microbial species from the MHO and healthy non-obese subjects in the GMrepo database. Further explorations were performed in the MHO mice model using a multiomics analysis to detect changes in the composition and function of the intestinal microbiome and associated metabolites.ResultsIn the human study, 314 matched metagenomic data were qualified for the final analysis. We identified seven significantly changed species possibly involved in MHO pathogenesis (MHO-enriched: Bacteroides vulgatus, Megamonas sp; MHO-depleted: Butyrivibrio crossotus, Faecalibacterium prausnitzii, Bacteroides cellulosilyticus; Eubacterium siraeum; Bacteroides massiliensis). In the murine study, we found 79 significantly-changed species which may have possible associations with the MHO phenotype. The depletion of Bacteroides cellulosilyticus was commonly recognized in the human and murine MHO phenotype. Consistent with the metagenomic data, liquid chromatography-mass spectrometry (LC/MS) revealed significantly changed gut metabolites, which may promote MHO pathogenesis by altering the amino acids and lipid metabolic pathways. In the microbe-metabolites interaction analysis, we identified certain fatty acids (Dodecanedioic acid, Arachidic Acid, Mevalonic acid, etc.) that were significantly correlated with the MHO-enriched or depleted species.ConclusionThis study provides insights into identifying specific microbes and metabolites that may involve in the development of obesity without metabolic disorders. Future modalities for MHO intervention may be further validated by targeting these bacteria and metabolites.

Food allergies are a leading cause of anaphylaxis, and allergen-specific immune responses in both the innate and the adaptive immune system play key roles in its pathogenesis. We conducted a comprehensive phenotypic and functional investigation of immune cell responses from nonallergic (NA) and peanut allergic (PA) participants cultured with media alone or peanut protein and found, surprisingly, that NK cell activation was strongly associated with the immune response to allergen in PA participants. Peanut-responsive NK cells manifested a distinct expression pattern in PA participants compared with NA participants. Allergen-activated NK cells expressed both Th2 and immune regulatory cytokines, hinting at a potential functional role in mediating and regulating the Th2 allergic response. Depletion of CD3+ T cells attenuated the response of NK cells to peanut-allergen stimulation, suggesting that peanut-responsive NK cells are T cell dependent. We also showed that oral immune therapy was associated with decreased NK responses to peanut allergen stimulation in vitro. These results demonstrate that NK cells are associated with the food-allergic immune response, and the magnitude of this mobilized cell population suggests that they play a functional role in allergic immunity.

ObjectiveTo conduct a cost-effectiveness analysis of drug-eluting beads transcatheter arterial chemoembolization (DEB-TACE) and conventional transcatheter arterial chemoembolization (cTACE) for first-line treatment of hepatocellular carcinoma (HCC) from the perspective of the Chinese healthcare system.MethodsBased on the real-world clinical data of HCC patients receiving interventional therapy, a partitioned survival model was constructed for cost-effectiveness analysis. The model period is 1 month, and the research time limit is 10 years. The incremental cost-effectiveness ratio (ICER) is used as the evaluation index. One-way sensitivity analysis and probabilistic sensitivity analysis were used to analyze the uncertainty of parameters to test the stability of the model results.ResultsThe ICER of the DEB-TACE group was 11,875.62 $/QALYs, which was lower than the willingness to pay threshold (WTP) of 31,499.23 $/QALYs. One-way sensitivity analysis suggested that the utility value of progression-free survival (PFS) in the DEB-TACE group had the greatest impact. Probabilistic sensitivity analysis showed that at the level of WTP of 31,499.23 $/QALYs, DEB-TACE had a cost-effective probability of 92%.ConclusionUnder the current economic level in my country, DEB-TACE is more cost-effective than cTACE in the treatment of HCC patients.

BackgroundDelayed post-polypectomy bleeding (DPPB) is the most common complication which occurs within 30 days after polypectomy, it has become rather common with the widespread of colorectal cancer screening. It is important to clarified predictors of DPPB and identify patients at high risk.Materials and methodsThis was a real-world retrospective study based on medical records from The First Affiliated Hospital of Nanjing Medical University. Cases of patients who underwent colonoscopic polypectomy between January 2016 and December 2020 were reviewed to identify risk factors of DPPB. We use the LASSO-Logistic regression analysis model to identify independent predictors and create a predictive model. The model finally got visualized by developing a nomogram.ResultsColonoscopic polypectomy was done on 16,925 patients in our study. DPPB occurred in 125 (0.74%) of these instances. In multivariate analysis, age, sex, hypertension, polyp location, polyp size, and operative modality were found to be independent risk factors and were integrated for the construction of a nomogram. The model’s C-index is 0.801 (95%CI: 0.761–0.846). We also found polyps located at the right semicolon and polyp ≥ 1 cm associated with active bleeding under the therapeutic colonoscopy.ConclusionYoung age, male, hypertension, polyp ≥ 1 cm, proximal colon location and operative modality were finally identified as significant predictors of DPPB. We developed and validated a nomogram which performs well in predicting the incidence of DPPB, the model we established can be used as a valuable screening tool to identify patients who are at high risk of bleeding.

Previous researches have emphasized a trypsin-centered theory of acute pancreatitis (AP) for more than a century. With additional studies into the pathogenesis of AP, new mechanisms have been explored. Among them, the role of immune response bears great importance. Pro-inflammatory substances, especially damage-associated molecular patterns (DAMPs), play an essential role in activating, signaling, and steering inflammation. Meanwhile, activated neutrophils attach great importance to the immune defense by forming neutrophil extracellular traps (NETs), which cause ductal obstruction, premature trypsinogen activation, and modulate inflammation. In this review, we discuss the latest advances in understanding the pathological role of DAMPs and NETs in AP and shed light on the flexible crosstalk between these vital inflammatory mediators. We, then highlight the potentially promising treatment for AP targeting DAMPs and NETs, with a focus on novel insights into the mechanism, diagnosis, and management of AP.

Commensal microbes cross talk with their colonized mucosa. We show that microbes and their cell wall components induce an inflammatory response in cultured human mucosal cells derived from the nonmalignant nasopharyngeal epithelium (NNE) cells in vitro. NNE cells show significant induction of NF-κB with nuclear shuttling and inflammatory gene response when exposed to Gram-positive bacteria (streptococci) or peptidoglycan (PGN), a component of the Gram-positive bacterial cell wall. This response is abrogated in nasopharyngeal carcinoma (NPC)–derived cell lines. The inflammatory response induced by NF-κB signaling was blocked at two levels in the tumor-derived cells. We found that NF-κB was largely trapped in lipid droplets (LDs) in the cytoplasm of the NPC-derived cells, while the increased expression of lysine-specific histone demethylase 1 (LSD1, a repressive nuclear factor) reduces the response mediated by remaining NF-κB at the promoters responding to inflammatory stimuli. This refractory response in NPC cells might be a consequence of long-term exposure to microbes in vivo during carcinogenic progression. It may contribute to the decreased antitumor immune responses in NPC, among others despite heavy T-helper cell infiltration, and thus facilitate tumor progression.

BackgroundPeripherally inserted central catheter (PICC) and centrally inserted totally implanted access port (PORT) are two types of intravenous infusion devices that are widely used in clinical practice. PORTs are more expensive to insert than PICCs but have fewer complications. Two cost-utility analyses of PICCs and PORTs in China have been published, but had conflicting findings. This study aimed to compare the cost-utility of PICCs and PORTs.MethodsWe conducted a prospective observational trial including 404 patients with cancer and a cross-sectional study to calculate cost and complications of a PICC and PORT. Utility was measured using the EuroQol five-dimensional questionnaire (EQ-5D-5L). A cost-utility analysis was performed from a healthcare system perspective in China.ResultsThe average total cost of PICCs and PORTs were ¥ 4,091.7 and ¥ 4,566.8, which yielded 0.46 and 0.475 quality-adjusted life-years (QALYs) in a 6-month dwell time, respectively. The incremental cost-utility ratio (ICUR) was ¥ 31,670.9 per QALY. A one-way sensitivity analysis showed that the base-case results were robust, and the probabilistic sensitivity analysis showed that at a willingness-to-pay (WTP) threshold of ¥ 80,976 per QALY (China's per capita GDP in 2021) the probability of a PORT being cost-effective was 96%.ConclusionPORTs were more cost-effective than PICCs for a 6 and 12-month dwell time. The total cost for a PORT was also less than that of a PICC. PORT is therefore recommended as a medium to long-term intravenous delivery device in clinical practice.

Plasma lipidomics has been commonly used for biomarker discovery. Studies in cancer have suggested a significant alteration of circulating metabolite profiles which is correlated with cancer characteristics and treatment outcome. However, the lipidomics characteristics of nasopharyngeal carcinoma (NPC) have rarely been studied. We previously described the phenomenon of lipid droplet accumulation in NPC cells and showed that such accumulation could be regulated by latent infection of Epstein–Barr virus (EBV). Here, we compared the plasma lipidome of NPC patients to that of healthy controls by liquid chromatography-tandem mass spectrometry (LC–MS/MS). We found 19 lipids (e.g., phosphatidylinositols 18:0/20:4 and 18:0/18:2 and free fatty acid 22:6) to be remarkably decreased, whereas 2 lipids (i.e., diacylglycerols 16:0/16:1 and 16:0/20:3) to be increased, in the plasma of NPC patients, compared with controls. Different lipid profiles were also observed between patients with different titers of EBV antibodies (e.g., EA-IgA and VCA-IgA) as well as between patients with and without lymph node or distant organ metastasis. In conclusion, plasma lipidomics might help to differentiate NPC cases from controls, whereas EBV infection might influence the risk and prognosis of NPC through modulating lipid metabolism in both tumor cells and peripheral blood.

Background and AimsThis study aimed to develop an interpretable random forest model for predicting severe acute pancreatitis (SAP).MethodsClinical and laboratory data of 648 patients with acute pancreatitis were retrospectively reviewed and randomly assigned to the training set and test set in a 3:1 ratio. Univariate analysis was used to select candidate predictors for the SAP. Random forest (RF) and logistic regression (LR) models were developed on the training sample. The prediction models were then applied to the test sample. The performance of the risk models was measured by calculating the area under the receiver operating characteristic (ROC) curves (AUC) and area under precision recall curve. We provide visualized interpretation by using local interpretable model-agnostic explanations (LIME).ResultsThe LR model was developed to predict SAP as the following function: -1.10-0.13×albumin (g/L) + 0.016 × serum creatinine (μmol/L) + 0.14 × glucose (mmol/L) + 1.63 × pleural effusion (0/1)(No/Yes). The coefficients of this formula were utilized to build a nomogram. The RF model consists of 16 variables identified by univariate analysis. It was developed and validated by a tenfold cross-validation on the training sample. Variables importance analysis suggested that blood urea nitrogen, serum creatinine, albumin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, calcium, and glucose were the most important seven predictors of SAP. The AUCs of RF model in tenfold cross-validation of the training set and the test set was 0.89 and 0.96, respectively. Both the area under precision recall curve and the diagnostic accuracy of the RF model were higher than that of both the LR model and the BISAP score. LIME plots were used to explain individualized prediction of the RF model.ConclusionsAn interpretable RF model exhibited the highest discriminatory performance in predicting SAP. Interpretation with LIME plots could be useful for individualized prediction in a clinical setting. A nomogram consisting of albumin, serum creatinine, glucose, and pleural effusion was useful for prediction of SAP.

Background and AimsThe aim of this study was to apply machine learning models and a nomogram to differentiate critically ill from non-critically ill COVID-19 pneumonia patients.MethodsClinical symptoms and signs, laboratory parameters, cytokine profile, and immune cellular data of 63 COVID-19 pneumonia patients were retrospectively reviewed. Outcomes were followed up until Mar 12, 2020. A logistic regression function (LR model), Random Forest, and XGBoost models were developed. The performance of these models was measured by area under receiver operating characteristic curve (AUC) analysis.ResultsUnivariate analysis revealed that there was a difference between critically and non-critically ill patients with respect to levels of interleukin-6, interleukin-10, T cells, CD4+ T, and CD8+ T cells. Interleukin-10 with an AUC of 0.86 was most useful predictor of critically ill patients with COVID-19 pneumonia. Ten variables (respiratory rate, neutrophil counts, aspartate transaminase, albumin, serum procalcitonin, D-dimer and B-type natriuretic peptide, CD4+ T cells, interleukin-6 and interleukin-10) were used as candidate predictors for LR model, Random Forest (RF) and XGBoost model application. The coefficients from LR model were utilized to build a nomogram. RF and XGBoost methods suggested that Interleukin-10 and interleukin-6 were the most important variables for severity of illness prediction. The mean AUC for LR, RF, and XGBoost model were 0.91, 0.89, and 0.93 respectively (in two-fold cross-validation). Individualized prediction by XGBoost model was explained by local interpretable model-agnostic explanations (LIME) plot.ConclusionsXGBoost exhibited the highest discriminatory performance for prediction of critically ill patients with COVID-19 pneumonia. It is inferred that the nomogram and visualized interpretation with LIME plot could be useful in the clinical setting. Additionally, interleukin-10 could serve as a useful predictor of critically ill patients with COVID-19 pneumonia.

Abstract Ambient air pollution exposure is associated with cardiovascular dysregulation and immune system alterations, yet no study has investigated both simultaneously in children. Understanding the multifaceted impacts may provide early clues for clinical intervention prior to actual disease presentation. We therefore determined the associations between exposure to multiple air pollutants and both immunological outcomes (methylation and protein expression of immune cell types associated with immune regulation) and cardiovascular outcomes (blood pressure) in a cohort of school-aged children (6–8 years; n = 221) living in a city with known elevated pollution levels. Exposure to fine particular matter (PM2.5), carbon monoxide (CO), and ozone (O3) was linked to altered methylation of most CpG sites for genes Foxp3, IL-4, IL-10 and IFN-g, all involved in immune regulation (e.g. higher PM2.5 exposure 1 month prior to the study visit was independently associated with methylation of the IL-4 CpG24 site (est = 0.16; P = 0.0095). Also, immune T helper cell types (Th1, Th2 and Th17) were associated with short-term exposure to PM2.5, O3 and CO (e.g. Th1 cells associated with PM2.5 at 30 days: est = − 0.34, P

Abstract Background Necrotizing enterocolitis (NEC) remains a fatal gastrointestinal disorder in neonates and has very limited therapeutic options. Sialylated human milk oligosaccharides (SHMOs) improve pathological changes in experimental NEC models. The objectives of this study were to investigate the involvement of NLRP3 inflammasome in NEC pathology and to explore the effects of SHMOs on toll-like receptor 4 (TLR4)/nuclear factor κB (NF-κB)/NLRP3 inflammatory pathway in experimental NEC. Methods The intestinal-tissue segments were collected from NEC infants, NLRP3 and caspase-1 positive cell were examined by immunohistochemistry. Newborn rats were hand-fed with formula containing or non-containing SHMOs (1500 mg/L) and exposed to hypoxia/cold stress to induce experimental NEC. The NEC pathological scores were evaluated; ileum protein expression of membrane TLR4 (mTLR4), inhibitor κB-α (IκB-α), NF-κB p65 subunit and phospho-NF-κB p65, as well as NLRP3 and caspase-1 were analyzed; ileum concentrations of interleukin-1β, interleukin-6, tumor necrosis factor-α (TNF-α) were also measured. Human colon epithelial Caco-2 cells were pre-treated with or without SHMOs and stimulated with TLR4 activator, lipopolysaccharide. Cell viabilities, mitochondrial membrane potential and supernatant matrix metalloprotease 2 (MMP-2) activities were analyzed. Results Increased frequencies of NLRP3 and caspase-1 positive cells were found in the lamina propria of damaged intestinal area of NEC neonates. SHMOs supplementation reduced NEC incidence and pathological damage scores of rats challenged with hypoxia/cold stress. Accumulation of interleukin-1β, interleukin-6 and TNF-α in NEC group were attenuated in SHMOs + NEC group. Protein expression of mTLR4, NLRP3 and caspase-1 were elevated, cytoplasmic IκB-α were reduced, nuclear phospho-NF-κB p65 were increased in the ileum of NEC rats. SHMOs supplementation ameliorated the elevation of mTLR4, NLRP3 and caspase-1, restored IκB-α in the cytoplasmic fraction and reduced phospho-NF-κB p65 in the nuclear fraction in the ileum of NEC rats. SHMOs pre-treatment improved Caco-2 cell viability, mitigated loss of mitochondrial membrane potential and modulated MMP-2 activities in the presence of lipopolysaccharide in-vitro. Conclusions This study provided clinical evidence of involvement of NLRP3 inflammasome in NEC pathology, and demonstrated the protective actions of SHMOs might be owing to the suppression of TLR4/NF-κB/NLRP3-mediated inflammation in NEC.

It is well known that hypercholesterolemia in the body has pro-inflammatory effects through the formation of inflammasomes and augmentation of TLR (Toll-like receptor) signaling, which gives rise to cardiovascular disease and neurodegenerative diseases. However, the interaction between cholesterol-related lipids and acute pancreatitis (AP) has not yet been summarized before. This hinders the consensus on the existence and clinical importance of cholesterol-associated AP. This review focuses on the possible interaction between AP and cholesterol-related lipids, which include total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein (Apo) A1, from the bench to the bedside. With a higher serum level of total cholesterol, LDL-C is associated with the severity of AP, while the persistent inflammation of AP is allied with a decrease in serum levels of cholesterol-related lipids. Therefore, an interaction between cholesterol-related lipids and AP is postulated. Cholesterol-related lipids should be recommended as risk factors and early predictors for measuring the severity of AP. Cholesterol-lowering drugs may play a role in the treatment and prevention of AP with hypercholesterolemia.

The emergence of brassica yellow virus (BrYV) has increasingly damaged crucifer crops in China in recent years. In 2020, a large number of oilseed rape in Jiangsu showed aberrant leaf color. A combined RNA-seq and RT-PCR analysis identified BrYV as the major viral pathogen. A subsequent field survey showed that the average incidence of BrYV was 32.04%. In addition to BrYV, turnip mosaic virus (TuMV) was also frequently detected. As a result, two near full-length BrYV isolates, BrYV-814NJLH and BrYV-NJ13, were cloned. Based on the newly obtained sequences and the reported BrYV and turnip yellow virus (TuYV) isolates, a phylogenetic analysis was performed, and it was found that all BrYV isolates share a common root with TuYV. Pairwise amino acid identity analysis revealed that both P2 and P3 were conserved in BrYV. Additionally, recombination analysis revealed seven recombinant events in BrYV as TuYV. We also attempted to determine BrYV infection by quantitative leaf color index, but no significant correlation was found between the two. Systemic observations indicated that BrYV-infected plants had different symptoms, such as no symptom, purple stem base and red old leaves. Overall, our work proves that BrYV is closely related to TuYV and could be considered as an epidemic strain for oilseed rape in Jiangsu.

Electronic structures and magnetotransport properties of topological Dirac semimetal (TDSM) nanoribbons are studied by adopting the tight-binding lattice model and the Landauer–Büttiker formula based on the non-equilibrium Green’s function. For concreteness, the TDSM material Cd _3 As _2 grown along the experimentally accessible [110] crystallographic direction is taken as an example. We found that the electronic structures of the TDSM nanoribbon depend on both the strength and direction of the magnetic field (MF). The transversal local charge density (LCD) distribution of the electronic states in the TDSM nanoribbon is moved gradually from the center toward the hinge of each surface as a [010] direction MF strength is increased, forming the two-sided hinge states. However, one-sided surface states are generated in the TDSM nanoribbon when a [001] direction MF is applied. As a result, one-sided hinge states can be achieved once a tilted MF is placed to the TDSM nanoribbon. The underlying physical mechanism of the desired one-sided hinge states is attributed to both the orbital and Zeeman effects of the MF, which is given by analytical analyses. In addition, typical Aharonov–Bohm interference patterns are observed in the charge conductance of the two-terminal TDSM nanoribbon with a tilted MF. This conductance behaviour originates from the unique interfering loop shaped by the one-sided hinge states. These findings may not only further our understanding on the external-field-induced higher-order (HO) topological phases but also provide an alternative method to probe the HO boundary states.

In order to solve the problem of wear failure during the service of the hot grinding discs, the microstructure changes and wear resistance of high-carbon hot grinding discs during quenching and tempering were investigated. Taking high chromium high carbon cast iron as the research object, the microstructure and performance of the heat-treated specimen were studied by means of metallographic microscope, X-ray diffraction, hardness tester and wear tester. The results show that the original microstructure consists of primary (Cr，Fe)7C3, eutectic (Cr，Fe)7C3, martensite and austenite. When tempering at a lower temperature, the carbides are not obviously changed and the matrix is tempered martensite and austenite; with the increase of temperature, the carbides gradually increases and the tempered martensite gradually decreases; the tempered martensite disappears and the matrix microstructure changes to ferrite and austenite over 450 ℃. The hardness first decreases slightly, then increases and finally decreases, and the maximum value is 63.4HRC at 450 ℃. The wear resistance of uniformly distributed carbides is increased by 2.53 times. The results of the effect of quenching and tempering process on the microstructure and wear resistance of high-carbon hot grinding disc provide a theoretical basis for improving the wear resistance and service life of high-carbon hot grinding disc.

Abstract In this article, we show unitarily invariant norm inequalities for sector 2 × 2 $2\times 2$ block matrices which extend and refine some recent results of Bourahli, Hirzallah, and Kittaneh (Positivity, 2020, https://doi.org/10.1007/s11117-020-00770-w ).

Allergens have been identified as potential triggers in patients with atopic dermatitis (AD). Patients with AD are highly sensitive to cockroach allergen. The underlying mechanism, however, remains undetermined. Here, we established a cockroach allergen–induced AD-like mouse model, and we demonstrate that repeated exposure to cockroach allergen led to aggravated mouse skin inflammation, characterized by increased type 2 immunity, type 2 innate lymphoid cells (ILC2s), and mast cells. Increased mast cells were also observed in patients with AD. Mast cell–deficient mice (KitW-sh/W-sh) showed diminished skin inflammation, suggesting that mast cells are required in allergen-induced skin inflammation. Furthermore, DC immunoreceptor (DCIR) is upregulated in skin mast cells of patients with AD and mediates allergen binding and uptake. DCIR–/– mice or reconstituted KitW-sh/W-sh mice with DCIR–/– mast cells showed a significant reduction in AD-like inflammation. Both in vitro and in vivo analyses demonstrate that DCIR–/– mast cells had reduced IgE-mediated mast cell activation and passive cutaneous anaphylaxis. Mechanistically, DCIR regulates allergen-induced IgE-mediated mast cell ROS generation and oxidation of calmodulin kinase II (ox-CaMKII). ROS-resistant CaMKII (MM-VVδ) prevents allergen-induced mast cell activation and inflammatory mediator release. Our study reveals a DCIR/ROS/CaMKII axis that controls allergen-induced mast cell activation and AD-like inflammation.

Chloroplast development is crucial for photosynthesis and plant growth and many factors are involved in its regulation. The regulatory mechanism differs in different green tissues, and previous studies have focused on chloroplasts in leaves. In this study, a mutant with sepal-specific chlorophyll-deficiency was observed in Brassica napus and named as df74. Genetic analysis indicated that the phenotype was controlled by a single recessive nuclear gene. The gene was located on chromosome C08 by bulked-segregant analysis with whole-genome sequencing, which was designated as BnC08.cds. To fine-map the BnC08.cds, a F2 population was created from the cross of df74 and Zhongshuang11 (ZS11). Finally, the BnC08.cds was fine-mapped in the region between the single-nucleotide polymorphism (SNP) markers M5 and M6, corresponding to a 228.72 kb interval of the B. napus “ZS11” genome. Eighteen genes were predicted in the target region, and it was speculated that BnaC08G0442100ZS was the most likely candidate gene based on the results of transcriptome analyses and sequence variation analyses. These results provide a foundation to explore the regulation of chloroplast development in sepals.