Structural heterogeneity in tetra-armed gels revealed by computer simulation: Evidence from a graph theory assisted characterization.

Designing homogeneous networks is considered one typical strategy for solving the problem of strength and toughness conflict of polymer network materials. Experimentalists have proposed the hypothesis of obtaining a structurally homogeneous hydrogel by crosslinking tetra-armed polymers, whose homogeneity was claimed to be verified by scattering characterization and other methods. Nevertheless, it is highly desirable to further evaluate this issue from other perspectives. In this study, a coarse-grained molecular dynamics simulation coupled with a stochastic reaction model is applied to reveal the topological structure of a polymer network synthesized by tetra-armed monomers as precursors. Two different scenarios, distinguished by whether internal cross-linking is allowed, are considered. We introduce the Dijkstra algorithm from graph theory to precisely characterize the network structure. The microscopic features of the network structure, e.g., loop size, dispersity, and size distribution, are obtained via the Dijkstra algorithm. By comparing the two reaction scenarios, Scenario II exhibits an overall more idealized structure. Our results demonstrate the feasibility of the Dijkstra algorithm for precisely characterizing the polymer network structure. We expect this work will provide a new insight for the evaluation and description of gel networks and further help to reveal the dynamic process of network formation.

SLE diagnosis research based on SERS combined with a multi-modal fusion method.

As artificial intelligence technology gains widespread adoption in biomedicine, the exploration of integrating biofluidic Raman spectroscopy for enhanced disease diagnosis opens up new prospects for the practical application of Raman spectroscopy in clinical settings. However, for systemic lupus erythematosus (SLE), origin Raman spectral data (ORS) have relatively weak signals, making it challenging to obtain ideal classification results. Although the surface enhancement technique can enhance the scattering signal of Raman spectroscopic data, the sensitivity of the SERS substrate to airborne impurities and the inhomogeneous distribution of hotspots degrade part of the signal. To fully utilize both kinds of data, this paper proposes a two-branch residual-attention network (DBRAN) fusion technique, which allows the ORS to complement the degraded portion and thus improve the model's classification accuracy. The features are extracted using the residual module, which retains the original features while extracting the deep features. At the same time, the study incorporates the attention module in both the upper and lower branches to handle the weight allocation of the two modal features more efficiently. The experimental results demonstrate that both the low-level fusion method and the intermediate-level fusion method can significantly improve the diagnostic accuracy of SLE disease classification compared with a single modality, in which the intermediate-level fusion of DBRAN achieves 100% classification accuracy, sensitivity, and specificity. The accuracy is improved by 10% and 7% compared with the ORS unimodal and the SERS unimodal modalities, respectively. The experiment, by fusing the multimodal spectral, realized rapid diagnosis of SLE disease by fusing multimodal spectral data, which provides a reference idea in the field of Raman spectroscopy and can be further promoted to clinical practical applications in the future.

Association between Per- and poly-fluoroalkyl substances and nonalcoholic fatty liver disease: a nested case-control study in northwest China.

Per- and poly-fluoroalkyl substances (PFAS) have been reported to have hepatotoxic effects. However, it is unclear whether they are linked to non-alcoholic fatty liver disease (NAFLD). This nested case-control study focused on the epidemiological links between PFAS and the prevalence of NAFLD. We selected 476 new cases of NAFLD and 952 age- and sex-matched controls from the Jinchang cohort population between 2014 and 2019. Serum concentrations of PFAS were measured using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Only PFAS with a detection rate of ≥ 90 % were included for analysis, which included PFPeA, PFOA, PFNA, PFHxS, PFOS, and 9Cl-PF3ONS. The relationship between single and co-exposure to PFAS and the occurrence of NAFLD was evaluated using conditional logistic regression, Quantile g-computation (QgC), and Bayesian kernel machine regression (BKMR) model. Logistic regression indicated that PFPeA, PFOA, and 9Cl-PF3ONS were positive correlation with the incidence of NAFLD after adjusting for confounders, with odds ratios (OR) and 95 % confidence interval (CI) of 3.13 (95 % CI: 2.53, 3.86), 1.39 (95 % CI: 1.12, 1.73), and 1.41 (95 % CI: 1.20, 1.66), respectively. PFNA, PFHxS, and PFOS were nonlinearly and negatively associated with the incidence of NAFLD, with OR (95 % CI) of 0.53 (0.46, 0.62), 0.83 (0.73, 0.95), and 0.52 (0.44, 0.61), respectively. QgC showed a significant joint effect of PFAS on NAFLD onset (OR: 1.52, 95 % CI: 1.24, 1.88). BKMR showed a weak positive trend between PFAS mixtures and NAFLD incidence. Positive correlations were primarily driven by PFPeA and 9Cl-PF3ONS, while negative correlations were mainly influenced by PFNA and PFOS. The BKMR model also suggested that there was an interaction between PFOS and PFNA and other four PFAS compounds. In conclusion, our findings suggest that individual and co-exposure to PFAS is associated with a risk of NAFLD onset.

Multimorbidity and mortality among older patients with coronary heart disease in Shenzhen, China.

BACKGROUND: The current understanding of the magnitude and consequences of multimorbidity in Chinese older adults with coronary heart disease (CHD) is insufficient. We aimed to assess the association and population-attributable fractions (PAFs) between multimorbidity and mortality among hospitalized older patients who were diagnosed with CHD in Shenzhen, China. METHODS: We conducted a retrospective cohort study of older Chinese patients (aged ≥ 65 years) who were diagnosed with CHD. Cox proportional hazards models were used to estimate the associations between multimorbidity and all-cause and cardiovascular disease (CVD) mortality. We also calculated the PAFs. RESULTS: The study comprised 76,455 older hospitalized patients who were diagnosed with CHD between January 1, 2016, and August 31, 2022. Among them, 70,217 (91.9%) had multimorbidity, defined as the presence of at least one of the predefined 14 chronic conditions. Those with cancer, hemorrhagic stroke and chronic liver disease had the worst overall death risk, with adjusted HRs (95% CIs) of 4.05 (3.77, 4.38), 2.22 (1.94, 2.53), and 1.85 (1.63, 2.11), respectively. For CVD mortality, the highest risk was observed for hemorrhagic stroke, ischemic stroke, and chronic kidney disease; the corresponding adjusted HRs (95% CIs) were 3.24 (2.77, 3.79), 1.91 (1.79, 2.04), and 1.81 (1.64, 1.99), respectively. All-cause mortality was mostly attributable to cancer, heart failure and ischemic stroke, with PAFs of 11.8, 10.2, and 9.1, respectively. As for CVD mortality, the leading PAFs were heart failure, ischemic stroke and diabetes; the corresponding PAFs were 18.0, 15.7, and 6.1, respectively. CONCLUSIONS: Multimorbidity was common and had a significant impact on mortality among older patients with CHD in Shenzhen, China. Cancer, heart failure, ischemic stroke and diabetes are the primary contributors to PAFs. Therefore, prioritizing improved treatment and management of these comorbidities is essential for the survival prognosis of CHD patients from a holistic public health perspective.

Liquid biopsy of oesophageal squamous cell carcinoma: implications in diagnosis, prognosis, and treatment monitoring.

Oesophageal squamous cell carcinoma (ESCC) is a common malignant tumour of the gastrointestinal tract. Early detection and access to appropriate treatment are crucial for the long-term survival of patients. However, limited diagnostic and monitoring methods are available for identifying early stage ESCC. Endoscopic screening and surgical resection are commonly used to diagnose and treat early ESCC. However, these methods have disadvantages, such as high recurrence, lethality, and mortality rates. Therefore, methods to improve early diagnosis of ESCC and reduce its mortality rate are urgently required. In 1961, Gary et al. proposed a novel liquid biopsy approach for clinical diagnosis. This involved examining exosomes, circulating tumour cells, circulating free DNA, and circulating free RNA in body fluids. The ability of liquid biopsy to obtain samples repeatedly, wide detection range, and fast detection speed make it a feasible option for non-invasive tumour detection. In clinical practice, liquid biopsy technology has gained popularity for early screening, diagnosis, treatment efficacy monitoring, and prognosis assessment. Thus, this is a highly promising examination method. However, there have been no comprehensive reviews on the four factors of liquid biopsy in the context of ESCC. This review aimed to analyse the progress of liquid biopsy research for ESCC, including its classification, components, and potential future applications.

Olympic gels formed through catenation of dsDNA rings regulated by topoisomerase II: A coarse-grained model.

Topological regulation of DNA by topoisomerases in cells is very crucial for life. We propose a coarse-grained model to study the catenation process of double-stranded DNA (dsDNA) rings regulated by topoisomerase II (TOP2) and provide a computational method to characterize the topological structures of the Olympic gels obtained. The function of TOP2 in the catenation of dsDNA rings is implicitly fulfilled by operating the length of a stretchable catch bond in the dsDNA ring. After the catenation reaction of initially noncatenated dsDNA rings in the solution, the Olympic gel is obtained and the interlocked topology of the dsDNA rings can be characterized by a computational method derived from the HOMFLY polynomial, based on which the catenation degree and the complexity of catenation are quantified. Detailed dependence of the catenation degree and the complexity of the catenated topology on key parameters, including the size of the transient broken gap and the duration time of the break on the dsDNA ring during operation by TOP2, the initial molar ratio of TOP2 to the dsDNA rings, and the reaction temperature, has been investigated.

The nuclear pore Y-complex functions as a platform for transcriptional regulation of FLOWERING LOCUS C in Arabidopsis.

The nuclear pore complex (NPC) has multiple functions beyond the nucleo-cytoplasmic transport of large molecules. Subnuclear compartmentalization of chromatin is critical for gene expression in animals and yeast. However, the mechanism by which the NPC regulates gene expression is poorly understood in plants. Here we report that the Y-complex (Nup107-160 complex, a subcomplex of the NPC) self-maintains its nucleoporin homeostasis and modulates FLOWERING LOCUS C (FLC) transcription via changing histone modifications at this locus. We show that Y-complex nucleoporins are intimately associated with FLC chromatin through their interactions with histone H2A at the nuclear membrane. Fluorescence in situ hybridization assays revealed that Nup96, a Y-complex nucleoporin, enhances FLC positioning at the nuclear periphery. Nup96 interacted with HISTONE DEACETYLASE 6 (HDA6), a key repressor of FLC expression via histone modification, at the nuclear membrane to attenuate HDA6-catalyzed deposition at the FLC locus and change histone modifications. Moreover, we demonstrate that Y-complex nucleoporins interact with RNA polymerase II to increase its occupancy at the FLC locus, facilitating transcription. Collectively, our findings identify an attractive mechanism for the Y-complex in regulating FLC expression via tethering the locus at the nuclear periphery and altering its histone modification.

Development, quality, and influencing factors of colonoscopy in China: results from the national census in 2013 and 2020.

Background and Aim: With the increasing burden of colorectal cancer (CRC), the practice of colonoscopy is gaining attention worldwide. However, it exhibits distinct trends between developing and developed countries. This study aims to explore its development and identify influencing factors in China. Methods: The Chinese Digestive Endoscopy Censuses were conducted twice in mainland China under the supervision of health authorities. Information regarding the practice of colonoscopy was collected through a structured online questionnaire. The authenticity of the data was evaluated through logical tests, and a random selection of endoscopic reports underwent manual validation by Quality Control Centers. Potential factors associated with colonoscopy were analyzed using real-world information. Results: From 2012 to 2019, the number of hospitals that performed colonoscopy increased from 3,210 to 6,325 (1.97-fold), and the volume increased from 5.83 to 12.92 million (2.21-fold). The utilization rate rose from 436.0 to 914.8 per 100,000 inhabitants (2.10-fold). However, there was an exacerbation of regional inequality in the adequacy of colonoscopy. Regions with higher incidence of CRC, higher gross domestic product per capita, more average numbers of endoscopists and tertiary hospitals tended to provide more accessible colonoscopy (P<0.001). Nationwide, the cecal intubation rate improved from 83.9% to 94.4% and the unadjusted adenoma detection rate (ADR) improved from 16.3% to 18.1%. Overall, hospital grading, educational background of endoscopists, economic income, and colonoscopy volume were observed as the significantly positive factors affecting ADR (P<0.05), but not the incidence of CRC or the number of endoscopists. Conclusions: Tremendous progress in colonoscopy has been made in China, but some issues needed timely reflection. Our findings provide timely evidence for better colonoscopy strategies and measures, such as quality control and medical education of endoscopists.

Nickel chloride promotes lung cancer invasion and metastasis by up-regulating the expression of E3 ubiquitin ligase TRIM31 through the IL-6/STAT3 signaling axis.

Nickel compounds are widely used in industries and daily life as important industrial products. Long-term exposure to nickel compounds has been associated with increased incidence and poor prognosis of lung cancer. However, the molecular mechanism by which exposure to nickel compounds induces the malignant phenotype of lung cancer cells remains unclear. In this study, we confirmed that nickel chloride (NiCl2) exposure promotes invasion and metastasis through IL-6/STAT3 both in vitro and vivo. Mechanistically, we found that NiCl2 mediated the transcriptional regulation of E3 ubiquitin ligase TRIM31 by SATAT3 phosphorylation, and promoted its up-regulation. Overexpression TRIM31 is an independent risk factor for lung cancer patients, and it promotes the invasion and metastasis of lung cancer cells. In addition, E3 ubiquitination ligase TRIM31 binds to its substrate TP53 protein in the RING region and accelerates TP53 protein ubiquitination and degradation. Functional recovery experiments showed that NiCl2 exposure promotes the invasion and metastasis ability of lung cancer and ubiquitination-mediated degradation of TP53 protein through the STAT3/TRIM31 axis. These findings reveal the role and mechanism of NiCl2 in lung cancer progression, indicating that STAT3 and TRIM31 may be promising targets for the treatment of lung cancer.

Construction and results of a comprehensive index for gastrointestinal health monitoring in China: a nationwide study.

Background: The disease burden of gastrointestinal disease (GD) in China is high, with significant variation across provinces. A comprehensive agreed set of indicators could guide rational resource allocation to support better GD outcomes. Methods: This study collected data from multiple sources, including national surveillance, surveys, registration systems, and scientific research. Literature reviews and Delphi methods were used to obtain monitoring indicators; the analytic hierarchy process was used to determine indicator weights. Findings: The China Gastrointestinal Health Index (GHI) system consisted of four dimensions and 46 indicators. The weight of the four dimensions from high to low included the prevalence of gastrointestinal non-neoplastic diseases and gastrointestinal neoplasms (GN) (0.3246), clinical treatment of GD (0.2884), prevention and control of risk factors (0.2606), and exposure to risk factors (0.1264). The highest indicator weight of GHI rank was the successful smoking cessation rate (0.1253), followed by the 5-year survival rate of GN (0.0905), and the examination rate of diagnostic oesophagogastroduodenoscopy (0.0661). The overall GHI for China in 2019 was 49.89, varying from 39.19 to 76.13 across all sub-regions. The top five sub-regions in the total GHI score were in the eastern region. Interpretation: GHI is the first system designed to monitor gastrointestinal health systematically. In the future, data from sub-regions of China should be used to test and improve the GHI system for its impact. Funding: This research was supported by the National Health Commission of China, the First Affiliated Hospital of Naval Medical University (2019YXK006), and the Science and Technology Commission of Shanghai Municipality (21Y31900100).

Progression from different blood glucose states to cardiovascular diseases: a prospective study based on multi-state model.

AIMS: To quantify the trajectories from normoglycaemia to pre-diabetes, subsequently to type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVD), and cardiovascular death, and the effects of risk factors on the rates of transition. METHODS AND RESULTS: We used data from the Jinchang Cohort of 42 585 adults aged 20-88 free of coronary heart disease (CHD) and stroke at baseline. A multistate model was applied for analysing the progression of CVD and its relation to various risk factors. During a median follow-up of 7 years, 7498 participants developed pre-diabetes, 2307 developed T2DM, 2499 developed CVD, and 324 died from CVD. Among 15 postulated transitions, transition from comorbid CHD and stroke to cardiovascular death had the highest rate (157.21/1000 person-years), followed by transition from stroke alone to cardiovascular death (69.31/1000 person-years) and transition from pre-diabetes to normoglycaemia (46.51/1000 person-years). Pre-diabetes had a sojourn time of 6.77 years, and controlling weight, blood lipids, blood pressure, and uric acid within normal limits may promote reversion to normoglycaemia. Among transitions to CHD alone and stroke alone, transition from T2DM had the highest rate (12.21/1000 and 12.16/1000 person-years), followed by transition from pre-diabetes (6.81/1000 and 4.93/1000 person-years) and normoglycaemia (3.28/1000 and 2.39/1000 person-years). Age and hypertension were associated with an accelerated rate for most transitions. Overweight/obesity, smoking, dyslipidaemia, and hyperuricaemia played crucial but different roles in transitions. CONCLUSION: Pre-diabetes was the optimal intervention stage in the disease trajectory. The derived transition rates, sojourn time, and influence factors could provide scientific support for the primary prevention of both T2DM and CVD.

Former single-outcome studies on the relationship between glycaemia and cardiovascular disease (CVD) may ignore the complexity and multi-transformations across the multiple stages from normoglycaemia to CVD in real-world setting. We aimed to quantify the trajectories from normoglycaemia to pre-diabetes, subsequently to type 2 diabetes, CVD, and cardiovascular death. Pre-diabetes was the optimal intervention stage in the disease trajectory. Transitions from CVD to death had much higher rates than other transitions. Age and hypertension were associated with an accelerated rate for most transitions. Overweight/obesity, smoking, dyslipidaemia, and hyperuricaemia played crucial but different roles in transitions.

Removal of inferior vena cava filter by open surgery after failure of endovenous retrieval.

Background: The permanent placement of inferior vena cava (IVC) filters may lead to numerous complications and their removal is recommended once the risk of pulmonary embolism is reduced. Removal of IVC filters by endovenous means is preferred. But failure of endovenous removal happens when recycling hooks penetrate the vein wall and filters are left in place for too long time. In these scenarios, open surgery may be effective for removal of IVC filters. We aimed to describe the surgical approach, outcomes, and 6-month follow-up of the removal of IVC filter by open surgery, after the failure of removal via the endovenous method. Methods: A total of 1,285 patients with retrievable IVC filters were admitted from July 2019 to June 2021, including 1,176 (91.5%) endovenous filter removals, and 24 (1.9%) open surgical IVC filter removals after the failure by endovenous method, of whom 21 (1.6%) were followed-up and eligible for analysis of the study. Patient characteristics, filter type, filter removal rate, IVC patency rate, and complications were retrospectively analyzed. Results: Twenty-one patients were left with IVC filters for 26 (10, 37) months, of which 17 (81.0%) patients had non-conical filters and 4 (19.0%) had conical filters; all 21 filters were successfully removed, with a 100% removal rate, no deaths, no serious complications, and no symptomatic pulmonary embolism. At the 3rd month follow-up after surgery and 3rd month follow-up after discontinuation of anticoagulation therapy, only 1 case (4.8%) had IVC occlusion, but without any occurrence of new lower limb deep venous thrombosis and silent pulmonary embolism. Conclusion: Open surgery can be used for the removal of IVC filters after failure of removal by endovenous method or when accompanied by complications without symptoms of pulmonary embolism. Open surgical approach can be used as an adjunctive clinical intervention for the removal of such filters.

Initialization of Nanowire or Cluster Growth Critically Controlled by the Effective V/III Ratio at the Early Nucleation Stage.

For self-catalyzed nanowires (NWs), reports on how the catalytic droplet initiates successful NW growth are still lacking, making it difficult to control the yield and often accompanying a high density of clusters. Here, we have performed a systematic study on this issue, which reveals that the effective V/III ratio at the initial growth stage is a critical factor that governs the NW growth yield. To initiate NW growth, the ratio should be high enough to allow the nucleation to extend to the entire contact area between the droplet and substrate, which can elevate the droplet off of the substrate, but it should not be too high in order to keep the droplet. This study also reveals that the cluster growth between NWs is also initiated from large droplets. This study provides a new angle from the growth condition to explain the cluster formation mechanism, which can guide high-yield NW growth.

Fasting plasma glucose and alanine aminotransferase on the risk of hepatocellular carcinoma: A nested case-control study.

BACKGROUND: The risk of hepatocellular carcinoma (HCC) is associated with a variety of factors. However, the possible association between the abnormal metabolism of fasting plasma glucose (FPG) and alanine aminotransferase (ALT) and the risk of HCC has not been widely studied. We examined this relationship based on a prospective cohort study. METHODS: 162 first-attack HCC cases during three follow-up periods (2014-2020) were selected as the case group. A control group of 648 participants was obtained by 1:4 matching of age (± 2 years) and sex with noncancer participants in the same period. Conditional logistic regression models, restricted cubic spline models, additive interaction models, and generalized additive models were used to explore the effects of FPG and ALT on the risk of HCC. RESULTS: After correction for confounding factors, we found that abnormal FPG and elevated ALT increased the risk of HCC, respectively. Compared with the normal FPG group, the risk of HCC was significantly increased in the impaired fasting glucose (IFG) (OR = 1.91, 95 %CI: 1.04, 3.50) and diabetes groups (OR = 2.12, 95 %CI: 1.24, 3.63). Compared with the lowest quartile of ALT, subjects in the fourth quartile had an 84 % increased risk of HCC (OR = 1.84, 95 %CI: 1.05-3.21). Moreover, there was an interaction between FPG and ALT on the risk of HCC, and 74 % of the HCC risk could be attributed to their synergistic effect (AP = 0.74, 95 %CI: 0.56-0.92). CONCLUSION: Abnormal FPG and elevated ALT are independent risk factors for HCC, and they have a synergistic effect on the risk of HCC. Therefore, serum FPG and ALT levels should be monitored to prevent the development of HCC.

Predictive value of serum apolipoprotein A-I in the organ failure of acute pancreatitis: a retrospective cohort study.

BACKGROUND: Organ failure (OF) largely governs the outcomes and mortality in patients with acute pancreatitis (AP), but there is a lack of optimal prognostic biomarker for OF. This study is designed to investigate whether the serum apolipoprotein A-I (Apo A-I) level can predict OF in patients with AP. METHODS: A total of 424 patients with AP were reviewed in the study, and we finally got 228 patients eligible for analysis. Patients were divided into two groups based on serum Apo A-I level. Demographic information and clinical materials were retrospectively collected. The primary outcome was the occurrence of OF. Univariate and multivariate binary logistic regression were conducted to analyze the relationship between Apo A-I and OF. Additionally, we used receiver operating characteristic analysis to clarify the predictive value of serum Apo A-I level for OF and mortality. RESULTS: Ninety-two patients and 136 patients were included in Apo A-I low and non-low groups, respectively. The occurrence of OF was significantly different in the two groups (35.9 vs. 9.6%, p < 0.001). Moreover, serum Apo A-I level markedly decreased across disease severity based on the 2012 Revised Atlanta Classification of AP. The decrease of serum apolipoprotein A-I was an independent risk factor for organ failure (OR: 6.216, 95% CI: 2.610, 14.806, p < 0.001). The area under the curve of serum Apo A-I was 0.828 and 0.889 for OF and mortality of AP, respectively. CONCLUSIONS: Serum Apo A-I level in the early stage of the disease has a high predictive value for OF of AP.

DeepDetect: Deep Learning of Peptide Detectability Enhanced by Peptide Digestibility and Its Application to DIA Library Reduction.

In tandem mass spectrometry-based proteomics, proteins are digested into peptides by specific protease(s), but generally only a fraction of peptides can be detected. To characterize detectable proteotypic peptides, we have developed a series of methods to predict peptide digestibility and detectability. Here, we propose a bidirectional long short-term memory (BiLSTM)-based algorithm, named DeepDetect, for the prediction of peptide detectability enhanced by peptide digestibility. Compared with existing algorithms, DeepDetect is featured by its improved prediction accuracy for a wide range of commonly used proteases, covering trypsin, ArgC, chymotrypsin, GluC, LysC, AspN, LysN, and LysargiNase. On 11 test data sets from E. coli, yeast, mouse, and human samples, DeepDetect achieved higher prediction accuracies than PepFormer, a state-of-the-art deep-learning-based peptide detectability prediction algorithm. The results further demonstrated that peptide digestibility can substantially enhance the performance of peptide detectability predictors. As an application, DeepDetect was used to reduce the in silico predicted spectral libraries in data-independent acquisition mass spectrometry data analysis. Experiments using DIA-NN software showed that DeepDetect can significantly accelerate the library search without loss of peptide and protein identification sensitivity.

Discovery of 2H-Indazole-3-carboxamide Derivatives as Novel Potent Prostanoid EP4 Receptor Antagonists for Colorectal Cancer Immunotherapy.

Nowadays, small-molecule drugs have become an indispensable part of tumor immunotherapy. Accumulating evidence has indicated that specifically blocking PGE2/EP4 signaling to induce robust antitumor immune response represents an attractive immunotherapy strategy. Herein, a 2H-indazole-3-carboxamide containing compound 1 was identified as a EP4 antagonist hit by screening our in-house small-molecule library. Systematic structure-activity relationship exploration leads to the discovery of compound 14, which displayed single-nanomolar EP4 antagonistic activity in a panel of cell functional assays, high subtype selectivity, and favorable drug-like profiles. Moreover, compound 14 profoundly inhibited the up-regulation of multiple immunosuppression-related genes in macrophages. Oral administration of compound 14, either as monotherapy or in combination with an anti-PD-1 antibody, significantly impaired tumor growth via enhancing cytotoxic CD8+ T cell-mediated antitumor immunity in a syngeneic colon cancer model. Thus, these results demonstrate the potential of compound 14 as a candidate for developing novel EP4 antagonists for tumor immunotherapy.

The long-term efficacy of transoral incisionless fundoplication with Medigus Ultrasonic Surgical Endostapler (MUSE) for gastroesophageal reflux disease.

BACKGROUND: To evaluate the long-term efficacy of transoral incisionless fundoplication (TIF) with Medigus Ultrasonic Surgical Endostapler (MUSE) for gastroesophageal reflux disease (GERD). METHODS: A total of 16 patients with proton pump inhibitor-dependent gastroesophageal reflux disease had undergone TIF by MUSE in Shanghai General Hospital （Shanghai, China）from March 2017 to December 2018. Patients were followed up at 6 months, and the GERD-health-related quality of life (GERD-HRQL) questionnaire score, the GERD questionnaire (GERD-Q) score, high-resolution esophageal manometry (HREM) and 24 h esophageal pH parameters, the Hill grade of the gastroesophageal flap valve (GEFV) and daily Proton pump inhibitor (PPI) consumption before and after procedure were compared. Patients also were followed up at 3 years and 5 years using a structured questionnaire via phone which evaluated symptoms of reflux, dose of PPI medication and side effects. RESULTS: Follow-up data were collected from 13 patients, ranging from 38 to 63 months, 53 months on average. 10/13 patients reported symptomatic improvement and daily PPI consumption was stopped or halved in 11/13. After procedure, the mean scores of GERD-HRQL and GERD-Q were significantly increased. The mean DeMeester score, the mean acid exposure time percentage and the mean number of acid reflux episodes were significantly lower. The mean rest pressure at lower esophageal sphincter (LES) had no significant difference. CONCLUSION: TIF by MUSE has significant efficacy in the treatment of PPI-dependent GERD, which can improve symptoms and life quality of patients, and reduce the acid exposure time for long-term. Chictr.org.cn. TRIAL REGISTRATION: ChiCTR2000034350.

Clinical outcomes of AngioJet pharmacomechanical thrombectomy versus catheter-directed thrombolysis for the treatment of filter-related caval thrombosis.

BACKGROUND: The inferior vena cava filter is utilized worldwide to intercept thrombi and to reduce the risk of fatal pulmonary embolism (PE). However, filter-related thrombosis is a complication of filter implantation. Endovascular methods such as AngioJet rheolytic thrombectomy (ART) and catheter-directed thrombolysis (CDT) can treat filter-related caval thrombosis, but the clinical outcomes of both treatment modalities have not been determined. AIM: To compare the treatment outcomes of AngioJet rheolytic thrombectomy vs catheter-directed thrombolysis in patients with filter-related caval thrombosis. METHODS: In this single-center retrospective study, 65 patients (34 males and 31 females; mean age: 59.0 ± 13.43 years) with intrafilter and inferior vena cava thrombosis were enrolled between January 2021 and August 2022. These patients were assigned to either the AngioJet group (n = 44) or the CDT group (n = 21). Clinical data and imaging information were collected. Evaluation measures included thrombus clearance rate, periprocedural complications, urokinase dosage, incidence of PE, limb circumference difference, length of stay, and filter removal rate. RESULTS: Technical success rates were 100% in the AngioJet and CDT groups. In the AngioJet group, grade II and grade III thrombus clearance was achieved in 26 (59.09%) and 14 (31.82%) patients, respectively. In the CDT group, grade II and grade III thrombus clearance was accomplished in 11 (52.38%) patients and 8 (38.10%) patients, respectively (P > 0.05).The peridiameter difference of the thigh was significantly reduced in patients from both groups after treatment (P < 0.05). The median dosage of urokinase was 0.08 (0.02, 0.25) million U in the AngioJet group and 1.50 (1.17, 1.83) million U in the CDT group (P < 0.05). Minor bleeding was shown in 4 (19.05%) patients in the CDT group, and when it was compared with that in the AngioJet group, the difference was statistically significant (P < 0.05). No major bleeding occurred. Seven (15.91%) patients in the AngioJet group had hemoglobinuria and 1 (4.76%) patient in the CDT group had bacteremia. There were 8 (18.18%) patients with PE in the AngioJet group and 4 (19.05%) patients in the CDT group before the intervention (P > 0.05). Computed tomography angiopulmonography (CTA) showed that PE was resolved after the intervention. New PE occurred in 4 (9.09%) patients in the AngioJet group and in 2 (9.52%) patients in the CDT group after theintervention (P > 0.05). These cases of PE were asymptomatic. The mean length of stay was longer in the CDT group (11.67 ± 5.34 d) than in the AngioJet group (10.64 ± 3.52 d) (P < 0.05). The filter was successfully retrieved in the first phase in 10 (47.62%) patients in the CDT group and in 15 (34.09%) patients in the AngioJet group (P > 0.05).Cumulative removal was accomplished in 17 (80.95%) out of 21 patients in the CDT group and in 42 (95.45%) out of 44 patients in the ART group (P > 0.05). The median indwelling time for patients with successful retrieval was 16 (13139) d in the CDT group and 59 (12231) d in the ART group (P > 0.05). CONCLUSION: Compared with catheter-directed thrombolysis, AngioJet rheolytic thrombectomy can achieve similar thrombus clearance effects, improve the filter retrieval rate, reduce the urokinase dosage and lower the risk of bleeding events in patients with filter-related caval thrombosis.

Mediating effect of metabolic diseases on the relationship between hyperuricemia and coronary heart disease.

BACKGROUND AND AIMS: Studies have shown that elevated serum uric acid (SUA) may increase the risk of coronary heart disease (CHD). However, it is still disputable how mediate effects between metabolic diseases and hyperuricemia affect the incidence of CHD. This study aimed to explore whether metabolic diseases may mediate the connection from hyperuricemia at baseline to the elevated incidence risk of CHD during follow-ups. METHODS AND RESULTS: Based on the Jinchang cohort, 48 001 subjects were followed for 9 years between June 2011 and December 2019. Multivariate-adjusted Cox regression models were applied to estimate hazard ratios (HRs) of CHD with 95% confidence intervals (CIs). Significantly increased risks of CHD were observed in hyperuricemia (HR:1.46, 95%CI:1.28, 1.67) when compared with normouricemia population. The mediating effect model further demonstrated that metabolic diseases could mediate the association between hyperuricemia and CHD pathogenesis, partially for the combined metabolic diseases with mediation effects of 45.12%, 25.24% for hypertension, 28.58% for overweight or obese status, 29.05% for hypertriglyceridemia, 6.70% for hypercholesterolemia, 3.52% for low high density lipoprotein cholesterol (HDL-C), and 6.51% for high low density lipoprotein cholesterol (LDL-C), respectively. CONCLUSIONS: Hyperuricemia significantly increased the risk of incident CHD, and this association was partly mediated by metabolic diseases.