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Abstract Background The safety and efficacy of vaccination against coronavirus disease 2019 (COVID-19) in patients with lymphangioleiomyomatosis (LAM) is still unclear. This study investigates COVID-19 vaccine hesitancy, vaccine safety and efficacy, and COVID-19 symptoms in LAM patients. Results In total, 181 LAM patients and 143 healthy individuals responded to the questionnaire. The vaccination rate of LAM patients was 77.34%, and 15.7% of vaccinated LAM patients experienced adverse events. Vaccination decreased the risk of LAM patients developing anorexia [OR: 0.17, 95% CI: (0.07, 0.43)], myalgia [OR: 0.34, 95% CI: (0.13, 0.84)], and ageusia [OR: 0.34, 95% CI: (0.14, 0.84)]. In LAM patients, a use of mTOR inhibitors reduced the risk of developing symptoms during COVID-19, including fatigue [OR: 0.18, 95% CI: (0.03, 0.95)], anorexia [OR: 0.30, 95% CI: (0.09, 0.96)], and ageusia [OR: 0.20, 95% CI: (0.06, 0.67)]. Conclusions Vaccination rates in the LAM population were lower than those in the general population, as 22.7% (41/181) of LAM patients had hesitations regarding the COVID-19 vaccine. However, the safety of COVID-19 vaccination in the LAM cohort was comparable to the healthy population, and COVID-19 vaccination decreased the incidence of COVID-19 symptoms in LAM patients. In addition, mTOR inhibitors seem not to determine a greater risk of complications in patients with LAM during COVID-19.

Clustering analysis of small watersheds is an effective tool for identifying the similarity of runoff generation and concentration. In this paper, 545 small watersheds in the hilly areas of Shandong Province were investigated, and 12 indicators representing their climate and subsurface characteristics were selected to identify communities based on hydrological similarity. We further analyzed the hydrological connections among the small watersheds within each community using three indicators (network mean, centrality, and k-core). Finally, the clustering results were evaluated on the basis of the small watershed flood peak modulus. The results of this complex network method indicate that the study area contained six large communities and nine small communities. The community-clustering results were reasonable and showed the interconnectedness of the watersheds within each community. The three network indicators adequately described the degree of similarity, the representativeness of the watersheds, and the spatial scales of similar hydrological features. This method should be helpful for addressing the issue of parameter transplantation in ungauged watersheds and implementation of a flood risk management strategy. HIGHLIGHTS Small watershed classification is conducted in a complex network approach.; Network evaluation metrics were used to represent hydrological linkages between small watersheds in the community.; The flood modulus of the small watersheds was calculated using the inference equation method for reasonableness verification.;

Ethylene thiourea (ETU), a metabolite of the fungicide ethylene bisdithiocarbamate (EBDC), has received great concern because of its harmful effects. ETU-induced anorectal malformations (ARMs) in rat models have been reported and widely used in the study of ARMs embryogenesis. Dysplasia of the lumbosacral spinal cord (LSSC), pelvic floor muscles (PFMs), and hindgut (HG) during intrauterine life affects postoperative defecation in patients with ARMs. However, the underlying toxic effects of ETU and pathological mechanisms in the three defecation-related tissues of fetuses with ARMs have not been reported. Thus, this study aimed to elucidate the molecular mechanisms involved in ARMs, with a focus on the dysregulation of miR-200b-3p and its downstream target tropomodulin 3 (TMOD3). The mRNA and protein levels of miR-200b-3p and TMOD3 in LSSC, PFMs, and HG of fetal rats with ARMs were evaluated by reverse transcription quantitative polymerase chain reaction and Western blotting (WB) on embryonic day 17 (E17). Further, a dual-luciferase reporter assay confirmed their targeting relationship. Gene silencing and overexpression of miR-200b-3p and TMOD3 were performed to verify their functions in HEK-293 T cells. Fetal rats with ARMs also received intra-amniotic microinjection of Ad-TMOD3 on E15, and key molecules in nuclear factor kappa (NF-κB) signaling and apoptosis were evaluated by WB on E21. Abnormally high levels of miR-200b-3p inhibited TMOD3 expression by binding with its 3′-untranslated region, leading to the activation of the non-canonical NF-κB signaling pathway, which is critical in the maldevelopment of LSSC, PFMs, and HG in ARMs rats. Furthermore, miR-200b-3p triggered apoptosis by directly targeting TMOD3. Notably, intra-amniotic Ad-TMOD3 microinjection revealed that the upregulation of TMOD3 expression mitigates the effects of miR-200b-3p on the activation of non-canonical NF-κB signaling and apoptosis in fetal rat model of ARMs. A novel miR-200b-3p/TMOD3/non-canonical NF-κB signaling axis triggered the massive apoptosis in LSSC, PFMs, and HG of ARMs, which was restored by the intra-amniotic injection of Ad-TMOD3 during embryogenesis. Our results indicate the potential of TMOD3 as a treatment target to restore defecation.

Abstract Background The aim of the retrospective cohort study was to investigate the prognostic effect of subchorionic hematomas (SCH) in the first trimester on pregnancy outcomes after euploid embryo transfer. Methods We retrospectively analyzed women achieving singleton pregnancy by PGT-A or PGT-SR from January 2017 to January 2022. Patients were enrolled in the study if they had a viable intrauterine pregnancy at ultrasound between 6 0/7 and 8 0/7 weeks of gestation. Pregnancy outcomes as well as the incidence of maternal complications were compared between patients with and without SCH. Logistic regression was used for adjusting for potential confounding factors. Results A total of 1539 women were included, of which 298 with SCH and 1241 with non-SCH. The early miscarriage rate in SCH group was significantly higher than that in the non-SCH group (10.1% vs. 5.6%, adjusted odds ratio [aOR] 1.99, 95% confidence interval [CI] 1.25–3.16, P = 0.003). The live birth rate in SCH group was significantly lower than that in the non-SCH group. (85.6% vs. 91.2%, aOR 0.57, 95% CI 0.39–0.84, P = 0.005). In addition, SCH group had an increased risk of hypertensive disorder of pregnancy (HDP) (8.9% vs. 5.2%, P = 0.022), especially in hematoma with bleeding (19.3% vs. 6.0%, P = 0.002). The incidence of gestational diabetes mellitus (GDM), major congenital abnormalities rate, normal birth weight rate and low birth weight rate were similar between the two groups. Conclusions The presence of SCH in the first trimester was associated with worse pregnancy outcomes after euploid embryo transfer, including an increased risk of early miscarriage and hypertensive disorder of pregnancy, along with a reduced live birth rate.

Chimeric antigen receptor T cell denoted as CAR-T therapy has realized incredible therapeutic advancements for B cell malignancy treatment. However, its therapeutic validity has yet to be successfully achieved in solid tumors. Different from hematological cancers, solid tumors are characterized by dysregulated blood vessels, dense extracellular matrix, and filled with immunosuppressive signals, which together result in CAR-T cells’ insufficient infiltration and rapid dysfunction. The insufficient recognition of tumor cells and tumor heterogeneity eventually causes cancer reoccurrences. In addition, CAR-T therapy also raises safety concerns, including potential cytokine release storm, on-target/off-tumor toxicities, and neuro-system side effects. Here we comprehensively review various targeting aspects, including CAR-T cell design, tumor modulation, and delivery strategy. We believe it is essential to rationally design a combinatory CAR-T therapy via constructing optimized CAR-T cells, directly manipulating tumor tissue microenvironments, and selecting the most suitable delivery strategy to achieve the optimal outcome in both safety and efficacy.

Anorectal malformations (ARMs) are congenital diseases that lead to postoperative fecal incontinence, constipation, and soiling, despite improvements in surgery; however, their pathological mechanisms remain unclear. Here, we report the role of microRNA-141-3p in maintaining homeostasis between apoptosis and autophagy in the lumbosacral defecation center of fetal rats with ARMs. Elevated microRNA-141-3p expression inhibited YIN-YANG-1 expression by binding its 3′ UTR, and repressed autophagy and triggered apoptosis simultaneously. Then, adenylate cyclase 3 was screened to be the downstream target gene of YIN-YANG-1 by chromatin immunoprecipitation sequencing experiments, and Yin Yang 1 could positively activate the transcription of adenylate cyclase 3 by directly interacting with the motif GAGATGG and ATGG in its promoter. Intraamniotic microinjection of adeno-rno-microRNA-141-3p-sponge-GFP in fetal rats with ARMs on embryonic day 15 restored apoptosis-autophagy homeostasis. These findings reveal that microRNA-141-3p upregulation impaired homeostasis between apoptosis and autophagy by inhibiting the YIN-YANG-1/adenylate cyclase 3 axis, and that intraamniotic injection of anti-microRNA-141-3p helped maintain homeostasis in the lumbosacral defecation center of ARMs during embryogenesis.

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths, with very limited therapeutic options available. This study aims to comprehensively depict the heterogeneity and identify prognostic targets for PDAC with single-cell RNA sequencing (scRNA-seq) analysis. Methods ScRNA-seq analysis was performed on 16 primary PDAC and three adjacent lesions. A series of analytical methods were applied for analysis in cell clustering, gene profiling, lineage trajectory analysis and cell-to-cell interactions. In vitro experiments including colony formation, wound healing and sphere formation assay were performed to assess the role of makers. Results A total of 32,480 cells were clustered into six major populations, among which the ductal cell cluster expressing high copy number variants (CNVs) was defined as malignant cells. Malignant cells were further subtyped into five subgroups which exhibited specific features in immunologic and metabolic activities. Pseudotime trajectory analysis indicated that components of various oncogenic pathways were differentially expressed along tumor progression. Furthermore, intensive substantial crosstalk between ductal cells and stromal cells was identified. Finally, genes (REG4 and SPINK1) screened out of differentially expressed genes (DEGs) were upregulated in PDAC cell lines. Silencing either of them significantly impaired proliferation, invasion, migration and stemness of PDAC cells. Conclusions Our findings offer a valuable resource for deciphering the heterogeneity of malignant ductal cells in PDAC. REG4 and SPINK1 are expected to be promising targets for PDAC therapy.

Abstract Insufficient tumor immunogenicity and immune escape from tumors remain common problems in all tumor immunotherapies. Recent studies have shown that pyroptosis, a form of programmed cell death that is accompanied by immune checkpoint inhibitors, can induce effective immunogenic cell death and long‐term immune activation. Therapeutic strategies to jointly induce pyroptosis and reverse immunosuppressive tumor microenvironments are promising for cancer immunotherapy. In this regard, a dual‐responsive supramolecular polymeric nanomedicine (NCSNPs) to self‐cascade amplify the benefits of cancer immunotherapy is designed. The NCSNPs are formulated by β‐cyclodextrin coupling nitric oxide (NO) donor, a pyroptosis activator, and NLG919, an indoleamine 2,3‐dioxygenase (IDO) inhibitor, and self‐assembled through host–guest molecular recognition and hydrophobic interaction to obtain nanoparticles. NCSNPs possess excellent tumor accumulation and bioavailability attributed to ingenious supramolecular engineering. The study not only confirms the occurrence of NO‐triggered pyroptosis in tumors for the first time but also reverses the immunosuppressive microenvironment in tumor sites via an IDO inhibitor by enhancing the infiltration of cytotoxic T lymphocytes, to achieve remarkable inhibition of tumor proliferation. Thus, this study provides a novel strategy for cancer immunotherapy.

Future network architectures are expected to be autonomous, intelligent, and service-based, posing new security challenges. To address these challenges, the Artificial Intelligence (AI) security service emerges as a promising solution. However, the complex service configurations and performance guarantees hinder the autonomous deployment of the AI security service. This paper proposes an autonomous deployment mechanism in Software-Defined Networking/Network Function Virtualization (SDN/NFV) enabled networks. First, our mechanism introduces user and decision planes on top of the control plane, enabling hierarchical intent expression and translation from user security intent to security policies. Then, we analyze the embedding problem of the AI-based Security Function Chain (AISFC) during security policy generation. We formulate the AISFC embedding problem as an Integer Linear Programming (ILP) task to minimize the total response delay. By decomposing it into AISF placement and routing, we design a heuristic algorithm with polynomial time complexity. Finally, we validate the proposed mechanism through a prototype system and numerical simulations, demonstrating its ability to autonomously translate, implement, and guarantee the user security intent. Comparative analysis shows that our approach considering the relationship between available computing resources and delay achieves smaller response delays than the baseline. Furthermore, our algorithm achieves a gap from optimality approximately 28.57% smaller than the greedy algorithm and supports networks that are 4.34 times larger in scale than the exact solution within a 2-second execution time.

Mollusca first evolve primitive immune cells (namely, haemocytes), which assemble a notable complex innate immune system, which are continuously produced through proliferation and differentiation and infused in the haemolymph. As a typical E3 ligase, CHIP is critical for immune cell turnover and homeostasis in vertebrates. In this study, a CHIP homolog (CgCHIP) with a high expression in haemocytes was identified in oysters to investigate its role in the proliferation and differentiation of ancient innate immune cells. CgCHIP exhibited a widespread distribution across all haemocyte subpopulations, and the knockdown of CgCHIP altered the composition of haemocytes as examined by flow cytometry. Mechanistically screened with bioinformatics and immunoprecipitation, a key haematopoietic transcription factor CgRunx was identified as a substrate of CgCHIP. Moreover, amino acids in the interacted intervals of CgCHIP and CgRunx were determined by molecular docking. Experimental evidence from an in vitro culture model of an agranulocyte subpopulation and an in vivo oyster model revealed that the knockdown of CgCHIP and CgRunx had opposing effects on agranulocyte (precursor cells) differentiation and granulocyte (effector cells) proliferation. In summary, CgCHIP negatively regulated agranulocyte differentiation and granulocyte proliferation by mediating the ubiquitination and degradation of CgRunx in oysters. These results offer insight into the involvement of ubiquitylation in controlling haemocyte turnover in primitive invertebrates.

The discovery of N6-methyladenosine (m6A) methylation and its role in translation has led to the emergence of a new field of research. Despite accumulating evidence suggesting that m6A methylation is essential for the pathogenesis of cancers and aging diseases by influencing RNA stability, localization, transformation, and translation efficiency, its role in normal and abnormal embryonic development remains unclear. An increasing number of studies are addressing the development of the nervous and gonadal systems during embryonic development, but only few are assessing that of the immune, hematopoietic, urinary, and respiratory systems. Additionally, these studies are limited by the requirement for reliable embryonic animal models and the difficulty in collecting tissue samples of fetuses during development. Multiple studies on the function of m6A methylation have used suitable cell lines to mimic the complex biological processes of fetal development or the early postnatal phase; hence, the research is still in the primary stage. Herein, we discuss current advances in the extensive biological functions of m6A methylation in the development and maldevelopment of embryos/fetuses and conclude that m6A modification occurs extensively during fetal development. Aberrant expression of m6A regulators is probably correlated with single or multiple defects in organogenesis during the intrauterine life. This comprehensive review will enhance our understanding of the pivotal role of m6A modifications involved in fetal development and examine future research directions in embryogenesis.

Abstract Achieving hemostasis effectively is essential for surgical success and excellent patient outcomes. However, it is challenging to develop hemostatic adhesives that are fast‐acting, strongly adherent, long‐lasting, and biocompatible for treating hemorrhage. In this study, a sequential crosslinking fibrin glue (SCFG) is developed, of which the first network of the fibrin glue forms in situ within 2 s to act as an initial physical barrier and locks the gelatin methacryloyl precursor for tight construction of the second network to enhance wet adhesion and durability for tissues covered with blood. The sequential crosslinking glue can provide large pressures (≈280 mmHg of burst pressure), makes strong (38 kPa of shear strength) and tough (≈60 J m−2 of interfacial toughness) interfaces with wet tissues, and outperforms commercial hemostatic agents and gelatin methacryloyl. SCFG are demonstrated as an effective and safe sealant to enhance the treatment outcomes of bleeding tissues in rat, rabbit, and pig models. The ultrafast gelation, strong adhesion and durability, excellent compatibility, and easy manufacture of SCFG make it a promising hemostatic adhesive for clinical applications.

Deep tight gas reservoirs are considered important hydrocarbon exploration targets. High-quality reservoir prediction is critical for successfully exploring and developing deeply buried tight sandstone gas. Previous research has found that the reservoir quality of deeply buried tight sandstones is controlled by diagenesis and sedimentary facies. However, the variation of diagenetic alterations in different facies is still poorly studied on deltaic tight gas sandstone. In this study, core analysis, wireline log data, and 3D seismic were studied for the characterization of diagenetic alterations and sedimentary facies. The tight sandstones were formed in braided river delta deposits. Gravel-bearing coarse-grained sandstone facies and cross-bedded sandstone facies developed in tight sandstones. The Gravel-bearing coarse-grained sandstone is formed in the mid-channel bar of deltaic distributary channels. The major diagenetic processes developed in the tight sandstone include compaction, cementation, and dissolution. Constructive diagenesis can generate secondary pores, mainly including dissolution and kaolinite metasomatism, which can effectively improve reservoir physical properties. Through the diagenesis alterations linked to different lithofacies in cored wells, there are obvious diagenesis variations in different lithofacies. Despite strong compaction, the reservoirs in coarse sandstone facies have developed internal dissolution. After compaction, cementation, and dissolution to increase porosity, the reservoir retains intergranular and secondary pores and forms relatively high-quality reservoirs. The fine sandstone facies with cross-bedding are strongly compacted, with internal ductile particles being compacted and deformed, and the particle orientation is clearly arranged. The reservoir is tight, and the development of dissolution in the reservoir is weak, resulting in poor reservoir quality. In addition, reservoirs located at the interface between sandstone and mudstone are often affected by diagenesis, resulting in the development of calcareous cementation, leading to poor reservoir quality. Therefore, high-quality reservoirs are mostly distributed in coarse sand lithofacies, mainly distributed in the mid-channel bar of distributary channel deposits. Sedimentary facies control the original physical properties of the reservoir with different content and texture; the quality of the original reservoir is subject to diagenetic alteration in different ways. The points in this study could offer insights better to predict deep tight reservoir quality in continental basins.

Water level prediction is an essential factor for the safe operation of pumping stations. However, due to the complex nonlinear relationship between the water level of the front pool of the pumping station and the influencing factors, the prediction of the water level is still inaccurate and untimely. Backpropagation (BP) neural network, improved particle swarm optimization-BP neural network (PSO-BP), support vector machine regression (SVR), and improved PSO-SVR were used to construct 4-h and 8-h ahead prediction models for pumping station prestation water levels. Mean absolute error, mean squared error (MSE), root mean square error (RMSE), mean absolute percentage error (MAPE), and R correlation coefficient were used as prediction evaluation metrics. This method is applied in the Baliwan Pumping Station, the highest pumping station in the South-to-North Water Diversion Eastern Route Project (SNWDERP). The results showed that the MSE, RMSE, and MAPE of the improved PSO-BP model were smaller than other models, whereas the R correlation coefficient was larger, confirming its high prediction accuracy. All models had higher prediction accuracy 4 h ahead than 8 h ahead. Combining the time-phased water level prediction method and hybrid machine learning can enhance the water level prediction accuracy of a pumping station pre-station. HIGHLIGHTS We propose a pumping station pre-station water level prediction model based on multiple machine learning algorithms.; The paper categorizes the data into the ice formation period, the aquatic grass period, and the normal scheduling period and compares them to ALL.; The effect of different foresight periods on forecast accuracy was analyzed.;

In clinical practice, pancreatic neuroendocrine neoplasms (pNENs) with a diameter smaller than 2 cm are commonly referred to as small pNENs. Due to their generally favorable biological characteristics, the diagnosis and treatment of small pNENs differ from other pNENs and are somewhat controversial. In response to this, the Chinese Pancreatic Surgery Association, Chinese Society of Surgery, Chinese Medical Association have developed a consensus on the diagnosis and treatment of small pNENs, which is based on evidence-based medicine and expert opinions. This consensus covers various topics, including concepts, disease assessment, treatment selection, follow-up, and other relevant aspects.

With rapid urbanization, retrieving information about residential complexes in a timely manner is essential for urban planning. To develop efficiency and accuracy of building extraction in residential complexes, a Segment Anything Model-based residential building instance segmentation method with an automated prompt generator was proposed combining LiDAR data and VHR remote sensing images in this study. Three key steps are included in this method: approximate footprint detection using LiDAR data, automatic prompt generation for the SAM, and residential building footprint extraction. By applying this method, residential building footprints were extracted in Pukou District, Nanjing, Jiangsu Province. Based on this, a comprehensive assessment model was constructed to systematically evaluate the spatial layout of urban complexes using six dimensions of assessment indicators. The results showed the following: (1) The proposed method was used to effectively extract residential building footprints. (2) The residential complexes in the study area were classified into four levels. The numbers of complexes classified as Excellent, Good, Average, and Poor were 10, 29, 16, and 1, respectively. Residential complexes of different levels exhibited varying spatial layouts and building distributions. The results provide a visual representation of the spatial distribution of residential complexes that belong to different levels within the study area, aiding in urban planning.

Abstract Background The purpose of the study was to investigate the ability of new parameters in distinguishing high‐risk patients of recurrence from isthmic papillary thyroid carcinomas (iPTCs). Methods One hundred sixteen iPTC patients who underwent total thyroidectomy were identified from 3461 PTC patients from 2014 to 2019. Tumor margin to trachea midline distance (TTD), maximum tumor size (TS), and transverse diameter of trachea (TD) were measured on CT images. Cox proportional hazard models served to identify risk factors associated with recurrence‐free survival (RFS). The iPTC prognostic formula (IPF = TD/(TTD − TS) − TD/TTD) was evaluated to assess the prognosis. RFS was conducted between the different groups using the Kaplan–Meier analysis. The receiver operating characteristic (ROC) curve of each parameter was drawn to predict recurrence. Results Central lymph node metastasis (CLNM) and extrathyroidal invasion in iPTC were 58.6% and 31.0%, respectively. Regional recurrence occurred in 16 (13.8%) patients, and no patient died or had distant metastasis. The 3‐ and 5‐year RFS of iPTC were 87.5% and 84.5%, respectively. Gender (p = 0.001) and PLNM (prelaryngeal lymph node metastasis) (p = 0.010) in cPTC (center of iPTC located between two imaginary lines perpendicular to the surface of the skin from the most lateral points of the trachea) and non‐cPTC (iPTC patients enrolled in this study excluding cPTC) groups differed significantly. A cut‐off point of tumor size >1.1 cm and IPF ≤5.57 were established to have significant differences in prognosis (p = 0.032 and p = 0.005, respectively). Multivariate analysis showed that IPF ≤5.57 was independent prognostic factor for RFS (HR: 4.415, 95%CI: 1.118–17.431, p = 0.034). Conclusion This study indicated the association between IPF and RFS in iPTC patients and established new models to assess risk factors for recurrence pre‐operation. IPF ≤5.57 was significantly associated with poor RFS and might be promising parameters for predicting prognosis and surgical decision‐making pre‐operation.

Summary: Accurate detection of liver lesions from multi-phase contrast-enhanced CT (CECT) scans is a fundamental step for precise liver diagnosis and treatment. However, the analysis of multi-phase contexts is heavily challenged by the misalignment caused by respiration coupled with the movement of organs. Here, we proposed an AI system for multi-phase liver lesion segmentation (named MULLET) for precise and fully automatic segmentation of real-patient CECT images. MULLET enables effectively embedding the important ROIs of CECT images and exploring multi-phase contexts by introducing a transformer-based attention mechanism. Evaluated on 1,229 CECT scans from 1,197 patients, MULLET demonstrated significant performance gains in terms of Dice, Recall, and F2 score, which are 5.80%, 6.57%, and 5.87% higher than state of the arts, respectively. MULLET has been successfully deployed in real-world settings. The deployed AI web server provides a powerful system to boost clinical workflows of liver lesion diagnosis and could be straightforwardly extended to general CECT analyses.

Abstract Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are prevalent critical illnesses with a high mortality rate among patients in intensive care units. Neutrophil extracellular traps (NETs) are implicated in the pathogenesis of ALI/ARDS and represent a promising therapeutic target. However, the clinical application of deoxyribonuclease I (DNase I), the only drug currently available to clear NETs, is limited due to the lack of precise and efficient delivery strategies. Therefore, targeted delivery of DNase I to the inflamed lung remains a critical issue to be addressed. Herein, a novel biomimetic DNase I delivery system is developed (DCNV) that employs genetically and bioorthogonally engineered cellular nanovesicles for pulmonary NETs clearance. The CXC motif chemokine receptor 2 overexpressed cellular nanovesicles can mimic the inflammatory chemotaxis of neutrophils in ALI/ARDS, leading to enhanced lung accumulation. Furthermore, DNase I immobilized through bioorthogonal chemistry exhibits remarkable enzymatic activity in NETs degradation, thus restraining inflammation and safeguarding lung tissue in the lipopolysaccharide‐induced ALI murine model. Collectively, the findings present a groundbreaking proof‐of‐concept in the utilization of biomimetic cellular nanovesicles to deliver DNase I for treating ALI/ARDS. This innovative strategy may usher in a new era in the development of pharmacological interventions for various inflammation‐related diseases.

Abstract Background The extent of pancreatoduodenectomy for pancreatic head cancer remains controversial, and more high‐level clinical evidence is needed. This study aimed to evaluate the outcome of extended pancreatoduodenectomy (EPD) with retroperitoneal nerve resection in pancreatic head cancer. Methods This multicenter randomized trial was performed at 6 Chinese high‐volume hospitals that enrolled patients between October 3, 2012, and September 21, 2017. Four hundred patients with stage I or II pancreatic head cancer and without specific pancreatic cancer treatments (preoperative chemotherapy or chemoradiation) within three months were randomly assigned to undergo standard pancreatoduodenectomy (SPD) or EPD, with the latter followed by dissection of additional lymph nodes (LNs), nerves and soft tissues 270° on the right side surrounding the superior mesenteric artery and celiac axis. The primary endpoint was overall survival (OS) by intention‐to‐treat (ITT). The secondary endpoints were disease‐free survival (DFS), mortality, morbidity, and postoperative pain intensity. Results The R1 rate was slightly lower with EPD (8.46%) than with SPD (12.56%). The morbidity and mortality rates were similar between the two groups. The median OS was similar in the EPD and SPD groups by ITT in the whole study cohort (23.0 vs. 20.2 months, P = 0.100), while the median DFS was superior in the EPD group (16.1 vs. 13.2 months, P = 0.031). Patients with preoperative CA19–9 < 200.0 U/mL had significantly improved OS and DFS with EPD (EPD vs. SPD, 30.8 vs. 20.9 months, P = 0.009; 23.4 vs. 13.5 months, P < 0.001). The EPD group exhibited significantly lower locoregional (16.48% vs. 35.20%, P < 0.001) and mesenteric LN recurrence rates (3.98% vs. 10.06%, P = 0.022). The EPD group exhibited less back pain 6 months postoperation than the SPD group. Conclusions EPD for pancreatic head cancer did not significantly improve OS, but patients with EPD treatment had significantly improved DFS. In the subgroup analysis, improvements in both OS and DFS in the EPD arm were observed in patients with preoperative CA19–9 < 200.0 U/mL. EPD could be used as an effective surgical procedure for patients with pancreatic head cancer, especially those with preoperative CA19–9 < 200.0 U/mL.

Abstract Background Variations in the red blood cell (RBC) lifespan can affect glycosylated hemoglobin (HbA1c) test values, but there is still a lack of evidence regarding how and to what degree the RBC lifespan influences HbA1c in the type 2 diabetes mellitus (T2DM) population owing to the restriction of traditional RBC lifespan–detection means. This study aimed to investigate the influence of RBC lifespan variation on HbA1c values in T2DM patients with a HbA1c detection value lower than 7%. Methods Patients with HbA1c

Investigating vegetation–climate interactions is critical for understanding behavioral patterns of terrestrial ecosystems and formulating food security strategies. However, the multi-spatiotemporal legacy effects of climate on terrestrial vegetation remain unclear. In this study, we examined the dynamic trends of vegetation distribution and climatic factors at multiple temporal and spatial scales. Moreover, using cross-wavelet transform, wavelet coherence transform, and partial correlation analysis, a paradigm framework was established to determine the multi-spatiotemporal legacy effect of climate on vegetation in China in 2000–2019, as well as the response of different vegetation types. The results indicate a significant greening trend in China, accompanied by a warming and wetting pattern over the past 20 years. The phase difference of the wavelet coherence transform in the time-frequency domain revealed remarkable legacy effects and regional variations, indicating a complicated relationship between vegetation and climate. Meanwhile, different vegetation types exhibited heterogeneous responses of legacy effect of precipitation and temperature on multi-spatiotemporal scales; moreover, the lag time in spring was shorter than that in summer and autumn. The average legacy effect on different vegetation types was approximately 1–2 months. Therefore, the heterogeneity of the legacy effects is a complicated process of dynamic variation, which can be summarized as the comprehensive characteristics of vegetation response to climate with regional discrepancy, ecosystem category, and multi-temporal scale. These findings advance our understanding regarding the preference of vegetation to hydrothermal conditions across biomes and ecosystems and provide a future framework for elucidating the dynamic response of vegetation to other more complex factors in this warmer world. Furthermore, our results emphasize that multi-spatiotemporal legacy effects should be incorporated into the vegetation–climate interaction model and the formulation of macro-environmental management policies.

Intermolecular (4 + 2) cycloaddition with alkynes is a powerful approach to construct isocoumarin moieties, however, regioselectivity remains challenging for the transition metal-catalyzed approach. Here, the authors report copper-catalyzed regioselective (4 + 2) annulations between diaryliodonium salts and alkynes to synthesize isocoumarin-type natural products.

BackgroundLong-term impact of sepsis on whole body systems is not well investigated. The aim of the study was to explore the potential association of neonatal/adult sepsis with several inflammation-related diseases in multiple physiological systems.MethodsInstrumental variables for neonatal and adult sepsis were collected from the public genome-wide association studies, which must satisfy the correlation, exclusivity and independence assumptions. Mendelian randomization methods (including random-effect inverse-variance weighted, MR-PRESSO, weighted median and MR-Egger) were used to determine the genetic association of neonatal/adult sepsis with asthma, allergy, rheumatoid arthritis, body mass index/obesity, type 1/type 2 diabetes and intelligence/dementia. Sensitivity analyses were conducted to assess heterogeneity and horizontal pleiotropy. The study was performed by TwoSampleMR in R software.ResultsThe inverse-variance weighted method reported that neonatal sepsis was related to the decreased level of body mass index (OR = 0.988, 95%CI = 0.980 ~ 0.997, P = 0.007), and adult sepsis was related to the decreased risk of obesity (OR = 0.785, 95%CI = 0.655 ~ 0.940, P = 0.009). These results were supported by the other Mendelian randomization methods. In addition, the study did not find any association of neonatal/adult sepsis with the other inflammation-related diseases. No heterogeneity and horizontal pleiotropy were found using sensitivity analyses.ConclusionSepsis had the potential to reduce the risk of obesity or body mass index level at a genetic level, both in neonates and in adults.

BackgroundEx vivo liver resection and autotransplantation (ELRAT) may provide an opportunity for R0 resection of conventionally unresectable hepatobiliary cancers and hepatic metastases. To date, few studies of the surgery for malignant tumors have been conducted and there are no known reports of in vivo partial hepatectomy followed by ELRAT (IPH-ELRAT) for malignant tumors.MethodsBetween December 2021 and November 2022, ten patients with malignant hepatobiliary primary cancers or hepatic metastases underwent ELRAT at our institution. We shared the surgical skills and postoperative prognoses of these patients were assessed.ResultsThe types of tumors were biliary tract cancer (BTC, n=8), hepatic metastasis of colonic carcinoma (n=1), and hepatic metastasis of small-bowel stromal tumor (n=1). Five patients underwent in vivo total hepatectomy followed by ex vivo liver resection and autotransplantation (ITH-ELRAT), The other five received in vivo partial hepatectomy followed by ex vivo liver resection and autotransplantation (IPH-ELRAT). Four patients underwent inferior vena cava replacement using artificial blood vessels. The survival rate of all ten patients one month after surgery was 100%. Nine patients (90%) are currently alive, with a median follow-up of 8.5 months (range 6–16.5 months). To date, seven of the nine surviving patients have had no cancer recurrence, including six with BTC.ConclusionsWe report the world first five cases that received IPH-ELRAT for malignancies. We also demonstrated relatively favorable outcomes in patients who underwent ELRAT. ELRAT may be a recommendable surgical option for selected patients with conventionally unresectable hepatobiliary malignant tumors.

Increasing evidence confirms that histone modification plays a critical role in preserving long-term immunological memory. Immune priming is a novel form of immunological memory recently verified in invertebrates. Toll-like receptor (TLR) signaling and cytokines have been reported to be involved in the immune priming of the Pacific oyster Crassostrea gigas. In the present study, the expression of Toll-like receptor 3 (CgTLR3), myeloid differentiation factor 88-2 (CgMyd88-2) and interleukin 17-1 (CgIL17-1) was found to be elevated in the hemocytes of C. gigas at 6 h after the secondary stimulation with Vibrio splendidus, which was significantly higher than that at 6 h after the primary stimulation (p < 0.05). A significant increase in histone H3 lysine 4 trimethylation (H3K4me3) enrichment was detected in the promoter region of the CgTLR3 gene at 7 d after the primary stimulation with inactivated V. splendidus (p < 0.05). After the treatment with a histone methyltransferase inhibitor (5′-methylthioadenosine, MTA), the level of H3K4me3 at the promoter of the CgTLR3 gene decreased significantly at 7 d after the primary stimulation with inactivated V. splendidus (p < 0.05), and the expression of CgTLR3, CgMyD88-2 and CgIL17-1 was significantly repressed at 6 h after the secondary stimulation with V. splendidus (p < 0.05). Conversely, the treatment with monomethyl fumarate (MEF, an inhibitor of histone demethylases) resulted in a significant increase in H3K4me3 enrichment levels at the CgTLR3 promoter at 7 d after the primary stimulation (p < 0.05), and the expression of CgTLR3, CgMyD88-2 and CgIL17-1 was observed to increase significantly at 6 h after the secondary stimulation (p < 0.05). These results suggested that H3K4me3 regulated MyD88-dependent TLR signaling in the hemocytes of C. gigas, which defined the role of histone modifications in invertebrate immune priming.

The use of neoadjuvant therapy (NAT) for pancreatic ductal adenocarcinoma remains controversial and limited. Therefore, this literature review aimed to assess the feasibility, safety, and efficacy of this treatment. A database search of peer-reviewed articles published in English between January 1990 and June 2021 in PubMed, MEDLINE, and the Web of Science was performed. Original articles, review articles, and meta-analyses relevant to the topic were selected. We found 2 to 4 cycles with FOLFIRINOX, gemcitabine plus nab-paclitaxel, gemcitabine plus S-1, or gemcitabine alone were the most acceptable treatments. Considering the risk of adverse events and cancer progression, NAT is considered safe and tolerable, with a comparable resection rate. Although NAT can result in moderate tumor responses and some extent of local control (improvement of complete resection rate and negative lymph node metastases), no obvious survival benefit is observed. To date, the survival benefits of NAT for resectable pancreatic ductal adenocarcinoma have been very limited. It is too early to say that NAT is the best treatment option for resectable pancreatic cancer.

Background: Primary liver cancer, around 75%–85% are hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China, but also may re-shape the nationwide diagnosis and treatment of liver cancer. Key Messages: The new guideline aims to encourage the implementation of evidence-based practice, and improve the national average five-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."

BackgroundCholangiocarcinoma (CCA) is a highly heterogeneous malignant tumor, and more than 60% of patients have recurrence and metastasis after surgery. The efficacy of postoperative adjuvant therapy for CCA remains unclear. This study aimed to explore whether adjuvant therapy benefits patients with CCA and examine the independent prognostic factors for overall survival (OS) and progression-free survival (PFS).MethodsPatients with CCA undergoing surgery were retrospectively enrolled in this study from June 2016 to June 2022. The chi-square test or Fisher exact test was used to analyze the correlation between clinicopathologic characteristics. Survival curves were plotted using the Kaplan-Meier method, and the Cox regression model was used for univariate and multivariate analysis to search for independent prognostic factors.ResultsOf the 215 eligible patients, 119 patients received adjuvant therapy, and the other 96 patients did not. The median follow-up was 37.5 months. The median OS of CCA patients with and without adjuvant therapy was 45 and 18 months (P < 0.001), respectively. The median PFS of CCA patients with and without adjuvant therapy was 34 and 8 months (P < 0.001), respectively. The Cox univariate and multivariate regression analysis showed that preoperative aspartate transaminase and carbohydrate antigen 19-9, microvascular invasion, lymph node metastasis, differentiation degree, and adjuvant therapy were independent prognostic factors for OS (all P values < 0.05). Preoperative carbohydrate antigen 125, microvascular invasion, lymph node metastasis, differentiation degree, and adjuvant therapy were independent prognostic factors for PFS (all P values < 0.05). The stratified analysis by TMN stage detected significant differences in the early stages (median OS [mOS]: P = 0.0128; median PFS [mPFS]: P = 0.0209) and advanced stages (mOS and mPFS: both P values < 0.001). Adjuvant therapy was also identified as a significantly favorable prognostic factor for OS and PFS in the early stages and advanced stages.ConclusionPostoperative adjuvant therapy can improve the prognosis of patients with CCA, even in the early stages and advanced stages. All data suggest that adjuvant therapy should be incorporated into the treatment of CCA in all cases, where appropriate.

A fast, reliable, and cost-effective liquid chromatography-tandem mass spectrometry method was established to determine the effects of the traditional Chinese medicine employed to treat coronavirus disease 2019, namely, Lianhua Qingwen granules, Huoxiang Zhengqi capsules, Jinhua Qinggan granules, Shufeng Jiedu capsules, and Angong Niuhuang pills, on the pharmacokinetics of lopinavir/ritonavir in rats. Blood samples were prepared using the protein precipitation method and atazanavir was selected as the internal standard (IS). Separation was performed on an Agilent ZORBAX eclipse plus C18 (2.1 mm × 50 mm, 1.8 μm) column using acetonitrile and water containing 0.1% formic acid as the mobile phase for gradient elution. The flow rate was 0.4 mL/min and the injection volume was 2 μL. Agilent Jet Stream electrospray ionization was used for mass spectrometry detection under positive ion multiple reaction monitoring mode at a transition of m/z 629.3→447.3 for lopinavir, m/z 721.3→296.1 for ritonavir, and m/z 705.4→168.1 for the IS. The method showed good linearity in the concentration range of 25–2500 ng/mL (r=0.9981) for lopinavir and 5–500 ng/mL (r=0.9984) for ritonavir. The intra-day and inter-day precision and accuracy were both within ±15%. Items, such as dilution reliability and residual effect, were also within the acceptable limits. The method was used to determine the effects of five types of traditional Chinese medicines on the pharmacokinetics of lopinavir/ritonavir in rats. The pharmacokinetic results showed that the half-life of ritonavir in the groups administered Lianhua Qingwen granules and Huoxiang Zhengqi capsules combined with lopinavir/ritonavir was prolonged by approximately 1.5- to 2-fold relative to that in the control group. Similarly, the pharmacokinetic parameters of lopinavir were altered. Overall, the results of this study offer important theoretical parameters for the effective clinical use of five types of traditional Chinese medicines combined with lopinavir/ritonavir to reduce the occurrence of clinical adverse reactions.

Aiming at the practical problems of external unknown disturbance and internal modeling uncertainty, when space tumbling target flies around in close range, a sliding mode controller (SMC) based on active disturbance rejection control (ADRC) technology is proposed to realize real-time estimation and compensation of “total disturbance.” Firstly, according to the motion characteristics of space tumbling target, the relative motion equation in rotating line of sight (RLOS) coordinate system is established; Secondly, the compound controller is designed, and the convergence of the nonlinear state expansion observer and the stability of the closed-loop system are analyzed based on the root locus method and Lyapunov function method respectively; Finally, the simulation results show that the SMC based on ADRC technology can effectively suppress the disturbance and overcome the chattering problem of traditional sliding mode controller. It has a good control quality, and strong robustness is an easy method for engineering practice.

Tumor resistance to apoptosis and the immunosuppressive tumor microenvironment are two main reasons for the poor outcomes of tumor treatment. Pyroptosis is a newly discovered form of programmed cell death, featuring surprising proinflammatory activity. Recent evidence shows that tumor cell pyroptosis leads to strong inflammatory responses and significant tumor regression, which is different from apoptotic cell death. Strategies based on different types of nanoparticles for pyroptosis induction have become a useful tool for tumor treatment. Reactive oxygen species (ROS) is considered an efficient way to cause pyroptosis, and ROS‐based nanotechnologies have been a powerful strategy for pyroptosis induction and cancer treatments. This review covers recent progress in ROS‐induced pyroptosis and nanotherapy to trigger ROS‐mediated pyroptosis in cancer.

Air pollution is a significant urban issue, with practical applications for pollution control, urban environmental management planning, and urban construction. However, owing to the complexity and differences in spatiotemporal changes for various types of pollution, it is challenging to establish a framework that can capture the spatiotemporal correlations of different types of air pollution and obtain high prediction accuracy. In this paper, we proposed a deep learning framework suitable for predicting various air pollutants: a graph convolutional temporal sliding long short-term memory (GT-LSTM) model. The hybrid integrated model combines graph convolutional networks and long short-term networks based on a strategy with temporal sliding. Herein, the graph convolution networks gather neighbor information for spatial dependency modeling based on the spatial adjacency matrices of different pollutants and the graph convolution operator with parameter sharing. LSTM networks with a temporal sliding strategy are used to learn dynamic air pollution changes for temporal dependency modeling. The framework was applied to predict the average concentrations of PM2.5, PM10, O3, CO, SO2, and NO2 in the Bejing-Tianjin-Hebei (BTH) region for the next 24 hours. Experiments demonstrated that the proposed GT-LSTM model could extract high-level spatiotemporal features and achieve higher accuracy and stability than state-of-the-art baselines. Advancement in this methodology can assist in providing decision support capabilities to mitigate air quality issues.

Abstract Background Circular RNAs (circRNAs), which are endogenous non-coding RNAs, are associated with various biological processes including development, homeostatic maintenance, and pathological responses. Accumulating evidence has implicated non-coding RNAs in cancer progression, and the role of circRNAs in particular has drawn wide attention. However, circRNA expression patterns and functions in hepatocellular carcinoma (HCC) remain poorly understood. Methods CircRNA sequencing was performed to screen differentially expressed circRNAs in HCC. Northern blotting, quantitative real-time polymerase chain reaction, nucleocytoplasmic fractionation, and fluorescence in situ hybridization analyses were conducted to evaluate the expression and localization of circSLC7A11 in HCC tissues and cells. CircSLC7A11 expression levels were modified in cultured HCC cell lines to explore the association between the expression of circSLC7A11 and the malignant behavior of these cells using several cell-based assays. The modified cells were implanted into immunocompetent nude mice to assess tumor growth and metastasis in vivo. We applied bioinformatics methods, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays to explore the mechanisms of circSLC7A11 in HCC. Results CircSLC7A11 (hsa_circ_0070975) was conserved and dramatically overexpressed in HCC tissues and cells. HCC patients showing high circSLC7A11 expression had worse prognoses. Our in vitro and in vivo experiments showed that circSLC7A11 markedly accelerated HCC progression and metastasis through the circSLC7A11/miR-330-3p/CDK1 axis. Conclusions The acceleration of HCC progression and metastasis by circSLC7A11 through the circSLC7A11/miR-330-3p/CDK1 axis suggests that circSLC7A11 is a potential novel diagnostic and therapeutic target for HCC treatment.

Abstract Humans have a limited postinjury regenerative ability. Therefore, cell-derived biomaterials have long been utilized for tissue repair. Cells with multipotent differentiation potential, such as stem cells, have been administered to patients for the treatment of various diseases. Researchers expected that these cells would mediate tissue repair and regeneration through their multipotency. However, increasing evidence has suggested that in most stem cell therapies, the paracrine effect but not cell differentiation or regeneration is the major driving force of tissue repair. Additionally, ethical and safety problems have limited the application of stem cell therapies. Therefore, nonliving cell-derived techniques such as extracellular vesicle (EV) therapy and cell membrane-based therapy to fulfil the unmet demand for tissue repair are important. Nonliving cell-derived biomaterials are safer and more controllable, and their efficacy is easier to enhance through bioengineering approaches. Here, we described the development and evolution from cell therapy to EV therapy and cell membrane-based therapy for tissue repair. Furthermore, the latest advances in nonliving cell-derived therapies empowered by advanced engineering techniques are emphatically reviewed, and their potential and challenges in the future are discussed. Graphical Abstract

Background: With the increasing popularity of traditional Chinese medicine (TCM) by the global community, how to teach basic knowledge of TCM to international students and improve the teaching quality are important issues for teachers of TCM. The present study was to analyze the perceptions from both students and teachers on how to improve TCM learning internationally. Methods: A cross-sectional national survey was conducted at 23 universities/colleges across China. A structured, self-reported on-line questionnaire was administered to 34 Chinese teachers who taught TCM course in English and to 1016 international undergraduates who were enrolled in the TCM course in China between 2017 and 2021. Results: Thirty-three (97.1%) teachers and 900 (88.6%) undergraduates agreed Chinese culture should be fully integrated into TCM courses. All teachers and 944 (92.9%) undergraduates thought that TCM had important significance in the clinical practice. All teachers and 995 (97.9%) undergraduates agreed that modern research of TCM is valuable. Thirty-three (97.1%) teachers and 959 (94.4%) undergraduates thought comparing traditional medicine in different countries with TCM can help the students better understand TCM. Thirty-two (94.1%) teachers and 962 (94.7%) undergraduates agreed on the use of practical teaching method with case reports. From the perceptions of the undergraduates, the top three beneficial learning styles were practice (34.3%), teacher's lectures (32.5%), case studies (10.4%). The first choice of learning mode was attending to face-to-face teaching (82.3%). The top three interesting contents were acupuncture (75.5%), Chinese herbal medicine (63.8%), and massage (55.0%). Conclusion: To improve TCM learning among international undergraduates majoring in conventional medicine, integration of Chinese culture into TCM course, comparison of traditional medicine in different countries with TCM, application of the teaching method with case reports, and emphasization of clinical practice as well as modern research on TCM should be fully considered.

Background: Intrahepatic Cholangiocarcinoma (iCCA) is a highly malignant tumor with limited treatment options that contributes largely to cancer-related deaths worldwide. Compared with traditional transcriptomic analysis, single-cell RNA sequencing (scRNA-seq) is emerging as a more advanced and popular tool for the in-depth exploration of cellular diversity and molecular complexity. As a next-generation proteasome inhibitor, MLN2238 presents better pharmacodynamics, pharmacokinetics, and therapeutic responses in various cancers. However, its effects and mechanisms of action in iCCA remain unknown.Methods: iCCA tumor heterogeneity was determined based on 4,239 qualified scRNA-seq data from 10 iCCA samples. The potential biological roles of proteasome-related genes in iCCA were investigated using a pseudo-trajectory reconstruction. The effect of MLN2238 on iCCA cell proliferation was estimated using the CCK-8, EdU, and clone formation assays. Flow cytometry was used to examine the effect of added MLN2238 on cell cycle and apoptosis levels. Autophagic flux was detected using AdPlus-mCherry-GFP-LC3B cells. ROS levels and mitochondrial membrane potential were determined using DCFH-DA probing and JC-1 staining. JNK activation and mitochondrial apoptosis were observed using western blotting and immunofluorescence microscopy, respectively. Finally, we used a tumor-bearing mouse model to validate its efficacy in vivo for iCCA treatment.Results: Proteasome-related genes were dysregulated in iCCA progression and expressed at higher levels in tumor tissues. MLN2238 suppressed cell proliferation, blocked the cell cycle in the G2/M phase, promoted apoptosis, and induced cytoprotective autophagy in iCCA cells. Furthermore, MLN2238 increased ROS levels and activated the JNK signaling pathway. Inhibition of ROS and JNK activation by NAC and SP600125 significantly reversed MLN2238-induced apoptosis. MLN2238 also suppressed the growth of iCCA tumors in vivo.Conclusion: Proteasome-related genes play pivotal roles in iCCA development. MLN2238, as a proteasome inhibitor, induces apoptosis in iCCA cells through ROS/JNK/mitochondrial signaling pathways, and hence, making MLN2238 a potential therapeutic choice for iCCA.

Since the discovery of the nuclear factor kappa B (NF-ĸB) transcription factor 36 years ago, many studies have linked the NF-ĸB signaling pathway to pathological and physiological processes, such as inflammation, immune response, and tumorigenesis. However, as the NF-ĸB signaling pathway is evolutionarily conserved from flies to humans, an increasing number of studies have focused on the impact of NF-ĸB signaling on developmental processes. While our understanding of the mechanisms underlying NF-ĸB signaling involved in tissue and organ development is limited, the numerous studies conducted in recent years have provided preliminary insights into these molecular mechanisms. In this review, we summarize the latest information on the molecular mechanisms behind NF-ĸB signaling involved in tissue and organ development, highlighting the role and significance of the NF-ĸB signaling pathway in developmental processes. This review elucidates the fact that the development of nearly all tissues is associated with NF-ĸB signaling, either directly or indirectly.

Peroxidasin (PXDN), also known as vascular peroxidase-1, is a newly discovered heme-containing peroxidase; it is involved in the formation of extracellular mesenchyme, and it catalyzes various substrate oxidation reactions in humans. However, the role and specific mechanism of PXDN in tumor are unclear, and no systematic pan-cancer studies on PXDN have been reported to date. This study employed data from multiple databases, including The Cancer Genome Atlas and The Genotype-Tissue Expression, to conduct a specific pan-cancer analysis of the effects of PXDN expression on cancer prognosis. Further, we evaluated the association of PXDN expression with DNA methylation status, tumor mutation burden, and microsatellite instability. Additionally, for the first time, the relationship of PXDN with the tumor microenvironment and infiltration of fibroblasts and different immune cells within different tumors was explored, and the possible molecular mechanism of the effect was also discussed. Our results provide a comprehensive understanding of the carcinogenicity of PXDN in different tumors and suggest that PXDN may be a potential target for tumor immunotherapy, providing a new candidate that could improve cancer clinical diagnosis and treatment.

Background: Circular RNA (circRNA) is a newly-discovered endogenous transcript that has been reported to participate in osteosarcoma (OS) progression. However, the underlying mechanism of circ_0051079 modulating OS development remains unclear. Methods: RNA expressions of circ_0051079, miR-625-5p and tripartite motif containing 66 (TRIM66) were detected by quantitative real-time polymerase chain reaction. Protein expression was checked by Western blot analysis. The functional effects of circ_0051079 on OS cell malignancy were investigated by cell counting kit-8, clonogenicity, transwell, tube formation and flow cytometry assays. The interactions among circ_0051079, miR-625-5p and TRIM66 were identified by dual-luciferase reporter and RNA immunoprecipitation assays. Mouse xenograft model assay was performed to elucidate the effects of circ_0051079 knockdown on tumor formation in vivo. Results: Circ_0051079 and TRIM66 expressions were significantly upregulated, but miR-625-5p was downregulated in OS tissues and cells compared with control groups. Circ_0051079 expression was significantly associated with tumor-node-metastasis stage and tumor size of OS patients. Circ_0051079 knockdown inhibited OS cell proliferation, migration and invasion, repressed angiogenesis but induced cell apoptosis, accompanied by the decreases of PCNA and Bcl-2 production and an increase of Bax production. MiR-625-5p, a target miRNA of circ_0051079, participated in regulating circ_0051079-induced effects. Also, TRIM66 was identified as a target mRNA of miR-625-5p, and partially attenuated the inhibitory effects of miR-625-5p in OS cells. Circ_0051079 modulated the Wnt/β-catenin pathway through TRIM66 in vitro. Importantly, circ_0051079 silencing reduced TRIM66 expression by interacting with miR-625-5p. Further, circ_0051079 depletion inhibited tumor formation in vivo. Conclusion: Circ_0051079 regulated OS development by the miR-625-5p/TRIM66/Wnt/β-catenin pathway, providing a novel therapeutic target for OS.

Ecological security patterns (ESPs) provide a solution for balancing the conflicts between ecological conservation and socio-economic development and maintaining sustainable regional development. Identifying sustainable ESPs should be a matter given attention to in order to meet future urban expansion needs. Based on multi-source eco-environmental datasets and remote sensing (RS) containing the history of land-use patterns, our study incorporated future land-use patterns into the ESP identification framework to reduce the potential impact of future urban expansion on the identified ESPs (i.e., ecological corridors and nodes) and to reserve space for future urban development from an urban development perspective. Considering the Changsha–Zhuzhou–Xiangtan (CZX) urban agglomeration, the results show that 57 corridors are extracted, within which 36 key corridors are mainly distributed in the Lukou and Wangcheng districts and Xiangtan and Changsha counties; an additional 21 potential corridors are mainly distributed in the urban built-up area and these corridors connect to Xiangjiang River or its tributary. In addition, 18 pinch points were identified, mainly located adjacent to the Xiangjiang River, Liuyang River, and Laodao River; 9 barrier points are distributed at the junctions of the main roads. A comparison of ESP identification with and without simulated land-use patterns showed the incorporation of future land-use patterns favoured sustainable ESP construction. Furthermore, we discuss the rationality and application of ESP identification from an urban development perspective and emphasize the trade-off between future land-use patterns and ecological conservation, better reflecting the forward-looking thinking of spatial planning.

Abstract Background Gastrointestinal stromal tumor (GIST) is a common tumor that originates from the alimentary system mesenchyme. Compared to typical gastrointestinal carcinomas, GISTs exhibit unique malignant behaviors. Bioinformatic tools and subsequent experiments were applied to investigate novel targets involved in GIST progression and imatinib resistance. Methods Differences in gene expression profiles between advanced and nonadvanced GISTs were comprehensively analyzed based on the Gene Expression Omnibus (GEO) dataset GSE136755. A protein–protein interaction (PPI) network was constructed to identify the potential target gene. Gene set enrichment analysis (GSEA) was used to elucidate relevant biological events related to the target gene based on the GSE47911 dataset. Subsequently, immunohistochemistry and Kaplan–Meier analysis were performed to validate the prognostic value of the target gene in GISTs. Overexpression of the target gene was conducted to analyze its function in the proliferation, apoptosis, and imatinib resistance of GIST/T1 cells. Results In the current study, a total of 606 differentially expressed genes (DEGs) were screened based on the GSE136755 dataset, and the upregulated DEGs in advanced GISTs were mainly involved in cell division through functional annotations. The intersecting hub gene, Aurora kinase A (AURKA), was identified by degree and bottleneck algorithms. GSEA revealed that AURKA was involved in cell cycle-related biological processes. Analysis of the Oncomine and GEPIA databases revealed a pattern of elevated AURKA expression in most human malignances. Clinical assays demonstrated that AURKA could be an independent prognostic factor for GISTs. Additionally, overexpression of AURKA was experimentally demonstrated to promote cell proliferation, inhibit cell apoptosis, and enhance imatinib resistance in GIST/T1 cells. Conclusions These findings indicated that overexpression of AURKA promoted GIST progression and enhanced imatinib resistance, implying that AURKA is a potential therapeutic target for GISTs.

Abstract. Acute pancreatitis (AP) is a common acute abdominal condition of the digestive system. In recent years, treatment concepts, methods, and strategies for the diagnosis of AP have advanced, and this has played an important role in promoting the standardization of AP diagnosis and treatment and improving the treatment quality of AP patients. On the basis of previous guidelines and expert consensus, this guideline adopts an evidence-based, problem-based expression; synthesizes important clinical research data at home and abroad in the most recent 5 years; and forms 29 recommendations through multidisciplinary expert discussion, including diagnosis, treatment, and follow-up. It is expected to provide evidence support for the treatment of AP in the clinical setting in China.

Abstract. The incidence of pancreatic cancer has been rising worldwide, and its clinical diagnosis and treatment remain a great challenge. To present the update and improvements in the clinical diagnosis and treatment of pancreatic cancer in recent years, Chinese Pancreatic Association, the Chinese Society of Surgery, Chinese Medical Association revised the Guidelines for the Diagnosis and Treatment of Pancreatic Cancer in China (2014) after reviewing evidence-based and problem-oriented literature published during 2015–2021, mainly focusing on highlight issues regarding diagnosis and surgical treatment of pancreatic cancer, conversion strategies for locally advanced pancreatic cancer, treatment of pancreatic cancer with oligo metastasis, adjuvant and neoadjuvant therapy, standardized processing of surgical specimens and evaluation of surgical margin status, systemic treatment for unresectable pancreatic cancer, genetic testing, as well as postoperative follow up of patients with pancreatic cancer. Forty recommendation items were finally proposed based on the above issues, and the quality of evidence and strength of recommendations were graded using the Grades of Recommendation, Assessment, Development, and Evaluation system. This guideline aims to standardize the clinical diagnosis and therapy, especially surgical treatment of pancreatic cancer in China, and further improve the prognosis of patients with pancreatic cancer.

Immunocyte migration to infection sites is important for host cellular defense, but the main types of migrating hemocytes and their mechanisms against pathogen invasions are unclear in invertebrates. In the present study, a population of hemocytes in the Pacific oyster Crassostrea gigas labeled with a fluorescein isothiocyanate (FITC)-conjugated Arg-Gly-Asp (RGD)-containing peptide was sorted. RGD+ hemocytes were characterized by a smaller cell size and cytoplasmic-nucleo ratio, fewer cytoplasmic granules, and higher levels of myeloperoxidase, reactive oxygen species, and intracellular free calcium concentration. RGD+ hemocytes exhibited a high level of migration activity, which was further induced after V. splendidus infection. Transcriptome analysis revealed that RGD+ hemocytes highly expressed a series of migration-related genes, which together with migration-promoting genes were significantly upregulated after V. splendidus infection. The neuroendocrine system was also proven to regulate the migration activity of RGD+ hemocytes, especially with the excitatory neuroendocrine factor dopamine, which promoted migration activity as confirmed by receptor blocking assays. Meanwhile, RGD+ hemocytes could highly express immunomodulatory factor interleukin (IL)-17s and their receptor genes, which was positively related to the production of antimicrobial peptides in whole hemocytes after V. splendidus infection. Collectively, this study identified a specific hemocyte population, i.e., RGD+ hemocytes, that shows high migration activity in response to pathogen infection and exerts a potential immunomodulatory role by highly expressing IL-17s that might enhance the hemocytes’ antimicrobial peptide production in oysters.

Claudin 18.2 (CLDN18.2), a tight junction (TJ) family protein controlling molecule exchange between cells, is frequently over-expressed in gastric cancer, pancreatic adenocarcinomas and in a fraction of non–small cell lung cancer cases. The tumor properties indicate that CLDN18.2 could be an attractive drug target for gastric and pancreatic cancers. In this study, we present effective strategies for developing anti-CLDN18.2 therapeutic candidates, based on variable domain of heavy chain of heavy chain antibodies (VHHs). CLDN18.2-specific VHHs were isolated by panning a phage display library from an alpaca immunized with a stable cell line highly expressing CLDN18.2. Humanized VHHs fused with human IgG1 Fc, as potential therapeutic candidates, exhibited desirable binding specificity and affinity to CLDN18.2. In vitro experiments showed that hu7v3-Fc was capable of eliciting both antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) on CLDN18.2 positive tumor cells. In the mouse xenograft model, the anti-tumor efficacy of hu7v3-Fc was significantly more potent than Zolbetuximab, the benchmark anti-CLDN18.2 monoclonal antibody. Moreover, in vivo biodistribution using zirconium-89 (89Zr) labeled antibodies demonstrated that hu7v3-Fc (89Zr-hu7v3-Fc) exhibited a better tumor penetration and a faster tumor uptake than Zolbetuximab (89Zr-Zolbetuximab), which might be attributed to its smaller size and higher affinity. Taken together, anti-CDLN18.2 hu7v3-Fc is a promising therapeutic agent for human CLDN18.2 positive cancers. Furthermore, hu7v3 has emerged as a potential module for novel CLDN18.2 related therapeutics.

BackgroundPulmonary infection is a leading cause of mortality in pediatric patients with hematologic malignancy (HM). In clinical settings, pulmonary pathogens are frequently undetectable, and empiric therapies may be costly, ineffective and lead to poor outcomes in this vulnerable population. Metagenomic next-generation sequencing (mNGS) enhances pathogen detection, but data on its application in pediatric patients with HM and pulmonary infections are scarce.MethodsWe retrospectively reviewed 55 pediatric patients with HM and pulmonary infection who were performed mNGS on bronchoalveolar lavage fluid from January 2020 to October 2021. The performances of mNGS methods and conventional microbiological methods in pathogenic diagnosis and subsequently antibiotic adjustment were investigated.ResultsA definite or probable microbial etiology of pulmonary infection was established for 50 of the 55 patients (90.9%) when mNGS was combined with conventional microbiological tests. The positive rate was 87.3% (48 of 55 patients) for mNGS versus 34.5% (19 of 55 patients) with conventional microbiological methods (P < 0.001). Bacteria, viruses and fungi were detected in 17/55 (30.9%), 25/55 (45.5%) and 19/55 (34.5%) cases using mNGS, respectively. Furthermore, 17 patients (30.9%) were identified as pulmonary mixed infections. Among the 50 pathogen-positive cases, 38% (19/50) were not completely pathogen-covered by empirical antibiotics and all of them were accordingly made an antibiotic adjustment. In the present study, the 30-day mortality rate was 7.3%.ConclusionmNGS is a valuable diagnostic tool to determine the etiology and appropriate treatment in pediatric patients with HM and pulmonary infection. In these vulnerable children with HM, pulmonary infections are life-threatening, so we recommend that mNGS should be considered as a front-line diagnostic test.