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Abstract Prostaglandin I2 synthase (PTGIS) is a member of the cytochrome P450 family. Studies have revealed that differential expression of the PTGIS gene is closely related to the pathological and physiological processes of many diseases, including breast cancer, oral squamous cell carcinoma, and head and neck cancer. However, the mechanism of action of the PTGIS gene in colorectal cancer is not fully understood. This study explored the role of PTGIS in colorectal cancer through comprehensive bioinformatics analysis and in vitro experiments, and found that the expression of PTGIS gene in colorectal cancer tissue was significantly lower than that in normal colorectal tissue (P

Abstract Research on biomarker-driven therapy and immune check-point blockade in non-small cell lung cancer (NSCLC) is rapidly evolving. The width and depth of clinical trials have also dramatically improved in an unprecedented speed. The personalized treatment paradigm evolved every year. In this review, we summarize the promising agents that have shifted the treatment paradigm for NSCLC patients across all stages, including targeted therapy and immunotherapy using checkpoint inhibitors. Based on recent evidence, we propose treatment algorithms for NSCLC and propose several unsolved clinical issues, which are being explored in ongoing clinical trials. The results of these trials are likely to impact future clinical practice.

Abstract Background ADJUVANT-CTONG1104 reported a favorable survival outcome from adjuvant gefitinib treatment over chemotherapy in EGFR-mutant non-small cell lung cancer (NSCLC) patients. However, heterogeneous benefit from EGFR-TKIs and chemotherapy demands further biomarker exploration for patient selection. Previously, we identified certain TCR sequences with predictive value for adjuvant therapies from the CTONG1104 trial and found a relationship between the TCR repertoire and genetic variations. It remains unknown which TCR sequences could further enhance the prediction for only adjuvant EGFR-TKI. Methods In this study, 57 tumor and 12 tumor-adjacent samples, respectively, from gefitinib-treated patients in the CTONG1104 were collected for TCR β gene sequencing. We attempted to constitute a predictive model for prognosis and favorable adjuvant EGFR-TKI outcome for patients with early-stage NSCLC and EGFR mutations. Results The TCR rearrangements demonstrated significant prediction for overall survival (OS). A combined model of high frequent Vβ7-3Jβ2-5 and Vβ24-1Jβ2-1 with lower frequent Vβ5-6Jβ2-7 and Vβ28Jβ2-2 constituted the best value for predicting OS (P

The efficacy of immunotherapy in advanced HER2‐mutated non‐small‐cell lung cancer (NSCLC) remains incomprehensively studied. A total of 107 NSCLC patients with de novo HER2 mutations were retrospectively studied at Guangdong Lung Cancer Institute [GLCI cohort, exon 20 insertions (ex20ins): 71.0%] to compare clinical/molecular features and immune checkpoint inhibitor (ICI)‐based therapy efficacy between patients with ex20ins and non‐ex20ins. Two external cohorts (TCGA, n = 21; META‐ICI, n = 30) were used for validation. In the GLCI cohort, 68.2% of patients displayed programmed death‐ligand 1 (PD‐L1) expression

Abstract Medial arterial calcification (MAC), a systemic vascular disease different from atherosclerosis, is associated with an increased incidence of cardiovascular events. Several studies have demonstrated that ambient temperature is one of the most important factors affecting cardiovascular events. However, there has been limited research on the effect of different ambient temperatures on MAC. In the present study, we showed that cold temperature exposure (CT) in mice slowed down the formation of vitamin D (VD)-induced vascular calcification compared with room temperature exposure (RT). To investigate the mechanism involved, we isolated plasma-derived exosomes from mice subjected to CT or RT for 30 days (CT-Exo or RT-Exo, respectively). Compared with RT-Exo, CT-Exo remarkably alleviated the calcification/senescence formation of vascular smooth muscle cells (VSMCs) and promoted autophagy by activating the phosphorylation of AMP-activated protein kinase (p-AMPK) and inhibiting phosphorylation of mammalian target of rapamycin (p-mTOR). At the same time, CT-Exo promoted autophagy in β-glycerophosphate (β-GP)-induced VSMCs. The number of autophagosomes and the expression of autophagy-related proteins ATG5 and LC3B increased, while the expression of p62 decreased. Based on a microRNA chip microarray assay and real-time polymerase chain reaction, miR-320a-3p was highly enriched in CT-Exo as well as thoracic aortic vessels in CT mice. miR-320a-3p downregulation in CT-Exo using AntagomiR-320a-3p inhibited autophagy and blunted its anti-calcification protective effect on VSMCs. Moreover, we identified that programmed cell death 4 (PDCD4) is a target of miR-320a-3p, and silencing PDCD4 increased autophagy and decreased calcification in VSMCs. Treatment with CT-Exo alleviated the formation of MAC in VD-treated mice, while these effects were partially reversed by GW4869. Furthermore, the anti-arterial calcification protective effects of CT-Exo were largely abolished by AntagomiR-320a-3p in VD-induced mice. In summary, we have highlighted that prolonged cold may be a good way to reduce the incidence of MAC. Specifically, miR-320a-3p from CT-Exo could protect against the initiation and progression of MAC via the AMPK/mTOR autophagy pathway. Graphic Abstract

Abstract Background Placenta accreta spectrum (PAS) disorder is a major cause of postpartum hemorrhage-associated maternal and fetal death, and novel methods for PAS screening are urgently needed for clinical application. Methods The purpose of this study was to develop new methods for PAS screening using serum biomarkers and clinical indicators. A total of 95 PAS cases and 137 controls were enrolled in a case–control study as cohort one, and 44 PAS cases and 35 controls in a prospective nested case–control study were enrolled as cohort two. All subjects were pregnant women of Chinese Han population. Biomarkers for PAS from maternal blood samples were screened based on high-throughput immunoassay and were further validated in three phases of cohort one. Screening models for PAS were generated using maternal serum biomarkers and clinical indicators, and were validated in two cohorts. The expression levels of biomarkers were analyzed using histopathological and immunohistochemical (IHC) techniques, and gene expression was examined by QPCR in the human placenta. Binary logistic regression models were built, and the area under the curve (AUC), sensitivity, specificity, and Youden index were calculated. Statistical analyses and model building were performed in SPSS and graphs were generated in GraphPad Prism. The independent-sample t test was used to compare numerical data between two groups. For nonparametric variables, a Mann–Whitney U test or a X 2 test was used. Results The results demonstrated that the serum levels of matrix metalloproteinase-1 (MMP-1), epidermal growth factor (EGF), and vascular endothelial growth factor-A (VEGF-A) were consistently higher, while the level of tissue-type plasminogen activator (tPA) was significantly lower in PAS patients compared with normal term controls and patients with pre-eclampsia (PE) and placenta previa (PP). IHC and QPCR analysis confirmed that the expression of the identified biomarkers significantly changed during the third trimester in human placenta. The generated screening model combining serum biomarkers and clinical indicators detected 87% of PAS cases with AUC of 0.94. Conclusions Serum biomarkers can be used for PAS screening with low expense and high clinical performance; therefore, it may help to develop a practicable method for clinical prenatal PAS screening.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by diverse clinical features. EEG biomarkers such as spectral power and functional connectivity have emerged as potential tools for enhancing early diagnosis and understanding of the neural processes underlying ASD. However, existing studies yield conflicting results, necessitating a comprehensive, data-driven analysis. We conducted a retrospective cross-sectional study involving 246 children with ASD and 42 control children. EEG was collected, and diverse EEG features, including spectral power and spectral coherence were extracted. Statistical inference methods, coupled with machine learning models, were employed to identify differences in EEG features between ASD and control groups and develop classification models for diagnostic purposes. Our analysis revealed statistically significant differences in spectral coherence, particularly in gamma and beta frequency bands, indicating elevated long range functional connectivity between frontal and parietal regions in the ASD group. Machine learning models achieved modest classification performance of ROC-AUC at 0.65. While machine learning approaches offer some discriminative power classifying individuals with ASD from controls, they also indicate the need for further refinement.

With the rapid growth of computer technology and multimedia technology, VR technology is regularly developed and applied to entire walks of life. This paper first introduces the VR double master teaching model into the practical teaching of Civics in colleges and universities (CU) and analyzes the shortcomings and limitations of the traditional teaching design scheme. Secondly, under the guidance of constructivist learning theory and contextual cognitive theory, as well as the basic theory of humanistic theory, combined with the characteristics of venue learning, and also with the implementation of gesture interaction technology and face expression detection technology with the help of depth sensors, a teaching design scheme with immersion and interactivity based on red VR venues is designed. The results show that the response time of logging into the business through the performance test of the VR Civics teaching system is 5.239s - 3s, and the thinking time is 2.271 s, which is in line with the result of logging in less than 3 s. Moreover, the Civics performance of students taught through VR has improved by 11.2 percentage points, and the teaching effect and system performance are in line with the practice expectation. It shows that the virtual reality technology proposed in this paper and Civics teaching have achieved an effective combination and realized the fundamental purpose of implementing moral education.

As an extensively employed plasticizer in industrial applications, di-2-ethylhexyl phthalate (DEHP) can induce apoptosis of mouse Leydig cells, yet the precise mechanism remains elusive. In the current study, we identified that DEHP could specially induced apoptosis in the Leydig cells of the testis tissue, accompanied with the upregulation of apoptosis-related protein in the TGF-β signaling pathway (ARTS) in the cells. Overexpression of ARTS significantly induced apoptosis of TM3 cells, while knockdown of ARTS inhibited apoptosis. Furthermore, DEHP-induced apoptosis of TM3 cells could be alleviated by knockdown of ARTS, which indicated that ARTS was involved in DEHP-induced apoptosis of mouse Leydig cells. Bioinformation assay predicts that there are four potential p53-responsive elements (p53-REs) located at − 6060, − 5726, − 5631 and − 5554 before the transcription start site of ARTS gene, implying that gene transcription of ARTS could be regulated by p53. Interestingly, DEHP was shown to specifically upregulate the expression of p53 in the Leydig cells of the testis tissue and TM3 cells. Consistently, p53 was proved to bind to the RE4 site of the ARTS gene promoter and transcriptionally activated the promoter-driven expression of the luciferase reporter gene. Overexpression of p53 could induce apoptosis of TM3 cells; while knockdown of p53 could not only rescue DEHP-induced apoptosis of the cells, but also inhibit DEHP-caused upregulation of ARTS. Meanwhile, we showed that oxidative stress could induce apoptosis of TM3 cells, accompanied with the increased protein levels of p53 and ARTS; while inhibition of oxidative stress dramatically alleviated DEHP-induced apoptosis and the up-regulation of p53 and ARTS. Taken together, these results indicated that DEHP-induced oxidative stress activates the p53-ARTS cascade to promote apoptosis of mouse Leydig cells.

Background Older adults with asthma have the greatest burden and worst outcomes, and there is increasing evidence that chronic cough (CC) is associated with asthma severity and poor prognosis. However, the clinical characteristics of older adult patients with both asthma and CC remain largely unknown. Methods Participants with stable asthma underwent two cough assessments within 3 months to define the presence of CC. Patients were divided into four groups based on CC and age (cut-off ≥60 years). Multidimensional assessment was performed at baseline, followed by a 12-month follow-up to investigate asthma exacerbations. Logistic regression models were used to explore the interaction effect of CC and age on asthma control and exacerbations. Results In total, 310 adult patients were prospectively recruited and divided into four groups: older CC group (n=46), older non-CC group (n=20), younger CC group (n=112) and younger non-CC group (n=132). Compared with the younger non-CC group, the older CC group had worse asthma control and quality of life and increased airflow obstruction. The older CC group showed an increase in moderate-to-severe exacerbations during the 12-month follow-up. There was a significant interaction effect of CC and ageing on the increased moderate-to-severe exacerbations (adjusted risk ratio 2.36, 95% CI 1.47–3.30). Conclusion Older asthma patients with CC have worse clinical outcomes, including worse asthma control and quality of life, increased airway obstruction and more frequent moderate-to-severe exacerbations, which can be partly explained by the interaction between CC and ageing.

As one of the most important phthalates, di-isononyl phthalate (DINP) has been widely used as a common plasticizer in the food and personal care products sectors. In our previous study, we found that DINP can induce autophagy of ovarian granulosa cells; while the underlying mechanism is unclear. In the study, we showed that DINP exposure could induce autophagy of ovarian granulosa cells and KGN cells, accompanied with the increase in the mRNA and protein level of DDIT4. Furthermore, overexpression of DDIT4 were shown to induce autophagy of KGN cells; while knockdown of DDIT4 inhibited DINP-induced autophagy, implying that DDIT4 played an important role in DINP-induced autophagy of ovarian granulosa cells. There were three putative binding sites of transcription factor ATF4 in the promoter region of DDIT4 gene, suggesting that DDIT4 might be regulated by ATF4. Herein, we found that overexpression of ATF4 could upregulate the expression of DDIT4 in KGN cells, while knockdown of ATF4 inhibited its expression. Subsequently, ATF4 was identified to bind to the promoter region of DDIT4 gene and promote its transcription. The expression of ATF4 was also increased in the DINP-exposed granulosa cells, and ATF4 overexpression promoted autophagy of KGN cells; whereas knockdown of ATF4 alleviated DINP-induced upregulation of DDIT4 and autophagy of the cells. Taken together, DINP triggered autophagy of ovarian granulosa cells through activating ATF4/DDIT4 signals.

γ-Hydroxyalkenals, 4-hydroxynonenal (HNE) and phospholipid esters of 4-hydroxy-8-oxooctenoic acid (HOOA-PL), are produced from the alkyl and carboxyl termini of arachidonyl phospholipids by radical-induced oxidative cleavage. Metabolism of HNE by Michael addition of glutathione (GSH) followed by reduction of the aldehyde carbonyl produces a GSH derivative of 1,4-dihydroxynonane (DHN)-GSH. Analogous biochemistry was anticipated to produce a GSH derivative of 5,8-dihydroxyoctanoic acid (DHOA-GSH) that has structural and functional similarity to the cysteinyl leukotriene (LT)C4. We now report that exposure of human retinal pigment epithelial cells to CoCl2, an in vitro model of hypoxia-induced oxidative stress, generates DHOA-GSH and two products of its peptidolysis, DHOA-CysGly and DHOA-Cys that resemble LTD4 and LTE4. Identification of these metabolites was confirmed by unambiguous chemical syntheses that also provided a heavy isotope labeled quantitative standard 13C215N-DHOA-GSH. The availability of pure samples of these arachidonate metabolites will enable assessment of their biological activities, and testing the hypothesis that øLTs promote pathological inflammation by serving as LT receptor agonists. Because LT biosynthetic enzymes, e.g., 5-lipoxygenase, are not involved in the generation of øLTs in vivo, inhibitors of LT biosynthesis, e.g., Zileuton, are not expected to prevent the generation of øLTs. On the other hand, if øLTs are leukotriene receptor agonists, then the therapeutic effects of leukotriene receptor antagonist drugs, e.g., Montelukast, may include inhibition not only of LT-induced but also øLT-induced LT receptor activation and signaling.

BackgroundLinezolid (LZD) is bactericidal against Mycobacterium tuberculosis, but it has treatment-limiting toxicities. A better understanding of exposure-response relationships governing LZD efficacy and toxicity will inform dosing strategies. Because in vitro monotherapy studies yielded conflicting results, we explored LZD pharmacokinetic/pharmacodynamic (PK/PD) relationships in vivo against actively and nonactively multiplying bacteria, including in combination with pretomanid.MethodsLinezolid multidose pharmacokinetics were modeled in mice. Dose-fractionation studies were performed in acute (net bacterial growth) and chronic (no net growth) infection models. In acute models, LZD was administered alone or with bacteriostatic or bactericidal pretomanid doses. Correlations between PK/PD parameters and lung colony-forming units (CFUs) and complete blood counts were assessed.ResultsOverall, time above minimum inhibitory concentration (T>MIC) correlated best with CFU decline. However, in growth-constrained models (ie, chronic infection, coadministration with pretomanid 50 mg/kg per day), area under the concentration-time curve over MIC (AUC/MIC) had similar explanatory power. Red blood cell counts correlated strongly with LZD minimum concentration (Cmin).ConclusionsAlthough T>MIC was the most consistent correlate of efficacy, AUC/MIC was equally predictive when bacterial multiplication was constrained by host immunity or pretomanid. In effective combination regimens, administering the same total LZD dose less frequently may be equally effective and cause less Cmin-dependent toxicity.

Porous nanofibrous membranes have ultrahigh specific surface areas and could be broadly employed in protein purification, enzyme immobilization, and biosensors with enhanced selectivity, sensitivity, and efficiency. However, large biomolecules, such as proteins, have hindered diffusion behavior in the micro-porous media, significantly reducing the benefits provided by the nanofibrous membranes. The study of protein diffusion in polyacrylonitrile (PAN) nanofibrous membranes produced under varied humidity and polymer concentration of electrospinning revealed that heterogeneous structures of the nanofibrous membranes possess much smaller effective pore sizes than the measured pore sizes, which significantly affects the diffusion of large molecules through the system though sizes of proteins and pH conditions also have great impacts. Only when the measured membrane pore size is at least 1000 times higher than the protein size, the diffusion behavior of the protein is predictable in the system. The results provide insights into the design and applications of proper nanofibrous materials for improved applications in protein purification and immobilizations.

Abstract Background Reconstruction of damaged tissues requires both surface hemostasis and tissue bridging. Tissues with damage resulting from physical trauma or surgical treatments may have arbitrary surface topographies, making tissue bridging challenging. Methods This study proposes a tissue adhesive in the form of adhesive cryogel particles (ACPs) made from chitosan, acrylic acid, 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS). The adhesion performance was examined by the 180-degree peel test to a collection of tissues including porcine heart, intestine, liver, muscle, and stomach. Cytotoxicity of ACPs was evaluated by cell proliferation of human normal liver cells (LO2) and human intestinal epithelial cells (Caco-2). The degree of inflammation and biodegradability were examined in dorsal subcutaneous rat models. The ability of ACPs to bridge irregular tissue defects was assessed using porcine heart, liver, and kidney as the ex vivo models. Furthermore, a model of repairing liver rupture in rats and an intestinal anastomosis in rabbits were established to verify the effectiveness, biocompatibility, and applicability in clinical surgery. Results ACPs are applicable to confined and irregular tissue defects, such as deep herringbone grooves in the parenchyma organs and annular sections in the cavernous organs. ACPs formed tough adhesion between tissues [(670.9 ± 50.1) J/m2 for the heart, (607.6 ± 30.0) J/m2 for the intestine, (473.7 ± 37.0) J/m2 for the liver, (186.1 ± 13.3) J/m2 for muscle, and (579.3 ± 32.3) J/m2 for the stomach]. ACPs showed considerable cytocompatibility in vitro study, with a high level of cell viability for 3 d [(98.8 ± 1.2) % for LO2 and (98.3 ± 1.6) % for Caco-2]. It has comparable inflammation repair in a ruptured rat liver (P = 0.58 compared with suture closure), the same with intestinal anastomosis in rabbits (P = 0.40 compared with suture anastomosis). Additionally, ACPs-based intestinal anastomosis (less than 30 s) was remarkably faster than the conventional suturing process (more than 10 min). When ACPs degrade after surgery, the tissues heal across the adhesion interface. Conclusions ACPs are promising as the adhesive for clinical operations and battlefield rescue, with the capability to bridge irregular tissue defects rapidly.

Abstract Background Activated immune cells (IC) in the tumor microenvironment (TME) are critical for anti-tumor efficacy. Greater understanding of the dynamic diversity and crosstalk between IC is needed to clarify their association with immune checkpoint inhibitor efficacy. Methods Patients from three tislelizumab monotherapy trials in solid tumors (NCT02407990, NCT04068519, NCT04004221) were retrospectively divided into subgroups by CD8+ T-cell and macrophage (Mφ) levels, assessed via multiplex immunohistochemistry (mIHC; n = 67) or gene expression profiling (GEP; n = 629). Results A trend of longer survival was observed in patients with both high CD8+ T-cell and Mφ levels versus other subgroups in the mIHC analysis (P = 0.11), which was confirmed with greater statistical significance in the GEP analysis (P = 0.0001). Co-existence of CD8+ T cells and Mφ was coupled with elevated CD8+ T-cell cytotoxicity, T-cell trafficking, MHC class I antigen presentation signatures/genes, and enrichment of the pro-inflammatory Mφ polarization pathway. Additionally, a high level of pro-inflammatory CD64+ Mφ density was associated with an immune-activated TME and survival benefit with tislelizumab (15.2 vs. 5.9 months for low density; P = 0.042). Spatial proximity analysis revealed that closer proximity between CD8+ T cells and CD64+ Mφ was associated with a survival benefit with tislelizumab (15.2 vs. 5.3 months for low proximity; P = 0.024). Conclusions These findings support the potential role of crosstalk between pro-inflammatory Mφ and cytotoxic T cells in the clinical benefit of tislelizumab. Trial registration NCT02407990, NCT04068519, NCT04004221.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by diverse clinical features. EEG biomarkers such as spectral power and functional connectivity have emerged as potential tools for enhancing early diagnosis and understanding of the neural processes underlying ASD. However, existing studies yield conflicting results, necessitating a comprehensive, data-driven analysis. We conducted a retrospective cross-sectional study involving 246 children with ASD and 42 control children. EEG was collected, and diverse EEG features, including spectral power and spectral coherence were extracted. Statistical inference methods, coupled with machine learning models, were employed to identify differences in EEG features between ASD and control groups and develop classification models for diagnostic purposes. Our analysis revealed statistically significant differences in spectral coherence, particularly in gamma and beta frequency bands, indicating elevated long range functional connectivity between frontal and parietal regions in the ASD group. Machine learning models achieved modest classification performance of ROC-AUC at 0.65. While machine learning approaches offer some discriminative power classifying individuals with ASD from controls, they also indicate the need for further refinement. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii is a widely spread opportunistic pathogen that can infect nearly all warm-blooded vertebrates and cause serious toxoplasmosis in immunosuppressed animals and patients. However, the relationship between the host's innate immune system and effector proteins is poorly understood, particularly with regard to how effectors antagonize cGAS-STING signaling during T. gondii infection. In this study, the ROP5 from the PRU strain of T. gondii was found to promote cGAS-STING-mediated immune responses. Mechanistically, ROP5 interacted with STING through predicted domain 2 and modulated cGAS-STING signaling in a predicted domain 3-dependent manner. Additionally, ROP5 strengthened cGAS-STING signaling by enhancing the K63-linked ubiquitination of STING. Consistently, ROP5 deficient PRU (PRUΔROP5) induced fewer type I IFN-related immune responses and replicated faster than the parental strain in RAW264.7 cells. Taken together, this study provides new insights into the mechanism by which ROP5 regulates T. gondii infection and provides new clues for strategies to prevent and control toxoplasmosis. [ABSTRACT FROM AUTHOR]

Cyclodepsipeptides are a large family of peptide-related natural products consisting of hydroxy and amino acids linked by amide and ester bonds. A number of cyclodepsipeptides have been isolated and characterized from fungi and bacteria. Most of them showed antitumor, antifungal, antiviral, antimalarial, and antitrypanosomal properties. Herein, this review summarizes the recent literatures (2010–2022) on the progress of cyclodepsipeptides from fungi and bacteria except for those of marine origin, in order to enrich our knowledge about their structural features and biological sources.