Raman spectroscopy for esophageal tumor diagnosis and delineation using machine learning and the portable Raman spectrometer.

Esophageal cancer is one of the leading causes of cancer-related deaths worldwide. The identification of residual tumor tissues in the surgical margin of esophageal cancer is essential for the treatment and prognosis of cancer patients. But the current diagnostic methods, either pathological frozen section or paraffin section examination, are laborious, time-consuming, and inconvenient. Raman spectroscopy is a label-free and non-invasive analytical technique that provides molecular information with high specificity. Here, we report the use of a portable Raman system and machine learning algorithms to achieve accurate diagnosis of esophageal tumor tissue in surgically resected specimens. We tested five machine learning-based classification methods, including k-Nearest Neighbors, Adaptive Boosting, Random Forest, Principal Component Analysis-Linear Discriminant Analysis, and Support Vector Machine (SVM). Among them, SVM shows the highest accuracy (88.61 %) in classifying the esophageal tumor and normal tissues. The portable Raman system demonstrates robust measurements with an acceptable focal plane shift of up to 3 mm, which enables large-area Raman mapping on resected tissues. Based on this, we finally achieve successful Raman visualization of tumor boundaries on surgical margin specimens, and the Raman measurement time is less than 5 min. This work provides a robust, convenient, accurate, and cost-effective tool for the diagnosis of esophageal cancer tumors, advancing toward Raman-based clinical intraoperative applications.

Hepatic artery infusion chemotherapy combined with camrelizumab plus rivoceranib for hepatocellular carcinoma with portal vein tumor thrombosis: a multicenter propensity score-matching analysis.

BACKGROUND: Portal vein tumor thrombosis (PVTT) signifies late-stage hepatocellular carcinoma (HCC) with high-risk progression and poor prognosis. As a standard treatment, sorafenib monotherapy has limited the efficacy in managing HCC with PVTT. Currently, both hepatic arterial infusion chemotherapy (HAIC) and the combination of camrelizumab and rivoceranib have shown favorable survival benefits for advanced HCC, surpassing the standard sorafenib treatment. In this study, we investigate the safety and efficacy of HAIC combined with camrelizumab and rivoceranib in treating HCC patients with PVTT. METHODS: From January 2020 to December 2021, HCC patients with PVTT, who received either a triple regime of HAIC combined with camrelizumab and rivoceranib or a dual regime of camrelizumab and rivoceranib as their first-line treatment, were reviewed for eligibility at four hospital centers in China. To balance any intergroup differences, propensity score matching (PSM) was applied. The aim of this study is to compare the efficacy of the dual and triple combination treatment regimens based on survival prognosis and tumor response and evaluate the safety based on the occurrence of adverse reactions. RESULT: In this study, a total of 411 patients who received either the triple treatment regime (HAIC combined with camrelizumab plus rivoceranib, referred to as the HAICCR group, n = 292) or the dual treatment regime (camrelizumab combined with rivoceranib, referred to as the CR group, n = 119) between January 2020 and December 2021 were included. The results showed that the HAICCR group exhibited significantly better overall survival (mOS: 19.60 months vs. 11.50 months, p < 0.0001) and progression-free survival (mPFS: 10.0 months vs. 5.6 months, p < 0.0001) compared to the CR group in the overall cohort. Moreover, the HAICCR group also had a significantly higher ORR (objective response rate, 55.5% vs. 42.0%, p = 0.013) and DCR (disease control rate, 89.0% vs. 79.0%) compared to the CR group. After PSM, a final matched cohort of 83 pairs was obtained, and the survival benefits were consistent in this cohort as well (mOS: 18.70 months vs. 11.0 months, p < 0.0001; mPFS: 10.0 months vs. 5.6 months, p < 0.0001). However, there was no significant difference in the ORR between the triple and dual combination regimes. Univariate and multivariate analysis showed that CTP (Child-Turcotte-Pugh) stage, ALBI (albumin-bilirubin index) grade, tumor number, and treatment regime were significant risk factors affecting overall survival, while AFP (α-fetoprotein) level, tumor number, metastasis, and treatment regime were significant risk factors affecting progression-free survival. As for safety, hypertension and hand-foot syndrome were the two most common adverse reactions in both groups, with no significant difference in the occurrence of adverse reactions between the two groups (p < 0.05). CONCLUSION: In the context of advanced HCC patients with PVTT, the combination regime of HAIC and camrelizumab plus rivoceranib demonstrates more excellent capacity for prolonging survival and offers a well-tolerated safety compared to the CR dual therapy approach. This triple regime represents a therapeutic modality of broad prospects and vast potential for HCC patients with PVTT.

Regulating the Electrode-Electrolyte Interfaces of Lithium-High Nickel Batteries via a Multifunctional Additive.

Lithium metal batteries with high nickel ternary (LiNixCoyMn1-x-yO2, x ≥ 0.8) as the cathode hold the promise to meet the demand of next-generation high energy density batteries. However, the unsatisfactory stability of electrode-electrolyte interfaces limits their practical applications. In this work, N-methyl-N-trimethylsilyltrifluoroacetamide (NMTFA) is suggested as a new functional electrolyte additive to stabilize the Li∥LiNi0.9Co0.05Mn0.05O2 chemistry by forming robust and effective electrode-electrolyte interphases, namely the anode-electrolyte interphase (AEI, or conventionally called SEI) and cathode-electrolyte interphase (CEI). The NMTFA-derived SEI/CEI greatly enhances the battery performance that a capacity retention of 82.1% after 200 cycles at 1C charge/discharge is achieved, significantly higher than that without NMTFA addition (52.5%). Moreover, the NMTFA also improves the thermal stability of the electrolyte and inhibits the hydrolysis of LiPF6. This work provides new clues for the optimization of electrolyte formulation for lithium-high nickel batteries through modulating interfaces.

Structural Analysis and Novel Mechanism of Enteromorpha prolifera Sulfated Polysaccharide in Preventing Type 2 Diabetes Mellitus.

A water-soluble polysaccharide (EP) was purified from edible algae Enteromorpha prolifera. Gel permeation chromatography (GPC), ion chromatography (IC), and fourier transform infrared (FT-IR) were performed to characterize its structure. EP was defined as a low molecular weight (6625 Da) composed of rhamnose, glucose, glucuronic acid, xylose, galactose, arabinose, and mannose. Moreover, it was a sulfated polysaccharide with a degree of substitution (DS) of 1.48. Then, the high-fat diet/streptozotocin (HFD/STZ) induced diabetic mouse model was established to support evidence for a novel hypoglycemic mechanism. Results showed that blood glucose (47.32%), liver index (7.65%), epididymal fat index (16.86%), serum total cholesterol (26.78%) and triglyceride (37.61%) in the high-dose EP (HEP) group were significantly lower than those in the HFD group. Noticeably, the content of liver glycogen in the HEP group was significantly higher (62.62%) than that in the HFD group, indicating the promotion of glycogen synthesis. These beneficial effects were attributed to significantly increased protein kinase B (AKT) phosphorylation and its downstream signaling response. Further studies showed that diabetic mice exhibited excessive O-GlcNAcylation level and high expression of O-linked ß-D-N-acetylglucosamine transferase (OGT), which were decreased by 62.21 and 30.43% in the HEP group. This result suggested that EP had a similar effect to OGT inhibitors, which restored AKT phosphorylation and prevented pathoglycemia. This work reveals a novel hypoglycemic mechanism of EP, providing a theoretical basis for further studies on its pharmacological properties in improvement of T2DM.

Insight into the High-Efficiency Benzo(a)pyrene Degradation Ability of Pseudomonas benzopyrenica BaP3 and Its Application in the Complete Bioremediation of Benzo(a)pyrene.

Polycyclic aromatic hydrocarbons (PAHs) are common carcinogens. Benzo(a)pyrene is one of the most difficult high-molecular-weight (HMW) PAHs to remove. Biodegradation has become an ideal method to eliminate PAH pollutants from the environment. The existing research is mostly limited to low-molecular-weight PAHs; there is little understanding of HMW PAHs, particularly benzo(a)pyrene. Research into the biodegradation of HMW PAHs contributes to the development of microbial metabolic mechanisms and also provides new systems for environmental treatments. Pseudomonas benzopyrenica BaP3 is a highly efficient benzo(a)pyrene-degrading strain that is isolated from soil samples, but its mechanism of degradation remains unknown. In this study, we aimed to clarify the high degradation efficiency mechanism of BaP3. The genes encoding Rhd1 and Rhd2 in strain BaP3 were characterized, and the results revealed that rhd1 was the critical factor for high degradation efficiency. Molecular docking and enzyme activity determinations confirmed this conclusion. A recombinant strain that could completely mineralize benzo(a)pyrene was also proposed for the first time. We explained the mechanism of the high-efficiency benzo(a)pyrene degradation ability of BaP3 to improve understanding of the degradation mechanism of highly toxic PAHs and to provide new solutions to practical applications via synthetic biology.

Multiparametric MRI-based model for prediction of local progression of hepatocellular carcinoma after thermal ablation.

PURPOSE: To develop a deep learning radiomics of multiparametric magnetic resonance imaging (DLRMM)-based model that incorporates preoperative and postoperative signatures for prediction of local tumor progression (LTP) after thermal ablation (TA) in hepatocellular carcinoma (HCC). METHODS: From May 2017 to October 2021, 417 eligible patients with HCC were retrospectively enrolled from three hospitals (one primary cohort [PC, n = 189] and two external test cohorts [ETCs][n = 135, 93]). DLRMM features were extracted from T1WI + C, T2WI, and DWI using ResNet18 model. An integrative model incorporating the DLRMM signature with clinicopathologic variables were further built to LTP risk stratification. The performance of these models were compared by areas under receiver operating characteristic curve (AUC) using DeLong test. RESULTS: A total of 1668 subsequences and 31,536 multiparametric MRI slice including T1WI, T2WI, and DWI were collected simultaneously. The DLRMM signatures were extracted from tumor and ablation zone, respectively. Ablative margin, multiple tumors, and tumor abutting major vessels were regarded as risk factors for LTP in clinical model. The AUC of DLRMM model were 0.864 in PC, 0.843 in ETC1, and 0.858 in ETC2, which was higher significantly than those in clinical model (p < 0.001). After integrating clinical variable, DLRMM model obtained significant improvement with AUC of 0.870-0.869 in three cohorts (all, p < 0.001), which can provide the risk stratification for overall survival of HCC patients. CONCLUSIONS: The DLRMM model is essential to identify LTP risk of HCC patients who underwent TA and may potentially benefit personalized decision-making.

High dietary copper intake induces perturbations in the gut microbiota and affects host ovarian follicle development.

Increasing evidence has shown that gut microbes play an important role in the reproductive endocrine system and the development of polycystic ovary syndrome (PCOS). However, whether environmental factors are involved in these gut microbiota alterations has seldom been studied. In this study, we aimed to explore the crucial role of an imbalanced gut microbiota on abnormal ovarian follicle development induced by Cu. A 1:1 matched case-control study with 181 PCOS patients and 181 controls was conducted using a propensity score matching protocol. Information regarding dietary Cu intake was obtained from a face-to-face dietary intake interview. Alterations in the gut microbiota were detected by high-throughput 16 S rDNA sequencing. The results showed that dietary Cu intake was positively correlated with the risk of PCOS, and the risk threshold was approximately 1.992 mg/d. Compared with those with dietary Cu intakes lower than 1.992 mg/d, those who had a higher dietary Cu intake had a 1.813-fold increased risk of PCOS (OR=1.813, 95% CI: 1.150-2.857). PCOS patients had a lower relative abundance of Bacteroides than controls (P = 0.003), and Bacteroides played a partial mediating role between dietary Cu exposure and PCOS (Pindirect effect=0.026, 95% CI: 0.002-0.072). In addition, an animal model of Cu exposure through the diet showed that Cu can induce gut microbiota disorder; increase serum levels of LPS, MDA, and IL-6; and alter host ovarian steroidogenesis to affect ovarian follicle development. Staphylococcus played a partial mediating role between Cu exposure and CYP17A1 (Pg_Staphylococcus=0.083, 95% CI: 0.001-0.228). Overall, this study shows that long-term exposure to high dietary Cu levels can affect the composition of the gut microbiota, cause inflammation and oxidative stress, and then interfere with hormone signaling, ultimately affecting ovarian follicle development.

Inhibition of miR-143-3p alleviates myocardial ischemia reperfusion injury via limiting mitochondria-mediated apoptosis.

MicroRNA (miR)-143-3p is a potential regulatory molecule in myocardial ischemia/reperfusion injury (MI/RI), wherein its expression and pathological effects remains controversial. Thus, a mouse MI/RI and cell hypoxia/reoxygenation (H/R) models were built for clarifying the miR-143-3p's role in MI/RI. Following myocardial ischemia for 30 min, mice underwent reperfusion for 3, 6, 12 and 24 h. It was found miR-143-3p increased in the ischemic heart tissue over time after reperfusion. Cardiomyocytes transfected with miR-143-3p were more susceptible to apoptosis. Mechanistically, miR-143-3p targeted B cell lymphoma 2 (bcl-2). And miR-143-3p inhibition reduced cardiomyocytes apoptosis upon H/R, whereas it was reversed by a specific bcl-2 inhibitor ABT-737. Of note, miR-143-3p inhibition upregulated bcl-2 with better mitochondrial membrane potential (Δψm), reduced cytoplasmic cytochrome c (cyto-c) and caspase proteins, and minimized infarction area in mice upon I/R. Collectively, inhibition of miR-143-3p might alleviate MI/RI via targeting bcl-2 to limit mitochondria-mediated apoptosis. To our knowledge, this study further clarifies the miR-143-3p's pathological role in the early stages of MI/RI, and inhibiting miR-143-3p could be an effective treatment for ischemic myocardial disease.

Insight into the Global Negative Regulation of Iron Scavenger 7-HT Biosynthesis by the SigW/RsiW System in Pseudomonas donghuensis HYS

7-Hydroxytropolone (7-HT) is a unique iron scavenger synthesized by Pseudomonas donghuensis HYS that has various biological activities in addition to functioning as a siderophore. P. donghuensis HYS is more pathogenic than P. aeruginosa toward Caenorhabditis elegans, an observation that is closely linked to the biosynthesis of 7-HT. The nonfluorescent siderophore (nfs) gene cluster is responsible for the orderly biosynthesis of 7-HT and represents a competitive advantage that contributes to the increased survival of P. donghuensis HYS; however, the regulatory mechanisms of 7-HT biosynthesis remain unclear. This study is the first to propose that the ECF σ factor has a regulatory effect on 7-HT biosynthesis. In total, 20 ECF σ factors were identified through genome-wide scanning, and their responses to extracellular ferrous ions were characterized. We found that SigW was both significantly upregulated under high-iron conditions and repressed by an adjacent anti-σ factor. RNA-Seq results suggest that the SigW/RsiW system is involved in iron metabolism and 7-HT biosynthesis. Combined with the siderophore phenotype, we also found that SigW could inhibit siderophore synthesis, and this inhibition can be relieved by RsiW. EMSA assays proved that SigW, when highly expressed, can directly bind to the promoter region of five operons of the nfs cluster to inhibit the transcription of the corresponding genes and consequently suppress 7-HT biosynthesis. In addition, SigW not only directly negatively regulates structural genes related to 7-HT synthesis but also inhibits the transcription of regulatory proteins, including of the Gac/Rsm cascade system. Taken together, our results highlight that the biosynthesis of 7-HT is negatively regulated by SigW and that the SigW/RsiW system is involved in mechanisms for the regulation of iron homeostasis in P. donghuensis HYS. As a result of this work, we identified a novel mechanism for the global negative regulation of 7-HT biosynthesis, complementing our understanding of the function of ECF σ factors in Pseudomonas.

Euclidean distance-based Raman spectroscopy (EDRS) for the prognosis analysis of gastric cancer: A solution to tumor heterogeneity.

The prognosis analysis of gastric cancer is critical for selection of treatments and development of advanced therapeutic methods. A prognosis approach that is accurate, fast, convenient, and of low cost for gastric cancers is in high demand. Raman spectroscopy is a label-free and non-destructive technique to provide molecular fingerprints of biological samples, holding promises for cancer prognosis. However, the major challenge of gastric cancer prognosis lies in the widely existing tumor heterogeneity, which leads to unexpected spectral variations within one type of samples. In this work, we have developed the Euclidean distance (ED)-based Raman spectroscopy (EDRS) method for the prognosis analysis of gastric cancer to eliminate the influence of tumor heterogeneity. Raman spectra were first collected on the slices of paraffin-preserved tumor tissues from gastric cancer patients. A standard spectrum to represent the 'worst prognostic tumor cells' was then established. The similarity between each spectrum of tissues and the standard spectrum was assessed by ED, to provide a direct assessment on the prognosis status. We have successfully classified the patients into poor and favorable prognosis groups, either based on the averaged regional ED values (sensitivity of 75 %, specificity of 96.8 %), or based on the minimal ED values at the patient level (sensitivity of 90 %, specificity of 100 %). EDRS was also investigated for survival analysis (AUC = 0.955), much better than the commonly applied post-neoadjuvant therapy (ypTNM) category (AUC = 0.718). Our work highlights EDRS as a rapid, accurate, low-cost and robust tool for heterogeneous cancer-related prognosis assessment and survival prediction, providing new insights for spectroscopic tumor analysis.

LncRNA NALT1 promotes colorectal cancer progression via targeting PEG10 by sponging microRNA-574-5p.

Colorectal cancer (CRC) is currently one of the commonest tumors and the main reason for cancer-related deaths worldwide. It has been reported that long non-coding RNAs (lncRNAs) act as important indicators and regulators in various cancers. There is an urgent need to explore new lncRNA biomarkers in CRC, as well as their functions and molecular mechanisms. NALT1 has been implicated in the occurrence of gastric cancer (GC). However, the detailed function and mechanism of NALT1 in CRC progress have not been reported. In this study, RT-qPCR was conducted to detect the expression of NALT1 in 76 CRC patients ranging from stages I through IV. To assess the biological function of NALT1, loss- and gain-of-function experiments were conducted both in vivo and in vitro. Moreover, RNA-seq, bioinformatics analysis, RNA pulldown assay, dual-luciferase reporter, Ago2-RIP, quantitative PCR, Western blot assays, and rescue experiments were performed to reveal the molecular mechanisms of competitive endogenous RNAs (ceRNAs). It was observed that high expression of NALT1 was markedly correlated with advanced cancer stage in the clinic. Functionally, NALT1 downregulation inhibited cell proliferation, migration and invasion, whereas NALT1 overexpression exhibited an opposite trend both in vivo and in vitro. Bioinformatics analysis, RNA pulldown, Ago2-RIP, and luciferase reporter assays showed that miRNA-574-5p was a target of NALT1. Additionally, dual-luciferase reporter assays, Ago2-RIP, and rescue experiments indicated that miRNA-574-5p could target the PEG10 gene directly. Our results suggested that NALT1 promoted CRC proliferation and migration by sponging miRNA-574-5p to upregulate PEG10 expression, and implied that NALT1 might act as a promising biomarker and therapeutic target for CRC.

Downregulation of SIRT3 Aggravates Lung Ischemia Reperfusion Injury by Increasing Mitochondrial Fission and Oxidative Stress through HIF-1α-Dependent Mechanisms.

Lung ischemia-reperfusion injury (LIRI) is a severe multifaceted pathological condition that can lead to poor patient outcome where oxidative stress and the resulting inflammatory response can trigger and exacerbate tissue damage in LIRI patients. Sirtuin3 (SIRT3), a member of the sirtuin family, protects against oxidative stress-related diseases. However, it remains unclear if and how SIRT3 alleviates lung injury induced by ischemia/reperfusion (I/R). Our previous study showed that lung tissue structures were severely damaged at 6 h after lung I/R in mice, however, repair of the injured lung tissue was significant at 24 h. In this study, we found that both SIRT3 mRNA and protein levels were markedly increased at 24 h after lung I/R in vivo. Meanwhile, inhibition of SIRT3 aggravated lung injury and inflammation, augmented mitochondrial fission and oxidative stress and increased Hypoxia-inducible factor-1α (HIF-1α) expression in vivo. The results suggest that SIRT3 may be an upstream regulator of HIF-1α expression. Knockdown of SIRT3 resulted in excessive mitochondrial fission and increased oxidative stress in vitro, and we found that knocking down the expression of HIF-1α alleviated these changes. This suggests that the SIRT3-HIF-1α signaling pathway is involved in regulating mitochondrial function and oxidative stress. Furthermore, inhibition of dynamin-related protein 1 (Drp-1) by the inhibitor of mitophagy, Mdivi-1, blocked mitochondrial fission and alleviated oxidative stress in vitro. Taken together, our results demonstrated that downregulation of SIRT3 aggravates LIRI by increasing mitochondrial fission and oxidative stress. Activation of SIRT3 inhibits mitochondrial fission and this mechanism may serve as a new therapeutic strategy to treat LIRI.

Bioinformatics analysis of C3 in brain low-grade gliomas as potential therapeutic target and promoting immune cell infiltration.

Low-grade gliomas is the malignant nervous tumor with distinct biological and clinical characteristics. Despite advances in diagnostic and therapeutic methods, how to significantly elongate the survival of low-grade gliomas is still challengeable. Complement 3, as the critical component in the innate immune system, plays an essential role in local immune response and participating into regulation of the epithelial-mesenchymal transition and tumor microenvironment. In this study, we systematically determined the expression levels and immunological roles of C3 in low-grade gliomas using various public databases. Then, we further identified the impact of C3 expression on immune cell infiltration compared to normal tissue, indicating the effect of cellular microenvironment on overall survival of LGG patients. We obtained clinical characteristics, transcriptome, and survival of C3 in LGG from the TCGA, GEPIA2.0, and cBioportal databases. Two differentially expressed genes (DEGs) were obtained, DEGs compared to normal tissue (DEG_G1) and DEGs between C3 high expression and C3 low expression in LGG patients (DEG_G2). By performing the GO analysis and protein-protein interaction (PPI) network of DEG_G1, we have identified the top-ranked 10 hub genes, which are highly associated with regulation of cell cycle. The gene set enrichment analysis demonstrated that overexpression of C3 in LGG patient is positively correlated with regulation of cell cycle. The relative PPI analysis and GSEA of DEG_G2 were performed and analysis results indicated that higher expression of C3 in the LGG can activate immune-related pathways. Finally, immune cell infiltration analysis of C3 in the LGG patients was employed and clearly indicated that higher neutrophil infiltration can worsen the survival of the LGG patients with higher expression of C3. These results were confirmed by the Human Protein Atlas database, in which expression level of C3 protein in gliomas patients always higher. This investigation implied that C3 can be as diagnostic biomarker and potential targets of precise therapy for the LGG patients.

[Role and regulatory mechanism of triggering receptor expressed on myeloid cells 2 in mice lung ischemia/reperfusion injury].

OBJECTIVE: To investigate the role and regulatory mechanism of triggering receptor expressed on myeloid cell 2 (TREM2) in mice lung ischemia/reperfusion injury (LIRI). METHODS: Thirty-six healthy male C57BL/6 mice were divided into six groups according to the random number method (n = 6): normal control group, and LIRI 2, 6, 12, 24, 48 hours group. Mice LIRI models were established by clamping the left hilum. The wet/dry weight ratio (W/D) of left lung tissue was measured. Lung injury was observed and evaluated by hematoxylin-eosin (HE) staining and electron microscopy. The levels of interleukins (IL-1ß, IL-18) in lung tissue were detected by enzyme linked immunosorbent assay (ELISA). The mRNA expressions of TREM2 and caspase-1 were determined by polymerase chain reaction (PCR). The protein expressions of TREM2, caspase-1, Gasdermin-D (GSDMD) were determined by Western blotting. RESULTS: At 2 hours after LIRI, lung injury began to appear, the lung ultrastructure changed, and the lung injury score increased; at 6 hours, the degree of lung injury was the most serious; after 12 hours, the lung injury gradually reduced and the lung injury score gradually decreased. Compared with the normal control group, lung W/D ratio and lung injury score of LIRI 2, 6, 12, 24, 48 hours groups were significantly higher, the differences were statistically significant (lung W/D ratio: 7.06±0.52, 8.34±0.17, 6.42±0.35, 5.34±0.25, 5.59±0.45 vs. 4.69±0.23; lung injury score: 5.50±0.54, 9.75±0.89, 5.88±0.84, 3.63±0.74, 4.13±0.64 vs. 1.13±0.35, all P < 0.05). Compared with the normal control group, the levels of IL-1ß and IL-18 in lung tissue were significantly increased at 2 hours after LIRI, reached a peak at 6 hours [IL-1ß (ng/L): 502.76±12.25 vs. 56.50±8.07, IL-18 (ng/L): 414.02±10.75 vs. 81.63±5.29, both P < 0.05], then decreased gradually, and were still significantly higher than the normal control group at 48 hours. The PCR and Western blotting showed that the expression of TREM2 was significantly lower than that in the normal control group at 2 hours after LIRI, and reached a valley at 6 hours [TREM2 mRNA (2-ΔΔCt): 0.47±0.05 vs. 1.02±0.05, TREM2/GAPDH: 0.23±0.13 vs. 0.48±0.17, both P < 0.05], then gradually increased, and reached the peak at 24 hours [TREM2 mRNA (2-ΔΔCt): 3.98±0.15 vs. 1.02±0.05, TREM2/GAPDH: 0.71±0.17 vs. 0.48±0.17, both P < 0.05]. The trend of expression of caspase-1 and GSDMD were opposite to that of TREM2, which increased at first and then decreased, and reached a peak at 6 hours after reperfusion [caspase-1 mRNA (2-ΔΔCt): 2.20±0.13 vs. 1.01±0.02, caspase-1/GAPDH: 0.64±0.02 vs. 0.20±0.06, GSDMD/GAPDH: 1.23±0.01 vs. 0.87±0.02, all P < 0.05]. CONCLUSIONS: TREM2 might be involved in LIRI in mice. The mechanism may be related to the effect of TREM2 on caspase-1-mediated pyroptosis.

New Xanthones with Antiagricultural Fungal Pathogen Activities from the Endophytic Fungus Diaporthe goulteri L17.

Six new xanthone dimers, diaporxanthones A-F (1-6), and an unusual xanthone monomer diaporxanthone G (7), in addition to seven known analogues (8-14), were isolated and identified from endophytic Diaporthe goulteri L17 harbored in the fruits of the salt-tolerant plant Vitex trifolia. The chemical structures of these metabolites were elucidated on the basis of nuclear magnetic resonance, high-resolution electrospray ionization mass spectrometry, and reported data in the literature. Their absolute configurations were established by single-crystal X-ray diffraction analysis together with time-dependent density functional theory electronic circular dichroism calculations. Among these compounds, compounds 1 and 6 exhibited moderate antifungal activities against Nectria sp. and Colletotrichum musae and compound 4 showed significant cytotoxicity against all selected five cancer cell lines.

A risk model developed based on tumor microenvironment predicts overall survival and associates with tumor immunity of patients with lung adenocarcinoma.

Tumor microenvironment (TME) has been reported to exhibit a crucial effect in lung cancer. Therefore, this study was aimed to investigate the genes associated with TME and develop a risk score to predict the overall survival (OS) of patients with lung adenocarcinoma (LUAD) based on these genes. The immune and stromal scores were generated by the ESTIMATE algorithm for LUAD patients in The Cancer Genome Atlas (TCGA) database. Differentially expressed gene and weighted gene co-expression network analyses were used to derive immune- and stromal-related genes. The Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression was applied for further selection and the selected genes were inputted into stepwise regression to develop TME-related risk score (TMErisk) which was further validated in Gene Expression Omnibus (GEO) datasets. TMErisk-related biological phenotypes were analyzed in function enrichment, tumor immune signature, and tumor mutation signature. The patient's response to immunotherapy was inferred by the tumor immune dysfunction and exclusion (TIDE) score and immunophenoscore (IPS). According to our results, TMErisk was developed based on SERPINE1, CX3CR1, CD200R1, GBP1, IRF1, STAP1, LOX, and OR7E47P. Furthermore, high TMErisk was identified as a poor factor for OS in TCGA and GEO datasets, as well as in subgroup analysis with different gender, smoking status, age, race, anatomic site, therapies, and tumor-node-metastasis (TNM) stages. Higher TMErisk is also associated negatively with the abundance of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and other stromal or immune cells. Several genes of the human leukocyte antigen (HLA) family and immune checkpoints were less expressed in the high-TMErisk group. Mutations of 19 genes occurred more frequently in the high-TMErisk group. These mutations may be associated with TME change and indicate patients' response to immunotherapy. According to our analyses, a lower TMErisk score may indicate better response and OS outcome of immunotherapy.

VX765, a Specific Caspase-1 Inhibitor, Alleviates Lung Ischemia Reperfusion Injury by Suppressing Endothelial Pyroptosis and Barrier Dysfunction.

Lung ischemia reperfusion injury (LIRI) is a complex pathophysiological process with high morbidity and mortality. An important pathophysiological characteristic of LIRI is endothelial barrier dysfunction, although the mechanism involved in this process remains unclear. VX765, a specific caspase-1 inhibitor, has been shown to have a protective effect against several diseases including sepsis, atherosclerosis, and glial inflammatory disease. The objective of this study was to determine whether VX765 had a protective effect in LIRI. The results showed that lung ischemia/reperfusion (I/R) and oxygen/glucose deprivation and reoxygenation (OGD/R) induced endothelial pyroptosis and barrier dysfunction characterized by an inflammatory response. Treatment with VX765 successfully alleviated I/R- and OGD/R-induced endothelial pyroptosis and barrier dysfunction by inhibiting caspase-1 in vivo and in vitro. In conclusion, these findings showed that VX765 provided effective protection against lung I/R-induced endothelial pyroptosis and barrier dysfunction.

CMTM family proteins 1-8: roles in cancer biological processes and potential clinical value.

The CKLF-like MARVEL transmembrane domain containing (CMTM) family of genes comprises CKLF and CMTM1-8 (previously called chemokine-like factor superfamily 1-8, CKLFSF1-8). The CMTM family proteins contain a structurally conserved MAL and related proteins for vesicle trafficking and membrane linking (MARVEL) domain. Dysregulated expression of multiple CMTM family members is a common feature in many human cancer types. CMTM proteins control critical biological processes in cancer development, including growth factor receptor activation and recycling, cell proliferation, apoptosis, metastasis, and immune evasion. Emerging in vivo and in vitro evidence indicates that the mechanisms of action of most CMTM proteins are complex and multifactorial. This review highlights new findings regarding the roles of CMTM1-8 in cancer, particularly in tumor growth, metastasis, and immune evasion. Additionally, the potential clinical value of CMTMs as novel drug targets or biomarkers is discussed.

m6A RNA Methylation in Cardiovascular Diseases.

Cardiovascular diseases (CVDs) remain the leading cause of death and disability worldwide, despite marked improvements in prevention, diagnosis, and early intervention. There is an urgent need to discover more effective therapeutic strategies, which would be facilitated by a more in-depth understanding of CVDs and their underlying molecular mechanisms. Recent advances in knowledge about epigenetic mechanisms, especially RNA methylation, have revealed a close relationship between epigenetic modifications and CVDs and have brought to potential novel targets for diagnosis and treatment. Here, we provide a review of recent studies exploring RNA N6-methyladenosine (m6A) modification, with particular emphasis on its role in CVDs, such as coronary heart disease, hypertension, cardiac hypertrophy, and heart failure. We also introduce the "life cycle" of m6A and its dominant function in several biological processes. Finally, we highlight the prospects of treatment based on interfering with m6A, which could have a transformative effect on clinical medicine.

Prognostic nomogram for predicting survival in patients with high grade endometrial stromal sarcoma: a Surveillance Epidemiology, and End Results database analysis.

OBJECTIVE: High grade endometrial stromal sarcoma is a rare and highly malignant tumor that lacks a prognostic model. The aim of this study was to develop a prognostic nomogram predicting the overall survival of patients with high grade endometrial stromal sarcoma. METHODS: Clinical data for patients were derived from the Surveillance Epidemiology, and End Results database. Cox analysis and Akaike's information criterion were used to construct the nomogram. The concordance index, time dependent receiver operating characteristic curve, and calibration plot were used to evaluate the discriminative and calibrating capability. The net reclassification index, integrated discrimination improvement, and concordance index change were also compared between the nomogram and the International Federation of Gynecology and Obstetrics (FIGO) stage. Clinical benefit was evaluated using decision curve analysis. The patients were separated into groups with low and high nomogram risk scores. Kaplan-Meier curve analysis and Cox analysis were used to investigate the survival difference between the two groups. RESULTS: The training and validation cohorts had 461 and 195 patients, respectively. A nomogram that incorporated disease stage, age, surgery, lymph node status, radiotherapy, and chemotherapy for predicting overall survival was established and validated. The concordance index of the nomogram was 0.734 (0.708-0.761) in the training cohort and 0.705 (0.659-0.751) in the validation cohort. The calibration plots showed a favorable calibrating ability of the nomogram. The 1 year and 3 year time dependent receiver operating characteristic curves showed the better discriminative ability of the nomogram than the staging system. The concordance index change, net reclassification index, and integrated discrimination improvement also indicated a significantly (p<0.05) better predictive power of the nomogram over disease stage. Furthermore, decision curve analysis suggested that the nomogram was clinically useful and had a larger clinical net benefit than disease stage alone. Patients with a high risk score had distinctly poorer survival than those with low risk scores. CONCLUSIONS: A prognostic nomogram in patients with high grade endometrial stromal sarcoma exhibited favorable prognostic discrimination and survival prediction ability compared with FIGO stage.