Neoadjuvant gemcitabine-cisplatin plus tislelizumab in persons with resectable muscle-invasive bladder cancer: a multicenter, single-arm, phase 2 trial.

Programmed death 1 blockade (tislelizumab) has been approved for metastatic urothelial carcinoma but not as part of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC). In this multicenter single-arm trial (ChiCTR2000037670), 65 participants with cT2-4aN0M0 MIBC received neoadjuvant gemcitabine-cisplatin plus tislelizumab; 57 of them underwent radical cystectomy (RC). The primary endpoint of pathologic complete response (pCR) rate was 50.9% (29/57, 95% confidence interval (CI) 37.3-64.4%) and the pathologic downstaging (secondary endpoint) rate was 75.4% (43/57, 95% CI 62.2-85.9%) in participants undergoing RC. Genomic and transcriptomic analyses revealed three MIBC molecular subtypes (S): S1 (immune-desert) with activated cell-cycle pathway, S2 (immune-excluded) with activated transforming growth factor-ß pathway and S3 (immune-inflamed) with upregulated interferon-α and interferon-γ response. Post hoc analysis showed pCR rates of 16% (3/19, S1), 77% (10/13, S2) and 80% (12/15, S3) (P = 0.006). In conclusion, neoadjuvant gemcitabine-cisplatin plus tislelizumab for MIBC was compatible with an enhanced pCR rate.

Life's Essential 8, genetic susceptibility, and risk of incident pancreatic cancer: A prospective cohort study.

The association between the American Heart Association (AHA) Life's Essential 8 (LE8) and the risk of pancreatic cancer (PC) remains unclear. Our goal was to assess the relationships between LE8, genetic susceptibility, and PC risk. This cohort consisted of 234,102 participants from the UK Biobank. The components of LE8 include diet, nicotine exposure, sleep, physical activity, blood glucose, body mass index, blood lipids, and blood pressure. LE8 is classified into three categories: low cardiovascular health (CVH), moderate CVH, and high CVH. Measurements were made using Cox proportional risk models to estimate impact of associations between LE8, genetic susceptibility, and incidence of PC in participants. Compared to participants with low LE8 scores, those with moderate and high LE8 scores had a 53% (HR, 0.47; 95% CI, 0.39-0.57) and 70% (HR, 0.30; 95% CI, 0.22-0.41) lower risk of developing PC, respectively. Interestingly, among individuals with high genetic risk, high LE8 scores were associated with greater benefits (HR, 0.24; 95% CI, 0.15-0.40), whereas the protective effect was weaker among those with low genetic risk (HR, 0.40; 95% CI, 0.21-0.75). Participants with a high LE8 score and a low polygenic risk score (PRS) had the lowest risk of PC (HR, 0.19; 95% CI: 0.11-0.33). Furthermore, we observed a significant additive interaction between LE8 and PRS. A higher LE8 score is associated with a lower risk of PC, especially for participants with a high PRS. These findings have important implications for participants most genetically predisposed to PC and for targeted strategies for PC prevention.

Negative regulation of CcPAL2 gene expression by the repressor transcription factor CcMYB4-12 modulates lignin and capsaicin biosynthesis in Capsicum chinense fruits.

Peppers globally renowned for their distinctive spicy flavor, have attracted significant research attention, particularly in understanding spiciness regulation. While the activator MYB's role in spiciness regulation is well-established, the involvement of repressor MYB factors remains unexplored. This study identified the MYB4 transcription factor through RNA-seq and genome-wide analysis as being associated with spiciness. Consequently, CcMYB4-2 and CcMYB4-12 were cloned from Hainan Huangdenglong peppers, both exhibiting nuclear subcellular localization. qRT-PCR analysis revealed that CcMYB4-2/4-12 had high expression levels during the accumulation period of capsaicin, but there were differences in their peak expression levels, which may be related to the formation of pepper spiciness. Heterologous expression in Arabidopsis thaliana resulted in significantly elevated CcMYB4-2/4-12 expression levels and reduced lignin content. In CcMYB4-2 silenced plants, PAL expression remained unchanged, while PAL expression significantly increased in CcMYB4-12 silenced plants, leading to elevated lignin content and reduced capsaicin content. Yeast one-hybrid (Y1H) and dual luciferase reporter assays (DLR) demonstrated that CcMYB4-2/4-12 inhibited the transcription of CcPAL2 by binding to its promoter. Notably, CcMYB4-12 exhibited more pronounced inhibition. Therefore, it is hypothesized that CcMYB4-12 plays a pivotal role in regulating lignin and capsaicin biosynthesis. This study elucidates the molecular mechanism of MYB4 binding to the PAL promoter, providing a foundational understanding for analyzing phenylpropanoid metabolism and its diverse branches. KEY MESSAGE: Through functional verification analysis of the repressor CcMYB4, transcriptional regulation experiments revealed that CcMYB4 can bind to the CcPAL2 promoter, negatively regulating the capsaicin biosynthesis in Capsicum chinense fruits.

Soil keystone viruses are regulators of ecosystem multifunctionality.

Ecosystem multifunctionality reflects the capacity of ecosystems to simultaneously maintain multiple functions which are essential bases for human sustainable development. Whereas viruses are a major component of the soil microbiome that drive ecosystem functions across biomes, the relationships between soil viral diversity and ecosystem multifunctionality remain under-studied. To address this critical knowledge gap, we employed a combination of amplicon and metagenomic sequencing to assess prokaryotic, fungal and viral diversity, and to link viruses to putative hosts. We described the features of viruses and their potential hosts in 154 soil samples from 29 farmlands and 25 forests distributed across China. Although 4,460 and 5,207 viral populations (vOTUs) were found in the farmlands and forests respectively, the diversity of specific vOTUs rather than overall soil viral diversity was positively correlated with ecosystem multifunctionality in both ecosystem types. Furthermore, the diversity of these keystone vOTUs, despite being 10-100 times lower than prokaryotic or fungal diversity, was a better predictor of ecosystem multifunctionality and more strongly associated with the relative abundances of prokaryotic genes related to soil nutrient cycling. Gemmatimonadota and Actinobacteria dominated the host community of soil keystone viruses in the farmlands and forests respectively, but were either absent or showed a significantly lower relative abundance in that of soil non-keystone viruses. These findings provide novel insights into the regulators of ecosystem multifunctionality and have important implications for the management of ecosystem functioning.

[Clinical advantage staging and underlying mechanisms of Wangbi Tablets against knee osteoarthritis based on "disease-formula" interaction network].

The clinical advantage staging and underlying mechanisms of Wangbi Tablets against knee osteoarthritis(KOA) were studied based on the "disease-formula" interaction network. Firstly, the clinical symptoms and related genes corresponding to Wangbi Tablets and KOA in the acute, remission, and recovery phases were collected from clinical guidelines/consensus and SoFDA database, and the putative targets of Wangbi Tablets were obtained from ETCM 2.0. Then, Jaccard similarity and cosine similarity were employed to assess the similarities of clinical symptoms, genes, and enriched pathways between Wangbi Tablets and KOA in different phases. The "disease-formula" interaction network of the drug targets and disease genes was constructed, and the key targets were screened by topological feature calculation. KEGG and Reactome database were used for the functional enrichment of the key targets, on the basis of which the functional characteristics of Wangbi Tablets against KOA in the acute, remission, and recovery phases were predicted. Finally, the SW1353 cells exposed to lipopolysaccharide were used to decipher the mechanism of Wangbi Tablets against KOA. The results showed that 92/3 921, 138/3 708, 139/3 800, and 196/3 946 clinical symptoms and the related genes corresponded to KOA in the acute, remission, and recovery phases and Wangbi Tablets were collected from SoFDA, and 260 putative targets of Wangbi Tablets were obtained from ETCM 2.0. Wangbi Tablets had highest similarity of clinical symptoms, genes, and enriched pathways with KOA in the remission phase and the secondary highest similarity with KOA in the recovery phase. The key targets of Wangbi Tablets mainly participated in the regulation of immunity-inflammation imbalance and exerted pain-relieving and bone-protecting effects to alleviate symptoms such as knee joint pain, joint swelling, soreness, fatigue, and dysfunction. Intriguingly, the key targets of Wangbi Tablets possessed antioxidant effects during KOA in the acute and remission phases, while they maintained material and energy metabolism homeostasis and protected vessels during KOA in the recovery phase. The cell experiment indicated that Wangbi Tablets down-regulated the expression of interleukin(IL)-6, IL-1ß, tumor necrosis factor-α(TNF-α), and Bcl-2-associated X protein(Bax)/B-cell lymphoma 2(Bcl-2) via regulating the phosphatidylinositol 3-kinase(PI3K)-protein kinase B(Akt) signaling pathway. The findings lay a theoretical foundation for further clarifying the clinical advantage stage and precise clinical application of Wangbi Tablets in treating KOA.

A synthetic bacterial consortium improved the phytoremediation efficiency of ryegrass on polymetallic contaminated soil.

Polymetallic contamination of soils caused by mining activities seriously threatens soil fertility, biodiversity and human health. Bioremediation is thought to be of low cost and has minimal environmental risk but its effectiveness needs to be improved. This study aimed to identify the combined effect of plant growth and microbial strains with different functions on the enhancement of bioremediation of polymetallic contaminated soil. The microbiological mechanism of bioremediation was explored by amplicon sequencing and gene prediction. Soil was collected from polymetallic mine wastelands and a non-contaminated site for use in a pot experiment. Remediation efficiency of this method was evaluated by planting ryegrass and applying a mixed bacterial consortium comprising P-solubilizing, N-fixing and SO4-reducing bacteria. The plant-microbe joint remediation method significantly enhanced the above-ground biomass of ryegrass and soil nutrient contents, and at the same time reduced the content of heavy metals in the plant shoots and soil. The application of the composite bacterial inoculum significantly affected the structure of soil bacterial communities and increased the bacterial diversity and complexity, and the stability of co-occurrence networks. The relative abundance of the multifunctional genera to which the strains belonged showed a significant positive correlation with the soil nutrient content. Genera related to carbon (C), nitrogen (N), phosphorus (P), and sulphur (S) cycling and heavy metal resistance showed an up-regulation trend in heavy metal-contaminated soils after the application of the mixed bacterial consortium. Also, bacterial strains with specific functions in the mixed consortium regulated the expression of genes involved in soil nutrient cycling, and thus assisted in making the soil self-sustainable after remediation. These results suggested that the remediation of heavy metal-contaminated soil needs to give priority to the use of multifunctional bacterial agents.

Unraveling the habitat preferences, ecological drivers, potential hosts, and auxiliary metabolism of soil giant viruses across China.

BACKGROUND: Soil giant viruses are increasingly believed to have profound effects on ecological functioning by infecting diverse eukaryotes. However, their biogeography and ecology remain poorly understood. RESULTS: In this study, we analyzed 333 soil metagenomes from 5 habitat types (farmland, forest, grassland, Gobi desert, and mine wasteland) across China and identified 533 distinct giant virus phylotypes affiliated with nine families, thereby greatly expanding the diversity of soil giant viruses. Among the nine families, Pithoviridae were the most diverse. The majority of phylotypes exhibited a heterogeneous distribution among habitat types, with a remarkably high proportion of unique phylotypes in mine wasteland. The abundances of phylotypes were negatively correlated with their environmental ranges. A total of 76 phylotypes recovered in this study were detectable in a published global topsoil metagenome dataset. Among climatic, geographical, edaphic, and biotic characteristics, soil eukaryotes were identified as the most important driver of beta-diversity of giant viral communities across habitat types. Moreover, co-occurrence network analysis revealed some pairings between giant viral phylotypes and eukaryotes (protozoa, fungi, and algae). Analysis of 44 medium- to high-quality giant virus genomes recovered from our metagenomes uncovered not only their highly shared functions but also their novel auxiliary metabolic genes related to carbon, sulfur, and phosphorus cycling. CONCLUSIONS: These findings extend our knowledge of diversity, habitat preferences, ecological drivers, potential hosts, and auxiliary metabolism of soil giant viruses. Video Abstract.

Genome-wide association study and candidate gene identification for agronomic traits in 182 upward-growing fruits of C. frutescens and C. annuum.

Pepper agronomic traits serve as pivotal indicators for characterizing germplasm attributes and correlations. It is important to study differential genotypic variation through phenotypic differences of target traits. Whole genome resequencing was used to sequence the whole genome among different individuals of species with known reference genomes and annotations, and based on this, differential analyses of individuals or populations were carried out to identify SNPs for agronomic traits related to pepper. This study conducted a genome-wide association study encompassing 26 key agronomic traits in 182 upward-growing fruits of C. frutescens and C. annuum. The population structure (phylogenetics, population structure, population principal component analysis, genetic relationship) and linkage disequilibrium analysis were realized to ensure the accuracy and reliability of GWAS results, and the optimal statistical model was determined. A total of 929 SNPs significantly associated with 26 agronomic traits, were identified, alongside the detection of 519 candidate genes within 100 kb region adjacent to these SNPs. Additionally, through gene annotation and expression pattern scrutiny, genes such as GAUT1, COP10, and DDB1 correlated with fruit traits in Capsicum frutescens and Capsicum annuum were validated via qRT-PCR. In the CH20 (Capsicum annuum) and YB-4 (Capsicum frutescens) cultivars, GAUT1 and COP10 were cloned with cDNA lengths of 1065 bp and 561 bp, respectively, exhibiting only a small number of single nucleotide variations and nucleotide deletions. This validation provides a robust reference for molecular marker-assisted breeding of pepper agronomic traits, offering both genetic resources and theoretical foundations for future endeavors in molecular marker-assisted breeding for pepper.

Gd(III)-Catalyzed Regio-, Diastereo-, and Enantioselective [4 + 2] Photocycloaddition of Naphthalene Derivatives.

Catalytic asymmetric dearomatization (CADA) reactions have evolved into an efficient strategy for accessing chiral polycyclic and spirocyclic scaffolds from readily available planar aromatics. Despite the significant developments, the CADA reaction of naphthalenes remains underdeveloped. Herein, we report a Gd(III)-catalyzed asymmetric dearomatization reaction of naphthalene with a chiral PyBox ligand via visible-light-enabled [4 + 2] cycloaddition. This reaction features application of a chiral Gd/PyBox complex, which regulates the reactivity and selectivity simultaneously, in excited-state catalysis. A wide range of functional groups is compatible with this protocol, giving the highly enantioenriched bridged polycycles in excellent yields (up to 96%) and selectivity (up to >20:1 chemoselectivity, >20:1 dr, >99% ee). The synthetic utility is demonstrated by a 2 mmol scale reaction, removal of directing group, and diversifications of products. Preliminary mechanistic experiments are performed to elucidate the reaction mechanism.

Multidrug resistance transporters P-gp and BCRP limit the efficacy of ATR inhibitor ceralasertib in cancer cells.

The therapeutic effect of chemotherapy and targeted therapy are known to be limited by drug resistance. Substantial evidence has shown that ATP-binding cassette (ABC) transporters P-gp and BCRP are significant contributors to multidrug resistance (MDR) in cancer cells. In this study, we demonstrated that a clinical-staged ATR inhibitor ceralasertib is susceptible to P-gp and BCRP-mediated MDR. The drug resistant cancer cells were less sensitive to ceralasertib compared to the parental cells. Moreover, ceralasertib resistance can be reversed by inhibiting the drug efflux activity of P-gp and BCRP. Interestingly, ceralasertib was able to downregulate the level of P-gp but not BCRP, suggesting a potential regulation between ATR signaling and P-gp expression. Furthermore, computational docking analysis predicted high affinities between ceralasertib and the drug-binding sites of P-gp and BCRP. In summary, overexpression of P-gp and BCRP are sufficient to confer cancer cells resistance to ceralasertib, underscoring their role as biomarkers for therapeutic efficacy.

Secular trends in the prevalence of meeting 24-hour movement guidelines among U.S. adolescents: evidence from NHANES 2007-2016.

Background: The 24-Hour Movement Guidelines (24-HMG) recommend a balanced combination of physical activity (PA), sedentary behavior (SB) and sleep (SLP) for optimal health. However, there is limited understanding of how well U.S. adolescents adhere to these guidelines. This study aims to analyze the prevalence trends of meeting the 24-HMG among a nationally representative sample of U.S. general adolescents. Methods: The study included 2,273 adolescents (55.3% boys) aged 16-19 who participated in the National Health and Nutrition Examination Surveys (NHANES) from 2007 to 2016. The researchers categorized the adolescents based on whether they met various PA, SB, and SLP recommendations, as well as different combinations of these recommendations, separately for boys and girls. The prevalence rate, weighted by survey data, was calculated along with a 95% confidence interval (CI) to assess the changes in meeting the 24-HMG among U.S. adolescents across different survey years and sociodemographic subgroups. Results: In the 2015-2016 cycle, approximately 6.3% of adolescents did not meet any of the three recommendations, while only 19.2% of adolescents achieved all three guidelines. Compliance with PA and SB recommendations among adolescents has decreased over time, from 72.5% (65.9% to 79.2%) to 64.2% (57.4% to 70.9%) for PA, and from 59.0% (49.6% to 68.4%) to 46.6% (37.8% to 55.5%) for SB, respectively, from 2007-2008 cycle to 2015-2016 cycle. Boys exhibited more favorable patterns in meeting different sets of recommendations compared to girls (p-value <0.001). This includes meeting both PA and SB guidelines (15.5% for boys and 11.1% for girls) and meeting both PA and SLP guidelines (19.5% for boys and 15.7% for girls). The level of parental education was found to have effect on meeting all three guidelines (Ptrend < 0.05). Conclusion: We analyzed ten consecutive years of representative NHANES data to evaluate the prevalence meeting 24-HMG and found that the proportion of adolescents aged 16-19 in the U.S. who adhered to all three movement guidelines simultaneously has consistently remained low throughout each survey cycle. Notably, there has been a significant decline in the proportion of adolescents meeting the SB guideline.

Cumulative effects of excess high-normal alanine aminotransferase levels in relation to new-onset metabolic dysfunction-associated fatty liver disease in China.

BACKGROUND: Within the normal range, elevated alanine aminotransferase (ALT) levels are associated with an increased risk of metabolic dysfunction-associated fatty liver disease (MAFLD). AIM: To investigate the associations between repeated high-normal ALT measurements and the risk of new-onset MAFLD prospectively. METHODS: A cohort of 3553 participants followed for four consecutive health examinations over 4 years was selected. The incidence rate, cumulative times, and equally and unequally weighted cumulative effects of excess high-normal ALT levels (ehALT) were measured. Cox proportional hazards regression was used to analyse the association between the cumulative effects of ehALT and the risk of new-onset MAFLD. RESULTS: A total of 83.13% of participants with MAFLD had normal ALT levels. The incidence rate of MAFLD showed a linear increasing trend in the cumulative ehALT group. Compared with those in the low-normal ALT group, the multivariate adjusted hazard ratios of the equally and unequally weighted cumulative effects of ehALT were 1.651 [95% confidence interval (CI): 1.199-2.273] and 1.535 (95%CI: 1.119-2.106) in the third quartile and 1.616 (95%CI: 1.162-2.246) and 1.580 (95%CI: 1.155-2.162) in the fourth quartile, respectively. CONCLUSION: Most participants with MAFLD had normal ALT levels. Long-term high-normal ALT levels were associated with a cumulative increased risk of new-onset MAFLD.

Diagnostic challenge and survival analysis of pulmonary oligometastases and primary lung cancer in breast cancer patients.

BACKGROUND: The aim of this study was to compare breast cancer patients with pulmonary oligometastases (POM) and primary lung cancer (PLC) and to assess whether there were differences in clinical features, CT features, and survival outcomes between the two groups. METHODS: From January 2010 to December 2021, the clinical records of 437 with malignant pulmonary nodules who had breast cancer patients were reviewed. POM was identified in 45 patients and PLC in 43 patients after the initial detection of pulmonary nodules. The clinicopathological characteristics, CT appearance of pulmonary nodules, and survival of the two groups were compared. RESULTS: Stage II to IV breast tumors (p < 0.001), high pathological grade of breast cancer (p = 0.001), low proportion of luminal-type breast cancer (p = 0.003), and the higher serum CYFRA 21-1 level (p = 0.046) were the clinical characteristics of pulmonary nodules suggestive of POM rather than PLC. The CT features of lung nodules indicative of PLC rather than POM were the subsolid component (p < 0.001), lobulation (p = 0.010), air bronchogram (p < 0.001) and pleural indentation (p = 0.004). Ten-year survival rate for PLC was 93.2%, which was higher compared with 57.8% in those with POM (p = 0.001). CONCLUSIONS: Elevated serum CYFRA 21-1 levels and late-stage breast cancer may be beneficial for the diagnosis of POM. CT imaging appearances of the subsolid component, lobulation, air bronchogram, and pleural indentation increase the likelihood of PLC. Breast cancer patients with PLC presented better survival with attentive monitoring than those with POM.

Fluorination of porphyrin ß-periphery boosts nickel(II)-catalyzed hydrogen evolution reaction.

Tunichlorin, the naturally occurring chlorophyll cofactor containing Ni(II) ion, sets up a golden standard for designing the electrocatalysts for hydrogen evolution reaction (HER) via ß-peripheral modification. Besides the fine-tuning of the porphyrin ß-periphery such as adjusting the aromatics (the saturated level of tetrapyrrole) or installing hydroxyl group (hydrogen bond network) to enhance the catalytic HER efficiency, here we report that ß-fluorination of porphyrin is also an important approach to increase the reactivity of Ni(II) center. Benefiting the previously reported derivatization of ß-fluorinated porpholactones, we constructed a ß-fluorinated tunichlorin mimic (6). Compared with the non-fluorinated analogs (1, 3, and 5), we found that 2, 4, and 6 exhibit significant electrocatalytic HER reactivity acceleration (in terms of turnover frequencies, TOF, s-1) of ca. 37, 170, 133-fold, respectively. Mechanism studies suggested that ß-fluorination negatively shifts the metal complexes' reduction potentials and accelerates the electron transfer process, both contributing to the boosting of HER reaction. Notably, 6 showed an 890-fold increase of TOFs than 1, demonstrating the combining advantages of the of fluorination, hydrogenation, and hydroxylation at porphyrin ß-periphery.

Overexpression of ABCC1 and ABCG2 confers resistance to talazoparib, a poly (ADP-Ribose) polymerase inhibitor.

AIMS: The overexpression of ABC transporters on cancer cell membranes is one of the most common causes of multidrug resistance (MDR). This study investigates the impact of ABCC1 and ABCG2 on the resistance to talazoparib (BMN-673), a potent poly (ADP-ribose) polymerase (PARP) inhibitor, in ovarian cancer treatment. METHODS: The cell viability test was used to indicate the effect of talazoparib in different cell lines. Computational molecular docking analysis was conducted to simulate the interaction between talazoparib and ABCC1 or ABCG2. The mechanism of talazoparib resistance was investigated by constructing talazoparib-resistant subline A2780/T4 from A2780 through drug selection with gradually increasing talazoparib concentration. RESULTS: Talazoparib cytotoxicity decreased in drug-selected or gene-transfected cell lines overexpressing ABCC1 or ABCG2 but can be restored by ABCC1 or ABCG2 inhibitors. Talazoparib competitively inhibited substrate drug efflux activity of ABCC1 or ABCG2. Upregulated ABCC1 and ABCG2 protein expression on the plasma membrane of A2780/T4 cells enhances resistance to other substrate drugs, which could be overcome by the knockout of either gene. In vivo experiments confirmed the retention of drug-resistant characteristics in tumor xenograft mouse models. CONCLUSIONS: The therapeutic efficacy of talazoparib in cancer may be compromised by its susceptibility to MDR, which is attributed to its interactions with the ABCC1 or ABCG2 transporters. The overexpression of these transporters can potentially diminish the therapeutic impact of talazoparib in cancer treatment.

SCpRh(III)-Catalyzed Asymmetric C-H Trifluoromethylalkylation of N-Methoxybenzamides with ß-Trifluoromethyl-α,ß-Unsaturated Ketones.

Asymmetric C-H trifluoromethylalkylation represents a novel and straightforward synthetic method for the construction of chiral CF3-containing compounds. However, the reported examples remain limited, given the challenges of reactivity and enantioselective control. Herein, we report a SCpRh(III)-catalyzed asymmetric aryl and alkenyl C-H trifluoromethylalkylation reaction with ß-trifluoromethyl-α,ß-unsaturated ketones. The chiral CF3-bearing adducts were obtained in moderate to good yields with high enantioselectivity (up to 81% yield and 96% ee). The reaction features mild conditions and broad substrate scope. The chiral CF3-bearing products could undergo diverse functional group transformations.

Neutrophil extracellular traps correlate with severity and prognosis in patients with ischemic stroke: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: A correlation between neutrophil extracellular traps (NETs) and ischemic stroke (IS) has been hypothesized, but the results of relevant studies remain controversial. The purpose was to determine whether NETs have an impact on ischemic stroke. METHODS: The studies on the correlation between NETs and IS were retrieved from CNKI, Wanfang Data, VIP, CBM, PubMed, Web of Science, Embase, and Cochrane databases by computer from the start of the database to December 2022. The study adhered to PRISMA guidelines. The PICOS model was used to create inclusion criteria. Two researchers screened the literature and extracted the relevant data. The quality of the included studies was evaluated using the NOS and the 11 items recommended by the AHRQ, and meta-analysis was completed using Stata 15.1 software. RESULTS: The researchers included 752 patients in 7 studies (4 case-control studies and 3 cross-sectional studies). The meta-analysis found NETs are positively associated with the severity of IS at the time of onset [r(95% CI) = 0.31(0.24, 0.38), P < 0.001]. NETs are positively associated with a worse prognosis of IS [r(95% CI) = 0.34(0.13, 0.53), P = 0.003]. CONCLUSION: The presence of NETs is positively related to the severity and prognosis of IS. Higher levels of NETs indicate a more severe disease and a poorer prognosis. Because the number and quality of included studies are limited, the above results must be supported by further high-quality studies. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/ , identifier: CRD42022356619.

GPX2 acts as an oncogene and cudraflavone C has an anti-tumor effect by suppressing GPX2-dependent Wnt/ß-catenin pathway in colorectal cancer cells.

Colorectal carcinoma (CRC) is a common cancer associated with poor prognosis, and cudraflavone C (Cud C) is a natural flavonol with reported anti-CRC capacity. However, the precise mechanisms underlying the anti-CRC effect require further demonstration. The aim of present study was to evaluate the impact of Cud C on the cell viability and apoptosis of CRC cells and to determine the underlying mechanisms. The Human Protein Atlas (THPA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases were used to analyze the expression status of glutathione peroxidase 2 (GPX2) in CRC. Cell viability was examined using cell counting kit-8 (CCK-8) assay. Flow cytometry was utilized to evaluate apoptosis. The levels of gene transcription and protein expression of GPX2, caspase-3, cleaved caspase-3), ß-catenin, and c-Myc were determined by RT-qPCR and Western blotting. Our results showed that GPX2 was overexpressed in CRC as compared to normal tissue and the extent of GPX2 overexpression is greatest in CRC when compared with other cancers according to GEPIA and THPA databases. GPX2 knockdown significantly suppressed the cell viability, induced apoptosis of CRC cell lines, and restrained the activity of Wnt/ß-catenin pathway. Cud C treatment decreased cell viability, induced apoptosis in CRC cell lines, and diminished the expression level of GPX2-dependent activation of Wnt/ß-catenin pathway, while such effects can be abolished by GPX2 overexpression. In conclusion, Cud C suppressed GPX2-dependent Wnt/ß-catenin pathway to exert anti-CRC function.

MRI-based radiomic models to predict surgical margin status and infer tumor immune microenvironment in breast cancer patients with breast-conserving surgery: a multicenter validation study.

OBJECTIVES: Accurate preoperative estimation of the risk of breast-conserving surgery (BCS) resection margin positivity would be beneficial to surgical planning. In this multicenter validation study, we developed an MRI-based radiomic model to predict the surgical margin status. METHODS: We retrospectively collected preoperative breast MRI of patients undergoing BCS from three hospitals (SYMH, n = 296; SYSUCC, n = 131; TSPH, n = 143). Radiomic-based model for risk prediction of the margin positivity was trained on the SYMH patients (7:3 ratio split for the training and testing cohorts), and externally validated in the SYSUCC and TSPH cohorts. The model was able to stratify patients into different subgroups with varied risk of margin positivity. Moreover, we used the immune-radiomic models and epithelial-mesenchymal transition (EMT) signature to infer the distribution patterns of immune cells and tumor cell EMT status under different marginal status. RESULTS: The AUCs of the radiomic-based model were 0.78 (0.66-0.90), 0.88 (0.79-0.96), and 0.76 (0.68-0.84) in the testing cohort and two external validation cohorts, respectively. The actual margin positivity rates ranged between 0-10% and 27.3-87.2% in low-risk and high-risk subgroups, respectively. Positive surgical margin was associated with higher levels of EMT and B cell infiltration in the tumor area, as well as the enrichment of B cells, immature dendritic cells, and neutrophil infiltration in the peritumoral area. CONCLUSIONS: This MRI-based predictive model can be used as a reliable tool to predict the risk of margin positivity of BCS. Tumor immune-microenvironment alteration was associated with surgical margin status. CLINICAL RELEVANCE STATEMENT: This study can assist the pre-operative planning of BCS. Further research on the tumor immune microenvironment of different resection margin states is expected to develop new margin evaluation indicators and decipher the internal mechanism. KEY POINTS: • The MRI-based radiomic prediction model (CSS model) incorporating features extracted from multiple sequences and segments could estimate the margin positivity risk of breast-conserving surgery. • The radiomic score of the CSS model allows risk stratification of patients undergoing breast-conserving surgery, which could assist in surgical planning. • With the help of MRI-based radiomics to estimate the components of the immune microenvironment, for the first time, it is found that the margin status of breast-conserving surgery is associated with the infiltration of immune cells in the microenvironment and the EMT status of breast tumor cells.