Whole-genome selection signature differences between Chaohu and Ji'an red ducks.

Assessing the genetic structure of local varieties and understanding their genetic data are crucial for effective management and preservation. However, the genetic differences among local breeds require further explanation. To enhance our understanding of their population structure and genetic diversity, we conducted a genome-wide comparative study of Chaohu and Ji'an Red ducks using genome sequence and restriction site-associated DNA sequencing technology. Our analysis revealed a distinct genetic distinction between the two breeds, leading to divided groups. The phylogenetic tree for Chaohu duck displayed two branches, potentially indicating minimal impact from artificial selection. Additionally, our ROH (runs of homozygosity) analysis revealed that Chaohu ducks had a lower average inbreeding coefficient than Ji'an Red ducks. We identified several genomic regions with high genetic similarity in these indigenous duck breeds. By conducting a selective sweep analysis, we identified 574 candidate genes associated with muscle growth (BMP2, ITGA8, MYLK, and PTCH1), fat deposits (ELOVL1 and HACD2), and pigmentation (ASIP and LOC101797494). These results offer valuable insights for the further enhancement and conservation of Chinese indigenous duck breeds.

Genetic mapping identifies SNP mutations in MITF-M promoter associated with melanin formation in Putian black duck.

The coloration of plumage in poultry species has substantial economic significance. Putian black ducks encompass 2 distinct strains characterized by black and white plumage variations resulting from selective breeding. This study aimed to identify the molecular mechanisms responsible for plumage coloration in these 2 distinct strains. A comprehensive genome-wide association study was conducted using DNA data sourced from a F2 segregating population, consisting of 71 individuals with black plumage and 39 individuals with white plumage, derived from these distinct 2 strains. This analysis revealed that 894 nucleotide polymorphisms and identified 58 candidate genes. Subsequent Gene Ontology and Kyoto Encyclopedia of Genes and Genomes coenrichment analyses identified MITF as a key candidate gene implicated in melanin biosynthesis. Furthermore, extensive screening of significant polymorphic loci within MITF was carried out via mass spectrometry in 3 distinct populations: 100 individuals with black plumage and 100 individuals with white plumage from the F0 generation; and 50 with black plumage form the F1 generation). Eighteen candidate polymorphic loci were identified demonstrating significant associations with variations in black and white plumage. Notably, 8 of these loci were located within the 2,000 bp region upstream of MITF-M. To validate the critical regulatory role of MITF-M in black and white plumage formation, a dual-fluorescence reporter system was constructed, and dual-fluorescence activity was assessed. The results revealed that the fluorescence activity at wild-type sites (corresponding to black plumage) was significantly higher than that at the mutant-type sites (associated with white plumage) (P < 0.01). To corroborate the pivotal role of MITF-M in black and white plumage formation, qPCR was employed to evaluate the expression levels of various MITF variants in black and white feather bulbs. This analysis demonstrated that only MITF-M exhibited specific expression in black feather bulbs. These results elucidate the central role of polymorphic mutations within the MITF promoter region in the regulation of black and white plumage coloration in Putian black ducks. This study extends our understanding of mechanisms governing duck plumage coloration and provides valuable molecular markers for future research in duck production and breeding based on plumage coloration.

A Mild Hyperthermia Hollow Carbon Nanozyme as Pyroptosis Inducer for Boosted Antitumor Immunity.

The immune checkpoint blockade (ICB) antibody immunotherapy has demonstrated clinical benefits for multiple cancers. However, the efficacy of immunotherapy in tumors is suppressed by deficient tumor immunogenicity and immunosuppressive tumor microenvironments. Pyroptosis, a form of programmed cell death, can release tumor antigens, activate effective tumor immunogenicity, and improve the efficiency of ICB, but efficient pyroptosis for tumor treatment is currently limited. Herein, we show a mild hyperthermia-enhanced pyroptosis-mediated immunotherapy based on hollow carbon nanozyme, which can specifically amplify oxidative stress-triggered pyroptosis and synchronously magnify pyroptosis-mediated anticancer responses in the tumor microenvironment. The hollow carbon sphere modified with iron and copper atoms (HCS-FeCu) with multiple enzyme-mimicking activities has been engineered to induce cell pyroptosis via the radical oxygen species (ROS)-Tom20-Bax-Caspase 3-gasdermin E (GSDME) signaling pathway under light activation. Both in vitro and in vivo antineoplastic results confirm the superiority of HCS-FeCu nanozyme-induced pyroptosis. Moreover, the mild photothermal-activated pyroptosis combining anti-PD-1 can enhance antitumor immunotherapy. Theoretical calculations further indicate that the mild photothermal stimulation generates high-energy electrons and enhances the interaction between the HCS-FeCu surface and adsorbed oxygen, facilitating molecular oxygen activation, which improves the ROS production efficiency. This work presents an approach that effectively transforms immunologically "cold" tumors into "hot" ones, with significant implications for clinical immunotherapy.

Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8+ T cell infiltration and functional transition.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy improves the survival of patients with advanced bladder cancer (BLCA); however, its overall effectiveness is limited, and many patients still develop immunotherapy resistance. The leucine-rich repeat and fibronectin type-III domain-containing protein (LRFN) family has previously been implicated in regulating brain dysfunction; however, the mechanisms underlying the effect of LRFN2 on the tumor microenvironment (TME) and immunotherapy remain unclear. METHODS: Here we combined bulk RNA sequencing, single-cell RNA sequencing, ProcartaPlex multiple immunoassays, functional experiments, and TissueFAXS panoramic tissue quantification assays to demonstrate that LRFN2 shapes a non-inflammatory TME in BLCA. RESULTS: First, comprehensive multiomics analysis identified LRFN2 as a novel immunosuppressive target specific to BLCA. We found that tumor-intrinsic LRFN2 inhibited the recruitment and functional transition of CD8+ T cells by reducing the secretion of pro-inflammatory cytokines and chemokines, and this mechanism was verified in vitro and in vivo. LRFN2 restrained antitumor immunity by inhibiting the infiltration, proliferation, and differentiation of CD8+ T cells in vitro. Furthermore, a spatial exclusivity relationship was observed between LRFN2+ tumor cells and CD8+ T cells and cell markers programmed cell death-1 (PD-1) and T cell factor 1 (TCF-1). Preclinically, LRFN2 knockdown significantly enhanced the efficacy of ICI therapy. Clinically, LRFN2 can predict immunotherapy responses in real-world and public immunotherapy cohorts. Our results reveal a new role for LRFN2 in tumor immune evasion by regulating chemokine secretion and inhibiting CD8+ T-cell recruitment and functional transition. CONCLUSIONS: Thus, LRFN2 represents a new target that can be combined with ICIs to provide a potential treatment option for BLCA.

Prediction of clinically significant prostate cancer using a novel 68Ga-PSMA PET-CT and multiparametric MRI-based model.

Background: There are some limitations in the commonly used methods for the detection of prostate cancer. There is a lack of nomograms based on multiparametric magnetic resonance imaging (mpMRI) and 68Ga-prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET-CT) for the prediction of prostate cancer. The study seeks to compare the performance of mpMRI and 68Ga-PSMA PET-CT, and design a novel predictive model capable of predicting clinically significant prostate cancer (csPCa) before biopsy based on a combination of 68Ga-PSMA PET-CT, mpMRI, and patient clinical parameters. Methods: From September 2020 to June 2021, we prospectively enrolled 112 consecutive patients with no prior history of prostate cancer who underwent both 68Ga-PSMA PET-CT and mpMRI prior to biopsy at our clinical center. Univariate and multivariate regression analyses were used to identify predictors of csPCa, with a predictive model and its nomogram incorporating 68Ga-PSMA PET-CT, mpMRI, and the clinical predictors then being generated. The constructed model was evaluated using receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis, and further validated with the internal and external cohorts. Results: The model incorporated prostate-specific antigen density (PSAd), Prostate Imaging Reporting and Data System (PI-RADS) category, and maximum standardized uptake value (SUVmax), and it exhibited excellent predictive efficacy when applying to evaluate both training and validation cohorts [area under the curve (AUC): 0.936 and 0.940, respectively]. Compared with SUVmax alone, the model demonstrated excellent diagnostic performance with improved specificity (0.910, 95% CI: 0.824-0.963) and positive predictive values (0.811, 95% CI: 0.648-0.920). Calibration curve and decision curve analysis further confirmed that the model exhibited a high degree of clinical net benefit and low error rate. Conclusions: The constructed model in this study was capable of accurately predicting csPCa prior to biopsy with excellent discriminative ability. As such, this model has the potential to be an effective non-invasive approach for the diagnosis of csPCa.

S100A5 Attenuates Efficiency of Anti-PD-L1/PD-1 Immunotherapy by Inhibiting CD8+ T Cell-Mediated Anti-Cancer Immunity in Bladder Carcinoma.

Although immune checkpoint blockade (ICB) therapies have been approved for bladder cancer (BLCA), only a minority of patients respond to these therapies, and there is an urgent need to explore combined therapies. Systematic multi-omics analysis identified S100A5 as a novel immunosuppressive target for BLCA. The expression of S100A5 in malignant cells inhibited CD8+ T cell recruitment by decreasing pro-inflammatory chemokine secretion. Furthermore, S100A5 attenuated effector T cell killing of cancer cells by inhibiting CD8+ T cell proliferation and cytotoxicity. In addition, S100A5 acted as an oncogene, thereby promoting tumor proliferation and invasion. Targeting S100A5 synergized with the efficacy of anti-PD-1 treatment by enhancing infiltration and cytotoxicity of CD8+ T cells in vivo. Clinically, there was a spatially exclusive relationship between S100A5+ tumor cells and CD8+ T cells in tissue microarrays. Moreover, S100A5 negatively correlated with immunotherapy efficacy in our real-world and several public immunotherapy cohorts. In summary, S100A5 shapes a non-inflamed tumor microenvironment in BLCA by inhibiting the secretion of pro-inflammatory chemokines and the recruitment and cytotoxicity of CD8+ T cells. Targeting S100A5 converts cold tumors into hot tumors, thus enhancing the efficacy of ICB therapy in BLCA.

A novel platelet risk score for stratifing the tumor immunophenotypes, treatment responses and prognosis in bladder carcinoma: results from real-world cohorts.

Background: Although the durable efficacy of immune checkpoint inhibitors (ICIs) in BLCA has been confirmed in numerous studies, not all patients benefit from their application in the clinic. Platelets are increasingly being found to be closely associated with cancer progression and metastasis; however, their comprehensive role in BLCA remains unclear. Methods: We comprehensively explored platelet expression patterns in BLCA patients using an integrated set of 244 related genes. Correlations between these platelet patterns with tumor microenvironment (TME) subtypes, immune characteristics and immunotherapy efficacies were explored. In addition, a platelet risk score (PRS) was generated for individual prognosis and verified the ability to predict prognosis, precise TME phenotypes, and immunotherapy efficacies. Results: Genes were clustered into two patterns that represented different TME phenotypes and had the ability to predict immunotherapy efficacy. We constructed a PRS that could predict individual prognosis with satisfactory accuracy using TCGA-BLCA. The results remained consistent when PRS was validated in the GSE32894 and Xiangya cohort. Moreover, we found that our PRS was positively related to tumor-infiltrating lymphocytes (TILs) in the TCGA-BLCA and Xiangya cohort. As expected, patients with higher PRS exhibited more sensitive to immunotherapy than patients with lower PRS. Finally, we discovered that a high PRS indicated a basal subtype of BLCA, whereas a low PRS indicated a luminal subtype. Conclusion: Platelet-related genes could predict TME phenotypes in BLCA. We constructed a PRS that could predict the TME, prognosis, immunotherapy efficacy, and molecular subtypes in BLCA.

Nitrogen-Centered Lactate Oxidase Nanozyme for Tumor Lactate Modulation and Microenvironment Remodeling.

Designing nanozymes that match natural enzymes have always been an attractive and challenging goal. In general, researchers mainly focus on the construction of metal centers and the control of non-metallic ligands of nanozyme to regulate their activities. However, this is not applicable to lactate oxidase, i.e., flavoenzymes with flavin mononucleotide (FMN)-dependent pathways. Herein, we propose a coordination strategy to mimic lactate oxidase based on engineering the electronic properties at the N center by modulating the Co number near N in the Cox-N nanocomposite. Benefitting from the manipulated coordination fields and electronic structure around the electron-rich N sites, Co4N/C possesses a precise recognition site for lactate and intermediate organization and optimizes the absorption energies for intermediates, leading to superior oxidation of the lactate α-C-sp(3)-H bond toward ketone. The optimized nanozyme delivers much improved anticancer efficacy by reversing the high lactate and the immunosuppressive state of the tumor microenvironment, subsequently achieving excellent tumor growth and distant metastasis inhibition. The developed Co4N/C NEs open a new window for building a bridge between chemical catalysis and biocatalysis.

BCAT2 Shapes a Noninflamed Tumor Microenvironment and Induces Resistance to Anti-PD-1/PD-L1 Immunotherapy by Negatively Regulating Proinflammatory Chemokines and Anticancer Immunity.

To improve response rate of monotherapy of immune checkpoint blockade (ICB), it is necessary to find an emerging target in combination therapy. Through analyzing tumor microenvironment (TME)-related indicators, it is validated that BCAT2 shapes a noninflamed TME in bladder cancer. The outcomes of multiomics indicate that BCAT2 has an inhibitory effect on cytotoxic lymphocyte recruitment by restraining activities of proinflammatory cytokine/chemokine-related pathways and T-cell-chemotaxis pathway. Immunoassays reveal that secretion of CD8+ T-cell-related chemokines keeps a robust negative correlation with BCAT2, generating a decreasing tendency of CD8+ T cells around BCAT2+ tumor cells from far to near. Cotreatment of BCAT2 deficiency and anti-PD-1 antibody has a synergistic effect in vivo, implying the potential of BCAT2 in combination therapy. Moreover, the value of BCAT2 in predicting efficacy of immunotherapy is validated in multiple immunotherapy cohorts. Together, as a key molecule in TME, BCAT2 is an emerging target in combination with ICB and a biomarker of guiding precision therapy.

A hypoxia risk score for prognosis prediction and tumor microenvironment in adrenocortical carcinoma.

Background: Adrenocortical carcinoma (ACC) is a rare malignant endocrine tumor derived from the adrenal cortex. Because of its highly aggressive nature, the prognosis of patients with adrenocortical carcinoma is not impressive. Hypoxia exists in the vast majority of solid tumors and contributes to invasion, metastasis, and drug resistance. This study aimed to reveal the role of hypoxia in Adrenocortical carcinoma and develop a hypoxia risk score (HRS) for Adrenocortical carcinoma prognostic prediction. Methods: Hypoxia-related genes were obtained from the Molecular Signatures Database. The training cohorts of patients with adrenocortical carcinoma were downloaded from The Cancer Genome Atlas, while another three validation cohorts with comprehensive survival data were collected from the Gene Expression Omnibus. In addition, we constructed a hypoxia classifier using a random survival forest model. Moreover, we explored the relationship between the hypoxia risk score and immunophenotype in adrenocortical carcinoma to evaluate the efficacy of immune check inhibitors (ICI) therapy and prognosis of patients. Results: HRS and tumor stage were identified as independent prognostic factors. HRS was negatively correlated with immune cycle activity, immune cell infiltration, and the T cell inflammatory score. Therefore, we considered the low hypoxia risk score group as the inflammatory immunophenotype, whereas the high HRS group was a non-inflammatory immunophenotype. In addition, the HRS was negatively related to the expression of common immune checkpoint molecules such as PD-L1, CD200, CTLA-4, and TIGIT, suggesting that patients with a lower hypoxia risk score respond better to immunotherapy. Conclusion: We developed and validated a novel hypoxia risk score to predict the immunophenotype and response of patients with adrenocortical carcinoma to immune check inhibitors therapy. These findings not only provide fresh prognostic indicators for adrenocortical carcinoma but also offer several promising treatment targets for this disease.

A novel signature to predict the neoadjuvant chemotherapy response of bladder carcinoma: Results from a territory multicenter real-world study.

Background: Although neoadjuvant chemotherapy (NAC) has become the standard treatment option for muscle invasive bladder carcinoma (MIBC), its application is still limited because of the lack of biomarkers for NAC prediction. Methods: We conducted a territory multicenter real-world study to summarize NAC practice in China and its associated clinicopathologic variables with NAC response. Then, we developed and validated a robust gene-based signature for accurate NAC prediction using weighted correlation network analysis (WGCNA), the least absolute shrinkage and selector operation (LASSO) algorithm, a multivariable binary logistic regression model, and immunohistochemistry (IHC). Results: In total, we collected 69 consecutive MIBC patients treated with NAC from four clinical centers. The application of NAC in the real world was relatively safe, with only two grade Ⅳ and seven grade Ⅲ AEs and no treatment-related deaths being reported. Among these patients, 16 patients gave up surgery after NAC, leaving 53 patients for further analysis. We divided them into pathological response and non-response groups and found that there were more patients with a higher grade and stage in the non-response group. Patients with a pathological response could benefit from a significant overall survival (OS) improvement. In addition, univariate and multivariate logistic analyses indicated that tumor grade and clinical T stage were both independent factors for predicting NAC response. Importantly, we developed and validated a five-gene-based risk score for extremely high predictive accuracy for NAC response. Conclusion: NAC was relatively safe and could significantly improve OS for MIBC patients in the real-world practice. Our five-gene-based risk score could guide personalized therapy and promote the application of NAC.

Gut Microbiota and Tumor Immune Escape: A New Perspective for Improving Tumor Immunotherapy.

The gut microbiota is a large symbiotic community of anaerobic and facultative aerobic bacteria inhabiting the human intestinal tract, and its activities significantly affect human health. Increasing evidence has suggested that the gut microbiome plays an important role in tumor-related immune regulation. In the tumor microenvironment (TME), the gut microbiome and its metabolites affect the differentiation and function of immune cells regulating the immune evasion of tumors. The gut microbiome can indirectly influence individual responses to various classical tumor immunotherapies, including immune checkpoint inhibitor therapy and adoptive immunotherapy. Microbial regulation through antibiotics, prebiotics, and fecal microbiota transplantation (FMT) optimize the composition of the gut microbiome, improving the efficacy of immunotherapy and bringing a new perspective and hope for tumor treatment.

Cuproptosis depicts tumor microenvironment phenotypes and predicts precision immunotherapy and prognosis in bladder carcinoma.

Background: Though immune checkpoint inhibitors (ICIs) exhibit durable efficacy in bladder carcinomas (BLCAs), there are still a large portion of patients insensitive to ICIs treatment. Methods: We systematically evaluated the cuproptosis patterns in BLCA patients based on 46 cuproptosis related genes and correlated these cuproptosis patterns with tumor microenvironment (TME) phenotypes and immunotherapy efficacies. Then, for individual patient's evaluation, we constructed a cuproptosis risk score (CRS) for prognosis and a cuproptosis signature for precise TME phenotypes and immunotherapy efficacies predicting. Results: Two distinct cuproptosis patterns were generated. These two patterns were consistent with inflamed and noninflamed TME phenotypes and had potential role for predicting immunotherapy efficacies. We constructed a CRS for predicting individual patient's prognosis with high accuracy in TCGA-BLCA. Importantly, this CRS could be well validated in external cohorts including GSE32894 and GSE13507. Then, we developed a cuproptosis signature and found it was significantly negative correlated with tumor-infiltrating lymphocytes (TILs) both in TCGA-BLCA and Xiangya cohorts. Moreover, we revealed that patients in the high cuproptosis signature group represented a noninflamed TME phenotype on the single cell level. As expected, patients in the high cuproptosis signature group showed less sensitive to immunotherapy. Finally, we found that the high and low cuproptosis signature groups were consistent with luminal and basal subtypes of BLCA respectively, which validated the role of signature in TME in terms of molecular subtypes. Conclusions: Cuproptosis patterns depict different TME phenotypes in BLCA. Our CRS and cuproptosis signature have potential role for predicting prognosis and immunotherapy efficacy, which might guide precise medicine.

Cuproptosis-related modification patterns depict the tumor microenvironment, precision immunotherapy, and prognosis of kidney renal clear cell carcinoma.

Background: Due to the different infiltration abundance of immune cells in tumor, the efficacy of immunotherapy varies widely among individuals. Recently, growing evidence suggested that cuproptosis has impact on cancer immunity profoundly. However, the comprehensive roles of cuproptosis-related genes in tumor microenvironment (TME) and in response to immunotherapy are still unclear. Methods: Based on 43 cuproptosis-related genes, we employed unsupervised clustering to identify cuproptosis-related patterns and single-sample gene set enrichment analysis algorithm to build a cuproptosis signature for individual patient's immune cell infiltration and efficacy of immune checkpoint blockade (ICB) evaluation. Then, the cuproptosis-related genes were narrowed down using univariate Cox regression model and least absolute shrinkage and selection operator algorithm. Finally, a cuproptosis risk score was built by random survival forest based on these narrowed-down genes. Results: Two distinct cuproptosis-related patterns were developed, with cuproptosis cluster 1 showing better prognosis and higher enrichment of immune-related pathways and infiltration of immune cells. For individual evaluation, the cuproptosis signature that we built could be used not only for predicting immune cell infiltration in TME but also for evaluating an individual's sensitivity to ICBs. Patients with higher cuproptosis signature scores exhibited more activated cancer immune processes, higher immune cell infiltration, and better curative efficacy of ICBs. Furthermore, a robust cuproptosis risk score indicated that patients with higher risk scores showed worse survival outcomes, which could be validated in internal and external validation cohorts. Ultimately, a nomogram which combined the risk score with the prognostic clinical factors was developed, and it showed excellent prediction accuracy for survival outcomes. Conclusion: Distinct cuproptosis-related patterns have significant differences on prognosis and immune cell infiltration in kidney renal clear cell carcinoma (KIRC). Cuproptosis signature and risk score are able to provide guidance for precision therapy and accurate prognosis prediction for patients with KIRC.

Neoadjuvant immunotherapy, chemotherapy, and combination therapy in muscle-invasive bladder cancer: A multi-center real-world retrospective study.

To parallelly compare the efficacy of neoadjuvant immunotherapy (tislelizumab), neoadjuvant chemotherapy (gemcitabine and cisplatin), and neoadjuvant combination therapy (tislelizumab + GC) in patients with muscle-invasive bladder cancer (MIBC) and explore the efficacy predictors, we perform a multi-center, real-world cohort study that enrolls 253 patients treated with neoadjuvant treatments (combination therapy: 98, chemotherapy: 107, and immunotherapy: 48) from 15 tertiary hospitals. We demonstrate that neoadjuvant combination therapy achieves the highest complete response rate and pathological downstaging rate compared with neoadjuvant immunotherapy or chemotherapy. We develop and validate an efficacy prediction model consisting of pretreatment clinical characteristics, which can pinpoint candidates to receive neoadjuvant combination therapy. We also preliminarily reveal that patients who achieve pathological complete response after neoadjuvant treatments plus maximal transurethral resection of the bladder tumor may be safe to receive bladder preservation therapy. Overall, this study highlights the benefit of neoadjuvant combination therapy based on tislelizumab for MIBC.

m6A-induced lncDBET promotes the malignant progression of bladder cancer through FABP5-mediated lipid metabolism.

The limited effect of adjuvant therapy for advanced bladder cancer (BCa) leads to a poor prognosis. Increasing evidence has shown that RNA N6-methyladenosine (m6A) modification plays important functional roles in tumorigenesis. Nevertheless, the role and mechanism of m6A-modified noncoding RNAs (ncRNAs) in BCa remain largely unknown. Methods: RT-PCR, western blotting and ONCOMINE dataset were used to determine the dominant m6A-related enzyme in BCa. M6A-lncRNA epitranscriptomic microarray was used to screen candidate targets of METTL14. RT-PCR, MeRIP and TCGA dataset were carried out to confirm the downstream target of METTL14. CHIRP/MS was conducted to identify the candidate proteins binding to lncDBET. RT-PCR, western blotting, RIP and KEGG analysis were used to confirm the target of lncDBET. The levels of METTL14, lncDBET and FABP5 were tested in vitro and in vivo. CCK-8, EdU, transwell and flow cytometry assays were performed to determine the oncogenic function of METTL14, lncDBET and FABP5, and their regulatory networks. Results: We identified that the m6A level of total RNA was elevated and that METTL14 was the dominant m6A-related enzyme in BCa. m6A modification mediated by METTL14 promoted the malignant progression of BCa by promoting the expression of lncDBET. Upregulated lncDBET activated the PPAR signalling pathway to promote the lipid metabolism of cancer cells through direct interaction with FABP5, thus promoting the malignant progression of BCa in vitro and in vivo. Conclusions: Our study establishes METTL14/lncDBET/FABP5 as a critical oncogenic axis in BCa.

Childhood maltreatment and impulsivity in offenders: Examining the mediating roles of self-compassion and cognitive reappraisal.

BACKGROUND: The higher impulsivity of offenders in prison is a challenge for prison intervention. Childhood maltreatment, one of the factors closely related to the generation and development of impulsivity, is also prevalent in offenders. Therefore, it is critical to investigate the underlying paths that generate impulsivity in offenders who have experienced childhood abuse. OBJECTIVE: Targeting positive protective factors, this study aimed to probe the mediating roles of self-compassion and cognitive reappraisal in the relationship between childhood maltreatment and impulsivity in offenders. METHODS: The participants included 2643 offenders, 1534 males and 1109 females. Each participant completed the appropriate questionnaires to measure childhood maltreatment, impulsivity, self-compassion, and cognitive reappraisal. The PROCESS macro was used to perform the mediation analysis and hypothesis testing. RESULTS: The findings showed that childhood maltreatment indirectly affected offenders' impulsivity through self-compassion and cognitive reappraisal, and the mediating effect of self-compassion was stronger than that of cognitive reappraisal. Further analyses found that sexual abuse indirectly affected impulsivity through self-compassion, and the remaining types of childhood maltreatment were associated with impulsivity in indirect pathways through self-compassion and cognitive reappraisal. CONCLUSIONS: The results suggest that reinforcing practical training in self-compassion and cognitive reappraisal, especially the former, might facilitate the reduction of impulsive symptoms among offenders with backgrounds of childhood maltreatment.

TGFß-Associated Signature Predicts Prognosis and Tumor Microenvironment Infiltration Characterization in Gastric Carcinoma.

Background: Gastric carcinoma (GC) is a carcinoma with a high incidence rate, and it is a deadly carcinoma globally. An effective tool, that is, able to predict different survival outcomes for GC patients receiving individualized treatments is deeply needed. Methods: In total, data from 975 GC patients were collected from TCGA-STAD, GSE15459, and GSE84437. Then, we performed a comprehensive unsupervised clustering analysis based on 54 TGFß-pathway-related genes and correlated these patterns with tumor microenvironment (TME) cell-infiltrating characteristics. WGCNA was then applied to find the module that had the closest relation with these patterns. The least absolute shrinkage and selection operator (LASSO) algorithm was combined with cross validation to narrow down variables and random survival forest (RSF) was used to create a risk score. Results: We identified two different TGFß regulation patterns and named them as TGFß Cluster 1 and Cluster 2. TGFß Cluster 1 was linked to significantly poorer survival outcomes and represented an inflamed TME subtype of GC. Using WGCNA, a module (magenta) with the closest association with the TGFß clusters was identified. After narrowing down the gene list by univariate Cox regression analysis, the LASSO algorithm and cross validation, four of the 243 genes in the magenta module were applied to build a risk score. The group with a higher risk score exhibited a considerably poorer survival outcome with high predictive accuracy. The risk score remained an independent risk factor in multivariate Cox analysis. Moreover, we validated this risk score using GSE15459 and GSE84437. Furthermore, we found that the group with a higher risk score represented an inflamed TME according to the evidence that the risk score was remarkably correlated with several steps of cancer immunity cycles and a majority of the infiltrating immune cells. Consistently, the risk score was significantly related to immune checkpoint genes and T cell-inflamed gene expression profiles (GEPs), indicating the value of predicting immunotherapy. Conclusions: We have developed and validated a TGFß-associated signature, that is, capable of predicting the survival outcome as well as depicting the TME immune characteristics of GC. In summary, this signature may contribute to precision medicine for GC.

A Cascade Nanozyme with Amplified Sonodynamic Therapeutic Effects through Comodulation of Hypoxia and Immunosuppression against Cancer.

The tumor microenvironment (TME) featured by immunosuppression and hypoxia is pivotal to cancer deterioration and metastasis. Thus, regulating the TME to improve cancer cell ablation efficiency has received extensive interest in oncotherapy. However, to reverse the immunosuppression and alleviate hypoxia simultaneously in the TME are major challenges for effective cancer therapy. Herein, a multifunctional platform based on Au nanoparticles and a carbon dots modified hollow black TiO2 nanosphere (HABT-C) with intrinsic cascade enzyme mimetic activities is prepared for reversing immunosuppression and alleviating hypoxia in the TME. The HABT-C NPs possess triple-enzyme mimetic activity to act as self-cascade nanozymes, which produce sufficient oxygen to alleviate hypoxia and generate abundant ROS. The theoretical analysis demonstrates that black TiO2 facilitates absorption of H2O and O2, separation of electron-holes, and generation of ROS, consequently amplifying the sonodynamic therapy (SDT) efficiency. Specifically, HABT-C exhibits favorable inhibition of immunosuppressive mediator expression, along with infiltrating of immune effector cells into the TME and reversing the immunosuppression in the TME. As a result, HABT-C can effectively kill tumor cells via eliciting immune infiltration, alleviating hypoxia, and improving SDT efficiency. This cascade nanozyme-based platform (HABT-C@HA) will provide a strategy for highly efficient SDT against cancer by modulation of hypoxia and immunosuppression in the TME.

miR-616-5p Promotes Invasion and Migration of Bladder Cancer via Downregulating NR2C2 Expression.

BACKGROUND: MicroRNAs, small non-coding RNA molecules with about 22 nucleotides in length, play a significant role in the development of bladder cancer. Previous studies found that miR-616-5p could promote the progress of cancers. However, its role in bladder cancer remains unclear. In the study, we aimed to demonstrate how miR-616-5p impacts the invasion and migration of bladder cancer and its potential downstream targets. METHODS: Firstly, qRT-PCR was used to detect the expression of miR-616-5p in normal bladder uroepithelial cell lines and bladder cancer cell lines. Then, chamber-transwell invasion and wound healing migration assays were used to detect the roles of miR-616-5p and NR2C2 in invasion and migration. Subsequently, Western blot was used to evaluate the regulation effects of miR-616-5p and NR2C2. Finally, luciferase assays were performed to manifest the mechanism of miR-616-5p and NR2C2 regulation. RESULTS: We found that miR-616-5p was upregulated in bladder cancer, and it could promote the invasion and migration of bladder cancer in vitro. Moreover, we demonstrated that NR2C2 was a downstream target of miR-616-5p. miR-616-5p could inhibit the expression of NR2C2 by binding to the 3'UTR of NR2C2 mRNA. Importantly, patients with a high expression of NR2C2 showed better prognoses in bladder cancer. CONCLUSIONS: This study identifies that miR-616-5p can promote bladder cancer progression via altering the expression of NR2C2. Therefore, identifying miR-616-5p expression levels might be a useful strategy for developing potential therapeutic targets in bladder cancer.