We have previously demonstrated abnormal gut microbial composition in castration-resistant prostate cancer (CRPC) patients, here we revealed the mechanism of gut microbiota-derived short-chain fatty ...acids (SCFAs) as a mediator linking CRPC microbiota dysbiosis and prostate cancer (PCa) progression. By using transgenic TRAMP mouse model, PCa patient samples, in vitro PCa cell transwell and macrophage recruitment assays, we examined the effects of CRPC fecal microbiota transplantation (FMT) and SCFAs on PCa progression. Our results showed that FMT with CRPC patients' fecal suspension increased SCFAs-producing gut microbiotas such as Ruminococcus, Alistipes, Phascolarctobaterium in TRAMP mice, and correspondingly raised their gut SCFAs (acetate and butyrate) levels. CRPC FMT or SCFAs supplementation significantly accelerated mice's PCa progression. In vitro, SCFAs enhanced PCa cells migration and invasion by inducing TLR3-triggered autophagy that further activated NF-κB and MAPK signalings. Meanwhile, autophagy of PCa cells released higher level of chemokine CCL20 that could reprogramme the tumor microenvironment by recruiting more macrophage infiltration and simultaneously polarizing them into M2 type, which in turn further strengthened PCa cells invasiveness. Finally in a cohort of 362 PCa patients, we demonstrated that CCL20 expression in prostate tissue was positively correlated with Gleason grade, pre-operative PSA, neural/seminal vesical invasion, and was negatively correlated with post-operative biochemical recurrence-free survival. Collectively, CRPC gut microbiota-derived SCFAs promoted PCa progression via inducing cancer cell autophagy and M2 macrophage polarization. CCL20 could become a biomarker for prediction of prognosis in PCa patients. Intervention of SCFAs-producing microbiotas may be a useful strategy in manipulation of CRPC.
Gut microbiota dysbiosis is related to cancer development and progression. Our previous study showed that
Ruminococcus
was more abundant in CRPC (Castration-resistant prostate cancer) than HSPC ...(Hormone-sensitive prostate cancer) individuals. Here, we determined the potential mechanism of microbiota dysbiosis in prostate cancer (PCa) progression. Metagenomics was used to verify the gut microbial discrepancies between CRPC and HSPC individuals. Fecal microbiota transplantation (FMT) was performed by transferring the fecal suspension of CRPC or HSPC individuals to TRAMP mice. Afterwards, the mice’s prostate histopathology and gut microbiota composition were determined. Since
Ruminococcus
was demonstrated to correlate with phospholipid metabolism, we used lipidomics to examine the mice’s fecal lipid profiles. The expression of LPCAT1 the key enzyme for phospholipid remodeling in mice prostate was also examined. Meanwhile, both microbial functions prediction and LPCAT1 GSEA analysis (Gene Set Enrichment Analysis) indicated DNA repair pathways, we further determined the expressions of RAD51 and DNA-PKcs in mice prostate. The results showed that gut
Ruminococcus
was significantly more abundant in CRPC individuals. FMT using CRPC feces accelerated mice’s PCa progression and increased their gut
Ruminococcus
abundance. Majority of fecal lipids including lysophosphatidylcholine and phosphatidylcholine were upregulated in CRPC FMT treated mice, accompanied with enhanced expressions of LPCAT1, RAD51, and DNA-PKcs in mice prostate. We reported an abundant colonization of
Ruminococcus
in the gut of CRPC individuals and mice receiving their fecal suspensions, and revealed the promotive capability of
Ruminococcus
in PCa progression
via
upregulating LPCAT1 and DNA repair protein expressions. The bacterium and its downstream pathways may become the targets of therapies for PCa in the future.
Background The effective treatment and prognosis prediction of bladder cancer (BLCA) remains a medical problem. Ferroptosis is an iron-dependent form of programmed cell death. Ferroptosis is closely ...related to tumour occurrence and progression, but the prognostic value of ferroptosis-related genes (FRGs) in BLCA remains to be further clarified. In this study, we identified an FRG signature with potential prognostic value for patients with BLCA. Methods The corresponding clinical data and mRNA expression profiles of BLCA patients were downloaded from The Cancer Genome Atlas (TCGA). Univariate Cox regression was used to extract FRGs related to survival time, and a Cox regression model was used to construct a multigene signature. Both principal component analysis (PCA) and single-sample gene set enrichment analysis (ssGSEA) were performed for functional annotation. Results Clinical traits were combined with FRGs, and 15 prognosis-related FRGs were identified by Cox regression. High expression of CISD1, GCLM, CRYAB, SLC7A11, TFRC, ACACA, ZEB1, SQLE, FADS2, ABCC1, G6PD and PGD was related to poor survival in BLCA patients. Multivariate Cox regression was used to construct a prognostic model with 7 FRGs that divided patients into two risk groups. Compared with that in the low-risk group, the overall survival (OS) of patients in the high-risk group was significantly lower (P < 0.001). In multivariate regression analysis, the risk score was shown to be an independent predictor of OS (HR = 1.772, P < 0.01). Receiver operating characteristic (ROC) curve analysis verified the predictive ability of the model. In addition, the two risk groups displayed different immune statuses in ssGSEA and different distributed patterns in PCA. Conclusion Our research suggests that a new gene model related to ferroptosis can be applied for the prognosis prediction of BLCA. Targeting FRGs may be a treatment option for BLCA. Keywords: Bladder cancer, Ferroptosis, Prognostic model, Gene signature, The Cancer genome atlas (TCGA)
Highlights
Electrospinning combined with structural engineering to construct 0D@2D@1D hierarchical heterogeneous interfaces.
A “mechanical response” model was constructed to explain the stress ...transfer mechanism of fibrous membranes with 2D@1D structures.
The “One for All” fibrous membrane combines excellent flexibility, mechanical properties, waterproof, and electromagnetic protection.
The development of wearable multifunctional electromagnetic protective fabrics with multifunctional, low cost, and high efficiency remains a challenge. Here, inspired by the unique flower branch shape of “Thunberg’s meadowsweet” in nature, a nanofibrous composite membrane with hierarchical structure was constructed. Integrating sophisticated 0D@2D@1D hierarchical structures with multiple heterointerfaces can fully unleash the multifunctional application potential of composite membrane. The targeted induction method was used to precisely regulate the formation site and morphology of the metal–organic framework precursor, and intelligently integrate multiple heterostructures to enhance dielectric polarization, which improves the impedance matching and loss mechanisms of the electromagnetic wave absorbing materials. Due to the synergistic enhancement of electrospinning-derived carbon nanofiber “stems”, MOF-derived carbon nanosheet “petals” and transition metal selenide nano-particle “stamens”, the Co
x
Se
y
/NiSe@CNSs@CNFs (CNCC) composite membrane obtains a minimum reflection loss value (RL
min
) of -68.40 dB at 2.6 mm and a maximum effective absorption bandwidth (EAB) of 8.88 GHz at a thin thickness of 2.0 mm with a filling amount of only 5 wt%. In addition, the multi-component and hierarchical heterostructure endow the fibrous membrane with excellent flexibility, water resistance, thermal management, and other multifunctional properties. This work provides unique perspectives for the precise design and rational application of multifunctional fabrics.
Background
Tumor immunological heterogeneity potentially influences the prognostic disparities among patients with clear cell renal cell carcinoma (ccRCC); however, there is a lack of macroscopic ...imaging tools that can be used to predict immune-related gene expression in ccRCC.
Methods
A novel non-invasive radiogenomics biomarker was constructed for immune-related gene expression in ccRCC. First, 520 ccRCC transcriptomic datasets from The Cancer Genome Atlas (TCGA) were analyzed using a non-negative matrix decomposition (NMF) clustering to identify immune-related molecular subtypes. Immune-related prognostic genes were analyzed through Cox regression and Gene Set Enrichment Analysis (GSEA). We then built a risk model based on an immune-related gene subset to predict prognosis in patients with ccRCC. CT images corresponding to the ccRCC patients in The Cancer Imaging Archive (TCIA) database were used to extract radiomic features. To stratify immune-related gene expression levels, extracted radiogenomics features were identified according to standard consecutive steps. A nomogram was built to combine radiogenomics and clinicopathological information through multivariate logistic regression to further enhance the radiogenomics model. Mann–Whitney U test and ROC curves were used to assess the effectiveness of the radiogenomics marker.
Results
NMF methods successfully clustered patients into diverse subtypes according to gene expression levels in the tumor microenvironment (TME). The relative abundance of 10 immune cell populations in each tissue was also analyzed. The immune-related genomic signature (consisting of eight genes) of the tumor was shown to be significantly associated with survival in patients with ccRCC in TCGA database. The immune-related genomic signature was delineated by grouping the signature expression as either low- or high-risk. Using TCIA database, we constructed a radiogenomics biomarker consisting of 11 radiomic features that were optimal predictors of immune-related gene signature expression levels, which demonstrated AUC (area under the ROC curve) values of 0.76 and 0.72 in the training and validation groups, respectively. The nomogram built by combining radiomics and clinical pathological information could further improve the predictive efficacy of the radiogenomics model (AUC = 0.81, 074).
Conclusions
The novel prognostic radiogenomics biomarker achieved excellent correlation with the immune-related gene expression status of patients with ccRCC and could successfully stratify the survival status of patients in TCGA database. It is anticipated that this work will assist in selecting precise clinical treatment strategies. This study may also lead to precise theranostics for patients with ccRCC in the future.
Kinases play critical role in clear-cell renal cell carcinoma (ccRCC). We aim to exploit novel kinase that is both protumorigenic and drugable in ccRCC.
Reproduction of public datasets with ...validation using microarray was performed to identify candidate gene. Functionality was studied using multi-omics with validation in vitro and in vivo.
6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) was differentially expressed showing significantly higher expression in tumor than in normal kidney. PFKFB4 overexpression was associated with advanced tumor grade, stage and worsened prognosis. PFKFB4-knockdown significantly impaired fitness in cell proliferation, migration and wound healing. Despite being recurrently deleted on 3p, PFKFN4 mRNA remained actively transcribed by HIF1α. Metabolomics showed overexpressed PFKFB4 showed enriched metabolites in pentose phosphate pathway (PPP). Phosphoproteomics and immunoprecipitation showed PFKFB4 also phosphorylated NCOA3 which interacted with FBP1 to counteract overactive PPP flux, forming a regulatory loop. PFKFB4-knockdown overcame resistance to Sunitinib in vitro and in vivo both in xenograft and tail-vein injection murine models.
We concluded PFKFB4 was associated with PPP activity and the fine-tuning of which was mediated by its phosphorylation of NCOA3. Targeting PFKFB4 held promise to combat resistance to Sunitinib.
Circular RNA UVRAG (circUVRAG), a type of non‐coding RNA, is derived and cyclized by part of the exon from the UVRAG gene. However, the role of circUVRAG in bladder cancer (BLCA) has not been ...reported. The purpose of the present study was therefore to characterize the role of circUVRAG in BLCA. Bioinformatics analysis showed interactive relationships among circUVRAG, microRNA‐223 (miR‐223), and fibroblast growth factor receptor 2 (FGFR2). Quantitative real‐time PCR was used to detect the expression of circUVRAG in BLCA cell lines. UM‐UC‐3 cells were stably transfected with siRNA against circUVRAG, and cell proliferation and migration ability were tested using the CCK8 assay, clone formation, and Transwell assays in vitro. Tumor xenograft formation and metastasis were determined using nude mice. Fluorescence in situ hybridization was used to confirm the subcellular localization of circUVRAG, and the luciferase reporter assay was used to confirm the relationships among circUVRAG, miR‐223, and FGFR2. Results showed that circUVRAG was upregulated in BLCA cell lines. Downregulation of circUVRAG expression suppressed proliferation and metastasis both in vitro and in vivo. Downregulation of circUVRAG suppressed FGFR2 expression by “sponging” miR‐223, which was confirmed by rescue experiments and luciferase reporter assay. Overall, the results showed that downregulation of circUVRAG suppressed the aggressive biological phenotype of BLCA. Taken together, silencing circular RNA UVRAG inhibited bladder cancer growth and metastasis by targeting the miR‐223/FGFR2 axis, which may provide a potential biomarker and therapeutic target for the management of BLCA.
This study found that silencing circular RNA UVRAG inhibited bladder cancer growth and metastasis by targeting the miR‐223/FGFR2 axis, which may provide a potential biomarker and therapeutic target for the management of BLCA.
BackgroundVirtual reality (VR) is a technology that produces a virtual manifestation of the real world. In recent years, VR has been increasingly used as a tool in medical education. The use of VR in ...medical education has large potential, as it allows for distance learning and training which may be challenging to deliver in real life. VR encompasses different tools and applications. There is a need to explore how VR has been employed in medical education to date.ObjectiveThe objective of this scoping review is to conceptualise the VR tools available and the applications of VR in undergraduate medical education as reported in the literature. This scoping review will identify any gaps in this field and provide suggestions for future research.Methods and analysisThe relevant studies will be examined using the Joanna Briggs Institute methodological framework for scoping studies. A comprehensive search from a total of six electronic databases and grey literature sources will be performed. The reference list of included studies will be screened for additional studies. The screening and data extraction will be done in parallel and independently by two review authors. Any discrepancies will be resolved through consensus or discussion with a third review author. A data extraction form has been developed using key themes from the research questions. The extracted data will be qualitatively analysed and presented in a diagrammatic or tabular form, alongside a narrative summary, in line with Preferred Reporting Items for Systematic Reviews and Meta-Analysis: extension for Scoping Reviews reporting guidelines.Ethics and disseminationAll data will be collected from published and grey literature. Ethics approval is therefore not a requirement. We will present our findings at relevant conferences and submit them for publications in peer-reviewed journals.
The magic bullet: Niclosamide Jiang, Haowen; Li, Albert M; Ye, Jiangbin
Frontiers in oncology,
11/2022, Letnik:
12
Journal Article
Recenzirano
Odprti dostop
The term 'magic bullet' is a scientific concept proposed by the German Nobel laureate Paul Ehrlich in 1907, describing a medicine that could specifically and efficiently target a disease without ...harming the body. Oncologists have been looking for a magic bullet for cancer therapy ever since. However, the current therapies for cancers-including chemotherapy, radiation therapy, hormone therapy, and targeted therapy-pose either pan-cytotoxicity or only single-target efficacy, precluding their ability to function as a magic bullet. Intriguingly, niclosamide, an FDA-approved drug for treating tapeworm infections with an excellent safety profile, displays broad anti-cancer activity in a variety of contexts. In particular, niclosamide inhibits multiple oncogenic pathways such as Wnt/β-catenin, Ras, Stat3, Notch, E2F-Myc, NF-κB, and mTOR and activates tumor suppressor signaling pathways such as p53, PP2A, and AMPK. Moreover, niclosamide potentially improves immunotherapy by modulating pathways such as PD-1/PDL-1. We recently discovered that niclosamide ethanolamine (NEN) reprograms cellular metabolism through its uncoupler function, consequently remodeling the cellular epigenetic landscape to promote differentiation. Inspired by the promising results from the pre-clinical studies, several clinical trials are ongoing to assess the therapeutic effect of niclosamide in cancer patients. This current review summarizes the functions, mechanism of action, and potential applications of niclosamide in cancer therapy as a magic bullet.
Activation and infiltration of macrophages in adipose tissue are closely linked to obesity and are implicated in the pathogenesis of metabolic diseases. Glutamine is an essential energy resource that ...supports the inflammatory activation of macrophages, however, the underlying mechanism remains unknown. We found that AMP-activated protein kinase (AMPK) was the key regulator for mitochondrial glutamine metabolism. Once inflammatory activation of macrophages, increased ATP production from glutaminolysis inhibited the activity of AMPK, then removed its inhibitory effect of glutamine metabolism, resulting in the succinate accumulation derived IL-1β production and secretion. Mechanically, macrophage AMPK phosphorylated at Ser60 of succinyl-CoA synthetase β subunit (SUCLA2) that was responsible for catalyzing the succinate production, decreases its activity resulting in the reduction of the succinate accumulation derived IL-1β production and secretion correspondingly. Moreover, myeloid cell-specific knockout of the α subunit of AMPK exacerbated obesity and insulin resistance through IL-1β production and secretion in macrophages. Both the obstruction of the IL-1β signaling pathway by the neutralizing antibody and the decreasing of IL-1β production and secretion by myeloid cell-specific knockout of IL-1β could repair insulin resistance and obesity derived by AMPK deficiency in macrophages. Our study revealed that AMPK-mediated SUCLA2 phosphorylation drove the mitochondrial glutamine metabolism and the IL-1β production and secretion in macrophages, and targeting macrophage AMPK-SUCLA2 pathway might be a potential strategy for obesity and insulin resistance therapy.
Disclosure
H.Jiang: None.
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