The present study aimed to explore the mechanism by which the immune landscape of the tumor microenvironment influences bladder cancer. CIBERSORT and ssGSEA analyses revealed that M2 macrophages accounted for the highest proportion from 22 subsets of tumor-infiltrating immune cells and were enriched in higher histologic grade and higher pathologic stage bladder cancer and ‘basal’ subtype of muscle invasive bladder cancer (MIBC). Kaplan-Meier survival curve analysis indicated that patients with high numbers of infiltrating M2 macrophages had worse overall and disease-specific survival rates. RNA sequencing and immunohistochemistry results indicated that M2 macrophages were enriched in MIBC and promoted angiogenesis. M2 macrophage infiltration was higher in bladder cancer tissues with mutant TP53, RB transcriptional corepressor 1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α, lysine methyltransferase 2A, lysine demethylase 6A and apolipoprotein B mRNA editing enzyme catalytic-polypeptide-like, but lower in tissues with mutant fibroblast growth factor receptor 3 (FGFR3), E74-like ETS transcription factor 3, PC4 and SFRS1 interacting protein 1 and transmembrane and coiled-coil domains 4. In addition, M2 macrophage infiltration was lower in the tissues with amplified FGFR3, erb-b2 receptor tyrosine kinase 2, BCL2-like 1, telomerase reverse transcriptase and tyrosine-3-monooxygenase/tryptophan-5-monooxygenase activation protein ζ, as well as in the tissues with deleted cyclin-dependent kinase inhibitor 2A, CREB binding protein, AT-rich interaction domain 1A, fragile histidine triad diadenosine triphosphatase, phosphodiesterase 4D, RAD51 paralog B, nuclear receptor corepressor 1 and protein tyrosine phosphatase receptor type D. Finally, seven micro (mi) RNAs (miR-214-5p, miR-223-3p, miR-155-5p, miR-199a-3p, miR-199b-3P, miR-146b-5p, miR-142-5p) which were expressed differentially in at least three mutant genes and were positively correlated with M2 macrophage infiltration as well as expressed highly in high grade bladder cancer were identified. Overall, the present study concluded that M2 macrophages are the predominant tumor-infiltrating immune cell in bladder cancer and differentially expressed miRNAs due to cancer-specific genomic alterations may be important drivers of M2 macrophage infiltration. These findings suggested that M2 macrophage infiltration may serve as a potential immunotherapy target in bladder cancer.

BackgroundTo examine the microbial profiles in parenchyma tissues in bladder cancer.MethodsTissue samples of cancerous bladder mucosa were collected from patients diagnosed with bladder cancer (22 carcinoma tissues and 12 adjacent normal tissues). The V3‐V4 region of the bacterial 16S rRNA gene was PCR amplified, followed by sequencing on an Illumina MiSeq platform. Bioinformatics analysis for microbial classification and functional assessment was performed to assess bladder microbiome diversity and variations.ResultsThe predominant phylum in both tissues was Proteobacteria. The cancerous tissues exhibited lower species richness and diversity. Beta diversity significantly differed between the cancerous and normal tissues. Lower relative abundances of the microbial genera Lactobacillus, Prevotella_9, as well as Ruminococcaceae were observed, whereas those of Cupriavidus spp., an unknown genus of family Brucellaceae, and Acinetobacter, Anoxybacillus, Escherichia‐Shigella, Geobacillus, Pelomonas, Ralstonia, and Sphingomonas were higher in the cancerous tissues. These findings indicate that these genera may be potentially utilized as biomarkers for bladder cancer. PICRUSt analysis revealed that several pathways involved in the metabolism of harmful chemical compounds were enriched in the cancer tissues, thereby providing evidence that environmental factors are strongly associated with bladder cancer etiology.ConclusionThis is the first study that has described and analyzed the dysbiotic motifs of urinary microbiota in the parenchymatous tissues of bladder cancer via 16S rRNA gene sequencing. Our results suggest that changes in the bladder microbiome may serve as biomarkers for bladder cancer, possibly assisting in disease screening and monitoring.

We present a procedure for bisecting a tetrahedron T successively into an infinite sequence of tetrahedral meshes ¡Tü , ZTX , ST1, ... , which has the following properties: (1) Each mesh !Tn is conforming.(2) There are a finite number of classes of similar tetrahedra in all the ¿Tn , n > 0. (3) For any tetrahedron T? in ¿T" , n(T") > cxn(T), where n is a tetrahedron shape measure and cx is a constant. (4) <5(T?) < c2(l/2)"/3«5(T), where

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