Biomimetic modification of macrophage membrane-coated prussian blue nanoparticles loaded with SN-38 to treat colorectal cancer by photothermal-chemotherapy.

SN-38 is the active metabolite of irinotecan and acts as an effective topoisomerase I inhibitor with therapeutic effects on many malignant tumors, including some drug-resistant cancers. However, the poor solubility, low bioavailability, and severe dose-dependent toxicity limits the clinical application of SN-38. Currently, emerging macrophage membrane-coated nanoparticles provide an efficient biomimetic approach to develop novel SN-38 formulations for the reduction of its side effects. Photothermal therapy (PTT) is a promising methods in tumor treatment to thermally ablate tumors using various materials such Prussian blue nanoparticles (NPs) and can combined with chemotherapy to synergistically work. There is no report that combined SN38 and photothermal therapy for the treatment of colorectal cancer (CRC). SN38-PB@CM NPs were constructed by loading SN-38 into macrophage cell membrane-coated hollow mesoporous Prussian blue (PB) NPs. The morphology, size and zeta potential were evaluated by transmission microscopy and dynamic light scatter (DLS). Coomassie bright blue staining was performed to assess total protein profile. The photothermal properties of it were also investigated via near-infrared imaging. CCK8 and calcein-AM/PI staining were used to evaluate cell viability. Flow cytometry was performed to assess cell apoptosis. The fluorescent microscopy was used to observe cellular uptake of SN38-PB@CM NPs to assess its internalization in vitro. The biodistribution, tumor-targeting efficacy, antitumor efficacy and safety of SN38-PB@CM NPs in vivo were assessed in CT26 tumor-bearing mice via In Vivo Imaging System. SN38-PB@CM NPs were successfully constructed and exhibited a uniform size distribution (140.5 ± 4.3 nm) and an excellent drug-loading capacity (5.61 ± 0.64%). SN38-PB@CM NPs showed stable release properties within 72 h. It can also enhance the selective intracellular delivery of SN38 in vitro and showed good near-infrared (NIR) photothermal properties. And the NPs showed excellent tumor targeting, effective photothermal therapy, improved biosafety and antitumor efficacy on CT26-bearing mice. Multifunctional SN38-PB@CM NPs could achieve improved biosafety, great tumor-targeting, high-efficiency PTT and excellent antitumor efficacy, which provided a promising and attractive combination therapy for the treatment of CRC.

Identification and validation of core genes in tumor-educated platelets for human gastrointestinal tumor diagnosis using network-based transcriptomic analysis.

Gastrointestinal (GI) tumors have increasing incidence worldwide with their underlying mechanisms still not being fully understood. The use of tumor-educated platelets (TEPs) in liquid biopsy is a newly-emerged blood-based cancer diagnostic method. Herein, we aimed to investigate the genomic changes of TEPs in GI tumor development and their potential functions using network-based meta-analysis combined with bioinformatic methods. We used a total of three eligible RNA-seq datasets, which were integrated using multiple meta-analysis methods on the NetworkAnalyst website, and identified 775 DEGs (differentially expressed genes; 51 up-regulated and 724 down-regulated genes) in GI tumor relative to healthy control (HC) samples. These TEP DEGs were mostly enriched in bone marrow-derived cell types and associated with gene ontology (GO) of "carcinoma" and could affect pathways of "Integrated Cancer Pathway" and "Generic transcription pathway" respectively for highly and lowly expressed DEGs. Combined network-based meta-analysis and protein-protein interaction (PPI) analysis identified cyclin dependent kinase 1 (CDK1) and heat shock protein family A (Hsp70) member 5 (HSPA5) to be the hub genes with the highest degree centrality (DC), being up-regulated and down-regulated in TEPs, respectively. GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that the hub genes were primarily related to cell cycle and division, nucleobase-containing compound and carbohydrate transport, and endoplasmic reticulum unfolded protein response. Additionally, the nomogram model suggested that the two-gene signature owns extraordinary predictive power for GI tumor diagnosis. Further, the two-gene signature was demonstrated to have potential value for metastatic GI tumor diagnosis. The expression levels of CDK1 and HSPA5 in clinical platelet samples were verified to be consistent with the results from bioinformatic analysis. This study identified a two-gene signature encompassing CDK1 and HSPA5 that can be used as a biomarker for GI tumor diagnosis and maybe even cancer-associated thrombosis (CAT)-related prognosis.

What is the context? Gastrointestinal (GI) tumors are now responsible for the majority of cancer-related mortalities worldwide.In the majority of cases of cancer, curative treatments are not recommended at the time of diagnosis. In this case, early screening and diagnosis is very important for overall tumor prognosis. Liquid biopsy emerged as a newly introduced minimally invasive approach for cancer diagnosis by detecting blood analytes as tumor-educated platelets (TEPs). Compared to tissue-based biopsies, liquid biopsies are less invasive, easy to access, convenient for serial tracking and better in eliminating intratumoral spatial heterogeneity. In recent years, specific gene signatures have been identified for cancer diagnosis, prognosis and prediction based on gene profiling data of TEPs. However, most of these studies were performed on the independent platelet profile datasets published on the Gene Expression Omnibus (GEO) database, which may harbor enormous heterogeneity. Additionally, few study revealed TEP mRNA functions and roles in GI tumors. Therefore, there's the need of using an integrated method to re-analyze these data, so we can gain new insights for GI tumor diagnosis.What is new? Herein, through network-based RNA-seq meta-analysis, we identified the CDK1-HSPA5 signature in TEPs that has the potential as a biomarker for diagnosing GI tumors. This is the first time, to our knowledge, that a shared transcriptional signature of tumor-educated platelets has been identified in human GI tumor patients based on meta-analysis. Additionally, we found the two-gene signature has potential value for metastatic GI tumor diagnosis. We also demonstrated that HSPA5 may have different roles in blood and tumor cells, so its expression deregulation in distinct types of tissue may have opposing diagnostic and prognostic values.What is the impact? Our work provides a novel biomarker for platelet-based GI tumor prediction and diagnosis, which may also be used as novel targets for thrombosis prevention during cancer development in the future.

A propensity score matching study of totally robotic right hemicolectomy versus robot-assisted right hemicolectomy.

To compare and analyze the differences in safety, feasibility and short-term efficacy between robot-assisted right hemicolectomy (RARH) and totally robotic right hemicolectomy (TRRH). We collected the information of 184 patients who underwent right hemicolectomy in the Second Xiangya Hospital of Central South University from July 2016 to December 2021. We matched 148 patients (74 with robot-assisted right hemicolectomy and 74 with totally robotic right hemicolectomy) to conduct a retrospective analysis of their clinical outcomes. The incision lengths were 5.14 ± 0.60 cm in the RARH group and 4.74 ± 0.55 cm in the TRRH (p < 0.001). The blood losses were 86.28 ± 52.57 mL in the RARH group and 69.19 ± 44.78 mL in the TRRH (p = 0.035). The operative times were 197.50 min (171.25-242.25) in the RARH group and 160.00 min (145.00-188.75) in the TRRH (p < 0.001). The postoperative hospital stays were 11.18 ± 4.32 days in the RARH group and 9.53 ± 4.42 days in the TRRH (p = 0.023). The NRS pain scores were 3.05 ± 0.23 in the RARH group and 2.96 ± 0.26 in the TRRH (p = 0.019). The abdominal drainage extraction times were 7.54 ± 1.44 days in the RARH group and 7.00 ± 1.25 days in the TRRH (p = 0.016). Postoperative complications in the RARH group are fewer than TRRH (p = 0.033). TRRH is safe and feasible. Compared with RARHs, the TRRHs resulted in shorter incision lengths, operative times, intraoperative blood losses, postoperative hospital stays, first flatus times, first liquid diet times, and drainage tube removal times, and they improved NRS pain scores and postoperative complication frequencies.

A systematic analysis of C5ORF46 in gastrointestinal tumors as a potential prognostic and immunological biomarker.

Background: Chromosome 5 open reading frame 46 (C5ORF46), also known as antimicrobial peptide with 64 amino acid residues (AP-64) and skin and saliva-secreted protein 1 (SSSP1), belongs to the family of open reading frame genes and encodes a small exosomal protein. C5ORF46 has been implicated in antibacterial activity and associated with patient prognosis in pancreatic cancer, colorectal cancer, and stomach cancer. These findings highlight the importance of C5ORF46 in gastrointestinal (GI) tumor inception and development. However, the prognostic and immunological value of C5ORF46 in human GI tumors remains largely unknown. In this study, we sought to explore the potential value of C5ORF46 in GI tumor prognosis and immunology. Method: RNA sequencing (RNA-seq) was performed on the tumor and tumor-adjacent normal samples we collected to identify potential target genes for GI tumors. Apart from our RNA-seq data, all original data were downloaded from The Cancer Genome Atlas (TCGA) database and integrated via Strawberry Perl (v 5.32.0) and R (v 4.1.1). The differential expression of C5ORF46 was examined with Oncomine, Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), Cancer Cell Line Encyclopedia (CCLE), the Human Protein Atlas (HPA) and TCGA databases. The c-BioPortal database was used to investigate the genomic alterations of C5ORF46. The effect of C5ORF46 on prognosis and clinical phenotypes was explored via bioinformatics analyses on the TCGA and GEPIA databases. We used the bioinformatics analyses based on the TCGA database to analyze tumor mutational burden (TMB), microsatellite instability (MSI), tumor immune cell infiltration, and the correlations between C5ORF46 expression and several immune-related genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was carried out via the DAVID website and presented as bubble charts using ShengXinRen online tools. Gene set enrichment analysis (GSEA) was performed using R scripts based on data downloaded from the GSEA website. Immunohistochemistry (IHC) was used to validate the expression of C5ORF46 in GI tumors. Results: The results of our RNA-seq data indicated a critical role for C5ORF46 in colon carcinogenesis. Consistently, we demonstrated that C5ORF46 was highly expressed in tumor tissues compared to normal tissues in human GI tumors. Moreover, a strong correlation was observed between C5ORF46 expression levels and patient prognosis, staging, TMB, MSI, and immune cell infiltration. Further, C5ORF46 presented as an important regulator in the tumor microenvironment (TME) and was active in the regulation of cancer immune functions. C5ORF46 is significantly correlated with genes regulating inflammation and immune responses. Conclusion: C5ORF46 may serve as a biomarker for GI tumor prognosis and immunology. C5ORF46 could be a novel target for GI tumor immunotherapy.

PPARGC1A affects inflammatory responses in photodynamic therapy (PDT)-treated inflammatory bowel disease (IBD).

BACKGROUND: Chronic inflammation of the gastrointestinal tract is a feature of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Targeting inflammatory signaling represents promising strategy for IBD treatment regimens. METHODS: Dextran sulfate sodium (DSS)-induced colitis model was established in mice. Histopathological examinations were conducted by H&E staining and IHC staining. IL-1ß, IL-10, and TNF-α were tested by ELISA kits. TargetScan was used to predict miRNAs that target PPARGC1A and luciferase activity assay was performed to validate the predicted binding. RESULTS: DSS-induced acute colitis model was successfully established in mice; photodynamic therapy (PDT) treatment partially improved DSS-induced colonic damages and cell inflammation. Microarray assays and integrative bioinformatics analysis identified PPARG coactivator 1 alpha (PPARGC1A) as a significantly differentially-expressed gene in PDT-treated IBD compared with non-treated IBD. PPARGC1A expression was downregulated in IBD clinical samples, DSS-induced colitis mice colons, and DSS-stimulated colonic epithelial cells, whereas partially upregulated by PDT treatment in DSS-stimulated cells. Single DSS stimulation significantly promoted cellular inflammation; PDT partially attenuated, whereas sh-PPARGC1A transduction further enhanced DSS effects on cancer cell inflammation. In colitis mice, DSS decreased PPRA-α and PPRA-γ proteins in mice colons; the in vivo effects of DSS were partially attenuated by PDT treatment, whereas amplified by sh-PPARGC1A transduction. Upstream miR-301a-3p targeted and inhibited PPARGC1A expression. CONCLUSIONS: Collectively, PPARGC1A, which is downregulated in DSS-induced acute colitis and DSS-stimulated colonic epithelial cells, could be upregulated by PDT treatment. PPARGC1A knockdown could attenuate PDT therapeutic effects on DSS-induced acute colitis and DSS-stimulated colonic epithelial cells.