Laparoscopy is non-inferior to open surgery for rectal cancer: A systematic review and meta-analysis.

BACKGROUND: Laparoscopic surgery has been endorsed by clinical guidelines for colon cancer, but not for rectal cancer on account of unapproved oncologic equivalence with open surgery. AIMS: We started this largest-to-date meta-analysis to comprehensively evaluate the safety and efficacy of laparoscopy in the treatment of rectal cancer compared with open surgery. MATERIALS & METHODS: Both randomized and nonrandomized controlled trials comparing laparoscopic proctectomy and open surgery between January 1990 and March 2020 were searched in PubMed, Cochrane Library and Embase Databases (PROSPERO registration number CRD42020211718). The data of intraoperative, pathological, postoperative and survival outcomes were compared between two groups. RESULTS: Twenty RCTs and 93 NRCTs including 216,615 patients fulfilled the inclusion criteria, with 48,888 patients received laparoscopic surgery and 167,727 patients underwent open surgery. Compared with open surgery, laparoscopic surgery group showed faster recovery, less complications and decreased mortality within 30 days. The positive rate of circumferential margin (RR = 0.79, 95% CI: 0.72 to 0.85, p < 0.0001) and distal margin (RR = 0.75, 95% CI: 0.66 to 0.85 p < 0.0001) was significantly reduced in the laparoscopic surgery group, but the completeness of total mesorectal excision showed no significant difference. The 3-year and 5-year local recurrence, disease-free survival and overall survival were all improved in the laparoscopic surgery group, while the distal recurrence did not differ significantly between the two approaches. CONCLUSION: Laparoscopy is non-inferior to open surgery for rectal cancer with respect to oncological outcomes and long-term survival. Moreover, laparoscopic surgery provides short-term advantages, including faster recovery and less complications.

A Novel Phenazine Analog, CPUL1, Suppresses Autophagic Flux and Proliferation in Hepatocellular Carcinoma: Insight from Integrated Transcriptomic and Metabolomic Analysis.

BACKGROUND: CPUL1, a phenazine analog, has demonstrated potent antitumor properties against hepatocellular carcinoma (HCC) and indicates a promising prospect in pharmaceutical development. However, the underlying mechanisms remain largely obscure. METHODS: Multiple HCC cell lines were used to investigate the in vitro effects of CPUL1. The antineoplastic properties of CPUL1 were assessed in vivo by establishing a xenograft nude mice model. After that, metabolomics, transcriptomics, and bioinformatics were integrated to elucidate the mechanisms underlying the therapeutic efficacy of CPUL1, highlighting an unanticipated involvement of autophagy dysregulation. RESULTS: CPUL1 suppressed HCC cell proliferation in vitro and in vivo, thereby endorsing the potential as a leading agent for HCC therapy. Integrative omics characterized a deteriorating scenario of metabolic debilitation with CPUL1, presenting an issue in the autophagy contribution of autophagy. Subsequent observations indicated that CPUL1 treatment could impede autophagic flow by suppressing autophagosome degradation rather than its formation, which supposedly exacerbated cellular damage triggered by metabolic impairment. Moreover, the observed late autophagosome degradation may be attributed to lysosome dysfunction, which is essential for the final stage of autophagy and cargo disposal. CONCLUSIONS: Our study comprehensively profiled the anti-hepatoma characteristics and molecular mechanisms of CPUL1, highlighting the implications of progressive metabolic failure. This could partially be ascribed to autophagy blockage, which supposedly conveyed nutritional deprivation and intensified cellular vulnerability to stress.

Development of an immune-related gene prognostic risk model and identification of an immune infiltration signature in the tumor microenvironment of colon cancer.

BACKGROUND: Colon cancer is a common and highly malignant tumor. Its incidence is increasing rapidly with poor prognosis. At present, immunotherapy is a rapidly developing treatment for colon cancer. The aim of this study was to construct a prognostic risk model based on immune genes for early diagnosis and accurate prognostic prediction of colon cancer. METHODS: Transcriptome data and clinical data were downloaded from the cancer Genome Atlas database. Immunity genes were obtained from ImmPort database. The differentially expressed transcription factors (TFs) were obtained from Cistrome database. Differentially expressed (DE) immune genes were identified in 473 cases of colon cancer and 41 cases of normal adjacent tissues. An immune-related prognostic model of colon cancer was established and its clinical applicability was verified. Among 318 tumor-related transcription factors, differentially expressed transcription factors were finally obtained, and a regulatory network was constructed according to the up-down regulatory relationship. RESULTS: A total of 477 DE immune genes (180 up-regulated and 297 down-regulated) were detected. We developed and validated twelve immune gene models for colon cancer, including SLC10A2, FABP4, FGF2, CCL28, IGKV1-6, IGLV6-57, ESM1, UCN, UTS2, VIP, IL1RL2, NGFR. The model was proved to be an independent prognostic variable with good prognostic ability. A total of 68 DE TFs (40 up-regulated and 23 down-regulated) were obtained. The regulation network between TF and immune genes was plotted by using TF as source node and immune genes as target node. In addition, Macrophage, Myeloid Dendritic cell and CD4+ T cell increased with the increase of risk score. CONCLUSION: We developed and validated twelve immune gene models for colon cancer, including SLC10A2, FABP4, FGF2, CCL28, IGKV1-6, IGLV6-57, ESM1, UCN, UTS2, VIP, IL1RL2, NGFR. This model can be used as a tool variable to predict the prognosis of colon cancer.

Isolation and proteomic profiling of urinary exosomes from patients with colorectal cancer.

Exosomes in the body fluid are effective cell-derived membranous structures transferring various molecules to mediate intercellular communication. The expression of protein in the urinary exosomes from the colorectal cancer (CRC) patients could reflect the characteristics of tumorigenesis. The urinary exosomes with globular membrane structure, the size of 30 ~ 100 nm and positive expression of CD9, CD63 and CD81 were successfully isolated from 9 CRC patients and 3 heathy adults using the density gradient ultracentrifugation. Proteome profiles revealed by label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) indicated that several proteins were differentially expressed among different stages of CRC. Compared with normal controls, 67 proteins in CRC urinary exosomes were upregulated and 74 proteins were downregulated. The bioinformatics analysis revealed the decreased proteins were related to ESCRT III complex disassembly. The CHMP family was further determined to be the hub of interaction network of proteins enriched in ESCRT signaling. The significant decrease of CHMP4A, CHMP4B, CHMP2A, CHMP2B and CHMP1B were respectively found in the total CRC group and distant metastasis group compared with NC group. Moreover, the CEACAM family also showed significant aberrant changes in the urinary exosomes of CRC patients. The CEACAM7 and CEACAM1 were increased in the CRC patients compared with healthy individuals (P < 0.05). Significant changes of proteomic profile could be found in the urinary exosomes in the CRC patients. The differential expressed urinary exosomes derived proteins showed potential usage in diagnosis and prognosis of CRC.

In vitro co-culture systems of hepatic and intestinal cells for cellular pharmacokinetic and pharmacodynamic studies of capecitabine against colorectal cancer.

BACKGROUND: As a prodrug of 5-fluorouracil (5-FU), orally administrated capecitabine (CAP) undergoes preliminary conversion into active metabolites in the liver and then releases 5-FU in the gut to exert the anti-tumor activity. Since metabolic changes of CAP play a key role in its activation, a single kind of intestinal or hepatic cell can never be used in vitro to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) nature. Hence, we aimed to establish a novel in vitro system to effectively assess the PK and PD of these kinds of prodrugs. METHODS: Co-culture cellular models were established by simultaneously using colorectal cancer (CRC) and hepatocarcinoma cell lines in one system. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis were used to evaluate cell viability and apoptosis, respectively. Apoptosis-related protein expression levels were measured using western blot analysis. A selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for cellular PK in co-culture models. RESULTS: CAP had little anti-proliferative effect on the five monolayer CRC cell lines (SW480, LoVo, HCT-8, HCT-116 and SW620) or the hepatocarcinoma cell line (HepG2). However, CAP exerted marked anti-tumor activities on each of the CRC cell lines in the co-culture models containing both CRC and hepatocarcinoma cell lines, although its effect on the five CRC cell lines varied. Moreover, after pre-incubation of CAP with HepG2 cells, the culture media containing the active metabolites of CAP also showed an anti-tumor effect on the five CRC cell lines, indicating the crucial role of hepatic cells in the activation of CAP. CONCLUSION: The simple and cost­effective co-culture models with both CRC and hepatocarcinoma cells could mimic the in vivo process of a prodrug dependent on metabolic conversion to active metabolites in the liver, providing a valuable strategy for evaluating the PK and PD characteristics of CAP-like prodrugs in vitro at the early stage of drug development.

Immunomagnetic-bead enriched culturomics (IMBEC) for isolating pathobionts from feces of colorectal cancer patients.

Culturomics employs various cultivating conditions to obtain different types of bacteria and new species. However, current culturomics lacks a highly efficient method for isolating specific pathobionts. Immunomagnetic bead technology, which uses magnetic beads conjugated with antibodies for capturing the antigen to realize enrichment of the targets, has been employed as an alternative method. In this study, we developed a novel method, immunomagnetic bead-enriched culturomics (IMBEC), in which magnetic bead-conjugated antibodies purified from the fecal samples of patients with colorectal cancer (CRC) were used to enrich and isolate potential pathobionts. A protocol for enriching potential pathobionts via immunomagnetic capture was developed by optimizing the concentrations of coupling reagents, NaCl, and detergent. The efficacy of pathobiont enrichment was compared between antibody-coated magnetic beads (antibody group) and nonconjugated blank magnetic beads (blank group). To determine the proinflammatory potential of isolates from both groups, we investigated their ability to induce cytokine production in THP-1 macrophages. This protocol was employed for isolating bacteria from 10 fecal samples of patients with CRC, which were simultaneously compared with those isolated from the blank group. A total of 209 bacterial species were isolated from both groups, including 173 from the antibody group, 160 from the blank group, and 124 from both groups. Bacteria isolated from the antibody group produced more proinflammatory cytokines than those isolated from the blank group. IMBEC is a promising method for relatively specific isolation of potential pathobionts for a particular disease of interest.

Development and validation of a liquid chromatography-tandem mass spectrometry method for CPUL1, a novel antitumor candidate compound, and its application to pharmacokinetic studies.

An active substance of pyrano[3,2-a]phenazine, also called CPUL1, is a synthesized phenazine derivative and displays broad-spectrum anticancer activities. Quantitative assessment of CPUL1 in biological samples has not been well established, hindering pharmaceutical development and application. According to international guidelines, a sensitive and selective liquid chromatography-tandem mass spectrometry method in negative ion mode was developed and validated for quantification of CPUL1 in human plasma, colorectal cancer cell lines, and rat plasma, whereby linearity and accuracy were demonstrated for the range of 1-1000 ng/ml. The validated liquid chromatography-tandem mass spectrometry method was successfully employed in pharmacokinetic studies of CPUL1 in vitro and in vivo. Notably, the cellular pharmacokinetic behavior of CPUL1 varies in colorectal cancer cell lines. Regarding the pharmacokinetic processes in vivo, oral absorption was less effective than an injection, with a bioavailability of 23.66%. CPUL1 was linearly eliminated after a single administration; however, it could accumulate in tissues (heart, liver, spleen, lung, and kidney) after multiple injections. In summary, this study established a capable bioanalytical method for CPUL1 and provided exploratory pharmacokinetic data, paving the way for use of this promising derivative in disease models.

Brain metastasis from colorectal cancer: Treatment, survival, and prognosis.

To investigate the clinical characteristics, survival, prognostic factors, and treatment of brain metastasis (BM) from colorectal cancer (CRC). Twenty-one patients with BM from CRC were retrospectively reviewed. Predictive factors for BM and prognostic factors after the diagnosis of BM were examined by univariate and multivariate COX analysis. The time from the development of extracranial metastases, including lung, bone, and liver, to the occurrence of BM was recorded separately. The median overall survival time was 7 months. In univariate prognostic analysis, median survival with multimodal therapy was better than that with unimodal therapy (10 months vs 3 months, P = .000). In addition, median survival with Karnofsky performance status (KPS) < 70, 1 BM lesion, primary tumor stage of II-III, extracranial lesions < 2, and no extracranial metastasis were much better than the other groups (P < .05 of all). Although there was not a significant difference in median survival between patients receiving combination treatment with bevacizumab and those who did not, treatment with bevacizumab was associated with better survival (10 months vs 5 months, P = .436). The time intervals from bone, liver, and lung metastases to BM were 3, 6.5, and 11 months, respectively. Based on multivariate Cox analysis, KPS and treatment modalities were independent prognosis factors (P = .039 and P = .000, respectively). CRC patients with a high KPS and multimodal treatment have improved survival.

Berberine suppresses the migration and invasion of colon cancer cells by inhibition of lipogenesis through modulation of promyelocytic leukemia zinc finger-mediated sterol-regulatory element binding proteins cleavage-activating protein ubiquitination.

OBJECTIVES: This study was aimed to explore whether and how berberine suppresses colon cancer cell metastasis via lipid modulation. METHODS: Lipid accumulation was measured by an oil red O staining kit. The expression of proteins and message RNA was detected by Western blot and quantitative real-time PCR. The interaction of sterol-regulatory element-binding proteins cleavage-activating protein (SCAP) with promyelocytic leukaemia zinc finger (PLZF) was confirmed by co-immunoprecipitation assay. Expressions of fatty acid synthase (FASN) and PLZF were knocked down by specific small interfering RNA. KEY FINDINGS: Berberine inhibited the migration and invasion of HCT-8, HCT-116 and HT-29 cells. Moreover, it was observed that berberine decreased lipid droplet accumulation. FASN knockdown abolished the inhibitory effects of berberine on cell migration and invasion. Further investigation revealed that berberine induced the ubiquitination degradation of SCAP. And PLZF interacted with SCAP and promoted its ubiquitination, which was inhibited by berberine treatment. Silence of PLZF impaired the effects of berberine on SCAP ubiquitination and lipogenesis. CONCLUSIONS: Berberine suppressed lipogenesis via promotion of PLZF-mediated SCAP ubiquitination, thereby inhibiting colon cancer cell metastasis.

Prognostic value of myosteatosis in patients with lung cancer: a systematic review and meta-analysis.

The prognostic value of myosteatosis has been widely investigated in lung cancer, yet conclusions remain controversial. The purpose of this meta-analysis was to illuminate this issue. Medline, Embase, Cochrane Library and Web of Science Core Collection online databases were systematically searched from inception to 24 September 2021. Newcastle-Ottawa Scale tool was applied to evaluate the quality of included studies. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) were used to examine prognostic value of myosteatosis. Subgroup analysis and sensitivity analysis were conducted to assess heterogeneity and stability of results. A total of 484 articles were screened from which 9 eligible studies involving 1667 patients were enrolled in this meta-analysis. Lung cancer patients with myosteatosis had significantly worse OS than patients without myosteatosis (HR 1.10, 95% CI 1.05-1.16, P < 0.001), both in six multivariate analysis (HR 1.46, 95% CI 1.16-1.85, P = 0.001) and in three univariate analysis (HR 1.08, 95% CI 1.03-1.14, P = 0.003). Pooled data from five studies using multivariate survival analysis also showed that patients with myosteatosis had a statistically significant unfavorable PFS (HR = 1.27, 95% CI 1.00-1.62, P = 0.049). Sensitivity analysis showed the result for OS was stable. But for PFS, the result was not robust. Myosteatosis might serve as an independent indicator of unfavorable survival outcomes for OS and PFS in lung cancer patients. Further studies are needed to confirm our results.

Metagenomics analysis of cultured mucosal bacteria from colorectal cancer and adjacent normal mucosal tissues.

Introduction. Colorectal cancer (CRC) is one of the most common cancers worldwide. Multiple risk factors are involved in CRC development, including age, genetics, lifestyle, diet and environment. Of these, the role of the gut microbiota in cancer biology is increasingly recognized.Hypothesis/Gap Statement. Micro-organisms have been widely detected in stool samples, but few mucosal samples have been detected and sequenced in depth.Aim. Analysis of cultured mucosal bacteria from colorectal cancer and adjacent normal mucosal tissues with metagenomics sequencing.Methodology. Twenty-eight paired tumour and non-tumour tissues from 14 patients undergoing surgery for CRC were analysed. We removed the influence of eukaryotic cells via culture. The composition of mucosal microbiota in intestinal mucosa were detected and analysed with metagenomic sequencing.Results. Compared with non-cultured mucosal sample, 80 % bacteria species could be detected after culture. Moreover, after culture, additional 30 % bacteria could be detected, compared with non-cultured samples. Since after culture it was difficult to estimate the original abundance of microbiome, we focused on the identification of the CRC tissue-specific species. There were 298 bacterial species, which could only be cultured and detected in CRC tissues. Myroides odoratimimus and Cellulophaga baltica could be isolated from all the tumour samples of 14 CRC patients, suggesting that these species may be related to tumour occurrence and development. Further functional analysis indicated that bacteria from CRC tissues showed more active functions, including basic metabolism, signal transduction and survival activities.Conclusion. We used a new method based on culture to implement information on prokaryotic taxa, and related functions, which samples were from colorectal tissues. This method is suitable for removing eukaryotic contamination and detecting micro-organisms from other tissues.

Identification of Biomarkers Associated with Hepatocellular Carcinoma Stem Cell Characteristics Based on Co-Expression Network Analysis of Transcriptome Data and Stemness Index.

Mounting evidence has revealed the key role of cancer stem cells in hepatocellular carcinoma (HCC) metastasis and therapy resistance, yet the genes maintaining HCC stem cell features remain to be explored. This study aimed to identify and validate the key biomarkers associated with HCC stemness. mRNA expression-based stemness index (mRNAsi) was calculating using one-class logistic regression algorithm. RNA-sequencing data and clinical information of HCC samples were downloaded from the cancer genome atlas (TCGA) and merged with the corresponding mRNAsi. We investigated the correlation between mRNAsi and HCC clinical characteristics, including tumor grades, pathologic stages, vascular invasion, and survival outcomes. Significant genes associated HCC stemness features were screened through weighted gene co-expression network analysis (WGCNA) and were functionally annotated using enrichment analysis. Protein-protein interaction network was constructed among significant genes and the key biomarkers were finally identified based on the maximal clique centrality (MCC) method. The expression of key biomarkers and its correlation with HCC clinical outcomes were validated using oncomine and gene expression omnibus (GEO) database. mR-NAsi was significantly higher in HCC tissues and gradually increased according to tumor grades and pathologic stages. Patients with vascular invasion or poor survival exhibited higher mRNAsi. Forty-four highly-correlated significant gens were screened through WGCNA and functionally related to cell cycle, cellular senescence, p53 signaling pathway, DNA replication, and mismatch repair. Four different GEO datasets confirmed that the expression levels of these 44 genes were notably higher in HCC tissues. We finally identified 15 key biomarkers (KIF4A, TTK, CCNB1, CDC20, NCAPG, CCNB2, CDC45, UBE2C, CENPA, AURKB, RRM2, CDCA8, BIRC5, TPX2, and KIF2C) through MCC method. The expression of these biomarkers was up-regulated in multiple types of cancers and showed a gradually increasing trend with HCC tumor grades. Furthermore, high expression levels of these biomarkers were also correlated with HCC metastasis, recurrence, sorafenib resistance, and poor overall survival. We identified 15 key biomarkers associated with HCC stemness features and these genes might serve as promising therapeutic targets for HCC.

Prognostic value of YKL-40 in colorectal carcinoma patients: A meta-analysis.

BACKGROUND: In recent years, the predictive role of YKL-40 for long-term survival in colorectal cancer patients has been gradually investigated. However, whether it is a reliable and valuable prognostic indicator for patients with colorectal carcinoma has not been verified. AIM: To identify the prognostic value of serum/plasma concentration of YKL-40 or expression status of YKL-40 in tumor cells in colorectal carcinoma patients. METHODS: Several electronic databases including the PubMed, EMBASE, Web of Science, CNKI, VIP and WanFang were searched for relevant studies. The hazard ratios (HR) and 95% confidence intervals (CI) were combined and the primary and secondary outcomes were overall survival (OS) and progression-free survival (PFS), respectively. All statistical analysis were conducted by STATA 15.0 software. RESULTS: A total of nine studies involving 2545 patients were included. The pooled results indicated that YKL-40 was significantly associated with poor OS (HR = 1.80, 95%CI: 1.32-2.45, P < 0.001) and PFS (HR = 1.62, 95%CI: 1.22-2.16, P = 0.001). Subgroup analysis stratified by the treatment, tumor type and source of YKL-40 showed similar results. CONCLUSION: Elevated serum/plasma concentration of YKL-40 or positive expression in tumor cells was related with worse prognosis of colorectal carcinoma patients. YKL-40 might serve as a novel and reliable indicator for the evaluation of prognosis in colorectal cancer.

Emerging Mechanisms and Disease Implications of Ferroptosis: Potential Applications of Natural Products.

Ferroptosis, a newly discovered form of regulatory cell death (RCD), has been demonstrated to be distinct from other types of RCD, such as apoptosis, necroptosis, and autophagy. Ferroptosis is characterized by iron-dependent lipid peroxidation and oxidative perturbation, and is inhibited by iron chelators and lipophilic antioxidants. This process is regulated by specific pathways and is implicated in diverse biological contexts, mainly including iron homeostasis, lipid metabolism, and glutathione metabolism. A large body of evidence suggests that ferroptosis is interrelated with various physiological and pathological processes, including tumor progression (neuro)degenerative diseases, and hepatic and renal failure. There is an urgent need for the discovery of novel effective ferroptosis-modulating compounds, even though some experimental reagents and approved clinical drugs have been well documented to have anti- or pro-ferroptotic properties. This review outlines recent advances in molecular mechanisms of the ferroptotic death process and discusses its multiple roles in diverse pathophysiological contexts. Furthermore, we summarize chemical compounds and natural products, that act as inducers or inhibitors of ferroptosis in the prevention and treatment of various diseases. Herein, it is particularly highlighted that natural products show promising prospects in ferroptosis-associated (adjuvant) therapy with unique advantages of having multiple components, multiple biotargets and slight side effects.

The Potential Clinical Value of Curcumin and its Derivatives in Colorectal Cancer.

BACKGROUND: Curcumin, a naturally occurring polyphenol, possesses pleiotropic pharmacologic properties, including anti-inflammatory and anti-oxidant activities. Epidemiological evidence suggests that curcumin intake is associated with a reduced risk of Colorectal Cancer (CRC), highlighting the enormous potential of this botanical agent in the prevention and treatment of CRC. OBJECTIVE: We summarize the anticancer activity of curcumin and its derivatives in CRC. METHODS: We conducted a literature review on the therapeutic effects of curcumin and its derivatives in CRC. RESULTS: In this review, a summary of the activities of curcumin in the treatment of CRC regarding its bioavailability, anticancer activity, modes of action, curcumin delivery systems have been provided based on the researches from preclinical experiments. Also, we discuss the therapeutic effects of curcumin derivatives in CRC. The human clinical trials that used curcumin or curcumin derivatives for the treatment of CRC are also highlighted here. CONCLUSION: Curcumin possesses great potential as a chemopreventive agent in CRC. Moreover, emerging evidence reveals that it can be an effective adjuvant to CRC therapy. To date, few studies have explored the anticolon cancer activity of curcumin formulation and curcumin derivatives in vivo; therefore, more works are needed to confirm their effectiveness. In clinical trials, curcumin treatment protocols (formulation, dose, and duration) vary among studies. However, these trials consistently point out that the compound is well-tolerated and safe, albeit with little consensus on its therapeutic efficacy.

Significant diagnostic value of circulating tumour cells in colorectal cancer.

Circulating tumour cells (CTCs) have potential utility in various clinical applications for cancer management. The present study focused on evaluating the diagnostic role of CTCs in colorectal cancer (CRC). A total of 89 blood samples from 59 patients diagnosed with CRC and 30 healthy individuals were collected for CTC detection. The Cyttel method is an improved CTC detection strategy, which combines negative enrichment with immunofluorescence and fluorescence in situ hybridization. This method effectively detected a significant increase in total CTCs in patients with CRC (49/59) compared with those in healthy controls (3/30). A cut-off value of 2 CTCs/3.2 ml blood yielded a sensitivity of 83.05% and a specificity of 100%. Additionally, three traditional serum tumour markers, namely carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9) and CA72-4, were examined by immunoassays. The diagnostic sensitivity of CTCs was much higher than that of CEA, CA19-9 and CA72-4 alone or in combination, particularly in patients with early stage CRC. The combined sensitivity of CTCs and CEA reached 91.53%, which was only slightly lower than the sensitivity of all four markers combined (CTCs + CEA + CA19-9 + CA72-4). CTCs with aneuploidy of chromosome 7 or 8 were carefully distinguished, and the associations among different types of CTCs, clinicopathological characteristics and overall survival were statistically analysed. Total CTCs were revealed to be significantly associated with tumour differentiation and nerve invasion. CTCs were more likely to be detected in poorly differentiated CRC tumours than in well- and moderately-differentiated tumours (P=0.026). Furthermore, to the best of our knowledge, the present study was the first to report that CTCs with multiploidy of chromosome 7 were significantly associated with TNM stage. These CTCs exhibited a high chance of being identified in the peripheral blood of patients with late-stage CRC (stage III-IV; P=0.031). The present study suggests that the combination of CTCs and CEA may serve as an effective potential diagnostic and prognostic indicator in patients with CRC. Detection of CTCs with aneuploidy may have increased specificity in predicting highly malignant and invasive tumours in CRC management.

The diagnostic and prognostic value of exosome-derived long non-coding RNAs in cancer patients: a meta-analysis.

PURPOSE: Exosome-derived long non-coding RNAs (lncRNAs) as novel biomarkers are widely investigated in various cancers, yet results remain controversial. The aim of this meta-analysis was to clarify the diagnostic and prognostic value of exosome-derived lncRNAs in cancer. METHODS: PubMed, Web of Science, EMBASE, CNKI, and WanFang online databases were comprehensively searched for eligible studies up to January, 2020. To evaluate the diagnostic effect, sensitivity, specificity, and area under the curve (AUC) were pooled. Threshold effect, subgroup analysis, and meta-regression were applied to explore heterogeneity. Deeks' funnel plot and sensitivity analysis were used to examine publication bias and stability of meta-analysis, respectively. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and recurrence free survival (RFS) were calculated to assess the prognostic value. RESULTS: A total of 29 eligible studies involving 3882 patients were enrolled in the meta-analysis, which included 26 on diagnosis and 11 on prognosis. For diagnosis analysis, the pooled sensitivity, specificity, and AUC were 0.83 (95% CI 0.78-0.87), 0.80 (95% CI 0.75-0.84), and 0.88 (95% CI 0.85-0.91), respectively. Meta-regression revealed that the cancer type acted as the potential source of heterogeneity. Sensitivity analysis and Deeks' funnel plot indicated that results were relatively robust and had no publication bias. For the prognosis analysis, results suggested that overexpression of exosome-derived lncRNAs which upregulated in cancer showed a significant association with poor OS (HR 2.21, 95% CI 1.79-2.71, p < 0.001). Conversely, overexpression of exosome-derived lncRNAs which downregulated in cancer was markedly related to better OS (HR 0.28, 95% CI 0.14-0.55, p < 0.001). CONCLUSION: This meta-analysis reveals that exosome-derived lncRNAs might serve as promising diagnostic and prognostic biomarkers for cancer. However, the clinical value of exosome-derived lncRNAs needs to be further confirmed.

Novel near-infrared fluorescent probe for live cell imaging.

Near infrared (NIR) fluorescent probes play a crucial role in biological system imaging. A novel NIR fluorescent probe, IR787, was designed in the present study. Compared with indocyanine green (ICG), IR787 showed lower background fluorescent interference and higher fluorescence enhancement. Fluorescence intensities were detected by a Cary Eclipse fluorescence spectrophotometer. The interference of intracellular ions (Cu2+, Ca2+, Mg2+ and Zn2+) on the measurement was negligible, which indicated a good photostability of IR787. MTT assay demonstrated that cell viability of human lung adenocarcinoma epithelial cell line A549 was not significantly affected by the use of the IR787 probe compared with the ICG probe. This result suggested that the IR787 probe was safe for in vitro cell imaging. In vitro NIR optical imaging experiments further revealed cellular uptake and strong intracellular NIR fluorescence of the IR787 probe in A549 cells. The excitation wavelength was 787 nm for IR787. Compared with the previously reported NIR fluorescent probe ICG, the IR787 NIR fluorescent probe had improved prospects for intracellular imaging. IR787 may play a pivotal role in the understanding cell biology, pharmacology and disease diagnosis.

Correction: Macrophage-derived CCL5 facilitates immune escape of colorectal cancer cells via the p65/STAT3-CSN5-PD-L1 pathway.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

FoxO3 reverses 5-fluorouracil resistance in human colorectal cancer cells by inhibiting the Nrf2/TR1 signaling pathway.

5-fluorouracil (5-FU) is widely used in chemotherapy for colorectal cancer (CRC), but a high rate of chemoresistance reduces its effectiveness in clinical treatment. We found remarkably decreased expression of forkhead box 3 (FoxO3) protein, a tumor inhibitor, in 5-FU-resistant SW620 and HCT-8 (SW620/5-FU and HCT-8/5-FU) cells. Moreover, FoxO3 overexpression sensitized SW620/5-FU and HCT-8/5-FU cells to 5-FU. Mechanistically, FoxO3 inhibited the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway by directly binding to Keap1 promoter. Thioredoxin reductase 1 (TR1), a pivotal target gene of Nrf2, was observed to promote 5-FU resistance by reducing intracellular ROS levels. Clinical data also revealed that significant upregulation of TR1 was associated with poor outcome in CRC patients. Auranofin (AUR), a FoxO3 agonist and TR1 inhibitor, enhanced the sensitivity of HCT-8/5-FU and SW620/5-FU cells to 5-FU in vitro and in vivo. Taken together, our results suggest that FoxO3 could reverse 5-FU resistance in CRC via inhibiting the Nrf2/TR1 signaling pathway, and increasing the level of intracellular reactive oxygen species. Chemotherapeutic agents targeting FoxO3 and/or TR1, including AUR, might be promising adjuvant sensitizers to reverse chemoresistance in 5-FU-resistant CRC.