TRIM29 facilitates gemcitabine resistance via MEK/ERK pathway and is modulated by circRPS29/miR-770-5p axis in PDAC.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. Chemotherapy based on gemcitabine (GEM) remains the first-line drug for patients with advanced PDAC. However, GEM resistance impairs its therapeutic effectiveness. Therefore, identifying effective therapeutic targets are urgently needed to overcome GEM resistance. METHODS: The clinical significance of Tripartite Motif Containing 29 (TRIM29) was identified by exploring GEO datasets and TCGA database and its potential biological functions were predicted by GSEA analysis. The regulatory axis was established by bioinformatics analysis and validated by mechanical experiments. Then, in vitro and in vivo assays were performed to validate the roles of TRIM29 in PDAC GEM resistance. RESULTS: High TRIM29 expression was associated with poor prognosis of PDAC and functional experiments demonstrated that TRIM29 promoted GEM resistance in PDAC GEM-resistant (GR) cells. Furthermore, we revealed that circRPS29 promoted TRIM29 expression via competitive interaction with miR-770-5p and then activated MEK/ERK signaling pathway. Additionally, both in vitro and in vivo functional experiments demonstrated that circRPS29/miR-770-5p/TRIM29 axis promoted PDAC GEM resistance via activating MEK/ERK signaling pathway. CONCLUSION: Our results identify the significance of the signaling axis, circRPS29/miR-770-5p/TRIM29-MEK/ERK, in PDAC GEM resistance, which will provide novel therapeutic targets for PDAC treatment.

PITPNC1 Suppress CD8+ T cell immune function and promote radioresistance in rectal cancer by modulating FASN/CD155.

BACKGROUND: Radioresistance is a primary factor contributing to the failure of rectal cancer treatment. Immune suppression plays a significant role in the development of radioresistance. We have investigated the potential role of phosphatidylinositol transfer protein cytoplasmic 1 (PITPNC1) in regulating immune suppression associated with radioresistance. METHODS: To elucidate the mechanisms by which PITPNC1 influences radioresistance, we established HT29, SW480, and MC38 radioresistant cell lines. The relationship between radioresistance and changes in the proportion of immune cells was verified through subcutaneous tumor models and flow cytometry. Changes in the expression levels of PITPNC1, FASN, and CD155 were determined using immunohistochemistry and western blotting techniques. The interplay between these proteins was investigated using immunofluorescence co-localization and immunoprecipitation assays. Additionally, siRNA and lentivirus-mediated gene knockdown or overexpression, as well as co-culture of tumor cells with PBMCs or CD8+ T cells and establishment of stable transgenic cell lines in vivo, were employed to validate the impact of the PITPNC1/FASN/CD155 pathway on CD8+ T cell immune function. RESULTS: Under irradiation, the apoptosis rate and expression of apoptosis-related proteins in radioresistant colorectal cancer cell lines were significantly decreased, while the cell proliferation rate increased. In radioresistant tumor-bearing mice, the proportion of CD8+ T cells and IFN-γ production within immune cells decreased. Immunohistochemical analysis of human and animal tissue specimens resistant to radiotherapy showed a significant increase in the expression levels of PITPNC1, FASN, and CD155. Gene knockdown and rescue experiments demonstrated that PITPNC1 can regulate the expression of CD155 on the surface of tumor cells through FASN. In addition, co-culture experiments and in vivo tumor-bearing experiments have shown that silencing PITPNC1 can inhibit FASN/CD155, enhance CD8+ T cell immune function, promote colorectal cancer cell death, and ultimately reduce radioresistance in tumor-bearing models. CONCLUSIONS: PITPNC1 regulates the expression of CD155 through FASN, inhibits CD8+ T cell immune function, and promotes radioresistance in rectal cancer.

CT-based radiomics nomograms for preoperative prediction of diffuse-type and signet ring cell gastric cancer: a multicenter development and validation cohort.

BACKGROUND: The prevalence of diffuse-type gastric cancer (GC), especially signet ring cell carcinoma (SRCC), has shown an upward trend in the past decades. This study aimed to develop computed tomography (CT) based radiomics nomograms to distinguish diffuse-type and SRCC GC preoperatively. METHODS: A total of 693 GC patients from two centers were retrospectively analyzed and divided into training, internal validation and external validation cohorts. Radiomics features were extracted from CT images, and the Lauren radiomics model was established with a support vector machine (SVM) classifier to identify diffuse-type GC. The Lauren radiomics nomogram integrating radiomics features score (Rad-score) and clinicopathological characteristics were developed and evaluated regarding prediction ability. Further, the SRCC radiomics nomogram designed to identify SRCC from diffuse-type GC was developed and evaluated following the same procedures. RESULTS: Multivariate analysis revealed that Rad-scores was significantly associated with diffuse-type GC and SRCC (p < 0.001). The Lauren radiomics nomogram showed promising prediction performance with an area under the curve (AUC) of 0.895 (95%CI, 0.957-0.932), 0.841 (95%CI, 0.781-0.901) and 0.893 (95%CI, 0.831-0.955) in each cohort. The SRCC radiomics nomogram also showed good discrimination, with AUC of 0.905 (95%CI,0.866-0.944), 0.845 (95%CI, 0.775-0.915) and 0.918 (95%CI, 0.842-0.994) in each cohort. The radiomics nomograms showed great model fitness and clinical usefulness by calibration curve and decision curve analysis. CONCLUSION: Our CT-based radiomics nomograms had the ability to identify the diffuse-type and SRCC GC, providing a non-invasive, efficient and preoperative diagnosis method. They may help guide preoperative clinical decision-making and benefit GC patients in the future.

Color mismatch and observer metamerism between conventional liquid crystal displays and organic light emitting diode displays.

Organic light emitting diode (OLED) displays use red, green, and blue primaries with a higher saturation level to produce larger color gamuts than conventional liquid crystal displays (LCD). No past study, however, experimentally investigated how such a difference between these two display types causes color mismatch and observer metamerism using the most widely used color matching functions (CMFs)-the CIE 1931 2° CMFs-for color calibration and specification. In this study, 50 human observers performed color matching tasks for six color stimuli with a field-of-view of 4.77° between four test displays (i.e., one LCD and three OLED) and a reference OLED display. The color gamuts of the LCD and OLED displays were similar to the sRGB and P3 standard color gamuts. It was found the CIE 1931 2° CMFs cannot accurately characterize the color matches between the LCD and OLED displays, with different chromaticities required to produce matched color appearance. Particularly, when the stimuli had matched color appearance, the chromaticities of the stimuli produced by the LCD display were all shifted towards the -u'+v' direction in the CIE 1976 u'v' chromaticity diagram in comparison to those produced by the OLED display. This suggested that using the CIE 1931 2° CMFs for display calibration would cause the colors shown on OLED displays to have a yellow-green tint if those on LCD displays appear neutral. In addition, a larger degree of observer metamerism was found between the LCD and OLED displays, while little differences, in terms of color mismatch and observer metamerism, were found between the OLED displays. The CIE 2006 2° CMFs were found to have better performance than the CIE 1931 2°, 1964 10°, and 2006 10° CMFs, which could be partially due to the size of the stimulus used in the experiment.

Mucormycosis-induced upper gastrointestinal ulcer perforation in immunocompetent patients: a report of two cases.

BACKGROUND: Gastrointestinal mucormycosis (GIM) is a rare, opportunistic fungal infection with poor prognosis. Clinically, it is difficult to diagnose GIM owing to its nonspecific clinical symptoms and poor suspicion. The estimated incidence of GIM is inaccurate, and most cases are diagnosed accidentally during surgery or upon postmortem examination. GIM usually occurs in patients with immune deficiencies or diabetes. Here, we report two cases of immunocompetent young patients with GIM who had good prognosis after treatment. Compared to other case reports on GIM, our cases had unusual infection sites and no obvious predisposing factors, which make it important to highlight these cases. CASE PRESENTATION: The first case was that of a 16-year-old immunocompetent boy who was admitted with gastrointestinal bleeding and perforation due to a gastric ulcer. Strategies used to arrest bleeding during emergency gastroscopy were unsuccessful. An adhesive mass was then discovered through laparoscopy. The patient underwent type II gastric resection. Pathological examination of the mass revealed bacterial infection and GIM. The second case was of a 33-year-old immunocompetent woman with a recent history of a lower leg sprain. The patient subsequently became critically ill and required ventilatory support. After hemodynamic stabilization and extubation, she presented with hematemesis due to exfoliation and necrosis of the stomach wall. The patient underwent total gastrectomy plus jejunostomy. The pathology results revealed severe bacterial infection and fungal infection that was confirmed as GIM. The patient fully recovered after receiving anti-infective and antifungal treatments. CONCLUSIONS: Neither patient was immunosuppressed, and both patients presented with gastrointestinal bleeding. GIM was confirmed via pathological examination. GIM is not limited to immunocompromised patients, and its diagnosis mainly relies on pathological examination. Early diagnosis, timely surgical treatment, and early administration of systemic drug treatment are fundamental to improving its prognosis.

Multifunctional AIE iridium (III) photosensitizer nanoparticles for two-photon-activated imaging and mitochondria targeting photodynamic therapy.

Developing novel photosensitizers for deep tissue imaging and efficient photodynamic therapy (PDT) remains a challenge because of the poor water solubility, low reactive oxygen species (ROS) generation efficiency, serve dark cytotoxicity, and weak absorption in the NIR region of conventional photosensitizers. Herein, cyclometalated iridium (III) complexes (Ir) with aggregation-induced emission (AIE) feature, high photoinduced ROS generation efficiency, two-photon excitation, and mitochondria-targeting capability were designed and further encapsulated into biocompatible nanoparticles (NPs). The Ir-NPs can be used to disturb redox homeostasis in vitro, result in mitochondrial dysfunction and cell apoptosis. Importantly, in vivo experiments demonstrated that the Ir-NPs presented obviously tumor-targeting ability, excellent antitumor effect, and low systematic dark-toxicity. Moreover, the Ir-NPs could serve as a two-photon imaging agent for deep tissue bioimaging with a penetration depth of up to 300 µm. This work presents a promising strategy for designing a clinical application of multifunctional Ir-NPs toward bioimaging and PDT.

The Association between Depression and Type 1 Diabetes Mellitus: Inflammatory Cytokines as Ferrymen in between?

The depression incidence is much higher in patients with diabetes mellitus (DM), and the majority of these cases remain under-diagnosed. Type 1 diabetes mellitus (T1D) is now widely thought to be an organ-specific autoimmune disease. As a chronic autoimmune condition, T1D is characterized by T cell-mediated selective loss of insulin-producing ß-cells. The age of onset of T1D is earlier than T2D, and T1D patients have an increased vulnerability to depression due to its diagnosis and treatment burden occurring in a period when the individuals are young. The literature has suggested that inflammatory cytokines play a wide role in both diseases. In this review, the mechanisms behind the initiation and propagation of the autoimmune response in T1D and depression are analyzed, and the contribution of cytokines to both conditions is discussed. This review outlines the immunological mechanism of T1D and depression, with a particular emphasis on the role of tumor necrosis factor-α (TNF-α), IL-1ß, and interferon-γ (IFN-γ) cytokines and their signaling pathways. The purpose of this review is to highlight the possible pathways of the cytokines shared by these two diseases via deciphering their cytokine cascades. They may provide a basic groundwork for future study of the possible mechanism that links these two diseases and to develop new compounds that target the same pathway but can conquer two diseases.

Detection of FAM172A expressed in circulating tumor cells is a feasible method to predict high-risk subgroups of colorectal cancer.

Previous studies used to enumerate circulating tumor cells to predict prognosis and therapeutic effect of colorectal cancer. However, increasing studies have shown that only circulating tumor cells enumeration was not enough to reflect the heterogeneous condition of tumor. In this study, we classified different metastatic-potential circulating tumor cells from colorectal cancer patients and measured FAM172A expression in circulating tumor cells to improve accuracy of clinical diagnosis and treatment of colorectal cancer. Blood samples were collected from 45 primary colorectal cancer patients. Circulating tumor cells were enriched by blood filtration using isolation by size of epithelial tumor cells, and in situ hybridization with RNA method was used to identify and discriminate subgroups of circulating tumor cells. Afterwards, FAM172A expression in individual circulating tumor cells was measured. Three circulating tumor cell subgroups (epithelial/biophenotypic/mesenchymal circulating tumor cells) were identified using epithelial-mesenchymal transition markers. In our research, mesenchymal circulating tumor cells significantly increased along with tumor progression, development of distant metastasis, and vascular invasion. Furthermore, FAM172A expression rate in mesenchymal circulating tumor cells was significantly higher than that in epithelial circulating tumor cells, which suggested that FAM172A may correlate with malignant degree of tumor. This hypothesis was further verified by FAM172A expression in mesenchymal circulating tumor cells, which was strictly related to tumor aggressiveness factors. Mesenchymal circulating tumor cells and FAM172A detection may predict highrisk stage II colorectal cancer. Our research proved that circulating tumor cells were feasible surrogate samples to detect gene expression and could serve as a predictive biomarker for tumor evaluation.

FAM172A is a tumor suppressor in colorectal carcinoma.

The present study was designed to elucidate the regulatory role of a novel protein FAM172A in carcinogenesis of colorectal carcinoma (CRC). Investigation of clinical samples using Western blotting showed that expression of FAM172A is significantly lower in cancerous tissues than in adjacent tissues. Furthermore, we constructed in vitro model for continuous overexpression and silencing of FAM172A with a retroviral vector system. FAM172A suppressed the proliferative and invasive potentials of LOVO cells as shown in MTT test, transwell migration assay, wound healing assay, 3D-culture morphologic study, and xenograft experiment. RT-PCR and Western blotting showed that FAM172A overexpression inhibited expressions of Cyclin D1, CDK2, MMP-2, MMP-9, PERK, elF2α, ATF6, XBP1, and GRP78, while FAM172A silencing induced their expressions. FAM172A might regulate ERS through PERK-elF2α, ATF6-XBP1-GRP78 signal pathway. The results implicated that FAM172A functioned as a tumor suppressor in colorectal carcinoma.

CPP2-p16MIS treatment-induced colon carcinoma cell death in vitro and prolonged lifespan of tumor-bearing mice.

BACKGROUND: Cell-penetrating peptides (CPPs) are a research hotspot due to their noninvasive delivery ability. Among the identified CPPs, the TAT and R8 peptides have been preferentially applied to transduction into different cells. However, this process is nonselective among various cells. Recent research suggested that CPP2 could selectively penetrate human colorectal cancer (CRC) cells. METHODS: Using in vitro experiments, the mean fluorescence intensity of fluorescein isothiocyanate-labeled CPPs (CPPs-FITC) incubated with different cell lines was compared to corroborate the colon tumor targeting ability of CPP2. The targeting ability of CPP2 was determined in the same way in tumor-bearing mice. We synthesized antitumor peptides by fusing CPP2 to the minimal inhibitory sequence of p16 (p16MIS), which had the ability to restore the function of lost p16, the expression of which was absent in tumor cell lines of various origins. The antitumor effect of the combined peptide was tested in both CRC cell lines and tumor-bearing mice. RESULTS: In each CRC cell line, the mean fluorescence intensity of CPP2-FITC was higher than that of the TAT-FITC (p < 0.001) and R8-FITC (p < 0.001) groups. CPP2-p16MIS, the targeting carrier, showed a higher antitumor response in the in vitro cell research. CPP2-p16MIS showed a prolonged mean lifespan of tumor-bearing mice, further characterizing its role in specific tumor-targeting ability in vivo. Survival analysis showed that the mice treated with CPP2-p16MIS had significantly longer survival than the mice treated with phosphate-buffered saline (p < 0.05) or those treated with control peptides, including the CPP2 (p < 0.05) and p16MIS (p < 0.05) groups. CONCLUSION: CPP2 could more selectively penetrate CRC cells than TAT or R8 as well as effectively deliver the p16MIS to the tumor.

Transcriptional regulation of gene expression by microRNAs as endogenous decoys of transcription factors.

BACKGROUND/AIMS: MicroRNAs (miRNAs) are known to produce post-transcriptional repression of gene expression. In light of the ability of decoy oligodeocynucleotides (ODNs) to sequestrate transcription factors (TFs) and the similar double-stranded structure between decoy ODNs and miRNAs, we proposed that miRNAs might act as endogenous decoy molecules to produce transcriptional regulation of gene expression. METHODS: Quantitative real-time RT-PCR analysis was used to measure the changes of miRNA and mRNA expression. Luciferase reporter gene activity assay was used to investigate the functional interaction between miRNAs and TFs. Electrophoresis mobility shift assay (EMSA) and modified chromatin immunoprecipitation assay (ChIP) were utilized to investigate the physical interactions between miRNAs and TFs. MTT cell viability assay and cellular DNA fragmentation ELISA were used to study apoptotic cell death. RESULTS: We presented here that miRNAs could regulate, either negatively or positively, gene expression at the transcriptional level through its decoy-like actions and this mechanism operates under physiological conditions to produce cellular functions. We identified the putative cis-elements for transcriptional factors NF-κB and NFAT in the mature miR-939 and miR-376a, respectively. We experimentally established the ability of these miRNAs to physically bind their respective target TFs, using EMSA and ChIP methods. We then utilized the luciferase reporter gene assay to characterize the specific regulation of luciferase gene activities by miR-939/pre-miR-939:NF-κB or miR-376a/pre-miR-376a:NFAT interactions. Moreover, miR-939 and miR-376a produced transcriptional regulation of endogenous genes Bcl-xL and FasL/miR-26 that are the transcriptional targets for NF-kB and NFAT, respectively, but are not post-transcriptional targets for these two miRNAs. Finally, interference of these miRNAs with NF-κB and NFAT demonstrated clear phenotypes at the cellular level as manifested by the regulation of neuroblastoma cell death by miR-939 and miR-376a. CONCLUSION: Our study identified a novel non-canonical mechanism of miRNAs and suggests that when considering the cellular function of miRNAs the decoy-like mechanism for transcriptional regulation (activation or repression) should be taken into account.

Polarizer-free imaging of liquid crystal lens.

An image processing method is proposed to realize polarizer-free imaging of liquid crystal lens. Images I(l) and I(nl) are captured sequentially in the lens and non-lens states of the LC lens, respectively, and are used to generate a final high contrast image. The proposal is tested by experiments. Clear and well focused images are obtained, even though no polarizer is employed in the imaging system.

Cell-free DNA methylation profiles enable early detection of colorectal and gastric cancer.

Colorectal cancer (CRC) and gastric cancer (GC) rank the top five common and lethal cancers worldwide. Early detection can significantly reduce the mortality of CRC and GC. However, current clinical screening methods including invasive endoscopic techniques and noninvasive fecal occult blood test screening tests/fecal immunochemical test have shown low sensitivity or unsatisfactory patient's compliance. Aberrant DNA methylation occurs frequently in tumorigenesis and cell-free DNA (cfDNA) methylation has shown the potential in multi-cancer detection. Herein, we aimed to explore the value of cfDNA methylation in the gastrointestinal cancer detection and develop a noninvasive method for CRC and GC detection. We applied targeted methylation sequencing on a total of 407 plasma samples from patients diagnosed with CRC, GC, and noncancerous gastrointestinal benign diseases (Non-Ca). By analyzing the methylation profiles of 34 CRC, 62 GC and 107 Non-Ca plasma samples in the training set (n=203), we identified 40,110 gastrointestinal cancer-specific markers and 63 tissue of origin (TOO) prediction markers. A new integrated model composed of gastrointestinal cancer detection and TOO prediction for three types of classification of CRC, GC and Non-Ca patients was further developed through logistic regression algorithm and validated in an independent validation set (n=103). The model achieved overall sensitivities of 83% and 81.3% at specificities of 81.5% and 80% for identifying gastrointestinal cancers in the test set and validation set, respectively. The detection sensitivities for GC and CRC were respectively 81.4% and 83.3% in the cohort of the test and validation sets. Among these true positive cancer samples, further TOO prediction showed accuracies of 95.8% and 95.8% for GC patients and accuracies of 86.7% and 93.3% for CRC patients, in test set and validation set, respectively. Collectively, we have identified novel cfDNA methylation biomarkers for CRC and GC detection and shown the promising potential of cfDNA as a noninvasive gastrointestinal cancer detection tool.

Glutamine metabolism targeting liposomes for synergistic chemosensitization and starvation therapy in ovarian cancer.

Platinum-based chemotherapy is a first-line therapeutic regimen against ovarian cancer (OC); however, the therapeutic potential is always reduced by glutamine metabolism. Herein, a valid strategy of inhibiting glutamine metabolism was proposed to cause tumor starvation and chemosensitization. Specifically, reactive oxygen species-responsive liposomes were developed to co-deliver cisplatin (CDDP) and bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) [C@B LPs]. The C@B LPs induced effective tumor cell starvation and significantly sensitized OC cells to CDDP by reducing glutathione generation to prevent CDDP detoxification, suppressing ATP production to avoid CDDP efflux, hindering nucleotide synthesis to aggravate DNA damage induced by CDDP, and blocking mammalian target of rapamycin (mTOR) signaling to promote cell apoptosis. More importantly, C@B LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs. STATEMENT OF SIGNIFICANCE: This work proposed a valid strategy of inhibiting glutamine metabolism to cause tumor starvation and chemosensitization. Specifically, ROS-responsive liposomes were developed to co-deliver cisplatin CDDP and BPTES [C@B LPs]. The C@B LPs induced effective tumor cell starvation and significantly sensitized OC cells to cisplatin by reducing glutathione generation to prevent cisplatin detoxification, suppressing ATP production to avoid cisplatin efflux, hindering nucleotide synthesis to aggravate DNA damage induced by cisplatin, and blocking mTOR signaling to promote cell apoptosis. More importantly, C@B LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs.

Clinical Efficacy of Laparoscopic-Assisted Proximal Gastrectomy with Postoperative Double-Channel Digestive Tract Reconstruction: A Case-Control Analysis.

Objective: To investigate the clinical effect of laparoscopic-assisted proximal gastrectomy with postoperative double-channel digestive tract reconstruction. Methods: A total of 40 patients with proximal gastric cancer who underwent gastrectomy in Zhujiang Hospital, Southern Medical University, were selected to collect relevant clinical data. They were divided into two groups according to their treatment methods: TG-RY group (total gastrectomy with Roux-en-Y reconstruction group) and PG-DT group (proximal gastrectomy with double tract reconstruction group). The general data, perioperative indicators, nutritional indicators, and postoperative complications of the two groups were analyzed and compared. Results: There was no statistical significance in the comparison of general data between the two groups, but the proportion of III stage patients of TNM stage in the PG-DT group was larger than that in the TG-RY group. Meanwhile, the intraoperative blood loss, postoperative hospital stay, and first exhaust time in PG-DT group were lower than those in TG-RY group (P < 0.05). After surgery, the nutritional indexes of the PG-DT group decreased, and the decrease degree was less than that of the TG-RY group, while the infection indicators of the PG-DT group increased less than that of the TG-RY group. Statistical analysis of postoperative complications showed that the total incidence of PG-DT group was lower than that of TG-RY group. Conclusion: Proximal gastric cancer resection and postoperative DTR anastomosis can effectively speed up the recovery of patients and reduce the incidence of postoperative complications, with good efficacy. This experiment provides evidence for the advantages of various postoperative anastomosis methods and also provides a reliable basis for clinicians' diagnosis and treatment, thus effectively improving patients' postoperative quality of life.

Effects of miR-939 and miR-376A on ulcerative colitis using a decoy strategy to inhibit NF-κB and NFAT expression.

The aim of this study was to explore the effects of miR-939 and miR-376A on the pathogenesis of ulcerative colitis (UC) by using a decoy strategy to regulate the expression of nuclear transcription factor kappa B (NF-κB) and nuclear factor of activated T cells (NFAT). Such strategies represent a potential novel treatment for UC. Quantitative polymerase chain reaction (qPCR) analysis was used to detect the differences between the expression of miR-939, miR-376a, NF-κB, NFAT in the tissue samples from the resting and active stages of UC and healthy controls, and analyzed the correlation. The electrophoretic mobility shift assay was used to validate the ability of miRNAs to bind to NF-κB and NFAT. The expression of components of the intestinal barrier in UC and changes in apoptosis-related factors were examined by western blotting, qPCR, and immunofluorescence. After a dextran sulfate sodium (DSS)-induced mouse model of UC was established, the morphological changes in the colonic tissues of mice, the changes in serum inflammatory factors, and the changes in urine protein or urine leukocytes, liver enzymes, and prothrombin time were measured to examine intestinal permeability. The expression of miR-939 and miR-376a in human UC tissue was significantly lower than that in the normal control tissue, and was negatively correlated with the expression of NF-κB and NFAT. miR-939 and miR-376a decoy strategies resulted in a beneficial increase in the expression of claudins, occludins, and ZO-1 protein and inhibited apoptosis in intestinal epithelial cells. The disease activity index of the UC model group was significantly higher than that of the normal control group. The expression of inflammatory factors in the decoy group was higher than that in the UC model group. Therefore, from the experimental results, it can be concluded that using miR-939 and miR-376a to trap NF-κB and NFAT inhibits the activation of transcription factors NF-κB and NFAT, which in turn inhibits the expression of inflammatory factors and results in partial recovery of the intestinal barrier in UC. The decoy strategy inhibited apoptosis in the target cells and had a therapeutic effect in the mice model of UC. This study provides new ideas for the development of future clinical therapies for UC.

The intestinal microbiota influences the microenvironment of metastatic colon cancer by targeting miRNAs.

This study aimed to investigate the molecular mechanisms through which the intestinal microbiota and microRNAs (miRNAs) participate in colon cancer metastasis. Intestinal flora data, and the GSE29621 (messenger RNA/long non-coding RNA [mRNA/lncRNA]) and GSE29622 (miRNA) datasets, were downloaded from The Cancer Gene Atlas and Gene Expression Omnibus databases, respectively. Immune-related cells in M1 vs. M0 samples were analyzed using the Wilcoxon test. Furthermore, an lncRNA-miRNA-mRNA (competing endogenous RNA [ceRNA]) network was constructed, and survival analysis of RNAs in the network was performed. A total of 16 miRNA-genus co-expression pairs containing eight microbial genera and 15 miRNAs were screened; notably, Porphyromonas and Bifidobacterium spp. were found to be associated with most miRNAs, and has-miR-3943 was targeted by most microbial genera. Furthermore, five immune cell types, including activated natural killer cells, M1 macrophages, resting mast cells, activated mast cells and neutrophils, were differentially accumulated between the M1 and M0 groups. Enrichment analysis suggested that mRNAs related to colon cancer metastasis were mainly involved in pathways related to bacterial and immune responses. Survival analysis revealed that TMEM176A and PALM3 in the ceRNA network were significantly associated with the prognosis of patients with colon cancer. In conclusion, this study revealed a potential mechanism by which the intestinal microbiota influences the colon cancer microenvironment by targeting miRNAs.

A novel DNA methylation marker to identify lymph node metastasis of colorectal cancer.

Lymph node metastasis (LNM) of colorectal cancer (CRC) is an important factor for both prognosis and treatment. Given the deficiencies of conventional tests, we aim to discover novel DNA methylation markers to efficiently identify LNM status of CRC. In this study, genome-wide methylation sequencing was performed in a cohort (n=30) using fresh CRC tissue to discover differentially methylated markers. These markers were subsequently validated with fluorescence quantitative PCR in a cohort (n=221), and the optimal marker was compared to conventional diagnostic methods. Meanwhile, immunohistochemistry was used to verify the effectiveness of the antibody corresponding to this marker in a cohort (n=56). LBX2 achieved an AUC of 0.87, specificity of 87.3%, sensitivity of 75.7%, and accuracy of 81.9%, which outperformed conventional methods including imaging (CT, PET-CT) with an AUC of 0.52, CA199 with an AUC of 0.58, CEA with an AUC of 0.56. LBX2 was also superior to clinicopathological indicators including the depth of tumor invasion and lymphatic invasion with an AUC of 0.61and 0.63 respectively. Moreover, the AUC of LBX2 antibody was 0.84, which was also better than these conventional methods. In conclusion, A novel methylation marker LBX2 could be used as a simple, cost-effective, and reliable diagnostic method for LNM of CRC.