Individuals with inflammatory bowel disease are at high risk of developing colitis‐associated cancer (CAC). Strategies to block the process from inflammatory bowel disease to CAC should be considered. In the experiment, we aim to explore the chemopreventive efficacy of the probiotic cocktail Bifico and its potential mechanism in azoxymethane and dextran sodium sulphate‐induced CAC in mice. Oral pretreatment of Bifico was adopted to evaluate its protective effect. The colorectums of 35 C57BL/6 mice were collected and examined for the degree of inflammation and tumorigenesis. Comparative 16S rRNA sequencing was carried out to observe Bifico‐target alterations in gene expression and microbiota structure. We found that pretreatment of Bifico alleviated intestinal inflammation and reduced tumor formation. Furthermore, we identified a subset of genes as potential targets of Bifico treatment, including CXCL1,CXCL2,CXCL3, and CXCL5, which are all ligands of C‐X‐C motif receptor 2 (CXCR2). The 16S rRNA sequencing showed that Bifico decreased the abundance of genera Desulfovibrio, Mucispirillum, and Odoribacter, and a bloom of genus Lactobacillus was detected. Notably, we found that an abundance of these Bifico‐target taxa was significantly associated with the expression of CXCR2 ligand genes. Our studies indicate that Bifico, given orally, can ameliorate CAC in mice through intervening with the possible link between Desulfovibrio, Mucispirillum, Odoribacter, Lactobacillus, and CXCR2 signaling.

Transcriptional deregulation initiated by oncogenic fusion proteins plays a vital role in leukemia. The prevailing view is that the oncogenic fusion protein PML/RARα, generated by the chromosome translocation t(15;17), functions as a transcriptional repressor in acute promyelocytic leukemia (APL). Here we provide rich evidence of how PML/RARα drives oncogenesis through both repressive and activating functions, particularly the importance of the newly identified activation role for the leukemogenesis of APL. The activating function of PML/RARα is achieved by recruiting both abundant P300 and HDAC1 and by the formation of super-enhancers. All-trans retinoic acid and arsenic trioxide, two widely used drugs in APL therapy, exert synergistic effects on controlling super-enhancer-associated PML/RARα-regulated targets in APL cells. We utilize a series of in vitro and in vivo experiments to demonstrate that PML/RARα-activated target gene GFI1 is necessary for the maintenance of APL cells, and that PML/RARα, likely oligomerized, transactivates GFI1 through chromatin conformation at the super-enhancer region. Finally, we profile GFI1 targets and reveal the interplay between GFI1 and PML/RARα on chromatin in co-regulating target genes. Our study provides genomic insight into the dual role of fusion transcription factors in transcriptional deregulation to drive leukemia development, highlighting the importance of globally dissecting regulatory circuits.

SMAD family member 1 (Smad1) have been involved in metastatic progression of many cancer types. However, the detailed molecular signalling pathway underlying the regulatory link between Smad1 and metastasis remains elusive. Here, we demonstrate that Smad1 promotes migration of colorectal cancer (CRC) cells by inducing Snail and Ajuba expression simultaneously, but no apparent effect on Twist1 expression. Remarkably, E-cadherin, the best known Snail/Ajuba target gene is downregulated by Smad1 expression. Further, depletion of Ajuba in HCT116 cells significantly dampens the cell migration capability induced by Smad1 overexpression, suggesting that Ajuba is required for Smad1 to induce cell migration. Moreover, clinical analysis shows a significant positive correlation between the level of Smad1 and Ajuba in CRC samples. Together, our data provides the first evidence of the regulatory network of Smad1/Snail/Ajuba axis in CRC migration, suggesting that Smad1 and Ajuba are potential new therapeutic targets and prognostic factors for CRC.

The alteration of the enteric nervous system (ENS) and its role in neuroimmune modulation remain obscure in the pathogenesis of inflammatory bowel diseases (IBDs). Here, by using the xCell tool and the latest immunolabeling-enabled three-dimensional (3D) imaging of solvent-cleared organs technique, we found severe pathological damage of the entire ENS and decreased expression of choline acetyltransferase (ChAT) in IBD patients. As a result, acetylcholine (ACh), a major neurotransmitter of the nervous system synthesized by ChAT, was greatly reduced in colon tissues of both IBD patients and colitis mice. Importantly, administration of ACh via enema remarkably ameliorated colitis, which was proved to be directly dependent on monocytic myeloid-derived suppressor cells (M-MDSCs). Furthermore, ACh was demonstrated to promote interleukin-10 secretion of M-MDSCs and suppress the inflammation through activating the nAChR/ERK pathway. The present data reveal that the cholinergic signaling pathway in the ENS is impaired during colitis and uncover an ACh-MDSCs neuroimmune regulatory pathway, which may offer promising therapeutic strategies for IBDs.

Abstract. The aim of the present study was to investigate the resistance of Acinetobacter baumannii, which was induced by cefepime (FEP), cefoperazone-sulbactam (SCF), tazobactam (TZP), levofloxacin (LEV), amikacin (AK), imipenem (IPM), and ciprofloxacin (CIP), in vitro. Multi-step drug resistance selection of 16 A. baumannii strains was performed using seven antibacterial agents (FEP, TZP, CIP, AK, IPM, SCF, and LEV). The minimum inhibitory concentration (MIC) was determined using the agar dilution method. Random amplified polymorphic DNA polymerase chain reaction was performed to analyze the genotypes and the carrying rates of aac (3) (8-to 128-fold) were noted in the MIC and different genotypes were showed in RAPD of the strains before and after performing the drug resistant test. PCR data revealed significant differences (P<0.05) between the carrying rates of resistant genes before and after drug induction, with the exception of rmtA, OXA-24, TEM-1, and IMP. Significant increases were demonstrated in the comparative adeB grayscale in strains that underwent drug induction when compared with the sensitive strains (55.69±43.11% vs. 10.08±26.35%; P=0.001). Findings of the present study suggest that the active efflux pump, adeB, has an important role in multidrug resistance of the A. baumannii induced by antibacterial agents in vitro. IntroductionAlthough carbapenems antibiotics remain the backbone therapy for severe suspected bacterial infections, resistance to this antimicrobial treatment has been increasingly reported (1). Thus, therapeutic options have become limited. Multidrug-resistance to antibiotics currently available, in particular in Gram-negative bacteria, has created a critical global medical challenge (2). Acinetobacter baumannii is frequently observed as a nosocomial infection, which causes high mortality, morbidity and hospitalization cost (3). Crude mortality rate and attributable mortality of the infection were reported to be 52 and 10-35%, respectively (4). Multidrug-resistant A. baumannii is considered as a leading cause of nosocomial infection, particularly in critically ill patients (5). A. baumannii has been reported to be resistant to a broad range of antimicrobial agents, and the tendency for its epidemic spread has subsequently extended (6). An increasing drug resistance of A. baumannii to carbapenems has been demonstrated by the SENTRY Antimicrobial Surveillance Program, whose objective was to report antimicrobial susceptibility and pathogen occurrence data for >40,000 episodes of BSI in 72 medical centers representing 22 nations since January 1997 (7). The emergence of multidrug and pandrug-resistant A. baumannii has caused major threats to the infection control and treatment plans in clinical practices (8). According to our knowledge, drug resistance of A. baumannii is closely related with the application of antibacterial agents. However, few studies have been performed to investigate whether a single antibacterial agent was able to induce pandrug resistance of A. baumannii. In the...

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Snail is a dedicated transcriptional repressor and acts as a master inducer of EMT and metastasis, yet the underlying signaling cascades triggered by Snail still remain elusive. Here, we report that Snail promotes colorectal cancer (CRC) migration by preventing non‐coding RNA LOC113230‐mediated degradation of argininosuccinate synthase 1 (ASS1). LOC113230 is a novel Snail target gene, and Snail binds to the functional E‐boxes within its proximal promoter to repress its expression in response to TGF‐β induction. Ectopic expression of LOC113230 potently suppresses CRC cell growth, migration, and lung metastasis in xenograft experiments. Mechanistically, LOC113230 acts as a scaffold to facilitate recruiting LRPPRC and the TRAF2 E3 ubiquitin ligase to ASS1, resulting in enhanced ubiquitination and degradation of ASS1 and decreased arginine synthesis. Moreover, elevated ASS1 expression is essential for CRC growth and migration. Collectively, these findings suggest that TGF‐β and Snail promote arginine synthesis via inhibiting LOC113230‐mediated LRPPRC/TRAF2/ASS1 complex assembly and this complex can serve as potential target for the development of new therapeutic approaches to treat CRC.

Staphylococcus enterotoxin A (SEA) is a powerful immunostimulant, which can stimulate T cells bearing certain T-cell receptor b-chain variable regions, when bound to major histocompatibility complex II molecules. In vivo administration of intact superantigen in sufficient therapeutic amounts risks unwanted cytotoxicity against normal cells. In this study, we used SEA fused with CD80 transmembrane region (named as SEAtm) driven by a-fetoprotein (AFP) enhancer/ promoter to reduce toxicity and to improve safety and efficiency in the application of SEA. We demonstrated that SEAtm by adenovirus from the AFP enhancer/promoter (AdAFPSEA) could be expressed on the surface of AFPproducing cell line Hepa1-6 instead of non-AFP-producing cell lines. Hepa1-6 infected by recombinant adenovirus stimulated proliferation of splenocytes and activated CD4 + and CD8 + T cells in vitro. After AdAFPSEA was injected into the subcutaneously established hepatoma in vivo, the expression of SEA was detected in tumor tissues, which subsequently induced tumor-specific cytotoxic T cells in spleen. Moreover, hepatocellular carcinoma (HCC) xenografts were suppressed by treatment with AdAFPSEA and the survival time of treated mice was prolonged. These findings suggest that membrane-expressed SEA by adenovirus from AdAFPSEA can generate stronger local and systemic antitumor responses against HCC.