Cancer-associated fibroblasts potentiate colorectal cancer progression by crosstalk of the IGF2-IGF1R and Hippo-YAP1 signaling pathways.

Colorectal cancer (CRC) is one of the most common cancers worldwide. The tumor microenvironment exerts crucial effects in driving CRC progression. Cancer-associated fibroblasts (CAFs) serve as one of the most important tumor microenvironment components promoting CRC progression. This study aimed to elucidate the novel molecular mechanisms of CAF-secreted insulin-like growth factor (IGF) 2 in colorectal carcinogenesis. Our results indicated that IGF2 was a prominent factor upregulated in CAFs compared with normal fibroblasts. CAF-derived conditioned media (CM) promoted tumor growth, migration, and invasion of HCT 116 and DLD-1 cells. IGF1R expression is significantly increased in CRC, serving as a potent receptor in response to IGF2 stimulation and predicting unfavorable outcomes for CRC patients. Apart from the PI3K-AKT pathway, RNA-seq analysis revealed that the YAP1-target signature serves as a prominent downstream effector to mediate the oncogenic signaling of IGF2-IGF1R. By single-cell RNA sequencing (scRNA-seq) and immunohistochemical validation, IGF2 was found to be predominantly secreted by CAFs, whereas IGF1R was expressed mainly by cancer cells. IGF2 triggers the nuclear accumulation of YAP1 and upregulates YAP1 target signatures; however, these effects were abolished by either IGF1R knockdown or inhibition with picropodophyllin (PPP), an IGF1R inhibitor. Using CRC organoid and in vivo studies, we found that cotargeting IGF1R and YAP1 with PPP and verteporfin (VP), a YAP1 inhibitor, enhanced antitumor effects compared with PPP treatment alone. In conclusion, this study revealed a novel molecular mechanism by which CAFs promote CRC progression. The findings highlight the translational potential of the IGF2-IGF1R-YAP1 axis as a prognostic biomarker and therapeutic target for CRC. © 2022 The Pathological Society of Great Britain and Ireland.

The E2F1-HOXB9/PBX2-CDK6 axis drives gastric tumorigenesis and serves as a therapeutic target in gastric cancer.

Homeobox genes include HOX and non-HOX genes. HOX proteins play fundamental roles during ontogenesis by interacting with other non-HOX gene-encoded partners and performing transcriptional functions, whereas aberrant activation of HOX family members drives tumorigenesis. In this study, gastric cancer (GC) expression microarray data indicated that HOXB9 is a prominent upregulated HOX member in GC samples significantly associated with clinical outcomes and advanced TNM stages. However, the functional role of HOXB9 in GC remains contradictory in previous reports, and the regulatory mechanisms are elusive. By in silico and experimental analyses, we found that HOXB9 was upregulated by a vital cell cycle-related transcription factor, E2F1. Depleting HOXB9 causes G1-phase cell cycle arrest by downregulating CDK6 and a subset of cell cycle-related genes. Meanwhile, HOXB9 contributes to cell division and maintains the cytoskeleton in GC cells. We verified that HOXB9 interacts with PBX2 to form a heterodimer, which transcriptionally upregulates CDK6. Knocking down CDK6 can phenocopy the tumor-suppressive effects caused by HOXB9 depletion. Blocking HOXB9 can enhance the anti-tumor effect of CDK6 inhibitors. In conclusion, we elucidate the oncogenic role of HOXB9 in GC and reveal CDK6 as its potent downstream effector. The E2F1-HOXB9/PBX2-CDK6 axis represents a novel mechanism driving gastric carcinogenesis and conveys prognostic and therapeutic implications. © 2023 The Pathological Society of Great Britain and Ireland.

Risk factors for sessile serrated lesions among Chinese patients undergoing colonoscopy.

BACKGROUND AND AIM: Serrated polyps have been recognized as a premalignant lesion accounting for a significant proportion of colorectal cancer. Limited data are available regarding the risk factors for colorectal sessile serrated lesions (SSLs). We aimed to investigate clinical risk factors of SSLs and compared them with colorectal adenomas in a study population of Chinese individuals. METHODS: A retrospective case-control study was performed in an academic tertiary-referral center in Hong Kong. Subjects with SSLs and adenomas were identified from the hospital pathology database from January 2010 to December 2020, and additional clinical data were retrieved from the electronic patient record system. We compared clinical features and risk factors of SSL patients with those without these lesions. RESULTS: A total of 2295 subjects were included in the study, including 459 subjects with SSLs, 918 subjects with adenomas, and 918 subjects with normal colonoscopy. By multivariable logistic regression, compared with normal subjects, patients with SSLs only were significantly more likely to have dyslipidemia (adjusted OR: 1.431, 95% CI 1.008-2.030) and diabetes mellitus (adjusted OR: 2.119, 95% CI 1.439-3.122). CONCLUSIONS: Dyslipidemia and diabetes were independent risk factors for SSLs. Our findings suggest these metabolic factors may be important for the risk of SSLs. The findings may improve our understanding of SSLs and shed light on patient selection for screening and risk stratification.

Research Trends on Clinical Helicobacter pylori Eradication: A Bibliometric Analysis from 1983 to 2020.

BACKGROUND: Numerous studies related to Helicobacter pylori (H. pylori) eradication have been published since the discovery of H. pylori. This study aimed to use a quantitative method to assess the development of this field. MATERIALS AND METHODS: We performed a search of related articles from Web of Science published in 1983-2020 using a combination of the search terms "H. pylori" and "eradication". Eligible studies were included after a two-stage screening process, and the following data were extracted: title, author, institution, country, study type, sample size, eradication regimen, publication year, number of citations, journal, and H-index. RESULTS: A total of 1402 studies were finally identified. The results showed that the period from 1994-2003 was the most influential period in this field. Italy and the USA were dominant countries in this field, while China's publication number increased sharply in the last ten years. Baylor College of Medicine was the most influential institution. Alimentary Pharmacology Therapeutics was the most productive journal. The effects of H. pylori eradication on peptic ulcers and gastric cancer and H. pylori eradication therapy were the most cited topics in this field. After the publish of Maastricht/Florence Ⅳ guideline, the research of quadruple therapy was more than triple therapy. Bismuth-containing quadruple therapy became the most focused regimen after Maastricht/Florence Ⅴ guideline. CONCLUSIONS: In this study, we summarized the characteristics of the publications; identified the most influential countries, institutions, journals; identified the popular research topics and eradication regimen of clinical H. pylori eradication.

Reduced lysosomal clearance of autophagosomes promotes survival and colonization of Helicobacter pylori.

Evasion of autophagy is key for intracellular survival of bacteria in host cells, but its involvement in persistent infection by Helicobacter pylori, a bacterium identified to invade gastric epithelial cells, remains obscure. The aim of this study was to functionally characterize the role of autophagy in H. pylori infection. Autophagy was assayed in H. pylori-infected human gastric epithelium and the functional role of autophagy was determined via genetic or pharmacological ablation of autophagy in mouse and cell line models of H. pylori infection. Here, we showed that H. pylori inhibited lysosomal function and thereby promoted the accumulation of autophagosomes in gastric epithelial cells. Importantly, inhibiting autophagosome formation by pharmacological inhibitors or genetic ablation of BECN1 or ATG5 reduced H. pylori intracellular survival, whereas inhibition of lysosomal functions exerted an opposite effect. Further experiments demonstrated that H. pylori inhibited lysosomal acidification and the retrograde trafficking of mannose-6-phosphate receptors, both of which are known to positively regulate lysosomal function. We conclude that H. pylori subverts autophagy into a pro-survival mechanism through inhibition of lysosomal clearance of autophagosomes. Disruption of autophagosome formation offers a novel strategy to reduce H. pylori colonization in human stomachs. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mucosal microbiome dysbiosis in gastric carcinogenesis.

OBJECTIVES: We aimed to characterise the microbial changes associated with histological stages of gastric tumourigenesis. DESIGN: We performed 16S rRNA gene analysis of gastric mucosal samples from 81 cases including superficial gastritis (SG), atrophic gastritis (AG), intestinal metaplasia (IM) and gastric cancer (GC) from Xi'an, China, to determine mucosal microbiome dysbiosis across stages of GC. We validated the results in mucosal samples of 126 cases from Inner Mongolia, China. RESULTS: We observed significant mucosa microbial dysbiosis in IM and GC subjects, with significant enrichment of 21 and depletion of 10 bacterial taxa in GC compared with SG (q<0.05). Microbial network analysis showed increasing correlation strengths among them with disease progression (p<0.001). Five GC-enriched bacterial taxa whose species identifications correspond to Peptostreptococcus stomatis, Streptococcus anginosus, Parvimonas micra, Slackia exigua and Dialister pneumosintes had significant centralities in the GC ecological network (p<0.05) and classified GC from SG with an area under the receiver-operating curve (AUC) of 0.82. Moreover, stronger interactions among gastric microbes were observed in Helicobacter pylori-negative samples compared with H. pylori-positive samples in SG and IM. The fold changes of selected bacteria, and strengths of their interactions were successfully validated in the Inner Mongolian cohort, in which the five bacterial markers distinguished GC from SG with an AUC of 0.81. CONCLUSIONS: In addition to microbial compositional changes, we identified differences in bacterial interactions across stages of gastric carcinogenesis. The significant enrichments and network centralities suggest potentially important roles of P. stomatis, D. pneumosintes, S. exigua, P. micra and S. anginosus in GC progression.

Combinatorial epigenetic deregulation by Helicobacter pylori and Epstein-Barr virus infections in gastric tumourigenesis.

Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodelling and microRNAs, convert environmental signals to transcriptional outputs but are commonly hijacked by pathogenic microorganisms. Recent advances in cancer epigenomics have shed new light on the importance of epigenetic deregulation in Helicobacter pylori- and Epstein-Barr virus (EBV)-driven gastric tumourigenesis. Moreover, it is becoming apparent that epigenetic mechanisms interact through crosstalk and feedback loops, which modify global gene expression patterns. The SWI/SNF remodelling complexes are commonly involved in gastric cancers associated with H. pylori or EBV through different mechanisms, including microRNA-mediated deregulation and genetic mutations. While H. pylori causes epigenetic silencing of tumour-suppressor genes to deregulate cellular pathways, EBV-positive tumours exhibit a widespread and distinctive DNA hypermethylation profile. Given the early successes of epigenetic drugs in haematological malignancies, further studies are mandated to enrich and translate our understanding of combinatorial epigenetic deregulation in gastric cancers into interventional strategies in the clinic. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Erratum: A novel probe for measuring tissue bioelectrical impedance to enhance pedicle screw placement in spinal surgery.

[This corrects the article on p. 2205 in vol. 10, PMID: 30093957.].

Serrated neoplasia in the colorectum: gut microbiota and molecular pathways.

Colorectal cancer (CRC) is a heterogeneous disease with different gene expression patterns. There are two major colorectal carcinogenesis pathways: conventional adenoma-carcinoma pathway and alternative serrated neoplasia pathway. Apart from the conventional pathway that is typically initiated by characteristic APC mutation and chromosomal instability, the serrated neoplasia pathway is mainly characterized by mutations of BRAF or KRAS, microsatellite instability (MSI), and CpG island methylator phenotype (CIMP). Despite the malignant potential of serrated lesions, they can be easily overlooked during endoscopy screening and even in pathological assessment due to its anatomical location, morphology, and histological features. It has been shown that environmental factors especially the gut microbial composition play a key role in CRC pathogenesis. Thus, the preferential localization of serrated lesions in specific intestine areas suggest that niche-specific microbiota composition might intertwined with host genetic perturbations during the development of serrated lesions. Although serrated lesions and conventional adenomas are biologically different, most studies have focused on conventional adenomas, while the pathophysiology and role of microorganisms in the development of serrated lesions remain elusive. In this review, we discuss on the role of gut microbiota in the serrated neoplasia pathway of colorectal carcinogenesis and its specific clinical and molecular features, and summarize the potential mechanisms involved.

Characterization of key amino acid substitutions and dynamics of the influenza virus H3N2 hemagglutinin.

The annual epidemics of seasonal influenza is partly attributed to the continued virus evolution. It is challenging to evaluate the effect of influenza virus mutations on evading population immunity. In this study, we introduce a novel statistical and computational approach to measure the dynamic molecular determinants underlying epidemics using effective mutations (EMs), and account for the time of waning mutation advantage against herd immunity by measuring the effective mutation periods (EMPs). Extensive analysis is performed on the sequencing and epidemiology data of H3N2 epidemics in ten regions from season to season. We systematically identified 46 EMs in the hemagglutinin (HA) gene, in which the majority were antigenic sites. Eight EMs were located in immunosubdominant stalk domain, an important target for developing broadly reactive antibodies. The EMs might provide timely information on key substitutions for influenza vaccines antigen design. The EMP suggested that major genetic variants of H3N2 circulated in Southeast Asia for an average duration of 4.5 years (SD 2.4) compared to a significantly shorter 2.0 years (SD 1.0) in temperate regions. The proposed method bridges population epidemics and molecular characteristics of infectious diseases, and would find broad applications in various pathogens mutation estimations.

Outcomes of respiratory viral-bacterial co-infection in adult hospitalized patients.

BACKGROUND: Viral infections of the respiratory tract represent a major global health concern. Co-infection with bacteria may contribute to severe disease and increased mortality in patients. Nevertheless, viral-bacterial co-infection patterns and their clinical outcomes have not been well characterized to date. This study aimed to evaluate the clinical features and outcomes of patients with viral-bacterial respiratory tract co-infections. METHODS: We included 19,361 patients with respiratory infection due to respiratory viruses [influenza A and B, respiratory syncytial virus (RSV), parainfluenza] and/or bacteria in four tertiary hospitals in Hong Kong from 2013 to 2017 using a large territory-wide healthcare database. All microbiological tests were conducted within 48 h of hospital admission. Four etiological groups were included: (1) viral infection alone; (2) bacterial infection alone; (3) laboratory-confirmed viral-bacterial co-infection and (4) clinically suspected viral-bacterial co-infection who were tested positive for respiratory virus and negative for bacteria but had received at least four days of antibiotics. Clinical features and outcomes were recorded for laboratory-confirmed viral-bacterial co-infection patients compared to other three groups as control. The primary outcome was 30-day mortality. Secondary outcomes were intensive care unit (ICU) admission and length of hospital stay. Propensity score matching estimated by binary logistic regression was used to adjust for the potential bias that may affect the association between outcomes and covariates. FINDINGS: Among 15,906 patients with respiratory viral infection, there were 8451 (53.1%) clinically suspected and 1,087 (6.8%) laboratory-confirmed viral-bacterial co-infection. Among all the bacterial species, Haemophilus influenzae (226/1,087, 20.8%), Pseudomonas aeruginosa (180/1087, 16.6%) and Streptococcus pneumoniae (123/1087, 11.3%) were the three most common bacterial pathogens in the laboratory-confirmed co-infection group. Respiratory viruses co-infected with non-pneumococcal streptococci or methicillin-resistant Staphylococcus aureus was associated with the highest death rate [9/30 (30%) and 13/48 (27.1%), respectively] in this cohort. Compared with other infection groups, patients with laboratory-confirmed co-infection had higher ICU admission rate (p < 0.001) and mortality rate at 30 days (p = 0.028), and these results persisted after adjustment for potential confounders using propensity score matching. Furthermore, patients with laboratory-confirmed co-infection had significantly higher mortality compared to patients with bacterial infection alone. INTERPRETATION: In our cohort, bacterial co-infection is common in hospitalized patients with viral respiratory tract infection and is associated with higher ICU admission rate and mortality. Therefore, active surveillance for bacterial co-infection and early antibiotic treatment may be required to improve outcomes in patients with respiratory viral infection.

Hederagenin potentiated cisplatin- and paclitaxel-mediated cytotoxicity by impairing autophagy in lung cancer cells.

Autophagy inhibition has been demonstrated to increase the efficacy of conventional chemotherapy. In this study, we identified hederagenin, a triterpenoid derived from Hedera helix, as a potent inhibitor of autophagy and then hypothesized that hederagenin might synergize with chemotherapeutic drugs (e.g., cisplatin and paclitaxel) to kill lung cancer cells. Firstly, we observed that hederagenin induced the increased autophagosomes in lung cancer cells concomitantly with the upregulation of LC3-II and p62, which indicated the impairment of autophagic flux. The colocalization assay indicated hederagenin could not block the fusion of lysosomes and autophagosomes, whereas the lysosomal acidification might be inhibited by hederagenin as revealed by the reduced staining of acidity-sensitive reagents (i.e., Lysotracker and acridine orange). The aberrant acidic environment then impaired the function of lysosome, which was evidenced by the decrease of mature cathepsin B and cathepsin D. Lastly, hederagenin, in agree with our hypothesis, promoted pro-apoptotic effect of cisplatin and paclitaxel with the accumulation of reactive oxygen species (ROS); while the synergistic effect could be abolished by the ROS scavenger, N-acetyl-L-cysteine. These data summarily demonstrated hederagenin-induced accumulation of ROS by blocking autophagic flux potentiated the cytotoxicity of cisplatin and paclitaxel in lung cancer cells.

Anaesthesia use in catheter ablation for atrial fibrillation: a systematic review and meta-analysis of observational studies.

OBJECTIVES: This meta-analysis and systematic review seeks to compare both characteristic parameters and procedural outcomes of atrial fibrillation (AF) catheter ablation in patients under general anaesthesia (GA)/deep sedation and mild/moderate sedation. BACKGROUND: Catheter ablation has become a widely applied intervention for treating symptomatic AF and arrhythmias that are refractory to medical therapy. It can be conducted through from mild sedation to GA. METHODS: PubMed and Embase were searched up to July 2018 for randomised controlled trials, cohort and observational studies that assessed the outcomes of catheter ablation under GA/deep sedation or mild/moderate sedation. Nine studies were included in this meta-analysis after screening with the inclusion and exclusion criteria. Heterogeneity between studies and publication bias was evaluated by I2 index and Egger's regression, respectively. RESULTS: Our meta-analysis found catheter AF ablation with GA/deep sedation to be associated with reduced risk of recurrence (RR: 0.79, 95% CI 0.56 to 1.13, p=0.20) and complications (RR: 0.95, 95% CI 0.64 to 1.42, p=0.82), though statistically insignificant. In terms of procedural parameters, there was no significant difference between the two groups for both procedural time (SMD: -0.13, 95% CI -0.90 to 0.63, p=0.74) and fluoroscopy time (SMD: -0.41, 95% CI -1.40 to 0.58, p=0.41). Univariate meta-regression did not reveal any covariates as a moderating factor for complication and recurrence risk. CONCLUSION: Apart from an increased likelihood of procedural success, ablation by GA/deep sedation was found to be non-significantly different from the mild/moderate sedation approach in both procedural parameters and outcome measures.

Deciphering the Role of microRNAs in Regulation of Immune Surveillance, Self-Tolerance and Allograft Transplant Outcome.

MicroRNAs are small non-coding RNAs that can modulate gene expression at posttranscriptional level, and they participate in almost all important biological processes. Immune system is elaborately regulated to maintain the equilibrium between immunity and tolerance. Recent studies have revealed significant functions of microRNAs in the maintenance of immune homeostasis using both cell and transgenic mouse models. In collaboration with various transcriptional factors and cytokines, microRNAs constitute an effective and flexible regulatory network governing the development and activation of immune cells; as well as maintenance of immune tolerance. In this review, microRNAs involved in T cell development, proliferation, and lineage differentiation will be summarized. Based on current knowledge, the function of microRNAs in establishing and maintaining immune tolerance will also be discussed in relation to determining the outcome of allograft transplantation.

Long non-coding RNAs in melanoma.

Melanoma is the most lethal cutaneous cancer with a highly aggressive and metastatic phenotype. While recent genetic and epigenetic studies have shed new insights into the mechanism of melanoma development, the involvement of regulatory non-coding RNAs remain unclear. Long non-coding RNAs (lncRNAs) are a group of endogenous non-protein-coding RNAs with the capacity to regulate gene expression at multiple levels. Recent evidences have shown that lncRNAs can regulate many cellular processes, such as cell proliferation, differentiation, migration and invasion. In the melanoma, deregulation of a number of lncRNAs, such as HOTAIR, MALAT1, BANCR, ANRIL, SPRY-IT1 and SAMMSON, have been reported. Our review summarizes the functional role of lncRNAs in melanoma and their potential clinical application for diagnosis, prognostication and treatment.

miR-10a-5p, miR-99a-5p and miR-21-5p are steroid-responsive circulating microRNAs.

Steroid-induced osteonecrosis of the femoral head (ONFH) is a common orthopedic disease. The lack of specific manifestations and effective diagnostic methods make it difficult for this disease to be diagnosed at early stages. Recent studies have shown that microRNAs (miRNA) participate in the development of steroid-induced ONFH, but there is limited research into the diagnostic use of circulating miRNAs. Blood samples from 23 human subjects (7 systemic lupus erythematosus (SLE) patients with steroid-induced ONFH; 7 SLE controls without ONFH; and 9 healthy controls) and 71 rats (19 with steroid-induced ONFH; 28 receiving steroids without ONFH; and 24 untreated controls) were collected to verify the abundance of changes of 6 previously identified ONFH-associated plasma miRNAs (miR-423-5p, miR-99a-5p, miR-10a-5p, miR-21-5p, miR-130a-3p and miR-6787-5p) by quantitative RT-PCR (Reverse Transcription-Polymerase Chain Reaction). In humans, the circulating levels of miR-10a-5p, miR-99a-5p and miR-21-5p were increased in SLE patients treated with cortico steroid regardless of ONFH status when compared with healthy controls. However, miR-423-5p, miR-6787-5p and miR-130a-3p showed no significant differences between the three groups. In the rat model, the success rate of steroid-induced ONFH was 40.4% (19/47) based on pathological examination and confirmation by micro-CT scan. Similar to human plasma, the circulating levels of miR-10a-5p, miR-99a-5p and miR-21-5p were increased in steroid-treated rats independent of ONFH development. The serum levels of miR-10a-5p, miR-99a-5p and miR-21-5p were increased by steroid treatment regardless of ONFH development in both humans and rats. These data suggested that miR-10a-5p, miR-99a-5p and miR-21-5p are steroid-responsive circulating miRNAs, but they are not specific for diagnosing steroid-induced ONFH.

A novel probe for measuring tissue bioelectrical impedance to enhance pedicle screw placement in spinal surgery.

Posterior spinal reconstruction with rods and pedicle screws has been widely used to corrects coliosis and other forms of degenerative spinal deformities. However, insertion of pedicle screwsis often clinically challenging, particularlyin patients with severe deformity. Bioelectrical impedance analysis is a technique that exploits the electrical properties of biological organs and tissues to indicate their compositions. Bioelectrical impedance measurement is non-invasive, simple, with adequate repeatability, and at a relatively low cost. In our study, we designed a bioelectrical impedance pedicle probe and use it to determine the bioelectrical impedance values in vitro and in vivo of different tissues relevant to pedicle screw insertion. We measured the bioelectrical impedance of different tissues relevant to pedicle screw placement in vitro and in vivo and explored the use of a prototype bioelectrical impedance pedicle probein guiding pedicle screw placement during spine surgery in animals. These data suggested that this novel bioelectrical impedance pedicle probe may be a new technique that has potential to offer accurate and safe placement of pedicle screws in spine surgery.

Modulation of chemoresponsiveness to platinum-based agents by microRNAs in cancer.

Ovarian cancer accounts for the highest mortality among all gynecologic cancers. Cytoreductive surgery followed by chemotherapy with a platinum-based agent (cisplatin or carboplatin) plus paclitaxel is the first-line option for treatment of epithelial ovarian cancer. However, primary or acquired resistance to platinum-based agents is a major clinical challenge. MicroRNAs are a group of small non-coding RNAs that regulate gene expression post-transcriptionally and may function as oncogenes or tumor-suppressor genes through extensive crosstalk with intracellular signaling pathways. Importantly, their dysregulation has been implicated in ovarian tumorigenesis. Pertinent to chemotherapy, increasing evidence has revealed that miRNAs can be directly linked to chemosensitivity to platinum-based agents in ovarian cancer. In this review, we summarize current evidence concerning the role of miRNAs in prediction and modulation of cellular responses to cisplatin and carboplatin in ovarian cancer.

Potential and use of bacterial small RNAs to combat drug resistance: a systematic review.

BACKGROUND: Over the decades, new antibacterial agents have been developed in an attempt to combat drug resistance, but they remain unsuccessful. Recently, a novel class of bacterial gene expression regulators, bacterial small RNAs (sRNAs), has received increasing attention toward their involvement in antibiotic resistance. This systematic review aimed to discuss the potential of these small molecules as antibacterial drug targets. METHODS: Two investigators performed a comprehensive search of MEDLINE, EmBase, and ISI Web of Knowledge from inception to October 2016, without restriction on language. We included all in vitro and in vivo studies investigating the role of bacterial sRNA in antibiotic resistance. Risk of bias of the included studies was assessed by a modified guideline of Systematic Review Center for Laboratory Animal Experimentation (SYRCLE). RESULTS: Initial search yielded 432 articles. After exclusion of non-original articles, 20 were included in this review. Of these, all studies examined bacterial-type strains only. There were neither relevant in vivo nor clinical studies. The SYRCLE scores ranged from to 5 to 7, with an average of 5.9. This implies a moderate risk of bias. sRNAs influenced the antibiotics susceptibility through modulation of gene expression relevant to efflux pumps, cell wall synthesis, and membrane proteins. CONCLUSION: Preclinical studies on bacterial-type strains suggest that modulation of sRNAs could enhance bacterial susceptibility to antibiotics. Further studies on clinical isolates and in vivo models are needed to elucidate the therapeutic value of sRNA modulation on treatment of multidrug-resistant bacterial infection.

C-X-C Motif Chemokine 10 Impairs Autophagy and Autolysosome Formation in Non-alcoholic Steatohepatitis.

C-X-C motif chemokine 10 (CXCL10) is a crucial pro-inflammatory factor in chronic hepatitis. Autophagy dysregulation is known to contribute to hepatic inflammatory injury. Hence, we investigated the regulatory effect of CXCL10 on the autophagosome-lysosome system during non-alcoholic fatty liver disease (NAFLD) development. The effect of CXCL10 ablation by neutralizing monoclonal antibody (mAb) or genetic knockout on autophagic flux was evaluated in cultured hepatocytes and animal models of NAFLD. Results demonstrated that CXCL10 ablation protected against hepatocyte injury in vitro and steatohepatitis development in mice. Autophagic flux impairment was rectified by CXCL10 inhibition using anti-CXCL10 mAb in AML-12 and HepG2 liver cell lines and primary hepatocytes as evidenced by the attenuated accumulation of p62/SQSTM1 and LC3-II proteins and increased autophagic protein degradation. Impaired autophagic flux was significantly restored by CXCL10 knockout or anti-CXCL10 mAb in mice. Bafilomycin A1, an inhibitor of autolysosome formation, abolished the rectifying effect of anti-CXCL10 mAb or CXCL10 knockdown in AML-12 and primary hepatocytes, indicating CXCL10 impaired late-stage autophagy in NAFLD. Anti-CXCL10 mAb treatment also increased the fusion of LC3-positive autophagosomes with lysosomes in HepG2 cells challenged with palmitic acid, suggesting that CXCL10 ablation restored autolysosome formation. Consistently, the number of autolysosomes was significantly increased by CXCL10 knockout in mice as shown by electron microscopy. In conclusion, upregulated CXCL10 in steatohepatitis impairs autophagic flux by reducing autolysosome formation, thereby inhibiting autophagic protein degradation and the accumulation of ubiquitinated proteins, leading to the development of steatohepatitis.