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Background The mitochondrial tRNA translation optimization 1 (MTO1) gene, which is closely related to defective mitochondrial oxidative phosphorylation, is an evolutionarily conserved protein expressed in high energy-demanding tissues and is associated with complex oxidative phosphorylation deficiency type 10 (COXPD10) in humans. Related cases and studies are still scarce and have not been reported in the Chinese region. Materials and methods Detailed clinical assessment was applied to the patient. Based on next-generation sequencing technology, we performed whole-exome sequencing of the patient and the parents. Sanger sequencing was used for validation. Bioinformatics software and protein simulations were used to predict the pathogenicity of the variants. Results The patient was diagnosed with a possible association with mitochondrial disease according to the clinical manifestations and physical examination. A novel frameshift mutation c.344delA (p. Asn115Thrfs*11) and a novel point mutation c.1055C > T (p. Thr352Met) in the MTO1 gene were identified. They were found to cause abnormal changes in amino acids and the protein by biochemical tools, indicating it may be pathogenic. Conclusion We present two novel and possibly pathogenic variants in the MTO1 gene in a Chinese Han family.

Zhaoyinqian Li,* Jingling Xie,* Jiaxin Yang, Siyi Liu, Zixuan Ding, Jingchen Hao, Yinhuan Ding, Zhangrui Zeng, Jinbo Liu Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinbo LiuDepartment of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Taiping Street, Luzhou, 646000, Sichuan, People’s Republic of ChinaTel +86 0830 3165730Email Liulab2019@163.comObjective: This study aimed to determine the clinical manifestations, antimicrobial resistance, molecular characteristics, and risk factors for ESKAPE pathogens infection in burn patients.Methods: A retrospective study of 187 burn patients infected with ESKAPE pathogens was conducted at the Department of Plastic and Burn Surgery of the Affiliated Hospital of Southwest Medical University (Luzhou, China) from October 2018 to June 2021. All strains were identified using a MicroScan WalkAway 96 Plus System, and antimicrobial susceptibilities were determined using the VITEK system or the disk diffusion method. The antimicrobial resistance genes of multi-drug resistant ESKAPE (MDR-ESKAPE) were detected by polymerase chain reaction (PCR). The multivariable logistic regression analysis was used to estimate the risk factors for ESKAPE infection and MDR-ESKAPE infection.Results: A total of 255 strains were isolated in various types of clinical specimens from 187 burn patients, of which 47.5% were ESKAPE pathogens (121/255). Among these, MDR-ESKAPE pathogens accounted for 55% (67/121). Additionally, aph3ʹIII, mecA, blaSHV, blaTEM, blaPDC, and blaSHV were the most prevalent genes detected in Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp., respectively. The independent risk factors for ESKAPE infection were total body surface area (TBSA) > 30– 50% (odds ratio [OR] = 10.428; 95% confidence interval [CI], 2.047 to 53.108), TBSA > 50% (OR = 15.534; 95% CI, 1.489 to 162.021), and parenteral nutrition (OR = 3.597; 95% CI, 1.098 to 11.787). No independent risk factors were found for MDR-ESKAPE infection.Conclusion: Clinical staff should be alert to the risk of nosocomial infection with ESKAPE pathogens in burn patients receiving parenteral nutrition and under TBSA > 30%. Full attention should also be paid to the ESKAPE resistance, strict adherence to infection control protocols for the rational use of antimicrobial agents, and enhanced clinical standardization of antimicrobial agents management.Keywords: burn, ESKAPE pathogens infection, antimicrobial resistance, risk factors

In recent years, an increasing number of studies have reported that intestinal microbiota have an important effect on tumour immunity by affecting the tumour microenvironment (TME). The intestinal microbiota are closely associated with various immune cells, such as T lymphocytes, natural killer cells (NK cells) and macrophages. Some bacteria, such as Akkermansia muciniphila (A. muciniphila) and Lactobacillus reuteri (L. reuteri), have been shown to improve the effect of tumour immunity. Furthermore, microbial imbalance, such as the increased abundance of Fusobacterium nucleatum (F. nucleatum) and Helicobacter hepaticus (H. hepaticus), generally causes tumour formation and progression. In addition, some microbiota also play important roles in tumour immunotherapy, especially PD‐L1‐related therapies. Therefore, what is the relationship between these processes and how do they affect each other? In this review, we summarize the interactions and corresponding mechanisms among the intestinal microbiota, immune system and TME to facilitate the research and development of new targeted drugs and provide new approaches to tumour therapy., We systematically explored the relationship among intestinal microbiota, immunity and tumour microenvironment. Besides, we also discussed the combined effect of gut microbiota and ICB. In short, the potential of gut microbiota in tumour therapy is promising.

Tumor metastasis is the leading cause of death in patients with colorectal cancer (CRC). Circular RNAs (circRNAs) have been shown to be involved in cancer progression. However, the regulatory mechanisms of circRNAs involved in CRC tumor metastasis are currently unknown. Methods: High-throughput sequencing was performed on 6 pairs of CRC and adjacent normal tissues to identify the expression profiles of mRNA and circRNA. circ1662 was assessed by RNA-ISH and IHC of a tissue chip. The function of circ1662 in CRC was evaluated by knocking down or overexpressing circ1662. MeRIP-qPCR, RIP-qPCR, and RNA pull-down were performed to determine the relationship between METTL3, circ1662, and YAP1. Results: A novel circRNA, circ1662, exhibited significantly higher expression in CRC tissues than paired normal tissues. High circ1662 expression was correlated with poor prognosis and tumor depth in patients with CRC. Functionally, circ1662 promoted CRC cell invasion and migration by controlling EMT in vitro and in vivo. Mechanistically, circ1662 directly bound to YAP1 and accelerated its nuclear accumulation to regulate the SMAD3 pathway. Additionally, circ1662 enhanced CRC invasion and migration depending on YAP1 and SMAD3. Interestingly, METTL3 induced circ1662 expression by binding its flanking sequences and installing m6A modifications. Clinically, circ1662 expression strongly correlated with METTL3 and YAP1 protein expression. Moreover, YAP1 expression was negatively correlated with SMAD3 expression. Conclusions: METTL3-induced circ1662 promoted CRC cell invasion and migration by accelerating YAP1 nuclear transport. This result implies that circ1662 is a new prognostic and therapeutic marker for CRC metastasis.

Background Glycolysis plays an essential role in the growth and metastasis of solid cancer and has received increasing attention in recent years. However, the complex regulatory mechanisms of tumour glycolysis remain elusive. This study aimed to explore the molecular effect and mechanism of the noncoding RNA miR-103a-3p on glycolysis in colorectal cancer (CRC). Methods We explored the effects of miR-103a-3p on glycolysis and the biological functions of CRC cells in vitro and in vivo. Furthermore, we investigated whether miR-103a-3p regulates HIF1A expression through the Hippo/YAP1 pathway, and evaluated the role of the miR-103a-3p-LATS2/SAV1-YAP1-HIF1A axis in promoting glycolysis and angiogenesis in CRC cells and contributed to invasion and metastasis of CRC cells. Results We found that miR-103a-3p was highly expressed in CRC tissues and cell lines compared with matched controls and the high expression of miR-103a-3p was associated with poor patient prognosis. Under hypoxic conditions, a high level of miR-103a-3p promoted the proliferation, invasion, migration, angiogenesis and glycolysis of CRC cells. Moreover, miR-103a-3p knockdown inhibited the growth, proliferation, and glycolysis of CRC cells and promoted the Hippo-YAP1 signalling pathway in nude mice in a xenograft model. Here, we demonstrated that miR-103a-3p could directly target LATS2 and SAV1. Subsequently, we verified that TEAD1, a transcriptional coactivator of Yes-associated protein 1 (YAP1), directly bound to the HIF1A promoter region and the YAP1 and TEAD1 proteins co-regulated the expression of HIF1A, thus promoting tumour glycolysis. Conclusions MiR-103a-3p, which is highly expressed in CRC cells, promotes HIF1A expression by targeting the core molecules LATS2 and SAV1 of the Hippo/YAP1 pathway, contributing to enhanced proliferation, invasion, migration, glycolysis and angiogenesis in CRC. Our study revealed the functional mechanisms of miR-103a-3p/YAP1/HIF1A axis in CRC glycolysis, which would provide potential intervention targets for molecular targeted therapy of CRC.

Bacteria are important regulators of carbon cycling in lakes and are central to sediment ecosystem processes. However, the sediment microbial communities and their respiratory responses to the lake wetland succession are poorly understood. In this study, we collected sediment samples from four different succession points (the Potamogeton lucens zone, the Scirpus tabernaemontani zone, the Scirpus triqueter zone, and the Juncus effusus zone) in the Caohai Wetland of the Guizhou Plateau (China). The bacterial communities at these succession points were studied using a high-throughput sequencing approach. The sediment microbial respiration (SR) was measured using static chambers in the field and basal respiration (BR) was determined in the laboratory. The results show that the dominant bacterial taxa in the sediment was Proteobacteria (34.7%), Chloroflexi (17.8%), Bacteroidetes (7.3%), Acidobacteria (6.6%), and Cyanobacteria (6.1%). Principal coordinate analysis showed that the microbial community structure differs significantly at different sampling points along the successional gradient, indicating that the bacterial community structure is sensitive to the lake wetland succession. Different hydrological regimes and soil characteristics such as $$\rm{NH}_4^+-N$$ , Fe2+, Mn2+, and sediment organic carbon (SOC) content may be important factors responsible for the differences in the sediment microbial characteristics of the different successional stages in the Caohai wetland. Additionally, it was found that the SR increased significantly from the P. lucens zone to the J. effusus zone, but BR had the opposite response. The shifts in the bacterial community structure along the successional gradient may be the main reason for the observed differences in sediment respiration.

Tumor drug resistance is a major challenge in the treatment of cancer. Noncoding RNAs (ncRNA) play a role in the progression of drug resistance. Recent studies have indicated that exosomes, with their in vitro and in vivo compatibility, are the best natural carrier of ncRNA, and their transport of ncRNA into cells could regulate drug resistance. Exosomal ncRNA impact drug resistance through participation in drug efflux, regulation of signaling pathways, and modification of the tumor microenvironment. In this review, we evaluate the mechanism of exosomal ncRNA related to tumor drug resistance, their role in different tumors, and potential clinical applications.

Background Increasing investigations indicate that long noncoding RNA (lncRNA) is responsible for diverse biological functions during the progression of cancer. However, its functions and underlying mechanisms remain elusive. Here, we investigated the MAFG-AS1- expression profile in esophageal squamous-cell carcinoma (ESCC) patients and explored its biological function and potential molecular mechanisms. Methods qRT-PCR and the GEPIA data base were used to evaluate expression levels of MAFG-AS1 in ESCC tissue and cells. WST1-proliferation, -migration, and -invasion assays were performed to define the role of MAFG-AS1 in ESCC. Potential molecular mechanisms of MAFG-AS1 were investigated with online bioinformatic analysis, qRT-PCR, and rescue assays. Results MAFG-AS1 was upregulated in 45 ESCC-tissue samples and cell lines compared to that of adjacent nontumor tissue and normal esophageal cells. Higher MAFG-AS1 expressionindicated poor survival. Gain- and loss-of-function experiments suggested that MAFG-AS1 promoted ESCC-cell proliferation, migration, and invasion. Molecular mechanism analysis and rescue assay showed that miR143 inhibitors partly abolished the suppression of MAFG-AS1 knockdown on EC109-cells proliferation. Moreover, we found that LASP1 specifically targeted miR143. Collectively, these data indicated that MAFG-AS1 served as a ceRNA to elevate LASP1 levels by sponging miR143, and played an oncogenic role in ESCC. Conclusion Our research findings demonstrate that MAFG-AS1 is a key regulator through a novel MAFG-AS1-miR143-LASP1 axis in ESCC development and progression, which may offer a potential therapeutic target for ESCC.

We attempt to explore the role of miR-217 during the process of type 2 diabetes mellitus (T2DM). Mouse β-TC-tet was dealt with 16.7 mM glucose (HG) to imitate the cells in T2DM. Cell proliferation and apoptosis were determined by cell counting kit-8 and flow cytometry. The correlation between miR-217 and Mafb was predicted with biological software and confirmed by dual lucifierase assay. Western blot was applied to detect protein expression. The data from GEO database exhibited that miR-217 was upregulated in T2DM patients. HG treatment upregulated the expression of miR-217, inhibited the proliferation, and promoted the apoptosis and inflammation of β-TC-tet cell. Depletion of miR-217 alleviated the damage of β-TC-tet cell caused by HG. Mafb was affirmed as a target of miR-217 and was negatively modulated by miR-217. Knockdown of Mafb attenuated the alleviation of miR-217 inhibitor on β-TC-tet cell damage. The expression of key proteins in NF-κB signaling pathway was upregulated by HG, and this upregulation tendency was inhibited by miR-217 inhibitor. Moreover, silencing Mafb could alleviate the inhibition of miR-217 inhibitor on these proteins. Our findings insinuated that inhibition of miR-217 could relieve β-TC-tet damage induced by HG through regulating Mafb and NF-κB signaling.

The dichotomy of cancer-regulatory genes into "oncogenes (OCGs)" and "tumor-suppressor genes (TSGs)" has greatly helped us in learning molecular details of tumor biology. SPDEF, known as the prostate-derived ETS factor, is reported to play a pivotal role in normal cell development and survival, which has also been endowed with dual characteristics in cancers. Breast cancer (BC) is a highly heterogeneous disease which becomes the leading reason for cancer-related fatality among women worldwide. The involvement of SPDEF in many aspects of BC has been postulated, whereas the mechanism governing the regulation of the pro- and anti-oncogenic activities of SPDEF in BC state remains poorly defined. In this review, we summarized SPDEF as the double agent involving in expression profiles, the regulatory mechanism in BC progression, as well as the role in diagnosis, treatment and prognosis of BC. The understanding of SPDEF duality has contributed to gain insight into the tumor biology and also add a new dimension to the new therapy targets for BC.

Global warming leads to deglaciations in high-elevation regions, which exposes deglaciated soils to microbial colonization. Disparity in year-to-year successional patterns of bacterial community and influencing factors in freshly deglaciated soils remain unclear.We explored the abundance of bacterial 16S rRNA gene and community succession in deglaciated soils along a 14-year chronosequence after deglaciation using qPCR and Illumina sequencing on the Tibetan Plateau. The results showed that the abundance of bacterial 16S rRNA gene gradually increased with increasing deglaciation age. Soil bacterial community succession was clustered into three deglaciation stages, which were the early (zero-year old), transitional (1–7 years old) and late (8–14 years old) stages. A significantly abrupt bacterial community succession occurred from the early to the transitional stage (P < 0.01), while a mild succession (P = 0.078) occurred from the transitional to the late stage. The bacterial community at the early and transitional stages were dominated by Proteobacteria, while the late stage was dominated by Actinobacteria. Less abundant ( < 10%) Acidobacteria, Gemmatimonadetes, Verrucomicrobia, Chloroflexi, Planctomycetes, unclassified bacteria dominantly occurred in the transition and late stage and Cyanobacteria in the early stage. Total organic carbon (24.7%), post deglaciation age (21%), pH (16.5%) and moisture (10.1%) significantly contributed (P < 0.05) to the variation of bacterial community succession. Our findings provided a new insight that short time-scale chronosequence is a good model to study yearly resolution of microbial community succession.

The tumour microenvironment (TME) constitutes the area surrounding the tumour during its development and has been demonstrated to play roles in cancer-related diseases through crosstalk with tumour cells. Circular RNAs (circRNAs) are a subpopulation of endogenous noncoding RNAs (ncRNAs) that are ubiquitously expressed in eukaryotes and have multiple biological functions in the regulation of cancer onset and progression. An increasing number of studies have shown that circRNAs participate in the multifaceted biological regulation of the TME. However, details on the mechanisms involved have remained elusive until now. In this review, we analyse the effects of circRNAs on the TME from various perspectives, including immune surveillance, angiogenesis, hypoxia, matrix remodelling, exo-circRNAs and chemoradiation resistance. Currently, the enormous potential for circRNA use in targeted therapy and as noninvasive biomarkers have drawn our attention. We emphasize the prospect of targeting circRNAs as an essential strategy to regulate TME, overcome cancer resistance and improve therapeutic outcomes.

Bacterial translocation is a phenomenon in which live bacteria or their products cross the intestinal barrier to other organs or the circulatory system. Gut translocation of bacteria has been reported in both animal models, and clinical trials often accompany acute pancreatitis and are believed to be linked to patient outcome, especially in severe acute pancreatitis. Therefore, the mechanisms of intestinal bacterial translocation in acute pancreatitis have become a topic of interest in recent years. This review discusses Bacterial translocation in acute pancreatitis, identifies possible mechanisms of action, and provides an overview of the methods used to detect Bacterial translocation in acute pancreatitis. This review also highlights areas that require further research.

Zhaoyinqian Li,&ast; Zixuan Ding,&ast; Jia Yang,&ast; Yao Liu, Xinrui Jin, Jingling Xie, Tingting Li, Yinhuan Ding, Zhangrui Zeng, Jinbo Liu Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinbo LiuDepartment of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, People’s Republic of ChinaTel/Fax +86 830 3165730Email Liulab2019@163.comBackground: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infection has attracted worldwide concern and became a serious challenge for clinical treatment. The aims of this study were to evaluate the molecular characteristics and risk factors for CRKP infection.Methods: All the CRKP strains were screened for antimicrobial resistance genes, virulence genes, and integron by polymerase chain reaction (PCR). Plasmid typing was performed by plasmid conjugation assay and PCR-based replicon typing (PBRT). The genetic environments of blaKPC-2 and blaNDM-1 were analyzed by using overlapping PCR and molecular typing was performed by multi-locus sequence typing (MLST). Risk factors for CRKP infection were analyzed by logistic regression model.Results: All the 66 CRKP isolates were multidrug-resistant, but all of them were susceptible to tigecycline and polymyxin B. Among the CRKP isolates, 42 blaKPC-2-positive strains were identified carrying IncFII plasmids. Meanwhile, 24 blaNDM-positive strains were found on lncX3 plasmids, including 20 blaNDM-1 isolates and 4 blaNDM-5 isolates. Most of CRKP isolates contained several virulence genes and the class I integron (intl1). The genetic environments of blaKPC-2 and blaNDM-1 revealed that the conserved regions (tnpA-tnpR-ISkpn8-blaKPC-2) and (blaNDM-1-bleMBL-trpF-tat) were associated with the dissemination of KPC-2 and NDM-1. ST11 was the most common type in this work. Hematological disease, tracheal cannula, and use of β-lactams and β-lactamase inhibitor combination were identified as independent risk factors for CRKP infection.Conclusion: This study established the resistance pattern, molecular characteristics, clonal relatedness, and risk factors of CRKP infection. The findings of the novel strain that co-harboring blaNDM-5 and blaIMP-4, and the novel ST4495 indicated that the brand-new types have spread in Southwest China, emphasizing the prevent and control the further dissemination of CRKP isolates are highly needed.Keywords: carbapenem-resistant Klebsiella pneumoniae, molecular characteristics, genetic environments, plasmid, risk factors

Zhaoyinqian Li,&ast; Zixuan Ding,&ast; Yao Liu, Xinrui Jin, Jingling Xie, Tingting Li, Zhangrui Zeng, Zhibin Wang, Jinbo Liu Department of Laboratory Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinbo LiuDepartment of Laboratory Medical, Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Luzhou, 646000, Sichuan, People’s Republic of ChinaTel/Fax +86 0830 3165730Email Liulab2019@163.comBackground: Acinetobacter baumannii is an important pathogen in clinical infections, and biofilm formation is an effective way for A. baumannii to survive under external pressures. In this study, the aims were to examine the antimicrobial resistance, biofilm formation, and biofilm-specific resistance in clinical isolates of A. baumannii.Materials and Methods: A total of 104 clinical A. baumannii isolates were collected from a large teaching hospital in Southwest China. The antibiotics susceptibilities were tested, and biofilm-forming ability was evaluated by crystal violet staining by confocal laser scanning microscopy (CLSM). Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), minimum biofilm inhibitory concentration (MBIC), and minimum biofilm eradication concentration (MBEC) of ciprofloxacin, meropenem, and ceftazidime were tested on selected strains by broth microdilution method. Biofilm-associated genes were detected by polymerase chain reaction (PCR), and expression of genes at planktonic stage and biofilm stage were analyzed by real-time reverse transcription PCR (RT-PCR).Results: Multidrug-resistant (MDR) isolates accounted for 65.4%, but no strain was resistant to tigecycline and polymyxin B. Moreover, non-MDR strains tended to form stronger biofilms than MDR strains, and a negative correlation between biofilm-forming ability and resistance profiles to each of tested antimicrobials were observed. The MBECs and MBICs of ciprofloxacin, ceftazidime, and meropenem were evidently increased compared with MICs and MBCs among all tested strains. Additionally, the biofilm formation ability of the csuD-positive strains was stronger than that of the csuD-negative strains. The strains in MDR group had higher carrying rate of csuA and csuD genes than non-MDR group, while non-MDR strains possessed more ompA gene than MDR group. Finally, abaI gene was significantly up-regulated after biofilm formation.Conclusion: These results revealed valuable data for the negative correlation between antimicrobial resistance and biofilm formation, as well as phenotypic and genotypic characteristics of biofilm formation in A. baumannii.Keywords: Acinetobacter baumannii, biofilm formation, antimicrobial resistance, gene expression

Early colonization and succession of soil microbial communities are essential for soil development and nutrient accumulation. Herein we focused on the changes in pioneer prokaryotic communities in rhizosphere and bulk soils along the high-elevation glacier retreat chronosequence, the northern Himalayas, Tibetan Plateau. Rhizosphere soils showed substantially higher levels of total organic carbon, total nitrogen, ammonium, and nitrate than bulk soils. The dominant prokaryotes were Proteobacteria, Actinobacteria, Acidobacteria, Chloroflexi, Crenarchaeota, Bacteroidetes, and Planctomycetes, which totally accounted for more than 75% in relative abundance. The dominant genus Candidatus Nitrososphaera occurred at each stage of the microbial succession. The richness and evenness of soil prokaryotes displayed mild succession along chronosequene. Linear discriminant analysis effect size (LEfSe) analysis demonstrated that Proteobacteria (especially Alphaproteobacteria) and Actinobacteria were significantly enriched in rhizosphere soils compared with bulk soils. Actinobacteria, SHA_109, and Thermoleophilia; Betaproteobacteria and OP1.MSBL6; and Planctomycetia and Verrucomicrobia were separately enriched at each of the three sample sites. The compositions of prokaryotic communities were substantially changed with bulk and rhizosphere soils and sampling sites, indicating that the communities were dominantly driven by plants and habitat-specific effects in the deglaciated soils. Additionally, the distance to the glacier terminus also played a significant role in driving the change of prokaryotic communities in both bulk and rhizosphere soils. Soil C/N ratio exhibited a greater effect on prokaryotic communities in bulk soils than rhizosphere soils. These results indicate that plants, habitat, and glacier retreat chronosequence collectively control prokaryotic community composition and succession.

Cancer metastasis is a symptom of adverse prognosis, a prime origin of therapy failure, and a lethal challenge for cancer patients. N6-methyladenosine (m6A), the most prevailing modification in messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) of higher eukaryotes, has attracted increasing attention. Growing studies have verified the pivotal roles of m6A methylation in controlling mRNAs and ncRNAs in diverse physiological processes. Remarkably, recent findings have showed that aberrant methylation of m6A-related RNAs could influence cancer metastasis. In this review, we illuminate how m6A modifiers act on mRNAs and ncRNAs and modulate metastasis in several cancers, and put forward the clinical application prospects of m6A methylation.

Background Noninvasive and effective methods of early diagnosis of colorectal cancer (CRC) are underexplored. Inflammation is known to play an important role in the tumor microenvironment of CRC. Therefore, the aim of this study was to elucidate novel inflammatory biomarkers related to early diagnosis and prognosis of CRC. Methods Based on the results from a multiplex assay and a pan-cancer screening of TCGA data with 18 cancer types, we identified several targeted biomarkers. We further confirmed these results using a trial cohort of 112 CRC patients and 151 controls (59 healthy donors, 52 colitis and 40 colorectal adenoma patients) by Elisa and immunohistochemistry (IHC). The biomarkers expression levels in CRC patients of different clinical stages were compared. The targeted biomarkers panel was developed using logistic regression model and was then validated using an independent cohort including 75 CRC patients and 90 controls (35 healthy donors, 20 colitis and 35 colorectal adenoma patients). Diagnostic accuracy was evaluated using area under the receiver-operating characteristic (ROC) curve and overall survival analysis was used for prognosis. Gene ontology (GO) analyses and Gene set enrichment analyses (GSEA) were performed to predict the function of the candidate biomarkers. Results CCL20 and IL-17A were identified as candidate biomarkers using multiplex assay and pan-cancer screening of TCGA data. Elisa and IHC demonstrated that both CCL20 and IL-17A levels were highly expressed in CRC patients, more especially in patients with advanced stage disease. A signature expression of the two biomarkers showed high diagnostic accuracy of CRC. Importantly, the diagnostic sensitivity and specificity were still satisfactory in the early stage and low carcinoembryonic antigen (CEA) level groups. Bioinformatics analysis revealed that CCL20 and IL-17A may be involved in CRC progression. In addition, the diagnostic performance of CCL20 and IL-17A in combination was superior to that of either marker alone. Conclusions Serum CCL20 and IL-17A levels were identified as independent prognostic markers for CRC. The CCL20-IL-17A panel exhibited a good performance in the diagnosis of early stage CRC.

Exosomes have emerged as critical mediators of intercellular communication, both locally and systemically, by regulating a diverse range of biological processes between cells. Circular RNA (circRNA) is a novel member of endogenous noncoding RNAs with widespread distribution and diverse cellular functions. Recently, circular RNAs have been identified for their enrichment and stability in exosomes. In this review, we outline the origin, biogenesis and function of exosomal circRNAs as well as their roles in various diseases. Although their precise roles and mechanisms of gene regulation remain largely elusive, exosomal circRNAs have potential applications as disease biomarkers and novel therapeutic targets.

Background Low back pain has become a serious social and economic burden and the leading cause of disability worldwide. Among a variety of pathophysiological triggers, intervertebral disc (IVD) degeneration plays a primary underlying role in causing such pain. Specifically, multiple independent endplate changes have been implicated in the initiation and progression of IVD degeneration. Methods In this study, we built a signaling network comprising both well-characterized IVD pathology-associated proteins as well as some potentially correlated proteins that have been associated with one or more of the currently known pathology-associated proteins. We then screened for the potential IVD degeneration-associated proteins using patients’ normal and degenerative endplate specimens. Short hairpin RNAs for receptor interacting serine/threonine kinase 1 (RIPK1) were constructed to examine the effects of RIPK1 knockdown in primary chondrocyte cells and in animal models of caudal vertebra intervertebral disc degeneration in vivo. Results RIPK1 was identified as a potential IVD degeneration-associated protein based on IVD pathology-associated signaling networks and the patients’ degenerated endplate specimens. Construction of the short hairpin RNAs was successful, with short-term RIPK1 knockdown triggering inflammation in the primary chondrocytes, while long-term knockdown triggered apoptosis through cleavage of the caspase 3 pathway, down-regulated NF-κB and mitogen-activating protein kinase (MAPK)s cascades, and decreased cell survival and inflammation. Animal models of caudal vertebra intervertebral disc degeneration further demonstrated that apoptosis was induced by up-regulation of tumor necrosis factor (TNF) accompanied by down-regulation of NF-κB and MAPKs cascades that are dependent on caspase and RIPK1. Conclusions These results provide proof-of-concept for developing novel therapies to combat IVD degeneration through interfering with RIPK1-mediated apoptosis signaling pathways especially in patients with RIPK1 abnormality. Electronic supplementary material The online version of this article (10.1186/s12967-019-1886-3) contains supplementary material, which is available to authorized users.

Summary Background Previous studies have demonstrated that the CXCL12/CXCR4 signaling axis is involved in the regulation of neuropathic pain (NP). Here, we performed experiments to test whether the CXCL12/CXCR4 signaling pathway contributes to the pathogenesis of neuropathic pain after spinal nerve ligation (SNL) via central sensitization mechanisms. Methods Neuropathic pain was induced and assessed in a SNL rat model. The expression and distribution of CXCL12 or CXCR4 were examined by immunofluorescence staining and western blot. The effects of CXCL12 rat peptide, CXCL12 neutralizing antibody, CXCR4 antagonist, and astrocyte metabolic inhibitor on pain hypersensitivity were explored by behavioral tests in naive or SNL rats. We measured the expression level of c‐Fos and CGRP to evaluate the sensitization of neurons by RT‐PCR. The activation of astrocyte and microglia was analyzed by measuring the level of GFAP and iba‐1. The mRNA levels of the pro‐inflammatory cytokines such as TNF‐α, IL‐1β, and IL‐6 and Connexin 30, Connexin 43, EAAT 1, EAAT 2 were also detected by RT‐PCR. Results First, we found that the expression of CXCL12 and CXCR4 was upregulated after SNL. CXCL12 was mainly expressed in the neurons while CXCR4 was expressed both in astrocytes and neurons in the spinal dorsal horn after SNL. Moreover, intrathecal administration of rat peptide, CXCL12, induced hypersensitivity in naive rats, which was partly reversed by fluorocitrate. In addition, the CXCL12 rat peptide increased mRNA levels of c‐Fos, GFAP, and iba‐1. A single intrathecal injection of CXCL12 neutralizing antibody transiently reversed neuropathic pain in the SNL rat model. Consecutive use of CXCL12 neutralizing antibody led to significant delay in the induction of neuropathic pain, and reduced the expression of GFAP and iba‐1 in the spinal dorsal horn. Finally, repeated intrathecal administration of the CXCR4 antagonist, AMD3100, significantly suppressed the initiation and duration of neuropathic pain. The mRNA levels of c‐Fos, CGRP, GFAP, iba‐1, and pro‐inflammatory cytokines, also including Connexin 30 and Connexin 43 were decreased after injection of AMD3100, while EAAT 1 and EAAT 2 mRNAs were increased. Conclusion We demonstrate that the CXCL12/CXCR4 signaling pathway contributes to the development and maintenance of neuropathic pain via central sensitization mechanisms. Importantly, intervening with CXCL12/CXCR4 presents an effective therapeutic approach to treat the neuropathic pain.

A new star, circular RNA (circRNA), is a class of noncoding RNA with a stable cyclic structure. Exonic circRNA mainly exists in the eukaryotic cytoplasm. Intronic circRNAs (ciRNA) and exonic circRNAs with introns (EIciRNA) are found in the nucleus. Recent evidences showed the functional diversity of circRNAs, which could be microRNA (miRNA) sponges, interact with protein or translate into small peptide. Due to the change of human eating habits, digestive cancer remains one of the most common cancers worldwide and it is prone to metastasis. Increasing studies have found a number of circRNAs using RNA sequencing technology and displayed double roles of circRNA in digestive cancer. In this review, we surveyed the biogenesis and regulation of circRNAs, discussed circRNA functions and clinical applications (especially circRNAs in exosome) in digestive cancers, which implied that circRNAs could be as potential biomarkers in diagnosis and treatment of digestive cancers in the future.

BackgroundLong noncoding RNAs (lncRNAs) regulate multiple biological effects in cancers. Recently, RNA methylation has been found to modify not only coding RNAs but also some noncoding RNAs. How RNA methylation affects lncRNAs to affect colorectal cancer (CRC) progression remains elusive.MethodsRNA-sequencing of cancer and normal tissues was analysed. LINC01559 in CRC was selected and verified by western blot (WB), quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). Functional experiments in vitro and in vivo were used to explore the biological functions of LINC01559 in CRC. The LINC01559/miR-106-5p/PTEN axis was explored at different levels of analysis, including fluorescence in situ hybridization (FISH), luciferase assays, and rescue experiments. RIP-sequencing, m6A RNA immunoprecipitation (MeRIP) assays and bioinformatic analysis were conducted to determine the upstream mechanism of LINC01559.ResultsLINC01559, identified by RNA-sequencing analysis, was downregulated in CRC tissues and cell lines compared with normal controls. Lower expression of LINC01559 in CRC patients predicted a poor prognosis. In addition, PTEN was found to be positively correlated with LINC01559, and bioinformatic analysis and in vitro experiments indicated that miR-106b-5p could be the link between LINC01559 and PTEN. Then, downregulated LINC01559 restored the malignant phenotype of CRC cells in vivo and in vitro, while cotransfection of si-LINC01559 and miR-106b-5p inhibitor neutralized this effect. Notably, METTL3 was found to be highly expressed in CRC, and the downregulation of METTL3 could inhibit the migration and invasion of CRC cells. Mechanistically, we found abundant m6A modification sites on LINC01559. Then, we uncovered these sites as potential targets of METTL3 through experiments in vivo.ConclusionThe results revealed a negative functional regulation of LINC01559/miR-106b-5p/PTEN axis in CRC progression, and explored a new mechanism of METTL3-mediated m6A modification on LINC01559 formation. These results elucidate a novel potential therapeutic target for CRC treatment.Trial registrationThe human cancer tissues used in this study were approved by Ethnics Committee of The First Affiliated Hospital of Zhengzhou University in December 19, 2019, and the TRN is 2019-KW-423.

Hypervirulent Klebsiella pneumoniae (hvKp) has been globally disseminated recently, especially in Asia. The purpose of this study was to identify the molecular characteristics, clinical manifestations, and clinical risk factors of hvKp infections among patients in a large teaching hospital. A retrospective study was conducted in 123 patients infected with K. pneumoniae at the Affiliated Hospital of Southwest Medical University (Luzhou, China) from October 2016 to November 2018. An isolate that positive for both PCR amplification of aerobactin gene and Galleria mellonella infection model was defined as hvKp. Overall, 43.1% (53/123) of K. pneumoniae isolates were hvKp. String tests were performed on all isolates, and MLSTs of all hvKp were conducted. The K1 ST23 isolates were the dominant clone of hvKp (35.8%). Univariate analysis revealed the following risk factors for hvKp: hepatic abscess (OR = 41.818 [95% CI, 5.379–335.086]), bacteremia (OR = 19.94 [95% CI, 5.565–71.446]), metastatic spread (OR = 19.938 [95% CI, 6.344–62.654]), CRP (OR = 1.008 [95% CI, 1.001–1.015]), nitroimidazole treatment (OR = 7.907 [95% CI, 1.652–37.843]), diabetes (OR = 3.067 [95% CI, 1.38–6.817]), and admission to positive culture interval (OR = 3.636 [95% CI, 1.524–8.678]). Moreover, Multivariate analysis implicated hepatic abscess (OR = 74.332 [95% CI, 3.121–1769.588]), bacteremia (OR = 28.388 [95% CI, 3.039–264.200]), and metastatic spread (OR = 19.391 [95% CI, 3.633–103.498]) as independent risk factors for hvKp infections. Thirteen of twenty-one tested antibiotics were founded resistance to non-hvKp, which is significantly greater than hvKp. Importantly, the ESBL-hvKp and MDR-hvKp were responsible for 7.5% and 15.1% in the hvKp group, respectively.

Multi-drug resistance (MDR) and hypervirulence (hv) were exhibited by different well-separated Klebsiella pneumoniae lineages in the past, but their convergence clones—MDR-hypervirulent K. pneumoniae (HvKPs)—both highly pathogenic and resistant to most available antibiotics, have increasingly been reported. In light of the clonal lineages and molecular characteristics of the studied MDR-HvKP strains found in the literature since 2014, this review discusses the epidemiology of MDR-HvKPs, in particular summarizing the three general aspects of plasmids-associated mechanisms underlying the formation of MDR-HvKPs clones: MDR-classic K. pneumoniae (cKPs) acquiring hv plasmids, hvKPs obtaining MDR plasmids, and the acquisition of hybrid plasmids harboring virulence and resistance determinants. A deeper understanding of epidemiological characteristics and possible formation mechanisms of MDR-HvKPs is greatly needed for the proper surveillance and management of this potential threat.

Dysregulation of MicroRNAs (miRNAs) cause various diseases in humans, and developing reliable methods to detect miRNAs is critical for molecular diagnostics and personalized medicine. This study developed a toehold-mediated target invasion combined with duplex-specificity nuclease (DSN)-assisted cyclic signal amplification fluorescent sensor. Herein, we take advantage of toehold-mediated target invasion process to ensure the high selectivity of miRNA determination, coupled with the unique cleavage properties of DSN to improve the sensitivity of the strategy significantly. Throughout the assay, the whole procedure of detection the target let-7a has a limit of detection (LOD) as low as 9.00 fM and an excellent linear range from 1 pM to 100 nM for no more than 60 min. The assay shows reasonable specificity in detecting mismatched miRNAs and can realize single-base discrimination in the let-7 families. Finally, the developed method was applied to detect the miRNAs extracted from human serum. The results were consistent with those based on the quantitative reverse transcription-polymerase chain reaction(qRT-PCR) method, which shows great potential application value in clinical molecular diagnostics and biological research.

Background There are limited data on vitamin D status of Sichuan province, and no investigation has been carried out on the correlations of 25(OH)D and BTMs between healthy Hans and Tibetans of Sichuan province. This study aimed to examine 25(OH)D levels around Sichuan province and to assess differences by ethnicity, age, gender, sunlight exposure, geographic location, and seasons. Methods Blood samples from 2317 healthy adults aged of 18 to 75 years and of Han and Tibetan ethnicities were collected in six regions and during four seasons. Serum 25(OH)D2 and 25(OH)D3 levels were measured by LC‐MS/MS method. Serum total P1NP and β‐CTX were measured by immunoassay. Results Participants aged 18‐40 years showed significantly lower 25(OH)D levels than participants aged 41‐75 years old (P, This multicenter cross‐sectional study showed that serum 25(OH)D levels of adults in Sichuan province among four seasons and different districts varied significantly (P

N6-methyladenosine (m6A), the most abundant modification in eukaryotic cells, regulates RNA transcription, processing, splicing, degradation, and translation. Circular RNA (circRNA) is a class of covalently closed RNA molecules characterized by universality, diversity, stability and conservatism of evolution. Accumulating evidence shows that both m6A modification and circRNAs participate in the pathogenesis of multiple diseases, such as cancers, neurological diseases, autoimmune diseases, and infertility. Recently, m6A modification has been identified for its enrichment and vital biological functions in regulating circRNAs. In this review, we summarize the role of m6A modification in the regulation and function of circRNAs. Moreover, we discuss the potential applications and possible future directions in the field.

This study aimed to identify the role and relationship with efflux pump of biofilm formation in Klebsiella pneumoniae. Sixty-one K. pneumoniae clinical isolates were collected between January and June of 2017 from the affiliated hospital of southwest medical university in Luzhou, China. The minimum inhibitory concentration (MIC) and minimum biofilm eradication concentration (MBEC) were determined using broth microdilution method. Crystal violet (CV) staining and confocal laser scanning microscope (CLSM) were used to monitor biofilm formation. Efflux pump expression was investigated qualitatively and quantitatively by polymerase chain reaction (PCR) and reverse transcriptase quantitative PCR (RT-qPCR). Crystal violet staining was performed to evaluate the effect of efflux pump inhibitor carbonyl cyanide m-chlorophenyl hydrazine (CCCP) on K. pneumoniae biofilms. Our results showed that crystal violet staining and CLSM had good consistency in biofilm detection. Biofilm formation was an independent biological behavior of the strain and measured at 24 h was reasonable. Biofilms up-regulated antimicrobial resistance and expression of efflux pump gene acrA, emrB, oqxA, and qacEΔ1 in K. pneumoniae. CCCP inhibited biofilms but dose-dependent effect was obvious. Altogether, our data demonstrates that biofilm formation, as well as its interaction with efflux pump, promotes antimicrobial resistance in K. pneumoniae.

Resistance to the chemotherapeutic drug cisplatin has been documented in various types of cancer, while the increased expression of β‑catenin has been observed in cisplatin‑resistant ovarian cancer. However, the involvement of β‑catenin in cisplatin resistance is unclear. The present study investigated the antitumor effect of cisplatin on the proliferation, invasion and apoptosis of breast cancer (BC) cells following β‑catenin silencing in BC, which is the most frequent type of malignancy among women. The expression of β‑catenin in BC tissues and cell lines was measured by reverse transcription‑quantitative polymerase chain reaction, and the association between expression levels and clinical characteristics was statistically analyzed. The viability of BC cell lines treated with siR‑β‑catenin or with siR‑β‑catenin and cisplatin in combination was determined using a Cell Counting Kit‑8 assay. The migratory and invasive abilities of BC cells treated with both siR‑β‑catenin and cisplatin were examined with Transwell assays. The CD44 antigen/intercellular adhesion molecule 1 expression ratio, cell cycle distribution and apoptosis levels of BC cells treated with siR‑β‑catenin and cisplatin in combination were detected by flow cytometry. The expression levels of apoptosis‑associated proteins, including caspase‑3/9, in the BC cells treated with both siR‑β‑catenin and cisplatin were investigated by western blot analysis. The levels of apoptosis in the BC cells following combined treatment with siR‑β‑catenin and cisplatin was further quantified by Hoechst 33342 staining. β‑catenin was identified to be highly expressed in BC tissues and cell lines and was associated with pathological stage and lymph node status. Following knockdown of β‑catenin expression, cisplatin treatment suppressed the viabilities, and the migratory and invasive capabilities of the T47D and MCF‑7 cells, and induced extensive apoptosis. β‑catenin knockdown upregulated caspase‑3/9 levels following cisplatin treatment and induced the apoptosis of T47D and MCF‑7 cells. In conclusion, β‑catenin may be of value as a therapeutic target during cisplatin treatment in patients with BC treated with cisplatin.

Background. COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has threatened every civilian as a global pandemic. The immune system poses the critical interactive chain between the human body and the virus. Here, we make efforts to examine whether comorbidity with type 2 diabetes (T2D) affects the immunological response in COVID-19 patients. Methods. We conducted a retrospective pilot study investigating immunological characteristics of confirmed cases of COVID-19 with or without comorbid T2D. Two subcohorts of sex- and age-matched participants were eligible for data analysis, of which 33 participants were with T2D and the remaining 37 were nondiabetic (NDM). Cellular immunity was assessed by flow cytometric determination of surface markers including CD3, CD4, CD8, CD19, CD16, and CD56 in peripheral blood. Levels of C reactive protein, immunoglobulin (IgG, IgM, IgA, and IgE), and complements (C3, C4) were detected by rate nephelometry immunoassay. And Th1/Th2 cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) were detected by Cytometric Bead Array. Results. Neutrophil counts were found to be significantly higher in the T2D group than in the NDM group and had a significant relevance with clinical severity. Lymphocyte frequencies showed no significant differences in the two groups. However, the proportions and absolute counts of T, Tc, Th, and NK cells decreased in both groups to different degrees. An abnormal increase in neutrophil count and a decrease in lymphocyte subpopulations may represent risk factors of COVID-19 severity. The level of IgG, IgM, IgA, C3, and C4 showed no significant difference between the two groups, while the IgE levels were higher in the T2D group than in the NDM group ( p < 0.05 ). Th1 cytokines including IFN-γ, TNF-α, and IL-6, as well as CRP, appeared significantly higher in the T2D group. Conclusions. The COVID-19 patients comorbid with T2D demonstrated distinguishable immunological parameters, which represented clinical relevancies with the predisposed disease severity in T2D.

Charcot-Marie-Tooth Disease (CMT) is the most common clinical genetic disease of the peripheral nervous system. Although many studies have focused on elucidating the pathogenesis of CMT, few focuses on achieving a systematic analysis of biology to decode the underlying pathological molecular mechanisms and the mechanism of its disease remains to be elucidated. So our study may provide further useful insights into the molecular mechanisms of CMT based on a systematic bioinformatics analysis. In the current study, by reviewing the literatures deposited in PUBMED, we identified 100 genes genetically related to CMT. Then, the functional features of the CMT-related genes were examined by R software and KOBAS, and the selected biological process crosstalk was visualized with the software Cytoscape. Moreover, CMT specific molecular network analysis was conducted by the Molecular Complex Detection (MCODE) Algorithm. The biological function enrichment analysis suggested that myelin sheath, axon, peripheral nervous system, mitochondrial function, various metabolic processes, and autophagy played important roles in CMT development. Aminoacyl-tRNA biosynthesis, metabolic pathways, and vasopressin-regulated water reabsorption were significantly enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway network, suggesting that these pathways may play key roles in CMT occurrence and development. According to the crosstalk, the biological processes could be roughly divided into a correlative module and two separate modules. MCODE clusters showed that in top 3 clusters, 13 of CMT-related genes were included in the network and 30 candidate genes were discovered which might be potentially related to CMT. The study may help to update the new understanding of the pathogenesis of CMT and expand the potential genes of CMT for further exploration.

The hepatitis C virus (HCV) NS5B protein is an RNA-dependent RNA polymerase that is required for viral genome replication and constitutes the most important target region for drugs being developed as direct-acting antivirals (DAAs) against HCV genotype 1. However, the extreme genetic variability leading to drug resistance mutations and genetic barriers has dramatically compromised the effectiveness of DAA therapy. The purpose of this study was to analyze the genetic variability of NS5B polymerase in HCV patients from different provinces of China to identify the impact of these resistance sites on genetic barriers. We analyzed 3489 NS5B sequences of HCV strains circulating in different regions of China, obtained from the GenBank database, 153 of which were from three cities in Sichuan Province (Yibin, Zigong and Zhangzhou). Sequence alignment was conducted using MEGA 6.0, the genetic information was translated into amino acids, and the percentage of polymorphic amino acid sites was calculated. The Vijver method was used to evaluate the occurrence of genetic barriers in HCV NS5B sequences. Blood samples were collected from 153 HCV patients from Sichuan for NS5B sequence analysis using real-time PCR and the Sanger method. Of the 17 antiviral drug resistance sites summarized from the published literature, nine were found in Chinese NS5B sequences, and C316Y was identified as the dominant mutation. Analysis of genetic barriers revealed that the probability of mutation to a drug-resistance-associated amino acid, in response to selective pressure from antiviral drugs was 100% at site 96 and 99.7% at site 282. Our study is the first to analyze the drug resistance sites and to evaluate genetic barriers in NS5B sequences that could affect the responsiveness of Chinese HCV patients to DAA therapy. The results provide a valuable basis for drug development and introduction of foreign-origin antiviral drugs in China that targeting the HCV NS5B region.

Mps One binder 1 (MOB1) is a core component of NDR/LATS kinase and a positive regulator of the Hippo signaling pathway. However, its role in neurite outgrowth still remains to be clarified. Here, we confirmed, for the first time, that MOB1 promoted neurite outgrowth and was involved in functional recovery after spinal cord injury (SCI) in mice. Mechanistically, we found that MOB1 stability was regulated by the PTEN-GSK3β axis. The MOB1 protein was significantly up-regulated in PTEN-knockdown neuronal cells. This effect was dependent on the lipid phosphatase activity of PTEN. Moreover, MOB1 was found to be a novel substrate for GSK3β that is phosphorylated on serine 146 and degraded via the ubiquitin-proteasome system (UPS). Finally, in vivo lentiviral-mediated silencing of PTEN promoted neurite outgrowth and functional recovery after SCI and this effect was reversed by down-regulation of MOB1. Taken together, this study provided mechanistic insight into how MOB1 acts as a novel and a necessary regulator in PTEN-GSK3β axis that controls neurite outgrowth after SCI.

Hepatocellular carcinoma (HCC) has a high recurrence rate and poor clinical outcome after currently used therapies, including radiofrequency ablation. To explore the possible mechanisms for the relapse of HCC, in the present study we focussed on long non-coding RNA (LncRNA), which has been reported to be involved in tumorigenesis. We identified an LncRNA P5848, whose expression level was up-regulated in tumor samples from HCC patients after radiofrequency ablation. As such, we speculated that LncRNA P5848 may play a role in tumor growth. Here we showed that LncRNA P5848, whose up-regulation can lead to HCC cancer cell proliferation and migration. In vitro and in vivo overexpression of LncRNA P5848 promoted cell growth, cell survival, and cell invasion, whereas LncRNA P5848 depletion exerts opposite effects. Mechanistically, we have found that ENO1 was the target of LncRNA P5848. LncRNA P5848 up-regulated the gene and protein expression level of ENO1, promoting tumor growth and cell survival. However, siRNA-mediated knockdown of ENO1 counteracted the effects of LncRNA P5848 on cancer cell growth, cell survival, and migration. Taken together, LncRNA P5848 promotes HCC development by up-regulating ENO1, indicating that LncRNA P5848-ENO1 axis is a potential therapeutic target for the treatment of HCC.

Noncoding RNAs (ncRNAs) can be divided into microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), pRNAs, and tRNAs. Traditionally, miRNAs exert their biological function mainly through the inhibition of translation via the induction of target RNA transcript degradation. lncRNAs and circRNAs were once considered to have no potential to code proteins. Here, we will review the current knowledge on ncRNAs in relation to their origins, characteristics, and functions. We will also review how ncRNAs work as competitive endogenous RNA, gene transcription and expression regulators, and RNA-binding protein sponges in colorectal cancer (CRC). Notably, except for the abovementioned mechanisms, recent advances revealed that lncRNAs can also act as the precursor of miRNAs, and a small portion of lncRNAs and circRNAs was verified to have the potential to code proteins, providing new evidence for the significance of ncRNAs in CRC tumorigenesis and development.

Exosomes are extracellular vesicles released by many cell types and have been attributed for their roles in many diseases including cancer. Exosomes secreted by tumor cells and stromal cells are critical mediators of intercellular communication in tumor microenvironments. Long noncoding RNAs (lncRNAs) are selectively sorted into exosomes and can regulate cancer onset and progression in a variety of ways. In this review, we summarize the characteristics of exosomal lncRNAs and their dysregulation in multiple types of cancer. We provide an overview of current research on exosomal lncRNAs in tumor microenvironments, especially the functions of exosomal lncRNAs in regulating tumor biology. A deeper understanding of the role of exosomal lncRNAs in the tumor microenvironment may help provide new diagnostic and prognostic markers for cancer.

Pseudomonas aeruginosan has emerged as an important pathogen elated to serious infections and nosocomial outbreaks worldwide. This study was conducted to understand the prevalence of aminoglycoside (AMG)-resistant P. aeruginosa in our hospital and to provide a scientific basis for control measures against nosocomial infections. Eighty-two strains of P. aeruginosa were isolated from clinical departments and divided into AMG-resistant strains and AMG-sensitive strains based on susceptibility test results. AMG-resistant strains were typed by drug resistance gene typing (DRGT) and protein typing. Five kinds of aminoglycoside-modifying enzyme (AME) genes were detected in the AMG-resistant group. AMG-resistant P. aeruginosa strains were classified into three types and six subtypes by DRGT. Four protein peaks, namely, 9900.02, 7600.04, 9101.25 and 10,372.87 Da, were significantly and differentially expressed between the two groups. AMG-resistant P. aeruginosa strains were also categorised into three types and six subtypes at the distance level of 10 by protein typing. AMG-resistant P. aeruginosa was cloned spread in our hospital; the timely implementation of nosocomial infection prevention and control strategies were needed in preventing outbreaks and epidemic of AMG-resistant P. aeruginosa. SELDI-TOF MS technology can be used for bacterial typing, which provides a new method of clinical epidemiological survey and nosocomial infection control.

Background Osteoarthritis (OA) is a degenerative disease of articular cartilage and its main pathological feature is cartilage destruction, but its specific pathogenesis is still debatable. The aim of this study was to explore the role of miR-337-3p in OA pathogenesis. Methods The expression of miR-337-3p and PTEN in osteoarthritic cartilage tissues was detected using quantitative real time PCR and western blot, respectively. The regulation of miR-337-3p on PTEN was examined by luciferase reporter gene assays. The manipulation of miR-337-3p and PTEN was mediated by siRNA interference technology. The cell viability was analyzed by MTT assays. Results MiR-337-3p expression was significantly down-regulated in osteoarthritic cartilage tissues compared with normal cartilage tissues. Further studies confirmed that miR-337-3p overexpression evidently promoted the proliferation and inhibited the apoptosis of OA chondrocytes. PTEN expression was significantly up-regulated in osteoarthritic cartilage tissues and was negatively regulated by miR-337-3p in chondrocytes. PTEN silencing could improve the proliferation of OA chondrocytes and increased pAKT protein expression in OA chondrocytes. Conclusion MiR-337-3p regulated OA chondrocytes proliferation through PTEN/AKT axis and thus involved in OA.

// Zhen-Qiang Sun 1, * , Chen Chen 1, * , Quan-Bo Zhou 1 , Jin-Bo Liu 1 , Shuai-Xi Yang 1 , Zhen Li 1 , Chun-Lin Ou 2 , Xian-Tao Sun 1 , Gui-Xian Wang 1 , Jun-Min Song 1 , Zhi-Yong Zhang 1 and Wei-Tang Yuan 1 1 Department of Anorectal Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052, China 2 Cancer Research Institute, Central South University, Changsha 410008, China * These authors have contributed equally to this work Correspondence to: Zhen-Qiang Sun, email: zqsun82@csu.edu.cn Wei-Tang Yuan, email: yuanweitang@zzu.edu.cn Jin-Bo Liu, email: 1999liujb@163.com Keywords: long non-coding RNA, LINC00959, colorectal cancer, epithelial-mesenchymal transition, biomarker Received: April 25, 2017 Accepted: August 26, 2017 Published: September 21, 2017 ABSTRACT Long non-coding RNAs (lncRNAs) are increasingly implicated in tumorigenesis and cancer progression. This study focused on the relationship between the lncRNA LINC00959 and colorectal cancer (CRC). We found that LINC00959 expression was lower in CRC tissues than normal colorectal mucosae. High LINC00959 expression was negatively associated with TNM stage, distant metastasis, and lymphatic metastasis, and correlated with a better prognosis in 87 CRC cases. In vitro , LINC00959 knockdown enhanced colon cancer cell proliferation, invasion, and migration; upregulated N-cadherin and vimentin; and downregulated E-cadherin and Caspase-3. LINC00959 overexpression produced the opposite effects. These data suggest that LINC00959 inhibits tumor cell invasion and migration by suppressing epithelial-mesenchymal transition and promotes apoptosis through Caspase-3. LINC00959 may be a tumor suppressor and useful prognostic biomarker in CRC.

Unraveling elevational diversity patterns of plants and animals has long been attracting scientific interests. However, whether soil microorganisms exhibit similar elevational patterns remains largely less explored, especially for functional microbial communities, such as ammonia oxidizers. Here, we investigated the diversity and distribution pattern of ammonia-oxidizing archaea (AOA) in meadow soils along an elevation gradient from 4400 m to the grassline at 5100 m on the Tibetan Plateau using terminal restriction fragment length polymorphism (T-RFLP) and sequencing methods by targeting amoA gene. Increasing elevations led to lower soil temperature and pH, but higher nutrients and water content. The results showed that AOA diversity and evenness monotonically increased with elevation, while richness was relatively stable. The increase of diversity and evenness was attributed to the growth inhibition of warm-adapted AOA phylotypes by lower temperature and the growth facilitation of cold-adapted AOA phylotypes by richer nutrients at higher elevations. Low temperature thus played an important role in the AOA growth and niche separation. The AOA community variation was explained by the combined effect of all soil properties (32.6%), and 8.1% of the total variation was individually explained by soil pH. The total AOA abundance decreased, whereas soil potential nitrification rate (PNR) increased with increasing elevations. Soil PNR positively correlated with the abundance of cold-adapted AOA phylotypes. Our findings suggest that low temperature plays an important role in AOA elevational diversity pattern and niche separation, rising the negative effects of warming on AOA diversity and soil nitrification process in the Tibetan region.

Induction of proinflammatory T cell immunity is augmented by innate dendritic cell (DC) maturation commonly initiated by TLR signaling. We demonstrate that ligation of TLR3, TLR4, and TLR9 induces murine DC production of complement components and local production of the anaphylatoxin C5a. In vitro, ex vivo, and in vivo analyses show that TLR-induced DC maturation, as assessed by surface phenotype, expression profiling by gene array, and functional ability to stimulate T cell responses, requires autocrine C3a receptor and C5a receptor (C3ar1/C5ar1) signaling. Studies using bone marrow chimeric animals and Foxp3-GFP/ERT2-Cre/dTomato fate-mapping mice show that TLR-initiated DC autocrine C3ar1/C5ar1 signaling causes expansion of effector T cells and instability of regulatory T cells and contributes to T cell–dependent transplant rejection. Together, our data position immune cell–derived complement production and autocrine/paracrine C3ar1/C5ar1 signaling as crucial intermediary processes that link TLR stimulation to DC maturation and the subsequent development of effector T cell responses.

// Zhenqiang Sun 1, * , Fuqi Wang 1, * , Quanbo Zhou 1 , Shuaixi Yang 1 , Xiantao Sun 1 , Guixian Wang 1 , Zhen Li 1 , Zhiyong Zhang 1 , Junmin Song 1 , Jinbo Liu 1 and Weitang Yuan 1 1 Department of Anorectal Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China * Co-first authors Correspondence to: Zhenqiang Sun, email: zqsun82@csu.edu.cn Weitang Yuan, email: yuanweitang@zzu.edu.cn Jinbo Liu, email: 1999liujb@163.com Keywords: colorectal cancer, CEA, tumor marker, prognosis Received: April 15, 2017 Accepted: May 05, 2017 Published: May 17, 2017 ABSTRACT We explored the prognostic significance of the pre-operative-to-post-operative serum carcinoembryonic antigen (pre-post-CEA) ratio in colorectal cancer (CRC). We detected pre- and post-operative CEA levels in 2035 CRC patients surgically treated at First Affiliated Hospital of Zhengzhou University between June 2001 and June 2011. Univariate analysis revealed the pre-post-CEA ratio is associated with distant metastasis and degree of tumor differentiation (both P < 0.05). Multivariate analysis showed that the pre-post-CEA ratio is associated with lymphatic and distant metastasis, tumor-node-metastasis (TNM) stage and degree of tumor differentiation (all P < 0.01). The pre-CEA levels, pre-post-CEA ratios, distant metastasis, TNM stage and degree of tumor differentiation were all associated with 5-yr overall survival (all P < 0.05) based on multivariate analysis. Consequently, pre-CEA levels, pre-post-CEA ratios, distant metastasis and TNM stage are independent risk factors for CRC. We have thus demonstrated that the pre-post-CEA ratio is a prognostic indicator for CRC patients.

Key Clinical Message Acquired hemophilia A might be caused by Ginkgo‐dipyridamolum especially by Ginkgo, and it was successfully treated with hemostasis and immune‐suppression therapy including methylprednisolone and cyclophosphamide.

N6-methyladenosine (m6A) methylation, one of the most common RNA modifications, has been reported to execute important functions that affect normal life activities and diseases. Most studies have suggested that m6A modification can affect the complexity of cancer progression by regulating biological functions related to cancer. M6A modification of noncoding RNAs regulates the cleavage, transport, stability, and degradation of noncoding RNAs themselves. It also regulates cell proliferation and metastasis, stem cell differentiation, and homeostasis in cancer by affecting the biological function of cells. Interestingly, noncoding RNAs also play significant roles in regulating these m6A modifications. Additionally, it is becoming increasingly clear that m6A and noncoding RNAs potentially contribute to the clinical application of cancer treatment. In this review, we summarize the effect of the interactions between m6A modifications and noncoding RNAs on the biological functions involved in cancer progression. In particular, we discuss the role of m6A and noncoding RNAs as possible potential biomarkers and therapeutic targets in the treatment of cancers.

Deep venous thrombosis (DVT) of the lower extremities is a common complication after total knee arthroplasty (TKA). This study aimed to investigate the potential associations between serum lipids and the risk of DVT after TKA in patients with primary knee osteoarthritis (OA). A total of 431 patients who received TKA caused by primary knee OA were randomly enrolled. According to the results of the color Doppler ultrasound of bilateral lower extremities deep veins on the third day postoperatively, patients were divided into DVT and non-DVT groups. Comparisons of preoperative serum levels of triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1, and apolipoprotein B were then performed by the Student’s t test, χ2 test, and multivariate logistic regression analysis. For females, DVT patients had a higher serum LDL-C level at baseline ( P = .043) compared with non-DVT patients. A higher LDL-C value was significantly associated with an elevated DVT risk following TKA in female patients ( P = .037). In female patients with primary knee OA, preoperative serum LDL-C level may have an association with DVT risk after TKA. The relatively small male sample size may limit the accuracy of the findings.

The present study aimed to investigate the potential biological functions of microRNA‑340 (miR‑340) in non‑small cell lung cancer (NSCLC) beyond its role as a critical regulator of tumorigenesis and tumor progression. The expression levels of miR‑340 and RAB27B were analyzed by reverse transcription‑quantitative polymerase chain reaction. Subsequently, the protein expression levels of RAB27A, RAB27B, RAB9A, RAB11A and BRAB21 were determined by western blot analysis. The expression levels of the aforementioned proteins in NSCLC tissues were analyzed by immunohistochemistry. RAB27B, as a potential target of miR‑340 was investigated via a dual‑luciferase reporter assay. The proliferative ability of PC9, A549 and BEAS‑2B cells was detected with a Cell Counting kit‑8 assay, while the migration and invasion of the NSCLC cells were analyzed using a Transwell assay. The results revealed that the expression levels of miR‑340 in the NSCLC cells were significantly decreased compared with those in normal cells (BEAS‑2B cells). RAB27B was proposed as a potential target gene of miR‑340, and its expression was notably increased in the NSCLC cells. miR‑340 overexpression inhibited the migration and invasion of the NSCLC cells by targeting RAB27B, while the knockdown of miR‑340 exerted opposite effects. On the whole, these findings indicate that the miR‑340/RAB27B axis may be actively involved in the occurrence of NSCLC. Thus, miR‑340 and RAB27B may be novel therapeutic targets for the treatment of NSCLC.

Long noncoding RNAs (lncRNAs) function as competing endogenous RNAs (ceRNAs). ceRNA networks may serve important roles in various tumors, as demonstrated by an increasing number of studies; however, papillary renal cell carcinoma (PRCC)‑associated ceRNA networks mediated by lncRNAs remain unknown. Increased knowledge of ceRNA networks in PRCC may aid the identification of novel targets and biomarkers in the treatment of PRCC. In the present study, a comprehensive investigation of mRNA, lncRNA, and microRNA (miRNA) expression in PRCC was conducted using sequencing data from The Cancer Genome Atlas. Differential expression (DE) profiles of mRNAs, lncRNAs and miRNAs were evaluated, with 1,970 mRNAs, 1,201 lncRNAs and 96 miRNAs identified as genes with significantly different expression between PRCC and control paracancerous tissues. Based on the identified DEmRNAs, a protein‑protein interaction network was generated using the STRING database. Furthermore, a ceRNA network for PRCC was determined using a targeted assay combined with the DE of miRNAs, mRNAs and lncRNAs, enabling the identification of important lncRNA‑miRNA and miRNA‑mRNA pairs. Analysis of the ceRNA network led to the extraction of a subnetwork and the identification of lncRNA maternally expressed 3 (MEG3), lncRNA PWRN1, miRNA (miR)‑508, miR‑21 and miR519 as important genes. Reverse transcription‑quantitative polymerase chain reaction analysis was conducted to validate the results of the bioinformatics analyses; it was revealed that lncRNA MEG3 expression levels were downregulated in PRCC tumor tissues compared with adjacent non‑tumor tissues. In addition, survival analysis was conducted to investigate the association between identified genes and the prognosis of patients with PRCC, indicating the potential involvement of 13 mRNAs, 15 lncRNAs and six miRNAs. In conclusion, the present study may improve understanding of the regulatory mechanisms of ceRNA networks in PRCC and provide novel insight for future studies of prognostic biomarkers and potential therapeutic targets.

Objective Liver metastasis, which contributes substantially to high mortality, is the most common recurrent mode of colon carcinoma. Thus, it is necessary to identify genes implicated in metastatic colonization of the liver in colon carcinoma. Methods We compared mRNA profiling in 18 normal colon mucosa (N), 20 primary tumors (T) and 19 liver metastases (M) samples from the dataset GSE49355 and GSE62321 of Gene Expression Omnibus (GEO) database. Gene ontology (GO) and pathways of the identified genes were analyzed. Co-expression network and protein-protein interaction (PPI) network were employed to identify the interaction relationship. Survival analyses based on The Cancer Genome Atlas (TCGA) database were used to further screening. Then, the candidate genes were validated by our data. Results We identified 22 specific genes related to liver metastasis and they were strongly associated with cell migration, adhesion, proliferation and immune response. Simultaneously, the results showed that C-X-C motif chemokine ligand 14 (CXCL14) might be a favorable prediction factor for survival of patients with colon carcinoma. Importantly, our validated data further suggested that lower CXCL14 represented poorer outcome and contributed to metastasis. Gene set enrichment analysis (GSEA) showed that CXCL14 was negatively related to the regulation of stem cell proliferation and epithelial to mesenchymal transition (EMT). Conclusions CXCL14 was identified as a crucial anti-metastasis regulator of colon carcinoma for the first time, and might provide novel therapeutic strategies for colon carcinoma patients to improve prognosis and prevent metastasis.