Upregulation of hsa-miR-141-3p promotes uterine cervical carcinoma progression via targeting dual-specificity protein phosphatase 1.

We aimed to explore the aberrant expression status of hsa-miR-141-3p and dual-specificity protein phosphatase 1 (DUSP1) and their relative mechanisms in uterine cervical carcinoma (UCC).Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was conducted to detect the expression of hsa-miR-141-3p. Immunohistochemical (IHC) staining was performed to examine the expression of DUSP1 in UCC. Gene chips and RNA-seq datasets were also obtained to assess the expression level. Integrated standardized mean difference (SMD) was calculated to evaluate the expression status of hsa-miR-141-3p in UCC tissues comprehensively. DUSP1-overexpression and hsa-miR-141-3p-inhibition HeLa cells were established, and CCK-8, transwell, wound healing, cell cycle, and apoptosis assays were implemented. The targets of hsa-miR-141-3p were obtained with online tools, and the combination of hsa-miR-141-3p and DUSP1 was validated via dual-luciferase reporter assay. Single-cell RNA-seq data were analyzed to explore hsa-miR-141-3p and DUSP1 in different cells. An integrated SMD of 1.41 (95% CI[0.45, 2.38], p = 0.0041) with 558 samples revealed the overexpression of hsa-miR-141-3p in UCC tissues. And the pooled SMD of -1.06 (95% CI[-1.45, -0.66], p < 0.0001) with 1,268 samples indicated the downregulation of DUSP1. Inhibition of hsa-miR-141-3p could upregulate DUSP1 expression and suppress invasiveness and metastasis of HeLa cells. Overexpression of DUSP1 could hamper proliferation, invasion, and migration and boost apoptosis and distribution of G1 phase. The dual-luciferase reporter assay validated the combination of hsa-miR-141-3p and DUSP1. Moreover, the targets of hsa-miR-141-3p were mainly enriched in the MAPK signaling pathway and activated in fibroblasts and endothelial cells. The current study illustrated the upregulation of hsa-miR-141-3p and the downregulation of DUSP1 in UCC tissues. Hsa-miR-141-3p could promote UCC progression by targeting DUSP1.

A Comprehensive Analysis of LYAR in Colorectal Cancer: Prognostic Marker and Therapeutic Target.

Background: Colorectal cancer (CRC) is a major global health challenge with a need for new biomarkers and therapeutic targets. This work aimed to investigate the biological mechanisms and clinical value of Ly1 antibody reactive (LYAR) in CRC. Methods: We analyzed LYAR mRNA expression across multiple public databases, including genotype-tissue expression, gene expression omnibus, Oncomine, and the cancer genome atlas, alongside in-house immunohistochemical data to evaluate LYAR protein expression in CRC and non-CRC colorectal tissues. Gene set enrichment analysis (GSEA) was used to elucidate LYAR's biological functions, and its impact on the tumor immune microenvironment was assessed using CIBERSORT, ESTIMATE, and single-cell RNA sequencing techniques. In addition, LYAR's association with clinicopathological features and patient prognosis was explored, and its influence on drug sensitivity was investigated using the Connectivity Map database. Results: LYAR was significantly upregulated in CRC tissues compared with non-CRC colorectal counterparts, associated with altered immune cell composition and enhanced RNA processing, splicing, and cell cycle regulation. High LYAR expression correlated with poor disease-free and overall survival, underscoring its prognostic value. GSEA revealed LYAR's involvement in critical cellular processes and pathways, including DNA repair, cell cycle, and mTORC1 signaling. Correlation analysis identified genes positively and negatively associated with LYAR, leading to the discovery of temsirolimus and WYE-354, mTOR inhibitors, as potential therapeutic agents for CRC. Furthermore, LYAR expression predicted increased sensitivity to cetuximab in RAS wild-type metastatic CRC, indicating its utility as a biomarker for treatment responsiveness. Conclusions: LYAR's upregulation in CRC highlights its potential as a biomarker for prognosis and therapeutic targeting, offering insights into CRC pathology and suggesting new avenues for treatment optimization.

Varied immune responses of HBV-specific B cells in patients undergoing pegylated interferon-alpha treatment for chronic hepatitis B.

BACKGROUND & AIMS: The changes in HBV-specific B cells in patients with chronic hepatitis B (CHB) undergoing pegylated interferon-α (PEG-IFNα) treatment and achieving functional cure remain unclear. We aimed to evaluate the alterations in HBV-specific B cells during treatment and therefore explored the mechanism of functional recovery of HBsAg-specific B cells. METHODS: We included 39 nucleos(t)ide analogue-treated patients with CHB who received sequential combination therapy with PEG-IFNα and eight treatment-naïve patients. HBV-specific B cells were characterized ex vivo using fluorescently labeled hepatitis B surface and core antigens (HBsAg and HBcAg). The frequency, phenotype, and subsets of HBV-specific B cells and follicular helper T cells (Tfh cells) were detected using flow cytometry. The functionality of HBV-specific B cells was quantified through ELISpot assays. RESULTS: During treatment, the fraction of activated memory B cells (MBCs) among HBsAg-specific B cells and the expression of IgG, CXCR3, and CD38 increased. The antibody-secretion capacity of HBsAg-specific B cells was only restored in patients achieving a functional cure after treatment and it positively correlated with serum hepatitis B surface antibody levels. The phenotype and function of HBsAg-specific B cells differed between patients with and without functional cure. Patients with functional cure exhibited IgG+ classical MBCs and plasmablasts among HBsAg-specific B cells. HBcAg-specific B cells displayed both attenuated antibody secretion with reduced IgG expression and an IgM+ atypical type of MBC after treatment, irrespective of functional cure. The number of CD40L+ Tfh cells increased after PEG-IFNα treatment and positively correlated with HBsAg-specific B-cell activation. CONCLUSIONS: After PEG-IFNα treatment, HBsAg- and HBcAg-specific B cells exhibit various changes in antibody secretion. Their functional differences are reflected in the alterations in phenotypes and subtypes. The presence of CD40L+ Tfh cells is associated with the active recovery of HBsAg-specific B cells. IMPACT AND IMPLICATIONS: HBV-related complications and hepatocellular carcinoma remain the leading causes of mortality from chronic liver disease worldwide, and a cure is rarely achieved with antiviral therapies. Elucidating the immunological mechanisms underlying the functional cure of patients with chronic hepatitis B offers a promising therapeutic strategy for viral clearance, e.g. via therapeutic vaccination. We analyzed the alterations in HBV-specific B cells in patients treated with pegylated interferon-α and identified novel pathways for immunotherapeutic boosting of B cell immunity.

A NAC transcription factor represses a module associated with xyloglucan content and regulates aluminum tolerance.

The transcriptional regulation of aluminum (Al) tolerance in plants is largely unknown, although Al toxicity restricts agricultural yields in acidic soils. Here, we identified a NAM, ATAF1/2, and cup-shaped cotyledon 2 (NAC) transcription factor that participates in Al tolerance in Arabidopsis (Arabidopsis thaliana). Al substantially induced the transcript and protein levels of ANAC070, and loss-of-function mutants showed remarkably increased Al sensitivity, implying a beneficial role of ANAC070 in plant tolerance to Al toxicity. Further investigation revealed that more Al accumulated in the roots of anac070 mutants, especially in root cell walls, accompanied by a higher hemicellulose and xyloglucan level, implying a possible interaction between ANAC070 and genes that encode proteins responsible for the modification of xyloglucan, including xyloglucan endo-transglycosylase/hydrolase (XTH) or ANAC017. Yeast 1-hybrid analysis revealed a potential interaction between ANAC070 and ANAC017, but not for other XTHs. Furthermore, dual-luciferase reporter assay, RT-qPCR, and GUS analysis revealed that ANAC070 could directly repress the transcript levels of ANAC017, and knockout of ANAC017 in the anac070 mutant partially restored its Al sensitivity phenotype, indicating that ANAC070 contributes to Al tolerance mechanisms other than suppression of ANAC017 expression. Further analysis revealed that the core transcription factor SENSITIVE TO PROTON RHIZOTOXICITY 1 (STOP1) and its target genes, which control Al tolerance in Arabidopsis, may also be involved in ANAC070-regulated Al tolerance. In summary, we identified a transcription factor, ANAC070, that represses the ANAC017-XTH31 module to regulate Al tolerance in Arabidopsis.

Increased LACTB2 Expression Regulates Oxidative Phosphorylation and mTORC1 Signaling of Colorectal Cancer.

This study aimed to investigate the mechanisms of LACTB2 in colorectal cancer (CRC). Microarrays and sequencing data of CRC were acquired from UCSC Xena, GTEx, Gene Expression Omnibus, and TCGA. Pooled analysis of the mRNA expression of LACTB2 in CRC was performed using Stata software. The protein expression of LACTB2 in CRC tissues was evaluated by immunohistochemistry. The relationship between immune cell infiltration and LACTB2 expression was investigated using CIBERSORT. The potential signaling pathways and biological mechanisms of LACTB2 were explored using GSEA, KEGG, and GO. Subsequently, further screening of small molecular compounds with potential therapeutic effects on CRC was conducted through the HERB database, followed by molecular docking studies of these compounds with the LACTB2 protein. The integration and analysis of expression data obtained from 2294 CRC samples and 1286 noncancerous colorectal samples showed that LACTB2 was highly expressed in CRC. Immunohistochemistry performed on in-house tissue samples confirmed that LACTB2 protein expression was upregulated in CRC. CIBERSORT revealed lower B cell infiltration levels in the high LACTB2 expression group than in the low expression group. GO, KEGG, and GSEA analyses showed that LACTB2 expression and genes positively correlating with it were mainly related to DNA synthesis and repair, mitochondrial translational elongation and translational termination, phosphorylation, and mTORC1 signaling. Finally, molecular docking simulations confirmed the ability of quercitin to target and bind to LACTB2. This is the first study to demonstrate that LACTB2 is upregulated in CRC. LACTB2 promotes colorectal tumorigenesis and tumor progression.

Circular RNA Expression of Peripheral Blood Mononuclear Cells Associated with Risk of Acute Exacerbation in Smoking Chronic Obstructive Pulmonary Disease.

Purpose: Circular RNAs (circRNAs) are newly identified endogenous non-coding RNAs that function as crucial gene modulators in the development of several diseases. By assessing the expression levels of circRNAs in peripheral blood mononuclear cells (PBMCs) from patients with chronic obstructive pulmonary disease (COPD), this study attempted to find new biomarkers for COPD screening. Patients and Methods: We confirmed altered circRNA expression in PBMCs of COPD (n=41) vs controls (n=29). Further analysis focused on the highest and lowest circRNA expression levels. The T-test is used to assess the statistical variances in circRNAs among COPD patients in the smoking and non-smoking cohorts. Additionally, among smokers, the Spearman correlation test assesses the association between circRNAs and clinical indicators. Results: Two circRNAs, hsa_circ_0042590 and hsa_circ_0049875, that were highly upregulated and downregulated in PBMCs from COPD patients were identified and verified. Smokers with COPD had lower hsa_circ_0042590 and higher hsa_circ_0049875, in comparison to non-smokers. There was a significant correlation (r=0.52, P<0.01) between the number of acute exacerbations (AEs) that smokers with COPD experienced in the previous year and the following year (r=0.67, P<0.001). Moreover, hsa_circ_0049875 was connected to the quantity of AEs in the year prior (r=0.68, P<0.0001) as well as the year after (r=0.72, P<0.0001). AUC: 0.79, 95% CI: 0.1210-0.3209, P<0.0001) for hsa_circ_0049875 showed a strong diagnostic value for COPD, according to ROC curve analysis. Hsa_circ_0042590 showed a close second with an AUC of 0.83 and 95% CI: -0.1972--0.0739 (P <0.0001). Conclusion: This research identified a strong correlation between smoking and hsa_circ_0049875 and hsa_circ_0042590 in COPD PBMCs. The number of AEs in the preceding and succeeding years was substantially linked with the existence of hsa_circ_0042590 and hsa_circ_0049875 in COPD patients who smoke. Additionally, according to our research, hsa_circ_0049875 and hsa_circ_0042590 may be valuable biomarkers for COPD diagnosis.

Diagnostic value of liver stiffness measurement combined with risk scores for esophagogastric variceal bleeding in patients with hepatitis B cirrhosis.

PURPOSE: To assess the predictive value of liver stiffness measurement (LSM) and three bleeding risk scoring systems for esophagogastric varices bleeding (EGVB) in patients with hepatitis B cirrhosis during hospitalization. METHODS: In this study, 210 patients who had hepatitis B cirrhosis were selected as the subjects. They were categorized into two groups based on whether EGVB occurred during hospitalization: a bleeding group (70 cases) and a non-bleeding group (140 cases). Logistic regression was used to analyze the factors related to the occurrence of EGVB, and the diagnostic performance was evaluated using a receiver operating characteristic (ROC) curve. RESULTS: Significant differences were observed between the two groups in systolic blood pressure, platelet count, albumin, urea nitrogen, LSM, pre-endoscopic Rockall score (PRS), Glasgow-Blatchford score (GBS), and AIMS65 score (P < 0.05). The correlation analysis showed that LSM had significant positive relationship with PRS, GBS and AIMS65 score. Logistic regression analysis revealed that LSM and GBS score were independent risk factors for EGVB occurrence during hospitalization. ROC curve analysis showed that the combined prediction model of LSM and GBS score had the best prediction performance for EGVB occurrence, with an ROC curve area of 0.811, which was significantly better than the three risk scoring systems (P < 0.05), but similar to the predicted value of LSM (P = 0.335). CONCLUSIONS: The combination of LSM and GBS score can significantly improve the predictive efficacy of EGVB occurrence in patients with hepatitis B cirrhosis during hospitalization, which has important clinical significance for patients' prognosis.

Determining optimal ALT cut-off values for predicting significant hepatic histological changes in patients with normal ALT in the grey zone of chronic hepatitis B virus infection.

BACKGROUND AND AIMS: We aimed to define gender-specific, optimal alanine aminotransferase (ALT) cut-off values for the prediction of significant liver histological changes (SLHC) in Chinese patients with grey zone (GZ) chronic hepatitis B (CHB) and normal ALT. METHODS: In a retrospective study, we included 1101 consecutive patients with GZ CHB and normal ALT assigned to training or internal validation cohorts. We included an independent cohort of 842 patients for external validation. We performed receiver operating characteristic (ROC) curve, smoothed curve fitting, and threshold effect analyses to determine optimal ALT cut-off values. Area under the curve (AUC) values were calculated to assess their predictive performance. RESULTS: A proportion of 79.3% of patients with GZ CHB and normal ALT (≤40 U/L) had SLHC. ROC curve analysis initially identified optimal ALT cut-off values of 29 U/L (male) and 22 U/L (female). After smoothed curve fitting and threshold effect analyses, new optimal cut-off values were 27 U/L for males and 24 U/L for females. AUCs for these values were 0.836 (male) and 0.833 (female) in the internal validation cohort, and 0.849 (male) and 0.844 (female) in the external validation cohort. The accuracy and discriminative ability of the newly defined ALT cut-off values were greater than those of the current recommendations. CONCLUSION: This study established novel optimal ALT cut-off values for more precise prediction of SLHC among Chinese patients with GZ CHB and normal ALT levels. This may help identify individuals who will benefit from timely antiviral therapy.

Clinical pharmacists' involvement in carbapenem antibiotics management at Wenzhou Integrated Hospital.

BACKGROUND: Carbapenem antibiotics are a pivotal solution for severe infections, particularly in hospital settings. The emergence of carbapenem-resistant bacteria owing to the irrational and extensive use of carbapenems underscores the need for meticulous management and rational use. Clinical pharmacists, with their specialized training and extensive knowledge, play a substantial role in ensuring the judicious use of carbapenem. This study aimed to elucidate the patterns of carbapenem use and shed light on the integral role played by clinical pharmacists in managing and promoting the rational use of carbapenem antibiotics at Wenzhou Integrated Traditional Chinese and Western Medicine Hospital. AIM: To analyze carbapenem use patterns in our hospital and role of clinical pharmacists in managing and promoting their rational use. METHODS: We performed a retrospective analysis of carbapenem use at our hospital between January 2019 and December 2021. Several key indicators, including the drug utilization index, defined daily doses (DDDs), proportion of antimicrobial drug costs to total hospitalization expenses, antibiotic utilization density, and utilization rates in different clinical departments were comprehensively analyzed. RESULTS: Between 2019 and 2021, there was a consistent decline in the consumption and sales of imipenem-cilastatin sodium, meropenem (0.3 g), and meropenem (0.5 g). Conversely, the DDDs of imipenem-cilastatin sodium for injection increased in 2020 and 2021 vs 2019, with a B/A value of 0.67, indicating a relatively higher drug cost. The DDDs of meropenem for injection (0.3 g) exhibited an overall upward trend, indicating an increasing clinical preference. However, the B/A values for 2020 and 2021 were both > 1, suggesting a relatively lower drug cost. The DDDs of meropenem for injection (0.5 g) demonstrated a progressive increase annually and consistently ranked first, indicating a high clinical preference with a B/A value of 1, signifying good alignment between economic and social benefits. CONCLUSION: Carbapenem use in our hospital was generally reasonable with a downward trend in consumption and sales over time. Clinical pharmacists play a pivotal role in promoting appropriate use of carbapenems.

Hepatitis B Virus Envelope Antigen and Hepatitis B Virus Surface Antigen Both Contribute to the Innate Immune Response During Persistent Hepatitis B Virus Infection.

This study aimed to investigate the changes of toll-like receptor 4 (TLR4), proinflammatory cytokine expression, hepatitis B virus surface antigen (HBsAg), and hepatitis B virus envelope antigen (HBeAg) expression as well as innate immune cell percentages in a mouse model of persistent hepatitis B virus (HBV) infection to better understand the innate immune response. Mouse models of persistent HBV infection, HBsAg expression, and HBeAg expression were developed using high-pressure tail-vein injection of recombinant adeno-associated viruses. Enzyme-linked immunosorbent assays (ELISAs) were used to determine the serum proinflammatory cytokine levels. Immunohistochemistry and western blot assays were used to detect TLR4 expression. Flow cytometric analysis was used to assess the percentage of innate immune cells in the whole blood. Persistent HBV infection, HBsAg expression, and HBeAg expression each significantly decreased the expression of TLR4. Persistent HBV infection significantly increased the percentages of T cells and monocytes, whereas it decreased the percentage of natural killer (NK) cells. Persistent HBeAg expression also decreased the percentage of NK cells, whereas persistent HBsAg expression increased the percentage of NK cells. Both persistent HBsAg and HBeAg expression increased the percentage of monocytes. However, both persistent HBsAg and HBeAg expression decreased the percentage of T cells. HBV as well as HBsAg and HBeAg showed similar effects on the expression of TLR4 and proinflammatory cytokines as well as the percentage of monocytes. Persistent HBV infection increased the percentage of T cells and decreased the percentage of NK cells, whereas only persistent HBeAg expression contributed to a decreased percentage of NK cells.

Liver Stiffness Measurement can Predict Liver Inflammation in Chronic Hepatitis B Patients with Normal Alanine Transaminase.

Background and Aims: To determine whether liver stiffness measurement (LSM) indicates liver inflammation in chronic hepatitis B (CHB) with different upper limits of normal (ULNs) for alanine aminotransferase (ALT). Methods: We grouped 439 CHB patients using different ULNs for ALT: cohort I, ≤40 U/L (439 subjects); cohort II, ≤35/25 U/L (males/females; 330 subjects); and cohort III, ≤30/19 U/L (males/females; 231 subjects). Furthermore, 84 and 96 CHB patients with normal ALT (≤40 U/L) formed the external and prospective validation groups, respectively. We evaluated the correlation between LSM and biopsy-confirmed liver inflammation, and determined diagnostic accuracy using area under the curve (AUC). A noninvasive LSM-based model was developed using multivariate logistic regression. Results: Fibrosis-adjusted LSM values significantly increased with increasing inflammation. The AUCs of LSM in cohorts I, II, and III were 0.799, 0.796, and 0.814, respectively, for significant inflammation (A≥2) and 0.779, 0.767, and 0.770, respectively, for severe inflammation (A=3). Cutoff LSM values in all cohorts for A≥2 and A=3 were 6.3 and 7.5 kPa, respectively. Internal, external, and prospective validations showed high diagnostic accuracy of LSM for A≥2 and A=3, and no significant differences in AUCs among the four groups. LSM and globulin independently predicted A≥2. The AUC of an LSM-globulin model for A≥2 exceeded those of globulin, ALT, and AST, but was similar to that of LSM. Conclusions: LSM predicted liver inflammation and guided the indication of antiviral therapy for CHB in patients with normal ALT.

Development a novel nomogram model for predicting significant hepatic histological changes in chronic hepatitis B virus carriers.

A proportion of chronic hepatitis B virus (HBV) carriers with normal alanine transaminase (ALT) present with significant liver histological changes (SLHC). To construct a noninvasive nomogram model to identify SLHC in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. The training cohort consisted of 732 chronic HBV carriers who were stratified into four sets according to different ULNs for ALT: chronic HBV carriers I, II, III, and IV. The external validation cohort comprised 277 chronic HBV carriers. Logistic regression and least absolute shrinkage and selection operator analyses were applied to develop a nomogram model to predict SLHC. A nomogram model-HBGP (based on hepatitis B surface antigen, gamma-glutamyl transpeptidase, and platelet count) demonstrated good performance in diagnosing SLHC with area under the curve (AUCs) of 0.866 (95% confidence interval [CI]: 0.839-0.892) and 0.885 (95% CI: 0.845-0.925) in the training and validation cohorts, respectively. Furthermore, HBGP displayed high diagnostic values for SLHC with AUCs of 0.866 (95% CI: 0.839-0.892), 0.868 (95% CI: 0.838-0.898), 0.865 (95% CI: 0.828-0.901), and 0.853 (95% CI: 0.798-0.908) in chronic HBV carriers I, II, III, and IV, respectively. Additionally, HBGP showed greater ability in predicting SLHC compared with the existing predictors. HBGP has shown high predictive performance for SLHC, and thus may lead to an informed decision on the initiation of antiviral treatment.

The role of tracheal wall injury in the development of benign airway stenosis in rabbits.

To investigate the role of tracheal wall injury in the development of benign airway stenosis in rabbits. Prospective study. We injured the tracheal walls of 28 New Zealand white rabbits using four different methods. Experimental group: Group A (n = 7, mild injury of tracheal mucosa by ordinary brush under bronchoscopy); Group B (n = 7, severe injury of tracheal mucosa by nylon brush under tracheotomy); Group C (n = 7, tracheal cartilage was injured by vascular clamp after tracheotomy); Group D (n = 7, the tracheal cartilage was injured with vascular forceps and the tracheal mucosa was injured with a nylon brush after tracheotomy). Bronchoscopy was performed on each experimental rabbit at 1, 2, 3 and 4 weeks after operation. High-resolution computed tomography (HRCT) and endobronchial optical coherence tomography (EB-OCT) were performed at 4 weeks, and the rabbits were sacrificed after the examination. Their gross and histological findings were comparatively determined whether the experimental rabbit stenosis was established. No airway stenosis was observed in group A. In group B, 28.57% of experimental rabbits developed tracheal stenosis (granulation tissue proliferation was observed in rabbits No. 2 and No. 6 at 1, 2 and 3 weeks after operation, and the tracheal scar contracture was observed in No.6 rabbit at 4 weeks after operation). Fourteen rabbits in group C and group D had tracheal stenosis caused by granulation tissue proliferation at 1, 2 and 3 weeks after operation. At the fourth week after operation, 71.43% of experimental rabbits had tracheal stenosis due to granulation tissue hyperplasia, 7.14% of experimental rabbits had tracheal stenosis due to scar contracture and granulation hyperplasia, and 21.43% of experimental rabbits had tracheal stenosis due to scar contracture. EB-OCT scan showed that the cartilage layer with low signal reflection band was discontinuous. The injury of cartilage is the key factor of benign airway stenosis. Acute injury of airway mucosa alone is unlikely to cause airway stenosis, but combined with cartilage injury may aggravate airway stenosis. EB-OCT can clearly identify the airway layers of rabbits, which is helpful to evaluate the damage of tracheal cartilage and mucosa. The diagnostic potential of this technique makes EB-OCT a promising approach for the study and monitoring of airway diseases.

AZGP1 Up-Regulation is a Potential Target for Andrographolide Reversing Radioresistance of Colorectal Cancer.

Background: Radiation resistance is a challenge that limits the therapeutic benefit of colorectal cancer (CRC) treatment, but the mechanism underlying CRC radiation resistance remains unclear. Andrographolide shows a broad-spectrum anti-tumor effect in various malignancies, including CRC, its effect and how it functions in CRC initiation, and radiation have not been established. This study aimed to explore the mechanism of CRC radiation resistance and the potential mechanisms of andrographolide on CRC radiation. Methods: Two acquired radioresistant cell lines were established and high throughput sequencing was employed to screen out the differentially expressed genes. The expression of AZGP1, which was upregulated in the acquired radioresistant tissues, was verified by microarray data recomputing. The common targets of andrographolide, CRC initiation, and radiation resistance were obtained, and the corresponding functional enrichment and pathway analysis were performed. The interaction between AZGP1 and andrographolide was investigated using molecular docking. Results: AZGP1 was upregulated in both the radioresistant cell model and microarray data. Moreover, AZGP1 was upregulated in cancerous colorectal tissue and displayed a tendency toward elevated expression in patients with an unfavorable prognosis. AZGP1 was identified as the common target of andrographolide, colorectal cancer initiation, and radiotherapy resistance. Ultimately, the protein structure of AZGP1 proved to be closely intertwined with the crystal texture of andrographolide. Conclusion: AZGP1 is recognized as a crucial factor for both CRC initiation and radioresistance. Andrographolide may affect the radioresistance of CRC via the targeting of AZGP1. Thus, the combination of andrographolide and AZGP1 intervention might be a promising strategy for improving the treatment benefit of CRC radiotherapy.

Gut microbiota of hepatitis B virus-infected patients in the immune-tolerant and immune-active phases and their implications in metabolite changes.

BACKGROUND: The microbes and metabolomics of microbiota dysbiosis in the gut in the different phases of hepatitis B virus (HBV) infection are not fully understood. AIM: To investigate the specific gut microbiota and metabolites of the immune-tolerant (IT) and immune-active (IA) phases of chronic hepatitis B (CHB). METHODS: Clinical fecal samples from healthy individuals and patients in the IT and IA phases of HBV infection were collected. Next, non-target metabolomics, bioinformatics, and 16S rDNA sequencing analyses were performed. RESULTS: A total of 293 different metabolites in 14 phyla, 22 classes, 29 orders, 51 families, and 190 genera were identified. The four phyla of Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria were the most abundant, accounting for 99.72%, 99.79%, and 99.55% in the healthy controls, IT-phase patients, and IA-phase patients, respectively. We further identified 16 genera with different richness in the IT phase and IA phase of HBV infection. Of the 134 named metabolites, 57 were upregulated and 77 were downregulated. A total of 101 different metabolic functions were predicted in this study, with 6 metabolic pathways having the highest enrichments, namely carbohydrate metabolism (14.85%), amino acid metabolism (12.87%), lipid metabolism (11.88%), metabolism of cofactors and vitamins (11.88%), xenobiotic biodegradation (9.9%), and metabolism of terpenoids and polyketides (7.92%). CONCLUSION: These findings provide observational evidence of compositional alterations of the gut microbiome and some related metabolites in patients with IT-phase or IA-phase HBV infection. Further studies should investigate whether microbiota modulation can facilitate the progression of CHB and the cause-effect relationship between the gut microbiota and CHB.

Comparison of operation time, efficacy and safety between through-the-scope stent and over-the-while stent in malignant central airway obstruction: a multi-center randomized control trial.

Background: Self-expandable metallic (SEM) airway stents are an important approach to treating malignant central airway obstruction (CAO). Standard over-the-while (OTW) stent needs the guidance of a guide-wire. It should be implanted under flouroscopy or the guidance of bronchoscope visualization. In this study, we evaluated the operation time and safety between OTW stent and a novel through-the-scope (TTS) SEM airway stent. Methods: In this multi-center, randomized, parallel-group superiority study, malignant CAO patients were enrolled randomly assigned (2:1) to the TTS stent implantation group (TTS group) or the standard OTW stent group (OTW group) in six sites across China. The entire process of all surgical procedures was recorded by video. Primary endpoint was the operation time of the airway stent implantation and secondary endpoint was the success rate of the stent implantation as well as its efficacy and safety. Results: From May 15, 2017, to December 30, 2018, 148 patients were enrolled from the six sites. We analyzed 134 patients (including 91 patients from the TTS group and 43 patients from the OTW group) according to the per-protocol set. There were no significant differences in the ages, genders, underlying diseases, and stenosis sites between the two groups. The operation time in the TTS group was significantly shorter than that in the OTW group (104±68 vs. 252±111 seconds, P<0.001). Compared to the OTW group, the efficacy of stent implantation (97.80% vs. 90.70%, P=0.093) and rate of first-time successful stent implantation (78.02% vs. 74.42%, P=0.668) were higher in the TTS group, but did not reach statistically significance. The rates of granulation (28.57% vs. 41.86%, P=0.128) and restenosis (15.38% vs. 30.23%, P=0.064) in the TTS group were slightly lower as compared with the OTW group without achieving statistical significance. Conclusions: The TTS stent implantation procedure time was significantly shorter than that of the OTW airway stent with similar efficacy and complications, which might reduce the risk and flexibility of stent implantation. Trial Registration: Chinese Clinical Trial Registry ChiCTR-IOR-17011431.