Serum ITIH5 as a novel diagnostic biomarker in cholangiocarcinoma.

Cholangiocarcinoma often remains undetected until advanced stages due to the lack of reliable diagnostic markers. Our goal was to identify a unique secretory protein for cholangiocarcinoma diagnosis and differentiation from other malignancies, benign hepatobiliary diseases, and chronic liver conditions. We conducted bulk RNA-seq analysis to identify genes specifically upregulated in cholangiocarcinoma but not in most other cancers, benign hepatobiliary diseases, and chronic liver diseases focusing on exocrine protein-encoding genes. Single-cell RNA sequencing examined subcellular distribution. Immunohistochemistry and enzyme-linked immunosorbent assays assessed tissue and serum expression. Diagnostic performance was evaluated via receiver-operating characteristic (ROC) analysis. Inter-alpha-trypsin inhibitor heavy chain family member five (ITIH5), a gene encoding an extracellular protein, is notably upregulated in cholangiocarcinoma. This elevation is not observed in most other cancer types, benign hepatobiliary diseases, or chronic liver disorders. It is specifically expressed by malignant cholangiocytes. ITIH5 expression in cholangiocarcinoma tissues exceeded that in nontumorous bile duct, hepatocellular carcinoma, and nontumorous hepatic tissues. Serum ITIH5 levels were elevated in cholangiocarcinoma compared with controls (hepatocellular carcinoma, benign diseases, chronic hepatitis B, and healthy individuals). ITIH5 yielded areas under the ROC curve (AUCs) from 0.839 to 0.851 distinguishing cholangiocarcinoma from controls. Combining ITIH5 with carbohydrate antigen 19-9 (CA19-9) enhanced CA19-9's diagnostic effectiveness. In conclusion, serum ITIH5 may serve as a novel noninvasive cholangiocarcinoma diagnostic marker.

Disruption of SLFN11 Deficiency-Induced CCL2 Signaling and Macrophage M2 Polarization Potentiates Anti-PD-1 Therapy Efficacy in Hepatocellular Carcinoma.

BACKGROUND & AIMS: The therapeutic effect of immune checkpoint inhibitors (ICIs) is poor in hepatocellular carcinoma (HCC) and varies greatly among individuals. Schlafen (SLFN) family members have important functions in immunity and oncology, but their roles in cancer immunobiology remain unclear. We aimed to investigate the role of the SLFN family in immune responses against HCC. METHODS: Transcriptome analysis was performed in human HCC tissues with or without response to ICIs. A humanized orthotopic HCC mouse model and a co-culture system were constructed, and cytometry by time-of-flight technology was used to explore the function and mechanism of SLFN11 in the immune context of HCC. RESULTS: SLFN11 was significantly up-regulated in tumors that responded to ICIs. Tumor-specific SLFN11 deficiency increased the infiltration of immunosuppressive macrophages and aggravated HCC progression. HCC cells with SLFN11 knockdown promoted macrophage migration and M2-like polarization in a C-C motif chemokine ligand 2-dependent manner, which in turn elevated their own PD-L1 expression by activating the nuclear factor-κB pathway. Mechanistically, SLFN11 suppressed the Notch pathway and C-C motif chemokine ligand 2 transcription by binding competitively with tripartite motif containing 21 to the RNA recognition motif 2 domain of RBM10, thereby inhibiting tripartite motif containing 21-mediated RBM10 degradation to stabilize RBM10 and promote NUMB exon 9 skipping. Pharmacologic antagonism of C-C motif chemokine receptor 2 potentiated the antitumor effect of anti-PD-1 in humanized mice bearing SLFN11 knockdown tumors. ICIs were more effective in patients with HCC with high serum SLFN11 levels. CONCLUSIONS: SLFN11 serves as a critical regulator of microenvironmental immune properties and an effective predictive biomarker of ICIs response in HCC. Blockade of C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 signaling sensitized SLFN11low HCC patients to ICI treatment.

Mutant p53 leads to low-grade IFN-I-induced inflammation and impairs cGAS-STING signalling in mice.

Type I interferons (IFN-Is) are a class of proinflammatory cytokines produced in response to viruses and environmental stimulations, resulting in chronic inflammation and even carcinogenesis. However, the connection between IFN-I and p53 mutation is poorly understood. Here, we investigated IFN-I status in the context of mutant p53 (p53N236S , p53S). We observed significant cytosolic double-stranded DNA (dsDNA) derived from nuclear heterochromatin in p53S cells, along with an increased expression of IFN-stimulated genes. Further study revealed that p53S promoted cyclic GMP-AMP synthase (cGAS) and IFN-regulatory factor 9 (IRF9) expression, thus activating the IFN-I pathway. However, p53S/S mice were more susceptible to herpes simplex virus 1 infection, and the cGAS-stimulator of IFN genes (STING) pathway showed a decline trend in p53S cells in response to poly(dA:dT) accompanied with decreased IFN-ß and IFN-stimulated genes, whereas the IRF9 increased in response to IFN-ß stimulation. Our results illustrated the p53S mutation leads to low-grade IFN-I-induced inflammation via consistent low activation of the cGAS-STING-IFN-I axis, and STAT1-IRF9 pathway, therefore, impairs the protective cGAS-STING signalling and IFN-I response encountered with exogenous DNA attack. These results suggested the dual molecular mechanisms of p53S mutation in inflammation regulation. Our results could be helping in further understanding of mutant p53 function in chronic inflammation and provide information for developing new therapeutic strategies for chronic inflammatory diseases or cancer.

Prediction model based on MRI morphological features for distinguishing benign and malignant thyroid nodules.

BACKGROUND: The low specificity of Thyroid Imaging Reporting and Data System (TI-RADS) for preoperative benign-malignant diagnosis leads to a large number of unnecessary biopsies. This study developed and validated a predictive model based on MRI morphological features to improve the specificity. METHODS: A retrospective analysis was conducted on 825 thyroid nodules pathologically confirmed postoperatively. Univariate and multivariate logistic regression were used to obtain ß coefficients, construct predictive models and nomogram incorporating MRI morphological features in the training cohort, and validated in the validation cohort. The discrimination, calibration, and decision curve analysis of the nomogram were performed. The diagnosis efficacy, area under the curve (AUC) and net reclassification index (NRI) were calculated and compared with TI-RADS. RESULTS: 572 thyroid nodules were included (training cohort: n = 397, validation cohort: n = 175). Age, low signal intensity on T2WI, restricted diffusion, reversed halo sign in delay phase, cystic degeneration and wash-out pattern were independent predictors of malignancy. The nomogram demonstrated good discrimination and calibration both in the training cohort (AUC = 0.972) and the validation cohort (AUC = 0.968). The accuracy, sensitivity, specificity, PPV, NPV and AUC of MRI-based prediction were 94.4%, 96.0%, 93.4%, 89.9%, 96.5% and 0.947, respectively. The MRI-based prediction model exhibited enhanced accuracy (NRI>0) in comparison to TI-RADSs. CONCLUSIONS: The prediction model for diagnosis of benign and malignant thyroid nodules demonstrated a more notable diagnostic efficacy than TI-RADS. Compared with the TI-RADSs, predictive model had better specificity along with a high sensitivity and can reduce overdiagnosis and unnecessary biopsies.

Structure and Peptidomes of Swine MHC Class I with Long Peptides Reveal the Cross-Species Characteristics of the Novel N-Terminal Extension Presentation Mode.

Antigenic peptide presentation by the MHC is essential for activating T cells. The current view is that the peptide termini are tethered within the closed Ag-binding groove of MHC class I (MHC-I). Recently, the N-terminal extension mode of peptide presentation has been observed in human MHC-I (HLA-I). In this study, we found that the N terminus of the long peptide can extend beyond the groove of swine MHC-I (SLA-1*0401), confirming that this phenomenon can occur across species. Removal of the N-terminal extra (P-1) residue of the RW12 peptide significantly reduced the folding efficiency of the complex, but truncation of the second half of the peptide did not. Consistent with previous reports, the second (P1) residue of the peptide is twisted, and its side chain is inserted into the A pocket to form two hydrogen bonds with polymorphic E63 and conserved Y159. Mutations of E63 disrupt the binding of the peptide, indicating that E63 is necessary for this peptide-binding mode. Compared with W167, which exists in most MHC-Is, SLA-I-specific S167 ensures an open N-terminal groove of SLA-1*0401, enabling the P-1 residue to extend from the groove. In this MHC class II-like peptide-binding mode, the A pocket is restrictive to the P1 residue and is affected by the polymorphic residues. The peptidomes and refolding data indicated that the open N-terminal groove of SLA-1*0401 allows one to three residues to extend out of the Ag-binding groove. These cross-species comparisons can help us better understand the characteristics of this N-terminal extension presentation mode.

Efficient Identification of Tembusu Virus CTL Epitopes in Inbred HBW/B4 Ducks Using a Novel MHC Class I-Restricted Epitope Screening Scheme.

The identification of MHC class I-restricted CTL epitopes in certain species, particularly nonmammals, remains a challenge. In this study, we developed a four-step identification scheme and confirmed its efficiency by identifying the Anpl-UAA*76-restricted CTL epitopes of Tembusu virus (TMUV) in inbred haplotype ducks HBW/B4. First, the peptide binding motif of Anpl-UAA*76 was determined by random peptide library in de novo liquid chromatography-tandem mass spectrometry, a novel nonbiased, data-independent acquisition method that we previously established. Second, a total of 38 TMUV peptides matching the motif were screened from the viral proteome, among which 11 peptides were conserved across the different TMUV strains. Third, the conserved TMUV peptides were refolded in vitro with Anpl-UAA*76 and Anpl-ß2-microglobulin to verify the results from the previous two steps. To clarify the structural basis of the obtained motif, we resolved the crystal structure of Anpl-UAA*76 with the TMUV NS3 peptide LRKRQLTVL and found that Asp34 is critical for the preferential binding of the B pocket to bind the second residue to arginine as an anchor residue. Fourth, the immunogenicity of the conserved TMUV peptides was tested in vivo using specific pathogen-free HBW/B4 ducks immunized with the attenuated TMUV vaccine. All 11 conserved TMUV epitopes could bind stably to Anpl-UAA*76 in vitro and stimulate the secretion of IFN-γ and lymphocyte proliferation, and three conserved and one nonconserved peptides were selected to evaluate the CTL responses in vivo by flow cytometry and their tetramers. We believe that this new scheme could improve the identification of MHC class I-restricted CTL epitopes, and our data provide a foundation for further study on duck anti-TMUV CTL immunity.

Protective effects of low-intensity pulsed ultrasound (LIPUS) against cerebral ischemic stroke in mice by promoting brain vascular remodeling via the inhibition of ROCK1/p-MLC2 signaling pathway.

Vascular remodeling is essential for patients with cerebral ischemic stroke (CIS). Our previous study proved that low-intensity pulsed ultrasound (LIPUS) could increase cortical hemodynamics. However, the effects and mechanisms of LIPUS on cerebral vascular remodeling after CIS are still unknown. In this study, we applied LIPUS to the mouse brain at 0.5 h after distal middle cerebral artery occlusion (dMCAO) and subsequently daily for a stimulation time of 30 min. Results showed that compared with the dMCAO group, LIPUS markedly increased cerebral blood flow (CBF), reduced brain swelling, and improved functional recovery at day 3 after CIS. LIPUS promoted leptomeningeal vasculature remodeling, enlarged vascular diameter, and increased the average vessel length and density at day 3 after CIS. Proteomic analysis highlighted that LIPUS mainly participated in the regulation of actin cytoskeleton pathway. Rho kinase 1 (ROCK1) was downregulated by LIPUS and participated in regulation of actin cytoskeleton. Subsequently, we verified that ROCK1 was mainly expressed in pericytes. Furthermore, we demonstrated that LIPUS inhibited ROCK1/p-MLC2 signaling pathway after CIS, which had positive effects on vascular remodeling and cerebral blood circulation. In conclusion, our preliminary study revealed the vascular remodeling effects and mechanism of LIPUS in CIS, provided evidence for potential clinical application of LIPUS.

Maternal inulin supplementation ameliorates prenatal methamphetamine exposure-induced hepatotoxicity and restores gut microbiota in mouse offspring.

Prenatal exposure to methamphetamine (METH) is an issue of global concern due to its adverse effects on offspring, particularly its impact on liver health, an area still not fully understood. Inulin, a recognized prebiotic, is thought to potentially ameliorate these developmental disorders and toxic injuries in progeny. To investigate the effects of prenatal METH exposure on the liver and the role of gut microbiota, we established a murine model, the subjects of which were exposed to METH prenatally and subsequently treated with inulin. Our findings indicate that prenatal METH exposure causes liver damage in offspring, as evidenced by a decreased liver index, histopathological changes, diminished glycogen synthesis, hepatic dysfunction, and alterations in mRNA profiles. Furthermore, it impairs the antioxidant system and induces oxidative stress, possibly due to changes in cecal microbiota and dysregulation of bile acid homeostasis. However, maternal inulin supplementation appears to restore the gut microbiota in offspring and mitigate the hepatotoxic effects induced by prenatal METH exposure. Our study provides definitive evidence of METH's transgenerational hepatotoxicity and suggests that maternal inulin supplementation could be an effective preventive strategy.

The gut microbiota contributes to methamphetamine-induced reproductive toxicity in male mice.

Methamphetamine (METH) is a psychostimulant drug belonging to the amphetamine-type stimulant class, known to exert male reproductive toxicity. Recent studies suggest that METH can disrupt the gut microbiota. Furthermore, the gut-testis axis concept has gained attention due to the potential link between gut microbiome dysfunction and reproductive health. Nonetheless, the role of the gut microbiota in mediating the impact of METH on male reproductive toxicity remains unclear. In this study, we employed a mouse model exposed to escalating doses of METH to assess sperm quality, testicular pathology, and reproductive hormone levels. The fecal microbiota transplantation method was employed to investigate the effect of gut microbiota on male reproductive toxicity. Transcriptomic, metabolomic, and microbiological analyses were conducted to explore the damage mechanism to the male reproductive system caused by METH. We found that METH exposure led to hormonal disorders, decreased sperm quality, and changes in the gut microbiota and testicular metabolome in mice. Testicular RNA sequencing revealed enrichment of several Gene Ontology terms associated with reproductive processes, as well as PI3K-Akt signaling pathways. FMT conveyed similar reproductive damage from METH-treated mice to healthy recipient mice. The aforementioned findings suggest that the gut microbiota plays a substantial role in facilitating the reproductive toxicity caused by METH, thereby highlighting a prospective avenue for therapeutic intervention in the context of METH-induced infertility.

Analysis of the Influencing Factors of Postoperative Constipation in Patients Undergoing Cardiovascular Surgery: A Cross-Sectional and Prospective Study.

BACKGROUND: The aim of this study was to estimate the potential influencing factors of postoperative constipation in patients undergoing cardiovascular surgery. METHODS: This study included a cohort of 379 patients who underwent cardiovascular surgery at Nanjing Drum Tower Hospital. The patient cohort was stratified into two groups based on the presence or absence of postoperative constipation. Utilizing logistic regression analysis, both univariate and multivariate analyses were conducted to elucidate the factors influencing defecation problems. The predictive accuracy of the findings was subsequently evaluated through the receiver operating characteristic (ROC) curve. RESULTS: Among the cohort of 379 patients subjected to cardiovascular surgery, a noteworthy 20.8% (n = 79) reported incidences of postoperative defecation issues. A multivariate logistic regression analysis showed that age (odds ratio (OR) = 1.063, 95% confidence interval (CI) 1.034-1.097, p < 0.001), operation time (OR = 1.004, 95% CI: 1.000-1.008, p = 0.028), ventilator usage time (OR = 1.032, 95% CI: 1.010-1.055, p = 0.004), polypharmacy (OR = 2.134, 95% CI: 1.069-4.321, p = 0.032), use of cough medicine (OR = 2.981, 95% CI: 1.271-6.942, p = 0.011) and psychological or behavioral barriers to defecation in the hospital environment (OR = 31.039, 95% CI: 14.313-73.179, p < 0.001) were independent risk factors for postoperative constipation in patients undergoing cardiovascular surgery. The area under the curve (AUC) for predicting postoperative constipation was 0.885. CONCLUSION: In the pursuit of optimizing postoperative recovery and mitigating postoperative constipation incidence, a targeted approach is imperative. Specifically, a focused intervention directed towards elderly patients, extended operation and prolonged ventilator durations, polypharmacy regimens, use of cough medicine, and those with psychological or behavioral barriers to defecation within the hospital milieu emerges as pivotal.

RNA-seq analysis reveals candidate genes associated with proliferation, invasion, and migration in BCL11A knockdown B-NHL cell lines.

B-cell lymphoma/leukemia 11A (BCL11A) is highly expressed in B-cell non-Hodgkin lymphoma (B-NHL), blocks cell differentiation, and inhibits cell apoptosis. However, little is known about BCL11A in the proliferation, invasion, and migration of B-NHL cells. Here, we found increased expression of BCL11A in B-NHL patients and cell lines. Knockdown of BCL11A suppressed the proliferation, invasion, and migration of B-NHL cells in vitro and reduced tumor growth in vivo. RNA sequencing (RNA-seq) and KEGG pathway analysis demonstrated that BCL11A-targeted genes were significantly enriched in the PI3K/AKT signaling pathway, focal adhesion, and extracellular matrix (ECM)-receptor interaction (including COL4A1, COL4A2, FN1, SPP1), and SPP1 was the most significantly downregulated gene. qRT‒PCR, western blotting, and immunohistochemistry revealed that silencing BCL11A reduced the expression level of SPP1 in Raji cells. Our study suggested that high level of BCL11A may promote B-NHL proliferation, invasion, and migration, and the BCL11A-SPP1 regulatory axis may play an important role in Burkitt's lymphoma.

Evaluation of ITGB1 expression as a predictor of the therapeutic effects of immune checkpoint inhibitors in gastric cancer.

BACKGROUND: Gastric cancer (CC) is a disease with high incidence and mortality rate. Immunotherapy is an important method for gastric cancer while lack of effective predictor. Integrins play an important role in the development. We aimed to explore the predictive value of ß1 integrin (ITGB1) as a predictor of immunnotherapy in gastric cancer. METHODS: Differential expression analysis was conducted using the Gene Expression Profiling Interactive Analysis (GEPIA) 2.0 and GEO databases. GEPIA data were used to evaluate the prognostic value of ITGB1 in gastric cancer (GC). Transcriptomic and clinical data of GC and normal tissues were downloaded from The Cancer Genome Atlas database, and the TIMER database was used to evaluate the association between ITGB1 and immune infiltration. Time-dependent receiver operating characteristic (ROC) curve analysis was used to determine the prognostic value of ITGB1. To verify ITGB1 expression at the protein level, immunohistochemical staining was conducted. In addition, to analyze the correlation of ITGB1 with PD-1 and PD-L1, we examined levels of PD-1 and PD-L1 by IHC and determined the predictive value of ITGB1 for anti-PD-1 therapy in GC by ROC curve analysis. RESULTS: Compared with normal tissues, analysis of GEPIA and data at protein levels showed significantly higher expression of ITGB1 in GC. In addition, higher expression of ITGB1 was associated with worse pathological G-staging and tumor T-staging, which suggested that ITGB1 is a risk factor for poor prognosis in GC. The level of ITGB1 expression was positively correlated with CD8 + T cells, neutrophils, macrophages, and dendritic cells. ITGB1 expression was also correlated with PD-L1 expression, and this was further verified at the protein level by immunohistochemical analysis. The area under the ROC curve was 0.808. CONCLUSION: ITGB1 may be a promising prognostic biomarker and effective predictor for anti-PD-1 therapy in GC. TRIAL REGISTRATION: Retrospectively registered.

Quantitative evaluation of diffusion-weighted MRI for differentiating benign and malignant thyroid nodules larger than 4 cm.

PURPOSE: Our study aimed to diagnose benign or malignant thyroid nodules larger than 4 cm using quantitative diffusion-weighted imaging (DWI) analysis. METHODS: Eighty-two thyroid nodules were investigated retrospectively and divided them into benign (n = 62) and malignant groups (n = 20). We calculated quantitative features DWI and apparent diffusion coefficient (ADC) signal intensity standard deviation (DWISD and ADCSD), DWI and ADC signal intensity ratio (DWISIR and ADCSIR), mean ADC and minimum ADC value (ADCmean and ADCmin) and ADC value standard deviation (ADCVSD). Univariate and multivariate logistic regression were conducted to identify independent predictors, and develop a prediction model. We performed receiver operating characteristic (ROC) analysis to determine the optimal threshold of risk factors, and constructed combined threshold models. Our study calculated diagnostic performance including area under the ROC curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and unnecessary biopsy rate of all models were calculated and compared them with the American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS) result. RESULTS: Two independent predictors of malignant nodules were identified by multivariate analysis: DWISIR (P = 0.007) and ADCmin (P < 0.001). The AUCs for multivariate prediction model, combined DWISIR and ADCmin thresholds model, combined DWISIR and ADCSIR thresholds model and ACR-TIRADS were 0.946 (0.896-0.996), 0.875 (0.759-0.991), 0.777 (0.648-0.907) and 0.722 (0.588-0.857). The combined DWISIR and ADCmin threshold model had the lowest unnecessary biopsy rate of 0%, compared with 56.3% for ACR-TIRADS. CONCLUSION: Quantitative DWI demonstrated favorable malignant thyroid nodule diagnostic efficacy. The combined DWISIR and ADCmin thresholds model significantly reduced the unnecessary biopsy rate.

Inulin alleviates neuroinflammation and oxidative stress induced by perinatal 2-ethylhexyl diphenyl phosphate (EHDPHP) exposure in female mice and offspring.

Organophosphorus flame retardants (OPFRs), including 2-ethylhexyl diphenyl phosphate (EHDPHP), are prevalent in everyday life due to their broad usage in fields such as healthcare, electronics, industry, and sports. These compounds, added to polymers through physical mixing, can leach into the environment, posing a risk to humans through direct contact or the food chain. Despite known associations with health issues like endocrine disruption, neurotoxicity, and reproductive toxicity, the implications of perinatal EHDPHP exposure on both mothers and offspring are still unclear. This study aimed to investigate the neuroinflammatory effects of EHDPHP and the potential mitigating role of inulin. Pregnant C57 mice were administered either a corn oil control or an EHDPHP solution (300 µg/kg bw/d) from gestation day 7 (GD7) to postnatal day 21 (PND21). Concurrently, mice were provided either regular drinking water or water supplemented with 1% inulin. We found that EHDPHP significantly increased the serum levels of IL-1ß, IL-6, and MDA, but decreased SOD levels in both mothers and pups. These effects were reversed by inulin supplementation. RNA-sequencing revealed that EHDPHP induced inflammation and oxidative stress through the TLR4/NF-κB pathway, which was mitigated by inulin. In conclusion, inulin ameliorated EHDPHP-induced neuroinflammation and oxidative stress in both mothers and offspring, highlighting its potential therapeutic role.

Conservative management of double teeth in molar teeth with pulp or periapical disease: a report of five cases and literature review.

BACKGROUND: Double teeth are usually the result of an abnormality in the developing tooth germ. Double teeth can occur in either the primary or permanent dentition, with the majority of cases concerning permanent teeth reported in the anterior teeth and less frequently in the molar teeth. CASE PRESENTATION: This report illustrates five cases of double teeth in molars with pulp and periapical disease, including one case of geminated teeth and four cases of fused teeth. Radiographic findings revealed the presence of extra teeth on the buccal aspect of the molar in five cases, with or without communication between the two root canal systems. Root canal treatment was performed by using CBCT and a dental operating microscope. The treatment outcome was good in all five cases. CONCLUSION: The diagnosis and treatment of double teeth requires special attention. The root canal system should be carefully explored to obtain a full understanding of the anatomy, allowing it to be fully cleaned and obturated. Proper anatomical structure analysis prior to treatment facilitates the development of an appropriate treatment plan, thereby increasing the likelihood of successful treatment both aesthetically and functionally.

A Comparison of Incomplete Resection Rate of Large and Small Colorectal Polyps by Cold Snare Polypectomy.

BACKGROUND & AIMS: There are limited data regarding the safety and efficacy of cold snare polypectomy (CSP) for large colorectal polyps. We evaluated factors affecting the clinical outcomes of CSP for polyps between 5 and 15 mm in size. METHODS: This was a prospective single-center observational study involving 1000 patients undergoing colonoscopy. Polyps (5-15 mm) were removed using CSP, and biopsies were taken from the resection margin. The primary outcome was the incomplete resection rate (IRR), and was determined by the presence of residual neoplasia on biopsy. Correlations between IRR and polyp size, morphology, histology, and resection time were assessed by generalized estimating equation model. RESULTS: A total of 440 neoplastic polyps were removed from 261 patients. The overall IRR was 2.27%, 1.98% for small (5-9 mm) vs 3.45% for large (10-15 mm) polyps (P = .411). In univariate analysis, the IRR was more likely to be related to sessile serrated lesions (odds ratio [OR], 6.93; 95% confidence interval [CI], 1.88-25.45; P = .004), piecemeal resection (OR, 11.83; 95% CI, 1.20-116.49; P = .034), and prolonged resection time >60 seconds (OR, 7.56; 95% CI, 1.75-32.69; P = .007). In multivariable regression analysis, sessile serrated lesions (OR, 6.45; 95% CI, 1.48-28.03; P = .013) and resection time (OR, 7.39; 95% CI, 1.48-36.96; P = .015, respectively) were independent risk factors for IRR. Immediate bleeding was more frequent with resection of large polyps (6.90% vs 1.42%; P = .003). No recurrence was seen on follow-up colonoscopy in 37 cases with large polyps. CONCLUSIONS: CSP is safe and effective for removal of colorectal polyps up to 15 mm in size, with a low IRR. (ClinicalTrials.gov; Number: NCT03647176).

Methamphetamine induces intestinal injury by altering gut microbiota and promoting inflammation in mice.

Methamphetamine (METH) is a psychostimulant abused worldwide. Its abuse induces intestinal toxicity. Moreover, the gut microbiota is altered by drugs, which induces intestinal injury. Whether gut microbiota mediates METH-induced intestinal toxicity remains to be validated. In the present study, wild-type and TLR4-/- mice were treated with METH. Gut microbiota was determined using 16S rRNA gene sequencing. Transcriptomics of the intestinal mucosa was performed by RNA-Sequencing. Blood levels of pro-inflammatory cytokines and lipopolysaccharide (LPS), the intestinal barrier, and inflammation were also assessed. METH treatment weakened the intestinal barrier and increased pro-inflammatory cytokines and LPS levels in the blood. Moreover, METH treatment significantly decreased the diversity of probiotics but increased the abundance of pathogenic gut microbiota, contributing to the over-production of LPS and disruption of intestinal barrier. Inflammatory pathways were enriched in the intestinal mucosa of METH-treated mice by KEGG analysis. Consistently, activation of the TLR4 pathway was determined in METH-treated mice, which confirmed intestinal inflammation. However, pretreatment with antibiotics or Tlr4 silencing significantly alleviated METH-induced gut microbiota dysbiosis, LPS over-production, intestinal inflammation, and disruption of the intestinal barrier. These findings suggested that the gut microbiota and LPS-mediated inflammation took an important role in METH-induced intestinal injury. Taken together, these findings suggest that METH-induced intestinal injury is mediated by gut microbiota dysbiosis and LPS-associated inflammation.

Identification and validation of EMT-immune-related prognostic biomarkers CDKN2A, CMTM8 and ILK in colon cancer.

Colon cancer (CC) is a disease with high incidence and mortality rate. The interaction between epithelial-mesenchymal transition (EMT) and immune status has important clinical significance. We aim to identify EMT-immune-related prognostic biomarkers in colon cancer. The GEO2R and GEPIA 2.0 were utilized to calculate the differential expression genes between CC and normal mucosa. Immport, InnateDB and EMTome databases were used to define EMT-immune-related genes. We conducted batch prognostic analysis by TCGA data. The expression patterns were verified by multiple datasets and lab experiments. GEPIA 2.0 and TIMER 2.0 were utilized to analyze the correlation of the hub genes with EMT markers and immune infiltration. GeneMANIA, STRING, and Metascape were used for co-expression and pathway enrichment analysis. Finally, we established a signature by the method of multivariate Cox regression analysis. CDKN2A, CMTM8 and ILK were filtered out as prognostic genes. CDKN2A and CMTM8 were up-regulated, while ILK was down-regulated in CC. CDKN2A was positively correlated with infiltration of macrophages, Th2 cells, Treg cells, and negatively correlated with NK cells. CMTM8 was negatively correlated with CD8+ T cells, dendritic cells, and NK cells. ILK was positively correlated with CD8+ T cells and dendritic cells. Moreover, CDKN2A, CMTM8 and ILK were significantly correlated with EMT markers. The three genes could participate in the TGF-ß pathway. The prognosis model established by the three hub genes was an independent prognosis factor, which can better predict the prognosis. CDKN2A, CMTM8 and ILK are promising prognostic biomarkers and may be potential therapeutic targets in colon cancer.

The regenerating protein 3A: a crucial molecular with dual roles in cancer.

INTRODUCTION: REG3A, a member of the third subclass of the Reg family, has been found in a variety of tissues but is not detected in immune cells. In the past decade, it has been determined that REG3A expression is regulated by injury, infection, inflammatory stimuli, and pro-cytokines via different signaling pathways, and it acts as a tissue-repair, bactericidal, and anti-inflammatory molecule in human diseases. Recently, the role of REG3A in cancer has received increasing attention. The present article aims to investigate the structure, expression, regulation, function of REG3A, and to highlight the potential role of REG3A in tumors. METHODS: A detailed literature search and data organization were conducted to find information about the role of REG3A in variety of physiological functions and tumors. RESULTS: Contradictory roles of REG3A have been reported in different tumor models. Some studies have demonstrated that high expression of REG3A in cancers can be oncogenic. Other studies have shown decreased REG3A expression in cancer cells as well as suppressed tumor growth. CONCLUSIONS: Taken together, better understanding of REG3A may lead to new insights that make it a potentially useful target for cancer therapy.

Flexible endoscopic identification and catheterization of congenital H-type tracheoesophageal fistula using a laryngeal mask.

Endoscopy for revealing the orifice of congenital H-type tracheoesophageal fistula (cTEF) is important for diagnostics and therapeutics. To facilitate the identification and catheterization of cTEF, we developed a new modified flexible endoscopy technique using a laryngeal mask with intermittent airflow. A retrospective case series study was conducted from April 2016 to July 2019 at a national regional children's medical center. Twelve infants with cTEF underwent this flexible endoscopy technique. The intermittent positive pressure airflow through laryngeal mask was able to reveal the orifice of cTEF easily in tracheal lumen. Under the visual flexible endoscope, cannulation with a 3-Fr ureteral catheter in fistula was successfully used in all cases. There were no immediate or delayed complications. This case series shows that the flexible endoscopy technique is a safe, easy, and technically efficient approach for diagnosis and cannulation of cTEF.