Circulating inflammatory cytokines influencing schizophrenia: a Mendelian randomization study.

Introduction: Schizophrenia (SCZ) is a severe psychiatric disorder whose pathophysiology remains elusive. Recent investigations have underscored the significance of systemic inflammation, particularly the impact of circulating inflammatory proteins, in SCZ. Methods: This study explores the potential causal association between certain inflammatory proteins and SCZ. Bidirectional Mendelian randomization (MR) analyses were conducted utilizing data from expansive genome-wide association studies (GWAS). Data regarding circulating inflammatory proteins were sourced from the GWAS Catalog database, encompassing 91 inflammatory cytokines. SCZ-related data were derived from the Finngen database, incorporating 47,696 cases and 359,290 controls. Analytical methods such as inverse variance weighted, MR-Egger, weighted median, simple mode, and weighted mode were employed to evaluate the association between inflammatory cytokines and SCZ. Sensitivity analyses were also performed to affirm the robustness of the results. Results: Following FDR adjustment, significant associations were observed between levels of inflammatory cytokines, including Fibroblast Growth Factor 5 (OR = 1.140, 95%CI = 1.045, 1.243, p = 0.003, FDR=0.015), C-C Motif Chemokine 4 (OR = 0.888, 95%CI = 0.816, 0.967, p = 0.006, FDR = 0.015), C-X-C Motif Chemokine 1 (OR = 0.833, 95%CI = 0.721, 0.962, p = 0.013, FDR = 0.064), and C-X-C Motif Chemokine 5 (OR = 0.870, 95%CI = 0.778, 0.973, p = 0.015, FDR = 0.074), and the risk of SCZ. Conclusion: Our results from MR analysis suggest a potential causal link between circulating inflammatory cytokines and SCZ, thereby enriching our understanding of the interactions between inflammation and SCZ. Furthermore, these insights provide a valuable foundation for devising therapeutic strategies targeting inflammation.

EUS­guided antegrade stenting for malignant jaundice following Roux­en­Y reconstruction: the treatment of multiple biliary strictures.

Multiple malignant biliary strictures are rare, and the application of multiple stents can achieve better drainage. EUS-guided biliary drainage (EUS-BD) can be offered as an alternative technique when ERCP unsuccessful. We applied Endoscopic ultrasonic guided antegrade stenting technique to treat a case of multiple biliary strictures following Roux-en-Y reconstruction.

Endoscopic management of stent displacement during EUS-guided pancreatic pseudocyst drainage.

The therapeutic effect of EUS-Guided Pancreatic Pseudocyst Drainage (EUS-PPD) is widely recognized, and intraoperative stent displacement is a rare but potentially serious condition. We report a case of the cyst stent displace into the cyst cavity during EUS-PPD, we successfully reduced the stent in time under the guidance of EUS and fluoroscopy in the final.

Endoscopic ultrasound combined with enteroscopy for bilioenterostomy stenosis after pancreatoduodenectomy. The first attempt of a two-person operation.

Bilioenterostomy stenosis is very challenging, and effective endoscopic treatment can prevent patients from undergoing surgery. We present a case of a patient with extremely narrow bilioenterostomy treated with simultaneous endoscopic ultrasonography and enteroscopy. It provides a new and feasible idea of endoscopic therapy for the treatment of such patients.

Genome-Wide Identification and Analysis of TCP Gene Family among Three Dendrobium Species.

Dendrobium orchids, which are among the most well-known species of orchids, are appreciated for their aesthetic appeal across the globe. Furthermore, due to their strict living conditions, they have accumulated high levels of active ingredients, resulting not only in their medicinal value but also in their strong ability to respond to harsh environments. The TCP gene family plays an important role in plant growth and development, and signal transduction. However, these genes have not been systematically investigated in Dendrobium species. In this study, we detected a total of 24, 23, and 14 candidate TCP members in the genome sequences of D. officinale, D. nobile, and D. chrysotoxum, respectively. These genes were classified into three clades on the basis of a phylogenetic analysis. The TCP gene numbers among Dendrobium species were still highly variable due to the independent loss of genes in the CIN clade. However, only three gene duplication events were detected, with only one tandem duplication event (DcTCP9/DcTCP10) in D. chrysotoxum and two pairs of paralogous DoTCP gene duplication events (DoTCP1/DoTCP23 and DoTCP16/DoTCP24) in D. officinale. A total of 25 cis-acting elements of TCPs related to hormone/stress and light responses were detected. Among them, the proportions of hormone response, light response, and stress response elements in D. officinale (100/421, 127/421, and 171/421) were similar to those in D. nobile (83/352, 87/352, and 161/352). Using qRT-PCR to determine their expression patterns under MeJA treatment, four DoTCPs (DoTCP2, DoTCP4, DoTCP6, and DoTCP14) were significantly upregulated under MeJA treatment, which indicates that TCP genes may play important roles in responding to stress. Under ABA treatment, seven DoTCPs (DoTCP3, DoTCP7, DoTCP9, DoTCP11, DoTCP14, DoTCP15, and DoTCP21) were significantly upregulated, indicating that TCP genes may also play an important role in hormone response. Therefore, these results can provide useful information for studying the evolution and function of TCP genes in Dendrobium species.

Bending the distal tip of a guidewire aids in cannulation of an occluded uncovered biliary metal stent.

Biliary metal stent implantation is an effective treatment for malignant obstructive jaundice. But it's well known that stents put in for a long time can become occluded and cause jaundice and cholangitis. At this time, endoscopic intervention is usually required to replace the stent or re-insert the stent. Re-cannulation for metal stent occlusion is challenging because the guide wire may pass through the side holes of the uncovered metal stents, resulting in prolonged surgical time and exposure to radiation. Here we present a small tip that may help endoscopists complete the re-cannulation of an uncovered metal stent in a very short time.

EUS-guided drainage for pancreatic duct stone combined with main pancreatic duct stenosis after pancreaticoduodenectomy: a case report.

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Identification of a hypoxia-related gene prognostic signature in colorectal cancer based on bulk and single-cell RNA-seq.

Colorectal cancer (CRC) is the most common and fatal tumor in the gastrointestinal system. Its incidence and mortality rate have increased in recent years. Hypoxia, a persistent physiological tumor feature, plays a vital role in CRC tumorigenesis, metastasis, and tumor microenvironment (TME). Therefore, we constructed a hypoxia-related gene (HRG) nomogram to predict overall survival (OS) and explored the role of HRGs in the CRC TME. The Cancer Genome Atlas (TCGA) dataset was used as the training set, and two Gene Expression Omnibus datasets (GSE39582 and GSE103479) were used as the testing sets. HRGs were identified using the Gene Set Enrichment Analysis (GSEA) database. An HRG prognostic model was constructed in the training set using the least absolute shrinkage and selection operator regression algorithm and validated in the testing sets. Then, we analyzed tumor-infiltrating cells (TICs) using the cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) algorithm. Furthermore, single-cell next-generation RNA sequencing (RNA-seq) was used to investigate HRG expression in different TICs in the GSE139555 dataset. Finally, reverse transcription polymerase chain reactions (RT-PCR) were used to validate HRG mRNA expression in ten pairs of CRC normal and cancer tissue samples. A six HRG prognostic signature was constructed, with a superior OS prediction ability in CRC patients (area under the receiver operating characteristic curve (AUC) at one year: 0.693, AUC at three years: 0.712, and AUC at five years: 0.780). GSEA enrichment analysis identified six pathways enriched in the high-risk group. The TIC analysis indicated that the high-risk group had lower T-cell expression and higher neutrophil expression than the low-risk group. Furthermore, immune-related genes had an inseparable relationship with the HRG prognostic signature. Based on single-cell RNA-seq data, we found elevated hexokinase 1 (HK1) and glucose-6-phosphate isomerase (GPI) gene expression in natural killer (NK) and CD8+ T cells. RT-PCR in ten CRC normal-tumor tissue pairs showed that expression of the signature's six HRGs varied differently in cancerous and paracancerous tissues. The constructed HRG signature successfully predicted the OS of whole-stage CRC patients. In addition, we showed that the signature's six HRGs were closely associated with the TME in CRC, where hypoxia inhibits the antitumor function of T cells.

Identification of Pyroptosis Gene Signature Related Molecular Pattern, Clinical Implication, and Tumor Immunity in Hepatocellular Carcinoma`.

BACKGROUND: Pyroptosis is a novel form of programmed cell death in cancers, which regulates tumor cell invasion, proliferation, and metastasis, thereby affecting the prognosis of cancer patients. However, the role of Pyroptosis-Related Genes (PGs) in Hepatocellular Carcinoma (HCC) remains unclear. METHODS: Somatic mutation, copy number variation, and expression of 41 PGs were assessed in HCC and normal liver from the TCGA dataset. The Least Absolute Shrinkage and Selection Operator (LASSO) was used to construct the prognostic model. K-M curves, ROC curves, nomograph, and univariate and multivariate Cox regression were conducted to evaluate the predictive value of PGs. Immune infiltration was analyzed by CIBERSOFT and ssGSEA algorithm. The expression of prognostic PGs was validated by qPCR. RESULTS: Significant mutation and copy number variation of PGs were found in HCC. These genes were involved in an inflammatory response. In addition, 9 out of 41 PGs were differentially expressed in HCC and found to correlate significantly with patient survival. Then, these signature genes were selected to build a prognosis model and were utilized to stratify HCC patients into high and low PGs-score groups. It showed that the high-PGs group had a worse prognosis. Univariate and multivariate Cox regression verified that PGs-score was an independent risk factor for HCC. By ROC curves and nomogram, we showed that PGs-score effectively predicted the 1-, 3-, and 5-year survival of HCC patients and correlated with AFP level and disease stage. Immune infiltration analysis further showed that tumor immunity correlated with the PGs-score, and the expression of immune checkpoint molecule was significantly enhanced in the high PGs group. The PGs-score was also validated in the external validation cohort (ICGC). Finally, the expression of 9 signature genes was validated in normal liver and HCC cell lines. CONCLUSION: This study elucidated the aberrant regulation of PGs in HCC, and those pyroptosisrelated genes may be applied as a prognostic factor of HCC.

Da-Chai-Hu-Tang Protects From Acute Intrahepatic Cholestasis by Inhibiting Hepatic Inflammation and Bile Accumulation via Activation of PPARα.

Cholestasis is caused by intrahepatic retention of excessive toxic bile acids and ultimately results in hepatic failure. Da-Chai-Hu-Tang (DCHT) has been used in China to treat liver and gallbladder diseases for over 1800 years. Here, we demonstrated that DCHT treatment prevented acute intrahepatic cholestasis with liver injury in response to α-naphthylisothiocyanate (ANIT) not to bile duct ligation (BDL) induced-extrahepatic cholestasis. ANIT (80 mg/kg) increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DBiL), total bilirubin (TBiL), and total bile acids (TBA) which was attenuated by DCHT treatment in a dose-dependent manner. DCHT treatment at high dose of 1.875 g/kg restored bile acid homeostasis, as evidenced by the recovery of the transcription of genes implicated in bile acid biosynthesis, uptake and efflux. DCHT treatment (1.875 g/kg) reversed ANIT-evoked disordered glutathione homeostasis (as determined by GSH/GSSG ratio) and increased in the mRNA levels for Il6, Il1b and Tnfa associated with liver inflammation. Using network pharmacology-based approaches, we identified 22 putative targets involved in DCHT treatment for intrahepatic cholestasis not extrahepatic cholestasis. In addition, as evidenced by dual-luciferase reporter assays, compounds from DCHT with high affinity of PPARα increased luciferase levels from a PPARα-driven reporter. PPARα agonist fenofibrate was able to mimic the cytoprotective effect of DCHT on intrahepatic cholestasis, which was abolished by the PPARα antagonist GW6471. KEGG enrichment and western blot analyses showed that signaling axes of JNK/IL-6/NF-κB/STAT3 related to PPARα might be the principal pathway DCHT affects intrahepatic cholestasis. Taken together, the present study provides compelling evidence that DCHT is a promising formula against acute intrahepatic cholestasis with hepatotoxicity which works via PPARα activation.

Cystic duct stones in postcholecystectomy Mirizzi syndrome - A novel endoscopic treatment.

Mirizzi syndrome is a rare type of cholelithiasis, and the main treatment is still surgery. The development of endoscopic technology has made surgeons more active in the management of rare diseases of the biliary tract and pancreas. Here we report that our center applied the new endoscopic method to treat a Mirizzi patient with residual cystic neck duct stones after laparoscopic cholecystectomy.

A novel cuproptosis-related prognostic gene signature and validation of differential expression in hepatocellular carcinoma.

Background: Cuproptosis is a newly discovered form of programmed cell death, which is characterized by accumulation of intra-cellular copper ion leading to the aggregation of lipoproteins and destabilization of Fe-S cluster proteins in mitochondrial metabolism, thereby affecting the prognosis of patients with cancer. However, the role of cuproptosis-related genes (CRGs) in hepatocellular carcinoma (HCC) remains elusive. Methods: Mutation signature, copy number variation and the expression of 10 CRGs were assessed in HCC from TCGA-LIHC dataset. ICGC-LIRI-JP dataset was used as further validation cohort. The least absolute shrinkage and selection operator (LASSO) was used to construct the prognostic model. Kaplan Meier curves, time-ROC curves, nomogram, univariate and multivariate Cox regression were utilized to evaluate the predictive efficacy of CRGs-score. Immune infiltration was analyzed by CIBERSOFT, ssGSEA algorithm, and TIMER database. The expression of prognostic CRGs was validated by qPCR both in-vitro and in-vivo. Drug sensitivity analysis was performed by pRRophetic. Results: All of the CRGs were differentially expressed in HCC and 5 out of them (CDKN2A, DLAT, GLS, LIPT1, MTF1) correlated with patient survival. These signature genes were selected by LASSO analysis to establish a prognosis model to stratify HCC patients into high and low CRGs-score subgroups. High CRGs-score was associated with a worse prognosis. Subsequently, univariate and multivariate Cox regression verified that CRGs-score was an independent cancer risk factor that correlated with clinical factors including stage and grade. Nomogram integrating the CRGs-score and clinical risk factors performed well to predict patient survival. Immune infiltration analysis further revealed that the expression of immune checkpoint genes was significantly enhanced in high CRGs-score group, especially PD-1 and PD-L1. An independent validation cohort (ICGC) confirmed that CRGs-score as a stable and universally applicable indicator in predicting HCC patient survival. Concordantly, the expression of five confirmed signature genes were also differentially expressed in human HCC cell lines and mouse HCC model. In addition, we also analyzed the sensitivity of 10 clinical targeted therapies between high and low CRGs-score groups. Conclusion: This study elucidated the role of dysregulated CRGs in HCC cohort, with validation with in-vitro and in-vivo models. The CRGs-score might be applied as a novel prognostic factor in HCC.

DNA Damage-Regulated Autophagy Modulator 1 (DRAM1) Mediates Autophagy and Apoptosis of Intestinal Epithelial Cells in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: DNA damage-regulated autophagy modulator 1 (DRAM1) is required for induction of autophagy and apoptosis. However, the influence of DRAM1 on the pathogenesis of inflammatory bowel disease (IBD) has not been explored. METHODS: DRAM1 expression was examined in the intestinal mucosa of patients with IBD and colons of colitis mice. We used a recombinant adeno-associated virus carrying small hairpain DRAM1 to knock down the DRAM1 gene to treat colitis in the mice. The effect of DRAM1 on autophagy and apoptosis of intestinal epithelial cells was explored. DRAM1-mediated interaction with the c-Jun N-terminal kinase (JNK) pathway was also examined. RESULTS: DRAM1 expression in the intestinal mucosa of the IBD patients was higher than that in the control participates. DRAM1 expression in the inflammatory cells in patients with Crohn's disease (CD) was lower than that in patients with ulcerative colitis (UC). Additionally, DRAM1 expression was correlated with the Simple Endoscopic Score for CD and the Mayo endoscopic score for UC. Serum levels of DRAM1 in the IBD group were substantially higher than those in the normal group. The knockdown of DRAM1 could alleviate colitis symptoms in mice. In in vitro experiments, knocking down DRAM1 could reduce autophagy and apoptosis levels. Mechanistically, DRAM1 may participate in the regulation of these two processes by positively regulating JNK activation. CONCLUSIONS: During intestinal inflammation, the upregulation of DRAM1 may promote the activation of JNK and further aggravate intestinal epithelium damage.

Reprogramming of m6A epitranscriptome is crucial for shaping of transcriptome and proteome in response to hypoxia.

Hypoxia causes a series of responses supporting cells to survive in harsh environments. Substantial post-transcriptional and translational regulation during hypoxia has been observed. However, detailed regulatory mechanism in response to hypoxia is still far from complete. RNA m6A modification has been proven to govern the life cycle of RNAs. Here, we reported that total m6A level of mRNAs was decreased during hypoxia, which might be mediated by the induction of m6A eraser, ALKBH5. Meanwhile, expression levels of most YTH family members of m6A readers were systematically down-regulated. Transcriptome-wide analysis of m6A revealed a drastic reprogramming of m6A epitranscriptome during cellular hypoxia. Integration of m6A epitranscriptome with either RNA-seq based transcriptome analysis or mass spectrometry (LC-MS/MS) based proteome analysis of cells upon hypoxic stress revealed that reprogramming of m6A epitranscriptome reshaped the transcriptome and proteome, thereby supporting efficient generation of energy for adaption to hypoxia. Moreover, ATP production was blocked when silencing an m6A eraser, ALKBH5, under hypoxic condition, demonstrating that m6A pathway is an important regulator during hypoxic response. Collectively, our studies indicate that crosstalk between m6A and HIF1 pathway is essential for cellular response to hypoxia, providing insights into the underlying molecular mechanisms during hypoxia.