Publications by authors named "Kaichun Wu"

323 Publications

Targeted imaging of esophageal adenocarcinoma with a near-infrared fluorescent peptide.

BMC Gastroenterol 2021 Jun 12;21(1):260. Epub 2021 Jun 12.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 Changle West Road, Xi'an, 710032, Shaanxi, People's Republic of China.

Background: Targeted optical imaging offers a noninvasive and accurate method for the early detection of gastrointestinal tumors, especially for flat appearances. In our previous study, a sequence of SNFYMPL (SNF) was identified as a specific peptide to bind to esophageal carcinoma using phage-display technology. This study aimed to evaluate the tumor-targeting efficacy of Cy5.5-conjugated SNF probe for imaging of esophageal carcinoma in vitro and in vivo.

Methods: The SNF-Cy5.5 probe was synthesized and then identified using High Performance Liquid Chromatography (HPLC) and mass spectrometry (MS). Confocal fluorescence imaging and Flow cytometry analysis were performed to evaluate the binding specificity and the receptor binding affinity of SNF-Cy5.5 to OE33. In vivo imaging was performed to evaluate the targeting ability of SNF-Cy5.5 to esophageal carcinoma.

Results: The confocal imaging and flow cytometry analysis showed that SNF-Cy5.5 bound specifically to the plasma membrane of OE33 cells with a high affinity. In vivo, for non-block group, SNF-Cy5.5 probe exhibited rapid OE33 tumor targeting during 24 h p.i. and excellent tumor-to-background contrast at 2 h p.i. For the block group, SNF-Cy5.5 was not observed in the mice after 4 h p.i. Ex vivo imaging also revealed that a higher fluorescent signal intensity value of the tumors was clearly observed in the non-block group than that in the block group (2.6 ± 0.32 × 10 vs. 0.8 ± 0.08 × 10, p < 0.05).

Conclusions: SNF-Cy5.5 was synthesized and characterized with a high efficiency and purity. The higher affinity, specificity, and tumor targeting efficacy of SNF-Cy5.5 were confirmed by in vitro and in vivo tests. SNF-Cy5.5 is a promising optical probe for the imaging of esophageal adenocarcinoma.
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http://dx.doi.org/10.1186/s12876-021-01840-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199829PMC
June 2021

Distinct basal brain functional activity and connectivity in the emotional-arousal network and thalamus in patients with functional constipation associated with anxiety and/or depressive disorders.

Psychosom Med 2021 Jun 11. Epub 2021 Jun 11.

Center for Brain Imaging, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710071, China State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China Department of Radiology, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710038, China Department of Psychiatry, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Objective: Functional constipation (FC) is a common gastrointestinal disorder. Anxiety and/or depressive disorders are common in patients with FC (FCAD). Brain dysfunction may play a role in FC, but the contribution of comorbid anxiety and/or depression in patients with FC is poorly understood.

Methods: Sixty-five FC patients and forty-two healthy controls (HC) were recruited, and hierarchical-clustering algorithm was used to classify FC patients into FCAD and patients without anxiety/depressive status (FCNAD) based on neuropsychological assessment. Resting-state functional Magnetic Resonance Imaging measures including fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity were employed to investigate brain functional differences.

Results: 37 patients were classified as FCAD and 28 patients were classified as FCNAD; both groups showed decreased activity (fALFF) than HC in the perigenual anterior cingulate cortex (pACC), dorsomedial prefrontal cortex (DMPFC) and precuneus; enhanced precentral gyrus (PreCen)-thalamus connectivity and attenuated precuneus-thalamus connectivity in FCAD/FCNAD highlighted the thalamus as a critical connectivity node in the brain network (PFWE < .05). FCAD also had decreased fALFF than FCNAD/HC in the orbitofrontal cortex (OFC) and thalamus, and increased OFC-hippocampus connectivity. In the FCNAD group, brain activities (pACC/DMPFC) and connection (precuneus-thalamus) had correlations only with symptoms; in the FCAD group, brain activities (OFC, pACC/DMPFC) and connectivities (OFC-hippocampus/PreCen-thalamus) showed correlations with both constipation symptoms and anxiety/depressive status ratings. Mediation analysis indicated the relationship between abdominal distension and OFC activity was completely mediated by anxiety in FCAD.

Conclusions: These findings provide evidence of differences in brain activity and functional connectivity between FCAD and FCNAD. It might help portray important clues for improving new treatment strategies.
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http://dx.doi.org/10.1097/PSY.0000000000000958DOI Listing
June 2021

IGF1-mediated HOXA13 overexpression promotes colorectal cancer metastasis through upregulating ACLY and IGF1R.

Cell Death Dis 2021 Jun 1;12(6):564. Epub 2021 Jun 1.

Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, China.

Metastasis is the major reason for the high mortality of colorectal cancer (CRC) patients and its molecular mechanism remains unclear. Here, we report a novel role of Homeobox A13 (HOXA13), a member of the Homeobox (HOX) family, in promoting CRC metastasis. The elevated expression of HOXA13 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in two independent CRC cohorts. Overexpression of HOXA13 promoted CRC metastasis whereas downregulation of HOXA13 suppressed CRC metastasis. Mechanistically, HOXA13 facilitated CRC metastasis by transactivating ATP-citrate lyase (ACLY) and insulin-like growth factor 1 receptor (IGF1R). Knockdown of ACLY and IGFIR inhibited HOXA13-medicated CRC metastasis, whereas ectopic overexpression of ACLY and IGFIR rescued the decreased CRC metastasis induced by HOXA13 knockdown. Furthermore, Insulin-like growth factor 1 (IGF1), the ligand of IGF1R, upregulated HOXA13 expression through the PI3K/AKT/HIF1α pathway. Knockdown of HOXA13 decreased IGF1-mediated CRC metastasis. In addition, the combined treatment of ACLY inhibitor ETC-1002 and IGF1R inhibitor Linsitinib dramatically suppressed HOXA13-mediated CRC metastasis. In conclusion, HOXA13 is a prognostic biomarker in CRC patients. Targeting the IGF1-HOXA13-IGF1R positive feedback loop may provide a potential therapeutic strategy for the treatment of HOXA13-driven CRC metastasis.
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http://dx.doi.org/10.1038/s41419-021-03833-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169856PMC
June 2021

Correction: SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7.

Oncogene 2021 Jun;40(24):4242-4243

Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.

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http://dx.doi.org/10.1038/s41388-021-01828-zDOI Listing
June 2021

HSP90-dependent PUS7 overexpression facilitates the metastasis of colorectal cancer cells by regulating LASP1 abundance.

J Exp Clin Cancer Res 2021 May 14;40(1):170. Epub 2021 May 14.

State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032, Xi'an, Shaanxi Province, China.

Background: Pseudouridine synthase (PUS) 7 is a member of the PUS family that catalyses pseudouridine formation. It has been shown to be involved in intellectual development and haematological malignancies. Nevertheless, the role and the underlying molecular mechanisms of PUS7 in solid tumours, such as colorectal cancer (CRC), remain unexplored. This study elucidated, for the first time, the role of PUS7 in CRC cell metastasis and the underlying mechanisms.

Methods: We conducted immunohistochemistry, qPCR, and western blotting to quantify the expression of PUS7 in CRC tissues as well as cell lines. Besides, diverse in vivo and in vitro functional tests were employed to establish the function of PUS7 in CRC. RNA-seq and proteome profiling analysis were also applied to identify the targets of PUS7. PUS7-interacting proteins were further uncovered using immunoprecipitation and mass spectrometry.

Results: Overexpression of PUS7 was observed in CRC tissues and was linked to advanced clinical stages and shorter overall survival. PUS7 silencing effectively repressed CRC cell metastasis, while its upregulation promoted metastasis, independently of the PUS7 catalytic activity. LASP1 was identified as a downstream effector of PUS7. Forced LASP1 expression abolished the metastasis suppression triggered by PUS7 silencing. Furthermore, HSP90 was identified as a client protein of PUS7, associated with the increased PUS7 abundance in CRC. NMS-E973, a specific HSP90 inhibitor, also showed higher anti-metastatic activity when combined with PUS7 repression. Importantly, in line with these results, in human CRC tissues, the expression of PUS7 was positively linked to the expression of HSP90 and LASP1, and patients co-expressing HSP90/PUS7/LASP1 showed a worse prognosis.

Conclusions: The HSP90-dependent PUS7 upregulation promotes CRC cell metastasis via the regulation of LASP1. Thus, targeting the HSP90/PUS7/LASP1 axis may be a novel approach for the treatment of CRC.
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http://dx.doi.org/10.1186/s13046-021-01951-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120699PMC
May 2021

Fecal Microbiota Transplantation as Therapy for Treatment of Active Ulcerative Colitis: A Systematic Review and Meta-Analysis.

Gastroenterol Res Pract 2021 23;2021:6612970. Epub 2021 Apr 23.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Medical University, Xi'an, Shaanxi Province 710032, China.

Aim: Increasing evidence supports the role of the gut microbiota in the etiology of ulcerative colitis (UC). Fecal microbiota transplantation (FMT) is a highly effective treatment against recurrent Clostridium difficile infection; however, its efficacy in UC is still controversial. A systematic review and meta-analysis was conducted to evaluate the efficacy and safety of FMT for treatment of active UC.

Methods: We searched Cochrane, Medline, Web of Science, and Embase from inception to February 2020. Randomized controlled trials (RCTs) recruiting adults with active UC, which compared FMT with controls, were eligible. The primary outcome was combined clinical remission with endoscopic remission/response. Secondary outcomes included clinical remission, endoscopic remission, and serious adverse events. Relative risk (RR) with 95% confidence interval (CI) is reported.

Results: Five RCTs with 292 participants were eligible for inclusion. When data were pooled for all patients, FMT was associated with a higher combined clinical remission with endoscopic remission/response; the RR of combined outcome not achieving after FMT vs. control was 0.79 (95% CI 0.70-0.88). FMT delivered via lower gastrointestinal route was superior to upper gastrointestinal route with regard to combined clinical remission with endoscopic remission/response (RR = 0.79, 95% CI 0.70-0.89). FMT with pooled donor stool (RR = 0.69, 95% CI 0.56-0.85) and higher frequency of administration (RR = 0.76, 95% CI 0.62-0.93) may be more effective with regard to clinical remission. There was no statistically significant difference in serious adverse events with FMT compared with controls (RR = 0.98, 95% CI 0.93-1.03).

Conclusion: FMT shows a promising perspective with comparable safety and favorable clinical efficacy for the treatment of active UC in the short term. However, further larger, more rigorously conducted RCTs of FMT in UC are still needed in order to resolve the controversial questions.
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http://dx.doi.org/10.1155/2021/6612970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088370PMC
April 2021

Delphinidin modulates JAK/STAT3 and MAPKinase signaling to induce apoptosis in HCT116 cells.

Environ Toxicol 2021 May 6. Epub 2021 May 6.

Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Delphinidin is an anthocyanin that belongs to the group of flavonoids that exert numerous biological activities. However, the molecular mechanisms underlying the anticancer effects of delphinidin remain poorly understood. In our study we analyzed delphinidin modulate STAT-3 and MAPKinase signaling thereby inhbits cell proliferation and promote apoptosis. Our study demonstrated that delphinidin treatment significantly reduced the viability of human colon cancer HCT116 in a concentration-dependent manner. We noticed that delphinidin effectively induced oxidative stress-mediated apoptosis by generating intracellular ROS, decreasing antioxidant levels, inducing lipid peroxidation, and single-strand break on colon cancer cells. In this study, we observed that delphinidin treatment alters the mitochondrial membrane potential, thereby induces apoptosis was closely associated with the induction of pro-apoptotic Bax, Caspase- 3,8 & 9, cytochrome C, and inhibition of anti-apoptotic protein expression. Studies on STAT-3 and MAPKinase signaling showed delphinidin inhibited the phosphorylation of these transcription factors' activity. Inhibition of STAT-3, p38, and ERK1/2 phosphorylation and modulation pro-apoptotic protein expression might be responsible for the anticancer activity of delphinidin in colon cancer cells.
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http://dx.doi.org/10.1002/tox.23152DOI Listing
May 2021

Water exchange-assisted vs. carbon dioxide-insufflated single-balloon enteroscopy: randomized controlled trial.

Endoscopy 2021 Mar 22. Epub 2021 Mar 22.

Fourth Military Medical University, State key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China, 710032., Xi'an, China.

Single-balloon enteroscopy (SBE) is a valuable but difficult modality for the diagnosis and treatment of small-bowel diseases. The water exchange (WE) method has the advantage of facilitating intubation during colonoscopy. Here, we evaluated the effects of WE on procedure-related variables related to SBE. This randomized controlled trial was conducted in a tertiary-care referral center in China. Patients with attempt at total enteroscopy (ATE) were randomly allocated to undergo WE-assisted (WE group) or carbon dioxide-insufflated enteroscopy (CO group). All patients were planned to undergo both antegrade and retrograde procedures. The primary outcome was the total enteroscopy rate (TER). Secondary outcomes included maximal insertion depth, positive findings, procedural time and adverse events. In total, 110 patients were enrolled, with 55 in each group. Baseline characteristics between the two groups were comparable. TER was achieved in 58.2% (32/55) of the WE group and 36.4% (20/55) of the control group (p=0.022). The estimated intubation depth was 521.2±101.4 cm in the WE group and 481.6±95.2 cm in the CO group (p=0.037). The insertion time was prolonged in the WE group compared with CO group (178.9±45.1 min vs. 154.2±27.6 min, p<0.001). Endoscopic findings and adverse events were comparable between the two groups. The WE method improved TER and increased intubation depth during SBE. The use of WE did not increase complications of enteroscopy. Clinical trial registation: https://clinicaltrials.gov/, NCT01942863.
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http://dx.doi.org/10.1055/a-1459-4571DOI Listing
March 2021

ARL4C might serve as a prognostic factor and a novel therapeutic target for gastric cancer: bioinformatics analyses and biological experiments.

J Cell Mol Med 2021 Apr 16;25(8):4014-4027. Epub 2021 Mar 16.

Department of Gastroenterology, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

The ADP-ribosylation factor-like proteins (ARLs) have been proved to regulate the malignant phenotypes of several cancers. However, the exact role of ARLs in gastric cancer (GC) remains elusive. In this study, we systematically investigate the expression status, interactive relations, potential pathways, genetic variations and clinical values of ARLs in GC. We find that ARLs are significantly dysregulated in GC and involved in various cancer-related pathways. Subsequently, machine learning models identify ARL4C as one of the two most significant clinical indicators among ARLs for GC. Furthermore, ARL4C silencing remarkably inhibits the growth and metastasis of GC cells both in vitro and in vivo. Moreover, enrichment analysis indicates that ARL4C is highly correlated with TGF-β1 signalling. Correspondingly, TGF-β1 treatment dramatically increases ARL4C expression and ARL4C knockdown inhibits the phosphorylation level of Smads, downstream factors of TGF-β1. Meanwhile, the coexpression of ARL4C and TGF-β1 worsens the prognosis of GC patients. Our work comprehensively demonstrates the crucial role of ARLs in the carcinogenesis of GC and the specific mechanisms underlying the GC-promoting effects of TGF-β1. More importantly, we uncover the great promise of ARL4C-targeted therapy in improving the efficacy of TGF-β1 inhibitors for GC patients.
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http://dx.doi.org/10.1111/jcmm.16366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051716PMC
April 2021

Association of systemic inflammation and body mass index with survival in patients with resectable gastric or gastroesophageal junction adenocarcinomas.

Cancer Biol Med 2021 Feb;18(1):283-297

State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital, Air Force Medical University of PLA, Xi'an 710032, China.

Objective: The systemic inflammation index and body mass index (BMI) are easily accessible markers that can predict mortality. However, the prognostic value of the combined use of these two markers remains unclear. The goal of this study was therefore to evaluate the association of these markers with outcomes based on a large cohort of patients with gastric cancer.

Methods: A total of 2,542 consecutive patients undergoing radical surgery for gastric or gastroesophageal junction adenocarcinoma between 2009 and 2014 were included. Systemic inflammation was quantified by the preoperative neutrophil-to-lymphocyte ratio (NLR). High systemic inflammation was defined as NLR ≥ 3, and underweight was defined as BMI < 18.5 kg/m.

Results: Among 2,542 patients, NLR ≥ 3 and underweight were common [627 (25%) and 349 (14%), respectively]. In the entire cohort, NLR ≥ 3 or underweight independently predicted overall survival (OS) [hazard ratio (HR): 1.236, 95% confidence interval (95% CI): 1.069-1.430; and HR: 1.600, 95% CI: 1.350-1.897, respectively] and recurrence-free survival (RFS) (HR: 1.230, 95% CI: 1.054-1.434; and HR: 1.658, 95% CI: 1.389-1.979, respectively). Patients with both NLR ≥ 3 and underweight ( neither) had much worse OS (HR: 2.445, 95% CI: 1.853-3.225) and RFS (HR: 2.405, 95% CI: 1.802-3.209). Furthermore, we observed similar results in subgroup analyses according to pathological stage, age, and postoperative chemotherapy.

Conclusions: Our results showed that preoperative elevated NLR and decreased BMI had a significant negative effect on survival. Underweight combined with severe inflammation could enhance prognostication. Taking active therapeutic measures to reduce inflammation and increase nutrition may help improve outcomes.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877168PMC
February 2021

Hypermethylation of as a Novel Tumor Suppressor Involved in Tumor Growth and Prognosis in Gastric Cancer.

Front Cell Dev Biol 2021 21;9:624871. Epub 2021 Jan 21.

State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases of the Air Force Medical University, Xi'an, China.

Background/aims: The role of DHRS3 in human cancer remains unclear. Our study explored the role of in gastric cancer (GC) and its clinicopathological significance and associated mechanisms.

Materials: Bisulfite-assisted genomic sequencing PCR and a Mass-Array system were used to evaluate and quantify the methylation levels of the promoter. The expression levels and biological function of was examined by both and assays. A two-way hierarchical cluster analysis was used to classify the methylation profiles, and the correlation between the methylation status of the promoter and the clinicopathological characteristics of GC were then assessed.

Results: The promoter was hypermethylated in GC samples, while the mRNA and protein levels of were significantly downregulated. Ectopic expression of in GC cells inhibited cell proliferation and migration , decreased tumor growth . methylation was correlated with histological type and poor differentiation of tumors. GC patients with high degrees of CpG 9.10 methylation had shorter survival times than those with lower methylation.

Conclusion: was hypermethylated and downregulated in GC patients. Reduced expression of is implicated in gastric carcinogenesis, which suggests is a tumor suppressor.
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http://dx.doi.org/10.3389/fcell.2021.624871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859350PMC
January 2021

NEK9, a novel effector of IL-6/STAT3, regulates metastasis of gastric cancer by targeting ARHGEF2 phosphorylation.

Theranostics 2021 1;11(5):2460-2474. Epub 2021 Jan 1.

State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China, 710032.

Inflammatory stimuli from the tumor microenvironment play important roles in cancer progression. However, the mechanism of promotion of cancer metastasis by inflammation in gastric cancer (GC) is poorly understood. The roles of NEK9 were validated loss-of-function and gain-of-function experiments in vitro and in an animal model of metastasis. Cytoskeletal reorganization-associated molecules were detected by GST pull-down. The regulation of ARHGEF2 by NEK9 was investigated by phosphoproteomics analysis, immunoprecipitation (IP) and in vitro kinase assay. The transcriptional regulation of miR-520f-3p was studied using luciferase reporter and chromatin immunoprecipitation (ChIP). The expression of these proteins in GC tissues was examined by immunohistochemistry. NEK9 directly regulates cell motility and RhoA activation in GC. The phosphorylation of ARHGEF2 by NEK9 is the key step of this process. NEK9 is a direct target of miR-520f-3p, which is transcriptionally suppressed by IL-6-mediated activation of STAT3. A decrease in miR-520f-3p leads to the amplification of IL-6/STAT3 by targeting GP130. A simultaneous elevation of the levels of NEK9, GP130 and p-STAT3 was confirmed in the lymph nodes and distant metastases. An increase in NEK9, GP130 and STAT3 is associated with reduced overall survival of GC patients. This study demonstrates that activation of STAT3 by IL-6 transcriptionally suppresses miR-520f-3p and diminishes the inhibitory effects of miR-520f-3p on NEK9 and GP130. An increase in GP130 enhances this signaling, and NEK9 directly influences cell motility and RhoA activation by targeting the phosphorylation of ARHGEF2. Targeting the IL-6-STAT3-NEK9 pathway may be a new strategy for GC treatment.
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http://dx.doi.org/10.7150/thno.53169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797683PMC
January 2021

CXCL12-mediated HOXB5 overexpression facilitates Colorectal Cancer metastasis through transactivating CXCR4 and ITGB3.

Theranostics 2021 1;11(6):2612-2633. Epub 2021 Jan 1.

State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.

Metastasis is the major reason for the high mortality of colorectal cancer (CRC). However, the molecular mechanism underlying CRC metastasis remains unclear. Here, we report a novel role of homeobox B5 (HOXB5), a member of the HOX family, in promoting CRC metastasis. The expression of HOXB5 and its target genes were examined by immunohistochemistry in human CRC. Chromatin immunoprecipitation and luciferase reporter assays were performed to measure the transcriptional regulation of target genes by HOXB5. The metastatic capacities of CRC cells were evaluated by lung and liver metastatic models. The elevated expression of HOXB5 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in CRC patients. HOXB5 expression was an independent and significant risk factor for the recurrence and survival in CRC patients. Overexpression of HOXB5 promoted CRC metastasis by transactivating metastatic related genes, C-X-C motif chemokine receptor 4 (CXCR4) and integrin subunit beta 3 (ITGB3). C-X-C motif chemokine ligand 12 (CXCL12), which is the ligand of CXCR4, upregulated HOXB5 expression through the extracellular regulated protein kinase (ERK)/ETS proto-oncogene 1, transcription factor (ETS1) pathway. The knockdown of HOXB5 decreased CXCL12-enhanced CRC metastasis. Furthermore, AMD3100, a specific CXCR4 inhibitor, significantly suppressed HOXB5-mediated CRC metastasis. HOXB5 expression was positively correlated with CXCR4 and ITGB3 expression in human CRC tissues, and patients with positive co-expression of HOXB5/CXCR4, or HOXB5/ITGB3 exhibited the worst prognosis. Our study implicates HOXB5 as a prognostic biomarker in CRC, and defines a CXCL12-HOXB5-CXCR4 positive feedback loop that plays an important role in promoting CRC metastasis.
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http://dx.doi.org/10.7150/thno.52199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806482PMC
January 2021

Comparing the Impact of Laparoscopic Sleeve Gastrectomy and Gastric Cancer Surgery on Resting-State Brain Activity and Functional Connectivity.

Front Neurosci 2020 26;14:614092. Epub 2020 Nov 26.

Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Laparoscopic sleeve gastrectomy (LSG) is one of the most performed bariatric surgeries in clinical practice. Growing neuroimaging evidence shows that LSG induces brain functional and structural alterations accompany with sustained weight-loss. Meanwhile, for clinical treatment of gastric cancer, stomach removal surgery is a similar procedure to LSG. It is unclear if the gastric cancer surgery (GCS) would induce the similar alterations in brain functions and structures as LSG, and it would help to clarify the specificity of the LSG. We recruited 24 obese patients who received LSG in the LSG group and 16 normal weight patients with gastric cancer who received GCS as the control group. Functional magnetic resonance imaging was employed to investigate the differences and similarity of surgery's impact on resting-state brain activity and functional connectivity (RSFC) between LSG and GCS groups. Both LSG and GCS groups showed increased activities in the posterior cingulate cortex (PCC) and supplementary motor area (SMA) as well as the decreased RSFC of PCC- dorsomedial prefrontal cortex and SMA- dorsolateral prefrontal cortex. There were decreased resting-state activity of hippocampus and putamen in LSG group and increases in GCS group. In LSG group, resting-state activities of hippocampus and putamen were correlated with craving for high-caloric food and body mass index after surgery, respectively. These findings suggest LSG induced alterations in resting-state activity and RSFC of hippocampus and putamen specifically regulate the obese state and overeating behaviors in obese patients.
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http://dx.doi.org/10.3389/fnins.2020.614092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726325PMC
November 2020

Digestive symptoms and liver injury in patients with coronavirus disease 2019 (COVID-19): A systematic review with meta-analysis.

JGH Open 2020 Dec 28;4(6):1047-1058. Epub 2020 Oct 28.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases Fourth Military Medical University Xi'an Shaanxi Province China.

Although most COVID-19 patients typically present with respiratory symptoms, many patients could experience digestive symptoms as the major complaint. We performed a systematic review and meta-analysis to investigate the exact prevalence of digestive symptoms and liver injury in COVID-19 patients and compare the difference between patients with and without digestive symptoms. PubMed, Embase, Ovid, Wanfang data, and CNKI were searched until 24 April 2020 to identify studies that reported digestive symptoms and liver injury in COVID-19 patients. A random-effect model was used to combine the data. Finally, 64 studies with 15 141 patients were included. The pooled rate of digestive symptoms and liver dysfunction was 31.8% (95 CI 21.0-42.5%, = 97.6%) and 27.4% (95 CI 16.9-37.9%, = 97.9%), respectively. Patients with digestive symptoms were more likely to present with fatigue (OR 2.28, 95 CI 1.66-3.14,  < 0.00001, = 31%), myalgia (OR 1.96, 95 CI 1.06-3.65, = 0.03, = 69%), and acute respiratory disease syndrome (ARDS) (OR 2.94, 95 CI 1.17-7.40, = 0.02, = 0) and had a trend to present as severe/critical type (OR 1.87, 95 CI 0.98-3.57, = 0.06, = 58%). Severe/critical patients were more likely to present with diarrhea (OR 2.02, 95 CI 1.16-3.50, = 0.01, = 64) and have high alanine aminotransferase (ALT) (OR 2.08, 95 CI 1.55-2.81,  < 0.00001, = 13%,) and aspartate aminotransferase (AST) (OR 3.53, 95 CI 2.76-4.51,  < 0.00001, = 0). The pooled rate of patients with digestive symptoms was 28.7% (95 CI 17.6-39.8%) and 42.8% (95 CI 23.4-62.3%) in studies from China and out of China, respectively. COVID-19 patients had a high rate of digestive symptoms and liver injury. Patients with digestive symptoms had a trend to develop severe/critical illness.
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http://dx.doi.org/10.1002/jgh3.12428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731824PMC
December 2020

Targeted versus universal tuberculosis chemoprophylaxis in 1968 patients with inflammatory bowel disease receiving anti-TNF therapy in a tuberculosis endemic region.

Aliment Pharmacol Ther 2021 02 12;53(3):390-399. Epub 2020 Dec 12.

Department of Gastroenterology, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, China.

Background: Anti-tumour necrosis factor (anti-TNF) therapy increases the risk of tuberculosis (TB). Given limitations of screening techniques, it remains uncertain if patients receiving anti-TNF in TB endemic regions should be screened for latent infection with chemoprophylaxis restricted to those with proven infection, or if all patients should receive chemoprophylaxis.

Aims: To compare the incidence of active TB with infliximab (IFX) following targeted and universal TB chemoprophylaxis, and to determine the rates of adverse events (AE) related to TB chemoprophylaxis METHODS: A multi-centre retrospective cohort study was performed at 18 hospitals in China of 1968 adult patients with IBD receiving IFX from 2009 to 2017. TB screening prior to IFX was performed with chest X-ray and/or computed tomography [CT] and immune reactivity testing (interferon-γ release assay and/or tuberculin skin test). Patients were followed-up for a minimum of 3 months after IFX discontinuation, or until last hospital visit if IFX therapy was ongoing. Targeted strategy was defined as TB chemoprophylaxis only for patients with a positive latent TB screen, with universal strategy defined as TB chemoprophylaxis for all patients.

Results: Mean follow-up was 1.07 ± 0.87 years with a total follow-up of 2102 patient-years. There were 1433 patients in the targeted and 483 patients in the universal TB chemoprophylaxis groups, with no significant difference in the incidence rates of active TB between groups (673.3 per 100 000 population per year vs 891.5 per 100 000 population per year, P = 0.60). In the targeted group, 55/1433 patients received TB chemoprophylaxis compared with 483/483 in the universal group, with significantly fewer AEs related to TB chemoprophylaxis in the targeted compared to the universal group (0.35% (5/1433) vs 6.8% (33/483), P < 0.05).

Conclusions: In this study of patients receiving IFX in a TB endemic area, universal chemoprophylaxis was not associated with a reduced risk of active TB when compared to a targeted chemoprophylaxis strategy, and AEs were more common. This supports the use of targeted TB chemoprophylaxis when anti-TNF therapy is initiated in TB endemic regions.
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http://dx.doi.org/10.1111/apt.16130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839545PMC
February 2021

NDRG2 regulates adherens junction integrity to restrict colitis and tumourigenesis.

EBioMedicine 2020 Nov 21;61:103068. Epub 2020 Oct 21.

The State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an 710032, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Xi'an 710032, China. Electronic address:

Background: Paracellular barriers play an important role in the pathogenesis of Inflammatory bowel disease (IBD) and maintain gut homeostasis. N-myc downstream-regulated gene 2 (NDRG2) has been reported to be a tumour suppressor gene and to inhibit colorectal cancer metastasis. However, whether NDRG2 affects colitis initiation and colitis-associated colorectal cancer is unclear.

Methods: Intestine-specific Ndrg2 deficiency mice (Ndrg2) were subjected to DSS- or TNBS-induced colitis, and AOM-DSS-induced colitis-associated tumour. HT29 cells, Caco2 cells, primary intestinal epithelial cells (IECs) from Ndrg2 mice, mouse embryo fibroblasts (MEFs) from systemic Ndrg2 knockout mice, HEK293 cells and human UC and DC specimens were used to investigate NDRG2 function in colitis and colitis-associated tumour.

Findings: Ndrg2 loss led to adherens junction (AJ) structure destruction via E-cadherin expression attenuation, resulting in diminished epithelial barrier function and increased intestinal epithelial permeability. Mechanistically, NDRG2 enhanced the interaction of E3 ligase FBXO11 with Snail, the repressor of E-cadherin, to promote Snail degradation by ubiquitination and maintained E-cadherin expression. In human ulcerative colitis patients, reduced NDRG2 expression is positively correlated with severe inflammation.

Interpretation: These findings demonstrate that NDRG2 is an essential colonic epithelial barrier regulator and plays an important role in gut homeostasis maintenance and colitis-associated tumour development.

Funding: National Natural Science Foundation of China (No. 81770523, 31571437, 81672751), Creative Research Groups of China (No. 81421003), State Key Laboratory of Cancer Biology Project (CBSKL2019ZZ11, CBSKL201406, CBSKL2017Z08 and CBSKL2017Z11), Fund for Distinguished Young Scholars of ShaanXi province (2019JC-22).
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http://dx.doi.org/10.1016/j.ebiom.2020.103068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581885PMC
November 2020

Personal Protective Equipment for Endoscopy in Low-Resource Settings During the COVID-19 Pandemic: Guidance From the World Gastroenterology Organisation.

J Clin Gastroenterol 2020 Nov/Dec;54(10):833-840

Department of Medicine, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

Performance of endoscopic procedures is associated with a risk of infection from COVID-19. This risk can be reduced by the use of personal protective equipment (PPE). However, shortage of PPE has emerged as an important issue in managing the pandemic in both traditionally high and low-resource areas. A group of clinicians and researchers from thirteen countries representing low, middle, and high-income areas has developed recommendations for optimal utilization of PPE before, during, and after gastrointestinal endoscopy with particular reference to low-resource situations. We determined that there is limited flexibility with regard to the utilization of PPE between ideal and low-resource settings. Some compromises are possible, especially with regard to PPE use, during endoscopic procedures. We have, therefore, also stressed the need to prevent transmission of COVID-19 by measures other than PPE and to conserve PPE by reduction of patient volume, limiting procedures to urgent or emergent, and reducing the number of staff and trainees involved in procedures. This guidance aims to optimize utilization of PPE and protection of health care providers.
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http://dx.doi.org/10.1097/MCG.0000000000001411DOI Listing
October 2020

IgA, albumin, and eosinopenia as early indicators of cytomegalovirus infection in patients with acute ulcerative colitis.

BMC Gastroenterol 2020 Sep 5;20(1):294. Epub 2020 Sep 5.

Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, 100730, P.R. China.

Background: Cytomegalovirus (CMV) infection can significantly complicate and worsen the condition of acute severe ulcerative colitis (UC) patients. We aimed to explore the predictive risk factors to prevent and identify CMV infection at an early stage in acute UC patients.

Methods: A total of 115 moderate-to-severe active UC patients from 17 hospitals throughout China were enrolled. Active CMV infection was diagnosed by one of the following: CMV pp65 antigens, CMV IgM antibodies or CMV DNA. We identified the independent risk factors by multivariate analyses.

Results: A total of 64 of 115 active UC patients had active CMV infection. Compared to the non-CMV-infected patients, the CMV-infected patients had a tendency to be male and to exhibit abdominal pain; fever; oral ulcers; eosinopenia; low albumin, immunoglobulin (Ig) A, IgM, and IgG levels; increased high-sensitivity C-reactive protein (hsCRP) levels; hyponatremia; pancolonic lesions; initial onset type; severe activity; and glucocorticoid (high-dose) and immunosuppressive agent use (P < 0.05). In further multivariate analyses, the use of high-dose glucocorticoids (OR 13.55, 95% CI 2.49-73.61, P < 0.01) and immunosuppressive agents (OR 11.23, 95% CI 1.05-119.99, P = 0.04) were independent risk factors for CMV infection. A decrease eosinophil and albumin levels were risk factors for CMV infection. With every 0.1*10^9/L decrease in the peripheral blood eosinophil level or 1 g/L decrease in the serum albumin level, the risk for CMV infection in UC patients increased by 5.21-fold (1/0.192) or 1.19-fold (1/0.839), respectively.

Conclusions: High-dose glucocorticoid and immunosuppressive agent treatment significantly increase the risk of CMV infection, and correcting eosinopenia and low albumin levels may help prevent CMV infection in UC patients.
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http://dx.doi.org/10.1186/s12876-020-01434-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487863PMC
September 2020

Efficacy and safety of adalimumab in Chinese patients with moderately to severely active Crohn's disease: results from a randomized trial.

Therap Adv Gastroenterol 2020 16;13:1756284820938960. Epub 2020 Jul 16.

Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, China.

Background And Aims: Efficacy of adalimumab in Crohn's disease (CD) has not been shown in China. The aim of this study was to evaluate the efficacy and safety of adalimumab in Chinese patients with CD.

Methods: This 26-week, multicenter, phase III study evaluated patients with moderately to severely active CD and elevated high-sensitivity C-reactive protein (⩾3 mg/l) who were naïve to anti-tumor necrosis factor therapy. Patients were randomized to double-blind adalimumab 160/80 mg at weeks 0/2 and 40 mg at weeks 4/6 or placebo at weeks 0/2 followed by blinded adalimumab 160/80 mg at weeks 4/6. At week 8, all patients received open-label 40 mg adalimumab every other week through week 26. The primary endpoint was clinical remission [CD activity index (CDAI) <150] at week 4. Clinical remission at week 26 was assessed in week-8 responders (decrease in CDAI ⩾70 points at week 8 from baseline) and compared with a clinically meaningful threshold of 30%. Adverse events (AEs) were recorded throughout the study.

Results: At baseline, 205 patients were enrolled, with mean [standard deviation (SD)] age of 32.9 (9.9) years and CD duration of 2.7 (3.0) years. At week 4, 38/102 patients (37%) receiving adalimumab and 7/103 (7%) receiving placebo ( < 0.001) achieved clinical remission. Among week-8 responders, 93/144 (65%) achieved clinical remission at week 26 ( < 0.001). No unexpected AEs and no malignancies, active tuberculosis, or deaths were reported.

Conclusions: Adalimumab induced and maintained remission in Chinese patients with CD. Safety results were consistent with the known safety profile of adalimumab.

Clinicaltrialsgov Identifier: NCT02499783.
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http://dx.doi.org/10.1177/1756284820938960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370564PMC
July 2020

Re-labeled GX1 dimer as a novel dual-functional probe targeting TGM2 for imaging and antiangiogenic therapy of gastric cancer.

Eur J Pharm Biopharm 2020 Sep 16;154:144-152. Epub 2020 Jul 16.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, China. Electronic address:

Purpose: The GX1 peptide (CGNSNPKSC) can specifically bind to TGM2 and possesses the ability to target the blood vessels of gastric cancer. This study intends to develop an integrated dual-functional probe with higher affinity, specificity and targeting and to characterize it in vivo and in vitro.

Methods: The dimer and tetramer of GX1 were prepared using cross-linked PEG and labeled with Tc. The best targeting probe [PEG-(GX1)] was selected by gamma camera imaging in nude mouse models of gastric cancer. Re-PEG-(GX1) was prepared and characterized through cell binding analysis and competitive inhibition experiments, gamma camera imaging, MTT analysis and flow cytometry, BLI, immunohistochemistry, HE staining and biochemical analysis.

Results: PEG-(GX1) bound specifically to Co-HUVEC with higher affinity than GX1. Re-PEG-(GX1) had better ability to target gastric cancer in tumor-bearing nude mice and higher T/H ratios than Re-GX1. Re-PEG-(GX1) inhibited the growth of Co-HUVEC and induced apoptosis, and its effects were more robust than those of Re-GX1. BLI showed that Re-PEG-(GX1) inhibited tumor proliferation in vivo with a stronger effect than Re-GX1. Compared with Re-GX1, Re-PEG-(GX1) suppressed tumor angiogenesis and tumor cell proliferation and induced tumor cell apoptosis in vivo. The Re-PEG-(GX1) group did not cause visible changes in liver and kidney morphology and function in vivo.

Conclusion: The dimer of GX1 was synthesized by using cross-linked PEG, and then Re-PEG-(GX1) was prepared. This radiopharmaceutical played both diagnostic and therapeutic functions, and gamma camera imaging could be utilized to detect the distribution of drugs in vivo during treatment. Through a series of experiments in vitro and in vivo, the feasibility of the drug was confirmed, and these results laid the foundation for the subsequent development and application of GX1.
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http://dx.doi.org/10.1016/j.ejpb.2020.07.015DOI Listing
September 2020

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology practice recommendations for medical management and monitoring of inflammatory bowel disease in Asia.

J Gastroenterol Hepatol 2021 Mar 29;36(3):637-645. Epub 2020 Jul 29.

Department of Gastroenterology, Peking Union Medical College, Beijing, China.

Inflammatory bowel disease (IBD) has increased in incidence and prevalence in Asian countries since the end of the 20th century. Moreover, differences in the cause, phenotypes, and natural history of IBD between the East and West have been recognized. Therefore, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have established recommendations on medical management of IBD in Asia. Initially, the committee members drafted 40 recommendations, which were then assessed according to Grading of Recommendations Assessment, Development and Evaluation. Eight statements were rejected as this indicated that consensus had not been reached. The recommendations encompass pretreatment evaluation; medical management of active IBD; medical management of IBD in remission; management of IBD during the periconception period and pregnancy; surveillance strategies for colitis-associated cancer; monitoring side effects of thiopurines and methotrexate; and infections in IBD.
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http://dx.doi.org/10.1111/jgh.15185DOI Listing
March 2021

SOX18 promotes gastric cancer metastasis through transactivating MCAM and CCL7.

Oncogene 2020 08 2;39(33):5536-5552. Epub 2020 Jul 2.

Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.

The therapeutic strategies for advanced gastric cancer (GC) remain unsatisfying and limited. Therefore, it is still imperative to fully elucidate the mechanisms underlying GC metastasis. Here, we report a novel role of SRY-box transcription factor 18 (SOX18), a member of the SOX family, in promoting GC metastasis. The elevated expression of SOX18 was positively correlated with distant metastasis, higher AJCC stage, and poor prognosis in human GC. SOX18 expression was an independent and significant risk factor for the recurrence and survival in GC patients. Up-regulation of SOX18 promoted GC invasion and metastasis, whereas down-regulation of SOX18 decreased GC invasion and metastasis. Melanoma cell adhesion molecule (MCAM) and C-C motif chemokine ligand 7 (CCL7) are direct transcriptional targets of SOX18. Knockdown of MCAM and CCL7 significantly decreased SOX18-mediated GC invasion and metastasis, while the stable overexpression of MCAM and CCL7 reversed the decrease in cell invasion and metastasis that was induced by the inhibition of SOX18. A mechanistic investigation indicated that the upregulation of SOX18 that was mediated by the CCL7-CCR1 pathway relied on the ERK/ELK1 pathway. SOX18 knockdown significantly reduced CCL7-enhanced GC invasion and metastasis. Furthermore, BX471, a specific CCR1 inhibitor, significantly reduced the SOX18-mediated GC invasion and metastasis. In human GC tissues, SOX18 expression was positively correlated with CCL7 and MCAM expression, and patients with positive coexpression of SOX18/CCL7 or SOX18/MCAM had the worst prognosis. In conclusion, we defined a CCL7-CCR1-SOX18 positive feedback loop that played a pivotal role in GC metastasis, and targeting this pathway may be a promising therapeutic option for the clinical management of GC.
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http://dx.doi.org/10.1038/s41388-020-1378-1DOI Listing
August 2020

Relationship between papilla-related variables and post endoscopic retrograde cholangiopancreatography pancreatitis: A multicenter, prospective study.

J Gastroenterol Hepatol 2020 Dec 29;35(12):2184-2191. Epub 2020 Jun 29.

National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

Background And Aim: Papilla with hooknose or long protruding shape may increase the difficulty of cannulation during endoscopic retrograde cholangiopancreatography (ERCP). However, the relationship between papilla anatomy and complications of ERCP has not been fully understood. We aimed to investigate the effect of major duodenal papilla morphology on post-ERCP pancreatitis (PEP) and the procedure of cannulation.

Methods: Patients with native papilla who underwent ERCP were recruited to this multicenter study. Papilla-related variables were collected, including the length of long axis (L), short axis (S) and opening width (OW), transverse fold, periampullary diverticulum (PAD), papilla location, orientation, swelling, and presence of duodenal stenosis. Demographic data and the procedure of cannulation were also prospectively evaluated. The primary outcome was PEP incidence. Multivariate analysis was used to identify high risk factors for PEP.

Results: Six hundred and fifty-eight patients were enrolled. Overall PEP incidence was 4.7% (31/658). The papilla of patients complicated with PEP had higher long to short axis (L/S) ratio (odds ratio [OR] 3.84, 95% confidence interval [CI]: 1.37-10.74, P = 0.010), higher long axis to opening width (L/OW) ratio (OR 1.35, 95%CI: 1.06-1.71, P = 0.014), more transverse folds (OR 2.53, 95%CI: 1.02-6.26, P = 0.044), and less periampullary diverticulum (OR 0.21, 95%CI: 0.06-0.70, P = 0.011). Multivariate analysis revealed that the indication of common bile duct stones, normal bilirubin, inadvertent pancreatic duct cannulation > 1, L/S ratio ≥ 1.5, and absence of PAD were independent risk factors for PEP.

Conclusion: Besides patient-related and procedure-related factors, papilla-related variables, such as L/S ratio and PAD, can be considered as a third type of factors associated with PEP (Clinicaltrials.gov number: NCT03550768).
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http://dx.doi.org/10.1111/jgh.15135DOI Listing
December 2020

Learning curve of double-guidewire technique by trainees during hands-on endoscopic retrograde cholangiopancreatography training.

J Gastroenterol Hepatol 2020 Dec 23;35(12):2176-2183. Epub 2020 Jun 23.

National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.

Background And Aims: Double-guidewire technique (DWT) has been successfully performed by experts in difficult biliary cannulation as an advanced technique. This study aimed to define the learning curve and safety of DWT by trainees during hands-on endoscopic retrograde cholangiopancreatography (ERCP) training.

Methods: Patients were eligible for inclusion in the study if the biliary cannulation was difficult and the pancreatic duct was inadvertently cannulated. DWT was performed by two trainees randomly under trainers' guidance. The primary outcome was the success rate of DWT biliary cannulation of trainees. Cumulative sum analysis was used to generate visual learning curves.

Results: A total of 60 patients with difficult cannulation were enrolled. The main indications for ERCP were common bile duct stones (65%) and biliary stricture (31.7%). The learning curve analysis showed that to achieve a 70% rate of successful DWT, 12 procedures were needed for trainee A and 15 for trainee B. Higher targeted success rate of DWT could be achieved if the number of DWT procedures increased. Compared with the early stage of learning DWT (case 1 to 15 for each trainee), trainees had significantly higher DWT success rate in the late stage (36.7% [11/30] vs 80% [24/30], P = 0.001). The final success rate of cannulation was 98.3% (59/60). The overall rate of post-ERCP pancreatitis and adverse events was 6.7% (4/60) and 8.3% (5/60), respectively.

Conclusions: Double-guidewire technique was safely performed by two novel trainees during hands-on ERCP training. Fifteen procedures may be enough for trainees to achieve the competency of performing DWT. (Clinicaltrials.gov number: NCT03707613).
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http://dx.doi.org/10.1111/jgh.15120DOI Listing
December 2020

Interleukin 1β-mediated HOXC10 Overexpression Promotes Hepatocellular Carcinoma Metastasis by Upregulating PDPK1 and VASP.

Theranostics 2020 19;10(8):3833-3848. Epub 2020 Feb 19.

State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, The fourthMilitary Medical University, Xi'an 710032, Shaanxi Province, China.

Metastasis and recurrence are the primary reasons for the high mortality rate of human hepatocellular carcinoma (HCC) patients. However, the exact mechanism underlying HCC metastasis remains unclear. The Homeobox (HOX) family proteins, which are a highly conserved transcription factor superfamily, play important roles in cancer metastasis. Here, we report a novel role of HOXC10, one of the most upregulated HOX genes in human HCC tissues, in promoting HCC metastasis. The expression of HOXC10 and its functional targets was detected by immunohistochemistry in two independent human HCC cohorts. Luciferase reporter and chromatin immunoprecipitation assays were used to measure the transcriptional regulation of target genes by HOXC10. The effect of HOXC10-mediated invasion and metastasis were analyzed by Transwell assays and by an orthotopic metastasis model. Elevated expression of HOXC10 was positively correlated with the loss of tumor encapsulation and with higher tumor-nodule-metastasis (TNM) stage and poor prognosis in human HCC. Overexpression of HOXC10 promoted HCC metastasis by upregulating metastasis-related genes, including 3-phosphoinositide-dependent protein kinase 1 (PDPK1) and vasodilator-stimulated phosphoprotein (VASP). Knockdown of PDPK1 and VASP inhibited HOXC10-enhanced HCC metastasis, whereas upregulation of PDPK1 and VASP rescued the decreased metastasis induced by HOXC10 knockdown. Interleukin-1β (IL-1β), which is the ligand of IL-1R1, upregulated HOXC10 expression through the c-Jun NH2-terminal kinase (JNK)/c-Jun pathway. HOXC10 knockdown significantly reduced IL-1β-mediated HCC metastasis. Furthermore, Anakinra, a specific antagonist of IL-1R1, inhibited IL-1β-induced HOXC10 upregulation and HCC metastasis. In human HCC tissues, HOXC10 expression was positively correlated with PDPK1, VASP and IL-1R1 expression, and patients with positive coexpression of HOXC10/PDPK1, HOXC10/VASP or IL-1R1/HOXC10 exhibited the poorest prognosis. Upregulated HOXC10 induced by IL-1β promotes HCC metastasis by transactivating PDPK1 and VASP expression. Thus, our study implicates HOXC10 as a prognostic biomarker, and targeting this pathway may be a promising therapeutic option for the clinical prevention of HCC metastasis.
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http://dx.doi.org/10.7150/thno.41712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069084PMC
May 2021

Mucoadhesive-to-penetrating controllable peptosomes-in-microspheres co-loaded with anti-miR-31 oligonucleotide and Curcumin for targeted colorectal cancer therapy.

Theranostics 2020 18;10(8):3594-3611. Epub 2020 Feb 18.

State Key Laboratories for Agrobiotechnology and Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Biological Sciences, China Agricultural University, Beijing, 100193, China.

Accumulating evidences indicate that nanomedicines greatly decrease the side effects and enhance the efficacy of colorectal cancer (CRC) treatment. In particular, the use of rectal delivery of nanomedicines, with advantages such as fast therapeutic effects and a diminishing hepatic first-pass effect, is currently emerging. We established a CRC targeted delivery system, in which α-lactalbumin peptosomes (PSs) co-loaded with a microRNA (miR)-31 inhibitor (miR-31i) and curcumin (Cur) were encapsuslated in thiolated TEMPO oxidized Konjac glucomannan (sOKGM) microspheres, referred as sOKGM-PS-miR-31i/Cur. The CRC targeting capability, drug release profiles, mucoadhesive-to-penetrating properties and therapeutic efficacy of sOKGM-PS-miR-31i/Cur delivery system were evaluated in colorectal cancer cells and azoxymethane-dextran sodium (AOM-DSS) induced tumor models. sOKGM-PS-miR-31i/Cur delivery system were stable in the harsh gastrointestinal environment after rectal or oral administration; and were also mucoadhesive due to disulfide bond interactions with the colonic mucus layer, resulting in an enhanced drug retention and local bioavailability in the colon. Concomitantly, the released PS-miR-31i/Cur PSs from the microsphere was mucus-penetrating, efficiently passing through the colonic mucus layer, and allowed Cur and miR-31i specifically target to colon tumor cells with the guide of CD133 targeting peptides. Consequently, rectal delivery of sOKGM-PS-miR-31i/Cur microspheres suppressed tumor growth in an azoxymethane-dextran sodium sulfate (AOM-DSS)-induced tumor model. sOKGM-PS-miR-31i/Cur microspheres are effective rectal delivery system with combined advantages of mucoadhesive and mucus-penetrating properties, representing a potent and viable therapeutic approach for CRC.
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http://dx.doi.org/10.7150/thno.40318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069075PMC
April 2021

Kinetic modeling and analysis of dynamic bioluminescence imaging of substrates administered by intraperitoneal injection.

Quant Imaging Med Surg 2020 Feb;10(2):389-396

Engineering Research Center of Molecular and Neuro Imaging of Ministry of Education & School of Life Science and Technology, Xidian University, Xi'an 710071, China.

Background: Bioluminescence imaging (BLI) has been found to have diverse applications in the life sciences and medical research due to its ease of use and high sensitivity. From kinetics analysis, dynamic imaging studies have significant advantages for diagnosis when compared to traditional static imaging studies. This work focuses on modeling and quantitatively analyzing the dynamic data produced from the intraperitoneal (IP) injection of D-luciferin in longitudinal BLI, aiming to provide a powerful tool for monitoring the growth of tumors.

Methods: We constructed a three-compartment pharmacokinetic (PK) model and employed the standard Michaelis-Menten (M-M) kinetics to investigate the dynamic BLI data produced from the IP injection of D-luciferin. The 3 compartments were the plasma compartment, the non-specific compartment, and the specific compartment. The validity of this PK model was tested by the dynamic BLI data of MKN28M-luc xenograft mice, along with the published longitudinal dynamic BLI data of B16F10-luc xenograft mice.

Results: The R-squares between the simulated lines and the measurement were 1 and 0.99, respectively, for the mice data and the published data. In addition, the 2 kinetic macroparameters obtained reflected the rate of tumor growth . In particular, the values of macroparameters A showed a significant dependence on tumor surface area.

Conclusions: The proposed PK model may be an effective tool for use in drug development programs and for monitoring the response of tumors to treatment.
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http://dx.doi.org/10.21037/qims.2020.01.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063274PMC
February 2020

Risk of Serious Ventricular Arrhythmia in Users of Gastrointestinal Medications: A Retrospective Cohort Study in China.

Adv Ther 2020 04 7;37(4):1564-1578. Epub 2020 Mar 7.

Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

Introduction: Clinical data have demonstrated prolongation of the QTc interval associated with domperidone use. The risk of serious ventricular arrhythmias (SVA) in clinical practice in China has not been investigated.

Methods: The incidence of SVA and all-cause cardiac arrest associated with medications for gastrointestinal disorders in China was assessed in a retrospective cohort study using information from electronic medical record databases from the Xijing and Guangzhou general hospitals. Inpatients and outpatients with at least one prescription for domperidone, mosapride/itopride, metoclopramide, a proton pump inhibitor (PPI), or histamine H receptor antagonist were identified in the hospital databases from January 1, 2009 to December 31, 2014.

Results: The inpatient exposure cohorts included 66,282 inpatients at Xijing and 23,643 inpatients at Guangzhou hospitals. There were 67 cases of SVA and two cases of SVA at the respective hospitals during the study period. Three cases (all at Xijing) occurred in patients prescribed domperidone (incidence rate 2.9/100 person-years (PYs), 95% CI 0.9-9.0) compared to 1.3/100 PYs (95% CI 0.2-8.9) for mosapride/itopride and 5.6/100 PYs (95% CI 4.4-7.2) for PPIs. The hazard ratio adjusted for age, sex, and co-morbidities for SVA in patients prescribed domperidone compared to PPIs was 0.79 (95% CI 0.25-2.56). There were 44 cases of all-cause cardiac arrest at Xijing and 21 at Guangzhou hospital. Three patients had received domperidone and all had underlying cardiovascular diseases.

Conclusions: SVA and cardiac arrest are very rare events in patients prescribed medications for gastrointestinal disorders in China. We found no evidence that domperidone carried a higher risk of SVA compared to other gastrointestinal medications.
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http://dx.doi.org/10.1007/s12325-020-01271-8DOI Listing
April 2020

SOX13 promotes colorectal cancer metastasis by transactivating SNAI2 and c-MET.

Oncogene 2020 04 28;39(17):3522-3540. Epub 2020 Feb 28.

Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.

Metastasis is a major cause of high recurrence and poor survival of patients with colorectal cancer (CRC), although the mechanisms associated with this process remain poorly understood. In this study, we report a novel mechanism by which SOX13 promotes CRC metastasis by transactivating SNAI2 and c-MET. SOX13 overexpression was significantly correlated with more aggressive clinicopathological features of CRC and indicated poor prognosis in two independent cohorts of CRC patients (cohort I, n = 363; cohort II, n = 390). Overexpression of SOX13-promoted CRC migration, invasion, and metastasis, whereas SOX13 downregulation caused the opposite effects. Further mechanistic investigation identified SNAI2 and MET as important target genes of SOX13 using serial deletion and site-directed mutagenesis luciferase reporter and chromatin immunoprecipitation (ChIP) assays, as well as functional complementation analyses. In addition, SOX13 was shown to be a direct target of HGF/STAT3 signaling, and the c-MET inhibitor crizotinib blocked the HGF/STAT3/SOX13/c-MET axis, significantly inhibiting SOX13-mediated CRC migration, invasion and metastasis. Moreover, in clinical CRC tissues, SOX13 expression was positively correlated with the expression of SNAI2, c-MET, and HGF. CRC patients with positive coexpression of SOX13/SNAI2, SOX13/c-MET, or HGF/SOX13 exhibited a worse prognosis. In summary, SOX13 is a promising prognostic biomarker in patients with CRC, and blocking the HGF/STAT3/SOX13/c-MET axis with crizotinib could be a new therapeutic strategy to prevent SOX13-mediated CRC metastasis.
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http://dx.doi.org/10.1038/s41388-020-1233-4DOI Listing
April 2020