Comparison of patency rates and complications with or without antithrombotic therapy following portal vein stent placement after pancreatic surgery, a systematic review and meta-analysis.

BACKGROUND: Portal vein stent placement is used for portal vein stenosis. However, reports on post-pancreatic surgery cases are rare. Whether antithrombotic therapy should be administered remains controversial. In this paper, we reviewed current data to evaluate the influence of antithrombosis on stent patency after pancreatic surgery. MATERIALS AND METHODS: This systematic review and meta-analysis compared studies in which patients did or did not receive antithrombotic therapy after portal vein stent placement. We compared patency after stent placement and complication rate. RESULTS: There were 22 (n=207) studies in which patients received antithrombotic therapy and 8 (n=61) in which patients did not receive therapy. Antithrombotic agents, such as aspirin, clopidogrel, heparin, and warfarin, were used. The overall patency rates were similar between the groups (79.2% in the antithrombosis group vs. 88.0% in the non-antithrombosis group). Subgroup analyses included those for the etiology of stenosis, types of antithrombotic agents, acute or chronic stenosis, and causes of stent stenosis. None revealed a significant difference between the patency rates in the antithrombosis and non-antithrombosis groups. However, bleeding complications only occurred in patients who received antithrombotic therapy. CONCLUSION: There is no significant benefit of antithrombotic therapy after portal vein stent placement following pancreatic surgery. Antithrombotic therapy should be performed with caution because it may cause complications, such as bleeding.

Percutaneous transhepatic stenting for acute superior mesenteric vein stenosis after pancreaticoduodenectomy with portal vein reconstruction: A case report.

BACKGROUND: Percutaneous transhepatic stent placement has become a common strategy for the postoperative treatment of portal vein (PV)/superior mesenteric veins (SMV) stenosis/occlusion. It has been widely used after liver transplantation surgery; however, reports on stent placement for acute PV/SMV stenosis after pancreatic surgery within postoperative 3 d are rare. CASE SUMMARY: Herein, we reported a case of intestinal edema and SMV stenosis 2 d after pancreatic surgery. The patient was successfully treated using stent grafts. Although the stenosis resolved after stent placement, complications, including bleeding, pancreatic fistula, bile leakage, and infection, made the treatment highly challenging. The use of anticoagulants was adjusted multiple times to prevent venous thromboembolism and the risk of bleeding. After careful treatment, the patient stabilized, and stent placement effectively managed postoperative PV/SMV stenosis. CONCLUSION: Stent placement is effective and feasible for treating acute PV/SMV stenosis after pancreatic surgery even within postoperative 3 d.

M6A RNA methylation in biliary tract cancer: the function roles and potential therapeutic implications.

Biliary tract cancers (BTCs) are relatively rare malignancies with a poor prognosis. For advanced BTCs, the efficacy of current chemotherapeutic approaches is limited. Consequently, there is an urgent need to deepen our understanding of the molecular mechanisms underlying BTC tumorigenesis and development for the exploration of effective targeted therapies. N6-methyladenosine (m6A), the most abundant RNA modifications in eukaryotes, is found usually dysregulated and involved in tumorigenesis, progression, and drug resistance in tumors. Numerous studies have confirmed that aberrant m6A regulators function as either oncogenes or tumor suppressors in BTCs by the reversible regulation of RNA metabolism, including splicing, export, degradation and translation. In this review, we summarized the current roles of the m6A regulators and their functional impacts on RNA fate in BTCs. The improved understanding of m6A modification in BTCs also provides a reasonable outlook for the exploration of new diagnostic strategies and efficient therapeutic targets.

YTHDF2 promotes gallbladder cancer progression and gemcitabine resistance via m6A-dependent DAPK3 degradation.

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic RNA and involved in the carcinogenesis of various malignancies. However, the functions and mechanisms of m6A in gallbladder cancer (GBC) remain unclear. In this study, we investigated the role and underlying mechanism of the RNA-binding protein YT521-B homology domain-containing family protein 2 (YTHDF2), an m6A reader, in GBC. Herein, we detected that YTHDF2 was remarkably upregulated in GBC tissues compared to normal gallbladder tissues. Functionally, YTHDF2 overexpression promoted the proliferation, tumor growth, migration, and invasion of GBC cells while inhibiting the apoptosis in vitro and in vivo. Conversely, YTHDF2 knockdown induced opposite results. Mechanistically, we further investigated the underlying mechanism by integrating RNA immunoprecipitation sequencing (RIP-seq), m6A-modified RIP-seq, and RNA sequencing, which revealed that death-associated protein kinase 3 (DAPK3) is a direct target of YTHDF2. YTHDF2 binds to the 3'-UTR of DAPK3 mRNA and facilitates its degradation in an m6A-dependent manner. DAPK3 inhibition restores the tumor-suppressive phenotype induced by YTHDF2 deficiency. Moreover, the YTHDF2/DAPK3 axis induces the resistance of GBC cells to gemcitabine. In conclusion, we reveal the oncogenic role of YTHDF2 in GBC, demonstrating that YTHDF2 increases the mRNA degradation of the tumor suppressor DAPK3 in an m6A-dependent way, which promotes GBC progression and desensitizes GBC cells to gemcitabine. Our findings provide novel insights into potential therapeutic strategies for GBC.

Construction of a prognostic model for HCC based on ferroptosis-related lncRNAs expression and its potential to predict the response and irAEs of immunotherapy.

Background: Ferroptosis is an iron-dependent programmed cell death process, and studies have confirmed that it plays an important regulatory role in the occurrence and development of various malignancies including hepatocellular carcinoma (HCC). In addition, the role of abnormally expressed long non-coding RNAs (lncRNAs) in regulating and driving the occurrence and development of HCC has attracted more and more attention. However, there is still a lack of research on the role of ferroptosis-related lncRNAs in the prognosis prediction of HCC patients. Method: In this study, we used the Pearson test method to analyze the association between differentially expressed lncRNAs and ferroptosis-related genes in HCC and normal tissues obtained from The Cancer Genome Atlas (TCGA), and found 68 aberrantly expressed and prognosis-related ferroptosis-related lncRNAs. Based on this, we established an HCC prognostic model composed of 12 ferroptosis-related lncRNAs. In addition, HCC patients were divided into a high-risk group and a low-risk group according to the risk score of this 12 ferroptosis-related lncRNAs prognostic model. Gene enrichment analysis indicated that ferroptosis-related lncRNA-based expression signatures may regulate HCC immune microenvironment signaling pathways through ferroptosis, chemical carcinogenesis-reactive oxygen species, and NK cell-mediated cytotoxicity pathways. In addition, immune cell correlation analysis showed that there were significant differences in immune infiltrating cell subtypes, such as Th cells, macrophages, monocytes, and Treg cells between the two groups. In addition, the expression of multiple immune checkpoint molecules was found to be significantly increased in the high-risk group (eg, PD1, CTLA-4, CD86, etc.). Results: Our research provides a new method for predicting prognosis using a ferroptosis-related lncRNA expression signature prognostic model in hepatocellular carcinoma. And it provides new tools for predicting patient response and adverse effects of immunotherapy. Conclusion: In conclusion, ferroptosis-related lncRNA expression signatures can be used to construct a prognostic prediction model to predict the overall survival of HCC patients, and can be used as an independent influencing factor for prognosis. Further analysis showed that ferroptosis-related lncRNAs may affect the efficacy of immunotherapy in patients with HCC by altering the tumor microenvironment, so this model may serve as a new indicator of the response and irAEs of HCC to immunotherapy.

Biliary Neuroendocrine Neoplasms: Analysis of Prognostic Factors and Development and Validation of a Nomogram.

BACKGROUND: For this study, we explored the prognostic profiles of biliary neuroendocrine neoplasms (NENs) patients and identified factors related to prognosis. Further, we developed and validated an effective nomogram to predict the overall survival (OS) of individual patients with biliary NENs. METHODS: We included a total of 446 biliary NENs patients from the SEER database. We used Kaplan-Meier curves to determine survival time. We employed univariate and multivariate Cox analyses to estimate hazard ratios to identify prognostic factors. We constructed a predictive nomogram based on the results of the multivariate analyses. In addition, we included 28 biliary NENs cases from our center as an external validation cohort. RESULTS: The median survival time of biliary NENs from the SEER database was 31 months, and the value of gallbladder NENs (23 months) was significantly shorter than that of the bile duct (45 months) and ampulla of Vater (33.5 months, p=0.023). Multivariate Cox analyses indicated that age, tumor size, pathological classification, SEER stage, and surgery were independent variables associated with survival. The constructed prognostic nomogram demonstrated good calibration and discrimination C-index values of 0.783 and 0.795 in the training and validation dataset, respectively. CONCLUSION: Age, tumor size, pathological classification, SEER stage, and surgery were predictors for the survival of biliary NENs. We developed a nomogram that could determine the 3-year and 5-year OS rates. Through validation of our central database, the novel nomogram is a useful tool for clinicians in estimating individual survival among biliary NENs patients.

Dynamic change of serum CA19-9 levels in benign and malignant patients with obstructive jaundice after biliary drainage and new correction formulas.

BACKGROUND: CA19-9 is one of the most widely used tumor markers in biliary-pancreatic diseases. The measured value may not factually reflect the genuine CA19-9 level secreted by tumor, which affected by biliary obstruction. There is an urgent need of developing a correction formula of CA19-9 in biliary obstructive patients to guide clinical practice and avoid making improper clinical decision. METHODS: Clinical characteristics were collected among patients undergoing biliary drainage in our hospital between January 2014 and January 2019. By comparing the malignant and benign patients statistically, dynamic change trend of CA19-9 levels after biliary drainage was obtained. The correction formulas of CA19-9 were generated by means of linear regression. RESULTS: 121 patients, including 102 malignant and 19 benign patients, were enrolled in this study. The baseline CA19-9 level of malignant patients is much higher than that of benign patients. Total bilirubin (TB) level was found to be not related with CA19-9 value (p = 0.109). The drop proportion of the average CA19-9 level in the malignant patients (39.2%, IQR -18.4-78.6%) was much lower than that in the benign patients (75.7%, IQR 58.1-86.6%) (p = 0.014). The correction formula, CA19-9True = 0.63 × CA19-9Measured - 20.3 (R2 = 0.693, p<0.001), was generated based on the linear relation between CA19-9 after drainage and CA19-9 before drainage in malignant patients, which had similar diagnostic value with true CA19-9 value. CONCLUSIONS: Quantitative correction formulas of CA19-9 considering the effect of biliary decompression was first proposed in this study, aiming to provide a more accurate CA19-9 level to make more accurate clinical decision and avoid making improper therapeutic schedule.

Biliary diversion increases resting energy expenditure leading to decreased blood glucose level in mice with type 2 diabetes.

AIMS/INTRODUCTION: Type 2 diabetes mellitus is a group of metabolism abnormalities in carbohydrates and energy. Our aim was to investigate resting energy expenditure (REE) and blood glucose changes after biliary diversion in mice with diabetes. MATERIALS AND METHODS: Male mice with diabetes were randomly divided into biliary diversion and sham groups. REE was detected by indirect calorimetry, the levels of fasting blood glucose, total bile acids and triiodothyronine were analyzed. After mice were killed, the weight amount of brown adipose tissue (BAT) and gastrocnemius was measured, and the expression level of G protein-coupled bile acid receptor and type 2 iodothyronine deiodinase in BAT and gastrocnemius were examined. RESULTS: The two groups of mice were pair-fed, the bodyweights (P < 0.001) and the fasting blood glucose level (P < 0.001) in the biliary diversion group significantly decreased 24 weeks after surgery. The intraperitoneal glucose tolerance test (P = 0.035) and oral glucose tolerance test (P = 0.027) showed improvement in glucose tolerance after surgery. The REE level significantly increased 24 weeks after surgery (P = 0.005), the levels of total bile acids (P = 0.014) and triiodothyronine (P < 0.001) increased at the 24th postoperative week. The weight ratio of BAT (P = 0.038) and gastrocnemius (P = 0.026) in the biliary diversion group were higher than that in the sham group. The expression of G protein-coupled bile acid receptor in BAT (P < 0.001) and gastrocnemius (P = 0.003) were upregulated after surgery, and the type 2 iodothyronine deiodinase expression also increased in BAT (P = 0.015) and gastrocnemius (P = 0.015). CONCLUSIONS: The REE level increased and the glucose metabolism improved in mice with diabetes after biliary diversion.

High-level expression and characterization of the thermostable leucine aminopeptidase Thelap from the thermophilic fungus Thermomyces lanuginosus in Aspergillus niger and its application in soy protein hydrolysis.

Leucine aminopeptidase (LAP), an exopeptidase that releases amino acid residues, especially leucine, from the N-terminus of polypeptides, is often applied to debitter protein hydrolysate in the food industry. However, there are no thermostable and high activity enzymes that can be used in the food industry. In this study, we obtained the highly active and thermostable leucine aminopeptidases screened from the thermophilic fungi Thermomyces lanuginosus, Talaromyces thermophilus, and Malbranchea cinnamomea. The activity of the recombinant leucine aminopeptidase Thelap was significantly increased to 2771.5 U/mL, as mediated by the CRISPR/Cas9 tool. The recombinant Thelap was easily purified from fermentation broth by Ni-affinity chromatography, and the specific activity of the purified Thelap was increased to 7449.6 U/mg. The recombinant Thelap showed optimal activity at pH 8.5 and 75 °C and remained above 70% of the maximum activity over a wide temperature range (30-80 °C). With regard to temperature stability, Thelap retained more than 90% activity when it was incubated at 65-75 °C for 2 h. K+ and Co2+ increased the enzyme activity of the recombinant Thelap, while Ba2+, Mn2+, Ni2+, Ca2+, Mg2+ and SDS inhibited its enzyme activity, and the inhibition capacity of Mg2+ was the weakest. Upon application in soy protein hydrolysis, Thelap could significantly increase the degree of hydrolysis and remove more hydrophobic amino acids from the N-terminal region of the polypeptide to decrease the bitterness.

Surgical management of Zollinger-Ellison syndrome: Classical considerations and current controversies.

Zollinger-Ellison syndrome (ZES) is characterized by gastric acid hypersecretion causing severe recurrent acid-related peptic disease. Excessive secretion of gastrin can now be effectively controlled with powerful proton pump inhibitors, but surgical management to control gastrinoma itself remains controversial. Based on a thorough literature review, we design a surgical algorithm for ZES and list some significant consensus findings and recommendations: (1) For sporadic ZES, surgery should be routinely undertaken as early as possible not only for patients with a precisely localized diagnosis but also for those with negative imaging findings. The surgical approach for sporadic ZES depends on the lesion location (including the duodenum, pancreas, lymph nodes, hepatobiliary tract, stomach, and some extremely rare sites such as the ovaries, heart, omentum, and jejunum). Intraoperative liver exploration and lymphadenectomy should be routinely performed; (2) For multiple endocrine neoplasia type 1-related ZES (MEN1/ZES), surgery should not be performed routinely except for lesions > 2 cm. An attempt to perform radical resection (pancreaticoduodenectomy followed by lymphadenectomy) can be made. The ameliorating effect of parathyroid surgery should be considered, and parathyroidectomy should be performed first before any abdominal surgery for ZES; and (3) For hepatic metastatic disease, hepatic resection should be routinely performed. Currently, liver transplantation is still considered an investigational therapeutic approach for ZES. Well-designed prospective studies are desperately needed to further verify and modify the current considerations.

A novel prognostic marker and immunogenic membrane antigen: prohibitin (PHB) in pancreatic cancer.

BACKGROUND: Previous study, using immunoblotting with IgG and membrane proteins, identified prohibitin (PHB) as a potential immunogenic membrane antigen. Now, investigate PHB expression and biological functions in pancreatic cancer. METHODS: PHB expression was analysed in PDAC cell lines, normal pancreas tissues, cancer tissues, PDAC patient sera and healthy volunteer sera using QRT-PCR, Western blotting, IHC, and ELISA, and a survival analysis and a COX regression analysis were performed. Low and high PHB expression levels were accomplished using RNA interference technology and gene transfer techniques. Cell proliferation, migration, and invasion, apoptosis-related proteins were assessed 48 h after transfection. RESULTS: PHB was generally expressed in the 8 tested PDAC cell lines. PHB was significantly increased in PDAC tissues and negatively correlated with overall survival (p < 0.01). PHB was an independent prognostic factor in PDAC (p < 0.01). PHB was increased in PDAC patient sera (p < 0.01). siRNA-PHB decreased cell growth, migration and invasion. However, PHB overexpression resulted in the opposite effects. Western blotting and Flow cytometric analysis revealed apoptosis inhibition in siRNA-PHB PDAC cells. CONCLUSIONS: PHB plays a key role in modulating the malignant phenotype and apoptosis induction, which may be a novel prognostic predictor and a candidate for targeted therapy against PDAC.

Review of the possible association between thyroid and breast carcinoma.

BACKGROUND: Thyroid and breast cancer are two of the malignant diseases with highest incidence in females. Based on clinical experience, breast and thyroid cancer often occur metachronously or synchronously. Therefore, thyroid and breast cancer might share some common etiological factors. The relationship between these diseases has attracted substantial attention, and because these two glands are both regulated by the hypothalamic-pituitary axis, such a relationship is not surprising. A study of this relationship will be useful for obtaining a better understanding of the mechanism by which these two malignancies co-occur. MAIN BODY: This study reviewed the progress in research on the roles of iodine intake, folate metabolism, obesity, gonadal hormones, and thyroid hormone in thyroid and breast cancer. These studies evaluating the etiological roles of these factors in linking breast and thyroid cancer might also improve our understanding and identify new therapeutic approaches, such as sodium/iodide symporter-mediated radioiodine therapy and thyroid-stimulating hormone receptor antagonists, for breast cancer. In addition, some specific treatments for each cancer, such as radiotherapy for breast cancer or radioactive iodine therapy for thyroid cancer, might be risk factors for secondary malignances, including breast and thyroid cancer. CONCLUSIONS: Studies of the precise relationship between the co-occurrence of breast and thyroid cancer will certainly improve our understanding of the biological behaviors of these two malignancies and direct evidence-based clinical practice.

E­cadherin is downregulated by microenvironmental changes in pancreatic cancer and induces EMT.

The aim of the present study was to research the effect of microenvironmental change on epithelial­mesenchymal transition (EMT) in pancreatic cancer cells and to determine the correlation between E­cadherin expression and the prognosis of pancreatic cancer patients. We established hypoxic, serum­deficient and TGF­ß­induced microenvironment models of pancreatic cancer cells and studied the changes in the mRNA and protein expression of EMT­related molecules, E­cadherin and vimentin, using western blot analysis and real­time PCR. Furthermore, immunohistochemistry was used to investigate E­cadherin expression in pancreatic cancer tissues, and survival analysis and COX regression analysis were conducted. In pancreatic cancer cells under hypoxic, serum­starved and TGF­ß­induced microenvironments, E­cadherin protein and mRNA levels were significantly decreased (P<0.05), while vimentin protein and mRNA expression levels were significantly increased (P<0.05). The results of immunohistochemistry showed that the protein level of E­cadherin in pancreatic cancer tissues was positively correlated with overall survival (P<0.01). The results of Cox regression analysis showed that E­cadherin was an independent prognostic factor in pancreatic cancer. In conclusion, E­cadherin expression was significantly decreased by microenvironment changes, and this decrease induced EMT in pancreatic cancer cells. E­cadherin is an independent prognostic marker in pancreatic cancer patients.

Methylseleninic Acid Provided at Nutritional Selenium Levels Inhibits Angiogenesis by Down-regulating Integrin ß3 Signaling.

Targeting angiogenesis has emerged as a promising strategy for cancer treatment. Methylseleninic acid (MSA) is a metabolite of selenium (Se) in animal cells that exhibits anti-oxidative and anti-cancer activities at levels exceeding Se nutritional requirements. However, it remains unclear whether MSA exerts its effects on cancer prevention by influencing angiogenesis within Se nutritional levels. Herein, we demonstrate that MSA inhibited angiogenesis at 2 µM, which falls in the range of moderate Se nutritional status. We found that MSA treatments at 2 µM increased cell adherence, while inhibiting cell migration and tube formation of HUVECs in vitro. Moreover, MSA effectively inhibited the sprouts of mouse aortic rings and neoangiogenesis in chick embryo chorioallantoic membrane. We also found that MSA down-regulated integrin ß3 at the levels of mRNA and protein, and disrupted clustering of integrin ß3 on the cell surface. Additionally, results showed that MSA inhibited the phosphorylation of AKT, IκBα, and NFκB. Overall, our results suggest that exogenous MSA inhibited angiogenesis at nutritional Se levels not only by down-regulating the expression of integrin ß3 but also by disorganizing the clustering of integrin ß3, which further inhibited the phosphorylation involving AKT, IκBα, NFκB. These findings provide novel mechanistic insight into the function of MSA for regulating angiogenesis and suggest that MSA could be a potential candidate or adjuvant for anti-tumor therapy in clinical settings.