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Evaluation of characteristics of left-sided colorectal perfusion in elderly patients by angiography

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (24)

BACKGROUND Handling of the inferior mesenteric artery (IMA) and maintaining anastomotic perfusion are important in radical resection of left-sided colorectal cancer. However, the branching of this artery and the drainage patterns of this vein vary among individuals, and the characteristics and perfusion region of this artery in elderly patients remain unclear. AIM To evaluate the characteristics and perfusion region of the IMA in elderly patients using angiography. METHODS We enrolled 154 patients (> 65 years old) who underwent digital subtraction angiography of the IMA. The characteristics, bifurcation, and distribution of the IMA and termination of the anastomotic perfusion of the left colon and rectum were examined using digital subtraction angiography. Collateral arterial arches and the IMA hemoperfusion region were also recorded. Perfusion regions were cross-referenced with clinical and anatomical features by the univariate analysis. RESULTS Of 154 patients, 25 (16.2%) had IMA lesions. The left colic artery arose independently from the IMA in 44.2% of patients, shared a trunk with the sigmoid artery in 35.1%, shared an opening with the sigmoid and superior rectal arteries in 16.9%, and was absent in 5.1%. The IMA perfusion region stopped at the splenic flexure in 50 (32.5%) patients. The collateral circulation existed in the colonic perfusion region, including the marginal artery (Drummond's artery), the ascending branch of the left colonic artery to supply the transverse colon, and the arc of Riolan with a frequency of 100%, 22.7%, and 1.9%, respectively. The IMA perfusion region was independently associated with the comorbidity of atherosclerosis, IMA atherosclerotic lesion, branching pattern, collateral circulation, and marginal artery integrity. CONCLUSION The IMA and its branches are prone to arteriosclerosis, and IMA perfusion may be interrupted at the splenic flexure in elderly patients. The applicability and precision of preoperative angiography for evaluating the IMA branching and perfusion patterns could facilitate geriatric laparoscopic left-sided colorectal cancer surgery with suspicion of poor IMA perfusion.

Transjugular intrahepatic portosystemic shunt for pyrrolizidine alkaloid-related hepatic sinusoidal obstruction syndrome

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (24)

BACKGROUND Treatments for hepatic sinusoidal obstruction syndrome (HSOS) are limited. AIM To evaluate transjugular intrahepatic portosystemic shunting (TIPS) as a treatment for pyrrolidine alkaloid-related HSOS (PA-HSOS). METHODS This retrospective analysis included patients with PA-HSOS admitted to the First Affiliated Hospital of the University of Science and Technology of China (June 2015 to January 2019). Baseline clinical characteristics and follow-up data were extracted from the medical records. All patients included in this study experienced failure of initial therapy. Patients were divided into the TIPS and conservative treatment groups according to the therapy they received. Liver function, maximal ascites depth, imaging characteristics, pathology findings, and survival were compared between groups. RESULTS The TIPS group included 37 patients (28 males), and the conservative treatment group included 17 patients (11 males). Baseline characteristics were similar between groups. There were two deaths in the TIPS group and seven deaths in the conservative treatment group during follow-up (3-48 mo). The 3-, 6-, 12- and 24-mo survival rates were 94.6%, 94.6%, 94.6% and 94.6%, respectively, in the TIPS group and 70.6%, 57.8%, 57.8% and 57.8%, respectively, in the conservative treatment group. Kaplan-Meier analysis revealed significantly longer survival for the TIPS group than for the conservative treatment group (P= 0.001). Compared with the pre-treatment value, maximal ascites depth was significantly lower at 1 wk, 2 wk, 1 mo, and 3 mo for the TIPS group (allP< 0.05) but not in the conservative treatment group. Contrast-enhanced computed tomography demonstrated the disappearance of patchy liver enhancement after TIPS. Pathology showed that liver congestion and hepatocyte swelling improved with time after TIPS placement. CONCLUSION TIPS may achieve better outcomes than conventional symptomatic treatment in patients with PA-HSOS.

Hepatoprotective effects ofHovenia dulcisseeds against alcoholic liver injury and related mechanisms investigatedvianetwork pharmacology

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (24)

BACKGROUND Alcoholic liver disease (ALD) is a worldwide health problem, and natural products have been shown to improve ALD due to their antioxidant activities. Some parts ofHovenia dulcis(H. dulcis), such as roots, peduncles, and stems, provide health benefits. Nevertheless, the effects and mechanisms ofH. dulcisseeds on ALD have not yet been fully elucidated. AIM To determineH. dulcisantioxidant activity, evaluate its effects against ALD, and investigate the related mechanismsvianetwork pharmacology. METHODS The antioxidant activity ofH. dulcisseed was determined by both ferric-reducing antioxidant power and trolox equivalent antioxidant capacity assays. The total phenolic and flavonoid contents were determined by Folin-Ciocalteu method and aluminum chloride colorimetry, respectively, and polysaccharide was determined by phenol-sulfuric acid method. The effects ofH. dulcisseeds against alcoholic liver injury were investigated in mice with water extract pretreatment for 7 days followed by alcohol administration. Moreover, the mechanisms of action were explored with network pharmacology. RESULTS The results showed thatH. dulcisseeds possessed strong antioxidant activity (245.11 +/- 10.17 mu mol Fe2+/g by ferric-reducing antioxidant power and 284.35 +/- 23.57 mu mol TE/g by trolox equivalent antioxidant capacity) and contained remarkable phenols and flavonoids, as well as a few polysaccharides.H. dulcisseeds attenuated alcohol-induced oxidative liver injury, showing reduced serum alanine and aspartate aminotransferases, alkaline phosphatase, and triglyceride, elevated hepatic glutathione, increased activities of superoxide dismutase and catalase, and reduced malondialdehyde and hepatic triglyceride. The results of network pharmacology analysis indicated that kaempferol, stigmasterol, and naringenin were the main bioactive compounds inH. dulcisseeds and that modulation of oxidative stress, inflammation, gut-derived products, and apoptosis were underlying mechanisms of the protective effects ofH. dulcisseeds on ALD. CONCLUSION The results of this study demonstrate thatH. dulcisseeds could be a good natural antioxidant source with protective effects on oxidative diseases such as ALD.

Recent progress in pulsed electric field ablation for liver cancer

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (24)

The number of liver cancer patients is likely to continue to increase in the coming decades due to the aging of the population and changing risk factors. Traditional treatments cannot meet the needs of all patients. New treatment methods evolved from pulsed electric field ablation are expected to lead to breakthroughs in the treatment of liver cancer. This paper reviews the safety and efficacy of irreversible electroporation in clinical studies, the methods to detect and evaluate its ablation effect, the improvements in equipment and its antitumor effect, and animal and clinical trials on electrochemotherapy. We also summarize studies on the most novel nanosecond pulsed electric field ablation techniquesin vitroandin vivo. These research results are certain to promote the progress of pulsed electric field in the treatment of liver cancer.

Long noncoding RNAs in gastric cancer: From molecular dissection to clinical application

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (24)

Long noncoding RNAs (lncRNAs) are important regulators of cell processes that are usually dysregulated in gastric cancer (GC). Based on their high specificity and ease of detection in tissues and body fluids, increasing attention has spurred the study of the roles of lncRNAs in GC patients. Thus, it is necessary to elucidate the molecular mechanisms and further explore the clinical applications of lncRNAs in GC. In this review, we summarize current knowledge to examine dysregulated lncRNAs in GC and their underlying molecular mechanisms and activities in GC, which involve microRNA sponging, mRNA stability, genetic variants, alternative splicing, transcription factor binding, and epigenetic modification. More significantly, the potential of lncRNAs as prognostic, circulating, and drug-resistant biomarkers for GC is also described. This review highlights the method of dissecting molecular mechanisms to explore the clinical application of lncRNAs in GC. Overall, this review offers assistance in using lncRNAs as novel candidates for molecular mechanisms and for the identification of revolutionary biomarkers for GC.

Extended lymphadenectomy in hilar cholangiocarcinoma: What it will bring?

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (24)

Lymph node dissection is always a hot issue in radical resection of hilar cholangiocarcinoma (HCCA). There are still controversies regarding whether some lymph nodes should be dissected, of which the para-aortic lymph nodes are the most controversial. This review synthesized findings in the literature using the PubMed database of articles in the English language published between 1990 and 2019 on the effectiveness of extended lymphadenectomy including para-aortic lymph nodes dissection in radical resection of HCCA. Hepatobiliary surgeons have basically achieved a consensus that enough lymph nodes should be obtained to accurately stage HCCA. Only a very small number of studies have focused on the effectiveness of extended lymphadenectomy including para-aortic nodes dissection on HCCA. They reported that extended lymphadenectomy can bring some survival benefits for patients with potential para-aortic lymph node metastasis and more lymph nodes can be obtained to make the patient's tumor staging more accurate without increasing the related complications. Extended lymphadenectomy should not be adopted for HCCA patients with intraoperatively confirmed distant lymph node metastases. For these patients, radical resection combined with postoperative adjuvant chemotherapy seems to be a better choice. A prospective, multicenter, randomized, controlled clinical study of regional lymphotomy and extended lymphadenectomy in HCCA should be conducted to guide clinical practice. A standardized extended lymphadenectomy may help to more accurately stage HCCA. Future studies are required to further assess whether extended lymphadenectomy can improve long-term survival in negative celiac, superior mesenteric, and para-aortic lymph node diseases.

Type I and type IIHelicobacter pyloriinfection status and their impact on gastrin and pepsinogen level in a gastric cancer prevalent area

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (25)

BACKGROUND Type IHelicobacter pylori(H. pylori) infection causes severe gastric inflammation and is a predisposing factor for gastric carcinogenesis. However, its infection status in stepwise gastric disease progression in this gastric cancer prevalent area has not been evaluated; it is also not known its impact on commonly used epidemiological gastric cancer risk markers such as gastrin-17 (G-17) and pepsinogens (PGs) during clinical practice. AIM To explore the prevalence of type I and type IIH. pyloriinfection status and their impact on G-17 and PG levels in clinical practice. METHODS Thirty-five hundred and seventy-two hospital admitted patients with upper gastrointestinal symptoms were examined, and 523 patients were enrolled in this study.H. pyloriinfection was confirmed by both(13)C-urea breath test and serological assay. Patients were divided into non-atrophic gastritis (NAG), non-atrophic gastritis with erosion (NAGE), chronic atrophic gastritis (CAG), peptic ulcers (PU) and gastric cancer (GC) groups. Their serological G-17, PG I and PG II values and PG I/PG II ratio were also measured. RESULTS A totalH. pyloriinfection rate of 3572 examined patients was 75.9%, the infection rate of 523 enrolled patients was 76.9%, among which type IH. pyloriinfection accounted for 72.4% (291/402) and type II was 27.6%; 88.4% of GC patients wereH. pyloripositive, and 84.2% of them were type I infection, only 11.6% of GC patients wereH. pylorinegative. Infection rates of type IH. pyloriin NAG, NAGE, CAG, PU and GC groups were 67.9%, 62.7%, 79.7%, 77.6% and 84.2%, respectively.H. pyloriinfection resulted in significantly higher G-17 and PG II values and decreased PG I/PG II ratio. Both types ofH. pyloriinduced higher G-17 level, but type I strain infection resulted in an increased PG II level and decreased PG I/PG II ratio in NAG, NAGE and CAG groups over uninfected controls. Overall PG I levels showed no difference among all disease groups and in the presence or absence ofH. pylori;in stratified analysis, its level was increased in GC and PU patients inH. pyloriand type IH. pylori-positive groups. CONCLUSION Type IH. pyloriinfection is the major form of infection in this geographic region, and a very low percentage (11.6%) of GC patients are not infected byH. pylori. Both types ofH. pyloriinduce an increase in G-17 level, while type IH. pyloriis the major strain that affects PG I and PG IIs level and PG I/PG II ratio in stepwise chronic gastric disease. The data provide insights intoH. pyloriinfection status and indicate the necessity and urgency for bacteria eradication and disease prevention in clinical practice.

Multiphase convolutional dense network for the classification of focal liver lesions on dynamic contrast-enhanced computed tomography

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (25)

BACKGROUND The accurate classification of focal liver lesions (FLLs) is essential to properly guide treatment options and predict prognosis. Dynamic contrast-enhanced computed tomography (DCE-CT) is still the cornerstone in the exact classification of FLLs due to its noninvasive nature, high scanning speed, and high-density resolution. Since their recent development, convolutional neural network-based deep learning techniques has been recognized to have high potential for image recognition tasks. AIM To develop and evaluate an automated multiphase convolutional dense network (MP-CDN) to classify FLLs on multiphase CT. METHODS A total of 517 FLLs scanned on a 320-detector CT scanner using a four-phase DCE-CT imaging protocol (including precontrast phase, arterial phase, portal venous phase, and delayed phase) from 2012 to 2017 were retrospectively enrolled. FLLs were classified into four categories: Category A, hepatocellular carcinoma (HCC); category B, liver metastases; category C, benign non-inflammatory FLLs including hemangiomas, focal nodular hyperplasias and adenomas; and category D, hepatic abscesses. Each category was split into a training set and test set in an approximate 8:2 ratio. An MP-CDN classifier with a sequential input of the four-phase CT images was developed to automatically classify FLLs. The classification performance of the model was evaluated on the test set; the accuracy and specificity were calculated from the confusion matrix, and the area under the receiver operating characteristic curve (AUC) was calculated from the SoftMax probability outputted from the last layer of the MP-CDN. RESULTS A total of 410 FLLs were used for training and 107 FLLs were used for testing. The mean classification accuracy of the test set was 81.3% (87/107). The accuracy/specificity of distinguishing each category from the others were 0.916/0.964, 0.925/0.905, 0.860/0.918, and 0.925/0.963 for HCC, metastases, benign non-inflammatory FLLs, and abscesses on the test set, respectively. The AUC (95% confidence interval) for differentiating each category from the others was 0.92 (0.837-0.992), 0.99 (0.967-1.00), 0.88 (0.795-0.955) and 0.96 (0.914-0.996) for HCC, metastases, benign non-inflammatory FLLs, and abscesses on the test set, respectively. CONCLUSION MP-CDN accurately classified FLLs detected on four-phase CT as HCC, metastases, benign non-inflammatory FLLs and hepatic abscesses and may assist radiologists in identifying the different types of FLLs.

Functionality is not an independent prognostic factor for pancreatic neuroendocrine tumors

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (25)

BACKGROUND Pancreatic neuroendocrine neoplasms (pNENs) that produce hormones leading to symptoms are classified as functional tumors, while others are classified as nonfunctional tumors. The traditional view is that functionality is a factor that affects the prognosis of pNEN patients. However, as the sample sizes of studies have increased, researches in recent years have proposed new viewpoints. AIM To assess whether functionality is an independent factor for predicting the prognosis of pNEN patients. METHODS From January 2004 to December 2016, data of patients who underwent surgery at the primary site for the treatment of pNENs from the Surveillance, Epidemiology, and End Results (SEER) database and West China Hospital database were retrospectively analyzed. RESULTS Contemporaneous data from the two databases were analyzed separately as two cohorts and then merged as the third cohort to create a large sample that was suitable for multivariate analysis. From the SEER database, age (P= 0.006) and T stage (P< 0.001) were independent risk factors affecting the survival. From the West China Hospital database, independent prognostic factors were age (P= 0.034), sex (P= 0.032), and grade (P= 0.039). The result of the cohort consisting of the combined populations from the two databases showed that race (P= 0.015), age (P= 0.002), sex (P= 0.032) and T stage (P< 0.001) were independent prognostic factors. In the West China Hospital database and in the total population, nonfunctional pNETs and other functional pNETs tended to have poorer prognoses than insulinoma. However, functionality was not associated with the survival time of patients with pNETs in the multivariate analysis. CONCLUSION Functionality is not associated with prognosis. Race, age, sex, and T stage are independent factors for predicting the survival of patients with pNETs.

Predictors of irreversible intestinal resection in patients with acute mesenteric venous thrombosis

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (25)

BACKGROUND Acute mesenteric venous thrombosis (AMVT) can cause a poor prognosis. Prompt transcatheter thrombolysis (TT) can achieve early mesenteric revascularization. However, irreversible intestinal ischemia still occurs and the mechanism is still unclear. AIM To evaluate the clinical outcomes of and to identify predictive factors for irreversible intestinal ischemia requiring surgical resection in AMVT patients treated by TT. METHODS The records of consecutive patients with AMVT treated by TT from January 2010 to October 2017 were retrospectively analyzed. We compared patients who required resection of irreversible intestinal ischemia to patients who did not require. RESULTS Among 58 patients, prompt TT was carried out 28.5 h after admission. A total of 42 (72.4%) patients underwent arteriovenous combined thrombolysis, and 16 (27.6%) underwent arterial thrombolysis alone. The overall 30-d mortality rate was 8.6%. Irreversible intestinal ischemia was indicated in 32 (55.2%) patients, who had a higher 30-d mortality and a longer in-hospital stay than patients without resection. The significant independent predictors of irreversible intestinal ischemia were Acute Physiology and Chronic Health Evaluation (APACHE) II score (odds ratio = 2.368, 95% confidence interval: 1.047-5.357,P= 0.038) and leukocytosis (odds ratio = 2.058, 95% confidence interval: 1.085-3.903,P= 0.027). Using the receiver operating characteristic curve, the cutoff values of the APACHE II score and leukocytosis for predicting the onset of irreversible intestinal ischemia were calculated to be 8.5 and 12 x 10(9)/L, respectively. CONCLUSION Prompt TT could achieve a favorable outcome in AMVT patients. High APACHE II score and leukocytosis can significantly predict the occurrence of irreversible intestinal ischemia. Therefore, close monitoring of these factors may help with the early identification of patients with irreversible intestinal ischemia, in whom ultimately surgical resection is required, before the initiation of TT.

Retrievable puncture anchor traction method for endoscopic ultrasound-guided gastroenterostomy: A porcine study

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (25)

BACKGROUND Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) is an alternative method for the surgical treatment of gastric outlet obstruction, but it is regarded as a challenging technique for endoscopists as the bowel is highly mobile and can tent away. Thus, the technique requires superb skill. In order to improve EUS-GE, we have developed a retrievable puncture anchor traction (RPAT) device for EUS-GE to address the issue of bowel tenting. AIM To evaluate the feasibility of RPAT-assisted EUS-GE using an animal model. METHODS Six Bama mini pigs each weighing between 15 and 20 kg underwent the RPAT-assisted EUS-GE procedure. Care was taken to ensure that the animals experienced minimal pain and discomfort. Two days prior to the procedure the animals were limited to a liquid diet. No oral intake was allowed on the day before the procedure. A fully covered metal stent was placed between the stomach and the intestine using the RPAT-assisted EUS-GE method. Infection in the animals was determined. Four weeks after the procedure, a standard gastroscope was inserted into the pig's intestine through a previously created fistula in order to check the status of the stents under anesthesia. The pig was euthanized after examination. RESULTS The RPAT-assisted EUS-GE method allowed placement of the stents with no complications in all six animals. All the pigs tolerated a regular diet within hours of the procedure. The animals were monitored for four weeks after the RPAT-assisted EUS-GE, during which time all of the animals exhibited normal eating behavior and no signs of infection were observed. Endoscopic imaging performed four weeks after the RPAT-assisted EUS-GE showed that the stents remained patent and stable in all the animals. No tissue overgrowth or ingrowth was observed in any case. Each animal had a mature fistula, and the stents were removed without significant bleeding. Autopsies of all six pigs revealed complete adhesion between the intestine and the stomach wall. CONCLUSION The RPAT method helps reduce mobility of the bowel. Therefore, the RPAT-assisted EUS-GE method is a minimally invasive treatment modality.

TBL1XR1 induces cell proliferation and inhibit cell apoptosis by the PI3K/AKT pathway in pancreatic ductal adenocarcinoma

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (25)

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors. Identification of diagnostic and therapeutic biomarkers for PDAC is urgently needed. Transducin (beta)-like 1 X-linked receptor 1 (TBL1XR1) has been linked to the progression of various human cancers. Nevertheless, the function and role of TBL1XR1 in pancreatic cancers are unclear. AIM To elucidate the function and potential mechanism of TBL1XR1 in the development of PDAC. METHODS Ninety patients with histologically-confirmed PDAC were included in this study. PDAC tumor samples and cell lines were used to determine the expression of TBL1XR1. CCK-8 assays and colony formation assays were carried out to assess PDAC cell viability. Flow cytometry was performed to measure the changes in the cell cycle and cell apoptosis. Changes in related protein expression were measured by western blot analysis. Animal analysis was conducted to confirm the impact of TBL1XR1in vivo. RESULTS Patients with TBL1XR1-positive tumors had worse overall survival than those with TBL1XR1-negative tumors. Moreover, we found that TBL1XR1 strongly promoted PDAC cell proliferation and inhibited PDAC cell apoptosis. Moreover, knockdown of TBL1XR1 induced G0/G1 phase arrest.In vivoanimal studies confirmed that TBL1XR1 accelerated tumor cell growth. The results of western blot analysis showed that TBL1XR1 might play a key role in regulating PDAC cell proliferation and apoptosisviathe PI3K/AKT pathway. CONCLUSION TBL1XR1 promoted PDAC cell progression and might be an effective diagnostic and therapeutic marker for pancreatic cancer.

Development of innovative tools for investigation of nutrient-gut interaction

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (25)

The gastrointestinal tract is the key interface between the ingesta and the human body. There is wide recognition that the gastrointestinal response to nutrients or bioactive compounds, particularly the secretion of numerous hormones, is critical to the regulation of appetite, body weight and blood glucose. This concept has led to an increasing focus on "gut-based" strategies for the management of metabolic disorders, including type 2 diabetes and obesity. Understanding the underlying mechanisms and downstream effects of nutrient-gut interactions is fundamental to effective translation of this knowledge to clinical practice. To this end, an array of research tools and platforms have been developed to better understand the mechanisms of gut hormone secretion from enteroendocrine cells. This review discusses the evolution ofin vitroandin vivomodels and the integration of innovative techniques that will ultimately enable the development of novel therapies for metabolic diseases.

Chinese expert consensus and practice guideline of totally implantable access port for digestive tract carcinomas

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (25)

Totally implantable access port is a fully implantable drug delivery system that is implanted subcutaneously and can be retained for a long time. Advantages of ports include a simple nursing process, low risk of infection and embolism, and high patient comfort. In order to promote the standardized application of ports in the treatment of digestive tract tumors and reduce port-related complications, the Chinese Research Hospital Association Digestive Tumor Committee, the Chinese Association of Upper Gastrointestinal Surgeons, the Chinese Gastric Cancer Association, and the Gastrointestinal Surgical Group of Chinese Surgical Society Affiliated to Chinese Medical Association have organized multidisciplinary expert discussions at the General Hospital of the People's Liberation Army and nation-wide expert letter reviews and on-site seminars, and formulated an expert consensus of the operation guidelines.

Combining protein arginine methyltransferase inhibitor and anti-programmed death-ligand-1 inhibits pancreatic cancer progression

期刊: WORLD JOURNAL OF GASTROENTEROLOGY, 2020; 26 (26)

BACKGROUND Immunotherapy targeting programmed death-1 (PD-1) or programmed death-ligand-1 (PD-L1) has been shown to be effective in a variety of malignancies but has poor efficacy in pancreatic ductal adenocarcinoma (PDAC). Studies have shown that PD-L1 expression in tumors is an important indicator of the efficacy of immunotherapy. Tumor cells usually evade chemotherapy and host immune surveillance by epigenetic changes. Protein arginine methylation is a common posttranslational modification. Protein arginine methyltransferase (PRMT) 1 is deregulated in a wide variety of cancer types, whose biological role in tumor immunity is undefined. AIM To investigate the combined effects and underlying mechanisms of anti-PD-L1 and type I PRMT inhibitor in pancreatic cancerin vivo. METHODS PT1001B is a novel type I PRMT inhibitor with strong activity and good selectivity. A mouse model of subcutaneous Panc02-derived tumors was used to evaluate drug efficacy, toxic and side effects, and tumor growthin vivo. By flow cytometry, we determined the expression of key immune checkpoint proteins, detected the apoptosis in tumor tissues, and analyzed the immune cells. Immunohistochemistry staining for cellular proliferation-associated nuclear protein Ki67, TUNEL assay, and PRMT1/PD-L1 immunofluorescence were used to elucidate the underlying molecular mechanism of the antitumor effect. RESULTS Cultured Panc02 cells did not express PD-L1in vitro, but tumor cells derived from Panc02 transplanted tumors expressed PD-L1. The therapeutic efficacy of anti-PD-L1 mAb was significantly enhanced by the addition of PT1001B as measured by tumor volume (1054.00 +/- 61.37 mm(3)vs555.80 +/- 74.42 mm(3),P< 0.01) and tumor weight (0.83 +/- 0.06 gvs0.38 +/- 0.02 g,P< 0.05). PT1001B improved antitumor immunity by inhibiting PD-L1 expression on tumor cells (32.74% +/- 5.89%vs17.95% +/- 1.92%,P< 0.05). The combination therapy upregulated tumor-infiltrating CD8+ T lymphocytes (23.75% +/- 3.20%vs73.34% +/- 4.35%,P< 0.01) and decreased PD-1+ leukocytes (35.77% +/- 3.30%vs6.48% +/- 1.08%,P< 0.001) in tumor tissue compared to the control. In addition, PT1001B amplified the inhibitory effect of anti-PD-L1 on tumor cell proliferation and enhanced the induction of tumor cell apoptosis. PRMT1 downregulation was correlated with PD-L1 downregulation. CONCLUSION PT1001B enhances antitumor immunity and combining it with anti-PD-L1 checkpoint inhibitors provides a potential strategy to overcome anti-PD-L1 resistance in PDAC.

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