Influence of immunosuppressive drugs on natural killer cells in therapeutic drug exposure in liver transplantation.

Background: Natural killer (NK) cells are enriched in the liver and are the main regulators in liver transplantation regarding rejection or tolerance, viral infection, or tumor recurrence. Immunosuppression consists of a triple drug standard regimen comprising tacrolimus (TAC) and corticosteroids (CS) with either mycophenolate mofetil (MMF) or sirolimus (SIR)/everolimus (EVE). The aim of this study was to evaluate the impact of trough levels of these regimens under clinical conditions and exposure on human NK-cell activity and function in order to better understand the antiviral and anti-tumor effects of mammalian target of rapamycin inhibitor (mTORI). Methods: Peripheral blood mononuclear cells (PBMCs) were collected from liver transplant recipients and healthy controls. Number and phenotypes of NK cells in vivo were analyzed by flow cytometry. In this study we simulated the immunosuppressive microenvironment in vitro. PBMCs were cultured at the clinically effective plasma concentration of drugs for 3 d to detect the effect of immunosuppressants on NK cells. Drug type and concentration: single drug [EVE, 5 ng/mL; SIR, 5 ng/mL; TAC, 5 ng/mL; cyclosporine A (CSA), 125 ng/mL; MMF, 15 µg/mL; CS, 0.5 µg/mL] and combined immunosuppressants (Group 1: TAC, 5 ng/mL + MMF, 15 µg/mL + CS, 0.5 µg/mL; Group 2: TAC, 5 ng/mL + SIR, 5 ng/mL + CS, 0.5 µg/mL; Group 3: TAC, 5 ng/mL + EVE, 5 ng/mL + CS, 0.5 µg/mL). In addition, NK cells were sorted from PBMCs and treated under the above conditions to detect NK cell killing function and RNA transcription characteristics. Results: CS significantly impaired the cytolytic activity of NK cells, followed by MMF and SIR/EVE. CS and TAC/CSA significantly decreased the secretion of IFN-γ and CD107a. NK cell function in liver transplant recipients was most pronouncedly inhibited by a triple immunosuppressive regimen, with CS playing the most prominent role compared with the other drugs. The MMF-containing regimen demonstrated a significant increase in the expression of suppressive genes, especially of the Siglec7/9 family. The SIR group had stronger NK cell activity compared with that of the MMF group, although liver transplantation patients have lower NK cell activity and function. Conclusions: Despite an overall comparable immunosuppressive efficiency in terms of prevention of acute rejection, a mTORIs-including regimen might be considered as having less impact on NK cell function.

Risk factors of perioperative complications and management with enhanced recovery after primary surgery in women with epithelial ovarian carcinoma in a single center.

The present study aimed to evaluate the postoperative complications and the impact of an enhanced recovery programme in patients who underwent primary surgery (including extensive upper abdominal surgery) for epithelial ovarian carcinoma (EOC). All patients with stage I-IV ovarian carcinoma who underwent primary surgery were identified, and postoperative complications were evaluated and graded according to the Clavien-Dindo classification. Of 161 patients, 46 (28.57%) underwent surgical staging, 27 (16.77%) standard cytoreduction, 12 (7.45%) en bloc debulking and 76 (47.20%) extraradical debulking. A total of 157 patients (97.52%) achieved optimal tumor reduction (<1 cm). The mean postoperative hospitalization time was 17.33±11.29 days after completion of the initial postoperative chemotherapy (IPC), and the IPC interval was 16.22±10.09 days. A total of 13 patients (8.07%) had grade 3 complications (9 with wound dehiscence, 3 with digestive tract leakage and 1 with a bladder fistula). A total of 2 patients (1.24%) had grade 4-5 complications [1 patient with severe pneumonia returned to the intensive care unit (ICU) for tracheotomy and respiration rehabilitation; the other patient died of septicemia on day 19]. The multivariate analysis of the preoperative factors revealed that a human epididymis protein 4 (HE4) level of ≥717 pM (P=0.015) and Federation International of Gynecology and Obstetrics (FIGO) stage IV (P=0.004; compared with stage IIIC) were associated with grade 3-5 complications. The bootstrap analysis revealed that a cancer antigen 125 (CA125) level of ≥1,012 U/ml (P=0.034), a HE4 level of ≥717 pM (P=0.007) and FIGO stage IV (P=0.002; compared with stage IIIC) were significantly associated with grade 3-5 complications. Meanwhile, the multivariate analysis of the postoperative factors did not reveal any risk factors associated with grade 3-5 complications; the bootstrap analysis revealed that only transfer to the ICU after surgery (P=0.026) was significantly associated with grade 3-5 complications. In conclusion, the study found that application of enhanced recovery after surgery protocols is feasible in patients with EOC, especially in those undergoing advanced extensive upper abdominal surgery, and CA125, HE4 and FIGO stage IV were related with the occurrence of adverse perioperative outcomes.

Fusing pre-trained convolutional neural networks features for multi-differentiated subtypes of liver cancer on histopathological images.

Liver cancer is a malignant tumor with high morbidity and mortality, which has a tremendous negative impact on human survival. However, it is a challenging task to recognize tens of thousands of histopathological images of liver cancer by naked eye, which poses numerous challenges to inexperienced clinicians. In addition, factors such as long time-consuming, tedious work and huge number of images impose a great burden on clinical diagnosis. Therefore, our study combines convolutional neural networks with histopathology images and adopts a feature fusion approach to help clinicians efficiently discriminate the differentiation types of primary hepatocellular carcinoma histopathology images, thus improving their diagnostic efficiency and relieving their work pressure. In this study, for the first time, 73 patients with different differentiation types of primary liver cancer tumors were classified. We performed an adequate classification evaluation of liver cancer differentiation types using four pre-trained deep convolutional neural networks and nine different machine learning (ML) classifiers on a dataset of liver cancer histopathology images with multiple differentiation types. And the test set accuracy, validation set accuracy, running time with different strategies, precision, recall and F1 value were used for adequate comparative evaluation. Proved by experimental results, fusion networks (FuNet) structure is a good choice, which covers both channel attention and spatial attention, and suppresses channel interference with less information. Meanwhile, it can clarify the importance of each spatial location by learning the weights of different locations in space, then apply it to the study of classification of multi-differentiated types of liver cancer. In addition, in most cases, the Stacking-based integrated learning classifier outperforms other ML classifiers in the classification task of multi-differentiation types of liver cancer with the FuNet fusion strategy after dimensionality reduction of the fused features by principle component analysis (PCA) features, and a satisfactory result of 72.46% is achieved in the test set, which has certain practicality.

Sequential metastasis to the liver and pancreas 4 years after gestational trophoblastic neoplasia: a case report.

This case report describes a 43-year-old female initially diagnosed with gestational trophoblastic neoplasia that then experienced metastasis to the liver and then subsequently to the pancreas nearly 4 years after the primary diagnosis. After resection of the body and tail of the pancreas, the postoperative histopathological examination confirmed a placental site trophoblastic tumour that had developed after several cycles of chemotherapy for the original primary tumour and the liver metastases. This type of sequential recurrence of gestational trophoblastic neoplasia in the primary site or metastatic sites, such as the liver or pancreas, can be cured by a comprehensive treatment strategy involving surgery and/or salvage chemotherapy and continuous follow-up over a long period, especially for patients with a high-risk status.

The IL-17A/IL-17RA Axis Is Not Related to Overall Survival and Cancer Stem Cell Modulation in Pancreatic Cancer.

(1) Background: IL-17A accelerates pancreatic intraepithelial neoplasia (PanIN) progression. In this study, we examined whether IL-17A/IL-17RA promotes pancreatic ductal adenocarcinoma (PDAC) aggressiveness in terms of survival and cancer stem cell modulation. (2) Methods: In vitro, the wound-healing assay, the sphere formation assay, and flow cytometry were applied to assess cancer stem cell features. In vivo, pancreatic tumors were induced in C57BL/6 mice using electroporation with oncogenic plasmids (P53-/- R172H; KrasG12V). Anti-IL-17 antibodies were administered as immunotherapy. We analyzed IL-17A/IL-17RA related survival using publicly available transcriptomic data (n = 903). (3) Results: IL-17A/IL-17RA expression was not related to survival in PDAC patients. IL-17A neither induces stem cell markers nor increases sphere formation and cell motility in vitro. Blocking the IL-17A/IL-17RA axis in a murine pancreatic cancer model did not improve the survival of mice, but reduced the tumor burden slightly. (4) Conclusions: IL-17A does not promote stem cell expansion in PDAC cell lines. Blocking IL-17A/IL-17RA signaling does not interfere with pancreatic cancer development and progression and may not be considered as a promising monotherapy for PDAC.

Incidence and potential predictors of thromboembolic events in epithelial ovarian carcinoma patients during perioperative period.

OBJECTIVE: To assess the incidence and the risk factors of venous thromboembolism (VTE) in patients with epithelial ovarian carcinoma (EOC) during the perioperative period. METHODS: A retrospective analysis was conducted on the patients with epithelial ovarian cancer treated in our hospital, between January 2017 and July 2019, and a comprehensive review of the medical documentation was performed to collect relevant data. We then analyzed the related factors of the thrombosis in the EOC patients, using univariate and multivariate analysis to identify significant risk factors for VTE, and bootstrap resampling method was used to verify the multivariate analysis results. The ROC curve methods were conducted to evaluate the diagnostic value for the prediction of VTE. RESULTS: We analyzed 233 cases of patients with EOC, of whom the incidence of VTE was 11.16%. According to multivariate and 5000 bootstrap samples analysis, preoperative D-dimer levels (>4.215 µg/ml, p = 0.041 and p = 0.032) and comorbid of cerebral infarction (p < 0.001 and p < 0.001) had statistical significance in predicting VTE events; bootstrap analysis also found the Alb, CA125, OCCC had statistical significance. While According to multivariate and 5000 bootstrap samples analysis, age (>50.5 years old, p = 0.019 and p = 0.002) and nonoptimal debulking surgery (p = 0.007 and p = 0.002) showed significance in predicting VTE after surgery; bootstrap analysis also found the D-dimer levels (>4.215 µg/ml) and tuberculosis had statistical significance. CONCLUSION: More effective thromboprophylaxis and pre-test assessment is necessary for EOC patients. For prediction VTE events, D-dimer levels (>4.215 µg/ml) were the independent predictors before operation. Age and debulking surgery were the independent predictors post operation.

An updated systematic review and meta-analysis of the use of octreotide for the prevention of postoperative complications after pancreatic resection.

BACKGROUND: The use of octreotide prophylaxis following pancreatic surgery is controversial. We aimed to evaluate the effectiveness of octreotide for the prevention of postoperative complications after pancreatic surgery through this systematic review and meta-analysis. METHODS: Literature databases (including the MEDLINE, EMBASE, and Cochrane databases) were searched systematically for relevant articles. Only randomized controlled trials (RCTs) were eligible for inclusion in our research. We extracted the basic information regarding the patients, intervention procedures, and all complications after pancreatic surgery and then performed the meta-analysis. RESULTS: Thirteen RCTs involving 2006 patients were identified. There were no differences between the octreotide group and the placebo group with regard to pancreatic fistulas (PFs) (relative risk [RR] = 0.79, 95% confidence interval [CI] = 0.62-0.99, P = .05), clinically significant PFs (RR = 1.01, 95% CI = 0.68-1.50, P = .95), mortality (RR = 1.21, 95% CI = 0.78-1.88, P = .40), biliary leakage (RR 0.84, 95% CI = 0.39-1.82, P = .66), delayed gastric emptying (RR = 0.83, 95% CI = 0.54-1.27, P = .39), abdominal infection (RR = 1.00, 95% CI = 0.66-1.52, P = 1.00), bleeding (RR = 1.16, 95% CI = 0.78-1.72, P = .46), pulmonary complications (RR = 0.73, 95% CI = 0.45-1.18, P = .20), overall complications (RR = 0.80, 95% CI = 0.64-1.01, P = .06), and reoperation rates (RR = 1.18, 95% CI = 0.77-1.81, P = .45). In the high-risk group, octreotide was no more effective at reducing PF formation than placebo (RR = 0.81, 95% CI = 0.67-1.00, P = .05). In addition, octreotide had no influence on the incidence of PF (RR = 0.38, 95% CI = 0.14-1.05, P = .06) after distal pancreatic resection and local pancreatic resection. CONCLUSION: The present best evidence suggests that prophylactic use of octreotide has no effect on reducing complications after pancreatic resection.

Effects of LncRNA Lnc-LIF-AS on cell proliferation, migration and invasion in a human cervical cancer cell line.

This study explored the effect of LncRNA Lnc-LIF-AS on cell proliferation, migration and invasion in the human cervical cancer (HCC) cell line SiHa. SiHa cells had the lowest expression of Lnc-LIF-AS in the 4 human cervical cancer cell lines (SiHa, ME-180, C-33A and HeLa) and were transfected and divided into the SiHa/con (transfected with pMIGRI) cell group, SiHa/Lnc-LIF-AS (transfected with pMIGRI-Lnc-LIF-AS) cell group, and SiHa/Lnc-LIF-AS-DN (transfected with pMIGRI-Lnc-LIF-AS-DN, in which the sequences overlapping with LIF mRNA was deleted) cell group. Overexpression of Lnc-LIF-AS could promote the proliferation, colony formation, invasion and migration in SiHa and ME-180 cells. And the low expression of Lnc-LIF-AS suppress the proliferation, colony formation invasion and migration in HeLa cells when the Lnc-LIF-AS expression has been suppressed. In the SiHa/Lnc-LIF-AS cells group, the cell cycle was mainly halted in the S phase and overexpression of Lnc-LIF-AS had no effect on the apoptosis of SiHa cells. Overexpression of Lnc-LIF-AS could promote the secretion of LIF in SiHa cells, and the supernatant from SiHa/Lnc-LIF-AS cells could promote cell proliferation in the SiHa/con cells. The STAT3 inhibitor could inhibit cell proliferation in the SiHa/Lnc-LIF-AS cells. The expression level of Lnc-LIF-AS in cervical cancer tissues was higher than that in normal tissues and the expression level of Lnc-LIF-AS was positively correlated with the level of LIF. In the SiHa/con and SiHa/Lnc-LIF-AS-DN cell groups, there were no significant differences in cell proliferation, cell migration and cell invasion. The overexpression of Lnc-LIF-AS can promote cell proliferation, migration and invasion in cervical cancer cells, and the core function domain of this lncRNA was located in the overlapping a 3'-UTR base sequence of LIF mRNA.

miR-221 Mediates Chemoresistance of Esophageal Adenocarcinoma by Direct Targeting of DKK2 Expression.

BACKGROUND: Chemoresistance is a main obstacle to effective esophageal cancer (EC) therapy. We hypothesize that altered expression of microRNAs (miRNAs) play a role in EC cancer progression and resistance to 5-fluorouracil (5-FU) based chemotherapeutic strategies. METHODS: Four pairs of esophageal adenocarcinoma (EAC) cell lines and corresponding 5-FU resistant variants were established. The expression levels of miRNAs previously shown to be involved in the general regulation of stem cell pathways were analyzed by qRT-PCR. The effects of selected miRNAs on proliferation, apoptosis, and chemosensitivity were evaluated both in vitro and in vivo. We identified a particular miRNA and analyzed its putative target genes in 14 pairs of human EC tumor specimens with surrounding normal tissue by qRT-PCR as well as Wnt pathway associated genes by immunohistochemistry in another 45 EAC tumor samples. RESULTS: MiR-221 was overexpressed in 5-FU resistant EC cell lines as well as in human EAC tissue. DKK2 was identified as a target gene for miR-221. Knockdown of miR-221 in 5-FU resistant cells resulted in reduced cell proliferation, increased apoptosis, restored chemosensitivity, and led to inactivation of the Wnt/ß-catenin pathway mediated by alteration in DKK2 expression. Moreover, miR-221 reduction resulted in alteration of EMT-associated genes such as E-cadherin and vimentin as well as significantly slower xenograft tumor growth in nude mice. RT profiler analysis identified a substantial dysregulation of 4 Wnt/ß-catenin signaling and chemoresistance target genes as a result of miR-221 modulation: CDH1, CD44, MYC, and ABCG2. CONCLUSION: MiR-221 controls 5-FU resistance of EC partly via modulation of Wnt/ß-catenin-EMT pathways by direct targeting of DKK2 expression. MiR-221 may serve as a prognostic marker and therapeutic target for patients with 5-FU resistant EAC.