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Abstract Background The objective of this study was to determine the role and regulatory mechanism of miR-380 in cholangiocarcinoma. Methods The TargetScan database and a dual-luciferase reporter assay system were used to determine if LIS1 was a target gene of miR-380. The Cell Counting Kit 8 assay, flow cytometry, and Transwell assay were used to detect the effects of miR-380 and LIS1 on the proliferation, S-phase ratio, and invasiveness of HCCC-9810/HuCCT1/QBC939 cells. Western blotting was used to determine the effect of miR-380 on MMP-2/p-AKT. Immunohistochemistry detected the regulatory effect of miR-380 on the expression of MMP-2/p-AKT/LIS1. Results Expression of miR-380 in cholangiocarcinoma was decreased but expression of LIS1 was increased. LIS1 was confirmed to be a target gene of miR-380. Transfection with miR-380 mimics inhibited the proliferation, S-phase arrest, and invasion of HCCC-9810/HuCCT1/QBC939 cells, and LIS1 reversed these inhibitory effects. miR-380 inhibitor promoted proliferation, S-phase ratio, and invasiveness of HCCC-9810/HuCCT1/QBC939 cells. si-LIS1 salvaged the promotive effect of miR-380 inhibitor. Overexpression of miR-380 inhibited expression of MMP-2/p-AKT/LIS1, but miR-380 inhibitor promoted their expression. Conclusion An imbalance of miR-380 expression is closely related to cholangiocarcinoma, and overexpression of miR-380 inhibits the expression of MMP-2/p-AKT by directly targeting LIS1.

Summary: Bats harbor highly virulent viruses that can infect other mammals, including humans, posing questions about their immune tolerance mechanisms. Bat cells employ multiple strategies to limit virus replication and virus-induced immunopathology, but the coexistence of bats and fatal viruses remains poorly understood. Here, we investigate the antiviral RNA interference pathway in bat cells and discover that they have an enhanced antiviral RNAi response, producing canonical viral small interfering RNAs upon Sindbis virus infection that are missing in human cells. Disruption of Dicer function results in increased viral load for three different RNA viruses in bat cells, indicating an interferon-independent antiviral pathway. Furthermore, our findings reveal the simultaneous engagement of Dicer and pattern-recognition receptors, such as retinoic acid-inducible gene I, with double-stranded RNA, suggesting that Dicer attenuates the interferon response initiation in bat cells. These insights advance our comprehension of the distinctive strategies bats employ to coexist with viruses.

PurposeTo explore the efficacy and safety of FOLFOXIRI plus cetuximab regimen as conversion therapy for patients with unresectable RAS/BRAF wild-type colorectal liver-limited metastases (CLM).Patients and methodsThis was a dual-center, phase II trial with the rate of no evidence of disease (NED) achieved as the primary endpoint. All enrolled patients with initially unresectable left-sided RAS/BRAF wild-type colorectal liver-limited metastases received a modified FOLFOXIRI plus cetuximab regimen as conversion therapy.ResultsBetween October 2019 and October 2021, fifteen patients were enrolled. Nine patients (60%) achieved NED. The overall response rate (ORR) was 92.9%, and the disease control rate (DCR) was 100%. The median relapse‐free survival (RFS) was 9 (95% CI: 0–20.7) months. The median progression-free survival (PFS) was 13.0 months (95% CI: 5.7-20.5), and the median overall survival (OS) was not reached. The most frequently occurring grade 3-4 adverse events were neutropenia (20%), peripheral neurotoxicity (13.3%), diarrhea (6.7%), and rash acneiform (6.7%).ConclusionThe FOLFOXIRI plus cetuximab regimen displayed tolerable toxicity and promising anti-tumor activity in terms of the rate of NED achieved and response rate in patients with initially unresectable left-sided RAS/BRAF wild-type CLM. This regimen merits further investigation.

Aiming at the miniaturization and portability requirements of the collaborative flight simulator used in long-endurance collaborative aerial bombardment training, the design concept of software-based distributed real-time flexible system is proposed based on the advantages and disadvantages of traditional simulators and simulation systems. The bomb-borne 1553B bus is simulated with completion of RTNet by RTX real-time operating system. Based on the process copy technology for two-level memory management, the system-level functional modules completed by hardware is abstracted to memory particles and software processes to realize the distributed flexible design of this system. Meanwhile, the flight track generator realized by the spline interpolation and the data intervention of distributed process-level image are proposed to be able to reproduce the flight scene more realistically. Finally, the functionality and perfor-mance of the simulator have been effectively verified in the multi-level collaborative test.

Abstract Background Spontaneous rupture is a life-threatening complication of hepatocellular carcinoma (HCC). Recent trends in surgical treatments avoid emergency hepatectomy (EH) and favor emergency transarterial embolization (TAE) followed by delayed hepatectomy (DH). Still, there is debate on which is the better treatment option and whether delaying hepatectomy increases peritoneal metastasis. Aim To provide evidence-based references for the optimal management of patients with spontaneously ruptured HCC by comparing the outcomes of EH and DH. Methods Literature on postoperative outcomes of EH and DH in patients with spontaneously ruptured HCC published between the date of the database establishment and May 2022, was identified in the PubMed, EMBASE, and Cochrane Library databases. Revman 5.3 software was used for statistical analyses. Results Nine publications were identified, including a total of 681 patients. Of those, 304 underwent EH, and 377 underwent TAE followed by DH. The meta-analysis results indicated that the in-hospital mortality rate in the EH patient group was significantly higher than that in the DH patient group (relative risk (RR) = 2.17, 95% confidence interval (CI) 1.03–4.57, p =0.04). There was no significant differences in the rates of postoperative complications (RR = 1.21, 95% CI 0.77–1.90, p = 0.40), postoperative hospital stay (WMD = − 0.64, 95% CI − 5.61–4.34, p = 0.80), recurrence (RR = 1.09, 95% CI 0.94–1.25, p = 0.27), peritoneal metastasis (RR = 1.06, 95% CI 0.66–1.71, p = 0.80), 1-year survival (RR = 0.91, 95% CI 0.80–1.02, p = 0.11), or 3-year survival (RR = 0.81, 95% CI 0.61–1.09, p = 0.17) in survivors between the two patient groups. Conclusion The postoperative outcomes of the spontaneously ruptured HCC survivors who received EH were similar to those who received emergency TAE followed by DH. However, the in-hospital mortality rate was higher in EH patients. Based on the findings, DH with TAE first strategy might be considered over EH as the first line treatment modality. However, these findings await further validation by future high-quality studies.

BackgroundSorafenib was the first drug approved for advanced hepatocellular carcinoma (HCC). However, it is limited by poor efficacy for HCC with portal vein tumor thrombus (PVTT). Some studies suggested that hepatic artery infusion chemotherapy (HAIC) could provide survival benefits to patients with advanced HCC with PVTT.AimThe study aimed to compare the efficacy of HAIC versus sorafenib in patients with HCC accompanied by PVTT.MethodsThe PubMed, Embase, and Cochrane Library databases were searched for studies published until September 2022. Statistical analyses were performed using Stata SE 15 software.ResultsEight studies with 672 patients, 403 in the HAIC group and 269 in the sorafenib group, were included in the meta-analysis. The rates of complete response (RR=3.88, 95%CI:1.35-11.16, P=0.01), partial response (RR=3.46, 95%CI:1.94-6.18, P

BackgroundThe spontaneous rupture of hepatocellular carcinoma (HCC) is associated with high mortality rates, and liver resection can provide better outcomes than other available treatments. However, the survival length of patients subjected to hepatectomy after spontaneous rupture of hepatocellular carcinoma remains controversial.MethodArticles reporting the comparison of the survival outcome between patients with rupture HCC (rHCC) and non-rupture HCC (nrHCC) from the inception until December 31, 2021 by PubMed, Web of Science, OVID, and the Cochrane Library databases were included. The high-quality propensity score matching analysis was used to investigate the impact of rupture on disease-free survival (DFS) and overall survival (OS) between the rHCC and nrHCC group with no heterogeneity.ResultA total of 606 patients from six cohort studies were included. The major baseline characteristics of the eligible patients were well balanced between rHCC and nrHCC group. The 1-, 3-, and 5-year hazard ratios of DFS were 3.45 (95% confidence interval [CI] 2.54–4.68), 3.63 (95% CI 2.87–4.60), and 3.72 (95% CI 2.93–4.72), respectively. The 1-, 3-, and 5-year hazard ratios of OS were 5.01 (95% CI 3.26–7.69), 5.49 (95% CI 4.08–7.39), and 4.20 (95% CI 3.20–5.51), respectively.ConclusionThe present meta-analysis demonstrated that the DSF and OS were significantly shorter in the rHCC group than in the nrHCC group, thus revealing that spontaneous HCC rupture was a predictor of poor survival.

Extramammary Paget’s disease (EMPD) is a rare cutaneous neoplasm with distant metastases and a poor prognosis. We report the case of a 63-year-old male patient exhibiting stage IV primary EMPD with neuroendocrine differentiation, and harboring a somatic mutation in AMER1. After four cycles of Anlotinib combined with Tislelizumab, the patient achieved partial response for the metastatic lesions according to mRECIST1.1 criteria. Total positron emission tomography and computed tomography (PET-CT) scans revealed a significant reduction in SUV from 18.9 to 5.3, and the serum CEA decreased to normal levels after the treatment regimen. However, the patient developed fractures of the fourth and fifth thoracic vertebrae during the treatment. Therefore, percutaneous vertebroplasty was performed, and the patient experienced severe postoperative pneumonia and died from pulmonary encephalopathy and respiratory failure in June 2021. The overall and progression-free survival of the patient after diagnosis were 9 and 8 months, respectively. During the systemic treatment, the patient suffered grade 1 rash in the back and thigh and grade 1 hypertension. Nevertheless, the combination treatment of anlotinib and tislelizumab had a favorable clinical outcome and provided a survival advantage, and should be considered a therapeutic option for patients with AMER1-mutant metastatic EMPD.

Purpose: To explore the efficacy and safety of FOLFOXIRI plus cetuximab regimen as conversion therapy for patients with unresectable RAS/BRAF wildtype colorectal liver-limited metastases (CLM). Patients and methods: This was a dual-center, phase II trial with the rate of no evidence of disease (NED) achieved as the primary endpoint. All enrolled patients with initially unresectable left-sided RAS/BRAF wild-type colorectal liver-limited metastases received a modified FOLFOXIRI plus cetuximab regimen as conversion therapy. Results: Between October 2019 and October 2021, fifteen patients were enrolled. Nine patients (60%) achieved NED. The overall response rate (ORR) was 92.9%, and the disease control rate (DCR) was 100%. The median relapsefree survival (RFS) was 9 (95% CI: 0-20.7) months. The median progression-free survival (PFS) was 13.0 months (95% CI: 5.7-20.5), and the median overall survival (OS) was not reached. The most frequently occurring grade 3-4 adverse events were neutropenia (20%), peripheral neurotoxicity (13.3%), diarrhea (6.7%), and rash acneiform (6.7%). Conclusion: The FOLFOXIRI plus cetuximab regimen displayed tolerable toxicity and promising anti-tumor activity in terms of the rate of NED achieved and response rate in patients with initially unresectable left-sided RAS/BRAF wildtype CLM. This regimen merits further investigation. [ABSTRACT FROM AUTHOR]

Abstract Background To compare the efficacy of endoscopic nasobiliary drainage (ENBD) and endoscopic biliary stenting (EBS) in preoperative biliary drainage (PBD). Methods ENBD and EBS related literature of patients with malignant biliary obstruction published before September 2019 were collected from PubMed, EMBASE, and Cochrane Library for comparison analysis. Revman 5.3 statistical software was used for analysis. Results Nine studies were used for our comparative study. A total of 1435 patients were included, which consisted of 813 in the ENBD group and 622 in the EBS group. Meta-analysis showed that patients with malignant biliary obstruction who received ENBD had reductions in the rates of preoperative cholangitis (RR = 0.46, 95% CI = 0.34–0.62, P < 0.00001), preoperative pancreatitis (RR = 0.69, 95% CI = 0.50–0.95, P = 0.02), stent dysfunction (RR = 0.58, 95% CI = 0.43–0.80, P = 0.0008), morbidity (RR = 0.77, 95% CI = 0.64–0.93, P = 0.007), and postoperative pancreatic fistula (RR = 0.65, 95% CI = 0.45–0.92, P = 0.02) compared with patients who received EBS. Conclusions The rates of preoperative cholangitis, preoperative pancreatitis, post-operative pancreatic fistula, stent dysfunction, and morbidity of ENBD patients were lower than those of EBS patients. In clinical practice, the physical condition of each patient and their tolerance should be fully considered. ENBD should be given priority. EBS should be replaced if stent dysfunction or intolerance occurs.

To establish a cutoff level of AMH which could help for the diagnosis of PCOS, to investigate the predictive value of AMH combined with androgens in Chinese women to diagnose PCOS. This is a prospective case control study, 550 women recruited (aged 20–40 years), in which 450 PCOS women recruited according to the Rotterdam criteria and 100 non-PCOS women in the control group were from the women for the pregnancy preparation examination. AMH were measured by the Elecsys AMH Plus immunoassay. Androgens and other sex hormone were measured. The validity of AMH toward the diagnosis of PCOS, or AMH combined with total testosterone, free testosterone, bioavailable testosterone and androstenedione was estimated by receiver operating characteristic (ROC)curves, and correlations between paired variables was estimated by Spearman's rank correlation coefficient. The cutoff value of AMH in Chinese reproductive-age women with PCOS is 4.64 ng/mL, AUC under the curve is 0.938, with 81.6% sensitivity, and 92.0% specificity. Total testosterone, free testosterone, bioactive testosterone, and androstenedione are significantly higher in women with PCOS of reproductive age than in controls. The combination of AMH and free testosterone resulted in a higher AUC of 94.8%, with higher sensitivity (86.1%) and excellent specificity (90.3%) for the prediction of PCOS. The Elecsys AMH Plus immunoassay, with a cutoff of 4.64 ng/mL, is a robust method for identifying PCOM to aid in PCOS diagnosis. The combination of AMH and free testosterone resulted in a higher AUC of 94.8% for the diagnose of PCOS. [ABSTRACT FROM AUTHOR]

Abstract Background Immune checkpoint inhibitors are not effective for pancreatic ductal adenocarcinoma (PDAC) as single agents. Vaccine therapy may sensitize PDACs to checkpoint inhibitor treatments. Annexin A2 (ANXA2) is a pro-metastasis protein, previously identified as a relevant PDAC antigen that is expressed by a GM-CSF-secreting allogenic whole pancreatic tumor cell vaccine (GVAX) to induce an anti-ANXA2 antibody response in patients with PDAC. We hypothesized that an ANXA2-targeting vaccine approach not only provokes an immune response but also mounts anti-tumor effects. Methods We developed a Listeria-based, ANXA2-targeting cancer immunotherapy (Lm-ANXA2) and investigated its effectiveness within two murine models of PDAC. Results We show that Lm-ANXA2 prolonged the survival in a transplant model of mouse PDACs. More importantly, priming with the Lm-ANXA2 treatment prior to administration of anti-PD-1 antibodies increased cure rates in the implanted PDAC model and resulted in objective tumor responses and prolonged survival in the genetically engineered spontaneous PDAC model. In tumors treated with Lm-ANXA2 followed by anti-PD-1 antibody, the T cells specific to ANXA2 had significantly increased INFγ expression. Conclusions For the first time, a listeria vaccine-based immunotherapy was shown to be able to induce a tumor antigen-specific T cell response within the tumor microenvironment of a “cold” tumor such as PDAC and sensitize the tumor to checkpoint inhibitor therapy. Moreover, this combination immunotherapy led to objective tumor responses and survival benefit in the mice with spontaneously developed PDAC tumors. Therefore, our study supports developing Lm-ANXA2 as a therapeutic agent in combination with anti-PD-1 antibody for PDAC treatment.

To improve the decision performance using historical decision data, this paper proposes a data-driven decision model based on local two-stage weighted ensemble learning. The assessments of historical alternatives are collected from a multicriteria framework. For each new alternative, a set of its similar alternatives is determined from historical alternatives using the K-Nearest Neighbor technique, and then a set of base classifiers (BCs) is generated by the historical assessments. Based on ensemble error and diversity of BCs in predicting the similar historical alternatives of the new alternative, a local two-stage weighted ensemble method is developed to learn the optimal BC weights for the new alternative. Such a learning process not only considers the changes of BCs' competence in facing different alternatives (instances) but also avoids falling into the dilemma of balancing the accuracy and diversity of BCs. By combining the continuous outputs of different BCs with the learned BC weights, the weighted ensemble outputs are obtained for the similar historical alternatives of the new alternative. Based on these outputs and the assessments of those similar historical alternatives on criteria, a linear optimization model is constructed to learn criterion weights. Using the learned criterion weights, the interpretable decision is performed. The advantages of the proposed decision model against four traditional decision models are validated by a real case study for the diagnosis of thyroid nodules. Thirty real datasets examine the competence of the proposed weighted ensemble method against mainstream ensemble methods and combination rules. [ABSTRACT FROM AUTHOR]