Efficacy and safety of EUS-guided coil embolization combined with endoscopic cyanoacrylate injection versus balloon-occluded retrograde transvenous obliteration for gastric varices with high-risk ectopic embolism: A multicenter and retrospective cohort study.

Background and Objectives: Gastric varices (GV) with spontaneous portosystemic shunt (SPSS) are associated with ectopic embolism in endoscopic cyanoacrylate. This study targeted to assess the efficacy and safety of EUS-guided coil embolization combined with endoscopic cyanoacrylate injection versus balloon-occluded retrograde transvenous obliteration (BRTO) for GV with high-risk ectopic embolism. Materials and Methods: We retrospectively analyzed six tertiary hospitals' 104 patients with GV at high-risk ectopic embolism (the narrowest diameter of SPSS was greater than or equal to 5 mm and the maximum diameter usually >8 mm) who underwent EUS-guided coil embolization combined with endoscopic cyanoacrylate injection or BRTO from January 2014 to December 2020. The outcomes included rebleeding, survival, and complications. Results: The EUS group and BRTO group contained 59 and 45 patients, respectively. The technical success rate between the two groups was similar (96.6% vs. 95.6%, P = 1.000). During the follow-up, both groups' 5-day rebleeding rate and 6-week mortality rate were 0%. One-year all-cause rebleeding rate (20.0% vs. 18.9%, P = 0.900) and 1-year mortality rate (2.0% vs. 0%, P = 1.000) in the EUS group were similar to the BRTO group. One patient experienced ectopic embolism in the EUS group, while the BRTO group did not. Both groups had similar mean days (16.0 [interquartile range (IQR), 12.0-19.0] vs. 16.5 [IQR, 11.8-26.0], P = 0.165) and cost of hospitalization (¥ 45950.6 [IQR, 39330.2-55768.2] vs. ¥ 51205.8 [IQR, 31628.8-74251.5], P = 0.680). Multivariate analysis showed that the narrowest diameter of the shunt (odds ratio [OR] = 1.86; 95% confidence interval [CI]: 1.062-3.258; P = 0.03) and content of hemoglobin (OR = 0.941; 95% CI: 0.892-0.992; P = 0.025) were the prognostic factors for survival. Conclusions: The efficacy and safety of EUS-guided coil embolization combined with endoscopic cyanoacrylate injection for GV with high-risk ectopic embolism are comparable to BRTO.

Exploration of turn-positive RT-PCR results and factors related to treatment outcome in COVID-19: A retrospective cohort study.

The cause of some patients with negative RT-PCR results experienced turn-positive after treatment remains unclear. In addition, understanding the correlation between changes in clinical data in the course of COVID-19 and treatment outcomes is of great importance in determining the prognosis of COVID-19. To perform cause analysis of RT-PCR turn-positive and the effective screening factors related to treatment outcome in COVID-19. Clinical data, including clinical manifestations, laboratory tests, radiography results, treatment methods and outcomes, were retrospectively collected and analyzed from January to March 2020 in Renmin Hospitals of Wuhan University. 116 COVID-19 patients (40 in recurrent group, 29 in recovered group and 47 in unrecovered group) were recruited. In the recurrent group, white blood cell, Neutrophils, prothrombin time, activated partial thromboplastin time, CD3, CD4, CD8, ratio of CD4/CD8, IgG and C4 complement were of significant difference among the baseline, negative and turn-positive time points. CD19 and CT scan results were found notable difference between recurrent group and recovered group. Odds from CD3, CD4, CD8, CD19, IgM, C3 complement, C4 complement and CT scan results validated associations with clinical outcomes of COVID-19. The so-called recurrence in some COVID-19 patients may be due to the false-negative of nucleic acid test results from nasopharyngeal swabs. Levels of CD3, CD4, CD8, CD19, IgM, C3 complement, C4 complement and CT results were significantly correlated with the outcome of COVID-19. The cellular immunity test could be beneficial to further screen the reliability of RT-PCR test on the basis of CT images.

Downregulation of GNAI3 Promotes the Pathogenesis of Methionine/Choline-Deficient Diet-Induced Nonalcoholic Fatty Liver Disease

Background/Aims@#The pathogenesis of nonalcoholic fatty liver disease (NAFLD) has not be fully elucidated, and the lack of therapeutic strategies for NAFLD is an urgent health problem. Guanine nucleotide binding protein, alpha inhibiting activity polypeptide 3 (GNAI3) participates in several biological processes, but its relationship with lipid metabolism and NAFLD has not yet been reported. We aimed to determine the function of GNAI3 in the development of NAFLD. @*Methods@#Mice were fed a methionine and choline-deficient diet to induce NAFLD. An NAFLD model in HepG2 cells was induced by free fatty acid treatment. GNAI3 levels in HepG2 cells were downregulated by shRNA. Protein levels of related proteins were evaluated by Western blotting, and mRNA levels were determined by quantitative reverse transcription polymerase chain reaction. Hematoxylin and eosin and Oil Red O staining were used to observe histological changes in liver tissue. @*Results@#The dysregulated hepatic lipid metabolism in the NAFLD mouse model was enhanced by GNAI3 knockout, which also provoked worse liver damage. In the NAFLD model in HepG2 cells, the downregulation of GNAI3 promoted cellular lipid accumulation and enhanced the changes in lipid metabolic enzyme levels. @*Conclusions@#This study demonstrates that GNAI3 participates in the development of NAFLD in both cellular and mouse models. The data indicate that GNAI3 is a potential new target for the treatment of NAFLD in humans.

Tumor-driven like macrophages induced by conditioned media from pancreatic ductal adenocarcinoma promote tumor metastasis via secreting IL-8.

Tumor-associated macrophages (TAMs) are abundant population of inflammatory cells which play an essential role in remodeling tumor microenvironment and tumor progression. Previously, we found the high density of TAMs was correlated with lymph node metastasis and poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Therefore, this study was designed to investigate the mechanisms of interaction between TAMs and PDAC. THP-1 monocytes were the exposure to conditioned media (CM) produced by PDAC cells; then, monocyte recruitment and macrophage differentiation were assessed. CM from PDAC attracted and polarized THP-1 monocytes to tumor-driven like macrophages. mRNA expression cytokine profiling and ELISA identified the IL-8 secretion was increasing in tumor-driven like macrophages, and STAT3 pathway was involved. Addition of exogenous recombinant human IL-8 promoted PDAC cells motility in vitro and metastasis in vivo via upregulating Twist expression, which mediated epithelial-mesenchymal transition in cancer cells. What is more, IL-8 expression level in tumor stroma by immunohistochemical analysis was related to lymph node metastasis, the number of tumor CD68 but not CD163 positive macrophages and patient outcome. Taken together, these findings shed light on the important interplay between cancer cells and TAMs in tumor microenvironment and suggested that IL-8 signaling might be a potential therapeutic target for PDAC.

Optimizing Evaluation Metrics for Multitask Learning via the Alternating Direction Method of Multipliers.

Multitask learning (MTL) aims to improve the generalization performance of multiple tasks by exploiting the shared factors among them. Various metrics (e.g., -score, area under the ROC curve) are used to evaluate the performances of MTL methods. Most existing MTL methods try to minimize either the misclassified errors for classification or the mean squared errors for regression. In this paper, we propose a method to directly optimize the evaluation metrics for a large family of MTL problems. The formulation of MTL that directly optimizes evaluation metrics is the combination of two parts: 1) a regularizer defined on the weight matrix over all tasks, in order to capture the relatedness of these tasks and 2) a sum of multiple structured hinge losses, each corresponding to a surrogate of some evaluation metric on one task. This formulation is challenging in optimization because both of its parts are nonsmooth. To tackle this issue, we propose a novel optimization procedure based on the alternating direction scheme of multipliers, where we decompose the whole optimization problem into a subproblem corresponding to the regularizer and another subproblem corresponding to the structured hinge losses. For a large family of MTL problems, the first subproblem has closed-form solutions. To solve the second subproblem, we propose an efficient primal-dual algorithm via coordinate ascent. Extensive evaluation results demonstrate that, in a large family of MTL problems, the proposed MTL method of directly optimization evaluation metrics has superior performance gains against the corresponding baseline methods.

Bmi1 combines with oncogenic KRAS to induce malignant transformation of human pancreatic duct cells in vitro.

It is critical to understand the pathogenesis of preinvasive stages of pancreatic duct adenocarcinoma (PDAC) for developing novel potential diagnostic and therapeutic targets. The polycomb group family member B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi1) is overexpressed and involved in cancer progression in PDAC; however, its role in the multistep malignant transformation of human pancreatic duct cells has not been directly demonstrated. In this study, we stably expressed Bmi1 in a model of telomerase-immortalized human pancreatic duct-derived cells (HPNE) and showed that Bmi1 promoted HPNE cell proliferation, migration, and invasion but not malignant transformation. We then used mutant KRASG12D as a second oncogene to transform HPNE cells and showed that it further enhanced Bmi1-induced malignant potential. More importantly, coexpression of KRASG12D and Bmi1 caused anchorage-independent growth transformation in vitro but still failed to produce tumors in nude mice. Finally, we found that mutant KRASG12D induced HPNE-Bmi1 cells to undergo partial epithelial-mesenchymal transition (EMT) likely via upregulation of snail. Knockdown of KRASG12D significantly reduced the expression of snail and vimentin at both the messenger RNA (mRNA) and protein level and further impaired the anchorage-independent growth capability of invasive cells. In summary, our findings demonstrate that coexpression of Bmi1 and KRASG12D could lead to transformation of HPNE cells in vitro and suggest potential new targets for diagnosis and treatment of PDAC.

Clinical significance of serum HBsAg levels, HBsAg/HBV DNA ratio, and association with liver inflammation activity in HBeAg-positive chronic hepatitis B / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To study the clinical significance of hepatitis B surface antigen (HBsAg) levels and HBsAg/hepatitis B virus (HBV) DNA ratio in relation to liver inflammation in HBeAg-positive chronic hepatitis B (CHB).</p><p><b>METHODS</b>One hundred and fifty-three Chinese patients with chronic HBV infection with HBeAg-positive status were enrolled in the study.Quantitative measurements were made for HBsAg levels by immunoassay (Architect HBsAg QT by Abbott Diagnostic) and HBV DNA by real-time fluorescence quantitative PCR.Levels of liver function markers were measured by standard methods.Liver biopsy specimens were obtained from all patients and used to score the histology (liver inflammation) activity index (HAI) and grade (G) the extent of necroinflammation.Statistical correlation analysis was performed to determine the association of HBsAg titre or HBsAg/HBV DNA ratio with the various parameters of liver injury.</p><p><b>RESULTS</b>HBsAg titre and HBsAg/HBV DNA ratio were significantly correlated (r =0.578, P less than 0.0001).A significant positive correlation (r =0.642, P less than 0.0001) was found between HBsAg titre and HBV DNA load, and a significant negative correlation was found between the HAI and HBsAg (r =-0.389, P less than 0.0001) and HBsAg/HBV DNA ratio (r =-0.307, P=0.000l).A significant positive correlation was found between alanine aminotransferase (ALT) level and the HAI (r =0.480, P less than 0.0001).Patients with G less than 2 necroinflammation had significantly higher HBsAg titre and HBsAg/HBV DNA ratio than patients with G more than or equal to 2 necroinflammation (both P less than 0.01) but similar levels ofHBV DNA.Generation of a receiver operating characteristic curve using G more than or equal to 2 as the positive index provided the following area under the curve (AUC) values:HBsAg titre, 0.700; HBsAg/HBV DNA ratio, 0.672; ALT level, 0.713.When the random chance AUC was 0.5, all levels of AUC were statistically significant (Pless than 0.001).HBsAg titre (sensitivity =76.92%) was more sensitive than ALT level (sensitivity =76.92%), and HBsAg/HBV DNA ratio (specificity =81.33%) was more specific than ALT level (specificity =81.33%).Youden's index for comprehensive evaluation using ALT was higher than those for HBsAg titre or HBsAg/HBV DNA ratio.When HBsAg and ALT were considered in parallel, the sensitivity increased to 94.08% and specificity rose to 85.60%.</p><p><b>CONCLUSION</b>HBsAg titre, HBsAg/HBV DNA ratio and ALT levels can be used as the index for judging the degree of liver inflammation in HBeAg-positive CHB patients.Higher sensitivity and specificity are attained when HBsAg and ALT are used in series or parallel.</p>

The quantitative baseline HBsAg level as a predictor for therapeutic effect among HBeAg -positive chronic hepatitis B patients treated with PEG -IFN α-2b / 预防医学

Objective To evaluate the predictive effect of baseline hepatitis B surface antigen (HBsAg)on virological response in HBeAg -positive chronic hepatitis B patients treated with pegylated interferon (PEG -IFN ) α-2b. Methods The retrospective analysis compared the treatment efficacy of PEG -IFN α-2b in 55 cases of HBeAg -positive chronic hepatitis B patients with different baseline HBsAg levels.Serum HBV DNA load was measured at baseline and after 1 2,24,and 48 weeks of the therapy.Virological response was defined as HBV DNA <1 000 IU /ml.Serum HBsAg titers were quantitatively assayed at baseline,1 2 and 24 weeks.Results 1 8 patients had baseline HBsAg levels greater than 20 000 IU /ml(Group A),26 patients had baseline HBsAg levels between 1 500 and 20 000 IU /ml(Group B)and 1 1 patients had baseline HBsAg levels less than 1 500 IU /ml(Group C)after 48 weeks treatment with PEG -IFNα-2b.The achieved virological response rates of the three groups were 1 6.67%,42.31 % and 63.64% respectively with a statistically significant difference between group A and C (P <0.05).1 3 patients had HBsAg levels declined greater than 0.5 log1 0 and 30 patients had HBsAg levels declined less than 0.5 log1 0 at week 1 2 and the achieved virological response rates were 1 6.67%,46.2% and 33.3% respectively without statistically significant difference (P >0.05).1 6 patients with HBsAg <br> levels greater than 20 000 IU /ml after treatment of 24 weeks did not achieve virological response after treatment of 48 weeks.Conclusion Baseline HBsAg levels in combination with HBV DNA quantitative value may become an effective predictor for guiding optimal therapy with PEG -IFN α-2b against HBeAg -positive chronic hepatitis B.

In vivo and in vitro antitumor effects of a staphylococcal enterotoxin A mutant (SEA-H61D).

In this study, we evaluated SEA-H61D, a staphylococcal enterotoxin A mutant without emetic activity, as an antitumor agent in vitro and in vivo. It showed that SEA-H61D could significantly inhibit the growth of many cancer cell lines in vitro at very low concentrations by activating human peripheral blood mononuclear cells (PBMCs). CD4+ and CD8+ T lymphocytes could be activated at a dose between 125 and 500 µg/kg. Systemic administration of SEA-H61D in vivo significantly inhibited tumor growth, with the treated group undergoing tumor necrosis and showing a strong infiltration of lymphocytes to the tumor area.

The pilot study of anti-tumor effects versus immunosuppression of Staphylococcal Enterotoxin C.

Superantigens tremendously activate T lymphocytes by recognizing the particular region on TCR Vbeta, by which cytotoxic T cells can be well armed to kill tumor cells. However, the obstacle exists in the fact that immunosuppression is induced adversely. Staphylococcal enterotoxins (SEs) are pyrogenic superantigens who invoke T lymphocytes cytotoxicity at a very low dosage where their endotoxic activity diminishes. Despite that the elaborate mechanisms are largely unknown, tumoricidal capacity of SEA and SEB has been well studied. In this study, we devoted our attention to evaluate Staphylococcal Enterotoxin C (SEC) regarding its tumoricidal activity versus immunosuppression. We proved with flow cytometry that SEC treatment on C57 mice resulted in a boost of the differentiation of T lymphocytes into CD4(+), CD8(+) subpopulations. In vitro, SEC causes increased IFNgamma release from human PBMC. Furthermore, in coculture SEC-treated human PBMC led to more death of cancer cell lines from a variety of origins. Systemic SEC treatment in mouse and rabbit models significantly decreases tumor growth. In tumor-bearing rabbits, tumor necrosis and strong infiltration of lymphocytes into tumor tissue were observed; the rabbits also benefit with less metastasic cancer cells in the lung. In the meantime, the induced cell immune responses, both T cell differentiation and PBMC IFNgamma release, declined as SEC concentration rose. Tumor growth data obtained from animal models are in accordance with the changes in immunity, in which tumor growth ceased to respond to high dosage SEC as it did to lower dosage. These observations on SEC investigation, particularly in aspect of dosage-related immunosuppression, are of significance to SEC therapeutic potential to cancer. Molecular mechanism underlying these findings warrants further intensive investigation.