The value of periportal hyperintensity sign from gadobenate dimeglumine-enhanced hepatobiliary phase MRI for predicting clinical outcomes in patients with decompensated cirrhosis.

OBJECTIVES: To determine the value of periportal hyperintensity sign from gadobenate dimeglumine (Gd-BOPTA)-enhanced hepatobiliary phase (HBP) magnetic resonance imaging (MRI) for predicting clinical outcomes in patients with decompensated cirrhosis. METHODS: A total of 199 cirrhotic patients who underwent Gd-BOPTA-enhanced MRI were divided into control group (n = 56) and decompensated cirrhosis group (n = 143). The presence of periportal hyperintensity sign on HBP MRI was recorded. The Cox regression model was used to investigate the association between periportal hyperintensity sign and clinical outcomes. RESULTS: There was a significant difference in the frequency of periportal hyperintensity sign on HBP between compensated and decompensated cirrhotic patients (p < 0.05). After a median follow-up of 29.0 months (range, 1.0-90.0 months), nine out of 143 patients (6.2%) with decompensated cirrhosis died. Periportal hyperintensity sign on HBP MRI was a significant risk factor for death (hazard ratio (HR) = 23.677; 95% confidence interval (CI) = 4.759-117.788; p = 0.0001), with an area under the curve (AUC) of 0.844 (95% CI = 0.774-0.899). Thirty patients (20.9%) developed further decompensation. Periportal hyperintensity sign on HBP MRI was also a significant risk factor for further decompensation (HR = 2.594; 95% CI = 1.140-5.903; p = 0.023). CONCLUSIONS: Periportal hyperintensity sign from Gd-BOPTA-enhanced HBP MRI is valuable for predicting clinical outcomes in patients with decompensated cirrhosis. CRITICAL RELEVANCE STATEMENT: Periportal hyperintensity sign from gadobenate dimeglumine-enhanced hepatobiliary phase magnetic resonance imaging is a new noninvasive method to predict clinical outcomes in patients with decompensated cirrhosis. KEY POINTS: • There was a significant difference in the frequency of periportal hyperintensity sign on HBP between compensated and decompensated cirrhotic patients. • Periportal hyperintensity sign on the hepatobiliary phase was a significant risk factor for death in patients with decompensated cirrhosis. • Periportal hyperintensity sign on the hepatobiliary phase was a significant risk factor for further decompensation in patients with decompensated cirrhosis.

Mnox Nanoenzyme Armed CAR-NK Cells Enhance Solid Tumor Immunotherapy by Alleviating the Immunosuppressive Microenvironment.

Adoptively transferred cells usually suffer from exhaustion, limited expansion, and poor infiltration, partially attributing to the complicated immunosuppressive microenvironment of solid tumors. Therefore, it is necessary to explore more effective strategies to improve the poor tumor microenvironment (TME) to efficaciously deliver and support extrinsic effector cells in vivo. Herein, an intelligent biodegradable hollow manganese dioxide nanoparticle (MnOX) that possesses peroxidase activity to catalyze excess H2O2 in the TME to produce oxygen and relieve the hypoxia of solid tumors is developed. MnOX nanoenzymes modified with CD56 antibody could specifically bind CAR-NK (chimeric antigen receptor modified natural killer) cells. It is demonstrated that CAR-NK cells incorporated with MnOX nanoenzymes effectively infiltrate into tumor tissues with an improved TME, which results in superior antitumor activity in solid tumor-bearing mice. The antibody connection between MnOX nanoenzymes and CAR-NK endows the lowest efficient dosage of MnOX. This study features a smart synergistic immunotherapy approach for solid tumors using MnOX nanoenzyme-armed CAR-NK cells, which would provide a valuable tool for immunocyte therapy in solid tumors.

The hepatic GABAergic system promotes liver macrophage M2 polarization and mediates HBV replication in mice.

Macrophages display functional phenotypic plasticity. Hepatitis B virus (HBV) infection induces polarizations of liver macrophages either to M1-like pro-inflammatory phenotype or to M2-like anti-inflammatory phenotype. Gamma-aminobutyric acid (GABA) signaling exists in various non-neuronal cells including hepatocytes and some immune cells. Here we report that macrophages express functional GABAergic signaling components and activation of type A GABA receptors (GABAARs) promotes M2-polarization thus advancing HBV replication. Notably, intraperitoneal injection of GABA or the GABAAR agonist muscimol increased HBV replication in HBV-carrier mice that were generated by hydrodynamical injection of adeno-associated virus/HBV1.2 plasmids (pAAV/HBV1.2). The GABA-augmented HBV replication in HBV-carrier mice was significantly reduced by the GABAAR inhibitor picrotoxin although picrotoxin had no significant effect on serum HBsAg levels in control HBV-carrier mice. Depletion of liver macrophages by liposomal clodronate treatment also significantly reduced the GABA-augmented HBV replication. Yet adoptive transfer of liver macrophages isolated from GABA-treated donor HBV-carrier mice into the liposomal clodronate-pretreated recipient HBV-carrier mice restored HBV replication. Moreover, GABA or muscimol treatment increased the expression of "M2" cytokines in macrophages, but had no direct effect on HBV replication in the HepG2.2.15 cells, HBV1.3-transfected Huh7, HepG2, or HepaRG cells, or HBV-infected Huh7-NTCP cells. Taken together, these results suggest that increasing GABA signaling in the liver promotes HBV replication in HBV-carrier mice by suppressing the immunity of liver macrophages, but not by increasing the susceptibility of hepatocytes to HBV infection. Our study shows that a previously unknown GABAergic system in liver macrophage has an essential role in HBV replication.

Fecal microbiota transplantation for irritable bowel syndrome: a systematic review and meta-analysis of randomized controlled trials.

Objective: Whether fecal microbiota transplantation (FMT) in patients with irritable bowel syndrome (IBS) is effective in improving outcomes remains controversial. We assessed the safety and efficacy of FMT for patients with IBS. Methods: In this systematic review and meta-analysis, we searched PubMed, Embase, Web of Science, the Cochrane Library, the clinicaltrials.gov and International Clinical Trials Registry Platform (ICTRP) up to February 25, 2022, updated to March 28, 2023. Randomized controlled trials (RCTs) compared the stool and capsule FMT with placebo in patients with IBS were included. Two authors independently assessed study eligibility, extracted the data, and assessed risk of bias. We did meta-analysis with RevMan, and the Stata software was used for sensitivity analysis and meta-regression. The GRADE system was used to assess the quality of evidences. Mean difference (MD) or standardized Mean difference (SMD) with 95% CI for continuous data, and risk ratios (RR) with 95% CI for dichotomous data were used with random-effects models. The primary outcomes included the clinical response rate and IBS-SSS score. This study is registered with PROSPERO: CRD42022328377. Results: Nineteen reports from nine RCTs were included finally. Compared with the placebo, a single stool FMT could significantly decrease the IBS-SSS score at 1 month (MD=-65.75, 95%CI [-129.37, -2.13]), 3 months (MD=-102.11, 95% CI [-141.98, -62.24]), 6 months (MD=-84.38, 95%CI [-158.79, -9.97]), 24 months (MD=-110.41, 95%CI [-145.37, -75.46]), and 36 months (MD=-104.71, 95%CI [-137.78, -71.64]). It also could improve the clinical response rate at 3 months (RR=1.91, 95% [1.12, 3.25]), 24 months (RR=2.97, 95% [1.94, 4.54]), and 36 months (RR=2.48, 95% [1.65, 3.72]), and increase the IBS-QoL score at 3 months, 24 months, and 36 months. FMT did not increase the serious adverse event. The risk of bias was low, and the quality of evidence based on GRADE system was moderate in the stool FMT group. However, we did not find positive effect of capsule FMT on patients with IBS based on the current available data. Conclusion: A single stool FMT is effective and safe for patients with IBS. However, some factors may affect the effectiveness of FMT, and the relationship between the gut microbiome and the effect of FMT for IBS is still unclear. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022328377.

Tim-4 reprograms cholesterol metabolism to suppress antiviral innate immunity by disturbing the Insig1-SCAP interaction in macrophages.

Accumulating evidence indicates that macrophages reshape their cholesterol metabolism in response to pathogens to support host defense. Intervention of host cholesterol homeostasis has emerged as a promising strategy for antiviral therapy. T cell immunoglobulin and mucin domain-containing molecule 4 (Tim-4) is indispensable in maintaining the homeostasis of macrophages. However, its role in antiviral innate immunity and cholesterol metabolism remains unknown. Here, we report that Tim-4 deficiency results in boosted interferon (IFN) signaling and decreased viral load. Mechanistically, Tim-4 disturbs the Insig1-SCAP interaction and promotes SCAP-SREBP2 complex translocation to the Golgi apparatus, eventually leading to the upregulation of cholesterol biosynthesis in macrophages, which limits the type I IFN response. Our findings demonstrate that Tim-4 suppresses type I IFN signaling by enhancing SREBP2 activation, delineating the role of Tim-4 in antiviral innate immunity and cholesterol metabolism, which sheds light on the mechanism by which Tim-4 orchestrates macrophage homeostasis.

Global research trends and hotspots of fecal microbiota transplantation: A bibliometric and visualization study.

Introduction: Fecal microbiota transplantation (FMT) has gained considerable attention in a variety of clinical research areas, and an increasing number of articles are being published. It is very critical to reveal the global status, future research trends, and hotspots in the FMT research and application. Methods: We searched the Web of Science Core Collection up to May 10, 2022, and only articles and review articles about FMT were included finally. CiteSpace 5.8.R3, VOSviewer 1.6.18, Scimago Graphica and Microsoft Office Excel 2019 were used for data analysis and visualization. The results included publication characteristics, Co-authorships analysis, Co-cited analysis, Co-occurrence analysis, and burst analysis. Results: Eleven thousand nine hundred seventy-two records were used for the analysis and visualization finally, these records were published between 1980 and 2022, and the publication about FMT is increasing year by year. Co-authorship analysis shown that the USA played a key role in this field. After data analysis and visualization, a total of 57 hotspots about FMT were produced. We summarized these hotspots and classified them into 7 grades according to the number of evidence sources. The evidence sources included top 25 of Web of Science categories, top 30 most Co-cited references, top 10 clusters of references, top 25 references with the strongest citation bursts, top 25 keywords with the most occurrence frequency, major 15 clusters of keywords, top 25 keywords with the strongest citation bursts, and top 35 disease keywords. Conclusion: This bibliometric analysis is expected to provide overall perspective for FMT. FMT has gained increasing attention and interest, there are many hotspots in this field, which may help researchers to explore new directions for future research.

Accuracy evaluation of combining gastroscopy, multi-slice spiral CT, Her-2, and tumor markers in gastric cancer staging diagnosis.

BACKGROUND: To evaluate the diagnostic accuracy of single gastroscopy, multi-slice spiral CT, HER-2 or tumor markers, and their combination in the diagnosis of gastric cancer. METHODS: A total of 98 patients with gastric cancer were selected as the research subjects. All patients underwent preoperative gastroscopy, MSCT, and the expression levels of HER-2, CEA, CA199, CA724, and CA242 were detected. A control group of 98 normal adults was selected to compare the risk factors for gastric cancer and to analyze the data. RESULTS: There was statistical significance in the expression of the 5 markers in tumor size (P < 0.05), but no statistical significance in other clinical data (P > 0.05). The tumor marker CEA in gastric mucosal tissue of patients with gastric cancer had the highest positive detection rate for gastric cancer, and the difference was statistically significant (P < 0.05) compared with gastroscopy, MSCT and other markers. The combined diagnosis had higher sensitivity, specificity and accuracy compared with the single diagnosis of gastric cancer staging, and the difference was statistically significant (P < 0.05). Compared with normal adults, patients with gastric cancer had statistically significant differences in diet, body mass index, and family genetic history (P < 0.05), while there was no statistically significant difference in whether they had type A blood (P > 0.05). CONCLUSION: The combined diagnosis of gastroscopy, MSCT, immunohistochemical marker Her-2, and tumor markers CEA, CA199, CA724, and CA242 can more accurately determine the clinical staging and lesion invasion depth of patients with gastric cancer and can significantly improve the sensitivity of diagnosis.

Switch receptor T3/28 improves long-term persistence and antitumor efficacy of CAR-T cells.

BACKGROUND: Chimeric antigen receptor (CAR) T cells have been successfully used in tumor immunotherapy due to their strong antitumor responses, especially in hematological malignancies such as B cell acute lymphoid leukemia. However, on-target off-tumor toxicity and poor persistence severely limit the clinical application of CAR-T cell therapy. METHODS: T-cell immunoglobulin mucin domain molecule 3 (TIM-3) was used to develop a second-generation 41BB CD19 CAR linked with a T3/28 chimera, in which truncated extracellular TIM-3 was fused with the CD28 transmembrane and cytoplasmic domains. The efficacy of T3/28 CAR-T cells was evaluated in vitro and in vivo. RESULTS: We demonstrated that the switch receptor T3/28 preserved the TCM phenotype, improved proliferative capacity, and reduced exhaustion of CAR-T cells, resulting in superior in vitro and in vivo antitumor activity in B lymphoma. Importantly, the switch receptor T3/28 substantially prolonged the persistence of CAR-T cells, and the interleukin-21/Stat3 axis probably contributed to the enhanced cytotoxicity of T3/28 CAR-T cells. CONCLUSION: Overall, the T3/28 chimera significantly prolonged the persistence of CAR-T cells, and T3/28 CAR-T cells possessed potent antitumor activity in mice, shedding new light on potential improvements in adoptive T cell therapies.

Surface specifically modified NK-92 cells with CD56 antibody conjugated superparamagnetic Fe3O4 nanoparticles for magnetic targeting immunotherapy of solid tumors.

Although there has been significant progress in the development of tumor immunotherapies, many challenges still exist for the treatment of solid tumors. Natural killer (NK) cells possess broad-spectrum cytotoxicity against tumors, but their limited migration and infiltration abilities restrict their application in solid tumor therapies. Here, we combined a facile and efficient magnetic-targeting strategy with NK cell-based therapy to develop a novel immunotherapy approach for treating solid tumors. Anti-CD56 antibodies were conjugated with Fe3O4 nanoparticles, which could specifically bind with NK-92 cells endowing them with a magnetic field driven targeting ability. These NK-Fe3O4 biohybrid nanoparticles were able to facilitate directional migration to the tumor site in vivo under external magnetic field guidance and efficiently inhibit tumor growth. These functionalized NK cells represent a novel approach for solid tumor therapy and may provide a promising modality for cancer interventions in the future.

Comparison of Periarticular Injection and Intra-articular Injection for Pain Management After Total Knee Arthroplasty: A Systematic Review and Meta-Analysis.

PURPOSE: Local infiltration analgesia, an essential component of multimodal analgesia after total knee arthroplasty (TKA), can be classified into periarticular injection (PAI) and intra-articular injection (IAI) as per administration techniques. Currently, there is no definite answer of the optimal choice between the two techniques. This meta-analysis aims to determine whether PAI provides superiority of pain relief and functional recovery than IAI after TKA. DESIGN: Systematic review and meta-analysis. METHODS: Comparative studies that compared PAI and IAI in patients after TKA were searched in the Embase, PubMed, MEDLINE, and the Cochrane Library databases. The primary outcomes were visual analog scale scores for pain and opioid consumption. The secondary outcomes were complications, function of recovery, and length of hospital stay. FINDINGS: Four randomized controlled trials and two case-controlled studies with a total of 769 patients were enrolled. There were no significant differences in mean visual analog scale scores at postoperative day 0 (P = .17) and day 1 (P = .27), maximum visual analog scale scores at day 0 (P = .89) and day 1 (P = .82), total opioid consumption at day 1 (P = .96), opioid complications (P = .15), and length of hospital stay (P = .84) between PAI and IAI. CONCLUSIONS: Based on the available evidence, PAI does not offer superior effects at pain control and discharge than IAI after TKA. However, owing to the limited sample size and heterogeneity of the included studies, further large well-designed randomized controlled trials are still needed to validate this conclusion. REGISTRATION: The protocol has been registered in the PROSPERO international database under number CRD42020165138.

Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages.

Tumor immunotherapy has shown great progress for the treatment of cancer; however, both endogenous and exogenous T cells are inhibited by the immunosuppressive tumor microenvironment. Tumor-associated macrophages (TAMs) in the microenvironment play pivotal and complex roles in tumor development and progression. Macrophages are categorized as M1 and M2 types. Relevant studies suggest that M2 TAMs correlate with poor prognosis. Colony-stimulating factor 1 receptor (CSF1R) controls the formation, differentiation and function of M2 macrophages, which helps tumors grow, metastasize and secrete immunosuppressive cytokines. The objectives of this study were to establish two types of third-generation chimeric antigen receptors (CARs) that could specifically target human CSF1R, and to introduce the CARs into NK92MI cells and normal human peripheral blood T cells through lentiviral transduction to produce CAR-natural killer (NK) and -T cells. We then tested their cytotoxicity against cell lines and peripheral blood monocytes expressing CSF1R. In vitro experiments confirmed that third-generation CARs had good target specificity and cytotoxicity. It was expected that CAR-NK and -T cells could specifically kill M2 TAMs in the tumor microenvironment and remove their inhibitory effect. Therefore, CSF1R-targeting CAR-NK and -T cells could represent a novel cellular immunotherapy strategy in conjunction with other antibody-based drugs and targeted therapeutics.

CAR-NK-92MI and CAR-CD19-T cells targeting CD19 antigen exhibit significant in vitro killing activity on mantle cell lymphoma / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the in vitro cytotoxicity of the chimeric antigen receptor-modified T cells and NK-92MI cells (CAR-NK-92MI cells) and CAR-CD19-T cells against mantle cell lymphoma (MCL). Methods: CAR-T cell technology, successfully obtained in clinical trial of B-lineage acute lymphoblastic leukemia (B-ALL) treatment, was used in this study. In the case of high expression of CD19 antigen in MCL, CAR- CD19-T cells and CAR- CD19-NK-92MI cells targeting CD19 antigen were generated, respectively. Then, their cytotoxicity against MCL cell lines was detected by LDH release assay and the results were verified by flow cytometry. Results: Compared with control group, both CAR-NK-92MI and CAR-CD19-T cells exhibited prominent killing effect against MCLcells（all P<0.01）; in addition, the two CAR cells exhibited high cytotoxicity against K562-CD19 cells but not on K562 cells（all P <0.01）. The death rate of MCL cells from CAR-NK-92MI group was 30%-40% more than that of control group, and the death rate of MCL from CAR-CD19-T group was 40%-50% more than that of control group. Conclusion: Both CAR-NK-92MI and CAR-CD19-T cells exhibited potent cytotoxicity against MCLcells in vitro.