Human umbilical cord mesenchymal stem cell transplantation for the treatment of acute-on-chronic liver failure: protocol for a multicentre random double-blind placebo-controlled trial.

INTRODUCTION: Acute-on-chronic liver failure (ACLF) is a prevalent and life-threatening liver disease with high short-term mortality. Although recent clinical trials on the use of mesenchymal stem cells (MSCs) for ACLF treatment have shown promising results, multicentre randomised controlled phase II clinical trials remain uncommon. The primary aim of this trial is to assess the safety and efficacy of different MSCs treatment courses for ACLF. METHODS AND ANALYSIS: This is a multicentre, double-blind, two-stage, randomised and placebo-controlled clinical trial. In the first stage, 150 patients with ACLF will be enrolled and randomly assigned to either a control group (50 cases) or an MSCs treatment group (100 cases). They will receive either a placebo or umbilical cord-derived MSCs (UC-MSCs) treatment three times (at weeks 0, 1 and 2). In the second stage, 28 days after the first UC-MSCs infusion, surviving patients in the MSCs treatment group will be further randomly divided into MSCs-short and MSCs-prolonged groups at a 1:1 ratio. They will receive two additional rounds of placebo or UC-MSCs treatment at weeks 4 and 5. The primary endpoints are the transplant-free survival rate and the incidence of treatment-related adverse events. Secondary endpoints include international normalised ratio, total bilirubin, serum albumin, blood urea nitrogen, model for end-stage liver disease score and Child-Turcotte-Pugh score. ETHICS AND DISSEMINATION: Ethical approval of this study has been obtained from the Fifth Medical Center of the Chinese PLA General Hospital (KY-2023-3-19-1). All results of the study will be submitted to international journals and international conferences for publication on completion of the study. TRIAL REGISTRATION NUMBER: NCT05985863.

Activation of CD14+ Monocytes via the IFN-γ Signaling Pathway Is Associated with Immune-Related Adverse Events in Hepatocellular Carcinoma Patients Receiving PD-1 Inhibition Combination Therapy.

(1) Background: Immune-related adverse events (irAEs) are a series of unique organ-specific inflammatory toxicities observed in patients with hepatocellular carcinoma (HCC) undergoing PD-1 inhibition combination therapy. The specific underlying mechanisms remain unclear. (2) Methods: We recruited 71 patients with HCC undergoing PD-1 inhibition combination therapy. These patients were then divided into two groups based on irAE occurrence: 34 had irAEs and 37 did not. Using Olink proteomics, we analyzed the aberrant inflammation-related proteins (IRPs) in these patient groups. For single-cell RNA sequencing (scRNA-seq) analysis, we collected peripheral blood mononuclear cells (PBMCs) from two representative patients at the pretreatment, irAE occurrence, and resolution stages. (3) Results: Our study revealed distinct plasma protein signatures in HCC patients experiencing irAEs after PD-1 inhibition combination therapy. We clarified the relationship between monocyte activation and irAEs, identified a strongly associated CD14-MC-CCL3 monocyte subset, and explored the role of the IFN-γ signaling pathway in monocyte activation during irAEs. (4) Conclusions: The activation of monocytes induced by the IFN-γ signaling pathway is an important mechanism underlying the occurrence of irAEs in HCC patients receiving PD-1 inhibition combination therapy.

Omicron neutralization character in patients with breast cancer and liver cancer after the nationwide omicron outbreak.

BACKGROUND: The surge in omicron variants has caused nationwide breakthrough infections in mainland China since the December 2022. In this study, we report the neutralization profiles of serum samples from the patients with breast cancer and the patients with liver cancer who had contracted subvariant breakthrough infections. METHODS: In this real-world study, we enrolled 143 COVID-19-vaccinated (81 and 62 patients with breast and liver cancers) and 105 unvaccinated patients with cancer (58 and 47 patients with breast and liver cancers) after omicron infection. Anti-spike receptor binding domain (RBD) IgGs and 50% pseudovirus neutralization titer (pVNT50) for the preceding (wild type), circulating omicron (BA.4-BA.5, and BF.7), and new subvariants (XBB.1.5) were comprehensively analyzed. RESULTS: Patients with liver cancer receiving booster doses had higher levels of anti-spike RBD IgG against circulating omicron (BA.4-BA.5, and BF.7) and a novel subvariant (XBB.1.5) compared to patients with breast cancer after breakthrough infection. Additionally, all vaccinated patients produced higher neutralizing antibody titers against circulating omicron (BA.4-BA.5, and BF.7) compared to unvaccinated patients. However, the unvaccinated patients produced higher neutralizing antibody against XBB.1.5 than vaccinated patients after Omicron infection, with this trend being more pronounced in breast cancer than in liver cancer patients. Moreover, we found that there was no correlation between anti-spike RBD IgG against wildtype virus and the neutralizing antibody titer, but a positive correlation between anti-spike RBD IgG and the neutralizing antibody against XBB.1.5 was found in unvaccinated patients. CONCLUSION: Our study found that there may be differences in vaccine response and protective effect against COVID-19 infection in patients with liver and breast cancer. Therefore, we recommend that COVID-19 vaccine strategies should be optimized based on vaccine components and immunology profiles of different patients with cancer.

HLA-mismatched allogeneic adoptive immune therapy in patients with severely immunosuppressed AIDS: a multicenter, open-label, controlled, phase 2a study.

Recurrent opportunistic infections (OIs) in patients with severely immunosuppressed AIDS remain an unresolved medical challenge despite advancements in antiretroviral therapy (ART). To address this gap, we developed an HLA-mismatched allogeneic adoptive immune therapy (AAIT) specifically targeting this patient population. The safety and efficacy of this novel therapeutic approach were preliminarily confirmed in our phase 1 trial. Subsequently, a multicenter, open-label, controlled, phase 2a trial was conducted to evaluate the efficacy of AAIT in combination with ART compared with the conventional ART-only regimen. No difference in the incidence of adverse events (AEs) was observed between the two groups at the 96-week follow-up. AAIT treatment improved CD4+ T cell recovery at weeks 72 (P = 0.048) and 96 (P = 0.024) compared to the Control Group. Additionally, stratified analysis of patients in the AAIT Group showed that donor/recipient sex mismatch was significantly associated with the likelihood of patients achieving an immunological response (OR = 8.667; 95% CI, 2.010-37.377; P = 0.004). These findings suggest that AAIT serves as a promising adjunct therapy for improving the outcomes of patients with severely immunosuppressed AIDS. Further studies are needed to elucidate the immunological mechanisms underlying AAIT and identify the subpopulations that respond optimally to this therapeutic approach. This trial is registered at www.clinicaltrials.gov (NCT04098770).Trial registration: ClinicalTrials.gov identifier: NCT04098770.Trial registration: ClinicalTrials.gov identifier: NCT02651376.

HBeAg induces neutrophils activation impairing NK cells function in patients with chronic hepatitis B.

BACKGROUND: The role of neutrophils in hepatitis B virus (HBV) infection has been a subject of debate due to their involvement in antiviral responses and immune regulation. This study aimed to elucidate the neutrophil characteristics in patients with chronic hepatitis B (CHB). METHODS: Through flow cytometry and ribonucleic acid-sequencing analysis, the phenotypes and counts of neutrophils were analyzed in patients with CHB. Moreover, the effects of HBeAg on neutrophils and the corresponding pattern recognition receptors were identified. Simultaneously, the cross-talk between neutrophils and natural killer (NK) cells was investigated. RESULTS: Neutrophils were activated in patients with CHB, characterized by higher expression levels of programmed death-ligand 1 (PD-L1), cluster of differentiation 86, and interleukin-8, and lower levels of CXC motif chemokine receptor (CXCR) 1 and CXCR2. Hepatitis B e antigen (HBeAg) partially induces neutrophil activation through the Toll-like receptor 2 (TLR2). A consistent upregulation of the TLR2 and HBeAg expression was observed in patients with CHB. Notably, the genes encoding molecules pivotal for NK-cell function upon NK receptor engagement enriched in neutrophils after HBeAg activation. The HBeAg-activated neutrophils demonstrated the ability to decrease the production of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) in NK cells, while the PD-1 and PD-L1 pathways partially mediated the immunosuppression. CONCLUSIONS: The immunosuppression of neutrophils induced by HBeAg suggests a novel pathogenic mechanism contributing to immune tolerance in patients with CHB.

Plasma proteomics-based biomarkers for predicting response to mesenchymal stem cell therapy in severe COVID-19.

BACKGROUND: The objective of this study was to identify potential biomarkers for predicting response to MSC therapy by pre-MSC treatment plasma proteomic profile in severe COVID-19 in order to optimize treatment choice. METHODS: A total of 58 patients selected from our previous RCT cohort were enrolled in this study. MSC responders (n = 35) were defined as whose resolution of lung consolidation ≥ 51.99% (the median value for resolution of lung consolidation) from pre-MSC to 28 days post-MSC treatment, while non-responders (n = 23) were defined as whose resolution of lung consolidation < 51.99%. Plasma before MSC treatment was detected using data-independent acquisition (DIA) proteomics. Multivariate logistic regression analysis was used to identify pre-MSC treatment plasma proteomic biomarkers that might distinguish between responders and non-responders to MSC therapy. RESULTS: In total, 1101 proteins were identified in plasma. Compared with the non-responders, the responders had three upregulated proteins (CSPG2, CTRB1, and OSCAR) and 10 downregulated proteins (ANXA1, AGRG6, CAPG, DDX55, KV133, LEG10, OXSR1, PICAL, PTGDS, and S100A8) in plasma before MSC treatment. Using logistic regression model, lower levels of DDX55, AGRG6, PICAL, and ANXA1 and higher levels of CTRB1 pre-MSC treatment were predictors of responders to MSC therapy, with AUC of the ROC at 0.910 (95% CI 0.818-1.000) in the training set. In the validation set, AUC of the ROC was 0.767 (95% CI 0.459-1.000). CONCLUSIONS: The responsiveness to MSC therapy appears to depend on baseline level of DDX55, AGRG6, PICAL, CTRB1, and ANXA1. Clinicians should take these factors into consideration when making decision to initiate MSC therapy in patients with severe COVID-19.

Safety of COVID-19 Vaccination in Patients With Breast Cancer: Cross-Sectional Study in China.

BACKGROUND: The widespread use of vaccines against the novel coronavirus disease (COVID-19) has become one of the most effective means to establish a population immune barrier. Patients with cancer are vulnerable to COVID-19 infection, adverse events, and high mortality, and should be the focus of epidemic prevention and treatment. However, real-world data on the safety of vaccines for patients with breast cancer are still scarce. OBJECTIVE: This study aims to compare the safety of COVID-19 vaccines between patients vaccinated before or after being diagnosed with breast cancer. METHODS: Patients with breast cancer who sought medical advice from October 2021 to December 2021 were screened. Those who received COVID-19 vaccines were enrolled in this study to analyze the safety of the vaccines. The primary outcome was patient-reported adverse events (AEs). All events after vaccine injection were retrospectively documented from the patients. RESULTS: A total of 15,455 patients with breast cancer from 41 hospitals in 20 provinces in China were screened, and 5766 patients who received COVID-19 vaccines were enrolled. Of those enrolled, 45.1% (n=2599) of patients received vaccines before breast cancer diagnosis, 41.3% (n=2379) were vaccinated after diagnosis, and 13.6% (n=784) did not known the accurate date of vaccination or cancer diagnosis. Among the patients vaccinated after diagnosis, 85.4% (n=2032) were vaccinated 1 year after cancer diagnosis and 95.4% (n=2270) were vaccinated during early-stage cancer. Of all 5766 vaccinated patients, 93.9% (n=5415) received an inactivated vaccine, 3.7% (n=213) received a recombinant subunit vaccine, and 2.4% (n=138) received other vaccines, including adenovirus and mRNA vaccines. In the first injection of vaccines, 24.4% (n=10, 95% CI 11.2-37.5) of patients who received an adenovirus vaccine reported AEs, compared to only 12.5% (n=677, 95% CI 11.6-13.4) of those who received an inactivated vaccine. Patients with metastatic breast cancer reported the highest incidence of AEs (n=18, 16.5%, 95% CI 9.5-23.5). Following the second injection, patients who received an inactivated vaccine (n=464, 8.7%, 95% CI 8.0-9.5) and those who received a recombinant vaccine (n=25, 8.7%, 95% CI 5.5-12.0) reported the same incidence of AEs. No significant differences in patient-reported AEs were found between the healthy population and patients with breast cancer (16.4% vs 16.9%, respectively); the most common AEs were local pain (11.1% vs 9.1%, respectively), fatigue (5.5% vs 6.3%, respectively), and muscle soreness (2.3% vs 3.6%, respectively). The type of vaccine and time window of vaccination had little impact on patient-reported AEs. CONCLUSIONS: Compared with patients vaccinated before breast cancer diagnosis, there were no significant differences in patient-reported AEs in the patients vaccinated after diagnosis. Thus, it is safe for patients with breast cancer, especially for those in the early stage, to receive COVID-19 vaccines. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200055509; https://tinyurl.com/33zzj882.

Effect of SARS-CoV-2 Breakthrough Infection on HIV Reservoirs and T-Cell Immune Recovery in 3-Dose Vaccinated People Living with HIV.

People living with human immunodeficiency virus (PLWH) are a vulnerable population with a higher risk of severe coronavirus disease 2019 (COVID-19); therefore, vaccination is recommended as a priority. Data on viral reservoirs and immunologic outcomes for PLWH breakthrough infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are currently limited. In this study, we investigated the effects of SARS-CoV-2 breakthrough infection on hematological parameters, human immunodeficiency virus (HIV) reservoir size, and T-cell recovery in PLWH receiving antiretroviral therapy (ART) after SARS-CoV-2 booster vaccination. The results indicated that during breakthrough infection, booster vaccination with homologous and heterologous vaccines was safe in PLWH after receiving two doses of inactivated vaccination. The absolute CD4 counts decreased in the heterologous group, whereas the CD8 counts decreased in the homologous booster group after breakthrough infection in PLWH. Breakthrough infection increased HIV reservoirs and was associated with increased T-cell activation in PLWH who received virally suppressed ART and a 3-dose vaccination. According to our data, the breakthrough infection of SARS-CoV-2 may put PLWH at a greater risk for increased HIV reservoirs, even if these individuals were virally suppressed with ART after 3-dose SARS-CoV-2 vaccination.

Human umbilical cord-derived mesenchymal stem cells for the treatment of decompensated cirrhosis (MSC-DLC-1): a dose-escalation, phase I trial protocol.

INTRODUCTION: There are limited therapeutic options to efficiently treat patients with decompensated liver cirrhosis. This trial aims to explore the efficacy and safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) for the treatment of patients with decompensated liver cirrhosis. METHODS AND ANALYSIS: This study is an open-label, dose-escalation, one-armed phase I trial. A single injection of UC-MSCs will be administered in a predetermined dose in each cohort (5.0×107, 1.0×108, 1.5×108 or 2.0×108 cells) according to the '3+3' rule. The primary evaluation measures will include the incidence of adverse events and the change in the Model for End-stage Liver Disease (MELD) score from baseline to the 28th day. Secondary evaluation measures will be evaluated at baseline and at each follow-up point. These measures will include the change in the MELD score from baseline to each follow-up point, the incidence of each complication associated with decompensated cirrhosis, liver transplant-free survival and the incidence of liver failure, among other relevant measures. All patients will be followed up for 24 months. This study will evaluate whether the use of UC-MSCs to treat patients with decompensated liver cirrhosis is safe and tolerable. ETHICS AND DISSEMINATION: The study has been approved by the Chinese People's Liberation Army General Hospital (Approval#: 2018-107-D-4). Once conducted, the results from the study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05227846.

Severe intestinal barrier damage in HIV-infected immunological non-responders.

The intestinal epithelial barrier plays an important role during human immunodeficiency virus (HIV) disease progression. However, the extent to which the intestinal epithelial barrier is damaged in immunological non-responders (INRs) and immunological responders (IRs) is largely unknown. In this study, we investigated and compared the levels of intestinal gland damage and related molecules, including the tight junction protein claudin-1, apoptosis marker caspase-3, HIV DNA, CD4+ T cell count, and inflammation marker tumor necrosis factor-α (TNF-α) among the IRs (n = 10), INRs (n = 8), and healthy controls (HCs, n = 7). Intestinal damage was not completely restored in both INRs and IRs and was more serious in INRs than that in IRs. Moreover, intestinal damage was positively correlated with HIV DNA levels and negatively correlated with CD4+ T cell counts. These results provide insight into understanding the characteristics of intestinal epithelial barrier damage between IRs and INRs.

The Imbalance Between Intestinal Th17 and Treg Cells Is Associated with an Incomplete Immune Reconstitution During Long-Term Antiretroviral Therapy in Patients with HIV.

Studies assessing the gut mucosal immune balance in HIV-infected patients using intestinal samples are scarce. In this study, we used intestinal mucosal specimens from the ileocecal region of seven immunological nonresponders (INRs), nine immunological responders (IRs), and six HIV-negative controls. We investigated T helper 17 (Th17) and T regulatory (Treg) cell counts and their ratio, zonula occludens-1 (ZO-1), intestinal fatty acid-binding protein (I-FABP), tumor necrosis factor-α, CD4+ T cell counts, HIV DNA, and cell-associated HIV RNA. The results showed that INRs had lower Th17 and higher Treg cell counts than IR, resulting in a significant difference in the Th17/Treg ratio between IRs and INRs. In addition, INRs had lower ZO-1 and higher I-FABP levels than IRs. The Th17/Treg ratio was positively associated with ZO-1 and negatively associated with I-FABP levels. There was a positive correlation between Th17/Treg ratio and CD4+ T cell counts and a negative correlation between the Th17/Treg ratio and HIV DNA in the intestine. Our study suggests that the imbalance of Th17/Treg in the intestine is a characteristic of incomplete immune reconstitution to antiretroviral therapy and is associated with intestinal damage.

Human mesenchymal stem cell therapy in severe COVID-19 patients: 2-year follow-up results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Long-term effects of human mesenchymal stem cell (MSC) treatment on COVID-19 patients have not been fully characterized. The aim of this study was to evaluate the safety and efficacy of a MSC treatment administered to severe COVID-19 patients enrolled in our previous randomized, double-blind, placebo-controlled clinical trial (NCT04288102). METHODS: A total of 100 patients experiencing severe COVID-19 received either MSC treatment (n = 65, 4 × 107 cells per infusion) or a placebo (n = 35) combined with standard of care on days 0, 3, and 6. Patients were subsequently evaluated 18 and 24 months after treatment to evaluate the long-term safety and efficacy of the MSC treatment. Outcomes measured included: 6-min walking distance (6-MWD), lung imaging, quality of life according to the Short Form 36 questionnaire (SF-36), COVID-19-related symptoms, titers of SARS-CoV-2 neutralizing antibodies, tumor markers, and MSC-related adverse events (AEs). FINDINGS: Two years after treatment, a marginally smaller proportion of patients had a 6-MWD below the lower limit of the normal range in the MSC group than in the placebo group (OR = 0.19, 95% CI: 0.04-0.80, Fisher's exact test, p = 0.015). At month 18, the general health score from the SF-36 was higher in the MSC group than in the placebo group (50.00 vs. 35.00, 95% CI: 0.00-20.00, Wilcoxon rank sum test, p = 0.018). Total severity score of lung imaging and the titer of neutralizing antibodies were similar between the two groups at months 18 and 24. There was no difference in AEs or tumor markers at the 2-year follow-up between the two groups. INTERPRETATION: Long-term safety was observed for the COVID-19 patients who received MSC treatment. However, efficacy of MSC treatment was not significantly sustained through the end of the 2-year follow-up period. FUNDING: The National Key Research and Development Program of China (2022YFA1105604, 2020YFC0860900, 2022YFC2304401), the specific research fund of The Innovation Platform for Academicians of Hainan Province (YSPTZX202216) and the Fund of National Clinical Center for Infectious Diseases, PLA General Hospital (NCRC-ID202105,413FZT6).

Epigenetic regulation of HBV-specific tumor-infiltrating T cells in HBV-related HCC.

BACKGROUND AND AIMS: HBV shapes the T-cell immune responses in HBV-related HCC. T cells can be recruited to the nidus, but limited T cells participate specifically in response to the HBV-related tumor microenvironment and HBV antigens. How epigenomic programs regulate T-cell compartments in virus-specific immune processes is unclear. APPROACH AND RESULTS: We developed Ti-ATAC-seq. 2 to map the T-cell receptor repertoire, epigenomic, and transcriptomic landscape of αß T cells at both the bulk-cell and single-cell levels in 54 patients with HCC. We deeply investigated HBV-specific T cells and HBV-related T-cell subsets that specifically responded to HBV antigens and the HBV + tumor microenvironment, respectively, characterizing their T-cell receptor clonality and specificity and performing epigenomic profiling. A shared program comprising NFKB1/2-, Proto-Oncogene, NF-KB Sub unit, NFATC2-, and NR4A1-associated unique T-cell receptor-downstream core epigenomic and transcriptomic regulome commonly regulated the differentiation of HBV-specific regulatory T-cell (Treg) cells and CD8 + exhausted T cells; this program was also selectively enriched in the HBV-related Treg-CTLA4 and CD8-exhausted T cell-thymocyte selection associated high mobility subsets and drove greater clonal expansion in HBV-related Treg-CTLA4 subset. Overall, 54% of the effector and memory HBV-specific T cells are governed by transcription factor motifs of activator protein 1, NFE2, and BACH1/2, which have been reported to be associated with prolonged patient relapse-free survival. Moreover, HBV-related tumor-infiltrating Tregs correlated with both increased viral titer and poor prognosis in patients. CONCLUSIONS: This study provides insight into the cellular and molecular basis of the epigenomic programs that regulate the differentiation and generation of HBV-related T cells from viral infection and HBV + HCC unique immune exhaustion.

Metabolic interventions improve HBV envelope-specific T-cell responses in patients with chronic hepatitis B.

BACKGROUND: Restoration of HBV-specific T cell immunity is a promising approach for the functional cure of chronic Hepatitis B (CHB), necessitating the development of valid assays to boost and monitor HBV-specific T cell responses in patients with CHB. METHODS: We analyzed hepatitis B virus (HBV) core- and envelope (env)-specific T cell responses using in vitro expanded peripheral blood mononuclear cells (PBMCs) from patients with CHB exhibiting different immunological phases, including immune tolerance (IT), immune activation (IA), inactive carrier (IC), and HBeAg-negative hepatitis (ENEG). Additionally, we evaluated the effects of metabolic interventions, including mitochondria-targeted antioxidants (MTA), polyphenolic compounds, and ACAT inhibitors (iACAT), on HBV-specific T-cell functionality. RESULTS: We found that HBV core- and env-specific T cell responses were finely coordinated and more profound in IC and ENEG than in the IT and IA stages. HBV env-specific T cells were more dysfunctional but prone to respond to metabolic interventions using MTA, iACAT, and polyphenolic compounds than HBV core-specific T-cells. The responsiveness of HBV env-specific T cells to metabolic interventions can be predicted by the eosinophil (EO) count and the coefficient of variation of red blood cell distribution width (RDW-CV). CONCLUSION: These findings may provide valuable information for metabolically invigorating HBV-specific T-cells to treat CHB.

Decreased granzyme-B expression in CD11c+CD8+ T cells associated with disease progression in patients with HBV-related hepatocellular carcinoma.

Introduction: CD11c+CD8+ T cells are an unconventional CD8+ T cell subset that exerts antiviral activity in infectious diseases. However, its characteristics in hepatocellular carcinoma (HCC) have not been elucidated. Methods: Twenty-six patients with hepatitis B virus (HBV)-related HCC and 25 healthy controls (HC) were enrolled. The frequency and phenotype of CD11c+CD8+ T cells in peripheral blood and tumors in situ were detected by flow cytometry and immunohistochemistry. Results: Both the HCC group and HC group had similar frequency and phenotype characteristics of CD11c+CD8+ T cells in the periphery. CD11c+CD8+ T cells were mainly composed of effector T cells, most of which were CD45RA+CCR7-. Compared with CD11c-CD8+ T cells, CD11c+CD8+ T cells had a higher proportion of CD38 and HLA-DR double positive, and expressed high levels of granzyme-B (GB) and degranulation marker CD107a, and produced high levels of interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ). However, the ability of degranulation and TNF-α production of CD11c+CD8+ T cells in patients with HCC were significantly lower than that in healthy controls. The GB expression level of peripheral CD11c+CD8+ T cells in patients with advanced stage of HCC was significantly lower than that in patients with early stage of HCC, and the GB expression level of liver-infiltrating CD11c+CD8+ T cells in tumor tissues was lower than that in non-tumor tissues. More importantly, the GB expression level of peripheral CD11c+CD8+ T cells was negatively correlated with tumor volume. Conclusions: These findings indicate that CD11c+CD8+ T cells may have potential anti-tumor activity and that GB+CD11c+CD8+ T cells are associated with disease progression in patients with HBV-related HCC.

Serum cytokine change profile associated with HBsAg loss during combination therapy with PEG-IFN-α in NAs-suppressed chronic hepatitis B patients.

Objective: The aim of this study was to explore the profile of cytokine changes during the combination therapy with pegylated interferon alpha (PEG-IFN-α) and its relationship with HBsAg loss in nucleos(t)ide analogs (NAs)-suppressed chronic hepatitis B patients. Methods: Seventy-six patients with chronic hepatitis B with HBsAg less than 1,500 IU/ml and HBV DNA negative after receiving ≥ 1-year NAs therapy were enrolled. Eighteen patients continued to take NAs monotherapy (the NAs group), and 58 patients received combination therapy with NAs and PEG-IFN-α (the Add-on group). The levels of IFNG, IL1B, IL1RN, IL2, IL4, IL6, IL10, IL12A, IL17A, CCL2, CCL3, CCL5, CXCL8, CXCL10, TNF, and CSF2 in peripheral blood during treatment were detected. Results: At week 48, 0.00% (0/18) in the NAs group and 25.86% (15/58) in the Add-on group achieved HBsAg loss. During 48 weeks of combined treatment, there was a transitory increase in the levels of ALT, IL1RN, IL2, and CCL2. Compared to the NAs group, CXCL8 and CXCL10 in the Add-on group remain higher after rising, yet CCL3 showed a continuously increasing trend. Mild and early increases in IL1B, CCL3, IL17A, IL2, IL4, IL6, and CXCL8 were associated with HBsAg loss or decrease >1 log, while sustained high levels of CCL5 and CXCL10 were associated with poor responses to Add-on therapy at week 48. Conclusions: The serum cytokine change profile is closely related to the response to the combination therapy with PEG-IFN-α and NAs, and may help to reveal the mechanism of functional cure and discover new immunological predictors and new therapeutic targets.

MRI/PAI Dual-modal Imaging-guided Precise Tracking of Bone Marrow-derived Mesenchymal Stem Cells Labeled with Nanoparticles for Treating Liver Cirrhosis.

Background and Aims: Stem cell transplantation is a potential treatment option for liver cirrhosis (LC). Accurately and noninvasively monitoring the distribution, migration, and prognosis of transplanted stem cells using imaging methods is important for in-depth study of the treatment mechanisms. Our study aimed to develop Au-Fe3O4 silica nanoparticles (NPs) as tracking nanoplatforms for dual-modal stem cell imaging. Methods: Au-Fe3O4 silica NPs were synthesized by seed-mediated growth method and co-precipitation. The efficiency and cytotoxicity of the NPs-labeled bone marrow-derived mesenchymal stem cells (BM-MSCs) were evaluated by Cell Counting Kit-8 assays, ICP-MS, phenotypic characterization, and histological staining. The biodistribution of labeled BM-MSCs injected through different routes (the hepatic artery or tail vein) into rats with LC was detected by magnetic resonance imaging (MRI), photoacoustic imaging (PAI), and Prussian blue staining. Results: Synthesized Au-Fe3O4 silica NPs consisted of a core (star-shaped Au NPs) and an outside silica layer doped with Fe3O4 NPs. After 24 h coincubation with 2.0 OD concentration of NPs, the viability of BM-MSCs was 77.91%±5.86% and the uptake of Au and Fe were (22.65±1.82) µg/mL and (234.03±11.47) µg/mL, respectively. The surface markers of labeled BM-MSCs unchanged significantly. Labeled BM-MSCs have osteogenic and adipogenic differentiation potential. Post injection in vivo, rat livers were hypointense on MRI and hyperintense on PAI. Prussian blue staining showed that more labeled BM-MSCs accumulated in the liver of the hepatic artery group. The severity of LC of the rats in the hepatic artery group was significantly alleviated. Conclusions: Au-Fe3O4 silica NPs were suitable MRI/PAI dual-modal imaging nanoplatforms for stem cell tracking in regenerative medicine. Transhepatic arterial infusion of BM-MSCs was the optimal route for the treatment of LC.

Distinct inflammation-related proteins associated with T cell immune recovery during chronic HIV-1 infection.

Chronic inflammation and T cell dysregulation persist in individuals infected with human immunodeficiency virus type 1 (HIV-1), even after successful antiretroviral treatment. The mechanism involved is not fully understood. Here, we used Olink proteomics to comprehensively analyze the aberrant inflammation-related proteins (IRPs) in chronic HIV-1-infected individuals, including in 24 treatment-naïve individuals, 33 immunological responders, and 38 immunological non-responders. T cell dysfunction was evaluated as T cell exhaustion, activation, and differentiation using flow cytometry. We identified a cluster of IRPs (cluster 7), including CXCL11, CXCL9, TNF, CXCL10, and IL18, which was closely associated with T cell dysregulation during chronic HIV-1 infection. Interestingly, IRPs in cluster 5, including ST1A1, CASP8, SIRT2, AXIN1, STAMBP, CD40, and IL7, were negatively correlated with the HIV-1 reservoir size. We also identified a combination of CDCP1, CXCL11, CST5, SLAMF1, TRANCE, and CD5, which may be useful for distinguishing immunological responders and immunological non-responders. In conclusion, the distinct inflammatory milieu is closely associated with immune restoration of T cells, and our results provide insight into immune dysregulation during chronic HIV-1 infection.

Synaptophysin-like 2 expression correlates with lymph node metastasis and poor prognosis in colorectal cancer patients.

BACKGROUND: Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. Synaptophysin-like 2 (SYPL2) is a neuroendocrine-related protein highly expressed in skeletal muscle and the tongue. The involvement of SYPL2 in CRC, including its level of expression and function, has not been evaluated. AIM: To evaluate the correlations of SYPL2 expression with lymph node metastasis (LNM) and prognosis in patients with CRC. METHODS: The levels of expression of SYPL2 in CRC and normal colorectal tissues were analyzed in multiple public and online databases. The associations between clinical variables and SYPL2 expression were evaluated statistically, and the associations between SYPL2 expression and prognosis in patients with CRC were analyzed using the Kaplan-Meier method and univariate/multivariate Cox regression analyses. SYPL2 expression was assessed in 20 paired CRC tissue and adjacent normal colorectal tissue samples obtained from Fuyang People's Hospital, and the associations between SYPL2 expression and the clinical characteristics of these patients were investigated. Correlations between the levels of expression of SYPL2 and key targeted genes were determined by Pearson's correlation analysis. The distribution of immune cells in these samples was calculated using the CIBERSORT algorithm. Gene set enrichment analysis (GSEA) was performed to evaluate the biofunction and pathways of SYPL2 in CRC. RESULTS: SYPL2 expression was significantly lower in CRC tissue samples than in normal colorectal tissue samples (P < 0.05). High SYPL2 levels in CRC tissues correlated significantly with LNM (P < 0.05) and a poorer patient prognosis, including significantly shorter overall survival (OS) [hazard ratio (HR) = 1.9, P < 0.05] and disease-free survival (HR = 1.6, P < 0.05). High SYPL2 expression was an independent risk factor for OS in both univariate (HR = 2.078, P = 0.014) and multivariate (HR = 1.754, P = 0.018) Cox regression analyses. In addition, SYPL2 expression correlated significantly with the expression of KDR (P < 0.0001, r = 0.47) and the BRAF V600E mutation (P < 0.05). Higher SYPL2 expression was associated with the enrichment of CD8 T-cells and M0 macrophages in the tumor microenvironment. GSEA revealed that SYPL2 was associated with the regulation of epithelial cell migration, vasculature development, pathways in cancer, and several vital tumor-related pathways. CONCLUSION: SYPL2 expression was lower in CRC tissue than in normal colorectal tissue. Higher SYPL2 expression in CRC was significantly associated with LNM and poorer survival.

Stem Cell Therapies for Chronic Liver Diseases: Progress and Challenges.

Chronic liver diseases have become a significant health issue worldwide and urgently require the development of novel therapeutic approaches, in addition to liver transplantation. Recent clinical and preclinical studies have shown that cell-based therapeutic strategies may contribute to the improvement of chronic liver diseases and offer new therapeutic options to restore liver function through their roles in tissue impairment and immunomodulation. In this review, we summarize the current progress and analyze the challenges for different types of cell therapies used in the treatment of chronic liver diseases currently explored in clinical trials and preclinical studies in animal models. We also discuss some critical issues regarding the use of mesenchymal stem cells (MSCs, the most extensive cell source of stem cells), including therapeutic dosage, transfusion routine, and pharmacokinetics/pharmacodynamics (PK/PD) of transfused MSCs.