Hepatitis B surface antigen impairs TLR4 signaling by upregulating A20 expression in monocytes.

Toll-like receptors (TLRs) play a crucial role in eliminating viral infection. Conversely, viruses have evolved various strategies to disrupt TLR signaling during chronic infection. In the case of hepatitis B virus (HBV), we previously reported that plasma hepatitis B surface antigen (HBsAg) is closely associated with impaired TLR responses in peripheral blood mononuclear cells from chronic hepatitis B (CHB) patients, but the reasons remain unclear. In this study, we investigated the mechanism by which HBsAg suppresses TLR4 signaling in monocyte cell lines. The monocyte cell line THP-1 was pretreated with HBsAg, followed by lipopolysaccharide (LPS) stimulation. Levels of proinflammatory cytokines and the activation of NF-κB, c-JNK, and ERK were examined. We found that HBsAg did not influence the LPS-induced activation of p65, but it disrupted NF-κB promoter activity through the ectopic expression of myeloid differentiation factor 88 (MyD88) and TAK1, suggesting that HBsAg can block downstream TLR4 signaling. Furthermore, we proved that LPS-induced polyubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) and the formation of the TRAF6-TAB2 complex were inhibited in HBsAg-pretreated cells. Interestingly, HBsAg led to a significant upregulation of A20, a ubiquitin-editing enzyme. Correspondingly, downregulation of A20 using siRNA restored LPS-mediated cytokines production, reflecting its crucial role in HBsAg-mediated inhibition of TLR4 signaling. These results demonstrated a novel mechanism by which HBsAg disrupts TLR4 signaling through the upregulation of A20, suggesting that targeting A20 may be a potential strategy to help restore monocyte functions. IMPORTANCE: Clearance HBsAg indicates a functional cure of HBV infection, but in chronic hepatitis B (CHB), it is hard to achieve. HBsAg has been found to regulate anti-viral immune responses, such as the activation of TLR. Our previous jobs proved that HBsAg negatively correlates with TLR2/4 activation in monocytes from CHB patients and blocks TLR2 ligand-indcuced IL-12 production in monocytes. However, how TLR4 signaling is affected by HBsAg remains unknown. In this study, we not only observed impaired TLR4 activation after pretreated monocytes with HBsAg but also identified HBsAg-induced A20 play a role in this impairment, which suggests that targeting A20 may be a viable strategy to restore monocyte functions in CHB.

GSH-responsive polymeric micelles-based augmented photoimmunotherapy synergized with PD-1 blockade for eliciting robust antitumor immunity against colon tumor.

Phototherapy is a promising antitumor modality, which consists of photothermal therapy (PTT) and photodynamic therapy (PDT). However, the efficacy of phototherapy is dramatically hampered by local hypoxia in tumors, overexpression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand-1 (PD-L1) on tumor cells. To address these issues, self-assembled multifunctional polymeric micelles (RIMNA) were developed to co-deliver photosensitizer indocyanine green (ICG), oxygenator MnO2, IDO inhibitor NLG919, and toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). It is worth noting that RIMNA polymeric micelles had good stability, uniform morphology, superior biocompatibility, and intensified PTT/PDT effect. What's more, RIMNA-mediated IDO inhibition combined with programmed death receptor-1 (PD-1)/PD-L1 blockade considerably improved immunosuppression and promoted immune activation. RIMNA-based photoimmunotherapy synergized with PD-1 antibody could remarkably inhibit primary tumor proliferation, as well as stimulate the immunity to greatly suppress lung metastasis and distant tumor growth. This study offers an efficient method to reinforce the efficacy of phototherapy and alleviate immunosuppression, thereby bringing clinical benefits to cancer treatment.

Temperature-Responsive "Nano-to-Micro" Transformed Polymersomes for Enhanced Ultrasound/Fluorescence Dual Imaging-Guided Tumor Phototherapy.

The perfect integration of microbubbles for efficient ultrasound imaging and nanocarriers for intelligent tumor-targeting delivery remains a challenge in precise tumor theranostics. Herein, we exquisitely fabricated laser-activated and targeted polymersomes (abbreviated as FIP-NPs) for simultaneously encapsulating the photosensitizer indocyanine green (ICG) and the phase change agent perfluorohexane (PFH). The formulated FIP-NPs were nanosize and effectively accumulated into tumors as observed by ICG fluorescence imaging. When the temperature rose above 56 °C, the encapsulated PFH transformed from liquid to gas and the FIP-NPs underwent balloon-like enlargement without structure destruction. Impressively, the enlarged FIP-NPs fused with adjacent polymersomes to form even larger microparticles. This temperature-responsive "nano-to-micro" transformation and fusion process was clearly demonstrated, and FIP-NPs showed greatly improved ultrasound signals. More importantly, FIP-NPs achieved dramatic antitumor efficacy through ICG-mediated phototherapy. Taken together, the novel polymersomes achieved excellent ultrasound/fluorescence dual imaging-guided tumor phototherapy, providing an optimistic candidate for the application of tumor theranostics.

Multifunctional Nanoparticle-Loaded Injectable Alginate Hydrogels with Deep Tumor Penetration for Enhanced Chemo-Immunotherapy of Cancer.

Chemo-immunotherapy has become a promising strategy for cancer treatment. However, the inability of the drugs to penetrate deeply into the tumor and form potent tumor vaccines in vivo severely restricts the antitumor effect of chemo-immunotherapy. In this work, an injectable sodium alginate platform is reported to promote penetration of the chemotherapeutic doxorubicin (DOX) and delivery of personalized tumor vaccines. The injectable multifunctional sodium alginate platform cross-links rapidly in the presence of physiological concentrations of Ca2+, forming a hydrogel that acts as a drug depot and releases loaded hyaluronidase (HAase), DOX, and micelles (IP-NPs) slowly and sustainedly. By degrading hyaluronic acid (HA) overexpressed in tumor tissue, HAase can make tumor tissue "loose" and favor other components to penetrate deeply. DOX induces potent immunogenic cell death (ICD) and produces tumor-associated antigens (TAAs), which could be effectively captured by polyethylenimine (PEI) coated IP-NPs micelles and form personalized tumor vaccines. The vaccines efficaciously facilitate the maturation of dendritic cells (DCs) and activation of T lymphocytes, thus producing long-term immune memory. Imiquimod (IMQ) loaded in the core could further activate the immune system and trigger a more robust antitumor immune effect. Hence, the research proposes a multifunctional drug delivery platform for the effective treatment of colorectal cancer.

Dual-Band Frequency Selective Surface with Different Polarization Selectivity for Wireless Communication Application.

This article proposes a dual-band, frequency- and polarization-selective surface. Multiple resonant modes are introduced using the U-shaped resonator with a ground via to achieve dual-band responses and polarization selectivity. Two symmetrically grounded U-shaped resonators are coupled through electrically coupled apertures in a common ground, resulting in a passband with two transmission zeros per polarization. A general design flowchart and additional examples at the S, X, and K-bands are presented as well. A prototype at X-band is analyzed, fabricated, and measured, showing the passband center frequencies of 9.68 GHz and 10.73 GHz, factional bandwidths of 3.45% and 3.48%, and insertion losses of 0.9 dB and 1.1 dB, respectively. Due to the high selectivity, small frequency ratio, low profile, and stable performance under oblique incidence, the proposed designs have application potential in wireless communication systems.

Proto-Oncogene FAM50A Can Regulate the Immune Microenvironment and Development of Hepatocellular Carcinoma In Vitro and In Vivo.

Hepatocellular carcinoma (HCC) is a vital global health problem. The characteristics are high morbidity, high mortality, difficulty in early diagnosis and insensitivity to chemotherapy. The main therapeutic schemes for treating HCC mainly include Tyrosine kinase inhibitors represented by sorafenib and lenvatinib. In recent years, immunotherapy for HCC has also achieved certain results. However, a great number of patients failed to benefit from systemic therapies. FAM50A belongs to the FAM50 family and can be used as a DNA-binding protein or transcription factor. It may take part in the splicing of RNA precursors. In studies of cancer, FAM50A has been demonstrated to participate in the progression of myeloid breast cancer and chronic lymphocytic leukemia. However, the effect of FAM50A on HCC is still unknown. In this study, we have demonstrated the cancer-promoting effects and diagnostic value of FAM50A in HCC using multiple databases and surgical samples. We identified the role of FAM50A in the tumor immune microenvironment (TIME) and immunotherapy efficacy in HCC. We also proved the effects of FAM50A on the malignancy of HCC in vitro and in vivo. In conclusion, we confirmed that FAM50A is an important proto-oncogene in HCC. FAM50A acts as a diagnostic marker, immunomodulator and therapeutic target for HCC.

CHINAT-CD4 Score Predicts Transplant-Free Survival in Patients with Acute-on-Chronic Liver Failure.

Aim: The early prognosis evaluation of acute-on-chronic liver failure (ACLF) is important to decrease its mortality. We aimed to develop a new score to accurately predict the outcome of patients with ACLF. Methods: A derivation set of 408 patients with hepatitis B virus-related ACLF (HBV-ACLF) based on the Asian Pacific Association for the Study of the Liver criteria is used to develop a prognostic score that was validated in 209 patients with HBV-ACLF and 195 patients with non-HBV-ACLF. Results: Seven factors were significantly related to the 28-day mortality and constituted a new score (CHINAT-CD4 = 0.320 × ln (creatinine) + 0.668 × hepatic encephalopathy score + 0.745 × ln (international normalized ratio) + 0.476 × ln (neutrophil) + 0.251 × ln (aspartate aminotransferase) + 0.411 × ln (total bilirubin) - 0.605 × ln (CD4+ T cells count)). The C-indices of the new score for the 28-/90-day mortality (0.810/0.806) outperformed those of the other seven scores (p≤0.05). The results were confirmed in a validation set (0.798/793 for HBV-ACLF; 0.790/0.788 for non-HBV-ACLF). The novel score based on CD4+ T cell count showed high predictive performance for the 28-/90-day mortality of ACLF. Conclusion: The novel score based on CD4+ T cell count can accurately predict the 28-/90-day mortality for patients with ACLF.

Spatio-temporal delivery of both intra- and extracellular toll-like receptor agonists for enhancing antigen-specific immune responses.

For cancer immunotherapy, triggering toll-like receptors (TLRs) in dendritic cells (DCs) can potentiate antigen-based immune responses. Nevertheless, to generate robust and long-lived immune responses, a well-designed nanovaccine should consider different locations of TLRs on DCs and co-deliver both antigens and TLR agonist combinations to synergistically induce optimal antitumor immunity. Herein, we fabricated lipid-polymer hybrid nanoparticles (LPNPs) to spatio-temporally deliver model antigen ovalbumin (OVA) on the surface of the lipid layer, TLR4 agonist monophosphoryl lipid A (MPLA) within the lipid layer, and TLR7 agonist imiquimod (IMQ) in the polymer core to synergistically activate DCs by both extra- and intra-cellular TLRs for enhancing adaptive immune responses. LPNPs-based nanovaccines exhibited a narrow size distribution at the mean diameter of 133.23 nm and zeta potential of -2.36 mV, showed a high OVA loading (around 70.83 µg/mg) and IMQ encapsulation efficiency (88.04%). Our data revealed that LPNPs-based nanovaccines showed great biocompatibility to immune cells and an excellent ability to enhance antigen internalization, thereby promoting DCs maturation and cytokines production. Compared to Free OVA, OVA-LPNPs promoted antigen uptake, lysosome escape, depot effect and migration to secondary lymphatic organs. In vivo immunization showed that IMQ-MPLA-OVA-LPNPs with dual agonists induced more powerful cellular and humoral immune responses. Moreover, prophylactic vaccination by IMQ-MPLA-OVA-LPNPs effectively suppressed tumor growth and increased survival efficacy. Hence, the nanovaccines we fabricated can effectively co-deliver antigens and different TLR agonists and realize coordinated stimulation of DCs in a spatio-temporal manner for enhanced immune responses, which provides a promising strategy for cancer immunotherapy.

Development and Validation of a Non-invasive Model to Predict Liver Histological Lesions in Chronic Hepatitis B Patients With Persistently Normal Alanine Aminotransferase and Detectable Viremia.

Background: A critical and controversial issue is whether antiviral therapy should be recommended in chronic hepatitis B virus (HBV) infection patients with persistently normal alanine aminotransferase (PNALT) and detectable HBV DNA. The study aimed to develop a non-invasive model for predicting significant liver histological changes (SLHC), which is the histological indication for antiviral therapy in chronic hepatitis B (CHB) patients with PNALT and detectable HBV DNA. Methods: 398 chronic HBV infection patients with PNALT and detectable HBV DNA who underwent liver biopsy were divided into the estimation set (n = 256) and validation set (n = 142). A multivariate logistic regression model was developed to predict SLHC in the estimation set, and the diagnostic performance was further validated in the validation set. Results: 132 patients (33.2%) with PNALT and detectable HBV DNA had SLHC. Aspartate aminotransferase (AST), cholinesterase (ChE), and liver stiffness measurement (LSM) were identified as the independent predictors of SLHC. The AUROC of the SLHC index, which combined AST, ChE, and LSM, was 0.824 and 0.816 in the estimation and validation set, respectively, for the prediction of SLHC. Applying the SLHC index ≤ 0.15, the presence of SLHC could be excluded with high negative predictive value in the estimation set (93.2%) and in the validation set (90.2%). Applying the SLHC index ≥ 0.55, the presence of SLHC could be considered with high positive predictive value in the estimation set (79.2%) and in the validation set (76.5%). Conclusion: The SLHC index provides a high accuracy in predicting liver histological indication for antiviral therapy in CHB patients with PNALT and detectable HBV DNA.

Effects of Content of Soil Rock Fragments on Soil Erodibility in China.

Soil erosion is serious in China-the soil in plateau and mountain areas contain a large of rock fragments, and their content and distribution have an important influence on soil erosion. However, there are still no complete results for calculating soil erodibility factor (K) that have corrected rock fragments in China. In this paper, the data available on rock fragments in the soil profile (RFP); rock fragments on the surface of the soil (RFS); and environmental factors such as elevation, terrain relief, slope, vegetation coverage (characterised by normalised difference vegetation index, NDVI), land use, precipitation, temperature, and soil type were used to explore the effects of content of soil rock fragments on calculating of K in China. The correlation analysis, typical sampling area analysis, and redundancy analysis were applied to analyse the effects of content of soil rock fragments on calculating of K and its relationship with environment factors. The results showed that (1) The rock fragments in the soil profile (RFP) increased K. The rock fragments on the surface (RFS) of the soil reduced K. The effect of both RFP and RFS reduced K. (2) The effect of rock fragments on K was most affected by elevation, followed by terrain relief, NDVI, slope, soil type, temperature, and precipitation, but had little correlation with land use. (3) The result of redundancy analysis showed elevation to be the main predominant factor of the effect of rock fragments on K. This study fully considered the effect of rock fragments on calculating of K and carried out a quantitative analysis of the factors affecting the effect of rock fragments on K, so as to provide necessary scientific basis for estimating K and evaluating soil erosion status in China more accurately.

Role of Immune Dysfunction in Acute-on-Chronic Liver Failure: From Pathogenesis to Clinical Prognosis.

The progression of acute-on-chronic liver failure (ACLF) is associated with various factors, including inflammatory cells, cytokines, inflammatory mediators, and the gut microbiome. Acute insult activates immune cells which provokes cytokine and chemokine cascades and subsequently initiates hepatic damage, aggressive systemic inflammatory response syndrome (SIRS), and high mortality in patients with ACLF. Immune soluble components not only play a critical role in disease progression but also potentially correlates with clinical disease severity indices including Child-Turcotte-Pugh score, the model for end-stage liver disease (MELD) score, and sequential organ failure (SOF) score. Several immune soluble components lead to a better understanding of the pathophysiological basis of ACLF, and precise immune mechanisms offer therapeutic targets for ACLF. However, there are a number of specific issues that were not addressed unambiguously, such as whether dysfunctional immune soluble components are the cause or outcome of ACLF. Further evaluation and validation of emerging and relevant biomarkers will facilitate the formulation of a potential score which, either alone or in combination with existing scoring systems, will improve the clinical outcome prognostication and therapeutic efficacy of patients with ACLF. Extensive research is required to find out the mechanisms responsible for disease severity and high mortality in patients with ACLF.

Dynamic Differences of Immunological Parameters Between Severe and Non-severe COVID-19 Patients.

OBJECTIVE: We aimed to compare the dynamic differences of immunological parameters between severe and non-severe COVID-19 patients. METHODS: The cytokine profiles and lymphocyte subsets of 664 patients with COVID-19 (31 severe cases and 633 non-severe cases) were longitudinally analyzed. RESULTS: Compared with non-severe cases, severe cases had a higher age (64 vs. 40 years, p<0.001), more common comorbidity (74.2% vs. 20.5%, p<0.001), and lymphopenia (0.7 vs. 1.4x109/L, p<0.001). Severe cases had markedly higher levels of IL-6, IL-8, and IL-10 from baseline to 35 days after admission than non-severe cases (p<0.001). No significant differences were observed in the dynamic levels of IL-1beta, IL-2, IL-4, IL-5, IL-12, IL-17, TNF-alpha, IFN-alpha, and IFN-gamma between severe and non-severe COVID-19 patients (p>0.05). The absolute counts of lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD45+ T cells were markedly lower in severe patients with COVID-19 compared with those in non-severe patients from baseline to 35 days after admission (p<0.001). No significant differences were observed in the dynamic levels of white cells count, CD19+ B cells count, and NK cells count between severe and non-severe COVID-19 patients (p>0.05). The decrease of T lymphocyte subsets reached its peak at day 1 to 3 after admission, and they gradually increased in the non-severe group, but sustained at low levels in the severe group at day 4 to 35 after admission. CONCLUSION: The dynamic changes of cytokine profiles and T lymphocyte subsets are related with the severity of COVID-19.

Analysis of the Spatial and Temporal Changes of NDVI and Its Driving Factors in the Wei and Jing River Basins.

This study aimed to explore the long-term vegetation cover change and its driving factors in the typical watershed of the Yellow River Basin. This research was based on the Google Earth Engine (GEE), a remote sensing cloud platform, and used the Landsat surface reflectance datasets and the Pearson correlation method to analyze the vegetation conditions in the areas above Xianyang on the Wei River and above Zhangjiashan on the Jing River. Random forest and decision tree models were used to analyze the effects of various climatic factors (precipitation, temperature, soil moisture, evapotranspiration, and drought index) on NDVI (normalized difference vegetation index). Then, based on the residual analysis method, the effects of human activities on NDVI were explored. The results showed that: (1) From 1987 to 2018, the NDVI of the two watersheds showed an increasing trend; in particular, after 2008, the average increase rate of NDVI in the growing season (April to September) increased from 0.0032/a and 0.003/a in the base period (1987-2008) to 0.0172/a and 0.01/a in the measurement period (2008-2018), for the Wei and Jing basins, respectively. In addition, the NDVI significantly increased from 21.78% and 31.32% in the baseline period (1987-2008) to 83.76% and 92.40% in the measurement period (2008-2018), respectively. (2) The random forest and classification and regression tree model (CART) can assess the contribution and sensitivity of various climate factors to NDVI. Precipitation, soil moisture, and temperature were found to be the three main factors that affect the NDVI of the study area, and their contributions were 37.05%, 26.42%, and 15.72%, respectively. The changes in precipitation and soil moisture in the entire Jing River Basin and the upper and middle reaches of the Wei River above Xianyang caused significant changes in NDVI. Furthermore, changes in precipitation and temperature led to significant changes in NDVI in the lower reaches of the Wei River. (3) The impact of human activities in the Wei and Jing basins on NDVI has gradually changed from negative to positive, which is mainly due to the implementation of soil and water conservation measures. The proportions of areas with positive effects of human activities were 80.88% and 81.95%, of which the proportions of areas with significant positive effects were 11.63% and 7.76%, respectively. These are mainly distributed in the upper reaches of the Wei River and the western and eastern regions of the Jing River. These areas are the key areas where soil and water conservation measures have been implemented in recent years, and the corresponding land use has transformed from cultivated land to forest and grassland. The negative effects accounted for 1.66% and 0.10% of the area, respectively, and were mainly caused by urban expansion and coal mining.

A Novel Prediction Model of COVID-19 Progression: A Retrospective Cohort Study.

INTRODUCTION: Estimating the risk of disease progression is of utmost importance for planning appropriate setting of care and treatment for patients with coronavirus disease 2019 (COVID-19). This study aimed to develop and validate a novel prediction model of COVID-19 progression. METHODS: In total, 814 patients in the training set were included to develop a novel scoring system; and 420 patients in the validation set were included to validate the model. RESULTS: A prediction score, called ACCCDL, was developed on the basis of six risk factors associated with COVID-19 progression: age, comorbidity, CD4+ T cell count, C-reactive protein (CRP), D-dimer, and lactate dehydrogenase (LDH). For predicting COVID-19 progression, the ACCCDL score yielded a significantly higher area under the receiver operating characteristic curve (AUROC) compared with the CALL score, CoLACD score, PH-COVID-19 score, neutrophil-lymphocyte ratio, and lymphocyte-monocyte ratio both in the training set (0.92, 0.84, 0.83, 0.83, 0.76, and 0.65, respectively) and in the validation set (0.97, 0.83, 0.83, 0.78, 0.74, and 0.60, respectively). Over 99% of patients with the ACCCDL score < 12 points will not progress to severe cases, and over 30% of patients with the ACCCDL score > 20 points will progress to severe cases. CONCLUSION: The ACCCDL score could stratify patients with at risk of COVID-19 progression, and was useful in regulating the large flow of patients with COVID-19 between primary health care and tertiary centers.

Efficacy Evaluation of Thymosin Alpha 1 in Non-severe Patients With COVID-19: A Retrospective Cohort Study Based on Propensity Score Matching.

Objective: Thymosin alpha 1 (Thymosin-α1) is a potential treatment for patients with COVID-19. We aimed to determine the effect of Thymosin-α1 in non-severe patients with COVID-19. Methods: We retrospectively enrolled 1,388 non-severe patients with COVID-19. The primary and secondary clinical outcomes were evaluated with comparisons between patients treated with or without Thymosin-α1 therapy. Results: Among 1,388 enrolled patients, 232 patients (16.7%) received both Thymosin-α1 therapy and standard therapy (Thymosin-α1 group), and 1,156 patients (83.3%) received standard therapy (control group). After propensity score matching (1:1 ratio), baseline characteristics were well-balanced between the Thymosin-α1 group and control group. The proportion of patients that progressed to severe COVID-19 is 2.17% for the Thymosin-α1 group and 2.71% for the control group (p = 0.736). The COVID-19-related mortality is 0.54% for the Thymosin-α1 group and 0 for the control group (p = 0.317). Compared with the control group, the Thymosin-α1 group had significantly shorter SARS-CoV-2 RNA shedding duration (13 vs. 16 days, p = 0.025) and hospital stay (14 vs. 18 days, p < 0.001). No statistically significant difference was found between the Thymosin-α1 group and control group in duration of symptoms (median, 4 vs. 3 days, p = 0.843) and antibiotic utilization rate (14.1% vs. 15.2%, p = 0.768). Conclusion: For non-severe patients with COVID-19, Thymosin-α1 can shorten viral RNA shedding duration and hospital stay but did not prevent COVID-19 progression and reduce COVID-19-related mortality rate.

Dynamic Changes in Liver Function Tests and Their Correlation with Illness Severity and Mortality in Patients with COVID-19: A Retrospective Cohort Study.

OBJECTIVE: To describe the longitudinal changes in liver function tests, and their association with illness severity and mortality in patients with COVID-19. METHODS: A retrospective cohort study of 1003 hospitalized patients with COVID-19 was conducted. Longitudinal liver function tests and clinical outcomes were analyzed. RESULTS: Abnormal liver function parameters were observed, both at admission (ALT 13.2%, AST 8.5%, ALP 2.0%, GGT 7.4%, LDH 37.6%, TBIL 4.0%, DBIL 7.8%, Albumin 10.1%) and peak hospitalization (ALT 29.4%, AST 17.5%, ALP 2.6%, GGT 13.4%, LDH 49.4%, TBIL 10.1%, DBIL 18.0%, Albumin 30.6%) in patients with COVID-19. Compared with non-severe patients, severe patients had markedly higher liver function parameters from baseline to 30 days after hospital admission. Abnormal ALT and LDH at hospital admission and some medications use (Hydroxychloroquine, Lopinavir/Ritonavir, and Traditional Chinese medicines) were associated with peak hospitalization ALT > 5× the upper limit unit of normal (ULN). On multivariate analysis, age >60 years, male, obesity, comorbidity, abnormal LDH and albumin at hospital admission and peak hospitalization were associated with progression to severe COVID-19 (OR > 1; p < 0.05). COX analysis revealed that ALT > 2 ULN (HR=7.0, p=0.011), AST > 2 ULN (HR=34.7, p < 0.001), and TBIL > 2 ULN (HR=54.6, p < 0.001) were associated with a higher mortality. CONCLUSION: Dynamic abnormalities of liver function parameters are common in hospitalized patients with COVID-19, and associated with illness severity and mortality.

Baseline serum exosome-derived miRNAs predict HBeAg seroconversion in chronic hepatitis B patients treated with peginterferon.

This study aimed to explore the value of baseline serum exosome-derived miRNAs for predicting HBeAg seroconversion in chronic hepatitis B (CHB) patients treated with peginterferon (Peg-IFN). A total of 120 treatment-naïve HBeAg-positive CHB patients who received Peg-IFN therapy (48 weeks) were enrolled. Next-generation sequencing was performed to screen the serum exosomal miRNAs that were associated with Peg-IFN treatment outcome, and qRT-PCR was used to validate them. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the predictive efficacy of biomarkers. Thirty-three patients (27.5%) achieved HBeAg seroconversion (response group), and 87 patients (72.5%) did not achieve HBeAg seroconversion (nonresponse group). In the identification cohort, 40 serum exosome-derived miRNAs were differentially expressed between the response group (four patients) and the nonresponse group (four patients). In the confirmation cohort, the expression levels of serum exosomal miR-194-5p (p < .001) and miR-22-3p (p < .001) were significantly downregulated in the response group (29 patients) compared to the nonresponse group (83 patients). Multivariate analysis identified baseline serum exosomal miR-194-5p, miR-22-3p, alanine aminotransferase (ALT), and HBV DNA as independent predictors of HBeAg seroconversion (all p < .05). The AUROCs of serum exosomal miRNAs (0.77 and 0.75 for miR-194-5p and miR-22-3p, respectively) were higher than that of ALT (0.70) and HBV DNA (0.69). The combination of exosomal miR-194-5p and miR-22-3p further improved the predictive performance with an AUROC of 0.82. Baseline serum exosomal miR-194-5p and miR-22-3p may serve as novel biomarkers to predict HBeAg seroconversion in CHB patients treated with Peg-IFN.

pH-sensitive and bubble-generating mesoporous silica-based nanoparticles for enhanced tumor combination therapy.

Chemotherapy has been a major option in clinic treatment of malignant tumors. However, single chemotherapy faces some drawbacks, such as multidrug resistance, severe side effects, which hinder its clinic application in tumor treatment. Multifunctional nanoparticles loading with chemotherapeutic agent and photosensitizer could be a promising way to efficiently conduct tumor combination therapy. In the current study, a novel pH-sensitive and bubble-generating mesoporous silica-based drug delivery system (denoted as M(a)D@PI-PEG-RGD) was constructed. Ammonium bicarbonate (NH4HCO3; abc) and chemotherapeutic agent doxorubicin (DOX) were loaded into the pores of mesoporous silica. Indocyanine green (ICG) as a photothermal and photodynamic agent was loaded onto the polydopamine (PDA) layer surface. The synthesized nanoparticles displayed a narrow polydispersity (PDI) and small particle size as characterized through dynamic light scattering-autosizer analysis. The nanoparticles also showed high targeting efficacy through RGD modification as indicated by cellular uptake and animal studies. DOX release analysis confirmed that the nanoparticles were pH-dependent and that NH4HCO3 accelerated drug release. At the same time, the nanoparticles had obvious photothermal and photodynamic effects performed by ICG which restrained tumor growth remarkably. In summary, the multifunctional nanoparticles presented a promising system for combination therapy.

Efficacy evaluation of intravenous immunoglobulin in non-severe patients with COVID-19: A retrospective cohort study based on propensity score matching.

OBJECTIVES: At the present time, there is an absence of any proven effective antiviral therapy for patients with coronavirus disease 2019 (COVID-19). The aim of this study was to assess the efficacy of intravenous immunoglobulin (IVIG) in non-severe patients with COVID-19. METHODS: A retrospective study based on propensity score matching (PSM) was designed. Primary outcomes included the severity and mortality rates. Secondary outcomes included the duration of fever, virus clearance time, length of hospital stay, and use of antibiotics. RESULTS: A total of 639 non-severe patients with COVID-19 were enrolled. Forty-five patients received IVIG therapy and 594 received non-IVIG therapy. After PSM (1:2 ratio), the baseline characteristics were well balanced between the IVIG group (n = 45) and control group (n = 90). No statistically significant difference was found between the IVIG group and control group in the duration of fever (median 3 vs 3 days, p = 0.667), virus clearance time (median 11 vs 10 days, p = 0.288), length of hospital stay (median 14 vs 13 days, p = 0.469), or use of antibiotics (40% vs 38.9%, p = 0.901). Meanwhile, compared to the IVIG group, no more patients in the control group progressed to severe disease (3.3% vs 6.6%, p = 0.376) or died (0 vs 2.2%, p = 0.156). CONCLUSIONS: In non-severe patients with COVID-19, no benefit was observed with IVIG therapy beyond standard therapy.

Using Next-generation Sequencing to Identify Novel Exosomal miRNAs as Biomarkers for Significant Hepatic Fibrosis.

OBJECTIVE: The aim of this study is to determine the role of serum exosomal miRNAs as potential non-invasive biomarkers for distinguishing no-or-mild fibrosis from significant fibrosis in patients with chronic hepatitis B (CHB). METHODS: Next-generation sequencing was used to identify fibrosis-related serum exosomal miRNAs in 9 CHB patients. The candidate exosomal miRNAs were further validated by qRT-PCR in 282 CHB patients. Receiver operating characteristic curves were generated to assess the diagnostic performance of exosomal miRNAs and other non-invasive models. RESULTS: Seventy-two miRNAs were differentially expressed in serum exosomes between patients with no-or-mild fibrosis and significant fibrosis. The expression of serum exosomal miR-92a-3p and miR-146a-5p progressively increased with the aggravation of liver fibrosis in the validation cohort. Multivariate analysis identified miR-92a-3p (P<0.001), miR-146a-5p (P<0.001), and liver stiffness measurement (LSM) (P=0.012) as independent predictors for significant fibrosis. The area under the receiver operating characteristic curve (AUROC) of exosomal miR-92a-3p (AUROC=0.88) was significantly higher than that of APRI (aspartate aminotransferase-to-platelet ratio index) (AUROC=0.72, P<0.001), FIB-4 (AUROC=0.71, P<0.001), and LSM (AUROC=0.80, P=0.022) for identifying significant fibrosis. Similarly, the AUROC of exosomal miR-146a-5p (AUROC=0.82) was also significantly better than that of APRI (AUROC=0.72, P=0.009), FIB-4 (AUROC=0.71, P=0.002), and comparable to LSM (AUROC=0.80, P=0.551) for discriminating significant fibrosis. CONCLUSION: Serum exosomal miR-92a-3p and miR-146a-5p are superior to APRI, FIB-4, and LSM for diagnosing significant fibrosis in CHB patients and offer a promising non-invasive alternative to liver biopsy.