Non-alcoholic fatty liver disease (NAFLD) is a metabolic stress liver injury that is closely related to obesity, insulin resistance, type 2 diabetes, atherosclerosis, and metabolic syndrome. The pathological features are diffuse hepatic vesicular steatosis, including non-alcoholic steatohepatitis, liver fibrosis, and even liver cancer. A variety of pathological outcomes cause serious harm to human health. At present, an increasing number of researchers are investigating the pathogenesis of NAFLD from the perspective of changes in the function of the intestinal barrier. The physical, chemical, immunological, and microbiological barriers in the intestinal tract constitute the complete intestinal barrier, which plays an important defensive role against the invasion of harmful substances from the intestines. Protecting the function of the intestinal barrier is a new way to treat NAFLD and its related diseases. In this perspective, we summarized the current knowledge of the role of the intestinal barrier in NAFLD.

To explore the metabolic changes and immune profiles in patients with COVID-19, we analyzed the data of patients with mild and severe COVID-19 as well as young children with COVID-19. Of the leukocytes, 47% (IQR, 33–59) were lymphocytes [2.5 × 10 9 /L (IQR, 2.2–3.3)], and monocytes were 0.51 × 10 9 /L (IQR, 0.45–0.57) in young children with COVID-19. In 32 mild COVID-19 patients, circulating monocytes were 0.45 × 10 9 /L (IQR, 0.36–0.64). Twenty-one severe patients had low PO 2 [57 mmHg (IQR, 50–73)] and SO 2 [90% (IQR, 86–93)] and high lactate dehydrogenase [580 U/L (IQR, 447–696)], cardiac troponin I [0.07 ng/mL (IQR, 0.02–0.30)], and pro-BNP [498 pg/mL (IQR, 241–1,726)]. Serum D-dimer and FDP were 9.89 mg/L (IQR, 3.62–22.85) and 32.7 mg/L (IQR, 12.8–81.9), and a large number of RBC (46/μL (IQR, 4–242) was presented in urine, a cue of disseminated intravascular coagulation (DIC) in severe patients. Three patients had comorbidity with diabetes, and 18 patients without diabetes also presented high blood glucose [7.4 mmol/L (IQR, 5.9–10.1)]. Fifteen of 21 (71%) severe cases had urine glucose +, and nine of 21 (43%) had urine ketone body +. The increased glucose was partially caused by reduced glucose consumption of cells. Severe cases had extraordinarily low serum uric acid [176 μmol/L (IQR, 131–256)]. In the late stage of COVID-19, severe cases had extremely low CD4 + T cells and CD8 + T cells, but unusually high neutrophils [6.5 × 10 9 /L (IQR, 4.8–9.6)], procalcitonin [0.27 ng/mL (IQR, 0.14–1.94)], C-reactive protein [66 mg/L (IQR, 25–114)] and an extremely high level of interleukin-6. Four of 21 (19%) severe cases had co-infection with fungi, and two of 21 (9%) severe cases had bacterial infection. Our findings suggest that, severe cases had acute respiratory distress syndrome (ARDS) I–III, and metabolic disorders of glucose, lipid, uric acid, etc., even multiple organ dysfunction (MODS) and DIC. Increased neutrophils and severe inflammatory responses were involved in ARDS, MODS, and DIC. With the dramatical decrease of T-lymphocytes, severe cases were susceptible to co-infect with bacteria and fungi in the late stage of COVID-19. In young children, extremely high lymphocytes and monocytes might be associated with the low morbidity of COVID-19. The significantly increased monocytes might play an important role in the recovery of patients with mild COVID-19.

CoronaVac (Sinovac), an inactivated vaccine for SARS-CoV-2, has been widely used for immunization. However, analysis of the underlying molecular mechanisms driving CoronaVac-induced immunity is still limited. Here, we applied a systems biology approach to understand the mechanisms behind the adaptive immune response to CoronaVac in a cohort of 50 volunteers immunized with 2 doses of CoronaVac. Vaccination with CoronaVac led to an integrated immune response that included several effector arms of the adaptive immune system including specific IgM/IgG, humoral response and other immune response, as well as the innate immune system as shown by complement activation. Metabolites associated with immunity were also identified implicating the role of metabolites in the humoral response, complement activation and other immune response. Networks associated with the TCA cycle and amino acids metabolic pathways, such as phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and glycine, serine and threonine metabolism were tightly coupled with immunity. Critically, we constructed a multifactorial response network (MRN) to analyze the underlying interactions and compared the signatures affected by CoronaVac immunization and SARS-CoV-2 infection to further identify immune signatures and related metabolic pathways altered by CoronaVac immunization. These results help us to understand the host response to vaccination of CoronaVac and highlight the utility of a systems biology approach in defining molecular correlates of protection to vaccination.

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CoronaVac (Sinovac), an inactivated vaccine for SARS-CoV-2, has been widely used for immunization. However, analysis of the underlying molecular mechanisms driving CoronaVac-induced immunity is still limited. Here, we applied a systems biology approach to understand the mechanisms behind the adaptive immune response to CoronaVac in a cohort of 50 volunteers immunized with 2 doses of CoronaVac. Vaccination with CoronaVac led to an integrated immune response that included several effector arms of the adaptive immune system including specific IgM/IgG, humoral response and other immune response, as well as the innate immune system as shown by complement activation. Metabolites associated with immunity were also identified implicating the role of metabolites in the humoral response, complement activation and other immune response. Networks associated with the TCA cycle and amino acids metabolic pathways, such as phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and glycine, serine and threonine metabolism were tightly coupled with immunity. Critically, we constructed a multifactorial response network (MRN) to analyze the underlying interactions and compared the signatures affected by CoronaVac immunization and SARS-CoV-2 infection to further identify immune signatures and related metabolic pathways altered by CoronaVac immunization. These results suggest that protective immunity against SARS-CoV-2 can be achieved via multiple mechanisms and highlights the utility of a systems biology approach in defining molecular correlates of protection to vaccination.

Nonalcoholic fatty liver disease (NAFLD) is a hepatic ailment with a rapidly increasing incidence in the human population due largely to dietary hyper nutrition and subsequent obesity. Discovering effective natural compounds and herbs against NAFLD can provide alternative and complementary medical treatments to current chemical pharmaceuticals. In this study, ICR male mice were fed a high-fat diet (HFD) in vivo and the AML12 cells were treated with palmitic acid (PA) in vitro. We explore the protective effect and potential mechanism of Chinese Herbal Formula (CHF03) against NAFLD by HE staining, transmission Electron Microscopy assay, Western blotting, and gene expression. In vivo, oxidative stress markers (GSH, GSH-px, MDA, SOD, and CAT) confirmed that CHF03 alleviated oxidative stress and abundance of NF-κB proteins indicating a reduction in inflammation and oxidative stress. The lower protein abundance of ACACA and FASN indicated a preventive effect on lipogenesis. Histological and ultrastructural observations revealed that CHF03 inhibited NAFLD. Expression of Srebf1, Fasn, and Acaca, which are associated with lipogenesis, were downregulated. In vitro, genes and proteins are expressed in a dose-dependent manner, consistent with those in the liver. CHF03 inhibited lipid accumulation and expression of NF-κB, nuclear transfer, and transcriptional activity in AML12 cells. The CHF03 might have a beneficial role in the prevention of hepatic steatosis by altering the expression of lipogenic genes and attenuating oxidative stress.

4138 Background: Pancreatic ductal adenocarcinoma（PDAC）is one of the most lethal malignancies worldwide and is characterized by extremely poor prognosis. Nab-paclitaxel plus gemcitabine has been recommended by international guidelines for first-line treatment of advanced PDAC but chemoresistance is difficult to avoid. Combination of immune checkpoint inhibitors (ICIs) and chemotherapy has demonstrated substantial promise for the treatment of several advanced malignancies. A few recent studies have begun to explore the effect of ICIs monotherapy or co in advanced PDAC with few meaningful results. KN046, a novel recombinant humanized bispecific antibody, can simultaneously block PD-1/PD-L1 and CTLA-4 pathways and restore T-cell immune response to tumor. The purpose of this study is to evaluate the efficacy and safety of KN046 plus nab-paclitaxel/gemcitabine as first-line treatment for unresectable locally advanced or metastatic PDAC. Methods: This ongoing phase II trial in China enrolled pts with histologically or cytologically confirmed unresectable locally advanced or metastatic PDAC who have ECOG PS of 0-1 and never received systemic anti-tumor therapy for advanced or metastatic diseases. KN046 (5mpk, Q2W) plus nab-paclitaxel (125mg/m2, D1, 8, 15, Q4W) and gemcitabine (1000mg/m2, D1, 8, 15, Q4W) were administered 4-6 cycles followed by KN046 (5mpk) maintenance therapy every 2 weeks. Tumour response was assessed according to RECIST 1.1 every 8 weeks. The primary endpoint is investigator-assessed ORR. Secondary endpoints are DCR, DOR, TTP, PFS, OS and safety. Results: As of December 15, 2020, 17 pts were enrolled, median (range) age was 56 (36-75) years, 9 pts ECOG 1, and 7 pts had liver metastases. Median KN046 exposure time was 9.5 wks. 9 pts were included in the efficacy analysis and 17 pts in the safety analysis. In best overall response assessment, there were 55.6% PR (5/9) and 33.3% SD (3/9). ORR was 55.6% (95% CI: 21.2̃86.3), and DCR was 88.9% (95% CI: 51.8̃99.7). The overall incidence of KN046 related treatment-emergent adverse events was 64.7%, with 29.4% were grade 3 TRAE. The most common KN046 related treatment-emergent adverse events (≥10%) were alanine aminotransferase increased (n = 5, 29.4%), nausea (n = 3, 17.6%), rash (n = 3, 17.6%), aspartate aminotransferase increased (n = 2, 11.8%), diarrhoea (n = 2, 11.8%), hyperphosphataemia (n = 2, 11.8%), pyrexia (n = 2, 11.8%), vomiting (n = 2, 11.8%). Conclusions: Combining KN046 with nab-paclitaxel and gemcitabine as first-line treatment for unresectable locally advanced or metastatic PDAC patients is safe and feasible, and lays the foundation for subsequent clinical trials. Clinical trial information: NCT04324307.

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