Development of a TMErisk model based on immune infiltration in tumour microenvironment to predict prognosis of immune checkpoint inhibitor treatment in hepatocellular carcinoma.

Immune checkpoint inhibitor (ICI) treatment has created the opportunity of improved outcome for patients with hepatocellular carcinoma (HCC). However, only a minority of HCC patients benefit from ICI treatment owing to poor treatment efficacy and safety concerns. There are few predictive factors that precisely stratify HCC responders to immunotherapy. In this study, we developed a tumour microenvironment risk (TMErisk) model to divide HCC patients into different immune subtypes and evaluated their prognosis. Our results indicated that virally mediated HCC patients who had more common tumour protein P53 (TP53) alterations with lower TMErisk scores were appropriate for ICI treatment. HCC patients with alcoholic hepatitis who more commonly harboured catenin beta 1 (CTNNB1) alterations with higher TMErisk scores could benefit from treatment with multi-tyrosine kinase inhibitors. The developed TMErisk model represents the first attempt to anticipate tumour tolerance of ICIs in the TME through the degree of immune infiltration in HCCs.

To be or not to be: The double-edged sword roles of liver progenitor cells.

Given the liver's remarkable and unique regenerative capacity, researchers have long focused on liver progenitor cells (LPCs) and liver cancer stem cells (LCSCs). LPCs can differentiate into both hepatocytes and cholangiocytes. However, the mechanism underlying cell conversion and its distinct contribution to liver homeostasis and tumorigenesis remain unclear. In this review, we discuss the complicated conversions involving LPCs and LCSCs. As the critical intermediate state in malignant transformation, LPCs play double-edged sword roles. LPCs are not only involved in hepatic wound-healing responses by supplementing liver cells and bile duct cells in the damaged liver but may transform into LCSCs under dysregulation of key signaling pathways, resulting in refractory malignant liver tumors. Because LPC lineages are temporally and spatially dynamic, we discuss crucial LPC subgroups and summarize regulatory factors correlating with the trajectories of LPCs and LCSCs in the liver tumor microenvironment. This review elaborates on the double-edged sword roles of LPCs to help understand the liver's regenerative potential and tumor heterogeneity. Understanding the sources and transformations of LPCs is essential in determining how to exploit their regenerative capacity in the future.

The Pharmacological Mechanism of Xiyanping Injection for the Treatment of Novel Coronavirus Pneumonia (COVID-19): Based on Network Pharmacology Strategy.

Purpose: The possible mechanism of Xiyanping injection treatment COVID-19 is discussed through the network pharmacology. Methods: Obtaining the chemical structure of Xiyanping injection through the patent application and obtaining control compounds I, II, III, IV, V, Yanhuning injection (VI, VII), Chuanhuning injection (VIII, IX), 10 compounds were analyzed by D3Targets-2019-nCoV. The human anti-COVID-19 gene in COVID-19 DisGeNET was intersected with the CTD Andrographolide target gene and then combined with D3Targets-2019-nCoV, resulting in 93 genes, using the Venny 2.1 platform. The PPI network was constructed by the String platform and Cytoscape 3.8.2 platform. The GO, KEGG, and tissue of the target were analyzed using the Metascape platform and DAVID platform. The gene expression in the respiratory system was analyzed using the ePlant platform. The CB-Dock is used for the docking verification and degree values of the first 20 genes. Results: Finally, 1599 GO and 291 KEGG results were obtained. GO is mostly associated with the cell stress response to chemicals, the cell response to oxidative stress, and the cell response to reactive oxygen species. In total, 218 KEGG pathway concentrations were related to infection and other diseases and 73 signaling pathways mostly related to inflammation and immune pathways, such as TNF signaling pathway and MAPK signaling pathway. The molecular docking results show that Xiyanping injection, compound III, has a good docking relationship with 20 target proteins such as HSP90AA1. Tissue has 22 genes that are pooled in the lungs. Conclusion: Xiyanping injection may inhibit the release of various inflammatory factors by inhibiting intracellular pathways such as MAPK and TNF. It acts on protein targets such as HSP90AA1 and plays a potential therapeutic role in COVID-19. Thus, compound III may be treated as a potential new drug for the treatment of COVID-19 and the Xiyanping injection may treat patients with COVID-19 infection.

Androgens drive sexual dimorphism in liver metastasis by promoting hepatic accumulation of neutrophils.

The liver is one of the most-favored distant metastatic sites for solid tumors, and interactions between cancer cells and components of the hepatic microenvironment are essential for liver metastasis (LM). Although sex is one of the determinants for primary liver cancer, sexual dimorphism in LM (SDLM) and the underlying mechanisms remain unclear. We herein demonstrate a significant male-biased SDLM, which is attributed to host androgen/androgen receptor (Ar) signaling that promotes hepatic seeding of tumor cells and subsequent outgrowth in a neutrophil-dependent manner. Mechanistically, androgen/Ar signaling promotes hepatic accumulation of neutrophils by promoting proliferation and development of neutrophil precursors in the bone marrow, as well as modulating hepatic recruitment of neutrophils and their functions. Antagonizing the androgen/Ar/neutrophil axis significantly mitigates LM in males. Our data thus reveal an important role of androgen in LM and suggest that androgen/Ar modulation represents a promising target for LM therapy in men.

Factors associated with prior acute pancreatitis episodes among patients with chronic pancreatitis.

BACKGROUND: The relationship between chronic pancreatitis (CP) and acute pancreatitis (AP) is complex and not well understood. CP could be preceded by antecedent episodes of AP. AIMS: The aim of this study was to explore both genetic and environmental factors associated with AP episodes before the diagnosis of CP. METHODS: This was a cross-sectional study including 1022 patients. Detailed demographic, genetic, and clinical data were collected. Based on the presence of AP episode(s) before diagnosis of CP, patients were divided into AP group (further classified into single episode of AP group and recurrent AP group) and non-AP group. Related factors among these groups were assessed using multivariate logistic regression model. RESULTS: Before diagnosis of CP, 737 patients (72.1%) had a history of AP. Smoking(P = 0.005) and heavy alcohol consumption(P = 0.002) were risk factors for AP while age at CP onset(P < 0.001), harboring the SPINK1 mutation(P < 0.001), diabetes(P < 0.001) and steatorrhea(P < 0.001) were protective factors. Further, alcoholic CP(P = 0.019) was the only independent risk factor for recurrent AP attacks while age at onset of CP(P < 0.001), pancreatic stones(P = 0.024). and pseudocysts(P = 0.018) served as protective factors. CONCLUSIONS: SPINK1 mutations served as protective factor for AP episodes, suggesting SPINK1 mutation might play a pathogenic role in CP occurrence with occult clinical manifestations.

Risk factors for sinistral portal hypertension and related variceal bleeding in patients with chronic pancreatitis.

OBJECTIVES: Sinistral portal hypertension (SPH) is an uncommon complication of chronic pancreatitis (CP) and can result in severe gastrointestinal bleeding. The aim of this study was to determine the prevalence and the potential risk factors for SPH and related gastrointestinal variceal bleeding in patients with CP. METHODS: We retrospectively reviewed all patients with SPH due to CP admitted to our hospital from July 2014 to June 2019 in this case-control study. Patients with CP without SPH were randomly selected as controls during the study period (case: control  =  1:2). The characteristics, medical history, course of CP, characteristics associated with SPH, and follow-up evaluations of the patients were documented in detail. The prevalence rate of SPH in patients with CP and related gastrointestinal bleeding was calculated. Risk factors for SPH and related variceal bleeding were analyzed using univariate or multivariate logistic regression analysis. RESULTS: The prevalence of SPH was 2.7% (89/3358) in patients with CP. Independent risk factors for SPH included alcohol consumption (P = 0.030), history of acute pancreatitis (P = 0.010), diabetes mellitus (P < 0.001), and pseudocysts (P < 0.001). Overall 17 (19.1%) patients suffered from related gastrointestinal bleeding. Between the bleeding and non-bleeding groups, there were significant differences in the types of CP, existence of stones, gastric varices diagnosed before bleeding, splenomegaly and hypersplenism by univariate analysis. CONCLUSION: SPH is a rare complication of CP that is associated with a relatively low risk of variceal bleeding.

[Pharmacokinetics and Bioequiavailability of Asparaginase in Asparaginase Nanospheres].

OBJECTIVE: To determine the pharmacokinetics and bioequivalence of self-assembled hyaluronic acid-graft-poly (ethylene glycol)/hydroxypropyl-beta-cyclodextrin hollow nanospheres loaded with asparaginase (AHHPs) in SD rats. METHODS: AHHPs were prepared and observed under transmission electron microscopy. Its size, Zeta potential and entrapment efficiency were detected. Asparaginase (AAS) activities were measured after intravenous injection of AHHPs or free AAS in rats. The pharmacokinetic parameters were calculated using software DAS 2.1.1 for bioequivalence assessment. RESULTS: The self-prepared AHHPs had an average particle size of (367.43 ± 2.72) nm, Zeta potential of (-15. 70 ± 1.25) mV, and average entrapment efficiency of (66.03 ± 3.81)%. The intravenous injection of AHHPs and free AAS produced an area under concentration-time Curve (AUC)(0-48 h) of (162.06 ± 4.01) U/mL · h and (46.38 ± 1.98) U/mL · h, AUC(0-∞) of (203.74 ± 12.91) U/mL · h and (51.44 ± 3.01) U/mL · h, mean residence time (MRT) (0-72h) of (4.35 ± 0.06) h and (1.76 ± 0.06) h, MRT(0-∞) of (7.53 ± 1.05) h and (2.44 ± 0.29) h, peak concentration (Cmax) of (30.37 ± 0.43) U/mL and (26.06 ± 0.88) U/mL, and time to peak concentration (Tmax) of (0.75 ± 0.00) h and (0.08 ± 0.00) h, respectively. Compared with free AAS, the AUC(0-48 h), AUC(0-∞), MRT(0-72 h), MRT(0-∞),Cmax and Tmax of AHHPs increased by 3.5, 4.0, 2.5, 3.1, 1.2 and 9.4 times, respectively. The 90% confidential intervals of AUC(0-48 h), AUC(0.∞) and Cmax of the tested formulation were 72.6%-74.0%, 72.3%-73.7%, 94.7%-96.3%, respectively. CONCLUSION: AHHPs can improve the bioavailability of AAS, extending its biological half-life in rats. AHHPs and free AAS are not bioequivalent.

[Pharmacokinetics study of curcumin solid lipid nanoparticles by intravenous injection in rats].

OBJECTIVE: To study the intravenous pharmacokinetics of curcumin solid lipid nanoparticles in SD rats. METHODS: Rats were administrated with (iv) curcumin solid lipid nanoparticles and curcumin solution (8.0 mg/kg), respectively. Blood samples were collected and curcumin in blood plasma was determined by HPLC. Compartmental pharmacokinetics was analyzed by DAS software. RESULTS: After intravenous administration, the AUC(0-t), AUC(0-infinity) and t(1/2) of curcumin solid lipid nanoparticles were 1.50-fold, 1.63-fold and 4.08-fold higher than those of curcumin solution as (173.09 ± 44.81) µg x h/L vs. (114.83 ± 13.19) µg x h/L, (196.56 ± 35.25) µg x h/L vs. (120.66 ± 13.95) µg x h/L and (5.95 ± 2.05) h vs. (1.46 ± 0.03) h. CONCLUSION: The curcumin solid lipid nanoparticles is eliminated more slowly. The bioavailability of curcumin in rats increases remarkably compared with that of curcumin solution after intravenous administration.

Comparison of microwave-assisted and conventional hydrodistillation in the extraction of essential oils from mango (Mangifera indica L.) flowers.

Microwave-assisted hydrodistillation (MAHD) is an advanced hydrodistillation (HD) technique, in which a microwave oven is used in the extraction process. MAHD and HD methods have been compared and evaluated for their effectiveness in the isolation of essential oils from fresh mango (Mangifera indica L.) flowers. MAHD offers important advantages over HD in terms of energy savings and extraction time (75 min against 4 h). The composition of the extracted essential oils was investigated by GC-FID and GC-MS. Results indicate that the use of microwave irradiation did not adversely influence the composition of the essential oils. MAHD was also found to be a green technology.

Validation of the central blood pressure estimation by the SphygmoCor system in Chinese.

BACKGROUND: Pulse wave analysis using the SphygmoCor system allows the estimation of central blood pressures (BP). However, there is controversy over its accuracy for clinical use. METHODS: In 45 patients undergoing coronary angiography, we compared the ascending aorta BPs measured by the invasive catheter with the estimations by the SphygmoCor system, using paired t-tests, simple correlation analysis, and Bland-Altman plots. RESULTS: The estimation of central systolic BP by SphygmoCor was lower, although statistically insignificant, than that measured by the catheter (144±29 vs. 148±30 mmHg; P=0.98). The standard deviation of the difference amounted to 17 mmHg. Both the measured and estimated central systolic BPs were significantly (P<0.001) lower than the brachial systolic BP (156±30 mmHg). The diastolic BP measured at the brachial artery (87±15 mmHg) and provided by SphygmoCor (90±15 mmHg) were systematically higher (P<0.001) than that measured by the catheter (74±13 mmHg). The SphygmoCor system underestimated the central pulse pressure by -20±14 mmHg compared with the catheter method. The correlation coefficients for systolic BP, diastolic BP, and pulse pressure between catheter measurements and the SphygmoCor estimations were 0.84, 0.60, and 0.82 (P<0.001), respectively. CONCLUSION: When the radial waveform was calibrated with the oscillometric brachial pressures, the SphygmoCor system could not provide accurate estimation of central BPs. The inaccurate measurement of cuff pressure was the major limiting factor for the use of the transfer function in the clinical settings.

Impact of angiographic and intravascular ultrasound features on clinical outcome after sirolimus-eluting stent implantation for de-novo lesions in nondiabetic and type 2 diabetic patients.

OBJECTIVES: This study aimed to evaluate the impact of angiographic and intravascular ultrasound (IVUS) features on clinical outcome in nondiabetic and type 2 diabetic patients after percutaneous coronary intervention (PCI) with sirolimus-eluting stent (SES) implantation. METHODS: Repeat coronary angiography with IVUS imaging was performed after SES-based PCI for de-novo lesions in 128 diabetic and 327 nondiabetic patients (189 lesions and 504 lesions, respectively). The rate of major adverse cardiac events including cardiac death, non fatal myocardial infarction (MI), and target lesion revascularization during clinical follow-up was recorded. RESULTS: In-stent and in-segment late loss, intimal hyperplasia volume, and percentage volumetric obstruction were similar, but stented external elastic membrane cross-sectional area and reference/stented segment ratio were lower in diabetic than in nondiabetic patients. Incomplete stent apposition (ISA) was less frequent, but occurrence of new coronary lesions was higher in diabetic than in nondiabetic patients. Despite similar target lesion revascularization, cumulative survival rates freedom from composite cardiac death and nonfatal MI or major adverse cardiac events were reduced in diabetic patients. Cox proportional hazards model identified diabetes, left ventricular ejection fraction, minimal stent CSA, maximal ISA area, atherosclerotic progression and lesion length as independent predictors of non fatal MI or mortality at follow-up. CONCLUSION: In diabetic patients, PCI with SES implantation neutralizes the excess risk of intimal hyperplasia and decreases occurrence of ISA, but could not modify the propensity of increased adverse clinical outcomes at follow-up.