Comparison of diagnostic performance of AFP, DCP and two diagnostic models in hepatocellular carcinoma: a retrospective study.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) may be diagnosed using the GAAP and ASAP models; our goal was to verify and evaluate their diagnostic effectiveness compared to alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), and AFP & DCP for both HCC and HCC caused by the hepatitis B virus (HBV). PATIENTS AND METHODS: GAAP and ASAP models were validated and compared using a retrospective investigation of 938 patients from our hospital between July 2020 and July 2021. RESULTS: Both the GAAP and ASAP models had better diagnostic efficacy than AFP, DCP, AFP & DCP. The GAAP model achieved better performance in section A for the detection of HCC and in section C for the detection of HBV-HCC than the ASAP model. The Hosmer-Lemeshow test showed that the GAAP and ASAP models were well-calibrated for the diagnoses of these two groups. To be more specific, the area under curve (AUC) of the GAAP model for HCC detection in section A was 0.862 [95% confidence interval (CI): 0.838-0.883], and that of the ASAP model was 0.850 [95% CI: 0.826-0.872]. The AUC of the GAAP model for HBV-HCC detection in section C was 0.897 [95% CI: 0.872-0.918], and that of the ASAP model was 0.878 [95% CI: 0.852-0.902]. CONCLUSIONS: The GAAP model was more accurate and reliable than the AFP, DCP, AFP and DCP, as well as the ASAP model in section A for the detection of HCC and in section C for the detection of HBV-HCC.

A Predominant Role of AtEDEM1 in Catalyzing a Rate-Limiting Demannosylation Step of an Arabidopsis Endoplasmic Reticulum-Associated Degradation Process.

Endoplasmic reticulum-associated degradation (ERAD) is a key cellular process for degrading misfolded proteins. It was well known that an asparagine (N)-linked glycan containing a free α1,6-mannose residue is a critical ERAD signal created by Homologous to α-mannosidase 1 (Htm1) in yeast and ER-Degradation Enhancing α-Mannosidase-like proteins (EDEMs) in mammals. An earlier study suggested that two Arabidopsis homologs of Htm1/EDEMs function redundantly in generating such a conserved N-glycan signal. Here we report that the Arabidopsis irb1 (reversal of bri1) mutants accumulate brassinosteroid-insensitive 1-5 (bri1-5), an ER-retained mutant variant of the brassinosteroid receptor BRI1 and are defective in one of the Arabidopsis Htm1/EDEM homologs, AtEDEM1. We show that the wild-type AtEDEM1, but not its catalytically inactive mutant, rescues irb1-1. Importantly, an insertional mutation of the Arabidopsis Asparagine-Linked Glycosylation 3 (ALG3), which causes N-linked glycosylation with truncated glycans carrying a different free α1,6-mannose residue, completely nullifies the inhibitory effect of irb1-1 on bri1-5 ERAD. Interestingly, an insertional mutation in AtEDEM2, the other Htm1/EDEM homolog, has no detectable effect on bri1-5 ERAD; however, it enhances the inhibitory effect of irb1-1 on bri1-5 degradation. Moreover, AtEDEM2 transgenes rescued the irb1-1 mutation with lower efficacy than AtEDEM1. Simultaneous elimination of AtEDEM1 and AtEDEM2 completely blocks generation of α1,6-mannose-exposed N-glycans on bri1-5, while overexpression of either AtEDEM1 or AtEDEM2 stimulates bri1-5 ERAD and enhances the bri1-5 dwarfism. We concluded that, despite its functional redundancy with AtEDEM2, AtEDEM1 plays a predominant role in promoting bri1-5 degradation.

Epidemiology of Drug- and Herb-Induced Liver Injury Assessed for Causality Using the Updated RUCAM in Two Hospitals from China.

Drug- and herb-induced liver injury (DILI and HILI) is an increasingly common and serious condition. Here, data for DILI and HILI patients from two large tertiary hospitals were retrospectively analyzed. Patient characteristics, causes and severity of DILI and HILI, the correlation between expression of p62 and the severity of DILI and HILI, treatment of DILI and HILI, and the prognostic factors of DILI and HILI were studied. A total of 82 patients with DILI and HILI were recruited for the study. Most patients presented with hepatocellular injury, followed by cholestatic injury and mixed injury. Our results indicate that traditional Chinese medicine or herbal and dietary supplements were the prevalent causal agents of HILI, which was characterized by higher frequencies of hepatocellular injury. Expression of p62 in the liver correlated with the severity of DILI and HILI. Improvements in the results of the liver enzymatic tests correlated with alanine transaminase (ALT) levels upon the first diagnosis of DILI and HILI and with the hepatocellular type of DILI and HILI. In conclusion, we provide an epidemiological assessment of DILI and HILI based on causality using the updated RUCAM on patients from two hospitals in China. ALT levels at first diagnosis and the hepatocellular type of injury may be prognostic factors of DILI and HILI.

Curcumin suppresses LGR5(+) colorectal cancer stem cells by inducing autophagy and via repressing TFAP2A-mediated ECM pathway.

Colorectal cancer stem cells (CSCs) have the potential for self-renewal, proliferation, and differentiation. And LGR5 is a stem cell marker gene of colorectal cancer. Curcumin can suppress oncogenicity of many cancer cells, yet the effect and mechanism of curcumin in LGR5(+) colorectal cancer stem cells (CSCs) have not been studied. In this study, we studied the effect of curcumin on LGR5(+) colorectal CSCs using the experiments of tumorsphere formation, cell viability and cell apoptosis. Then autophagy analysis, RNA-Seq, and real-time PCR were used to identify the mechanism responsible for the inhibition of LGR5(+) colorectal CSCs. Our results showed that curcumin inhibited tumorsphere formation, decreased cell viability in a dose-dependent manner, and also promoted apoptosis of LGR5(+) colorectal CSCs. Next, we found curcumin induced autophagy of LGR5(+) colorectal CSCs. When LGR5(+) colorectal CSCs were co-treated with curcumin and the autophagy inhibitor (hydroxychloroquine), curcumin-induced cell proliferation inhibition decreased. In addition, we also found that curcumin inhibited the extracellular matrix (ECM)-receptor interaction pathway via the downregulation of the following genes: GP1BB, COL9A3, COMP, AGRN, ITGB4, LAMA5, COL2A1, ITGB6, ITGA1, and TNC. Further, these genes were transcriptionally regulated by TFAP2A, and the high expression of TFAP2A was associated with poor prognosis in colorectal cancer. In conclusion, curcumin suppressed LGR5(+) colorectal CSCs, potentially by inducing autophagy and repressing the oncogenic TFAP2A-mediated ECM pathway.

Rational Use of Tocilizumab in the Treatment of Novel Coronavirus Pneumonia.

Since December 2019, a novel coronavirus pneumonia (COVID-19) has broken out in Wuhan, China and spread rapidly. Recent studies have found that ⁓ 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. IL-6 is one of the key cytokines involved in infection-induced cytokine storm. Tocilizumab, which is the IL-6 receptor antagonist, has been approved by the US FDA for the treatment of cytokine release syndrome (CRS), is expected to treat cytokine storm caused by COVID-19 and is now in clinical trials. In this paper, we will elaborate the role of cytokine storm in COVID-19, the mechanism of tocilizumab on cytokine storm and the key points of pharmaceutical care based on the actual clinical application for COVID-19 in our hospital, the latest research reports, clinical trial progress of tocilizumab, drug instruction from the US FDA, and "Diagnosis and Treatment Plan of Novel Coronavirus Pneumonia (seventh trial edition)" in China, so as to provide reference for the treatment of COVID-19.

PAWH1 and PAWH2 are plant-specific components of an Arabidopsis endoplasmic reticulum-associated degradation complex.

Endoplasmic reticulum-associated degradation (ERAD) is a unique mechanism to degrade misfolded proteins via complexes containing several highly-conserved ER-anchored ubiquitin ligases such as HMG-CoA reductase degradation1 (Hrd1). Arabidopsis has a similar Hrd1-containing ERAD machinery; however, our knowledge of this complex is limited. Here we report two closely-related Arabidopsis proteins, Protein Associated With Hrd1-1 (PAWH1) and PAWH2, which share a conserved domain with yeast Altered Inheritance of Mitochondria24. PAWH1 and PAWH2 localize to the ER membrane and associate with Hrd1 via EMS-mutagenized Bri1 Suppressor7 (EBS7), a plant-specific component of the Hrd1 complex. Simultaneously elimination of two PAWHs constitutively activates the unfolded protein response and compromises stress tolerance. Importantly, the pawh1 pawh2 double mutation reduces the protein abundance of EBS7 and Hrd1 and inhibits degradation of several ERAD substrates. Our study not only discovers additional plant-specific components of the Arabidopsis Hrd1 complex but also reveals a distinct mechanism for regulating the Hrd1 stability.

A Temperature-Sensitive Misfolded bri1-301 Receptor Requires Its Kinase Activity to Promote Growth.

BRASSINOSTEROID-INSENSITIVE1 (BRI1) is a leucine-rich-repeat receptor-like kinase that functions as the cell surface receptor for brassinosteroids (BRs). Previous studies showed that BRI1 requires its kinase activity to transduce the extracellular BR signal into the nucleus. Among the many reported mutant bri1 alleles, bri1-301 is unique, as its glycine-989-to-isoleucine mutation completely inhibits its kinase activity in vitro but only gives rise to a weak dwarf phenotype compared with strong or null bri1 alleles, raising the question of whether kinase activity is essential for the biological function of BRI1. Here, we show that the Arabidopsis (Arabidopsis thaliana) bri1-301 mutant receptor exhibits weak BR-triggered phosphorylation in vivo and absolutely requires its kinase activity for the limited growth that occurs in the bri1-301 mutant. We also show that bri1-301 is a temperature-sensitive misfolded protein that is rapidly degraded in the endoplasmic reticulum and at the plasma membrane by yet unknown mechanisms. A temperature increase from 22°C to 29°C reduced the protein stability and biochemical activity of bri1-301, likely due to temperature-enhanced protein misfolding. The bri1-301 protein could be used as a model to study the degradation machinery for misfolded membrane proteins with cytosolic structural lesions and the plasma membrane-associated protein quality-control mechanism.