Hepatocellular carcinoma (HCC) is a cancer with extremely high mortality. Epithelial‐mesenchymal transition (EMT) may play an important role in the occurrence, invasion and prognosis of HCC; however, ...its relationship with immunity in HCC has not yet been studied. Therefore, we investigated the diagnostic and prognostic values of EMT and explored its potential connections with tumorigenic immune infiltrates in HCC. We first proposed a quantitative metric of EMT activity, the EMT score. After applying this metric to 20 datasets from the Integrative Molecular Database of Hepatocellular Carcinoma, the Cancer Genome Atlas, and the Gene Expression Omnibus, we explored the ability of the EMT score to stratify across sample types. We then applied the EMT score for survival analysis and to differentiate patients with/without vascular invasion to test its prognostic value. We also collected and calculated data on the abundance of immune cells and immune cell markers in HCC and investigated their correlations with EMT scores. Finally, we synthesized and analyzed 20 datasets and constructed an EMT‐gene‐immune linkage network. The results showed higher EMT scores in HCC samples than in cirrhotic and normal livers. The cases with higher EMT scores also showed poorer performance in terms of prognostic factors such as vascular invasion and overall survival time. Our research demonstrated a broad correlation between EMT and the tumor immune microenvironment, and we uncovered multiple potential linkers associated with both EMT and immunity. Studying EMT has clinical relevance and high diagnostic and prognostic value for HCC.
Epithelial‐mesenchymal transition (EMT) may play an important role in the occurrence, invasion, and prognosis of hepatocellular carcinoma (HCC); however, its relationship with immunity in HCC has not yet been studied. Therefore, we investigated the diagnostic and prognostic values of EMT and explored its potential connections with tumorigenic immune infiltrates in HCC.
Protein acetylation emerged as a key regulatory mechanism for many cellular processes. We used genetic analysis of Saccharomyces cerevisiae to identify Esa1 as a histone acetyltransferase required ...for autophagy. We further identified the autophagy signaling component Atg3 as a substrate for Esa1. Specifically, acetylation of K19 and K48 of Atg3 regulated autophagy by controlling Atg3 and Atg8 interaction and lipidation of Atg8. Starvation induced transient K19-K48 acetylation through spatial and temporal regulation of the localization of acetylase Esa1 and the deacetylase Rpd3 on pre-autophagosomal structures (PASs) and their interaction with Atg3. Attenuation of K19-K48 acetylation was associated with attenuation of autophagy. Increased K19-K48 acetylation after deletion of the deacetylase Rpd3 caused increased autophagy. Thus, protein acetylation contributes to control of autophagy.
Modification of target molecules by ubiquitin or ubiquitin-like (Ubl) proteins is generally reversible. Little is known, however, about the physiological function of the reverse reaction, ...deconjugation. Atg8 is a unique Ubl protein whose conjugation target is the lipid phosphatidylethanolamine (PE). Atg8 functions in the formation of double-membrane autophagosomes, a central step in the well-conserved intracellular degradation pathway of macroautophagy (hereafter autophagy). Here we show that the deconjugation of Atg8−PE by the cysteine protease Atg4 plays dual roles in the formation of autophagosomes. During the early stage of autophagosome formation, deconjugation releases Atg8 from non-autophagosomal membranes to maintain a proper supply of Atg8. At a later stage, the release of Atg8 from intermediate autophagosomal membranes facilitates the maturation of these structures into fusion-capable autophagosomes. These results provide new insights into the functions of Atg8−PE and its deconjugation.
Mutations in the gene encoding hepatocystin/80K-H (PRKCSH) cause autosomal-dominant polycystic liver disease (ADPLD). Hepatocystin functions in the processing of nascent glycoproteins as the ...noncatalytic beta subunit of glucosidase II (Glu II) and regulates calcium release from endoplasmic reticulum (ER) through the inositol 1,4,5-trisphosphate receptor (IP3R). Little is known, however, on how cells respond to a deficiency of hepatocystin. In this study, we demonstrate that knockdown of hepatocystin induces autophagy, the major intracellular degradation pathway essential for cellular health. Ectopic expression of wild-type hepatocystin, but not pathogenic mutants, rescues the siRNA-induced effect. Our data indicate that the induction of autophagy by hepatocystin deficiency is mediated through mammalian target of rapamycin (mTOR). Despite the resulting severe reduction in Glu II activity, the unfolded protein response (UPR) pathway is not disturbed. Furthermore, the inhibition of IP3R-mediated transient calcium flux is not required for the induction of autophagy. These results provide new insights into the function of hepatocysin and the regulation of autophagy.
AIM：To investigate if non-alcoholic fatty liver disease （NAFLD） is an early mediator for prediction of metabolic syndrome,and if liver B-ultrasound can be used for its diagnosis.METHODS：We classified ...861 obese children （6-16 years old） into three subgroups：group 0 （normal liver in ultrasound and normal transaminases）;group 1 （fatty liver in ultrasound and normal transaminases）;and group 2 （fatty liver in ultrasound and elevated transaminases）.We measured the body mass index,waist and hip circumference,blood pressure,fasting blood glucose,insulin,homeostasis model assessment of insulin resistance （HOMA-IR）,whole-body insulin sensitivity index （WBISI）,lipid profile and transaminases in all the participants.The risk of developing metabolic syndrome （MS） was assessed according to the degree of liver fatty infiltration based on the B-ultrasound examination.RESULTS：Among the 861 obese children,587 （68.18%） were classified as having NAFLD,and 221 （25.67%） as having MS.The prevalence of MS in NAFLD children （groups 1 and 2） was 37.64% （221/587）,which was much higher than that in non-NAFLD group （group 0,12.04%） （P 0.01）.There were significantly higher incidences concerning every component of MS in group 2 compared with group 0 （P 0.05）.The incidence of NAFLD in MS patients was 84.61% （187/221）,which was significantly higher than that of hypertension （57.46%,127/221） and glucose metabolic anomalies （22.62%,50/221）,and almost equal to the prevalence of dyslipidemia （89.14%,197/221）.Based on the B-ultrasound scales,the presence of moderate and severe liver fatty infiltration carried a high risk of hypertension odds ratio （OR）：2.18,95% confidence interval （95% CI）：1.27-3.75,dyslipidemia （OR：7.99,95% CI：4.34-14.73）,impaired fasting glucose （OR：3.65,95% CI：1.04-12.85）,and whole MS （OR：3.77;95% CI：1.90-7.47,P 0.01）.The state of insulin resistance （calculated by HOMA-IR and WBISI） deteriorated as the degree of fatty infiltration increased.CONCLUSION：NAFLD is not only a liver disease,but also an early mediator that reflects metabolic disorder,and liver B-ultrasound can be a useful tool for MS screening.
Modification of target molecules by ubiquitin or ubiquitin-like (Ubl) proteins is generally reversible. Little is known, however, about the physiological function of the reverse reaction, ...deconjugation. Atg8 is a unique Ubl protein whose conjugation target is the lipid phosphatidylethanolamine (PE). Atg8 functions in the formation of double-membrane autophagosomes, a central step in the well-conserved intracellular degradation pathway of macroautophagy (hereafter autophagy). Here we show that the deconjugation of Atg8−PE by the cysteine protease Atg4 plays dual roles in the formation of autophagosomes. During the early stage of autophagosome formation, deconjugation releases Atg8 from non-autophagosomal membranes to maintain a proper supply of Atg8. At a later stage, the release of Atg8 from intermediate autophagosomal membranes facilitates the maturation of these structures into fusion-capable autophagosomes. These results provide new insights into the functions of Atg8−PE and its deconjugation.
Delirium is a severe acute neuropsychiatric syndrome that commonly occurs in the elderly and is considered an independent risk factor for later dementia. However, given its inherent complexity, few ...animal models of delirium have been established and the mechanism underlying the onset of delirium remains elusive. Here, we conducted a comparison of three mouse models of delirium induced by clinically relevant risk factors, including anesthesia with surgery (AS), systemic inflammation, and neurotransmission modulation. We found that both bacterial lipopolysaccharide (LPS) and cholinergic receptor antagonist scopolamine (Scop) induction reduced neuronal activities in the delirium-related brain network, with the latter presenting a similar pattern of reduction as found in delirium patients. Consistently, Scop injection resulted in reversible cognitive impairment with hyperactive behavior. No loss of cholinergic neurons was found with treatment, but hippocampal synaptic functions were affected. These findings provide further clues regarding the mechanism underlying delirium onset and demonstrate the successful application of the Scop injection model in mimicking delirium-like phenotypes in mice.
Background
No studies have examined endogenous insulin secretion in pediatric patients with type 1 diabetes in China using the gold-standard mixed-meal tolerance test. Because the latter is ...labor-intensive, we examined simpler surrogate markers of endogenous insulin secretion in Chinese youth, as previously reported for a European population.
Methods
Participants were 57 children and adolescents with type 1 diabetes aged 4.4–16.8 years (56% females). We performed 120-minute mixed-meal tolerance tests with serum C-peptide (CP) measurements every 30 minutes. Severe insulin deficiency (SID) was defined as CP peak < 0.2 nmol/L. Urine CP and creatinine levels were measured at 0 and 120 minutes.
Results
Twenty-five (44%) patients had SID. Fasting CP levels missed one case (96% sensitivity) with no false positives (100% specificity). While the 120-minute urine CP/creatinine had 100% sensitivity, it yielded markedly lower specificity (63%). Every 1-year increase in diabetes duration and 1-year decrease in age at diagnosis were associated with 37% (
P
< 0.001) and 20% (
P
= 0.005) reductions in serum CP area-under-the-curve, respectively. Thus, 86% of children aged < 5 years had SID compared to none among patients aged ≥ 11 years.
Conclusions
Simple fasting CP measurements could be used to detect most SID cases in Chinese youth with type 1 diabetes. Fasting CP is a far more reliable measure of endogenous insulin secretion than the more commonly used insulin dose. Therefore, it could more precisely determine insulin secretory capacity to target those who could benefit, if treatments to preserve residual insulin secretion are developed.
PDF
