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High recurrence and chemoresistance drive the high mortality in hepatocellular carcinoma (HCC). Although cancer stem cells are considered to be the source of recurrent and chemoresistant tumors, they remain poorly defined in HCC. Tonicity-responsive enhancer binding protein (TonEBP) is elevated in almost all HCC tumors and associated with recurrence and death. We aimed to identify function of TonEBP in stemness and chemoresistance of liver cancer.<br /><br /> Tumors obtained from 280 HCC patients were analyzed by immunohistochemical analyses. Stemness and chemoresistance of liver CSCs (LCSCs) were investigated using cell culture. Tumor-initiating activity was measured by implanting LCSCs into BALB/c nude mice.<br /><br /> Expression of TonEBP is higher in LCSCs in HCC cell lines and correlated with markers of LCSCs whose expression is significantly associated with poor prognosis of HCC patients. [https://www.selleckchem.com/products/sr-18292.html read more] TonEBP mediates ATM-mediated activation of NF-κB, which stimulates the promoter of a key stem cell transcription factor SOX2. As expected, TonEBP is required for the tumorigenesis and self-renewal of LSCSs. Cisplatin induces the recruitment of the ERCC1/XPF dimer to the chromatin in a TonEBP-dependent manner leading to DNA repair and cisplatin resistance. The cisplatin-induced inflammation in LSCSs is also dependent on the TonEBP-ERCC1/XPF complex, and leads to enhanced stemness via the ATM-NF-κB-SOX2 pathway. In HCC patients, tumor expression of ERCC1/XPF predicts recurrence and death in a TonEBP-dependent manner.<br /><br /> TonEBP promotes stemness and cisplatin resistance of HCC via ATM-NF-κB. TonEBP is a key regulator of LCSCs and a promising therapeutic target for HCC and its recurrence.<br /><br />TonEBP promotes stemness and cisplatin resistance of HCC via ATM-NF-κB. TonEBP is a key regulator of LCSCs and a promising therapeutic target for HCC and its recurrence.<br /><br /> This study aimed to establish and validate a novel scoring system based on a nomogram for the differential diagnosis of malignant pleural effusion (MPE) and benign pleural effusion (BPE).<br /><br /> Patients with PE and confirmed aetiology who underwent diagnostic thoracentesis were included in this study. One retrospective set (N=1261) was used to develop and internally validate the predictive model. The clinical, radiological and laboratory features were collected and subjected to logistic regression analyses. The primary predictive model was displayed as a nomogram and then modified into a novel scoring system, which was externally validated in an independent set (N=172).<br /><br /> The novel scoring system was composed of fever (3 points), erythrocyte sedimentation rate (4 points), effusion adenosine deaminase (7 points), serum carcinoembryonic antigen (CEA) (4 points), effusion CEA (10 points) and effusion/serum CEA (8 points). With a cutoff value of 15 points, the area under the curve, specificity and sensitivity for identifying MPE were 0.913, 89.10%, and 82.63%, respectively, in the training set, 0.922, 93.48%, 81.51%, respectively, in the internal validation set and 0.912, 87.61%, 81.36%, respectively, in the external validation set. Moreover, this scoring system was exclusively applied to distinguish lung cancer with PE from tuberculous pleurisy and showed a favourable diagnostic performance in the training and validation sets.<br /><br /> This novel scoring system was developed from a retrospective study and externally validated in an independent set based on six easily accessible clinical variables, and it exhibited good diagnostic performance for identifying MPE.<br /><br /> NFSC grants (no. 81572942, no. 81800094).<br /><br />NFSC grants (no. 81572942, no. 81800094).<br /><br /> PRR (Pattern Recognition Receptor) agonists have been widely tested as potent vaccine adjuvants. TLR7 (Toll-Like Receptor 7) and NOD2 (nucleotide-binding oligomerization domain 2) are key innate receptors widely expressed at mucosal levels.<br /><br /> Here, we evaluated the immunostimulatory properties of a novel hybrid chemical compound designed to stimulate both TLR7 and NOD2 receptors.<br /><br /> The combined TLR7/NOD2 agonist showed increase efficacy than TLR7L or NOD2L agonists alone or combined in different in vitro models. Dual TLR7/NOD2 agonist efficiently stimulates TLR7 and NOD2, and promotes the maturation and reprogramming of human dendritic cells, as well as the secretion of pro-inflammatory or adaptive cytokines. This molecule also strongly induces autophagy in human cells which is a major intracellular degradation system that delivers cytoplasmic constituents to lysosomes in both MHC class I and II-restricted antigen presentation. In vivo, TLR7/NOD2L agonist is a potent adjuvant after intranasal administration with NP-p24 HIV vaccine, inducing high-quality humoral and adaptive responses both in systemic and mucosal compartments. Use of TLR7/NOD2L adjuvant improves very significantly the protection of mice against an intranasal challenge with a vaccinia virus expressing the p24.<br /><br /> Dual TLR7/NOD2L agonist is a very potent and versatile vaccine adjuvant and promote very efficiently both systemic and mucosal immunity.<br /><br /> This work was supported by Sidaction.<br /><br />This work was supported by Sidaction.<br /><br /> Impaired or hyperactive pancreas regeneration after injury would cause exocrine insufficiency or recurrent / chronic pancreatitis and potentially carcinogenesis. Macrophages are the most abundant immune cells in the regenerative pancreas, however their phenotype and role remain poorly defined.<br /><br /> Using caerulein-induced acute pancreatitis (AP) model, we examined the dynamic landscape of pancreatic macrophages throughout the acute inflammation to regeneration phases by flow cytometric and RNA-seq analyses. Liposome depletion of macrophages, Il4ra<br /><br /> mice as well as inhibitors were used to elucidate the role and regulatory mechanism of macrophages during pancreatic regeneration.<br /><br /> We found that M1 macrophages dominated in the pro-inflammatory phase of AP, while M2-like macrophages dominated during pancreas repair/regeneration. Depletion of macrophages at early or late regenerative stage dramatically blocked the acinar-ductal metaplasia (ADM) or delayed inflammation resolution, respectively. Moreover, alternative activation of macrophages was partially dependent on IL-4RA signaling, and ECM/AKT activation in pancreatic macrophages facilitated inflammation resolution during tissue regeneration.<br /><br /> Our findings illustrate a dynamic phenotype and function of macrophages during AP repair/regeneration, helping us better understand the mechanism of pancreatic regeneration and providing clues for novel therapeutic strategy.<br /><br />Our findings illustrate a dynamic phenotype and function of macrophages during AP repair/regeneration, helping us better understand the mechanism of pancreatic regeneration and providing clues for novel therapeutic strategy.<br /><br /> Abnormalities of lipid metabolism contributing to the autism spectrum disorder (ASD) pathogenesis have been suggested, but the mechanisms are not fully understood. We aimed to characterize the lipid metabolism in ASD and to explore a biomarker for clinical evaluation.<br /><br /> An age-matched case-control study was designed. Lipidomics was conducted using the plasma samples from 30 children with ASD compared to 30 typical developmental control (TD) children. Large-scale lipoprotein analyses were also conducted using the serum samples from 152 children with ASD compared to 122 TD children. Data comparing ASD to TD subjects were evaluated using univariate (Mann-Whitney test) and multivariate analyses (conditional logistic regression analysis) for main analyses using cofounders (diagnosis, sex, age, height, weight, and BMI), Spearman rank correlation coefficient, and discriminant analyses.<br /><br /> Forty-eight significant metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function were identified in the plasma of ASD children by lipidomics. Among these, increased fatty acids (FAs), such as omega-3 (n-3) and omega-6 (n-6), showed correlations with clinical social interaction score and ASD diagnosis. Specific reductions of very-low-density lipoprotein (VLDL) and apoprotein B (APOB) in serum of ASD children also were found by large-scale lipoprotein analysis. VLDL-specific reduction in ASD was correlated with APOB, indicating VLDL-specific dyslipidaemia associated with APOB in ASD children.<br /><br /> Our results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation, providing novel insights into the lipid metabolism underlying ASD pathophysiology.<br /><br /> This study was supported mainly by MEXT, Japan.<br /><br />This study was supported mainly by MEXT, Japan.<br /><br /> Abnormalities of functional activation and cortical volume in brain regions involved in the neurobiology of fear and anxiety have been implicated in the pathophysiology of social anxiety disorder (SAD). However, few studies have performed separate measurements of cortical thickness (CT) and cortical surface area (CSA) which reflect different neurobiological processes. link2 Thus, we aimed to explore the cortical morphological anomaly separately in SAD using FreeSurfer.<br /><br /> High-resolution structural magnetic resonance images were obtained from 32 non-comorbid never-treated adult SAD patients and 32 demography-matched healthy controls. Cortical morphometry indices including CT and CSA were separately determined by FreeSurfer and compared between the two groups via whole-brain vertex-wise analysis, while partial correlation analysis using age and gender as covariates were conducted.<br /><br /> The patients with SAD showed decreased CT but increased CSA near-symmetrically in the bilateral prefrontal cortex (PFC) of the dorsolateral, dorsomedial, and ventromedial subdivisions, as well as the right lateral orbitofrontal cortex; increased CSA in the left superior temporal gyrus (STG) was also observed in SAD. The CSA in the left PFC was negatively correlated with the disease duration.<br /><br /> As the balloon model hypothesis suggests that the tangentially stretched cortex may cause dissociations in cortical morphometry and affect the cortical capacity for information processing, our findings of dissociated morphological alterations in the PFC and cortical expansion in the STG may reflect the morphological alterations of the functional reorganization in those regions, and highlight the important role of those structures in the pathophysiology and neurobiology of SAD.<br /><br /> This study was funded by the National Natural Science Foundation of China (Grant Nos. 31700964, 31800963, 81621003, and 81820108018).<br /><br />This study was funded by the National Natural Science Foundation of China (Grant Nos. 31700964, 31800963, 81621003, and 81820108018).<br /><br /> Head and neck squamous cell carcinoma is a heterogeneous disease with respect to the anatomic site of the primary tumor. On the other hand, it is highly recurrent, and once metastatic, it is associated with poor prognosis. TP53 is the most commonly mutated gene in primary disease. TP53 mutations occur in different structural elements of the protein while the biological outcome can be diverse.<br /><br /> Here we aimed to find differences in the mutation profile of TP53 in primary and metastatic disease and the impact of TP53 mutations in metastasis, specific copy number alterations, tumor mutation burden and response to immune checkpoint inhibitors. Somatic mutation and clinical data for 512 primary and 134 metastatic biopsies were studied.<br /><br /> Overall TP53 mutation frequency is significantly lower in metastases compared to primary tumors. link3 One the other hand, missense mutations in the DNA binding region are significantly enriched in metastases and are associated with a common fragile site in chromosome 11, leading to amplification and overexpression of genes with established role in metastasis.