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Graphical abstract, Highlights • The development of scientific research in CIBP was elaborated in a complete and clear perspective. • The possible mechanisms, including the new achievements in central sensitization, glial cell activation, acid environment, of CIBP were reviewed. • Several key molecules and treatments as well as the potential targets and promising therapies were also briefly reviewed. • The challenges we faced and the future directions are also summarized and elaborated., Background Cancer-induced Bone Pain (CIBP) is an important factor affecting their quality of life of cancer survivors. In addition, current clinical practice and scientific research suggest that neuropathic pain is a representative component of CIBP. However, given the variability of cancer conditions and the complexity of neuropathic pain, related mechanisms have been continuously supplemented but have not been perfected. Aim of Review Therefore, the current review highlights the latest progress in basic research on the field and proposes potential therapeutic targets, representative drugs and upcoming therapies. Key Scientific Concepts of Review Notably, factors such as central sensitization, neuroinflammation, glial cell activation and an acidic environment are considered to be related to neuropathic pain in CIBP. Nonetheless, further research is needed to ascertain the mechanism of CIBP in order to develop highly effective drugs. Moreover, more attention needs to be paid to the care of patients with advanced cancer.

Nonalcoholic fatty liver disease (NAFLD) has become one of the most prominent causes of chronic liver diseases and malignancies. However, few therapy has been approved. Radix Bupleuri (RB) is the most frequently used herbal medicine for the treatment of liver diseases. In the current study, we aim to systemically evaluate the therapeutic effects of saikosaponin A (SSa) and saikosaponin D (SSd), the major bioactive monomers in RB, against NAFLD and to investigate the underlying mechanisms. Our results demonstrated that both SSa and SSd improved diet-induced NAFLD. Integrative lipidomic and transcriptomic analysis revealed that SSa and SSd modulated glycerolipid metabolism by regulating related genes, like Lipe and Lipg. SSd profoundly suppressed the fatty acid biosynthesis by downregulating Fasn and Acaca expression and promoted fatty acid degradation by inducing Acox1 and Cpt1a expression. Bioinformatic analysis further predicted the implication of master transcription factors, including peroxisome proliferator-activated receptor alpha (PPARα), in the protective effects of SSa and SSd. These results were further confirmed in vitro in mouse primary hepatocytes. In summary, our study uncoded the complicated mechanisms underlying the promising anti-steatosis activities of saikosaponins (SSs), and provided critical evidence inspiring the discovery of innovative therapies based on SSa and SSd for the treatment of NAFLD and related complications., Graphical abstract Saikosaponins A and D (SSa and SSd) significantly alleviated diet-induced nonalcoholic fatty liver diseases by promoting promoted glycerolipid and fatty acid metabolism, as unraveled by integrative transcriptomic and lipidomic analysis.Image 1

OBJECTIVE. Vocal turn taking is an important predictor of language development in children with and without hearing loss. Most studies have examined vocal turn taking in mother-child dyads without considering the multitalker context in a child’s life. The present study investigates the quantity of vocal turns between deaf and hard-of-hearing children and multiple members of their social environment. DESIGN. Participants were 52 families with children who used hearing aids (HA, mean age 26.3 months) or cochlear implants (CI, mean age 63.2 months) and 27 families with normal-hearing (NH, mean age 26.6 months) children. The Language ENvironment Analysis system estimated the number of conversational turns per hour (CTC/hr) between all family members (i.e., adult female, adult male, target child and other child) during full-day recordings over a period of about one year. RESULTS. The CTC/hr was lower between the target child and the adult female or adult male in the CI compared to the HA and NH groups. Initially, CTC/hr was higher between the target child and the adult female than between the adult male or the other child. As the child’s age increased, turn taking between the target child and the adult female increased in comparison to that between the target child and the adult male. Over time, turn taking between the target child and the other child increased and exceeded turn taking between the target child and the adult caregivers. The increase was observed earlier in families with siblings compared to those without. CONCLUSIONS. The quantity of vocal turn taking depends on the degree of child hearing loss and the relationship between the children and the members of their social environment. Longitudinally, the positive effect of an assistive device on the quantity of turns between the children and their family members was found. The effect was stronger in families with siblings.

Objective. This study aims to explore circ_0058063 effect on multiple myeloma cells malignant phenotype and its feasible mechanism. Methods. We selected 47 cases of multiple myeloma tissues and 47 cases of normal bone marrow tissues and then used RT-qPCR method to test circ_0058063 and miR-635 expression in the tissues. Myeloma cells RPMI8226 were transfected with si-circ_0058063, miR-635 mimic, and si-circ_0058063 + anti-miR-635, respectively. Then, we adopt CCK-8 method, flow cytometry method, and Transwell and western blot methods to detect the influences of knockdown of circ_0058063 or miR-635 overexpression on RPMI8226 cell proliferation, apoptosis, migration, and invasion and also Ki-67, Bax, Bcl-2, MMP-2, and MMP-9 protein expression. The dual luciferase reporter gene assay experiment proved that it has regulatory relationship between circ_0058063 and miR-635. Results. circ_0058063 expression of multiple myeloma was higher than that in normal bone marrow tissue ( P < 0.05 ), while miR-635 expression was lower than that in normal bone marrow tissue ( P < 0.05 ). Knockdown of circ_0058063 or overexpression of miR-635 could reduce proliferation capacity, migration, invasion cell quantities, and Ki-67, MMP-2, MMP-9, and Bcl-2 protein expression ( P < 0.05 ), while increasing apoptosis rate together with Bax protein expression ( P < 0.05 ). circ_0058063 targets to negatively regulate miR-635, while knocking down miR-635 reverses the influences of knocking down circ_0058063 on RPMI8226 proliferation, apoptosis, migration, and invasion. Conclusion. circ_0058063 expression increased in multiple myeloma tissues. Knocking down its expression may inhibit myeloma proliferation, migration, and invasion by targeting and upregulating miR-635 and also promote cell apoptosis. As for multiple myeloma treatment, circ_0058063/miR-635 may provide new molecular targets.

Interferon-induced with helicase C domain 1 (IFIH1) is a cytosolic sensor of dsRNA that induces an anti-viral Type I interferon (IFN) state. A gain-of-function mutation in IFIH1 can cause increased Type I IFN activity and is clinically associated with Aicardi-Goutieres syndrome (AGS). AGS is a multisystem disease, characterized as an early-onset progressive encephalopathy with basal ganglia calcification and systemic lupus erythematosus-like features. Gastrointestinal manifestation is rare in AGS patients. We described a 10-year-old female patient with a heterozygous IFIH1 gene mutation who presented with gastrointestinal colitis, cystitis and very severe diarrhea as initial major manifestations of AGS. Proteinuria with high titer of antinuclear antibody and anti-double-stranded DNA was found in this patient. She also had growth retardation and a history of seizures (about two episodes each year) but without attacks until 7 years old. Serum cytokines detected by flow cytometry indicated extremely high level of interleukin 6 (1970.1 pg/ml) and IFN-α (204.1 pg/ml). A contrast-enhanced CT scan of the whole abdomen and an intestinal hydro-MRI indicated that the walls of her stomach, small bowel, colon, and bladder were in various degrees of edema and thickened states. Whole exome sequencing analysis indicated that she harbors an IFIH1 heterozygous mutation (c.2336G > A (p.R779H)) in both blood and intestinal samples. Abundant inflammatory cells infiltration into the intestinal epithelium was observed by immunohistochemical staining. Positive staining of caspase 4 and caspase 5 suggested that the signaling pathway of pyroptosis was involved in the mechanism of intestinal inflammation in AGS. Diarrhea was significantly improved after steroids and intravenous immunoglobulin treatments. Gastrointestinal colitis and cystitis can be rare manifestations of AGS with IFIH1 mutation. Caspase and its related inflammasome pathway may involve in the pathogenesis of AGS.

BACKGROUND Acute-on-chronic liver failure (ACLF) patients have a high short-term mortality rate, and the severity evaluation of ACLF is necessary for prognostication. Therefore, it was meaningful to evaluate the association between type 2 diabetic mellitus (DM) and ACLF and further explore the feasibility of using DM as a prognostic indicator in ACLF patients. The association between type 2 DM and the prognosis of patients with severe liver disease remains unclear. AIM To examine the effect of type 2 DM on the prognosis of patients with ACLF. METHODS Clinical data from 222 ACLF patients were collected and analyzed. The patients were categorized into two groups depending on whether they had DM or not, and the clinical data of ACLF patients were measured within 48 h after admission. Complications of ACLF were documented during treatment, such as hepatic encephalopathy, hepatorenal syndrome, acute upper gastrointestinal hemorrhage, and spontaneous peritonitis (SBP). Values of laboratory parameters, complication rates, and hospital mortality rates were compared between two groups. RESULTS Among 222 ACLF patients, 38 cases were categorized into DM groups, the mean age was 56.32 years and 73.68% were male. The prognosis of ACLF patients was significantly correlated with DM in univariate [hazard ratio (HR) = 2.4, 95% confidence interval (CI) =1.5-3.7, P < 0.001] and multivariable analysis (HR = 3.17, 95%CI =1.82-5.523, P < 0.001). The incident of SBP (34.21% vs 13.59%, P = 0.038) and other infections like lung, urinary, blood, and cholecyst (44.74% vs 28.26%, P = 0.046) were higher in DM patients than non-DM counterparts. In addition, the ACLF patients with DM tended to have a high mortality rate (P < 0.001). Cumulative survival time was also significantly shorter in the ACLF patients with DM than non-DM. CONCLUSION A significant association between DM and the prognosis of ACLF patients was found in China. The ACLF patients with DM had higher incidence of hospital mortality and infection than those without DM.

DNA methylation is an important epigenetic change in carcinogenesis. However, the function and mechanism of DNA methylation dysregulation in nasopharyngeal carcinoma (NPC) is still largely unclear. Our previous genome-wide microarray data showed that NFAT1 is one of the most hypermethylated transcription factor genes in NPC tissues. Here, we found that NFAT1 hypermethylation contributes to its down-regulation in NPC. NFAT1 overexpression inhibited cell migration, invasion, and epithelial-mesenchymal transition in vitro and tumor metastasis in vivo. We further established that the tumor suppressor effect of NFAT1 is mediated by its inactivation of ITGA6 transcription. Our findings suggest the significance of activating NFAT1/ITGA6 signaling in aggressive NPC, defining a novel critical signaling mechanism that drives NPC invasion and metastasis and providing a novel target for future personalized therapy.

Angelicae Sinensis Radix (Danggui) and Ligusticum Chuanxiong Rhizoma (Chuan Xiong) herb-pair (DC) have been frequently used in Traditional Chinese medicine (TCM) prescriptions for hundreds of years to prevent vascular diseases and alleviate pain. However, the mechanism of DC herb-pair in the prevention of liver fibrosis development was still unclear. In the present study, the effects and mechanisms of DC herb-pair on liver fibrosis were examined using network pharmacology and mouse fibrotic model. Based on the network pharmacological analysis of 13 bioactive ingredients found in DC, a total of 46 targets and 71 pathways related to anti-fibrosis effects were obtained, which was associated with mitogen-activated protein kinase (MAPK) signal pathway, hepatic inflammation and fibrotic response. Furthermore, this hypothesis was verified using carbon tetrachloride (CCl4)-induced fibrosis model. Measurement of liver functional enzyme activities and histopathological examination showed that DC dramatically reduced bile acid levels, inflammatory cell infiltration and collagen deposition caused by CCl4. The increased expression of liver fibrosis markers, such as collagen 1, fibronectin, α-smooth muscle actin (α-SMA) and transforming growth factor-β (TGF-β), and inflammatory factors, such as chemokine (C-C motif) ligand 2 (MCP-1), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and IL-6 in fibrotic mice were significantly downregulated by DC herb-pair through regulation of extracellular signal-regulated kinase 1/2 (ERK1/2)-protein kinase B (AKT) signaling pathways. Collectively, these results suggest that DC prevents the development of liver fibrosis by inhibiting collagen deposition, decreasing inflammatory reactions and bile acid accumulation, which provides insights into the mechanisms of herb-pair in improving liver fibrosis.

Maternal vitamin supplementation has been demonstrated to reduce the risks of a number of neurodevelopmental diseases in children. Autism spectrum disorder (ASD) is a group of neurodevelopment defects with high prevalence but without satisfactory therapy. The present work detected the effects of pregnancy supplementation with folic acid (FA) at different doses on rat models of ASD induced by prenatal exposure to valproic acid (VPA), an anti-epileptic increasing the risk of ASD when administered during pregnancy. The results show that maternal FA supplementation at a high dose (4 mg kg-1) prevented the delay in growth and development, and the deficits in social communicative behaviors and repetitive behaviors, possibly by restoring the increased dendritic spine density and rectifying the over-expression of synaptic proteins associated with excitatory neurons and the lower expression with inhibitory ones. The results provided experimental evidence suggesting a possible role of maternal FA supplementation in preventing ASD.

Objective: Circulating cell-free Epstein-Barr virus (EBV) DNA has been shown to be a valuable biomarker for population screening and prognostic surveillance for nasopharyngeal carcinoma (NPC). Despite important insights into the biology of persistence, few studies have addressed the clinical significance of cell-based EBV-DNA loads in peripheral blood cells (PBCs). Methods: A prospective observational cohort study was conducted involving 1,063 newly diagnosed, locoregionally-advanced NPC patients at Sun Yat-sen University Cancer Center from 2005 to 2007. Cox regression analysis was conducted to identify the association of PBC EBV DNA loads to overall survival (OS) and other prognostic outcomes. Prognostic nomograms were developed based on PBC EBV DNA loads to predict survival outcomes for NPC patients. Results: After a median follow-up of 108 months, patients with higher PBC EBV-DNA loads had significantly worse OS [hazard ratio (HR) of medium, medium-high, and high vs. low were 1.50, 1.52, and 1.85 respectively; Ptrend < 0.001]. Similar results were found for progression-free survival and distant metastasis-free survival. The concordance index of the prognostic nomogram for predicting OS in the training set and validation set were 0.70 and 0.66, respectively. Our data showed that the PBC EBV DNA load was an independent and robust survival biomarker, which remained significant even after adjusting for plasma EBV DNA loads in a subset of 205 patients of the cohort (HR: 1.88; P = 0.025). Importantly, a combination of PBC EBV DNA load and plasma EBV DNA load improved the predicted OS. Conclusions: The EBV-DNA load in PBCs may be an independent prognosis marker for NPC patients.

Background Conditional survival (CS) provides dynamic prognostic estimates by considering the patients existing survival time. Since CS for endemic nasopharyngeal carcinoma (NPC) is lacking, we aimed to assess the CS of endemic NPC and establish a web‐based calculator to predict individualized, conditional site‐specific recurrence risk. Methods Using an NPC‐specific database with a big‐data intelligence platform, 10,058 endemic patients with non‐metastatic stage I–IVA NPC receiving intensity‐modulated radiotherapy with or without chemotherapy between April 2009 and December 2015 were investigated. Crude CS estimates of conditional overall survival (COS), conditional disease‐free survival (CDFS), conditional locoregional relapse‐free survival (CLRRFS), conditional distant metastasis‐free survival (CDMFS), and conditional NPC‐specific survival (CNPC‐SS) were calculated. Covariate‐adjusted CS estimates were generated using inverse probability weighting. A prediction model was established using competing risk models and was externally validated with an independent, non‐metastatic stage I–IVA NPC cohort undergoing intensity‐modulated radiotherapy with or without chemotherapy (n = 601) at another institution. Results The median follow‐up of the primary cohort was 67.2 months. The 5‐year COS, CDFS, CLRRFS, CDMFS, and CNPC‐SS increased from 86.2%, 78.1%, 89.8%, 87.3%, and 87.6% at diagnosis to 87.3%, 87.7%, 94.4%, 96.0%, and 90.1%, respectively, for an existing survival time of 3 years since diagnosis. Differences in CS estimates between prognostic factor subgroups of each endpoint were noticeable at diagnosis but diminished with time, whereas an ever‐increasing disparity in CS between different age subgroups was observed over time. Notably, the prognoses of patients that were poor at diagnosis improved greatly as patients survived longer. For individualized CS predictions, we developed a web‐based model to estimate the conditional risk of local (C‐index, 0.656), regional (0.667), bone (0.742), lung (0.681), and liver (0.711) recurrence, which significantly outperformed the current staging system (P < 0.001). The performance of this web‐based model was further validated using an external validation cohort (median follow‐up, 61.3 months), with C‐indices of 0.672, 0.736, 0.754, 0.663, and 0.721, respectively. Conclusions We characterized the CS of endemic NPC in the largest cohort to date. Moreover, we established a web‐based calculator to predict the CS of site‐specific recurrence, which may help to tailor individualized, risk‐based, time‐adapted follow‐up strategies.

Frontier evidence suggests that dysregulation of long noncoding RNAs (lncRNA) is ubiquitous in all human tumors, indicating that lncRNAs might have essential roles in tumorigenesis. Therefore, an in-depth study of the roles of lncRNA in nasopharyngeal carcinoma (NPC) carcinogenesis might be helpful to provide novel therapeutic targets. Here we report that lncRNA TINCR was significantly upregulated in NPC and was associated positively with poor survival. Silencing TINCR inhibited NPC progression and cisplatin resistance. Mechanistically, TINCR bound ACLY and protected it from ubiquitin degradation to maintain total cellular acetyl-CoA levels. Accumulation of cellular acetyl-CoA promoted de novo lipid biosynthesis and histone H3K27 acetylation, which ultimately regulated the peptidyl arginine deiminase 1 (PADI1)–MAPK–MMP2/9 pathway. In addition, insulin-like growth factor 2 mRNA-binding protein 3 interacted with TINCR and slowed its decay, which partially accounted for TINCR upregulation in NPC. These findings demonstrate that TINCR acts as a crucial driver of NPC progression and chemoresistance and highlights the newly identified TINCR–ACLY–PADI1–MAPK–MMP2/9 axis as a potential therapeutic target in NPC. Significance: TINCR-mediated regulation of a PADI1–MAPK–MMP2/9 signaling pathway plays a critical role in NPC progression and chemoresistance, marking TINCR as a viable therapeutic target in this disease.

Objective. We sought to evaluate the association between femoral neck (FN) and lumbar spine (LS) bone mineral densities (BMDs) with severity of chronic kidney disease (CKD) and prevalence of osteopenia or osteoporosis (OP) among the CKD group. Methods. Cross-sectional data from 11050 participants aged ≥20 years from the National Health and Nutrition Examination Survey (NHANES) were analyzed. Specifically, Pearson correlation was applied to analyze the relationship between BMD and estimated glomerular filtration rate (eGFR). General linear models (GLMs) were adjusted for potential confounders and used to analyze mean BMD, based on CKD and CKD stages. Results. FN BMD was positively correlated with the eGFR in the total and male CKD, but not in the female CKD population. LS BMD was not significantly associated with eGFR. After controlling for partial correlations, FN T-score was positively correlated with the eGFR in the total at-risk population. According to FN BMD, OP prevalence was positively associated with CKD stage. However, according to LS BMD, there was no significant association between OP and CKD stage. Conclusion. Our results may explain the higher prevalence of hip fracture, relative to that of the spine, among CKD patients and generate meaningful insights to guide care, prevention, and treatment regimens for CKD patients. However, the fact that this was a cross-sectional study may limit the possibility of drawing concrete conclusions. Nevertheless, these findings open up a new frontier for further studies to uncover the higher decrease of FN BMD compared to LS BMD among CKD cases.

Study design A longitudinal cohort study. Objective The objective of this study was to evaluate the prognostic factors and determine the difference between different surgery scopes. Nomograms were constructed and validated to predict overall survival (OS) and cancer-specific survival (CSS) of sacrum/pelvic chondrosarcoma (SC) patients. Summary of background data Chondrosarcoma is a bone malignancy which is reported to be resistant to both chemotherapy and radiotherapy. Therefore, surgery is the most preferred treatment method. However, this remains a great challenge due to the complex anatomy of the area. Materials and methods Data from the Surveillance, Epidemiology, and End Results (SEER) database of patients with conventional SC between 1998 and 2016 was retrieved for analysis. Cox analysis was used to estimate the mortality hazards ratios among patients. Propensity score matching was used to compare different surgery scope. Nomograms were constructed to predict the OS and CSS of patients with SC. Results A total of 377 patients were included in this study. The cutoff value for tumor size was considered to be 118 mm. The concordance indices (C-index) value for nomogram predictions of CSS were 0.871. Following propensity score matching, 158 patients were selected for the second time and its result showed no significant difference between the scope of surgery. Conclusions Tumor size was considered to be closely related to the outcome of SC. There is no significant difference in the scope of surgery and limb salvage can be considered. The nomograms can precisely predict OS and CSS in patients with SC. These could help clinicians to perform survival assessments and identify patients at high risk. Level of evidence Level IV.

Nasopharyngeal carcinoma (NPC), the most common head and neck cancer, is characterized by distinct geographic distribution and familial aggregation. Multiple risk factors, including host genetics, environmental factor and EBV infection, have been linked to the development of NPC, particularly in the familial clustering cases. However, the cause of NPC endemicity remains enigmatic due possibly to the complicated interplay between these risk factors. Recently, positive Epstein-Barr virus (EBV) DNA loads at nasopharyngeal (NP) cavity has been found to reflect NPC development and applied in NPC screening. To examine whether the increased NP EBV loads could aggregate in the families and be affected by host genetics and environmental factor, EBV loads were obtained by 510 NP brushing samples from eligible unaffected individuals, who have 2 or more relatives affected with NPC, in 116 high-risk NPC families. The correlation of relative pairs was estimated using S.A.G.E. (version 6.4, 2016), and host heritability of NP EBV loads was calculated with variance component models using SOLAR (version 8.4.2, 2019). In result, significant correlations of EBV loads were observed between parent-offspring pairs and sibling-sibling pairs (P

Background. The relationship of uric acid (UA) with the thyroid function among healthy individuals remains unclear. We aimed to examine the relationship between UA contents and thyroid hormone levels in healthy Chinese individuals. Methods. This was a cross-sectional study of 1186 Chinese adults (736 men and 450 women) who underwent a health check-up at the Huadong Hospital Affiliated to Fudan University (Shanghai, China) between January 1, 2010 and July 31, 2018. Clinical and thyroid hormone levels were compared in different UA groups (in male and menopause women groups, MG1: UA < 5 mg/dL; MG2: 5 mg/dL ≤ UA< 7 mg/dL; and MG3: UA ≥ 7 mg/dL; in female groups, FG1 to FG3 represent the UA levels of

Context Fish oil and omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have anti-inflammatory properties, but their effect on psoriasis and its comorbidities remains inconclusive. Objective The aim of this quantitative systematic review was to evaluate the efficacy and safety of fish oil and its components in the treatment of psoriasis and its comorbidities. Data Sources PubMed, Embase, Cochrane Central Register of Controlled Trials, China Network Knowledge Infrastructure, China Science and Technology Journal Database, and Wanfang databases were searched from inception to March 30, 2019. Study Selection Randomized controlled trials were eligible for inclusion if they measured the effect of fish oil and its components in the treatment of patients with psoriasis. Data Extraction Eighteen randomized controlled trials involving 927 study participants were included. Results Monotherapy with fish oil or ω-3 PUFAs had no effect on the Psoriasis Area and Severity Index (PASI) score (P = 0.47), lesion area (P = 0.34), or pruritus (P = 0.62). Fish oil or ω-3 PUFAs combined with conventional treatments, however, resulted in a decreased PASI score (mean difference [MD], −3.92; 95%CI, −6.15 to −1.69; P = 0.0006) and lesion area (MD, −30.00; 95%CI, −33.82 to −26.18; P Conclusions Overall, when combined with conventional treatments, fish oil and its components may have beneficial effects on psoriasis and its comorbidities, including obesity, cardiovascular disease, and metabolic disease. Systematic Review Registration PROSPERO registration number CRD42019128631.

Diabetes mellituse has been one of the major diseases in the world due to the high percentage of diabetics in the global population and the increasing growth rate of its onset. Identifying individual physiological characteristics, e.g., insulin sensitivity and glucose effectiveness and others, is extremely important in developing effective drugs and investigating genetic pathways causing the defects in these physiological responses. Intravenous glucose tolerance test (IVGTT) is such a protocol to determine an individual insulin sensitivity and glucose effectiveness indices. In this paper, we propose a stochastic delay differential equation model for the IVGTT protocol attempting to develop a method to increase the accuracy of parameter estimation. We first study the existence and uniqueness of the global positive solution and its asymptotic behavior of the stochastic path close to the steady state of the corresponding deterministic model. Then we develop a maximum likelihood estimation method to estimate the parameters involved in the proposed model. Our simulation studies numerically confirm our theoretical findings and demonstrate that the proposed model with estimated parameters can improve the fitness of clinical data.

Rationale: Multiple gastric cancer (MGC) is characterized by the presence of more than two different tumors in the stomach. However, the clonal relationship and carcinogenesis of MGC remain unclear. We investigated the clonal relationship and role of germline mutations in the carcinogenesis of MGC. Methods: We gathered 16 multiple gastric cancer patients. Thirty-three tumor samples and sixteen normal gastric tissue or blood samples were obtained from January 2016 to December 2017. We also conducted analyses for 208 gastric cancer and 49 esophagogastric junction cancer (GC-EGJ) tumors from TCGA. DNA extraction from our samples was conducted for whole-exome sequencing (WES). Results: Tumor mutation burden (TMB) was not statistically significant within database and our data in the GC-EGJ (P=0.0591) and GC groups (P=0.3113). The mutation spectrum and signatures also showed uniform distributions in GC and GC-EGJ groups within our data and TCGA database. Among sixteen patients, four were identified as monoclonal, in which 11, 10, 26 and 6 somatic mutations were shared within different tumors of P7, P8, P9 and P16, respectively. However, no common mutation between different tumors of the same patient was found among the other 12 patients. After identifying predisposing genes, we found that germline MSH2 and NCOR2 mutations were significantly dominant in 8/12 and 10/12 of genetic MGC patients. Additionally, all patients were identified with MSH2 mutations in cancer samples of those genetic MGC patients. Taking genetic MGCs as a whole, we identified that TP53 were significantly mutated in 14 of 25 tumor samples. Main conclusions: WES analyses are suggestive of monoclonal and polyclonal origin of MGC, which may promote the classification of MGC into genetic and metastatic MGC. For patients with genetic MGC, germline MSH2 X314_splice variants may contribute to carcinogenesis, thus prompting the consideration of more radical surgery and/or anti-PD-1/PD-L1 therapy.

Objective:Inhibitory control is a key deficit in patients with schizophrenia. This study aims to test whether emotions can facilitate inhibition in patients with schizophrenia when they increase attention to inhibitory process.Method:A total of 36 patients with schizophrenia and 36 healthy controls completed an emotional stop-signal task. The task involved selective responses to “Go” stimuli and stopped response when emotional or neutral stop cues occurred.Results:In all conditions, patients with schizophrenia took longer time to inhibit response compared with healthy controls, indicating an overall impairment in response inhibition. Importantly, patients with schizophrenia and controls acquired similar size of benefit from the negative stop cues, showing as reduced reaction time to negative than neutral stop cues. However, the negative stop cues impaired subsequent Go performance only in patients with schizophrenia, indicating additional cost of the negative stop cues for patients with schizophrenia. In both groups, the positive stop cues did not have any significant influence on response inhibition.Conclusions:These findings provide novel evidence for the benefit of emotional stop cues on inhibitory control in patients with schizophrenia and reveal different after-effects of emotional enhancement effect in patients and healthy populations. The findings may help develop effective interventions for improving inhibitory control in patients with schizophrenia and other clinical populations.

Inflammation and neuronal apoptosis contribute to the progression of secondary injury after spinal cord injury (SCI) and are targets for SCI therapy; autophagy is reported to suppress apoptosis in neuronal cells and M2 polarization may attenuate inflammatory response in microglia, while both are negatively regulated by mTORC1 signalling. We hypothesize that mTORC1 suppression may have dual effects on inflammation and neuronal apoptosis and may be a feasible approach for SCI therapy. In this study, we evaluate a novel inhibitor of mTORC1 signalling, Astragaloside IV (AS‐IV), in vitro and in vivo. Our results showed that AS‐IV may suppress mTORC1 signalling both in neuronal cells and microglial cells in vitro and in vivo. AS‐IV treatment may stimulate autophagy in neuronal cells and protect them against apoptosis through autophagy regulation; it may also promote M2 polarization in microglial cells and attenuate neuroinflammation. In vivo, rats were intraperitoneally injected with AS‐IV (10 mg/kg/d) after SCI, behavioural and histological evaluations showed that AS‐IV may promote functional recovery in rats after SCI. We propose that mTORC1 suppression may attenuate both microglial inflammatory response and neuronal apoptosis and promote functional recovery after SCI, while AS‐IV may become a novel therapeutic medicine for SCI.

Whether primary tumor resection is beneficial in patients with metastatic nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) remains unclear. This study aimed to investigate whether palliative resection of primary tumor affected the survival of patients with stage IV NF-pNETs.We collected data from patients with stage IV NF-pNET registered in the Surveillance, Epidemiology, and End Results database from 2004 to 2015. Risk-adjusted Cox proportional hazard regression analysis and propensity score-matched analysis were used to analyze overall survival (OS) and cancer-specific survival (CSS) of patients.In total, 1974 stage IV NF-pNETs patients were identified, of whom 392 (19.9%) received palliative primary tumor resection. The latter exhibited significantly prolonged OS (hazard ratio = 2.514, 95% confidence interval: 2.081-3.037, P 0.001) and CSS (hazard ratio = 2.634, 95% confidence interval: 2.159-3.213, P 0.001) in multivariate Cox regression analysis. According to propensity score-matched results, patients without primary tumor resection had worse OS and CSS.This study demonstrates that there is a significant correlation between palliative resection of primary tumor and survival benefit. Therefore, resection could be considered as an additional treatment option in this specific patient population.

Objective To evaluate the efficacy and safety of low dose baricitinib in children with refractory or severe juvenile dermatomyositis(JDM) in a real-world setting. Methods A monocentric retrospective real-world study was conducted, in which fourteen refractory and one severe newly diagnosed JDM patients were included. These patients were all treated by low dose baricitinib (below the recommended dose) combined with corticosteroids and or immunosuppressive agents. Clinical data were collected at the baseline and 4, 12, 24 weeks after baricitinib implication. Treatment response (complete response, CR, Partial response, PR and non-response,NR) was evaluated using both the Paediatric Rheumatology International Trials Organization (PRINTO) remission criteria and skin Disease Activity Score (DAS). All the adverse events (AEs) were recorded. Results After baricitinib treatment, all 15 patients showed improvement of skin involvement, including 14 patients with recurrent skin rashes and one newly diagnosed JDM. Calcinosis stabilized in two patients (2/3) and partially regressed in one. Four patients (4/15) had interstitial lung disease (ILD), which normalized in one, improved in two and stabilized in one. One patient complicated with macrophage activation syndrome (MAS) achieved clinical remission. CR was achieved in 3/15 patients, ranging from 4 to 12 weeks after baricitinib initiation. Five patients (5/15) got PR 4 to 24 weeks after baricitinib use. Daily steroid dosage was decreased from 0.632 mg/kg to 0.357 mg/kg (P = 0.043) at 24 weeks in all responders. However, there was no statistically difference in muscle improvement. One patient was stopped using baricitinib because of varicella zoster virus infection, while no other serious side effect was observed in this study. Conclusion Low dose baricitinib had efficacy and was safe to applied in refractory or severe JDM patients, especially for recurrent skin rashes. Baricitinib may also be helpful for JDM complicated with ILD and MAS.

Chronic inflammation in response to persistent exogenous stimuli or damage results in liver fibrosis, which subsequently progresses into malignant liver diseases with high morbidity and mortality. Ferulic acid (FA) is a phenolic acid widely isolated from abundant plants and exhibits multiple biological activities including anti-oxidant, anti-inflammation and enhancement of immune responses. Adenosine monophosphate-activated protein kinase (AMPK) functions as a critical energy sensor and is regulated through the phosphorylation of liver kinases like LKB1 or dephosphorylation by protein tyrosine phosphatases (PTPs). However, the role of FA in carbon tetrachloride (CCl4)-induced chronic inflammation and liver fibrosis and AMPK activation has not been elucidated. Here we reported that FA ameliorated CCl4-induced inflammation and fibrotic liver damage in mice as indicated by reduced levels of serum liver function enzyme activities and decreased expression of genes and proteins associated with fibrogenesis. Additionally, FA inhibited hepatic oxidative stress, macrophage activation and HSC activation via AMPK phosphorylation in different liver cells. Mechanically, without the participation of LKB1, FA-induced anti-inflammatory and anti-fibrotic effects were abrogated by a specific AMPK inhibitor, compound C. Combining with the results of molecular docking, surface plasmon resonance and co-immunoprecipitation assays, we further demonstrated that FA directly bound to and inhibited PTP1B, an enzyme responsible for dephosphorylating key protein kinases, and eventually leading to the phosphorylation of AMPK. In summary, our results indicated that FA alleviated oxidative stress, hepatic inflammation and fibrotic response in livers through PTP1B-AMPK signaling pathways. Taken together, we provide novel insights into the potential of FA as a natural product-derived therapeutic agent for the treatment of fibrotic liver injury.

To determine the cutaneous effects of in utero and lactational exposure to the AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), pregnant C57BL/6J mice were exposed by gavage to a vehicle or 5 μg TCDD/kg body weight at embryonic day 12 and epidermal barrier formation and function were studied in their offspring from postnatal day 1 (P1) through adulthood. TCDD-exposed pups were born with acanthosis. This effect was AHR-dependent and subsided by P6 with no evidence of subsequent inflammatory dermatitis. The challenge of adult mice with MC903 showed similar inflammatory responses in control and treated animals, indicating no long-term immunosuppression to this chemical. Chloracne-like sebaceous gland hypoplasia and cyst formation were observed in TCDD-exposed P21 mice, with concomitant microbiome dysbiosis. These effects were reversed by P35. CYP1A1 and CYP1B1 expression in the skin was increased in the exposed mice until P21, then declined. Both CYP proteins co-localized with LRIG1-expressing progenitor cells at the infundibulum. CYP1B1 protein also co-localized with a second stem cell niche in the isthmus. These results indicate that this exposure to TCDD causes a chloracne-like effect without inflammation. Transient activation of the AhR, due to the shorter half-life of TCDD in mice, likely contributes to the reversibility of these effects.

Postpartum depression (PPD) is a mental disorder that affects pregnant women around the world, with serious consequences for mothers, families, and children. Its pathogenesis remains unclear, and medications for treating PPD that can be used during lactation remain to be identified. 919 syrup (919 TJ) is a Chinese herbal medicine that has been shown to be beneficial in the treatment of postpartum depression in both clinical and experimental studies. The mechanism of action of 919 TJ is unclear. 919 syrup is ingested orally, making the potential interaction between the drug and the gut microbiome impossible to ignore. We therefore hypothesized that 919 syrup could improve the symptoms of postpartum depression by affecting the structure and function of the intestinal flora, thereby altering hippocampal metabolism. We compared changes in hippocampal metabolism, fecal metabolism, and intestinal microflora of control BALB/c mice, mice with induced untreated PPD, and mice with induced PPD treated with 919 TJ, and found that 4-aminobutyric acid (GABA) in the hippocampus corresponded with PPD behaviors. Based on changes in GABA levels, multiple key gut bacterial species (Mucispirillum schaedleri, Bifidobacterium pseudolongum, Desulfovibrio piger, Alloprevotella tannerae, Bacteroides sp.2.1.33B and Prevotella sp. CAG:755) were associated with PPD. Metabolic markers that may represent the function of the intestinal microbiota in mice with PPD were identified (Met-Arg, urocanic acid, thioetheramide-PC, L-pipecolic acid, and linoleoyl ethanolamide). The relationship between these factors is not a simple one-to-one correspondence, but more likely a network of staggered functions. We therefore believe that the composition and function of the entire intestinal flora should be emphasized in research studying the gut and PPD, rather than changes in the abundance of individual bacterial species. The introduction of this concept of “GutBalance” may help clarify the relationship between gut bacteria and systemic disease.

Background The purpose of this study was to explore the efficacy and safety of high intensity focused ultrasound (HIFU) in gastric cancer with liver metastasis (GCLM) patients who were contraindicated for either hepatectomy or radiofrequency ablation (RFA). Methods This is a prospective, observational study on GCLM patients with 1–3 liver metastases. The primary gastric lesions were thoroughly resected and any case that exhibited extra-hepatic metastasis was excluded. A 1:2:2 propensity score-matching analysis was performed using a logistic regression model on the HIFU group, best supportive care (BSC) group, and palliative chemotherapy (PC) group. The primary endpoints include progression-free survival (PFS) and overall survival (OS). Results Forty patients were finally included, there were 8 cases in HIFU group, 16 cases in BSC group, and 16 cases in PC group. The median follow-up time for the entire cohort was 10 months. The median PFS was 16.5 months in HIFU group, 2 months in BSC group, and 5 months in PC group. The median OS was 27.5 months in the HIFU group, 7 months in the BSC group, and 11.5 months in the PC group. Additionally, no grade 3 or higher adverse events occurred in the HIFU group. Conclusion The results of this study showed that HIFU treatment could improve the long-term prognosis of GCLM patients without a significant increase in the occurrence of adverse events. Compared with PC and BSC, HIFU is the preferred treatment option when GCLM patients without extra-hepatic metastasis are unable to undergo either surgery or RFA.

Hypocalcemia is a common complication after total thyroidectomy; however, hypomagnesemia is also frequently detected, and its role is often disregarded. We report a 72-year-old woman who underwent total thyroidectomy with neck dissection and subsequently developed atrial fibrillation due to hypocalcemia and hypomagnesemia. The pathophysiology of hypomagnesemia after total thyroidectomy and its significance in calcium homeostasis is described.

Ethnopharmacological relevance ‘Ershiwuwei Shanhu’ Pill (ESP) is a classic Tibetan medicine to treat neurological disorders in nervous system, especially for neurological pains and epilepsy. It contains many Tibet-specific mineral medicines, among which Halloysite (Halloysitum rubrum, HR) was regarded as the main active one. As mineral medicines contain heavy metals with poor solubility, the doubts about its safety restricted its clinical application and further development. Aim of the study A 7-day acute toxicity of ESP and its main active mineral medicine HR was systematically studied for investigating the safety of ESP and exploring the role of HR in ESP's potential toxicity. Materials and methods In this study, the acute oral toxicity assessment of formula-ESP and HR were performed on rats for 7 days at doses equivalent to 10 (1 g/kg) and 40 times (4 g/kg) the typical clinical dose (0.1 g/kg). 1H NMR based metabolomics profiling, aided with biochemical analysis and histopathology, was conducted to explore the global metabolic changes in the livers and kidneys of the administrated rats. Results High-dose HR caused oxidative stress, energy metabolism disorders, purine metabolism impairments and amino acid metabolism imbalance in rats, resulting in hepatotoxicity and nephrotoxicity, which in accordance with the increased biochemical index in blood (ALT, AST, BUN and CRE). ESP (low-dose) induced metabolites changes were far more less than HR in livers, showcasing the distinct advantage of formula in reducing toxicity. Furthermore, low-dose ESP disturbed renal metabolism in a way similar to high-dose HR, which implies that HR might be the major source of the potential nephrotoxicity of ESP. Conclusion HR exhibited potential hepatoxicity and nephrotoxicity, but the formula- ‘Ershiwuwei Shanhu’ Pill which contains HR is considered relatively safe.

Sulforaphane (SFN) can effectively induce nuclear factor E2–related factor 2 (Nrf2), and zinc (Zn) can effectively induce metallothionein (MT), both of which have been shown to protect against diabetic cardiomyopathy (DCM). However, it is unclear whether combined treatment with SFN and Zn offers better cardiac protection than either one alone. Here, we treated 5‐week‐old OVE mice that spontaneously develop type 1 diabetes with SFN and/or Zn for 18 weeks. Cardiac dysfunction, by echocardiography, and pathological alterations and remodelling, shown by cardiac hypertrophy, fibrosis, inflammation and oxidative damage, examined by histopathology, Western blotting and real‐time PCR, were observed in OVE mice. All these dysfunction and pathological abnormalities seen in OVE mice were attenuated in OVE mice with treatment of either SFN, Zn or SFN/Zn, and the combined treatment with SFN/Zn was better than single treatments at ameliorating DCM. In addition, combined SFN and Zn treatment increased Nrf2 function and MT expression in the heart of OVE mice to a greater extent than SFN or Zn alone. This indicates that the dual activation of Nrf2 and MT by combined treatment with SFN and Zn may be more effective than monotherapy at preventing the development of DCM via complementary, additive mechanisms.

Epstein‐Barr virus (EBV) reactivation, reflected by aberrantly increased levels of various serological antibodies, has been suggested to be an early indicator of nasopharyngeal carcinoma (NPC) onset and progression. We have previously suggested that certain lifestyle and dietary factors were associated with elevated serological levels of the antibody against various EBV antigens namely VCA, Zta, EBNA1, and oral EBV DNA loads among healthy population. It remains unclear whether these potential environmental factors would also influence EBV serological antibodies in NPC patients. We conducted an epidemiological study to evaluate the associations between such environmental factors and EBV antibody levels among 1701 NPC patients in South China. Pretreatment serums were collected and examined for VCA‐IgA and EA‐IgA by immunoenzymatic assays and antienzyme rate (AER) of EBV DNase‐specific neutralizing antibody. We found that consumption of Canton‐style herbal tea was significantly correlated with increased serological antibody levels of VCA‐IgA and EA‐IgA, with adjusted ORs of 1.35 (95% CI: 1.03‐1.76) and 1.32 (95% CI: 1.01‐1.73), respectively, in the weekly intake frequency stratum, while not related to AER of EBV DNase‐specific neutralizing antibody. Smoking was found to be not only an apparent risk factor for higher antibody levels of AER in stage III‐IV patients (OR = 1.60, 95% CI: 1.11‐2.30), but also associated closely with NPC stage at diagnosis (OR = 2.17, 95% CI: 1.47‐3.22), with dose‐response effects. In conclusion, we found consumption of Canton‐style herbal tea and cigarette smoking were in positive associations with elevated EBV antibodies in NPC patients, which may be of public health significance for the primary prevention of EBV‐associated diseases especially NPC.

Gastric cancer is the fourth most common cancer worldwide and the third most common in Asia, with a high mortality. Photodynamic therapy (PDT) is a new treatment for cancer. With advantages of minimum invasiveness, small adverse side effects and high selectivity, PDT can be used as palliative treatment for patients with advanced gastric cancer. YLG I, also known as 2-(1 hexyloxyethyl)-2-devinyl porphin e6 trisodium salt (HCE6), is a recently developed photosensitizer. A previous study showed that HCE6 significantly inhibited the growth of QBC939 human cholangiocarcinoma cells. However, the effects and mechanisms of HCE6 on gastric cancer cell suppression are not known. In this study, we investigated the effects of HCE6 on the human gastric cancer cell line MKN45 and found that at the concentration of 2.0 mg/L, HCE6 almost completely killed MKN45 cells at a light intensity of 3.6 J/cm². RNAseq results confirmed that mitochondria and endoplasmic reticulum (ER)-mediated apoptosis was involved in the effects of HCE6 on cell death, and we also found that HCE6 induced chromosome conformational changes in the early phase of apoptosis. The results of our study help elucidate the molecular mechanisms underlying HCE6-mediated inhibition of gastric cancer cell growth and provide a theoretical basis and molecular targets for the treatment of gastric cancer.

Context: Surgical intervention is imperative when spinal tuberculosis (TB) is accompanied by severe spinal damage or kyphotic deformity. As one-stage anterior-only or posterior-only surgery for thoracic and lumbar spinal TB has many disadvantages, combined anterior-posterior surgery was proposed to be a more effective strategy. Objective: To examine the clinical outcomes of one-stage combined anterior-posterior surgery for patients with spinal TB. Design: Retrospective investigation design. Setting: All patients were enrolled at the Hangzhou Red Cross Hospital between August 2002 and October 2014. Participants: Sixty-seven patients with thoracic and lumbar spinal TB were studied. Interventions: All patients were treated with one-stage surgery using a combined anterior-posterior approach. Outcome measures: The patients were evaluated preoperatively and postoperatively by measuring their neurological function using the visual analogue scale (VAS) and the Frankel grades, and spinal deformity using the Cobb angle and radiological examinations. All patients were followed up for at least 11 months and up to 96 months. Results: There was a significant postoperative improvement in neurological outcomes, according to VAS scores and Frankel grades. Kyphotic angles were corrected significantly and were maintained during the final follow-up. Bone fusion was achieved within 4–7 months. Conclusion: One-stage surgical treatment via a combined anterior-posterior approach is an effective and feasible method for treating spinal TB.

Background As an acute febrile and inflammatory disease, Kawasaki disease (KD) could develop Kawasaki disease shock syndrome (KDSS) sometimes. However its pathogenesis was still not well known. This study was to learn more about the clinical features and evaluate the role of cytokines in the pathogenesis of KDSS. Methods We collected clinical and laboratory data retrospectively for all patients with KDSS(KDSS, n = 27)who were hospitalized at our hospital from Jan 2014 to Oct 2017. For patient with KDSS, we randomly identified 43 patients with KD as control subjects (KD, n = 43). Clinical features, laboratory evaluations were collected. Cytokines IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ in serum were assayed using flow cytometric bead array. Results The patients with KDSS were older age (43.41 ± 31.42 vs 28.81 ± 21.51 months, P

Background: Tropomyosin-1 (TPM1) has long been known to be an actin-binding cytoskeletal protein. Multiple recent studies have revealed that TPM1 is down-regulated in various malignant tumors, including renal cell carcinoma (RCC). Methods: To further verify its role in RCC, transfection of a reconstructed plasmid was used to bi-directionally regulate TPM1 levels. A colony formation assay, tube formation assay and invasion assay were adopted to assess cell proliferation, angiogenesis and metastasis, respectively, in the 786-O and ACHN cell lines. The xenograft tumor sizes were measured, and the microvessel density (MVD) was quantified. Western blot and immunohistochemistry (IHC) were used to detect key proteins involved in these processes. Results: The colony formation assay and xenograft tumor models illustrated that TPM1 up-regulation inhibited RCC cell proliferation. The tube formation assay and detection of vascular endothelial growth factor (VEGF) and cluster of differentiation 34 (CD34) in xenografts revealed that TPM1 up-regulation inhibited angiogenesis in RCC. The invasion assay and detection of the E-cadherin and matrix metalloproteinases 9 (MMP-9) levels in xenografts demonstrated that TPM1 up-regulation inhibited tumor metastasis in RCC. Opposing effects were absent in TPM1 down-regulation models. Conclusions: TPM1 functions as a tumor suppressor with respect to cell proliferation, angiogenesis and metastasis in RCC, suggesting that it is a potential therapeutic target for advanced RCC.

Lacking quantitative evaluations of competing risk data of nasopharyngeal carcinoma (NPC), we aimed to evaluate the probability of NPC- and other cause-specific mortality (NPC-SM; OCSM) and develop competing risk nomograms to quantify survival differences.Using the institutional big-data intelligence platform, 7251 NPC patients undergoing intensity-modulated radiotherapy between 2009-2014 were identified to establish nomograms based on Fine and Gray's competing risk analysis.The 5-year NPC-SM and OCSM of the cohort were 13.1% and 1.2%, respectively, and elevated 5-year OCSMs were observed in patients aged ≥65 years (5.5%) or with severe comorbidities (4.3%). Age was most predictive of OCSM: patients aged 55-64 and ≥65 years exhibited subdistribution hazard ratios (SHRs) of 2.70 (95% confidence interval [CI], 1.64-4.4; P .001) and 5.78 (95% CI, 3.32-10.08; P .001), respectively. Comorbidity measured using the Charlson Comorbidity Index (CCI) was also strongly predictive of OCSM: patients with CCI scores of 1 and ≥2 exhibited SHRs of 2.33 (95% CI, 1.46-3.71; P .001) and 2.58 (95% CI, 1.16-5.73; P = .020), respectively. All validated factors were integrated into the competing nomograms: age, sex, histology type, tumor and node stages, plasma Epstein-Barr virus-DNA level, lactate dehydrogenase level, and C-reactive protein (CRP) level into the NPC-SM model (concordance [c]-index = 0.743); and age, CCI, Albumin level, and CRP level into the OCSM model (c-index = 0.793).OCSM represents a significant competing event for NPC-SM in elderly patients and patients with comorbidities. We present the first prognostic nomograms to quantify competing risks, which may help to tailor individualized treatment.

Background: The purpose of this study was to explore the efficacy and safety of high intensity focused ultrasound (HIFU) in gastric cancer with liver metastasis (GCLM) patients who were contraindicated for either hepatectomy or radiofrequency ablation (RFA).Methods: This is a prospective, observational study on GCLM patients with 1-3 liver metastases. The primary gastric lesions were thoroughly resected and any case that exhibited extra-hepatic metastasis was excluded. A 1:2:2 propensity score-matching analysis was performed using a logistic regression model on the HIFU group, best supportive care (BSC) group, and palliative chemotherapy (PC) group. The primary endpoints include progression-free survival (PFS) and overall survival (OS). Results: Forty patients were finally included, there were 8 cases in HIFU group, 16 cases in BSC group, and 16 cases in PC group. The median follow-up time for the entire cohort was 10 months. The median PFS was 16.5 months in HIFU group, 2 months in BSC group, and 5 months in PC group. The median OS was 27.5 months in the HIFU group, 7 months in the BSC group, and 11.5 months in the PC group. Additionally, no grade 3 or higher adverse events occurred in the HIFU group.Conclusion: The results of this study showed that HIFU treatment could improve the long-term prognosis of GCLM patients without a significant increase in the occurrence of adverse events. Compared with PC and BSC, HIFU is the preferred treatment option when GCLM patients without extra-hepatic metastasis are unable to undergo either surgery or RFA.

Schizotypy, a subclinical group at risk for schizophrenia, has been found to show impairments in response inhibition. However, it remains unclear whether this impairment is accompanied by outright stopping (reactive inhibition) or preparation for stopping (proactive inhibition). We recruited 20 schizotypy and 24 non-schizotypy individuals to perform a modified stop-signal task with electroencephalographic (EEG) data recorded. This task consists of three conditions based on the probability of stop signal: 0% (no stop trials, only go trials), 17% (17% stop trials), and 33% (33% stop trials), the conditions were indicated by the colour of go stimuli. For proactive inhibition (go trials), individuals with schizotypy exhibited significantly lesser increase in go response time (RT) as the stop signal probability increasing compared to non-schizotypy individuals. Individuals with schizotypy also exhibited significantly increased N1 amplitude on all levels of stop signal probability and increased P3 amplitude in the 17% stop condition compared with non-schizotypy individuals. For reactive inhibition (stop trials), individuals with schizotypy exhibited significantly longer stop signal reaction time (SSRT) in both 17% and 33% stop conditions and smaller N2 amplitude on stop trials in the 17% stop condition than non-schizotypy individuals. These findings suggest that individuals with schizotypy were impaired in both proactive and reactive response inhibition at behavioural and neural levels.

Background Nasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV) associated cancer, exhibits an extremely high incidence in southern Chinese. Given that human leukocyte antigen (HLA) plays critical roles in antigen presentation and relates to NPC susceptibility, it is speculated that certain HLA variants may affect EBV reactivation, which is a key pathogenic factor of NPC. Therefore, we attempted to identify HLA alleles associated with the indicator of EBV reactivation, Zta‐IgA, in healthy males from NPC endemic area. Methods HLA alleles of 1078 healthy males in southern China from the 21‐RCCP study were imputed using genome‐wide single nucleotide polymorphism data. EBV Zta‐IgA in blood samples were measured using an enzyme‐linked immunosorbent assay. Multiple logistic regression analysis was used to evaluate the effect of HLA allele on Zta‐IgA serological status and its potential joint association with smoking. The binding affinity for Zta‐peptide was predicted using NetMHCIIpan 4.0. Results HLA‐DRB1*09:01 was found to be associated with a higher risk of Zta‐IgA seropositivity (odds ratio = 1.80, 95% confidence interval = 1.32–2.45; p = 1.82 × 10−4). Compared with non‐smokers without HLA‐DRB1*09:01, the effect size increased to 2.19‐ and 3.70‐fold for the light and heavy smokers carrying HLA‐DRB1*09:01, respectively. Furthermore, HLA‐DRB1*09:01 showed a stronger binding affinity to Zta peptide than other HLA‐DRB1 alleles. Conclusions Our study highlighted the pivotal role of genetic HLA variants in EBV reactivation and the etiology of NPC. Smokers with HLA‐DRB1*09:01 have a significantly higher risk of being Zta‐IgA seropositive, which indicates the necessity of smoking cessation in certain high‐risk populations and also provide clues for further research on the etiology of NPC., We conducted an association study for human leukocyte antigen (HLA) alleles and Epstein–Barr virus Zta‐IgA serological status in healthy males from a nasopharyngeal carcinoma endemic area. We found that HLA‐DRB1*09:01 was associated with a high risk of Zta‐IgA seropositivity and the effect increased when combined with smoking. In silico prediction indicated that HLA‐DRB1*09:01 had a distinctive binding motif pattern and a stronger binding affinity to Zta peptide in comparison with other HLA‐DRB1 alleles.

Summary Cardiac hypertrophy is an adaptive response to all forms of heart disease, including hypertension, myocardial infarction, and cardiomyopathy. Cyclooxygenase-2 (COX-2) overexpression results in inflammatory response, cardiac cell apoptosis, and hypertrophy in adult heart after injury. However, immune response-mediated cardiac hypertrophy and fibrosis have not been well documented in injured neonatal heart. This study showed that cardiac hypertrophy and fibrosis are significantly attenuated in celecoxib (a selective COX-2 inhibitor)-treated P8 ICR mice after cryoinjury. Molecular and cellular profiling of immune response shows that celecoxib inhibits the production of cytokines and the expression of adhesion molecular genes, increases the recruitment of M1-like macrophage at wound site, and alleviates cardiac hypertrophy and fibrosis. Furthermore, celecoxib administration improves cardiac function at 4 weeks after injury. These results demonstrate that COX-2 inhibition promotes the recruitment of M1-like macrophages during early wound healing, which may contribute to the suppression of cardiac hypertrophy and fibrosis after injury., Graphical abstract, Highlights • Cryoinjury successfully induces cardiac hypertrophy and fibrosis in P8 ICR mice • COX-2 inhibition alleviates cardiac hypertrophy and fibrosis after cryoinjury • MCP-1 significantly increases in COX-2 inhibition • COX-2 inhibition improves cardiac repair in P8 ICR mice by recruiting M1-like macrophages, Animal Physiology; Molecular Physiology; Molecular Biology

Background We aimed at determining the influence of old age on lymph node metastasis (LNM) and prognosis in T1 colorectal cancer (CRC). Methods We collected data from eligible patients in Surveillance, Epidemiology, and End Results database between 2004 and 2015. Independent predictors of LNM were identified by logistic regression analysis. Cox regression analysis, propensity score-matched analysis, and competing risks analysis were used to analyze the associations between old age and lymph node (LN) status and to validate the prognostic value of old age on cancer-specific survival (CSS). Results In total, 10,092 patients were identified. Among them, 6,423 patients (63.6%) had greater than or equal to 12 examined lymph nodes (LNE ≥12), and 5,777 patients (57.7%) were 65 years or older. The observed rate of LNM was 4.6% (15 out of 325) in T1 CRC elderly patients, with tumor size

Background As the prevalence of hepatitis steatosis (HS) increases, the prevalence of HS among those with chronic hepatitis B (CHB) may also be increasing but data on the effect of HS on CHB disease progression are lacking. Aims To determine the prevalence of HS in CHB and associated factors, prevalence of fibrosis and its association with HS. Methods Two researchers independently searched the literature and extracted data. We included full-length original articles of adults with CHB that evaluated. Prevalence estimates were pooled using a random-effects model. Associations between HS and fibrosis were assessed by pooled odds ratios (ORs) or mean differences (MD). Results Of the 2821 records screened, 54 eligible studies (28 648 patients) were analysed. The pooled prevalence of HS in CHB was 32.8% (95% CI, 28.9-37.0) with higher prevalence in men and obese patients. Older age, male sex and metabolic factors were associated with HS while an inverse association was observed between HS and HBeAg (OR 0.82, 95% CI, 0.75-0.91) and HBV DNA levels (MD -0.38, 95% CI -1.16--0.42). The pooled prevalence of significant fibrosis (≥F2 or ≥F3) was similar between patients with CHB with or without HS (40.1% vs 42.22%, P = 0.68). HS was not significantly associated with fibrosis (pooled OR 0.87, 95% CI 0.54-1.39, 20 studies, 6232 patients). Conclusions Approximately 30% of patients with CHB had HS, which was positively associated with male sex, diabetes and metabolic factors, and was negatively associated with HBeAg and HBV DNA. HS was not significantly associated with increased fibrosis.

Cyst nematodes are able to infect a wide range of crop species and are regarded as a major threat in crop production. In response to invasion of cyst nematodes, plants activate their innate immune system to defend themselves by conferring basal and host-specific defense responses depending on the plant genotype. Basal defense is dependent on the detection of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), while host-specific defense mainly relies on the activation of canonical and non-canonical resistance (R) genes or quantitative trait loci (QTL). Currently, application of R genes and QTLs in crop species is a major approach to control cyst nematode in crop cultivation. However, emerging virulent cyst nematode field populations are threatening crop production due to host genetic selection by the application of a limited set of resistance genes in current crop cultivars. To counteract this problem, increased knowledge about the mechanisms involved in host-specific resistance mediated by R genes and QTLs to cyst nematodes is indispensable to improve their efficient and sustainable use in field crops. Despite the identification of an increasing number of resistance traits to cyst nematodes in various crops, the underlying genes and defense mechanisms are often unknown. In the last decade, indebt studies on the functioning of a number of cyst nematode R genes and QTLs have revealed novel insights in how plants respond to cyst nematode infection by the activation of host-specific defense responses. This review presents current knowledge of molecular and cellular mechanisms involved in the recognition of cyst nematodes, the activation of defense signaling and resistance response types mediated by R genes or QTLs. Finally, future directions for research are proposed to develop management strategies to better control cyst nematodes in crop cultivation.

The present study is aimed at investigating the association of NFE2L2 gene polymorphisms with risk and clinical characteristics of acute type A aortic dissection (AAAD) in a Han Chinese population. Six SNPs (rs1806649, rs13001694, rs2364723, rs35652124, rs6721961, and rs2706110) in NFE2L2 were genotyped using SNaPshot Multiplex Kit in 94 adult patients diagnosed with AAAD at our hospital, and 208 healthy Han Chinese subjects from the 1000 Genomes Project were served as the control group. The CC genotype of rs2364723 (CC versus (GC+GG), OR = 2.069 , 95% CI: 1.222-3.502, p = 0.006 ) and CC genotype of rs35652124 (CC versus (CT+TT), OR = 1.889 , 95% CI: 1.112-3.210, p = 0.018 ) were identified as risk factors for AAAD. Multivariable linear regression analysis revealed that the CC genotype of rs2364723 ( β = 5.031 , 95% CI: 1.878-8.183, p = 0.002 ) and CC genotype of rs35652124 ( β = 4.751 , 95% CI: 1.544-7.958, p = 0.004 ) were associated with increased maximum ascending aorta diameter of AAAD. Patients carrying rs2364723 CC genotype had a higher incidence of coronary artery involvement (31% vs. 12%, p = 0.027 ), while patients carrying rs35652124 CC genotype had a higher incidence of brain ischemia (9% vs. 0%, p = 0.045 ). In conclusion, NFE2L2 gene polymorphisms were correlated with risk and severity of AAAD in Han Chinese population.

Spinal cord injury (SCI) is a major cause of physical disability and leads to patient dissatisfaction with their quality of life. Patients with SCI usually exhibit severe clinical symptoms, including sensory and motor dysfunction below the injured levels, paraplegia, quadriplegia and urinary retention, which can exacerbate the substantial medical and social burdens. The major pathological change observed in SCI is inflammatory reaction, which induces demyelination, axonal degeneration, and the apoptosis and necrosis of neurons. Traditional medical treatments are mainly focused on the recovery of motor function and prevention of complications. To date, numerous studies have been conducted to explore the cellular and molecular mechanism of SCI and have proposed lots of effective treatments, but the clinical applications are still limited due to the complex pathogenesis and poor prognosis after SCI. Endocrine hormones are kinds of molecules that are synthesized by specialized endocrine organs and can participate in the regulation of multiple physiological activities, and their protective effects on several disorders have been widely discussed. In addition, many studies have identified that endocrine hormones can promote nerve regeneration and functional recovery in individuals with central nervous system diseases. Therefore, studies investigating the clinical applications of endocrine hormones as treatments for SCI are necessary. In this review, we described the neuroprotective roles of several endocrine hormones in SCI; endocrine hormone administration reduces cell death and promotes functional repair after SCI. We also proposed novel therapies for SCI.

Our study aims to investigate the impact of miR-224 on cell migration and invasion in colorectal cancer (CRC) as well as its molecular mechanisms. The results showed that miR-224 was significantly upregulated in CRC compared to normal tissues via the TCGA database. Overexpression of miR-224 promoted CRC cell migration and invasion, while inhibition of miR-224 demonstrated the opposite result via transwell assays. In addition, we found that BTRC was a target gene of miR-224 through the miRecords database and dual-luciferase assay, while western blot together with RT-qPCR showed that inhibition of miR-224 led to elevated BTRC expression in protein level but not in mRNA level, and also decreased the expression of β-catenin. In reference to the Human Protein Atlas, BTRC protein expression was higher in normal tissues than in CRC tissues. In conclusion, miR-224 regulates its target BTRC protein expression and its related Wnt/β-catenin pathway. Its impact on cell migration and invasion in CRC cells suggested that miR-224 could be a prospective therapeutic target for early-stage non-metastatic CRC.

Aggressive inflammation is an important pathological process of secondary injury in acute spinal cord injury (SCI). However, traditional treatments of secondary injury in acute SCI have achieved little success. Novel biomaterials combined with small molecule drugs are considered as a potential treatment for SCI. Baricitinib, a highly selective JAK1/JAK2 inhibitor, can effectively inhibit the JAK2/STAT3 pathway involved in the modulation of inflammation. However, to evaluate Baricitinib's therapeutic effect on SCI remains to be confirmed. In this study, we designed an injectable PLGA-PEG-PLGA thermos-sensitive hydrogel with baricitinib (Bari-P hydrogel) and measured its efficacy, physical and biological properties in vitro. In the SCI rat, Bari-P hydrogel was injected into the injured spinal cord. Neuronal regeneration was evaluated at 3 days and 4 weeks after surgery by determining the inflammatory cytokine levels, behavioral tests, and histological analysis. The hydrogel can gel in the body, disintegrate almost within 72 h and achieve drug release. Baricitinib can effectively inhibit the JAK2/STAT3 pathway of microglia in vitro; while in vivo experiments show that Bari-P hydrogel treatment can inhibit the phosphorylation of JAK2, STAT3 and suppress the production of inflammatory cytokines, and reduces neuronal apoptosis. Histopathological analysis and behavioral tests showed that Bari-P hydrogel reduced neuronal apoptosis in the early stage of injury and later promoted functional recovery. In summary, Bari-P hydrogel reduced neuronal apoptosis and promoted functional recovery in spinal cord injured rats by inhibiting the JAK2-STAT3 pathway and controlling the expression of inflammatory cytokines in the early stages of injury.

Objective: To delve into the correlation between miR-92b expression in peripheral plasma and hypertension, heart disease and cerebral hemorrhage. Methods: We enrolled 204 patients hospitalized in our institution from March 2016 to May 2017, including patients with hypertension (group B), hypertensive left ventricular hypertrophy (HTN-LVH) (group C), HTN-LVH complicated heart failure (group D), with 68 cases each group, and recruited another 60 healthy volunteers as control group (group A). Our team compared miR-92b level in peripheral plasma, and ultrasound indexes among the four groups and inquired into their correlation. The patients were followed up to assay miR-92b level in the peripheral plasma, cerebral edema volume and cerebral hematoma volume before and after treatment. Results: (1) In contrast to group B, the LVDs and LVMI in group C, D waxed, whereas LVEF and E/A waned (PConclusion: miR-92b expression in peripheral plasma of patients with hypertension, myocardial hypertrophy and cerebral hemorrhage is down-regulated. miR-92b probably harbors a defensive impact and participates in the pathophysiological process of hypertension, heart disease and cerebral hemorrhage.