Search

Background Gene dosage imbalance caused by copy number variations (CNVs) is a prominent contributor to brain disorders. In particular, 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder and schizophrenia, respectively. The mechanism underlying these diametric contributions remains unclear. Methods We established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs. To assess the functional consequences of altered CYFIP1 levels, we performed systematic investigations on behavioral, electrophysiological, and biochemical phenotypes in both mouse models. In addition, we utilized RNA immunoprecipitation sequencing (RIP-seq) analysis to reveal molecular targets of CYFIP1 in vivo. Results Cyfip1 loss-of-function and gain-of function mouse models exhibited distinct and shared behavioral abnormalities related to autism spectrum disorder and schizophrenia. RIP-seq analysis identified messenger RNA targets of CYFIP1 in vivo, including postsynaptic NMDA receptor (NMDAR) complex components. In addition, these mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses because of dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in these mouse models with diametric Cyfip1 dosages rescues behavioral abnormalities. Conclusions CYFIP1 regulates protein translation of NMDAR and associated complex components at synapses to maintain normal synaptic functions and behaviors. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4α)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4α expression, while silencing PXR upregulated HNF4α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16α-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4α‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.

Aim: Given the importance of FOXM1 in the treatment of ovarian cancer, we aimed to identify an excellent specific inhibitor and examined its underlying therapeutic effect. Materials & methods: The binding statistics for FDI-6 with FOXM1 were calculated through computer-aided drug design. We selected XST-119 through virtual screening, performed surface plasmon resonance and in vitro cell antiproliferative activity analysis and evaluated its antitumor efficacy in a mouse model. Results: XST-119 had significantly higher affinity for FOXM1 and antiproliferative activity than FDI-6. XST-119 had a definite inhibitory activity in a xenograft mouse model. Conclusion: We identified XST-119, a FOXM1 inhibitor, with better efficacy for treatment of ovarian cancer. FOXM1 binding sites for small molecules are also highlighted, which may provide the foundation for further drug discovery.

Early diagnosis and timely surgical Kasai portoenterostomy greatly improve the survival of patients with biliary atresia (BA), a neonatal cholestatic disease, which has encouraged investigators to develop newborn screening for BA. In this study, we used ultraperformance liquid chromatography-triple quadrupole mass spectrometry-based targeted metabolomics profiling to identify potential BA biomarkers in dried blood spots (DBS) collected from BA patients (n = 21) and healthy controls (n = 100). A distinctive metabolic profile comprising eight significantly differentially expressed metabolites, taurohyocholic acid (THCA), glutamic acid, 2-hydroxyglutaric acid, ketoleucine, indoleacetic acid, alpha-ketoisovaleric acid, glycocholic acid, and taurocholic acid (TCA), clearly distinguished BA infants from control neonates. Three metabolites, THCA, 2-hydroxyglutaric acid, and indoleacetic acid, were selected using linear regression and receiver operating characteristic (ROC) curve analysis and model construction. The area under the ROC curve for this model to discriminate between BA and comparison infants was 0.938 (95% confidence interval, CI: 0.874-1.000). A cutoff value of -0.336 produced a sensitivity of 90.48% (95% CI: 69.62% - 98.83%) and specificity of 92% (95% CI: 84.84% - 96.48%). In conclusion, the results suggest that metabolic markers in DBS obtained from newborns have a great potential for BA screening.

INTRODUCTION Nonsteroidal anti-inflammatory drugs (NSAIDs) are regarded as nephrotoxins. Children commonly use NSAIDs and are susceptible to nephropathy, but the relationship between acute kidney injury (AKI) and use of NSAIDs is not well examined yet. OBJECTIVE To evaluate the relationship between AKI and use of NSAIDs in hospitalized pediatric patients who are susceptible to nephropathy. METHODS We conducted this systematic review and meta-analysis of observational studies by searching PubMed, Embase, and Cochrane Database for articles published up to June 1, 2020. Reports included involved children (age

BackgroundMETamplification plays an important role in the development of non-small-cell lung cancer (NSCLC) either de novo or in resistance to epidermal growth factor receptor tyrosine–kinase inhibitor (EGFR-TKI) settings. Fluorescence in situ hybridization (FISH) is the standard method forMETamplification. With more and more discoveries of oncogenic driver genes, next-generation sequencing (NGS) plays a significant role in precision oncology. Meanwhile, the role of NGS inMETamplification remains uncertain.MethodsForty patients diagnosed with advanced NSCLC were included. FISH and NGS were conducted prior to MET inhibitors treatment.METamplification by FISH was defined as a MET/CEP7 ratio of > 2.0 and/or copy number (CN) > 5.METamplification by NGS was defined as gene copy number (GCN) ≥ 5.ResultsThe concordance rate among FISH and NGS was 62.5% (25/40).METamplification identified by FISH showed the optimal predictive value. The partial response (PR) rate was 68.0% (17/25 withMETamplification) vs. 6.7% (1/15 withoutMETamplification); the median progression-free survival (PFS) was 5.4 months versus 1.0 months (P METamplification identified by NGS failed to distinguish significant clinical outcomes. The PR rate was 60.0% (6/10, withMETGCN ≥ 5) vs. 40.0% (12/30, withMETGCN ConclusionsMETamplification identified by FISH remains the optimal biomarker to identify suitable candidates for MET-TKI therapy. In comparison, amplification identified by NGS seems not as robust to be effective predictive biomarker. Further exploration is needed regarding the focal amplification by NGS in predicting the efficacy.

Background Although open reduction and internal fixation (ORIF) is recommended for lateral condylar humerus fractures (LCHFs) displaced by > 4 mm, several studies have reported the use of closed reduction and percutaneous pinning (CRPP) to treat LCHFs with significant displacement. However, little is known about the clinical differences between these two surgical techniques. This study aimed to compare the therapeutic effects of CRPP and ORIF in treating LCHFs displaced by > 4 mm. Methods We retrospectively reviewed pediatric LCHFs displaced by > 4 mm treated with either CRPP or ORIF at our center from June 2019 to October 2020. Song and Milch fracture classifications were used. Variables such as age at injury, sex, side injured, fracture displacement, fracture type, operating time, postoperative treatment, and complications were compared between the two techniques. Results One hundred twenty LCHFs met inclusion criteria. There were 36 Milch type I and 84 type II LCHFs, and 69 Song stage 4 and 51 stage 5 LCHFs. CRPP was performed in 45 cases and ORIF in 75 cases. No differences were found in age, sex, side injured, preoperative displacement, postoperative displacement, and length of immobilization between the CRPP and ORIF groups. There was a difference between operation time and pin duration. The CRPP group had shorter operation times and pin duration, and required no additional operations to remove internal pins. The average follow-up duration was 13.9 months. All patients achieved fracture union, and no complications such as infection, nonunion, delayed union, osteonecrosis, fishtail deformity, cubitus varus or valgus, or pain were recorded during follow-up. Bone spurs, lateral prominences, and decreased carrying angle were common complications in all groups. No obvious cubitus varus was observed. Unaesthetic scars were only observed in the ORIF groups. No differences in range of motion or elbow function was found among the different therapies. Conclusions Both CRPP and ORIF can achieve satisfactory clinical outcomes in treating LCHFs displaced by > 4 mm. No differences were found in complications or prognoses between the two groups. However, CRPP shows some advantages over ORIF, like less invasive surgery, no obvious scarring, and no need for secondary surgery with anesthesia for pin removal.

Patients with cardiovascular comorbidity are less tolerant to cardiotoxic drugs and should be treated with reduced doses to prevent cardiotoxicity. However, the safe‐equivalent dose of antitumor drugs in patients with cardiovascular disease/risk is difficult to predict because they are usually excluded from clinical trials as a result of ethical considerations. In this study, a translational quantitative system pharmacology‐pharmacokinetic‐pharmacodynamic (QSP‐PK‐PD) model was developed based on preclinical study to predict the safe‐equivalence dose of doxorubicin in patients with or without cardiovascular disease. Virtual clinical trials were conducted to validate the translational QSP‐PK‐PD model. The model replicated several experimental and clinical observations: the left ventricular ejection fraction (LVEF) was reduced and the left ventricular end‐diastolic volume (LVEDV) was elevated in systolic dysfunction rats, the LVEF was preserved and LVEDV reduced in diastolic dysfunction rats, and patients with preexisting cardiovascular disease were more vulnerable to doxorubicin‐induced cardiac dysfunction than cardiovascular healthy patients. A parameter sensitivity analysis showed that doxorubicin‐induced cardiovascular dysfunction was mainly determined by the sensitivity of cardiomyocytes to cardiotoxic drugs and the baseline value of LVEDV, reflected in LVEF change percentage from the baseline. Blood pressure was the least sensitive factor affecting doxorubicin‐induced cardiotoxicity.

Background Hepatocyte senescence is a core event that mediates the occurrence and development of alcoholic liver disease. Nuclear factor of activated T-cells 4 (NFATc4) is a key driver of nonalcoholic steatohepatitis. However, little was known about the implication of NFATc4 for alcoholic liver disease. This study was aimed to investigate the role of NFATc4 in hepatocyte senescence and further elucidate the underlying mechanism. Methods Real-time PCR, Western blot, immunofluorescence staining, and enzyme-linked immunosorbent assay were performed to explore the role of NFATc4 in hepatocyte senescence. Results NFATc4 was induced in ethanol-incubated hepatocytes. NFATc4 knockdown recovered cell viability and reduced the release of aspartate transaminase, alanine transaminase, and lactic dehydrogenase from ethanol-incubated hepatocytes. NFATc4 knockdown protected mice from alcoholic liver injury and inflammation. NFATc4 knockdown counteracted ethanol-induced hepatocyte senescence, evidenced by decreased senescence-associated β-galactosidase positivity and reduced p16, p21, HMGA1, and γH2AX, which was validated in in vivo studies. Peroxisome proliferator-activated receptor (PPAR)γ was inhibited by NFATc4 in ethanol-treated hepatocytes. PPARγ deficiency abrogated the inhibitory effects of NFATc4 knockdown on hepatocyte senescence, oxidative stress, and hepatic steatosis in mice with alcoholic liver disease. Conclusions This work discovered that ethanol enhanced NFATc4 expression, which further triggered hepatocyte senescence via repression of PPARγ.

Background Previous studies reported the prognostic value of the atherogenic index of plasma (AIP) in the course of atherosclerosis and other cardiovascular diseases (CVDs). Still, the predictive utility of the AIP is unknown among patients with type 2 diabetes mellitus (T2DM). Methods This was a secondary analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, which randomized 10,251 patients with long-lasting T2DM. ROC curve analysis was used to determine an optimal threshold for AIP, and the study population was divided into high and low AIP groups. Univariable and multivariable Cox proportional hazards regression analyses were used to determine the association between AIP and primary (major adverse cardiovascular events [MACEs], including nonfatal myocardial infarction, nonfatal stroke, and/or death from cardiovascular causes) and secondary outcomes (all-cause mortality). Stratified analyses were performed to control for the confounding factors. Results AIP was an independent risk factor for the prognosis of T2DM (HR = 1.309; 95% CI 1.084–1.581; P = 0.005). The threshold for AIP was determined to be 0.34 in the study population. After adjustments for confounding factors, multivariable analysis showed that AIP was associated with the risk of MACEs (Model 1: HR = 1.333, 95% CI 1.205–1.474, P P = 0.016; Model 3: HR = 1.194, 95% CI 1.049–1.360, P = 0.007), all-cause mortality (Model 1: HR = 1.184, 95% CI 1.077–1.303, P P P = 0.036), and nonfatal myocardial infarction (Model 1: HR = 1.447, 95% CI 1.255–1.669, P P = 0.015; Model 3: HR = 1.284, 95% CI 1.071–1.539, P = 0.007). Subgroup stratified analyses showed that AIP might interact with sex, a classical risk factor of cardiovascular events. Conclusions This study showed that AIP might be a strong biomarker that could be used to predict the risk of cardiovascular events in patients with T2DM. Trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000620.

Pulmonary fibrosis (PF) is a chronic and progressively fatal disease, but clinically available therapeutic drugs are limited due to efficacy and side effects. The possible mechanism of pulmonary fibrosis includes the damage of alveolar epithelial cells II (AEC2), and activation of immune cells such as macrophages. The ions released from bioceramics have shown the activity in stimulating soft tissue derived cells such as fibroblasts, endothelia cells and epithelia cells, and regulating macrophage polarization. Therefore, this study proposes an “ion therapy” approach based on the active ions of bioceramic materials, and investigates the therapeutic effect of bioactive ions derived from calcium silicate (CS) bioceramics on mouse models of pulmonary fibrosis. We demonstrate that silicate ions significantly reduce pulmonary fibrosis by simultaneously regulating the functions of AEC2 and macrophages. This result suggests potential clinical applications of ion therapy for lung fibrosis., Graphical abstract Image 1, Highlights ● A novel treatment of pulmonary fibrosis based on ion therapy using bioactive ionic solution derived from silicate bioceramics (CS) was demonstrated. ● CS solution can stimulate the alveolar epithelial cells to repair damaged lung tissue. ● CS solution can regulate immune cells to inhibit inflammatory factor secretion and reduce the number of inflammatory cells in lung tissue.

Immunotherapy is currently an important adjuvant therapy for malignant tumors besides surgical treatment. However, the heterogeneity and low immunogenicity of the tumor are two main challenges of the immunotherapy. Here, we have constructed a nanoplatform (CP@mRBC-PpIX) to realize reversion of the tumor acidosis and hypoxia through alkali and oxygen generation triggered by tumor acidosis. By targeting tumor universal features other than endogenous biomarkers, it was found that CP@mRBC-PpIX could polarize tumor-associated macrophages to anti-tumor M1 phenotype macrophages to enhance tumor immune response. Furthermore, under regional light irradiation, the reactive oxygen species produced by photosensitizers located in CP@mRBC-PpIX could increase the immunogenicity of tumors, so that tumor changes from an immunosuppressive "cold tumor" to an immunogenic "hot tumor," thereby increasing the infiltration and response of T cells, further amplifying the effect of immunotherapy. This strategy circumvented the problem of tumor heterogeneity to realize a kind of broad-spectrum immunotherapy, which could effectively prevent tumor metastasis and recurrence.

Background Heart transplantation (HTx) remains the gold-standard treatment for end-stage heart failure. The aim of this study was to establish a risk-prediction model for assessing prognosis of HTx using machine-learning approach. Methods Consecutive recipients of orthotopic HTx at our institute between January 1st, 2015 and December 31st, 2018 were included in this study. The primary outcome was 1-year mortality. Least absolute shrinkage and selection operator method was used to select variables and seven different machine-learning approaches were employed to develop the risk-prediction model. Bootstrap method was used for model validation. Shapley Additive exPlanations (SHAP) method was used for model interpretation. Results 381 recipients were included with average age of 43.783 years old. Albumin, recipient age and left atrium diameter ranked top three most important variables that affected the 1-year mortality of HTx. Other important variables included red blood cell, hemoglobin, lymphocyte%, smoking history, use of lyophilized rhBNP, use of Levosimendan, hypertension, cardiac surgery history, malignancy and endotracheal intubation history. Random Forest (RF) model achieved the best area under curves (AUC) of 0.801 and gradient boosting machine (GBM) showed the best sensitivity of 0.271. SHAP method was introduced to display the RF model's predicting processes of “survival” or “death” in individual level. Conclusions We established the risk-prediction model for postoperative prognosis of HTx patients by using machine learning method and demonstrated that the RF model performed the highest discrimination with the largest AUC when validated. This prediction model could help to recognize high-risk HTx recipients, provide personalized therapy plan and reduce organ wastage.

Interleukin (IL)‐7 is known to enhance the macrophages cytotoxic activity and that macrophages play a pivotal role in the development and progression of myocardial ischaemia/reperfusion (I/R) injury. However, the effects of IL‐7 on macrophages infiltration and polarization in myocardial I/R injury are currently unclear. This study aimed to evaluate the effects of the IL‐7 expression on myocardial I/R injury and their relationship with macrophages. The data showed that IL‐7 expression in mouse heart tissue increases following I/R injury and that IL‐7 knockout or anti‐IL‐7 antibody treatment significantly improve I/R injury, including reduction in myocardial infarction area, a serum troponin T level decreases and an improvement in cardiac function. On the other hand, recombinant IL‐7 (rIL‐7) supplementation induces opposite effects and the anti‐IL‐7 antibody significantly reduces the cardiomyocyte apoptosis and macrophage infiltration. rIL‐7 cannot directly cause apoptosis, but it can induce cardiomyocyte apoptosis through macrophages, in addition to increase the macrophages migration in vitro. Anti‐IL‐7 antibody affects the cytokine production in T helper (Th) 1 and Th2 cells and also promotes the macrophages differentiation to M2 macrophages. However, anti‐IL‐7 antibody does not reduce the M1 macrophage number, and it only increases the ratio of M2/M1 macrophages in mice heart tissues after I/R injury. Taking together, these data reveal that IL‐7 plays an intensifying role in myocardial I/R injury by promoting cardiomyocyte apoptosis through the regulation of macrophage infiltration and polarization.

BACKGROUND: In recent years, ultrasound elastography (USE) has been the main diagnostic technique for benign and malignant thyroid nodules. However, it cannot display the blood flow signals of nodules with smaller diameters clearly, which decreases its diagnostic accuracy. METHODS: Chinese and English databases were searched using “ultrasonic elastography”, “benign and malignant thyroid nodules”, and “diagnose” as the search terms. RevMan 5.3 software was used for meta-analysis. RESULTS: A total of 11 randomized controlled trials (RCTs) were included. Eight articles analyzed clinical symptoms, and the heterogeneity test results were Chi(2) =7.46, df=7, I(2)=6%, and P=0.38; and Z=11.44, OR =14.58, 95% confidential interval (CI): 9.21–23.07, and P

Objective The Corona Virus Disease-19 (COVID-19) pandemic has evolved into the largest public health event in the world. Earlier COVID-19 studies have reported that the pandemic caused widespread impacts on mental health and sleep in the general population. However, it remains largely unknown how the prevalence of mental health problems and sleep disturbance developed and interacted in adolescents at different times in the epidemic. Methods 831 teenagers (aged 14–19) underwent a longitudinal follow-up study to evaluate the prevalence of mental health problems and sleep disturbance among adolescents before, during, and after the COVID-19 breakout in China and to explore the interaction between mental health and sleep across the three measurements. The chronotype, anxiety and depression level, sleep quality, and insomnia were investigated during each measurement. Results The adolescents had delayed sleep onset and sleep offset time, longer sleep duration during the quarantine than before and after the epidemic, whereas their chronotype tended to morning type during the epidemic. Yet, the highest prevalence of anxiety, depression, poor sleeper, and insomnia symptoms were observed before but not during the COVID-19 breakout. The females and adolescents who were eveningness type showed significantly higher anxiety and depression levels, poorer sleep quality, and severe insomnia status than the males and the intermediate and morning types. Sleep disturbance was positively associated with mental problems among three measurements. Pre-measured depression level significantly predicted sleep disturbance level at follow-ups. Conclusion These findings suggested that adolescents' high prevalence of mental health and sleep problems occurred before the COVID breakout and decreased during and after the epidemic. Gender and chronotype were significant risk factors associated with affective and sleep disturbances. Depression positively predicted later sleep problems, but not vice versa.

We aimed to establish and validate a user-friendly and clinically practical nomogram for estimating the probability of echocardiographic left ventricular hypertrophy (echo-LVH) indexed to BSA among hypertensive patients from northern China.A total of 4954 hypertensive patients were recruited from a population-based cohort study from January 2012 to August 2013. The dataset was randomly split into two sets: training (n = 3303) and validation (n = 1651). Three nomograms were initially constructed. That is the Cornell product nomogram, the non-ECG nomogram, and the integrated nomogram which integrated non-ECG risk factors and Cornell-voltage duration product. The least absolute shrinkage and selection operator strategies were employed to screen for non-ECG features. The performance of the nomograms was evaluated using discrimination, calibration, and decision curve analysis (DCA). The net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were also calculated.The AUCs, NRIs, IDIs, and DCA curves of the nomograms demonstrated that the integrated nomogram performed best among all three nomograms. The integrated nomogram incorporated age, sex, educational level, hypertension duration, SBP, DBP, eGFR, sleep duration, tea consumption, and the Cornell-voltage duration product. The AUC was 0.758 and had a good calibration (Hosmer-Lemeshow test, P = 0.73). Internal validation showed an acceptable AUC of 0.735 and good calibration was preserved (Hosmer-Lemeshow test, P = 0.19). The integrated nomogram was clinically beneficial across a range of thresholds of 10-50%.The integrated nomogram is a convenient and reliable tool that enables early identification of hypertensive patients at high odds of LVH and can assist clinicians in their decision-making.

Herba Lysimachiae inhibits synovial damage in osteoarthritis via regulating two biolabels (integrin alpha 2b/beta 3). However, the relevant active ingredients are still unknown. Here, the active ingredients of herbal medicines were analyzed based on the liquid chromatography-tandem mass spectrometry technology and public bioinformatics platforms. The liquid chromatography-tandem mass spectrometry technology was used for compound analysis, and public databases (PubChem BioAssay and STRING) were applied to establish the links between herbal compounds and both biolabels, and identify which herbal compounds may regulate these biolabels. Subsequently, osteoarthritis model was used to confirm the results. Totally, ninety compounds in Herba Lysimachiae were identified based on the liquid chromatography-tandem mass spectrometry technology. Bioinformatics analysis showed that five compounds (myricetin, fisetin, esculetin, 7-hydroxycoumarin-4-acetic acid, and caffeic acid) may synergistically regulate biolabels through 11 targets, which may be the active ingredients of Herba Lysimachiae for osteoarthritis treatment. In the verification experiments, five compounds markedly suppressed the overexpression of biolabels in the synovium of the osteoarthritis model. In conclusion, the present study effectively and rapidly analyzed the active ingredients of Herba Lysimachiae for osteoarthritis treatment. This article is protected by copyright. All rights reserved.

Metastasis is the leading cause of death in breast cancer patients. Osthole, as an active compound detected in the traditional Chinese medicine Wenshen Zhuanggu Formula, has shown a promising anti-metastatic activity in human breast cancer cells, but the underlying mechanisms remain ambiguous. In this study we elucidated the anti-metastatic mechanisms of osthole in highly metastatic breast cancer cells and a zebrafish xenograft model. We showed that the expression of integrin α3 (ITGα3) and integrin β5 (ITGβ5) was upregulated in highly metastatic MDA-MB-231, MDA-MB-231BO breast cancer cell lines but was downregulated in poorly metastatic MCF-7 breast cancer cell line, which might be the key targets of osthole's anti-metastatic action. Furthermore, we showed that knockdown of ITGα3 and ITGβ5 attenuated breast cancer cell migration and invasion possibly via suppression of FAK/Src/Rac1 pathway, whereas overexpression of ITGα3 and ITGβ5 caused the opposite effects. Consistently, osthole significantly inhibited breast cancer metastasis by downregulating ITGα3/ITGβ5 signaling in vitro and in vivo. These results provide new evidence that osthole may be developed as a candidate therapeutic drug for metastatic breast cancer.

Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP), an RNA-binding protein that can regulate the translation of specific mRNAs. In this study, we developed an FXS human forebrain organoid model and observed that the loss of FMRP led to dysregulated neurogenesis, neuronal maturation and neuronal excitability. Bulk and single-cell gene expression analyses of FXS forebrain organoids revealed that the loss of FMRP altered gene expression in a cell-type-specific manner. The developmental deficits in FXS forebrain organoids could be rescued by inhibiting the phosphoinositide 3-kinase pathway but not the metabotropic glutamate pathway disrupted in the FXS mouse model. We identified a large number of human-specific mRNAs bound by FMRP. One of these human-specific FMRP targets, CHD2, contributed to the altered gene expression in FXS organoids. Collectively, our study revealed molecular, cellular and electrophysiological abnormalities associated with the loss of FMRP during human brain development.

Deletion of the neurofibromatosis 1 (NF1) gene is common, but NF1 rearrangement or fusion has rarely been reported in peripheral nerve sheath tumors. Here, we present a case of malignant peripheral nerve sheath tumor (MPNST) in a 36-year-old Chinese female. Histologically, the lesion was composed of spindle cells with moderate atypia, immature bone, and atypical cartilage elements. Fluorescence in situ hybridization (FISH) for USP6 revealed green-orange split signals, strongly suggesting the presence of USP6 rearrangement. Subsequent next-generation sequencing-based technology analyses revealed t(17,17) (p13.2, q11.2) intrachromosomal translocation resulting in a novel NF1-SCIMP fusion gene along with NF1 deletion. However, USP6 fusion was not identified. To the best of our knowledge, this is the first case with a confirmed NF1 gene fusion partner in a peripheral nerve sheath tumor. Notably, rearrangement of the SCIMP may cause a pitfall in the interpretation of USP6 FISH results.

Chemotherapy continues to be the most commonly applied strategy for cancer. Despite the impressive clinical success obtained with several drugs, increasing numbers of (multi)drug-resistant tumors are reported. To overcome this shortcoming, novel drug candidates and delivery systems are urgently needed. Herein, a therapeutic copper polypyridine complex encapsulated in natural nanocarrier apoferritin is reported. The generated nanoparticles showed higher cytotoxicity toward various (drug-resistant) cancer cell lines than noncancerous cells. The study of the mechanism revealed that the compound triggers cell autophagy-dependent apoptosis. Promisingly, upon injection of the nanodrug conjugate into the bloodstream of a mouse model bearing a multidrug-resistant colon tumor, a strong tumor growth inhibition effect was observed. To date, this is the first study describing the encapsulation of a copper complex in apoferritin that acts by autophagy-dependent apoptosis.

Kangxian ruangan (KXRG) is a traditional Chinese medicine (TCM) formula consisting of 12 herbs. TCM syndrome differentiation proposes that KXRG exerts pharmacological effects against nonalcoholic fatty liver disease (NAFLD) fibrosis. This work investigates the effect of KXRG on NAFLD fibrosis in vivo and in vitro. In vivo, the NAFLD fibrosis model was constructed in Wistar rats using methionine- and choline-deficient (MCD) diet, followed by KXRG (0.92 g/kg/d) treatment for 8 weeks. In vitro, primary hepatic stellate cells (HSCs) were activated using platelet-derived growth factor (PDGF) and treated with KXRG. Molecular mechanisms underlying fibrosis were investigated. After 8 weeks, compared with the control groups, the histological lesions, degree of fibrosis, and inflammatory reaction increased with the MCD diet as demonstrated by histological changes and increased fibrosis-related (α-SMA, TGF-β, COL1A1, and desmin, P < 0.01 ) and inflammation-related factors (TNF-α, MCP-1, and F4/80, P < 0.01 ), whereas they decreased with KXRG treatment ( P < 0.01 ). KXRG not only inhibited the proliferation of activated HSCs and promoted their apoptosis but also resulted in G0-G1 arrest. Furthermore, KXRG suppressed HSC activation ( P < 0.01 ), collagen synthesis ( P < 0.01 ), and α-SMA expression ( P < 0.01 ) with PDGF stimulation. In both the MCD diet-induced animal model and PDGF-induced cell model, KXRG inhibited TGF-β and TLR4 signaling ( P < 0.01 ), similar to corresponding small-molecule inhibitors. These results demonstrated that KXRG might exert suppressive effects against NAFLD fibrosis via regulating TGF-β and TLR4 signaling. KXRG may act as a natural and potent therapeutic agent against NAFLD.

BackgroundTo verify the efficacy and safety of an inexpensive standardized regimen for multidrug-resistant tuberculosis (MDR-TB) with low resistance to isoniazid (INH), a multicenter prospective study was conducted in eastern China.MethodsPatients diagnosed as MDR-TB with low concentration INH resistance and rifampicin resistance, second-line/injectable agents sensitive were prospectively enrolled, given the regimen of Amikacin (Ak)–Fluoroquinolones (FQs)–Cycloserine (Cs)–Protionamide (Pto)–PasiniaZid (Pa)–Pyrazinamide (Z) for 6 months followed by 12 months of FQs–Cs–Pto–Pa–Z, and then followed up for treatment outcomes and adverse events (AEs).ResultsA total of 114 patients were enrolled into the study. The overall favorable treatment rate was 79.8% (91/114). Among 91 cases with favorable treatment, 75.4% (86/114) were cured and 4.4% (5/114) were completed treatment. Regarding to unfavorable outcomes, among 23 cases, 8.8% (10/114) had failures, 8.8% (10/114) losing follow up, 0.9% (1/114) had treatment terminated due to intolerance to drugs and 1.8% (2/114) died. Treatment favorable rate was significantly higher in newly treated MDR-TB (91.7%, 33/36) than that in retreated MDR-TB (74.4%, 58/78,p0.03). The investigators recorded 42 AEs occurrences in 30 of 114 patients (26.3%). Clinicians rated most AEs as mild or moderate (95.24%, 40/42).ConclusionsThe regimen was proved to be effective, safe and inexpensive. It is suitable for specific drug resistant population, especially for newly-treated patients, which could be expected to be developed into a short-course regimen.Clinical trials registrationChina Clinical Trial Registry ChiCTR-OPC-16009380

In recent years, with the development of RNA sequencing technology and bioinformatics methods, the epigenetic modification of RNA based on N6-methyladenosine (m6A) has gradually become a research hotspot in the field of bioscience. m6A is the most abundant internal modification in eukaryotic messenger RNAs (mRNAs). m6A methylation modification can dynamically and reversibly regulate RNA transport, localization, translation and degradation through the interaction of methyltransferase, demethylase and reading protein. m6A methylation can regulate the expression of proto-oncogenes and tumor suppressor genes at the epigenetic modification level to affect tumor occurrence and metastasis. The morbidity and mortality of esophageal cancer (EC) are still high worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common tissue subtype of EC. This article reviews the related concepts, biological functions and recent advances of m6A methylation in ESCC, and looks forward to the prospect of m6A methylation as a new diagnostic biomarker and potential therapeutic target for ESCC.

DMB (6,7-dichloro-2-methylsulfonyl-3-Ntert-butylaminoquinoxaline) is a quinoxaline-based compound that has been investigated as a glucagon-like peptide-1 receptor (GLP-1R) agonist. To clarify anti-osteoporosis effect of DMB, an osteoporotic mice model was established by ovariectomy (OVX) operation. The OVX mice were given intraperitoneally DMB, exendin-4 (EX-4), or 17β-estradiol (E2) for two months. Then bone mass and structure, and bone morphometric parameters were examined by micro-CT. Weight gain and food consumption, bone turnover markers, and biomechanical strength of the femur were tested, and bone histomorphometry was analyzed. The food intake and weight gain was obviously reduced by E2 or EX-4, but not DMB. However, DMB or EX-4 treatment obviously inhibited skeletal deterioration and enhanced bone strength. The improvement involved in the increased osteoblast number and level of bone formation markers, and reduced osteoclasts number and level of bone resorption markers. In addition, DMB was found to stimulate osteoblastogenesis-related marker gene expression. These results demonstrated that DMB ameliorated bone loss mainly via induction of bone formation, which suggests that the small molecule compound might be applied to the management of postmenopausal osteoporosis.

BACKGROUND The aim of our study is to investigate the impact of the simple breathing exercises (LHP's respiratory rehabilitation for pulmonary fibrosis, LHP's RRPF) on patients with idiopathic pulmonary fibrosis (IPF). METHODS (I) The safety and effectiveness of LHP's RRPF were first verified in 20 healthy individuals. (II) A total of 101 patients with IPF administrated in Shanghai Pulmonary Hospital between January 2015 and May 2017 were screened, and 82 cases were randomly assigned to receive a 12-month LHP's RRPF program (exercise group) or usual medical care (control group). Lung function, chest X-ray, 6-minute walk distance (6MWD), quality of life (St. George's Respiratory Questionnaire, SGRQ), and EKG were measured at the 6th and 12th month during the trial. RESULTS At the 6th month visit, the exercise group showed improved SGRQ score and lung function parameters (FVC, FEV1, and DLCO). At the 12th months visit, the exercise group had significantly improved SGRQ score, 6MWD, and lung function (FVC, FEV1, and DLCO) compared to the control group (P

Purpose Skin cancer is the most common, yet oftentimes preventable, cancer type in the United States. Exposure to ultraviolet radiation from sunlight is the most prominent environmental risk factor for skin cancer. Besides environmental exposure, demographic characteristics such as race, age, and socioeconomic status may make some groups more vulnerable. An exploratory spatial clustering method is described for identifying clusters of vulnerability to skin cancer incidence and mortality based on composite indices, which combine data from environmental and demographic risk factors. Methods Based on county-level ultraviolet data and demographic risk factors, two vulnerability indices for skin cancer were generated using an additive percentile rank approach. With these indices, univariate local Moran's I spatial autocorrelation identified significant clusters, or hotspots, of neighboring counties with high overall vulnerability indices. Clusters were identified separately for skin cancer incidence and mortality. Results Counties with high vulnerabilities were spatially distributed across the United States in a pattern that generally increased to the South and West. Clusters of counties with high skin cancer incidence vulnerability were mostly observed in Utah and Colorado, even with highly conservative levels of significance. Meanwhile, clusters for skin cancer mortality vulnerability were observed in southern Alabama and west Florida as well as across north Alabama, north Georgia and up through the Tennessee-North Carolina area. Conclusions Future skin cancer research and screening initiatives may use these innovative composite vulnerability indices and identified clusters to better target resources based on anticipated risk from underlying demographic and environmental factors.

BackgroundBoth N6-methyladenosine (m6A) modification and lncRNAs play an important role in the carcinogenesis and cancer inhibition of ovarian cancer (OC). However, lncRNAs involved in m6A regulation (LI-m6As) have never been reported in OC. Herein, we aimed to identify and validate a signature based on LI-m6A for OC.MethodsRNA sequencing profiles with corresponding clinical information associated with OC and 23 m6A regulators were extracted from TCGA. The Pearson correlation coefficient (PCC) between lncRNAs and 23 m6A regulators (|PCC|> 0.4 and p ResultsThe training cohort involving 258 OC patients and the validation cohort involving 111 OC patients were downloaded from TCGA. According to the PCC between the m6A regulators and lncRNAs, 129 LI-m6As were obtained to perform univariate Cox regression analysis and then 10 significant prognostic LI-m6As were identified. A prognostic signature containing four LI-m6As (AC010894.3, ACAP2-IT1, CACNA1G-AS1, and UBA6-AS1) was constructed according to the LASSO Cox regression analysis of the 10 LI-m6As. The prognostic signature was validated to show completely opposite prognostic value in the two risk groups and adverse overall survival (OS) in several clinicopathological characteristics. GSEA indicated that differentially expressed genes in disparate risk groups were enriched in several tumor-related pathways. At the same time, we found significant differences in some immune cells and chemotherapeutic agents between the two groups. An alternative lncRNA, CACNA1G-AS1, was proven to be upregulated in 30 OC specimens and 3 OC cell lines relative to control. Furthermore, knockdown of CACNA1G‐AS1 was proven to restrain the multiplication capacity of OC cells.ConclusionsBased on the four LI-m6As (AC010894.3, ACAP2-IT1, CACNA1G-AS1, and UBA6-AS1), the risk model we identified can independently predict the OS and therapeutic value of OC. CACNA1G‐AS1 was preliminarily proved to be a malignant lncRNA.

Background Microwave ablation (MWA) and radiofrequency ablation (RFA) have recently attracted interest as minimally invasive treatment modalities for papillary thyroid carcinoma (PTC). However, the ablation outcomes of T1N0M0 PTC are not well characterized. Purpose To evaluate the efficacy and safety of thermal ablation (MWA or RFA) of solitary T1N0M0 PTC in patients who were ineligible for (due to presence of comorbid cardiovascular disease, renal failure, other malignancy, etc) or who refused surgery. Materials and Methods This was a retrospective multicenter study of 847 patients (660 women) who underwent thermal ablation for PTC (673 T1a, 174 T1b) between March 2015 and March 2020; of these patients, 645 underwent MWA and 202 underwent RFA. The mean age of patients was 46 years ± 11 (standard deviation) (age range, 18-81 years); the mean follow-up time was 22 months ± 13 (range, 6-60 months). Changes in tumor size and volume and the rates of technical success, tumor disappearance, disease progression, and complications were assessed. Results The technical success rate was 100%. Relative to preablation measurements, the maximum diameter and volume of the ablation zone increased during the 1st month after ablation (P < .001), whereas there was no difference by the 3rd month; subsequently, the tumors showed reduction in size at 6, 9, and 12 months (all P < .001). Complete disappearance of tumors occurred in 68% of patients (577 of 847; 69% [466 of 673] in the T1a group vs 64% [111 of 174] in the T1b group; P < .001). The postablation disease progression rate was 1.1% (nine of 847 patients; 0.9% [six of 673 patients] in the T1a group vs 1.7% [three of 174 patients] in the T1b group; P = .54). The overall complication rate was 3.4% (29 of 847 patients; 2.7% [18 of 673 patients] in the T1a group vs 6.3% [11 of 174 patients] in the T1b group; P = .02). Conclusion This multicenter study provided evidence that thermal ablation is an effective and safe treatment option in selected -patients with solitary T1N0M0 papillary thyroid carcinoma. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Baek and Cho in this issue.

Background Dermatofibrosarcoma protuberans (DFSP) is a superficial fibroblastic tumor characterized by high rate of local recurrence and low metastatic potential. Fibrosarcomatous transformation can rarely arise in DFSP either de novo or as recurrent, which represents a form of tumor progression and carries an increased risk of metastasis over classic DFSP. Cytogenetically, DFSP is characterized by a recurrent unbalanced chromosome translocation t (17;22)(q22;q13), leading to the formation of COL1A1-PDGFB fusion transcript that is present in more than 90% of cases. Alternative fusions involving the PDGFD with partners of COL6A3 or EMILIN2 have recently been documented in less than 2% of cases. Herein, we report a DFSP with fibrosarcomtous morphology harboring a novel TNC-PDGFD fusion. Case presentation A 54-year-old female presented with a slowly growing mass in the right thigh. Excision demonstrated a 2-cm ovoid, well-circumscribed, gray-white, mass. Microscopic examination revealed a partially encapsulated subcutaneous nodule without dermal connection. The neoplasm was composed of cellular and fairly uniform spindle cells with brisk mitoses, arranged in elongated fascicles and herringbone patterns, with focal collagenized stroma. The neoplastic cells were positive for CD34 and smooth muscle actin. Fluorescence in-situ hybridization analyses showed negative for COL1A1-PDGFB fusion as well as NTRK1/2/3 rearrangements. A subsequent RNA sequencing detected an in-frame fusion between exon 15 of TNC and exon 6 of PDGFD. This fusion was further confirmed by nested reverse transcription polymerase chain reaction amplification followed by Sanger sequencing. A diagnosis of fibrosarcomatous DFSP was rendered and the patient was in good status at a follow-up of 12 months after the operation. Conclusions We report a fibrosarcomatous DFSP with novel TNC-PDGFD fusion, which adds to the pathologic and genetic spectrum of PDGFD-rearranged DFSP.

Introduction D-CARE, an international, phase 3, randomized, double-blind, placebo-controlled study in women with early-stage breast cancer at high risk of disease recurrence, failed to meet its primary endpoint—improvement in bone metastasis-free survival (BMFS) with adjuvant denosumab vs placebo injections. As a result of the limitations of assessing BMFS, which includes relapse in bone with and without extraskeletal recurrences and deaths from any cause, the prespecified exploratory bone endpoints’ analysis may provide a more clinically meaningful effect of denosumab in this disease setting. Methods The study enrolled women (aged ≥ 18 years) with histologically confirmed stage II/III breast cancer. Patients treated with adjuvant/neoadjuvant chemotherapy meeting inclusion criteria were randomly assigned 1:1 to receive either denosumab (120 mg) or placebo subcutaneously every 3–4 weeks for about 6 months and then every 3 months for a total treatment duration of 5 years. Five prespecified exploratory bone endpoints and post hoc subgroup analysis based on age (

Dwarfism has been depicted in various Chinese art forms including literature, sculpture, and painting. This article examines several representative Chinese works of art from different ages of Chinese history, in order to glimpse the living situations of people with dwarfism, their professions and social status, as well as the social attitude toward them in China. We highlight “山海经” (Shan Hai Jing, translated as the Classic of Mountains and Seas), a remarkable collection of myths and illustrations which documented the existence of dwarf communities where the residents were capable of producing high‐quality grains. Representations from sculptures and paintings frequently captured the images of individuals with dwarfism in royal courts, which showed their remarkable performance skills and social ability. There are also works of art associating dwarfism with rituals. In addition to portraying ordinary individuals with humble social status, there was one particular individual with dwarfism named Yan Zi (晏子) who was highly regarded as a figure of wisdom. Throughout the long Chinese history, dwarfism had been portrayed in art as either positive, neutral or derogatory, which reflected the fact that people with dwarfism, while short in stature, are usually intellectually normal, generally skillful, and often talented, in short, like the general population.

We constructed a reaction-based near-infrared fluorescent probe (Niap) to specifically identify alkaline phosphatase (ALP) with fast red fluorescence enhancement. Based on the positive concentration-dependent manner between the fluorescent intensity of the Niap and ALP, probe Niap was used to study the ALP enrichment and variation in golden apple snails (Pomacea canaliculata) exposed to the molluscicide candidate PPU06. After treatment with different concentrations of PPU06 over various times, three organs of the surviving snails, liver, stomach and plantaris, were frozen and sectioned for fluorescent imaging experiments. With increased PPU06 concentration, red fluorescence substantially increased in the liver and reached a maximum within 24 h when the PPU06 concentration was 0.75 mg/L. No obvious changes in the stomach or foot plantaris were found. It showed PPU06 caused liver injury and stimulated the increase of ALP in the liver of P. canaliculata. This study demonstrates a rapid ALP fluorescent identification method that can be used to study the effects of PPU06 on P. canaliculata. It also provides optical evidence that may aid in the discovery of new chemistry for snail control.

BACKGROUND To explore the clinical efficacy, safety, and prevention of major adverse reactions of the non-steroidal anti-inflammatory drug celecoxib combined with OxyContin and Pregabalin in the treatment of cancerous pudendal neuralgia. METHODS A total of 51 patients presenting with pelvic malignancies with cancerous pudendal neuralgia were selected, and random number table method was used to allocate them to either the experimental group (n=27) or control group (n=24). The control group was treated with OxyContin combined with Pregabalin, and the experimental group was treated with Celecoxib on the basis of the control group. RESULTS At 24 hours after treatment, the clinical effective rate of the experimental group was 92.6%, which was significantly higher than the 66.7% of the control group (P

Background The optimal dose and fractionation scheme of stereotactic body radiation therapy (SBRT) for hepatocellular carcinoma (HCC) remains unclear due to different tolerated liver volumes and degrees of cirrhosis. In this study, we aimed to verify the dose-survival relationship to optimize dose selection for treatment of HCC. Methods This multicenter retrospective study included 602 patients with HCC, treated with SBRT between January 2011 and March 2017. The SBRT dosage was classified into high dose, moderate dose, and low dose levels: SaRT (BED10 ≥ 100 Gy), SbRT (EQD2 > 74 Gy to BED10 2 Results The median tumor size was 5.6 cm (interquartile range [IQR] 1.1–21.0 cm). The median follow-up time was 50.0 months (IQR 6–100 months). High radiotherapy dose correlated with better outcomes. After classifying into the SaRT, SbRT, and ScRT groups, three notably different curves were obtained for long-term post-SBRT survival and intrahepatic control. On multivariate analysis, higher radiation dose was associated with improved OS, PFS, and intrahepatic control. Conclusions If tolerated by normal tissue, we recommend SaRT (BED10 ≥ 100 Gy) as a first-line ablative dose or SbRT (EQD2 ≥ 74 Gy) as a second-line radical dose. Otherwise, ScRT (EQD2

Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

Scavenger receptor class B type I (SR-BI) protein is an integral membrane glycoprotein. SR-BI is emerging as a multifunctional protein, which regulates autophagy, efferocytosis, cell survival and inflammation. It is well known that SR-BI plays a critical role in lipoprotein metabolism by mediating cholesteryl esters selective uptake and the bi-directional flux of free cholesterol. Recently, SR-BI has also been identified as a potential marker for cancer diagnosis, prognosis, or even a treatment target. Natural products are a promising source for the discovery of new drug leads. Multiple natural products were identified to regulate SR-BI protein expression. There are still a number of challenges in modulating SR-BI expression in cancer and in using natural products for modulation of such protein expression. In this review, our purpose is to discuss the relationship between SR-BI protein and cancer, and the molecular mechanisms regulating SR-BI expression, as well as to provide an overview of natural products that regulate SR-BI expression.

Human emotion and emotional behaviors emerge at early stages in development through interactions with the environment. Yet, the neural mechanisms underlying how we learn about and learn to regulate emotions, and how they unfold over development, still remain largely elusive. Advances in the newly emerging field of developmental cognitive and affective neuroscience have moved toward a multi-disciplinary approach, by integrating non-invasive neuroimaging, developmental psychology, psychophysiology and computational modeling techniques. Such multi-disciplinary approach represents the new frontier in the fields of human cognitive and affective neuroscience, and has the potential to revolutionize our understanding of the complex neural mechanisms underlying both typical and atypical development of human emotion and related behaviors. Recent researches in cognitive neuroscience of human emotion and emotional development have made it possible to synthesize these findings. In this review, we summarized recent advances and proposed a model to explain how various risk factors affected emotional brain systems and networks across life span mainly from childhood through adolescence into adulthood, and why different affective disorders emerged in individuals at different times in their lives. Given that emotion-related mental illness such as anxiety and depression is global, pervasive and rapidly increasing in our contemporary society, we also discussed the future directions in developmental cognitive and affective neuroscience in the context of mental health and education. Altogether, understanding the neurobiological mechanisms underlying human emotion and related (mal) adaptive behaviors has the potential to remedy emotion-related maladaptation, promote mental health, and optimize education programs.

Background Critical illness is associated with cognitive, physical, and psychological impairments; however, evidence of the severity and frequency of impairments in Chinese survivors of mechanical ventilation in an intensive care unit (ICU) remains limited. Our aim was to investigate the incidence and severity of impairments in Chinese survivors of mechanical ventilation in ICU and to explore risk factors influencing specific impairments. Methods Patients discharged alive after mechanical ventilation in a large general ICU for ≥2 days were enrolled in this single-center cross-sectional study. Survivors were evaluated using measures of functional disability (Activity of Daily Living Scale), and post-traumatic stress disorder (PTSD, The Impact of Event Scale-Revised) via telephone interview. Multivariable analysis was conducted. Results Data were obtained from 130 consenting survivors. At follow-up (mean: 19.64 months), among those in part-time or full-time employment prior to admission, only 45.1% had returned to work. Further, 29.2% of survivors had clear disabilities affecting daily living. Deficits in activities of daily living (ADL) were mainly characterized by impairment of instrumental ADL. Predictors of ADL in mechanically ventilated survivors included age, ICU admission diagnosis, and Acute Physiology And Chronic Health Evaluation II (APACHE II) score, which accounted for 33.5% of total variance. Furthermore, 17.7% of participants had symptoms consistent with PTSD. ICU length of stay was the only predictor of PTSD, and accounted for 7.5% of total variance. Conclusions ICU survivors of mechanical ventilation in China face negative impacts on employment, and commonly have ADL impairment and PTSD. Age, ICU admission diagnosis, and APACHE II score were key factors influencing ADL, while ICU length of stay was the only factor affecting PTSD. These findings suggest that some survivors who have had certain exposures may warrant closer follow-up, and systematic interventions for these high-risk survivors should be developed in China.

BACKGROUND Computed tomography (CT) and magnetic resonance imaging (MRI) are both capable of predicting microvascular invasion (MVI) in hepatocellular carcinoma (HCC). However, which modality is better is unknown. PURPOSE To intraindividually compare CT and MRI for predicting MVI in solitary HCC and investigate the added value of radiomics analyses. STUDY TYPE Retrospective. SUBJECTS Included were 402 consecutive patients with HCC (training set:validation set = 300:102). FIELD STRENGTH/SEQUENCE T2-weighted, diffusion-weighted, and contrast-enhanced T1-weighted imaging MRI at 3.0T and contrast-enhanced CT. ASSESSMENT CT- and MR-based radiomics signatures (RS) were constructed using the least absolute shrinkage and selection operator regression. CT- and MR-based radiologic (R) and radiologic-radiomics (RR) models were developed by univariate and multivariate logistic regression. The performance of the RS/models was compared between two modalities. To investigate the added value of RS, the performance of the R models was compared with the RR models in HCC of all sizes and 2-5 cm in size. STATISTICAL TESTS Model performance was quantified by the area under the receiver operating characteristic curve (AUC) and compared using the Delong test. RESULTS Histopathologic MVI was identified in 161 patients (training set:validation set = 130:31). MRI-based RS/models tended to have a marginally higher AUC than CT-based RS/models (AUCs of CT vs. MRI, P: RS, 0.801 vs. 0.804, 0.96; R model, 0.809 vs. 0.832, 0.09; RR model, 0.835 vs. 0.872, 0.54). The improvement of RR models over R models in all sizes was not significant (P = 0.21 at CT and 0.09 at MRI), whereas the improvement in 2-5 cm was significant at MRI (P

Background Multiple sclerosis (MS) is a chronic illness involving the central nervous system (CNS) that is characterised by inflammation, demyelination, and degenerative changes. Dalfampridine is one of the available treatments for MS symptoms and comorbidities. This meta-analysis aimed to assess the safety and benefits of dalfampridine versus placebo in MS by summarising data deriving from previously published clinical randomised controlled studies (RCTs). Results A total of 9 RCTs were included in this meta-analysis, involving 1691 participants. There were significant differences between dalfampridine and placebo in terms of decreased 12-item Multiple Sclerosis Walking Scale score (weighted mean difference [WMD] = − 3.68, 95% confidence interval [CI] [− 5.55, − 1.80], p = 0.0001), improved response to the timed 25-foot walk test (relative risk [RR] = 2.57, 95% CI [1.04, 6.33], p = 0.04), increased 6-min walk test (WMD = 18.40, 95% CI [1.30, 35.51], p = 0.03), increased 9-Hole Peg Test score (WMD = 1.33, 95% CI [0.60, 2.05], p = 0.0004), and increased Symbol Digit Modalities Test score (WMD = 4.47, 95% CI [3.91, 5.02], p p = 0.002). Conclusion Dalfampridine exerts positive effects on walking ability, finger dexterity, and cognitive function. Treatment should be administered under the guidance of a physician or pharmacist given the higher incidence of adverse events.

Background:. Recent studies suggest that a healthy diet helps to prevent the development of Alzheimer disease (AD). This study aimed to investigate whether spicy food consumption is associated with cognition and cerebrospinal fluid (CSF) biomarkers of AD in the Chinese population. Methods:. We enrolled 55 AD patients and 55 age- and gender-matched cognitively normal (CN) subjects in a case-control study, as well as a cohort of 131 participants without subjective cognitive decline (non-AD) in a cross-sectional study. Spicy food consumption was assessed using the Food Frequency Questionnaire (FFQ). Associations of FFQ scores with cognition and CSF biomarkers of AD were analyzed. Results:. In the case-control study, spicy food consumption was lower in AD patients than that in CNs (4.0 [4.0–8.0] vs. 8.0 [4.5–10.0], P

Background Heart transplantation (HTx) of brain-dead donors in China has not been reported, not to mention analysis of donors with different brain death mechanisms. The present study aimed to compare clinical outcomes between HTx of traumatically brain-injured (TBI) and non-TBI donors, as well as to establish a risk-prediction model of mortality. Methods All patients undergoing HTx at our institute between January 1st, 2015 and December 31st, 2018 were dichotomized according to cause of donor death, and outcomes between the two groups were compared based on propensity score matching (PSM). The primary endpoint was all-cause mortality. Secondary endpoints included cardiac allograft vasculopathy and other postoperative complications. Results 342 eligible HTx recipients were included. TBI grafts accounted for 62.87% (215/342). 121 pairs of candidates were generated from PSM. Actuarial and risk-adjusted survival were similar between TBI and non-TBI groups. Risk factors associated with all-cause mortality included recipient age > 60y (HR = 2.781, p = .002), history of cardiac surgery (HR = 2.186, p = .032), chronic kidney disease (HR = 2.948, p = .033) and smoking (HR = 0.465, p = .041), as well as donor age > 45y (HR = 2.701, p = .003) and BMI > 25 kg/m2 (HR = 2.025, p = .045). The risk-prediction model was established successfully based on specific preoperative variables and high-risk group with a score>10 had nearly fourfold increase in mortality (HR = 3.726, p Conclusions In this largest single-center cohort from China, we found similar survival and rates of complications between HTx recipients with TBI and non-TBI donors. The risk-prediction model may help to identify high-risked recipients and donors and optimize organ-sharing.

Background: Lung cancer has the highest mortality rate among cancers worldwide, with non-small cell lung cancer (NSCLC) the most common type. Increasing evidence shows that PHB2 is highly expressed in other cancer types; however, the effects of PHB2 in NSCLC are currently poorly understood. Method: PHB2 expression and its clinical relevance in NSCLC tumor tissues were analyzed using a tissue microarray. The biological role of PHB2 in NSCLC was investigated in vitro and in vivo using immunohistochemistry and immunofluorescence staining, gene expression knockdown and overexpression, cell proliferation assay, flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, wound healing assay, Transwell assay, western blot analysis, qRT-PCR, coimmunoprecipitation, and mass spectrometry analysis. Results: Our major finding is that PHB2 facilitates tumorigenesis in NSCLC by interacting with and stabilizing RACK1, which further induces activation of downstream tumor-promoting effectors. PHB2 was found to be overexpressed in NSCLC tumor tissues, and its expression was correlated with clinicopathological features. Furthermore, PHB2 overexpression promoted proliferation, migration, and invasion, whereas PHB2 knockdown enhanced apoptosis in NSCLC cells. The stimulating effect of PHB2 on tumorigenesis was also verified in vivo. In addition, PHB2 interacted with RACK1 and increased its expression through posttranslational modification, which further induced activation of the Akt and FAK pathways. Conclusions: Our results reveal the effects of PHB2 on tumorigenesis and its regulation of RACK1 and RACK1-associated proteins and downstream signaling in NSCLC. We believe that the crosstalk between PHB2 and RACK1 provides us with a great opportunity to design and develop novel therapeutic strategies for NSCLC.

Our previous work demonstrated that Piwil2 reactivated by the human papillomavirus oncoproteins E6 and E7 may reprogram somatic cells into tumor-initiating cells (TICs), which contribute to cervical neoplasia lesions. Maintaining the stemness of TICs is critical for the progression of cervical lesions. Here, we determined that canonical Wnt signaling was aberrantly activated in HaCaT cells transfected with lentivirus expressing Piwil2 and in cervical lesion specimens of low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, and invasive carcinoma. Blocking the β-catenin and CREB binding protein interaction with ICG-001 significantly downregulated the reprogramming factors c-Myc, Nanog, Oct4, Sox2, and Klf4, thus leading to cell differentiation and preventing tumorigenicity in Piwil2-overexpressing HaCaT cells. Similarly, Piwil2 also critically regulated the canonical Wnt signaling pathway in cervical cancer. We further demonstrated that ICG-001 increased cisplatin sensitivity and significantly suppressed tumor growth of cervical cancer alone or in combination with cisplatin both in vitro and in vivo. The β-catenin/ CREB binding protein-mediated transcription activated by Piwil2 is essential for the maintenance of TICs, therefore contributing to the progression of cervical oncogenesis.

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a poor prognosis due to the high incidence of invasion and metastasis-related progression. However, the underlying mechanism remains elusive, and valuable biomarkers for predicting invasion, metastasis, and poor prognosis of HCC patients are still lacking. Methods: Immunohistochemistry (IHC) was performed on HCC tissues (n = 325), and the correlations between MST4 expression of the clinical HCC tissues, the clinicopathologic features, and survival were further evaluated. The effects of MST4 on HCC cell migratory and invasive properties in vitro were evaluated by Transwell and Boyden assays. The intrahepatic metastasis mouse model was established to evaluate the HCC metastasis in vivo. The PI3K inhibitor, LY294002, and a specific siRNA against Snail1 were used to investigate the roles of PI3K/AKT pathway and Snail1 in MST4-regulated EMT, migration, and invasion of HCC cells, respectively. Results: In this study, by comprehensively analyzing our clinical data, we discovered that low MST4 expression is highly associated with the advanced progression of HCC and serves as a prognostic biomarker for HCC patients of clinical-stage III-IV. Functional studies indicate that MST4 inactivation induces epithelial-to-mesenchymal transition (EMT) of HCC cells, promotes their migratory and invasive potential in vitro, and facilitates their intrahepatic metastasis in vivo, whereas MST4 overexpression exhibits the opposite phenotypes. Mechanistically, MST4 inactivation elevates the expression and nuclear translocation of Snail1, a key EMT transcription factor (EMT-TF), through the PI3K/AKT signaling pathway, thus inducing the EMT phenotype of HCC cells, and enhancing their invasive and metastatic potential. Moreover, a negative correlation between MST4 and p-AKT, Snail1, and Ki67 and a positive correlation between MST4 and E-cadherin were determined in clinical HCC samples. Conclusions: Our findings indicate that MST4 suppresses EMT, invasion, and metastasis of HCC cells by modulating the PI3K/AKT/Snail1 axis, suggesting that MST4 may be a potential prognostic biomarker for aggressive and metastatic HCC.

Point-of-care (POC) testing for Toxoplasma infection has the potential to revolutionize diagnosis and management of toxoplasmosis, especially in high-risk populations in areas with significant environmental contamination and poor health infrastructure precluding appropriate follow-up and preventing access to medical care. Toxoplasmosis is a significant public health challenge in Morocco, with a relatively heavy burden of infection and, to this point, minimal investment nationally to address this infection. Herein, we analyse the performance of a novel, low-cost rapid test using fingerstick-derived whole blood from 632 women (82 of whom were pregnant) from slums, educational centres, and from nomad groups across different geographical regions (i.e. oceanic, mountainous) of Morocco. The POC test was highly sensitive and specific from all settings. In the first group of 283 women, sera were tested by Platelia ELISA IgG and IgM along with fingerstick whole blood test. Then a matrix study with 349 women was performed in which fingerstick – POC test results and serum obtained by venipuncture contemporaneously were compared. These results show high POC test performance (Sensitivity: 96.4% [IC95 90.6–98.9%]; Specificity: 99.6% [IC95 97.3–99.9%]) and high prevalence of Toxoplasma infection among women living in rural and mountainous areas, and in urban areas with lower educational levels. The high performance of POC test confirms that it can reduce the need for venipuncture and clinical infrastructure in a low-resource setting. It can be used to efficiently perform seroprevalence determinations in large group settings across a range of demographics, and potentially expands healthcare access, thereby preventing human suffering.

Gastric cancer (GC) is a major global cancer burden, and only HER2-targeted therapies have been approved in first line clinical therapy. CLDN18.2 has been regarded as a potential therapeutic target for gastrointestinal tumors, and global clinical trials have been in process. Hence, the precise, efficient, and noninvasive detection of CLDN18.2 expression is important for the effective application of this attractive target. A high similarity of protein sequence between CLDN18.1 and -18.2 made RNA become more suitable for the detection of CLDN18.2 expression. In this study, CLDN18.2 molecular beacon (MB) with a stem-loop hairpin structure was optimized by phosphorothioate and 2'-O-methyl for stability and efficiency. The MB could recognize CLDN18.2 RNA rapidly. Its resolution and selectivity has been verified in several model cells, demonstrating that MB can distinguish CLDN18.2 expression in several model cells. Furthermore, it was applied successfully to the circulating tumor cell (CTC) assay. The concordance in the expression of CLDN18.2 between CTCs and tissue biopsy is 100% (negative: 3 vs 3; positive: 7 vs 7), indicating that CLDN18.2 RNA detection in CTCs based on a MB will be a promising approach for searching potential patients to CLDN 18.2 targeted drug.