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To retrospectively analyze and compare the relationship between the success rate of patient-derived xenograft (PDX) modeling of osteosarcoma and prognosis (3-year overall survival rate and disease-free survival rate) and incidence of lung metastasis.The sample group consisted of 57 osteosarcoma patients with definite pathological diagnoses from Shanghai General Hospital from 2015-2017. PDX models in 57 patients were analyzed by retrospective analyses. Among the patients currently inoculated, 20 were tumorigenic in the PDX model, and 37 were nontumorigenic. According to the tumorigenicity of PDXs, the corresponding osteosarcoma patients were divided into two groups. The effects of clinically related indicators on the model were retrospectively compared. The patients were followed, and the 3-year survival, 3-year disease-free survival (DFS), and lung metastasis rates were collected. The relationship between the modeling success and patient prognosis was investigated.In the chemotherapy-treated group, the PDX modeling success rate was 17.4%, and in the nonchemotherapy group, the success rate was 47.1%. The success of PDX modeling was related to whether patients received chemotherapy. The success rate of PDX modeling is significantly reduced after receiving chemotherapy. The 3-year overall survival rate of the PDX-grafted group was 49.23%, and that of the PDX-nongrafted group was 65.71%. There was a significant difference between the two groups, showing a strong negative correlation between the 3-year survival rate and the success rate of the PDX model. The 3-year disease-free survival rate of the PDX-grafted group was 29.54%. The 3-year DFS of the PDX-nongrafted group was 50.34%. There was a significant difference between the two groups. Lower grafted rates indicate a higher DFS rate. The incidence of lung metastasis in the PDX-grafted group was 32.4%, and that in the nongrafted group was 13.1%. There was a significant difference between the two groups. The successful establishment of the PDX model indicates that patients are more likely to have lung metastases.The success of PDX modeling often indicates poor prognosis (low 3-year overall survival rate and disease-free survival rate) and a greater possibility of lung metastasis. Therefore, PDX modeling in osteosarcoma patients can accurately predict the prognosis of patients and the risk of lung metastasis in advance to help us develop better therapeutic strategies.

The effectively early detection and determination of disease progression of gastric cancer (GC) are still required. An emerging demand for identifying the novel targets adherent to cancer cells has been still challenged since those valuable profilings not only could act as for early gastric tumor discovery but also being potential therapeutic views. We have retrospectively analyzed GC biopsies to identify those specific target peptides in association with disease progression. We have detected the polypeptide by liquid mass technology initiated BIO-HIGH innovational assay technology for tumor-specific target peptide identification. We have validated the accessibility and feasibility of multiple target cytotoxic T-lymphocyte for the assessment of potential molecular markers by equally comparing the frequencies of tumor peptides' loci identified in 138 GC patients. The aim was to separate peripheral blood lymphocytes by density gradient centrifugation and use specific target peptides in in vitro culture of lymphocytes. The Cell Counting Kit-8 assay was set up to prove the lymphocytes' proliferation stimulated by identified peptides. Both of GC-specific peptide and shared peptide were detected in the peripheral blood, and the frequencies and quantities were correlated with disease status and cancer differentiation, in which BHGa1510 (78%), BHGa1310 (66%), BHGa0910 (57%), BHGa0310 (54%), BHGa0210 (40%), BHGa0810 (35%), BHGa0110 (33%), and BHGa1410 (30%) were apparently scoped out as high-frequency (HF) peptides could be potentially specific tumor markers. Moreover, BHGa1410 was significantly associated with cancer progression, and BHGa0910 and BHGa0210 were significantly associated with TNM stage. The IHC data have shown that both the HF BHGa1510 and HF BHGa1310 were expressions by 100% in contrast with paracancerous tissues of 40% (p < 0.05) and 33%, respectively (p < 0.05). Those specific peptide pools could be valued in assessment of advanced tumor and differential status in GC patients.

Background Epidemiological studies have investigated the short-term effects of meteorological factors and air pollution on the incidence of hand, foot, and mouth disease (HFMD). Several meteorological indicators, such as relative humidity and the diurnal temperature range (DTR), significantly modify the relationship between short-term exposure to temperature and HFMD incidence. However, it remains unclear whether (and how) long-term air pollution levels modify the short-term relationships of HFMD incidence with meteorological factors and air pollution. Methods We obtained daily data on meteorological factors, air pollutants, and HFMD counts in children from 21 prefecture-level cities in Sichuan Province in Southwest China from 2015 to 2017. First, we constructed a distributed lag nonlinear model (DLNM) at each prefecture-level site to evaluate the short-term impacts of meteorological variables and air pollutants on HFMD incidence. Then, we assessed the pooled effects of the exposures and incorporated long-term city-specific air pollutant indicators as meta-predictors to examine their potential modification effects by performing multivariate meta-regression models. Results We found that long-term SO2 and CO concentrations significantly modified the short-term relationships between climatic variables and HFMD incidence. Specifically, high concentrations of CO (P = 0.027) and SO2 (P = 0.039) reduced the risk of HFMD at low temperatures. The relationship between relative humidity and HFMD incidence was weakened at high SO2 concentrations (P = 0.024), especially when the relative humidity was below the median level. When the minimum relative humidity (32%) was compared to the median relative humidity (77%), the risk ratio (RR) was 0.77 (95% CI: 0.51–1.17) in the 90th percentile of SO2 (19.6 μg/m3) and 0.41 (95% CI: 0.27–0.64) in the 10th percentile of SO2 (10.6 μg/m3). Conclusion Our results indicated that long-term SO2 and CO levels modified the short-term associations between HFMD incidence in children and meteorological variables. These findings may inform health authorities to optimize targeted public health policies including reducing ambient air pollution and reinforcing self-protective actions to weaken the adverse health impacts of environmental factors on HFMD incidence.

Fine particulate matter (PM

Neonatal congenital heart disease (CHD) is the most common congenital anomaly. As a practical matter of people's livelihood, cardiac ultrasonography was performed on potential CHD children in 11 cities eastern China. In this study, we aimed to document the birth prevalence of CHD and its socioeconomic and geographical distribution, as supported by this public health policy. In this study, the diagnosis of CHD was made based on echocardiography. Geographical and socioeconomic factors were determined by the Statistical Bulletin on National Economic and Social Development (SBNESD). 51857 newborns from the Network Platform for Congenital Heart Disease (NPCHD) from January to December 2019 in 11 cities eastern China were included. The total birth prevalence of CHD was 5.79 per 1000 births. The study on the low-income areas, mountainous areas, areas with low medical institution bed level, and with high qualification of medical personnel reported a signifcantly higher birth prevalence of CHD compared with high-income cities, flat areas, areas with high medical institution bed level, and with low qualification of medical personnel. ASD, VSD, PDA, PS, TOF, atrioventricular septal defect, coarctation of the aorta, TAPVD, TGA and pulmonary atresia are the most frequent subtypes. ASD, VSD, PDA, PS, atrioventricular septal defect, coarctation of the aorta and pulmonary atresia showed a female preponderance, while TOF, TGA and TAPVD showed a male preponderance. Our study gives a relatively realistic prevalence of CHD after cardiac ultrasound examination of newborns suspected positive with CHD. Significant differences across geographical regions, income levels, and health service access were observed. In the future, population-wide cardiac ultrasound screening, prospective birth defect registries, and systematic medical follow-up programs covering the entire eastern or even China are needed to determine the exact birth prevalence.

Background Poorly differentiated gastric neuroendocrine neoplasms (PDGNENs) include gastric neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma, which are highly malignant and rare tumors, and their incidence has increased over the past few decades. However, the clinicopathological features and outcomes of patients with PDGNENs have not been completely elucidated. Aim To investigate the clinicopathological characteristics and prognostic factors of patients with PDGNENs. Methods The data from seven centers in China from March 2007 to November 2019 were analyzed retrospectively. Results Among the 232 patients with PDGNENs, 191 (82.3%) were male, with an average age of 62.83 ± 9.11 years. One hundred and thirteen (49.34%) of 229 patients had a stage III disease and 86 (37.55%) had stage IV disease. Three (1.58%) of 190 patients had no clinical symptoms, while 187 (98.42%) patients presented clinical symptoms. The tumors were mainly (89.17%) solitary and located in the upper third of the stomach (cardia and fundus of stomach: 115/215, 53.49%). Most lesions were ulcers (157/232, 67.67%), with an average diameter of 4.66 ± 2.77 cm. In terms of tumor invasion, the majority of tumors invaded the serosa (116/198, 58.58%). The median survival time of the 232 patients was 13.50 mo (7, 31 mo), and the overall 1-year, 3-year, and 5-year survival rates were 49%, 19%, and 5%, respectively. According to univariate analysis, tumor number, tumor diameter, gastric invasion status, American Joint Committee on Cancer (AJCC) stage, and distant metastasis status were prognostic factors for patients with PDGNENs. Multivariate analysis showed that tumor number, tumor diameter, AJCC stage, and distant metastasis status were independent prognostic factors for patients with PDGNENs. Conclusion The overall prognosis of patients with PDGNENs is poor. The outcomes of patients with a tumor diameter > 5 cm, multiple tumors, and stage IV tumors are worse than those of other patients.

Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

This research examined the role of mothers' self-worth and self-improvement goals in their responses to children's performance in the United States (80% European American) and Hong Kong (100% Chinese). Mothers (N = 330) were induced to prioritize self-worth or self-improvement among children (Mage = 10.24 years; 48% girls) . Mothers induced to prioritize self-worth (vs. self-improvement) used more success-oriented responses in both regions (ds = 0.53 and 0.35). Mothers induced to prioritize self-improvement (vs. self-worth) used more failure-oriented responses only in the United States (d = 0.29). Mothers' success-oriented responses predicted more positive beliefs and affect in a cognitive task among children (βs = .10-.18). Taken together, the findings support the importance of parents' goals in the socialization process.

Objective A large number of studies have shown that stem cells from human exfoliated deciduous teeth (SHED) has a protective effect on brain damage, but its specific mechanism is unclear. This research focused on the effect of microRNA (miR)-26a that transmitted by SHED in intracerebral hemorrhage (ICH). Methods SHED were extracted from deciduous teeth of healthy children and miR-26a expression in SHED was altered through transfection, and then the SHED were conducted with neuron differentiated induction, expression of β3 tubulin, MAP-2 and glial fibrillary acidic protein (GFAP), number of dendritic spines and cell proliferation were detected. ICH rat models were established by stereotactic injection of collagenase VII into the left striatum and the modeled rats were injected with miR-26a mimic or inhibitor-transfected SHED suspension. Then, the brain water content, blood-brain barrier permeability, pathological changes, and injury and apoptosis in the nervous cells in brain were assessed. The expression of miR-26a and CTGF in SHED and rats’ brain tissues was evaluated and the target relation between miR-26a and CTGF was detected. Results In SHED after induction, upregulated miR-26a could increase number of dendritic spines, cell proliferation, and expression of β3 tubulin, MAP-2 and GFAP, and restrain CTGF expression. In rat models, SHED engineered to overexpress miR-26a could attenuate brain water content, Evans blue content, apoptosis, pathological injury and expression of CTGF and Bax, while promoted number of Nissl bodies and expression of Bcl-2 in the nervous cells in brain in ICH rats. Furthermore, miR-26a competitively bound to CTGF. Conclusion Our findings provided the evidence that SHED could transmit miR-26a to protect ICH rats from cerebral injury by repressing CTGF, which may contribute to ICH therapy.

Vesicular chloride/proton exchangers of the CLC family are critically involved in the function of the endosomal-lysosomal pathway. Their dysfunction leads to severe disorders including intellectual disability and epilepsy for ClC-4, Dent's disease for ClC-5, and lysosomal storage disease and osteopetrosis for ClC-7. Here, we report a de novo variant p.Glu200Ala (p.E200A; c.599A>C) of the late endosomal ClC-6, encoded by CLCN6, in a patient with West syndrome (WS), severe developmental delay, autism, movement disorder, microcephaly, facial dysmorphism, and visual impairment. Mutation of this conserved glutamate uncouples chloride transport from proton antiport by ClC-6. This affects organellar ion homeostasis and was shown to be deleterious for other CLCs. In this study, we found that upon heterologous expression, the ClC-6 E200A variant caused autophagosome accumulation and impaired the clearance of autophagosomes by blocking autophagosome-lysosome fusion. Our study provides clinical and functional support for an association between CLCN6 variants and WS. Our findings also provide novel insights into the molecular mechanisms underlying the pathogenesis of WS, suggesting an involvement of autophagic-lysosomal dysfunction.

Pathogenic infections, particularly caused by Gram-positive bacteria (G+), pose a serious threat to human health, and therefore the fast and accurate discrimination of G+ bacteria from Gram-negative bacteria (G-) and fungi is highly desirable. Organic molecules with facile synthesis, robust photostability, good biocompatibility, and high selectivity toward pathogens are urgently needed in the clinical diagnosis and therapy. To this end, herein we report the synthesis of two naphthalimide-based bioprobes named tetraphenylethylene-naphthalimide (TPE-NIM) and triphenylamine-naphthalimide (TPA-NIM) with aggregation-induced emission (AIE) characteristic. First, the staining capacity of the designed AIEgens toward six kinds of bacteria and two kinds of fungi was evaluated. Both TPE-NIM and TPA-NIM showed a high degree of binding/imaging selectivity for G+ bacteria over G- bacteria and fungi via a wash-free protocol. Second, the two AIEgens had the ability to visualize the biofilms formed by G+ bacteria (Staphylococcus aureus) and can quickly track the G+ bacteria (Staphylococcus aureus) in red blood cell suspensions. Third, we have revealed that electrostatic attraction and hydrophobic interaction both contribute to the selective binding of the AIEgens toward G+ bacteria. In view of the high binding/imaging specificity toward G+ bacteria, low hemolysis rates, and low toxicity toward the bacterial cells, these AIEgens can be applied for the clinical detection of pathogenic infections caused by G+ bacteria and broaden the theranostic applications of AIE materials.

Plasma membrane (PM), a fundamental building component of a cell, is responsible for a variety of cell functions and biological processes. However, it is still challenging to acquire its morphology and morphological variation information via an effective approach. Herein, we report a PM imaging study regarding an aggregation-induced emission luminogen (AIEgen) called tetraphenylethylene-naphthalimide+ (TPE-NIM+), which is derived from our previously reported tetraphenylethylene-naphthalimide (TPE-NIM). The designed AIEgen (TPE-NIM+) shows significant characteristics of ultrafast staining, high photostability, wash-free property, and long retention time at the PM, which can structurally be correlated with its positively charged quaternary amine and hydrophobic moiety. TPE-NIM+ is further applied for staining of different cell lines, proving its universal PM imaging capability. Most importantly, we demonstrate that TPE-NIM+ can clearly delineate the contours of densely packed living cells with high cytocompatibility. Therefore, TPE-NIM+ as a PM imaging reagent superior to currently available commercial PM dyes shall find a number of applications in the biological/biomedical fields and even beyond.

Postmenopausal osteoporosis (PMOP) is one of the most common metabolic bone diseases in postmenopausal women. Increasing evidence has indicated that microRNAs (miRNAs) play vital regulatory roles during osteoporosis progression. This study aimed to investigate the potential function of miR-23b-3p in the osteogenic differentiation of human bone marrow mesenchymal stem cells (hMSCs). PMOP was induced in mice by bilateral ovariectomy. X-ray absorptiometry was applied to detect BMD and BMC in PMOP mice. Luciferase reporter assay and RIP assay were utilized to investigate the relationship between miR-23b-3p and MRC2. We found the upregulation of miR-23b-3p in bone tissues of PMOP mice. Silencing of miR-23b-3p relieved PMOP in mice. Moreover, miR-23b-3p knockdown facilitated the osteogenic differentiation of hMSCs by increasing the expression of Runx2, OCN, Osterix and promoting ALP activity. Mechanistically, MRC2 is a downstream target gene of miR-23b-3p. MRC2 knockdown significantly rescued the promoting effect of lenti-miR-23b-3p inhibitor on osteogenic differentiation of hMSCs. Furthermore, miR-23b-3p targeted MRC2 to inhibit the Wnt/β-catenin pathway during the osteogenic differentiation of hMSCs. In summary, inhibition of miR-23b-3p alleviates PMOP by targeting MRC2 to inhibit the Wnt/β-catenin signaling, which may provide a novel molecular insight for osteoporosis therapy.

The Chengyu Metropolitan Area (CYMA), located in the Sichuan Basin, is an unevenly developed region with high PM

Aim: To explore the prognostic value of the systemic inflammatory response index (SIRI) and peripheral blood T-cell subsets in patients with hepatocellular carcinoma (HCC) and the relationship between them. Materials & methods: We treated 352 patients with HCC with sorafenib and/or immune checkpoint inhibitors (ICIs) and analyzed SIRI and peripheral blood T cells. Results: SIRI was an independent prognostic factor for patients with HCC receiving systemic therapy. Patients with high SIRI and low baseline peripheral blood T-cell counts showed a poor response to ICIs. SIRI was significantly and negatively correlated with CD3+, CD4+ and CD8+ T-cell counts. Conclusion: SIRI markers can be employed to noninvasively assess the presence of cancer-promoting inflammation in the tumor microenvironment and predict the efficacy of targeted therapy and immunotherapy.

This research examined the idea that children's inferences about their parents' goals for them is a possible mechanism by which parents' responses to their children's performance contribute to children's psychological functioning. American (N = 447; Mage = 13.24 years; 49% girls; 95% European American) and Chinese (N = 439; Mage = 13.36 years; 52% girls) early adolescents reported on parents' responses to their performance, parents' self-worth and self-improvement goals for them, and their psychological functioning (e.g., subjective well-being) twice over a year. The more parents used success-oriented responses, the more their children inferred they held self-worth goals, which predicted enhanced psychological functioning among children over time. The more parents used failure responses, the more their children inferred they held self-improvement goals, but this did not underlie the tendency for parents' failure responses to predict poorer psychological functioning over time. These pathways tended to be stronger in the United States than China. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Background Cerebral folate deficiency (CFD) is a neurological disease, hallmarked by remarkable low concentrations of 5-methyltetrahydrofolic acid (5-MTHF) in cerebrospinal fluid (CSF). The primary causes of CFD include the presence of folate receptor (FR) autoantibodies, defects of FR encoding gene FOLR1, mitochondrial diseases and congenital abnormalities in folate metabolism. Case presentation Here we first present a Chinese male CFD patient whose seizure onset at 2 years old with convulsive status epilepticus. Magnetic Resonance Imaging (MRI) revealed the development of encephalomalacia, laminar necrosis in multiple lobes of the brain and cerebellar atrophy. Whole Exome Sequencing (WES) uncovered a homozygous missense variant of c.524G > T (p.C175F) in FOLR1 gene. Further laboratory tests demonstrated the extremely low level of 5-MTHF in the CSF from this patient, which was attributed to cerebral folate transport deficiency. Following the intravenous and oral treatment of calcium folinate, the concentrations of 5-MTHF in CSF were recovered to the normal range and seizure symptoms were relieved as well. Conclusions One novel variation of FOLR1 was firstly identified from a Chinese male patient with tonic-clonic seizures, developmental delay, and ataxia. The WES and laboratory results elucidated the etiology of the symptoms. Clinical outcomes were improved by early diagnosis and proper treatment.

To characterize the role of two long non-coding RNAs (lncRNAs), LINC01133 and LINC01243, in endometrial carcinoma (EC) pathogenesis. LINC01133 is an lncRNA that has been implicated in many cancers, and LINC01243 is a newly identified lncRNA identified from the NCBI GEO database. We studied the effect of LINC01133 and LINC01243 on EC malignancy using siRNA knockdown and real-time quantitative polymerase chain reaction (RT-qPCR), flow cytometry, Annexin V-FITC/propidium iodide double staining, Transwell, and scratch invasion assays in two EC cell lines (Ishikawa and HEC-1-A cells). We first confirmed the partial knockdown of both LINC01133 and LINC01243 expression in Ishikawa and HEC-1-A cells using RT-qPCR. Following confirmation of lncRNA knockdown, we assessed the effect of knockdown on EC malignancy. We observed reduced EC cell proliferation using the CCK-8 assay, as well as cell cycle arrest and increased apoptosis in both EC cell lines. Furthermore, Transwell and scratch invasion assays revealed decreased migration and invasion of the two EC cell lines, respectively. We demonstrated that LINC01133 and LINC01243 expression are associated with EC development and progression. Our findings suggest a potential role for these lncRNAs as novel EC biomarkers.

To elucidate the processes underlying the cultural construction of adolescence, this research examined youth's stereotypes about teens in Hong Kong and Chongqing, a relatively less developed city in Mainland China. Youth (N = 1,269) reported on their teen stereotypes and problem behavior in the fall and spring of 7th grade. Youth in Hong Kong (vs. Chongqing) saw adolescence as a time of dampened family obligation as well as heightened individuation from parents, disengagement from school, and orientation toward peers. The tendency for youth in Hong Kong (vs. Chongqing) to see teens as less obligated to their family and more disengaged from school undergirded their greater problem behavior over the 7th grade, with problem behavior appearing to contribute to the maintenance of the two stereotypes. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Angiogenesis is critical for re‐establishing the blood supply to the surviving myocardium after myocardial infarction (MI). Long non‐coding RNA ANRIL (lncRNA‐ANRIL) has been reported to regulate endothelial functions in cardiovascular diseases. This study was to determine the role of lncRNA‐ANRIL in Akt regulation and cardiac functions after MI. Human umbilical vein endothelial cells (HUVECs) were exposed to oxygen‐glucose deprivation (OGD) to mimic in vivo ischaemia. The MI model in mice was induced by ligating left anterior descending coronary artery. OGD remarkably decreased lncRNA‐ANRIL expression level, reduced the phosphorylated levels of Akt and eNOS proteins, and inhibited NO release and cell viability, which were duplicated by shRNA‐mediated gene knockdown of lncRNA‐ANRIL. Conversely, all these effects induced by OGD were abolished by adenovirus‐mediated overexpression of lncRNA‐ANRIL in HUVECs. Further, OGD impaired cell migrations and tube formations in HUVECs, which were reversed by lncRNA‐ANRIL overexpression or Akt up‐regulation. RNA immunoprecipitation analysis indicated that the affinity of lncRNA‐ANRIL to Akt protein was increased in OGD‐treated cells. In animal studies, adenovirus‐mediated lncRNA‐ANRIL overexpression increased the phosphorylated levels of Akt and eNOS, promoted post‐ischaemic angiogenesis and improved heart functions in mice with MI surgery. LncRNA‐ANRIL regulates Akt phosphorylation to improve endothelial functions, which promotes angiogenesis and improves cardiac functions in mice following MI. In this perspective, targeting lncRNA‐ANRIL/Akt may be considered to develop a drug to treat angiogenesis‐related diseases.

Background Pulmonary fibrosis (PF) is a chronic and progressive interstitial lung disease. Buyang Huanwu Tang (BYHWT), a classical traditional Chinese medicine formula, has been widely utilized for the treatment of PF in China. This present study aimed to explore the mechanism of BYHWT in the treatment of PF in vitro. Methods TGF-β1 stimulated human alveolar epithelial A549 cells were used as in vitro model for PF. Post the treatment of BYHWT, cell viability was measured by MTT assay, and cell morphology was observed under microscope. The epithelial-to-mesenchymal transition (EMT) markers (E-cadherin, Vimentin) and collagen I (Col I) were detected by western blot, immunofluorescence staining and real-time quantitative polymerase chain reaction. With the co-administration of activators (IGF-1, SC79) and inhibitors (LY294002, MK2206), the effect of BYHWT on PI3K/Akt pathway was analyzed by western blot. Results BYHWT inhibited cell growth, and prevented cell morphology changed from epithelial to fibroblasts in TGF-β1 induced A549 cells. BYHWT decreased Vimentin and Col I, while increased E-cadherin at both protein and mRNA levels. Moreover, phosphorylation of PI3K (p-PI3K) and phosphorylation of Akt (p-Akt) were significantly down-regulated by BYHWT in TGF-β1 stimulated A549 cells. Conclusion These results indicate that BYHWT suppressed TGF-β1-induced collagen accumulation and EMT of A549 cells by inhibiting the PI3K/Akt signaling pathway. These findings suggest that BYHWT may have potential for the treatment of PF.

Heterozygous variants of KCNQ2 can cause KCNQ2 associated neurodevelopmental disorder, mainly are benign (familial) neonatal or infantile epilepsy (B(F)NE or B(F)IE) and developmental epileptic encephalopathy(DEE). Moreover, some intermediate phenotypes, including intellectual disability (ID), and myokymia are related to the gene.We collected a non-syndromic ID male patient with a novel KCNQ2 missense variant. Whole cell electrophysiology, western blotting, and immunofluorescence were adopted to analyze the variant's functional alterations.The patient presented with global developmental delay since his infancy. He still had profound ID but did not have epilepsy at the adolescence. The de novo KCNQ2 variant p.R75C (NM_172107) in the NH2 domain identified here showed a slightly hyperpolarized shift of activation curves and larger current density in homomeric configurations, which could be abolished in co-expression with Kv7.2 or Kv7.3 wild-type. Western blotting and immunocytochemistry supported that the expression of variant p.R75C is lower than the Kv7.2 wild-type. The findings indicated variant p.R75C causes mild gain-of-function (GOF) of Kv7.2 channel.We report a non-syndromic ID patient with a KCNQ2 mild GOF variant, adding evidence for this rare clinical phenotype in the disorder. We propose that individuals with KCNQ2 GOF variants are prone to have cognitive impairments.

FASTKD2 encodes an RNA-binding protein, which is a key post-transcriptional regulator of mitochondrial gene expression. Mutations in FASTKD2 have recently been found in mitochondrial encephalomyopathy, which is characterized by a deficiency in mitochondrial function. To date, seven patients have been reported. Six patients were identified with nonsense or frameshift mutations in the FASTKD2 gene, and only one patient harbored a missense mutation and a nonsense mutation. Here, we identified a novel FASTKD2 homozygous mutation, c.911 T C, in a patient diagnosed with Lennox-Gastaut syndrome. We observed that the expression of FASTKD2 and the levels of mitochondrial 16 S rRNA were lower in the patient than in the unaffected controls. In conclusion, the missense mutation c.911 T C caused loss of function in FASTKD2, which was associated with a new phenotype, Lennox-Gastaut syndrome.

Most spatial models include a spatial weights matrix (W) derived from the first law of geography to adjust the spatial dependence to fulfill the independence assumption. In various fields such as epidemiological and environmental studies, the spatial dependence often shows clustering (or geographic discontinuity) due to natural or social factors. In such cases, adjustment using the first-law-of-geography-based W might be inappropriate and leads to inaccuracy estimations and loss of statistical power. In this work, we propose a series of data-driven Ws (DDWs) built following the spatial pattern identified by the scan statistic, which can be easily carried out using existing tools such as SaTScan software. The DDWs take both the clustering (or discontinuous) and the intuitive first-law-of-geographic-based spatial dependence into consideration. Aiming at two common purposes in epidemiology studies (ie, estimating the effect value of explanatory variable X and estimating the risk of each spatial unit in disease mapping), the common spatial autoregressive models and the Leroux-prior-based conditional autoregressive (CAR) models were selected to evaluate performance of DDWs, respectively. Both simulation and case studies show that our DDWs achieve considerably better performance than the classic W in datasets with clustering (or discontinuous) spatial dependence. Furthermore, the latest published density-based spatial clustering models, aiming at dealing with such clustering (or discontinuity) spatial dependence in disease mapping, were also compared as references. The DDWs, incorporated into the CAR models, still show considerable advantage, especially in the datasets for common diseases.

Ferroptosis is caused by lipid peroxidation and iron accumulation and can cause cell death. Abnormally expressed iron transporters are involved in ferroptosis in a variety of diseases. ZRT/IRT-like protein 14 (ZIP14) is a transport protein that can mediate cellular uptake of iron, zinc, and manganese. Herein, we have tested the hypothesis that the divalent metal transporter ZIP14 is involved in the initiation of ferroptosis in diabetic nephropathy (DN). DN was induced in 8-week-old male rats by streptozotocin before analysis of the degree of renal tubular injury. In addition, an in vitro model of DN in human kidney proximal tubular cell line was used. We showed that ZIP14 was up-regulated and ferrous iron (Fe2+) levels increased both in vivo and in vitro. Expression of glutathione peroxidase 4 and the level of glutathione were reduced, whereas that of malondialdehyde (MDA) increased. Ferrostatin-1 (Fer-1) treatment reduced the expression of ZIP14 and the levels of Fe2+ and MDA, which is consistent with ferroptosis. Fer-1 improved kidney function in DN rats. This was characterized by urine levels of protein-to-creatinine ratio, α1-microglobulin, and N-acetyl-β-D-glucosaminidase. Our study demonstrates a novel role for ZIP14 in diabetic kidney injury mediated by ferroptosis, and suggests a potential new therapeutic approach for the treatment of diabetic nephropathy.

Mutations in γ-aminobutyric acid (GABA) transporter 1 (GAT-1)-encoding SLC6A1 have been associated with myoclonic atonic epilepsy and other phenotypes. We determined the patho-mechanisms of the mutant GAT-1, in order to identify treatment targets.We conducted whole-exome sequencing of patients with myoclonic atonic epilepsy (MAE) and characterized the seizure phenotypes and EEG patterns. We studied the protein stability and structural changes with homology modeling and machine learning tools. We characterized the function and trafficking of the mutant GAT-1 withWe identified four novel SLC6A1 variants associated with MAE and 2 to 4 Hz spike-wave discharges as a common EEG feature. Machine learning tools predicted that the variant proteins are destabilized. The variant protein had reduced expression and reduced GABA uptake due to endoplasmic reticular retention. The consistent observation was made in cortical and thalamic astrocytes from variant-knockin mice and human iPSC-derived astrocytes. The Slc6aSLC6A1 variants in various locations of the protein peptides can cause MAE with similar seizure phenotypes and EEG features. Reduced GABA uptake is due to decreased functional GAT-1, which, in thalamic astrocytes, could result in increased extracellular GABA accumulation and enhanced tonic inhibition, leading to seizures and abnormal EEGs.

The purpose of this qualitative study was to describe the health-promoting behaviours of patients with hyperuricaemia and influencing factors.A descriptive qualitative design was used to gain insight into the personal experience of health promotion behaviour in patients with hyperuricaemia.Sixteen patients were sampled in face-to-face interviews with maximum variation, and the data were transcribed verbatim. The data analysis was based on the phrases of thematic analysis outlined by Braun and Clarke (2006).Four main themes were identified in the data: (a) Perception of disease; (b) Motivation to change health-promoting behaviour; (c) Strategies for health-promoting behaviour; and (d) Encounter obstacles to change health-promoting behaviour.

Osteosarcoma (OS) is a primary malignant bone tumor that most commonly affects children, adolescents, and young adults. Here, we comprehensively analyze genomic, epigenomic and transcriptomic data from 121 OS patients. Somatic mutations are diverse within the cohort, and only TP53 is significantly mutated. Through unsupervised integrative clustering of the multi-omics data, we classify OS into four subtypes with distinct molecular features and clinical prognosis: (1) Immune activated (S-IA), (2) Immune suppressed (S-IS), (3) Homologous recombination deficiency dominant (S-HRD), and (4) MYC driven (S-MD). MYC amplification with HR proficiency tumors is identified with a high oxidative phosphorylation signature resulting in resistance to neoadjuvant chemotherapy. Potential therapeutic targets are identified for each subtype, including platinum-based chemotherapy, immune checkpoint inhibitors, anti-VEGFR, anti-MYC and PARPi-based synthetic lethal strategies. Our comprehensive integrated characterization provides a valuable resource that deepens our understanding of the disease, and may guide future clinical strategies for the precision treatment of OS.

Background Hand, foot, and mouth disease (HFMD) is a serious threat among children in China. Some studies have found that air pollution is associated with HFMD incidence, but the results showed heterogeneity. In this study, we aimed to explore the heterogeneity of associations between air pollutants and the number of HFMD cases and to identify significant socioeconomic effect modifiers. Methods We collected daily surveillance data on HFMD cases in those aged less than 15 years, air pollution variables and meteorological variables from 2015 to 2017 in the basin area of Sichuan Province. We also collected socioeconomic indicator data. We conducted a two-stage multicity time-series analysis. In the first stage, we constructed a distributed lag nonlinear model (DLNM) to obtain cumulative exposure-response curves between each air pollutant and the numbers of HFMD cases for every city. In the second stage, we carried out a multivariable meta-regression to merge the estimations in the first stage and to identify significant socioeconomic effect modifiers. Results We found that PM10, NO2 and O3 concentrations were associated with the number of HFMD cases. An inverted V-shaped association between PM10 and the number of HFMD cases was observed. The overall NO2-HFMD association was a hockey-stick shape. For the relationships of PM10, SO2, NO2, O3 and CO with HFMD counts, approximately 58.5%, 48.4%, 51.0%, 55.6% and 52.5% of the heterogeneity could be explained, respectively. The proportion of primary school students, population density, urbanization rate, number of licensed physicians and number of hospital beds explained part of the heterogeneity and modified the relationships. Conclusion Our study explored the heterogeneity of associations between air pollutants and HFMD counts. The proportion of primary school students, population density, urbanization rate, number of licensed physicians and number of hospital beds could modify the relationships. The results can serve as a reference for relevant public health decision making.

ObjectivesHand, foot, and mouth disease (HFMD) is a viral infectious disease that poses a substantial threat in the Asia-Pacific region. It is widely reported that meteorological factors are associated with HFMD. However, the relationships between air pollutants and HFMD are still controversial. In addition, the interactive effects between meteorological factors and air pollutants on HFMD remain unknown. To fill this research gap, we conducted a time-series study.DesignA time-series study.Setting and participantsDaily cases of HFMD as well as meteorological and air pollution data were collected in Chengdu from 2011 to 2017. A total of 184 610 HFMD cases under the age of 15 were included in our study.Outcome measuresDistributed lag nonlinear models were used to investigate the relationships between HFMD and environmental factors, including mean temperature, relative humidity, SO2, NO2, and PM10. Then, the relative excess risk due to interaction (RERI) and the proportion attributable to interaction were calculated to quantitatively evaluate the interactions between meteorological factors and air pollutants on HFMD. Bivariate response surface models were used to visually display the interactive effects.ResultsThe cumulative exposure–response curves of SO2and NO2were inverted ‘V’-shaped and ‘M’-shaped, respectively, and the risk of HFMD gradually decreased with increasing PM10concentrations. We found that there were synergistic interactions between mean temperature and SO2, relative humidity and SO2, as well as relative humidity and PM10on HFMD, with individualRERIs of 0.334 (95% CI 0.119 to 0.548), 0.428 (95% CI 0.214 to 0.642) and 0.501 (95% CI 0.262 to 0.741), respectively, indicating that the effects of SO2and PM10on HFMD were stronger under high temperature (>17.3°C) or high humidity (>80.0%) conditions.ConclusionsThere were interactive effects between meteorological factors and air pollutants on HFMD. Our findings could provide guidance for targeted and timely preventive and control measures for HFMD.

Studies have shown that human umbilical cord mesenchymal stem cells (hUCMSCs) could ameliorate liver fibrosis (LF) through inhibiting the activation of hepatic stellate cells (HSCs). However, the specific mechanisms have not been studied clearly. The purpose of this study was to explore the possible mechanism of hepatocyte growth factor (HGF)-transfected hUCMSCs in inhibiting the proliferation and activation of HSCs-T6. The upper and lower double-cell coculture system was established among HGF-hUCMSCs, LV5-NC-hUCMSCs, hUCMSCs, and HSCs-T6 in experimental groups; HSCs-T6 were cultured alone as control group. After coculturing for 1, 2, and 3 days, results showed that HGF-transfected hUCMSCs could decrease cell viability of HSCs-T6 and promote apoptosis; inhibit their activation and reduce the expression of Collagen I, Collagen III, TGF-β1, Smad2 and Smad3, which may be related to inhibiting the activation of TGF-β1/Smads signaling pathway. These findings suggested that HGF-transfected hUCMSCs may be used as an alternative and novel therapeutic approach for the treatment of LF.

Background Autism spectrum disorder (ASD), a neurodevelopmental disorder, is featured by impaired social communication and restricted and repetitive behaviors and interests. ASD and comorbid neurodevelopmental disorders (ASD-NDDs), especially epilepsy and intellectual disability (ID)/global developmental delay (GDD) are frequently presented in genetic disorders. The aim of this study was to explore the clinical and genetic profile of ASD in combination with epilepsy or ID/GDD. Methods We retrospectively analyzed the clinical characteristics, and genetic spectrum of pediatric patients presenting ASD-NDDs with proven genetic etiology. The pathogenicity of variants was conducted by molecular geneticists and clinicians complied with the guidelines of the American College of Medical Genetics and Genomics (ACMG). Results Among 154 patients with ASD-NDDs, 79 (51.3%) patients gained a genetic diagnosis. Most patients (78/79, 98.7%) had comorbid ID or GDD, and 49 (49/79, 62.0%) had comorbid epilepsy. The clinical characteristics of those 79 patients were varied. 87 genetic variants were found among the 79 pedigrees. Most of the involved genes have roles in gene expression regulation (GER) and neuronal communication (NC). Most genes have been proven to be ASD-related genes, and some of them were not reported to contribute to ASD previously. Conclusion We summarized the genetic and clinical profile of 79 ASD-NDDs patients with proven genetic etiology. The genetic spectrum of ASD was expanded, and we highlighted a novel possible ASD candidate gene PRTG.

Background Physical activity is related to many positive health outcomes, yet activity levels of many children are low. Researchers have suggested that family-based interventions may improve physical activity behaviors of both children and their parents. In this study, we evaluated the “Active 1 + FUN” program, which was designed based on tenets of self-determination theory. Intervention components included free sporting equipment, ten coach-led workshops and activity sessions, and one booster session. Methods We evaluated the intervention program using a randomized controlled trial. One hundred seventy-one families were randomly allocated to either an experimental group or a wait-list control group. Participants were exposed to program contents over a nine-month period, while families in the control did not receive any form of intervention. Measured constructs included moderate-to-vigorous physical activity, co-physical activity behaviors, fundamental movement skills, BMI, and several self-reported questionnaire outcomes. Hierarchical linear modeling was used to compare changes in measured outcomes across the two groups. Results No significant intervention effects were found for children’s and parents’ accelerometer-measured moderate-to-vigorous physical activity, or their co-physical activity. However, in terms of children’s fundamental movement skills, a significant Time*Group interaction (B = 0.52, 95% CI [0.07, 0.96] for Times 1 to 2; B = 0.24, 95% CI [0.01, 0.48] for Times 1 to 3) in favor of the experimental group was found. Conclusions Results suggested that the “Active 1 + FUN” program was effective in improving children’s fundamental movement skills. Additional research is needed to examine how family-based initiatives could effectively improve physical activity behaviors too. Trial registration ANZCTR, ACTRN12618001524280. Registered 11 September 2018, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375660.

Purpose The ongoing coronavirus disease 2019 (COVID-19) epidemic increasingly threatens the public health security worldwide. We aimed to identify high-risk areas of COVID-19 and understand how socioeconomic factors are associated with the spatial distribution of COVID-19 in China, which may help other countries control the epidemic. Methods We analyzed the data of COVID-19 cases from 30 provinces in mainland China (outside of Hubei) from 16 January 2020 to 31 March 2020, considering the data of demographic, economic, health, and transportation factors. Global autocorrelation analysis and Bayesian spatial models were used to present the spatial pattern of COVID-19 and explore the relationship between COVID-19 risk and various factors. Results Global Moran’s I statistics of COVID-19 incidences was 0.31 (P Conclusion Our results suggested that COVID-19 risk was positively associated with the level of economic development and population movements. Blocking population movement and reducing local exposures are effective in preventing the local transmission of COVID-19.

Myeloid differentiation factor 88 (MyD88) is a universal and essential adaptor protein required for the Toll-like receptors (TLRs) pathway activation in invertebrates as well as in vertebrates. Herein, we characterized a MyD88 (Pt-MyD88) cDNA sequence in the swimming crab (Portunus trituberculatus). The Pt-MyD88 ORF is predicted to encode 469 peptides with an N-terminal death domain and a typical C-terminal TIR domain. Real-Time quantitative PCR analysis showed that the Pt-MyD88 transcriptions were constitutively expressed in hemocytes, gill, intestine, heart and muscle in normal crab. The expressions of Pt-MyD88 would be down-regulated by V. alginolyticus or LPS challenge, and be up-regulated by WSSV infection in hemocytes. Intracellular localization showed Pt-MyD88 was distributed mainly in the cytoplasm when it was over-expressed in human cell HEK293T or in Drosophila Schneider 2 (S2). Functionally, over-expression of Pt-MyD88 could either activate the NF-κB in HEK293T cells or activate the promoters of Drosophila antimicrobial peptide genes (AMPs) in S2 cell. In primary cultured hemocytes of swimming crab, after Pt-MyD88 was knocked-down by specific long double strand RNA, the expression of anti-lipopolysaccharide factor1 (ALF1), hyastatin3, crustin1 and crustin3 have been significantly inhibited, while the expression of other AMPs is normal compared to non-specific dsRNA treated cells.

This research examined a cultural socialization model in which differences in Chinese and American parents' goals for children foster differences in children's emotional distress via parents' responses to children's performance. Chinese and American mothers and their children (N = 397; Mage = 13.19 years) participated in a 2-wave study spanning a year. Mothers reported on their self-improvement (i.e., children striving to improve) and self-worth (i.e., children feeling worthy) goals, as well as responses to children's performance. Children reported on their emotional distress (e.g., anxiety and depression). Chinese (vs. American) mothers' greater endorsement of self-improvement goals predicted their more frequent use of failure-oriented responses (e.g., highlighting children's mistakes), which accounted for Chinese (vs. American) children's heightened emotional distress over time. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Rho-associated protein kinases (ROCKs) are ubiquitously expressed in most adult tissues, and are involved in modulating the cytoskeleton, protein synthesis and degradation pathways, synaptic function, and autophagy to list a few. A few ROCK inhibitors, such as fasudil and netarsudil, are approved for clinical use. Here we present a new ROCK inhibitor, boronic acid containing HSD1590, which is more potent than netarsudil at binding to or inhibiting ROCK enzymatic activities. This compound exhibits single digit nanomolar binding to ROCK (Kds 2 nM) and subnanomolar enzymatic inhibition profile (ROCK2 IC50 is 0.5 nM for HSD1590. Netarsudil, an FDA-approved drug, inhibited ROCK2 with IC50 = 11 nM under similar conditions). Whereas netarsudil was cytotoxic to breast cancer cell line, MDA-MB-231 (greater than 80% growth inhibition at concentrations greater than 5 μM), HSD1590 displayed low cytotoxicity to MDA-MB-231. Interestingly, at 1 μM HSD1590 inhibited the migration of MDA-MB-231 whereas netarsudil did not.

Objective PhytoSERM is a selective estrogen receptor beta (ERβ) modulator comprised of three phytoestrogens: genistein, daidzein, and S-equol. The PhytoSERM formulation promotes estrogenic action in the brain while largely inactive or inhibitory in reproductive tissue. A phase Ib/IIa clinical trial (ClinicalTrial.gov ID: NCT01723917) of PhytoSERM demonstrated safety and pharmacokinetics profile of PhytoSERM. While this study was not powered for efficacy analysis, we conducted a pilot, retrospective analysis to identify potential responders to PhytoSERM treatment, and to determine the optimal populations to pursue in a phase II clinical trial of efficacy of the PhytoSERM formulation. Methods In this retrospective analysis involving 46 participants (n = 16, placebo; n = 18, 50 mg/d PhytoSERM; and n = 12, 100 mg/d PhytoSERM), the therapeutic effect of PhytoSERM was stratified by 2 genetic risk modulators for Alzheimer's disease: mitochondrial haplogroup and APOE genotype. Results Our retrospective responder analysis indicated that participants on 50 mg of daily PhytoSERM (PS50) for 12 weeks significantly reduced hot flash frequency compared with their baseline (mean [95% CI])-1.61, [-2.79, -0.42], P = 0.007). Participants on 50 mg of PhytoSERM also had significantly greater reduction in hot flash frequency at 12 weeks compared with the placebo group (-1.38, -0.17 [median PS50, median placebo], P = 0.04). Fifty milligrams of daily PhytoSERM also preserved cognitive function in certain aspects of verbal learning and executive function. Our analysis further suggests that mitochondrial haplogroup and APOE genotype can modify PhytoSERM response. Conclusion Our data support a precision medicine approach for further development of PhytoSERM as a safe and effective alternative to hormone therapy for menopause-associated hot flash and cognitive decline. While definitive determination of PhytoSERM efficacy is limited by the small sample size, these data provide a reasonable rationale to extend analyses to a larger study set powered to address statistical significance.

Supplemental Digital Content is available in the text, Background: Advanced technology has become a valuable tool in etiological studies of intellectual disability/global developmental delay (ID/GDD). The present study investigated the role of genetic analysis to confirm the etiology in ID/GDD patients where the cause of the disease was uncertain in central China. Methods: We evaluated 1051 ID/GDD children aged 6 months to 18 years from March 2009 to April 2017. Data concerning basic clinical manifestations were collected, and the method of etiology confirmation was recorded. Genome-wide copy number variations (CNVs) detection and high-throughput sequencing of exons in the targeted regions was performed to identify genetically-based etiologies. We compared the incidence of different methods used to confirm ID/GDD etiology among groups with differing degrees of ID/GDD using the Chi-square or Fisher exact probability test. Results: We recruited 1051 children with mild (367, 34.9%), moderate (301, 28.6%), severe (310, 29.5%), and profoundly severe (73, 6.9%) ID/GDD. The main causes of ID/GDD in the children assessed were perinatal factors, such as acquired brain injury, as well as single gene imbalance and chromosomal gene mutation. We identified karyotype and/or CNVs variation in 46/96 (47.9%) of cases in severe ID/GDD patients, which was significantly higher than those with mild and moderate ID/GDD of 34/96 (35.4%) and 15/96 (15.6%), respectively. A total of 331/536 (61.8%) patients with clear etiology have undergone genetic analysis while 262/515 (50.9%) patients with unclear etiology have undergone genetic analysis (χ2 = 12.645, P

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the authors and the Editor-in-Chief as the validity of the data cannot be guaranteed. The journal was initially contacted by the corresponding author to report that, when the authors verified post publication PTEN as their former target of miR-140-3p, they found that treatment with miR-140-3p or miR-155-5p antagomir increased PTEN protein levels in patient-derived chordoma cells without having a significant effect on the malignancy of the tumor cells. The journal further requested the author to provide more information about their post publication findings with regard to this article. However, the author was not able to fulfil this request.

Aim: To compare the performance of first-line paclitaxel liposome + oxaliplatin and SOX (tegafur/gimeracil/oteracil + oxaliplatin) in advanced gastric cancer patients. Materials & methods: Stage IIb–IV gastric cancer patients underwent either first-line paclitaxel liposome + oxaliplatin (n = 52) or SOX (n = 69) between 2010–2013, and followed up until 2015 or death. Results: Both groups had similar objective response rate (p = 0.48) and disease control rate (p = 0.992) after two chemotherapy cycles, median progression-free survival (p = 0.495) and median overall survival (p = 0.208). Liposome group had significantly lower rate of grade I–II platelet decline and liver function damage (p = 0.04 and 0.019). Multivariate COX regression identified pre-treatment neutrophil-to-lymphocyte ratio as an independent prognostic factor. Conclusion: First-line paclitaxel liposome + oxaliplatin has comparable efficacy, but causes reduced adverse reactions in advanced gastric cancer as compared with SOX.

Osteosarcoma is the most common primary malignant bone tumor. Raddeanin A (RA) is an active oleanane-type triterpenoid saponin extracted from the traditional Chinese herb Anemone raddeana Regel that exerts antitumor activity against several cancer types. However, the effect of RA on osteosarcoma remains unclear. In the present study, we showed that RA inhibited proliferation and induced apoptosis of osteosarcoma cells in a dose- and time-dependent way in vitro and in vivo. RA treatment resulted in excessive reactive oxygen species (ROS) generation and JNK and ERK1/2 activation. Apoptosis induction was evaluated by the activation of caspase-3, caspase-8, and caspase-9 and poly-ADP ribose polymerase (PARP) cleavage. RA-induced cell death was significantly restored by the ROS scavenger glutathione (GSH), the pharmacological inhibitor of JNK SP600125, or specific JNK knockdown by shRNA. Additionally, signal transducer and activator of transcription 3 (STAT3) activation was suppressed by RA in human osteosarcoma, and this suppression was restored by GSH, SP600125, and JNK-shRNA. Further investigation showed that STAT3 phosphorylation was increased after JNK knockdown. In a tibial xenograft tumor model, RA induced osteosarcoma apoptosis and notably inhibited tumor growth. Taken together, our results show that RA suppresses proliferation and induces apoptosis by modulating the JNK/c-Jun and STAT3 signaling pathways in human osteosarcoma. Therefore, RA may be a promising candidate antitumor drug for osteosarcoma intervention.

Hand, foot, and mouth disease (HFMD) is a common childhood infection that causes a substantial disease burden in the Asia-Pacific region. Various climate variables, such as humidity and temperature, have been associated with HFMD. However, few studies have assessed the impact of PM10 on childhood HFMD. This study investigated the association between PM10 and HFMD. We fitted a standard distributed lag non-linear model to investigate the temporal lagged relationship between PM10 and HFMD, and then further assessed whether this relationship varied by gender and pathogen. Between 2011 and 2015, a total of 122,564 HFMD cases under 15 years of age were reported in Chengdu. The PM10-HFMD associations were shown to be non-linear in all subgroups, with the peak at 101–218 μg/m3. Male children were more sensitive to PM10 effects. For pathogen-specific relative risks, we found that the risk estimates were generally higher in cases of CVA16 infection. Our study provides evidence that PM10 increases the risk of HFMD. Authorities and parents should be fully aware of the impact of PM10 on childhood HFMD. Furthermore, appropriate protective measures should be taken to reduce risks.

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents, with highly aggressive behavior and early systemic metastasis. The survival rates for osteosarcoma remain unchanged over the past two decades. Studies aiming to find new or alternative therapies for patients with refractory osteosarcoma are urgently needed. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor (TKI), has exhibited encouraging clinical activity in NSLCC and soft tissue sarcoma, whereas its effect on osteosarcoma has not been studied. In our study, we investigated the anti-tumor activity and underlying mechanism of anlotinib in osteosarcoma. Various in vitro and in vivo models of human osteosarcoma were used to determine the anti-proliferative, anti-angiogenesis and anti-metastasis efficacy of anlotinib. Our results showed that anlotinib suppressed tumor growth and increased the chemo-sensitivity of osteosarcoma. In addition, anlotinib inhibited migration and invasion in osteosarcoma cells. Furthermore, in order to explore the anti-tumor mechanism of anlotinib, phospho-RTK antibody arrays were performed. These analyses confirmed that anlotinib suppressed the phosphorylation of MET, VEGFR2 and the downstream signaling pathway activation. Moreover, we demonstrated that anlotinib blocked hepatocyte growth factor (HGF)-induced cell migration, invasion and VEGF-induced angiogenesis. Notably, a 143B-Luc orthotopic osteosarcoma model further showed that anlotinib significantly inhibited growth and lung metastasis of implanted tumor cells. Our preclinical work indicates that anlotinib acts as a novel inhibitor of VEGFR2 and MET that blocks tumorigenesis in osteosarcoma, which could be translated into future clinical trials.

Osteosarcoma (OS) is the most common primary bone malignancy in adolescents. One major obstacle for current OS treatment is drug-resistance. Raddeanin A (RA), an oleanane-type triterpenoid saponin, exerts anti-tumor effects in several tumor models, but the effect of RA in human drug-resistant OS remained to be elucidated. In the present study, we investigated the anti-tumor effects of RA in both drug-sensitive and drug-resistant OS cells and its underlying mechanism. RA inhibited cell proliferation and colony formation and induced apoptotic cell death in a dose-dependent manner in both drug-sensitive and drug-resistant cells. Moreover, RA exposure resulted in the inhibition of interleukin-6 (IL-6)-induced JAK2/STAT3 signaling pathway activation and target gene expression in both drug-sensitive and drug-resistant cells. Meanwhile, we observed significantly increased MDR1 and STAT3 expression in drug-resistant OS cells compared with parental cells. STAT3 overexpression promoted chemo-resistance and MDR1 protein expression in both drug-sensitive OS cells and drug-resistant OS cells, while inhibiting STAT3 with siRNA sensitized OS cells to doxorubicin treatment. In addition, RA synergistically increased doxorubicin toxicity by increasing its cellular uptake, ablating efflux and downregulating MDR1 in drug-resistant cells with attenuation of STAT3 Phosphorylation. Finally, RA suppressed in vivo tumor growth and induced apoptosis in nude mouse using drug-resistant OS tibia orthotopic model. Taken together, RA is a promising potential therapeutic for the treatment of doxorubicin resistance in OS.

Signal transducer and activator of transcription 3 (STAT3) plays essential roles in cancer progression and has been considered as a promising target for cancer therapy. Here, we used a dual luciferase assay to identify that pectolinarigenin inhibited STAT3 transcriptional activity. Further, results showed pectolinarigenin inhibited constitutive and IL6 induced STAT3 signaling, diminished the accumulation of STAT3 in the nucleus, dimerization and blocked STAT3 DNA binding activity. Mechanism investigations indicated that pectolinarigenin disturbed the STAT3/DNMT1/HDAC1 complex formation in the promoter region of SHP-1, which reversely mediates STAT3 signaling, leading to the upregulation of SHP-1 expression in osteosarcoma. We also found pectolinarigenin significantly suppressed osteosarcoma growth, induced apoptosis. In addition, pectolinarigenin blocked tumor cells migration, invasion and reserved EMT phenotype. In spontaneous tibial injection and patient-derived xenograft models of osteosarcoma, we identified administration (i.p.) of pectolinarigenin (20 mg/kg/2 days and 50 mg/kg/2 days) blocked STAT3 activation and disturbed tumor growth and metastasis with superior pharmacodynamic properties. Taken together, our findings demonstrate that pectolinarigenin may be a candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity.

Treatment-refractory auditory hallucinations (TRAH) in schizophrenia often do not improve with pharmacotherapy. We performed a meta-analysis of randomized, double-blind, sham-controlled clinical trials (RCTs) that systematically examined the therapeutic effects and tolerability of adjunctive active versus sham active transcranial direct current stimulation (tDCS) for auditory hallucinations as measured by the Auditory Hallucination Rating Scale (AHRS) in schizophrenia patients with TRAH.Relevant data were extracted, checked and analyzed using the Review Manager, Version 5.3 by three independent investigators.Eight double-blind RCTs covering 329 schizophrenia patients (168 in active tDCS group, 161 in sham tDCS group) were included. Although no advantage of active tDCS on auditory hallucinations [7 RCTs, n = 224; standardized mean difference (SMD): - 0.33 (95% confidence interval (CI): - 0.71, 0.05), P = 0.09; IThis meta-analysis demonstrated that the effects of tDCS for auditory hallucinations symptoms were influenced by the tDCS parameters. Twice-daily stimulation and ≥ 10 stimulation sessions may be needed to improve auditory hallucinations symptoms in schizophrenia with TRAH.

Congenital heart diseases (CHD) are the most common birth defects, and the early diagnosis of CHD is crucial for CHD therapy. However, there are relatively few studies on intelligent auscultation for pediatric CHD, due to the fact that effective cooperation of the patient is required for the acquisition of useable heart sounds by electronic stethoscopes, yet the quality of heart sounds in pediatric is poor compared to adults due to the factors such as crying and breath sounds. This paper presents a novel pediatric CHD intelligent auscultation method based on electronic stethoscope. Firstly, a pediatric CHD heart sound database with a total of 941 PCG signal is established. Then a segment-based heart sound segmentation algorithm is proposed, which is based on PCG segment to achieve the segmentation of cardiac cycles, and therefore can reduce the influence of local noise to the global. Finally, the accurate classification of CHD is achieved using a majority voting classifier with Random Forest and Adaboost classifier based on 84 features containing time domain and frequency domain. Experimental results show that the performance of the proposed method is competitive, and the accuracy, sensitivity, specificity and f1-score of classification for CHD are 0.953, 0.946, 0.961 and 0.953 respectively.