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The incidence of extrauterine growth retardation (EUGR) varies considerably in different countries due to the distinct definitions and inclusion criteria of individual studies. Most studies included small for gestational age (SGA) very preterm infants (VPIs), resulting in a higher incidence of EUGR. Experts have suggested the accurate definition of "EUGR" in SGA infants is not "true EUGR". The postnatal growth curve of multiple premature births also differs from that of singletons. As far as we know, there is no study about relationship between singleton-non-SGA preterm infants and EUGR.To analyze the factors influencing EUGR among VPIs who were singleton-non-SGA in China.A prospective-multicenter study was conducted in 28 hospitals distributed through China from September 2019 to December 2020. The clinical data on singleton-non-SGA among VPIs were divided into EUGR group (n = 692) and non-EUGR group (n = 912).Compared to non-EUGR group, the mean gestational age (GA), mean birth weight (BW) and percentage of BW in Fenton curve in EUGR group were lower (P0.001 for all). The incidence of EUGR among distinct GA groups (classifications of GA28weeks, 28-28The overall incidence of EUGR was 43.1% among singleton-non-SGA VPIs in China. Raising the full-course antenatal steroids usage, reducing the incidence of moderate and severe BPD, attaching importance to the management of enteral nutrition in VPIs and increasing the weight growth velocity can reduce the incidence of EUGR.

Smads, part of signaling cascades that represent downstream pathways of the TGF-β super family proteins, are pleiotropic cytokines with important role in mediating cell proliferation, homeostasis, differentiation, apoptosis and immune response. However, the specific functions of Smads remain unknown in crustaceans. In the present study, the drosophila mothers against decapentaplegic protein gene 1 (Smad1) was firstly identified and characterized from the Red Swamp Crayfish Procambarus clarkii. The obtained cDNA sequence of pcSmad1was 2, 503 bp long with a 1, 488 bp open reading fame, which encoded a putative protein of 496 amino acids. Furthermore, pcSmad1 responded to both Aeromonas hydrophila and WSSV challenge, suggesting the involvement of pcSmad1 in innate immune responses. Knockdown of pcSmad1 in vivo dramatically increased the expressions of NF-κB signaling genes and anti-lipopolysaccharide factor genes. Additionally, overexpression of pcSmad1 in HEK293T cells could markedly activate NF-κB signaling. Taken together, these results indicated that pcSmad1 played an immune-regulatory role in crayfish's innate immunity, which may provide a better understanding of TGF-β superfamily members in crustacean.

Atherosclerosis (AS) is the most common cardiovascular disease (CVD). Currently, it is widely believed that R-TFA and I-TFA may cause different biological effects. In the present study, we aim to elucidate the effect of mixed R-TFA derived from butter on the development of AS in high-fat diet-fed ApoE

Background. Oxidative stress plays a role in carcinogenesis. This study explores the roles of oxidative stress-related genes (OSRGs) in lung adenocarcinoma (LAC). Besides, we construct a risk score model of OSRGs that evaluates the prognosis of LAC patients. Methods. OSRGs were downloaded from the Gene Set Enrichment Analysis (GSEA) website. The expression levels of OSRGs were confirmed in LAC tissues of the TCGA database. GO and KEGG analyses were used to evaluate the roles and mechanisms of oxidative stress-related differentially expressed genes (DEGs). Survival, ROC, Cox analysis, and AIC method were used to screen the prognostic DEGs in LAC patients. Subsequently, we constructed a risk score model of OSRGs and a nomogram. Further, this work investigated the values of the risk score model in LAC progression and the relationship between the risk score model and immune infiltration. Results. We discovered 163 oxidative stress-related DEGs in LAC, involving cellular response to oxidative stress and reactive oxygen species. Besides, the areas under the curve of CCNA2, CDC25C, ERO1A, CDK1, PLK1, ITGB4, and GJB2 were 0.970, 0.984, 0.984, 0.945, 0.984, 0.771, and 0.959, respectively. This indicates that these OSRGs have diagnosis values of LAC and are significantly related to the overall survival of LAC patients. ERO1A, CDC25C, and ITGB4 overexpressions were independent risk factors for the poor prognosis of LAC patients and were associated with risk scores in the risk model. High-risk score levels affected the poor prognosis of LAC patients. Notably, a high-risk score may be implicated in LAC progression via cell cycle, DNA replication, mismatch repair, and other mechanisms. Further, ERO1A, CDC25C, and ITGB4 expression levels were related to the immune infiltrating cells of LAC, including mast cells, NK cells, and CD8 T cells. Conclusion. In summary, ERO1A, CDC25C, and ITGB4 of OSRGs are associated with poor prognosis of LAC patients. We confirmed that the risk model based on the ERO1A, CDC25C, and ITGB4 is expected to assess the prognosis of LAC patients.

Chimeric antigen receptor (CAR) T cell therapy is a novel therapeutic approach that uses gene editing techniques and lentiviral transduction to engineer T cells so that they can effectively kill tumors. However, CAR T cell therapy still has some drawbacks: many patients who received CAR T cell therapy and achieve remission, still had tumor relapse and treatment resistance, which may be due to tumor immune escape and CAR T cell dysfunction. To overcome tumor relapse, more researches are being done to optimize CAR T cell therapy to make it more precise and personalized, including screening for more specific tumor antigens, developing novel CAR T cells, and combinatorial treatment approaches. In this review, we will discuss the mechanisms as well as the progress of research on overcoming plans.

The present study investigated the association between the presence of periodontitis and aortic calcification (AC) risk among Chinese adults. A total of 6059 individuals who underwent regular health check-ups and received a diagnosis of periodontitis between 2009 and 2016 were included. The outcome was AC, assessed by a chest low-dose spiral CT scan. Cox proportional hazards regression analysis was used to assess the association between periodontitis and AC risk after adjusting for several confounders. After a median follow-up period of 2.3 years (interquartile range: 1.03–4.97 years), 843 cases of AC were identified, with 532 (12.13%) and 311 (18.59%) patients in the non-periodontitis group and periodontitis group, respectively. Multivariate analyses demonstrated that, compared with those without periodontitis, the hazard ratio and 95% confidence interval for AC risk in participants with periodontitis was 1.18 (1.02–1.36) ( P = .025) in the fully adjusted model. Stratified analyses showed that the positive relationship between periodontitis and AC was more evident in males and participants interaction = .005 and .004, respectively). Our results show that the presence of periodontitis was positively associated with AC among Chinese adults, especially among males and younger participants.

To investigate the effects of sacubitril/valsartan (S/V) on cardiopulmonary function and blood pressure response to exercise during hospitalization in patients with acute myocardial infarction (AMI) based on the cardiopulmonary exercise test (CPET).A total of 265 AMI patients were treated with either perindopril or S/V within 24 hours of admission. CPET was completed for all patients before discharge. There were 182 cases in the perindopril group and 83 cases in the S/V group.The proportion of exercise oscillatory ventilation (EOV) was higher in the S/V group than in the perindopril group (10.8%Treatment with S/V was able to reduce the exercise blood pressure in patients with AMI during hospitalization, but did not significantly improve the VO

Semen is a known vector for both human immunodeficiency virus (HIV) infection and transmission. However, the distribution and characteristics of HIV-infected cells in semen remain unclear. Investigating the possibility of transmission through the spermatozoon in semen is of great clinical significance to improve the strategies for exposure prevention and assisted reproduction for HIV-infected partners. Twenty-six HIV-infected patients, including twelve treatment-naïve (TN) patients and fourteen antiretroviral treated (ART) patients, were enrolled in this study. HIV p24 protein in spermatozoa was detected using imaging flow cytometry and immunohistochemistry, and HIV RNA was identified using next-generation RNAscope

The study aimed to investigate the incidence of and risk factors for liver damage in patients with human immunodeficiency virus type-1 (HIV-1) mono-infection receiving antiretroviral therapy (ART).We retrospectively analyzed the clinical data of patients who were diagnosed with HIV-1 infection and initiated ART from January to December 2017. Among them, 382 patients with HIV-1 mono-infection and normal baseline liver function were included in the analysis. The incidence of liver damage at each follow-up point, and possible risk factors for liver damage were evaluated via COX regression survival analyses.The overall incidence of liver damage (grade I-IV) was 27.23% (interquartile range [IQR]: 26.38%-28.72%). Grade I liver damage was most common and accounted for 22.13% of cases (IQR: 21.06%-24.04%), while grade II liver damage accounted for 3.40% of cases (IQR: 3.19%-4.26%). COX regression and survival analyses revealed that baseline body mass index (BMI), alanine aminotransferase (ALT) level, CD4Liver damage is common in patients with HIV-1 mono-infection undergoing ART. Patients with risk factors for liver damage should be well-informed before the initiation of ART, and liver function should be closely monitored during ART even in patients with normal liver function before ART.

Hepatitis E virus-related acute liver failure (HEV-ALF) rapidly worsens and has a high mortality. However, no simple and specific parameters for predicting short-term mortality are available.A derivation cohort including 97 patients with HEV-ALF and another validation cohort were enrolled. Laboratory and clinical parameters were recorded. Platelet count, model for end-stage liver disease (MELD), and King's College criteria (KCC) were separately used for predicting mortality, and the levels of cytokines associated with systemic inflammation, platelet production, and platelet activation were measured.Platelet counts were significantly lower in patients with HEV-ALF, and nonsurvivors had lower platelet counts than survivors (p 0.001). Platelet count was an independent risk factor for predicting 28- and 90-day mortality in patients with HEV-ALF. The AUROC of the baseline platelet count (cutoff, 131 × 10Decreased platelet count is a simple and reliable indicator for predicting 28- and 90-day mortality in patients with HEV-ALF. Overactivation of platelets is an important risk for platelet counts decrease, and treatment aiming at platelet count recovery may be considered.

Invasion and metastasis of breast cancer cells is an important cause of death in breast cancer patients. In the tumor microenvironment, M2 polarization of macrophages can promote the invasion and metastasis of tumor cells. OVOL2 is an evolutionarily conserved transcription regulator, but its effect in macrophages has not been described previously. The aim of this study was to investigate the effects of OVOL2 on macrophage polarity and the role of these effects in the tumor metastasis. We found that overexpression of OVOL2 in macrophages significantly inhibited M2 polarization and thus inhibits breast cancer metastasis. We propose a novel mechanism in which OVOL2 inhibits M2 polarization of macrophages and thus reduces their ability to induce invasion and metastasis of breast cancer. By shedding new light on the regulation of metastasis in cancers, our study provides a new strategy for the targeted therapy of cancer.

Multidrug-resistant (MDR) Staphylococcus aureus biofilms have emerged as a serious threat to human health. Recently, the development of antibiotic replacement therapy has gained much attention due to the potential application of bacteriocin. The present study sought to evaluate the antibacterial effect of bacteriocin XJS01 against MDR S. aureus, a previously reported bacteriocin against S. aureus strain 2612:1606BL1486 (S. aureus_26, an MDR strain demonstrated here), and its potential application as an antibiofilm agent. The minimum bactericide concentration of XJS01 against MDR S. aureus_26 was 33.18 μg/mL. XJS01 exhibited excellent storage stability and resistance against acid and reduced the density of established MDR S. aureus_26 biofilm. The hemolytic and HEK293T cytotoxicity activities of XJS01 and the histological analyses in mice confirmed its safety. Moreover, XJS01 effectively disrupted the MDR S. aureus_26 biofilm established on the skin wound surface and reduced the biofilm-isolated bacteria, thereby decreasing the release of pro-inflammatory cytokines and the proliferation of alternatively activated macrophages. Compared to mupirocin, XJS01 exhibited an excellent therapeutic effect on mice skin wounds, confirming it to be a potential alternative to antibiotics.

Immunotherapy is recognised as an attractive method for the treatment of cancer, and numerous treatment strategies have emerged over recent years. Investigations of the tumour microenvironment (TME) have led to the identification of many potential therapeutic targets and methods. However, many recently applied immunotherapies are based on previously identified strategies, such as boosting the immune response by combining commonly used stimulators, and the release of drugs through changes in pH. Although methodological improvements such as structural optimisation and combining strategies can be undertaken, applying those novel targets and methods in immunotherapy remains an important goal. In this review, we summarise the latest research on the TME, and discuss how small molecules, immune cells, and their interactions with tumour cells can be regulated in the TME. Additionally, the techniques currently employed for delivery of these agents to the TME are also mentioned. Strategies to modulate cell phenotypes and interactions between immune cells and tumours are mainly discussed. We consider both modulatory and targeting methods aiming to bridge the gap between the TME and chemical modulation thereof.

Congenital hyperinsulinism (CHI), a major cause of persistent and recurrent hypoglycemia in infancy and childhood. Numerous pathogenic genes have been associated with 14 known genetic subtypes of CHI. Adenosine triphosphate-sensitive potassium channel hyperinsulinism (KATP-HI) is the most common and most severe subtype, accounting for 40–50% of CHI cases. Short-chain 3-hydroxyacyl-coenzyme A dehydrogenase hyperinsulinism (SCHAD-HI) is a rare subtype that accounts for less than 1% of all CHI cases that are caused by homozygous mutations in the hydroxyacyl-coenzyme A dehydrogenase (HADH) gene. This review provided a systematic description of the genetic pathogenesis and current progress in the diagnosis and treatment of SCHAD-HI to improve our understanding of this disease.

Amyloid proteins can aggregate into insoluble fibrils and form amyloid deposits in the human brain, which is the hallmark of many neurodegenerative diseases. Promising strategies toward pathological amyloid proteins and deposition include investigating inhibitors that can disrupt amyloid aggregation or induce misfolding protein degradation. In this review, recent progress of peptide-based inhibitors, including amyloid sequence–derived inhibitors, designed peptides, and peptide mimics, is highlighted. Based on the increased understanding of peptide design and precise amyloid structures, these peptides exhibit advanced inhibitory activities against fibrous aggregation as well as enhanced druggability.

Chronic inflammation and T cell dysregulation persist in individuals infected with human immunodeficiency virus type 1 (HIV-1), even after successful antiretroviral treatment. The mechanism involved is not fully understood. Here, we used Olink proteomics to comprehensively analyze the aberrant inflammation-related proteins (IRPs) in chronic HIV-1-infected individuals, including in 24 treatment-naïve individuals, 33 immunological responders, and 38 immunological non-responders. T cell dysfunction was evaluated as T cell exhaustion, activation, and differentiation using flow cytometry. We identified a cluster of IRPs (cluster 7), including CXCL11, CXCL9, TNF, CXCL10, and IL18, which was closely associated with T cell dysregulation during chronic HIV-1 infection. Interestingly, IRPs in cluster 5, including ST1A1, CASP8, SIRT2, AXIN1, STAMBP, CD40, and IL7, were negatively correlated with the HIV-1 reservoir size. We also identified a combination of CDCP1, CXCL11, CST5, SLAMF1, TRANCE, and CD5, which may be useful for distinguishing immunological responders and immunological non-responders. In conclusion, the distinct inflammatory milieu is closely associated with immune restoration of T cells, and our results provide insight into immune dysregulation during chronic HIV-1 infection.

Purpose: Bladder cancer treatment remains a major clinical challenge due to therapy resistance and a high recurrence rate. Profiling intratumor heterogeneity can reveal the molecular mechanism of bladder cancer recurrence. Experimental Design: Here, we performed single-cell RNA sequencing and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) on tumors from 13 patients with low recurrence risk, high recurrence risk, and recurrent bladder cancer. Results: Our study generated a comprehensive cancer-cell atlas consisting of 54,971 single cells and identified distinct cell subpopulations. We found that the cancer stem-cell subpopulation is enriched during bladder cancer recurrence with elevated expression of EZH2. We further defined a subpopulation-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the NCAM1 gene, thereby inactivating the cell invasive and stemness transcriptional program. Furthermore, taking advantage of this large single-cell dataset, we elucidated the spectrum of epithelial–mesenchymal transition (EMT) in clinical samples and revealed distinct EMT features associated with bladder cancer subtypes. We identified that TCF7 promotes EMT in corroboration with single-cell ATAC with high-throughput sequencing (scATAC-seq) analysis. Additionally, we constructed regulatory networks specific to recurrent bladder cancer. Conclusions: Our study and analytic approaches herein provide a rich resource for the further study of cancer stem cells and EMT in the bladder cancer research field.

Esophageal squamous cell carcinoma (ESCC) is a malignant tumor that commonly occurs worldwide. Usually, Asia, especially China, has a high incidence of esophageal cancer. ESCC often has a poor outcome because of a late diagnosis and lack of effective treatments. To build foundations for the early diagnosis and treatment of ESCC, we used the gene expression datasets GSE20347 and GSE17351 from the GEO database and a private dataset to uncover differentially expressed genes (DEGs) and key genes in ESCC. Notably, we found that replication factor C subunit 4 (RFC4) and guanine monophosphate synthase (GMPS) were upregulated but have been rarely studied in ESCC. In particular, to the best of our knowledge, our study is the first to explore GMPS and ESCC. Furthermore, we found that high levels of RFC4 and GMPS expression may result from an increase in DNA copy number alterations. Furthermore, RFC4 and GMPS were both upregulated in the early stage and early nodal metastases of esophageal carcinoma. The expression of RFC4 was strongly correlated with GMPS. In addition, we explored the relationship between RFC4 and GMPS expression and tumor-infiltrating immune cells (TILs) in esophageal carcinoma. The results showed that the levels of RFC4 and GMPS increased with a decrease in some tumor-infiltrating cells. Upregulated RFC4 and GMPS with high TILs indicate a worse prognosis. In summary, our study shows that RFC4 and GMPS have potential as biomarkers for the early diagnosis of ESCC and may played a crucial role in the process of tumor immunity in ESCC.

Background: Abnormal expression and function of long non-coding RNAs (lncRNAs) are closely related to the pathogenesis of systemic lupus erythematosus (SLE). In this study, we aimed to investigate the association of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) gene single-nucleotide polymorphisms (SNPs) with susceptibility and clinical characteristics of SLE patients. Methods: A case-control study including 489 SLE patients and 492 healthy controls was conducted. Four MALAT-1 SNPs (rs4102217, rs591291, rs11227209, and rs619586) were genotyped in all subjects, their correlation with SLE susceptibility and clinical characteristics were also analyzed. Results: Results showed that the rs4102217 locus was associated with the risk of SLE. In recessive models, the GG+CG genotype of rs4102217 was associated with the decreased risk of SLE compared to CC ( p = 0.036, OR = 0.348, 95% CI: 0.124–0.975). In additive models, the GG genotype of rs4102217 was associated with the decreased risk of SLE compared to CC ( p = 0.040, OR = 0.355, 95% CI: 0.127–0.996). However, no association was found between MALAT-1 gene polymorphism and clinical manifestations of SLE (all p > 0.05). Conclusion: In summary, MALAT-1 rs4102217 is associated with susceptibility to SLE, suggesting that MALAT-1 may play a role in SLE.

Purpose Henagliflozin is a highly selective and effective sodium glucose co-transporter (SGLT)-2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the effects of meal intake on the pharmacokinetic properties of henagliflozin, and to understand the excretion pathways of henagliflozin in humans. Methods In this Phase I, randomized, open-label, single-dose, two-period crossover study, 12 healthy male Chinese volunteers were randomized to receive either henagliflozin 10 mg in the fasted condition followed by henagliflozin 10 mg in the fed condition, or the reverse schedule, with the two administrations separated by a washout period of at least 7 days. Samples of blood, urine, and feces were collected and analyzed for the investigation of the pharmacokinetic profile and excretion pathways in the fasted and fed conditions. Any adverse events that occurred throughout the study were recorded for tolerability assessment. Findings After the administration of a single oral dose of henagliflozin, mean (SD) plasma AUC0–∞ and Cmax were 1200 (274) h · ng/mL and 179 (48.8) ng/mL, respectively, in the fasted state and were decreased to 971 (245) h · ng/mL and 115 (34.2) ng/mL in the fed state. The fed/fasted ratios (90% CIs) of the geometric mean values of Cmax, AUC0–t, and AUC0–∞ were 64% (54%–76%), 80% (76%–85%), and 80% (76%–85%), respectively. The median (range) Tmax was prolonged from 1.5 (1–3) hours in the fasted condition to 2 (1.5–6) hours in the fed condition. Mass-balance testing revealed that henagliflozin was eliminated primarily as the parent drug in feces and as glucuronide metabolites in urine. In the fasted state, the cumulative excretion percentages of the parent drug and its metabolites to dose in feces and urine were 40.6% and 33.9%, respectively. The values in the fed condition were changed to 50.4% and 25.5%, respectively. These findings suggest that postprandial administration decreases the absorption rate and the extent of henagliflozin exposure in humans, but has no effect on the metabolism or elimination of the drug. Implications In the present study, the consumption of a high-fat meal prior to henagliflozin administration was associated with reductions in AUC0–∞ and Cmax of 19.4% and 36.4%, respectively. However, based on the analysis of the pharmacokinetic/pharmacodynamic findings on henagliflozin, this slight change may not have clinical significance. Mass balance of henagliflozin in humans was achieved with ∼75% of the administered dose recovered in excretions within 4 days after administration whether in the fasted or fed state. These findings suggest that henagliflozin tablets can be administered with or without food.

Objective The aim of this study was to investigate whether declining mobility and muscle strength predict new-onset hypertension in suburban-dwelling elderly individuals. Methods This study was designed as a longitudinal prospective cohort study. It was comprised of 362 individuals (mean age = 67.8 ± 6.2; 157 men) without hypertension at baseline. At baseline, all participants completed health questionnaires and underwent measurements of mobility [the Timed Up and Go test (TUGT) and 4-m walking test] and muscle strength (grip strength). At 1-year follow-up, we determined the number of participants who had developed new-onset hypertension. We then evaluated the relationship between above metrics and the development of hypertension. Results In the present study, 94 (26.0%) participants developed hypertension after 1 year. After adjusting for mixed factors, the TUGT scores [hazard ratio = 1.15; 95% confidence interval (CI), 1.10–1.31; P = 0.030] were positively associated with the development of hypertension, while the 4-m walking test scores (hazard ratio = 0.07; 95% CI, 0.01–0.47; P = 0.007) showed an inverse relationship with hypertension incidence. Grip strength (hazard ratio = 1.03; 95% CI, 0.99–1.06; P = 0.098) was not significantly associated with hypertension incidence. Conclusion Our results indicate that people with declining mobility are significantly more likely to develop hypertension. Hence, improving mobility could be protective against hypertension for elderly individuals.

Long non-coding RNAs (lncRNAs) are the new regulators and biomarkers for various tumors. However, in cervical cancer (CC), the potential roles of lncRNAs are not well characterized. This research aimed at exploring the roles of MEOX2 antisense RNA 1(MEOX2-AS1) in CC progression and the underlying mechanisms. The examination of MEOX2-AS1 levels in CC specimens and cell lines was conducted by RT-PCR. Loss-of-function experiments were performed for the assays of proliferation, migration, and invasion of CC cells after various treatments. Animal experiments were applied for the determination of the effects of MEOX2-AS1 in vivo. Bioinformatics analysis, together with dual-luciferase reporter assays, was applied to demonstrate the possible relationships among MEOX2-AS1, miR-143-3p and VDAC1. In the paper, we reported that MEOX2-AS1 levels were distinctly upregulated in CC cells and tissues, and higher MEOX2-AS1 expressions indicated a poor clinical outcome. Besides, STAT1 could activate transcriptions of MEOX2-AS1 by binding directly to its promoter region. The silence of MEOX2-AS1 suppressed the metastatic and proliferative ability of CC cells, as revealed by functional assays. Mechanistically, MEOX2-AS1 sponged miR-143-3p to regulate VDAC1 expressions. Furthermore, miR-143-3p inhibitor reversed the anti-proliferation and anti-metastasis effect of MEOX2-AS1 knockdown. Overall, the data indicated that the MEOX2-AS1/miR-143-3p/VDAC1 pathway participated in CC progression, making it a novel therapeutic target for CC cures., Graphical abstract

In this study, three new germacranolide sesquiterpenes (1-3), together with six related known analogues (4-9) were isolated from the whole plant of Carpesium cernuum. Their structures were established by a combination of extensive NMR spectroscopic analysis, HR-ESIMS data, and ECD calculations. The anti-leukemia activities of all compounds towards three cell lines (HEL, KG-1a, and K562) were evaluated in vitro. Compounds 1-3 exhibited moderate cytotoxicity with IC50 values ranging from 1.59 to 5.47 μmol·L-1. Mechanistic studies indicated that 2 induced apoptosis by decreasing anti-apoptotic protein Bcl-2 and activating the caspase family in K562 cells. These results suggest that compound 2 is a potential anti-leukemia agent.

ConspectusCancer vaccines provide an efficient strategy to enhance tumor-specific immune responses by redeploying immune systems. Despite the approval of the first cancer vaccine (Sipuleucel-T) by the U.S. Food and Drug Administration in 2010, most therapeutic cancer vaccines fail in clinical trials. Basically, tumor-specific immune responses rely on not only T-cell but also B-cell immunity, which indicates that cancer vaccines should leverage both arms of the adaptive immune system. For example, CD8

Traditional Chinese medicine(TCM) preparations in medical institutions are an important source of research and development(Ramp;D) of TCM new drug. With years of usage in therapy, these preparationsapos; safety and effectiveness have generally been validated in clinic. However, there are still a few disadvantages in TCM new medicine development, such as similar prescriptions, excessive prescription ingredients, too broad clinical orientation, lack of solid clinical data, issue in pharmaceutical quality control, and intellectual property disputes. Nowadays, the Three-Combined Evaluation System has strengthened policy support for the new TCM Ramp;D. In order to improve the success rate of TCM Ramp;D, due to the difficulties within, this paper proposes the process of transforming TCM preparations in medical institutions into new TCM and advocates the evaluation for druggability based on Human Use Experience(HUE). The potencial preparations ought to follow traditional Chinese Medical theory, sufficient HUE data in indication, syndrome type of TCM, target population, usage, dosage, and course of treatment are required. Particular attention should be paid to the source, evolution, and improvement process of prescription, and evaluate the dosage, ingredients, and herb resources of prescription. To assess the feasibility of mass production, it is necessary to determine whether the pharmaceutical process is mostly consistent with the new drug and whether the dosage form is reasonable. By summarizing the clinical application of the preparations, the whole picture of its clinical application would be reveal as much as possible. It is beneficial to evaluate its clinical value and Ramp;D prospect. In consideration of the lack of clinical safety data of preparations, safety profile needs to be collected according to the prescription. The quality of clinical data needs to be evaluated by focusing on the integrity and accuracy of data to reduce bias and confusion. Significant care should be paid to intellectual property protection to avoid legal disputes.

Hypersampones A-C (

OBJECTIVE: To study the value of autotaxin (an autocrine motility factor) level in serum and bronchoalveolar lavage fluid (BALF) in predicting refractory Mycoplasma pneumoniae pneumonia (RMPP) in children and its correlation with interleukin-6 (IL-6), interleukin-8 (IL-8), and C-reactive protein (CRP). METHODS: A retrospective analysis was performed on 238 children with Mycoplasma pneumoniae pneumonia who were admitted from January 2019 to December 2021. According to disease severity, they were divided into two groups: RMPP (n=82) and general Mycoplasma pneumoniae pneumonia (GMPP; n=156). The two groups were compared in terms of the levels of autotaxin, IL-6, IL-8, and CRP in serum and BALF to study the value of autotaxin level in serum and BALF in predicting RMPP in children, as well as the correlation of autotaxin level with IL-6, IL-8, and CRP in children with RMPP. RESULTS: Compared with the GMPP group, the RMPP group had significantly higher levels of autotaxin, IL-6, IL-8, and CRP in serum and BALF (P

OBJECTIVE To investigate whether continuous infusion of propofol at a subhypnotic dose prevents nausea and vomiting following carboprost administration at cesarean delivery. METHODS A prospective, randomized, double-blind, placebo-controlled trial conducted at West China Second University Hospital, from June 28, 2017 to January 30, 2018. Pregnant women were randomly allocated to propofol or saline infusion immediately before receiving carboprost at cesarean delivery under combined spinal-epidural (CSE) anesthesia. Propofol was given at an infusion rate of 1.0 mg/kg/h following a loading dose of 0.3 mg/kg. Primary outcome was incidence of intraoperative nausea and vomiting (IONV). Potential sedative effect of propofol infusion was assessed using Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scoring and continuous Bispectral Index (BIS) monitoring. RESULTS The incidence of IONV was lower in patients who received propofol compared with saline (46.7% vs 76.7%, OR 0.27; 95% CI, 0.092-0.78, P = 0.016 for nausea; 26.7% vs 53.3%, OR 0.50; 95% CI, 0.25-0.95, P = 0.032 for retching; 10.0% vs 50.0%, OR 0.11; 95% CI, 0.03-0.44, P

To analyze clinical characteristics and potential predictors of disease severity in patients with COVID-19.Clinical data from 64 patients with COVID-19 were retrospectively analyzed. Of the 64 patients, 37 were male and 27 were female. Their mean age was 47.8 years, 43 (67.2%) cases were non-severe, 21 (32.8%) were severe, and 2 patients (3.1%) died. Age and serum ferritin were significantly associated with COVID-19 severity. Repeated monitoring of ferritin, interleukin-6, C-reactive protein, lactic acid dehydrogenase, and erythrocyte sedimentation rate during COVID-19 treatment may assist the prediction of disease severity and evaluation of treatment effects. There were no significant differences in the duration of severe illness or the number of days on high-level respiratory support between a low-dose methylprednisolone group and a high-dose methylprednisolone group. The mean number of days in hospital in the high dose group was higher than that in the low-dose group. Repeated monitoring of ferritin, interleukin-6, C-reactive protein, lactic acid dehydrogenase, and erythrocyte sedimentation rate during COVID-19 treatment may assist the prediction of disease severity and evaluation of treatment effects.

Background: Abnormal expression and function of long non-coding RNAs (lncRNAs) are closely related to the pathogenesis of systemic lupus erythematosus (SLE). In this study, we aimed to investigate the association of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) gene single-nucleotide polymorphisms (SNPs) with susceptibility and clinical characteristics of SLE patients. Methods: A case-control study including 489 SLE patients and 492 healthy controls was conducted. Four MALAT-1 SNPs (rs4102217, rs591291, rs11227209, and rs619586) were genotyped in all subjects, their correlation with SLE susceptibility and clinical characteristics were also analyzed. Results: Results showed that the rs4102217 locus was associated with the risk of SLE. In recessive models, the GG+CG genotype of rs4102217 was associated with the decreased risk of SLE compared to CC (p = 0.036, OR = 0.348, 95% CI: 0.124-0.975). In additive models, the GG genotype of rs4102217 was associated with the decreased risk of SLE compared to CC (p = 0.040, OR = 0.355, 95% CI: 0.127-0.996). However, no association was found between MALAT-1 gene polymorphism and clinical manifestations of SLE (all p > 0.05). Conclusion: In summary, MALAT-1 rs4102217 is associated with susceptibility to SLE, suggesting that MALAT-1 may play a role in SLE.

A chlorine e6 (Ce6) and curcumin (Cur) based self-delivery nanomedicine (CeCu) is prepared for chemotherapy sensitized photodynamic therapy (PDT). The chemotherapeutic agent of Cur could inhibit the TrxR activity to destroy the cellular ROS-defence system for enhanced PDT, which provides synergistic effects for tumor precision therapy in consideration of the unfavorable tumor microenvironments.

A novel STING agonist, CDGSF, ipsilaterally modified with phosphorothioate and fluorine, was synthesized. The phosphorothioate in CDGSF might be a site for covalent conjugation. Injection of CDGSF generated an immunogenic ("hot") tumor microenvironment to suppress melanoma, more efficiently than dithio CDG. In particular, immunization with SARS-CoV-2 spike protein using CDGSF as an adjuvant elicited an exceptionally high antibody titer and a robust T cell response, overcoming the drawbacks of aluminum hydroxide. These results highlighted the therapeutic potential of CDGSF for cancer immunotherapy and the adjuvant potential of the STING agonist in the SARS-CoV-2 vaccine for the first time.

ObjectiveTo evaluate the efficacy of enhanced external counterpulsation (EECP) in the prevention of contrast-induced nephropathy (CIN) in patients with combined chronic kidney disease (CKD) and diabetes mellitus (DM) by comparing the changes in renal function-related indicators in patients before and after coronary angiography (CAG) or percutaneous coronary intervention (PCI).MethodsThere were 230 subjects consecutively included in the study. Of these, 30 cases with DM underwent rehydration therapy, and 200 cases underwent EECP therapy in addition to rehydration therapy, comprising 53 patients with DM and 147 patients without. All the patients were tested to measure the renal function indicators before and after CAG/PCI.ResultsThe postoperative results of blood urea nitrogen (BUN), serum creatinine (Scr), estimated glomerular filtration rate (eGFR), B2 microglobulin, and high-sensitivity C-reactive protein in the three groups showed a statistically significant difference (P < 0.05). After EECP therapy, patients with DM showed a significant decrease in BUN (9.1 ± 4.2 vs. 7.2 ± 3.0, t = 3.899, P < 0.001) and a significant increase in eGFR (41.5 ± 12.7 vs. 44.0 ± 15.6, t = −2.031, P = 0.047), while the patients without DM showed a more significant difference (P < 0.001). Patients with DM showed a lower percentage of elevated Scr (66.7% vs. 43.4%, P = 0.042), a higher percentage of elevated eGFR (30.0% vs. 52.8%, P = 0.044), and a lower incidence of CIN (16.7% vs. 3.8%, P = 0.042) after EECP therapy.ConclusionTreatment with EECP can reduce Scr in patients with combined CKD and DM post CAG/PCI, increase eGFR, and decrease the incidence of CIN.

Deletions involving the

Recent studies highlighted that CD8+ T cells are necessary for restraining reservoir in HIV-1-infected individuals who undergo antiretroviral therapy (ART), whereas the underlying cellular and molecular mechanisms remain largely unknown. Here, we enrolled 60 virologically suppressed HIV-1-infected individuals, to assess the correlations of the effector molecules and phenotypic subsets of CD8+ T cells with HIV-1 DNA and cell-associated unspliced RNA (CA usRNA). We found that the levels of HIV-1 DNA and usRNA correlated positively with the percentage of CCL4+CCL5- CD8+ central memory cells (TCM) while negatively with CCL4-CCL5+ CD8+ terminally differentiated effector memory cells (TEMRA). Moreover, a virtual memory CD8+ T cell (TVM) subset was enriched in CCL4-CCL5+ TEMRA cells and phenotypically distinctive from CCL4+ TCM subset, supported by single-cell RNA-Seq data. Specifically, TVM cells showed superior cytotoxicity potentially driven by T-bet and RUNX3, while CCL4+ TCM subset displayed a suppressive phenotype dominated by JUNB and CREM. In viral inhibition assays, TVM cells inhibited HIV-1 reactivation more effectively than non-TVM CD8+ T cells, which was dependent on CCL5 secretion. Our study highlights CCL5-secreting TVM cells subset as a potential determinant of HIV-1 reservoir size. This might be helpful to design CD8+ T cell-based therapeutic strategies for cure of the disease.

β-Thalassemia major (β-TM) is an inherited disorder of hemoglobin (Hb) production, which can cause severe anemia. A compromised immune system has been observed in patients with β-TM, whereas cytokines have a major role in immune modulation. Interleukin-4 (IL-4), IL-8, IL-13 and transforming growth factor-β (TGF-β) are critical in initiating pro-inflammatory responses, and the serum levels of those cytokines may be involved in the pathophysiology of β-thalassemia (β-thal). To assess this hypothesis, we studied 23 pediatric patients with β-TM by measuring serum levels of IL-4, IL-8, IL-13 and TGF-β, as well as evaluating infection frequency per year, total number of transfusions and serum ferritin (SF) levels, together with age-matched healthy controls. We found that patients with β-thal had higher IL-8, IL-13 and TGF-β concentrations than normal controls, whereas markedly decreased serum IL-4 level was documented in patients with β-TM. Serum IL-4 level of β-thal patients showed a negative significant correlation with infection frequency, total number of transfusions and SF levels. On the contrary, serum levels of IL-8, IL-13 and TGF-β exerted a positive relationship with those clinical parameters. Taken together, our study implies that dysregulated cytokine profile might contribute to iron overloads and impair immune cell functions, thus serving as useful biomarkers for diagnosis and evaluation of β-TM in the future. Our study sheds new light on the pathogenesis of β-TM.

Objective To investigate the value of contrast-enhanced computed tomography (CECT) radiomics features in predicting the efficacy of epirubicin combined with ifosfamide in patients with pulmonary metastases from soft tissue sarcoma. Methods A retrospective analysis of 51 patients with pulmonary metastases from soft tissue sarcoma who received the chemotherapy regimen of epirubicin combined with ifosfamide was performed, and efficacy was evaluated by Recist1.1. ROIs (1 or 2) were selected for each patient. Lung metastases were used as target lesions (86 target lesions total), and the patients were divided into a progression group (n = 29) and a non-progressive group (n = 57); the latter included a stable group (n = 34) and a partial response group (n = 23). Information on lung metastases was extracted from CECT images before chemotherapy, and all lesions were delineated by ITK-SNAP software manually or semiautomatically. The decision tree classifier had a better performance in all radiomics models. A receiver operating characteristic curve was plotted to evaluate the predictive performance of the radiomics model. Results In total, 851 CECT radiomics features were extracted for each target lesion and finally reduced to 2 radiomics features, which were then used to construct a radiomics model. Areas under the curves of the model for predicting lesion progression were 0.917 and 0.856 in training and testing groups, respectively. Conclusion The model established based on the radiomics features of CECT before treatment has certain predictive value for assessing the efficacy of chemotherapy for patients with soft tissue sarcoma lung metastases.

The Huayu-Qiangshen-Tongbi (HQT) decoction, a Chinese medical formula, has been identified to show a potent therapeutic effect on rheumatoid arthritis (RA). However, the specific molecular mechanism of HQT in RA has not been well studied. In the present study, LPS-treated human rheumatoid fibroblast-like synoviocyte (FLS) MH7A cells and collagen-induced arthritis (CIA) mice were utilized as

Objectives To fully assess the quality of the guidelines for the management of malignant pleural effusions (MPE) and ascites and reveal the heterogeneity of recommendations and possible reasons among guidelines. Methods A systematic search was performed in the database to obtain guidelines for the management of MPE and ascites. The AGREE IIGtool was used to assess the quality of these guidelines. The Measurement Scale of Rate of Agreement (MSRA) was introduced to assess the scientific agreement of formulated recommendations for the management of MPE and ascites among guidelines, and evidence supporting these recommendations was extracted and analyzed. Results Nine guidelines were identified. Only 4 guidelines scored more than 60% and are worth recommending. Recommendations were also heterogeneous among guidelines for the management of MPE, and the main reasons were the different emphases of the recommendations for the treatment of MPE, the contradictions in recommendations, and the unreasonably cited evidence for MPE. Conclusions The quality of the management guidelines for patients with MPE and malignant ascites was highly variable. Specific improvement of the factors leading to the heterogeneity of recommendations will be a reasonable and effective way for developers to upgrade the recommendations in the guidelines for MPE.

In clinical practice, PTB patients have concurrent many types of comorbidities such as pneumonia, liver disorder, diabetes mellitus, hematological disorder, and malnutrition. Detecting and treating specific comorbidities and preventing their development are important for PTB patients. However, the prevalence of most comorbid conditions in patients with PTB is not well described. We conducted a large-scale, multicenter, observational study to elucidate and illustrate the prevalence rates of major comorbidities in inpatients at 21 hospitals in China. The 19 specific comorbidities were selected for analysis in this patient cohort, and stratified the inpatient cohort according to age and gender. A total of 355,929 PTB inpatients were included, with a male:female ratio of 1.98 and the proportion of ≥ 65 years PTB inpatients was the most. Approximately 70% of PTB inpatients had at least one defined type of comorbidity. The prevalence of 19 specific comorbidities in inpatients with PTB was analyzed, with pneumonia being the most common comorbidity. The prevalence of most comorbidities was higher in males with PTB except thyroid disorders, mental health disorders, etc. The prevalence of defined most comorbidities in patients with PTB tended to increase with increasing age, although some specific comorbidities tended to increase initially then decrease with increasing age. Our study describes multiple clinically important comorbidities among PTB inpatients, and their prevalence between different gender and age groups. The results will enhance the clinical aptitude of physicians who treat patients with PTB to recognize, diagnose, and treat PTB comorbidities early.

Qingqing Wu,1,2 Xiaodong Wang,3 Qian Chen,1,2 Yang Zou,1,2 Xiaoyan Xu,1,2 Tingting Li,1,2 Chen Yu,1,2 Fu Zhu,1,2 Kanyin E Zhang,4 Jingying Jia,1,2 Yanmei Liu1,2 1Center Laboratory, Shanghai Xuhui Central Hospital, Shanghai, People’s Republic of China; 2Shanghai Engineering Research Center of Phase I Clinical Research & Quality Consistency Evaluation for Drugs, Shanghai, People’s Republic of China; 3Changzhou Siyao Pharmaceuticals Co., Ltd, Jiangsu, People’s Republic of China; 4ViaClinical Ltd, Shanghai, People’s Republic of ChinaCorrespondence: Yanmei LiuCenter Laboratory, Shanghai Xuhui Central Hospital, No. 966, Huaihai Road(M), Shanghai, People’s Republic of ChinaTel/Fax +86-21-54030254Email ymliu@shxh-centerlab.comPurpose: To compare the bioequivalence of two formulations of valsartan (80 mg capsules) under fasting and fed conditions in healthy Chinese volunteers using a full-replicate study design.Methods: A total of 78 Subjects were randomly assigned to fasting cohort (n = 48) or fed cohort (n = 30). Each cohort includes 4 single-dose observation periods and 3-day washout periods. Blood samples were collected at designed time point. Plasma concentration of valsartan was analyzed by a validated LC-MS/MS method. Noncompartmental analysis method was employed to determine the pharmacokinetic parameters. Based on the within-subject standard deviation (SWR) of the reference formulation, either reference-scaled average bioequivalence (RSABE) or average bioequivalence (ABE) method was used to evaluate the bioequivalence of the two formulations.Results: Under fasting conditions, the RSABE method was used to evaluate the bioequivalence of Cmax (SWR> 0.294), while ABE method was used to evaluate the bioequivalence of AUC0-t and AUC0-∞. The geometric mean ratio (GMR) of the test/reference for Cmax was 99.52%, and the 95% upper confidence bound was < 0. For AUC0-t and AUC0-∞ comparisons, GMRs were 102.07% and 101.92%, and the 90% CIs of the test/reference were 96.28%– 108.21%, 96.28%– 107.88%, respectively. Under fed conditions, the SWR value of Cmax, AUC0-t and AUC0-∞ all exceeded the cutoff value of 0.294 and therefore, the RSABE method was used. The GMRs for Cmax, AUC0-t and AUC0-∞ were 98.78%, 103.33% and 103.08%, respectively, while the 95% upper confidence bound values were all < 0. These results all met the bioequivalence criteria for highly variable drugs. All adverse events were mild and transient.Conclusion: In this study, the generic formulation of valsartan 80 mg capsule was considered to be bioequivalent to the reference product under both fasting and fed conditions, and satisfied the requirements for marketing in China.NMPA Registration No: CTR20181422.Keywords: valsartan, bioequivalence, replicate, pharmacokinetics, safety

Introduction: COVID-19 has become a global health security issue, it has caused more than half a million deaths worldwide so far, the treatment strategies are the most concerned issues for clinicians. In this study, the treatments and outcomes in 40 pediatric patients diagnosed with COVID-19 and treated with different drugs were evaluated. Methodology: All cases were diagnosed with COVID-19 nucleic acid positive by using RT-PCR or clinical manifestations, imaging specific characteristics and epidemiological clinical diagnosis. The biological information and first symptom of all cases were collect. A variety of treatments were employed and the outcomes were evaluated by Cox regression analysis. Multivariable analysis was performed to evaluate cure rate at 14 days with different drug treatment. Results: The average length of hospital stay was 10.4 days. The cure rate was increased with the treatment time extended and 90% of pediatric patients were cured and discharged after 14 days’ treatment. And multivariable analysis results proved that none of the covariates were related to the cure rate at 14 days with different drug treatment since p values were over 0.05. Conclusions: Multivariable analysis suggested that the present drug treatments cannot significantly shorten the clinical cure time and improve the cure rate of children with COVID-19.

Healthcare workers (HCWs) are at high risk of occupational exposure to the new pandemic human coronavirus, SARS-CoV-2, and are a source of nosocomial transmission in airborne infectious isolation rooms (AIIRs). Here, we performed comprehensive environmental contamination surveillance to evaluate the risk of viral transmission in AIIRs with 115 rooms in three buildings at the Shanghai Public Health Clinical Center, Shanghai, during the treatment of 334 patients infected with SARS-CoV-2. The results showed that the risk of airborne transmission of SARS-CoV-2 in AIIRs was low (1.62%, 25/1544) due to the directional airflow and strong environmental hygiene procedures. However, we detected viral RNA on the surface of foot-operated openers and bathroom sinks in AIIRs (viral load: 55.00–3154.50 copies/mL). This might be a source of contamination to connecting corridors and object surfaces through the footwear and gloves used by HCWs. The risk of infection was eliminated by the use of disposable footwear covers and the application of more effective environmental and personal hygiene measures. With the help of effective infection control procedures, none of 290 HCWs was infected when working in the AIIRs at this hospital. This study has provided information pertinent for infection control in AIIRs during the treatment of COVID-19 patients. Electronic supplementary material The online version of this article (10.1007/s12250-020-00301-7) contains supplementary material, which is available to authorized users.

Clinical response to immunotherapy is closely associated with the immunosuppressive tumour microenvironment (TME), and influenced by the dynamic interaction between tumour cells and lymphatic endothelial cells (LECs). Here, we show that high levels of miR-142-5p positively correlate with indoleamine 2,3-dioxygenase (IDO) expression in tumour-associated lymphatic vessels in advanced cervical squamous cell carcinoma (CSCC). The miR-142-5p is transferred by CSCC-secreted exosomes into LECs to exhaust CD8+ T cells via the up-regulation of lymphatic IDO expression, which was abrogated by an IDO inhibitor. Mechanistically, miR-142-5p directly down-regulates lymphatic AT-rich interactive domain-containing protein 2 (ARID2) expression, inhibits DNA methyltransferase 1 (DNMT1) recruitment to interferon (IFN)-γ promoter, and enhances IFN-γ transcription by suppressing promoter methylation, thereby leading to elevated IDO activity. Furthermore, increased serum exosomal miR-142-5p levels and the consequent IDO activity positively correlate with CSCC progression. In conclusion, exosomes secreted by CSCC cells deliver miR-142-5p to LECs and induce IDO expression via ARID2–DNMT1–IFN-γ signalling to suppress and exhaust CD8+ T cells. Our study suggests that LECs act as an integral component of the immune checkpoint(s) in the TME and may serve as a potential new target for CSCC diagnosis and treatment.

Copper nanoclusters (Cu NCs) as emerging luminescent metal NCs are gaining increasing attention owing to the comparatively low cost and high abundance of the Cu element in nature. However, it remains challenging to manipulate the optical properties of Cu NCs. Unlike most dispersed Cu NCs, whose luminescence efficiency was restricted by nonexcited relaxation, the Cu NCs confined in a porous poly-l-cysteine (poly-l-Cys) film were generated controllably with enhanced electrochemiluminescence (ECL) by in situ electrochemical reduction. Specifically, poly-l-Cys provided a porous structure to regulate the generation of Cu NCs within its holes, which not only increased the restriction on the intramolecular vibration and rotation of the ligands but also expedited the electron transfer near the electrode surface, reflecting in an enhancement of the ECL signal and efficiency. As an application of the confined Cu NCs, an ECL biosensor with high performance was constructed skillfully for highly sensitive detection of alkaline phosphatase (ALP), which adopted Cu NCs as the ECL luminophore and poly-l-Cys as a coreaction accelerator in a novel ECL ternary system (Cu NCs/S2O82-/poly-l-Cys). Furthermore, an ingenious target amplification based on the combination of a DNA walker and click chemistry was developed to convert ALP to DNA strands efficiently, achieving great improvement in the recognition efficiency. As a result, the biosensor had a low detection limit (9.5 × 10-7 U·L-1) and a wide linear range (10-8-10-2 U·L-1) for ALP detection, which showed great promise for the detection of non-nucleic acid targets and the diagnosis of diseases.

Purpose Surufatinib is a potent and orally active small-molecule tyrosine kinase inhibitor targeting VEGFRs 1 to 3, FGFR-1, and CSF-1R, and thus may exert antitumor and antiangiogenic effects. The objective of this study was to determine the tolerability and effects of food intake on the pharmacokinetic properties of surufatinib in healthy Chinese subjects. Methods A total of 24 healthy Chinese male subjects aged between 18 and 55 years were enrolled. Subjects were administered a single dose of surufatinib 250–mg capsules in the fasted and fed states in succession. Pharmacokinetic analysis was performed through the collection of blood samples at predose and at several time points after surufatinib administration. Tolerability assessments comprised physical examination including vital sign measurements, laboratory testing, and ECG to determine adverse events (AEs). Findings The 90% CIs of the geometric mean ratios of AUC0–t and AUC0–∞ in the fasted and fed states was within 0.80 to 1.25; and for Cmax, within 0.70 to 1.43, indicating that food had no effect on the bioavailability of surufatinib in these healthy Chinese male subjects. Food intake delayed the time to peak absorption of surufatinib, as the median Tmax in the fed state was longer than that in the fasted state (4.0 vs 2.0 h). Surufatinib was marginally excreted from urine (mean [SD] cumulative excretion fraction, 1.2% [0.4%]). AEs occurred in 7 of the 24 subjects (29.2%) and included upper respiratory tract infection, dizziness, merycism, intervertebral disc protrusion, influenza-like disease, hematuria, prostatitis, and elevated blood urea nitrogen. All AEs were grade 1 or 2. Implications The bioavailability of surufatinib was not affected by food intake prior to dosing. However, food intake led to delated Tmax of surufatinib. The tolerability of a single oral dose of surufatinib 250 mg in the fasted and fed states was favorable in these healthy Chinese male subjects. These results indicate that surufatinib capsules could be administered before or after meals. ClinicalTrials.gov identifier: NCT02320409.

Background The goal of this study was to determine whether Levey-Jennings charts, which are widely used in clinical laboratories, can be used to create standardized internal quality controls (IQCs) for prenatal molecular diagnosis. Methods Aneuploid amniocyte lines with trisomy 13, 21, and 18, and 47,XXY were established by transfection with SV40LTag-pcDNA3.1(−)and combined at different ratios to generate aneuploidy chimeric quality-control cell mixtures A to H. These quality-control cells were then used to calculate the $$ \overline{\mathrm{X}} $$ X ¯ , $$ \overline{\mathrm{X}} $$ X ¯ ±1 standard deviation (SD), $$ \overline{\mathrm{X}} $$ X ¯ ±2 SD, and $$ \overline{\mathrm{X}} $$ X ¯ ±3 SD values to develop standardized IQCs for methods used for the prenatal diagnosis of aneuploidies such as FISH. Results Methods for constructing aneuploid amniocyte lines were developed and a set of quality-control cells (A-H) were prepared. The $$ \overline{\mathrm{X}} $$ X ¯ ±1 SD, $$ \overline{\mathrm{X}} $$ X ¯ ±2 SD, and $$ \overline{\mathrm{X}} $$ X ¯ ±3 SD values of these quality-control cells for trisomy 13 and 21 were 10.2 ± 1.7, 10.2 ± 3.4, and 10.2 ± 5.1, and 90.3 ± 2.3, 90.3 ± 4.6, and 90.3 ± 6.9, respectively. Based on the values and Levey-Jennings charts, a set of standardized IQCs for prenatal diagnosis such as FISH were established. Conclusions This method resolves the problems of a shortage of quality-control materials and a lack of quality-control charts in prenatal molecular diagnosis such as NIPT, NGS, aCGH/SNP, PCR, and FISH. Levey-Jennings chart-based IQCs for prenatal diagnosis such as FISH can be used to easily monitor whether IQC results are within acceptable limits, and then infer whether the diagnostic results for clinical samples are reliable. We expect that this standardized IQC will be useful for a wide range of molecular diagnostic laboratories.

Distant metastasis is the major cause of short survival in ccRCC patients. However, the development of effective therapies for metastatic ccRCC is limited. Herein, we reported that ETV4 was selected from among 150 relevant genes with in vivo evidence of promoting metastasis. In this study, we identified that ETV4 promoted ccRCC cell migration and metastasis in vitro and in vivo, and a positive correlation between ETV4 and FOSL1 expression was found in ccRCC tissues and cell lines. Further investigation suggested that ETV4 increase FOSL1 expression through direct binding with the FOSL1 promoter. Furthermore, ETV4/FOSL1 was proved as a novel upstream and downstream causal relationship in ccRCC in an AKT dependent manner. In addition, both ETV4 and FOSL1 serve as an independent, unfavorable ccRCC prognostic indicator, and the accumulation of the ETV4 and FOSL1 in ccRCC patients result in a worse survival outcome in ccRCC patients. Taken together, our results suggest that the ETV4/FOSL1 axis acts as a prognostic biomarker and ETV4 directly up-regulates FOSL1 by binding with its promoter in a PI3K-AKT dependent manner, leading to metastasis and disease progression of ccRCC.

Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer with highly aggressive and metastatic potential in which distant metastasis is the main reason for treatment failure. Till present, the underlying molecular mechanisms of NPC metastasis remains poorly understood. Here, we identified S100 calcium-binding protein A14 (S100A14) as a functional regulator suppressing NPC metastasis by inhibiting the NF-kB signaling pathway and reversing the epithelial-mesenchymal transition (EMT). S100A14 was found to be downregulated in highly metastatic NPC cells and tissues. Immunohistochemical staining of 202 NPC samples revealed that lower S100A14 expression was significantly correlated with shorter patient overall survival (OS) and distant metastasis-free survival (DMFS). S100A14 was also found as an independent prognostic factor for favorable survival. Gain- and loss-of-function studies confirmed that S100A14 suppressed the in vitro and in vivo motility of NPC cells. Mechanistically, S100A14 promoted the ubiquitin-proteasome-mediated degradation of interleukin-1 receptor-associated kinase 1 (IRAK1) to suppress NPC cellular migration. Moreover, S100A14 and IRAK1 established a feedback loop that could be disrupted by the IRAK1 inhibitor T2457. Overall, our findings showed that the S100A14-IRAK1 feedback loop could be a promising therapeutic target for NPC metastasis.