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Circular RNAs (circRNAs) are involved in multiple physiological processes. However, whether circRNAs function as the indicators of lung adenocarcinoma (LUAD) remains unclear. Three LUAD-related microarray datasets were downloaded from the Gene Expression Omnibus database, and overlapping differentially expressed circRNAs (DECs) in LUAD were identified. circ_0007618 and circ_0029426 were revealed to be significantly dysregulated in LUAD and verified in LUAD tissues and serum obtained in this study. Subsequently, the overall survival curve and receiver operating characteristics curve analyses were performed to evaluate the prognosis, sensitivity, and specificity of circ_0007618 and circ_0029426 for LUAD diagnosis. The results indicate that the combination of circ_0007618 and circ_0029426 is a potential biomarker for LUAD diagnosis and prognosis. TargetScan and miRDB were used to predict interactions between microRNAs (miRNAs) and circRNAs/mRNAs. A circRNA-miRNA-mRNA network was established for LUAD diagnosis. The Kyoto Encyclopedia of Genes and Genomes and protein-protein interaction network identified four hub genes. In conclusion, circ_0007618 and circ_0029426 may be novel biomarkers for LUAD diagnosis and prognosis. For LUAD diagnosis, PIK3CA and NRAS, and KRAS and ETS1, were targeted by circ_0007618 and circ_0029426, respectively.

LY01008 had been identified as being highly similar to the bevacizumab reference product in the pharmacy and pharmacology terms. The primary objective of this study was to compare the pharmacokinetic characteristics of the biosimilar candidate LY01008 with that of the bevacizumab (AvastinIn this double-blind, parallel-group, phase I study, 102 male subjects aged 18-45 years were randomized 1:1 to receive a single intravenous infusion of 3 mg/kg LY01008 or bevacizumab. Before the pivotal section, 12 healthy male subjects receiving a single intravenous (IV) infusion of 0.5 mg/kg or 1.5 mg/kg LY01008 were screened to verify the safety and tolerability of LY01008. Primary endpoints included the area under the concentration-time curve (AUC) from time zero to the last quantifiable time point (AUCThe geometric mean ratios (GMRs) (90% confidence intervals, CIs) of AUCLY01008, a recombinant humanized monoclonal antibody (mAb) against vascular endothelial growth factor (VEGF), displayed pharmacokinetic similarity to bevacizumab, and good safety and tolerability profiles. The data from this trial provide fundamental information for further development.Clinical trial registration ID: CTR20170191.

Just noticeable difference (JND) of natural images refers to the maximum pixel intensity change magnitude that typical human visual system (HVS) cannot perceive. Existing efforts on JND estimation mainly dedicate to modeling the diverse masking effects in either/both spatial or/and frequency domains, and then fusing them into an overall JND estimate. In this work, we turn to a dramatically different way to address this problem with a top-down design philosophy. Instead of explicitly formulating and fusing different masking effects in a bottom-up way, the proposed JND estimation model dedicates to first predicting a critical perceptual lossless (CPL) counterpart of the original image and then calculating the difference map between the original image and the predicted CPL image as the JND map. We conduct subjective experiments to determine the critical points of 500 images and find that the distribution of cumulative normalized KLT coefficient energy values over all 500 images at these critical points can be well characterized by a Weibull distribution. Given a testing image, its corresponding critical point is determined by a simple weighted average scheme where the weights are determined by a fitted Weibull distribution function. The performance of the proposed JND model is evaluated explicitly with direct JND prediction and implicitly with two applications including JND-guided noise injection and JND-guided image compression. Experimental results have demonstrated that our proposed JND model can achieve better performance than several latest JND models. In addition, we also compare the proposed JND model with existing visual difference predicator (VDP) metrics in terms of the capability in distortion detection and discrimination. The results indicate that our JND model also has a good performance in this task., 16 pages, 16 figures

Aim: To screen and identify the potential biomarkers co-existing in plasma and serum of patients with non-small-cell lung cancer (NSCLC), and establish appropriate diagnostic models. Methods: A cohort of 195 plasma samples and 180 serum samples were obtained from healthy controls (HCs), adenocarcinoma (AdC) and squamous cell carcinoma (SqCC) patients enrolled from the First Affiliated Hospital of Nanjing Medical University. Metabolites in plasma and serum were analyzed by GC-MS. Results: Hypoxanthine was found to have good performance in the differential diagnosis of NSCLC (including AdC and SqCC) and HC (area under the receiver operating characteristic [AUROC] ≥0.85). Combinations of metabolites could be used for differential diagnosis of NSCLC and HC (AUROC >0.93), AdC and HC (AUROC >0.91), SqCC and HC (AUROC >0.95), AdC and SqCC (AUROC >0.72). Conclusions: Metabolomics based on GC-MS can screen and identify the differential metabolites coexisting in plasma and serum of patients with NSCLC, and prediction models established by this method can be used for the differential diagnosis of patients with NSCLC.

OBJECTIVES Our goal was to investigate whether laboratory signatures on admission could be used to identify risk stratification and different tolerance to hypothermic circulatory arrest in acute type A aortic dissection surgery. METHODS Patients from 10 Chinese hospitals participating in the Additive Anti-inflammatory Action for Aortopathy & Arteriopathy (5A) study were randomly divided into derivation and validation cohorts at a ratio of 7:3 to develop and validate a simple risk score model using preoperative variables associated with in-hospital mortality using multivariable logistic regression. The performance of the model was assessed using the area under the receiver operating characteristic curve. Subgroup analyses were performed to investigate whether the laboratory signature-based risk stratification could differentiate the tolerance to hypothermic circulatory arrest. RESULTS There were 1443 patients and 954 patients in the derivation and validation cohorts, respectively. Multivariable analysis showed the associations of older age, larger body mass index, lower platelet–neutrophile ratio, higher lymphocyte–monocyte ratio, higher D-dimer, lower fibrinogen and lower estimated glomerular filtration rate with in-hospital death, incorporated to develop a simple risk model (5A laboratory risk score), with an area under the receiver operating characteristic of 0.736 (95% confidence interval 0.700–0.771) and 0.715 (95% CI 0.681–0.750) in the derivation and validation cohorts, respectively. Patients at low risk were more tolerant to hypothermic circulatory arrest than those at middle to high risk in terms of in-hospital mortality [odds ratio 1.814 (0.222–14.846); odds ratio 1.824 (1.137–2.926) (P = 0.996)]. CONCLUSIONS The 5A laboratory-based risk score model reflecting inflammatory, immune, coagulation and metabolic pathways provided adequate discrimination performances in in-hospital mortality prediction, which contributed to differentiating the tolerance to hypothermic circulatory arrest in acute type A aortic dissection surgery. Clinical Trials. gov number NCT04918108

We explored the protective effect of spironolactone on cardiac function in the patients undergoing coronary artery bypass grafting (CABG) by determining serum hypoxia-inducible factor-1α (HIF-1α) before and after CABG. We used the propensity score matching method retrospectively to select 174 patients undergoing CABG in our hospital from March 2018 to December 2019. Of the 174 patients, 87 patients taking spironolactone for more than 3 months before CABG were used as a test group and other 87 patients who were not taking spironolactone as a control group. In all patients, serum HIF-1α and troponin I levels were determined before as well as 24 hours and 7 days after CABG, serum N-terminal probrain natriuretic peptide (NT-proBNP) level was determined before as well as 12, 24, and 36 hours after CABG, and electrocardiographic monitoring was performed within 36 hours after CABG. The results indicated that there were no significant differences in the HIF-1α level between the test group and the control group before and 7 days after CABG, but the HIF-1α level was significantly lower in the test group than that in the control group 24 hours after CABG (P < 0.01). The 2 groups were not significantly different in the troponin I level at any time point. There was no significant difference in the serum NT-proBNP level between the test group and the control group before CABG, but NT-proBNP (BNP) levels were all significantly lower in the test group than those in the control group at postoperative 12, 24, and 36 hour time points (all P

Aim To explore the biological function of miR-425/PAK4 axis in proliferation, metastasis, and apoptosis of ovarian cancer (OC) cells. Methods qRT-PCR and Western blot were adopted to examine miR-425 and PAK4 expressions in OC tissues and cell lines. Cell counting kit-8 (CCK-8) and BrdU assays were applied to detect the proliferation ability of OC cells, and Transwell assay was adopted to assess the migration and invasion of OC cells. Flow cytometry was employed to evaluate the apoptosis of OC cells. The interaction between miR-425 and PAK4 was predicted and verified by bioinformatics analysis and dual luciferase reporter gene assay, respectively. Results miR-425 was reduced in OC tissues and cell lines, and its underexpression was in evident correlation with the shorter overall survival time of OC patients. miR-425 impeded OC cell proliferation, migration, and invasion, and accelerated apoptosis. Additionally, PAK4 was validated as the target of miR-425, and the cotransfection of PAK4 reversed the antitumor effect of miR-425. Conclusion miR-425 suppresses the proliferation, migration, and invasion of OC cells and enhances apoptosis via inhibiting PAK4, and it is expected to be a prognostic indicator and therapeutic target for the patients with OC.

Objectives To investigate the perioperative outcomes of patients who underwent uniport video‐assisted thoracoscopic (VATS) segmentectomy for identifying the intersegmental boundary line (IBL) by the near‐infrared fluorescence imaging with the intravenous indocyanine green (ICG) method or the modified inflation‐deflation (MID) method and assess the feasibility and effectiveness of the ICG fluorescence (ICGF)‐based method. Methods We retrospectively analyzed the perioperative data in total 198 consecutive patients who underwent uniport VATS segmentectomy between February 2018 and August 2020. With the guidance of a preoperative imaging interpretation and analysis system (IQQA‐3D), the targeted segment structures could be precisely identified and dissected, and then the IBL was confirmed by the ICGF‐based method or the MID method. The clinical effectiveness and postoperative complications of the two methods were evaluated. Results An IBL was visible in 98% of patients in the ICGF‐based group, even with low doses of ICG. The ICGF‐based group was significantly associated with a shorter IBL clear presentation time (23.6 ± 4.4 vs. 23.6 ± 4.4 s) (p, Based on a large amount of clinical data, we found that the identification rate of IBL via ICGF‐based method is comparable to the traditional MID method which is the globally accepted. Our study shows that the ICGF‐based method can highly accurately identify the IBL and make anatomical segmentectomy easier and faster, and it helps to ensure sufficient resection margins, and therefore has the potential to be a feasible and effective technique to facilitate the quality of uniport VATS segmentectomy.

SHR0534 is being developed for type-2 diabetes mellitus. Herein the tolerability, safety, pharmacokinetics and pharmacodynamics of SHR0534 in healthy Chinese subjects were assessed in a phase-I, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study. Forty subjects were randomized 4:1 to receive SHR0534 at the dose of 10, 25, 50 or 100 mg, or placebo, and another eleven subjects were allocated to either the 5 mg group or the placebo group at an 8:3 ratio. All subjects received a single dose on day 1, followed by a 9-day washout and once-daily administrations for 14 consecutive days. Serial samples were collected, and vital signs, electrocardiograms, laboratory tests, urinalysis and adverse events (AEs) were recorded. All doses of SHR0534 were safe and well tolerated with infrequent, generally mild-to-moderate AEs and no serious AEs in the study. SHR0534 was absorbed with a

Blocking host cell death is an important virulence strategy employed by many bacterial pathogens. We recently reported that Shigella flexneri inhibits host pyroptosis by delivering a type III secretion system (T3SS) effector OspC3 that catalyzes a novel arginine ADP-riboxanation modification on caspase-4/11. Here, we investigated the OspC3 homologue CopC from Chromobacterium violaceum, an opportunistic but sometimes deadly bacterial pathogen. CopC bears the same arginine ADP-riboxanase activity as OspC3, but with a different substrate specificity. Through proteomic analysis, we first identified host calmodulin (CaM) as a binding partner of CopC. The analyses additionally revealed that CopC preferably modifies apoptotic caspases including caspase-7, -8 and -9. This results in suppression of both extrinsic and intrinsic apoptosis programs in C. violaceum-infected cells. Biochemical reconstitution showed that CopC requires binding to CaM, specifically in the calcium-free state, to achieve efficient ADP-riboxanation of the caspases. We determined crystal structure of the CaM-CopC-CASP7 ternary complex, which illustrates the caspase recognition mechanism and a unique CaM-binding mode in CopC. Structure-directed mutagenesis validated the functional significance of CaM binding for stimulating CopC modification of its caspase substrates. CopC adopts an ADP-ribosyltransferase-like fold with a unique His-Phe-Glu catalytic triad, featuring two acidic residues critical for site-specific arginine ADP-riboxanation. Our study expands and deepens our understanding of the OspC family of ADP-riboxanase effectors.

Aim: To investigate the anticancer effects and action mechanism of graphene oxide (GO) in colorectal cancer (CRC). Materials & methods: Anticancer effects and mechanisms of GO in CRC were investigated both in vivo and in vitro. Results: GO significantly inhibited tumor growth both in vitro and in vivo. GO was able to enter HCT116 cells through endocytosis. GO treatment resulted in cytotoxicity, reactive oxygen species (ROS) production, apoptosis, autophagy and activation of the AMPK/mTOR/ULK1 signal pathway. However, ROS scavenger N-acetylcysteine (NAC) attenuated the above effects and restored the effects of GO on protein expressions related to apoptosis, autophagy and AMPK/mTOR/ULK1 signal pathways. Conclusion: GO exerts anticancer effects against CRC via ROS-dependent AMPK/mTOR/ULK-1 pathway-related autophagy and apoptosis.

To test the hypothesis that ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome, caused by dominant mutation inThis cohort study systematically evaluated 27 patients with ROSAH syndrome for inflammatory features and investigated the effect ofThe majority of the cohort carried the p.Thr237Met mutation but we also identified a new ROSAH-associated mutation, p.Tyr254Cys.Nearly all patients exhibited at least one feature consistent with inflammation including recurrent fever, headaches with meningeal enhancement and premature basal ganglia/brainstem mineralisation on MRI, deforming arthritis and AA amyloidosis. However, there was significant phenotypic variation, even within families and some adults lacked functional visual deficits. While anti-TNF and anti-IL-1 therapies suppressed systemic inflammation and improved quality of life, anti-IL-6 (tocilizumab) was the only anticytokine therapy that improved intraocular inflammation (two of two patients).Patients' primary samples and in vitro assays with mutated ALPK1 constructs showed immune activation with increased NF-κB signalling, STAT1 phosphorylation and interferon gene expression signature. Knock-in mice with theROSAH syndrome is an autoinflammatory disease caused by gain-of-function mutations in

Background. Video-assisted thoracoscopic segmentectomy has been considered to be an effective management in properly selected patients. Given the substantial technical difficulties, uniportal thoracoscopic segmentectomy is a challenging surgical procedure. The purpose of this study was to investigate the learning curve for uniportal thoracoscopic segmentectomy procedures. Methods. Prospectively collected data were retrospectively analyzed for a series of 124 consecutive patients undergoing uniportal thoracoscopic segmentectomy from August 2016 to September 2018. The learning curve for uniportal thoracoscopic segmentectomy was studied using cumulative sum (CUSUM) combined with risk-adjusted cumulative sum (RA-CUSUM) methods. Results. According to the CUSUM combined with the RA-CUSUM analyses, the learning curve for uniportal thoracoscopic segmentectomy was composed of three well-differentiated phases: cases 1 to 24, cases 25 to 57, and cases 58 to 124. With the procedures proceeded orderly, the operation time tends to progressively decrease. Conclusions. The uniportal thoracoscopic segmentectomy is considered to be a feasible and safe surgical procedure that can be taught to surgeons through a proctored learning curve. The data of the present study indicate that the inflection point for completion the learning curve was reached after a considerable number of 57 cases.

Salmonella enterica serovar Typhimurium, an intracellular Gram-negative bacterial pathogen, employs two type III secretion systems to deliver virulence effector proteins to host cells. One such effector, SseK3, is a Golgi-targeting arginine GlcNAc transferase. Here, we show that SseK3 colocalizes with cis-Golgi via lipid binding. Arg-GlcNAc-omics profiling reveals that SseK3 modifies Rab1 and some phylogenetically related Rab GTPases. These modifications are dependent on C-termini of Rabs but independent of the GTP- or GDP-bound forms. Arginine GlcNAcylation occurs in the switch II region and the third α-helix and severely disturbs the function of Rab1. The arginine GlcNAc transferase activity of SseK3 is required for the replication of Salmonella in RAW264.7 macrophages and bacterial virulence in the mouse model of Salmonella infection. Therefore, this SseK3 mechanism of action represents a new understanding of the strategy adopted by Salmonella to target host trafficking systems., Meng, Zhuang, Peng et al. study the role of a Golgi-targeting arginine GlcNAc transferase, SseK3, in the pathogenesis of Salmonella enterica. Through R-GlcNAcylated proteome analysis, they identify Rab proteins as targets for SseK3 as well as their modification sites. They demonstrate that SseK3 GlcNAc transferase activity is required for bacterial virulence in vitro and in vivo.

Exploration of changes in eye movement at different flight conditions can enrich scholarly understanding of situation awareness (SA) and inform new scanning behavior training techniques for efficient and effective pilot education. The SA requirements for pilots vary from mission to mission. Eye tracking is often used to analyze various attention allocation and SA acquisition processes at work in different missions. Pilot eye movements were measured during a climbing task and circling task using a cockpit-based simulator. Results of situation awareness rating technique (SART) tests show that there are significant differences between attention processes during climbing versus circling flight tasks. Fixation frequency during climbing is lower than in the circling task. Additionally, saccade frequency and average fixation time in the climbing task are markedly higher than those in the circling task. Wilcoxon test results show that the pilot has a higher fixation count and fixation time during the circling phase in out-view (OV) areas of interest (AOI) than during the climbing phase. Notably, the attention probability is higher in climbing task than in circling task when the current area of fixation (AOF) is in the head-up display (HUD) AOI and the next fixation area is in the instrumentation panel left (IPL); when the current AOF is in the out-view right (OVR) and the next AOF is HUD, the attention probability is higher in climbing task than in circling task; when the current fixation is in the IPL and the next fixation probability is to the out-view left (OVL), the attention probability is higher in task climbing task than in circling task. In terms of the Markov stationary distribution, the Wilcoxon test shows that, when IPL AOI is the area of the maximum probability of fixation in both tasks, the attention probability of HUD AOI and instrumentation panel right (IPR) is higher in climbing task than in circling task. Circling tasks require efficient eye movement patterns accompanied by strict attention distribution, which yields high SA level and flight performance when performed properly. This paper summarizes the attention characteristics at different flight phases and various requirements of different tasks according to pilot eye movement tracking results. Similar activities, as routine training, can enhance the efficiency of a novice pilot’s attention distribution.

This study aimed to evaluate the bioequivalence (BE) of 2 formulations of the 10-mg rivaroxaban tablet. The study was a randomized, open-label, 4-period, crossover study that included 28 healthy subjects in fasting or fed conditions. The pharmacokinetic parameters were determined based on the concentrations of rivaroxaban using high-performance liquid chromatography with a tandem mass spectrometer detector. In each of the 4 study periods with fasting or fed conditions, a single dose of test or reference product was administered. Rivaroxaban concentrations in plasma were determined using a validated liquid chromatography with a tandem mass spectrometer detector method. The pharmacokinetic parameters assessed were the area under the plasma concentration-time curve (AUC0-t , AUC0-∞ ), the peak plasma concentration of the drug (Cmax ), time to achieve Cmax , elimination half-life, within-subject variability of test drug, and within-subject variability of reference drug. The geometric mean ratio (90%CI) of the test drug/reference drug for rivaroxaban was 90.38% to 103.60% for AUC0-t in fasting conditions and 90.13% to 100.42% in fed conditions. The AUC0-∞ s were 89.94% to 102.50% and 90.14% to 100.45% under fasting and fed conditions, respectively. The Cmax values were 90.58% to 105.01% and 96.36% to 108.07% in these 2 conditions, respectively. All 90%CIs for test drug/reference drug geometric mean ratio were ≤2.5. The 90%CIs for test/reference AUC ratio and Cmax ratio were within the acceptable range for BE. There were no adverse events encountered during this BE study. The study's results indicated that the 2 formulations of the rivaroxaban tablet were bioequivalent.

BACKGROUND The aim of this study was to assess a radiomic scheme that combines image features from digital mammography and dynamic contrast-enhanced MRI to improve classification accuracy of nonpalpable breast lesion (NBL) with Breast Imaging-Reporting and Data System (BI-RADS) 3-5 microcalcifications-only in mammography. MATERIAL AND METHODS This retrospective study was approved by the Internal Research Review and Ethical Committee of our hospital. We included 81 patients who underwent a three-dimensional digital breast X-ray wire positioning for local resection between October 2012 and November 2016. All patients underwent breast MRI and mammography before the treatment, and all obtained pathological confirmation. According to the pathological results, 41 patients with benign lesions were assigned to the benign group and 40 patients with malignant lesions were assigned to the malignant group. We used the random forest algorithm to select significant features and to test the single and multimodal classifiers using the Leave-One-Out-Cross-Validation method. An area under the receiver operating characteristic curve was also used to evaluate its discriminating performance. RESULTS The multimodal classifier achieved AUC of 0.903, with a sensitivity of 82.5% and a specificity of 80.48%, which was better than any single modality. CONCLUSIONS Multimodal radiomics classification shows promising power in discriminating malignant lesions from benign lesions in NBL patients with BI-RADS 3-5 microcalcifications-only in mammography.

This study investigated the pharmacokinetics and pharmacodynamics properties, safety and tolerability of cetagliptin.Forty-eight healthy subjects were enrolled in this study. Three cohorts were investigated in sequential order: 50, 100 and 200 mg cetagliptin. Positive control (sitagliptin 100 mg) was designed as open label. Blood samples were collected and analysed for pharmacokinetic and pharmacodynamic properties. Safety and tolerability were assessed throughout the study.Following multiple oral doses, cetagliptin was rapidly absorbed and reached peak plasma concentrations after approximately 1.0-1.5 hours. Plasma cetagliptin concentrations increased at a rate greater than dose. Accumulation of cetagliptin was modest, and steady state was generally achieved at day 5. Doses ≥50 mg of cetagliptin administered once daily will result in sustained dipeptidyl peptidase-4 (DPP-4) inhibition (≥80%). The plasma concentration giving 50% of maximum drug effect of DPP-4 inhibition for cetagliptin (5.29 ng/mL) was lower than that of sitagliptin (7.03 ng/mL). Active glucagon-like-1 peptide (GLP-1) concentrations were significantly increased in the cetagliptin groups by 2.3- to 3.1-fold at day 1 and 3.1- to 3.6-fold at steady state compared with that of placebo, and active GLP-1 concentrations were increased with increasing dose. Compared with sitagliptin, doses ≥100 mg once daily of cetagliptin produced postprandial increases in active GLP-1 level and induced to long-lasting glucose-lowering efficacy. Cetagliptin was well tolerated across all doses studied.Cetagliptin demonstrates the great potential for treatment with type 2 diabetes patients based on the inhibition of DPP-4, the increase in GLP-1 and insulin, the decrease in glucose, and might be more effective in DPP-4 inhibition than sitagliptin.

Background and objectives Cetagliptin is a highly selective dipeptidyl peptidase-4 inhibitor under development to treat type 2 diabetes mellitus. This first-in-human study was conducted to characterise the pharmacokinetics, pharmacodynamics and tolerability of single-ascending oral doses of cetagliptin in healthy subjects. In addition, the effect of food on pharmacokinetics was evaluated. Methods Study 1 enrolled 66 healthy subjects in a double-blind, randomised, placebo-controlled, single-dose escalation study; sitagliptin was employed as a positive open-label control. Forty-four subjects were assigned to seven cohorts (cetagliptin 12.5, 25, 50, 100, 200, 300 or 400 mg); 12 subjects were assigned to the placebo group. The remaining ten subjects received sitagliptin 100 mg as the positive control. Blood, urine and faeces were collected for the pharmacokinetic analysis and determination of plasma dipeptidyl peptidase-4 inhibition, active glucagon-like peptide-1, glucose and insulin levels. In Study 2, 14 healthy subjects were assigned to a randomised, open-label, two-period crossover study, and received a single oral dose of cetagliptin 100 mg in the fasted state or after a high-fat meal, with a 14-day washout period between treatments. Blood samples were collected to evaluate the effects of food on the pharmacokinetics of cetagliptin. Results Following administration of a single oral dose, cetagliptin was rapidly absorbed, presenting a median time to maximum concentration of 1.0-3.25 h. The terminal half-life ranged between 25.8 and 41.3 h, which was considerably longer than that of sitagliptin. The area under the plasma concentration-time curve was approximately dose proportional between 25 mg and 400 mg, and the increase in maximum concentration was greater than dose proportional. The unchanged drug was mainly excreted in the urine (27.2-46.2% of dose) and minimally via the faeces (1.4% of dose). Dipeptidyl peptidase-4 inhibition, an increase in active glucagon-like peptide-1 and a slight decrease in blood glucose were observed, whereas insulin was not significantly altered when compared with placebo. The weighted average dipeptidyl peptidase-4 inhibition by cetagliptin 100 mg was higher than that mediated by sitagliptin 100 mg. Cetagliptin was well tolerated up to a single oral dose of 400 mg. No food effects were noted. Conclusions Cetagliptin inhibited plasma dipeptidyl peptidase-4 activity, increased levels of active glucagon-like peptide-1 and was well tolerated at single doses up to 400 mg, eliciting no dose-limiting toxicity in healthy volunteers. Food did not affect the pharmacokinetics of cetagliptin. Clinical trial registration The studies were registered at http://www.chinadrugtrials.org.cn (Nos. CTR20180167 and CTR20181331).

The ontogenetic sleep hypothesis suggested that rapid eye movement (REM) sleep is ontogenetically primitive. Namely, REM sleep plays an imperative role in the maturation of the central nervous system. In coincidence with a rapidly developing brain during the early period of life, a remarkably large amount of REM sleep has been identified in numerous behavioral and polysomnographic studies across species. The abundant REM sleep appears to serve to optimize a cerebral state suitable for homeostasis and inherent neuronal activities favorable to brain maturation, ranging from neuronal differentiation, migration, and myelination to synaptic formation and elimination. Progressively more studies in Mammalia have provided the underlying mechanisms involved in some REM sleep-related disorders (e.g., narcolepsy, autism, attention deficit hyperactivity disorder (ADHD)). We summarize the remarkable alterations of polysomnographic, behavioral, and physiological characteristics in humans and Mammalia. Through a comprehensive review, we offer a hybrid of animal and human findings, demonstrating that early-life REM sleep disturbances constitute a common feature of many neurodevelopmental disorders. Our review may assist and promote investigations of the underlying mechanisms, functions, and neurodevelopmental diseases involved in REM sleep during early life.

SY-004, a dual-acting full glucokinase activator, is under development to provide a dose-dependent improvement of glucose control. This study aimed to assess the tolerability, safety, and pharmacokinetic and pharmacodynamic properties of SY-004 in healthy Chinese adults.Two study participants were administered 2 mg of SY-004 in the 2-mg cohort, whereas 6 study participants were randomized with 4 study participants receiving SY-004 and 2 receiving placebo in the 20-mg cohort. In each of other 3 dose cohorts (40, 80, and 120 mg), 12 participants were randomized in a 10:2 ratio to receive single oral SY-004 capsules or placebos. Drug concentrations, glucose and insulin levels, and safety data were assessed and analyzed. Noncompartmental analysis was used to determine SY-004 pharmacokinetic parameters.SY-004 was generally well tolerated. Nine of the 44 study participants reported 17 treatment-related adverse events, and most treatment-related adverse events were mild. SY-004 had approximately dose-proportional increases in systemic exposure. The mean tSY-004, a new potential glucokinase activator, had favorable safety profiles and good PK characteristics. The glucose-lowering effects were slightly dose related. The SY-004 data in healthy Chinese adults supports further development.gov identifier: NCT03171623.

We investigated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) environmental contamination in 2 rooms of a quarantine hotel after 2 presymptomatic persons who stayed there were laboratory-confirmed as having coronavirus disease. We detected SARS-CoV-2 RNA on 8 (36%) of 22 surfaces, as well as on the pillow cover, sheet, and duvet cover.

The gasdermins are a family of recently identified pore-forming effector proteins that cause membrane permeabilization and pyroptosis, a lytic pro-inflammatory type of cell death. Gasdermins contain a cytotoxic N-terminal domain and a C-terminal repressor domain connected by a flexible linker. Proteolytic cleavage between these two domains releases the intramolecular inhibition on the cytotoxic domain, allowing it to insert into cell membranes and form large oligomeric pores, which disrupts ion homeostasis and induces cell death. Gasdermin-induced pyroptosis plays a prominent role in many hereditary diseases and (auto)inflammatory disorders as well as in cancer. In this Review, we discuss recent developments in gasdermin research with a focus on mechanisms that control gasdermin activation, pore formation and functional consequences of gasdermin-induced membrane permeabilization.

Objectives At present, the modified inflation-deflation method is accepted and widely used in the clinic, but the near-infrared (NIR) fluorescence imaging with intravenous indocyanine green (ICG) method can also delineate the intersegmental demarcation. However, whether the two methods identify that the intersegmental plane is concordant with each other and match the real intersegmental demarcation is still unknown. Methods Between March 2019 to July 2019, 19 consecutive segmentectomies were performed, using both methods to delineate the intersegmental plane, in order to evaluate and verify whether the intersegmental plane results created by the two methods were concordant and matched the real intersegmental demarcation. Results Segmentectomies were carried out using uniportal video-assisted thoracic surgery (UVATS) successfully with no intraoperative conversions or ICG-related complications and only three cases (15.8%) with postoperative complications related to the operation. The intersegmental plane generated by the NIR fluorescence imaging with intravenous ICG method was found to be totally concordant with the modified inflation-deflation method that was approaching the real intersegmental demarcation in all 19 cases. Conclusions Both methods revealed the intersegmental plane clearly, and the NIR fluorescence imaging with intravenous ICG method was found to be totally concordant with the modified inflation-deflation method, which is highly concordant with the real intersegmental demarcation. NIR fluorescence imaging with intravenous ICG method may be more popular because of its safety, efficiency, and less complicated restrictions, especially in patients with pulmonary emphysema. Low doses of ICG do not affect the rate of identification of the intersegmental plane and is safer from drug toxicology.

Netrin-1 exhibits anti-inflammatory properties. Netrin-1 could alleviate brain injury of subarachnoid hemorrhage (SAH) rat. This study was designed to discern the utility of serum netrin-1 as a biomarker for assessing the severity and prognosis of patients with aneurysmal SAH.Netrin-1 concentrations were gauged in serum from 104 patients and 104 controls. Hemorrhagic clinical and radiological severity was assessed utilizing World Federation of Neurological Surgeons (WFNS) score, modified Fisher score, and Hunt Hess score. Glasgow Outcome Scale (GOS) score was recorded at 6 months after SAH. GOS score of 1-3 was considered as a poor outcome.Patients showed substantially lower serum netrin-1 concentrations than controls (median, 237.9 pg/ml; interquartile range, 189.6-271.2 pg/ml vs. median, 815.4 pg/ml; interquartile range, 581.8-990.4 pg/ml). Netrin-1 concentrations were independently correlated with WNFS score, modified Fisher score, Hunt Hess score and serum C-reactive protein concentrations (t = -4.667, -3.792, -4.304 and - 3.549 respectively). Area under ROC curve was 0.837 (95% CI, 0.752-0.902) for predicting 6-month poor prognosis. Serum netrin-1 concentrations229.3 pg/ml emerged as an independent prognostic predictor (odds ratio, 14.316; 95% confidence interval, 5.032-40.726).Serum netrin-1 might represent a potential biomarker for reflecting severity, inflammation and prognosis of human aneurysmal SAH.

Monitoring of the cytosolic compartment by the innate immune system for pathogen-encoded products or pathogen activities often enables the activation of a subset of caspases. In most cases, the cytosolic surveillance pathways are coupled to activation of caspase-1 via canonical inflammasome complexes. A related set of caspases, caspase-11 in rodents and caspase-4 and caspase-5 in humans, monitors the cytosol for bacterial lipopolysaccharide (LPS). Direct activation of caspase-11, caspase-4 and caspase-5 by intracellular LPS elicits the lytic cell death called ‘pyroptosis’, which occurs in multiple cell types. The pyroptosis is executed by the pore-forming protein GSDMD, which is activated by cleavage mediated by caspase-11, caspase-4 or caspase-5. In monocytes, formation of GSDMD pores can induce activation of the NLRP3 inflammasome for maturation of the cytokines IL-1β and IL-18. Caspase-11-mediated pyroptosis in response to cytosolic LPS is critical for antibacterial defense and septic shock. Here we review the emerging literature on the sensing of cytosolic LPS and its regulation and pathophysiological functions. Comprehensive immunity requires that cells sense intracellular pathogens. In their Review, Shao and colleagues describe mechanisms for the recognition of intracellular lipopolysaccharide and its essential role in responses to Gram-negative bacteria.

The associations of vegetable and fruit intake with liver cancer risk have been inconsistent based on epidemiological studies. The present study aimed to quantitatively evaluate these associations with prospective cohort studies. A systematic literature search was performed with PubMed and Scopus databases up to June 2019. Multivariate-adjusted relative risks (RRs) with a corresponding 95% confidence interval (CI) for the highest versus lowest category were pooled by using a random-effects model. Pre-specified subgroup and univariate meta-regression analyses were performed to identify the sources of heterogeneity. Dose–response analysis was conducted by using the variance weighted least squares regression model. Nine independent prospective cohort studies with 1703 liver cancer events and 1 326 176 participants were included for data synthesis. The summary estimates showed that higher vegetable intake was associated with a 39% (95%CI: 0.50, 0.75) reduction in liver cancer risk, with no significant between-study heterogeneity (P = 0.057). Dose–response analysis indicated that the risk of liver cancer was reduced by 4% (95%CI: 0.97, 0.95; P for trend

Background High incidence of asymptomatic venous thromboembolism (VTE) has been observed in severe COVID‐19 patients, but the characteristics of symptomatic VTE in general COVID‐19 patients have not been described. Objectives To comprehensively explore the prevalence and reliable risk prediction for VTE in COVID‐19 patients. Methods/Results This retrospective study enrolled all COVID‐19 patients with a subsequent VTE in 16 centers in China from January 1 to March 31, 2020. A total of 2779 patients were confirmed with COVID‐19. In comparison to 23,434 non‐COVID‐19 medical inpatients, the odds ratios (ORs) for developing symptomatic VTE in severe and non‐severe hospitalized COVID‐19 patients were 5.94 (95% confidence interval [CI] 3.91–10.09) and 2.79 (95% CI 1.43–5.60), respectively. When 104 VTE cases and 208 non‐VTE cases were compared, pulmonary embolism cases had a higher rate for in‐hospital death (OR 6.74, 95% CI 2.18–20.81). VTE developed at a median of 21 days (interquartile range 13.25–31) since onset. Independent factors for VTE were advancing age, cancer, longer interval from symptom onset to admission, lower fibrinogen and higher D‐dimer on admission, and D‐dimer increment (DI) ≥1.5‐fold; of these, DI ≥1.5‐fold had the most significant association (OR 14.18, 95% CI 6.25–32.18, p = 2.23 × 10−10). A novel model consisting of three simple coagulation variables (fibrinogen and D‐dimer levels on admission, and DI ≥1.5‐fold) showed good prediction for symptomatic VTE (area under the curve 0.865, 95% CI 0.822–0.907, sensitivity 0.930, specificity 0.710). Conclusions There is an excess risk of VTE in hospitalized COVID‐19 patients. This novel model can aid early identification of patients who are at high risk for VTE.

Fungal infections of the central nervous system (CNS) may lead to life-threatening meningitis. Itraconazole (ITZ) is an effective antifungal agent that can be used to treat various fungal infections; however, its poor solubility along with poor permeability of the blood-brain barrier (BBB) prevents it from treating meningitis. Receptor mediated transcytosis (RMT) shows modest efficacy in BBB crossing, while affinity and saturability of interactions between ligands and receptors account for the limited efficacy of RMT in crossing the BBB. Mild hyperthermia could temporarily disrupt the BBB to increase its permeability. Therefore, we speculated that the combination of mild hyperthermia with RMT could potentially increase BBB permeability of ITZ leading to improved efficacy in fungal meningitis. Here, we have constructed for the first time, apolipoprotein E (Apo E) mimicked peptide COG1410 modified polydopamine (PDA)-coated bovine serum albumin nanoparticles (ApoE-PDA@ITZ-NPs). Different levels of COG1410-modified NPs were prepared and characterized. ApoE-PDA@ITZ-NPs have a superior photothermal effect under 808 nm light irradiation and exhibited favorable plasma stability and photothermal stability. Moreover, the cellular uptake of nanoparticles increased with an increase in COG1410. H-ApoE-PDA@ITZ-NPs increased cellular uptake and in vitro BBB permeability by 4.2-fold and 4.8-fold, respectively, compared to the ITZ-NPs. Live imaging implied that H-ApoE-PDA@ITZ-NPs could significantly increase the distribution of ITZ in the brain under 808 nm light irradiation. Histopathological analysis of periodic acid-Schiff-stained brain sections of the H-ApoE-PDA@ITZ-NP treated C. albicans meningitis model indicated that H-ApoE-PDA@ITZ-NPs showed superior antifungal activity after 808 nm light irradiation. Hence, we report ApoE-PDA@ITZ-NPs in tandem with 808 nm irradiation as a novel strategy of RMT combination with a photothermal effect in enhancing BBB permeability to facilitate drug accumulation in the brain region and enhance the therapeutic efficacy of ITZ in meningitis.

Bacterial flagellin can elicit production of TLR5-mediated IL-22 and NLRC4-mediated IL-18 cytokines that act in concert to cure and prevent rotavirus (RV) infection. This study investigated the mechanism by which these cyto-kines act to impede RV. Although IL-18 and IL-22 induce each other's expression, we found that IL-18 and IL-22 both impeded RV independently of one another and did so by distinct mechanisms that involved activation of their cognate receptors in intestinal epithelial cells (IEC). IL-22 drove IEC proliferation and migration toward villus tips, which resulted in increased extrusion of highly differentiated IEC that serve as the site of RV replication. In contrast, IL-18 induced cell death of RV-infected IEC thus directly interrupting the RV replication cycle, resulting in spewing of incompetent virus into the intestinal lumen and causing a rapid drop in the number of RV-infected IEC. Together, these actions resulted in rapid and complete expulsion of RV, even in hosts with severely compromised immune systems. These results suggest that a cocktail of IL-18 and IL-22 might be a means of treating viral infections that preferentially target short-lived epithelial cells.

The high-mobility group box-1 (HMGB1) protein is implicated in the development of various cancers and their proliferation. According to its function, HMGB1 shuttles between the cell nucleus and cytoplasm, assisting with nucleosome stabilization and gene transcription, or localizing in the cell membrane for outgrowth. The clinicopathologic and prognostic significance of these different subcellular locations and their correlation has been unclear in colorectal cancer (CRC). We found significantly higher rates of nuclear HMGB1 expression in CRC and colorectal adenoma tissue samples (84.0% and 92.6%, respectively) than in normal colorectal tissue (15.0%) and a significantly higher rate of positive cytoplasmic HMGB1 expression in CRC tissue (25.2%) compared with colorectal adenoma (11.8%) and normal colorectal tissue (0.0%). Positive cytoplasmic HMGB1 expression was associated with high-grade CRC, a poor prognosis, and was negatively correlated with strongly positive nuclear HMGB1 expression in CRC tissue specimens (r = – 0.377, P = 0.000). CRC patients with strongly positive nuclear HMGB1 expression had a better survival prognosis than other CRC patients. Preventing nuclear plasma translocation of HMGB1 may be a new strategy for CRC management.

Globalagliatin, a glucokinase activator, plays a vital role in glucose homeostasis. The aim of this study was to assess the safety, pharmacokinetics, and pharmacodynamics of globalagliatin in Chinese patients with type 2 diabetes. In this dose-titration study, 24 patients were randomized (3:1 ratio) to receive globalagliatin or placebo. The 28-day titration was divided into two stages, each comprising 12 subjects. In stage I (low-dose), globalagliatin or placebo was administered at ascending doses of 20, 40, 80, and 120 mg once daily, increased at weekly intervals. As the treatment was well tolerated, stage II (high-dose) was initiated, with ascending doses of 80, 160, 240, and 320 mg. Safety, pharmacokinetic and pharmacodynamic analysis were conducted. Following once-daily titration with ascending doses of globalagliatin of 20–120 mg (stage I) and 80–320 mg (stage II) for 7 days, globalagliatin caused mildly high incidences of hypoglycemia and hypertriglyceridemia. The mean maximum plasma concentration (Cmax) of globalagliatin increased from 7.76 to 138.13 ng/mL (stage I), and 29.36 to 471.50 ng/mL (stage II), which occurred at 3–5 h post-dose. A steady state was achieved after 7 days of once-daily dosing in stage I and stage II, respectively. Mean area under the plasma-concentration curve for steady-state 24-h interval (AUC0-24) increased from 106.13 to 2461.95 ng·h/mL (stage I) and 369.71 to 9218.38 ng·h/mL (stage II). Fasting plasma glucose (FPG) decreased continuously during the titration period. Compared with the placebo, high-dose globalagliatin significantly increased the reductions in FPG, the area under the curve of 24-h glucose levels, and glycated albumin, with least-squares mean changes (relative to baseline) of − 4.08 mmol/L (95% CI − 5.05 to − 3.12) (P

The associations between copper and zinc intake with the risk of inflammatory bowel disease (IBD) and fecal incontinence symptoms in the general population are not well understood. This study aims to evaluate the associations of zinc and copper intake with the risk of IBD and fecal incontinence symptoms in adults aged ≥ 20 years using data from the 2009-2010 National Health and Nutritional Examination Surveys (NHANES) (N = 5593). The presence of IBD was analyzed from the NHANES data, directly querying the presence or absence of ulcerative colitis (UC) and Crohn's disease (CD). Fecal incontinence symptoms including accidental bowel leakage of gas, mucus, liquid, or solid stool were determined by using the bowel health questionnaire. Multivariable logistic regressions models were performed controlling for confounding factors (dietary, lifestyle, psychological, and health conditions). No associations between either zinc or copper intake with IBD were found. However, zinc intake was independently associated with increased risk of bowel leakage of gas or liquid. Compared with quartile 1, the multivariate-adjusted ORs (95%CI) of bowel leakage of gas across quartiles 2-4 of zinc intake were 1.41 (1.15-1.71), 1.30 (1.00-1.68), and 1.61 (1.16-2.23). Likewise, there was a trend for higher odds of bowel leakage of liquid among participants in the higher zinc intake. Compared with quartile 1, the multivariate-adjusted ORs (95%CI) of bowel leakage of liquid across quartiles 2-4 of zinc intake were 3.55 (0.94-13.41), 3.65 (1.27-10.47), and 5.06 (1.25-20.50). Future prospective studies are warranted to confirm these findings.

Microbial pathogens have evolved complex mechanisms to interface with host cells in order to evade host defenses and replicate. However, mammalian innate immune receptors detect the presence of molecules unique to the microbial world or sense the activity of virulence factors, activating antimicrobial and inflammatory pathways. We focus on how studies of the major virulence factor of one group of microbial pathogens, the type III secretion system (T3SS) of human pathogenic

BACKGROUND Cerebral ischemia-reperfusion injury is a form of serious nervous system injury. Activation of the PI3K/Akt pathway can effectively relieve cerebral ischemia-reperfusion injury. miR-214 can target and inhibit the expression of PTEN, thereby alleviating its inhibitory effect on the PI3K/Akt pathway. Moreover, lncRNA NEAT1 was reported to affect proliferation and metastasis of tumor cells by targeting and suppressing the expression of miR-214. However, whether lncRNA NEAT1 affects the cerebral ischemia-reperfusion-induced damage by regulating the miR-214/PTEN/PI3K/Akt pathway is unclear. MATERIAL AND METHODS The miR-214 agomir and miR-214 antagomir were designed and injected into the encephalocele of MCAO rats. Next, the production of oxidative stress kinase and apoptosis of brain cells were detected using commercial kits. The levels of PTEN, PI3K, Akt, p-Akt, and VEGF in brain tissues were determined. Next, the targeting effect of lncRNA NEAT1 and miR-214 was determined with luciferase reporter assay. RESULTS Overexpression of miR-214 relieved the apoptosis and oxidative stress of brain tissues. Overexpression of miR-214 promoted the expression of PI3K, Akt, p-Akt, and VEGF by inhibiting the production of PTEN. However, overexpression of lncRNA NEAT1 repressed the remission effect of miR-214 on cerebral ischemia-reperfusion-induced damage and inhibited the production of PI3K, Akt, p-Akt, and VEGF by rescuing the levels of PTEN. CONCLUSIONS lncRNA NEAT1 aggravates cerebral ischemia-reperfusion injury by abolishing the activation effect of miR-214 on the PI3K/Akt pathway.

The clinical characteristics of patients with COVID-19 were analysed to determine the factors influencing the prognosis and virus shedding time to facilitate early detection of disease progression. Logistic regression analysis was used to explore the relationships among prognosis, clinical characteristics and laboratory indexes. The predictive value of this model was assessed with receiver operating characteristic curve analysis, calibration and internal validation. The viral shedding duration was calculated using the Kaplan–Meier method, and the prognostic factors were analysed by univariate log-rank analysis and the Cox proportional hazards model. A retrospective study was carried out with patients with COVID-19 in Tianjin, China. A total of 185 patients were included, 27 (14.59%) of whom were severely ill at the time of discharge and three (1.6%) of whom died. Our findings demonstrate that patients with an advanced age, diabetes, a low PaO2/FiO2 value and delayed treatment should be carefully monitored for disease progression to reduce the incidence of severe disease. Hypoproteinaemia and the fever duration warrant special attention. Timely interventions in symptomatic patients and a time from symptom onset to treatment

INTRODUCTION: This study is conducted to observe the effects of cognitive load on the visual search and attention allocation strategies of pilots. Research on pilots’ visual search strategies can provide valuable information regarding attention distribution and transformation, as well as useful situation awareness (SA) predictions.METHODS: A total of 18 pilots performed flight tasks in a two-condition (high and low cognitive load) within-subject experiment to compare their flight performance and eye movement indicators. Eye movements were tracked during the flight mission by a portable eye-tracking device.RESULTS: Compared to the low cognitive load task, in the high cognitive load task, the subjects exhibited shorter average fixation times (M = 420.38, SD = 60.56), higher fixation frequencies (M = 2.27, SD = 0.30), and lower saccade frequencies (M = 2.7, SD = 0.31). Their flight performance was better during the low cognitive load task, as evidenced by the lower entropy (M = 0.11, SD = 0.03) of their eye movements. Analysis of fixation time percentages and fixation counts showed that the distribution of attention to each area of interest was adjusted dynamically over the course of the given task.DISCUSSION: Significant differences were observed in both fixation order and fixation frequency across the instrument array. When the cognitive load is high, the subjects used more efficient eye movement patterns and search strategies accompanying a higher level of SA.Lu T, Lou Z, Shao F, Li Y, You X. Attention and entropy in simulated flight with varying cognitive loads. Aerosp Med Hum Perform. 2020; 91(6):489–495.

Ensartinib is a novel, potent and highly selective inhibitor of anaplastic lymphoma kinase (ALK) that has promising clinical activity and low toxicity in patients with ALK-positive non-small cell lung cancer. This study was conducted to investigate the pharmacokinetics, metabolism and excretion of ensartinib following a single 200 mg/100 μCi oral dose of radiolabeled ensartinib to healthy subjects.Six healthy male subjects were enrolled and administrated an oral suspension in a fasted state. Blood, urine and feces were collected. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of ensartinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and characterization.The mean total recovery was 101.21% of the radiolabeled dose with 91.00% and 10.21% excreted in feces and urine, respectively. Unchanged ensartinib was the predominant drug-related component in urine and feces, representing 4.39% and 38.12% of the administered dose, respectively. Unchanged ensartinib and its metabolite M465 were the major circulating components, accounting for the same 27.45% of the plasma total radioactivity (AUCIt was well tolerated in the six healthy male subjects following a single oral administration of 200 mg/100 μCi dose of ensartinib. Besides unchanged ensartinib, metabolite of M465 was the predominant circulating drug-related component. The drug was primarily eliminated in feces.ClinicalTrials.gov NCT03804541.

To determine the absorption, distribution, metabolism and excretion of abivertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced non-small cell lung cancer (NSCLC).Seven patients with advanced NSCLC were given a single 200 mg/83 μCi oral suspension of [The mean recovery was 82.16%, with 2.38 and 79.78% of the radioactive dose excreted in urine and faeces, respectively. The unchanged abivertinib was the major radioactive component detected in plasma within the first 24 hours after dosing, accounting for 59.17% of the total drug-related radioactivity. Abivertinib in urine accounted for only 0.96% of the administered dose, whereas in faeces it accounted for 33.36%. Eight metabolites were detected and characterised in plasma, among which MII-7, a product of cysteine glycine conjugate, was the only circulating metabolite, accounting for approximate 10.6% of the total drug-related exposure. MII-2 (an abivertinib cysteine-glycine adduct) and M7 (a reduced product of abivertinib) were the 2 major metabolites in the excreta, accounting for 20.0 and 12.4%, respectively, of the drug-related radioactivity in faeces.Following a single oral administration, the unchanged abivertinib was the predominant drug-related material in plasma, urine and faeces. The drug-related materials were primarily eliminated via the faecal route. Direct glutathione conjugation of abivertinib played a significant role in the metabolic clearance and metabolite exposure of abivertinib.

Background Uniportal video-assisted thoracic surgery (UVATS) technique has been increasingly used for many thoracic diseases. Whether UVATS has equivalent or better perioperative outcomes for pulmonary sequestration (PS) patients remains controversial. Our study aimed to evaluate the feasibility of UVATS in anatomical lung resection for pulmonary sequestration. Methods A total of 24 patients with PS including fifteen males and nine females with the mean age of 40 (range, 18–65) years old, who had received completely UVATS anatomical lung resection for PS in Nanjing Chest Hospital between January 2016 and December 2018 were retrospectively reviewed. Related clinical data were retrieved from hospital records and analyzed. Results All 24 patients had been treated with the UAVTS approach successfully without aberrant artery ruptured or massive hemorrhage, and no patients died during the perioperative period. Overall mean surgery time was 102 mins (range, 55–150 min), the mean blood loss was 94 ml (range, 10-300 ml), the mean days of chest tube maintained were 4 days (range,1-10 days), and the mean postoperative hospitalization days was 6 days (range,2-11 days). All patients were cured, without cough, fever, hemoptysis, and so on, associated with PS, occurring during the average follow-up of 17 months (range, 3-35 months). Conclusions Our preliminary results revealed that anatomical lung resection by UVATS is a safe and feasible mini-invasive technique for PS patients, which might be associated with less postoperative pain, reduced paresthesia, better cosmetic results, and faster recovery.

Chronic HIV-1 infection is generally characterized by progressive CD4(+) T cell depletion due to direct and bystander death that is closely associated with persistent HIV-1 replication and an inflammatory environment in vivo. The mechanisms underlying the loss of CD4(+) T cells in patients with chronic HIV-1 infection are incompletely understood. In this study, we simultaneously monitored caspase-1 and caspase-3 activation in circulating CD4(+) T cells, which revealed that pyroptotic and apoptotic CD4(+) T cells are distinct cell populations with different phenotypic characteristics. Levels of pyroptosis and apoptosis in CD4(+) T cells were significantly elevated during chronic HIV-1 infection, and decreased following effective antiretroviral therapy. Notably, the occurrence of pyroptosis was further confirmed by elevated gasdermin D activation in lymph nodes of HIV-1–infected individuals. Mechanistically, caspase-1 activation closely correlated with the inflammatory marker expression and was shown to occur through NLRP3 inflammasome activation driven by virus-dependent and/or -independent ROS production, while caspase-3 activation in CD4(+) T cells was more closely related to T cell activation status. Hence, our findings show that NLRP3-dependent pyroptosis plays an essential role in CD4(+) T cell loss in HIV-1–infected patients and implicate pyroptosis signaling as a target for anti–HIV-1 treatment.

Background Although there are lots of variations of pulmonary veins including dangerous type that could cause serious complications during surgery, limited information has been reported about these variations. We have experienced an extremely rare anomaly of the right superior pulmonary vein during right superior lobectomy. We used a technique called “non fissure” to manage the right superior pulmonary vein, and the results were satisfactory. Case presentation A 66-year-old woman with lung nodules visited our hospital. Chest computed tomography revealed multiple ground glass nodules in the right lung, the main pulmonary nodule was 11 mm in diameter and presented mixed density. The patient had a previous history of rectal cancer surgery. Contrast-enhanced three-dimensional computed tomography showed that the right superior pulmonary vein abnormally ran between the pulmonary artery trunk and the right main bronchus. We performed a right superior lobectomy and lymph node sampling by uniportal video-assisted thoracoscopic surgery. The pathological findings showed microinvasive adenocarcinoma with no lymphatic metastasis. She was discharged 7 days after surgery without any surgical complications. Conclusions Although the variation of pulmonary vein is uncommon, it is dangerous to misidentify in the operation. Preoperative three-dimensional computed tomography is useful for avoiding unexpected bleeding. The technique “no fissure” might be a useful way to manage the variation of pulmonary vein.

Tylerdipine hydrochloride (KBP-5660) is a novel L/T-type dual calcium channel blocker developed for the treatment of hypertension. We aimed to study the pharmacokinetics, safety and tolerability of tylerdipine in healthy Chinese subjects. Two double-blind, randomized, dose-escalation studies were conducted that included a total of 88 healthy subjects: (1) a single-ascending dose (SAD) study; and (2) a multiple-ascending dose (MAD) study. In the SAD study, 64 subjects were randomly assigned to receive a single dose of 0.5, 2.5, 5, 10, 15, 20, 25, or 30 mg of tylerdipine or placebo. In the MAD study, 24 subjects were randomly assigned to receive 10 or 20 mg of tylerdipine or placebo once daily for 9 days. Blood samples were collected at the designated time points for pharmacokinetic analyses. Safety assessments were conducted throughout the study. Following a single oral dose of tylerdipine of 5–30 mg, the mean maximum plasma concentration (Cmax) increased from 0.9993 to 10.11 ng/ml; mean area under the plasma-concentration curve (AUC) from time zero to 72 h increased from 4.332 to 73.95 h·ng/ml. AUC increased in a greater than dose-proportional manner, whereas Cmax exhibited a rough but non-typical dose-proportionality increase. In the MAD study, steady-state conditions were achieved after 1 week of daily dosing in both dose groups. Accumulation of tylerdipine was low, with accumulation ratios (RAUC) of less than 1.65. All adverse events were assessed as mild or moderate. Tylerdipine hydrochloride was safe and well tolerated. The exposure (AUC) of tylerdipine over the dose range of 5–30 mg increased in a greater than dose-proportional manner, while Cmax exhibited a rough but non-typical dose proportionality increase. A slight accumulation of tylerdipine was observed following multiple dosing. CTR20140862 and CTR20150660.

For quantitative assaying tylerdipine hydrochloride, and its two primary metabolites (M2 and M4) in human urine, two sensitive and accurate LC-MS/MS methods were firstly developed and validated, where multiple reaction monitoring (MRM) was applied under positive electrospray ionization mode for tylerdipine and negative electrospray ionization mode for M2/M4, respectively. Urinary proteins were precipitated using acetonitrile, and deuterated isotopes of tylerdipine and M4 ([D5]‑tylerdipine and [D6]-M4) were used as internal standards. Triton X-100, a good surfactant, was used to prevent the adsorption. An Agilent Poroshell 120 column was employed for chromatographic separation of the analytes with the mobile phases of 2 mM ammonium formate solution (containing 0.1% formic acid) and acetonitrile (45:55 for tylerdipine and 75:25 for the M2/M4, v/v). Flow rate was 0.3 mL/min. Calibration curves for tylerdipine, M2 and M4 in urine were linear over the ranges of 0.02–10 ng/mL, 2–1500 ng/mL and 0.5–200 ng/mL, respectively. The precision, accuracy, specificity and stability of two methods all evaluated and achieved the acceptable criteria. The LC-MS/MS methods were successfully applied to assay urinary excretion of tylerdipine and the metabolites in healthy Chinese subjects who orally received a single dose of 20 mg tylerdipine tablet. Generally, the urinary excretion of the two primary metabolites accounted for 11.7% of the total dose of tylerdipine in healthy Chinese subjects, while little tylerdipine was recovered in urine.

This study aimed to determine whether the back-propagation artificial neural network (BP-ANN) model could be constructed to accurately in predicting early occlusion of bilateral plastic stent placement for inoperable hilar cholangiocarcinoma (HCA).A total of 288 patients from the An Hui provincial Hospital were randomly divided into the training cohort (80%) and the internal testing cohort (20%). The predictive accuracy of the BP-ANN for predicting early occlusion of bilateral plastic stent placement of inoperable HCA was measured by the area under the curve (AUC) on receiver operating characteristic (ROC) curve analysis. The results were compared with those obtained using the conventional multivariate logistic regression analysis.Multivariate analysis revealed that cancer stage (P=0.005) and Bismuth stage (P=0.003) were independently and significantly associated with early stent occlusion. In the training cohort, BP-ANN had larger AUC than the multivariate logistic regression model (P=0.00049). In the internal testing cohort, the AUC of the BP-ANN had larger AUC than the multivariate logistic regression model (P=0.02142).This study showed that the BP-ANN model is a good predictive tool. It performed better than the conventional and commonly used statistical model in predicting early occlusion of bilateral plastic stent placement for inoperable HCA.

Background & Aims Gasdermin D (GSDMD)-executed programmed necrosis is involved in inflammation and controls interleukin (IL)-1β release. However, the role of GSDMD in non-alcoholic steatohepatitis (NASH) remains unclear. We investigated the role of GSDMD in the pathogenesis of steatohepatitis. Methods Human liver tissues from patients with non-alcoholic fatty liver disease (NAFLD) and control individuals were obtained to evaluate GSDMD expression. Gsdmd knockout ( Gsdmd −/− ) mice, obese db/db mice and their wild-type (WT) littermates were fed with methionine-choline deficient (MCD) or control diet to induce steatohepatitis. The Gsdmd −/− and WT mice were also used in a high-fat diet (HFD)-induced NAFLD model. In addition, Alb-Cre mice were administered an adeno-associated virus (AAV) vector that expressed the gasdermin-N domain (AAV9-FLEX-GSDMD-N) and were fed with either MCD or control diet for 10 days. Results GSDMD and its pyroptosis-inducing fragment GSDMD-N were upregulated in liver tissues of human NAFLD/NASH. Importantly, hepatic GSDMD-N protein levels were significantly higher in human NASH and correlated with the NAFLD activity score and fibrosis. GSDMD-N remained a potential biomarker for the diagnosis of NASH. MCD-fed Gsdmd −/− mice exhibit decreased severity of steatosis and inflammation compared with WT littermates. GSDMD was associated with the secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and MCP-1 [CCL2]) and persistent activation of the NF-ĸB signaling pathway. Gsdmd −/− mice showed lower steatosis, mainly because of reduced expression of the lipogenic gene Srebp1c ( Srebf1 ) and upregulated expression of lipolytic genes, including Pparα , Aco [Klk15] , Lcad [Acadl] , Cyp4a10 and Cyp4a14 . Alb-Cre mice administered with AAV9-FLEX-GSDMD-N showed significantly aggravated steatohepatitis when fed with MCD diet. Conclusion As an executor of pyroptosis, GSDMD plays a key role in the pathogenesis of steatohepatitis, by controlling cytokine secretion, NF-ĸB activation, and lipogenesis. Lay summary Non-alcoholic fatty liver disease has become one of the most feared chronic liver diseases, because it is the most rapidly growing indication for adult liver transplantation and a major cause of hepatocellular carcinoma. However, the mechanisms involved in the transformation of simple steatosis to steatohepatitis remain unclear. Herein, we show that gasdermin D driven pyroptosis is prominent in patients with non-alcoholic steatohepatitis (NASH), and gasdermin-N domain remains a potential biomarker for the diagnosis of NASH. Gasdermin D plays a key role in the pathogenesis of NASH by regulating lipogenesis, the inflammatory response, and the NF-ĸB signaling pathway, revealing potential treatment targets for NASH in humans.

Immunosignal hybridization chain reaction (isHCR) combines antibody-antigen interactions with hybridization chain reaction (HCR) technology, which results in amplification of immunofluorescence signals by up to two to three orders of magnitude with low background. isHCR's highly modular and easily adaptable design enables the technique to be applied broadly, and we further optimized its use in multiplexed imaging and in state-of-the-art tissue expansion and clearing techniques.

Objective We aimed to 1) develop physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models of a novel midazolam rectal gel in healthy adults, 2) assess the contribution of different physiologically relevant factors in rectal absorption, and 3) to provide supports for future clinical studies of midazolam rectal gel. Methods We developed the rectal PBPK model after built the intravenous and the oral PBPK model. Then, the physiological progress of rectal route was described in terms of the drug release, the rectal absorption and the particle first-pass elimination. Next, the validated PBPK model was combined with the sigmoid Emax PD model. This PBPK/PD model was used to identify the dose range and the critical parameters to ensure safety sedation. Results Based on the simulations, the recommended maximum dose for adults’ sedation was 15 mg. And the retention time of midazolam rectal gel should be longer than 3 h to reach over 80% pharmacokinetics and pharmacodynamics effects. Conclusion We successfully developed a PBPK/PD model for the midazolam rectal gel, which accurately described the PK/PD behavior in healthy adults and indicated the transit time of rectum was the most sensitive parameter for absorption. This PBPK/PD model would be expected to support the future clinical studies and pediatric application.

BACKGROUND Coiled-coil domain containing 34 (CCDC34) promotes cell proliferation and invasive properties in human cancer. The aim of this study was to compare the expression of CCDC34 in pancreatic adenocarcinoma with normal pancreatic tissue, and to evaluate the prognostic significance of CCDC34 expression in patients with pancreatic adenocarcinoma, using bioinformatics. MATERIAL AND METHODS The expression and prognostic value of CCDC34 were initially predicted using Oncomine and The Cancer Genome Atlas (TCGA) databases. Pancreatic adenocarcinoma tissue samples (N=90) and matched normal pancreatic tissues (N=90) were studied using immunohistochemistry to measure CCDC34 protein expression levels. Univariate Kaplan-Meier, and multivariate Cox analysis were used to determine the prognostic role of CCDC34 expression. RESULTS Oncomine and TCGA databases predicted that CCDC34 mRNA expression levels were significantly increased in pancreatic adenocarcinoma compared with normal pancreatic tissues (P