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AbstractA total of 162 non-small cell lung cancer (NSCLC) patients were divided into discovery (N = 68) and validation (N = 94) groups. Nine Janus kinase/Signal transducer and activator of transcription (JAK/STAT) pathway-related single nucleotide polymorphisms were selected to explore the potential associations between genetic polymorphisms and adverse drug reactions (ADRs). The TT genotype of STAT6 rs324011 was significantly associated with severe ADRs in the recessive genetic model (TT vs.CC + CT, OR = 13.5, 95% CI = 2.12–86.09, p = 0.006 in the discovery group; OR = 8.41, 95% CI = 1.95–36.19, p = 0.004 in the validation group). The T allele was associated with a higher incidence of severe ADRs than was the C allele of rs324011 (OR = 3.67, 95% CI = 1.46–9.19, p = 0.006 in the discovery group; OR = 3.17, 95% CI = 1.44–6.99, p = 0.004 in the validation group). Patients with the CC genotype in STAT3 rs1053023 (and rs1053005) or the TT genotype of STAT6 rs324011 were likely to experience severe epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) related ADRs.

AbstractWe aimed to investigate the prognostic role of genetic variants of VEGF in advanced NSCLC patients treated with platinum-based chemotherapy. A total of 196 patients with advanced NSCLC treated with first-line platinum-based chemotherapy were enrolled. We evaluated the relationship between VEGF polymorphisms and efficacy outcomes and chemotherapy toxicity. We found that rs699947, rs833061 and rs1005230 were in full linkage disequilibrium. Patients with CC genotype of rs833061 had a significant longer PFS than TT genotype (CC vs TT, HR = 1.67, 95%CI = 1.01−2.76, P = 0.043). Patients harbouring CC genotype had longer PFS compared with CT genotype (P < 0.001). Moreover, CC genotypes conferred a significantly increased PFS compared to CT and TT genotype in dominant model (CC vs CT + TT, HR = 1.95, 95%CI = 1.23−3.10, P = 0.005). Patients carrying TT genotype of rs833061 had improved both ORR (HR = 0.54, 95%CI = 0.30−0.98, P = 0.041) and DCR (HR = 0.37, 95%CI = 0.20−0.66, P = 0.001) than non-TT patients. Furthermore, no association was found between any rs833061 alleles and adverse events (P = 0.425), but patients carrying rs1570360 AA genotype were more likely to experience grade 3−4 toxicities (P = 0.004) (GG vs AA, HR = 3.16, 95%CI = 1.26−7.94, P = 0.015). In conclusion, the variant homozygote CC of rs833061 exhibited a better prognosis based on association analysis. The present study provides reference for the future study of platinum-based chemotherapy response and toxicity.

Exosomes are critical mediators of intercellular communication. Exosomal circular RNAs (circRNAs) have been reported to play critical roles in the development of chemoresistance in various tumors, including gastric cancer. However, the role of exosomal circ_0063526 in cisplatin (CDDP) resistance of gastric cancer is still unclear. The expression of circ_0063526, microRNA-449a (miR-449a) and serine hydroxymethyltransferase 2 (SHMT2) mRNA was determined by quantitative real-time PCR (qRT-PCR). Cell viability was assessed by the Cell Counting Kit-8 assay. Cell migration and invasion were evaluated by the transwell assay and wound healing assay. Western blot assay was used to measure the protein expression of light Chain 3 (LC3) I/II, p62 and SHMT2. Exosomes were detected using transmission electron microscopy. The size distribution of exosomes was analyzed by nanoparticle tracking analysis. The interaction between miR-449a and circ_0063526 or SHMT2 was confirmed by a dual-luciferase reporter and RNA pull-down assays. Circ_0063526 expression was increased in gastric cancer tissues and cells and CDDP-resistant cells. Extracellular circ_0063526 could be packaged into exosomes and transmitted to sensitive cells, thus disseminating CDDP resistance. Knockdown of exosomal circ_0063526 inhibited CDDP resistance via suppressing migration, invasion and autophagy in gastric cancer cells. Moreover, circ_0063526 was identified as a molecular sponge of miR-449a to upregulate SHMT2 expression. Further, exosomal circ_0063526 regulated SHMT2 expression to enhance CDDP resistance of gastric cancer cells. Additionally, high expression of exosomal circ_0063526 in serum was associated with poor response to CDDP treatment in gastric cancer patients. Exosomal circ_0063526 facilitated CDDP resistance in gastric cancer via regulating the miR-449a/SHMT2 axis.

Objective. Epilepsy is a chronic brain disease with recurrent seizures. Autophagy plays a crucial role in the progression of epilepsy. This study aimed to explore the function and intrinsic mechanism of the long non‐coding RNA (lncRNA) UCA1/miR‐132‐3p/ATG16L1 axis in epilepsy via regulation of autophagy. Methods. The expression of lncRNA UCA1, miR‐132‐3p and ATG16L1 was measured in serum from epileptic patients by quantitative RT‐PCR. A SH‐SY5Y cell model was further constructed using retinoic acid to investigate the UCA1/miR‐132‐3p/ATG16L1 axis by quantitative RT‐PCR, western blotting, fluorescence in situhybridisation, RNA immunoprecipitation, chromatin immunoprecipitation, and a dual‐luciferase reporter gene assay. Results. In the serum of epileptic patients, the level of lncRNA UCA1 and ATG16L1 was reduced and miR‐132‐3p elevated, compared to controls. Similarly, in the SH‐SY5Y cell model, the level of lncRNA UCA1 and ATG16L1 was reduced and miR‐132‐3p elevated in retinoic acid‐treated cells; lncRNA UCA1 was mainly located in the cytoplasm. lncRNA UCA1 overexpression was shown to promote autophagic gene expression, which was reversed by miR‐132‐3p overexpression. Moreover, autophagic gene expression induced by miR‐132‐3p knockdown was reversed by ATG16L1 knockdown. Based on precipitation assays, lncRNA UCA1 and miR‐132‐3p were shown to form a complex with the transcription factor, EZH2, and miR‐132‐3p was shown to interact with ATG16L1 based on a luciferase assay. Finally, lncRNA UCA1 was shown to negatively regulate miR‐132‐3p expression, and miR‐132‐3p was shown to negatively regulate ATG16L1. Significance. In this cell model, lncRNA UCA1 promotes autophagic gene expression via epigenetic regulation mediated by ATG16L1 and miR‐132‐3p.

The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) lowered the diagnostic criteria for hypertension. We aimed to explore whether clustering of multiple risk factors are associated with the risk of new-onset hypertension defined by the 2017 ACC/AHA Hypertension Guideline. Subjects who attended ≥2 annual health examinations without baseline hypertension and cardiovascular disease were included. Hypertension was defined according to the 2017 ACC/AHA Hypertension Guideline. Seven predefined risk factors, including age, resting heart rate, overweight or obesity, dyslipidemia, hyperuricemia, impaired glucose regulation, and a poor estimated glomerular filtration rate, were analyzed. A composite, individual-level, cumulative score incorporating these seven risk factors (no = 0 point; yes = 1 point; total range of 0–7 points) was calculated. The association between the cumulative score and the risk of hypertension was analyzed using a Cox regression model. A total of 4424 (21.6%) of 20,190 subjects included had new-onset hypertension during a follow-up duration of 3.6 years. Compared with subjects with 0 points, the adjusted hazard ratios (95% confidence intervals) for the development of hypertension for those with 1, 2, 3, and ≥4 points were 1.21 (1.07–1.38), 1.34 (1.19–1.52), 1.44 (1.26–1.63), and 1.64 (1.44–1.87), respectively (P< 0.001), after adjustment for sex and baseline blood pressure. Age, resting heart rate, overweight/obesity, dyslipidemia, hyperuricemia, impaired glucose regulation, and a poor estimated glomerular filtration rate are associated with an increased risk of future hypertension. When these factors are combined, there is an accumulated increase in risk.

Objective: This study aimed to explore the clinical effect of levetiracetam in the treatment of children with epilepsy. Methods: 136 children with epilepsy were selected from January 2017 to December 2017. According to the random number table method, they were divided into the experimental group and the conventional group, with 68 cases in each group. The conventional group was treated with valproate, while the experimental group was treated with levetiracetam. The effective rate, the cognitive function and the frequency of clonic seizures in the two groups were compared. Results: There was no significant difference in the total effective rate between the two groups (P>0.05). There was no significant difference in attention, executive ability, abstract and orientation scores between the two groups before treatment (P>0.05). After treatment, the focus of attention (106.54±6.56), executive ability (105.76±6.77), abstract and directional score (106.65±6.57) were significantly higher than that of the conventional group. The difference in the two groups was statistically significant (P<0.05). After 3 months of treatment, the frequency of myoclonic seizures (9.22±0.95) and the frequency of tonic-clonic seizures (11.68±1.36) were found to be significantly lower than those of the conventional group, and the difference between the two groups was statistically significant (P<0.05). Conclusion: Levetiracetam is effective in the treatment of children with epilepsy. It can effectively improve the cognitive function of the patients, reduce the frequency of myoclonic seizures and tonic-clonic seizures, and has a high promotion value.

A known cause of seizure-induced respiratory arrest is the deficiency in serotonergic neurotransmission. Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme of central serotonin (5-hydroxytryptamine) synthesis which converts l-tryptophan to 5-hydroxytryptophan. A recent study revealed a reduction in TPH2 protein expression in the brainstems of DBA/1 mice that developed recurrent seizure-induced respiratory arrest, whereas the activity of this protein was unexplored. Thus this study aims to investigate the association between intrinsic 5-hydroxytryptamine synthesis in the brainstem and the susceptibility for sudden unexpected death in epilepsy in DBA/1 mice. The effect of LY393558, a potent 5-hydroxytryptamine reuptake inhibitor with 5-HT1B/1Dreceptor antagonist properties, on seizure-induced respiratory arrest evoked by acoustic stimulation was also examined in DBA/1 mice. ELISA results showed significantly decreased TPH2 activity in the brainstems of untreated DBA/1 mice than that of C57BL/6J mice. Moreover, the concentrations of 5-hydroxytryptamine, 5-hydroxytryptophan and 5-HIAA in the brainstems of DBA/1 mice with or without acoustic stimulation were significantly lower than that of C57BL/6J mice. Acute administration of LY393558 also significantly reduced seizure-induced respiratory arrest in DBA/1 mice. These observations provide novel evidences for the hypothesis that 5-hydroxytryptamine deficiency might be a potential cause of seizure-induced respiratory arrest.

Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) plays key roles in controlling cardiac metabolism and function. Myocardial energy expenditure (MEE) can reflect myocardial energy metabolism and cardiac function. Whether the variation of PGC-1α can influence MEE levels in chronic heart failure (CHF) is unclear. Therefore, we investigated the relationship between PGC-1α and MEE.

The first phloroglucinol-triterpenoid hybrids, myrtphlotritins A–E (1–5), were rapidly recognized and isolated from two species of Myrtaceae by employing the building blocks-based molecular network (BBMN) strategy. Compounds 1–5featured new carbon skeletons in which phloroglucinol derivatives were coupled with lupane- and dammarane-type triterpenoids through different linkage patterns. Their structures and absolute configurations were elucidated by comprehensive analysis of spectroscopic data and quantum chemical calculations. Biosynthetic pathways for compounds 1–5were proposed on the basis of the coexisting precursors. Guided by the biogenetic pathways, the biomimetic synthesis of compound 1was also achieved. Additionally, compounds 2, 3, and 5exhibited potent antiviral activities against herpes simplex virus type-1 (HSV-1) infection, and compounds 2and 5displayed significant anti-inflammatory activities on RAW 264.7 cells.

To observe and compare the efficacy differences between combined Jin’s three-needle and rehabilitation training and rehabilitation training alone for hemiplegia following an ischemic stroke.A total of 94 cases who met the inclusion criteria were randomized into an observation group using combined Jin’s three-needle and rehabilitation training and a control group using rehabilitation training alone. The therapeutic efficacies were then assessed respectively before treatment, 14 d and 28 d after treatment using neurological deficient scale (NDS) and short-form Fugl-Meyer assessment (SFFMA) scale.After treatment, the NDS and SFFMA scores in both groups were significantly improved (P<0.05); after 28-day treatment, the inter-group comparison showed a statistical significance (P<0.05).Combined Jin’s three-needle and rehabilitation training and rehabilitation training alone can both enhance the nerve function recovery of patients with post-stroke hemiplegia and improve their motor function; however, the former could obtain better effects than the latter.

Distributed software systems often intertwine the handling of application functionalities with distribution related issues including location transparent access to services, workload allocation among different hosts, adaptation to changing conditions of the network. In the paper, a computational reflection based distributed query model is proposed. The model uses computational reflection to divide the distributed query system into two levels: the meta level and the base level. Meta objects that existed in the meta level are responsible for control and description of the base level, hence the state change of the base level could be captured by the meta level and be controlled according to the meta level’s reaction. The advantages of the model are that adapt different changes such as data resources in the network, network conditions, query plan, and provide the capability of fault tolerance.

Objective: A meta-analysis was performed to compare the efficacy and safety of antithrombotic therapy with non-vitamin K antagonist oral anticoagulants (NOACs) versusstandard care in patients after successful transcatheter aortic valve replacement (TAVR).Methods: A systematic search of PubMed, Cochrane Central Register of Controlled Trials, and EMBASE databases and ClinicalTrials.govwebsite (through 21 October 2020) was performed. Risk ratios (RRs) with 95% confidence intervals (CIs) for all outcomes were calculated using random-effects models.Results: Twelve studies (two studies were randomized controlled trials) comprising 6943 patients were included (5299 had indications for oral anticoagulation (OAC) and 1644 had none). No significant differences were found between NOACs and the standard care in the incidences of all stroke, a composite endpoint, and major/life-threatening bleeding. NOACs were associated with lower all-cause mortality than vitamin K antagonists (VKAs) in post-TAVR patients with indications for OAC after more than 1 year of follow-up [RR = 0.64; 95% CI, (0.42, 0.96); p= 0.03], whereas NOACs exhibited poor outcomes than antiplatelet therapy (APT) in patients without indications for OAC [RR = 1.66; 95% CI, (1.12, 2.45); p= 0.01]. In the prevention of valve thrombosis, NOACs and VKAs were not significantly different in patients with indications for OAC [RR = 0.66; 95% CI, (0.24, 1.84); p= 0.43], whereas NOACs were better than APT in patients without indications for OAC [RR = 0.19; 95% CI, (0.04, 0.83); p= 0.03].Conclusions: In patients with indications for OAC, post-TAVR antithrombotic therapy with NOACs was more favorable due to its lower all-cause mortality after more than 1 year of follow-up. In those without indications for OAC, NOACs presented poorer outcomes due to its higher all-cause mortality.

A hybrid binary subtracted joint transform correlator was constructed using a Bi12SiO12(BSO) spatial light modulator and a laser scanner. The usefulness of this system was confirmed experimentally using a large number of binary and halL-tone images as the reference patterns.

The use of moment invariants in the frequency plane is proposed for pattern recognition. Moment invariants are theoretically derived in the case of translation, rotation, and changes of size and brightness. The usefulness of the moment invariants is shown by numerical experiments using Chinese characters and model car images with grey-level intensities.

A hybrid system is proposed that performs joint transform correlation with a multireference by use of a self-generated threshold function.

The steep eastern margin of the Tibetan Plateau is thought to have developed in the Cenozoic by brittle crustal thickening or lower crustal flow related to India‐Asia collision. However, our data indicate that Late Triassic crustal shortening and voluminous magmatism contributed to crustal thickening and topography of the region. Sr/Y ratios of intermediate to silicic magmatic rocks reflect mineral assemblages in the magma source and can be used to constrain crustal thickness. The Sr/Y ratios from the Songpan‐Ganzi Fold Belt in the eastern Tibetan Plateau indicate that the eastern margin of the plateau achieved a crustal thickness ranging from 44 ± 6 to 67 ± 9 km during ca. 220 to 190 Ma. An average elevation of 2,600 ± 300 m at ca. 211 Ma is deduced based on average crustal thickness of 55 ± 2 km assuming Airy isostatic compensation. The thickened crust and high topography of the eastern margin of the Tibetan Plateau during the Late Triassic is supported by intense shortening and voluminous magmatism, contemporaneous Barrovian metamorphism, and the development of a foreland basin. Our data indicate that the eastern margin of the Tibetan Plateau was initially built during the Late Triassic, and this area has a long history of crustal thickening and mountain building. Eastern margin of the Tibetan Plateau reached an average crustal thickness of 55 ± 2 km during ca. 220 to 190 MaThis margin attained an average elevation of 2,600 ± 300 m due to crustal thickening and magma underplating during this time intervalLate Triassic crustal thickening marks the initial growth of the present‐day eastern margin of the Tibetan Plateau

Two kinds of modification of the joint transform correlator to perform pattern matching are proposed and the mechanisms are analyzed. Simulation and experimental results show that pattern matching is executed correctly by the modified JTCs; it is shown that one of the two modified joint transform correlators is equivalent to matched filtering and the other corresponds to pure-phase-only filtering.