ABSTRACT: Acute liver injury (ALI) is an important medical problem that requires effective therapy. Astaxanthin (AST) is a carotenoid, and the beneficial effects of astaxanthin, including anti-oxidative, anti-inflammatory and anti-tumour activities, have been identified. The present study was designed to elucidate the protective effects of astaxanthin against ALI and their underlying mechanisms. RAW264.7 macrophages were treated with dimethyl sulfoxide combined with different doses of astaxanthin for 12 h. Mice were fed with or without astaxanthin for up to 7 days. LPS was administered to induce inflammation. We assessed histopathology, oxidative stress, inflammation and apoptosis .The results indicated that astaxanthin attenuated LPS-induced oxidative stress, inflammation and cell apoptosis both in vivo and in vitro. In vivo and in vitro experiments showed that astaxanthin down regulated the nuclear factor-kappa beta (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2) and NLR family pyrin domain containing 3 (NLRP3) signalling pathways, inhibiting the LPS-induced inflammatory response, oxidative stress and cell apoptosis, and alleviating LPS-induced ALI in mice. ABSTRACT (ALI therapy AST (AST carotenoid antioxidative, antioxidative anti oxidative, anti-oxidative antiinflammatory antitumour tumour activities identified mechanisms RAW2647 RAW RAW264 RAW264. 1 h days histopathology LPSinduced induced factorkappa kappa NFκB, NFκB NF κB , (NF-κB) 2related related Nrf2 Nrf (Nrf2 NLRP3 NLRP (NLRP3 pathways response mice RAW26 (NF-κB (Nrf (NLRP RAW2

RESUMO: A lesão hepática aguda (ALI) é um problema médico importante que requer terapia eficaz. A astaxantina (AST) é um carotenóide, e os efeitos benéficos da astaxantina, incluindo atividades antioxidantes, anti-inflamatórias e antitumorais, foram identificados. O presente estudo foi desenhado para elucidar os efeitos protetores da astaxantina contra ALI e seus mecanismos subjacentes. Macrófagos RAW264.7 foram tratados com dimetil sulfóxido combinado com diferentes doses de astaxantina por 12 h. Os camundongos foram alimentados com ou sem astaxantina por até sete dias. O LPS foi administrado para induzir a inflamação. Histopatologia, estresse oxidativo, inflamação e apoptose foram avaliados. Os resultados indicaram que a astaxantina atenuou o estresse oxidativo induzido por LPS, inflamação e apoptose celular in vivo e in vitro. Experimentos in vivo e in vitro mostraram que a astaxantina regulou negativamente as vias de sinalização do fator nuclear-kappa beta (NF-κB), fator nuclear 2 relacionado ao eritróide 2 (Nrf2) e domínio de pirina da família NLR contendo 3 (NLRP3), inibindo o LPS- resposta inflamatória induzida, estresse oxidativo e apoptose celular e alívio da ALI induzida por LPS em camundongos. RESUMO (ALI eficaz AST (AST carotenóide antioxidantes antiinflamatórias anti inflamatórias antitumorais identificados subjacentes RAW2647 RAW RAW264 7 RAW264. 1 h dias Histopatologia avaliados nuclearkappa kappa NFκB, NFκB NF κB , (NF-κB) Nrf2 Nrf (Nrf2 NLRP3, NLRP3 NLRP (NLRP3) RAW26 (NF-κB (Nrf (NLRP3 RAW2 (NLRP

Abstract Background Glomus Tumor (GT) are benign neoplasms that originate from mesenchymal cells. It presents as tenderness and cold allodynia in the digits, especially in the subungual region. There are a few studies that investigated the mechanism of pain. Objectives To analyze the clinical-pathologic characteristics of GT and to identify the expression of IL-1β, IL-6, and CGRP in it, further, to explore the possible mechanism of pain. Methods The clinical and pathological data of 60 GT patients were retrospectively analyzed. Tissue microarrays and immunohistochemistry were used to measure the expression of IL-1β, IL-6 and CGRP. Results GT is more common in females and the ratio of male to was near to 1:2, mostly in middle-aged people. It often occurs in fingertips, especially the thumbs. Patients often present with spontaneous pain, tenderness, and cold hypersensitivity. Both the two pain mediators IL-1β and IL-6 were highly expressed in GT cells of patients with and without cold hypersensitivity. While CGRP was not expressed in GT. Study limitations Low sample size and further research is needed to explore the specific mechanism. Conclusions IL-1β and IL-6 were highly expressed in GT cells, suggesting that IL-1β and IL-6 have certain nociceptive roles in GT. In the 4 patients with cold intolerance, the intensity of IL-1β and IL-6 staining was also strong, suggesting that they may not play a role in the cold hypersensitivity. However, since there are only 4 patients with cold intolerance, it’s necessary to conduct further in-depth research using a larger sample size. The specific role of CGRP in GT has not been found yet. (GT digits region clinicalpathologic pathologic IL1β, IL1β ILβ IL 1β, 1β β IL6, IL6 6, 6 it analyzed IL- 12, 12 1 2, 2 1:2 middleaged middle aged people fingertips thumbs hypersensitivity intolerance strong However its s indepth depth yet 1:

In this study, Al-Si-Cu-Mg composites reinforced with Silicon carbide (SiC) particles and/or Carbon nanotubes (CNTs) were fabricated using semi-solid stirring casting technology (SSC). The aim of the study was to investigate the influence of SiC and/or CNTs on the mechanical properties, microstructural evolution, and deformation mechanisms of the Al-Si-Cu-Mg alloy. The findings indicated that the presence of SiC/CNTs in the composite had a significant effect on refining the α-Al phase and altering its grain orientation. Additionally, the results obtained from EBSD and TEM revealed that the microstructure of the Al-Si-Cu-Mg-SiC/CNTs hybrid composite (HAMC) underwent dynamic recrystallization (DRX) and static recrystallization (SRX), resulting in a fine equiaxed recrystallized structure. This process also led to the formation of high-angle grain boundaries (HAGBs) through dislocation rearrangement. The SiC particles were evenly distributed within the matrix, ensuring good interface bonding between SiC and α-Al phases. Moreover, the CNTs reacted with the matrix, resulting in the in-situ formation of the Al4C3 phase at the interface. The addition of SiC/CNTs significantly increased the tensile strength of HAMC at 25°C and 250°C, from 319MPa and 178MPa to 438MPa and 331MPa. Examination of the fracture surface of the hybrid composite unveiled that void formation occurred primarily at the regions surrounding the matrix-particle interface. AlSiCuMg Al Si Cu Mg (SiC andor or (CNTs semisolid semi solid SSC. SSC . (SSC) properties evolution alloy SiCCNTs αAl α orientation Additionally AlSiCuMgSiC/CNTs AlSiCuMgSiCCNTs (HAMC DRX (DRX SRX, SRX , (SRX) structure highangle high angle HAGBs (HAGBs rearrangement matrix phases Moreover insitu situ AlC C Al4C 25C 25 250C 250 250°C MPa 331MPa matrixparticle particle (SSC AlSiCuMgSiC (SRX 2

ABSTRACT Through a long-term micro-area positioning experiment (2006-2017), the precise fertilization locations of spring maize (Zea mays L.) in Jilin, China, were investigated using an embedded cement bucket pot. The effects of different fertilization placements and additional application of organic manure on maize yield, biomass, grain nutrient uptake, and soil fertility were examined. Six treatments were designed: base fertilizer + topdressing shallow application (BF1TD1); base fertilizer deep + topdressing shallow application (BF2TD1); base fertilizer + topdressing deep application (BF1TD2); base fertilizer deep + topdressing deep application (BF2TD2); base fertilizer + topdressing + organic manure shallow application (BF1TD1 + OS); and base fertilizer + topdressing shallow application + organic manure deep application (BF1TD1 + OD). After 12 years of continuous experimentation, the findings revealed that BF2TD2, BF1TD1 + OS, and BF1TD1 + OD exhibited 10.59 %, 25.17 %, and 29.34 % higher average yields than BF1TD1, respectively. Deep topdressing was more beneficial in increasing maize yield and nutrient accumulation, and additionally, increasing the use of organic fertilizer enhanced plant biomass and nutrient uptake. Over the 12 years considered, the soil organic matter in the 0-20 cm and 20-40 cm layers increased by 45.96 % and 80.61 %, respectively, and the soil pH increased from 0.38 to 0.48. In general, the deep application of organic manure was more beneficial for soil retention as it can increase soil fertility in the 0-40 cm layer. Considering the high yield and nutrient absorption and utilization of maize, technical advancement for soil fertilizer in whole-field tillage layers was crucial. longterm long term microarea micro area 20062017, 20062017 2006 2017 , (2006-2017) Zea L. L Jilin China pot uptake examined designed BFTD BF TD (BF1TD1) BF2TD1 (BF2TD1) BF1TD2 (BF1TD2) BF2TD2 (BF2TD2) (BF1TD OS OS) OD. . OD) 1 experimentation BF1TD 1059 10 59 10.5 2517 25 17 25.1 2934 29 34 29.3 respectively accumulation additionally considered 020 0 20 0-2 2040 40 20-4 4596 45 96 45.9 8061 80 61 80.6 038 38 0.3 048 48 0.48 general 040 0-4 layer wholefield whole field crucial 2006201 200 201 (2006-2017 BF2TD (BF2TD1 (BF1TD2 (BF2TD2 105 5 10. 251 2 25. 293 3 29. 02 0- 204 4 20- 459 9 45. 806 8 6 80. 03 0. 04 0.4 200620 (2006-201 (BF2TD 20062 (2006-20 (2006-2 (2006- (2006 (200 (20 (2 (

Abstract Background In contemporary society, with the accelerated pace of work and life, more and more people feel different degrees of stress. Long-term stress may not only lead to insomnia, but also to mental health problems (e.g., anxiety and depression), which has a significant impact on people's quality of life and mental health. Objective This study primarily investigates the mechanism through which stress affects sleep quality among college students. Methods We conducted research on 1653 Chinese college students using four scales with high reliability and validity: stress, the Pittsburgh Sleep Quality Index, social anxiety, and rumination. Results The study found: (1) Stress can significantly and positively predict sleep quality and rumination; (2) Rumination can positively predict social anxiety; (3) Social anxiety can positively predict sleep quality; (4) Stress can affect sleep quality through social anxiety and rumination separately, and stress can also affect sleep quality through the chained mediation of rumination and social anxiety. Conclusion This study reveals the relationship and mechanisms between stress and sleep quality. It not only deepens the research on the impact of stress on sleep quality but also provides theoretical support and new methods for mental health professionals to help clients improve their sleep quality. In practice, in addition to using some common psychological intervention methods to help individuals reduce stress, we should pay more attention to how to help clients reduce rumination and social anxiety, This is significant in improving the quality of an individual's sleep. society Longterm Long term insomnia e.g., eg e g (e.g. depression, depression , depression) peoples s 165 validity Index found 1 (1 2 (2 3 (3 4 (4 separately practice individual e.g. (e.g 16 ( e.g

Resumo Fundamento: O antibiótico quimioterápico antraciclina doxorrubicina (DOX) pode induzir cardiotoxicidade cumulativa e levar à disfunção cardíaca. RNAs não codificantes longos (lncRNAs) podem funcionar como importantes reguladores na lesão miocárdica induzida por DOX. Objetivo: Este estudo tem como objetivo investigar o papel funcional e o mecanismo molecular do RNA antisense lncRNA OXCT1 1 (OXCT1-AS1) na lesão celular miocárdica induzida por DOX in vitro. Métodos: Cardiomiócitos humanos (AC16) foram estimulados com DOX para induzir um modelo de lesão celular miocárdica. A expressão de OXCT1-AS1, miR-874-3p e BDH1 em células AC16 foi determinada por RT-qPCR. A viabilidade das células AC16 foi medida pelo ensaio XTT. A citometria de fluxo foi empregada para avaliar a apoptose de células AC16. Western blotting foi utilizado para avaliar os níveis proteicos de marcadores relacionados à apoptose. O ensaio repórter de luciferase dupla foi conduzido para verificar a capacidade de ligação entre miR-874-3p e OXCT1-AS1 e entre miR-874-3p e BDH1. O valor de p<0,05 indicou significância estatística. Resultados: A expressão de OXCT1-AS1 foi diminuída em células AC16 tratadas com DOX. A superexpressão de OXCT1-AS1 reverteu a redução da viabilidade celular e a promoção da apoptose celular causada pela DOX. OXCT1-AS1 está ligado competitivamente ao miR-874-3p para regular positivamente o BDH1. A superexpressão de BDH1 restaurou a viabilidade das células AC16 e suprimiu a apoptose celular sob estimulação com DOX. A derrubada do BDH1 reverteu a atenuação da apoptose de células AC16 mediada por OXCT1-AS1 sob tratamento com DOX. Conclusão: LncRNA OXCT1-AS1 protege células miocárdicas humanas AC16 da apoptose induzida por DOX através do eixo miR-874-3p/BDH1. Fundamento (DOX cardíaca lncRNAs (lncRNAs Objetivo OXCT OXCT1AS1 OXCTAS AS1 AS (OXCT1-AS1 vitro Métodos AC (AC16 OXCT1AS1, AS1, miR8743p miRp miR 874 3p p BDH AC1 RTqPCR. RTqPCR RT qPCR. qPCR RT-qPCR XTT OXCT1-AS p005 0 05 p<0,0 estatística Resultados Conclusão miR8743p/BDH1. miR8743pBDH1 miRpBDH 3p/BDH1. miR-874-3p/BDH1 OXCT1AS (OXCT1-AS (AC1 87 p00 p<0, miR8743p/BDH1 pBDH miR8743pBDH 3pBDH1 3p/BDH1 miR-874-3p/BDH (AC 8 p0 p<0 miR8743p/BDH 3pBDH 3p/BDH p<

Abstract Background: The anthracycline chemotherapeutic antibiotic doxorubicin (DOX) can induce cumulative cardiotoxicity and lead to cardiac dysfunction. Long non-coding RNAs (lncRNAs) can function as important regulators in DOX-induced myocardial injury. Objective: This study aims to investigate the functional role and molecular mechanism of lncRNA OXCT1 antisense RNA 1 (OXCT1-AS1) in DOX-induced myocardial cell injury in vitro. Methods: Human cardiomyocytes (AC16) were stimulated with DOX to induce a myocardial cell injury model. OXCT1-AS1, miR-874-3p, and BDH1 expression in AC16 cells were determined by RT-qPCR. AC16 cell viability was measured by XTT assay. Flow cytometry was employed to assess the apoptosis of AC16 cells. Western blotting was used to evaluate protein levels of apoptosis-related markers. Dual-luciferase reporter assay was conducted to verify the binding ability between miR-874-3p and OXCT1-AS1 and between miR-874-3p and BDH1. The value of p<0.05 indicated statistical significance. Results: OXCT1-AS1 expression was decreased in DOX-treated AC16 cells. Overexpression of OXCT1-AS1 reversed the reduction of cell viability and promotion of cell apoptosis caused by DOX. OXCT1-AS1 is competitively bound to miR-874-3p to upregulate BDH1. BDH1 overexpression restored AC16 cell viability and suppressed cell apoptosis under DOX stimulation. Knocking down BDH1 reversed OXCT1-AS1-mediated attenuation of AC16 cell apoptosis under DOX treatment. Conclusion: LncRNA OXCT1-AS1 protects human myocardial cells AC16 from DOX-induced apoptosis via the miR-874-3p/BDH1 axis. Background (DOX dysfunction noncoding non coding lncRNAs (lncRNAs DOXinduced induced Objective OXCT OXCT1AS1 OXCTAS AS1 AS (OXCT1-AS1 vitro Methods AC (AC16 model OXCT1AS1, AS1, miR8743p, miR8743p miRp miR 874 3p, 3p p BDH AC1 RTqPCR. RTqPCR RT qPCR. qPCR RT-qPCR apoptosisrelated related markers Dualluciferase Dual luciferase OXCT1-AS p005 0 05 p<0.0 significance Results DOXtreated treated stimulation OXCT1AS1mediated OXCTASmediated mediated treatment Conclusion miR8743p/BDH1 miR8743pBDH1 miRpBDH 3p/BDH1 miR-874-3p/BDH axis OXCT1AS (OXCT1-AS (AC1 87 p00 p<0. miR8743p/BDH pBDH miR8743pBDH 3pBDH1 3p/BDH (AC 8 p0 p<0 3pBDH p<

Abstract Fast calculations are widely required in the traditional applications and the emerging digital twin fields. For those considerations, a novel physics-based fast algorithm, namely generalized rotation-superposition method, is proposed for fast calculating linear elastic responses of generalized rotationally axisymmetric structures under arbitrary mechanical loads. This improved method breaks through the limitations of the previous basic rotation-superposition method in rotational similarity of load and structural axisymmetry, and greatly expands its application scope. In this paper, firstly, the basic theory of the rotation-superposition algorithm is introduced; secondly, the theoretical model of the generalized rotation-superposition method is established; thirdly, the effectiveness and accuracy are verified by using finite element simulations; finally, through a complex case study, the applicability of the generalized rotation-superposition method for complex engineering problems and its advantages in efficiently obtaining massive amounts of data are further illustrated. fields considerations physicsbased physics based rotationsuperposition rotation superposition loads axisymmetry scope paper firstly introduced secondly established thirdly simulations finally study illustrated

The overexpression of P-glycoprotein (P-gp/ABCB1) is a leading cause of multidrug resistance (MDR). Hence, it is crucial to discover effective pharmaceuticals that counteract ABCB1-mediated multidrug resistance. FRAX486 is a p21-activated kinase (PAK) inhibitor. The objective of this study was to investigate whether FRAX486 can reverse ABCB1-mediated multidrug resistance, while also exploring its mechanism of action. The CCK8 assay demonstrated that FRAX486 significantly reversed ABCB1-mediated multidrug resistance. Furthermore, western blotting and immunofluorescence experiments revealed that FRAX486 had no impact on expression level and intracellular localization of ABCB1. Notably, FRAX486 was found to enhance intracellular drug accumulation and reduce efflux, resulting in the reversal of multidrug resistance. Docking analysis also indicated a strong affinity between FRAX486 and ABCB1. This study highlights the ability of FRAX486 to reverse ABCB1-mediated multidrug resistance and provides valuable insights for its clinical application. Pglycoprotein P glycoprotein Pgp/ABCB1 PgpABCB1 PgpABCB gp/ABCB1 gp ABCB1 ABCB (P-gp/ABCB1 MDR. MDR . (MDR) Hence ABCB1mediated ABCBmediated mediated FRAX FRAX48 p21activated pactivated p21 activated p PAK (PAK inhibitor action CCK Furthermore Notably efflux application Pgp Pgp/ABCB gpABCB1 gpABCB gp/ABCB (P-gp/ABCB (MDR FRAX4 p2

Emerging evidence demonstrates that curcumin has an inhibitory effect on non-small cell lung cancer (NSCLC), and its targets and mechanism of action need further exploration. The goal of this study was to explore the potential targets and mechanism of curcumin against NSCLC by network pharmacology, bioinformatics, and experimental validation, thereby providing more insight into combination treatment with curcumin for NSCLC in preclinical and clinical research. Curcumin targets against NSCLC were predicted based on HIT2.0, STD, CTD, and DisGeNET, and the core targets were analyzed via protein-protein interaction network construction (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and molecular docking. The gene expression levels of samples in A549 cells, NCI-H460, and curcumin treated groups were detected by real-time quantitative PCR. A total of 67 common targets between curcumin and NSCLC were collected by screening public databases. GO and KEGG analysis suggested that curcumin treatment of NSCLC mainly involves cancer-related pathways, such as PI3K-AKT signaling pathway, Foxo signaling pathway, microRNAs, MAPK signaling pathway, HIF-1 signaling pathway, etc. The targets with the highest degree were identified through the PPI network, namely CASP3, CTNNB1, JUN, IL6, MAPK3, HIF1A, STAT3, AKT1, TP53, CCND1, VEGFA, and EGFR. The results of the in vitro experiments showed that curcumin treatment of NSCLC down-regulated the gene expressions of CCND1, CASP3, HIF1A, IL-6, MAPK3, STAT3, AKT1, and TP53. Our findings revealed that curcumin functions as a potential therapeutic candidate for NSCLC by suppressing multiple signaling pathways and interacting with multiple gene targets. nonsmall non small NSCLC, , (NSCLC) exploration pharmacology bioinformatics validation research HIT20 HIT HIT2 0 HIT2.0 STD CTD DisGeNET proteinprotein protein PPI, (PPI) GO, (GO) KEGG, (KEGG) docking A54 cells NCIH460, NCIH460 NCIH NCI H460, H460 H NCI-H460 realtime real time PCR 6 databases cancerrelated related PI3KAKT PIKAKT PI3K AKT PI K pathway microRNAs HIF1 HIF 1 HIF- etc CASP3 CASP CTNNB1 CTNNB JUN IL6 IL MAPK3 HIF1A HIFA STAT3 STAT AKT1 TP53 TP CCND1 CCND VEGFA EGFR downregulated down regulated 6, IL-6 (NSCLC HIT2. (PPI (GO (KEGG A5 NCIH46 H46 NCI-H46 KAKT PIK TP5 IL- NCIH4 H4 NCI-H4 NCI-H

Abstract Introduction: Propofol is a widely used anesthetic and its dose is closely related to aging. Telomere length (TL) is a unique heritable trait, and emerging as a biomarker of aging, health and disease. Telomerase RNA component (TERC) plays an important role in maintaining TL. We proposed a hypothesis that propofol dose in general anesthesia can be predicted by measuring TL before operation, which greatly reduced the risk of anesthesia, especially the elderly. Methods: The association between the propofol dose in anesthesia induction and: TL in the DNA of peripheral blood leukocytes; body weight; sex; difference of the Bispectral Index (BIS) before and after anesthesia induction in patients was evaluated by multivariable linear regression analyses. The mutation at the 5’end or 3’end of TERC was detected. We recruited 100 patients of elective surgery. Results: We found that propofol dose in anesthesia induction was clearly correlated significantly with TL (r = 0.78, p < 0.001), body weight (r = 0.84, p = 0.004), sex (r = 0.83, p= 0.84, p = 0.004), sex (r = 0.83, p = 0.004), and difference of BIS before and after anesthesia induction (r = 0.85, p = 0.029). By comparing the absolute values of standardized regression coefficients (0.58, 0.21, 0.19, and 0.12) of the four variables, it can be seen that TL contributes the most to the propofol dose in anesthesia induction. However, the mutation at the 5’ end or 3’ end of TERC was not found. Conclusions: These findings provide preliminary evidence that the propofol dose in anesthesia induction was clearly correlated with genetically determined TL. TL may be a promising predictor of the propofol dose, which is beneficial to improve the safety of anesthesia and reduce perioperative complications. Introduction aging (TL trait disease (TERC operation elderly Methods leukocytes (BIS analyses 5end 5 3end 3 detected 10 surgery Results r 078 0 78 0.78 0.001, 0001 0.001 , 001 0.001) 084 84 0.84 0.004, 0004 0.004 004 0.004) 083 83 0.83 085 85 0.85 0.029. 0029 0.029 . 029 0.029) 0.58, 058 58 (0.58 021 21 0.21 019 19 0.19 0.12 012 12 variables However Conclusions complications 1 07 7 0.7 000 0.00 00 08 8 0.8 002 0.02 02 0.58 05 (0.5 2 0.2 01 0.1 0. 0.0 0.5 (0. (0 (

Abstract Objective: To investigate the optimal timing of initial intravenous immunoglobulin (IVIG) treatment in Kawasaki disease (KD) patients. Methods: KD patients were classified as the early group (day 1-4), conventional group (day 5-7), conventional group (day 8-10), and late group (after day 10). Differences among the groups were analyzed by ANOVA and Chi-square analysis. Predictors of IVIG resistance and the optimal cut-off value were determined by multiple logistic regression analyses and receiver operating characteristic (ROC) curve analysis. Results: There were no significant differences in IVIG resistance among the 4 groups (p = 0.335). The sensitivity analysis also confirmed no difference in the IVIG resistance between those who started the initial IVIG ≤ day 7 of illness and those who received IVIG >day 7 of illness (p = 0.761). In addition, patients who received IVIG administration more than 7 days from the onset had a higher proportion of coronary artery abnormalities (p = 0.034) and longer length of hospitalization (p = 0.033) than those who started IVIG administration less than 7 days. The optimal cut-off value of initial IVIG administration time for predicting IVIG resistance was >7 days, with a sensitivity of 75.25% and specificity of 82.41%. Conclusions: IVIG therapy within 7 days of illness is found to be more effective for reducing the risk of coronary artery abnormalities than those who received IVIG >day 7 of illness. IVIG treatment within the 7 days of illness seems to be the optimal therapeutic window of IVIG. However, further prospective studies with long-term follow-up are required. Objective (IVIG (KD Methods 14, 14 1 , 1-4) 57, 57 5 5-7) 810, 810 8 10 8-10) after 10. . 10) Chisquare Chi square cutoff cut off ROC (ROC Results p 0.335. 0335 0.335 0 335 0.335) 0.761. 0761 0.761 761 0.761) addition 0.034 0034 034 0.033 0033 033 > 7525 75 25 75.25 8241 82 41 82.41% Conclusions However longterm long term followup follow up required 1-4 5-7 81 8-10 0.33 33 076 0.76 76 0.03 003 03 752 2 75.2 824 82.41 1- 5- 8-1 0.3 3 07 0.7 0.0 00 75. 82.4 8- 0. 82.

Abstract Background Neuropathic pain typically refers to the pain caused by somatosensory system injury or diseases, which is usually characterized by ambulatory pain, allodynia, and hyperalgesia. Nitric oxide produced by neuronal nitric oxide synthase (nNOS) in the spinal dorsal cord might serve a predominant role in regulating the algesia of neuropathic pain. The high efficacy and safety, as well as the plausible ability in providing comfort, entitle dexmedetomidine (DEX) to an effective anesthetic adjuvant. The aim of this study was to investigate the effect of DEX on the expression of nNOS in spinal dorsal cord in a rat model with chronic neuropathic pain. Methods Male Sprague Dawley (SD) rats were randomly assigned into three groups: sham operation group (sham), (of the sciatic nerve) operation (CCI) group, and dexmedetomidine (DEX) group. Chronic neuropathic pain models in the CCI and DEX groups were established by sciatic nerve ligation. The thermal withdrawal latency (TWL) was measured on day 1 before operation and on day 1, 3, 7 and 14 after operation. Six animals were sacrificed after TWL measurement on day 7, and 14 days after operation, in each group, the L4–6 segment of the spinal cords was extracted for determination of nNOS expression by immunohistochemistry. Results Compared with the sham group, the TWL threshold was significantly decreased and the expression of nNOS was up-regulated after operation in the CCI and DEX groups. Compared with the CCI grou[, the TWL threshold was significantly increased and the expression of nNOS was significantly down-regulated on day 7 and 14 days after operation in the DEX group. Conclusion Down-regulated nNOS in the spinal dorsal cord is involved in the attenuation of neuropathic pain by DEX. diseases allodynia hyperalgesia (nNOS safety comfort (DEX adjuvant SD (SD sham, , (sham) (CCI ligation (TWL 3 L46 L L4 6 L4– immunohistochemistry upregulated up regulated grou, grou grou[ downregulated down Downregulated Down (sham

Resumo Antecedentes A dor neuropática refere-se tipicamente à dor causada por lesões ou doenças do sistema somatossensorial. De modo geral, é caracterizada por dor à ambulação, alodinia e hiperalgesia. O óxido nítrico produzido pela enzima óxido nítrico sintase neuronal (nNOS) na medula espinhal dorsal pode ter um papel predominante na regulação da dor neuropática. A alta eficácia e segurança, bem como a plausível capacidade de proporcionar conforto, faz com que a dexmedetomidina (DEX) seja um adjuvante anestésico eficaz. O objetivo deste estudo foi investigar o efeito da DEX na expressão de nNOS na medula espinhal dorsal em um modelo de ratos com dor neuropática crônica. Métodos Ratos Sprague Dawley (SD) machos foram distribuídos aleatoriamente em três grupos: grupo de cirurgia simulada (sham), grupo de cirurgia (do nervo ciático; CCI) e grupo dexmedetomidina (DEX). Os modelos de dor neuropática crônica nos grupos CCI e DEX foram estabelecidos por ligadura do nervo ciático. A latência de retirada térmica (TWL) foi medida no dia 1 antes da cirurgia e nos dias 1, 3, 7 e 14 após o procedimento. Seis animais de cada grupo foram eutanasiados após a medida de TWL nos dias 7 e 14 após a cirurgia e o segmento L4-6 da medula espinhal foi extraído para determinação da expressão de nNOS por imuno-histoquímica. Resultados Em comparação ao grupo sham, o limiar de TWL diminuiu significativamente e a expressão de nNOS foi regulada de maneira positiva após a cirurgia nos grupos CCI e DEX. Comparado ao grupo CCI, o limiar de TWL aumentou de forma significativa e a expressão de nNOS caiu significativamente diminuída nos dia 7 e 14 após a cirurgia no grupo DEX. Conclusão A regulação negativa de nNOS na medula espinhal dorsal está envolvida na atenuação da dor neuropática pela DEX. referese refere se somatossensorial geral ambulação hiperalgesia (nNOS segurança conforto (DEX eficaz SD (SD sham , (sham) ciático . (TWL 3 procedimento L46 L L4 6 L4- imunohistoquímica. imunohistoquímica imuno histoquímica. histoquímica imuno-histoquímica (sham

Abstract Background Early risk stratification with simple biomarkers is essential in patients with non-ST segment-elevation myocardial infarction (NSTEMI). Objective This study aimed to evaluate the association between plasma big endothelin-1 (ET-1) level and the SYNTAX score (SS) in patients with NSTEMI. Methods A total of 766 patients with NSTEMI undergoing coronary angiography were recruited. Patients were divided into three groups: low SS (≤22), intermediate SS (23-32), and high SS (>32). Spearman correlation, smooth curve fitting, logistic regression, and receiver operating characteristic (ROC) curve analysis were performed to evaluate the association between plasma big ET-1 level and the SS. A p-value <0.05 was considered statistically significant. Results There was a significant correlation between the big ET-1 and the SS (r=0.378, p<0.001). The smoothing curve indicated a positive correlation between the plasma big ET-1 level and the SS. The ROC curve analysis showed that the area under the curve was 0.695 (0.661-0.727) and the optimal cutoff of plasma big ET-1 level was 0.35pmol/l. Logistic regression showed that elevated big ET-1 was an independent predictor of intermediate-high SS in patients with NSTEMI, whether entered as a continuous variable [OR (95% CI): 1.110 (1.053-1.170), p<0.001] or as a categorical variable [OR (95% CI): 2.962 (2.073-4.233), p<0.001]. Conclusion In patients with NSTEMI, the plasma big ET-1 level was significantly correlated with the SS. Elevated plasma big ET-1 level was an independent predictor for intermediate-high SS. nonST non ST segmentelevation segment elevation . (NSTEMI) endothelin1 endothelin 1 endothelin- ET1 ET (ET-1 (SS 76 recruited groups ≤22, 22 ≤22 , (≤22) 2332, 2332 23 32 (23-32) >32. >32 (>32) fitting (ROC ET- pvalue p value 005 0 05 <0.0 r=0.378, r0378 r 378 (r=0.378 p<0.001. p0001 p<0.001 001 p<0.001) 0695 695 0.69 0.6610.727 06610727 0.661 0.727 661 727 (0.661-0.727 035pmoll pmoll 35pmol l pmol 0.35pmol/l intermediatehigh OR 95% 95 (95 CI CI) 1110 110 1.11 1.0531.170, 10531170 1.053 1.170 053 170 (1.053-1.170) 2962 2 962 2.96 2.0734.233, 20734233 2.073 4.233 073 4 233 (2.073-4.233) (NSTEMI (ET- 7 ≤2 (≤22 3 (23-32 >3 (>32 00 <0. r=0.378 r037 37 (r=0.37 p000 p<0.00 069 69 0.6 6610 0.6610.72 0661072 0661 0.66 0727 0.72 66 72 (0.661-0.72 9 (9 111 11 1.1 0531 1.0531.170 1053117 1053 1.05 1170 1.17 17 (1.053-1.170 296 96 2.9 0734 2.0734.233 2073423 2073 2.07 4233 4.23 07 (2.073-4.233 (ET ≤ (≤2 (23-3 > (>3 <0 r=0.37 r03 (r=0.3 p00 p<0.0 06 6 0. 0.6610.7 066107 066 072 0.7 (0.661-0.7 ( 1. 1.0531.17 105311 105 1.0 117 (1.053-1.17 29 2. 2.0734.23 207342 207 2.0 423 4.2 (2.073-4.23 (≤ (23- (> < r=0.3 r0 (r=0. p0 p<0. 0.6610. 06610 (0.661-0. 1.0531.1 10531 10 (1.053-1.1 2.0734.2 20734 20 42 4. (2.073-4.2 (23 r=0. (r=0 p<0 0.6610 (0.661-0 1.0531. (1.053-1. 2.0734. (2.073-4. (2 r=0 (r= p< (0.661- 1.0531 (1.053-1 2.0734 (2.073-4 r= (r (0.661 (1.053- (2.073- (0.66 (1.053 (2.073 (0.6 (1.05 (2.07 (0. (1.0 (2.0 (0 (1. (2. (1

Resumo Fundamento A estratificação de risco precoce com biomarcadores simples é essencial em pacientes com infarto do miocárdio sem supradesnivelamento do segmento ST (IAMSSST). Objetivo Este estudo tem o objetivo de avaliar a associação entre nível de big endotelina-1 plasmática (ET-1) e o escore SYNTAX (SS) em pacientes com IAMSSST. Métodos Foram recrutados 766 pacientes com IAMSSST que passaram por angiografia coronária. Os pacientes foram divididos em três grupos: SS baixo (≤22), SS intermediário (23-32), e SS alto (>32). A correlação de Spearman, o ajuste de curva suave, a regressão logística, e a análise de curva característica de operação do receptor (ROC) foram realizados para avaliar a associação entre o nível de big ET-1 plasmática e o SS. Um p-valor <0.05 foi considerado estatisticamente significativo. Resultados Foi identificada uma correlação significativa entre a big ET-1 e o SS (r=0,378, p<0,001). A curva suavizada indicou uma correlação positiva entre o nível de big ET-1 plasmática e o SS. A análise de curva ROC demonstrou que a área sob a curva foi de 0,695 (0,661-0,727) e o ponto de corte ideal do nível de big ET-1 plasmática foi de 0,35 pmol/l. A regressão logística demonstrou que a big ET-1 elevada era um preditor independente de SS intermediário a alto em pacientes com IAMSSST, seja como variável contínua [RC (IC 95%: 1,110 (1,053-1,170), p<0,001] ou como variável categórica [RC (IC 95%: 2,962 (2,073-4,233), p<0,001]. Conclusão Em pacientes com IAMSSST, o nível de big ET-1 plasmática estava significativamente correlacionado ao SS. O nível de big ET-1 plasmática elevado foi um preditor independente para SS intermediário a alto. . (IAMSSST) endotelina1 endotelina 1 endotelina- ET1 ET (ET-1 (SS 76 coronária grupos ≤22, 22 ≤22 , (≤22) 2332, 2332 23 32 (23-32) >32. >32 (>32) Spearman suave (ROC ET- pvalor p valor 005 0 05 <0.0 significativo r=0,378, r0378 r 378 (r=0,378 p<0,001. p0001 p<0,001 001 p<0,001) 0695 695 0,69 0,6610,727 06610727 0,661 0,727 661 727 (0,661-0,727 035 35 0,3 pmoll pmol l pmol/l RC IC 95% 95 1110 110 1,11 1,0531,170, 10531170 1,053 1,170 053 170 (1,053-1,170) 2962 2 962 2,96 2,0734,233, 20734233 2,073 4,233 073 4 233 (2,073-4,233) (IAMSSST (ET- 7 ≤2 (≤22 3 (23-32 >3 (>32 00 <0. r=0,378 r037 37 (r=0,37 p000 p<0,00 069 69 0,6 6610 0,6610,72 0661072 0661 0,66 0727 0,72 66 72 (0,661-0,72 03 0, 9 111 11 1,1 0531 1,0531,170 1053117 1053 1,05 1170 1,17 17 (1,053-1,170 296 96 2,9 0734 2,0734,233 2073423 2073 2,07 4233 4,23 07 (2,073-4,233 (ET ≤ (≤2 (23-3 > (>3 <0 r=0,37 r03 (r=0,3 p00 p<0,0 06 6 0,6610,7 066107 066 072 0,7 (0,661-0,7 1, 1,0531,17 105311 105 1,0 117 (1,053-1,17 29 2, 2,0734,23 207342 207 2,0 423 4,2 (2,073-4,23 (≤ (23- (> < r=0,3 r0 (r=0, p0 p<0, 0,6610, 06610 (0,661-0, 1,0531,1 10531 10 (1,053-1,1 2,0734,2 20734 20 42 4, (2,073-4,2 ( (23 r=0, (r=0 p<0 0,6610 (0,661-0 1,0531, (1,053-1, 2,0734, (2,073-4, (2 r=0 (r= p< (0,661- 1,0531 (1,053-1 2,0734 (2,073-4 r= (r (0,661 (1,053- (2,073- (0,66 (1,053 (2,073 (0,6 (1,05 (2,07 (0, (1,0 (2,0 (0 (1, (2, (1

Abstract Objective: To analyze the value of serum miRNA-122 expression in the diagnosis, severity, and prognosis of Acute Cerebral Infarction (ACI) and the correlation mechanism of serum miRNA-122 on the proliferation and apoptosis of vascular endothelial cells in ACI. Method: A total of 60 patients with ACI who were admitted to the emergency department of the Taizhou People’s Hospital from January 1, 2019, to December 30, 2019, and 30 healthy controls during the same period were selected. General clinical data of all patients at admission were collected. Including age, sex, medical history, and inflammatory factors (C-Reactive Protein [CRP], Interleukin-6 [IL-6], Procalcitonin [PCT], Neutrophil Gelatinase-Associated Lipid carrier protein [NGAL]). The National Institutes of Health Stroke Scale (NIHSS) score at admission and short-term prognosis (the Modified Rankin Score [mRS]) score at 3 months after onset were recorded. The expression level of miRNA-122 in the serum of patients with ACI and normal controls was detected by reverse-transcription quantitative Real-Time Polymerase Chain Reaction (RT-QPCR), and the correlation between the expression level of miRNA-122 in the serum of patients with ACI and the level of inflammatory factors, NIHSS and mRS scores were analyzed. The expression levels of miRNA-122 in the serum of patients with ACI, normal people, and Human Umbilical cord Endothelial Cells (HUVECs) cultured in a blank control group were detected by RT-QPCR and statistically analyzed. MTT and flow cytometry was used to compare the proliferation and apoptosis of vascular endothelial cells in the miRNA-122 mimics and inhibitors transfection groups and the corresponding negative control group. The mRNA and protein levels of apoptosis-related factors Bax, Bcl-2, Caspase-3, and angiogenesis-related proteins Hes1, Notch1, Vascular Endothelial Growth Factors (VEGF), and CCNG1 were detected by RT-QPCR and Western blot. Bioinformatics methods predicted CCNG1 to be the target of miRNA-122, and the direct targeting relationship between CCNG1 and miRNA-122 was verified by a dual-luciferase reporting assay. Result: Serum miRNA-122 expression in patients with ACI was significantly higher than that in healthy controls, with an area under the receiver operating characteristic curve of 0.929, 95% Confidence Interval of 0.875‒0.983, and an optimal cut-off value of 1.397. The expression levels of CRP, IL-6, and NGAL in patients with ACI were higher than those in healthy control groups, p < 0.05; miRNA-122 was positively correlated with CPR, IL-6, NIHSS score, and mRS score. At 48h and 72h, the proliferation rate of HUVECs cells in the miRNA-122 mimics group decreased and the apoptosis rate increased. Cell proliferation rate increased, and apoptosis rate decreased significantly in the groups transfected with miRNA-122 inhibitors. The mRNA and protein levels of pro-apoptotic factors Bax and caspase-3 were significantly increased in the miRNA-122 mimics transfection group, while those of anti-apoptotic factor Bcl-2 were significantly decreased compared to those of the control group. The expression of Bax and Caspase-3 decreased, and the expression of anti-apoptotic factor Bcl-2 increased in the transfected miRNA-122 inhibitors group. mRNA expression levels of Hes1, Notch1, VEGF, and CCNG1 in the miRNA-122 mimic transfected group were significantly decreased, while mRNA expression levels in the miRNA-122 inhibitors transfected group were significantly increased. Bioinformatics showed that there was a miRNA-122 binding site in the 3′UTR region of CCNG1, and dual luciferase assay confirmed that CCNG1 was the target of miRNA-122. Objective miRNA122 miRNA 122 miRNA-12 diagnosis severity (ACI Method 6 Peoples People s 1 2019 selected collected age sex history CReactive C Reactive CRP , [CRP] Interleukin6 Interleukin Interleukin- IL6, IL6 IL [IL-6] PCT, PCT [PCT] GelatinaseAssociated Gelatinase Associated NGAL. . [NGAL]) (NIHSS shortterm short term [mRS] recorded reversetranscription reverse transcription RealTime Real Time RTQPCR, RTQPCR RT QPCR (RT-QPCR) analyzed people (HUVECs apoptosisrelated related Bcl2, Bcl2 Bcl 2, 2 Caspase3, Caspase3 Caspase 3, angiogenesisrelated angiogenesis Hes1 Hes Notch1 Notch VEGF (VEGF) CCNG blot miRNA122, 122, dualluciferase Result 0929 0 929 0.929 95 08750983 875 983 0.875‒0.983 cutoff cut off 1397 397 1.397 6, IL-6 0.05 005 05 CPR h 72h proapoptotic pro apoptotic caspase3 caspase caspase- antiapoptotic anti Bcl- Caspase- 3UTR UTR miRNA122. 122. miRNA12 12 miRNA-1 201 [CRP [IL-6 [PCT [NGAL] [mRS (RT-QPCR (VEGF 092 92 0.92 9 0875098 87 98 0.875‒0.98 139 39 1.39 IL- 0.0 00 miRNA1 miRNA- 20 [IL- [NGAL 09 0.9 087509 8 0.875‒0.9 13 1.3 0. [IL 08750 0.875‒0. 1. 0875 0.875‒0 087 0.875‒ 08 0.875 0.87 0.8

SUMMARY A 71-year-old woman with recurrent papillary thyroid carcinoma (PTC) was referred to our hospital. A computed tomography scan revealed extensive recurrence in the neck, invading sternocleidomastoid muscle, internal jugular vein, sternal end of the clavicle, strap muscle and skin; and lateral compartment and subclavian lymph nodes were also involved. Multiple pulmonary micrometastases also noticed. The tumor was considered unresectable; however, the patient was unwilling to accept highly invasive surgery. Therefore, we initiated neoadjuvant therapy with anlotinib, 12mg p.o. daily with a 2-week on/1-week off regimen. The tumor shrunk to resectable state after 4 cycles of treatment, and after 3 weeks of withdrawal, successful surgical resection without gross tumor residual was performed. Pathology confirmed as classic PTC harboring coexistent TERT promoter and BRAFV600E mutations by NGS. After anlotinib therapy, apoptosis induction was observed, and proliferation increased, which was due to three weeks of anlotinib withdraw. Structual recurrence was recorded at 6 months after operation due to no further treatment was taken. Our finding suggests that anlotinib could represent as a good treatment option for patients with locally advanced (with or without distant metastasis) PTC; Anlotinib treatment resulted in sufficient reduction of the tumor mass to enable total thyroidectomy and radioactive iodine treatment, providing long-term control of the disease. 71yearold yearold 71 year old (PTC hospital neck vein clavicle skin involved noticed unresectable however surgery Therefore mg po p o p.o 2week week 2 on/1week on1week onweek on/1 on 1 regimen withdrawal performed BRAFVE BRAFV E NGS observed increased withdraw taken metastasis longterm long term disease 7 1week on1 on/