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Anti-CTLA-4 antibodies faced challenges due to frequent adverse events and limited efficacy, which spurred the exploration of next-generation CTLA-4 therapeutics to balance regulatory T cells (Tregs) depletion and CD8 T cells activation. CCR8, identified primarily on tumor-infiltrating Tregs, has become a target of interest due to the anti-tumor effects demonstrated by CCR8 antibody-mediated Tregs depletion. Single-cell RNA sequencing analysis reveals that CCR8-positive Tregs constitute a small subset, with concurrent expression of CCR8 and CTLA-4. Consequently, we proposed a novel bispecific antibody targeting CCR8 and CTLA-4 that had the potential to enhance T cell activation while selectively depleting intratumor Tregs. The candidate molecule 2MW4691 was developed in a tetravalent symmetric format, maintaining a strong binding affinity for CCR8 while exhibiting relatively weaker CTLA-4 binding. This selective binding ability allowed 2MW4691 to target and deplete tumor-infiltrating Tregs with higher specificity. In vitro assays verified the antibody's capacity for antibody-dependent cellular cytotoxicity (ADCC) to Tregs with high level of CTLA-4 expression, but not CD8 T cells with relatively low level of CTLA-4 on cell surface. Also, 2MW4691 inhibited the CTLA-4 pathway and enhanced T cell activation. The in vivo therapeutic efficacy of 2MW4691 was further demonstrated using hCCR8 or hCTLA-4 humanized mouse models and hCCR8/hCTLA-4 double knock-in mouse models. In cynomolgus monkeys, 2MW4691 was well-tolerated, exhibited the anticipated pharmacokinetic profile, and had a minimal impact on the peripheral T cell population. The promising preclinical results supported the further evaluation of 2MW4691 as a next-generation Treg-based therapeutics in clinical trials.
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Anticorpos Biespecíficos , Linfócitos T CD8-Positivos , Antígeno CTLA-4 , Linfócitos T Reguladores , Animais , Camundongos , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/imunologia , Anticorpos Biespecíficos/uso terapêutico , Humanos , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T CD8-Positivos/imunologia , Receptores CCR8/imunologia , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Transdução de Sinais/efeitos dos fármacos , Feminino , Ensaios Antitumorais Modelo de Xenoenxerto , Macaca fascicularisRESUMO
Osteoarthritis (OA) is one of the most common diseases of the skeleton. Long non-coding RNAs (lncRNAs) are emerging as key players in OA pathogenesis. This work sets out to determine the function of lncRNA MALAT1 in OA and the mechanisms by which it does so. Mesenchymal stem cells isolated from the human synovial membrane are called hSMSCs. The hSMSCs' surface markers were studied using flow cytometry. To determine whether or not hSMSC might differentiate, researchers used a number of different culture settings and labeling techniques. The expression levels of associated genes and proteins were determined using quantitative real-time polymerase chain reaction (RT-qPCR), western blotting (WB), and immunostaining. A dual luciferase reporter experiment and RNA immunoprecipitation (RIP) test demonstrated the direct association between miR-212-5p and MALAT1 or MyD88. MALAT1 was downregulated during the chondrogenic differentiation of hSMSCs, and underexpression of MALAT1 promotes chondrogenesis in hSMSCs. Using dual luciferase reporter and RIP assays facilitated the identification of MALAT1 as a competitive endogenous RNA (ceRNA) that sequesters miR-212-5p. Additionally, the expression of MYD88 was regulated by MALAT1 through direct binding with miR-212-5p. Significantly, the effects of MALAT1 on the chondrogenic differentiation of hSMSCs were counteracted by miR-212-5p/MYD88. Furthermore, our in vivo investigation revealed that the inhibition of MALAT1 mitigated osteoarthritis progression in rat models. In conclusion, the promotion of chondrogenic differentiation in hSMSCs and the protective effect on cartilage tissue in OA can be achieved by suppressing MALAT1, which regulates the miR-212-5p/MyD88 axis.
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Células-Tronco Mesenquimais , MicroRNAs , Osteoartrite do Joelho , RNA Longo não Codificante , Animais , Humanos , Ratos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Condrogênese , Luciferases/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismoRESUMO
Many advanced materials are designed for the removal of heavy metal ions from water. However, materials for eliminating trace heavy metal ions from wastewater to meet drinking water standards remain a major challenge. Herein, epoxy group-functionalized open-cellular beads are synthesized by UV polymerization of a water-in-oil-in-water system. The epoxy groups are further transformed into diethylenetriaminepentaacetic acid (DTPA) with hexamethylene diamine as a bridging agent. The resulting material (DTPA@polyHIPE beads) can eliminate trace Cu(II), Cr(III), Pb(II), Fe(III), or Cd(II) from water. When 0.15 g of DTPA@polyHIPE beads are used to adsorb metal ions of 20 mg in 100 mL of water, the residue concentrations of Cu(II), Cr(III), Pb(II), Fe(III), and Cd(II) are reduced to 0.08, 0.06, 0.02, 0.09, and 0.07 mg/L, respectively. The adsorption efficiencies of the beads for these ions are all higher than 99.55%. The adsorbent is durable and exhibits good recyclability by retaining an adsorption capacity of ≥91% after 5 cycles. The negative values of ΔG in the adsorption process indicate that the adsorption is feasible and spontaneous. The chemical adsorption follows the Freundlich adsorption model, indicating a multilayer heterogeneous adsorption. The DTPA@polyHIPE beads have a great potential application in dealing with trace heavy metal ion polluted water.
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BACKGROUND: Spatial hearing is a critical feature in daily life. However, there is quite a range in hearing loss patients regarding the effect of bone conduction device on localization performance. OBJECTIVES: To analyze the localization performance in patients with bilateral conductive or mixed hearing loss fitted with one Baha® Attract system. MATERIALS AND METHODS: This prospective study included 12 patients who had followed up for more than one year. The parameters analyzed included (1) audiological results: sound field threshold, speech discrimination scores (SDSs), and sound localization test, and (2) functional results: scores for the Speech, Spatial and Qualities of Hearing Scale (SSQ) and the Chinese translation of the Spatial Hearing Questionnaire (C-SHQ). RESULTS: The audiological assessments showed a reduction of 28.5 dB in the mean sound field thresholds and improvements of 61.7% in the SDSs for disyllabic words. The root mean square error improved slightly with the Baha® Attract system. Patients showed promising results in the functional questionnaire assessments, with significant improvements in the SSQ and C-SHQ scores. CONCLUSIONS: Although most patients were not able to localize sound accurately after surgery, the change in the scores of the SSQ and C-SHQ indicated that the Baha® Attract system could improve spatial hearing.
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Auxiliares de Audição , Perda Auditiva , Localização de Som , Percepção da Fala , Humanos , Estudos Prospectivos , Audição , Perda Auditiva CondutivaRESUMO
Based on the size- and shape-selective sorption, 13X molecular sieves were developed as solid-phase extraction adsorbents to cleanup serum extract for the determination of polybrominated diphenyl ethers. The important parameters affecting the cleanup efficiency were investigated including the amount of sorbents, the type, and volume of solvents. Under the optimized conditions, the capacity for removing impurities was evaluated via gel permeation chromatography and gas chromatography with mass spectrometry. The results demonstrated that up to 99% of lipids in corn oil (13 mg) can be removed after cleanup, and endogenous compounds in serum can also be effectively eliminated. The cleanup efficiency is not only superior to hydrophile-lipophile balance column, but also close to acid silica gel and multifunction impurity sorbents. Generally, the developed cleanup method exhibited higher recovery for polybrominated diphenyl ethers with more than four bromines, especially for nona- and deca-brominated diphenyl ethers (99.1-117.8%). The cleanup method can be coupled with gas chromatography and tandem mass spectrometry for polybrominated diphenyl ethers analysis in human serum. The method detection limits were 0.01-0.27 ng/mL and average recovery was 50.9-113.3%, except 2,3',4',6-tetrabrominated, 2,3',4,4',6-pentabrominated, and 2,3,3',4,4',5',6-heptabrominated diphenyl ethers. 2,2',4,5'-Tetrabrominated diphenyl ethers had the highest detection frequency (95%) in human serum, whereas decabrominated diphenyl ethers had the maximum mean concentration (0.50 ng/mL).
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Éteres Difenil Halogenados , Extração em Fase Sólida , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Extração em Fase Sólida/métodos , Espectrometria de Massas em Tandem/métodosRESUMO
BACKGROUND: Revision total hip arthroplasty (THA) has been a challenge for surgeons. The purpose of this study was to explore the short-to mid-term clinical and radiological outcomes of Chinese patients who underwent revision THA using a new off-the-shelf three-dimensional (3D)-printed trabecular titanium (TT) acetabular cup by comparison with a conventional porous coated titanium acetabular cup, to provide a reference for the recommendation of this prostheses. METHODS: A retrospective analysis of 57 patients (57 hips) who received revision THA was performed from January 2016 to June 2019. A total of 23 patients received 3D-printed cups (observation group) and 34 patients received non-3D-printed cups (control group). Clinical scores including Visual Analogue Scale (VAS), Harris Hip Score (HHS) and Short Form 36 (SF-36), upward movement of the hip center of rotation(HCOR)and limb-length discrepancy (LLD), stabilization and bone ingrowth of cups were compared between two groups. The multivariate linear regression was used to determine the factors potentially influencing the HHS score. Postoperative complications in the two groups were also recorded. RESULTS: All 57 patients were routinely followed up. The average follow-up durations in the control and observation groups were 43.57 ± 13.68 (24-65) months and 41.82 ± 11.44 (24-64) months, respectively (p = 0.618). The postoperative clinical scores significantly improved in both groups compared to the preoperative scores (p < 0.001). The VAS score did not significantly differ between the groups at 3 (p = 0.946) or 12 (p = 0.681) months postoperatively, or at the last follow-up (p = 0.885). The HHS score did not significantly differ between the groups at 3 months (p = 0.378) postoperatively but differed at 12 months (p < 0.001) postoperatively and the last follow-up (p < 0.001). The SF-36 score did not significantly differ between the groups at 3 months (p = 0.289) postoperatively, but was significantly different at 12 months (p < 0.001) postoperatively and the last follow-up (p < 0.001). Compared with the control group, the postoperative recovery of HCOR and LLD was better in the observation group. All cups remained stable, with no loosening throughout the follow-up period. But the observation group had a significantly better rate of bone ingrowth compared to the control group (p = 0.037). Multivariate linear regression analysis showed that different cup types, upward movement of the HCOR, and LLD influenced the HHS score at the last follow-up (p < 0.001, p = 0.005, respectively). None of the patients exhibited severe postoperative complications. CONCLUSION: The new off-the-shelf 3D-printed TT acetabular cup demonstrated encouraging short-to mid-term clinical outcomes in Chinese patients. It can effectively relieve pain, improve hip function, provide satisfactory biological fixation and high survival rate. But further follow up is necessary to assess its long-term outcomes.
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Complicações Pós-Operatórias , Titânio , China , Humanos , Reoperação , Estudos RetrospectivosRESUMO
BACKGROUND: Osteoarthritis (OA) is the most prevalent chronic joint disease, and is hard to be cured at present. Cytokine receptor-like factor 1 (CRLF1) has been identified as an upregulated gene in OA cartilage. However, the precise identities and functions of CRLF1 in OA progression have remained to be fully elucidated. METHODS: We used a murine model of injury-induced OA (destabilization of medial meniscus, DMM) and BMSCs to investigate the specific biological functions and mechanisms of CRLF1. RESULTS: We found that CRLF1 was significantly increased in the DMM surgery-induced OA model and was down-regulated during chondrogenic differentiation of BMSCs. Luciferase reporter assays showed that CRLF1 was a direct target of miR-320 in BMSCs. miR-320 can reverse the effect of CRLF1 on cell proliferation, apoptosis and chondrogenic differentiation of BMSCs. Furthermore, knockdown of CRLF1 or over-expression of miR-320 can inhibit the apoptosis of primary chondrocytes. CONCLUSION: Suppression of CRLF1 promotes the chondrogenic differentiation of BMSCs and protects cartilage tissue from damage in osteoarthritis via activation of miR-320.
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Cartilagem/metabolismo , Diferenciação Celular/genética , Condrogênese/genética , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/genética , Osteoartrite/genética , Receptores de Citocinas/genética , Regiões 3' não Traduzidas/genética , Animais , Apoptose/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Condrócitos/citologia , Condrócitos/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Osteoartrite/metabolismo , Receptores de Citocinas/metabolismoRESUMO
Human exposure to bisphenols has rarely been reported. The most important challenges in this regard are the sensitivity and accuracy of the analytical methods employed. Dansyl chloride derivatization prior to high-performance liquid chromatography-tandem mass spectrometry has been prevalently employed to improve sensitivity. However, the dose effect of the derivatization reagent on the reaction products is not well understood, especially for reactants with two or more active groups. This study investigated the mass ratio of dansyl chloride to bisphenols and found the mass ratio played a vital role in changing the composition of derivatives; further, the optimal ratio for obtaining di-substituted derivatives was confirmed. Under optimal conditions, solid-phase extraction followed by dansyl chloride derivatization coupled with high-performance liquid chromatography-tandem mass spectrometry was used to detect eight bisphenols in human serum samples. The method detection limits of the eight bisphenols were 0.025-0.28 ng/mL, and the recoveries were 72.9-121.7% by spiking bisphenols (2, 5, and 20 ng/mL) into bovine serum. The detection frequencies of bisphenol A and bisphenol F in 73 serum samples obtained from children from Guangzhou were 41.1% and 71.2%, respectively, while the detection frequencies of other bisphenols were below 20%. The concentrations of bisphenol A and bisphenol F were < 0.28-8.0 ng/mL and < 0.028-7.6 ng/mL, respectively.
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Compostos Benzidrílicos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Compostos de Dansil/análise , Fenóis/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Calibragem , Bovinos , Criança , China , Exposição Ambiental , Desenho de Equipamento , Humanos , Reprodutibilidade dos Testes , Soro/metabolismo , Extração em Fase Sólida , TemperaturaRESUMO
Gastrointestinal stromal tumors (GISTs) are resistant to traditional chemotherapy but are responsive to the tyrosine kinase inhibitors imatinib and sunitinib. The use of these agents has improved the outcome for patients but is associated with adverse effects, including hypothyroidism. Multiple mechanisms of this effect have been proposed, including decreased iodine organification and glandular capillary regression. Here we report the finding of consumptive hypothyroidism caused by marked overexpression of the thyroid hormone-inactivating enzyme type 3 iodothyronine deiodinase (D3) within the tumor. Affected patients warrant increased monitoring and may require supernormal thyroid hormone supplementation.
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Neoplasias Gastrointestinais/enzimologia , Tumores do Estroma Gastrointestinal/enzimologia , Hipotireoidismo/enzimologia , Hipotireoidismo/etiologia , Iodeto Peroxidase/metabolismo , Hormônios Tireóideos/deficiência , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/diagnóstico por imagem , Tumores do Estroma Gastrointestinal/complicações , Tumores do Estroma Gastrointestinal/diagnóstico por imagem , Humanos , Iodeto Peroxidase/genética , Masculino , Pessoa de Meia-Idade , Radiografia AbdominalRESUMO
The BACH2 gene regulates B cell differentiation and function and has been reported to be a shared susceptibility gene for several autoimmune diseases. Our previous genome-wide association study (GWAS) indicated that several single nucleotide polymorphisms (SNPs) in the BACH2 gene are associated with Graves' disease (GD) in the Chinese Han population; however, the association did not achieve genome-wide significance levels. Recently, this association of BACH2 with GD was confirmed in Caucasians in the UK population, but fine mapping in this region has not yet been reported. Here, we provide a refined analysis of a 331-kb region in the BACH2 gene, which harbors 359 SNPs, using GWAS data from 1,442 GD patients and 1,468 controls. The SNPs rs2474619 and rs9344996 were implied as the independent variants associated with GD by forward and two-locus logistic regression analysis. We genotyped eight out of 10 tagSNPs with P < 1 × 10(-3) in 3,508 GD patients and 3,209 controls, the results also showed that rs2474619 was independently associated with GD in the combined population from GWAS and the second stage (P = 1.81 × 10(-5)). The rs2474619 and rs9344996 were further genotyped in the third stage cohorts, and rs2474619 showed evidence of association with GD at genome-wide significance levels in the combined population (P = 3.28 × 10(-8), odds ratio = 1.13). The association of rs9344996 with GD can be explained by its linkage to rs2474619 in the combined population. Our study clearly demonstrated that BACH2 is a susceptibility gene for GD in the Chinese Han population and further supported rs2474619, in intron 2 of BACH2, is the best association signal with GD. However, the mechanism by which BACH2 confers increased risk of GD requires further study.
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Fatores de Transcrição de Zíper de Leucina Básica/genética , Etnicidade/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doença de Graves/genética , Doenças Autoimunes/genética , Sequência de Bases , China , Primers do DNA , Humanos , Modelos Logísticos , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Cell-free seminal mRNA (cfs-mRNA) and microRNA (cfs-miRNA) have been found in human ejaculate and reported as promising noninvasive biomarkers for disorders of male reproductive organs and forensic identification. However, seminal plasma is particularly challenging for RNA extraction due to its complicated composition and high content of protein, DNA, and polysaccharide. Here, we report a novel, simple, and reliable method for the isolation of cfs-mRNA and cfs-miRNA from human semen based on our previous findings of their physical nature. Seminal microvesicles (0.1-0.5 µm in diameter), which contain the majority of cfs-mRNA, were enriched by a microfilter. Protein complexes, which most cfs-miRNA is bound with, were enriched by an ultrafilter. Harvesting the complexes or microvesicles, in which RNAs exist, avoided the influence of other components in human semen, thus favoring RNA isolation and purification. This new method can efficiently isolate cfs-mRNA and cfs-miRNA separately based on their physical nature, with high RNA purity, and low DNA contamination. It may also be applied or modified to isolate cell-free RNAs in other fluids.
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Filtração/métodos , MicroRNAs/isolamento & purificação , RNA Mensageiro/isolamento & purificação , Sêmen/química , Filtração/instrumentação , Humanos , Masculino , MicroRNAs/química , MicroRNAs/metabolismo , RNA Mensageiro/química , RNA Mensageiro/metabolismo , Sêmen/citologiaRESUMO
Phosphaturic mesenchymal tumors (PMT) are rare and distinctive tumors that typically result in paraneoplastic syndrome known as tumor-induced osteomalacia (TIO). We report a case of bilateral osteoporotic femoral neck fracture caused by PMT. PMT was surgically resected, followed by sequential treatment of bilateral femoral neck fractures with total hip arthroplasty (THA). A 49-year-old perimenopausal woman experienced consistent bone pain with limb weakness persisting for over 2 years. Initially, she was diagnosed with early osteonecrosis of the femoral head and received nonsurgical treatment. However, from 2020 to 2022, her pain extended to the bilateral shoulders and knees with increased intensity. She had no positive family history or any other genetic diseases, and her menstrual cycles were regular. Physical examination revealed tenderness at the midpoints of the bilateral groin and restricted bilateral hip range of motion, with grade 3/5 muscle strength in both lower extremities. Laboratory findings revealed moderate anemia (hemoglobin 66 g/L), leukopenia (2.70 × 109/L), neutropenia (1.28 × 109/L), hypophosphatemia (0.36 mmol/L), high alkaline phosphatase activity (308.00 U/L), and normal serum calcium (2.22 mmol/L). After surgery, additional examinations were performed to explore the cause of hypophosphatemic osteomalacia. After definitive diagnosis, the patient underwent tumor resection via T11 laminectomy on August 6, 2022. Six months after the second THA, the patient regained normal gait with satisfactory hip movement function without recurrence of PMT-associated osteomalacia or prosthesis loosening. By providing detailed clinical data and a diagnostic and treatment approach, we aimed to improve the clinical understanding of femoral neck fractures caused by TIO.
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Fraturas do Colo Femoral , Neoplasias de Tecido Conjuntivo , Osteomalacia , Síndromes Paraneoplásicas , Humanos , Feminino , Osteomalacia/etiologia , Pessoa de Meia-Idade , Fraturas do Colo Femoral/cirurgia , Fraturas do Colo Femoral/etiologia , Fraturas do Colo Femoral/complicações , Síndromes Paraneoplásicas/etiologia , Neoplasias de Tecido Conjuntivo/etiologia , Neoplasias de Tecido Conjuntivo/diagnóstico , Neoplasias de Tecido Conjuntivo/cirurgia , Hipofosfatemia/etiologia , Artroplastia de QuadrilRESUMO
Using dodecyl acrylate as a raw material and 2-Cyanoprop-2-yl-dithiobenzoate as a chain transfer agent, poly(dodecyl acrylate) is synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Using poly(dodecyl acrylate) as stabilizers, narrowly dispersed poly(ε-caprolactone) microspheres with particle sizes ranging from 0.5 to 1.5 µm are successfully synthesized by ring-opening dispersion polymerization. The effects of the molecular weight of poly(dodecyl acrylate), the volume proportion of mixed solvent (i.e., 1,4-dioxane/heptane), and the reaction temperature on the particle size and its distribution are investigated. With careful control of the synthesis condition, microspheres can be obtained with a particle size distribution of 1.09 (Dw/Dn). The average particle size of poly(ε-caprolactone) microspheres decreased with the increase in the molecular weight of poly(dodecyl acrylate) and increased with the increase in the relative content of 1,4-dioxane. The uniformity of microspheres decreased with the increase in the polymerization temperature.
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Purpose: To assess the alterations in bone mineral density and bone turnover marker concentrations following the administration of denosumab and romosozumab therapies in patients with osteoporosis. Methods: PubMed was searched for studies published until January 28, 2023, that investigated the clinical efficacy and bone turnover marker changes of denosumab and romosozumab in the treatment of osteoporosis, with a minimum follow-up of 3 months in each study. Studies were screened, and data on changes in bone mineral density (BMD), P1NP, and TRACP-5b levels after treatment were extracted and included in the analysis. Results: Six studies were analyzed. At 3 months after treatment, the romosozumab group showed greater changes in lumbar BMD and bone turnover markers. BMD of total hip and femoral neck was relatively delayed. Beginning at 6 to 12 months, romosozumab showed greater changes in bone mineral density and markers of bone turnover. Conclusion: Both romosozumab and denosumab have antiosteoporotic effects, with greater effects on BMD and bone turnover markers observed within 12 months of romosozumab treatment. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023395034.
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Conservadores da Densidade Óssea , Osteoporose , Humanos , Densidade Óssea , Denosumab/farmacologia , Denosumab/uso terapêutico , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose/tratamento farmacológico , Osteoporose/induzido quimicamenteRESUMO
Accumulating evidence suggests that adipose tissue is the main source of pro-inflammatory molecules that predispose individuals to insulin resistance. Stevioside (SVS) is a widely used sweetener with multiple beneficial effects for diabetic patients. In this study, we investigated the effect of SVS on insulin resistance and the pro-inflammatory state of adipose tissue in mice fed with a high-fat diet (HFD). Oral administration of SVS for 1month had no effect on body weight, but it significantly improved fasting glucose, basal insulin levels, glucose tolerance and whole body insulin sensitivity. Interestingly, these changes were accompanied with decreased expression levels of several inflammatory cytokines in adipose tissue, including TNF-α, IL6, IL10, IL1ß, KC, MIP-1α, CD11b and CD14. Moreover, macrophage infiltration in adipose tissue was remarkably reduced by SVS. Finally, SVS significantly suppressed the nuclear factor-kappa b (NF-κB) signaling pathway in adipose tissue. Collectively, these results suggested that SVS may ameliorate insulin resistance in HFD-fed mice by attenuating adipose tissue inflammation and inhibiting the NF-κB pathway.
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Tecido Adiposo/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Diterpenos do Tipo Caurano/administração & dosagem , Glucosídeos/administração & dosagem , Inflamação/tratamento farmacológico , Resistência à Insulina , NF-kappa B/antagonistas & inibidores , Edulcorantes/administração & dosagem , Tecido Adiposo/patologia , Animais , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Regulação para Baixo , Teste de Tolerância a Glucose , Inflamação/metabolismo , Inflamação/patologia , Insulina/farmacologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossínteseRESUMO
OBJECTIVE: To explore the correlations of the polymorphisms of phosphodiesterase 8B (PDE8B) gene with Hyperthyroxinemia in Chinese Han population. METHODS: A case-control study of genotype 657366 SNPs was performed by Illumina Human660-Quad BeadChips in 98 Hyperthyroxinemia patients and 1300 controls. And 25 SNPs within PDE8B gene intron 1 were used for association analyses. RESULTS: Allele frequencies of 5 SNPS in PDE8B gene intron 1 showed significant differences between the case and control groups (P < 0.05). In comparison with the control group, the genotypic distributions of rs7714529 (χ(2) = 6.430, P = 0.040), rs12514694 (χ(2) = 7.191, P = 0.027) and rs10066802 (χ(2) = 9.213, P = 0.010) in H-TSH group had significant differences. Haplotype AGTAG (rs7702192/rs7714529/rs251421/rs12514694/rs10066802) was over-represented in hyperthyrotropinemia cases versus the control group. CONCLUSION: PDE8B gene polymorphisms may be correlated with Hyperthyroxinemia in Chinese Han population. And it may provide new concepts for the treatment of thyroid dysfunction.
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3',5'-AMP Cíclico Fosfodiesterases/genética , Hipertireoxinemia/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Povo Asiático/genética , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Pessoa de Meia-IdadeRESUMO
Objective:To analyze the clinical characteristics of unilateral acoustic neuromaï¼ANï¼ with normal hearing, so as to provide evidence for early identification AN. Methods:Clinical datas from 73 patients of unilateral AN with normal hearing of Otorhinolaryngology Head and Neck Surgery of Beijing Tiantan Hospital affiliated of Capital Medical University from August 2019 to April 2022 admitted to department were retrospectively analyzed. All patients underwent pure tone audiometryï¼PTAï¼, speech discrimination scoreï¼SDSï¼, auditory brainstem responseï¼ABRï¼, distortion product otoacoustic emissionï¼DPOAEï¼ and head enhanced MRI. Results:The incidence of normal hearing among patients with AN was 10.7%. Maleâ¶female=1â¶2.2; the mean age of the patients wasï¼37.3±9.4ï¼ years; the mean tumor size wasï¼24.2±11.2ï¼ mm. Tinnitus was the most common reason for visit; the patients who had headache and dizziness had larger tumors. Surgery was the main treatment, and the patients who underwent surgery had larger tumors than those of follow-up. Heterogeneous tumors were the most common type of MRI, homogeneous tumors were smaller than heterogeneous and cystic tumors. The sensitivity of ABR in the diagnosis of AN with normal hearing was 95.9%, and that of ≥20 mm tumors was 100%; prolonged â ¤-waves were the most common, patients with â ¤-wave deletion had larger tumors than those with normal or prolonged â ¤-waves. Patients who had the longer the â ¤-wave and the longer difference between â -â ¤ wave had larger tumors. DPOAE was not elicited at full frequency in 11 patients. There was no statistically significant difference in age among patients with different symptoms, treatments, types of MRI, ABR and DPOAE. Conclusion:AN of normal hearing was most common in 30-39 years old women. Patients had different symptoms, phenotypes of MRI and ABR. Patients with normal hearing who had tinnitus, dizziness, headache, facial paraesthesia, and recovery after sudden haring loss can be further examination of ABR and DPOAE for early identification AN. The sensitivity of ABR in diagnosis of hearing normal AN was 95.9%, and the abnormal type of â ¤-wave is related to tumor size.
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Neuroma Acústico , Zumbido , Feminino , Humanos , Zumbido/diagnóstico , Neuroma Acústico/diagnóstico , Neuroma Acústico/complicações , Neuroma Acústico/patologia , Estudos Retrospectivos , Tontura/complicações , Limiar Auditivo , Audição , Potenciais Evocados Auditivos do Tronco Encefálico , Vertigem/complicações , Audiometria de Tons Puros/efeitos adversosRESUMO
Polychlorinated naphthalenes (PCNs) have a structure similar to that of polychlorinated biphenyls (PCBs) and represent a new type of persistent organic pollutants (POPs) that are widely present in the environment and biological communities. PCNs can migrate and transform via different environmental media, which severely affects the health of humans and organisms. Researchers have devoted considerable focus on ambient air pollution. Although the current ambient air quality has not yet limited the concentration of PCNs, the Stockholm Convention has required parties to prohibit and eliminate their production and use. As one of the contracting parties, China is obligated to improve its environmental monitoring. In other words, the development of a method for monitoring PCNs in ambient air is important for understanding ambient air quality and safeguarding human health. PCNs are generally present at trace levels (pg/m3) in ambient air. To achieve accurate quantification of PCNs, high demands are raised on the methods for extraction, purification, and instrumental analysis, which can directly affect the efficiency, accuracy, and sensitivity of a method. Considering the trace-level presence of PCNs in ambient air and the high efficiency and accuracy of the analytical method, accelerated solvent extraction (ASE), combined with column chromatography using a multilayer silica gel column and a neutral alumina column, was established for the extraction and purification of PCNs in ambient air. The important parameters involved in the aforementioned steps, such as the type of extraction and volume of elution solvent, were optimized. The results indicated that dichloromethane-hexane (1â¶1, v/v) was the best extraction solvent for the recovery of PCNs. Hexane and dichloromethane-hexane (5â¶95, v/v) were used as the elution solvents for the multi-silica gel column and neutral alumina column, respectively. Isotope dilution gas chromatography-triple quadrupole mass spectrometry (GC-MS/MS) was used to quantify the target compounds. Gas chromatographic parameters, such as temperature program conditions and inlet temperature, were also optimized. The oven temperature program was as follows: 80 â for 1 min, 80 â to 160 â at 15 â/min, 160 â to 265 â at 3 â/min, and 265 â to 280 â at 5 â/min, followed by holding the temperature at 280 â for 10 min. The inlet temperature was set at 260 â. The optimal characteristics of ion pair, collision energy, and ion source temperature were determined by optimizing the key mass spectrometry parameters. The developed instrumental method, combined with suitable sample preparation techniques, was used to determine the concentrations of PCNs in ambient air samples. Quality control (QC) and quality assurance (QA) were performed by adding isotope internal standards before sampling, extraction, and injection analysis to monitor the entire analysis process. The relative standard deviations (RSDs) of the relative response factors (RRFs) for trichloronaphthalene to octachloronaphthalene were less than 16% in the concentration range of 2-100 ng/mL. The method detection limits (MDLs) for PCN homologues were in the range of 1-3 pg/m3(calculated using a sample volume of 288 m3). The precision and accuracy of this method for determining PCNs in ambient air samples were evaluated using a spiked matrix. The average spiked recoveries of trichloronaphthalene to octachloronaphthalene were 89.0%-119.4%, 98.6%-122.5% and 93.7%-124.5% at low, medium, and high spiked concentrations (20, 50, and 90 ng/mL), respectively. The RSDs of the assay results were 1.9%-7.0%, 1.6%-6.6%, and 1.0%-4.8%, respectively. During the entire analysis process, the average recoveries of the sampling and extracted internal standards were 136.2%-146.0% and 42.4%-78.1%, respectively, and the corresponding RSDs were 5.6%-7.5% and 2.7%-17.5%. Thus, this method meets the requirements of trace analysis and exhibits good parallelism, high sensitivity, high accuracy, and good precision, and it is suitable for the accurate quantitative determination of trichloronaphthalene to octachloronaphthalene in ambient air.
Assuntos
Hexanos , Naftalenos , Óxido de Alumínio , Cromatografia Gasosa-Espectrometria de Massas/métodos , Hexanos/análise , Humanos , Isótopos , Cloreto de Metileno/análise , Naftalenos/análise , Sílica Gel , Solventes/análise , Espectrometria de Massas em Tandem/métodosRESUMO
Residual levels and accumulation characteristics of six hazardous heavy metal elements (As, Cd, Hg, Tl, Pb, and U) and seven essential heavy metal elements (Cr, Mn, Fe, Ni, Cu, Zn, and Se) were investigated in 17 kinds of frequently consumed foodstuffs collected from 33 cities distributed in five regions of China. The concentrations of the detected metals were lower than the maximum limits promulgated by the Chinese government except Pb and inorganic As (iAs). Foods of aquatic origin and terrestrial plant origin exhibited high potentials to accumulate heavy metals, especially algae and shellfish. The calculated hazard index (HI) of heavy metal exposure via consumption of foodstuffs were 2.93-5.01 for adults in the five surveyed region, implying the co-exposure of heavy metals via food consumption would lead to potential non-carcinogenic risks. iAs was the predominant contributor to HI values with the average contribution of 40.5% in all five regions. Consumption of terrestrial plant origin foods contributed 76.9% of HI values induced by heavy metal exposure. The calculated target cancer risks of iAs in the five regions were 5 × 10-4-1 × 10-3, all exceeding the acceptable level of 10-4, indicating it is necessary and urgent to reduce the contamination of iAs in foodstuffs on the Chinese markets.
Assuntos
Metais Pesados , Poluentes do Solo , China , Cidades , Monitoramento Ambiental , Chumbo , Metais Pesados/análise , Medição de Risco , Poluentes do Solo/análiseRESUMO
Understanding the underlying molecular mechanisms behind ADE of SARS-CoV-2 is critical for development of safe and effective therapies. Here, we report that two neutralizing mAbs, MW01 and MW05, could enhance the infection of SARS-CoV-2 pseudovirus on FcγRIIB-expressing B cells. X-ray crystal structure determination and S trimer-binding modeling showed that MW01 and MW05 could bind to RBDs in S trimer with both "up" and "down" states. While, the neutralizing mAb MW07, which has no ADE activity only binds to RBD in S trimer with "up" state. Monovalent MW01 and MW05 completely diminished the ADE activity compared with their bivalent counterparts. Moreover, both macropinocytosis and endocytosis are confirmed involving in ADE of SARS-CoV-2 pseudoviral infection. Blocking endosome transportation and lysosome acidification could inhibit the ADE activity mediated by MW05. Together, our results identified a novel ADE mechanism of SARS-CoV-2 pseudovirus in vitro, FcγRIIB-mediated uptake of SARS-CoV-2/mAb complex with bivalent interaction.