Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 661
Filtrar
1.
Environ Pollut ; 292(Pt A): 118362, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34648836

RESUMO

The fetus is prenatally exposed to a mixture of organochlorine pesticides (OCPs), mercury (Hg), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and selenium (Se) through maternal seafood consumption in real-life scenario. Prenatal exposure to these contaminants and nutrients has been suggested to affect thyroid hormone (TH) status in newborns, but the potential relationships between them are unclear and the joint effects of the mixture are seldom analyzed. The aim of the study is to investigate the associations of prenatal exposure to a mixture of OCPs, Hg, DHA, EPA and Se with TH parameters in newborns. 228 mother-infant pairs in Shanghai, China were included. We measured 20 OCPs, total Hg, DHA, EPA and Se in cord blood samples as exposure variables. The total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH) levels and the FT3/FT4 ratio in cord serum were determined as outcomes. Using linear regression models, generalized additive models and Bayesian kernel machine regression, we found dose-response relationships of the mixture component with outcomes: among the contaminants, p,p'-DDE was the most important positive predictor of TT3, while HCB was predominantly positively associated with FT3 and the FT3/FT4 ratio, indicating different mechanisms underlying these relationships; among the nutrients, EPA was first found to be positively related to the FT3/FT4 ratio. Additionally, we found suggestive evidence of interactions between p,p'-DDE and HCB on both TT3 and FT3, and EPA by HCB interactions for TT3, FT3 and FT3/FT4 ratio. However, the overall effects of the mixture on thyroid hormone parameters were not significant. Our result suggests that prenatal exposure to p,p'-DDE, HCB and EPA as part of a mixture might affect thyroid function of newborns in independent and interactive ways. The potential biological mechanisms merit further investigation.


Assuntos
Mercúrio , Praguicidas , Teorema de Bayes , China , Feminino , Sangue Fetal , Humanos , Recém-Nascido , Nutrientes , Gravidez , Hormônios Tireóideos , Tireotropina , Tiroxina
2.
Interdiscip Sci ; 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34817803

RESUMO

In 2002, our research group observed a gene clustering pattern based on the base frequency of A versus T at the second codon position in the genome of Vibrio cholera and found that the functional category distribution of genes in the two clusters was different. With the availability of a large number of sequenced genomes, we performed a systematic investigation of A2-T2 distribution and found that 2694 out of 2764 prokaryotic genomes have an optimal clustering number of two, indicating a consistent pattern. Analysis of the functional categories of the coding genes in each cluster in 1483 prokaryotic genomes indicated, that 99.33% of the genomes exhibited a significant difference (p < 0.01) in function distribution between the two clusters. Specifically, functional category P was overrepresented in the small cluster of 98.65% of genomes, whereas categories J, K, and L were overrepresented in the larger cluster of over 98.52% of genomes. Lineage analysis uncovered that these preferences appear consistently across all phyla. Overall, our work revealed an almost universal clustering pattern based on the relative frequency of A2 versus T2 and its role in functional category preference. These findings will promote the understanding of the rationality of theoretical prediction of functional classes of genes from their nucleotide sequences and how protein function is determined by DNA sequence.

3.
J Hazard Mater ; 424(Pt C): 127550, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34740158

RESUMO

Significant progress has been achieved on radionuclide transport in fractured rocks due to worldwide urgent needs for geological disposal of high-level radioactive waste (HLW). Transport models designed with accurately constrained parameters are a fundamental prerequisite to assess the long-term safety of repositories constructed in deep formations. Focusing on geological disposal systems of HLW, this study comprehensively reviews the behavoir of radionuclides and transport processes in multi-scale fractured rocks. Three issues in transport modeling are emphasized: 1) determining parameters of radionuclide transport models in various scales from laboratory- to field-scale experiments, 2) upscaling physical and chemical parameters across scales, and 3) characterizing fracture structures for radionuclide transport simulations. A broad spectrum of contents is covered relevant to radionuclide transport, including laboratory and field scale experiments, analytical and numerical solutions, parameter upscaling, and conceptual model developments. This paper also discusses the latest progress of radionuclide migration in multi-scale fractured rocks and the most promising development trends in the future. It provides valuable insights into understanding radionuclide transport and long-term safety assessment for HLW geological repository.

4.
Micromachines (Basel) ; 12(11)2021 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-34832808

RESUMO

Giant magnetostrictive transducer with micro and nano precision has a wide application prospect in the field of remote sensing. However, excessive heat loss of components could generate during the energy conversion and transfer from electric energy to magnetic energy, and magnetic energy to mechanical energy, thereby affecting its long-term service and also reducing energy utilization. In this paper, a new magnetostrictive transducer is proposed and its excitation coil, internal and external magnetic circuit are optimized from the perspective of reducing heat loss. With the help of theoretical and finite element analysis, the response law between key parameters and heat loss of key components are summarized, which provides a basis for reducing heat loss. Finally, according to the optimization scheme, the prototype is processed, and the temperature rise and dynamic output performance of the transducer are tested by constructing an experimental setup. The results show that the transducer has a low temperature rise and good frequency response characteristics, which can provide support for long-time precise actuation on-orbit.

6.
ACS Omega ; 6(44): 29459-29470, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34778618

RESUMO

In this paper, an improved heat exchanger network (HEN) synthesis method based on the comprehensive learning particle swarm optimizer algorithm (CLPSO) is proposed to synthesize HENs without stream splits. Compared with the standard particle swarm algorithm, CLPSO employs a novel learning strategy that preserves the diversity of the swarm to discourage premature convergence. However, while the algorithm's global exploration capability is enhanced, the local search capability decreases and the convergence speed becomes slow. In addition, the solution quality of CLPSO is largely determined by the randomly generated particles' best previous position (pbest) during initialization. Hence, the solution may be unstable due to different pbest. For the abovementioned considerations, this paper proposes a new HEN initialization and renovation method to improve the quality of pbest, reduce the initial cost, and retain the obtained optimization results as much as possible in the optimization process to speed up the convergence of the algorithm. Four typical cases are simulated to verify the effectiveness of the proposed method. This method only needs a single-level optimization algorithm to obtain high-quality solutions, which will give it a bright prospect in research and application.

7.
Front Oncol ; 11: 757650, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34796112

RESUMO

Long non-coding RNAs (lncRNAs) serve essential roles on various biological functions. Previous studies have indicated that lncRNAs are involved in the occurrence, growth and infiltration of brain tumors. LncRNA H19 is key regulator in the pathogenesis of gliomas, but the underlying mechanisms of H19-regulated tumor progression remain unknown. Therefore, we investigated the effects and mechanism of action of lncRNA H19 on the homeostasis of glioma cells. As a novel oncogenic factor, up-regulation of H19 was able to promote the proliferation of glioma cells by targeting miR-200a. Furthermore, elevated miR-200a levels could reverse H19-induced cell growth and metastasis. Overexpression of miR-200a could significantly suppress the proliferation, migration and invasion of glioma cells. These biological behavior changes in glioma cells were dependent on the binding to potential target genes including CDK6 and ZEB1. CDK6 could promote cell proliferation and its expression was remarkably increased in glioma. In addition, up-regulation of miR-200a lead to reduction of CDK6 expression and inhibit the proliferation of glioma cells. ZEB1 could be a putative target gene of miR-200a in glioma cells. Thus, miR-200a might suppress cell invasion and migration through down-regulating ZEB1. Moreover, overexpression of miR-200a resulted in down-regulation of ZEB1 and further inhibited malignant phenotype of glioma cells. In summary, our findings suggested that the expression of H19 was elevated in glioma, which could promote the growth, invasion and migration of tumor cells via H19/miR-200a/CDK6/ZEB1 axis. This novel signaling pathway may be a promising candidate for the diagnosis and targeted treatment of glioma.

8.
J Opt Soc Am A Opt Image Sci Vis ; 38(8): 1214-1223, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34613315

RESUMO

Laguerre-Gaussian (LG) beams with vortex phase possess a handedness, which would produce chiroptical interactions with chiral matter and may be used to probe structural chirality of matter. In this paper, we numerically investigate the light scattering of LG vortex beams by chiral particles. Using the vector potential method, the electric and magnetic field components of the incident LG vortex beams are derived. The method of moments (MoM) based on surface integral equations (SIEs) is applied to solve the scattering problems involving arbitrarily shaped chiral particles. The numerical results for the differential scattering cross sections (DSCSs) of several selected chiral particles illuminated by LG vortex beams are presented and analyzed. In particular, we show how the DSCSs depend on the chiral parameter of the particles and on the parameters describing the incident LG vortex beams, including the topological charge, the state of circular polarization, and the beam waist. This research may provide useful insights into the interaction of vortex beams with chiral particles and its further applications.

9.
J Biomol Struct Dyn ; : 1-10, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596010

RESUMO

The nicotinic acetylcholine receptors (nAChR) are made of subunits evolved from a common ancestor. Despite the similarity in their sequences and structures, the properties of these subunits vary significantly. Thus, identifying the evolution features and function-related sites specific to each subunit is essential for understanding the characteristics of the subunits and the receptors assembled by them. In this study, we examined the sequence features of the nine neuronal nAChRs subunits from representative vertebrate species. Analysis revealed that all the subunits were subject to strong purifying selection in evolution, and each was under a unique pattern of selection pressures. At the same time, the functional constraints were not uniform within each subunit, with different domains in the molecule being subject to different selection pressures. We also detected potential positive selection events in the subunits or subunit clusters, and identified the sites might be associated with the function specificity of each subunit. Furthermore, positive selection at some domains might contribute to the diversity of subunit function; for example, the ß9 strand might be related to the agonist specificity of α subunit in heteromeric receptor and ß4-ß5 linker could be involved in Ca2+ permeability. Subunits α7, α4 and ß2 subunits possess a strong adaptability in vertebrates. Our results highlighted the importance of tracking functional differentiation in protein sequence underlying functional properties of nAChRs. In summary, our work may provide clues on understanding the diversity and the function specificity of the nAChR subunits, as well as the receptors co-assembled by them.Communicated by Ramaswamy H. Sarma.

10.
Cell Death Dis ; 12(11): 983, 2021 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-34686650

RESUMO

Chronic and persistent inflammation is a well-known carcinogenesis promoter. Hepatocellular carcinoma (HCC) is one of the most common inflammation-associated cancers; most HCCs arise in the setting of chronic inflammation and hepatic injury. Both NF-κB and STAT3 are important regulators of inflammation. Centrosomal P4.1-associated protein (CPAP), a centrosomal protein that participates primarily in centrosome functions, is overexpressed in HCC and can increase TNF-α-mediated NF-κB activation and IL-6-induced STAT3 activation. A transgenic (Tg) mouse model with hepatocyte-specific CPAP expression was established to investigate the physiological role of CPAP in hepatocarcinogenesis. Obvious inflammatory cell accumulation and fatty change were observed in the livers of CPAP Tg mice. The alanine aminotransferase (ALT) level and the expression levels of inflammatory genes, such as IL-6, IL-1ß and TNF-α, were higher in CPAP Tg mice than in wild type (WT) mice. High-dose/short-term treatment with diethylnitrosamine (DEN) increased the ALT level, proinflammatory gene expression levels, and STAT3 and NF-κB activation in CPAP Tg mice; low-dose/long-term DEN treatment induced more severe liver tumor formation in CPAP Tg mice than in WT mice. CPAP can increase the expression of chemokine (C-C motif) ligand 16 (CCL-16), an important chemotactic cytokine, in human hepatocytes. CCL-16 expression is positively correlated with CPAP and TNF-α mRNA expression in the peritumoral part of HCC. In summary, these results suggest that CPAP may promote hepatocarcinogenesis through enhancing the inflammation pathway via increasing the expression of CCL-16.

11.
Nano Lett ; 21(20): 8650-8656, 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34609149

RESUMO

A perovskite microlaser is potentially valuable for integrated photonics due to its excellent properties. The artificial microlasers were mostly made on polycrystalline films. Though a perovskite single crystal has significantly improved properties in comparison with its polycrystalline counterpart, an artificial microlaser based on single-crystal perovskite has been much less explored due to the difficulty in producing an ultrathin-single-crystal (UTSC) film. Here we show a device processing based on a perovskite UTSC film, confirming the high performance of the UTSC device with a quality factor of 1250. The single-crystal device shows 4.5 times the quality factor and 8 times the radiation intensity in comparison with its polycrystalline counterpart. The experiment first proved that hybrid perovskite microlasers with a subwavelength fine structure can be processed by focused ion beams (FIB). In addition, a wavelength-tunable distributed feedback (DFB) laser is demonstrated, with a tuning range of ∼4.6 nm. The research provides an easily applicable approach for perovskite photonic devices with excellent performance.

12.
Bioorg Med Chem ; 49: 116438, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34610571

RESUMO

Liver fibrosis is one of the most common pathological consequences of chronic liver diseases (CLD). To develop effective antifibrotic strategies, a novel class of 1-(substituted phenyl)-1,8-naphthalidine-3-carboxamide derivatives were designed and synthesized. By means of the collagen type I α 1 (COL1A1)-based screening and cytotoxicity assay in human hepatic stellate cell (HSC) line LX-2, seven compounds were screened out from total 60 derivatives with high inhibitory effect and relatively low cytotoxicity for further COL1A1 mRNA expression analysis. It was found that compound 17f and 19g dose-dependently inhibited the expression of fibrogenic markers, including α-smooth muscle actin (α-SMA), matrix metalloprotein 2 (MMP-2), connective tissue growth factor (CTGF) and transforming growth factor ß1 (TGFß1) on both mRNA and protein levels. Further mechanism studies indicated that they might suppress the hepatic fibrogenesis via inhibiting both PI3K/AKT/Smad and non-Smad JAK2/STAT3 signaling pathways. Furthermore, 19g administration attenuated hepatic histopathological injury and collagen accumulation, and reduced fibrogenesis-associated protein expression in liver tissues of bile duct ligation (BDL) rats, showing significant antifibrotic effect in vivo. These findings identified 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents, and provided valuable information for further structure optimization.

13.
J Clin Med ; 10(19)2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34640546

RESUMO

BACKGROUND: The A-Line Autoregressive Index (AAI), which is derived from auditory evoked potentials, has been used for determining anesthetic depth. This study verified the correlation between AAI values and the corresponding end-tidal concentrations of sevoflurane during general anesthesia induction. METHODS: Thirty young male adults undergoing elective minor orthopedic surgery were sequentially allocated to receive inspiratory 3%, 5%, or 6% sevoflurane for mask induction, followed by mechanical ventilation after tracheal intubation. The inspiratory, end-tidal and estimated jugular bulb concentrations of sevoflurane were recorded at three target AAI values: below 20, below 10, and at the start of burst suppression. RESULTS: The mean time to loss of consciousness in the 6% sevoflurane group was shorter than that in the 5% and 3% groups; however, the groups had comparable AAI values (range: 16-45). The 6% group had a higher end-tidal concentration (4.5% ± 0.2% vs. 3.8% ± 0.2%, p < 0.05) than did the 5% group, despite having the same target anesthetic levels by AAI score ≤10, whereas the estimated jugular bulb concentrations were comparable (1.9% vs. 1.9%) in both groups. CONCLUSIONS: Following mechanical ventilation with inspiratory 3%, 5%, or 6% sevoflurane, the end-tidal concentrations were discrepant at the same end points of AAI levels, despite similar estimated jugular bulb concentrations of sevoflurane. Thus, conventional alveolar concentration may overestimate anesthesia depth during rapid wash-in of sevoflurane.

14.
Zool Res ; 42(5): 650-659, 2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34472226

RESUMO

Phosphatidylserine (PS) is distributed asymmetrically in the plasma membrane of eukaryotic cells. Phosphatidylserine flippase (P4-ATPase) transports PS from the outer leaflet of the lipid bilayer to the inner leaflet of the membrane to maintain PS asymmetry. The ß subunit TMEM30A is indispensable for transport and proper function of P4-ATPase. Previous studies have shown that the ATP11A and TMEM30A complex is the molecular switch for myotube formation. However, the role of Tmem30a in skeletal muscle regeneration remains elusive. In the current study, Tmem30a was highly expressed in the tibialis anterior (TA) muscles of dystrophin-null ( mdx) mice and BaCl 2-induced muscle injury model mice. We generated a satellite cell (SC)-specific Tmem30a conditional knockout (cKO) mouse model to investigate the role of Tmem30a in skeletal muscle regeneration. The regenerative ability of cKO mice was evaluated by analyzing the number and diameter of regenerated SCs after the TA muscles were injured by BaCl 2-injection. Compared to the control mice, the cKO mice showed decreased Pax7 + and MYH3 + SCs, indicating diminished SC proliferation, and decreased expression of muscular regulatory factors (MYOD and MYOG), suggesting impaired myoblast proliferation in skeletal muscle regeneration. Taken together, these results demonstrate the essential role of Tmem30a in skeletal muscle regeneration.


Assuntos
Proteínas de Membrana/metabolismo , Músculo Esquelético/fisiologia , Regeneração/fisiologia , Células Satélites de Músculo Esquelético/metabolismo , Animais , Proliferação de Células , Distrofina/genética , Distrofina/metabolismo , Antagonistas de Estrogênios/toxicidade , Regulação da Expressão Gênica/fisiologia , Genótipo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos mdx , Camundongos Knockout , Músculo Esquelético/efeitos dos fármacos , Proteína MyoD/genética , Proteína MyoD/metabolismo , Miogenina/genética , Miogenina/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Fator de Transcrição PAX7/genética , Fator de Transcrição PAX7/metabolismo , Regeneração/genética , Tamoxifeno/toxicidade
15.
Mitochondrial DNA B Resour ; 6(10): 2806-2807, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34514134

RESUMO

Apatura laverna is subordinate to Apatura Fabricius of Nymphalidae, and endemic to China. The complete mitochondrial genome of A. laverna was sequenced and analyzed in the study. The length of the complete mitogenome is 15,187 bp, including 37 genes and a control region. COI gene initiate with a CGA codon, the rest 12 genes start with typical ATN. Eleven of 13 PCGs have a complete stop codon TAN except for COII and ND4 have a single T. The phylogenetic analyses support that A. laverna has a close relationship with the clade including A. metis and A. ilia.

16.
Comput Struct Biotechnol J ; 19: 4042-4048, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34527183

RESUMO

Studies on codon property would deepen our understanding of the origin of primitive life and enlighten biotechnical application. Here, we proposed a quantitative measurement of codon-amino acid association and found that seven out of 13 physicochemical properties have stronger associations with the nucleotide identity at the second codon position, indicating that protein structure and function may associate more closely with it than the other two sites. When extending the effect of codon-amino acid association to protein level, it was found that the correlation between the second codon position (measured by the relative frequencies of nucleobase T and A at this codon site) and hydrophobicity (by the form of GRAVY value) became stronger with 96% genomes having R > 0.90 and p < 1e-60. Furthermore, we revealed that informational genes encoding proteins have lower GRAVY values than operational proteins (p < 3e-37) in both prokaryotic and eukaryotic genomes. The above results reveal a complete link from codon identity (A2 versus T2) to amino acid property (hydrophilic versus hydrophobic) and then to protein functions (informational versus operational). Hence, our work may help to understand how the nucleotide sequence determines protein function.

17.
BMC Biol ; 19(1): 200, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503495

RESUMO

BACKGROUND: Although oocyte quality is the dominant factor determining embryo quality, few studies have been conducted to evaluate embryo quality based on the metabolites related to the oocyte. With quantification of the follicular fluid (FF) metabolites, in assisted reproductive technology (ART), this study sought to evaluate the embryo or oocyte quality through an informative approach. RESULTS: An evaluation model consisting of 17 features was generated to distinguish the embryo quality on day 3 post-fertilization, and phosphatidylcholines (PCs) were the key contributors to the evaluation. The model was extended to the patients under different ages and hyperstimulations, and the features were further enriched to facilitate the evaluation of the embryo quality. The metabolites were clustered through pathway analysis, leading to a hypothesis that accumulation of arachidonic acid induced by PCs might weaken embryo quality on day 3 post-fertilization. CONCLUSIONS: A discriminating model with metabolic features elicited from follicular fluid was established, which enabled the evaluation of the embryo or oocyte quality even under certain clinical conditions, and the increase of PCs in follicular fluid implies the attenuation of embryo quality on day 3 post-fertilization.

18.
BMJ Open ; 11(9): e053755, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34548370

RESUMO

INTRODUCTION: Lateral ankle sprains are one of the most common musculoskeletal injuries. Up to 70% of individuals who sustain lateral ankle sprains develop chronic ankle instability (CAI). Balance training has been used in patients with CAI, but the evidence for its efficacy is inconsistent. This systematic review and meta-analysis aims to determine the short-term (end of the treatment period) and long-term (6 months after treatment) effectiveness of balance training for patients with CAI. METHODS AND ANALYSIS: We will search PubMed, EMBASE, the Cochrane Library, Ovid, EBSCO-host, Pedro, ClinicalKey, ScienceDirect, Springer, China National Knowledge Infrastructure, Technology Periodical Database (VIP), WanFang Data and China Biology Medicine for reports of randomised trials of balance training in patients with CAI, from inception to 1 October 2021. The language will be restricted to English and Chinese, and articles will be screened and collected by two reviewers independently. Dynamic balance and functional ankle instability are the primary outcomes of this study. Secondary outcomes include pain, ankle range of motion, ankle strength and health-related quality of life. Review Manager V.5.3 software will be used for meta-analysis, and stratification analysis will be conducted for study quality according to the Jadad score. Subgroup and sensitivity analyses will be conducted. Grading of Recommendations, Assessment, Development and Evaluation will be used to assess confidence in the cumulative evidence. The protocol follows the Cochrane Handbook for Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guidelines. ETHICS AND DISSEMINATION: Ethical approval is not required for literature-based studies. The results will be disseminated through peer-reviewed publications.


Assuntos
Tornozelo , Qualidade de Vida , Gerenciamento de Dados , Humanos , Metanálise como Assunto , Projetos de Pesquisa , Revisões Sistemáticas como Assunto
19.
Arthritis Rheumatol ; 2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34423919

RESUMO

OBJECTIVE: To investigate the role of PF-06650833, a highly potent and selective small-molecule inhibitor of interleukin-1-associated kinase 4 (IRAK4), in autoimmune pathophysiology in vitro, in vivo, and in the clinical setting. METHODS: Rheumatoid arthritis (RA) inflammatory pathophysiology was modeled in vitro through 1) stimulation of primary human macrophages with anti-citrullinated protein antibody immune complexes (ICs), 2) RA fibroblast-like synoviocyte (FLS) cultures stimulated with Toll-like receptor (TLR) ligands, as well as 3) additional human primary cell cocultures exposed to inflammatory stimuli. Systemic lupus erythematosus (SLE) pathophysiology was simulated in human neutrophils, dendritic cells, B cells, and peripheral blood mononuclear cells stimulated with TLR ligands and SLE patient ICs. PF-06650833 was evaluated in vivo in the rat collagen-induced arthritis (CIA) model and the mouse pristane-induced and MRL/lpr models of lupus. Finally, RNA sequencing data generated with whole blood samples from a phase I multiple-ascending-dose clinical trial of PF-06650833 were used to test in vivo human pharmacology. RESULTS: In vitro, PF-06650833 inhibited human primary cell inflammatory responses to physiologically relevant stimuli generated with RA and SLE patient plasma. In vivo, PF-06650833 reduced circulating autoantibody levels in the pristane-induced and MRL/lpr murine models of lupus and protected against CIA in rats. In a phase I clinical trial (NCT02485769), PF-06650833 demonstrated in vivo pharmacologic action pertinent to SLE by reducing whole blood interferon gene signature expression in healthy volunteers. CONCLUSION: These data demonstrate that inhibition of IRAK4 kinase activity can reduce levels of inflammation markers in humans and provide confidence in the rationale for clinical development of IRAK4 inhibitors for rheumatologic indications.

20.
Gland Surg ; 10(7): 2255-2265, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34422596

RESUMO

Background: Dual-targeted therapy is currently the standard adjuvant treatment for human epidermal growth factor receptor 2-positive (HER2+) and lymph node-positive (LN+) breast cancer. However, the optimal therapeutic strategy for patients with HER2+ and lymph node-negative (LN-) breast cancer remains unclear. This population-based study aimed to explore the factors associated with survival in patients with HER2+ and LN- breast cancer, and develop a survival-predicting nomogram in the era of trastuzumab-based single-targeted therapy. Methods: We collected the clinicopathological information of HER2+ and LN- breast cancer patients who underwent chemotherapy and surgery from The Surveillance, Epidemiology, and End Results (SEER) database (2010-2016, the Trastuzumab-based single-targeted therapy era). We subsequently explored the risk factors for breast cancer-specific survival (BCSS) and overall survival (OS) using a Cox proportional hazards regression model, aiming to identify subgroups with worse prognosis, which would indicate potential demand for dual-targeted therapy. Three- and 5-year survival probability-predictive nomograms were established and subjected to bootstrap internal validation. The concordance index (C-index) and calibration curve were applied to evaluate the performance of the model. Results: After data cleansing, a total of 13,755 patients were included in the current analysis. Using univariate and multivariate Cox proportional hazards regression, higher clinical T stage, hormone receptors-negative (HR-), and partial mastectomy without radiotherapy were identified as independent risk factors for BCSS and OS in patients with HER2+ and LN- breast cancer. Nomograms for 3- and 5-year BCSS and OS incorporating the selected prognostic factors were established. Calibration curves verified good consistency between the actual and nomogram-predicted survival probability. The C-index values of the BCSS and OS predictions and 95% confidence interval (CI) were 0.773 (0.740-0.806) and 0.764 (0.737-0.791), respectively. Conclusions: Higher clinical T stage, HR-, and partial mastectomy without radiotherapy predicted worse prognosis in patients with HER2+ and LN- breast cancer. In clinical practice, patients can be recommended for single-targeted or dual-targeted therapy according to the individualized factors.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...