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PURPOSE: Intermittent hypoxia (IH) mimicking obstructive sleep apnea (OSA) has been confirmed to induce tumor lung metastasis via oxidative stress and inflammation responses. Follistatin-like 1 (Fstl1), as a matricellular protein, plays critical roles in inflammatory diseases and cancer. This study aimed to investigate the effect and mechanism of Fstl1 on OSA-IH-induced tumor lung metastasis. METHODS: Fstl1+/+ or Fstl1+/- mice inoculated with B16F10 melanoma cells were exposed to OSA-IH. The number and area of mouse lung metastatic colonies were assessed. Markers for tumor metastasis, oxidative stress, and inflammation in lung melanoma tissue or B16F10 melanoma cells were quantified by western blotting, qRT-PCR, and immunohistochemistry. The migration of B16F10 cells was examined by wound healing assay. RESULTS: Fstl1 levels are decreased in lung tissues from OSA-IH injured mice inoculated with melanoma cells. Fstl1-deficient mice were highly susceptible to the OSA-IH model of melanoma lung metastasis, as assessed by increased number and area of lung metastatic colonies, and by the elevated levels of HIF-1α, Vegf, N-cadherin, and E-cadherin. Lung melanoma tissue in Fstl1+/- mice provided evidence of increased oxidative stress, as determined by increased levels of NRF2 and P22phox and decreased level of Sod2, as well as increased inflammatory response, as determined by elevated levels of NF-κB P65, Tnf-α and Il-6. Conversely, stable overexpression of Fstl1 in B16F10 cells under OSA-IH exposure attenuated the migration of B16F10 cells and levels of tumor-related markers, as well as decreased oxidative stress and inflammatory responses. CONCLUSION: These results suggest that Fstl1 may protect against OSA-IH-induced tumor lung metastasis through oxidative stress and inflammatory responses. Fstl1 may serve as a promising target for OSA-related cancer.
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Proteínas Relacionadas à Folistatina , Neoplasias Pulmonares , Melanoma , Apneia Obstrutiva do Sono , Animais , Camundongos , Folistatina , Proteínas Relacionadas à Folistatina/genética , Hipóxia/metabolismo , Inflamação/metabolismo , Neoplasias Pulmonares/patologia , Apneia Obstrutiva do Sono/metabolismoRESUMO
Allosteric regulation, the most direct and efficient way of regulating protein function, is induced by the binding of a ligand at one site that is topographically distinct from an orthosteric site. Allosteric Database (ASD, available online at http://mdl.shsmu.edu.cn/ASD) has been developed to provide comprehensive information featuring allosteric regulation. With increasing data, fundamental questions pertaining to allostery are currently receiving more attention from the mechanism of allosteric changes in an individual protein to the entire effect of the changes in the interconnected network in the cell. Thus, the following novel features were added to this updated version: (i) structural mechanisms of more than 1600 allosteric actions were elucidated by a comparison of site structures before and after the binding of an modulator; (ii) 261 allosteric networks were identified to unveil how the allosteric action in a single protein would propagate to affect downstream proteins; (iii) two of the largest human allosteromes, protein kinases and GPCRs, were thoroughly constructed; and (iv) web interface and data organization were completely redesigned for efficient access. In addition, allosteric data have largely expanded in this update. These updates are useful for facilitating the investigation of allosteric mechanisms, dynamic networks and drug discoveries.
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Regulação Alostérica , Bases de Dados de Proteínas , Descoberta de Drogas , Humanos , Internet , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Proteínas/química , Proteínas/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Transdução de SinaisRESUMO
UNLABELLED: Allosteric ligands have increasingly gained attention as potential therapeutic agents due to their higher target selectivity and lower toxicity compared with classic orthosteric ligands. Despite the great interest in the development of allosteric drugs as a new tactic in drug discovery, the understanding of the ligand-protein interactions underlying allosteric binding represents a key challenge. Herein, we introduce Alloscore, a web server that predicts the binding affinities of allosteric ligand-protein interactions. This method exhibits prominent performance in describing allosteric binding and could be useful in allosteric virtual screening and the structural optimization of allosteric agonists/antagonists. AVAILABILITY AND IMPLEMENTATION: The Alloscore server and tutorials are freely available at http://mdl.shsmu.edu.cn/alloscore CONTACT: jian.zhang@sjtu.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Proteínas/metabolismo , Sítio Alostérico , Descoberta de Drogas , LigantesRESUMO
It is now established that the specificity in signaling of signal transducer and activator of transcription 3 (STAT3) is mediated by the SH2 domain of STAT3, which mediates its interaction with the phosphopeptide docking sites displayed by receptors and JAKs, dimerization and subsequent DNA binding. Thus, we aimed to identify and design a class of strong potential small molecular inhibitors of STAT3 for the discovery and development of novel anticancer agents. Several classes of small molecules have been identified as STAT3 inhibitors after structure-based screening of the STAT3 SH2 domain. Next, we detected the activity of these inhibitors using fluorescence polarization (FP) and identified the growth inhibition of DU145 and MDA-MB-468 cells using the CCK-8 assay. Consequently, B9 inhibits the proliferation of tumor cells harboring abnormal activation of STAT3, such as, MDA-MB-468, MDA-MB-231 and DU145. However, there is little inhibition of MCF-7 cells. In addition, The Kd of B9 to STAT3 (I634S/Q635G) is 22.75µM compared to 4.59µM for WT as analyzed by SPR. The phosphorylation of STAT3 in MDA-MB-468 cells was obviously decreased after treatment with B9 at the preconceived concentration of 30µM, as detected using immunoblotting. Here, we evaluated the effect of B9 on the migration of MDA-MB-468 cells. Taken together, our results indicate a novel small molecule that decreases STAT3 activation and function of the STAT3 signaling pathway, thereby inducing an antitumor response in human breast cancer cells harboring constitutively active STAT3.
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Antineoplásicos/farmacologia , Neoplasias/patologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Fosforilação , Ressonância de Plasmônio de SuperfícieRESUMO
PURPOSE: The aim of this study was to investigate the sex-dependent difference in P-glycoprotein activity as measured by the probe drug talinolol. METHODS: A randomized, single-blind, parallel study was carried out in 20 healthy male and 20 healthy female volunteers. The pharmacokinetics of talinolol were measured after single oral dosing of 50-mg tablet and the pharmacokinetic parameters for male and female subjects were compared after excluding the potential influence of P-gp genetic polymorphisms. RESULTS: Talinolol AUC(0-48h) in the female subjects was 23.5% (p = 0.003) higher than that of male subjects. There was no significant sex difference in weight-corrected oral clearance, AUC, or other PK parameters. CONCLUSION: The AUC and other PK data of talinolol, corrected for body weight, did not differ between genders after oral administration. The observed sex difference in talinolol systemic exposure is of little clinical relevance. The overall activity of P-gp shows no sex-related difference.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Antagonistas de Receptores Adrenérgicos beta 1/farmacocinética , Polimorfismo Genético , Propanolaminas/farmacocinética , Adulto , Área Sob a Curva , Feminino , Genótipo , Humanos , Masculino , Caracteres Sexuais , Método Simples-CegoRESUMO
BACKGROUND: Adjuvant radiation therapy is commonly administered to breast cancer patients who received breast-conserving surgery. However, lengthy treatment times of standard radiotherapy pose certain challenges. Here, we performed a prospective controlled study comparing standard radiation to hypofractionated radiotherapy in terms of efficacy and outcome. MATERIAL AND METHODS: Eighty breast cancer patients (tumor stage pT1-2N0-1M0) who had undergone breast-conservation surgery were randomly divided into 2 groups (40 patients/group). The experimental group received 43.2 Gy to the whole breast in 18 fractions for 24 days with a concomitant boost (50.4 Gy) to the tumor bed. The control group received 45 Gy to the whole breast in 25 fractions for 44 days with a boost to the tumor bed of 59 Gy. Survival, locoregional recurrence, adverse effects, and aesthetic results were all considered for analysis. RESULTS: The following criteria were included as part of study follow-up: local control, survival, adverse skin reactions, cosmetic outcome, and hematological toxicity. At a median follow-up of 27 months (follow-up rate 100%), there were no statistical differences in any of the categories between the 2 groups. The 2-year survival rate of both groups was 100% without any locoregional recurrence. Although there was some skin toxicity, these instances were not severe and they cleared on their own within 6 weeks. The most common problems encountered by patients were breast fibrosis and altered pigmentation. CONCLUSIONS: A shortened whole-breast hypofractionated irradiation schedule with a concomitant boost is as effective as standard radiation and may be a reasonable alternative following breast conservation surgery.
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Neoplasias da Mama/radioterapia , Fracionamento da Dose de Radiação , Mastectomia Segmentar , Neoplasias da Mama/cirurgia , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
MOTIVATION: The use of allosteric modulators as preferred therapeutic agents against classic orthosteric ligands has colossal advantages, including higher specificity, fewer side effects and lower toxicity. Therefore, the computational prediction of allosteric sites in proteins is receiving increased attention in the field of drug discovery. Allosite is a newly developed automatic tool for the prediction of allosteric sites in proteins of interest and is now available through a web server. AVAILABILITY: The Allosite server and tutorials are freely available at http://mdl.shsmu.edu.cn/AST CONTACT: jian.zhang@sjtu.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Proteínas/química , Software , Algoritmos , Sítio Alostérico , Descoberta de Drogas , Ligantes , Proteínas/metabolismoRESUMO
Absorption-free Bragg reflector has been studied in ions doped in crystals. We propose a new scheme using Zeeman sublevels of atoms to construct an absorption-free Bragg reflector with practical laser power. Its spatial period of refractive index equals half of the wavelength of the incident standing-wave coupling light. The proposal is simulated in a helium atom scheme, and can be extended to alkali earth atoms.
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We propose an efficient scheme in helium or alkaline earth atomic vapor to achieve a parity-time symmetric Bragg structure using coherent lights. Unidirectional invisibility can be realized in this scheme, i.e., the atomic vapor shows total transparency for probe light incident from one particular direction, but exhibits enhanced Bragg reflection for probe from the opposite side. By changing the relative phase between the coherent lights, this direction can easily be manipulated, providing a convenient way for investigating special properties of ð«ð¯ -symmetric Bragg structures.
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Fenômenos Ópticos , Simulação por Computador , Modelos Teóricos , Análise Numérica Assistida por Computador , VolatilizaçãoRESUMO
The direct pump method now used in excited state Faraday anomalous dispersion optical filters (ES-FADOFs) requires that the transition between the target and the ground state is an electric dipole allowed transition and that a laser that operates at the exact pump wavelength is available. This is not always satisfied in practice. An indirect laser pump method for ES-FADOF is proposed and experimentally realized. Compared with the commonly used direct pump method, this indirect pump method can reach the same performance using lasers at very different wavelengths. This method can greatly extend the wavelength range of FADOF and provide a novel scheme for ES-FADOF design.
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BACKGROUND: The small bowel is one of the critical organs involved in gastrointestinal complications in cervical cancer treated with postoperative intensity modulated radiotherapy. Even with modest doses of radiation therapy (45-50Gy), the risk of severe injury from postoperative radiation therapy is between 5% and 15%. Up to now, a predictive model of acute GI complications of the small bowel has been established with the aid of Quantitative Analyses of Normal Tissue Effects in the Clinic. However, the correlation between dose-volume effect and chronic GI complications of the small bowel has not been extensively investigated. In the article, the correlation has been studied preliminarily. METHODS: This study analyzed 84 patients who underwent postoperative IMRT. The organ at risk that was contoured was the small bowel loops. DVH parameters subjected to analysis included maximum and mean dose, the volume of these organs receiving more than 30, 40, and 50 Gy (V30-50 volume) and the volume of V30-50 to total volume (V30-50 ratio). Association between DVH parameters or clinical factors and the incidence of grade 1-2 chronic GI complications were evaluated. RESULTS: Body position and RT total dose are significantly associated with grade 1-2 chronic GI complications after postoperative IMRT in early-stage cervical cancer patients. Maximum dose and V40 ratio of the small bowel loops were significantly associated with chronic GI complications (P < 0.05). The optimal threshold were 5586 cGy (maximum dose) and 28% (V40 ratio) of the small bowel loops. CONCLUSIONS: Maximum dose and V40 ratio of the small bowel loops should be considered synthetically before postoperative IMRT for early-stage cervical cancer.
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Gastroenteropatias/etiologia , Lesões por Radiação , Neoplasias do Colo do Útero/complicações , Neoplasias do Colo do Útero/terapia , Adulto , Doença Crônica , Feminino , Seguimentos , Humanos , Histerectomia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Curva ROC , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada , Fatores de Risco , Neoplasias do Colo do Útero/patologiaRESUMO
The quantitative characterization of rock mass and stress changes induced by mining activities is crucial for structural stability monitoring and disaster early warning. This paper investigates the time-space-intensity distribution of microseismic sources during the pillar-free large-area continuous extraction. Furthermore, it explores a method involving collaborative evolution patterns of the velocity field and spatial b-value to identify stress and structural changes at the panel stope. Results show that anomalous zones in wave velocities and b-values form at the intersections of extraction drifts, strike drifts, cross drifts, and connection roadways influenced by mining activities, as well as in footwall ore-rock contacts, often accompanied by the nucleation of microseismic events. The synergistic use of wave velocity fields and spatial b-value models reveals the relationship between stress migration behavior and stope structure changes due to mining disturbances. The velocity field primarily reflects macroscopic changes in the structure and stress distribution, while spatial b-values further explain stress gradients in specific areas. Additionally, we have advanced the identification of an instability disaster at the connection roadway and cross drift intersection based on increases in wave velocity and abnormal changes in b-value. This paper demonstrates the potential of risk identification using the proposed method, providing insights into predicting geotechnical engineering disasters in complex stress environments.
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In order to promote the application of WFAS standard, General Requirements for the Risk Control in the Safe Use of Acupuncture and the safe practice of acupuncture technology worldwide, the paper introduces the developing process and main contents of this standard, explains the developing purpose, scope, ideas, methods and basis, and analyzes the definition of the relevant terms. Through strictly complied with the development procedure of standard, the terms related to acupuncture risk in this standard are defined. The connotations of 5 special terms are clarified, i.e. "acupuncture risks" "adverse events of acupuncture" "adverse reactions of acupuncture" "acupuncture accidents" and "acupuncture negligence". The range, rank, control flow and source of risk, as well as the control measures are determined. The standard extracts the underlying common problems and basic requirement of the safe practice of acupuncture so as to lay a framework for the development of the relevant technical standards of acupuncture.
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Terapia por Acupuntura , RegistrosRESUMO
Follistatin-like 1 (FSTL1) is a cancer-related matricellular secretory protein with contradictory organ-specific roles. Its contribution to the pathogenesis of cervical carcinoma is still not clear. Meanwhile, it is necessary to identify novel candidate genes to understand cervical carcinoma's pathogenesis further and find potential therapeutic targets. We collected cervical carcinoma samples and matched adjacent tissues from patients with the locally-advanced disease and used cervical carcinoma cell lines HeLa and C33A to evaluate the effects of FSTL1 on CC cells. The mRNA transcription and protein expression of FSTL1 in cervical carcinoma tumor biopsy tissues were lower than those of matched adjacent tissues. Patients with a lower ratio of FSTL1 mRNA between the tumor and its matched adjacent tissues showed a correlation with the advanced cervical carcinoma FIGO stages. High expression of FSTL1 markedly inhibited the proliferation, motility, and invasion of HeLa and C33A. Regarding mechanism, FSTL1 plays its role by negatively regulating the BMP4/Smad1/5/9 signaling. Our study has demonstrated the tumor suppressor effect of FSTL1, and these findings suggested a potential therapeutic target and biomarker for cervical carcinoma.
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To enhance the clinical applicability of guidelines and provide more effective guidance for clinical practice, a clinical value assessment was conducted during the development of the World Federation of Acupuncture-Moxibustion Societies (WFAS) Clinical Practice Guideline of Acupuncture and Moxibustion for Migraine, which involved the evaluation of 59 acupuncture and moxibustion treatment protocols from randomized controlled trials (RCTs). This article introduced the methodology, content and results of the clinical value assessment of RCT-based acupuncture and moxibustion treatment protocols, which involved the integration of historical and contemporary medical evidence and expert consensus. It served as a methodological reference for the future development of acupuncture and moxibustion clinical practice guidelines.
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Terapia por Acupuntura , Acupuntura , Transtornos de Enxaqueca , Moxibustão , Humanos , Terapia por Acupuntura/métodos , Protocolos Clínicos , Transtornos de Enxaqueca/terapiaRESUMO
It is aimed to evaluate the effectiveness and provide evidence-based medical support for acupuncture as a prophylactic treatment for migraines. Randomized controlled trials (RCTs) from inception to April 2022 are included in 14 databases. Pairwise meta-analysis is conducted using STATA software V14.0, while Windows Bayesian Inference Using Gibbs Sampling (WinBUGS V.1.4.3) is applied to generate Bayesian Network Meta-analysis (NMA) using Markov chain Monte Carlo algorithm. Forty RCTs are included, with 4405 participants. The effectiveness of six acupuncture techniques, three types of prophylactic drugs, and psychotherapy are compared and ranked. Acupuncture outperformed prophylactic drugs in terms of diminishing visual analog scale (VAS) score, migraine attack frequency, and days during the treatment and at the 12-week follow-up. At the 12-week follow-up, the effectiveness of various interventions is ranked as follows: manual acupuncture (MA) > electroacupuncture (EA) > calcium antagonists (CA) in reducing VAS score; MA > EA > CA in reducing migraine attack frequency; MA > EA > ß-receptor blocker and CA in reducing headache attack days. Acupuncture is a promising treatment for migraine prevention. The best option of acupuncture for improving various migraine outcomes has changed over time. However, the quality of included trials and NMA inconsistency limited the credibility of the conclusion.
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BACKGROUND: Non-small cell lung cancer (NSCLC) is a common cancer in the United States. Previous studies have shown that circular RNAs (circRNAs) can affect NSCLC progression, but its regulatory mechanism is still indistinct. In this study, we unfold the roles of circular RNA_0007385 in NSCLC tissues and cells. METHODS: Expression levels of circ_0007385, microRNA-493-3p (miR-493-3p) and Ras-related protein Rab-22A (RAB22A) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) in NSCLC tissues and cells. Cell proliferation, apoptosis and stemness were examined by cell counting kit 8 (CCK8) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry analysis and sphere-formation assay. The interaction between miR-493-3p and circ_0007385 or RAB22A was forecasted by bioinformatic analysis and detected by dual-luciferase reporter assay, RNA immunoprecipitation (RIP) and RNA pulldown assays. In vivo experiments were implemented to verify the effect of circ_0007385 in vivo. RESULTS: Expression of circ_0007385 and RAB22A increased, whereas miR-493-3p level was decreased in NSCLC tissues in contrast to that in normal tissues. For functional analysis, circ_0007385 deficiency inhibited cell proliferation and stemness, whereas it promoted cell apoptosis in NSCLC cells. Mechanically, circ_0007385 acted as a miR-493-3p sponge to modulate RAB22A expression. Moreover, circ_0007385 could regulate the development of NSCLC by sponging miR-493-3p to regulate the expression of RAB22A. In addition, circ_0007385 silence also attenuated tumor growth in vivo. CONCLUSIONS: Circ_0007385 promoted NSCLC progression by sponging miR-493-3p to increase RAB22A expression, which also offered an underlying targeted therapy for NSCLC treatment.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , Apoptose , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/genética , Humanos , Neoplasias Pulmonares/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismoRESUMO
Stroke is an acute cerebrovascular disease with high incidence, high mortality, and high disability rate. Determining the location and volume of the disease in MR images promotes accurate stroke diagnosis and surgical planning. Therefore, the automatic recognition and segmentation of stroke lesions has important clinical significance for large-scale stroke imaging analysis. There are some problems in the segmentation of stroke lesions, such as imbalance of the front and back scenes, uncertainty of position, and unclear boundary. To meet this challenge, this paper proposes a cross-attention and deep supervision UNet (CADS-UNet) to segment chronic stroke lesions from T1-weighted MR images. Specifically, we propose a cross-spatial attention module, which is different from the usual self-attention module. The location information interactively selects encode features and decode features to enrich the lost spatial focus. At the same time, the channel attention mechanism is used to screen the channel characteristics. Finally, combined with deep supervision and mixed loss, the model is supervised more accurately. We compared and verified the model on the authoritative open dataset "Anatomical Tracings of Lesions After Stroke" (Atlas), which fully proved the effectiveness of our model.
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Professor WU Zhong-chao's clinical experience of "dredging stagnation and collaterals" acupuncture for migraine is summarized. Professor WU proposes that occiput-nape dysfunction, meridians-tendons dysfunction and stagnation of collaterals due to obstruction of excess-evil could lead to migraine. As such, migraine is treated by comprehensive treatment of adjusting occiput-nape functional zone, relaxing meridians-tendons and blood-letting combined with fire acupuncture.
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Terapia por Acupuntura , Acupuntura , Meridianos , Transtornos de Enxaqueca , Pontos de Acupuntura , Humanos , Transtornos de Enxaqueca/terapiaRESUMO
Objectives: The purpose of this study was to observe the clinical efficacy of the reinforcing and circulation-promoting protocol of acupuncture and moxibustion in treatment of refractory chronic low back pain, analyze therapeutic principles to obtain treatment efficacy, and develop new therapeutic principles to treat chronic low back pain. Methods: Twenty-four patients from the registry of patients suffering from refractory chronic low back pain were invited to our self-controlled case series, which was conducted in "real-world" settings. We implemented the reinforcing and circulation-promoting protocol of acupuncture and moxibustion to treat these patients and used the Visual Analogue Scale (VAS) and the Oswestry Disability Index (ODI) as the observation indices. Results: All 24 patients completed the treatment of acupuncture and moxibustion. The VAS of low back pain was 6.83 ± 2.18 before treatment and 2.13 ± 1.45 after treatment. The difference before and after treatment was significant (P < 0.001). The ODI was 28.21 ± 13.06 before treatment and 16.63 ± 7.20 after treatment. Their difference before and after treatment was significant (P < 0.001). Conclusion: The reinforcing and circulation-promoting protocol of acupuncture and moxibustion is effective in treating refractory chronic low back pain mainly because low back pain can be significantly relieved and motor function can be promoted. This trial was registered with AMCTR-OOO-17000045 (3 December 2016).