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2.
Oncol Lett ; 25(1): 42, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36589668

RESUMO

Lung cancer is one of the leading causes of cancer mortality worldwide. As it is often first diagnosed only when cancer metastasis has already occurred, the development of effective biomarkers for the risk prediction of cancer metastasis, followed by stringent monitoring and the early treatment of high-risk patients, is essential for improving patient survival. Cancer cells exhibit alterations in metabolic pathways that enable them to maintain rapid growth and proliferation, which are quite different from the metabolic pathways of normal cells. Fumarate hydratase (FH, fumarase) is a well-known tricarboxylic acid cycle enzyme that catalyzes the reversible hydration/dehydration of fumarate to malate. The current study sought to investigate the relationship between FH expression levels and the outcome of patients with lung cancer. FH was knocked down in lung cancer cells using shRNA or overexpressed using a vector, and the effect on migration ability was assessed. Furthermore, the role of AMP-activated protein kinase (AMPK) phosphorylation and disabled homolog 2 in the underlying mechanism was investigated using an AMPK inhibitor approach. The results showed that in lung cancer tissues, low FH expression was associated with lymph node metastasis, tumor histology and recurrence. In addition, patients with low FH expression exhibited a poor overall survival in comparison with patients having high FH expression. When FH was overexpressed in lung cancer cells, cell migration was reduced with no effect on cell proliferation. Furthermore, the level of phosphorylated (p-)AMPK, an energy sensor molecule, was upregulated when FH was knocked down in lung cancer cells, and the inhibition of p-AMPK led to an increase in the expression of disabled homolog 2, a tumor suppressor protein. These findings suggest that FH may serve as an effective biomarker for predicting the prognosis of lung cancer and as a therapeutic mediator.

3.
Nat Ecol Evol ; 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36593289

RESUMO

Human de novo genes can originate from neutral long non-coding RNA (lncRNA) loci and are evolutionarily significant in general, yet how and why this all-or-nothing transition to functionality happens remains unclear. Here, in 74 human/hominoid-specific de novo genes, we identified distinctive U1 elements and RNA splice-related sequences accounting for RNA nuclear export, differentiating mRNAs from lncRNAs, and driving the origin of de novo genes from lncRNA loci. The polymorphic sites facilitating the lncRNA-mRNA conversion through regulating nuclear export are selectively constrained, maintaining a boundary that differentiates mRNAs from lncRNAs. The functional new genes actively passing through it thus showed a mode of pre-adaptive origin, in that they acquire functions along with the achievement of their coding potential. As a proof of concept, we verified the regulations of splicing and U1 recognition on the nuclear export efficiency of one of these genes, the ENSG00000205704, in human neural progenitor cells. Notably, knock-out or over-expression of this gene in human embryonic stem cells accelerates or delays the neuronal maturation of cortical organoids, respectively. The transgenic mice with ectopically expressed ENSG00000205704 showed enlarged brains with cortical expansion. We thus demonstrate the key roles of nuclear export in de novo gene origin. These newly originated genes should reflect the novel uniqueness of human brain development.

4.
Int Immunopharmacol ; 115: 109706, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36638664

RESUMO

Influenza A viruses (IAV), significant respiratory pathogenic agents, cause seasonal epidemics and global pandemics in intra- and interannual cycles. Despite effective therapies targeting viral proteins, the continuous generation of drug-resistant IAV strains is challenging. Therefore, exploring novel host-specific antiviral treatment strategies is urgently needed. Here, we found that lidocaine, widely used for local anesthesia and sedation, significantly inhibited H1N1(PR8) replication in macrophages. Interestingly, its antiviral effect did not depend on the inhibition of voltage-gated sodium channels (VGSC), the main target of lidocaine for anesthesia. Lidocaine significantly upregulated early IFN-I, interferon α4 (IFNα4) mRNA, and protein levels, but not those of early IFNß in mouse RAW 264.7 cell line and human THP-1 derived macrophages. Knocking out IFNα4 by CRISPR-Cas9 partly reversed lidocaine's inhibition of PR8 replication in macrophages. Mechanistically, lidocaine upregulated IFNα4 by activating TANK-binding kinase 1 (TBK1)-IRF7 and JNK-AP1 signaling pathways. These findings indicate that lidocaine has an incredible antiviral potential by enhancing IFN-I signaling in macrophages. In conclusion, our results indicate the potential auxiliary role of lidocaine for anti-influenza A virus therapy and even for anti-SARS-CoV-2 virus therapy, especially in the absence of a specific medicine.

5.
Biometrics ; 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36645553

RESUMO

Post-market active safety monitoring is important for the timely capture of safety signals associated with exposure to a new vaccine or drug. The group sequential analysis is a common method employed in safety surveillance. Specifically, it compares the post-vaccination incidence of adverse event (AE) in a vaccinated population with a pre-specified reference level by sequentially conducting hypothesis testing during the surveillance. When the number of AEs is "too high", a safety signal is identified. If the null hypothesis is never rejected, the vaccine is considered safe. Such an approach doesn't account for either the variation in determining the reference risk from a control population or the seasonality effect. Furthermore, not rejecting the null could be due to a lack of power and cannot always be interpreted as proof of safety. In this paper, we proposed a new group sequential test procedure fully accounting for both seasonality and variation from the historical controls. More importantly, we proposed to construct a confidence interval for the relative AE risk between the exposed and control groups at the end of the study, which can be used to quantify the safety of the vaccine. The proposed method is illustrated via real data examples on anaphylaxis and examined by extensive simulation studies. This article is protected by copyright. All rights reserved.

6.
Stat Med ; 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36653933

RESUMO

The pattern of the difference between two survival curves we often observe in randomized clinical trials for evaluating immunotherapy is not proportional hazards; the treatment effect typically appears several months after the initiation of the treatment (ie, delayed difference pattern). The commonly used logrank test and hazard ratio estimation approach will be suboptimal concerning testing and estimation for those trials. The long-term restricted mean survival time (LT-RMST) approach is a promising alternative for detecting the treatment effect that potentially appears later in the study. A challenge in employing the LT-RMST approach is that it must specify a lower end of the time window in addition to a truncation time point that the RMST requires. There are several investigations and suggestions regarding the choice of the truncation time point for the RMST. However, little has been investigated to address the choice of the lower end of the time window. In this paper, we propose a flexible LT-RMST-based test/estimation approach that does not require users to specify a lower end of the time window. Numerical studies demonstrated that the potential power loss by adopting this flexibility was minimal, compared to the standard LT-RMST approach using a prespecified lower end of the time window. The proposed method is flexible and can offer higher power than the RMST-based approach when the delayed treatment effect is expected. Also, it provides a robust estimate of the magnitude of the treatment effect and its confidence interval that corresponds to the test result.

7.
Gut ; 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36631249

RESUMO

OBJECTIVE: Growing evidence indicates that tumour cells exhibit characteristics similar to their lineage progenitor cells. We found that S100 calcium binding protein A10 (S100A10) exhibited an expression pattern similar to that of liver progenitor genes. However, the role of S100A10 in hepatocellular carcinoma (HCC) progression is unclear. Furthermore, extracellular vesicles (EVs) are critical mediators of tumourigenesis and metastasis, but the extracellular functions of S100A10, particularly those related to EVs (EV-S100A10), are unknown. DESIGN: The functions and mechanisms of S100A10 and EV-S100A10 in HCC progression were investigated in vitro and in vivo. Neutralising antibody (NA) to S100A10 was used to evaluate the significance of EV-S100A10. RESULTS: Functionally, S100A10 promoted HCC initiation, self-renewal, chemoresistance and metastasis in vitro and in vivo. Of significance, we found that S100A10 was secreted by HCC cells into EVs both in vitro and in the plasma of patients with HCC. S100A10-enriched EVs enhanced the stemness and metastatic ability of HCC cells, upregulated epidermal growth factor receptor (EGFR), AKT and ERK signalling, and promoted epithelial-mesenchymal transition. EV-S100A10 also functioned as a chemoattractant in HCC cell motility. Of significance, S100A10 governed the protein cargos in EVs and mediated the binding of MMP2, fibronectin and EGF to EV membranes through physical binding with integrin αⅤ. Importantly, blockage of EV-S100A10 with S100A10-NA significantly abrogated these enhancing effects. CONCLUSION: Altogether, our results uncovered that S100A10 promotes HCC progression significantly via its transfer in EVs and regulating the protein cargoes of EVs. EV-S100A10 may be a potential therapeutic target and biomarker for HCC progression.

8.
Signal Transduct Target Ther ; 8(1): 39, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36650130

RESUMO

Nucleic acid drugs have the advantages of rich target selection, simple in design, good and enduring effect. They have been demonstrated to have irreplaceable superiority in brain disease treatment, while vectors are a decisive factor in therapeutic efficacy. Strict physiological barriers, such as degradation and clearance in circulation, blood-brain barrier, cellular uptake, endosome/lysosome barriers, release, obstruct the delivery of nucleic acid drugs to the brain by the vectors. Nucleic acid drugs against a single target are inefficient in treating brain diseases of complex pathogenesis. Differences between individual patients lead to severe uncertainties in brain disease treatment with nucleic acid drugs. In this Review, we briefly summarize the classification of nucleic acid drugs. Next, we discuss physiological barriers during drug delivery and universal coping strategies and introduce the application methods of these universal strategies to nucleic acid drug vectors. Subsequently, we explore nucleic acid drug-based multidrug regimens for the combination treatment of brain diseases and the construction of the corresponding vectors. In the following, we address the feasibility of patient stratification and personalized therapy through diagnostic information from medical imaging and the manner of introducing contrast agents into vectors. Finally, we take a perspective on the future feasibility and remaining challenges of vector-based integrated diagnosis and gene therapy for brain diseases.


Assuntos
Encefalopatias , Ácidos Nucleicos , Humanos , Preparações Farmacêuticas , Ácidos Nucleicos/genética , Ácidos Nucleicos/uso terapêutico , Terapia Genética , Encefalopatias/diagnóstico , Encefalopatias/tratamento farmacológico , Encefalopatias/genética , Sistemas de Liberação de Medicamentos/métodos
9.
J Proteome Res ; 22(1): 36-46, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36564034

RESUMO

Fatty aldehydes (FALs) are involved in various biological processes, and their abnormal metabolism is related to the occurrence and development of neurological diseases. Because of their low ionization efficiency, methods for in situ detection and mass spectrometry imaging (MSI) analysis of FALs remain underreported. On-tissue chemical tagging of hardly ionizable target analytes with easily ionized moieties can improve ionization efficiency and detection sensitivity in MSI experiments. In this study, an on-tissue chemical derivatization-air-flow-assisted desorption electrospray ionization-MSI method was developed to visualize FALs in the rat brain. The method showed high sensitivity and specificity, allowing the use of in situ high-resolution MS3 to identify FALs. The methodology was applied to investigate the region-specific distribution of FALs in the brains of control and diabetic encephalopathy (DE) rats. In DE rats, FALs were found to be significantly enriched in various brain regions, especially in the cerebral cortex, hippocampus, and amygdala. Thus, increased FAL levels and oxidative stress occurred in a region-dependent manner, which may contribute to cognitive function deficits in DE. In summary, we provide a novel method for the in situ detection of FALs in biological tissues as well as new insights into the potential pathogenesis of DE.


Assuntos
Diabetes Mellitus , Espectrometria de Massas por Ionização por Electrospray , Ratos , Animais , Espectrometria de Massas por Ionização por Electrospray/métodos , Aldeídos , Encéfalo/diagnóstico por imagem , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos
10.
Anal Chem ; 95(2): 889-897, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36537841

RESUMO

The time since deposition (TSD) of latent fingermarks (LFMs) serves as "witnesses" for crime scene reconstructions. Nevertheless, existing TSD prediction approaches focused on either physical or chemical aging parameters leading to inaccurate estimation. A novel label-free protocol has been developed, where both physical ridge patterns and lipid oxide (LipOx) degradation kinetics are realized using optical microscopy and scanning electrochemical microscopy (SECM) and combined for TSD prediction. Specifically, the surface interrogation (SI)-SECM titration was utilized to monitor the LipOx degradation in LFM arrays aligned by hole array masks, through which we derived the LipOx degradation function. After establishing the relationship between several titration parameters and titrated area by experimental and numerical simulation methods, the titrated area could be reasonably estimated and subsequently used to calculate the surface coverage of LipOx. Results demonstrated that the tip transient revealed the LipOx coverage of deposited LFMs. Notably, LipOx coverage was found to increase during the first day and then decrease over time, whose degradation rate was susceptible to light. Thus, TSD candidates of an LFM could be limited to two values through the established function. Due to the nonmonotonic trend of LipOx aging, a physical parameter "the gray value ratio (GVR) of furrows to ridges" was proposed to exclude irrelevant TSD through support vector machine (SVM) classification. Ultimately, we predicted TSDs of seven LFMs with estimation errors of 2.2-26.8%. Overall, our strategy, with the outperformed capability of gleaning physical and electrochemical information on LFMs, can provide a truly label-free way of studying LFMs and hold great promise for multidimensional fingerprint information analysis.


Assuntos
Bezafibrato , Microscopia
11.
J Colloid Interface Sci ; 634: 630-641, 2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36549211

RESUMO

Designing efficient electrocatalysts to improve the overall water splitting and urea electrolysis efficiency for hydrogen generation can greatly solve the dilemma of energy shortage and environmental pollution. In this work, Co8FeS8@CoFe-MOF/NF heterojunction arrays were fabricated by embedding sulfides into the surface of metal-organic frameworks (MOFs) nanosheets as multifunctional electrocatalyst. The introduction of sulfide on CoFe-MOF/NF can not only adjust the electronic structure (electron-rich state) and change the surface properties (more hydrophilic), but also increase the active area to enhance the catalytic activity. The in situ Raman shows Co8FeS8@CoFe-MOF/NF is more easily to generate active species at low potentials and generates a higher content of active ß-MOOH phase than CoFe-MOF/NF. Therefore, the Co8FeS8@CoFe-MOF/NF exhibits excellent oxygen evolution reaction (OER) performance with an overpotential of 213 mV at 10 mA cm-2. Furthermore, when used as a urea oxidation reaction (UOR), only an ultralow potential of 1.311 V at 10 mA cm-2. More importantly, the assembled two-electrode drives overall water splitting and urea electrolysis with cell voltages of 1.62 V and 1.55 V at 10 mA cm-2, respectively. This work provides insights into the preparation of electrocatalysts with multifunctional heterostructure arrays for hydrogen production.

12.
J Environ Manage ; 328: 116962, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36470002

RESUMO

The present study experimentally quantified the pyrolysis behaviors of waste solvent-based automotive paint sludge (OAPS) and water-based automotive paint sludge (WAPS) at four different heating rates using thermogravimetric-Fourier transform infrared (TG-FTIR) spectrometry and pyrolysis-gas chromatography-mass (Py-GC/MS) spectrometry analyses. Flynn-Wall-Ozawa (FWO) and Kissinger-Akahira-Sunose (KAS) methods combined with the master-plots method were employed to investigate the pyrolysis kinetics and reaction mechanisms of waste automotive paint sludge. Three reaction stages and three reaction peaks in stage 2 were distinguished for both OAPS and WAPS degradation. The average activation energy (Ea) estimates for OAPS (FWO: 179.09 kJ/mol; KAS: 168.28 kJ/mol) were slightly higher than WAPS (FWO: 175.90 kJ/mol; KAS: 164.80 kJ/mol) according to FWO and KAS methods. The main pyrolysis reaction mechanisms of both OAPS and WAPS closely matched with the order-based model corresponding to 3rd and 2nd order random nucleation on an individual particle. The evolved gas species of CH4, CO2, phenols, NH3, H2O, and CO from OAPS and WAPS pyrolysis were identified by TG-FTIR. According to Py-GC/MS, hydrocarbons (47.2%) and O-components (42.7%) were relatively large after OAPS and WAPS pyrolysis, respectively. Melamine was the most abundant N-component product after pyrolysis of OAPS (5.8%) and WAPS (4.8%).

13.
Lancet Public Health ; 7(12): e1027-e1040, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36462514

RESUMO

BACKGROUND: Temporal trends and geographical variations in cardiovascular disease attributable to high systolic blood pressure in China are not yet fully understood. The aim of this study was to quantify the cardiovascular disease burden attributable to high systolic blood pressure at national and provincial levels in China. METHODS: In this population-based study, we evaluated systolic blood pressure and estimated the number of deaths, age-standardised mortality rates, and years of life lost (YLLs) due to cardiovascular disease and its subcategories (including ischaemic heart disease, ischaemic stroke, haemorrhagic stroke, and other cardiovascular diseases) attributable to high systolic blood pressure, at the national level and by 31 provincial levels, in China, from 2005 to 2018. We pooled blood pressure data of 1·30 million adults aged 25 years and older from the China Chronic Disease and Risk Factor Surveillance project, the China National Nutrition Survey, and the China Hypertension Survey. We applied a temporal-spatial Bayesian hierarchical model to estimate age-specific, sex-specific, province-specific, and year-specific average systolic blood pressure, and a comparative risk assessment method to compute the cardiovascular disease burden attributable to high systolic blood pressure by age, sex, year, and province. FINDINGS: Nationally, age-standardised mean systolic blood pressure was 132·5 mm Hg (95% uncertainty interval [UI] 124·6-140·3) in men and 129·4 mm Hg (121·7 to 137·2) in women. 2·67 million (95% UI 2·61 to 2·72) cardiovascular disease deaths in China were attributable to high systolic blood pressure, including 1·12 million deaths (1·07 to 1·16) due to ischaemic heart disease, 0·63 million deaths (0·60 to 0·65) due to ischaemic stroke, 0·58 million deaths (0·57 to 0·60) due to haemorrhagic stroke, and 0·34 million deaths (0·32 to 0·36) due to other cardiovascular disease. The age-standardised cardiovascular disease mortality rates associated with high systolic blood pressure were 268·99 per 100 000 people (95% UI 264·11 to 273·51) in 2005 and 220·84 per 100 000 people (216·30 to 224·76) in 2018, a percentage change of -17·90%; the rate changed by an average of -1·50% (95% UI -1·55% to -1·45%) per year from 2005 to 2018 nationally. YLL rates for total cardiovascular disease caused by high systolic blood pressure varied substantially across provinces, ranging from 3078·33 (95% UI 2807·40 to 3303·57) per 100 000 people in Beijing to 7189·98 (95% UI 6817·18 to 7507·99) per 100 000 people in Heilongjiang in 2018. Age-standardised YLL rates for ischaemic heart disease and ischaemic stroke attributable to high systolic blood pressure were particularly high in northeastern provinces, including Heilongjiang, Liaoning, and Jilin. INTERPRETATION: The deaths and YLLs for cardiovascular disease attributable to high systolic blood pressure in China increased between 2005 and 2018, and age-standardised cardiovascular disease mortality rates decreased in the same timeframe. Our findings could help policy makers in promoting blood pressure control measures and implementing effective and locally adapted preventive interventions to reduce the prevalence of high systolic blood pressure and reduce the burden of systolic blood pressure-related cardiovascular disease in China. FUNDING: China National Key Research and Development Program, China National Science & Technology Pillar Program, and National Health Commission of the People's Republic of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Isquemia Encefálica , Doenças Cardiovasculares , Acidente Vascular Cerebral Hemorrágico , AVC Isquêmico , Isquemia Miocárdica , Acidente Vascular Cerebral , Adulto , Masculino , Feminino , Humanos , Doenças Cardiovasculares/epidemiologia , Pressão Sanguínea , Teorema de Bayes , Pesquisa , Isquemia Miocárdica/epidemiologia , China/epidemiologia
14.
J Biopharm Stat ; : 1-18, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36469552

RESUMO

Use of historical data has become a hot topic recently, considered to provide a way to reduce patient burden, lower drug development cost, and make innovative therapies available to patients earlier. In a single-arm study designed to examine the benefit of an experimental treatment, there is often a desire to compare the outcomes of patients receiving the new intervention with those receiving a control treatment, which can be extracted from sources such as historical trials or electronic medical records. Since the treatment is not randomly assigned, there is a need to adjust for the potential imbalance in key patient characteristics between the current study and historical controls. If the outcome of interest is measured longitudinally and subject to random missing, the required adjustment becomes more complicated. In this paper, we propose a doubly robust adjustment procedure specifically designed for longitudinal data analysis with missing data. The proposed method yields valid analysis results, if either the propensity score model or the mixed effects model for repeated measures (MMRM) regression model is correctly specified. An extensive numerical study is conducted to examine the performance of the proposed method. Data from a real clinical trial comparing with historical data are analyzed as an example applying the proposed procedure.

15.
Chem Sci ; 13(46): 13893-13897, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36544726

RESUMO

A novel polyene cyclization using the allene group as the initiator has been successfully developed. This methodology provides an efficient strategy for the construction of an abietane-type tricyclic skeleton with a functionalizable C2-C3 double bond and features a wide substrate scope and excellent stereoselectivities. Potential utility of this approach has been well demonstrated by the collective total synthesis of seven abietane-type diterpenoids. Specifically, (±)-2,3-dihydroxyferruginol and (±)-2,3-dihydroxy-15,16-dinor-ent-pimar-8,11,13-triene were synthesized for the first time.

16.
Ann Neurol ; 2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36511519

RESUMO

OBJECTIVE: To study pareidolias, or perceived meaningful objects in a meaningless stimulus, in patients across the Lewy body (LB) disease spectrum, where most do not report hallucinations or delusions. METHODS: We studied illusory responses on the Noise Pareidolia Task in 300 participants [38 cognitively-impaired LB, 65 cognitively-unimpaired LB, 51 Alzheimer's disease-spectrum (AD-s), 146 Controls]. Pairwise between-group comparisons examined how diagnosis impacts the number of illusory responses. Ordinal regression analysis compared the number of illusory responses across diagnosis groups, adjusting for age, sex, and education. Analyses were repeated after removing participants with reported hallucinations or delusions. RESULTS: Cognitively-impaired LB participants were 12.3, 4.9, and 4.6 times more likely than Control, cognitively-unimpaired LB, and AD-s participants, respectively, to endorse illusory responses. After adjusting for age, sex and education, the probability of endorsing one or more illusory response was 61% in the cognitively-impaired LB group, compared to 26% in AD-s, 25% in cognitively-unimpaired LB, and 12% in Control participants. All results were similar after repeated analysis only in participants without hallucinations or delusions. In LB without hallucinations or delusions, 52% with mild cognitive impairment and 66.7% with dementia endorsed at least one illusory response. INTERPRETATION: We found illusory responses are common in cognitively impaired LB patients, including those without any reported psychosis. Our data suggest that, prior to the onset of hallucinations and delusions, the Noise Pareidolia Task can easily be used to screen for unobtrusive pareidolias in all LB patients. This article is protected by copyright. All rights reserved.

17.
Int J Mol Sci ; 23(24)2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36555673

RESUMO

Prostate cancer is a major public health concern and one of the most prevalent forms of cancer worldwide. The definition of altered signaling pathways implicated in this complex disease is thus essential. In this context, abnormal expression of the receptor of Macrophage Colony-Stimulating Factor-1 (M-CSF or CSF-1) has been described in prostate cancer cells. Yet, outcomes of this expression remain unknown. Using mouse and human prostate cancer cell lines, this study has investigated the functionality of the wild-type CSF-1 receptor in prostate tumor cells and identified molecular mechanisms underlying its ligand-induced activation. Here, we showed that upon CSF-1 binding, the receptor autophosphorylates and activates multiple signaling pathways in prostate tumor cells. Biological experiments demonstrated that the CSF-1R/CSF-1 axis conferred significant advantages in cell growth and cell invasion in vitro. Mouse xenograft experiments showed that CSF-1R expression promoted the aggressiveness of prostate tumor cells. In particular, we demonstrated that the ligand-activated CSF-1R increased the expression of spp1 transcript encoding for osteopontin, a key player in cancer development and metastasis. Therefore, this study highlights that the CSF-1 receptor is fully functional in a prostate cancer cell and may be a potential therapeutic target for the treatment of prostate cancer.


Assuntos
Osteopontina , Neoplasias da Próstata , Receptor de Fator Estimulador de Colônias de Macrófagos , Animais , Humanos , Masculino , Camundongos , Ligantes , Fator Estimulador de Colônias de Macrófagos/metabolismo , Osteopontina/genética , Neoplasias da Próstata/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/genética , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo
18.
J Am Heart Assoc ; 11(24): e026136, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36533626

RESUMO

Background Supervised exercise therapy (SET) is the first-line therapy for walking impairment in peripheral artery disease (PAD). This study evaluated the association between attendance at SET and improved walking performance, compared with a control group, in PAD. Methods and Results Data from 2 randomized clinical trials of SET for PAD were combined. In each trial, participants were randomized to 3 times weekly supervised treadmill exercise or an attention control group for 6 months (maximum, 77 exercise sessions). Participants randomized to SET were categorized into tertiles, according to the proportion of exercise sessions they attended. Results adjusted for age, sex, race, baseline walking performance, comorbidities, and other potential confounders. A total of 272 participants with PAD (mean age, 67.9±9.3 years; 44% women; 61% Black race) were included. For participants randomized to SET, tertiles of attendance rates at exercise sessions were as follows: 11% to 68% (N=45), 69% to <85% (N=46), and ≥85% (N=46). Compared with control, mean improvement in 6-minute walk was significantly greater in each SET tertile: mean (95% CI) for tertile 1, 27.9 m (1.3-54.4 m; P=0.04), tertile 2, 38.2 m (12.2-64.2 m; P=0.001), and tertile 3, 56.9 m (29.9-83.8 m; P<0.0001). Among participants randomized to SET, greater SET attendance was associated with greater improvement in 6-minute walk distance (overall P for trend=0.025). Compared with control, improvement in maximal treadmill walking time was greater in each SET attendance tertile: tertile 1 (3.3 minutes [95% CI, 1.7-4.8 minutes]; P<0.0001), tertile 2 (3.8 minutes [95% CI, 2.3-5.3 minutes]; P<0.0001), and tertile 3 (5.4 minutes [95% CI, 3.9-7.0 minutes]; P:<0.0001). Among participants randomized to SET, greater attendance at SET was not significantly associated with greater improvement in maximal treadmill walking time (overall P for trend=0.064). Conclusions Among people with PAD randomized to SET, better attendance at exercise sessions was associated with significantly greater 6-minute walk improvement. Among all participants with PAD, even relatively low SET attendance was associated with significantly greater improvement in walking performance, compared with a control group who did not exercise. Registration URL: https://clinicaltrials.gov/ct2/show/NCT01408901. URL: https://clinicaltrials.gov/ct2/show/NCT00106327.


Assuntos
Doença Arterial Periférica , Humanos , Feminino , Pessoa de Meia-Idade , Idoso , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/terapia , Exercício Físico , Caminhada , Terapia por Exercício/métodos , Claudicação Intermitente/terapia
20.
Vasc Med ; : 1358863X221143152, 2022 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-36567551

RESUMO

BACKGROUND: This study evaluated the association of smoking with mitochondrial function in gastrocnemius muscle of people with peripheral artery disease (PAD). METHODS: Participants were enrolled from Chicago, Illinois and consented to gastrocnemius biopsy. Mitochondrial oxidative capacity was measured in muscle with respirometry. Abundance of voltage-dependent anion channel (VDAC) (mitochondrial membrane abundance), peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) (mitochondrial biogenesis), and electron transport chain complexes I-V were measured with Western blot. RESULTS: Fourteen of 31 people with PAD (age 72.1 years, ABI 0.64) smoked cigarettes currently. Overall, there were no significant differences in mitochondrial oxidative capacity between PAD participants who currently smoked and those not currently smoking (complex I+II-mediated oxidative phosphorylation: 86.6 vs 78.3 pmolO2/s/mg, respectively [p = 0.39]). Among participants with PAD, those who currently smoked had a higher abundance of PGC-1α (p < 0.01), VDAC (p = 0.022), complex I (p = 0.021), and complex III (p = 0.021) proteins compared to those not currently smoking. People with PAD who currently smoked had lower oxidative capacity per VDAC unit (complex I+II-mediated oxidative phosphorylation [137.4 vs 231.8 arbitrary units, p = 0.030]) compared to people with PAD not currently smoking. Among people without PAD, there were no significant differences in any mitochondrial measures between currently smoking (n = 5) and those not currently smoking (n = 63). CONCLUSIONS: Among people with PAD, cigarette smoking may stimulate mitochondrial biogenesis to compensate for reduced oxidative capacity per unit of mitochondrial membrane, resulting in no difference in overall mitochondrial oxidative capacity according to current smoking status among people with PAD. However, these results were cross-sectional and a longitudinal study is needed.

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