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1.
Front Mol Neurosci ; 15: 880858, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35571367

RESUMO

While various septin GTPases have been reported for their physiological functions, their roles in orchestrating complex cognitive/emotional functions in adult mammals remained scarcely explored. A comprehensive behavioral test battery was administered to two sexes of 12-week-old Septin-14 (SEPT14) knockout (KO) and wild-type (WT) mice. The sexually dimorphic effects of brain SEPT14 KO on inhibitory avoidance (IA) and hippocampal mGluR5 expression were noticed with greater IA latency and elevated mGluR5 level exclusively in male KO mice. Moreover, SEPT14 KO appeared to be associated with stress-provoked anxiety increase in a stress-related navigation task regardless of animals' sexes. While male and female WT mice demonstrated comparable cell proliferation in the dorsal and ventral hippocampal dentate gyrus (DG), both sexes of SEPT14 KO mice had increased cell proliferation in the ventral DG. Finally, male and female SEPT14 KO mice displayed dampened observational fear conditioning magnitude and learning-provoked corticosterone secretion as compared to their same-sex WT mice. These results, taken together, prompt us to conclude that male, but not female, mice lacking the Septin-14 gene may exhibit increased aversive emotion-related learning and dorsal/ventral hippocampal mGluR5 expressions. Moreover, deletion of SEPT14 may be associated with elevated ventral hippocampal DG cell proliferation and stress-provoked anxiety-like behavior, while dampening vicarious fear conditioning magnitudes.

2.
Nature ; 2022 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-35576971

RESUMO

Tuft cells are a rare chemosensory lineage that coordinates immune and neural responses to foreign pathogens in mucosal tissues1. Recent studies have also revealed tuft cell-like human tumors2,3, particularly as a variant form of small cell lung cancer (SCLC). Both normal and neoplastic tuft cells share a genetic requirement for the transcription factor POU2F32,4, although the transcriptional mechanisms that generate this cell type are poorly understood. Here we show that binding of POU2F3 to the uncharacterized proteins C11orf53 and COLCA2 (renamed here OCA-T1 and OCA-T2, respectively) is critical in the tuft cell lineage. OCA-T1 and OCA-T2 are paralogs of the B cell-specific coactivator OCA-B, which are encoded in a gene cluster and harbor a conserved peptide that binds to class II POU transcription factors and octamer motif DNA in a bivalent manner. We demonstrate that binding between POU2F3 and OCA-T1 or OCA-T2 is essential in tuft cell-like SCLC. In addition, we generated OCA-T1 knockout mice, which are viable but lack tuft cells in several mucosal tissues. These findings reveal the POU2F3-OCA-T complex as the master regulator of tuft cell identity and a prominent molecular vulnerability of tuft cell-like SCLC.

3.
Environ Pollut ; 305: 119132, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35381304

RESUMO

Plume chasing is cost-effective, measuring individual, on-road vehicular emissions. Whereas, wake-flow-generated turbulence results in intermittent, rapid pollutant dilution and substantial fluctuating concentrations right behind the vehicle being chased. The sampling duration is therefore one of the important factors for acquiring representative (average) concentrations, which, however, has been seldom addressed. This paper, which is based on the detailed spatio-temporal dispersion data after a heavy-duty truck calculated by large-eddy simulation (LES), examines how sampling duration affects the uncertainty of the measured concentrations in plume chasing. The tailpipe dispersion is largely driven by the jet-like flows through the vehicle underbody with approximate Gaussian concentration distribution for x ≤ 0.6h, where x is the distance after the vehicle and h the characteristic vehicle size. Thereafter for x ≥ 0.6h, the major recirculation plays an important role in near-wake pollutant transport whose concentrations are highly fluctuating and positively shewed. Plume chasing for a longer sampling duration is more favourable but is logistically impractical in busy traffic. Sampling duration, also known as averaging time in the statistical analysis, thus has a crucial role in sampling accuracy. With a longer sampling (averaging) duration, the sample mean concentration converges to the population mean, improving the sample reliability. However, this effect is less pronounced in long sampling duration. The sampling accuracy is also influenced by the locations of sampling points. For the region x > 0.6h, the sampling accuracy is degraded to a large extent. As a result, acceptable sample mean is hardly achievable. Finally, frequency analysis unveils the mechanism leading to the variance in concentration measurements which is attributed to sampling duration. Those data with frequency higher than the sampling frequency are filtered out by moving average in the statistical analyses.


Assuntos
Poluentes Atmosféricos , Poluentes Ambientais , Poluentes Atmosféricos/análise , Monitoramento Ambiental/métodos , Poluentes Ambientais/análise , Reprodutibilidade dos Testes , Emissões de Veículos/análise
4.
Sensors (Basel) ; 22(6)2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35336265

RESUMO

The accurate and reliable monitoring of ventilation parameters is key to intelligent ventilation systems. In order to realize the visualization of airflow, it is essential to solve the airflow reconstruction problem using few sensors. In this study, a new concept called independent cut set that depends on the structure of the underlying graph is presented to determine the minimum number and location of sensors. We evaluated its effectiveness in a coal mine owned by Jinmei Corporation Limited (Jinmei Co., Ltd., Shanghai, China). Our results indicated that fewer than 30% of tunnels needed to have wind speed sensors set up to reconstruct the well-posed airflow of all the tunnels (>200 in some mines). The results showed that the algorithm was feasible. The reconstructed air volume of the ventilation network using this algorithm was the same as the actual air volume. The algorithm provides theoretical support for flow reconstruction.


Assuntos
Respiração , Ventilação , Ar Condicionado , Algoritmos , China
5.
Chem Soc Rev ; 51(7): 2416-2430, 2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35275147

RESUMO

Nanoscale chemical and structural characterization of single biomolecules and assemblies is of paramount importance for applications in biology and medicine. It aims to describe the molecular structure of biomolecules and their interaction with unprecedented spatial resolution to better comprehend underlying molecular mechanisms of biological processes involved in cell activity and diseases. Tip-enhanced Raman scattering (TERS) spectroscopy appears particularly appealing to reach these objectives. This state-of-the-art TERS technique is as versatile as it is ultrasensitive. To perform a successful TERS experiment, special care and a thorough methodology for the preparation of the TERS system, the TERS probe tip, and sample are needed. Intense efforts have been deployed to characterize nucleic acids, proteins and peptides, lipid membranes, and more complex systems such as cells and viruses using TERS. Although the vast majority of studies have first been performed in dry conditions, they have allowed for several scientific breakthroughs. These include DNA and RNA sequencing, and the determination of relationships between protein structure and biological function by the use of increasingly exploitative chemometric tools for spectral data analysis. The nanoscale determination of the secondary structure of amyloid fibrils, protofibrils and oligomers implicated in neurodegenerative diseases could, for instance, be connected with the toxicity of these species, amyloid formation pathways, and their interaction with phospholipids. Single particles of different viral strains could be distinguished from one another by comparison of their protein and lipid contents. In addition, TERS has allowed for the evermore accurate description of the molecular organization of lipid membranes. Very recent advances also demonstrated the possibility to carry out TERS in aqueous medium, which opens thrilling perspectives for the TERS technique in biological, biomedical, and potential clinical applications.


Assuntos
Ácidos Nucleicos , Análise Espectral Raman , Amiloide , Ácidos Nucleicos/química , Peptídeos , Estrutura Secundária de Proteína , Análise Espectral Raman/métodos
6.
Sci Adv ; 8(5): eabl7575, 2022 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-35108043

RESUMO

Vehicle emissions are the most important source of air pollution in the urban environment worldwide, and their detection and control are critical for protecting public health. Here, we report the use of on-road remote sensing (RS) technology for fast, accurate, and cost-effective identification of high-emitting vehicles as an enforcement program for improving urban air quality. Using large emission datasets from chassis dynamometer testing, RS, and air quality monitoring, we found that significant percentages of in-use petrol and LPG vehicles failed the emission standards, particularly the high-mileage fleets. The RS enforcement program greatly cleaned these fleets, in terms of high-emitter percentages, fleet average emissions, roadside and ambient pollutant concentrations, and emission inventory. The challenges of the current enforcement program are conservative setting of cut points, single-lane measurement sites, and lack of application experience in diesel vehicles. Developing more accurate and vertical RS systems will improve and extend their applications.

7.
Artigo em Inglês | MEDLINE | ID: mdl-35124270

RESUMO

BACKGROUND & AIMS: The influence of nonalcoholic fatty liver disease (NAFLD) on the long-term risk of cirrhosis and hepatocellular carcinoma (HCC) in Asian populations has not been widely investigated. METHODS: We enrolled 129,374 adults aged 30 years and older, all of whom participated in a health screening program from 2008 through 2013, were seronegative for hepatitis B surface antigen and anti-hepatitis C virus antibodies, and had limited daily alcohol consumption (<20 g/d for men and <10 g/d for women). Abdominal ultrasonography was performed to determine the presence of NAFLD. The participants were divided into the following groups: NAFLD with increased or normal liver enzyme levels, and non-NAFLD with normal liver enzyme levels. The incidences of cirrhosis and HCC were determined through computerized data linkage with nationwide registries. Cox proportional hazard models were used to estimate the hazard ratios of NAFLD on the risks of cirrhosis and HCC. RESULTS: The incidence rates of cirrhosis and HCC increased as follows: non-NAFLD with normal liver enzyme levels (n = 66,801; 51%), NAFLD with normal liver enzyme levels (n = 41,461; 32%), and NAFLD with increased liver enzyme levels (n = 21,112; 16%). In the NAFLD group with increased liver enzyme levels and the NAFLD group with normal liver enzyme levels, the corresponding multivariate-adjusted hazard ratios for cirrhosis were 3.51 (95% confidence interval [CI]: 2.36-5.22) and 0.73 (95% CI: 0.46-1.16), and for HCC were 1.91 (95% CI: 1.08-3.38) and 0.57 (95% CI: 0.31-1.04), respectively, compared with the non-NAFLD group (P for trend < .001). The findings were consistent after restricting the analysis to nonobese individuals (body mass index, <25 kg/m2) and nonobese individuals without diabetes (P < .05). CONCLUSIONS: Individuals with NAFLD and increased liver enzyme levels showed significantly higher risks for cirrhosis and HCC and should be monitored.

8.
Artigo em Inglês | MEDLINE | ID: mdl-35162347

RESUMO

This study explores factors related to delayed emergency medical treatment for acute myocardial infarction patients on Kinmen Island. A cross-sectional study was performed in the only hospital in Kinmen Island. The study group consisted of 116 patients diagnosed with acute myocardial infarction (AMI, ICD-10 codes: I21.9) from November 2015 to May 2019. The binary logistic regression analyses were performed for the inferential statistical analysis. The mean age of the study group was 63.0 ± 14.5 years, 39.7% of the patients arrived at the emergency medicine longer than 6 h after the onset of symptoms. The related factors for delayed arrival the hospital emergency medicine department were female sex, age over 65 years, less than nine years' education, and Killip Class, but only Killip Class reached the significant difference of statistics (OR = 3.616, 95% C.I. = 1.574 to 8.310, p = 0.002), and patients with delayed arrival times (>6 h) were found to have a higher percentage of Killip Class ≥ II. Therefore, it is essential to remind the physicians to proceed with risk stratification for acute coronary syndrome patients. In addition, health authorities should provide effective programs to increase awareness of the symptoms and timely treatment of acute myocardial infraction to the general public, especially the elderly.


Assuntos
Infarto do Miocárdio , Idoso , Estudos Transversais , Tratamento de Emergência , Feminino , Hospitais , Humanos , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/terapia
9.
Sci Rep ; 12(1): 127, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-34996992

RESUMO

Identification of new genetic markers may improve the prediction of colorectal cancer prognosis. Our objective was to examine genome-wide associations of germline genetic variants with disease-specific survival in an analysis of 16,964 cases of colorectal cancer. We analyzed genotype and colorectal cancer-specific survival data from a consortium of 15 studies. Approximately 7.5 million SNPs were examined under the log-additive model using Cox proportional hazards models, adjusting for clinical factors and principal components. Additionally, we ran secondary analyses stratifying by tumor site and disease stage. We used a genome-wide p-value threshold of 5 × 10-8 to assess statistical significance. No variants were statistically significantly associated with disease-specific survival in the full case analysis or in the stage-stratified analyses. Three SNPs were statistically significantly associated with disease-specific survival for cases with tumors located in the distal colon (rs698022, HR = 1.48, CI 1.30-1.69, p = 8.47 × 10-9) and the proximal colon (rs189655236, HR = 2.14, 95% CI 1.65-2.77, p = 9.19 × 10-9 and rs144717887, HR = 2.01, 95% CI 1.57-2.58, p = 3.14 × 10-8), whereas no associations were detected for rectal tumors. Findings from this large genome-wide association study highlight the potential for anatomical-site-stratified genome-wide studies to identify germline genetic risk variants associated with colorectal cancer-specific survival. Larger sample sizes and further replication efforts are needed to more fully interpret these findings.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Loci Gênicos , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Medição de Risco , Fatores de Risco , Adulto Jovem
10.
Sci China Life Sci ; 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35060074

RESUMO

Metagenomic explorations of the Earth's biosphere enable the discovery of previously unknown bacterial lineages of phylogenetic and ecological significance. Here, we retrieved 11 metagenomic-assembled genomes (MAGs) affiliated to three new monophyletic bacterial lineages from the seawater of the Yap Trench. Phylogenomic analysis revealed that each lineage is a new bacterial candidate phylum, subsequently named Candidatus Qinglongiota, Candidatus Heilongiota, and Candidatus Canglongiota. Metabolic reconstruction of genomes from the three phyla suggested that they adopt a versatile lifestyle, with the potential to utilize various types of sugars, proteins, and/or short-chain fatty acids through anaerobic pathways. This was further confirmed by a global distribution map of the three phyla, indicating a preference for oxygen-limited or particle-attached niches, such as anoxic sedimentary environments. Of note, Candidatus Canglongiota genomes harbor genes for the complete Wood- Ljungdahl pathway and sulfate reduction that are similar to those identified in some sulfate-reducing bacteria. Evolutionary analysis indicated that gene gain and loss events, and horizontal gene transfer (HGT) play important roles in shaping the genomic and metabolic features of the three new phyla. This study presents the genomic insight into the ecology, metabolism, and evolution of three new phyla, which broadens the phylum-level diversity within the domain Bacteria.

11.
Artigo em Inglês | MEDLINE | ID: mdl-35055528

RESUMO

Soil construction and revegetation are essential for ecological restoration in mining areas. The influence of vegetation on the horizontal and vertical distribution patterns of soil properties should be fully understood. However, most studies on reconstructed soils in mining areas only concentrate on the surface soil, without exploring the vertical variations in soil properties. Overall, this study aims to explore the potential mechanisms by which surface vegetation exerts some influence on the spatial distribution of soil physicochemical properties, and to provide some insight into revegetation and soil reclamation in mining areas. Descriptive statistics and one-way analysis of variance (one-way ANOVA) were employed to evaluate the differences in the soil physicochemical properties in horizontal and vertical directions under different land-use types in the south dump of Antaibao opencast mine in Pingshuo, Shanxi Province, China. The main results of this study are as follows: (1) In the horizontal direction, except for the strong variation (variation coefficient ≥ 100%) in soil organic matter (SOM) content at some depths, the degree of variation in other soil physicochemical properties at various depths was moderate or weak (variation coefficient < 100%). The soil physicochemical properties gradually remained constant after years of reclamation. In the vertical direction, the soil bulk density (SBD), soil porosity, SOM content, soil C/N ratio, soil total nitrogen (STN) content, soil available phosphorus (SAP) content, and soil available potassium (SAK) content showed significant variations (p < 0.05) between soil depths. In contrast, no significant difference was found for other physicochemical properties. (2) The SBD, STN, SAK, soil porosity, and soil clay content were significantly different (p < 0.05) under different vegetation cover types, but the influence of vegetation on other soil physicochemical properties seemed to be limited. The results reveal that trees have a stronger ability to reduce soil grain sizes and enhance SAP contents than shrubs or herbs; however, the beneficial effects of herbs on the physicochemical properties of shallow soil are more obvious than those of trees and shrubs. (3) This study indicates that more shrubs and trees should be planted in the areas with low vegetation coverage, and more measures should be taken to improve soil physicochemical properties in order to prevent the occurrence of large-scale degradation. The reconstruction of soil structure should be preferentially considered in the process of soil reconstruction and revegetation in areas under similar conditions. Herbs should first be planted in the early reclamation stage. At the same time, shrubs or trees can be adopted in the middle and late stages of vegetation reconstruction in order to achieve comprehensive revegetation.


Assuntos
Mineração , Solo , China , Nitrogênio/análise , Solo/química , Árvores
12.
Artigo em Inglês | MEDLINE | ID: mdl-35083688

RESUMO

Considering the significant influence of mercury (Hg) contamination on the land reclamation inopencast coalmine, the spatial distribution patterns and ecological risks of Hg were investigated and the regulating factors of Hg mobility were determined in the South Dump of the Pingshuo opencast coalmine. The results show that the total Hg (HgT) contents of most soil samples (83.7%) vary from 6 to 50 µg kg-1, while the potential ecological risk index (EIHg) values of most samples (79.8%) are lower than 80, indicating that most reclaimed soils are in relatively good conditions and the soil samples at high to very high ecological risk are mainly collected near the backfilled coal gangue. Moreover, the kriging maps of the geo-accumulation index (Igeo) indicate that the uncontaminated areas (Igeo < 0) and Hg-contaminated areas (Igeo > 0) in topsoil (0-10 cm) are roughly divided by an "east-west arc" while the Hg-contaminated areas in other soil horizons are characterized by a "point distribution pattern". The slight Hg contamination in topsoil is mainly triggered by the atmospheric Hg deposition from the nearby coal-fired power plant, while the Hg contamination in other soil horizons should be attributed to the weathering and spontaneous combustion of coal gangue. On the other hand, Pearson's correlation analyses show that HgT contents were positively correlated with clay (r = 0.31, P < 0.01) and SOC (r = 0.53, P < 0.01) contents. This study can provide some insight for the land reclamation measures in the opencast coalmine.

13.
Food Chem ; 374: 131631, 2022 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-34838403

RESUMO

Seafood substitutions is a global problem and come under the spotlight in recent years. In Taiwan, Greenland halibut is usually substituted for the cod because of its lower price. Nowadays, DNA technology is widely used for fish species identifications; however, it still has concern about the DNA of processed fishery products might be destroyed. This study was designed to develop a proteomic-based method for fish and fishery product authentication by using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) with Sequential window acquisition of all theoretical fragment ion spectra (SWATH). The protein biomarkers from the meat of Alaska pollock, Atlantic cod, and Greenland halibut were identified and validated for species authentication of cod and corresponding fishery products, which might prevent consumer substitutions and fish product mislabeling. Besides, the E. coli proteins can be measured from existing SWATH-MS data though retrospective analysis successfully, it might present the quality of fish meat.


Assuntos
Proteômica , Espectrometria de Massas em Tandem , Animais , Escherichia coli , Pesqueiros , Estudos Retrospectivos
14.
Int J Cancer ; 150(9): 1447-1454, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-34888857

RESUMO

Elevated blood levels of C-reactive protein (CRP) have been linked to colorectal cancer (CRC) survival. We evaluated genetic variants associated with CRP levels and their interactions with sex and lifestyle factors in association with CRC-specific mortality. Our study included 16 142 CRC cases from the International Survival Analysis in Colorectal Cancer Consortium. We identified 618 common single nucleotide polymorphisms (SNPs) associated with CRP levels from the NHGRI-EBI GWAS Catalog. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between SNPs and CRC-specific mortality adjusting for age, sex, genotyping platform/study and principal components. We investigated their interactions with sex and lifestyle factors using likelihood ratio tests. Of 5472 (33.9%) deaths accrued over up to 10 years of follow-up, 3547 (64.8%) were due to CRC. No variants were associated with CRC-specific mortality after multiple comparison correction. We observed strong evidence of interaction between variant rs1933736 at FRK gene and sex in relation to CRC-specific mortality (corrected Pinteraction  = .0004); women had higher CRC-specific mortality associated with the minor allele (HR = 1.11, 95% CI = 1.04-1.19) whereas an inverse association was observed for men (HR = 0.88, 95% CI = 0.82-0.94). There was no evidence of interactions between CRP-associated SNPs and alcohol, obesity or smoking. Our study observed a significant interaction between sex and a CRP-associated variant in relation to CRC-specific mortality. Future replication of this association and functional annotation of the variant are needed.


Assuntos
Proteína C-Reativa , Neoplasias Colorretais , Proteína C-Reativa/análise , Proteína C-Reativa/genética , Feminino , Humanos , Estilo de Vida , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Análise de Sobrevida
15.
Cancer Discov ; 12(2): 450-467, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34531253

RESUMO

An enhanced requirement for nutrients is a hallmark property of cancer cells. Here, we optimized an in vivo genetic screening strategy in acute myeloid leukemia (AML), which led to the identification of the myo-inositol transporter SLC5A3 as a dependency in this disease. We demonstrate that SLC5A3 is essential to support a myo-inositol auxotrophy in AML. The commonality among SLC5A3-dependent AML lines is the transcriptional silencing of ISYNA1, which encodes the rate-limiting enzyme for myo-inositol biosynthesis, inositol-3-phosphate synthase 1. We use gain- and loss-of-function experiments to reveal a synthetic lethal genetic interaction between ISYNA1 and SLC5A3 in AML, which function redundantly to sustain intracellular myo-inositol. Transcriptional silencing and DNA hypermethylation of ISYNA1 occur in a recurrent manner in human AML patient samples, in association with IDH1/IDH2 and CEBPA mutations. Our findings reveal myo-inositol as a nutrient dependency in AML caused by the aberrant silencing of a biosynthetic enzyme. SIGNIFICANCE: We show how epigenetic silencing can provoke a nutrient dependency in AML by exploiting a synthetic lethality relationship between biosynthesis and transport of myo-inositol. Blocking the function of this solute carrier may have therapeutic potential in an epigenetically defined subset of AML.This article is highlighted in the In This Issue feature, p. 275.


Assuntos
Proteínas de Choque Térmico/genética , Inositol/biossíntese , Leucemia Mieloide Aguda/tratamento farmacológico , Simportadores/genética , Animais , Biologia do Desenvolvimento , Humanos , Camundongos
16.
Cancer Lett ; 528: 31-44, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34942306

RESUMO

The CDK4/6 inhibitor, palbociclib has recently entered clinic-trial stage for breast cancer treatment. However, translating its efficacy to other solid tumors has been challenging, especially for aggressive solid tumors. We found that the effect of palbociclib as a single agent was limited due to primary and acquired resistance in multiple ovarian cancer (OC) models. Among these, patient-derived organoid and xenograft models are two most representative models of drug responsiveness in patients with OC. In preclinical models, this study demonstrated that activated MAPK/PI3K-AKT pathway and cell cycle-related proteins induced the resistance to palbociclib, which was overcome by the addition of the bromodomain protein 4 (BRD4) inhibitor AZD5153. Moreover, this study revealed that AZD5153 and palbociclib had a synergistic lethal effect on inducing the cell cycle arrest and increasing apoptosis, even in RB-deficient cell lines. Based on these results, it is anticipated that this class of drugs, including AZD5153, which inhibit the cell cycle-related protein and MAPK/PI3K-AKT pathway, will exhibit synergistic effects with palbociclib in OC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Ciclo Celular/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazóis/uso terapêutico , Piridazinas/uso terapêutico , Piridinas/uso terapêutico , Animais , Antineoplásicos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Feminino , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Camundongos , Piperazinas/farmacologia , Pirazóis/farmacologia , Piridazinas/farmacologia , Piridinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Exp Med ; 219(1)2022 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-34825915

RESUMO

Targeted therapies represent attractive combination partners with immune checkpoint blockade (ICB) to increase the population of patients who benefit or to interdict the emergence of resistance. We demonstrate that targeting WEE1 up-regulates immune signaling through the double-stranded RNA (dsRNA) viral defense pathway with subsequent responsiveness to immune checkpoint blockade even in cGAS/STING-deficient tumors, which is a typical phenotype across multiple cancer types. WEE1 inhibition increases endogenous retroviral elements (ERVs) expression by relieving SETDB1/H3K9me3 repression through down-regulating FOXM1. ERVs trigger dsRNA stress and interferon response, increasing recruitment of anti-tumor T cells with concurrent PD-L1 elevation in multiple tumor models. Furthermore, combining WEE1 inhibition and PD-L1 blockade induced striking tumor regression in a CD8+ T cell-dependent manner. A WEE1 inhibition-induced viral defense signature provides a potentially informative biomarker for patient selection for combination therapy with WEE1 and ICB. WEE1 inhibition stimulates anti-tumor immunity and enhances sensitivity to ICB, providing a rationale for the combination of WEE1 inhibitors and ICB in clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Retrovirus Endógenos/genética , Neoplasias Experimentais/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , RNA de Cadeia Dupla/genética , Transdução de Sinais/efeitos dos fármacos , Células A549 , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Retrovirus Endógenos/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/farmacologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacologia , RNA de Cadeia Dupla/metabolismo , Transdução de Sinais/genética , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Carga Tumoral/imunologia
18.
Molecules ; 26(23)2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34885924

RESUMO

Zn(II) complexes bearing tris[3-(2-pyridyl)-pyrazolyl] borate (Tppy) ligand (1-3) was synthesized and examined by spectroscopic and analytical tools. Mononuclear [TppyZnCl] (1) has a Zn(II) centre with one arm (pyrazolyl-pyridyl) dangling outside the coordination sphere which is a novel finding in TppyZn(II) chemistry. In complex [TppyZn(H2O)][BF4] (2) hydrogen bonding interaction of aqua moiety stabilizes the dangling arm. In addition, solution state behaviour of complex 1 confirms the tridentate binding mode and reactivity studies show the exogenous axial substituents used to form the [TppyZnN3] (3). The complexes (1-3) were tested for their ability to bind with Calf thymus (CT) DNA and Bovine serum albumin (BSA) wherein they revealed to exhibit good binding constant values with both the biomolecules in the order of 104-105 M-1. The intercalative binding mode with CT DNA was confirmed from the UV-Visible absorption, viscosity, and ethidium bromide (EB) DNA displacement studies. Further, the complexes were tested for in vitro cytotoxic ability on four triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, MDA-MB-468, HCC1937, and Hs 578T). All three complexes (1-3) exhibited good IC50 values (6.81 to 16.87 µM for 24 h as seen from the MTS assay) results which indicated that these complexes were found to be potential anticancer agents against the TNBC cells.


Assuntos
Antineoplásicos/farmacologia , Boratos/farmacologia , Complexos de Coordenação/farmacologia , Pirazóis/farmacologia , Zinco/farmacologia , Animais , Antineoplásicos/química , Boratos/química , Bovinos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , DNA/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Pirazóis/química , Zinco/química
19.
JGH Open ; 5(12): 1363-1372, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34950780

RESUMO

BACKGROUND AND AIM: Chronic hepatitis C virus (HCV) infection, long-term alcohol use, cigarette smoking, and obesity are the major risk factors for hepatocellular carcinoma (HCC) in the United States, but the disease risk varies substantially among individuals with these factors, suggesting host susceptibility to and gene-environment interactions in HCC. To address genetic susceptibility to HCC, we conducted a genome-wide association study (GWAS). METHODS: Two case-control studies on HCC were conducted in the United States. DNA samples were genotyped using the Illumian microarray chip with over 710 000 single nucleotide polymorphisms (SNPs). We compared these SNPs between 705 HCC cases and 1455 population controls for their associations with HCC and verified our findings in additional studies. RESULTS: In this GWAS, we found that two SNPs were associated with HCC at P < 5E-8 and six SNPs at P < 5E-6 after adjusting for age, sex, and the top three principal components (PCs). Five of the SNPs in chromosome 22q13.31, three in PNPLA3 (rs2281135, rs2896019, and rs4823173) and two in SAMM50 (rs3761472, rs3827385), were replicated in a small US case-control study and a cohort study in Singapore. The associations remained significant after adjusting for body mass index and HCV infection. Meta-analysis of multiple datasets indicated that these SNPs were significantly associated with HCC. CONCLUSIONS: SNPs in PNPLA3 and SAMM50 are known risk loci for nonalcoholic fatty liver disease (NAFLD) and are suspected to be associated with HCC. Our GWAS demonstrated the associations of these SNPs with HCC in a US population. Biological mechanisms underlying the relationship remain to be elucidated.

20.
Am J Cancer Res ; 11(10): 4900-4918, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34765299

RESUMO

Paired-like homeodomain transcription factor 2 (PITX2) is well known to play an essential role in normal embryonic development. Emerging evidence suggests that PITX2 may be involved in human tumorigenesis, but the role of PITX2 in tumour progression remains largely unclear. The expression levels of PITX2 in lung cancer cells were determined by qRT-PCR and Western blot analyses. Gain- and loss-of-function experiments were conducted to investigate the biological roles of PITX2 in the phenotype of lung cancer cells. Immunofluorescence staining and transmission electron microscopy were used to observe autophagy. The expression level and clinical significance of PITX2 were determined in a Taiwanese cohort and the Gene Expression Omnibus (GEO) database, respectively. Here, we show that PITX2B is the most abundant isoform of the bicoid homeodomain family in lung cancer cells. The enforced expression of PITX2B promoted lung cancer tumorigenesis and progression in vitro and in vivo. The mechanistic analysis revealed that the nuclear localization of PITX2B is correlated with its oncogenic functions and two important nuclear localization signals. In addition, PITX2B knockdown in lung cancer cells caused a marked increase in autophagy and apoptosis, suggesting that PITX2B plays an important role in lung cancer cell survival. Moreover, a high expression of PITX2B was associated with a poor overall survival (P<0.05) in both Taiwanese non-small-cell lung cancer patients and GEO lung cancer cohorts. These results provide new insight into the contribution of PITX2B to lung cancer progression, implicate PITX2B as an important component of cell survival signals and further establish PITX2B as a therapeutic target for lung cancer treatment.

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