RESUMO
NRAS mutations are most frequently observed in hematological malignancies and are also common in some solid tumors such as melanoma and colon cancer. Despite its pivotal role in oncogenesis, no effective therapies targeting NRAS has been developed. Targeting NRAS localization to the plasma membrane (PM) is a promising strategy for cancer therapy, as its signaling requires PM localization. However, the process governing NRAS translocation from the Golgi apparatus to the PM after lipid modification remains elusive. This study identifies GOLGA7 as a crucial factor controlling NRAS' PM translocation, demonstrating that its depletion blocks NRAS, but not HRAS, KRAS4A and KRAS4B, translocating to PM. GOLGA7 is known to stabilize the palmitoyltransferase ZDHHC9 for NRAS and HRAS palmitoylation, but we found that GOLGA7 depletion does not affect NRAS' palmitoylation level. Further studies show that loss of GOLGA7 disrupts NRAS anterograde trafficking, leading to its cis-Golgi accumulation. Remarkably, depleting GOLGA7 effectively inhibits cell proliferation in multiple NRAS-mutant cancer cell lines and attenuates NRASG12D-induced oncogenic transformation in vivo. These findings elucidate a specific intracellular trafficking route for NRAS under GOLGA7 regulation, highlighting GOLGA7 as a promising therapeutic target for NRAS-driven cancers.
Assuntos
Lipoilação , Transdução de Sinais , Membrana Celular/metabolismo , Linhagem Celular , Mutação , Complexo de Golgi/metabolismoRESUMO
INTRODUCTION: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. METHODS: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. RESULTS: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. DISCUSSION: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. HIGHLIGHTS: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.
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Doença de Alzheimer , População Norte-Americana , Humanos , Doença de Alzheimer/genética , Projetos Piloto , Asiático/genética , Canadá , Fatores de RiscoRESUMO
INTRODUCTION: Most Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA). METHODS: We applied principal component analysis using Gaussian mixture models and an Ashkenazi Jewish (AJ) reference genome-wide association study (GWAS) data set to identify Ashkenazi Jews ascertained in GWAS (n = 42,682), whole genome sequencing (WGS, n = 16,815), and whole exome sequencing (WES, n = 20,504) data sets. The association of AD was tested genome wide (GW) in the GWAS and WGS data sets and exome wide (EW) in all three data sets (EW). Gene-based analyses were performed using aggregated rare variants. RESULTS: In addition to apolipoprotein E (APOE), GW analyses (1355 cases and 1661 controls) revealed associations with TREM2 R47H (p = 9.66 × 10-9 ), rs541586606 near RAB3B (p = 5.01 × 10-8 ), and rs760573036 between SPOCK3 and ANXA10 (p = 6.32 × 10-8 ). In EW analyses (1504 cases and 2047 controls), study-wide significant association was observed with rs1003710 near SMAP2 (p = 1.91 × 10-7 ). A significant gene-based association was identified with GIPR (p = 7.34 × 10-7 ). DISCUSSION: Our results highlight the efficacy of founder populations for AD genetic studies.
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Doença de Alzheimer , Estudo de Associação Genômica Ampla , Humanos , Judeus/genética , Predisposição Genética para Doença/genética , Doença de Alzheimer/genética , Etnicidade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
RAS genes are the most commonly mutated in human cancers and play critical roles in tumor initiation, progression, and drug resistance. Identification of targets that block RAS signaling is pivotal to develop therapies for RAS-related cancer. As RAS translocation to the plasma membrane (PM) is essential for its effective signal transduction, we devised a high-content screening assay to search for genes regulating KRAS membrane association. We found that the tyrosine phosphatase PTPN2 regulates the plasma membrane localization of KRAS. Knockdown of PTPN2 reduced the proliferation and promoted apoptosis in KRAS-dependent cancer cells, but not in KRAS-independent cells. Mechanistically, PTPN2 negatively regulates tyrosine phosphorylation of KRAS, which, in turn, affects the activation KRAS and its downstream signaling. Consistently, analysis of the TCGA database demonstrates that high expression of PTPN2 is significantly associated with poor prognosis of patients with KRAS-mutant pancreatic adenocarcinoma. These results indicate that PTPN2 is a key regulator of KRAS and may serve as a new target for therapy of KRAS-driven cancer.
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Biomarcadores Tumorais/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Mutação , Neoplasias/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Células Tumorais CultivadasRESUMO
BACKGROUND: Mycoplasma pneumoniae is a common pathogen that causes community-acquired pneumonia in school-age children. Macrolides are considered a first-line treatment for M. pneumoniae infection in children, but macrolide-refractory M. pneumoniae (MRMP) strains have become more common. In this study, we assessed the efficacy of tetracyclines and fluoroquinolones in MRMP treatment in children through a systematic review and meta-analysis. METHODS: Two reviewers individually searched 10 electronic databases (Medline/Pubmed, Embase, the Cochrane Library, and core Korean, Chinese, and Japanese journals) for papers published from January 1, 1990 to March 8, 2018. The following data for each treatment group were extracted from the selected studies: intervention (tetracyclines and fluoroquinolones/comparator), patient characteristics (age and sex), and outcomes (fever duration, hospital stay length, treatment success rate, and defervescence rates 24, 48, and 72 h after starting treatment). RESULTS: Eight studies involving 537 participants were included. Fever duration and hospital stay length were shorter in the tetracycline group than in the macrolide group (weighted mean difference [WMD] = - 1.45, 95% confidence interval [CI]: - 2.55 to - 0.36, P = 0.009; and WMD = - 3.33, 95% CI: - 4.32 to - 2.35, P < 0.00001, respectively). The therapeutic efficacy was significantly higher in the tetracycline group than in the macrolide group (odds ratio [OR]: 8.80, 95% CI: 3.12-24.82). With regard to defervescence rate, patients in the tetracycline group showed significant improvement compared to those in the macrolide group (defervescence rate after 24 h, OR: 5.34, 95% CI: 1.81-15.75; after 48 h, OR 18.37, 95% CI: 8.87-38.03; and after 72 h, OR: 40.77, 95% CI: 6.15-270.12). There were no differences in fever improvement within 24 h in patients in the fluoroquinolone group compared to those in the macrolide group (OR: 1.11, 95% CI: 0.25-5.00), although the defervescence rate was higher after 48 h in the fluoroquinolone group (OR: 2.78, 95% CI: 1.41-5.51). CONCLUSION: Tetracyclines may shorten fever duration and hospital stay length in patients with MRMP infection. Fluoroquinolones may achieve defervescence within 48 h in patients with MRMP infection. However, these results should be carefully interpreted as only a small number of studies were included, and they were heterogeneous.
Assuntos
Mycoplasma pneumoniae , Pneumonia por Mycoplasma , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Criança , Farmacorresistência Bacteriana , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Humanos , Macrolídeos/farmacologia , Macrolídeos/uso terapêutico , Pneumonia por Mycoplasma/tratamento farmacológico , Tetraciclinas/farmacologia , Tetraciclinas/uso terapêuticoRESUMO
Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide that responds poorly to existing therapies. The Casein kinase 1 (CK1) isoforms CK1δ and CK1ε are reported to be highly expressed in several tumor types, and both genetic and pharmacological inhibition of CK1δ/ε activity has deleterious effects on tumor cell growth. IC261, an CK1δ/ε selectively inhibitor, shows anti-tumor effect against pancreatic tumor and glioblastoma, but its role in HCC remains poorly characterized. In our research, IC261 displayed time- and dose-dependent inhibition of HCC cell proliferation, and induced G2/M arrest and cell apoptosis in vitro. However, the anti-tumor effects of IC261 was independent of CK1δ/ε. Additionally, IC261 was verified to induce centrosome fragmentation during mitosis independent of CK1δ status, and intraperitoneal injection of IC261 to HCCLM3 xenograft models inhibited tumor growth. Taken together, our data indicated that IC261 has therapeutic potential for HCC.
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Carcinoma Hepatocelular/tratamento farmacológico , Caseína Quinase 1 épsilon/antagonistas & inibidores , Caseína Quinase Idelta/antagonistas & inibidores , Indóis/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Floroglucinol/análogos & derivados , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Carcinoma Hepatocelular/metabolismo , Caseína Quinase 1 épsilon/metabolismo , Caseína Quinase Idelta/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Humanos , Indóis/farmacologia , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Floroglucinol/farmacologia , Floroglucinol/uso terapêutico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
BACKGROUND Depression is a common disorder linked with high levels of chronicity, psycho-social and physical problems, and suicide. Here, we assessed the antidepressant effects of the hydromethanolic extract of Taraxacum officinale and investigated the underlying mechanism. MATERIAL AND METHODS Antidepressant effects were examined by use of the tail suspension test (TST). Concentrations of corticosterone, dopamine, noradrenaline, and adrenaline were examined by biochemical assays. The mRNA expression was assessed by quantitative RT-PCR. Phytochemical analysis was performed by LC/MS. RESULTS The results showed that the extract at the dosage of 50 and 100 mg/kg significantly (p<0.01) alleviated the TST-induced immobility in the mice, and the effects were comparable to the antidepressant drug Bupropion, which was used as the positive control. Investigation of the underlying mechanism revealed that the T. officinale extract exerts it effects by significantly (p<0.05) decreasing the levels of corticosterone and increasing the concentrations of dopamine, noradrenaline, and adrenaline. Further, the extract also increased the expression of brain-derived neurotrophic factor (Bdnf), which was associated with significant (p<0.05) decrease in the expression of mitogen-activated protein kinase phosphatase-1 (Mkp-1), indicative of the antidepressant potential of T. officinale. Finally, the active constituents of the extract, which include isoetin, hesperidin, naringenin, Kaempferol, sinapinic, and gallic acid, were also identified, which could potentially be responsible for its antidepressant effects. CONCLUSIONS In conclusion, T. officinale exerts significant antidepressant effects in a mouse model of depression by inhibition of corticosterone levels and modulation of Mkp-1 and Bdnf expression.
Assuntos
Depressão/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Taraxacum/metabolismo , Animais , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corticosterona/metabolismo , Depressão/metabolismo , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Dopamina/análise , Fosfatase 1 de Especificidade Dupla/efeitos dos fármacos , Fosfatase 1 de Especificidade Dupla/metabolismo , Epinefrina/análise , Masculino , Camundongos , Camundongos Endogâmicos ICR , Norepinefrina/análise , Fitoterapia/métodos , Extratos Vegetais/farmacologia , Folhas de Planta/metabolismo , Estresse Psicológico/metabolismo , Natação , Taraxacum/fisiologiaRESUMO
BACKGROUND: Mycoplasma pneumoniae is one of the most common pathogens causing community acquired pneumonia in children. Although the rate of macrolide-refractory Mycoplasma pneumoniae (MRMP) has increased, systemic glucocorticoids as a treatment option has not been validated yet. The purpose of this study was to assess the efficacy of glucocorticoids add-on in the treatment of MRMP in children through systematic review and meta-analysis. METHODS: Data sources A systematic literature search was conducted using ten electronic bibliographic databases including English, Korean, Chinese and Japanese languages, up to March 8, 2018. Study selection The study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist and selected randomized control trials which compared the efficacy of glucocorticoids add-on to macrolide in the treatment of MRMP in children. Data extraction Two independent reviewers extracted: primary outcomes as hospital days, fever duration, and change in C-reactive protein (CRP) and main analysis was performed through meta-analysis with random effects model. RESULTS: Twenty-four unique randomized controlled trials met the inclusion criteria. The mean length of hospital stay in glucocorticoids treatment group was significantly shorter than that in conventional macrolide-treatment group (Weighted mean difference (WMD) = - 4.03 days). The mean length of fever duration was significantly shorter in the glucocorticoid treatment group in comparison with the conventional treatment group (WMD = -3.32 days). Level of CRP after treatment was significantly lower in the glucocorticoid treatment group than that in the conventional treatment group (WMD = -16.03). Sensitivity analysis and subgroup analysis showed no significant improvement in heterogeneity. As limitations of the study, most of the studies included were from a single country and we were unable to control for heterogeneity across interventions, lack of standardized measures, and different time points of assessments across studies. CONCLUSIONS: Glucocorticoid add-on treatment for MRMP can significantly shorten the duration of fever and hospital stay and decrease the level of CRP. These results should be confirmed by adequately powered studies in the future.
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Antibacterianos/uso terapêutico , Glucocorticoides/uso terapêutico , Macrolídeos/uso terapêutico , Pneumonia por Mycoplasma/tratamento farmacológico , Proteína C-Reativa/metabolismo , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Febre , Humanos , Tempo de Internação , Masculino , Mycoplasma pneumoniae , Pneumonia por Mycoplasma/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Falha de Tratamento , Resultado do TratamentoRESUMO
The ability of indoor plants to purify benzene pollution is the basic basis for the selection of plants for ecological remediation of indoor benzene pollution. In this study, the purification rate and the purification amount per unit leaf area of 13 test plants at three benzene concentrations were determined by indoor fumigation experiments, and the benzene absorption and purification abilityability of indoor plants were comprehensively evaluated. The results showed that (1) there was a significant correlation between benzene concentration and purification rate and purification amount per unit leaf area. (2) At the three concentrations, Spathiphyllum floribundum showed the highest purification rate and Sansevieria trifasciata var. laurentii showed the highest purification per unit leaf area. (3) The combined results showed that Sansevieria trifasciata var. laurentii, Spathiphyllum floribundum and Aloe arborescens were the strongest absorbers and purifiers, while Podocarpus nagi and Anthurium andraeanum 'Pink champin' had the weakest absorption and purification capacity. The results of this study provide a theoretical basis and reference for the selection of plants with strong capacities to adsorb and purify benzene pollution in indoor air.
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Poluição do Ar em Ambientes Fechados , Benzeno , Benzeno/isolamento & purificação , Poluição do Ar em Ambientes Fechados/análise , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/isolamento & purificação , Plantas/química , Folhas de Planta/química , Biodegradação Ambiental , AdsorçãoRESUMO
Targeted and immunotherapy combined with interventional therapy can improve the prognosis of advanced cancer patients, and it has become a hot spot to find the new therapeutic schemes, but most of which are not satisfactory. Single-cell RNA sequencing was performed in PDX mouse models with or without TCC therapy. 2-'O-Methylation modification and multiplex immunofluorescence staining were used to explore the function and mechanism of SAMD4B in the immune context of HCC. Here, we propose for the first time a synergistic immunochemotherapy that exerts a potent antitumour effect for patients with advanced hepatocellular carcinoma (HCC) in clinical practice based on three common antitumour drugs and found that HCC patients with new synergistic immunochemotherapy had better three-year overall survival (p = 0.004) and significantly higher survival ratio (increased by 2.3 times) than the control group. We further reveal the immunoregulatory mechanism of synergistic immunochemotherapy through 2'-O-Methylation modification mediated by SAMD4B, a tumour suppressor gene. Mechanistically, SAMD4B, increased by the reduced mutations of upstream genes NOTCH1 and NOTCH2, affected the instability of APOA2 mRNA by 2-'O-Methylation modification of the C-terminus. The decreased APOA2 further attenuated programmed death ligand 1 (PD-L1) level with a direct interaction pattern. The high-SAMD4B tumour tissues contained fewer native CD29+CD8+ T cells, which improved immune microenvironment to achieve the effect of antitumour effect. Overall, we developed a potent synergistic immunochemotherapy strategy that exerts an efficient anti-HCC effect inducing SAMD4B-APOA2-PD-L1 axis to inhibit tumour immune evasion.
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Antígeno B7-H1 , Carcinoma Hepatocelular , Imunoterapia , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Animais , Humanos , Camundongos , Imunoterapia/métodos , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Masculino , Microambiente Tumoral , FemininoRESUMO
Tourists have been attracted to world heritage sites (WHSs) by their Outstanding Universal Value (OUV). In view of the Stimulus-Organism-Response (S-O-R) framework and the theory of attitude and behavior, by employing 563 tourist samples from Mount Sanqingshan National Park, and using structural equation modeling, we examine tourist behavioral intention for heritage conservation, and the following conclusions were drawn: (1) the S-O-R theory revealed the behavioral intentions of tourists to protect WHSs; (2) as a stimulus, tourists' value perception and destination attachment were positively affected by the OUV attractiveness, and their perceived value had a positive influence on heritage conservation, although the hypothesis of destination attachment to heritage conservation was not supported; (3) heritage-conservation education and knowledge positively influenced tourists' behavioral intentions towards heritage protection, and tourists' heritage protection attitude had a positive influence on their behavioral intention; and (4) a framework of the influence mechanism for tourists' heritage conservation based on the S-O-R theory was proposed, while tourists' cognitive and affective attitudes impacted on heritage protection intention which, in turn, further enhanced the tourists' perception of the OUV. Conclusively, the measures and implications were proposed for improving conservation and management of WHSs, in particular to achieve the sustainable development of the tourist industry and world heritage sites.
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Atitude , Intenção , Desenvolvimento Sustentável , Conhecimento , Parques RecreativosRESUMO
An efficient energy scheduling strategy of a charging station is crucial for stabilizing the electricity market and accommodating the charging demand of electric vehicles (EVs). Most of the existing studies on energy scheduling strategies fail to coordinate the process of energy purchasing and distribution and, thus, cannot balance the energy supply and demand. Besides, the existence of multiple charging stations in a complex scenario makes it difficult to develop a unified schedule strategy for different charging stations. In order to solve these problems, we propose a multiagent reinforcement learning (MARL) method to learn the optimal energy purchasing strategy and an online heuristic dispatching scheme to develop a energy distribution strategy in this article. Unlike the traditional scheduling methods, the two proposed strategies are coordinated with each other in both temporal and spatial dimensions to develop the unified energy scheduling strategy for charging stations. Specifically, the proposed MARL method combines the multiagent deep deterministic policy gradient (MADDPG) principles for learning purchasing strategy and a long short-term memory (LSTM) neural network for predicting the charging demand of EVs. Moreover, a multistep reward function is developed to accelerate the learning process. The proposed method is verified by comprehensive simulation experiments based on real data of the electricity market in Chicago. The experiment results show that the proposed method can achieve better performance than other state-of-the-art energy scheduling methods in the charging market in terms of the economic profits and users' satisfaction ratio.
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Aprendizagem , Reforço Psicológico , Recompensa , Simulação por Computador , Sistemas ComputacionaisRESUMO
A World Heritage Site is a masterpiece of mankind and/or nature that possesses outstanding universal value (OUV). In this regard, the 5Cs strategic objectives (credibility, communication, capacity-building, conservation, and community) set by the World Heritage Committee have become a main issue for WHS sustainable development. As one of the key stakeholders of WHS, tourist's perceived OUV attractiveness, congestion, and attitudinal behavior have significant implications for heritage protection and tourism's sustainable development. Based on the perspectives of OUV attractiveness and perceived tourist crowding, and taking into account destination attachment, the influencing factors and mechanisms of tourist satisfaction are investigated. In view of the 536 questionnaire responses from tourists of Mount Sanqingshan National Park, the structural equation modeling approach was employed to study tourist satisfaction. The conclusions were sketched: (1) tourist crowding perception did not have a significant negative effect on OUV attractiveness; destination attachment, and tourist satisfaction, and the degree of crowding perception was low; (2) the OUV attractiveness has a significant positive influence on destination attachment and tourist satisfaction, which fully highlights the charm of OUV and its important role in shaping tourists' attitudes/behaviors; (3) destination attachment has a significant positive effect on tourist satisfaction, indicating that tourists' heritage-place attachment contributes to tourist satisfaction. Finally, the analysis of tourism crowding, OUV, and the satisfaction framework proposed broaden the horizons of visitor satisfaction research, which is also a positive response to the strategic objectives of the 5Cs of WHS, with some practical implications for heritage preservation and visitor management in World Heritage Sites.
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CDH1 deficiency is common in diffuse gastric cancer and triple negative breast cancer patients, both of which still lack effective therapeutics. ROS1 inhibition results in synthetic lethality in CDH1-deficient cancers, but often leads to adaptive resistance. Here, we demonstrate that upregulation of the FAK activity accompanies the emergence of resistance to ROS1 inhibitor therapy in gastric and breast CDH1-deficient cancers. FAK inhibition, either by FAK inhibitors or by knocking down its expression, resulted in higher cytotoxicity potency of the ROS1 inhibitor in CDH1-deficient cancer cell lines. Co-treatment of mice with the FAK inhibitor and ROS1 inhibitors also showed synergistic effects against CDH1-deficient cancers. Mechanistically, ROS1 inhibitors induce the FAK-YAP-TRX signaling, decreasing oxidative stress-related DNA damage and consequently reducing their anti-cancer effects. The FAK inhibitor suppresses the aberrant FAK-YAP-TRX signaling, reinforcing ROS1 inhibitor's cytotoxicity towards cancer cells. These findings support the use of FAK and ROS1 inhibitors as a combination therapeutic strategy in CDH1-deficient triple negative breast cancer and diffuse gastric cancer patients.
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Neoplasias Gástricas , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas/metabolismo , Antígenos CD , Caderinas/genéticaRESUMO
Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.
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TMPRSS2 is a transmembrane serine protease and plays a pivotal role in coronavirus disease 2019 (COVID-19). However, the correlation of TMPRSS2 with prognosis and immune infiltration in tumors has not yet been explored. Here, we analyzed the expression of TMPRSS2 in Oncomine and TIMER databases, the correlation between TMPRSS2 and overall survival in the PrognoScan, Kaplan-Meier plotter, and GEPIA databases. The association between TMPRSS2 and immune infiltration levels was investigated in the TIMER database. In addition, the prognosis of TMPRSS2 related to immune cells in cancers was analyzed. Quantitative real-time PCR (qRT-PCR) confirmed that TMPRSS2 was upregulated in lung adenocarcinoma (LUAD) and downregulated in breast invasive carcinoma (BRCA). We demonstrated that high TMPRSS2 expression was associated with favorable prognosis in LUAD, but it was associated with poor prognosis in BRCA. Interestingly, we found that TMPRSS2 expression was significantly correlated with immune infiltration of B cells, CD4+ T cells, macrophages, and dendritic cells in LUAD, and it was positively correlated with the infiltrating levels of CD8+ T cells, CD4+ T cells, neutrophils, and dendric cells in BRCA. Consistent with the prognosis of TMPRSS2 in LUAD and BRCA, the high expression level of TMPRSS2 has a favorable prognosis in enriched immune cells such as B cells, macrophages, and CD4+ T cells in LUAD, and it has a poor prognosis in CD4+ T cells and CD8+ T cells in BRCA. In conclusion, our results indicate that the prognosis of TMPRSS2 in LUAD and BRCA is significantly correlated with immune cells infiltration. Our study comprehensively revealed the relationship between the prognosis of TMPRSS2 in pan-cancers and tumor immunity.
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More than 85% of patients with uveal melanoma (UM) carry a GNAQ or GNA11 mutation at a hotspot codon (Q209) that encodes G protein α subunit q/11 polypeptides (Gαq/11). GNAQ/11 relies on palmitoylation for membrane association and signal transduction. Despite the palmitoylation of GNAQ/11 was discovered long before, its implication in UM remains unclear. Here, results of palmitoylation-targeted mutagenesis and chemical interference approaches revealed that the loss of GNAQ/11 palmitoylation substantially affected tumor cell proliferation and survival in UM cells. Palmitoylation inhibition through the mutation of palmitoylation sites suppressed GNAQ/11Q209L-induced malignant transformation in NIH3T3 cells. Importantly, the palmitoylation-deficient oncogenic GNAQ/11 failed to rescue the cell death initiated by the knock down of endogenous GNAQ/11 oncogenes in UM cells, which are much more dependent on Gαq/11 signaling for cell survival and proliferation than other melanoma cells without GNAQ/11 mutations. Furthermore, the palmitoylation inhibitor, 2-bromopalmitate, also specifically disrupted Gαq/11 downstream signaling by interfering with the MAPK pathway and BCL2 survival pathway in GNAQ/11-mutant UM cells and showed a notable synergistic effect when applied in combination with the BCL2 inhibitor, ABT-199, in vitro. The findings validate that GNAQ/11 palmitoylation plays a critical role in UM and may serve as a promising therapeutic target for GNAQ/11-driven UM.
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Melanoma , Neoplasias Uveais , Humanos , Camundongos , Animais , Lipoilação , Células NIH 3T3 , Neoplasias Uveais/genética , Melanoma/genética , Proliferação de Células , Proteínas Proto-Oncogênicas c-bcl-2 , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genéticaRESUMO
Genetic influence on lung functions has been identified in previous studies; however, the relative longitudinal effects of genetic factors and their interactions with smoking on lung function remain unclear. Here, we identified the longitudinal effects of genetic variants on lung function by determining single nucleotide polymorphism (SNP) heritability and genetic correlations, and by analyzing interactions with smoking. Subject-specific means and annual change rates were calculated for eight spirometric measures obtained from 6622 Korean adults aged 40−69 years every two years for 14 years, and their heritabilities were estimated separately. Statistically significant (p < 0.05) heritability for the subject-specific means of all spirometric measures (8~32%) and change rates of forced expiratory volume in 1 s to forced vital capacity ratio (FEV1/FVC; 16%) and post-bronchodilator FEV1/FVC (17%) were detected. Significant genetic correlations of the change rate with the subject-specific mean were observed for FEV1/FVC (ρg = 0.64) and post-bronchodilator FEV1/FVC (ρg = 0.47). Furthermore, post-bronchodilator FEV1/FVC showed significant heritability of SNP-by-smoking interaction (hGXS2 = 0.4) for the annual change rate. The GWAS also detected genome-wide significant SNPs for FEV1 (rs4793538), FEV1/FVC (rs2704589, rs62201158, and rs9391733), and post-bronchodilator FEV1/FVC (rs2445936). We found statistically significant evidence of heritability role on the change in lung function, and this was shared with the effects on cross-sectional measurements. We also found some evidence of interaction with smoking for the change of lung function.
Assuntos
Broncodilatadores , Pulmão , Adulto , Idoso , Broncodilatadores/farmacologia , Estudos Transversais , Volume Expiratório Forçado/genética , Humanos , Pessoa de Meia-Idade , Capacidade Vital/genéticaRESUMO
Cullin-RING E3 ubiquitin ligase (CRL)-4 is a member of the large CRL family in eukaryotes. It plays important roles in a wide range of cellular processes, organismal development, and physiological and pathological conditions. DDB1- and CUL4-associated factor 8 (DCAF8) is a WD40 repeat-containing protein, which serves as a substrate receptor for CRL4. The physiological role of DCAF8 is unknown. In this study, we constructed Dcaf8 knockout mice. Homozygous mice were viable with no noticeable abnormalities. However, the fertility of Dcaf8-deficient male mice was markedly impaired, consistent with the high expression of DCAF8 in adult mouse testis. Sperm movement characteristics, including progressive motility, path velocity, progressive velocity, and track speed, were significantly lower in Dcaf8 knockout mice than in wild-type (WT) mice. However, the total motility was similar between WT and Dcaf8 knockout sperm. More than 40% of spermatids in Dcaf8 knockout mice showed pronounced morphological abnormalities with typical bent head malformation. The acrosome and nucleus of Dcaf8 knockout sperm looked similar to those of WT sperm. In vitro tests showed that the fertilization rate of Dcaf8 knockout mice was significantly reduced. The results demonstrated that DCAF8 plays a critical role in spermatogenesis, and DCAF8 is a key component of CRL4 function in the reproductive system.
Assuntos
Fator VIII , Espermatogênese , Animais , Proteínas Culina/genética , Proteínas de Ligação a DNA/genética , Masculino , Camundongos , Camundongos Knockout , Espermatogênese/genética , Ubiquitina-Proteína LigasesRESUMO
FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor prognosis. Multiple FLT3 inhibitors are in various stages of clinical evaluation. However, resistance to FLT3 inhibitors resulting from acquired point mutations in tyrosine kinase domain (TKD) have limited the sustained efficacy of treatments, and a "gatekeeper" mutation (F691L) is resistant to most available FLT3 inhibitors. Thus, new FLT3 inhibitors against both FLT3 internal tandem duplication (FLT3-ITD) and FLT3-TKD mutations (including F691L) are urgently sought. Herein, we identified KX2-391 as a dual FLT3 and tubulin inhibitor and investigated its efficacy and mechanisms in overcoming drug-resistant FLT3-ITD-TKD mutations in AML. KX2-391 exhibited potent growth inhibitory and apoptosis promoting effects on diverse AML cell lines harboring FLT3-ITD mutations and AC220-resistant mutations at the D835 and F691 residues in TKD and inhibited FLT3 phosphorylation and its downstream signaling targets. Orally administered KX2-391 significantly prolonged the survival of a murine leukemia model induced by FLT3-ITD-F691L. KX2-391 also significantly inhibited the growth of 4 primary AML cells expressing FLT3-ITD and 2 primary AML cells expressing FLT3-ITD-D835Y. Our preclinical data highlight KX2-391 as a promising FLT3 inhibitor for the treatment of AML patients harboring FLT3 mutations, especially refractory/relapsed patients with F691L and other FLT3-TKD mutations.