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1.
Drug Resist Updat ; 68: 100957, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36990047

RESUMO

Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the treatment of patients with EGFR-mutant lung adenocarcinoma. Our previous work found that a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1), HKB99, restrains erlotinib resistance in lung adenocarcinoma cells. However, the role of HKB99 in osimertinib resistance and its underlying molecular mechanism remains to be elucidated. Herein, we found that IL-6/JAK2/STAT3 signaling pathway is aberrantly activated in both erlotinib and osimertinib resistant cells. Importantly, HKB99 significantly blocks the interaction of PGAM1 with JAK2 and STAT3 via the allosteric sites of PGAM1, which leads to inactivation of JAK2/STAT3 and thereby disrupts IL-6/JAK2/STAT3 signaling pathway. Consequently, HKB99 remarkably restores EGFR inhibitor sensitivity and exerts synergistic tumoricidal effect. Additionally, HKB99 alone or in combination with osimertinib down-regulated the level of p-STAT3 in xenograft tumor models. Collectively, this study identifies PGAM1 as a key regulator in IL-6/JAK2/STAT3 axis in the development of resistance to EGFR inhibitors, which could serve as a therapeutic target in lung adenocarcinoma with acquired resistance to EGFR inhibitors.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Interleucina-6/genética , Interleucina-6/farmacologia , Interleucina-6/uso terapêutico , Fosfoglicerato Mutase/metabolismo , Fosfoglicerato Mutase/farmacologia , Resistencia a Medicamentos Antineoplásicos , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Receptores ErbB , Transdução de Sinais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Linhagem Celular Tumoral , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Janus Quinase 2/farmacologia
2.
Environ Res ; 212(Pt C): 113435, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35580666

RESUMO

Solar radiation is the external driving force of the Earth's climate system. In different spatial and temporal scales, meteorological elements have different responses and lag periods to solar activity (SA), climatic oscillation (CO), geographic factors (GF) and other influencing factors. However, such studies are not abundant and in-depth in the world. To further understand the "solar-climate-water resource" system, this study considers China as the study area and investigates the monthly data of temperature (T) and precipitation (P) during 1900-2020 that were obtained from 3836 grid stations. The strong interaction and lag distribution between T or P with SA and CO were studied and influence weights of SA, CO, and geographical factors (GF) of each grid station were calculated. A multivariate hysteretic decomposition model was established to simulate and quantitatively decompose the periodic lag considering the factors of the earth's revolution. It is found that the strong interaction/lag periods obtained in a long-time scale can be decomposed into several periods shorter than the SA period. The distribution of strong interaction/lag periods is nested with topography and echoes with cities. The underlying surface conditions and urbanization are also important factors affecting the T and P lag. There are two distinct dividing lines in the lag period and influencing factor pattern of T and P. The T dividing line moves through valleys where water or mountain ranges meet, where the gap facilitates monsoon movement across regions, while the P dividing line is a zone of dramatic terrain, where tall mountains block water vapor transport. In the lag trend of T, the northern region of China has the longest lag period, and the lag period of surrounding regions tends to converge to the northern region. The lag period caused by SN in southwest China is larger than that in northwest China, while the lag effect of CO is opposite in the above two regions. The lag trend of P also has the above characteristics, but the difference is that the lag period in central China is the longest.


Assuntos
Clima , Atividade Solar , China , Cidades , Mudança Climática , Temperatura
3.
Acta Pharmacol Sin ; 42(4): 613-623, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32704041

RESUMO

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have achieved satisfactory clinical effects in the therapy of non-small cell lung cancer (NSCLC), but acquired resistance limits their clinical application. NRF2 has been shown to enhance the resistance to apoptosis induced by radiotherapy and some chemotherapy. In this study, we investigated the role of NRF2 in resistance to EGFR-TKIs. We showed that NRF2 protein levels were markedly increased in a panel of EGFR-TKI-resistant NSCLC cell lines due to slow degradation of NRF2 protein. NRF2 knockdown overcame the resistance to EGFR-TKIs in HCC827ER and HCC827GR cells. Furthermore, we demonstrated that NRF2 imparted EGFR-TKIs resistance in HCC827 cells via upregulation of GPX4 and SOD2, and suppression of GPX4 and SOD2 reversed resistance to EGFR-TKIs. Thus, we conclude that targeting NRF2-GPX4/SOD2 pathway is a potential strategy for overcoming resistance to EGFR-TKIs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias Pulmonares/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Superóxido Dismutase/metabolismo , Carbolinas/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/fisiologia , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/farmacologia , Gefitinibe/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Fator 2 Relacionado a NF-E2/genética , Inibidores de Proteínas Quinases/farmacologia , RNA Interferente Pequeno/farmacologia , Superóxido Dismutase/genética , Regulação para Cima/fisiologia
4.
Acta Pharmacol Sin ; 42(1): 115-119, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32404981

RESUMO

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, remains a major challenge in the targeted therapy of non-small cell lung cancer (NSCLC). HKB99 is a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1) that preferentially suppresses cell proliferation and induces more apoptosis in acquired erlotinib-resistant HCC827ER cells compared with its parental HCC827 cells. In this study we identified the molecular biomarkers for HKB99 response in erlotinib-resistant HCC827ER cells. We showed that HCC827ER cells displayed enhanced invasive pseudopodia structures as well as downregulated plasminogen activator inhibitor-2 (PAI-2). Meanwhile, PAI-2 knockdown by siPAI-2 candidates decreased the sensitivity of HCC827 parental cells to erlotinib. Moreover, HKB99 (5 µM) preferentially inhibited the invasive pseudopodia formation and increased the level of PAI-2 in HCC827ER cells. Collectively, this study provides new insight into the role of PAI-2 in regulating the sensitivity of erlotinib resistant NSCLC cells to PGAM1 inhibitor. Furthermore, PAI-2 level might be considered as a potential biomarker for predicting the efficacy of the PGAM1 allosteric inhibitor on the erlotinib resistant NSCLC cells.


Assuntos
Antracenos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Fosfoglicerato Mutase/antagonistas & inibidores , Sulfonamidas/farmacologia , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Cloridrato de Erlotinib/farmacologia , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/metabolismo , Fosfoglicerato Mutase/genética , Pseudópodes/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
5.
BMC Bioinformatics ; 20(1): 449, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477006

RESUMO

BACKGROUND: Hodgkin Lymphoma (HL) is a type of aggressive malignancy in lymphoma that has high incidence in young adults and elderly patients. Identification of reliable diagnostic markers and efficient therapeutic targets are especially important for the diagnosis and treatment of HL. Although many HL-related molecules have been identified, our understanding on the molecular mechanisms underlying the disease is still far from complete due to its complex and heterogeneous characteristics. In such situation, exploring the molecular mechanisms underlying HL via systems biology approaches provides a promising option. In this study, we try to elucidate the molecular mechanisms related to the disease and identify potential pharmaceutical targets from a network-based perspective. RESULTS: We constructed a series of network models. Based on the analysis of these networks, we attempted to identify the biomarkers and elucidate the molecular mechanisms underlying HL. Initially, we built three different but related protein networks, i.e., background network, HL-basic network and HL-specific network. By analyzing these three networks, we investigated the connection characteristic of the HL-related proteins. Subsequently, we explored the miRNA regulation on HL-specific network and analyzed three kinds of simple regulation patterns, i.e., co-regulation of protein pairs, as well as the direct and indirect regulation of triple proteins. Finally, we constructed a simplified protein network combined with the regulation of miRNAs on proteins to better understand the relation between HL-related proteins and miRNAs. CONCLUSIONS: We find that the HL-related proteins are more likely to connect with each other compared to other proteins. Moreover, the HL-specific network can be further divided into five sub-networks and 49 proteins as the backbone of HL-specific network make up and connect these 5 sub-networks. Thus, they may be closely associated with HL. In addition, we find that the co-regulation of protein pairs is the main regulatory pattern of miRNAs on the protein network in the HL-specific network. According to the regulation of miRNA on protein network, we have identified 5 core miRNAs as the potential biomarkers for diagnostic of HL. Finally, several protein pathways have been identified to closely associated with HL, which provides deep insights into underlying mechanism of HL.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Doença de Hodgkin/patologia , MicroRNAs/genética , Mapas de Interação de Proteínas , Perfilação da Expressão Gênica , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Humanos , Biologia de Sistemas
6.
Metabolomics ; 15(4): 52, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30911937

RESUMO

INTRODUCTION: Specific oncogenotypes can produce distinct metabolic changes in cancer. Recently it is considered that metabolic reprograming contributes heavily to drug resistance. Aldehyde dehydrogenase 1A1 (ALDH1A1), is overexpressed in drug resistant lung adenocarcinomas and may be the cause of acquired drug resistance. However, how ALDH1A1 affects metabolic profiling in lung adenocarcinoma cells remains elusive. OBJECTIVE: We sought to investigate metabolic alterations induced by ALDH1A1 in lung adenocarcinoma in order to better understand the reprogramming and metabolic mechanism of resistance induced by ALDH1A1. METHODS: Metabolic alterations in lung adenocarcinoma HCC827-ALDH1A1 cells were analyzed by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). HCC827-ALDH1A1 metabolic signatures were extracted by univariate and multivariate statistical analysis. Furthermore, metabolite enrichment analysis and pathway analysis were performed using MetaboAnalyst 4.0 software. RESULTS: Twenty-two metabolites were positively identified using authentic standards, including uridine monophosphate (UMP), uridine diphosphate (UDP), adenosine diphosphate (ADP), malic acid, malonyl-coenzyme A, nicotinamide adenine dinucleotide (NAD), coenzyme A and so on. Furthermore, metabolic pathway analysis revealed several dysregulated pathways in HCC827-ALDH1A1 cells, including nucleotide metabolism, urea cycle, tricarboxylic acid (TCA) cycle, and glycerol phospholipid metabolism etc. CONCLUSION: Lung cancer is the most frequent cause of cancer-related deaths worldwide. Nearly all patients eventually undergo disease progression due to acquired resistance. Mechanisms of biological acquired resistance need to be identified. Our study identified altered metabolites in HCC827-ALDH1A1 cells, enhancing our knowledge of lung adenocarcinoma metabolic alterations induced by ALDH1A1, creating a novel therapeutic pathway. These metabolic signatures of ALDH1A1 overexpression may shed light on molecular mechanisms in drug-resistant tumors, and on candidate drug targets. Furthermore, new molecular targets may provide the foundation for potential anticancer strategies for lung cancer therapy.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Família Aldeído Desidrogenase 1/genética , Família Aldeído Desidrogenase 1/metabolismo , Retinal Desidrogenase/genética , Retinal Desidrogenase/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/metabolismo , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Redes e Vias Metabólicas , Metabolômica/métodos , Espectrometria de Massas em Tandem/métodos
8.
Global Biogeochem Cycles ; 29(6): 775-792, 2015 06.
Artigo em Inglês | MEDLINE | ID: mdl-27642229

RESUMO

Soil is the largest organic carbon (C) pool of terrestrial ecosystems, and C loss from soil accounts for a large proportion of land-atmosphere C exchange. Therefore, a small change in soil organic C (SOC) can affect atmospheric carbon dioxide (CO2) concentration and climate change. In the past decades, a wide variety of studies have been conducted to quantify global SOC stocks and soil C exchange with the atmosphere through site measurements, inventories, and empirical/process-based modeling. However, these estimates are highly uncertain, and identifying major driving forces controlling soil C dynamics remains a key research challenge. This study has compiled century-long (1901-2010) estimates of SOC storage and heterotrophic respiration (Rh) from 10 terrestrial biosphere models (TBMs) in the Multi-scale Synthesis and Terrestrial Model Intercomparison Project and two observation-based data sets. The 10 TBM ensemble shows that global SOC estimate ranges from 425 to 2111 Pg C (1 Pg = 1015 g) with a median value of 1158 Pg C in 2010. The models estimate a broad range of Rh from 35 to 69 Pg C yr-1 with a median value of 51 Pg C yr-1 during 2001-2010. The largest uncertainty in SOC stocks exists in the 40-65°N latitude whereas the largest cross-model divergence in Rh are in the tropics. The modeled SOC change during 1901-2010 ranges from -70 Pg C to 86 Pg C, but in some models the SOC change has a different sign from the change of total C stock, implying very different contribution of vegetation and soil pools in determining the terrestrial C budget among models. The model ensemble-estimated mean residence time of SOC shows a reduction of 3.4 years over the past century, which accelerate C cycling through the land biosphere. All the models agreed that climate and land use changes decreased SOC stocks, while elevated atmospheric CO2 and nitrogen deposition over intact ecosystems increased SOC stocks-even though the responses varied significantly among models. Model representations of temperature and moisture sensitivity, nutrient limitation, and land use partially explain the divergent estimates of global SOC stocks and soil C fluxes in this study. In addition, a major source of systematic error in model estimations relates to nonmodeled SOC storage in wetlands and peatlands, as well as to old C storage in deep soil layers.

9.
ScientificWorldJournal ; 2015: 384086, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25642451

RESUMO

Agricultural water is the main reason for the rapid decline of the NCP groundwater levels. It is of vital importance for the NCP sustainable agricultural development to master the ETa and its CWP. In this paper, the EBEM model was developed according to the theory of energy balance. From 2001 to 2006, the winter wheat ETa and CWP were estimated, and the spatial and temporal variations and their influencing factors were studied in the Hebei Plain. The results indicate that the EBEM model performed well by applying MODIS data to estimate the daily net radiation and ETa. For the daytime net radiation, the relative error between the estimation and the measurement amounted to 8.2% and the SEE was 0.82 MJ m(-2)/day. The average ETa deviation between the estimates and the measures amounted to 0.86 mm daily, and the SE was 1.2 mm. The spatial variations indicated that the major distribution of ETa ranged from 350 to 450 mm, which trended downward within the study area from west to east. In the study period, the winter wheat CWP was mainly distributed between 0.29 and 1.67 kg/m(3). In space, the CWP was higher in the west than in the east.


Assuntos
Água Subterrânea , Transpiração Vegetal , Triticum/metabolismo , China , Modelos Teóricos , Tecnologia de Sensoriamento Remoto , Solo , Tempo (Meteorologia)
10.
J Air Waste Manag Assoc ; 64(4): 419-35, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24843913

RESUMO

UNLABELLED: Motivated by the question of whether and how a state-of-the-art regional chemical transport model (CTM) can facilitate characterization of CO2 spatiotemporal variability and verify CO2 fossil-fuel emissions, we for the first time applied the Community Multiscale Air Quality (CMAQ) model to simulate CO2. This paper presents methods, input data, and initial results for CO2 simulation using CMAQ over the contiguous United States in October 2007. Modeling experiments have been performed to understand the roles of fossil-fuel emissions, biosphere-atmosphere exchange, and meteorology in regulating the spatial distribution of CO2 near the surface over the contiguous United States. Three sets of net ecosystem exchange (NEE) fluxes were used as input to assess the impact of uncertainty of NEE on CO2 concentrations simulated by CMAQ. Observational data from six tall tower sites across the country were used to evaluate model performance. In particular, at the Boulder Atmospheric Observatory (BAO), a tall tower site that receives urban emissions from Denver CO, the CMAQ model using hourly varying, high-resolution CO2 fossil-fuel emissions from the Vulcan inventory and Carbon Tracker optimized NEE reproduced the observed diurnal profile of CO2 reasonably well but with a low bias in the early morning. The spatial distribution of CO2 was found to correlate with NO(x), SO2, and CO, because of their similar fossil-fuel emission sources and common transport processes. These initial results from CMAQ demonstrate the potential of using a regional CTM to help interpret CO2 observations and understand CO2 variability in space and time. The ability to simulate a full suite of air pollutants in CMAQ will also facilitate investigations of their use as tracers for CO2 source attribution. This work serves as a proof of concept and the foundation for more comprehensive examinations of CO2 spatiotemporal variability and various uncertainties in the future. IMPLICATIONS: Atmospheric CO2 has long been modeled and studied on continental to global scales to understand the global carbon cycle. This work demonstrates the potential of modeling and studying CO2 variability at fine spatiotemporal scales with CMAQ, which has been applied extensively, to study traditionally regulated air pollutants. The abundant observational records of these air pollutants and successful experience in studying and reducing their emissions may be useful for verifying CO2 emissions. Although there remains much more to further investigate, this work opens up a discussion on whether and how to study CO2 as an air pollutant.


Assuntos
Poluentes Atmosféricos/análise , Dióxido de Carbono/análise , Monóxido de Carbono/análise , Monitoramento Ambiental/métodos , Combustíveis Fósseis , Modelos Teóricos , Dióxido de Enxofre/análise , Atmosfera/química , Clima , Óxido Nitroso/análise , Material Particulado/análise , Análise Espaço-Temporal , Estados Unidos
11.
J Stomatol Oral Maxillofac Surg ; 124(2): 101309, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36252929

RESUMO

OBJECTIVE: This study aimed to determine the incidence and clinicopathological patterns of metastatic carcinoma of the parotid gland. METHOD: Ninety patients with parotid gland metastases admitted to our hospital between January 2003 and December 2018 were included in this study. Clinical and pathological data were obtained from the medical records and follow-ups. Kaplan-Meier analysis was used to assess overall survival of patients. RESULTS: Among the 90 patients, parotid gland metastases originated from the head and neck in 86 (95.6%), from non-head and neck in 4 (4.4%), from the oral cavity in 30(33.3%), and from the eyelid in 21 (23.3%). Among the 85 cases with parotid gland lymph node metastasis, 45 (52.9%) were diagnosed with extra-lymph node metastasis. The capsule of the parotid lymph nodes was thinner than that of the cervical lymph nodes (P < 0.05). Hematogenous metastases to the parotid gland (only five cases) were rare, mainly from the non-head and neck malignancies. Patients with oral squamous cell carcinoma and meibomian adenocarcinoma with parotid metastatic disease had poorer overall survival (P < 0.05). CONCLUSION: Eastern China population analysis showed that parotid gland metastases usually arise from oral squamous cell carcinoma and eyelid, but rarely from cutaneous squamous cell carcinoma. Most cases metastasize to the parotid lymph nodes via the lymphatic system and are prone to extranodal extension with little or no facial nerve involvement. These findings have important implications for the treatment of metastatic parotid malignancies.


Assuntos
Neoplasias Bucais , Neoplasias Parotídeas , Neoplasias Cutâneas , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , População do Leste Asiático , Metástase Linfática , Neoplasias Bucais/patologia , Glândula Parótida/patologia , Neoplasias Parotídeas/epidemiologia , Neoplasias Parotídeas/secundário , Neoplasias Cutâneas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
13.
Cell Chem Biol ; 30(6): 591-605.e4, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37263275

RESUMO

The cGAS-STING pathway has long been recognized as playing a crucial role in immune surveillance and tumor suppression. Here, we show that when the pathway is activated in a cancer-cell-autonomous response manner, it confers drug resistance. Targeted or conventional chemotherapy drugs promoted cytosolic DNA accumulation in cancer cells, activating the cGAS-STING pathway and downstream TBK1-IRF3/NF-κB signaling. This cancer cell-intrinsic response enabled the cells to counteract drug stress, allowing treatment resistance to be acquired and maintained. Blockade of stimulator of interferon genes (STING) signaling delayed and overcame resistance in models in vitro and in vivo. This finding uncovers an alternative face of cGAS-STING signaling other than the well-reported modulation of microenvironmental immune cells. It also implies a caution for the combination of STING agonist with targeted or conventional chemotherapy drug treatment, a strategy prevailing in current clinical trials.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Proteínas de Membrana , Neoplasias , Nucleotidiltransferases , DNA/metabolismo , Neoplasias/tratamento farmacológico , NF-kappa B/metabolismo , Nucleotidiltransferases/metabolismo , Transdução de Sinais , Proteínas de Membrana/metabolismo
14.
Front Oncol ; 12: 1031944, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36338767

RESUMO

Cells experience both endogenous and exogenous DNA damage daily. To maintain genome integrity and suppress tumorigenesis, individuals have evolutionarily acquired a series of repair functions, termed DNA damage response (DDR), to repair DNA damage and ensure the accurate transmission of genetic information. Defects in DNA damage repair pathways may lead to various diseases, including tumors. Accumulating evidence suggests that alterations in DDR-related genes, such as somatic or germline mutations, single nucleotide polymorphisms (SNPs), and promoter methylation, are closely related to the occurrence, development, and treatment of head and neck squamous cell carcinoma (HNSCC). Despite recent advances in surgery combined with radiotherapy, chemotherapy, or immunotherapy, there has been no substantial improvement in the survival rate of patients with HNSCC. Therefore, targeting DNA repair pathways may be a promising treatment for HNSCC. In this review, we summarized the sources of DNA damage and DNA damage repair pathways. Further, the role of DNA damage repair pathways in the development of HNSCC and the application of small molecule inhibitors targeting these pathways in the treatment of HNSCC were focused.

15.
Sci Bull (Beijing) ; 67(5): 547-556, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36546176

RESUMO

Reconstruction of natural streamflow is fundamental to the sustainable management of water resources. In China, previous reconstructions from sparse and poor-quality gauge measurements have led to large biases in simulation of the interannual and seasonal variability of natural flows. Here we use a well-trained and tested land surface model coupled to a routing model with flow direction correction to reconstruct the first high-quality gauge-based natural streamflow dataset for China, covering all its 330 catchments during the period from 1961 to 2018. A stronger positive linear relationship holds between upstream routing cells and drainage areas, after flow direction correction to 330 catchments. We also introduce a parameter-uncertainty analysis framework including sensitivity analysis, optimization, and regionalization, which further minimizes biases between modeled and inferred natural streamflow from natural or near-natural gauges. The resulting behavior of the natural hydrological system is represented properly by the model which achieves high skill metric values of the monthly streamflow, with about 83% of the 330 catchments having Nash-Sutcliffe efficiency coefficient (NSE) > 0.7, and about 56% of the 330 catchments having Kling-Gupta efficiency coefficient (KGE) > 0.7. The proposed construction scheme has important implications for similar simulation studies in other regions, and the developed low bias long-term national datasets by statistical postprocessing should be useful in supporting river management activities in China.


Assuntos
Rios , Recursos Hídricos , Simulação por Computador , Hidrologia , China
16.
Cancer Res ; 82(19): 3516-3531, 2022 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-36193649

RESUMO

Emerging evidence demonstrates that the dysregulated metabolic enzymes can accelerate tumorigenesis and progression via both metabolic and nonmetabolic functions. Further elucidation of the role of metabolic enzymes in EGFR inhibitor resistance and metastasis, two of the leading causes of death in lung adenocarcinoma, could help improve patient outcomes. Here, we found that aberrant upregulation of phosphoserine aminotransferase 1 (PSAT1) confers erlotinib resistance and tumor metastasis in lung adenocarcinoma. Depletion of PSAT1 restored sensitivity to erlotinib and synergistically augmented the tumoricidal effect. Mechanistically, inhibition of PSAT1 activated the ROS-dependent JNK/c-Jun pathway to induce cell apoptosis. In addition, PSAT1 interacted with IQGAP1, subsequently activating STAT3-mediated cell migration independent of its metabolic activity. Clinical analyses showed that PSAT1 expression positively correlated with the progression of human lung adenocarcinoma. Collectively, these findings reveal the multifunctionality of PSAT1 in promoting tumor malignancy through its metabolic and nonmetabolic activities. SIGNIFICANCE: Metabolic and nonmetabolic functions of PSAT1 confer EGFR inhibitor resistance and promote metastasis in lung adenocarcinoma, suggesting therapeutic targeting of PSAT1 may attenuate the malignant features of lung cancer.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Cloridrato de Erlotinib/farmacologia , Cloridrato de Erlotinib/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transaminases/metabolismo
17.
J Mol Graph Model ; 109: 108027, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34534891

RESUMO

Aß42 peptides can form helix and sheet structure under different conditions. The conformational conversion is closely associated with Aß peptides aggregation and their neurotoxicity. But the transition from helix to sheet is not be clearly understood. In this study we performed microsecond timescale MD simulations of Aß42 peptide to investigate the conformation transition from α-helix to ß-sheet. Markov state model (MSM) was built to facilitate identification of crucial intermediate states and possible transition pathway. Based on the analysis, we found that the region Y10-A21 in the middle of Aß42 peptide plays an initial role in this transition. MSM model revealed that the collapse of helical structure in this region might trigger the formation of sheet structure. Moreover, we further simulated the aggregation of Aß42 peptides with different conformations. We found that the Aß42 peptides forming sheet structure have higher aggregation potential compared with peptides with helix structure. These results demonstrate that we can prevent the aggregation of Aß42 peptides by stabilizing the helix structure in the region of Y10-A21. In addition, this study provides new insight into better understanding the conformational transition and aggregation of Aß42 peptides.


Assuntos
Peptídeos beta-Amiloides , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos , Conformação Proteica em alfa-Hélice
18.
Sci Total Environ ; 796: 148993, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34273830

RESUMO

The characteristics of soil respiration (Rs) in semiarid regions are important with regard to the carbon cycle of complex underlying surfaces and estimation of carbon emissions from regional ecosystems. During the growing season (May-September 2016), in situ observations of Rs were obtained concurrently with measurements of soil bacteria (Bs), soil moisture (Ms), and soil temperature (Ts) at depths of 0-10 cm, in a dune-meadow cascade ecosystem. Results showed that Rs differences among the various ecosystems were significant (P < 0.01), the intensity of Rs in meadows was twice stronger than that in dunes. The average values of Rs presenting a declined trend follows MPA (11.19 µmol m-2 s-1) > MAF (7.75) > SSG (6.78) > SMAH (5.02) > SFAH (4.8) > FLC (4.28) > SBG (3.09). An extremely significant (p < 0.01) positive correlated power relationship can be found between Rs and Bs, which could explain 62.41%-86.56% of the variation in Rs in the various ecosystems. Field capacity and the saturated water content were the key demarcation points for the interactive relationship between Rs and Ms, which showing a significant (P < 0.05) positive correlated power relationship in dunes, in contrast, it presenting a significant (P < 0.05) negative correlated exponential relationship in meadows. Rs was positively exponentially correlated with Ts, significant (P < 0.05) in meadows and nonsignificant (P > 0.05) in dunes. Future research should be strengthened to consider multiple growing seasons experiencing various climatic conditions for accurate estimation of terrestrial carbon emissions in arid and semiarid ecosystems.


Assuntos
Ecossistema , Solo , Ciclo do Carbono , Pradaria , Respiração
19.
Sci Total Environ ; 795: 148736, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34247070

RESUMO

Accurately estimating evapotranspiration (ET) for meadow wetland ecosystems is of great significance for water management in semiarid regions. Taking a meadow wetland ecosystem in the Horqin Sandy Land as an example, this study coupled the Ball-Berry canopy stomatal conductance model to Penman-Monteith (P-M) model and Shuttleworth-Wallace (S-W) model, and the improved P-M model and SWH model were calibrated and validated by long-term (2013-2018 growing seasons) eddy covariance (EC) measurements. The results indicated that the improved P-M model and SWH model performed well either at half-hourly or daily timescales, with high coefficient of determination (R2) and index of agreement (IA) and low root mean square error (RMSE). Generally, the SWH model performed better than the improved P-M model, especially under the low leaf area index (LAI) conditions. In addition, in the growing seasons from 2013 to 2018, the mean ET measured by the EC system was 2.78 mm/d, which was approximately equal to the mean modeled ET from the SWH model (2.75 mm/d) and slightly higher than the mean modeled ET from the improved P-M model (2.34 mm/d). The improved P-M model and SWH model were highly sensitive to the parameter in estimating canopy surface resistance and to vapor pressure deficit (VPD) in meteorological variables.


Assuntos
Ecossistema , Transpiração Vegetal , Pradaria , Água , Áreas Alagadas
20.
Sci Total Environ ; 794: 148684, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34214805

RESUMO

Soil respiration (RS) is affected by many factors and shows significant diurnal and seasonal changes at different spatial and temporal scales. However, in a semi-arid steppe, the mechanism of the dynamic influence of environmental factors on RS is not clear, and the effect of subtle changes of soil water on RS under drought stress is yet to be explored. Therefore, Xilin River Basin, was the study area and a hydrological gradient on the four ecosystems for RS and hydrometeorological monitoring was selected. We proposed the use of dynamic sunrise and sunset time to distinguish day from night and determine related statistics. Additionally, we analyzed the temporal variation of RS and its response process and mechanism for hydrometeorological factors during the growing season and at daily scales. Further, we quantitatively simulated the RS of 594 scenarios in different growing season stages, ecosystems, and precipitation patterns. Results showed that: (1) in the hydrological gradient belt, different ecosystems exhibited the same trend but different characteristics of RS regulation. From May to November 2020, RS was 2.34-3.89, 1.89-5.97, 1.90-5.27 and 2.29-3.45 gC m-2 day-1 for the four ecosystems. (2) The use of dynamic sunrise and sunset time to distinguish day and night can more accurately describe the statistical value of each variable, which exhibits remarkable feasibility in daily scale research. (3) The changes in RS were adequately explained by temperature at various time scales, and the photosynthetically active radiation was positively correlated with RS at the daily scale. The special soil water content (MS) condition in the study area was not sufficient to explain RS. (4) Precipitation can affect RS by changing soil and air; however, only when precipitation exceeds the effective precipitation threshold of 0.6 ± 0.3 mm, it significantly affects RS.


Assuntos
Ecossistema , Solo , China , Pradaria , Respiração , Estações do Ano
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