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1.
Artigo em Inglês | MEDLINE | ID: mdl-36125687

RESUMO

The aim of this study is to further investigate the single and cumulative associations of SO2 on outpatient visits for conjunctivitis. Data from outpatient visits, air pollutants, and meteorology was collected by the Eye Center of the Second Affiliated Hospital of the Zhejiang University School of Medicine, the Environmental Protection Department of Zhejiang Province, and the Meteorological Administration of Zhejiang Province from July 1, 2014, to November 30, 2019. A Poisson generalized linear regression model (PGLM), combined with a distributed lag nonlinear model (DLNM), was employed to analyze the association between SO2 and outpatient visits for conjunctivitis using PM2.5 and NO2 as covariates. Of the 539,649 outpatients for conjunctivitis recruited for analysis, 58.1% were female. Obvious single associations of SO2 were observed in outpatient visits for conjunctivitis, which is consistent with our previous results using a time-stratified case crossover design. A delay in the associations of SO2 on outpatient visits for conjunctivitis was further confirmed, with the longest lag being 12 days. The strongest lag effect was found at lag 0-11 with RR95th vs 25th = 1.30 (1.24, 1.37), and RR90h vs 25th = 1.23 (1.18, 1.28). Furthermore, the results showed that old people may be more sensitive to the associations of SO2 than adults and the younger ones. Our study provides the first evidence that outpatient visits for conjunctivitis are positively associated with both single and cumulative air pollutant SO2 exposure, suggesting that people especially elders had better to decrease outdoor activities when the SO2 concentration is above safe level.

2.
Artigo em Inglês | MEDLINE | ID: mdl-36137841

RESUMO

OBJECTIVES: The prognosis of patients with locally advanced esophageal squamous cell carcinoma with different recurrence backgrounds is highly heterogeneous. This study aims to explore the effects of recurrence patterns on prognosis. METHODS: The phase III, multicenter, prospective NEOCRTEC5010 trial enrolled 451 patients with stage IIB-III esophageal squamous cell carcinoma randomly assigned to neoadjuvant chemoradiotherapy combined with surgery (NCRT group) or surgery alone (S group) and followed them long-term. We investigated the effects of recurrence patterns on survival in patients undergoing radical esophagectomy. RESULTS: In total, 353 patients were included in the study. The 5-year overall survival of patients with different recurrence patterns was significantly different: recurrence versus recurrence-free (17.8% vs 89.2%; P < .001), early recurrence versus late recurrence (4.6% vs 51.2%; P < .001), and distant metastasis versus locoregional recurrence (17.0% vs 20.0%; P = .666). Patients with early recurrence had significantly shorter survival after recurrence than those with late recurrence (hazard ratio, 1.541; 95% confidence interval, 1.047-2.268, P = .028). There was no significant difference in postrecurrence survival between patients with distant metastasis and locoregional recurrence (hazard ratio, 1.181; 95% confidence interval, 0.804-1.734; P = .396). Multivariate logistic analysis showed that pN1 stage, lymph node dissection <20, and lack of response to NCRT were independent risk factors for postoperative early recurrence. Multivariate Cox regression suggested that NCRT, age ≥60 years, early recurrence, and the pN1 stage were independent risk factors for shortened survival after recurrence. CONCLUSIONS: Prerecurrence primary tumor stage is inaccurate in predicting postrecurrence survival. In contrast, recurrence patterns can guide follow-up while also predicting postrecurrence survival. NCRT prolongs disease-free survival but is associated with a worse prognosis in patients with recurrence, especially early recurrence.

3.
Front Pharmacol ; 13: 959978, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059984

RESUMO

Purpose: Our previous study observed that human induced pluripotent stem cell (HiPSC)-derived lentoid bodies (LBs) became cloudy with extended culture time, partially mimicking the progress of human age-related cataracts (ARCs) in a dish. In the present study, lanosterol, a potential anticataract drug, was used to further verify the value of this model in drug screening for cataract treatment. Methods: Mature LBs on day 25, which were differentiated from HiPSCs using the "fried egg" method, were continually cultured and treated with either dimethyl sulfoxide (control) or lanosterol. The LBs' shape and opacity alterations were examined using light microscopy and mean gray value evaluation. The soluble and insoluble proteins were examined through SDS-PAGE gel electrophoresis combined with Coomassie blue staining. The protein aggregations were examined with immunofluorescence. Results: The mature LBs became cloudy with an extended culture time, and the opacification of the LBs was partially prevented by lanosterol treatment. There was less increase in insoluble proteins in the lanosterol-treated LBs than in the control group. There were also fewer cells containing aggregated protein (αA-crystallin and αB-crystallin) puncta in the lanosterol-treated LBs than in the control LBs. Conclusion: It was found that the opacification of LBs could be delayed by lanosterol treatment, which could be achieved by reducing protein aggregation, suggesting a promising HiPSC-derived drug-screening model for Age-related cataract.

4.
Int J Mol Sci ; 23(16)2022 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-36012343

RESUMO

Crop growth and yield often face sophisticated environmental stresses, especially the low availability of mineral nutrients in soils, such as deficiencies of nitrogen, phosphorus, potassium, and others. Thus, it is of great importance to understand the mechanisms of crop response to mineral nutrient deficiencies, as a basis to contribute to genetic improvement and breeding of crop varieties with high nutrient efficiency for sustainable agriculture. With the advent of large-scale omics approaches, the metabolome based on mass spectrometry has been employed as a powerful and useful technique to dissect the biochemical, molecular, and genetic bases of metabolisms in many crops. Numerous metabolites have been demonstrated to play essential roles in plant growth and cellular stress response to nutrient limitations. Therefore, the purpose of this review was to summarize the recent advances in the dissection of crop metabolism responses to deficiencies of mineral nutrients, as well as the underlying adaptive mechanisms. This review is intended to provide insights into and perspectives on developing crop varieties with high nutrient efficiency through metabolite-based crop improvement.


Assuntos
Nitrogênio , Fósforo , Metaboloma , Minerais , Nitrogênio/metabolismo , Nutrientes/análise , Fósforo/metabolismo , Melhoramento Vegetal , Potássio
5.
Front Public Health ; 10: 963257, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36033732

RESUMO

Aims: Antidepressants have aroused wide public concern due to their widespread presence in water and their harm to human health and environment. This study was designed to evaluate the contribution of wastewater treatment plants (WWTPs) to the presence of antidepressants in the surface water. Methods: Data was evaluated by analyzing water samples collected from the influent, effluent, upstream and downstream of the WWTPs on the rivers of interest in Hangzhou, Zhejiang Province, China. Besides, the study also assessed the impact of the release of antidepressants from WWTPs to the surface water on the drinking water. An automatic solid-phase extraction combined with ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry (UPLC-MS/MS) was used to detect antidepressants. Results: The most abundant compound was venlafaxine, followed by citalopram, sertraline, and fluvoxamine with concentrations between 0.6 and 87 ng/L. Antidepressants showed maximum concentrations at the effluent outlets of the WWTPs, and greater concentrations were found downstream than upstream of the WWTPs in Qiantang River. The results of source water and finished water showed that the detection concentration was lower than the detection limit of the method. Conclusions: The less impact of the release of antidepressants from WWTPs to the surface water on the drinking water was identified. Nevertheless, these compounds were hardly removed by wastewater treatment processes. Thus, their risks deserve close attention.


Assuntos
Água Potável , Poluentes Químicos da Água , Purificação da Água , Antidepressivos , China , Cromatografia Líquida , Monitoramento Ambiental , Humanos , Espectrometria de Massas em Tandem
6.
Biochem Biophys Res Commun ; 625: 16-22, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-35944359

RESUMO

Esophageal cancer is one of the most common malignant tumors worldwide and half of the patients present tumor metastasis at initial diagnosis. CXCR4 has been reported to be upregulated in esophageal cancer tissues and associated with tumor metastasis. However, the upstream transcriptional regulator of CXCR4 in esophageal cancer is still unclear. In this study, we found that transcription factor FOXA2 directly bound on the CXCR4 promoter region and activated its expression in esophageal cancer cells. The expression of FOXA2 was upregulated in esophageal cancer tissues and positively correlated with CXCR4. Moreover, knockout of FOXA2 significantly inhibited esophageal cancer migration and metastasis, which can be rescued by ectopically expressed CXCR4. Taken together, we reveal a novel transcriptional activator of CXCR4 in esophageal cancer, which might provide new strategies for esophageal cancer treatment.


Assuntos
Neoplasias Esofágicas , Receptores CXCR4 , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Esofágicas/patologia , Regulação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Fator 3-beta Nuclear de Hepatócito/genética , Fator 3-beta Nuclear de Hepatócito/metabolismo , Humanos , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo
7.
World J Gastroenterol ; 28(21): 2361-2382, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35800181

RESUMO

BACKGROUND: Primary liver cancer (PLC) is a major contributor to cancer-related deaths. Data on global and country-specific levels and trends of PLC are essential for understanding the effects of this disease and helping policymakers to allocate resources. AIM: To investigate the association between the burden of PLC and socioeconomic development status. METHODS: Cancer mortality and incidence rates were obtained from the Global Burden of Disease (GBD) 2019, and the data were stratified by country and territory, sex, and the Socio-demographic Index (SDI) level. The association between the attributable etiology of PLC and socioeconomic development status, represented using the SDI, was described. The attributable etiology of PLC included hepatitis B, hepatitis C, alcohol use, and nonalcoholic steatohepatitis. The association between the attributable etiology of PLC and SDI was further stratified by sex and geographical location. A confidence analysis was also performed based on bootstrap draw. RESULTS: The age-standardized incidence rate of PLC was 6.5 [95% confidence intervals (CI): 5.9-7.2] per 100000 person-years, which decreased by -27.5% (-37.0 to -16.6) from 1990 to 2019. Several countries located in East Asia, South Asia, West Africa, and North Africa shouldered the heaviest burden of PLC in 2019. In terms of incidence rates, the first leading underlying cause of PLC identified was hepatitis B, followed by hepatitis C, alcohol use, and nonalcoholic steatohepatitis. Regarding stratification using the SDI, the incidence rate of PLC was the highest for high and middle SDI locations. Further, the leading attributable etiologies of PLC were hepatitis B for the middle and high middle SDI locations while hepatitis C and nonalcoholic steatohepatitis for the high SDI locations. CONCLUSION: The pronounced association between socioeconomic development status and PLC burden indicates socioeconomic development status affects attributable etiologies for PLC. GBD 2019 data are valuable for policymakers implementing PLC cost-effective interventions.


Assuntos
Hepatite B , Hepatite C , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Saúde Global , Hepatite B/complicações , Hepatite B/epidemiologia , Hepatite C/complicações , Hepatite C/epidemiologia , Humanos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Anos de Vida Ajustados por Qualidade de Vida , Fatores Socioeconômicos
8.
Chemosphere ; 307(Pt 1): 135676, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35842053

RESUMO

To evaluate the body burdens of heavy metals and explore the impact of environmental metal exposure on ribosomal DNA (rDNA) or mitochondrial DNA (mtDNA) copy number (CN) variation in school-age children living near a municipal waste incinerator (MWI), we conducted a follow-up study in 2019. A total of 146 sixth-grade children from a primary school located 1.2 km away from the MWI were recruited for our study. Metals, including vanadium (V), chromium (Cr), manganese (Mn), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), selenium (Se), cadmium (Cd), stannum (Sn), stibium (Sb), thallium (Tl), and lead (Pb), were determined by an inductively coupled plasma mass spectrometer method. Real-time qPCR was used to measure the rDNA and mtDNA CN. The blood metal levels followed this order: Zn > Cu > Se > Pb > Mn > Sb > As > Ni > Cd > Co > Cr > Sn > V > Tl. Blood Cr level was significantly correlated with 18 S, 2.5 S, and 45 S CN (ß = -0.25, -0.22, -0.26, p < 0.05); Ni was correlated with 5 S (ß = -0.36, p < 0.01); Cu was correlated with 28 S, 18 S, and 5.8 S (ß = -0.24, -0.24, -0.23, p < 0.05); while Zn was correlated with 18 S, 5.8 S, and 45 S (ß = -0.28, -0.32, -0.26, p < 0.05). In conclusion, school-age children living near the MWI had lower blood metal levels compared to children recruited in 2013, while rDNA CN loss was found to be correlated to several heavy metals in these children.

9.
Artigo em Inglês | MEDLINE | ID: mdl-35658129

RESUMO

The performance degradation of perovskite solar cells (PSCs) under harsh environment (e.g., heat, moisture, light) is one of the greatest challenges for their commercialization. Herein, a conjugated sulfide 2-mercaptobenzimidazole (2MBI) is applied to significantly improve the photovoltaic properties and thermal stability of PSCs. When treated with heat, 2MBI cross-links with each other on the perovskite surface to facilitate charge transportation, suppress the escape of volatile species, and guide the rearrangement of surface perovskite grains. PSCs with 2MBI modification reach a PCE as high as 21.7% and maintain high-efficiency output during and after thermodestruction at 85 °C, while the unmodified ones suffer severe degradation. Unencapsulated devices after thermodestruction achieve over 98% of initial efficiency after 40-day storage under ambient conditions.

10.
Sci Total Environ ; 838(Pt 4): 156563, 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-35690207

RESUMO

This study was the first to explore the effect of airborne fine particulate matter (PM2.5) exposure on the inner blood-retinal barrier (iBRB). In this study, retinal vascular permeability and diameter were enhanced in the PM2.5-exposed animal model (1 mg/mL PM2.5, 10 µL per eye, 4 times per day, 3 days), together with observable retinal edema and increased inflammation level in retina. PM2.5-induced cell damage in human retinal microvascular endothelial cells (HRMECs) occurred in a time- and dose-dependent manner. Decreased cell viability, proliferation, migration, and angiogenesis, as well as increased apoptosis and inflammation, were observed. Iron overload and excessive lipid oxidation were also discovered after PM2.5 exposure (25, 50, and 100 µg/mL PM2.5 for 24 h), along with significantly altered expression of ferroptosis-related genes, such as prostaglandin-endoperoxide synthase 2, glutathione peroxidase 4, and ferritin heavy chain 1. Moreover, Ferrostatin-1, an inhibitor of ferroptosis, evidently alleviated the PM2.5-induced cytotoxicity of HRMECs. The present study investigated the in vivo effects of PM2.5 on retinas, revealing that PM2.5 exposure induced retinal inflammation, vascular dilatation, and caused damage to the iBRB. The crucial role of ferroptosis was discovered during PM2.5-induced HRMEC cytotoxicity and dysfunction, indicating a potential precautionary target in air pollution-associated retinal vascular diseases.


Assuntos
Ferroptose , Material Particulado , Animais , Barreira Hematorretiniana , Células Endoteliais/metabolismo , Inflamação/induzido quimicamente , Material Particulado/metabolismo , Material Particulado/toxicidade , Retina
11.
Chem Commun (Camb) ; 58(55): 7662-7665, 2022 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-35726543

RESUMO

The kinetic assembly pathways of a newly synthesized amphiphilic aza-BODIPY dye 1 were tuned by using H2O as a co-solvent in MeOH. Accordingly, the biphasic aggregation pathways resulting in kinetically-trapped and thermodynamically stable aggregates of 1 were established and the multiple cyclic seeded living supramolecular polymerization of this dye was realized.


Assuntos
Compostos de Boro , Água , Cinética , Polimerização
12.
Proc Natl Acad Sci U S A ; 119(25): e2206046119, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35704758

RESUMO

Nuclear speckles are non-membrane-bound organelles known as storage sites for messenger RNA (mRNA) processing and splicing factors. More recently, nuclear speckles have also been implicated in splicing and export of a subset of mRNAs, including the influenza virus M mRNA that encodes proteins required for viral entry, trafficking, and budding. However, little is known about how nuclear speckles are assembled or regulated. Here, we uncovered a role for the cellular protein kinase TAO2 as a constituent of nuclear speckles and as a factor required for the integrity of these nuclear bodies and for their functions in pre-mRNA splicing and trafficking. We found that a nuclear pool of TAO2 is localized at nuclear speckles and interacts with nuclear speckle factors involved in RNA splicing and nuclear export, including SRSF1 and Aly/Ref. Depletion of TAO2 or inhibition of its kinase activity disrupts nuclear speckle structure, decreasing the levels of several proteins involved in nuclear speckle assembly and splicing, including SC35 and SON. Consequently, splicing and nuclear export of influenza virus M mRNA were severely compromised and caused a disruption in the virus life cycle. In fact, low levels of TAO2 led to a decrease in viral protein levels and inhibited viral replication. Additionally, depletion or inhibition of TAO2 resulted in abnormal expression of a subset of mRNAs with key roles in viral replication and immunity. Together, these findings uncovered a function of TAO2 in nuclear speckle formation and function and revealed host requirements and vulnerabilities for influenza infection.


Assuntos
Núcleo Celular , Salpicos Nucleares , Proteínas Quinases , Splicing de RNA , Transporte Ativo do Núcleo Celular , Núcleo Celular/enzimologia , Células HeLa , Humanos , Proteínas Quinases/metabolismo , RNA/metabolismo , RNA Mensageiro/metabolismo , Fatores de Processamento de Serina-Arginina/genética
13.
Cancer Cell Int ; 22(1): 205, 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35642057

RESUMO

BACKGROUND: Colorectal cancer (CRC) is one of the three major cancers in the world and is the cancer with the most liver metastasis. The present study aimed to investigate the role of metallothionein 2A (MT2A) in the modulation of CRC cell proliferation and liver metastasis, as well as its molecular mechanisms. METHODS: The expression profile of metallothionein 2A (MT2A) in colorectal cancer retrieved from TCGA, GEO and Oncomine database. The biological effect of MT2A overexpression was investigated mainly involving cell proliferation and migration in CRC cells as well as growth and metastasis in CRC animal models. To explore the specific mechanism of MT2A metastasis in CRC, transcriptome sequencing was used to compare the overall expression difference between the control group and the MT2A overexpression group. RESULTS: Metallothionein 2A (MT2A) was downregulated in the tumor tissues of patients with CRC compared to adjacent normal tissues and was related to the tumor M stage of patients. MT2A overexpression inhibited CRC cell proliferation and migration in cells, as well as growth and metastasis in CRC animal models. While knockdown of MT2A had the opposite effect in cells. Western blotting confirmed that MT2A overexpression promoted the phosphorylation of MST1, LAST2 and YAP1, thereby inhibiting the Hippo signaling pathway. Additionally, specific inhibitors of MST1/2 inhibited MT2A overexpression-mediated phosphorylation and relieved the inhibition of the Hippo signaling pathway, thus promoting cell proliferation. Immunohistochemistry in subcutaneous grafts and liver metastases further confirmed this result. CONCLUSIONS: Our results suggested that MT2A is involved in CRC growth and liver metastasis. Therefore, MT2A and MST1 may be potential therapeutic targets for patients with CRC, especially those with liver metastases.

14.
Comput Struct Biotechnol J ; 20: 2212-2222, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35530743

RESUMO

Coronavirus disease 2019 (COVID-19) caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide as a severe pandemic and caused enormous global health and economical damage. Since December 2019, more than 197 million cases have been reported, causing 4.2 million deaths. In the settings of pandemic it is an urgent necessity for the development of an effective COVID-19 treatment. While in-vitro screening of hundreds of antibodies isolated from convalescent patients is challenging due to its high cost, use of computational methods may provide an attractive solution in selecting the top candidates. Here, we developed a computational approach (SARS-AB) for binding prediction of spike protein SARS-CoV-2 with monoclonal antibodies. We validated our approach using existing structures in the protein data bank (PDB), and demonstrated its prediction power in antibody-spike protein binding prediction. We further tested its performance using antibody sequences from the literature where crystal structure is not available, and observed a high prediction accuracy (AUC = 99.6%). Finally, we demonstrated that SARS-AB can be used to design effective antibodies against novel SARS-CoV-2 mutants that might escape the current antibody protections. We believe that SARS-AB can significantly accelerate the discovery of neutralizing antibodies against SARS-CoV-2 and its mutants.

15.
Small ; 18(22): e2107161, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35527340

RESUMO

All-inorganic lead-free Cs3 Cu2 I5  perovskite-derivant quantum dots (QDs) have attracted tremendous attention due to their nontoxicity and unique optoelectronic properties. However, the traditional hot-injection method requires high temperatures and multiple ligands to confine the growth of QDs. Herein, a strategy is reported to spontaneously synthesize ultrasmall Cs3 Cu2 I5  QDs within metal-organic-frameworks (MOFs) MOF-74 at room temperature (RT) with an average diameter of 4.33 nm. The obtained Cs3 Cu2 I5  QDs exhibit an evident deep-blue emission with Commission Internationale de L'Eclairage coordinates of (0.17, 0.07), owing to the strong quantum confinement effect. Due to the protection of MOF-74, the Cs3 Cu2 I5  QDs demonstrate superior stability, and the photoluminescence quantum yield retains 89% of the initial value after the storage of 1440 h under the environment with relative humidity exceeding 70%. Besides, triplet-triplet annihilation upconversion emission is observed within the composite of Cs3 Cu2 I5 @MOF-74, which brings out apparent temperature-dependent photoluminescence. This study reveals a facile method for fabricating ultrasmall lead-free perovskite-derivant QDs at RT without multiple ligands. Besides, the temperature-dependent photoluminescence of Cs3 Cu2 I5 @MOF-74 may open up a new way to develop the applications of temperature sensors or other related optoelectronic devices.

16.
Artigo em Inglês | MEDLINE | ID: mdl-35597825

RESUMO

Chronic obstructive pulmonary disease (COPD) is a leading cause of death in people aged over 60 years old. Research has been reported that ambient temperature and diurnal temperature range (DTR), as representative indices of temperature variability, are contributors to the development and exacerbation of COPD. However, few studies are available in Chinese population. In this study, we aimed to assess the associations of temperature variability on COPD mortality in a fast developing city in China. Using the mortality surveillance system, we obtained a total of 7,863 deaths attributed to COPD from 2014 to 2016. Quasi-Poisson generalized linear regression with distributed lag non-linear model was applied to explore the associations between temperature variability and COPD deaths, after controlling for the potential confounders, including relative humidity, day of week, public holiday, and long-term trend. A J-shaped association of DTR and a reversely J-shaped association of temperature for COPD mortality were observed. Risk estimates showed that the relative risks (RRs) of COPD mortality with extreme high DTR at lag 0 and 0-7 days were 1.045 (95% CI: 0.949-1.151) and 1.460 (95% CI: 1.118-1.908), and the extreme high temperature at lag 0 and 0-7 days were 1.090 (95% CI: 0.945-1.256) and 1.352 (95% CI: 1.163-1.572). Our findings suggest that short-term exposure to extreme temperature was associated with mortality for COPD in Hangzhou. The evidence has implications for policy decision-making and targeted interventions.

17.
Cancer Immunol Res ; 10(7): 829-843, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35561311

RESUMO

The MYC oncogene is frequently amplified in triple-negative breast cancer (TNBC). Here, we show that MYC suppression induces immune-related hallmark gene set expression and tumor-infiltrating T cells in MYC-hyperactivated TNBCs. Mechanistically, MYC repressed stimulator of interferon genes (STING) expression via direct binding to the STING1 enhancer region, resulting in downregulation of the T-cell chemokines CCL5, CXCL10, and CXCL11. In primary and metastatic TNBC cohorts, tumors with high MYC expression or activity exhibited low STING expression. Using a CRISPR-mediated enhancer perturbation approach, we demonstrated that MYC-driven immune evasion is mediated by STING repression. STING repression induced resistance to PD-L1 blockade in mouse models of TNBC. Finally, a small-molecule inhibitor of MYC combined with PD-L1 blockade elicited a durable response in immune-cold TNBC with high MYC expression, suggesting a strategy to restore PD-L1 inhibitor sensitivity in MYC-overexpressing TNBC.


Assuntos
Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias de Mama Triplo Negativas , Animais , Antígeno B7-H1 , Linhagem Celular Tumoral , Repressão Epigenética , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Evasão da Resposta Imune , Camundongos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
18.
Mol Cell ; 82(13): 2415-2426.e5, 2022 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-35477005

RESUMO

The NF-κB essential modulator (NEMO) is a regulatory subunit of the IκB kinase (IKK) complex that phosphorylates the NF-κB inhibitors IκBs. NEMO mediates IKK activation by binding to polyubiquitin chains (polyUb). Here, we show that Lys63(K63)-linked or linear polyUb binding to NEMO robustly induced the formation of liquid-like droplets in which IKK was activated. This liquid phase separation of NEMO was driven by multivalent interactions between NEMO and polyUb. Both the NEMO ubiquitin-binding (NUB) domain and the zinc-finger (ZF) domain of NEMO mediated binding to polyUb and contributed to NEMO phase separation and IKK activation in cells. Moreover, NEMO mutations associated with human immunodeficiency impaired its phase separation. These results demonstrate that polyUb activates IKK and NF-κB signaling by promoting the phase separation of NEMO.


Assuntos
NF-kappa B , Poliubiquitina , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , NF-kappa B/metabolismo , Poliubiquitina/genética , Transdução de Sinais , Ubiquitina/metabolismo
19.
Mol Cell ; 82(8): 1390-1397, 2022 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-35452608

RESUMO

We asked experts from different fields-from genome maintenance and proteostasis to organelle degradation via ubiquitin and autophagy-"What does quality control mean to you?" Despite their diverse backgrounds, they converge on and discuss the importance of continuous quality control at all levels, context, communication, timing, decisions on whether to repair or remove, and the significance of dysregulated quality control in disease.


Assuntos
Autofagia , Ubiquitina , Proteostase , Ubiquitina/genética , Ubiquitina/metabolismo
20.
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