RESUMO
Lactylation is a lactate-induced post-translational modification best known for its roles in epigenetic regulation. Herein, we demonstrate that MRE11, a crucial homologous recombination (HR) protein, is lactylated at K673 by the CBP acetyltransferase in response to DNA damage and dependent on ATM phosphorylation of the latter. MRE11 lactylation promotes its binding to DNA, facilitating DNA end resection and HR. Inhibition of CBP or LDH downregulated MRE11 lactylation, impaired HR, and enhanced chemosensitivity of tumor cells in patient-derived xenograft and organoid models. A cell-penetrating peptide that specifically blocks MRE11 lactylation inhibited HR and sensitized cancer cells to cisplatin and PARPi. These findings unveil lactylation as a key regulator of HR, providing fresh insights into the ways in which cellular metabolism is linked to DSB repair. They also imply that the Warburg effect can confer chemoresistance through enhancing HR and suggest a potential therapeutic strategy of targeting MRE11 lactylation to mitigate the effects.
Assuntos
Proteínas de Ligação a DNA , Proteína Homóloga a MRE11 , Reparo de DNA por Recombinação , Humanos , DNA , Quebras de DNA de Cadeia Dupla , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Recombinação Homóloga , Proteína Homóloga a MRE11/metabolismo , Ácido Láctico/metabolismoRESUMO
Repair of DNA double-strand breaks (DSBs) elicits three-dimensional (3D) chromatin topological changes. A recent finding reveals that 53BP1 assembles into a 3D chromatin topology pattern around DSBs. How this formation of a higher-order structure is configured and regulated remains enigmatic. Here, we report that SLFN5 is a critical factor for 53BP1 topological arrangement at DSBs. Using super-resolution imaging, we find that SLFN5 binds to 53BP1 chromatin domains to assemble a higher-order microdomain architecture by driving damaged chromatin dynamics at both DSBs and deprotected telomeres. Mechanistically, we propose that 53BP1 topology is shaped by two processes: (1) chromatin mobility driven by the SLFN5-LINC-microtubule axis and (2) the assembly of 53BP1 oligomers mediated by SLFN5. In mammals, SLFN5 deficiency disrupts the DSB repair topology and impairs non-homologous end joining, telomere fusions, class switch recombination, and sensitivity to poly (ADP-ribose) polymerase inhibitor. We establish a molecular mechanism that shapes higher-order chromatin topologies to safeguard genomic stability.
Assuntos
Cromatina , Reparo do DNA , Animais , Cromatina/genética , Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Mamíferos/metabolismo , Proteínas de Ligação a Telômeros/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo , Proteínas de Ciclo Celular/metabolismoRESUMO
The impact of tobacco exposure on health varies by race and ethnicity and is closely tied to internal nicotine dose, a marker of carcinogen uptake. DNA methylation is strongly responsive to smoking status and may mediate health effects, but study of associations with internal dose is limited. We performed a blood leukocyte epigenome-wide association study (EWAS) of urinary total nicotine equivalents (TNEs; a measure of nicotine uptake) and DNA methylation measured using the MethylationEPIC v1.0 BeadChip (EPIC) in six racial and ethnic groups across three cohort studies. In the Multiethnic Cohort Study (discovery, n = 1994), TNEs were associated with differential methylation at 408 CpG sites across >250 genomic regions (p < 9 × 10-8). The top significant sites were annotated to AHRR, F2RL3, RARA, GPR15, PRSS23, and 2q37.1, all of which had decreasing methylation with increasing TNEs. We identified 45 novel CpG sites, of which 42 were unique to the EPIC array and eight annotated to genes not previously linked with smoking-related DNA methylation. The most significant signal in a novel gene was cg03748458 in MIR383;SGCZ. Fifty-one of the 408 discovery sites were validated in the Singapore Chinese Health Study (n = 340) and the Southern Community Cohort Study (n = 394) (Bonferroni corrected p < 1.23 × 10-4). Significant heterogeneity by race and ethnicity was detected for CpG sites in MYO1G and CYTH1. Furthermore, TNEs significantly mediated the association between cigarettes per day and DNA methylation at 15 sites (average 22.5%-44.3% proportion mediated). Our multiethnic study highlights the transethnic and ethnic-specific methylation associations with internal nicotine dose, a strong predictor of smoking-related morbidities.
Assuntos
MicroRNAs , Fumantes , Humanos , Nicotina , Epigênese Genética/genética , Epigenoma , Estudos de Coortes , Estudos Prospectivos , Estudo de Associação Genômica Ampla , Metilação de DNA/genética , Ilhas de CpG/genética , Receptores de Peptídeos/genética , Receptores Acoplados a Proteínas G/genéticaRESUMO
Programmed death ligand 1 (PD-L1, also called B7-H1) is an immune checkpoint protein that inhibits immune function through its binding of the programmed cell death protein 1 (PD-1) receptor. Clinically approved antibodies block extracellular PD-1 and PD-L1 binding, yet the role of intracellular PD-L1 in cancer remains poorly understood. Here, we discovered that intracellular PD-L1 acts as an RNA binding protein that regulates the mRNA stability of NBS1, BRCA1, and other DNA damage-related genes. Through competition with the RNA exosome, intracellular PD-L1 protects targeted RNAs from degradation, thereby increasing cellular resistance to DNA damage. RNA immunoprecipitation and RNA-seq experiments demonstrated that PD-L1 regulates RNA stability genome-wide. Furthermore, we developed a PD-L1 antibody, H1A, which abrogates the interaction of PD-L1 with CMTM6, thereby promoting PD-L1 degradation. Intracellular PD-L1 may be a potential therapeutic target to enhance the efficacy of radiotherapy and chemotherapy in cancer through the inhibition of DNA damage response and repair.
Assuntos
Antígeno B7-H1/genética , Reparo do DNA , DNA de Neoplasias/genética , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Regulação Neoplásica da Expressão Gênica , Receptor de Morte Celular Programada 1/genética , Animais , Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Dano ao DNA , DNA de Neoplasias/metabolismo , Complexo Multienzimático de Ribonucleases do Exossomo/metabolismo , Raios gama/uso terapêutico , Células HCT116 , Células HeLa , Humanos , Proteínas com Domínio MARVEL , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Proteínas da Mielina , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Proteólise/efeitos dos fármacos , Proteólise/efeitos da radiação , Estabilidade de RNA/efeitos dos fármacos , Estabilidade de RNA/efeitos da radiação , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Nuclear actin-based movements support DNA double-strand break (DSB) repair. However, molecular determinants that promote filamentous actin (F-actin) formation on the damaged chromatin remain undefined. Here we describe the DYRK1A kinase as a nuclear activity that promotes local F-actin assembly to support DSB mobility and repair, accomplished in part by its targeting of actin nucleator spire homolog 1 (Spir1). Indeed, perturbing DYRK1A-dependent phosphorylation of S482 mis-regulated Spir1 accumulation at damaged-modified chromatin, and led to compromised DSB-associated actin polymerization and attenuated DNA repair. Our findings uncover a role of the DYRK1A-Spir1 axis in nuclear actin dynamics during early DSB responses, and highlight the intricate details of nuclear cytoskeletal network in DSB repair and genome stability maintenance.
RESUMO
BACKGROUND AND AIMS: Despite the substantial impact of environmental factors, individuals with a family history of liver cancer have an increased risk for HCC. However, genetic factors have not been studied systematically by genome-wide approaches in large numbers of individuals from European descent populations (EDP). APPROACH AND RESULTS: We conducted a 2-stage genome-wide association study (GWAS) on HCC not affected by HBV infections. A total of 1872 HCC cases and 2907 controls were included in the discovery stage, and 1200 HCC cases and 1832 controls in the validation. We analyzed the discovery and validation samples separately and then conducted a meta-analysis. All analyses were conducted in the presence and absence of HCV. The liability-scale heritability was 24.4% for overall HCC. Five regions with significant ORs (95% CI) were identified for nonviral HCC: 3p22.1, MOBP , rs9842969, (0.51, [0.40-0.65]); 5p15.33, TERT , rs2242652, (0.70, (0.62-0.79]); 19q13.11, TM6SF2 , rs58542926, (1.49, [1.29-1.72]); 19p13.11 MAU2 , rs58489806, (1.53, (1.33-1.75]); and 22q13.31, PNPLA3 , rs738409, (1.66, [1.51-1.83]). One region was identified for HCV-induced HCC: 6p21.31, human leukocyte antigen DQ beta 1, rs9275224, (0.79, [0.74-0.84]). A combination of homozygous variants of PNPLA3 and TERT showing a 6.5-fold higher risk for nonviral-related HCC compared to individuals lacking these genotypes. This observation suggests that gene-gene interactions may identify individuals at elevated risk for developing HCC. CONCLUSIONS: Our GWAS highlights novel genetic susceptibility of nonviral HCC among European descent populations from North America with substantial heritability. Selected genetic influences were observed for HCV-positive HCC. Our findings indicate the importance of genetic susceptibility to HCC development.
Assuntos
Carcinoma Hepatocelular , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/genética , Masculino , Feminino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Estudos de Casos e Controles , Polimorfismo de Nucleotídeo Único , Idoso , Loci Gênicos , População Branca/genéticaRESUMO
Stability and localization of p53 is essential for its tumor suppressor function. Ubiquitination by the E3 ubiquitin ligase Mdm2 is the major regulatory mechanism of p53, which induces p53 nuclear export and degradation. However, it is unclear whether ubiquitinated cytoplasmic p53 can be recycled. Here, we report that USP10, a cytoplasmic ubiquitin-specific protease, deubiquitinates p53, reversing Mdm2-induced p53 nuclear export and degradation. After DNA damage, USP10 is stabilized, and a fraction of USP10 translocates to the nucleus to activate p53. The translocation and stabilization of USP10 is regulated by ATM -mediated phosphorylation of USP10 at Thr42 and Ser337. Finally, USP10 suppresses tumor cell growth in cells with wild-type p53, with USP10 expression downregulated in a high percentage of clear cell carcinomas, known to have few p53 mutations. These findings reveal USP10 to be a novel regulator of p53, providing an alternative mechanism of p53 inhibition in cancers with wild-type p53.
Assuntos
Regulação Neoplásica da Expressão Gênica , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina Tiolesterase/metabolismo , Transporte Ativo do Núcleo Celular , Proteínas Mutadas de Ataxia Telangiectasia , Carcinoma de Células Renais/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Células HCT116 , Humanos , Neoplasias Renais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Estabilidade Proteica , Proteína Supressora de Tumor p53/análise , Proteínas Supressoras de Tumor/metabolismo , UbiquitinaçãoRESUMO
We evaluated whether aflatoxin B1 (AFB1 ) exposure was associated with later risk of developing gallbladder cancer (GBC). We measured AFB1 -lysine albumin adducts in baseline samples from the Shanghai Cohort Study of 18 244 men aged 45 to 64 years (recruited 1986-1989). We included 84 GBC cases with sufficient serum and 168 controls matched on age at sample collection, date of blood draw and residence. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for detectable vs non-detectable AFB1 -lysine albumin adducts and gallbladder cancer. AFB1 -lysine albumin adducts were detected in 50.0% of GBC cases, and risk of GBC was twice as high in those with detectable vs undetectable levels (OR = 2.0, 95% CI = 1.0-3.9). ORs ranged from 1.8 (95% CI = 0.75-4.3) for 0.5 to <1.75 pg/mg vs undetectable adduct levels to 2.2 (95% CI = 0.91-5.6) for >3.36 pg/mg vs undetectable, suggesting a dose-response (Ptrend = .05). When restricted to cases diagnosed before the median time to diagnosis after blood draw (18.4 years), results were similar (OR = 2.2, 95% CI = 0.80-5.8) to those for the entire follow-up duration. The OR was 9.4 (95% CI = 1.7-51.1) for individuals with detectable AFB1 -lysine albumin adducts and self-reported gallstones compared to individuals with neither. Participants with detectable AFB1 -lysine albumin adducts at baseline had increased risk of developing GBC, replicating the previously observed association between AFB1 exposure and providing the first evidence of temporality.
Assuntos
Aflatoxinas , Neoplasias da Vesícula Biliar , Masculino , Humanos , Aflatoxinas/toxicidade , Aflatoxinas/análise , Neoplasias da Vesícula Biliar/induzido quimicamente , Neoplasias da Vesícula Biliar/epidemiologia , Estudos de Casos e Controles , Lisina , Estudos de Coortes , China/epidemiologia , Aflatoxina B1/efeitos adversos , Aflatoxina B1/análise , AlbuminasRESUMO
Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. In order to assess this association among Asian women, a total of 308,949 female participants from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). A total of 3,119 primary lung cancer cases and 2247 lung cancer deaths were identified with a mean follow-up of 16.4 years. Parous women had a lower risk of lung cancer incidence and mortality as compared with nulliparous women, with HRs of 0.82 (95% CI = 0.70-0.96) and 0.78 (95% CI = 0.65-0.94). The protective association of parity and lung cancer incidence was greater among ever-smokers (HR = 0.66, 95% CI = 0.49-0.87) than in never-smokers (HR = 0.90, 95% CI = 0.74-1.09) (P-interaction = 0.029). Compared with age at first delivery ≤20 years, older age at first delivery (21-25, ≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Women who ever used hormone replacements had a higher likelihood of developing non-small cell lung cancer (HR = 1.31, 95% CI = 1.02-1.68), compared to those who never used hormone replacements. Future studies are needed to assess the underlying mechanisms, the relationships within these female reproductive factors, and the potential changes in smoking habits over time.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Gravidez , Feminino , Humanos , Incidência , Estudos Prospectivos , Neoplasias Pulmonares/epidemiologia , Ásia/epidemiologia , Hormônios , Fatores de Risco , Modelos de Riscos ProporcionaisRESUMO
The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16-1.70 for 17 years and older vs. 13-14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50-4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08-2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort.
Assuntos
Neoplasias da Vesícula Biliar , Menarca , Humanos , Feminino , Neoplasias da Vesícula Biliar/epidemiologia , Neoplasias da Vesícula Biliar/etiologia , Pessoa de Meia-Idade , Fatores de Risco , Adulto , Ásia/epidemiologia , Idoso , Estudos de Coortes , História Reprodutiva , Modelos de Riscos Proporcionais , Menopausa , Fatores Etários , Adolescente , ParidadeRESUMO
Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m2 ); normal (18.5-22.9 kg/m2 ); overweight (23-24.9 kg/m2 ); and obese (25+ kg/m2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.
Assuntos
Neoplasias do Sistema Biliar , Colelitíase , Masculino , Feminino , Humanos , Obesidade/complicações , Obesidade/epidemiologia , Sobrepeso/epidemiologia , Fatores de Risco , Estudos de Coortes , Ásia/epidemiologia , Neoplasias do Sistema Biliar/epidemiologia , Colelitíase/complicações , Colelitíase/epidemiologia , Índice de Massa CorporalRESUMO
There has been growing evidence suggesting that diabetes may be associated with increased liver cancer risk. However, studies conducted in Asian countries are limited. This project considered data of 968,738 adults pooled from 20 cohort studies of Asia Cohort Consortium to examine the association between baseline diabetes and liver cancer incidence and mortality. Cox proportional hazard model and competing risk approach was used for pooled data. Two-stage meta-analysis across studies was also done. There were 839,194 subjects with valid data regarding liver cancer incidence (5654 liver cancer cases [48.29/100,000 person-years]), follow-up time and baseline diabetes (44,781 with diabetes [5.3%]). There were 747,198 subjects with valid data regarding liver cancer mortality (5020 liver cancer deaths [44.03/100,000 person-years]), follow-up time and baseline diabetes (43,243 with diabetes [5.8%]). Hazard ratio (HR) (95% confidence interval [95%CI]) of liver cancer diagnosis in those with vs. without baseline diabetes was 1.97 (1.79, 2.16) (p < .0001) after adjusting for baseline age, gender, body mass index, tobacco smoking, alcohol use, and heterogeneity across studies (n = 586,072; events = 4620). Baseline diabetes was associated with increased cumulative incidence of death due to liver cancer (adjusted HR (95%CI) = 1.97 (1.79, 2.18); p < .0001) (n = 595,193; events = 4110). A two-stage meta-analytic approach showed similar results. This paper adds important population-based evidence to current literature regarding the increased incidence and mortality of liver cancer in adults with diabetes. The analysis of data pooled from 20 studies of different Asian countries and the meta-analysis across studies with large number of subjects makes the results robust.
Assuntos
Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/mortalidade , Incidência , Ásia/epidemiologia , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Estudos de Coortes , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/mortalidade , Fatores de Risco , Modelos de Riscos Proporcionais , IdosoRESUMO
Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E-06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.
Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/genética , Anormalidades Congênitas/genética , Ductos Paramesonéfricos/anormalidades , Ductos Paramesonéfricos/crescimento & desenvolvimento , Mutação , Ductos Mesonéfricos/crescimento & desenvolvimento , Adulto , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 7/genética , Códon sem Sentido , Feminino , Estudos de Associação Genética , Pleiotropia Genética , Proteínas Homeobox A10/genética , Proteínas de Homeodomínio/genética , Humanos , Fator de Transcrição PAX8/genética , Herança Paterna , Penetrância , Proteínas com Domínio T/genética , Fatores de Transcrição/genética , Proteínas Wnt/genética , Ductos Mesonéfricos/anormalidadesRESUMO
Severe aplastic anaemia (SAA) is a rare and life-threatening bone marrow failure disorder. We used data from the transplant outcomes in aplastic anaemia study to characterize mosaic chromosomal alterations (mCAs) in the peripheral blood of 738 patients with acquired SAA and evaluate their associations with telomere length (TL) and survival post-haematopoietic cell transplant (HCT). The median age at HCT was 20.4 years (range = 0.2-77.4). Patients with SAA had shorter TL than expected for their age (median TL percentile for age: 35.7th; range <1-99.99). mCAs were detected in 211 patients (28.6%), with chr6p copy-neutral loss of heterozygosity (6p-CNLOH) in 15.9% and chr7 loss in 3.0% of the patients; chrX loss was detected in 4.1% of female patients. Negative correlations between mCA cell fraction and measured TL (r = -0.14, p = 0.0002), and possibly genetically predicted TL (r = -0.07, p = 0.06) were noted. The post-HCT 3-year survival probability was low in patients with chr7 loss (39% vs. 72% in patients with chr6-CNLOH, 60% in patients with other mCAs and 70% in patients with no mCAs; p-log rank = 0.001). In multivariable analysis, short TL (p = 0.01), but not chr7 loss (p = 0.29), was associated with worse post-HCT survival. TL may guide clinical decisions in patients with SAA.
RESUMO
BACKGROUND: Low-dose CT screening can reduce lung cancer-related mortality. However, most screen-detected pulmonary abnormalities do not develop into cancer and it often remains challenging to identify malignant nodules, particularly among indeterminate nodules. We aimed to develop and assess prediction models based on radiological features to discriminate between benign and malignant pulmonary lesions detected on a baseline screen. METHODS: Using four international lung cancer screening studies, we extracted 2060 radiomic features for each of 16 797 nodules (513 malignant) among 6865 participants. After filtering out low-quality radiomic features, 642 radiomic and 9 epidemiological features remained for model development. We used cross-validation and grid search to assess three machine learning (ML) models (eXtreme Gradient Boosted Trees, random forest, least absolute shrinkage and selection operator (LASSO)) for their ability to accurately predict risk of malignancy for pulmonary nodules. We report model performance based on the area under the curve (AUC) and calibration metrics in the held-out test set. RESULTS: The LASSO model yielded the best predictive performance in cross-validation and was fit in the full training set based on optimised hyperparameters. Our radiomics model had a test-set AUC of 0.93 (95% CI 0.90 to 0.96) and outperformed the established Pan-Canadian Early Detection of Lung Cancer model (AUC 0.87, 95% CI 0.85 to 0.89) for nodule assessment. Our model performed well among both solid (AUC 0.93, 95% CI 0.89 to 0.97) and subsolid nodules (AUC 0.91, 95% CI 0.85 to 0.95). CONCLUSIONS: We developed highly accurate ML models based on radiomic and epidemiological features from four international lung cancer screening studies that may be suitable for assessing indeterminate screen-detected pulmonary nodules for risk of malignancy.
Assuntos
Neoplasias Pulmonares , Nódulos Pulmonares Múltiplos , Humanos , Neoplasias Pulmonares/diagnóstico , Detecção Precoce de Câncer , Radiômica , Tomografia Computadorizada por Raios X , Canadá , Nódulos Pulmonares Múltiplos/patologia , Aprendizado de Máquina , Estudos RetrospectivosRESUMO
Transition metal dichalcogenide TiSe2 exhibits a superconducting dome within a low pressure range of 2-4 GPa, which peaks with the maximal transition temperature Tc of ≈1.8 K. Here it is reported that applying high pressure induces a new superconducting state in TiSe2, which starts at ≈16 GPa with a substantially higher Tc that reaches 5.6 K at ≈21.5 GPa with no sign of decline. Combining high-throughput first-principles structure search, X-ray diffraction, and Raman spectroscopy measurements up to 30 GPa, It is found that TiSe2 undergoes a first-order structural transition from the 1T phase under ambient pressure to a new 4O phase under high pressure. Comparative ab initio calculations reveal that while the conventional phonon-mediated pairing mechanism may account for the superconductivity observed in 1T-TiSe2 under low pressure, the electron-phonon coupling of 4O-TiSe2 is too weak to induce a superconducting state whose transition temperature is as high as 5.6 K under high pressure. The new superconducting state found in pressurized TiSe2 requires further study on its underlying mechanism.
RESUMO
A novel cyclic chalcone fluorescent probe C-PN was synthesized to detect ONOO-. After reaction with peroxynitrite, the double bond of C-PN in the cyclic chalcone structure was disconnected, which caused the change of intramolecular charge transfer (ICT) effect, emitting blue fluorescence and quenching orange red fluorescence. Visible to the naked eye, the color of the probe solution changed. The probe showed low sensitivity (detection limit = 20.2 nm), short response time (less than 60 s) at low concentration of ONOO-, good visibility, and good selectivity and stability for ONOO-.
RESUMO
Polaritons-hybrid light-matter excitations-enable nanoscale control of light. Particularly large polariton field confinement and long lifetimes can be found in graphene and materials consisting of two-dimensional layers bound by weak van der Waals forces1,2 (vdW materials). These polaritons can be tuned by electric fields3,4 or by material thickness5, leading to applications including nanolasers6, tunable infrared and terahertz detectors7, and molecular sensors8. Polaritons with anisotropic propagation along the surface of vdW materials have been predicted, caused by in-plane anisotropic structural and electronic properties9. In such materials, elliptic and hyperbolic in-plane polariton dispersion can be expected (for example, plasmon polaritons in black phosphorus9), the latter leading to an enhanced density of optical states and ray-like directional propagation along the surface. However, observation of anisotropic polariton propagation in natural materials has so far remained elusive. Here we report anisotropic polariton propagation along the surface of α-MoO3, a natural vdW material. By infrared nano-imaging and nano-spectroscopy of semiconducting α-MoO3 flakes and disks, we visualize and verify phonon polaritons with elliptic and hyperbolic in-plane dispersion, and with wavelengths (up to 60 times smaller than the corresponding photon wavelengths) comparable to those of graphene plasmon polaritons and boron nitride phonon polaritons3-5. From signal oscillations in real-space images we measure polariton amplitude lifetimes of 8 picoseconds, which is more than ten times larger than that of graphene plasmon polaritons at room temperature10. They are also a factor of about four larger than the best values so far reported for phonon polaritons in isotopically engineered boron nitride11 and for graphene plasmon polaritons at low temperatures12. In-plane anisotropic and ultra-low-loss polaritons in vdW materials could enable directional and strong light-matter interactions, nanoscale directional energy transfer and integrated flat optics in applications ranging from bio-sensing to quantum nanophotonics.
RESUMO
The AMP-activated protein kinase (AMPK) is the master regulator of metabolic homeostasis by sensing cellular energy status. When intracellular ATP levels decrease during energy stress, AMPK is initially activated through AMP or ADP binding and phosphorylation of a threonine residue (Thr-172) within the activation loop of its kinase domain. Here we report a key molecular mechanism by which AMPK activation is amplified under energy stress. We found that ubiquitination on AMPKα blocks AMPKα phosphorylation by LKB1. The deubiquitinase USP10 specifically removes ubiquitination on AMPKα to facilitate AMPKα phosphorylation by LKB1. Under energy stress, USP10 activity in turn is enhanced through AMPK-mediated phosphorylation of Ser76 of USP10. Thus, USP10 and AMPK form a key feedforward loop ensuring amplification of AMPK activation in response to fluctuation of cellular energy status. Disruption of this feedforward loop leads to improper AMPK activation and multiple metabolic defects.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Ubiquitina Tiolesterase/química , Ubiquitina Tiolesterase/metabolismo , Animais , Metabolismo Energético , Ativação Enzimática , Células HCT116 , Células HEK293 , Humanos , Camundongos , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Serina/metabolismo , UbiquitinaçãoRESUMO
The exposure to an unhealthy environment in utero can lead to the occurrence of cardiovascular diseases in the offspring. Glucocorticoids (GC) are essential for normal development and maturation of fetal organs and is a first-line treatment for pregnant women affected by autoimmune diseases. However, excess prenatal GC exposure might program the development of fetal organs and cause a number of chronic diseases in later life. Our previous studies indicated that cardiac functions were significantly compromised in rat offspring prenatally exposed to the synthetic glucocorticoid dexamethasone (DEX), only after ischemia-reperfusion. In the present study, we further observed that DNA hypermethylation of bone morphogenetic protein 4 (Bmp4) promoter in cardiomyocytes caused by prenatal DEX exposure substantially dampened the binding activity of transcription factor HIF-1α induced by cardiac ischemia. Therefore, prenatal DEX exposure inhibits the induction of BMP4 upon I/R and attenuates the protective effects of BMP4 in cardiomyocytes, which eventually manifests as malfunction of the adult heart. Moreover, we employed two cardiac-specific Bmp4 knock-in mouse models and found that in vivo BMP4 overexpression could rescue the cardiac dysfunction caused by prenatal GC exposure. In depth mechanistic research revealed that BMP4 protects the cardiomyocytes from mitophagy and apoptosis by attenuating mitochondrial PGC-1α expression in a p-Smad and Parkin-dependent manner. These findings suggest that prenatal GC exposure increases the susceptibility of the offspring's heart to a "second strike" after birth, due to the failure of hypoxia-induced HIF-1α transactivation of the hypermethylated Bmp4 promoter in cardiomyocytes. Pretreatment with the DNA methylation inhibitor, 5-Aza-2'-deoxycytidine, could be a potential therapeutic method for this programming effect of GC exposure during pregnancy on neonatal cardiac dysfunction.