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1.
Cell Rep ; 36(9): 109621, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34469741

RESUMO

Radiotherapy (RT) resistance is a major cause of treatment failure in cancers that use definitive RT as their primary treatment modality. This study identifies the cancer/testis (CT) antigen G antigen (GAGE) as a mediator of radio resistance in cervical cancers. Elevated GAGE expression positively associates with de novo RT resistance in clinical samples. GAGE, specifically the GAGE12 protein variant, confers RT resistance through synemin-dependent chromatin localization, promoting the association of histone deacetylase 1/2 (HDAC1/2) to its inhibitor actin. This cumulates to elevated histone 3 lysine 56 acetylation (H3K56Ac) levels, increased chromatin accessibility, and improved DNA repair efficiency. Molecular or pharmacological disruption of the GAGE-associated complex restores radiosensitivity. Molecularly, this study demonstrates the role of GAGE in the regulation of chromatin dynamics. Clinically, this study puts forward the utility of GAGE as a pre-screening biomarker to identify poor responders at initial diagnosis and the therapeutic potential of agents that target GAGE and its associated complex in combination with radiotherapy to improve outcomes.

2.
Sci Rep ; 11(1): 17822, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497343

RESUMO

Existing data on the prognosis and clinicopathological features of patients with metastatic renal cell carcinoma (mRCC) are limited. This study aims to investigate the prognostic value and clinicopathological features of different metastatic sites in patients with mRCC. A dataset from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database consisting of 18 registries (1973-2015) was selected for a retrospective mRCC cohort study. Information was included on the metastatic sites in lung, bone, liver, and brain. Kaplan-Meier analysis was applied to compare the survival distribution. Univariate and multivariate Cox regression models were used to analyze survival outcomes. From the SEER database, a total of 10,410 patients with primary mRCC from 2010 to 2015 were enrolled in this cohort study. Analysis indicated that 54.9%, 37.7%, 19.5%, and 10.4% of patients were found to have lung, bone, liver, and brain metastasis, respectively. There was a significantly higher risk for sarcomatoid RCC patients to develop liver metastasis as compared to patients with clear cell RCC. The median survival for patients with lung, bone, liver, or brain metastasis was 7 months, 7 months, 4 months, and 5 months, respectively. Various clinicopathological features and prognostic values are associated with different metastatic sites. Understanding these differences may enable targeted pre-treatment assessment of primary mRCC and personalized curative intervention for patients.

3.
BMC Biol ; 19(1): 200, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503495

RESUMO

BACKGROUND: Although oocyte quality is the dominant factor determining embryo quality, few studies have been conducted to evaluate embryo quality based on the metabolites related to the oocyte. With quantification of the follicular fluid (FF) metabolites, in assisted reproductive technology (ART), this study sought to evaluate the embryo or oocyte quality through an informative approach. RESULTS: An evaluation model consisting of 17 features was generated to distinguish the embryo quality on day 3 post-fertilization, and phosphatidylcholines (PCs) were the key contributors to the evaluation. The model was extended to the patients under different ages and hyperstimulations, and the features were further enriched to facilitate the evaluation of the embryo quality. The metabolites were clustered through pathway analysis, leading to a hypothesis that accumulation of arachidonic acid induced by PCs might weaken embryo quality on day 3 post-fertilization. CONCLUSIONS: A discriminating model with metabolic features elicited from follicular fluid was established, which enabled the evaluation of the embryo or oocyte quality even under certain clinical conditions, and the increase of PCs in follicular fluid implies the attenuation of embryo quality on day 3 post-fertilization.

4.
Nurs Open ; 8(3): 1098-1107, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34482653

RESUMO

AIM: Cancer patients have long been found to have multiple types of unmet needs during their survivorship. Composite psychological instruments are essential for measuring the unmet needs of cancer patients. The objective of this study was to evaluate the psychometric properties of the Short-Form Survivor Unmet Needs Survey (SF-SUNS)-Chinese version. DESIGN: A cross-sectional survey. METHODS: The Chinese version was developed using the standard Functional Assessment of Chronic Illness Therapy (FACIT) translation methodology and 428 Chinese cancer patients participated in the survey between 2016-2017. Inter-rater reliability, exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were calculated. RESULTS: Confirmatory factor analysis supported the four-factor structure with good model fit. Cronbach's alpha of 0.894 for the overall scale and intra-class correlation coefficients (0.869-0.884) indicated that reliability was satisfactory. The EFA extracted four factors with eigenvalues greater than 1 and these factors explained 50.68% of the total variance. The Chinese version of SF-SUNS was confirmed to have the potential to become a useful and valid instrument. It could contribute to the assessment of unmet needs among Chinese cancer patients with accuracy and with respect to Chinese culture and context. This measurement of unmet needs may help promote cancer management and nursing quality. Clinical nurses and researchers could use the simple assessment tool to target the individual needs of Chinese cancer patients and then provide more personalized care efficiently.


Assuntos
Neoplasias , Sobreviventes , China/epidemiologia , Estudos Transversais , Humanos , Neoplasias/epidemiologia , Reprodutibilidade dos Testes
5.
Artigo em Inglês | MEDLINE | ID: mdl-34514792

RESUMO

Ga2O3 is a popular material for research on solar-blind ultraviolet detectors. However, its absorption cutoff edge is 253 nm, which is not an ideal cutoff edge of 280 nm. In this work, by adjusting the ratio of In/Ga elements in the films, a high-quality (In0.11Ga0.89)2O3 film with an absorption cutoff edge of 280 nm was obtained, which owns a uniform surface and preferred orientation. On this basis, a solar-blind ultraviolet photovoltaic detector was constructed based on the Pt/(In0.11Ga0.89)2O3/n-Si heterojunction. When the device is exposed to 254 nm UV light, its open-circuit voltage (VOC) can reach 354 mV. Under 0 V bias, the device has a responsivity of 0.48 mA/W with a rise time of 0.47 s and a decay time of 0.37 s; under -7 V bias, the device achieves a responsivity of 16.96 mA/W with a rise time of 0.17 s and a decay time of 0.33 s. The spectral response characteristics of the device show that it has a selective response to solar-blind ultraviolet light (cutoff wavelength is 280 nm) with a rejection ratio (R254 nm/R310 nm), which is greater by more than two orders of magnitude. This work provides a good reference for adjusting the band gap of Ga2O3-based films and broadening their application fields.

6.
Int J Epidemiol ; 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34468722

RESUMO

BACKGROUND: Accumulating evidence suggests that consuming coffee may lower the risk of death, but evidence regarding tea consumption in Asians is limited. We examined the association between coffee and tea consumption and mortality in Asian populations. METHODS: We used data from 12 prospective cohort studies including 248 050 men and 280 454 women from the Asia Cohort Consortium conducted in China, Japan, Korea and Singapore. We estimated the study-specific association of coffee, green tea and black tea consumption with mortality using Cox proportional-hazards regression models and the pooled study-specific hazard ratios (HRs) using a random-effects model. RESULTS: In total, 94 744 deaths were identified during the follow-up, which ranged from an average of 6.5 to 22.7 years. Compared with coffee non-drinkers, men and women who drank at least five cups of coffee per day had a 24% [95% confidence interval (CI) 17%, 29%] and a 28% (95% CI 19%, 37%) lower risk of all-cause mortality, respectively. Similarly, we found inverse associations for coffee consumption with cardiovascular disease (CVD)-specific and cancer-specific mortality among both men and women. Green tea consumption was associated with lower risk of mortality from all causes, CVD and other causes but not from cancer. The association of drinking green tea with CVD-specific mortality was particularly strong, with HRs (95% CIs) of 0.79 (0.68, 0.91) for men and 0.78 (0.68, 0.90) for women who drank at least five cups per day of green tea compared with non-drinkers. The association between black tea consumption and mortality was weak, with no clear trends noted across the categories of consumption. CONCLUSIONS: In Asian populations, coffee consumption is associated with a lower risk of death overall and with lower risks of death from CVD and cancer. Green tea consumption is associated with lower risks of death from all causes and CVD.

7.
J Hazard Mater ; 416: 126246, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34492992

RESUMO

Bacterial chemotaxis can improve the efficiency of aromatic compound degradation, however, knowledge of how bacteria sense high-molecular-weight polycyclic aromatic hydrocarbons (HMW-PAHs), is limited. Here, the chemotactic responses of Novosphingobium pentaromativorans US6-1 to 9 aromatic compounds were investigated. The results showed that US6-1 chemotactically responded to phenanthrene (PHE), pyrene (PYR), benzo[a]pyrene (BaP) and their six metabolites. Six methyl-accepting chemotaxis proteins (MCPs) were annotated from US6-1 genome, four of which contained putative ligand-binding domains (LBDs). To confirm whether these four MCPs were involved in triggering chemotaxis toward PAHs, the MCP mutants were constructed. Observations showed a loss of the chemotactic responses to benzoate, phthalate, PHE and BaP only in the mutant ∆mcp03030. Surface plasmon resonance (SPR) assays further confirmed that MCP03030LBD specifically bound phthalate, PHE, PYR and BaP, while MCP18870LBD bound only PYR. The mutant ∆mcp03030-∆mcp18870 was then constructed and was shown to have lost the chemotactic response to 5 aromatic compounds. Combined with the effects of outer membrane transporter deletion on chemotaxis and MCP deletion on the PAH degradation, our study demonstrated that the chemoreceptors MCP03030 and MCP18870 can recognize PAHs and their metabolites in the periplasm, triggering metabolism-dependent and metabolism-independent chemotaxis, and be linked with HMW-PAH biodegradation.


Assuntos
Hidrocarbonetos Policíclicos Aromáticos , Sphingomonadaceae , Biodegradação Ambiental , Quimiotaxia , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Sphingomonadaceae/genética
8.
ACS Biomater Sci Eng ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34543012

RESUMO

The study of cell migration on biomaterials is of great significance in tissue engineering and regenerative medicine. In recent years, there has been increasing evidence that the physical properties of the extracellular matrix (ECM), such as surface topography, affect various cellular behaviors such as proliferation, adhesion, and migration. However, the biological mechanism of surface topography influencing cellular behavior is still unclear. In this study, we prepared polycaprolactone (PCL) fibrous materials with different surface microstructures by solvent casting, electrospinning, and self-induced crystallization. The corresponding topographical structure obtained is a two-dimensional (2D) flat surface, 2.5-dimensional (2.5D) fibers, and three-dimensional (3D) fibers with a multilevel microstructure. We then investigated the effects of the complex topographical structure on endothelial cell migration. Our study demonstrates that cells can sense the changes of micro- and nanomorphology on the surface of materials, adapt to the physical environment through biochemical reactions, and regulate actin polymerization and directional migration through Rac1 and Cdc42. The cells on the nanofibers are elongated spindles, and the positive feedback of cell adhesion and actin polymerization along the fiber direction makes the plasma membrane continue to protrude, promoting cell polarization and directional migration. This study might provide new insights into the biomaterial design, especially those used for artificial vascular grafts.

9.
Chem Asian J ; 2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34546656

RESUMO

Covalent organic frameworks (COFs) are promising materials for membrane separation thanks to their adjustable topological structures and surface properties of nanopores. Herein, a melamine (Me) doped COF membrane was fabricated by chemically doping the melamine monomer into TpPa COF, which is formed by the condensation reaction between the 1,3,5-triformylphloroglucinol (Tp) and p-phenylenediamine (Pa) monomers via interfacial polymerization . The introduction of melamine monomer allows altering both the pore structure and pore surface of the TpPa COF membrane, leading to enhanced hydrogen purification performance. Specifically, the separation factor of H 2 /CO 2 gas mixture by using the melamine doped TpPa COF (TpPaMe COF) membrane reaches 12.7, with hydrogen permeance of 727 GPU, in sharp contrast to the relatively low separation factor and gas permeance of 7.5 and 618 GPU of the undoped TpPa membrane. Besides, the TpPaMe COF membrane shows good running stability, with H 2 /CO 2 separation performance well surpasses the Robeson 2008 upper bound.

10.
Br J Neurosurg ; : 1-8, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34542381

RESUMO

OBJECTIVE: Resection of high-grade glioma with sodium fluorescein can improve the resection rate of the glioma and improve survival. However, it is unclear whether the yellow fluorescence boundary of the high-grade glioma is consistent with the actual boundary of the tumor. This study explores the yellow fluorescence boundary and the actual tumor boundary in high-grade glioma surgery. METHODS: This is a retrospective analysis of 10 patients with high-grade gliomas who underwent tumor visualization with sodium fluorescein. After staining of the tumor, random selections of both developed and non-developed yellow fluorescent border tissue at the fluorescence chromogenic boundary were made, followed by pathological examination. Claudin-5, an important component of the tight connections between vascular endothelial cells, was assessed by immunohistochemistry and qRT-PCR in the tumor and surrounding tissues in order to determine the tumor cell content of the tissue, blood-brain barrier damage, and vascular proliferation. The yellow fluorescence boundary was compared with the actual tumor boundary and the results analyzed. RESULTS: Tumor cells were still detected outside the yellow fluorescence boundary during high-grade glioma surgery (P < 0.05). Claudin-5 expression was higher in high-grade gliomas than in adjacent normal tissues (P < 0.05), while disconnected Claudin-5 expression was associated with intraoperative yellow fluorescence imaging (r = 0.67). CONCLUSIONS: There is a difference between the yellow fluorescence boundary and the actual boundary of the tumor in high-grade glioma, and there are glioma cell infiltrations in the brain tissue of the undeveloped yellow fluorescent border. To ensure patient recovery and function, it is recommended that tumor resection be expanded based on yellow fluorescence visualization. Claudin-5 is overall up-regulated in high-grade gliomas, but some Claudin-5 expression is disconnected. This Claudin-5 expression pattern may be related to the development of yellow fluorescence.

11.
Acta Pharmacol Sin ; 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34480112

RESUMO

Acute lung injury (ALI) and its severe form acute respiratory distress syndrome (ARDS) are known as the common causes of respiratory failure in critically ill patients. Myeloid differentiation 2 (MD2), a co-receptor of toll like receptor 4 (TLR4), plays an important role in LPS-induced ALI in mice. Since MD2 inhibition by pharmacological inhibitors or gene knockout significantly attenuates ALI in animal models, MD2 has become an attractive target for the treatment of ALI. In this study we identified two chalcone-derived compounds, 7w and 7x, as new MD2 inhibitors, and investigated the therapeutic effects of 7x and 7w in LPS-induced ALI mouse model. In molecular docking analysis we found that 7w and 7x, formed pi-pi stacking interactions with Phe151 residue of the MD2 protein. The direct binding was confirmed by surface plasmon resonance analysis (with KD value of 96.2 and 31.2 µM, respectively) and by bis-ANS displacement assay. 7w and 7x (2.5, 10 µM) also dose-dependently inhibited the interaction between lipopolysaccharide (LPS) and rhMD2 and LPS-MD2-TLR4 complex formation. In mouse peritoneal macrophages, 7w and 7x (1.25-10 µM) dose-dependently inhibited LPS-induced inflammatory responses, MAPKs (JNK, ERK and P38) phosphorylation as well as NF-κB activation. Finally, oral administration of 7w or 7x (10 mg ·kg-1 per day, for 7 days prior LPS challenge) in ALI mouse model significantly alleviated LPS-induced lung injury, pulmonary edema, lung permeability, inflammatory cells infiltration, inflammatory cytokines expression and MD2/TLR4 complex formation. In summary, we identify 7w and 7x as new MD2 inhibitors to inhibit inflammatory response both in vitro and in vivo, proving the therapeutic potential of 7w and 7x for ALI and inflammatory diseases.

12.
Hum Reprod Update ; 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34473268

RESUMO

BACKGROUND: Preimplantation genetic testing (PGT) includes methods that allow embryos to be tested for severe inherited diseases or chromosomal abnormalities. In addition to IVF/ICSI and repeated freezing and thawing of the embryos, PGT requires a biopsy to obtain embryonic genetic material for analysis. However, the potential effects of PGT on obstetric and neonatal outcomes are currently uncertain. OBJECTIVE AND RATIONALE: This study aimed to investigate whether pregnancies conceived after PGT were associated with a higher risk of adverse obstetric and neonatal outcomes compared with spontaneously conceived (SC) pregnancies or pregnancies conceived after IVF/ICSI. SEARCH METHODS: PubMed, EMBASE, MEDLINE, Web of Science and The Cochrane Library entries from January 1990 to January 2021 were searched. The primary outcomes in this study were low birth weight (LBW) and congenital malformations (CMs), and the secondary outcomes included gestational age, preterm delivery (PTD), very preterm delivery (VPTD), birth weight (BW), very low birth weight (VLBW), neonatal intensive care unit (NICU) admission, hypertensive disorders of pregnancy (HDP), gestational diabetes, placenta previa and preterm premature rupture of membranes (PROM). We further pooled the results of PGT singleton pregnancies. Subgroup analyses included preimplantation genetic diagnosis (PGD), preimplantation genetic screening (PGS), cleavage-stage biopsy combined with fresh embryo transfer (CB-ET) and blastocyst biopsy combined with frozen-thawed embryo transfer (BB-FET). OUTCOMES: This meta-analysis included 15 studies involving 3682 babies born from PGT pregnancies, 127 719 babies born from IVF/ICSI pregnancies and 915 222 babies born from SC pregnancies. The relative risk (RR) of LBW was higher in PGT pregnancies compared with SC pregnancies (RR = 3.95, 95% confidence interval [CI]: 2.32-6.72), but the risk of CMs was not different between the two groups. The pooled results for the risks of LBW and CMs were similar in PGT and IVF/ICSI pregnancies. The risks of PTD (RR = 3.12, 95% CI: 2.67-3.64) and HDP (RR = 3.12, 95% CI: 2.18-4.47) were significantly higher in PGT pregnancies compared with SC pregnancies. Lower gestational age (mean difference [MD] = -0.76 weeks, 95% CI -1.17 to -0.34) and BW (MD = -163.80 g, 95% CI: -299.35 to -28.24) were also noted for PGT pregnancies compared with SC pregnancies. Nevertheless, compared with IVF/ICSI pregnancies, the risks of VPTD and VLBW in PGT pregnancies were significantly decreased by 41% and 30%, respectively, although the risk of HDP was still significantly increased by 50% in PGT pregnancies compared with IVF/ICSI pregnancies. The combined results of obstetric and neonatal outcomes of PGT and IVF/ICSI singleton pregnancies were consistent with the overall results. Further subgroup analyses indicated that both PGD and PGS pregnancies were associated with a higher risk of PTD and a lower gestational age compared with SC pregnancies. WIDER IMPLICATIONS: This meta-analysis showed that PGT pregnancies may be associated with increased risks of LBW, PTD and HDP compared with SC pregnancies. The overall obstetric and neonatal outcomes of PGT pregnancies are favourable compared with those of IVF/ICSI pregnancies, although PGT pregnancies were associated with a higher risk of HDP. However, because the number of studies that could be included was limited, more randomised controlled trials and prospective cohort studies are needed to confirm these conclusions.

13.
PLoS Comput Biol ; 17(9): e1009370, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34529671

RESUMO

Three-dimensional structures of proteins can provide important clues into the efficacy of personalized treatment. We perform a structural analysis of variants within three inherited lysosomal storage disorders, comparing variants responsive to pharmacological chaperone treatment to those unresponsive to such treatment. We find that predicted ΔΔG of mutation is higher on average for variants unresponsive to treatment, in the case of datasets for both Fabry disease and Pompe disease, in line with previous findings. Using both a single decision tree and an advanced machine learning approach based on the larger Fabry dataset, we correctly predict responsiveness of three Gaucher disease variants, and we provide predictions for untested variants. Many variants are predicted to be responsive to treatment, suggesting that drug-based treatments may be effective for a number of variants in Gaucher disease. In our analysis, we observe dependence on a topological feature reporting on contact arrangements which is likely connected to the order of folding of protein residues, and we provide a potential justification for this observation based on steady-state cellular kinetics.

14.
Nat Commun ; 12(1): 5318, 2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34518541

RESUMO

Identifying transcription factors (TFs) whose DNA bindings are altered by genetic variants that regulate susceptibility genes is imperative to understand transcriptional dysregulation in disease etiology. Here, we develop a statistical framework to analyze extensive ChIP-seq and GWAS data and identify 22 breast cancer risk-associated TFs. We find that, by analyzing genetic variations of TF-DNA bindings, the interaction of FOXA1 with co-factors such as ESR1 and E2F1, and the interaction of TFs with chromatin features (i.e., enhancers) play a key role in breast cancer susceptibility. Using genetic variants occupied by the 22 TFs, transcriptome-wide association analyses identify 52 previously unreported breast cancer susceptibility genes, including seven with evidence of essentiality from functional screens in breast relevant cell lines. We show that FOXA1 and co-factors form a core TF-transcriptional network regulating the susceptibility genes. Our findings provide additional insights into genetic variations of TF-DNA bindings (particularly for FOXA1) underlying breast cancer susceptibility.

15.
Cancer Commun (Lond) ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34520132

RESUMO

BACKGROUND: DNA methylation and gene expression are known to play important roles in the etiology of human diseases such as prostate cancer (PCa). However, it has not yet been possible to incorporate information of DNA methylation and gene expression into polygenic risk scores (PRSs). Here, we aimed to develop and validate an improved PRS for PCa risk by incorporating genetically predicted gene expression and DNA methylation, and other genomic information using an integrative method. METHODS: Using data from the PRACTICAL consortium, we derived multiple sets of genetic scores, including those based on available single-nucleotide polymorphisms through widely used methods of pruning and thresholding, LDpred, LDpred-funt, AnnoPred, and EBPRS, as well as PRS constructed using the genetically predicted gene expression and DNA methylation through a revised pruning and thresholding strategy. In the tuning step, using the UK Biobank data (1458 prevalent cases and 1467 controls), we selected PRSs with the best performance. Using an independent set of data from the UK Biobank, we developed an integrative PRS combining information from individual scores. Furthermore, in the testing step, we tested the performance of the integrative PRS in another independent set of UK Biobank data of incident cases and controls. RESULTS: Our constructed PRS had improved performance (C statistics: 76.1%) over PRSs constructed by individual benchmark methods (from 69.6% to 74.7%). Furthermore, our new PRS had much higher risk assessment power than family history. The overall net reclassification improvement was 69.0% by adding PRS to the baseline model compared with 12.5% by adding family history. CONCLUSIONS: We developed and validated a new PRS which may improve the utility in predicting the risk of developing PCa. Our innovative method can also be applied to other human diseases to improve risk prediction across multiple outcomes.

16.
Phys Chem Chem Phys ; 23(35): 19289-19296, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34525146

RESUMO

The conformations of 1,7DSU and its stepwise solvation by up to 5 water molecules were explored using supersonic-jet Fourier transform microwave spectroscopy with the supplement of theoretical calculations. Experimentally, the rotational spectra of the most stable structures of the monomer, monohydrate and dihydrate were observed and assigned. The characteristics of the stability and intermolecular interaction topologies of the 1,7DSU monomer and its hydrated clusters were obtained by CREST conformational sampling followed by B3LYP-D3(BJ)/def2-TZVP geometrical optimizations and MP2/aug-cc-pVTZ single-point energy calculations. The first water molecule links to the 1,7DSU monomer through an OwH⋯O hydrogen bond. The water molecules tend to aggregate with each other and form cyclic structures for the n = 2-5 clusters. The interactions between water and the 1,7DSU monomer as well as those between water and water were revealed. The analyses of non-covalent interactions and the natural bond orbital suggest that the OwH⋯O1,7DSU, OwH⋯Ow, and CH⋯Ow hydrogen bonds play a prominent role in structural stability.

17.
Artigo em Inglês | MEDLINE | ID: mdl-34497089

RESUMO

Background The role of methylation in pancreatic cancer (PC) risk remains unclear. We integrated genome and methylome data to identify CpG sites (CpGs) with the genetically predicted methylation to be associated with PC risk. We also studied gene expression to understand the identified associations. Methods Using genetic data and white blood cell methylation data from 1,595 subjects of European descent, we built genetic models to predict DNA methylation levels. After internal and external validation, we applied prediction models with satisfactory performance to the genetic data of 8,280 PC cases and 6,728 controls of European ancestry to investigate the associations of predicted methylation with PC risk. For associated CpGs, we compared their measured levels in pancreatic tumor vs benign tissue. Results We identified 45 CpGs at nine loci showing an association with PC risk, including 15 CpGs showing an association independent from identified risk variants. We observed significant correlations between predicted methylation of 16 of the 45 CpGs and predicted expression of eight adjacent genes, of which six genes showed associations with PC risk. Of the 45 CpGs, we were able to compare measured methylation of 16 in pancreatic tumor versus benign pancreatic tissue. Of them, six showed differentiated methylation. Conclusions We identified methylation biomarker candidates associated with PC using genetic instruments and added additional insights into the role of methylation in regulating gene expression in PC development. Impact: A comprehensive study using genetic instruments identifies 45 CpG sites at nine genomic loci for PC risk.

18.
Acta Pharmacol Sin ; 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497374

RESUMO

The epigenetic modification of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a crucial role in cccDNA transcription and viral persistence. Interferon-α (IFN-α) is a pivotal agent against HBV cccDNA. However, the mechanism by which IFN-α modulates the epigenetic regulation of cccDNA remains poorly understood. In this study, we report that IFN-α2b enhances the histone deacetylase 3 (HDAC3)-mediated de-2-hydroxyisobutyrylation of histone H4 lysine 8 (H4K8) on HBV cccDNA minichromosome to restrict the cccDNA transcription in liver. By screening acetyltransferases and deacetylases, we identified that HDAC3 was an effective restrictor of HBV transcription and replication. Moreover, we found that HDAC3 was able to mediate the de-2-hydroxyisobutyrylation of H4K8 in HBV-expressing hepatoma cells. Then, the 2-hydroxyisobutyrylation of histone H4K8 (H4K8hib) was identified on the HBV cccDNA minichromosome, promoting the HBV transcription and replication. The H4K8hib was regulated by HDAC3 depending on its deacetylase domain in the system. The low level of HDAC3 and high level of H4K8hib were observed in the liver tissues from HBV-infected human liver-chimeric mice. The levels of H4K8hib on HBV cccDNA minichromosome were significantly elevated in the liver biopsy specimens from clinical hepatitis B patients, which was consistent with the high transcriptional activity of cccDNA. Strikingly, IFN-α2b effectively facilitated the histone H4K8 de-2-hydroxyisobutyrylation mediated by HDAC3 on the HBV cccDNA minichromosome in primary human hepatocytes and hepatoma cells, leading to the inhibition of HBV transcription and replication. Our finding provides new insights into the mechanism by which IFN-α modulates the epigenetic regulation of HBV cccDNA minichromosome.

19.
JAMA Netw Open ; 4(9): e2122837, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34477853

RESUMO

Importance: The association between long sleep duration and mortality appears stronger in East Asian populations than in North American or European populations. Objectives: To assess the sex-specific association between sleep duration and all-cause and major-cause mortality in a pooled longitudinal cohort and to stratify the association by age and body mass index. Design, Setting, and Participants: This cohort study of individual-level data from 9 cohorts in the Asia Cohort Consortium was performed from January 1, 1984, to December 31, 2002. The final population included participants from Japan, China, Singapore, and Korea. Mean (SD) follow-up time was 14.0 (5.0) years for men and 13.4 (5.3) years for women. Data analysis was performed from August 1, 2018, to May 31, 2021. Exposures: Self-reported sleep duration, with 7 hours as the reference category. Main Outcomes and Measures: Mortality, including deaths from all causes, cardiovascular disease, cancer, and other causes. Sex-specific hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression with shared frailty models adjusted for age and the key self-reported covariates of marital status, body mass index, smoking status, alcohol consumption, physical activity, history of diabetes and hypertension, and menopausal status (for women). Results: For 322 721 participants (mean [SD] age, 54.5 [9.2] years; 178 542 [55.3%] female), 19 419 deaths occurred among men (mean [SD] age of men, 53.6 [9.0] years) and 13 768 deaths among women (mean [SD] age of women, 55.3 [9.2] years). A sleep duration of 7 hours was the nadir for associations with all-cause, cardiovascular disease, and other-cause mortality in both men and women, whereas 8 hours was the mode sleep duration among men and the second most common sleep duration among women. The association between sleep duration and all-cause mortality was J-shaped for both men and women. The greatest association for all-cause mortality was with sleep durations of 10 hours or longer for both men (hazard ratio [HR], 1.34; 95% CI, 1.26-1.44) and women (HR, 1.48; 95% CI, 1.36-1.61). Sex was a significant modifier of the association between sleep duration and mortality from cardiovascular disease (χ25 = 13.47, P = .02), cancer (χ25 = 16.04, P = .007), and other causes (χ25 = 12.79, P = .03). Age was a significant modifier of the associations among men only (all-cause mortality: χ25 = 41.49, P < .001; cancer: χ25 = 27.94, P < .001; other-cause mortality: χ25 = 24.51, P < .001). Conclusions and Relevance: The findings of this cohort study suggest that sleep duration is a behavioral risk factor for mortality in both men and women. Age was a modifier of the association between sleep duration in men but not in women. Sleep duration recommendations in these populations may need to be considered in the context of sex and age.

20.
Hum Genet ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34487234

RESUMO

Single germline nucleotide pathogenic variants have been identified in 12 breast cancer predisposition genes, but structural deletions in these genes remain poorly characterized. We conducted in-depth whole genome sequencing (WGS) in genomic DNA samples obtained from 1340 invasive breast cancer cases and 675 controls of African ancestry. We identified 25 deletions in the intragenic regions of ten established breast cancer predisposition genes based on a consensus call from six state-of-the-art SV callers. Overall, no significant case-control difference was found in the frequency of these deletions. However, 1.0% of cases and 0.3% of controls carried any of the eight putative protein-truncating rare deletions located in BRCA1, BRCA2, CDH1, TP53, NF1, RAD51D, RAD51C and CHEK2, resulting in an odds ratio (OR) of 3.29 (95% CI 0.74-30.16). We also identified a low-frequency deletion in NF1 associated with breast cancer risk (OR 1.93, 95% CI 1.14-3.42). In addition, we detected 56 deletions, including six putative protein-truncating deletions, in suspected breast predisposition genes. This is the first large study to systematically search for structural deletions in breast cancer predisposition genes. Many of the deletions, particularly those resulting in protein truncations, are likely to be pathogenic. Results from this study, if confirmed in future large-scale studies, could have significant implications for genetic testing for this common cancer.

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