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1.
Artigo em Inglês | MEDLINE | ID: mdl-33864522

RESUMO

BACKGROUND: Establish patient-derived tumor xenograft (PDTX) from advanced GICs and assess the clinical value and applicability of PDTX for the treatment of advanced gastrointestinal cancers. METHODS: Patients with advanced GICs were enrolled in a registered multi-center clinical study (ChiCTR-OOC-17012731). The performance of PDTX was evaluated by analyzing factors that affect the engraftment rate, comparing the histological consistency between primary tumors and tumorgrafts, examining the concordance between the drug effectiveness in PDTXs and clinical responses, and identifying genetic variants and other factors associated with prognosis. RESULTS: Thirty-three patients were enrolled in the study with the engraftment rate of 75.8% (25/33). The success of engraftment was independent of age, cancer types, pathological stages of tumors, and particularly sampling methods. Tumorgrafts retained the same histopathological characteristics as primary tumors. Forty-nine regimens involving 28 drugs were tested in seventeen tumorgrafts. The median time for drug testing was 134.5 days. Follow-up information was obtained about 10 regimens from 9 patients. The concordance of drug effectiveness between PDTXs and clinical responses was 100%. The tumor mutation burden (TMB) was correlated with the effectiveness of single drug regimens, while the outgrowth time of tumorgrafts was associated with the effectiveness of combined regimens. CONCLUSION: The engraftment rate in advanced GICs was higher than that of other cancers and meets the acceptable standard for applying personalized therapeutic strategies. Tumorgrafts from PDTX kept attributes of the primary tumor. Predictions from PDTX modeling closely agreed with clinical drug responses. PDTX may already be clinically applicable for personalized medication in advanced GICs.

2.
J Transl Med ; 19(1): 127, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771173

RESUMO

BACKGROUND: Lung cancer is the most common cancer and cause of cancer-related mortality worldwide, increasing evidence indicated that there was a significant correlation between tumors and the long non-coding RNAs (lncRNAs), as well as tumor immune infiltration, but their role in early lung adenocarcinoma (LUAD) are still unclear. METHODS: Gene expression data and corresponding clinical data of early-stage LUAD patients were downloaded from GEO and TCGA databases. 24 kinds of tumor-infiltrating immune cells were analyzed by quantity analysis and univariate cox regression analysis, we divided patients into two subgroups using consensus clustering, recognized the differentially expressed genes (DEGs) in the subgroups, then, established lncRNA risk signature by least absolute shrinkage and selection operator (LASSO) regression. RESULTS: A total of 718 patients were enrolled in this study, including 246 from GSE31210 dataset, 127 from GSE50081 dataset and 345 from TCGA-LUAD. We identified that Th2 cells, TFH, NK CD56dim cells and Mast cells were prognosis-related(p < 0.05), then established a 5-lncRNA risk signature (risk score = 0.374600616* LINC00857 + 0.173825706* LINC01116 + (- 0.021398903)* DRAIC + (- 0.113658256)* LINC01140 + (- 0.008403702)* XIST), and draw a nomogram showed that the signature had a well prediction accuracy and discrimination. CONCLUSIONS: We identified 4 immune infiltrating cells related to the prognosis of early-stage LUAD, and established a novel 5 immune-related lncRNA signature for predicting patients' prognosis.

3.
Curr Diab Rep ; 21(3): 10, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33616838

RESUMO

PURPOSE OF REVIEW: Understanding barriers to self-management behaviors and glycemic stability may inform specific needs for behavior change in adolescents and young adults with type 1 diabetes (T1D). The current review aims to systematically synthesize the literature on the relationships between executive functioning, self-management, and A1C in adolescents and young adults with T1D. Fifteen studies were retained in the current review. Study quality assessment for the majority of the studies were "Fair" or "Good." RECENT FINDINGS: This review highlights several advances in research design, including use of longitudinal designs, data from multiple informants, and use of objective measures. Adolescents and young adults reported that more executive functioning weaknesses were related to decreased self-management behaviors and higher A1C. The current review demonstrated that self-perceived executive functioning weaknesses negatively impact self-management behaviors and A1C. Future research is needed to determine the utility of objective measures in assessing the relationships between executive functioning, T1D self-management, and A1C.

4.
BMC Med Imaging ; 21(1): 8, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407215

RESUMO

BACKGROUND: To evaluate different stages of liver fibrosis in cynomolgus monkeys by comparing magnetic resonance-perfusion weighted imaging (MR-PWI) quantitative and semi-quantitative parameters, and confirm the best detection indicators for diagnosis of liver fibrosis. METHODS: A liver fibrosis model of different stages (S0-S4) was established in cynomolgus monkeys. The changes in MR-PWI quantitative and semi-quantitative parameters with the progression of liver fibrosis were investigated. RESULTS: MR-PWI quantitative parameters gradually decreased with the progression of liver fibrosis. Hepatic arterial perfusion index (HPI) was found to increase with the progression of liver fibrosis and significant differences of HPI between each group were observed. There was a highly positive correlation between HPI and the stages of liver fibrosis. Receiver operating characteristic (ROC) curve analysis showed that HPI had the highest efficacy of the MR-PWI quantitative parameters for the diagnosis of liver fibrosis. The MR-PW semi-quantitative parameters gradually reduced with the progression of liver fibrosis, and the differences were statistically significant between stages S3-S4 and S0-S2. Time to peak (TPP) gradually extended and showed a positive correlation with the stages of liver fibrosis. TTP had the highest efficacy of the semi-quantitative parameters for diagnosis of liver fibrosis. CONCLUSIONS: Both the MR-PWI quantitative and semi-quantitative parameters of the liver fibrosis model in cynomolgus monkeys varied at different stages of liver fibrosis, and HPI and TTP were the best detection indices for quantitative and semi-quantitative evaluation of liver fibrosis, respectively.

5.
Eur J Med Chem ; : 113023, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33248853

RESUMO

A series of pyrido [2, 3-d]pyrimidin-7(8H)-ones were designed and synthesized as new selective orally bioavailable Threonine Tyrosine Kinase (TTK) inhibitors. One of the representative compounds, 5o, exhibited strong binding affinity with a Kd value of 0.15 nM, but was significantly less potent against a panel of 402 wild-type kinases at 100 nM. The compound also potently inhibited the kinase activity of TTK with an IC50 value of 23 nM, induced chromosome missegregation and aneuploidy, and suppressed proliferation of a panel of human cancer cell lines with low µM IC50 values. Compound 5o demonstrated good oral pharmacokinetic properties with a bioavailability value of 45.3% when administered at a dose of 25 mg/kg in rats. Moreover, a combination therapy of 5o with paclitaxel displayed promising in vivo efficacy against the HCT-116 human colon cancer xenograft model in nude mice with a Tumor Growth Inhibition (TGI) value of 78%. Inhibitor 5o may provide a new research tool for further validating therapeutic potential of TTK inhibition.

6.
J Med Chem ; 63(23): 14404-14424, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33225706

RESUMO

KRAS, the most frequently mutated oncogene, plays a predominant role in driving initiation and progression of cancers. Decades of effort to target KRAS using small molecules has been unsuccessful, causing KRAS to be considered an "undruggable" cancer target. However, this view began to change recently, as drug discovery techniques have developed several KRAS G12C allosteric inhibitors that are currently being evaluated in clinical trials. Herein we provide an in-depth analysis of the structure and binding pockets of KRAS, medicinal chemistry optimization processes, and the biological characterization of small-molecule inhibitors that directly target KRAS, including covalent allosteric inhibitors specific for the G12C mutant, GTP-competitive inhibitors targeting the nucleotide-binding site, and protein-protein interaction inhibitors that bind in the switch I/II pocket or the A59 site. Additionally, we propose potential challenges faced by these new classes of KRAS inhibitors under clinical evaluation.

7.
Plant Signal Behav ; 15(12): 1827782, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33040671

RESUMO

Dopamine (3-hydroxytyramine or 3,4-dihydroxyphenethylamine) has many functions in animals, but also shows several other functions in plants. Since the discovery of dopamine in plants in 1968, many studies have provided insight into physiological and biochemical functions, and stress responses of this molecule. In this review, we describe the biosynthesis of dopamine, as well as its role in plant growth and development. In addition, endogenous or exogenously applied dopamine improved the tolerance against several abiotic stresses, such as drought, salt, and nutrient stress. There are also several studies that dopamine contributes to the plant immune response against plant disease. Dopamine affects the expression of many abiotic stresses related genes, which highlights its role as a multi-regulatory molecule and can coordinate many aspects of plant development. Our review emphasized the effects of dopamine against environmental stresses along with future research directions, which will help improve the yield of eco-friendly crops and ensure food security.

8.
J Pediatr Psychol ; 45(10): 1166-1176, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33083838

RESUMO

OBJECTIVE: The objectives were to identify profiles of school-age children with overweight and obesity (OW/OB) from rural counties based on patterns of diet, activity, and sleep, to examine demographic predictors, and to examine whether profiles were differentially associated with psychosocial functioning. METHODS: Participants included 163 children (Mage = 9.8) and parents. Children wore accelerometers to assess physical activity and sleep duration. Consumption of fruits and vegetables (F/V) and sugar-sweetened beverages (SSB) was assessed with a food frequency questionnaire. Self-report of emotional, social, and academic health-related quality of life (HRQOL), peer victimization, social skills, and social problem behaviors was collected, as well as parent-report of HRQOL. Latent variable mixture modeling (LVMM) was conducted. RESULTS: Sleep did not significantly contribute to profile differentiation and was removed. Four profiles emerged: (a) Low F/V + Low SSB + Low activity, (b) Low F/V + Low SSB + Moderate activity, (c) High F/V + High SSB + Low activity, and (d) Moderate F/V + Moderate SSB + High activity. Older children were more likely to be in profile 1. After controlling for child age, parents of children in profile 1 reported significantly lower child social HRQOL than parents of children in profiles 2 and 4. Children in profile 4 reported experiencing significantly lower victimization than those in profile 3. CONCLUSIONS: There are subgroups of rural children with OW/OB that engage in various combinations of healthy and unhealthy behaviors. LVMM has the potential to inform future interventions and identify needs of groups of children with OW/OB.

9.
Med Sci Monit ; 26: e923567, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985495

RESUMO

BACKGROUND Existing research evidence indicates that breast cancer patients have different degrees of cognitive dysfunction after chemotherapy, and polymorphisms in 3 genes (catechol-O-methyltransferase, COMT; apolipoprotein E, APOE; and brain-derived neurotrophic factor, BDNF) have been associated with cognitive impairment. However, the role of these 3 gene polymorphisms in modulating cognitive impairment in breast cancer survivors with varying hormonal receptor expression is not clear at present. To explore the effects of genetic polymorphisms in BDNF, APOE, and COMT on the regulation of prospective memory impairments induced by chemotherapy in breast cancer patients with various expression levels of estrogen receptor (ER) and progesterone receptor (PR). MATERIAL AND METHODS A total of 232 patients with breast cancer (113 with ER-/PR- and 119 with ER+/PR+) were evaluated before and after chemotherapy for cognitive function, including prospective memory. Following previously published sequencing procedures, we assessed 6 single-nucleotide polymorphisms (SNPs), including BDNF (rs6265), APOE (rs429358, rs7412), and COMT (rs165599, rs4680, rs737865). RESULTS The patients showed poorer prospective memory scores after chemotherapy than before chemotherapy. Furthermore, the ER-/PR- group showed poorer event-based prospective memory (EBPM) scores than the ER+/PR+ group (z=-7.831, p<0.01) after chemotherapy. The patients with the COMT rs737865G/G genotype, compared with those with the A/A and A/G genotypes, showed a linear EBPM performance (ß=1.499, 95% confidence interval (CI)=1.017~2.211) and were less likely to have memory impairment. In contrast, APOE and BDNF polymorphisms did not influence cognitive performance. CONCLUSIONS The patterns of hormonal receptor expression may be related to prospective memory impairments induced by chemotherapy in breast cancer patients. Furthermore, the COMT polymorphism (rs737865) was linearly related to the extent of deficits in EBPM and may represent a potential genetic marker of risk for cognitive deficits triggered by chemotherapy in patients with breast cancer.

10.
Artigo em Inglês | MEDLINE | ID: mdl-32882530

RESUMO

A new type of immunomagnetic bead based on the metal-organic framework materials (MOFs) and the magnetic core (Fe3O4) was prepared for analysis of the mycotoxins in food samples. The MOF conjugated with the monoclonal antibodies (McAbs) was coated on the surface of Fe3O4 beads by reversed-phase microemulsion method, which could purify deoxynivalenol (DON), zearalenone (ZEN), T-2, and HT-2 mycotoxins at the same time. The composite (Fe3O4@AMP&ZnCl2@McAbs) was characterized by Transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FTIR), and Energy dispersive spectroscopy (EDS) mapping. The results showed that the synthesis of the composite was successful. The maximum toxin adsorption capacity per 100 mg of composite was DON 688.26 ng, ZEN 864.98 ng, and T-2/HT-2 2801.80 ng, and in adding recovery experiment, the recovery of four mycotoxins decreased slightly with the increase of usage times, but still maintained a high adsorption rate and stability. For effectiveness comparison and evaluation, the composite and commercial DZTMS-PREP immune affinity column were used to treat three samples of corn, wheat, and oat flour, and the purification effect of the two pretreatment methods on the four toxins was similar.

11.
Med Oncol ; 37(9): 77, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32743717

RESUMO

The molecular mechanisms underlying colon cancer lesions at different sites are not entirely clear. Herein, we aimed to explore location-specific gene profiles related to the pathogenesis of colon cancer and to identify their function. The robust rank aggregation (RRA) method was used to integrate colon cancer microarray datasets and screen differentially expressed gene (DEG) profiles between left- and right-sided colon cancers. Then, weighted gene co-expression network analysis (WGCNA) was performed to cluster the DEGs into modules and identify hub genes. The selected hub genes were validated using The Cancer Genome Atlas dataset and clinical tissues. We assessed the association of selected hub genes with the methylation status in immune cells. In total, 905 DEGs were identified by RRA; five gene modules and 18 hub genes were related to the clinical traits of colon cancer by WGCNA. Four hub genes were selected and shown to be associated with colon cancers on different sides and distant metastasis in the validation analysis. The four hub genes showed a low methylation status, and their expression was significantly associated with methylation status. Positive correlations were observed between the four hub genes and tumor purity and among the four types of immune cells. Gene set enrichment analysis revealed that the four hub genes were mainly involved in two cancer-related pathways. In conclusion, this study identified a set of location-specific genes related to the pathogenesis of colon cancer. These four hub genes may act as novel candidate targets for the treatment of colon cancer.

12.
Am J Transl Res ; 12(6): 3046-3056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32655829

RESUMO

To investigate changes in cytokine (IL-1ß, TNF-α and IL-4) levels before and after chemotherapy and their correlation with cognitive impairment in early-stage breast cancer (BC) patients, the 190 BC patients enrolled in this study were divided into two groups: a before chemotherapy group (BCG) and an after chemotherapy group (ACG). The BCG was also divided into two subgroups according to the cognitive assessment results: one group with normal cognition (CNG) and one group with impaired cognition (CIG). Plasma cytokine levels (IL-1ß, TNF-α, and IL-4) were evaluated in all patients. The mini-mental state examination (MMSE), prospective and retrospective memory questionnaire (PRMQ), and functional assessment of cancer therapy-cognitive function version 3 (FACT-Cog, version 3) were used to evaluate patients' self-perceived cognitive impairments. Furthermore, their quality of life (QOL) was evaluated. Plasma IL-1ß, TNF-α and IL-4 levels were higher in the ACG than in the BCG (Z = -3.089, -2.458 and -1.987; P = 0.002, 0.014, and 0.047; respectively). Moreover, plasma IL-1ß, TNF-α and IL-4 levels were higher in the CIG than in the CNG (Z = -4.353, -3.383 and -2.522; P = 0.000, 0.001 and 0.012; respectively). Furthermore, a correlation was noted between cognition (MMSE, retrospective memory (RM), prospective memory (PM), and FACT-Cog scores) and QOL in BC patients (r = -0.790, 0.852, 0.847 and 0.937, respectively), and a correlation was observed between cognition and cytokine levels (IL-1ß, TNF-α, and IL-4) in BC patients (r = -0.681, -0.572 and -0.626; respectively). The present results indicated that changes in cytokine levels may occur in BC patients with chemotherapy-related cognitive impairment (CRCI). We also found that CRCI was associated with QOL after chemotherapy in BC patients. This study provides a theoretical basis for the improvement of QOL in BC patients.

13.
Integr Cancer Ther ; 19: 1534735420938450, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32683997

RESUMO

Objective: To evaluate the effectiveness and feasibility of Managing Cancer and Living Meaningfully (CALM), which is used to reduce chemotherapy-related cognitive impairment (CRCI), relieve psychological distress, and improve quality of life (QOL) in Chinese breast cancer survivors (BCs). Methods: Seventy-four BCs were enrolled in this study. All patients were randomly assigned to either the CALM group or the care as usual (CAU) group. All patients were evaluated by the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), Distress Thermometer (DT), and the Functional Assessment of Cancer Therapy-Breast (FACT-B) before and after CALM or CAU application to BCs with CRCI. We compared the differences in all these scores between the CALM group and the control group and analyzed the correlation between cognitive function and QOL. Results: Compared with the CAU group, the performance of the CALM group on the FACT-Cog, DT, and FACT-B showed significant differences before and after CALM (t = -18.909, -5.180, -32.421, P = .000, .000, .000, respectively). Finally, there was a positive correlation between cognitive function and QOL in breast cancer patients before (r = 0.579, P = .000) and after (r = 0.797, P = .000) treatment. Conclusions: The present results indicated that CALM has salutary effects on the improvement of cognitive impairment and QOL and relieves psychological distress in breast cancer patients, which may be due to a positive correlation between psychological distress and cognitive function or QOL.

14.
Eur J Med Chem ; 203: 112552, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32702585

RESUMO

Neurotrophic receptor tyrosine kinase (NTRK) fusions are oncogenic drivers for a variety of adult and pediatric tumors, validated by the US FDA approval of small molecular Trk inhibitors Larotrectinib (1, LOXO-101) and Entrectinib (2). However, gene mutation mediated resistance becomes a major challenge for Trk inhibitor therapies. Herein, we report the design, synthesis and Structure-Activity Relationship investigation of a series of 3-vinylindazole derivatives as new Trk inhibitors with low nanomolar potencies. A representative compound, 7mb, binds to TrkA/B/C with Kd values of 1.6, 3.1 and 4.9 nM, and suppresses their kinase functions with IC50 values of 1.6, 2.9 and 2.0 nM, respectively, but is obviously less potent for the majority of a panel of 403 wild-type kinases in a KINOMEscan selectivity investigation. The compound also potently suppresses proliferation of a panel of BaF3 cells stably transformed with NTRK fusions with IC50 values in low nM ranges. Additionally, the compound exhibits strong inhibition against the Larotrectinib-resistant cells with NTRK1-G667C or NTRK3-G696A mutations with IC50 values of 0.031 and 0.018 µM, respectively. Although the relatively poor oral bioavailability of 7mb will limit its further development, this compound may be utilized a lead molecule for further structural optimization.

15.
J Am Heart Assoc ; 9(12): e015513, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32476536

RESUMO

Background Aberrant activation of the NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat-containing receptor family pyrin domain-containing 3) inflammasome is thought to play a causative role in atherosclerosis. NLRP3 is kept in an inactive ubiquitinated state to avoid unwanted NLRP3 inflammasome activation. This study aimed to test the hypothesis that pharmacologic manipulating of NLRP3 ubiquitination blunts the assembly and activation of the NLRP3 inflammasome and protects against vascular inflammation and atherosclerosis. Since genetic studies yielded mixed results about the role for this inflammasome in atherosclerosis in low-density lipoprotein receptor- or apolipoprotein E-deficient mice, this study attempted to clarify the discrepancy with the pharmacologic approach using both models. Methods and Results We provided the first evidence demonstrating that tranilast facilitates NLRP3 ubiquitination. We showed that tranilast restricted NLRP3 oligomerization and inhibited NLRP3 inflammasome assembly. Tranilast markedly suppressed NLRP3 inflammasome activation in low-density lipoprotein receptor- and apolipoprotein E-deficient macrophages. Through reconstitution of the NLRP3 inflammasome in human embryonic kidney 293T cells, we found that tranilast directly limited NLRP3 inflammasome activation. By adopting different regimens for tranilast treatment of low-density lipoprotein receptor- and apolipoprotein E-deficient mice, we demonstrated that tranilast blunted the initiation and progression of atherosclerosis. Mice receiving tranilast displayed a significant reduction in atherosclerotic lesion size, concomitant with a pronounced decline in macrophage content and expression of inflammatory molecules in the plaques compared with the control group. Moreover, tranilast treatment of mice substantially hindered the expression and activation of the NLRP3 inflammasome in the atherosclerotic lesions. Conclusions Tranilast potently enhances NLRP3 ubiquitination, blunts the assembly and activation of the NLRP3 inflammasome, and ameliorates vascular inflammation and atherosclerosis in both low-density lipoprotein receptor- and apolipoprotein E-deficient mice.

16.
Nature ; 580(7805): 658-662, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32350467

RESUMO

R-type bacteriocins are minimal contractile nanomachines that hold promise as precision antibiotics1-4. Each bactericidal complex uses a collar to bridge a hollow tube with a contractile sheath loaded in a metastable state by a baseplate scaffold1,2. Fine-tuning of such nucleic acid-free protein machines for precision medicine calls for an atomic description of the entire complex and contraction mechanism, which is not available from baseplate structures of the (DNA-containing) T4 bacteriophage5. Here we report the atomic model of the complete R2 pyocin in its pre-contraction and post-contraction states, each containing 384 subunits of 11 unique atomic models of 10 gene products. Comparison of these structures suggests the following sequence of events during pyocin contraction: tail fibres trigger lateral dissociation of baseplate triplexes; the dissociation then initiates a cascade of events leading to sheath contraction; and this contraction converts chemical energy into mechanical force to drive the iron-tipped tube across the bacterial cell surface, killing the bacterium.

17.
J Med Chem ; 63(19): 10726-10741, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-32432477

RESUMO

Clinically acquired resistance to small molecule kinase inhibitors (SMKIs) has become a major "unmet clinical need" in cancer therapy. To date, there are six SMKIs to be approved for the treatment of cancer patients through targeting of clinically acquired resistance caused by on-target mutations. These are mainly focused on the mutant kinases Bcr-Abl T315I, EGFR T790M, and ALK L1196M. Herein, we summarize the major medicinal chemistry strategies employed in the discovery of these representative SMKIs, such as avoiding steric hindrance, making additional interactions with mutated residues, and forming a covalent bond with an active site cysteine to override resistance observed for reversible inhibitors. Additionally, we also briefly describe allosteric kinase inhibitors and proteolysis targeting chimera (PROTAC) as two other potential strategies while addressing future opportunities in this area.

18.
Cell Prolif ; 53(6): e12826, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32419250

RESUMO

OBJECTIVES: BCL2 family proteins have been widely studied over the past decade due to their essential roles in apoptosis, oncogenesis and anti-cancer therapy. However, the similarities and differences in the spatial pattern of the BCL2 gene family within the context of chromatin have not been well characterized. We sought to fill this knowledge gap by assessing correlations between gene alteration, gene expression, chromatin accessibility, and clinical outcomes in gynaecologic and breast cancer. MATERIALS AND METHODS: In this study, the molecular characteristics of the BCL2 gene family in gynaecologic cancer were systematically analysed by integrating multi-omics datasets, including transcriptomics, chromatin accessibility, copy number variation, methylomics and clinical outcome. RESULTS: We evaluated spatiotemporal associations between long-range regulation peaks and tumour heterogeneity. Differential expression of the BCL2 family was coupled with widespread chromatin accessibility changes in gynaecologic cancer, accompanied by highly heterogeneous distal non-coding accessibility surrounding the BCL2L1 gene loci. A relationship was also identified between gene expression, gene amplification, enhancer signatures, DNA methylation and overall patient survival. Prognostic analysis implied clinical correlations with BAD, BIK and BAK1. A shared protein regulatory network was established in which the co-mutation signature of TP53 and PIK3CA was linked to the BCL2L1 gene. CONCLUSIONS: Our results provide the first systematic identification of the molecular features of the BCL2 family under the spatial pattern of chromatin in gynaecologic and breast cancer. These findings broaden the therapeutic scope of the BCL2 family to the non-coding region by including a significantly conserved distal region overlaying an enhancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias dos Genitais Femininos/genética , Família Multigênica , Proteínas Proto-Oncogênicas c-bcl-2/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Cromatina/metabolismo , Metilação de DNA , Elementos Facilitadores Genéticos , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias dos Genitais Femininos/metabolismo , Neoplasias dos Genitais Femininos/mortalidade , Humanos , Estimativa de Kaplan-Meier , Prognóstico , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/metabolismo
19.
Sci Total Environ ; 730: 138888, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32402961

RESUMO

Eastern China has been facing severe winter haze pollution due mainly to secondary aerosol. Existing studies have suggested that stagnant weather or fast chemical production led to frequent haze in this region. However, few works focus on the linkage between secondary production of sulfate, nitrate, and ammonium (SNA) and synoptic conditions, and their joint contribution to PM2.5. In this study, by combining in-situ measurements on meteorology and aerosol chemical composition at three main cities together with a regional model with improved diagnose scheme, we investigated the chemical formation and accumulation of main secondary composition, i.e. SNA under typical synoptic conditions. It is indicated that SNA did play a vital role in haze pollution across eastern China, contributing more than 40% to PM2.5 mass concentration. As most fast developing region, the Yangtze River Delta (YRD) was slightly polluted during stable weather with local chemical production accounting for 61% SNA pollution. While under the influence of cold front, the pollution was aggravated and advection transport became the predominant contributive process (85%). Nevertheless, the chemical production of SNA was notably enhanced due to the uplift of air pollutant and elevated humidity ahead of the cold front, which then facilitated the heterogeneous and aqueous-phase oxidation of precursors. We also found the substantial difference in the phase equilibrium of nitrate over the land surface and ocean due to changes in temperature, ammonia availability and dry deposition. This study highlights the close link between synoptic weather and chemical production, and the resultant vertical and spatial heterogeneity of pollution.

20.
Mol Cancer ; 19(1): 90, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404161

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond to first-generation EGFR inhibitors; however, the efficacy of these drugs is limited by acquired resistance driven by the EGFR T790M mutation. The discovery of third-generation EGFR inhibitors overcoming EGFR T790M and their new resistance mechanisms have attracted much attention. METHODS: We examined the antitumor activities and potential resistance mechanism of a novel EGFR third-generation inhibitor in vitro and in vivo using ELISA, SRB assay, immunoblotting, flow cytometric analysis, kinase array, qRT-PCR and tumor xenograft models. The clinical effect on a patient was evaluated by computed tomography scan. RESULTS: We identified compound ASK120067 as a novel inhibitor of EGFR T790M, with selectivity over EGFR WT. ASK120067 exhibited potent anti-proliferation activity in tumor cells harboring EGFR T790M (NCI-H1975) and sensitizing mutations (PC-9 and HCC827) while showed moderate or weak inhibition in cells expressing EGFR WT. Oral administration of ASK120067 induced tumor regression in NSCLC xenograft models and in a PDX model harboring EGFR T790M. The treatment of one patient with advanced EGFR T790M-positive NSCLC was described as proof of principle. Moreover, we found that hyperphosphorylation of Ack1 and the subsequent activation of antiapoptotic signaling via the AKT pathway contributed to ASK120067 resistance. Concomitant targeting of EGFR and Ack1 effectively overrode the acquired resistance of ASK120067 both in vitro and in vivo. CONCLUSIONS: Our results idenfity ASK120067 as a promising third-generation EGFR inhibitor and reveal for the first time that Ack1 activation as a novel resistance mechanism to EGFR inhibitors that guide to potential combination strategy.

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