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1.
Addict Biol ; : e12875, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32031744

RESUMO

The development of opioid addiction involves DNA methylation. Accordingly, the DNA demethylation, induced by ten-eleven translocation (Tet) enzymes, may represent a novel approach to prevent opioid addiction. The present study examined the role of TET1 and TET3 in the development of morphine-seeking behavior in rats. We showed that 1 day of morphine self-administration (SA) training upregulated TET3 but not TET1 expression in the hippocampal CA1. With 7 days of morphine SA training, the expression of TET3 in the CA1 returned to the baseline level, while the TET1 expression was downregulated. No change of TET1 and TET3 in the nucleus accumbens shell was observed in morphine SA trained rats, or in the yoked morphine rats, or in rats trained for saccharin SA. Furthermore, we found that knocking down TET3 expression in the CA1 accelerated the acquisition of morphine SA, while overexpression of the catalytic domain of TET1 in the CA1 attenuated the acquisition. Together, these findings suggest that TET1 and TET3 in the CA1 are important epigenetic modulators involved in the morphine-seeking behavior and provide a new strategy in the treatment of opioid addiction.

2.
Int Immunopharmacol ; 81: 106227, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32078941

RESUMO

Small molecule inhibitors have proven useful in the treatment of a variety of tumors, but they are often limited by unsustainable benefits and confer resistance quickly. Immunotherapy can result in durable clinical responses, but activity only occurs in a minority of patients. The unfavorable tumor microenvironment (TME) is an important factor limiting immunotherapy. An appropriate understanding of how small molecule inhibitors modulate the TME may optimize the combination of targeted treatment and immunotherapy in managing tumors. In this study, we found that transient treatment with sunitinib malate inhibited the disorganized extension of tumor vessels, pericytes and collagen IV but increased the relative ratio of pericyte-wrapping blood vessels with alleviated hypoxia in tumors, which resulted from tumor vascular normalization. Sunitinib malate increased infiltration of CD8+ T cells and decreased regulatory T cells (Tregs), accompanied by inhibited expression of TGF-ß1 and IL-10 and increased CCL-28, IFN-γ and IL-12, but no significant inhibition of myeloid-derived suppressor cells (MDSCs) was observed. In addition, sunitinib malate increased the levels of PD-1 and PD-L1 in TME, combined with anti-PD-1 therapy showed a significant reduction in tumor burden compared with either monotherapy, suggesting that anti-PD-1 therapy is reasonable after sunitinib malate treatment.

3.
BMC Cancer ; 20(1): 83, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005111

RESUMO

BACKGROUND: Gene expression profiling has consistently identified three molecular subtypes of lung adenocarcinoma that have prognostic implications. To facilitate stratification of patients with this disease into similar molecular subtypes, we developed and validated a simple, mutually exclusive classification. METHODS: Mutational status of EGFR, KRAS, and TP53 was used to define seven mutually exclusive molecular subtypes. A development cohort of 283 cytology specimens of lung adenocarcinoma was used to evaluate the associations between the proposed classification and clinicopathologic variables including demographic characteristics, smoking history, fluorescence in situ hybridization and molecular results. For validation and prognostic assessment, 63 of the 283 cytology specimens with available survival data were combined with a separate cohort of 428 surgical pathology specimens of lung adenocarcinoma. RESULTS: The proposed classification yielded significant associations between these molecular subtypes and clinical and prognostic features. We found better overall survival in patients who underwent surgery and had tumors enriched for EGFR mutations. Worse overall survival was associated with older age, stage IV disease, and tumors with co-mutations in KRAS and TP53. Interestingly, neither chemotherapy nor radiation therapy showed benefit to overall survival. CONCLUSIONS: The mutational status of EGFR, KRAS, and TP53 can be used to easily classify lung adenocarcinoma patients into seven subtypes that show a relationship with prognosis, especially in patients who underwent surgery, and these subtypes are similar to classifications based on more complex genomic methods reported previously.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32069396

RESUMO

Multi-emissive sensors are being actively pursued owning to their ratiometric luminescent detection capability which demonstrates better sensitivity and selectivity than conventional single-emission sensors. Herein we present a trichromatic white-light-emitting MOF composite (Z3) by simultaneously incorporating red/green-emitting platinum/ruthenium complex cations into porous blue-emitting bio-MOF-1 through post-synthetic modification. With the help of three-dimensional (3-D) dual-ratiometric luminescence recognition method, and unique turn on responses of the red emission toward amine compounds (ACs) , including NH3 and aliphatic amines, via confinement-induced luminescence enhancement effect, Z3 can work as a dual-ratiometric luminescent sensor for discrimination 7 out of 11 AC vapors. This work not only provides a new AC sensing mechanism (confinement effect) that can induce "turn on" response but also proves that the accuracy and selectivity of composite sensor can be greatly improved through the combination of 3-D recognition method and the confinement effect. Thus it open up fresh opportunities to develop composite sensors with excellent sensing and differentiating ability.

6.
Small ; 16(5): e1905737, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31916670

RESUMO

Conventional lithium-sulfur batteries often suffer from fatal problems such as high flammability, polysulfide shuttling, and lithium dendrites growth. Here, highly-safe lithium-sulfur batteries based on flame-retardant electrolyte (dimethoxyether/1,1,2,2-tetrafluoroethyl 2,2,3,3-tetrafluoropropyl ether) coupled with functional separator (nanoconductive carbon-coated cellulose nonwoven) to resolve aforementioned bottle-neck issues are demonstrated. It is found that this flame-retardant electrolyte exhibits excellent flame retardancy and low solubility of polysulfide. In addition, Li/Li symmetrical cells using such flame-retardant electrolyte deliver extraordinary long-term cycling stability (less than 10 mV overpotential) for over 2500 h at 1.0 mA cm-2 and 1.0 mAh cm-2 . Moreover, bare sulfur cathode-based lithium-sulfur batteries using this flame retardant electrolyte coupled with nanoconductive carbon-coated cellulose separator can retain 83.6% discharge capacity after 200 cycles at 0.5 C. Under high charge/discharge rate (4 C), lithium-sulfur cells still show high charge/discharge capacity of ≈350 mAh g-1 . Even at an elevated temperature of 60 °C, discharge capacity of 870 mAh g-1 can be retained. More importantly, high-loading bare sulfur cathode (4 mg cm-2 )-based lithium-sulfur batteries can also deliver high charge/discharge capacity over 806 mAh g-1 after 56 cycles. Undoubtedly, the strategy of flame retardant electrolyte coupled with carbon-coated separator enlightens highly safe lithium-sulfur batteries at a wide range of temperature.

7.
Clin Cancer Res ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911545

RESUMO

BACKGROUND: Tumor genomic features have been of particular interest because of their potential impact on the tumor immune microenvironment and response to immunotherapy. Due to the substantial heterogeneity, an integrative approach incorporating diverse molecular features is needed to characterize immunological features underlying primary resistance to immunotherapy and for the establishment of novel predictive biomarkers. METHODS: We developed a pan-cancer deep machine-learning model integrating tumor mutation burden, microsatellite instability and somatic copy number alterations to classify tumors of different types into different genomic clusters, assessed the immune microenvironment in each genomic cluster and the association of each genomic cluster with response to immunotherapy. RESULTS: Our model grouped 8,646 tumors of 29 cancer types from the Cancer Genome Atlas into four genomic clusters. Analysis of RNA-sequencing data revealed distinct immune microenvironment in tumors of each genomic class. Furthermore, applying this model to tumors from two melanoma immunotherapy clinical cohorts demonstrated that patients with melanoma of different genomic classes achieved different benefit from immunotherapy. Interestingly, tumors in cluster 4 demonstrated a cold immune microenvironment and lack of benefit from immunotherapy despite high microsatellite instability burden. CONCLUSION: Our study provides a proof-for-principle that deep learning modeling may have the potential to discover intrinsic statistical cross-modality correlations of multifactorial input data to dissect the molecular mechanisms underlying primary resistance to immunotherapy, which likely involves multiple factors from both the tumor and host at different molecular levels.

8.
J Dig Dis ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953907

RESUMO

OBJECTIVE: We aimed to evaluate the efficacy of living-donor liver transplantation (LDLT) in children with tyrosinemia type I. METHODS: Ten patients were diagnosed with tyrosinemia type I and underwent LDLT between June 2013 and April 2019 at Ren-Ji Hospital. Cirrhosis was the transplantation indication in all 10 patients, and HCC was suspected in 9 patients. Outcomes, including liver function, metabolism restoration, life quality and physical development, were analyzed after LDLT. RESULTS: All recipients were alive with normal liver function after a median follow-up of 49-month. Pathological examination indicated HCC in 1 patient, dysplasia in 5 patients, and cirrhosis in all. The median AFP level dropped from 2520ng/mL to a normal level after LDLT, and no recurrence of HCC was detected during follow-up. Tyrosine metabolism was restored to its normal level with normalized plasma tyrosine and succinylacetone concentration. Besides, urinary succinylacetone excretion decreased significantly during the follow-up. Furthermore, LDLT improved the renal tubular function, as evidenced by the normalized plasma phosphate concentration and by improved eGFR. Severe rickets symptoms, including spontaneous fractures and bone pain, were also ameliorated. Improved motor function was reported by all patients' parents during the follow-up period. Dietary restriction and supplementary medicine were no longer required, associated with favorable catch-up growth and improved life quality. Complete resolution of hypertrophic cardiomyopathy was observed one-year after LDLT in one patient. All donors survived the operation without any complications or compromised working ability. CONCLUSION: LDLT is a safe and effective treatment for tyrosinemia type I patients with end-stage liver disease. This article is protected by copyright. All rights reserved.

9.
J Psychopharmacol ; : 269881119895521, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31909693

RESUMO

BACKGROUND: Identifying neural substrates that are differentially affected by drugs of abuse and natural rewards is key to finding a target for an efficacious treatment for substance abuse. Melanin-concentrating hormone is a polypeptide with an inhibitory effect on the mesolimbic dopamine system. Here we test the hypothesis that melanin-concentrating hormone in the lateral hypothalamus and nucleus accumbens shell is differentially involved in the regulation of morphine and food-rewarded behaviors. METHODS: Male Sprague-Dawley rats were trained with morphine (5.0 mg/kg, subcutaneously) or food pellets (standard chow, 10-14 g) to induce a conditioned place preference, immediately followed by extinction training. Melanin-concentrating hormone (1.0 µg/side) or saline was infused into the nucleus accumbens shell or lateral hypothalamus before the reinstatement primed by morphine or food, and locomotor activity was simultaneously monitored. As the comparison, melanin-concentrating hormone was also microinjected into the nucleus accumbens shell or lateral hypothalamus before the expression of food or morphine-induced conditioned place preference. RESULTS: Microinfusion of melanin-concentrating hormone into the nucleus accumbens shell (but not into the lateral hypothalamus) prevented the reinstatement of morphine conditioned place preference but had no effect on the reinstatement of food conditioned place preference. In contrast, microinfusion of melanin-concentrating hormone into the lateral hypothalamus (but not in the nucleus accumbens shell) inhibited the reinstatement of food conditioned place preference but had no effect on the reinstatement of morphine conditioned place preference. CONCLUSIONS: These results suggest a clear double dissociation of melanin-concentrating hormone in morphine/food rewarding behaviors and melanin-concentrating hormone in the nucleus accumbens shell. Melanin-concentrating hormone could be a potential target for therapeutic intervention for morphine abuse without affecting natural rewards.

10.
Mol Pharm ; 17(1): 84-97, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31794225

RESUMO

As a BCS II drug, the atypical antipsychotic agent lurasidone hydrochloride (LH) has low oral bioavailability mainly because of its poor aqueous solubility/dissolution. Unexpectedly, amorphous LH exhibited a much lower dissolution than that of its stable crystalline form arising from its gelation during the dissolution process. In the current study, a supramolecular coamorphous system of LH with l-cysteine hydrochloride (CYS) was prepared and characterized by powder X-ray diffraction and differential scanning calorimetry. Surprisingly, in comparison to crystalline and amorphous LH, such a coamorphous system dramatically enhanced solubility (at least ∼50-fold in the physiological pH range) and dissolution (∼1200-fold) of LH, and exhibited superior physical stability under long-term storage condition. More importantly, the coamorphous system was able to eliminate gelation of amorphous LH during dissolution. In order to further explore the mechanism of such improvement, the internal interactions of the coamorphous system in the solid state and in aqueous solution were investigated. Fourier transform infrared spectroscopy, Raman spectroscopy, and solid-state 13C NMR suggested that intermolecular hydrogen bonds formed between the nitrogen atom in the benzisothiazole ring of LH and the NH3+ group of CYS after coamorphization. A fluorescence quenching test with a Stern-Volmer plot and density functional theory modeling, phase-solubility study, and NMR test in D2O indicated that ground-state complexation occurred between LH and CYS in aqueous solution, which contributed to the solubility and dissolution enhancement of LH. The current study offers a promising strategy to overcome poor solubility/dissolution and be able to eliminate gelation of amorphous materials by coamorphization and complexation.

11.
Kidney Blood Press Res ; 45(1): 84-94, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31794962

RESUMO

BACKGROUND AND OBJECTIVES: This study was to characterize the association of cumulative exposure to increased high-sensitivity C-reactive protein (hs-CRP) with chronic kidney diseases (CKD). METHODS: We included 35,194 participants with hs-CRP measured at three examinations in 2006, 2008, 2010. Participants were classified into nonexposed group (hs-CRP <3.0 mg/L in all 3 examinations), 1-exposed group (hs-CRP ≥3.0 mg/L in 1 of the 3 examinations), 2-exposed group (hs-CRP ≥3.0 mg/L in 2 of the 3 examinations), and 3-exposed group (hs-CRP ≥3.0 mg/L in 3 examinations). Cox proportional hazards models were used to assess the association of cumulative hs-CRP with incident CKD. CKD includes an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or urinary protein positive. RESULTS: The study showed the risk of CKD as the number of years of exposure to hs-CRP increases. Participants in 3-exposed group had significantly increased CKD risk with hazard ratio (HR) (95% confidence interval, CI) of 1.70 (1.49-1.93), in comparison with 1.47 (1.34-1.62) for participants in the 2-exposed group, and 1.08 (1.00-1.16) for those in the 1-exposed group (p < 0.01); meanwhile, the similar and significant associations were also observed for eGFR <60 mL/min/1.73 m2, proteinuria positive, in participants of the 3-exposed group in comparison with the nonexposed group, with respective HRs (95% CI) of 1.27 (1.01-1.58) and 2.27 (1.87-2.76). CONCLUSIONS: Cumulative exposure to hs-CRP was associated with a subsequent increased risk of CKD and was of great value to risk prediction.

12.
Int J Radiat Oncol Biol Phys ; 106(2): 349-357, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31678224

RESUMO

PURPOSE: NCT01725165 was a phase II prospective trial in which patients with non-small cell lung cancer were randomized to local consolidative therapy (LCT) versus maintenance therapy or observation (MT/O). METHODS AND MATERIALS: Peripheral blood from patients enrolled on NCT01725165 were labeled as (1) baseline, (2) early follow-up (FU) if obtained in the first or second FU evaluation (6-18 weeks), and (3) late FU if obtained in the third to sixth FU evaluations (22-50 weeks). All patients who underwent LCT and were included in this analysis received radiation. Among 49 randomized patients, 21 patients underwent T cell CDR3 variable region sequencing using immunoSEQ, 31 patients underwent circulating tumor DNA (ctDNA) analysis using next-generation sequencing with a 1021 cancer gene panel, and cytokine concentration was assayed in 19 patients using enzyme-linked immunosorbent assay. All analyses were exploratory and not corrected for multiple testing. RESULTS: No associations were identified between baseline T cell repertoire and ctDNA metrics with patient outcomes. Among baseline cytokines, interleukin 1α was the only cytokine associated with both overall survival (hazard ratio, 0.02; 95% confidence interval, 0.1-0.5; P = .0006) and progression-free survival (hazard ratio, 0.5; 95% confidence interval, 0.2-0.9; P = .03). At early FU, LCT was associated with decreased ctDNA burden, including lower number of detected mutations (median, 2 [interquartile range {IQR}, 1-6] vs 6 [IQR, 4-18]) and decreased average variable allele frequency (VAF; median, 0.006 [IQR, 0.003-0.010] vs 0.011 [IQR, 0.007-0.014]) compared with MT/O. Among 6 patients with serial ctDNA analysis, a rise in ctDNA detected mutation burden preceded clinical progression by 6.7 months. At early FU, LCT was associated with changes in T cell clonality that suggested oligoclonal expansion specifically increased T cell clonality (median, 0.15 [IQR, 0.12-0.24] vs 0.10 [IQR, 0.05-0.13]) and frequency of top 10 clones (median, 0.14 [IQR, 0.06-0.18] vs 0.21[IQR, 0.19-0.28]). CONCLUSION: LCT was associated with decreased ctDNA burden and oligoclonal expansion at early FU timepoints. Baseline interleukin 1α was associated with improved patient outcomes.

13.
Clin Lung Cancer ; 21(1): 37-46.e7, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31447303

RESUMO

BACKGROUND: Local consolidative therapy (LCT) to optimize disease control is an evolving management paradigm in non-small-cell lung cancer (NSCLC) patients who present with a limited metastatic disease burden. We hypothesized that LCT to all sites of disease would be associated with improved overall survival (OS) among patients with synchronous oligometastatic NSCLC. PATIENTS AND METHODS: Patients presenting to a single institution (2000-2017) with stage IV NSCLC and ≤ 3 synchronous metastases were identified. Intrathoracic nodal disease was counted as one site. Landmark and propensity-adjusted Cox regression analyses were performed to identify factors associated with OS. RESULTS: Of 194 patients, 143 (74%) had 2 or 3 sites of metastasis. LCT was delivered to all sites of disease in 121 patients (62%), to some but not all sites in 52 (27%), and were not used in 21 (11%). Comprehensive LCT was independently associated with improved OS (hazard ratio [HR] = 0.67; 95% confidence interval [CI], 0.46-0.97; P = .034), with the greatest therapeutic effect among patients without thoracic nodal disease, bone metastases, or > 1 metastatic site. Among patients who underwent comprehensive LCT, tumor histology (squamous: HR = 2.32; 95% CI, 1.28-4.22; P = .006), intrathoracic disease burden (T3-4: HR = 1.67; 95% CI, 0.97-2.86; P = .065; N3: HR = 1.90; 95% CI, 0.90-4.03; P = .093), and bone metastases (HR = 1.74; 95% CI, 1.02-3.00; P = .044) were associated with poor OS. CONCLUSION: Comprehensive LCT was associated with improved OS in this large cohort of patients with synchronous oligometastatic NSCLC. These results support ongoing prospective efforts to characterize the therapeutic benefits associated with this management strategy.

14.
Ann Thorac Surg ; 109(2): 358-366, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31550464

RESUMO

BACKGROUND: High tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are leading biomarkers in metastatic non-small cell lung cancer (NSCLC) and predict favorable response to checkpoint inhibitors. We sought to identify clinicopathologic characteristics associated with elevated TMB and PD-L1 expression among patients who underwent resection for NSCLC. METHODS: NSCLC patients undergoing primary resection (2016-2018) were prospectively enrolled in an immunogenomic profiling project. Multiplex immunofluorescence quantified densities (cells/mm2) of CD3+, CD3+CD8+, CD3+CD8+PD-1+, malignant cells (MCs), MCsPD-L1+, CD68+, CD68+PD-L1+, and CD20+ cells. Whole-exome sequencing quantified TMB (mutations/megabase). TMB and MCsPD-L1+ were dichotomized according to the median of each. RESULTS: A total of 55 patients completed multiplex immunofluorescence and whole-exome sequencing profiling. In this sample, 41.8% (23 of 55) had pathologic stage I disease. Median TMB and MCsPD-L1+ were 3.91 and 0.62 cells/mm2, respectively. TMB was higher among smokers (P = .001) and tumors with lymphovascular invasion (LVI) (P = .051). TMB was positively correlated with densities of MCsPD-L1+ (r = 0.293, P = .030), CD68+PD-L1+ (r = 0.289, P = .033), and CD20+ (r = 0.310, P = .043) cells. The density of MCsPD-L1+ was associated with increased CD3+CD8+ (r = 0.319, P = .018) and CD68+PD-L1+ (r = 0.371, P = .005) cells. Patients with PD-L1HighTMBHigh tumors (30.9%, 17 of 55) had higher intratumoral densities of CD3+, CD3+CD8+, CD68+, CD68+PD-L1+, and CD20+ cells. On multivariable analysis LVI was associated with synchronous elevated TMB and PD-L1 expression (odds ratio 3.53, P = .039). CONCLUSIONS: NSCLC tumors with elevated TMB and PD-L1 expression are associated with LVI and increased intratumoral immune cell infiltration. These findings may potentially improve patient selection for checkpoint inhibitor therapy trials in the adjuvant setting.

15.
Aging Clin Exp Res ; 32(1): 21-27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30863943

RESUMO

BACKGROUND: Whether vitamin D receptor (VDR) genetic variants influence individual susceptibility to neurodegenerative disorders remains controversial. AIMS: This meta-analysis was conducted to analyze correlations of VDR genetic variants with two types of most common neurodegenerative disorders, Parkinson's disease (PD) and Alzheimer's disease (AD). METHODS: Systematic literature research of PubMed and Embase was performed to identify eligible articles. Q test and I2 statistic were employed to decide whether pooled analyses would be performed with random-effect models (REMs) or fixed-effect models (FEMs). All statistical analyses were conducted with Review Manager. RESULTS: Totally sixteen studies were enrolled for analyses. Among these eligible studies, ten studies were about PD (2356 cases and 2815 controls) and six studies were about AD (1256 cases and 1205 controls). Pooled overall analyses suggested that VDR rs7975232 (additive model: p = 0.03, OR = 1.19, 95% CI 1.01-1.39) and rs2228570 (recessive model: p < 0.008, OR = 1.26, 95% CI 1.06-1.50; allele model: p < 0.001, OR = 0.80, 95% CI 0.71-0.91) variants were significantly correlated with PD, and VDR rs731236 (dominant model: p = 0.003, OR = 0.70, 95% CI 0.56-0.89; additive model: p = 0.02, OR = 1.32, 95% CI 1.06-1.66; allele model: p = 0.02, OR = 0.82, 95% CI 0.69-0.96) variant was significantly correlated with AD. Further subgroup analyses by ethnicity revealed that the positive results were mainly driven by the Asians, whereas no significant associations were observed in Caucasians. CONCLUSION: Our meta-analysis suggested that VDR rs7975232 and rs2228570 variants might serve as genetic biomarkers of PD, whereas VDR rs731236 variant might serve as a genetic biomarker of AD.

16.
Pest Manag Sci ; 76(2): 807-817, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31400044

RESUMO

BACKGROUND: The use of exo-16,17-dihydro-gibberellin A5-13-acetate (DHGA5 ) in agriculture has been limited by its low synthetic yield. This study was aimed at optimizing the synthetic route of DHGA5 , designing and synthesizing new derivatives with strong plant growth inhibitory activities. RESULTS: Previous synthetic methods were replaced with a shorter, milder and faster reaction route with higher yield (76.3%) of DHGA5 . Based on this novel route, a series of new derivatives were designed and synthesized using DHGA5 as a lead compound and characterized and evaluated for biological activities in Arabidopsis thaliana. Among the 15 tested derivatives, compound 14j showed a lower medium inhibition concentration (IC50 , 73 µm) in Arabidopsis than that of DHGA5 (91 µm). Gibberellin deficient mutant assay further revealed that 14j had very different activities compared to DHGA5 as it specifically inhibits gibberellin biosynthetic pathways. In addition, 14j does not influence the interaction between gibberellin receptors (GID1) and the master growth repressor (RGA) based on yeast two-hybrid assay. CONCLUSION: The optimized synthetic route provides a promising method for large-scale preparation of DHGA5 . Our biological assays indicate that 14j likely acts on gibberellin signaling elements other than GID1. These results indicate that novel plant growth regulators can be developed. © 2019 Society of Chemical Industry.

17.
Int J Cancer ; 146(5): 1359-1368, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31241775

RESUMO

Tumor heterogeneity was associated with treatment outcome of metastatic cancers but few studies have examined whether tumor heterogeneity in circulating tumor DNA (ctDNA) can be used to predict treatment outcome. ctDNA analysis was performed in 37 HER2-positive metastatic breast cancer patients treated with pyrotinib. Patients with high tumor heterogeneity had significantly worse PFS outcomes, with a median PFS of 30.0 weeks vs. 60.0 weeks for patients with low tumor heterogeneity (hazard ratio [HR], 2.9; p = 0.02). Patients with trunk resistance mutations receiving pyrotinib monotherapy had worse outcomes (HR, 4.5; p = 0.03), with a median PFS of 7.8 weeks vs. 27.4 weeks for those with branch resistance mutations or without any resistance mutations in baseline ctDNA. Longitudinal monitoring of 21 patients during treatment showed that the molecular tumor burden index ([mTBI] a measure of the percentage of ctDNA in samples) was positively correlated with tumor size as evaluated by computed tomography (p < 0.0001, Pearson r = 0.52) and detected disease progression 8-16 weeks earlier. Our current findings suggested that ctDNA could be used to assess tumor heterogeneity and predict treatment outcomes. Furthermore, the mTBI is better for assessing therapeutic response than single gene mutations and might supplement the current therapeutic response evaluation system.

18.
ACS Appl Mater Interfaces ; 12(3): 3531-3538, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31859470

RESUMO

Perovskite solar cells (PSCs) have attracted tremendous attention because of their rapidly growing efficiency and low cost. However, the efficiency of scalably deposited PSCs, especially spray-coated devices, is still lagging far behind that of spin-coated devices because of the complicated crystallization of coated precursor ink. Here, we show a precursor ink with an ultrawide processing window (more than 40 min) for spray-coating by adjusting the precursor component, which benefits the scalable deposition of perovskite films. Coupled with antisolvent extraction and addition of methylamine chloride to perovskite ink, high-quality perovskite films were achieved with large-scale uniformity. A power conversion efficiency (PCE) of 18.5% for rigid sprayed PSCs and 16.15% for flexible sprayed PSCs were achieved. At the square-centimeter level, sprayed PSCs on rigid and flexible substrates were achieved with PCEs of 15.07 and 13.21%, respectively. The one-step single-pass spraying method for versatility substrates at a deposition rate of 540 m h-1 brings great prospects for commercialization of PSCs.

20.
BMC Cancer ; 19(1): 1168, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791278

RESUMO

BACKGROUND: Adult Ewing sarcoma (ES) is a rare disease, the optimal treatment model is unknown. This study aimed to retrospectively analyze treatment-related prognostic factors of nonspinal ES in Chinese adults. METHODS: Eighty-one patients treated between January 2005 and December 2017 were included in the present study. Thirty-three (40.7%) presented with metastatic disease at diagnosis. Eight patients were submitted to primary surgery followed by chemotherapy, while 73 patients received chemotherapy before and after surgery and/or local radiotherapy. The chemotherapy regimen included 8-17 cycles of vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE) every 3 weeks. Clinical outcomes and safety were analyzed. RESULTS: VDC/IE chemotherapy was well tolerated in adult patients with ES. Multivariate Cox regression analyses revealed that chemotherapy of at least 12 cycles was a favorable independent prognostic factor of event-free survival (hazard ratio, 0.558; 95% confidence interval, 0.323-0.965; P = 0.037) and overall survival (hazard ratio, 0.424; 95% confidence interval, 0.240-0.748; P = 0.003). Similarly, a low frequency of chemotherapy delays was an independent prognostic factor of improved OS (hazard ratio, 0.438; 95% confidence interval, 0.217-0.887; P = 0.022). CONCLUSION: Our study suggests that adults with ES should be treated with an aggressive multidisciplinary approach, intensive chemotherapy with adequate cycles and appropriate intervals can be recommended in this group.

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