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1.
Ophthalmic Res ; 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33652438

RESUMO

INTRODUCTION: Amlyopia always presents with monocular and binocular dysfunction. In this study, we aim to investage the efficacy of alternative occlusion using liquid crystal glasses versus continuous occlusion therapy using traditional patches for treating amblyopia. METHODS: Eligible subjects with anisometropic amblyopia were randomized into two groups: alternative flicker glass (AFG) or patching group. In the AFG group, subjects were instructed to wear the flicker glasses for 1 hour a day. The AFG is a lightweight spectacle frame with liquid crystal lenses that provide direct square-wave alternating occlusion, which were pre-programmed at temporal frequency of 7Hz. In the patching group, the patients were prescribed to wear traditional patches for 2 hours a day. The best corrected visual acuity (BCVA), contrast sensitivity function (CSF) and stereoacuity were measured at the baseline, 3 and 12 weeks. RESULTS: In this pilot study, a total of forty children were recruited, with twenty in the AFG group. Mean BCVA improved by 0.17±0.14logMAR (95% CI=0.10 to 0.23) in the AFG group, while 0.18±0.18logMAR (95% CI=0.09 to 0.26) in the patching group from baseline to 12 weeks. The improvement of BCVA in both groups were significant (both P<0.01), while no significant difference between the groups (P=0.82). The CSF of both low and high spatial frequencies exhibited significant improvement at 12 weeks in the AFG group (P<0.01, respectively), while just have a significant improvement at low spatial frequency in the patching group (P<0.01). The stereoacuity significantly improved by 504.00±848.00 (95% CI= -900.88 to -107.12) arc seconds in the AFG group (P<0.05), while 263.50± 639.55 (95% CI=-562.82 to 35.82) arc seconds in the patching group (P>0.05). CONCLUSION: Alternative flicker glass was effective in improving both monocular and binocular function, which was most likely achieved by reducing the suppression and promoting binocular fusion. This therapy exhibited promise as an alternative method for amblyopia treatment.

2.
Stat Med ; 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33650708

RESUMO

Unlike chemotherapy, the maximum tolerated dose (MTD) of molecularly targeted agents and immunotherapy may not pose significant clinical benefit over the lower doses. By simultaneously considering both toxicity and efficacy endpoints, phase I/II trials can identify a more clinically meaningful dose for subsequent phase II trials than traditional toxicity-based phase I trials in terms of risk-benefit tradeoff. To strengthen and simplify the current practice of phase I/II trials, we propose a utility-based toxicity probability interval (uTPI) design for finding the optimal biological dose, based on a numerical utility that provides a clinically meaningful, one-dimensional summary representation of the patient's bivariate toxicity and efficacy outcome. The uTPI design does not rely on any parametric specification of the dose-response relationship, and it directly models the dose desirability through a quasi binomial likelihood. Toxicity probability intervals are used to screen out overly toxic dose levels, and then the dose escalation/de-escalation decisions are made adaptively by comparing the posterior desirability distributions of the adjacent levels of the current dose. The uTPI design is flexible in accommodating various dose desirability formulations, while only requiring minimum design parameters. It has a clear decision structure such that a dose-assignment decision table can be calculated before the trial starts and can be used throughout the trial, which simplifies the practical implementation of the design. Extensive simulation studies demonstrate that the proposed uTPI design yields desirable as well as robust performance under various scenarios.

3.
Eur Radiol ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33569617

RESUMO

OBJECTIVES: To develop and compare several machine learning models to predict occult cervical lymph node (LN) metastasis in early-stage oral tongue squamous cell cancer (OTSCC) from preoperative MRI texture features. MATERIALS AND METHODS: We retrospectively enrolled 116 patients with early-stage OTSCC (cT1-2N0) who had been surgically treated by tumor excision and elective neck dissection (END). For each patient, we extracted 86 texture features from T2-weighted imaging (T2WI) and contrast-enhanced T1-weighted imaging (ceT1WI), respectively. Dimension reduction was performed in three consecutive steps: reproducibility analysis, collinearity analysis, and information gain algorithm. Models were created using six machine learning methods, including logistic regression (LR), random forest (RF), naïve Bayes (NB), support vector machine (SVM), AdaBoost, and neural network (NN). Their performance was assessed using tenfold cross-validation. RESULTS: Occult LN metastasis was pathologically detected in 42.2% (49/116) of the patients. No significant association was identified between node status and patients' gender, age, or clinical T stage. Dimension reduction steps selected 6 texture features. The NB model gave the best overall performance, which correctly classified the nodal status in 74.1% (86/116) of the carcinomas, with an AUC of 0.802. CONCLUSION: Machine learning-based MRI texture analysis offers a feasible tool for preoperative prediction of occult cervical node metastasis in early-stage OTSCC. KEY POINTS: • A machine learning-based MRI texture analysis approach was adopted to predict occult cervical node metastasis in early-stage OTSCC with no evidence of node involvement on conventional images. • Six texture features from T2WI and ceT1WI of preoperative MRI were selected to construct the predictive model. • After comparing six machine learning methods, naïve Bayes (NB) achieved the best performance by correctly identifying the node status in 74.1% of the patients, using tenfold cross-validation.

4.
Gynecol Oncol ; 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33551196

RESUMO

PURPOSE: To evaluate the effect of dasatinib therapy on EphA2 signaling in cancers of women with measurable (biopsy amenable) advanced-stage, chemo-naïve primary or recurrent endometrial cancer. Preliminary efficacy was also assessed. PATIENTS AND METHODS: We performed a pilot study of single-agent dasatinib lead-in, followed by triplet dasatinib, paclitaxel, and carboplatin. We measured the downstream effectors of EphA2 signaling in pre- and post-dasatinib treatment biopsy tissue samples; we also determined the severity of adverse events and patients' progression-free survival and overall survival durations. RESULTS: Eighteen patients were recruited and given dasatinib (150 mg orally daily for 14 days), followed by paclitaxel, carboplatin and dasatinib (daily) for six cycles (21-day cycles). Seventeen patients were evaluable for toxicity and 11 patients for response. A reverse phase protein array and proximity ligation assay revealed that CRAF/BRAF dimerization, caveolin-1 level, and Notch pathway signaling were predictive of response and resistance to dasatinib. Overall, the objective response rate was 45% (95% CI: 17%-77%), with median progression-free survival duration of 10.5 months and median overall survival duration of 30.4 months. The most common grade 3 or 4 adverse events were neutropenia (76%), thrombocytopenia (53%), anemia (53%), and fatigue (12%). CONCLUSIONS: Caveolin-1 expression, in combination with CRAF/BRAF heterodimerization, is associated with resistance to EphA2 targeting by dasatinib. The triplet combination showed interesting clinical activity in endometrial cancer with acceptable toxicity. Pretreatment with dasatinib may accentuate combination therapy toxicity.

5.
Stat Med ; 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33540472

RESUMO

Development of cancer screening biomarkers usually follows the Early Detection Research Network 5-Phase guideline in Pepe et al. A key feature of this guide is that the phased development follows a sequential order, moving to the next phase only when the current phase study is complete and has met its target performance. Motivated by a newly funded Newly onset Diabetes cohort study, we propose a design evaluating new biomarkers to discriminate between cases and controls in the presence of an existing screening test. The proposed design achieves two goals: (1) avoiding bias in estimating sensitivity or specificity in predicting cancer at a given time period prior to clinical diagnosis, using data from both screening detected cancers in Phase IV study and clinically diagnosed cancers in Phase III study; and (2) building a panel with biomarkers for Phase III and IV studies based on all data. A simulation study shows that the proposed design outperforms both a conventional method using data in Phase III arm only and a naive method using data in Phase III and IV arms ignoring the difference between the time of screening the detected cancer and the time of clinical diagnosis. The proposed design yields a smaller standard error of the estimation and increases the statistical power to confirm biomarker performance. This proposed method has the potential to shorten the cancer screening biomarker development process, use resources more effectively, and bring benefits to patients quickly.

6.
JAMA Netw Open ; 4(2): e2037563, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33595664

RESUMO

Importance: The cohort size of phase 1 clinical trials and thus the timing of the interim decisions are typically prespecified in the trial protocol. During trial implementation, however, the cohort size often deviates from the planned one, which shifts the schedule of the interims. Despite its pervasiveness in phase 1 trials, the association of cohort size deviation with the operating characteristics of these trials is not clear. Objective: To explore the association between cohort size deviation and the operating characteristics of phase 1 clinical trials. Design, Setting, and Participants: In this cross-sectional simulation study, a review was conducted of 102 phase 1 dose-escalation trials published between January 2017 and May 2018 in 3 peer-reviewed journals (Journal of Clinical Oncology, Clinical Cancer Research, and Cancer). After exclusion of studies that did not report the cohort size, 45 trials remained for analysis. Based on the analysis results, a simulation study was performed to systematically investigate the association of cohort size deviation with the operating characteristics of the trials. Main Outcomes and Measures: The prevalence of cohort size deviation and the percentage of correct selection of the maximum tolerated dose. Results: Of the 45 reviewed trials, 10 (22.2%) adhered strictly to the planned cohort size. The simulation study showed that when cohort size deviation was random, it had little association with the performance of novel model-based and model-assisted designs (mean reduction in the percentage of correct selection of the maximum tolerated dose was 0.87 percentage point for the continual reassessment method and 0.84 percentage point for the bayesian optimal interval design). When the cohort size deviation was informative and made based on the observed data on toxicity (eg, if dose-limiting toxicity was observed, the size of the next or current cohort was reduced or expanded), the variation of the design performance increased. The range of the change in the percentage of correct selection was -3.7 to 1.3 percentage points for the continual reassessment method and -4.5 to 0 percentage points for the bayesian optimal interval design. Conclusions and Relevance: The findings suggest that when novel phase 1 clinical trial designs are used, some cohort size deviation is acceptable and has little association with the performance of the designs. These deviations may be used by expert investigators to properly interpret the data, ensure safety, and leverage flexibility in the protocol.

7.
Int J Hyperthermia ; 38(1): 288-295, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33615955

RESUMO

PURPOSE: To compare the survival benefit, pain control and safety of low-power cumulative and traditional high-intensity focused ultrasound (HIFU) for metastatic pancreatic cancer. METHOD: We retrospectively analyzed 55 patients with metastatic pancreatic cancer who received HIFU treatment between January 2008 and April 2014 in our department. 23 patients received low-power cumulative HIFU treatment (L group), 32 received the traditional HIFU treatment (T group). Performance status, cancer-related pain and serum biochemistry results were assessed before and after treatment. All patients were followed up until death. The survival rate and adverse events of the two groups were compared. RESULTS: The baseline characteristics of the two groups were generally well balanced (p > 0.05). The average KPS score after treatment was significantly improved in both groups compared with the baseline score. 36 patients exhibited tumor-related pain at baseline. The pain response rate was significantly higher in the L group (92.3%) than in the T group (52.2%) (p = 0.025). The median overall survival (OS) for the L group was 7.0 months, which was significantly longer than that of the T group (p = 0.000). The 3-month and 6-month survival rates were higher in the L group. The adverse events in both groups included abdominal pain, elevated C-reactive protein (CRP) and elevated amylase. The incidence was lower in the L group than in the T group. CONCLUSION: Compared with traditional HIFU treatment, low-power cumulative HIFU treatment showed a significantly higher pain relief rate and survival benefit with a better safety profile in patients with metastatic pancreatic cancer.

8.
J Phys Chem B ; 125(6): 1568-1581, 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33555880

RESUMO

A new force field has been created for simulating hydrated alanine polypeptides using the adaptive force matching (AFM) method. Only density functional theory calculations using the Perdew-Burke-Ernzerhof exchange-correlation functional and the D3 dispersion correction were used to fit the force field. The new force field, AFM2020, predicts NMR scalar coupling constants for hydrated homopolymeric alanine in better agreements with experimental data than several other models including those fitted directly to such data. For Ala7, the new force field shows about 15% helical conformations, 20% conformation in the ß basin, and 65% polyproline II. The predicted helical population of short hydrated alanine is higher than previous estimates based on the same experimental data. Gas-phase simulations indicate that the force field developed by AFM solution-phase data is likely to produce a reasonable conformation distribution when hydration water is no longer present, such as the interior of a protein.

9.
Cancer Biol Med ; 18(1): 215-226, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33628596

RESUMO

Objective: In some patients with adenomatous polyposis, an identifiable pathogenic variant of known associated genes cannot be found. Researchers have studied this for decades; however, few new genes have been identified. Methods: Adenomatous polyposis coli (APC) negative polyposis patients were identified through next-generation sequencing and multiplex ligation-dependent probe amplification. Then, whole-exome sequencing (WES) was used to determine candidate genes harboring pathogenic variants. Functional experiments were performed to explore their effects. Subsequently, using Sanger sequencing, we found other polyposis patients carrying variants of the DUOX2 gene, encoding dual oxidase 2, and analyzed them. Results: From 88 patients with suspected familial adenomatous polyposis, 25 unrelated APC negative polyposis patients were identified. Based on the WES results of 3 patients and 2 healthy relatives from a family, the germline nonsense variant (c.1588A>T; p.K530X) of the DUOX2 gene was speculated to play a decisive role in the pedigree in relation to adenomatous polyposis. During functional experiments, we observed that the truncated protein, hDuox2 K530, was overexpressed in the adenoma in a carrier of the DUOX2 nonsense variant, causing abnormal cell proliferation through endoplasmic reticulum (ER) retention. In addition, we found two unrelated APC negative patients carrying DUOX2 missense variants (c.3329G>A, p.R1110Q; c.4027C>T, p.L1343F). Given the results of the in silico analysis, these two missense variants might exert a negative influence on the function of hDuox2. Conclusions: To our knowledge, this is the first study that reports the possible association of DUOX2 germline variants with adenomatous polyposis. With an autosomal dominant inheritance, it causes ER retention, inducing an unfolded protein response.

10.
Anim Biotechnol ; : 1-19, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33635178

RESUMO

The genetic diversity and population structures of five Chongqing local chicken populations were investigated using by 24 microsatellite markers. Results revealed that the mean number of alleles (NA) ranged from 7.08 (Daninghe chicken, DN) to 8.46 (Nanchuan chicken, NC). The highest observed heterozygosity (HO) and expected heterozygosity (HE) were observed in DN (HO = 0.7252; HE = 0.7409) and the lowest HO and HE were observed in XS (Xiushan native chicken [XS], HO = 0.5910 and HE = 0.6697). The inbreeding coefficient (FIS) within population ranged from 0.022 (DN) to 0.119 (XS). Among the 24 microsatellite markers, four loci (MCW0111, MCW0016, ADL0278, and MCW0104) deviated from the Hardy-Weinberg equilibrium in all the studied populations. The results of population polygenetic analysis based on Nei's genetic distance and STRUCTURE software showed that the clustering of the five populations was incomplete consistent with geographical distribution. Moreover, a large number of gene flows were widespread among different populations, suggesting that genetic material exchanges occurred due to human activities and migration which was also verified by PCoA. In summary, this study preliminarily showed that Chongqing local chicken populations had rich genetic diversity and remarkable genetic divergence, but still high risk in conversion. These findings would be useful to the management of conservation strategies and the utilization of local chicken populations in further.

11.
Clin Transl Sci ; 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33503305

RESUMO

The investigational NEDD8-activating enzyme inhibitor pevonedistat is being evaluated in combination with azacitidine versus single-agent azacitidine in patients with higher-risk myelodysplastic syndrome (higher-risk MDS), higher-risk chronic myelomonocytic leukemia (higher-risk CMML), or low-blast acute myeloid leukemia (AML) in a Phase 3 trial PANTHER. To support Asia-inclusive global development, we applied multiregional clinical trial (MRCT) principles of the International Conference on Harmonisation E17 guidelines by evaluating similarity in drug-related and disease-related intrinsic and extrinsic factors. A PubMed literature review (January 2000-November 2019) supported similarity in epidemiology of higher-risk MDS, AML, and CMML in Western and East Asian populations. Furthermore, the treatment of MDS/AML was similar in both East Asian and Western regions, with the same dose of azacitidine being the standard of care. Median overall survival in MDS following azacitidine treatment was generally comparable across regions, and the types and frequencies of molecular alterations in AML and MDS were comparable. Dose-escalation studies established the same maximum tolerated dose of pevonedistat in combination with azacitidine in Western and East Asian populations. Pevonedistat clearance was similar across races. Taken together, conservation of drug-related and disease-related intrinsic and extrinsic factors supported design of an Asia-inclusive Phase 3 trial and a pooled East Asian region. A sample size of ~ 30 East Asian patients (of ~ 450 randomized) was estimated as needed to demonstrate consistency in efficacy relative to the global population. This analysis is presented as an exemplar to illustrate application of clinical pharmacology and translational science principles in designing Asia-inclusive MRCTs.

12.
JCO Clin Cancer Inform ; 5: 91-101, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33439726

RESUMO

PURPOSE: Using novel Bayesian adaptive designs has great potential to improve the efficiency of early-phase clinical trials. A major barrier for clinical researchers to adopt novel designs is the lack of easy-to-use software. Our purpose is to develop a user-friendly software platform to implement novel clinical trial designs that address various challenges in early-phase dose-finding trials. METHODS: We used R Shiny to develop a web-based software platform to facilitate the use of recent novel adaptive designs. RESULTS: We developed a web-based software suite, called Bayesian optimal interval (BOIN) suite, which includes R Shiny applications to handle various clinical settings, including single-agent phase I trials with and without prior information, trials with late-onset toxicity, trials to find the optimal biological dose based on risk-benefit trade-off, and drug combination trials to find a single maximum tolerated dose (MTD) or the MTD contour. The applications are built using the same software architecture to ensure the best and a uniform user experience, and they are developed using a proven software development standard operating procedure to ensure accuracy, robustness, and reproducibility. The suite is freely available with internet access and a web browser without the need of installing any other software. CONCLUSION: The BOIN suite allows clinical researchers to design various types of early-phase clinical trials under a unified framework. This work is extremely important because it not only advances the clinical research and drug development by facilitating the use of novel trial designs with optimal performance but also enhances collaborations between biostatisticians and clinicians by disseminating novel statistical methodology to broader scientific communities through user-friendly software. The BOIN suite establishes a KISS principle: keep it simple, but smart.

13.
Dermatol Ther ; : e14816, 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33497505

RESUMO

Myxofibrosarcoma is a common soft-tissue sarcoma in elderly patients, characterized by an infiltrative growth pattern and a high risk for persistent local recurrence. A 35-years-old woman was diagnosed with myxofibrosarcoma on the right upper arm and the tumor is surgically resected. The tumor relapsed 7 months later. Then the patient received five cycles of low power cumulative high-intensity focused ultrasound (HIFU) treatments, which completely ablated the tumor without complications. Now the patient is disease free with a high quality of life more than 30 months. This case indicates HIFU ablation might be a novel, promising therapy for recurrent myxofibrosarcoma.

14.
Chem Biol Drug Des ; 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33506609

RESUMO

Lack of novel antifungal agents and severe drug resistance has led to high incidence and associated mortality of invasive fungal infections. To tackle the challenges, novel antifungal agents with anti-resistant potency are highly desirable. Thus, derivatives of curcumin were synthesized to restore the effectiveness of fluconazole (FLC) against FLC-resistant Candida spp. and structure-activity relationships were then discussed. Some novel derivatives showed promising features as novel antifungal lead compounds. Of them, compound 4 showed good alone or synergistic antifungal activity against FLC-resistant Candida spp. Moreover, compound 4 was proven as a potent inhibitor of Candida albicans biofilm formation and yeast-to-hypha morphological transition whether used alone or in combination with FLC, which was further confirmed by the inhibitory effect on cellular surface hydrophobicity of C. albicans. Compound 4 also inhibits intracellular ATP production of C. albicans and disrupts membrane permeability of C. albicans when used in combination with FLC. The results highlighted the potential of curcumin derivatives to overcome fluconazole-related and biofilm-related drug resistance.

15.
Arch Toxicol ; 95(3): 949-958, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33458792

RESUMO

Azoxymethane (AOM) is a widely used carcinogen to study chemical-induced colorectal carcinogenesis and is an agent for studying fulminant hepatic failure. The inter-strain susceptibility to acute toxicity by AOM has been reported, but its association with host genetics or gut microbiota remains largely unexplored. Here a cohort of genetically diverse Collaborative Cross (CC) mice was used to assess the contribution of host genetics and the gut microbiome to AOM-induced acute toxicity. We observed variation in AOM-induced acute liver failure across CC strains. Quantitative trait loci (QTL) analysis revealed three chromosome regions significantly associated with AOM toxicity. Genes located within these QTL, including peroxisome proliferator-activated receptor alpha (Ppara), were enriched for enzyme activator and nucleoside-triphosphatase regulator activity. We further demonstrated that the protein level of PPARα in liver tissues from sensitive strains was remarkably lower compared to levels in resistant strains, consistent with protective role of PPAR family in liver injury. We discovered that the abundance levels of gut microbial families Anaeroplasmataceae, Ruminococcaceae, Lactobacillaceae, Akkermansiaceae and Clostridiaceae were significantly higher in the sensitive strains compared to the resistant strains. Using a random forest classifier method, we determined that the relative abundance levels of these microbial families predicted AOM toxicity with the area under the receiver-operating curve (AUC) of 0.75. Combining the three genetic loci and five microbial families increased the predictive accuracy of AOM toxicity (AUC of 0.99). Moreover, we found that Ruminococcaceae and Lactobacillaceae acted as mediators between host genetics and AOM toxicity. In conclusion, this study shows that host genetics and specific microbiome members play a critical role in AOM-induced acute toxicity, which provides a framework for analysis of the health effects from environmental toxicants.

16.
Biometrics ; 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33438761

RESUMO

Precision medicine relies on the idea that, for a particular targeted agent, only a subpopulation of patients is sensitive to it and thus may benefit from it therapeutically. In practice, it is often assumed based on preclinical data that a treatment-sensitive subpopulation is known, and moreover that the agent is substantively efficacious in that subpopulation. Due to important differences between preclinical settings and human biology, however, data from patients treated with a new targeted agent often show that one or both of these assumptions are false. This paper provides a Bayesian randomized group sequential enrichment design that compares an experimental treatment to a control based on survival time and uses early response as an ancillary outcome to assist with adaptive variable selection and enrichment. Initially, the design enrolls patients under broad eligibility criteria. At each interim decision, submodels for regression of response and survival time on a baseline covariate vector and treatment are fit; variable selection is used to identify a covariate subvector that characterizes treatment-sensitive patients and determines a personalized benefit index, and comparative superiority and futility decisions are made. Enrollment of each cohort is restricted to the most recent adaptively identified treatment-sensitive patients. Group sequential decision cutoffs are calibrated to control overall type I error and account for the adaptive enrollment restriction. The design provides a basis for precision medicine by identifying a treatment-sensitive subpopulation, if it exists, and determining whether the experimental treatment is superior to the control in that subpopulation. A simulation study shows that the proposed design reliably identifies a sensitive subpopulation, yields much higher generalized power compared to several existing enrichment designs and a conventional all-comers group sequential design, and is robust.

17.
Food Chem ; 338: 127928, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32919374

RESUMO

We investigated the inhibitory effect and binding mechanism of four selected compounds (ascorbic acid, l-cysteine, glutathione, and citric acid) on membrane-bound polyphenol oxidases (mPPO) using spectroscopic and molecular docking techniques. Kinetic analysis demonstrated that these inhibitors reversibly inhibited the mPPO activity. Fluorescence spectroscopy revealed that the intrinsic fluorescence intensity of mPPO was quenched by inhibitors with a single class of the inhibition site on mPPO. Amino acid residues His 180, His 201, His 366, Cys 184, Glu 328, and Asn 333 were the important binding sites in the active center. These sites were identified using molecular docking techniques. Our findings suggested that the inhibitors were allosterically bound to the active center of mPPO through hydrogen bonds and ion contacts. This study provides new insights into the active site residues responsible for catalyzing mPPO and provides applicable information about the design of mPPO inhibitors.


Assuntos
Catecol Oxidase/metabolismo , Malus/enzimologia , Simulação de Acoplamento Molecular , Proteínas de Plantas/metabolismo , Regulação Alostérica , Ácido Ascórbico/química , Ácido Ascórbico/metabolismo , Sítios de Ligação , Catecol Oxidase/antagonistas & inibidores , Cisteína/química , Cisteína/metabolismo , Glutationa/química , Glutationa/metabolismo , Cinética , Proteínas de Plantas/antagonistas & inibidores , Espectrometria de Fluorescência
18.
EMBO Rep ; 22(2): e50967, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33372411

RESUMO

Lysine succinylation (Ksucc) is an evolutionarily conserved and widespread post-translational modification. Histone acetyltransferase 1 (HAT1) is a type B histone acetyltransferase, regulating the acetylation of both histone and non-histone proteins. However, the role of HAT1 in succinylation modulation remains unclear. Here, we employ a quantitative proteomics approach to study succinylation in HepG2 cancer cells and find that HAT1 modulates lysine succinylation on various proteins including histones and non-histones. HAT1 succinylates histone H3 on K122, contributing to epigenetic regulation and gene expression in cancer cells. Moreover, HAT1 catalyzes the succinylation of PGAM1 on K99, resulting in its increased enzymatic activity and the stimulation of glycolytic flux in cancer cells. Clinically, HAT1 is significantly elevated in liver cancer, pancreatic cancer, and cholangiocarcinoma tissues. Functionally, HAT1 succinyltransferase activity and the succinylation of PGAM1 by HAT1 play critical roles in promoting tumor progression in vitro and in vivo. Thus, we conclude that HAT1 is a succinyltransferase for histones and non-histones in tumorigenesis.

19.
Ophthalmic Res ; 64(1): 128-138, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33326987

RESUMO

PURPOSE: The purpose of this study was to determine the retinal microvasculature in myopic patients after refractive surgery. METHODS: Thirty-six right eyes of 36 patients who undertook femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) were imaged using optical coherence tomography angiography preoperatively, 1-week, 1-month, and 3-month postoperation, respectively. Vessel density was analyzed after the correction of magnification, and results were correlated with clinical manifestations, including spherical equivalent (SE), amplitude of accommodation, intraocular pressure, and axial length. RESULTS: There was a significant decrease in microvascular density 1-week postoperation compared to preoperative measurement (p < 0.05), and it recovered 1-month postoperation. Microvascular densities in superficial vascular plexus (r = 0.528, p < 0.01), deep vascular plexus (r = 0.500, p < 0.01), and retinal vascular network (r = 0.390, p < 0.05) were all positively correlated with the decrease of the SE 1-week postoperation. CONCLUSION: The transient alteration of the retinal microvasculature after refractive surgery appeared to recover quickly, which may not impact the visual function after FS-LASIK.

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