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1.
J Mater Chem B ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33001118

RESUMO

Developing new strategies to enhance drug accumulation in the tumor and therapeutic efficacy is of great importance in the field of tumor therapy. Herein, a peanut-like multifunctional nanomedicine (CuS-PGH NMs) made of CuS nanoparticles encapsulated in poly(l-lysine)(PLL)/glucose oxidase (GOx)-hyaluronic acid (HA) shells has been constructed via layer-by-layer (LbL) assembly, and shows good biocompatibility and effective multi-gradient therapy. Because of the enhanced permeability and retention (EPR) effect, the CuS-PGH NMs could significantly enhance the cellular uptake by tumors overexpressing CD44 receptors, which respond to hyaluronidase (HAase)-triggered surface charge conversion. Once internalized by the tumor, GOx was the first to be exposed and could effectively deplete endogenous glucose for starvation therapy, and the excess H2O2 was then converted into highly toxic hydroxyl radicals (˙OH) via a Cu+-mediated Fenton-like reaction for chemodynamic therapy (CDT). Meanwhile, the as-obtained Cu+ ions accompanied the regenerated less-active Cu2+ ions. Interestingly, the high content of H2O2 could, in turn, accelerate Cu2+/Cu+ conversion to promote the Cu+-H2O2 reaction for enhanced chemodynamic therapy (CDT), thereby achieving efficient tumor growth suppression via synergistic starvation/CDT therapy. Subsequently, owing to the strong NIR-II absorption capability of CuS-PGH NMs, effective photothermal tumor ablation of the weakened tumor cells could be realized with the precise guidance of NIR-II PAI. This multi-gradient therapeutic strategy has been demonstrated to have excellent antitumor activity with minimal nonspecific damages, and offers a new avenue to precise tumor therapy.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33037726

RESUMO

Nifekalant has been used in the treatment of atrial arrhythmia recently. However, there is no consensus on the preferable nifekalant dose to treat atrial fibrillation (AF). The purpose of this study was to explore efficacy and safety of different doses of nifekalant in the cardioversion of persistent AF. The study was a single-center, randomized controlled trial. All subjects received nifekalant or placebo intravenously, and the nifekalant was given at the dosage of 0.3, 0.4 or 0.5mg/kg. Primary efficacy endpoint: compared with 0.3mg group, the rate of cardioversion to sinus rhythm from AF in 0.4mg and 0.5mg group was higher. The 0.4mg/kg and 0.5mg/kg doses were associated with a similar magnitude of efficacy (P>0.05). Secondary efficacy endpoint: termination rates of AF in the group of 0.4mg and 0.5mg were higher than 0.3mg. Primary safety endpoint: the rate of Torsades de Pointes or ventricular fibrillation was numerically lower in the 0.4mg group than 0.5mg group (P=0.02). Secondary safety endpoint: The rates of the majority of other common drug-related adverse events in the group of 0.5mg and 0.4mg were higher than the 0.3mg group. A 0.4mg/kg dose of intravenous nifekalant may be recommended during the radiofrequency ablation for persistent AF considering the benefit-risk profile. (ClinicalTrials.gov number: NCT04209959).

3.
Ecotoxicol Environ Saf ; 206: 111406, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33007542

RESUMO

Environmental air pollutants pose significant threats to public health, especially the toxicity and diseases caused by the atmospheric fine particulate matters (PM2.5). Since the health risks vary with both the concentrations and compositions of PM2.5 which are determined by aerosol sources, how are their toxic effects relevant to the pollution level becomes an important issue, such as the haze episodes covering clean and polluted days. With the transition from non-pollution to pollution stage, daily PM2.5 samples were collected from both the urban and industrial areas of Nanjing city, eastern China, covering a typical haze event in autumn-winter. Their unpropitious effects on human lung epithelial cells (A549) were compared by in vitro toxicity assays and chemical component analysis. Both air levels and cytotoxic effects of PM2.5 varied with the transition of haze event. Although the concentration of PM2.5 in air is of course the highest in pollution stage driven by local stable meteorological condition, unit mass of them posed higher toxicity (lower cell viability and higher IL-6) but induced lower cell oxidative (evidences of ROS and NQO1 mRNA expression) and inflammatory cytokine TNF-α responses than those particles during non-pollution stage. These patterns were explained by the metals and water-soluble components decreased with the haze development. Non-soluble particulate carbonaceous aerosol compositions might play a significant role in inducing cytotoxicity. Moreover, the regional pattern of episode pollution weakened the spatial variation within a city scale. Since the haze development intensified both the quantity and toxicity of PM2.5 in air, the health risks of overall aerosol exposure were synthetically amplified during haze weather, so the increased air particles with higher toxic components from fuel combustion sources should be key targets of pollution control.

4.
Medicine (Baltimore) ; 99(40): e22276, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019402

RESUMO

INTRODUCTION: Thyroid nodules are scattered lesions caused by abnormal local growth of thyroid cells. In recent years, their prevalence rate has been rising gradually, and the probability of cancerations has also been increasing gradually. Therefore, we must pay more attention to them and carry out early intervention. However, at present, most of the intervention measures for patients with thyroid nodules are mainly clinical observation and follow-up, and no clear and effective drug intervention therapy has been proposed. The curative effect of acupuncture on thyroid nodules has been proved clinically. However, as there is no clear mechanism of action, no specific operation methods or Suggestions, it is necessary to make a systematic evaluation of acupuncture therapy, so as to lay a foundation for further research in the future. METHODS AND ANALYSIS: The following databases will be searched from their inception to June 2020: Electronic database includes PubMed, Embase, Cochrane Library, Web of Science, Nature, Science online, Chinese Biomedical Database WanFang, VIP medicine information, and China National Knowledge Infrastructure (CNKI). Primary outcomes: Color ultrasound of thyroid and cervical lymph nodes, FT3, FT4, TSH, TGAB, TPOAB, insulin resistance index (HOMA-IR). Data will be extracted by 2 researchers independently, risk of bias of the meta-analysis will be evaluated based on the Cochrane Handbook for Systematic Reviews of Interventions. All data analysis will be conducted by data statistics software Review Manager V.5.3. and Stata V.12.0. RESULTS: The results of this study will systematically evaluate the efficacy and safety of acupuncture therapy for patients with thyroid nodule. CONCLUSION: Through the systematic review of this study, the evidence of the treatment of thyroid nodule by acupuncture has been summarized so far, so as to provide guidance for further promoting the application of acupuncture therapy in patients with thyroid nodule. ETHICS AND DISSEMINATION: This study is a systematic review, the outcomes are based on the published evidence, so examination and agreement by the ethics committee are not required in this study. We intend to publish the study results in a journal or conference presentations. OPEN SCIENCE FRA NETWORK (OSF) REGISTRATION NUMBER: August 18, 2020. osf.io/uzck4. (https://osf.io/uzck4).

5.
Medicine (Baltimore) ; 99(40): e22377, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019413

RESUMO

INTRODUCTION: Diabetic nephropathy (DN) is one of the most common and serious microvascular complications in patients with diabetes, which seriously affects their life quality and survival time. large dose herb Fuling or compound prescription contain large dose Fuling for treatment of DN has already been confirmed. However, due to the lack of evidence, there is no specific method or suggestion, so it is necessary to carry out systematic evaluation on Fuling and provide effective evidence for further research. METHODS AND ANALYSIS: The following databases will be searched from their inception to June 2020: Electronic database includes PubMed, Embase, Cochrane Library, Web of Science, Nature, Science online, Chinese Biomedical Database WangFang, VIP medicine information, and China National Knowledge Infrastructure (CNKI). Primary outcomes:24-hurinary-albumin, Urinary albumin-to-creatinine ratio. Additional outcomes: Serum creatinine, Blood urea nitrogen, Glomerular filtration rate, Endogenous creatinine clearance rate. Data will be extracted by 2 researchers independently, risk of bias of the meta-analysis will be evaluated based on the Cochrane Handbook for Systematic Reviews of Interventions. All data analysis will be conducted by data statistics software Review Manager V.5.3. and Stata V.12.0. RESULTS: The results of this study will systematically evaluate the effectiveness and safety of large dose Fuling intervention for people with DN. CONCLUSION: The systematic review of this study will summarize the current published evidence of large dose Fuling for the treatment of DN, which can further guide the promotion and application of it. ETHICS AND DISSEMINATION: This study is a systematic review, the outcomes are based on the published evidence, so examination and agreement by the ethics committee are not required in this study. We intend to publish the study results in a journal or conference presentations. OPEN SCIENCE FRAMEWORK (OSF) REGISTRATION NUMBER: August 24, 2020. osf.io/ym2c6. (https://osf.io/ym2c6).

6.
BMC Womens Health ; 20(1): 226, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33032583

RESUMO

BACKGROUND: Irregular menstrual cycles including the length of cycles and menses, and heavy menstrual blood loss are linked to many gynaecological diseases. Obesity has been reported to be associated with irregular menstrual cycles. However, to date, most studies investigating this association are focused on adolescence or university students. Whether this association is also seen in adult women, especially women who had a history of birth has not been fully investigated. METHODS: Questionnaire data were collected from 1012 women aged 17 to 53 years. Data on age, weight and height, gravida, the length of menstrual cycles and menses, and the number of pads used during menses were collected. Factors associated with menstrual cycle according to BMI categories were analysed. RESULTS: There were no differences in the length of menstrual cycles and menses in women of different body mass index (BMI) groups. However, there was a significant difference in menstrual blood loss in women of different BMI categories. The odds ratio of having heavy menstrual blood loss in obese women was 2.28 (95% CL: 1.244, 4.193), compared to women with normal weight, while there was no difference in the odds ratio of having heavy menstrual blood loss in overweight, compared to normal weight, women. In contrast, the odds ratio of having heavy menstrual blood loss in underweight women was 0.4034 (95% CL: 0.224, 0.725), compared to women with normal weight. CONCLUSION: Although BMI was not correlated with the length of menstrual cycle and menses, BMI is positively associated with menstrual blood loss. Our data suggest that BMI influences menstrual blood loss in women of reproductive age and weight control is important in women's reproductive years.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33055192

RESUMO

BACKGROUND AND OBJECTIVES: Several clinical practice guidelines noted the potential benefits of urate-lowering therapy on cardiovascular disease and CKD progression; however, the effect of this regimen remains uncertain. In this systematic review, we aimed to evaluate the efficacy of urate-lowering therapy on major adverse cardiovascular events, all-cause mortality, kidney failure events, BP, and GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We systematically searched MEDLINE, Embase, and the Cochrane databases for trials published through July 2020. We included prospective, randomized, controlled trials assessing the effects of urate-lowering therapy for at least 6 months on cardiovascular or kidney outcomes. Relevant information was extracted into a spreadsheet by two authors independently. Treatment effects were summarized using random effects meta-analysis. RESULTS: We identified 28 trials including a total of 6458 participants with 506 major adverse cardiovascular events and 266 kidney failure events. Overall urate-lowering therapy did not show benefits on major adverse cardiovascular events (risk ratio, 0.93; 95% confidence interval, 0.74 to 1.18) and all-cause mortality (risk ratio, 1.04; 95% confidence interval, 0.78 to 1.39) or kidney failure (risk ratio, 0.97; 95% confidence interval, 0.61 to 1.54). Nevertheless, urate-lowering therapy attenuated the decline in the slope of GFR (weighted mean difference, 1.18 ml/min per 1.73 m2 per year; 95% confidence interval, 0.44 to 1.91) and lowered the mean BP (systolic BP: weighted mean difference, -3.45 mm Hg; 95% confidence interval, -6.10 to -0.80; diastolic BP: weighted mean difference, -2.02 mm Hg; 95% confidence interval, -3.25 to -0.78). There was no significant difference (risk ratio, 1.01; 95% confidence interval, 0.94 to 1.08) in the risk of adverse events between the participants receiving urate-lowering therapy and the control group. CONCLUSIONS: Urate-lowering therapy did not produce benefits on the clinical outcomes, including major adverse cardiovascular events, all-cause mortality, and kidney failure. Thus, there is insufficient evidence to support urate lowering in patients to improve kidney and cardiovascular outcomes.

9.
BMC Cancer ; 20(1): 1002, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33059606

RESUMO

BACKGROUND: The relationship between sarcopenia and the prognoses of patients with gastric neuroendocrine neoplasms (g-NENs) is unclear. This study was designed to explore the effects of sarcopenia on short-term and long-term outcomes of patients with g-NENs after radical gastrectomy. METHODS: This study retrospectively collected data from 138 patients with g-NENs after radical gastrectomy. The skeletal muscle index (SMI) diagnostic threshold for sarcopenia was determined using X-tile software. Cox regression analyses were performed to determine the independent risk factors for 3-year overall survival (OS) and 3-year recurrence-free survival (RFS). RESULTS: In this study, 59 patients (42.8%) were diagnosed with sarcopenia. Among patients in the sarcopenia group and nonsarcopenia group, the incidences of total postoperative complications were 33.9 and 30.4%, incidences of serious postoperative complications were 0 and 3.7%, incidences of postoperative surgical complications were 13.6 and 15.2%, and incidences of postoperative systemic complications were 20.3 and 15.2%, respectively (all p > 0.05). The 3-year OS and RFS rates were significantly worse in the sarcopenia group than in the nonsarcopenia group (OS: 42.37% vs 65.82%, p = 0.004; RFS: 52.54% vs 68.35%, p = 0.036). The multivariate analysis revealed a relation between sarcopenia and the long-term prognoses of patients with g-NENs. A stratified analysis based on the pathological type revealed that the Kaplan-Meier curve was only significantly different in patients with gastric mixed adenoneuroendocrine carcinoma (gMANEC) (OS: 40.00% vs 71.79%, p = 0.007; RFS: 51.43% vs 74.36%, p = 0.026); furthermore, the multivariate analysis identified sarcopenia as an independent risk factor for patients with gMANEC (p < 0.05). CONCLUSIONS: Sarcopenia is not related to the short-term prognoses of patients with g-NENs. Sarcopenia is an independent risk factor for patients with gMANEC after radical surgery.

10.
Genome Biol ; 21(1): 257, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33023639

RESUMO

Prime editing is a novel and universal CRISPR/Cas-derived precision genome-editing technology that has been recently developed. However, low efficiency of prime editing has been shown in transgenic rice lines. We hypothesize that enhancing pegRNA expression could improve prime-editing efficiency. In this report, we describe two strategies for enhancing pegRNA expression. We construct a prime editing vector harboring two pegRNA variants for W542L and S621I double mutations in ZmALS1 and ZmALS2. Compared with previous reports in rice, we achieve much higher prime-editing efficiency in maize. Our results are inspiring and provide a direction for the optimization of plant prime editors.

11.
Lancet Infect Dis ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33031750

RESUMO

BACKGROUND: Since 1997, epidemics of hand, foot, and mouth disease associated with enterovirus A71 (EV-A71) have affected children younger than 5 years in the Asia-Pacific region, including mainland China. EV-A71 vaccines have been licensed for use in children aged 6-71 months in China, but not for infants younger than 6 months. We aimed to assess the dynamics of maternal EV-A71 antibodies to inform choice of potential vaccination strategies to protect infants younger than 6 months, because they have a substantial burden of disease. METHODS: We did a longitudinal cohort study with mother-neonate pairs in local hospitals in southern China during 2013-18. We collected cord blood from neonates and venous blood from mothers at delivery. We followed up and collected blood samples from the children at ages 2, 4, 6, 12, 24, and 36 months and tested for the presence of neutralising antibodies against EV-A71 with virus neutralisation assays. Seropositivity, or protective titre, was defined as a neutralisation antibody titre of 16 or higher. We estimated the seroprevalence, geometric mean titre (GMT), and transfer ratio of maternal antibodies. We used a binomial distribution to derive the 95% CIs of seroprevalence. Seropositivity between mothers and neonates was compared by use of an agreement (κ), while GMTs were compared by use of paired Student's t tests. FINDINGS: Between Sept 20, 2013, and Oct 14, 2015, 1054 mothers with 1066 neonates were enrolled. The EV-A71 GMT was similar among pairs of neonates (22·7, 95% CI 20·8-24·9) and mothers (22·1, 95% CI 20·2-24·1; p=0·20). The mean transfer ratio of maternal antibodies was 1·03 (95% CI 0·98-1·08). Although 705 (66%) of 1066 neonates acquired protective concentrations of EV-A71 antibodies from mothers, these declined rapidly, with a half-life of 42 days (95% CI 40-44). The time to loss of protective immunity was extended to 5 months in neonates with mothers who had titres of 128 or higher. By age 30 months, 28% of children had become seropositive because of natural infection. INTERPRETATION: EV-A71 maternal antibodies were efficiently transferred to neonates, but declined quickly to below the protective threshold, particularly among those whose mothers had low antibody titres. Our findings suggest that maternal vaccination could be explored to provide neonatal protection against EV-A71 through maternal antibodies. Catch-up vaccination between ages 6 months to 5 years could provide protection to the approximately 30-90% of children that have not had natural EV-A71 infection by that age. FUNDING: National Science Fund for Distinguished Young Scholars, National Natural Science Foundation of China.

12.
Hypertension ; 76(5): 1491-1505, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33026915

RESUMO

The pathogenesis of preeclampsia, a pregnancy-related disease, is not completely understood. The primary cilium transduces a diverse array of signaling pathways important for vital cellular activities. Primary cilia were reported to facilitate trophoblastic cell invasion. We hypothesized their further functions in trophoblasts and were interested in related molecular mechanisms. We systematically examined the presence, length and percentage of the primary cilium, its mediated signal transduction, and its connection to trophoblast function. Various cellular and molecular methods were used including immunofluorescence staining, spheroid formation, gene analysis, invasion and tube formation assays with trophoblastic cell lines, primary trophoblasts, and placental tissues. We show that primary cilia are present in various trophoblastic cell lines derived from first trimester placentas. Cilia are also observable in primary trophoblasts, though in a small quantity. Importantly, primary cilia are shortened in trophoblastic cells derived from preeclamptic placentas. Mechanistically, interleukin-6, tumor necrosis factor-α or sera from patients with preeclampsia are able to reduce the length of primary cilia and impair the important sonic hedgehog signaling pathway. Functionally, trophoblastic cells with defective cilia display severe failures in their key functions, like migration, invasion and tube formation, also observed in trophoblastic cells depleted of the intraflagellar transport protein 88. This is accompanied by reduced gene expression of matrix metallopeptidases, vascular endothelial growth factor, and placental growth factor. This work highlights the significance of primary cilia in the functions of trophoblastic cells. Dysfunctional cilia may lead to compromised migration, invasion, and endothelial remodeling of trophoblastic cells, contributing to the development of preeclampsia.

13.
Artigo em Inglês | MEDLINE | ID: mdl-33029947

RESUMO

Associations between adult attention-deficit/hyperactivity disorder (ADHD) symptoms and dietary habits have not been well established and the underlying mechanisms remain unclear. We explored these associations using a Swedish population-based twin study with 17,999 individuals aged 20-47 years. We estimated correlations between inattention and hyperactivity/impulsivity with dietary habits and fitted twin models to determine the genetic and environmental contributions. Dietary habits were defined as (a) consumption of food groups, (b) consumption of food items rich in particular macronutrients, and (c) healthy and unhealthy dietary patterns. At the phenotypic level, inattention was positively correlated with seafood, high-fat, high-sugar, high-protein food consumptions, and unhealthy dietary pattern, with correlation coefficients ranging from 0.03 (95%CI: 0.01, 0.05) to 0.13 (95% CI: 0.11, 0.15). Inattention was negatively correlated with fruits, vegetables consumptions and healthy dietary pattern, with correlation coefficients ranging from -0.06 (95%CI: -0.08, -0.04) to -0.07 (95%CI: -0.09, -0.05). Hyperactivity/impulsivity and dietary habits showed similar but weaker patterns compared to inattention. All associations remained stable across age, sex and socioeconomic status. Nonshared environmental effects contributed substantially to the correlations of inattention (56-60%) and hyperactivity/impulsivity (63-80%) with dietary habits. The highest and lowest genetic correlations were between inattention and high-sugar food (rA = .16, 95% CI: 0.07, 0.25), and between hyperactivity/impulsivity and unhealthy dietary pattern (rA = .05, 95% CI: -0.05, 0.14), respectively. We found phenotypic and etiological overlap between ADHD and dietary habits, although these associations were weak. Our findings contribute to a better understanding of common etiological pathways between ADHD symptoms and various dietary habits.

14.
Aging (Albany NY) ; 122020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33052878

RESUMO

The effect of POC1 centriolar protein A (POC1A) on gastric cancer (GC) has not been clearly defined. In this study, POC1A expression and clinical information in patients with GC were analyzed. Multiple databases were used to investigate the genes that were co-expressed with POC1A and genes whose changes co-occurred with genetic alternations of POC1A. Moreover, the TISIDB and TIMER databases were used to analyze immune infiltration. The GSE54129 GC dataset and LASSO regression model (tumor vs. normal) were employed, and 6 significant differentially expressed genes (LAMP5, CEBPB, ARMC9, PAOX, VMP1, POC1A) were identified. POC1A was selected for its high expression in adjacent tissues, which was confirmed with IHC. High POC1A expression was related to better overall and recurrence-free survival. GO and KEGG analyses demonstrated that POC1A may regulate the cell cycle, DNA replication and cell growth. Furthermore, POC1A was found to be correlated with immune infiltration levels in GC according to the TISIDB and TIMER databases. These findings indicate that POC1A acts as a tumor suppressor in GC by regulating the cell cycle and cell growth. In addition, POC1A preferentially regulates the immune infiltration of GC via several immune genes. However, the specific mechanism requires further study.

15.
J Integr Med ; 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33069626

RESUMO

OBJECTIVE: Traditional Chinese medicine plays a significant role in the treatment of the pandemic of coronavirus disease 2019 (COVID-19). Tanreqing Capsule (TRQC) was used in the treatment of COVID-19 patients in the Shanghai Public Health Clinical Center. This study aimed to investigate the clinical efficacy of TRQC in the treatment of COVID-19. METHODS: A retrospective cohort study was conducted on 82 patients who had laboratory-confirmed mild and moderate COVID-19; patients were treated with TRQC in one designated hospital. The treatment and control groups consisted of 25 and 57 cases, respectively. The treatment group was given TRQC orally three times a day, three pills each time, in addition to conventional Western medicine treatments which were also administered to the control group. The clinical efficacy indicators, such as the negative conversion time of pharyngeal swab nucleic acid, the negative conversion time of fecal nucleic acid, the duration of negative conversion of pharyngeal-fecal nucleic acid, and the improvement in the level of immune indicators such as T-cell subsets (CD3, CD4 and CD45) were monitored. RESULTS: COVID-19 patients in the treatment group, compared to the control group, had a shorter negative conversion time of fecal nucleic acid (4 vs. 9 days, P = 0.047) and a shorter interval of negative conversion of pharyngeal-fecal nucleic acid (0 vs. 2 days, P = 0.042). The level of CD3+ T cells increased in the treatment group compared to the control group ([317.09 ± 274.39] vs. [175.02 ± 239.95] counts/µL, P = 0.030). No statistically significant differences were detected in the median improvement in levels of CD4+ T cells (173 vs. 107 counts/µL, P = 0.208) and CD45+ T cells (366 vs. 141 counts/µL, P = 0.117) between the treatment and control groups. CONCLUSION: Significant reductions in the negative conversion time of fecal nucleic acid and the duration of negative conversion of pharyngeal-fecal nucleic acid were identified in the treatment group as compared to the control group, illustrating the potential therapeutic benefits of using TRQC as a complement to conventional medicine in patients with mild and moderate COVID-19. The underlying mechanism may be related to the improved levels of the immune indicator CD3+ T cells.

16.
Radiother Oncol ; 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33039424

RESUMO

PURPOSE: The delineation of the clinical target volume (CTV) is a crucial, laborious and subjective step in cervical cancer radiotherapy. The aim of this study was to propose and evaluate a novel end-to-end convolutional neural network (CNN) for fully automatic and accurate CTV in cervical cancer. METHODS: A total of 237 computed tomography (CT) scans of patients with locally advanced cervical cancer were collected and evaluated. A novel 2.5D CNN network, called DpnUNet, was developed for CTV delineation and further applied for CTV and organ-at-risk (OAR) delineation simultaneously. Comprehensive comparisons and experiments were performed. The mean Dice similarity coefficient (DSC), 95th percentile Hausdorff distance (95HD) and subjective evaluation were used to assess the performance of this method. RESULTS: The mean DSC and 95HD values were 0.86 and 5.34mm for the delineated CTVs. The clinical experts' subjective assessments showed that 90% of the predicted contours were acceptable for clinical usage. The mean DSC and 95HD values were 0.91 and 4.05mm for bladder, 0.85 and 2.16mm for bone marrow, 0.90 and 1.27mm for left femoral head, 0.90 and 1.51mm for right femoral head, 0.82 and 4.29mm for rectum, 0.85 and 4.35mm for bowel bag, 0.82 and 4.96mm for spinal cord respectively. The average delineation time for one patient's CT images was within 15 seconds. CONCLUSION: The experimental results demonstrate that the CTV and OARs delineated for cervical cancer by DpnUNet was in close agreement with the ground truth. DpnUNet could significantly reduce the radiation oncologists' contouring time.

17.
Bioorg Med Chem ; 28(23): 115756, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-33002682

RESUMO

We describe the total synthesis of tutuilamide A, a potent porcine pancreatic elastase (PPE) inhibitor and a representative member of the 3-amino-6-hydroxy-2-piperidone (Ahp) cyclodepsipeptide family, isolated from marine cyanobacteria. The Ahp unit serves as a pharmacophore and the adjacent 2-amino-2-butenoic acid (Abu) is a main driver of the selectivity among serine proteases. We adapted our previous convergent strategy to generate the macrocycle, common with lyngbyastatin 7 and related elastase inhibitors, and then appended the tutuilamide A-specific side chain bearing a vinyl chloride. Tutuilamide A and lyngbyastatin 7 were evaluated side by side for the inhibition of the disease-relevant human neutrophil elastase (HNE). Tutuilamide A and lyngbyastatin 7 were approximately equipotent against HNE, while tutuilamide A was previously shown to be more active against PPE compared with lyngbyastatin 7, further demonstrating that the side chain provides opportunities to not only modulate potency but also selectivity among proteases of the same function from different organisms. Profiling of tutuilamide A against mainly human serine proteases revealed high selectivity for HNE (IC50 0.73 nM) and pleiotropic activity against kallikrein 7 (KLK7, IC50 5.0 nM), without affecting other kallikreins, similarly to lyngbyastatin 7 (IC50 0.85 nM for HNE and 3.1 nM for KLK7). A comprehensive molecular docking study for elastases and KLK7 afforded deeper insight into the intricate differences between inhibitor interactions with HNE and PPE, accounting for the differential activities for both compounds. The synthesis and molecular studies serve as a proof-of-concept that the macrocyclic scaffold can be diversified to fine-tune the activity of serine protease inhibitors.

18.
Perfusion ; : 267659120965921, 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33070762

RESUMO

OBJECTIVE: To investigate effects of Shengmai injection (SMI) postconditioning on myocardial ischemia-reperfusion injury (MIRI) in isolated rat hearts. MATERIALS AND METHODS: A total of thirty isolated hearts were randomly divided into three groups: Sham group, I/R group and SMI group. Sham group was continuously perfused with K-H solution for 120 minutes. I/R group and SMI group were given balanced perfusion for 30 min followed by reperfusion for 60 min, with an interval of 30 min, and those in the SMI group were given postconditioning with 1% SMI during the first 10 min of reperfusion. The left ventricular function, markers of myocardial injury, endothelial cell injury and oxidative stress injury were measured at 30 minutes after equilibration (t0), 30 minutes after ischemia (t2) and 60 minutes after reperfusion (t3). RESULTS: The results showed that there was no significant difference for all observation indexes at t0. Compared with the Sham group, real portfolio project and coronary arterial flow rate and the activity of superoxide dismutase were significantly decreased in the I/R group, whereas those in the SMI group were significantly higher. Left ventricular end-diastolic pressure, the concentrate of malondialdehyde, lactate dehydrogenase, cTn-I, hyaluronic acid, heparin sulphate, syndecan-1 in the I/R group were markedly higher than those in the Sham group, whereas those in the SMI group were significantly lower. CONCLUSION: In summary, the present study indicated that 1% SMI postconditioning can alleviate the detachment of endothelial cell glycoprotein envelope induced by myocardial ischemia-reperfusion injury, and its mechanism is probably related to the inhibition of the oxidative stress injury.

19.
Front Immunol ; 11: 2048, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072070

RESUMO

Combination therapy with inhibitors of cytotoxic T lymphocyte-associated protein (CTLA)4 and programmed death (PD)-1 has demonstrated efficacy in cancer patients. However, there is little information on CTLA4 and PD-1 expression levels and their clinical significance across diverse cancers. In this study, we addressed this question by analyzing PD-1 and CTLA4 levels in 33 different types of cancer along with their prognostic significance using The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia datasets. Liver hepatocellular carcinoma (LIHC) patients receiving cytokine-induced killer cell (CIK) immunotherapy at Sun Yat-sen University cancer center were enrolled for survival analysis. The correlation between PD-1/CTLA4 expression and cancer immunity was also analyzed. The results showed that PD-1 and CTLA4 transcript levels varied across cancer cell lines, with aberrant expression detected in certain cancer types; Kaplan-Meier analysis with the Cox proportional hazards model showed that this was closely related to overall survival in breast invasive carcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, acute myeloid leukemialymphoma, uterine corpus endometrial carcinoma, and uveal melanoma in TCGA. High serum PD-1 and CTLA4 levels predicted better survival in LIHC patients receiving CIK therapy. PD-1 and CTLA4 levels were found to be significantly correlated with the degree of tumor cell infiltration using Tumor Immune Estimation Resource, Estimating Relative Subsets of RNA Transcripts, and Estimation of Stromal and immune Cells in Malignant Tumor Tissues Using Expression Data as well as with tumor-infiltrating lymphocyte marker expression; they were also related to tumor mutation burden, microsatellite instability, mismatch repair, and the expression of DNA methyltransferases in some cancer types. Gene set enrichment analysis of 33 cancer types provided further evidence for associations between PD-1/CTLA4 levels and cancer development and immunocyte infiltration. Thus, PD-1 and CTLA4 play important roles in tumorigenesis and tumor immunity and can serve as prognostic biomarkers in different cancer types.

20.
Biotechnol Bioeng ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33073356

RESUMO

AcCHMO, a cyclohexanone monooxygenase from Acinetobacter calcoaceticus, is a typical type I Baeyer-Villiger monooxygenase (BVMO). We previously obtained the AcCHMOM6 mutant, which oxidizes omeprazole sulfide (OPS) to the chiral sulfoxide drug esomeprazole. To further improve the catalytic efficiency of the AcCHMOM6 mutant, a focused mutagenesis strategy was adopted at the intersections of the FAD-binding domain, NADPH-binding domain and α-helical domain based on structural characteristics of AcCHMO. By using focused mutagenesis and subsequent global evolution two key residues (L55 and P497) at the intersections of the domains were identified. Mutant of L55Y improved catalytic efficiency significantly, whereas the P497S mutant alleviated substrate inhibition remarkably. AcCHMOM7 (L55Y/P497S) was obtained by combining the two mutations, which increased the specific activity from 18.5 (M6) to 108 U/g, and an increase in the K i of the substrate OPS from 34 to 265 µM. The results indicate that catalytic performance can be elevated by modification of the sensitive sites at the intersection of the domains of AcCHMO. The results also provided some insights for engineering of other type I BVMOs or other multi-domain proteins. This article is protected by copyright. All rights reserved.

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