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1.
Cancer Med ; 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32181596

RESUMO

BACKGROUND: Anlotinib is a novel, orally administered, multitarget receptor tyrosine kinase inhibitor. It functions by inhibiting tumor angiogenesis and proliferative signaling pathways. In this study, we aimed to investigate the efficacy and safety of anlotinib plus epirubicin in a sarcoma patient-derived xenografts (PDX) model. METHODS: We firstly established a PDX model using fresh tumor tissues that were surgically removed from a patient diagnosed with malignant fibrous histiocytoma. Thirty-six PDX models were divided into six groups and treated with anlotinib alone (low-dose, 1.5 or high-dose, 3.0 mg/kg/day, oral gavage), or with anlotinib plus epirubicin (3.0 mg/kg/once weekly, i.p.) when the tumors grew to 150-200 mm3 . After 5 weeks of treatment, the mice were sacrificed, and the tumors were measured by weight and processed for IHC and H&E staining. IHC staining was performed to detect CD31, EGFR, MVD, and Ki-67 on paraffin sections. H&E stainings were performed to examine the microcosmic changes that occurred in the tumor tissues and myocardium, respectively. RESULTS: After 5 weeks, treatment with anlotinib or epirubicin alone significantly inhibited tumor growth in the sarcoma PDX model compared with the vehicle control. Tumor volume in the high-dose anlotinib group was significantly smaller than the low-dose anlotinib group (P < .001). Combined high-dose anlotinib and epirubicin treatment resulted in the most pronounced tumor inhibition. In the groups treated with the anlotinib-containing regimen, the expression levels of CD31, EGFR, MVD, and Ki-67 were significantly low. The weight in each group had no statistical differences; the same applied to the hepatic function, cardiac function, and toxicity. CONCLUSIONS: High-dose anlotinib combined with epirubicin was an effective and safe therapy for STS.

2.
JAMA Netw Open ; 3(1): e1919132, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31922563

RESUMO

Importance: Clostridioides difficile infection is the most frequent health care-associated infection in the United States. However, exposure to this organism might occur outside the health care setting. Objective: To examine whether exposure to environmental factors, such as livestock farms, is associated with a higher probability of being colonized with C difficile at hospital admission. Design, Setting, and Participants: This retrospective cohort study was conducted from May 1, 2017, to June 30, 2018, at a teaching-affiliated hospital in Milwaukee, Wisconsin. All consecutive patients underwent C difficile screening using a nucleic acid amplification test at hospital admission. Data analyses were performed from July 2018 to October 2019. Exposures: The distances from patient residence to the nearest livestock farms, meat processing plants, raw materials services, and sewage facilities were measured in addition to risk factors previously evaluated in other studies. Main Outcomes and Measures: The main outcome was a positive result on C difficile screening tests performed within 72 hours of hospital admission. Results: A total of 3043 patients admitted to the hospital were included in the final analysis. Of those, 1564 (51.4%) were women and 2074 (68.9%) were white, with a mean (SD) age of 62.0 (15.9) years; 978 patients (32.1%) were admitted to hematology-oncology units. At first admission, 318 patients (10.4%) were detected through testing as C difficile carriers. Multivariable logistic regression analyses were performed on a stratified sample of patients based on hematology-oncology admission status. These analyses indicated that although patients admitted to hematology-oncology units were 35% more likely to be colonized with C difficile, no significant association existed between their sociodemographic and economic characteristics or health care and environmental exposures and the likelihood of a positive C difficile test result. In contrast, among patients admitted to non-hematology-oncology units, comorbidities increased the likelihood for colonization by more than 4 times; women had 60% greater colonization than men, and a history of recent hospitalization (ie, within the preceding 6 months) increased the likelihood of colonization by 70%. Residential proximity to livestock farms were all significantly associated with a higher likelihood of a positive C difficile test result. Residential proximity to livestock farms more than doubled the probability of C difficile colonization in patients admitted to non-hematology-oncology units. Conclusions and Relevance: A shorter distance between residence and livestock farms was associated with C difficile colonization. Knowledge of the epidemiology of C difficile in the community surrounding the hospital is important, as it has potential implications for the incidence of hospital-onset C difficile infection.

3.
Eur J Med Chem ; 187: 111904, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31806537

RESUMO

Aiming to develop potent autotaxin (ATX) inhibitors for fibrosis diseases, a novel series of tetrahydropyrido[4,3-d]pyrimidine derivatives was designed and synthesized based on our previous study. The enzymatic assay combined with anti-proliferative activities against cardiac fibroblasts (CFs) and hepatic stellate cell (HSC) in vitro were applied for preliminary evaluation of anti-fibrosis potency of target compounds, resulting in two outstanding ATX inhibitors 8b and 10g with the IC50 values in a nanomolar range (24.6 and 15.3 nM). Differently, 8b was the most prominent compound against CFs with inhibition ratio of 81.5%, while 10g exhibited the maximum inhibition ratio of 83.7% against t-HSC/Cl-6 cells. In the further pharmacological evaluations in vivo, collagen deposition assay demonstrated the conspicuous capacity of 8b to suppress TGF-ß-mediated cardiac fibrosis. Simultaneously, H&E and Masson stains assays of mice liver validated 10g as an excellent anti-hepatofibrosis candidate, which reduced CCl4-induced hepatic fibrosis level prominently. Besides, the molecular binding models identified the essential interactions between 8b and ATX which was coincided with the SARs.

4.
Oncol Lett ; 18(6): 6443-6450, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31807167

RESUMO

Desmoid tumors (DTs), derived from the abdomen, are a type of rare and aggressive borderline tumor exhibiting high recurrence and malignant potential. The aim of the present study was to investigate the clinicopathological and molecular characteristics of abdominal DT in a Chinese population and to provide clues for selecting the optimal treatment strategy for different types of abdominal DT. The clinicopathological data of 15 consecutive patients with DT was collected. Matched fresh-frozen tumor tissues and peripheral blood samples were used to detect mutations of adenomatous polyposis coli gene (APC), ß-catenin (CTNNB1) and MutY DNA glycosylase (MUTYH) using Sanger sequencing. Pearson's test was conducted to analyze the differences between sporadic DT and familial adenomatous polyposis (FAP) associated with DT. Time to progress (TTP) and overall survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. A review of the patient clinicopathological characteristics revealed that FAP-associated DT exhibited a higher rate of abdominal surgery history (P=0.011), with no significant differences in any other characteristics. Sequencing revealed that mutations in the APC, CTNNB1 and MUTYH genes were common in DT, and only one patient harbored no mutations in these genes. Survival analyses revealed that patients with FAP exhibited shorter TTP (P=0.030). Log-rank test demonstrated a tendency towards shorter TTP in the cases where an R2 resection was performed (P=0.072) and a tendency towards poor prognosis in the cases of DT associated with FAP (P=0.087). In conclusion, Abdominal DTs were prone to occur in patients with FAP with a history of abdominal surgery. Mutations in the APC, CTNNB1 and MUTYH genes were detected in patients with DTs. To the best of our knowledge, this is the first study of abdominal DT occurrence in patients with MUTYH-associated FAP. The prognosis of DT associated with FAP may be worse compared with that of sporadic DT.

5.
Ther Adv Musculoskelet Dis ; 11: 1759720X19885559, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31723357

RESUMO

Background: Infection remains a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). This study aimed to establish a clinical prediction model for the 3-month all-cause mortality of invasive infection events in patients with SLE in the emergency department. Methods: SLE patients complicated with invasive infection admitted into the emergency department were included in this study. Patient's demographic, clinical, and laboratory characteristics on admission were retrospectively collected as baseline data and compared between the deceased and the survivors. Independent predictors were identified by multivariable logistic regression analysis. A prediction model for all-cause mortality was established and evaluated by receiver operating characteristic (ROC) curve analysis. Results: A total of 130 eligible patients were collected with a cumulative 38.5% 3-month mortality. Lymphocyte count <800/ul, urea >7.6mmol/l, maximum prednisone dose in the past ⩾60 mg/d, quick Sequential Organ Failure Assessment (qSOFA) score, and age at baseline were independent predictors for all-cause mortality (LUPHAS). In contrast, a history of hydroxychloroquine use was protective. In a combined, odds ratio-weighted LUPHAS scoring system (score 3-22), patients were categorized to three groups: low-risk (score 3-9), medium-risk (score 10-15), and high-risk (score 16-22), with mortalities of 4.9% (2/41), 45.9% (28/61), and 78.3% (18/23) respectively. ROC curve analysis indicated that a LUPHAS score could effectively predict all-cause mortality [area under the curve (AUC) = 0.86, CI 95% 0.79-0.92]. In addition, LUPHAS score performed better than the qSOFA score alone (AUC = 0.69, CI 95% 0.59-0.78), or CURB-65 score (AUC = 0.69, CI 95% 0.59-0.80) in the subgroup of lung infections (n = 108). Conclusions: Based on a large emergency cohort of lupus patients complicated with invasive infection, the LUPHAS score was established to predict the short-term all-cause mortality, which could be a promising applicable tool for risk stratification in clinical practice.

6.
Hortic Res ; 6: 108, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31645963

RESUMO

Pepper species (Capsicum spp.) are widely used as food, spice, decoration, and medicine. Despite the recent old-world culinary impact, more than 50 commercially recognized pod types have been recorded worldwide from three taxonomic complexes (A, B, and P). The current study aimed to apply a pan-plastome approach to resolve the plastomic boundaries among those complexes and identify effective loci for the taxonomical resolution and molecular identification of the studied species/varieties. High-resolution pan-plastomes of five species and two varieties were assembled and compared from 321 accessions. Phyloplastomic and network analyses clarified the taxonomic position of the studied species/varieties and revealed a pronounced number of accessions to be the rare and endemic species, C. galapagoense, that were mistakenly labeled as C. annuum var. glabriusculum among others. Similarly, some NCBI-deposited plastomes were clustered differently from their labels. The rpl23-trnI intergenic spacer contained a 44 bp tandem repeat that, in addition to other InDels, was capable of discriminating the investigated Capsicum species/varieties. The rps16-trnQ/rbcL-accD/ycf3-trnS gene set was determined to be sufficiently polymorphic to retrieve the complete phyloplastomic signal among the studied Capsicum spp. The pan-plastome approach was shown to be useful in resolving the taxonomical complexes, settling the incomplete lineage sorting conflict and developing a molecular marker set for Capsicum spp. identification.

7.
Autophagy ; : 1-15, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31512556

RESUMO

More evidence is emerging of the roles long non-coding RNAs (lncRNAs) play as regulatory factors in a variety of biological processes, but the mechanisms underlying the function of lncRNAs in acute myocardial infarction (AMI) have not been explicitly delineated. The present study identified the lncRNA 2810403D21Rik/AK007586/Mirf (myocardial infarction-regulatory factor), that inhibited macroautophagy/autophagy by modulating Mir26a (microRNA 26a). Inhibition of Mir26a led to cardiac injury both in vitro and in vivo, whereas overexpression of Mir26a attenuated ischemic stress-induced cell death by activating autophagy through targeting Usp15 (ubiquitin specific peptidase 15). More importantly, 2810403D21Rik/Mirf acted as a competitive endogenous RNA (ceRNA) of Mir26a; forced expression of 2810403D21Rik/Mirf downregulated Mir26a to inhibit autophagy. In contrast, loss of 2810403D21Rik/Mirf resulted in upregulation of Mir26a to promote autophagy and alleviate cardiac injury, which in turn improved cardiac function in MI mice. This study identified a lncRNA 2810403D21Rik/Mirf that functions as an anti-autophagic molecule via ceRNA activity toward Mir26a. Our findings suggest that knockdown of 2810403D21Rik/Mirf might be a novel therapeutic approach for cardiac diseases associated with autophagy. Abbreviations: 3-MA: 3-methyladenine; AAV-9: adenovirus associated virus-9; agoMir26a: cholesterol-conjugated Mir26a mimic; AMI: acute myocardial infarction; AMO-26a: Mir26a inhibitor; ATG: autophagy related; BECN1: beclin 1; ceRNA: competitive endogenous RNAs; EF: ejection fraction; f-2810403D21Rik/Mirf: fragment encompassing the Mir26a binding site; FS: fraction shortening; GFP-mRFP: a plasmid expressing green fluorescent protein-monomeric red fluorescent protein; lncRNA: long non-coding RNA; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; Mirf: myocardial infarction-regulatory factor; miRNAs: microRNAs; NC: negative control; NMCMs: neonatal mice cardiomyocytes; shRNA: short hairpin RNA; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; Usp15: ubiquitin specific peptidase 15.

8.
Aggress Behav ; 45(6): 662-670, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31436326

RESUMO

Based on the General Aggression Model (GAM), the current study investigated the interactive effect of personal factors (e.g., sensation-seeking) and situational factors (e.g., violent video games exposure [VVGE]) on the trait aggressive behavior, and the mediating role of individual difference trait (e.g., moral disengagement, anger, and hostility). We recruited 547 undergraduates (48.45% male) from five Chinese universities. The results showed that VVGE was positively associated with moral disengagement, disinhibition, and the four aggressive traits (physical aggression, verbal aggression, anger, and hostility), which were positively associated with each other. Moral disengagement was positively associated with both the disinhibition and the four aggressive traits. Disinhibition was positively associated with the four aggressive traits as well. When controlled for gender, moral disengagement, anger, and hostility wholly mediated the relationship between VVGE and aggression, but the moderation effect of disinhibition was not significant. These findings support the framework of GAM and indicate that moral disengagement, anger, and hostility may be the factors that increase the risk of a higher level of aggression following repeated exposure to violent video games.

9.
Cancer ; 125(21): 3818-3827, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31287559

RESUMO

BACKGROUND: Cancer contributes substantially to the life expectancy gap between US blacks and whites, and racial cancer disparities remain stubborn to eradicate. Disparities vary geographically, suggesting that they are not inevitable. METHODS: The authors examined the relationship between housing discrimination and the size of cancer disparities across large US metropolitan statistical areas (MSAs). MSA-level cancer disparities were measured using data from the US Centers for Disease Control and Prevention. Mortgage discrimination for each MSA was estimated using the Home Mortgage Disclosure Act database, and MSA racial segregation was determined using US Census data. Patterns of housing discrimination and cancer disparities were mapped, and the associations between these place-based factors and cancer disparities across MSAs were measured. RESULTS: Black-to-white cancer mortality disparities (rate ratios) varied geographically, ranging from 1.50 to 0.86; 88% of mortality ratios were >1, indicating higher mortality for blacks. In areas with greater mortgage discrimination, the gap between black and white cancer mortality rates was larger (correlation coefficient [r] = 0.32; P = .001). This relationship persisted in sex-specific analyses (males, r = 0.37; P < .001; females, r = 0.23; P = .02) and in models controlling for confounders. In contrast, segregation was inconsistently associated with disparities. Adjusting for incidence disparities attenuated, but did not eliminate, the correlation between mortgage discrimination and mortality disparities (r = 0.22-0.24), suggesting that cancer incidence and survival each account for part of the mortality disparity. CONCLUSIONS: Mortgage discrimination is associated with larger black-to-white cancer mortality disparities. Some areas are exceptions to this trend. Examination of these exceptions and of policies related to housing discrimination may offer novel strategies for explaining and eliminating cancer disparities.

10.
Biosci Rep ; 39(7)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31273058

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, debilitating disease with unknown etiopathogenesis. Previous reports have reported that long non-coding RNAs (lncRNAs) were involved in various pathophysiological processes. However, the role of lncRNAs in IPF has not been fully described. We aimed to explore the relationship between miR-15a and lncRNA PFAR and its function in pulmonary fibrosis. Biological information analysis and luciferase were used to identify targeted binding of lncRNA PFAR and miR-15a. Western blot, quantitative reverse transcription-PCR (qRT-PCR) and immunofluorescence staining were conducted to detect fibrosis-related factors. Fibroblasts proliferation were analyzed using 5-ethynyl-2'-deoxyuridine (EdU) staining and fibroblasts migration ability were measured using wound-healing scratch assay. We identified that lncRNA PFAR has a binding site with miR-15a and luciferase reporter assays demonstrated their combinative relationship. Our results showed that silencing PFAR attenuated TGF-ß1 induced fibrogenesis in primary lung fibroblasts. And miR-15a antagonized the function of PFAR and inhibited PFAR induced extracellular collagen deposition, fibroblasts proliferation, migration and differentiation. In conclusion, our results revealed that PFAR functions as a competitive endogenous RNA (ceRNA) by acting as a sponge for miR-15a, revealing a potential regulatory network involving PFAR and miR-15a with a role in the modulation of YAP1-Twist expression. This mechanism may contribute to a better understanding of pulmonary fibrosis pathogenesis and treatment method.

11.
Biochem Biophys Res Commun ; 517(2): 272-277, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31349969

RESUMO

QT interval prolongation and depolarization of resting membrane potential (RMP) were found in acute myocardial infarction (MI) which is involved in the arrhythmogenic mechanism and raising the risk to initiate torsade de pointes. However, clinical anti-arrhythmic agents that primarily act on QT interval and RMP are not currently available. Our objective was to determine whether Apelin, an endogenous peptide ligand of receptor APJ, affects QT interval and RMP and underlying mechanisms. To test this viewpoint, mice were subjected to MI by ligating the left main coronary artery and Apelin was applied through tail vein at 5 min prior coronary occlusion in tested group. Compared to MI group, pretreatment of Apelin (15 µg/kg) shortened QTc and QT interval induced by MI, significantly elevated RMP and shortened action potential duration (APD) by increased IK1 currents recorded using whole-cell patch technique from cardiomyocytes underwent MI. In cultured neonatal mouse cardiomyocytes, Apelin (1 µmol/L) restored hypoxia-induced Kir2.1 down-regulation, which was abolished by IP3K inhibitor LY-294002. Additionally, Apelin elicited a time-dependent increase in phosphorylation of Akt leading to increase in PI3-kinase activity. These results showed that Apelin enhanced IK1/Kir2.1 currents via IP3K pathway as by rescue ischemia- and hypoxia-induced RMP depolarization and prolongation of QT interval, which may prevent or cure acute ischemic-mediated arrhythmias. This study brings new information to anti-arrhythmic theories and provides a potential target for the clinical management of acute ischemia-related arrhythmias.

12.
J Phys Condens Matter ; 31(38): 385702, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31189138

RESUMO

The (Zr1-x T x )3Al3C5 (T = Hf, Nb, and V) series can be potential candidates to extend the domain of MAX phases. In this work, the structures and properties of (Zr1-x T x )3Al3C5 (T = Hf, Nb, and V) are studied using first-principles calculations. The obtained structural parameters are in good accordance with previously reported data in the literature. Based on the phase stability investigations, the potentially stable layered (Zr1-x T x )3Al3C5 (T = Hf, Nb, and V) solid solutions are proposed, which confirms that Zr3Al3C5 and Hf3Al3C5 can be synthesized. The substitution, especially with group VB transitional metals, endows layered (Zr1-x T x )3Al3C5 series with greatly enhanced mechanical and thermal properties. It is indicated that the bulk modulus B of all the three systems increase with increasing substitution concentration x. A significant increase in the ratio of bulk modulus to shear modulus, B/G, is found with increasing V concentration, which corresponds to the improved ductility. Moreover, solid solutions with V substitution, (Zr1-x V x )3Al3C5, yield a larger effect on thermal conductivity with respect to x, indicating flexible modulation of the thermal conductivity of (Zr1-x V x )3Al3C5 by V substitution can be achieved, which may promote them as promising coating materials. The intrinsic mechanism involved in the enhancements of the mechanical and thermal properties were elucidated through thorough electronic band structure analysis. The difference in the electronic structure and bonding between Zr and T in (Zr1-x T x )3Al3C5 compounds are shown to account for the abnormal variations in their properties.

13.
Cell Death Dis ; 10(6): 430, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160581

RESUMO

Unraveling the noncoding RNA expression networks governing cancer initiation and development is essential while remains largely uncompleted in retroperitoneal liposarcoma (RLS). Through RNA-seq technologies and computational biology, deregulated long noncoding RNAs (lncRNAs) are being identified and reveal that lncRNAs are implicated in serial steps of RLS development. High-throughput sequencing with computational methods for assembling the transcriptome of five paired RLS patient's tissues. We found that long intergenic noncoding RNA 423 (linc00423) was downregulated in RLS tissues. Gain-of-function assays revealed that overexpressed linc00423 obviously inhibited RLS cell growth in vitro and in vivo. Additionally, RNA sequence, RNA-pulldown and RIP assays evidenced that linc00423 involved in MAPK signaling pathway via destabilizing of nuclear factor of activated T-cells 3 (NFATC3). Summing up, our findings demonstrated that linc00423 acted as the tumor suppressor in RLS cells through regulating the protein level of NFATC3 at a post-transcriptional level and negatively regulated the MAPK signaling pathway at a transcriptional level. Linc00423 might serve as a candidate prognostic biomarker and a target for novel therapies of RLS patients.

14.
Crit Rev Oncol Hematol ; 139: 16-23, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31112878

RESUMO

Paclitaxel-induced peripheral neuropathy is a common reason for dose reduction or early cessation of therapy. Nab-paclitaxel was developed to provide additional clinical benefits and overcome the safety drawbacks of solvent-based paclitaxel. However, the incidence of peripheral neuropathy induced by nab-paclitaxel was reported higher than solvent-based paclitaxel but evidence remains inconsistent. Therefore, we conducted a meta-analysis to compare the incidence and severity of peripheral neuropathy between nab-paclitaxel and solvent-based paclitaxel mono-chemotherapy. In total, 24 articles were included in this meta-analysis. Results revealed the incidence of peripheral neuropathy induced by nab-paclitaxel was higher than solvent-based paclitaxel. The dosage and assessment method could influence the comparison of the incidence and severity of peripheral neuropathy between nab-paclitaxel and solvent-based paclitaxel. Current evidence suggests the incidence of peripheral neuropathy induced by nab-paclitaxel was higher than solvent-based paclitaxel among cancer patients received mono-chemotherapy. When received nab-paclitaxel, more attention should be paid to peripheral neuropathy.


Assuntos
Albuminas/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Neoplasias/tratamento farmacológico , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/epidemiologia , Solventes/efeitos adversos , Humanos , Incidência , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Prognóstico
15.
Cancer Manag Res ; 11: 3215-3225, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114361

RESUMO

Background: The aim of the study was to build and validate practical nomograms to better predict the overall survival (OS) and cancer-specific survival (CSS) of the patients with soft tissue sarcomas (STS) who underwent surgery. Methods: Patient data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. We identified 8804 patients who underwent surgery with STS between 2007 and 2015, and randomly divided them into the training (n=6164) and validation (n=2640) cohorts. The Cox regression analysis and cumulative incidence function were performed to identify the independent prognostic factors associated with OS and CSS, respectively. The performance of the nomograms was evaluated using Harrell's concordance index (C-index) and the calibration curves. Decision curve analysis (DCA) was introduced to compare the clinical practicality between the nomograms and the AJCC staging system. Results: Eight independent prognostic factors for OS and seven for CSS were determined and then used to build the nomograms for 3- and 5-year OS and CSS, respectively. The C-indexes of the nomograms for predicting OS were 0.788 in the internal validation and 0.823 in external validation, significantly higher than C-index of the AJCC staging system (P<0.001). The similar results were obtained in the validation cohort. Internal and external calibration curves for the predicting 3- and 5-year OS and CSS showed excellent agreement between the prediction and the actual survival outcomes. In addition, DCA demonstrated that our nomograms were superior over the AJCC staging system with obtaining more clinical net benefits. Conclusions: We established and validated the nomograms that could accurately predict the 3- and 5-year OS and CSS for STS patients who underwent surgery. The nomograms showed more robust and applicable performance than the AJCC staging system for predicting OS and CSS.

16.
Ther Drug Monit ; 41(5): 582-590, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31045869

RESUMO

BACKGROUND: As the first-line treatment of gastrointestinal stromal tumor (GIST), the pharmacokinetic and pharmacodynamic of imatinib (IM) were characterized by marked interindividual variability. Pharmacogenetics of IM involved metabolic enzymes and transporters have been extensively reported, but the results remained inconsistent. This study investigated the effect of genetic variants in hepatocyte nuclear factor 4 alpha (HNF4α, encoded by gene NR2A1), a pivotal transcriptional regulator of drug disposition genes, on dose-adjusted IM-free plasma levels and related adverse reactions in Chinese GIST patients. METHODS: Five common polymorphisms of NR2A1 (rs3818247, rs1884613, rs2071197, rs2425640, and rs736824) were genotyped in 70 Chinese GIST patients who had been administered IM 300-600 mg/d. The free IM trough plasma levels were determined based on a method of ultrafiltration coupled with high performance liquid chromatography-tandem mass spectrometry. RESULTS: There were wide interpatient variations in free plasma levels of IM (range, 9.50-67.50 ng/mL), in which significant sex differences were observed (P < 0.01). The dose-adjusted IM-free plasma levels showed a significant negative correlation with body surface area (r = -0.302, P = 0.012). Although there were no significant effects of NR2A1 polymorphisms on dose-adjusted IM-free plasma levels among the study population, polymorphism in rs736824 was found to be significantly associated with dose-adjusted IM-free plasma levels in male subjects (P = 0.031). For the IM-related adverse reaction, polymorphisms in rs3818247 were found to be significantly associated with periorbital edema (P = 0.032). In addition, no significant correlations were found between IM-free plasma levels and IM-related adverse reactions, except for the correlation of IM-free plasma levels with periorbital edema among male patients (P = 0.013). CONCLUSIONS: The research demonstrated that NR2A1 polymorphisms may act as contributors of IM pharmacokinetics and responses in Chinese GIST patients. This represents an attractive opportunity for IM therapy optimization, worth testing in clinical trials.

17.
Environ Toxicol Chem ; 38(9): 2073-2081, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31099934

RESUMO

The exogenous organic pollutant linear alkylbenzene sulfonate (LAS) is frequently detected in water. Myriophyllum spicatum L., a submerged aquatic plant, is a popular choice for phytoremediation. The present study investigated the growth and physiological responses of M. spicatum to different concentrations of LAS (0, 0.1, 0.5, 1, 10, 50, 100, and 500 mg/L) after 14 and 28 d of treatment. After 14 d, higher LAS doses (50-100 mg/L) significantly reduced the growth of M. spicatum compared with controls. Plants died at 500 mg/L LAS. Chlorophyll a and total chlorophyll contents were markedly increased at higher doses of LAS (10-100 mg/L). Significantly enhanced peroxidase (POD) activity was found at 50 mg/L of LAS, and decreased superoxide dismutase (SOD) activity at 100 mg/L of LAS; other indices showed no significant changes under LAS stress. After 28 d, no significant effect was observed on the growth of plants exposed to LAS doses of 0.1 to 100 mg/L, whereas plants died at 500 mg/L LAS. Compared with controls. SOD activity increased significantly at 0.1 mg/L LAS and maintained the same level as controls at higher concentrations. At all LAS exposures, POD activity was higher than that of controls. Other indices for M. spicatum were not remarkably changed at 28 d. Our results indicate that the oxidative damage to M. spicatum caused by LAS stress after 28 d is clearly less than such damage at 14 d. Environ Toxicol Chem 2019;38:2073-2081. © 2019 SETAC.

18.
Plant J ; 99(4): 763-783, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31009127

RESUMO

Pepper is an important vegetable with great economic value and unique biological features. In the past few years, significant development has been made toward understanding the huge complex pepper genome; however, pepper functional genomics has not been well studied. To better understand the pepper gene structure and pepper gene regulation, we conducted full-length mRNA sequencing by PacBio sequencing and obtained 57 862 high-quality full-length mRNA sequences derived from 18 362 previously annotated and 5769 newly detected genes. New gene models were built that combined the full-length mRNA sequences and corrected approximately 500 fragmented gene models from previous annotations. Based on the full-length mRNA, we identified 4114 and 5880 pepper genes forming natural antisense transcript (NAT) genes in-cis and in-trans, respectively. Most of these genes accumulate small RNAs in their overlapping regions. By analyzing these NAT gene expression patterns in our transcriptome data, we identified many NAT pairs responsive to a variety of biological processes in pepper. Pepper formate dehydrogenase 1 (FDH1), which is required for R-gene-mediated disease resistance, may be regulated by nat-siRNAs and participate in a positive feedback loop in salicylic acid biosynthesis during resistance responses. Several cis-NAT pairs and subgroups of trans-NAT genes were responsive to pepper pericarp and placenta development, which may play roles in capsanthin and capsaicin biosynthesis. Using a comparative genomics approach, the evolutionary mechanisms of cis-NATs were investigated, and we found that an increase in intergenic sequences accounted for the loss of most cis-NATs, while transposon insertion contributed to the formation of most new cis-NATs. OPEN RESEARCH BADGES: This article has earned an Open Data Badge for making publicly available the digitally-shareable data necessary to reproduce the reported results. The data is available at http://bigd.big.ac.cn/gsa Accession number, CRA001412.

19.
BMC Cancer ; 19(1): 335, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961559

RESUMO

BACKGROUND: Here we describe the treatments and prognosis for metachronous metastases from gastroenteropancreatic neuroendocrine tumors (GEP-NETs) after initial R0 surgical resection at a large center in China. METHODS: The clinicopathological data and survival outcomes for 108 patients (median age, 54.0 years) with metachronous hepatic metastatic GEP-NETs disease who were initially treated using R0 surgical resection between August 2003 and July 2014 were analyzed using one-way comparisons, survival analysis, and a predictive nomogram. RESULTS: Fifty-five (50.9%) patients had pancreatic NETs and 92 (85.2%) had G2 primary tumors. For treatment of the hepatic metastases, 48 (44.4%) patients received liver-directed local treatment (metastasectomy, radiofrequency ablation, transcatheter arterial chemoembolization, etc.), 15 (13.9%) received systemic treatment (interferon, somatostatin analogs, etc.), and 45 (41.7%) received both treatments. Multivariable analyses revealed that OS was associated with hepatic tumor number (P < 0.001), treatment modality (P = 0.045), and elevated Ki-67 index between the metastatic and primary lesions (P = 0.027). The predictive nomogram C-index was 0.63. CONCLUSIONS: A higher Ki-67 index in metastases compared to primary tumor was an independent factor for poor prognosis. Local treatment was associated with prolonged survival of hepatic metastatic GEP-NET patients. Optimal treatment strategies based on clinicopathological characteristics should be developed.


Assuntos
Neoplasias Intestinais/patologia , Neoplasias Hepáticas/terapia , Tumores Neuroendócrinos/patologia , Nomogramas , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/patologia , Antineoplásicos/uso terapêutico , Ablação por Cateter , Quimioembolização Terapêutica , China/epidemiologia , Feminino , Seguimentos , Humanos , Neoplasias Intestinais/mortalidade , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Tumores Neuroendócrinos/mortalidade , Neoplasias Pancreáticas/mortalidade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/mortalidade , Análise de Sobrevida , Resultado do Tratamento
20.
Oxid Med Cell Longev ; 2019: 3142732, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30881589

RESUMO

Peripheral neuropathy is the major dose-limiting side effect of paclitaxel (PTX), affecting both the quality of life and the survival of cancer patients. Nab-paclitaxel (nab-PTX) was developed to provide additional clinical benefits and overcome the safety drawbacks of solvent-based PTX. However, the prevalence of peripheral neuropathy induced by nab-PTX was reported higher than that induced by solvent-based PTX. Upon investigation, oxidative stress plays a major role in the toxicity of nab-PTX. In order to assess if the antioxidant alphalipoic acid (α-LA) could prevent the nab-PTX-induced peripheral neuropathy, Sprague-Dawley (SD) rats were treated with three doses of α-LA (15, 30, and 60 mg/kg in normal saline, i.p., q.d. (days 1-30)) and/or nab-PTX (7.4 mg/kg in normal saline, i.v., q.w. (days 8, 15, and 22)). Body weight and peripheral neuropathy were measured and assessed regularly during the study. The assessment of peripheral neuropathy was performed by the von Frey and acetone tests. A tumor xenograft model of pancreatic cancer was used to assess the impact of α-LA on the antitumor effect of nab-PTX. Results showed that α-LA significantly ameliorated the peripheral neuropathy induced by nab-PTX (p < 0.05) without promoting tumor growth or reducing the chemotherapeutic effect of nab-PTX in a tumor xenograft model. Moreover, α-LA might significantly reverse the superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) levels altered by nab-PTX in the serum and the spinal cord of rats. Furthermore, α-LA could reverse the mRNA and protein expressions of Nrf2 (nuclear factor erythroid 2-related factor 2) and three Nrf2-responsive genes (HO-1, γ-GCLC, and NQO1) altered by nab-PTX in the dorsal root ganglion (DRG) of rats. In conclusion, our study suggests that α-LA could prevent oxidative stress and peripheral neuropathy in nab-PTX-treated rats through the Nrf2 signalling pathway without diminishing chemotherapeutic effect.


Assuntos
Albuminas/efeitos adversos , Antioxidantes/uso terapêutico , Fator 2 Relacionado a NF-E2/metabolismo , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Ácido Tióctico/uso terapêutico , Albuminas/farmacologia , Animais , Antioxidantes/farmacologia , Masculino , Estresse Oxidativo , Paclitaxel/farmacologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Ácido Tióctico/farmacologia
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