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1.
Artículo en Inglés | MEDLINE | ID: mdl-32424838

RESUMEN

BACKGROUND AND AIM: Long noncoding RNA TRPM2-AS has emerged as a novel regulator in cancer initiation and progression of various cancers. However, the function and underlying mechanism of TRPM2-AS in the progression of gastric cancer (GC) remain poorly understood. METHODS: GEO and TCGA databases were used for isolation of differential lncRNAs expression. TRPM2-AS expression levels in GC tissues and cells were measured by qPCR method. TRPM2-AS subcellular location was detected by fluorescence in situ hybridization analysis. The functional roles of TRPM2-AS in cells was analyzed by loss and gain function assays. RESULTS: By using bioinformatics and qPCR methods, TRPM2-AS expression levels were proved to be upregulated in GSE70880 dataset, TCGA database and 26 GC tissues, which was partly induced by SP1. The results of clinical assays showed that TRPM2-AS could be an indicator for early-stage GC diagnosis. FISH analysis showed that TRPM2-AS locate both in nucleus and cytoplasm. Functional experiments displayed that knockdown of TRPM2-AS inhibited proliferation, migration and invasion in GC cells. Furthermore, depression of TRPM2-AS suppressed cell growth though promotion of cell apoptosis. The expression levels of cleaved PARP, caspase 9, caspase 3 and Bax were significantly increased in BGC823 with TRPM2-AS knockdown. In addition, knockdown of TRPM2-AS reduced STAT3 and phosphorylate STAT3, increased p38 MAPK, phosphorylate p38 MAPK. CONCLUSIONS: This study demonstrated that SP1 regulated TRPM2-AS is involved in GC cell apoptosis probably via p38 MAPK and STAT3 pathways, indicating that TRPM2-AS might be a potential therapeutic target in GC.

2.
iScience ; : 101160, 2020 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-32405622

RESUMEN

The ongoing outbreak of the novel coronavirus pneumonia COVID-19 has caused great number of cases and deaths, but our understanding about the pathogen SARS-CoV-2 remains largely unclear. The attachment of the virus with the cell-surface receptor and a co-factor is the first step for the infection. Here, bioinformatics approaches combining human-virus protein interaction prediction and protein docking based on crystal structures have revealed the high affinity between human dipeptidyl peptidase 4 (DPP4) and the spike (S) receptor-binding domain of SARS-CoV-2. Intriguingly, the crucial binding residues of DPP4 are identical to those as bound to the MERS-CoV-S. Moreover, E484 insertion and adjacent substitutions should be most essential for this DPP4-binding ability acquirement of SARS-CoV-2-S compared with SARS-CoV-S. This potential utilization of DPP4 as a binding target for SARS-CoV-2 may offer novel insight into the viral pathogenesis, and help the surveillance and therapeutics strategy for meeting the challenge of COVID-19.

3.
Artículo en Inglés | MEDLINE | ID: mdl-32409270

RESUMEN

INTRODUCTION: There is some debate over the best treatment for anterior-superior iliac spine (ASIS) avulsion fractures, although non-surgical treatment can achieve the same results as open surgery. HYPOTHESIS: Absorbable screws can be safely used for ASIS avulsion fractures in children and adolescents. AIM OF THE STUDY: Here, we compared patients on whom no surgery was performed with those who underwent open surgery and investigated the feasibility of using absorbable screws as a new fixation material for treating ASIS avulsion fractures in children and adolescents. PATIENTS AND METHODS: We retrospectively analyzed the data of 59 patients diagnosed with ASIS avulsion fractures in our hospital between January 2009 and December 2016. Based on the clinical data, these patients were assigned into group A (non-surgical group) and group B (absorbable screws group). After the inclusion and exclusion criteria were applied, patients' clinical records, including radiographs, were analyzed. All patients were assessed for range of motion (ROM) and by X-ray as they returned to activity. Evaluation of hip function was done by calculating the American Academy of Orthopedic Surgeons (AAOS) lower limb and hip scores. RESULTS: According to AAOS scores, there were significant differences between the two groups at the first and third months postoperatively (p=0.003), but by the sixth and twelfth months, there was no significant difference (p=0.42). Significant differences were also observed between both groups regarding callus growth on radiographs, time to resume sporting activities, and occurrence of complications such as meralgia paresthetica. All complications resolved by 6 months follow-up. CONCLUSION: Our study agrees with previous reports, absorbable screws can be safely used for ASIS avulsion fractures with greater than 1.5cm displacement in children and adolescents. In comparison with non-surgical therapy, our results indicate that absorbable screws are associated with shorter recovery time and lesser early complications. LEVEL OF EVIDENCE: IV, retrospective study with control group.

4.
J Clin Lab Anal ; : e23357, 2020 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-32420681

RESUMEN

BACKGROUND: Although long intergenic non-protein coding RNA 691 (LINC00691) has been functionally identified in several tumors, the association between LINC00691 and non-small-cell lung cancer (NSCLC) has not been reported. The objective of our study was to explore the clinical significance of LINC00691 in NSCLC. METHODS: RT-PCR was performed to detect LINC00691 levels in 177 pairs of human NSCLC tissues and matched normal lung specimens. A chi-squared test was used to analyze the possible influence of LINC00691 on the clinical progress of NSCLC. Kaplan-Meier methods were used to determine differences in patient survival. The prognostic value of survival variables was evaluated using univariate and multivariate analyses. RESULTS: We found that LINC00691 levels were increased in tumor specimens compared with matched normal lung tissues (P < .01). Increased LINC00691 levels correlated with lymph node metastasis (P = .025) and advanced TNM stage (P = .002) in NSCLC patients. Moreover, clinical investigations revealed that NSCLC patients with high LINC00691 expression had a shorter overall survival than those with low LINC00691 expression (P = .0042). Finally, Cox regression assays confirmed LINC00691 as an independent prognostic factor for NSCLC patients. CONCLUSIONS: The aberrant expression of LINC00691 may function as a reliable marker for the progression and prognosis of NSCLC in patients.

5.
Colloids Surf B Biointerfaces ; 193: 111099, 2020 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-32408261

RESUMEN

Bacterial infections are currently a major concern to human health. Amino acid-based supramolecular polymer hydrogels, which boast intrinsic antibacterial activity, are an important solution due to their good biocompatibility, cost effectiveness, and tunable structural properties. Herein, we reported three types of transparent supramolecular hydrogel with intrinsic antibacterial activity from self-assembly of commercially available Fmoc-tryptophan (Fmoc-W), Fmoc-methionine (Fmoc-M), and Fmoc-tyrosine (Fmoc-Y). The resulting hydrogels selectively inhibited the growth of Gram-positive bacteria. Moreover, the order of antibacterial activity was Fmoc-W hydrogel > Fmoc-M hydrogel > Fmoc-Y hydrogel. The critical aggregation concentration (CAC) values were found at concentrations of approximately 0.0293, 0.1172, and 0.4688 mM for Fmoc-W, Fmoc-M, and Fmoc-Y, respectively. Transmission electron microscope (TEM) images revealed rigid and aligned nanofibers for Fmoc-W hydrogel, while flexible nanofibers for Fmoc-M hydrogel and Fmoc-Y hydrogel. The results indicated that stronger aggregation capability of the gelator and the synergistic nanostructural morphology with more rigid and aligned nanofibers can lead to higher antibacterial activity of its corresponding hydrogel. In addition, the molecular arrangements of Fmoc-amino acids in the hydrogels may also contribute to their antibacterial activity. These results can guide the rational design, fabrication, and future application of other self-assembled amino acid-based hydrogels with excellent antibacterial activity.

6.
Artículo en Inglés | MEDLINE | ID: mdl-32439242

RESUMEN

INTRODUCTION: To examine the effects and safety of oxytocin administered intramuscularly or intravenously for preventing postpartum hemorrhage (PPH) in the third stage of labor after vaginal deliveries. MATERIAL AND METHODS: Before data extraction, the review was registered with the PROSPERO International Prospective Register of Systematic Reviews (registration No. CRD42019145912). We searched the published electronic databases, including Medline, EMBASE, PubMed, Web of Science, CNKI, VIP, Wanfang, the Cochrane Library, clinicaltrial.gov and PROSPERO database, from their inception until February 2019. We included all randomized controlled trials (RCTs) comparing intramuscular and intravenous oxytocin administered just after the birth of the anterior shoulder or soon after the birth of the baby during a vaginal delivery. The primary outcomes were the incidence of PPH and severe PPH. PPH was defined as a blood loss ≥500 ml within 24 hours after vaginal birth. Severe PPH refers to a clinically estimated blood loss equal to or greater than 1000 mL within 24 hours after vaginal birth. Statistical heterogeneity was assessed by the I2 test, the Cochran Q statistic and the Galbraith plot for heterogeneity. RESULTS: Six RCTs, including 7320 women undergoing vaginal delivery, were identified in the meta-analysis. Women who were randomized to have intravenous oxytocin for the third stage of labor had a significantly lower incidence of PPH (relative risk 1.35, 95% CI 1.11-1.64, p = 0.003), severe PPH (relative risk 1.61, 95% CI 1.05-2.46, p = 0.03) and blood transfusion (relative risk 2.50, 95% CI 1.37-4.59, p = 0.003) compared with those who were randomized to have intramuscular oxytocin during the third stage of labor after vaginal delivery. There was no significant difference with regard to changes in hemoglobin level, third stage of labor duration, mean postpartum blood loss, or the incidences of a need for additional uterotonics and of retained placenta or manual removal of placenta between groups. CONCLUSIONS: For women in the third stage of labor who are undergoing a vaginal delivery, the use of intravenous oxytocin reduces the incidence of PPH, severe PPH and blood transfusion and does not increase the risk of adverse effects compared with intramuscular oxytocin.

7.
J Zhejiang Univ Sci B ; 21(4): 305-314, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32253840

RESUMEN

To investigate associations between central visual function and inner retinal structure in primary open-angle glaucoma (POAG). This study enrolled 78 POAG patients and 58 healthy controls. POAG was classified into early glaucoma and moderate to advanced glaucoma. The following tests were performed on all participants: isolated-check visual evoked potential (icVEP) testing, 24-2 standard automated perimetry (SAP), and Cirrus optical coherence tomography (OCT) examinations. Signal-to-noise ratio (SNR) measures obtained from icVEP responses to isolated checks presented at four depths of modulation (DOMs; 8%, 14%, 22%, and 32%) were explored. Mean macular sensitivity (mMS) was assessed by calculating the mean sensitivities of central 12 SAP points. Ganglion cell layer+ inner plexiform layer thickness (GCL+IPLT) and peripapillary retinal nerve fiber layer thickness (pRNFLT) were measured by OCT scanning. For each group of subjects, linear relationships among the following measures were analyzed: SNR, mMS, GCL+IPLT, and pRNFLT. SNR, mMS, GCL+IPLT, and pRNFLT were all more significantly decreased in glaucoma than in controls (P<0.001). A significant positive association was found between SNR at 14% DOM and GCL+IPLT at the inferior sector in early glaucoma (r=0.465, P=0.004). In moderate to advanced glaucoma, significant correlations were found between SNR at 32% DOM and mean GCL+IPLT (r=0.364, P=0.023), superior GCL+IPLT (r=0.358, P=0.025), and mean pRNFLT (r=0.396, P=0.025). In addition, in moderate to advanced glaucoma, there were significant correlations between mMS and all relevant measures of retinal thickness (r=0.330-0.663, P< 0.010). In early glaucoma, significant correlations were found between mean mMS and minimum GCL+IPLT (r=0.373, P=0.023), and between inferior mMS and superior GCL+IPLT (r=0.470, P=0.003). Linear models provided a good explanation for the relationship between SNR and inner retinal thickness (IRT), whereas nonlinear models better explained the relationship between mMS and IRT. In early glaucoma, both SNR and mMS were related moderately and significantly to IRT, whereas in moderate to advanced glaucoma, mMS was more strongly correlated with IRT than SNR.

8.
Biotechnol Bioeng ; 2020 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-32270472

RESUMEN

Diverse applications of bacterial cellulose (BC) have different requirements in terms of its structural characteristics. culturing Komagataeibacter xylinus CGMCC 2955, BC structure changes with alterations in oxygen tension. Here, the K. xylinus CGMCC 2955 transcriptome was analyzed under different oxygen tensions. Transcriptome and genome analysis indicated that BC structure is related to the rate of BC synthesis and cell growth, and galU is an essential gene that controls the carbon metabolic flux between the BC synthesis pathway and the pentose phosphate (PP) pathway. The CRISPR interference (CRISPRi) system was utilized in K. xylinus CGMCC 2955 to control the expression levels of galU. By overexpressing galU and interfering with different sites of galU sequences using CRISPRi, we obtained strains with varying expression levels of galU (3.20-3014.84%). By testing the characteristics of BC, we found that the porosity of BC (range: 62.99-90.66%) was negative with galU expression levels. However, the crystallinity of BC (range: 56.25-85.99%) was positive with galU expression levels; galU expression levels in engineered strains were lower than those in the control strains. Herein, we propose a new method for regulating the structure of BC to provide a theoretical basis for its application in different fields.

9.
Am J Hematol ; 2020 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-32249963

RESUMEN

This multi-institutional study retrospectively evaluated clinicopathologic and genetic characteristics in 351 patients with core-binding-factor acute myeloid leukemia (CBF-AML), comprising 69 therapy-related (t-CBF-AML) and 282 de novo cases. The T-CBF-AML patients were older, had lower WBC counts, and slightly higher hemoglobin than patients with de novo disease. Secondary cytogenetic abnormalities were more frequent in patients with de novo disease than t-CBF-AML (57.1% vs 41.1%, P = .026). Patients with secondary cytogenetic abnormalities had longer overall survival (OS) than those without abnormalities (median 190 vs 87 months, P = .021); trisomy 8, trisomy 22, and loss of the X or Y chromosome were associated with longer OS. In the 165 cases performed of targeted gene sequencing, pathogenic mutations were detected in 75.7% of cases, and were more frequent in de novo than in therapy-related disease (P = .013). Mutations were found in N/KRAS (37.0%), FLT3 (27.8%), KIT (17.2%), TET2 (4.9%), and ASXL1 (3.9%). The TET2 mutations were associated with shorter OS (P = .012) while N/KRAS mutation was associated with longer OS in t(8;21) AML patients (P = .001). The KIT mutation did not show prognostic significance in this cohort. Although they received similar therapy, t-CBF-AML patients had shorter OS than de novo patients (median 69 vs 190 months, P = .038). In multivariate analysis of all patients, older age and absence of any secondary cytogenetic abnormalities were significant predictors of shorter OS. Among the t-CBF-AML subset, age and hemoglobin were significant on multivariate analysis. This study demonstrated that although de novo and t-CBF-AML patients share many features, t-CBF-AML patients have worse clinical outcome than de novo patients.

10.
Cancer Med ; 2020 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-32281275

RESUMEN

BACKGROUND: The treatment outcomes and prognosis of lymphoma are affected by various factors such as hospital types. This study was to describe the temporal trend in the survival of lymphoma in an academic center in China. METHODS: A total of 3840 consecutive patients with lymphoma diagnosed between 1996 and 2015 were reviewed. Eighty patients were excluded, and finally, 3760 patients were analyzed in this study. The cohort was divided into four groups according to calendar periods at diagnosis: 1996-2000, 2001-2005, 2006-2010, and 2010-2015. The overall survival (OS) rates among the four groups were compared. RESULTS: The 5- and 10-year OS for the whole cohort were 62% and 52%, respectively. The 5-year OS of patient with classic Hodgkin lymphoma (cHL), mature B-cell lymphoma (BCL), and peripheral T-cell lymphoma (PTCL) were 79%, 63%, and 50%, respectively. Among mature BCL, the 5-year OS was highest in follicular lymphoma (77.8%), followed by Burkitt lymphoma (76.5%), marginal zone lymphoma (74.1%), diffuse large B-cell lymphoma (61.5%), small lymphocytic lymphoma/chronic lymphocytic leukemia (55.1%), and mantle cell lymphoma (44.3%). Among PTCL, the 5-year OS was highest in ALK+anaplastic large cell lymphoma (79.0%), followed by ALK-anaplastic large cell lymphoma (63.1%), natural killer/T-cell lymphoma (57.7%), angioimmunoblastic T-cell lymphoma (34.9%, and peripheral T-cell lymphoma not otherwise specified (27.6%). Significant improvement in the survival of lymphoma was observed, with the 5-year OS increasing from 48% in 1996-2000 to 65% in 2011-2015 (P < .001). The 5-year OS of patients with cHL, mature BCL, and PTCL changed from 55%, 49%, and 41% in 1996-2000 to 79%, 65%, and 51% in 2011-2015, respectively (P values were .014, .002, and .592, respectively). CONCLUSION: The survival of most types of lymphoma such as cHL and mature BCL, rather than PTCL, was improved significantly during the past two decades.

11.
Zhongguo Zhong Yao Za Zhi ; 45(5): 1174-1179, 2020 Mar.
Artículo en Chino | MEDLINE | ID: mdl-32237462

RESUMEN

In order to explore the characteristics of traditional Chinese medicine(TCM) syndromes and medications in patients with colonic malignant tumors in China, the clinical data of patients with colonic malignant tumors from the information system of 33 Grade-A tertiary hospitals in China from 2001 to 2016 were extracted and a descriptive analysis was conducted on their disease characteristics, syndrome distribution, drug characteristics and treatment status. A total of 22 691 patients with colonic malignancies nationwide were included in the analysis, with male to female ratio of 1.59∶1, median age of 62 years, susceptible age of 50-79 years. Postoperative patients with colonic malignant tumors accounted for 47.10%, and patients with liver metastases reached 36.02%. Among the 520 patients with colonic malignant tumors, the top three TCM syndromes were: spleen deficiency syndrome(21%), Qi and Yin deficiency syndrome(17%) and liver and stomach disharmony syndrome(15%). The most frequently used Western medicine for patients with colonic malignant tumors was anti-metabolite cytotoxicity(61.23%), most frequently used in combination with platinum-based cytotoxic drugs(support degree 42.40%).The top three Western medicines were oxaliplatin(42.26%), leucovorin injection(38.58%) and dexamethasone(34.67%). The most frequently used traditional Chinese medicine type was heat-clearing and detoxifying drugs(39.59%), most frequently used in combination with Qi replenishing and body resistance strengthening drugs(support degree 12.72%). The top three traditional Chinese medicines were compound Kushen Injection(14.62%), Shenqi Fuzheng Injection(10.18%) and Aidi Injection(6.48%). This study shows that spleen and Qi deficiency may be the dominant syndrome of colonic malignant tumor, and chemotherapy is one of the main treatment methods. Traditional Chinese medicine has shown unique advantages in alleviating the toxic and side effects of chemotherapy and preventing recurrence and metastasis, so integrated TCM and Western medicine can significantly improve the clinical efficacy.

12.
BMJ Glob Health ; 5(3): e002063, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32341805

RESUMEN

Introduction: We aimed to integrate all available epidemiological evidence to characterise an exposure-response model of ambient fine particulate matter (PM2.5) and the risk of chronic kidney disease (CKD) across the spectrum of PM2.5 concentrations experienced by humans. We then estimated the global and national burden of CKD attributable to PM2.5. Methods: We collected data from prior studies on the association of PM2.5 with CKD and used an integrative meta-regression approach to build non-linear exposure-response models of the risk of CKD associated with PM2.5 exposure. We then estimated the 2017 global and national incidence, prevalence, disability-adjusted life-years (DALYs) and deaths due to CKD attributable to PM2.5 in 194 countries and territories. Burden estimates were generated by linkage of risk estimates to Global Burden of Disease study datasets. Results: The exposure-response function exhibited evidence of an increase in risk with increasing PM2.5 concentrations, where the rate of risk increase gradually attenuated at higher PM2.5 concentrations. Globally, in 2017, there were 3 284 358.2 (95% UI 2 800 710.5 to 3 747 046.1) incident and 122 409 460.2 (108 142 312.2 to 136 424 137.9) prevalent cases of CKD attributable to PM2.5, and 6 593 134.6 (5 705 180.4 to 7 479 818.4) DALYs and 211 019.2 (184 292.5 to 236 520.4) deaths due to CKD attributable to PM2.5. The burden was disproportionately borne by low income and lower middle income countries and exhibited substantial geographic variability, even among countries with similar levels of sociodemographic development. Globally, 72.8% of prevalent cases of CKD attributable to PM2.5 and 74.2% of DALYs due to CKD attributable to PM2.5 were due to concentrations above 10 µg/m3, the WHO air quality guidelines. Conclusion: The global burden of CKD attributable to PM2.5 is substantial, varies by geography and is disproportionally borne by disadvantaged countries. Most of the burden is associated with PM2.5 levels above the WHO guidelines, suggesting that achieving those targets may yield reduction in CKD burden.

13.
Sci Total Environ ; 723: 137967, 2020 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-32217402

RESUMEN

Non-road construction equipment (NRCE) is an important source of atmospheric pollution in many developing and urbanizing countries such as China. However, NRCE source is frequently ignored and failed to be identified in the processing of the source apportionment for atmospheric pollution due to the little knowledge on its chemical fingerprint. In this study, seven types of NRCE are selected with the objectives of quantifying the emission factors of fine particulate matter (PM2.5) (EFPM) and exploring their potential chemical fingerprints. Our results show that the NRCE EFPM in the working modes are ~2-3 times higher than those in idling modes, suggesting the important role of engine operating conditions in producing primary PM2.5. As expected, carbonaceous aerosol is the dominant specie of PM2.5, with a wide range of 64-95%. And, the ratio of organic carbon to elemental carbon displays a systematical decrease trend with the increase of engine rated powers. The analysis results show that NRCE PM2.5 chemical compositions are highly correlated with the engine rated powers. In addition, we confirm that the ratio of vanadium and nickel can be used as a good tracer of NREC emission, which is distinct from other key combustion sources such as industry and ship emission. Taken together, this study reveals the emission characteristics of NRCE-related particles and urgently calls on that the NRCE source should be considered in the source apportionment models in the future.

14.
Glycobiology ; 2020 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-32149341

RESUMEN

Tuberculosis (TB) is the leading infectious cause of mortality worldwide, especially in developing countries. However, effective means for TB diagnosis, especially for bacillus negative (Bn) TB laboratory diagnosis are urgently needed. In the present study, serum IgG from each tuberculosis patients and healthy controls was purified using affinity chromatography. The samples were then analyzed using mass spectrometry (MS) and ultra performance liquid chromatography (UPLC) methods. We quantitatively assessed the changes of serum IgG galactosylation in 567 human serum samples including 377 pulmonary TB patients and 190 healthy donors (HDs). We found significantly more agalactosylated (G0) vs monogalactosylated (G1) and digalactosylated (G2) N-glycans of IgG in TB patients, including smear negative TB patients, than in HDs. The detection rate of TB diagnostic performance by MS for IgG-Gal-Ratio G0/(G1 + G2 × 2) is 90.48% for bacillus positive (Bp) and 73.16% for Bn TB patients. Further, combination of MS method with other routine laboratory TB diagnostic methods significantly increased the detection rate to 91.01%~98.39%. Similar results were observed in Mycobacterium tuberculosis (M.tb) infection mouse models. The decrease in galactosylation of IgG in TB patients were also qualitatively confirmed using specific lectin blot assay. Using above techniques we can discriminate the content of IgG G0 with terminal N-acetylglucosamine and IgG-Gal-Ratio G0/(G1 + G2 × 2) between TB patients and HDs. Our data suggest that quantitative analysis of serum-based IgG-Gal-Ratio G0/(G1 + G2 × 2) could be used for TB auxiliary diagnosis with high effectiveness and feasibility, and its combination with other routine laboratory TB diagnostic methods could remarkably improve the detection rate.

15.
Mar Drugs ; 18(3)2020 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-32150903

RESUMEN

In recent years, there has been a revival of interest in phenotypic-based drug discovery (PDD) due to target-based drug discovery (TDD) falling below expectations. Both PDD and TDD have their unique advantages and should be used as complementary methods in drug discovery. The PhenoTarget approach combines the strengths of the PDD and TDD approaches. Phenotypic screening is conducted initially to detect cellular active components and the hits are then screened against a panel of putative targets. This PhenoTarget protocol can be equally applied to pure compound libraries as well as natural product fractions. Here we described the use of the PhenoTarget approach to identify an anti-tuberculosis lead compound. Fractions from Polycarpa aurata were identified with activity against Mycobacterium tuberculosis H37Rv. Native magnetic resonance mass spectrometry (MRMS) against a panel of 37 proteins from Mycobacterium proteomes showed that a fraction from a 95% ethanol re-extraction specifically formed a protein-ligand complex with Rv1466, a putative uncharacterized Mycobacterium tuberculosis protein. The natural product responsible was isolated and characterized to be polycarpine. The molecular weight of the ligand bound to Rv1466, 233 Da, was half the molecular weight of polycarpine less one proton, indicating that polycarpine formed a covalent bond with Rv1466.

16.
Sci Rep ; 10(1): 4586, 2020 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-32165691

RESUMEN

Epidemiologic observations suggest that exposure to ambient fine particulate matter (PM2.5) is associated with increased risk of chronic kidney disease (CKD) and diabetes, a causal driver of CKD. We evaluated whether diabetes mediates the association between PM2.5 and CKD. A cohort of 2,444,157 United States veterans were followed over a median 8.5 years. Environmental Protection Agency data provided PM2.5 exposure levels. Regression models assessed associations and their proportion mediated. A 10 µg/m3 increase in PM2.5 was associated with increased odds of having a diabetes diagnosis (odds ratio: 1.18, 95% CI: 1.06-1.32), use of diabetes medication (1.22, 1.07-1.39), and increased risk of incident eGFR <60 ml/min/1.73 m2 (hazard ratio:1.20, 95% CI: 1.13-1.29), incident CKD (1.28, 1.18-1.39), ≥30% decline in eGFR (1.23, 1.15-1.33), and end-stage renal disease (ESRD) or ≥50% decline in eGFR (1.17, 1.05-1.30). Diabetes mediated 4.7% (4.3-5.7%) of the association of PM2.5 with incident eGFR <60 ml/min/1.73 m2, 4.8% (4.2-5.8%) with incident CKD, 5.8% (5.0-7.0%) with ≥30% decline in eGFR, and 17.0% (13.1-20.4%) with ESRD or ≥50% decline in eGFR. Diabetes minimally mediated the association between PM2.5 and kidney outcomes. The findings will help inform more accurate estimates of the burden of diabetes and burden of kidney disease attributable to PM2.5 pollution.

17.
Mol Pharm ; 17(4): 1415-1427, 2020 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-32159961

RESUMEN

The therapeutic efficacy of chemotherapy in many types of hematological malignancies and solid tumors is dramatically hindered by multidrug resistance (MDR). This work presents a combination strategy of pretreatment of MDA-MB-231/MDR1 cells with quercetin (QU) followed by doxorubicin (DOX) to overcome MDR, which can be delivered by mixed micelles composed of the reduction-sensitive hyaluronic acid-based conjugate and d-α-tocopheryl poly(ethylene glycol) 1000 succinate. The combination strategy can enhance the cytotoxicity of DOX on MDA-MB-231/MDR1 cells by increasing intracellular DOX accumulation and facilitating DOX-induced apoptosis. The probable MDR reversal mechanisms are that the pretreatment cells with QU-loaded mixed micelles downregulate P-glycoprotein expression to decrease DOX efflux as well as initiate mitochondria-dependent apoptotic pathways to accelerate DOX-induced apoptosis. In addition, this combination strategy can not only potentiate in vivo tumor-targeting efficiency but also enhance the antitumor effect in MDA-MB-231/MDR1-bearing nude mice without toxicity or side effects. This research suggests that the co-administration of natural compounds and chemotherapeutic drugs could be an effective strategy to overcome tumor MDR, which deserves further exploration.

18.
APMIS ; 2020 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-32048364

RESUMEN

Renal cell carcinoma with sarcomatoid differentiation (RCCs) is rare, accounting for 1-8% of all RCC histological subtypes. In this study, we examined 139 patients with RCCs and aimed to explore their clinicopathologic features and prognostic factors. From January 2007 to January 2019, patients who were pathologically diagnosed with RCCs were included in this retrospective study. Data on clinicopathologic features and overall survival were collected. The expression of CK, vimentin, CK7, and CD10 in the sarcomatoid regions of RCCs was detected. The Kaplan-Meier curves and log-rank tests were used to describe the effect of clinicopathologic characteristics on overall survival. A Cox regression model was used to evaluate risk factors for prognosis. A total of 139 patients with RCCs were identified. The median age at diagnosis was 60 years. The median survival time of all patients was 39 months. The three- and five-year survival rates were 50.2% and 44.0%, respectively. A high pathologic T stage (pT3 and pT4), microvascular invasion, and lymph node metastasis were significant predictors of prognosis. Pathologic T4 stage and lymph node metastasis were independent prognostic factors for overall survival in patients with RCCs. Furthermore, the expression of CD10 was a prognostic factor for overall survival. In this study, a relatively large cohort of patients with RCCs was analyzed. We summarized the clinicopathologic features of RCCs and explored the risk factors for prognosis. Our findings may provide valuable prediction for clinical strategy.

19.
Metabolism ; 105: 154189, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32105664

RESUMEN

BACKGROUND: Sprouty (SPRY) proteins play critical roles in controlling cell proliferation, differentiation, and survival by inhibiting receptor tyrosine kinase (RTK)-mediated extracellular signal-regulated kinase (ERK) signaling. Recent studies have demonstrated that SPRY4 negatively regulates angiogenesis and tumor growth. However, whether SPRY4 regulates osteogenic and/or adipogenic differentiation of mesenchymal stem cells remains to be explored. RESULTS: In this study, we investigated the expression pattern of Spry4 and found that its expression was regulated during the differentiation of mouse marrow stromal progenitor cells and increased in the metaphysis of ovariectomized mice. In vitro loss-of-function and gain-of-function studies demonstrated that SPRY4 inhibited osteogenic differentiation and stimulated adipogenic differentiation of progenitor cells. In vivo experiments showed that silencing of Spry4 in the marrow of C57BL/6 mice blocked fat accumulation and promoted osteoblast differentiation in ovariectomized mice. Mechanistic investigations revealed the inhibitory effect of SPRY4 on canonical wingless-type MMTV integration site (Wnt) signaling and ERK pathway. ERK1/2 was shown to interact with low-density lipoprotein receptor-related protein 6 (LRP6) and activate the canonical Wnt signaling pathway. Inactivation of Wnt signaling attenuated the inhibition of adipogenic differentiation and stimulation of osteogenic differentiation by Spry4 small interfering RNA (siRNA). Finally, promoter study revealed that ß-catenin transcriptionally inhibited the expression of Spry4. CONCLUSIONS: Our study for the first time suggests that a novel SPRY4-ERK1/2-Wnt/ß-catenin regulatory loop exists in marrow stromal progenitor cells and plays a key role in cell fate determination. It also highlights the potential of SPRY4 as a novel therapeutic target for the treatment of metabolic bone disorders such as osteoporosis.


Asunto(s)
Adipogénesis/genética , Adipogénesis/fisiología , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Sistema de Señalización de MAP Quinasas/genética , Sistema de Señalización de MAP Quinasas/fisiología , Células Madre Mesenquimatosas/fisiología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/fisiología , Osteogénesis/genética , Osteogénesis/fisiología , Vía de Señalización Wnt/genética , Vía de Señalización Wnt/fisiología , beta Catenina/genética , beta Catenina/fisiología , Animales , Médula Ósea/metabolismo , Femenino , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/fisiología , Ratones , Ratones Endogámicos C57BL , Ovariectomía , ARN Interferente Pequeño/farmacología
20.
J Pediatr Orthop ; 2020 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-32011548

RESUMEN

BACKGROUND: The standard treatment for supracondylar humeral fractures (SHFs) in children is closed reduction and percutaneous Kirschner (K)-wire fixation. In patients who present >14 days after injury and show callus formation, this procedure cannot be performed. There are 2 options in these cases: functional exercises with osteotomy performed at a later stage if cubitus varus is present, or immediate open reduction and percutaneous K-wire fixation. This study aimed to evaluate the outcomes of K-wire fixation through an anterior approach in children with neglected SHF and identify factors predicting the outcomes. METHODS: This retrospective study assessed the files of 32 children treated for neglected SHF at our hospital between June 2015 and May 2018. An incision was made along the anterior transverse groove of the elbow. The callus was removed, the fracture was reduced, and K-wire fixation was performed. The outcome evaluation included the radiological Baumann angle, pin fixation construct, carrying angles, and the functional outcome was Mayo Elbow Performance Score and Flynn criteria. Binary regression analysis compared the functional outcome as the dependent variable with age, time from injury to operation, operation time, and the amount of callus. RESULTS: The interval between injury and operation was 14 to 40 days (average, 22.4 d). Patients were followed for 12 to 36 months (average, 21.5 mo). Fracture healing took 5 to 8 weeks (average, 6.6 wk). No patient had a vascular injury or compartment syndrome. Twelve patients were intraoperatively assessed for radial and median nerve injury. No nerve repair was required. All nerve injuries recovered within 3 months. No iatrogenic ulnar nerve injury occurred. One patient had an infected incision. Binary regression analysis showed that the time elapsed between injury and operation (P=0.033) and Gartland type (P=0.008) were inversely correlated with outcomes; the longer the duration, the poorer the outcomes. CONCLUSIONS: The functional outcomes after open reduction and K-wire fixation through an anterior approach were poorer with longer time to surgery and Gartland type. LEVEL OF EVIDENCE: Level III.

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