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1.
Biomed Pharmacother ; 121: 109425, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31726370

RESUMO

Gastric carcinoma (GC) is still one of the most common digestive system neoplasms and the primary reason for malignant cancer-associated death. Long non-coding RNAs (lncRNAs) have been reported to play critical roles in GC progression. In this study, we demonstrated that lncRNA testis development-related gene 1 (TDRG1) is markedly upregulated in clinical GC tissues and GC cells. High level of lncRNA TDRG1 correlates with the metastasis and prognosis of patients with GC. Overexpression of lncRNA TDRG1 promotes GC growth and metastatic-related traits in vitro and in vivo, and silencing TDRG1 causes opposite results. We future find that TDRG1 is inversely associated with miR-873-5p and positively modulates the expression of hepatoma-derived growth factor (HDGF), a functional target gene of miR-873-5p. Finally, lncRNA TDRG1 regulates the progression of GC through regulating miR-873-5p/HDGF pathway. Taken together, our data uncover the crucial function of TDRG1-miR-873-5p-HDGF axis in human gastric cancer.

2.
Talanta ; 207: 120288, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31594593

RESUMO

The exploration of advanced photoactive materials with fine photoelectrochemical (PEC) performance is always the hot subject in PEC bioanalysis. Herein, Mn-doped CdS nanocrystals (CdS:Mn)-sensitized 2D/2D heterostructured g-C3N4-MoS2 was prepared and served as photoactive matrix of PEC sensing platform for myoglobin (Myo) detection using CuO nanoparticles labeled anti-Myo (anti-Myo-CuO) conjugates as signal amplification tags. The heterostructured g-C3N4-MoS2 could effectively promote the electron transfer and evidently restrain the recombination of electron-hole pairs, producing the high photocurrent response. Upon loaded CdS:Mn on the heterostructured g-C3N4-MoS2 to form co-sensitized structure, the photocurrent further gives a dramatically increase. To proof the performance of the co-sensitized structure in PEC bioanalysis, a sandwich type PEC immunosensor was designed by using the co-sensitized structure as photomatrix, Myo as model protein, and anti-Myo-CuO conjugates as amplifying tags. The introduction of anti-Myo-CuO conjugates in this system could significantly quench the PEC response of the sensing interface owing to the competition of the light-generated electron, poor conductivity and steric hindrance of the anti-Myo-CuO conjugates. In virtue of synergistic amplification of the CdS:Mn sensitized heterostructured g-C3N4-MoS2 and the anti-Myo-CuO conjugates, the immunosensor could respond down to 0.42 pg mL-1 Myo with a detectable range of 1.0 pg mL-1 to 50 ng mL-1. Moreover, this PEC platform demonstrates high specificity and sensitivity for Myo detection in real biological matrices. This strategy may furnish new insights for applications of novel 2D/2D heterostructures in PEC bioanalysis.

3.
J Microbiol Methods ; : 105798, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31790778

RESUMO

The promoter of the srf operon (PsrfA) had been used to construct a cell-density-dependent expression system in B. subtilis in our previous work. The PsrfA and its derivative PsrfA12 showed good performance of heterologous protein expression in B. subtilis. In this work, using green fluorescent protein (GFP) and ß-galactosidase (LacZ) as the reporter proteins, the host feasibility and expression characteristics of the PsrfA and PsrfA12 in E. coli were identified. The prominent green fluorescence shooted by laser scanning confocal microscope, fluorescence intensity measured by spectrophotometer and the distinct protein bands detected by SDS-PAGE demonstrated that the GFP could be largely expressed under the control of the PsrfA and PsrfA12 in the E. coli host strain of BL21 (DE3) and JM109 and the expression of GFP in strain BL21 (DE3) was much higher than that of in strain JM109. Meanwhile, the promoter PsrfA 12 was much stronger than PsrfA to the extent that the GFP controlled by PsrfA12 in strain BL21 (DE3) was leaked into the supernatant. And the fluorescence intensity detected in the supernatant of the recombinant strain BL21 (DE3) containing PsrfA12 was 10.25-fold higher than that of strain JM109 containing PsrfA. Moreover, the LacZ could also be produced by PsrfA and PsrfA12 in strain BL21 (DE3) and JM109 and the strain JM109 showed better performance than BL21 (DE3) in expressing LacZ. The LacZ activity controlled by PsrfA and PsrfA12 in JM109 were separately 2.47-fold and 2.36-fold higher than that of in strain BL21 (DE3). This work will broaden the applied range of the PsrfA and enrich the efficient toolbar for cross-species gene expression or module construction in E. coli and B. subtilis.

4.
Med Mycol ; 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31711175

RESUMO

Bud emergence 46 (BEM46), a member of the α/ß hydrolase superfamily, has been reported to be essential for polarized growth in Neurospora crassa. However, the role of BEM46 in aspergillus fumigatus (A. fumigatus) remains unclear. In this study, we constructed an A. fumigatus strain expressing BEM46 fused with enhanced green fluorescent protein, and a Δbem46 mutant, to explore the localization and the role of growth of BEM46 in A. fumigatus, respectively. Confocal laser scanning microscopy revealed that BEM46 was dominantly expressed in the sites where hyphae germinated from conidia in A. fumigatus. When compared with the control strain, the Δbem46 mutant exhibited insignificant morphological changes but delayed germination. No significant changes were found regarding the radial growth of both strains in response to various antifungal agents. These results suggest that BEM46 plays an essential role in timely germination in A. fumigatus. From the observation of fluorescence localization, we infer that that BEM46 might be involved in polarized growth in A. fumigatus.

5.
Org Lett ; 21(22): 9228-9231, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31680529

RESUMO

Visible light-mediated cascade remote oxyfluoroalkylation of alkenes under mild conditions is developed for the first time. The key point of this transformation is the incorporation of alkene fluoroalkylation-initiated remote benzyl C-H bond activation via a 1,5-H shift in a highly controlled site-selective manner and Kornblum reaction with dimethyl sulfoxide as the oxidant. With this method, a broad array of fluoroalkyl groups were introduced into a double bond to produce 1,6-fluoroalkylated ketones at room temperature.

6.
Public Health Nutr ; : 1-9, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31666145

RESUMO

OBJECTIVE: To examine the associations between overall diet quality and hearing function among middle-older aged adults in the USA. DESIGN: Cross-sectional analysis. Diet quality was examined using the Mediterranean Diet Score (MDS), using data from a single 24 h dietary recall. Hearing function was objectively measured by audiometry assessments and hearing loss, including high- and low-frequency hearing loss, was defined as pure-tone averages at specific ranges of hearing frequencies >25 dB. Weighted logistic regression analyses were performed to examine the associations of MDS (scored 0-9, categorized at the median as ≤3 or >3) with hearing loss and high- and low-frequency hearing loss. SETTING: National Health and Nutrition Examination Surveys 2000-2006 and 2009-2012. PARTICIPANTS: Adults aged ≥50 years (n 1639) with valid dietary and audiometry assessments. RESULTS: After adjusting for potential confounders, a non-significant trend for a protective association of higher MDS was observed for hearing loss (OR = 0·78; 95 % CI 0·49, 1·23). A significant inverse association was observed for high-frequency hearing loss (OR = 0·64; 95 % CI 0·43, 0·95). No association was found for low-frequency hearing loss among women; however, higher MDS was significantly associated with higher odds of low-frequency hearing loss among men (OR = 2·63; 95 % CI 1·39, 4·95). CONCLUSIONS: Among middle-older aged adults, adherence to a Mediterranean-style diet was inversely associated with hearing loss, including those at high hearing frequencies, among older adults. However, a detrimental association was observed at low hearing frequencies among men. Future investigations with a longitudinal design are needed to clarify the associations between diet quality and hearing loss.

7.
BMC Cancer ; 19(1): 1157, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779593

RESUMO

BACKGROUND: Cervical cancer (CC), causing significant morbidity and mortality worldwide, is one of the most common gynecological malignancies in women. SFN has been reported as a potential prognostic marker with apparent high expression in tumors. Nevertheless, the function mechanism of SFN is not clear yet in CC. METHODS: The relative expressions of RNAs were detected by real-time quantitative PCR (RT-qPCR). Colony formation assay, EdU stained assay and CCK-8 assay were to check cell proliferation ability in CC. Flow cytometry and apoptosis related proteins analysis were used to measure cells apoptosis capacity. Luciferase reporter assay and RNA pull down assay were to verify the molecular mechanism. RESULTS: SFN was highly expressed in CC tissues and CC cell lines compared with normal tissues and normal cell line. After interfering SFN, cell proliferation, migration and invasion ability was inhibited as well as cell apoptosis ability was promoted. In subsequence, miR-383-5p exhibited conspicuous low expression in CC tissues. And miR-383-5p was found to bind to SFN and have anti-cancerous effects in CC. Moreover, LINC01128 displayed remarkable high expression in CC tissues. Besides, LINC01128 shortage could reduce the expression of SFN at mRNA and protein levels. And the affinity between LINC01128 and miR-383-5p was verified. In the end, it was proved that LINC01128 could enhance cell proliferation, migration and invasion as well as inhibit cell apoptosis by binding with miR-383-5p and upregulating SFN. CONCLUSION: LINC01128 expedited cells cellular process in CC by binding with miR-383-5p to release SFN.

8.
Mediators Inflamm ; 2019: 1769374, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772499

RESUMO

Intraperitoneal adhesion is a common complication after abdominal surgery, which seriously affects the quality of life of patients. HuoXueTongFu Formula (HXTF) plays an important role in the prevention and treatment of intraperitoneal adhesions. However, the molecular-related mechanisms are still not fully known. In this study, the model of Intrapetitoneal adhesion was established by cecum abrasion and treated with HXTF for one week. RAW264.7 cells were given LPS, IFN-γ, IL-4, HXTF-medicated serum, and PPAR-γ agonist/antagonist, respectively. Histopathology, flow cytometry, ELISA, real-time PCR, and Western blotting were used to further detect the related protein, M1/M2 polarization tendency, and PPAR-γ nuclear translocation. The deposition of collagen fibres reduced in the local area of rats after the operation with HXTF treatment. Similar to IL-4, HXTF induced a tendency for macrophages to polarize toward M2 and promoted peroxisome proliferator-activated receptor-gamma (PPAR-γ) nuclear translocation. Furthermore, the use of HXTF and PPAR-γ agonists downregulated macrophage M1 polarization-related factors IL-1, IL-6, and TNF-alpha and upregulated M2 polarization-related factors IL-4, IL-10, and TGF-beta 1. Meanwhile, the use of HXTF and PPAR-γ agonists downregulated the SOCS3/JAK2/STAT1 pathway and activated the SOCS1/STAT6/PPAR-γ pathway. These results show that HXTF may reduce intraperitoneal adhesion by inducing macrophage M2 polarization and regulating the SOCS/JAK2/STAT/PPAR-γ pathway.

9.
Int J Mol Sci ; 20(23)2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31779255

RESUMO

Many members of the WRKY family regulate plant growth and development. Recent studies have shown that members of the WRKY family, specifically WRKY13, play various roles in the regulation of plant stress resistance. To study the function of WRKY family members in peony, the PlWRKY13 gene (KY271095) was cloned from peony leaves. Sequence analysis and subcellular localization results revealed that PlWRKY13 has no introns, belongs to the type IIc subgroup of the WRKY family, and functions in the nucleus. The expression pattern of PlWRKY13 was analysed via real-time quantitative RT-PCR (qRT-PCR), which showed that the expression of PlWRKY13 was induced by four types of abiotic stress, low-temperature, high-temperature, waterlogging and salt stress, and was positively upregulated in response to these stresses. In addition, the expression of PlWRKY13 tended to first decrease and then increase after infection with Alternaria tenuissima. Virus-induced gene silencing (VIGS) technology was used to explore the function of PlWRKY13 in the resistance of Paeonia lactiflora to fungal infection further, and the results showed that PlWRKY13-silenced plants displayed increased sensitivity to A. tenuissima. The infection was more severe and the disease index (DI) significantly greater in the PlWRKY13-silenced plants than in the control plants, and the expression of pathogenesis-related (PR) genes was also significantly altered in the PlWRKY13-silenced plants compared with the control plants. The contents of the endogenous hormones jasmonic acid (JA) and salicylic acid (SA) were measured, and the results showed that the JA content increased gradually after infection with A. tenuissima and that JA may play an active role in the resistance of P. lactiflora to pathogen infection, while the SA content decreased after PlWRKY13 silencing. The contents of the two hormones decreased overall, suggesting that they are related to the transcription of PlWRKY13 and that PlWRKY13 may be involved in the disease-resistance pathway mediated by JA and SA. In summary, the results of our study showed that PlWRKY13 expression was induced by stress and had a positive effect on the resistance of P. lactiflora to fungal infection.

10.
Mol Pharm ; 16(12): 5076-5084, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31670968

RESUMO

Progesterone (PG) is an essential sex hormone with a variety of important biological functions, but its insolubility leads to low bioavailability of most water-based formulations. What is more, the commercial oil-based formulations often cause severe side effects after long-term injection due to poor tissue absorption of oil. Herein, we report an aseptic bottom-up method utilizing emulsion freeze-drying technology that produces size-controllable, highly bioavailable, and water-based PG nanocrystal injection. The key factors that can determine the features of nanocrystals were investigated, including solvents, water-to-oil ratio, drug concentrations, type of surfactants, temperature in freeze-drying process, and lyoprotectants. Mechanisms of crystal growth formation process for PG nanocrystals were also analyzed theoretically. The prepared water-based PG nanocrystal suspension injection (PG/NSI) not only showed quick dissolution behaviors but also had significantly improved bioavailability in vivo. Therefore, this method can effectively control the size of nanocrystals, enhance bioavailability of insoluble drugs, and produce aseptic water-based nanocrystals that can be directly used for injection. Moreover, this method can also be used to prepare nanocrystals with the desired size under aseptic conditions for other poorly water-soluble drugs.

11.
Gene ; : 144262, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31759987

RESUMO

Neuroblastoma is an extracranial solid tumor that mainly occurs in childhood. Mutations of NRAS gene have been described in several cancers. However, whether NRAS gene polymorphisms can predict the risk of neuroblastoma have not been investigated. We hypothesized that variations of NRAS gene contribute to neuroblastoma predisposition. Therefore, we conducted a multi-center case-control study using 263 cases and 715 controls to examine the association of NRAS gene rs2273267 A>T polymorphism and neuroblastoma risk. We calculated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to assess the strength of the associations. Relative to those with AA genotype, subjects with AT/TT genotype had reduced neuroblastoma risk (adjusted OR = 0.72, 95% CI = 0.54-0.96, P = 0.024). Stratified analysis revealed that rs2273267 AT/TT carriers were less likely to develop neuroblastoma for patients with tumor originating from the adrenal gland (adjusted OR = 0.67, 95% CI = 0.45-0.99, P = 0.047) and clinical stages III + IV (adjusted OR = 0.57, 95% CI = 0.36-0.90, P = 0.015). Our findings underline the likely importance of NRAS gene rs2273267 A>T in the risk of neuroblastoma. Further independent case-control studies with functional analysis are needed to verify the role of NRAS gene rs2273267 A>T polymorphism in the risk of neuroblastoma.

12.
Clin Chem Lab Med ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31782945

RESUMO

Background Both the thrombo-inflammatory prognostic score (TIPS) and the quick sequential (sepsis-related) organ failure assessment (qSOFA) are quick prognostic scores for sepsis during the early phase, while either of two scores has limited prognostic value for sepsis patients. This study aimed to evaluate whether TIPS adds more information of sepsis risk stratification for qSOFA. Methods This was a retrospective cohort study of patients with sepsis in the emergency department (ED). We performed a receiver-operating characteristic curve, integrated discrimination improvement (IDI), net reclassification improvement (NRI) and decision-curve analysis (DCA) analyses to investigate whether TIPS can improve qSOFA for risk prediction in patients with sepsis. The primary endpoint was mortality and the secondary endpoints were mechanical ventilation and admission to the intensive care unit (ICU) during the 28-day follow-up. Results We identified 821 patients with sepsis. We randomly assigned the patients' data to a derivation group (n = 498; n = 112 died during the 28-days follow-up) or to a validation group (n = 323; n = 61). The addition of TIPS to qSOFA (T-qSOFA) improved the area under the curve (AUC) from 0.724 to 0.824 (p < 0.001) for predicting 28-day mortality. The discrimination improvement was confirmed by an IDI of 0.092 (p < 0.001). Addition of TIPS to the qSOFA resulted in a NRI of 0.247 (p < 0.001). The DCA showed that the net benefit of T-qSOFA was higher than that of TIPS or qSOFA for any threshold probabilities. Conclusions The prognostic value of qSOFA for patients with sepsis was enhanced by adding the TIPS score on admission for risk prediction in patients with sepsis during early phases in the ED.

13.
Comput Intell Neurosci ; 2019: 8490364, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687007

RESUMO

In recent years, with the explosion of multimedia data from search engines, social media, and e-commerce platforms, there is an urgent need for fast retrieval methods for massive big data. Hashing is widely used in large-scale and high-dimensional data search because of its low storage cost and fast query speed. Thanks to the great success of deep learning in many fields, the deep learning method has been introduced into hashing retrieval, and it uses a deep neural network to learn image features and hash codes simultaneously. Compared with the traditional hashing methods, it has better performance. However, existing deep hashing methods have some limitations; for example, most methods consider only one kind of supervised loss, which leads to insufficient utilization of supervised information. To address this issue, we proposed a triplet deep hashing method with joint supervised loss based on the convolutional neural network (JLTDH) in this work. The proposed method JLTDH combines triplet likelihood loss and linear classification loss; moreover, the triplet supervised label is adopted, which contains richer supervised information than that of the pointwise and pairwise labels. At the same time, in order to overcome the cubic increase in the number of triplets and make triplet training more effective, we adopt a novel triplet selection method. The whole process is divided into two stages: In the first stage, taking the triplets generated by the triplet selection method as the input of the CNN, the three CNNs with shared weights are used for image feature learning, and the last layer of the network outputs a preliminary hash code. In the second stage, relying on the hash code of the first stage and the joint loss function, the neural network model is further optimized so that the generated hash code has higher query precision. We perform extensive experiments on the three public benchmark datasets CIFAR-10, NUS-WIDE, and MS-COCO. Experimental results demonstrate that the proposed method outperforms the compared methods, and the method is also superior to all previous deep hashing methods based on the triplet label.

14.
Oxid Med Cell Longev ; 2019: 4957878, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31687081

RESUMO

Bovine herpesvirus type 1 (BoHV-1) is a significant cofactor for bovine respiratory disease complex (BRDC), the most important inflammatory disease in cattle. BoHV-1 infection in cell cultures induces overproduction of pathogenic reactive oxygen species (ROS) and the depletion of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), a master transcriptional factor regulating a panel of antioxidant and cellular defense genes in response to oxidative stress. In this study, we reported that the virus productive infection in MDBK cells at the later stage significantly decreased the expression levels of heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO1) proteins, the canonical downstream targets regulated by Nrf2, inhibited Nrf2 acetylation, reduced the accumulation of Nrf2 proteins in the nucleus, and relocalized nuclear Nrf2 proteins to form dot-like staining patterns in confocal microscope assay. The differential expression of Kelch-like ECH associated protein 1 (KEAP1) and DJ-1 proteins as well as the decreased association between KEAP1 and DJ-1 promoted Nrf2 degradation through the ubiquitin proteasome pathway. These data indicated that the BoHV-1 infection may significantly suppress the Nrf2 signaling pathway. Moreover, we found that there was an association between Nrf2 and LaminA/C, H3K9ac, and H3K18ac, and the binding ratios were altered following the virus infection. Taken together, for the first time, we provided evidence showing that BoHV-1 infection inhibited the Nrf2 signaling pathway by complicated mechanisms including promoting Nrf2 degradation, relocalization of nuclear Nrf2, and inhibition of Nrf2 acetylation.

15.
Clin Infect Dis ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31701144

RESUMO

BACKGROUND: Using the results of a site assessment survey performed at clinics throughout Washington DC, we studied the impact of clinic-level factors on antiretroviral therapy (ART) initiation and viral suppression (VS) among people living with HIV (PLWH). METHODS: This was a retrospective analysis from the DC Cohort, an observational clinical cohort of PLWH from 2011-2018. We included data from PLWH not on ART and not virally suppressed at enrollment. Outcomes were ART initiation and VS (HIV RNA <200 copies/mL). A clinic survey captured information on care delivery (clinical services, adherence services, patient monitoring services, e.g.) and clinic characteristics (types of providers, availability of evenings/weekends sessions, e.g.). Multivariate marginal Cox regression models were generated to identify factors associated with time to ART initiation and VS. RESULTS: Multiple clinic-level factors were associated with ART initiation, including retention in care monitoring and medication dispensing review (aHR = 1.34 to 1.40, p<0.05 for both). Furthermore, multiple factors were associated with VS, including retention in HIV care monitoring, medication dispensing review, presence of a peer interventionist (aHR ranging from 1.35 to 1.72, p<0.05 for all). In multivariable models evaluating different combinations of clinic-level factors, enhanced adherence services (aHR 1.37 (95% CI 1.18, 1.58), medication dispensing review (aHR 1.22, 95% CI 1,10, 1.36), and availability of opioid treatment (aHR 1.26 (95% CI 1.01, 1.57) were all associated with time to VS. CONCLUSIONS: The observed association between clinic-level factors and ART initiation/VS suggests that the presence of specific clinic services may facilitate achievement of HIV treatment goals.

16.
Breast Cancer ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31728872

RESUMO

BACKGROUND: Breast cancer has become a dangerous killer for the female, which seriously threatened women's life, leading to huge pressures to society. The present study assessed the mechanism underlying the involvement of bone marrow tyrosine kinase on chromosome X (BMX) in breast cancer development. METHODS: The expression of BMX was examined by qPCR and immunohistochemistry. The effect of BMX on cell proliferation and migration was detected by Clone formation assay and Transwell assay. In vitro study, the correlation of BMX with Wnt/ß-catenin pathway was explored by western blot and TOP/FOP flash assay. RESULTS: In the present study, we found that BMX was up-regulated in breast cancer, which was associated with the tumor differentiation and TNM stage. Oncogenic BMX enhanced the ability of breast cancer cell proliferation and migration. Furthermore, BMX could up-regulate the protein expression levels of p-ß-catenin (Y142), p-ß-catenin(Y654) and inhibit the expression level of p-ß-catenin (S33/37), thus activating Wnt/ß-catenin pathway in MCF-7 and MDA-MB-231 cells. In addition, we revealed that BMX promoted GSK3ß phosphorylation, which suppressed the degradation of ß-catenin. CONCLUSIONS: In this study, we identified that BMX-activated Wnt/ß-catenin signaling pathway, playing an oncogenic role in breast cancer, suggesting that BMX could become a potential treatment target of breast cancer.

17.
J Med Chem ; 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31738550

RESUMO

Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaines were designed, synthesized and assayed, leading to the discovery of a benzylamine derivative (compound 4, SLL-039) as a highly selective and potent κ opioid agonist (κ, Ki=0.47 nM, κ/µ=682, κ/δ=283), which was confirmed by functional assays in vitro and antinociceptive assays in vivo. The in vivo effect could be blocked by pretreatment with the selective κ antagonist nor-BNI. Moreover, this compound did not induce sedation, a common dose limiting effect of κ opioid receptor agonists, at its analgesic dose compared to U50,488H. The dissociation of sedation/antinociception found in SLL-039 was assumed to be correlated with the occupation of its benzamide motif in a unique subsite involving V1182.63, W124EL1 and E209EL2.

18.
Sci Rep ; 9(1): 17220, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748650

RESUMO

Cooperating gene mutations are typically required to transform normal cells enabling growth in soft agar or in immunodeficient mice. For example, mutations in Kras and transformation-related protein 53 (Trp53) are known to transform a variety of mesenchymal and epithelial cells in vitro and in vivo. Identifying other genes that can cooperate with oncogenic Kras and substitute for Trp53 mutation has the potential to lead to new insights into mechanisms of carcinogenesis. Here, we applied a genome-wide CRISPR/Cas9 knockout screen in KrasG12D immortalized mouse embryonic fibroblasts (MEFs) to search for genes that when mutated cooperate with oncogenic Kras to induce transformation. We also tested if mutation of the identified candidate genes could cooperate with KrasG12D to generate primary sarcomas in mice. In addition to identifying the well-known tumor suppressor cyclin dependent kinase inhibitor 2A (Cdkn2a), whose alternative reading frame product p19 activates Trp53, we also identified other putative tumor suppressors, such as F-box/WD repeat-containing protein 7 (Fbxw7) and solute carrier family 9 member 3 (Slc9a3). Remarkably, the TCGA database indicates that both FBXW7 and SLC9A3 are commonly co-mutated with KRAS in human cancers. However, we found that only mutation of Trp53 or Cdkn2a, but not Fbxw7 or Slc9a3 can cooperate with KrasG12D to generate primary sarcomas in mice. These results show that mutations in oncogenic Kras and either Fbxw7 or Slc9a3 are sufficient for transformation in vitro, but not for in vivo sarcomagenesis.

19.
Orthop Surg ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31750626

RESUMO

OBJECTIVES: Treatment for osteoporotic vertebral fracture (OVF) with cord compression is challenging and it usually requires surgical interventions to decompress nerves and restore spinal sequences. To describe a novel surgical strategy for treating OVFs with cord compression. METHODS: This is a single-center retrospective analysis. The inclusion criteria were Frankel grade C-E, single level T10 -L2 . Between January 2008 and December 2016, a total of 56 OVF patients (47 females and nine males, with an average age of 72 years (66-88 years), comprising of eight grade C, 23 grade D, and 25 grade E patients) were enrolled. The treatment algorithm included preoperative evaluation by MRI, extension CT, and radiography to classify the OVFs as type 1.1 (reducible, stable; n = 13), type1.2 (reducible, unstable; n = 16), type 2 (irreducible; n = 19) or type 2M (modifier; n = 8). Vertebroplasty (VP)/kyphoplasty (KP) was applied in type 1.1. VP/KP with posterior fixation and posterolateral fusion was applied in type 1.2. And additional laminectomy/osteotomy was used in type 2, except in a modifier group (2M) where same procedure as applied for type 1.2 was used. VAS, ODI, Cobb angle, Frankel functional grade, and complications were recorded. RESULTS: Thirteen cases were classified as type 1.1, 16 cases as type 1.2, 19 cases as type 2, and eight cases as type 2M. The follow-up period was 38.9 months (range, 24-108 months). All patients were followed-up in at least 24 months, in which time four patients died, two patients were lost at the last follow-up, and 50 patients completed the full study. The total VAS and ODI improved from 8 (7, 9) and 75.5% (67.2%, 80.0%) preoperatively to 2 (1, 3) and 31% (24.0%, 37.0%) on conclusion, respectively (P < 0.01). The local kyphotic angle was corrected from 22.3° (17.1°, 33. 8°) preoperatively to 10.4° (6.4°, 15.3°) on conclusion (P < 0.01). Twenty-three patients had achieved neurological recovery on conclusion (42E, 8D, P < 0.01). Asymptotic cement leakage was observed in 17/56 cases (30.4%), 6/56 in the affected vertebra (10.7%), and 24/330 in the screw trajectory (7.3%). At 2 years postoperatively, 11 new VFs had occurred in nine patients (16.1%), including VFs in nine adjacent segments that all occurred within 1 year after surgery. No cement migration or implant failure was noted. CONCLUSION: The novel surgical strategy for treating OVFs with cord compression consists of the most tailored and least invasive treatment for each patient. The positive mid- and long-term clinical and radiological outcomes observed could represent a step forward in devising the proposed algorithm.

20.
Artigo em Inglês | MEDLINE | ID: mdl-31691843

RESUMO

PURPOSE: Cerebral blood flow (CBF) and glucose metabolism are important and significant factors in ischaemic cerebrovascular disease. The objective of this study was to use quantitative hybrid PET/MR to evaluate the effects of surgery treatment on the symptomatic unilateral internal carotid artery/middle cerebral artery steno-occlusive disease. METHODS: Fifteen patients diagnosed with ischaemic cerebrovascular disease were evaluated using a hybrid TOF PET/MR system (Signa, GE Healthcare). The CBF value measured by arterial spin labelling (ASL) and the standardized uptake value ratio (SUVR) measured by 18F-FDG PET were obtained, except for the infarct area and its contralateral side, before and after bypass surgery. The asymmetry index (AI) was calculated from the CBF and SUVR of the ipsilateral and contralateral cerebral hemispheres, respectively. The ΔCBF and ΔSUVR were calculated as the percent changes of CBF and SUVR between before and after surgery, and paired t tests were used to determine whether a significant change occurred. Spearman's rank correlation was also used to compare CBF with glucose metabolism in the same region. RESULTS: The analysis primarily revealed that after bypass surgery, a statistically significant increase occurred in the CBF on the affected side (P < 0.01). The postprocedural SUVR was not significantly higher than the preprocedural SUVR (P > 0.05). However, the postprocedural AI values for CBF and SUVR were significantly lower after surgery than before surgery (P < 0.01). A significant correlation was found between the AI values for preoperative CBF and SUVR on the ipsilateral hemisphere (P < 0.01). CONCLUSIONS: The present study demonstrates that a combination of ASL and 18F-FDG PET could be used to simultaneously analyse changes in patients' cerebral haemodynamic patterns and metabolism between before and after superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery. This therefore represents an essential tool for the evaluation of critical haemodynamic and metabolic status in patients with symptomatic unilateral ischaemic cerebrovascular disease.

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