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1.
Ultrasound Med Biol ; 46(1): 90-107, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31668943

RESUMO

The PIK3 CA gene encodes the p110α protein subunit and is one of the most efficient cancer genes in solid and hematological tumors including hepatocellular carcinoma (HCC). There are currently ongoing therapies against tumors based on PIK3 CA inhibition. Because microRNAs (miRNAs) play an important role in post-transcriptional regulation and are also involved in the inhibition of PIK3 CA expression to suppress cancer cell proliferation, overexpression of tumor-suppressive miRNA is a promising therapeutic approach for HCC therapy. The successful and localized delivery of miRNA overexpression vectors (pre-miRNA plasmids) is very important in improving the therapeutic efficacy of this miRNA therapy strategy. In the study described here, submicron acoustic phase-shifted nanodroplets were used to efficiently deliver pre-miRNA plasmid in vitro and in vivo for HCC therapy under focused ultrasound (US) activation. Briefly, six miRNAs, inhibiting PIK3 CA and downregulated in HCC, were selected through summary and analysis of the currently existing literature data. Quantitative real-time polymerase chain reaction (qRT-PCR), Western blot and cell apoptosis assay revealed that pre-miR-139, -203a, -378a and -422a plasmids among the six miRNA overexpression vectors could suppress growth of the hepatoma cell line SMMC-7721. These four pre-miRNA plasmids were then electrostatically adhered to positively charged lipid-shelled nanodroplets to obtain plasmid-loaded nanodroplets (PLNDs). The PLND-generated microbubbles oscillated and even collapsed under US exposure to release the loaded pre-miRNA plasmids and enhance their cellular uptake through consequent sonoporation, that is, formation of small pores on the cell membrane induced by the mechanical effects of PLND cavitation. Fluorescence microscopy results revealed that PLNDs could effectively deliver the aforementioned four pre-miRNA plasmids into SMMC-7721 cells in vitro under 1.2-MHz 60-cycle sinusoid US exposure with a peak negative pressure >5.5 MPa at a 40-Hz pulse repetition frequency. Plasmid delivery efficiency and cell viability positively correlated with the inertial cavitation dose that was determined mainly by peak negative pressure. Furthermore, PLNDs combined with US were evaluated in vivo to deliver these four pre-miRNAs plasmids and verify their therapeutic efficacy in subcutaneous tumor of the mouse xenograft HCC model. The results revealed that the PLNDs loaded with pre-miR-139 and -378a plasmids could effectively suppress tumor growth after US treatment. Thus, combination of pre-miRNA PLNDs with US activation seems to constitute a potential strategy for HCC therapy.

2.
Insect Sci ; 27(1): 14-21, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31246335

RESUMO

Manipulating an exogenous or endogenous gene of interest at a defined level is critical for a wide variety of experiments. The Gal4/UAS system has been widely used to direct gene expression for studying complex genetic and biological problems in Drosophila melanogaster and other model organisms. Driven by a given tissue-specific Gal4, expressing UAS-transgene or UAS-RNAi (RNA interference) could be used to up- or down-regulate target gene expression, respectively. However, the efficiency of the Gal4/UAS system is roughly predefined by properties of transposon vector constructs and the insertion site in the transgenic stock. Here, we describe a simple way to modulate optomotor blind (omb) expression levels in its endogenous expression region of the wing disc. We co-expressed UAS-omb and UAS-omb-RNAi together under the control of dpp-Gal4 driver which is expressed in the omb expression region of the wing pouch. The repression effect is more sensitive to temperature than that of overexpression. At low temperature, overexpression plays a dominant role but the efficiency is attenuated by UAS-omb-RNAi. In contrast, at high temperature RNAi predominates in gene expression regulation. By this strategy, we could manipulate omb expression levels at a moderate level. It allows us to manipulate omb expression levels in the same tissue between overexpression and repression at different stages by temperature control.

3.
BMC Pregnancy Childbirth ; 19(1): 393, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666022

RESUMO

BACKGROUND: This study aims to investigate the influencing factors of pregnancy after laparoscopic oviduct anastomosis. METHODS: The data of 156 cases of laparoscopic oviduct anastomosis in our hospital were analyzed. RESULTS: The pregnancy rate decreased with age (P < 0.005). The pregnancy rate after six years of anastomosis was higher in those with ligation (P < 0.005). The postoperative pregnancy rate significantly increased in subjects with oviduct lengths of > 7 cm (P < 0.01). The pregnancy rate of isthmus end-to-end anastomosis was higher (P < 0.005). The pregnancy rate after bilateral tubal recanalization was higher than that after unilateral tubal recanalization (P < 0.005). The pregnancy rate after laparoscopic tubal ligation and laparoscopic anastomosis was higher than that of open tubal ligation and laparoscopic anastomosis (P < 0.005). CONCLUSION: The pregnancy rate after laparoscopic oviduct anastomosis is higher in subjects below 35 years old, with a ligation duration of < 6 years, and a length of oviduct of > 7 cm, and those who underwent isthmus anastomosis and laparoscopic oviduct ligation and recanalization.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31718964

RESUMO

Fluorescent sensor has been noticed in detecting system due to its sensitive, selective, operational simplicity and low cost. We designed a coumarin-connected carboxylic indolium sensor molecule that is water-soluble and cytomembrane-permeable. This infrared (IR) emitter is selectively sensitive towards cyanide detection in aqueous media according to CN- nucleophilic attack on the indole C=N function. Upon the addition of CN- anion, the color of sensor in water varied from blue to colorless by naked eyes and fluorescence quenching was observed by spectroscopic method. This was because the intramolecular charge transfer (ICT) effect occurred when the fluorescent sensor was added with CN-. The minimum detection limit of the sensor's fluorescence response to CN- is 4.44 × 10-7 mol/L. Furthermore, the cytotoxicity test shows the sensor has lower cytotoxicity, and indicates that this sensor can be utilized for practical detection of trace cyanide in wastewater.

5.
Plant Mol Biol ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722090

RESUMO

KEY MESSAGE: We developed a machine learning-based model to identify the hidden labels of m6A candidates from noisy m6A-seq data. Peak-calling approaches, such as MeRIP-seq or m6A-seq, are commonly used to map m6A modifications. However, these technologies can only map m6A sites with 100-200 nt resolution and cannot reveal the precise location or the number of modified residues in a transcript. To address this challenge, we developed a novel machine learning-based approach, named HLMethy, to assign labels to m6A candidates from noisy m6A-seq data. The multiple instance learning framework was adopted and two different training strategies were used to generate the classification model. To test the performance of our model, the m6A sites with single-base resolution were used and our model achieved comparable performance against existing instance-level predictors, which suggest that our model has the potential to improve the data quality of m6A-seq at reduced costs. What's more, our generic framework can be extended to other newly found modifications that are found by peak-calling approaches. The source code of HLMethy is available at https://github.com/liuze-nwafu/HLMethy.

6.
Dent Mater J ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694998

RESUMO

This study was to prepare and screen a novel root canal sealing agent modified by polyhexamethylene biguanide (PHMB) that was in accordance with the ISO 6876:2001 standard and to study its physical and antimicrobial properties. The modified sealers were produced by mixing a certain amount of zinc oxide with eugenol containing different concentrations of PHMB (0.05, 0.1, 0.2, 0.4, 0.6 and 0.8%) at a ratio of 1:1 (w/v). The setting time, flow, film thickness, solubility and dimensional change after solidifying were assessed to screen out the modified sealing agents that the physical properties met the mentioned standards. The modified direct contact test (DCT) was used to evaluate the antimicrobial activity against Enterococcus faecalis. The results suggested that when the concentrations of PHMB were 0.05, 0.1 and 0.2%, the modified root canal sealers showed the best performance in physical and antimicrobial properties.

7.
Int J Mol Sci ; 20(22)2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703422

RESUMO

The chrysanthemum foliar nematode (CFN), Aphelenchoides ritzemabosi, is a migratory, plant-parasitic nematode that is widely distributed and infects the aboveground parts of many plants. The fatty acid- and retinoid-binding proteins (FAR) are nematode-specific proteins that are involved in the development, reproduction, and infection of nematodes and are secreted into the tissues to disrupt the plant defense reaction. In this study, we obtained the full-length sequence of the FAR gene (Ar-far-1) from CFN, which is 727 bp and includes a 546 bp ORF that encodes 181 amino acids. Ar-FAR-1 from CFN has the highest sequence similarity to Ab-FAR-1 from A. besseyi, and they are located within the same branch of the phylogenetic tree. Fluorescence-based ligand-binding analysis confirmed that recombinant Ar-FAR-1 was bound to fatty acids and retinol. Ar-far-1 mRNA was expressed in the muscle layer, intestine, female genital system, and egg of CFN, and more highly expressed in females than in males among the four developmental stages of CFN. We demonstrated that the reproduction number and infection capacity of CFN decreased significantly when Ar-far-1 was effectively silenced by in vitro RNAi. Ar-far-1 plays an important role in the development, reproduction, infectivity, and pathogenesis of CFN and may be used as an effective target gene for the control of CFN. The results provide meaningful data about the parasitic and pathogenic genes of CFN to study the interaction mechanism between plant-parasitic nematodes and hosts.

8.
Chin J Nat Med ; 17(10): 721-728, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31703752

RESUMO

Garlic (Allium sativum) is a widely known medicinal plant, potential of which remains to be fully evaluated. Its wide-range beneficial effects appear to be relevant for treatment and prevention of atherosclerosis and related diseases. It is generally believed that garlic-based preparations are able to improve lipid profile in humans, inhibit cholesterol biosynthesis, suppress low density lipoprotein oxidation, modulate blood pressure, suppress platelet aggregation, lower plasma fibrinogen level and increase fibrinolytic activity, thus providing clinically relevant cardioprotective and anti-atherosclerotic effects. It is important to assess the level of evidence available for different protective effects of garlic and to understand the underlying mechanisms. This information will allow adequate integration of garlic-based preparations to clinical practice. In this review, we discuss the mechanisms of anti-atherosclerotic effects of garlic preparations, focusing on antihyperlipidemic, hypotensive, anti-platelet and direct anti-atherosclerotic activities of the medicinal plant. We also provide an overview of available meta-analyses and a number of clinical trials that assess the beneficial effects of garlic.

9.
Int J Biol Sci ; 15(12): 2627-2640, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754335

RESUMO

Emerging evidence indicates that microRNAs (miRNAs) play fundamental roles in the pathogenesis of multiple diseases, including acute lung injury (ALI). Here, we discovered that miR-199a-3p was significantly downregulated in ALI lung tissues using a microarray analysis. In vitro lipopolysaccharide (LPS) treatment of the human epithelial cell line A549 and the human macrophage cell line U937 caused a decrease of miR-199a-3p. Mechanically, miR-199a-3p specifically bound to the 3'-untranslated region (3'-UTR) of NLRP1 (nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 1), a critical member of inflammasomes. Ectopic overexpression or downregulation of miR-199a-3p resulted in the repression or induction of NLRP1, respectively, thereby downregulating or activating its downstream events. Moreover, transcription factor FOXP3 (forkhead box P3) was able to specifically bind to the promoter of miR-199a-3p. Knockdown or overexpression of FOXP3 resulted in a decrease or induction miR-199a-3p expression, respectively. Using immunoprecipitation (IP), mass spectrometry and co-IP assays, we found that FOXP3 formed a transcriptional complex with HDAC1 (histone deacetylase 1) and CtBP2 (C-terminal-binding protein 2). Collectively, our results suggested that the CtBP2-HDAC1-FOXP3 transcriptional complex (CHFTC) could specifically bind to the promoter of miR-199a-3p and repress its expression. Downregulation of miR-199a-3p eliminated its inhibition of NLRP1, causing activation of NLRP1 and cleavage of pro-IL-1ß and pro-IL-18 mediated by Caspase-1. The secretion of IL-1ß and IL-18 further aggravated the inflammatory response and resulted in the occurrence of ALI.

10.
Nat Commun ; 10(1): 4930, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666514

RESUMO

Metallic lithium affords the highest theoretical capacity and lowest electrochemical potential and is viewed as a leading contender as an anode for high-energy-density rechargeable batteries. However, the poor wettability of molten lithium does not allow it to spread across the surface of lithiophobic substrates, hindering the production and application of this anode. Here we report a general chemical strategy to overcome this dilemma by reacting molten lithium with functional organic coatings or elemental additives. The Gibbs formation energy and newly formed chemical bonds are found to be the governing factor for the wetting behavior. As a result of the improved wettability, a series of ultrathin lithium of 10-20 µm thick is obtained together with impressive electrochemical performance in lithium metal batteries. These findings provide an overall guide for tuning the wettability of molten lithium and offer an affordable strategy for the large-scale production of ultrathin lithium, and could be further extended to other alkali metals, such as sodium and potassium.

11.
Sci Rep ; 9(1): 16811, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727908

RESUMO

Vitamin C (VC) and vitamin D (VD) have been widely used as the dietary supplements and in treatment of diseases both independently and in combination. Whether there is a connection between their pathways is critical for their therapeutic applications. Using whole-genome expression profiles, we performed multiple measures of associations, networks, eQTL mappings and expressions of key genes of interest in VC and VD functions. Several key genes in their pathways were found to be associated. Gc and Rgn play important roles connecting VC and VD pathways in mice. The r values of expression levels between Gc and Rgn in mouse spleen, liver, lung, and kidney are 0.937, 0.558, 0.901, and 0.617, respectively. The expression QTLs of Gc and Rgn are mapped onto the same locations, i.e., 68-76 MB in chromosome 7 and 26-36 MB in chromosome 9. In humans, there are positive correlations between CYP27B1 and SLC23A1 expression levels in kidney (r = 0.733) and spleen (r = 0.424). SLC23A2 and RXRA are minimally associated in both mouse and human. These data indicate that pathways of VC and VD are not independent but affect each other, and this effect is different between mice and humans during VC and VD synthesis and transportation.

12.
Eur J Med Chem ; : 111897, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31761382

RESUMO

Diosgenin, a naturally occurring steroidal saponin, has been confirmed to possess potent anticancer properties. In the current work, two series of novel diosgenin derivatives bearing 1,3,4-oxadiazole (6a-6e and 7a-7e) or 1,3,4-thiadiazole (8a-8e and 9a-9e) moieties were designed, synthesized and evaluated for their cytotoxicities in four human cancer cell lines (HepG2, A549, MCF-7 and HCT-116) and normal human gastric epithelial cells (GES-1) using the MTT assay in vitro. The results showed that compounds 8d and 9d exhibited significant cytotoxic activities against the HepG2 and A549 cells, being more potent than their parent compound diosgenin. Furthermore, the 1,3,4-thiadiazole series of compounds generally exhibited stronger cytotoxicity compared with the 1,3,4-oxadiazole series against HepG2 and A549 cells, and the substitution of 3-pyridyl group at the C5 position of the 1,3,4-thiadiazole ring was the preferred option for these compounds to display significant cytotoxic activities. Compound 8d showed potent cytotoxic activity against A549 cell line (IC50 = 3.93 µM) and was 6.7-fold more potent than diosgenin (IC50 = 26.41 µM). Moreover, compound 8d displayed low toxicity against GES-1 cells (IC50 = 420.4 µM), showing specificity between normal and tumor cells. Further cellular mechanism studies in A549 cells indicated that compound 8d triggered the mitochondrial-mediated apoptosis by decreasing mitochondrial membrane potential, which was associated with up-regulation of Bax, down-regulation of Bcl-2 and activation levels of the caspase cascade. The above results indicated that compound 8d may be used as a promising skeleton for antitumor agents with improved efficacy.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31731315

RESUMO

OBJECTIVES: We explore midterm results after surgical treatment of partial anomalous pulmonary venous connection (PAPVC) to superior vena cava (SVC) in our institution. METHODS: From 2008 to 2017, 78 patients underwent surgical repair for PAPVC to SVC. Patients were divided into three groups based on surgical techniques: Single-patch repair (n = 20, group A), double-patch repair (n = 31, group B), and Warden repair (n = 27, group C). Their median age was 1.9 years (range: 3 months-13.8 years); median weight was 11.4 kg (range: 4.4-39.7 kg). Clinical, electrocardiographic and echocardiographic were available for all patients. RESULTS: There were no early or late mortality. The mean follow-up duration was 1.8 ± 2.1 years (range: 0.6 months to 8 years). No pulmonary venous obstruction occurred and no residual left-to-right shunts sustained during the follow-up. Reoperation for SVC obstruction was required: 1 (5.3%) in group A, 1 (3.2%) in group B, and 2 (7.4%) in group C (p = 0.78). Four patients (3 in group B, 1 in group C, p = 0.7) presented transient rhythm disturbance at discharge and one patient in group B remains nonsinus rhythm during follow-up. Pacemaker was not required in all patients. CONCLUSION: PAPVC to SVC can be safely managed by multiple techniques. Careful manipulation nearby sinus node must be emphasized during double-patch repair to prevent injury of sinus node. Obstruction of postoperative SVC stenosis should be paid attention to after Warden procedure. For young patients, operation should not be performed that early, but until preschool age.

14.
Food Res Int ; 126: 108595, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31732076

RESUMO

Increasing evidence shows that the gut microbiota contributes to the occurrence and development of colitis. Kudingcha (KDC), made from the leaves of Ilex kudingcha, could mitigate inflammation, however, little is known about the relationship between modulatory effect on gut microbiota by KDC and improvement of colitis. In this study, the attenuating effects of KDC extract (KDCE) on dextran sulfate sodium (DSS)-induced colitis and gut microbiota in C57BL/6 mice were investigated. It was found that the supplementation of KDCE could alleviate typical symptoms of IBD including weight loss, colon shortening, intestinal barrier damage, and decreases in the colitis disease activity index and pro-inflammatory cytokines. Moreover, KDCE supplementation could reverse the alteration of gut microbiota in the colitic mice by increasing the abundances of potential beneficial bacteria, e.g. Odoribacter, Prevotella and Helicobacter, and decreasing the abundances of potential harmful bacteria, e.g. Parabacteroides, Bacteroides, Turicibacter, Parasutterella and Lachnospiraceae. The levels of short-chain fatty acids in feces, cecum contents and serum were also regulated by KDCE. Furthermore, the correlation analysis suggested that KDCE could attenuate DSS-induced colitis which might be related to the alteration of gut microbiota. Therefore, the modulation of gut microbiota by KDCE might be a potential strategy for improving inflammation-driven diseases.

15.
J Transl Med ; 17(1): 354, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31665029

RESUMO

BACKGROUND: Pituitary adenoma and meningioma are the most common benign tumors in the central nervous system. Pituitary adenoma associated with meningioma (PAM) is a rare disease and the clinical features and mechanisms of PAM are unclear. METHODS: We summarized the clinical data of 57 PAM patients and compared with sporadic pituitary adenoma (SPA) and sporadic meningioma (SM). 5 pituitary adenomas of PAM and 5 SPAs were performed ceRNA microarray. qRT-PCR, Western Blot, siMEN1 and rapamycin inhibition experiment were validated for ceRNA microarray. RESULTS: Clinical variable analyses revealed that significant correlations between PAM and female sex as well as older age when compared with SPA and significant correlations between PAM and transitional meningioma as well as older age when compared with SM. Additionally, the characteristics of PAM were significantly different for MEN1 patients. Functional experiments showed lower expression of MEN1 can upregulate mTOR signaling, in accordance with the result of ceRNA microarray. Rapamycin treatment promotes apoptosis in primary pituitary adenoma and meningioma cells of PAM. CONCLUSIONS: MEN1 plays an important role in PAM by upregulating mTOR signaling pathway. Rapamycin represents a potential therapeutic strategy for PAM in the future.

16.
Ying Yong Sheng Tai Xue Bao ; 30(10): 3605-3614, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31621249

RESUMO

As an important component of global nitrogen (N) biogeochemical cycle, atmospheric N deposition refers to the removal process of reactive N, including oxidized N (NOy) and reduced N (NHx), from the atmosphere to earth surface through dry and wet deposition. Nitrogen deposition can exert important impacts on the structure and functioning of both terrestrial and aquatic ecosystems. Increasing N deposition poses a potential threat to natural ecosystems and human health. It is a challenge to accurately monitor the composition and flux of dry and wet N deposition in different ecosystems, using a unified technology. Here, we reviewed the research progress on monitoring methods of dry and wet N deposition in China and aboard, including micrometeorology, inferential method, model estimation, surrogate surface, precipitation collection, and ion exchange resin methods. We further discussed the advantages and disadvantages of each method in terms of its applications at regional, national, and global scales. This review would provide a methodological support to establish national monitoring network for atmospheric N deposition.


Assuntos
Poluentes Atmosféricos , Nitrogênio , Atmosfera , China , Ecossistema , Monitoramento Ambiental , Humanos
17.
Hear Res ; 384: 107813, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31655347

RESUMO

Sounds delivered to the ear move the tympanic membrane (TM), which drives the middle-ear (ME) ossicles and transfers the acoustic energy to the cochlea. Perforations of the TM result in hearing loss because of less efficient sound conduction through the ME. The patterns of TM motions, and thus ME sound transmission, vary with frequency and depend on many factors, including the TM thickness. In this study, we measured TM thickness, auditory brainstem responses (ABR), and ME transmission immediately following a controlled pars tensa perforation and after 4 weeks of spontaneous recovery in a gerbil model. It is found that after recovery, the hearing thresholds showed a sloping pattern across frequencies: almost back to normal levels at frequencies between 2 and 8 kHz, sloping loss in the low (<2 kHz) and mid-frequency (8-30 kHz) range, and little restoration at frequencies above 30 kHz. This pattern was confirmed by the measured ME pressure gains. The thickness of the healed TM did not return to normal but was 2-3 times thicker over a significant portion of the membrane. The increased thickness was not limited to the perforated area but expanded into intact regions adjacent to the perforation, which led to an increased thickness in general. Combined, these results suggest that TM thickness is an important factor in determining its vibration patterns and efficiency to transfer sounds to the ossicles and thus influencing ME sound transmission, especially for high-frequency sounds. The results provided both structural and functional observations to explain the conductive hearing loss seen in patients with abnormal TMs, e.g., caused by otitis media, spontaneously healed post-perforation, or repaired via tympanoplasty in the clinic.

18.
Clin Sci (Lond) ; 133(20): 2069-2084, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31654062

RESUMO

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor (TGF)-ß superfamily. The rejuvenative effect of GDF11 has been called into question recently, and its role in liver regeneration is unclear. Here, we investigated the pathophysiologic role of GDF11, as well as its plausible signaling mechanisms in a mouse model of partial hepatectomy (PH). We demonstrated that both serum and hepatic GDF11 protein expression increased following PH. Treatment with adeno-associated viruses-GDF11 and recombinant GDF11 protein severely impaired liver regeneration, whereas inhibition of GDF11 activity with neutralizing antibodies significantly improved liver regeneration after PH. In vitro, GDF11 treatment significantly delayed cell proliferation and induced cell-cycle arrest in α mouse liver 12 (AML12) cells. Moreover, GDF11 activated TGF-ß-SMAD2/3 signaling pathway. Inhibition of GDF11-induced SMAD2/3 activity significantly blocked GDF11-mediated reduction in cell proliferation both in vivo and in vitro. In the clinical setting, GDF11 levels were significantly elevated in patients after hepatectomy. Collectively, these results indicate that rather than a 'rejuvenating' agent, GDF11 impairs liver regeneration after PH. Suppression of cell-cycle progression via TGF-ß-SMAD2/3 signaling pathway may be a key mechanism by which GDF11 inhibits liver regeneration.

19.
J Biomed Inform ; 100: 103303, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31610264

RESUMO

Utilizing clinical observational data to estimate individualized treatment effects (ITE) is a challenging task, as confounding inevitably exists in clinical data. Most of the existing models for ITE estimation tackle this problem by creating unbiased estimators of the treatment effects. Although valuable, learning a balanced representation is sometimes directly opposed to the objective of learning an effective and discriminative model for ITE estimation. We propose a novel hybrid model bridging multi-task deep learning and K-nearest neighbors (KNN) for ITE estimation. In detail, the proposed model firstly adopts multi-task deep learning to extract both outcome-predictive and treatment-specific latent representations from Electronic Health Records (EHR), by jointly performing the outcome prediction and treatment category classification. Thereafter, we estimate counterfactual outcomes by KNN based on the learned hidden representations. We validate the proposed model on a widely used semi-simulated dataset, i.e. IHDP, and a real-world clinical dataset consisting of 736 heart failure (HF) patients. The performance of our model remains robust and reaches 1.7 and 0.23 in terms of Precision in the estimation of heterogeneous effect (PEHE) and average treatment effect (ATE), respectively, on IHDP dataset, and 0.703 and 0.796 in terms of accuracy and F1 score respectively, on HF dataset. The results demonstrate that the proposed model achieves competitive performance over state-of-the-art models. In addition, the results reveal several findings which are consistent with existing medical domain knowledge, and discover certain suggestive hypotheses that could be validated through further investigations in the clinical domain.

20.
EBioMedicine ; 48: 316-331, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31648990

RESUMO

BACKGROUND: Metastasis is a major obstacle in the treatment of bladder cancer (BC). Circular RNAs exert various functions in the aggressive biological behaviour of cancers. In this study, we aimed to elucidate how circPICALM influences BC metastasis. METHODS: The expression of circPICALM was analysed by real-time PCR. The tumourigenic properties of BC cells were evaluated using in vitro migration, invasion, and wound healing assays and an in vivo footpad model. The interaction between circPICALM and miR-1265 was confirmed by pull-down and dual-luciferase reporter assays and biotin-labelled miRNA capture. The interaction of STEAP4 and focal adhesion kinase (FAK) was confirmed by co-immunoprecipitation. FINDINGS: CircPICALM was downregulated in BC tissues, and low circPICALM expression was related to advanced T stage, high grade, lymph node positivity and poor overall survival. Overexpression of circPICALM inhibited the metastasis of BC cells, and DHX9 negatively regulated circPICALM levels. CircPICALM colocalized with miR-1265 and acted as a sponge for this miRNA, and the pro-invasion effect of miR-1265 was abolished by circPICALM overexpression. STEAP4, a target of miR-1265, suppressed metastasis; it bound to FAK to prevent autophosphorylation at Y397 and influenced EMT in BC cells. INTERPRETATION: CircPICALM can inhibit BC metastasis and bind to miR-1265 to block its pro-invasion activity. STEAP4 is a target of miR-1265 and is related to FAK phosphorylation and EMT. FUND: This research was supported by National Natural Science Foundation of China, No.81772728, National Natural Science Foundation of China, No.81772719, National Natural Science Foundation of China No.81572514.

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