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1.
Brain Res Bull ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31669104

RESUMO

Glial cell line-derived neurotrophic factor (GDNF) has neurotrophic activity for the survival of dopaminergic neurons, which is under active investigation for Parkinson's disease (PD) therapy. FLZ is a potential new drug for PD treatment. However, it is unclear whether neurotrophic activity contributes to the neuroprotective effects of FLZ. Here we found that FLZ markedly improved the function of dopaminergic neurons in primary mesencephalic neuron/glia cultures. Further investigation demonstrated that astroglia were required for FLZ to function as a neurotrophic regulator, as FLZ failed to show neurotrophic effects in the absence of astroglia. We clarified that GDNF was responsible for the neurotrophic effects of FLZ since FLZ selectively stimulated GDNF production, which was confirmed by the finding that the neurotrophic effect of FLZ was attenuated by GDNF-neutralizing antibody. Mechanistic study demonstrated that GDNF induction by FLZ was CREB-dependent and that PI3K/Akt was the main pathway regulating CREB activity, which was confirmed by in vivo studies. We also validated that the induction of GDNF by FLZ contributed to PD treatment in vivo. In conclusion, the present data provided evidence that FLZ had robust neurotrophic effects on dopaminergic neurons through sustained induction of GDNF in astroglia by activating the PI3K/Akt/CREB pathway.

2.
Eur J Surg Oncol ; 2019 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-31564475

RESUMO

BACKGROUND: Recently, researchers have tried to predict patient prognosis using biomarker expression in cancer patients. The aim of this study was to develop a nomogram predicting the 5-year recurrence-free probability (RFP) of gastric cancer patients using prognostic biomarker gene expression. METHODS: We enrolled 360 patients in the training data set to develop the predictive model and nomogram. We analyzed the patients' general variables and the gene expression levels of 10 prognostic biomarker candidates between the nonrecurrence and recurrence groups. We also performed external validation using 420 patients from the validation data set. RESULTS: The final nomogram was composed of age, sex, and the expression levels of CAPZA, PPase, OCT-1, PRDX4, gamma-enolase, and c-Myc. The five-year RFPs were 89%, 75%, 54% and 32% for the patients in the low-risk, intermediate-risk, high-risk and very-high-risk groups in the development cohort, respectively. In the external validation cohort, the 5-year RFPs were 89%, 75%, 63% and 60%, respectively. The areas under the curve were 0.718 (95% CI, 0.65-0.78) and 0.640 (95% CI, 0.57-0.70) for the training and validation data sets, respectively. The RFP Kaplan-Meier curves were significantly different among the 4 groups in the training and validation data sets (p < 0.0001). CONCLUSION: This newly developed nomogram using gene expression can predict the 5-year RFP for gastric cancer patients after surgical treatment. We hope that this nomogram will help in the therapeutic decision between endoscopic treatment and gastrectomy.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31645307

RESUMO

BACKGROUND: The incidence of acute myeloid leukemia (AML) increases with age. The overall prognosis remains poor for older patients. Studies on the efficacy of decitabine, an epigenetic agent, in older patients with AML have reported conflicting results. MATERIALS AND METHODS: For this meta-analysis, we performed a literature search and collected 38 studies (including 3298 patients with AML) to evaluate the role of decitabine in elderly patients with AML. We used complete response (CR) or overall response (OR) rate as indicators of effectiveness. RESULTS: Patients treated with decitabine have a higher CR/OR rate than those treated with low-dose cytarabine (CR, 2.60; 95% confidence interval [CI], 1.64-4.14; OR, 4.88; 95% CI, 1.98-12.04) or CAG/HAG (low-dose epirubicin and cytarabine with granulocyte stimulating factor/low-dose homoharringtonine and cytarabine with granulocyte stimulating factor) regimens (CR, 2.53; 95% CI, 1.98-3.23; OR, 2.89; 95% CI, 2.24-3.73). However, patients treated with decitabine had a CR rate equivalent to those treated with intensive chemotherapy (CR, 0.58; 95% CI, 0.28-1.22; P = .15). Use of decitabine in combination with other regimens resulted in a higher CR/OR rate than did use of decitabine alone (P < .001); there was no significant difference in infection rates and early death rates (P > .05). CONCLUSION: The findings presented in this article show that decitabine is effective and safe for the treatment of older patients with AML.

4.
Bioresour Technol ; 294: 122188, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31569044

RESUMO

In this work, wrapped granular activated carbon (GAC) and acclimated sludge were employed to enhance the efficiency of the dry anaerobic digestion of swine manure in semi-continuous tests. The addition of wrapped GAC increased the volumetric biogas production rate by 10.6%, and the removal efficiencies of TS and VS were enhanced by 5.3% and 6.6%, respectively. The concentration of total volatile fatty acids (TVFA) was 30.3% lower in the GAC reactor, but the total ammonia nitrogen (TAN) content was 15.3% higher. Inoculating with acclimated sludge helped the system survive unfavorable conditions, where the TAN and TVFA contents were around 5,200 mg/L and 8,800 mg/L, respectively, but it failed to improve the biogas production efficiency. The mechanisms that allowed GAC to increase the production of biogas were related to the improved hydrolysis process, enhanced microbial adhesion, the provision of electronic bridges, and enrichment of functional microorganism.

5.
Aging (Albany NY) ; 11(19): 8526-8541, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597121

RESUMO

Ninjurin 2 (NINJ2) is a novel adhesion molecule. Its expression and potential function in human colorectal cancer (CRC) cells are studied. We show that NINJ2 is overexpressed in established (HT-29) and primary CRC cells and in human colon cancer tissues. Its expression level is low in colon epithelial cells and normal colon tissues. NINJ2 shRNA or knockout (by CRSIPR/Cas9) potently inhibited human CRC cell survival and proliferation, while significantly inducing cell apoptosis. Conversely, lentivirus-mediated NINJ2 overexpression promoted CRC cell proliferation. NINJ2 co-immunoprecipitated with multiple RTKs (EGFR, PDGFRα/ß and FGFR) in CRC cells and human colon cancer tissues. In HT-29 cells, RTKs' downstream signalings, Akt and Erk, were significantly inhibited by NINJ2 shRNA or knockout, but augmented following ectopic NINJ2 overexpression. In vivo, NINJ2-silenced or NINJ2-knockout CRC xenografts grew significantly slower than the control xenografts. Akt-Erk activation was largely inhibited in CRC xenografts with NINJ2 silencing or knockout. Taken together, NINJ2 overexpression promotes CRC cell growth in vitro and in vivo.

6.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 50(3): 433-437, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31631614

RESUMO

Objective: To identify risk factors associated with thyroid nodular lesions in patients with acromegaly. Methods: Clinical and thyroid ultrasonography data of patients with acromegaly diagnosed in the West China Hospital of Sichuan University from May 2009 to January 2018 were reviewed and analyzed. Multivariate linear regression models were established to identify factors associated with thyroid volumes and size of thyroid nodules. Multivariate binary logistic regression models were established to determine risk factors associated with thyroid nodules in patients with acromegaly. Results: Of the 240 acromegaly patients, 70 received thyroid ultrasonography and 56 had thyroid nodules (56/70, 80%). The patients with thyroid nodules had a longer median duration of acromegaly than 14 patients who without thyroid nodules (8.0 years vs. 3.0 years, P<0.05), but had a similar mean age and female to male ratio with the latter. The risk of thyroid nodules increased with the duration of acromegaly (odds ratio=1.306, 95% confidence interval (1.010, 1.688), P=0.042). The level of random growth hormone was linearly correlated with thyroid volumes. Gender, age, and serum growth hormone were not predictors of thyroid nodules in patients with acromegaly. Conclusion: Duration of acromegaly is an independent predictor of thyroid nodules.

7.
BMC Plant Biol ; 19(1): 418, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604418

RESUMO

BACKGROUND: So far, little is known in detail about mating systems of woody bamboos. Paternity analysis of offspring improved our understanding of these systems, and contributed to their germplasm conservation and genetic improvement. RESULTS: In this study, a paternity analysis of offspring from two consecutive mass or sporadically flowering events of Dendrocalamus membranaceus and D. sinicus were conducted to determine their mating system and pollen dispersal using the program COLONY based on simple sequence repeat (SSR) markers. Two sporadically flowering populations of D. sinicus (C1, C2) obtained relatively high paternity assignments rates (69.0-71.4%). Meanwhile, among three populations of D. membranaceus, the sporadically flowering population A also had much higher paternity assignments rates (56.4%) than mass flowering populations B1(28.6%) and B2 (42.5%). Both D. membranaceus and D. sinicus had mixed mating systems while their mating patterns were variable depending on pollination conditions. The maximum pollen dispersal distances were 90 m and 4378 m for D. membranaceus and D. sinicus populations, respectively, and the mating distances of these two species focused on ranges of ca. 0-50 m and 0-1500 m, respectively. CONCLUSIONS: These results revealed for the first time variable mating patterns in woody bamboos. This suggests half-sib seeds from the same bamboo clump may have different male parents and it is crucial to clarify genetic origin in woody bamboos' breeding programs. The results also indicate the importance of pollinators in the mating systems of tropical woody bamboos.

8.
Korean Circ J ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31642213

RESUMO

BACKGROUND AND OBJECTIVES: The impact of SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery score (SS) and SS II in patients who receive percutaneous coronary intervention with second-generation everolimus-eluting stents (EES) has not been fully validated. METHODS: The SS, SS II were calculated in 1,248 patients with left main and/or 3-vessel disease treated with EES. Patient-oriented composite endpoint (POCE; all-cause death, any myocardial infarction (MI), any revascularization) and target lesion failure (TLF: cardiac death, target-vessel MI, target lesion revascularization) were analyzed. RESULTS: The mean SS was 21.1±9.6. Three-year POCE increased according to the SS group (15.2% vs. 19.9% vs. 27.4% for low (≤22), intermediate (≥23, ≤32), high (≥33) SS groups, p<0.001). By multivariate Cox proportional hazard analysis, SS group was an independent predictor of 3-year POCE (hazard ratio, 1.324; 95% confidence interval, 1.095-1.601; p=0.004). The receiver operating characteristic curves revealed that the SS II was superior to the SS for 3-year POCE prediction (area under the curve [AUC]: 0.611 vs. 0.669 for SS vs. SS II, p=0.019), but not for 3-year TLF (AUC: 0.631 vs. 0.660 for SS vs. SS II, p=0.996). In subgroup analysis, SS II was superior to SS in patients with cardiovascular clinical risk factors, and in those presenting as stable angina. CONCLUSIONS: The usefulness of SS and SS II was still valid in patients with left main and/or 3-vessel disease. SS II was superior to SS for the prediction of patient-oriented outcomes, but not for lesion-oriented outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00698607 ClinicalTrials.gov Identifier: NCT01605721.

9.
Atherosclerosis ; 290: 125-135, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31614249

RESUMO

BACKGROUND AND AIMS: Hyperlipidemia-induced atherosclerosis is the major cause of heart attack and stroke in humans. However, pathological details and molecular mechanisms underlying early atherogenesis remain incompletely characterized. This study explored the early events of atherogenesis in a hypercholesterolemic zebrafish model in vivo. METHODS: We used transparent transgenic zebrafish larvae Tg(lysc:EGFP), Tg(mpx:EGFP), Tg(mpeg1:EGFP), Tg(flk1:EGFP) or Tg(lysc:EGFP/flk1:mCherry), together with fluorescently labeled control and high cholesterol diets (HCD), to dynamically investigate the early development of atherosclerosis with confocal in vivo. Endothelial cells with green fluorescence were sorted by fluorescence-activated cell sorting (FACS) to detect gene expression. Moreover, we treated hypercholesterolemic zebrafish model in vivo or human umbilical vein endothelial cells (HUVEC) in vitro with rosiglitazone, an agonist of peroxisome proliferator-activated receptor γ (PPARγ). RESULTS: We found that HCD-induced endothelial inflammation was an earlier pathological alteration than myeloid cells/neutrophils accumulation and lipid deposition in zebrafish vascular vessels of HCD-fed zebrafish. Endothelial inflammation was characterized by down-regulation of anti-inflammatory PPARγ and upregulation of pro-inflammatory tumor necrosis factor α (TNF-α) and interleukin-1ß (IL-1ß). Pharmacological treatment with rosiglitazone reversed the decrease in the expression of PPARγ and decreased expression of TNF-α and IL-1ß in HCD-fed zebrafish. Moreover, rosiglitazone ameliorated myeloid cells accumulation and lipid deposition in HCD-fed zebrafish in vivo. CONCLUSIONS: Hyperlipidemia-induced endothelial inflammation happens earlier than myeloid cell neutrophils accumulation in vascular vessels, and neutrophils accumulation is prior to lipid deposition during the initial stage of atherosclerosis. Early alleviation of inflammation induced by HCD would have a prophylactic effect for the initial development of atherosclerosis.

10.
Medicine (Baltimore) ; 98(40): e17218, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577712

RESUMO

Health examination is an important method for early detection of people with different risk of stroke. This study estimates the risk of stroke and identify risk factors for people who underwent health examinations at the Health Examination Center at West China Hospital, Sichuan University from July 2014 to February 2018.A total of 31,464 people were recruited in this study and divided into 3 groups (low risk, moderate risk, and high risk) according to risk of stroke. We explored possible factors associated with the risk of stroke by using multivariable stepwise logistic regression analysis.Among the participants, 17,959 were at low risk, 11,825 were at moderate risk, and 1680 were at high risk. Age, smoking, alcohol consumption, body mass index, uric acid, diastolic pressure, systolic pressure, triglycerides, low-density lipoprotein cholesterol, glucose, and brachial-ankle pulse wave velocity (baPWV) were independent significant risk factors for stroke, whereas high-density lipoprotein cholesterol was an independent protective factor for stroke. Interestingly, with increasing age, the percentage of people at moderate or high risk of stroke was increased. The percentages of people at moderate and high risk of stroke were also increased with respect to the stages of baPWV.This study showed that >40% of the participants were at moderate or high risk of stroke, especially the older participants. Several factors were related to the risk of stroke, especially baPWV. Some preventive action may be adopted early, and more attention can be paid to the health examination population.


Assuntos
Exame Físico/estatística & dados numéricos , Acidente Vascular Cerebral/epidemiologia , Adulto , Fatores Etários , Consumo de Bebidas Alcoólicas/epidemiologia , Índice Tornozelo-Braço , Pressão Sanguínea , Índice de Massa Corporal , China/epidemiologia , Fumar Cigarros/epidemiologia , Estudos Transversais , Feminino , Humanos , Estilo de Vida , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Fatores Sexuais , Fatores Socioeconômicos
11.
Sci Rep ; 9(1): 13305, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527644

RESUMO

Triple-negative breast cancer (TNBC) is a heterogeneous disease comprising several subtypes. Androgen-receptor (AR) signaling has been targeted by several investigational agents in luminal AR subtype TNBCs. Bromodomain (BRD) and extra-terminal motif (BET) protein inhibitors have been shown to attenuate AR signaling in metastatic castration-resistant prostate cancer and to overcome enzalutamide resistance. We demonstrated potent anti-tumor effects of the BET inhibitor JQ1 against AR-positive TNBC cell lines using cell viability and cell cycle analysis. To reveal the mechanisms of JQ1 effects, multiplex gene expression analysis and immunoblotting assays were used. We examined in vivo effects of JQ1 in a xenograft model of AR expressing TNBC. JQ1 exhibited its anti-proliferative activity by inducing apoptosis and cell cycle arrest. JQ1 activity was not mediated by MYC downregulation. Instead, JQ1 blocked the interactions among the ATPase-family AAA-domain-containing 2 protein (ATAD2), BRD2, BRD4, and AR; effectively suppressing the expression of AR associated targets. In addition, JQ1 showed significant anti-tumor activity in vivo in TNBC xenograft mouse models as a monotherapy and in combination with anti-AR therapy. Taken together, our results showed that the BET inhibitor JQ1 is a promising therapeutic agent for the treatment of AR-positive TNBC.

12.
EuroIntervention ; 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31543496

RESUMO

AIMS: We aimed to understand the association between stent length and clinical outcomes after percutaneous coronary intervention (PCI) using newer generation drug-eluting stents (DES). METHODS AND RESULTS: We analysed 9,217 patients who underwent stenting for a single lesion, from the GRAND-DES registry, a patient-level pooled registry including 5 Korean multicenter DES registries. The median follow-up duration was 730 days (interquartile range 708 to 752 days). 8,035 patients were classified under the short stent group (≤40mm), and 1,182 under the long stent group (>40mm). The primary endpoint was target lesion failure (TLF). Long stent (>40mm) was significantly associated with higher TLF (IPTW adjusted HR:1.88, 95% CI:1.67-2.13; p<0.001), and definite or probable stent thrombosis (IPTW adjusted HR:2.20, 95% CI:1.51-3.20; p<0.001). In the landmark analysis, the incidence of TLF was significantly higher in long stent during the first 30 days after PCI (log-rank p=0.001), and also after 30 days (log-rank p<0.001). Long stent was associated with a higher risk of early stent thrombosis (log-rank p=0.001), but not with that for late stent thrombosis (log-rank p=0.887). CONCLUSIONS: In the contemporary 2nd generation DES era, stenting longer than 40mm continues to be associated with less favourable clinical outcomes such as TLF, and stent thrombosis.

13.
Cancer Immunol Res ; 7(10): 1605-1618, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31387898

RESUMO

Tumor-associated myeloid cells are one of the prominent components of solid tumors, serving as major immune regulators for the tumor microenvironment (TME) and an obstacle for immune-checkpoint blocking (ICB) therapy. However, it remains unclear how metabolic processes regulate the generation of suppressive myeloid cells in the TME. Here, we found that hematopoietic precursor cells are enriched in the tissues of several types of human cancer and can differentiate into immature myeloid cells (IMC). Tumor-infiltrating IMCs are highly immunosuppressive, glycolytic, and proliferative, as indicated by high levels of M-CSFR, Glut1, and Ki67. To elucidate the role of metabolism in regulating the generation of IMCs, we induced suppressive IMCs from hematopoietic precursor cells with GM-CSF and G-CSF in vitro We found that the generation of suppressive IMCs was accompanied by increased glycolysis, but not affected by glucose deprivation due to alternative catabolism. Generation of IMCs relied on glutaminolysis, regardless of glucose availability. Glutamine metabolism not only supported the expansion of IMCs with glutamine-derived α-ketoglutarate but also regulated the suppressive capacity through the glutamate-NMDA receptor axis. Moreover, inhibition of glutaminase GLS1 enhanced the therapeutic efficacy of anti-PD-L1 treatment, with reduced arginase 1+ myeloid cells, increased CD8+, IFNγ+ and granzyme B+ T cells, and delayed tumor growth in an ICB-resistant mouse model. Our work identified a novel regulatory mechanism of glutamine metabolism in controlling the generation of suppressive IMCs in the TME.

14.
Medicine (Baltimore) ; 98(32): e16769, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393398

RESUMO

BACKGROUND: Postcholecystectomy syndrome (PCS) is a term used to describe the persistence of biliary colic or right upper quadrant abdominal pain with a variety of postoperative gastrointestinal symptoms. Acupuncture and related treatments have shown clinical effects for PCS in many studies. But the systematic reviews and meta-analyses for them are lacking. We aim to evaluate the efficacy and safety of acupuncture on the treatment of PCS. METHODS: We will search 8 electronic databases, including the Web of Science, PubMed, Cochrane Library, Embase, and 4 Chinese databases (CBM, Wanfang, VIP, and CNKI databases), and additional sources (WHO ICTRP, ChiCTR, Clinical Trials, Grey Literature Database), for potentially eligible studies. Literature retrieval, screening, and data extraction will be conducted by 2 researchers independently. In case of disagreement, a 3rd party shall be consulted to assist judgment. We will use RevmanV.5.3 to perform a fixed effect meta-analysis on the data of clinical homogeneity studies, and evidence's level will be assessed through the method for GRADE. RESULTS: This systematic review and meta-analysis will put a high-quality synthesis of the efficacy and safety of acupuncture treatment in PCS. CONCLUSION: The conclusion of this systematic review will provide evidence to assess acupuncture therapy is an efficacy and safe intervention to treat and control PCS. ETHICS AND DISSEMINATION: Since this article does not involve patients' private data, no ethical approval is required. The agreement will be disseminated by peer-reviewed journals or conference reports. TRIAL REGISTRATION NUMBER: PROSPERO CRD4201929287.


Assuntos
Terapia por Acupuntura/métodos , Síndrome Pós-Colecistectomia/terapia , Humanos , Projetos de Pesquisa
15.
Orthop Surg ; 11(4): 613-619, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31387160

RESUMO

OBJECTIVE: To develop a novel screw positioning method to improve the treatment of unstable thoracolumbar fractures. METHODS: A total of 72 patients with unstable thoracolumbar fractures who were treated with anterior screw-rod interfixation from January 2011 to October 2015 were included in this clinical study. Those patients included 48 male and 24 female patients with an average age of 45.10 years (range, 26-63 years). Patients were randomly divided into two groups: an observation group (n = 36) and a control group (n = 36). The quadrant positioning method was used for screw insertion in the observation group during the operation, while the traditional screw positioning method was used in the control group. The quadrant positioning method targeted four quadrants, including the superior anterior (SA), superior posterior (SP), inferior anterior (IA) and inferior posterior (IP) quadrants, while for the traditional screw positioning, four screws were inserted into the vertebral bodies above and below the excision. Patients were followed up for approximately 40 months to record recovery. Clinical and radiological records, local angle and fractured vertebra body height, clinical outcomes, complications, neurological improvement, and fusion rate were recorded and compared between the two groups. RESULTS: The quadrant positioning method was successfully used for anterior screw insertion. The quadrant center in the lateral view of the vertebral body was well marked, and screws were easily located on the scheduled quadrant. Blood loss (BL), hospital stay (HS), and operation time (OP) in the observation group were 749.40 ± 379.90 mL, 17.10 ± 4.10 days, and 167.40 ± 44.70 min, respectively. While those parameters in the control group were 1198.40 ± 339.27 mL, 23.22 ± 3.77 days, and 221.47 ± 32.15 min, respectively. The average operation time and hospital stay time were significantly shorter, and blood loss was significantly less in the observation group than in the control group (P < 0.05). Local angle and vertebral body height were markedly improved and 1-2 grade improvement was achieved in patients with neurological deficits in both groups. Both groups of patients achieved bony fusion during follow-up. No incision infection or internal fixation failure was observed in the two groups, and complications including cerebrospinal fluid and chylous leakage and hemothorax were resolved. CONCLUSIONS: The quadrant positioning method can shorten operation time, reduce blood loss, and accelerate postoperative recovery. The technique provides an effective method for screw insertion for double screw-rod instrumentation fixation in the treatment of thoracolumbar fracture via the anterior approach.

16.
Eur Heart J ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31419281

RESUMO

AIMS: Proprotein convertase subtilisin/kexin type-9 (PCSK9), a molecular determinant of low-density lipoprotein (LDL) receptor (LDLR) fate, has emerged as a promising therapeutic target for atherosclerotic cardiovascular diseases. However, the precise mechanism by which PCSK9 regulates the internalization and lysosomal degradation of LDLR is unknown. Recently, we identified adenylyl cyclase-associated protein 1 (CAP1) as a receptor for human resistin whose globular C-terminus is structurally similar to the C-terminal cysteine-rich domain (CRD) of PCSK9. Herein, we investigated the role of CAP1 in PCSK9-mediated lysosomal degradation of LDLR and plasma LDL cholesterol (LDL-C) levels. METHODS AND RESULTS: The direct binding between PCSK9 and CAP1 was confirmed by immunoprecipitation assay, far-western blot, biomolecular fluorescence complementation, and surface plasmon resonance assay. Fine mapping revealed that the CRD of PCSK9 binds with the Src homology 3 binding domain (SH3BD) of CAP1. Two loss-of-function polymorphisms found in human PCSK9 (S668R and G670E in CRD) were attributed to a defective interaction with CAP1. siRNA against CAP1 reduced the PCSK9-mediated degradation of LDLR in vitro. We generated CAP1 knock-out mice and found that the viable heterozygous CAP1 knock-out mice had higher protein levels of LDLR and lower LDL-C levels in the liver and plasma, respectively, than the control mice. Mechanistic analysis revealed that PCSK9-induced endocytosis and lysosomal degradation of LDLR were mediated by caveolin but not by clathrin, and they were dependent on binding between CAP1 and caveolin-1. CONCLUSION: We identified CAP1 as a new binding partner of PCSK9 and a key mediator of caveolae-dependent endocytosis and lysosomal degradation of LDLR.

17.
J Mater Chem B ; 7(31): 4734-4750, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31389961

RESUMO

Brain tumors, especially the most prevalent and aggressive glioblastoma, remain among the deadliest of all types of cancer due to inefficient theranostic options. They have a limited therapeutic window because of physiological barriers such as the blood-brain barrier (BBB), blood cerebrospinal fluid (CSF) barrier and interstitial fluid (ISF) that restrict the penetration of imaging probes and therapeutic drugs. In order to achieve more accurate brain tumor diagnosis and better therapeutic effects, many strategies have been explored; among them multifunctional nanoparticles offer a novel and potential opportunity depending on their size effects, and their optical, magnetic, photodynamic and other properties. After modification, nanoparticles can cross the BBB and specifically accumulate in the tumor site, thereby achieving accurate tumor imaging and drug release. This review is focused on various types of nanoparticles that are being used for improving nano-carriers of diagnostic and therapeutic agents into brain tumors and also provides a concise summary of various multifunctional theranostic strategies, particularly in clinical applications. In this manner, we provide evidence for the key role of nanoparticle based diagnosis and therapy systems in brain tumors.

18.
Gastric Cancer ; 2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31377880

RESUMO

BACKGROUND: Development of high-performance serum biomarkers will likely improve treatment outcomes of patients with gastric cancer (GC). We previously identified the candidate serum markers, anosmin 1 (ANOS1), dihydropyrimidinase-like 3 (DPYSL3), and melanoma-associated antigen D2 (MAGE-D2) and evaluated their clinical significance through a single-center retrospective analysis. Here we conducted a prospective multicenter observational study aimed at validating the diagnostic performance of these potential markers. METHODS: We analyzed serum levels before and after surgery of the three potential biomarkers in patients with GC and healthy volunteers. Quantification of serum and GC tissue levels was performed using an ELISA. RESULTS: Area under the curve (AUC) values that discriminated patients with GC from healthy controls were - 0.7058, 0.6188, and 0.5031 for ANOS1, DPYSL3, and MAGED2, respectively. The sensitivity and specificity of the ANOS1 assay were 0.36 and 0.85, respectively. The AUC value of ANOS1 that discriminated patients with stage I GC from healthy controls was 0.7131. Serum ANOS1 levels were significantly elevated in patients with stage I GC compared with those of healthy controls (median 1179 ng/ml and 461 ng/ml, respectively, P < 0.0001) and decreased after resection of primary GC lesions (P < 0.0001). The combination of serum ANOS1 and DPYSL3 levels increased the AUC value that discriminated patients with GC from healthy controls. Serum levels of ANOS1 did not significantly correlate with those of carcinoembryonic antigen, carbohydrate antigen 19-9, or other markers of inflammation. CONCLUSIONS: Serum levels of ANOS1 may serve as a useful diagnostic tool for managing GC.

19.
Schizophr Res ; 212: 6-14, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31387828

RESUMO

The present study aimed to explore the relationship between autistic and schizotypal traits in the non-clinical population. We first conducted a meta-analysis to quantify the correlation between self-reported autistic traits and the three dimensions of schizotypal traits (positive, negative and disorganization). The strongest correlation was found between autistic traits and negative schizotypal traits (r = 0.536, 95% CI [0.481, 0.586]), followed by the disorganization (r = 0.355, 95% CI [0.304, 0.404]) and positive (r = 0.256, 95% CI [0.208, 0.302]) dimensions. To visualize the partial correlations between dimensional behavioural traits, we constructed a network model based on a large sample of college students (N = 2469). Negative schizotypal traits were strongly correlated with autistic social/communicative deficits, whereas positive schizotypal traits were inversely correlated with autistic-like traits, lending support to the psychosis-autism diametrical model. Disentangling the overlapping and diametrical structure of autism and schizophrenia may help to elucidate the aetiology of these two neurodevelopmental disorders.

20.
Hepatology ; 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31393024

RESUMO

BACKGROUND AND AIMS: Hepatic ischemia-reperfusion (I/R) injury remains a major challenge affecting the morbidity and mortality of liver transplantation. Effective strategies to improve liver function after hepatic I/R injury are limited. Six-transmembrane epithelial antigen of the prostate 3 (Steap3), a key regulator of iron uptake, was reported to be involved in immunity and apoptotic processes in various cell types. However, the role of Steap3 in hepatic I/R-induced liver damage remains largely unclear. APPROACH AND RESULTS: In the present study, we found that Steap3 expression was significantly up-regulated in liver tissue from mice subjected to hepatic I/R surgery and primary hepatocytes challenged with hypoxia/reoxygenation insult. Subsequently, global Steap3 knockout (Steap3-KO) mice, hepatocyte-specific Steap3 transgenic (Steap3-HTG) mice, and their corresponding controls were subjected to partial hepatic warm I/R injury. Hepatic histology, the inflammatory response, and apoptosis were monitored to assess liver damage. The molecular mechanisms of Steap3 function were explored in vivo and in vitro. The results demonstrated that, compared with control mice, Steap3-KO mice exhibited alleviated liver damage after hepatic I/R injury, as shown by smaller necrotic areas, lower serum transaminase levels, decreased apoptosis rates, and reduced inflammatory cell infiltration, whereas Steap3-HTG mice had the opposite phenotype. Further molecular experiments showed that Steap3 deficiency could inhibit transforming growth factor-ß-activated kinase 1 (TAK1) activation and downstream c-Jun N-terminal kinase (JNK) and p38 signaling during hepatic I/R injury. CONCLUSIONS: Steap3 is a mediator of hepatic I/R injury that functions by regulating inflammatory responses as well as apoptosis through TAK1-dependent activation of the JNK/p38 pathways. Targeting hepatocytes, Steap3 may be a promising approach to protect the liver against I/R injury.

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