In previous research, we found α-enolase to be inversely correlated with progression-free and overall survival in lung cancer patients and detected α-enolase on the surface of lung cancer cells. ...Based on these findings, we hypothesized that surface α-enolase has a significant role in cancer metastasis and tested this hypothesis in the current study. We found that α-enolase was co-immunoprecipitated with urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, and plasminogen in lung cancer cells and interacted with these proteins in a cell-free dot blotting assay, which can be interrupted by α-enolase-specific antibody. α-Enolase in lung cancer cells co-localized with these proteins and was present at the site of pericellular degradation of extracellular matrix components. Treatment with antibody against α-enolase in vitro suppressed cell-associated plasminogen and matrix metalloproteinase activation, collagen and gelatin degradation, and cell invasion. Examination of the effect of treatment with shRNA plasmids revealed that down regulation of α-enolase decreases extracellular matrix degradation by and the invasion capacity of lung cancer cells. Adoptive transfer of α-enolase-specific antibody to mice resulted in accumulation of antibody in subcutaneous tumor and inhibited the formation of tumor metastasis in lung and bone. This study demonstrated that surface α-enolase promotes extracellular matrix degradation and invasion of cancer cells and that targeting surface α-enolase is a promising approach to suppress tumor metastasis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The purpose of this phase I clinical trial is to assess the safety and tolerability of allogeneic adipose tissue‐derived stem cells (ADSCs) among chronic kidney disease (CKD) patients. 12 eligible ...CKD patients with an estimated glomerular filtration rate (eGFR) of 15–44 ml/min/1.73 m2 received one dose of intravenous allogeneic ADSCs (ELIXCYTE®), as 3 groups: 3 low dose (6.4 × 107 cells in total of 8 ml), 3 middle dose (19.2 × 107 cells in total of 24 ml) and 6 high dose (32.0 × 107 cells in total of 40 ml) of ELIXCYTE® and evaluated after 48 weeks. Primary endpoint was the safety profiles in terms of incidence of adverse events (AEs) and serious adverse event (SAE). Two subjects in high dose group experienced a total of 2 treatment‐related AEs which are Grade 1 slow speech and Grade 1 bradyphrenia after the infusion. One subject in middle dose group experienced an SAE unlikely related to treatment, grade 2 proteinuria. No fatal AE was reported in this study. An increase in eGFR was observed in 7 out of 12 subjects (58%) at Week 24 and in 6 of 12 subjects (50%) by Week 48. By Week 24, an increase in eGFR by more than 20% among all CKD patients with baseline eGFR ≧ 30 ml/min/1.73 m2 as compared to only 2 subjects in baseline eGFR < 30 ml/min/1.73 m2 group. No significant reduction in proteinuria was noted among all subjects. This phase I trial demonstrated single‐dose intravenous ELIXCYTE was well tolerated in moderate‐to‐severe CKD patients and its preliminary efficacy warrants future studies.
Toll‐like receptors (TLRs) are important sensors that recognize pathogen‐associated molecular patterns. Generally, TLR9 is known to recognize bacterial or viral DNA but not viral RNA and initiate an ...immune response. Herein, we demonstrate that infection with dengue virus (DENV), an RNA virus, activates TLR9 in human dendritic cells (DCs). DENV infection induces release of mitochondrial DNA (mtDNA) into the cytosol and activates TLR9 signaling pathways, leading to production of interferons (IFNs). The DENV‐induced mtDNA release involves reactive oxygen species generation and inflammasome activation. DENV infection disrupts the association between transcription factor A mitochondria (TFAM) and mtDNA and activates the mitochondrial permeability transition pores. The side‐by‐side comparison of TLR9 and cyclic GMP‐AMP synthase (cGAS) knockdown reveals that both cGAS and TLR9 comparably contribute to DENV‐induced immune activation. The significance of TLR9 in DENV‐induced immune response is also confirmed in examination with the bone marrow‐derived DCs prepared from Tlr9‐knockout mice. Our study unravels a previously unrecognized phenomenon in which infection with an RNA virus, DENV, activates TLR9 signaling by inducing mtDNA release in human DCs.
Synopsis
Infection of human dendritic cells with a dengue RNA virus activates TLR9—known to recognize bacterial or viral DNA but not viral RNA—through inducing mitochondrial DNA release into the cytosol.
Infection of human DCs with DENV induces ROS generation, inflammasome activation, oxidization of mtDNA and opening of the mitochondrial permeability transition pores resulting in the release of both non‐oxidized and oxidized mtDNA into the cytosol.
Cytosolic mtDNA increases TLR9 expression, binds to TLR9 and induces immune activation such as anti‐viral interferon production.
The significance of TLR9 in DENV infection is confirmed by examining bone marrow‐derived dendritic cells prepared from Tlr9‐knockout mice.
Infection of human dendritic cells with a dengue RNA virus activates TLR9—known to recognize bacterial or viral DNA but not viral RNA—through inducing mitochondrial DNA release into the cytosol.
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib, are effective for non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, these ...patients eventually develop resistance to EGFR-TKI. The goal of the present study was to investigate the involvement of autophagy in gefitinib resistance. We developed gefitinib-resistant cells (PC-9/gef) from PC-9 cells (containing exon 19 deletion EGFR) after long-term exposure in gefitinib. PC-9/gef cells (B4 and E3) were 200-fold more resistant to gefitinib than PC-9/wt cells. Compared with PC-9/wt cells, both PC-9/gefB4 and PC-9/gefE3 cells demonstrated higher basal LC3-II levels which were inhibited by 3-methyladenine (3-MA, an autophagy inhibitor) and potentiated by chloroquine (CQ, an inhibitor of autophagolysosomes formation), indicating elevated autophagy in PC-9/gef cells. 3-MA and CQ concentration-dependently inhibited cell survival of both PC-9wt and PC-9/gef cells, suggesting that autophagy may be pro-survival. Furthermore, gefitinib increased LC3-II levels and autolysosome formation in both PC-9/wt cells and PC-9/gef cells. In PC-9/wt cells, CQ potentiated the cytotoxicity by low gefitinib (3 nM). Moreover, CQ overcame the acquired gefitinib resistance in PC-9/gef cells by enhancing gefitinib-induced cytotoxicity, activation of caspase 3 and poly (ADP-ribose) polymerase cleavage. Using an in vivo model xenografting with PC-9/wt and PC-9/gefB4 cells, oral administration of gefitinib (50 mg/kg) completely inhibited the tumor growth of PC-9/wt but not PC-9/gefB4cells. Combination of CQ (75 mg/kg, i.p.) and gefitinib was more effective than gefitinib alone in reducing the tumor growth of PC-9/gefB4. Our data suggest that inhibition of autophagy may be a therapeutic strategy to overcome acquired resistance of gefitinib in EGFR mutation NSCLC patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study investigated the characteristics of patients with different chronic kidney disease (CKD) stages according to various body mass index (BMI) categories and determined the influence of BMI in ...renal function deterioration. We conducted a multicenter, longitudinal cohort study based on the Epidemiology and Risk Factors Surveillance of CKD project (2008-2013) and National Health Insurance Research Database (2001-2013). A total of 7357 patients with CKD aged 20-85 years from 14 hospitals were included in the study. A higher male sex, diabetes mellitus (DM) and hypertension were noted among overweight and obese CKD patients, while more cancer prevalence was noted among underweight CKD patients. Charlson comorbidity index was significantly higher and correlated with BMI among late CKD patients. Patients with BMI < 18.5 kg/m
exhibited non-significantly higher events of eGFR decline events in both early and late CKD stages than other BMI groups. BMI alone is not a determinant of CKD progression among our Taiwanese CKD patients. Obesity should be re-defined and body weight manipulation should be individualized in CKD patients.
Herein, a single-phase dc permanent magnet motor (PMM) operated at direct current (dc) was proposed, affected by a type of alternating current (ac) signal >5% and frequency between 50 and 3000 Hz to ...explore characteristics such as noise, vibration, and motor power efficiency. The finite-element method (FEA) was used to model the motor and the transient results of the core flux and current were simulated. The noise level of the motor was experimentally determined for the motor under normal dc power operation subjected to higher hybrid power supply. This indicates that the vibration displacement (mm) and velocity (mm/s) vary, while acceleration <inline-formula> <tex-math notation="LaTeX">({\mathrm {mm/s}}^{2}) </tex-math></inline-formula> is linearly stable. From the experimental results, the vibration is inversely proportional to the noise. The lower noise level is only observed under medium frequency, similar to a bathtub curve. In addition, when the motor is operated at a low frequency of 50-500 Hz, the characteristics of the power performance were increased more than 1.5 times, including real power P (real power, Watt), apparent power S (apparent power, VA), and reactive power Q (reactive power, VAR), which is much higher than the high-frequency power signal at frequency >500 Hz, gradually stabilizing the motor power. Moreover, a hybrid ac signal of up to 15% was added to the motor system at a frequency between 50 and 500 Hz, drastically changing the displacement and vibration by up to 1.36 times. However, at high frequencies of >1 kHz, the power and noise increase slightly before reaching the steady state.
Abstract
The escape of bladder cancer from immunosurveillance causes monotherapy to exhibit poor efficacy; therefore, designing a multifunctional nanoparticle that boosts programmed cell death and ...immunoactivation has potential as a treatment strategy. Herein, we developed a facile one-pot coprecipitation reaction to fabricate cluster-structured nanoparticles (CNPs) assembled from Fe
3
O
4
and iron chlorophyll (Chl/Fe) photosensitizers. This nanoassembled CNP, as a multifunctional theranostic agent, could perform red-NIR fluorescence and change the redox balance by the photoinduction of reactive oxygen species (ROS) and attenuate iron-mediated lipid peroxidation by the induction of a Fenton-like reaction. The intravesical instillation of Fe
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O
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@Chl/Fe CNPs modified with 4-carboxyphenylboronic acid (CPBA) may target the BC wall through glycoproteins in the BC cavity, allowing local killing of cancer cells by photodynamic therapy (PDT)-induced singlet oxygen and causing chemodynamic therapy (CDT)-mediated ferroptosis. An interesting possibility is reprogramming of the tumor microenvironment from immunosuppressive to immunostimulatory after PDT-CDT treatment, which was demonstrated by the reduction of PD-L1 (lower “off” signal to the effector immune cells), IDO-1, TGF-β, and M2-like macrophages and the induction of CD8
+
T cells on BC sections. Moreover, the intravesical instillation of Fe
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O
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@Chl/Fe CNPs may enhance the large-area distribution on the BC wall, improving antitumor efficacy and increasing survival rates from 0 to 91.7%. Our theranostic CNPs not only demonstrated combined PDT-CDT-induced cytotoxicity, ROS production, and ferroptosis to facilitate treatment efficacy but also opened up new horizons for eliminating the immunosuppressive effect by simultaneous PDT-CDT.
Hyperuricemia has been proven to be an independent risk factor for chronic kidney disease (CKD). However, the role of hyperuricemia in the progression of CKD remains unclear. Thus, we performed a ...systematic review and meta-analysis to evaluate the efficacy and safety of febuxostat, a first line urate-lowering agent, in CKD patients with hyperuricemia.
We have systematically searched for randomized controlled trials assessing the efficacy and safety of febuxostat versus control in CKD patients with hyperuricemia through MEDLINE, PubMed, EMBASE, and Cochrane databases. All statistical analyses were conducted by using the statistical package Review Manager, version 5.3.5. Heterogeneity was assessed using the Cochrane Q and I tests and summary statistics were reported with 95% confidence interval. Two-tailed test was used for analysis and a P value of <.05 is considered statistically significant.
Eleven eligible trials with 1317 participants were included in the meta-analysis. A significant reduction in serum uric acid was found in the febuxostat treated group. Also, a significant higher eGFR was found in the febuxostat treated group among CKD stage 3 and 4 patients. No significant difference of major complication or death was identified between treatment and control groups.
The meta-analysis showed that other than its urate-lowering effect, febuxostat presented a reno-protective effect in CKD patients. More studies with larger sample sizes and higher quality are required to clarify the role of febuxostat use in the progression of CKD.
Thin film electrocatalysts allow strong binding and intimate electrical contact with electrodes, rapid mass transfer during reaction, and are generally more durable than powder electrocatalysts, ...which is particularly beneficial for gas evolution reactions. In this work, using cobalt manganese oxyhydroxide, an oxygen evolution reaction (OER) electrocatalyst that can be grown directly on various electrodes as a model system, it is demonstrated that breaking a continuous film into discontinuous patches can significantly enhance the overall OER performance without sacrificing long‐term stability even under elevated electrocatalytic stress. Discontinuous films with higher edge‐to‐area ratios exhibits reduced overpotentials, increased turnover frequency, and more pronounced current increase after electrochemical conditioning. Operando Raman spectroscopy studies during electrocatalysis reveal that the film edges require lower potential barrier for activation. Introducing discontinuity into thin film electrocatalysis can thus lead to the realization of high performance yet highly robust systems for harsh gas evolution reactions.
A discontinuous cobalt manganese oxyhydroxide (CMOH) film, which is deposited on gold‐coated pyramidal substrates, shows much higher atom efficiency and performance in the oxygen evolution reaction (OER) than completely continuous ones. The heterojunction edges facilitate charge transport and kinetics. This concept is highly valuable to reduce the quantity of catalysts, while gaining even better, durable OER activity.
The kidney harbors one of the strongest circadian clocks in the body. Kidney failure has long been known to cause circadian sleep disturbances. Using an adenine-induced model of chronic kidney ...disease (CKD) in mice, we probe the possibility that such sleep disturbances originate from aberrant circadian rhythms in kidney. Under the CKD condition, mice developed unstable behavioral circadian rhythms. When observed in isolation in vitro, the pacing of the master clock, the suprachiasmatic nucleus (SCN), remained uncompromised, while the kidney clock became a less robust circadian oscillator with a longer period. We find this analogous to the silencing of a strong slave clock in the brain, the choroid plexus, which alters the pacing of the SCN. We propose that the kidney also contributes to overall circadian timekeeping at the whole-body level, through bottom-up feedback in the hierarchical structure of the mammalian circadian clocks.
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