Cancer stem cell (CSC) theory has drawn much attention, with evidence supporting the contribution of stem cells to tumor initiation, relapse, and therapy resistance.
To screen drugs that target CSCs ...to improve the current treatment outcome and overcome drug resistance in patients with lung cancer.
We used publicly available embryonic stem cell and CSC-associated gene signatures to query the Connectivity Map for potential drugs that can, at least in part, reverse the gene expression profile of CSCs. High scores were noted for several phenothiazine-like antipsychotic drugs, including trifluoperazine. We then treated lung CSCs with different EGFR mutation status with trifluoperazine to examine its anti-CSC properties. Lung CSCs resistant to epidermal growth factor receptor-tyrosine kinase inhibitor or cisplatin were treated with trifluoperazine plus gefitinib or trifluoperazine plus cisplatin. Animal models were used for in vivo validation of the anti-CSC effect and synergistic effect of trifluoperazine with gefitinib.
We demonstrated that trifluoperazine inhibited CSC tumor spheroid formation and down-regulated the expression of CSC markers (CD44/CD133). Trifluoperazine inhibited Wnt/β-catenin signaling in gefitinib-resistant lung cancer spheroids. The combination of trifluoperazine with either gefitinib or cisplatin overcame drug resistance in lung CSCs. Trifluoperazine inhibited the tumor growth and enhanced the inhibitory activity of gefitinib in lung cancer metastatic and orthotopic CSC animal models.
Using in silico drug screening by Connectivity Map followed by empirical validations, we repurposed an existing phenothiazine-like antipsychotic drug, trifluoperazine, as a potential anti-CSC agent that could overcome epidermal growth factor receptor-tyrosine kinase inhibitor and chemotherapy resistance.
Summary
Background
There remains an unmet need for convenient biomarkers to assess the risks of discontinuing nucleos(t)ide analogues (NAs) in chronic hepatitis B (CHB).
Aim
To investigate if ...hepatitis B core‐related antigen (HBcrAg) is an independent of surface antigen (HBsAg) for risk prediction of NA cessation.
Methods
This prospective multicentre study enrolled 135 CHB patients who stopped entecavir or tenofovir after achieving viral remission for a median of 25.2 months. All patients stopped NA with negative HBeAg and undetectable viral DNA, and were then observed for clinical relapse and HBsAg loss. Predictors including HBsAg and HBcrAg levels were explored using Cox proportional hazard model and weighted to develop a risk score.
Results
During a median follow‐up of 25.9 months, clinical relapse and HBsAg loss occurred in 66 and eight patients, respectively, with a 5‐year cumulative incidence of 56.1% (95% CI 46.7‐66.0%) and 8.8% (95% CI 4.3‐17.4%), respectively. HBcrAg was an independent relapse predictor, as well as HBsAg, age, ALT and tenofovir use. A score (SCALE‐B) was calculated by the equation of 35*HBsAg (log IU/mL) + 20*HBcrAg (log U/mL) + 2*age (year) + ALT (U/L) + 40 for tenofovir use. The concordance rates for clinical relapse were 0.87, 0.88, 0.87, 0.85 and 0.90 at 1, 2, 3, 4 and 5 years, respectively. Moreover, HBsAg loss occurred exclusively in low‐risk patients predicted by the score.
Conclusions
Serum HBcrAg and HBsAg levels were independent predictors of off‐NA relapse and can be factored into a risk score to guide treatment cessation in patients with CHB.
Inherited retinal dystrophies (IRDs) are a group of rare eye diseases caused by gene mutations that result in the degradation of cone and rod photoreceptors or the retinal pigment epithelium. Retinal ...degradation progress is often irreversible, with clinical manifestations including color or night blindness, peripheral visual defects and subsequent vision loss. Thus, gene therapies that restore functional retinal proteins by either replenishing unmutated genes or truncating mutated genes are needed. Coincidentally, the eye's accessibility and immune-privileged status along with major advances in gene identification and gene delivery systems heralded gene therapies for IRDs. Among these clinical trials, voretigene neparvovec-rzyl (Luxturna), an adeno-associated virus vector-based gene therapy drug, was approved by the FDA for treating patients with confirmed biallelic
mutation-associated Leber Congenital Amaurosis (LCA) in 2017. This review includes current IRD gene therapy clinical trials and further summarizes preclinical studies and therapeutic strategies for LCA, including adeno-associated virus-based gene augmentation therapy, 11-cis-retinal replacement, RNA-based antisense oligonucleotide therapy and CRISPR-Cas9 gene-editing therapy. Understanding the gene therapy development for LCA may accelerate and predict the potential hurdles of future therapeutics translation. It may also serve as the template for the research and development of treatment for other IRDs.
This article presents an acoustic DSP processor containing a neural network core for intelligent hearing assistive devices. The processor includes the accelerators for convolutional neural networks ...(CNNs) and fast Fourier transform (FFT). The CNN-based speech enhancement algorithm predicts the desired mask for the Fourier spectrogram of the speech signal to enhance speech intelligibility. Several design techniques are applied to enable efficient hardware mapping. The computational complexity for the CNN can be reduced by 23.6% by frame sharing, and a fast mask generation + partial sums pre-computation technique further reduces output latency by up to 64%. The size of the memory for the model is reduced by 75% using weight quantization. FFT is implemented by leveraging the packing algorithm to reduce the computational complexity by 43%. Reconfigurable processing elements are shared to support both FFT and CNN, realizing a saving in the area of 42%. In addition, input sharing and output sharing are used to, respectively, reduce data movements by 94% and 75%. A reordered FFT structure also eliminates up to 256 multiplexers. Fabricated in a 40-nm CMOS technology, the chip's core area is 4.2 mm 2 and the power dissipation is 2.17 mW at a clock frequency of 5 MHz from a 0.6-V supply. The embedded CNN accelerator supports both convolutional and fully connected (FC) layers and achieves a comparable energy efficiency with state-of-the-art CNN accelerators, despite the flexibility for FFT. The speech intelligibility is enhanced by up to 41% in the low SNR regime.
Best dystrophy (BD), also termed best vitelliform macular dystrophy (BVMD), is a juvenile-onset form of macular degeneration and can cause central visual loss. Unfortunately, there is no clear ...definite therapy for BD or improving the visual function on this progressive disease. The human induced pluripotent stem cell (iPSC) system has been recently applied as an effective tool for genetic consultation and chemical drug screening. In this study, we developed patient-specific induced pluripotent stem cells (BD-iPSCs) from BD patient-derived dental pulp stromal cells and then differentiated BD-iPSCs into retinal pigment epithelial cells (BD-RPEs). BD-RPEs were used as an expandable platform for in vitro candidate drug screening. Compared with unaffected sibling-derived iPSC-derived RPE cells (Ctrl-RPEs), BD-RPEs exhibited typical RPE-specific markers with a lower expression of the tight junction protein ZO-1 and Bestrophin-1 (BEST1), as well as reduced phagocytic capabilities. Notably, among all candidate drugs, curcumin was the most effective for upregulating both the BEST1 and ZO-1 genes in BD-RPEs. Using the iPSC-based drug-screening platform, we further found that curcumin can significantly improve the mRNA expression levels of Best gene in BD-iPSC-derived RPEs. Importantly, we demonstrated that curcumin-loaded PLGA nanoparticles (Cur-NPs) were efficiently internalized by BD-RPEs. The Cur-NPs-based controlled release formulation further increased the expression of ZO-1 and Bestrophin-1, and promoted the function of phagocytosis and voltage-dependent calcium channels in BD-iPSC-derived RPEs. We further demonstrated that Cur-NPs enhanced the expression of antioxidant enzymes with a decrease in intracellular ROS production and hydrogen peroxide-induced oxidative stress. Collectively, these data supported that Cur-NPs provide a potential cytoprotective effect by regulating the anti-oxidative abilities of degenerated RPEs. In addition, the application of patient-specific iPSCs provides an effective platform for drug screening and personalized medicine in incurable diseases.
We aimed to compare the efficacy of genotypic resistance–guided therapy vs empirical therapy for eradication of refractory Helicobacter pylori infection in randomized controlled trials.
We performed ...2 multicenter, open-label trials of patients with H pylori infection (20 years or older) failed by 2 or more previous treatment regimens, from October 2012 through September 2017 in Taiwan. The patients were randomly assigned to groups given genotypic resistance–guided therapy for 14 days (n = 21 in trial 1, n = 205 in trial 2) or empirical therapy according to medication history for 14 days (n = 20 in trial 1, n = 205 in trial 2). Patients received sequential therapy containing esomeprazole and amoxicillin for the first 7 days, followed by esomeprazole and metronidazole, with levofloxacin, clarithromycin, or tetracycline (doxycycline in trial 1, tetracycline in trial 2) for another 7 days (all given twice daily) based on genotype markers of resistance determined from gastric biopsy specimens (group A) or empirical therapy according to medication history. Resistance-associated mutations in 23S ribosomal RNA or gyrase A were identified by polymerase chain reaction with direct sequencing. Eradication status was determined by 13C-urea breath test. The primary outcome was eradication rate.
H pylori infection was eradicated in 17 of 21 (81%) patients receiving genotype resistance–guided therapy and 12 of 20 (60%) patients receiving empirical therapy (P = .181) in trial 1. This trial was terminated ahead of schedule due to the low rate of eradication in patients given doxycycline sequential therapy (15 of 26 57.7%). In trial 2, H pylori infection was eradicated in 160 of 205 (78%) patients receiving genotype resistance–guided therapy and 148 of 205 (72.2%) patients receiving empirical therapy (P = .170), according to intent to treat analysis. The frequencies of adverse effects and compliance did not differ significantly between groups.
Properly designed empirical therapy, based on medication history, is an acceptable alternative to genotypic resistance–guided therapy for eradication of refractory H pylori infection after consideration of accessibility, cost, and patient preference. ClinicalTrials.gov ID: NCT01725906.
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Antiviral therapy for patients with non-cirrhotic chronic hepatitis B and minimally raised alanine aminotransferase (ALT) is controversial. We aimed to investigate the efficacy and safety of ...tenofovir disoproxil fumarate in reducing the risk of disease progression in this patient population.
TORCH-B is a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial done at six teaching hospitals in Taiwan that enrolled patients with chronic hepatitis B. Eligible patients were aged 25–70 years and had substantial viraemia (viral DNA >2000 IU/mL) and minimally raised serum ALT concentrations more than one-fold but less than two-fold the upper limit of normal (ULN). Exclusion criteria included liver cirrhosis and previous antiviral treatment. Eligible participants were randomly assigned (1:1), stratified by site with a fixed block size of ten, to receive either 300 mg of oral tenofovir disoproxil fumarate or placebo once daily for 3 years. The participants, investigators, research coordinators, pathologists, laboratory personnel, and staff involved in patient care or assessment were masked to treatment assignment. 0·5 mg/day of oral entecavir was added to rescue acute hepatitis flare. The coprimary outcomes were change in necroinflammation severity on the Knodell scale and change in fibrosis stage on the Ishak scale and were evaluated in the modified intention-to-treat population, which comprised all patients with paired liver biopsies. Safety was evaluated in all patients who were randomly assigned. This trial is registered at ClinicalTrials.gov, NCT01522625, and is completed.
From Jan 30, 2012, to Nov 10, 2015, 875 patients were screened and 160 were randomly assigned to receive either tenofovir disoproxil fumarate (n=79) or placebo (n=81). The coprimary outcomes were assessed in 146 patients (73 in each group). Liver fibrosis progressed (an increase of ≥1 stage) in 19 (26%, 95% CI 17–38) of 73 patients in the tenofovir disoproxil fumarate group and in 34 (47%, 35–59) of 73 patients in the placebo group (relative risk RR 0·56, 95% CI 0·35–0·88; p=0·013), whereas necroinflammation progressed (an increase of ≥2 points) in five (7%, 95% CI 2–15) patients in the tenofovir disoproxil fumarate group and in 12 (16%, 9–27) patients in the placebo group (RR 0·42, 95% CI 0·15–1·12; p=0·084). Two (3%) of 79 patients in the tenofovir disoproxil fumarate group and 13 (16%) of 81 patients in the placebo group had acute hepatitis flare requiring add-on entecavir (RR 0·16, 95% CI 0·04–0·68; p=0·013). The two groups were otherwise similar in occurrences of adverse events. No patients died.
Tenofovir disoproxil fumarate reduces the risk of progression in liver fibrosis in patients with chronic hepatitis B and minimally raised ALT, but its effect on necroinflammation is non-significant.
The Taiwan Ministry of Science and Technology, E-Da Hospital, the Taipei Institute of Pathology, Gilead Sciences.
The photochemical reaction of peroxy radical (RO2·) and NO has been identified by field and forest studies as important source of organic nitrates (RONO2) in the atmosphere. However, this traditional ...pathway is not sufficient to explain the high concentration of RONO2. Hence, a new source of the tropospheric RONO2 from the dark reactions of nitric acid (HNO3) with aliphatic aldehydes (C1–C5) under catalysis is provided and examined for the first time by high-level quantum chemistry. The findings show that the reaction between HCHO and HNO3, which produces HOCH2ONO2, can be catalyzed by a series of metal-free catalysts (NH3, CH3NH2, CH3NHCH3, H2O, HNO3, H2SO4, HCOOH, HOOCCOOH). At 296 K, the effective rate constant for the bimolecular HNO3–HCHO reaction under the catalysis of CH3NH2 or CH3NHCH3 can be sufficiently accelerated by 5–8 order of magnitudes through this new loss pathway for HNO3 or HCHO to become competitive with the conventional loss pathway for their photochemical reactions with ·OH radical. Significantly, this new HOCH2ONO2 formation pathway from the dark reaction of HCHO with CH3NH3+NO3−/(CH3)2NH + NO3− was more favorable than the recognized source of RO2· with NO. Efficient catalysis performance of CH3NH2 and CH3NHCH3 is mainly attributed to their excellent proton receptivity capacity by activating the O–H bond of HNO3 to form stable organic nitrates (CH3NH3+NO3− and (CH3)2NH + NO3−) in the rate-determining step transition states. In the case of only considering the barrier, H2SO4 is the best catalyst among the investigated inorganic and organic acids, and dicarboxylic acid (HOOCCOOH) is stronger than monocarboxylic acid HCOOH in facilitating the RONO2 formation reaction. These new findings deepen our understanding on the unexpected source of organic nitrate and loss pathway of HNO3 or HCHO under catalysis in highly polluted regions.
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•Kinetics and mechanism for reactions of HNO3 with C1–C5 aliphatic aldehydes were studied.•Role of water, acids, and alkalies on the HNO3/HCHO reaction were analyzed.•A new loss pathway for HCHO was identified via amine-catalyzed HNO3/HCHO reaction.•An unexpected source of RONO2 with the help of catalysts was proposed and verified.•The proposed new source of RONO2 was more favorable than that of RO2·/NO reaction.
The role of urate‐lowering therapy (ULT) for the primary prevention of cardiovascular (CV) events has been widely discussed, but its evidence for the secondary prevention of myocardial infarction ...(MI) is limited. Therefore, we conduct a population‐based, propensity score‐matched cohort study to investigate the CV outcomes among patients with post‐MI with and without ULT. A total of 19,042 newly diagnosed in‐hospital patients with MI were selected using the Taiwan National Health Insurance Database between January 1, 2005, and December 31, 2016. After 1:1 propensity score matching with covariates, patients with MI with (n = 963) and without (n = 963) ULT were selected for further analysis. The primary outcome was the all‐cause mortality and the secondary outcomes were composite CV outcomes, including hospitalization for recurrent MI, stroke, heart failure, and cardiac arrhythmias. ULT users were associated with lower all‐cause mortality (adjusted hazard ratio (adjHR), 0.67; 95% confidence interval (CI), 0.51–0.87) compared to the ULT nonusers. In addition, ULT users had a significantly lower risk of recurrent MI, which needed revascularization by percutaneous coronary intervention or coronary artery bypass grafting (adjHR, 0.67; 95% CI, 0.53–0.86) than the ULT nonusers. The primary and secondary outcomes were not different between patients with post‐MI who received uricosuric agents and xanthine oxidase inhibitors. The anti‐inflammatory effect of ULT plays an essential role in MI management. From a real‐world setting, this study shows that ULT is associated with the lower risk of all‐cause mortality in patients with post‐MI. In addition, the result shows the possible lower incidence of repeat revascularization procedures in the ULT users.
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