Current clinical challenges of prostate cancer management are to restrict tumor growth and prohibit metastasis. AICAR (5-aminoimidazole-4-carbox-amide-1-β-d-ribofuranoside), an AMP-activated protein ...kinase (AMPK) agonist, has demonstrated antitumor activities for several types of cancers. However, the activity of AICAR on the cell growth and metastasis of prostate cancer has not been extensively studied. Herein we examine the effects of AICAR on the cell growth and metastasis of prostate cancer cells. Cell growth was performed by MTT assay and soft agar assay; cell apoptosis was examined by Annexin V/propidium iodide (PI) staining and poly ADP ribose polymerase (PARP) cleavage western blot, while cell migration and invasion were evaluated by wound-healing assay and transwell assay respectively. Epithelial-mesenchymal transition (EMT)-related protein expression and AMPK/mTOR-dependent signaling axis were analyzed by western blot. In addition, we also tested the effect of AICAR on the chemosensitivity to docetaxel using MTT assay. Our results indicated that AICAR inhibits cell growth in prostate cancer cells, but not in non-cancerous prostate cells. In addition, our results demonstrated that AICAR induces apoptosis, attenuates transforming growth factor (TGF)-β-induced cell migration, invasion and EMT-related protein expression, and enhances the chemosensitivity to docetaxel in prostate cancer cells through regulating the AMPK/mTOR-dependent pathway. These findings support AICAR as a potential therapeutic agent for the treatment of prostate cancer.
The repeated measurements of heart rate variability (HRV) is more relevant than a single HRV measurement in predicting patient prognosis but is less addressed previously. This prospective study aimed ...to investigate the association between repeated measurements of HRV and long-term mortality in chronic hemodialysis patients. The 164 patients (65.0 ± 13.1 years; woman, 57.3%) were enrolled from June 1, 2010, to August 31, 2010, and received four HRV measurements (before and during the index hemodialysis session) after the enrollment. The baseline characteristic and clinical variables, including mortality, were documented. The joint modeling method and Cox regression were used for statistical analyses. After an 8-year follow-up, 79 patients expired, and 85 patients survived. We found that higher normalized high-frequency (nHF) (hazard ratio HR 1.033) as well as lower very-low-frequency (HR 0.990), Variance (HR 0.991), normalized low-frequency (HR 0.999, P = 0.006), and low-frequency/high-frequency ratio (HR 0.796) were independent predictors for cardiovascular mortality. Whereas the independent predictors for infection-associated mortality included higher nHF (HR 1.033) as well as higher age (HR 19.29) and lower serum albumin (HR 0.01, P = 0.001). (all P < 0.001 unless otherwise stated) In conclusion, HRV measurement predicts long-term mortality among hemodialysis patients.
Prolonged treatment with cisplatin (CDDP) frequently develops chemoresistance. We have previously shown that p22phox, an endoplasmic reticulum (ER) membrane protein, confers CDDP resistance by ...blocking CDDP nuclear entry in oral squamous cell carcinoma (OSCC) cells; however, the underlying mechanism remains unresolved. Using a fluorescent dye-labeled CDDP, here we show that CDDP can bind to p22phox in both cell-based and cell-free contexts. Subsequent detection of CDDP-peptide interaction by the Tris-Tricine-based electrophoresis revealed that GA-30, a synthetic peptide matching a region of the cytosolic domain of p22phox, could interact with CDDP. These results were further confirmed by liquid chromatography-mass spectrometry (LC-MS) analysis, from which MA-11, an 11-amino acid subdomain of the GA-30 domain, could largely account for the interaction. Amino acid substitutions at Cys50, Met65 and Met73, but not His72, significantly impaired the binding between CDDP and the GA-30 domain, thereby suggesting the potential CDDP-binding residues in p22phox protein. Consistently, the p22phox point mutations at Cys50, Met65 and Met73, but not His72, resensitized OSCC cells to CDDP-induced cytotoxicity and apoptosis. Finally, p22phox might have binding specificity for the platinum drugs, including CDDP, carboplatin and oxaliplatin. Together, we have not only identified p22phox as a novel CDDP-binding protein, but further highlighted the importance of such a drug-protein interaction in drug resistance.
Arsenic is a well-established human carcinogen and is considered a health risk worldwide, especially where groundwater is consumed as drinking water. In 2018, bladder and kidney cancers were the 14th ...and 17th leading causes of global cancer mortality, respectively. Our aim was to investigate the association between arsenic exposure, DNA damage, and the incidence of bladder and kidney cancers. A total of 788 participants aged ≥40 years were enrolled in a prospective cohort study in Taiwan between 1991 and 1994, with follow-up between 2011 and 2014. Well-water and first-morning spot urine samples were collected between 1991 and 1994 to estimate arsenic exposure, and the baseline urinary levels of 8-Oxo-2′-deoxyguanosine (8-OHdG) and N7-methylguanine (N7-MeG) were quantified to assess DNA lesions. The Cox proportional hazard model was used to estimate the effects of arsenic exposure and DNA adduct levels on the risk of bladder or kidney cancer. Urinary arsenic species were associated with significantly increased 8-OHdG and N7-MeG after adjusting for age, sex, and cigarette smoking. Only non-statistically significant mediation effects of 8-OHdG were observed. In a fully adjusted Cox model, participants with arsenic exposure and urinary 8-OHdG levels higher than the median had a higher risk of bladder cancer (HR = 4.60, confidence interval: 1.43–14.85). Overall, the combined effects of high cumulative arsenic exposure from artesian well-water and advanced DNA damage predicted the risk of bladder cancer.
•The subjects were followed for two decades in an arseniasis endemic area of northeastern Taiwan.•The urinary 8-OHdG and N7-MeG positively associated with cumulative well arsenic exposure.•Arsenic exposure and 8-OHdG have joint effects on risk of kidney/bladder cancer.
Abstract The ability to trace transplanted stem cells and monitor their tissue biodistribution is prerequisite to an understanding of cellular migration after transplantation. Therefore, a new ...magnetic resonance imaging (MRI) contrast agent made of gadolinium hexanedione nanoparticles (GdH-NPs) was developed as a cell tracking agent. The GdH-NPs were fabricated by the microemulsion process. The physical characteristics, biocompatibility, and T1-MRI signal enhancement of these NPs were analyzed and evaluated for stem cell tracking. In this study, the size of the synthesized GdH-NPs was about 140 nm, and it had greater image enhancement ability than commercial gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA). From the biocompability test, we found GdH-NPs were nontoxic for human mesenchymal stem cells (hMSCs). The expression of surface antigens of hMSCs after culture with GdH-NPs was examined, and it showed no difference from the control group. The results of transmission electron microscopy (TEM) imaging for labeled hMSCs showed GdH-NPs were accumulated in the cells by the endocytotic pathway. The accumulation of GdH-NPs in hMSCs was three times higher in comparison to Gd-DTPA. Human MSCs labeled with low concentration of GdH-NPs (10 μg/mL) hold better signals in cellular MR image. We conclude GdH-NPs can be used to label hMSCs in vitro with greater T1 image-enhancing property and without affecting cell quality. Finally, GdH-NPs have great potential as a contrast agent for stem cell tracking by MRI methodology.
This research discusses the wave propagation behavior and attenuation mechanism of the elastic metamaterial with locally resonant sub-structure. The dispersion relation of the single resonance ...system, i.e., periodic spring mass system with sub-structure, could be derived based on lattice dynamics and the band gap could be easily identified. The dynamically equivalent properties, i.e., mass and elastic property, of the single resonance system are derived and found to be frequency dependent. Negative effective properties are found in the vicinity of the local resonance. It is examined whether the band gap always coincides with the frequency range of negative effective properties. The wave attenuation mechanism and the characteristic dynamic behavior of the elastic metamaterial are also studied from the energy point of view. From the analysis, it is clarified that the coupled Bragg-resonance band gap is much wider than the narrow-banded local resonance and the corresponding effective material properties at band gap could be either positive or negative. However, the band gap is totally overlapping with the frequency range of negative effective properties for the metamaterial with band gap purely caused by local resonance. The presented analysis can be extended to other forms of elastic metamaterials involving periodic resonator structures.
Mutations in genes involved in the production, migration, or differentiation of cortical neurons often lead to malformations of cortical development (MCDs). However, many genetic mutations involved ...in MCD pathogenesis remain unidentified. Here we developed a genetic screening paradigm based on transposon-mediated somatic mutagenesis by in utero electroporation and the inability of mutant neuronal precursors to migrate to the cortex and identified 33 candidate MCD genes. Consistent with the screen, several genes have already been implicated in neural development and disorders. Functional disruption of the candidate genes by RNAi or CRISPR/Cas9 causes altered neuronal distributions that resemble human cortical dysplasia. To verify potential clinical relevance of these candidate genes, we analyzed somatic mutations in brain tissue from patients with focal cortical dysplasia and found that mutations are enriched in these candidate genes. These results demonstrate that this approach is able to identify potential mouse genes involved in cortical development and MCD pathogenesis.
Purpose
Positron emission tomography/computed tomography (PET/CT) is an important tool for tumor staging or treatment response evaluation, especially for lung tumors. However, the captured static PET ...image could be blurry due to patients' free breathing, resulting in decreased image quality and incorrect quantitative values. This study aimed to evaluate whether the Q.Static scan mode with the novel PET list data-driven gated (DDG) technique decreases the lesion blurring problems in the PET/CT images of patients with lung cancer.
Methods
Data of 194 patients with lung tumors were retrospectively reviewed. DDG Q.Static scan mode was set up in three beds to cover the whole chest and the upper abdomen in the routine PET/CT scans and was activated automatically when sensing significant respiratory motion. Routine reconstruction algorithm was applied for data analysis. Only the lesions in the motion-corrected areas were measured and calculated for statistics.
Results
Among the 194 patients, 124 had at least one bed that activated the DDG Q.Static procedure. However, only 49 out of the 124 patients showed lesions in their activated beds. Compared with the non-corrected data, the DDG Q.Static data showed improved accuracy with increased SUV
max
and SUV
mean
of 8.52% (9.20 ± 5.42 to 9.74 ± 5.42) and 8.65% (6.11 ± 3.68 to 6.48 ± 3.68), respectively. In addition, metabolic tumor volume was reduced from 6.54 ± 8.58 to 5.55 ± 7.33 (14.79% reduction). For subjective image quality, the DDG Q.Static data scored higher than the non-corrected data.
Conclusion
This study showed that the quantitative values and image quality were improved after the correction. Therefore, the DDG Q.Static technique is an effective method to correct motion artifacts in PET/CT scans.
To evaluate risk factors for epileptic seizures or status epilepticus (SE) in patients concomitantly receiving valproic acid (VPA) and carbapenems.
Adult patients in the intensive care units (ICUs) ...who concomitantly received VPA and carbapenems from 2007 to 2017 were included. The impacts of different carbapenems on serum concentration of VPA were compared.
Among 162 patients included, 104 (64.2%) and 45 (27.8%) developed epileptic seizures and SE, respectively. The risk factors for epileptic seizures were age (per year increase, adjusted odds ratio aOR, 1.03), initial antiepileptic regimen (monotherapy and polytherapy, aOR, 0.43 and 0.18, respectively), and VPA serum concentration after concomitant carbapenem administration (per 1 μg/mL increase, aOR, 0.96). VPA serum concentration after concomitant carbapenem administration was an independent risk factor for SE (per μg/mL increase, aOR, 0.98). Concomitant imipenem/cilastatin administration did not significantly decrease VPA serum concentration compared to that by meropenem or ertapenem. The length of stay and number of days on ventilation after concomitant carbapenem administration in the ICUs were significantly more in those with epileptic seizures or SE.
Carbapenems decreased VPA serum concentration and increased the risk of epileptic seizures and SE, which led to increased length of ICU stay.
•Decrease valproic acid concentrations concomitantly receiving carbapenems is known.•Varying effects of different carbapenems on valproic acid serum concentrations.•Imipenem/cilastatin has the least effect on serum valproic acid concentrations.•Therapeutic drug monitoring is needed, when initiating or discontinuing carbapenems.
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