The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis

BACKGROUND: Patients with ER-negative breast tumors are among the most difficult to treat and exhibit low survival rates due, in part, to metastasis from the breast to various distal sites. Aryl hydrocarbon receptor (AHR) ligands show promise as antimetastatic drugs for estrogen receptor (ER)-negative breast cancer. METHODS: Triple negative MDA-MB-231 breast cancer cells were treated with eight AHR-active pharmaceuticals including 4-hydroxtamoxifen, flutamide leflunomide, mexiletine, nimodipine, omeprazole, sulindac and tranilast, and the effects of these compounds on cell proliferation (MTT assay) and cell migration (Boyden chamber assay) were examined. The role of the AHR in mediating inhibition of MDA-MB-231 cell invasion was investigated by RNA interference (RNAi) and knockdown of AHR or cotreatment with AHR agonists. Lung metastasis of MDA-MB-231 cells was evaluated in mice administered cells by tail vein injection and prometastatic gene expression was examined by immunohistochemistry. RESULTS: We showed that only the proton pump inhibitor omeprazole decreased MDA-MB-231 breast cancer cell invasion in vitro. Omeprazole also significantly decreased MDA-MB-231 cancer cell metastasis to the lung in a mouse model (tail vein injection), and in vitro studies showed that omeprazole decreased expression of at least two prometastatic genes, namely matrix metalloproteinase-9 (MMP-9) and C-X-C chemokine receptor 4 (CXCR4). Results of RNA interference studies confirmed that omeprazole-mediated downregulation of CXCR4 (but not MMP-9) was AHR-dependent. Chromatin immunoprecipitation assays demonstrated that omeprazole recruited the AHR to regions in the CXCR4 promoter that contain dioxin response elements (DREs) and this was accompanied by the loss of pol II on the promoter and decreased expression of CXCR4. CONCLUSIONS: AHR-active pharmaceuticals such as omeprazole that decrease breast cancer cell invasion and metastasis may have important clinical applications for late stage breast cancer chemotherapy

A case of diabetic ketoacidosis with posterior cerebral artery territory ischemic stroke mimicking uncal herniation

In diabetic ketoacidosis, hyperglycemia and ketosis result in cerebral vasculitis, which can cause cerebral edema and thrombosis. A previously healthy, 12-year-old girl visited the emergency department with a history of vomiting, polydipsia, polyuria, decreased mentality, and a 7 kg (12%) weight loss within 1 week. She showed laboratory features of severe diabetic ketoacidosis, stuporous mentality, respiratory failure, and unilateral fixed mydriasis with contralateral hemiparesis. However, brain magnetic resonance imaging showed multifocal ischemic stroke mainly involving the left posterior cerebral artery territory, instead of uncal herniation. This case highlights the possible occurrence of ischemic stroke in children with early-stage diabetes mellitus

Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma

The orphan nuclear receptor NR4A1 exhibits pro-oncogenic activity in cancer cell lines. NR4A1 activates mTOR signaling, regulates genes such as thioredoxin domain containing 5 and isocitrate dehydrogenase 1 that maintain low oxidative stress, and coactivates specificity protein 1 (Sp1)-regulated pro-survival and growth promoting genes. Transfection of renal cell carcinoma (RCC) ACHN and 786-O cells with oligonucleotides that target NR4A1 results in a 40-60% decrease in cell proliferation and induction of apoptosis. Moreover, knockdown of NR4A1 in RCC cells decreased bcl-2, survivin and epidermal growth factor receptor expression, inhibited of mTOR signaling, induced oxidative and endoplasmic reticulum stress, and decreased TXNDC5 and IDH1. We have recently demonstrated that selected 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compounds including the p-hydroxyphenyl (DIM-C-pPhOH) and p-carboxymethyl (DIM-C-pPhCO2Me) analogs bind NR4A1 and act as antagonists. Both DIM-C-pPhOH and DIM-C-pPhCO2Me inhibited growth and induced apoptosis in ACHN and 786-O cells, and the functional and genomic effects of the NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. These results indicate that NR4A1 antagonists target multiple growth promoting and pro-survival pathways in RCC cells and in tumors (xenograft) and represent a novel chemotherapy for treating RCC

Mechanism of Action of Phenethylisothiocyanate and Other Reactive Oxygen Species-Inducing Anticancer Agents

Reactive oxygen species (ROS)-inducing anticancer agents such as phenethylisothiocyanate (PEITC) activate stress pathways for killing cancer cells. Here we demonstrate that PEITC-induced ROS decreased expression of microRNA 27a (miR-27a)/miR-20a:miR-17-5p and induced miR-regulated ZBTB10/ZBTB4 and ZBTB34 transcriptional repressors, which, in turn, downregulate specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells. Decreased expression of miR-27a/miR-20a:miR-17-5p by PEITC-induced ROS is a key step in triggering the miR-ZBTB Sp cascade leading to downregulation of Sp TFs, and this is due to ROS-dependent epigenetic effects associated with genome-wide shifts in repressor complexes, resulting in decreased expression of Myc and the Myc-regulated miRs. Knockdown of Sp1 alone by RNA interference also induced apoptosis and decreased pancreatic cancer cell growth and invasion, indicating that downregulation of Sp transcription factors is an important common mechanism of action for PEITC and other ROS-inducing anticancer agents

Relationships among Disability, Quality of Life, and Physical Fitness in Lumbar Spinal Stenosis: An Investigation of Elderly Korean Women

Study DesignA cross-sectional, case-control study.PurposeTo investigate associations between physical fitness measures and disabilities related to back pain and quality of life (QOL) by the presence of symptomatic lumbar spinal stenosis (LSS) in elderly Korean women.Overview of LiteratureLSS leads to decreased functioning and reduced QOL. However, correlations among physical fitness, disability, and QOL have not been investigated in elderly women with LSS.MethodsParticipants included women aged 65 years and older (n=192), divided into a study group (n=38) and a control group (n=154) based on the presence/absence of LSS. All participants underwent physical function and fitness tests. Oswestry disability index (ODI) scores and EuroQol five-dimensional questionnaire (EQ-5D-5L) scores were used to assess disability and health-related QOL.ResultsThe results for the handgrip strength, sit-and-reach, functional reach, and timed up and go (TUG) tests were significantly higher in the control group than the LSS group. ODI scores were significantly higher and EQ-5D-5L scores significantly lower in the LSS group. TUG and functional reach test scores were significantly correlated with ODI scores, and handgrip strength was strongly interrelated with ODI and EQ-5D-5L scores in the LSS group. No other physical fitness measures showed statistically significant relationships with ODI or EQ-5D-5L scores.ConclusionsIn elderly Korean women with LSS, back pain-related disability and QOL are significantly associated with some physical fitness parameters such as handgrip strength. Handgrip strength reflects general muscle strength, which is significantly interrelated with the level of disability and QOL. Our results suggest that enhancing generalized muscle strength helps to reduce disability due to back pain and improve QOL in patients with LSS

Definitions of unfavorable surgical outcomes and their risk factors based on disability score after spine surgery for lumbar spinal stenosis

Risk factors for unfavorable surgical outcomes are dependent on the definitions of the unfavorable surgical outcomes. The aims of this study were to compare risk factors for each unfavorable surgical outcome according to two different definitions of unfavorable surgical outcomes after surgery for lumbar spinal stenosis (LSS) as well as compare the clinical course from the preoperative period to 3 years postoperatively between cases with favorable and unfavorable outcomes according to the two different definitions. Overall, 295 patients who underwent spine surgery for LSS and a follow-up evaluation at 3 years postoperatively were enrolled and divided into favorable and unfavorable groups, based on two different definitions for unfavorable surgical outcomes, as evaluated at 12 months postoperatively: the patient-reported outcome (PRO) and minimal clinically important difference (MCID) methods. In the PRO method, patients with a postoperative Oswestry Disability Index (ODI) score > 22 were considered as having an unfavorable outcome, whereas in the MCID method, those with a postoperative ODI score that changed < 12.8 points from the preoperative value were classified as having an unfavorable outcome. As a primary outcome, risk factors for unfavorable surgical outcomes according to each definition were investigated at 12 months postoperatively. In the PRO method, female sex (P = 0.011; odds ratio (OR): 2.340), elementary school attainment (vs. university attainment; P = 0.035; OR: 2.875), and higher preoperative ODI score (P = 0.028; OR: 2.340) were associated with higher odds for an unfavorable surgical outcome. In the MCID method, a higher preoperative ODI score was associated with higher odds (P < 0.001; OR: 0.920) of a favorable surgical outcome. In the PRO method, the favorable outcome group demonstrated significantly lower visual analog scale for back and leg pain and lower ODI scores than the unfavorable outcome group at 3 years postoperatively, whereas in the MCID method, clinical outcomes were not different between the two groups at 3 years postoperatively. A higher preoperative ODI score may be a risk factor for postoperative ODI > 22 after surgery for LSS. It may also be associated with higher odds for improvements in the ODI score of > 12.8.This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2016R1A2B3012850)

Does gender influence the impact of impaired renal function on prognosis after ST-segment elevated myocardial infarction?

Background: A limited number of studies have investigated the impact of gender on renal function and clinical outcomes after ST-segment elevated myocardial infarction (STEMI), and these studies have provided discrepant results.Methods and Results: This study was based on a retrospective cohort, the Korean Acute Myocardial Infarction Registry (KAMIR). Patients (n = 7,679) with a discharge diagnosis of STEMI were analyzed to investigate association of gender with renal function and clinical outcomes. Compared to men, women were older and exhibited more comorbidity, including impaired renal function. Women showed higher mortality compared to men (1-month mortality,5.6% in men vs. 12.6% in women, p &lt; 0.001; 1-year mortality, 6.8% in men vs. 14.4% in women, p &lt; 0.001). The risk of death proportionally increased as estimated glomerular filtration rate (eGFR) decreased in both genders. After adjusting for potential confounders, hazard ratios for women did not significantly differ from those for men at each eGFR level.The interaction test showed no significant interaction between gender and eGFR in 1-month mortality and 1-year mortality.Conclusions: Impaired renal function was an independent prognostic factor after STEMI in both genders, and the impact of impaired renal function on prognosis after STEMI did not significantly differ between genders

A Novel Biomarker of Coronary Atherosclerosis: Serum DKK1 Concentration Correlates with Coronary Artery Calcification and Atherosclerotic Plaques

DKK1 modulates Wnt signaling, which is involved in the atherosclerosis. However, no data exist regarding the usefulness of measuring serum DKK1 concentration in predicting coronary atherosclerosis. A total of 270 consecutive patients (62.8 ± 11.2 yr; 70% male) were included. A contrast-enhanced 64-slice coronary MDCT was performed to identify the presence of atherosclerotic plaques. Agatston calcium scores (CS) were calculated to quantify the coronary artery calcification (CAC). DKK1 concentrations were measured by enzyme-linked immunosorbent assay. For each subsequent DKK1 quartile, there was a significant increase in CAC (P = 0.004) and the number of segments with coronary atherosclerosis (P < 0.001). In addition, DKK1 concentration was significantly higher in patients with atherosclerotic plaques, regardless of plaque composition (P = 0.01). Multivariate analysis identified DKK1 as an independent risk factor for the presence of coronary atherosclerotic plaque. The adjusted odds ratio for coronary atherosclerotic plaque was 4.88 (95% CI, 1.67 to 14.25) for highest versus lowest quartile of the DKK1 levels. Furthermore, patients with DKK1 concentrations ≥ 68.6 pg/mL demonstrated coronary atherosclerotic plaques even when they had low CS. Serum DKK1 concentrations correlate with the coronary atherosclerosis and play an independent role in predicting the presence of coronary atherosclerosis