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Bijangi-Vishehsaraei, K.; Reza Saadatzadeh, M.; Wang, H.; Nguyen, A.; Kamocka, M.M.; Cai, W.; Cohen-Gadol, A.A.; Halum, S.L.; Sarkaria, J.N.; Pollok, K.E.; Safa, A.R. |
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Title |
Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways |
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Journal Article |
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Year |
2017 |
Publication |
Journal of Neurosurgery |
Abbreviated Journal |
J Neurosurg |
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1-12 |
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CCCP = carbonyl cyanide m-chlorophenylhydrazone; DMSO = dimethyl sulfoxide; DSB = double-strand break; EGF = epidermal growth factor; FACS = fluorescence-activated cell sorting; FGF = fibroblast growth factor; GBM = glioblastoma; GSC = glioblastoma stem cell; IC50 = 50% inhibition of cell survival; MRC = mitochondrial respiratory chain; MSC = mesenchymal stromal cell; NAC = N-acetylcysteine; NSG = nonobese diabetic scid gamma; PE = phycoerythrin; ROS = reactive oxygen species; SFN = sulforaphane; SSB = single-strand break; apoptosis; cancer stem cells; glioblastoma; oncology; sulforaphane |
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Abstract |
OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)-a constituent of cruciferous vegetables with a multitargeted effect-as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of gamma-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell-induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10. CONCLUSIONS These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy. |
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Departments of 2 Pharmacology and Toxicology and |
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0022-3085 |
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PMID:28059653 |
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96613 |
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Klumpp, L.; Sezgin, E.C.; Skardelly, M.; Eckert, F.; Huber, S.M. |
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KCa3.1 channels and glioblastoma: in vitro studies |
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Journal Article |
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2017 |
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Current Neuropharmacology |
Abbreviated Journal |
Curr Neuropharmacol |
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γH2AX foci; Aldh1a3; Gbm; GSCs; IKCa; Kcnn4; Sk4; radioresistance |
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Several tumor entities including brain tumors aberrantly overexpress intermediate conductance Ca2+ activated KCa3.1 K+ channels. These channels contribute significantly to the transformed phenotype of the tumor cells. By modulating membrane potential, cell volume, Ca2+ signals and the respiration chain, KCa3.1 channels in both, plasma and inner mitochondrial membrane, have been demonstrated to regulate many cellular processes such as migration and tissue invasion, metastasis, cell cycle progression, oxygen consumption and metabolism, DNA damage response and cell death of cancer cells. Moreover, KCa3.1 channels have been shown to crucially contribute to resistance against radiotherapy suggesting KCa3.1 channels as promising new targets of future anti-cancer therapies. The present article summarizes our current knowledge of the molecular signaling upstream and downstream and the effector functions of KCa3.1 channel activity in tumor cells in general and in glioblastoma cells in particular. In addition, it presents original in vitro data on KCa3.1 channel expression in subtypes of glioblastoma stem(-like) cells proposing KCa3.1 as marker for the mesenchymal subgroup of cancer stem cells. Moreover, the data suggest that KCa3.1 contributes to the therapy resistance of mesenchymal glioblastoma stem cells. |
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Department of Radiation Oncology University of Tubingen Hoppe-Seyler-Str. 3 72076 Tubingen. Germany |
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1570-159X |
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PMID:28786347 |
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ref @ user @ |
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96571 |
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Piovezan, R.D.; Hirotsu, C.; Feres, M.C.; Cintra, F.D.; Andersen, M.L.; Tufik, S.; Poyares, D. |
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Title |
Obstructive sleep apnea and objective short sleep duration are independently associated with the risk of serum vitamin D deficiency |
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Journal Article |
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Year |
2017 |
Publication |
PloS one |
Abbreviated Journal |
PLoS One |
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12 |
Issue |
7 |
Pages |
e0180901 |
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Adult; African Continental Ancestry Group; Cross-Sectional Studies; Diabetes Mellitus/physiopathology; European Continental Ancestry Group; Female; Humans; Hypertension/physiopathology; Male; Middle Aged; Obesity/physiopathology; Polysomnography; Risk Factors; Sedentary Lifestyle; Severity of Illness Index; Sleep/physiology; Sleep Apnea, Obstructive/blood/*complications/ethnology/physiopathology; Sleep Wake Disorders/blood/*complications/ethnology/physiopathology; Smoking/physiopathology; Surveys and Questionnaires; Vitamin D/*blood; Vitamin D Deficiency/blood/*complications/ethnology/physiopathology |
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BACKGROUND: Studies demonstrate an association between vitamin D (25(OH)D) deficiency and sleep disturbances, such as obstructive sleep apnea (OSA) and short sleep duration. However, to date, no studies have concurrently and objectively evaluated the effect of these factors on 25(OH)D. OBJECTIVES: To evaluate whether OSA and objective short sleep duration are independently associated with reduced 25(OH)D in an adult population sample. METHODS: A cross-sectional study included 657 individuals from the city of Sao Paulo, Brazil, as part of the ERA project. Participants fulfilled questionnaires and underwent clinical evaluation, polysomnography and blood sample collection for 25(OH)D quantification. OSA was classified into three categories (mild, moderate and severe). The risk of 25(OH)D deficiency was considered as levels<30 ng/mL. Short sleep duration was defined as total sleep time<6 hours. RESULTS: The risk of 25(OH)D deficiency was observed in 59.5% of the sample, affecting more individuals of the female gender, obese, with African American ethnicity, and those that were smokers, sedentary and presented hypertension and diabetes. In the final logistic model adjusted for age, gender, ethnicity, obesity, smoking, hypertension, diabetes, sedentary lifestyle, seasonality and creatinine serum levels, both OSA and short sleep duration showed significant independent associations with the risk of 25(OH)D deficiency (moderate OSA: OR for 25(OH)D<30 = 2.21, 95% CI: 1.35-3.64, p<0.01; severe OSA: OR for 25(OH)D<30 = 1.78, 95% CI: 1.06-3.00, p = 0.03; short sleep duration: OR for 25(OH)D<30 = 1.61, 95% CI: 1.15-2.26, p = 0.01). After a subgroup analysis, similar results were observed only in participants >/=50 years. CONCLUSION: OSA and short sleep duration are independently associated with the risk of 25(OH)D deficiency in an adult population. Age-related changes in vitamin D metabolism and the frequency of sleep disorders may be involved in these associations. Future studies exploring whether 25(OH)D levels may modulate OSA and sleep curtailment-related outcomes are needed. |
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Department of Psychobiology, Universidade Federal de Sao Paulo, Sao Paulo, Sao Paulo, Brazil |
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1932-6203 |
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PMID:28686746 |
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ref @ user @ |
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98016 |
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Kane, S.P.; Hanes, S.D. |
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Unexplained increases in serum vancomycin concentration in a morbidly obese patient |
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Journal Article |
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Year |
2017 |
Publication |
Intensive & Critical Care Nursing |
Abbreviated Journal |
Intensive Crit Care Nurs |
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39 |
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55-58 |
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Anti-Bacterial Agents/administration & dosage/therapeutic use; Cross Reactions/physiology; Drug-Related Side Effects and Adverse Reactions/*physiopathology; Female; Humans; Middle Aged; Obesity, Morbid/*drug therapy/physiopathology; Pneumonia, Ventilator-Associated/drug therapy/prevention & control; Vancomycin/*administration & dosage/therapeutic use; Central venous catheters; Critical care; Drug monitoring; Infectious disease; Medication safety; Vancomycin |
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INTRODUCTION: To report a case of increases in vancomycin concentrations without additional vancomycin doses being given. CASE STUDY: A 64 year-old morbidly obese female received three total doses of vancomycin for surgical prophylaxis and for ventilator-associated pneumonia. Subsequent vancomycin concentrations from the patient's central venous catheter (CVC) demonstrated increasing drug levels from 27.1 to 45.9mcg/mL despite no additional vancomycin being given and proper line flushing prior to sample collection. There is no clear explanation for the increase in the patient's vancomycin concentration. Drug leaching from the CVC, enterohepatic recycling, drug redistribution from adipose or other tissues, and assay cross-reactivity with other medications are all potential explanations for the increased vancomycin concentrations. CONCLUSION: This case report describes an unexplained increase in vancomycin concentrations and reinforces both the fallibility of laboratory testing and that unusual circumstances do occur. Several potential causes are hypothesised with CVC drug leaching being the most likely. Nurses and other healthcare providers with similar scenarios should consider a peripheral blood sample to rule out the potential for CVC drug leaching as a possible explanation. |
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Department of Pharmacy Practice, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States. Electronic address: scott.hanes@rosalindfranklin.edu |
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0964-3397 |
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PMID:27899248 |
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ref @ user @ |
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98971 |
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Author |
Kane, S.P.; Hanes, S.D. |
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Title |
Unexplained increases in serum vancomycin concentration in a morbidly obese patient |
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Journal Article |
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Year |
2017 |
Publication |
Intensive & Critical Care Nursing |
Abbreviated Journal |
Intensive Crit Care Nurs |
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39 |
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55-58 |
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Anti-Bacterial Agents/administration & dosage/therapeutic use; Cross Reactions/physiology; Drug-Related Side Effects and Adverse Reactions/*physiopathology; Female; Humans; Middle Aged; Obesity, Morbid/*drug therapy/physiopathology; Pneumonia, Ventilator-Associated/drug therapy/prevention & control; Vancomycin/*administration & dosage/therapeutic use; Central venous catheters; Critical care; Drug monitoring; Infectious disease; Medication safety; Vancomycin |
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INTRODUCTION: To report a case of increases in vancomycin concentrations without additional vancomycin doses being given. CASE STUDY: A 64 year-old morbidly obese female received three total doses of vancomycin for surgical prophylaxis and for ventilator-associated pneumonia. Subsequent vancomycin concentrations from the patient's central venous catheter (CVC) demonstrated increasing drug levels from 27.1 to 45.9mcg/mL despite no additional vancomycin being given and proper line flushing prior to sample collection. There is no clear explanation for the increase in the patient's vancomycin concentration. Drug leaching from the CVC, enterohepatic recycling, drug redistribution from adipose or other tissues, and assay cross-reactivity with other medications are all potential explanations for the increased vancomycin concentrations. CONCLUSION: This case report describes an unexplained increase in vancomycin concentrations and reinforces both the fallibility of laboratory testing and that unusual circumstances do occur. Several potential causes are hypothesised with CVC drug leaching being the most likely. Nurses and other healthcare providers with similar scenarios should consider a peripheral blood sample to rule out the potential for CVC drug leaching as a possible explanation. |
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Department of Pharmacy Practice, Rosalind Franklin University of Medicine and Science, North Chicago, IL, United States. Electronic address: scott.hanes@rosalindfranklin.edu |
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0964-3397 |
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PMID:27899248 |
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ref @ user @ |
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100001 |
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