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1.
Eur J Prosthodont Restor Dent ; 31(3): 254-261, 2023 Aug 31.
Article in English | MEDLINE | ID: mdl-36927605

ABSTRACT

To evaluate the ethanol wet-bonding protocol with a universal adhesive in etch-andrinse and self-etch modes on microleakage and microtensile bond strength (µTBS) of resin composite to different dentin depth. Molars were distributed into groups according to protocol and dentin depth: universal adhesive (C - control), ethanol + universal adhesive (E), and phosphoric acid etch + ethanol + universal adhesive (PA+E). All protocols were applied to dentin at superficial, middle and deep depths. The specimens (n = 10) were submitted to microleakage and µTBS tests. Half of specimens were submitted to thermocycling (10,000 cycles; 5∘C/55∘C). Data were submitted to Spearman correlation (µTBS x microleakage) and three-way ANOVA (protocol, aging and depth), followed by Bonferroni post hoc test (α=0.05). PA+E group showed highest µTBS and lowest microleakage mean values in 24h. All groups presented similar µTBS mean values after thermocycling. The deep dentin showed less stable µTBS results. PA+E group presented highest microleakage mean values after thermocycling. Spearman's correlation showed a strong correlation between microleakage and µTBS. The PA+E group improved immediate adhesion and E group promoted a more stable µTBS in the long-term adhesion of universal adhesive. The aging for all protocols jeopardized the stability of the hybrid layer. The ethanol wet bonding technique associated with universal adhesive has enhanced the immediate result of the resin composite adhesion.


Subject(s)
Dental Bonding , Dental Cements , Dental Cements/pharmacology , Dentin-Bonding Agents/chemistry , Dental Bonding/methods , Resin Cements/chemistry , Tensile Strength , Dentin , Composite Resins/chemistry , Materials Testing
2.
Reprod Domest Anim ; 48(6): 984-8, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23782220

ABSTRACT

The main objective of this study was to determine if administration of meloxicam, a cyclooxygenase (COX) two inhibitor, to heifers in which embryo transfer (ET) is more difficult and requires a greater manipulation of the tract, would be beneficial. Nulliparous recipient heifers were divided in two groups: CON (n = 102), in which animals received 10 ml of saline IM (the same volume of meloxicam) and MEL (n = 105) animals that were treated with meloxicam. According to the degree in passing the catheter, recipients from both groups were classified as Grade I, easy (< 60 s), and Grade II (more than 80 s), difficult. Immediately after embryo transfer, MEL recipients received an injection of 200 mg of meloxicam (10 ml).There was no difference in the pregnancy rates on Day 35 considering animals which presented Grade I cervix independently whether the treatment was performed or not (p = 0.22). There was a statistical difference in the pregnancy rates (p < 0.01) between both groups (49.0% and 66.7% for CON and MEL, respectively) when cervical grade was not considered, on Day 35. Considering the animals that presented Grade II cervix, the pregnancy rate was higher for MEL (21.15% and 78.84%, respectively) in both examinations (p < 0.01).The authors concluded that meloxicam had a positive influence on general pregnancy rate of treated heifers in comparison to non-treated heifers. It was also observed that pregnancy rate was not influenced by meloxicam administration in Grade I heifers. Treatment increased the pregnancy rate of Grade II heifers.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cattle/physiology , Embryo Transfer/veterinary , Fertilization in Vitro/veterinary , Thiazines/pharmacology , Thiazoles/pharmacology , Animals , Embryo Culture Techniques/veterinary , Female , Meloxicam , Pregnancy
3.
Oper Dent ; 37(4): 386-96, 2012.
Article in English | MEDLINE | ID: mdl-22335305

ABSTRACT

This study evaluated the effect of dentin pretreatment with 2% chlorhexidine (CHX) or 24% ethylenediamine tetra-acetic acid gel (EDTA) on the dentin microtensile bond strength (µTBS) of resin cements. Composite blocks were luted to superficial noncarious human dentin (n=10) using two resin cements (RelyX ARC [ARC] and RelyX U100 [U100]) and three dentin pretreatments (without pretreatment-control, CHX, and EDTA). CHX was applied for 60 seconds on the acid-etched dentin in the ARC/CHX group, and for the same time on smear layer-covered dentin in the U100/CHX group. EDTA was applied for 45 seconds on smear-covered dentin in the U100/EDTA group, and it replaced phosphoric acid conditioning in the ARC/EDTA group for 60 seconds. After storage in water for 24 hours, specimens were prepared for microtensile bond strength testing. The results were submitted to two-way analysis of variance (ANOVA) followed by Tukey test. ARC produced significantly higher µTBS (p<0.05) compared to the U100, except when EDTA was used. For ARC, no pretreatment and CHX produced higher µTBS than EDTA. For U100, EDTA produced higher µTBS; no statistical difference occurred between CHX pretreatment and when no pretreatment was performed. While CHX did not affect immediate dentin bond strength of both cements, EDTA improved bond strength of U100, but it reduced dentin bond strength of ARC.


Subject(s)
Chlorhexidine/chemistry , Dental Bonding , Dentin/ultrastructure , Edetic Acid/chemistry , Matrix Metalloproteinase Inhibitors , Resin Cements/chemistry , Acid Etching, Dental/methods , Bisphenol A-Glycidyl Methacrylate/chemistry , Composite Resins/chemistry , Dental Stress Analysis/instrumentation , Humans , Materials Testing , Methacrylates/chemistry , Microscopy, Electron, Scanning , Polyethylene Glycols/chemistry , Polymethacrylic Acids/chemistry , Smear Layer , Stress, Mechanical , Surface Properties , Tensile Strength , Time Factors , Water/chemistry
4.
Neurosci Lett ; 714: 134560, 2020 01 01.
Article in English | MEDLINE | ID: mdl-31622649

ABSTRACT

INTRODUCTION: Ketamine (KET) is an anesthetic agent widely used in human and veterinary medicine. According to studies, KET is associated to direct neutorotoxic damages due to its capacity to induce oxidative stress. Because of the free radical generation in the organism and its relation with diseases' development, there is a growing interest to study antioxidant molecules, such as gallic acid (GA), a natural phenolic compound. AIM: Evaluate the GA antioxidant potential for the prevention of oxidative damage in the brain and liver tissue of rats exposed to acute KET administration. MATERIAL AND METHODS: 32 Wistar male rats received GA (by gavage, 13.5 mg/kg) for three consecutive days, 24 h after the last GA dose, animals were anesthetized with KET (50 mg/kg, i.m.). All animals were euthanized by decapitation 60 min after KET administration. The liver, brain cortex and hippocampus were removed and homogenized for biochemical analysis. RESULTS: In brain cortex, KET increased reactive species (RS) generation, protein carbonyls (PC) levels and reduced non-protein thiols (NPSH) levels, while GA pre-treatment reduced PC and increased NPSH levels. KET increased PC and decreased NPSH levels in the hippocampus, and GA reduced PC and NPSH levels. In the liver, no difference was observed in the RS generation, while KET induced and increase of PC levels and decreased NPSH levels, while GA pre-treatment prevented it. CONCLUSION: GA administration can prevent oxidative damage caused by acute KET administration and minimize its noxious effects. Further studies are needed to evidence GA antioxidant properties regarding KET chronic use.


Subject(s)
Anesthetics, Dissociative/toxicity , Cerebral Cortex/drug effects , Gallic Acid/pharmacology , Hippocampus/drug effects , Ketamine/toxicity , Liver/drug effects , Oxidative Stress/drug effects , Reactive Oxygen Species/metabolism , Animals , Brain/drug effects , Brain/metabolism , Cerebral Cortex/metabolism , Hippocampus/metabolism , Lipid Peroxidation/drug effects , Liver/metabolism , Male , Protein Carbonylation/drug effects , Rats , Rats, Wistar , Sulfhydryl Compounds/metabolism , Thiobarbituric Acid Reactive Substances/metabolism
5.
Reprod Domest Anim ; 44 Suppl 2: 251-4, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19754580

ABSTRACT

The present study describes the ultrastructural characteristics of cat oocytes before maturation and after 12- and 24-h in vitro maturation (IVM). Oocytes were recovered from pre-pubertal and adult queen ovaries after ovariohysterectomy and a proportion were stored in glutaraldehyde at 4 degrees C until examination by transmission electronic microscopy (TEM). Those selected for maturation were cultured before TEM in DMEM for 12 and 24 h at 38 degrees C in a humidified environment of 5% O(2), 5% CO(2) and 90% N(2). Specimens were divided into six groups: non-matured oocytes from pre-pubertal queens (PP0), non-matured oocytes from adult queens (A0), 12-h in vitro matured oocytes from pre-pubertal queens (PP12), 12-h in vitro matured oocytes from adult queens (A12), 24-h in vitro matured oocytes from pre-pubertal queens (PP24) and 24-h in vitro matured oocytes from adult queens (A24). Across the treatment groups, it was possible to observe differences in the thickness of the perivitelline space, the penetration of cumulus cell projections forming a junctional complex, distribution and density of small vesicles, lipid droplets, microvilli, mitochondria and cortical granules and variable degrees of development of Golgi complexes. These findings demonstrated that ultrastructural analysis of oocytes matured in vitro is a valuable tool to evaluate oocyte cytoplasmic maturation and that this IVM protocol was efficient in inducing gradual morphological changes necessary for cytoplasmic maturation of pre-pubertal and adult cat oocytes.


Subject(s)
Cats , Oocytes/ultrastructure , Ovary/physiology , Animals , Cells, Cultured , Female , Granulosa Cells/ultrastructure , Sexual Maturation
6.
Braz J Microbiol ; 40(2): 367-72, 2009 Apr.
Article in English | MEDLINE | ID: mdl-24031374

ABSTRACT

A comparative study on the potential of some biological agents to perform the hydrolysis of stevioside was carried out, aiming at establishing an alternative methodology to achieve the aglycon steviol or its rearranged derivative isosteviol, in high yields to be used in the preparation of novel bioactive compounds. Hydrolysis reactions were performed by using filamentous fungi (Aspergillus niger, Rhizopus stolonifer and Rhizopus arrhizus), a yeast (Saccharomyces cerevisiae) and enzymes (pancreatin and lipases PL250 and VFL 8000). Pancreatin showed the best hydrolytic activity, furnishing isosteviol at 93.9% of yield, at pH 4.0, using toluene as a co-solvent. Steviol was produced using both pancreatin at pH 7.0 (20.2% yield) and A. niger at pH 7 (20.8% yield).

7.
Int Endod J ; 41(6): 476-84, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18355254

ABSTRACT

AIM: To test the hypothesis that the composition of endodontic sealer cements and the time elapsed between root filling and fibreglass post fixation interferes with adhesion to root canal dentine. METHODOLOGY: Sixty bovine incisor roots were divided into five groups (n = 12): CI, unfilled; SI, filled with a calcium hydroxide-based cement-Sealer 26, and immediate post fixation; S7, Sealer 26 and post fixation after 7 days; EI, filled with a zinc oxide and eugenol-based cement-Endofill and immediate fixation; and E7 Endofill and post fixation after 7 days. The posts were cemented with adhesive system and dual resin cement. Ten roots were cross-sectioned to obtain two 1-mm-thick discs for each cervical (TC), middle (TM) and apical (TA) third of the prepared root portion. The posts were submitted to a micropush-out test. The other two teeth were evaluated using scanning electron microscopy to analyse the bond interface. Data were analysed using anova, Tukey and Dunnett tests (P < 0.05). RESULTS: Group EI was associated with a significant reduction in bond strength values irrespective of the root region; TC = 3.50 MPa (P = 0.0001); TM = 2.22 MPa (P = 0.0043) and TA = 1.45 MPa (P = 0.003). Region of canal had an influence on the values for the cement used in group E7, in which only the TA presented differences from the CI. CONCLUSIONS: Endofill interfered negatively with the bond to root dentine along its full length and in the TA when post fixation was delayed for 7 days. Bond strength decreased from crown to apex in all groups.


Subject(s)
Dental Cements/chemistry , Dental Marginal Adaptation , Dentin/drug effects , Post and Core Technique , Root Canal Filling Materials/chemistry , Root Canal Obturation/methods , Animals , Bismuth/chemistry , Bismuth/therapeutic use , Calcium Hydroxide/chemistry , Calcium Hydroxide/therapeutic use , Cattle , Dental Bonding/methods , Dental Prosthesis Retention/methods , Dental Stress Analysis , Drug Interactions , Glass/chemistry , In Vitro Techniques , Incisor , Resin Cements/chemistry , Resin Cements/therapeutic use , Root Canal Filling Materials/therapeutic use , Stress, Mechanical , Surface Properties , Time Factors , Tooth Root/drug effects , Zinc Oxide-Eugenol Cement/chemistry , Zinc Oxide-Eugenol Cement/therapeutic use
8.
Vet J ; 240: 27-30, 2018 Oct.
Article in English | MEDLINE | ID: mdl-30268329

ABSTRACT

This study evaluated the variability of the peripheral perfusion index (PI) in 22 anaesthetised female dogs undergoing elective ovariohysterectomy and examined the relationship between peripheral PI and heart rate, blood pressure, blood pH, end tidal CO2 (EtCO2), O2 saturation (SpO2), core-peripheral temperature gradient (ΔTc-p), partial pressure of CO2 (PCO2), and concentrations of glucose, cortisol, lactate and bicarbonate (HCO3-). Blood pH, lactate and glucose concentrations were determined 15, 30, 45min into the ovariohysterectomy procedure and after extubation. Cortisol concentrations were assessed before anaesthesia and after extubation. Other variables were recorded at every 5min throughout the ovariohysterectomy procedure. Hyperglycaemia was observed in 59% of bitches during surgery, but serum cortisol concentrations remained unchanged. Most measures of perfusion (ΔTc-p, pH, PCO2, EtCO2, SpO2) and heart rate remained unchanged throughout anaesthesia and did not correlate with peripheral PI. Mean arterial pressure increased during the ovariohysterectomy procedure, while peripheral PI decreased, resulting in negative correlations between these variables at 30 and 45min. Lactate concentrations decreased from baseline to the time of measurement post-extubation. Peripheral PI gradually decreased during the ovariohysterectomy procedure, probably reflecting vasoconstriction induced by nociceptive stimuli. Using lactate concentrations as the reference standard for peripheral perfusion, low peripheral PI in healthy bitches undergoing ovariohysterectomy might not represent peripheral hypoperfusion.


Subject(s)
Blood Circulation/physiology , Dogs/physiology , Elective Surgical Procedures/veterinary , Hysterectomy/veterinary , Ovariectomy/veterinary , Anesthesia/veterinary , Animals , Female , Reproducibility of Results
9.
Oncogene ; 34(23): 2978-90, 2015 Jun 04.
Article in English | MEDLINE | ID: mdl-25132270

ABSTRACT

Checkpoint kinase 1 (CHK1) is a key component of the ATR (ataxia telangiectasia-mutated and Rad3-related)-dependent DNA damage response pathway that protect cells from replication stress, a cell intrinsic phenomenon enhanced by oncogenic transformation. Here, we show that CHK1 is overexpressed and hyperactivated in T-cell acute lymphoblastic leukemia (T-ALL). CHEK1 mRNA is highly abundant in patients of the proliferative T-ALL subgroup and leukemia cells exhibit constitutively elevated levels of the replication stress marker phospho-RPA32 and the DNA damage marker γH2AX. Importantly, pharmacologic inhibition of CHK1 using PF-004777736 or CHK1 short hairpin RNA-mediated silencing impairs T-ALL cell proliferation and viability. CHK1 inactivation results in the accumulation of cells with incompletely replicated DNA, ensuing DNA damage, ATM/CHK2 activation and subsequent ATM- and caspase-3-dependent apoptosis. In contrast to normal thymocytes, primary T-ALL cells are sensitive to therapeutic doses of PF-004777736, even in the presence of stromal or interleukin-7 survival signals. Moreover, CHK1 inhibition significantly delays in vivo growth of xenotransplanted T-ALL tumors. We conclude that CHK1 is critical for T-ALL proliferation and viability by downmodulating replication stress and preventing ATM/caspase-3-dependent cell death. Pharmacologic inhibition of CHK1 may be a promising therapeutic alternative for T-ALL treatment.


Subject(s)
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Protein Kinases/genetics , Protein Kinases/metabolism , Animals , Ataxia Telangiectasia Mutated Proteins/metabolism , Benzodiazepinones/administration & dosage , Benzodiazepinones/pharmacology , Caspase 3/metabolism , Cell Cycle , Cell Line, Tumor , Cell Proliferation , Cell Survival , Checkpoint Kinase 1 , DNA Damage , DNA Replication , Gene Knockdown Techniques , Humans , Mice , Neoplasm Transplantation , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Pyrazoles/administration & dosage , Pyrazoles/pharmacology , Thymocytes/metabolism
10.
J Clin Densitom ; 3(4): 391-3, 2000.
Article in English | MEDLINE | ID: mdl-11175920

ABSTRACT

Conditions and artifacts such as aortic calcification, osteophytes, hip prostheses, and metallic objects can mislead the results of dual energy X-ray absorptiometry (DXA) scanning of the spine and hip. Gluteal silicon implants increasingly are being used for aesthetic purposes by women in Brazil, some of whom are at an age of high risk for the development of postmenopausal osteoporosis. We herein report a case of a woman whose hip bone mineral density by DXA clearly increased after the placement of bilateral gluteal implants of silicon. This case demonstrates the importance of inquiring about the presence of this artifact to avoid unnecessary evaluation of hip bone densitometry in these situations.


Subject(s)
Bone Density , Hip/physiology , Prostheses and Implants , Silicone Elastomers , Absorptiometry, Photon , Adult , Buttocks , Female , Humans
11.
Nucl Med Commun ; 6(7): 389-95, 1985 Jul.
Article in English | MEDLINE | ID: mdl-3900831

ABSTRACT

A new technique for lung inhalation scintigraphy is reported, developing a new aerosol system, based on the original system of Taplin [1]. With two small compact polypropylene reservoirs, this 99Tcm DTPA technique allowed continuous breathing during the inhalation period. This system proved to be a useful alternative to that using radioactive gases and the system of Taplin, due to its low cost and the ease with which several projections may be obtained.


Subject(s)
Lung/diagnostic imaging , Adult , Aerosols , Humans , Methods , Pentetic Acid/administration & dosage , Radionuclide Imaging , Technetium/administration & dosage , Technetium Tc 99m Pentetate
12.
J Adhes Dent ; 3(4): 315-24, 2001.
Article in English | MEDLINE | ID: mdl-11893047

ABSTRACT

PURPOSE: To determine the correlation between the tubule density (TD) and the area occupied by solid dentin (ASD) with the bond strength of one conventional and one self-etching adhesive system to dentin. MATERIALS AND METHODS: The crown of extracted human third molars was transversally sectioned with a diamond saw to expose either superficial, middle, or deep dentin. The three groups of dentin surfaces were randomly divided and bonded with either Clearfil Liner Bond 2V (LB) or Prime & Bond 2.1 (PB) adhesive systems according to manufacturer's directions. Resin composite buildup crowns (10.0 mm high) were incrementally constructed on the bonded surfaces and the teeth stored in water at 37 degrees C. After 24 h of storage, the teeth were vertically, serially sectioned in both x and y directions to obtain several bonded sticks of approximately 0.7 mm2 cross-sectional area. Each stick was tested in tension in a EMIC DL-500 tester at 0.5 mm/min until failure. After testing, the dentin side of the fractured specimen was gently abraded with a 1000-grit SiC paper, etched with 37% phosphoric acid for 15 s and allowed to air dry. SEM micrographs at 1000x and 4000x magnification were taken to permit calculation of the TD (number of tubules/mm2) and ASD (% of total area) at the site of fracture. Correlation between TD and ASD with the bond strength data was performed by linear regression. All statistical analysis was done with alpha = 0.05. RESULTS: Overall bond strength (MPa) for LB was 26.0 +/- 10.2, and 42.6 +/- 15.2 for PB. There was a significant direct relationship between bond strength and ASD for both materials (r2 = 0.20, p < 0.05 and r2 = 0.66, p < 0.01, respectively for LB and PB). PB bond strength dropped significantly as the TD increased (r2 = 0.63, p < 0.05), while LB was not sensitive to TD (r2 = 0.05, p > 0.05). Mean bond strength of PB was significantly higher than LB for both superficial and middle dentin (p < 0.05), while there was no significant difference for deep dentin (p > 0.05). CONCLUSION: Regional variations in TD and ASD may modify bond strength of both conventional and self-etching adhesive systems. Bonding sites with larger ASD seem to yield higher bond strengths regardless of the type of adhesive system used.


Subject(s)
Dental Bonding , Dentin-Bonding Agents/chemistry , Dentin/ultrastructure , Silicon Dioxide , Zirconium , Acetone/chemistry , Acid Etching, Dental , Analysis of Variance , Carbon Compounds, Inorganic , Composite Resins/chemistry , Crowns , Humans , Linear Models , Methacrylates/chemistry , Microscopy, Electron, Scanning , Molar, Third , Phosphoric Acids/chemistry , Polymethacrylic Acids/chemistry , Silicon Compounds , Statistics as Topic , Stress, Mechanical , Surface Properties , Temperature , Tensile Strength , Time Factors , Water/chemistry
13.
Arq Bras Cardiol ; 65(5): 423-5, 1995 Nov.
Article in Portuguese | MEDLINE | ID: mdl-8729860

ABSTRACT

PURPOSE: To evaluate septal perfusion and contractility in patients with left bundle branch block (LBBB). METHODS: Twenty patients were submitted to myocardial scintigraphy with Tecnecium-99m isontrile after exercise and dipyridamole infusion. The septal contractility was observed during the radionuclide ventriculography. All patients were submitted to coronariography. RESULTS: Twenty patients were studied and 17 (85%) had a normal left anterior descending (LAD) artery. Nine (53%) patients had abnormalities in septal perfusion after the exercise and 2 (12%) after dipyridamole infusion. All patients had abnormalities in septal contractility during the radionuclide ventriculography. CONCLUSION: The myocardial scintigraphy after dipyridamole infusion showed better specificity in the diagnosis of a LAD lesion. The radionuclide ventriculography was an efficient method to evaluate the septal contraction abnormalities in patients with LBBB.


Subject(s)
Bundle-Branch Block/diagnostic imaging , Coronary Disease/diagnostic imaging , Radiopharmaceuticals , Technetium Tc 99m Sestamibi , Bundle-Branch Block/complications , Coronary Disease/complications , Dipyridamole , Heart Septum/diagnostic imaging , Humans , Middle Aged , Prospective Studies , Radionuclide Ventriculography
14.
Oper Dent ; 39(1): E16-21, 2014.
Article in English | MEDLINE | ID: mdl-23848068

ABSTRACT

INTRODUCTION: Commonly, resin composites/cements fail to achieve proper bonding to fiber posts when their surfaces have not been previously etched. This study evaluated the effect of the concentration and application mode of hydrogen peroxide on the surface topography and bond strength of resin composite to glass-fiber posts. METHODS AND MATERIALS: Fiber posts were immersed in 24% or 35% solutions (a high-concentration bleaching agent) of hydrogen peroxide (H2O2), or these solutions were applied over the post surface using a microbrush (n=10). Posts without any treatment were used as a control. After etching, the posts were silanated and an adhesive was applied. The posts were positioned in a mold, and a resin composite was incrementally inserted and light-cured. The post/resin assembly was serially sectioned into several beams that were subjected to a tensile bond strength test. The data were subjected to the two-way analysis of variance and Tukey test (α=0.05). The Dunnet's test was used to compare the experimental conditions to the control. The surface topography was analyzed using scanning electronic microscopy. RESULTS: The non-etched post presented a relatively smooth surface without fiber exposure. Except for the application of 24% H2O2, the other experimental conditions increased the number of exposed fibers and bond strength in relation to the control. Although immersion resulted in higher values for the 24% H2O2 application, the mode of application did not alter bond strength when 35% H2O2 was used. CONCLUSIONS: The effect of the mode of application of H2O2 depended on its level of concentration. A high-concentration bleaching agent improved the bond strength of the resin composite to the post surface, regardless of which mode was used.


Subject(s)
Dental Etching/methods , Post and Core Technique , Tooth Bleaching Agents/therapeutic use , Composite Resins/therapeutic use , Dental Bonding/methods , Dental Bonding/standards , Dental Stress Analysis , Glass , Humans , Hydrogen Peroxide/therapeutic use , Microscopy, Electron , Surface Properties
15.
Leukemia ; 28(3): 543-53, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24253024

ABSTRACT

Constitutively active casein kinase 2 (CK2) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL). CK2 phosphorylates PTEN (phosphatase and tensin homolog) tumor suppressor, resulting in PTEN stabilization and functional inactivation. Downregulation of PTEN activity has an impact on PI3K/Akt/mTOR signaling, which is of fundamental importance for T-ALL cell survival. These observations lend compelling weight to the application of CK2 inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of CX-4945-a novel, highly specific, orally available, ATP-competitive inhibitor of CK2α. We show that CX-4945 treatment induced apoptosis in T-ALL cell lines and patient T lymphoblasts. CX-4945 downregulated PI3K/Akt/mTOR signaling in leukemic cells. Notably, CX-4945 affected the unfolded protein response (UPR), as demonstrated by a significant decrease in the levels of the main UPR regulator GRP78/BIP, and led to apoptosis via upregulation of the ER stress/UPR cell death mediators IRE1α and CHOP. In vivo administration of CX-4945 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth. Our findings indicate that modulation of the ER stress/UPR signaling through CK2 inhibition could be exploited for inducing apoptosis in T-ALL cells and that CX-4945 may be an efficient treatment for those T-ALLs displaying upregulation of CK2α/PI3K/Akt/mTOR signaling.


Subject(s)
Antineoplastic Agents/therapeutic use , Casein Kinase II/antagonists & inhibitors , Naphthyridines/therapeutic use , Neoplasm Proteins/metabolism , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Signal Transduction , Unfolded Protein Response , Animals , Cell Division , Endoplasmic Reticulum Chaperone BiP , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Proteins/chemistry , Phenazines , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
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