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1.
J Mech Behav Biomed Mater ; 53: 455-462, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26410178

ABSTRACT

We report herein the effects of Ultrasonic Nano-crystal Surface Modification (UNSM), a severe surface plastic deformation process, on the microstructure, mechanical (hardness, wear), wettability and biocompatibility properties of NiTi shape memory alloy. Complete surface amorphization of NiTi was achieved by this process, which was confirmed by X-ray diffraction and high-resolution transmission electron microscopy. The wear resistance of the samples after UNSM processing was significantly improved compared with the non-processed samples due to increased surface hardness of the alloy by this process. In addition, cell culture study demonstrated that the biocompatibility of the samples after UNSM processing has not been compromised compared to the non-processed sample. The combination of high wear resistance and good biocompatibility makes UNSM an appealing process for treating alloy-based biomedical devices.


Subject(s)
Alloys/chemistry , Mechanical Phenomena , Nanoparticles/chemistry , Nickel/chemistry , Titanium/chemistry , Ultrasonic Waves , Alloys/pharmacology , Humans , Materials Testing , Mesenchymal Stem Cells/drug effects , Surface Properties , Tissue Engineering
2.
Leukemia ; 30(1): 104-11, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26205085

ABSTRACT

It is generally accepted that intracellular oxidative stress induced by proteasome inhibitors is a byproduct of endoplasmic reticulum (ER) stress. Here we report a mechanism underlying the ability of proteasome inhibitors bortezomib (BTZ) and carfilzomib (CFZ) to directly induce oxidative and ER stresses in multiple myeloma (MM) cells via transcriptional repression of a gene encoding mitochondrial thioredoxin reductase (TXNRD2). TXNRD2 is critical for maintenance of intracellular red-ox status and detoxification of reactive oxygen species. Depletion of TXNRD2 to the levels detected in BTZ- or CFZ-treated cells causes oxidative stress, ER stress and death similar to those induced by proteasome inhibitors. Reciprocally, restoration of near-wildtype TXNRD2 amounts in MM cells treated with proteasome inhibitors reduces oxidative stress, ER stress and cell death by ~46%, ~35% and ~50%, respectively, compared with cells with unrestored TXNRD2 levels. Moreover, cells from three MM cell lines selected for resistance to BTZ demonstrate elevated levels of TXNRD2, indirectly confirming its functional role in BTZ resistance. Accordingly, ectopic expression of TXNRD2 in MM cell xenografts in immunocompromised mice blunts therapeutic effects of BTZ. Our data identify TXNRD2 as a potentially clinically relevant target, inhibition of which is critical for proteasome inhibitor-dependent cytotoxicity, oxidative stress and ER stress.


Subject(s)
Multiple Myeloma/drug therapy , Proteasome Inhibitors/therapeutic use , Thioredoxin Reductase 2/physiology , Animals , Apoptosis/drug effects , Bortezomib/pharmacology , Cell Line, Tumor , Endoplasmic Reticulum Stress/drug effects , Female , Humans , Mice , Multiple Myeloma/enzymology , Multiple Myeloma/pathology , Oxidative Stress , Reactive Oxygen Species/metabolism
3.
Oncogene ; 31(12): 1484-92, 2012 Mar 22.
Article in English | MEDLINE | ID: mdl-21822300

ABSTRACT

Oncoprotein C-MYC is overexpressed in human metastatic melanomas and melanoma-derived cells where it is required for the suppression of oncogene-induced senescence (OIS). The genetic events that maintain high levels of C-MYC in melanoma cells and their role in OIS are unknown. Here we report that C-MYC in cells from several randomly chosen melanoma lines was upregulated at the protein level, and largely because of the increased protein stability. Of all known regulators of C-MYC stability, levels of B56α subunit of the PP2A tumor suppressor complex were substantially suppressed in all human melanoma cells compared with normal melanocytes. Accordingly, immunohistochemical analysis revealed that the lowest and the highest amounts of PP2A-B56α were predominantly detected in metastatic melanoma tissues and in primary melanomas from patients with good clinical outcome, respectively. Importantly, PP2A-B56α overexpression suppressed C-MYC in melanoma cells and induced OIS, whereas depletion of PP2A-B56α in normal human melanocytes upregulated C-MYC protein levels and suppressed BRAF(V600E)- and, less efficiently, NRAS(Q61R)-induced senescence. Our data reveal a mechanism of C-MYC overexpression in melanoma cells and identify a functional role for PP2A-B56α in OIS of melanocytic cells.


Subject(s)
Genes, myc , Melanoma/genetics , Protein Phosphatase 2/metabolism , Cell Line, Tumor , Cellular Senescence , Humans , Melanocytes/metabolism , Melanoma/secondary , Protein Stability , Up-Regulation
4.
J Bone Joint Surg Br ; 93(10): 1296-9, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21969424

ABSTRACT

Robots have been used in surgery since the late 1980s. Orthopaedic surgery began to incorporate robotic technology in 1992, with the introduction of ROBODOC, for the planning and performance of total hip replacement. The use of robotic systems has subsequently increased, with promising short-term radiological outcomes when compared with traditional orthopaedic procedures. Robotic systems can be classified into two categories: autonomous and haptic (or surgeon-guided). Passive surgery systems, which represent a third type of technology, have also been adopted recently by orthopaedic surgeons. While autonomous systems have fallen out of favour, tactile systems with technological improvements have become widely used. Specifically, the use of tactile and passive robotic systems in unicompartmental knee replacement (UKR) has addressed some of the historical mechanisms of failure of non-robotic UKR. These systems assist with increasing the accuracy of the alignment of the components and produce more consistent ligament balance. Short-term improvements in clinical and radiological outcomes have increased the popularity of robot-assisted UKR. Robot-assisted orthopaedic surgery has the potential for improving surgical outcomes. We discuss the different types of robotic systems available for use in orthopaedics and consider the indication, contraindications and limitations of these technologies.


Subject(s)
Orthopedic Procedures/methods , Robotics/methods , Surgery, Computer-Assisted/methods , Arthroplasty, Replacement, Knee/instrumentation , Arthroplasty, Replacement, Knee/methods , Humans , Orthopedic Procedures/instrumentation , Robotics/instrumentation , Surgery, Computer-Assisted/adverse effects , Surgery, Computer-Assisted/instrumentation
5.
Oncogene ; 27(52): 6623-34, 2008 Nov 06.
Article in English | MEDLINE | ID: mdl-18679422

ABSTRACT

Malignant melanomas often harbor activating mutations in BRAF (V600E) or, less frequently, in NRAS (Q61R). Intriguingly, the same mutations have been detected at higher incidences in benign nevi, which are largely composed of senescent melanocytes. Overexpression of BRAF(V600E) or NRAS(Q61R) in human melanocytes in vitro has been shown to induce senescence, although via different mechanisms. How oncogene-induced senescence is overcome during melanoma progression remains unclear. Here, we report that in the majority of analysed BRAF(V600E)- or NRAS(Q61R)-expressing melanoma cells, C-MYC depletion induced different yet overlapping sets of senescence phenotypes that are characteristic of normal melanocytes undergoing senescence due to overexpression of BRAF(V600E) or NRAS(Q61R), respectively. These senescence phenotypes were p16(INK4A)- or p53-independent, however, several of them were suppressed by genetic or pharmacological inhibition of BRAF(V600E) or phosphoinositide 3-kinase pathways, including rapamycin-mediated inhibition of mTOR-raptor in NRAS(Q61R)-expressing melanoma cells. Reciprocally, overexpression of C-MYC in normal melanocytes suppressed BRAF(V600E)-induced senescence more efficiently than NRAS(Q61R)-induced senescence, which agrees with the generally higher rates of activating mutations in BRAF than NRAS gene in human cutaneous melanomas. Our data suggest that one of the major functions of C-MYC overexpression in melanoma progression is to continuous suppress BRAF(V600E)- or NRAS(Q61R)-dependent senescence programs.


Subject(s)
Cellular Senescence , Gene Expression , Melanoma/genetics , Melanoma/pathology , Proto-Oncogene Proteins c-myc/genetics , Proto-Oncogene Proteins c-myc/metabolism , Cell Line, Tumor , Cellular Senescence/drug effects , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Disease Progression , Gene Deletion , Humans , Melanocytes/metabolism , Melanoma/enzymology , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinase Kinases/metabolism , Neoplasm Metastasis/genetics , Neoplasm Metastasis/pathology , Phenotype , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , ras Proteins/genetics , ras Proteins/metabolism
6.
Oncogene ; 27(13): 1905-15, 2008 Mar 20.
Article in English | MEDLINE | ID: mdl-17906696

ABSTRACT

A major role for c-Myc in the proliferation of normal cells is attributed to its ability to promote progression through G(1) and into S phase of the cell cycle. The absolute requirement of c-Myc for cell cycle progression in human tumor cells has not been comprehensively addressed. In the present work, we used a lentiviral-based short hairpin RNA (shRNA) expression vector to stably reduce c-Myc expression in a large number of human tumor cell lines and in three different types of normal human cells. In all cases, cell proliferation was severely inhibited, with normal cells ultimately undergoing G(0)/G(1) growth arrest. In contrast, tumor cells demonstrated a much more variable cell cycle response with cells from several lines accumulating in S or G(2)/M phases. Moreover, in some tumor lines, the phase of cell cycle arrest caused by inhibition of c-Myc could be altered by depleting tumor suppressor protein p53 or its transcriptional target p21(CIP/WAF). Our data suggest that, as in the case of normal cells, c-Myc is essential for sustaining proliferation of human tumor cells. However its rate-limiting role in cell cycle control is variable and is reliant upon the status of other cell cycle regulators.


Subject(s)
Cell Cycle/physiology , Cell Proliferation , Neoplasms/metabolism , Neoplasms/pathology , Proto-Oncogene Proteins c-myc/deficiency , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Fibroblasts/cytology , Fibroblasts/metabolism , Flow Cytometry , Green Fluorescent Proteins/metabolism , Humans , Immunoblotting , Keratinocytes/cytology , Keratinocytes/metabolism , Melanocytes/cytology , Melanocytes/metabolism , Neoplasms/genetics , Proto-Oncogene Proteins c-myc/genetics , RNA, Small Interfering/pharmacology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism
7.
Dis Esophagus ; 15(1): 39-45, 2002.
Article in English | MEDLINE | ID: mdl-12060041

ABSTRACT

We evaluated the reasons for current practices in managing Barrett's esophagus. Using a questionnaire, we assessed the practices and beliefs of 162 Californian gastroenterologists in managing Barrett's esophagus, using descriptive statistics as well as multivariate logistic regression. Out of the 103 respondents, 87% screened for Barrett's esophagus in patients with > 12 months of reflux symptoms, but only 72% believed that screening would improve survival, and 48% believed it to be cost-effective. In total, 98% surveyed patients with long-segment Barrett's esophagus at least biennially (76% thought this would improve survival and 49% believed it to be cost-effective) and 82% surveyed short-segment Barrett's esophagus at least biennially (57% thought this would improve survival and 30% believed it to be cost-effective). Finally, 44% surveyed microscopic intestinal metaplasia at least biennially (26% thought this would improve survival and 11% believed it to be cost-effective). In total, 18% performed endoscopic ablation, whereas 3% referred patients with low-grade dysplasia and 85% referred patients with high-grade dysplasia for esophagectomy. Finally, 81% treated asymptomatic Barrett's esophagus patients with proton pump inhibitors, but only 56% believed that this would reduce the risk of cancer. Logistic regression showed that the only independent factor predictive of surveillance practices was belief in efficacy. Practice patterns tend to be more aggressive than those recommended by recent guidelines and those reported by previous surveys. Medico-legal considerations affect practice substantially.


Subject(s)
Attitude of Health Personnel , Barrett Esophagus/diagnosis , Barrett Esophagus/therapy , Clinical Competence , Diagnostic Tests, Routine/statistics & numerical data , Esophageal Neoplasms/prevention & control , Practice Patterns, Physicians'/statistics & numerical data , California , Cost-Benefit Analysis , Female , Gastroenterology/methods , Gastroesophageal Reflux/drug therapy , Health Care Surveys , Humans , Logistic Models , Male , Multivariate Analysis , Prognosis , Proton Pump Inhibitors , Proton Pumps/administration & dosage , Surveys and Questionnaires , Treatment Outcome
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