Publications by authors named "Anthony T Yeung"

34 Publications

Retrospective analysis of accuracy and positive predictive value of preoperative lumbar MRI grading after successful outcome following outpatient endoscopic decompression for lumbar foraminal and lateral recess stenosis.

Clin Neurol Neurosurg 2019 06 5;181:52. Epub 2019 Apr 5.

Center For Advanced Spine Care of Southern Arizona, Surgical Institute of Tucson, 4787 E. Camp Lowell Drive, 85712, Tucson, AZ, United States; Department of Orthopaedics, Fundación Universitaria Sanitas, Bogotá, D.C., Colombia. Electronic address:

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http://dx.doi.org/10.1016/j.clineuro.2019.03.011DOI Listing
June 2019

The State of the Art in Minimally Invasive Spine Surgery.

Biomed Res Int 2017;2017:6194016. Epub 2017 Feb 28.

Department of Orthopedics, West China Hospital of Sichuan University, Chengdu, China.

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http://dx.doi.org/10.1155/2017/6194016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350391PMC
October 2018

Haploinsufficiency in tumor predisposition syndromes: altered genomic transcription in morphologically normal cells heterozygous for VHL or TSC mutation.

Oncotarget 2017 Mar;8(11):17628-17642

Cancer Biology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Tumor suppressor genes and their effector pathways have been identified for many dominantly heritable cancers, enabling efforts to intervene early in the course of disease. Our approach on the subject of early intervention was to investigate gene expression patterns of morphologically normal "one-hit" cells before they become hemizygous or homozygous for the inherited mutant gene which is usually required for tumor formation. Here, we studied histologically non-transformed renal epithelial cells from patients with inherited disorders that predispose to renal tumors, including von Hippel-Lindau (VHL) disease and Tuberous Sclerosis (TSC). As controls, we studied histologically normal cells from non-cancerous renal epithelium of patients with sporadic clear cell renal cell carcinoma (ccRCC). Gene expression analyses of VHLmut/wt or TSC1/2mut/wt versus wild-type (WT) cells revealed transcriptomic alterations previously implicated in the transition to precancerous renal lesions. For example, the gene expression changes in VHLmut/wt cells were consistent with activation of the hypoxia response, associated, in part, with the "Warburg effect". Knockdown of any remaining VHL mRNA using shRNA induced secondary expression changes, such as activation of NFκB and interferon pathways, that are fundamentally important in the development of RCC. We posit that this is a general pattern of hereditary cancer predisposition, wherein haploinsufficiency for VHL or TSC1/2, or potentially other tumor susceptibility genes, is sufficient to promote development of early lesions, while cancer results from inactivation of the remaining normal allele. The gene expression changes identified here are related to the metabolic basis of renal cancer and may constitute suitable targets for early intervention.
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http://dx.doi.org/10.18632/oncotarget.12192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392274PMC
March 2017

Foreword, Percutaneous and Endoscopic MIS Special Issue.

Authors:
Anthony T Yeung

Int J Spine Surg 2014 1;8. Epub 2014 Dec 1.

Desert Institute for Spine Care, Phoenix, AZ, USA.

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http://dx.doi.org/10.14444/1014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4325496PMC
February 2015

Potential prognostic biomarkers of pancreatic cancer.

Pancreas 2014 Jan;43(1):22-7

From the *Department of Surgical Oncology, †Developmental Therapeutics, and Departments of ‡ Biostatistics, §Pathology, and ∥Gastroenterology, Fox Chase Cancer Center, Philadelphia, PA.

Objectives: We evaluated whether pancreatic main duct fluid can provide protein biomarkers with prognostic value.

Methods: Mass spectrometry proteomics was applied to as little as 20µL of fluid collected at the time of tumor surgical resection. Biomarker proteins identified for 27 patients were correlated with clinical outcomes.

Results: Thirteen patients had pancreatic ductal adenocarcinomas, 4 had intraductal papillary mucinous neoplasm with in situ adenocarcinoma, 5 had ampullary adenocarcinomas, 2 had intraductal papillary mucinous neoplasms, and 3 had benign diseases. In pathologic stage II or higher pancreatic ductal adenocarcinoma, moderate or high expression of S100A8 or S100A9 proteins was associated with a median disease recurrence-free survival of 5.8 months compared with 17.3 months in patients with low expression (P = 0.002). Median overall survival was 12.6 versus 27 months for patients with moderate to high versus low S100A8 and A9 expression (P = 0.02).

Conclusions: This analysis suggests distinct proteomic signatures for pancreatic cancer. Patients in our study with elevated levels of S100A8 or A9 in the ductal fluid, a near absence of pancreatic enzymes, and high levels of mucins were found to have significantly worse prognosis. Although further validation is needed to corroborate these findings, analysis of pancreatic ductal fluid is a promising tool for identifying biomarkers of interest.
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http://dx.doi.org/10.1097/MPA.0b013e3182a6867eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859961PMC
January 2014

Immunodepletion plasma proteomics by tripleTOF 5600 and Orbitrap elite/LTQ-Orbitrap Velos/Q exactive mass spectrometers.

J Proteome Res 2013 Oct 19;12(10):4351-65. Epub 2013 Sep 19.

Fox Chase Cancer Center, Philadelphia, PA 19111.

Plasma proteomic experiments performed rapidly and economically using several of the latest high-resolution mass spectrometers were compared. Four quantitative hyperfractionated plasma proteomics experiments were analyzed in replicates by two AB SCIEX TripleTOF 5600 and three Thermo Scientific Orbitrap (Elite/LTQ-Orbitrap Velos/Q Exactive) instruments. Each experiment compared two iTRAQ isobaric-labeled immunodepleted plasma proteomes, provided as 30 labeled peptide fractions, and 480 LC-MS/MS runs delivered >250 GB of data in 2 months. Several analysis algorithms were compared. At 1% false discovery rate, the relative comparative findings concluded that the Thermo Scientific Q Exactive Mass Spectrometer resulted in the highest number of identified proteins and unique sequences with iTRAQ quantitation. The confidence of iTRAQ fold-change for each protein is dependent on the overall ion statistics (Mascot Protein Score) attainable by each instrument. The benchmarking also suggested how to further improve the mass spectrometry parameters and HPLC conditions. Our findings highlight the special challenges presented by the low abundance peptide ions of iTRAQ plasma proteome because the dynamic range of plasma protein abundance is uniquely high compared with cell lysates, necessitating high instrument sensitivity.
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http://dx.doi.org/10.1021/pr400307uDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817719PMC
October 2013

Assessment of two immunodepletion methods: off-target effects and variations in immunodepletion efficiency may confound plasma proteomics.

J Proteome Res 2012 Dec 29;11(12):5947-58. Epub 2012 Oct 29.

Developmental Therapeutics Program, Fox Chase Cancer Center, Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19111, United States.

Immunodepletion of abundant plasma proteins increases the depth of proteome penetration by mass spectrometry. However, the nature and extent of immunodepletion and the effect of off-target depletion on the quantitative comparison of the residual proteins have not been critically addressed. We performed mass spectrometry label-free quantitation to determine which proteins were immunodepleted and by how much. Two immunodepletion resins were compared: Qproteome (Qiagen) which removes albumin+immunoglobulins and Seppro IgY14+SuperMix (Sigma-Aldrich) which removes 14 target proteins plus a number of unidentified proteins. Plasma collected by P100 proteomic plasma collection tubes (BD) from 20 human subjects was individually immunodepleted to minimize potential variability, prior to pooling. The abundant proteins were quantified better when using only albumin+immunoglobulins removal (Qproteome), while lower abundance proteins were evaluated better using exhaustive immunodepletion (Seppro IgY14+SuperMix). The latter resin removed at least 155 proteins, 38% of the plasma proteome in protein number and 94% of plasma protein in mass. The depth of immunodepletion likely accounts for the effectiveness of this resin in revealing low abundance proteins. However, the more profound immunodepletion achieved with the IgY14+SuperMix may lead to false-positive fold-changes between comparison groups if the reproducibility and efficiency of the depletion of a given protein are not considered.
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http://dx.doi.org/10.1021/pr300686kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518753PMC
December 2012

In-vivo Endoscopic Visualization of Patho-anatomy in Symptomatic Degenerative Conditions of the Lumbar Spine II: Intradiscal, Foraminal, and Central Canal Decompression.

Surg Technol Int 2011 Dec;21:299-319

Spine Endoscopist, Mission Spine, Pune, India.

The patho-anatomy in an aging spine is partly defined by Rauschning's anatomic cryosections. Theories of pain generation and principles of minimally invasive spine surgery are suggested by close examination of these specimens. If the visualized patho-anatomy can be studied in vivo in a partially sedated patient by spinal probing, spinal pain can be better understood, and rational endoscopic treatment options may then evolve.1 A 1997 IRB-approved study provided evidence that endoscopic transforaminal surgery was feasible for the treatment of a wide spectrum of degenerative conditions in the lumbar spine. The technique incorporated evocative chromo-discography to correlate reproduction of pain with in-vivo probing of patho-anatomy. Laser and radiofrequency ablation augmented mechanical decompression to obtain pain relief.1-3 Endoscopic visualization of patho-anatomy ranging from annular tears to spondylolisthesis and stenosis provided clinical evidence that foraminal decompression, ablation, and irrigation could effectively treat these visualized painful conditions with minimal morbidity. This resulted in a better understanding of the pain generators in the lumbar spine, opening up options for surgical pain management.1-5 The procedure does not burn any bridges for more traditional surgical techniques. The learning curve may be steep for some and long for others, but results are very good, concomitant with each individual surgeon overcoming his personal learning curve.
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December 2011

Isobaric labeling and data normalization without requiring protein quantitation.

J Biomol Tech 2012 Apr;23(1):11-23

Developmental Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111-2497, USA.

Isobaric multiplexed quantitative proteomics can complement high-resolution sample isolation techniques. Here, we report a simple workflow exponentially modified protein abundance index (emPAI)-MW deconvolution (EMMOL) for normalizing isobaric reporter ratios within and between experiments, where small or unknown amounts of protein are used. EMMOL deconvolutes the isobaric tags for relative and absolute quantification (iTRAQ) data to yield the quantity of each protein of each sample in the pool, a new approach that enables the comparison of many samples without including a channel of reference standard. Moreover, EMMOL allows using a sufficient quantity of control sample to facilitate the peptide fractionation (isoelectric-focusing was used in this report), and mass spectrometry MS/MS sequencing yet relies on the broad dynamic range of iTRAQ quantitation to compare relative protein abundance. We demonstrated EMMOL by comparing four pooled samples with 20-fold range differences in protein abundance and performed data normalization without using prior knowledge of the amounts of proteins in each sample, simulating an iTRAQ experiment without protein quantitation prior to labeling. We used emPAI, the target protein MW, and the iTRAQ reporter ratios to calculate the amount of each protein in each of the four channels. Importantly, the EMMOL-delineated proteomes from separate iTRAQ experiments can be assorted for comparison without using a reference sample. We observed no compression of expression in iTRAQ ratios over a 20-fold range for all protein abundances. To complement this ability to analyze minute samples, we report an optimized iTRAQ labeling protocol for using 5 μg protein as the starting material.
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http://dx.doi.org/10.7171/jbt.12-2301-002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313697PMC
April 2012

APC +/- alters colonic fibroblast proteome in FAP.

Oncotarget 2011 Mar;2(3):197-208

Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

Here we compared the proteomes of primary fibroblast cultures derived from morphologically normal colonic mucosa of familial adenomatous polyposis (FAP) patients with those obtained from unaffected controls. The expression signature of about 19% of total fibroblast proteins separates FAP mutation carriers from unaffected controls (P < 0.01). More than 4,000 protein spots were quantified by 2D PAGE analysis, identifying 368 non-redundant proteins and 400 of their isoforms. Specifically, all three classes of cytoskeletal filaments and their regulatory proteins were altered as were oxidative stress response proteins. Given that FAP fibroblasts showed heightened sensitivity to transformation by KiMSV and SV40 including elevated levels of the p53 protein, events controlled in large measure by the Ras suppressor protein-1 (RSU-1) and oncogenic DJ-1, here we show decreased RSU1 and augmented DJ-1 expression in both fibroblasts and crypt-derived epithelial cells from morphologically normal colonic mucosa of FAP gene-carriers. The results indicate that heterozygosity for a mutant APC tumor suppressor gene alters the proteomes of both colon-derived normal fibroblasts in a gene-specific manner, consistent with a "one-hit" effect.
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http://dx.doi.org/10.18632/oncotarget.241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195363PMC
March 2011

Alteration of Differentiation Potentials by Modulating GATA Transcription Factors in Murine Embryonic Stem Cells.

Stem Cells Int 2010 May 11;2010:602068. Epub 2010 May 11.

Miller School of Medicine, University of Miami, 1550 NW 10th Avenue (M877), Miami, FL 33156, USA.

Background. Mouse embryonic stem (ES) cells can be differentiated in vitro by aggregation and/or retinoic acid (RA) treatment. The principal differentiation lineage in vitro is extraembryonic primitive endoderm. Dab2, Laminin, GATA4, GATA5, and GATA6 are expressed in embryonic primitive endoderm and play critical roles in its lineage commitment. Results. We found that in the absence of GATA4 or GATA5, RA-induced primitive endoderm differentiation of ES cells was reduced. GATA4 (-/-) ES cells express higher level of GATA5, GATA6, and hepatocyte nuclear factor 4 alpha marker of visceral endoderm lineage. GATA5 (-/-) ES cells express higher level of alpha fetoprotein marker of early liver development. GATA6 (-/-) ES cells express higher level of GATA5 as well as mesoderm and cardiomyocyte markers which are collagen III alpha-1 and tropomyosin1 alpha. Thus, deletion of GATA6 precluded endoderm differentiation but promoted mesoderm lineages. Conclusions. GATA4, GATA5, and GATA6 each convey a unique gene expression pattern and influences ES cell differentiation. We showed that ES cells can be directed to avoid differentiating into primitive endoderm and to adopt unique lineages in vitro by modulating GATA factors. The finding offers a potential approach to produce desirable cell types from ES cells, useful for regenerative cell therapy.
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http://dx.doi.org/10.4061/2010/602068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956456PMC
May 2010

A Phosphotyrosine Proteomic Screen Identifies Multiple Tyrosine Kinase Signaling Pathways Aberrantly Activated in Malignant Mesothelioma.

Genes Cancer 2010 May;1(5):493-505

Cancer Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111.

Malignant mesothelioma (MM) is a highly aggressive cancer that is refractory to all current chemotherapeutic regimens. Therefore, uncovering new rational therapeutic targets is imperative in the field. Tyrosine kinase signaling pathways are aberrantly activated in many human cancers and are currently being targeted for chemotherapeutic intervention. Thus, we sought to identify tyrosine kinases hyperactivated in MM. An unbiased phosphotyrosine proteomic screen was employed to identify tyrosine kinases activated in human MM cell lines. From this screen, we have identified novel signaling molecules, such as JAK1, STAT1, cortactin (CTTN), FER, p130Cas (BCAR1), SRC and FYN as tyrosine phosphorylated in human MM cell lines. Additionally, STAT1 and SRC family kinases (SFK) were confirmed to be active in primary MM specimens. We also confirmed that known signal transduction pathways previously implicated in MM, such as EGFR and MET signaling axes, are co-activated in the majority of human MM specimens and cell lines tested. EGFR, MET, and SFK appear to be co-activated in a significant proportion of MM cell lines, and dual inhibition of these kinases was demonstrated to be more efficacious for inhibiting MM cell viability and downstream effector signaling than inhibition of a single tyrosine kinase. Consequently, these data suggest that TKI mono-therapy may not represent an efficacious strategy for the treatment of MM, due to multiple tyrosine kinases potentially signaling redundantly to cellular pathways involved in tumor cell survival and proliferation.
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http://dx.doi.org/10.1177/1947601910375273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909631PMC
May 2010

Altered gene expression in morphologically normal epithelial cells from heterozygous carriers of BRCA1 or BRCA2 mutations.

Cancer Prev Res (Phila) 2010 Jan;3(1):48-61

Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

We hypothesized that cells bearing a single inherited "hit" in a tumor suppressor gene express an altered mRNA repertoire that may identify targets for measures that could delay or even prevent progression to carcinoma. We report here on the transcriptomes of primary breast and ovarian epithelial cells cultured from BRCA1 and BRCA2 mutation carriers and controls. Our comparison analyses identified multiple changes in gene expression, in both tissues for both mutations, which were validated independently by real-time reverse transcription-PCR analysis. Several of the differentially expressed genes had been previously proposed as cancer markers, including mammaglobin in breast cancer and serum amyloid in ovarian cancer. These findings show that heterozygosity for a mutant tumor suppressor gene can alter the expression profiles of phenotypically normal epithelial cells in a gene-specific manner; these detectable effects of "one hit" represent early molecular changes in tumorigenesis that may serve as novel biomarkers of cancer risk and as targets for chemoprevention.
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http://dx.doi.org/10.1158/1940-6207.CAPR-09-0078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804937PMC
January 2010

Proteomic analyses of pancreatic cyst fluids.

Pancreas 2009 Mar;38(2):e33-42

From the Divisions of *Basic Science, daggerMedical Science, and double daggerPopulation Science, Fox Chase Cancer Center, Philadelphia, PA.

Objectives: There are currently no diagnostic indicators that are consistently reliable, obtainable, and conclusive for diagnosing and risk-stratifying pancreatic cysts. Proteomic analyses were performed to explore pancreatic cyst fluids to yield effective diagnostic biomarkers.

Methods: We have prospectively recruited 20 research participants and prepared their pancreatic cyst fluids specifically for proteomic analyses. Proteomic approaches applied were as follows: (1) matrix-assisted laser-desorption-ionization time-of-flight mass spectrometry peptidomics with LC/MS/MS (HPLC-tandem mass spectrometry) protein identification; (2) 2-dimensional gel electrophoresis; (3) GeLC/MS/MS (tryptic digestion of proteins fractionated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and identified by LC/MS/MS).

Results: Sequencing of more than 350 free peptides showed that exopeptidase activities rendered peptidomics of cyst fluids unreliable; protein nicking by proteases in the cyst fluids produced hundreds of protein spots from the major proteins, making 2-dimensional gel proteomics unmanageable; GeLC/MS/MS revealed a panel of potential biomarker proteins that correlated with carcinoembryonic antigen (CEA).

Conclusions: Two homologs of amylase, solubilized molecules of 4 mucins, 4 solubilized CEA-related cell adhesion molecules (CEACAMs), and 4 S100 homologs may be candidate biomarkers to facilitate future pancreatic cyst diagnosis and risk-stratification. This approach required less than 40 microL of cyst fluid per sample, offering the possibility to analyze cysts smaller than 1 cm in diameter.
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http://dx.doi.org/10.1097/MPA.0b013e318193a08fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2681236PMC
March 2009

Molecular mechanisms of action of imatinib mesylate in human ovarian cancer: a proteomic analysis.

Cancer Genomics Proteomics 2008 May-Aug;5(3-4):137-49

Division of Basic Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, Pennsylvania 19111-2497, USA.

Background: Imatinib mesylate (Gleevec, Novartis, Basel, Switzerland) is a small-molecule tyrosine kinase inhibitor with activity against ABL, BCR-ABL, c-KIT, and PDGFR alpha. Several clinical trials have evaluated the efficacy and safety of imatinib in patients with ovarian carcinoma who have persistent or recurrent disease following front-line platinum/taxane based chemotherapy. However, there is limited pre-clinical and clinical data on the molecular targets and action of imatinib in ovarian cancer.

Materials And Methods: Human ovarian cancer cells (A2780) were treated with imatinib mesylate for either 6 or 24 h. We employed a 2D (two-dimensional) gel electrophoresis and mass spectrometry-based proteomics approach to identify protein expression patterns and signaling pathways that were altered in response to imatinib. Cells were analyzed for PDGFR alpha and AKT expression, which were then correlated with imatinib sensitivity.

Results: Using 2D gel electrophoresis of overlapping pH ranges from pH 4 to 11, about 4,000 protein spots could be analyzed reproducibly. Proteins whose levels changed between twofold to 30 fold were grouped according to whether changes were in the same direction at both time points of treatment with respect to the control, or changed their levels only at one of the time points.

Conclusion: Differentially regulated proteins following imatinib treatment of A2780 cells involved the regulation of actin cytoskeleton, metabolic pathways, cell cycle, cell proliferation, apoptosis, cell junctions, and signal transduction. Thus, exposure of cells to imatinib produces complex changes in the cell that require further investigation.
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October 2008

One-hit effects in cancer: altered proteome of morphologically normal colon crypts in familial adenomatous polyposis.

Cancer Res 2008 Sep;68(18):7579-86

Division of Basic Science, Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA.

We studied patients with Familial Adenomatous Polyposis (FAP) because they are virtually certain to develop colon cancer, and because much is known about the causative APC gene. We hypothesized that the inherited heterozygous mutation itself leads to changes in the proteome of morphologically normal crypts and the proteins that changed may represent targets for preventive and therapeutic agents. We determined the differential protein expression of morphologically normal colon crypts of FAP patients versus those of individuals without the mutation, using two-dimensional gel electrophoresis, mass spectrometry, and validation by two-dimensional gel Western blotting. Approximately 13% of 1,695 identified proteins were abnormally expressed in the morphologically normal crypts of APC mutation carriers, indicating that a colon crypt cell under the one-hit state is already abnormal. Many of the expression changes affect pathways consistent with the function of the APC protein, including apoptosis, cell adhesion, cell motility, cytoskeletal organization and biogenesis, mitosis, transcription, and oxidative stress response. Thus, heterozygosity for a mutant APC tumor suppressor gene alters the proteome of normal-appearing crypt cells in a gene-specific manner, consistent with a detectable one-hit event. These changes may represent the earliest biomarkers of colorectal cancer development, potentially leading to the identification of molecular targets for cancer prevention.
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http://dx.doi.org/10.1158/0008-5472.CAN-08-0856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562578PMC
September 2008

Minimally invasive techniques for the management of lumbar disc herniation.

Orthop Clin North Am 2007 Jul;38(3):363-72; abstract vi

Arizona Institute for Minimally Invasive Spine Care, Phoenix, AZ 85020, USA.

Traditionally, minimally invasive techniques for surgical discectomy have been defined as smaller incisions, tubular retractors, microscopically assisted tissue dissection, and conservative removal of only extruded or sequestered nucleus pulposus with preservation of the annulus. The first truly minimally invasive technique was chymopapain dissolution of the nucleus pulposus. Other percutaneous techniques followed; however, none were as efficacious as the gold standard of microlumbar discectomy until endoscopically visualized methods evolved to allow visualized mechanical discectomy through the foramen. In experienced hands, such a technique is as effective as microlumbar discectomy and results in less surgical morbidity for herniations that are appropriate for this minimally invasive endoscopic surgical portal that completely avoids traumatizing the normal anatomy of the dorsal musculature and ligamentous structures.
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http://dx.doi.org/10.1016/j.ocl.2007.04.005DOI Listing
July 2007

Recombinant nucleases CEL I from celery and SP I from spinach for mutation detection.

BMC Biotechnol 2007 Jun 1;7:29. Epub 2007 Jun 1.

Basic Science, Fox Chase Cancer Center, Philadelphia, PA, USA.

Background: The detection of unknown mutations is important in research and medicine. For this purpose, a mismatch-specific endonuclease CEL I from celery has been established as a useful tool in high throughput projects. Previously, CEL I-like activities were described only in a variety of plants and could not be expressed in an active form in bacteria.

Results: We describe expression of active recombinant plant mismatch endonucleases and modification of their activities. We also report the cloning of a CEL I ortholog from Spinacia oleracea (spinach) which we termed SP I nuclease. Active CEL I and SP I nucleases were expressed as C-terminal hexahistidine fusions and affinity purified from the cell culture media. Both recombinant enzymes were active in mutation detection in BRCA1 gene of patient-derived DNA. Native SP nuclease purified from spinach is unable to incise at single-nucleotide substitutions and loops containing a guanine nucleotide, but the recombinant SP I nuclease can cut at these sites.

Conclusion: The insect cell-expressed CEL I orthologs may not be identical to their native counterparts purified from plant tissues. The present expression system should facilitate further development of CEL I-based mutation detection technologies.
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http://dx.doi.org/10.1186/1472-6750-7-29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1896157PMC
June 2007

Searchable high-resolution 2D gel proteome of the human colon crypt.

J Proteome Res 2007 Jun 20;6(6):2232-8. Epub 2007 Apr 20.

Division of Basic Science, Medical Science, and Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

We seek alterations in protein patterns at the earliest possible step on the path to cancer, namely, in cells of the target tissue from normal persons versus the corresponding normally appearing cells from persons who are heterozygous for mutation in a tumor suppressor gene that predisposes strongly to carcinoma in that tissue. To begin a systematic comparison of the proteomes of cells from normal and from neoplastic colons, we have undertaken the isolation of human colon crypts that are derived from the normal-appearing mucosa of left (descending) colon of patients with sporadic colorectal cancer. Two-dimensional (2D) gel electrophoresis is a proteomic approach that excels in the resolution of protein isoforms. Here, we document the practicality of this approach with human samples using gels of three overlapping pH ranges. For the first time, about 800 nonredundant proteins and 900 isoforms from purified human colonic crypts were identified, permitting an assessment of the contributions of protein isoforms. These interactive, searchable, hyperlink-enabled proteome maps and gene ontology analyses will facilitate future studies to discover the earliest markers and intervention targets during progression to colon cancer.
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http://dx.doi.org/10.1021/pr060641eDOI Listing
June 2007

A comparison of the degree of lateral recess and foraminal enlargement with facet preservation in the treatment of lumbar stenosis with standard surgical tools versus a novel powered filing instrument: a cadaver study.

SAS J 2007 1;1(4):135-42. Epub 2007 Nov 1.

The Arizona Institute for Minimally Invasive Spine Care, Phoenix, Arizona.

Background: The SurgiFile (SurgiFile, Inc., Carlsbad, California) is a specialized tool designed for the treatment of lateral recess and foraminal stenosis that allows surgeons to internally expand and decompress the entire length of the neural foramen while preserving the integrity of the overlying facet complex.

Methods: We used two cadaveric specimens in this study. After they removed the lamina and spinous processes of L2, L3, L4, and L5 from the dorsal spine, fellowship-trained spinal surgeons used the standard tools and the SurgiFile to the best of their experience and ability on alternating sides of each level to decompress the lateral recess and neural foramen while still preserving at least 50% of the dorsal facet complex. Using preoperative and postoperative fine-cut CT scans with axial and sagittal reconstructions, we evaluated the degree of decompression and the amount of preserved facet complex using analytical tests and recording the measurements.

Results: The difference between the proximal recess and lateral foramen of the groups was statistically significant in the axial CT images. On sagittal reconstruction CT images, the difference between the two groups was significant (P < 0.05, Wilcoxon) only for the lateral foramen. Although a strong trend toward better area change was evident for the proximal recess measurements in the experimental tool sides, this did not achieve statistical significance. Macroscopic and CT scans measurements showed that the amount of facetectomy for adequate decompression with the SurgiFile was less than the amount achieved with the standard tools.

Conclusions: For the treatment of spinal stenosis, this novel powered-file instrument provides surgeons with a new means of decompressing the lateral recess and neural foramina. In this cadaveric study, procedures performed with the SurgiFile tool showed a statistically superior degree of decompression as compared with the standard surgical instruments and techniques.
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http://dx.doi.org/10.1016/SASJ-2007-0107-NT-R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365583PMC
March 2015

The Evolution and Advancement of Endoscopic Foraminal Surgery: One Surgeon's Experience Incorporating Adjunctive Techologies.

Authors:
Anthony T Yeung

SAS J 2007 1;1(3):108-17. Epub 2007 Aug 1.

The Arizona Institute for Minimally Invasive Spine Care, Phoenix, Arizona.

Background: Endoscopic spine surgery has evolved gradually through improvements in endoscope design, instrumentation, and surgical techniques. The ability to visualize and treat painful pathology endoscopically through the foramen has opened the door for the diagnosis and treatment of degenerative conditions of the lumbar spine (from T10 to S1). Other endoscopic techniques for treating a painful disc have been focused on a posterior approach and has been compared with micro-lumbar discectomy. These procedures have not been more effective than open microdiscectomy but are less invasive, have less surgical morbidity, and allow for more rapid surgical recovery. Spinal decompression and fusion was the fallback procedure when nonsurgical treatment or discectomy failed to relieve sciatica and back pain. Foraminal endoscopic surgery, however, provides a truly minimally invasive alternative approach to the pathoanatomy of the lumbar spine because it preserves the multifidus muscle, maintains motion, and eliminates or, at worst, delays the need for fusion.

Methods: The following developments helped facilitate the evolution of a transforaminal endoscopic surgery procedure for disc herniations from a foraminal disc decompression, also known as percutaneous endoscopic lumbar discectomy, to a more complete foraminal surgical technique that can address spinal stenosis and spinal instability. This expanded capability gives foraminal endoscopic surgery distinct advantages and flexibility for certain painful degenerative conditions compared with open surgery. Advancement of the technique occurred when needle trajectory and placement was refined to better target each type of herniation with precise needle and cannula positioning directed at the herniation. New instrumentation and inclusion of a biportal technique also facilitated removal of extruded, migrated, and sequestered disc herniations. The further development of foraminoscopes with larger working channels and high speed burrs to remove bone more efficiently, along with recognition of foraminal pathoanatomy in the foramen, led to the identification and treatment of other painful degenerative conditions of the lumbar spine such as failed back surgery syndrome, recurrent disc herniations, lateral foraminal stenosis, degenerative spondylolisthesis, and isthmic spondylolisthesis. A summary of the endoscopic techniques currently used and trademarked by the author as the YESS technique include: (1) a published protocol for optimal needle and instrument placement calculated by lines drawn on the skin from the C-arm image; (2) evocative chromodiscography by the operating surgeon with nonionic radiologic contrast and indigo carmine dye to confirm concordant pain production and to stain tissue in contact with the injectate; (3) selective endoscopic discectomy, which targets the removal of loose degenerative nucleus stained differentially by indigo carmine dye; (4) thermal annuloplasty, a visualized radiofrequency thermal modulation of disc and annular defects guided by vital tissue staining; (5) endoscopic foraminoplasty, a decompression of the lateral and subarticular recess, including disc and foraminal degenerative and isthmic spondylolisthesis; (6) visually and radiologically guided exploration of the epidural space; (7) probing the hidden zone of MacNab for normal nerves (and branches of spinal nerves known as furcal nerves) versus anomalous autonomic nerves in the foramen; and (8) a uniportal and biportal technique for inside-out removal of extruded and sequestered nucleus pulposus.

Results: Endoscopic foraminal surgical procedures are not limited to disc decompression. The approaches and techniques allow access to the lumbar spine for treatment of conditions ranging from discogenic pain to failed back surgery syndrome (most commonly caused by residual or recurrent disc herniation and lateral recess stenosis). More than 3000 patients have undergone endoscopic posterolateral surgical exploration and decompression by the author since 1991. The first 80 patients reported formed the basis for expansion of techniques as new instruments and adjunctive therapy methods were added to selective endoscopic discectomy and thermal annuloplasty. New anatomic and pathoanatomic conditions were reported as they were encountered.

Conclusions: New skills will become desirable and necessary for the spine surgeon to keep up with endoscopic technology in spine care. The emphasis is on visualization of painful pathoanatomy and preservation of mobility. A new focus is on nucleus replacement, annular repair, annular reinforcement, biologics, and even transforaminal interbody fusion as the procedure of last resort. The transforaminal surgical approach to the lumbar spine can allow for minimally invasive access without negatively affecting and destabilizing the multifidus muscle.
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http://dx.doi.org/10.1016/SASJ-2006-0014-RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365579PMC
March 2015

The learning curve in foraminal endoscopic discectomy: experience needed to achieve a 90% success rate.

SAS J 2007 1;1(3):100-7. Epub 2007 Aug 1.

Squaw Peak Surgical Facility, Phoenix, Arizona.

Background: We sought to construct a general methodology for objectively quantifying the learning curve associated with any surgical technique and to determine the number of cases needed to achieve a success rate of 90% for the technique of transforaminal endoscopic lumbar discectomy. To our knowledge, no other studies have observed the learning curve of endoscopic lumbar discectomy by transforaminal approach.

Methods: We studied the learning curve of 1 orthopedic surgeon who had had experience performing open spine surgery and knee and shoulder arthroscopic surgery, but not endoscopic spine surgery. We studied 144 patients who had an endoscopic lumbar discectomy by transforaminal approach (using the Yeung Endoscopic Surgery System). We evaluated results with modified MacNab criteria and used a questionnaire to determine the patients' satisfaction with the surgery. The average follow-up period was 24 months. We used an algorithm, analyzing the patient outcome and the surgical time evolution, to determine the case at which a success rate of 90% good/excellent results was reached.

Results: The cut for the calculated learning curve was placed at case no. 72; i.e., the results in the first 72 cases were 75% good/excellent, 18% fair, and 7% poor, and the results in the following 72 cases were 90.3% good/excellent, 9.7% fair, and 0% poor.

Conclusions: A methodology to calculate the learning curve of a surgical procedure was developed. A learning curve of 72 cases was needed to reach the goal of 90% of good/excellent results for transforaminal endoscopic lumbar discectomy.

Clinical Relevance: The method developed to establish the learning curve of a surgical procedure, based on outcome and surgical time, may be used to assess any new procedure. With respect to the transforaminal endoscopic technique, the determination of a specific number of cases (72) needed to master (achieve 90% excellent/ good results) could help orient surgeons willing to adopt this technique.
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http://dx.doi.org/10.1016/SASJ-2007-0005-RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365578PMC
March 2015

In-vivo endoscopic visualization of patho-anatomy in painful degenerative conditions of the lumbar spine.

Surg Technol Int 2006 ;15:243-56

Arizona Institute for Minimally Invasive Spine Care, Phoenix, Arizona, USA.

The degenerative processes in an aging spine have been defined traditionally only by our knowledge of the biology of disc and facet degeneration, as well as interpretation of post-mortem cryosections by forensic anatomist Wolfgang Rauschning, M.D. In this chapter, visualization of in-vivo patho-anatomy in a degenerating disc and spinal segment is demonstrated at surgery using the Yeung Endoscopic Spine System (Y.E.S.S.), (Richard Wolf Surgical Instrument Company, Vernon Hills, IL, USA). An Institutional Review Board (IRB)-approved study of endoscopic treatment for degenerative conditions of the lumbar spine incorporated intraoperative probing under local anesthesia and endoscopic treatment of the visualized patho-anatomy. An intraoperative evocative chromo-discogram, using indigocarmine, was used to elicit discogenic pain and label the fissured and degenerative nucleus pulposus for surgical removal and thermal modulation. Painful patho-anatomy was probed in a conscious patient. The most common endoscopic finding was Inflammatory tissue in the disc and annulus. Inflammation was correlated with the presence of annular tears. Patho-physiologic changes that affect the exiting nerve, which contains the Dorsal Root Ganglion (DRG), was associated with stenotic and chemical irritation. Unavoidable postoperative dysesthesia was associated with the presence of an inflammatory membrane, and removal or thermal coagulation of "anomalous" furcal nerves in the foramen that branched off of the exiting spinal nerve. Neo-angiogenesis and neurogenesis in the inflammatory membrane present in the foraminal triangle was a new finding not reported in traditional clinical studies. Visualization and treatment of pathologic findings inside (annular tears) and outside the disc in Herniated Nucleus Pulposus (HNP), synovial cysts, foraminal stenosis, central stenosis, spondylolisthesis, is demonstrated. The endoscopic foraminal approach to the spine and disc is a technique that provides access to patho-anatomy in the lumbar spine not usually feasible with traditional surgical methods. Favorable surgical results allow for continued evolution of the endoscopic method, concomitant with the continued evolution of endoscopic spinal surgery.
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December 2006

Controversy about pseudo-Kümmell's disease.

Pain Physician 2003 Oct;6(4):540; author reply 542

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October 2003

Characterization of a periplasmic S1-like nuclease coded by the Mesorhizobium loti symbiosis island.

Biochem Biophys Res Commun 2006 Apr 28;343(1):77-84. Epub 2006 Feb 28.

Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.

DNA sequences encoding hypothetical proteins homologous to S1 nuclease from Aspergillus oryzae are found in many organisms including fungi, plants, pathogenic bacteria, and eukaryotic parasites. One of these is the M1 nuclease of Mesorhizobium loti which we demonstrate herein to be an enzymatically active, soluble, and stable S1 homolog that lacks the extensive mannosyl-glycosylation found in eukaryotic S1 nuclease homologs. We have expressed the cloned M1 protein in M. loti and purified recombinant native M1 to near homogeneity and have also isolated a homogeneous M1 carboxy-terminal hexahistidine tag fusion protein. Mass spectrometry and N-terminal Edman degradation sequencing confirmed the protein identity. The enzymatic properties of the purified M1 nuclease are similar to those of S1. At acidic pH M1 is 25 times more active on single-stranded DNA than on double-stranded DNA and 3 times more active on single-stranded DNA than on single-stranded RNA. At neutral pH the RNase activity of M1 exceeds the DNase activity. M1 nicks supercoiled RF-I plasmid DNA and rapidly cuts the phosphodiester bond across from the nick in the resultant relaxed RF-II plasmid DNA. Therefore, M1 represents an active bacterial S1 homolog in spite of great sequence divergence. The biochemical characterization of M1 nuclease supports our sequence alignment that reveals the minimal 21 amino acid residues that are necessarily conserved for the structure and functions of this enzyme family. The ability of M1 to degrade RNA at neutral pH implies previously unappreciated roles of these nucleases in biological systems.
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http://dx.doi.org/10.1016/j.bbrc.2006.02.117DOI Listing
April 2006

Enzymatic mutation detection technologies.

Biotechniques 2005 May;38(5):749-58

Fox Chase Cancer Center, Philadelphia, PA 19111-2497, USA.

Mutation is as necessary for life as fidelity is in DNA replication. The study of mutations reveals the normal functions of genes, messages, proteins, the causes of many diseases, and the variability of responses among individuals. Indeed, recent mutations that have not yet become polymorphisms are often deleterious and pertinent to the disease history of afflicted individuals. This review discusses the principles behind a variety of methods for the detection of mutations and factors that should be considered in future methods design. One enzymatic approach in particular using orthologs of the CEL I nuclease that show high specificity for all mismatches, appears to be easy and robust. Further developments of this and other methods will allow mutation detection to become an integral component of individualized medicine.
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http://dx.doi.org/10.2144/05385RV01DOI Listing
May 2005

Altered gene expression in phenotypically normal renal cells from carriers of tumor suppressor gene mutations.

Cancer Biol Ther 2004 Dec 9;3(12):1313-21. Epub 2004 Dec 9.

Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

Background: The inherently complex signaling networks of tumors result from genetic and epigenetic alterations that occur during cancer initiation and progression.

Methods: In an attempt to identify early molecular changes associated with dominantly inherited predisposition to "two-hit" renal tumors, the expression profiles of primary cultures of phenotypically normal renal epithelial cells from individuals bearing a germline mutation in either the von Hippel-Lindau (VHL) or the tuberous sclerosis complex (TSC) gene were compared to that of renal epithelial cells from control nonmutation carriers by microarray analysis.

Results: Reliability of the microarray data from pooled samples was confirmed by real-time RT-PCR. Principal Component Analysis revealed substantial differences in the gene expression profiles of the renal epithelial cells from VHL and TSC mutation carriers. In several instances, the microarray data confirm our present knowledge of the cellular pathways affected by biallelic VHL and TSC mutations.

Conclusions: These findings demonstrate that heterozygosity for a mutant tumor suppressor gene may alter the expression profiles of phenotypically normal epithelial cells in a gene-specific manner. Detectable effects of "one-hit" represent early molecular changes in tumorigenesis that may serve as targets for chemopreventive intervention.
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http://dx.doi.org/10.4161/cbt.3.12.1459DOI Listing
December 2004

Posterolateral transforaminal selective endoscopic discectomy and thermal annuloplasty for chronic lumbar discogenic pain: a minimal access visualized intradiscal surgical procedure.

Spine J 2004 Sep-Oct;4(5):564-73

1245 16th Street, #202, Santa Monica, CA 90404, USA.

Background Context: Chronic lumbar discogenic pain (CLDP) impairs the patient's physical abilities to function within the normal physiologic loading ranges of activities of daily living. The pathogenesis of CLDP is multifactorial and not well understood. Conservative therapeutic regimens often fail to achieve sufficient pain relief. Surgical options vary greatly in surgical invasiveness as well as outcome. Definitive surgical treatment is often 360-degree fusion. The morbidity associated with this approach is significant, considering that only 65% to 80% of patients obtain satisfactory clinical results. This has spawned interest in minimally invasive surgical options, such as intradiscal electrothermal therapy (IDET; ORATEC Interventions, Inc., Menlo Park, CA), but results are conflicting.

Purpose: The authors describe their surgical technique of minimal access posterolateral transforaminal selective endoscopic discectomy (SED) and bipolar radiofrequency thermal annuloplasty to treat CLDP. The procedure's rationale is based on the hypothesis that annular defects are the focal points of chronic exposure between neural sensory receptors in the defect and the inflammatogenic nucleus pulposus. In contrast to other percutaneous procedures, this technique allows direct visualization and targeting of the disc nucleus and annular fissures. Our 2-year clinical result is reported.

Study Design/setting: This is a retrospective review of consecutive surgical cases performed by one surgeon (ATY). The procedures were carried out from January 1997 to December 1999. Each patient has a minimum postoperative follow-up of 2 years.

Patient Sample: A total of 113 patients met the generally accepted clinical criteria for chronic lumbar discogenic pain and were selected for the procedure.

Outcome Measures: Two outcome measures were used for clinical assessment: a surgeon-based modified MacNab method and a patient-based questionnaire. A mandatory poor result was given to any patient who had repeat spine surgery at the same level or has indicated dissatisfaction with the surgical result on the questionnaire response.

Method: After meeting CLDP selection criteria, provocation contrast/indigo carmine dye discography was performed. This test was used to confirm the suspected discs as pain generators. The subject surgery then followed. Only cases with one and two levels of confirmed painful discs were entered into the study. The nonoperating author (PMT) analyzed the data.

Results: Using the surgeon assessment method, 17 patients (15%) had excellent results, 32 patients (28.3%) had good results, 34 patients (30.1%) had fair results and 30 patients (26.5%) had poor results. Of the 30 patients in the poor result group, 12 reported either no improvement or worsening, and refused further surgical treatment. Of the remaining 18 patients in the poor group, 8 had spinal fusion, 3 had laminectomy and 7 had repeat spinal endoscopic surgery. The patient-based questionnaire yielded similar percentages in each category. However, only 73.5% of the 113 patients returned the survey questionnaire. There were no aborted procedures, unexpected hemorrhage, device-related complications, neurologic deficits, perioperative deaths or late instability.

Conclusions: Posterolateral transforaminal SED and radiofrequency thermal annuloplasty were used to interrupt the purported annular defect pain sensitization process, thought to be necessary in the genesis of chronic lumbar discogenic pain. Lack of clinical benefit from the subject procedure did not degrade any subsequent surgical or nonsurgical treatment options. The experience gained from this study warrants further investigation into the cellular and molecular processes that provided back pain relief in these patients.
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http://dx.doi.org/10.1016/j.spinee.2004.01.014DOI Listing
January 2005

Analyzing alkaline proteins in human colon crypt proteome.

J Proteome Res 2004 Jul-Aug;3(4):821-33

Basic Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

Normal human colon crypt protein extract was resolved by two-dimensional gel electrophoresis using pH 6-11 immobilized pH gradient strips in the first dimension. The optimized isoelectric focusing protocol includes cup-loading sample application at the anode and 1.2% hydroxyethyl disulfide (DeStreak), 15% 2-propanol and 5% glycerol in the rehydration buffer. Spots were well resolved across the entire pH range up to 11. A total of 311 protein spots were identified by mass spectrometry and peptide mass mapping. After combining isoforms, 231 nonredundant proteins were grouped into 16 categories according to their subcellular locations, and 17 categories according to their physiological functions. Histone proteins, ribosomal proteins and mitochondrial proteins were among the well-resolved highest p/ proteins. Application of this protocol to the analysis of normal and neoplastic colon crypts will contribute to the proteomic study of colorectal tumorigenesis since a significant portion of the human proteins is in basic pH range.
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http://dx.doi.org/10.1021/pr049942jDOI Listing
January 2005

Ultraviolet irradiation of cells.

Methods Mol Biol 2004 ;285:133-7

Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA, USA.

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http://dx.doi.org/10.1385/1-59259-822-6:133DOI Listing
October 2004
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