Publications by authors named "Jeffrey Bond"

67 Publications

Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion.

Cancer Res 2021 12 5;81(23):5818-5832. Epub 2021 Oct 5.

Translational Genomics Research Institute (TGen), Phoenix, Arizona.

Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here the genomic and transcriptomic landscapes of R/R solid tumors from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated tumors at diagnosis, with one-third of tumors classified as having a pediatric high TMB. Prior chemotherapy exposure influenced the mutational landscape of these R/R tumors, with more than 40% of tumors demonstrating mutational signatures associated with platinum or temozolomide chemotherapy and two tumors showing treatment-associated hypermutation. Immunogenomic profiling found a heterogenous pattern of neoantigen and MHC class I expression and a general absence of immune infiltration. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology clusters associated with development, immune signaling, and cellular signaling pathways. While the landscapes of these R/R tumors reflected those of their corresponding untreated tumors at diagnosis, important exceptions were observed, suggestive of tumor evolution, treatment resistance mechanisms, and mutagenic etiologies of treatment. SIGNIFICANCE: Tumor heterogeneity, chemotherapy exposure, and tumor evolution contribute to the molecular profiles and increased mutational burden that occur in treatment-refractory and relapsed childhood solid tumors.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1033DOI Listing
December 2021

The MDM2 inhibitor CGM097 combined with the BET inhibitor OTX015 induces cell death and inhibits tumor growth in models of neuroblastoma.

Cancer Med 2020 11 9;9(21):8144-8158. Epub 2020 Oct 9.

Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital, Grand Rapids, MI, USA.

Background: Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, with amplification of the oncogene MYCN being a hallmark of high-risk disease and poor prognosis. Although less frequent, overexpression of MYC is similarly an indicator of poor prognosis. Most NB tumors initially respond to chemotherapy, however, most will relapse, resulting in chemoresistant disease. After relapse, there is growing evidence of p53 inactivation. MYC/MYCN and MDM2 have been shown to interact and contribute to NB growth and disease progression. MDM2 inhibitors and Bromodomain and Extra-Terminal domain (BET) inhibitors have both shown promise in treating NB by increasing the expression of p53 and decreasing MYC/MYCN expression, respectively. Our study focuses on the combined treatment of a MDM2 inhibitor (CGM097) with a BET inhibitor (OTX015) in neuroblastoma.

Methods: Two p53 wild-type and two p53 mutant established neuroblastoma cells lines were used to test this combination. Ray design assays were used to test whether this combination was synergistically cytotoxic to NB cells. Western blots were performed to check signaling pathways of interest after drug treatment. IncuCyte imaging and flow cytometry were utilized to quantify the apoptotic and cytostatic effects of these drugs on NB cells. In vivo studies were carried out to test the antitumor effect of this combination in a living host.

Results: The combination of CGM097 and OTX015 resulted in p53 activation, decreased expression of MYC family proteins and a subsequent synergistic increase in NB cell death.

Conclusion: This study warrants further investigation into the combination of MDM2 inhibitors and BET inhibitors for the treatment in NB.
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http://dx.doi.org/10.1002/cam4.3407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643634PMC
November 2020

Cell surface vimentin-positive circulating tumor cell-based relapse prediction in a long-term longitudinal study of postremission neuroblastoma patients.

Int J Cancer 2020 12 23;147(12):3550-3559. Epub 2020 Jun 23.

Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Neuroblastoma (NB) is a deadly childhood disease that carries a 50% chance of relapse for anyone in remission and similar level of 5-year survival. We investigated the value of our proprietary approach-cell surface vimentin (CSV) positive circulating tumor cells (CTC) to monitor treatment response and predict relapse in NB patients under remission in a Phase II long-term preventative clinical trial. We longitudinally analyzed peripheral blood samples from 93 patients for 27 cycles (~25 months) and discovered that the presence of CSV CTCs in the first two sequential samples (baseline, cycle 4 [month 3-4]) was a significant indicator of earlier relapse. We observed strong correlation between relapse-free survival (RFS) and lack of CSV CTCs in first 4 cycles of therapy (95%). There was sensitivity reaching 100% in predicting RFS in patients who had neither CSV CTCs nor MycN amplification. Of note, the low number of CSV CTCs seems equivalent to low tumor load because the prevention therapy difluoromethylornithine yields faster reduction of relapse risk when none or only 1-2 CSV CTCs (every 6 mL) are present in the blood samples compared to >3 CSV CTCs. To the best of our knowledge, this is the first study that directly observes CTCs in under remission NB patients for relapse prediction and the first to gather sequential CSV CTC data in any study in a long-term longitudinal manner.
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http://dx.doi.org/10.1002/ijc.33140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839076PMC
December 2020

Maintenance DFMO Increases Survival in High Risk Neuroblastoma.

Sci Rep 2018 09 27;8(1):14445. Epub 2018 Sep 27.

Medical University of South Carolina, Charleston, USA.

High risk neuroblastoma (HRNB) accounts for 15% of all pediatric cancer deaths. Despite aggressive therapy approximately half of patients will relapse, typically with only transient responses to second-line therapy. This study evaluated the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) as maintenance therapy to prevent relapse following completion of standard therapy (Stratum 1) or after salvage therapy for relapsed/refractory disease (Stratum 2). This Phase II single agent, single arm multicenter study enrolled from June 2012 to February 2016. Subjects received 2 years of oral DFMO (750 ± 250 mg/m twice daily). Event free survival (EFS) and overall survival (OS) were determined on an intention-to-treat (ITT) basis. 101 subjects enrolled on Stratum 1 and 100 were eligible for ITT analysis; two-year EFS was 84% (±4%) and OS 97% (±2%). 39 subjects enrolled on Stratum 2, with a two-year EFS of 54% (±8%) and OS 84% (±6%). DFMO was well tolerated. The median survival time is not yet defined for either stratum. DFMO maintenance therapy for HRNB in remission is safe and associated with high EFS and OS. Targeting ODC represents a novel therapeutic mechanism that may provide a new strategy for preventing relapse in children with HRNB.
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http://dx.doi.org/10.1038/s41598-018-32659-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160434PMC
September 2018

Molecular Guided Therapy Provides Sustained Clinical Response in Refractory Choroid Plexus Carcinoma.

Front Pharmacol 2017 25;8:652. Epub 2017 Sep 25.

Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital at Spectrum HealthGrand Rapids, MI, United States.

Choroid plexus carcinomas (CPCs) are rare, aggressive pediatric brain tumors with no established curative therapy for relapsed disease, and poor survival rates. Mutation or dysfunction correlates with poor or no survival outcome in CPCs. Here, we report the case of a 4 month-old female who presented with disseminated CPC. After initial response to tumor resection and adjuvant-chemotherapy, the tumor recurred and metastasized with no response to aggressive relapse therapy suggesting genetic predisposition. This patient was then enrolled to a Molecular Guided Therapy Clinical Trial. Genomic profiling of patient tumor and normal sample identified a germline mutation with loss of heterozygosity, somatic mutations including , and aberrant activation of biological pathways. The mutations were not targetable for therapy. However, targeting the altered biological pathways (mTOR, PDGFRB, FGF2, HDAC) guided identification of possibly beneficial treatment with a combination of sirolimus, thalidomide, sunitinib, and vorinostat. This therapy led to 92% reduction in tumor size with no serious adverse events, excellent quality of life and long term survival.
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http://dx.doi.org/10.3389/fphar.2017.00652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622196PMC
September 2017

The molecular signature of murine T cell homeostatic proliferation reveals both inflammatory and immune inhibition patterns.

J Autoimmun 2017 Aug 24;82:47-61. Epub 2017 May 24.

Department of Medicine, The University of Vermont College of Medicine, Burlington, VT 05405-0068, USA.

T lymphocyte homeostatic proliferation, driven by the engagement of T cell antigen receptor with self-peptide/major histocompatibility complexes, and signaling through the common γ-chain-containing cytokine receptors, is critical for the maintenance of the T cell compartment and is regulated by the Fas death receptor (Fas, CD95). In the absence of Fas, Fas-deficient lymphoproliferation spontaneous mutation (lpr) mice accumulate homeostatically expanded T cells. The functional consequences of sequential rounds of homeostatic expansion are not well defined. We thus examined the gene expression profiles of murine wild-type and Fas-deficient lpr CD8 T cell subsets that have undergone different amounts of homeostatic proliferation as defined by their level of CD44 expression, and the CD4CD8TCRαβ T cell subset that results from extensive homeostatic expansion of CD8 T cells. Our studies show that recurrent T cell homeostatic proliferation results in global gene expression changes, including the progressive upregulation of both cytolytic proteins such as Fas-Ligand and granzyme B as well as inhibitory proteins such as programmed cell death protein 1 (PD-1) and lymphocyte activating 3 (Lag3). These findings provide an explanation for how augmented T cell homeostatic expansion could lead to the frequently observed clinical paradox of simultaneous autoinflammatory and immunodeficiency syndromes and provide further insight into the regulatory programs that control chronically stimulated T cells.
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http://dx.doi.org/10.1016/j.jaut.2017.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902411PMC
August 2017

Tolcapone induces oxidative stress leading to apoptosis and inhibition of tumor growth in Neuroblastoma.

Cancer Med 2017 Jun 21;6(6):1341-1352. Epub 2017 Apr 21.

Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital, Grand Rapids, Michigan.

Catechol-O-methyltransferase (COMT) is an enzyme that inactivates dopamine and other catecholamines by O-methylation. Tolcapone, a drug commonly used in the treatment of Parkinson's disease, is a potent inhibitor of COMT and previous studies indicate that Tolcapone increases the bioavailability of dopamine in cells. In this study, we demonstrate that Tolcapone kills neuroblastoma (NB) cells in preclinical models by inhibition of COMT. Treating four established NB cells lines (SMS-KCNR, SH-SY5Y, BE(2)-C, CHLA-90) and two primary NB cell lines with Tolcapone for 48 h decreased cell viability in a dose-dependent manner, with IncuCyte imaging and Western blotting indicating that cell death was due to caspase-3-mediated apoptosis. Tolcapone also increased ROS while simultaneously decreasing ATP-per-cell in NB cells. Additionally, COMT was inhibited by siRNA in NB cells and showed similar increases in apoptotic markers compared to Tolcapone. In vivo xenograft models displayed inhibition of tumor growth and a significant decrease in time-to-event in mice treated with Tolcapone compared to untreated mice. These results indicate that Tolcapone is cytotoxic to neuroblastoma cells and invite further studies into Tolcapone as a promising novel therapy for the treatment of neuroblastoma.
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http://dx.doi.org/10.1002/cam4.1065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463066PMC
June 2017

Probing the activity of NTHL1 orthologs by targeting conserved amino acid residues.

DNA Repair (Amst) 2017 05 6;53:43-51. Epub 2017 Mar 6.

Department of Microbiology and Molecular Genetics, The Markey Center for Molecular Genetics, University of Vermont, Stafford Hall, 95 Carrigan Drive, Burlington, VT 05405-0068, United States. Electronic address:

The base excision repair DNA glycosylases, EcoNth and hNTHL1, are homologous, with reported overlapping yet different substrate specificities. The catalytic amino acid residues are known and are identical between the two enzymes although the exact structures of the substrate binding pockets remain to be determined. We sought to explore the sequence basis of substrate differences using a phylogeny-based design of site-directed mutations. Mutations were made for each enzyme in the vicinity of the active site and we examined these variants for glycosylase and lyase activity. Single turnover kinetics were done on a subgroup of these, comparing activity on two lesions, 5,6-dihydrouracil and 5,6-dihydrothymine, with different opposite bases. We report that wild type hNTHL1 and EcoNth are remarkably alike with respect to the specificity of the glycosylase reaction, and although hNTHL1 is a much slower enzyme than EcoNth, the tighter binding of hNTHL1 compensates, resulting in similar k/K values for both enzymes with each of the substrates tested. For the hNTHL1 variant Gln287Ala, the specificity for substrates positioned opposite G is lost, but not that of substrates positioned opposite A, suggesting a discrimination role for this residue. The EcoNth Thr121 residue influences enzyme binding to DNA, as binding is significantly reduced with the Thr121Ala variant. Finally, we present evidence that hNTHL1 Asp144, unlike the analogous EcoNth residue Asp44, may be involved in resolving the glycosylase transition state.
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http://dx.doi.org/10.1016/j.dnarep.2017.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421317PMC
May 2017

RAD51 variant proteins from human lung and kidney tumors exhibit DNA strand exchange defects.

DNA Repair (Amst) 2016 06 25;42:44-55. Epub 2016 Apr 25.

Department of Biochemistry, University of Vermont College of Medicine, Burlington, VT 05405, United States; Department of Microbiology & Molecular Genetics, University of Vermont College of Medicine, Burlington, VT, 05405 United States; University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT 05405 United States. Electronic address:

In human cells, error-free repair of DNA double-strand breaks requires the DNA pairing and strand exchange activities of RAD51 recombinase. Activation of RAD51 recombination activities requires the assembly of RAD51 presynaptic filaments on the single-stranded DNA that forms at resected DSB ends. Mutations in proteins that control presynaptic filament assembly, such as BRCA2, and in RAD51 itself, are associated with human breast cancer. Here we describe the properties of two mutations in RAD51 protein that derive from human lung and kidney tumors, respectively. Sequence variants Q268P and Q272L both map to the DNA binding loop 2 (L2) region of RAD51, a motif that is involved in DNA binding and in the allosteric activation of ATP hydrolysis and DNA strand exchange activities. Both mutations alter the thermal stability, DNA binding, and ATPase properties of RAD51, however both variants retain intrinsic DNA strand exchange activity towards oligonucleotide substrates under optimized conditions. In contrast, both Q268P and Q272L variants exhibit drastically reduced DNA strand exchange activity in reaction mixtures containing long homologous ssDNA and dsDNA substrates and human RPA protein. Mixtures of wild-type and variant proteins also exhibit reduced DNA strand exchange activity, suggesting that heterozygous mutations could negatively affect DNA recombination and repair processes in vivo. Together, the findings of this study suggest that hypomorphic missense mutations in RAD51 protein could be drivers of genomic instability in cancer cells, and thereby contribute to the etiology of metastatic disease.
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http://dx.doi.org/10.1016/j.dnarep.2016.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884548PMC
June 2016

A Phase I Trial of DFMO Targeting Polyamine Addiction in Patients with Relapsed/Refractory Neuroblastoma.

PLoS One 2015 27;10(5):e0127246. Epub 2015 May 27.

College of Human Medicine, Michigan State University, Grand Rapids, Michigan, United States of America; University of Hawaii at Hilo, The Daniel K. Inouye College of Pharmacy, Hilo, Hawaii, United States of America.

Background: Neuroblastoma (NB) is the most common cancer in infancy and most frequent cause of death from extracranial solid tumors in children. Ornithine decarboxylase (ODC) expression is an independent indicator of poor prognosis in NB patients. This study investigated safety, response, pharmacokinetics, genetic and metabolic factors associated with ODC in a clinical trial of the ODC inhibitor difluoromethylornithine (DFMO) ± etoposide for patients with relapsed or refractory NB.

Methods And Findings: Twenty-one patients participated in a phase I study of daily oral DFMO alone for three weeks, followed by additional three-week cycles of DFMO plus daily oral etoposide. No dose limiting toxicities (DLTs) were identified in patients taking doses of DFMO between 500-1500 mg/m2 orally twice a day. DFMO pharmacokinetics, single nucleotide polymorphisms (SNPs) in the ODC gene and urinary levels of substrates for the tissue polyamine exporter were measured. Urinary polyamine levels varied among patients at baseline. Patients with the minor T-allele at rs2302616 of the ODC gene had higher baseline levels (p=0.02) of, and larger decreases in, total urinary polyamines during the first cycle of DFMO therapy (p=0.003) and had median progression free survival (PFS) that was over three times longer, compared to patients with the major G allele at this locus although this last result was not statistically significant (p=0.07). Six of 18 evaluable patients were progression free during the trial period with three patients continuing progression free at 663, 1559 and 1573 days after initiating treatment. Median progression-free survival was less among patients having increased urinary polyamines, especially diacetylspermine, although this result was not statistically significant (p=0.056).

Conclusions: DFMO doses of 500-1500 mg/m2/day are safe and well tolerated in children with relapsed NB. Children with the minor T allele at rs2302616 of the ODC gene with relapsed or refractory NB had higher levels of urinary polyamine markers and responded better to therapy containing DFMO, compared to those with the major G allele at this locus. These findings suggest that this patient subset may display dependence on polyamines and be uniquely susceptible to therapies targeting this pathway.

Trial Registration: Clinicaltrials.gov NCT#01059071.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127246PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446210PMC
April 2016

A 50-Year-Old Woman With Cowden Syndrome and Joint Pains.

Arthritis Care Res (Hoboken) 2015 Nov;67(11):1604-8

Mayo Clinic College of Medicine, Rochester, Minnesota.

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http://dx.doi.org/10.1002/acr.22616DOI Listing
November 2015

Variability of the Ischiofemoral Space Relative to Femur Position: An Ultrasound Study.

PM R 2015 Sep 12;7(9):930-937. Epub 2015 Mar 12.

Department of Physical Medicine and Rehabilitation, Mayo Clinic Sports Medicine Center, 600 Hennepin Ave, #310, Minneapolis, MN 55403.

Background: Ischiofemoral impingement is caused by compression of the quadratus femoris muscle between the ischial tuberosity and lesser trochanter. The evaluation of ischiofemoral impingement includes radiologic studies to evaluate the ischiofemoral space dimensions. No prior study has evaluated the effect of femoral position on ischiofemoral space dimensions.

Objective: To determine whether the dimensions of the ischiofemoral space vary with changes in femoral position.

Design: Cross-sectional study.

Setting: Academic institution.

Participants: Six male and four female subjects with no hip pain and no history of hip disorders or surgery were selected to participate in the study. The subjects' mean age was 31.5 years; mean height, 176.8 cm; mean weight, 70.2 kg; and mean body mass index, 23.6 kg/m(2).

Methods: Ultrasound was used to measure the ischiofemoral space in bilateral gluteal regions of each volunteer. The volunteers underwent imaging in a prone position. The ischiofemoral space was measured with the femur in 9 different positions created through various combinations of frontal (15° abduction, neutral, and 15° adduction) and transverse (30° internal rotation, neutral, and 30° external rotation) plane hip motions.

Main Outcome Measurements: The narrowest ischiofemoral interval, defined as the narrowest distance between the medial cortex of the lesser trochanter and the lateral cortex of the ischial tuberosity.

Results: The anatomic landmarks used to measure the ischiofemoral space were easily identified in all subjects. The frontal plane main effect (F2,18 = 38.611) was statistically significant (P < .001), as was the transverse plane main effect (F2,18 = 82.452, P < .001). These findings indicated that there was a statistically significant difference in ischiofemoral space according to hip position in the frontal and transverse planes. The largest ischiofemoral space measurement occurred with the hip in abduction and internal rotation (51.8 mm; 95% confidence interval [CI], 49.2-54.5 mm), whereas hip adduction and external rotation resulted in the narrowest ischiofemoral space measurement (30.8 mm; 95% CI, 25.5-36.0 mm). The largest difference was between the adduction-external rotation and the abduction-internal rotation positions (mean difference = 21.1 mm; 95% CI, 13.7-28.5 mm; P < .001), and the smallest difference was between the adducted-neutral rotation and the abducted-external rotation positions (mean difference = 0.23 mm; 95% CI, -8.07-8.55 mm; P = .99).

Conclusions: Femoral position affects ischiofemoral space dimensions. The ischiofemoral space widens with abduction and internal rotation and narrows with adduction and external rotation, and thus femoral position should be considered when imaging and measuring the ischiofemoral space.
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http://dx.doi.org/10.1016/j.pmrj.2015.03.010DOI Listing
September 2015

Feasibility of implementing molecular-guided therapy for the treatment of patients with relapsed or refractory neuroblastoma.

Cancer Med 2015 Jun 26;4(6):871-86. Epub 2015 Feb 26.

Translational Genomics Research Institute, Phoenix, Arizona.

The primary objective of the study was to evaluate the feasibility and safety of a process which would utilize genome-wide expression data from tumor biopsies to support individualized treatment decisions. Current treatment options for recurrent neuroblastoma are limited and ineffective, with a survival rate of <10%. Molecular profiling may provide data which will enable the practitioner to select the most appropriate therapeutic option for individual patients, thus improving outcomes. Sixteen patients with neuroblastoma were enrolled of which fourteen were eligible for this study. Feasibility was defined as completion of tumor biopsy, pathological evaluation, RNA quality control, gene expression profiling, bioinformatics analysis, generation of a drug prediction report, molecular tumor board yielding a treatment plan, independent medical monitor review, and treatment initiation within a 21 day period. All eligible biopsies passed histopathology and RNA quality control. Expression profiling by microarray and RNA sequencing were mutually validated. The average time from biopsy to report generation was 5.9 days and from biopsy to initiation of treatment was 12.4 days. No serious adverse events were observed and all adverse events were expected. Clinical benefit was seen in 64% of patients as stabilization of disease for at least one cycle of therapy or partial response. The overall response rate was 7% and the progression free survival was 59 days. This study demonstrates the feasibility and safety of performing real-time genomic profiling to guide treatment decision making for pediatric neuroblastoma patients.
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http://dx.doi.org/10.1002/cam4.436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472210PMC
June 2015

PCI-24781 (abexinostat), a novel histone deacetylase inhibitor, induces reactive oxygen species-dependent apoptosis and is synergistic with bortezomib in neuroblastoma.

J Cancer Ther Res 2013 Dec;2:21

Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, VT.

In this study, we investigated the cytotoxic effects of a broad-spectrum histone deacetylase (HDAC) inhibitor, PCI-24781, alone and in combination with the proteasome inhibitor bortezomib in neuroblastoma cell lines. The combination was shown to induce synergistic cytotoxity involving the formation of reactive oxygen species. The cleavage of caspase-3 and PARP, as determined by western blotting, indicated that cell death was primarily due to apoptosis. Xenograft mouse models indicated increased survival among animals treated with this combination. The Notch signaling pathway and MYCN gene expression were quantified by reverse transcription-polymerase chain reaction (PCR) in cells treated with PCI-24781 and bortezomib, alone and in combination. Notch pathway expression increased in response to an HDAC inhibitor. NFKB1 and MYCN were both significantly down regulated. Our results suggest that PCI-24781 and bortezomib are synergistic in neuroblastoma cell lines and may be a new therapeutic strategy for this disease.
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http://dx.doi.org/10.7243/2049-7962-2-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266584PMC
December 2013

Targeting ornithine decarboxylase reverses the LIN28/Let-7 axis and inhibits glycolytic metabolism in neuroblastoma.

Oncotarget 2015 Jan;6(1):196-206

Pediatric Oncology Translational Research Program, Helen DeVos Children's Hospital, Grand Rapids, MI, USA. College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.

LIN28 has emerged as an oncogenic driver in a number of cancers, including neuroblastoma (NB). Overexpression of LIN28 correlates with poor outcome in NB, therefore drugs that impact the LIN28/Let-7 pathway could be beneficial in treating NB patients. The LIN28/Let-7 pathway affects many cellular processes including the regulation of cancer stem cells and glycolytic metabolism. Polyamines, regulated by ornithine decarboxylase (ODC) modulate eIF-5A which is a direct regulator of the LIN28/Let-7 axis. We propose that therapy inhibiting ODC will restore balance to the LIN28/Let-7 axis, suppress glycolytic metabolism, and decrease MYCN protein expression in NB. Difluoromethylornithine (DFMO) is an inhibitor of ODC in clinical trials for children with NB. In vitro experiments using NB cell lines, BE(2)-C, SMS-KCNR, and CHLA90 show that DFMO treatment reduced LIN28B and MYCN protein levels and increased Let-7 miRNA and decreased neurosphere formation. Glycolytic metabolic activity decreased with DFMO treatment in vivo. Additionally, sensitivity to DFMO treatment correlated with LIN28B overexpression (BE(2)-C>SMS-KCNR>CHLA90). This is the first study to demonstrate that DFMO treatment restores balance to the LIN28/Let-7 axis and inhibits glycolytic metabolism and neurosphere formation in NB and that PET scans may be a meaningful imaging tool to evaluate the therapeutic effects of DFMO treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381588PMC
http://dx.doi.org/10.18632/oncotarget.2768DOI Listing
January 2015

A simple method of measuring tibial tubercle to trochlear groove distance on MRI: description of a novel and reliable technique.

Knee Surg Sports Traumatol Arthrosc 2016 Mar 29;24(3):879-84. Epub 2014 Oct 29.

Department of Orthopedic Surgery and the Sports Medicine Center, Mayo Clinic and Mayo Foundation, Mayo Clinic 200 First St., SW, Rochester, MN, 55905, USA.

Purpose: Tibial tubercle-trochlear groove (TT-TG) distance is a variable that helps guide surgical decision-making in patients with patellar instability. The purpose of this study was to compare the accuracy and reliability of an MRI TT-TG measuring technique using a simple external alignment method to a previously validated gold standard technique that requires advanced software read by radiologists.

Methods: TT-TG was calculated by MRI on 59 knees with a clinical diagnosis of patellar instability in a blinded and randomized fashion by two musculoskeletal radiologists using advanced software and by two orthopaedists using the study technique which utilizes measurements taken on a simple electronic imaging platform. Interrater reliability between the two radiologists and the two orthopaedists and intermethods reliability between the two techniques were calculated using interclass correlation coefficients (ICC) and concordance correlation coefficients (CCC). ICC and CCC values greater than 0.75 were considered to represent excellent agreement.

Results: The mean TT-TG distance was 14.7 mm (Standard Deviation (SD) 4.87 mm) and 15.4 mm (SD 5.41) as measured by the radiologists and orthopaedists, respectively. Excellent interobserver agreement was noted between the radiologists (ICC 0.941; CCC 0.941), the orthopaedists (ICC 0.978; CCC 0.976), and the two techniques (ICC 0.941; CCC 0.933).

Conclusion: The simple TT-TG distance measurement technique analysed in this study resulted in excellent agreement and reliability as compared to the gold standard technique. This method can predictably be performed by orthopaedic surgeons without advanced radiologic software.

Level Of Evidence: II.
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http://dx.doi.org/10.1007/s00167-014-3405-7DOI Listing
March 2016

Posttraumatic fat necrosis presenting as prepatellar loose bodies in an adolescent football player.

PM R 2014 Aug 31;6(8):749-52. Epub 2013 Dec 31.

Department of Physical Medicine and Rehabilitation, Mayo Clinic, W14 Mayo Building, 200 1st Street SW, Rochester, MN 55905; Department of Radiology, and Department of Anatomy, Mayo Clinic College of Medicine, Mayo Clinic Sports Medicine Center, Rochester, MN(‖). Electronic address:

A 16-year-old high school football player presented with 4 months of anterior knee pain and small, mobile, prepatellar "lumps" after falling onto an opponent's cleat. He reported knee pain primarily during knee flexion and direct pressure during squatting and kneeling. Knee radiographs were unremarkable. Ultrasonography revealed multiple, freely mobile, subcutaneous nodules of variable size and echogenicity in the prepatellar region. Analysis of magnetic resonance imaging suggested possible fat necrosis but was nondiagnostic. The patient opted for surgical exploration, at which time multiple, opalescent subcutaneous nodules were removed. Pathology was consistent with encapsulated fat necrosis. After surgery, his symptoms resolved, and he returned to sports without restrictions.
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http://dx.doi.org/10.1016/j.pmrj.2013.12.010DOI Listing
August 2014

Global analysis of the sporulation pathway of Clostridium difficile.

PLoS Genet 2013 8;9(8):e1003660. Epub 2013 Aug 8.

Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, USA.

The Gram-positive, spore-forming pathogen Clostridium difficile is the leading definable cause of healthcare-associated diarrhea worldwide. C. difficile infections are difficult to treat because of their frequent recurrence, which can cause life-threatening complications such as pseudomembranous colitis. The spores of C. difficile are responsible for these high rates of recurrence, since they are the major transmissive form of the organism and resistant to antibiotics and many disinfectants. Despite the importance of spores to the pathogenesis of C. difficile, little is known about their composition or formation. Based on studies in Bacillus subtilis and other Clostridium spp., the sigma factors σ(F), σ(E), σ(G), and σ(K) are predicted to control the transcription of genes required for sporulation, although their specific functions vary depending on the organism. In order to determine the roles of σ(F), σ(E), σ(G), and σ(K) in regulating C. difficile sporulation, we generated loss-of-function mutations in genes encoding these sporulation sigma factors and performed RNA-Sequencing to identify specific sigma factor-dependent genes. This analysis identified 224 genes whose expression was collectively activated by sporulation sigma factors: 183 were σ(F)-dependent, 169 were σ(E)-dependent, 34 were σ(G)-dependent, and 31 were σ(K)-dependent. In contrast with B. subtilis, C. difficile σ(E) was dispensable for σ(G) activation, σ(G) was dispensable for σ(K) activation, and σ(F) was required for post-translationally activating σ(G). Collectively, these results provide the first genome-wide transcriptional analysis of genes induced by specific sporulation sigma factors in the Clostridia and highlight that diverse mechanisms regulate sporulation sigma factor activity in the Firmicutes.
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http://dx.doi.org/10.1371/journal.pgen.1003660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738446PMC
March 2014

Histamine H(3) receptor integrates peripheral inflammatory signals in the neurogenic control of immune responses and autoimmune disease susceptibility.

PLoS One 2013 22;8(7):e62743. Epub 2013 Jul 22.

Department of Medicine, Immunobiology Program, University of Vermont, Burlington, Vermont, USA.

Histamine H(3) receptor (Hrh3/H(3)R) is primarily expressed by neurons in the central nervous system (CNS) where it functions as a presynaptic inhibitory autoreceptor and heteroreceptor. Previously, we identified an H(3)R-mediated central component in susceptibility to experimental allergic encephalomyelitis (EAE), the principal autoimmune model of multiple sclerosis (MS), related to neurogenic control of blood brain barrier permeability and peripheral T cell effector responses. Furthermore, we identified Hrh3 as a positional candidate for the EAE susceptibility locus Eae8. Here, we characterize Hrh3 polymorphisms between EAE-susceptible and resistant SJL and B10.S mice, respectively, and show that Hrh3 isoform expression in the CNS is differentially regulated by acute peripheral inflammatory stimuli in an allele-specific fashion. Next, we show that Hrh3 is not expressed in any subpopulations of the immune compartment, and that secondary lymphoid tissue is anatomically poised to be regulated by central H(3)R signaling. Accordingly, using transcriptome analysis, we show that, inflammatory stimuli elicit unique transcriptional profiles in the lymph nodes of H(3)RKO mice compared to WT mice, which is indicative of negative regulation of peripheral immune responses by central H(3)R signaling. These results further support a functional link between the neurogenic control of T cell responses and susceptibility to CNS autoimmune disease coincident with acute and/or chronic peripheral inflammation. Pharmacological targeting of H(3)R may therefore be useful in preventing the development and formation of new lesions in MS, thereby limiting disease progression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062743PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718788PMC
February 2014

CT and MRI measurements of tibial tubercle-trochlear groove distances are not equivalent in patients with patellar instability.

Am J Sports Med 2013 Aug 15;41(8):1835-40. Epub 2013 Jul 15.

Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.

Background: Tibial tubercle-trochlear groove distance (TT-TG) is a commonly used measurement for surgical decision making in patients with patellofemoral malalignment and instability. This measurement has historically been performed utilizing axial computed tomography (CT). More recently, magnetic resonance imaging (MRI) has been proposed as an equivalent method, but this has not yet been fully validated.

Purpose: To determine the reliability of TT-TG distance measurements on both MRI and CT and to determine whether the measurements are interchangeable with one another.

Study Design: Cohort study (diagnosis); Level of evidence, 2.

Methods: All patients with patellar instability who underwent both CT and MRI of the knee from 2003 to 2011 were included (n = 59 knees in 54 patients). Two fellowship-trained musculoskeletal radiologists measured the TT-TG distances for each patient by CT and MRI in a randomized, blinded fashion. Interobserver reliability was calculated between radiologists for both imaging modalities, and intermethod reliability was calculated between the 2 imaging modalities. The results are reported using intraclass correlation coefficients (ICCs) and Bland-Altman analysis.

Results: The 59 knees had a mean TT-TG distance of 16.9 mm (range, 8.3-25.8 mm) by CT and 14.7 mm (range, 1.5-25.1 mm) by MRI. Interobserver reliability between the radiologists was considered excellent for both CT and MRI (ICC = 0.777 and 0.843, respectively). When comparing CT to MRI, the ICC was considered only fair for each of the raters (0.532 and 0.539). Eleven patients (19%) had a TT-TG distance of ≥20 mm on CT preoperatively and underwent distal realignment by tibial tubercle osteotomy. In this surgical subgroup, the mean TT-TG distance was 22.5 mm (range, 19.8-25.8 mm) by CT and only 18.7 mm (range, 14.4-22.8 mm) by MRI for a mean difference of 3.80 mm (P < .001).

Conclusion: The TT-TG distance can be measured with excellent interrater reliability on both MRI and CT; however, the values derived from these 2 tests may not be interchangeable. This observation should be taken into consideration when MRI is used for surgical planning because MRI may underestimate the TT-TG distance when compared with CT.
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http://dx.doi.org/10.1177/0363546513484895DOI Listing
August 2013

Decreased range of motion is associated with structural hip deformity in asymptomatic adolescent athletes.

Am J Sports Med 2013 Jul 22;41(7):1519-25. Epub 2013 May 22.

Department of Orthopedic Surgery, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.

Background: Decreased hip range of motion (ROM) is a common finding in patients with femoroacetabular impingement (FAI).

Purpose: To report the prevalence of decreased hip ROM in asymptomatic adolescent athletes and to correlate examination findings to signs of FAI on radiographs and magnetic resonance imaging (MRI).

Study Design: Cross-sectional study (prevalence); Level of evidence, 3.

Methods: A total of 226 adolescent athletes presenting for state-mandated preparticipation physical examinations were assessed. Hip internal rotation was measured with the participant supine and the hip flexed to 90°. All participants with ≤10° of internal rotation were invited to return for standard radiographs and MRI of both hips. An age-matched control group, with >10° of internal rotation, underwent MRI examination only. Twenty-six athletes (13 study and 13 control) returned for clinical and radiographic examinations.

Results: Nineteen athletes (34 hips, 8%) were found to have <10° of internal rotation. Eight athletes (13 hips, 3%) also had a positive anterior impingement sign. Thirteen of 19 athletes participated in the radiographic portion of the study. Of these 13 participants, 4 had limited internal rotation unilaterally, leaving 22 hips in the study group. Eight of 13 participants (15 hips, 68%) had a cam-type deformity evident on plain radiographs, and 4 participants (7 hips, 32%) had a positive radiographic crossover sign. The average α angle measured from radial MRI sequences was 58.1° in the study group versus 44.3° in the control group (P < .001). Fifteen hips (68%) in the study group had abnormal MRI findings within the acetabular labrum or cartilage compared with 10 of 26 hips (38%) in the control group (odds ratio, 3.4; P = .078).

Conclusion: Eight percent of asymptomatic teenagers had limited internal rotation on examination; 68% of these had radiographic findings suggestive of FAI. More than two thirds of these participants had evidence of asymptomatic hip pathological lesions on MRI.
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http://dx.doi.org/10.1177/0363546513488748DOI Listing
July 2013

Milk yield responses to changes in milking frequency during early lactation are associated with coordinated and persistent changes in mammary gene expression.

BMC Genomics 2013 May 2;14:296. Epub 2013 May 2.

Background: The lactating mammary gland responds to changes in milking frequency by modulating milk production. This response is locally regulated and, in dairy cows, the udder is particularly sensitive during early lactation. Relative to cows milked twice-daily throughout lactation, those milked four-times-daily for just the first 3 weeks of lactation produce more milk throughout that lactation. We hypothesized that the milk yield response would be associated with increased mammary cell turnover and changes in gene expression during frequent milking and persisting thereafter. Cows were assigned to unilateral frequent milking (UFM; left udder halves milked twice-daily; right udder halves milked four-times daily) on days 1 to 21 of lactation, followed by twice-daily milking for the remainder of lactation. Relative to udder halves milked twice-daily, those milked four-times produced more milk during UFM; the difference in milk yield declined acutely upon cessation of UFM after day 21, but remained significantly elevated thereafter. We obtained mammary biopsies from both udder halves on days 21, 23, and 40 of lactation.

Results: Mammary cell proliferation and apoptosis were not affected by milking frequency. We identified 75 genes that were differentially expressed between paired udder halves on day 21 but exhibited a reversal of differential expression on day 23. Among those genes, we identified four clusters characterized by similar temporal patterns of differential expression. Two clusters (11 genes) were positively correlated with changes in milk yield and were differentially expressed on day 21 of lactation only, indicating involvement in the initial milk yield response. Two other clusters (64 genes) were negatively correlated with changes in milk yield. Twenty-nine of the 75 genes were also differentially expressed on day 40 of lactation.

Conclusions: Changes in milking frequency during early lactation did not alter mammary cell population dynamics, but were associated with coordinated changes in mammary expression of at least 75 genes. Twenty-nine of those genes were differentially expressed 19 days after cessation of treatment, implicating them in the persistent milk yield response. We conclude that we have identified a novel transcriptional signature that may mediate the adaptive response to changes in milking frequency.
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http://dx.doi.org/10.1186/1471-2164-14-296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658990PMC
May 2013

Comparative RNA-Seq and microarray analysis of gene expression changes in B-cell lymphomas of Canis familiaris.

PLoS One 2013 4;8(4):e61088. Epub 2013 Apr 4.

Laboratory of Translational Medicine, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.

Comparative oncology is a developing research discipline that is being used to assist our understanding of human neoplastic diseases. Companion canines are a preferred animal oncology model due to spontaneous tumor development and similarity to human disease at the pathophysiological level. We use a paired RNA sequencing (RNA-Seq)/microarray analysis of a set of four normal canine lymph nodes and ten canine lymphoma fine needle aspirates to identify technical biases and variation between the technologies and convergence on biological disease pathways. Surrogate Variable Analysis (SVA) provides a formal multivariate analysis of the combined RNA-Seq/microarray data set. Applying SVA to the data allows us to decompose variation into contributions associated with transcript abundance, differences between the technology, and latent variation within each technology. A substantial and highly statistically significant component of the variation reflects transcript abundance, and RNA-Seq appeared more sensitive for detection of transcripts expressed at low levels. Latent random variation among RNA-Seq samples is also distinct in character from that impacting microarray samples. In particular, we observed variation between RNA-Seq samples that reflects transcript GC content. Platform-independent variable decomposition without a priori knowledge of the sources of variation using SVA represents a generalizable method for accomplishing cross-platform data analysis. We identified genes differentially expressed between normal lymph nodes of disease free dogs and a subset of the diseased dogs diagnosed with B-cell lymphoma using each technology. There is statistically significant overlap between the RNA-Seq and microarray sets of differentially expressed genes. Analysis of overlapping genes in the context of biological systems suggests elevated expression and activity of PI3K signaling in B-cell lymphoma biopsies compared with normal biopsies, consistent with literature describing successful use of drugs targeting this pathway in lymphomas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0061088PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3617154PMC
November 2013

Identification of Orch3, a locus controlling dominant resistance to autoimmune orchitis, as kinesin family member 1C.

PLoS Genet 2012 27;8(12):e1003140. Epub 2012 Dec 27.

Department of Medicine/Immunobiology Program, University of Vermont, Burlington, Vermont, United States of America.

Experimental autoimmune orchitis (EAO), the principal model of non-infectious testicular inflammatory disease, can be induced in susceptible mouse strains by immunization with autologous testicular homogenate and appropriate adjuvants. As previously established, the genome of DBA/2J mice encodes genes that are capable of conferring dominant resistance to EAO, while the genome of BALB/cByJ mice does not and they are therefore susceptible to EAO. In a genome scan, we previously identified Orch3 as the major quantitative trait locus controlling dominant resistance to EAO and mapped it to chromosome 11. Here, by utilizing a forward genetic approach, we identified kinesin family member 1C (Kif1c) as a positional candidate for Orch3 and, using a transgenic approach, demonstrated that Kif1c is Orch3. Mechanistically, we showed that the resistant Kif1c(D2) allele leads to a reduced antigen-specific T cell proliferative response as a consequence of decreased MHC class II expression by antigen presenting cells, and that the L(578) → P(578) and S(1027) → P(1027) polymorphisms distinguishing the BALB/cByJ and DBA/2J alleles, respectively, can play a role in transcriptional regulation. These findings may provide mechanistic insight into how polymorphism in other kinesins such as KIF21B and KIF5A influence susceptibility and resistance to human autoimmune diseases.
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http://dx.doi.org/10.1371/journal.pgen.1003140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531464PMC
May 2013

Musculotendinous infraspinatus rupture and shoulder weakness.

J Clin Neuromuscul Dis 2011 Dec;13(2):95-7

Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.

We report a patient with bilateral simultaneous onset of weakness of shoulder lateral rotation due to musculotendinous infraspinatus rupture that occurred after shoulder steroid injections. Disruption of the musculotendinous junction of the infraspinatus is a rare recently described entity. Electromyography is normal, and magnetic resonance image findings are characteristic.
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http://dx.doi.org/10.1097/CND.0b013e3182212559DOI Listing
December 2011

Mammary gland morphological and gene expression changes underlying pregnancy protection of breast cancer tumorigenesis.

Physiol Genomics 2012 Jan 15;44(1):76-88. Epub 2011 Nov 15.

Laboratory of Lactation and Mammary Gland Biology, Department of Animal Science, University of Vermont, Burlington, Vermont, USA.

A full-term pregnancy early in life reduces lifetime risk of developing breast cancer, and the effect can be mimicked in rodents by full-term pregnancy or short-term treatment with exogenous estrogen and progesterone. To gain insight into the protective mechanism, 15 3-mo-old postpubertal virgin Lewis rats were randomly assigned to three groups: control (C), pregnancy (P), or hormone (H). The P group animals underwent a full-term pregnancy, and H group animals were implanted subcutaneously with silastic capsules filled with ethynyl estradiol and megesterol acetate for 21 days. C and P animals were implanted with sham capsules. On day 21 capsules were removed, which was followed by a 49-day involution period, euthanasia, and mammary tissue collection. Global gene expression was measured using Rat Genome 230.2 Arrays. Histological analysis revealed that P and H treatments induced sustained morphological changes in the mammary gland with significantly increased percentages of mammary parenchyma and stromal tissues and higher ratio of stroma to parenchyma. Transcriptome analysis showed that P and H treatments induced sustained global changes in gene expression in the mammary gland. Analysis of commonly up- and downregulated genes in P and H relative to C treatment showed increased expression of three matrix metallopeptidases (Mmp3, 8, and 12), more differentiated mammary phenotype, enhanced innate and adaptive immunity, and reduced cell proliferation and angiogenic signatures. The sustained morphological and global gene expression changes in mammary tissue after pregnancy and hormone treatment may function together to provide the protective effect against breast cancer.
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http://dx.doi.org/10.1152/physiolgenomics.00056.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116391PMC
January 2012

Using shifts in amino acid frequency and substitution rate to identify latent structural characters in base-excision repair enzymes.

PLoS One 2011 6;6(10):e25246. Epub 2011 Oct 6.

Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, Vermont, United States of America.

Protein evolution includes the birth and death of structural motifs. For example, a zinc finger or a salt bridge may be present in some, but not all, members of a protein family. We propose that such transitions are manifest in sequence phylogenies as concerted shifts in substitution rates of amino acids that are neighbors in a representative structure. First, we identified rate shifts in a quartet from the Fpg/Nei family of base excision repair enzymes using a method developed by Xun Gu and coworkers. We found the shifts to be spatially correlated, more precisely, associated with a flexible loop involved in bacterial Fpg substrate specificity. Consistent with our result, sequences and structures provide convincing evidence that this loop plays a very different role in other family members. Second, then, we developed a method for identifying latent protein structural characters (LSC) given a set of homologous sequences based on Gu's method and proximity in a high-resolution structure. Third, we identified LSC and assigned states of LSC to clades within the Fpg/Nei family of base excision repair enzymes. We describe seven LSC; an accompanying Proteopedia page (http://proteopedia.org/wiki/index.php/Fpg_Nei_Protein_Family) describes these in greater detail and facilitates 3D viewing. The LSC we found provided a surprisingly complete picture of the interaction of the protein with the DNA capturing familiar examples, such as a Zn finger, as well as more subtle interactions. Their preponderance is consistent with an important role as phylogenetic characters. Phylogenetic inference based on LSC provided convincing evidence of independent losses of Zn fingers. Structural motifs may serve as important phylogenetic characters and modeling transitions involving structural motifs may provide a much deeper understanding of protein evolution.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0025246PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3188539PMC
February 2012
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