Publications by authors named "Alexis Jones"

34 Publications

Impact of a year-round school calendar on children's BMI and fitness: Final outcomes from a natural experiment.

Pediatr Obes 2021 Mar 25:e12789. Epub 2021 Mar 25.

Department of Exercise Science, University of South Carolina, Columbia, South Carolina, USA.

Background: Structure may mitigate children's accelerated summer BMI gain and cardiorespiratory-fitness (CRF) loss.

Objectives: Examine BMI and CRF change during school and summer for year-round and traditional calendar school children.

Methods: Three schools (N = 2279, 1 year-round) participated in this natural experiment. Children's BMI z-score (zBMI) and CRF (PACER laps) were measured from 2017 to 2019 each May/August. Mixed effects regression estimated monthly zBMI and CRF change during school/summer. Secondary analyses examined differences by weight status and race. Spline regression models estimated zBMI and CRF growth from kindergarten-sixth grade.

Results: Compared to traditional school, children attending a year-round school gained more zBMI (difference = 0.015; 95CI = 0.002, 0.028) during school, and less zBMI (difference = -0.029; 95CI = -0.041, -0.018), and more CRF (difference = 0.834; 95CI = 0.575, 1.093) monthly during summer. Differences by weight status and race were observed during summer and school. Growth models demonstrated that the magnitude of overall zBMI and CRF change from kindergarten-sixth grade was similar for year-round or traditional school children.

Conclusions: Contrary to traditional school children zBMI increased during the traditional 9-month school calendar and zBMI decreased during the traditional summer vacation for year-round school children. Structured summer programming may mitigate accelerated summer BMI gain and CRF loss especially for overweight or obese, and/or Black children.
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http://dx.doi.org/10.1111/ijpo.12789DOI Listing
March 2021

Comparison of multichannel and single-channel wrist-based devices with polysomnography to measure sleep in children and adolescents.

J Clin Sleep Med 2021 Apr;17(4):645-652

Department of Exercise Science, University of South Carolina, Columbia, South Carolina.

Study Objectives: To compare sleep parameters produced by the Fitbit Charge 3 (Fitbit) and Actigraph GT9X accelerometer (Actigraph) to polysomnography in children and adolescents.

Methods: Participants (n = 56, ages 9.2 ± 3.3 years) wore a Fitbit and an Actigraph on their nondominant wrist concurrently with polysomnography during an overnight observation at a children's sleep laboratory. Total sleep time, sleep efficiency, wake after sleep onset, sleep onset, and sleep offset were extracted from the Fitabase and Actilife software packages, respectively, with the Sadeh algorithm. Bland-Altman plots were used to assess the agreement between wearable devices and polysomnography.

Results: Seventy-nine percent of participants were diagnosed with OSA. Compared with polysomnography, the Fitbit and the Actigraph underestimated total sleep time by 6.1 minutes (absolute mean bias [AMB] = 27.7 minutes) and 31.5 minutes (AMB = 38.2 minutes), respectively. The Fitbit overestimated sleep efficiency by 3.0% (AMB = 6.3%), and the Actigraph underestimated sleep efficiency by 12.9% (AMB = 13.2%). The Fitbit overestimated wake after sleep onset by 18.8 minutes (AMB = 23.9 minutes), and the Actigraph overestimated wake after sleep onset by 56.1 minutes (AMB = 54.7 minutes). In addition, the Fitbit and the Actigraph underestimated sleep onset by 1.2 minutes (AMB = 13.9 minutes) and 10.2 minutes (AMB = 18.1 minutes), respectively. Finally, the Fitbit and the Actigraph overestimated sleep offset by 6.0 minutes (AMB = 12.0 minutes) and 10.5 minutes (AMB = 12.6 minutes). Linear regression indicated significant trends, with the Fitbit underestimating wake after sleep onset and sleep efficiency at higher values.

Conclusions: The Fitbit provided comparable and in some instances better sleep estimates with polysomnography compared to the Actigraph. Findings support the use of multichannel devices to measure sleep in children and adolescents. Additional studies are needed in healthy children over several nights and in free-living settings.
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http://dx.doi.org/10.5664/jcsm.8980DOI Listing
April 2021

Derivation of stable embryonic stem cell-like, but transcriptionally heterogenous, induced pluripotent stem cells from non-permissive mouse strains.

Mamm Genome 2020 12 4;31(9-12):263-286. Epub 2020 Oct 4.

Texas A&M Institute for Genome Sciences and Society, Texas A&M University, College Station, TX, 77843, USA.

Genetic background is known to play a role in the ability to derive pluripotent, embryonic stem cells (ESC), a trait referred to as permissiveness. Previously we demonstrated that induced pluripotent stem cells (iPSC) can be readily derived from non-permissive mouse strains by addition of serum-based media supplemented with GSK3B and MEK inhibitors, termed 2iS media, 3 days into reprogramming. Here, we describe the derivation of second type of iPSC colony from non-permissive mouse strains that can be stably maintained independently of 2iS media. The resulting cells display transcriptional heterogeneity similar to that observed in ESC from permissive genetic backgrounds derived in conventional serum containing media supplemented with leukemia inhibitor factor. However, unlike previous studies that report exclusive subpopulations, we observe both exclusive and simultaneous expression of naive and primed cell surface markers. Herein, we explore shifts in pluripotency in the presence of 2iS and characterize heterogenous subpopulations to determine their pluripotent state and role in heterogenous iPSCs derived from the non-permissive NOD/ShiLtJ strain. We conclude that heterogeneity is a naturally occurring, necessary quality of stem cells that allows for the maintenance of pluripotency. This study further demonstrates the efficacy of the 2iS reprogramming technique. It is also the first study to derive stable ESC-like stem cells from the non-permissive NOD/ShiLtJ and WSB/EiJ strains, enabling easier and broader research possibilities into pluripotency for these and similar non-permissive mouse strains and species.
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http://dx.doi.org/10.1007/s00335-020-09849-xDOI Listing
December 2020

Gastrointestinal synthetic epithelial linings.

Sci Transl Med 2020 08;12(558)

Department of Chemical Engineering and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Epithelial tissues line the organs of the body, providing an initial protective barrier as well as a surface for nutrient and drug absorption. Here, we identified enzymatic components present in the gastrointestinal epithelium that can serve as selective means for tissue-directed polymerization. We focused on the small intestine, given its role in drug and nutrient absorption and identified catalase as an essential enzyme with the potential to catalyze polymerization and growth of synthetic biomaterial layers. We demonstrated that the polymerization of dopamine by catalase yields strong tissue adhesion. We characterized the mechanism and specificity of the polymerization in segments of the gastrointestinal tracts of pigs and humans ex vivo. Moreover, we demonstrated proof of concept for application of these gastrointestinal synthetic epithelial linings for drug delivery, enzymatic immobilization for digestive supplementation, and nutritional modulation through transient barrier formation in pigs. This catalase-based approach to in situ biomaterial generation may have broad indications for gastrointestinal applications.
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http://dx.doi.org/10.1126/scitranslmed.abc0441DOI Listing
August 2020

Draft Genome Sequences of Six Strains Isolated from the Rhizosphere of Wheat Grown in Cadmium-Contaminated Soil.

Microbiol Resour Announc 2020 Aug 20;9(34). Epub 2020 Aug 20.

School of Biological, Environmental, and Earth Sciences, University of Southern Mississippi, Hattiesburg, Mississippi, USA

This study presents high-quality draft genome assemblies of six bacterial strains isolated from the roots of wheat grown in soil contaminated with cadmium. The results of this study will help to elucidate at the molecular level how heavy metals affect interactions between beneficial rhizobacteria and crop plants.
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http://dx.doi.org/10.1128/MRA.00676-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441233PMC
August 2020

Leveraging Systematic Functional Analysis to Benchmark an Framework Distinguishes Driver from Passenger MEK Mutants in Cancer.

Cancer Res 2020 10 8;80(19):4233-4243. Epub 2020 Jul 8.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

Despite significant advances in cancer precision medicine, a significant hurdle to its broader adoption remains the multitude of variants of unknown significance identified by clinical tumor sequencing and the lack of biologically validated methods to distinguish between functional and benign variants. Here we used functional data on and mutations generated in real-time within a co-clinical trial framework to benchmark the predictive value of a three-part methodology. Our computational approach to variant classification incorporated hotspot analysis, three-dimensional molecular dynamics simulation, and sequence paralogy. prediction accurately distinguished functional from benign and mutants, yet drug sensitivity varied widely among activating mutant alleles. These results suggest that multifaceted modeling can inform patient accrual to MEK/ERK inhibitor clinical trials, but computational methods need to be paired with laboratory- and clinic-based efforts designed to unravel variabilities in drug response. SIGNIFICANCE: Leveraging prospective functional characterization of MEK1/2 mutants, it was found that hotspot analysis, molecular dynamics simulation, and sequence paralogy are complementary tools that can robustly prioritize variants for biologic, therapeutic, and clinical validation..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541597PMC
October 2020

Belimumab after B cell depletion therapy in patients with systemic lupus erythematosus (BEAT Lupus) protocol: a prospective multicentre, double-blind, randomised, placebo-controlled, 52-week phase II clinical trial.

BMJ Open 2019 12 16;9(12):e032569. Epub 2019 Dec 16.

Centre for Rheumatology, Division of Medicine, University College London, London, UK

Introduction: Few treatment options exist for patients with systemic lupus erythematosus (SLE) who fail conventional therapy. Although widely used to treat lupus, the efficacy of B cell depletion therapy using rituximab has not been demonstrated in randomised clinical trials. Following rituximab, elevated levels of serum B cell activating factor (BAFF) have been associated with failure to remit or subsequent lupus relapse. The administration of belimumab, a monoclonal antibody specific for BAFF and approved for lupus therapy, could potentiate the efficacy of rituximab and enable longer periods of disease remission. The aim of this trial is to assess the safety and efficacy of belimumab following rituximab in patients with SLE.

Methods And Analysis: BEAT Lupus is a double-blind, randomised, placebo controlled, phase II clinical trial. Patients with SLE commencing a treatment cycle of rituximab (two 1g infusions, 2 weeks apart) as standard of care will be randomised to receive belimumab or placebo, 4 to 8 weeks following the first rituximab infusion. Belimumab or placebo infusions are administered for 52 weeks. The primary outcome measure is anti-double stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes include measures of adverse events, lupus disease activity and cumulative steroid dose. The kinetics of B cell repopulation will be assessed in a subgroup of participants. Belimumab administration after rituximab may provide a novel therapeutic pathway for patients with active lupus if safety is demonstrated in this proof of concept study, and lower anti-dsDNA antibodies levels are achieved in those patients treated with belimumab compared with placebo.

Ethics And Dissemination: The protocol has been reviewed and approved by the Hampstead Research Ethics Committee - London (reference 16/LO/1024). Trial information is available at https://www.isrctn.com/ISRCTN47873003, and the results of this trial will be submitted for publication in relevant peer-reviewed journals. Key findings will also be presented at national and international conferences.

Trial Registration Number: ISRCTN47873; date assigned to the registry: 28 November 2016. The stage is pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-032569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937022PMC
December 2019

An Anterior Cruciate Ligament Failure Mechanism.

Am J Sports Med 2019 07;47(9):2067-2076

Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, USA.

Background: Nearly three-quarters of anterior cruciate ligament (ACL) injuries occur as "noncontact" failures from routine athletic maneuvers. Recent in vitro studies revealed that repetitive strenuous submaximal knee loading known to especially strain the ACL can lead to its fatigue failure, often at the ACL femoral enthesis.

Hypothesis: ACL failure can be caused by accumulated tissue fatigue damage: specifically, chemical and structural evidence of this fatigue process will be found at the femoral enthesis of ACLs from tested cadaveric knees, as well as in ACL explants removed from patients undergoing ACL reconstruction.

Study Design: Controlled laboratory study.

Methods: One knee from each of 7 pairs of adult cadaveric knees were repetitively loaded under 4 times-body weight simulated pivot landings known to strain the ACL submaximally while the contralateral, unloaded knee was used as a comparison. The chemical and structural changes associated with this repetitive loading were characterized at the ACL femoral enthesis at multiple hierarchical collagen levels by employing atomic force microscopy (AFM), AFM-infrared spectroscopy, molecular targeting with a fluorescently labeled collagen hybridizing peptide, and second harmonic imaging microscopy. Explants from ACL femoral entheses from the injured knee of 5 patients with noncontact ACL failure were also characterized via similar methods.

Results: AFM-infrared spectroscopy and collagen hybridizing peptide binding indicate that the characteristic molecular damage was an unraveling of the collagen molecular triple helix. AFM detected disruption of collagen fibrils in the forms of reduced topographical surface thickness and the induction of ~30- to 100-nm voids in the collagen fibril matrix for mechanically tested samples. Second harmonic imaging microscopy detected the induction of ~10- to 100-µm regions where the noncentrosymmetric structure of collagen had been disrupted. These mechanically induced changes, ranging from molecular to microscale disruption of normal collagen structure, represent a previously unreported aspect of tissue fatigue damage in noncontact ACL failure. Confirmatory evidence came from the explants of 5 patients undergoing ACL reconstruction, which exhibited the same pattern of molecular, nanoscale, and microscale structural damage detected in the mechanically tested cadaveric samples.

Conclusion: The authors found evidence of accumulated damage to collagen fibrils and fibers at the ACL femoral enthesis at the time of surgery for noncontact ACL failure. This tissue damage was similar to that found in donor knees subjected in vitro to repetitive 4 times-body weight impulsive 3-dimensional loading known to cause a fatigue failure of the ACL.

Clinical Relevance: These findings suggest that some ACL injuries may be due to an exacerbation of preexisting hierarchical tissue damage from activities known to place larger-than-normal loads on the ACL. Too rapid an increase in these activities could cause ACL tissue damage to accumulate across length scales, thereby affecting ACL structural integrity before it has time to repair. Prevention necessitates an understanding of how ACL loading magnitude and frequency are anabolic, neutral, or catabolic to the ligament.
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http://dx.doi.org/10.1177/0363546519854450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905051PMC
July 2019

Performance of magnetic resonance imaging in the diagnosis of axial spondyloarthritis: a systematic literature review.

Rheumatology (Oxford) 2019 11;58(11):1955-1965

Department of Rheumatology, University College London Hospitals NHS Foundation Trust, London, UK.

Objectives: To summarize the evidence on the performance of MRI for the diagnosis of axial SpA.

Methods: This was a systematic literature review of all studies from January 2013 to March 2017 including adult patients with clinically suspected axial SpA undergoing MRI. Studies from a previously published systematic literature review up to January 2013 were also included.

Results: Thirty-one studies were included. Six studies demonstrated good sensitivity and specificity for SI joint (SIJ) bone marrow oedema (BMO). Specificity was increased by the presence of other structural lesions alongside BMO, particularly erosions or fat infiltration. Four studies addressed the utility of SIJ fat infiltration, finding good sensitivity but poor specificity. SIJ erosions showed good specificity in five studies. Studies addressing high T1 signal in the SIJ, fluid signal in the SIJ, ankylosis, sclerosis, capsulitis, backfill and vacuum phenomenon reported limited diagnostic value. In the spine, four studies reported moderate sensitivity and specificity for corner inflammatory lesions, and four reported poor sensitivity and specificity for spinal fat infiltration. Five studies evaluated the added value of spinal MRI over SIJ MRI alone, with variable results depending on the cohort. Six studies addressed the effect of acquisition parameters on diagnostic accuracy: fat-saturated T2-weighted imaging and short tau inversion recovery (STIR) imaging showed comparable utility in identifying BMO. Three studies showed that gadolinium was of minimal added value in the detection of BMO.

Conclusions: These results confirmed the diagnostic utility of MRI in axial SpA. Performance varied according to the characteristics of the cohort and the number and combination of MRI lesions considered.
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http://dx.doi.org/10.1093/rheumatology/kez172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812711PMC
November 2019

Recommendations for acquisition and interpretation of MRI of the spine and sacroiliac joints in the diagnosis of axial spondyloarthritis in the UK.

Rheumatology (Oxford) 2019 10;58(10):1831-1838

Department of Rheumatology, University College London Hospitals NHS Foundation Trust, London.

Objectives: To develop evidence-based recommendations on the use of MRI in the diagnosis of axial SpA (axSpA).

Methods: A working group comprising nine rheumatologists and nine musculoskeletal radiologists with an interest in axSpA was established, with support from the British Society of Spondyloarthritis (BRITSpA). Two meetings were held. In the first meeting, research questions were formulated. In the second meeting, the results of a systematic literature review designed to inform the recommendations were reviewed. An anonymized Delphi process was used to formulate the final set of recommendations. For each recommendation, the level of evidence and strength of recommendation was determined. The level of agreement was assessed using a 0-10 numerical rating scale.

Results: Two overarching principles were formulated, as follows: The diagnosis of axSpA is based on clinical, laboratory and imaging features (overarching principle 1), and patients with axSpA can have isolated inflammation of either the sacroiliac joints or the spine (overarching principle 2). Seven recommendations addressing the use of MRI in the assessment of patients with suspected axSpA were formulated, covering topics including recommended sequences, anatomical coverage, acquisition parameters and interpretation of active and structural MRI lesions. The level of agreement for each recommendation was very high (range 8.8-9.8).

Conclusion: A joint rheumatology and radiology consensus on the acquisition and interpretation of MRI in axSpA diagnosis was achieved, and a research agenda formulated. This consensus should help standardize practice around MRI and ensure a more informed, consistent approach to the diagnosis of axSpA.
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http://dx.doi.org/10.1093/rheumatology/kez173DOI Listing
October 2019

Real benefits of ultrasound evaluation of hand and foot synovitis for better characterisation of the disease activity in rheumatoid arthritis.

Eur Radiol 2019 Nov 26;29(11):6345-6354. Epub 2019 Apr 26.

Department of Rheumatology, University College London Hospitals NHS Trust, 250 Euston Road, London, NW1 2PG, UK.

Objectives: Optimal management of rheumatoid arthritis (RA) depends on accurate evaluation of disease activity. Foot synovitis is not included in the most used RA outcome measure (DAS-28 score). The aim of this study was to investigate how musculoskeletal ultrasound (MSK-US) examination of hand and feet correlate with the disease activity score (DAS-28 score). We also explored whether performing MSK-US assessments of hands alone compared with hands and feet underestimates the disease activity in RA.

Methods: This is a real-life cross-sectional study of 101 patients (51 with RA and 50 with other musculoskeletal conditions) with inflammatory small joint pain, who underwent MSK-US examination of hands and feet.

Results: MSK-US-detected hand synovitis was found in 18/51 (35.3%) RA patients and 16/50 (32%) of those with other musculoskeletal conditions (p = 0.96), while foot synovitis was detected in 18/51 (35.3%) and 12/50 (24%) patients, respectively (p = 0.78). DAS-28 did not correlate with any of the US outcome measures in patients with RA. Six out of 13 (46.1%) RA patients in remission, 7/14 (50%) with low disease activity and 18/32 (56.2%) with moderate disease activity (according to DAS-28 definition) had active synovitis as assessed by the MSK-US examination of their hands and feet. MSK-US-detected synovitis led to treatment escalation in 26/51 (51%) RA patients.

Conclusion: This study emphasises that MSK-US examination of hands and feet has led to optimised management of the majority of RA patients, which would have not been possible otherwise, because of the lack of correlation between DAS-28 assessment and MSK-US outcomes.

Key Points: • The most used disease activity score in rheumatoid arthritis (DAS-28) did not correlate with US outcome measures derived from hands and feet examination. • DAS-28 did not differentiate between RA patients with subclinical active synovitis versus well-controlled disease on US. • As a result of US examination of the hands and feet, 51% RA patients had their immunosuppressive treatment optimised.
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http://dx.doi.org/10.1007/s00330-019-06187-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795612PMC
November 2019

A comparison of response in the presence or absence of a delay in induction therapy with bortezomib, lenalidomide, and dexamethasone.

J Oncol Pharm Pract 2019 Oct 30;25(7):1692-1698. Epub 2018 Nov 30.

1 Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, NC, USA.

Purpose: Lenalidomide, bortezomib, and dexamethasone (RVd) has emerged as a preferred induction therapy in multiple myeloma (MM) in the United States. Due to lenalidomide's teratogenic risk, patients and prescribers must comply with a risk evaluation and mitigation strategy (REMS) program. The REMS program limits dispensing to certain third-party specialty pharmacies, whose average prescription fill times are longer than in-house specialty pharmacies. In practice, a delay in procurement of lenalidomide may mean that patients start therapy with only bortezomib and dexamethasone, delaying the start of more effective triplet therapy. The primary objective of this study is to determine if a delay from start of bortezomib and dexamethasone to start of triplet therapy with lenalidomide impacts rate of achievement of very good partial response (VGPR) after four cycles of RVd.

Methods: This was a single-center retrospective review of adults with newly diagnosed MM who received RVd induction therapy at University of North Carolina Medical Center between April 2014 and June 2017. Patients who started lenalidomide ≥10 days after bortezomib comprised the "Delay" group, while those who started lenalidomide concurrently with bortezomib or within 1-9 days after bortezomib comprised the "No Delay" group. The primary outcome was VGPR or better response rate after four cycles of RVd.

Results: Thirty-eight patients met inclusion criteria. Nine patients (23.7%) experienced any delay in initiation of lenalidomide, with a mean delay of 7.8 days (range 1-18). Four patients (10.5%) experienced a delay ≥10 days. No patients in the Delay group were of reproductive potential, compared to 8.8% in the No Delay group ( = 0.54). VGPR or better response rate did not differ between the Delay and No Delay groups (66.7% vs. 58.8%,  = 0.79). The mean number of lenalidomide prescriptions generated per RVd cycle was 1.35 (range 1-5, SD 0.74).

Conclusions: This study did not demonstrate an effect on clinical response after delays ≥10 days between bortezomib and lenalidomide initiation. No patients in the delay group were females of reproductive potential, which is the primary target for increased safety behind the REMS program.
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http://dx.doi.org/10.1177/1078155218815283DOI Listing
October 2019

Permissiveness to form pluripotent stem cells may be an evolutionarily derived characteristic in Mus musculus.

Sci Rep 2018 10 2;8(1):14706. Epub 2018 Oct 2.

Texas A&M Institute for Genome Sciences and Society, Texas A&M University, College Station, TX, USA.

Mus musculus is the only known species from which embryonic stem cells (ESC) can be isolated under conditions requiring only leukemia inhibitory factor (LIF). Other species are non-permissive in LIF media, and form developmentally primed epiblast stem cells (EpiSC) similar to cells derived from post-implantation, egg cylinders. To evaluate whether non-permissiveness extends to induced pluripotent stem cells (iPSC), we derived iPSC from the eight founder strains of the mouse Collaborative Cross. Two strains, NOD/ShiLtJ and the WSB/EiJ, were non-permissive, consistent with the previous classification of NOD/ShiLtJ as non-permissive to ESC derivation. We determined non-permissiveness is recessive, and that non-permissive genomes do not compliment. We overcame iPSC non-permissiveness by using GSK3B and MEK inhibitors with serum, a technique we termed 2iS reprogramming. Although used for ESC derivation, GSK3B and MEK inhibitors have not been used during iPSC reprogramming because they inhibit survival of progenitor differentiated cells. iPSC derived in 2iS are more transcriptionally similar to ESC than EpiSC, indicating that 2iS reprogramming acts to overcome genetic background constraints. Finally, of species tested for ESC or iPSC derivation, only some M. musculus strains are permissive under LIF culture conditions suggesting that this is an evolutionarily derived characteristic in the M. musculus lineage.
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http://dx.doi.org/10.1038/s41598-018-32116-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168588PMC
October 2018

Outcome measures of disease activity for rare autoimmune rheumatic diseases.

Br J Hosp Med (Lond) 2018 Jul;79(7):396-401

Consultant, Department of Rheumatology, University College London Hospital NHS Trust, London.

Systemic lupus erythematosus, scleroderma, myositis and Sjögren's syndrome are rare, complex, multi-systemic rheumatic diseases associated with significant morbidity and mortality. Thorough assessments of disease activity are required to guide clinical management and assess response to new therapies in clinical trials. This article reviews the commonly used outcome measures to assess this group of diseases and discusses the limitations of their use.
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http://dx.doi.org/10.12968/hmed.2018.79.7.396DOI Listing
July 2018

Biologics for treating axial spondyloarthritis.

Expert Opin Biol Ther 2018 06 7;18(6):641-652. Epub 2018 May 7.

e Centre for Rheumatology & MRC Centre for Neuromuscular Diseases , University College London , London , United Kingdom of Great Britain and Northern Ireland.

Introduction: Spondyloarthritis (SpA) encompasses a heterogeneous group of diseases sharing genetic, immunological, clinical and imaging features. Axial spondyloarthritis (axSpA) refers to a subgroup characterised predominately by inflammation of the axial skeleton with subsequent symptoms of chronic (often inflammatory) back pain and sacroiliitis. There is a strong association with the major histocompatibility complex (MHC) class I allele human leukocyte antigen (HLA) B27. In the last decade, there has been significant progress in earlier detection of the disease and the molecular mechanisms involved in its pathogenesis. The subsequent introduction of anti-tumour necrosis factor (TNF) has revolutionised the treatment of patients with axSpA.

Areas Covered: In this article, we review the current biologic therapies for axSpA, the emergence of biosimilars, predictors of response, primary and secondary failure and new biologics on the horizon.

Expert Opinion: There have been significant advances in the treatment of axSpA. Beyond the clear efficacy of anti-TNF inhibition, IL-17 offers an alternative therapeutic target and there is promise from inhibition of the IL-17/IL-23 pathway and small molecules, such as Janus kinase (JAK) inhibitors. Biosimilars have offered greater affordability and choice within this increasingly growing field of therapeutics.
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http://dx.doi.org/10.1080/14712598.2018.1468884DOI Listing
June 2018

Comparison of Weight-Based Dosing Strategies for Intravenous Immunoglobulin in Patients with Hematologic Malignancies.

Pharmacotherapy 2017 12 27;37(12):1530-1536. Epub 2017 Nov 27.

Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, North Carolina.

Study Objective: Intravenous immunoglobulin (IVIG) is a weight-based therapy used to treat and prevent infections in patients with hematologic malignancies. IVIG doses were calculated traditionally using actual body weight (ABW). However, limited pharmacokinetic data suggest dosing strategies using ideal body weight (IBW) or adjusted body weight (adjBW) may be appropriate given the small volume of distribution of IVIG. Our objective was to compare the effectiveness of using a precision-dosing strategy (IBW or adjBW) with a traditional-dosing strategy (ABW) for IVIG in patients with hematologic malignancies or those undergoing hematopoietic stem cell transplant, as well as to perform an IVIG drug use analysis.

Design: Retrospective cohort study.

Setting: Academic medical center.

Patients: Between April 2014 and September 2016, 209 IVIG encounters met inclusion criteria for the primary outcome. Of those encounters, 125 were dosed using the traditional-dosing strategy, and 84 used the precision-dosing strategy.

Measurements And Main Results: The primary outcome was infection rate within 30 days of IVIG administration. Secondary outcomes included 60-day infection rate, immunoglobulin G (IgG)-level response (IgG higher than 400 mg/dl), and realized and potential IVIG savings. No difference in 30-day infection rate between precision- and traditional-dosing strategies was identified (15.5% vs 16%, respectively, p=0.823). Similarly, no difference was identified in the 60-day infection rate between groups (23.2% vs 19.8%, respectively, p=0.568). Levels of IgG obtained after IVIG repletion showed a treatment response rate of 86% in both groups. Use of a precision-dosing strategy achieved $2600/month in institutional savings with the opportunity for an additional $4600/month in savings with complete adherence to this dosing strategy.

Conclusion: No differences in infection rate and IgG-level response were identified when a precision-dosing strategy was used. Implementation of an IVIG precision-dosing strategy provided institutional cost savings.
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http://dx.doi.org/10.1002/phar.2047DOI Listing
December 2017

Cortisol and Alpha-amylase changes during an Ultra-Running Event.

Int J Exerc Sci 2017;10(4):531-540. Epub 2017 Jul 1.

Medical Laboratory Sciences, Northeastern State University, Broken Arrow, OK, USA.

Elevated stress hormone concentrations can positively affect an athlete's overall performance during a competition, and in many cases, are necessary to be able to perform exercise. During extreme exercise, the body's ability to utilize energy efficiently can affect an athlete's performance. Elevated hormonal concentrations can have many benefits in regards to an athlete's overall performance during a competition. The purpose of this study was to examine the effects of long distance running, such as seen during an ultra-running event (distances beyond 26.2 miles), on the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis production of cortisol (CORT) as compared to autonomic nervous system production of salivary alpha-amylase (AA). Despite the well-known effects of exercise on CORT and AA response, it is unclear what effect running beyond the marathon distance has on these levels. This study investigates what effect long duration cardio exercise, such as running up to 100K (kilometers) distance, has on the neuroendocrine system, by means of saliva samples provided by participants signed up for an ultra-marathon event. The findings of this study show that the autonomic nervous system may present a response signal during physical stress that is independent of the HPA axis response. At distances beyond the marathon length, the production of CORT and AA was found to be suppressed for athletes, which could help them in their continued performance. Furthermore, this study recognizes a difference in the overall male and female response to stress in regards to CORT and AA production.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466402PMC
July 2017

Folate-Binding Protein Self-Aggregation Drives Agglomeration of Folic Acid Targeted Iron Oxide Nanoparticles.

Bioconjug Chem 2017 01 28;28(1):81-87. Epub 2016 Nov 28.

Department of Chemistry, ‡Department of Biomedical Engineering, §Department of Physics, and ∥Program in Macromolecular Science and Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.

Folate-conjugated nanomaterials have been widely investigated for drug and imaging-agent delivery. In this work, two folic acid (FA) conjugated iron oxide particles (IOP), a ∼40 nm diameter FA-IOP and a ∼450 nm diameter FA-IOP(FA-SeraMag), were synthesized. Both particles aggregated in the presence of serum folate-binding protein (FBP) at physiological concentration and buffer conditions. Mixing 0.01% w/w FA-conjugated iron oxide particles with FBP-induced agglomeration generated an average hydrodynamic particle diameter of 3800 ± 1100 nm for ∼40 nm FA-IOP and 4030 ± 1100 nm for FA-SeraMag as measured by dynamic light scattering (DLS). The presence of excess human serum albumin (HSA) (600 μM) did not prevent agglomeration of the ∼40 nm FA-IOP; however, it did inhibit agglomeration of FA-SeraMag. Atomic force microscopy measurement provided additional insight into particle morphology with the detection of individual particles in the agglomerate. This behavior is an example of a triggered cascade. A protein structural change is induced by FA binding, and the structural change favors aggregation of the ∼4 nm diameter FBPs on the particle surface; this further triggers the agglomeration of both the ∼40 and ∼450 nm diameter IOPs.
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http://dx.doi.org/10.1021/acs.bioconjchem.6b00526DOI Listing
January 2017

Reversible methanol addition to copper Schiff base complexes: a kinetic, structural and spectroscopic study of reactions at azomethine C[double bond, length as m-dash]N bonds.

Dalton Trans 2016 Oct;45(40):15791-15799

Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, KY, 40292 USA.

The reversible methanolysis of an azomethine C[double bond, length as m-dash]N in a series of copper(ii) Schiff base complexes has been investigated through combined spectroscopic, structural, and kinetic studies. Pentadentate copper(ii) complexes [L-Cu(X)]Y (L = 1,2-bis[(1-methyl-2-imidazolyl)methyleneamino]ethane; X = Y = ClO (1); X = Y = TfO (2); X = Y = BF (3); X = HO, Y = (ClO) (4) spontaneously add methanol in a ligand centered reaction to yield stable, isolable hemiaminal ether product complexes 5-8. In methanol free solution, 5-8 spontaneously release alcohol to regenerate 1-4. The methanol addition reaction is first-order in methanol and first-order in complex with second-order rate constants varying from 1.1 × 10 to 187 × 10 M s dependent on the donor ability of the axial ligand. Rate constants for methanol elimination vary from 0.67 to 3.7 × 10 s with dependence on the counterion and water content of the solvent. Equilibrium constants for methanolysis range from 1.5 to 51 M. Structural comparisons of the Schiff base complexes 1-4 and the hemiaminal ether complexes 5-8 suggest methanol addition is favored by the release of ligand strain associated with three planar five-membered chelates in 1-4.
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http://dx.doi.org/10.1039/c6dt01955bDOI Listing
October 2016

Estrogen and voluntary exercise interact to attenuate stress-induced corticosterone release but not anxiety-like behaviors in female rats.

Behav Brain Res 2016 09 28;311:279-286. Epub 2016 May 28.

Department of Pharmacology and Physiology, Oklahoma State University-Center for Health Sciences, Tulsa, OK 74107-1898, United States. Electronic address:

The beneficial effects of physical exercise to reduce anxiety and depression and to alleviate stress are increasingly supported in research studies. The role of ovarian hormones in interactions between exercise and anxiety/stress has important implications for women's health, given that women are at increased risk of developing anxiety-related disorders, particularly during and after the menopausal transition. In these experiments, we tested the hypothesis that estrogen enhances the positive impact of exercise on stress responses by investigating the combined effects of exercise and estrogen on anxiety-like behaviors and stress hormone levels in female rats after an acute stressor. Ovariectomized female rats with or without estrogen were given access to running wheels for one or three days of voluntary running immediately after or two days prior to being subjected to restraint stress. We found that voluntary running was not effective at reducing anxiety-like behaviors, whether or not rats were subjected to restraint stress. In contrast, stress-induced elevations of stress hormone levels were attenuated by exercise experience in estrogen-treated rats, but were increased in rats without estrogen. These results suggest that voluntary exercise may be more effective at reducing stress hormone levels if estrogen is present. Additionally, exercise experience, or the distance run, may be important in reducing stress.
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http://dx.doi.org/10.1016/j.bbr.2016.05.058DOI Listing
September 2016

Commentaries on Viewpoint: Reappraisal of the acute, moderate intensity exercise-catecholamines interaction effect on speed of cognition: Role of the vagal/NTS afferent pathway.

J Appl Physiol (1985) 2016 Mar;120(6):659-60

Northeastern State University-Broken Arrow CampusUniversity Witten-HerdeckeUniversity of Applied Science and Medical UniversityFederal University of Rio de JaneiroLithuanian Sports UniversityUniversity of Bern.

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http://dx.doi.org/10.1152/japplphysiol.01055.2015DOI Listing
March 2016

History dependence of the electromyogram: Implications for isometric steady-state EMG parameters following a lengthening or shortening contraction.

J Electromyogr Kinesiol 2016 Apr 15;27:30-8. Epub 2016 Feb 15.

Faculty of Kinesiology, Human Performance Laboratory, University of Calgary, 2500 University Dr. NW, Calgary, Alberta T2N 1N4, Canada. Electronic address:

Residual force enhancement (RFE) and force depression (FD) refer to an increased or decreased force following an active lengthening or shortening contraction, respectively, relative to the isometric force produced at the same activation level and muscle length. Our intent was to determine if EMG characteristics differed in the RFE or FD states compared with a purely isometric reference contraction for maximal and submaximal voluntary activation of the adductor pollicis muscle. Quantifying these alterations to EMG in history-dependent states allows for more accurate modeling approaches for movement control in the future. For maximal voluntary contractions (MVC), RFE was 6-15% (P<0.001) and FD was 12-19% (P<0.001). The median frequency of the EMG was not different between RFE, FD and isometric reference contractions for the 100% and 40% MVC intensities (P>0.05). However, root mean square EMG (EMGRMS) amplitude for the submaximal contractions was higher in the FD and lower in the RFE state, respectively (P<0.05). For maximal contractions, EMGRMS was lower for the FD state but was the same for the RFE state compared to the isometric reference contractions (P>0.05). Neuromuscular efficiency (NME; force/EMG) was lower in the force depressed state and higher in the force enhanced state (P<0.05) compared to the isometric reference contractions. EMG spectral properties were not altered between the force-enhanced and depressed states relative to the isometric reference contractions, while EMG amplitude measures were.
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http://dx.doi.org/10.1016/j.jelekin.2016.01.008DOI Listing
April 2016

A sodium channel variant in Aedes aegypti as a candidate pathogen sensor for viral-associated molecular patterns.

Biochem Biophys Res Commun 2015 Aug 15;463(4):1203-9. Epub 2015 Jun 15.

Departments of Neurology, Pathology and Program in Cellular and Molecular Pathology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA. Electronic address:

Recent work demonstrated that a splice variant of a human macrophage voltage-gated sodium channel expressed on endosomes acts as an intracellular sensor for dsRNA, a viral-associated molecular pattern. Here our goal was to identify a candidate gene in a clinically relevant invertebrate model with related cellular and pattern recognition properties. The para gene in drosophila and other insects encodes voltage-gated sodium channels with similar electrophysiological properties to those found in vertebrate excitable membranes. A database search revealed that the AAEL006019 gene in Aedes aegypti, the yellow fever mosquito, encodes a voltage-gated sodium channel that is distinct from genes that encode para-like sodium channels. As compared to para-like channels, the protein products from this gene have deletions in the N-terminus and in the DII-DIII linker region. When over-expressed in an Aedes aegypti cell line, CCL-125, the AAEL006019 channel demonstrated cytoplasmic expression on vesicular-like organelles. Electrophysiologic analysis revealed that the channel mediates small inward currents that are enhanced by synthetic mimics of viral-derived ssRNA, R848 and ORN02, but not the dsRNA mimic, poly I:C. R848 treatment of CCL-125 cells that express high levels of the channels led to increased expression of RelA and Ago2, two mediators of insect innate immunity. These results suggest that the AAEL006019 channel acts as an intracellular pathogen sensor for ssRNA molecular patterns.
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http://dx.doi.org/10.1016/j.bbrc.2015.06.085DOI Listing
August 2015

Disruption of insect isoprenoid biosynthesis with pyridinium bisphosphonates.

Insect Biochem Mol Biol 2015 Aug 11;63:113-23. Epub 2015 Jun 11.

Natural Resources Canada, Canadian Forest Service, Laurentian Forestry Centre, 1055 du P.E.P.S., C.P. 10380, Stn. Sainte-Foy, Quebec City, QC G1V 4C7, Canada.

Farnesyl diphosphate synthase (FPPS) catalyzes the condensation of the non-allylic diphosphate, isopentenyl diphosphate (IPP; C5), with the allylic diphosphate primer dimethylallyl diphosphate (DMAPP; C5) to generate the C15 prenyl chain (FPP) used for protein prenylation as well as sterol and terpene biosynthesis. Here, we designed and prepared a series of pyridinium bisphosphonate (PyrBP) compounds, with the aim of selectively inhibiting FPPS of the lepidopteran insect order. FPPSs of Drosophila melanogaster and the spruce budworm, Choristoneura fumiferana, were inhibited by several PyrBPs, and as hypothesized, larger bisphosphonates were more selective for the lepidopteran protein and completely inactive towards dipteran and vertebrate FPPSs. Cell growth of a D. melanogaster cell line was adversely affected by exposure to PyrPBs that were strongly inhibitory to insect FPPS, although their effect was less pronounced than that observed upon exposure to the electron transport disrupter, chlorfenapyr. To assess the impact of PyrBPs on lepidopteran insect growth and development, we performed feeding and topical studies, using the tobacco hornworm, Manduca sexta, as our insect model. The free acid form of a PyrBP and a known bisphosphonate inhibitor of vertebrate FPPS, alendronate, had little to no effect on larval M. sexta; however, the topical application of more lipophilic ester PyrBPs caused decreased growth, incomplete larval molting, cuticle darkening at the site of application, and for those insects that survived, the formation of larval-pupal hybrids. To gain a better understanding of the structural differences that produce selective lepidopteran FPPS inhibition, homology models of C. fumiferana and D. melanogaster FPPS (CfFPPS2, and DmFPPS) were prepared. Docking of substrates and PyrBPs demonstrates that differences at the -3 and -4 positions relative to the first aspartate rich motif (FARM) are important factors in the ability of the lepidopteran enzyme to produce homologous isoprenoid structure and to be selectively inhibited by larger PyrBPs.
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http://dx.doi.org/10.1016/j.ibmb.2015.05.006DOI Listing
August 2015

Human macrophage SCN5A activates an innate immune signaling pathway for antiviral host defense.

J Biol Chem 2014 Dec 3;289(51):35326-40. Epub 2014 Nov 3.

From the Department of Neurology and Program in Cellular and Molecular Pathology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706 and the William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705

Pattern recognition receptors contain a binding domain for pathogen-associated molecular patterns coupled to a signaling domain that regulates transcription of host immune response genes. Here, a novel mechanism that links pathogen recognition to channel activation and downstream signaling is proposed. We demonstrate that an intracellular sodium channel variant, human macrophage SCN5A, initiates signaling and transcription through a calcium-dependent isoform of adenylate cyclase, ADCY8, and the transcription factor, ATF2. Pharmacological stimulation with a channel agonist or treatment with cytoplasmic poly(I:C), a mimic of viral dsRNA, activates this pathway to regulate expression of SP100-related genes and interferon β. Electrophysiological analysis reveals that the SCN5A variant mediates nonselective outward currents and a small, but detectable, inward current. Intracellular poly(I:C) markedly augments an inward voltage-sensitive sodium current and inhibits the outward nonselective current. These results suggest human macrophage SCN5A initiates signaling in an innate immune pathway relevant to antiviral host defense. It is postulated that SCN5A is a novel pathogen sensor and that this pathway represents a channel activation-dependent mechanism of transcriptional regulation.
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http://dx.doi.org/10.1074/jbc.M114.611962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271219PMC
December 2014

Time to diagnosis of axial spondylarthritis in clinical practice: signs of improving awareness?

Rheumatology (Oxford) 2014 Nov 19;53(11):2126-7. Epub 2014 Aug 19.

Department of Rheumatology, St Peter's Hospital, Chertsey, Surrey, St George's Hospital Medical School, London, Department of Rheumatology, Defence Medical Rehabilitation Unit, Headley Court, Surrey, Department of Rheumatology, Addenbrooke's Hospital, Cambridge, Academic Department of Military Rehabilitation, Defence Medical Rehabilitation Centre Headley Court, Epsom, Surrey and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK. Department of Rheumatology, St Peter's Hospital, Chertsey, Surrey, St George's Hospital Medical School, London, Department of Rheumatology, Defence Medical Rehabilitation Unit, Headley Court, Surrey, Department of Rheumatology, Addenbrooke's Hospital, Cambridge, Academic Department of Military Rehabilitation, Defence Medical Rehabilitation Centre Headley Court, Epsom, Surrey and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.

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http://dx.doi.org/10.1093/rheumatology/keu294DOI Listing
November 2014

Loss of NF1 in cutaneous melanoma is associated with RAS activation and MEK dependence.

Cancer Res 2014 Apr 27;74(8):2340-50. Epub 2014 Feb 27.

Authors' Affiliations: Louis V. Gerstner, Jr. Graduate School of Biomedical Science; Human Oncology and Pathogenesis Program; Departments of Pediatrics, Pathology, and Medicine; Programs in Molecular Pharmacology and Chemistry; Computational Biology; Ludwig Collaborative Lab, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles; Departments of Epidemiology and Biostatistics and Medicine, and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.

Melanoma is a disease characterized by lesions that activate ERK. Although 70% of cutaneous melanomas harbor activating mutations in the BRAF and NRAS genes, the alterations that drive tumor progression in the remaining 30% are largely undefined. Vemurafenib, a selective inhibitor of RAF kinases, has clinical utility restricted to BRAF-mutant tumors. MEK inhibitors, which have shown clinical activity in NRAS-mutant melanoma, may be effective in other ERK pathway-dependent settings. Here, we investigated a panel of melanoma cell lines wild type for BRAF and NRAS to determine the genetic alteration driving their transformation and their dependence on ERK signaling in order to elucidate a candidate set for MEK inhibitor treatment. A cohort of the BRAF/RAS wild type cell lines with high levels of RAS-GTP had loss of NF1, a RAS GTPase activating protein. In these cell lines, the MEK inhibitor PD0325901 inhibited ERK phosphorylation, but also relieved feedback inhibition of RAS, resulting in induction of pMEK and a rapid rebound in ERK signaling. In contrast, the MEK inhibitor trametinib impaired the adaptive response of cells to ERK inhibition, leading to sustained suppression of ERK signaling and significant antitumor effects. Notably, alterations in NF1 frequently co-occurred with RAS and BRAF alterations in melanoma. In the setting of BRAF(V600E), NF1 loss abrogated negative feedback on RAS activation, resulting in elevated activation of RAS-GTP and resistance to RAF, but not MEK, inhibitors. We conclude that loss of NF1 is common in cutaneous melanoma and is associated with RAS activation, MEK-dependence, and resistance to RAF inhibition.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-2625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005042PMC
April 2014

Hass avocado modulates postprandial vascular reactivity and postprandial inflammatory responses to a hamburger meal in healthy volunteers.

Food Funct 2013 Feb;4(3):384-91

UCLA Center for Human Nutrition, David Geffen School of Medicine at UCLA, 900 Veteran Avenue, Room 12-217 12-217 Warren Hall Box 951742, Los Angeles, California 90095, USA.

Hass avocados are rich in monounsaturated fatty acids (oleic acid) and antioxidants (carotenoids, tocopherols, polyphenols) and are often eaten as a slice in a sandwich containing hamburger or other meats. Hamburger meat forms lipid peroxides during cooking. After ingestion, the stomach functions as a bioreactor generating additional lipid peroxides and this process can be inhibited when antioxidants are ingested together with the meat. The present pilot study was conducted to investigate the postprandial effect of the addition of 68 g of avocado to a hamburger on vasodilation and inflammation. Eleven healthy subjects on two separate occasions consumed either a 250 g hamburger patty alone (ca. 436 cal and 25 g fat) or together with 68 grams of avocado flesh (an additional 114 cal and 11 g of fat for a total of 550 cal and 36 g fat), a common culinary combination, to assess effects on vascular health. Using the standard peripheral arterial tonometry (PAT) method to calculate the PAT index, we observed significant vasoconstriction 2 hours following hamburger ingestion (2.19 ± 0.36 vs. 1.56 ± 0.21, p = 0.0007), which did not occur when the avocado flesh was ingested together with the burger (2.17 ± 0.57 vs. 2.08 ± 0.51, NS p = 0.68). Peripheral blood mononuclear cells were isolated from postprandial blood samples and the Ikappa-B alpha (IκBα) protein concentration was determined to assess effects on inflammation. At 3 hours, there was a significant preservation of IκBα (131% vs. 58%, p = 0.03) when avocado was consumed with the meat compared to meat alone, consistent with reduced activation of the NF-kappa B (NFκB) inflammatory pathway. IL-6 increased significantly at 4 hours in postprandial serum after consumption of the hamburger, but no change was observed when avocado was added. Postprandial serum triglyceride concentration increased, but did not further increase when avocado was ingested with the burger compared to burger alone despite the added fat and calories from the avocado. These observations are suggestive of beneficial anti-inflammatory and vascular health effects of ingesting added Hass avocado with a hamburger patty.
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http://dx.doi.org/10.1039/c2fo30226hDOI Listing
February 2013

Reversal by RARα agonist Am580 of c-Myc-induced imbalance in RARα/RARγ expression during MMTV-Myc tumorigenesis.

Breast Cancer Res 2012 Aug 24;14(4):R121. Epub 2012 Aug 24.

Introduction: Retinoic acid signaling plays key roles in embryonic development and in maintaining the differentiated status of adult tissues. Recently, the nuclear retinoic acid receptor (RAR) isotypes α, β and γ were found to play specific functions in the expansion and differentiation of the stem compartments of various tissues. For instance, RARγ appears to be involved in stem cell compartment expansion, while RARα and RARβ are implicated in the subsequent cell differentiation. We found that over-expressing c-Myc in normal mouse mammary epithelium and in a c-Myc-driven transgenic model of mammary cancer, disrupts the balance between RARγ and RARα/β in favor of RARγ.

Methods: The effects of c-Myc on RAR isotype expression were evaluated in normal mouse mammary epithelium, mammary tumor cells obtained from the MMTV-Myc transgenic mouse model as well as human normal immortalized breast epithelial and breast cancer cell lines. The in vivo effect of the RARα-selective agonist 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carboxamido]benzoic acid (Am580) was examined in the MMTV-Myc mouse model of mammary tumorigenesis.

Results: Modulation of the RARα/β to RARγ expression in mammary glands of normal mice, oncomice, and human mammary cell lines through the alteration of RAR-target gene expression affected cell proliferation, survival and tumor growth. Treatment of MMTV-Myc mice with the RARα-selective agonist Am580 led to significant inhibition of mammary tumor growth (~90%, P<0.001), lung metastasis (P<0.01) and extended tumor latency in 63% of mice. Immunocytochemical analysis showed that in these mice, RARα responsive genes such as Cyp26A1, E-cadherin, cellular retinol-binding protein 1 (CRBP1) and p27, were up-regulated. In contrast, the mammary gland tumors of mice that responded poorly to Am580 treatment (37%) expressed significantly higher levels of RARγ. In vitro experiments indicated that the rise in RARγ was functionally linked to promotion of tumor growth and inhibition of differentiation. Thus, activation of the RARα pathway is linked to tumor growth inhibition, differentiation and cell death.

Conclusions: The functional consequence of the interplay between c-Myc oncogene expression and the RARγ to RARα/β balance suggests that prevalence of RARγ over-RARα/β expression levels in breast cancer accompanied by c-Myc amplification or over-expression in breast cancer should be predictive of response to treatment with RARα-isotype-specific agonists and warrant monitoring during clinical trials.
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http://dx.doi.org/10.1186/bcr3247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3680916PMC
August 2012