Publications by authors named "Rachel Dixon"

12 Publications

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High penetrance of myeloid neoplasia with diverse clinical and cytogenetic features in three siblings with a familial GATA2 deficiency.

Cancer Genet 2021 Apr 23;256-257:77-80. Epub 2021 Apr 23.

Manchester Academic Health Science Centre; Department of Paediatric Haematology and Oncology, Royal Manchester Children's Hospital, Manchester NHS Foundation Trust Manchester, UK; Stem Cell and Leukaemia Proteomics Laboratory, Faculty of Medical and Human Sciences, Division of Cancer Studies, University of Manchester, UK; Department of Paediatric and Adolescent Oncology, The Christie NHS Foundation Trust, Manchester, UK. Electronic address:

Pathogenic germ-line variants in GATA2 (GATA2-deficiency) can cause childhood myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML), and can be associated with distinct clinical syndromic features. However, penetrance and genotype-phenotype correlations are incompletely understood. Here we report on the clinically diverse features of three siblings affected by GATA2c.1021_1031del over an 18-year period, all initially presenting in childhood and adolescence with MDS and AML with monosomy 7 (-7), and one also with trisomy 8 (+8). The siblings inherited a GATA2c.1021_1031del from their father who remains asymptomatic in his sixth decade. The two younger sisters are well after unrelated haematopoietic stem cell transplantation (HSCT), while the first boy died of severe chronic lung disease after sibling HSCT from his youngest sister, who subsequently also developed GATA2-deficiency associated MDS. This family illustrates high penetrance with variable genotype/phenotype correlation within one generation with GATA2-deficiency. We surmise that the lung disease post sibling HSCT was also caused by the GATA2-deficiency. The experience with this family underlines the necessity for GATA2 analysis in all apparently sporadic childhood and teenage MDS and AML with -7 also in the absence of a family history or other clinical features, and rigorous genetic testing in siblings. Moreover, our findings support the arguments for pre-emptive HSCT in variant-carrying siblings.
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http://dx.doi.org/10.1016/j.cancergen.2021.04.002DOI Listing
April 2021

Variations in institutional review board processes and consent requirements for trauma research: an EAST multicenter survey.

Trauma Surg Acute Care Open 2018 30;3(1):e000176. Epub 2018 May 30.

Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Oversight of human subject research has evolved considerably since its inception. However, previous studies identified a lack of consistency of institutional review board (IRB) determination for the type of review required and whether informed consent is necessary, especially for prospective observational studies, which pose minimal risk of harm. We hypothesized that there is significant inter-institution variation in IRB requirements for the type of review and necessity of informed consent, especially for prospective observational trials without blood/tissue utilization. We also sought to describe investigators' and IRB members' attitudes toward the type of review and need for consent. Eastern Association for the Surgery of Trauma (EAST) and IRB members were sent an electronic survey on IRB review and informed consent requirement. We performed descriptive analyses as well as Fisher's exact test to determine differences between EAST and IRB members' responses. The response rate for EAST members from 113 institutions was 13.5%, whereas a convenience sample of IRB members from 14 institutions had a response rate of 64.4%. Requirement for full IRB review for retrospective studies using patient identifiers was reported by zero IRB member compared with 13.1% of EAST members (p=0.05). Regarding prospective observational trials without blood/tissue collection, 48.1% of EAST members reported their institutions required a full IRB review compared with 9.5% of IRB members (p=0.01). For prospective observational trials with blood/tissue collection, 80% of EAST members indicated requirement to submit a full IRB review compared with only 13.6% of IRB members (p<0.001). Most EAST members (78.6%) stated that informed consent is not ethically necessary in prospective observational trials without blood/tissue collection, whereas most IRB members thought that informed consent was ethically necessary (63.6%, p<0.001). There is significant variation in perception and practice regarding the level of review for prospective observational studies and whether informed consent is necessary. We recommend future interdisciplinary efforts between researchers and IRBs should occur to better standardize local IRB efforts.

Level Of Evidence: IV.
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http://dx.doi.org/10.1136/tsaco-2018-000176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976138PMC
May 2018

Paying it forward: Four-year analysis of the Eastern Association for the Surgery of Trauma Mentoring Program.

J Trauma Acute Care Surg 2017 07;83(1):165-169

From the Division of Trauma and Surgical Critical Care, Department of Surgery (T.L.Z.), University of Miami Miller School of Medicine, Miami, Florida; Naval Medical Center (T.M.P.), Portsmouth, Virginia; Eastern Association for the Surgery of Trauma (R.D.), Chicago, Illinois; Department of Surgery (A.P.E.), Boonshoft School of Medicine, Wright State University, Dayton, Ohio; US Army Medical Research and Materiel Command (K.R.G.), Fort Detrick, Maryland; Section of General Surgery, Trauma and Surgical Critical Care, Department of Surgery (K.A.D.), Yale School of Medicine, New Haven, Connecticut; Division of Trauma and Acute Care Surgery, Department of Surgery, Baylor Scott & White, Texas A & M University College of Medicine, Temple, Texas; Department of Surgery (S.J.K.), University of South Florida Morsani, Tampa; Lawnwood Regional Medical Center (S.J.K.), Fort Pierce, FL; Division of Acute Care and Trauma Surgery, Department of Surgery (N.A.S.), University of Rochester Medical Center, Rochester, New York; Division of Trauma, Emergency General Surgery, and Surgical Critical Care, Departments of Surgery, Neurosurgery, and Hearing and Speech Sciences, Section of Surgical Sciences (M.B.P.), Vanderbilt Brain Institute, Vanderbilt Center for Health Services Research, Vanderbilt University Medical Center; Surgical Service, General Surgery Section (M.B.P.), Nashville VA Medical Center; and Tennessee Valley Healthcare System (M.B.P.), US Department of Veterans Affairs, Nashville, Tennessee.

Background: Mentorship programs in surgery are used to overcome barriers to clinical and academic productivity, research success, and work-life balance. We sought to determine if the Eastern Association for the Surgery of Trauma (EAST) Mentoring Program has met its goals of fostering academic and personal growth in young acute care surgeons.

Methods: We conducted a systematic program evaluation of EAST Mentoring Program's first 4 years. Demographic information was collected from EAST records, mentorship program applications, and mentee-mentor career development plans. We reviewed the career development plans for thematic commonalities and results of a structured, online questionnaire distributed since program inception. A mixed methods approach was used to better understand the program goals from both mentee and mentor perspectives, as well as attitudes and barriers regarding the perceived success of this career development program.

Results: During 2012 to 2015, 65 mentoring dyads were paired and 60 completed the program. Of 184 surveys distributed, 108 were returned (57% response rate). Respondents were evenly distributed between mentees and mentors (53 vs. 55, p = 0.768). In participant surveys, mentoring relationships were viewed to focus on research (45%), "sticky situations" (e.g., communication, work-life balance) (27%), education (18%), or administrative issues (10%). Mentees were more focused on research and education versus mentors (74% vs. 50%; p = 0.040). Mentees felt that goals were "always" or "usually" met versus mentors (89% vs. 77%; p = 0.096). Two barriers to successful mentorship included time and communication, with most pairs communicating by email. Most respondents (91%) planned to continue the relationship beyond the EAST Mentoring Program and recommended the experience to colleagues.

Conclusion: Mentee satisfaction with the EAST Mentoring Program was high. Mentoring is a beneficial tool to promote success among EAST's young members, but differences exist between mentee and mentor perceptions. Revising communication expectations and time commitment to improve career development may help our young acute care surgeons.
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http://dx.doi.org/10.1097/TA.0000000000001493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5488724PMC
July 2017

Synthesis of cyclic pyranopterin monophosphate, a biosynthetic intermediate in the molybdenum cofactor pathway.

J Med Chem 2013 Feb 19;56(4):1730-8. Epub 2013 Feb 19.

Carbohydrate Chemistry Team, Callaghan Innovation, P.O. Box 31-310, Lower Hutt 5040, New Zealand.

Cyclic pyranopterin monophosphate (1), isolated from bacterial culture, has previously been shown to be effective in restoring normal function of molybdenum enzymes in molybdenum cofactor (MoCo)-deficient mice and human patients. Described here is a synthesis of 1 hydrobromide (1·HBr) employing in the key step a Viscontini reaction between 2,5,6-triamino-3,4-dihydropyrimidin-4-one dihydrochloride and D-galactose phenylhydrazone to give the pyranopterin (5aS,6R,7R,8R,9aR)-2-amino-6,7-dihydroxy-8-(hydroxymethyl)-3H,4H,5H,5aH,6H,7H,8H,9aH,10H-pyrano[3,2-g]pteridin-4-one (10) and establishing all four stereocenters found in 1. Compound 10, characterized spectroscopically and by X-ray crystallography, was transformed through a selectively protected tri-tert-butoxycarbonylamino intermediate into a highly crystalline tetracyclic phosphate ester (15). The latter underwent a Swern oxidation and then deprotection to give 1·HBr. Synthesized 1·HBr had in vitro efficacy comparable to that of 1 of bacterial origin as demonstrated by its enzymatic conversion into mature MoCo and subsequent reconstitution of MoCo-free human sulfite oxidase-molybdenum domain yielding a fully active enzyme. The described synthesis has the potential for scale up.
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http://dx.doi.org/10.1021/jm301855rDOI Listing
February 2013

tert-Butyl (2R,4aR,5aR,11aS,12R,12aR)-8-[bis-(tert-but-oxycarbon-yl)amino]-12-hydroxy-2-meth-oxy-2,10-dioxo-4,4a,5a,6,9,10,11,11a,12,12a-deca-hydro-2H-1,3,5-trioxa-6,7,9,11-tetra-aza-2λ(5)-phosphatetra-cene-6-carboxyl-ate methanol monosolvate monohydrate.

Acta Crystallogr Sect E Struct Rep Online 2012 Jul 30;68(Pt 7):o2250-1. Epub 2012 Jun 30.

The title compound, C(26)H(40)N(5)O(13)P·CH(3)OH·H(2)O, crystallizes with one water and one methanol mol-ecule providing important crystal-binding inter-actions. The compound has the unusual feature of having two but-oxy-carbonyl groups bound to one N atom. The conventional attractive hydrogen bonds involving hy-droxy, amine and water donors include bifurcations at both donors and acceptors with novel R(1) (2)(6) and R(2) (1)(6) motifs. These are supplemented by C-H⋯O inter-actions between adjacent mol-ecules forming chain and R(2) (2)(10) ring motifs.
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http://dx.doi.org/10.1107/S160053681202867XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394038PMC
July 2012

Antineoplastic agents. 548. Synthesis of iodo- and diiodocombstatin phosphate prodrugs.

J Nat Prod 2012 Mar 10;75(3):385-93. Epub 2012 Feb 10.

Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604, United States.

Toward the objective of designing a structurally modified analogue of the combretastatin A-4 phosphate prodrug (1b) with the potential for increased specificity toward thyroid carcinoma, synthesis of a series of iodocombstatin phosphate (11a-h) and diiodocombstatin phosphate prodrugs (12a-h) has been accomplished. The diiodo series was obtained via 8a and 9c from condensation of 4 and 6, and the iodo sequence involved a parallel pathway. Both series of iodocombstatins were found to display significant to powerful inhibition of the growth of a panel of human cancer cell lines and of the murine P388 lymphocytic leukemia cell line. Of the diiodo series, 12a was also found to markedly inhibit growth of pediatric neuroblastoma, and monoiodocombstatin 9a strongly inhibited HUVEC growth. Overall, the strongest activity was found against the breast, CNS, leukemia, lung, and prostate cancer cell lines and the least activity against the pancreas and colon lines. Parallel biological investigations of tubulin interaction, antiangiogenesis, and antimicrobial effects were also conducted.
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http://dx.doi.org/10.1021/np200797xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313684PMC
March 2012

Discovery of a highly potent series of TLR7 agonists.

Bioorg Med Chem Lett 2011 Oct 4;21(19):5939-43. Epub 2011 Aug 4.

Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK.

The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.
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http://dx.doi.org/10.1016/j.bmcl.2011.07.076DOI Listing
October 2011

Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection.

Bioorg Med Chem Lett 2011 Apr 16;21(8):2389-93. Epub 2011 Mar 16.

Discovery Chemistry, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK.

The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.
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http://dx.doi.org/10.1016/j.bmcl.2011.02.092DOI Listing
April 2011

Kinetic resolution of racemic pyrrolidine-2,5-diones using chiral oxazaborolidine catalysts.

Chem Commun (Camb) 2008 May 11(19):2218-20. Epub 2008 Mar 11.

GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, UK SG1 2NY.

Kinetic resolution of racemic C-3 substituted pyrrolidine-2,5-diones has been achieved for the first time using highly efficient oxazaborolidine catalysts derived from cis-1-amino-indan-2-ol.
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http://dx.doi.org/10.1039/b800510aDOI Listing
May 2008

Nitric oxide regulates neutrophil migration through microparticle formation.

Am J Pathol 2008 Jan 13;172(1):265-73. Epub 2007 Dec 13.

Cardiovascular Research Unit, University of Sheffield, School of Medicine and Biomedical Sciences, LU112 L Floor Royal Hallamshire Hospital, Glossop Rd., Sheffield S10 2JF UK.

The role of nitric oxide (NO) in regulating neutrophil migration has been investigated. Human neutrophil migration to interleukin (IL)-8 (1 nmol/L) was measured after a 1-hour incubation using a 96-well chemotaxis plate assay. The NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) significantly (P < 0.001) enhanced IL-8-induced migration by up to 45%. Anti-CD18 significantly (P < 0.001) inhibited both IL-8-induced and L-NAME enhanced migration. Antibodies to L-selectin or PSGL-1 had no effect on IL-8-induced migration but prevented the increased migration to IL-8 induced by L-NAME. L-NAME induced generation of neutrophil-derived microparticles that was significantly (P < 0.01) greater than untreated neutrophils or D-NAME. This microparticle formation was dependent on calpain activity and superoxide production. Only microparticles from L-NAME and not untreated or D-NAME-treated neutrophils induced a significant (P < 0.01) increase in IL-8-induced migration and transendothelial migration. Pretreatment of microparticles with antibodies to L-selectin (DREG-200) or PSGL-1 (PL-1) significantly (P < 0.001) inhibited this effect. The ability of L-NAME-induced microparticles to enhance migration was found to be dependent on the number of microparticles produced and not an increase in microparticle surface L-selectin or PSGL-1 expression. These data show that NO can modulate neutrophil migration by regulating microparticle formation.
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http://dx.doi.org/10.2353/ajpath.2008.070069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189628PMC
January 2008

Total and semisynthesis and in vitro studies of both enantiomers of 20-fluorocamptothecin.

Bioorg Med Chem Lett 2005 Nov;15(21):4736-40

Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.

Both enantiomers of 20-fluorocamptothecin and the racemate have been prepared by total synthesis. The (R)-enantiomer is essentially inactive in a topoisomerase-I/DNA assay, while the (S)-enantiomer is much less active than (20S)-camptothecin. The lactone ring of 20-fluorocamptothecin hydrolyzes more rapidly than that of camptothecin in PBS. The results provide insight into the role of the 20-hydroxy group in the binding of camptothecin to topoisomerase-I and DNA.
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http://dx.doi.org/10.1016/j.bmcl.2005.07.074DOI Listing
November 2005