Publications by authors named "Robert Orr"

77 Publications

Extensive bony sarcoidosis of the head and neck region: a rare presentation.

BMJ Case Rep 2021 Jan 18;14(1). Epub 2021 Jan 18.

Oral and Maxillofacial Surgery, Chesterfield Royal Hospital NHS Foundation Trust, Chesterfield, Derbyshire, UK.

We present a rare case of sarcoidosis with extensive bony destruction of the maxillofacial and skull base bones. A 65-year-old woman was referred with an asymptomatic, non-healing dental socket. Examination revealed an oroantral fistula that was biopsied and repaired under general anaesthesia. Investigations included plain and cross-sectional imaging. Serological tests, in particular ACE, were normal. Histology showed benign florid granulomatous inflammation. At 6 months, the patient remained asymptomatic. She was re-referred 3 years later with further bony destruction of her maxilla and mandible. Repeat imaging showed intrathoracic lymphadenopathy and skull base involvement. Repeat biopsy confirmed granulomatous inflammation. Given the pulmonary, histological and radiological findings, a sarcoidosis diagnosis was made. Following multidisciplinary team meetings, the patient was treated with methotrexate and arrangements made for close monitoring. This case highlights the need for a consensus in identifying, treating and developing a follow-up protocol in such patients.
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http://dx.doi.org/10.1136/bcr-2020-237105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813348PMC
January 2021

Glandular Odontogenic Cyst with Metaplastic Cartilage: Report of an Unusual Case and Literature Review.

Head Neck Pathol 2020 Oct 26. Epub 2020 Oct 26.

Academic Unit of Oral and Maxillofacial Medicine and Pathology, School of Clinical Dentistry, 19 Claremont Crescent, Sheffield, UK.

Glandular odontogenic cysts are rare odontogenic cysts with a wide range of histopathological features. In this paper we describe the clinical and pathological features of an unusual case of a glandular odontogenic cyst with metaplastic cartilage. The previous literature of odontogenic cysts presenting with metaplastic cartilage is reviewed alongside a discussion of the differential diagnoses. To our knowledge this is the first reported case of a glandular odontogenic cyst with metaplastic cartilage.
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http://dx.doi.org/10.1007/s12105-020-01239-8DOI Listing
October 2020

Rab-E and its interaction with myosin XI are essential for polarised cell growth.

New Phytol 2021 02 28;229(4):1924-1936. Epub 2020 Nov 28.

Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, MA, 01609, USA.

The fundamental process of polarised exocytosis requires the interconnected activity of molecular motors trafficking vesicular cargo within a dynamic cytoskeletal network. In plants, few mechanistic details are known about how molecular motors, such as myosin XI, associate with their secretory cargo to support the ubiquitous processes of polarised growth and cell division. Live-cell imaging coupled with targeted gene knockouts and a high-throughput RNAi assay enabled the first characterisation of the loss of Rab-E function. Yeast two-hybrid and subsequent in silico structural prediction uncovered a specific interaction between Rab-E and myosin XI that is conserved between P. patens and A. thaliana. Rab-E co-localises with myosin XI at sites of active exocytosis, and at the growing tip both proteins are spatiotemporally coupled. Rab-E is required for normal plant growth in P. patens and the rab-E and myosin XI phenotypes are rescued by A. thaliana's Rab-E1c and myosin XI-K/E, respectively. Both PpMyoXI and AtMyoXI-K interact with PpRabE14, and the interaction is specifically mediated by PpMyoXI residue V1422. This interaction is required for polarised growth. Our results suggest that the interaction of Rab-E and myosin XI is a conserved feature of polarised growth in plants.
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http://dx.doi.org/10.1111/nph.17023DOI Listing
February 2021

Robust Survival-Based RNA Interference of Gene Families Using in Tandem Silencing of Adenine Phosphoribosyltransferase.

Plant Physiol 2020 10 6;184(2):607-619. Epub 2020 Aug 6.

Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, Massachusetts 01609

RNA interference (RNAi) enables flexible and dynamic interrogation of entire gene families or essential genes without the need for exogenous proteins, unlike CRISPR-Cas technology. Unfortunately, isolation of plants undergoing potent gene silencing requires laborious design, visual screening, and physical separation for downstream characterization. Here, we developed an adenine phosphoribosyltransferase (APT)-based RNAi technology (APTi) in that improves upon the multiple limitations of current RNAi techniques. APTi exploits the prosurvival output of transiently silencing in the presence of 2-fluoroadenine, thereby establishing survival itself as a reporter of RNAi. To maximize the silencing efficacy of gene targets, we created vectors that facilitate insertion of any gene target sequence in tandem with the APT silencing motif. We tested the efficacy of APTi with two gene families, the actin-dependent motor, myosin XI (a,b), and the putative chitin receptor Lyk5 (a,b,c). The APTi approach resulted in a homogenous population of transient mutants specific for our gene targets with zero surviving background plants within 8 d. The observed mutants directly corresponded to a maximal 93% reduction of myosin XI protein and complete loss of chitin-induced calcium spiking in the Lyk5-RNAi background. The positive selection nature of APTi represents a fundamental improvement in RNAi technology and will contribute to the growing demand for technologies amenable to high-throughput phenotyping.
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http://dx.doi.org/10.1104/pp.20.00865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536682PMC
October 2020

Orchestrating cell morphology from the inside out - using polarized cell expansion in plants as a model.

Curr Opin Cell Biol 2020 02 20;62:46-53. Epub 2019 Sep 20.

Department of Biological Sciences, Dartmouth College, Hanover, NH 03755, United States. Electronic address:

Intracellular organization forms the basis of changes in the extracellular matrix. In walled cells, these changes are essential for morphogenesis and growth. The highly polarized cells of mosses and liverworts together with root hairs and pollen tubes are geometrically simple cells that develop in the absence of complex tissue-scale signaling, providing an excellent model to study cell polarity. Recent advances present a unifying theme where the cytoskeleton and its associated motors work in coordination with vesicle trafficking. This coordination results in a recycling system near the cell tip, where endocytosed molecules are sorted and combined with exocytic cargo driving growth. Interestingly, functional similarities between filamentous fungi and plants promise to advance our understanding of cell polarization and growth across kingdoms.
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http://dx.doi.org/10.1016/j.ceb.2019.08.004DOI Listing
February 2020

Design, synthesis and biological evaluation of indane derived GPR40 agoPAMs.

Bioorg Med Chem Lett 2019 07 2;29(14):1842-1848. Epub 2019 May 2.

Discovery Chemistry, Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.

GPR40 (FFAR1 or FFA1) is a G protein-coupled receptor, primarily expressed in pancreatic islet β-cells and intestinal enteroendocrine cells. When activated by fatty acids, GPR40 elicits increased insulin secretion from islet β-cells only in the presence of elevated glucose levels. Towards this end, studies were undertaken towards discovering a novel GPR40 Agonist whose mode of action is via Positive Allosteric Modulation of the GPR40 receptor (AgoPAM). Efforts were made to identify a suitable GPR40 AgoPAM tool molecule to investigate mechanism of action and de-risk liver toxicity of GPR40 AgoPAMs due to reactive acyl-glucuronide (AG) metabolites.
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http://dx.doi.org/10.1016/j.bmcl.2019.04.050DOI Listing
July 2019

Standard Operating Procedures for Biospecimen Collection, Processing, and Storage: From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer.

Pancreas 2018 Nov/Dec;47(10):1213-1221

Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, and Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH.

High-quality and well-annotated biorepositories are needed to better understand the pathophysiology and biologic mechanisms of chronic pancreatitis (CP) and its consequences. We report a methodology for the development of a robust standard operating procedure (SOP) for a biorepository based on the experience of the clinical centers within the consortium to study Chronic Pancreatitis, Diabetes and Pancreas Cancer Clinical Centers (CPDPC), supported by the National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases as a unique multidisciplinary model to study CP, diabetes, and pancreatic cancer in both children and adults. Standard operating procedures from the CPDPC centers were evaluated and consolidated. The literature was reviewed for standard biorepository operating procedures that facilitated downstream molecular analysis. The existing literature on biobanking practices was harmonized with the SOPs from the clinical centers to produce a biorepository for pancreatic research. This article reports the methods and basic principles behind the creation of SOPs to develop a biorepository for the CPDPC. These will serve as a guide for investigators developing biorepositories in pancreas research. Rigorous and meticulous adherence to standardized biospecimen collection will facilitate investigations to better understand the pathophysiology and biologic mechanisms of CP, diabetes, and pancreatic cancer.
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http://dx.doi.org/10.1097/MPA.0000000000001171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197069PMC
March 2019

Structure-Activity Relationship of Novel and Selective Biaryl-Chroman GPR40 AgoPAMs.

ACS Med Chem Lett 2018 Jul 14;9(7):685-690. Epub 2018 Jun 14.

Departments of Discovery Chemistry, Process Chemistry, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, In Vivo Pharmacology, and In Vitro Pharmacology, Merck & Co., Inc., Kenilworth, New Jersey 07033, United States.

A series of biaryl chromans exhibiting potent and selective agonism for the GPR40 receptor with positive allosteric modulation of endogenous ligands (AgoPAM) were discovered as potential therapeutics for the treatment of type II diabetes. Optimization of physicochemical properties through modification of the pendant aryl rings resulted in the identification of compound , which possesses an improved metabolic profile while demonstrating sustained glucose lowering.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047031PMC
July 2018

Intraamniotic Zika virus inoculation of pregnant rhesus macaques produces fetal neurologic disease.

Nat Commun 2018 06 20;9(1):2414. Epub 2018 Jun 20.

California National Primate Research Center, University of California, 1 Shields Avenue, Davis, CA, 95616, USA.

Zika virus (ZIKV) infection of pregnant women can cause fetal microcephaly and other neurologic defects. We describe the development of a non-human primate model to better understand fetal pathogenesis. To reliably induce fetal infection at defined times, four pregnant rhesus macaques are inoculated intravenously and intraamniotically with ZIKV at gestational day (GD) 41, 50, 64, or 90, corresponding to first and second trimester of gestation. The GD41-inoculated animal, experiencing fetal death 7 days later, has high virus levels in fetal and placental tissues, implicating ZIKV as cause of death. The other three fetuses are carried to near term and euthanized; while none display gross microcephaly, all show ZIKV RNA in many tissues, especially in the brain, which exhibits calcifications and reduced neural precursor cells. Given that this model consistently recapitulates neurologic defects of human congenital Zika syndrome, it is highly relevant to unravel determinants of fetal neuropathogenesis and to explore interventions.
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http://dx.doi.org/10.1038/s41467-018-04777-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010452PMC
June 2018

Conditional genetic screen in Physcomitrella patens reveals a novel microtubule depolymerizing-end-tracking protein.

PLoS Genet 2018 05 10;14(5):e1007221. Epub 2018 May 10.

Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, MA.

Our ability to identify genes that participate in cell growth and division is limited because their loss often leads to lethality. A solution to this is to isolate conditional mutants where the phenotype is visible under restrictive conditions. Here, we capitalize on the haploid growth-phase of the moss Physcomitrella patens to identify conditional loss-of-growth (CLoG) mutants with impaired growth at high temperature. We used whole-genome sequencing of pooled segregants to pinpoint the lesion of one of these mutants (clog1) and validated the identified mutation by rescuing the conditional phenotype by homologous recombination. We found that CLoG1 is a novel and ancient gene conserved in plants. At the restrictive temperature, clog1 plants have smaller cells but can complete cell division, indicating an important role of CLoG1 in cell growth, but not an essential role in cell division. Fluorescent protein fusions of CLoG1 indicate it is localized to microtubules with a bias towards depolymerizing microtubule ends. Silencing CLoG1 decreases microtubule dynamics, suggesting that CLoG1 plays a critical role in regulating microtubule dynamics. By discovering a novel gene critical for plant growth, our work demonstrates that P. patens is an excellent genetic system to study genes with a fundamental role in plant cell growth.
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http://dx.doi.org/10.1371/journal.pgen.1007221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944918PMC
May 2018

Selective Formation of Functionalized α-Quaternary Malononitriles toward 5,5-Disubstituted Pyrrolopyrimidinones.

Org Lett 2017 09 16;19(17):4448-4451. Epub 2017 Aug 16.

Discovery Chemistry, Merck & Co., Inc. , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.

A modular, selective approach to complex α-tertiary substituted malononitriles is reported. The method takes advantage of β-ester-substituted α,α-dinitrile alkenes as highly reactive, chemoselective electrophiles for 1,4-additions with organometallic nucleophiles to produce functionally and sterically dense all-carbon quaternary centers. In the presence of a chiral ester auxiliary bearing an aromatic ring, the 1,4-addition occurs with good to excellent selectivity due to favorable cation-π interactions. The highly functionalized malononitriles represent versatile building blocks and can be applied toward efficient, highly selective syntheses of 5,5-disubstituted pyrrolopyrimidinones.
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http://dx.doi.org/10.1021/acs.orglett.7b01930DOI Listing
September 2017

Development of a stereoselective and scalable process for the preparation of a methylcyclobutanol-pyridyl ether.

Bioorg Med Chem 2018 02 11;26(4):938-944. Epub 2017 Jul 11.

Department of Process Research and Development, Merck & Co., Inc, Kenilworth, NJ 07033, USA.

The evolution of a scalable process for the preparation of methylcyclobutanol-pyridyl ether 1 is described. Key aspects of this development including careful control of the stereochemistry, elimination of chromatography, and application to kilogram-scale synthesis are addressed.
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http://dx.doi.org/10.1016/j.bmc.2017.07.018DOI Listing
February 2018

The protecting-group free selective 3'-functionalization of nucleosides.

Chem Sci 2017 Apr 18;8(4):2804-2810. Epub 2017 Jan 18.

Department of Process Research & Development , MRL , Merck & Co., Inc. , Rahway , NJ 07065 , USA . Email: ; Email:

The direct and chemoselective 3'-phosphoramidation, phosphorylation and acylation of nucleosides are described. Upon the discovery of a novel 3'-phosphorylamidation of therapeutic nucleoside analogues with DBU, we explored the mechanism of this rare selectivity through a combination of NMR spectroscopy and computational studies. The NMR and computational findings allowed us to develop a predictive computational model that accurately assesses the potential for 3'-functionalization for a broad range of nucleosides and nucleoside mimetics. The synthetic utility of this model was exemplified by demonstration on a broad scope of nucleosides and electrophiles yielding targets that were previously only accessible a protection/deprotection sequence or an enzymatic approach.
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http://dx.doi.org/10.1039/c6sc05081fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426439PMC
April 2017

Synthesis of the γ-Secretase Modulator MK-8428.

J Org Chem 2017 03 6;82(6):2957-2964. Epub 2017 Mar 6.

Department of Process Research, MRL, Merck & Co., Inc. , Rahway, New Jersey 07065, United States.

The synthesis of the γ-secretase modulator MK-8428 (1) is described. The synthesis is highlighted by an enzyme-catalyzed reaction to access 3,4,5-trifluoro-(S)-phenylglycine, a 1-pot activation/displacement/deprotection sequence to introduce the aminooxy functionality and a dehydrative intramolecular cyclization under mild conditions to form the oxadiazine heterocycle of 1. In situ reaction monitoring was employed to understand the deleterious role of water during the formation of a methanesulfonate ester in the 1-pot activation/displacement/deprotection sequence.
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http://dx.doi.org/10.1021/acs.joc.6b02979DOI Listing
March 2017

Design and Synthesis of Novel, Selective GPR40 AgoPAMs.

ACS Med Chem Lett 2017 Feb 23;8(2):221-226. Epub 2017 Jan 23.

Departments of Discovery Chemistry, Process Chemistry, Drug Metabolism and Pharmacokinetics, In Vivo Pharmacology, and In Vitro Pharmacology, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.

GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.
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http://dx.doi.org/10.1021/acsmedchemlett.6b00443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304298PMC
February 2017

Discovery of phenyl acetamides as potent and selective GPR119 agonists.

Bioorg Med Chem Lett 2017 03 1;27(5):1124-1128. Epub 2017 Feb 1.

Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.

The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and improved physicochemical properties. Pharmacokinetic data of compound 17 in rat, dog and rhesus will be described. Compound 17 was suitable for QD dosing based on its predicted human half-life, and its projected human dose was much lower than that of the recently reported structurally-related benzyloxy compound 2. Compound 17 was selected as a tool compound candidate for NHP (Non-Human Primate) efficacy studies.
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http://dx.doi.org/10.1016/j.bmcl.2017.01.091DOI Listing
March 2017

The uses of medical oaths in the twenty-first century.

Authors:
Robert D Orr

Pharos Alpha Omega Alpha Honor Med Soc Autumn 2016;79(4):55

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February 2018

Predisposing Characteristics of Adjacent Segment Disease After Lumbar Fusion.

Spine (Phila Pa 1976) 2016 Jul;41(14):1167-1172

Department of Neurological Surgery, Johns Hopkins Medical Center, Baltimore, MD.

Study Design: Retrospective Review.

Objective: The aim of this study was to determine medical, radiographic, and surgical risk factors for the development of adjacent segment disease (ASD) after lumbar fusion.

Summary Of Background Data: ASD is a recognized outcome of spinal fusion that leads to increased costs and debilitating symptoms for patients. However, a comprehensive understanding of risk factors for the development of this surgical outcome does not exist.

Methods: The medical records of patients who received their first lumbar fusion for any indication were retrospectively examined for preoperative medical comorbidities and medications, as well as surgical approach and perioperative complications. A blinded reviewer assessed radiographs for each patient to examine sagittal alignment after fusion. Multivariable logistic regression was used to model the risk of developing ASD on the basis of one or more predictors.

Results: A total of 137 patients fit the inclusion criteria; 9% required a follow-up operation for degeneration at segments adjacent to the fusion. The ASD group had a mean follow-up of 21.1 months prior to revision surgery and an overall follow-up of 41.0 months. The average follow-up in the control group was 14.0 months. Statistically significant independent predictors of developing ASD included antidepressant use [odds ratio (OR) = 5.4], diagnosis of degenerative scoliosis (OR = 34.2), fusion of L4-S1 (OR = 56.5), having no decompressions adjacent to the fusion, and low sacral slope (OR = 0.9). No patient who developed ASD received a decompression adjacent to the fusion such that an OR could not be generated for this independent predictor.

Conclusion: This study is the first to use a combination of medical, surgical, and postoperative sagittal balance as risk factors for the development of adjacent segment disease after lumbar fusion. The awareness of these risk factors may allow for better patient selection and surgical technique to decrease the probability of acquiring this adverse outcome.

Level Of Evidence: 4.
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http://dx.doi.org/10.1097/BRS.0000000000001493DOI Listing
July 2016

Diagnosis of giant cell arteritis: when should we biopsy the temporal artery?

Br J Oral Maxillofac Surg 2016 Apr 16;54(3):327-30. Epub 2016 Jan 16.

Oral and Maxillofacial department Chesterfield Royal Hospital.

Giant cell arteritis (GCA) can be diagnosed histopathologically by biopsy of the temporal artery, and clinically using the 5-point score of the 1990 American College of Rheumatology (ACR) classification. We aimed to find out whether some patients are referred for biopsy unnecessarily. We audited all referrals (n=100) made to the Department of Oral and Maxillofacial Surgery over 34 months, and used the ACR classification to find out whether patients had had a clinical diagnosis of GCA at referral (ACR score: 3 or more). We then compared them with the result of the biopsy. Of the 100 referred, 98 had a biopsy, and of them, 15 were diagnosed with GCA (2 results were not included). Thirteen of the 15 had already been diagnosed clinically (based on the ACR classification) at referral. Our results gave an ACR specificity of 96% (95% CI: 85% to 99%) but only 20% sensitivity (95% CI: 11% to 32%). There was a linear correlation of high ACR scores with histopathological confirmation. Biopsy is most beneficial when there is a degree of diagnostic uncertainty (ACR: 1 or 2), an atypical presentation, or when steroids may be relatively contraindicated. On the basis of our study, we designed a new referral form for biopsy based on the ACR criteria.
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http://dx.doi.org/10.1016/j.bjoms.2015.12.013DOI Listing
April 2016

Enantioselective Synthesis of α-Methyl-β-cyclopropyldihydrocinnamates.

J Org Chem 2016 Feb 25;81(3):824-30. Epub 2016 Jan 25.

Department of Process and Analytical Chemistry, Merck Research Laboratories , Rahway, New Jersey 07065, United States.

α- and β-substitution of dihydrocinnamates has been shown to increase the biological activity of various drug candidates. Recently, we identified enantio- and diastereopure α-methyl-β-cyclopropyldihydrocinnamates to be important pharmacophores in one of our drug discovery programs and endeavored to devise an asymmetric hydrogenation strategy to improve access to this valuable framework. We used high throughput experimentation to define stereoconvergent Suzuki-Miyaura cross-coupling conditions affording (Z)-α-methyl-β-cyclopropylcinnamates and subsequent ruthenium-catalyzed asymmetric hydrogenation conditions affording the desired products in excellent enantio- and diastereoselectivities. These conditions were executed on multigram to kilogram scale to provide three key enantiopure α-methyl-β-cyclopropyldihydrocinnamates with high selectivity.
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http://dx.doi.org/10.1021/acs.joc.5b02296DOI Listing
February 2016

Demographic data for urinary Acute Kidney Injury (AKI) marker [IGFBP7]·[TIMP2] reference range determinations.

Data Brief 2015 Dec 5;5:888-92. Epub 2015 Nov 5.

Department of Pathology, Center for Advanced Laboratory Medicine, University of California, San Diego Health Systems, San Diego, CA, USA.

This data in brief describes characteristics of chronic stable comorbid patients who were included in reference range studies of [IGFBP7]·[TIMP-2] "Reference Intervals of Urinary Acute Kidney Injury (AKI) Markers [IGFBP7]·[TIMP2] in Apparently Healthy Subjects and Chronic Comorbid Subjects without AKI" [1]. In order to determine the specificity of [IGFBP7]·[TIMP-2] for identifying patients at risk of developing AKI we studied a cohort with nine broad classification of disease who did not have AKI. Details regarding the population that was targeted for inclusion in the study are also described. Finally, we present data on the inclusion criteria for the healthy subjects used in this investigation to determine the reference range.
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http://dx.doi.org/10.1016/j.dib.2015.10.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669474PMC
December 2015

Reference intervals of urinary acute kidney injury (AKI) markers [IGFBP7]∙[TIMP2] in apparently healthy subjects and chronic comorbid subjects without AKI.

Clin Chim Acta 2016 Jan 10;452:32-7. Epub 2015 Nov 10.

Department of Pathology, Center for Advanced Laboratory Medicine, University of California-San Diego Health Systems, San Diego, CA, United States. Electronic address:

Background: Insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2) have demonstrated significantly improved diagnostic performance in assessing risk for acute kidney injury (AKI) compared with existing biomarkers. We present the findings of a multi-site trial to determine the reference intervals for these biomarkers in apparently healthy adults and those with stable chronic morbid conditions without AKI.

Methods: A urine specimen was collected from apparently healthy subjects (N=378) and subjects with at least one stable chronic morbidity (N=372). Specimens were kept frozen until analysis with the NephroCheck® Test (Astute Medical). The test is comprised of fluorescence immunoassays for IGFBP7 and TIMP-2 and is used with the Astute140® Meter which quantifies the concentration of each biomarker. The meter multiplies the concentrations of IGFBP7 and TIMP-2 and displays the result as a numerical value ([IGFBP7]∙[TIMP-2]) expressed in (ng/ml)(2)/1000 which is called the AKIRisk™ Score.

Results: The reference intervals (inner 95%) for [IGFBP7]∙[TIMP-2] in all subjects (N=750), apparently healthy subjects, and subjects with stable chronic morbidities were 0.04-2.22, 0.04-2.25, and 0.05-2.20 (ng/ml)(2)/1000 respectively. There was no statistical difference between reference intervals for apparently healthy and chronic stable morbid cohorts (p=0.42).

Conclusions: Our investigation showed that urine [IGFBP7]∙[TIMP-2] values were not elevated in patients with stable chronic morbidities who did not have AKI.
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http://dx.doi.org/10.1016/j.cca.2015.10.029DOI Listing
January 2016

Development of a novel tricyclic class of potent and selective FIXa inhibitors.

Bioorg Med Chem Lett 2015 Nov 31;25(22):5437-43. Epub 2015 Jul 31.

Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.

Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
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http://dx.doi.org/10.1016/j.bmcl.2015.07.078DOI Listing
November 2015

Incorporating spirituality into patient care.

Authors:
Robert D Orr

AMA J Ethics 2015 May 1;17(5):409-15. Epub 2015 May 1.

Author of Medical Ethics and the Faith Factor.

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http://dx.doi.org/10.1001/journalofethics.2015.17.5.spec1-1505DOI Listing
May 2015

Development of a novel class of potent and selective FIXa inhibitors.

Bioorg Med Chem Lett 2015 Nov 29;25(21):4945-4949. Epub 2015 Apr 29.

Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.

Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
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http://dx.doi.org/10.1016/j.bmcl.2015.04.057DOI Listing
November 2015

Development of a palladium-catalyzed α-arylation of cyclopropyl nitriles.

Org Lett 2014 Dec 4;16(24):6314-7. Epub 2014 Dec 4.

Department of Process Chemistry, Merck Research Laboratories , 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.

1,1-Disubstituted aryl cyclopropyl nitriles are useful moieties in biologically active compounds and provide access to a range of cyclopropyl derivatives. Herein, we describe the development of a palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl, and cyclopentyl nitriles that affords these functional groups in one step from a variety of aryl bromides in good to excellent yields. Furthermore, we demonstrate the transformation of aryl cyclopropyl nitriles into aryl trifluoromethyl cyclopropanes.
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http://dx.doi.org/10.1021/ol5030426DOI Listing
December 2014

The long and winding road part 2. The CLP patient's journey, 0-21 years.

Dent Update 2014 Jan-Feb;41(1):20-2, 24-6

Unlabelled: Patients with a cleft lip and palate (CLP) deformity require the highest standard of care that the NHS can provide and this requires multidisciplinary care from teams located in regional cleft centres. Care of these cases is from birth to adulthood and requires several phases of intervention, corresponding to the stages of facial and dental development. Management ideally starts pre-natally, following the initial diagnosis, and occasionally pre-surgical appliances are prescribed. The lip is ideally repaired within three months, followed by palate closure between 12 and 18 months. Careful monitoring is required in the first few years and ENT referral, where necessary, will diagnose middle ear infection, which commonly affects CLP patients. Speech therapy is an integral part of the ongoing care. Excellent oral hygiene is essential and preventive dietary advice must be given and regularly reinforced. Orthodontic expansion is often needed at 9 years of age in preparation for a bone graft and, once the permanent dentition erupts, definitive orthodontic treatment will be required. Maxillary forward growth may have been constrained by scarring from previous surgery, so orthognathic correction may be required on growth completion. Final orthodontic alignment and high quality restorative care will allow the patients to have a pleasing aesthetic result. CLP patients and their families will need continuing support from medical and dental consultants, specialist nurses, health visitors, speech and language specialists and, perhaps, psychologists. The first article in this series of two outlined the principles of care for the CLP patient and this second part illustrates this with a case report, documenting one patient's journey from birth to 21 years of age.

Clinical Relevance: A successful outcome for CLP patients requires a sound dentition.The general dental practitioner role is vital to establish and maintain excellent oral hygiene, a healthy diet and good routine preventive and restorative care. Understanding the total needs of CLP patients can help the dentist to provide high quality care as part of the multidisciplinary management.
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http://dx.doi.org/10.12968/denu.2014.41.1.20DOI Listing
April 2014

The long and winding road--the journey of a cleft lip and palate patient part 1.

Dent Update 2013 Dec;40(10):791-4, 796-8

Chesterfield Royal Hospital, Calow, Chesterfield, S44 5BL, UK.

Unlabelled: Patients with a cleft lip and palate (CLP) deformity require the highest standard of care that can be provided and this requires multidisciplinary care from teams located in regional cleft centres. Care of these cases is from birth to adulthood and requires several phases of intervention, corresponding to the stages of facial and dental development. Management ideally starts pre-natally, following the initial diagnosis, and occasionally pre-surgical appliances are prescribed. The lip is ideally repaired within three months, followed by palate closure between 12 and 18 months. Careful monitoring is required in the first few years and ENT referral, where necessary, will diagnose middle ear infection, which commonly affects CLP patients. Speech therapy is an integral part of the ongoing care. Excellent oral hygiene is essential and preventive dietary advice must be given and regularly reinforced. Orthodontic expansion is often needed at 9 years of age in preparation for a bone graft and, once the permanent dentition erupts, definitive orthodontic treatment will be required. Maxillary forward growth may have been constrained by scarring from previous surgery, so orthognathic correction may be required on growth completion. Final orthodontic alignment and high quality restorative care will allow the patients to have a pleasing aesthetic result. CLP patients and their families will need continuing support from medical and dental consultants, specialist nurses, health visitors, speech and language specialists and, perhaps, psychologists. These two articles outline the principles of care for the CLP patient and, secondly, illustrate this with a case report, documenting one patient's journey from birth to 21 years of age.

Clinical Relevance: A successful outcome for CLP patients requires a sound dentition.The general dental practitioner role is vital to establish and maintain excellent oral hygiene, a healthy diet and good routine preventive and restorative care. Understanding the total needs of CLP patients can help the dentist to provide high quality care as part of the multidisciplinary management.
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http://dx.doi.org/10.12968/denu.2013.40.10.791DOI Listing
December 2013

Incidence and outcome of graft resorption in anterior lumbar interbody fusion: using femoral ring allografts and recombinant human bone morphogenetic protein-2.

Spine (Phila Pa 1976) 2014 Mar;39(5):374-80

*Department of Orthopaedics, Cleveland Clinic, Cleveland, OH; and †Center for Spine Health, Lutheran Hospital, Cleveland, OH.

Study Design: Retrospective cohort.

Objective: To determine the incidence of resorption after anterior lumbar interbody fusion (ALIF) and its effect on outcome.

Summary Of Background Data: Recombinant human bone morphogenetic protein-2 (rhBMP-2) used in ALIF has been associated with a 0.5% to 82% incidence of resorption. This has been described as either a complication or part of the natural history. We postulate that early resorption (≤4 mo) in ALIF using femoral ring allograft augmented with rhBMP-2 supplemented with posterior instrumentation has no effect on outcome.

Methods: Institutional review board-approved retrospective 60 chart cohort study of ALIF using femoral ring allograft-augmented rhBMP-2 supplemented with posterior instrumentation from May 5, 2005, to April 6, 2010. Two groups were based upon the presence or absence of early graft resorption (≤4 mo). Patients were seen prior to surgery and postoperatively until 29 ± 20 months (last visit). Follow-up visual analogue scale pain scores and radiographical evidence of fusion were measured and compared between the 2 groups.

Results: Sixty patients, 27 females and 33 males had follow-up for 29 ± 20 months. Group 1 (33 patients, 45 levels) and group 2 (27 patients, 36 levels) were identical in age (P = 0.62), sex distribution (P = 0.43), preoperative pain score (P = 0.63), and in the rhBMP-2 dose per level (P = 0.77). There were no significant group differences in postoperative visual analogue scale scores but a trend to higher fusion rate in group 1 was seen (P = 0.07) at 6 months. There was a 40% incidence of early resorption with no significant differences in visual analogue scale scores or fusion rate between both groups.

Conclusion: There is a 40% incidence of early resorption (≤4 mo) that had no significant effect on pain score or fusion rate. Resorption should be considered part of the fusion process and not necessarily a complication.

Level Of Evidence: 3.
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http://dx.doi.org/10.1097/BRS.0000000000000145DOI Listing
March 2014

Sclerosing odontogenic carcinoma in the maxilla: a rare primary intraosseous carcinoma.

Oral Surg Oral Med Oral Pathol Oral Radiol 2013 Oct 6;116(4):e283-6. Epub 2013 Apr 6.

Specialist Trainee Registrar, Sheffield Teaching Hospitals, Sheffield, United Kingdom.

Sclerosing Odontogenic Carcinoma (SOC) was first described by Koutlas et al. in 2008. SOC is a low-grade odontogenic carcinoma, which presents as an expansile radiolucency that causes tooth displacement and root resorption. It is locally aggressive but reports suggest a very low probability of regional or distant metastasis. SOC contains small nests and thin cords of small cuboidal or polygonal epithelial cells with cytoplasmic clearing. Pleomorphism and mitoses are not prominent. Skeletal muscle and perineural infiltration with stromal sclerosis is characteristic. Immunohistochemically, SOC stains for cytokeratins (CK) 5/6 and 19, and e-cadherin. Nuclear staining with p63 is also positive. CK20, carcinoembryonic antigen and CAM 5.2 are negative. We report a rare entity of primary intraosseous carcinoma of the maxilla which has the clinical and histological markers of SOC. Occurrence in the maxilla has been reported only once before in the literature.
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http://dx.doi.org/10.1016/j.oooo.2013.01.018DOI Listing
October 2013