Publications by authors named "Brian Knight"

44 Publications

Mode of action and human relevance assessment of male CD-1 mouse renal adenocarcinoma associated with lifetime exposure to empagliflozin.

J Appl Toxicol 2022 Apr 7. Epub 2022 Apr 7.

Nonclinical Drug Safety, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut, USA.

Inhibition of sodium-glucose cotransporter-2 (SGLT2) has been shown to be a safe and efficacious approach to support managing Type 2 diabetes. In the 2-year carcinogenicity study with the SGLT2 inhibitor empagliflozin in CD-1 mice, an increased incidence of renal tubular adenomas and carcinomas was identified in the male high-dose group but was not observed in female mice. An integrated review of available nonclinical data was conducted to establish a mode-of-action hypothesis for male mouse-specific tumorigenesis. Five key events were identified through systematic analysis to form the proposed mode-of-action: (1) Background kidney pathology in CD-1 mice sensitizes the strain to (2) pharmacology-related diuretic effects associated with SGLT2 inhib ition. (3) In male mice, metabolic demand increases with the formation of a sex- and species-specific empagliflozin metabolite. These features converge to (4) deplete oxidative stress handling reserve, driving (5) constitutive cellular proliferation in male CD-1 mice. The proposed mode of action requires all five key events for empagliflozin to present a carcinogenicity risk in the CD-1 mouse. Considering that empagliflozin is not genotoxic in the standard battery of genotoxicity tests, and not all five key events are present in the context of female mice, rats, or humans, nor for other osmotic diuretics or other SGLT2 inhibitors, the observed male mouse renal tumors are not considered relevant to humans.
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http://dx.doi.org/10.1002/jat.4329DOI Listing
April 2022

Dinitrogen Coordination to a High-Spin Diiron(I/II) Species.

Angew Chem Int Ed Engl 2022 May 31;61(22):e202202329. Epub 2022 Mar 31.

Center for Catalysis and Florida Center for Heterocyclic Chemistry, Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.

Dinitrogen coordination to iron centers underpins industrial and biological fixation in the Haber-Bosch process and by the FeM cofactors in the nitrogenase enzymes. The latter employ local high-spin metal centers; however, iron-dinitrogen coordination chemistry remains dominated by low-valent states, contrasting the enzyme systems. Here, we report a high-spin mixed-valent cis-(μ-1,2-dinitrogen)diiron(I/II) complex [(FeBr) (μ-N )L ] (2), where [L ] is a bis(β-diketiminate) cyclophane. Field-applied Mössbauer spectra, dc and ac magnetic susceptibility measurements, and computational methods support a delocalized S= / Fe N unit with D=-5.23 cm and consequent slow magnetic relaxation.
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http://dx.doi.org/10.1002/anie.202202329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117494PMC
May 2022

A predictive model for additions to -alkyl pyridiniums.

Chem Commun (Camb) 2021 Mar;57(21):2693-2696

Department of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way, Tallahassee, FL 32306, USA.

Disclosed in this communication is a thorough study on the dearomative addition of organomagnesium nucleophiles to N-alkyl pyridinium electrophiles. The regiochemical outcomes have observable and predictable trends associated with the substituent patterns on the pyridinium electrophile. Often, the substituent effects can be either additive, giving high selectivities, or ablative, giving competing outcomes. Additionally, the nature of the organometallic nucleophilic component was also investigated for its role in the regioselective outcome. The effects of either reactive component are important to both the overall reactivity and site of nucleophilic addition. The utility of these observed trends is demonstrated in a concise, dearomative synthesis of a tricyclic compound shown to have insecticidal activity.
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http://dx.doi.org/10.1039/d1cc00056jDOI Listing
March 2021

Mini Review: The Last Mile-Opportunities and Challenges for Machine Learning in Digital Toxicologic Pathology.

Toxicol Pathol 2021 06 16;49(4):714-719. Epub 2021 Feb 16.

Charles River Laboratories, Pathology, Ashland, OH, USA.

The 2019 manuscript by the Special Interest Group on Digital Pathology and Image Analysis of the Society of Toxicologic pathology suggested that a synergism between artificial intelligence (AI) and machine learning (ML) technologies and digital toxicologic pathology would improve the daily workflow and future impact of toxicologic pathologists globally. Now 2 years later, the authors of this review consider whether, in their opinion, there is any evidence that supports that thesis. Specifically, we consider the opportunities and challenges for applying ML (the study of computer algorithms that are able to learn from example data and extrapolate the learned information to unseen data) algorithms in toxicologic pathology and how regulatory bodies are navigating this rapidly evolving field. Although we see similarities with the "Last Mile" metaphor, the weight of evidence suggests that toxicologic pathologists should approach ML with an equal dose of skepticism and enthusiasm. There are increasing opportunities for impact in our field that leave the authors cautiously excited and optimistic. Toxicologic pathologists have the opportunity to critically evaluate ML applications with a "call-to-arms" mentality. Why should we be late adopters? There is ample evidence to encourage engagement, growth, and leadership in this field.
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http://dx.doi.org/10.1177/0192623321990375DOI Listing
June 2021

Synthetic Factors Governing Access to Tris(β-diketimine) Cyclophanes versus Tripodal Tri-β-aminoenones.

J Org Chem 2020 11 27;85(21):13579-13588. Epub 2020 Oct 27.

Center for Catalysis and Florida Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, 214 Leigh Hall, P.O. Box 117200, Gainesville, Florida 32611, United States.

Tris(β-diketimine) cyclophanes are an important ligand class for investigating cooperative multimetallic interactions of bioinorganic clusters. Discussed herein are the synthetic factors governing access to tris(β-diketimine) cyclophanes versus tripodal tri-β-aminoenones. Cyclophanes bearing Me, Et, and MeO cap substituents and β-Me, Et, or Ph arm substituents are obtained, and a modified condensation method produced α-Me β-Me cyclophane. These operationally simple procedures produce the ligands in gram quantities and in 22-94% yields.
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http://dx.doi.org/10.1021/acs.joc.0c01708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729927PMC
November 2020

Evaluating Metal Ion Identity on Catalytic Silylation of Dinitrogen Using a Series of Trimetallic Complexes.

Eur J Inorg Chem 2020 Apr 21;2020(15-16):1519-1524. Epub 2020 Feb 21.

Center for Catalysis, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200 (USA).

We report catalytic silylation of dinitrogen to tris(trimethylsilyl)amine by a series of trinuclear first row transition metal complexes (M = Cr, Mn, Fe, Co, Ni) housed in our tris(β-diketiminate) cyclophane ( ). Yields are expectedly dependent on metal ion type ranging from 14 to 199 equiv NH /complex after protonolysis for the Mn to Co congeners, respectively. For the series of complexes, the number of turnovers trend observed is Co > Fe > Cr > Ni > Mn, consistent with prior reports of greater efficacy of Co over Fe in other ligand systems for this reaction.
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http://dx.doi.org/10.1002/ejic.201901335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566828PMC
April 2020

Return to Recreational Sport Following Lumbar Fusion.

Clin Spine Surg 2020 05;33(4):E174-E177

Department of Orthopaedic Surgery, UC Irvine Medical Center, Orange.

Study Design: This was a retrospective questionnaire study at a single academic medical center.

Objective: The objective of this study was to obtain information on rates of return to sport following lumbar fusion as well as sport-specific effects to improve evidence-based preoperative patient counseling.

Summary Of Background Data: Lumbar spinal fusion is one of the fastest-growing surgical procedures, with the majority being in patients aged 60 years and older. Remaining active is an important consideration for elderly patients undergoing lumbar spinal fusion. Golf, swimming, and biking are common forms of recreational exercise for an older population in whom lumbar fusion is often performed. There is a lack of data in the current literature regarding rates of return to recreational sporting activities following elective lumbar fusion.

Methods: Following Institutional Review Board approval, all patients undergoing lumbar fusion at a single institution from 2012 to 2016 were screened and included in this study. A minimum of 1-year postoperative follow-up was required. A total of 117 patients were identified undergoing single-level or multilevel lumbar fusion during this time period. The average age was 63 years. Questionnaires were obtained to screen and identify patients who participated in 1 of 3 recreational sports before surgery (golf, swimming, and biking). Preoperative and postoperative collected outcome measures were then compared using the Student t test.

Results: Of the 117 identified lumbar fusion patients, 32 patients (27%) participated in 1 of the 3 most common recreational sporting activities of golf, swimming, or biking. Within the golf cohort (n=13), 100% of patients returned to recreational golfing postoperatively. There was a statistically significant reduction in Visual Analog Scale (VAS) pain scores postoperatively (6.3±3.7-1.8±2.4, P=0.01). Driving distance was reduced postoperatively (223.3±42.7-212.1±44.4 yards, P=0.042) and handicaps increased (12.8±8.4-17.0±11.4, P=0.02). Within the swimming cohort (n=9), 100% of patients returned to recreational swimming following lumbar fusion. There was a statistically significant reduction in VAS pain scores postoperatively (9.1±1.7-2.2±2.3, P=0.01). There was a trend towards increased amounts of swimming (times per week) postoperatively, however, this was not statistically significant (2.1±1.7-3.7±1.5, P=0.10). Within the biking cohort (n=10), 100% of patients returned to recreational biking following lumbar fusion. There was a statistically significant reduction in VAS pain scores postoperatively (6.7±4.0-1.3±1.7, P=0.03). There was a trend towards increased amounts of biking (times per week) postoperatively, however, this was not statistically significant (2.5±1.8-3.7±1.6 postoperatively, P=0.20).

Conclusions: In the cohort of patients from this study who partook in golfing, swimming or bicycling, 100% were able to return to their respective sport by 3-9 months postoperatively and all had a significant reduction in pain. With regards to golfers, lumbar fusion likely has an adverse effect on their golfing ability with an increase in handicap and an expected reduction in driving distance.
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http://dx.doi.org/10.1097/BSD.0000000000000980DOI Listing
May 2020

Society of Toxicologic Pathology Digital Pathology and Image Analysis Special Interest Group Article*: Opinion on the Application of Artificial Intelligence and Machine Learning to Digital Toxicologic Pathology.

Toxicol Pathol 2020 02 23;48(2):277-294. Epub 2019 Oct 23.

Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.

Toxicologic pathology is transitioning from analog to digital methods. This transition seems inevitable due to a host of ongoing social and medical technological forces. Of these, artificial intelligence (AI) and in particular machine learning (ML) are globally disruptive, rapidly growing sectors of technology whose impact on the long-established field of histopathology is quickly being realized. The development of increasing numbers of algorithms, peering ever deeper into the histopathological space, has demonstrated to the scientific community that AI pathology platforms are now poised to truly impact the future of precision and personalized medicine. However, as with all great technological advances, there are implementation and adoption challenges. This review aims to define common and relevant AI and ML terminology, describe data generation and interpretation, outline current and potential future business cases, discuss validation and regulatory hurdles, and most importantly, propose how overcoming the challenges of this burgeoning technology may shape toxicologic pathology for years to come, enabling pathologists to contribute even more effectively to answering scientific questions and solving global health issues. [Box: see text].
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http://dx.doi.org/10.1177/0192623319881401DOI Listing
February 2020

Direct oral anticoagulant (DOAC) reversal: Andexxa versus 4 factor prothrombin concentrates.

Transfus Apher Sci 2020 Apr 1;59(2):102649. Epub 2019 Oct 1.

University of California Irvine, School of Medicine, 101 The City Drive South, Orange, CA 92868, United States.

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http://dx.doi.org/10.1016/j.transci.2019.09.002DOI Listing
April 2020

A Prospective Evaluation of Point of Care Ultrasound Teaching in Switzerland.

J Med Ultrasound 2019 Apr-Jun;27(2):92-96. Epub 2019 Feb 26.

Department of Emergency Medicine, University of California Irvine, Irvine, California, USA.

Context: As the utility of point-of-care ultrasound (POCUS) continues to expand in the medical field, there is a need for effective educational methods. In Switzerland, medical education follows the European model and lasts 6 years, focusing on preclinical training during the first 2 years. No previous studies have evaluated the optimal time for teaching ultrasound in European medical education.

Aims: The aim of this study is to provide ultrasound training to medical students in Switzerland at varying times during their clinical training to determine if the level of training plays a role in their ability to comprehend and to apply basic POCUS skills.

Methods: We performed an observational study utilizing a convenience sample of Swiss medical students between July 11, 2016 and August 6, 2016. They were taught a 2-day POCUS course by five American-trained 1-year medical students. Following this course, students were evaluated with written and clinical examination.

Results: 100 Swiss medical students were enrolled in the study. A total of 59 of these students were early clinical students, and 41 students were late clinical students. A two-tailed -test was performed and demonstrated that the late clinical students performed better than the early clinical students on the written assessment; however, no difference was found in clinical skill.

Conclusion: Our data suggest that Swiss medical students can learn and perform POCUS after a 2-day instructional taught by trained 1-year American medical students. No difference was found between students in early clinical training and late clinical training for the ability to perform POCUS.
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http://dx.doi.org/10.4103/JMU.JMU_57_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607874PMC
February 2019

Isolation of chloride- and hydride-bridged tri-iron and -zinc clusters in a tris(β-oxo-δ-diimine) cyclophane ligand.

Dalton Trans 2019 Jul;48(26):9570-9575

Department of Chemistry, Center for Catalysis, University of Florida, Gainesville, FL 32611-7200, USA.

A cyclophane ligand (H6L) bearing three β-oxo-δ-diimine arms and the corresponding tri-iron and -zinc complexes in which the metal ions are bridged by either chlorides, viz. Fe3Cl3(H3L) (1) and Zn3Cl3(H3L) (2), or hydrides, viz. Fe3H3(H3L) (3), Zn3H3(H3L) (4), were synthesized and characterized. 1 adopts a chair-shaped C3v-symmetric [Fe3(μ-Cl)3]3+ cluster wherein only one hemisphere of the ligand is metallated and the other three ketoimine sites remain protonated as evidenced by single crystal X-ray diffraction and vibrational and NMR spectroscopic analyses. 3 and 4 were synthesized by substitution of the bridging chlorides in 1 and 2 using KBEt3H and are accessed with retention of the three protonated ketoimine sites.
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http://dx.doi.org/10.1039/c9dt00799gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610688PMC
July 2019

Catalytic Silylation of Dinitrogen by a Family of Triiron Complexes.

ACS Catal 2018 Aug 19;8(8):7208-7212. Epub 2018 Jul 19.

Center for Catalysis and Florida Center for Heterocyclic Chemistry, Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.

A series of triiron complexes supported by a tris(β-diketiminate)cyclophane ( ) catalyze the reduction of dinitrogen to tris(trimethylsilyl)amine using KC and MeSiCl. Employing FeBr affords 83 ± 7 equiv. NH /complex after protonolysis, which is a 50% yield based on reducing equivalents. The series of triiron compounds tested evidences the subtle effects of ancillary donors, including halides, hydrides, sulfides, and carbonyl ligands, and metal oxidation state on N(SiMe) yield, and highlight Fe(μ-N) as a common species in product mixtures. These results suggest that ancillary ligands can be abstracted with Lewis acids under reducing conditions.
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http://dx.doi.org/10.1021/acscatal.8b02021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296492PMC
August 2018

Pathogenesis of Renal Injury and Gene Expression Changes in the Male CD-1 Mouse Associated with Exposure to Empagliflozin.

Toxicol Pathol 2018 08 26;46(6):671-682. Epub 2018 Jun 26.

1 Nonclinical Drug Safety, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.

An increased incidence of renal tubular adenomas and carcinomas was identified in the 2-year CD-1 mouse carcinogenicity study with empagliflozin (sodium-glucose transporter 2 inhibitor) in high dose (1,000 mg/kg/day) male mice. A 13-week mouse renal investigative pathogenesis study was conducted with empagliflozin to evaluate dose dependency and temporal onset of nonneoplastic degenerative/regenerative renal tubular and molecular (genes, pathways) changes which precede neoplasia. Male and female CD-1 mice were given daily oral doses of 0, 100, 300, or 1,000 mg/kg/day (corresponding carcinogenicity study dose levels) for 1, 2, 4, 8, or 13 weeks. The maximum expected pharmacology with secondary osmotic diuresis was observed by week 1 at ≥100 mg/kg/day in both genders. Histopathologic kidney changes were first detected after 4 weeks of dosing in the male 1,000 mg/kg/day dose group, with progressive increases in the incidence and/or number of findings in this dose group so that they were more readily detected during weeks 8 and 13. Changes detected starting on week 4 consisted of minimal single-cell necrosis and minimal increases in mitotic figures. These changes persisted at an increased incidence at weeks 8 and 13 and were accompanied by minimal to mild tubular epithelial karyomegaly, minimal proximal convoluted tubular epithelial cell hyperplasia, and a corresponding increase in Ki-67-positive nuclei in epithelial cells of the proximal convoluted tubules. There were no corresponding changes in serum chemistry or urinalysis parameters indicative of any physiologically meaningful effect on renal function and thus these findings were not considered to be adverse. Similar changes were not identified in lower-dose groups in males nor were they present in females of any dose group. RNA-sequencing analysis revealed male mouse-specific changes in kidney over 13 weeks of dosing at 1,000 mg/kg/day. Treatment-related changes included genes and pathways related to p53-regulated cell cycle and proliferation, transforming growth factor β, oxidative stress, and renal injury and the number of genes with significant expression change dramatically increased at week 13. These treatment-related changes in genes and pathways were predominant in high-dose males and complemented the observed temporal renal tubular changes. Overall, these mouse investigative study results support the role of early empagliflozin-related degenerative/regenerative changes only observed in high-dose male CD-1 mice as a key contributing feature to a nongenotoxic mode of renal tumor pathogenesis.
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http://dx.doi.org/10.1177/0192623318784514DOI Listing
August 2018

Scientific and Regulatory Policy Committee Points to Consider: Data Visualization for Clinical and Anatomic Pathologists.

Toxicol Pathol 2018 07 29;46(5):476-487. Epub 2018 May 29.

6 Lovelace Biomedical, Albuquerque, NM, USA.

Assessment and communication of toxicology data are fundamental components of the work performed by veterinary anatomic and clinical pathologists involved in toxicology research. In recent years, there has been an evolution in the number and variety of software tools designed to facilitate the evaluation and presentation of toxicity study data. A working group of the Society of Toxicologic Pathology Scientific and Regulatory Policy Committee reviewed existing and emerging visualization technologies. This Points to Consider article reviews some of the currently available data visualization options, describes the utility of different types of graphical displays, and explores potential areas of controversy and ambiguity encountered with the use of these tools.
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http://dx.doi.org/10.1177/0192623318778733DOI Listing
July 2018

Reactivity of hydride bridges in a high-spin [Fe(μ-H)] cluster: reversible H/CO exchange and Fe-H/B-F bond metathesis.

Chem Sci 2017 May 11;8(5):4123-4129. Epub 2017 Apr 11.

Center for Catalysis , University of Florida , 214 Leigh Hall P.O. Box 117200 , Gainesville , FL 32611 , USA . Email:

The triiron trihydride complex FeH () [where is a tris(β-diketiminate)cyclophanate] reacts with CO and with BF·OEt to afford (FeCO)Fe(μ-H) () and FeF (), respectively. Variable-temperature and applied-field Mössbauer spectroscopy support the assignment of two high-spin (HS) iron(i) centers and one HS iron(ii) ion in . Preliminary studies support a CO-induced reductive elimination of H from , rather than CO trapping a species from an equilibrium mixture. This complex reacts with H to regenerate under a dihydrogen atmosphere, which represents a rare example of reversible CO/H exchange and the first to occur at high-spin metal centers, as well as the first example of a reversible multielectron redox reaction at a designed high-spin metal cluster. The formation of proceeds through a previously unreported net fluoride-for-hydride substitution, and is surprisingly chemically inert to Si-H bonds and points to an unexpectedly large difference between the Fe-F and Fe-H bonds in this high-spin system.
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http://dx.doi.org/10.1039/c6sc05583dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443887PMC
May 2017

An impedance-based approach using human iPSC-derived cardiomyocytes significantly improves in vitro prediction of in vivo cardiotox liabilities.

Toxicol Appl Pharmacol 2017 08 22;329:121-127. Epub 2017 May 22.

Boehringer-Ingelheim Pharmaceuticals, Ridgefield, CT, USA.

Current in vitro approaches to cardiac safety testing typically focus on mechanistic ion channel testing to predict in vivo proarrhythmic potential. Outside of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, structural and functional cardiotoxicity related to chronic dosing effects are of great concern as these effects can impact compound attrition. Development and implementation of an in vitro cardiotoxicity screening platform that effectively identifies these liabilities early in the discovery process should reduce costly attrition and decrease preclinical development time. Impedence platforms have the potential to accurately identify structural and functional cardiotoxicity and have sufficient throughput to be included in a multi-parametric optimization approach. Human induced pluripotent stem cell cardiomyocytes (hIPSC-CMs) have demonstrated utility in cardiac safety and toxicity screening. The work described here leverages these advantages to assess the predictive value of data generated by two impedance platforms. The response of hIPSC-CMs to compounds with known or predicted cardiac functional or structural toxicity was determined. The compounds elicited cardiac activities and/or effects on "macro" impedance often associated with overt structural or cellular toxicity, detachment, or hypertrophy. These assays correctly predicted in vivo cardiotox findings for 81% of the compounds tested and did not identify false positives. In addition, internal or literature C values from in vivo studies correlated within 4 fold of the in vitro observations. The work presented here demonstrates the predictive power of impedance platforms with hIPSC-CMs and provides a means toward accelerating lead candidate selection by assessing preclinical cardiac safety earlier in the drug discovery process.
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http://dx.doi.org/10.1016/j.taap.2017.05.023DOI Listing
August 2017

Graphical display of histopathology data from toxicology studies for drug discovery and development: An industry perspective.

Regul Toxicol Pharmacol 2016 Dec 18;82:167-172. Epub 2016 Oct 18.

Integrated Nonclinical Development Solutions (INDS) Incorporated, 6111 Jackson Road, Suite 100, Ann Arbor, MI 48103, USA.

Histopathology data comprise a critical component of pharmaceutical toxicology studies and are typically presented as finding incidence counts and severity scores per organ, and tabulated on multiple pages which can be challenging for review and aggregation of results. However, the SEND (Standard for Exchange of Nonclinical Data) standard provides a means for collecting and managing histopathology data in a uniform fashion which can allow informatics systems to archive, display and analyze data in novel ways. Various software applications have become available to convert histopathology data into graphical displays for analyses. A subgroup of the FDA-PhUSE Nonclinical Working Group conducted intra-industry surveys regarding the use of graphical displays of histopathology data. Visual cues, use-cases, the value of cross-domain and cross-study visualizations, and limitations were topics for discussion in the context of the surveys. The subgroup came to the following conclusions. Graphical displays appear advantageous as a communication tool to both pathologists and non-pathologists, and provide an efficient means for communicating pathology findings to project teams. Graphics can support hypothesis-generation which could include cross-domain interactive visualizations and/-or aggregating large datasets from multiple studies to observe and/or display patterns and trends. Incorporation of the SEND standard will provide a platform by which visualization tools will be able to aggregate, select and display information from complex and disparate datasets.
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http://dx.doi.org/10.1016/j.yrtph.2016.10.009DOI Listing
December 2016

Palladium(II)-Catalyzed ortho-Arylation of Aromatic Alcohols with a Readily Attachable and Cleavable Molecular Scaffold.

Chemistry 2016 Sep 5;22(37):13054-8. Epub 2016 Aug 5.

Department of Chemistry, University of Georgia, Athens, GA, 30602, USA.

A palladium(II)-catalyzed C-H arylation process of alcohols has been developed. The strategy utilizes a novel quinoline-based hemiacetal scaffold that can direct the selective C-H bond functionalization. This reaction provides a useful method to construct biaryl compounds of benzyl alcohols in good to excellent yields. The new molecular scaffold can be readily attached, removed, and recovered.
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http://dx.doi.org/10.1002/chem.201602844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984652PMC
September 2016

Pilot Randomized Study of a Gratitude Journaling Intervention on Heart Rate Variability and Inflammatory Biomarkers in Patients With Stage B Heart Failure.

Psychosom Med 2016 Jul-Aug;78(6):667-76

From the Departments of Psychiatry (Redwine, Henry, Chinh, Jain, Rutledge), Family Medicine and Public Health (Pung, Wilson, Mills), and Medicine (Knight, Greenberg, Maisel), University of California, San Diego, California.

Objective: Stage B, asymptomatic heart failure (HF) presents a therapeutic window for attenuating disease progression and development of HF symptoms, and improving quality of life. Gratitude, the practice of appreciating positive life features, is highly related to quality of life, leading to development of promising clinical interventions. However, few gratitude studies have investigated objective measures of physical health; most relied on self-report measures. We conducted a pilot study in Stage B HF patients to examine whether gratitude journaling improved biomarkers related to HF prognosis.

Methods: Patients (n = 70; mean [standard deviation] age = 66.2 [7.6] years) were randomized to an 8-week gratitude journaling intervention or treatment as usual. Baseline (T1) assessments included the six-item Gratitude Questionnaire, resting heart rate variability (HRV), and an inflammatory biomarker index. At T2 (midintervention), the six-item Gratitude Questionnaire was measured. At T3 (postintervention), T1 measures were repeated but also included a gratitude journaling task.

Results: The gratitude intervention was associated with improved trait gratitude scores (F = 6.0, p = .017, η = 0.10), reduced inflammatory biomarker index score over time (F = 9.7, p = .004, η = 0.21), and increased parasympathetic HRV responses during the gratitude journaling task (F = 4.2, p = .036, η = 0.15), compared with treatment as usual. However, there were no resting preintervention to postintervention group differences in HRV (p values > .10).

Conclusions: Gratitude journaling may improve biomarkers related to HF morbidity, such as reduced inflammation; large-scale studies with active control conditions are needed to confirm these findings.

Trial Registration: Clinicaltrials.govidentifier:NCT01615094.
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http://dx.doi.org/10.1097/PSY.0000000000000316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927423PMC
July 2017

The design of a readily attachable and cleavable molecular scaffold for -selective C-H alkenylation of arene alcohols.

Chem Sci 2016 Mar 14;7(3):1982-1987. Epub 2015 Dec 14.

Department of Chemistry , University of Georgia , Athens , GA 30602 , USA . Email:

We describe herein the design of a novel molecular scaffold that can induce facile oxidative olefinations when attached to alcohols. Benzylic, homo-, and bishomobenzylic alcohols are utilized. The scaffold can act as a protecting group for the alcohol in other transformations, and it is recoverable in excellent yield. The overall sequence can also be telescoped without purifications of intermediates, representing a net alcohol-based directed -alkenylation.
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http://dx.doi.org/10.1039/c5sc03948gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966905PMC
March 2016

New Targets in the Drug Treatment of Heart Failure.

Drugs 2016 Feb;76(2):187-201

University of California, San Diego Medical Center, San Diego, CA, USA.

Heart failure is a complex syndrome that has been a major contributor to readmissions into hospitals in the USA. Currently, a large number of medications are being used to treat the symptoms of the disease-digoxin, diuretics, renin-angiotensin-aldosterone system inhibitors, β-blockers, and vasodilators. There is no doubt that the given pharmaceutical therapy has been effective in lowering hospital readmission rates and prolonging life in individual chronic heart failure patients. Despite this, admission rates following heart failure hospitalization remain high, resulting in a substantial financial strain on healthcare institutions. Clearly, there is much room for improvement in heart failure therapy and management in reducing readmission rates. In this review, we address the unmet needs in the current drug treatment of chronic heart failure and describe novel drug targets that are currently under investigation.
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http://dx.doi.org/10.1007/s40265-015-0498-3DOI Listing
February 2016

An analysis of the complementary stereoselective alkylations of imidazolidinone derivatives toward α-quaternary proline-based amino amides.

Tetrahedron 2015 Sep 9;71(35):5814-5823. Epub 2015 May 9.

Department of Chemistry, University of Georgia, Athens, GA 30602, United States.

Alkylations of proline-based imidazolidinones are described based on the principle of self-regeneration of stereocenters (SRS), affording high levels of either the or configured products. Stereoselectivity is dictated solely on the nature of the "temporary" group, where isobutyraldehyde-derived imidazolidinones provide the configured products and 1-naphthaldehyde-derived imidazolidinones afford the complementary configured products. These stereodivergent products can be readily cleaved to afford both α-alkylated proline enantiomers from readily available L-proline. A series of imidazolidinones were alkylated to investigate the origin of the -selectivity. Potential contributions toward the observed -selectivity are discussed on the basis of these experiments, suggesting a refined hypothesis for selectivity may be in order.
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http://dx.doi.org/10.1016/j.tet.2015.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241292PMC
September 2015

Nonclinical safety of the sodium-glucose cotransporter 2 inhibitor empagliflozin.

Int J Toxicol 2014 Nov-Dec;33(6):436-49. Epub 2014 Sep 26.

Nonclinical Drug Safety, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA.

Empagliflozin, a selective inhibitor of the renal tubular sodium-glucose cotransporter 2, was developed for treatment of type 2 diabetes mellitus. Nonclinical safety of empagliflozin was studied in a battery of tests to support global market authorization. Safety pharmacology studies indicated no effect of empagliflozin on measures of respiratory or central nervous system function in rats or cardiovascular safety in telemeterized dogs. In CD-1 mouse, Wistar Han rat, or beagle dogs up to 13, 26, or 52 weeks of treatment, respectively, empagliflozin exhibited a toxicity profile consistent with secondary supratherapeutic pharmacology related to glucose loss and included decreased body weight and body fat, increased food consumption, diarrhea, dehydration, decreased serum glucose and increases in other serum parameters reflective of increased protein catabolism, gluconeogenesis, and electrolyte imbalances, and urinary changes such as polyuria and glucosuria. Microscopic changes were consistently observed in kidney and included tubular nephropathy and interstitial nephritis (dog), renal mineralization (rat) and tubular epithelial cell karyomegaly, single cell necrosis, cystic hyperplasia, and hypertrophy (mouse). Empagliflozin was not genotoxic. Empagliflozin was not carcinogenic in female mice or female rats. Renal adenoma and carcinoma were induced in male mice only at exposures 45 times the maximum clinical dose. These tumors were associated with a spectrum of nonneoplastic changes suggestive of a nongenotoxic, cytotoxic, and cellular proliferation-driven mechanism. In male rats, testicular interstitial cell tumors and hemangiomas of the mesenteric lymph node were observed; both tumors are common in rats and are unlikely to be relevant to humans. These studies demonstrate the nonclinical safety of empagliflozin.
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http://dx.doi.org/10.1177/1091581814551648DOI Listing
September 2015

Complementary stereochemical outcomes in proline-based self-regenerations of stereocenters.

Org Lett 2014 Jan 30;16(2):432-5. Epub 2013 Dec 30.

Department of Chemistry, Colorado State University , Fort Collins, Colorado 80523, United States.

Stereoselective alkylations of proline-based amino amides are described, where high levels of either a cis or trans configuration can be attained simply by the choice of the aminal group. Isobutryaldehyde-derived aminals provide the cis configuration, while 1-naphthaldehyde-derived aminals engender the complementary trans configuration.
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http://dx.doi.org/10.1021/ol403320dDOI Listing
January 2014

Assessment of inhibin B as a biomarker of testicular injury following administration of carbendazim, cetrorelix, or 1,2-dibromo-3-chloropropane in Wistar han rats.

Birth Defects Res B Dev Reprod Toxicol 2013 Feb 30;98(1):17-28. Epub 2013 Jan 30.

Nonclinical Drug Safety US, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA.

Although histopathology is considered the gold standard for assessing testicular toxicity in the nonclinical setting, identification of noninvasive biomarkers for testicular injury are desirable to improve safety monitoring capabilities for clinical trials. Inhibin B has been investigated as a noninvasive biomarker for testicular toxicity. This study investigates the correlation of Inhibin B in Wistar Han rats with the onset and reversibility of testicular histopathology from classical testicular toxicants carbendazim, cetrorelix acetate (CTX), and 1,2-dibromo-3-chloropropane (DBCP). The dose regimen included Interim (day 8), Drug (day 29), and nondosing Recovery (day 58) Phases. Inhibin B was not effective at predicting the onset of carbendazim- or CTX-mediated testicular pathology in rats. Inhibin B was reduced by DBCP administration at the end of the Drug Phase only, acting as a leading indicator of the onset of testicular toxicity before the onset of germ cell depletion. However, since Inhibin B was only decreased at the end of the Dosing Phase and not at the Recovery Phase, when the onset of testicular pathology occurred, it is unclear if monitoring Inhibin B would provide sufficient advanced warning for the onset of testicular pathology. Furthermore, follicle stimulating hormone was decreased following CTX and DBCP administration in the Interim Phase and CTX in the Drug Phase. Inhibin B has limited predictive capacity as a leading testicular biomarker in rats.
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http://dx.doi.org/10.1002/bdrb.21045DOI Listing
February 2013

Evaluation of phosphatidylinositol-4-kinase IIIα as a hepatitis C virus drug target.

J Virol 2012 Nov 15;86(21):11595-607. Epub 2012 Aug 15.

Boehringer Ingelheim Ltd., Laval, Quebec, Canada.

Phosphatidylinositol-4-kinase IIIα (PI4KIIIα) is an essential host cell factor for hepatitis C virus (HCV) replication. An N-terminally truncated 130-kDa form was used to reconstitute an in vitro biochemical lipid kinase assay that was optimized for small-molecule compound screening and identified potent and specific inhibitors. Cell culture studies with PI4KIIIα inhibitors demonstrated that the kinase activity was essential for HCV RNA replication. Two PI4KIIIα inhibitors were used to select cell lines harboring HCV replicon mutants with a 20-fold loss in sensitivity to the compounds. Reverse genetic mapping isolated an NS4B-NS5A segment that rescued HCV RNA replication in PIK4IIIα-deficient cells. HCV RNA replication occurs on specialized membranous webs, and this study with PIK4IIIα inhibitor-resistant mutants provides a genetic link between NS4B/NS5A functions and PI4-phosphate lipid metabolism. A comprehensive assessment of PI4KIIIα as a drug target included its evaluation for pharmacologic intervention in vivo through conditional transgenic murine lines that mimic target-specific inhibition in adult mice. Homozygotes that induce a knockout of the kinase domain or knock in a single amino acid substitution, kinase-defective PI4KIIIα, displayed a lethal phenotype with a fairly widespread mucosal epithelial degeneration of the gastrointestinal tract. This essential host physiologic role raises doubt about the pursuit of PI4KIIIα inhibitors for treatment of chronic HCV infection.
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http://dx.doi.org/10.1128/JVI.01320-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486294PMC
November 2012

Scientific and Regulatory Policy Committee (SRPC) paper: validation of digital pathology systems in the regulated nonclinical environment.

Toxicol Pathol 2013 Jan 21;41(1):115-24. Epub 2012 Jun 21.

Charles River Laboratories, Lees Summit, MO 64082, USA.

Digital Pathology Systems (DPS) are dynamic, image-based computer systems that enable the acquisition, management, and interpretation of pathology information generated from digitized glass slides. This article provides a roadmap for (1) qualification of a whole slide scanner (WSS) during a validation project, (2) validation of software required to generate the whole slide image (WSI), and (3) an introduction to visual digital image evaluation and image analysis. It describes a validation approach that can be utilized when validating a DPS. It is not the intent of this article to provide guidance on when validation of DPS is required. Rather, the article focuses on technical aspects of validation of the WSS system (WSS, IT infrastructure, and associated software) portion of a DPS and covers the processes of setting up the WSS for scanning a glass slide through saving a WSI on a server. Validation of a computerized system, such as a DPS, for use in a regulated nonclinical environment is governed by Code of Federal Regulations (CFR) Title 21 part 11: Electronic Records; Electronic Signature and predicate rules associated with Good Laboratory Practices documents including 21 CFR part 58. Similar regulation and predicate rules apply in the European Union and Japan.
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http://dx.doi.org/10.1177/0192623312451162DOI Listing
January 2013

Genomic-derived markers for early detection of calcineurin inhibitor immunosuppressant-mediated nephrotoxicity.

Toxicol Sci 2011 Nov 24;124(1):23-34. Epub 2011 Aug 24.

Environmental Stress and Cancer Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.

Calcineurin inhibitor (CI) therapy has been associated with chronic nephrotoxicity, which limits its long-term utility for suppression of allograft rejection. In order to understand the mechanisms of the toxicity, we analyzed gene expression changes that underlie the development of CI immunosuppressant-mediated nephrotoxicity in male Sprague-Dawley rats dosed daily with cyclosporine (CsA; 2.5 or 25 mg/kg/day), FK506 (0.6 or 6 mg/kg/day), or rapamycin (1 or 10 mg/kg/day) for 1, 7, 14, or 28 days. A significant increase in blood urea nitrogen was observed in animals treated with CsA (high) or FK506 (high) for 14 and 28 days. Histopathological examination revealed tubular basophilia and mineralization in animals given CsA (high) or FK506 (low and high). We identified a group of genes whose expression in rat kidney is correlated with CI-induced kidney injury. Among these genes are two genes, Slc12a3 and kidney-specific Wnk1 (KS-Wnk1), that are known to be involved in sodium transport in the distal nephrons and could potentially be involved in the mechanism of CI-induced nephrotoxicity. The downregulation of NCC (the Na-Cl cotransporter coded by Slc12a3) in rat kidney following CI treatment was confirmed by immunohistochemical staining, and the downregulation of KS-Wnk1 was confirmed by quantitative real-time-polymerase chain reaction (qRT-PCR). We hypothesize that decreased expression of Slc12a3 and KS-Wnk1 could alter the sodium chloride reabsorption in the distal tubules and contribute to the prolonged activation of the renin-angiotensin system, a demonstrated contributor to the development of CI-induced nephrotoxicity in both animal models and clinical settings. Therefore, if validated as biomarkers in humans, SLC12A3 and KS-WNK1 could potentially be useful in the early detection and reduction of CI-related nephrotoxicity in immunosuppressed transplant patients when monitoring the health of kidney xenographs in clinical practice.
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http://dx.doi.org/10.1093/toxsci/kfr217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196657PMC
November 2011

A twenty-eight-day mechanistic time course study in the rhesus monkey with hepatitis C virus protease inhibitor BILN 2061.

Toxicol Pathol 2011 Apr 25;39(3):496-501. Epub 2011 Mar 25.

Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877-0368, USA.

BILN 2061 is a potent, reversible inhibitor of hepatitis C virus NS3/NS4A serine protease. Early clinical proof of principle with the drug was offset by the results of subsequent safety studies in Rhesus monkeys revealing cardiotoxicity that featured myocardial vacuolation corresponding to mitochondrial swelling. Here we describe an investigation into the nature, onset, and reversibility of the lesion, and an assessment of potentially predictive biomarkers for the change. Rhesus monkeys were orally administered 1,000 mg/kg/day BILN 2061 and either necropsied after one, three, fourteen, or twenty-eight doses or afforded a ten-week recovery period. The results of electrocardiographic and plasma troponin I and T measurements were unaffected by BILN 2061, but cardiac myocytic vacuolation, correlated with mitochondrial swelling, was observed after three or more doses. Echocardiographic traces obtained after twenty-eight consecutive days of dosing revealed two animals with diminished left ventricular cardiac ejection fraction. One animal was immediately necropsied and exhibited marked cardiotoxicity. The other was afforded a ten-week treatment-free period during which the left ventricular ejection fraction returned to normal. All recovery animal hearts were microscopically and ultrastructurally normal. High-dose BILN 2061 cardiotoxicity in Rhesus monkeys appeared early in the treatment regimen and exhibited reversibility. A reliable biomarker has yet to be identified.
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http://dx.doi.org/10.1177/0192623311398276DOI Listing
April 2011

Assessment of the environmental fate and effects of the PPARgamma receptor agonist, pioglitazone.

Chemosphere 2011 Apr;83(4):391-9

Takeda Global Research & Development Center, Inc., One Takeda Parkway, Deerfield, IL 60015, USA.

The environmental fate and effects of pioglitazone prescribed for the treatment of type 2 diabetes were evaluated in an environmental risk assessment following the European Medicines Agency (EMA) "Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use"; EMEA/CHMP/SWP/4447/00. A predicted environment concentration (PEC) for surface water was estimated at 0.023μgL(-1), (action limit of 0.01μgL(-1)) triggering a comprehensive battery of laboratory evaluations. Pioglitazone and its major metabolites were determined not to significantly adsorb to sewage solids, were not persistent in the aquatic environment, did not bioaccumulate and were non-toxic to aquatic organisms. Pioglitazone does not pose an unacceptable risk to groundwater supplies, with concentrations not anticipated to be a risk to aquatic organisms or human drinking water supplies. Pioglitazone does not pose a risk of secondary poisoning.
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http://dx.doi.org/10.1016/j.chemosphere.2010.12.090DOI Listing
April 2011
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