Frank J. Geoly

Unique nonclinical safety profile of PF-06835919, a ketohexokinase inhibitor, highlights a species-dependent mechanism

Jun Zhou, Christopher Houle, Frank J. Geoly, Sarah N. Campion et autres

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Restoration of branched chain amino acid catabolism improves kidney function in preclinical cardiovascular-kidney-metabolic syndrome models

Eliza Bollinger, George Williams, Mary Piper, Kimberly L. Steen et autres

INTRODUCTION: Patients with metabolic syndrome and heart failure (HF) often have accompanying kidney dysfunction, which was recently defined as cardiovascular-kidney-metabolic (CKM) syndrome. Prior metabolomics profiling of metabolic syndrome patients identified a plasma branched chain amino acid (BCAA) signature, and BCAAs themselves are …

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Scientific and Regulatory Policy Committee Points to Consider: Review of the United States Food and Drug Administration (FDA) Guidance on Pathology Peer Review in Nonclinical Toxicology Studies

Kevin S. McDorman, Bindu Bennet, Karyn Colman, James Fikes et autres

. The stated purpose of the FDA guidance is to provide information to sponsors, applicants, and nonclinical laboratory personnel regarding the management and conduct of histopathology peer review as part of nonclinical toxicology studies conducted in compliance with good laboratory practice (GLP) …

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Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels

Rachel J. Roth Flach, Eliza Bollinger, Allan R. Reyes, Brigitte Laforest et autres

Branched chain amino acid (BCAA) catabolic impairments have been implicated in several diseases. Branched chain ketoacid dehydrogenase (BCKDH) controls the rate limiting step in BCAA degradation, the activity of which is inhibited by BCKDH kinase (BDK)-mediated phosphorylation. Screening efforts to discover BDK …

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BDK inhibition acts as a catabolic switch to mimic fasting and improve metabolism in mice

Eliza Bollinger, Matthew Peloquin, Jenna Libera, Bina Albuquerque et autres

Branched chain amino acid (BCAA) catabolic defects are implicated to be causal determinates of multiple diseases. This work aimed to better understand how enhancing BCAA catabolism affected metabolic homeostasis as well as the mechanisms underlying these improvements. The rate limiting step of …

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Pathology Peer Review

Frank J. Geoly, Bindu Bennet, James Fikes, Jerry F. Hardisty

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Contributors

Rick R. Adler, Famke Aeffner, Laura E. Armstrong, Dmitri Artemov et autres

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Toxicologic Pathology Forum: Opinion on Obligatory Microscopic Examination of Intermediate-Dose Groups in Toxicity Studies With Biotherapeutics in Cynomolgus Monkeys

Cecilia Parrula, Zuhal Dincer, Frank J. Geoly, Maria Cristina De Vera Mudry et autres

In nonrodent toxicity studies that are usually conducted in cynomolgus monkeys or beagle dogs, the added value of examining all tissues from all dose groups (current practice) versus all tissues in only control and high-dose groups and target tissues in intermediate-dose groups …

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Human sebum requires de novo lipogenesis, which is increased in acne vulgaris and suppressed by acetyl-CoA carboxylase inhibition

William P. Esler, Gregory J. Tesz, Marc K. Hellerstein, Carine Beysen et autres

Sebum plays important physiological roles in human skin. Excess sebum production contributes to the pathogenesis of acne vulgaris, and suppression of sebum production reduces acne incidence and severity. We demonstrate that sebum production in humans depends on local flux through the de …

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A Comparison of Multiple Histotechnical and Morphological Methods for Measuring Hepatic Lipids in NASH Models

Alan Opsahl, Danielle M. Crowell, Yutian Zhan, Frank J. Geoly et autres

Nonalcoholic steatohepatitis (NASH) is a progressive syndrome in which fat (usually in the form of triglycerides) accumulates in the liver (steatosis), accompanied by inflammation and fibrosis in non‐alcoholic patients. Lipid accumulation occurs in intracellular vesicles in hepatocytes, typically producing a macrovesicular histologic …

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The Application of Paraphenylenediamine Staining for Assessment of Phospholipidosis

Norimitsu Shirai, Frank J. Geoly, Walter F. Bobrowski, Carlin V. Okerberg

Drug-induced phospholipidosis is characterized by intracellular accumulation of phospholipids with lamellar bodies in cells exposed to xenobiotics. Demonstration of the lamellar bodies by transmission electron microscopy (TEM) is the hallmark for a definitive diagnosis of phospholipidosis. However, the preparation of tissue samples …

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Regulatory Forum Opinion Piece*

Frank J. Geoly

In the context of monoclonal antibody drug development, tissue cross-reactivity (TCR) studies are immunohistochemical (IHC) studies conducted on a broad panel of normal body tissues, using the antibody therapeutic as the primary reagent. The ICH S6 guidance states that these studies are …

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