Prodrug Strategy to Address Impaired Oral Absorption of a Weakly Basic TYK2 Inhibitor Caused by a Gastric Acid-Reducing Agent.

The pH-dependent solubility of the weakly basic TYK2 inhibitor posed a risk to its advancement, given that drugs with such profiles have exhibited drug-drug interaction (DDI) with stomach acid-reducing agents in humans. In a rat model of pH dependence, preadministration of famotidine caused a 2.4-fold lower exposure of when compared to control rats, implying that pH-dependent oral absorption can reduce the active drug's exposure and translate to subtherapeutic treatment.

Discovery and Optimization of Aryl Piperidinone Ureas as Selective Formyl Peptide Receptor 2 Agonists.

We report the discovery and optimization of aryl piperidinone urea formyl peptide receptor 2 (FPR2) agonists from a weakly active high-throughput screening (HTS) hit to potent and selective agonists with favorable efficacy in acute models. A basis for the selectivity for FPR2 over FPR1 is proposed based on docking molecules into recently reported FPR2 and FPR1 cryoEM structures. Compounds from the new scaffold reported in this study exhibited superior potency and selectivity and favorable ADME profiles.

Discovery of (BMS-986172) as a Highly Potent MGAT2 Inhibitor that Achieved Targeted Efficacious Exposures at a Low Human Dose for the Treatment of Metabolic Disorders.

A series of dihydropyridinone (DHP) compounds was prepared and evaluated for MGAT2 activity. The efforts led to the identification of novel tetrazolones with potent MGAT2 inhibitory activity and favorable profiles. Further tests of select analogues in mouse models revealed significant reduction in food intake and body weight.

Predictors of Intraoperative Difficulty and Postoperative Examination Abnormalities in 164 Orbital Operations.

Background: Although orbital fractures are common, prediction of outcomes in orbital surgery can be quite challenging.

Purpose: We aim to identify predictors of intraoperative difficulty, operating time, and postoperative examination abnormalities in subjects undergoing post-traumatic orbital reconstructions.

Study Design, Setting, And Sample: This is a retrospective cohort study of all consecutive orbital operations performed at a private, Level 1 trauma center in Portland, Oregon, USA over an 82-month period.

Structure-activity relationship study of central pyridine-derived TYK2 JH2 inhibitors: Optimization of the PK profile through C4' and C6 variations.

Efforts directed at improving potency and preparing structurally different TYK2 JH2 inhibitors from the first generation of compounds such as 1a led to the SAR study of new central pyridyl based analogs 2-4. The current SAR study resulted in the identification of 4h as a potent and selective TYK2 JH2 inhibitor with distinct structural differences from 1a. In this manuscript, the in vitro and in vivo profiles of 4h are described.

Discovery of novel pyridinones as MGAT2 inhibitors for the treatment of metabolic disorders.

Inhibition of monoacylglycerol transferase 2 (MGAT2) has recently emerged as a potential therapeutic strategy for the treatment of metabolic diseases such as obesity, diabetes and non-alcoholic steatohepatitis (NASH). Metabolism studies with our clinical lead (1) suggested variability in in vitro glucuronidation rates in liver microsomes across species, which made projection of human doses challenging. In addition, the observation of deconjugation of the C3-C4 double bond in the dihydropyridinone ring of 1 in solution had the potential to complicate its clinical development.

Optimization of physicochemical properties of pyrrolidine GPR40 AgoPAMs results in a differentiated profile with improved pharmacokinetics and reduced off-target activities.

GPR40 AgoPAMs are highly effective antidiabetic agents that have a dual mechanism of action, stimulating both glucose-dependent insulin and GLP-1 secretion. The early lipophilic, aromatic pyrrolidine and dihydropyrazole GPR40 AgoPAMs from our laboratory were highly efficacious in lowering plasma glucose levels in rodents but possessed off-target activities and triggered rebound hyperglycemia in rats at high doses. A focus on increasing molecular complexity through saturation and chirality in combination with reducing polarity for the pyrrolidine AgoPAM chemotype resulted in the discovery of compound 46, which shows significantly reduced off-target activities as well as improved aqueous solubility, rapid absorption, and linear PK.

MGAT2 inhibitor decreases liver fibrosis and inflammation in murine NASH models and reduces body weight in human adults with obesity.

Monoacylglycerol acyltransferase 2 (MGAT2) is an important enzyme highly expressed in the human small intestine and liver for the regulation of triglyceride absorption and homeostasis. We report that treatment with BMS-963272, a potent and selective MGAT2 inhibitor, decreased inflammation and fibrosis in CDAHFD and STAM, two murine nonalcoholic steatohepatitis (NASH) models. In high-fat-diet-treated cynomolgus monkeys, in contrast to a selective diacylglycerol acyltransferase 1 (DGAT1) inhibitor, BMS-963272 did not cause diarrhea.

Molecular Mechanisms of Desensitization Underlying the Differential Effects of Formyl Peptide Receptor 2 Agonists on Cardiac Structure-Function Post Myocardial Infarction.

Formyl peptide receptor 2 (FPR2) plays an integral role in the transition of macrophages from a pro-inflammatory program to one that is pro-resolving. FPR2-mediated stimulation of resolution post myocardial infarction has demonstrated efficacy in rodent models and is hypothesized to reduce progression into heart failure. FPR2 agonists that promote long-lasting receptor internalization can lead to persistent desensitization and diminished therapeutic benefits.

Fellowship Training in Oral and Maxillofacial Surgery: Opportunities and Outcomes.

The pursuit of fellowship training stems from one's desire to master a focused area of surgery. Successful applicants tend to have published articles and participated in other scholarly activities. They commonly have a mentor within the subspecialty of their interest.

Discovery of Heteroaryl Urea Isosteres for Formyl Peptide Receptor 2 Agonists.

Formyl peptide receptor 2 (FPR2) agonists have shown efficacy in inflammatory-driven animal disease models and have the potential to treat a range of diseases. Many reported synthetic agonists contain a phenylurea, which appears to be necessary for activity in the reported chemotypes. We set out to find isosteres for the phenylurea and focused our efforts on heteroaryl rings.

Interdisciplinary prosthetic rehabilitation following bilateral maxillectomy with total upper lip and unilateral zygoma resection: A clinical report.

This clinical report describes the design and fabrication of an implant-retained and soft-tissue-supported obturator prosthesis and a magnetic retained midfacial prosthesis for a patient with a midfacial defect following bilateral total maxillectomy, removal of the left zygoma, and excision of the entire upper lip. The patient underwent multiple head and neck surgeries for 4 separate primary oral cancers, 1 recurrence, and 1 pulmonary metastasis. The definitive obturator prosthesis was retained by 1 zygomatic implant with soft-tissue support and retention.

Screening Hit to Clinical Candidate: Discovery of BMS-963272, a Potent, Selective MGAT2 Inhibitor for the Treatment of Metabolic Disorders.

MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound (hMGAT2 IC = 175 nM) as a hit. Compound had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability.

Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy.

Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J.

Selective FPR2 Agonism Promotes a Proresolution Macrophage Phenotype and Improves Cardiac Structure-Function Post Myocardial Infarction.

Dysregulated inflammation following myocardial infarction (MI) leads to maladaptive healing and remodeling. The study characterized and evaluated a selective formyl peptide receptor 2 (FPR2) agonist BMS-986235 in cellular assays and in rodents undergoing MI. BMS-986235 activated G proteins and promoted β-arrestin recruitment, enhanced phagocytosis and neutrophil apoptosis, regulated chemotaxis, and stimulated interleukin-10 and monocyte chemoattractant protein-1 gene expression.

Updates in Management of Craniomaxillofacial Gunshot Wounds and Reconstruction of the Mandible.

This article includes updates in the management of mandibular trauma and reconstruction as they relate to maxillomandibular fixation screws, custom hardware, virtual surgical planning, and protocols for use of computer-aided surgery and navigation when managing composite defects from gunshot injuries to the face.

The Buccal Fat Pad Flap.

This article presents an overview of the history of the buccal fat pad flap, its relevant anatomy, and its indications and contraindications. The surgical technique for its harvest is described, as are the postoperative care and possible complications.

Does the Lack of Gender-Specific Apnea-Hypopnea Index Cutoff for Obstructive Sleep Apnea Impact Surgical Selection?

Purpose: The apnea-hypopnea index (AHI) is the parameter on which the severity of obstructive sleep apnea (OSA) is based and is also the determinant for both clinicians and third-party payers for surgical procedures. The purpose of this retrospective cross-sectional chart review is to examine differences in symptoms and AHI between men and women with OSA and whether this may impact timing and selection of surgical care.

Methods: Retrospective cross-sectional study of patients aged 18 years and older who presented at a single center for surgical evaluation of OSA from January 2017 to 2020.

Management of Zygomaticomaxillary Complex Fractures Utilizing Intraoperative 3-Dimensional Imaging: The ZYGOMAS Protocol.

Purpose: Utilization of technology to aid in the assessment, planning, and management of complex craniomaxillofacial injuries is increasingly common. Limited data exist regarding the implication of intraoperative CT/3-Dimensional imaging on decision making in the management of zygomaticomaxillary complex (ZMC) fractures. This study characterizes the utilization of the intraoperative CT scanner for ZMC fracture surgery and analyzes the impact of the intraoperative CT scanner on fracture management.

Transoral robotic surgery and neck dissection for HPV-positive oropharyngeal carcinoma: Importance of nodal count in survival.

Background: In this study we determine the survival in patients with HPV-positive oropharyngeal carcinoma treated with transoral robotic surgery (TORS), neck dissection and risk-adapted adjuvant therapy.

Methods: We retrospectively identified 122 patients with HPV-positive oropharyngeal carcinoma treated with TORS and neck dissection between 2011 and 2018. Survival probability was calculated.

Preservation of Post-Infarction Cardiac Structure and Function via Long-Term Oral Formyl Peptide Receptor Agonist Treatment.

Dysregulated inflammation following myocardial infarction (MI) promotes left ventricular (LV) remodeling and loss of function. Targeting inflammation resolution by activating formyl peptide receptors (FPRs) may limit adverse remodeling and progression towards heart failure. This study characterized the cellular and signaling properties of Compound 43 (Cmpd43), a dual FPR1/FPR2 agonist, and examined whether Cmpd43 treatment improves LV and infarct remodeling in rodent MI models.

Four Practical Reconstructive Techniques Using the Transantral Approach to the Orbital Floor Without the Need for an Endoscope.

Fractures of the orbital floor have traditionally been treated through transorbital approaches. Transconjunctival approaches risk entropion, whereas transcutaneous approaches risk ectropion or hypertrophic scarring. The intraoral transantral approach to the orbital floor has the advantage of minimizing the risk of any eyelid changes while providing appropriate access to reduce the herniated orbital contents and restore orbital volume.

Application of ultrasound-guided cholecystocentesis to the evaluation of the metabolite profiling in bile of dogs and cynomolgus monkeys.

In this study, we describe a novel approach for collecting bile from dogs and cynomolgus monkeys for metabolite profiling, ultrasound-guided cholecystocentesis (UCC). Sampling bile by UCC twice within 24 hours was well tolerated by dogs and monkeys. In studies with atorvastatin (ATV) the metabolite profiles were similar in bile obtained through UCC and from bile duct-cannulated (BDC) dogs.

Infection prevalence and patterns in self-inflicted gunshot wounds to the face.

Objective: Self-inflicted gunshot wounds (SIGSWs) to the craniomaxillofacial region are uncommon injuries but are associated with a high mortality rate. Therefore, treating these patients is a rare occurrence even in the largest trauma centers. As with many rare conditions, data specifically addressing this injury pattern are scarce.

What Is the Role of Elective Neck Dissection in the Management of Patients With Buccal Squamous Cell Carcinoma and Clinically Negative Neck?

Purpose: Buccal squamous cell carcinoma (BSCC) is rare in the United States. Given its location, few anatomic barriers to spread exist and it has been found to have a high locoregional recurrence rate. The role of elective neck dissection (END) in patients with clinically negative neck (N0) is not clear.