Identification of Small Molecule Inhibitors and Ligand Directed Degraders of Calcium/Calmodulin Dependent Protein Kinase Kinase 1 and 2 (CaMKK1/2).

CaMKK2 signals through AMPK-dependent and AMPK-independent pathways to trigger cellular outputs including proliferation, differentiation, and migration, resulting in changes to metabolism, bone mass accrual, neuronal function, hematopoiesis, and immunity. CAMKK2 is upregulated in tumors including hepatocellular carcinoma, prostate, breast, and gastric cancer, and genetic deletion in myeloid cells results in increased antitumor immunity in several syngeneic models. Validation of the biological roles of CaMKK2 has relied on genetic deletion or small molecule inhibitors with activity against several biological targets.

Small molecule allosteric inhibitors of RORγt block Th17-dependent inflammation and associated gene expression in vivo.

Retinoic acid receptor-related orphan nuclear receptor (ROR) γt is a member of the RORC nuclear hormone receptor family of transcription factors. RORγt functions as a critical regulator of thymopoiesis and immune responses. RORγt is expressed in multiple immune cell populations including Th17 cells, where its primary function is regulation of immune responses to bacteria and fungi through IL-17A production.

Intermolecular Crossed [2 + 2] Cycloaddition Promoted by Visible-Light Triplet Photosensitization: Expedient Access to Polysubstituted 2-Oxaspiro[3.3]heptanes.

This paper describes an intermolecular cross-selective [2 + 2] photocycloaddition reaction of exocyclic arylidene oxetanes, azetidines, and cyclobutanes with simple electron-deficient alkenes. The reaction takes place under mild conditions using a commercially available Ir(III) photosensitizer upon blue light irradiation. This transformation provides access to a range of polysubstituted 2-oxaspiro[3.

Discovery of Selective, Covalent FGFR4 Inhibitors with Antitumor Activity in Models of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) accounts for a majority of primary liver cancer and is one of the most common forms of cancer worldwide. Aberrant signaling of the FGF19-FGFR4 pathway leads to HCC in mice and is hypothesized to be a driver in FGF19 amplified HCC in humans. Multiple small molecule inhibitors have been pursued as targeted therapies for HCC in recent years, including several selective FGFR4 inhibitors that are currently being evaluated in clinical trials.

Tobacco use and neurogenesis: A theoretical review of pathophysiological mechanism affecting the outcome of peripheral nerve regeneration.

Peripheral nerve injury often requires medical intervention. Unfortunately, many patients never have a full recovery, despite a multi-disciplinary approach, including operative intervention and physical and/or occupational therapy. Outcomes are multifactorial, but are largely affected by the original injury severity, and patient comorbidities.

Compound flap from the great toe and vascularized joints from the second toe for posttraumatic thumb reconstruction at the level of the proximal metacarpal bone.

The purpose of this study is to describe the harvesting technique, anatomic variations, and clinical applications of a compound flap from the great toe and vascularized joint from the second toe used for thumb reconstruction. Five fresh cadaver dissections were studied, focusing attention on the dorsal or plantar vascular dominance, position of the communicating branch between the dorsal and plantar system, the Gilbert classification, and the size of the first dorsal metatarsal artery (FDMA) and first plantar metatarsal artery (FPMA) to the great toe and second toe. Five compound flaps were performed on five patients with traumatic thumb amputation at the level of proximal metacarpal bone.