A New Synthesis of Enantiopure Amine Fragment: An Important Intermediate to the Anti-HIV Drug Lenacapavir.

Herein, we describe a new seven-step approach to prepare ()-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (()-) from the inexpensive 2-(3,5-difluorophenyl)acetic acid. The key steps in the sequence include (1) the Weinreb amide-based ketone synthesis to provide an entry point to the core structure; (2) simple functional group transformations to afford the racemic amine -; and (3) dynamic kinetic resolution (DKR) to access the chiral amine ()-. This seven-step process delivered the enantiopure amine ()- in an overall isolated yield of approximately 15%.

Practical Synthesis of 7-Bromo-4-chloro-1-indazol-3-amine: An Important Intermediate to Lenacapavir.

7-Bromo-4-chloro-1-indazol-3-amine is a heterocyclic fragment used in the synthesis of Lenacapavir, a potent capsid inhibitor for the treatment of HIV-1 infections. In this manuscript, we describe a new approach to synthesizing 7-bromo-4-chloro-1-indazol-3-amine from inexpensive 2,6-dichlorobenzonitrile. This synthetic method utilizes a two-step sequence including regioselective bromination and heterocycle formation with hydrazine to give the desired product in an overall isolated yield of 38-45%.

A Multicenter Evaluation of Treatment-associated Changes in Body Composition in Men With Germ Cell Tumors of the Testis: Implications for Adverse Events and Complications.

Objective: To characterize changes in body composition following cytotoxic chemotherapy for germ cell carcinoma of the testis (GCT) and quantify associations between body composition metrics and chemotherapy-associated adverse events (AEs) and post-retroperitoneal lymph node dissection (RPLND) complications.

Materials And Methods: This retrospective multi-center study included 216 men with GCT treated with cytotoxic chemotherapy and/or RPLND (2005-2020). We measured body composition including skeletal muscle (SMI), visceral adipose (VAI,), subcutaneous adipose (SAI), and fat mass (FMI) indices on computed tomography.

Changes in skeletal muscle and adipose tissue during cytotoxic chemotherapy for testicular germ cell carcinoma and associations with adverse events.

Objectives: To quantify changes in body composition during cytotoxic chemotherapy for germ cell carcinoma of the testis (GCT) and evaluate associations between change in skeletal muscle and adipose tissue and chemotherapy-associated adverse events.

Materials And Methods: This retrospective single-institution study evaluated men with GCT treated with cytotoxic chemotherapy from 2005 to 2018. We measured skeletal muscle index (SMI [cm/m]), skeletal muscle density (SMD [Hounsfield Units (HU)]), skeletal muscle gauge (SMG [cm²*HU/m²]), fat mass index (FMI [kg/m]), visceral adipose index (VAI [cm/m]), and subcutaneous adipose index (SAI [cm/m]) on axial computed tomography images at the level of the third lumbar vertebra within 75 days before and after chemotherapy.

Catalytic Enantioselective Synthesis of α-Difunctionalized Cyclic Sulfones.

As saturated heterocyclic building blocks become increasingly popular in medicinal chemistry and drug discovery programs, expansion of the synthetic toolkit to novel stereofunctionalized heterocycles is a priority. Herein, we report the development of a palladium-catalyzed decarboxylative asymmetric allylic alkylation reaction to access a broad range of enantioenriched α-difunctionalized 5- and 6-membered sulfones from easily accessible racemic starting materials. The allylic alkylation step was found to occur with high levels of enantioselectivity as a result of a palladium-mediated dynamic kinetic resolution of / enolate intermediates.

Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Thietane 1,1-Dioxides.

A palladium-catalyzed decarboxylative asymmetric allylic alkylation of thietane 1,1-dioxides via linear enolate intermediates from racemic starting materials has been developed. This process installs an α-sulfonyl tetrasubstituted stereogenic center with high enantioselectivity. The potential to transform the alkylated products to novel types of enantioenriched spirocycles for medicinal chemistry applications has also been demonstrated.

Recognizing and Managing Adverse Events in Y-90 Radioembolization.

Transarterial radioembolization using yttrium-90 (Y-90) microspheres is an important therapy in the management of unresectable primary liver tumors or hepatic metastases. While radioembolization is generally well-tolerated, it is not free from adverse events, and familiarity with the prevention and treatment of radioembolization-specific complications is an important component of patient care. This article aims to review radioembolization-specific toxicities stratified by hepatic, extrahepatic, and systemic effects, with a focus on preventing and mitigating radioembolization-induced morbidity.

Custom 3-Dimensional Printed Ultrasound-Compatible Vascular Access Models: Training Medical Students for Vascular Access.

Purpose: To generate 3-dimensional (3D) printed ultrasound (US)-compatible vascular models (3DPVAM) and test them for noninferiority in training medical students in femoral artery access.

Materials And Methods: A 3DPVAM of normal femoral artery (FA) anatomy was developed from an anonymized computerized tomography (CT) examination. Students were randomized to a 3DPVAM or a commercial model (CM) simulation experience (SE) for US-guided FA access.

Synergistic actions of blocking angiopoietin-2 and tumor necrosis factor-α in suppressing remodeling of blood vessels and lymphatics in airway inflammation.

Remodeling of blood vessels and lymphatics are prominent features of sustained inflammation. Angiopoietin-2 (Ang2)/Tie2 receptor signaling and tumor necrosis factor-α (TNF)/TNF receptor signaling are known to contribute to these changes in airway inflammation after Mycoplasma pulmonis infection in mice. We determined whether Ang2 and TNF are both essential for the remodeling on blood vessels and lymphatics, and thereby influence the actions of one another.

IL-7 production in murine lymphatic endothelial cells and induction in the setting of peripheral lymphopenia.

IL-7 is a required factor for T-cell homeostasis. Because of low expression levels and poor reagent availability, the cellular sources of IL-7 have proven challenging to characterize. In this study, we describe a reporter mouse in which enhanced GFP is expressed from the endogenous Il7 locus.

The Salmonella SPI2 effector SseI mediates long-term systemic infection by modulating host cell migration.

Host-adapted strains of Salmonella enterica cause systemic infections and have the ability to persist systemically for long periods of time despite the presence of a robust immune response. Chronically infected hosts are asymptomatic and transmit disease to naïve hosts via fecal shedding of bacteria, thereby serving as a critical reservoir for disease. We show that the bacterial effector protein SseI (also called SrfH), which is translocated into host cells by the Salmonella Pathogenicity Island 2 (SPI2) type III secretion system (T3SS), is required for Salmonella typhimurium to maintain a long-term chronic systemic infection in mice.

Gonadal stromal tumor in black male.

A twenty-five-year-old black male presented with a right testicular mass which had progressively increased in size over three years. He was in good health and noted no other general abnormalities. Taking all malignant precautions, excisional biopsy of the lesion revealed gonadal stromal tumor by frozen section.