Hepatic Hedgehog Signaling Participates in the Crosstalk between Liver and Adipose Tissue in Mice by Regulating FGF21.

The Hedgehog signaling pathway regulates many processes during embryogenesis and the homeostasis of adult organs. Recent data suggest that central metabolic processes and signaling cascades in the liver are controlled by the Hedgehog pathway and that changes in hepatic Hedgehog activity also affect peripheral tissues, such as the reproductive organs in females. Here, we show that hepatocyte-specific deletion of the Hedgehog pathway is associated with the dramatic expansion of adipose tissue in mice, the overall phenotype of which does not correspond to the classical outcome of insulin resistance-associated diabetes type 2 obesity. Rather, we show that alterations in the Hedgehog signaling pathway in the liver lead to a metabolic phenotype that is resembling metabolically healthy obesity. Mechanistically, we identified an indirect influence on the hepatic secretion of the fibroblast growth factor 21, which is regulated by a series of signaling cascades that are directly transcriptionally linked to the activity of the Hedgehog transcription factor GLI1. The results of this study impressively show that the metabolic balance of the entire organism is maintained via the activity of morphogenic signaling pathways, such as the Hedgehog cascade. Obviously, several pathways are orchestrated to facilitate liver metabolic status to peripheral organs, such as adipose tissue.

53BP1 Accumulation in Circulating Tumor Cells Identifies Chemotherapy-Responsive Metastatic Breast Cancer Patients.

Evidence suggests that the DNA end-binding protein p53-binding protein 1 (53BP1) is down-regulated in subsets of breast cancer. Circulating tumor cells (CTCs) provide accessible "biopsy material" to track cell traits and functions and their alterations during treatment. Here, we prospectively monitored the 53BP1 status in CTCs from 67 metastatic breast cancer (MBC) patients with HER2- CTCs and known hormone receptor (HR) status of the primary tumor and/or metastases before, during, and at the end of chemotherapeutic treatment with Eribulin. Nuclear 53BP1 staining and genomic integrity were evaluated by immunocytochemical and whole-genome-amplification-based polymerase chain reaction (PCR) analysis, respectively. Comparative analysis of CTCs from patients with triple-negative and HR+ tumors revealed elevated 53BP1 levels in CTCs from patients with HR+ metastases, particularly following chemotherapeutic treatment. Differences in nuclear 53BP1 signals did not correlate with genomic integrity in CTCs at baseline or with nuclear γH2AX signals in MBC cell lines, indicating that 53BP1 detected features beyond DNA damage. Kaplan-Meier analysis revealed an increasing association between nuclear 53BP1-positivity and progression-free survival (PFS) during chemotherapy until the final visit. Our data suggest that 53BP1 detection in CTCs could be a useful marker to capture dynamic changes of chemotherapeutic responsiveness in triple-negative and HR+ MBC.

Concerns that an opioid antidote could "make things worse": Profiles of risk compensation beliefs using the Naloxone-Related Risk Compensation Beliefs (NaRRC-B) scale.

Background and aims: As opioid overdose death rates reach epidemic proportions in the United States, the widespread distribution of naloxone is imperative to save lives. However, concerns that people who use drugs will engage in riskier drug behaviors if they have access to naloxone remain prevalent, and the measurement scales to assess these risk compensation concerns remain under researched. This study aims to examine the validity of the Naloxone-Related Risk Compensation Beliefs (NaRRC-B) scale and to understand the effect of overdose education and naloxone distribution (OEND) training on risk compensation beliefs across demographic and professional populations. Methods: A total of 1424 participants, 803 police officers, 137 emergency medical services (EMS)/fire personnel, and 484 clinical treatment and social service providers were administered surveys before and after attending an OEND training. Survey items measured the endorsement of opioid overdose knowledge and attitudes, as well as risk compensation beliefs. Results: Police and EMS/fire personnel expressed greater endorsement of risk compensation beliefs than clinical treatment and social service providers at both pre- and post-OEND training. Although endorsement of risk compensation beliefs was significantly reduced in each of the 3 groups after the training, reductions were greatest among EMS/fire personnel, followed by providers, then police. Moreover, younger, male, and black participants endorsed greater beliefs in risk compensatory behaviors as compared with their older, female, and white counterparts. Conclusion: This study validated a novel measure of naloxone-related risk compensation beliefs and suggests participating in OEND trainings decreases beliefs in naloxone-related risk compensation behaviors. OEND trainings should consider addressing concerns about naloxone "enabling" drug use, particularly in law enforcement settings, to continue to reduce stigma surrounding naloxone availability.

An Intramolecular Nitrone-Olefin Dipolar Cycloaddition-Based Approach to Total Synthesis of the Cylindricine and Lepadiformine Marine Alkaloids.

A synthetic route to the cylindricine skeleton as well as to the reported structure of the marine alkaloid lepadiformine has been achieved using an intramolecular nitrone/1,3-diene dipolar cycloaddition as the key step. The synthesis began with sequential alkylations of acetone oxime to afford key intermediate oxime 30, which contains all of the carbons necessary to form the tricyclic skeleton of the alkaloids. Nitrone 40, available from oxime 30 by standard transformations, underwent an intramolecular 1,3-dipolar cycloaddition to provide isoxazolidine 43. Related 1,3-dipolar cycloadditions were also explored on two additional nitrone-olefin substrates 41 and 42, which were prepared in a manner similar to that of 40. The tricyclic alkaloid core 52 was formed stereoselectively by a tandem oxidation-Michael addition of amino alcohol 49 derived from isoxazolidine 43. Cleavage of the O-phenyl ether of 52 provided 2-epi-cylindricine C (53). Several unsuccessful attempts were made to convert 52 to cylindricine C by epimerization at C2. Tricyclic ketone 52 was deoxygenated to give amine 59, whose structure and relative stereochemistry were confirmed by single-crystal X-ray analysis of its picrate salt. Removal of the O-phenyl protecting group from 59 provided tricyclic amino alcohol 60 having the putative structure of lepadiformine, but whose NMR data did not correspond to those of the natural product.