Wnt/ß-catenin signaling is a therapeutic target in anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy that has consistently shown Wnt/ß-catenin (canonical) signaling activation in various study populations. There are currently no targetable treatments for BRAF-wildtype ATC and a lack of effective treatment for BRAFV600EATC. Our aim is to identify whether Wnt inhibitors could be potential therapeutic agents for ATC patients with limited treatment options. METHODS: In this Institutional Review Board-approved study, we utilize a cohort of 32 ATCs and 20 non-neoplastic multinodular goiters (MNG). We also use 4 ATC spheroid cell lines (THJ-16T, THJ-21T, THJ-29T, and THJ-11T) and two primary patient-derived ATC organoid cultures (VWL-T5 and VWL-T60). Finally, we use a murine xenograft mouse model of ATC for in vivo treatment studies. RESULTS: Using a large patient cohort, we demonstrate that this near-universal Wnt signaling activation is associated with ligand expression- rather than being mutationally-driven. We show that pyrvinium pamoate, a potent Wnt inhibitor, exhibits in vitro efficacy against both ATC cell lines and primary patient-derived ATC organoids VWL-T5 (p < 0.05) and VWL-T60 (p < 0.01) Finally, using a murine xenograft model of ATC, we show that pyrvinium significantly delays the growth of ATC tumors in THJ-16T (p < 0.005) and THJ-21T (p < 0.001). CONCLUSIONS: We tested Wnt inhibitor treatment, both in vitro and in vivo, as a potential novel therapy for this highly lethal disease. Future large-scale studies utilizing multiple Wnt inhibitors will lay the foundation for the development of these novel therapies for patients with ATC.

A Review of the Clinical Pharmacology of Pelacarsen: A Lipoprotein(a)-Lowering Agent.

Patients with genetically associated elevated lipoprotein(a) [Lp(a)] levels are at greater risk for coronary artery disease, heart attack, stroke, and peripheral arterial disease. To date, there are no US FDA-approved drug therapies that are designed to target Lp(a) with the goal of lowering the Lp(a) level in patients who have increased risk. The American College of Cardiology (ACC) has provided guidelines on how to use traditional lipid profiles to assess the risk of atherosclerotic cardiovascular disease (ASCVD); however, even with the emergence of statin add-on therapies such as ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, some populations with elevated Lp(a) biomarkers remain at an increased risk for cardiovascular (CV) disease. Residual CV risk has led researchers to inquire about how lowering Lp(a) can be used as a potential preventative therapy in reducing CV events. This review aims to present and discuss the current clinical and scientific evidence pertaining to pelacarsen.

Contaminants of Emerging Concern in the Lower Volta River, Ghana, West Africa: The Agriculture, Aquaculture, and Urban Development Nexus.

Contaminants of emerging concern (CECs) are ubiquitous in aquatic environments across all continents and are relatively well known in the developed world. However, few studies have investigated their presence and biological effects in low- and middle-income countries. We provide a survey of CEC presence in the Volta River, Ghana, and examine the microbial consequences of anthropogenic activities along this economically and ecologically important African river. Water and sediment samples were taken by boat or from shore at 14 sites spanning 118 km of river course from the Volta estuary to the Akosombo dam. Sample extracts were prepared for targeted analysis of antimicrobial CECs, N,N-diethyl-meta-toluamide, and per- and polyfluoroalkyl substances (PFAS; water only). Concurrent samples were extracted to characterize the microbial community and antibiotic-resistant genes (ARGs). Antibiotics and PFAS (PFAS, 2-20 ng/L) were found in all water samples; however, their concentrations were usually in the low nanograms per liter range and lower than reported for other African, European, and North American studies. N,N-Diethyl-meta-toluamide was present in all samples. The number of different genes detected (between one and 10) and total ARG concentrations varied in both water (9.1 × 10-6 to 8.2 × 10-3 ) and sediment (2.2 × 10-4 to 5.3 × 10-2 ), with increases in gene variety at sites linked to urban development, sand mining, agriculture, and shellfish processing. Total ARG concentration spikes in sediment samples were associated with agriculture. No correlations between water quality parameters, CEC presence, and/or ARGs were noted. The presence of CECs in the lower Volta River highlights their global reach. The overall low concentrations of CECs detected is encouraging and, coupled with mitigation measures, can stymie future CEC pollution in the Volta River. Environ Toxicol Chem 2022;41:369-381. © 2021 SETAC.