Assessing methods for detecting Alexandrium catenella (Dinophyceae) and paralytic shellfish toxins in Southeast Alaska.

Blooms of Alexandrium catenella threaten to disrupt subsistence, recreational, and commercial shellfish harvest in Alaska, as the paralytic shellfish toxins (PSTs) produced pose a serious public health risk and can lead to costly shutdowns for shellfish farmers. Current methods of PST detection in the region range from monitoring programs utilizing net tows to detect A. catenella to direct shellfish tissue testing via mouse bioassay (MBA) for commercial aquaculture harvest, as well as various optional testing methods for subsistence and recreational harvesters. The efficacy and feasibility of these methods vary, and they have not been directly compared in Southeast Alaska. In this study, we sought to assess and compare A. catenella and PST early detection methods to determine which can provide the most effective and accurate warning of A. catenella blooms or PST events. We found microscope counts to be variable and prone to missing lower numbers of A. catenella, which may be indicative of bloom formation. However, quantitative polymerase chain reaction (qPCR) significantly correlated with microscope counts and was able to effectively detect even low numbers of A. catenella on all sampling days. Paralytic shellfish toxin concentrations measured by enzyme-linked immunosorbent assay and MBA significantly correlated with each other, qPCR, and some microscope counts. These results show that qPCR is an effective tool for both monitoring A. catenella and serving as a proxy for PSTs. Further work is needed to refine qPCR protocols in this system to provide bloom warnings on an actionable timescale for the aquaculture industry and other shellfish harvesters. Integr Environ Assess Manag 2024;00:1-14. © 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response.

PURPOSE: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. PATIENTS AND METHODS: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed. RESULTS: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062). CONCLUSIONS: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non-small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633.

Effect of 4-nonylphenol on the immune response of the Pacific oyster Crassostrea gigas following bacterial infection with Vibrio campbellii.

The xenoestrogen 4-nonylphenol (NP) is a ubiquitous aquatic pollutant and has been shown to impair reproduction, development, growth and, more recently, immune function in marine invertebrates. We investigated the effects of short-term (7 d) exposure to low (2 µg l-1) and high (100 µg l-1) levels of NP on cellular and humoral elements of the innate immune response of Crassostrea gigas to a bacterial challenge. To this end, we measured 1) total hemocyte counts (THC), 2) relative transcript abundance of ten immune-related genes (defh1, defh2, bigdef1, bigdef2, bpi, lysozyme-1, galectin, C-type lectin 2, timp, and transglutaminase) in the hemocytes, gill and mantle, and 3) hemolymph plasma lysozyme activity, following experimental Vibrio campbellii infection. Both low and high levels of NP were found to repress a bacteria-induced increase in THC observed in the control oysters. While several genes were differentially expressed following bacterial introduction (bigdef2, bpi, lysozyme-1, timp, transglutaminase), only two genes (bpi in the hemocytes, transglutaminase in the mantle) exhibited a different bacteria-induced expression profile following NP exposure, relative to the control oysters. Independently of infection-status, exposure to NP also altered mRNA transcript abundance of several genes (bpi, galectin, C-type lectin 2) in naïve, saline-injected oysters. Finally, plasma lysozyme activity levels were significantly higher in low dose NP-treated oysters (both naïve and bacteria challenged) relative to control oysters. Combined, these results suggest that exposure to ecologically-relevant (low) and extreme (high) levels of NP can alter both cellular and humoral elements of the innate immune response in C. gigas, an aquaculture species of global economic importance.

Rapid and accurate determination of the lignin content of lignocellulosic biomass by solid-state NMR.

Biofuels and biomaterials, produced from lignocellulosic feedstock, require facile access to cellulose and hemicellulose to be competitive with petroleum processing and sugar-based fermentation. Physical-chemical barriers resulting from lignin complicates the hydrolysis biomass into fermentable sugars. Thus, the amount of lignin within a substrate is critical in determining biomass processing. The application of 13C cross-polarization, magic-angle spinning, and solid-state nuclear magnetic resonance for the direct quantification of lignin content in biomass is examined. Using a standard curve constructed from pristine lignin and cellulose, the lignin content of a biomass sample is accurately determined through direct measurement without chemical or enzymatic pre-treatment.

Nerve injury induces glial cell line-derived neurotrophic factor (GDNF) expression in Schwann cells through purinergic signaling and the PKC-PKD pathway.

Upon peripheral nerve injury, specific molecular events, including increases in the expression of selected neurotrophic factors, are initiated to prepare the tissue for regeneration. However, the mechanisms underlying these events and the nature of the cells involved are poorly understood. We used the injury-induced upregulation of glial cell-derived neurotrophic factor (GDNF) expression as a tool to gain insights into these processes. We found that both myelinating and nonmyelinating Schwann cells are responsible for the dramatic increase in GDNF expression after injury. We also demonstrate that the GDNF upregulation is mediated by a signaling cascade involving activation of Schwann cell purinergic receptors, followed by protein kinase C signaling which activates protein kinase D (PKD), which leads to increased GDNF transcription. Given the potent effects of GDNF on survival and repair of injured peripheral neurons, we propose that targeting these pathways may yield therapeutic tools to treat peripheral nerve injury and neuropathies.