Effects of water quality on palladium-induced olfactory toxicity and bioaccumulation in rainbow trout (Oncorhynchus mykiss).

Through emission processes, palladium (Pd) particulates from industrial sources are introduced into a range of ecosystems including freshwater environments. Despite this, research on Pd-induced bioaccumulation, uptake, and toxicity is limited for freshwater fishes. Unlike other metals, there are currently no regulations or protective guidelines to limit Pd release into aquatic systems, indicating a global absence of measures addressing its environmental impact. To assess the olfactory toxicity potential of Pd, the present study aimed to explore Pd accumulation in olfactory tissues, olfactory disruption, and oxidative stress in rainbow trout (Oncorhynchus mykiss) following waterborne Pd exposure. Olfactory sensitivity, measured by electro-olfactography, demonstrated that Pd inhibits multiple pathways of the olfactory system following 96 h of Pd exposure. In this study, the concentrations of Pd for inhibition of olfactory function by 20% (2.5 µg/L; IC20) and 50% (19 µg/L; IC50) were established. Rainbow trout were then exposed to IC20 and IC50 Pd concentrations in combination with varying exposure conditions, as changes in water quality alter the toxicity of metals. Independent to Pd, increased water hardness resulted in decreased olfactory perception owing to ion competition at the olfactory epithelium. No other environmental parameter in this study significantly influenced Pd-induced olfactory toxicity. Membrane-associated Pd was measured at the olfactory rosette and gill following exposure; however, this accumulation did not translate to oxidative stress as measured by the production of malondialdehyde. Our data suggest that Pd is toxic to rainbow trout via waterborne contamination near field-measured levels. This study further demonstrated Pd bioavailability and uptake at water-adjacent tissues, adding to our collective understanding of the toxicological profile of Pd. Taken together, our results provide novel insights into the olfactory toxicity in fish following Pd exposure. Integr Environ Assess Manag 2024;00:1-13. © 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

A two-stage adaptive clinical trial design with data-driven subgroup identification at interim analysis.

In this paper, we consider randomized controlled clinical trials comparing two treatments in efficacy assessment using a time to event outcome. We assume a relatively small number of candidate biomarkers available in the beginning of the trial, which may help define an efficacy subgroup which shows differential treatment effect. The efficacy subgroup is to be defined by one or two biomarkers and cut-offs that are unknown to the investigator and must be learned from the data. We propose a two-stage adaptive design with a pre-planned interim analysis and a final analysis. At the interim, several subgroup-finding algorithms are evaluated to search for a subgroup with enhanced survival for treated versus placebo. Conditional powers computed based on the subgroup and the overall population are used to make decision at the interim to terminate the study for futility, continue the study as planned, or conduct sample size recalculation for the subgroup or the overall population. At the final analysis, combination tests together with closed testing procedures are used to determine efficacy in the subgroup or the overall population. We conducted simulation studies to compare our proposed procedures with several subgroup-identification methods in terms of a novel utility function and several other measures. This research demonstrated the benefit of incorporating data-driven subgroup selection into adaptive clinical trial designs.

Assessment of Streptococcus mutans biofilms on orthodontic adhesives over 7 days.

INTRODUCTION: The purpose of this study was to compare the metabolism of Streptococcus mutans biofilms after 1-7 days of growth on different orthodontic adhesives. METHODS: Specimens of 6 commercial orthodontic adhesives were fabricated in custom-made molds and polymerized using a light-emitting diode light-curing unit. Bioluminescent S mutans (UA159:JM10) biofilms were grown on ultraviolet-sterilized specimens for 1, 3, 5, and 7 days (n = 18 biofilms/d/product) in anaerobic conditions at 37°C. The metabolism of biofilms (relative luminescence unit [RLU]) was measured 0, 2, 4, and 6 minutes after exposure to D-luciferin solution using a microplate reader. A linear mixed-effects model was used to analyze the logarithm of RLU (log RLU). The model included fixed effects of products, days, and minutes. Tukey-Kramer post-hoc tests were then performed on the significant predictors of log RLU (α = 0.05). RESULTS: Days (P <0.0001) and minutes (P <0.0001) were independent predictors of log RLU, but the products were not (P = 0.5869). After adjusting for minutes, the log RLU was analyzed with a post-hoc test, and all differences between days were significant with the exceptions of day 3 from day 5 (P = 0.0731) and day 5 from day 7 (P = 0.8802). After adjusting for day, log RLU was analyzed with a post-hoc test and all differences in minutes were significant. CONCLUSIONS: No significant differences in the metabolism of S mutans biofilms were observed among the 6 orthodontic adhesives. Biofilms that were grown for 3 days demonstrated the highest levels of biofilm metabolism as evidenced by higher mean log RLU values relative to 1, 5, and 7-day growth durations.

Molecular Targeting of HuR Oncoprotein Suppresses MITF and Induces Apoptosis in Melanoma Cells.

BACKGROUND: Treatment of metastatic melanoma possesses challenges due to drug resistance and metastases. Recent advances in targeted therapy and immunotherapy have shown clinical benefits in melanoma patients with increased survival. However, a subset of patients who initially respond to targeted therapy relapse and succumb to the disease. Therefore, efforts to identify new therapeutic targets are underway. Due to its role in stabilizing several oncoproteins' mRNA, the human antigen R (HuR) has been shown as a promising molecular target for cancer therapy. However, little is known about its potential role in melanoma treatment. METHODS: In this study, we tested the impact of siRNA-mediated gene silencing of HuR in human melanoma (MeWo, A375) and normal melanocyte cells in vitro. Cells were treated with HuR siRNA encapsulated in a lipid nanoparticle (NP) either alone or in combination with MEK inhibitor (U0126) and subjected to cell viability, cell-cycle, apoptosis, Western blotting, and cell migration and invasion assays. Cells that were untreated or treated with control siRNA-NP (C-NP) were included as controls. RESULTS: HuR-NP treatment significantly reduced the expression of HuR and HuR-regulated oncoproteins, induced G1 cell cycle arrest, activated apoptosis signaling cascade, and mitigated melanoma cells' aggressiveness while sparing normal melanocytes. Furthermore, we demonstrated that HuR-NP treatment significantly reduced the expression of the microphthalmia-associated transcription factor (MITF) in both MeWo and MITF-overexpressing MeWo cells (p < 0.05). Finally, combining HuR-NP with U0126 resulted in synergistic antitumor activity against MeWo cells (p < 0.01). CONCLUSION: HuR-NP exhibited antitumor activity in melanoma cells independent of their oncogenic B-RAF mutational status. Additionally, combinatorial therapy incorporating MEK inhibitor holds promise in overriding MITF-mediated drug resistance in melanoma.

Surgical Treatment of Tethered Cord Syndrome in Adults: A Systematic Review and Meta-Analysis.

OBJECTIVE: In the healthy spine, the spinal cord moves unimpeded with spinal fluid pulsation in the rostral and caudal directions. When a portion of the spinal cord becomes attached to lesions within the spinal column, excess strain can cause signs and symptoms such as pain, motor deficits, sensory deficits, bladder dysfunction, and bowel dysfunction. This condition is termed tethered cord syndrome. There are no clear guidelines for offering surgical intervention, although there is a general consensus that worsening signs and symptoms increase the likelihood that patients will need surgery. METHODS: In this article, we conduct a systematic review and meta-analysis for all available literature within the Ovid (MEDLINE), PubMed, and Google Scholar databases to evaluate common symptoms among patients with tethered cord and to examine how surgery affects symptoms. RESULTS: Within the cohort of 730 patients, 708 (97%) were treated surgically by a detethering procedure. The most common preoperative sign or symptom was pain (81%), followed by motor deficits (63%), sensory deficits (61%), bladder dysfunction (56%), and bowel dysfunction (15%). One percent of patients had no deficit or symptom. Pain was the symptom that was most responsive to surgery, with 81% of patients reporting that their pain improved after detethering. CONCLUSIONS: Tethered cord syndrome should be included in the differential diagnosis in patients presenting with back or leg pain, somatosensory symptoms of the lower extremities, muscular weakness, urodynamic dysfunction, or bowel dysfunction. After a definitive diagnosis is made, patients should be counseled about surgical detethering as an option.

Associations of biological stress markers in hurricane survivors: Heartrate variability, Interleukin-2 and Interleukin-6 in depression and PTSD.

OBJECTIVE: Inflammatory and immunologic cytokines and vagal activity have important roles in health and mental health, and may influence each other. The authors assessed relationships of representative biomarkers linked to disaster exposure-heart rate variability (HRV) with Interleukin-2 (IL-2, cell-medicated immunity) and Interleukin-6 (IL-6, pro-inflammatory and pro-immunologic), stratified by psychiatric diagnosis. DESIGN: Participants were assessed for psychiatric diagnosis, IL-2, IL-6, HRV, and HR reactivity to trauma reminders. SETTING: Outpatient university psychiatry clinics in Oklahoma City and Tulsa. PARTICIPANTS: Relocated Katrina survivors and demographically matched controls, not on psychiatric, cardiovascular, or inflammatory medications. MAIN OUTCOME MEASURES: SCID-IV, baseline serum IL-2 and IL-6, HRV through power spectral analysis. RESULTS: Survivors had higher sympathetic and lower parasympathetic activity at baseline and lower parasympathetic HR reactivity than controls, with flattened parasympathetic reactivity in the presence of depression and of post-traumatic stress disorder (PTSD). Survivors' IL-2 and IL-6 did not differ from controls and did not differ in PTSD or depression. Depressed survivors' sympathetic reactivity correlated negatively with IL-2 and parasympathetic reactivity correlated positively with IL-2. CONCLUSIONS: HRV differed after hurricane exposure and with survivors& depression and/or PTSD, more sensitively capturing somatic sequelae than assessed cytokines. Higher sympathetic HR reactivity associated with lower immuno-logic IL-2 may indicate a double biological "hit" in depressed disaster survivors, possibly rendering them more vulnerable to cardiovascular and immunologic illness as well as depression. Associations of HRV with IL-2 may support reciprocal influences of cytokines and vagal activity. Lack of significant correlations of IL-6 with HRV measures is consistent with its pleiotropic role.

Discovery of Compounds that Positively Modulate the High Affinity Choline Transporter.

Cholinergic hypofunction is associated with decreased attention and cognitive deficits in the central nervous system in addition to compromised motor function. Consequently, stimulation of cholinergic neurotransmission is a rational therapeutic approach for the potential treatment of a variety of neurological conditions. High affinity choline uptake (HACU) into acetylcholine (ACh)-synthesizing neurons is critically mediated by the sodium- and pH-dependent high-affinity choline transporter (CHT, encoded by the SLC5A7 gene). This transporter is comparatively well-characterized but otherwise unexplored as a potential drug target. We therefore sought to identify small molecules that would enable testing of the hypothesis that positive modulation of CHT mediated transport would enhance activity-dependent cholinergic signaling. We utilized existing and novel screening techniques for their ability to reveal both positive and negative modulation of CHT using literature tools. A screening campaign was initiated with a bespoke compound library comprising both the Pfizer Chemogenomic Library (CGL) of 2,753 molecules designed specifically to help enable the elucidation of new mechanisms in phenotypic screens and 887 compounds from a virtual screening campaign to select molecules with field-based similarities to reported negative and positive allosteric modulators. We identified a number of previously unknown active and structurally distinct molecules that could be used as tools to further explore CHT biology or as a starting point for further medicinal chemistry.