The toxicity and environmental persistence of anthropogenic per- and poly-fluoroalkyl substances (PFAS) are of global concern. To address legacy PFAS concerns in the United States, industry developed ...numerous replacement PFAS that commonly are treated as confidential information. To investigate the distribution of PFAS in New Jersey, soils collected from across the state were subjected to nontargeted mass-spectral analyses. Ten chloroperfluoropolyether carboxylates were tentatively identified, with at least three congeners in all samples. Nine congeners are ≥(CF
)
Distinct chemical formulas and structures, as well as geographic distribution, suggest airborne transport from an industrial source. Lighter congeners dispersed more widely than heavier congeners, with the most widely dispersed detected in an in-stock New Hampshire sample. Additional data were used to develop a legacy-PFAS fingerprint for historical PFAS sources in New Jersey.
Per- and polyfluoroalkyl substances (PFAS) make up a widespread, environmentally persistent class of anthropogenic chemicals that are widely used in industrial and consumer products and frequently ...detected in environmental media. Concerns over potential human health impacts from long-term exposure to legacy PFAS (long-chain perfluoroalkyl acids) resulted in the use of PFAS with alternative structures. Nontargeted environmental monitoring has been crucial in identifying the existence and transport of emerging PFAS in environmental media. Previous work in an industrially impacted region of southwestern New Jersey has shown consistently elevated levels of legacy PFAS, motivating additional examination by nontargeted mass spectrometry to identify emerging PFAS contamination. This study applied nontargeted analysis to water samples collected in Gloucester and Salem counties in southwestern New Jersey, revealing the existence of a series of chloro-perfluoro-polyether carboxylates and related PFAS species, believed to originate from a regional, industrial PFAS user. There is sparse publicly available toxicity information for the emerging chemical species, but estimated concentrations exceeded the state drinking water standards for perfluorooctanoic acid and perfluorononanoic acid. Nontargeted analysis was used to estimate the effectiveness of point-of-entry water treatment systems for removal of the emerging species and reduced the abundance of PFAS by >90%.
Immunotherapy has dramatically transformed the cancer treatment landscape largely due to the efficacy of immune checkpoint inhibitors (ICIs). Although ICIs have shown promising results for many ...patients, the low response rates in many cancers highlight the ongoing challenges in cancer treatment. Cytotoxic T lymphocytes (CTLs) execute their cell-killing function via two distinct mechanisms: a fast-acting, perforin-mediated process and a slower, Fas ligand (FasL)-driven pathway. Evidence also suggests that the preferred killing mechanism of CTLs depends on the antigenicity of tumor cells. To determine the critical factors affecting responses to ICIs, we construct an ordinary differential equation model describing in vivo tumor-immune dynamics in the presence of active or blocked PD-1/PD-L1 immune checkpoint. Specifically, we identify important aspects of the tumor-immune landscape that affect tumor size and composition in the short and long term. We also generate a virtual cohort of mice with diverse tumor and immune attributes to simulate the outcomes of immune checkpoint blockade in a heterogeneous population. By identifying key tumor and immune characteristics associated with tumor elimination, dormancy, and escape, we predict which fraction of a population potentially responds well to ICIs and ways to enhance therapeutic outcomes with combination therapy.
Bladder cancer is an increasingly prevalent global disease that continues to cause morbidity and mortality despite recent advances in treatment. Immune checkpoint inhibitors (ICI) and fibroblast ...growth factor receptor (FGFR)-targeted therapeutics have had modest success in bladder cancer when used as monotherapy. Emerging data suggests that the combination of these two therapies could lead to improved clinical outcomes, but the optimal strategy for combining these agents remains uncertain. Mathematical models, specifically agent-based models (ABMs), have shown recent successes in uncovering the multiscale dynamics that shape the trajectory of cancer. They have enabled the optimization of treatment methods and the identification of novel therapeutic strategies. To assess the combined effects of anti-PD-1 and anti-FGFR3 small molecule inhibitors (SMI) on tumor growth and the immune response, we built an ABM that captures key facets of tumor heterogeneity and CD8
T cell phenotypes, their spatial interactions, and their response to therapeutic pressures. Our model quantifies how tumor antigenicity and FGFR3 activating mutations impact disease trajectory and response to anti-PD-1 antibodies and anti-FGFR3 SMI. We find that even a small population of weakly antigenic tumor cells bearing an FGFR3 mutation can render the tumor resistant to combination therapy. However, highly antigenic tumors can overcome therapeutic resistance mediated by FGFR3 mutation. The optimal therapy depends on the strength of the FGFR3 signaling pathway. Under certain conditions, ICI alone is optimal; in others, ICI followed by anti-FGFR3 therapy is best. These results indicate the need to quantify FGFR3 signaling and the fitness advantage conferred on bladder cancer cells harboring this mutation. This ABM approach may enable rationally designed treatment plans to improve clinical outcomes.
Analogous behavioral assays are needed across animal models and human patients to improve translational research. Here, we examined the extent to which performance in the Morris water maze - the most ...frequently used behavioral assay of spatial learning and memory in rodents - translates to humans. We designed a virtual version of the assay for human subjects that includes the visible-target training, hidden-target learning, and probe trials that are typically administered in the mouse version. We compared transgenic mice that express human amyloid precursor protein (hAPP) and patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD) to evaluate the sensitivity of performance measures in detecting deficits. Patients performed normally during visible-target training, while hAPP mice showed procedural learning deficits. In hidden-target learning and probe trials, hAPP mice and MCI-AD patients showed similar deficits in learning and remembering the target location. In addition, we have provided recommendations for selecting performance measures and sample sizes to make these assays sensitive to learning and memory deficits in humans with MCI-AD and in mouse models. Together, our results demonstrate that with careful study design and analysis, the Morris maze is a sensitive assay for detecting AD-relevant impairments across species.
Toll-like receptor 5 (TLR5) recognizes bacterial flagellin and activates host inflammatory responses. In this study, we examine the nature of the TLR5-flagellin interaction. With deletional, ...insertional and alanine-scanning mutagenesis, we precisely mapped the TLR5 recognition site on flagellin to a cluster of 13 amino acid residues that participate in intermolecular interactions within flagellar protofilaments and that are required for bacterial motility. The recognition site is buried in the flagellar filament, and monomeric flagellin, but not the filamentous molecule, stimulated TLR5. Finally, flagellin coprecipitated with TLR5, indicating close physical interaction between the molecules. These studies demonstrate the exquisite ability of the innate immune system to precisely target a conserved site on flagellin that is essential for bacterial motility.
•Discrimination learning was assessed during three conditions of opioid exposure.•Learning was not affected by self-administered oxycodone.•Learning was impaired during withdrawal via naltrexone and ...abrupt discontinuation.•Impairment of learning was concordant with autonomic signs of opioid withdrawal.
Prescription opioid abuse continues to be a public health concern of epidemic proportions. Notwithstanding the extensive literature regarding opioid action, there has been little systematic research regarding the effects of opioid dependence and withdrawal on aspects of cognition-related behavior in laboratory animals. The present studies examined the effects of the prescription opioid oxycodone on learning processes in nonhuman primates.
The ability of subjects to repeatedly learn novel touchscreen-based visual discriminations was examined during three conditions of opioid exposure. Discrimination learning was examined, first, during oxycodone self-administration (3-hr sessions, 0.1 mg/kg/injection) and, next, during non-contingent chronic treatment with oxycodone (10 mg/kg/day). Finally, discrimination learning was re-examined during antagonist-precipitated opioid withdrawal (0.001-0.1 mg/kg naltrexone) and, subsequently, following abrupt discontinuation of oxycodone treatment.
Although motoric behavior was disrupted by oxycodone, neither the development of discrimination learning nor steady-state performance were impaired following oxycodone self-administration or during non-contingent chronic oxycodone treatment. However, discrimination learning was substantially impaired during oxycodone withdrawal, whether elicited by naltrexone or by abrupt oxycodone discontinuation. Moreover, these learning impairments were concordant with autonomic signs of opioid withdrawal.
Taken together, the present studies indicate that impairment of learning processes can accompany the unconditioned signs of opioid withdrawal.
We reviewed the treatment of patients with prostate cancer that has spread to lymph nodes outside the pelvis without further systemic spread. There is evidence that treatment of the primary prostate ...tumor improves outcomes in these patients and that treatment targeting distant lymph node metastases can delay the start of systemic treatment.
It remains unclear whether men with hormone-sensitive prostate cancer (PCa) metastasized to nonregional lymph nodes (M1a) benefit from prostate-directed therapy (PDT) and/or metastasis-directed therapy (MDT).
To systematically summarize the literature regarding oncological outcomes of de novo and recurrent M1a PCa patients treated with PDT and/or MDT.
We searched Medline (Ovid), Embase, and Scopus according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for reports on oncological outcomes of de novo or recurrent hormone-sensitive M1a PCa patients treated with PDT (radical prostatectomy or radiotherapy) and/or MDT (nodal radiotherapy or salvage lymph node dissection) with or without androgen deprivation therapy. A descriptive data synthesis and a methodological quality assessment were performed to evaluate the impact of PDT and/or MDT on survival in M1a PCa patients.
A total of 6136 articles were screened and 24 studies were included in this systematic review. In de novo M1a PCa patients, PDT was associated with improved oncological outcomes compared with no PDT. In recurrent M1a PCa, MDT could delay the need for systemic treatment in a selection of patients, but high-level evidence from prospective phase III randomized controlled trials is still awaited.
This systematic review summarized the limited literature data on the management of M1a PCa. Subgroup analyses suggest a role for PDT plus systemic therapy in de novo M1a PCa. MDT to distant nodal metastases delayed the need for systemic therapy in recurrent disease, but robust data are lacking. The predominantly retrospective nature of the included studies and significant heterogeneity in study designs limit the strength of evidence.
We reviewed the treatment of patients with prostate cancer that has spread to lymph nodes outside the pelvis without metastases in other organ systems. There is evidence that treatment of the primary prostate tumor improves outcomes in well-selected patients and that treatment targeting distant lymph node metastases can delay the start of systemic treatment.
Abstract
Bladder cancer is an increasingly prevalent global disease that continues to cause morbidity and mortality despite recent advances in treatment. Immune checkpoint inhibitors (ICI) and ...FGFR-targeted therapeutics have had limited success in bladder cancer when used as monotherapy. Emerging data suggests that the combination of these two therapies could lead to improved clinical outcomes. The optimal strategy for combining these agents remains uncertain. Mathematical models, and more specifically agent-based models (ABMs), have shown recent successes in uncovering the multiscale dynamics that shape the trajectory of cancer. They have enabled the optimization of treatment methods and identification of novel therapeutic strategies. To assess the combined effects of anti-PD-1 antibodies and anti-FGFR3 small molecule inhibitors (SMI) on tumor growth and the immune response, we built an ABM that captures key facets of tumor heterogeneity and CD8+ T cell compartments, their spatial interactions, and their response to therapeutic pressures. With our model, we quantify how tumor antigenicity and FGFR3 activating mutations impact disease trajectory and response to anti-PD-1 antibodies and anti-FGFR3 SMI. We find that even a small population of weakly antigenic tumor cells bearing an FGFR3 mutation can render the tumor resistant to combination therapy. However, highly antigenic tumors can overcome therapeutic resistance mediated by FGFR3 mutation. The optimal therapy depends on the strength of the FGFR3 signaling pathway. Under certain conditions, ICI alone is optimal; in others, ICI followed by anti-FGFR3 therapy is best. These results point to the need to quantify FGFR3 signaling and the fitness advantage conferred on bladder cancer cells harboring this mutation. Employing this ABM modeling approach may enable rationally designed treatment plans to improve clinical outcomes.
Citation Format: Daniel R. Bergman, Erica Trujillo, Lie Li, Alexander T. Pearson, Randy Sweis, Trachette L. Jackson. Dysregulated FGFR3 signaling alters immune landscape in bladder cancer and presents therapeutic possibilities abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6547.
Animal communication has long been thought to be subject to pressures and constraints associated with social relationships. However, our understanding of how the nature and quality of social ...relationships relates to the use and evolution of communication is limited by a lack of directly comparable methods across multiple levels of analysis. Here, we analysed observational data from 111 wild groups belonging to 26 non-human primate species, to test how vocal communication relates to dominance style (the strictness with which a dominance hierarchy is enforced, ranging from ‘despotic’ to ‘tolerant’). At the individual-level, we found that dominant individuals who were more tolerant vocalized at a higher rate than their despotic counterparts. This indicates that tolerance within a relationship may place pressure on the dominant partner to communicate more during social interactions. At the species-level, however, despotic species exhibited a larger repertoire of hierarchy-related vocalizations than their tolerant counterparts. Findings suggest primate signals are used and evolve in tandem with the nature of interactions that characterize individuals' social relationships.
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