Biomarkers Of Effect Research Articles

Association of arsenic exposure with PDGF-BB in vitro and in a South Texas population exposed through drinking water.

Association of arsenic exposure with PDGF-BB in vitro and in a South Texas population exposed through drinking water.

Quantification of 3‑chloro-7‑hydroxy-4-methylcoumarin (CHMC) in urine as a biomarker of coumaphos exposure by high-performance liquid chromatography-fluorescence detection (HPLC-FLD).

Quantification of 3‑chloro-7‑hydroxy-4-methylcoumarin (CHMC) in urine as a biomarker of coumaphos exposure by high-performance liquid chromatography-fluorescence detection (HPLC-FLD).

Conceptual GeoHealth Framework for Disaster Response Research: Case Study for Wildland Urban Interface (WUI) Fires and Data Integration

With climate change contributing to an increase in frequency and severity of extreme weather events like wildfires, droughts, and hurricanes, there is a growing need for coordinated research efforts to understand the impact of these events on human health. Specialized research frameworks can help interdisciplinary teams organize and visualize complex exposure‐health pathways, identify knowledge gaps, and enhance coordination and communication across diverse groups of stakeholders. This article describes the development and application of a conceptual framework for wildfire‐related exposures and human health outcomes. This framework serves as a tool for integrating data resources and mapping known and hypothesized connections, between complex wildfire exposures and human health outcomes, across the lifecycle of a wildland urban interface (WUI) fire. We also demonstrate the utility and flexibility of this framework for disaster research settings through two example applications. The first demonstrates an application for studying WUI fires and respiratory health outcomes, and the second example shows how the framework can be expanded to visualize exposure and health modeling with potential biomarkers of exposure and effect. Our GeoHealth Framework for WUI Fires illustrates complex linkages between wildfire related exposures and health outcomes and highlights areas for future study. Given the destruction and complexity of WUI fires, this framework provides an important resource that can assist with evaluating these complex exposure‐health relationships, guiding and coordinating data collection, and informing communities and decision‐makers to improve response, recovery, and future preparedness for such events in the United States and globally.

P16 hypermethylation is a potential cause of oxidative stress due to long-term exposure to hexavalent chromium.

Exposure to hexavalent chromium can result in severe health issues such as skin irritation, respiratory irritation, and cancer. This study aimed to examine the potential link between occupational exposure to hexavalent chromium, oxidative stress, and changes in gene methylation levels. This study measured biomarkers of oxidative stress (malondialdehyde, glutathione, 8-hydroxy-2'- deoxyguanosine) and the methylation status at the promoter of cyclin-dependent kinase inhibitor 2A (p16) gene, known for its frequent methylation-mediated silencing in human cancers. A total of 192 workers (99 males and 93 females) from electroplating factories exposed to hexavalent chromium were included, along with 80 controls (35 males and 45 females). The results showed that electroplating workers had a lower glutathione level but a higher methylation status of p16 gene promoter compared to the control group. This study suggests that the methylation status of p16 could serve as a biomarker for the epigenetic effects of chromium exposure, and it reveals a negative association between oxidative stress levels and the methylation of tumor suppressor p16.

Occupational pesticide use and relative leukocyte telomere length in the biomarkers of exposure and effect in agriculture study.

Occupational pesticide use and relative leukocyte telomere length in the biomarkers of exposure and effect in agriculture study.

FORESIGHT NEUROSCIENCE: THE IMPORTANCE OF FAMILY MEDICAL ASSESSMENT IN FAMILY LAW

Introduction:Assessing the family context in relation to mental health involves identifying causal factors, mainly in neurodevelopment, since the temporal variation of cause and effect in the neurobiology of family interactions can be directed to develop a specific clinical assessment of the child's neurodevelopment phase, through specific clinical biomarkers of cause and effect. Objective: To reflect on the facts of mental health complications in children and adults, which are being neglected by professionals, and through clinical identification and organic dysfunctions that are present in the pre-divorce periods and are complicated as in cases of parental alienation.Methods: After the bibliographic review, we synthesized a model of neurodysfunctional personality in the family environment and the clinical assessment with a generative view of perception and second-person neuroscience, with a "Bayesian" computational method, which was guided by a theoretical method and robust clinical empiricism. We outlined theoretical implications and mechanisms of social predictive perception, neuromaladaptive predominant behaviors, and clinical syntheses that organize and clarify some situations of family conflicts in family courts and, at the same time, significantly influence the physical and mental health of children and family members. Results and Discussion: Unequivocally, we are facing a social and child health setback, through professional malpractice in Family Law courts, which not only determines certain health outcomes, but also establishes parental relationships in the next generations, in senility and in the prevention of chronic diseases. Conclusion: The current lack of care in the mental health of the family and children has an impact on occupational health, and legal professionals, social assistants, and doctors must obtain this knowledge and awareness about the child psychological abuse that is occurring. This work points out a problem and suggests organized methods in clinical and neuroscience, such as the evaluation of the microstructure of ONCs personality which identifies intrusive, externalizing, and egocentric characteristics, parental capacity, and mentalism. These are innovations in objective operationalization for forensic medicine and family law.

Occupational exposure to wildland firefighting and its effects on systemic DNA damage.

Occupational exposure to wildland firefighting and its effects on systemic DNA damage.

Exposure and coexposure to cocaine and benzoylecgonine at environmentally relevant levels cause long-term oxidative effects in zebrafish.

Exposure and coexposure to cocaine and benzoylecgonine at environmentally relevant levels cause long-term oxidative effects in zebrafish.

Can Drug-Induced Yawning Serve as a Biomarker for Drug Safety and Effectiveness?

Background/Objectives: Yawning, a common physiological behavior, has emerged as a potential biomarker for drug responsiveness and side effects. This scoping review synthesizes current evidence on drug-induced yawning (DIY), focusing on its neurobiological mechanisms and clinical implications. Methods: A scoping review (INPLASY registration number: INPLASY202540048) was conducted using PubMed, Scopus, and Web of Science, including studies published in the past decade. The review adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and Cochrane Handbook guidelines, ensuring systematic selection. Selected articles led to the analysis of 10 relevant studies encompassing 473 participants. Studies were evaluated for relevance to DIY, neurobiology, and clinical applications, with thematic analysis used to synthesize findings. Results: Four key themes emerged. (1) Yawning patterns: DIY involves frequent episodes (up to 80 yawns/day), varying by drug type and dosage. (2) Neurobiological mechanisms: Yawning is mediated by serotonin, dopamine, and oxytocin pathways, particularly via 5-HT2C and μ-opioid receptors. (3) Drug responsiveness: DIY is linked to SSRIs, opioids, and dopamine agonists. SSRIs induce yawning, while opioids suppress it, reflecting distinct neurochemical effects. (4) Clinical implications: Yawning may serve as a non-invasive biomarker for drug efficacy and side effects, particularly in opioid withdrawal and SSRI monitoring. Conclusions: DIY holds promise as a biomarker for drug safety and effectiveness, but research is limited by small sample sizes, methodological variability, and the absence of standardized yawning metrics. Future studies should establish consistent measures, account for interindividual variability, and evaluate DIY’s long-term clinical utility across diverse populations.

Inflammatory markers in prostate cancer: potential roles in risk stratification and immune profiling.

Inflammation plays a critical role in prostate cancer (PCa) pathophysiology, yet the diagnostic value of specific inflammatory markers remains unclear. This study evaluates the association between circulating and tissue inflammatory markers with PCa presence and their potential as biomarkers for risk stratification. This prospective study analyzed serum and prostate biopsy samples from 60 patients with PCa and 22 cancer-free controls. Concentrations of inflammatory markers, including IL-2, IL-4, IL-10, IL-13, IL-33, Oncostatin M, TNFα, PDGF-BB, and TREM-1, were measured using Luminex technology. Statistical analyses included the Mann-Whitney test, logistic regression, and ROC curve analysis to assess differences and diagnostic performance. PCa patients exhibited significantly higher serum levels of IL-2 (p = 0.001), IL-10 (p < 0.001), IL-33 (p < 0.001), Oncostatin M (p = 0.018), and TNFα (p = 0.017) compared to controls. In contrast, biopsy tissue levels of IL-4 (p < 0.001), IL-10 (p < 0.001), IL-13 (p = 0.004), Oncostatin M (p = 0.012), PDGF-BB (p = 0.039), and TREM-1 (p = 0.013) were significantly lower in PCa patients, suggesting an inverse association. IL-10 (inverse) and IL-4 (inverse) in biopsy tissue showed high specificity in ROC analysis (AUC = 0.788 and 0.804, respectively), while IL-2 and IL-33 in serum were positively associated with PCa risk. This study suggests that IL-4, IL-10, and IL-13 in biopsy tissue may serve as biomarkers of a protective effect, while elevated IL-2 and IL-33 in serum are associated with an increased risk of PCa. These findings highlight the potential of inflammatory markers in PCa risk stratification, warranting further investigation in larger cohorts.

Occupational Exposure to Pesticides Among Farmworkers in Morocco: A Study Framework for Endocrine and Epigenetic Effect Assessment.

Pesticides are compounds of major use in agriculture worldwide. Nevertheless, many pesticide chemicals are classified as endocrine disruptors and potentially carcinogens. Farmers and farmworkers are particularly exposed and are at high risk of developing health-related impairments. In Morocco, the lack of awareness towards pesticide hazards and the inappropriate application of safety measures might increase the exposure as well as the risks of health concerns. In this paper, we present the framework of a study designed to assess pesticide exposure among Moroccan farmers and farmworkers and to evaluate potential health effects, namely endocrine and epigenetic impacts. Human biological monitoring will be conducted to determine pesticide levels in urine following the development and validation of sensitive chromatography methods (SPE, UPLC-MS/MS). Biomarkers of exposure include a set of parent and metabolite pesticide compounds (organophosphates, pyrethroids, triazines and urea-based pesticides). Thyroid and reproductive hormones (TSH, T3, T4, FSH and LH) as well as global and specific DNA methylation markers (5-mC, 5-hmC, N6-mA, THRB and LHR) are selected as biomarkers of effects. This provides guiding steps and methods to perform reliable exposure evaluation and health impact assessment. This study aims to expand the current knowledge on the endocrine and epigenetic risks related to pesticides, especially in low- and middle-income countries.

The Fire Fighter Cancer Cohort Study: Protocol for a Longitudinal Occupational Cohort Study.

Firefighters are at an increased risk of cancer and other health conditions compared with the general population. However, the specific exposures and mechanisms contributing to these risks are not fully understood. This information is critical to formulate and test protective interventions. The purpose of the Fire Fighter Cancer Cohort Study (FFCCS) is to conduct community-engaged research with the fire service to advance the evaluation and reduction of firefighter exposures, along with understanding and mitigating effects leading to an increased risk of cancer and other health conditions. This involves establishing a long-term (>30 years) firefighter multicenter prospective cohort study. The structure of the FFCCS includes a fire service oversight and planning board to provide guidance and foster communication between researchers and fire organizations; a data coordinating center overseeing survey data collection and data management; an exposure assessment center working with quantitative exposure data to construct a firefighter job exposure matrix; and a biomarker analysis center, including a biorepository. Together, the centers evaluate the association between firefighter exposures and toxic health effects. Firefighter research liaisons are involved in all phases of the research. The FFCCS research design primarily uses a set of core and project-specific survey questions accompanied by a collection of biological samples (blood and urine) for the analysis of biomarkers of exposure and effect. Data and samples are collected upon entry into the study, with subsequent collection after eligible exposures, and at intervals (eg, 1-2 years) after enrollment. FFCCS data collection and analysis have been developed to evaluate unique exposures for specific firefighter groups; cancer risks; and end points in addition to cancer, such as reproductive outcomes. Recruitment is carried out with coordination from partnering fire departments and eligible participants, including active career and volunteer firefighters in the United States. The FFCCS protocol development was first funded by the US Federal Emergency Management Agency in 2016, with enrollment beginning in February 2018. As of September 2024, >6200 participants from >275 departments across 31 states have enrolled, including recruit and incumbent firefighters. Biological samples have been analyzed for measures of exposure and effect. Specific groups enrolled in the FFCCS include career and volunteer structural firefighters, women firefighters, trainers, fire investigators, wildland firefighters, firefighters responding to wildland-urban interface fires, and airport firefighters. Peer-reviewed published results include measurement of exposures and the toxic effects of firefighting exposure. Whenever possible, research results are provided back to individual participants. The FFCCS is a unique, community-engaged, multicenter prospective cohort study focused on the fire service. Study results contribute to the evaluation of exposures, effects, and preventive interventions across multiple sectors of the US fire service, with broad implications nationally. DERR1-10.2196/70522.

Sex-Specific Formation of 1,2:3,4-Diepoxybutane-Derived Hemoglobin Adducts in 1,3-Butadiene-Exposed Workers.

1,3-Butadiene (BD) is an important industrial chemical that is classified as a human carcinogen. BD carcinogenicity has been attributed to several reactive epoxide metabolites, and the formation of highly mutagenic 1,2:3,4-diepoxybutane (DEB) has been suggested to drive mutagenesis and carcinogenesis at exposures experienced in humans. We report herein the formation of DEB-specific N,N-(2,3-dihydroxy-1,4-butadiyl)-valine (pyr-Val) in occupationally BD-exposed workers as an indirect biomarker of DEB-induced mutagenicity. pyr-Val was determined in BD-monomer and -polymer plant workers that had been previously analyzed for several other biomarkers of exposure and effect. In this second study, pyr-Val was detected in 92 out of 94 (98%) individuals, ranging from 0.001 to 0.697 pmol/g of globin. Surprisingly, pyr-Val was observed in 43 of 44 administrative control subjects not known to be exposed to BD, suggesting environmental sources of BD. The mean ± SD amounts of pyr-Val were 0.049 ± 0.044, 0.029 ± 0.032, 0.030 ± 0.035, and 0.074 ± 0.093 pmol/g globin in female control, female exposed, male control, and male exposed, respectively, clearly demonstrating the formation of DEB in environmentally and occupationally exposed BD workers. The amounts of pyr-Val found in this study suggest that humans are much less efficient in the formation of DEB than mice or rats at similar BD exposures. The formation of pyr-Val was lower than that associated with increased mutagenesis in rodents.

Abstract 1978: Circulating rare events as a biomarker of anti-tumoral effect of ketamine therapy in non-small cell lung cancer

Abstract Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide, with surgical resection (with or without adjuvant chemotherapy) often being the recommended treatment for resectable localized disease. However, even with curative-intent resections, 30% to 55% of localized NSCLC patients experience recurrence and will die from the disease. Tumor-associated cells detected in peripheral blood, referred to here as circulating rare events, are believed to play a key role in metastatic dissemination, underscoring their potential as indicators of treatment response and recurrence risk. Recent retrospective analyses have revealed that the use of intraoperative Ketamine (Ket) during primary tumor resection surgery is associated with a lower recurrence rate, suggesting a potential utility in cancer treatment beyond its approved indication as an adjunct anesthetic. The study presented here investigates the effects of different anesthetic protocols on circulating rare events in NSCLC patients, specifically comparing Ket and dexmedetomidine (Dex) (also commonly employed as an adjunct anesthetic), to assess whether Ket exhibits anti-tumor effects and modulates the systemic tumor environment. Peripheral blood samples (n=60) were collected from 22 early-stage NSCLC patients undergoing primary tumor resection, with samples taken preoperatively (before surgical incision and after surgical closure) and at a three-week follow-up. Circulating rare events were identified through advanced imaging and phenotypic analysis and validated by comparison to blood samples from normal donors, which served as controls. Results indicated no significant differences between the anesthetic agents in pre- and post-surgery samples; however, at the three-week follow-up, Ket was associated with a higher incidence of circulating rare events and an increase in a specific cellular phenotype consistent with endothelial cells. These findings suggest that Ket may influence tumor vasculature and enhance tumor shedding, which could lead to a better prognosis after tumor resection in lung cancer patients. This highlights the potential of Ket as a perioperative agent that modulates tumor biology, as demonstrated by increased rare cell detection, and supports further investigation into a possibly expanded role in surgical oncology for potential to improve long-term outcomes in NSCLC patients. Citation Format: Anya Shah, Stephanie Shishido, Jeremy Mason, George W. Fischer, David Amar, Dawn Desiderio, Joseph R. Scarpa, David R. Jones, Amitabh Gulati, Alessia Pedoto, Alessandro De Camilli, Cosmin Guaran, Jacob C. Jackson, Alexandra Lewis, Michelle Zanone, Lucy Nystrom, Howard Scher, Ethan Barnett, Joshua Mincer, Peter Kuhn. Circulating rare events as a biomarker of anti-tumoral effect of ketamine therapy in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1978.

Abstract 69: Integrin αVβ3 targeted PET/CT for the assessment of bevacizumab therapy in patient-derived glioblastoma xenografts

Abstract Introduction: Glioblastoma continues to be the most aggressive type of brain cancer. Standard treatment includes surgical resection, concomitant chemoradiation therapy (CRT) with temozolomide (TMZ) followed by adjuvant TMZ (Stupp’s regimen). Bevacizumab (BEV), a monoclonal antibody targeting vascular endothelial growth factor (VEGF) A, is approved for recurrent glioblastoma with no significant benefit in the total population of recurrent glioblastoma patients. However, responders to BEV experience clinical improvement and prolonged survival. Nevertheless, no predictive biomarker for treatment effect has been identified. This study evaluates tumor angiogenesis using [68Ga]Ga-NODAGA-E[c(RGDyK)]2 (RGD2) PET/CT targeting integrin αVβ3 to predict response to BEV combined with conventional therapy in patient-derived xenograft (PDX) models with postoperative primary or recurrent glioblastoma, aiming to guide clinical patient selection. Experimental procedures: Tumors from four patients with primary or recurrent glioblastoma were enrolled for preclinical efficacy evaluation in PDX models (PDX 1-4) to receive BEV monotherapy, Stupp’s plus BEV, Stupp’s alone, or saline. PDX patient tissue were selected based on clinical treatment regimen. PET/CT with RGD2 was performed at baseline and post-therapy. To assess the correlation between treatment efficacy and tracer uptake, tumor uptake of RGD2 was compared with survival outcomes. Immunohistochemistry (IHC) was used to assess glioblastoma and angiogenesis markers. Results: PDX models with increased uptake of RGD2 at baseline (PDX 1: 6.2±0.66 max%ID/g) showed better response rate to Stupp’s plus BEV compared with PDX models with low uptake (PDX 3: 2.1±0.25 max%ID/g). PDX models of both primary (PDX 1) and recurrent (PDX 4) glioblastoma had better survival with Stupp’s plus BEV therapy compared with BEV monotherapy, Stupp’s, and saline. PDX 1 treated with Stupp’s plus BEV had better survival with a median survival time of 70 days (95% CI: 63-77 days) compared with BEV monotherapy (p&amp;lt;0.0001), Stupp’s (p&amp;lt;0.05), and controls (p&amp;lt;0.0001). Additionally, PDX 4 treated with Stupp’s plus BEV had better survival with a median survival time of 49 days (95% CI: 42-56 days) compared with BEV monotherapy (p&amp;lt;0.0001), Stupp’s (p=0.0009), and controls (p&amp;lt;0.0001). IHC showed upregulated angiogenesis markers (CD31, CD34, VEGF, and integrin αvβ3) in PDX tumors with high RGD2uptake. Conclusion: Our results indicate that RGD2 can be used as a predictive biomarker for treatment response to BEV in PDX models of glioblastoma. Translationally, RGD2 PET imaging could be used in clinical settings to predict responses to BEV combination therapy. Furthermore, our results support the investigation of BEV in clinical trials as part of first-line adjuvant therapy, potentially advancing its role in improving treatment outcomes in glioblastoma patients. Citation Format: Anne Skovsbo Clausen, Ida Vang Andersen, Malene Martini Clausen, Aleena Azam, Julie van Krimpen Mortensen, Emilie Graae Lund, Thomas Haargaard Urup, Andreas Kjaer. Integrin αVβ3-targeted PET/CT for the assessment of bevacizumab therapy in patient-derived glioblastoma xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 69.

Abstract 6950: VRK1 as a novel therapeutic target in small cell neuroendocrine carcinoma of the uterine cervix via mitochondrial dysfunction

Abstract [Objective] Small cell neuroendocrine carcinoma of the uterine cervix (SCNEC) is a rare cancer with a poor prognosis, highlighting the pressing need for effective pharmacotherapies. Our previous proteomic analysis identified vaccinia-related kinase 1 (VRK1) as one of the proteins highly expressed in SCNEC compared to squamous cell carcinoma (SCC) and adenocarcinoma (AC). VRK1 is a member of the VRK family of Ser-Thr kinases, and its overexpression is associated with poor prognosis in various cancers. It is also expected to be a potential synthetic-lethal drug target in VRK2-low/null cancers. This study aims to investigate the potential of VRK1 as a therapeutic target for SCNEC. [Methods] To examine VRK1 and VRK2 expression levels across different histological types of cervical cancer, immunohistochemistry was performed on clinical samples, including five SCNEC cases, 34 SCC cases, and seven AC cases. The effect of VRK1 on tumor growth was assessed in vitro (2D and 3D cultures) and in vivo (xenograft model) by shRNA-mediated knockdown of VRK1 (shVRK1) and its control (shCont). Gene Set Enrichment Analysis (GSEA) was conducted on RNA-seq data extracted from mouse xenograft tumors to compare shCont and shVRK1. Conditions with exposure to reactive oxygen species (ROS) were generated using hydrogen peroxide (H2O2). Mitochondrial function was evaluated through changes in mitochondrial membrane potential and mitochondrial protein expression. [Results] VRK1 expression exhibited variability in SCC and AC but was consistently high across all SCNEC samples. In 2D cultures, VRK1 knockdown demonstrated limited effects on cell proliferation; however, it significantly inhibited tumor growth in 3D cultures and in vivo xenograft models. GSEA revealed that mitochondrial translation and gene expression pathways were the most suppressed in shVRK1 tumors compared to shCont. Subsequent in vitro and in vivo experiments revealed that VRK1 knockdown had a stronger tumor growth inhibitory effect under conditions with exposure to ROS, driven by the combined influence of the tumor microenvironment and the tumor's high energy metabolism, and this was accompanied by mitochondrial dysfunction. Furthermore, VRK2 expression, a potential biomarker of VRK1's effects, was confirmed to be characteristically low in SCNEC. [Conclusion] SCNEC is characterized by high VRK1 expression and low VRK2 expression. VRK1 knockdown suppresses tumor growth via mitochondrial dysfunction, particularly in vivo. These findings suggest that VRK1 is a promising therapeutic target for the treatment of SCNEC. Citation Format: Mariya Kobayashi, Satoshi Nakagawa, Yusuke Ishii, Yuji Kamei, Mizuki Kanda, Tatsuo Masuda, Mamoru Kakuda, Kosuke Hiramatsu, Tadashi Iwamiya, Shinya Matsuzaki, Masahiro Inoue, Yutaka Ueda. VRK1 as a novel therapeutic target in small cell neuroendocrine carcinoma of the uterine cervix via mitochondrial dysfunction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6950.

The Effect of Dopaminergic Therapy in Parkinson's Disease: A Graph Theory Analysis.

Background: Dopaminergic therapy (DT) is the gold standard pharmacological treatment for Parkinson's disease (PD). Currently, understanding the neuromodulation effect in the brain of PD after DT is important for doctors to optimize doses and identify the adverse effects of medication. The objective of this study is to investigate the brain connectivity alteration with and without DT in PD using resting-state EEG. Methods: Graph theory (GT) is an efficient technique for analyzing brain connectivity alteration in healthy and patient groups. We applied GT analyses on three groups, namely healthy control (HC), Parkinson with medication OFF (PD-OFF), and Parkinson with medication ON (PD-ON). Results: Using the clustering coefficient (CC), participation coefficient (PC), and small-worldness (SW) properties of GT, we showed that PD-ON patients' brain connectivity normalized towards healthy group brain connectivity due to DT. This normalization effect appeared in the brain connectivity of all EEG frequency bands, such as theta, alpha, beta-1, beta-2, and gamma except the delta band. We also analyzed region-wise brain connectivity between 10 regions of interest (ROIs) (right and left frontal, right and left temporal, right and left parietal, right and left occipital, upper and lower midline regions) at the scalp level and compared across conditions. During PD-ON, we observed a significant decrease in alpha band connectivity between right frontal and left parietal (p-value 0.0432) and right frontal and left occipital (p-value 0.008) as well as right frontal and right temporal (p-value 0.041). Conclusion: These findings offer new insights into how dopaminergic therapy modulates brain connectivity across frequency bands and highlight the continuous elevation of both the segregation and small-worldness of the delta band even after medication as a potential biomarker for adverse effects due to medication. Additionally, reduced frontal alpha band connectivity is associated with cognitive impairment and levodopa-induced dyskinesia, highlighting its potential role in Parkinson's disease progression. This study underscores the need for personalized treatments that address both motor and non-motor symptoms in PD patients.

Developments in Toxicity Testing with Duckweeds.

Duckweeds are a family of small floating macrophytes (the Lemnaceae) that inhabit quiet freshwaters worldwide. They have long been employed to determine toxicity to higher plants in the aquatic environment, and standardized national and international protocols have been developed for this purpose using two representative species. While these protocols, which assess the growth of the leaf-like fronds of the tested duckweed, are indeed suitable and still frequently used for detecting the toxicity of water-borne substances to aquatic higher plant life, they are cumbersome and lengthy, determine endpoints rather than depict toxicity timelines, and provide no information as to the mechanisms involved in the indicated toxicity. Progress has been made in downscaling, shortening and improving the standardized assay procedures, and the use of alternative duckweed species, protocols and endpoints for detecting toxicity has been explored. Biomarkers of toxic effect have long been determined concomitantly with testing for toxicity itself, and their potential for the assessment of toxicity has recently been greatly expanded by transcriptomic, proteomic and metabolomic techniques complemented by FITR spectroscopy, transformation and genotoxicity and timescale toxicity testing. Improved modern biomarker analysis can help to both better understand the mechanisms underlying toxicity and facilitate the identification of unknown toxins.

Abstract A006: Differential therapeutic vulnerabilities and opportunities for smokers and never-smokers based on physiological and adaptive landscapes of lung adenocarcinoma

Abstract Tobacco smoke both has a somatic mutagenic effect and also alters the physiology and microenvironment within the lung. Physiological effects likely influence the extent to which mutations confer proliferative or survival advantages underlying oncogenesis. However, the contributions of these mutagenic and physiological effects to oncogenesis have not previously been quantified. Because the efficacy of such therapies is dependent on the adaptive benefit conferred by the targeted mutations, this quantification is crucial for the development, testing, and application of targeted therapeutics. We therefore quantified these effects in lung adenocarcinoma (LUAD) by deconvolving the prevalence of mutations in ever-smoker (ES) LUAD samples and never-smoker (NS) LUAD samples into distinct components of mutation, selection, and selective epistasis on a gene-by-gene level. Accounting for a broadly elevated mutation rate across genes in ES-LUAD, we find that several mutations—including those in KRAS, KEAP1, and STK11—contribute stronger adaptive benefits in ES-LUAD, while several others—including those in EGFR, PIK3CA, and MET—contribute stronger adaptive benefits in NS-LUAD. Examining the strength of pairwise selective epistasis, we find that tobacco smoke alters epistatic relationships within LUAD: ES-LUAD exhibits more frequent synergy of adaptive effects, and markedly less frequent antagonism. We also find an underappreciated role for higher-order epistasis in guiding the evolution of cancer, including frequent sub-additive higher-order epistasis, and instances of emergent synergistic interactions between multiple mutations. We provide even greater nuance to the effect of tobacco smoke on the adaptive benefit of mutations by quantifying the adaptive effects of somatic mutations across a continuous spectrum of tobacco smoke burden. We then identify the molecular pathways implicated in the altered adaptive landscape of ES-LUAD. Finally, we quantify the power of measures of adaptive effects in the contexts of smoking history and epistasis to predict differential patient response to targeted therapeutics and response of experimental models to gene inhibition. Our inference that mutations of EGFR contribute a multi-fold greater adaptive benefit in NS-LUAD than in ES-LUAD predicts a stronger response to EGFR inhibitors among never-smokers than ever-smokers, a result validated by numerous clinical studies. This analysis demonstrates that tobacco smoke alters the adaptive landscape of LUAD. It also provides quantitative measures of the adaptive benefit conferred by mutations to oncogenesis across somatic genetic backgrounds and burdens of tobacco smoke. These measures facilitate precision medicine both by informing the development and testing of targeted therapeutics—for example by identifying high effect mutations or biomarkers of response to new targeted therapeutics—as well as by providing predictions of genetic vulnerabilities that can be further explored through functional genetic approaches in experimental models. Citation Format: Krishna Dasari, Jorge A Alfaro-Murillo, Jeffrey P Townsend. Differential therapeutic vulnerabilities and opportunities for smokers and never-smokers based on physiological and adaptive landscapes of lung adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A006.

Plasma Circulating lncRNAs: MALAT1 and NEAT1 as Biomarkers of Radiation-Induced Adverse Effects in Laryngeal Cancer Patients.

Background: The majority of head and neck cancers (HNCs) occur in the larynx. In clinical practice, adverse effects are frequently observed in laryngeal cancer (LC) patients undergoing radiotherapy (RT). Therefore, investigating markers that can predict these unfavorable events is of interest. Long non-coding RNAs (lncRNAs) have emerged as potential biomarkers for the early identification of patients susceptible to post-RT toxicity. MALAT1 and NEAT1 regulate various cellular processes, the inflammatory response, and resistance to anti-cancer treatments; however, their impact on the portability of post-RT adverse effects remains unknown. The aim of this study was to evaluate the clinical value of two plasma-circulating lncRNAs, MALAT1 and NEAT1, as predictive biomarkers for post-RT adverse effects in LC patients. Methods: The expression levels of the studied lncRNAs were determined using real-time quantitative reverse transcription PCR (qRT-PCR) in plasma samples obtained from 70 LC patients before the initiation of RT. These levels were then correlated with patient outcomes. Results: A low expression of MALAT1 was associated with a significantly higher probability of anemia, liver failure, and severe malnutrition (OR = 5.36; p = 0.040, OR = 6.07; p = 0.037, OR = 9.75; p < 0.001, respectively) after the completion of RT. Similarly, patients with low NEAT1 expression had a significantly higher risk of anemia, liver failure, and mild or severe malnutrition (OR = 5.26; p = 0.020, OR = 5.70; p = 0.016, OR = 13.09; p = 0.002, respectively). Simultaneous lower expression levels of both lncRNAs were significantly associated with shorter median overall survival (OS) in RT-treated LC patients (HR = 5.44; p = 0.001). Conclusions: The analysis of MALAT1 and NEAT1 expression indicates clinical utility in predicting toxic events induced by RT-based therapy.