Biological Impact Research Articles

Emerging Roles of Xanthine Oxidoreductase in Chronic Kidney Disease.

Xanthine Oxidoreductase (XOR) is a ubiquitous, essential enzyme responsible for the terminal steps of purine catabolism, ultimately producing uric acid that is eliminated by the kidneys. XOR is also a physiological source of superoxide ion, hydrogen peroxide, and nitric oxide, which can function as second messengers in the activation of various physiological pathways, as well as contribute to the development and the progression of chronic conditions including kidney diseases, which are increasing in prevalence worldwide. XOR activity can promote oxidative distress, endothelial dysfunction, and inflammation through the biological effects of reactive oxygen species; nitric oxide and uric acid are the major products of XOR activity. However, the complex relationship of these reactions in disease settings has long been debated, and the environmental influences and genetics remain largely unknown. In this review, we give an overview of the biochemistry, biology, environmental, and current clinical impact of XOR in the kidney. Finally, we highlight recent genetic studies linking XOR and risk for kidney disease, igniting enthusiasm for future biomarker development and novel therapeutic approaches targeting XOR.

Rapid assessment of invasion front and biological impact of the invasive fish Coreoperca herzi using quantitative eDNA metabarcoding

Rapid assessment of invasion front and biological impact of the invasive fish Coreoperca herzi using quantitative eDNA metabarcoding

Abstract IA020: Functional studies of genetic variation using precision genome editing

Abstract Tumor genomes often harbor a complex spectrum of single nucleotide mutations, small indels, and large chromosome rearrangements that can perturb coding and non-coding regions of the genome in ways that remain poorly understood. The mutational processes responsible for the genesis of these events are also not static; instead, they continue to operate throughout disease evolution and further diversify the genetic and phenotypic landscape of cancer cells. Mounting evidence suggests that tumor genotype can be an important determinant of disease progression and therapy response, such as by modulating the sensitivity or resistance of cancer cells to mutant-specific drugs. These types of observations have motivated efforts to treat cancers with genome-informed therapies, highlighting the need to understand how different genetic variants precisely affect gene function and overall tumor phenotypes. Variant-function maps that provide a mechanistic understanding of the biology driven by cancer-associated mutations are needed to design these types of treatment strategies. Precision genome editing technologies like base and prime editing are uniquely suited to tackle this problem. Nevertheless, deploying these methods for systematic variant-function studies and disease modeling in vivo has not been straightforward due to lack of robust and scalable platforms capable of assessing editing efficiency and precision, particularly at endogenous loci. With this goal in mind, we previously developed and applied high-throughput base editing ‘sensor’ approaches that link endogenous genome editing outcomes with synthetic DNA-based readouts and cellular fitness measurements. Using these approaches, we showed that several uncharacterized mutant p53 alleles drive cancer cell proliferation and in vivo tumor development. Building upon this work, we recently developed new prime editing guide RNA design tools and sensor-based approaches that similarly couple quantitative editing outcomes to cellular fitness, allowing us to significantly expand the breadth of cancer-associated mutations that can be interrogated using these precision genome editing technologies. In this talk, I will describe ongoing work using base and prime editing sensor libraries to probe the biological impact of thousands of functionally-distinct genetic variants in diverse types of protein-coding genes and families to learn how these influence various cancer phenotypes. I will also discuss how the implementation of these modular technologies will allow researchers to functionally disentangle the impact of endogenous and exogenous mutational processes on functional selection and tumor evolution with close to single base pair resolution. This generalizable precision genome editing framework will facilitate the functional interrogation of genetic variants across diverse biological contexts, providing much needed insight into cancer variant-function relationships that could be leveraged to develop more precise cancer treatment paradigms, including synthetic lethal therapies that exploit tumor genotype. Citation Format: Francisco J. Sánchez-Rivera, Samuel I. Gould, Alexandra N. Wuest, Kexin Dong, Grace A. Johnson, Alvin Hsu, Varun K. Narendra, Ondine Atwa, Stuart S. Levine, David R. Liu. Functional studies of genetic variation using precision genome editing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA020.

SNX16 is required for hepatocellular carcinoma survival via modulating the EGFR-AKT signaling pathway

Sorting nexin 16 (SNX16), a pivotal sorting nexin, emerges in tumor progression complexity, fueling research interest. However, SNX16’s biological impact and molecular underpinnings in hepatocellular carcinoma (HCC) remain elusive. This study probes SNX16’s function, clinical relevance via mRNA, and protein expression in HCC. Overexpression/knockdown assays of SNX16 were employed to elucidate impacts on HCC cell invasion, proliferation, and EMT. Additionally, the study delved into SNX16’s regulation of the EGFR-AKT signaling cascade mechanism. SNX16 overexpression in HCC correlates with poor patient survival; enhancing proliferation, migration, invasion, and tumorigenicity, while SNX16 knockdown suppresses these processes. SNX16 downregulation curbs phospho-EGFR, dampening AKT signaling. EGFR suppression counters SNX16-overexpression-induced HCC proliferation, motility, and invasiveness. Our findings delineate SNX16’s regulatory role in HCC, implicating it as a prospective therapeutic target.

MTOR: Its Critical Role in Metabolic Diseases, Cancer, and the Aging Process.

The mammalian target of rapamycin (mTOR) is a pivotal regulator, integrating diverse environmental signals to control fundamental cellular functions, such as protein synthesis, cell growth, survival, and apoptosis. Embedded in a complex network of signaling pathways, mTOR dysregulation is implicated in the onset and progression of a range of human diseases, including metabolic disorders such as diabetes and cardiovascular diseases, as well as various cancers. mTOR also has a notable role in aging. Given its extensive biological impact, mTOR signaling is a prime therapeutic target for addressing these complex conditions. The development of mTOR inhibitors has proven advantageous in numerous research domains. This review delves into the significance of mTOR signaling, highlighting the critical components of this intricate network that contribute to disease. Additionally, it addresses the latest findings on mTOR inhibitors and their clinical implications. The review also emphasizes the importance of developing more effective next-generation mTOR inhibitors with dual functions to efficiently target the mTOR pathways. A comprehensive understanding of mTOR signaling will enable the development of effective therapeutic strategies for managing diseases associated with mTOR dysregulation.

Dual analysis of IL-8 in non-small cell lung cancer: A clinical perspective on protein and RNA evaluation via imaging mass cytometry.

e15068 Background: The cytokine Interleukin-8 (IL-8) plays a pivotal role in the tumorigenesis and progression of non-small cell lung cancer (NSCLC), influencing both the tumor microenvironment and immune escape mechanisms. Given its significance, accurately assessing IL-8 levels at the protein and RNA levels could provide valuable insights into its prognostic value and inform therapeutic targeting strategies. This study utilizes imaging mass cytometry (IMC) to conduct a comprehensive evaluation of IL-8 expression in NSCLC, integrating both protein presence and gene expression analysis within the spatial context of the tumor microenvironment. Methods: Our approach leverages the capabilities of IMC to simultaneously detect protein and RNA levels of IL-8 in NSCLC tissue samples. For protein analysis, antibodies tagged with heavy metal isotopes specifically target IL-8, allowing for precise quantification and spatial localization within the tumor. Concurrently, RNA detection is achieved through hybridization probes designed for IL-8 mRNA, enabling the direct observation of gene expression patterns. This method provides a unique opportunity to correlate IL-8's protein abundance with its mRNA expression, offering insights into the regulatory mechanisms at play and their impact on the tumor's behavior and patient outcomes. Results: Preliminary data demonstrate a marked heterogeneity in IL-8 distribution at both the protein and RNA levels, with distinct patterns emerging that relate to tumor aggressiveness and immune infiltration. High IL-8 expression, identified through our integrated IMC approach, correlates with poor prognosis and reduced response to standard therapies, underscoring its potential as a biomarker for NSCLC management. Furthermore, the spatial analysis afforded by IMC highlights the microenvironmental niches where IL-8-mediated interactions could drive tumor progression and immune evasion. Conclusions: By employing IMC for the dual analysis of IL-8 protein and RNA in NSCLC, our study provides a comprehensive view of this cytokine's role in lung cancer pathology. The ability to visualize and quantify IL-8 expression within the spatial context of the tumor microenvironment opens new avenues for understanding its biological impact and for developing targeted therapies. Our findings advocate for the inclusion of IL-8 in the biomarker panel for NSCLC, with potential implications for patient stratification and personalized treatment planning. Future research will focus on expanding these observations to a larger cohort and exploring the therapeutic modulation of IL-8 as a strategy for improving NSCLC outcomes.

Survey of long term survivors of oral cancer: Looking beyond cancer biology.

6087 Background: While surgery is the main stay of treatment for early stage oral cancers, advanced stages require adjuvant treatments in the form of radiotherapy or concurrent radiotherapy. Yet, the effectiveness of these interventions is not solely determined by clinical measures but also by personal factors such as individual motivation, support from loved ones, and financial security. These aspects might explain the survival rate variations among patients who, despite having similar prognostic categories and stages of disease, show differing outcomes. The role of social determinants in influencing patient survival, apart from the acknowledged impact of disease biology, is not well understood. Methods: All treatment-naive oral cavity cancer patients who underwent definitive treatment during 2014 to 2018 at our institute and are alive for more than five years were selected for this study. A custom investigator-administered questionnaire was developed and it had 32 questions under six domains- personal, habit history, financial, social, functional, and emotional. The study was approved by the institutional ethics committee. Of the 1787 potential participants, we found that 219 had expired, only 442 patients agreed to answer the questionnaire, while 45 refused to participate. The rest of the patients were not reachable telephonically. Results: This survey had 442 patients, of which 90% were males, with a mean age of 52.1 years. The most common site of the presentation was buccal mucosa (60%), and 59% presented in the locally advanced stage. Post-operatively, 71% received adjuvant therapy. All patients were motivated to undergo the radical treatments and had their family support. However, post-treatment, about 10% of individuals experienced a change in marital status. Financial constraints did affect 20% of patients during and after treatment, and more than 70% had their out-of-pocket expenditure above 50% of the total cost. While 80% did not have trouble attending social functions, 46% reported trouble eating socially. However, this was more common for patients who received adjuvant treatment (p < 0.001). About 21% reported shoulder dysfunction and body discomfort. However, no statistically significant associations could be drawn for any of the domains of the questionnaire when compared to patients between the early and late stages. Shoulder discomfort was experienced more by patients who were treated for tongue cancer (p-value 0.010). Conclusions: The results of this study shed light on the challenges faced by long-term survivors of oral cancer following radical treatment regimens. More than half of patients reported that out-of-pocket expenses constituted more than half of their total treatment costs. A notable minority of people suffer from shoulder dysfunction, suggesting there is a clear opportunity for advancements in reconstruction and rehabilitation.

Domain-based analysis of RUNX1somatic mutations in myeloid neoplasms.

6542 Background: RUNX1is a master regulator of hematopoiesis. ELN2022 risk stratification categorizes RUNX1 as an AML/MDS gene associated with poor prognosis. Functional domains in RUNX1are the Runt homology domain (RHD) and a transactivation domain (TAD), with DNA binding and co-activator recruitment functions, respectively. Domain-based analysis can elucidate the functional and biological impact of somatic RUNX1mutations, which have not yet been reported in the literature. Methods: Sequencing data from Karmanos Cancer Institute and a publicly available meta-analytic cohort [Awada et al., Blood 2021, Kewan et al., Nature Communications 2023, cBioPortal (Cerami et al., 2012) and AACR GENIE (v 13.1)] were used to construct a larger dataset of 16,565 patients with myeloid neoplasms. Baseline clinical and molecular characteristics were noted. The chi-square test was used to study various parameters described, and Kaplan-Meier curves were used to estimate survival. Results: RUNX1was mutated in 10.8% (1804/16,565) of patients. Median OS (mOS) for RUNX1MT vs. RUNX1WT was significantly worse at 16.4 vs 23.4 mos. (p < 0.0001). 990 patients with somatic mutations were studied; germline variants were screened and excluded if VAF was between 40-60%. Among somatic RUNX1MT patients, primary AML was the most frequent at 52.8%, followed by secondary AML-35.7% and MDS-9%. Most patients had mutations in the RHD (53.8%), followed by TAD (22%), and the remaining in non-RHD, non-TAD zones (NRNT). There was no statistically significant difference in OS by domain stratification; TAD had the numerically least mOS at 13.6 mos, RHD at 16.1 mos, and NRNT at 20.4 mos. The median age of patients was 70.9 (62-76) years, similar across domains. TAD patients were less likely to be male when compared to RHD (47% vs. 56%, p=0.04). No specific enrichment of disease type or abnormal karyotype was observed across domains. Co-mutational profiles across RHD and TAD domains among all diseases showed spliceosome co-signature enriched in RHD vs. TAD (59% vs. 46%, p=0.01). NPM1was noted to be inversely correlated with RUNX1 in general, with 1% and 3.5% in RHD and TAD. ASXL1was the most frequently distributed co-mutation in both groups, but not statistically different (41% vs. 33%, p=0.11). TAD patients with spliceosome co-mutation had worse mOS (11.4 mos) than those without spliceosome mutation (16.2 mos, p=0.02) or RHD patients with spliceosome co-mutation (16 mos, p=0.001). Missense mutations were strongly associated with RHD (55.3% vs. 7.9%); p <0.00001, while frameshift mutations were enriched in TAD (24.1% vs. 69.8%); p<0.0001. Conclusions: Domain-based analysis of somatic RUNX1MT myeloid neoplasms reveals TAD mutation to be common in females, frequently a frameshift mutation, and numerically has the worst survival. There appears to be a unique spliceosome signature enrichment in RHD compared to TAD, with worse OS in TAD patients with spliceosome co-mutations overall.

Flower Power: An Overview on Chemistry and Biological Impact of Selected Essential Oils from Blossoms

AbstractNatural raw materials such as essential oils have received more and more attention in recent decades, whether in the food industry, as flavorings and preservatives, or as insecticides and insect repellents. They are, furthermore, very popular as fragrances in perfumes, cosmetics, and household products. In addition, aromatherapy is widely used to complement conventional medicine. This review summarizes investigations on the chemical composition and the most important biological impacts of essential oils and volatile compounds extracted from selected aromatic blossoms, including Lavandula angustifolia, Matricaria recutita, Rosa x damascena, Jasminum grandiflorum, Citrus x aurantium, Cananga odorata, and Michelia alba. The literature was collected from PubMed, Google Scholar, and Science Direct. Blossom essential oils discussed in this work are used in a wide variety of clinical issues. The application is consistently described as safe in studies and meta-analyses, although there are notes that using essential oils can also have side effects, especially dermatologically. However, it can be considered as confirmed that essential oils have positive influences on humans and can improve quality of life in patients with psychiatric disorders, critically ill patients, and patients in other exceptional situations. Although the positive effect of essential oils from blossoms has repeatedly been reported, evidence-based clinical investigations are still underrepresented, and the need for research is demanded.

Sunscreen use during recreational activities on a French Atlantic beach: release of UV filters at sea and influence of air temperature.

Organic UV filters are emerging contaminants in personal care products such as sunscreens. The toxicity of numerous of these UV filter compounds has been demonstrated in several marine taxa. However, whilst the biological impact has already been largely demonstrated, the anthropogenic drivers leading to UV filter contamination still need to be identified. In this work, a survey was conducted on a site of the French Atlantic Coast (i) to describe beachgoers' behaviours (sunscreen use and beach frequentation), (ii) provide an estimation of the UV filters released at sea and (iii) highlight the effect of air temperature on these behaviours and on the release of UV filters. In parallel with these estimations of the UV filters released at sea, in situ chemical measurements were performed. By comparing the results of both approaches, this interdisciplinary work provides an insight of how the observations of beachgoers' behaviour modulations and attendance level fluctuations could be used to prevent UV filter contaminations and ultimately manage the ecotoxicological risk.

Examining the risk of immune checkpoint inhibitor-related toxicity among patients with melanoma and their history of cannabis use.

e21539 Background: With cannabis use rising due to better availability for recreational and medicinal uses, there is a need for studies examining cannabinoids interactions. Immune Checkpoint Inhibitors have been increasing in popularity among metastatic cancer patients like those with melanoma. The biological impact of cannabis is mediated in part by the CB1 and CB2 receptors present in the endocannabinoid system that is present in the immune system. ICI therapy also targets the immune system through manipulating PD-1/PD-L1 receptors to induce cancer cell death. Therefore, concurrent cannabis use with ICI therapy could have potentiating effects on toxicities and negatively impact efficacy. There is limited information in the literature examining this and therefore the goal was to examine the impact of ICI toxicity risk among melanoma patients on any form of ICI therapy. Methods: A retrospective cohort study was conducted using TriNetX, a multicenter database comprised of ~100 million patients across 84 healthcare organizations. Adults ( > 17 years) from 2012-2023 were identified based on ICI-therapy initiation within 1 month of malignant melanoma diagnosis. Patients were then stratified by history of those with and without cannabis use disorder. ICI toxicity categories were determined a priori and included cardiac, nephrological, gastrointestinal, endocrine, respiratory, ocular, hematological, hepatological, musculoskeletal, and neurological toxicities. 1:1 propensity score matching was conducted to control for comorbidities and demographics. Adjusted hazard ratios (aHR) with 95% CI were calculated at 1-year follow-up after therapy initiation for ICI toxicities between the cohorts. aHR was estimated using the Cox proportional hazard model. Results: A total 14589 melanoma patients who underwent ICI therapy were identified where 2.3% had history of cannabis use. Matching revealed two balanced cohorts of 344 patients. Melanoma patients with a history of cannabis use did not have any significant differences with controls for cardiotoxicity (aHR[95%CI] = 0.94[0.54,1.6]), Nephrotoxicity (0.86[0.51,1.5]), GI toxicity (1.44[0.95,2.2]), endocrine toxicity (1.2[0.82,1.8]), respiratory toxicity (0.93[0.55,1.6]), ocular toxicity (0.63[0.25,1.6]), hematologic toxicity (1.04[0.7,1.6]), neurotoxicity (1.04[0.6,1.7]), liver toxicity (1.41[0.78,2.5]), or musculoskeletal toxicity (1.53[0.62,3.8]). Conclusions: With cannabis use rising due in part to recreational use and in part to medical marijuana, the implications of use must be a topic of research. Cannabis use among melanoma patients did not provide any significant differences in risk of developing ICI-therapy-related toxicities. Additional studies are needed to validate this finding.

Characterization and clinical significance of hemolysis after pulsed-field ablation for atrial fibrillation: insights from a multicentric analysis

Abstract Background Pulsed-field ablation is a novel non-thermal ablation modality which is being increasingly used in clinical practice for the treatment of atrial fibrillation (AF). While the susceptibility of erythrocytes to electroporation is well-established, the effect of cardiac PFA technologies on erythrocyte destruction has not been described so far. Purpose The aim of this study was to investigate whether PFA induces clinically significant hemolysis. Methods We included 187 patients undergoing AF catheter ablation with either PFA (n=145) or RFA (n=42) at four high-volume centers. PFA was performed using a pentaspline catheter (biphasic, bipolar pulses of 2kV) and RFA with a 3.5 mm irrigated-tip catheter (40-60 W). The lesion set comprised pulmonary vein isolation (PVI) for paroxysmal AF and PVI ± additional lesions/lines for persistent AF. Established biomarkers of hemolysis, anemia and renal function were analyzed in blood samples obtained at baseline (T1), at the end of ablation (T2) and 24 hours after the procedure (T3). Results Baseline characteristics were well-balanced between groups (65.5 ± 9.6 years, 72.7% male, p>0.05). The ablation procedures comprised a mean of 61.4 ± 27.2 deliveries (PFA group) and a mean RF duration of 31.0 ± 16.3 min (RFA group). Atrial ablation in addition to PVI was performed in 55.2% vs. 61.9% patients, respectively (p=0.469). The direct hemolysis marker free plasma hemoglobin was significantly higher with PFA (592.8 ± 330.6 mg/dl) than with RFA (186.6 ± 215.8 mg/dl, p<0.001) at the end of ablation. A strong correlation was found between free plasma hemoglobin and PFA deliveries (Pearson r=0.615, p<0.001). PFA was further associated with a 2.2-fold increase in bilirubin (21.3 ± 11.3 vs. 9.6 ± 4.7 µmol/l), a 2.4-fold decrease in haptoglobin (0.5 ± 0.4 vs. 1.2 ± 0.4 g/l) and a 1.8-fold increase in LDH (352.7 ± 115.7 vs. 192.2 ± 51.6 U/l, T3 vs. T1, all p<0.001). There were no significant changes in bilirubin and haptoglobin in the RFA group (p>0.05). A slight decrease in red blood cells, hemoglobin and hematocrit was detected after both PFA and RFA (Abstract Figure), with no significant differences between groups (all p>0.05). While mean creatinine levels and glomerular filtration rates did not significantly change after ablation in either group, acute kidney injury occurred in 4/124 (3.2%) with PFA vs. 0/32 (0%) with RFA (p=0.303). Conclusion Intravascular hemolysis is a frequent finding after PFA for AF and increases with the number of PFA deliveries. While PFA was not associated with clinically significant anemia, the incidence of acute kidney injury in the present study warrants future large-scale investigations assessing the biological impact and nephrotoxicity of PFA-induced hemolysis.Abstract Figure

Navigating the 'moral hazard' argument in synthetic biology's application.

Synthetic biology has immense potential to ameliorate widespread environmental damage. The promise of such technology could, however, be argued to potentially risk the public, industry or governments not curtailing their environmentally damaging behavior or even worse exploit the possibility of this technology to do further damage. In such cases, there is the risk of a worse outcome than if the technology was not deployed. This risk is often couched as an objection to new technologies, that the technology produces a moral hazard. This paper describes how to navigate a moral hazard argument and mitigate the possibility of a moral hazard. Navigating moral hazard arguments and mitigating the possibility of a moral hazard will improve the public and environmental impact of synthetic biology.

#1996 Identification of the biological bases associated with the mTOR-I-related podocytopathy through high-resolution mass spectrometry

Abstract Background and Aims mTOR inhibitors (mTOR-I) often cause podocytopathy with the development of proteinuria (sometimes in the nephrotic range) in kidney transplant patients, but the biological mechanisms underlying this effect have been only partially defined. Method Immortalized human podocytes were treated in vitro with different everolimus (EVE) doses (10, 100, 200, 500 nM) for 24 h. Total cell lysates and supernatants were subjected to high-resolution mass spectrometry (Proteomics analysis). Innovative tests were used for bioinformatics analysis, including the Support Vector machine (SVM) and partial least squares discriminant analysis (PLS-DA). The results were validated in vitro and in human urine samples from 30 patients treated with EVE-based immunosuppressive treatment, using various molecular biology techniques (western blot, ELISA). Results Proteomic evaluation identified more than 7000 differentially expressed proteins. Among these, after a conservative statistical analysis, 78 showed an expression level significantly and directly correlated with EVE dosage. Functional analysis of the selected proteins showed a biological interconnection that involved several pathways, including kinases, cell cycle regulation, epithelial–mesenchymal transition, and protein synthesis. Osteopontin (SPP1) and Polo Like Kinase 2 (PLK2) were two of the most significantly correlated proteins (p < 0.00001, FDR<0.5%). The data were then confirmed through biomolecular experiments in vitro and in vivo in urine samples from kidney transplant recipients who received immunosuppressive treatment with EVE. Conclusion This study, for the first time, analyzed the biological impact of mTOR-I on podocytes, helping to understand not only the molecular basis of its therapeutic effect but also the biological reasons underlying their adverse events (particularly proteinuria). Validation of our data on larger cohorts of patients treated with this category of drugs will help identify new therapeutic targets to minimize adverse effects.

The nematode Caenorhabditis elegans enhances tolerance to landfill leachate stress by increasing trehalose synthesis.

The burgeoning issue of landfill leachate, exacerbated by urbanization, necessitates evaluating its biological impact, traditionally overshadowed by physical and chemical assessments. This study harnesses Caenorhabditis elegans, a model organism, to elucidate the physiological toxicity of landfill leachate subjected to different treatment processes: nanofiltration reverse osmosis tail water (NFRO), membrane bioreactor (MBR), and raw leachate (RAW). Our investigation focuses on the modulation of sugar metabolism, particularly trehalose-a disaccharide serving dual functions as an energy source and an anti-adversity molecule in invertebrates. Upon exposure, C. elegans showcased a 60-70% reduction in glucose and glycogen levels alongside a significant trehalose increase, highlighting an adaptive response to environmental stress by augmenting trehalose synthesis. Notably, trehalose-related genes in the NFRO group were up-regulated, contrasting with the MBR and RAW groups, where trehalose synthesis genes outpaced decomposition genes by 20-30 times. These findings suggest that C. elegans predominantly counters landfill leachate-induced stress through trehalose accumulation. This research not only provides insights into the differential impact of leachate treatment methods on C. elegans but also proposes a molecular framework for assessing the environmental repercussions of landfill leachate, contributing to the development of novel strategies for pollution mitigation and environmental preservation.

Rare Earth Element Accumulation in Fiddler Crabs (Minuca rapax) from the Rio Doce Tropical Estuary Strongly Affected by Mine Tailings Following the Fundão Disaster.

A mining tailing dam rupture in Brazil in November 2015 released millions of tons of mining waste into the Rio Doce ecosystem, leading to long-term aquatic ecosystem impacts. Although multiple lines of evidence indicate tailings associations with potentially toxic elements in estuarine sediments and biological impact and bioaccumulation pathways in fishes, the extent of contamination in base benthic species is still largely unknown. Moreover, Rare Earth Elements (REE) have not received any attention in this regard. This study assessed REE in fiddler crabs (Minuca rapax) sampled from the Rio Doce estuary in 2017, nearly 2years after the disaster. The ΣREE in crab hepatopancreas and muscle were high (327.83mgkg-1 w.w. and 33.84mgkg-1 w.w., respectively, compared to other assessments in crabs, indicating a preference for REE bioaccumulation in the hepatopancreas compared to muscle. Neodimium, La, and Ce were detected at the highest concentrations. The REE from the Rio Doce Basin were, thus, transported and deposited in the estuary with the mine tailings slurry, leading to bioaccumulation in crabs. This may lead to trophic effects and other ecological impacts not readily measured by typical impact assessment studies, revealing an invisible and not typically acknowledged damage to the Rio Doce estuary.

The Biological Impact of Some Phosphonic and Phosphinic Acid Derivatives on Human Osteosarcoma.

Osteosarcoma malignancy currently represents a major health problem; therefore, the need for new therapy approaches is of great interest. In this regard, the current study aims to evaluate the anti-neoplastic potential of a newly developed phosphinic acid derivative (2-carboxyethylphenylphosphinic acid) and, subsequently, to outline its pharmaco-toxicological profile by employing two different in vitro human cell cultures (keratinocytes-HaCaT-and osteosarcoma SAOS-2 cells), employing different techniques (MTT assay, cell morphology assessment, LDH assay, Hoechst staining and RT-PCR). Additionally, the results obtained are compared with three commercially available phosphorus-containing compounds (P1, P2, P3). The results recorded for the newly developed compound (P4) revealed good biocompatibility (cell viability of 77%) when concentrations up to 5 mM were used on HaCaT cells for 24 h. Also, the HaCaT cultures showed no significant morphological alterations or gene modulation, thus achieving a biosafety profile even superior to some of the commercial products tested herein. Moreover, in terms of anti-osteosarcoma activity, 2-carboxyethylphenylphosphinic acid expressed promising activity on SAOS-2 monolayers, the cells showing viability of only 55%, as well as apoptosis features and important gene expression modulation, especially Bid downregulation. Therefore, the newly developed compound should be considered a promising candidate for further in vitro and in vivo research related to osteosarcoma therapy.

Somatic structural variants drive distinct modes of oncogenesis in melanoma.

The diversity of structural variants (SVs) in melanoma and how they impact oncogenesis are incompletely known. We performed harmonized analysis of SVs across melanoma histological and genomic subtypes, and we identified distinct global properties between subtypes. These included the frequency and size of SVs and SV classes, their relation to chromothripsis events, and the role of topologically associated domain (TAD) boundary altering SVs on cancer-related genes. Following our prior identification of double-stranded break repair deficiency in a subset of triple wild-type cutaneous melanoma, we identified MRE11 and NBN loss-of-function SVs in melanomas with this mutational signature. Experimental knockouts of MRE11 and NBN, followed by olaparib cell viability assays in melanoma cells, indicated that dysregulation of each of these genes may cause sensitivity to PARPi in cutaneous melanomas. Broadly, harmonized analysis of melanoma SVs revealed distinct global genomic properties and molecular drivers, which may have biological and therapeutic impact.

The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma

AbstractAcquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IgH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing data from 1173 MM samples. By integrating molecular time and structural variants within early chromosomal duplications, we indeed identified pregain deletions in 9.4% of patients with an HY karyotype without IgH translocations, challenging acquisition of an HY karyotype as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSGs) and/or oncogenes in 2.4% of patients with an HY karyotype without IgH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to postgain deletions as novel driver mechanisms in MM. Using multiomics approaches to investigate their biologic impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both the oncogene and TSG activity despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM.

Biological impact and therapeutic potential of a novel camptothecin derivative (FLQY2) in pancreatic cancer through inactivation of the PDK1/AKT/mTOR pathway

BackgroundCamptothecin (CPT), a pentacyclic alkaloid with antitumor properties, is derived from the Camptotheca acuminata. Topotecan and irinotecan (CPT derivatives) were first approved by the Food and Drug Administration for cancer treatment over 25 years ago and remain key anticancer drugs today. However, their use is often limited by clinical toxicity. Despite extensive development efforts, many of these derivatives have not succeeded clinically, particularly in their effectiveness against pancreatic cancer which remains modest. Aim of the studyThis study aimed to evaluate the therapeutic activity of FLQY2, a CPT derivative synthesized in our laboratory, against pancreatic cancer, comparing its efficacy and mechanism of action with those of established clinical drugs. MethodsThe cytotoxic effects of FLQY2 on cancer cells were assessed using an MTT assay. Patient-derived organoid (PDO) models were employed to compare the sensitivity of FLQY2 to existing clinical drugs across various cancers. The impact of FLQY2 on apoptosis and cell cycle arrest in Mia Paca-2 pancreatic cancer cells was examined through flow cytometry. Transcriptomic and proteomic analyses were conducted to explore the underlying mechanisms of FLQY2′s antitumor activity. Western blotting was used to determine the levels of proteins regulated by FLQY2. Additionally, the antitumor efficacy of FLQY2 in vivo was evaluated in a pancreatic cancer xenograft model. ResultsFLQY2 demonstrated (1) potent cytotoxicity; (2) superior tumor-suppressive activity in PDO models compared to current clinical drugs such as gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, ivosidenib, infinitinib, and lenvatinib; (3) significantly greater tumor inhibition than paclitaxel liposomes in a pancreatic cancer xenograft model; (4) robust antitumor effects, closely associated with the inhibition of the TOP I and PDK1/AKT/mTOR signaling pathways. In vitro studies revealed that FLQY2 inhibited cell proliferation, colony formation, induced apoptosis, and caused cell cycle arrest at nanomolar concentrations. Furthermore, the combination of FLQY2 and gemcitabine exhibited significant inhibitory and synergistic effects. ConclusionThe study confirmed the involvement of topoisomerase I and the PDK1/AKT/mTOR pathways in mediating the antitumor activity of FLQY2 in treating Mia Paca-2 pancreatic cancer. Therefore, FLQY2 has potential as a novel therapeutic option for patients with pancreatic cancer.