Risk Of Toxicity Research Articles

Influence of nitric oxide donor on the physiological quality of seeds of Myrcia retorta Cambess

Brazil, with its vast biodiversity, is home to several species of the Myrtaceae family with significant ornamental potential that is still underutilized. Myrcia retorta Cambess is a endemic Brazilian plant wich stands out as a promising species for ornamental cultivation. The objective of this study was to evaluate the effect of the nitric oxide donor S-nitrosoglutathione (GSNO) on the germination of M. retorta seeds, with the aim of optimizing germination conditions for the domestication of this species. The seeds were divided into two batches based on their morphology: Batch 1 (spherical seeds) and Batch 2 (flattened seeds). The seeds were treated with five concentrations of GSNO (0, 2.5, 5, 10, and 15 mM) and the parameters evaluated included germination percentage, shoot and root length, and time to stabilization of germination. In batch 1, doses of 2.5 mM and 5 mM GSNO resulted in faster germination stabilization (6 and 7 days, respectively) compared to the control (9 days). In addition, these doses increased germination percentage by 15% and 12%, respectively. However, higher concentrations (10 mM and 15 mM) were found to be phytotoxic, reducing shoot length by 30% and 45% and root length by 28% and 42%, respectively. In batch 2, although no statistically significant differences were observed, a trend towards reduced germination and growth with increasing GSNO doses was observed. It is concluded that GSNO positively affects the germination and initial development of M. retorta at low concentrations, especially in spherical seeds, suggesting its potential in the domestication process of the species for ornamental purposes. However, doses higher than 5 mM should be avoided due to toxicity risks, highlighting the need to optimize concentrations for practical application.

Toxic effects of chlorpyrifos on biochemical composition, enzyme activity and gill surface ultrastructure of three species of small fishes from India.

The effects of chlorpyrifos, a frequently detected organophosphate in aquatic ecosystems, on biochemical (protein and glycogen) contents and oxidative enzyme activities (catalase and lipid peroxidation) in liver, muscle and gill tissues of three freshwater fish Trichogaster fasciata, Mystus vittatus and Heteropneustes fossilis were evaluated after 21-day exposure to 1 and 10% of 96h LC50 of this pesticide, which were 1.63 and 16.3µg L-1; 5.87 and 58.7µg L-1 and 2.12 and 21.2µg L-1, respectively. On comparing with control, significant reductions in protein concentration were found in liver, muscle and gill of the three fishes treated with both higher as well as lower concentrations of the pesticide except in gill of M. vittatus and liver of H. fossilis treated with the lower concentrations. Glycogen content reductions were significant in the liver and muscle of the fishes, as well as gill tissue of T. fasciata treated with the two pesticide concentrations. Significant elevations of catalase activity were found in liver of the three fishes treated with the higher concentrations, in muscle tissues of both T. fasciata and M. vittatus treated with both the concentrations and in gills of the three fishes except H. fossilis treated with the lower concentration of the pesticide. Significant elevations of lipid peroxidation level were also found in liver of all the three fish species treated with the higher concentrations, in the muscle tissue of M. vittatus as well as in the gill of T. fasciata and H. fossilis treated with both the concentrations of the pesticide. Chlorpyrifos exposed gill ultrastructure of T. fasciata, M. vittatus and H. fossilis revealed concentration-dependent effects of the pesticide on gill surface ultrastructure which include distortion of primary and secondary lamellae, deterioration of pavement cell and microridge structures, extrusion of red blood cells (RBCs), secretion of mucous layer on filament, sloughing of primary lamellae and clumping of secondary lamellae. The present study parameters could serve as useful biomarkers for evaluating the risk of pesticide toxicity to fish. These findings also point out the possible health risks to the consumers of these fish captured from contaminated water bodies.

Association between tumor location and toxicity outcomes after stereotactic radiosurgery for brain metastases.

Toxicities associated with stereotactic radiosurgery (SRS) are important when considering treatment and supportive management for patients with brain metastases. We herein assessed the association between brain metastasis location and risk of toxicity after SRS. We conducted a retrospective institutional review of patients treated with SRS for brain metastases between 2008 and 2023. Outcomes included radiation necrosis, seizure, local failure, and overall survival (OS). We reviewed 215 patients treated to 605 metastases (median diameter 10mm, IQR 5-17 mm), in the frontal (34%), cerebellar (19%), parietal (16%), temporal (13%), and occipital (13%) regions. Median follow-up was 16 months (IQR 7-36). New-onset seizures developed in 11% (19/174) of patients without prior seizure and was higher in patients with motor or sensory cortex lesions (12/48, 25%) on multivariate analysis (MVA, P = 0.02). SRS-related grade ≥ 2 symptomatic radionecrosis occurred in 6% (33/605) of lesions and correlated with larger metastasis volume (P < 0.001) and renal cell carcinoma histology (P < 0.05), while supratentorial location was nearly significant (MVA, P = 0.06). Median OS across all patients was 16 months (95% CI 12-20). Patients with symptomatic radiation necrosis had a longer median survival compared to those who did not (43 vs. 14 months, P = 0.002), which remained significant alongside Karnofsky performance status and extracranial disease on MVA. Brain metastasis location in the motor or sensory cortex is associated with increased risk of new-onset seizure following SRS and may warrant consideration of steroid and/or anti-epileptic prophylaxis. Symptomatic radiation necrosis is uncommon in the cerebellum and may be increasing with improvements in survival.

Potential Adverse Drug Events Identified with Decision Support Algorithms from Janusmed Risk Profile—A Retrospective Population-Based Study in a Swedish Region

Adverse drug events (ADEs) occur frequently and are a common cause of suffering, hospitalizations, or death, and can be caused by harmful combinations of medications. One method used to prevent ADEs is by using clinical decision support systems (CDSSs). Janusmed Risk Profile is a CDSS evaluating the risk for nine common or serious ADEs resulting from combined pharmacodynamic effects. The aim of this study was to examine the prevalence of potential ADEs identified using CDSS algorithms from Janusmed Risk Profile. This retrospective, cross-sectional study covered the population of a Swedish region (n = 246,010 inhabitants in year 2020) using data on all medications dispensed and administered. More than 20% of patients had an increased risk of bleeding, constipation, orthostatism, or renal toxicity based on their medications. The proportion of patients with an increased risk varied from 3.5% to almost 30% across the nine categories of ADEs. A higher age was associated with an increased risk of potential ADEs and there were gender differences. A cluster analysis identified groups of patients with an increased risk for several categories of ADEs. This study shows that combinations of medications that could increase the risk of ADEs are common. Future studies should examine how this correlates with observed ADEs.

Impact of deep inspiration breath hold, surface-guided radiotherapy, and daily CBCT on the organs at risk in breast cancer radiotherapy.

The goal of the study was to assess the impact of deep inspiration breath hold technique (DIBH), surface-guided radiotherapy (SGRT), and daily kilovoltage cone-beam computed tomography (kV-CBCT) on the dose to organs at risk (OAR) in left-sided breast cancer radiotherapy. Twenty-six consecutive left-sided breast cancer patients treated using Volumetric Intensity Modulated Arc Therapy (VMAT), DIBH, SGRT, and a hypofractionated regimen were retrospectively evaluated in this study. Dose parameters were extracted from dose-volume histograms (DVH). The Wilcoxon Matched Pairs test was used to test dose parameters obtained in free breathing (FB) and DIBH for statistical significance. Multivariable analysis of variance (ANOVA) and receiver operating characteristics (ROC) analysis were used to identify parameters and cut-off points associated with the reduction of the mean heart dose (MHD) by DIBH. Based on published models, the risk of cardiac and lung toxicity (pneumonitis) using SGRT or daily kV-CBCT was estimated and compared. DIBH substantially reduced the MHD (median, 43.6%; range, 4.2% to 75.1%; P < 0.00001). The risk of cardiac toxicity using SGRT increased by 1%, compared to 3.6% to 20.5% using daily kV-CBCT. No significant difference in the risk of radiation-induced pneumonitis using SGRT versus daily kV-CBCT was detected. The ANOVA revealed the relative increase of the left lung volume by DIBH as the only significant impact factor for the MHD. The ROC analysis of this parameter showed an area under the curve (AUC) of 0.89 (95%CI, 0.71 to 0.98; P < 0.0001). DIBH can substantially reduce the MHD in left-sided breast cancer patients treated with modern radiotherapy techniques and hypofractionation. Patient setup using SGRT compared to daily kV-CBCT may be the preferred option for many patients. In our patient cohort, the relative reduction of the left lung volume by DIBH can be used as a predictor to select patients who benefit from DIBH.

Single-point mutated lanmodulin as a high-performance MRI contrast agent for vascular and kidney imaging.

Magnetic resonance imaging contrast agents can enhance diagnostic precision but often face limitations such as short imaging windows, low tissue specificity, suboptimal contrast enhancement, or potential toxicity, which affect resolution and long-term monitoring. Here, we present a protein contrast agent based on lanmodulin, engineered with a single-point mutation at position 108 from N to D to yield maximum gadolinium binding sites. After loading with Gd3+ ions, the resulting protein complex, LanND-Gd, exhibits efficient renal clearance, high relaxivity, and prolonged renal retention compared to commercial agents. LanND-Gd enables high-performance visualization of whole-body structures and brain vasculature in male mice at a resolution finer than one hundred micrometers. In male ischemia mouse models, LanND-Gd also improves kidney dysfunction monitoring while minimizing risks of neural toxicity or immunogenic reactions. This protein-based contrast agent offers superior image quality, improved biocompatibility, and extended imaging timeframes, promising significant advancements in magnetic resonance-based diagnostics and patient outcomes.

Disseminated intravascular coagulation is an underestimated but fatal adverse event associated with blinatumomab therapy: A pharmacovigilance analysis of FAERS.

Hematologic adverse events (AEs) are common and serious toxicities in patients with hematologic malignancies undergoing blinatumomab therapy. However, restrictive selection criteria in pivotal clinical trials can lead to an underestimation of rare but fatal toxicities. In this study, we systematically analyzed hematologic AEs associated with blinatumomab using the Food and Drug Administration Adverse Event Reporting System (FAERS) from October 2014 to December 2023. Disproportionate analysis was performed to identify overreported AEs, with a reporting odds ratio (ROR), and a lower bound of the 95% confidence interval (ROR025) exceeding one considered significant. Additionally, adjusted mortality rates and risk ratios (RR) of the top 10 reported hematologic AEs were calculated using a logistic regression model. Among 4745 blinatumomab-related cases, 418 (8.81%) involved hematologic AEs. We identified 22 significantly overreporting hematologic AEs compared to the full database, with myelosuppression (n = 39 [9.33%], ROR025 = 8.04), disseminated intravascular coagulation (DIC, n = 31 [7.42%], ROR025 = 15.14), and bone marrow failure (n = 14 [3.35%], ROR025 = 3.41) notably underestimated in clinical trials. DIC resulted in a substantial mortality rate of 45.16%. Finally, DIC was found to be independently associated with death in a multivariable logistic regression analysis (RR = 2.47 [95% CI: 1.11-3.83]). These findings could aid clinicians in the early detection of these rarely reported but fatal hematologic AEs, thereby reducing the risk of severe toxicities in blinatumomab recipients.

Abstract 4118451: A Real-world Evaluation of Longitudinal Healthcare Expenses in a Health System Registry of Type-2 Diabetes Mellitus and Cardiovascular Disease Enabled by the 21 st Century Cures Act

Background: An evaluation of the longitudinal burden of healthcare expenses in type-2 diabetes mellitus (T2DM) is limited to self-selected cohorts and claims-based or self-reported spending. Leveraging the 21 st Century Cures Act rule that made reporting hospital-level service prices mandatory, we demonstrate healthcare spending in T2DM with and without cardiovascular disease in a diverse multisite EHR-based T2DM cohort. Methods: Patients with T2DM seeking regular care (≥ 1 visit/2 years) across 5 hospitals and a large outpatient network (2013-2023) in the Yale New Haven Health System (YNHHS). Cohorts were defined by the presence of atherosclerotic cardiovascular disease (ASCVD) and/or heart failure (HF) before or up to 1 year after the T2DM diagnosis. We used the YNHHS chargemaster file to extract Medicare and insurance-negotiated cash prices. We linked census data using residential zip codes to estimate household income, used multivariable logistic regression to identify factors associated with financial hardship (health expenses &gt;20% of income), and evaluated expenses during the last year of life. All values were inflation-adjusted to 2023 US$. Results: Overall, 106881 patients with T2DM followed for 5.4 years (3.1-7.5) had 147919 hospitalizations, representing $3.41B in expected healthcare expenses. 8% of patients with T2DM without ASCVD/HF, 14% with ASCVD, 23% with HF, and 28% with ASCVD and HF had a financial obligation for healthcare above the threshold for financial hardship. Compared with White patients, Black and Hispanic patients were more likely, and Asians were less likely to have financial hardship (OR: Black, 1.81 [1.73-1.91]; Hispanic, 1.39 [1.31-1.48]; Asian, 0.46 [0.37-0.57]), after accounting for age, sex, and comorbidities. Comorbid HF at baseline portended 2x higher odds of financial hardship (OR: HF, 2.20 [2.00-2.42]; ASCVD and HF, 1.98 [1.84-2.14]) compared with T2DM alone. Care in the last year of life represented 72-80% of overall health expenses, with 55-61% of patients at risk for financial hardship across cohorts. Conclusion: A digital individualized expense-linked registry of patients enabled by recent US price transparency rules defined that annually, one-fifth of patients with T2DM and cardiovascular disease had healthcare events exceeding 20% of their annual income, and vulnerable racial/ethnic minorities were at high risk for financial toxicity.

EXTH-82. TUMOR ORGANOID PREDICTED THERAPEUTIC RESPONSES TO NOVEL EPIGENETIC DRUGS VIA HIGH-THROUGHPUT SCREENING

Abstract INTRODUCTION The treatment choices for pediatric brain tumors are still very limited. Epigenetic therapy emerges as a promising option recently. The lack of in vitro models that represent tumors in vivo and can be scalable for large scale drug screening is major barrier. We have developed tumor organoids from patient-derived orthotopic xenograft and performed a multi-stage high throughput screening for single or combined epigenetic agents and radiation therapy in tumor organoids. METHOD Primary xenograft tumor cells were cultured in matrix and cancer stem cell culture medium in 384-well plates. Radiation sensitivity was examined at 5 different doses. Epigen40 (40 drugs/compounds) targeting various epigenetic modifications was used alone to identify agents with the most cell killing (4 doses for up to 19 days). The drugs that showed partial activity were combined with radiation (at 5 doses) to evaluate additive or synergistic effects. The anti-tumor efficacy of selected drug was then evaluated in vivo. RESULTS The conditions of organoid growth and screen variability were optimized. 7 tumor organoids including 4 glioblastomas and 3 medulloblastomas were successfully established and characterized. The different radio-sensitivities were observed among these models. 7 compounds (JIB-04, SP2509, AS-8351, GSK J4 HCI, 3-Deazaneplanocin A HCL, Chaetocin, TC-E-5003) were shown to effectively suppress organoid growth. Chaetocin, methyltransferase SUV39H inhibitor, demonstrated broadly active and highly potent inhibition across all 7 tested organoids. In addition, bioinformatic analysis identified a subset of epigenetic inhibitors combined with radiation that produced additive anti-tumor activities in vitro. Unfortunately, in vivo treatment of Chaetocin (0.25mg/kg) didn’t convey consistent anti-tumor effects as shown in vitro whereas a high risk of drug toxicity to the mice. CONCLUSION Tumor organoids were successfully developed from primary tumors. With our optimized assay using primary tumor organoids and a multi-stage high throughput drug screening, a novel panel of epigenetic drugs that effective alone or additively with radiation was identified.

Periprosthetic seromas and athird space effect after high-dose methotrexate.

Besides surgery, chemotherapy including high-dose methotrexate is amainstay of osteosarcoma treatment. Methotrexate is known to accumulate in tissues and cavities, so-called third spaces (e.g., periprosthetic seromas) leading to local toxicity and delayed elimination (third space effect). We compared the concentrations of methotrexate in serum and periprosthetic seromas to evaluate apotential toxic risk based on athird space effect. In 45 osteosarcoma patients who were treated with endoprosthesis and high-dose methotrexate (HDMTX) between 1991 and 2011 we retrospectively analyzed methotrexate concentrations in periprosthetic seromas and serum. Differences were assessed by means of the Wilcoxon test. A total of 112 periprosthetic seroma punctures were performed in 18out of 45patients. At 24 h the periprosthetic seroma concentrations were in median 14.86-fold (range 1.49-42.97-fold, p = 0.001), at 48 h in median 8.50-fold (range 1.36-52.56, p < 0.001) and at 72 h in median 2.66-fold (range 0.66-5.82, p = 0.015) of the corresponding serum concentrations. At 24 h highly toxic concentrations (≥ 20 μmol/l) were observed in 30% of all analyzed seromas (median 109.83 μmol/l, range 4.91-170.71 μmol/l). Asignificantly higher serum concentration (range 0.16-0.75 μmol/l, median 0.36 µmol/l) was found in patients with prior puncture than patients without puncture at 45 h after HDMTX. Methotrexate concentrations of periprosthetic seromas are significantly higher than corresponding serum concentrations possibly contributing to athird space effect. To avoid severe adverse effects punctures of these effusions should be considered.

Unlocking Neuraminidase Inhibitors: Insights from Natural Products through Pharmacophore Modeling, Virtual Screening, and Molecular Docking

Background: Neuraminidase enzyme plays a major role in the life cycle of influenza viruses. Targeting neuraminidases is a key strategy in preventing and treating influenza A and B spread by inhibiting the release of new viral particles from infected cells. Developing new neuraminidase inhibitors with enhanced efficacy and reduced risk of resistance is the ultimate of ongoing research. Objective: In this study, we tried to shed light on molecules of natural origin that inhibit neuraminidase enzyme by utilizing different aspects of in silico studies. Methods: The work started by generating structure-based pharmacophore, later used for the virtual screening of electronic libraries constructed from chemical and natural compounds. Hits raised from virtual screening were subjected to molecular docking to assess and explain different modes of interactions with the neuraminidase enzyme. Drug likeness and ADME filters were applied to choose compounds that may be taken effectively by oral route with good gastrointestinal absorption and acceptable pharmacokinetics with respect to Lipinski and Ghose rules. The hits were also inspected for toxicity risks, including mutagenic, tumorigenic, irritant, and reproductive effects. Results: 7 features of the generated pharmacophore from the potent inhibitor Oselatamiver were the base for virtual screening. The results obtained by database screening highlighted 4 natural compounds listed in the COCONUT library (CNP 0125691 (Penicitrinol K), CNP0256196 (Frenolicin D), CNP 0138184, and CNP 0206296) as potential neuraminidase inhibitors. The compounds showed a similar interaction profile to Oseltamivir by molecular docking with high binding affinity. The key residue TYR 406 hydrogen bonded to Penicitrinol and Frenolicin D as well as to Oseltamevir. The 4 natural compounds exerted drug-like properties and promising pharmacokinetic characters. Toxicity risks estimations put Penicitrinol K and Frenolicin as devoted to mutagenic, tumorigenic, irritant and reproductive potentials. Penicitrinol K and Frenolicin are assigned for further in vitro and in vivo studies as promising neuraminidase inhibitors. Conclusion: Penicitrinol K, and Frenolicin D are promising natural neuraminidase inhibitors, exhibiting favourable drug-like properties and low toxicity risks in addition to showing the pattern of interaction profiles with neuraminidase enzymes similar to the known drug Oseltamivir contributing to the development of effective antiviral therapies against influenza, suggesting further in vitro and in vivo evaluation.

Cancer survivors and cardiovascular diseases: from preventive strategies to treatment.

During the last decades, progress in the treatment of oncological diseases has led to an increase in the survival of cancer patients: cancer survivors (CS). Thus, the incidence of CS has increased enormously, in both adult CS and childhood and adolescent CS. Unfortunately, CS treated with anthracyclines, chest radiotherapy (RT) and other potentially cardiotoxic drugs have a higher risk of cardiovascular (CV) toxicity: heart failure with reduced ejection fraction (HFrEF), valve diseases, coronary artery diseases, vascular diseases and pericardial diseases. In fact, chest irradiation can cause coronary artery diseases that can be latent until at least 10 years after exposure; also, valvular heart diseases can appear after >20 years following irradiation; heart failure may appear later, several years after anticancer drugs or RT. Therefore, it is very important to stratify the CV risk of cancer patients at the end of cardiotoxic drugs, to plan the most appropriate long-term surveillance program, in accordance with 2022 ESC Guidelines on Cardio-Oncology, to prevent late cardiovascular complications. Monitoring of cancer patients must not stop during anticancer treatment but it must continue afterwards, depending on the patient's CV risk. CV toxicity risk should be reassessed 5 years after therapy to organize long-term follow-up. Considering late cardiotoxicity in CS, our review aims to evaluate the incidence of cardiovascular diseases in CS, their mechanisms, surveillance protocols, preventive strategies, diagnosis and treatment.

Chronotherapy in head and neck cancer: A systematic review and meta-analysis.

Optimizing the timing of radiotherapy and chemotherapy tailored to the body's biological clock (i.e., chronotherapy) might improve treatment efficacy and reduce side effects. This systematic review evaluated the effect of chrono-radiotherapy and chrono-chemotherapy on treatment efficacy, toxicity and adverse events in head and neck cancer (HNC) patients from prospective and retrospective studies published between the date of database inception until March 2024. The primary outcome measures for chrono-radiotherapy were treatment efficacy and incidence of grade ≥3 oral mucositis, and the main outcome measures for chrono-chemotherapy were objective response rate (ORR) and overall toxicity and adverse events. Of 7349 records identified, 22 studies with 3366 patients were included (chrono-radiotherapy = 9 and chrono-chemotherapy = 13). HNC patients who underwent chrono-radiotherapy had 31% less risk of developing severe oral mucositis (grade ≥3) compared to evening radiotherapy (risk ratio: 0.69, 95% CI: 0.53-0.90, p < 0.05). Further, HNC patients who underwent chrono-chemotherapy using platinum-based and antimetabolite agents had 73% less risk of lower ORR compared to nontime-stipulated chemotherapy (risk ratio: 0.27, 95% CI: 0.09-0.84, p < 0.05). In addition, HNC patients who underwent chrono-chemotherapy had 41% less risk of lower overall toxicity and adverse events in comparison to nontime-stipulated chemotherapy (risk ratio: 0.59, 95% CI: 0.47-0.72, p < 0.05). In conclusion, chrono-chemotherapy studies showed evidence of improved treatment efficacy, while in chrono-radiotherapy it was maintained. Chrono-radiotherapy and chrono-chemotherapy studies provide evidence of reduced toxicity and adverse events. However, optimized circadian-based multicentric clinical studies are needed to support chrono-radiotherapy and chrono-chemotherapy in managing HNC.

Anti-retinal Autoantibodies in Hydroxychloroquine Eye Toxicity.

Autoimmune retinopathy and hydroxychloroquine (HCQ)-related retinal toxicity share many similarities, raising the possibility autoimmunity plays a role in HCQ retinopathy. The objective of this study is to determine whether patients diagnosed with HCQ retinal toxicity are more likely to have circulating antiretinal autoantibodies (AAbs) compared to controls. We tested plasma samples for the presence of anti-retinal AAbs by immunoblotting in 270 patients with systemic lupus erythematosus (SLE) receiving HCQ. We then evaluated for the presence of HCQ retinal toxicity and other baseline risk factors for HCQ toxicity through chart review. Frequency of specific anti-retinal AAbs in patients with HCQ retinal toxicity was compared to those with no retinal toxicity via multivariate logistic regression. Patients with HCQ retinal toxicity had a higher likelihood of testing positive for anti-arrestin AAbs (60.7% vs 30.6%, P = 0.001) and anti-pyruvate kinase M2 AAbs (46.4% vs 28.1%, P = 0.05). Patients with HCQ eye toxicity also had a higher number of total anti-retinal AAbs (mean 3.0 ± 2.40 vs 2.04 ± 1.7, P = 0.01). In multivariate analysis accounting for risk factors associated for HCQ eye toxicity, the presence of anti-arrestin antibodies was associated with a 3.2-fold increase in the odds of developing HCQ eye toxicity. Anti-retinal AAbs were more common in patients with SLE with HCQ retinal toxicity. When controlling for risk factors associated with HCQ toxicity, anti-arrestin AAbs were associated with increased odds for the development of eye toxicity, suggesting a potential role for anti-retinal AAbs as a biomarker of HCQ eye toxicity.

Risk assessment and sources associated with potentially toxic elements in suspended particulate matter: A karst river perspective in active mining area

Study regionDaiyang River Basin, a typical karst river basin impacted by mining activities in Guizhou, Southwest China. Study focusRivers are fundamental components of regional water security, but they are facing potentially toxic elements (PTEs) pollution caused by mining activities. This study investigated the concentration, behavior, risks and sources of nine PTEs in suspended particulate matter (SPM) from mining-impacted karst rivers, which are essential for the safety and management of karst water environments. New hydrological insights for the regionThe contents of Cr, Ni, Cu, Zn, As, Cd, Sb and Hg exceeded the corresponding local soil background values, with Zn and Cu being the most important pollutants. These elements caused a very high potential toxicity risk to the basin and unacceptable carcinogenic and non-carcinogenic risks to the local residents. Correlation analysis and the positive matrix factorization (PMF) model indicated that Ni, Cd, Zn and Cu were mainly derived from mixed sources of geological background and anthropogenic activities (30.95 %), Hg, Sb, and As were related to coal mining and combustion sources (28.91 %), while Pb, As, Cr and Sb were mainly contributed by natural sources (40.15 %). Furthermore, mixed sources, mining-related sources and As were identified as priority control factors in the study area. These insights can provide powerful support for decision-makers to develop control policies and reduce PTEs pollution in karst areas.

Pollution and Ecological Risk Assessment of Potentially Toxic Elements in Sediments Along the Fluvial-to-Marine Transition Zone of the Don River

The quality of sediments in the mixing zone of river freshwater and marine saline water as an important geochemical barrier for potentially toxic elements (PTEs) remains poorly understood. This study aims to analyze the current pollution with PTEs and associated ecological risks in sediments of the Don River delta and the surrounding area of the Taganrog Bay of the Sea of Azov (Russia). The PTE content was determined in fifty-four collected samples using the WDXRF and assessed using geochemical and ecotoxicological indicators. The source of Cr, Mn, Ni and Pb is mainly river runoff, and Cu, Zn and Cd are from a variety of anthropogenic sources. As shown by the assessment of the geoaccumulation index (Igeo), single pollution index (PI) and contamination factor (CF), these elements are the priority pollutants. According to these estimates, high and very high contamination of sediments in the estuarine zone of the Don River with Cd and Pb was detected in 72–94% and 2–57% of samples, respectively. However, environmental risks are determined almost exclusively by the level of Cd. Total contamination as assessed by the Nemerow pollution index (NPI), modified degree of contamination (mCd) and metal pollution index (MPI) is of concern in 83–98% of the samples studied. The most heavily polluted sediments are in the vicinity of residential areas of the Taganrog Bay. Despite the lower average pollution levels of deltaic sediments, freshwater biota are exposed to higher potential toxic risks of adverse effects by PTE, particularly from Ni and Pb. Thus, the complex hydrological regime and uneven anthropogenic impact predetermine the geochemical state of the sediments of the estuarine zone of the Don River.

Population-pharmacokinetic/pharmacodynamic model of atractylodes lancea (Thunb.) DC. administration in patients with advanced-stage intrahepatic cholangiocarcinoma: a dosage prediction

BackgroundA recent phase 2A clinical study of Atractylodes lancea (Thunb.) DC. (AL) in patients with advanced-stage intrahepatic cholangiocarcinoma (iCCA) demonstrated significant reduction of the risk of tumor progression and mortality with a dose ranging from 1,000 to 2,000 mg. The present study aimed to determine the potential dosage regimen of AL for further phase 2B clinical study.MethodsPlasma-concentration time profiles of total AL bioactivity and clinical efficacy in patients with advanced-stage iCCA were obtained from Phase 2 A study. The population pharmacokinetic (pop-PK) model was developed. The pop-PK model and Monte-Carlo (MC) simulation, in conjunction with maximum concentration of AL (Cmax) as a cut-off criterion, was performed and validated with clinical data. The optimal model was used to simulate further dosage regimens and clinical efficacy of AL.ResultsThe pop-PK properties of total AL bioactivity were best described by a compartmental model with zero-order absorption (without delay) and linear clearance. None of the investigated covariates improved model accuracy.The developed pop-PK with MC simulations following once-daily dosing of 1,000 mg and 2,000 mg adequately predicted the clinical efficacy (tumor progression and mortality). The once-daily dose of 2,500 mg is recommended for further phase 2B clinical study due to its relatively high efficacy on tumor progression inhibition (73%) and mortality rate reduction (71%) without excessive number of the administered capsules (23 capsules) and low risk of toxicities (<5%).ConclusionsThe applied pop-PK model with MC simulation, along with the appropriate cut-off pharmacokinetic parameters, can be used as a potential tool for supporting dosage prediction and selection for clinical studies, and thus reducing the rate of drug development failures.Trial registrationwww.thaiclinicaltrials.org, WHO ICTRP search, TCTR20210129007, Registed 29 January 2021.

Relationship between SLCO1B1 polymorphisms and methotrexate intolerance in Mexican children with juvenile idiopathic arthritis.

The most frequent adverse events (AEs) of methotrexate (MTX) are gastrointestinal symptoms and hepatotoxicity, which can affect its adherence, leading to reduced effectiveness. The SLCO1B1 gene codes for a liver protein (OATP1B1) responsible for drug transportation. Genetic variations within the SLCO1B1 gene locus impact drug transport, leading to altered pharmacokinetic profiles, delayed MTX clearance, and increased risk of toxicity. This study aimed to determine the association between single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene (rs4149056, rs2306283) with the development of AEs in patients with juvenile idiopathic arthritis (JIA) treated with MTX. We performed an observational retrospective study to analyze the relationship between SNPs in the SLCO1B1 gene and the development of AEs in pediatric patients treated with MTX for JIA. Thirty patients with JIA were included, 22 females (73.3%), with a median age of 11years (IQR 8.3-15). The most frequent JIA subtype was rheumatoid factor-positive polyarthritis (36.7%). Twenty patients (66.7%) reported AEs. The *1B haplotype was the most frequent in this group (53.3%) and conferred a higher risk of developing AEs (OR = 3.89, 95% CI = 1.23 -12.29, p = 0.03). Patients with the allele *1B may benefit from lower doses of MTX. SLCO1B1 genotyping is a promising technique to identify patients at higher risk of AEs during treatment with MTX, thus requiring dose optimization.

Analysis of sagittal plane cine magnetic resonance imaging for measurement of pancreatic tumor residual motion during breath hold and evaluation of gating margins used in radiotherapy treatment.

In pancreatic radiotherapy, residual tumor motion during treatment increases the risk of toxicity. Cine imaging acquired during magnetic resonance guided radiotherapy (MRgRT) enables real-time treatment gating in response to anatomical motion, which can reduce this risk; however, treatment gating can negatively impact the efficiency of treatment. This study aimed to quantify the extent of residual tumor motion during breath hold and evaluate the appropriateness of the treatment gating margins used in current clinical practice. Cine imaging acquired during pancreatic MRgRT of 11 patients on the ViewRay MRIdian was analyzed. The total duration of treatment analyzed was 12 h 13 min. Improved methods for processing and analyzing cine imaging were developed: breath holds were systematically separated with frequency analysis, residual motion was measured with consideration of both the tracking structure contour and centroid, and residual motion measurements were supported by phantom measurements of image scaling, resolution, and noise. Residual motion was measured at angles 0°, 45°, 90°, and 135° to the superior-inferior (SI) direction. Total residual motion was measured by combining directional measurements. The minimum tracking structure displacement resolvable through cine imaging was found to be 1.5mm; therefore, residual motion analysis was limited to 1.5mm spatial resolution. Total residual motion was contained within margins ±1.5, ±3, and ±4.5mm with mean percentage frequencies of 97.0%, 91.1%, and 67.8%. Most residual motion was observed in the SI direction, and significantly more residual motion was measured for the tracking structure contour than the centroid. The results demonstrate that patients are largely able to maintain breath hold positions to within a 3mm margin, thus provide evidence that supports the use of a 3mm gating margin in clinical practice. Residual motion frequently exceeded 1.5mm so a reduction in gating margin would have an undesirable impact on treatment efficiency.

Sex Disparities in Cancer Immunotherapy: A Review

Cancer immunotherapy has revolutionized cancer treatment, particularly through immune checkpoint inhibitors (ICIs) targeting proteins like PD-1, PD-L1, and CTLA-4. While these therapies have shown significant survival benefits across various cancers, sex-based disparities in treatment response and outcomes have emerged. This review explores the mechanisms behind these differences, focusing on genetic, hormonal, and immune system variations between male and female patients. Women tend to exhibit stronger immune responses due to the presence of two X chromosomes and the immunostimulatory effects of estrogen, which enhances immune activity. Conversely, men’s single X chromosome and the immunosuppressive effects of testosterone contribute to a less vigorous immune response. These biological differences manifest in clinical outcomes, with men generally experiencing better overall survival rates from ICIs, while women are more prone to immune-related adverse events (irAEs), including autoimmune toxicities. However, in certain cases, women may demonstrate more robust long-term survival benefits from treatments such as CTLA-4 inhibitors, despite higher toxicity risks. Beyond ICIs, sex disparities also extend to adoptive cell therapies (ACT) and cancer vaccines, where female patients often display stronger immune responses but face increased risks of side effects, necessitating personalized approaches to therapy. The review also discusses emerging research on the tumor microenvironment (TME), gut microbiome, and sex-specific pharmacokinetics and pharmacodynamics as contributing factors to these disparities. Understanding these mechanisms is critical for improving cancer immunotherapy outcomes for both sexes. Future research should focus on investigating the role of sex hormones, the microbiome, and developing biomarkers to better predict responses to immunotherapy. Clinically, the findings highlight the need for tailored treatment strategies that account for sex-specific differences, aiming for more equitable and effective cancer care. Keywords: Cancer immunotherapy, Immune checkpoint inhibitors (ICIs), Sex-based disparities, PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors