Search

Researchers have studied potential corrected QT interval (QTc) prolongation from drug-drug interactions (DDIs), raising unresolved questions about their real-world impact. This retrospective case-crossover study investigated the effects of QT-prolonging drugs and DDIs on QTc prolongation in hospitalized patients aged 45 years and above. The cohort comprised patients who had multiple hospitalizations and developed QTc prolongation (QTc > 500 ms or an increase of >60 ms from baseline) at least 24 hours after admission between 2011 and 2019. Conditional logistic regression compared drug exposure between hospitalizations with QTc prolongation (case window) and those without (reference window). Among 2,276 patients (mean age 71; 43.8% female), the use of QT-prolonging drugs significantly increased the risk of QTc prolongation (odds ratio: 2.42 (95% confidence interval: 1.95-3.02)). The risk was higher with drugs of "known risks" (OR: 3.78 (2.91-4.90)) and "conditional risk" (OR: 2.08 (1.65-2.62)). DDIs, particularly involving multiple "known risk" drugs (OR: 7.86 (4.96-12.45)), strong cytochrome P450 enzyme inhibitors (OR: 5.57 (2.75-11.30)), or the concurrent use of ≥4 QT-prolonging drugs with any risk (OR: 5.28 (3.96-7.03)) substantially increased the risk. Cautious prescribing for patients with multiple risk factors is important to minimize the likelihood of QTc prolongation. However, when considering enhanced monitoring or drug choices, it is crucial to carefully evaluate the overall risk of QT prolongation against the benefits of treatment to ensure optimal patient care., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Background: Cancer metastasis is the leading cause of cancer-related deaths, underscoring the importance of understanding its underlying mechanisms. Hepatocellular carcinoma (HCC), a highly malignant type of cancer, was selected as our research model., Material and Methods: We aimed to develop high-metastatic cell lines using in vitro and in vivo selection strategies and identify critical metastasis-related genes through microarray analyses by comparing them with parental cells., Results: Our results showed that the high-metastatic cell lines exhibited significantly stronger invasion abilities than parental cells. Microarray analyses identified cytidine deaminase (CDA), a gene associated with systemic chemotherapy resistance, as one of the overexpressed genes in the high-metastatic cells. Data analysis from The Cancer Genome Atlas Program revealed that while CDA is downregulated in HCC, patients with high CDA expression tend to have poorer prognoses. Cell models confirmed that CDA overexpression enhances cell migration and invasion, whereas CDA knockdown inhibits these abilities. Investigating the key molecules involved in the epithelial-mesenchymal transition (EMT), we found that CDA overexpression increases the expression of fascin, N-cadherin, β-catenin, and snail while decreasing E-cadherin expression. Conversely, CDA knockdown produced opposite results. Additionally, we discovered that CDA regulates NF-κB signaling, which controls the expression of N-cadherin, thereby promoting the invasion capability of HCC cells., Conclusions: We isolated highly metastatic cells and identified potential HCC metastasis-related genes. CDA promotes cell invasion by regulating EMT through the NF-κB pathway. Future studies are warranted to explore the potential of CDA as a biomarker for prognosis and therapeutic decision-making., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Regulatory guidance for global drug development relies on animal studies to evaluate safety risks for humans, including risk of reproductive toxicity. Weight-of-evidence approaches (WoE) are increasingly becoming acceptable to evaluate risk. A WoE for developmental risk of monoclonal antibodies (mAbs) was evaluated for its ability to retrospectively characterize risk and to determine the need for further in vivo testing based on the remaining uncertainty. Reproductive toxicity studies of 65 mAbs were reviewed and compared to the WoE. Developmental toxicities were absent in 52/65 (80%) mAbs. Lack of toxicity was correctly predicted in 29/52 (56%) cases. False positive and equivocal predictions were made in 9/52 (17%) and 14/52 (27%) cases. For 3/65 (5%) mAbs, the findings were equivocal. Of mAbs with developmental toxicity findings (10/65, 15%), the WoE correctly anticipated pharmacology based reproductive toxicity without any false negative predictions in 9/10 (90%) cases, and in the remaining case (1/10, 10%) an in vivo study was recommended due to equivocal WoE outcome. Therefore, this WoE approach could characterize presence and absence of developmental risk without animal studies. The current WoE could have reduced the need for developmental toxicity studies by 42% without loss of important patient information in the label., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Radioactivity in coastal sediments in northern Vietnam was examined using data from five sediment cores to assess radioactivity concentrations and radiation risk indices. Radiation risk indices included radium equivalent activity (Ra eq ), the absorbed dose rate (ADR), the annual effective dose equivalent (AEDE), the activity utilization index (AUI), the external hazard index (H ex ), the representative level gamma index (I γr ), and the annual gonadal effective dose rate (AGDE). The radioactivity concentrations of 40 K, 232 Th, 226 Ra, 238 U, and 137 Cs were 567, 56.1, 35.1, 37.9, and 1.18 Bq/kg, respectively. The average concentrations of 40 K, 232 Th, 226 Ra, and 238 U were above the global average at five sites, except for 137 Cs, which was low. The Ra eq , H ex , and AUI indices were below the recommended values, while the AEDE, ADR, AGDE, and I γr indices were above the recommended values. Moreover, 40 K, 232 Th, 226 Ra, and 238 U had significant impacts on the radiation hazard indices Ra eq , ADR, AEDE, I γr , AUI, H ex , and AGDE. There are three coastal sediment groups on the northern coast of Vietnam: Group 1 has a higher radioactivity and radiation risk index than Group 2 but a lower value than Group 3. Group 3 had the highest radioactivity and radiation risk index. The values of 40 K, 232 Th, 226 Ra, and 238 U and the ADR, AUI, I γr , and AGDE indices in the sediment threaten the living environment.

Background: While hyperuricemia has been correlated with cardiovascular (CV) diseases, further evidence is required to evaluate the implications of stable serum uric acid (sUA) levels, especially concerning low sUA. This study aimed to investigate prolonged stable sUA levels and CV events/mortality., Methods: We conducted a retrospective cohort study at a medical center using electronic medical records linked with the national claims database. Patients with at least two sUA measurements, with intervals ranging from 6 months to 4 years, were included. The mean of the first two eligible sUA measurements were analyzed, stratified by sex. Outcomes of interest comprised major adverse cardiovascular events (MACE), heart failure hospitalization, CV and all-cause mortality., Results: This study included 33,096 patients (follow-up: men 6.6 years, women 6.4 years). After multivariable adjustment, cubic spline models showed that long-term high sUA levels were consistently associated with a higher risk of MACE, heart failure hospitalization, CV and all-cause mortality. A U-shaped association was observed between sUA levels and all-cause mortality in both sexes and between sUA levels and CV mortality in women. The impact of sUA, especially lower levels, on CV events and mortality was more pronounced in women than in men., Conclusion: Long-term high sUA levels are consistently associated with increased risk of CV events and mortality. A U-shaped association between sUA levels and all-cause mortality was observed in both men and women and was pronounced in women. The findings underscore the importance of considering sUA levels, especially in women, when assessing CV risk., (© 2024 The Authors.)

Advanced therapy medicinal products (ATMPs) are among the most complex pharmaceuticals with high human specificity. Species differences severely limit the clinical relevance of in vivo data. We conducted interviews with stakeholders involved in ATMP development about their perspective on the use of in vivo studies, the perceived hurdles and associated potential solutions regarding non-clinical development of ATMPs. In total, 17 stakeholders from 9 different countries were interviewed. A workshop was held with key stakeholders to further discuss major topics identified from the interviews. Conducting in vivo studies remains the status quo for ATMPs development. The hurdles identified included determining the amount of information required before clinical entry and effective use of limited human samples to understand a treatment or for clinical monitoring. A number of key points defined the need for future in vivo studies as well as improved application and implementation of New Approach Methodology (NAM)-based approach for products within a well-known modality or technology platform. These included data transparency, understanding of the added value of in vivo studies, and continuous advancement, evaluation, and qualification of NAMs. Based on the outcome of the discussions, a roadmap with practical steps towards a human-centric safety assessment of ATMPs was established., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Human platelet lysates (HPLs) from allogeneic platelet concentrates (PCs) are biomaterials, which are rich in various trophic factors, increasingly used in regenerative medicine and biotherapy. Understanding how preparation methods influence the HPL protein profile, biological function, and clinical outcomes is crucial. Our study sheds light on the proteomes and functionality of different HPLs, with the aim of advancing their scientifically grounded clinical applications. To achieve this, PCs suspended in plasma underwent three distinct processing methods, resulting in seven HPL types. We used three characterization techniques: label-free proteomics and tandem mass tag (TMT)-based quantitative proteomics, both before and after the immunodepletion of abundant plasma proteins. Bioinformatic tools assessed the proteome, and western blotting validated our quantitative proteomics data. Subsequent pre-clinical studies with fluorescent labeling and label-free proteomics were used as a proof of concept for brain diffusion. Our findings revealed 1441 proteins detected using the label-free method, 952 proteins from the TMT experiment before and after depletion, and 1114 proteins from the subsequent TMT experiment on depleted HPLs. Most detected proteins were cytoplasmic, playing key roles in catalysis, hemostasis, and immune responses. Notably, the processing methodologies significantly influenced HPL compositions, their canonical pathways, and, consequently, their functionality. Each HPL exhibited specific abundant proteins, providing valuable insight for tailored clinical applications. Immunoblotting results for selected proteins corroborated our quantitative proteomics data. The diffusion and differential effects to the hippocampus of a neuroprotective HPL administered intranasally to mice were demonstrated. This proteomics study advances our understanding of HPLs, suggesting ways to standardize and customize their production for better clinical efficacy in regenerative medicine and biotherapy. Proteomic analyses also offered objective evidence that HPPL, upon intranasal delivery, not only effectively diffuses to the hippocampus but also alters protein expression in mice, bolstering its potential as a treatment for memory impairments., Competing Interests: T.B. is one co-founder of Invenis Biotherapies and is listed as the inventor on patent applications owned by Taipei Medical University and University of Lille. The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Author(s).)

Electric-arc-furnace (EAF) steelmaking uses scrap iron and steel as raw materials. Scrap iron and steel originate from complex sources and may contain heavy metal components which can leach into the environment over time due to wear-and-tear. A by-product of the EAF steelmaking process is oxidizing slag, and approximately 1.2 million metric tons is produced every year in Taiwan alone. This study investigated substitution of natural aggregates with oxidizing slag in dense-graded asphalt concrete. We evaluated the water resistance and asphalt film thickness of the oxidizing slag substituted asphalt concrete and further explored the performance of oxidizing slag as paving material. We determined the dissolved and total amounts of heavy metals in the oxidizing slag, comparing these results with current regulatory controls to assess the environmental compatibility of the oxidizing slag. We found that due to the complicated sources of oxidizing slag, the basic properties should be analyzed on a batch-to-batch basis. Furthermore, we recommend trial mixing before upscaling the production of oxidizing slag substituted dense-graded asphalt concrete to confirm the mixing time required to achieve uniformity. The results also show that in comparison to natural aggregates used in asphalt concrete, oxidizing slag exhibits superior performance in terms of increased asphalt film thickness and improved water resistance. Furthermore, oxidizing slag as an aggregate material was associated with decreased heavy metal leaching and reduced environmental pollution. The results of the toxicity characteristic leaching procedure (TCLP) met regulatory requirements. However, the microwave-assisted aqua-regia digestion procedure showed heavy metal concentrations exceeding the monitoring standards for food crops. Considering environmental compatibility, it is recommended that controlling the total amount of heavy metals in oxidizing slag should be included in regulatory requirements. Furthermore, we should prohibit the use of materials such as oxidizing slag and other steel furnace slag in the roadways adjacent to edible crop farmlands., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)