Relevant Doses Research Articles

Evaluation of drug-drug interaction between rosuvastatin and tacrolimus and the risk of hepatic injury in rats.

Multimorbidity, therapeutic complexity, and polypharmacy, which greatly increases the risk of drug-drug interactions (DDIs) and adverse medical outcomes, have become important and growing challenges in clinical practice. Statins are frequently prescribed to manage post-transplant dyslipidemia and reduce overall cardiovascular risk in solid organ transplant recipients. This study aimed to determine whether rosuvastatin has significant DDIs with tacrolimus (the first-line immunosuppressant) and to evaluate the risk of hepatotoxicity associated with concomitant therapy. We first studied whether a rat model could be established to assess the magnitude of rosuvastatin-tacrolimus DDI. The liver function index and histopathological examination were performed to investigate the characteristics of hepatotoxicity in the presence and absence of DDI. The clinical DDI potential between rosuvastatin and tacrolimus was also explored. Single-dose intravenous administration of tacrolimus did not significantly affect the area under the plasma concentration-time curve (AUC0-∞), clearance (CL), and volume of distribution at steady-state (Vss) of rosuvastatin in rats, despite a 96.7% increase in the rosuvastatin maximum plasma concentration (P = 0.024). Multiple doses of intravenous tacrolimus had no effect on the systemic disposition of rosuvastatin, but significantly increased aspartate transaminase (AST) by 42.6% (P = 0.043). Multiple doses of intravenous tacrolimus and rosuvastatin significantly altered the disposition of rosuvastatin, reducing alanine aminotransferase(ALT) and AST by 38.3% (P = 0.040) and 31.6% (P = 0.019), respectively. Histological evaluation of the liver specimens revealed patterns of drug-induced liver injury in rats. At clinically relevant doses, tacrolimus was predicted to be unable to cause pharmacokinetic interactions with rosuvastatin through basic models. The concomitant administration of tacrolimus and rosuvastatin has a minor impact on rosuvastatin pharmacokinetics; however, mild hepatotoxicity has been observed in rats.

An investigation of the drug release kinetics of 3D-Printed two compartment Theophylline and Prednisolone tablets.

Pharmaceutical 3D printing (3DP) not only offers the possibility of dose personalization but also the co-administration of multiple active pharmaceutical ingredients (APIs) in one combination tablet. In this study, Theophylline (TPH) and Prednisolone (PSL) were printed as bi-tablets, which are single tablets with two distinct separate compartments. New findings show that the combination therapy of TPH with systemic corticosteroids shows a highly synergistic effect in the treatment of pulmonary diseases. For TPH, a drug with a narrow therapeutic window (NTW), precise sustained release requirements are mandatory, while PSL requires immediate drug release and is individually administered in doses specifically tied to the treatment progression. The study aims to understand the extent to which the combination of two tablet compartments influences the individual drug dissolution kinetics of the respective single compartments. Utilizing a full factorial statistical experimental design, various practically relevant doses were produced, investigated for their drug release, analyzed using different mathematical model fits, and compared with respective mono-tablets. The results show that the sustained drug release of TPH is not significantly influenced by the addition of a second compartment in relationship to respective doses. Individualization of bi-tablet doses while maintaining similar release profiles is possible with the given design setup, as release curves still show high similarity. In all tablet designs, PSL release occurred sufficiently fast, with the release rate correlating to the surface area-to-volume ratio (SA/V) as the main determining parameter.

NO-mediated DNA damage induced by polystyrene nanoparticles triggers program cell death in mesenchymal stem cells

Daily contact with considerable amounts of polystyrene nanoparticles (PSNPs) may cause harmful effects on the living organisms, through mechanisms that are not fully understood. The study aimed to evaluate the cytotoxic and genotoxic effects of PSNPs (size 200 nm and 40 nm) in mesenchymal stem cells (MSCs). In order to estimate cellular uptake and retention of nanoplastics, PSNP-treated cells have been analyzed by transmission electron microscopy. For assessing morphology and viability of MSCs after PSNP treatment at two environmentally relevant doses (0.47 and 4.7 μl/ml) for 24 hours, HE and Giemsa staining were performed. Annexin V‑FITC/PI assay was used to quantify PSNPs-mediated cell death. Genotoxicity of PSNPs was evaluated by Comet test. The capacity of PSNPs to trigger the production of free radicals in MSCs was also evaluated. TEM confirmed endocytosis of PSNPs. Decreased cell volume, nuclear hyperchromatism, edge aggregation, and formation of densely stained apoptotic bodies, indicated that PSNP-treated MSCs undergo apoptosis. The presented data showed that both concentration of PS particles significantly increased early apoptotic cell death in comparison to untreated cells. Moreover, both doses of PSNPs significantly increased the genetic damage index in MSCs in dose-dependent manner. In conclusion, PSNPs penetrate, accumulate and induce cytotoxic and genotoxic damage in MSCs.

Reciprocal and non-reciprocal effects of clinically relevant SETBP1 protein dosage changes.

Many genes in the human genome encode proteins that are dosage sensitive, meaning they require protein levels within a narrow range to properly execute function. To investigate if clinically relevant variation in protein levels impacts the same downstream pathways in human disease, we generated cell models of two SETBP1 syndromes: Schinzel-Giedion Syndrome (SGS) and SETBP1 haploinsufficiency disease (SHD), where SGS is caused by too much protein, and SHD is caused by not enough SETBP1. Using patient and sex-matched healthy first-degree relatives from both SGS and SHD SETBP1 cases, we assessed how SETBP1 protein dosage affects downstream pathways in human forebrain progenitor cells. We find that extremes of SETBP1 protein dose reciprocally influence important signalling molecules such as AKT, suggesting that the SETBP1 protein operates within a narrow dosage range and that extreme doses are detrimental. We identified SETBP1 nuclear bodies as interacting with the nuclear lamina and suggest that SETBP1 may organize higher order chromatin structure via links to the nuclear envelope. SETBP1 protein doses may exert significant influence on global gene expression patterns via these SETBP1 nuclear bodies. This work provides evidence for the importance of SETBP1 protein dose in human brain development, with implications for two neurodevelopmental disorders.

Sodium Butyrate: A Multifaceted Modulator in Colorectal Cancer Therapy

Background and Objectives: Sodium butyrate (NaB) is a potent modulator of cancer-related gene networks. However, its precise mechanisms of action and effects at elevated doses remain insufficiently explored. This study investigated the impact of NaB at physiologically relevant doses on key cellular metrics (viability, confluence, cell number, morphology, nuclear integrity) and a comprehensive set of apoptosis and proliferation regulators (including underexplored genes) in colorectal cancer (CRC) cells. Materials and Methods: Human HCT-116 cells were treated with increasing NaB concentrations (0–20 mM). Cell viability, confluence, number, morphology, and nuclear integrity were assessed using MTT and imaging assays. RT-PCR was used to determine changes in the expression of critical pro-apoptotic players (BAX, CASP3, PUMA, TP53), anti-apoptotic facilitators (BCL-2, MCL-1), cell division regulators (PCNA, Ki-67, CDKN1), and inflammation genes (NF-κB). Results: This study provides the first exploration of MCL-1 and PCNA modulation by NaB in the context of CRC and HCT-116 cells, offering significant translational insights. All treatments reduced cell viability, confluence, and number in a dose-dependent manner (p < 0.0001). Gene expression revealed dose-related increases in most pro-apoptotic markers (BAX, CASP3, PUMA; p < 0.001), and decreases for the other genes (p < 0.001). BAX emerged as the most responsive gene to NaB, while TP53 showed minimal sensitivity, supporting NaB’s effectiveness in p53-compromised phenotypes. Nuclear condensation and fragmentation at higher NaB doses confirmed apoptotic induction. Conclusions: NaB can modulate critical apoptotic and cell cycle genes, disrupt tumor cell proliferation, and overcome resistance mechanisms associated with anti-apoptotic regulators such as MCL-1. By targeting both short-term and long-term anti-apoptotic defenses, NaB shows promise as a preventive and therapeutic agent in CRC, particularly in high-risk phenotypes with compromised p53 functionality. These findings support its potential for integration into combination therapies or dietary interventions aimed at enhancing colonic butyrate levels.

Unseen Threats: The Long-term Impact of PET-Microplastics on Development of Male Reproductive Over a Lifetime.

The physical abrasion of plastics from simple everyday entered the food chain, with associated risks recently emphasized. Although many studies have reported the adverse effects of microplastics (MPs) on human, the reproductive implications of continuous exposure to physically abraded polyethylene terephthalate (PET)-MPs remain unexplored. Ingestion of physically abraded PET-MPs (size range: 50-100µm) in mice from 5 to 34 weeks of age at an annual intake relevant dose of MPs (5 mgweek-1) significantly impaired male reproductive function. Reductions in seminiferous tubule diameter and epithelial height are observed (p <0.0001), with 32.2% decrease in Leydig cells and 24.3% reduction in testosterone levels (p <0.05). The epididymis shows marked deterioration in all regions, with total sperm concentration significantly reduce from 17.0 × 10⁶ to 5.3 × 10⁶ (p <0.01) and decrease motility. Transcriptome analysis demonstrates downregulation of genes related with gonadotropin-releasing hormone secretion, testosterone biosynthesis, and Meiosin gene, which is for crucial spermatogenesis. Continuous ingestion of physically abraded PET-MPs from plastic bottles adversely affected testicular and epididymal functions, leading to hormonal imbalances and abnormal sperm production. These findings raise concerns about the impact of commonly used plastics on male reproductive development, highlighting potential risks for future generations.

Visualizing lipid nanoparticle trafficking for mRNA vaccine delivery in non-human primates.

mRNA delivered using lipid nanoparticles (LNPs) has become an important subunit vaccine modality, but mechanisms of action for mRNA vaccines remain incompletely understood. Here, we synthesized a metal chelator-lipid conjugate enabling positron emission tomography (PET) tracer labeling of LNP/mRNA vaccines for quantitative visualization of vaccine trafficking in live mice and non-human primates (NHPs). Following i.m. injection, we observed LNPs distributing through injected muscle tissue, simultaneous with rapid trafficking to draining lymph nodes (dLNs). Deltoid injection of LNPs mimicking human vaccine administration led to stochastic LNP delivery to 3 different sets of dLNs. LNP uptake in dLNs was confirmed by histology, and cellular analysis of tissues via flow cytometry identified antigen-presenting cells as the primary cell type responsible for early LNP uptake and mRNA translation. These results provide insights into the biodistribution of mRNA vaccines administered at clinically relevant doses, injection volumes, and injection sites in an important large animal model for vaccine development.

TAK-994 Mechanistic Investigation into Drug-Induced Liver Injury.

The frequency of drug-induced liver injury (DILI) in clinical trials remains a challenge for drug developers despite advances in human hepatotoxicity models and improvements in reducing liver-related attrition in preclinical species. TAK-994, an oral orexin receptor 2 agonist, was withdrawn from phase II clinical trials due to the appearance of severe DILI. Here, we investigate the likely mechanism of TAK-994 DILI in hepatic cell culture systems examined cytotoxicity, mitochondrial toxicity, impact on drug transporter proteins, and covalent binding. Hepatic liabilities were absent in rat and non-human primate safety studies, however, murine studies initiated during clinical trials revealed hepatic single-cell necrosis following cytochrome P450 induction at clinically relevant doses. Hepatic cell culture experiments uncovered wide margins to known mechanisms of intrinsic DILI, including cytotoxicity (>100× Cmax/IC50), mitochondrial toxicity (>100× Cmax/IC50), and bile salt efflux pump inhibition (>20× Css, avg/IC50). A potential covalent binding liability was uncovered with TAK-994 following hepatic metabolism consistent with idiosyncratic DILI and the delayed-onset clinical toxicity. Although idiosyncratic DILI is challenging to detect preclinically, reductions in total daily dose and covalent binding can reduce the covalent body binding burden and, subsequently, the clinical incidence of idiosyncratic DILI.

Intestinal Barrier Damage and Growth Retardation Caused by Exposure to Polystyrene Nanoplastics Through Lactation Milk in Developing Mice.

Microplastics, defined as plastic fragments smaller than 5 mm, degrade from larger pollutants, with nanoscale microplastic particles presenting significant biological interactions. This study investigates the toxic effects of polystyrene nanoplastics (PS-NPs) on juvenile mice, which were exposed through lactation milk and drinking water at concentrations of 0.01 mg/mL, 0.1 mg/mL, and 1 mg/mL. The results show that PS-NP exposure during lactation and juvenile periods caused delayed weight gain and impaired organ development, particularly in the liver and kidneys, without causing functional abnormalities or toxic injuries. The primary toxicity of PS-NPs was observed in the intestinal tract, including shortened villi, disrupted tight junctions, inhibited epithelial cell proliferation, and oxidative stress responses. These findings highlight the importance of evaluating the developmental toxicity of nanoplastics at environmentally relevant doses.

[Gly14]-Humanin ameliorates high glucose-induced endothelial senescence via SIRT6

High glucose (HG) induced endothelial senescence is related to endothelial dysfunction and cardiovascular complications in diabetic patients. Humanin, a member of mitochondrial derived peptides (MDPs), is thought to contribute to aging-related cardiovascular protection. The goal of the study is to explore the pathogenesis of HG-induced endothelial senescence and potential anti-senescent effects of Humanin. Human umbilical vein endothelial cells (HUVECs) were exposed to glucose to induce senescence, determined by β-galactosidase staining and the expressions of p21, p53, and p16. A clinically relevant dose of HG (15 mM, HG) induced endothelial senescence after 72 h incubation without elevated apoptosis. HG-induced senescence was attributed to the induction of reactive oxygen species (ROS) caused by SIRT6 downregulation, as ROS inhibitor N-acetyl cysteine blocked HG-induced senescence, while inactivation of SIRT6 increased ROS levels and promoted senescence. Strikingly. pretreatment with [Gly14]-Humanin (HNG) antagonized the downregulation of SIRT6 in response to HG and alleviated ROS production and cell senescence. HG-induced reduction of SIRT6 results in ROS overproduction and endothelial senescence. Humanin protects against HG-induced endothelial senescence via SIRT6. This study provides new directions for biological products related to Humanin to be a potential candidate for the prevention of vascular aging in diabetes.

Direct engulfment of synapses by overactivated microglia due to cadmium exposure and the protective role of Nrf2.

Cadmium (Cd), a notorious environmental pollutant, has been linked to neurological disorders, but the underlying mechanism remains elusive. We aimed to explore the role of microglia in Cd-induced synaptic damages at environmentally relevant doses and whether microglia directly engulf synaptic structures. Nrf2 is deeply implicated in the status of microglial activation; therefore, we also investigated whether it is involved in the above process. Nrf2 knockout mice and wild-type mice were used to explore prolonged Cd exposure-induced synaptic damages, learning-memory impairments, and microglial activation. We also created Nrf2 knockdown (KD) BV2 microglia to investigate the role of cell-specific Nrf2 in Cd-induced microglial activation. Finally, we developed co-culture systems of either Nrf2-KD or Scramble microglia and primary neurons or HT22 neurons to study the effects of Nrf2-regulated microglial activation on synaptic damages induced by Cd. Moreover, the direct engulfment, a main avenue in microglia that may be responsible for Cd-induced synaptic damages and regulated by Nrf2, was specifically studied in vivo and in vitro, along with underlying specific mechanisms. We found that Cd exposure induced microglial overactivation, and Cd-overactivated microglia impaired synapses through direct engulfment of synaptic structures, which may contribute to learning-memory impairments. Both fractalkine and complement pathways underlay microglial engulfment of synapses due to Cd exposure. Nrf2 was essential in preventing microglial overactivation and subsequent direct engulfment, thus preventing the consequent synaptic damages due to Cd exposure. Overall, the findings suggest that Cd-overactivated microglia damage synapses through direct engulfment, resulting from the activation of fractalkine and complement pathways.

Proposal to Reclassify SCCPs Under International Regulations on Ship Recycling to Enhance Environmental and Human Health Protection

Short-chain chlorinated paraffins (SCCPs) are ubiquitous environmental pollutants that have been detected in various human tissues and organs. Based on the results of numerous studies indicating that exposure to environmentally relevant doses could induce harm to humans and animals, they have been listed in Annex A (Elimination) of the Stockholm Convention on Persistent Organic Pollutants. They are also listed as hazardous materials likely to lead to significant adverse effects on human health or the environment by the International Convention for the Safe and Environmentally Sound Recycling of Ships (Hong Kong Convention) and the EU Ship Recycling Regulation (EU SRR). This paper analyzes recent literature on the environmental and human health impacts of SCCPs and the actual practice of shipbreaking to demonstrate that the current treatment of SCCPs under these two regulations does not provide sufficient protection for human health and the environment. Based on the presented data, it is proposed that SCCPs should be reclassified as materials whose installation or use is prohibited in shipyards, ship repair yards, and ships by the EU SRR and the Hong Kong Convention.

Dexmedetomidine suppresses glucose-stimulated insulin secretion in pancreatic β-cells.

Proper glycemic control is crucial for patient management in critical care, including perioperative care, and can influence patient prognosis. Blood glucose concentration determines insulin secretion and sensitivity and affects the intricate balance between the glucose metabolism. Human and other animal studies have demonstrated that perioperative drugs, including volatile anesthetics and intravenous anesthetics, affect glucose-stimulated insulin secretion (GSIS). Dexmedetomidine (DEX) decreases insulin release and affects glucose metabolism; however, the specific mechanism underlying this phenomenon remains largely unknown. Thus, we investigated the effect and mechanism of DEX on insulin secretion using mouse and rat pancreatic β-cell-derived MIN6 and INS-1 cell lines and primary pancreatic β-cells/islets extracted from mice. The amount of insulin secreted into the culture medium was determined using an enzyme-linked immunosorbent assay. Cell viability, cytotoxicity, and electrophysiological effects were investigated. Clinically relevant doses of DEX suppressed GSIS in MIN6 cells, INS-1 cells, and pancreatic β-cells/islets. Furthermore, DEX suppressed insulin secretion facilitated by insulinotropic factors. There was no significant difference in oxygen consumption rate, intracellular ATP levels, or caspase-3/7 activity. Electrophysiological evaluation using the patch-clamp method showed that DEX did not affect ATP-sensitive potassium (KATP) channels, voltage-dependent potassium channels, or voltage-gated calcium channels. We demonstrated that clinically relevant doses of DEX significantly suppressed GSIS. These findings suggest that DEX inhibits a signaling pathway via α2-adrenoceptor or insulin vesicle exocytosis, resulting in GSIS suppression. Our results support the hypothesis that DEX suppresses insulin secretion and reveal some underlying mechanisms.

Environmentally-relevant doses of bisphenol A and S exposure in utero disrupt germ cell programming across generations resolved by single nucleus multi-omics.

Exposure to endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), disrupts reproduction across generations. Germ cell epigenetic alterations are proposed to bridge transgenerational reproductive defects resulting from EDCs. Previously, we have shown that prenatal exposure to environmentally relevant doses of BPA or its substitute, BPS, caused transgenerationally maintained reproductive impairments associated with neonatal spermatogonial epigenetic changes in male mice. While epigenetic alterations in germ cells can lead to transgenerational phenotypic variations, the mechanisms sustaining these changes across generations remain unclear. This study aimed to systematically elucidate the mechanism of transgenerational inherence by prenatal BPA and BPS exposure in the murine germline from F1 to F3 generations at both transcriptomic and epigenetic levels. BPA or BPS with doses of 0 (vehicle control), 0.5, 50, or 1000 µg/kg/b.w./day was orally administered to pregnant CD-1 females (F0) from gestational day 7 to birth. Sperm counts and motility were examined in F1, F2, and F3 adult males. THY1 + germ cells on postnatal day 6 from F1, F2, and F3 males at a dose of 50 µg/kg/b.w./day were used for analysis by single-nucleus (sn) multi-omics (paired snRNA-seq and snATAC-seq on the same nucleus). Prenatal exposure to BPA and BPS with 0.5, 50, and 1000 µg/kg/b.w./day reduced sperm counts in mice across F1 to F3 generations. In the F1 neonatal germ cells, ancestral BPA or BPS exposure with 50 µg/kg/b.w./day resulted in increased differentially expressed genes (DEGs) associated with spermatogonial differentiation. It also disrupted the balance between maintaining the undifferentiated and differentiating spermatogonial populations. Differentially accessible peaks (DAPs) by snATAC-seq were primarily located in the promoter regions, with elevated activity of key transcription factors, including SP1, SP4, and DMRT1. Throughout F1-F3 generations, biological processes related to mitosis/meiosis and metabolic pathways were substantially up-regulated in BPA-or BPS-exposed groups. While the quantities of DEGs and DAPs were similar in F1 and F2 spermatogonia, with both showing a significant reduction in F3. Notably, approximately 80% of DAPs in F1 and F2 spermatogonia overlapped with histone post-translational modifications linked to transcription activation, such as H3K4me1/2/3 and H3K27ac. Although BPA exerted more potent effects on gene expression in F1 spermatogonia, BPS induced longer-lasting effects on spermatogonial differentiation across F1 to F3 males. Interestingly, DMRT1 motif activity was persistently elevated across all three generations following ancestral BPA or BPS exposure. Our work provides the first systematic analyses for understanding the transgenerational dynamics of gene expression and chromatin landscape following prenatal exposure to BPA or BPS in neonatal spermatogonia. These results suggest that prenatal exposure to environmentally relevant doses of BPA or BPS alters chromatin accessibility and transcription factor motif activities, consequently contributing to disrupted transcriptional levels in neonatal germ cells, and some are sustained to F3 generations, ultimately leading to the reduction of sperm counts in adults.

P94 REX-7117 is a highly potent and selective oral STAT3 inhibitor that has demonstrated potential efficacy and safety differentiation versus JAK/TYK2 targeting in preclinical models of psoriasis

Abstract Inhibition of key cytokine pathways, including IL-23 and IL-17, has translated into transformative efficacy in plaque psoriasis, psoriatic arthritis and other inflammatory diseases. There is a strong unmet need to develop oral medicines which match the efficacy of biologics. Additionally, current small molecule JAK/TYK2 inhibitors are associated with on-target safety signals, including opportunistic infections and dysregulated haematologic homeostasis (anaemia, thrombocytopenia). Oral selective STAT3 inhibitors represent an opportunity to target psoriatic pathogenesis by inhibiting clinically validated inflammatory mediators, such as IL-23 and IL-6 cytokines. The STAT3 SH2 domain mediates both binding to the cytokine receptor and transcriptional activity, and therefore is an attractive therapeutic target. Recludix has developed an innovative and proprietary SH2 domain platform that has enabled the discovery of a new class of small molecule inhibitors of these previously undruggable protein domains. REX-7117 is the first orally available, reversible, SH2 domain-targeting STAT3 inhibitor. REX-7117 demonstrates low nanomolar potency in biochemical and primary human cellular assays, is highly selective across the SH2 family, including other STAT proteins, and inhibits IL-6 and IL-23 driven Th17 cell function. Unlike JAK1/2 and TYK2 inhibitors, REX-7117 does not impair broader immune responses, such as Th1 cell activity, innate interferon-dependent anti-viral immunity, or growth factor signalling critical for haematologic homeostasis. In dogs and mice, REX-7117 achieves deep, durable, and selective STAT3 inhibition at clinically relevant oral doses and exhibits comparable efficacy to an IL-17 antibody in rodent models of plaque psoriasis. Selective STAT3 inhibition has the potential to combine the efficacy of clinically validated biologics with the convenience of oral administration, while avoiding known safety concerns observed with the broader activity of JAK and TYK2 inhibitors.

Repurposing of lonafarnib as a treatment for SARS-CoV-2 infection.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes Coronavirus disease 2019 (COVID-19), has emerged as a global pandemic pathogen with high mortality. While treatments have been developed to reduce morbidity and mortality of COVID-19, more antivirals with broad-spectrum activities are still needed. Here we identified lonafarnib (LNF), a Food and Drug Administration (FDA)-approved drug inhibitor of cellular farnesyltransferase (FTase), as an effective anti-SARS-CoV-2 agent. LNF inhibited SARS-CoV-2 infection and acted synergistically with known anti-SARS antivirals. LNF was equally active against diverse SARS-CoV-2 variants. Mechanistic studies suggested that LNF targeted multiple steps of viral life cycle. Using other structurally diverse FTase inhibitors and LNF-resistant FTase mutant, we demonstrated a key role of FTase in SARS-CoV-2 life cycle. To demonstrate in vivo efficacy, we infected SARS-CoV-2 susceptible humanized mice expressing human angiotensin-converting enzyme 2 (ACE2) and treated them with LNF. LNF at clinically relevant dose suppressed viral titer in the respiratory tract and improved pulmonary pathology and clinical parameters. Our study demonstrated that LNF, an approved oral drug with excellent human safety data, is a promising antiviral against SARS-CoV-2 that warrants further clinical assessment for treatment of COVID-19 and potentially other viral infections.

Predicting cisplatin tolerability in older adults with head and neck cancer - Insights for improved chemoradiation outcomes.

Cumulative cisplatin doses of ≥ 200 mg/m2 improve survival in adults with head-and-neck squamous cell carcinoma (HNSCC) undergoing chemoradiation, but many older adults with HNSCC cannot receive this prognostically relevant dose due to toxicities. This study aims to develop predictive models to assess the likelihood of older adults with HNSCC receiving ≥ 200 mg/m2 cisplatin during chemoradiation. 366 patients from the SENIOR database, an international cohort of adults ≥ 65 years with HNSCC, received definitive chemoradiation with single-agent cisplatin and were analyzed. A Generalized Linear Model (GLM), Support Vector Machine (SVM), and Random Forest Model (RFM) were trained and compared for their performance in predicting a cumulative cisplatin dose of ≥ 200 mg/m2. 195 (53 %) patients achieved a cumulative cisplatin dose of ≥ 200 mg/m2. In the GLM, laryngeal carcinoma (β = 1.37, p = 0.01), tumoral p16 positivity (β = 0.69, p = 0.04), higher hemoglobin levels (β = 0.26, p = 0.002), elevated C-reactive protein (CRP) concentration (β = 0.02, p = 0.003), and increased estimated glomerular filtration rate (eGFR) (β = 0.02, p = 0.008) were associated with a higher probability of reaching ≥ 200 mg/m2 cisplatin. Hemoglobin, CRP, eGFR, and p16 status constituted the most important features in the SVM and RFM. AUC values for the GLM, SVM, and RFM were 0.70 (95 % CI, 0.67-0.73), 0.71 (95 % CI, 0.68-0.73), and 0.73 (95 % CI, 0.71-0.75), respectively. We developed predictive models to support clinicians in identifying older adults with HNSCC capable of tolerating ≥ 200 mg/m2 cumulative cisplatin during chemoradiation. Once validated, these models could improve personalized treatments and enhance shared decision-making in older adults with HNSCC.

Lowering the affinity of single-chain monovalent BBB shuttle scFc-scFv8D3 prolongs its half-life and increases brain concentration

Monoclonal antibody therapeutics is a massively growing field. Progress in providing monoclonal antibody therapeutics to treat brain disorders is complicated, due to the impermeability of the blood-brain barrier (BBB) to large macromolecular structures. To date, the most successful approach for delivering antibody therapeutics to the brain is by targeting the transferrin receptor (TfR) using anti-TfR BBB shuttles, with the 8D3 antibody being one of the most extensively studied in the field. The strategy of fine-tuning TfR binding affinity has shown promise, with previous results showing an improved brain delivery of bivalent 8D3-BBB constructs. In the current study, a fine-tuning TfR affinity strategy has been employed to improve single-chain variable fragment (scFv) 8D3 (scFv8D3) affinity mutants. Initially, in silico protein-protein docking analysis was performed to identify amino acids (AAs) likely to contribute to 8D3s TfR binding affinity. Mutating the identified AAs resulted in decreased TfR binding affinity, increased blood half-life and increased brain concentration. As monovalent BBB shuttles are seemingly superior for delivering antibodies at therapeutically relevant doses, our findings and approach may be relevant for optimizing brain delivery.

The combined effect of environmentally relevant doses of glyphosate and high temperature: An integrated and multibiomarker approach to delineate redox status and behavior in Danio rerio.

Glyphosate, a pesticide commonly found in aquatic ecosystems, affects this habitat and nontarget organisms such as fish. The increase in water temperature, linked to factors such as climate change, poses a considerable threat. Despite extensive ecotoxicological research, we still do not know the real individual and specific consequences of continued exposure to glyphosate and high temperatures, simulating a scenario where the aquatic environment remains contaminated and temperatures continue to rise. Therefore, in this study, we examined the effects of exposure to environmentally relevant concentrations of glyphosate, active ingredient glyphosate (GAI), and glyphosate-based herbicide (GBH) in combination with high temperature (34°C) in adult zebrafish (Danio rerio). The fish were acclimated to 28 or 34°C for 96h. The exposure to 225 and 450μgL-1 (GBH or GAI) at 28 or 34°C for 7days. We analyzed behavioral endpoints (anxiety-like response, sociability, and aggressivity) and biochemical biomarkers of the brain and muscle (oxidative stress). Anxiety-like responses and decreased sociability were disrupted by the combination of glyphosate and high temperature. Furthermore, there is a decrease in Acetylcholinesterase activity in the brain, and an increase in Lipid Peroxidation, Protein Carbonylation, Acetylcholinesterase activity, and Glutathione S-Transferase activity in the muscle. These results demonstrated oxidative stress, anxiety-like behavior and decreased sociability caused by glyphosate and high temperature. We concluded that the combined effects of glyphosate and high temperature affected redox homeostasis and behavior, emphasizing that the field of glyphosate pollution should be carefully considered when evaluating the effects of climate change.

Antineoplastic therapy affects the in vitro phenotype and functionality of healthy human bone marrow-derived mesenchymal stromal cells

While antineoplastic therapies aim to specifically target cancer cells, they may also exert adverse effects on healthy tissues, like healthy hematopoietic stem and progenitor cells (HSPC), leading to hematotoxicity as a common side effect. Mesenchymal stromal cells (MSC) are a major component of the bone marrow (BM) microenvironment, regulating normal hematopoiesis, while their susceptibility to anticancer therapies and contribution to therapy-related hematotoxicity remains largely unexplored. To address this, we investigated the effects of etoposide, temozolomide, 5-azacitidine, and venetoclax on healthy BM-derived MSC functionality. Doses below therapeutic effects of etoposide (0.1–0.25 µM) inhibited cellular growth and induced cellular senescence in healthy MSC, accompanied by an increased mRNA expression of CDKN1A, decreased trilineage differentiation capacity, and insufficient hematopoietic support. Pharmacological doses of 5-azacitidine (2.5 µM) shifted MSC differentiation capacity by inhibiting osteogenic capacity but enhancing the chondrogenic lineage, as demonstrated by histochemical staining and on mRNA level. At the highest clinically relevant dose, neither venetoclax (40 nM) nor temozolomide (100 µM) exerted any effects on MSC but clearly inhibited cellular growth of cancer cell lines and primary healthy HSPC, pointing to damage to hematopoietic cells as a major driver of hematotoxicity of these two compounds. Our findings show that besides HSPC, also MSC are sensitive to certain antineoplastic agents, resulting in molecular and functional alterations that may contribute to therapy-related myelosuppression. Understanding these interactions could be helpful for the development of strategies to preserve BM MSC functionality during different kinds of anticancer therapies.