Female reproductive toxicity of chronic exposure to perfluorohexane sulfonate (PFHxS) under the confounding factor of dietary protein deficiency.

Pharmacomicrobiomics in blood cancers: How the gut microbiome and its metabolites shape drug efficacy and toxicity.

Antibiotic allergies remain one of the most frequently documented drug allergies in clinical records. It is well established that only a small proportion-estimated at 5% to 10%-represents true immune-mediated hypersensitivity. Mislabelling can contribute to the development of antimicrobial resistance via prescription of suboptimal antimicrobial therapy (i.e. unnecessary avoidance of first-line antibiotics), increased use of broad-spectrum agents, and complications such as drug toxicity. This guideline, developed by the European Society of Clinical Microbiology and Infectious Diseases, provides evidence-based recommendations for the clinical evaluation and management of patients with reported antibiotic allergies. It is aimed at nonallergist clinicians and seeks to harmonize practice across healthcare settings in Europe and beyond. The guideline was developed by a multidisciplinary panel of 16 experts in infectious diseases, allergy, pharmacy, paediatrics and clinical microbiology, following a modified GRADE-ADOLOPMENT process. Systematic searches were conducted in PubMed and the Trip Database (2015-2023) to identify relevant guidelines, complemented by an additional systematic search for primary studies (2021-2024). The included guidelines were assessed using the AGREE Global Rating Scale. Four existing guidelines, from 2022 and 2023, met methodological quality criteria and were included. Key questions were identified and prioritized by the panel, and relevant data were extracted using piloted Evidence to Decision framework sheets. The panel developed recommendations by adopting, adapting or formulating new recommendations, through an iterative work-up and consensus process. All recommendations were finalized through panel discussion and formal voting, with consensus defined as agreement by ≥ 80% of members. The guideline recommends a structured clinical assessment to evaluate a reported antibiotic allergy, taking into consideration the characteristics of the index reaction. Where the clinical history suggests a very low or low likelihood of true allergy, direct delabelling or performing a controlled drug challenge test is appropriate. By supporting allergy evaluation and prudent prescribing practices, the recommendations aim to improve individual patient outcomes and reinforce antimicrobial stewardship goals.

Gamabufotalin impedes NSCLC progression by inhibiting the mitochondrial factor CHCHD2 and modulating XAF1 expression.

A decoction-inspired genetic algorithm and PPO reinforcement learning for intelligent molecular discovery: Anti-colorectal cancer candidates from the tiao-pi AnChang formula.

The clinical success of small-molecule drugs in treating pancreatic and prostate cancer patients has been both promising and challenging. Whereas patients with advanced-stage tumours have significant initial responses to chemotherapy, many have experienced rapid resistance, metastasis and recurrence after curative-intent surgery. Traditional tubulin inhibitors are widely used in cancer treatment, but their effectiveness is often limited by drug resistance and toxicity. SB-216, a novel colchicine-binding site inhibitor (CBSI), has been reported to demonstrate potential efficacy in overcoming paclitaxel (PTX) resistance in a melanoma xenograft model (A375/TxR) and inhibiting spontaneous metastasis. We evaluated SB-216 as a therapeutic option for advanced malignancies, specifically castration-resistant prostate cancer (CRPC) and pancreatic ductal adenocarcinoma (PDAC). We conducted preclinical evaluations of SB-216 in CRPC parental and taxane-resistant lines. Additionally, we investigated the effects of SB-216 on PDAC cells, xenograft models and patient-derived models. In vitro, SB-216 potently induces G2/M phase cell cycle arrest, inhibits cell proliferation, colony formation and cell migration in a concentration-dependent manner. In vivo, SB-216 significantly attenuates tumour growth in prostate cancer xenograft models, overcomes PTX resistance and confers a survival benefit at a dose of 2 mg kg-1 without affecting body weight. SB-216 also inhibits the growth of PDAC xenograft tumours and the growth of patient-derived cells and organoids. Our findings suggest that SB-216 is a promising candidate as a new generation of anti-mitotic agents for advanced cancer, and further exploration in combination with other agents is warranted.

A nitrogen-rich Eu-MOF for ultrasensitive fluorescence detection of 6-mercaptopurine and 6-thioguanine.

Sodium stibogluconate is an effective but toxic Sb-containing antileishmanial drug. Despite having been in clinical use for over half a century, the chemical structure of this small-molecule drug remains unknown. Historically, the drug has been thought to comprise an intractable mixture of interconverting species. We report here nuclear magnetic resonance (NMR) spectroscopic experiments that provide the first evidence that the reaction between gluconate and [Sb(OH)6]- produces primarily one molecular species. Multidimensional experiments allow the NMR resonances of this species to be fully assigned. Further experiments on authentic samples and clinical preparations of sodium stibogluconate confirm that the primary product of the reaction of gluconate and [Sb(OH)6]- is the predominant antimony-containing component of the drug. The thermodynamic stability of this predominant species was assessed using a combination of 1H and 121Sb NMR spectroscopic measurements, which afforded a value of K=1006M-1 for its formation from gluconate and [Sb(OH)6]-.

Alginates are a family of linear anionic polysaccharides produced by brown algae and some bacteria and consist of 1→4 linked β-d-mannuronic acid (M), and its C5-epimer α-l-guluronic acid (G). Research has shown that oligoguluronates possess biofilm disruption properties, which combined with their high water-solubility and low toxicity, represent ideal candidates for creating novel bifunctional antifungal compounds. The progressive increase in antifungal resistance is a major global human health threat. This intrinsic resistance illustrates the need to develop improved antifungal drugs with greater efficacy against antifungal growth, while also reducing the potential for drug toxicity, resistance and tolerance. Amphotericin B is a polyene macrolide antifungal with broad specificity but has poor water solubility and is limited by infusion-related reactions and nephrotoxicity. In this work, we developed two types of Alginate-Amphotericin B conjugates with low molecular weight oligoguluronates conjugated through the reducing end. Conjugation to amphotericin B was through the carboxylic acid group or the amine group. The Alginate-Amphotericin B conjugates have reduced toxicity towards liver cells (HepG2) and kidney cells (LLC-PK1) and highly improved solubility characteristics, while maintaining anti-fungal activity.

Transplantation is a life-saving therapy but carries significant risks, including rejection, graft-versus-host disease, infection, and malignancy, which can lead to graft failure and death. These complications arise from the interaction between the recipient's immune system and the transplanted organ, requiring long-term toxic drugs to prevent immune injury. Traditional genetic pre-transplant assessment focuses on ABO and 11 human leukocyte antigen (HLA) genes, but advancing technologies now allow for the assessment of many more genes relevant to transplant success. Using Oxford Nanopore Technology's (ONT) adaptive sampling approach, we have built a comprehensive proof-of-principle test to preemptively profile blood group and HLA phenotypes at the DNA sequence and methylation level. This test does not require preamplification, enrichment or enzymatic conversion, and can be easily adapted to enrich up to 10% of the human genome, including the complete HLA locus (5.5Mb) and all currently listed International Society of Blood Transfusion (ISBT) blood group genes. This rapid all-in-one test currently achieves up to 370x (median 250x) region of interest coverage at a 4-day turnaround and a data quality that is suitable for blood group and HLA genotyping, which matched or outperformed gold standard assays. As a field, we have dramatically reduced early post-transplant immune injury using molecular diagnostics and structural biology. Here, we demonstrate proof-of-concept of a personalized transplant risk assessment, which can be adapted to profile additional genes or genomic regions within minutes and yields multi-genic typing data at a 4-day turnaround. This approach represents the next step in refining precision medicine, improving patient outcomes, reducing healthcare costs, and enhancing life quality for transplant recipients.

Dihydropyridine calcium channel blockers are commonly prescribed to treat hypertension. In overdose they can induce cardiovascular collapse and multiorgan dysfunction with very lethal outcomes. Modern resin hemoadsorption devices can be useful for enhancing the elimination of these drugs in refractory cases. The authors present the case of a Caucasian male in his 70s who intentionally ingested 150mg of amlodipine and was subsequently admitted to the intensive care unit with refractory vasoplegic shock. Drug clearance using hemoadsorption was attempted via the use of a styrene resin filter (Jafron HA230) with concurrent hemodynamic stabilization and successful patient outcome. This case highlights a possible emerging role of HA therapy in mitigating toxic effects of protein and lipid-bound toxins in severe poisoning. Further research is essential to define standardized guidelines for its use in managing drug toxicity.

The toxic drug supply and overdose epidemic in North America has led to deaths, reduced quality of life, and emotional burdens, especially for harm reduction workers who experience stress from grief and trauma. This study aims to evaluate the benefits and harms of working in overdose prevention hotlines and to identify strategies to reduce stress and trauma for lived-experience operators in these settings. We conducted a sequential mixed-methods study comprising 11 qualitative interviews and a survey with 15 operators and volunteers with Canada's National Overdose Response Service (NORS). The study explored operator challenges, compassion fatigue, and quality of life with previously validated quality of life surveys (ProQOL), while also assessing the perceived effectiveness of the hotline in reducing overdose deaths, mental health impacts, and emergency medical service call-outs. From our qualitative interviews, 3 major themes emerged including (1) The duality of remote overdose response work including: tension between flexibility, accessibility, and supportive team dynamics, with ethical challenges, lack of physical presence, and complex client interactions. (2) Emotional burden and stress in a remote context and: (3) Meaning, purpose, and peer connection as drivers of fulfilment. Overall, most participants ranked their burnout levels as low (13/15 (86.6%)), compassion satisfaction as high (13/15 (86.6%)), and secondary traumatic stress as low (14/15 (93.3%)). This study reveals that work with overdose prevention hotlines is both rewarding and sustainable, with operators experiencing low burnout, low secondary traumatic stress, and high compassion satisfaction. The flexibility, strong team support, and inclusive approach of NORS make remote harm reduction a viable model for aiding marginalized individuals effectively in the overdose crisis.

BackgroundThe toxic unregulated drug supply in North America continues to produce high rates of drug deaths. In response, several harm reduction interventions have been introduced and/or expanded, including take-home naloxone (THN). Estimating the impact is challenged by a lack of complete reporting data.ObjectiveThe aim of this study was to estimate the impact of interventions on drug deaths in British Columbia from January 2019 to September 2024.MethodsWe extended on a Bayesian hierarchical Markov chain model of drug poisoning events including interventions for overdose prevention sites and opioid agonist treatment. The extended model uses the reported number of THN kits used and distributed and all kits shipped to sites. These data are incorporated into the likelihood to estimate THN kit use during an opioid poisoning event by region and site type. Simulation studies evaluated the model's performance.ResultsThe estimated probability of THN kit use during an opioid poisoning event was 42.98% (95% credible interval [CrI]: 41.12-44.84) for kits distributed from community sites and 13.41% (95% CrI: 12.57-14.40) for overdose prevention sites. Correctional centers, pharmacy, and emergency department THN kits all had the lowest probability of use at 0.12% (95% CrI: 0.11-0.13), 1.04% (95% CrI: 0.96-1.13), and 0.65% (95% CrI: 0.60-0.71), respectively. The combined rate of deaths averted was 1,294 (95% CrI: 1,138-1,438) per 100,000 persons who inject drugs, which represents 78% (95% CrI: 76-80) of potential deaths.ConclusionDespite the increasing toxicity of the illegal drug supply, harm reduction interventions including THN have had a large impact on the number of drug deaths. Estimates of the impact of THN based on reported use alone would greatly underestimate the total impact.HighlightsWe developed a novel Bayesian hierarchical model to estimate take-home naloxone (THN) kit use during opioid poisonings using incomplete but complementary program and surveillance data.The model provides site-specific and regional estimates of kit use, highlighting significant differences by site type and geography.Simulation studies show the model can estimate the probability of THN kit use under realistic data limitations, supporting its use in policy evaluation.Public health decision makers can use this method to better assess and optimize harm reduction programs when direct usage data are scarce.

Platinum-based anticancer agents are extensively used in clinical chemotherapy but often cause severe nephrotoxicity, which limits their clinical utility. To address this critical challenge, we designed and validated two benzothiazole-derived near-infrared dual-channel fluorescent probes, BTXPI and BTXVI, featuring an innovative "dual-lock" mechanism. These probes adopt a channel-selective dual-lock mechanism: the red channel is a single-lock mode specifically activated by high viscosity, while the green channel is a strict dual-lock mode triggered only by the coexistence of bisulfite (HSO3-) and high viscosity. These probes enable the simultaneous quantification of cellular microenvironmental viscosity and HSO3- concentration─two key biomarkers associated with cisplatin (DDP)-induced acute kidney injury (AKI). By comparing imaging data from confocal microscopy and super-resolution structured illumination microscopy (SIM), we further highlighted the intrinsic limitations of conventional confocal imaging in analyzing subcellular colocalization events, as it may lead to false-positive results due to diffraction limits. Using these probes, we systematically elucidated the differential nephrotoxicity of three platinum-based drugs (cisplatin, carboplatin, and oxaliplatin) in murine models, identified DDP as the most nephrotoxic agent, and evaluated the efficacy of four renoprotective agents (l-carnitine, N-acetylcysteine, methylprednisolone, and astragaloside IV). Notably, the combination of DDP with these renoprotective agents effectively alleviated renal injury without compromising the antitumor potency of DDP. Our dual-lock probes thus provide a robust set of chemical tools for deciphering the dynamic fluctuations of multiple pathophysiologically relevant parameters in complex biological systems, assessing drug toxicity, and optimizing combination therapeutic regimens for safe and effective cancer chemotherapy.

Current preclinical models face challenges in recapitulating organ-level interactions affecting drug safety, and there has been little investigation into drug toxicity and related DILI. We present a pump-less gut-liver-on-chip, enabling integrated analysis of drug exposure-toxicity relationships and inter-organ pharmacological interactions. The platform incorporates a polarized intestinal barrier with a quadruple-cell co-cultured liver spheroid. Through simulation and comparative evaluation of oral versus systemic drug administration, we demonstrated the critical role of the intestinal barrier in modulating drug exposure, corresponding toxic responses and first-pass effects. Temporal profiling revealed progressive hepatic injury mechanisms involving mitochondrial dysfunction and activation of the apoptotic pathway. Pharmacological inhibition of cytochrome P450 attenuated victim-induced oxidative stress without affecting hepatic drug exposure, confirming enzyme-related bioactivation as the toxicity mechanism. Furthermore, transporter-mediated drug-drug interactions were functionally replicated, with perpetrator compounds altering substrate pharmacokinetics through competitive efflux inhibition and modified intestinal disposition. The ability of the platform to monitor drug exposure-toxicity relationships and drug-drug interactions was validated using combinations of perpetrator and victim drugs. This integrated approach advances applications of organ-on-chips by establishing causal relationships between drug exposure and toxicity, resolving the progression of temporal toxicity, and modeling drug-drug interactions, which are critical factors in predicting clinical hepatotoxicity and complex pharmacokinetic interactions.

Utilizing nanotechnology to deliver multiple anticancer drugs holds the potential to enhance the anticancer effect. However, most drug carriers have limitations such as their own toxicity and low drug loading rate. Besides, depleting the excessive glutathione (GSH) in tumor cells not only induces ferroptosis in cancer cells but also has the potential to enhance photodynamic therapy. Inspired by previous work, hydroxyl groups were introduced into the ferroptosis inducer cinnamaldehyde to enhance its hydrogen bond interaction with the photosensitizer chlorins e6, thereby constructing stable self-assembled nanodrugs in solution and naming them TC. The prepared nanodrugs possess high drug loading capacity and acidic-responsive release properties, enabling efficient accumulation in tumor tissues. The TC not only consumes GSH through 3, 4, 5-trihydroxycinnamic aldehyde and down-regulate glutathione peroxidase 4, but also generates reactive oxygen species under irradiation, thereby increasing the level of lipid peroxidation and causing cancer cell apoptosis as well as ferroptosis. Additionally, the immunogenic cell death caused by combined therapy releases tumor-associated antigens, enhances antitumor immune responses, and inhibits tumor growth and metastasis in vivo and in vitro experiments, with no obvious toxicity. This study offers a unique molecular assembly modification strategy for the construction of self-assembled nanoplatforms to advance the field of carrier-free nanodrug.

Fulminant disseminated tuberculosis (TB) presenting as Landouzy sepsis is rare but carries high mortality. When complicated by acute respiratory distress syndrome (ARDS) and multiorgan failure, evidence for optimal management, including extracorporeal membrane oxygenation (ECMO) and modified antituberculous regimens, remains limited. We describe a 23-year-old man with miliary tuberculosis who developed Landouzy sepsis, ARDS, hepatic dysfunction, and refractory hypoxemia requiring veno-venous (VV) and subsequent veno-veno-venous (VVV) ECMO for six weeks. Standard anti-TB treatment for susceptible mycobacteria was withheld due to liver injury most likely related to antituberculous drug toxicity. Despite initial treatment with isoniazid, rifampicin, and ethambutol, rising bilirubin prompted rifampicin discontinuation and transition to an individualized regimen including ethambutol, isoniazid, levofloxacin, bedaquiline, and amikacin. Corticosteroid therapy was started for suspected secondary organizing pneumonia during persistent hypercapnic respiratory failure, followed by clinical improvement. The course was complicated by thrombocytopenia, pneumothorax, arrhythmia, plasma exchange-dependent hyperbilirubinemia, and amikacin-associated sensorineural hearing loss. Microbiological clearance was achieved, organ dysfunction progressively recovered, and first-line therapy was successfully reintroduced after stabilization. The patient was ultimately discharged without oxygen requirement and started a rehabilitation program. This case highlights that even life-threatening tuberculosis with multiorgan failure can be survivable. Early diagnosis, flexible adaptation of anti-TB therapy, and prolonged ECMO support within multidisciplinary care were key to clinical recovery.

Azo(bis)pyrazole-Ciprofloxacin Conjugates: Tuning Photopharmacological Performance Through Structural Engineering.

Exploration of the Anticancer Efficacy and In Silico Drug Screening Study of Fe(II) and Fe(III) Complexes of Schiff Base and Phenanthroline Ligand.

Conventional chemotherapy for cancer treatment suffers from three major problems which include systemic toxicity and poor drug absorption and its inability to target specific tumors. Researchers developed nanoparticle-based drug delivery systems (NDDS) to solve these problems. The system achieves controlled drug release and enhanced drug absorption through the EPR mechanism and delivers drugs directly to specific cells.The researchers conducted a study to develop and test PLGA-based nanoparticles that carry docetaxel (DTX) as a breast cancer treatment, which they designed to use folic acid (FA) for receptor-based active drug delivery. The researchers produced DTX-loaded PLGA nanoparticles through the nanoprecipitation method, which they analyzed to determine their particle size and zeta potential and polydispersity index (PDI) and encapsulation efficiency (EE%) and morphology through dynamic light scattering (DLS) and transmission electron microscopy (TEM) analysis. The researchers tested the drug release of the sample by using phosphate-buffered saline (PBS) at two different pH values which included 7.4 and 5.0. The researchers used the MTT assay to study cytotoxicity effects on MCF-7 breast cancer cells and L929 normal fibroblast cells, while they tracked cellular uptake through confocal microscopy with rhodamine B-labeled nanoparticles. The optimized DTX-FA-PLGA-NPs showed a particle size of 182.4 nanometers with a standard deviation of 6.3 nanometers and a zeta potential measurement of −28.7 millivolts with a standard deviation of 1.4 millivolts and a PDI measurement of 0.18 with a standard deviation of 0.03 and an EE measurement of 87.6 with a standard deviation of 2.1 percent. The TEM analysis showed that the particles had a spherical shape and their surfaces appeared smooth. The invitro release profiles showed a dual phase pattern which started with an initial burst release of approximately 28 percent within four hours and continued until 85 percent of the substance was released after 72 hours with an increased release rate occurring at pH 5.0 which simulated the conditions found inside endosomes. The MTT assay showed that DTX-FA-PLGANPs had an IC50 value of 38.5 nM against MCF-7 cells which was significantly less than the IC50 value of free DTX which measured 112.3 nM and the IC50 value of non-targeted nanoparticles which measured 79.4 nM. The L929 cells showed no signs of cytotoxicity at all. The study demonstrated that FA-functionalized nanoparticles could be better internalized by MCF-7 cells which highly express folate receptors according to confocal microscopy results. The PLGA nanoparticles which have FA functionality show potential as a biocompatible delivery system that targets docetaxel to breast cancer cells while achieving better cancer cell killing effects and selective targeting abilities than both the free drug and the non-targeted drug delivery systems. The research findings require in-vivo studies to assess their potential for practical applications