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Historically, human breast cancer has been modeled largely in vitro using long-established cell lines primarily in two-dimensional culture, but also in three-dimensional cultures of varying cellular and molecular complexities. A subset of cell line models has also been used in vivo as cell line-derived xenografts (CDX). While outstanding for conducting detailed molecular analysis of regulatory mechanisms that may function in vivo, results of drug response studies using long-established cell lines have largely failed to translate clinically. In an attempt to address this shortcoming, many laboratories have succeeded in developing clinically annotated patient-derived xenograft (PDX) models of human cancers, including breast, in a variety of host systems. While immunocompromised mice are the predominant host, the immunocompromised rat and pig, zebrafish, as well as the chicken egg chorioallantoic membrane (CAM) have also emerged as potential host platforms to help address perceived shortcomings of immunocompromised mice. With any modeling platform, the two main issues to be resolved are criteria for “credentialing” the models as valid models to represent human cancer, and utility with respect to the ability to generate clinically relevant translational research data. Such data are beginning to emerge, particularly with the activities of PDX consortia such as the NCI PDXNet Program, EuroPDX, and the International Breast Cancer Consortium, as well as a host of pharmaceutical companies and contract research organizations (CRO). This review focuses primarily on these important aspects of PDX-related research, with a focus on breast cancer.

Cardiac glycosides (CGs) have a long history of treating cardiac diseases. However, recent reports have suggested that CGs also possess anticancer and antiviral activities. The primary mechanism of action of these anticancer agents is by suppressing the Na+/k+-ATPase by decreasing the intracellular K+ and increasing the Na+ and Ca2+. Additionally, CGs were known to act as inhibitors of IL8 production, DNA topoisomerase I and II, anoikis prevention and suppression of several target genes responsible for the inhibition of cancer cell proliferation. Moreover, CGs were reported to be effective against several DNA and RNA viral species such as influenza, human cytomegalovirus, herpes simplex virus, coronavirus, tick-borne encephalitis (TBE) virus and Ebola virus. CGs were reported to suppress the HIV-1 gene expression, viral protein translation and alters viral pre-mRNA splicing to inhibit the viral replication. To date, four CGs (Anvirzel, UNBS1450, PBI05204 and digoxin) were in clinical trials for their anticancer activity. This review encapsulates the current knowledge about CGs as anticancer and antiviral drugs in isolation and in combination with some other drugs to enhance their efficiency. Further studies of this class of biomolecules are necessary to determine their possible inhibitory role in cancer and viral diseases.

β-lactam antibiotics (BLAs) are crucial molecules among antibacterial drugs, but the increasing emergence of resistance to them, developed by bacteria producing β-lactamase enzymes (BLEs), is becoming one of the major warnings to the global public health. Since only a small number of novel antibiotics are in development, a current clinical approach to limit this phenomenon consists of administering proper combinations of β-lactam antibiotics (BLAs) and β-lactamase inhibitors (BLEsIs). Unfortunately, while few clinically approved BLEsIs are capable of inhibiting most class-A and -C serine β-lactamases (SBLEs) and some carbapenemases of class D, they are unable to inhibit most part of the carbapenem hydrolyzing enzymes of class D and the worrying metallo-β-lactamases (MBLEs) of class B. Particularly, MBLEs are a set of enzymes that catalyzes the hydrolysis of a broad range of BLAs by a zinc-mediated mechanism, and currently no clinically available molecule capable of inhibiting MBLEs exists. Additionally, new types of alarming “superbugs”, were found to produce the New Delhi metallo-β-lactamases (NDMs) encoded by increasing variants of a plasmid-mediated gene capable of rapidly spreading among bacteria of the same species and even among different species. Particularly, NDM-1 possesses a flexible hydrolysis mechanism that inactivates all BLAs, except for aztreonam. The present review provides first an overview of existing BLAs and the most clinically relevant BLEs detected so far. Then, the BLEsIs and their most common associations with BLAs already clinically applied and those still in development are reviewed.

The specific pathogenesis underlying inflammatory bowel disease is complex, and it is even more difficult to decipher the pathophysiology to explain for the similarities and differences between two of its major subtypes, Crohn's disease and ulcerative colitis (UC). Animal models are indispensable to pry into mechanistic details that will facilitate better preclinical drug/therapy design to target specific components involved in the disease pathogenesis. This review focuses on common animal models that are particularly useful for the study of UC and its therapeutic strategy. Recent reports of the latest compounds, therapeutic strategies, and approaches tested on UC animal models are also discussed.

Conjugated polymer nanoparticles (CPNs) have emerged as advanced polymeric nanoplatforms in biomedical applications by virtue of extraordinary properties including high fluorescence brightness, large absorption coefficients of one and two-photons, and excellent photostability and colloidal stability in water and physiological medium. In addition, low cytotoxicity, easy functionalization, and the ability to modify CPN photochemical properties by the incorporation of dopants, convert them into excellent theranostic agents with multifunctionality for imaging and treatment. In this work, CPNs were designed and synthesized by incorporating a metal oxide magnetic core (Fe3O4 and NiFe2O4 nanoparticles, 5 nm) into their matrix during the nanoprecipitation method. This modification allowed the in vivo monitoring of nanoparticles in animal models using magnetic resonance imaging (MRI) and intravital fluorescence, techniques widely used for intracranial tumors evaluation. The modified CPNs were assessed in vivo in glioblastoma (GBM) bearing mice, both heterotopic and orthotopic developed models. Biodistribution studies were performed with MRI acquisitions and fluorescence images up to 24 h after the i.v. nanoparticles administration. The resulting IONP-doped CPNs were biocompatible in GBM tumor cells in vitro with an excellent cell incorporation depending on nanoparticle concentration exposure. IONP-doped CPNs were detected in tumor and excretory organs of the heterotopic GBM model after i.v. and i.t. injection. However, in the orthotopic GBM model, the size of the nanoparticles is probably hindering a higher effect on intratumorally T2-weighted images (T2WI) signals and T2 values. The photodynamic therapy (PDT)—cytotoxicity of CPNs was not either affected by the IONPs incorporation into the nanoparticles.

Preclinical and clinical xenotransplantation trials have shown that successful outcomes depend on a number of factors including the prevention of xenozoonoses. Preclinical trials involving pig kidneys and hearts transplanted into various non-human primates have revealed the potential impact of pig pathogens being present in the transplanted organ/tissue, mainly viruses. The concept of “designated pathogen-free donor animals” was developed to ensure elimination of pathogens during the breeding of donor animals to mitigate this occurrence. This is a challenging process as confirmation of presence and absence of some pathogen, in particular for latent viruses, requires a validated armamentarium of direct and indirect tests. The importance of using the correct diagnostic regimen was highlighted during the first pig-to-man cardiac transplantation with both porcine cytomegalovirus (PCMV), also known as porcine roseolovirus (PRV), and porcine circovirus (PCV) detected in the transplanted organ and in the patient. To further improve xenotransplantation and to achieve trials in Europe it is important that we use these data to inform process for diagnostics both in donor and recipients before and after xenotransplantation to ensure safety. As part of this sensitive and specific pathogen detection systems should be validated and readily available.

Introduction and hypothesisPolypropylene (PP) mesh for the treatment of pelvic organ prolapse (POP) has raised substantial concerns over long-term complications, leading to its ban in multiple countries. In response, emerging materials are being explored as alternatives for prolapse surgery. Preclinical animal models have historically played a pivotal role in validating medical devices, prior to clinical trials. Successful translation of these materials necessitates the identification of suitable animal models that replicate the female human pelvis and its biomechanical properties. Preclinical in vivo testing assesses the safety of surgical mesh and treatment efficacy in preventing POP recurrence.MethodsThe research critically reviews animal models used for preclinical pelvic mesh testing over the last decade and proposes a promising model for future preclinical studies.ResultsRats were the most common mammal used for toxicity and biocompatibility investigations through abdominal implantation. Although non-human primates serve as a gold standard for efficacy testing, ethical considerations limit their use owing to their close biological and cognitive resemblance to humans. Consequently, sheep were the most preferred large animal model owing to their reproductive system similarities and propensity for spontaneous POP following parity.ConclusionThe study contributes valuable insights into the selection of appropriate animal models for preclinical pelvic mesh testing, offering guidance that is crucial for enhancing the safety and efficacy of novel surgical interventions in the treatment of POP.

Even though reunion of bone fracture confronts clinicians, mesenchymal stromal cells (MSCs) are investigated to be curative in bone fracture. This study aimed to explore the application potential of MSCs for healing bone fractures. By inputting search terms and retrieving studies published up to March 2021, multiple databases, including PubMed, EMBASE, Web of Science, and Cochrane Library, were searched to identify eligible studies. The mean difference (MD) and 95% confidence interval (95% CI) were calculated to analyze the main results in the meta-analysis. Data analysis was performed using Engauge Digitizer 10.8 and R Software. Of the 31 articles, 26 were preclinical studies (n = 913), and 5 were clinical trials (n = 335). Preclinically, MSCs therapy significantly augmented the progress of bone regeneration [(bone volume over tissue volume (MD7.35, p < 0.01)], despite some non-significant effects (on the callus index, bone strength, work to failure, and stiffness). Clinically, the MSC group had a significantly reduced incidence of poor recovery (odds ratio (OR) 0.30, p < 0.01); however, a significant decrease in healing time was not observed in the MSC group (MD 2.47, p = 0.26). In summary, our data suggest that patients with bone fractures benefited from MSC administration and that MSCs are a potentially useful agent for bone regeneration. Despite these satisfactory outcomes, larger randomised clinical trials (RCTs) are necessary to confirm these findings.

Parkinson’s disease (PD) remains a major challenge for translational neuroscience, with an increasing global prevalence and persistent unmet therapeutic needs. While its classical motor symptoms, such as bradykinesia, rigidity, and tremor, are well characterized, the clinical spectrum extends to diverse and often disabling non-motor manifestations, including hyposmia, constipation, and sleep disturbances. These features typically precede motor deficits and may dominate the late stages of disease. Despite decades of research, existing treatments remain primarily symptomatic and fail to halt disease progression. This situation has driven the development of a broad repertoire of preclinical models—ranging from in vitro cellular systems to complex animal models—to better understand pathogenesis and identify disease-modifying strategies. However, significant translational gaps persist, partly due to limitations in how well these models recapitulate the heterogeneity and complexity of human PD. In this review, we critically examine the main preclinical models available for PD, assessing their strengths and weaknesses for modeling both motor and non-motor features. We discuss recent advances, persistent challenges, and highlight key considerations for improving the predictive value of experimental models in drug discovery for Parkinson’s disease.

Background Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. Methods To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. Results Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. Conclusions We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.