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Objective: Airway replacement is a challenging surgical intervention and remains an unmet clinical need. Due to the risk of airway stenosis, anastomotic separation, poor vascularization, and necrosis, it is necessary to establish the gold-standard outcomes of tracheal replacement. In this study, we use a large animal autograft model to assess long-term outcomes following tracheal replacement. Methods: Four New Zealand White rabbits underwent tracheal autograft surgery and were observed for 6 months. Clinical and radiographic surveillance were recorded, and grafts were analyzed histologically and radiographically at endpoint. Results: All animals survived to the endpoint with minimal respiratory symptoms and normal growth rates. No complications were observed. Computed tomography scans of the post-surgical airway demonstrated graft patency at all time points. Histological sections showed no sign of stenosis or necrosis with preservation of the native structure of the trachea. Conclusion: We established benchmarks for airway replacement. Our findings suggest that a rabbit model of tracheal autograft with direct reimplantation is feasible and does not result in graft stenosis or airway collapse. [ABSTRACT FROM AUTHOR]

Proton magnetic resonance spectroscopic imaging (1H‐MRSI) is a powerful tool that enables the multidimensional non‐invasive mapping of the neurochemical profile at high resolution over the entire brain. The constant demand for higher spatial resolution in 1H‐MRSI has led to increased interest in post‐processing‐based denoising methods aimed at reducing noise variance. The aim of the present study was to implement two noise‐reduction techniques, Marchenko–Pastur principal component analysis (MP‐PCA) based denoising and low‐rank total generalized variation (LR‐TGV) reconstruction, and to test their potential with and impact on preclinical 14.1 T fast in vivo 1H‐FID‐MRSI datasets. Since there is no known ground truth for in vivo metabolite maps, additional evaluations of the performance of both noise‐reduction strategies were conducted using Monte Carlo simulations. Results showed that both denoising techniques increased the apparent signal‐to‐noise ratio (SNR) while preserving noise properties in each spectrum for both in vivo and Monte Carlo datasets. Relative metabolite concentrations were not significantly altered by either method and brain regional differences were preserved in both synthetic and in vivo datasets. Increased precision of metabolite estimates was observed for the two methods, with inconsistencies noted for lower‐concentration metabolites. Our study provided a framework for how to evaluate the performance of MP‐PCA and LR‐TGV methods for preclinical 1H‐FID MRSI data at 14.1 T. While gains in apparent SNR and precision were observed, concentration estimations ought to be treated with care, especially for low‐concentration metabolites. [ABSTRACT FROM AUTHOR]

Preclinical animal models are crucial for advancing the clinical management of acute respiratory distress syndrome (ARDS). However, there is a lack of positive findings from preclinical studies that translate into clinical practice. One possible reason for this is the inadequate optimization of positive end-expiratory pressure (PEEP) during injury development in animal models. Insufficient PEEP levels can lead to the inclusion of subjects with mild lung injury, resulting in erroneous conclusions. Therefore, it is important to prioritize PEEP optimization in preclinical ARDS models to achieve consistent and clinically relevant lung injury. A study conducted on an ovine model of ARDS found that optimizing PEEP during injury development can significantly alter injury levels and align them more accurately with clinical practice. Future preclinical studies should also incorporate clinically relevant adjunctive therapies to better replicate the complexity of ARDS in real-world scenarios. [Extracted from the article]

Background. Influenza and SARS-CoV-2 viruses are two highly variable pathogens. We have developed a candidate bivalent live vaccine based on the strain of licensed A/Leningrad/17-based cold-adapted live attenuated influenza vaccine (LAIV) of H3N2 subtype, which expressed SARS-CoV-2 immunogenic T-cell epitopes. A cassette encoding fragments of S and N proteins of SARS-CoV-2 was inserted into the influenza NA gene using the P2A autocleavage site. In this study, we present the results of preclinical evaluation of the developed bivalent vaccine in a non-human primate model. Methods. Rhesus macaques (Macaca mulatta) (n = 3 per group) were immunized intranasally with 7.5 lg EID50 of the LAIV/CoV-2 bivalent vaccine, a control non-modified H3N2 LAIV or a placebo (chorioallantoic fluid) using a sprayer device, twice, with a 28-day interval. The blood samples were collected at days 0, 3, 28 and 35 for hematological and biochemical assessment. Safety was also assessed by monitoring body weight, body temperature and clinical signs of the disease. Immune responses to influenza virus were assessed both by determining serum antibody titers in hemagglutination inhibition assay, microneutralization assay and IgG ELISA. T-cell responses were measured both to influenza and SARS-CoV-2 antigens using ELISPOT and flow cytometry. Three weeks after the second immunization, animals were challenged with 105 PFU of Delta SARS-CoV-2. The body temperature, weight and challenge virus shedding were monitored for 5 days post-challenge. In addition, virus titers in various organs and histopathology were evaluated on day 6 after SARS-CoV-2 infection. Results. There was no toxic effect of the immunizations on the hematological and coagulation hemostasis of animals. No difference in the dynamics of the average weight and thermometry results were found between the groups of animals. Both LAIV and LAIV/CoV-2 variants poorly replicated in the upper respiratory tract of rhesus macaques. Nevertheless, despite this low level of virus shedding, influenza-specific serum IgG responses were detected in the group of monkeys immunized with the LAIV/CoV-2 bivalent but not in the LAIV group. Furthermore, T-cell responses to both influenza and SARS-CoV-2 viruses were detected in the LAIV/CoV-2 vaccine group only. The animals were generally resistant to SARS-CoV-2 challenge, with minimal virus shedding in the placebo and LAIV groups. Histopathological changes in vaccinated animals were decreased compared to the PBS group, suggesting a protective effect of the chimeric vaccine candidate. Conclusions. The candidate bivalent vaccine was safe and immunogenic for non-human primates and warrants its further evaluation in clinical trials. [ABSTRACT FROM AUTHOR]

The objective of the study is to investigate the safety, feasibility, and degradation profile of a novel Mg alloy-based bioresorbable coronary scaffold (JFK-PRODUCT BRS) with thin struts (110 μm). Polymer- or Mg alloy-based BRSs have not replaced nondegradable metal stents because of the higher prevalence of scaffold thrombosis and restenosis in clinical practice; these poor clinical outcomes were due to inadequate scaffold designs, including thick struts (more than 150 μm) and their inappropriate degradation processes. Fourteen healthy pigs received 17 JFK-PRODUCT BRSs in the coronary arteries and were sacrificed at 1, 6, 12, 18, and 26 months after implantation. Angiography, optical coherence tomography, microfocus X-ray computed tomography (µCT), scanning electron microscopy with energy-dispersive X-ray spectrometry (SEM–EDX), and histopathological evaluation were performed. The JFK-PRODUCT had a median percent late recoil of 11.28% at 1 month. The µCT observation confirmed that scaffold discontinuity reached 64.8% at 12 months with increased scaffold inner area thereafter, suggesting artery positive remodeling. The inflammation was mild, peaked at 18 months, and decreased thereafter. The SEM–EDX analysis demonstrated gradual degradation of the scaffold with formation of inorganic deposits, presumed to be calcium phosphates. It also revealed the disappearance of calcium phosphates at 26 months, achieving almost complete replacement of the scaffold by biocomponents. The current study demonstrated the safety and feasibility of JFK-PRODUCT with a lower acute recoil rate despite its thin struts. The scaffolds were almost completely disappeared at 26 months after implantation. [ABSTRACT FROM AUTHOR]

Translocator protein (TSPO) is involved in several cellular mechanisms such as steroidogenesis, immunomodulation, cell proliferation and differentiation. Overexpressed in several neurodegenerative diseases and brain cancer, TSPO radioligands have been developed over the last 20 years in positron emission tomography (PET) imaging. Recently, TSPO radioligands have extended beyond their initial application due to their specific binding to activated macrophages, making them a compelling biomarker for deciphering the intricacies of the tumor microenvironment (TME). In this review, we synthesized recent progress from the evaluation of TSPO-specific PET tracers in various peripheral tumor models and highlighted the hurdles and limitations associated with heterogeneous uptake in healthy tissue and tumor regions to achieve the clinical development of such a radiotracer. • Translocator protein (TSPO) specific radioligands may be useful to explore cancer using PET imaging (Positron Emission Tomography). • TSPO is a compelling biomarker for deciphering the intricacies of the tumor microenvironment. • Recent progress from the evaluation of TSPO-specific PET tracers in various peripheral tumor models has been performed. • Hurdles and limitations associated with heterogeneous uptake in healthy tissue and tumor regions persist to achieve clinical applications. [ABSTRACT FROM AUTHOR]

In 2020, the top 10 causes of death among children and adolescents between the ages of 1 and 19 years old included cancer, congenital anomalies, heart disease, and chronic respiratory disease; all these conditions are potentially treatable with medical intervention. However, children exhibit specific physiological and developmental characteristics that can significantly impact drug pharmacokinetics, pharmacodynamics, and safety profile. These factors illustrate the importance of a heightened focus on pediatric drug development. Traditional drugs lack proper circulation, permeability, targeting, accumulation, and release, and they often require dose adjustments or modifications, which can result in suboptimal therapeutic outcomes and increased risks of adverse effects in pediatric patients. Nanomedicines have emerged as efficient drug delivery systems because of their unique properties, which can improve the solubility and stability of drugs by encapsulating them in different forms of nanoparticles. This review discusses the challenges of pediatric therapy, and the current state of nanomedicines for pediatric diseases in terms of Food and Drug Administration‐approved nanomedicines, the types of diseases treated or diagnosed, and preclinical studies that have the potential to be translated to the clinic. In summary, nanomedicine holds significant potential for addressing the unique and pressing challenges associated with diagnosing and treating pediatric diseases. [ABSTRACT FROM AUTHOR]

Iron is considered as an attractive alternative material for bioresorbable scaffolds (BRS). The sirolimus eluting iron bioresorbable scaffold (IBS), developed by Biotyx Medical (Shenzhen, China), is the only iron-based BRS with an ultrathin-wall design. The study aims to investigate the long-term efficacy, safety, biocompatibility, and lumen changes during the biodegradation process of the IBS in a porcine model. A total of 90 IBSs and 70 cobalt-chromium everolimus eluting stents (EES) were randomly implanted into nonatherosclerotic coronary artery of healthy mini swine. The multimodality assessments including coronary angiography, optical coherence tomography, micro-computed tomography, magnetic resonance imaging, real-time polymerase chain reaction (PCR), and histopathological evaluations, were performed at different time points. There was no statistical difference in area stenosis between IBS group and EES group at 6 months, 1year, 2 years and 5 years. Although the scaffolded vessels narrowed at 9 months, expansive remodeling with increased mean lumen area was found at 3 and 5 years. The IBS struts remained intact at 6 months, and the corrosion was detectable at 9 months. At 5 years, the iron struts were completely degraded and absorbed in situ, without in-scaffold restenosis or thrombosis, lumen collapse, aneurysm formation, and chronic inflammation. No local or systemic toxicity and abnormal histopathologic manifestation were found in all experiments. Results from real-time PCR indicated that no sign of iron overload was reported in scaffolded segments. Therefore, the IBS shows comparable efficacy, safety, and biocompatibility with EES, and late lumen enlargement is considered as a unique feature in the IBS-implanted vessels.

Context Diabetic nephropathy (DN) is a major complication of diabetes mellitus and is the leading cause of kidney disease in patients undergoing renal replacement therapy. DN is associated with an increased risk of death in patients with diabetes. Conventional therapy for DN includes intensive control of blood glucose level and blood pressure and renin–angiotensin system blockade. However, this approach has limited treatment effects on DN. Therefore, identifying novel drugs to delay the progression of DN is urgently needed. Proanthocyanidin (PA) has been shown to exert potentially beneficial effects on DN. However, the protective mechanism and efficacy are yet to be elucidated.Objective This study evaluates the efficacy and potential mechanisms of PA in animal models of DN.Methods Preclinical studies were searched from Chinese National Knowledge Infrastructure, PubMed, Web of Science, Embase, and Google Scholar databases, with the search deadline of August 2023. Keywords (‘diabetic nephropathies’, ‘nephropathies, diabetic’, ‘diabetic kidney diseases’, ‘proanthocyanidin’, ‘anthocyanidin polymers’, ‘procyanidins’, ‘animal*’, ‘rat’, and ‘mice’) were used to search the databases. RevMan 5.3 was used for statistical analysis.Results A total of 22 studies involving 538 animals were included in this analysis. The pooled results indicated that PA therapy significantly improved kidney function and reduced proteinuria and blood glucose levels. The protective mechanism of PA was associated with anti-inflammatory, antioxidant, antifibrotic, and antiapoptotic effects; inhibition of endoplasmic reticulum stress; and alleviation of mitochondrial dysfunction and dyslipidemia.Conclusion These findings suggest that PA alleviates DN by mediating multiple targets and pathways.

Ferroptosis represents a distinct form of cell death that is not associated with necrosis, autophagy, apoptosis, or pyroptosis. It is characterised by intracellular iron-dependent lipid peroxidation. The current literature indicates that a number of botanical drugs and isolated metabolites can modulate ferroptosis, thereby exerting inhibitory effects on lung cancer cells or animal models. The aim of this review is to elucidate the mechanisms through which botanical drugs and isolated metabolites regulate ferroptosis in the context of lung cancer, thereby providing potential insights into lung cancer treatment. It is crucial to highlight that these preclinical findings should not be interpreted as evidence that these treatments can be immediately translated into clinical applications. In the future, we will continue to study the pharmacology, pharmacokinetics and toxicology of these drugs, as well as evaluating their efficacy and safety in clinical trials, with the aim of providing new approaches to the development of new agents for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

The hinotori™ Surgical Robot System (hinotori™, Medicaroid, Kobe, Japan) is increasingly being utilized primarily in urology and adult surgery; however, data on its application in pediatric surgery are lacking. This preclinical study aimed to evaluate the limitations of this system for accurate suturing in small cavities designed for pediatric and neonatal applications. Two trained operators performed simple ligature sutures (easy task [ET]) and hepaticojejunostomy sutures (difficult task [DT]) within five differently sized boxes, ranging from 5123 to 125 mL. The suture time, number of internal and external instrument/instrument collisions, instrument/box collisions, and suture accuracy were evaluated. The suture accuracy was assessed using the A-Lap Mini endoscopic surgery skill assessment system. As a result, an increase in the number of collisions and extended suturing times were observed in boxes with volumes smaller than 215 mL. Despite these variations, there were no significant differences between the boxes, and all tasks were precisely performed in all boxes (p = 0.10 for the ET and p = 1.00 for the DT). These findings demonstrate the capability of the hinotori™ system to perform precise suturing techniques within tightly confined simulated neonatal cavities as small as 125 mL. To advance the integration of pediatric robotic surgery utilizing the hinotori™ system, additional trials comparing it with conventional laparoscopic and thoracoscopic techniques using pediatric and animal models are necessary to assess its clinical safety and applicability. [ABSTRACT FROM AUTHOR]

Background: Inhibition of HDAC6 has been proposed as a broadly applicable therapeutic strategy for Charcot–Marie–Tooth disease (CMT). Inhibition of HDAC6 increases the acetylation of proteins important in axonal trafficking, such as α‐tubulin and Miro, and has been shown to be efficacious in several preclinical studies using mouse models of CMT. Aims: Here, we sought to expand on previous preclinical studies by testing the effect of genetic deletion of Hdac6 on mice carrying a humanized knockin allele of Gars1, a model of CMT‐type 2D. Methods: Gars1ΔETAQ mice were bred to an Hdac6 knockout strain, and the resulting offspring were evaluated for clinically relevant outcomes. Results: The genetic deletion of Hdac6 increased α‐tubulin acetylation in the sciatic nerves of both wild‐type and Gars1ΔETAQ mice. However, when tested at 5 weeks of age, the Gars1ΔETAQ mice lacking Hdac6 showed no changes in body weight, muscle atrophy, grip strength or endurance, sciatic motor nerve conduction velocity, compound muscle action potential amplitude, or peripheral nerve histopathology compared to Gars1ΔETAQ mice with intact Hdac6. Interpretation: Our results differ from those of two previous studies that demonstrated the benefit of the HDAC6 inhibitor tubastatin A in mouse models of CMT2D. While we cannot fully explain the different outcomes, our results offer a counterexample to the benefit of inhibiting HDAC6 in CMT2D, suggesting additional research is necessary. [ABSTRACT FROM AUTHOR]

Achondroplasia (ACH), the most common form of disproportionate short stature, is caused by gain–of–function point mutations in fibroblast growth factor receptor 3 (FGFR3). Abnormally elevated activation of FGFR3 modulates chondrocyte proliferation and differentiation via multiple signaling pathways, such as the MAPK pathway. Using a mouse model mimicking ACH (Fgfr3Y367C/+), we have previously shown that daily treatment with infigratinib (BGJ398), a selective and orally bioavailable FGFR1-3 inhibitor, at a dose of 2 mg/kg, significantly increased bone growth. In this study, we investigated the activity of infigratinib administered at substantially lower doses (0.2 and 0.5 mg/kg, given once daily) and using an intermittent dosing regimen (1 mg/kg every 3 days). Following a 15–day treatment period, these low dosages were sufficient to observe significant improvement of clinical hallmarks of ACH such as growth of the axial and appendicular skeleton and skull development. Immunohistological labeling demonstrated the positive impact of infigratinib on chondrocyte differentiation in the cartilage growth plate and the cartilage end plate of the vertebrae. Macroscopic and microcomputed analyses showed enlargement of the foramen magnum area at the skull base, thus improving foramen magnum stenosis, a well–recognized complication in ACH. No changes in FGF23 or phosphorus levels were observed, indicating that the treatment did not modify phosphate homeostasis. This proof–of–concept study demonstrates that infigratinib administered at low doses has the potential to be a safe and effective therapeutic option for children with ACH. [ABSTRACT FROM AUTHOR]

BackgroundWHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is an ultra-rare, combined primary immunodeficiency and chronic neutropenic disorder characterized by a range of clinical presentations, including peripheral neutropenia, lymphopenia, and recurrent infections. WHIM syndrome is most often caused by gain-of-function mutations in the gene encoding C-X-C chemokine receptor 4 (CXCR4). As such, inhibition of CXCR4 with XOLREMDI® (mavorixafor), an orally bioavailable CXCR4 antagonist, demonstrated clinically meaningful increases in absolute neutrophil and lymphocyte counts and concomitant reduction in infections in patients with WHIM syndrome, resulting in its recent U.S. Food and Drug Administration approval. The impact of CXCR4 antagonism on other aspects of the pathobiology in WHIM syndrome, such as lymphopoiesis and leukocyte trafficking between primary and secondary lymphoid organs, is less understood.MethodsIn the current study, the effects of CXCR4 antagonism on leukocyte trafficking and distribution in primary and secondary lymphoid organs were investigated in a mouse model of WHIM syndrome carrying the heterozygous Cxcr41013 mutation. Cxcr4+/1013 and Cxcr4 wild-type mice received the orally bioavailable CXCR4 antagonist X4-185. Blood, spleen and bone marrow samples were collected for numeration, flow cytometry, and functional studies.ResultsCxcr4+/1013 mice exhibited profound peripheral blood leukopenia as seen in patients with WHIM syndrome. CXCR4 antagonism corrected circulating leukopenia and mobilized functional neutrophils without disrupting granulopoiesis in the bone marrow of Cxcr4+/1013 mice. Furthermore, Cxcr4+/1013 displayed aberrant splenic T and B-cell counts and frequency. Treatment with X4-185 normalized splenic T-cell abnormalities, correcting the reduced CD8+ T-cell numbers, restoring the CD4/CD8 T-cell ratio, and ameliorating peripheral blood T-cell lymphopenia. In addition, CXCR4 antagonism was able to correct the abnormal frequencies and numbers of splenic marginal zone and follicular B cells in Cxcr4+/1013 mice, and ultimately normalize B-cell lymphopenia in the peripheral circulation.ConclusionsOur study provides comprehensive evidence that oral dosing with a CXCR4 antagonist can effectively correct WHIM-associated neutrophil and lymphocyte abnormalities in a mouse model of WHIM syndrome. These findings extend our understanding of how targeting the dysregulated CXCR4 signaling pathway can ameliorate the pathogenesis of WHIM syndrome.

Abstract Scientific progress heavily relies on rigorous research, adherence to scientific standards, and transparent reporting. Animal models play a crucial role in advancing biomedical research, especially in the field of gene therapy. Animal models are vital tools in preclinical research, allowing scientists to predict outcomes and understand complex biological processes. The selection of appropriate animal models is critical, considering factors such as physiological and pathophysiological similarities, availability, and ethical considerations. Animal models continue to be indispensable tools in preclinical gene therapy research. Advancements in genetic engineering and model selection have improved the fidelity and relevance of these models. As gene therapy research progresses, careful consideration of animal models and transparent reporting will contribute to the development of effective therapies for various genetic disorders and diseases. This comprehensive review explores the use of animal models in preclinical gene therapy studies for approved products up to September 2023. The study encompasses 47 approved gene therapy products, with a focus on preclinical trials. This comprehensive analysis serves as a valuable reference for researchers in the gene therapy field, aiding in the selection of suitable animal models for their preclinical investigations.

The bispecific antibody tarperprumig (ALXN1820) was developed as a treatment option for diseases involving dysregulated complement alternative pathway (AP) activity that could be administered in small volumes, either subcutaneously or intravenously. Tarperprumig incorporates a C-terminal variable domain of a heavy chain only antibody (VHH) that binds properdin (FP) connected via a flexible linker to an N-terminal VHH that binds human serum albumin (HSA). The purified bispecific VHH antibody exhibits an experimental molecular weight average of 27.4 kDa and can be formulated at > 100 mg/mL. Tarperprumig binds tightly to FP and HSA with sub-nanomolar affinity at pH 7.4 and can associate simultaneously with FP and HSA to form a ternary complex. Tarperprumig potently and dose-dependently inhibits to completion in vitro AP-dependent complement C5b-9 formation, AP-dependent hemolysis, and the AP deposition of C3, FP and C9. X-ray crystallography revealed that the isolated FP-binding VHH recognizes the thrombospondin repeat 5 domain of FP, thereby preventing FP from binding to the AP convertase owing to severe steric hindrance. Tarperprumig cross-reacts with cynomolgus monkey FP and serum albumin. In summary, tarperprumig exhibits properties tailored for subcutaneous administration and is currently in clinical development for the treatment of complement AP-related disorders.

To develop and validate a 3D simulation model to calculate laser ablation (LA) zone size and estimate the volume of treated tissue for thyroid applications, a model was developed, taking into account dynamic optical and thermal properties of tissue change. For validation, ten Yorkshire swines were equally divided into two cohorts and underwent thyroid LA at 3 W/1,400 J and 3 W/1,800 J respectively with a 1064-nm multi-source laser (Echolaser X4 with Orblaze™ technology; ElEn SpA, Calenzano, Italy). The dataset was analyzed employing key statistical measures such as mean and standard deviation (SD). Model simulation data were compared with animal gross histology. Experimental data for longitudinal length, width (transverse length), ablation volume and sphericity were 11.0 mm, 10.0 mm, 0.6 mL and 0.91, respectively at 1,400 J and 14.6 mm, 12.4 mm, 1.12 mL and 0.83, respectively at 1,800 J. Gross histology data showed excellent reproducibility of the ablation zone among same laser settings; for both 1,400 J and 1,800 J, the SD of the in vivo parameters was ≤ 0.7 mm, except for width at 1,800 J, for which the SD was 1.1 mm. Simulated data for longitudinal length, width, ablation volume and sphericity were 11.6 mm, 10.0 mm, 0.62 mL and 0.88, respectively at 1,400 J and 14.2 mm, 12.0 mm, 1.06 mL and 0.84, respectively at 1,800 J. Experimental data for ablation volume, sphericity coefficient, and longitudinal and transverse lengths of thermal damaged area showed good agreement with the simulation data. Simulation datasets were successfully incorporated into proprietary planning software (Echolaser Smart Interface, Elesta SpA, Calenzano, Italy) to provide guidance for LA of papillary thyroid microcarcinomas. Our mathematical model showed good predictability of coagulative necrosis when compared with data from in vivo animal experiments. [ABSTRACT FROM AUTHOR]

Background: Acacia aroma (A. aroma), or Tusca, is a South American plant frequently used in medicine. We recently reported the antiulcer effect of two Tusca leaf extracts in rats: a 5% infusion and a 10% hydroalcoholic. This study aimed to investigate the in vitro cytotoxicity and the in vivo oral subchronic toxicity of these two extracts in rats. Methods: Cytotoxicity was evaluated through cell viability assays using the 50% lethal concentration (LC50) on lung cells, which was calculated for each extract. Oral subchronic toxicity was studied in Wistar rats, and the clinical parameters were determined during a 90-day treatment period. Following the experimental period, biochemical parameters were analyzed, and histopathological analyses of the stomach, liver, and kidneys were performed. Results: The in vitro cytotoxicity was low in both extracts (LC50=966.78±48.34 µg/ml for the 5% infusion and 562.28±28.11 µg/ml for the 10% hydroalcoholic extract). The in vivo clinical, behavioral, and biochemical parameters, body weight, and food intake had no significant differences (P=0.05) compared to the control group. There were also no histopathological alterations in the analyzed organs. Conclusion: The present study contributes to expanding the knowledge on the safety of the two extracts derived from A. aroma (5% infusion and 10% hydroalcoholic). Therefore, the extracts can possibly be used in the treatment or prevention of gastric diseases in future studies. [ABSTRACT FROM AUTHOR]

Introduction: Cardiac contractility modulation (CCM) is a medical device‐based therapy delivering non‐excitatory electrical stimulations to the heart to enhance cardiac function in heart failure (HF) patients. The lack of human in vitro tools to assess CCM hinders our understanding of CCM mechanisms of action. Here, we introduce a novel chronic (i.e., 2‐day) in vitro CCM assay to evaluate the effects of CCM in a human 3D microphysiological system consisting of engineered cardiac tissues (ECTs). Methods: Cryopreserved human induced pluripotent stem cell‐derived cardiomyocytes were used to generate 3D ECTs. The ECTs were cultured, incorporating human primary ventricular cardiac fibroblasts and a fibrin‐based gel. Electrical stimulation was applied using two separate pulse generators for the CCM group and control group. Contractile properties and intracellular calcium were measured, and a cardiac gene quantitative PCR screen was conducted. Results: Chronic CCM increased contraction amplitude and duration, enhanced intracellular calcium transient amplitude, and altered gene expression related to HF (i.e., natriuretic peptide B, NPPB) and excitation‐contraction coupling (i.e., sodium‐ calcium exchanger, SLC8). Conclusion: These data represent the first study of chronic CCM in a 3D ECT model, providing a nonclinical tool to assess the effects of cardiac electrophysiology medical device signals complementing in vivo animal studies. The methodology established a standardized 3D ECT‐based in vitro testbed for chronic CCM, allowing evaluation of physiological and molecular effects on human cardiac tissues. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) lacks three common receptors, making traditional treatments less effective. This review highlights the importance of radiotherapy and emerging therapeutic strategies to enhance treatment outcomes in TNBC. We conducted a literature search on PubMed for publications from 2000 to 2023 to discuss the critical role of radiotherapy in managing TNBC, emphasizing its applications from locoregional control to improving survival rates. The review explores molecular mechanisms underlying TNBC's radiotherapy response, including DNA damage repair and apoptosis, with a focus on BRCA1/2 mutations and Poly (ADP-ribose) polymerase (PARP) inhibition. We summarize preclinical and clinical research on radiosensitization strategies, from gene-targeted therapies to immunotherapy combinations, and the impact of post-mastectomy radiation therapy on locoregional control. The potential of personalized treatment approaches, integrating molecular profiling, targeted radiosensitizers, and the synergistic effects of radiotherapy with immunotherapy, is also discussed. Future TNBC treatment strategies should focus on precision medicine, integrating immunotherapy, developing novel radiosensitizers, and targeting biological pathways to overcome radioresistance. The integration of radiomics and artificial intelligence offers promising avenues for enhancing treatment personalization and efficacy, aiming to improve patient outcomes in TNBC. [ABSTRACT FROM AUTHOR]

Vitamin D3, a fat-soluble vitamin known for its critical function in calcium homeostasis and bone health, is gaining interest for its anticancer properties. Observational studies have suggested a negative relationship between vitamin D levels and the incidence of some malignancies throughout the years, prompting substantial investigation to find its anticancer effects. The purpose of this comprehensive review is to investigate the diverse function of vitamin D3 in cancer prevention and therapy. We explored the molecular mechanism underlying its effects on cancer cells, which range from cell cycle control and death to angiogenesis and immune response modulation. Insights from in vitro and in vivo studies provide valuable evidence supporting its anticancer potential. Furthermore, we look at epidemiological and clinical studies that investigate the relationship between vitamin D3 levels and cancer risk or treatment results. Vitamin D3 supplementation's safety profile and cost-effectiveness increase its attractiveness as an adjuvant therapy in conjunction with traditional treatment regimens. Our critical review of the current literature provides an in-depth understanding of vitamin D3's anticancer effect, covering the obstacles and possibilities in realizing its promise for cancer prevention and therapy. The findings of this study might pave the way for the development of innovative treatment techniques that take use of the advantages of vitamin D3 to fight cancer and improve patient care. As research progresses, a better understanding of vitamin D3's anticancer processes will surely simplify its incorporation into personalized cancer care techniques, hence enhancing patient outcomes in the battle against cancer. [ABSTRACT FROM AUTHOR]

Scientific progress heavily relies on rigorous research, adherence to scientific standards, and transparent reporting. Animal models play a crucial role in advancing biomedical research, especially in the field of gene therapy. Animal models are vital tools in preclinical research, allowing scientists to predict outcomes and understand complex biological processes. The selection of appropriate animal models is critical, considering factors such as physiological and pathophysiological similarities, availability, and ethical considerations. Animal models continue to be indispensable tools in preclinical gene therapy research. Advancements in genetic engineering and model selection have improved the fidelity and relevance of these models. As gene therapy research progresses, careful consideration of animal models and transparent reporting will contribute to the development of effective therapies for various genetic disorders and diseases. This comprehensive review explores the use of animal models in preclinical gene therapy studies for approved products up to September 2023. The study encompasses 47 approved gene therapy products, with a focus on preclinical trials. This comprehensive analysis serves as a valuable reference for researchers in the gene therapy field, aiding in the selection of suitable animal models for their preclinical investigations. [ABSTRACT FROM AUTHOR]

Background: Scutellaria baicalensis, the dry root of scutellaria baicalensis georgi, is a traditional Chinese medicine with long. In clinic, scutellaria baicalensis is commonly used in prescription for the treatment of depression. Additionally, numerous pre-clinical studies have shown that Scutellaria baicalensis and its active constituents are effective for depression. In this study, we aims to systematically review the roles of scutellaria baicalensis in depression and summarize the possible mechanism. Methods: A systematic review and meta-analysis were conducted to analyze the existing studies on the effects of scutellaria baicalensis on depression in animal models. Briefly, we searched electronic databases including Pubmed and Embase for preclinical trial studies from inception to September 2023. The items in each study were evaluated by two independent reviewers, and meta-analyses were performed on scutellaria baicalensis-induced behavioral changes in the study. Finally, random effects model is used to collect data. Results: A total of 49 studies were identified, and 13 studies were included in the final analysis. They all reported the different antidepressant effects of scutellaria baicalensis and the underlying biological mechanisms. Among the included 13 studies, the results of eight articles SPT[SMD = -2.80, 95%CI(-4.03, -1.57), p < 0.01], the results of the nine articles OFT[SMD = -2.38, 95%CI(-3.53, -1.23), p < 0.01], and the results of two articles NSFT[SMD = -2.98, 95%CI(-3.94, -2.02), p < 0.01] were significantly different from the control group. The risk of bias was moderate in all studies, however, there was a significant heterogeneity among studies. Conclusion: These results preliminarily suggest that scutellaria baicalensis can alleviate depressive behaviors and modulate underlying mechanisms, which is expected to be a promising antidepressant. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the utilization of novel Avatera system in urological operations according to the IDEAL-D framework recommendations for high-risk invasive surgical devices. Materials and Methods: Three surgeons attempted to perform 23 upper and lower urinary tract operations on human cadavers and in live porcine models using the Avatera system. Total operative time and the duration of the substeps were evaluated. Surgical performance was assessed with the Global Evaluative Assessment of Robotic Skills (GEARS) score. Suturing was rated using the technical checklist for the assessment of suturing in robotic surgery. Attending surgeons rated their satisfaction with the Avatera system on a scale of 1–5. Results and Limitation: Seventeen out of 18 operations performed on cadavers were completed, while one pyeloplasty was discontinued. All five operations performed in porcine models were completed. Although 1 pig was euthanized on the fifth postoperative day, its symptoms were unrelated to surgery. Mean GEARS and Suturing scores in the upper urinary tract were 29 ± 0.7 and 29.5 ± 0.95, respectively, and in the lower urinary 28.5 ± 1.2 and 29.5 ± 0.5, respectively. Surgeons' satisfaction was high or very high for all procedures. Conclusions: The Avatera system was associated with good surgical performance and high surgeons' satisfaction rates. All urological procedures performed were shown to be feasible, with comparable risks to other robot-assisted surgery systems. [ABSTRACT FROM AUTHOR]

Although diabetes mellitus negatively affects post-ischaemic stroke injury and recovery, its impact on intracerebral haemorrhage (ICH) remains uncertain. This study aimed to investigate the effect of experimental diabetes (ED) on ICH-induced injury and neurological impairment. Sprague-Dawley rats were induced with ED 2 weeks before ICH induction. Animals were randomly assigned to four groups: 1)Healthy; 2)ICH; 3)ED; 4)ED-ICH. ICH and ED-ICH groups showed similar functional assessment. The ED-ICH group exhibited significantly lower haemorrhage volume compared with the ICH group, except at 1 mo. The oedema/ICH volume ratio and cistern displacement ratio were significantly higher in the ED-ICH group. Vascular markers revealed greater expression of α-SMA in the ED groups (ED and ED-ICH) compared with ICH. Conversely, the ICH groups (ED-ICH and ICH) exhibited higher levels of VEGF compared to the healthy and ED groups. An assessment of myelin tract integrity showed an increase in fractional anisotropy in the ED and ED-ICH groups compared with ICH. The ED group showed higher cryomyelin expression than the ED-ICH and ICH groups. Additionally, the ED groups (ED and ED-ICH) displayed higher expression of MOG and Olig-2 than ICH. As for inflammation, MCP-1 levels were significantly lower in the ED-ICH groups compared with the ICH group. Notably, ED did not aggravate the neurological outcome; however, it results in greater ICH-related brain oedema, greater brain structure displacement and lower haemorrhage volume. ED influences the cerebral vascularisation with an increase in vascular thickness, limits the inflammatory response and attenuates the deleterious effect of ICH on white matter integrity.

Over 4% of the global population is estimated to live with autoimmune disease, necessitating immunosuppressive treatment that is often chronic, not curative, and carries associated risks. B cells have emerged as key players in disease pathogenesis, as evidenced by partial responsiveness to B cell depletion by antibody-based therapies. However, these treatments often have transient effects due to incomplete depletion of tissue-resident B cells. Chimeric antigen receptor (CAR) T cells targeting B cells have demonstrated efficacy in refractory systemic lupus erythematosus. To this end, we developed an anti-CD19 CAR T cell product candidate, CABA-201, containing a clinically evaluated fully human CD19 binder (IC78) with a 4-1BB costimulatory domain and CD3 zeta stimulation domain for treatment refractory autoimmune disease. Here, we demonstrate specific cytotoxic activity of CABA-201 against CD19+ Nalm6 cells with no off-target effects on primary human cells. Novel examination of CABA-201 generated from primary T cells from multiple patients with autoimmune disease displayed robust CAR surface expression and effective elimination of the intended target autologous CD19+ B cells in vitro. Together, these findings support the tolerability and activity of CABA-201 for clinical development in patients with autoimmune disease.

Introduction. Due to the ability of the influenza virus to mutate, it is necessary to constantly search for new drugs with preventive and direct antiviral effects.The aim of the study is to investigate the protective antiviral properties of the drug Thymogen®, a dosed nasal spray, on a model of lethal influenza pneumonia in laboratory animals.Material and methods. White mature mice were selected for the experiment on the antiviral activity of the tested drug samples against H1N1 influenza virus; the mice were divided into the following groups (30 animals each): two negative control groups; two groups receiving Thymogen®, a dosed nasal spray (before and after infection); one group of animals received Tamiflu®, and one received Hexoral®. The mortality of animals with influenza pneumonia was assessed; histological and morphometric analyses were also carried out.Results and discussion. The morphological picture of the lungs of animals correlated with their protective activity when analyzing the survival of animals. The normalization of tissue structure was pronounced the most in the group of animals infected with the virus, pre-incubated with Thymogen®, a dosed nasal spray, and in the group receiving Tamiflu®. Moreover, the viral load in the lungs was lower by 1.5 and 1.2 orders of magnitude in the group receiving Thymogen®, dosed nasal spray, compared to the negative control group (the 3rd and the 6th days of the experiment, respectively), which corresponds to a decrease in the intensity of viral reproduction by 31.6 and 15.8 times

Abstract Background The overall confidence in the results of systematic reviews including animal models can be heterogeneous. We assessed the methodological quality of systematic reviews including animal models in dentistry as well as the overall confidence in the results of those systematic reviews. Material & methods PubMed, Web of Science and Scopus were searched for systematic reviews including animal studies in dentistry published later than January 2010 until 18th of July 2022. Overall confidence in the results was assessed using a modified version of the A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) checklist. Checklist items were rated as yes, partial yes, no and not applicable. Linear regression analysis was used to investigate associations between systematic review characteristics and the overall adherence to the AMSTAR-2 checklist. The overall confidence in the results was calculated based on the number of critical and non-critical weaknesses presented in the AMSTAR-2 items and rated as high, moderate, low and critical low. Results Of initially 951 retrieved systematic reviews, 190 were included in the study. The overall confidence in the results was low in 43 (22.6%) and critically low in 133 (70.0%) systematic reviews. While some AMSTAR-2 items were regularly reported (e.g. conflict of interest, selection in duplicate), others were not (e.g. funding: n = 1; 0.5%). Multivariable linear regression analysis showed that the adherence scores of AMSTAR-2 was significantly associated with publication year, journal impact factor (IF), topic, and the use of tools to assess risk of bias (RoB) of the systematic reviews. Conclusion Although the methodological quality of dental systematic reviews of animal models improved over the years, it is still suboptimal. The overall confidence in the results was mostly low or critically low. Systematic reviews, which were published later, published in a journal with a higher IF, focused on non-surgery topics, and used at least one tool to assess RoB correlated with greater adherence to the AMSTAR-2 guidelines.

Sepsis is an increasingly worldwide problem; it is currently regarded as a complex life-threatening dysfunction of one or more organs as a result of dysregulated host immune response to infections. The heart is one of the most affected organs, as roughly 10% to 70% of sepsis cases are estimated to turn into sepsis-induced cardiomyopathy (SIC). SIC can be defined as a reversible myocardial dysfunction characterized by dilated ventricles, impaired contractility, and decreased ejection fraction. Mitochondria play a critical role in the normal functioning of cardiac tissues as the heart is highly dependent on its production of adenosine triphosphate (ATP), its damage during SIC includes morphology impairment, mitophagy, biogenesis disequilibrium, electron transport chain disturbance, molecular damage from the actions of pro-inflammatory cytokines and many other different impairments that are major contributing factors to the severity of SIC. Although mitochondria-targeted therapies usage is still inadequate in clinical settings, the preclinical study outcomes promise that the implementation of these therapies may effectively treat SIC. This review summarizes the different therapeutic strategies targeting mitochondria structure, quality, and quantity abnormalities for the treatment of SIC. [ABSTRACT FROM AUTHOR]

AbstractWuzhuyu decoction (WZYD) is a well-known classic traditional Chinese medicine prescription and has been widely used to treat headache, nausea, vomiting, insomnia, etc. However, little published information is available about its safety. Our aim was to investigate the acute and subacute oral toxicity of WZYD extract in rats following the technical guidelines from China’s National Medical Products Administration (NMPA) for single and repeated doses toxicity studies of drugs. Acute oral toxicity was assessed in rats via oral administration of WZYD extract at 4 g/kg three times within a day followed by a 14-day observation period. To evaluate the subacute toxicity, rats were orally administered with WZYD extract at doses of 0, 0.44, 1.33, and 4 g/kg for 28 days. The items examined included clinical signs, body weight, food consumption, hematological and biochemical parameters, bone marrow smear, organ index, and histopathology. After the rats were administered with 12 g/kg (3 × 4 g/kg) WZYD extract, no mortality and toxic effects were observed during the observation period. In the subacute toxicity study, WZYD extract did not cause any significant treatment-related abnormality in each examined item of rats, so the no observed adverse effect level (NOAEL) of WZYD extract for 28 days orally administered to rats is considered to be 4 g/kg, which is approximately 80-fold of its clinical proposed dosage. [ABSTRACT FROM AUTHOR]

Since its introduction in 2011, the Rat Grimace Scale (RGS) has proven to be a valuable tool for pain assessment in preclinical studies. This scale includes the assessment of four functional units to quantify pain responses in rats. By observing and assessing changes such as orbital tightening, nose/cheek flattening, ear changes, whisker change researchers can objectively assess the severity of pain experienced by animals. In our article, we offer an overview of a various studies applying this method across surgical and postoperative pain models, inflammatory pain models, orthodontic and orofacial pain models, neuropathic pain models, and others. This study specifically investigates the effectiveness of the RGS in assessing pain in rats, with a particular focus on a nitroglycerin-induced migraine model. The article underscores the humane and non-invasive nature of the RGS, aligning with current ethical standards in animal research. Additionally, it explores the potential application of the RGS across diverse disciplines, including neuroscience, pharmacology, and veterinary medicine. The study also addresses limitations and biases in the current pain assessment methods, proposing future research directions to enhance accuracy and ethical practices in animal pain research. The development of an automated RGS system capable of identifying facial action units in rat images and predicting RGS scores has become imperative to to reduce the labor intensity of the image acquisition and scoring process. [ABSTRACT FROM AUTHOR]

Cannabinoids interact with Cannabinoid Receptors (CBRs) and some related non-cannabinoid transcription factors within neurological and non-neuronal-specific receptors. The current review has covered pharmacological molecular mechanisms during an epileptic attack and provided a beneficial therapeutic approach for the treatment of neurological disorders. CBRs and new targets may be involved in Cannabidiol (CBD) effects. Although it has a low affinity for both CB1 and CB2 receptors, CBD can effectively block CB1 receptors when concentrations are high. The following are numerous potential CBD goals: (A) Blocking GPR55 receptors; (B) Systematic desensitization of TRPV1 channels; (C) Suppressing adenosine re-uptake transporters; (D) Regulating GABA production; and (E) Influencing the Endocannabinoid networks. According to the current review, numerous outstanding cannabis formulations are currently being developed and proven in numerous clinical studies. Nevertheless, more research is urgently needed to determine the best dosage and proportions of cannabinoids for reducing seizure frequency. This study needs to take place in huge, rising randomized clinical trials that really can reveal the rewards and drawbacks of cannabinoids in controlled patients. Furthermore, there is a lot of significant variation in the experimental approaches performed, particularly when it comes to the length of immunosuppressive drugs, dosages, and delivery methods in animal models. So, reproducing the existing results using comparable methods will be one of the biggest challenges in the additional investigation. [ABSTRACT FROM AUTHOR]

The use of doxorubicin (DOX) chemotherapy is restricted due to dose-dependent cardiotoxicity. Pyridoxamine (PM) is a vitamin B6 derivative with favorable effects on diverse cardiovascular diseases, suggesting a cardioprotective effect on DOX-induced cardiotoxicity. The cardioprotective nature of PM was investigated in a rat model of DOX-induced cardiotoxicity. Six-week-old female Sprague Dawley rats were treated intravenously with 2 mg/kg DOX or saline (CTRL) weekly for eight weeks. Two other groups received PM via the drinking water next to DOX (DOX+PM) or saline (CTRL+PM). Echocardiography, strain analysis, and hemodynamic measurements were performed to evaluate cardiac function. Fibrotic remodeling, myocardial inflammation, oxidative stress, apoptosis, and ferroptosis were evaluated by various in vitro techniques. PM significantly attenuated DOX-induced left ventricular (LV) dilated cardiomyopathy and limited TGF-β1-related LV fibrotic remodeling and macrophage-driven myocardial inflammation. PM protected against DOX-induced ferroptosis, as evidenced by restored DOX-induced disturbance of redox balance, improved cytosolic and mitochondrial iron regulation, and reduced mitochondrial damage at the gene level. In conclusion, PM attenuated the development of cardiac damage after DOX treatment by reducing myocardial fibrosis, inflammation, and mitochondrial damage and by restoring redox and iron regulation at the gene level, suggesting that PM may be a novel cardioprotective strategy for DOX-induced cardiomyopathy. [ABSTRACT FROM AUTHOR]

The FDA Modernization Act 2.0 has brought nonclinical drug evaluation into a new era. In vitro models are widely used and play an important role in modern drug development and evaluation, including early candidate drug screening and preclinical drug efficacy and toxicity assessment. Driven by regulatory steering and facilitated by well-defined physiology, novel in vitro skin models are emerging rapidly, becoming the most advanced area in alternative testing research. The revolutionary technologies bring us many in vitro skin models, either laboratory-developed or commercially available, which were all built to emulate the structure of the natural skin to recapitulate the skin's physiological function and particular skin pathology. During the model development, how to achieve balance among complexity, accessibility, capability, and cost-effectiveness remains the core challenge for researchers. This review attempts to introduce the existing in vitro skin models, align them on different dimensions, such as structural complexity, functional maturity, and screening throughput, and provide an update on their current application in various scenarios within the scope of chemical testing and drug development, including testing in genotoxicity, phototoxicity, skin sensitization, corrosion/irritation. Overall, the review will summarize a general strategy for in vitro skin model to enhance future model invention, application, and translation in drug development and evaluation. [ABSTRACT FROM AUTHOR]

Simple Summary: This research article reports the complete process of the fabrication and characterization of a targeted radioisotope nanocarrier platform designed for the theranostic management of prostate cancer. The state-of-the-art radiation synthesis of poly(acrylic acid) nanogels is followed by functionalization and radiolabeling, as well as both in vitro and in vivo assessment of the nanoplatform's performance. Despite the need for further optimization of the system, our research is an outstanding example of radionanomedicine applications in the field of theranostic cancer management. Despite the tremendous development of oncology, prostate cancer remains a debilitating malignancy. One of the most promising approaches to addressing this issue is to exploit the advancements of nanomedicine in combination with well-established nuclear medicine and radiotherapy. Following this idea, we have developed a radioisotope nanocarrier platform of electron-beam-synthesized nanogels based on poly(acrylic acid). We have developed a functionalization protocol, showing the very high (>97%) efficiency of the conjugation in targeting a ligand–bombesin derivative. This engineered peptide can bind gastrin-releasing peptide receptors overexpressed in prostate cancer cells; moreover, it bears a radioisotope-chelating moiety. Our nanoplatform exhibits very promising performance in vitro; the radiolabeled nanocarriers maintained high radiochemical purity of >90% in both the labeling buffer and human serum for up to 14 days. The application of the targeted nanocarrier allowed also effective and specific uptake in PC-3 prostate cancer cells, up to almost 30% after 4 h, which is a statistically significant improvement in comparison to carrier-free radiolabeled peptides. Although our system requires further studies for more promising results in vivo, our study represents a vital advancement in radionanomedicine—one of many steps that will lead to effective therapy for castration-resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Propofol, a commonly used intravenous anesthetic, has demonstrated potential in protecting against myocardial ischemia/reperfusion injury (MIRI) based on preclinical animal studies. However, the clinical benefits of propofol in this context are subject to debate. We conducted a systematic search across eight databases to identify all relevant animal studies investigating the preventive effects of propofol on MIRI until October 30, 2023. We assessed the methodological quality of the included studies using SYRCLE's bias risk tool. Statistical analysis was performed using STATA 15.1. The primary outcome measures analyzed in this study were myocardial infarct size (IS) and myocardial injury biomarkers. This study presents a comprehensive analysis of 48 relevant animal studies investigating propofol's preventive effects on MIRI. Propofol administration demonstrated a reduction in myocardial IS and decreased levels of myocardial injury biomarkers (CK-MB, LDH, cTnI). Moreover, propofol improved myocardial function parameters (+dp/dtmax, -dP/dtmax, LVEF, LVFS), exhibited favorable effects on inflammatory markers (IL-6, TNF-α) and oxidative stress markers (SOD, MDA), and reduced myocardial cell apoptotic index (AI). These findings suggest propofol exerts cardioprotective effects by reducing myocardial injury, decreasing infarct size, and improving heart function. However, the absence of animal models that accurately represent comorbidities such as aging and hypertension, as well as inconsistent administration methods that align with clinical practice, may hinder its clinical translation. Further robust investigations are required to validate these findings, elucidate the underlying mechanisms of propofol, and facilitate its potential translation into clinical practice.

Introduction. In Russia, almost half of the cases of acute intestinal infections of established etiology in 2022 are due to rotavirus infection (RVI). There is no specific treatment for rotavirus gastroenteritis. There is a need to develop modern, effective and safe vaccines to combat rotavirus infection that are not capable of multiplying (replicating) in the body of the vaccinated person. A promising approach is to create vaccines based on virus-like particles (VLPs). Objective. Study of the safety and immunogenicity of a vaccine against rotavirus infection based on virus-like particles of human rotavirus A in newborn minipigs with multiple intramuscular administration. Materials and methods. Newborn minipigs were used as an animal model in this study. The safety of the tested vaccine was assessed based on thermometry data, clinical examination, body weight gain, clinical and biochemical blood parameters, as well as necropsy and histological examination. When studying the immunogenic properties of the Gam-VLP-rota vaccine in doses of 30 and 120 µg, the cellular, humoral and secretory immune response was studied. Results. The results of assessing the general condition of animals during the immunization period, data from clinical, laboratory and pathomorphological studies indicate the safety of the vaccine against human rotavirus infection based on VLP (Gam-VLP-rota) when administered three times intramuscularly. Good local tolerance of the tested vaccine was demonstrated. The results of the assessment of humoral immunity indicate the formation of a stable immune response after three-time immunization with Gam-VLP-rota, stimulation of the production of antigen-specific IgG antibodies and their functional activity to neutralize human rotavirus A. It was shown that following the triple immunization with the minimum tested concentration of 30 µg/dose, animals developed a cell-mediated immune response. The results of the IgA titer in blood serum and intestinal lavages indicate the formation of both a systemic immunological response and the formation of specific secretory immunity to human rotavirus A. Conclusion. Thus, three-time intramuscular immunization of minipigs with the Gam-VLP-rota vaccine forms stable protective humoral and cellular immunity in experimental animals. Evaluated vaccine is safe and has good local tolerability.

Abstract Background This systematic review and meta-analysis aimed to evaluate the efficacy of engineered extracellular vesicles (EEVs) in the treatment of ischemic stroke (IS) in preclinical studies and to compare them with natural extracellular vesicles (EVs). The systematic review provides an up-to-date overview of the current state of the literature on the use of EEVs for IS and informs future research in this area. Methods We searched PubMed, EMBASE, Web of Science, Cochrane Library, and Scopus databases for peer-reviewed preclinical studies on the therapeutic effect of EEVs on IS.Databases ranged from the inception to August 1, 2023. The outcome measures included infarct volumes, neurological scores, behavioral scores, apoptosis rates, numbers of neurons, and levels of IL-1β, IL-6, and TNF-α. The CAMARADES checklist was used to assess the quality and bias risks of the studies. All statistical analyses were performed using RevMan 5.4 software. Results A total of 28 studies involving 1760 animals met the inclusion criteria. The results of the meta-analysis showed that compared to natural EVs, EEVs reduced infarct volume (percentage: SMD = -2.33, 95% CI: -2.92, -1.73; size: SMD = -2.36, 95% CI: -4.09, -0.63), improved neurological scores (mNSS: SMD = -1.78, 95% CI: -2.39, -1.17; Zea Longa: SMD = -2.75, 95% CI: -3.79, -1.71), promoted behavioral recovery (rotarod test: SMD = 2.50, 95% CI: 1.81, 3.18; grid-walking test: SMD = -3.45, 95% CI: -5.15, -1.75; adhesive removal test: SMD = -2.60, 95% CI: -4.27, -0.93; morris water maze test: SMD = -3.91, 95% CI: -7.03, -0.79), and reduced the release of proinflammatory factors (IL-1β: SMD = -2.02, 95% CI: -2.77, -1.27; IL-6: SMD = -3.01, 95% CI: -4.47, -1.55; TNF-α: SMD = -2.72, 95% CI: -4.30, -1.13), increasing the number of neurons (apoptosis rate: SMD = -2.24, 95% CI: -3.32, -1.16; the number of neurons: SMD = 3.70, 95% CI: 2.44, 4.96). The funnel plots for the two main outcome measures were asymmetric, indicating publication bias. The median score on the CAMARADES checklist was 7 points (IQR: 6–9). Conclusions This meta-analysis shows that EEVs are superior to natural EVs for the treatment of IS. However, research in this field is still at an early stage, and more research is needed to fully understand the potential therapeutic mechanism of EEVs and their potential use in the treatment of IS. PROSPERO registration number CRD42022368744.

Optogenetic gene therapies offer a promising strategy for restoring vision to patients with retinal degenerative diseases, such as retinitis pigmentosa (RP). Several clinical trials have begun in this area using different vectors and optogenetic proteins (Clinical Identifiers: NCT02556736, NCT03326336, NCT04945772, and NCT04278131). Here we present preclinical efficacy and safety data for the NCT04278131 trial, which uses an AAV2 vector and Chronos as the optogenetic protein. Efficacy was assessed in mice in a dose-dependent manner using electroretinograms (ERGs). Safety was assessed in rats, nonhuman primates, and mice, using several tests, including immunohistochemical analyses and cell counts (rats), electroretinograms (nonhuman primates), and ocular toxicology assays (mice). The results showed that Chronos-expressing vectors were efficacious over a broad range of vector doses and stimulating light intensities, and were well tolerated: no test article-related findings were observed in the anatomical and electrophysiological assays performed.

Intravesical infusion of chemotherapeutics is highly recommended by several clinical guidelines for treating nonmuscle invasive bladder cancer (NMIBC). However, cytotoxic chemotherapeutics can cause a series of side effects, which greatly limits their application. Herein, a starvation therapy strategy was proposed, and elafibranor (ELA) was validated as a safe chemotherapeutic for NMIBC. The results showed that 20 μM ELA was sufficient to inhibit the proliferation and migration of bladder cancer cells and increase the level of intracellular reactive oxygen species (ROS). Furthermore, 2 mg/kg ELA treatment blocked the growth of primary tumors in an immunodeficient model by inhibiting proliferation and inducing apoptosis and improved the survival time of immunocompetent model mice. ELA treatment up to 10 mg/kg met the general safety requirements. We also established a patient-derived conditional reprogramming cell (CRC) model to assess the clinical translational potential of ELA. The antitumor effect and antitumor specificity of ELA treatment were confirmed. This work not only identified a promising chemotherapeutic for NMIBC but also provided a potential methodological system for drug discovery.

ABSTRACT Drug repositioning seeks to discover new applications for a drug that has already been approved in the market, resulting in faster and lower cost solutions, generally used for diseases that receive little investment, such as cutaneous leishmaniasis. In this context, hesperidin, commercially approved as Daflon®, is a flavonoid that belongs to the chalcones group, a class that has antileishmanial potential. The present study evaluated the in vitro and in vivo antileishmanial activity of commercial hesperidin. Hesperidin (9 to 0.56 mg mL-1) was tested against promastigote and amastigote forms of four dermotropic species of Leishmania, namely L. (L.) amazonensis, L. (V.) guyanensis, L. (V.) braziliensis and L. (V.) naiffi. For the in vivo tests, hamsters were infected in the snout and the lesions were treated with intralesional hesperidin. The treatment effectiveness was assessed by measuring the total volume of the lesion on the snout and determining the parasitic load. The in vitro results showed moderate toxicity in murine macrophages, with higher efficacy in L. (L.) amazonensis when compared to the other species tested. The in vivo results showed that hesperidin was able to gradually reduce the size of lesions by L. (L.) amazonensis, although it did not induce clinical and parasitological cure. Thus, hesperidin showed potential in in vitro tests against L. (L.) amazonensis and further studies with new formulations and experimental treatment schemes should be carried out.

Simple Summary: To date, there has been no definite experimental evidence for the significance of circulating tumor cells (CTCs) as an indicator to estimate the chemotherapeutic effect in cancer patients. We previously reported a transient increase in CTC number 1 week after single-dose chemotherapy in human breast, lung, and gastric cancer xenograft mouse models. In the present study, we extensively examined the dynamics of both CTCs and tumor tissues after single and repetitive doses of chemotherapy in two human pancreatic cancer xenograft models to understand the mechanistic aspect of CTC mobilization after chemotherapy. We confirmed the transient increase in CTC number 1–2 weeks after chemotherapy and proposed a hypothesis that transient CTC mobilization after chemotherapy occurs by the shedding of growth-arrested tumor cells into disrupted tumor blood vessels in the primary tumor tissues 1–2 weeks after chemotherapy, which corresponds to the maximal destructive phase of primary tumor tissues before tissue repair and regeneration. Mobilization of CTCs after various types of therapy, such as radiation therapy, has been reported, but systematic study of CTCs after chemotherapy remained quite limited. In this study, we sequentially examined CTC numbers after single-dose and repetitive-dose chemotherapy, including FORFIRINOX (FFX) and Gemcitabine and nab-Paclitaxel (GnP) using two pancreatic cancer xenograft models. CTC was detected by the immunocytology-based microfluidic platform. We further examined the dynamic change in the histology of primary tumor tissues during chemotherapy. We confirmed a transient increase in CTCs 1–2 weeks after single-dose and repetitive-dose of FFX/GnP chemotherapy. Histological examination of the primary tumors revealed that the peak period of CTC at 1–2 weeks after chemotherapy corresponded to the maximal destructive phase consisting of cell cycle arrest, apoptosis of tumor cells, and blood vessel destruction without secondary reparative tissue reactions and regeneration of tumor cells. These findings indicate that mobilization of CTCs early after chemotherapy is mediated by the shedding of degenerated tumor cells into the disrupted blood vessels driven by the pure destructive histological changes in primary tumor tissues. These results suggest that sequential CTC monitoring during chemotherapy can be a useful liquid biopsy diagnostic tool to predict tumor chemosensitivity and resistance in preclinical and clinical settings. [ABSTRACT FROM AUTHOR]

Background: Pulsed‐field ablation (PFA) has emerged as a nonthermal energy source for cardiac ablation, with potential safety advantages over radiofrequency ablation (RFA) and cryoballoon ablation. Objective: To report the preclinical results of a novel hexaspline PFA catheter for pulmonary vein isolation (PVI), and to verify the influence of PFA on esophagus by comparing with RFA. Methods: This study included a total of 15 canines for the efficacy and safety study and four swine for the esophageal safety study. The 15 canines were divided into an acute cohort (n = 3), a 30‐day follow‐up cohort (n = 5) and a 90‐day follow‐up cohort (n = 7), PVI was performed with the novel hexaspline PFA ablation catheter. In the esophageal safety study, four swine were divided into PFA cohort (n = 2) and RFA cohort (n = 2), esophageal injury swine model was adopted, the esophagus was intubated with an esophageal balloon retractor, under fluoroscopy, the DV8 device was inflated with a mixture of saline and contrast and rotated to displace the esophagus rightward and anteriorly toward the ablation catheter in the inferior vena cava (IVC) and right inferior pulmonary vein (PV). Nine PFA applications were delivered at four locations on IVC and two locations on the right inferior PV in the PFA cohort, six RFA applications were delivered at each location in the RFA group. Histopathological analysis of all PVs, esophagus, IVC, and the adjacent lungs was performed. Results: Acute PV isolation was achieved in all 15 canines (100%), with energy delivery times of less than 3 min/animal. In the 30 and 90 days group, the overall success rates were 88.9% and 88.5% per PVs, respectively. Two right superior pulmonary veins (RSPVs) in the 30‐day group, two RSPVs and one left superior PV in the 90‐day group with recovered potentials. At follow‐up, gross pathological examination revealed the lesions around the PVs were continuous and transmural. Masson's trichrome staining revealed the myocardial cells in the PVs became fibrotic, but small arteries and nervous tissue were preserved. Results of swine esophageal injury model revealed the esophageal luminal surface was smooth and without evidence for esophageal injury in the PFA group, whereas obvious ulceration was detected on the esophagus tunica mucosa in the RFA group. Conclusion: In the chronic canine study, PFA‐based PVI were safe and effective with demonstrable sparing of nerves and venous tissue. Compared with RFA, there was also good evidence for safety of PFA, avoiding PV stenosis and esophageal injury. This preclinical study provided the scientific basis for the first‐in‐human endocardial PFA studies. [ABSTRACT FROM AUTHOR]

Resveratrol (RES) has extensively been utilized to treat osteoporosis (OP) in animal models. However, the anti‐OP effects of RES have not been tested during clinical application due to the lack of evidence and poor knowledge of the underlying mechanisms. Moreover, there is little preclinical evidence to support the use of RES in the management of OP. In the present paper, we conducted a preclinical systematic review and meta‐analysis to assess the efficacy of RES in animal OP models. The potential mechanisms underlying the efficacy of RES against OP were summarized. The online databases PubMed, CNKI, EMBASE, Wanfang, Web of Science, Chinese Biomedical Literature, Cochrane Library, and Chinese VIP were retrieved from inception to December 2021. The CAMARADES 10‐item quality checklist was utilized to assess the risk of bias of the included studies. STATA 12.0 software was employed to analyze the data. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Thirteen studies containing 248 animals were included yielding a mean risk of bias score of 5.54 (range 4–7). The pooled estimates showed that the administration of RES could significantly elevate the bone mineral density (BMD) both at femur (SMD = 2.536; 95% CI = 1.950–3.122; p < 0.001) and lumbar spine (SMD = 1.363; 95% CI = 0894–1.832; p < 0.001), bone volume over total volume (BV/TV) (SMD = 2.543; 95% CI = 2.023–3.062; p < 0.001), trabecular linear density (Tb.N) (SMD = 2.724; 95% CI = 2.186–3.262; p < 0.001) and trabecular thickness (Tb.Th) (SMD = 1.745; 95% CI = 1.294–2.196; p < 0.001), while serum phosphorus (S‐P) (SMD = −2.168; 95% CI = −2.753 to −1.583; p < 0.001) and trabecular separation (Tb.Sp) (SMD = −2.856; 95% CI = −4.218 to −1.494; p < 0.001) were significantly reduced in animal OP models. No significant change in serum calcium (S‐Ca) (SMD = −2.448; 95% CI = −5.255–0.360; p = 0.087) was observed after RES treatment. Furthermore, RES could significantly improve the bone biomechanical indexes: bone maximum load (BML) (SMD = 2.563; 95% CI = 1.827–3.299; p < 0.001) and connectivity density (Conn.D) (SMD = 1.512; 95% CI = 0.909–2.116; p < 0.001) and decrease the structural model index (SMI) (SMD = −2.522; 95% CI = −3.243 to −1.801; p < 0.001). Overall, the present study revealed that RES has huge prospects as a medicine or dietary supplement for the clinical treatment of OP. High‐quality studies with stringent designs and larger sample sizes are warranted to substantiate our conclusion. [ABSTRACT FROM AUTHOR]

Background: This systematic review and meta-analysis aimed to evaluate the efficacy of engineered extracellular vesicles (EEVs) in the treatment of ischemic stroke (IS) in preclinical studies and to compare them with natural extracellular vesicles (EVs). The systematic review provides an up-to-date overview of the current state of the literature on the use of EEVs for IS and informs future research in this area. Methods: We searched PubMed, EMBASE, Web of Science, Cochrane Library, and Scopus databases for peer-reviewed preclinical studies on the therapeutic effect of EEVs on IS.Databases ranged from the inception to August 1, 2023. The outcome measures included infarct volumes, neurological scores, behavioral scores, apoptosis rates, numbers of neurons, and levels of IL-1β, IL-6, and TNF-α. The CAMARADES checklist was used to assess the quality and bias risks of the studies. All statistical analyses were performed using RevMan 5.4 software. Results: A total of 28 studies involving 1760 animals met the inclusion criteria. The results of the meta-analysis showed that compared to natural EVs, EEVs reduced infarct volume (percentage: SMD = -2.33, 95% CI: -2.92, -1.73; size: SMD = -2.36, 95% CI: -4.09, -0.63), improved neurological scores (mNSS: SMD = -1.78, 95% CI: -2.39, -1.17; Zea Longa: SMD = -2.75, 95% CI: -3.79, -1.71), promoted behavioral recovery (rotarod test: SMD = 2.50, 95% CI: 1.81, 3.18; grid-walking test: SMD = -3.45, 95% CI: -5.15, -1.75; adhesive removal test: SMD = -2.60, 95% CI: -4.27, -0.93; morris water maze test: SMD = -3.91, 95% CI: -7.03, -0.79), and reduced the release of proinflammatory factors (IL-1β: SMD = -2.02, 95% CI: -2.77, -1.27; IL-6: SMD = -3.01, 95% CI: -4.47, -1.55; TNF-α: SMD = -2.72, 95% CI: -4.30, -1.13), increasing the number of neurons (apoptosis rate: SMD = -2.24, 95% CI: -3.32, -1.16; the number of neurons: SMD = 3.70, 95% CI: 2.44, 4.96). The funnel plots for the two main outcome measures were asymmetric, indicating publication bias. The median score on the CAMARADES checklist was 7 points (IQR: 6–9). Conclusions: This meta-analysis shows that EEVs are superior to natural EVs for the treatment of IS. However, research in this field is still at an early stage, and more research is needed to fully understand the potential therapeutic mechanism of EEVs and their potential use in the treatment of IS. PROSPERO registration number: CRD42022368744. [ABSTRACT FROM AUTHOR]

Exosomes are cell-derived nanovesicles, circulating in different body fluids, and acting as an intercellular mechanism. They can be purified from culture media of different cell types and carry an enriched content of various protein and nucleic acid molecules originating from their parental cells. It was indicated that the exosomal cargo can mediate immune responses via many signaling pathways. Over recent years, the therapeutic effects of various exosome types were broadly investigated in many preclinical studies. Herein, we present an update on recent preclinical studies on exosomes as therapeutic and/or delivery agents for various applications. The exosome origin, structural modifications, natural or loaded active ingredients, size, and research outcomes were summarized for various diseases. Overall, the present article provides an overview of the latest exosome research interests and developments to clear the way for the clinical study design and application. [Display omitted] • An update on recent preclinical studies of exosomes as therapeutics is provided. • Various diseases and applications of exosomes are covered in the present overview. • The exosome origin, structural modifications, and active agents are summarized. • The present review can clear the way for the clinical study design and application. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer, representing approximately 85% of cases. The diagnosis is often made in the middle and late stages, necessitating systemic treatment as the primary therapeutic option. Despite sorafenib being the established standard of care for advanced HCC in the past decade, the efficacy of systemic therapy remains unsatisfactory, highlighting the need for novel treatment modalities. Recent breakthroughs in immunotherapy have shown promise in HCC treatment, particularly with immune checkpoint inhibitors (ICIs). However, the response rate to ICIs is currently limited to approximately 15%-20% of HCC patients. Recently, ICIs demonstrated greater efficacy in "hot" tumors, highlighting the urgency to devise more effective approaches to transform "cold" tumors into "hot" tumors, thereby enhancing the therapeutic potential of ICIs. This review presented an updated summary of the factors influencing the effectiveness of immunotherapy in HCC treatment, identified potential combination therapies that may improve patient response rates to ICIs, and offered an overview of ongoing clinical trials focusing on ICI-based combination therapy. [ABSTRACT FROM AUTHOR]