Preclinical Research Articles

Oligodendrocyte Injury in Multiple Sclerosis.

Introduction: Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS), marked by inflammation, demyelination, and significant oligodendrocyte injury. This disease arises from a complex interplay of genetic predispositions and environmental triggers that drive immune-mediated damage to oligodendrocytes and myelin proteins. This research paper explores the multifaceted aspects of oligodendrocyte injury in MS, ranging from underlying pathophysiological mechanisms to potential therapeutic interventions and translational implications for clinical practice. Oligodendrocyte damage in MS occurs via multiple mechanisms, including metabolic stress, oxidative damage, and cytokine-induced apoptosis, mainly mediated by interferon-gamma (IFN-γ) signaling. This process exacerbates neuroinflammation and contributes to disease progression. Emerging therapeutic strategies, such as targeting metabolic pathways, reducing oxidative stress, and enhancing autophagy, have demonstrated potential in preclinical studies. Furthermore, stem cell therapies are being explored for their ability to regenerate oligodendrocytes and restore myelin integrity. Conclusions: The intricate interplay among oligodendrocyte injury, demyelination, and neuroinflammation is central to multiple sclerosis (MS) pathogenesis. Oligodendrocytes safeguard myelin in the CNS, facing challenges from immune attacks to metabolic stress. Understanding oligodendrocyte dysfunction is vital for targeted therapies that suppress immune damage and promote remyelination and CNS repair. MS's etiology,

Nanoparticle innovations in targeted cancer therapy: advancements in antibody-drug conjugates.

Antibody-drug conjugates (ADCs) have emerged as a promising strategy in targeted cancer therapy, enabling the precise delivery of cytotoxic agents to tumor sites while minimizing systemic toxicity. However, traditional ADCs face significant limitations, including restricted drug loading capacity, where an optimal drug-to-antibody ratio (DAR) is crucial; low DARs may lead to insufficient potency, while high DARs can cause rapid clearance and increased toxicity. Additionally, ADCs often suffer from instability in circulation due to the potential for premature release of cytotoxic agents, resulting in off-target effects and reduced therapeutic efficacy. Furthermore, their large size can impede adequate penetration into solid tumors, particularly in heterogeneous environments with varying antigen expressions. This review explores the innovative use of nanoparticles as carriers for ADCs, which offers a multifaceted approach to enhance therapeutic efficacy. By leveraging the unique properties of nanoparticles, such as their small size and ability to exploit the enhanced permeability and retention (EPR) effect, researchers can improve drug stability, prolong circulation time, and achieve more effective tumor targeting. Recent studies demonstrate that nanoparticle-encapsulated ADCs can significantly enhance treatment outcomes while reducing off-target effects, as evidenced by improved targeting capabilities and reduced toxicity in preclinical models. Despite the promising advancements, challenges remain, including potential nanoparticle toxicity and manufacturing complexities. This review aims to provide a comprehensive overview of the current research on nanoparticle-encapsulated ADCs. It highlights their potential to transform cancer treatment and offers insights into future directions for optimizing these advanced therapeutic strategies.

FORCE platform overcomes barriers of oligonucleotide delivery to muscle and corrects myotonic dystrophy features in preclinical models

BackgroundWe developed the FORCETM platform to overcome limitations of oligonucleotide delivery to muscle and enable their applicability to neuromuscular disorders. The platform consists of an antigen-binding fragment, highly specific for the human transferrin receptor 1 (TfR1), conjugated to an oligonucleotide via a cleavable valine-citrulline linker. Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by expanded CUG triplets in the DMPK RNA, which sequester splicing proteins in the nucleus, lead to spliceopathy, and drive disease progression.MethodsMultiple surrogate conjugates were generated to characterize the FORCE platform. DYNE-101 is the conjugate designed to target DMPK and correct spliceopathy for the treatment of DM1. HSALR and TfR1hu/mu;DMSXLTg/Tg mice were used as models of myotonic dystrophy, the latter expresses human TfR1 and a human DMPK RNA with >1,000 CUG repeats. Cynomolgus monkeys were used to determine translatability of DYNE-101 pharmacology to higher species.ResultsIn HSALR mice, a surrogate FORCE conjugate achieves durable correction of spliceopathy and improves myotonia to a greater extent than unconjugated ASO. In patient-derived myoblasts, DYNE-101 reduces DMPK RNA and nuclear foci, consequently improving spliceopathy. In TfR1hu/mu;DMSXLTg/Tg mice, DYNE-101 reduces mutant DMPK RNA in muscle, thereby correcting splicing. Reduction of DMPK foci in cardiomyocyte nuclei accompanies these effects. Low monthly dosing of DYNE-101 in TfR1hu/mu;DMSXLWT/Tg mice or cynomolgus monkeys leads to a profound reduction of DMPK expression in muscle.ConclusionsThese data validate FORCE as a drug delivery platform and support the notion that DM1 may be treatable with low and infrequent dosing of DYNE-101.

Novel Therapies for Right Ventricular Failure.

Traditionally viewed as a passive player in circulation, the right ventricle (RV) has become a pivotal force in hemodynamics. RV failure (RVF) is a recognized complication of primary cardiac and pulmonary vascular disorders and is associated with a poor prognosis. Unlike treatments for left ventricular failure (LVF), strategies such as adrenoceptor signaling inhibition and renin-angiotensin system modulation have shown limited success in RVF. This review aims to reassure about the progress in RVF treatment by exploring the potential of contemporary therapies for heart failure, including angiotensin receptor andneprilysin inhibitors, sodium-glucose co-transporter 2 inhibitors, and soluble guanylate cyclase stimulators, which may be beneficial for treating RV failure, particularly when associated with left heart failure. Additionally, it examines novel therapies currently in the pipeline. Over the past decade, a new wave of RVF therapies has emerged, both pharmacological and device-centered. Novel pharmacological interventions targeting metabolism, calcium homeostasis, oxidative stress, extracellular matrix remodeling, endothelial function, and inflammation have shown significant promise in preclinical studies. There is also a burgeoning interest in the potential of epigenetic modifications as therapeutic targets for RVF. Undoubtedly, a deeper understanding of the mechanisms underlying RV failure, both with and without pulmonary hypertension, is urgently needed. This knowledge is not just a theoretical pursuit, but a crucial step that could lead to the development of pharmacological and cell-based therapeutic options that directly target the RV and pulmonary vasculature, aligning with the principles of precision medicine.

Sotatercept in pulmonary hypertension and beyond.

Sotatercept binds free activins by mimicking the extracellular domain of the activin receptor type IIA (ACTRIIA). Additional ligands are BMP/TGF-beta, GDF8, GDF11 and BMP10. The binding with activins leads to the inhibition of the signalling pathway and the deactivation of the bone morphogenic protein (BMP) receptor type 2. In this way, sotatercept activates an antiproliferative signalling to the cells of the pulmonary arteries and arterioles with the aim of rebalancing the proliferative and antiproliferative pathway that characterizes the pulmonary arterial hypertension (PAH). Sotatercept is indicated for the treatment of group 1 PAH in combination with drugs that act through the endothelin receptor, nitric oxide or prostacyclin. Its effects, demonstrated in the STELLAR study, are the improvement of exercise capacity and the FC-WHO functional class, together with the reduction of the risk of clinical worsening events. In addition to its antiremodeling effects on the pulmonary circulation, sotatercept has several haematological effects that could suggest its use in the treatment of some blood disorders other than PAH. In this review, we will discuss the effects of the drug on PAH and in parallel provide an in-depth overview of its application in haematological disorders, focusing on clinical and preclinical studies.

Intranasal administration of antiseizure drugs using new formulation trends: one step closer to reach clinical trials.

Although there are numerous options for epilepsy treatment, its effective control continues unsatisfactory. Thus, search for alternative therapeutic options to improve the efficacy/safety binomial of drugs becomes very attractive to investigate. In this context, intranasal administration of antiseizure drugs formulated on state-of-the-art nanosystems can be a promising strategy. This work gives a comprehensive overview of different intranasal nanosystems for antiseizure drugs administration developed and evaluated on preclinical studies over the last 10 years and published in 'PubMed' and 'Web of Science' databases. Additionally, it highlights their pharmaceutical critical quality attributes and in vivo pharmacological outputs that might infer possible results when transposing to clinical trials. Research into optimized nanosystems encapsulating antiseizure drugs to enhance direct nose-to-brain delivery increased over the last years. Particularly, the interest in formulating first and second generation antiseizure drugs in nanoparticles are here highlighted, been demonstrated its in vivo safety and improvement on pharmacokinetic and efficacy outputs. Still, none of them were brought to clinical trials. Thus, considering the existing barriers between preclinical and clinical trials, if supported by robust and targeted quality by design approaches, intranasal drug delivery can be presented as a valid and superior alternative for epilepsy treatment.

Role of neuropeptide Y in development of valproate-induced eating behaviour disorder

Background. Eating behaviour disorder (EBD) induced by valproic acid (VPA) is one of the components of the pathogenesis of a serious complication of therapy with VPA and its salts such as VPA-induced metabolic syndrome (MetS). About 20% of patients receiving VPA have weight gain, which is also a consequence of altered eating behaviour in such patients. Substances such as neuropeptide Y (NPY), leptin, orexin and ghrelin are involved in the regulation of eating behaviour. NPY has received special attention in recent years because it is one of the most potent brain orexigenic peptides and its expression level directly affects the quantity and quality of food intake. NPY overexpression is associated with EBD, food preferences, obesity, and MetS.Objective: to review preclinical and clinical studies of NPY role as a potential sensitive and specific serum biomarker of VPA-EBD, secondary weight gain and VPA-MetS development in children and adults with epilepsy.Material and methods. We analyzed Russian and foreign publications submitted to eLibrary, PubMed/MEDLINE, Scopus, and Google Scholar databases between 2014 and 2024. The full-text articles in Russian and English (original studies, systematic reviews, meta-analyses, Cochrane reviews, and clinical cases) were analyzed. After the selection procedure, 53 out of 1105 publications retrieved by query keywords were included in the analysis.Results. VPA-EDB refers to multifactorial diseases, requiring to take into account the additive contribution of external (food education, eating habits of the patient and family members) and internal (key hormones and neuropeptides regulating appetite and food preferences, the dose and duration of VPA intake, the metabolic rate of VPA) factors while assessing a risk of its development. NPY-associated VPA-EDB affects dietary preferences in favor of high-calorie food and beverages, increases the frequency of meals, the risks of insulin resistance, hyperglycemia as one of the major domains in MetS pathogenesis.Conclusion. VPA-EBD requires timely diagnosis, as it can cause VPA-MetS. NPY is an important biomarker of VPA-EBD, because recent studies have convincingly demonstrated that this neuropeptide is involved in the regulation of eating behavior in patients with epilepsy.

State-of-the-Art Liver Cancer Organoids: Modeling Cancer Stem Cell Heterogeneity for Personalized Treatment.

Liver cancer poses a global health challenge with limited therapeutic options. Notably, the limited success of current therapies in patients with primary liver cancers (PLCs) may be attributed to the high heterogeneity of both hepatocellular carcinoma (HCCs) and intrahepatic cholangiocarcinoma (iCCAs). This heterogeneity evolves over time as tumor-initiating stem cells, or cancer stem cells (CSCs), undergo (epi)genetic alterations or encounter microenvironmental changes within the tumor microenvironment. These modifications enable CSCs to exhibit plasticity, differentiating into various resistant tumor cell types. Addressing this challenge requires urgent efforts to develop personalized treatments guided by biomarkers, with a specific focus on targeting CSCs. The lack of effective precision treatments for PLCs is partly due to the scarcity of ex vivo preclinical models that accurately capture the complexity of CSC-related tumors and can predict therapeutic responses. Fortunately, recent advancements in the establishment of patient-derived liver cancer cell lines and organoids have opened new avenues for precision medicine research. Notably, patient-derived organoid (PDO) cultures have demonstrated self-assembly and self-renewal capabilities, retaining essential characteristics of their respective in vivo tissues, including both inter- and intratumoral heterogeneities. The emergence of PDOs derived from PLCs serves as patient avatars, enabling preclinical investigations for patient stratification, screening of anticancer drugs, efficacy testing, and thereby advancing the field of precision medicine. This review offers a comprehensive summary of the advancements in constructing PLC-derived PDO models. Emphasis is placed on the role of CSCs, which not only contribute significantly to the establishment of PDO cultures but also faithfully capture tumor heterogeneity and the ensuing development of therapy resistance. The exploration of PDOs' benefits in personalized medicine research is undertaken, including a discussion of their limitations, particularly in terms of culture conditions, reproducibility, and scalability.

Quantification and prediction of human fetal (-)-Δ9-tetrahydrocannabinol/(±)-11-OH-Δ9-tetrahydrocannabinol exposure during pregnancy to inform fetal cannabis toxicity

Prenatal cannabis use is associated with neurodevelopmental deficits, likely due to exposure to the psychoactive cannabinoid, (-)-Δ9-tetrahydrocannabinol, and its active metabolite, (±)-11-OH-Δ9-tetrahydrocannabinol. To determine causality, preclinical studies mimicking human fetal cannabinoid exposure must be conducted. Here we show cannabinoid concentrations across gestation in maternal plasma and paired fetal tissues in trimester 1 and 2 and maternal plasma and fetal umbilical venous plasma in trimester 3. The mean ± SD trimester 1 and 2 (-)-Δ9-tetrahydrocannabinol fetal brain/maternal plasma is 0.50 ± 0.18 (n = 3), 0.45 ± 0.28 (n = 14), respectively; trimester 3 (-)-Δ9-tetrahydrocannabinol umbilical venous plasma/maternal plasma is 0.35 ± 0.13 (n = 18). To predict fetal cannabinoid exposure at different prenatal cannabis doses (oral or inhaled), we used a verified maternal-fetal physiologically based pharmacokinetic model. At an inhalational and oral dose of 10 mg (-)-Δ9-tetrahydrocannabinol, the model-predicted average fetal brain steady-state (-)-Δ9-tetrahydrocannabinol/(±)-11-OH-Δ9-tetrahydrocannabinol concentrations, at gestational week 15, are 3.7/7.0 nM and 0.73/8.9 nM, respectively. Our maternal-fetal physiologically based pharmacokinetic model can guide future studies to inform risks associated with prenatal cannabis use.

Current status of nanofat in the management of knee osteoarthritis: A systematic review

BACKGROUND Osteoarthritis (OA) is a prevalent joint disorder requiring innovative treatment approaches. AIM To evaluate the use of nanofat, a specialized form of adipose tissue-derived cells, in the treatment of OA, by examining its efficacy, safety profile, mechanisms of action, comparative effectiveness, and long-term outcomes. METHODS A comprehensive review of preclinical studies, clinical trials, and in vitro investigations was conducted. The included studies provided insights into the potential role of nanofat in OA treatment, addressing its efficacy, safety profile, mechanisms of action, comparative effectiveness, and long-term outcomes. RESULTS Clinical studies consistently reported the efficacy of nanofat in providing pain relief and functional improvement in patients with OA. Local adverse events were limited to the injection site, such as localized pain and inflammation, and resolved within a few days to weeks. Systemic adverse events were rare, and no significant long-term complications were observed. Mechanistically, nanofat was found to enhance chondrocyte proliferation, reduce inflammation, and promote angiogenesis, thereby contributing to its therapeutic effects. CONCLUSION Nanofat therapy holds promise as a therapeutic option for managing OA, providing pain relief, functional improvement, and potential tissue regeneration. The safety profile of nanofat treatment appears favorable, but long-term data are still limited. Standardized protocols, larger randomized controlled trials, longer follow-up periods, and cost-effectiveness evaluations are warranted to establish optimal protocols, comparative effectiveness, and long-term outcomes. Despite current limitations, nanofat therapy demonstrates translational potential and should be considered in clinical practice for OA treatment, with careful patient selection and monitoring.

Biologically relevant integration of transcriptomics profiles from cancer cell lines, patient-derived xenografts, and clinical tumors using deep learning.

Cell lines and patient-derived xenografts are essential to cancer research; however, the results derived from such models often lack clinical translatability, as they do not fully recapitulate the complex cancer biology. Identifying preclinical models that sufficiently resemble the biological characteristics of clinical tumors across different cancers is critically important. Here, we developed MOBER, Multi-Origin Batch Effect Remover method, to simultaneously extract biologically meaningful embeddings while removing confounder information. Applying MOBER on 932 cancer cell lines, 434 patient-derived tumor xenografts, and 11,159 clinical tumors, we identified preclinical models with greatest transcriptional fidelity to clinical tumors and models that are transcriptionally unrepresentative of their respective clinical tumors. MOBER allows for transformation of transcriptional profiles of preclinical models to resemble the ones of clinical tumors and, therefore, can be used to improve the clinical translation of insights gained from preclinical models. MOBER is a versatile batch effect removal method applicable to diverse transcriptomic datasets, enabling integration of multiple datasets simultaneously.

Biofabricated 3D Intestinal Models as an Alternative to Animal-Based Approaches for Drug Toxicity Assays.

The main challenge in new drug development is accurately predicting the human response in preclinical models. In this study, we developed three different intestinal barrier models using advanced biofabrication techniques: (i) a manual model containing Caco-2 and HT-29 cells on a collagen bed, (ii) a manual model with a Caco-2/HT-29 layer on a HDFn-laden collagen layer, and (iii) a 3D bioprinted model incorporating both cellular layers. Each model was rigorously tested for its ability to simulate a functional intestinal membrane. All models successfully replicated the structural and functional aspects of the intestinal barrier. The 3D bioprinted intestinal model, however, demonstrated superior epithelial barrier integrity enhanced tight junction formation, microvilli development, and increased mucus production. When subjected to Ibuprofen, the 3D bioprinted model provided a more predictive response, underscoring its potential as a reliable in vitro tool for drug toxicity testing. Our 3D bioprinted intestinal model presents a robust and predictive platform for drug toxicity assessments, significantly reducing the need for animal testing. This model not only aligns with ethical testing protocols but also offers enhanced accuracy in predicting human responses, thereby advancing the field of drug development.

A phase I study of MLN4924 and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome

PurposeRelapsed and/or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome continue to have a poor prognosis with limited treatment options despite advancements in rational combination and targeted therapies. Belinostat (an HDAC inhibitor) and Pevonedistat (a NEDD8 inhibitor) have each been independently studied in hematologic malignancies and have tolerable safety profiles with limited single-agent activity. Preclinical studies in AML cell lines and primary AML cells show the combination to be highly synergistic, particularly in high-risk phenotypes such as p53 mutant and FLT-3-ITD positive cells. Here, we present the safety, pharmacokinetics and pharmacodynamics of belinostat and pevonedistat in a dose escalation Phase I study in AML and High-Risk MDS.MethodsEighteen patients (16 with AML, 2 with MDS) were treated at 5 dose levels (belinostat 800–1000 mg/m2, pevonedistat 20–50 mg/m2). Safety and tolerability were assessed according to protocol defined dose limiting toxicities (DLTs). Correlative pharmacokinetic and pharmacodynamic analyses were performed.ResultsNo dose limiting toxicities were noted. Most Grade 3 or 4 toxicities were hematologic in nature. The best response was stable disease in four patients, and complete remission in one patient who qualified as an exceptional responder. Pharmakokinetic studies revealed no association between drug exposure and best response. Pharmacodynamic RT-PCR studies demonstrated post-treatment increases in several proteins, including quantitative increases in the oxidative stress protein NQO1, ferroptosis protein SLC7A11, and GSR, linked to glutathione metabolism and oxidative stress, as did the anti-oxidants SRXN1 and TXNRD1.ConclusionsPatterns of post-treatment changes in correlative pharmacodynamic parameters may suggest possible mechanistic changes in the DNA damage response, oxidative damage, and ferroptosis pathways. The combination of pevonedistat plus belinosat is safe in an adult relapsed and/or refractory AML/High-Risk MDS population with modest but notable activity in this heavily treated, high risk population. Our findings also raise the possibility that certain extremely poor prognosis AML patients may respond to a regimen combining two targeted agents that have little or no activity when administered individually.Trial registrationClinicalTrials.gov ID NCT03772925, first posted 12/12/2018; CTEP Identifier 10246.

Exploring the anticancer activities of Sulfur and magnesium oxide through integration of deep learning and fuzzy rough set analyses based on the features of Vidarabine alkaloid

Drug discovery and development is a challenging and time-consuming process. Laboratory experiments conducted on Vidarabine showed IC50 6.97 µg∕mL, 25.78 µg∕mL, and ˃ 100 µg∕mL against non-small Lung cancer (A-549), Human Melanoma (A-375), and Human epidermoid Skin carcinoma (skin/epidermis) (A-431) respectively. To address these challenges, this paper presents an Artificial Intelligence (AI) model that combines the capabilities of Deep Learning (DL) to identify potential new drug candidates, Fuzzy Rough Set (FRS) theory to determine the most important chemical compound features, Explainable Artificial Intelligence (XAI) to explain the features’ importance in the last layer, and medicinal chemistry to rediscover anticancer drugs based on natural products like Vidarabine. The proposed model aims to identify potential new drug candidates. By analyzing the results from laboratory experiments on Vidarabine, the model identifies Sulfur and magnesium oxide (MgO) as new potential anticancer agents. The proposed model selected Sulfur and MgO based on Interpreting their promising features, and further laboratory experiments were conducted to validate the model’s predictions. The results demonstrated that, while Vidarabine was inactive against the A-431 cell line (IC50 ˃ 100 µg∕mL), Sulfur and MgO exhibited significant anticancer activity (IC50 4.55 and 17.29 µg/ml respectively). Sulfur displayed strong activity against A-549 and A-375 cell lines (IC50 3.06 and 1.86 µg/ml respectively) better than Vidarabine (IC50 6.97 and 25.78 µg/ml respectively). However, MgO showed weaker activity against these two cell lines. This paper emphasizes the importance of uncovering hidden chemical features that may not be discernible without the assistance of AI. This highlights the ability of AI to discover novel compounds with therapeutic potential, which can significantly impact the field of drug discovery. The promising anticancer activity exhibited by Sulfur and MgO warrants further preclinical studies.

Exploring the Potential Use of Probiotics, Prebiotics, Synbiotics, and Postbiotics as Adjuvants for Modulating the Vaginal Microbiome: a Bibliometric Review.

Women's health is related to several factors that include physical, mental, and reproductive health. Additionally, the vaginal microbiota modulation performs a fundamental role in the regulation of physiological homeostasis and dysbiosis, which provides us a potential overview of the use of different biotic agents and their implications for female health. The objective of this work was propitiated insights and conception about the influence of probiotics, prebiotics, synbiotics, and postbiotics as adjuvants for prevention/treatment on the main infections that can affect women's health. Therefore, seventy-one studies published in the Web of Science Core Collection database from 1999 to 2024 were evaluated and performed to a bibliometric analysis employing the VOSviewer software for scientific mapping and network analysis. Our results suggest that administration of biotic agents as adjuvants are relevant for the prevention and/or treatment of the main diseases that affect female health, since they contribute to a healthy vaginal microbiota through anti-inflammatory and antimicrobial activities. Most clinical studies have demonstrated the effectiveness of intervention using probiotics to the detriment of other biotic agents in women's health, being bacterial vaginosis, polycystic ovary syndrome, and vulvovaginal candidiasis, the main diseases evaluated. However, preclinical studies have emphasized that the inhibition of pathogens responsible for the process of vaginal dysbiosis may be due to the formation of biofilm and the synthesis of compounds that could prevent the adhesion of these microorganisms. Future perspectives point to the beneficial modulation of the vaginal microbiota by biotic agents as a promising adjuvant approach to improve women's health.

Further Validating the Robotic Microsurgery Platform through Preclinical Studies on Rat Femoral Artery and Vein.

This research aims to validate the proficiency and accuracy of the robotic microsurgery platform using rat femoral vessel model. A total of 256 rat femoral vessels were performed, half using robotic and the other by manual microanastomosis by eight microsurgeons with less than 5 years of experience given eight trials (rats) each. Vessel demographics, proficiency (duration of suture and Structured Assessment of Robotic Microsurgical Skills [SARMS]), and accuracy (patency and scanning electron microscopic [SEM]) were analyzed between the two groups. Using the robot, an average of four trials was needed to reach a plateau in total anastomosis time and patency. Significant more time was required for each vessel anastomosis (34.33 vs. 21.63 minutes on the eighth trial, p < 0.001) one factor being a higher number of sutures compared with the handsewn group (artery: 7.86 ± 0.51 vs. 5.86 ± 0.67, p = 0.035, vein: 12.63 ± 0.49 vs. 9.57 ± 0.99, p = 0.055). The SARMS scores became nonsignificant between the two groups on the fourth trial. The SEM showed a higher tendency of unevenly spaced sutures, infolding, and tears in the vessel wall for the handsewn group. Using the robot, similar patency, accuracy, and proficiency can be reached through a fast but steep learning process within four trials (anastomosis of eight vessels) as the handsewn group. The robotic anastomosis may take longer time, but this is due to the increased number of sutures reflecting higher precision and accuracy. Further insight of precision and accuracy was found through the SEM demonstrating the possibility of the robot to prevent unexpected and unwanted complications.

Targeting TRPC channels for control of arthritis-induced bone erosion.

Arthritis leads to bone erosion due to an imbalance between osteoclast and osteoblast function. Our prior investigations revealed that the Ca2+-selective ion channel, Orai1, is critical for osteoclast maturation. Here, we show that the small-molecule ELP-004 preferentially inhibits transient receptor potential canonical (TRPC) channels. While ELP-004 minimally affected physiological RANKL-induced osteoclast maturation in murine bone marrow- and spleen-derived myeloid cells (BMSMCs) and human PBMC-derived cells, it potently interfered with osteoclast maturation driven by TNFα or LTB4. The contribution of TRPC channels to osteoclastogenesis was examined using BMSMCs derived from TRPC4-/- or TRPC(1-7)-/- mice, again revealing preferential interference with osteoclastogenesis driven by proinflammatory cytokines. ELP-004 also reduced bone erosion in a mouse model of rheumatoid arthritis. These investigations reveal TRPC channels as critical mediators of inflammatory bone erosion and provide insight into the major target of ELP-004, a drug currently in preclinical testing as a therapeutic for inflammatory arthritis.

Photoprotective Effects of Phytochemicals on Blue Light-Induced Retinal Damage: Current Evidence and Future Perspectives

The widespread use of light-emitting diodes (LEDs) has increased blue light (BL) exposure, raising concerns about its potential adverse effects on ocular health. Prolonged exposure to BL has been implicated in the pathogenesis of various retinal disorders, including age-related macular degeneration (AMD), primarily through mechanisms involving oxidative stress and inflammation mediated by the overproduction of reactive oxygen species (ROS). This review synthesizes current evidence on the photoprotective properties of dietary bioactive compounds, (e.g., anthocyanins, curcumin, quercetin, myricetin, and resveratrol), with a focus on their potential to mitigate BL-induced retinal damage. Accumulating research suggests that dietary antioxidants, particularly polyphenols, may offer photoprotective benefits. These phytochemicals act by neutralizing ROS and enhancing the retina’s endogenous antioxidant capacity. Based on these findings, this review advocates for a food-first approach in future investigations, emphasizing the development of evidence-based dietary recommendations to bolster retinal health and mitigate the risk of BL-related ocular diseases. Considering the current lack of empirical clinical studies examining the impact of BL on human ocular health, future research in the field of BL hazard should prioritize two key approaches: conducting large-scale epidemiological dietary surveys and implementing clinical trials on functional ingredients that have demonstrated beneficial effects against photodamage in preclinical animal studies.

Gadolinium oxide nanoparticles as a multimodal contrast enhancement agent for pre-clinical proton imaging

Orthotopic tumor models in pre-clinical translational research are becoming increasingly popular, raising the demands on accurate tumor localization prior to irradiation. This task remains challenging both in x-ray and proton computed tomography (xCT and pCT, respectively), due to the limited contrast of tumor tissue compared to the surrounding tissue. We investigate the feasibility of gadolinium oxide nanoparticles as a multimodal contrast enhancement agent for both imaging modalities. We performed proton radiographies at the experimental room of the Trento Proton Therapy Center using a MiniPIX-Timepix detector and dispersions of gadolinium oxide nanoparticles in sunflower oil with mass fractions up to 8wt%. To determine the minimum nanoparticle concentration required for the detectability of small structures, pCT images of a cylindrical water phantom with cavities of varying gadolinium oxide concentration were simulated using a dedicated FLUKA Monte Carlo framework. These findings are complemented by simulating pCT at dose levels from 80 mGy to 320 mGy of artificially modified murine xCT data, mimicking different levels of gadolinium oxide accumulation inside a fictitious tumor volume. To compare the results obtained for proton imaging to x-ray imaging, cone-beam CT images of a cylindrical PMMA phantom with cavities of dispersions of oil and gadolinium oxide nanoparticles with mass fractions up to 8wt% were acquired at a commercial pre-clinical irradiation setup. For proton radiography, considerable contrast enhancement was found for a mass fraction of 4wt%. Slightly lower values were found for the simulated pCT images at imaging doses below 200 mGy. In contrast, full detectability of small gadolinium oxide loaded structures in xCT at comparable imaging dose is already achieved for 0.5wt%. Achieving such concentrations required for pCT imaging inside a tumor volume inin-vivoexperiments may be challenging, yet it might be feasible using different targeting and/or injection strategies.

Investigation into Drug-Induced Liver Damage Using Multimodal Mass Spectrometry Imaging.

Drug toxicity during the development of candidate pharmaceuticals is the leading cause of discontinuation in preclinical drug discovery and development. Traditionally, the cause of the toxicity is often determined by histological examination, clinical pathology, and the detection of drugs and/or metabolites by liquid chromatography-mass spectrometry (LC-MS). While these techniques individually provide information on the pathological effects of the drug and the detection of metabolites, they cannot provide specific molecular spatial information without additional experiments. Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) is a powerful, label-free technique for the simultaneous detection of pharmaceuticals, metabolites, and endogenous chemical species in tissue sections, which makes it suitable for mechanistic toxicological studies to directly correlate the distribution of the drug and its metabolites with histological findings. This capability was demonstrated by the analysis of the liver from dogs dosed with discontinued drug compound B and its N-desmethyl metabolite, compound A. Histological examination showed multifocal hepatocellular necrosis, bile duct hyperplasia, periportal fibrosis, and chronic inflammation. MALDI-MSI analysis of liver tissue dosed with only compound A indicated that liver lesions were associated exclusively with the parent compound, whereas liver lesions with compound B showed the presence of the parent compound and its two metabolites (compound A and an N-oxide metabolite). Using both positive and negative ion modes, simultaneous detection and identification of endogenous molecular markers of the connective tissue, blood vessels, liver parenchyma, and bile duct epithelium was achieved, allowing optimal visualization of histological lesions by mass spectrometry imaging.