Search Results (281)

Gastrointestinal (GI) cancers represent a significant global health burden, with high morbidity and mortality often linked to late-stage detection and metastatic disease. The progression of these malignancies is critically driven by angiogenesis, the formation of new blood vessels, and the surrounding dynamic tumor microenvironment (TME), a complex ecosystem comprising various cell types and non-cellular components. This comprehensive review, based on a systematic search of the PubMed database, synthesizes the existing literature to define the intertwined roles of angiogenesis and the TME in GI tumorigenesis. The TME’s influence creates conditions favorable for tumor growth, invasion, and metastasis, but sometimes induces resistance to current therapies. Available therapeutic strategies for inhibiting angiogenesis involve antibodies and oral tyrosine kinase inhibitors, while immune modulation within the tumor microenvironment is mainly achieved through checkpoint inhibitor antibodies and chemotherapy. Creative emerging strategies encompassing cellular therapies, bispecific antibodies, and new targets such as CD40, DLL4, and Ang2, amongst others, are focused on inhibiting proangiogenic pathways more profoundly, reversing resistance to prior drugs, and modulating the TME to enhance therapeutic efficacy. A deeper understanding of the complex interactions between components of the TME is crucial for addressing the unmet need for novel and effective therapeutic interventions against aggressive GI cancers. Full article

Lymphangiogenesis, the formation of new lymphatic vessels, is essential for embryonic development and the maintenance of tissue fluid balance, as well as for responding to physiological challenges such as injury, inflammation, and oedema. This process is also aberrantly activated in pathological conditions including lymphatic anomalies and cancer. Understanding the molecular and cellular mechanisms regulating induced lymphangiogenesis in various conditions is critical for the development of novel anti- or pro-lymphangiogenic therapeutic strategies. In recent years, the zebrafish has emerged as an important model organism for studying both physiological and pathological lymphangiogenesis. Its optical transparency, conserved lymphatic architecture and signalling pathways, and amenability to genetic manipulation and drug screening make it an especially well-suited model. In this review, we highlight zebrafish models used to investigate induced lymphangiogenesis in the context of regeneration, inflammation, fluid imbalance, and congenital lymphatic anomalies. We will also demonstrate how zebrafish are used to discover new drugs targeting lymphatic vessels under various conditions. Finally, we will discuss the current limitations of using zebrafish to model induced lymphangiogenesis and highlight potential future directions. The findings presented in this review underscore the undeniable value the zebrafish model brings to lymphatic research and therapeutic discovery. Full article

Retinal ischemia is implicated in ocular diseases involving aberrant neovessel proliferation that characterizes proliferative retinopathies. Their therapy still remains confined to the intravitreal administration of anti-vascular endothelial growth factor (VEGF) medication, which is limited by side effects and progressive reduction in efficacy. Mimicking neovascular diseases in rodents, although of great help for translating fundamental mechanistic findings and assessing therapeutic potential in humans, is limited by the rodent’s short life span, which prevents retinal vessel proliferation over time. However, the oxygen-induced retinopathy (OIR) model, which mimics retinopathy of prematurity, seems to meet some criteria that are common to proliferative retinopathies. The present review provides insight into preclinical models and their suitability to mimic proliferative retinopathies. Further considerations will be applied to emerging approaches and advanced methodologies for the management of proliferative retinopathies, leading to the identification of new therapeutic targets, including our contribution in the field. Major emphasis is given to the possibility of using systemic therapies either alone or in combination with intravitreal anti-VEGF administration to maximize clinical benefits by combining drugs with different modes of action. This review is concluded by an in-depth discussion on future advancements and a critical view of preclinical finding translatability. Despite the major effort of preclinical and clinical research to develop novel therapies, the blockade of VEGF activity still remains the only treatment for proliferative retinopathies for more than twenty years since its first therapeutic application. Full article

Despite notable advancements in clinical care, cardiovascular disease (CVD) remains a leading global cause of mortality. Encompassing a wide range of heart and blood vessel disorders, CVD requires targeted prevention and treatment strategies to mitigate its public health impact. In recent years, extracellular vesicles (EVs) have emerged as crucial mediators of intercellular communication, influencing key processes such as vascular remodeling, inflammation, and immune responses in CVDs. EVs, including exosomes and microvesicles, carry bioactive molecules such as miRNAs, proteins, and lipids that contribute to disease progression. They are released by various cell types, including platelets, erythrocytes, leukocytes, endothelial cells, and cardiomyocytes, each playing distinct roles in cardiovascular homeostasis and pathology. Given their presence in circulating blood and other body fluids, EVs are increasingly recognized as promising non-invasive biomarkers for CVD diagnosis and prognosis. Furthermore, EV-based therapeutic strategies, including engineered EVs for targeted drug delivery, are being explored for treating atherosclerosis, myocardial infarction, heart failure, and hypertension. However, challenges remain regarding the standardization of EV isolation and characterization techniques, which are critical for their clinical implementation. This review highlights the diverse roles of EVs in CVD pathophysiology, their potential as diagnostic and prognostic biomarkers, and emerging therapeutic applications, clearing the way for their integration into cardiovascular precision medicine. Full article

Rheumatoid arthritis (RA) is a progressive and systemic autoimmune disease, characterized by a chronic inflammatory process, affecting the lining of the synovial joints, many body organs/systems, and blood vessels. Its pathological hallmarks are hyperplasic synovium, bone erosion, and progressive joint destruction. Rheumatoid arthritis affects over 20 million people, with a worldwide prevalence of 0.5–1.0%, exhibiting gender, ethnic, and geographical differences. The progressive disability severely impairs physical motion and quality of life and is finally leading to a shortened life span. The pathogenesis of RA is a complex and still poorly understood process in which genetic and environmental factors are principally associated. Current treatment mostly relies on conventional/non-biological disease-modifying anti-rheumatic drugs (cDMARDs), analgesics, non-steroidal anti-inflammatory drugs, glucocorticoids, steroids, immunosuppresants, and biologic DMARDs, which only control inflammation and pain. Along with side effects (drug toxicity and intolerance), these anti-rheumatic drugs possess limited efficacy. Therefore, the discovery of novel multi-target therapeutics with an improved safety profile that function as inhibitors of RA-linked signaling systems are in high demand, and this is in the interest of both patients and clinicians. Plant-derived extracts, nutritional supplements, dietary medicine, and molecules with anti-inflammatory activity represent promising adjuvant agents or alternatives for RA therapeutics. This review not only aims to discuss the basic features of RA pathogenesis, risk factors, and signaling pathways but also highlights the research progress in pre-clinical RA in in vitro and in vivo models, revealing new avenues in the management of the disease in terms of comprehensive multidisciplinary strategies originating from medicinal plants and plant-derived molecules. Full article

Arteriovenous malformations (AVMs) are congenital vascular anomalies defined by abnormal direct connections between arteries and veins due to their complex structure or endovascular approaches. Pharmacological strategies targeting the underlying molecular mechanisms are thus gaining increasing attention in an effort to determine the mechanism involved in AVM regulation. In this study, we examined 30 human tissue samples, comprising 10 vascular samples, 10 human fibroblasts derived from AVM tissue, and 10 vascular samples derived from healthy individuals. The pharmacological agents thalidomide, U0126, and rapamycin were applied to the isolated endothelial cells (ECs). The pharmacological treatments reduced the proliferation of AVM ECs and downregulated miR-135b-5p, a biomarker associated with AVMs. The expression levels of angiogenesis-related genes, including VEGF, ANG2, FSTL1, and MARCKS, decreased; in comparison, CSPG4, a gene related to capillary networks, was upregulated. Following analysis of these findings, skin samples from 10 AVM patients were reprogrammed into induced pluripotent stem cells (iPSCs) to generate AVM blood vessel organoids. Treatment of these AVM blood vessel organoids with thalidomide, U0126, and rapamycin resulted in a reduction in the expression of the EC markers CD31 and α-SMA. The establishment of AVM blood vessel organoids offers a physiologically relevant in vitro model for disease characterization and drug screening. The authors of future studies should aim to refine this model using advanced techniques, such as microfluidic systems, to more efficiently replicate AVMs’ pathology and support the development of personalized therapies. Full article

Stroke, the third leading cause of death worldwide, is a major cause of functional disability. Cerebral ischemia causes a rapid elevation of adenosine, the main neuromodulator in the brain. The inhibition of adenosine A2A receptors (A2ARs) has been introduced as a potential target in neurodegenerative disorders involving extracellular adenosine elevation. Istradefylline, a selective A2AR antagonist, has been approved for Parkinson’s disease (PD) adjunctive therapy and showed neuroprotective effects in PD and Alzheimer’s disease. However, the role of A2ARs in post-stroke neuronal damage and behavioral deficits remains unclear. We recently showed that A2AR antagonism prevented the adenosine-induced post-hypoxia synaptic potentiation of glutamatergic neurotransmission following the hypoxia/reperfusion of hippocampal slices. Here, we investigated the potential neuroprotective effects of istradefylline in male Sprague-Dawley rats subjected to pial vessel disruption (PVD) used to model a small-vessel stroke. Rats were treated with either a vehicle control or istradefylline (3 mg/kg i.p.) following PVD surgery for three days. Istradefylline administration prevented anxiety and depressive-like behaviors caused by PVD stroke. In addition, istradefylline significantly attenuated ischemia-induced cognitive impairment and motor deficits. Moreover, istradefylline markedly reduced hippocampal neurodegeneration, as well as GFAP/Iba-1, TNF-α, nNOS, and iNOS levels after PVD, but prevented the downregulation of anti-inflammatory markers TGF-β1 and IL-4. Together, these results suggest a molecular link between stroke and PD and that the anti-PD drug istradefylline displays translational potential for drug repurposing as a neuroprotective agent for cerebral ischemic damage. Full article

Tumour-associated angiogenesis plays a key role at all stages of cancer development and progression by providing a nutrient supply, promoting the creation of protective niches for therapy-resistant cancer stem cells, and supporting the metastatic cascade. Therapeutic strategies aimed at vascular targeting, including vessel disruption and/or normalisation, have yielded promising but inconsistent results, pointing to the need to set up reliable models dissecting the steps of the angiogenic process, as well as the ways to interfere with them, to improve patients’ outcomes while limiting side effects. Murine models have successfully contributed to both translational and pre-clinical cancer research, but they are time-consuming, expensive, and cannot recapitulate the genetic heterogeneity of cancer inside its native microenvironment. Non-animal technologies (NATs) are rapidly emerging as invaluable human-centric tools to reproduce the complex and dynamic tumour ecosystem, particularly the tumour-associated vasculature. In the present review, we summarise the currently available NATs able to mimic the vascular structure and functions with progressively increasing complexity, starting from two-dimensional static cultures to the more sophisticated tri-dimensional dynamic ones, patient-derived cultures, the perfused engineered microvasculature, and in silico models. We emphasise the added value of a “one health” approach to cancer research, including studies on spontaneously occurring tumours in companion animals devoid of the ethical concerns associated with traditional animal studies. The limitations of the present tools regarding broader use in pre-clinical oncology, and their translational potential in terms of new target identification, drug development, and personalised therapy, are also discussed. Full article

The tumor microenvironment (TME) is a unique ecosystem that surrounds tumor tissues. The TME is composed of extracellular matrix, immune cells, blood vessels, stromal cells, and fibroblasts. These environments enhance cancer development, progression, and metastasis. Recent success in immune checkpoint blockade also supports the importance of the TME and immune cells residing in the tumor niche. Although the TME can be identified in almost all cancer types, the role of the TME may not be similar among different cancer types. Regulatory T cells (Tregs) play a pivotal role in immune homeostasis and are frequently found in the TME. Owing to their suppressive function, Tregs are often considered unfavorable factors that allow the immune escape of cancer cells. However, the presence of Tregs is not always linked to an unfavorable phenotype, which can be explained by the heterogeneity and plasticity of Tregs. In this review, the current understanding of the role of Tregs in TME is addressed for each cancer cell type. Moreover, recently a therapeutic approach targeting Tregs infiltrating in the TME has been developed including drug antibody conjugate, immunotoxin, and FOXP3 inhibiting peptide. Thus, understanding the role of Tregs in the TME may lead to the development of novel therapies that directly target the TME. Full article

Background/Objectives: We sought to confirm the performance and safety of the Pantera Lux paclitaxel-coated balloon (pDCB) when used as per the instructions for use at a single high-volume center. Methods: In this retrospective analysis, 386 consecutive patients were categorized into three groups: the treatment of drug-eluting stent in-stent restenosis (DES-ISR) lesions (n = 191), bare-metal stent in-stent restenosis (BMS-ISR) lesions (n = 127), and de novo lesions (n = 68). The primary endpoint at 12 months was target-lesion revascularization (TLR). Secondary endpoints were device success, target-vessel myocardial infarction (TV-MI), and cardiac death. Results: The baseline characteristics were balanced between the groups, with a median age of 71.3 years, 25% being female, 32% being diabetic. The majority presented with chronic coronary syndrome (82.9%). Type C lesions were more often observed in the DES-IRS group as compared with the BMS-IRS and de novo groups (15.6% vs. 7.9% vs. 7.4%, p < 0.001). Cutting balloons were more often used in the DES-IRS group (41.0% vs. 19.7% vs. 1.5%, p < 0.001). The residual stenosis rate was 7.6% vs. 3.3% vs. 7.3% (p = 0.002). The TLR at 12 months was 8.9% vs. 2.4% vs. 1.5% (p = 0.013). Device success was achieved in 98.8% vs. 98.5% vs. 100% of cases (p = 0.8). TV-MI occurred in 3.2% vs. 0.8% vs. 1.5% (p = 0.5) and cardiac death in 2.6% vs. 0.0% vs. 2.9% (p = 0.13) in DES-IRS vs. BMS-IRS vs. de novo lesions. Conclusions: In this single-center observation, we confirmed the safety and efficacy of the Pantera Lux paclitaxel-coated balloon for the treatment of DES-IRS, BMS-IRS, and de novo lesions with low TLR rates at 12 months. Full article

This research focuses on the development, design, implementation, and testing (with complete hardware and software integration) of a 6D Electromagnetic Actuation (EMA) system for the precise control and navigation of micro/nanorobots (MNRs) in high-viscosity fluids, addressing critical challenges in targeted drug delivery within complex biological environments, such as blood vessels. The primary objective is to overcome limitations in the actuation efficiency, trajectory stability, and accurate path-tracking of MNRs. The EMA system utilizes three controllable orthogonal pairs of Helmholtz coils to generate uniform magnetic fields, which magnetize and steer MNRs in 3D for orientation. Another three controllable orthogonal pairs of Helmholtz coils generate uniform magnetic fields for the precise 3D orientation and steering of MNRs. Additionally, three orthogonal pairs of Maxwell coils generate uniform magnetic field gradients, enabling efficient propulsion in dynamic 3D fluidic environments in real time. This hardware configuration is complemented by three high-resolution digital microscopes that provide real-time visual feedback, enable the dynamic tracking of MNRs, and facilitate an effective closed-loop control mechanism. The implemented closed-loop control technique aimed to enhance trajectory accuracy, minimize deviations, and ensure the stable movement of MNRs along predefined paths. The system’s functionality, operation, and performance were tested and verified through various experiments, focusing on hardware, software integration, and the control algorithm. The experimental results show the developed system’s ability to activate MNRs of different sizes (1 mm and 0.5 mm) along selected desired trajectories. Additionally, the EMA system can stably position the MNR at any point within the 3D fluidic environment, effectively counteracting gravitational forces while adhering to established safety standards for electromagnetic exposure to ensure biocompatibility and regulatory compliance. Full article

Background: In patients with coronary artery disease, bare-metal stents (BMS) are considered a safer but less effective treatment than drug-eluting stents (DES). Oral colchicine therapy may compensate for this limitation of BMS. This randomized trial compared the cost-effectiveness of two different revascularization strategies during percutaneous coronary intervention (PCI). Methods: Between March 2020 and April 2022, 410 patients were randomly treated with PCI with BMS plus colchicine (BMS-CO: 205 patients) or DES (205 patients) The patients in the BMS-CO group received 0.5 mg oral doses of colchicine for 3 months. The primary endpoint was major adverse cardiac and cerebrovascular events (MACEs), defined as the composite of death, myocardial infarction, stroke, or target vessel revascularization (TVR), and the costs of each treatment strategy. The secondary endpoints included the individual components of MACEs. Results: No significant differences were observed in baseline characteristics, and 76% of the patients presented with acute coronary syndromes. The median follow-up period was 36.8 months. Five percent of the patients in the BMS-CO group discontinued study medication. The cumulative incidence of MACEs was not significantly different, with 12.7% in the BMS-CO group and 15.6% in the DES2G group (p = 0.39) as well individual components of the clinical endpoint. The cumulative costs were lower in the BMS-CO group than in the DES2G group (USD 4826.4 ± 2512 vs. USD 5708 ± 3637, p < 0.001). Conclusions: In the 3 years, the DES strategy failed to be cost-saving compared to BMS-CO. However, due to the small sample size, the equivalence in clinical outcomes with both strategies can occur by chance (NCT04382443). Full article

Background: A drug-coated balloon (DCB) is an emerging treatment technology for percutaneous coronary intervention (PCI). However, the prognostic factors of PCI with a DCB remain fully determined. Chronic kidney disease (CKD) is an independent predictor of adverse outcomes in patients with coronary artery disease (CAD) who underwent PCI. The aim of this present study was to clarify the impact of CKD on prognosis in CAD patients who underwent PCI with a DCB. Methods: We enrolled 252 consecutive patients with CAD who underwent PCI with a DCB from 2015 to 2023. The endpoints of this study were composite events including all-cause death, myocardial infarction, target vessel revascularization, stroke, and major bleeding. Results: The prevalence rate of CKD was 48%. Patients with CKD were older and had higher prevalence of hypertension and diabetes mellitus than those without. Kaplan–Meier analysis revealed a significantly higher composite event rate in patients with CKD (log-rank test, p = 0.003). In the multivariate Cox proportional hazards analysis, CKD was independently associated with composite events after adjusting for confounding factors (adjusted hazard ratio 1.985, 95% confidence intervals 1.157–3.406, p = 0.013), mainly driven by all-cause deaths. Conclusions: CKD was associated with unfavorable outcomes in CAD patients who underwent PCI with a DCB. Full article

The “angiogenesis switch”—defined as the active process by which solid tumors develop their own circulation—plays an important role in both tumoral growth and propagation. As the malignant tumor grows and reaches a critical size, the metabolic needs as a function of an ever-increasing distance to the nearest emergent blood vessel, can no longer be covered by the microenvironment of the peritumoral tissue. Although a relatively discrete process, the “angiogenic switch” acts as a limiting stage of tumoral development present from the avascular hyperplasia phase to the vascularized neoplastic phase, providing support for tumor expansion and metastasis. Over time, research has focused on blocking the angiogenetic pathways (such as VEGF/VEGFR signaling axis) leading to the development of targeted therapeutic agents such as Bevacizumab. Objectives: We conducted a review of the molecular principles of tumoral angiogenesis and we tried to follow the history of Bevacizumab from its first approval for human usage 20 years ago to current days, focusing on the impact this agent had in solid tumor therapy. A comprehensive review of clinical trials pertaining to Bevacizumab (from the era of the preclinic trials leading to approval for human usage, to the more recent randomized trial focusing on combination targeted therapy) further details the role of this drug. We aimed to establish if this ancient drug continues to have a place in modern oncology. Conclusions: Bevacizumab, one of the first drugs targeting tumoral microenvironment, remains one of the most important oncologic agents blocking the VEGF/VEGFR angiogenic pathway. otherwise, history of 20 years marked by numerous controversies (ranging from methodological errors of clinical trials to withdrawal of approval for human usage in breast cancer patients, from discussions about severe side effects to resistance to therapy and limited efficacity), Bevacizumab continues to provide an optimal therapeutic option for many solid tumors that previously had little to no means of treatment, improving otherwise bleak outcomes. Even in the era of personalized precision oncology, Bevacizumab continues to be a key element in many therapeutic regimens both as monotherapy and in combination with newer targeted agents. Full article

Drug-coated balloons (DCBs) are designed to deliver an anti-proliferative drug to the stenotic vessel to combat restenosis after an angioplasty treatment. However, significant drug loss can occur during device navigation toward the lesion site, thus reducing the delivery efficiency and increasing the off-target drug loss. In this framework, this study aimed to design a novel in vitro setup to estimate the drug loss due to blood flow–coating interaction during tracking. The system consists of a millifluidic chamber, able to host small drug-coated flat patches representative of DCBs, connected at the inlet to a syringe pump able to provide an ad hoc flow and, at the outlet, to a vial collecting the testing fluid with possible drug removed from the specimen. Unlike other studies, the device presented here uniquely evaluates flow-related drug loss from smaller-scale DCB samples, making it a precise, easy-to-use, and efficient assessment tool. In order to define proper boundary conditions for these washing off tests, computational fluid dynamics (CFD) models of a DCB in an idealized vessel were developed to estimate the wall shear stresses (WSSs) experienced in vivo by the device when inserted into leg arteries. From these simulations, different target WSSs were identified as of interest to be replicated in the in vitro setup. A combined analytical–CFD approach was followed to design the testing system and set the flow rates to be imposed to generate the desired WSSs. Finally, a proof-of-concept study was performed by testing eight coated flat specimens and analyzing drug content via high-performance liquid chromatography (HPLC). Results indicated different amounts of drug loss according to the different imposed WSSs and confirmed the suitability of the designed system to assess the washing off resistance of different drug coatings for angioplasty balloons. Full article