Search Results (3,381)

Impairment in blood supply to the brain deprives its cells of the much-needed nutrients and molecules such as oxygen and glucose necessary for its development, growth and survival. This will set up a host of pathological processes such as impaired homeostasis, energy failure, excitotoxicity, oxidative stress, impaired protein synthesis, inflammation, cytokine-mediated toxicity and impairment of blood–brain barrier. These pathological processes will result in the damage or death of the cells depending on the extent of the deprivation. Similarly, they will impair synthesis of acetylcholine (Ach) and norepinephrine (NE), which are important neurotransmitters in the cholinergic and adrenergic systems responsible for cellular communication and functions. Thus, interventions to help arrest and/or modulate the initial and subsequent pathological states and help recover the functions of the brain are needed. One of such interventions is vagus nerve stimulation, which helps activate the cholinergic and the adrenergic systems via projections of the afferent fibers of the vagus nerve to the nucleus of the solitary tract (NTS). Activation of the cholinergic and the adrenergic systems results in reduction in pro-inflammatory factors such as tumor necrosis α, increase in pro-angiogenic factors and increase in firing of adrenergic neurons in the central nervous system (CNS). Full article

Cellular senescence and polyploidy are fundamental stress responses that shape cancer progression and therapeutic outcomes. While senescence initially suppresses tumor growth, senescent cells accumulate in aging and therapy-exposed tissues and actively remodel the tumor microenvironment through the senescence-associated secretory phenotype (SASP) and extracellular matrix (ECM) reorganization. Senescent stromal cells increase collagen deposition and generate disordered matrix architectures, as evidenced by enhanced second harmonic generation (SHG) signal and increased anisotropic variation across in vitro systems, 3D co-culture models, and fibrotic lung tissues. These biochemical and mechanical alterations promote cancer cell plasticity and create conditions permissive for disease progression. Polyploid giant cancer cells (PGCCs) are a rare but highly resilient cancer cell population enriched under genotoxic stress. PGCCs arise through mitotic failure, including mitotic slippage and cytokinesis defects, and can survive chemotherapy and radiation due to their altered cell-cycle regulation. Emerging evidence indicates that senescence-driven microenvironments promote the formation of PGCCs and multinucleated cells, linking ECM remodeling and mechanical stress to polyploidization. Functionally, PGCCs exhibit abnormal cytoskeletal and nuclear mechanics that support migratory persistence and enable survival within hostile tumor environments. In addition, PGCCs can promote the survival of neighboring cancer cells during treatment, suggesting a stromal-like role in establishing therapy-resistant niches. These cells can persist in a dormant state and later generate proliferative progeny, contributing to tumor recurrence and metastasis. Together, these findings support a model in which senescent niches may promote PGCC formation, persistence, and tumor repopulation. Targeting both senescence-associated microenvironments and PGCC-specific survival mechanisms may improve long-term therapeutic outcomes. Full article

Chronic inflammation is a well-established risk factor for cancer progression. This review aims to determine how persistent inflammatory signaling reshapes the tissue microenvironment to favor tumor cell proliferation, survival, and progression. It also discusses the role of cytokines such as IL-6 and TGF-β, reactive oxygen species (ROS), and the transcription factors NF-κB and STAT3 in inflammation and in the tumor microenvironment. Sustained activation of these pathways promotes genomic instability, loss of tumor suppressor gene function, enhanced oncogene expression, and resistance to apoptosis, collectively facilitating malignant transformation and tumor development. The key novelty of this review lies in integrating these interconnected networks with new evidence to clarify how they drive cancer initiation and progression. Furthermore, we discuss the therapeutic potential of plant-derived bioactive compounds, with a particular emphasis on curcumin. Curcumin exhibits significant anti-inflammatory and anticancer effects through inhibition of NF-κB and STAT3 signaling and its downstream targets, thereby attenuating inflammation-driven tumorigenesis. However, its clinical application is limited by poor bioavailability. Finally, this review highlights current strategies to overcome these limitations and future directions for optimizing curcumin-based interventions in inflammation-associated diseases. Full article

Background/Objectives: The present study aims to test three different types of PMMA (Fotodent Guide—3D printed (M1), Aidite Temp—milled (M2), Duracryl—self-polymerized (M3) on HFIB-G and on OECM-1. Methods: The two cell types (HFIB-G and OECM-1) were kept in contact with the materials, Fotodent Guide, Aidite Temp, and Duracryl (n = 6), for 24 and 48 h, and subsequently subjected to the following tests: MTT, LDH, NO (according to ISO 10993-5:2009), and immunofluorescent detection of proteins associated with autophagy and apoptosis (mitochondria and caspases 3/7; detection of autophagosomes). Statistical interpretation was made using t-test and ANOVA (* p < 0.05; ** p < 0.01; *** p < 0.001). Results: The MTT assay revealed a reduction in cell viability for all tested materials on gingival fibroblasts compared to control cells, with the most pronounced decrease observed for the 3D-printed material (M1 viability 66.77% for 24 and 52.45% 48 h—p < 0.001), while the self-polymerizing resin (M3 viability 85.92% for 24 h and 85.63% for 48 h) showed the highest level of cellular tolerance (p < 0.001 at 24 h and p < 0.01 at 48 h). Regarding OECM-1 cells, all materials reduced cell viability, particularly M3 after 48 h of incubation (viability 61.79%—p < 0.001). LDH levels generally indicated low membrane damage for all materials. Statistically significant increases in NO levels were recorded for both cell types, suggesting a mild proinflammatory response, especially for M2 OECM-1 48 h—p < 0.05 and M3 (HFIB-G 48 h—p < 0.05, OECM-1 48 h p < 0.05). For both 24 and 48 h, fluorescence analysis demonstrated a significant increase in mitochondrial activity in gingival fibroblasts (p < 0.001), whereas tumor cells exhibited a significantly decreased mitochondrial activity (p < 0.001), particularly for the 3D-printed material M1 (p < 0.001). Caspase-3/7 expression increased in gingival fibroblasts incubated with materials for 24 and 48 h (p < 0.001), while tumor cells showed reduced caspase activity both after 24 and 48 h (p < 0.001). Autophagosome formation decreased initially in fibroblasts at 24 h (p < 0.001) but increased significantly after 48 h (p < 0.001), while tumor cells generally showed enhanced autophagic activity under most experimental conditions (p < 0.001). Conclusions: Our results suggest that all three PMMA-based materials exhibit acceptable biocompatibility profiles, of more than 70%, according to ISO 10993-5:2009, although cellular responses vary depending on the manufacturing technique and the cellular model used. In our study conditions, self-polymerized resin (M3) was the most compatible with gingival fibroblasts, while the 3D-printed and CAD/CAM milled materials (M1 and M2) had a more pronounced impact on cells’ viability and metabolic activity. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide despite advances in screening, navigational bronchoscopy, and systemic therapies. Diagnostic and therapeutic limitations persist, including uncertainty regarding intraprocedural tissue adequacy during biopsy sampling and constraints of existing ablative modalities for tumors located near critical thoracic structures. This review examines two emerging technologies: Full-Field Optical Coherence Tomography-based Dynamic Cell Imaging (DCI) and monopolar biphasic Pulsed Electric Field (PEF) ablation as complementary emerging technologies that may address these gaps. The Van Gogh™ Microscopy System (CellTivity Scientific, Inc.) utilizes DCI to enable real-time visualization of cellular metabolic activity without tissue destruction, providing functional information regarding tissue viability and microstructural morphology. The Aliya^® PEF ablation system (Galvanize Therapeutics, Inc.) delivers biphasic high-voltage electrical pulses that induce non-thermal tumor cell death while preserving extracellular matrix architecture, potentially allowing treatment near sensitive thoracic structures such as airways, vasculature, and pleura. Early preclinical studies and initial clinical experience suggest that DCI can facilitate rapid intraprocedural assessment of biopsy adequacy, while PEF ablation may provide reproducible focal tumor destruction with a favorable safety profile near critical structures. Although the current evidence base remains limited to early-phase studies and feasibility trials, the convergence of real-time biologic tissue assessment with structurally preserving ablation technologies introduces the possibility of integrating diagnostic confirmation and local therapy within a single procedural workflow. This review summarizes the mechanistic rationale, emerging evidence, and potential clinical applications of these technologies and proposes a conceptual “See and Strike” framework within these two emerging technologies. The methodological limitations, workflow considerations, and future research directions required to validate this approach are also discussed. Prospective multicenter trials and long-term oncologic outcomes will be necessary before widespread clinical adoption. Full article

Background: Aspirin, initially recognized for its anti-inflammatory, antipyretic and analgesic properties, holds a prominent role in the treatment of cardiovascular disease. The utility of aspirin in cancer therapeutics has been explored and stratified into COX-dependent and -independent mechanisms. COX2 gene expression has been demonstrated to be significantly upregulated in colorectal cancer and various other gastrointestinal malignancies including pancreatic, esophageal, and gastric cancer. This study investigates the relationship of aspirin use and outcomes in patients with colorectal cancer. Methods: The Nationwide Inpatient Sample (NIS) database from 2017 to 2022 was analyzed for patients age > 18 who were hospitalized for colorectal cancer and its decompensations using ICD-10 diagnostic codes. These patients were further stratified based on the long-term use of aspirin. The principal outcome of this investigation are the odds of in-hospital mortality, with secondary outcomes including odds of pulmonary embolism, portal vein thrombosis, acute kidney injury, septic shock, requiring an ICU level of care and odds of hepatic, pulmonary, gastrointestinal and peritoneal or retroperitoneal metastatic disease. Multivariate logistic regression accounting for hospital and patient characteristics was implemented for analysis, with the Charlson Comorbidity Index used to adjust for coexisting comorbidity burden; a p-value (p) of <0.05 was considered statistically significant. Results: In our analysis of the NIS, 596,160 patients were identified with colorectal cancer and 11.7% (69,750) of this population were identified with long-term use of aspirin. Aspirin use was identified to have a significantly reduced odds of in-patient mortality (adjusted odds ratio) [aOR] 0.530, p value < 0.001 95% CI (confidence interval): 0.460–0.617. Patients with aspirin use also demonstrated significantly reduced odds of adverse outcomes and gastrointestinal, hepatic, pulmonary and retroperitoneal/peritoneal metastasis; (aOR 0.606, 95% CI: 0.564–0.653, p < 0.001), (aOR 0.628, 95% CI: 0.582–0.678, p < 0.001), (aOR 0.676, 95% CI: 0.605–0.755, p < 0.001) and (aOR 0.751, 95% CI: 0.685–0.825, p < 0.001) respectively. Conclusions: In recent years, there has been an alarming increase in incidence of colorectal cancer, particularly amongst younger individuals with increased associated mortality. This mortality increase, albeit alarming, is a driving force for treatment innovation with continual examination of our repertoire of medications for possible repurposed applications. COX2-mediated signaling serves as a key promotor of tumorigenic molecular signaling that directly contributes to tumor cell proliferation, angiogenesis and metastasis in colorectal cancer. Aspirin use and its inhibitory action on COX2 demonstrated a significantly reduced odds of in-hospital mortality. Aspirin use is also associated with significantly reduced odds of developing metastatic disease to the liver, gastrointestinal system, lungs and peritoneum in patients with colorectal cancer. These findings convey that aspirin use reduces the likelihood of in-hospital mortality, major comorbid conditions and of developing metastatic disease as compared to those who do not use aspirin. Full article

Endometriosis is a chronic estrogen-dependent inflammatory disease affecting approximately 10% of women of reproductive age and characterized by ectopic endometrial-like tissue growth. Although traditionally considered a benign gynecological condition, increasing evidence indicates that endometriosis shares several molecular and cellular features with malignant processes, including enhanced proliferation, resistance to apoptosis, invasive behavior, and the ability to remodel the surrounding microenvironment. Recent studies suggest that dysregulated estrogen signaling, particularly the imbalance between estrogen receptor subtypes, plays a central role in driving these processes and may contribute to the persistence and progression of ectopic lesions. In parallel, also the involvement of stem or progenitor cells has been highly investigated because they may support lesion establishment, cellular plasticity, and long-term disease maintenance. These mechanisms overlap with pathways commonly involved in tumor initiation and progression. Recognizing endometriosis as a stem cell-driven and estrogen-dependent condition, the perspective, in both clinical management and therapeutic strategies fields, can change. Indeed, it is essential to emphasize that endometriosis is a benign condition and that the risk of developing an associated tumor is very low, approximately 1.5–2%. This review aims to discuss current evidence on the molecular aspects, focusing on estrogen signaling, stem cell-related mechanisms, and inflammatory and microenvironmental pathways that contribute to disease development. By highlighting these mechanisms, an integrated perspective on the pathophysiology of endometriosis is provided, also to outline potential implications for biomarker discovery and targeted therapeutic strategies. Full article

Sigmar1 is a multifunctional molecular chaperone protein located on the Mitochondria-associated endoplasmic reticulum membranes (MAM). Recent studies have shown that Sigmar1 is not only a regulatory protein involved in cellular stress responses but also plays a significant role in the process of autophagy. It regulates the initiation and progression of autophagy by influencing multiple autophagy-related signaling pathways and interacting with key proteins such as LC3 and GABARAP. This regulation exhibits a dual nature. On one hand, it can induce protective autophagy, helping cells cope with stress such as oxidative stress and endoplasmic reticulum stress, thereby playing a protective role in the progression of diseases such as neurodegenerative disorders and cardiovascular diseases. On the other hand, in certain cancers, Sigmar1 may also promote tumor cell survival through autophagy regulation, thereby exacerbating disease progression. Consequently, developing agonists and antagonists targeting Sigmar1 has become a highly promising therapeutic strategy. This review provides a systematic overview of recent advances in the biological characterization of Sigmar1 and its molecular mechanisms in regulating autophagy. It summarizes the multifaceted roles of Sigmar1 in various diseases and discusses current research progress and the application prospects of Sigmar1 agonists and antagonists, aiming to establish a theoretical foundation for the development of novel Sigmar1-based therapeutic strategies for human diseases. Full article

Background and Objectives: Neuroblastoma represents the most common extracranial solid tumor in childhood and is associated with a poor prognosis in high-risk cases. Amygdalin, a naturally occurring cyanogenic glycoside, has been reported to exhibit anti-tumor properties in various cancer models; however, its effects on neuroblastoma cells remain insufficiently characterized. The present study was conducted with the objective of investigating the effects of amygdalin on cell proliferation, apoptosis, and invasion in SH-SY5Y neuroblastoma cells in vitro. Materials and Methods: The SH-SY5Y neuroblastoma cells were cultivated under the optimal conditions for their growth. The cytotoxic effect of amygdalin was determined using the CCK8 assay, which is dose- and time-dependent. Total RNA isolation was performed using Trizol. Subsequently, a process of cDNA synthesis was initiated. The real-time PCR method was utilized to ascertain alterations in the expression levels of mRNA molecules associated with apoptosis, namely Bax, Bcl2, caspase-3, caspase-7, caspase-8, caspase-9, caspase-10, NFkB, and invasion-related genes MMP2, MMP9, TIMP1, and TIMP3. Furthermore, alterations in NFkB levels were examined through the utilization of the ELISA method. Results: The IC50 value of amygdalin in SH-SY5Y cells was determined to be 112.7 µM at 24 h. Amygdalin demonstrated a dose-dependent cytotoxic effect on neuroblastoma cells. Furthermore, the study revealed that the drug induced apoptosis through the upregulation of BAX and BID, and the downregulation of BCL-2 and NF-κB. This process led to a reduction in cell proliferation. Furthermore, the study demonstrated an anti-invasive effect through the downregulation of MMP9 and the upregulation of TIMP1 and TIMP3. In addition, a substantial decrease in NF-κB protein concentration was observed. Conclusions: These findings demonstrate that amygdalin exerts anti-proliferative, pro-apoptotic, and anti-invasive effects in SH-SY5Y neuroblastoma cells in vitro. Amygdalin may represent a promising natural compound for further investigation as a potential therapeutic agent in neuroblastoma. Full article

Glioma, the most common and aggressive primary brain tumor, presents significant clinical management challenges due to difficulties in blood–brain barrier penetration, high tumor heterogeneity, and susceptibility to drug resistance and recurrence, leading to an extremely poor prognosis. Traditional Chinese Medicine (TCM), particularly its derived active ingredients and herbal formulations, with its advantages of multi-component, multi-target, and holistic regulation, demonstrates significant potential in the comprehensive treatment of this disease. This review systematically outlines the research progress in TCM for combating glioma. Regarding mechanisms of action, active TCM components not only directly inhibit tumors by inducing cell apoptosis but also exert synergistic therapeutic effects via multiple pathways. These include remodeling the immunosuppressive microenvironment, activating novel cell death programs such as ferroptosis and immunogenic cell death, intervening in tumor metabolic reprogramming, and reversing chemotherapy resistance. In terms of overcoming delivery barriers, drug delivery systems represented by nanocarriers, liposomes, and extracellular vesicles, combined with the penetration-enhancing effects of aromatic orifice-opening herbs (a class of TCM medicinals traditionally used to “open the orifices” and awaken the mind, now recognized to transiently enhance BBB permeability), have significantly improved the brain-targeting efficiency and bioavailability of TCM components. For clinical translation, a number of innovative drugs derived from TCM, such as elemene, cinobufagin, and ACT001, are currently under clinical investigation, with initial results showing efficacy in prolonging survival and improving quality of life. In the future, by integrating the analysis of multi-target synergistic mechanisms, promoting the clinical translation of intelligent drug delivery systems, and conducting high-quality clinical research on integrated Chinese and Western medicine, TCM is expected to provide a new generation of integrated treatment strategies for glioma that combines holistic and precision medicine. Full article

Cancer stem cells (CSCs) are a distinct subpopulation within a tumor that play an important role in tumor initiation, metastasis, therapeutic resistance, and cancer relapse. Their persistence is strongly influenced by the tumor microenvironment (TME), which provides a range of biological signals that maintain stemness, promote immune evasion, and resistance to cancer treatment. Therefore, effective targeting of CSCs is essential to improve therapeutic efficacy. In this review, we summarize the key characteristics of CSCs and their niche within the TME, emphasizing their interactions with immune cells, stromal components, and secreted factors. We also discuss the major challenges in targeting CSCs, including immune evasion, metabolic constraints, and intratumoral heterogeneity. We further highlight current and emerging immunotherapeutic strategies targeting CSCs, including immune checkpoint inhibitors, cancer vaccines, monoclonal antibodies, nanobodies, bispecific antibodies, antibody-drug conjugates (ADCs), CAR-T and CAR-NK cell therapies, oncolytic viruses, as well as innovative approaches such as targeted protein degradation. Finally, we emphasize the importance of a combinatorial approach that integrates CSCs targeting with modulation of the TME. Together, these strategies may lead to more durable responses, enhance therapy efficacy and reduce the risk of tumor recurrence. Full article

Objectives: An infectious trigger can initiate a systemic inflammatory response, which in turn activates immune cells and causes the release of various mediators. Local mediators, such as resolvin D1 (RvD1), actively interact with immune cells to promote the resolution of inflammation. This study aimed to determine the impact of RvD1 on the inflammatory response mediated by monocytes in response to LPS. Methods: To investigate the mechanism by which RvD1 affects the monocyte-mediated inflammatory response to LPS, human THP-1 monocytic cells were treated with LPS, RvD1, or vehicle for 24 h. Inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α), were measured using enzyme-linked immunosorbent assay (ELISA). RNA sequencing (RNA-seq) was used to identify differentially expressed genes (DEGs). The NF-κB and MAPK p38 signaling pathways were validated using real-time quantitative PCR (RT-qPCR) and Western blotting (WB). Results: RvD1 diminished the levels of IL-1β and TNF-α in LPS-induced inflammation. RvD1 significantly enhanced the mRNA expression of CREB, NRF2, and BCL-2. In addition, RvD1 significantly decreased the mRNA expression of CASP3. RvD1 regulated the inflammatory process in human monocytic THP-1 cells via the NF-κB p65 (MyD88, p65) and p38 MAPK signaling pathways (p38, BCL-2) and further suppressed the expression of apoptotic factors (PI3K, caspase-3). Conclusions: RvD1 has been shown to exert pro-resolving effects by regulating the anti-apoptotic gene BCL-2 and activating the NF-κB p65 and MAPK p38 signaling pathways. Full article

Background/Objectives: Nutritional strategies targeting redox and immune pathways may help to stabilize redox hemodynamics and support immune competence. Controlled physiological stress models allow examination of how nutrients influence dynamic antioxidant and inflammatory responses. Methods: In this randomized, double-blind, placebo-controlled trial (RCT), 39 healthy, moderately active men (supplement group: n = 20; placebo group: n = 19) received a yeast cell-derived formulation containing β-glucans and micronutrients or placebo for 8 weeks. Two standardized high-intensity interval training (HIIT) sessions (PRE/POST) transiently induced oxidative and inflammatory stress. Outcomes included reactive oxygen species (ROS; whole-blood EPR), total antioxidant capacity (FRAP), superoxide dismutase (SOD), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and upper respiratory tract infection (URTI) incidence and duration. Results: Prior to the intervention period, acute supplement intake resulted in a more pronounced reduction in ROS from 0′ to 60′ compared with placebo (−6.2%; p ≈ 0.14). After eight weeks, fasting FRAP increased only in the supplemented group (p < 0.01). Mixed-model repeated-measures ANOVA demonstrated significant time × group interactions for FRAP in both PRE and POST assessments, indicating differential temporal trajectories. The chronic FRAP increase correlated with the acute ROS reduction (p < 0.05; r² = 0.21). SOD activity was higher in the supplemented group at 60′ in the POST assessment (p < 0.05), and a significant time × group interaction was observed for SOD in POST. TNF-α decreased across the intervention in participants with elevated baseline values, whereas individuals with low initial concentrations showed no change. The supplemented group reported shorter URTI duration (−1.4 days; d = 0.34) and fewer prolonged episodes (>10 days: 5% vs. 15.8%), although these differences were not statistically significant. Conclusions: Eight weeks of supplementation with a yeast cell-derived formulation containing β-glucans and micronutrients was associated with differences in selected redox-related markers, including FRAP and SOD, without altering exercise-induced ROS dynamics. The observed patterns suggest subtle modifications in antioxidant-related response characteristics under standardized physiological stress. These findings warrant further investigation in larger and more heterogeneous cohorts, particularly in populations exposed to higher oxidative or inflammatory burden. Full article

Background/Aim: Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and is characterized by high genetic heterogeneity and poor prognosis. TP53 is the most frequently mutated gene in LUAD and plays a critical role in tumor initiation, progression, and therapeutic resistance. The present study aimed to prioritize TP53-associated drug repurposing candidates in LUAD using an integrative in silico approach. Materials and Methods: A total of 1309 TP53-associated compounds were retrieved from the Gene2Drug database. Drug sensitivity profiles of lung adenocarcinoma cell lines were evaluated using PRISM Repurposing Public 22Q2 viability data obtained from the DepMap platform. Candidate compounds were ranked according to Gene2Drug significance scores (p < 1 × 10⁻³), and compounds with concordant sensitivity patterns in PRISM data were prioritized. Results: LUAD cell lines showed the strongest sensitivity to atropine (p = 6.83 × 10⁻⁵). Additionally, LUAD cell lines displayed consistent sensitivity signals for dropropizine (p = 8.47 × 10⁻³), terazosin (p = 1.11 × 10⁻³), morantel (p = 9.05 × 10⁻³), netilmicin (p = 8.37 × 10⁻³), altretamine (p = 9.82 × 10⁻³), and perphenazine (p = 9.58 × 10⁻³). These findings indicate that several non-oncology drugs exhibit distinct and reproducible sensitivity profiles in LUAD cell lines. Conclusions: Based on TP53-associated drug sensitivity profiles, this in silico analysis identifies atropine among the prioritized candidates, showing the strongest TP53-associated sensitivity signal in LUAD cell lines. Although experimental validation is required, the integration of independent computational datasets provides a robust framework for candidate prioritization and our findings provide a rationale for further preclinical investigation of atropine and related compounds in LUAD. Full article

Background: Vascular abnormalities (VAs) are a broad category of disorders that include vascular malformations (inadequate embryologic blood vessel development) and vascular tumors (characterized by vascular cell hyperplasia). This sometimes-complicated pathology is increasingly being treated with mTOR inhibitors, particularly sirolimus (rapamycin). Only a limited number of neonates treated with sirolimus have been reported in the literature to date, and there is no consensus regarding the optimal treatment regimen for vascular anomalies in this population. The objective of our narrative review is to summarize the most recent information from the specialized literature regarding the efficacy and safety of sirolimus in newborns. Methods: A methodological search was performed through the available data concerning the indications and safety when using sirolimus to treat VAs in newborns. We evaluated articles from the Embase and PubMed academic search engines using the following search terms: (vascular anomalies OR vascular tumors OR venous malformations OR lymphatic malformations OR capillary malformations) AND (neonate) AND (sirolimus OR rapamycin). Results: We identified a lack of consensus regarding indications for treatment initiation, optimal dosing regimens, and duration of therapy. In most published studies, neonates were analyzed within broader pediatric cohorts that included patients up to 18 years of age, rather than as a distinct population. Moreover, only a limited number of investigations have specifically focused on neonates treated with sirolimus and evaluated outcomes from a neonatal subgroup perspective. The available evidence largely consists of isolated case series and reports describing sirolimus use in fetuses and neonates, most commonly for lymphatic malformations or kaposiform hemangioendothelioma; in some instances, sirolimus was administered in combination with propranolol, corticosteroids, or other therapeutic modalities. Nevertheless, across studies and case reports involving fetuses or neonates, sirolimus is generally reported to be effective and well tolerated, with adverse effects that are minimal and reversible. Conclusions: For neonates and even fetuses with large, complex VAs, sirolimus appears to be an effective treatment with no serious adverse events reported to date. Decisions regarding off-label sirolimus initiation should be made by a multidisciplinary team, and parents must be thoroughly informed about potential adverse events. Well-designed randomized controlled trials or high-quality observational studies are needed to further evaluate the efficacy and safety of sirolimus in the neonatal population. Full article