BACKGROUND:Kaposiform hemangioendothelioma (KHE) is an aggressive vascular tumor that primarily affects young children. This study aims to comprehensively analyze research trends and review current clinical treatments in KHE. MATERIALS AND METHODS:Publications related to KHE from 1993 to 2024 were retrieved from the Web of Science Core Collection database and analyzed bibliometrically using VOSviewer, CiteSpace, and the R package "bibliometrix." Additionally, studies involving clinical treatment were further reviewed to analyze therapeutic efficacy and associated adverse events (AEs). RESULTS:A total of 320 publications were included. An overall upward trajectory in annual publication counts was observed. The majority of top-cited papers originated from hospitals in the United States. Pediatric Dermatology was the most productive journal, and the most co-cited journal was the Journal of Pediatrics. The United States was the most collaborative, while China was the most productive. Sichuan University ranked as the top research institution, with Yi Ji from its affiliated West China Hospital having the highest H-index. Current research topics mainly focus on clinical characteristics and sirolimus treatment of KHE. Regarding the clinical treatments for KHE, sirolimus has emerged as the primary drug for KHE treatment due to its superior efficacy over other agents, with upper respiratory tract infections and oral mucositis being the most common AEs. CONCLUSION:This study is the first bibliometric analysis to provide a comprehensive overview of current research topics and trends in KHE. In addition, our results showed that sirolimus has emerged as the primary drug for KHE treatment.

BACKGROUND:Infantile hemangioma (IH) is the most common benign tumor in infancy and severely affects aesthetics and function. Hemangioma-derived endothelial cells (HemECs) are the main cellular component of IH and contribute to angiogenesis in IH. TGF-β1 (transforming growth factor β1) can induce endothelial-to-mesenchymal transition (EndoMT). Few studies have investigated the role and mechanism of TGF-β1-mediated EndoMT in IH angiogenesis. METHODS:The expression of EndoMT markers in IH samples was evaluated via multiplexed immunofluorescence assay. Lentiviruses and small interfering RNA were used to regulate gene expression. Targeted lipidomic analysis was subsequently conducted. Protein interactions between TGF-β1 and potential effectors were examined. Biological changes in function were measured by migration, invasion, and tube formation in vitro and vessel formation in vivo. Autophagy-related structures were detected via transmission electron microscopy. BALB/C-nude mice were used for the hemangioma model. RESULTS:In this study, the active participation of EndoMT in proliferating IH was verified. TGF-β1OE (TGF-β1 overexpression) induced EndoMT and promoted the migration, invasion, and angiogenic abilities of HemECs. In addition, TGF-β1OE decreased the protein expression of CPT1A (carnitine palmitoyltransferase 1A). TGF-β1 treatment decreased the levels of L-palmitoylcarnitine (a downstream metabolite of CPT1A) in HemECs. Supplementation with L-palmitoylcarnitine partly reversed the functional changes caused by CPT1AKD (CPT1A knockdown). Furthermore, the effect of TGF-β1OE+overexpression model of CPT1A was similar to that of CPT1AKD+L-palmitoylcarnitine in regulating the functional behaviors of HemECs. R(+) propranolol inhibited HemECs EndoMT and vessel formation in vivo. CONCLUSIONS:TGF-β1-mediated EndoMT promotes angiogenesis in IH. Targeting TGF-β1 could be a promising therapeutic strategy for inhibiting IH progression.

BACKGROUND:Oral propranolol is the first-line treatment for problematic infantile hemangiomas (IHs) requiring systematic therapy. Several retrospective studies have reported the successful treatment of facial IHs with propranolol. In this study, the authors conducted a prospective trial to evaluate the long-term outcomes of oral propranolol use in patients with facial IHs. METHODS:The primary outcome was the clinical response 4 years after treatment. RESULTS:A total of 272 patients were analyzed, including 38 patients (14.0%) with ulcerated IHs. Four years after treatment, propranolol treatment had resulted in no/minimal sequelae in 232 patients (85.3%). A total of 265 patients (97.4%) reported a durable response to propranolol therapy. Major rebound occurred in 16.9% of patients after propranolol discontinuation. Additional surgery and laser treatment were required in 8.1% and 8.8% of patients, respectively. Logistic regression analyses revealed that age 3 months or older (95% CI, 1.488 to 31.023; P = 0.013), nasal IH (95% CI, 2.143 to 97.571; P = 0.006), and hemangioma ulceration (95% CI, 2.673 to 49.034; P = 0.001) were independent factors predictive of long-term severe/significant sequelae. Segmental subtype (95% CI, 2.081 to 45.597; P = 0.004), mixed IH (95% CI, 3.249 to 26.841; P < 0.001), and lip IH (95% CI, 2.224 to 92.278; P = 0.005) were independent risk factors for major rebound. CONCLUSIONS:In this large cohort of patients with facial IHs, propranolol treatment was effective and induced no/minimal sequelae at 4 years after treatment. However, long-term severe/significant sequelae and major rebound after propranolol treatment remain challenges.

Objective: The diagnosis of abdominal lymphatic malformations (ALMs) is often overlooked in clinical practice. However, reports in the literature about ALMs are limited to case reports and series with small sample sizes. This study aimed to review our currently available data to describe the clinical characteristics of ALMs and evaluate the risk factors for acute abdomen caused by ALMs. Methods: We reviewed the records of patients with ALMs who were diagnosed between December 2008 and January 2023 in our institution. The associations between acute abdomen and ALMs were analyzed based on single-factor and multivariate logistic regression analyses. Results: This study included 345 patients with pathologically confirmed ALMs, with a slight female predominance of 1:1.4. Approximately 39.1% (135/345) of patients were asymptomatic, and 24.6% (85/345) presented with acute abdomen. Among the ALMs in the cohort, 42.6% (147/345) were retroperitoneal lymphatic malformations (LMs). The maximal lesion dimensions in patients with acute abdomen and nonacute abdomen were 10.0 cm and 7.8 cm, respectively, with no significant difference based on multivariate analyses. Children were more likely to develop acute abdomen than adults were (P = . 002: odds ratio, 5.128: 95% confidence interval, 1.835-14.326). ALMs accompanying acute abdomen were more common for lesions involving the small intestinal mesentery (P = . 023: odds ratio, 2.926: 95% confidence interval, 1.157-7.400). Conclusions: ALMs are rare with an insidious onset, and retroperitoneal LMs are the most common ALMs, followed by jejunal mesenteric LMs. Our retrospective analysis suggested that young age and small intestinal mesenteric lymphatic malformation are independent risk factors for acute abdomen with ALMs. (J Vasc Surg Venous Lymphat Disord 2025:13:101969.)

Cardiovascular diseases, mainly caused by atherosclerosis, are the leading causes of morbidity and mortality worldwide. Despite the discrepancies in clinical manifestations between different abnormalities, atherosclerosis shares similar pathophysiological processes, such as mitochondrial dysfunction. Cardiolipin (CL) is a conserved mitochondria-specific lipid that contributes to the cristae structure of the inner mitochondrial membrane (IMM). Alterations in the CL, including oxidative modification, reduced quantity, and abnormal localization, contribute to the onset and progression of atherosclerosis. In this review, we summarize the knowledge that CL is involved in the pathogenesis of atherosclerosis. On the one hand, CL and its oxidative modification promote the progression of atherosclerosis via several mechanisms, including oxidative stress, apoptosis, and inflammation in response to stress. On the other hand, CL externalizes to the outer mitochondrial membrane (OMM) and acts as the pivotal “eat-me” signal in mitophagy, removing dysfunctional mitochondria and safeguarding against the progression of atherosclerosis. Given the imbalance between proatherogenic and antiatherogenic effects, we provide our understanding of the roles of the CL and its oxidative modification in atherosclerotic cardiovascular diseases, in addition to potential therapeutic strategies aimed at restoring the CL. Briefly, CL is far more than a structural IMM lipid; broader significances of the evolutionarily conserved lipid need to be explored.

Infantile hemangioma (IH) is the most common benign tumor in infants and usually resolves on its own. However, a small portion of IH cases are accompanied by serious complications and other problems, impacting the physical and psychological health of the children affected. The pathogenesis of IH is highly controversial. Studies have shown that abnormal blood vessel formation is an important pathological basis for the development of IH. Compared with that in normal tissues, the equilibrium of blood vessel growth at the tumor site is disrupted, and interactions among other types of cells, such as immune cells, promote the rapid proliferation and migration of vascular tissue cells and the construction of vascular networks. Currently, propranolol is the most common systemic drug used to inhibit the growth of IHs and accelerate their regression. The purpose of this review is to provide the latest research on the mechanisms of angiogenesis in IH. We discuss the possible roles of three major factors, namely, estrogen, hypoxia, and inflammation, in the development of IH. Additionally, we summarize the key roles of tumor cell subpopulations, such as pericytes, in the proliferation and regression of IH considering evidence from the past few years, with an emphasis on the possible mechanisms of propranolol in the treatment of IH. Angiogenesis is an important event during the development of IH, and an in-depth understanding of the molecular mechanisms of angiogenesis will provide new insights into the biology and clinical treatment of IH.

Infantile hemangioma (IH) is the most common benign tumor in children. However, the exact pathogenesis of IH remains unclear. Integrated nontargeted and targeted metabolic analyses were performed to obtain insight into the possible pathogenic mechanism of IH. The results of nontargeted metabolic analysis showed that 216 and 128 differential metabolites (DMs) were identified between hemangioma-derived endothelial cells (HemECs) and HUVECs in positive-ion and negative-ion models, respectively. In both models, these DMs were predominantly enriched in pathways related to amino acid metabolism, including aminoacyl-tRNA biosynthesis and arginine and proline metabolism. Then, targeted metabolic analysis of amino acids was further performed to further clarify HemEC metabolism. A total of 22 amino acid metabolites were identified, among which only 16 metabolites, including glutamine, arginine and asparagine, were significantly differentially expressed between HemECs and HUVECs. These significant amino acids were significantly enriched in 10 metabolic pathways, including ‘alanine, aspartate and glutamate metabolism’, ‘arginine biosynthesis’, ‘arginine and proline metabolism’, and ‘glycine, serine and threonine metabolism’. The results of our study revealed that amino acid metabolism is involved in IH. Key differential amino acid metabolites, including glutamine, asparagine and arginine, may play an important role in regulating HemEC metabolism.

Aging is widespread worldwide and a significant risk factor for cardiovascular disease (CVD). Mechanisms underlying aging have attracted considerable attention in recent years. Remarkably, aging and CVD overlap in numerous ways, with deregulated nutrient sensing as a common mechanism and lifestyle as a communal modifier. Interestingly, lifestyle triggers or suppresses multiple nutrient-related signaling pathways. In this review, we first present the composition of the nutrient-sensing network (NSN) and its metabolic impact on aging and CVD. Secondly, we review how risk factors closely associated with CVD, including adverse life states such as sedentary behavior, sleep disorders, high-fat diet, and psychosocial stress, contribute to aging and CVD, with a focus on the bridging role of the NSN. Finally, we focus on the positive effects of beneficial dietary interventions, specifically dietary restriction and the Mediterranean diet, on the regulation of nutrient metabolism and the delayed effects of aging and CVD that depend on the balance of the NSN. In summary, we expound on the interaction between lifestyle, NSN, aging, and CVD.

Objective:To analyze the clinical features, differential diagnosis, treatment and prognosis of complex lymphatic malformations.Methods:The clinical data of patients with complex lymphatic malformation were retrospectively analyzed from April 2010 to April 2022 in the Multidisciplinary Outpatient Department of the Vascular Disease Team of West China Hospital, Sichuan University. All patients were diagnosed with complex lymphatic malformation after consultation with multidisciplinary experts in pediatric surgery, radiology, plastic surgery, pathology, rehabilitation and other departments. The clinical manifestations, blood routine, coagulation function, magnetic resonance imaging and treatment methods of the patients were analyzed. According to the follow-up and disease results, the patients were divided into improvement, stability, progress and death.Results:A total of 18 patients with complex lymphatic malformations were included in the study, including 6 males and 12 females. The age of first diagnosis ranged from 1 month to 29 years old, and the median age was 2.5 years old. Patients were followed up and treated for 0.4 to 12.0 years, with an average follow-up of 3.5 years. Ten patients had pleural and pericardial effusion; 15 patients had visceral involvement which showed multifocal changes in imaging examinations; 9 cases were accompanied by bone destruction, which in Gorham-Stout disease patients broke through the cortex while in generalized lymphatic anomalies it did not; 14 patients had various degrees of coagulation abnormalities, of which 8 patients with severe coagulation dysfunction were all diagnosed as kaposiform lymphangiomatosis. Of the 18 patients, one kaposiform lymphangiomatosis patient died; six patients progressed; eight patients were stable; and three patients improved.Conclusion:The clinical characteristics of patients with complex lymphatic malformations are systemic, diverse and complex. The clinical symptoms of patients with diffuse lymphatic malformation accompanied by involvement of bone and multiple internal organs, chest and abdominal effusion, and coagulation dysfunction should be considered as complex lymphatic malformation. However, due to overlapping clinical characteristics of each subtypes, it is difficult to distinguish patients with complex lymphatic malformation, and the curative effect and prognosis are poor. Precision targeted drugs are the future research direction for the treatment of such diseases.

Protein Z (PZ), a vitamin-K-dependent anticoagulant glycoprotein, is reported to be highly expressed in various malignant tissues and correlated with a poor prognosis in patients with lung cancer. This study aimed to investigate the pathological activity of PZ on lung cancer cell migration, invasion, and metastasis. PZ was assessed by Western blot in three non-small-cell lung cancer cell lines (A549, H1299, and H1975). Meanwhile,western blot was used to detect the expression of EMT pathway-related proteins (Slug, Vimentin, and N-cadherin) in the A549 cells knocked down with siRNA. The cellular proliferation, migration, and invasion were detected by Cell Counting Kit (CCK)-8, wound healing, and Transwell assays in the A549 cells. The results showed that PZ expression was higher in A549, H1299, and H1975 cells, according to Western blot. CCK-8, wound healing, and Transwell assays showed that knockdown of PZ significantly decreased cellular proliferation, migration, and invasion, as well as the protein levels of Slug, Vimentin, and N-cadherin in the A549 cells. In conclusion, the pro-metastasis activity of PZ may modulate the epithelial-mesenchymal transition pathway in lung cancer A549 cells.

Abstract Transfer RNA‐derived small RNAs (tsRNAs) are fragments that originate from mature or precursor tRNAs and are a subclass of sRNAs. With the development of high‐throughput sequencing techniques, the real feature of tsRNAs has gradually been revealed. tsRNAs are functional fragments of distinct lengths produced by the cleavage of mature or precursor tRNAs by different ribonuclease enzymes. tsRNAs exert extensive functions, including gene silencing, translational regulation, and reverse transcriptional regulation, affecting cell viability and differentiation and participating in pathological processes of various diseases, including central nervous system (CNS) diseases. Emerging sequencing evidence indicates that tsRNAs are expressed differently in various CNS diseases, preliminary suggesting that tsRNAs are involved in the occurrence and progression of neurodegenerative diseases, stroke, glioma, epilepsy, and other CNS diseases. In addition, significant differences expression of extracellular tsRNAs in circulating or cerebrospinal fluid between patients and normal individuals have demonstrated the diagnostic and prognostic value of tsRNAs as biomarkers for liquid biopsy. In this review, we provide a detailed summary of the biogenesis, function, and chemical modification of tsRNAs, focusing on the current status and prospects of research on tsRNAs in neurodegenerative diseases, stroke, glioma, epilepsy, and others.

Objectives Patients with vascular anomalies (VAs) who receive oral sirolimus may be at high risk of infectious complications. Antibiotic prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) has been advocated. However, there have been few evidence-based analyses on this topic. This study assessed the effect of prophylactic TMP-SMZ on the incidence of infections in VA patients receiving sirolimus monotherapy. Methods A retrospective, multicenter chart review was performed on all VA patients receiving sirolimus treatment from August, 2013 to January, 2021. Results Before January 2017, 112 patients were treated with sirolimus without antibiotic prophylaxis. In the subsequent period, 195 patients were treated with TMP-SMZ for at least 12 months during sirolimus therapy. The percentage of patients with at least one serious infection during the initial 12 months of sirolimus treatment did not differ between the groups (difference, 1.1%; 95% CI − 7.0–8.0%). We observed no difference in the incidence of individual infection or total adverse events between the groups. The rate of sirolimus discontinuation due to adverse events did not differ significantly between groups. Conclusions We demonstrated that prophylactic TMP-SMZ does not decrease the incidence of infection or improve tolerance in VA patients receiving sirolimus monotherapy.

Treatment with sirolimus, an inhibitor of the mammalian target of rapamycin pathway, has improved the prognosis of patients with kaposiform hemangioendothelioma (KHE). However, the efficacy, durability and tolerability of long-term sirolimus treatment in patients with KHE have not been well elucidated. We performed efficacy and safety assessments based on more than 4.5 years of follow-up in patients receiving sirolimus therapy for KHE. One hundred sixty-seven patients were analyzed, including 102 (61.1%) patients with the Kasabach-Merritt phenomenon (KMP). Follow-up was conducted after a median of 56.0 months. A total of 154 (92.2%) patients had a durable response to sirolimus treatment. No difference in durable response was found between patients without KMP and patients with KMP (95.4% vs 90.2%; difference, 5.2%; 95% confidence interval [CI], -4.0% to 13.1%). Rebound growth occurred in 17.3% of patients upon sirolimus discontinuation. Early treatment discontinuation (odds ratio [OR]: 3.103; 95% CI: 1.529-6.299; P = .002) and mixed lesion type (OR: 2.271; 95% CI: 0.901-5.727; P = .047) were associated with tumor rebound growth. No KHE-related deaths occurred in this cohort. At the last follow-up, approximately 17.4% of patients had active disease and/or changes in body structures to a variable extent. Serious adverse events occurred most commonly during the first year of sirolimus therapy. Follow-up of almost 4.5 years demonstrated that the efficacy of sirolimus persisted over time and that long-term treatment with sirolimus was not associated with unacceptable cumulative toxicities. However, nonresponse, tumor relapse and long-term sequelae remained challenges despite intensified and prolonged sirolimus therapy.

Background Infantile hemangioma (IH) is the most common tumor among infants, but the exact pathogenesis of IH is largely unknown. Our previous study revealed that glucose metabolism may play an important role in the pathogenesis of IH and that the inhibition of the glycolytic key enzyme phosphofructokinase-1 suppresses angiogenesis in IH. 6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) is a metabolic enzyme that converts fructose-6-bisphosphate to fructose-2,6-bisphosphate (F-2,6-BP), which is the most potent allosteric activator of the rate-limiting enzyme phosphofructokinase-1. This study was performed to explore the role of PFKFB3 in IH.Methods Microarray analysis was performed to screen the differentially expressed genes (DEGs) between proliferating and involuting IH tissues. PFKFB3 expression was examined by western blot and immunohistochemistry analyses. Cell migration, apoptosis and tube formation were analyzed. Metabolic analyses were performed to investigate the effect of PFKFB3 inhibition by PFK15. Mouse models were established to examine the effect of PFKFB3 inhibition in vivo.Results PFKFB3 was identified as one of the most significant DEGs and was more highly expressed in proliferating IH tissues and hemangioma-derived endothelial cells (HemECs) than in involuting IH tissues and human umbilical vein endothelial cells, respectively. PFKFB3 inhibition by PFK15 suppressed HemEC glucose metabolism mainly by affecting glycolytic metabolite metabolism and decreasing the glycolytic flux. Moreover, PFK15 inhibited HemEC angiogenesis and migration and induced apoptosis via activation of the apoptosis pathway. Treatment with the combination of PFK15 with propranolol had a synergistic inhibitory effect on HemECs. Moreover, PFKFB3 knockdown markedly suppressed HemEC angiogenesis. Mechanistically, inhibition of PFKFB3 suppressed the PI3K-Akt signaling pathway and induced apoptotic cell death. More importantly, the suppression of PFKFB3 by PFK15 or shPFKFB3 led to markedly reduced tumor growth in vivo.Conclusions Our findings suggest that PFKFB3 inhibition can suppress IH angiogenesis and induce apoptosis. Thus, targeting PFKFB3 may be a novel therapeutic strategy for IH.

Infantile hemangioma (IH) is the most common benign tumor in children. Propranolol is the first-line treatment for IH, but the underlying mechanism of propranolol treatment in IH is not completely understood. Integrated transcriptional and metabolic analyses were performed to investigate the metabolic changes in hemangioma-derived endothelial cells (HemECs) after propranolol treatment. The findings were then further validated through independent cell experiments using a Seahorse XFp analyzer, Western blotting, immunohistochemistry and mitochondrial functional assays. Thirty-four differentially expressed metabolites, including the glycolysis metabolites glucose 6-phosphate, fructose 6-phosphate and fructose 1,6-bisphosphate, were identified by targeted metabolomics. A KEGG pathway enrichment analysis showed that the disturbances in these metabolites were highly related to glucose metabolism-related pathways, including the pentose phosphate pathway, the Warburg effect, glycolysis and the citric acid cycle. Transcriptional analysis revealed that metabolism-related pathways, including glycine, serine and threonine metabolism, tyrosine metabolism, and glutathione metabolism, were highly enriched. Moreover, integration of the metabolomic and transcriptomic data revealed that glucose metabolism-related pathways, particularly glycolysis, were altered after propranolol treatment. Cell experiments demonstrated that HemECs exhibited higher levels of glycolysis than human umbilical vein ECs (HUVECs) and that propranolol suppressed glycolysis in HemECs. In conclusion, propranolol inhibited glucose metabolism in HemECs by suppressing glucose metabolic pathways, particularly glycolysis.

Sirolimus and everolimus have been widely used in children. These mammalian target of rapamycin (mTOR) inhibitors have shown excellent efficacy not only in organ transplant patients as immunosuppressive agents but also in patients with some other diseases. However, whether mTOR inhibitors can affect the growth and development of children is of great concern. In this study, using zebrafish models, we discovered that sirolimus and everolimus could slow the development of zebrafish, affecting indicators such as survival, hatching, deformities, body length, and movement. In addition to these basic indicators, sirolimus and everolimus had certain slowing effects on the growth and development of the nervous system, blood vessels, and the immune system. These effects were dose dependent. When the drug concentration reached or exceeded 0.5 μM, the impacts of sirolimus and everolimus were very significant. More interestingly, the impact was transient. Over time, the various manifestations of experimental embryos gradually approached those of control embryos. We also compared the effects of sirolimus and everolimus on zebrafish, and we revealed that there was no significant difference between these drugs in terms of their effects. In summary, the dose of sirolimus and everolimus in children should be strictly controlled, and the drug concentration should be monitored over time. Otherwise, drug overdosing may have a certain impact on the growth and development of children.