Aortic calcification correlates with pseudoaneurysm or penetrating aortic ulcer of different etiologies.

Chronic risk factors for pseudoaneurysm (PSA) or penetrating aortic ulcer (PAU) have not been fully clarified. This study aims to evaluate the association of aortic calcification with PSA or PAU of different etiologies. Totally 77 pseudoaneurysms, 80 PAU, and 160 healthy controls (HCs) were retrospectively included, of which 30 were infected, 34 were immunological, and 93 were atherosclerotic etiologies. The aortic calcification status, position of aortic tears/ulcers, and risk factors for disease or acute aortic syndrome (AAS) were identified. Atherosclerotic patients aged more than 65 and infective patients aged more than 60 had significantly higher calcification scores. The immunological group had a lower level of calcification in the infrarenal aorta. For patients of infective or atherosclerotic etiology, 60% (18/30) and 60.22% (56/93) of the tears/ulcers occurred at the aortic parts with the highest level of calcification. Patients with longitudinal calcification exceeding 1/3 of the aortic arch had an increased risk of acquiring diseases (OR = 13.231). The presence of longitudinal calcification of the descending aorta or cross-sectional calcification of the infrarenal aorta increased the risks of acquiring diseases (OR = 8.484 and 8.804). After adjusting for age, longitudinal calcification of the descending aorta exceeding 1/3 length was found to be associated with AAS (OR = 4.662). Tears/ulcers of pseudoaneurysm and PAU were both generally found at the part of the aorta with most calcification. Distinct aorta calcification characteristics were observed for lesions of different etiologies. Longitudinal thoracic and cross-sectional infrarenal abdominal aortic calcification increased the risk of acquiring diseases, and descending aortic calcification was associated with symptomatic patients.

FAM3A reshapes VSMC fate specification in abdominal aortic aneurysm by regulating KLF4 ubiquitination.

Reprogramming of vascular smooth muscle cell (VSMC) differentiation plays an essential role in abdominal aortic aneurysm (AAA). However, the underlying mechanisms are still unclear. We explore the expression of FAM3A, a newly identified metabolic cytokine, and whether and how FAM3A regulates VSMC differentiation in AAA. We discover that FAM3A is decreased in the aortas and plasma in AAA patients and murine models. Overexpression or supplementation of FAM3A significantly attenuate the AAA formation, manifested by maintenance of the well-differentiated VSMC status and inhibition of VSMC transformation toward macrophage-, chondrocyte-, osteogenic-, mesenchymal-, and fibroblast-like cell subpopulations. Importantly, FAM3A induces KLF4 ubiquitination and reduces its phosphorylation and nuclear localization. Here, we report FAM3A as a VSMC fate-shaping regulator in AAA and reveal the underlying mechanism associated with KLF4 ubiquitination and stability, which may lead to the development of strategies based on FAM3A to restore VSMC homeostasis in AAA.

Autologous fat or adipose-derived stem cell grafting in systemic sclerosis treatment: a systematic review and meta-analysis.

OBJECTIVES: Systemic sclerosis (SSc) is characterised by vasculopathy and progressive fibrosis of the skin. The aim of this article is to analyse and summarise the efficacy and safety of autologous fat (AF), stromal vascular fraction (SVF) and adipose-derived stem cell (ADSC) grafting in the treatment of SSc, providing evidence for clinical application. METHODS: The research involves the efficacy and safety of AF, SVF and ADSC grafting in the treatment of patients with SSc. The studies were screened and selected independently by two authors based on pre-specified criteria. The data extraction and quality assessment were also performed independently by two authors. RESULTS: Fifteen studies were eligible for inclusion. Skin thickness reduced following SVF or AF therapy, but there was no significant difference. All measures used to assess fingertip symptoms revealed a significant improvement. Notably, SVF and AF were found to have the most impact on Raynaud's phenomenon improvement. The ADSC group improved the most in terms of finger pain alleviation. SVF reported the highest proportion of adverse events, accounting for approximately half of the cases. CONCLUSIONS: AF, SVF, and ADSC all displayed therapeutic effects of improving SSc, but differences existed in the effects on different symptoms. Plastic surgeons should choose the most suitable treatment strategy after comprehensively evaluating the patient's clinical manifestations.

Identification of Novel Plasma Biomarkers for Abdominal Aortic Aneurysm by Protein Array Analysis.

Abdominal aortic aneurysm (AAA) is a potentially life-threatening disease that is common in the aging population. Currently, there are no approved diagnostic biomarkers or therapeutic drugs for AAA. We aimed to identify novel plasma biomarkers or potential therapeutic targets for AAA using a high-throughput protein array-based method. Proteomics expression profiles were investigated in plasma from AAA patients and healthy controls (HC) using 440-cytokine protein array analysis. Several promising biomarkers were further validated in independent cohorts using enzyme-linked immunosorbent assay (ELISA). Thirty-nine differentially expressed plasma proteins were identified between AAA and HC. Legumain (LGMN) was significantly higher in AAA patients and was validated in another large cohort. Additionally, "AAA without diabetes" (AAN) patients and "AAA complicated with type 2 diabetes mellitus" (AAM) patients had different cytokine expression patterns in their plasma, and nine plasma proteins were differentially expressed among the AAN, AAM, and HC subjects. Delta-like protein 1 (DLL1), receptor tyrosine-protein kinase erbB-3 (ERBB3), and dipeptidyl peptidase 4 (DPPIV) were significantly higher in AAM than in AAN. This study identified several promising plasma biomarkers of AAA. Their role as therapeutic targets for AAA warrants further investigation.

Intravenous Leiomyomatosis Complicated by Arteriovenous Fistula: Case Series and Literature Review.

Background: Uterine intravenous leiomyomatosis (IVL), a rare type of uterine leiomyoma, is defined by the intravascular proliferation of a histologically benign smooth muscle cell tumor. Pelvic arteriovenous fistula (AVF) is a rare vascular malformation that is most commonly congenital, post-traumatic, or iatrogenic. The link between leiomyomatosis and AVF has received little attention in the medical literature. Results: We provide a case series of seven patients, four of whom were from our center, who had IVL complicated by a pelvic AVF. The symptoms of right heart failure were noted as swelling in the abdomen and two legs as well as a significant amount of ascites. Coil embolization of AVFs may be beneficial in minimizing bleeding during IVL surgery. A review of all accessible literature published on IVLs from 2000 to 2020 was conducted, and data were retrieved from 78 papers totaling 262 cases. Complications and recurrence were associated with pelvic mass excision and intravascular remnant tumor, respectively. Conclusion: Intravenous leiomyomatosis combined with AVF aggravates congestion symptoms of surrounding organs. It is worth noting the uncommon combination of AVF and IVL, stressing the importance of a thorough assessment and surgical approach in IVL treatment.

Different gene co-expression patterns of aortic intima-media and adventitia in thoracic aortic aneurysm.

BACKGROUND: Due to permanent aortic dilation, thoracic aortic aneurysm (TAA) is a life-threatening disease. Once ruptured, TAA has a high lethality and disability rate. Although studies have focused on transcriptomic alterations in TAA, more detailed analysis is still lacking, especially the different aortic intima-media and adventitia roles. This study aimed to identify the different co-expression patterns between the aortic intima-media and the adventitia underlying the aortic dilation. METHODS: We analyzed the gene expression profiles obtained from Gene Expression Omnibus (GEO, GSE26155) database. With a false discovery rate (FDR) < 0.05 and |log2FC| ≥ 1, 56 and 33 differential genes in the intima-media and adventitia, respectively, between the non-dilated and dilated status. Gene ontology (GO) and gene set enrichment analysis revealed that degranulation and activation of neutrophils play an essential role in the intima-media of dilated aortas. Through weighted gene co-expression network analysis (WGCNA), we identified essential co-expressed modules and hub genes to explore the biological functions of the dysregulated genes. RESULTS: Functional pathway analysis suggested that lipid metabolism, C-C motif chemokine pathways were significantly enriched in the adventitia, whereas ribosome proteins and related mRNA translation pathways were closely related to intima and media. Furthermore, the ssGSEA analysis indicated that macrophages, helper T cells, and neutrophils were higher in the intima-media of the dilated thoracic aorta. Finally, we validated the critical findings of the study with the murine model of TAA. CONCLUSION: This study identified and verified hub genes and pathways in aortic intima-media and adventitia prominently associated with aortic dilation, providing practical understanding in the perspective of searching for new molecular targets.

Gut microbiome alterations in hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) is a rare disease with wide intra- and interindividual clinical variation. There are no reliable indicators available in clinical practice to predict the onset and severity of HAE. Uncovering the changes in the gut microbiota in HAE patients may offer insight into a missing piece of the pathogenesis and help explain the clinical heterogeneity. OBJECTIVE: Explore whether dysbiosis exists in patients with HAE and whether there are biomarkers to indicate the episodes. METHODS: Fecal samples and clinical data were collected from patients with C1-inhibitor-related HAE and their healthy family members. Patients were grouped on the basis of the most recent conditions of HAE episodes and major clinical manifestations. The gut microbiota was evaluated by sequencing the 16S ribosomal RNA gene and analyzed for diversity. RESULTS: Microbial richness and diversity were significantly reduced among patients who had recent HAE attacks, especially for those presenting with abdominal symptoms (P = .003 and P = .048 compared with healthy controls and patients with no recent episodes, respectively). Decreased Firmicutes and increased Proteobacteria were found among the individuals with a recent episode, along with a marked increase of pathogenic bacteria on the basis of the predictive functional profiling. Dysbiosis was restored after regular use of danazol or tranexamic acid. A combined biomarker composed of Bifidobacterium, Lachnospira, Paraprevotella, Desulfovibrio, and Staphylococcus was proposed to detect the recent edema episodes. CONCLUSION: We reported alterations of the gut microbiome in patients with HAE and explored the possible role of bacteria in the etiology of edema episodes, which may provide new clues for the prediction of disease course, clinical treatment, and therapeutic evaluation.

The potential role of chemotaxis and the complement system in the formation and progression of thoracic aortic aneurysms inferred from the weighted gene coexpression network analysis.

BACKGROUND: Thoracic aortic aneurysm (TAA) can be life-threatening due to the progressive weakening and dilatation of the aortic wall. Once the aortic wall has ruptured, no effective pharmaceutical therapies are available. However, studies on TAA at the gene expression level are limited. Our study aimed to identify the driver genes and critical pathways of TAA through gene coexpression networks. METHODS: We analyzed the genetic data of TAA patients from a public database by weighted gene coexpression network analysis (WGCNA). Modules with clinical significance were identified, and the differentially expressed genes (DEGs) were intersected with the genes in these modules. Gene Ontology and pathway enrichment analyses were performed. Finally, hub genes that might be driving factors of TAA were identified. Furthermore, we evaluated the diagnostic accuracy of these genes and analyzed the composition of immune cells using the CIBERSORT algorithm. RESULTS: We identified 256 DEGs and two modules with clinical significance. The immune response, including leukocyte adhesion, mononuclear cell proliferation and T cell activation, was identified by functional enrichment analysis. CX3CR1, C3, and C3AR1 were the top 3 hub genes in the module correlated with TAA, and the areas under the curve (AUCs) by receiver operating characteristic (ROC) analysis of all the hub genes exceeded 0.7. Finally, we found that the proportions of infiltrating immune cells in TAA and normal tissues were different, especially in terms of macrophages and natural killer (NK) cells. CONCLUSION: Chemotaxis and the complement system were identified as crucial pathways in TAA, and macrophages with interactive immune cells may regulate this pathological process.

Immune checkpoint inhibitors in advanced or metastatic mucosal melanoma: a systematic review.

BACKGROUND: Conventional cytotoxic chemotherapy offers minor benefit to patients with mucosal melanoma (MM). Although immune checkpoint inhibitors (ICIs) have become the preferred approach in patients with advanced or metastatic cutaneous melanoma, the evidence of their clinical use for MM is still limited. This systematic review aims to summarize the efficacy and safety of ICIs in advanced or metastatic MM. METHODS: We searched electronic databases, conference abstracts, clinical trial registers and reference lists for relevant studies. The primary outcomes included the overall response rate (ORR), median progression-free survival (PFS), median overall survival (OS), one-year PFS rate, and one-year OS rate. RESULTS: This review identified 13 studies assessing anti-CTLA-4 monotherapy, 22 studies assessing anti-PD-1 monotherapy, two studies assessing anti-CTLA-4 and anti-PD-1 combination therapy, one study assessing anti-PD-1 antibodies combined with axitinib, and three studies assessing anti-PD-1 antibodies combined with radiotherapy. For most patients who received ipilimumab monotherapy, the ORR ranged from 0% to 17%, the median PFS was less than 5 months, and the median OS was less than 10 months. For patients who received nivolumab or pembrolizumab monotherapy, most studies showed an ORR of more than 15% and a median OS of more than 11 months. The combined administration of anti-CTLA-4 and anti-PD-1 agents showed benefits over single-agent therapy with an ORR of more than 33.3%. In a phase Ib trial of toripalimab in combination with axitinib, approximately half of patients had complete or partial responses. Three retrospective studies that investigated anti-PD-1 antibodies combined with radiotherapy showed an ORR of more than 50%, which was higher than each single modality treatment. CONCLUSIONS: Immune checkpoint inhibitors, especially anti-PD-1 monoclonal antibodies alone and in combination with anti-CTLA-4 monoclonal antibodies or other modalities, are promising treatment options for advanced or metastatic MM. However, high-level evidence is still needed to support the clinical application.

CA19-9 elevation as an indication to start salvage treatment in surveillance after pancreatic cancer resection.

BACKGROUND: CA19-9 is the most commonly used tumor marker in the diagnosis, prognosis and surveillance of pancreatic cancer. We hypothesized that CA19-9 elevation can be taken as an indication to start salvage treatment in surveillance after resection. METHODS: From January 2014 and July 2017, 80 pancreatic cancer patients who underwent R0 surgical resection and received adjuvant chemotherapy were included. RESULTS: Twenty-six (32.5%) patients started salvage treatment at the time of CA19-9 elevation without radiological evidence of recurrence. Fifty-four (67.5%) patients treated conventionally before recurrence was confirmed by radiological examinations. Sixty (75%) patients had CA19-9 elevation that preceded radiographic recurrence by about 3 months. In the intervention group, the median DFS (23.6 months vs. 12.1 months, P < 0.001) and OS (28.1 months vs. 20.7 months, P = 0.049) were significantly longer than those in the control group. CONCLUSIONS: CA19-9 elevation could preceded recurrence confirmed by radiographic examinations in most patients. Tumor marker-guided salvage treatment can significantly prolong disease-free survival and overall survival in patients under surveillance after pancreatic cancer resection.