ABSTRACT
OBJECTIVE: Only 5% of patients with popliteal artery aneurysms (PAAs) are female. Evidence on PAA treatment and outcomes in women is therefore scarce. The POPART Registry provides one of Europe's largest data collections regarding PAA treatment. Data on clinical presentation, aneurysm morphology, and perioperative outcomes after open surgical PAA repair in women will be presented. METHODS: POPART is a multicenter, noninterventional registry for open and endovascular PAA repair, with 42 participating centers in Germany and Luxembourg. All patients aged >18 years who have been treated for PAA since 2010 are eligible for study inclusion. Data collection is based on an online electronic case report form. RESULTS: Of the 1236 PAAs, 58 (4.8%) were in women. There were no significant differences in age or cardiopulmonary comorbidities. However, female patients had a lower prevalence of contralateral PAAs and abdominal aortic aneurysms (P < .05). PAAs in women were more likely to be symptomatic before surgery (65.5% vs 49.4%; P = .017), with 19% of women presenting with acute limb ischemia (vs 11%; P = .067). Women had smaller aneurysm diameters than men (22.5 mm vs 27 mm; P = .004) and became symptomatic at smaller diameters (20 mm vs 26 mm; P = .002). Only 8.6% of women and 11.6% of men underwent endovascular aneurysm repair (P > .05); therefore, the perioperative outcome analysis focused on open surgical repair. In total, 23.5% of women and 16.9% of men developed perioperative complications (P > .05). There were no differences in major cardiovascular events (P > .05), but women showed a higher incidence of impaired wound healing (15.7% vs 7.2%; P = .05) and major amputation (5.9% vs 1.1%; P = .027). Female sex was significantly associated with the need for nonvascular reinterventions within 30 days after surgery (odds ratio: 2.48, 95% confidence interval: 1.26-4.88), whereas no significant differences in the odds for vascular reinterventions were observed (odds ratio: 1.98, 95% confidence interval: 0.68-5.77). In the multiple logistic regression model, female sex, symptomatic PAAs, poor quality of outflow vessels, and graft material other than vein graft were independently associated with perioperative reinterventions. CONCLUSIONS: Women have smaller PAAs, are more likely to be symptomatic before treatment, and are more often affected by nonvascular reinterventions in the perioperative course. As our understanding of aneurysmatic diseases in women continues to expand, sex-specific treatment strategies and screening options for women in well-selected cohorts with modified screening protocols should be continuously re-evaluated.
Subject(s)
Aortic Aneurysm, Abdominal , Arterial Occlusive Diseases , Blood Vessel Prosthesis Implantation , Endovascular Procedures , Popliteal Artery Aneurysm , Male , Humans , Female , Aortic Aneurysm, Abdominal/surgery , Endovascular Procedures/adverse effects , Endovascular Procedures/methods , Blood Vessel Prosthesis Implantation/adverse effects , Arterial Occlusive Diseases/surgery , Popliteal Artery/diagnostic imaging , Popliteal Artery/surgery , Treatment Outcome , Retrospective Studies , Risk FactorsABSTRACT
Since the beginning of the twentieth century and the implementation of anesthesia and antisepsis, the knowledge and possibilities in treatment of vascular injury has continuously improved. We are currently experiencing improvements in the preclinical management due to various damage control procedures. Depending on the type of vascular injury (blunt, sharp, with or without defect) the treatment can be conservative in individual cases but in most cases endovascular or open vascular surgery is necessary. In the twenty-first century the surgical treatment by direct suture or replacement of the vessel by a graft is increasingly being supplemented by various endovascular procedures.
Subject(s)
Blood Vessel Prosthesis Implantation , Endovascular Procedures , Vascular System Injuries , Wounds, Nonpenetrating , Humans , Retrospective Studies , Treatment Outcome , Vascular System Injuries/surgery , Wounds, Nonpenetrating/surgeryABSTRACT
OBJECTIVE: In this study the activation of HMGA2 and overexpression by FGF1-driven stimulation of adipose tissue derived stem cells (ADSCs) in adipose tissue tumors were analyzed. In addition, the expression of HMGA2 and PPAR-gamma mRNA were quantified in canine subcutaneous abdominal adipose tissue from normal and overweight purebred dogs. DESIGN AND METHODS: ADSCs and adipose tissue explants stimulated with FGF1 followed by gene expression analyses of HMGA2 and p14(Arf) using Western-blot and qRT-PCR. Furthermore, canine subcutaneous white adipose tissue (WAT) were analyzed by qRT-PCR for their expression of HMGA2 and PPAR-gamma. RESULTS: ADSCs and adipose tissue explants are able to execute a HMGA2 response upon FGF1 stimulation. FGF1 enhances proliferation of ADSCs by a HMGA2-dependent mechanism. In lipomas increase of HMGA2 is accompanied by increased expression of p14(Arf) . Furthermore, a significantly elevated level of HMGA2 in overweight dogs and a negative correlation between the expression of HMGA2 and PPAR-gamma in subcutaneous cWAT were noted. CONCLUSIONS: These results suggest that WAT contains cells that as essential part of adipogenesis up-regulate HMGA2 resulting from growth factor stimulation. In subgroups of lipoma, constitutive activation of HMGA2 due to rearrangements replaces the temporal response triggered by growth factors.
Subject(s)
HMGA2 Protein/metabolism , Lipoma/metabolism , Subcutaneous Fat, Abdominal/cytology , Adipogenesis/genetics , Adipogenesis/physiology , Animals , Cell Proliferation , Cells, Cultured , Disease Models, Animal , Dogs , Female , Fibroblast Growth Factor 1/pharmacology , Gene Rearrangement , HMGA2 Protein/genetics , Humans , Male , Overweight/genetics , Overweight/metabolism , PPAR gamma/genetics , PPAR gamma/metabolism , RNA Interference , RNA, Messenger/genetics , RNA, Messenger/metabolism , Stem Cells/metabolism , Tumor Suppressor Protein p14ARF/genetics , Tumor Suppressor Protein p14ARF/metabolism , Up-RegulationABSTRACT
There is a clear link between overweight, gain of white adipose tissue, and diabetes type 2 (T2D). The molecular mechanism of the gain of adipose tissue is linked with the expression of high mobility group protein AT-hook 2 (HMGA2), and recent studies revealed an association with a SNP near HMGA2. In this study, we investigated the gene expression of HMGA2, p14 (Arf) , CDKN1A, and BAX in human abdominal subcutaneous white adipose tissue from 157 patients. We found a significant higher HMGA2 expression in obese individuals than in non-obese patients. Furthermore, the HMGA2 expression in white adipose tissue in patient with type 2 diabetes was significantly higher than in nondiabetic patients. There is an association between the DNA-binding nonhistone protein HMGA2 and the risk of developing T2D that remains mechanistically unexplained so far. Likewise, p14(Arf), an inducer of cellular senescence, has been associated with the occurrence of T2D. The data of the present study provide evidence that both proteins act within the same network to drive proliferation of adipose tissue stem and precursor cells, senescence, and increased risk of T2D, respectively.
ABSTRACT
HMGA2 is a major regulator of benign tumorigenesis from mesenchyme-derived tissues and stem-cell self-renewal. It has been postulated that HMGA2 mediates its critical function by decreasing p16(Ink4a)/p14(Arf) expression and cellular senescence. To repress the oncogenic activity of HMGA2, the lin-28-let-7 axis is thought to increasingly repress the expression of HMGA2 with age. To understand the HMGA2-p14(Arf) -relationship in benign tumorigenesis, we performed a series of experiments on mesenchymal stem-cells, i.e., the proposed cells of origin of lipomas and uterine leiomyomas. The expression of both genes was inversely correlated during senescence in vitro but contrary to the expectations in adipose tissue derived stem cells (ADSCs) stimulation of HMGA2 by FGF1 increased the expression of p14(Arf) . Based on the assumption that in ADSCs p14(Arf) is repressing HMGA2, siRNA silencing of p14(Arf) was performed resulting in a significant upregulation of HMGA2. To see if p14(Arf) can repress HMGA2 by a TP53-dependent mechanism, nutlin-3, a known MDM2 antagonist, was used which not only increased the activity of the senescence, associated markers p21 and beta-galactosidase, but also decreased the expression of HMGA2, suggesting that p14(Arf) indeed influences HMGA2 by a p53-dependent mechanism because nutlin-3 stabilizes p53. Accordingly, the HMGA2 response triggered by serum was reduced by treatment of ADSCs with nutlin-3. As to the interaction between HMGA2 and p14(Arf) in benign tumorigenesis, we propose a model where akin to MSC self-renewal during tissue repair the simultaneous increase of p14(Arf) with HMGA2 ensures genomic stability, whereas in turn p14(Arf) can repress HMGA2 via TP53.
Subject(s)
Cellular Senescence , HMGA2 Protein/antagonists & inhibitors , Mesenchymal Stem Cells/metabolism , Tumor Suppressor Protein p14ARF/metabolism , Animals , Cell Line, Tumor , Cell Proliferation , Dogs , Gene Expression Regulation, Neoplastic , Genes, Regulator , HMGA2 Protein/genetics , HMGA2 Protein/metabolism , Humans , Mesenchymal Stem Cells/cytology , Neoplasms/metabolismABSTRACT
HMGB1 is a high mobility group protein that can act either as a DNA binding protein or extracellularly as a cytokine-like danger signal. Extracellular HMGB1, either actively secreted or passively released by necrotic cells, is linked to inflammation and cancer. Herein, the results of a study to quantify the expression of HMGB1 in lymphomas by quantitative real-time RT-PCR are presented. HMGB1 expression was analysed in 18 non-Hodgkin lymphomas and two lymphoma cell lines. 11/18 primary lymphomas expressed HMGB1 mRNA at a level exceeding the average of normal lymph nodes. Immunohistochemistry showed that HMGB1 positivity is confined to the lymphoma cells. No correlation between HMGB1 expression and grading was found. However, a high percentage of lymphomas is overexpressing a danger-signalling protein. This protein can support the growth and angiogenesis of lymphoma cells in a paracrine way when released e.g. due to necrosis. Thus it constitutes an interesting therapeutic target as well.
Subject(s)
HMGB1 Protein/genetics , Lymphoma, Non-Hodgkin/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , HMGB1 Protein/metabolism , Humans , Lymph Nodes/metabolism , Lymph Nodes/pathology , Lymphoma, Non-Hodgkin/metabolism , Lymphoma, Non-Hodgkin/pathology , Male , Middle Aged , Necrosis , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Neoplasm/genetics , RNA, Neoplasm/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, CulturedABSTRACT
One of the major characteristics of atherosclerosis is the migration of smooth muscle cells (SMC) from the tunica media to the intima, caused by alterations in the environment, e.g. mechanical, chemical, or immunologic injuries of the arterial walls. A group of molecules that may act as a main regulator of SMC phenotype switching is formed by the so-called HMGA1 high-mobility group proteins. One target gene of the HMGA1 protein, playing a major role in the development of atherosclerotic lesions, is CD44. The expression of CD44 is regulated by IL-1beta, but binding of HMGA1 potentiates the transactivation of the CD44 promoter. In this study, the HMGA1 expression of human atherosclerotic plaque samples was examined. Compared to the non-active components, all major components of the well-developed atherosclerotic plaques showed strong positivity of the high-mobility group protein HMGA1 in their activated areas, e.g. neointimal SMCs, macrophages, newly built blood vessels. This report is the first to describe HMGA1 as one of the first mediators in the development of human atherosclerotic plaques.