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AIMS: Cardiac amyloidosis (CA) is associated with various complications, and one of them are thromboembolic events (TEEs), which can significantly impact patients' quality of life. Predicting and managing the risk of these TEEs in patients without atrial fibrillation (AF) pose significant challenges, as many occur independently of AF presence. Several predictors, particularly echocardiographic ones, have been linked to an increased risk, but there is no consensus on stratification or preventive treatment. The main objective was to determine the prevalence of TEEs in a cohort of CA patients without AF and identify echocardiographic predictors. METHODS: A retrospective, single-center study including confirmed CA patients. A prespecified list of variables was defined, and only patients with at least 70â¯% of these variables were included. Risk rates were analyzed through binary logistic regression, with a significance level set at pâ¯<â¯0.05. RESULTS: 75 patients were included. Baseline characteristics are depicted in Fig. 1. Fifteen TEEs (20â¯%) were described, with 80â¯% being ischemic strokes. While diastolic dysfunction and pulmonary systolic arterial pressure (PSAP) were predictors in univariate analysis, the multivariate backward LR model identified interventricular septum diameter (IVSD) as the sole predictor, OR 1.280 (1.061-1.543), pâ¯=â¯0.010. It is also interesting to mention that analyzing the increase of every 3â¯mm in SIV, the chance of developing ETES was: ORâ¯=â¯2.095 (1.195-3.671), pâ¯=â¯0.010. CONCLUSIONS: An IVSD evaluated by echocardiography demonstrated good performance capacity as a factor associated with TEEs in this cohort of patients with AC without AF. For every 3â¯mm increase in IVSD, the risk of developing TEEs doubles.
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BACKGROUND: This report describes the authors' experience with 150 consecutive robotic pancreatoduodenectomies. METHODS: The study enrolled 150 consecutive patients who underwent robotic pancreatoduodenectomy between 2018 and 2023. Pre- and intraoperative variables such as age, gender, indication, operation time, diagnosis, and tumor size were analyzed. The patients were divided into two groups. Group 1 comprised the first 75 patients, and group 2 comprised the last 75 cases. The median age of the patients was 62.4 years and did not differ between the two groups. RESULTS: Morbidity was lower in group 2. The mortality rate was 0.7% at 30 days and 1.3% at 90 days, and there was no difference between the groups. There was a significant reduction (p < 0.05) in operative time, resection time, reconstruction time, and conversion to open surgery in group 2. Partial resection of the portal vein was performed in 17 patients and more common in group 2 (p < 0.01). The number of resected lymph nodes was higher in group 2. The indication for pancreatoduodenectomy did not differ between the two groups. There was no difference in tumor size or clinical characteristics of the patients. CONCLUSIONS: The robotic platform is useful for pancreatoduodenectomy, facilitates adequate lymphadenectomy, and is helpful for digestive tract reconstruction after resection. Robotic pancreatoduodenectomy is safe and feasible for selected patients. It should be performed in specialized centers by surgeons experienced in open and minimally invasive pancreatic surgery.
Subject(s)
Pancreaticoduodenectomy , Pericardium , Robotic Surgical Procedures , Humans , Pancreaticoduodenectomy/methods , Pancreaticoduodenectomy/adverse effects , Robotic Surgical Procedures/methods , Pericardium/transplantation , Animals , Cattle , Plastic Surgery Procedures/methods , Portal Vein/surgery , Pancreatic Neoplasms/surgery , Anastomosis, Surgical/methodsABSTRACT
Vaccinia-related kinase 1 (VRK1) and the δ and ε isoforms of casein kinase 1 (CK1) are linked to various disease-relevant pathways. However, the lack of tool compounds for these kinases has significantly hampered our understanding of their cellular functions and therapeutic potential. Here, we describe the structure-based development of potent inhibitors of VRK1, a kinase highly expressed in various tumor types and crucial for cell proliferation and genome integrity. Kinome-wide profiling revealed that our compounds also inhibit CK1δ and CK1ε. We demonstrate that dihydropteridinones 35 and 36 mimic the cellular outcomes of VRK1 depletion. Complementary studies with existing CK1δ and CK1ε inhibitors suggest that these kinases may play overlapping roles in cell proliferation and genome instability. Together, our findings highlight the potential of VRK1 inhibition in treating p53-deficient tumors and possibly enhancing the efficacy of existing cancer therapies that target DNA stability or cell division.
Subject(s)
Protein Kinase Inhibitors , Protein Serine-Threonine Kinases , Pteridines , Humans , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Pteridines/pharmacology , Pteridines/chemistry , Pteridines/chemical synthesis , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/metabolism , Cell Proliferation/drug effects , Structure-Activity Relationship , Casein Kinase Idelta/antagonists & inhibitors , Casein Kinase Idelta/metabolism , Casein Kinase 1 epsilon/antagonists & inhibitors , Casein Kinase 1 epsilon/metabolism , Cell Line, TumorABSTRACT
Among the stimuli able to prevent early decreases in bone mineralization, exercise has a noticeable role per se as the source of mechanical stimulus or through lean tissue enlargement by its increasing of tensional stimulus. However, prevention strategies, including exercise, generally do not establish the moment in life when attention should begin to be paid to bone integrity, according to age group- and sex-related differences. Thus, this study analyzed the relationship between variables from the diagnosis of total and regional body composition, muscle strength, and bone mineral content (BMC) of femurs in young adult males. Thirty-four young Caucasian men (24.9 ± 8.6 years) had their body composition and bone density assessed by dual X-ray absorptiometry. The subjects performed a one-repetition maximum test (1-RM) in a bench press, front pulley, seated-row, push press, arm curl, triceps pulley, leg flexion, leg extension, and 45° leg press for the assessment of muscle strength in upper and lower limbs in single- and multi-joint exercises. Lean tissue mass in the trunk and upper and lower limbs were related to femoral BMC (Pearson coefficient ranging from 0.55 to 0.72, p < 0.01), and 1-RM values for different exercises involving both upper and lower limbs also correlated with femoral BMC (Pearson coefficients ranging from 0.34 to 0.46, p < 0.05). Taken together, these correlations suggest that muscle mass and strength are positively linked with the magnitude of femoral mass in men, even in early adulthood. Hence, the importance of an enhanced muscle mass and strength to the health of femoral bones in young adults was highlighted.
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AIM: The present study evaluated whether topiramate (TPM) treatment during the peripubertal period affects vascular parameters of male rats and whether oxidative stress plays a role in these changes. MAIN METHODS: Rats were treated with TPM (41 mg/kg/day, gavage) or vehicle (CTR group) from the postnatal day (PND) 28 to 50. At PND 51 and 120 the rats were evaluated for: thoracic aorta reactivity to phenylephrine, in the presence (Endo+) or absence of endothelium (Endo-), to acetylcholine and to sodium nitroprusside (SNP), aortic thickness and endothelial nitric oxide synthase (eNOS) expression. In serum were analyzed: the antioxidant capacity by ferric reducing antioxidant power assay; endogenous antioxidant reduced glutathione, and superoxide anion. Results were expressed as mean ± s.e.m., differences when p < 0.05. STATISTICS: Two-way ANOVA (and Tukey's) or Student t-test. KEY FINDINGS: At PND 51, the contraction induced by phenylephrine in Endo+ ring was higher in TPM when compared to CTR. At PND 120, the aortic sensitivity to acetylcholine in TPM rats was reduced in comparison with CTR. The aortic eNOs expression and the aortic thickness were similar between the groups. At PND 51 and 120, TPM group presented a decrease in antioxidants when compared to CTR groups and at PND 120, in TPM group the superoxide anion was increased. SIGNIFICANCE: Taken together, the treatment of rats with TPM during peripubertal period promoted permanent impairment of endothelial function probably mediated by oxidative stress.
Subject(s)
Acetylcholine , Antioxidants , Rats , Animals , Male , Antioxidants/pharmacology , Antioxidants/metabolism , Topiramate/pharmacology , Acetylcholine/metabolism , Superoxides/metabolism , Endothelium, Vascular/metabolism , Nitric Oxide Synthase Type III/metabolism , Oxidative Stress , Aorta, Thoracic/metabolism , Phenylephrine/pharmacology , Nitric Oxide/metabolismABSTRACT
Caused by four serotypes, dengue fever is a major public health concern worldwide. Current modeling efforts have mostly focused on primary and heterologous secondary infections, assuming that lifelong immunity prevents reinfections by the same serotype. However, recent findings challenge this assumption, prompting a reevaluation of dengue immunity dynamics. In this study, we develop a within-host modeling framework to explore different scenarios of dengue infections. Unlike previous studies, we go beyond a deterministic framework, considering individual immunological variability. Both deterministic and stochastic models are calibrated using empirical data on viral load and antibody (IgM and IgG) concentrations for all dengue serotypes, incorporating confidence intervals derived from stochastic realizations. With good agreement between the mean of the stochastic realizations and the mean field solution for each model, our approach not only successfully captures primary and heterologous secondary infection dynamics facilitated by antibody-dependent enhancement (ADE) but also provides, for the first time, insights into homotypic reinfection dynamics. Our study discusses the relevance of homotypic reinfections in dengue transmission at the population level, highlighting potential implications for disease prevention and control strategies.
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BACKGROUND: The aim of this study was to analyse transcriptomic differences between primary and recurrent high-grade serous ovarian carcinoma (HGSOC) to identify prognostic biomarkers. METHODS: We analysed 19 paired primary and recurrent HGSOC samples using targeted RNA sequencing. We selected the best candidates using in silico survival and pathway analysis and validated the biomarkers using immunohistochemistry on a cohort of 44 paired samples, an additional cohort of 504 primary HGSOCs and explored their function. RESULTS: We identified 233 differential expressed genes. Twenty-three showed a significant prognostic value for PFS and OS in silico. Seven markers (AHRR, COL5A2, FABP4, HMGCS2, ITGA5, SFRP2 and WNT9B) were chosen for validation at the protein level. AHRR expression was higher in primary tumours (p < 0.0001) and correlated with better patient survival (p < 0.05). Stromal SFRP2 expression was higher in recurrent samples (p = 0.009) and protein expression in primary tumours was associated with worse patient survival (p = 0.022). In multivariate analysis, tumour AHRR and SFRP2 remained independent prognostic markers. In vitro studies supported the anti-tumorigenic role of AHRR and the oncogenic function of SFRP2. CONCLUSIONS: Our results underline the relevance of AHRR and SFRP2 proteins in aryl-hydrocarbon receptor and Wnt-signalling, respectively, and might lead to establishing them as biomarkers in HGSOC.
Subject(s)
Cystadenocarcinoma, Serous , Ovarian Neoplasms , Female , Humans , Prognosis , Ovarian Neoplasms/pathology , Gene Expression Profiling , Biomarkers, Tumor/genetics , Cystadenocarcinoma, Serous/pathology , Membrane Proteins/genetics , Repressor Proteins/genetics , Basic Helix-Loop-Helix Transcription Factors/geneticsABSTRACT
Replacing crude oil as the primary industrial source of carbon-based chemicals has become crucial for both environmental and resource sustainability reasons. In this scenario, wood arises as an excellent candidate, whilst depolymerization approaches have emerged as promising strategies to unlock the lignin potential as a resource in the production of high-value organic chemicals. However, many drawbacks, such as toxic solvents, expensive catalysts, high energy inputs, and poor product selectivity have represented major challenges to this task. Herein, we present an unprecedented approach using electrocatalysis for the simultaneous depolymerization and dearomatization of lignin in aqueous medium under ambient conditions. By employing water/sodium carbonate as a solvent system, we demonstrated a pathway for selectively depolymerizing lignin under reductive electrochemical conditions using carbon as an electrocatalyst. After reductive electrocatalysis, the presence of aromatic compounds was no longer detected via nuclear magnetic resonance (NMR) spectroscopy. Further characterization by NMR, FTIR spectroscopy, and mass spectrometry revealed the major presences of sodium levulinate, sodium 4-hydroxyvalerate, sodium formate, and sodium acetate as products. By achieving a complete dearomatization, valuable aliphatic intermediates with enhanced reactivity were selectively obtained, opening new avenues for further synthesis of many different organic chemicals, and contributing to a more sustainable and circular economy.
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In pursuit of a suitable scaffold material for cardiac valve tissue engineering applications, an acellular, electrospun, biodegradable polyester carbonate urethane urea (PECUU) scaffold was evaluated as a pulmonary valve leaflet replacement in vivo. In sheep (n = 8), a single pulmonary valve leaflet was replaced with a PECUU leaflet and followed for 1, 6, and 12 weeks. Implanted leaflet function was assessed in vivo by echocardiography. Explanted samples were studied for gross pathology, microscopic changes in the extracellular matrix, host cellular re-population, and immune responses, and for biomechanical properties. PECUU leaflets showed normal leaflet motion at implant, but decreased leaflet motion and dimensions at 6 weeks. The leaflets accumulated α-SMA and CD45 positive cells, with surfaces covered with endothelial cells (CD31+). New collagen formation occurred (Picrosirius Red). Accumulated tissue thickness correlated with the decrease in leaflet motion. The PECUU scaffolds had histologic evidence of scaffold degradation and an accumulation of pro-inflammatory/M1 and anti-inflammatory/M2 macrophages over time in vivo. The extent of inflammatory cell accumulation correlated with tissue formation and polymer degradation but was also associated with leaflet thickening and decreased leaflet motion. Future studies should explore pre-implant seeding of polymer scaffolds, more advanced polymer fabrication methods able to more closely approximate native tissue structure and function, and other techniques to control and balance the degradation of biomaterials and new tissue formation by modulation of the host immune response.
Subject(s)
Heart Valve Prosthesis , Pulmonary Valve , Animals , Sheep , Endothelial Cells , Tissue Scaffolds/chemistry , Biocompatible Materials , Polymers , Polyesters , Tissue Engineering/methodsABSTRACT
Despite its vital importance for establishing proper cardiovascular function, the process through which the vasculature develops and matures postnatally remains poorly understood. From a clinical perspective, an ability to mechanistically model the developmental time course in arteries and veins, as well as to predict how various pathologies and therapeutic interventions alter the affected vessels, promises to improve treatment strategies and long-term clinical outcomes, particularly in pediatric patients suffering from congenital heart defects. In the present study, we conducted a multiscale investigation into the postnatal development of the murine thoracic aorta, examining key allometric relations as well as relationships between in vivo mechanical stresses, collagen and elastin expression, and the gradual accumulation of load-bearing constituents within the aortic wall. Our findings suggest that the production of fibrillar collagens in the developing aorta associates strongly with the ratio of circumferential stresses between systole and diastole, hence emphasizing the importance of a pulsatile mechanobiological stimulus. Moreover, rates of collagen turnover and elastic fiber compaction can be inferred directly by synthesizing transcriptional data and quantitative histological measurements of evolving collagen and elastin content. Consistent with previous studies, we also observed that wall shear stresses acting on the aorta are similar at birth and in maturity, supporting the hypothesis that at least some stress targets are established early in development and maintained thereafter, thus providing a possible homeostatic basis to guide future experiments and inform future predictive modeling.
Subject(s)
Aorta , Elastin , Infant, Newborn , Humans , Animals , Mice , Child , Elastin/metabolism , Aorta, Thoracic/pathology , Collagen/metabolism , Fibrillar Collagens/metabolism , Stress, MechanicalABSTRACT
The rational design and implementation of synthetic mammalian communication systems can unravel fundamental design principles of cell communication circuits and offer a framework for engineering of designer cell consortia with potential applications in cell therapeutics. Here, we develop the foundations of an orthogonal, and scalable mammalian synthetic communication platform that exploits the programmability of synthetic receptors and selective affinity and tunability of diffusing coiled-coil peptides. Leveraging the ability of coiled-coils to exclusively bind to a cognate receptor, we demonstrate orthogonal receptor activation and Boolean logic operations at the receptor level. We show intercellular communication based on synthetic receptors and secreted multidomain coiled-coils and demonstrate a three-cell population system that can perform AND gate logic. Finally, we show CC-GEMS receptor-dependent therapeutic protein expression. Our work provides a modular and scalable framework for the engineering of complex cell consortia, with the potential to expand the aptitude of cell therapeutics and diagnostics.
Subject(s)
Receptors, Artificial , Animals , Protein Engineering , Peptides/chemistry , Cell Communication , Synthetic Biology , MammalsABSTRACT
Collagen is the most abundant protein in mammals; it exhibits a hierarchical organization and provides structural support to a wide range of soft tissues, including blood vessels. The architecture of collagen fibrils dictates vascular stiffness and strength, and changes therein can contribute to disease progression. While transmission electron microscopy (TEM) is routinely used to examine collagen fibrils under normal and pathological conditions, computational tools that enable fast and minimally subjective quantitative assessment remain lacking. In the present study, we describe a novel semi-automated image processing and statistical modeling pipeline for segmenting individual collagen fibrils from TEM images and quantifying key metrics of interest, including fibril cross-sectional area and aspect ratio. For validation, we show first-of-their-kind illustrative results for adventitial collagen in the thoracic aorta from three different mouse models.
Subject(s)
Collagen , Electrons , Mice , Animals , Collagen/metabolism , Microscopy, Electron, Transmission , Extracellular Matrix/metabolism , Image Processing, Computer-Assisted , Mammals/metabolismABSTRACT
BACKGROUND: Minimally invasive pancreatoduodenectomy (PD) is one of the most complex procedures in oncologic surgery. We present a video of robotic portomesenteric reconstruction with bovine pericardial graft during PD. METHODS: A 52-year-old woman was referred with a mass in the head of the pancreas. The tumor was in contact with the portomesenteric axis. The multidisciplinary team decided to perform an upfront resection. The surgery was performed as a pylorus-preserving pancreaticoduodenectomy with lymphadenectomy. The superior mesenteric artery first approach was used to expose the head of the pancreas, so that the entire surgical specimen was attached only through the tumor invasion of the portomesenteric axis. After resection of the invaded portomesenteric axis, its large extension precluded primary reconstruction, so a bovine pericardial graft was used for venous reconstruction. After completion of the venous anastomosis, reconstruction of the digestive tract was performed as usual. RESULTS: Surgical time was 430 min; clamp time was 55 min; and portomesenteric reconstruction took 41 min. Estimated blood loss was 320 mL without transfusion. Pathology confirmed T3N1 ductal adenocarcinoma with free margins. No pancreatic or biliary fistula was observed, and she was discharged on postoperative day 8. A postoperative examination confirmed the patency of the graft. The patient is doing well 6 months after surgery and has no signs of the disease. CONCLUSIONS: A bovine pericardial graft is useful for reconstruction and readily available, eliminating the need to harvest an autologous vein or use synthetic grafts. This procedure can be safely performed with the robotic platform.
Subject(s)
Pancreatic Neoplasms , Robotic Surgical Procedures , Female , Humans , Cattle , Animals , Middle Aged , Pancreaticoduodenectomy/methods , Pancreatic Neoplasms/surgery , Robotic Surgical Procedures/methods , Portal Vein/surgery , Pancreas/surgeryABSTRACT
Low-density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is a member of the LDL receptor family and has often been discussed as a tumor suppressor gene, as its down-regulation is correlated with a poor prognosis in multiple carcinoma entities. Due to the high metastasis rate into the fatty peritoneal cavity and current research findings showing a dysregulation of lipid metabolism in tubo-ovarian high-grade serous carcinoma (HGSC), we questioned the prognostic impact of the LRP1B protein expression. We examined a well-characterized large cohort of 571 patients with primary HGSC and analyzed the LRP1B protein expression via immunohistochemical staining (both in tumor and stroma cells separately), performed precise bioimage analysis with QuPath, and calculated the prognostic impact using SPSS. Our results demonstrate that LRP1B functions as a significant prognostic marker for overall survival (OS) and progression-free survival (PFS) in HGSC on the protein level. High cytoplasmic expression of LRP1B in tumor, stroma, and combined tumor and stroma cells has a significantly positive association with a mean prolongation of the OS by 42 months (P = .005), 29 months (P = .005), and 25 months (P = .001), respectively. Additionally, the mean PFS was 18 months longer in tumor (P = .002), 19 months in stroma (P = .004), and 19 months in both cell types combined (P = .01). Our results remained significant in multivariate analysis. We envision LRP1B as a potential prognostic tool that could help us understand the functional role of lipid metabolism in advanced HGSC, especially regarding liposomal medications.
Subject(s)
Cystadenocarcinoma, Serous , Fallopian Tube Neoplasms , Ovarian Neoplasms , Female , Humans , Ovarian Neoplasms/pathology , Prognosis , Cystadenocarcinoma, Serous/pathology , Progression-Free Survival , Fallopian Tube Neoplasms/pathology , Receptors, LDL/therapeutic useABSTRACT
BACKGROUND: The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays a crucial role in regulating the immune system's response to tumors, but its exact role in cancer, especially in high-grade serous ovarian cancer (HGSOC), remains controversial. We aimed to investigate the prognostic impact of IDO1 expression and its correlation with tumor-infiltrating lymphocytes (TILs) in HGSOC. METHODS: Immunohistochemical (IHC) staining and bioimage analysis using the QuPath software were employed to assess IDO1 protein expression in a well-characterized cohort of 507 patients with primary HGSOC. Statistical evaluation was performed using SPSS, and in silico validation considering IDO1 mRNA expression in bulk and single-cell gene expression datasets was conducted. Additionally, IDO1 expression in interferon-gamma (IFNG) stimulated HGSOC cell lines was analyzed. RESULTS: Our findings revealed that IDO1 protein and mRNA expression serve as positive prognostic markers for overall survival (OS) and progression-free survival (PFS) in HGSOC. High IDO1 expression was associated with a significant improvement in OS by 21 months (p < 0.001) and PFS by 6 months (p = 0.016). Notably, elevated IDO1 expression correlated with an increased number of CD3+ (p < 0.001), CD4+ (p < 0.001), and CD8+ TILs (p < 0.001). Furthermore, high IDO1 mRNA expression and protein level were found to be associated with enhanced responsiveness to pro-inflammatory cytokines, particularly IFNG. CONCLUSIONS: Our study provides evidence that IDO1 expression serves as a positive prognostic marker in HGSOC and is associated with an increased number of CD3+, CD4+ and CD8+ TILs. Understanding the intricate relationship between IDO1, TILs, and the tumor microenvironment may hold the key to improving outcomes in HGSOC.
Subject(s)
Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/pathology , Lymphocytes, Tumor-Infiltrating , Prognosis , Carcinoma, Ovarian Epithelial/pathology , RNA, Messenger , Tumor Microenvironment/geneticsABSTRACT
PURPOSE: The GeparX study investigated whether denosumab as add-on treatment to nab-paclitaxel-based neoadjuvant chemotherapy (NACT) with two different schedules (125 mg/m² weekly vs. day 1, 8 every 22 days) may increase pathologic complete response (pCR) rate. The addition of denosumab to NACT did not improve pCR rates as recently published. In this study, we investigated whether receptor activator of nuclear factor-kappa B (RANK) expression, as part of the denosumab target pathway: (i) may retrospectively identify a subgroup of patients with additional clinical benefit of denosumab or (ii) may predict response to nab-paclitaxel NACT. EXPERIMENTAL DESIGN: RANK protein was IHC-stained on pre-therapeutic core biopsies from patients of the GeparX study (n = 667) with the antibody RANK/Envision System HRP (DAB) and was analyzed for the percentage of membranous RANK tumor cell staining (>5% RANKhigh vs. ≤5% RANKlow). RESULTS: We could not identify any patient subgroup with differential response under denosumab add-on treatment in patients with RANKhigh expression [139/667, 20.8%; OR, 0.86; 95% confidence interval (CI), 0.44-1.68; P = 0.667] or RANKlow expression (528/667 (79.2%) OR, 1.10; 95% CI, 0.78-1.56; P = 0.589; Pinteraction = 0.528). However, the pCR rate was higher in the RANKhigh subgroup compared with RANKlow (50% vs. 39%; OR, 1.52; 95% CI, 1.04-2.21; P = 0.037). RANK expression constituted an independent predictor of response to NACT frequently in patients with luminal-like subtype (HR+/HER2-; OR, 2.98; 95% CI, 1.30-6.79; P = 0.010). No predictive value of RANK expression among the different nab-paclitaxel regimens was observed. CONCLUSION: We report RANK expression to be an independent predictive biomarker for response to NACT in patients with luminal-like breast cancer.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Receptor Activator of Nuclear Factor-kappa B/genetics , Neoadjuvant Therapy , Retrospective Studies , Denosumab/therapeutic use , Receptor, ErbB-2/metabolism , Paclitaxel , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Treatment OutcomeABSTRACT
BACKGROUND: Transmural failure of the aorta is responsible for substantial morbidity and mortality; it occurs when mechanical stress exceeds strength. The aortic root and ascending aorta are susceptible to dissection and rupture in Marfan syndrome, a connective tissue disorder characterized by a progressive reduction in elastic fiber integrity. Whereas competent elastic fibers endow the aorta with compliance and resilience, cross-linked collagen fibers confer stiffness and strength. We hypothesized that postnatal reductions in matrix cross-linking increase aortopathy when turnover rates are high. METHODS: We combined ex vivo biaxial mechanical testing with multimodality histological examinations to quantify expected age- and sex-dependent structural vulnerability of the ascending aorta in Fbn1C1041G/+ Marfan versus wild-type mice without and with 4-week exposures to ß-aminopropionitrile, an inhibitor of lysyl oxidase-mediated cross-linking of newly synthesized elastic and collagen fibers. RESULTS: We found a strong ß-aminopropionitrile-associated sexual dimorphism in aortic dilatation in Marfan mice and aortic rupture in wild-type mice, with dilatation correlating with compromised elastic fiber integrity and rupture correlating with compromised collagen fibril organization. A lower incidence of rupture of ß-aminopropionitrile-exposed Marfan aortas associated with increased lysyl oxidase, suggesting a compensatory remodeling of collagen that slows disease progression in the otherwise compromised Fbn1C1041G/+ aorta. CONCLUSIONS: Collagen fiber structure and function in the Marfan aorta are augmented, in part, by increased lysyl oxidase in female and especially male mice, which improves structural integrity, particularly via fibrils in the adventitia. Preserving or promoting collagen cross-linking may represent a therapeutic target for an otherwise vulnerable aorta.