Deposition Of Elastic Fibers Research Articles

Alpha-7 Nicotinic Receptor Agonist Protects Mice Against Pulmonary Emphysema Induced by Elastase.

Pulmonary emphysema is a primary component of chronic obstructive pulmonary disease (COPD), a life-threatening disorder characterized by lung inflammation and restricted airflow, primarily resulting from the destruction of small airways and alveolar walls. Cumulative evidence suggests that nicotinic receptors, especially the α7 subtype (α7nAChR), is required for anti-inflammatory cholinergic responses. We postulated that the stimulation of α7nAChR could offer therapeutic benefits in the context of pulmonary emphysema. To investigate this, we assessed the potential protective effects of PNU-282987, a selective α7nAChR agonist, using an experimental emphysema model. Male mice (C57BL/6) were submitted to a nasal instillation of porcine pancreatic elastase (PPE) (50µl, 0.667IU) to induce emphysema. Treatment with PNU-282987 (2.0mg/kg, ip) was performed pre and post-emphysema induction by measuring anti-inflammatory effects (inflammatory cells, cytokines) as well as anti-remodeling and anti-oxidant effects. Elastase-induced emphysema led to an increase in the number of α7nAChR-positive cells in the lungs. Notably, both groups treated with PNU-282987 (prior to and following emphysema induction) exhibited a significant decrease in the number of α7nAChR-positive cells. Furthermore, both groups treated with PNU-282987 demonstrated decreased levels of macrophages, IL-6, IL-1β, collagen, and elastic fiber deposition. Additionally, both groups exhibited reduced STAT3 phosphorylation and lower levels of SOCS3. Of particular note, in the post-treated group, PNU-282987 successfully attenuated alveolar enlargement, decreased IL-17 and TNF-α levels, and reduced the recruitment of polymorphonuclear cells to the lung parenchyma. Significantly, it is worth noting that MLA, an antagonist of α7nAChR, counteracted the protective effects of PNU-282987 in relation to certain crucial inflammatory parameters. In summary, these findings unequivocally demonstrate the protective abilities of α7nAChR against elastase-induced emphysema, strongly supporting α7nAChR as a pivotal therapeutic target for ameliorating pulmonary emphysema.

S100A4 Is a Key Facilitator of Thoracic Aortic Dissection.

Background: Thoracic aortic dissection (TAD) is one of the cardiovascular diseases with high incidence and fatality rates. Vascular smooth muscle cells (VSMCs) play a vital role in TAD formation. Recent studies have shown that extracellular S100A4 may participate in VSMCs regulation. However, the mechanism(s) underlying this association remains elusive. Consequently, this study investigated the role of S100A4 in VSMCs regulation and TAD formation. Methods: Hub genes were screened based on the transcriptome data of aortic dissection in the Gene Expression Synthesis database. Three-week-old male S100A4 overexpression (AAV9- S100A4 OE) and S100A4 knockdown (AAV9- S100A4 KD) mice were exposed to β-aminopropionitrile monofumarate through drinking water for 28 days to create the murine TAD model. Results: S100A4 was observed to be the hub gene in aortic dissection. Furthermore, overexpression of S100A4 was exacerbated, whereas inhibition of S100A4 significantly improved TAD progression. In the TAD model, the S100A4 was observed to aggravate the phenotypic transition of VSMCs. Additionally, lysyl oxidase (LOX) was an important target of S100A4 in TAD. S100A4 interacted with LOX in VSMCs, reduced mature LOX (m-LOX), and decreased elastic fiber deposition, thereby disrupting extracellular matrix homeostasis and promoting TAD development. Elastic fiber deposition in human aortic tissues was negatively correlated with the expression of S100A4, which in turn, was negatively correlated with LOX. Conclusions: Our data showed that S100A4 modulates TADprogression, induces lysosomal degradation of m-LOX, and reduces the deposition of elastic fibers by interacting with LOX, thus contributing to the disruption of extracellular matrix homeostasis in TAD. These findings suggest that S100A4 may be a new target for the prevention and treatment of TAD.

Elastic fibers define embryonic tissue stiffness to enable buckling morphogenesis of the small intestine

During embryonic development, tissues must possess precise material properties to ensure that cell-generated forces give rise to the stereotyped morphologies of developing organs. However, the question of how material properties are established and regulated during development remains understudied. Here, we aim to address these broader questions through the study of intestinal looping, a process by which the initially straight intestinal tube buckles into loops, permitting ordered packing within the body cavity. Looping results from elongation of the tube against the constraint of an attached tissue, the dorsal mesentery, which is elastically stretched by the elongating tube to nearly triple its length. This elastic energy storage allows the mesentery to provide stable compressive forces that ultimately buckle the tube into loops. Beginning with a transcriptomic analysis of the mesentery, we identified widespread upregulation of extracellular matrix related genes during looping, including genes related to elastic fiber deposition. Combining molecular and mechanical analyses, we conclude that elastin confers tensile stiffness to the mesentery, enabling its mechanical role in organizing the developing small intestine. These results shed light on the role of elastin as a driver of morphogenesis that extends beyond its more established role in resisting cyclic deformation in adult tissues.

Postnatal growth restriction impairs rat lung structure and function.

The negative impact of nutritional deficits in the development of bronchopulmonary dysplasia is well recognized, yet mechanisms by which nutrition alters lung outcomes and nutritional strategies that optimize development and protect the lung remain elusive. Here, we use a rat model to assess the isolated effects of postnatal nutrition on lung structural development without concomitant lung injury. We hypothesize that postnatal growth restriction (PGR) impairs lung structure and function, critical mediators of lung development, and fatty acid profiles at postnatal day 21 in the rat. Rat pups were cross-fostered at birth to rat dams with litter sizes of 8 (control) or 16 (PGR). Lung structure and function, as well as serum and lung tissue fatty acids, and lung molecular mediators of development, were measured. Male and female PGR rat pups had thicker airspace walls, decreased lung compliance, and increased tissue damping. Male rats also had increased lung elastance, increased lung elastin protein abundance, and lysol oxidase expression, and increased elastic fiber deposition. Female rat lungs had increased conducting airway resistance and reduced levels of docosahexaenoic acid in lung tissue. We conclude that PGR impairs lung structure and function in both male and female rats, with sex-divergent changes in lung molecular mediators of development.

Combined Fractional CO 2 Laser With Intradermal Platelet-Rich Plasma versus Fractional CO 2 Laser Alone in the Treatment of Striae Distensae.

Striae distensae (SD) or stretch marks are common cutaneous conditions that occur because of the stretching of the dermis.OBJECTIVE To evaluate and compare the efficacy of fractional carbon dioxide (CO 2 ) laser alone versus combined fractional CO 2 laser with platelet-rich plasma (PRP) in SD treatment. Thirty adult female patients with SD (SR and SA) were enrolled. In each patient, a split-lesion design was conducted as follows: pairs of SD on both sides of the midline were selected and allocated to groups A and B. Group A: was treated with combined fractional CO 2 laser with intradermal PRP. Group B: was treated with fractional CO 2 laser alone. Skin biopsies were taken from the lesions before and after treatment for histopathologic evaluation. In group A, a significant excellent improvement of the SD was achieved more than in group B ( p = .007) and the mean of improvement was significantly higher (60.33 ± 26.49) than that in group B (43.80 ± 27.43) ( p -value = .001). Group A was also associated with a more significant dermal deposition of collagen and elastic fibers. Combined fractional CO 2 laser with PRP was more effective than fractional CO 2 laser alone for the treatment of SD.

Targeting Epidermal Growth Factor Receptor to Stimulate Elastic Matrix Regenerative Repair.

Abdominal aortic aneurysms (AAAs) represent a multifactorial, proteolytic disorder involving disintegration of the matrix structure within the AAA wall. Intrinsic deficiency of adult vascular cells to regenerate and repair the wall elastic matrix, which contributes to vessel stretch and recoil, is a major clinical challenge to therapeutic reversal of AAA growth. In this study, we investigate the involvement of epidermal growth factor receptor-mitogen activated protein kinase (EGFR-MAPK) pathway in the activation of aneurysmal smooth muscle cells (SMCs) by neutrophil elastase, and how EGFR can be targeted for elastic matrix regeneration. We have demonstrated that neutrophil elastase activates EGFR and downregulates expression level of key elastin homeostasis genes (elastin, crosslinking enzyme-lysyl oxidase, and fibulin4) between a dose range of 1-10 μg/mL (p < 0.05). It also incites downstream proteolytic outcomes by upregulating p-extracellular signal-regulated kinase (ERK)1/2 (p < 0.0001) and matrix metalloprotease 2 (MMP2) at a protein level, which is significantly downregulated upon EGFR-specific inhibition by tyrosine kinase inhibitor AG1478 (p-ERK1/2 and MMP2 [p < 0.05]). Moreover, we have shown that EGFR inhibition suppresses collagen amounts in aneurysmal SMCs (p < 0.05) and promotes robust formation of elastic fibers by enhancing its deposition in the extracellular space. Hence, the EGFR-MAPK pathway in aneurysmal cells can be targeted to provide therapeutic effects toward stimulating vascular matrix regeneration. Impact statement Proteolytic disorders such as aortal expansions, called abdominal aortic aneurysms (AAAs), are characterized by naturally irreversible enzymatic breakdown and loss of elastic fibers, a problem that has not yet been surmounted by existing tissue engineering approaches. In this work, we show, for the first time, how epidermal growth factor receptor (EGFR) inhibition provides downstream benefits in elastic fiber assembly and deposition in aneurysmal smooth muscle cell cultures. This work can open future possibilities for development of EGFR-targeted drug-based therapies not only for vessel wall repair in AAAs but also other proteolytically compromised elastic tissues.

The Role of an Aqueous Extract of Cactus on Histopancreatic Architecture in Streptozotocin Induced Diabetes Mellitus in Wistar Rats

Herbs have been used as medicinal for several years to cure or rather manage different ailments such as diabetes mellitus. This is very common in rural settings of sub-saharan Africa and is now being adopted in urban areas. Opunta species have widely been seen to contain antihyperglycaemic effects. To evaluate the antihyperglycaemic and histopancreatic effect of aqueous extract of prickly pear cactus (Opuntia species) cladodes in streptozotocin-induced diabetic male Wistar rats in vivo. This was a laboratory based research conducted at Mulungushi University involving 30 wistar rats (Rattus norvegicus) that weighed between 160-200 g which were randomly selected into five groups (6 per cage); normal control, diabetic control, diabetic +metformin, diabetic +cactus and cactus only group. Initial blood glucose levels were obtained from the tail and record then Diabetes mellitus was induced using a single intraperitoneal dose of streptozotocin (70mg/kg BW) and established a persistent state of hyperglycemia after 72hours. The aqueous cactus extract of 100 mg/kg BW and metformin of 100 mg/kg BW was administered orally using intragastric cannula daily for a period of 4 weeks. At the end of the fourth week, Diabetes + cactus and diabetes + metformin groups body weights were statistically significant when compared to the diabetic group (P&lt;0.05). While diabetic group was statistically significant when compared to normal control (P&lt;0.05). The relative weight of the pancreas in diabetic group was statistically significant to other groups (P&lt;0.05). The blood glucose in diabetic + cactus was normoglycaemic at 3rd week, Diabetic + metformin group when compared to diabetic group was statistically significant (P&lt;0.05). The normal control and cactus only groups maintained normoglycaemic till the end of the 4th week. The histological findings of the normal control and cactus only group showed normal pancreatic cytoarchitecture. Diabetes group showed high degree of disorganization in the cytoarchitecture in the islet with reduction in β cell mass and deposition of elastic fibres. The Diabetic+Metformin group showed slight decrease in the cell mass (β cells) and elastic fibres were extensively deposited. Diabetic+Cactus treated group exhibited normal histology of the pancreas with increased number of β cells. Opuntia species are able to lower elevated blood glucose levels and ameliorate the effects of STZ on the pancreatic morphology

Mouse Knockout Models for Pelvic Organ Prolapse: a Systematic Review.

Mouse knockout (KO) models of pelvic organ prolapse (POP) have contributed mechanistic evidence for the role of connective tissue defects, specifically impaired elastic matrix remodeling. Our objective was to summarize what mouse KO models for POP are available and what have we learned from these mouse models about the pathophysiological mechanisms of POP development. We conducted a systematic review and reported narrative findings according to PRISMA guidelines. Two independent reviewers searched PubMed, Scopus and Embase for relevant manuscripts and conference abstracts for the time frame of January 1, 2000, to March 31, 2021. Conference abstracts were limited to the past 5years. The search strategy resulted in 294 total titles. We ultimately included 25 articles and an additional 11 conference abstracts. Five KO models have been studied: Loxl1, Fbln5, Fbln3, Hoxa11 and Upii-sv40t. Loxl1 and Fbln5 KO models have provided the most reliable and predictable POP phenotype. Loxl1 KO mice develop POP primarily from failure to heal after giving birth, whereas Fbln5 KO mice develop POP with aging. These mouse KO models have been used for a wide variety of investigations including genetic pathways involved in development of POP, biomechanical properties of the pelvic floor, elastic fiber deposition, POP therapies and the pathophysiology associated with mesh complications. Mouse KO models have proved to be a valuable tool in the study of specific genes and their role in the development and progression of POP. They may be useful to study POP treatments and POP complications.

Deletion of type VIII collagen reduces blood pressure, increases carotid artery functional distensibility and promotes elastin deposition

Arterial stiffening is a significant predictor of cardiovascular disease development and mortality. In elastic arteries, stiffening refers to the loss and fragmentation of elastic fibers, with a progressive increase in collagen fibers. Type VIII collagen (Col-8) is highly expressed developmentally, and then once again dramatically upregulated in aged and diseased vessels characterized by arterial stiffening. Yet its biophysical impact on the vessel wall remains unknown. The purpose of this study was to test the hypothesis that Col-8 functions as a matrix scaffold to maintain vessel integrity during extracellular matrix (ECM) development. These changes are predicted to persist into the adult vasculature, and we have tested this in our investigation. Through our in vivo and in vitro studies, we have determined a novel interaction between Col-8 and elastin. Mice deficient in Col-8 (Col8−/−) had reduced baseline blood pressure and increased arterial compliance, indicating an enhanced Windkessel effect in conducting arteries. Differences in both the ECM composition and VSMC activity resulted in Col8−/− carotid arteries that displayed increased crosslinked elastin and functional distensibility, but enhanced catecholamine-induced VSMC contractility. In vitro studies revealed that the absence of Col-8 dramatically increased tropoelastin mRNA and elastic fiber deposition in the ECM, which was decreased with exogenous Col-8 treatment. These findings suggest a causative role for Col-8 in reducing mRNA levels of tropoelastin and the presence of elastic fibers in the matrix. Moreover, we also found that Col-8 and elastin have opposing effects on VSMC phenotype, the former promoting a synthetic phenotype, whereas the latter confers quiescence. These studies further our understanding of Col-8 function and open a promising new area of investigation related to elastin biology.

Histological Evidence of Wound Healing Improvement in Rats Treated with Oral Administration of Hydroalcoholic Extract of Vitis labrusca.

Plant extracts rich in phenolic compounds have been demonstrated to accelerate wound healing, but their use by oral route has been poorly studied. The leaves of Vitis labrusca are rich in phenolic acids and flavonoids. The goal of this study was to assess the healing properties of the oral administration of hydroalcoholic extract of V. labrusca leaves (HEVL) in a murine model. HEVL was obtained by Soxhlet and dynamic maceration, and their yield and phenolic acids and flavonoid contents were determined. For the wound healing assay, 8 mm wounds were performed on the back of 48 Wistar rats, assigned into four groups (n = 12): CTR (distilled water), HEVL100, HEVL200, and HEVL300 (HEVL at 100, 200, and 300 mg/kg, respectively). On days 7 and 14, wound closure rates were assessed, and the healing wounds were subjected to histological analysis. Soxhlet-obtained extract was selected for the wound healing assay because it provided a higher yield and phenolic acid and flavonoid contents. HEVL significantly reduced leukocytosis in the peripheral blood (p < 0.05), accelerated wound closure (p < 0.05), and improved collagenization (p < 0.05) on day 7, as well as enhanced the epidermal tissue thickness (p < 0.001) and elastic fiber deposition on day 14 (p < 0.01). Furthermore, HEVL promoted an increase in the histological grading of wound healing on both days 7 and 14 (p < 0.01). The doses of 200 and 300 mg/kg provided better results than 100 mg/Kg. Our data provide histological evidence that the oral administration of HEVL improves wound healing in rodents. Therefore, the extract can be a potential oral medicine for healing purposes.

Differences in the response in the dermis of the tails of young and old SD rats to treatment with bipolar RF.

The passing of the years is marked by intrinsic (chronological) and extrinsic aging, caused by photoaging, which is characterized by a decrease in collagen and the deposition of abnormal elastic fibers in the dermis. The use of bipolar radiofrequency (RF) increases fibroblast proliferation and differentiation, accompanied by collagen synthesis and a subsequent increase in connective tissue, and it is not known whether the biological effects of this type of radiofrequency on the dermis are similar regardless of the age of the individual or whether such effects are altered by the aging process itself. The objective was to perform a histological study of the changes in the tail dermis of young and old rats after submitting them to bipolar RF, to determine cell proliferation and volume of connective tissue. One part of the rat tail was fixed in formol and processed for light microscopy and another part processed for electron microscopy. The number of fibroblasts/unit area and cells positive to nuclear proliferation antigen was higher in young animals. Significant differences were observed regarding expression of HSP-47 protein, and the value was always lower in old rats. No significant differences were observed in the percentage of connective tissue. No histological alterations were observed in any rats. Treatment with RF increased the number of fibroblasts located in the connective tissue of the young rats. In addition, the effect of a single treatment on the population of fibroblasts in young animals was sufficient to activate the synthesis of new collagen.

A step closer to elastogenesis on demand; Inducing mature elastic fibre deposition in a natural biomaterial scaffold

Elastic fibres play a key role in bodily functions where fatigue resistance and elastic recovery are necessary while regulating phenotype, proliferation and migration in cells. While in vivo elastic fibres are created at a late foetal stage, a major obstacle in the development of engineered tissue is that human vascular smooth muscle cells (hVSMCs), one of the principal elastogenic cells, are unable to spontaneously promote elastogenesis in vitro. Therefore, the overall aim of this study was to activate elastogenesis in vitro by hVSMCs seeded in fibrin, collagen, glycosaminoglycan (FCG) scaffolds, following the addition of recombinant human tropoelastin. This combination of scaffold, tropoelastin and cells induced the deposition of elastin and formation of lamellar maturing elastic fibres, similar to those found in skin, blood vessels and heart valves. Furthermore, higher numbers of maturing branched elastic fibres were synthesised when a higher cell density was used and by drop-loading tropoelastin onto cell-seeded FCG scaffolds prior to adding growth medium. The addition of tropoelastin showed no effect on cell proliferation or mechanical properties of the scaffold which remained dimensionally stable throughout. With these results, we have established a natural biomaterial scaffold that can undergo controlled elastogenesis on demand, suitable for tissue engineering applications.

Elastic fibres in alcoholic liver disease

The literature on the contribution of elastic fibre deposition to alcohol-related liver disease (ARLD) is limited. We studied: (1) 180 liver biopsies from ARLD patients; (2) 20 ARLD explant livers; (3) 213 liver biopsies with non-ARLD injury. Elastic fibres were assessed in terms of their distribution around hepatocytes [pericellular elastosis (PCE)] and within bridging fibrous septa (septal elastosis) and scored using a semiquantitative system. We also investigated the composition of the elastic fibres (oxytalan, elaunin and mature elastic fibres) in 20 cases. PCE was associated with steatohepatitis in ARLD patients and with ARLD when compared to non-ARLD cases (p < 0.001). Oxytalan fibres were identified in PCE in ARLD biopsies and broken dense perisinusoidal mature elastic fibres in explanted livers. Septal elastosis increased from intermediate to advanced fibrosis stage. Early septal elastosis contained oxytalan fibres, whereas septal elastosis at more advanced stages contained mainly mature elastic fibres. PCE is a typical feature of steatohepatitis in ARLD and includes oxytalan fibres. Septal elastosis is a gradual process with a transition from oxytalan to mature elastic fibres usually present in explanted livers. There may be different dynamics in the assembly and reabsorption of pericellular and septal elastic fibres, and a potential role for stratification of patients with advanced stage ARLD.

H2S attenuates oxidative stress via Nrf2/NF-κB signaling to regulate restenosis after percutaneous transluminal angioplasty.

Restenosis after angioplasty of peripheral arteries is a clinical problem involving oxidative stress. Hydrogen sulfide (H2S) participates in oxidative stress regulation and activates nuclear factor erythroid 2-related factor 2 (Nrf2). This study investigated the effect of H2S and Nrf2 on restenosis-induced arterial injury. Using an in vivo rat model of restenosis, we investigated whether H2S inhibits restenosis after percutaneous transluminal angioplasty (PTA) and the oxidative stress-related mechanisms implicated therein. The involvement of Nrf2 was explored using Nrf2-shRNA. Neointimal formation and the deposition of elastic fibers were assessed histologically. Inflammatory cytokine secretion and the expression of proteins associated with oxidative stress and inflammation were evaluated. The artery of rats subjected to restenosis showed increased arterial intimal thickness, with prominent elastic fiber deposition. Sodium hydrosulfide (NaHS), an H2S donor, counteracted these changes in vivo. Restenosis caused a decrease in anti-oxidative stress signaling. This phenomenon was inhibited by NaHS, but Nrf2-shRNA counteracted the effects of NaHS. In terms of inflammation, inflammatory cytokines were upregulated, whereas NaHS suppressed the induced inflammatory reaction. Similarly, Nrf2 downregulation blocked the effect of NaHS. In vitro studies using aortic endothelial and vascular smooth muscle cells isolated from experimental animals showed consistent results as those of in vivo studies, and the participation of the nuclear factor-kappa B signaling pathway was demonstrated. Collectively, H2S played a role in regulating post-PTA restenosis by alleviating oxidative stress, modulating anti-oxidant defense, and targeting Nrf2-related pathways via nuclear factor-kappa B signaling.

Combined microneedling with topical application of platelet-rich plasma versus microneedling alone in the treatment of stria distensae: clinicopathological analysis

Background Striae distensae (SD) are common skin conditions. Objectives This study was done to test the hypothesis that ‘the use of microneedling (MN) before platelet-rich plasma (PRP) application will allow for deeper penetration and therefore, augment its efficacy in the treatment of SD.’ Patients and methods Forty patients with SD were divided into (i) Group I, the patients were treated with MN only, and (ii) Group II, the patients were treated with combined MN-PRP. The clinical improvement was evaluated by two dermatologists. Skin biopsies were obtained before and after therapy to examine immunohistological changes. Results As compared to the use of MN alone, therapy with combined MN-PRP was associated with: (i) a marked to the excellent improvement of the skin lesions of SD, (ii) a more significant deposition of collagen and elastic fibers, (iii) increased proliferative activity in the epidermis, and (iv) a decreased caspase-3 protein expression values in the epidermis. Conclusions This study proved that the combined MN-PRP is more effective than MN alone for the treatment of the lesions of SD. The underlying molecular mechanisms are open for future studies.

Elastic Fibers Density: a New Parameter of Improvement of NAFLD in Bariatric Surgery Patients

Obesity is a major risk factor for nonalcoholic fatty liver disease (NAFLD), affecting 25% of the worldwide population. Weight loss through bariatric surgery can improve much of the liver steatosis, inflammation, and fibrosis. However, it is not known whether there is reversal of the elastic fiber deposition process, triggered by hepatic damage and related to worse prognosis. Individuals submitted to bariatric surgery at our institution, from March 2016 to June 2017, with intraoperative liver biopsy confirming NAFLD were approached. Those who consented were submitted to a second liver biopsy 1year later and were included. Specimens were sliced and stained with hematoxylin-eosin and Sirius red for histological assessment according to Brunt's criteria and with orcein for digital analysis morphometrics using ImageJ®. Quantification of elastic fibers was accomplished by corrected integrated density. Thirty-seven patients were included. Body mass index, metabolic markers, NAFLD activity score, and fibrosis improved 1year after the procedure. The elastic fiber density showed a significant decrease: 239.3 × 103 absorbance micrometer2 (141.08-645.32) to 74.62 × 103 absorbance micrometer2 (57.42-145.17), p = 0.007. Liver elastic fiber density decreases with the reversal of NAFLD through weight loss.

Whole exome sequencing in patients with Williams–Beuren syndrome followed by disease modeling in mice points to four novel pathways that may modify stenosis risk

Supravalvular aortic stenosis (SVAS) is a narrowing of the aorta caused by elastin (ELN) haploinsufficiency. SVAS severity varies among patients with Williams-Beuren syndrome (WBS), a rare disorder that removes one copy of ELN and 25-27 other genes. Twenty percent of children with WBS require one or more invasive and often risky procedures to correct the defect while 30% have no appreciable stenosis, despite sharing the same basic genetic lesion. There is no known medical therapy. Consequently, identifying genes that modify SVAS offers the potential for novel modifier-based therapeutics. To improve statistical power in our rare-disease cohort (N = 104 exomes), we utilized extreme-phenotype cohorting, functional variant filtration and pathway-based analysis. Gene set enrichment analysis of exome-wide association data identified increased adaptive immune system variant burden among genes associated with SVAS severity. Additional enrichment, using only potentially pathogenic variants known to differ in frequency between the extreme phenotype subsets, identified significant association of SVAS severity with not only immune pathway genes, but also genes involved with the extracellular matrix, G protein-coupled receptor signaling and lipid metabolism using both SKAT-O and RQTest. Complementary studies in Eln+/-; Rag1-/- mice, which lack a functional adaptive immune system, showed improvement in cardiovascular features of ELN insufficiency. Similarly, studies in mixed background Eln+/- mice confirmed that variations in genes that increase elastic fiber deposition also had positive impact on aortic caliber. By using tools to improve statistical power in combination with orthogonal analyses in mice, we detected four main pathways that contribute to SVAS risk.

Comparison Of Amount Of Elastin Fibres With Histopathological Parameters And Elastography In Breast Carcinoma

Background: Breast carcinoma is the most fre­quently diagnosed cancer and the chief cause of cancer deaths among women worldwide. Cancer registry data shows that incidence of carcinoma breast ranges from 19.3 to 89.7 per 100,000 population (India) and a total of 27.5% cases of cancers in Karnataka. The normal breast tissue is comprised of two major compartments, the epithelium and the stroma. Normally elastic tissue can be seen in periductal and perivascular region of breast. Elastosis, characterized by deposition of elastic fibers in the stroma of infiltrating ductal carcinoma was first described by Cheatle and Cutler, but extensively studied by Shivas & Douglas and others. Several methods for visual grading of elastosis have been proposed but all are semi quantitative and subjective and are dependent on the experience of the observed. Methods: Blocks of all 87 cases were retrieved from the histopathological section, department of Pathology of our institute. Data regarding the demographic details, clinical presentation of the cases are obtained from the medical record section of our medical record section of our college. The slides were stained with Verhoeff’s van Gieson stain and were screened by two pathologists. Result: Out of 87 cases studied only 1 case showed elastin fibers score 0, 18 cases showed score 1, 46 cases showed score 2 and 22 cases showed score 3. There was statistical significant correlation between Tumor stage and amount of paratumoral elastin fibers. There was no statistical correlation between Tumor grade, Tumor size, Nodes, Nottingham prognostic index and Modified tsukba scoring and paratumoral elastosis. Out of 87 cases the ER IHC was done in only 23 cases out of which 10 cases showed positivity on Allred scoring and 13 cases were negative. For Progesterone receptors out of 23 cases 9 cases were positive on Allred scoring and 14 were negative and hence the correlation could not be done. The HER2neu was done in 23 cases out of 87 cases where the positivity was seen in 07 cases and it was equivocal in 03 cases and negative in 13 cases. Conclusion: Our results strongly indicate the presence of Peritumoral elastosis and the lower tumor grade. The paratumoral elastosis and lower tumor stage. Whether and how elastosis is mechanically involved in tumor development and progress requires further study.

INTRAORAL EPIDERMOID CYST WITH EXTENSIVE ELASTOFIBROMATOUS CHANGES: AN EXTREMELY RARE FINDING

Epidermoid cysts (ECs) are rare and occur in the head and neck region with an incidence from 1.6% to 7%. In the oral cavity, EC represents less than 0.01% of all cysts. To date, approximately 80 EC cases have been reported. We report a case of a 26-year-old man who developed a large EC in the midline floor of the mouth, leading to speech and swallowing difficulties and causing swelling in the submental region. Ultrasonography and fine needle aspiration confirmed the cystic nature of the lesion. The lesion was surgically excised by intraoral approach, and microscopically revealed an EC associated with extensive elastofibromatous changes in the cystic capsule. The pathogenesis of the abnormal deposition of elastic fibers is unknown; however, degenerative phenomenon, disturbed production, genetic predisposition, or trauma have been considered. To the best of our knowledge, this is the first report of elastofibromatous changes in an intraoral EC.

610 Hibiscus abelmoschus seed extract induces remodelling of the papillary dermal fibrillin-rich microfibrils

Hibiscus abelmoschus seed extract is used in anti-ageing cosmetics and improves both the firmness of skin and reduces the appearance of wrinkles. Whilst it promotes collagen production, less is known about its wider impact upon the remodelling of the dermal extracellular matrix (ECM). In this study we investigated its effects upon the expression and deposition of key ECM biomarkers. A formulation containing the botanical derivative was prepared as an oil in water gel cream and applied to photoaged extensor forearm of healthy individuals (n=9; aged 61-79). The test product and vehicle control (30 μl) were re-applied every 4 days over a 12-day period under occlusion; all-trans retinoic acid (RA; 0.025%) was applied for the final 4 days, as a positive control. Skin biopsies (3 mm diameter) were obtained from all sites and the expression of selected biomarkers compared against baseline biopsies derived from an area of untreated but occluded extensor forearm skin. Epidermal thickness was significantly increased in skin treated with RA (63.6 ± 23 μm) compared to baseline (37.1 ± 5.8 μm; p< 0.0001). Epidermal convolution, and elastic fibre deposition, as determined by Weigert’s Fuchsin staining, were found to be unaffected by any of the applications. Using a semi-quantitative ordinal scale to assess de novo ECM deposition, papillary dermal fibrillin-rich microfibrils were found to be significantly increased in response to treatment with H. abelmoschus (3.42 ± 0.53, p<0.01) or RA (3.4 ± 0.46, p<0.01) compared to the baseline (2.48 ± 0.52). There was no significant difference between the baseline and the vehicle control (vehicle, 2.99 ± 0.85). This study suggests that remodelling and new synthesis of papillary dermal fibrillin-rich microfibrils, induced by the H. abelmoschus seed extract, may contribute towards the marked improvement in the appearance of age-related wrinkles when included in over-the-counter anti-ageing cosmetics.