A multi-institutional study from the US ROPE consortium examining factors associated with endocrine surgery exposure for general surgery residents.

BACKGROUND: Prior analyses of general surgery resident case logs have indicated a decline in the number of endocrine procedures performed during residency. This study aimed to identify factors contributing to the endocrine operative experience of general surgery residents and compare those who matched in endocrine surgery fellowship with those who did not. METHODS: We analyzed the case log data of graduates from 18 general surgery residency programs in the US Resident Operative Experience Consortium over an 11-year period. RESULTS: Of the 1,240 residents we included, 17 (1%) matched into endocrine surgery fellowships. Those who matched treated more total endocrine cases, including more thyroid, parathyroid, and adrenal cases, than those who did not (81 vs 37, respectively, P < .01). Program-level factors associated with increased endocrine volume included endocrine-specific rotations (+10, confidence interval 8-12, P < .01), endocrine-trained faculty (+8, confidence interval 7-10, P < .01), and program co-location with otolaryngology residency (+5, confidence interval 2 -8, P < .01) or endocrine surgery fellowship (+4, confidence interval 2-6, P < .01). Factors associated with decreased endocrine volume included bottom 50th percentile in National Institute of Health funding (-10, confidence interval -12 to -8, P < .01) and endocrine-focused otolaryngologists (-3, confidence interval -4 to -1, P < .01). CONCLUSION: Several characteristics are associated with a robust endocrine experience and pursuit of an endocrine surgery fellowship. Modifiable factors include optimizing the recruitment of dedicated endocrine surgeons and the inclusion of endocrine surgery rotations in general surgery residency.

The national rate of malignancy among Bethesda III, IV, and V thyroid nodules is higher than expected: A NSQIP analysis.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology was formalized in 2007 to stratify cytologic specimens based on their risk of malignancy. Several studies have reported significant variations between their institutional rate of malignancy compared to the Bethesda System for Reporting Thyroid Cytopathology. The objective of this study was to determine the national rate of malignancy for Bethesda III, Bethesda IV, and Bethesda V thyroid nodules. METHODS: From 2016 to 2019, patients with preoperative thyroid cytopathology and pathology results in National Surgical Quality Improvement database were included. The rate of malignancy was compared to the median the Bethesda System for Reporting Thyroid Cytopathology 2017, and risk factors associated with malignancy were identified for Bethesda III, Bethesda IV, and Bethesda V specimens. RESULTS: In total, 13,121 patients with preoperative cytopathology and postresection pathology were identified. The national rate of malignancy was significantly higher than the Bethesda System for Reporting Thyroid Cytopathology 2017 for Bethesda III (36.2% vs 12.0%, P < .01), Bethesda IV (36.7% vs 25.0%, P < .01), and Bethesda V (91.1% vs 52.5%, P < .01) specimens. Male sex was significantly associated with malignancy in Bethesda III, Bethesda IV, and Bethesda V nodules (Bethesda III, odds ratio: 1.20, [1.01-1.42]; Bethesda IV, odds ratio: 1.47, [1.27-1.71]; Bethesda V, odds ratio: 1.28, [1.03-1.58]). Younger age was associated with malignancy in Bethesda III patients under 55 (odds ratio: 1.23, [1.06-1.42]), Bethesda IV patients under 42 (odds ratio: 1.23, [1.06-1.43]), and Bethesda V patients aged less than 47 (odds ratio: 1.38, [1.15-1.67]). CONCLUSIONS: This is the largest cohort study to describe the national rate of malignancy for Bethesda III, IV, and V specimens in the United States. These results reveal the national rate of malignancy is higher than the implied rate of malignancy reported to patients based on the Bethesda System for Reporting Thyroid Cytopathology. We recommend counseling patients regarding this increased rate of malignancy to set appropriate expectations after surgical intervention.

Targeting Autophagy in Thyroid Cancer: EMT, Apoptosis, and Cancer Stem Cells.

Autophagy is a highly conserved recycling process through which cellular homeostasis is achieved and maintained. With respect to cancer biology, autophagy acts as a double-edged sword supporting tumor cells during times of metabolic and therapeutic stress, while also inhibiting tumor development by promoting genomic stability. Accumulating evidence suggests that autophagy plays a role in thyroid cancer, acting to promote tumor cell viability and metastatic disease through maintenance of cancer stem cells (CSCs), supporting epithelial-to-mesenchymal transition (EMT), and preventing tumor cell death. Intriguingly, well-differentiated thyroid cancer is more prevalent in women as compared to men, though the underlying molecular biology driving this disparity has not yet been elucidated. Several studies have demonstrated that autophagy inhibitors may augment the anti-cancer effects of known thyroid cancer therapies. Autophagy modulation has become an attractive target for improving outcomes in thyroid cancer. This review aims to provide a comprehensive picture of the current knowledge regarding the role of autophagy in thyroid cancer, focusing on the potential mechanism(s) through which inhibition of autophagy may enhance cancer therapy and outcomes.

Minimally Invasive Surgery for Resectable Adrenocortical Carcinoma: A Nationwide Analysis.

INTRODUCTION: The utilization of minimally invasive surgery (MIS) for adrenocortical carcinoma (ACC) remains controversial due to concerns regarding the quality of surgical resection and subsequent oncologic risks. Current guidelines recommend open resections for all cases of suspected ACC independent of size; however, there has been increased adoption of MIS for ACC over time. We sought to determine whether the rise in the utilization of MIS is associated with worse survival outcomes for ACC. METHODS: The National Cancer Database was queried for patients with ACC who underwent surgical resection between 2010 and 2017. Patient selection, oncologic outcomes, and overall survival were compared among patients who received an MIS approach (laparoscopic or robotic) versus an open approach. RESULTS: A total of 1483 patients underwent ACC resection with 982 (66.2%) patients undergoing an open approach and 501 (33.8%) receiving an MIS operation. The overall utilization of MIS for ACC increased significantly after 2013 (37.7% versus 29.5%, P < 0.01). There was no difference in overall survival between MIS and open resections on univariable (log-rank P = 0.12) analysis. On multivariable analysis, survival was improved in MIS patients versus open resection (Hazard ratio: 0.83, 95% CI: [0.70-0.99]). Notably, survival remained comparable among patients who underwent resection for large ACCs (6-10 cm, log-rank P = 0.66) and giant ACCs (>10 cm, log-rank P = 0.24), irrespective of operative approach. CONCLUSIONS: Our findings suggest that in appropriately selected patients with ACC, MIS can be performed safely without a significant decrease in overall survival, independent of size. We recommend consideration of a minimally-invasive approach for adrenal masses despite size >6 cm.

Gender Disparities in Academic Productivity and Promotion Among Endocrine Surgery Faculty.

INTRODUCTION: Academic rank and metrics such as total publications (pubs) and H-index are indicators to measure academic achievement. This study aims to determine whether there are gender differences in academic productivity or faculty appointments among endocrine surgeons in the United States. METHODS: A database was generated from the American Association of Endocrine Surgeons (AAES) website. Community or academic practice was designated by institution affiliation and faculty appointment. Academic metrics, including pubs, H-index, and weighted-RCR (relative citation ratio), were obtained from public databases. RESULTS: A total of 258 AAES members were affiliated with an academic institution. The majority were men (58%). Overall, men in endocrine surgery had higher academic metrics: pubs (56.0 [26-134], 23.0 [11-56], P < 0.0001), H-index (19.0 [11-35], 9.0 [5-21], P < 0.0001), weighted-RCR (63.5 [22-193], 24.1 [8-74], P < 0.005) and rank (associate professor or professor, P < 0.0001). Subgroup analysis accounting for time in practice found no difference in total publications, weighted RCR, or faculty appointments between genders in practice for 0-5 y. However, among surgeons in practice for 6-10 y, men had higher academic metrics (pubs: 31.0 [16-79], 18.5 [9-33]; RCR: 46.0 [14-102], 13.3 [9-34]) and faculty appointments (all P < 0.05). CONCLUSIONS: There are gender disparities in academic productivity and faculty appointment among US endocrine surgeons. While junior faculty show no gender differences in most indicators of academic productivity or rank, men with 6-10 y in practice have higher average academic metrics and rank. Whether the absence of gender disparities among junior faculty is a sustainable reflection of recent efforts to encourage equal mentorship and professional opportunities or whether disparities will manifest as faculty progress remains to be determined.

Surgery Is Underutilized in the Management of Tertiary Hyperparathyroidism.

INTRODUCTION: Tertiary hyperparathyroidism (3HPT) is observed in up to 40% of renal transplant patients. Standard guidelines defining 3HPT and indications for operative intervention are not well described. METHODS: We conducted a retrospective, single-institution cohort study of patients who underwent renal transplant between January 1, 2012 and January 30, 2018, with a minimum of 13-month follow-up and at least 1 y of allograft function. We defined 3HPT as having elevated serum level parathyroid hormone (>88 pg/mL) after successful renal transplantation or multiple instances of elevated serum calcium starting at least 3 mo after transplant. We compared graft failure rates after stratifying the cohort based on management strategy: expectant, medical management with cinacalcet, and parathyroidectomy. RESULTS: Out of the 381 transplanted patients with functional grafts at 1 y, 178 patients (46.6%) were found to have 3HPT. One hundred twenty-nine patients (72.5%) were managed expectantly without medications, 35 patients (19.7%) were managed medically, and 14 patients (7.8%) were managed with parathyroidectomy. Twenty-two patients (17.1%) in the observation group had graft failure, 4 patients (11.4%) in the medically managed group had graft failure, and 0 patients in the surgery group had graft failure. Surgical intervention was associated with decreased renal allograft failure when compared to the combined cohort of nonoperative 3HPT patients (P = 0.03). All patients who underwent parathyroidectomy were cured and did not have graft failure as of December 30, 2019. Calcium elevation, but not PTH elevation, was associated with referral for parathyroidectomy on multivariable logistic regression analysis (P < 0.01). CONCLUSIONS: At our institution, the referral rate for parathyroidectomy among patients with 3HPT remains low. Parathyroidectomy was associated with high cure rates and reduced graft failure. Surgery may be underutilized in the management of 3HPT.

Biglycan Promotes Cancer Stem Cell Properties, NFκB Signaling and Metastatic Potential in Breast Cancer Cells.

It is a major challenge to treat metastasis due to the presence of heterogenous BCSCs. Therefore, it is important to identify new molecular targets and their underlying molecular mechanisms in various BCSCs to improve treatment of breast cancer metastasis. Here, we performed RNA sequencing on two distinct co-existing BCSC populations, ALDH+ and CD29hi CD61+ from PyMT mammary tumor cells and detected upregulation of biglycan (BGN) in these BCSCs. Genetic depletion of BGN reduced BCSC proportions and tumorsphere formation. Furthermore, BCSC associated aggressive traits such as migration and invasion were significantly reduced by depletion of BGN. Glycolytic and mitochondrial metabolic assays also revealed that BCSCs exhibited decreased metabolism upon loss of BGN. BCSCs showed decreased activation of the NFκB transcription factor, p65, and phospho-IκB levels upon BGN ablation, indicating regulation of NFκB pathway by BGN. To further support our data, we also characterized CD24-/CD44+ BCSCs from human luminal MCF-7 breast cancer cells. These CD24-/CD44+ BCSCs similarly exhibited reduced tumorigenic phenotypes, metabolism and attenuation of NFκB pathway after knockdown of BGN. Finally, loss of BGN in ALDH+ and CD29hi CD61+ BCSCs showed decreased metastatic potential, suggesting BGN serves as an important therapeutic target in BCSCs for treating metastasis of breast cancer.

Avoiding delays in time to renal transplantation: Pretransplant thyroid malignancy does not affect patient or graft survival after renal transplantation.

BACKGROUND: Pretransplant malignancy is associated with decreased patient and graft survival. Current US guidelines recommend a 2- to 5-year, tumor-free waiting period before transplantation. No large studies have examined the specific, modern day risk of pretransplant thyroid malignancy on patient and graft survival after renal transplant. METHODS: The United Network for Organ Sharing database was queried for all adult isolated renal transplant recipients between 2003 and 2019. Patient characteristics, rates of post-transplant malignancy, and survival were compared between patients with pretransplant thyroid malignancy and without pretransplant thyroid malignancy. RESULTS: Eighty-six patients had pretransplant thyroid malignancy diagnosed after listing and before renal transplantation. Both overall and graft survival were similar between cohorts (P > .05). There was no significant association between pretransplant thyroid malignancy and patient (hazard ratio: 0.66; P = .31) or graft (hazard ratio:0.32; P = .11) survival on multivariate analysis. Waitlist duration for pretransplant thyroid malignancy patients was significantly increased (1,444 vs 438 days; P < .01), which translated to increased dialysis duration (2,234 vs 1,201 days, P < .01). Pretransplant thyroid malignancy patients did not experience increased post-transplant malignancy (P = .21). CONCLUSION: Given no association with decreased patient or allograft survival, our findings suggest that pretransplant thyroid malignancy patients are unnecessarily subjected to increased wait-list duration before transplant. We recommend an individualized approach for pretransplant thyroid malignancy patients diagnosed before or after listing.

Thyroid nodules >4 cm with atypia of undetermined significance cytology independently associate with malignant pathology.

BACKGROUND: The risk of malignancy from nodules with atypia of undetermined significance cytology is estimated between 5% and 15%, though more recent studies suggest rates upwards of 48%. This study sought to characterize preoperative predictors of malignancy to aid in clinical decision-making. METHODS: We performed a single institution retrospective review of all adult patients with unilateral thyroid nodules demonstrating atypia of undetermined significance cytology between March 1, 2013 and June 1, 2019 who underwent surgical resection (n = 266). Univariate and multivariate logistical analysis was performed using clinical and demographic variables to identify potential preoperative characteristics associated with malignant disease. RESULTS: Malignancy was identified on final pathology in 24.7% of patients with atypia of undetermined significance cytology. Age, sex, exposure to ionizing radiation, family history of thyroid cancer, Hashimoto's disease, Afirma suspicious results, and smoking were not associated with malignancy on both univariate and multivariate analysis. Nodule size >4 cm was independently associated with malignancy risk on both univariate (odds ratio 2.44, 1.09-5.43, P < .03) and multivariate (odds ratio 2.96, 1.27-6.87, P < .02) analysis. CONCLUSION: The results of this study demonstrate that nodules with atypia of undetermined significance cytology >4 cm are strongly associated with malignancy. We recommend strong consideration of surgery for all patients with thyroid nodules >4 cm and atypia of undetermined significance cytology.

Inhibition of autophagy mitigates cell migration and invasion in thyroid cancer.

BACKGROUND: Autophagy is a highly conserved process for maintaining cellular homeostasis. Upregulation of autophagy promotes metastasis by promoting the cancer stem cell state while also stimulating tumor cell migration and invasion. We hypothesized that autophagy upregulation would be critical for cancer stem cell maintenance as well as cellular migration and invasion in thyroid cancer. METHODS: Validated papillary (MDA-T32, MDA-T68), follicular (FTC-133), and anaplastic (ATC-8505c) human thyroid cancer cell lines in culture were first assessed for autophagic capacity after bafilomycin clamping. Cancer stem cells were quantified by flow cytometry for aldehyde dehydrogenase and thyrosphere formation assay. Scratch migration and Matrigel invasion assays were performed in the presence of known autophagy inhibitors: Lys05, chloroquine, and FIP200siRNA. RESULTS: Autophagy activity was observed across all cell lines. Thyrosphere formation, aldehyde dehydrogenase activity, and CD44 expression were reduced with inhibition of autophagy in MDA-T32, MDA-T68, FTC-133, and 8505c cells. Similarly, cell migration and invasion were attenuated: 42% (FIP200siRNA), 78% (Lys05), P < .001 in MDA-T32 cells; 54% (FIP200siRNA), 67% (Lys05), P < .001 in MDA-T68 cells; 73% (FIP200siRNA), 71% (Lys05), P < .001) in FTC-133 cells; and 60% (FIP200siRNA), 90% (Lys05), P < .001 in 8505c cells. Invasion assays demonstrated a 73%, 39%, 75%, and 65.1% reduction in the presence of Lys05 in T32, T68, FTC-133, and 8505c cells, respectively. We observed similar reductions in invasion with FIP200siRNA: 61%, 62%, 55%, and 81.4% in T32, T68, FTC-133, and 8505c cells. CONCLUSION: Autophagy is upregulated across multiple thyroid cancer subtypes. In thyroid cancer cell lines, inhibition of autophagy attenuates cancer stem cell viability, cell migration, and invasion suggesting a role for autophagy in the progression of thyroid cancer. Greater understanding of autophagy regulation in thyroid cancer will aid in developing targeted therapeutics.

Heterogeneity within molecular subtypes of breast cancer.

Breast cancer is the quintessential example of how molecular characterization of tumor biology guides therapeutic decisions. From the discovery of the estrogen receptor to current clinical molecular profiles to evolving single-cell analytics, the characterization and compartmentalization of breast cancer into divergent subtypes is clear. However, competing with this divergent model of breast cancer is the recognition of intratumoral heterogeneity, which acknowledges the possibility that multiple different subtypes exist within a single tumor. Intratumoral heterogeneity is driven by both intrinsic effects of the tumor cells themselves as well as extrinsic effects from the surrounding microenvironment. There is emerging evidence that these intratumoral molecular subtypes are not static; rather, plasticity between divergent subtypes is possible. Interconversion between seemingly different subtypes within a tumor drives tumor progression, metastases, and treatment resistance. Therapeutic strategies must, therefore, contend with changing phenotypes in an individual patient's tumor. Identifying targetable drivers of molecular heterogeneity may improve treatment durability and disease progression.

Pathologic Features Associated With Molecular Subtypes of Well-Differentiated Thyroid Cancer.

OBJECTIVE: To determine the association between pathologic features and molecular classes (BRAF-like, RAS-like, and non-BRAF-like non-RAS-like [NBNR]). METHODS: Retrospective review of a merged database containing 676 patients, 84% (571/676) were assigned to a molecular class from publicly accessible sequenced data of thyroid neoplasms. RESULTS: The merged cohort included 571 neoplasms: 353 (62%) BRAF-like, 172 (30%) RAS-like, and 46 (8.1%) NBNR. Lymph node metastasis (any N1 disease) was present in 166/337 (49%) of BRAF-like, 23/164 (14%) of RAS-like, and 0/46 (0%) of NBNR and are significantly different (P < .001). Gross extra-thyroidal extension was observed in 27 patients, including 24/331 (7%) of BRAF-like, 2/160 (1%) of RAS-like, and 1/46 (2%) of NBNR (P = .01). N1B lymph node metastases or T4 disease was present in 74/333 (22%) of BRAF-like, 10/160 (6%) of RAS-like, and 1/46 (2%) of NBNR (P < .0001). Distant metastasis was present in 4/151 (2.6%) of BRAF-like, 2/50 (4%) of RAS-like and 0/46 for NBNR (P = .627). Angioinvasion was present in 0/81 (0%) of BRAF-like, 3/53 (6%) of RAS-like, and 3/46 (7%) of NBNR (P = .08); and multifocality was present in 27/81 (33%) of BRAF-like, 9/53 (17%) of RAS-like, and 1/46 (2%) for NBNR (P = .0001). CONCLUSION: Pathological features of metastasis, gross extra-thyroidal extension, and multifocality were more prevalent in BRAF-like samples compared to RAS-like and NBNR. A trend towards increased frequency of angioinvasion in RAS-like and NBNR cancers compared to BRAF-like samples was observed. Further studies are needed to evaluate if preoperative knowledge of molecular mutations in thyroid tumors aids in decision-making regarding extent of surgery.

Circulating BRAFV600E Levels Correlate with Treatment in Patients with Thyroid Carcinoma.

BACKGROUND: BRAFV600E is the most common mutation in papillary thyroid carcinoma (PTC) and can be associated with aggressive disease. Previously, a highly sensitive blood RNA-based BRAFV600E assay was reported. The objective of this study was to assess the correlation of BRAFV600E circulating tumor RNA levels with surgical and medical treatment. METHODS: Circulating BRAFV600E levels were assessed in (i) a murine model of undifferentiated (anaplastic) thyroid carcinoma with known BRAFV600E mutation undergoing BRAFV600E-inhibitor (BRAFi) treatment, and (ii) in 111 patients enrolled prior to thyroidectomy (n = 86) or treatment of advanced recurrent or metastatic PTC (n = 25). Blood samples were drawn for BRAFV600E analysis before and after treatment. Testing characteristics were assessed and positivity criteria optimized. Changes in blood BRAFV600E values were assessed and compared to clinical characteristics and response to therapy. RESULTS: In a murine model of anaplastic thyroid carcinoma with BRAFV600E mutation, blood BRAFV600E RNA correlated with tumor volume in animals treated with BRAFi. In tissue BRAFV600E-positive (n = 36) patients undergoing initial surgery for PTC, blood BRAFV600E levels declined postoperatively (median 370.0-178.5 fg/ng; p = 0.002). In four patients with metastatic or poorly differentiated thyroid carcinoma receiving targeted therapies, blood BRAFV600E declined following therapy and corresponded with radiographic evidence of partial response or stable disease. CONCLUSIONS: This study shows the correlation of blood BRAFV600E levels in response to treatment in both an established animal model of thyroid cancer and in patients with BRAFV600E-positive tumors with all stages of disease. This assay represents an alternative biomarker in patients with positive thyroglobulin antibodies, and tumors, which do not express thyroglobulin.

Detection of Circulating BRAF(V600E) in Patients with Papillary Thyroid Carcinoma.

BRAF(V600E) is a common mutation in papillary thyroid carcinoma (PTC) correlated with aggressive features. Our objective was to assess the feasibility and accuracy of a novel RNA-based blood assay to identify individuals with a high-risk tumor mutation in patients with PTC. Patients with benign or malignant thyroid disorders were included between September 2013 and July 2014 before either thyroidectomy (n = 62) or treatment of recurrent or metastatic PTC (n = 8). RNA was isolated from peripheral blood lymphocytes and reverse transcribed and followed by two rounds of nested PCR amplification with a restriction digest specific for wild-type BRAF. BRAF(V600E) levels were quantified with standardization curves. Circulating BRAF(V600E) levels were compared with BRAF mutation status from surgical pathologic DNA-based tissue assays. Testing characteristics and receiving-operator curve using tissue results as the gold standard were assessed. Matched blood and tissue assays for BRAF(V600E) were performed on 70 patients with PTC (stages I to IV, n = 48) or other (n = 22) thyroid tumors. Sixty-three percent of PTC patients tested positive for BRAF(V600E) with conventional tissue assays on surgical specimens. The correlation between the RNA-based blood assay and tissue BRAF status was 0.71. PTC patients harbor detectable BRAF(V600E) circulating tumor cells. This blood assay is feasible and has potential as a biomarker for prognosis, surveillance, clinical decision making, and assessment of treatment response to BRAF-targeted therapies.

Late onset venous thoracic outlet syndrome following clavicle non-union fracture: A case report.

A 59-year-old woman was admitted three times over a six-month period with recurrent upper extremity deep venous thrombosis (UEDVT). It was determined that this patient was suffering from an unusual presentation of Paget-Schröetter syndrome secondary to a 20-year-old non-union of a midshaft clavicle fracture. Following thrombolysis the patient underwent resection and plate fixation of the clavicle fracture non-union. Despite the anatomic proximity of the subclavian vessels to the clavicle, vascular complications from fracture are rare. Treatment of midshaft clavicle fractures is often non-operative. Non-union rates are generally less than 10%, and easily treated secondarily without complication. Clavicular pseudo-arthroses from trauma have been implicated in the development of the thoracic outlet syndromes, however, onset 20 years after fracture has never before been reported.

Noncanonical TGFß signaling contributes to aortic aneurysm progression in Marfan syndrome mice.

Transforming growth factor-ß (TGFß) signaling drives aneurysm progression in multiple disorders, including Marfan syndrome (MFS), and therapies that inhibit this signaling cascade are in clinical trials. TGFß can stimulate multiple intracellular signaling pathways, but it is unclear which of these pathways drives aortic disease and, when inhibited, which result in disease amelioration. Here we show that extracellular signal-regulated kinase (ERK) 1 and 2 and Smad2 are activated in a mouse model of MFS, and both are inhibited by therapies directed against TGFß. Whereas selective inhibition of ERK1/2 activation ameliorated aortic growth, Smad4 deficiency exacerbated aortic disease and caused premature death in MFS mice. Smad4-deficient MFS mice uniquely showed activation of Jun N-terminal kinase-1 (JNK1), and a JNK antagonist ameliorated aortic growth in MFS mice that lacked or retained full Smad4 expression. Thus, noncanonical (Smad-independent) TGFß signaling is a prominent driver of aortic disease in MFS mice, and inhibition of the ERK1/2 or JNK1 pathways is a potential therapeutic strategy for the disease.

Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism.

Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor-ß (TGFß) signaling in the aorta, but losartan uniquely inhibited TGFß-mediated activation of extracellular signal-regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.