Correction to: Heregulin ?1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells

© 2018 The Author(s). After the publication of this work [1], an error was noticed in Fig. 2b and Fig. 4b as well as Fig. 4b. and Fig. 5d. Images of the ERK1/2 blots were accidentally duplicated. In Fig. 5a. and Fig. 5c., the last lane for p-ERK1/2 was mistakenly cropped out of the final image. The original blot for Fig. 4b., "total EGFR" (or lane 2) is shown below to avoid any misunderstanding of the data. We apologize for this error, which did not affect any of the interpretations or conclusions of the article

Heregulin β1 drives gefitinib-resistant growth and invasion in tamoxifen-resistant MCF-7 breast cancer cells

Introduction Resistance to anti-epidermal growth factor receptor (anti-EGFR) therapies is an emerging clinical problem. The efficacy of anti-EGFR therapies can be influenced by the presence of heregulins (HRGs), which can bind erbB3/4 receptors and can activate alternative signalling pathways. In the present study we have examined whether HRG signalling can circumvent EGFR blockade in an EGFR-positive tamoxifen-resistant MCF-7 (Tam-R) breast cancer cell line. Methods Tam-R cells, incubated with the selective EGFR tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839), were exposed to HRGβ1 and the effects on erbB receptor dimerization profiles and on activation of associated downstream signalling components were assessed by immunoprecipitation, western blotting and immunocytochemistry. The effects of HRGβ1 on gefitinib-treated Tam-R cell growth and invasion were also examined, and HRGβ1 expression levels were assessed in breast cancer tissue by immunohistochemistry to address the potential clinical relevance of such a resistance mechanism. Results In Tam-R cells, HRGβ1 promoted erbB3/erbB2 and erbB3/EGFR heterodimerization, promoted ERK1/2 and AKT pathway activation and increased cell proliferation and invasion. Gefitinib prevented HRGβ1-driven erbB3/EGFR heterodimerization, ERK1/2 activation and Tam-R cell proliferation, but HRGβ1-driven erbB3/erbB2 heterodimerization, AKT activation and Tam-R cell invasion were maintained. A combination of gefitinib and the phosphatidylinositol 3-kinase inhibitor LY294002 effectively blocked HRGβ1-mediated intracellular signalling activity, growth and invasion in Tam-R cells. Similarly, targeting erbB2 with trastuzumab in combination with gefitinib in Tam-R cells reduced HRGβ1-induced erbB2 and ERK1/2 activity; however, HRGβ1-driven AKT activity and cell growth were maintained while cell invasion was significantly enhanced with this combination. In clinical tissue all samples demonstrated cytoplasmic tumour epithelial HRGβ1 protein staining, with expression correlating with EGFR positivity and activation of both AKT and ERK1/2. Conclusion HRGβ1 can overcome the inhibitory effects of gefitinib on cell growth and invasion in Tam-R cells through promotion of erbB3/erbB2 heterodimerization and activation of the phosphatidylinositol 3-kinase/AKT signalling pathway. This may have implications for the effectiveness of anti-EGFR therapies in breast cancer as HRGβ1 is enriched in many EGFR-positive breast tumours

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats

In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Development’s (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security

Natural orifice transesophageal thoracoscopic surgery: A review of the current state

Since the concept of Natural Orifice Translumenal Endoscopic Surgery (NOTES) was introduced, it has continued to gain significantly in popularity and enthusiasm for its potential clinical applications. The ability to perform conventional laparoscopic and thoracoscopic procedures without the creation of scars and perhaps faster and less painful recovery has prompted a worldwide devotion to further this field. While intra-abdominal NOTES has rapidly transitioned from animal models to human trials, applying the NOTES concept to perform thoracic procedures has been slower to gain momentum. The goal of this review is to summarize the current state of transesophageal NOTES thoracoscopy by looking at its potential for diagnostic and therapeutic interventions as well as the challenges in transitioning to human trials

Natural orifice transesophageal mediastinoscopy and thoracoscopy

Background: Thoracoscopy and mediastinoscopy are common procedures with painful incisions and prominent scars. A natural orifice transesophageal endoscopic surgical (NOTES) approach could reduce pain, eliminate intercostal neuralgia, provide access to the posterior mediastinal compartment, and improve cosmesis. In addition NOTES esophageal access routes also have the potential to replace conventional thoracoscopic approaches for medial or hilar lesions. Methods: Five healthy Yorkshire swine underwent nonsurvival natural orifice transesophageal mediastinoscopy and thoracoscopy under general anesthesia. An 8- to 9.8-mm video endoscope was introduced into the esophagus, and a 10-cm submucosal tunnel was created with blunt dissection. The endoscope then was passed through the muscular layers of the esophagus into the mediastinal space. The mediastinal compartment, pleura, lung, mediastinal lymph nodes, thoracic duct, vagus nerves, and exterior surface of the esophagus were identified. Mediastinal lymph node resection was easily accomplished. For thoracoscopy, a small incision was created through the pleura, and the endoscope was introduced into the thoracic cavity. The lung, chest wall, pleura, pericardium, and diaphragmatic surface were identified. Pleural biopsies were obtained with endoscopic forceps. The endoscope was withdrawn and the procedure terminated. Results: Mediastinal and thoracic structures could be identified without difficulty via a transesophageal approach. Lymph node resection was easily accomplished. Pleural biopsy under direct visualization was feasible. Selective mainstem bronchus intubation and collapse of the ipsilateral lung facilitated thoracoscopy. In one animal, an inadvertent 4-mm lung incision resulted in a pneumothorax. This was decompressed with a small venting intercostal incision, and the remainder of the procedure was completed without difficulty. Conclusions: Transesophageal endoscopic mediastinoscopy, lymph node resection, thoracoscopy, and pleural biopsy are feasible and provide excellent visualization of mediastinal and intrathoracic structures. Survival studies will be needed to confirm the safety of this approach

Natural orifice transesophageal mediastinoscopy and thoracoscopy: a survival series in swine

Introduction: Transesophageal endoscopic mediastinoscopy (MX) and thoracoscopy (TX) could reduce pain, eliminate intercostal neuralgia, provide better access to the posterior mediastinal compartment and pulmonary hilum, and improve cosmesis. The purpose of this study was to demonstrate the feasibility of transesophageal natural orifice translumenal endoscopic surgery (NOTES) and to determine the complications that might be seen in surviving animals. Methods: Using cap endoscopic mucosal resection and blunt dissection, a 15–20 cm submucosal tunnel was created in the esophagus and an endoscope passed through the tunnel into the mediastinum. One swine underwent MX; three swine underwent both MX and TX. The mediastinal compartment, hilar lymph nodes, pleura, lung, and esophagus were identified. Esophageal closure was obtained via submucosal tunnel flap-valve alone (two swine) or reinforcement with mucosal clips (two swine). The esophagus, mediastinum, and thorax were examined at necropsy. The esophagus was excised and sent for pathological examination. Results: NOTES MX and TX provided excellent visualization of mediastinal and thoracic structures. Pleural biopsy was easily accomplished. All animals survived the procedure, ate well, and showed no ill effects. Swine were sacrificed at either 8 or 12 days postoperatively. At necropsy, mild atelectasis was noted in each animal. One animal (mucosal clip closure) developed a fluid collection in the submucosal tunnel. There was no evidence of mediastinitis or thoracic contamination in any animals. Conclusions: Transesophageal endoscopic mediastinoscopy and thoracoscopy provide excellent visualization of mediastinal and intrathoracic structures. Pleural biopsy can be easily obtained under direct visualization. Structures that are difficult to visualize via traditional cervical mediastinoscopy and thoracoscopy are seen well with this approach. The submucosal tunnel creates a flap-valve that, alone, may be sufficient for preventing esophageal leak. These procedures can be performed safely in swine with short-term survival. Further study with a larger sample size and longer survival is warranted