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Xin Zhang - One of the best experts on this subject based on the ideXlab platform.
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Lacrimal Gland budding requires pi3k dependent suppression of egf signaling
Science Advances, 2021Co-Authors: Qian Wang, Chenqi Tao, Abdul Hannan, Sungtae Yoon, Xuanyu Min, John Peregrin, Jean J Zhao, Xin ZhangAbstract:The patterning of epithelial buds is determined by the underlying signaling network. Here, we study the cross-talk between phosphoinositide 3-kinase (PI3K) and Ras signaling during Lacrimal Gland budding morphogenesis. Our results show that PI3K is activated by both the p85-mediated insulin-like growth factor (IGF) and Ras-mediated fibroblast growth factor (FGF) signaling. On the other hand, PI3K also promotes extracellular signal-regulated kinase (ERK) signaling via a direct interaction with Ras. Both PI3K and ERK are upstream regulators of mammalian target of rapamycin (mTOR), and, together, they prevent expansion of epidermal growth factor (EGF) receptor expression from the Lacrimal Gland stalk to the bud region. We further show that this suppression of EGF signaling is necessary for induction of Lacrimal Gland buds. These results reveal that the interplay between PI3K, mitogen-activated protein kinase, and mTOR mediates the cross-talk among FGF, IGF, and EGF signaling in support of Lacrimal Gland development.
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Lacrimal Gland development from signaling interactions to regenerative medicine
PMC, 2017Co-Authors: Ankur Garg, Xin ZhangAbstract:The Lacrimal Gland plays a pivotal role in keeping the ocular surface lubricated, and protecting it from environmental exposure and insult. Dysfunction of the Lacrimal Gland results in deficiency of the aqueous component of the tear film, which can cause dryness of the ocular surface, also known as the aqueous-deficient dry eye disease. Left untreated, this disease can lead to significant morbidity, including frequent eye infections, corneal ulcerations, and vision loss. Current therapies do not treat the underlying deficiency of the Lacrimal Gland, but merely provide symptomatic relief. To develop more sustainable and physiological therapies, such as in vivo Lacrimal Gland regeneration or bioengineered Lacrimal Gland implants, a thorough understanding of Lacrimal Gland development at the molecular level is of paramount importance. Based on the structural and functional similarities between rodent and human eye development, extensive studies have been undertaken to investigate the signaling and transcriptional mechanisms of Lacrimal Gland development using mouse as a model system. In this review, we describe the current understanding of the extrinsic signaling interactions and the intrinsic transcriptional network governing Lacrimal Gland morphogenesis, as well as recent advances in the field of regenerative medicine aimed at treating dry eye disease. Developmental Dynamics 246:970-980, 2017. © 2017 Wiley Periodicals, Inc.
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alx4 relays sequential fgf signaling to induce Lacrimal Gland morphogenesis
PMC, 2017Co-Authors: Ankur Garg, Mukesh Bansal, Noriko Gotoh, Gensheng Feng, Jian Zhong, Fen Wang, Ariana Kariminejad, Steven E Brooks, Xin ZhangAbstract:The sequential use of signaling pathways is essential for the guidance of pluripotent progenitors into diverse cell fates. Here, we show that Shp2 exclusively mediates FGF but not PDGF signaling in the neural crest to control Lacrimal Gland development. In addition to preventing p53-independent apoptosis and promoting the migration of Sox10-expressing neural crests, Shp2 is also required for expression of the homeodomain transcription factor Alx4, which directly controls Fgf10 expression in the periocular mesenchyme that is necessary for Lacrimal Gland induction. We show that Alx4 binds an Fgf10 intronic element conserved in terrestrial but not aquatic animals, underlying the evolutionary emergence of the Lacrimal Gland system in response to an airy environment. Inactivation of ALX4/Alx4 causes Lacrimal Gland aplasia in both human and mouse. These results reveal a key role of Alx4 in mediating FGF-Shp2-FGF signaling in the neural crest for Lacrimal Gland development.
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glycosaminoglycan dependent restriction of fgf diffusion is necessary for Lacrimal Gland development
Development, 2012Co-Authors: Yi Pan, Christian Carbe, Andrea Powers, Kay Grobe, Xin ZhangAbstract:Glycosaminoglycans (GAGs) play a central role in embryonic development by regulating the movement and signaling of morphogens. We have previously demonstrated that GAGs are the co-receptors for Fgf10 signaling in the Lacrimal Gland epithelium, but their function in the Fgf10-producing periocular mesenchyme is still poorly understood. In this study, we have generated a mesenchymal ablation of UDP-glucose dehydrogenase (Ugdh), an essential biosynthetic enzyme for GAGs. Although Fgf10 RNA is expressed normally in the periocular mesenchyme, Ugdh mutation leads to excessive dispersion of Fgf10 protein, which fails to elicit an FGF signaling response or budding morphogenesis in the presumptive Lacrimal Gland epithelium. This is supported by genetic rescue experiments in which the Ugdh Lacrimal Gland defect is ameliorated by constitutive Ras activation in the epithelium but not in the mesenchyme. We further show that Lacrimal Gland development requires the mesenchymal expression of the heparan sulfate N-sulfation genes Ndst1 and Ndst2 but not the 6-O and 2-O-sulfation genes Hs6st1, Hs6st2 and Hs2st. Taken together, these results demonstrate that mesenchymal GAG controls Lacrimal Gland induction by restricting the diffusion of Fgf10.
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bud specific n sulfation of heparan sulfate regulates shp2 dependent fgf signaling during Lacrimal Gland induction
Development, 2007Co-Authors: Yi Pan, Gensheng Feng, Christian Carbe, Andrea Powers, Kay Grobe, Eric E Zhang, Jeffrey D Esko, Xin ZhangAbstract:Preferential outgrowth of the bud cells forms the basis of branching morphogenesis. Here, we show that Lacrimal Gland development requires specific modification of heparan sulfates by Ndst genes at the tip of the Lacrimal Gland bud. Systemic and conditional knockout experiments demonstrate the tissue specific requirement of Ndst1 and Ndst2 in the Lacrimal Gland epithelial, but not mesenchymal, cells, and the functional importance of Ndst1 in Fgf10-Fgfr2b, but not of Fgf1-Fgfr2b, complex formation. Consistent with this, Fgf10-induced ectopic Lacrimal Gland budding in explant cultures is dependent upon Ndst gene dose, and epithelial deletion of Fgfr2 abolishes Lacrimal Gland budding, its specific modification of heparan sulfate and its phosphorylation of Shp2 (Ptpn11 - Mouse Genome Informatics). Finally, we show that genetic ablation of Ndst1, Fgfr2 or Shp2 disrupts ERK signaling in Lacrimal Gland budding. Given the evolutionarily conserved roles of these genes, the localized activation of the Ndst-Fgfr-Shp2 genetic cascade is probably a general regulatory mechanism of FGF signaling in branching morphogenesis.
Bita Esmaeli - One of the best experts on this subject based on the ideXlab platform.
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an update on tumors of the Lacrimal Gland
Asia-Pacific journal of ophthalmology, 2017Co-Authors: Simon Andreasen, Bita Esmaeli, Sarah Linéa Von Holstein, Peter Kristian Rasmussen, Lauge Hjorth Mikkelsen, Steffen HeegaardAbstract:Lacrimal Gland tumors are rare and constitute a wide spectrum of different entities ranging from benign epithelial and lymphoid lesions to high-grade carcinomas, lymphomas, and sarcomas with large differences in prognosis and clinical management. The symptoms and findings of a Lacrimal Gland lesion are a growing mass at the site of the Lacrimal Gland, including displacement of the eyeball, decreased motility, diplopia, and ptosis. Pain is the cardinal symptom of an adenoid cystic carcinoma. Radiological findings characteristically include an oval, well-demarcated mass for benign lesions whereas malignant lesions typically display calcifications, destruction of bone, and invasion of adjacent structures. The diagnosis ultimately relies on histology, as does the choice of treatment and the prognosis. In recent years, the understanding of the biology of numerous types of Lacrimal Gland neoplasia has improved and the choice of treatment has changed accordingly and holds further promise for future targeted therapies. Treatment of benign epithelial lesions is surgical excision whereas carcinomas often require adjuvant radiotherapy and/or chemotherapy. In contrast, the cornerstone in management of lymphoid lesions is chemotherapy, often including a monoclonal antibody. This article presents an update on the clinical, radiological, histological, and molecular features, along with treatment strategies for tumors of the Lacrimal Gland.
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current treatment of Lacrimal Gland carcinoma
Current Opinion in Ophthalmology, 2016Co-Authors: Kyung In Woo, Yoon Duck Kim, Bita EsmaeliAbstract:Purpose of reviewThe traditional treatment for Lacrimal Gland carcinoma is orbital exenteration followed by radiation therapy. However, orbital exenteration does not prevent distant relapse and death, and some patients experience local–regional recurrence after exenteration. More recently, eye-spari
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eye sparing multidisciplinary approach for the management of Lacrimal Gland carcinoma
Head and Neck-journal for The Sciences and Specialties of The Head and Neck, 2016Co-Authors: Bita Esmaeli, Merrill S. Kies, Diana Bell, Vivian T Yin, Ehab Y Hanna, William N William, Steven J FrankAbstract:Background We analyzed local control and early ocular toxicity after eye-sparing management of Lacrimal Gland carcinoma. Methods For consecutive patients with Lacrimal Gland carcinoma treated during 2007 to 2014, we reviewed tumor characteristics, treatment details, ocular toxic effects, and recurrence. Results Twenty patients, median age 55 years, were treated for Lacrimal Gland carcinoma during the study period; 11 had globe-sparing surgery. Seven patients had adenoid cystic carcinoma, 2 had carcinoma ex pleomorphic adenoma, and 1 each had high-grade and low-grade adenocarcinoma. Ten patients underwent postoperative radiotherapy, median 60 Gy (range, 52–64 Gy), 6 with concurrent chemotherapy. At a median of 30 months after radiation, all patients had dry eye syndrome, and 1 patient had severe corneal and conjunctival damage leading to enucleation. All 11 patients were disease free at last contact, median follow-up after surgery of 33 months. Conclusion An eye-sparing approach with surgery followed by adjuvant radiotherapy or chemoradiotherapy is feasible for selected patients with Lacrimal Gland carcinoma and is associated with a reasonable locoregional control and ocular toxicity profile. © 2016 Wiley Periodicals, Inc. Head Neck, 2016
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mutational landscape of Lacrimal Gland carcinomas and implications for treatment
Head and Neck-journal for The Sciences and Specialties of The Head and Neck, 2016Co-Authors: Diana Bell, Matthew C Sniegowski, Khalida Wani, Victor G Prieto, Bita EsmaeliAbstract:Background Lacrimal Gland carcinomas are rare. Identification of molecular abnormalities underlying Lacrimal Gland carcinogenesis is critical to the development of new targeted therapies for Lacrimal Gland carcinomas. The purpose of our study was to look for mutations that can be targeted as new treatments for Lacrimal Gland carcinomas. Methods Genomic DNA from patients with Lacrimal Gland epithelial neoplasms was analyzed. The Sequenom matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass ARRAY platform was used to profile 168 common oncogenic point mutations in 40 genes. Mutation frequency was assessed overall and by histologic diagnosis. These genetic mutations were then correlated with clinical outcomes in the patients. Results The study included 14 men and 10 women with a median age of 45 years (range, 17–75 years). The histologic diagnoses were as follows: adenoid cystic carcinoma (n = 16), low-grade carcinoma ex pleomorphic adenoma (n = 2), high-grade carcinoma ex pleomorphic adenoma (n = 2), squamous carcinoma (n = 1), and pleomorphic adenoma (n = 3). Analysis revealed 18 oncogenic mutations in 13 patients: KRAS mutations in 10 patients (46%), NRAS mutations in 2 patients (8%), MET mutations in 3 patients (13%), PIK3CA mutation in 1 patient (4%), and BRAF mutation in no patients. About half of the patients with adenoid cystic carcinoma had oncogenic mutations (7 of 16; 44%). Of the 16 patients with adenoid cystic carcinoma, 5 had KRAS mutations, 1 had MET mutations, and 1 had an NRAS mutation. Conclusion KRAS, NRAS, and MET mutations are frequent in epithelial neoplasms of the Lacrimal Gland, with the highest rate of mutations found in adenoid cystic carcinoma. Therapies targeting these genes may be effective treatments for Lacrimal Gland carcinomas. © 2015 Wiley Periodicals, Head Neck, 2015
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management of Lacrimal Gland carcinoma lessons from the literature in the past 40 years
Ophthalmic Plastic and Reconstructive Surgery, 2016Co-Authors: Kyung In Woo, Arim Yeom, Bita EsmaeliAbstract:Purpose To review the published literature on management strategies for Lacrimal Gland carcinomas. Methods Review of relevant articles in PubMed published in English from the year of 1970 through September 2014. Results A review of literature suggests that treatment strategies for adenoid cystic carcinoma of Lacrimal Gland are varied, but local control does not necessarily prevent future delayed distant relapse. Tumor size and histologic features of Lacrimal Gland carcinoma seem to be important prognostic features. With improved imaging modalities providing better tumor diagnosis and staging, and availability of more focused radiation delivery techniques, multimodality globe sparing management of Lacrimal Gland carcinomas may be possible in selected cases. The availability of targeted drugs based on the molecular signature of an individual Lacrimal Gland carcinoma may offer possible targeted treatments for patients with nonresectable or metastatic disease. Conclusion Given the rarity of Lacrimal Gland carcinoma, multi-institutional studies and consistent reporting of size and histologic type of tumors in the literature may be prudent. Particularly, multimodality globe-sparing treatment strategies should be studied further.
Steffen Heegaard - One of the best experts on this subject based on the ideXlab platform.
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genomic and immunohistochemical characterisation of a Lacrimal Gland oncocytoma and review of literature
Oncology Letters, 2017Co-Authors: Lauge Hjorth Mikkelsen, Simon Andreasen, Goran Stenman, Linea Melchior, Marta Persson, Jeppe Dyrberg Andersen, Vania Pereira, Peter B Toft, Niels Morling, Steffen HeegaardAbstract:The aim of the present study was to report the genetic and immunohistochemical profile of a rare case of Lacrimal Gland oncocytoma. A 20-year-old male underwent magnetic resonance imaging (MRI) due to viral encephalitis. Notably, the MRI revealed a multicystic tumor in the left Lacrimal Gland. A lateral orbitotomy was performed and the tumor was completely excised. Four months following surgery, the patient was free of symptoms. Histopathologically, the tumor was composed of large, eosinophilic and polyhedral cells with small round nuclei. The tumor cells stained strongly for antimitochondrial antibody MU213-UC, cytokeratin (CK) 5/6, CK 7, CK 17, CK 8/18 and CK 19. The final diagnosis was an oncocytoma of the Lacrimal Gland without any signs of malignancy. Array-based comparative genomic hybridisation demonstrated a gain of one copy of chromosome 8 and loss of one copy of chromosome 22 as the sole genomic imbalances. These chromosomal alterations have not previously been identified in oncocytoma and may be specific to Lacrimal Gland oncocytoma. Sequencing of the mitochondrial genome demonstrated multiple alterations of the NADH-ubiquinone oxidoreductase chain 5 (ND5) gene involved in mitochondrial oxidative phosphorylation. This may support the notion of a common genetic background of oncocytic lesions in the Lacrimal Gland and other anatomical sites.
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an update on tumors of the Lacrimal Gland
Asia-Pacific journal of ophthalmology, 2017Co-Authors: Simon Andreasen, Bita Esmaeli, Sarah Linéa Von Holstein, Peter Kristian Rasmussen, Lauge Hjorth Mikkelsen, Steffen HeegaardAbstract:Lacrimal Gland tumors are rare and constitute a wide spectrum of different entities ranging from benign epithelial and lymphoid lesions to high-grade carcinomas, lymphomas, and sarcomas with large differences in prognosis and clinical management. The symptoms and findings of a Lacrimal Gland lesion are a growing mass at the site of the Lacrimal Gland, including displacement of the eyeball, decreased motility, diplopia, and ptosis. Pain is the cardinal symptom of an adenoid cystic carcinoma. Radiological findings characteristically include an oval, well-demarcated mass for benign lesions whereas malignant lesions typically display calcifications, destruction of bone, and invasion of adjacent structures. The diagnosis ultimately relies on histology, as does the choice of treatment and the prognosis. In recent years, the understanding of the biology of numerous types of Lacrimal Gland neoplasia has improved and the choice of treatment has changed accordingly and holds further promise for future targeted therapies. Treatment of benign epithelial lesions is surgical excision whereas carcinomas often require adjuvant radiotherapy and/or chemotherapy. In contrast, the cornerstone in management of lymphoid lesions is chemotherapy, often including a monoclonal antibody. This article presents an update on the clinical, radiological, histological, and molecular features, along with treatment strategies for tumors of the Lacrimal Gland.
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Plexiform Neurofibroma Involving the Lacrimal Gland
Karger Publishers, 2017Co-Authors: Mikael Hofsli, Nico Gampenrieder, Steffen HeegaardAbstract:Background: To present a rare case of a 2-year-old girl with neurofibromatosis type 1 (NF1) who presented with ptosis of the right upper eyelid along with a tumor in the eyelid. Methods: A magnetic resonance imaging scan of the orbit revealed a solid tumor located extraconally at the site of the right Lacrimal Gland. A transcranial orbitotomy was performed. Results: Histopathological examination demonstrated expanded nerve branches/fascicles cut in various planes in between normal Lacrimal Gland acini. These findings were consistent with a plexiform neurofibroma presumably deriving from the Lacrimal nerve and/or a supraorbital nerve branch. Conclusion: This is the first case of a plexiform neurofibroma involving the Lacrimal Gland ever described and the tumor shows similarities with neurofibroma in other salivary Glands with a high recurrence rate. Plexiform neurofibromas are frequently seen in patients with NF1 and rarely undergo malignant transformation
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Tumors of the Lacrimal Gland.
Seminars in Diagnostic Pathology, 2015Co-Authors: Sarah Linéa Von Holstein, Peter Kristian Rasmussen, Steffen HeegaardAbstract:Tumors of the Lacrimal Gland comprise a wide spectrum, of which the most common demonstrate epithelial and lymphoid differentiation. The diagnosis of Lacrimal Gland tumors depends primarily on histological evaluation, as do the choice of treatment and prognosis. For some Lacrimal Gland neoplasms, such as adenoid cystic carcinoma, the outlook is grave. Optimal treatment for several Lacrimal Gland tumors is also a matter of controversy. However, recent progress has been made in the molecular and genetic understanding of tumorigenesis for such lesions. This article presents an overview of the histopathology of Lacrimal Gland tumors, together with their epidemiological features, clinical characteristics, and treatment strategies.
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Lacrimal Gland lesions in denmark between 1974 and 2007
Acta Ophthalmologica, 2013Co-Authors: Sarah Linéa Von Holstein, Jan Ulrik Prause, Marianne Hamilton Therkildsen, Goran Stenman, Volkert Siersma, Steffen HeegaardAbstract:. Purpose: To evaluate the incidence rate, distribution, patient characteristics and indications for surgical intervention of Lacrimal Gland lesions in Denmark between 1974 and 2007. Material and methods: All biopsied/surgically removed Lacrimal Gland lesions in Denmark during the period 1974–2007 were identified by searching two population-based registries. Specimens were collected and re-evaluated. The following data were collected: age, gender, indications for surgical intervention and local recurrence. Results: A total of 232 lesions from 210 patients with a histologically verified lesion of the Lacrimal Gland were included. The incidence rate of Lacrimal Gland lesions was 1.3/1 000 000/year. The overall annual age- and gender-adjusted incidence rate more than doubled during the study period, owing to an increase in non-malignant lesions. Approximately half of the lesions were neoplasms (119) and 55% (66) of these were malignant. Dacryops constituted 10% (24), inflammatory lesions 27% (62), normal tissue 12% (27), benign tumours 23% (53) and malignant tumours 29% (66). Patients with malignant neoplasms were significantly older than patients with benign neoplasms (63 versus 48 years, p < 0.001). The indication for surgical intervention was suspicion of a tumour in more than 90% of the neoplastic lesions and in 30% of the non-neoplastic lesions. Conclusion: Lacrimal Gland lesions that require surgical evaluation are rare in the Danish population and represent a wide spectrum of diagnoses, mostly benign. The overall incidence rate of biopsied Lacrimal Gland lesions is increasing.
Vinay K. Aakalu - One of the best experts on this subject based on the ideXlab platform.
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Human Lacrimal Gland Gene Expression
PloS one, 2017Co-Authors: Vinay K. Aakalu, Sowmya Parameswaran, Mark Maienschein-cline, Neil Bahroos, Dhara Shah, Marwan Ali, Subramanian KrishnakumarAbstract:BACKGROUND The study of human Lacrimal Gland biology and development is limited. Lacrimal Gland tissue is damaged or poorly functional in a number of disease states including dry eye disease. Development of cell based therapies for Lacrimal Gland diseases requires a better understanding of the gene expression and signaling pathways in Lacrimal Gland. Differential gene expression analysis between Lacrimal Gland and other embryologically similar tissues may be helpful in furthering our understanding of Lacrimal Gland development. METHODS We performed global gene expression analysis of human Lacrimal Gland tissue using Affymetrix ® gene expression arrays. Primary data from our laboratory was compared with datasets available in the NLM GEO database for other surface ectodermal tissues including salivary Gland, skin, conjunctiva and corneal epithelium. RESULTS The analysis revealed statistically significant difference in the gene expression of Lacrimal Gland tissue compared to other ectodermal tissues. The Lacrimal Gland specific, cell surface secretory protein encoding genes and critical signaling pathways which distinguish Lacrimal Gland from other ectodermal tissues are described. CONCLUSIONS Differential gene expression in human Lacrimal Gland compared with other ectodermal tissue types revealed interesting patterns which may serve as the basis for future studies in directed differentiation among other areas.
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RT-PCR analysis of human main Lacrimal Gland tissue.
2016Co-Authors: Dhara Shah, Marwan Ali, Zeeshan Pasha, Assraa Jassim Jaboori, Sarmad H. Jassim, Sandeep Jain, Vinay K. AakaluAbstract:RT-PCR of main Lacrimal Gland tissue shows expression of histatin-1, purported Lacrimal markers E-cad and lactoferrin.
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Epidemiological Trends in Malignant Lacrimal Gland Tumors
Otolaryngology-Head and Neck Surgery, 2014Co-Authors: Michael T. Andreoli, Vinay K. Aakalu, Pete SetabutrAbstract:ObjectiveTo describe epidemiological trends in Lacrimal Gland malignancies in the United States.Study DesignRetrospective database review.SettingMulticenter registry.Subjects and MethodsA total of 702 malignant tumors of the Lacrimal Gland from the Surveillance, Epidemiology, and End Results database were included in the study. Disease-specific and overall survival were the primary outcome measures. Kaplan-Meier survival curves were generated for multiple patient and tumor characteristics, including race, histology, TNM tumor stage, age at diagnosis, radiotherapy, gender, and tumor grade. Cox proportional hazards regression was performed to assess the impact of patient and tumor characteristics on survival.ResultsLymphoma (58.0%), adenoid cystic carcinoma (13.4%), adenocarcinoma (3.8%), and mucoepidermoid carcinoma (3.6%) accounted for most tumors. Lymphoma was associated with more favorable survival rates, while adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma were associated with w...
Matthew W Leewing - One of the best experts on this subject based on the ideXlab platform.
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rosai dorfman disease presenting as bilateral Lacrimal Gland enlargement
American Journal of Ophthalmology, 2001Co-Authors: Matthew W Leewing, Allan Oryschak, Gurcharan Attariwala, Michael AshenhurstAbstract:Abstract PURPOSE: To report a patient with bilateral Lacrimal Gland enlargement as the initial manifestation of Rosai–Dorfman disease. METHODS: Case report. RESULTS: A 14-year-old female presented with left Lacrimal Gland enlargement followed by right Lacrimal Gland enlargement 11 weeks later. Bilateral Lacrimal Gland biopsies were performed, and histopathologic examination revealed the diagnosis of Rosai–Dorfman disease. CONCLUSION: Patients with Rosai–Dorfman disease may present with bilateral Lacrimal Gland swelling in the absence of lymphadenopathy. Rosai–Dorfman disease should be considered in the differential diagnosis of bilateral Lacrimal Gland enlargement.
