Agola JO, Jim PA, Ward HH, BasuRay S, Wandinger‐Ness A. Rab GTPases as regulators of endocytosis, targets of disease and therapeutic opportunities.
Rab GTPases are well‐recognized targets in human ...disease, although are underexplored therapeutically. Elucidation of how mutant or dysregulated Rab GTPases and accessory proteins contribute to organ specific and systemic disease remains an area of intensive study and an essential foundation for effective drug targeting. Mutation of Rab GTPases or associated regulatory proteins causes numerous human genetic diseases. Cancer, neurodegeneration and diabetes represent examples of acquired human diseases resulting from the up‐ or downregulation or aberrant function of Rab GTPases. The broad range of physiologic processes and organ systems affected by altered Rab GTPase activity is based on pivotal roles in responding to cell signaling and metabolic demand through the coordinated regulation of membrane trafficking. The Rab‐regulated processes of cargo sorting, cytoskeletal translocation of vesicles and appropriate fusion with the target membranes control cell metabolism, viability, growth and differentiation. In this review, we focus on Rab GTPase roles in endocytosis to illustrate normal function and the consequences of dysregulation resulting in human disease. Selected examples are designed to illustrate how defects in Rab GTPase cascades alter endocytic trafficking that underlie neurologic, lipid storage, and metabolic bone disorders as well as cancer. Perspectives on potential therapeutic modulation of GTPase activity through small molecule interventions are provided.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Surgical Resection of Rare Esophageal Cancers Saddoughi, Sahar A., MD, PhD; Taswell, Jim, PA-C; Harmsen, William S., MS ...
The Annals of thoracic surgery,
01/2016, Volume:
101, Issue:
1
Journal Article
Peer reviewed
Open access
Background Although surgical resection of adenocarcinoma or squamous cell carcinoma of the esophagus is standard practice, the treatment strategy for other malignant rare esophageal cancers is still ...under debate. The aim of this study was to examine the treatment of rare malignant esophageal cancers and to evaluate the survival of these patients. Methods A retrospective review of all esophagectomies performed at Mayo Clinic from 1980 to 2014 (approximately 4,000 cases) identified 24 patients with histologic features other than adenocarcinoma or squamous cell carcinoma. Their medical records were reviewed for demographics, presenting symptoms, evaluation, surgical management, pathologic features, and short-term and long-term outcome. Results Pathologic identifications included small cell carcinoma, lymphoma, and undifferentiated carcinoma in 4 (16.7%) patients each and neuroendocrine, melanoma, leiomyosarcoma, sarcomatoid, sarcoma, and gastrointestinal stromal tumor in 2 (8.3%) patients each. The most common presenting symptoms included dysphasia in 91.7% patients (22/24), pain in 75.0% (18/24), and weight loss in 62.5% (15/24). Preoperative evaluation included barium swallow in 91.7% (22/24), computed tomography in 91.7% (22/24), positron emission tomography in 54.2% (13/24), esophagogastroduodenoscopy in 100% (24/24), and endoscopic ultrasonography in 29.2% (7/24) patients. The location of the tumor was at the gastroesophageal junction in 41.7% (10/24). There was no operative mortality, and 13 patients (54.16%) had at least one postoperative adverse event. The 1-year survival after esophagectomy was 69.7%, the 5-year survival was 42.7%, and the 10-year survival was 37.4%. Conclusions Esophageal cancer with pathologic features other than squamous cell carcinoma or adenocarcinoma is rare. Esophagectomy for rare types of malignant esophageal cancers should be considered part of the effective treatment paradigm.
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