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- 저자 : Zucker, Hava (검색결과 2 건)
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The NEAT Predictive Model for Survival in Patients with Advanced Cancer
Amanda Zucker,Chiaojung Jillian Tsai,John Loscalzo,Pedro Calves,Johnny Kao 대한암학회 2018 Cancer Research and Treatment Vol.50 No.4
Purpose We previously developed a model to more accurately predict life expectancy for stage IV cancer patients referred to radiation oncology. The goals of this study are to validate this model and to compare competing published models. Materials and Methods From May 2012 to March 2015, 280 consecutive patients with stage IV cancer were prospectively evaluated by a single radiation oncologist. Patients were separated into training, validation and combined sets. The NEAT model evaluated number of active tumors (“N”), Eastern Cooperative Oncology Group performance status (“E”), albumin (“A”) and primary tumor site (“T”). The Odette Cancer Center model validated performance status, bone only metastases and primary tumor site. The Harvard TEACHH model investigated primary tumor type, performance status, age, prior chemotherapy courses, liver metastases, and hospitalization within 3 months. Cox multivariable analyses and logistical regression were utilized to compare model performance. Results Number of active tumors, performance status, albumin, primary tumor site, prior hospitalization within the last 3 months, and liver metastases predicted overall survival on uinvariate and multivariable analysis (p < 0.05 for all). The NEAT model separated patients into four prognostic groups with median survivals of 24.9, 14.8, 4.0, and 1.2 months, respectively (p < 0.001). The NEAT model had a C-index of 0.76 with a Nagelkerke’s R2 of 0.54 suggesting good discrimination, calibration and total performance compared to competing prognostic models. Conclusion The NEAT model warrants further investigation as a clinically useful approach to predict survival in patients with stage IV cancer.
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Autophagy is a major regulator of beta cell insulin homeostasis
Riahi, Yael,Wikstrom, Jakob D.,Bachar-Wikstrom, Etty,Polin, Nava,Zucker, Hava,Lee, Myung-Shik,Quan, Wenying,Haataja, Leena,Liu, Ming,Arvan, Peter,Cerasi, Erol,Leibowitz, Gil Springer-Verlag 2016 Diabetologia Vol.59 No.7
<P>Aims/hypothesis We studied the role of protein degradation pathways in the regulation of insulin production and secretion and hypothesised that autophagy regulates proinsulin degradation, thereby modulating beta cell function. Methods Proinsulin localisation in autophagosomes was demonstrated by confocal and electron microscopy. Autophagy was inhibited by knockdown of autophagy-related (ATG) proteins and using the H+-ATPase inhibitor bafilomycin-A1. Proinsulin and insulin content and secretion were assessed in static incubations by ELISA and RIA. Results Confocal and electron microscopy showed proinsulin localised in autophagosomes and lysosomes. Beta-Atg7(-/-) mice had proinsulin-containing sequestosome 1 (p62 [also known as SQSTM1])(+) aggregates in beta cells, indicating proinsulin is regulated by autophagy in vivo. Short-term bafilomycin-A1 treatment and ATG5/7 knockdown increased steady-state proinsulin and hormone precursor chromogranin A content. ATG5/7 knockdown also increased glucose- and non-fuel-stimulated insulin secretion. Finally, mutated forms of proinsulin that are irreparably misfolded and trapped in the endoplasmic reticulum are more resistant to degradation by autophagy. Conclusions/interpretation In the beta cell, transport-competent secretory peptide precursors, including proinsulin, are regulated by autophagy, whereas efficient clearance of transport-incompetent mutated forms of proinsulin by alternative degradative pathways may be necessary to avoid beta cell proteotoxicity. Reduction of autophagic degradation of proinsulin increases its residency in the secretory pathway, followed by enhanced secretion in response to stimuli.</P>
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