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摘要： Objectives: Clear Cell Ovarian Carcinoma (CCOC) is known for its chemoresistance, high rates of relapse, and poor overall survival. Despite this, upfront treatment has remained relatively unchanged for decades. The objective of this study was to compare demographic and pathologic characteristics of patients with rapidly progressive versus chemo-sensitive advanced stage (III or IV) CCOC in order to better identify a cohort of patients who may benefit from innovative upfront treatment strategies. Methods: After IRB approval, patients diagnosed with CCOC between 2008 and 2020 at our University were identified and reviewed. Demographic information including age, parity, and menopausal status at time of diagnosis was collected in addition to tumor data such as percent clear cell and the presence or absence of coexisting endometriosis. Those diagnosed with stage I or II disease and those who have not yet completed adjuvant therapy were excluded. Progression-free survival (time from chemotherapy completion to progression or death) was estimated with a Kaplan-Meier curve. Patients were divided into one of two cohorts: chemo-sensitive (lack of progression or death at one year from chemotherapy completion) or rapidly progressive (evidence of progression or death within one year) and cohorts were compared using Wilcoxon rank-sum tests and Fisher's exact tests. Results: Thirty-four patients met inclusion criteria. All subjects underwent surgical staging or debulking and adjuvant platinum/taxane chemotherapy. Median progression-free survival was 6.1 months (95% confidence interval: 3.3-24.3 months). Thirteen patients (43.3%) were identified as chemo-sensitive, and seventeen (56.7%) as rapid progressors. Four patients did not have enough follow-up to be classified. All rapid progressors recurred or progressed within seven months of primary chemotherapy completion. The cohort of patients with rapidly progressive disease were younger (median age 53 vs 64, p=0.048) and more likely t

关键词： Crystal structure   Citrate synthase   Hymenobacter sp   PAMC 26554   Domain movement   X-ray crystallography   NADH BINDING-SITE  

摘要： Citrate synthase (CS) catalyzes the formation of citrate and coenzyme A from acetyl-CoA and oxaloacetate. CS exists in two forms: type I and type II. We determined the citrate-bound crystal structure of type II CS from the Hymenobacter sp. PAMC 26554 bacterium (HyCS; isolated from Antarctic lichen). Citrate molecules bound to a cleft between the large and small domains of HyCS. Structural comparison of HyCS with other type II CSs revealed that type II CSs have a highly conserved flexible hinge region (residues G264-P265 in HyCS), enabling correct positioning of active site residues. Notably, the catalytic His266 residue of HyCS interacted with Trp262 in the inactive (unliganded open) state of other type II CSs, whereas the His266 residue moved to the active site via a small-domain swing motion, interacting with the bound citrate in the closed conformation of HyCS. However, type I CSs lack this tryptophan residue and face-to-edge interactions. Thus, type II CSs might have a unique domain-motion control mechanism enabling a tight allosteric regulation. An activity assay using a W262A mutant showed a Hill coefficient of 2.4; thus, the interaction between Trp262 and His266 was closely related to the positive cooperative ligand binding of type II CS. (c) 2021 Published by Elsevier B.V.