Chronic partial unloading restores β-adrenergic responsiveness and reverses receptor downregulation in failing rat hearts

ObjectivesMechanical unloading with a left ventricular assist device promotes “reverse remodeling,” including restoration of β-adrenergic receptor signaling and function. We compared the effects of partial unloading and complete unloading on β-adrenergic responsiveness and gene expressions in failing rat hearts by use of heterotopic heart–lung or heart transplantation models.MethodsFour weeks after ligation of the left anterior descending artery in Lewis rats, rats with heart failure were divided into 3 groups: infarcted hearts and lungs transplanted into the recipient rats (heart failure–partial unloading, n = 8); infarcted hearts transplanted into the recipient rats (heart failure–complete unloading, n = 7); infarcted (heart failure, n = 8) hearts without transplantation. Normal rats (n = 7) were used as controls. Papillary muscle function and gene expressions were studied at 2 or 4 weeks after transplantation.ResultsIn 2-week models, baseline developed tension of papillary muscles significantly increased in heart failure–partial unloading and heart failure–complete unloading compared with heart failure (0.15 ± 0.07 and 0.12 ± 0.05 g/mm2 vs 0.02 ± 0.01 g/mm2, P < .05). However, in 4-week models, they decreased to 0.11 ± 0.03 and 0.10 ± 0.03 g/mm2. In 4-week but not in 2-week models, the increase from baseline in baseline developed tension produced by β-adrenergic stimulation (isoproterenol, 10−8 and 10−7 mol/L) was significantly increased in heart failure–partial unloading compared with heart failure–complete unloading and heart failure (P < .05). The mRNA expressions of brain natriuretic peptide and β1- and β2-adrenergic receptors were normalized in both 2- and 4-week models of heart failure–partial unloading.ConclusionsChronic partial unloading but not complete unloading improved β-adrenergic responsiveness and normalized brain natriuretic peptide and β1- and β2-adrenergic receptor mRNA expressions in the failing rat hearts

Analysis of cell cycle-related proteins in gastric intramucosal differentiated-type cancers based on mucin phenotypes: a novel hypothesis of early gastric carcinogenesis based on mucin phenotype

<p>Abstract</p> <p>Background</p> <p>Abnormalities of cell cycle regulators are common features in human cancers, and several of these factors are associated with the early development of gastric cancers. However, recent studies have shown that gastric cancer tumorigenesis was characterized by mucin expression. Thus, expression patterns of cell cycle-related proteins were investigated in the early phase of differentiated-type gastric cancers to ascertain any mechanistic relationships with mucin phenotypes.</p> <p>Methods</p> <p>Immunostaining for Cyclins D1, A, E, and p21, p27, p53 and β-catenin was used to examine impairments of the cell cycle in 190 gastric intramucosal differentiated-type cancers. Mucin phenotypes were determined by the expressions of MUC5AC, MUC6, MUC2 and CD10. A Ki-67 positive rate (PR) was also examined.</p> <p>Results</p> <p>Overexpressions of p53, cyclin D1 and cyclin A were significantly more frequent in a gastric phenotype than an intestinal phenotype. Cyclin A was overexpressed in a mixed phenotype compared with an intestinal phenotype, while p27 overexpression was more frequent in an intestinal phenotype than in a mixed phenotype. Reduction of p21 was a common feature of the gastric intramucosal differentiated-type cancers examined.</p> <p>Conclusions</p> <p>Our results suggest that the levels of some cell cycle regulators appear to be associated with mucin phenotypes of early gastric differentiated-type cancers.</p

Mucin expression in gastric- and gastro-oesophageal signet-ring cell cancer: results from a comprehensive literature review and a large cohort study of Caucasian and Asian gastric cancer

Background: The literature on the prognostic relevance of signet-ring cell (SRC) histology in gastric cancer (GC) is controversial which is most likely related to inconsistent SRC classification based on haematoxylin–eosin staining. We hypothesised that mucin stains can consistently identify SRC-GC and predict GC patient outcome. Methods: We performed a comprehensive literature review on mucin stains in SRC-GC and characterised the mucin expression in 851 Caucasian GC and 410 Asian GC using Alcian Blue (AB)-Periodic Acid-Schiff (PAS), MUC2 (intestinal-type mucin), and MUC5AC (gastric-type mucin). The relationship between mucin expression and histological phenotype [poorly cohesive (PC) including proportion of SRCs, non-poorly cohesive (non-PC), or mucinous (MC)], clinicopathological variables, and patient outcome was analysed. Results: Depending on mucin expression and cut-offs, the positivity rates of SRC-GC reported in the literature varied from 6 to 100%. Patients with MUC2 positive SRC-GC or SRC-GC with (gastro)intestinal phenotype had poorest outcome. In our cohort study, PC with ≥ 10% SRCs expressed more frequently MUC2, MUC5AC, and ABPAS (p < 0.001, p = 0.004 and p < 0.001, respectively). Caucasians with AB positive GC or combined ABPAS-MUC2 positive and MUC5AC negative had poorest outcome (all p = 0.002). This association was not seen in Asian patients. Conclusions: This is the first study to suggest that mucin stains do not help to differentiate between SRC-GC and non-SRC-GC. However, mucin stains appear to be able to identify GC patients with different outcome. To our surprise, the relationship between outcome and mucin expression seems to differ between Caucasian and Asian GC patients which warrants further investigations

スピロノラクトン ワ サシツ ヨウリョウ ゲンショウ シュジュツ ノ マンセイキ ニ オケル シンゾウ リモデリング オ カンワサセル

京都大学0048新制・課程博士博士(医学)甲第14489号医博第3334号新制||医||974(附属図書館)UT51-2009-D201京都大学大学院医学研究科外科系専攻(主査)教授 福田 和彦, 教授 伊達 洋至, 教授 小池 薫学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA