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1.
Arterioscler Thromb Vasc Biol ; 41(1): 360-376, 2021 01.
Article in English | MEDLINE | ID: mdl-33086872

ABSTRACT

OBJECTIVE: Enhancement of LCAT (lecithin:cholesterol acyltransferase) activity has possibility to be beneficial for atherosclerosis. To evaluate this concept, we characterized our novel, orally administered, small-molecule LCAT activator DS-8190a, which was created from high-throughput screening and subsequent derivatization. We also focused on its mechanism of LCAT activation and the therapeutic activity with improvement of HDL (high-density lipoprotein) functionality. Approach and Results: DS-8190a activated human and cynomolgus monkey but not mouse LCAT enzymes in vitro. DS-8190a was orally administered to cynomolgus monkeys and dose dependently increased LCAT activity (2.0-fold in 3 mg/kg group on day 7), resulting in HDL cholesterol elevation without drastic changes of non-HDL cholesterol. Atheroprotective effects were then evaluated using Ldl-r KO×hLcat Tg mice fed a Western diet for 8 weeks. DS-8190a treatment achieved significant reduction of atherosclerotic lesion area (48.3% reduction in 10 mg/kg treatment group). Furthermore, we conducted reverse cholesterol transport study using Ldl-r KO×hLcat Tg mice intraperitoneally injected with J774A.1 cells loaded with [3H]-cholesterol and confirmed significant increases of [3H] count in plasma (1.4-fold) and feces (1.4-fold on day 2 and 1.5-fold on day3) in the DS-8190a-treated group. With regard to the molecular mechanism involved, direct binding of DS-8190a to human LCAT protein was confirmed by 2 different approaches: affinity purification by DS-8190a-immobilized beads and thermal shift assay. In addition, the candidate binding site of DS-8190a in human LCAT protein was identified by photoaffinity labeling. CONCLUSIONS: This study demonstrates the potential of DS-8190a as a novel therapeutic for atherosclerosis. In addition, this compound proves that a small-molecule direct LCAT activator can achieve HDL-C elevation in monkey and reduction of atherosclerotic lesion area with enhanced HDL function in rodent.


Subject(s)
Atherosclerosis/prevention & control , Enzyme Activators/pharmacology , Phosphatidylcholine-Sterol O-Acyltransferase/metabolism , Plaque, Atherosclerotic , Animals , Atherosclerosis/enzymology , Atherosclerosis/genetics , Atherosclerosis/pathology , Cell Line , Cholesterol, HDL/blood , Disease Models, Animal , Enzyme Activation , Humans , Macaca fascicularis , Macrophages/drug effects , Macrophages/enzymology , Male , Mice, Inbred C57BL , Mice, Knockout , Phosphatidylcholine-Sterol O-Acyltransferase/genetics , Receptors, LDL/deficiency , Receptors, LDL/genetics , Species Specificity , Up-Regulation
2.
Eur J Cardiothorac Surg ; 54(6): 1081-1084, 2018 12 01.
Article in English | MEDLINE | ID: mdl-29733357

ABSTRACT

OBJECTIVES: This study aimed to elucidate the physiological feasibility of aortic valve neocuspidization (AVNeo) by comparing the aortic annulus dimensions between patients after AVNeo and patients with normal aortic valves. METHODS: From December 2010 to October 2017, we performed AVNeo for various aortic valve pathologies in 147 patients. Of these patients, the aortic annulus dimensions were measured in 25 patients who underwent AVNeo for aortic valve disease as follow-up examination and compared with those measured in 15 patients who had normal aortic valves. Measurements were recorded using electrocardiography-gated transthoracic echocardiography. RESULTS: No significant differences in the aortic annulus dimensions were observed between the patients who had undergone AVNeo and those who had normal aortic valves. In a cardiac cycle, the annulus area in the systolic phase was consistently larger than that in the diastolic phase, which was a physiological condition. CONCLUSIONS: The movement of the aortic annulus after AVNeo is comparable with that of the aortic annulus of a normal aortic valve. Thus, AVNeo can be regarded as a more physiological operation in that it maintains the characteristics of the aortic valve similar to those of a normal aortic valve.


Subject(s)
Aortic Valve , Echocardiography , Heart Valve Diseases , Adult , Aged , Aged, 80 and over , Aortic Valve/anatomy & histology , Aortic Valve/diagnostic imaging , Aortic Valve/pathology , Aortic Valve/surgery , Case-Control Studies , Female , Heart Valve Diseases/diagnostic imaging , Heart Valve Diseases/epidemiology , Heart Valve Diseases/surgery , Humans , Male , Middle Aged
3.
Cancer Sci ; 96(12): 844-57, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16367903

ABSTRACT

Previous studies suggest that some S100 proteins are involved in the progression of certain types of cancer. However, no comprehensive data is currently available on the expression of S100 family genes in lung adenocarcinomas. Oligonucleotide array, quantitative reverse transcription-polymerase chain reaction and western blot analyses of lung adenocarcinoma cell lines and bronchiolar epithelial cells (SAEC and NHBE) revealed that S100A2 and S100A4 were the most strikingly downregulated and upregulated members of the S100 family, respectively. Immunohistochemical analyses of 94 primary lung adenocarcinomas showed that positive S100A2 expression (33/94, 35.1%) was significantly associated with lymphatic invasion (P=0.0233) and positive S100A4 expression (19/94, 20.2%) with vascular invasion (P=0.0454). Interestingly, a strong inverse relationship was found between S100A4 and p53 expression (P=0.0008). Survival analyses showed that S100A4 positivity was associated with poor patient prognosis (P=0.042). S100A2 positivity was not associated with patient survival when the whole patient group was analyzed; however, S100A2 positivity was a favorable prognostic indicator in patients with p53-negative tumors (P=0.0448). Finally, we used oligonucleotide array analyses and identified potential S100A2 and S100A4 target genes involved in cancer progression: S100A2 induced RUNX3 and REPRIMO; S100A4 induced EZRIN, RUNX1 and WISP1; S100A2 repressed EGFR, NFKB2 and RELA2; and S100A4 repressed ANXA10 and IL1RN. Thus, the present study demonstrates involvement of S100A2 and S100A4 in the progression of lung adenocarcinomas and an inverse association between S100A4 and p53 expression, and provides a list of targets regulated by S100A2 and S100A4.


Subject(s)
Adenocarcinoma/genetics , Chemotactic Factors/genetics , Gene Expression Regulation, Neoplastic , Genes, p53 , Lung Neoplasms/genetics , S100 Proteins/genetics , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Base Sequence , Bronchi/cytology , Cell Line , Cell Line, Tumor , DNA Primers , Female , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , Respiratory Mucosa/cytology , Reverse Transcriptase Polymerase Chain Reaction/methods , S100 Calcium-Binding Protein A4 , Survival Analysis
4.
Pathol Int ; 54(9): 675-81, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15363035

ABSTRACT

To clarify the association of the P27 degradation pathway proteins, Skp2 and Jab1, with the development and progression of lung adenocarcinoma (AD), we immunohistochemically investigated Skp2 and Jab1 expression together with P27- and Ki-67-labeling in 110 lung AD and 11 atypical adenomatous hyperplasia (AAH) and analyzed the relationship between the expression of these proteins and the clinicopathological factors. High Skp2 or Jab1 expression was frequent in lung AD (52/110, 47%, and 59/110, 54%, respectively), and high expression of Jab1 was also frequent in AAH (4/11, 36%), while it was not observed in normal bronchiolar epithelium. The P27 labeling index (LI) was reciprocally correlated with high Skp2 and Jab1 expression, and a higher Ki-67 LI was significantly correlated with high Skp2 and Jab1 expression. However, low P27 expression did not correlate with a higher Ki-67 LI. High Skp2 lung AD showed significant correlation with blood and lymphatic vessel invasion, which low P27 expression did not correlate with. Furthermore, high Skp2 expression in lung AD was significantly correlated with a poor outcome for patients. Thus, Skp2 and Jab1 regulate P27 degradation, and might contribute to the development and progression of lung AD through P27-mediated and -unmediated mechanisms.


Subject(s)
Adenocarcinoma/metabolism , Cell Cycle Proteins/metabolism , DNA-Binding Proteins/metabolism , Lung Neoplasms/metabolism , S-Phase Kinase-Associated Proteins/metabolism , Transcription Factors/metabolism , Tumor Suppressor Proteins/metabolism , Adenocarcinoma/mortality , Adenocarcinoma/secondary , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , COP9 Signalosome Complex , Cell Count , Cyclin-Dependent Kinase Inhibitor p27 , Disease Progression , Female , Humans , Immunoenzyme Techniques , Intracellular Signaling Peptides and Proteins , Japan/epidemiology , Ki-67 Antigen/metabolism , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Peptide Hydrolases , Survival Rate
5.
Gan To Kagaku Ryoho ; 30(7): 977-80, 2003 Jul.
Article in Japanese | MEDLINE | ID: mdl-12894713

ABSTRACT

We experienced a case in which severe alveolar hemorrhage occurred in the course of gefitinib therapy. A 56-year-old man with non-small cell lung cancer had been treated with CDDP + CPT-11, CDDP + GEM + VNR, CDDP + TXT. After the chemotherapy with these regimens was found to be ineffective, daily oral gefitinib was started. Four weeks later, the patient complained of cough, bloody sputum and dyspnea. Chest X-ray and CT showed bilateral infiltrations with air bronchogram. Fiberoptic bronchoscopy revealed alveolar hemorrhage with an increase of lymphocytes in the BALF. After the cessation of gefitinib therapy and the administration of steroid, he gradually recovered.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/adverse effects , Hemorrhage/etiology , Lung Diseases/etiology , Lung Neoplasms/drug therapy , Quinazolines/adverse effects , Gefitinib , Humans , Male , Middle Aged , Pulmonary Alveoli , Respiratory Insufficiency/etiology
6.
Gan To Kagaku Ryoho ; 30(5): 595-8, 2003 May.
Article in Japanese | MEDLINE | ID: mdl-12795088

ABSTRACT

Thymic carcinoma was indistinct for criteria of clinicopathological diagnosis. Recently it gets easier to diagnose thymic carcinoma, because of progression of WHO classification and immunohistochemical technique. Commonly, patients are men and in sixties. Common symptoms are chest pain and dyspnea. Most cases are advanced, over Stage III of the Masaoka's classification. Combined therapies e.g. operation, chemotherapy and radiation were done, but complete resection is difficult. Prognosis is poor, the 3- and 5-year survival is 48.7% and 40.6%.


Subject(s)
Thymus Neoplasms/diagnosis , Thymus Neoplasms/therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Prognosis , Radiotherapy, Adjuvant , Survival Rate , Thymectomy , Thymoma/diagnosis , Thymoma/mortality , Thymoma/therapy , Thymus Neoplasms/mortality
7.
Pathol Res Pract ; 199(11): 713-21, 2003.
Article in English | MEDLINE | ID: mdl-14708637

ABSTRACT

Basaloid squamous carcinoma (BSC) is a rare variant of squamous cell carcinoma (SCC). In this study, clinicopathological and immunohistochemical characteristics of 12 superficial esophageal BSCs were examined and compared with those of typical superficial SCCs. Eight cases were classified into an elevated type, and the other four into a depressed type. High-grade intraepithelial neoplasia was not observed around the invasive lesions in five cases, and only BSC components were apparent. High-grade intraepithelial neoplasia was demonstrated in seven cases, five of which had both BSC and SCC components in the invasive lesion. A cribriform growth pattern, comedo-type necrosis, and hyaline deposits were conspicuous histological findings. CK14 was positively stained in 90% of the series, but the proportion of positive cells was small in most cases. Type IV collagen was increased or well preserved in the basement membrane in 70% of cases, but heparan sulfate was decreased in the majority. In comparison with SCCs, lymphatic permeation was observed less frequently. However, regarding the frequencies of venous permeation, nodal metastasis, p53 protein expression, and Ki-67 labeling index, no significant differences were noted. Thus, esophageal BSCs demonstrate the pathological features characteristic of an early stage, but pathological parameters related to biological behavior do not significantly vary from those typical of SCCs.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Aged , Aged, 80 and over , Female , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasm Invasiveness
8.
Virchows Arch ; 441(4): 350-7, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12404060

ABSTRACT

Endoscopic mucosal resection (EMR) has been performed for intramucosal carcinomas with excellent results. To evaluate invasion depth of superficial esophageal squamous cell carcinomas (SESCCs) accurately, it is important to elucidate vertical and horizontal growth features. Using 179 specimens of SESCC taken by EMR, various factors associated with vertical and horizontal growth were examined pathologically to determine which were correlated with invasion depth, classified for this purpose into four levels, m1, m2, m3, and sm. Maximum tumor diameter, including high-grade intraepithelial neoplasia, differed between m1 and m2 cases and for invasive lesions between m2 and m3. Maximum tumor thickness varied between m1 and m2, m2 and m3, and m3 and sm. Multivariate analysis showed tumor thickness and diameter of invasion to be correlated with submucosal invasion. Tumor thickness and depth of the depressed lesions were correlated in depressed/flat type cases. In elevated type cases the thickness of the tumor did not differentiate between m3 and sm. Shape of the elevated lesion also influenced the invasion depth. Frequency of infiltrating type tumors, composed of irregular and small invading nests, was higher with sm than m3. To differentiate m3 and sm tumor the classification of gross type, thickness, depth of depressed lesions, shape of elevated lesions, and invasion patterns should all be evaluated.


Subject(s)
Carcinoma, Squamous Cell/pathology , Esophageal Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/surgery , Esophageal Neoplasms/surgery , Esophagoscopy , Female , Humans , Male , Middle Aged , Neoplasm Invasiveness
9.
J Med Chem ; 45(11): 2150-9, 2002 May 23.
Article in English | MEDLINE | ID: mdl-12014953

ABSTRACT

Beta-adrenergic receptor kinase 1 (betaARK1) and cyclic adenosine 5'-monophosphate-dependent protein kinase A (PKA) have structurally similar adenine-binding pockets but have different physiologic functions. To obtain specific betaARK1 inhibitors, a two step rational drug design process was used. First, a search was conducted on three-dimensional models of commercially available compounds to find compounds that fit the adenine-binding pocket of betaARK1. Second, a comparative docking study that focused on the differences between the adenine-binding pockets of the two enzymes was used to evaluate the binding specificity of each compound that inhibited betaARK1 activity. The results of these analyses yielded three betaARK1-selective inhibitor leads from 11 candidates, a hit rate for selectivity of 27%. Although the IC50 values of these compounds for betaARK1 ranged from only 1.3 x 10(-4) M to 5.6 x 10(-4) M, the compounds did not inhibit PKA at concentrations up to 1.0 x 10(-3) M. Thus, the present study shows the usefulness of a rational drug design strategy in finding specific kinase inhibitors for proteins with similar drug target binding sites.


Subject(s)
Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Binding Sites , Cyclic AMP-Dependent Protein Kinases/chemistry , Databases, Factual , Drug Design , Models, Molecular , Protein Conformation , Structure-Activity Relationship , beta-Adrenergic Receptor Kinases
10.
Eur Radiol ; 12 Suppl 3: S155-7, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12522629

ABSTRACT

Chronic pneumonitis of infancy (CPI) is a very rare lung disease in infants and young children. We report a 33-day-old infant with CPI, focusing on the radiologic aspects of the disease. Chest radiographs showed variable and non-specific appearances including ground-glass shadowing, consolidation, volume loss, and hyperinflation. Dense alveolar opacities progressed as CPI advanced. The radiologic features of our case reflected pathologic changes.


Subject(s)
Pneumonia/diagnosis , Autopsy , C-Reactive Protein/metabolism , Chronic Disease , Diagnostic Errors , Disease Progression , Humans , Infant , Male , Pneumonia/blood , Pneumonia/pathology , Radiographic Image Enhancement
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