Synthesis of 2,3-difunctionalized 4-nitropyrroles.
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Carbon Dioxide↗
Biomedical subjects
T Hida
Publications and source records attributed to T Hida.
Genetic alteration of the beta-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion.
The beta-catenin gene (CTNNB1) has been shown to be genetically mutated in various human malignancies. To determine whether the beta-catenin gene is responsible for oncogenesis in thoracic malignancies, we searched for the mutation in 166 lung cancers (90 primary tumors and 76 cell lines), one blastoma and 10 malignant mesotheliomas (two primary tumors and eight cell lines). Among the lung cancers, including 43 small cell lung cancers (SCLCs) and 123 non-small cell lung cancers (NSCLCs), we identified four alterations in exon 3, which is the target region of mutation for stabilizing beta-catenin. One primary adenocarcinoma had a somatic mutation from C to G, leading to an amino acid substitution from Ser to Cys at codon 37. Among the cell lines, SCLC NCI-H1092 had a mutation from A to G, leading to an Asp to Gly substitution at codon 6, NSCLC HCC15 had a mutation from C to T, leading to a Ser to Phe substitution at codon 45, and NSCLC NCI-H358 had a mutation from A to G, leading to a Thr to Ala substitution at codon 75. One blastoma also had a somatic mutation from C to G, leading to a Ser to Cys substitution at codon 37. Among the 10 malignant mesotheliomas, we identified a homozygous deletion in the NCI-H28 cell line. Cloning of the rearranged fragment from NCI-H28 indicated that all the exons except exon 1 of the beta-catenin gene are deleted and that the deletion junction is 13 kb downstream from exon 1. Furthermore, Northern blot analysis of 26 lung cancer and eight mesothelioma cell line RNAs detected ubiquitous expression of the beta-catenin messages except NCI-H28, although Western blot analysis showed that relatively less amounts of protein products were expressed in some of lung cancer cell lines. Our findings suggest that the beta-catenin gene is infrequently mutated in lung cancer and that the NCI-H28 homozygous deletion of the beta-catenin gene might indicate the possibility of a new tumor suppressor gene residing in this region at 3p21.3, where various types of human cancers show frequent allelic loss.
Base Sequence↗
Multi-faceted analyses of a highly metastatic human lung cancer cell line NCI-H460-LNM35 suggest mimicry of inflammatory cells in metastasis.
This study established and characterized low-metastatic revertant and parental clones of a highly metastatic human lung cancer cell line, NCI-H460-LNM35 (hereafter referred to as LNM35). Expression-profiling analysis revealed that up-regulation of various proinflammatory cytokines and angiogenic chemotactic chemokines was present in LNM35. Further, while COX-2 itself is known to be inducible in inflammation, COX-2 expression levels correlated well with the capabilities of these clones for not only in vitro motility and invasion but also in vivo metastasis, and COX-2 inhibitors were shown for the first time to reduce lung cancer metastasis in vivo. These findings suggest that lung cancer cells may mimic inflammatory cells in the process of metastasis.
Animals↗
Syntheses and evaluation of quinoline derivatives as novel retinoic acid receptor alpha antagonists.
In the course of studies on novel retinoids, we have designed and synthesized a series of quinoline derivatives. One of them, 4-[5-[8-(1-methylethyl)-4-phenyl-2-quinolinyl]-1H-2-pyrrolyl]benzoic acid (12f) shows potent RARalpha-selective antagonistic activity.
Aldehydes↗
[Long-term survival of hormone-refractory prostate cancer: a case report].
Although prostate cancer initially responds well to endocrine therapy, it becomes resistant to the therapy a few years later, and is called hormone-refractory cancer. In general, hormone-refractory prostate cancer is resistant to all kinds of therapy and the prognosis is extremely poor. Here we report an unusual case of a person with hormone-refractory prostate cancer, who has been surviving for more than 5 years after being diagnosed as having this type of cancer. A 75-year-old man was diagnosed with prostate cancer (poorly differentiated adenocarcinoma, T3 N0 M1, stage D2) and initial endocrine therapy combined with castration and estrogen was effective. Four years later, the tumor marker of prostate-specific antigen (PSA) increased and the cancer was thought to be hormone-independent, refractory state. Alteration of antiandrogen from chlormadinone acetate to flutamide was effective and PSA was kept at low levels for 6 months. When PSA rose again, we started oral chemotherapy with tegafur.uracil. PSA decreased to normal range (complete response) and remained stable for 10 months. After that, a rapid increase of PSA was controlled for 7 months by oral chemotherapy with estramustine phosphate sodium and VP-16. This case indicates that alteration of antiandrogens or oral chemotherapy may be useful in some cases with hormone-refractory prostate cancer.
Adenocarcinoma↗
Evaluation of retinal damage induced by air/fluid exchange using a trypan blue inclusion test in rabbits.
PURPOSE: To investigate whether retina damaged in the process of air/fluid exchange could be visualized in situ using trypan blue staining. METHODS: Vitrectomy and air/fluid exchange with continuous air infusion for various periods of time was performed in adult pigmented rabbits, followed by injection of 0.4% trypan blue solution into the vitreous cavity. Retinal staining was evaluated intraoperatively under the operating microscope and by light microscopy after enucleation. RESULTS: Intraoperative examination showed localized trypan blue staining of areas of the retina opposite the infusion cannula. Light microscopy of the same areas revealed intranuclear trypan blue inclusion in the retina. CONCLUSION: Trypan blue staining allows for the immediate in situ evaluation of damage to the retina associated with air/fluid exchange and continuous air infusion in rabbit eyes.
Air↗
Protective function of p27(KIP1) against apoptosis in small cell lung cancer cells in unfavorable microenvironments.
A previous study of ours unexpectedly found that in contrast to frequent reductions in non-small cell lung cancer, high expression of the p27(KIP1) cyclin-dependent kinase (CDK) inhibitor was retained in virtually all small cell lung cancers (SCLCs), suggesting the possibility of high expression of nonfunctional p27(KIP1) in this virulent tumor. The study presented here, however, shows that p27(KIP1) in SCLC biochemically functions as a CDK inhibitor, clearly showing induction apparently associated with G(1)/G(0) arrest and efficient binding to and inhibition of the cyclin E-CDK2 complex. Interestingly, induction of p27(KIP1) seems to confer on SCLC cells the ability to survive under culture conditions unfavorable for cell growth such as a lack of nutrients and hypoxia. Subsequent experiments manipulating p27(KIP1) levels by using a sense p27(KIP1) expression construct or an antisense oligonucleotide supported this notion. These observations suggest that high expression of p27(KIP1) in vivo may favor the survival of SCLC by preventing apoptosis in a microenvironment unfavorable for cell proliferation.
Animals↗
Novel mutation in the PML/RARalpha chimeric gene exhibits dramatically decreased ligand-binding activity and confers acquired resistance to retinoic acid in acute promyelocytic leukemia.
OBJECTIVE: All-trans retinoic acid (RA) resistance in acute promyelocytic leukemia (APL) has been a serious clinical problem in differentiation-inducing therapy. However, the mechanisms underlying acquired RA resistance in APL patients are not well understood. MATERIALS AND METHODS: We recently established a spontaneous RA-resistant APL cell line (UF-1) from a patient and used this cell line as an excellent in vitro model for RA-resistant clinical situations. We investigated the structural and functional abnormalities of chimeric PML/RARalpha gene in UF-1 cells and preserved materials from the original patient. RESULTS: A novel point mutation was detected in the ligand-binding (E) domain of the RARalpha portion of the PML/RARalpha gene in UF-1 cells. This mutation resulted in amino acid substitution of Arg611 (CGG) for Trp611 (TGG) in the short-form PML/RARalpha protein, which corresponded to Arg276 in wild-type RARalpha. Importantly, the same mutation was also detected in the preserved materials from the original patient. COS-1 cells were transiently transfected with cDNA encoding wild-type and mutant PML/RARalpha constructed by site-directed mutagenesis and performed RA-binding assay. Interestingly, RA-binding activity was dramatically decreased in the mutant PML/RARalpha compared with that of the wild-type chimeric protein, suggesting that this single amino acid substitution is critical for RA binding. CONCLUSIONS: These results strongly suggest that a novel point mutation in the ligand-binding domain of the RARalpha portion (Arg611) of the chimeric PML/RARalpha gene decreased sensitivity to all-trans RA. We conclude that acquisition of the PML/RARalpha mutation is one possible mechanism for development of RA resistance in patients with APL in vivo.
Amino Acid Sequence↗
Existence of retinoic acid-receptor-independent retinoid X-receptor-dependent pathway in myeloid cell function.
We previously reported that ER-27191 (4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylmethyl)anthra[1,2-b]pyrrol-3-yl]benzoic acid) is a potent antagonist of retinoic acid receptor (RAR), and ER-35795 ((2E,4E,6E)-7-[1-(1-methylethyl)-8-chloro-1,2,3,4-tetrahydroquinolin-6-yl]-6-fluoro-3-methyl-2,4,6-nonatrienoic acid) is a novel retinoid X receptor (RXR)-specific agonist. By using these compounds, we investigated whether distinct RAR-dependent and RXR-dependent pathways operate to mediate the diverse activities of retinoids, particularly, the effects of the RXR pathway on cellular function. ER-27191 completely antagonized HL60 cell differentiation induced by all-trans-retinoic acid (atRA). However, the differentiation induced by the ER-35795 was not antagonized at all by the RAR antagonist, but was inhibited by an RXR homodimer antagonist (LGD100754, (2E,4E,6Z)-7-(3-n-propoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-3-methylocta-2,4,6-trienoic acid). Its agonistic action on RXR/RAR heterodimer, on the other hand, was neutralized by the RAR antagonist. During HL60 cell differentiation, atRA induced RARbeta mRNA, while the RXR had no effect. Interestingly, a functional RXR-pathway was also seen in lipopolysaccharide-induced inhibition of mouse splenocyte proliferation. These results strongly suggest the existence of a pharmacological RXR-dependent pathway that is activated by a ligand that can bind to RXR.
Animals↗
[Anterior turbinectomy: experimental and clinical study].
INTRODUCTION: Minimal cross-sectional areas situated at the anterior end of the inferior turbinate have the most influence on nasal patency. To improve persistent nasal obstruction, 2 types of inferior turbinectomies--conventional complete resection including the anterior and posterior mucosa and anterior resection of the anterior mucosa--were conducted and preoperative and postoperative nasal patency and stuffy sensation were compared and analyze. OBJECTS AND METHODS: Cases undergoing 2 types of turbinectomies between July 1997 and March 2000 numbered 63--conventional in 32 (64 sides) and anterior in 31 (62 sides). Anterior, posterior, and total nasal volume and minimal cross-sectional area were evaluated pre- and postoperatively using an acoustic rhinometer. The stuffy sensation was similarly evaluated by the visual analog scale (VAS). RESULTS: All nasal volumes showed postoperative increase under conventional treatments. Anterior and posterior volumes significantly increased under anterior treatment. Comparing the results of postoperative volume posterior volume was significantly larger under conventional treatment than under anterior treatment. Stuffy sensation significantly improved by VAS in both types of turbinectomy, with no significant difference between them. CONCLUSION: Anterior treatment to solely increase nasal volume at the minimal cross sectional area showed equal postoperative improvement in VAS under conventional treatment.
Acoustics↗
[A case of choroidal hemangioma with bullous exudative retinal detachment treated successfully by transpupillary thermotherapy].
BACKGROUND: Choroidal hemangioma associated with bullous retinal detachment may be difficult to treat, due to varying results with conventional laser photocoagulation, radiotherapy, or surgical drainage. Here we report on a case of extensive bullous retinal detachment secondary to circumscribed choroidal hemangioma that was resolved after combined treatment with vitrectomy, silicone oil tamponade, and transpupillary thermotherapy. CASE: A 29-year-old woman presented with a large choroidal hemangioma in her right eye associated with serous retinal detachment. The tumor measured 8 disc diameters in size and was located in the inferotemporal macula, abutting the fovea. RESULTS: Laser photocoagulation of the tumor was unsuccessful in inducing absorption of subretinal fluid. Because of progressive bullous retinal detachment, surgery was performed consisting of external drainage of subretinal fluid, vitrectomy, endolaser photocoagulation of the tumor, and silicone oil tamponade. The silicone oil was removed four weeks postoperatively at which time almost complete resolution of the retinal detachment was observed. However, retinal detachment recurred eight weeks later, and transpupillary thermotherapy was then applied to the tumor. By four weeks after transpupillary thermotherapy, total reabsorption of subretinal fluid, visual acuity improvement, and decreased height of the choroidal hemangioma were noted. CONCLUSION: Transpupillary thermotherapy is an effective treatment for serous retinal detachment associated with choroidal hemangioma.
Adult↗
Discovery of novel and potent retinoic acid receptor alpha agonists: syntheses and evaluation of benzofuranyl-pyrrole and benzothiophenyl-pyrrole derivatives.
In the course of our studies on retinoic acid receptor (RAR) agonists, we have designed and synthesized a series of benzofuran and benzothiophene derivatives. Some of these compounds (1a,b,e,f,j) markedly inhibited LPS-induced B-lymphocyte proliferation and exerted RARalpha selectivity. One of them, 4-[5-(4,7-dimethylbenzofuran-2-yl)pyrrol-2-yl]benzoic acid (1b), when orally administered significantly inhibited mouse antibody production and delayed type hypersensitivity (DTH) responses from a dose of 0.1 mg/kg.
Administration, Oral↗
Establishment and characterization of a human lung cancer cell line NCI-H460-LNM35 with consistent lymphogenous metastasis via both subcutaneous and orthotopic propagation.
Lymphogenous metastasis is a common feature of human lung cancers, but very little is known about the underlying mechanism. In the present study, in vivo selection was carried out to obtain a highly lymphogenous metastatic subline of a human large cell carcinoma of the lung, NCI-H460. The resulting subline, termed NCI-H460-LNM35 (LNM35), was shown to metastasize to regional lymph nodes with a 100% incidence not only as a result of orthotopic intrabronchial (i.b.) implantation, but also as a result of conventional s.c. implantation. LNM35 has a short latency period, allowing for the collection of experimental data within 28 days after i.b. inoculation and 45 days after s.c. inoculation. It was noted that orthotopically i.b.-propagated LNM35 closely mimicked the clinical manifestations of human lung cancer patients by infiltrating into lymphatic vessels and metastasizing to the mediastinal lymph nodes. The LNM35 cell line is, to the best of our knowledge, the first human lung cancer cell line to be reported as having lymphogenous metastatic properties, and the observed 100% incidence by s.c. inoculation gives LNM35 a significant advantage even over previously reported human cancer cell lines of other origins. Comparisons between LNM35 and its parental NCI-H460 cell lines were also made with regard to expression levels and/or activities of various molecules that are thought to play a part in the metastatic process. We show here that the expression of cyclooxygenase 2 is increased in LNM35 and that a specific cyclooxygenase 2 inhibitor, nimesulide, can inhibit the invasion of LNM35 in vitro through Matrigel containing basement membrane components.
Animals↗
Novel retinoic acid receptor alpha agonists: syntheses and evaluation of pyrazole derivatives.
We have designed and synthesized a series of pyrazole derivatives as candidate retinoic acid receptor (RAR) agonists. One of them, 4-[5-(1, 5-diisopropyl-1H-3-pyrazolyl)-1H-2-pyrrolyl]benzoic acid (11b), which possesses a 2,5-disubstituted pyrrole moiety, showed selective transactivation activity for the RAR alpha receptor, and had highly potent cell-differentiating activity on HL-60 cells.
Binding, Competitive↗
Syntheses and evaluation of naphthalenyl- and chromenyl-pyrrolyl-benzoic acids as potent and selective retinoic acid receptor alpha agonists.
Synthesis and structure activity relationships (SAR) of RAR alpha-selective agonists are discussed. 4-[5-(5,8-Dimethyl-2H-3-chromenyl)-1H-2-pyrrolyl]benzoic acid (12a), which possesses a flat structural moiety and an oxygen atom at the hydrophobic part, showed highly selective transactivation activity at the RAR alpha receptor.
Benzoates↗
Syntheses and structure-activity relationships of 5,6,7, 8-tetrahydro-5,5,8,8-tetramethyl-2-quinoxaline derivatives with retinoic acid receptor alpha agonistic activity.
In the course of our studies on retinoic acid receptor (RAR) agonists, we have designed and synthesized a series of quinoxaline derivatives. One of them, 4-[5-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-quinoxalinyl)-1H-2-pyrrolyl]benzoic acid (3a), which possesses a 2,5-disubstituted pyrrole moiety, showed selectivity for the RARalpha receptor and exerted highly potent cell-differentiating activity on HL-60 cells.
Benzoates↗
Ultrasound biomicroscopy for examination of the sclerotomy site in eyes with proliferative diabetic retinopathy after vitrectomy.
PURPOSE: We evaluated the capability of ultrasound biomicroscopy (UBM) to predict fibrovascular proliferation at sclerotomy sites in eyes with postoperative vitreous hemorrhage due to proliferative diabetic retinopathy (PDR). METHODS: Ultrasound biomicroscopy was used for examining the sclerotomy sites in 13 eyes of 11 patients with PDR experiencing postoperative vitreous hemorrhage (PDR group). Thirty-nine sclerotomy sites (all entry sites of each eye) were examined before reoperation, and the UBM images were compared with findings obtained during revision of the vitrectomy. Thirteen eyes of 13 patients undergoing vitrectomy for nondiabetic diseases were used as controls and examined after vitrectomy. RESULTS: The UBM images were classified into the following four categories: A, tent; B, spheroid; C, trapezoid; and N, none. The findings were distributed as follows in the PDR group: category A, 18%; B, 5%; C, 56%; and N, 21 %; and as follows in the control group: category A, 28%; B, 5%; C, 5%; and N, 62%. In the PDR group, 11 of 12 sclerotomy sites disclosing fibrovascular proliferation possessed the trapezoidal image. Mean length of trapezoidal base was 2.49+/-0.97 mm and 1.51+/-0.75 mm in the groups with and without fibrovascular proliferation, respectively (P<0.01). The average relative reflectivity of the trapezoidal image against the sclera was 0.501+/-0.169 in the fibrovascular proliferation group and 0.891+/-0.183 in the fibrous ingrowth group (P<0.01). CONCLUSION: Ultrasound biomicroscopy is useful in detecting fibrovascular proliferation at sclerotomy sites because a large and low-reflecting trapezoidal UBM image is highly correlated to its presence.
Adult↗
Ultrastructural and immunohistochemical findings in five patients with vitreomacular traction syndrome.
OBJECTIVE: To evaluate pathologic features of vitreomacular traction syndrome (VMT). METHODS: Preretinal membranes removed from five patients during vitreous surgery for VMT syndrome were evaluated by electron microscopy (n = 4) and immunohistochemistry (n = 1). RESULTS: Electron microscopic examination revealed large segments of internal limiting lamina (ILL) in three of the four cases. Other extracellular features included two types of abnormal collagen fibrils, determined to be type I and fibrous long-spacing collagen. The myofibrocyte was the predominant cell type in all cases. Collagen types I, II, and III, as well as glial fibrillary acidic protein and vimentin, were identified by immunohistochemistry. CONCLUSIONS: Epiretinal membranes in eyes with VMT syndrome adhered tightly to the ILL with abnormal collagen and contractile elements that included myofibrocytes.
Aged↗