146 results on '"Nishigaki, R."'
Search Results
2. A new mouse model for Down syndrome
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Kazuki, Y., Schulz, T. C., Shinohara, T., Kadota, M., Nishigaki, R., Inoue, T., Kimura, M., Kai, Y., Abe, S., Shirayoshi, Y., Oshimura, M., and Lubec, G., editor
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- 2003
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Catalog
3. The possible involvement of mutagenic and carcinogenic heterocyclic amines in human cancer
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Totsuka, Y, primary, Nishigaki, R, additional, Sugimura, T, additional, and Wakabayashi, K, additional
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- 2006
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4. A new mouse model for Down syndrome
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Kazuki, Y., primary, Schulz, T. C., additional, Shinohara, T., additional, Kadota, M., additional, Nishigaki, R., additional, Inoue, T., additional, Kimura, M., additional, Kai, Y., additional, Abe, S., additional, Shirayoshi, Y., additional, and Oshimura, M., additional more...
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- 2003
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5. Mutagens formed from β-carbolines with aromatic amines
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Totsuka, Y, Takamura-Enya, T, Nishigaki, R, Sugimura, T, and Wakabayashi, K
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- 2004
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6. Proteomic signatures and aberrations of mouse embryonic stem cells containing a single human chromosome 21 in neuronal differentiation: An in vitro model of down syndrome
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Kadota, M., Nishigaki, R., Wang, C.C., Toda, T., Shirayoshi, Y., Inoue, T., Gojobori, T., Ikeo, K., Rogers, M.S., and Oshimura, M.
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- 2004
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7. A new mouse model for Down syndrome
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Kazuki Y, Tc, Schulz, Shinohara T, Kadota M, Nishigaki R, Inoue T, Kimura M, Yoshiteru Kai, Abe S, Shirayoshi Y, and Oshimura M
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Disease Models, Animal ,Mice ,Phenotype ,Chimera ,Chromosomes, Human, Pair 21 ,Animals ,Humans ,Mice, Transgenic ,Down Syndrome - Abstract
Trisomy 21 (Ts21) is the most common live-born human aneuploidy and results in a constellation of features known as Down syndrome (DS). Ts21 is a frequent cause of congenital heart defects and the leading genetic cause of mental retardation. Although overexpression of a gene(s) or gene cluster on human chromosome 21 (Chr 21) or the genome imbalance by Ts21 has been suggested to play a key role in bringing about the diverse DS phenotypes, little is known about the molecular mechanisms underlying the various phenotypes associated with DS. Four approaches have been used to model DS to investigate the gene dosage effects of an extra copy of Chr 21 on various phenotypes; 1) Transgenic mice overexpressing a single gene from Chr 21, 2) YAC/BAC/PAC transgenic mice containing a single gene or genes on Chr 21, 3) Mice with intact/partial trisomy 16, a region with homology to human Chr 21 and 4) Human Chr 21 transchromosomal (Tc) mice. Here we review our new model system for the study of DS using the Tc technology, including the biological effects of an additional Chr 21 in vivo and in vitro. more...
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- 2004
8. 1312 POSTER Content Analysis of Pamphlets Provided by Pharmaceutical Companies for the Medical Usage of Oncology Pharmaceuticals
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Saito, M., primary, Ryushima, Y., additional, Yonemori, K., additional, Hirakawa, A., additional, Nishigaki, R., additional, Makino, Y., additional, Yokote, N., additional, Ando, M., additional, Fujiwara, Y., additional, and Yamamoto, H., additional more...
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- 2011
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9. 14 - The possible involvement of mutagenic and carcinogenic heterocyclic amines in human cancer
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Totsuka, Y., Nishigaki, R., Sugimura, T., and Wakabayashi, K.
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- 2006
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10. Risk factors for development of postoperative hypertension
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Nishigaki, R., primary, Ito, A., additional, Kamei, J., additional, Takahashi, T., additional, and Fujii, E., additional
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- 2001
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11. Contribution of pharmacists with expertise in infectious diseases to appropriate individualized vancomycin dosing
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Nakashima, T., Koido, K., Baba, H., Otsuka, R., Okinaka, K., Sano, T., Nishigaki, R., Hashimoto, H., Otsuka, T., Esaki, M., and Terakado, H.
- Abstract
Background/aim: Dose adjustment of vancomycin (VCM) is important in improving clinical outcomes and avoiding adverse effects such as nephrotoxicity. Although pharmacist-managed VCM therapy has been reported to optimize treatment, there are no studies focused on pharmacist expertise to date. In this study, we compared the contribution of pharmacists trained for infectious diseases and general pharmacists to dose adjustment of VCM.Patients and methods:We retrospectively investigated VCM trough concentration after dose adjustment by both trained (n = 67) and general (without special training for infectious diseases; n = 85) pharmacists. We also compared the incidence of nephrotoxicity during VCM treatment in both groups.Results:The rate of achieving therapeutic VCM trough concentration (10–20 μg/mL) was higher in the trained group than in the control group (80.6vs.54.1%, p < 0.001). No significant differences in incidence of nephrotoxicity were observed between the two groups (p = 0.744). Trained pharmacists could contribute more successfully to the achievement of therapeutic VCM concentration ranges without increasing the risk of nephrotoxicity. more...
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- 2018
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12. Risk factors for development of postoperative hypertension
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Fujii E, Junzo Kamei, Ito A, Tomoko Takahashi, and Nishigaki R
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Adult ,Male ,Surgical stress ,Hemodynamics ,Postoperative Complications ,Japan ,Risk Factors ,Humans ,Medicine ,Risk factor ,Digestive System Surgical Procedures ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Incidence ,Hypertensive urgency ,Odds ratio ,Middle Aged ,Logistic Models ,Blood pressure ,Anesthesia ,Hypertension ,Regression Analysis ,Female ,business ,Body mass index ,Postoperative Hypertension - Abstract
One hundred and eighty-nine patients who underwent digestive tract surgery were studied to investigate risk factors for the development of postoperative hypertension. We examined factors related to maximum postoperative systolic blood pressure and postoperative hypertensive urgency, a sign of postoperative hypertension. Data collected included blood pressure, age, sex, body mass index (BMI), medical history, total water balance and grade of surgical stress. Maximum postoperative systolic blood pressure and incidence of postoperative hypertensive urgency were the dependent variables. Mean preoperative systolic blood pressure, age and BMI were significantly related to maximum postoperative systolic blood pressure and postoperative hypertensive urgency. In addition, the grade of surgical stress was significantly related to maximum postoperative systolic blood pressure. In analyses of multiple variables, the adjusted odds ratio for postoperative hypertensive urgency was 1.16 for every 1 mmHg increase in mean preoperative systolic blood pressure, 1.05 for every 1 year increase in age and 0.82 for every 1 kg/m2 increase in BMI. These findings may have important clinical implications for the prevention of postoperative hypertension. more...
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- 2001
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13. Recent advances in sonodynamic approach to cancer therapy
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Umemura, S., primary, Kawabata, K., additional, Sasaki, K., additional, Yumita, N., additional, Umemura, K., additional, and Nishigaki, R., additional
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- 1996
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14. Proteomic signatures and aberrations of mouse embryonic stem cells containing a single human chromosome 21 in neuronal differentiation: An in vitro model of down syndrome
- Author
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Kadota, M., Nishigaki, R., Wang, C.C., Toda, T., Shirayoshi, Y., Inoue, T., Gojobori, T., Ikeo, K., Rogers, M.S., and Oshimura, M.
- Subjects
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DOWN syndrome , *EMBRYONIC stem cells , *HUMAN cloning , *SPECTRUM analysis - Abstract
Neurodegeneration in fetal development of Down syndrome (DS) patients is proposed to result in apparent neuropathological abnormalities and to contribute to the phenotypic characteristics of mental retardation and premature development of Alzheimer disease. In order to identify the aberrant and specific genes involved in the early differentiation of DS neurons, we have utilized an in vitro neuronal differentiation system of mouse ES cells containing a single human chromosome 21 (TT2F/hChr21) with TT2F parental ES cells as a control. The paired protein extracts from TT2F and TT2F/hChr21 cells at several stages of neuronal differentiation were subjected to two-dimensional polyacrylamide gel electrophoresisprotein separation followed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry to identify the proteins differentially expressed between TT2F and TT2F/hChr21 cells. We provide here a novel set of specific gene products altered in early differentiating DS neuronal cells, which differs from that identified in adult or fetal brain with DS. The aberrant protein expression in early differentiating neurons, due to the hChr21 gene dosage effects or chromosomal imbalance, may affect neuronal outgrowth, proliferation and differentiation, producing developmental abnormalities in neural patterning, which eventually leads to formation of a suboptimal functioning neuronal network in DS. [Copyright &y& Elsevier] more...
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- 2005
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15. Sonodynamically induced effect of rose bengal on isolated sarcoma 180 cells.
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Umemura, Shin-ichiro, Yumita, Nagahiko, Umemura, Koshiro, Nishigaki, Ryuichiro, Umemura, S, Yumita, N, Umemura, K, and Nishigaki, R
- Abstract
Purpose: The ultrasonically induced effect of rose bengal (RB) on isolated tumor cells was investigated.Methods: Sarcoma 180 cells were suspended in air-saturated phosphate-buffered saline and exposed to ultrasound in standing wave mode for up to 60 s in the presence and absence of RB. Cell viability was determined by the ability to exclude trypan blue.Results: The rate of inducing cell damage by ultrasound was enhanced two to three times with 160 microM RB. while no cell damage was observed with RB alone. This enhancement was significantly inhibited by histidine.Conclusions: Ultrasonically induced in vitro cell damage was significantly enhanced by RB. A sonochemical mechanism may be suggested since the enhancement was significantly inhibited by an active oxygen scavenger. [ABSTRACT FROM AUTHOR] more...- Published
- 1999
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16. Structures and Biological Properties of DNA Adducts Derived from N-Nitroso Bile Acid Conjugates
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Totsuka, Y., Nishigaki, R., Enomoto, S., Takamura-Enya, T., Masumura, K.-i., Nohmi, T., Kawahara, N., Sugimura, T., and Wakabayashi, K.
- Abstract
A kind of N-nitrosobile acid conjugate, N-nitrosotaurocholic acid (NO-TCA), was incubated with calf thymus DNA, and formation of an adduct was detected by the 32P-postlabeling method under nuclease P1 conditions. To examine the nucleotides containing the adduct from NO-TCA, each of 2-deoxyribonucleotide 3-monophosphates (3-dAp, 3-dGp, 3-dCp, or 3-Tp) was incubated with NO-TCA. The same adduct spot was detected in the reaction of NO-TCA with 3-dCp. The structure of this adduct was determined to be 3-ethanesulfonic acid-dC by several spectrometry techniques. Moreover, bulky adducts containing bile acid moiety were also produced from the reaction of NO-TCA with 3-dCp and 3-dAp. From comparison with spectral data for authentic compounds, these adducts were concluded to be N4-cholyl-dC and N6-cholyl-dA. N4-Cholyl-dC and N6-cholyl-dA were also detected in calf thymus DNA treated with NO-TCA. In addition, 3-ethanesulfonic acid-dC and N4-deoxycholyl-dC were found to be produced from N-nitrosotaurodeoxycholic acid (NO-TDCA) with dC. NO-TCA and NO-TDCA induced mutations in Salmonella typhimurium TA100 but not in TA98. Mutational spectrum analysis revealed that NO-TCA induced G to A transitions predominantly. When NO-TCA (250 mg/kg) was singly administered to male Wistar rats by gavage, both ethanesulfonic acid-dC and N4-cholyl-dC could be detected in the glandular stomach and colon. The levels of ethanesulfonic acid-dC were 0.22−0.29 per 106 nucleotides, but values for N4-cholyl-dC were about 500-fold lower. These observations suggest that N-nitroso bile acid conjugates, NO-TCA and NO-TDCA, may induce G to A base substitutions in genes via DNA adduct formation, producing ethanesulfonic acid- and/or (deoxy)cholic acid-DNA and, therefore, may be related to human carcinogenesis as endogenous mutagens. more...
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- 2005
17. Analysis of HPRT and supF Mutations Caused by Pierisin-1, a Guanine Specific ADP-Ribosylating Toxin Derived from the Cabbage Butterfly
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Totsuka, Y., Kawanishi, M., Nishigaki, R., Matsukawa, K., Yagi, T., Takamura-Enya, T., Watanabe, M., Sugimura, T., and Wakabayashi, K.
- Abstract
Pierisin-1, an ADP-ribosylating toxin derived from the cabbage butterfly, Pieris rapae, induces apoptosis in various mammalian cell lines. We recently reported that the target for ADP ribosylation by pierisin-1 is the 2-deoxyguanosine residue in DNA. To examine whether pierisin-1 would induce mutations in mammalian cell genes, we conducted a mutational analysis for the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in pierisin-1-treated Chinese hamster lung (CHL) cells. N2-(ADP-ribos-1-yl)-2-deoxyguanosine was detected by the 32P-postlabeling method in CHL cells after treatment with pierisin-1 at doses of 2−32 ng/mL; adduct levels were 1.1−12.0 per 106 nucleotides. Pierisin-1 induced mutations in the HPRT gene dose-dependently, and the frequency was 38 times higher than the control, at a dose of 32 ng/mL. To confirm that mono(ADP-ribosyl)ated dG itself leads to mutations, the pierisin-1-treated DNA of plasmid pMY189 bearing the supF gene was used for mutational analysis. The mutation frequency of the supF gene treated with 2−8 μg/mL of pierisin-1 was 17−40-fold the control value. Mutation spectrum analysis showed that single base substitutions dominated in both HPRT and supF genes. Among these, transversions were predominant, and more than 70% of the base substitutions occurred at G:C base pairs in both genes. The most frequent mutations were G:C to C:G, followed by G:C to T:A in HPRT gene, whereas G:C to T:A transversions dominated in the supF gene. Our results indicate that pierisin-1 produced N2-(ADP-ribos-1-yl)-2-deoxyguanosine and this guanine-adduct could lead to mutations in the HPRT and supF genes. These findings could provide very useful information for understanding the biological significance of pierisin-1. more...
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- 2003
18. Effect of chlorpromazine on intestinal absorption of sulfamethoxazole in rats
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Manabu Hanano, Tatsuji Iga, Hee Chung Yong, and Nishigaki R
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Male ,Cell Membrane Permeability ,Sulfamethoxazole ,Chlorpromazine ,Absorption (skin) ,Pharmacology ,Rat Small Intestine ,Intestinal absorption ,medicine ,Animals ,Intestinal Mucosa ,Phospholipids ,Total blood ,Chemistry ,Proteins ,Rats, Inbred Strains ,Blood flow ,Hydrogen-Ion Concentration ,Rats ,Kinetics ,Intestinal Absorption ,Regional Blood Flow ,Perfusion ,medicine.drug - Abstract
The effect of chlorpromazine (CPZ) on the intestinal absorption of sulfamethoxazole (SMZ) was studied in isolated perfused rat small intestine by comparing two determinants, i.e. the epithelial permeability and the intestinal blood flow. The appearance rate of SMZ in blood in the presence of CPZ decreased to one-half of the control without CPZ. The pH of perfusion solution was significantly decreased by CPZ after 10 min perfusion. According to the Winne's absorption model, CPZ did not change the apparent epithelial permeability of SMZ, but decreased the epithelial permeability of unionized SMZ due to the decrease in the pH of perfusion solution by CPZ. It was also suggested that CPZ decreased the fraction of the total blood flow rate in the subepithelial capillaries to less than one-half. more...
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- 1983
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19. Structure of DNA Adduct Formed with Aminophenylnorharman, Being Responsible for the Comutagenic Action of Norharman with Aniline
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Totsuka, Y., Takamura-Enya, T., Kawahara, N., Nishigaki, R., Sugimura, T., and Wakabayashi, K.
- Abstract
A mutagenic heterocyclic amine (HCA), 9-(4-aminophenyl)-9H-pyrido[3,4-b]indole (aminophenylnorharman, APNH), is produced in the presence of S9 mix by the reaction of norharman and aniline, both of which are nonmutagenic and abundantly present in our environment. It has been previously reported that APNH-DNA adducts were detected in DNA of Salmonella typhimurium strain incubated with APNH and S9 mix. In the present study, we examined the structures of APNH-DNA adducts using the 32P-postlabeling method and various spectrometry techniques. When the reaction mixture of N-acetoxy-APNH and 2-deoxyguanosine 3-monophosphate (3-dGp) was analyzed, three adduct spots (two major and one minor) were observed by 32P-postlabeling under modified-standard conditions. No adduct formation was observed for reaction mixtures of N-acetoxy-APNH with 3-dAp, 3-dTp, or 3-dCp. The two major adduct spots (spots 1 and 2) detected by TLC were extracted and subjected to HPLC along with the standards 3,5-pdGp-C8-APNH and 5-pdG-C8-APNH, which were independently chemically synthesized. On the basis of the results of co-chromatography, spots 1 and 2 were identified to be 5-monophosphate and 3,5-diphosphate forms of dG-C8-APNH. When the extract of spot 2 (3,5-pdGp-C8-APNH) was further digested with nuclease P1 and phosphodiesterase I, a spot corresponding to spot 1 (5-pdG-C8-APNH) was newly observed on TLC. From these observations, both of the two major spots were concluded to be dG-C8-APNH. A similar DNA adduct pattern to that apparent in vitro was observed in various organs of F344 rats fed 40 ppm of APNH for 4 weeks. The levels of APNH-DNA adducts were highest in the liver and colon, with RAL values of 1.31 ± 0.26 and 1.32 ± 0.11 adducts/107nucleotides, respectively. Thus, APNH was demonstrated to form DNA adducts primarily at the C-8 position of guanine residues in vitro and in vivo, like other mutagenic and carcinogenic HCAs. more...
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- 2002
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20. Sonodynamically-induced cell damage with fluorinated anthracycline derivative, FAD104
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Yumita, N., Umemura, S.-I., Kaneuchi, M., Okano, Y., Magario, N., Ishizaki, M., Shimizu, K., Sano, Y., Umemura, K., and Nishigaki, R.
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- 1998
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21. Sonodynamically-induced in vitro cell damage enhanced by adriamycin
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Umemura, S.-I., Yumita, N., Okano, Y., Kaneuchi, M., Magario, N., Ishizaki, M., Shimizu, K., Sano, Y., Umemura, K., and Nishigaki, R.
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- 1997
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22. Sonodynamically induced antitumor effect of pheophorbide a
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Umemura, K., Yumita, N., Nishigaki, R., and Umemura, S.-I.
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- 1996
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23. The effect of dosage form on absorption of vitamin A into lymph
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Shoji Awazu, Nishigaki R, Tohru Fuwa, and Manabu Hanano
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Vitamin ,Male ,medicine.medical_specialty ,Administration, Oral ,Absorption (skin) ,Thoracic duct ,Dosage form ,Absorption ,chemistry.chemical_compound ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Triolein ,Vitamin A ,Micelles ,Triglycerides ,Broad band ,General Chemistry ,General Medicine ,Rats ,Solutions ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Emulsions ,Lymph - Abstract
Some effects of dosage form on absorption of vitamin A into thoracic duct were studied in rats fed vitamin A. Forty-five % of administered vitamin A was recovered in lymph when vitamin A was given in micellar solution form, while 29% of administered vitamin A was recovered when vitamin A was given in triolein solution form. The time courses of appearance of vitamin A in lymph of these two kinds of preparation were very different one another. Vitamin A appearance in lymph showed a sharp peak between 1 and 2 hr after the administration in micellar solution form and indicated the almost complete absorption of vitamin A, while it showed a broad band over 4 hr after the administration in oily solution form. The time courses of vitamin A in serum did not exactly reflect those in lymph. more...
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- 1976
24. Determination of extraction constant, true partition coefficient and formation constant of ion-pair complexes of quaternary ammonium salts, tetrabutylammonium bromide and isopropamide iodide.with some organic anions by a solvent extraction technique
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Shim, C.K., primary, Nishigaki, R., additional, Iga, T., additional, and Hanano, M., additional
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- 1981
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25. Sonodynamic approach to tumor treatment
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Umemura, S., primary, Kawabata, K., additional, Yumita, N., additional, Nishigaki, R., additional, and Umemura, K., additional
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26. Sonochemical activation of hematoporphyrin: a potential modality for cancer treatment
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Umemura, S.-I., primary, Yumita, N., additional, Nishigaki, R., additional, and Umemura, K., additional
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27. Sonochemical activation of hematoporphyrin: a potential modality for cancer treatment.
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Umemura, S.-I., Yumita, N., Nishigaki, R., and Umemura, K.
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- 1989
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28. Sonodynamic approach to tumor treatment.
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Umemura, S., Kawabata, K., Yumita, N., Nishigaki, R., and Umemura, K.
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- 1992
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29. In vitro hemolysis using a switched spiral focal field.
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Umemura, S., Kawabata, K., Magario, N., Yumita, N., Nishigaki, R., and Unemura, K.
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- 1991
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30. Correction: Urinary dipeptidase 1 and trefoil factor 1 are promising biomarkers for early diagnosis of colorectal cancer.
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Okuda Y, Shimura T, Abe Y, Iwasaki H, Nishigaki R, Fukusada S, Sugimura N, Kitagawa M, Yamada T, Taguchi A, and Kataoka H
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- 2024
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31. BRAF K601E-mutated metastatic colorectal cancer in response to combination therapy with encorafenib, binimetinib, and cetuximab: A case report.
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Sasaki M, Shimura T, Nishie H, Kuroyanagi K, Kanno T, Fukusada S, Sugimura N, Mizuno Y, Nukui T, Uno K, Kojima Y, Nishigaki R, Tanaka M, Ozeki K, Kubota E, and Kataoka H
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Background: BRAF mutation has been recognized as a negative prognostic marker for metastatic colorectal cancer (mCRC), but these data are from common BRAF V600E-mutated mCRC. Combination therapy of BRAF inhibitor and anti-epidermal growth factor receptor (EGFR) antibody has been approved for BRAF V600E-mutated mCRC. However, BRAF non-V600 mutations are rare mutations, and their clinical behavior is not understood. Moreover, the BRAF K601E mutation is extremely rare in mCRC, and there have been no reports on its specific treatment., Case Summary: Herein, we report the case of a 59-year-old female with super aggressive mCRC with multiple metastases, which extended to whole body including mediastinal to abdominal lymph nodes, bones, pleura, and peritoneum. The companion diagnostics of tumor tissues showed RAS/BRAF wild-type without microsatellite instability. She received chemotherapy with mFOLFOX6 (oxaliplatin plus infusional 5-fluorouracil [5-FU] and leucovorin) plus panitumumab, following FOLFIRI (irinotecan plus infusional 5-FU and leucovorin) plus ramucirumab. For the next regimen selection, a comprehensive genomic profiling panel was performed and revealed a BRAF K601E mutation, which was not covered in the initial companion diagnostics. After disease progression, a combination of encorafenib, binimetinib, and cetuximab was selected as third-line chemotherapy. The serum levels of tumor markers were immediately decreased accompanied by improvements in pleural effusion and ascites. However, the disease progressed again, and best supportive care was done instead., Conclusion: This case offers novel insights into the clinical behaviors of BRAF non-V600E-mCRC, potentially advancing personalized therapy for rare and aggressive cases., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.) more...
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- 2024
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32. Urinary dipeptidase 1 and trefoil factor 1 are promising biomarkers for early diagnosis of colorectal cancer.
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Okuda Y, Shimura T, Abe Y, Iwasaki H, Nishigaki R, Fukusada S, Sugimura N, Kitagawa M, Yamada T, Taguchi A, and Kataoka H
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- Humans, Male, Female, Middle Aged, Aged, Case-Control Studies, Neoplasm Staging, Enzyme-Linked Immunosorbent Assay, Adult, Sensitivity and Specificity, Adenoma diagnosis, Adenoma urine, GPI-Linked Proteins, Colorectal Neoplasms diagnosis, Colorectal Neoplasms urine, Biomarkers, Tumor urine, Biomarkers, Tumor blood, Early Detection of Cancer methods, Trefoil Factor-1 urine, Dipeptidases urine, Dipeptidases blood
- Abstract
Background: Currently utilized serum tumor markers and fecal immunochemical tests do not have sufficient diagnostic power for colorectal cancer (CRC) due to their low sensitivities. To establish non-invasive urinary protein biomarkers for early CRC diagnosis, we performed stepwise analyses employing urine samples from CRCs and healthy controls (HCs)., Methods: Among 474 urine samples, 363 age- and sex-matched participants (188 HCs, 175 stage 0-III CRCs) were randomly divided into discovery (16 HCs, 16 CRCs), training (110 HCs, 110 CRCs), and validation (62 HCs, 49 CRCs) cohorts., Results: Of the 23 urinary protein candidates comprehensively identified from mass spectrometry in the discovery cohort, urinary levels of dipeptidase 1 (uDPEP1) and Trefoil factor1 (uTFF1) were the two most significant diagnostic biomarkers for CRC in both training and validation cohorts using enzyme-linked immunosorbent assays. A urinary biomarker panel comprising uDPEP1 and uTFF1 significantly distinguished CRCs from HCs, showing area under the curves of 0.825-0.956 for stage 0-III CRC and 0.792-0.852 for stage 0/I CRC. uDPEP1 and uTFF1 also significantly distinguished colorectal adenoma (CRA) patients from HCs, with uDPEP1 and uTFF1 increasing significantly in the order of HCs, CRA patients, and CRC patients. Moreover, expression levels of DPEP1 and TFF1 were also significantly higher in the serum and tumor tissues of CRC, compared to HCs and normal tissues, respectively., Conclusions: This study established a promising and non-invasive urinary protein biomarker panel, which enables the early detection of CRC with high sensitivity., (© 2024. Japanese Society of Gastroenterology.) more...
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- 2024
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33. Unanticipated pathological clearance in two cases of clinical T4b dMMR/MSI-h advanced colorectal cancer: the potential of immune checkpoint inhibitors despite positive positron-emission tomography results.
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Nakamura D, Yanagita T, Fujii Y, Watanabe K, Suzuki T, Ushigome H, Nishigaki R, Sugimura N, Tanaka M, Ogawa R, Takahashi H, Shimura T, Hotta Y, Matsuo Y, Kondo M, Furukawa-Hibi Y, and Takiguchi S
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Background: The standard treatment for colorectal cancer consists of surgery and chemotherapy, which can be combined to improve outcomes. Immune checkpoint inhibitors (ICI) are a significant advancement in the standard treatment of metastatic, unresectable colorectal cancer with deficient mismatch repair (dMMR). However, limited data are available about the use of ICI in the neoadjuvant and conversion settings. Here, we present two cases treated with ICI., Case Presentation: Case 1: A 75-year-old male with a large, borderline resectable rectal cancer diagnosed as cT4bN1bM0 who underwent neoadjuvant chemotherapy, followed by combination ICI consisting of ipilimumab and nivolumab. After four courses of ICI, the tumor significantly shrank, but positron emission tomography still showed a positive result and R0 resection was performed. Pathological analysis revealed no residual cancer cells. The patient has been monitored without adjuvant chemotherapy, and no recurrences have occurred after one year. Case 2: A 60-year-old male with locally advanced sigmoid colon cancer who received neoadjuvant treatment with pembrolizumab. The tumor partially shrank after three courses, and continued pembrolizumab monotherapy resulted in further tumor shrinkage which still showed positive positron emission tomography. Curative sigmoidectomy with partial resection of the ileum and bladder was performed, and the pathological outcome was pCR. There was no viable tumor in the specimen. The patient has been monitored without adjuvant chemotherapy for six months, and no recurrence has been observed., Conclusions: The present study reports two cases, including a large, borderline resectable rectal cancer after failure of chemotherapy followed by combination treatment with nivolumab and ipilimumab and one case of sigmoid colon cancer after pembrolizumab treatment, which resulted in pathological complete response. However, it remains unknown whether ICI therapy can replace surgery or diminish the optimal extent of resection, or whether adjuvant chemotherapy is needed after surgery in the case of achieving pCR after ICI therapy. Overall, this case report suggests that ICI before colorectal surgery can be effective and potentially a 'watch-and-wait" strategy could be used for cases in which ICI is effective., (© 2024. The Author(s).) more...
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- 2024
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34. Ulcerative Colitis with Oral Extension of Squamous Epithelium.
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Ozeki K, Nishigaki R, Kanno T, and Kataoka H
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- Humans, Epithelium, Colitis, Ulcerative complications, Carcinoma, Squamous Cell
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- 2024
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35. Osteopontin secreted from obese adipocytes enhances angiogenesis and promotes progression of pancreatic ductal adenocarcinoma in obesity.
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Fukusada S, Shimura T, Natsume M, Nishigaki R, Okuda Y, Iwasaki H, Sugimura N, Kitagawa M, Katano T, Tanaka M, Ozeki K, Kubota E, Hayashi K, and Kataoka H
- Subjects
- Humans, Mice, Animals, Osteopontin metabolism, Endothelial Cells metabolism, Angiogenesis, Adipocytes metabolism, Adipocytes pathology, Obesity complications, Obesity metabolism, Cell Proliferation, Pancreatic Neoplasms pathology, Carcinoma, Pancreatic Ductal pathology
- Abstract
Purpose: Obesity is a risk factor and poor prognostic factor for pancreatic ductal adenocarcinoma (PDAC), but the underlying mechanisms remain unclear., Methods: PDAC cells and obese visceral adipocytes (O-Ad) derived from mice and humans were used to analyze interactions between the two cell types, and human microvascular endothelial cells were used for angiogenesis assay. A xenograft mouse model with subcutaneously injected PDAC cells was used for animal studies. The relationship between visceral fat and prognosis was analyzed using resected tissues from PDAC patients with and without obesity., Results: Conditioned media (CM) from O-Ad significantly increased PDAC cell growth and migration and angiogenic capacity in both human and mice cells, and blocking osteopontin (OPN) in O-Ad canceled O-Ad-induced effects in both mouse and human cells. In addition, O-Ad directly increased the migratory and tube-forming capacities of endothelial cells, while blocking OPN canceled these effects. O-Ad increased AKT phosphorylation and VEGFA expression in both PDAC and endothelial cells, and OPN inhibition in O-Ad canceled those O-Ad-induced effects. In the xenograft model, PDAC tumor volume was significantly increased in obese mice compared with lean mice, whereas blocking OPN significantly inhibited obesity-accelerated tumor growth. OPN expression in adipose tissues adjacent to human PDAC tumor was significantly higher in obese patients than in non-obese patients. In PDAC patients with obesity, high OPN expression in adipose tissues was significantly associated with poor prognosis., Conclusion: Obese adipocytes trigger aggressive transformation in PDAC cells to induce PDAC progression and accelerate angiogenesis via OPN secretion., (© 2023. Springer Nature Switzerland AG.) more...
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- 2024
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36. Clinical Impact of Proton Pump Inhibitor and Potassium-Competitive Acid Blocker for Predicting the Curability of Endoscopic Resection in Ulcerative Early Gastric Cancer.
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Uno K, Shimura T, Inaguma S, Kuroyanagi K, Nishigaki R, Kanno T, Sasaki M, Fukusada S, Sugimura N, Mizuno Y, Nukui T, Kojima Y, Tanaka M, Ozeki K, Kubota E, Takahashi S, and Kataoka H
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- Humans, Male, Female, Retrospective Studies, Middle Aged, Aged, Gastric Mucosa pathology, Gastric Mucosa surgery, Gastric Mucosa diagnostic imaging, Treatment Outcome, Gastroscopy methods, Adult, Neoplasm Invasiveness, Aged, 80 and over, Early Detection of Cancer methods, Stomach Neoplasms surgery, Stomach Neoplasms pathology, Stomach Neoplasms drug therapy, Proton Pump Inhibitors therapeutic use, Proton Pump Inhibitors administration & dosage, Endoscopic Mucosal Resection methods, Stomach Ulcer drug therapy, Stomach Ulcer etiology, Stomach Ulcer pathology, Stomach Ulcer diagnosis
- Abstract
Introduction: Endoscopic diagnosis is essential for predicting the curability of early gastric cancer (EGC; R0 resection) before treatment, but the relationship between ulcerative lesions and clinical outcomes remains unclear. We aimed to investigate the effect of proton pump inhibitor (PPI) or potassium-competitive acid blocker (P-CAB) on the morphological changes of ulcerative EGCs and its relevance to the clinical outcomes., Methods: Altogether, 143 patients with differentiated ulcerative EGC that were resected by endoscopic submucosal dissection were retrospectively identified and divided into the following two cohorts depending on their PPI/P-CAB administration status: PPI/P-CAB (n = 76) and non-PPI/P-CAB (n = 67) cohorts. Furthermore, in each cohort, the patients were further divided into the improved and unimproved subgroups based on the ulcerative changes., Results: In the PPI/P-CAB cohort, the deep submucosal invasion and lymphovascular invasion rates were significantly higher in the unimproved subgroup than in the improved subgroup, resulting in a significantly lower R0 resection rate. Contrarily, no significant differences were found between the two subgroups in the non-PPI/P-CAB cohort. The significance of PPI/P-CAB administration was observed only in the ulcerative EGCs with open-type atrophy (R0 resection rate; improved vs. unimproved, 90.9% vs. 48.0%, p = 0.001). When the finding of improved ulcer with PPI/P-CAB administration was used as the indication of endoscopic resection in ulcerative EGCs with open-type atrophy, high sensitivity (78.9%) and accuracy (76.3%) rates for the curability were observed, which were higher than those of conventional endoscopic diagnosis alone (p = 0.021)., Conclusion: PPI or P-CAB administration might contribute to the potential selection of ulcerative EGCs, enabling endoscopic curative resection., (© 2024 S. Karger AG, Basel.) more...
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- 2024
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37. [Influence of the Use of a Closed System Drug Transfer Device on the Preparation Time of Anticancer Drugs].
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Nakashima T, Tsukiji K, Kubo A, Nishigaki R, Watabe D, Saito Y, Akagi T, and Hashimoto H
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- Time Factors, Humans, Occupational Exposure, Needles, Molecular Targeted Therapy, Antineoplastic Agents administration & dosage, Drug Compounding methods
- Abstract
A closed system drug transfer device (CSTD) helps to minimize unnecessary exposure of healthcare workers such as pharmacists to hazardous drugs. One of the concerns in using CSTDs to prepare anticancer drugs is their influence on preparation time. Therefore, we compared the time needed to prepare anticancer drugs with the CSTDs NEOSHIELD
® and BD PhaSeal® system and with an injection needle. In the comparison of NEOSHIELD® and an injection needle, the preparation time of the liquid formulations of the cytotoxic drugs irinotecan, eribulin, cisplatin, docetaxel, and paclitaxel was significantly shorter with the injection needle and that of gemcitabine was significantly shorter with NEOSHIELD® , but that of oxaliplatin, carboplatin, and doxorubicin was not significantly different between the two methods; the preparation time of the liquid formulations of the molecular-targeted drugs atezolizumab, obinutuzumab, cetuximab, daratumumab and vorhyaluronidase alfa, nivolumab, ramucirumab, and rituximab was significantly shorter with NEOSHIELD® and that of bevacizumab and pembrolizumab was significantly shorter with the injection needle; and the preparation time of the lyophilized formulation of cytotoxic and molecular-targeted drugs was not significantly different between the two methods. In the comparison of NEOSHIELD® and BD PhaSeal® system, the preparation time of cyclophosphamide and ifosfamide was significantly shorter with NEOSHIELD® , but that of bendamustine was not significantly different between the two CSTDs. In conclusion, these results suggest that the preparation time with CSTDs may be similar to or shorter than that with an injection needle, depending on the type of CSTD and the drug formulation and type. more...- Published
- 2024
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38. Characteristic endoscopic findings of gastrointestinal malignant lymphomas other than mucosa-associated lymphoid tissue lymphoma.
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Kanno T, Katano T, Shimura T, Nishigaki R, Kojima Y, Sasaki M, Okuda Y, Sugimura N, Fukusada S, Mizuno Y, Iwasaki H, Nishie H, Tanaka M, Ozeki K, Kubota E, Tanida S, and Kataoka H
- Subjects
- Humans, Retrospective Studies, Ulcer, Gastrointestinal Neoplasms diagnosis, Gastrointestinal Neoplasms pathology, Lymphoma, B-Cell, Marginal Zone diagnosis, Lymphoma, B-Cell, Marginal Zone pathology, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Background and Study Aims: The gastrointestinal (GI) tract is the most common site of extra-nodal involvement for non-Hodgkin's lymphoma (NHL). The features of GI NHLs remain unclear. The aim of this study was to clarify endoscopic characteristics of GI NHLs., Patients and Methods: We retrospectively analyzed the morphological characteristics of 63 GI malignant lymphomas other than mucosa-associated lymphoid tissue lymphoma. Lesions were diagnosed between 2005 and 2020. Macroscopic findings were classified into five subtypes: superficial (S); protruding without ulcer (P); protruding with ulcer (PU); fungating (F); and multiple nodules (MN)., Results: Thirty-one lesions in the stomach were classified as S type in 3 cases (9.6%), P type in 6 (19%), PU type in 13 (42%), and F type in 9 (29%). In the stomach, the ulcerated phenotype was more frequent for diffuse large B-cell lymphoma (DLBCL) (89.5%) than for other histological types (41.7%; P = 0.01). In the intestine, 23 tumors were classified as S type in 4 cases (17%), P type in 1 (4%), PU type in 6 (26%), F type in 1 (4%), and MN in 11 (48%). Eleven of the 14 cases (78.6%) of intestinal follicular lymphoma lesions showed MN type. In the colon, eight tumors were classified as S type in 2 cases (25%), P type in 2 (25%), PU type in 1 (13%), and F type in 3 (38%)., Conclusion: We have clarified the endoscopic features of GI NHL using macroscopic classifications. The ulcerated phenotype was the most frequent endoscopic finding for DLBCL., Competing Interests: The authors declare that they have no conflict of interest, (© Acta Gastro-Enterologica Belgica.) more...
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- 2022
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39. A Novel Urinary miRNA Biomarker for Early Detection of Colorectal Cancer.
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Iwasaki H, Shimura T, Kitagawa M, Yamada T, Nishigaki R, Fukusada S, Okuda Y, Katano T, Horike SI, and Kataoka H
- Abstract
Since noninvasive biomarkers as an alternative to invasive colonoscopy to detect colorectal cancer (CRC) are desired, we conducted this study to determine the urinary biomarker consisting of microRNAs (miRNAs). In total, 415 age- and sex-matched participants, including 206 patients with CRC and 209 healthy controls (HCs), were randomly divided into three groups: (1) the discovery cohort (CRC, n = 3; HC, n = 6); (2) the training cohort (140 pairs); and (3) the validation cohort (63 pairs). Among 11 urinary miRNAs with aberrant expressions between the two groups, miR-129-1-3p and miR-566 were significantly independent biomarkers that detect CRC. The panel consisting of two miRNAs could distinguish patients with CRC from HC participants with an area under the curve (AUC) = 0.811 in the training cohort. This panel showed good efficacy with an AUC = 0.868 in the validation cohort. This urinary biomarker combining miR-129-1-3p and miR-566 could detect even stage 0/I CRC effectively with an AUC = 0.845. Moreover, the expression levels of both miR-129-1-3p and miR-566 were significantly higher in primary tumor tissues than in adjacent normal tissue. Our established novel biomarker consisting of urinary miR-129-1-3p and miR-566 enables noninvasive and early detection of CRC. more...
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- 2022
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40. Novel and Simple Criteria for Predicting Mortality of Peptic Ulcer Disease.
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Iwasaki H, Shimura T, Yamada T, Nishigaki R, Okuda Y, Fukusada S, Ozeki T, Kitagawa M, Katano T, Tanaka M, Nishie H, Ozeki K, Kubota E, Tanida S, and Kataoka H
- Subjects
- Area Under Curve, Humans, Risk Assessment, Risk Factors, Gastrointestinal Hemorrhage, Peptic Ulcer diagnosis
- Abstract
Objective Conventional risk scores of peptic ulcer disease (PUD) are based on many parameters, and their application in clinical practice is therefore limited. The aim of this study was to establish simple and reliable criteria for predicting PUD-associated mortality. Methods A total of 499 patients with PUD were divided into 2 groups: the training cohort (n=333) and the validation cohort (n=166). To minimize selection bias due to missing values, we used imputed datasets generated by the multiple imputation method (training-cohort dataset, n=33,300; validation-cohort dataset, n=16,600). Results In the training-cohort dataset, the heart rate-to-systolic blood pressure ratio (HR/SBP) and serum albumin (s-Alb) level were significant independent predictive factors for mortality according to the multivariate analysis [HR/SBP, odds ratio (OR): 1.72; 95% confidence interval (CI), 1.06-2.80, p=0.028; s-Alb, OR: 0.23, 95% CI, 0.11-0.51, p<0.001]. The model comprising HR/SBP and s-Alb was able to detect mortality due to PUD with an area under the curve (AUC) of 0.855. In the validation-cohort dataset, this model also showed good efficacy with an AUC of 0.835. The novel criteria combining HR/SBP and s-Alb developed by a decision tree analysis showed 73.3% sensitivity and 87.6% specificity for predicting mortality in the total-cohort dataset. Our criteria were superior to the Glasgow Blatchford and Rockall scores and similar to the AIMS65 and Progetto Nazionale Emorragia Digestiva scores for predicting mortality. Conclusion The combination of the HR/SBP ratio and s-Alb level is a good predictor of mortality in patients with PUD. more...
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- 2021
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41. Urinary microRNA biomarkers for detecting the presence of esophageal cancer.
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Okuda Y, Shimura T, Iwasaki H, Fukusada S, Nishigaki R, Kitagawa M, Katano T, Okamoto Y, Yamada T, Horike SI, and Kataoka H
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- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor urine, Case-Control Studies, Cell Line, Tumor, Esophageal Neoplasms pathology, Esophageal Neoplasms urine, Esophageal Squamous Cell Carcinoma pathology, Esophageal Squamous Cell Carcinoma urine, Female, Humans, Male, Middle Aged, Young Adult, Esophageal Neoplasms diagnosis, Esophageal Squamous Cell Carcinoma diagnosis, MicroRNAs urine
- Abstract
Esophageal cancer (EC) including esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC) generally exhibits poor prognosis; hence, a noninvasive biomarker enabling early detection is necessary. Age- and sex-matched 150 healthy controls (HCs) and 43 patients with ESCC were randomly divided into two groups: 9 individuals in the discovery cohort for microarray analysis and 184 individuals in the training/test cohort with cross-validation for qRT-PCR analysis. Using 152 urine samples (144 HCs and 8 EACs), we validated the urinary miRNA biomarkers for EAC diagnosis. Among eight miRNAs selected in the discovery cohort, urinary levels of five miRNAs (miR-1273f, miR-619-5p, miR-150-3p, miR-4327, and miR-3135b) were significantly higher in the ESCC group than in the HC group, in the training/test cohort. Consistently, these five urinary miRNAs were significantly different between HC and ESCC in both training and test sets. Especially, urinary miR-1273f and miR-619-5p showed excellent values of area under the curve (AUC) ≥ 0.80 for diagnosing stage I ESCC. Similarly, the EAC group had significantly higher urinary levels of these five miRNAs than the HC group, with AUC values of approximately 0.80. The present study established novel urinary miRNA biomarkers that can early detect ESCC and EAC. more...
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- 2021
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42. Safety and Evidence of Off-Label Use of Approved Drugs at the National Cancer Center Hospital in Japan.
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Bun S, Yonemori K, Sunadoi H, Nishigaki R, Noguchi E, Okusaka T, Nishida T, and Fujiwara Y
- Subjects
- Cancer Care Facilities, Japan, Off-Label Use, Retrospective Studies, Tokyo, Neoplasms drug therapy, Pharmaceutical Preparations
- Abstract
Purpose: In Japan, for pharmaceutical products to be covered by public medical insurance, their efficacy and safety must first be confirmed in clinical trials. To our knowledge, this study is the first investigation into the off-label use of pharmaceutical products at a high-volume cancer treatment center in Japan. The objective of this study is to explore the framework necessary for future pharmaceutical development and regulatory approval in the field of oncology by surveying the frequency of and indications for off-label use of pharmaceutical products at the National Cancer Center Hospital in Tokyo, Japan., Materials and Methods: The pharmaceutical products used off-label in daily practice from 2003 to 2015 at the National Cancer Center Hospital were retrospectively examined based on applications that had been submitted to an internal review committee requesting off-label use., Results: A total of 1,390 applications were submitted during the study period. The most frequently used supporting documents were the results of phase II trials, followed by case series and phase III trials. The cancer most frequently treated with off-label drugs was sarcoma (15.1%), followed by urologic cancer (9.2%) and GI cancer (7.6%)., Conclusion: As reported in previous studies, pharmaceutical products were generally used off-label for the treatment of rare cancers, for which large-scale clinical trials are difficult to conduct. Continued discussion of the types of frameworks that are needed to guide pharmaceutical development is necessary., Competing Interests: Conflicts of Interest Statement:The authors have declared that no competing interests exist. more...
- Published
- 2021
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43. Relationship between Immunophenotype and Clinicopathological Findings for Superficial Nonampullary Duodenal Epithelial Tumor.
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Fukusada S, Shimura T, Iwasaki H, Okuda Y, Katano T, Nishigaki R, Ozeki T, Kitagawa M, Nishie H, Tanaka M, Ozeki K, Kubota E, Tanida S, and Kataoka H
- Subjects
- Duodenum pathology, Humans, Hyperplasia pathology, Stomach, Adenocarcinoma pathology, Duodenal Neoplasms pathology
- Abstract
Introduction: The natural history and prognosis of superficial nonampullary duodenal epithelial tumors (SNADETs) remain uncertain. We elucidated the relationship between immunophenotype and clinicopathological features., Materials and Methods: A total of 98 SNADETs were divided into 3 groups according to immunohistochemical findings: gastric phenotype (G type), gastrointestinal phenotype (GI type), and intestinal phenotype (I type). Cellular dysplasia was divided into low-grade dysplasia and high-grade dysplasia/adenocarcinoma (≥HGD). White opaque substance (WOS) deposition was categorized into diffuse WOS, partial WOS, and no WOS, based on endoscopic findings., Results: Of the 98 SNADETs, 4 lesions (4.1%) were G type, 32 lesions (32.7%) were GI type, and 62 lesions (63.2%) were I type. All G-type SNADETs were located in the oral side of the papilla including the bulb, and the rate of bulbar lesions was significantly higher in the G type than in the GI and I types (p = 0.004). The most frequent type of WOS was no WOS (4/4, 100%) for G type, partial WOS (19/32, 59.4%) for GI type, and diffuse WOS (34/62, 54.8%) for I type (p < 0.001), and loss of intestinal character was significantly correlated with WOS deficiency. GI/I-type SNADETs with partial or no WOS and G-type SNADETs were associated with ≥HGD. Additionally, the frequency of ≥HGD lesion was significantly higher in the CD10-negative group than in the CD10-positive group (57.1 vs. 19.8%, p = 0.043)., Conclusion: Pathological intestinal character was correlated with the presence of WOS, and CD10 loss was associated with malignant potential of SNADETs., (© 2021 S. Karger AG, Basel.) more...
- Published
- 2021
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44. Serum Exosomal Dicer Is a Useful Biomarker for Early Detection of Differentiated Gastric Adenocarcinoma.
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Okuda Y, Shimura T, Iwasaki H, Katano T, Kitagawa M, Nishigaki R, Fukusada S, Natsume M, Tanaka M, Nishie H, Ozeki K, Yamada T, and Kataoka H
- Subjects
- Biomarkers, Tumor, Humans, Adenocarcinoma diagnosis, DEAD-box RNA Helicases blood, Exosomes, MicroRNAs, Ribonuclease III blood, Stomach Neoplasms diagnosis
- Abstract
Background and Aim: A recent basic study identified that Dicer is contained in exosomes derived from cancer cells and plays crucial roles in microRNA maturation and cancer development. Based on this novel basic concept, we analyzed the usefulness of serum exosomal Dicer as a diagnostic biomarker for gastrointestinal cancers., Methods: Enrolled participants (691) were categorized into 3 groups: gastric cancer (GC) cohort, 183 patients (90 healthy controls (HCs) and 93 GC patients); esophageal cancer (EC) cohort, 115 patients (90 HCs and 25 EC patients); and colorectal cancer (CRC) cohort, 188 patients (92 HCs and 96 CRC patients) after age- and sex matching using the propensity score. The quality of isolated serum exosomes was validated with an electron microscope, particle size analyzer, and exosome marker, CD63., Results: Serum exosomal Dicer was significantly higher in the GC group than in the HC group (p = 0.004), whereas no significant differences were found in both EC and CRC cohorts. Serum exosomal Dicer was significantly higher in only differentiated gastric adenocarcinoma and not in the undifferentiated type. Moreover, serum exosomal Dicer showed no significant differences regardless of Helicobacter pylori (H. pylori) status. The biomarker panel combining serum exosomal Dicer with H. pylori status distinguished between HC and differentiated GC patients with an area under the curve (AUC) of 0.762. As for early-stage diagnosis, this combination distinguished between HC and stage I differentiated GC with an AUC = 0.758., Conclusions: Serum exosomal Dicer is a potential noninvasive diagnostic biomarker for early detection of differentiated gastric adenocarcinoma., (© 2020 S. Karger AG, Basel.) more...
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- 2021
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45. Inhibition of GCN2 sensitizes ASNS-low cancer cells to asparaginase by disrupting the amino acid response.
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Nakamura A, Nambu T, Ebara S, Hasegawa Y, Toyoshima K, Tsuchiya Y, Tomita D, Fujimoto J, Kurasawa O, Takahara C, Ando A, Nishigaki R, Satomi Y, Hata A, and Hara T
- Subjects
- Amino Acids genetics, Aspartate-Ammonia Ligase genetics, Cell Line, Tumor, Humans, Neoplasm Proteins genetics, Neoplasms enzymology, Neoplasms genetics, Neoplasms pathology, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Amino Acids metabolism, Asparaginase pharmacology, Aspartate-Ammonia Ligase metabolism, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins metabolism, Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors
- Abstract
General control nonderepressible 2 (GCN2) plays a major role in the cellular response to amino acid limitation. Although maintenance of amino acid homeostasis is critical for tumor growth, the contribution of GCN2 to cancer cell survival and proliferation is poorly understood. In this study, we generated GCN2 inhibitors and demonstrated that inhibition of GCN2 sensitizes cancer cells with low basal-level expression of asparagine synthetase (ASNS) to the antileukemic agent l-asparaginase (ASNase) in vitro and in vivo. We first tested acute lymphoblastic leukemia (ALL) cells and showed that treatment with GCN2 inhibitors rendered ALL cells sensitive to ASNase by preventing the induction of ASNS, resulting in reduced levels of de novo protein synthesis. Comprehensive gene-expression profiling revealed that combined treatment with ASNase and GCN2 inhibitors induced the stress-activated MAPK pathway, thereby triggering apoptosis. By using cell-panel analyses, we also showed that acute myelogenous leukemia and pancreatic cancer cells were highly sensitive to the combined treatment. Notably, basal ASNS expression at protein levels was significantly correlated with sensitivity to combined treatment. These results provide mechanistic insights into the role of GCN2 in the amino acid response and a rationale for further investigation of GCN2 inhibitors for the treatment of cancer., Competing Interests: Conflict of interest statement: The authors are employees of Takeda Pharmaceutical Company Limited. more...
- Published
- 2018
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46. Monosodium glutamate ingestion during the development period reduces aggression mediated by the vagus nerve in a rat model of attention deficit-hyperactivity disorder.
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Nishigaki R, Yokoyama Y, Shimizu Y, Marumoto R, Misumi S, Ueda Y, Ishida A, Shibuya Y, and Hida H
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- Animals, Anxiety pathology, Anxiety physiopathology, Anxiety therapy, Attention Deficit Disorder with Hyperactivity pathology, Attention Deficit Disorder with Hyperactivity physiopathology, Blood Pressure, Brain pathology, Brain physiopathology, Cell Death, Cells, Cultured, Coculture Techniques, Disease Models, Animal, Glutamic Acid blood, L-Lactate Dehydrogenase metabolism, Male, Neurons pathology, Neurons physiology, Rats, Inbred SHR, Rats, Wistar, Vagotomy, Vagus Nerve pathology, Aggression, Attention Deficit Disorder with Hyperactivity psychology, Attention Deficit Disorder with Hyperactivity therapy, Flavoring Agents administration & dosage, Sodium Glutamate administration & dosage, Vagus Nerve physiopathology
- Abstract
We used an umami substance, monosodium glutamate (MSG), as a simple stimulant to clarify the mechanism of the formation of emotional behavior. A 60 mM MSG solution was fed to spontaneously hypertensive rats (SHR), used as a model of attention-deficit hyperactivity disorder, from postnatal day 25 for 5 weeks kept in isolation. Emotional behaviors (anxiety and aggression) were then assessed by the open-field test, cylinder test and social interaction test. MSG ingestion during the developmental period resulted in a significant reduction in aggressive behavior but had few effects on anxiety-like behavior. Several experiments were performed to identify the reason for the reduced aggression with MSG intake. Blood pressure in the MSG-treated SHR was comparable to that of the controls during development. Argyrophil III staining to detect the very early phase of neuronal damage revealed no evidence of injury by MSG in aggression-related brain areas. Assessment of plasma amino acids revealed that glutamate levels remained constant (∼80 μM) with MSG ingestion, except for a transient increase after fasting (∼700 μM). However, lactate dehydrogenase assay in an in vitro blood-brain barrier model showed that cell toxicity was not induced by indirect MSG application even at 700 μM, confirming that MSG ingestion caused minimal neuronal damage. Finally, vagotomy at the sub-diaphragmatic level before MSG ingestion blocked its effect on aggressive behavior in the isolated SHR. The data suggest that MSG ingestion during the developmental period can reduce aggressive behavior in an attention deficit-hyperactivity disorder model rat, mediated by gut-brain interaction., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.) more...
- Published
- 2018
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47. Disorganization of Oligodendrocyte Development in the Layer II/III of the Sensorimotor Cortex Causes Motor Coordination Dysfunction in a Model of White Matter Injury in Neonatal Rats.
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Ueda Y, Misumi S, Suzuki M, Ogawa S, Nishigaki R, Ishida A, Jung CG, and Hida H
- Subjects
- Animals, Animals, Newborn, Disease Models, Animal, Hypoxia-Ischemia, Brain metabolism, Male, Rats, Wistar, Axons metabolism, Myelin Sheath metabolism, Oligodendroglia metabolism, White Matter metabolism
- Abstract
We previously established neonatal white matter injury (WMI) model rat that is made by right common carotid artery dissection at postnatal day 3, followed by 6% hypoxia for 60 min. This model has fewer oligodendrocyte progenitor cells and reduced myelin basic protein (MBP) positive areas in the sensorimotor cortex, but shows no apparent neuronal loss. However, how motor deficits are induced in this model is unclear. To elucidate the relationship between myelination disturbance and concomitant motor deficits, we first performed motor function tests (gait analysis, grip test, horizontal ladder test) and then analyzed myelination patterns in the sensorimotor cortex using transmission electron microscopy (TEM) and Contactin associated protein 1 (Caspr) staining in the neonatal WMI rats in adulthood. Behavioral tests revealed imbalanced motor coordination in this model. Motor deficit scores were higher in the neonatal WMI model, while hindlimb ladder stepping scores and forelimb grasping force were comparable to controls. Prolonged forelimb swing times and decreased hindlimb paw angles on the injured side were revealed by gait analysis. TEM revealed no change in myelinated axon number and the area g-ratio in the layer II/III of the cortex. Electromyographical durations and latencies in the gluteus maximus in response to electrical stimulation of the brain area were unchanged in the model. Caspr staining revealed fewer positive dots in layers II/III of the WMI cortex, indicating fewer and/or longer myelin sheath. These data suggest that disorganization of oligodendrocyte development in layers II/III of the sensorimotor cortex relates to imbalanced motor coordination in the neonatal WMI model rat. more...
- Published
- 2018
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48. Discovery of Novel and Potent Stearoyl Coenzyme A Desaturase 1 (SCD1) Inhibitors as Anticancer Agents.
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Imamura K, Tomita N, Kawakita Y, Ito Y, Ono K, Nii N, Miyazaki T, Yonemori K, Tawada M, Sumi H, Satoh Y, Yamamoto Y, Miyahisa I, Sasaki M, Satomi Y, Hirayama M, Nishigaki R, and Maezaki H
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Colonic Neoplasms drug therapy, Drug Evaluation, Preclinical, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, HCT116 Cells, Humans, Inhibitory Concentration 50, Mice, Mice, Inbred BALB C, Mice, Nude, Microsomes, Liver metabolism, Oxadiazoles pharmacokinetics, Oxadiazoles therapeutic use, Oxadiazoles toxicity, Piperidines chemistry, Piperidines metabolism, Piperidines pharmacology, Protein Binding, Pyridazines pharmacokinetics, Pyridazines therapeutic use, Pyridazines toxicity, Spiro Compounds chemistry, Stearoyl-CoA Desaturase metabolism, Structure-Activity Relationship, Transplantation, Heterologous, Antineoplastic Agents chemistry, Enzyme Inhibitors chemical synthesis, Oxadiazoles chemical synthesis, Pyridazines chemical synthesis, Stearoyl-CoA Desaturase antagonists & inhibitors
- Abstract
A lead compound A was identified previously as an stearoyl coenzyme A desaturase (SCD) inhibitor during research on potential treatments for obesity. This compound showed high SCD1 binding affinity, but a poor pharmacokinetic (PK) profile and limited chemical accessibility, making it suboptimal for use in anticancer research. To identify potent SCD1 inhibitors with more promising PK profiles, we newly designed a series of 'non-spiro' 4, 4-disubstituted piperidine derivatives based on molecular modeling studies. As a result, we discovered compound 1a, which retained moderate SCD1 binding affinity. Optimization around 1a was accelerated by analyzing Hansch-Fujita and Hammett constants to obtain 4-phenyl-4-(trifluoromethyl)piperidine derivative 1n. Fine-tuning of the azole moiety of 1n led to compound 1o (T-3764518), which retained nanomolar affinity and exhibited an excellent PK profile. Reflecting the good potency and PK profile, orally administrated compound 1o showed significant pharmacodynamic (PD) marker reduction (at 0.3mg/kg, bid) in HCT116 mouse xenograft model and tumor growth suppression (at 1mg/kg, bid) in 786-O mouse xenograft model. In conclusion, we identified a new series of SCD1 inhibitors, represented by compound 1o, which represents a promising new chemical tool suitable for the study of SCD1 biology as well as the potential development of novel anticancer therapies., (Copyright © 2017 Elsevier Ltd. All rights reserved.) more...
- Published
- 2017
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49. In vitro and in vivo antitumor activities of T-3764518, a novel and orally available small molecule stearoyl-CoA desaturase 1 inhibitor.
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Nishizawa S, Sumi H, Satoh Y, Yamamoto Y, Kitazawa S, Honda K, Araki H, Kakoi K, Imamura K, Sasaki M, Miyahisa I, Satomi Y, Nishigaki R, Hirayama M, Aoyama K, Maezaki H, and Hara T
- Subjects
- Administration, Oral, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents metabolism, Apoptosis drug effects, Biological Availability, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Endoplasmic Reticulum Stress drug effects, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacokinetics, Fatty Acids metabolism, HCT116 Cells, Humans, Mice, Oxadiazoles administration & dosage, Oxadiazoles metabolism, Pyridazines administration & dosage, Pyridazines metabolism, Stearoyl-CoA Desaturase metabolism, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Enzyme Inhibitors pharmacology, Oxadiazoles pharmacokinetics, Oxadiazoles pharmacology, Pyridazines pharmacokinetics, Pyridazines pharmacology, Stearoyl-CoA Desaturase antagonists & inhibitors, Xenograft Model Antitumor Assays
- Abstract
Most cancer cells are characterized by elevated lipid biosynthesis. The rapid proliferation of cancer cells requires de novo synthesis of fatty acids. Stearoyl-CoA desaturase-1 (SCD1), a key enzyme for lipogenesis, is overexpressed in various types of cancer and plays an important role in cancer cell proliferation. Therefore, it has been studied as a candidate target for cancer therapy. In this study, we demonstrate the pharmacological properties of T-3764518, a novel and orally available small molecule inhibitor of SCD1. T-3764518 inhibited stearoyl-CoA desaturase-catalyzed conversion of stearoyl-CoA to oleoyl-CoA in colorectal cancer HCT-116 cells and their growth. Further, it slowed tumor growth in an HCT-116 and a mesothelioma MSTO-211H mouse xenograft model. Comprehensive lipidomic analyses revealed that T-3764518 increases the membrane ratio of saturated: unsaturated fatty acids in various lipid species such as phosphatidylcholines and diacylglycerols in both cultured cells and HCT-116 xenografts. Treatment-associated lipidomic changes were followed by activated endoplasmic reticulum (ER) stress responses such as increased immunoglobulin heavy chain-binding protein expression in HCT-116 cells. These T-3764518-induced changes led to an increase in cleaved poly (ADP-ribose) polymerase 1 (PARP1), a marker of apoptosis. Additionally, bovine serum albumin conjugated with oleic acid, an SCD1 product, prevented cell growth inhibition and ER stress responses by T-3764518, indicating that these outcomes were not attributable to off-target effects. These results indicate that T-3764518 is a promising new anticancer drug candidate., (Copyright © 2017 Elsevier B.V. All rights reserved.) more...
- Published
- 2017
- Full Text
- View/download PDF
50. Dysfunction in Motor Coordination in Neonatal White Matter Injury Model Without Apparent Neuron Loss.
- Author
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Misumi S, Ueda Y, Nishigaki R, Suzuki M, Ishida A, Jung CG, and Hida H
- Subjects
- Animals, Animals, Newborn, Apoptosis, Disease Models, Animal, Down-Regulation genetics, Hindlimb physiopathology, Hypoxia-Ischemia, Brain pathology, Hypoxia-Ischemia, Brain physiopathology, Male, Myelin Sheath metabolism, Neuroglia pathology, Pyramidal Tracts pathology, Pyramidal Tracts physiopathology, Rats, Wistar, Sensorimotor Cortex pathology, Sensorimotor Cortex physiopathology, Staining and Labeling, Up-Regulation genetics, White Matter pathology, Motor Activity, Neurons pathology, White Matter injuries, White Matter physiopathology
- Abstract
We made a white matter injury (WMI) model with mild hindlimb dysfunction by right common carotid artery occlusion followed by 6% oxygen for 60 min at postnatal day 3 (P3), in which actively proliferating oligodendrocyte (OL) progenitors are mainly damaged. To know whether this model is appropriate for cell therapy using OL progenitors, the pathological response to mild hypoxia-ischemia (H-I) in neurons and OL lineage cells and myelination failure were investigated along with gene expression analysis. In WMI model rats, coordinated motor function, as assessed by the accelerating rotarod test, was impaired. The dysfunction was accompanied by myelination failure in layers I-IV of the sensorimotor cortex. Although several oligo2-positive OLs stained positive for active caspase 3 in the cortex and white matter at 24 h after H-I, few NeuN-positive neurons were apoptotic. Argyrophil-III staining for damaged neurons revealed no increase in the number of degenerating cells in the model. Moreover, the total number of NeuN-positive neurons in the cortex was comparable to that of controls 7 days later. Retrograde labeling of the corticospinal tract with Fluoro-Gold revealed no significant loss of layer V neurons. In addition, no decrease in the numbers of cortical projecting neurons and layers V-VI neurons in both motor and sensory areas was observed. Interestingly, the numbers of inhibitory GABAergic cells immunoreactive for parvalbumin, calretinin, or somatostatin were preserved in the P26 cortex. Gene expression analysis at P5 revealed 98 upregulated and 65 downregulated genes that may relate to cell survival, myelin loss, and differentiation of OLs. These data suggest that impaired motor coordination was not induced by neuron loss but, rather, myelination failure in layers I-IV. As OL lineage cells are mainly damaged, this WMI model might be useful for cell-based therapy by replacing OL progenitors. more...
- Published
- 2016
- Full Text
- View/download PDF
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