Biomedical subjects

Hiroshi Yoshino

Publications and source records attributed to Hiroshi Yoshino.

15 recordsLinked to original sources

PubMed2006

[A case of recurrent breast cancer with life-threatening multiple lung metastasis markedly responding to CMF as third-line chemotherapy].

A 35-year-old woman with taxane and anthracycline-resistant recurrent breast cancer with multiple lung metastasis and carcinomatous lymphangitis was treated with CMF as third-line chemotherapy. A complete response was achieved,and the toxicities were tolerable. We thought that CMF could be a useful regimen as third-line chemotherapy for metastatic breast cancer.

Adult↗

PubMed2005

In vitro drug resistance to imatinib and mutation of ABL gene in childhood Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia.

Imatinib, the ABL kinase inhibitor, is used not only for Philadelphia chromosome-positive (Ph + ) chronic myelogenous leukemia, but also for Ph + acute lymphoblastic leukemia (ALL), although resistance to the drug tends to develop in an early stage of the clinical course. We describe a childhood refractory Ph + ALL patient in whom progressive resistance to imatinib was correlated with the appearance of a mutation in the BCR-ABL kinase domain and in vitro drug resistance to imatinib as determined by the methyl-thiazol-tetrazolium (MTT) assay. A missense mutation of T to C (Y253H) of the ABL gene was identified in the resistant clone, suggesting that this mutation may play an etiological role in the rapid loss of drug sensitivity.

Benzamides↗

PubMed2005

[Cell transplantation for periodontal diseases. A novel periodontal tissue regenerative therapy using bone marrow mesenchymal stem cells].

A major goal of periodontal therapy is to reconstruct healthy periodontium destroyed by periodontal diseases. Basic studies have revealed that transplantation of mesenchymal stem cells (MSC) into periodontal defects promotes regeneration of periodontal tissue. We have developed a novel method for periodontal therapy using MSC. Human bone marrow cells are obtained from the iliac crest and expanded in vitro at Cell and Tissue Engineering Center in Hiroshima University Hospital. MSC are, then, isolated and mixed with Atelocollagen at final concentrations of 2 x 10(7) cells/mL. These MSC in Atelocollagen are transplanted into periodontal osseous defects at the periodontal surgery. The results in all seven patients who received the own MSC transplantation have shown good clinical course. Further basic studies and the continuous clinical trial are needed to prove the effectiveness of the clinical application.

Humans↗

PubMed2005

[A case of primary small intestinal cancer accompanied by virchow lymph node metastasis undergoing TS-1 treatment].

A 72-year-old female was admitted to our hospital with the complaint of left neck lymph node swelling. Abdominal computed tomography (CT) revealed wall thickening of the small intestine and multiple lymph node metastases. Barium meal study of the small intestine showed circular stenosis. The patient was operated on under a diagnosis of tumor of the small intestine and left neck lymph node swelling. Needle biopsy of the left neck lymph node and partial resection of the small intestine was done without regional lymph node dissection because of Virchow lymph node metastasis. On the resected material a 5 x 4 cm type 2 tumor was identified. Pathological findings included poorly-differentiated adenocarcinoma, si (bladder), n 4, P 0, ly 3, v 3, H 0, M(-), Stage IV. The patient received the chemotherapy with TS-1. TS-1(80 mg/body/day) orally administered for 4 weeks followed by a drug-free 2-week period as one course. CT revealed that the metastatic lesion had shrunk markedly after the second course. A complete response (CR) was observed after one year. There were no drug side effects. At present, 3 years and 9 months after the operation, cervical and abdominal CT reveals no evidence of enlargement of the cervical and intraperitoneal lymph nodes.

Adenocarcinoma↗

PubMed2004

Synthesis and evaluation of novel pyrimido-acridone, -phenoxadine, and -carbazole as topoisomerase II inhibitors.

As part of a series of studies to discover new topoisomerase II inhibitors, novel pyrimidoacridones, pyrimidophenoxadines, and pyrimidocarbazoles were synthesized, and in vitro and in vivo antitumor activities and DNA-protein and/or DNA-topoisomerase II cross-linking activity as an indicator of topoisomerase II-DNA cleavable complex formation were evaluated. The pyrimidocarbazoles possessed high in vitro and in vivo potencies. Compound 26 (ER-37326), 8-acetyl-2-[2-(dimethylamino)ethyl]-1H-pyrimido[5,6,1-jk]carbazole-1,3(2H)-dione, showed in vitro growth inhibitory activity with respective IC(50) values of 0.049 microM and 0.35 microM against mouse leukemia P388 and human oral cancer KB. In vivo, this compound inhibited the tumor growth of mouse sarcoma M5076 implanted into mice with T/C values of 42% and 13% at 3.13 and 6.25 mg/kg/d respectively without significantly affecting the body weight. In addition, compound 26 (ER-37326) increased the formation of DNA-topoisomerase II cross-linking in P388 cells.

Acridines↗

PubMed2003

Expression of endothelins and their receptors in cells from human periodontal tissues.

OBJECTIVE: The present study investigated the presence of ET-1 in gingival crevicular fluid (GCF) from patients with periodontitis, and the expression of endothelins (ETs) and their receptors mRNA in cultured cells from human periodontal tissues. BACKGROUND: ET was originally discovered as a potent vasoconstrictive peptide from endothelial cells. It has been reported that ETs are produced by various cells besides endothelial cells. ETs are related to inflammatory and sclerotic lesions, such as arteriolosclerosis and hepatic cirrhosis. Therefore, ETs may be involved in periodontal disease. However, the roles of ETs in development and progression of periodontal disease are not clear. METHODS: ET-1 released from the cultured cells was measured by enzyme-linked immunosorbent assay. mRNA expressions for ETs and their receptors were examined by reverse transcription-polymerase chain reaction and Northern blotting analysis. RESULTS: ET-1 levels in GCF from patients with periodontitis were higher than those from healthy subjects. Human gingival keratinocytes (HGK) expressed mRNA for ETs and their receptors, ET-Ar and ET-Br. ET-1 mRNA expression and ET-1 peptide production from HGK were enhanced by interleukin-1beta and tumor necrosis factor-alpha. CONCLUSIONS: These results suggest that ET-1 plays a significant role in periodontal disease.

Adult↗

PubMed2003

A novel carbazole topoisomerase II poison, ER-37328: potent tumoricidal activity against human solid tumors in vitro and in vivo.

We have discovered a novel topoisomerase II (topo II) poison, ER-37328 (12,13-dihydro-5-[2-(dimethylamino)ethyl]-4H-benzo[c]pyrimido[5,6,1-jk]carbazole-4,6,10(5H,11H)-trione hydrochloride), which shows potent tumor regression activity against Colon 38 cancer inoculated s.c. Here, we describe studies on the cell-killing activity against a panel of human cancer cell lines and the antitumor activity of ER-37328 against human tumor xenografts. In a cell-killing assay involving 1-h drug treatment, ER-37328 showed more potent cell-killing activity (50% lethal concentrations (LC50s) ranging from 2.9 to 20 microM) than etoposide (LC50s>60 microM) against a panel of human cancer cell lines. ER-37328 induced double-stranded DNA cleavage, an indicator of topo II-DNA cleavable complex formation, within 1 h in MX-1 cells, and the extent of cleavage showed a bell-shaped relationship to drug concentration, with the maximum at 2.5 microM. After removal of the drug (2.5 microM) at 1 h, incubation was continued in drug-free medium, and the amount of cleaved DNA decreased. However, at 10 microM, which is close to the LC50s against MX-1 cells, DNA cleavage was not detected immediately after 1-h treatment, but appeared and increased after drug removal. This result may explain the potent cell-killing activity of ER-37328 in the 1-h treatment. In vivo, ER-37328 showed potent tumor regression activity against MX-1 and NS-3 tumors. Moreover, ER-37328 had a different antitumor spectrum from irinotecan or cisplatin against human tumor xenografts. In conclusion, ER-37328 is a promising topo II poison with strong cell killing activity in vitro and tumor regression activity in vivo, and is a candidate for the clinical treatment of malignant solid tumors.

Adenocarcinoma↗

PubMed2003

Application of Quick Environment Exposure Sensitivity Inventory (QEESI) for Japanese population: study of reliability and validity of the questionnaire.

A standardized questionnaire has not been established for screening or diagnostic assessment of patients with multiple chemical sensitivity (MCS) in Japan. In the US, Miller and Prihoda (1999a,b) developed a questionnaire that could be used internationally, the Quick Environment Exposure Sensitivity Inventory (QEESI), to assist researchers and clinicians in evaluating patients and populations for chemical sensitivity. The Japanese version of QEESI was subsequently translated by Ishikawa and Miyata (1999). The present study was performed to investigate the reliability and validity of QEESI (Japanese version) for research purposes and for evaluation of patients with MCS in Japan. A total of 498 subjects were recruited from the general population of Miyagi prefecture, Japan. The factor structure in QEESI was analyzed with 40 items on four subscales except for the items in 'Masking' using principal components analysis with Promax rotation. The results showed that 30 items on three subscales, 'Chemical Inhalant Intolerances,' 'Symptom Severity,' and 'Life Impact' except for 'Other Intolerances' were consistent with those reported for the US population by Miller and Prihoda (1999a). Cronbach's alpha reliability coefficient ranged between 0.87 and 0.94 indicating high internal consistency in the 30 items on three subscales. Next, we compared the mean scores on three subscales of QEESI in two groups: 131 self-reported MCS group who were new outpatients at the Environmental Medical Center in Kitasato Institute Hospital, and 131 members of the general population (controls) who were matched for both gender and age with the self-reported MCS group. Mean scores on each subscale for the self-reported MCS group were significantly greater than those for controls (P <0.001). Mean scores on all of the 30 items on three subscales for the self-reported MCS group were also significantly greater than for the controls (P <0.001). These findings indicated that the 30 items on three subscales in QEESI can be used for surveys and for diagnostic assessment of patients with MCS as well as for comparative studies between patients in Japan and in other countries.

Adult↗

PubMed2003

Neurotrophins in cultured cells from periodontal tissues.

We review the basic functions of neurotrophins and their receptors and discuss the expression and functions of neurotrophins and their specific receptors based on recent data using cultured cells from human periodontal tissues. Neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) play crucial roles in the differentiation and survival of neural cells. Neurotrophins activate 2 different receptor classes: the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB, and TrkC) and the p75 receptor, a member of the tumor necrosis factor receptor superfamily. Neurotrophins regulate both cell death and cell survival through activations of Trk receptors and/or p75 neurotrophin receptor. It has been reported that neurotrophins are also produced from non-neuronal cells, such as leukocytes, osteoblasts, or fibroblasts, and act in many other ways on non-neuronal cells. Neurotrophin expression during bone fracture healing is especially interesting, and neurotrophins are now implicated in hard tissue regeneration. It is well known that neurotrophins and their receptors are expressed in tooth development. Recent studies have found that neurotrophins and Trk receptors are expressed in mouse osteoblastic cell lines. Human periodontal ligament cells, human gingival fibroblasts, and human gingival keratinocytes expressed mRNA for NGF and TrkA. The secretion of bioactive NGF peptides from human periodontal ligament cells and human gingival keratinocytes was confirmed by bioassay using PC12 cells (rat adrenal pheochromocytoma cells). The expression of NGF and TrkA.mRNA was regulated by interleukin (IL)-1beta. NGF increased DNA synthesis and expressions of mRNA for bone-related proteins, alkaline phosphatase, and osteopontin in human periodontal ligament cells. Neurotrophins and Trk receptors expressed in human periodontal tissue may contribute to regeneration as well as innervation of periodontal tissue through local autocrine and paracrine pathways. Recent data suggest that some functions of neurotrophins and Trk receptors relate to periodontal disease and periodontal tissue regeneration. However, in vivo studies will be required to clarify the roles of neurotrophins and their receptors, including p75, in periodontal disease and periodontal tissue regeneration.

Alkaline Phosphatase↗

PubMed2002

Synthesis and biological evaluation of N-(7-indolyl)-3-pyridinesulfonamide derivatives as potent antitumor agents.

We herein report the synthesis and antitumor activity of E7070 analogues containing a 3-pyridinesulfonamide moiety. E7070 was selected from our sulfonamide-based compound collections, currently undergoing Phase II clinical trials because of its tolerable toxicity profile and some antitumor responses in the Phase I setting. Of the analogues examined, ER-35745, a 6-amino-3-pyridinesulfonamide derivative, demonstrated significant oral efficacy against the HCT116 human colon carcinoma xenograft in nude mice.

Animals↗

PubMed2002

Osteoprotegerin levels increased by interleukin-1beta in human periodontal ligament cells are suppressed through prostaglandin E(2) synthesized de novo.

Osteoprotegerin (OPG) is a novel tumor necrosis factor receptor superfamily that inhibits osteoclast differentiation, activity, and survival. Interleukin-1beta (IL-1beta) increases OPG expression. IL-1beta also increases prostaglandin E(2) (PGE(2)) production and stimulates bone resorption. In the present study, we examined the involvement of PGE(2) in IL-1beta-induced increases in OPG levels in human periodontal ligament cells (HPL cells) in an effort to clarify apparently conflicting IL-1beta actions on bone resorption and understand IL-1beta-induced increases in secretion of OPG and PGE(2) in HPL cells. 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole, a mRNA synthesis inhibitor, partly inhibited the increase in OPG mRNA levels induced by IL-1beta. Cycloheximide, a protein synthesis inhibitor, enhanced the stimulatory effect of IL-1beta. Etodolac, a selective cyclooxygenase-2 inhibitor, suppressed the increase in PGE(2) levels. Furthermore, etodolac reinforced the promotion of OPG expression by IL-1beta at the mRNA and protein levels. PGE(2) added to cultures of HPL cells decreased OPG mRNA levels in a dose- and time- dependent manner. These findings suggest that the increase in OPG levels induced by IL-1beta in HPL cells is suppressed through PGE(2) synthesized de novo.

Base Sequence↗

PubMed2002

Antitumor activity of ER-37328, a novel carbazole topoisomerase II inhibitor.

DNA topoisomerase II has been shown to be an important therapeutic target in cancer chemotherapy. Here, we describe studies on the antitumor activity of a novel topoisomerase II inhibitor, ER-37328 [12,13-dihydro-5-[2-(dimethylamino)ethyl]-4H-benzo[c]pyrimido[5,6,1- jk]carbazole-4,6,10(5H,11H)-trione hydrochloride]. ER-37328 inhibited topoisomerase II activity at 10 times lower concentration than etoposide in relaxation assay and induced double-strand DNA cleavage within 1 h in murine leukemia P388 cells, in a bell-shaped manner with respect to drug concentration. The maximum amount of DNA cleavage was obtained at 2 microM. Like etoposide, ER-37328 (2 microM) induced topoisomerase II-DNA cross-linking in P388 cells. A spectroscopic study of ER-37328 mixed with DNA demonstrated that ER-37328 has apparent binding activity to DNA. ER-37328 showed potent growth-inhibitory activity against a panel of 21 human cancer cell lines [mean (50% growth-inhibitory concentration) GI50 = 59 nM]. COMPARE analysis according to the National Cancer Institute screening protocol showed that the pattern of the growth-inhibitory effect of ER-37328 was similar to that of etoposide, but different from that of doxorubicin. Studies on etoposide-, amsacrine [4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)]-, and camptothecin-resistant P388 cell lines showed that: (a) etoposide- and m-AMSA-resistant P388 cell lines were partially resistant to ER-37328 compared with the parental cell line; and (b) a camptothecin-resistant cell line showed no cross-resistance to ER-37328. In addition, ER-37328 overcame P-glycoprotein-mediated resistance. In vivo, ER-37328 produced potent tumor regression of Colon 38 carcinoma inoculated s.c., and its activity was superior to that of etoposide or doxorubicin. These results indicate that ER-37328 inhibits topoisomerase II activity through the formation of topoisomerase II-DNA cleavable complex and has potent antitumor activity both in vitro and in vivo.

Amsacrine↗

PubMed2002

Profiling novel sulfonamide antitumor agents with cell-based phenotypic screens and array-based gene expression analysis.

A series of small molecules from sulfonamide-focused libraries have been evaluated in these laboratories to discover novel antitumor agents. Cell-based screens using flow cytometric analysis revealed the presence of two distinct classes of cell cycle inhibitors in this series; one (including E7010 and ER-67865) arrested mitosis by preventing tubulin polymerization; and the other (including E7070 and ER-68487) caused a decrease in the S-phase fraction along with cell cycle perturbation in G1 and/or G2 via an unknown mechanism(s). To further characterize both classes of antitumor sulfonamides with respect to their effects on gene expression, we used oligonucleotide microarray analysis for representative compounds. Consistent with the phenotypic observations, essentially the same transcription profiles were found between E7010 and ER-67865 and also between E7070 and ER-68487. However, there was very little overlap between genes affected by E7010 and E7070. As a characteristic expression change for microtubule-depolymerizing agents, the down-regulation of alpha-tubulin transcripts was evident in both E7010- and ER-67865-treated cells. On the other hand, E7070 and ER-68487 repressed significantly the expression of a variety of genes involved in metabolic processes, cell cycle progression, immune response, and signal transduction. Of the compounds examined, E7010 and E7070 have progressed to clinical trials, demonstrating some objective responses in the Phase I setting. Described herein is profiling of novel anticancer drug candidates from the sulfonamide class based on phenotypic screens and gene expression analysis. This includes a translational research that may suggest potentially useful markers for pharmacodynamic drug assessment in clinic.

Antineoplastic Agents↗

PubMed2001

Hematopoietic capability of CD34+ cord blood cells: a comparison with CD34+ adult bone marrow cells.

The characteristics of hematopoietic progenitor and stem cell (HPC/HSC) populations in mammals vary according to their ontogenic stage. In humans, HPC/HSCs from umbilical cord blood (CB) are increasingly used as an alternative to HPC/HSCs from adult bone marrow (BM) for the treatment of various hematologic disorders. How the hematopoietic activity of progenitor and stem cells in CB differs from that in adult BM remains unclear, however. We compared CD34+ cells, a hematopoietic cell population, in CB with those in adult BM using phenotypic subpopulations analyzed by flow cytometry, the colony-forming activity in methylcellulose clonal cultures, and the repopulating ability of these cells in NOD/Shi-scid (NOD/SCID) mice. Although the proportion of CD34+ cells was higher in adult BM than in CB mononuclear cells, the more immature subpopulations, CD34+ CD33- and CD34+ CD38- cells, were present in higher proportions in CD34+ CB cells. Clonal culture assay showed that more multipotential progenitors were present in CD34+ CB cells. When transplanted into NOD/SCID mice. CD34+ adult BM cells could not reconstitute human hematopoiesis in recipient BM, but CD34+ CB cells achieved a high level of engraftment, indicating that CD34+ CB cells possess a greater repopulating ability. These results demonstrated that human hematopoiesis changes with development from fetus to adult. Furthermore, CD34+ CB cells contained a greater number of primitive hematopoietic cells, including HSCs, than did adult BM, suggesting the usefulness of CD34+ CB cells not only as a graft for therapeutic HSC transplantation but also as a target cell population for ex vivo expansion of transplantable HSCs and for gene transfer in gene therapy.

Adult↗

PubMedDate not supplied

Brain-derived neurotrophic factor enhances periodontal tissue regeneration.

To address whether brain-derived neurotrophic factor (BDNF) could be involved in periodontal tissue regeneration, we examined the effects of BDNF on proliferation and the expression of bone (cementum)- related proteins (osteopontin, bone morphogenetic protein [BMP]-2, type I collagen, alkaline phosphatase [ALPase], and osteocalcin) in cultures of human periodontal ligament (HPL) cells, which are thought to be prerequisite for periodontal tissue regeneration, and on proliferation and angiogenesis in human endothelial cells. Furthermore, we examined the effect of BDNF on the regeneration of periodontal tissues in experimentally induced periodontal defects in dogs. BDNF elevated the expression of ALPase and osteocalcin mRNAs and increased the synthesis of osteopontin, BMP-2, and type I collagen DNA in HPL cells. BDNF stimulated mRNA expression of vascular endothelial growth factor-B and tenascin-X, and proliferation and angiogenesis in human endothelial cells. In vivo studies showed that BDNF stimulated the formation of new alveolar bone cementum and connective new fibers, which were inserted into the newly formed cementum and bone. BDNF also stimulated blood capillary formation. These findings suggest that the regulation of functioning of periodontal ligament cells and endothelial cells by BDNF results in the promotion of periodontal tissue regeneration.

Alkaline Phosphatase↗