Scattering-angle dependence of the magnetic circular dichroism of resonant inelastic X-ray scattering.
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Journal Article↗
Biomedical subjects
T Tominaga
Publications and source records attributed to T Tominaga.
High-resolution crystals of the HU mutant K38N from Bacillus stearothermophilus.
The DNA-binding protein HU is ubiquitous in the prokaryotic cell. It is a major protein component of isolated nucleoids and is believed to control the tertiary structure of prokaryotic DNA. The Bacillus stearothermophilus HU (BstHU) mutants obtained by mutagenesis have been investigated. Crystallization experiments of BstHU-K38N (Lys38 is substituted with Asn) resulted in two forms of crystals suitable for high-resolution x-ray analysis. The first form belongs to the monoclinic space group C2 with unit-cell dimensions of a = 90.1 A, b = 43.5 A, c = 63.7 A, and beta = 135.1 degrees, and it diffracts x rays to 1.5-A resolution. The second form belongs to the tetragonal space group I41 with a = b = 62.6 A and c = 43.3 A, and it diffracts up to 1.8-A resolution.
Bacterial Proteins↗
Phase II study of KRN8602, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride, MX2 x HCl in patients with metastatic breast cancer.
PURPOSE: KRN8602 (3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin hydrochloride, MX2 x HCl) is a newly developed anthracycline that has been found to be effective against multidrug-resistant tumor cells in vitro and in vivo. In order to clinically confirm these promising preclinical observations, we performed a phase II trial of KRN8602 in patients with anthracycline-resistant metastatic breast cancer. METHODS: Of 41 patients registered with metastatic breast cancer, 37 were eligible and were given at least two cycles of KRN8602 15 mg/m2 per day at 3-4 week intervals by intravenous bolus injection on days 1, 2, and 3. RESULTS: Of the 37 patients, 6 (16.2%, with a 95% confidence interval of 4.3-28.1%) had a partial response (PR). No complete responses (CRs) were observed. The difference between response rates according to prior history of anthracycline administration was not significant. Myelosuppression was moderately severe, with grade 3 or 4 leukopenia occurring in 65%. Severe nausea/vomiting was observed in 44% of the patients. CONCLUSIONS: The results indicate that KRN8602 has modest activity in refractory metastatic breast cancer and is associated with relatively severe toxicity. Furthermore, the preclinical finding that KRN8602 overcomes anthracycline resistance was not reliably reproduced in this clinical phase II trial.
Adult↗
Meta-analysis of trials comparing toremifene with tamoxifen and factors predicting outcome of antiestrogen therapy in postmenopausal women with breast cancer.
Meta-analysis of all clinical data was conducted to compare toremifene 40-60 mg/day (TOR) with tamoxifen 20-40 mg/day (TAM) in postmenopausal women with estrogen receptor (ER) positive or ER unknown advanced breast cancer and assess factors predicting treatment outcome. Data from five randomized parallel group studies (all studies) were combined. Efficacy variables were the response rate in all studies and also the time to treatment failure and survival in the three major studies (pivotal studies). Of the 1421 patients, 725 received TOR and 696 TAM. Response rates were 24.0% and 25.3%, respectively (p = 0.675) with 95% confidence interval (95% CI) for the difference -5.3 to 3.4. Of the 1157 patients in the pivotal studies, 75% had progressed and 50% expired. Median treatment times were 4.9 months in TOR and 5.3 months in TAM groups (p = 0.762, hazard ratio 0.98 with 95% CI 0.87-1.11). Median survival times were 31.0 (TOR) and 33.1 (TAM) months (p = 0.758, hazard ratio 0.98 with 95% CI 0.83-1.15). All results are consistent with the criteria of statistical equivalence between TOR and TAM. More patients in TAM (20%) than in TOR (14%, p = 0.007) discontinued the treatment prematurely but overall the treatments were well tolerated. As the treatments were equally effective all data were analyzed together for predictive factors. High tumor ER concentration, long disease free time, soft tissue metastases, few metastatic sites, and good performance status all independently predicted longer survival (p<0.001). Previous adjuvant tamoxifen predicted shorter survival (p = 0.008). Objective response to treatment or disease stabilization for at least 12 months both predicted prolonged survival (p = 0.001). TOR 60 mg/day and TAM are equally effective and well tolerated in the treatment of advanced breast cancer in postmenopausal women. Probability of survival may be predicted based on patient characteristics and on the initial response to the treatment.
Aged↗
A case of pelvic arteriovenous malformation in a male.
BACKGROUND: Congenital pelvic arteriovenous malformation (AVM) is rare especially in males. We present a case of pelvic AVM in a 38-year-old male. He was admitted to our hospital with left flank abdominal pain and painless gross hematuria. METHODS/DISCUSSION: Pelvic computed tomography demonstrated a homogeneous contrast-enhanced mass, 6 cm in diameter. For diagnosis, non-invasive magnetic resonance imaging (MRI) and color Doppler ultrasonography were very useful in our case. Though the treatment is controversial, we decided to monitor his clinical course.
Abdominal Pain↗
A phase I/II study of continuous intra-arterial chemotherapy using an implantable reservoir for the treatment of liver metastases from breast cancer: a Japan Clinical Oncology Group (JCOG) study 9113. JCOG Breast Cancer Study Group.
BACKGROUND: Liver metastasis from breast cancer has a poor prognosis. While there are some reports of good response rates of hepatic metastasis from breast cancer by hepatic intra-arterial infusion chemotherapy, no phase I study including pharmacokinetic analysis has been reported. We performed a phase I/II study of intra-arterial infusion chemotherapy using adriamycin and 5-fluorouracil to find the maximum tolerated dose and response rate in patients with advanced or recurrent breast cancer. METHODS: A hepatic arterial catheter with an access port was inserted into the proper hepatic artery. Patients received 30 mg/m2 adriamycin on days 1 and 8 and 100 mg/m2 5-fluorouracil at level 1, 200 mg/m2 at level 2,300 mg/m2 at level 3 and 400 mg/m2 at level 4 continuously from day 1 through day 14 every 28 days. At least two cycles were required before evaluation. Twenty-eight patients were entered into this study and 26 patients were evaluable. Seventeen patients had hepatic metastasis only, although nine patients had additional metastasis to other sites. RESULTS: Dose-limiting toxicity of thrombocytopenia and neurotoxicity occurred at level 4. Leukocytopenia (ECOG grade 3-4) was observed in five (19%), thrombocytopenia in three (12%) and anemia in two (8%) patients. There were 11 catheter-related complications which were not dose dependent. Seven out of 13 evaluable patients (54%) responded at level 3. The median duration of response was 5.8 months (range, 1-23+) and median survival was 25.3 months (range, 6.2-54.7+). CONCLUSION: Hepatic arterial infusion therapy appears to be safe and effective but catheter-related complications must be overcome before starting a phase III trial.
Adolescent↗
Direct evidence of in vivo nitric oxide production and inducible nitric oxide synthase mRNA expression in the brain of living rat during experimental meningitis.
To detect endogenous nitric oxide (NO) produced in a rat bacterial meningitis model, the authors applied an electron paramagnetic resonance (EPR) NO-trapping technique. Iron complex with N,N-diethyldithiocarbamate were used as a trapping agent. Experimental meningitis was induced by a mixture of lipopolysaccharide and interferon-gamma. Sequential changes of NO formation under meningitis were observed in rat brain tissue by using X-band (9 GHz) EPR spectroscopy, and endogenous NO was detected in the head of a living rat with a 700-MHz EPR system. Inducible NO synthase mRNA expression in the brain tissues also was proven by using a reverse transcriptase-polymerase chain reaction technique.
Animals↗
Quantitative analysis of cerebrospinal fluid flow in patients with cervical spondylosis using cine phase-contrast magnetic resonance imaging.
OBJECTIVE: To investigate changes in the cerebrospinal fluid flow in patients with cervical spondylosis using cine phase-contrast magnetic resonance (MR) imaging. METHODS: The participants included 44 healthy volunteers, 11 asymptomatic patients with evidence of degenerative changes of the cervical spine revealed by MR imaging but no neurological symptoms referable to those abnormalities, and 23 symptomatic patients with myelopathy who underwent surgery. Cervical spondylotic myelopathy was evaluated using the Japanese Orthopedic Association scores, and the percentage reduction of the transverse cord area at the level of maximum cord compression was measured on T1-weighted magnetic resonance images. A cine phase-contrast MR pulse sequence with peripheral gating was used to measure the cerebrospinal fluid flow direction and velocity in the ventral subarachnoid spaces at the C1 and T1 levels. RESULTS: The velocity waveforms produced by plotting flow velocity at 16 intervals during one cardiac cycle significantly differed among the healthy volunteers, asymptomatic patients, and preoperative symptomatic patients. However, velocity waveforms did not differ between the healthy volunteers and the postoperative patients at the C1 level. Decreases of flow velocity were significantly correlated with the severity of myelopathy and the percentage reduction of cord area. Patients with severe myelopathy (Japanese Orthopedic Association score of 0-9 points) or greater than 30% reduction of cord area showed significantly decreased flow velocity compared with those with mild myelopathy (Japanese Orthopedic Association score of 10-17 points) or less than 30% reduction of cord area. Changes in flow velocity were not correlated with multiplicity of the lesion or the level of maximum cord compression. Postoperative improvement of flow velocity was not correlated with neurological recovery. CONCLUSION: Cine phase-contrast MR imaging allows quantitative and noninvasive assessment of changes in cerebrospinal fluid flow in patients with cervical spondylosis.
Adult↗
Somatic mutation of the APC gene in thyroid carcinoma associated with familial adenomatous polyposis.
We report the existence of both germline and somatic mutations of the APC gene in thyroid carcinomas from familial adenomatous polyposis (FAP) patients. One papillary thyroid carcinoma from a 210-year-old woman, with germline mutation of the APC gene (TCA to TGA at codon 1110), showed a somatic mutation of AAAAC deletion between codons 1060 and 1063. Another somatic mutation of CAG to TAG at codon 886 was also found in one of multiple thyroid carcinomas from a 26-year-old woman with attenuated FAP and germline mutation at codon 175 (C deletion). This is the first evidence that total absence of the normal function of the APC gene is involved in development of thyroid carcinomas in FAP.
Adenomatous Polyposis Coli↗
Immunohistochemical detection of JC virus in nontumorous renal tissue of a patient with renal cancer but without progressive multifocal leukoencephalopathy.
We performed immunohistochemical staining on the nontumorous renal tissue of 45 patients with renal cancer but without progressive multifocal encephalopathy using JCV-specific antibody. For one patient we found positive staining of the nuclei of the renal collecting ducts. Immunoelectron microscopic examination of the positive cell nuclei revealed electron-dense polyomavirus-like particles.
Antibodies, Viral↗
A randomized controlled comparative study of oral medroxyprogesterone acetate 1,200 and 600 mg in patients with advanced or recurrent breast cancer.
A randomized controlled comparative study of oral medroxyprogesterone acetate (MPA) 1,200 mg (arm I) and 600 mg (arm II) was conducted in 80 patients with advanced or recurrent breast cancer. There were no significant differences between arm I and arm II in terms of response rate, duration of response and survival, or in terms of incidence and severity of adverse reactions. The lowest serum MPA concentration in responders tended to be higher than that in nonresponders. In the cohort of this study, the lowest concentration in partial response was 17.4 ng/ml, suggesting that this level may be the required minimum serum concentration.
Antineoplastic Agents, Hormonal↗
A key function of non-planar membranes and their associated microtubular ribbons in contractile vacuole membrane dynamics is revealed by electrophysiologically controlled fixation of Paramecium.
The contractile vacuole complex of the fresh water protozoan Paramecium multimicronucleatum exhibits periodic exocytotic activity. This keeps cytosolic osmolarity at a constant value. The contractile vacuole, the central exocytotic vesicle of the complex, becomes disconnected from its surrounding radial arms and rounds before its fluid content is expelled. We previously proposed a hypothesis that the rounding of the contractile vacuole corresponds to an increase in its membrane tension and that a periodic increase in membrane tension governs the exocytotic cycle. We also proposed a hypothesis that transformation of excess planar membrane of the contractile vacuole into 40 nm diameter tubules, that remain continuous with the contractile vacuole membrane, is a primary cause for the tension development in the planar membrane. In order to investigate tension development further, we have examined electron microscopically the contractile vacuole membrane at the rounding phase. To do this, we developed a computer-aided system to fix the cell precisely at the time that the contractile vacuole exhibited rounding. In this system a decrease in the electrical potential across the contractile vacuole membrane that accompanied the vacuole's rounding was monitored through a fine-tipped microelectrode inserted directly into the in vivo contractile vacuole. A decrease in membrane potential was used to generate an electric signal that activated an injector for injecting a fixative through a microcapillary against the cell at the precise time of rounding. Subsequent electron micrographs of the contractile vacuole membrane clearly demonstrated that numerous approximately 40 nm membrane-bound tubules formed in the vicinity of the vacuole's microtubule ribbons when the vacuole showed rounding. This finding suggested that membrane tubulation was the cause for topographical isolation of excess membrane from the planar membrane during the periodic rounding of the contractile vacuole. This together with stereo-pair images of the contractile vacuole complex membranes suggested that the microtubule ribbons were intimately involved in enhancing this membrane tubulation activity. Electron micrographs of the contractile vacuole complexes also showed that decorated tubules came to lie abnormally close to the contractile vacuole in these impaled cells. This suggested that the contractile vacuole was capable of utilizing the smooth spongiome membrane that lies around the ampullae and the collecting canals to increase its size.
Animals↗
Specific targeting immunotherapy of cancer with bispecific antibodies.
In order to enhance cell mediated cytotoxicity, bispecific antibodies (BsAbs), molecules combining two or more antibodies with different antigenic specificities, have been developed as new agents for immunotherapy. Our recent studies revealed that simultaneous administration of two kinds of BsAbs (anti-tumor x anti-CD3 plus anti-tumor x anti-CD28) together with lymphokine activated killer cells with a T cell phenotype (T-LAK cells) inhibited growth of human xenotransplanted tumors in severe combined immunodeficient (SCID) mice, while single BsAb was without effect. Three kinds of BsAbs (anti-tumor x anti-CD3, anti-tumor x anti-CD28, anti-tumor x anti-CD2) showed the highest cytotoxicity against tumor cells when given simultaneously with T-LAK cells or peripheral blood mononuclear cells in vitro and in vivo. BsAbs can be preserved for immediate application, while cytotoxic T lymphocytes (CTLs) must be made-to-order, and are time-consuming to prepare. Tumor associated antigens, such as MAGE antigens, SART antigens, MUC1 antigen, c-erbB 2 antigen or cancer/testis antigens can be served to target antigens for BsAb production. By conjugation with antibodies to effector cells (anti-CD3, anti-CD28, anti-CD16, anti-CD64, anti-CD89 or anti-CD2), many kinds of BsAbs can be produced to cover most types of cancers from different organs. Therefore this strategy might be ubiquitously applicable to most malignancies.
Animals↗
Use of porous hydroxyapatite graft containing recombinant human bone morphogenetic protein-2 for cervical fusion in a caprine model.
OBJECT: The efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) for enhancing anterior cervical spine interbody fusion when added to a porous hydroxyapatite (HA) graft was investigated. METHODS: Fourteen mature goats underwent three-level anterior discectomies after induction of endotracheal anesthesia. Porous HA grafts that contained 0, 5, and 50 microg of rhBMP-2 were placed concurrently with anterior cervical spine plates to achieve interbody fusion. The fusion rate, radiological findings, biomechanical stiffness, and histological appearance were evaluated in 42 spinal units immediately and again at 4 and 12 weeks after graft and plate placement. At 12 weeks postsurgery, manual testing showed a 100% fusion rate in the spines with HA grafts containing high-dose rhBMP-2; however, only a 50% fusion rate was shown in spines with grafts that contained no or low-dose rhBMP-2. On radiographic and histological studies the process of solid fusion was seen to be more advanced in relation to the use of larger amounts of rhBMP-2. Biomechanical testing demonstrated significantly higher stiffness values for grafts that contained high-dose rhBMP-2 than those without rhBMP-2 in flexion at 4 weeks, as well as in flexion, extension, and lateral bending tests at 12 weeks. Histological analysis demonstrated that rhBMP-2 increased the amount of bone apposition on the surface of the implants and promoted bone formation in the porous structure without increasing the penetration distance. CONCLUSIONS: Through osteogenesis at the fusion site, the addition of rhBMP-2 to a porous HA ceramic graft enhances the rate of anterior cervical fusion.
Animals↗
[Recent development of oral anti-cancer drugs for breast cancer].
Oral anti-cancer drugs play an important role in the treatment of breast cancer. Because these hormonal agents are related to mammary carcinogenesis and tumor growth, they are used not only for therapy but also to prevent the onset of the disease. Tamoxifen, toremifene, fadrozole and other aromatase inhibitors, goserelin, leuprolin and MPA are used widely in Japan as hormonal anti-cancer drugs. In addition oral anti-cancer chemotherapeutic agents, such as cyclophosphamide, 5-FU, 5'-DFUR, FT and UFT are used for breast cancer. The combination of these hormonal and chemotherapeutic agents produces good clinical results in curing the disease. Oral drugs are superior to injected drugs with regard to the QOL of patients.
Administration, Oral↗
Significance of thymidine phosphorylase as a marker of protumor monocytes in breast cancer.
Tumor-associated monocytic cells (TAMs) are a major component of the stroma responsible for tumor formation. TAMs generate various kinds of mediators for their function, one of which is thymidine phosphorylase (TP). TP is an angiogenic enzyme that is known to be up-regulated in tumor tissues. Here, we focused on the clinical implication of TP expression in TAMs by studying 229 primary breast carcinoma tissues. Immunohistochemical analysis demonstrated that monocytic TP+ tumors had a significantly worse prognosis than did monocytic TP- tumors (P < 0.01, log-rank test). A multivariate analysis confirmed that monocytic TP status provided an independent prognostic value (P < 0.0001). Furthermore, of interest was that monocytic TP status could categorize the CD68+ patients, who had an extensive accumulation of CD68+ TAMs, into two subgroups with strikingly contrasting prognoses: a good prognostic monocytic TP- group and a poor prognostic monocytic TP+ group. This indicates that there are both antitumor and protumor types of TAM. Subanalysis showed that microvessel density was significantly increased in CD68+/monocytic TP+ tumors compared with CD68+/monocytic TP- tumors. Experimentally, TAMs are known to function in diverse manners, antitumor and protumor; however, little is known about clinically recognizable markers to characterize the TAMs in histological sections. TP might be such a marker, which would be useful for identifying the character of TAMs, particularly the protumor phenotype.
Adult↗
[Progress in breast cancer treatment over a quarter of a century].
The treatment of breast cancer has changed greatly over the last 25 years in Japan. The use of Halsted's surgical procedure has been reduced in breast conserving treatment, and even the ommision of axillary dissection has been argued recently. On the other hand, endocrine therapy has progressed remarkably with acceptance of tamoxifen in the clinic. Approval of LH-RH analogs and aromatase inhibitors has brought a new era in breast cancer treatment. The introduction of adriamycin, a powerful anticancer drug brought about a rapid increase in response rate and the development of oral type 5-fluorouracil (5-FU) derivatives made new treatments possible. S-1 and capecitabine, newly licensed 5-FU derivatives developed in Japan, have attracted notice worldwide. In 1992 the Japan Breast Cancer Society was founded and the level of breast cancer research in Japan has improved remarkably. Treatment results are now camparable to those of western countries.
Antineoplastic Agents↗
[Docetaxel as a single agent in cases of advanced/recurrent breast cancer previously treated with anthracycline].
Docetaxel 60 mg/m2 was administered via 1-hour intravenous infusion every 3-4 weeks to 20 patients with advanced/recurrent breast cancer who had previously received anthracycline therapy. The overall response rate was 30.0% (6/20), with 1 complete remission and 5 partial remissions. The median response duration was 120 days. Response rates classified by recurrence site were soft tissues 43.0%, liver 33.3%, lung 33.3%, and bone 23.1%, respectively. Stable disease (prolonged NC) which continued more than 6 months was observed in patients with bone metastasis. Grade 3-4 leukocytopenia and neutropenia were observed in 45.0% and 55.0%, respectively. Grade 3-4 leukocytopenia and neutropenia were frequently seen in patients who had received anthracycline of more than 500 mg/body as first-line chemotherapy. Docetaxel thus seems to be effective in patients with advanced/recurrent breast cancer who are refractory to anthracycline therapy.
Adult↗