Biomedical subjects
Publications and source records attributed to Shigeru Sasaki.
Hereby we report our observations derived from the study of a huge cross-sectional sample of the general population that metabolic risk factors (RFs) tend to cluster into metabolic syndrome (MS). The clustering trend was considered to be intensified with 4-5 RFs.
PURPOSE: We conducted a multicenter prospective study to evaluate the efficacy and safety of reduced-dose three-course CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) followed by involved-field radiotherapy for elderly patients with localized aggressive non-Hodgkin's lymphoma. The primary endpoint was compliance with the combined modality. METHODS AND MATERIALS: This study included untreated patients, > or =70 years old, with diffuse aggressive lymphoma, Stage IA or contiguous nonbulky Stage IIA. 80%-CHOP (cyclophosphamide 600 mg/m(2), doxorubicin 40 mg/m(2), vincristine 1.1 mg/m(2), and prednisolone at 80 mg/day for 5 days) was repeated every 3 weeks. After three cycles of chemotherapy, involved-field radiotherapy was performed with a radiation dose of 30-50 Gy in 15-28 fractions. RESULTS: Twenty-four patients with a median age of 75 years (range, 70-84 years) were enrolled. The compliance rate of the protocol study was 87.5% (95% confidence interval [CI], 67.6-97.3). Three patients received only two cycles of chemotherapy because of toxicity or second neoplasm. There were no deaths caused by severe toxicity. The 3-year progression-free and overall survival rates were 83.1% (95% CI, 75.4-90.8) and 82.9% (95% CI, 75.1-90.6), respectively. CONCLUSION: Three-course 80%-CHOP followed by involved-field radiotherapy may be safe for administration to elderly patients over 70 years old. The next step is to evaluate three-course 80%-CHOP and rituximab followed by radiotherapy in elderly patients with localized disease.
BACKGROUND: Three prospective randomized clinical trials (RCT) in the 1990s demonstrated the survival benefit of postmastectomy radiotherapy (PMRT) for patients with locally advanced breast cancer. The present study was performed to evaluate whether the Patterns of Care Study (PCS) fulfills a role in monitoring the patterns of changes in clinical practices in Japan. METHODS: The first survey (JPCS-1) involved 79 Japanese facilities by two-stage cluster sampling of facilities and patients, and was carried out during 1998-2000. JPCS-1 included 1124 patients with breast cancer who were treated between 1995 and 1997. The second survey (JPCS-2) was carried out during 2001-2003, involving 827 patients who were treated between 1999 and 2001 in 76 facilities. RESULTS: Patients with adverse risk factors, including pathologically axillary positive nodes (> or =4) and/or advanced primary disease (pT3-4) accounted for 57% of the patients who received PMRT in JPCS-1 and 72% of those in JPCS-2 (P = 0.039). The multiple radiotherapy target volume including the chest wall and regional lymph nodes was applied in 18% of the patients in JPCS-1 and 44% of those in JPCS-2 (P < 0.001). However, the dose distribution was calculated in only 42% of the patients in both surveys (P = 0.467). CONCLUSIONS: The eligibility and the target volume for PMRT were influenced by the outcome of RCT, but the quality of radiotherapy did not improve sufficiently. The PCS survey is useful to monitor the changes in patterns of clinical practice and can clarify some problems with radiotherapy techniques.
Crowded triarylphosphines possessing ferrocenyl groups [(4-ferrocenyl-2,6-diisopropylphenyl)(n)(2,4,6-triisopropylphenyl)(3-n)P (5a, n = 1; 5b, n = 2; 5c, n = 3)] were synthesized by the reaction of the corresponding arylcopper(I) reagents with the diarylchlorophosphines. Structures of the triarylphosphines were studied by 1H, 13C, and 31P NMR spectroscopies, and the characteristic patterns of the proton signals of the 2,6-isopropyl groups and upfielded 31P chemical shifts suggest structural similarities of the triarylphosphine moiety to the previously reported tris(2,4,6-triisopropylphenyl)phosphine (2). X-ray crystallography of 5c also revealed that the structure around the phosphorus is similar to that of 1, where the average bond angle and length around the phosphorus atom are 110.8 degrees and 1.854 A, respectively. According to the electrochemical measurements, phosphines 5a, 5b, and 5c are reversibly oxidized in two, three, and four steps, respectively, which suggests significant electronic interaction among the triarylphosphine and the ferrocene redox centers as well as weak interaction among the ferrocene redox centers. The EPR spectra obtained at cryogenic temperature after oxidation of phosphines 5a, 5b, and 5c are superpositions of those for the cation radicals of the crowded triarylphosphine and ferricinium. The solution spectra obtained at 293 K, which consist of two lines typical of the cation radical of the crowded triarylphosphines, become weaker as the number of the ferrocenyl groups increases and the cation radical of 5c does not show EPR signals. These findings suggest not only instability of the tetra(cation radical) of 5c but also the course of oxidation where the ferrocenyl groups in the periphery of the molecules are oxidized at first.
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A linearized plasmid DNA, in which tandem repeats of 400bp flank the breakpoints, was transfected into vertebrate cells, and breakpoint junctions of plasmid DNA circularized in the cells were analyzed to assess the repair activities against DNA double-strand break (DSB) by non-homologous end joining and homology-directed repair (i.e., homologous recombinational repair and single-strand annealing). The circularization by non-homologous end joining repair of the breakpoints depended on the expression of DNA-PKcs, while that by homology-directed repair through the repeats depended on the length of the repeats, indicating that these two DSB repair activities can be rapidly assessed by this assay. Predominance in circularization by either non-homologous end joining or homology-directed repair differed among cells examined, and circularization was exclusively undertaken by homology-directed repair in DT40 cells known to show a high homologous recombination rate against gene-targeting vectors. Thus, this assay will be helpful in studies on mechanisms and inter-cellular variations of DSB repair.
PURPOSE: To present the results of a process survey on breast-conserving therapy (BCT) in Japan from 1995 to 1997. METHODS AND MATERIALS: From September 1998 to December 1999, data on the treatment process of 865 randomly selected BCT patients were collected by extramural audits. RESULTS: For primary surgery, wide excision or tumorectomy was performed in 372 patients (43.0%), and quadrantectomy or segmental mastectomy was performed in 493 patients (57%). The extent of axillary dissection was equal or beyond Level II in 590 patients (68.2%). Systemic chemotherapy was administered to 103 of 160 node-positive patients (64.4%) and 180 of 569 node-negative patients (31.6%). Tamoxifen was administered to 234 of 323 hormone receptor-positive patients (72.5%) and 68 of 130 hormone receptor-negative patients (52.3%). Photon energy of 10 MV was administered for whole breast irradiation in 38 patients (4.4%) without bolus. CONCLUSIONS: The extent of surgical resection for BCT was large in Japan. Pathologic assessment and the technique of radiation therapy were apparently suboptimal in some cases. Information on prognostic/predictive factors was not fully utilized to individualize systemic adjuvant therapy. Establishment and widespread use of guidelines for BCT for in Japan are desirable. Repeated surveys will demonstrate how such guidelines affect clinical practices.
Phosphaquinomethane and phosphathienoquinomethanes sterically protected by Mes* (Mes* = 2,4,6-tri-tert-butylphenyl) were synthesized by 1,6-dehydration of the corresponding 4-phosphinoaryl carbinols. Structural similarities to the conventional quinoid compounds were revealed by 1H, 13C, and 31P NMR study and further confirmed by X-ray crystallography of the phosphathienoquinomethane. The corresponding anion radicals were generated by reduction with sodium, and considerable delocalization of an unpaired electron was demonstrated by EPR.
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The elevation of plasma L-arginine levels stimulates nitric oxide (NO) synthesis, but the underlying mechanisms are not yet understood. We examined the role of physiological changes in pulmonary arteries on endogenous NO production. Male Wistar rats were divided into following groups: (1) control rats receiving normal water orally, (2) ARG rats receiving L-arginine water orally, (3) MCT rats injected with monocrotaline (MCT) on day 0 and receiving normal water orally, and (4) MCT+ARG rats injected with MCT on day 0 and receiving L-arginine water orally. The rats were studied after 23 days of dietary intervention. In MCT+ARG rats, supplemental L-arginine exhibited a significant pulmonary vasodilatory effect, as shown by a decreased pulmonary arterial pressure (PAP) (P<0.001), decreased right ventricular hypertrophy (P<0.01), and improved endothelium-dependent relaxation (P<0.01). Also L-arginine inhibited the elevation of plasma endothelin-1 (P<0.01). Oral L-arginine administration increased plasma L-arginine levels about twofold, but in only MCT+ARG rats (i.e., not in ARG rats) did the urinary nitrate excretion significantly increase (P<0.05), which is an indicator of endogenous NO formation. Oral administration of L-arginine is effective against pulmonary vascular remodeling. The data also suggest that the initial elevation of PAP is important for the induction of endogenous NO synthesis.
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Monoclonal antibodies (mAbs) against growth factors or their receptors have been revealed to be effective therapeutic agents for solid tumors. Trastuzumab (humanized anti-HER2 mAb) is the first mAb approved for the treatment of a solid tumor, metastatic breast cancer. Large-scale phase III clinical trials are now ongoing to further evaluate the additive effects on chemotherapy and the efficacy as a maintenance monotherapy. Another anti-HER2 mAb CH401 that we developed also seems to have good potential. This chimeric mAb completely suppressed the growth of established human tumor xenografts in SCID mice after a single injection. Furthermore, CH401 characteristically showed much stronger induction of apoptosis in HER2-overexpressing gastric cancer cells compared to trastuzumab. Additional targets now being intensively evaluated are epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). Both cetuximab (chimeric anti-EGFR mAb) and bevacizumab (humanized anti-VEGF mAb) have recently been shown to be of clinical value for metastatic colorectal cancer. Anti-idiotype mAbs are unique as active immunotherapeutic agents, and survival benefits have been observed in clinical trials for solid tumors.
With the development of MRI and MRA, many unruptured aneurysms have been detected and treated. Nevertheless, not a few false-positive and false-negative cases are found. We investigate aneurysms that were suspected after screening MRA at the neurosurgical outpatient clinic and the features of aneurysms detected not with MRA but with DSA were studied. Seventy-six patients (85 aneurysms) were suspected due to screening MRA and DSA was performed in 64 (71 aneurysms) of them. Correct diagnosis of cerebral aneurysms with MRA was obtained in 44 patients (45 aneurysms, 63.4%), while false-negative cases were found in 17 patients (plus 20 aneurysms) and false-positive cases in 7 patients (10 aneurysms). The accuracy was 97.2% in ACA, 93% in MCA, 94.4% in VA-BA, and 78.9% in IC, while the sensitivity 100%, 88.2%, 81.8%, 64.7% and the specificity 96.5%, 94.4%, 96.7%, 91.9%, respectively. The features of aneurysms correctly diagnosed with MRA were relatively large ACA, including AcoA, MCA and VA-BA aneurysms, whereas the features of aneurysms undetected with MRA were small IC aneurysms (1-3mm in diameter), especially at the C2-3 portion. These aneurysms at the C2-3 portion or at unusual portions tended to be difficult to detect even with 3D-CTA. Though most of the aneurysms detected with DSA but not with MRA tended to be small and not interventionally treated in the present study, we should pay attention to the fact that these aneurysms are overlooked despite the possibility that they may become enlarged or rupture. Though ruptured aneurysms were surgically treated with only MRA or 3D-CTA without conventional angiography in these days, we recommend the examination of the unruptured cases, which are usually asymptomatic and not hasty, with precise inspection by target MIP, high-performance 3D-CTA or DSA.
OBJECTIVE: To evaluate the clinical usefulness of the "diagnostic score"for the detection of choriocarcinoma in persistent gestational trophoblastic disease without histologic findings. STUDY DESIGN: We reviewed the clinical records of and histologic reports on all 809 patients with persistent gestational trophoblastic disease treated with surgery and chemotherapy in Japan. There were 347 cases of choriocarcinoma and 462 cases of invasive mole with histologic confirmation. We retrospectively applied the diagnostic score to all the patients. RESULTS: The sensitivity of the score for choriocarcinoma (the true positive rate of the score for histologic diagnosis of choriocarcinoma) was 91.4%. The specificity of the score (the true positive rate of the score for the histologic diagnosis of invasive mole) was 94.1%. The accuracy of the score was 92.8%. CONCLUSION: The diagnostic score is a unique scoring system for differentiating choriocarcinoma clinically from persistent gestational trophoblastic disease without histologic findings and for selecting the most appropriate chemotherapy. Proper management in the early stages strongly influences the outcome of these diseases. The scoring system should be very useful for comparing the nearly true incidence and treatment results with choriocarcinoma between nations.
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Swift elimination of undesirable cells is an important feature in tumour suppression and immunity. The tumour suppressor p53 and interferon-alpha and -beta (IFN-alpha/beta) are essential for the induction of apoptosis in cancerous cells and in antiviral immune responses, respectively, but little is known about their interrelationship. Here we show that transcription of the p53 gene is induced by IFN-alpha/beta, accompanied by an increase in p53 protein level. IFN-alpha/beta signalling itself does not activate p53; rather, it contributes to boosting p53 responses to stress signals. We show examples in which p53 gene induction by IFN-alpha/beta contributes to tumour suppression. Furthermore, we show that p53 is activated in virally infected cells to evoke an apoptotic response and that p53 is critical for antiviral defence of the host. Our study reveals a hitherto unrecognized link between p53 and IFN-alpha/beta in tumour suppression and antiviral immunity, which may have therapeutic implications.
Interstitial deletions of the chromosome 9p21 segment encoding the p16/CDKN2A tumor suppressor gene (i.e., 9p21 deletions) are frequently observed in a variety of human cancers. A majority of these deletions in lymphoid leukemia have been indicated to be mediated by illegitimate V(D)J recombination. In the present study, to elucidate the molecular processes of 9p21 deletions in nonlymphocytic malignancies, breakpoints for these deletions were analysed in 21 lung cancer cell lines and 32 nonlymphocytic cancer cell lines of nine other histological types. In all, 32 breakpoints in 21 lung cancer cell lines and 56 breakpoints in 32 nonlung cancer cell lines were mapped in a 450-kb segment encompassing the CDKN2A locus with a 10-kb resolution. The largest number of breakpoints (i.e., seven breakpoints in lung cancer and 12 breakpoints in nonlung cancers) was mapped in a 10-kb region containing the CDKN2A gene. More precise mapping of these seven and 12 breakpoints revealed that none of these breakpoints were located within 50-bp intervals to each other in this 10 kb region. Cloning and sequencing of breakpoints in 18 representative cell lines (six lung and 12 nonlung cancers) further revealed that there were no significant homologies among breakpoints in these 18 cell lines. In 11 (61%) cell lines, 1-5-bp nucleotides were overlapped at breakpoint junctions. These results indicate that DNA double-strand breaks triggering 9p21 deletions do not occur at specific DNA sequences, although they preferentially occur in or near the CDKN2A locus. It was also indicated that two broken DNA ends are rejoined by nonhomologous end-joining repair, preferentially utilizing microhomologies of DNA ends, in the occurrence of 9p21 deletions.
BACKGROUND: Cardiotrophin-1 (CT-1) reduces arterial blood pressure by activating nitric oxide synthesis. This study attempted to elucidate the effect of CT-1 on pulmonary arteries of pulmonary hypertensive rats. METHODS: Pulmonary hypertension was induced in rats in a hypoxic chamber containing 10% to 11% oxygen. Rats kept in the hypoxic environment received either recombinant mouse CT-1 at a concentration of 50 micro g/kg (CT-1+hypoxia group, n = 21) or phosphate-buffered saline (hypoxia group, n = 30) once per day. Control rats housed in room air also received either the equivalent concentration of CT-1 (CT-1+normoxia group, n = 18) or phosphate-buffered saline (normoxia group, n = 39). Pulmonary arterial pressure, pulmonary vasorelaxation, and ventricular hypertrophy were measured. RESULTS: The mean pulmonary arterial pressures were as follows (from lowest to highest; p values are relative to the hypoxia group): normoxia group (20.3 +/- 4.0 mm Hg, p < 0.0001), CT-1+normoxia group (21.1 +/- 2.4 mm Hg, p < 0.0001), CT-1+hypoxia group (27.9 +/- 4.1 mm Hg, p = 0.0019), and hypoxia group (33.9 +/- 6.6 mm Hg). The endothelium-dependent vasorelaxation value was largest in the normoxia group (59.5% +/- 17.4%, p < 0.0001), with it decreasing in the other groups in the following order (p values are relative to the hypoxia group): CT-1+normoxia group (52.8% +/- 15.5%, p = 0.0005), CT-1+hypoxia group (42.3% +/- 14.8%, p = 0.0061), and hypoxia group (17.4% +/- 4.8%). Right ventricular hypertrophy was significant only in the hypoxia group. CONCLUSIONS: Our results demonstrate that treatment with CT-1 in a chronic hypoxic pulmonary hypertension model protects the endothelial function of the pulmonary artery; decreases pulmonary arterial pressure; and attenuates right ventricular hypertrophy.