Biomedical subjects
Publications and source records attributed to M Kitajima.
A novel alkaloid, lycoposerramine-A (1), which has a 1,2,4-oxadiazolidin-5-one residue in the molecule, was isolated from the club moss Lycopodium serratum Thunb. The structure was determined by spectroscopic and X-ray analyses. [structure: see text]
Maspin belongs to a tumor suppressing protein which is usually expressed highly in myoepithelial cells, and is significantly downregulated in breast cancer cells. We focused on identifying the correlation between maspin expression and the clinicopathological features of human breast cancer tissues using immunohistochemistry. There was a significant correlation in that maspin-positive tumor specimens showed a low pathological grade of malignancy, such as a lower infiltration of the tumor into the surrounding tissue and a downregulation of c-erbB2 expression. Moreover, maspin-positive cases showed a significant decrease in tumor vessels positively stained with anti-factor VIII-related antigen antibody. These results suggest that maspin production in myoepithelial cells could downregulate the malignant phenotype of breast cancer.
The small intestinal damage induced by the methotrexate (MTX) treatment results in malabsorption and diarrhea. The fluoresceinated methotrexate (F-MTX) may possibly be useful to study such effects of MTX on the small intestine. The purpose of this study is to characterize the transport of F-MTX in the small intestine in order to use it as a membrane transport and cellular marker of MTX. The transport of F-MTX in the rat small intestine (jejunum) was examined in the in vitro everted segments of the intestine. The uptake was pH-dependent and showed a maximal effect at pH 6.0, which was the same as the results of MTX previously reported. Further, it was temperature-dependent and was inhibited by metabolic inhibitors, dinitrophenol and sodium azide, and by MTX. The transport kinetics at pH 6.0 in the mucosal solution and at pH 7.4 in the serosal solution was saturable with Km of 0.48 +/- 0.23 microM and Vmax of 0.66 +/- 0.24 pmol/cm/min and in addition, the passive diffusion was observed there. These results suggested that the transport of F-MTX was energy-dependent and was mediated by the same transporter as that of MTX, although, in addition to it, other transport mechanism might contribute to the F-MTX transport. Therefore F-MTX will be of great use to investigate the MTX transport system in the normal and diseased states of small intestine, using various fluorescence techniques like visualization of membrane-associated transport proteins.
BACKGROUND AND OBJECTIVES: We investigated whether the clinicopathologic characteristics and prognosis of lung cancer in younger patients differ from those of older patients. METHODS: Among 2,763 lung cancer patients treated during the period from April of 1972 to April of 1997, we retrospectively investigated the clinical features and prognosis of 53 patients under 40 years of age (young group) and compared them with the findings of 1,886 patients with 60 years of age or older (elderly group). RESULTS: The proportion of female patients in the younger group was significantly higher than that in the elderly group (39.6% vs. 24.1%). The young group had a significantly higher proportion of adenocarcinoma (75.5% vs. 44.8%) and stage III-IV disease (73.6% vs. 59.2%) and a significantly lower proportion of squamous cell carcinoma (3.8% vs. 32.1%). Regarding the selection of therapy, in the young group, a significantly lower proportion of patients underwent surgical therapy (35.8% vs. 41.5%) and a significantly higher proportion of those (37.7% vs. 16.4%) received chemotherapy. The overall survival between the young and elderly groups was not significantly different. Moreover, the 5-year survival rate of the patients undergoing a surgical resection was 56.1% in the young group and 44.8% in the elderly group (P = 0.0615). CONCLUSIONS: This study suggests that the prognosis of young patients with lung cancer is at least equivalent to that of older patients; therefore, they should be managed according to the general therapeutic guidelines.
BACKGROUND: To determine the role of tumor necrosis factor (TNF) and interleukin (IL)-1 in small-intestinal ischemia-reperfusion (I-R) injury, we investigated the effect of FR 167653, a specific IL-1 and TNF inhibitor, on warm I-R injury of the rat small intestine. MATERIALS AND METHODS: Male rats treated with either saline (NS group) or FR 167653 (FR group) underwent 150 min of warm small-intestinal ischemia by applying a vascular clip at the origin of the superior mesenteric artery. In addition to the survival analyses, we investigated plasma TNF-alpha and endotoxin levels, intestinal tissue TNF-alpha and IL-1beta levels, hematocrit values and the amount of exudates in the intestinal lumen, glutamic aspartate aminotransferase (AST), and histological findings up to 120 min after reperfusion. RESULTS: TNF-alpha and IL-1beta levels in the intestinal tissue, and plasma TNF-alpha and endotoxin levels, were significantly (P < 0.05) reduced in the FR group. Severe mucosal damage on histological findings (120 min after reperfusion) and a large amount of intraluminal exudates (60 min after reperfusion) were shown in the NS group, but these findings were significantly (P < 0.05) ameliorated in the FR group. Serum AST levels in the NS group increased 120 min after reperfusion, but this change was significantly (P<0.05) reduced in the FR group. The 30-day survival rate was 80% in the FR group and 30% in the NS group (P<0.05). CONCLUSIONS: Dual inhibition of TNF and IL-1 effectively alleviated intestinal I-R injury, suggesting the key role of TNF and IL-1 in this pathophysiology.
PURPOSE: In the present study, four bone metabolic markers were examined to clarify them meaning and clinical value in the detection of bone metastasis (BM) from breast cancer. METHODS: we examined serum carboxyterminal telopeptide of type I collagen (ICTP), tartrate resistant acid phosphatase (TRACP), total alkaline phosphatase (ALP) and urinary type I collagen cross-linked N-telopeptides (NTx) as potential markers. These bone markers were evaluated simultaneously in 156 breast cancer patients; 114 patients without metastasis (group A), 23 patients with BM (group B) and 19 patients with metastasis at sites other than bone (group C). RESULTS: The mean values of ICTP and TRACP in group B were significantly greater than those in group A. Group B consisted of the patients with varying degrees of BM and variation in their treatments. The patients in group B were divided into BM (+) and BM (++) according to hot spots in bone scan. ICTP and TRACP were elevated in BM (++) patients compared to BM (+) patients (p<0.05). The values of ICTP and TRACP of the twelve patients without treatment in group B were significantly higher than those in group A. In the treated patients of group B, the mean values of ICTP and TRACP were lower in responders and cases of stable disease than those with progression. NTx and ALP were inferior to ICTP and TRACP for clinical evaluation of BM. CONCLUSIONS: We confirmed that ICTP and TRACP might be useful markers for screening and monitoring BM in breast cancer.
Juliano and Ling initially reported the expression of a 170 kDa glycoprotein in the membrane of Chinese hamster ovarian cells in 1976, and named this glycoprotein P-glycoprotein (P-gp) based on its predicted role of causing "permeability" of the cell membrane. After much research on anthracycline-resistance, this P-gp was finally characterized as a multidrug-resistant protein coded by the mdr1 gene. Multidrug resistance associated protein (MRP) was initially cloned from H69AR, a human small cell-lung carcinoma cell line which is resistant to doxorubicin (DXR) but does not express P-gp. MRP also excretes substrates through the cell membrane using energy from ATP catabolism. The substrate of MRP is conjugated with glutathione before active efflux from cell membrane. Recently, membrane transporter proteins were re-categorized as members of "ATP-Binding Cassette transporter"(ABC-transporter) superfamily, as shown at http://www.med.rug.nl/mdl/humanabc.htm and http://www.gene.ucl.ac.uk/nomenclature/genefamily/abc.html. A total of ABC transporters have been defined, and MDR1 and multidrug resistance associated protein 1 (MRP1) were reclassified as ABCB1 and ABCC1, respectively. Their associated superfamilies include 11 and 13 other protein, in addition to ABCB and ABCC, respectively. Lung resistance-related protein (LRP) is not a member of the superfamily of ABC transporter proteins, because it shows nuclear membrane expression and transports substrate between nucleus and cytoplasm. LRP was initially cloned from a non-small cell lung carcinoma cell line, SW1573/2R120 which is resistant to DXR, vincristine, etoposide and gramicidin D and does not express P-gp. The mechanisms of resistance remains unclear, and why some resistant cell lines express P-gp and others express MRP and/or LRP is likewise unclear.
Our purpose was to evaluate and compare the performance of ultra-fast single-shot T2-weighted sequences: echo-planar imaging (EPI) versus half-Fourier single-shot turbo spin-echo (HASTE) and to assess the usefulness of their combined reading. Comparative experiments on a phantom as well as a prospective clinical study in 47 patients were done. Axial images acquired with the following methods were compared: (a) HASTE; (b) segmented HASTE (s-HASTE); (c) single-shot spin-echo EPI (SE-EPI); and (d) gradient-echo EPI (GREEPI). Quantitative and qualitative criteria as well as lesion detectability were analyzed against the "gold standard" fast spin-echo (FSE) sequence. For contrast and contrast-to-noise ratio (CNR) between gray and white matter, GRE-EPI was best. The visibility of small markedly hyperintense lesion was best with HASTE and s-HASTE in the clinical study. Small hyperintense lesions were detected equally well with all four sequences, although all performed significantly worse than FSE. The two HASTE variants were better than the EPIs for the extraaxial lesions. The combination of the GRE-EPI and s-HASTE was judged best, and sometimes superior to the FSE image. HASTE or EPI alone cannot substitute for FSE in the screening evaluation of the brain. However, together, EPI and HASTE could provide comparable diagnostic information to that of FSE because their combination compensates for their individual limitations.
OBJECTIVE: To determine whether elevated midpregnancy maternal serum lipid levels predict newborn weight at term and the risk of large for gestational age (LGA) infants in women with positive diabetic screen but normal glucose tolerance test. METHODS: Japanese gravidas who had positive diabetic screens and normal 75-g oral glucose tolerance tests (GTT) at 24--32 weeks were enrolled. Subjects with complications, including diabetes, hypertension, or fetal anomalies were excluded, as were women with multifetal gestations. Fasting serum triglyceride, free fatty acids, and total cholesterol levels were measured at the time of GTT. We tested the association between maternal variables and birth weight by univariable analysis. We used multivariable analysis to test whether the association between fasting lipids and birth weight was independent of prepregnant maternal body mass index (BMI), maternal weight gain during pregnancy, and plasma glucose levels at GTT. We also used multiple logistic regression analysis to determine whether maternal hyperlipidemia, defined as more than the 75th percentile of each lipid, is a risk factor for having an LGA infant. RESULTS: We enrolled 146 subjects. Among measured maternal lipids, only triglyceride levels correlated with birth weight in univariable analysis (r = 0.22, P =.009). Birth weight also was correlated with prepregnant maternal BMI (r = 0.18, P =.04) and fasting plasma glucose levels (r = 0.17, P =.04). The association between maternal fasting triglyceride level and birth weight remained significant after adjusting for prepregnant BMI, maternal weight gain, fasting plasma glucose levels, fetal gender, and gestational age at birth (P =.01). Logistic regression analysis showed that fasting maternal hypertriglyceridemia (over 259 mg/dL) was the significant predictor of LGA infants, independent of prepregnant BMI, maternal weight gain, and maternal plasma glucose levels (odds ratio 11.6; 95% confidence interval 1.1, 122; P =.04). CONCLUSION: In women with positive diabetic screens but normal GTTs, fasting triglyceride levels at 24-32 weeks correlated positively with newborn weight at term, independent of maternal plasma glucose levels and obesity. Maternal fasting serum triglyceride levels in midpregnancy might be an independent predictor of fetal macrosomia in those women.
A new prenylated flavone, named artoindonesianin L (1), was isolated from Artocarpus rotunda (Hout) Panzer (Moraceae). Its structure was elucidated as on the basis of spectroscopic evidence. Along with this new compound, four known phenolic compounds were also isolated from this plant and identified as artonins M (2) and E (3), cycloartobiloxanthone (4) and artonin O (5). All these compounds showed significant cytotoxicity against murine P388 leukemia cells.
Two new prenylated compounds, the benzoquinone atrovirinone (1) and the depsidone atrovirisidone (2), were isolated from the roots of Garcinia atroviridis. Their structures were determined on the basis of the analysis of spectroscopic data. While compound 2 showed some cytotoxicity against HeLa cells, both compounds 1 and 2 were only mildly inhibitory toward Bacillus cereus and Staphylococcus aureus.
Two new alkaloids, norpandamarilactonine-A (1) and -B (2), which have a pyrrolidinyl-alpha,beta-unsaturated gamma-lactone moiety as in the known pandamarilactonine alkaloids, were isolated from the leaves of Pandanus amaryllifolius. Their structures were determined by spectroscopic analysis and total synthesis.
The cyclin D1 protein is one of the cell cycle regulators required for cell cycle progression through G1 phase to S phase. The cyclin D1-cyclin-dependent kinase (CDK) system is thought to control the cell cycle through mediating extracellular signals from mitogens, such as epidermal growth factor (EGF). In this study, we attempted to examine the therapeutic effect of cyclin D1 antisense oligonucleotides (AS/D1) on cell proliferation and apoptosis of the gastric cancer cell line MKN-74, in the presence and absence of EGF-stimulation. Evaluation of cell survival and DNA synthesis revealed that enhanced cell growth following EGF-stimulation was completely inhibited by a 24 h pre-incubation with 100 nM AD/D1. This inhibition was down to 19.3% compared with maximal DNA synthesis after stimulation with 3 nM EGF alone. Western blotting demonstrated that while EGF-stimulation led to cyclin D1 over-expression, AS/D1 inhibited cyclin D1 protein expression. We also demonstrated the induction of apoptosis in MKN-74 cells by AS/D1. In conclusion, EGF-stimulated MKN-74 cell proliferation was inhibited by AS/D1, which could overcome EGF-induced cyclin D1 over-expression. AS/D1 also affected cell survival by inducing apoptosis through cell cycle arrest following cyclin D1 depletion. Thus, AS/D1 may be a candidate for use as a novel cancer therapy specifically targeted against the over-expression of cyclin D1 enhanced by EGF in malignant cells.
Mechanisms underlying tumor sensitivity to the antitumor agent UCN-01 (7-hydroxystaurosporine) were examined in the nude mouse model using three human tumor xenografts, two pancreatic cancers (PAN-3-JCK and CRL 1420) and a breast cancer (MX-1). UCN-01 antitumor activity was evaluated in terms of relative tumor weights in treated and untreated mice bearing the tumor xenografts. The activity of cyclin-dependent kinase 2 (CDK2), levels of p21 and p27 proteins, pRb status and cell cycle were evaluated. Induction of p21 and apoptosis were also assessed immunohistochemically in CRL 1420. UCN-01 was administered intraperitoneally at a dose of either 5 or 10 mg / kg daily for 5 days followed by a further 5 injections after an interval of 2 days. UCN-01 significantly suppressed the growth of both pancreatic cancers, but was ineffective against MX-1. p21 protein expression was markedly induced in the UCN-01-sensitive pancreatic carcinoma xenografts at both doses, but p21 induction was only evident in the UCN-01-resistant MX-1 at 10 mg / kg. MX-1 exhibited CDK2 activity that was 6-fold higher than that of pancreatic cancer strains, which may explain the resistance of MX-1 to UCN-01 despite the induction of p21 at the dose of 10 mg / kg. The UCN-01-sensitive tumors exhibited G1 arrest and increased levels of apoptosis, changes not observed in resistant MX-1. In conclusion, it appears that a determining factor of in vivo UCN-01 sensitivity involves the balance of CDK2 kinase activity and p21 protein induction, resulting in augmented pRb phosphorylation, G1 cell cycle arrest and apoptosis.
The flavonoid nobiletin (5,6,7,8,3',4'-hexamethoxyflavone), found in Citrus depressa Rutaceae, a popular citrus fruit in Okinawa, Japan, reportedly inhibits the production of pro-matrix metalloproteinase (proMMP)-1, 3, and 9 in rabbit synovial fibroblasts in vitro. In the present study, we demonstrated the inhibitory effects of nobiletin on the proliferation of the cancer cell line, TMK- 1, and its production of MMPs. In the SCID mouse model, we found that nobiletin inhibited the formation of peritoneal dissemination nodules from TMK-1. The enzymatic activity of MMP-9 expressed in culture medium obtained from a co-culture of TMK-1 and mouse fibroblastic cells was inhibited by nobiletin in a concentration-dependent manner. In the SCID mouse model, total weight of dissemination nodules was significantly lower in the treated group compared with the vehicle control group (0.07 g vs. 0.78 g, P = 0.0059). The total number of dissemination nodules was also significantly lower than in the vehicle control group (7.5 vs. 69.3 / body, P = 0.0001). These results suggest that nobiletin may be a candidate anti-metastatic drug for prevention of peritoneal dissemination of gastric cancer.
Minimally invasive surgery has rapidly changed the performance of surgical practice in a wide range of surgical specialities in the last decade of the 20th century. The marked progress in endoscopic surgery has been conducted especially in general and digestive surgery. The Department of Surgery, School of Medicine, Keio University has contributed to the development and establishment of endoscopic surgery in every subspeciality of general and digestive surgery. Our achievements include the development of original methods for laparoscopic wedge gastrectomy and endoscopic thyroidectomy, establishment of surgical techniques in endoscopic surgery for esophageal, gastric, colorectal and hepatobiliary diseases, and the introduction of robotics and tele-communicative technologies to endoscopic surgery.
BACKGROUND AND PURPOSE: The diagnosis of dural sinus thrombosis is often difficult because of its variable and nonspecific clinical presentation and the overlapping signal intensities of thrombosis and venous flow on conventional MR images and MR venograms. We compared 3D contrast-enhanced magnetization-prepared rapid gradient-echo (MP-RAGE) sequences with 2D time-of-flight (TOF) MR venography, digital subtraction angiography (DSA), and conventional spin-echo (SE) MR imaging for the assessment of normal and abnormal dural sinuses. METHODS: In a phantom study, a plastic tube with pulsating flow was used to simulate the intracranial dural sinus. With 3D MP-RAGE, a variety of flow velocities, contrast material concentrations, and angulations between the phantom flow tube and the plane of acquisition were tested to measure their relationship to signal-to-noise ratio (SNR). In a clinical study, 35 patients, including 18 with suspected dural sinus thrombosis, were studied with both MR imaging and DSA. Receiver operating characteristic (ROC) analysis was performed in a blinded fashion using DSA as the reference standard. RESULTS: With the phantom, the SNR of flow increased with increasing contrast concentration, but was not affected by the angle between the tube and scan slab. There was no relationship between SNR and velocity when the contrast concentration was 1.0 mmol/L or greater. In the clinical study, dural sinus thrombosis as well as the normal anatomy of the dural sinuses were seen better with 3D contrast-enhanced MP-RAGE than with 2D-TOF MR venography. Three-dimensional contrast-enhanced MP-RAGE showed the highest diagnostic confidence on ROC curves in the diagnosis of thrombosis. CONCLUSION: Three-dimensional contrast-enhanced MP-RAGE is superior to 2D-TOF MR venography and conventional SE MR imaging in the depiction of normal venous structures and the diagnosis of dural sinus thrombosis, and is a potential alternative to DSA.
The clinical outcome of hepatopancreatoduodenectomy (HPD) carried out in 14 patients in our institute was evaluated retrospectively. In principle, HPD is performed in patients with far-advanced biliary carcinoma extending from the level of the liver to pancreas directly or via metastatic lymph nodes around the head of the pancreas. However, the survival periods after surgery did not improve, contrary to expectations. Curative surgery was not achieved in most patients who underwent HPD, even if resection of the portal vein or hepatoduodenal ligament was performed during surgery. Severe lymphatic, vascular, and neural involvement along the hepatoduodenal ligament existed in those patients. In addition, it is possible that they already had micrometastases to other organs based on a study of the pattern of recurrence after surgery. Quality of life did not appear to improve unless the patients survived more than one year. These findings suggest that HPD may be appropriate for patients in earlier disease stages than those in our series to achieve longer survival. However, HPD is associated with high rates of postoperative complications and operative mortality, especially after pancreatoduodenectomy with liver resection involving more than right hepatectomy. We need to establish the appropriate indications for HPD and improve the safety of the procedure.