Prediction of 1H Singlet Relaxation via Intermolecular Dipolar Couplings Using the Molecular Dynamics Method.

Dissolution dynamic nuclear polarization has been applied in various fields, including chemistry, biology, and medical science. To expand the scope of these applications, the nuclear singlet state, which is decoherence-free against dipolar relaxation between spin pairs, has been studied experimentally, theoretically, and numerically. The singlet state composed of proton spins is used in several applications, such as enhanced polarization preservation, molecular tagging to probe slow dynamic processes, and detection of ligand-protein complexes. In this study, we predict the lifetimes of the nuclear spin states composed of proton spin pairs using the molecular dynamics method and quantum chemistry simulations. We consider intramolecular dipolar, intermolecular dipolar between solvent and solute, chemical shift anisotropy, and spin-rotation interactions. In particular, the relaxation rate of intermolecular dipolar interactions is calculated using the molecular dynamics method for various solvents. The calculated values and the experimental values are of the same order of magnitude. Our program would provide insight into the molecular design of several NMR applications and would be helpful in predicting the nuclear spin relaxation time of synthetic molecules in advance.

Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies.

BACKGROUND: The aim of this study was to determine the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of OPB-51602, an oral, direct signal transduction activator of transcription 3 (STAT3) inhibitor, in patients with refractory solid tumors. PATIENTS AND METHODS: Three cohorts were studied: cohort A, a sequential dose escalation of OPB-51602 administered intermittently (days 1-14 every 21 days); cohort B, an expansion cohort evaluating the dose lower than the MTD; cohort C, evaluating continuous daily dosing. RESULTS: Fifty-one patients were studied at 2, 4, and 5 mg per day dosing. The MTD was 5 mg; first-cycle dose-limiting toxicities (DLTs) were grade 3 hyponatremia in one patient, and grade 3 dehydration in another. Intermittent dosing of both 2 and 4 mg doses were tolerable, and the recommended phase II dose was 4 mg. Cohort B investigated 4 mg intermittently, whereas cohort C investigated 4 mg continuously. Common toxicities included fatigue, nausea/vomiting, diarrhea, anorexia, and early-onset peripheral neuropathy. Drug-induced pneumonitis occurred in two patients in cohort C. Continuous dosing was associated with a higher incidence of peripheral neuropathy and a lower mean relative dose intensity, compared with intermittent dosing. Steady-state pharmacokinetics was characterized by high oral clearance, mean elimination half-life ranging from 44 to 61 h, and a large terminal-phase volume of distribution. An active metabolite, OPB-51822, accumulated to a greater extent than OPB-51602. Flow cytometry of peripheral blood mononuclear cells demonstrated pSTAT3 (Tyr(705)) inhibition following exposure. Two patients achieved partial responses at 5 mg intermittently and 4 mg continuously; both had epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor exposure. CONCLUSION: OPB-51602 demonstrates promising antitumor activity, particularly in NSCLC. Its long half-life and poorer tolerability of continuous dosing, compared with intermittent dosing, suggest that less frequent dosing should be explored. CLINICALTRIALSGOV IDENTIFIER: NCT01184807.

Prevention of postoperative pulmonary complications through intensive preoperative respiratory rehabilitation in patients with esophageal cancer.

Postoperative pulmonary complications (PPCs) after esophagectomy have been reported to occur in 15.9-30% of patients and lead to increased postoperative morbidity and mortality, prolonged duration of hospital stay, and additional medical costs. The purpose of this retrospective cohort study was to investigate the possible prevention of PPCs by intensive preoperative respiratory rehabilitation in esophageal cancer patients who underwent esophagectomy. The subjects included 100 patients (87 males and 13 females with mean age 66.5 ± 8.6 years) who underwent esophagectomy. They were divided into two groups: 63 patients (53 males and 10 females with mean age 67.4 ± 9.0 years) in the preoperative rehabilitation (PR) group and 37 patients (34 males and 3 females with mean age 65.0 ± 7.8 years) in the non-PR (NPR) group. The PR group received sufficient preoperative respiratory rehabilitation for >7 days, and the NPR group insufficiently received preoperative respiratory rehabilitation or none at all. The results of the logistic regression analysis and multivariate analysis to correct for all considerable confounding factors revealed the rates of PPCs of 6.4% and 24.3% in the PR group and NPR group, respectively. The PR group demonstrated a significantly less incidence rate of PPCs than the NPR group (odds ratio: 0.14, 95% confidential interval: 0.02~0.64). [Correction added after online publication 25 June 2012: confidence interval has been changed from -1.86~ -0.22] This study showed that the intensive preoperative respiratory rehabilitation reduced PPCs in esophageal cancer patients who underwent esophagectomy.

Histological evaluation of internally-fixed osteochondral lesions of the knee.

We evaluated the histological changes before and after fixation in ten knees of ten patients with osteochondritis dissecans who had undergone fixation of the unstable lesions. There were seven males and three females with a mean age of 15 years (11 to 22). The procedure was performed either using bio-absorbable pins only or in combination with an autologous osteochondral plug. A needle biopsy was done at the time of fixation and at the time of a second-look arthroscopy at a mean of 7.8 months (6 to 9) after surgery. The biopsy specimens at the second-look arthroscopy showed significant improvement in the histological grading score compared with the pre-fixation scores (p < 0.01). In the specimens at the second-look arthroscopy, the extracellular matrix was stained more densely than at the time of fixation, especially in the middle to deep layers of the articular cartilage. Our findings show that articular cartilage regenerates after fixation of an unstable lesion in osteochondritis dissecans.

Behavior of endocrine disrupting chemicals in Johkasou improved septic tank in Japan.

The behavior of estrogens (estrone: E1, 17beta-estradiol: E2, estriol: E3 and ethinylestradiol: EE2) and an androgen (testosterone) in the water and sludge from Johkasou in Japan was investigated. The concentrations of E1, E2, E3 and testosterone in water samples from the Johkasou were 33-500, N.D. approximately 150, N.D. approximately 6,700 and 500 ng/L, respectively. In sludge samples, the concentrations of E1, E2, E3, and testostrerone were N.D. approximately 39, N.D. approximately 6.7, N.D. approximately 60 and 0.2-9.0 ng/L, respectively. EE2 was not detected in all samples. The removal rates of E1, E2, E3 and testosterone in Johkasou were 45%-91%, 66%-100%, 90%-100%, and about 90%, respectively.

Frequency and characteristics of endometrial carcinoma and atypical hyperplasia detected on routine infertility investigations in young women: a report of six cases.

Infertility patients are known to be at increased risk of endometrial carcinoma (EC) and atypical hyperplasia (AH). However, the incidence and clinical features of EC and AH in these patients remain to be clarified. In this study, we examined the rate at which a routine infertility workup revealed EC/AH and investigated the clinicopathological features of EC/AH detected in this way. Among patients diagnosed with EC or AH at the Jichi Medical University Hospital between the 10-year period from 1997 to 2006, six patients were referred from Tochigi Central Clinic, a specialized infertility facility. We report the clinicopathological features of these patients and calculate the incidence of EC/AH in patients who underwent infertility investigations at Tochigi Central Clinic. All six patients were younger than 40 and had early stage disease (final diagnosis: EC stage IA: 3, EC stage IB: 1, AH: 2). A total of 19 826 patients underwent routine infertility investigations at Tochigi Central Clinic during the same period. The incidence of EC/AH detected from these investigations was 0.03% (6/19 826) and that of EC was 0.02% (4/19 826): 5-10 times higher than the overall incidence in Japanese women of the same age. Routine infertility investigations may provide an opportunity to examine the corpus uteri of young women in whom examination is otherwise limited, contributing to the early detection of EC/AH.

Flowering response of rice to photoperiod and temperature: a QTL analysis using a phenological model.

In this study we have attempted to quantify the thermal and photoperiodical responses of rice (Oryza sativa L.) flowering time QTLs jointly by a 'date-of-planting' field experiment of a mapping population, and a 'phenological model' analysis that separately parameterizes the two responses, based on daily temperature, daily photoperiod and flowering date. For this purpose, the 'three-stage Beta model', which parameterizes the sensitivity to temperature (parameter alpha), the sensitivity to photoperiod (parameter beta), and earliness under optimal conditions (10 h photoperiod at 30 degrees C) (parameter G), was applied to 'Nipponbare' x 'Kasalath' backcross inbred lines that were transplanted on five dates. QTLs for the beta value were detected in the four known flowering time QTL (Hd1, Hd2, Hd6 and Hd8) regions, while QTLs for the G value were detected only in the Hd1 and Hd2 regions. This result was consistent with previous reports on near-isogenic lines (NILs) of Hd1, Hd2 and Hd6, where these loci were involved in photoperiod sensitivity, and where Hd1 and Hd2 conferred altered flowering under both 10 and 14 h photoperiods, while Hd6 action was only affected by the 14 h photoperiod. Hd8 was shown to control photoperiod sensitivity for the first time. Interestingly, Hd1 and Hd2 were associated with a QTL for the alpha value, which might support the previous hypothesis that the process of photoinduction depends on temperature. These results demonstrate that our approach can effectively quantify environmental responses of flowering time QTLs without controlled environments or NILs.

Morphology of microphase separated domains in rod-coil copolymer melts.

We investigate the morphology of microphase separated domains in diblock copolymers where each chain consists of a stiff rod block and a flexible coil block. A simplified phenomenological model system is introduced, which is coarse-grained in terms of the local concentration difference between the two blocks and the local director field of the rod part. Computer simulations of this set of time-evolution equations in two dimensions show in the weak segregation regime that the elastic energy in the rod-block rich domains affects drastically the structures of microphase separated domains. A coil-to-rod transition is incorporated into the model system to examine the elastic and anisotropic effects. The effects of the external electric field are also investigated to control the domain morphology.

Treatment for ovarian hyperstimulation syndrome using an oral dopamine prodrug, docarpamine.

Dopamine treatment constitutes a major advance towards the management of severe ovarian hyperstimulation syndrome (OHSS) by causing renal and mesenteric vasodilatation as well as diuretic and positive inotropic actions. Docarpamine, an oral dopamine prodrug, is converted into dopamine after enteral administration, and the generated dopamine causes renal vasodilatation and diuresis. The purpose of this study was to assess whether docarpamine had beneficial effects in patients with OHSS. Twenty-seven patients, hospitalized because of OHSS and refractory to the initial therapy with intravenous albumin, were treated by docarpamine, after informed consent had been obtained. A 750-mg tablet of docarpamine was taken every 8 h. In some cases, the plasma levels of free dopamine were measured. The daily urinary outputs before and 1, 2, 3 and 4 days after the docarpamine treatment were 839 +/- 424 ml, 1121 +/- 608 ml, 1168 +/- 504 ml, 1325 +/- 815 ml and 1133 +/- 509 ml, respectively. There were significant differences between the first and each of the others (p < 0.05). In 19 (86.4%) of 22 patients treated, clinical symptoms associated with ascites were gradually improved after administrating docarpamine. The plasma free dopamine concentration rose to as high as 55.9 +/- 33.2 mg/ml during the first hour, which corresponded to the usual intravenous drip infusion treatment with dopamine. Moreover, there were no major adverse effects of docarpamine in this study. This was the first demonstration of docarpamine treatment in patients with intravenous albumin-resistant OHSS. Although no effect was seen in pregnant women, diuresis was increased in some women, and ascites decreased. These findings indicate that oral docarpamine administration could be one of the options in the management of patients with OHSS using dopamine therapy.

A rise of the serum level of von Willebrand factor occurs before clinical manifestation of the severe form of ovarian hyperstimulation syndrome.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) appears to be caused by increased capillary permeability in the vascular endothelial cells. Such cells secrete excess amounts of von Willebrand factor (vWF), a large adhesive glycoprotein. METHODS: We retrospectively evaluated the circulating levels of vWF and of vascular endothelial growth factor (VEGF) twice, on the days of oocyte retrieval and embryo transfer, in 46 women who developed early-onset OHSS. RESULTS: Nineteen, 14, and 13 women developed mild, moderate, and severe OHSS, respectively. Inconsistent changes were observed in the VEGF during oocyte retrieval and embryo transfer. However, the net increase in serum vWF during that period showed an increase in absolute value at the time of embryo transfer that paralleled an increase in the severity of OHSS. That is, in mild OHSS, the serum vWF increased from 140 +/- 44 to 164 +/- 28%; in moderate OHSS, it increased from 113 +/- 47 to 186 +/- 22%; and in severe OHSS, it increased from 120 +/- 35 to 274 +/- 63%. All 9 women with a vWF level > 230% at embryo transfer developed severe OHSS, while 9 of 13 women with severe OHSS exhibited a vWF > 230% at embryo transfer. CONCLUSION: The results suggest that a rise of the serum level of vWF occurs prior to clinical manifestation of OHSS in patients with severe OHSS but not in patients with mild OHSS.

Effects of low-intensity aerobic training on the high-density lipoprotein cholesterol concentration in healthy elderly subjects.

The concentration of high-density lipoprotein cholesterol (HDL-C) is inversely correlated with the risk of coronary heart disease. The effects of low-intensity aerobic training on serum HDL-C and other lipoprotein concentrations were examined in healthy elderly subjects. The subjects were randomly assigned to two groups matched for sex, age, height, and weight. The training group (n = 20, 10 men and 10 women aged 67 +/- 4 years) participated in a supervised physical exercise regimen using a bicycle ergometer at an intensity of 50% estimated maximal oxygen consumption (VO2max) for 60 minutes two to four times per week for 5 months. In contrast, the control group (n = 20, 10 men and 10 women aged 68 +/- 4 years) did not perform any particular physical training. The training protocol resulted in significant increases in the VO2max (P < .05), HDL-C, HDL2-C, and HDL2-C/HDL3-C ratio (P < .01). The change in HDL2-C (r = .57, P < .01) and HDL2-C/HDL3-C (r = .63, P < .01) was positively associated with an increase in the total exercise duration per week. In addition, the total weekly exercise duration also showed a significant positive relationship with HDL-C (r = .75, P < .01), HDL2-C (r = .81, P < .01), and HDL2-C/HDL3-C (r = .71, P < .01) after the training period. The changes in body weight and the VO2max were not significantly correlated with any lipid parameters. Low-intensity aerobic training may improve the profile of HDL-C and its subfractions in healthy elderly subjects. Also, the total exercise duration may be an important factor for improving HDL-C and HDL2-C in elderly subjects.

[Exercise therapy].

Accumulating evidence indicates that physically active subject have lower all cause morbidity and mortality than those of sedentary subject. It has been established that low intensity aerobic training improve coronary risk by increasing HDL, HDL2-cholesterol, apolipoprotein-AI and HDL-C/TC, and decreasing triglyceride. Also low intensity training lowers blood pressure and improve insulin resistance. It would be suggested that regular aerobic training may decrease in fibrinogen, platelet aggregation and PAI-1 antigen, and increase in t-PA activity. The low intensity training at 50% VO2max for 60 min/day, 3 times a week can be recommended to exercise therapy in the wide-variety of subjects including coronary heart disease.

[The effects of low intensity aerobic training on the physiological indexes and the quality of life in middle-aged white collar workers].

The effects of short-term low intensity aerobic training on the physiological indexes and the Quality of Life were examined in 43 middle-aged White Collar Workers. Training was carried out for 205 +/- 117 minutes/week, at least 2-3 times/week for 2 months on a cycle ergometer or walking with intensity level set at the 50% VO2max. Following this training protocol, thirty-six men (exercise group) completed the 2-month training program and 7 men dropped out (the dropout group). In the exercise group, both the VO2max (l/min) and VO2max/wt increased significantly (VO2max (l/min): P < 0.05. VO2max/wt: P < 0.01), whereas the weight, body mass index, %fat, fat (kg) and the waist hip ratio (WHR) decreased significantly (WHR: P < 0.05, others: P < 0.01) after 2 months. In addition, the DBP and serum TC, LDL-c/HDL-c decreased significantly (LDL-c/HDL-c: P < 0.01, others: P < 0.05) whereas the HDL-c increased significantly (P < 0.05). A modified Croog questionnaire was used to assess the subject's Quality of Life. The questionnaire consisted of 59 questions and the overall assessment was based on eight components. Regarding the Quality of Life, physical symptoms, work performance and satisfaction, total Quality of Life all improved significantly (physical symptoms, P < 0.05; others: P < 0.01) and social participation also tended to improve (P < 0.08). There was a significantly negative correlation between the initial Quality of Life and the changes in the Quality of Life (6 of the 8 components). In the all subjects, there was a significantly positive correlation between the changes in physical symptoms and the changes in VO2max/wt (r = 0.36, P < 0.05). In the dropout group, the FBS increased significantly (P < 0.05) but no other variables regarding the Quality of Life significantly changed after 2 months. In conclusion the above results suggest that short-term low intensity aerobic training in the present study can help improve the physiological indexes, VO2max and Quality of Life in middle-aged White Collar Workers and the observed improvement in the Quality of Life was also found to be greater in the subjects with a low Quality of Life than in those with a high Quality of Life.

Successful metaphase chromosome analysis of human elongated spermatids using mouse oocytes.

Human elongated spermatids from azoospermic patients were inserted into mouse oocytes by intracytoplasmic sperm injection (ICSI). The injection resulted in survival rates of 46.5% (180 out of 387) and activation rates of 36.1% (65 out of 180). The rate of two pronuclear (2PN) formation was 35.4% (23 out of 65). Only 34.8% (eight out of 23) metaphase chromosome spreads from 2PN zygotes could be analysed; however, all were of normal karyotype. Cytogenetic analysis at the first metaphase revealed that human elongated spermatid chromosomes were able to undergo replication in a heterogeneous environment.

Expression of matrix metalloproteinase 2 (MMP-2), membrane-type 1 MMP and tissue inhibitor of metalloproteinase 2 and activation of proMMP-2 in pancreatic duct adenocarcinomas in hamsters treated with N-nitrosobis(2-oxopropyl)amine.

In order to assess the significance of changes in metalloproteinase activity in pancreatic carcinogenesis, the expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9, respectively), tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2, and membrane-type 1 MMP (MT1-MMP) and MT2-MMP in ductal lesions in a rapid-production model for pancreatic duct carcinomas (PCs) in hamsters initiated with N-nitrosobis(2-oxopropyl)amine (BOP) and in subcutaneous transplantable tumors of hamster pancreatic duct carcinoma (HPDs) was investigated. Northern analysis revealed MMP-2, MMP-9, TIMP-2 and MT1-MMP mRNAs to be overexpressed in PCs. Immunohistochemically, elevated levels of MMP-2 were apparent in early duct epithelial hyperplasias and staining increased from atypical hyperplasias to carcinomas. Gelatin zymography demonstrated clear activation of proMMP-2 but not proMMP-9 in both of primary and HPD tumors, the MT1-MMP mRNA level and proMMP-2 activation being significantly correlated (r = 0.893, P < 0.001). In our rapid production model, 0.1 and 0.2% OPB-3206, an inhibitor of MMPs, given in the diet after two cycles of augmentation pressures for 48 days decreased the incidence and number of carcinomas. Gelatin zymography demonstrated that OPB-3206 inhibited activation of proMMP-2 in pancreatic cancer tissues. These results indicate that overexpression of MMP-2, TIMP-2 and MT1-MMP, and cell surface activation of proMMP-2 by MT1-MMP, are involved in the development of PCs, and that MMP-2 expression at the protein level appears in the early phase of pancreatic duct carcinogenesis. OPB-3206 may be a candidate chemopreventive agent for pancreatic ductal adenocarcinomas.

Inhibition of spontaneous rat osteosarcoma lung metastasis by 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4-dihydroc arbostyril, a novel matrix metalloproteinase inhibitor.

In the present experiment, we examined the effects of OPB-3206, 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl]amino-1-methoxy-3,4- dihydrocarbostyril, a novel metalloproteinase inhibitor, on the growth and metastasis of transplantable osteosarcomas (spontaneous osteosarcoma, selected lung metastatic lesions; S-SLM), which were previously established in rats. OPB-3206 inhibited the activities of interstitial collagenase, gelatinases A and B, and stromelysin in vitro. After oral administration to rats, its serum concentration peaked at 40 min and the drug was no longer detectable at 8 h. When OPB-3206 was orally administered at 0%, 0.1% and 0.4% in the diet for 4 weeks, starting 7 days after subcutaneous transplantation of osteosarcomas to male Fischer 344 rats, numbers of lung metastatic nodules were significantly reduced by the highest dose, while the growth of subcutaneous tumors was not affected. Zymographic analysis showed the presence of pro matrix metalloproteinase (proMMP)-2, proMMP-9 and MMP-9 activities in S-SLM. In animals fed 0.4% OPB-3206, the activity of proMMP-9 was increased, but that for MMP-9 had become undetectable. The results thus suggest that OPB-3206 selectively inhibits lung metastasis of rat transplantable osteosarcomas by inhibiting MMP-9 activation.

Blood pressure lowering effect of low intensity aerobic training in elderly hypertensive patients.

PURPOSE: The purpose of this investigation was to determine the effect of 9 months of low intensity aerobic training on blood pressure in elderly hypertensive patients who were receiving antihypertensive medication. METHODS: The training group (N = 13; mean age 75.4 +/- 5.4 yr) agreed to take part in physical training using a treadmill with an exercise intensity at the blood lactate threshold (LT) for 30 min three to six times a week for 9 months. The rest (N = 13; mean age 73.1 +/- 4.2 yr) served as controls. RESULTS: The resting systolic (-15 +/- 8 mm Hg), mean (-11 +/- 6 mm Hg), and diastolic blood pressures (-9 +/- 9 mm Hg) decreased significantly after 3 months of training and the blood pressure of all participants stabilized at a significantly lower level by the end of the study (9 months) in the training group, whereas no significant changes in blood pressure were found in the control group. Both the pretraining systolic and diastolic blood pressure of those recruited patients negatively correlated with those changes after the training (SBP: P < 0.01; DBP: P < 0.05, respectively). After 1 month of detraining in five patients, the blood pressure levels were similar to those in the pretraining state. The LT increased significantly in the training group (P < 0.01). CONCLUSION: In conclusion, an additional antihypertensive effect of mild aerobic training at the LT was confirmed in elderly patients receiving antihypertensive medication. The cessation of such training in five patients, however, resulted in a relatively rapid return to pretraining levels within a month.

Material analysis end-station of the Hyogo-ken beamline at SPring-8.

Plans to construct surface-analysis equipment which will be placed on beamline BL24XU of SPring-8 are presented. There are three experimental hutches in BL24XU, which are available simultaneously by using diamond monochromators as beam splitters. The purpose of the surface-analysis equipment is the simultaneous measurement of fluorescent and diffracted X-rays in grazing-incidence geometry. The instrument is equipped with a solid-state detector (SSD) and a flat position-sensitive proportional counter (PSPC) combined with analysing crystals for X-ray fluorescence (XRF) analysis. A curved PSPC and the goniometer that mounts the SSD used for XRF are also installed for X-ray diffraction. X-ray fluorescence holography and polarized X-ray emission spectroscopy modes are available, so three-dimensional images of atomic configurations and also the anisotropic structure of materials will be studied.

A new synthetic matrix metalloproteinase inhibitor modulates both angiogenesis and urokinase type plasminogen activator activity.

Proteolytic degradation of the extracellular matrix is essential to angiogenesis. Two families of proteases, the serine proteases of plasminogen activator/plasmin system and the matrix metalloproteinases (MMPs) are closely involved in these processes. The treatment of mice with a diet containing a new synthetic MMP inhibitor, OPB-3206: 3S-[4-(N-hydroxyamino)-2R-isobutylsuccinyl] amino-1methoxy-3, 4-dihydrocarbostyril, abrogated the development of new vessels in a rat corneal assay, and in a mouse Matrigel assay. In an in vitro angiogenesis model, OPB-3206 inhibited the migration and the tube formation of bovine aortic endothelial cells at 10-100 times lower concentrations than those required to inhibit the growth of these cells. OPB-3206 as well as other MMP inhibitory drugs, batimastat/BB-94 and marimastat/BB-2516, also selectively inhibited tubular morphogenesis in vitro. OPB-3206 reduced the activities of interstitial collagenase and type IV collagenase, but the concentrations of 50% inhibition against these MMPs were much higher than those of BB-94 and BB-2516. However, this new compound also inhibited urokinase type plasminogen activator activity on fibrin zymogram, while BB-94 and BB-2516 did not. Furthermore, the addition of urokinase type plasminogen activator reduced the inhibitory effect of the tubular morphogenesis of vascular endothelial cells by OPB-3206. The treatment of mice with a diet containing this new compound also reduced the growth of implanted mammary carcinomas as well as the lung metastasis of colon carcinoma. The anti-angiogenic effect of OPB-3206 appeared to be associated with its inhibition of tumor growth and metastasis.