BINOL-Al catalysed asymmetric cyclization and amplification: preparation of optically active menthol analogs.

We report a highly selective asymmetric ring-closing ene reaction catalysed by aluminum complexes with chiral BINOL. This reaction yields optically active 6-membered cyclized alcohols from unsaturated aldehydes, with good diastereo- and enantioselectivities. Asymmetric amplification of this reaction was investigated by varying the ee of the BINOL employed in the catalyst.

A dual catalyst system provides the shortest pathway for L-menthol synthesis.

We have demonstrated that a combination of enantiopure 2-diarylmethylpyrrolidines and heterogeneous Pd/BaSO(4) is an efficient catalytic system for the asymmetric hydrogenation of citral, specifically, a mixture of E-citral and Z-citral in any ratio, and that citronellal is obtained with high enantioselectivity. This dual catalyst system provides a new and more economical route to L-menthol.

Intake of dissolved organic matter from deep seawater inhibits atherosclerosis progression.

Dissolved organic matter (DOM) in seawater can be defined as the fraction of organic matter that passes through a filter of sub micron pore size. In this study, we have examined the effect of DOM of deep seawater (DSW) from Pacific Ocean on platelet aggregation and atherosclerosis progression. DSW was passed through a series of filters and then through an Octadecyl C18 filter; the retained substance in ethanol was designated as C18 extractable DOM (C18-DOM). Our studies showed that C18-DOM treatment inhibited platelet aggregation, P-selectin expression and activity of COX-1 significantly. C18-DOM increased the expression of anti-atherogenic molecule namely heme oxygenase-1 in endothelial cells and all these data showed that C18-DOM is exhibiting aspirin-like effects. Moreover our in vivo studies showed that C18-DOM feeding slowed remarkably the progression of atherosclerosis. Our study demonstrated a novel biological effect of oceanic DOM, which has several important implications, including a possible therapeutic strategy for atherosclerosis.

Radiological imaging features of invasive micropapillary carcinoma of the breast and axillary lymph nodes.

Invasive micropapillary carcinoma of the breast is of growing clinical significance. The purpose of this study was to identify the radiological imaging features for this type of breast carcinoma and the axillary lymph nodes. The study population consisted of 30 breast cancer patients (8 invasive micropapillary carcinomas and 22 other types of invasive ductal carcinoma). The breast lesions were evaluated with mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging (MRI) prior to neoadjuvant chemotherapy. The pathological outcome of the axillary lymph nodes in 27 patients was correlated with the sonographic findings. Only contrast-enhanced MRI showed characteristic findings for invasive micropapillary carcinoma. Although invasive micropapillary carcinoma is commonly irregular in shape (7/8) compared with other types of invasive carcinoma (6/22) (p=0.012, chi(2) test), a careful interpretation of radiological imaging to identify lesion borders helped the complete clearance of cancer cells from 6/8 patients with invasive micropapillary carcinoma in one-time breast conservative surgery. The positive and negative predictive values of sonography in diagnosing axillary lymph node metastases in cases of invasive micropapillary carcinoma were 100 and 50%, respectively. In conclusion, contrast-enhanced MRI reveals the irregular shape of invasive micropapillary carcinoma and helps conservative breast surgery to be performed safely. The pathological analysis of axillary nodes in cases of invasive micropapillary carcinoma may prove to be indispensable due to the relatively low negative predictive value of sonography.

Biphasic elevation of bilirubin oxidation during myocardial ischemia reperfusion.

BACKGROUND: The time course of oxidative stress involving nitric oxide (NO) after myocardial ischemia reperfusion (MIR) has not been elucidated in detail, so the present study was designed to assess the dynamics of oxidative stress after MIR, urinary excretion of oxidized bilirubin metabolites (ie, biopyrrins) and their generation in various organs. METHODS AND RESULTS: Rat models of MIR were created by occluding the left coronary artery for 30 min followed by 48 h of reperfusion. Levels of urinary biopyrrins increased biphasically at 8 h and 24 h after MIR. Biopyrrins were upregulated in the lungs at 8 h after MIR, according to immunohistochemistry and ELISA, and at 24 h biopyrrin expression was increased in the heart and lungs. The NO synthase inhibitor, NG-monomethyl-L-arginine, significantly diminished biopyrrin synthesis in the heart and lungs at 24 h, but not in the lungs at 8 h after MIR. Hemodynamic assessment revealed increased left ventricle end-diastolic pressure, suggesting that lung congestion influences pulmonary biopyrrin formation. CONCLUSIONS: The dynamics of urinary biopyrrins might reflect earlier biopyrrin generation in the lungs and delayed formation in both the lungs and heart when NO is involved. Therefore, urinary biopyrrins can serve as a useful marker of systemic oxidative stress after MIR.

The local injection of peritoneal macrophages induces neovascularization in rat ischemic hind limb muscles.

Macrophages play a pivotal role in the development of newly formed vascular networks, in addition to their normal immunological functions. This research focuses on peritoneal macrophages as a novel source in cell implantation therapy for ischemic diseases. In this study, production of angiogenic growth factors by peritoneal macrophages and its in vivo effect of neovascularization were evaluated. Mononuclear cells from the peritoneal cavity (P-MNCs) enriched with macrophages were isolated and stimulated with hypoxia and interleukin-1beta (IL-1beta) to mimic an ischemic tissue environment in vitro. Expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) of mRNA in P-MNCs was apparently enhanced by hypoxic stimulation, and the production of VEGF protein was also augmented by hypoxia and IL-1beta. A rat ischemic hind limb model was created and P-MNCs (8 x 10(6)/limb) were injected into the ischemic muscles. The blood flow, which was assessed using the colored microsphere method, showed that the percentage blood flow was significantly increased by P-MNCs injection 4 weeks after surgery (48.3 +/- 16.8% in noninjected ischemic limb vs. 84.3 +/- 13.0% in the P-MNCs-injected limb). A histological analysis revealed that the number of capillaries detected by alkaline phosphatase staining was increased in the P-MNCs group 4 weeks after injection. Furthermore, the number of alpha-smooth muscle actin-positive vessels also showed a significant increase following P-MNC injection. The injected P-MNCs labeled with fluorescence were detected in the interstitial space of ischemic muscles, and VEGF protein expression of the implanted cells was confirmed by immunohistochemistry. These results indicate that peritoneal macrophages stimulate capillary formation and arteriogenesis in the ischemic limbs, possibly through the production of angiogenic growth factors. These findings suggest that the physiological angiogenic property of peritoneal macrophages could therefore be utilized for neovascularization in cell implantation therapy.

Inhibition of neointimal hyperplasia development by MCI-186 is correlated with downregulation of nuclear factor-kappaB pathway.

BACKGROUND: Atherosclerosis is a progressing inflammatory response mediated by various signaling molecules among which nuclear factor kappaB (NF-kappaB) is thought to have a pivotal role. This study demonstrated the efficacy of antioxidant MCI-186 in preventing the progression of atherosclerosis by inhibiting signaling molecules such as NF-kappaB. METHODS AND RESULTS: Balloon injury of intima was performed in the right common carotid artery of Japanese male white rabbits, which were then fed a 1% high cholesterol diet for 4 weeks, after assigning them to either the control (n=7) or MCI-186 (0.5 mg .kg(-1) . day(-1), n=7) group. Histological analysis revealed a reduction in neointimal thickness and lipid deposition in the subendothelial area of the MCI-186 group. Immunohistochemical analysis revealed attenuation of E-selectin expression, macrophage migration and proliferation of smooth muscle cells in the MCI-186 treated group. In in vitro studies, rabbit aorta smooth muscle cells were incubated with rIL-1betain either the presence or absence of MCI-186. MCI-186 significantly inhibited rIL-1beta-induced proliferation of smooth muscle cells from rabbit aorta, as well as the activation of NF-kappaB. Moreover, western blot analysis showed the inhibitory action of MCI-186 on the nuclear translocation of NF-kappaB in human umbilical vein endothelial cells under rIL-1betastimulation. CONCLUSIONS: MCI-186 could provide a novel therapeutic strategy for atherosclerosis by inhibiting the NF-kappaB pathway.

Perforating branches of the internal thoracic artery in women with breast cancer: an anatomical study for breast-conservation surgery.

Breast reconstruction after breast-conservation surgery is an important issue for breast cancer patients. Various factors are associated with complications, of which blood flow is one of the more important. The perforating branches of the internal thoracic artery (ITA) are key contributors to blood flow in the anterior chest wall. The present study examined the distributions and depths of the perforating branches of the internal thoracic artery using a multi-detector row-computed tomography (MDCT) angiography. The subjects in this prospective study comprised of 38 women with suspected breast cancer who underwent MDCT angiography. The images were analyzed on computer using transverse MDCT source data and volume renderings. A total of 47 perforating branches were found, with 27 (57.4%) originating in the second, 6 (12.8%) in the third and fourth, 5 (10.6%) in the first and 2 branches (4.3%) originating in the fifth intercostal space, with one branch (2.1%) originating opposite the first intercostal space. A strong correlation was identified between the distance from the skin to the branch and adipose thickness at the shallowest and deepest points (P<0.001). The distributions and depths of the perforating branches of ITA identified in this study may be helpful in immediate breast reconstruction following mastectomy or breast-conserving surgery.

Sentinel lymph node detection using computed tomography lymphography is accurate after neoadjuvant chemotherapy for breast cancer.

For breast cancer patients who have undergone neoadjuvant chemotherapy (NAC), a sentinel lymph node biopsy (SLNB) has not been recommended until recently. This is due to the possible lymph-flow interruption caused by fibrotic changes following chemotherapy and possible increases in false-negative cases. We investigated the changes in the lymph-flow and the detection of sentinel lymph nodes (SLNs) using computed tomography (CT) lymphography before and after NAC. We enrolled 53 patients with breast cancer who had undergone CT lymphography between May 2004 and April 2006. In total, 75 examinations were performed; 44 before NAC and 31 just after NAC. The CT lymphography procedures were approved by the medical ethics committee of our university. After a comprehensive explanation, written informed consent was obtained from all the patients, prior to enrollment in the study. Differences in changes in the lymph-flow, detection of SLNs, and changes in the number of detected SLNs were examined before and after NAC. Differences in the categoric variables were analyzed using the Chi-square test or Fisher's exact test. The identification rate (90.5%) of the SLNs following NAC was higher than the one before NAC (79.5%). However, no statistically significant difference was noted. No interruptions to the lymph-flow prevented the detection of SLNs by NAC. By performing CT lymphography before and after NAC, the interruption to the lymph-flow can be checked and the site of SLNs can be identified prior to surgery. We found that SLNB is recommended for breast cancer patients with or without NAC.

Diagnostic accuracy of mammography, ultrasonography and magnetic resonance imaging in the detection of intraductal spread of breast cancer following neoadjuvant chemotherapy.

The purpose of this study is to evaluate the accuracy of mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging for the diagnosis of intraductal spread of breast cancer following preoperative neoadjuvant chemotherapy. We evaluated a total of 168 areas of normal breast tissue outside the mass in 42 consecutive female patients with breast cancer using each imaging modality both before and after neoadjuvant chemotherapy. Neoadjuvant chemotherapy comprised two to four cycles of adriamycin-based CAF regimen. Multivariate analysis indicated that calcification on mammography and size of hypoechoic structures on ultrasonography prior to neoadjuvant chemotherapy shows a correlation with intraductal spread on pathologic study. Our study reveals that mammography and ultrasonography are useful in avoiding residual cancer cells caused by intraductal spread following conservative breast surgery.

5-HT2 receptor blocker sarpogrelate prevents downregulation of antiapoptotic protein Bcl-2 and protects the heart against ischemia-reperfusion injury.

Even though reperfusion is the treatment of choice in patients admitted with acute myocardial infarction, reperfusion itself has been demonstrated to activate various pathological factors especially following procedures of cardiac revascularization. 5-hydroxytryptamine (5HT) is one such factor activated during reperfusion and is known to trigger the post ischemic contractile dysfunction and pathological apoptosis. Here we demonstrate the potential effects of the 5-HT(2)A antagonist sarpogrelate in protecting the myocardium against reperfusion injury of heart. Male Wistar rats weighing between 220 and 240 g were subjected to 30 min left coronary artery (LCA) occlusion and 120 min reperfusion. Sarpogrelate (4 mg/kg) was infused intravenously for 30 min either before LCA occlusion or at reperfusion. Following reperfusion the samples were collected for infarction area, immunohistochemistry, western blotting and myocardial metabolite analysis. Sarpogrelate infusion before ischemia resulted in (a) significant recovery of post ischemic cardiac functions (LVDP, EDP), (b) significant reduction in the infarct size among the risk area after triphenyl tetrazolium chloride staining (p<0.001), (c) decreased tissue water content (p<0.05), (d) well preserved myocardial ATP (p<0.05), (e) reduction in Bcl-2 downregulation and caspase 3 activation and (g) less prevalence of apoptotic cells (3.1+/-0.4% to 15.2+/-0.6%, drug versus control). Treating the rats with sarpogrelate during reperfusion also showed similar results. This study thus demonstrates the protective effects of sarpogrelate and supports the role for 5-HT2A inhibition in preventing the reperfusion injury of the heart.

Sentinel node biopsy in breast cancer patients treated with neoadjuvant chemotherapy.

A sentinel node biopsy (SNB) has been proved to be an accurate method to estimate the axillary lymph node status as a replacement for axillary lymph node dissection (AxLND) in patients with early breast cancer who have not been treated with neoadjuvant chemotherapy (NAC). We examined the feasibility and accuracy of performing SNB after NAC. Seventy breast cancer patients treated with NAC were enrolled in the current study during the period between March 2001 and June 2005. NAC performed preoperatively consisted of three to four times of CAF chemotherapy. Moreover, intra-arterial (subclavian artery and internal mammary artery) infusion of epirubicin and 5-fluorouracil was performed in addition to systemic CAF chemotherapy once to three times in patients with large breast tumors or bulky axillary lymph node metastases. The sentinel nodes were successfully identified in 63 out of 70 patients (identification rate: 90%). The mean number of sentinel nodes removed per patient was 1.5 (range 1-6). Of the 43 patients in whom AxLND was performed after the sentinel nodes were identified, 19 (44.2%) had positive sentinel nodes. In 8 of those 19 patients, the sentinel node was the only cancer positive lymph node. Among the 24 patients who had negative sentinel nodes it was found that one patient had a confirmed false negative result, thus yielding a false negative rate of 5%, and a sensitivity of 95%. There was no false negative patient who had a clinically negative lymph node status (N0) before NAC (17 patients), whereas the false negative rate was 6.3% in the subgroup of patients with a clinically positive lymph node status (N1, N2) before NAC (26 patients). As a result, SNB after NAC is thus considered to be able to effectively predict the axillary lymph node status in patients with a clinically negative lymph node status before NAC.

Hydrophilic bile salt ursodeoxycholic acid protects myocardium against reperfusion injury in a PI3K/Akt dependent pathway.

The opening of mitochondrial permeability transition pore (PTP) during reperfusion injury of heart has been well demonstrated and thus controlling PTP would attenuate the myocardial damage and cell death. Ursodeoxycholic acid (UDCA) is a hydrophilic bile salt and has been shown to prevent apoptosis in hepatocytes by inhibiting the opening of PTP. Here we demonstrate the role of UDCA in preventing the reperfusion injury of heart through its ability to inhibit PTP. Wistar rats underwent 30 min left coronary artery occlusion (LCA) followed by 180 min reperfusion after treatment with 40 mg/kg per iv infusion of UDCA over 30 min before LCA occlusion. Other groups of rats were treated with PTP agonist atractyloside(5 mg/kg) or PI3 kinase inhibitor wortmannin (16 ug/kg) before UDCA treatment. UDCA treatment prior to LCA occlusion, activated phosphorylation of Akt and Bad. Phosphorylating Bad prevented its translocation in to mitochondria, there by preventing the down regulation of Bcl-2 expression and PTP opening. This was confirmed by reduced cytochrome C release from intramitochondrial space in to the cytosol and hence reduced cell death either by apoptosis (4.8 vs 11.8%, P<0.001, UDCA treated against control group) or necrosis (reduced MI area in UDCA treated group (22.1%) compared to control group(46.4%), P<0.001). In contrast, inhibition of Akt activation with PI3K inhibitor wortmannin or opening the PTP with atractyloside abolished, UDCA mediated cytoprotective effects. Studies on primary culture cardiomyocytes also confirmed our in vivo results of UDCA on cell survival. These results altogether demonstrate that UDCA protect the heart against reperfusion injury by inhibiting the PTP in a PI3K/Akt dependent pathway.

MCI-186 inhibits tumor growth through suppression of EGFR phosphorylation and cell cycle arrest.

BACKGROUND: It has been suggested that radicals stimulate tumor cell growth. We examined if the hydroxyl radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), affects tumor growth in vitro. MATERIALS AND METHODS: Human hepatocarcinoma HepG2, mesothelioma MSTO-211H, gastric carcinoma TMK-1 and breast carcinoma MCF-7 were used for cell proliferation assay. Cell cycle analysis was performed using propidium iodide for fluorescence activated cell sorter. By Western blotting, EGF receptor (EGFR) phosphorylation and EGFR expression were analyzed. RESULTS: Growth inhibition was observed from 10 microM to 300 microM of MCI-186 in a dose-dependent manner. Cell cycle analysis revealed that MCI-186 arrested the cell cycle at the G0/G1-phase. MCI-186 inhibited EGF-stimulated cell growth. The phosphorylation level of EGFR was decreased by MCI-186, but the EGFR level was unchanged. CONCLUSION: From the data obtained, we suggest that tumor inhibition by MCI-186 was due, at least in part, to the modulation of EGFR signaling and cell cycle arrest.

Utility of initial MRI for predicting extent of residual disease after neoadjuvant chemotherapy: analysis of 70 breast cancer patients.

This study was performed to evaluate the utility of initial MRI in predicting the extent of residual disease following neoadjuvant chemotherapy (NAC). The study population consisted of 70 patients with breast cancer (unilateral, n=69; bilateral, n=1) (mean age 51 years) who underwent magnetic resonance imaging (MRI) with gadolinium enhancement both before and after NAC. Basic NAC was comprised of cyclophosphamide, pirarubicin, and 5-fluorouracil. MRI features were compared with pathological diagnosis following surgery. MRI features of breast cancer before NAC were classified as either solitary nodular (SN) (n=33) (47%), or multiple nodular and/or unlocalized dendritic (MN/UD) (n=38) (53%). MRI typing was independent of NAC in 68 tumors (SN, n=32; MN/UD, n=36) (96%, p<0.0001). All except one of the 33 SN tumors (97%) displayed negative margins. In addition, 5 of the 33 SN tumors (15%) displayed pathological complete response (pCR). Conversely, all 5 requiring total glandectomy due to wide infiltration and all except one of the 17 (94%) displaying positive margins necessitating extended resection were classified as MN/UD. Only SN-type tumors on initial MRI have the possibility of pCR after NAC. MN/UD tumors could possess margins necessitating expanded excision or total glandectomy. Morphological concepts based on MRI can prove useful in surgical planning and predicting the extent of residual disease after NAC.

Ischemic preconditioning prevents reperfusion heart injury in cardiac hypertrophy by activation of mitochondrial KATP channels.

BACKGROUND: Cardiac hypertrophy has been demonstrated to decreases the ATP-sensitive potassium channels (K(ATP)), the major protective mechanism following the energy depletion, a common condition seen during the reperfusion after open heart surgery. In this study we have demonstrated the role of ischemic preconditioning (IP) in preventing the reperfusion injury of the hypertrophied heart by activation of the depleted K(ATP) channels. METHODS: Pressure overload left ventricular hypertrophy was induced in 6 weeks old male Wistar rats by supra renal transverse abdominal aortic constriction and the study was conducted 10-12 weeks later. Hypertrophied rats were subjected to IP protocols by four episodes of 3 min ischemia each being separated by 10 min reperfusion, followed by 30 min of sustained ischemia and 120 min of reperfusion with or without treating the rats with K(ATP) channel antagonists 5-hydroxydecanoic acid (10 mg/kg per i.v.) or glibenclamide (1 mg/kg per i.v.), 10 min before the sustained ischemia. RESULTS: IP resulted in (a) less incidence of ventricular arrhythmias (b) less area of myocardial infarction (9.3% vs. 48.1%, IP to control) (c) less tissue water content (76.5% vs. 94.8%, IP to control) (d) well preserved myocardial ATP content (P<0.001 from control) content and (e) much fewer apoptotic cells (4.7% vs. 13.2%, IP to control). Pre treating the rats with the K(ATP) channel inhibitors before sustained ischemia resulted in inhibition of these protective effects of IP on cardiac hypertrophy. CONCLUSION: The above results, therefore, suggest to us that IP by activation of K(ATP) channels can afford protection against the ischemia-reperfusion injury in the hypertrophied heart.

Mitochondrial permeability transition-pore inhibition enhances functional recovery after long-time hypothermic heart preservation.

OBJECTIVES: Long-time preservation of the donor heart before transplantation is associated with mitochondrial damages resulting in functional deterioration after transplantation, although the exact mechanism behind this is still uncertain. Here, we have demonstrated the opening of a nonspecific pore in the inner membrane of the mitochondria, the mitochondrial permeability transition pore (PTP), as one of the reasons responsible for this functional deterioration. METHODS: After 30 minutes of perfusion with the Krebs Henseleit buffer at 37 degrees C in working mode, hearts from Wistar rats were arrested with ice-cold St. Thomas cardioplegic solution and preserved University of Wisconsin solution at 4 degrees C with or without inhibiting the PTP with cyclosporin A (CsA) (0.2 microM). After 12 hours, the hearts were reperfused for 60 minutes at 37 degrees C with or without perfusing the hearts during first 15 minutes of reperfusion with PTP openers lonidamine (30 microM) or atractyloside (20 microM). RESULTS: Inhibiting PTP with CsA resulted in (a) significant recovery of cardiac functions, (b) well-preserved myocardial adenosine triphosphate (ATP) levels (P<0.001), (c) less myocardial water content (P<0.01), (d) less mitochondrial swelling and cytochrome C release, and (e) up-regulation of Bcl-2 expression compared with the control hearts without PTP inhibition. These effects are completely inhibited on opening the PTP before preservation, resulting in poor recovery of cardiac functions, loss of myocardial ATP, and severe mitochondrial swelling. CONCLUSION: The present study demonstrates the potential role of mitochondrial PTP after long- time hypothermic preservation of the heart, and therefore, regulation of PTP would prolong the preservation time of donor hearts.

Second window of ischemic preconditioning regulates mitochondrial permeability transition pore by enhancing Bcl-2 expression.

OBJECTIVE: The second window of protection (SWOP) following brief coronary artery occlusion begins at 24 h and may last up to 72 h and occurs via many unknown mechanisms. We investigated the role of the mitochondrial permeability transition pore (PTP), a non specific pore in the inner membrane of the mitochondria in this phenomenon. METHODS: Ischemic preconditioning (IP) was induced in Wistar rats by left coronary artery occlusion (four, 3-min episodes separated by 10 min of reperfusion) on day 1. On day 2, ischemia was induced with 30 min of ischemia and 120 min of reperfusion in IP and control rats. RESULTS: IP rats showed decreased myocardial infarction (MI) area vs. non-IP control rats (15.32 vs. 45.6%). Furthermore, IP rats had preserved cardiac function (heart rate, rate pressure product, coronary flow and aortic flow) and myocardial ATP (P<0.03), decreased tissue water content (73.2 vs. 90.6%), increased expression of Bcl-2, and less mitochondrial swelling, cytochrome C release and apoptosis (2.6 vs. 12.4%) when compared to sham-operated rats. Activation of the permeability transition pore with PTP activators lonidamine (10 mg/kg body weight) or atractyloside (5 mg/kg body weight) before the sustained ischemia on day 2 resulted in complete abolition of SWOP-mediated cytoprotective effects. These agents had no effect on the cytoprotective effects that took place during the first window of preconditioning. CONCLUSION: The cytoprotective effects of SWOP are dependent on PTP activation state and may involve upregulation of Bcl-2 expression.

CT findings of breast cancer with clinically complete response following neoadjuvant chemotherapy--histological correlation.

In breast cancer patients, several regimens of neoadjuvant chemotherapy have been developed in order to achieve prognostic advantages for individual patients. Though some percentages of breast cancer patients show clinically complete response to neoadjuvant chemotherapy, the histopathological specimens of these patients demonstrate a considerably high frequency of the existence of residual disease. In this study, we aimed to evaluate the therapeutic effect of neoadjuvant chemotherapy for breast cancer patients showing clinically complete response (cCR) to neoadjuvant chemotherapy, using thin-section (5 mm) helical CT (prone position) with bolus injection of contrast agent. Between April 1994 and March 2002, 9 patients with breast cancer showing cCR to the neoadjuvant chemotherapy, who had undergone thin-section CT study both before and following neoadjuvant chemotherapy, enrolled in the study. The mean age of the patients was 46.2 years and all of them were female. The clinical stages were, 8 patients in stage II, and one in stage IIIA. In the CT evaluation, residual disease was visualized in 5 out of the 9 patients. Histopathological examination disclosed the existence of residual cancers in 6 out of the 9 patients, but only non-invasive cancer was revealed in 1 out of the 6. As patients having residual disease composed only of non-invasive cancer are classified into the pathologically complete response group according to the WHO classification, 4 out of these 9 patients showing clinically complete response to the neoadjuvant chemotherapy were classified into pCR (pathologically complete response) group, and another 5 were classified into the pPR (pathologically partial response) group. As a result, the diagnostic accuracy of the second CT study performed after neoadjuvant chemotherapy was evaluated as 77.8%, with a sensitivity of 80.0%, a specificity of 75.0%, a positive predictive value (PPV) of 80.0%, and a negative predictive value (NPV) of 75.0%. Therefore, for precise evaluation of the neoadjuvant chemotherapeutic effect for breast cancer, thin-section CT studies are considered to be essential.

Antioxidant MCI-186 inhibits mitochondrial permeability transition pore and upregulates Bcl-2 expression.

Reperfusion after a period of ischemia is associated with the formation of reactive oxygen species (ROS) and Ca2+ overload resulting in the opening of a nonspecific pore in the inner membrane of the mitochondria, called the mitochondrial permeability transition pore (PTP), leading to cell damage. Although endogenous antioxidants are activated because of oxidative stress following ischemia, their levels are not high enough to prevent reperfusion injury. Hence there is always a need for exogenous supplement of antioxidants, especially after acute ischemia. Here we demonstrated the effects of the antioxidant 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186) in preventing reperfusion injury of the heart by inhibition of PTP opening. Ischemia (30 min) by left coronary artery (LCA) occlusion and reperfusion (120 min) in Wistar rats after pretreatment with MCI-186 (10 mg/kg iv) infusion starting from 30 min before LCA occlusion resulted in 1) less area of myocardial infarction (19.2% vs. 61.6%), 2) well-maintained myocardial ATP content (P < 0.03 vs. control), 3) decreased mitochondrial swelling and reduced cytochrome c release, 4) increased expression of BCl-2, 5) lower prevalence of apoptotic cells (14.3% vs. 2.9%), and 6) reduced DNA fragmentation in the MCI-186-treated group. These cytoprotective effects of MCI-186 were inhibited on opening PTP before MCI-186 treatment with the PTP activators lonidamine (10 mg/kg iv) or atractyloside (5 mg/kg iv) but failed to inhibit the protective effects exerted by another antioxidant, allopurinol, suggesting that the PTP inhibiting property is specific for MCI-186. These results demonstrate that the radical scavenger MCI-186, by inhibiting the opening of the PTP, prevents necrosis and cytochrome c release and hence pathological apoptosis.