Publications by authors named "Motohiro Takeda"

43 Publications

Development of silica-coated silver iodide nanoparticles and their biodistribution.

Tohoku J Exp Med 2012 12;228(4):317-23

Department of Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Japan.

Nanomaterials have great potential in the field of medicine and have been studied extensively. In a previous study, we addressed the potential of silver iodide (AgI) as X-ray contrast media, because it possessed high imaging ability in the measurement by X-ray computed tomography (X-CT) in vitro, and its surface can be modified with many functional groups. We developed the method of silica coating to make AgI nanoparticles more stable and uniform in size. However, the safety and metabolism of nanoparticles in vivo remains to be determined. The objective of the present study was to evaluate the in vivo biodistribution of silica-coated AgI nanoparticles (SAgINPs). X-CT, transmission electron microscopy (TEM), and inductively coupled plasma atomic emission spectrometry (ICP-AES) were performed prior to and at intervals following the intravenous administration of SAgINPs to rats and rabbits. ICP-AES is a spectral technique that can determine the presence and concentrations of metal samples. The X-CT study showed long-period enhancement in the liver and spleen, but not in the bladder of rats. The TEM study demonstrated that SAgINPs were found in hepatocytes. Using ICP-AES, Ag was detected in the bile juice of rabbits, but not found in the urine of these animals, suggesting that SAgINPs are excreted via the liver. This study shows the quantitative biodistribution of silica-coated nanoparticles for the first time, indicating that our silica coating technique is useful for development of nanoparticles with hepatic excretion. In conclusion, the SAgINPs may provide X-ray contrast media with high imaging ability and biocompatibility.
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http://dx.doi.org/10.1620/tjem.228.317DOI Listing
December 2012

Synthesis of high concentration colloid solution of silica-coated AgI nanoparticles.

J Nanosci Nanotechnol 2012 Aug;12(8):6741-5

College of Engineering, Ibaraki University, Hitachi, Ibaraki 316-8511, Japan.

Methods for high concentration silica-coated silver iodide (AgI/SiO2) particles, which could be practically used as X-ray contrast agent, were examined. The first was a single-step method, which was to prepare AgI nanoparticles at an AgI concentration of 5 x 10(-3) M and coat the AgI nanoparticles with silica shell by a Stöber method. The second was a multiple-step method, which was to repeat a step for preparing a AgI/SiO2 particle colloid solution with 10(-3) M AgI 5 times for adjusting a final AgI concentration to 5 x 10(-3) M. In the two methods, dominant particle aggregation took place, though core-shell particles were also produced. The third was a salting-out method, which was to salt out AgI/SiO2 particles in their colloid solution prepared at an AgI concentration of 10(-3) M, remove supernatant by decantation, and redisperse the particles in a fresh solvent. Consequently, AgI/SiO2 particles with an AgI concentration as high as 0.05 M were successfully prepared with the salting-out method, and their core-shell structure was not damaged during the salting-out.
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http://dx.doi.org/10.1166/jnn.2012.4531DOI Listing
August 2012

Blood oxygenation using microbubble suspensions.

Eur Biophys J 2012 Jun 3;41(6):571-8. Epub 2012 Apr 3.

Department of Biomedical Engineering, Graduate School of Engineering, Okayama University of Science, 1-1, Okayama 700-0005, Japan.

Microbubbles have been used in a variety of fields and have unique properties, for example shrinking collapse, long lifetime, efficient gas solubility, a negatively charged surface, and the ability to produce free radicals. In medicine, microbubbles have been used mainly as diagnostic aids to scan various organs of the body, and they have recently been investigated for use in drug and gene delivery. However, there have been no reports of blood oxygenation by use of oxygen microbubble fluids without shell reagents. In this study, we demonstrated that nano or microbubbles can achieve oxygen supersaturation of fluids, and may be sufficiently small and safe for infusion into blood vessels. Although Po(2) increases in fluids resulting from use of microbubbles were inhibited by polar solvents, normal saline solution (NSS) was little affected. Thus, NSS is suitable for production of oxygen-rich fluid. In addition, oxygen microbubble NSS effectively improved hypoxic conditions in blood. Thus, use of oxygen microbubble (nanobubble) fluids is a potentially effective novel method for oxygenation of hypoxic tissues, for infection control, and for anticancer treatment.
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http://dx.doi.org/10.1007/s00249-012-0811-yDOI Listing
June 2012

Synthesis and pharmacological characterization of potent, selective, and orally bioavailable isoindoline class dipeptidyl peptidase IV inhibitors.

Org Med Chem Lett 2011 Sep 12;1(1). Epub 2011 Sep 12.

Central Research Laboratory, Sanwa Kagaku Kenkyusho, Co,, Ltd,, 363 Shiosaki, Hokusei-cho, Inabe-city, Mie 511-0406, Japan.

Focused structure-activity relationships of isoindoline class DPP-IV inhibitors have led to the discovery of 4b as a highly selective, potent inhibitor of DPP-IV. In vivo studies in Wistar/ST rats showed that 4b was converted into the strongly active metabolite 4l in high yield, resulting in good in vivo efficacy for antihyperglycemic activity.
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http://dx.doi.org/10.1186/2191-2858-1-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3305890PMC
September 2011

Discovery and pharmacological characterization of N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (anagliptin hydrochloride salt) as a potent and selective DPP-IV inhibitor.

Bioorg Med Chem 2011 Dec 2;19(23):7221-7. Epub 2011 Oct 2.

Central Research Laboratory, Sanwa Kagaku Kenkyusho, Co. Ltd, 363 Shiosaki, Hokusei-cho, Inabe-city, Mie 511-0406, Japan.

In the course of our program for discovery of novel DPP-IV inhibitors, a series of pyrazolo[1,5-a]pyrimidines were found to be novel DPP-IV inhibitors. We identified N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (4a) and described its pharmacological profiles.
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http://dx.doi.org/10.1016/j.bmc.2011.09.043DOI Listing
December 2011

In vivo imaging of the molecular distribution of the VEGF receptor during angiogenesis in a mouse model of ischemia.

Blood 2011 Sep 5;118(13):e93-e100. Epub 2011 Aug 5.

Department of Nano-Medical Science, Graduate School of Medicine, Tohoku University, Sendai, Japan.

Vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis and has been applied to medical therapy. However, because vascular imaging at the molecular level is impossible, the detailed in vivo dynamics of VEGF and its receptor (VEGFR) remain unknown. In this study, to understand the molecular distribution of VEGF and the VEGFR, we prepared ischemic mice with a new surgical method and induced angiogenesis in the gastrocnemius muscle. Then, we made a VEGF-conjugated fluorescence nanoparticle and performed staining of VEGFR-expressing cells with the fluorescent probe, demonstrating the high affinity of the probe for VEGFR. To observe the physiologic molecular distribution of VEGFR, we performed in vivo single-particle imaging of gastrocnemius in the ischemic leg with the fluorescent probe. The results suggested that only a 3-fold difference of VEGFR distribution is involved in the formation of branched vasculature in angiogenesis, although previous ex vivo data showed a 13-fold difference in its distribution, indicating that a method inducing a several-fold local increase of VEGFR concentration may be effective in generating site-specific angiogenesis in ischemic disease. This new in vivo imaging of ischemic mice could make useful contributions to understanding the mechanisms of angiogenesis and to developing a VEGFR-related drug.
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http://dx.doi.org/10.1182/blood-2010-12-322842DOI Listing
September 2011

Control of shell thickness in silica-coating of Au nanoparticles and their X-ray imaging properties.

J Colloid Interface Sci 2011 Jun 22;358(2):329-33. Epub 2011 Jan 22.

Department of Biomolecular Functional Engineering, College of Engineering, Ibaraki University, Ibaraki 316-8511, Japan.

This paper describes a performance of precise control of shell thickness in silica-coating of Au nanoparticles based on a sol-gel process, and an investigation into X-ray imaging properties for the silica-coated Au (Au/SiO(2)) particles. The Au nanoparticles with a size of 16.9±1.2 nm prepared through a conventional citrate reduction method were used as core particles. The Au nanoparticles were silica-coated with a sol-gel reaction using tetraethylorthosilicate (TEOS) as a silica source, sodium hydroxide (NaOH) as a catalyst, and (3-aminopropyl) trimethoxysilane (APMS) as a silane coupling agent. An increase in TEOS concentration resulted in an increase in shell thickness. Under certain concentrations of Au, H(2)O, NaOH, and APMS, the Au/SiO(2) particles with silica shell thickness of 6.0-61.0 nm were produced with varying TEOS concentration. Absorption peak wavelength of surface plasmon resonance of the Au/SiO(2) colloid solution depended on silica shell thickness, which agreed approximately with the predictions by Mie theory. The as-prepared colloid solution could be concentrated up to an Au concentration of 0.19 M with salting-out and centrifugation. The concentrated colloid solution showed an X-ray image with high contrast, and a computed tomography value for the colloid solution with an Au concentration of 0.129 M was achieved 1329.7±52.7 HU.
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http://dx.doi.org/10.1016/j.jcis.2011.01.058DOI Listing
June 2011

Synthesis of silica-coated AgI nanoparticles and immobilization of proteins on them.

J Nanosci Nanotechnol 2010 Nov;10(11):7758-61

College of Engineering, Ibaraki University, Hitachi, Ibaraki 316-8511, Japan.

This paper describes a method for preparing silica-coated silver iodide (AgI/SiO2) particles and immobilizing proteins on the AgI/SiO2 particles. Colloid solution of AgI particles was prepared by mixing AgClO4 aqueous solution and KI aqueous solution. Silica-coating of the AgI particles was performed by adding 3-mercaptopropyltrimethoxysilane, tetraethylorthosilicate/ethanol solution and NaOH aqueous solution successively to the AgI colloid solution. TEM observation revealed that the AgI nanoparticles were coated with uniform silica shell. The AgI/SiO2 particles were surface-modified with 3-aminopropyltrimethoxysilane and succinic anhydride. It was confirmed by XPS measurement that amino group or carboxyl group was introduced onto the AgI/SiO2 particles. Protein-immobilization was performed in aqueous solution with bovine serum albumin (BSA) in the presence of the surface-modified AgI/SiO2 particles. UV-VIS absorption spectroscopy revealed that the BSA was adsorbed on the surface-modified particles.
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http://dx.doi.org/10.1166/jnn.2010.2838DOI Listing
November 2010

Uniform silica coated fluorescent nanoparticles: synthetic method, improved light stability and application to visualize lymph network tracer.

PLoS One 2010 Oct 18;5(10):e13167. Epub 2010 Oct 18.

Department of Nano-Medical Science, Graduate School of Medicine, Tohoku University, Sendai, Miyagi, Japan.

Background: The sentinel lymph node biopsy (SLNB) was developed as a new modality in the surgical diagnosis of lymph node metastases. Dye and radioisotope are major tracers for the detection of sentinel lymph nodes (SLN). Dye tends to excessively infiltrate into the interstitium due to their small size (less than several nanometers), resulting in difficulties in maintaining clear surgical fields. Radioisotopes are available in limited number of hospitals. Fluorescent nanoparticles are good candidates for SLN tracer to solve these problems, as we can choose suitable particle size and fluorescence wavelength of near-infrared. However, the use of nanoparticles faces safety issues, and many attempts have been performed by giving insulating coats on nanoparticles. In addition, the preparation of the uniform insulating layer is important to decrease variations in the quality as an SLN tracer.

Methodology/principal Findings: We herein succeeded in coating fluorescent polystyrene nanoparticles of 40 nm with uniform silica layer of 13 nm by the modified Stöber method. The light stability of silica coated nanoparticles was 1.3-fold greater than noncoated nanoparticles. The popliteal lymph node could be visualized by the silica coated nanoparticles with injection in the rat feet.

Conclusions/significance: The silica coated nanoparticles in lymph nodes could be observed by transmission electron microscope, suggesting that our silica coating method is useful as a SLN tracer with highly precise distribution of nanoparticles in histological evaluation. We also demonstrated for the first time that a prolonged enhancement of SLN is caused by the phagocytosis of fluorescent nanoparticles by both macrophages and dendritic cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013167PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956628PMC
October 2010

Designing a clinical education program for engineers: the ESTEEM Project.

J Interprof Care 2010 Nov;24(6):738-41

Department of Biomedical Engineering, Tohoku University, Sendai, Japan.

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http://dx.doi.org/10.3109/13561820903564714DOI Listing
November 2010

Comparison of core needle biopsy (CNB) and surgical specimens for accurate preoperative evaluation of ER, PgR and HER2 status of breast cancer patients.

Cancer Sci 2010 Sep;101(9):2074-9

Department of Surgical Oncology, Tohoku University Graduate School of Medicine, Miyagi, Japan.

The roles of core needle biopsy (CNB) have become well established as an important preoperative diagnostic method for breast lesions. We examined the concordance of histological types, nuclear grades, hormone receptors, and human epidermal growth factor receptor 2 (HER2) status between CNB and surgical specimens in 353 cases. In addition, we analyzed the correlation between the number of CNB specimens obtained and accuracy of histological factors in order to explore the optimal number of CNB specimens. Between CNB and surgical specimens, concordance rates of histological type, nuclear grade, estrogen receptor (ER), and progesterone receptor (PgR) status (cut-off 0-<1%, 1-10%, and 10%<), and HER2 were 84.4%, 81.3%, 92.9%, and 89.3%, respectively. In 52 of 353 patients who were histopathologically diagnosed as ductal carcinoma in situ (DCIS) by CNB, final diagnosis was changed in to invasive ductal carcinoma (IDC) in surgical specimens. Statistically significant differences were detected in the discrepancy of the following factors between CNB and subsequent surgical specimens: histological types, nuclear grade, and PgR, between patients who received four or more cores and those who had received three or less cores. In addition, a similar tendency was also detected in estrogen receptor (ER) and HER2 as in the above, and the cases that received four cores reached to 100% concordance in diagnosis between CNB and surgical specimens. Therefore, the optimal numbers of CNB were considered four at least in assessing the histological type, invasion, nuclear grade, hormone receptor status, and HER2 status of individual patients in the preoperative setting.
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http://dx.doi.org/10.1111/j.1349-7006.2010.01630.xDOI Listing
September 2010

The correlation between ultrasonographic findings and pathologic features in breast disorders.

Jpn J Clin Oncol 2010 Oct 21;40(10):905-12. Epub 2010 May 21.

Department of Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.

Objective: Breast ultrasonography has gained widespread acceptance as a diagnostic tool for the evaluation of human breast disorders. It is important to evaluate the correlation of ultrasonography findings with the corresponding histopathological features.

Method: We retrospectively reviewed the 154 cases of breast disorders. We evaluated the correlation the ultrasonography findings and carcinoma cells extension with their corresponding histopathological findings. In addition, we also studied the information on estimation of histological types and cancer extension used by the other modalities such as computed tomography and magnetic resonance imaging.

Results: The concordance rate for margins between ultrasonography findings and histopathological features was 91.6% (P < 0.001) and that for boundary zone was 87.0% (P < 0.001). Histopathological correlation of internal and posterior echoes demonstrated that internal low echo masses were composed of fibroblastic cells with marked collagenization in the stroma, or the cases in which carcinoma cells proliferated in a monotonous, solid and/or expanding manners. Attenuation of posterior echo was detected in the cases associated with hyperplasia of collagenized fibroblastic stroma. An increased cellularity in the mass with prominent large tumor nests and little fibrous stroma demonstrated the accentuation or no alterations of the posterior echo. The concordance rate of borders was 84.4% (P < 0.001). The correlation between estimated histological type by ultrasonography diagnosis and actual histological types was 87.0%. An overall detection rate of carcinoma extension by ultrasonography was 86.4%. In addition, an overall detection rate of carcinoma extension by ultrasonography, magnetic resonance imaging and computed tomography was 93.8%.

Conclusion: These results demonstrated correlation between histopathological and ultrasonographic findings of the breast lesions is cardinal for quality control or improving the quality of ultrasonography.
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http://dx.doi.org/10.1093/jjco/hyq070DOI Listing
October 2010

Nano-imaging of the lymph network structure with quantum dots.

Nanotechnology 2010 May 14;21(18):185103. Epub 2010 Apr 14.

Department of Nano-Medical Science, Graduate School of Medicine, Tohoku University, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.

Sentinel lymph node diagnosis contributes to operative strategy in cancer surgery. During lymph node metastasis, cancer cells first reach the sentinel lymph node (SLN) via lymph flow. To perform SLN biopsy effectively, it is important that cancer cells are detected with high sensitivity in SLN connected to the tumor site. Here we present a method to visualize a high-risk area in the SLN for lymph node metastasis with a high degree of accuracy. Quantum dots (QDs), bright fluorescent nanoparticles, were endoscopically injected into the gastrointestinal wall of pigs, and their signal was specifically detected in the SLN with a laparoscopic device. Single-particle imaging under a confocal microscope showed that the QDs were distributed heterogeneously in the SLN and that their distribution marked the inflow locus of afferent lymphatic vessels where lymph node metastasis begins. Moreover, we developed a method using cellular marker conjugated QDs that visualizes specific cells in SLNs, suggesting that this method can be applied for the detection of cancer cells in sentinel lymph nodes using tumor-specific-molecular conjugated QDs. These results show that our method might significantly increase the detection rate of cancer metastasis in SLNs.
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http://dx.doi.org/10.1088/0957-4484/21/18/185103DOI Listing
May 2010

Activation of caspases and apoptosis in response to low-voltage electric pulses.

Oncol Rep 2010 May;23(5):1425-33

Department of Bioengineering and Robotics, Tohoku University, 980-8579 Sendai, Japan.

Few studies have examined apoptosis induced by low-voltage electric pulses (LVEPs). LVEP-induce changes in membrane potential that are below the membrane breakdown threshold and increase membrane permeability without electroporation (pore formation) through the transport of extracellular substances via phagocytosis. We demonstrated that propidium iodide uptake and apoptosis increased in accordance with the duration and number of LVEPs in B16 cells, which showed relatively good viability under mild electric field conditions. We showed that LVEP-induced apoptosis was achieved through caspase-8 and -9 activation and subsequent caspase-3 activation. Long-duration LVEPs caused only mild cell damage, such that the apoptosis ratio (apoptosis/total cell death) in electric pulse-treated cells was similar to that in non-treated control cells. To assess the relative degree of caspase dependency in LVEP-induced apoptosis, the apoptosis rate and caspase-3 activity were analyzed using a pan-caspase inhibitor (Z-VAD-FMK). Z-VAD-FMK treatment inhibited, but did not abolish, LVEP-induced apoptosis, indicating that caspases other than caspase-3 participate in this pathway. Moreover, LVEP treatment inhibited cell growth, suggesting that LVEP treatment may be a valuable anticancer therapy. Although the mechanism of LVEP-induced apoptosis remains unclear, it may be related to dysfunctional membrane transport of Ca2+ and other extracellular substances involved in caspase activation.
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http://dx.doi.org/10.3892/or_00000780DOI Listing
May 2010

Total-circumference intraoperative frozen section analysis reduces margin-positive rate in breast-conservation surgery.

Jpn J Clin Oncol 2010 Jun 26;40(6):513-20. Epub 2010 Feb 26.

Department of Surgical Oncology, Tohoku University School of Medicine, Sendai 980-8574, Japan.

Objective: One problem existing in breast-conservation surgery is ipsilateral breast tumour recurrence, and one of its major risk factors is surgical margin positivity. We therefore investigated whether total-circumference surgical margin examination can reduce surgical margin-positive rates.

Methods: A total of 122 cases were examined after BCS was performed between March 2004 and March 2006. After partial mastectomy, specimens were taken from the remnant breast side along the total-circumference of the mammary gland (width, approximately 5 mm). Intraoperative frozen section analysis was performed for those specimens. Margin-positive cases were defined as those showing malignancy within
Results: If intraoperative frozen section analysis had not been performed, 33 cases (27%) would have been diagnosed as margin-positive. However, it reduced the number of margin-positive cases to 12 (9.8%), and final margin-positivity rates were thus significantly reduced (P < 0.001). As for the accuracy of intraoperative frozen section analysis, sensitivity was 78.6%, specificity was 100%, correct diagnosis rate was 95.1%, positive predictive value was 100% and negative predictive value was 94.0%. False-negatives were caused by the detection of malignancy as revealed in permanent specimens. Margin-positive sites were not limited to the nipple and distal (peripheral) sites, with equivalent margin-positive cases found laterally.

Conclusions: Total-circumference surgical margin examination by IFSA for BCS significantly reduced margin-positive rates from 27% to 9.8%.
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http://dx.doi.org/10.1093/jjco/hyq006DOI Listing
June 2010

Size-selective growth and stabilization of small CdSe nanoparticles in aqueous solution.

ACS Nano 2010 Jan;4(1):121-8

Center for Interdisciplinary Research, Tohoku University, Sendai 980-8578, Japan.

Using cysteine and its derivatives as capping molecules, we investigated the influence of the physical structure and chemical nature of capping molecules on the selective growth and stabilization of small CdSe nanoparticles (NPs) in aqueous solution at room temperature. Our investigations revealed specific roles for each functional group of cysteine, and we could correlate this structure and nature of the capping molecules with the size, size restriction, size distribution, and stability of the NPs. For selective growth and stabilization of the NPs in aqueous solution, their capping molecules should have at least one functional group with strong nucleophilicity as well as another free, charged functional group. Capping molecules acting as a monodentate ligand were more effective than those acting as a bidentate ligand for restricting the NPs to a smaller size, whereas the former was less effective than the latter for getting a narrower NP size distribution. Capping molecules with relatively bulky spatial geometry near the ligand-NP interface resulted in the formation of NPs with poor short- and long-term stabilities, whereas those having relatively compact spatial geometry near the interface led to NPs with at least moderate short-term stability. We saw that capping molecules having relatively compact outermost spatial geometry led to NPs with excellent long-term stability, whereas those having relatively bulky outermost spatial geometry produced NPs with at most only moderate long-term stability. Our results clearly showed general trends for the possibility of selective growth of stable semiconductor NPs with particular sizes in aqueous solution.
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http://dx.doi.org/10.1021/nn901570mDOI Listing
January 2010

Capecitabine monotherapy is efficient and safe in all line settings in patients with metastatic and advanced breast cancer.

Jpn J Clin Oncol 2010 Mar 3;40(3):188-93. Epub 2009 Nov 3.

Division of Surgical Oncology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan.

Objective: Capecitabine is effective and well tolerated in patients with anthracycline- and/or taxane-pre-treated metastatic breast cancer. We compared the efficacy and safety of capecitabine monotherapy between 1st, 2nd, 3rd and > or =4th line settings for advanced and metastatic breast cancer pre-treated with/without anthracycline and taxanes.

Methods: Subjects comprised 84 patients with histologically confirmed advanced or metastatic breast cancer and at least one measurable metastatic lesion. We evaluated time to disease progression (TTP), response rate (RR) and clinical benefit rate (CBR) for 1st (n = 17), 2nd (n = 28), 3rd (n = 23) and > or =4th (n = 16) line setting treatments of capecitabine monotherapy.

Results: Median number of cycles of capecitabine monotherapy was 12 cycles in 1st line, 11 cycles in 2nd line, 9 cycles in 3rd line and 11 cycles in > or =4th line. RR and CBR were 23.5% and 58.8% in 1st line, 21.4% and 53.6% in 2nd line, 21.7% and 52.2% in 3rd line, and 18.8% and 50.0% in > or =4th line, respectively. No significant differences in TTP were seen between each line setting (P = 0.843).

Conclusions: Capecitabine monotherapy is effective and well tolerated in all line settings of chemotherapy in patients with metastatic or advanced breast cancer, and is suitable for outpatient therapy.
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http://dx.doi.org/10.1093/jjco/hyp145DOI Listing
March 2010

Dynamics of different-sized solid-state nanocrystals as tracers for a drug-delivery system in the interstitium of a human tumor xenograft.

Breast Cancer Res 2009 3;11(4):R43. Epub 2009 Jul 3.

Division of Surgical Oncology, Tohoku University Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

Introduction: Recent anticancer drugs have been made larger to pass selectively through tumor vessels and stay in the interstitium. Understanding drug movement in association with its size at the single-molecule level and estimating the time needed to reach the targeted organ is indispensable for optimizing drug delivery because single cell-targeted therapy is the ongoing paradigm. This report describes the tracking of single solid nanoparticles in tumor xenografts and the estimation of arrival time.

Methods: Different-sized nanoparticles measuring 20, 40, and 100 nm were injected into the tail vein of the female Balb/c nu/nu mice bearing human breast cancer on their backs. The movements of the nanoparticles were visualized through the dorsal skin-fold chamber with the high-speed confocal microscopy that we manufactured.

Results: An analysis of the particle trajectories revealed diffusion to be inversely related to the particle size and position in the tumor, whereas the velocity of the directed movement was related to the position. The difference in the velocity was the greatest for 40-nm particles in the perivascular to the intercellular region: difference = 5.8 nm/s. The arrival time of individual nanoparticles at tumor cells was simulated. The estimated times for the 20-, 40-, and 100-nm particles to reach the tumor cells were 158.0, 218.5, and 389.4 minutes, respectively, after extravasation.

Conclusions: This result suggests that the particle size can be individually designed for each goal. These data and methods are also important for understanding drug pharmacokinetics. Although this method may be subject to interference by surface molecules attached on the particles, it has the potential to elucidate the pharmacokinetics involved in constructing novel drug-delivery systems involving cell-targeted therapy.
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http://dx.doi.org/10.1186/bcr2330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750102PMC
February 2010

Measurement of individual red blood cell motions under high hematocrit conditions using a confocal micro-PTV system.

Ann Biomed Eng 2009 Aug 12;37(8):1546-59. Epub 2009 Jun 12.

Department of Bioengineering and Robotics, Graduate School of Engineering, Tohoku University, 6-6-01 Aoba, Sendai 980-8579, Japan.

Developments in optical experimental techniques have helped in elucidating how blood flows through microvessels. Although initial developments were encouraging, studies on the flow properties of blood in microcirculation have been limited by several technical factors, such as poor spatial resolution and difficulty obtaining quantitative detailed measurements at such small scales. Recent advances in computing, microscopy, and digital image processing techniques have made it possible to combine a particle tracking velocimetry (PTV) system with a confocal microscope. We document the development of a confocal micro-PTV measurement system for capturing the dynamic flow behavior of red blood cells (RBCs) in concentrated suspensions. Measurements were performed at several depths through 100-mum glass capillaries. The confocal micro-PTV system was able to detect both translational and rotational motions of individual RBCs flowing in concentrated suspensions. Our results provide evidence that RBCs in dilute suspensions (3% hematocrit) tended to follow approximately linear trajectories, whereas RBCs in concentrated suspensions (20% hematocrit) exhibited transversal displacements of about 2% from the original path. Direct and quantitative measurements indicated that the plasma layer appeared to enhance the fluctuations in RBC trajectories owing to decreased obstruction in transversal movements caused by other RBCs. Using optical sectioning and subsequent image contrast and resolution enhancement, the system provides previously unobtainable information on the motion of RBCs, including the trajectories of two or more RBCs interacting in the same focal plane and RBC dispersion coefficients in different focal planes.
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http://dx.doi.org/10.1007/s10439-009-9732-zDOI Listing
August 2009

Effects of unique biomedical education programs for engineers: REDEEM and ESTEEM projects.

Adv Physiol Educ 2009 Jun;33(2):91-7

Department of Bioengineering and Robotics, Tohoku University, Sendai, Japan.

Current engineering applications in the medical arena are extremely progressive. However, it is rather difficult for medical doctors and engineers to discuss issues because they do not always understand one another's jargon or ways of thinking. Ideally, medical engineers should become acquainted with medicine, and engineers should be able to understand how medical doctors think. Tohoku University in Japan has managed a number of unique reeducation programs for working engineers. Recurrent Education for the Development of Engineering Enhanced Medicine has been offered as a basic learning course since 2004, and Education through Synergetic Training for Engineering Enhanced Medicine has been offered as an advanced learning course since 2006. These programs, which were developed especially for engineers, consist of interactive, modular, and disease-based lectures (case studies) and substantial laboratory work. As a result of taking these courses, all students obtained better objective outcomes, on tests, and subjective outcomes, through student satisfaction. In this article, we report on our unique biomedical education programs for engineers and their effects on working engineers.
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http://dx.doi.org/10.1152/advan.90120.2008DOI Listing
June 2009

Phase II study of capecitabine and trastuzumab combination chemotherapy in patients with HER2 overexpressing metastatic breast cancers resistant to both anthracyclines and taxanes.

Cancer Chemother Pharmacol 2009 Jul 12;64(2):361-9. Epub 2008 Dec 12.

Department of Surgical Oncology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

Purpose: The purpose of this study was to investigate the activity of capecitabine and trastuzumab in patients with HER2-overexpressing metastatic breast cancer resistant to both anthracyclines and taxanes.

Method: From June 2003 and May 2006, 40 female patients with measurable or assessable metastatic breast cancer were enrolled and data from 38 patients were reviewed extramurally and analyzed. Patients were treated with weekly trastuzumab given at a dose of 2 mg/kg/day over 90 min (4 mg/kg/day on the first infusion) and capecitabine given at a dose 1,657 mg/m(2)/day during 21 days with a subsequent pause of 7 days. This cycle was repeated every 28 days. The primary endpoint was overall survival and secondary endpoints were progression-free survival and response rate.

Result: A median of 4.5 cycles (range 1-9 cycles) were delivered. The median age was 53 (range 30-69 years). Median overall survival and progression-free survival was 22.3 and 4.1 months, respectively. Survival rate at 1 and 2 year was 81.6 and 47.4%, respectively. Response rate was 18.4% (95% CI, 7.7-34.3%). All evaluable patients have responded with two CR (5.3%), 5 PR (13.2%), 20 SD (52.6%), 8 PD (21.1%) and 3 NE (7.9%). Regarding the hematological toxicities, grade 1/2/3 neutropenia, grade 1/2 anemia, grade 1 thrombocytopenia and grade 1/2 liver dysfunction were also common. No treatment-related death was reported.

Conclusion: The combination of capecitabine and trastuzumab is active and well-tolerated in patients with HER2-overexpressing breast caner resistant to both anthracyclines and taxanes.
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http://dx.doi.org/10.1007/s00280-008-0882-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688618PMC
July 2009

Frictional characteristics of erythrocytes on coated glass plates subject to inclined centrifugal forces.

J Biomech Eng 2008 Oct;130(5):051007

Graduate School of Engineering, Tohoku University, 6-6 Aramaki-Aoba, Aoba-ku, Sendai 980-8579, Japan.

In recent years a diamond-like carbon (DLC) film and a 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer have attracted attention as coating materials for implantable artificial organs or devices. When these materials are coated on vascular devices, compatibility to blood is an important problem. The present paper focuses on friction characteristics of erythrocytes to these coating materials in a medium. With an inclined centrifuge microscope developed by the authors, observation was made for erythrocytes moving on flat glass plates with and without coating in a medium of plasma or saline under the effect of inclined centrifugal force. Friction characteristics of erythrocytes with respect to these coating materials were then measured and compared to each other to characterize DLC and MPC as coating materials. The friction characteristics of erythrocytes in plasma using the DLC-coated and noncoated glass plates are similar, changing approximately proportional to the 0.5th power of the cell velocity. The cells stick to these plates in saline as well, implying the influence of plasma protein. The results using the MPC-coated plate in plasma are similar to those of the other plates for large cell velocities, but deviate from the other results with decreased cell velocity. The results change nearly proportional to the 0.75th power of the cell velocity in the range of small velocities. The results for the MPC-coated plate in saline are similar to that in plasma but somewhat smaller, implying that the friction characteristics for the MPC-coated plate are essentially independent of plasma protein.
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http://dx.doi.org/10.1115/1.2948420DOI Listing
October 2008

Age-specific interval breast cancers in Japan: estimation of the proper sensitivity of screening using a population-based cancer registry.

Cancer Sci 2008 Nov 15;99(11):2264-7. Epub 2008 Sep 15.

Division of Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Japan.

The age-specific sensitivity of a screening program was investigated using a population-based cancer registry as a source of false-negative cancer cases. A population-based screening program for breast cancer was run using either clinical breast examinations (CBE) alone or mammography combined with CBE in the Miyagi Prefecture from 1997 to 2002. Interval cancers were newly identified by linking the screening records to the population-based cancer registry to estimate the number of false-negative cases of screening program. Among 112 071 women screened by mammography combined with CBE, the number of detected cancers, false-negative cases and the sensitivity were 289, 22 and 92.9%, respectively, based on the reports from participating municipalities. The number of newly found false-negative cases and corrected sensitivity when using the registry were 34 and 83.8%, respectively. In detected cancers, the sensitivity of screening by mammography combined with CBE in women ranging from 40 to 49 years of age based on a population-based cancer registry was much lower than that in women 50-59 and 60-69 years of age (40-49: 18, 71.4%, 50-59: 19, 85.8%, 60-69: 19, 87.2%). These data suggest that the accurate outcome of an evaluation of breast cancer screening must include the use of a population-based cancer registry for detecting false-negative cases. Screening by mammography combined with CBE may therefore not be sufficiently sensitive for women ranging from 40 to 49 years of age.
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http://dx.doi.org/10.1111/j.1349-7006.2008.00926.xDOI Listing
November 2008

Early diagnosis of cancer by detecting the chemiluminescence of hematoporphyrins in peripheral blood lymphocytes.

Tohoku J Exp Med 2008 Sep;216(1):47-52

New Industry Creation Hatchery Center, Tohoku University, Sendai, Japan.

Early detection and optimal treatment are the most effective means to improve cancer mortality. Mass screening for cancer has yielded a marked reduction of cancer mortality in the United States. Simple and effective methods are expected for screening of malignancy. Hematoporphyrin derivatives (HPDs) are known to accumulate in cancer cells; thus, HPD has been used for local diagnosis and photodynamic therapy of cancer. The lymphocytes of cancer patients also demonstrate the active uptake of HPD and this phenomenon has been applied for the diagnosis of cancer. In the present study, we have developed a novel method for measurement of the chemiluminescence of HPD in peripheral blood lymphocytes. HPD is composed of hematoporphyrin and its oligomers. Seven cancer patients and seven controls were recruited for this study. The primary cancers included two prostate cancers (one without metastasis and the other with lung metastasis), a renal cancer, a lung adenocarcinoma with systemic metastasis, two gallbladder cancers with lung metastasis, and a colon cancer with liver metastasis. HPD in lymphocytes was measured using a highly sensitive chemiluminescence analyzer with laser light irradiation to detect photoemission by (1)O(2) from HPD. The intensity of chemiluminescence exhibited a linear correlation with the concentrations of HPD. In addition, the level of HPD in lymphocytes was significantly higher in cancer patients than that in healthy volunteers (p < 0.05). These results suggest that detection of the chemiluminescence of HPD in lymphocytes could be a sensitive and simple method for cancer diagnosis and screening.
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http://dx.doi.org/10.1620/tjem.216.47DOI Listing
September 2008

[In vivo single molecular fluorescence imaging for analysis of pharmacokinetics].

Gan To Kagaku Ryoho 2008 Aug;35(8):1277-80

Division of Nano-Medical Science, Graduate School of Medicine, Tohoku University, Sendai, Japan.

Nano-materials are expected for research on molecular imaging of pharmacokinetics. We measured in vivo migration of CdSe nano-particles(Quantum Dots(QDs))conjugated with monoclonal anti-HER2 antibody(trastuzumab)in tumor vessel to breast cancer cells. We established a high resolution in vivo 3D microscopic system for a novel imaging method at single molecular level. The HER2 protein expressed in cancer cells and its dynamics were visualized by QDs in vivo at the spatial resolution of 30 nm. It suggests future utilization of the system in medical applications to improve the drug delivery system to target primary and metastatic tumors for made-to-order treatment. Future innovation in cancer imaging by nano-technology and novel measurement technology will provide great improvement, not only in the clinical field, but also in basic medical science. Advances in nano-biotechnology have great potential to improve prevention, diagnosis and treatment of human disease.
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August 2008

Radial dispersion of red blood cells in blood flowing through glass capillaries: the role of hematocrit and geometry.

J Biomech 2008 Jul 26;41(10):2188-96. Epub 2008 Jun 26.

Department of Bioengineering and Robotics, Graduate School of Engineering, Tohoku University, 6-6-01 Aoba, 980-8579 Sendai, Miagi, Japan.

The flow properties of blood in the microcirculation depend strongly on the hematocrit (Hct), microvessel geometry, and cell properties. Previous in vitro studies have measured the radial displacement of red blood cells (RBCs) at concentrated suspensions using conventional microscopes. However, to measure the RBCs motion they used transparent suspensions of ghost red cells, which may have different physical properties than normal RBCs. The present study introduces a new approach (confocal micro-PTV) to measure the motion of labeled RBCs flowing in concentrated suspensions of normal RBCs. The ability of confocal systems to obtain thin in-focus planes allowed us to measure the radial position of individual RBCs accurately and to consequently measure the interaction between multiple labeled RBCs. All the measurements were performed in the center plane of both 50 and 100 microm glass capillaries at Reynolds numbers (Re) from 0.003 to 0.005 using Hcts from 2% to 35%. To quantify the motion and interaction of multiple RBCs, we used the RBC radial dispersion (D(yy)). Our results clearly demonstrate that D(yy) strongly depends on the Hct. The RBCs exhibited higher D(yy) at radial positions between 0.4 and 0.8R and lower D(yy) at locations adjacent to the wall (0.8-1R) and around the middle of the capillary (0-0.2R). The present work also demonstrates that D(yy) tends to decrease with a decrease in the diameter. The information provided by this study not only complements previous investigations on microhemorheology of both dilute and concentrated suspensions of RBCs, but also shows the influence of both Hct and geometry on the radial dispersion of RBCs. This information is important for a better understanding of blood mass transport mechanisms under both physiological and pathological conditions.
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http://dx.doi.org/10.1016/j.jbiomech.2008.04.033DOI Listing
July 2008

Overexpression of calmodulin in pancreatic beta cells induces diabetic nephropathy.

J Am Soc Nephrol 2008 Sep 4;19(9):1701-11. Epub 2008 Jun 4.

Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.

Recently, endothelial dysfunction induced by an uncoupling of vascular endothelial growth factor (VEGF) and nitric oxide has been implicated in the pathogenesis of diabetic nephropathy (DN). Investigating the pathogenesis of DN has been limited, however, because of the lack of animal models that mimic the human disease. In this report, pancreatic beta cell-specific calmodulin-overexpressing transgenic (CaMTg) mice, a potential new model of DN, are characterized with particular emphasis on VEGF and related molecules. CaMTg mice developed hyperglycemia at 3 wk and persistent proteinuria by 3 mo. Morphometric analysis showed considerable increases in the glomerular and mesangial areas with deposition of type IV collagen. Moreover, the pathologic hallmarks of human DN (mesangiolysis, Kimmelstiel-Wilson-like nodular lesions, exudative lesions, and hyalinosis of afferent and efferent arteries with neovascularization) were observed. In addition, increased VEGF expression was associated with an increased number of peritubular capillaries. Expression of endothelial nitric oxidase synthase was reduced and that of VEGF was markedly elevated in CaMTg mice kidney compared with nontransgenic mice. No differences in VEGF receptor-1 or VEGF receptor-2 expression were observed between CaMTg mice and nontransgenic kidneys. In summary, CaMTg mice develop most of the distinguishing lesions of human DN, and the elevated VEGF expression in the setting of diminished endothelial nitric oxide synthase expression may lead to endothelial proliferation and dysfunction. This model may prove useful in the study of the pathogenesis and treatment of DN.
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http://dx.doi.org/10.1681/ASN.2006121358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518429PMC
September 2008

In vivo single molecular imaging and sentinel node navigation by nanotechnology for molecular targeting drug-delivery systems and tailor-made medicine.

Breast Cancer 2008 ;15(2):145-52

Department of Surgical Oncology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

The recent advances in nanotechnology have a great potential to improve the prevention, diagnosis, and treatment of human diseases. Nanomaterials for medical applications are expected to grasp pharmacokinetics and the toxicity for application to medical treatment on the aspect of safety of the nanomaterials and nanodevices. We describe a generation of CdSe nanoparticles [quantum dots (QDs)] conjugated with monoclonal anti-HER2 antibody (Trastuzumab), for single molecular in vivo imaging of breast cancer cells. We established a high-resolution in vivo 3D microscopic system for a novel imaging method at the molecular level. The cancer cells expressing HER2 protein were visualized by the nanoparticles in vivo at subcellular resolution, suggesting future utilization of the system in medical applications to improve drug-delivery systems to target the primary and metastatic tumors for made-to-order treatment. We also describe sentinel node navigation using fluorescent nanoparticles for breast cancer surgery in experimental model, which have shown the potential to be an alternative to existing tracers in the detection of the sentinel node if we select the appropriate particle size and wavelength. Future innovation in cancer imaging by nanotechnology and novel measurement technology will provide great improvement, not only in the clinical field but also in basic medical science for the development of medicine.
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http://dx.doi.org/10.1007/s12282-008-0037-0DOI Listing
January 2009

Significance of irradiation in breast-conserving treatment: comparison of local recurrence rates in irradiated and nonirradiated groups.

Int J Clin Oncol 2008 Feb 29;13(1):12-7. Epub 2008 Feb 29.

Division of Surgical Oncology, Tohoku University School of Medicine, Sendai, 980-8574, Japan.

Breast-conserving treatment (BCT) is a standard therapy for early breast cancer. Many reports have described the effectiveness of post-BCT radiation therapy. However, the post-BCT local recurrence rate of only 5% to 10% indicates that radiation therapy may be unnecessary in many cases. To accurately select those patients who do not require post-BCT radiation therapy, we investigated the significance of irradiation in BCT by comparing local recurrence rates in irradiated and nonirradiated patients, grouped according to clinicopathological criteria that we evaluated. The patients were divided into two groups: a previous-criteria group and a present-criteria group. The former group included 85 patients in whom only two factors were considered as the criteria for radiation therapy: margin-positivity and lymphatic metastasis-positivity. The latter group included 318 patients in whom three additional factors were also considered: lymphatic invasion, intraductal extension, and metachronous/synchronous bilateral breast cancer. The use of five clinicopathological factors rather than two as the criteria for irradiation led to an increase in the irradiation ratio from 47.1% to 63.2% and a decrease in local recurrence from 12.9% to 2.2%. Because of the short average follow-up period of this study, further careful, regular follow-up and randomized comparative studies are required. It may also be necessary to include the patient age and margin condition as mandatory criteria for irradiation.
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http://dx.doi.org/10.1007/s10147-007-0723-5DOI Listing
February 2008

Aqueous-phase synthesis of ultra-stable small CdSe nanoparticles.

J Nanosci Nanotechnol 2007 Nov;7(11):3750-3

Center for Interdisciplinary Research, Tohoku University, Aoba-ku, Sendai 980-8578, Japan.

Very stable and small CdSe nanoparticles (NPs) were synthesized from the aqueous solutions containing L-cysteine (Cys) at room temperature. The Cys-capped CdSe NPs showed a very sharp excitonic peak at 420 nm. Its very small full width at half maximum (18 nm) indicates very high quality of the CdSe NPs. Their absorption features experienced little change over a month, implying an excellent stability of the CdSe NPs. The synthesis conditions were very critical to the optical property and stability of the CdSe NPs: only those prepared at specific conditions (n(Se-precursor)/n(Cd-precursor) = 0.25-0.5, n(Cys)/n(Cd-precursor) = approximately 9, pH = approximately 12) showed very sharp absorption peaks and maintained an excellent stability against time. Under these conditions, the peaks always appear at nearly the same wavelength, indicating that these NPs are selectively stable and grow at a particular size and structure.
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November 2007
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