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Supplementary Table 1, Figure 1 from Epigenetic Inactivation of the Potential Tumor Suppressor Gene FOXF1 in Breast Cancer

The expression of several members of the FOX gene family is known to be altered in a variety of cancers. We show that in breast cancer, FOXF1 gene is a target of epigenetic inactivation and that its gene product exhibits tumor-suppressive properties. Loss or downregulation of FOXF1 expression is associated with FOXF1 promoter hypermethylation in breast cancer cell lines and in invasive ductal carcinomas. Methylation of FOXF1 in invasive ductal carcinoma (37.6% of 117 cases) correlated with high tumor grade. Pharmacologic unmasking of epigenetic silencing in breast cancer cells restored FOXF1 expression. Re-expression of FOXF1 in breast cancer cells with epigenetically silenced FOXF1 genes led to G1 arrest concurrent with or without apoptosis to suppress both in vitro cell growth and in vivo tumor formation. FOXF1-induced G1 arrest resulted from a blockage at G1-S transition of the cell cycle through inhibition of the CDK2-RB-E2F cascade. Small interfering RNA–mediated depletion of FOXF1 in breast cancer cells led to increased DNA re-replication, suggesting that FOXF1 is required for maintaining the stringency of DNA replication and genomic stability. Furthermore, expression profiling of cell cycle regulatory genes showed that abrogation of FOXF1 function resulted in increased expression of E2F-induced genes involved in promoting the progression of S and G2 phases. Therefore, our studies have identified FOXF1 as a potential tumor suppressor gene that is epigenetically silenced in breast cancer, which plays an essential role in regulating cell cycle progression to maintain genomic stability. Cancer Res; 70(14); 6047–58. ©2010 AACR.

Supplementary Figure 2 from Epigenetic Inactivation of the Potential Tumor Suppressor Gene FOXF1 in Breast Cancer

Supplementary Methods from Epigenetic Inactivation of the Potential Tumor Suppressor Gene FOXF1 in Breast Cancer

Supplementary Table 2 from Epigenetic Inactivation of the Potential Tumor Suppressor Gene FOXF1 in Breast Cancer

Prion diseases are transmissible and progressive neurodegenerative disorders characterized by abnormal prion protein (PrP

The complete sequence of the mitochondrial genome (mitogenome) of

Each prion strain has its own characteristics and the efficacy of anti-prion drugs varies. Screening of prion disease therapeutics is typically evaluated by measuring amounts of protease-resistant prion protein (PrP-res). However, it remains unclear whether such measurements correlate with seeding activity, which can be evaluated by real-time quaking-induced conversion (RT-QuIC). In this study, the effects of anti-prion compounds pentosan polysulfate (PPS), Congo red, and alprenolol were measured in N2a58 cells infected with Fukuoka-1 (FK1) or 22L strain. The compounds abolished PrP-res and seeding activity, except for N2a58/FK1 treated with PPS. Interestingly, the seeding activity of N2a58/FK1 was much lower in the presence of PPS, but that was maintained thereafter; indeed, when PPS was removed, seeding activity and PrP-res gradually recovered to their original levels. These results indicate that prion latent infection is induced by PPS in a strain-dependent manner. Furthermore, for protein misfolding cyclic amplification (PMCA), the anti-prion effect of PPS decreased in FK1 compared to 22L, suggesting that the difference in effect observed between these two occurs at the level of the direct conversion. Our findings demonstrate that the advantages of RT-QuIC and PMCA can be exploited for more accurate assessment of therapeutic drug screening, reflecting strain differences.

Each prion strain has its own characteristics and the efficacy of anti-prion drugs varies. Screening of prion disease therapeutics is typically evaluated by measuring amounts of protease-resistant prion protein (PrP-res). However, it remains unclear whether such measurements correlate with seeding activity, which is evaluated by real-time quaking-induced conversion (RT-QuIC). In this study, the effects of anti-prion compounds pentosan polysulfate (PPS), Congo red, and alprenolol were measured in N2a58 cells infected with Fukuoka-1 (FK1) or 22L strain. The compounds abolished PrP-res and seeding activity, except for N2a58/FK1 treated with PPS. Interestingly, the seeding activity of N2a58/FK1, which was reduced in the presence of PPS, was not lost and remained at low levels. However, upon removal of PPS, both were gradually restored to their original levels. These results indicate that low-level persistent prion infection keeping measurable seeding activity is induced by PPS in a strain-dependent manner. Furthermore, for protein misfolding cyclic amplification (PMCA), the anti-prion effect of PPS decreased in FK1 compared to 22L, suggesting that the differences occur at the level of the direct conversion. Our findings demonstrate that the advantages of RT-QuIC and PMCA can be exploited for more accurate assessment of therapeutic drug screening, reflecting strain differences.

Real-time quaking-induced conversion (RT-QUIC) assays using Escherichia coli-derived purified recombinant prion protein (rPrP) enable us to amplify a trace amount of the abnormal form of PrP (PrPSc) from specimens. This technique can be useful for the early diagnosis of both human and animal prion diseases and the assessment of prion contamination. In the present study, we demonstrated that there are strain-specific differences in the RT-QUIC reactions between an atypical form of bovine spongiform encephalopathy (BSE), l-BSE, and classical BSE (C-BSE). Whereas mouse rPrP (rMoPrP) was efficiently converted to amyloid fibrils in the presence of PrPSc seed derived from either l-BSE or C-BSE, hamster rPrP (rHaPrP) was converted only in l-BSE, not C-BSE. These characteristics were preserved in the second round reaction, but gradually weakened in the subsequent rounds and were completely lost by the fifth round, most likely due to the selective growth advantage of nonspecific rPrP amyloid fibrils in the RT-QUIC. Our findings further enhance the discrimination of prion strains using RT-QUIC, and further our understanding of the molecular basis of prion strains.

We experienced two cases of primary pulmonary amyloidosis with a localized consolidation. Case 1 is a 80-year-old man, who was found to have an abnormal chest nodular shadow with blurred margin at a medical examination. Chest computed tomography( CT) showed a localized consolidation on the periphery of the upper lobe of the right lung. A CT-guided biopsy was performed. Case 2 is a 66-year-old woman, who was found to have an abnormal chest opacity at a medical examination. Chest CT showed a localized gathering of small nodules in the right lower lobe. Gradual enlargement was noted by follow up CT and the accumulation of fluorodeoxyglucose (FDG) was shown by PET/CT. In consideration of primary lung cancer or malignant lymphoma, right lower lobectomy was performed. Both cases were pathologically diagnosed as pulmonary amyloidosis. Since no findings of amyloid deposits in other organs or of existence of any blood disorders, a diagnosis of primary pulmonary amyloidosis was made.

The molecular basis underlying the conversion of normal prion protein (PrPC) into abnormal prion protein (PrPSc) has not been fully elucidated. The protein-misfolding cyclic amplification (PMCA) technique, which can amplify PrPSc in vitro with the use of intermittent sonication, mimics the process of in vivo PrPSc replication. Accumulating evidence suggests that co-factors other than PrP may play a crucial role in the faithful replication of PrPSc. In conventional PMCA, brain homogenates (BHs) from normal animals are used as the PrPC substrate. Since BHs contain many impurities, it is difficult to identify the co-factors using conventional PMCA. Thus, we developed a modified PMCA system using baculovirus and insect cell-derived recombinant PrP as a substrate (insect cell PMCA; iPMCA). We demonstrated that nucleic acids and glycosaminoglycans (GAGs) such as heparan sulfate (HS) or its analogue heparin (HP) are critical for PrPSc amplification in iPMCA. Of note, the addition of HS or HP restored the conversion efficiency in iPMCA under nucleic acid-depleted conditions. Moreover, the iPMCA products were infectious and preserved the strain properties of the input seed PrPSc. These data suggest that not only nucleic acids but also some GAGs play an important role in facilitating faithful replication of prions, at least in vitro.

BACKGROUND: Trastuzumab (Tz) is assumed to prime antibody-dependent cellular cytotoxicity (ADCC); however, it remains unclear whether Tz therapy can clinically induce adaptive cellular immunity. OBJECTIVE: Adaptive Cellular Immune Effect of Tz Therapy. METHODS: This study included 29 surgical invasive breast carcinomas administered neoadjuvant chemotherapy with Tz (15 cases) or without Tz (14 cases). The numbers of immunoreactive cells (CD4, CD8, CD56, and Fox-P3) in three different compartments (intratumoral, adjacent stromal, and distant stromal) were determined. RESULTS: The average number of adjacent stromal CD4-positive, CD8-positive, and Fox-P3-positive cells in the Tz+ group was significantly greater than that in the Tz− group (p = 0.036, 0.0049, and 0.043, respectively). However, the number of Fox-P3-positive cells was much less than that of CD4-positive cells. Moreover, distant stromal CD4-positive and CD8-positive cells in the Tz+ group was also significantly greater than that of the Tz− group (p = 0.029 and 0.032, respectively). Only a small number of CD56-positive natural killer cells, playing a main role in ADCC, accumulated at the tumor site after Tz therapy. CONCLUSIONS: The results suggest that Tz therapy induces adaptive cellular immunity, including infiltration of both CD4-positive helper T cells and CD8-positive cytotoxic T cells into the breast carcinoma lesion.

Using cell culture and animal models of prion diseases, Ishibashi et al. show that type I interferon signalling interferes with prion infection in mammals. A selective type I interferon receptor agonist inhibits prion invasion and prolongs survival of prion-infected mice, suggesting potential clinical applications., Infectious prions comprising abnormal prion protein, which is produced by structural conversion of normal prion protein, are responsible for transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease in humans. Prions are infectious agents that do not possess a genome and the pathogenic protein was not thought to evoke any immune response. Although we previously reported that interferon regulatory factor 3 (IRF3) was likely to be involved in the pathogenesis of prion diseases, suggesting the protective role of host innate immune responses mediated by IRF3 signalling, this remained to be clarified. Here, we investigated the reciprocal interactions of type I interferon evoked by IRF3 activation and prion infection and found that infecting prions cause the suppression of endogenous interferon expression. Conversely, treatment with recombinant interferons in an ex vivo model was able to inhibit prion infection. In addition, cells and mice deficient in type I interferon receptor (subunit interferon alpha/beta receptor 1), exhibited higher susceptibility to 22L-prion infection. Moreover, in in vivo and ex vivo prion-infected models, treatment with RO8191, a selective type I interferon receptor agonist, inhibited prion invasion and prolonged the survival period of infected mice. Taken together, these data indicated that the interferon signalling interferes with prion propagation and some interferon-stimulated genes might play protective roles in the brain. These findings may allow for the development of new strategies to combat fatal diseases.

BACKGROUND:Ductal carcinoma in situ (DCIS) of the breast is heterogeneous in terms of the risk of progression to invasive ductal carcinoma (IDC). To treat DCIS appropriately for its progression risk, we classified individual DCIS by its profile of genomic changes into 2 groups and correlated them with clinicopathological progression factors., METHODS:We used surgically resected, formalin-fixed, paraffin-embedded tissues of 22 DCIS and 30 IDC lesions. We performed immunohistochemical intrinsic subtyping, array-based comparative genomic hybridization, and unsupervised clustering., RESULTS:The samples were divided into 2 major clusters, A and B. Cluster A showed a greater number of gene and chromosome copy number alterations, a larger IDC/DCIS ratio, a higher frequency of nonluminal subtype, a lower frequency of luminal subtype, and a higher nuclear grade, when compared with cluster B. However, there was no difference in the frequencies of lymph node metastasis between clusters A and B. We identified 9 breast-cancer-related genes, including TP53 and GATA3, that highly contributed to the discrimination of A and B clusters., CONCLUSION:Classification of breast tumors into rapidly progressive cluster A and the other (cluster B) may contributeto select the treatment appropriate for their progression risk.

Trastuzumab (Tz) is assumed to prime antibody-dependent cellular cytotoxicity (ADCC); however, it remains unclear whether Tz therapy can clinically induce adaptive cellular immunity.Adaptive Cellular Immune Effect of Tz Therapy.This study included 29 surgical invasive breast carcinomas administered neoadjuvant chemotherapy with Tz (15 cases) or without Tz (14 cases). The numbers of immunoreactive cells (CD4, CD8, CD56, and Fox-P3) in three different compartments (intratumoral, adjacent stromal, and distant stromal) were determined.The average number of adjacent stromal CD4-positive, CD8-positive, and Fox-P3-positive cells in the Tz+ group was significantly greater than that in the Tz- group (p = 0.036, 0.0049, and 0.043, respectively). However, the number of Fox-P3-positive cells was much less than that of CD4-positive cells. Moreover, distant stromal CD4-positive and CD8-positive cells in the Tz+ group was also significantly greater than that of the Tz- group (p = 0.029 and 0.032, respectively). Only a small number of CD56-positive natural killer cells, playing a main role in ADCC, accumulated at the tumor site after Tz therapy.The results suggest that Tz therapy induces adaptive cellular immunity, including infiltration of both CD4-positive helper T cells and CD8-positive cytotoxic T cells into the breast carcinoma lesion.

Summary: Plants tailor immune responses to defend against pathogens with different lifestyles. In this process, antagonism between the immune hormones salicylic acid (SA) and jasmonic acid (JA) optimizes transcriptional signatures specifically to the attacker encountered. Antagonism is controlled by the transcription cofactor NPR1. The indispensable role of NPR1 in activating SA-responsive genes is well understood, but how it functions as a repressor of JA-responsive genes remains unclear. Here, we demonstrate that SA-induced NPR1 is recruited to JA-responsive promoter regions that are co-occupied by a JA-induced transcription complex consisting of the MYC2 activator and MED25 Mediator subunit. In the presence of SA, NPR1 physically associates with JA-induced MYC2 and inhibits transcriptional activation by disrupting its interaction with MED25. Importantly, NPR1-mediated inhibition of MYC2 is a major immune mechanism for suppressing pathogen virulence. Thus, NPR1 orchestrates the immune transcriptome not only by activating SA-responsive genes but also by acting as a corepressor of JA-responsive MYC2.

Prion diseases are a group of fatal neurodegenerative disorders caused by accumulation of proteinaceous infectious particles, or prions, which mainly consist of the abnormally folded, amyloidogenic prion protein, designated PrPSc. PrPSc is produced through conformational conversion of the cellular isoform of prion protein, PrPC, in the brain. To date, no effective therapies for prion diseases have been developed. In this study, we incidentally noticed that mouse neuroblastoma N2a cells persistently infected with 22L scrapie prions, termed N2aC24L1-3 cells, reduced PrPSc levels when cultured in advanced Dulbecco’s modified eagle medium (DMEM) but not in classic DMEM. PrPC levels remained unchanged in prion-uninfected parent N2aC24 cells cultured in advanced DMEM. These results suggest that advanced DMEM may contain an anti-prion compound(s). We then successfully identified ethanolamine in advanced DMEM has an anti-prion activity. Ethanolamine reduced PrPSc levels in N2aC24L1-3 cells, but not PrPC levels in N2aC24 cells. Also, oral administration of ethanolamine through drinking water delayed prion disease in mice intracerebrally inoculated with RML scrapie prions. These results suggest that ethanolamine could be a new anti-prion compound.

Cell transplantation therapy offers great potential to improve impairments after stroke. However, the importance of donor age on therapeutic efficacy is unclear. We investigated the regenerative capacity of transplanted cells focusing on donor age (young vs. old) for ischaemic stroke. The quantities of human mesenchymal stem cell (hMSC) secreted brain-derived neurotrophic factor in vitro and of monocyte chemotactic protein-1 at day 7 in vivo were both significantly higher for young hMSC compared with old hMSC. Male Sprague-Dawley rats subjected to transient middle cerebral artery occlusion that received young hMSC (trans-arterially at 24 h after stroke) showed better behavioural recovery with prevention of brain atrophy compared with rats that received old hMSC. Histological analysis of the peri-infarct cortex showed that rats treated with young hMSC had significantly fewer microglia and more vessels covered with pericytes. Interestingly, migration of neural stem/progenitor cells expressing Musashi-1 positively correlated with astrocyte process alignment, which was more pronounced for young hMSC. Aging of hMSC may be a critical factor that affects cell therapy outcomes, and transplantation of young hMSC appears to provide better functional recovery through anti-inflammatory effects, vessel maturation, and neurogenesis potentially by the dominance of trophic factor secretion.

This study proposes large force generation by a robotic manipulator by means of providing series elastic actuators exploiting mechanical resonance to it instead of powerful actuators. To this end, the authors designed and assembled a prototype of series elastic actuator that resonates at around 1.0 Hz on the basis of its model and identified parameters, and carried out preliminary experiments with it and a load. The prototype actuator consists of a geared DC motor with an encoder and an elastic element. The elastic element is made of two torsion springs so that it can generate torque in both directions. It was confirmed in the preliminary experiments that the prototype actuator resonated at around 0.7 Hz. In addition, in order to prove efficacy of mechanical resonance for large force generation, output torque of the prototype actuator with the elastic element and without it was estimated using their identified physical parameters and dynamics, and compared them. The estimation results showed that the prototype actuator exploiting mechanical resonance generated 2.24 times larger torque than the one without the elastic element.

Combination chemotherapy with pertuzumab, trastuzumab, and docetaxel is recommended as the first-line treatment for patients with HER2-positive unresectable or metastatic breast cancer. We report 2 cases of unresectable breast cancer for which pertuzumab, trastuzumab, and docetaxel therapy was effective. Case 1: A woman in her 40s was diagnosed with TxN3aM0, Stage ⅢC, HER2-positive, hormone receptor-positive advanced breast cancer. After administration of 6 courses of pertuzumab, trastuzumab, and docetaxel therapy, she underwent surgery(Bt+Ax[Ⅱ]). Histopathological examination revealed that chemotherapy effect was Grade 3. Case 2: A woman in her 60s was diagnosed with de novo Stage Ⅳ, HER2- positive, hormone receptor-negative breast cancer. She was administered 8 courses of pertuzumab, trastuzumab, and docetaxel therapy as the third-line treatment, because she initially refused treatment. Thereafter, she underwent surgery(Bt+Ax [Ⅰ]). In both cases, histopathological examination revealed complete response after chemotherapy. Thus, combination therapy of pertuzumab and trastuzumab may improve the prognosis in patients with HER2-positive breast cancer.

Human prion diseases are neurodegenerative disorders caused by abnormally folded prion proteins in the central nervous system. These proteins can be detected using the quaking-induced conversion assay. Compared with other bioassays, this assay is extremely sensitive and was used in the present study to determine prion distribution in sporadic Creutzfeldt-Jakob disease patients at autopsy. Although infectivity of the sporadic form is thought to be restricted within the central nervous system, results showed that prion-seeding activities reach 106/g from a 50% seeding dose in non-neuronal tissues, suggesting that prion-seeding activity exists in non-neural organs, and we suggested that non-neural tissues of 106/g SD50 did not exist the infectivity., Highlights • Prion-seeding activities reach 106/g from a 50% seeding dose in non-neuronal tissues. • Results suggest that prion-seeding activity exists in neural and non-neural organs. A major problem for the diagnosis and management of human prion diseases is the lack of rapid and high-sensitive assays to measure low prion levels. Recent studies have tried to measure prion concentrations in non-neuronal tissues, but prion levels were not sufficient. Therefore, we developed the RT-QuIC method to measure prion-seeding activity in the non-neuronal, human tissues. The SD50 levels in the spleen, kidney, lung, and liver were 5.0–6.5, with different SD50 levels in the individual cases.

We propose IM6D, a novel real-time magnetic motion-tracking system using multiple identifiable, tiny, lightweight, wireless and occlusion-free markers. It provides reasonable accuracy and update rates and an appropriate working space for dexterous 3D interaction. Our system follows a novel electromagnetic induction principle to externally excite wireless LC coils and uses an externally located pickup coil array to track each of the LC coils with 5-DOF. We apply this principle to design a practical motion-tracking system using multiple markers with 6-DOF and to achieve reliable tracking with reasonable speed. We also solved the principle's inherent dead-angle problem. Based on this method, we simulated the configuration of parameters for designing a system with scalability for dexterous 3D motion. We implemented an actual system and applied a parallel computation structure to increase the tracking speed. We also built some examples to show how well our system works for actual situations.

A 70-year-old woman presenting with abdominal pain was admitted to our hospital. Abdominal contrast CT revealed a small intestine tumor of 10 cm with active bleeding and performed partial resection of the small intestine including tumor. Pathological findings were high risk GIST of the small intestine because of spindle cells and c-kit positive. Imatinib 400mg/day as adjuvant chemotherapy was administered. However administration was stopped for 15 days because of the Grade 4 erythema multiforme. Recurrence of peritoneal dissemination was observed in 2 years after surgery and tumor resection was performed, but complete resection was difficult. Within 5 years after surgery, tumor resection was performed on a total of 5 times peritoneal disseminative recurrences, and it was possible to avoid the appearance of symptoms due to tumor augmentation.

We report 3 cases of multiple GIST of the small intestine in 3 patients with NF1 who have been followed for over 5 years. All patients presented with melena, and tumors of the small intestine suspected to be GIST were found on endoscopy. We performed partial resections of the small intestine for all 3 patients. After surgery, 1 patient had residual tumors that gradually enlarged during 8 year 2 months and another had residual tumors that have been stable for 8 years. In the third patient, we resected all the tumors, and there has been no sign of recurrence in 6 year 1 month.

Survival of Stage IV gastric cancer is poor. We report 2 cases of Stage IV gastric cancer with positive peritoneal washing cytology or peritoneal dissemination that were successfully treated with gastrectomy and hyperthermic intraperitoneal chemotherapy( HIPEC)followed by systemic chemotherapy. Case 1: A 59-year-old woman. She was diagnosed with advanced gastric cancer and underwent gastrectomy with HIPEC. Her peritoneal washing cytology was positive during the gastrectomy. After the surgery, she underwent chemotherapy consisting of 8 courses of combination S-1 plus CPT-11 and 19 courses of PTX. It has been 5 years and 7 months since she had the surgery and she survives without recurrence of the cancer. Case 2: A 60-year-old woman. She was diagnosed with advanced gastric cancer and peritoneal dissemination(peritoneal cancer index: 3 points). She underwent gastrectomy, hemi-colectomy, and HIPEC. After the surgery, she underwent chemotherapy, 35 courses of combination S-1 plus PSK/DOC, and 13 courses of S-1 plus PSK. It has been 5 years since her surgery and she survives without exacerbation of the cancer. These cases suggest a gastrectomy and HIPEC followed by systemic chemotherapy may represent an effective treatment for advanced gastric cancer with a small amount of peritoneal metastasis.

A 62-year-old woman visited our hospital because of dysphagia. She was diagnosed with upper-middle esophageal type 4 cancer, which was 9 cm in length, according to the results of endoscopy. Squamous cell carcinoma was demonstrated using endoscopic biopsy. A CT scan revealed that the tumor had directly invaded into the trachea(cT4). Chemoradiotherapy(CRT) (5-FU and CDDP with 50 Gy of radiation)was administered. Although CT after CRT resulted in shrinkage of the tumor and no further tracheal invasion, esophageal stenosis remained. Therefore, salvage surgery(subtotal esophagectomy with 3-field lymph node dissection)was performed. Pathologically, no carcinoma cells were found in the resected specimen and a com- plete response(grade 3)was diagnosed. The patient received adjuvant chemotherapy(tegafur/uracil at 300mg/day per os) for 1 year. The patient is alive with no relapse of carcinoma more than 5 years after the first treatment.

An 80's woman was diagnosed with eccrine porocarcinoma of the head in 2010.T he tumor was removed surgically but relapsed in the cervical and axillary lymph nodes 2 years later.The patient underwent surgery, and received systemic chemotherapy and radiation.Chest CT after treatment revealed an irregular mass and thickened skin in the left breast.Core needle biopsy specimens were used to diagnose metastasis of eccrine porocarcinoma.A wide excision with a 1 cm margin was performed under local anesthesia.After surgery, supraclavicular lymph node recurrence was detected.The patient received palliative care because there was no effective treatment available.Eccrine porocarcinoma is a rare malignant tumor of the intraepidermal sweat duct.Breast metastasis from malignant disease is also rare.To our knowledge, breast metastasis of eccrine porocarcinoma has not been reported.

The plasticity of Zr–Cu enriched hypoeutectic Zr–Cu–Ni–Al cast glassy alloys (CGAs) was investigated to determine their tensile elongation as a solid at room temperature, and their precise thermoplastic moldability in a supercooled liquid state. The viscosity of the supercooled liquids was measured by using a penetration viscometer at a high-speed heating rate of 400 K/min. The results obtained show that with an increase in the Zr content, the glass transition temperature (Tg) tends to decrease, whereas the crystallization temperature (Tx) tends to increase. We observed tensile elongation with plural sliding shear bands in the Zr–Cu enriched Zr65Cu20Ni5Al10 CGAs at room temperature. Furthermore, the hypoeutectic Zr65Cu18Ni7Al10 CGA exhibits the widest ΔTx (=Tx−Tg) of about 170 K, with a low viscosity in the order of 105 Pa s being observed in the supercooled liquid under a heating rate of 400 K/min. The potential for printing micro-patterns on the surface of a glassy Zr65Cu18Ni7Al10 alloy is demonstrated by means of tough nanocrystalline Ni–W electro-plating molds.

We describe our approach that derives reliable 6-DOF information including the translation and the rotation of a rigid marker in a 3D space from a set of insufficient 5-DOF measurements. As a practical example, we carefully constructed a prototype and its design and evaluated it in our 3D dexterous motion-tracking system, IM6D, which is our novel real-time magnetic 3D motion-tracking system that uses multiple identifiable, tiny, lightweight, wireless, and occlusion-free markers. The system contains two key technologies; a 6-DOF computation algorithm and a marker design for 6D marker. The 6-DOF computation algorithm computes the result of complete 6-DOF information including translation and rotation in 3D space for a single rigid marker that consists of three LC coils. We propose several possible approaches for implementation, including geometric, matrix-based kinematics, and computational approaches. In addition, we introduce workflow to find an optimal marker design for the system to achieve the best compromise between its smallness and accuracy based on the tracking principle. We experimentally compare the performances of some typical marker prototypes with different layouts of LC coils. Finally, we also show another experimental result to prove the effectiveness of the results from the solutions in these two problems.

Background: Goshajinkigan (GJG) is used for the treatment of several neurological symptoms. We investigated the efficacy of GJG and mecobalamin (B12) against neurotoxicity associated with docetaxel (DOC) in breast cancer patients. Materials and Methods: Sixty breast cancer patients were treated with DOC. Thirty-three patients (GJG group) received oral administration of 7.5 g/day GJG and 27 patients (B12 group) received oral administration of 1500 μg/day B12. Neuropathy was evaluated according to DEB-NTC (Neurotoxicity Criteria of Debiopharm), Common Terminology Criteria for Adverse Events (NCI-CTC) ver. 3.0, and a visual analogue scale (VAS). This study employed a randomized open design. Results: The incidence of neuropathy was 39.3% in the GJG group, and 88.9% in the B12 group (p

Background: We compared treatment completion rates and safety of docetaxel and cyclophosphamide sixcycle therapy (TC6) with docetaxel followed by 5FU, epirubicin and cyclophosphamide (T-FEC) therapy in Japanese patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Materials and Methods: We administered TC6 q3w or T-FEC q3w to HER2-negative breast cancer patients. The primary endpoint of this trial was toxicity. As second endpoints, the treatment completion rate and relative dose intensity were evaluated. Results: The TC6 and T-FEC group consisted of 22 and 21 patients, respectively. Concerning hematological toxicity, grade 3 or higher adverse reactions included neutropenia and febrile neutropenia. As non-hematological adverse events, exanthema and peripheral neuropathy were frequently reported in the TC6 group, whereas more patients of the T-FEC group reported nausea and vomiting. In TC6, the treatment completion rate was 86.4% and the relative dose intensity of docetaxel was 93.2%. In T-FEC, the values were 95.2% and 98.9%, respectively. Conclusions: These results suggest that TC6 is tolerable in Japanese, and that this regimen can also be performed in outpatient clinics. However, with the TC6 regimen, the compliance was slightly lower than with the T-FEC regimen, and supportive therapy needs to be managed appropriately.

Background: Although taxanes have become a key chemotherapeutic drug in breast cancer treatment. Taxanes inhibit the growth of cancer cells by disrupting the functioning of their microtubules; however, the microtubules of nerve cells are also affected by this process, which can cause neurological disorders. The Kampo medicine Goshajinkigan (GJG) is a traditional Japanese medicine that is used for the treatment of several neurological symptoms including pain and numbness, GJG is comprised of 10 herbs, each of which contains numerous active ingredients. Recently, GJG has been reported to prevent anticancer drug-induced peripheral neuropathy in colorectal cancer. We performed the present prospective randomized study to confirm the effects of GJG and mecobalamin (B12) against docetaxel (DOC)-associated peripheral neurotoxicity in breast cancer patients. Patients and method: Between May 2007 and April 2011, 60 breast cancer patients were treated with DOC. Thirty-three patients (GJG group) received oral administration of 7.5 g/day GJG and 27 patients (B12 group) received oral administration of 1500 μg/day B12. The patients were treated with TC (75mg/m2 docetaxel and 600 mg/m2 cyclophosphamide) every 3 weeks for 4 cycles, docetaxel alone (100mg/m2) every 3 weeks for 4 cycles, and XT (900mg/m2 capecitabine administered orally twice a day on days 1–14 plus 60 mg/m2 docetaxel) every 3 weeks for 6 cycles. Peripheral neuropathy was evaluated during every course according to DEB-NTC (Neurotoxicity Criteria of Debiopharm), Common Terminology Criteria for Adverse Events (NCI-CTC) ver.3.0, and a visual analogue scale (VAS). Results: The median age of the GJG group was 58 years old (35 to 70 years old), the B12 group was 55 years old (33 to 69 years old), and they were all females. For the regimens, in the GJG group, TC, DOC only, and XT were administered in 19 cases, 13 cases and 1 case, respectively. In the B12 group, they were 15 cases, 11 cases and 12 cases, respectively. The cumulative dose of DOC was 338.5 mg/m2 in the GJG group, and 340 mg/m2 in the B12 group. Peripheral neuropathy occurred significantly less frequently in the GJG group (39.3%) than the B12 group (88.9%) (p < 0.01). In the GJG group, grade 1 DEB-NTC was observed in 2 cases, grade 2 in 5 cases and grade 3 in 5 cases. Grade 1 NCI-CTC was observed in 7 cases, grade 2 in 6 cases. In the B12 group, grades 1, 2 and 3 DEB-NTC were observed in one case, 12 cases and 12 cases, respectively; and grades 1, 2 and 3 NCI-CTC were observed in 11 cases, 12 cases and one case. The mean VAS scores for numbness after chemotherapy were 2.7 in the GJG group and 4.9 in the B12 group (p < 0.01). The incidence of grade 2/3 peripheral neuropathy was lower in the GJG group than the B12 group. Peripheral neuropathy was significantly controlled in the GJG group. Conclusion: The present study is the first prospective control study to prove the efficacy of GJG against docetaxel-induced peripheral neuropathy in breast cancer patients. Our findings suggest that DOC-associated peripheral neurotoxicity can be suppressed by the administration of GJG. It will be necessary to confirm the usefulness of GJG in larger prospective studies. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-11.

Accidental transmission of prions during neurosurgery has been reported as a consequence of re-using contaminated surgical instruments. Several decontamination methods have been studied using the 263K-hamster prion; however, no studies have directly evaluated human prions. A newly developed in vitro amplification system, designated real-time quaking-induced conversion (RT-QuIC), has allowed the activity of abnormal prion proteins to be assessed within a few days. RT-QuIC using human recombinant prion protein (PrP) showed high sensitivity for prions as the detection limit of our assay was estimated as 0.12 fg of active prions. We applied this method to detect human prion activity on stainless steel wire. When we put wires contaminated with human Creutzfeldt–Jakob disease brain tissue directly into the test tube, typical PrP-amyloid formation was observed within 48 hours, and we could detect the activity of prions at 50% seeding dose on the wire from 102.8 to 105.8 SD50. Using this method, we also confirmed that the seeding activities on the wire were removed following treatment with NaOH. As seeding activity closely correlated with the infectivity of prions using the bioassay, this wire-QuIC assay will be useful for the direct evaluation of decontamination methods for human prions.

Removal of pathogenic organisms from reprocessed surgical instruments is essential to prevent iatrogenic infections. Some bacteria can make persistent biofilms on medical devices. Contamination of non-disposable equipment with prions also represents a serious risk to surgical patients. Efficient disinfection of prions from endoscopes and other instruments such as high-resolution cameras remains problematic because these instruments do not tolerate aggressive chemical or heat treatments. Herein, we develop a new washing system that uses both the alkaline and acidic water produced by electrolysis. Electrolyzed acidic water, containing HCl and HOCl as active substances, has been reported to be an effective disinfectant. A 0.15% NaCl solution was electrolyzed and used immediately to wash bio-contaminated stainless steel model systems with alkaline water (pH 11.9) with sonication, and then with acidic water (pH 2.7) without sonication. Two bacterial species (Staphylococcus aureus and Pseudomonas aeruginosa) and a fungus (Candida albicans) were effectively removed or inactivated by the washing process. In addition, this process effectively removed or inactivated prions from the stainless steel surfaces. This washing system will be potentially useful for the disinfection of clinical devices such as neuroendoscopes because electrolyzed water is gentle to both patients and equipment and is environmentally sound.

TC (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 q3w) combination is used for neoadjuvant/adjuvant chemotherapy in primary breast cancer. The incidence of allergic reaction is reportedly more common in patients who receive docetaxel before cyclophosphamide. This study aims to determine the significance of cyclophosphamide and docetaxel administration sequence. Prospective analysis was performed of 49 consecutive patients treated with TC for stage I–IIB breast cancer from March 2010 to June 2011. Premedication was administered with granisetron, dexamethasone, and chlorpheniramine. Patient charts were reviewed for completion rate and adverse events. Two-tailed Fisher exact test was used to evaluate adverse events between prior cyclophosphamide and prior docetaxel. Of 49 patients, 26 received docetaxel prior to cyclophosphamide and 23 received cyclophosphamide before docetaxel. There were no differences in patient characteristics between the two groups. Completion rates were 95.6 % in the prior cyclophosphamide group, and 100 % in the prior docetaxel group. The relative dose intensities of docetaxel and cyclophosphamide were 94.5 and 94.8 % in the prior cyclophosphamide group, and 98.5 and 98.7 % in the prior docetaxel group (p

The tolerance and safety associated with the administration order of the anthracycline and taxane drugs have not been evaluated.Breast cancer patients with node-positive or high-risk patients with node-negative were eligible. The feasibility and toxicity were evaluated in the following regimens--arm A, 3 courses of fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2) and cyclophosphamide 500 mg/m(2) (FEC) followed by 3 courses of docetaxel 100 mg/m(2) (DOC); arm B, 3 courses of DOC followed by 3 courses of FEC.Forty-two patients were registered. The relative dose intensity was 94.2 % for FEC and 97.8 % for DOC in arm A, and 98.9 % for DOC and 95.2 % for FEC in arm B. In arm A, grade 3 or higher hematological toxicity was observed in nine patients, and febrile neutropenia developed in three patients with FEC. In arm B, grade 3 or higher hematological toxicity was observed in seven patients, but febrile neutropenia was not noted in any patient.The regimens in both arms A and B were safe regarding adjuvant chemotherapy for early breast cancer. However, DOC followed by FEC might be more tolerable. Further studies will maximize the results obtained with DOC followed by FEC.

Prions, the causative agents of prion diseases, are immunologically tolerated because their major component, prion protein (PrP), is a host-encoded molecule. Therefore, no effective prion vaccines have been developed. We previously showed that heterologous bovine and sheep PrP immunizations of mice overcame tolerance by an antigenic mimicry mechanism to efficiently induce anti-PrP auto-antibodies (Abs), significantly prolonging incubation times in mice subsequently infected with the mouse-adapted Fukuoka-1 prion. These results prompted us to investigate if non-mammal derived molecules able to antigenically mimic anti-prion epitopes, could act as prion vaccines. We show here that immunization of mice with recombinant succinylarginine dihydrolase, a bacterial enzyme with a peptide sequence similar to an anti-prion epitope, induced anti-PrP auto-Abs with anti-prion activity and significantly retarded survival times of the mice subsequently infected with Fukuoka-1 prions. These results might open a way for development of a new type of antigenic mimicry-based prion vaccine., Vaccine, 29(50), pp.9321-9328; 2011

We first verified that a single chain Fv fragment against prion protein (anti-PrP scFv) was secreted by HEK293T cells and prevented prion replication in infected cells. We then stably expressed anti-PrP scFv in brain-engraftable murine microglial cells and intracerebrally injected these cells into mice before or after infection with prions. Interestingly, the injection before or at an early time point after infection attenuated the infection marginally but significantly prolonged survival times of the mice. These suggest that the ex vivo gene transfer of anti-PrP scFvs using brain-engraftable cells could be a possible immunotherapeutic approach against prion diseases.

This study presents a new method that enables the detection of sentinel lymph nodes (SLN) with high sensitivity using indocyanine green (ICG) fluorescence imaging.This study enrolled 128 patients with clinically node-negative breast cancer. Fluorescence imaging was obtained after ICG was injected into the areola. Subcutaneous lymphatic channels were immediately visible.Lymphatic channels and SLN were successfully visualized in all patients. One lymphatic channel was 60%, two channels were 24%, and three channels were 16%. The number of fluorescence SLN ranged from 1 to 6, and blue-dyed SLN ranged from 0 to 3. In the latter, SLN were not identified in 44 patients. Nineteen patients had pathologically identified lymph node metastases. All of them were recognized by fluorescence imaging, but 8 patients had lymph nodes with metastases were not identified by dye method.This ICG fluorescence imaging technique is feasible and safe for detecting SLN in a less invasive manner than conventional mapping, with real-time observations.

大腿ヘルニア術後9年目に同側に閉鎖孔ヘルニアを発症し自然還納後，局所麻酔下・経鼠径法にて待期手術を行った症例を経験したので文献的考察を加えて報告する．症例は89歳女性，9年前左大腿ヘルニア（McVay法）手術既往有り．主訴は腹痛，嘔吐．腹部CTにて左閉鎖孔ヘルニア嵌頓・小腸閉塞と診断された．外科医の診察時には症状消失していたので緊急手術対応とせず経過観察入院とした．翌日の腹部CTでは嵌頓・腸閉塞は消失していた．第6病日に膨潤麻酔・経鼠径法にて手術を行った．Direct Kugel Patch（DK）のみでは閉鎖孔と鼠径管後壁までカバーが不可能であったのでDKとPROLENE Hernia System（PHS）を併用して閉鎖孔および鼠径管後壁の修復を行った．経過良好で術後7日目に退院した．嵌頓のない閉鎖孔ヘルニアでは局所麻酔下・経鼠径法による修復は低侵襲手術として高齢者には有用であると考えられた．

（目的）成人鼠径部ヘルニアに関する多施設前向き症例登録データを用いて，日本ヘルニア学会「鼠径部ヘルニア分類改訂版」（新分類）の検証と各病型による手術術式を検討した．（方法）2009年５月より10月の期間，滋賀ヘルニア研究会15施設において成人鼠径部ヘルニア327症例を前向き症例登録し，集積したデータを解析した．（結果）初発鼠径部ヘルニア308例について，術者が判定した術者分類（新分類を用いるように依頼）はＩ-１:5.2％，Ｉ-２:46.1％，Ｉ-３:14.0％，II-１:5.2％，II-２:6.2％，II-３:14.0％，III:4.2％，IV:2.6％であった。I型で施設間のばらつきが目立ち，ヘルニア門直径から推測した新分類ではI-１が1.6％となった．Tension free repairが89％を占め，Direct Kugel（DK）法49％，Plug-mesh（PM）法23％，PHS法16％であった．I型ではヘルニア門が大きくなるほどPM法の使用頻度が低下し，DK法とPHS法はPM法と比較してII型で多く採用されていた．（結語）ヘルニア分類とtension free repairに用いられるメッシュの種類・サイズなどに一定の傾向を認めることから，将来，新分類をヘルニア診療ガイドラインに用いることができる可能性が示された．しかし，施設間で分類の病型頻度に差がみられ，新分類の普及やヘルニア門の径判定法の周知などに関して，日本ヘルニア学会およびわれわれ研究会側の努力も必要と考えられる．

The expression of several members of the FOX gene family is known to be altered in a variety of cancers. We show that in breast cancer, FOXF1 gene is a target of epigenetic inactivation and that its gene product exhibits tumor-suppressive properties. Loss or downregulation of FOXF1 expression is associated with FOXF1 promoter hypermethylation in breast cancer cell lines and in invasive ductal carcinomas. Methylation of FOXF1 in invasive ductal carcinoma (37.6% of 117 cases) correlated with high tumor grade. Pharmacologic unmasking of epigenetic silencing in breast cancer cells restored FOXF1 expression. Re-expression of FOXF1 in breast cancer cells with epigenetically silenced FOXF1 genes led to G1 arrest concurrent with or without apoptosis to suppress both in vitro cell growth and in vivo tumor formation. FOXF1-induced G1 arrest resulted from a blockage at G1-S transition of the cell cycle through inhibition of the CDK2-RB-E2F cascade. Small interfering RNA–mediated depletion of FOXF1 in breast cancer cells led to increased DNA re-replication, suggesting that FOXF1 is required for maintaining the stringency of DNA replication and genomic stability. Furthermore, expression profiling of cell cycle regulatory genes showed that abrogation of FOXF1 function resulted in increased expression of E2F-induced genes involved in promoting the progression of S and G2 phases. Therefore, our studies have identified FOXF1 as a potential tumor suppressor gene that is epigenetically silenced in breast cancer, which plays an essential role in regulating cell cycle progression to maintain genomic stability. Cancer Res; 70(14); 6047–58. ©2010 AACR.

e16191Background: To elucidate recurrence pathophysiology after gastrointestinal cancer surgery, the prognostic effect of peritoneal cancer cell spillage during surgery was evaluated in patients (p...