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1.  Increased expression of interleukin-6 predicts poor response to chemoradiotherapy and unfavorable prognosis in oral squamous cell carcinoma 
Oncology Reports  2015;33(5):2161-2168.
Recent studies have revealed that cancer cells are exacerbated by chronic inflammation. The present study examined the immunohistochemical expression for interleukin-6 (IL-6), a pleiotropic inflammatory cytokine, in oral squamous cell carcinoma (OSCC) to elucidate the association of IL-6 expression with tumor progression, chemoresistance and prognosis. Seventy-eight patients with primary OSCC were analyzed by immunohistochemical staining for IL-6. These labeling indexes (LIs) were calculated and evaluated in association with the clinicopathologic characteristics and prognosis in the OSCC patients. The patients were divided into three groups as follows: negative group = LI <5%; low IL-6 group = 5% ≤ LI <30%; high IL-6 group = LI ≥30%. The patient numbers of the negative, low and high expression groups were 24, 22 and 32, respectively. In the high IL-6 expression group, IL-6 receptor (IL-6R), phospho-signal tranducer and activator of transcription 3 (p-STAT3) were also detected in almost all the cancer cells. The prevalence of the cervical lymph node or the distant metastasis in the high expression group was significantly higher than those in the negative and low expression groups. Furthermore, the high expression group had a significantly poorer tumor response to the preoperative chemoradiotherapy and a more unfavourable prognosis than the negative and the low expression groups. Interestingly, IL-6, IL-6R and p-STAT3 were expressed in the residual cancer cells of all the patients in the high expression group with poor response to chemoradiotherapy. These results suggested that IL-6 signaling possibly is involved in the progression and treatment-resistance of OSCC and IL-6 expression in cancer cells could be a useful predictive factor of poor response to chemoradiotherapy and unfavorable prognosis.
doi:10.3892/or.2015.3838
PMCID: PMC4391588  PMID: 25761055
interleukin-6; oral squamous cell carcinoma; p-STAT3; chemoradiotherapy; chemoresistance; prognosis; tumor response; inflammation
2.  Implant stability and bone remodeling up to 84 days of implantation with an initial static strain. An in vivo and theoretical investigation 
Clinical Oral Implants Research  2016;27(10):1310-1316.
Abstract
Objectives
When implants are inserted, the initial implant stability is dependent on the mechanical stability. To increase the initial stability, it was hypothesized that bone condensation implants will enhance the mechanical stability initially and that the moderately rough surface will further contribute to the secondary stability by enhanced osseointegration. It was further hypothesized that as the healing progresses the difference in removal torque will diminish. In addition, a 3D model was developed to simulate the interfacial shear strength. This was converted to a theoretical removal torque that was compared to the removal torque obtained in vivo.
Material and methods
Condensation implants, inducing bone strains of 0.015, were installed into the left tibia of 24 rabbits. Non‐condensation implants were installed into the right tibia. All implants had a moderately rough surface. The implants had an implantation time of 7, 28, or 84 days before the removal torque was measured. The interfacial shear strength at different healing time was estimated by the means of finite element method.
Results
At 7 days of healing, the condensation implant had an increased removal torque compared to the non‐bone‐condensation implant. At 28 and 84 days of healing, there was no difference in removal torque. The simulated interfacial shear strength ratios of bone condensation implants at different implantation time were in line with the in vivo data.
Conclusions
Moderately rough implants that initially induce bone strain during installation have increased stability during the early healing period. In addition, the finite element method may be used to evaluate differences in interlocking capacity.
doi:10.1111/clr.12748
PMCID: PMC5066632  PMID: 26762885
bone condensation; implant stability; in vivo; remodeling; static strain
3.  The Alteration of the Epidermal Basement Membrane Complex of Human Nevus Tissue and Keratinocyte Attachment after High Hydrostatic Pressurization 
BioMed Research International  2016;2016:1320909.
We previously reported that human nevus tissue was inactivated after high hydrostatic pressure (HHP) higher than 200 MPa and that human cultured epidermis (hCE) engrafted on the pressurized nevus at 200 MPa but not at 1000 MPa. In this study, we explore the changes to the epidermal basement membrane in detail and elucidate the cause of the difference in hCE engraftment. Nevus specimens of 8 mm in diameter were divided into five groups (control and 100, 200, 500, and 1000 MPa). Immediately after HHP, immunohistochemical staining was performed to detect the presence of laminin-332 and type VII collagen, and the specimens were observed by transmission electron microscopy (TEM). hCE was placed on the pressurized nevus specimens in the 200, 500, and 1000 MPa groups and implanted into the subcutis of nude mice; the specimens were harvested at 14 days after implantation. Then, human keratinocytes were seeded on the pressurized nevus and the attachment was evaluated. The immunohistochemical staining results revealed that the control and 100 MPa, 200 MPa, and 500 MPa groups were positive for type VII collagen and laminin-332 immediately after HHP. TEM showed that, in all of the groups, the lamina densa existed; however, anchoring fibrils were not clearly observed in the 500 or 1000 MPa groups. Although the hCE took in the 200 and 500 MPa groups, keratinocyte attachment was only confirmed in the 200 MPa group. This result indicates that HHP at 200 MPa is preferable for inactivating nevus tissue to allow its reuse for skin reconstruction in the clinical setting.
doi:10.1155/2016/1320909
PMCID: PMC5056241  PMID: 27747221
4.  Genome sequence of Aspergillus luchuensis NBRC 4314 
Awamori is a traditional distilled beverage made from steamed Thai-Indica rice in Okinawa, Japan. For brewing the liquor, two microbes, local kuro (black) koji mold Aspergillus luchuensis and awamori yeast Saccharomyces cerevisiae are involved. In contrast, that yeasts are used for ethanol fermentation throughout the world, a characteristic of Japanese fermentation industries is the use of Aspergillus molds as a source of enzymes for the maceration and saccharification of raw materials. Here we report the draft genome of a kuro (black) koji mold, A. luchuensis NBRC 4314 (RIB 2604). The total length of nonredundant sequences was nearly 34.7 Mb, comprising approximately 2,300 contigs with 16 telomere-like sequences. In total, 11,691 genes were predicted to encode proteins. Most of the housekeeping genes, such as transcription factors and N-and O-glycosylation system, were conserved with respect to Aspergillus niger and Aspergillus oryzae. An alternative oxidase and acid-stable α-amylase regarding citric acid production and fermentation at a low pH as well as a unique glutamic peptidase were also found in the genome. Furthermore, key biosynthetic gene clusters of ochratoxin A and fumonisin B were absent when compared with A. niger genome, showing the safety of A. luchuensis for food and beverage production. This genome information will facilitate not only comparative genomics with industrial kuro-koji molds, but also molecular breeding of the molds in improvements of awamori fermentation.
doi:10.1093/dnares/dsw032
PMCID: PMC5144674  PMID: 27651094
Aspergillus luchuensis; kuro (black) koji mold; genome sequence
5.  An Exploratory Clinical Trial of a Novel Treatment for Giant Congenital Melanocytic Nevi Combining Inactivated Autologous Nevus Tissue by High Hydrostatic Pressure and a Cultured Epidermal Autograft: Study Protocol 
JMIR Research Protocols  2016;5(3):e162.
Background
Giant congenital melanocytic nevi (GCMNs) are large brown to black skin lesions that appear at birth and are associated with a risk of malignant transformation. It is often difficult to reconstruct large full-thickness skin defects after the removal of GCMNs.
Objective
To overcome this difficulty we developed a novel treatment to inactivate nevus tissue and reconstruct the skin defect using the nevus tissue itself. For this research, we designed an exploratory clinical study to investigate the safety and efficacy of a novel treatment combining the engraftment of autologous nevus tissue inactivated by high hydrostatic pressurization with a cultured epidermal autograft (CEA).
Methods
Patients with congenital melanocytic nevi that were not expected to be closed by primary closure will be recruited for the present study. The target number of nevi is 10. The full-thickness nevus of the target is removed and pressurized at 200 MPa for 10 minutes. The pressurized and inactivated nevus is sutured to the original site. A small section of the patient’s normal skin is taken from around the nevus region and a CEA is prepared after a 3-week culturing process. The CEA is then grafted onto the engrafted inactivated nevus at four weeks after its retransplantation. The primary endpoint is the engraftment of the CEA at 8 weeks after its transplantation and is defined as being engrafted when the engraftment area of the inactivated nevus is 60% or more of the pretransplantation nevus area and when 80% or more of the transplanted inactivated nevus is epithelialized.
Results
The study protocol was approved by the Institutional Review Board of Kansai Medical University (No. 1520-2, January 5, 2016: version 1.3). The study opened for recruitment in February 2016.
Conclusions
This protocol is designed to show feasibility in delivering a novel treatment combining the engraftment of inactivated autologous nevus tissue and CEA. This is the first-in-man clinical trial of this treatment, and it should be a promising treatment of patients suffering from GCMN.
Trial Registration
University Hospital Medical Information Network: UMIN000020732; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000022198 (Archived by WebCite at http://www.webcitation.org/6jLZH2vDN)
doi:10.2196/resprot.6195
PMCID: PMC4999532  PMID: 27515295
giant congenital melanocytic nevi; cultured epidermal autograft; high hydrostatic pressurization; inactivation
7.  A randomized controlled study comparing a vessel sealing system with the conventional technique in axillary lymph node dissection for primary breast cancer 
SpringerPlus  2016;5(1):1004.
Objective
This study aimed to compare the efficacy and safety of the newest bipolar vessel sealing system (BVSS; LigaSure™ Small Jaw) to that of conventional technique in axillary dissection.
Methods
Sixty-one patients with breast cancer were randomized to a conventional dissection surgical technique (CONV group; n = 30) by scalpel and monopolar cautery or that using a vessel sealing system (BVSS group; n = 31).
Results
There was a significant difference between both groups in the mean number of days until drain removal (6.4 ± 2.9 vs. 8.2 ± 3.8 days; P value = 0.033), and the mean total volume of drainage fluid (365.3 ± 242.2 vs. 625.1 ± 446.6 mL; P value = 0.009). The incidence of seroma was similar in both groups (43.3 vs. 37.9 %; P value = 0.673). There was no statistically significant difference in axillary dissection operating time (66 vs. 70 min; P value = 0.371), or the mean volume of blood loss (18.2 ± 31.1 vs. 20.6 ± 26.3 mL; P value = 0.663).
Conclusions
Our results suggest that BVSS is a more effective device when compared to the conventional techniques in axillary dissection.
doi:10.1186/s40064-016-2710-7
PMCID: PMC4937003  PMID: 27398279
Breast cancer; Vessel sealing system; Axillary lymph node dissection; Randomized controlled trial
8.  Decreased DNA Methylation in the Shati/Nat8l Promoter in Both Patients with Schizophrenia and a Methamphetamine-Induced Murine Model of Schizophrenia-Like Phenotype 
PLoS ONE  2016;11(6):e0157959.
The number of patients with schizophrenia has increased over the past decade. Previously, many studies have been performed to establish its diagnostic criteria, prophylactic methods, and effective therapies. In this study, we analyzed whether the ratios of DNA methylation in CpG islands of the Shati/Nat8l is decreased in model mice of schizophrenia-like phenotype using genomic DNA collected from brain regions and peripheral blood, since the mouse model of schizophrenia-like phenotype, mice treated repeatedly with methamphetamine showed increase of Shati/Nat8l mRNA expression in our previous experiment. The ratios of Shati/Nat8l CpG island methylation were significantly decreased in both the nucleus accumbens and the peripheral blood of model mice compared with those of control mice. We also investigated Shati/Nat8l methylation in the blood of patients with schizophrenia. We found that Shati/Nat8l CpG island methylation ratios were lower in the patients with schizophrenia than in the healthy controls, which is consistent with our findings in the mice model. To our knowledge, this is the first study to show similar alterations in methylation status of a particular genomic DNA site in both the brain and peripheral blood of mice. Furthermore, the same phenomenon was observed in corresponding human genomic sequences of the DNA extracted from the peripheral blood of patients with schizophrenia. Based on our findings, DNA methylation profiles of the CpG island of Shati/Nat8l might be a diagnostic biomarker of schizophrenia.
doi:10.1371/journal.pone.0157959
PMCID: PMC4922576  PMID: 27348532
9.  Tongue squamous cell carcinoma producing both parathyroid hormone-related protein and granulocyte colony-stimulating factor: a case report and literature review 
Background
Paraneoplastic syndrome generally results from tumor-derived hormones or peptides that cause metabolic derangements. Common metabolic conditions include hyponatremia, hypercalcemia, hypoglycemia, and Cushing’s syndrome. Herein, we report a very rare case of tongue carcinoma presenting with leukocytosis and hypercalcemia.
Case presentation
A 57-year-old man was admitted to our hospital with tongue squamous cell carcinoma (cT4aN0M0, stage IV). He underwent radical resection following preoperative chemoradiotherapy, but locoregional recurrence was detected 2 months after surgery. He presented with marked leukocytosis and hypercalcemia with elevated serum levels of granulocyte colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTHrP). He was therefore managed with intravenous fluids, furosemide, prednisolone, elcatonin, and pamidronate. However, the patient died 1 month later of carcinomatous pleuritis following distant metastasis to the lung. Immunohistochemical analyses of the resected specimens revealed positive staining for PTHrP and G-CSF in the cancer cells.
Conclusions
In this case, it was considered that tumor-derived G-CSF and PTHrP caused leukocytosis and hypercalcemia.
doi:10.1186/s12957-016-0918-1
PMCID: PMC4912775  PMID: 27316348
Squamous cell carcinoma; Parathyroid hormone-related protein; Granulocyte colony-stimulating factor
10.  A Comparison of Conventional Collagen Sponge and Collagen-Gelatin Sponge in Wound Healing 
BioMed Research International  2016;2016:4567146.
The objective of this study was to compare the effectiveness of the collagen-gelatin sponge (CGS) with that of the collagen sponge (CS) in dermis-like tissue regeneration. CGS, which achieves the sustained release of basic fibroblast growth factor (bFGF), is a promising material in wound healing. In the present study, we evaluated and compared CGSs and conventional CSs. We prepared 8 mm full-thickness skin defects on the backs of rats. Either CGSs or CSs were impregnated with normal saline solution (NSS) or 7 μg/cm2 of bFGF solution and implanted into the defects. At 1 and 2 weeks after implantation, tissue specimens were obtained from the rats of each group (n = 3, total n = 24). The wound area, neoepithelial length, dermis-like tissue area, and the number and area of capillaries were evaluated at 1 and 2 weeks after implantation. There were no significant differences in the CGS without bFGF and CS groups. Significant improvements were observed in the neoepithelial length, the dermis-like tissue area, and the number of newly formed capillaries in the group of rats that received CGSs impregnated with bFGF. The effects on epithelialization, granulation, and vascularization of wound healing demonstrated that, as a scaffold, CGSs are equal or superior to conventional CSs.
doi:10.1155/2016/4567146
PMCID: PMC4863089  PMID: 27218103
11.  Ultraflexible organic photonic skin 
Science Advances  2016;2(4):e1501856.
Optoelectronic electronic skins, or e-skins, introduce electronic sensing and displays on the surface of human skin.
Thin-film electronics intimately laminated onto the skin imperceptibly equip the human body with electronic components for health-monitoring and information technologies. When electronic devices are worn, the mechanical flexibility and/or stretchability of thin-film devices helps to minimize the stress and discomfort associated with wear because of their conformability and softness. For industrial applications, it is important to fabricate wearable devices using processing methods that maximize throughput and minimize cost. We demonstrate ultraflexible and conformable three-color, highly efficient polymer light-emitting diodes (PLEDs) and organic photodetectors (OPDs) to realize optoelectronic skins (oe-skins) that introduce multiple electronic functionalities such as sensing and displays on the surface of human skin. The total thickness of the devices, including the substrate and encapsulation layer, is only 3 μm, which is one order of magnitude thinner than the epidermal layer of human skin. By integrating green and red PLEDs with OPDs, we fabricate an ultraflexible reflective pulse oximeter. The device unobtrusively measures the oxygen concentration of blood when laminated on a finger. On-skin seven-segment digital displays and color indicators can visualize data directly on the body.
doi:10.1126/sciadv.1501856
PMCID: PMC4846460  PMID: 27152354
PLED; organic photo detector; pulse oximeter; flexible electronics
12.  Clinicopathological evaluation of pre-operative chemoradiotherapy with S-1 as a treatment for locally advanced oral squamous cell carcinoma 
Oncology Letters  2016;11(5):3369-3376.
The administration of pre-operative chemotherapy with S-1 and concurrent radiotherapy at a total dose of 30 Gy was clinicopathologically evaluated as a treatment for locally advanced oral squamous cell carcinoma (OSCC) in the present study. The participants comprised 81 patients with OSCC, consisting of 29 patients with stage II disease, 12 patients with stage III disease and 40 patients with stage IV disease. All patients received a total radiation dose of 30 Gy in daily fractions of 2 Gy, 5 times a week, for 3 weeks, and the patients were concurrently administered S-1 at a dose of 80–120 mg, twice daily, over 4 consecutive weeks. Radical surgery was performed in all cases at 2–6 weeks subsequent to the end of pre-operative chemoradiotherapy. The most common adverse event was oropharyngeal mucositis, but this was transient in all patients. No severe hematological or non-hematological toxicities were observed. The clinical and histopathological response rates were 70.4 and 75.3%, respectively. Post-operatively, local failure developed in 6 patients (7.4%) and neck failure developed in 2 patients (2.5%). Distant metastases were found in 7 patients (8.6%). The overall survival rate, disease-specific survival rate and locoregional control rate at 5 years were 87.7, 89.9 and 90.6%, respectively. Locoregional recurrence occurred more frequently in patients that demonstrated a poor histopathological response compared with patients that demonstrated a good response (P<0.01). These results indicate that pre-operative S-1 chemotherapy with radiotherapy at a total dose of 30 Gy is feasible and effective for patients with locally advanced OSCC, and that little or no histopathological response may be a risk factor for locoregional recurrence in this treatment.
doi:10.3892/ol.2016.4411
PMCID: PMC4841072  PMID: 27123119
oral squamous cell carcinoma; preoperative treatment; chemoradiotherapy; S-1; survival rate
13.  Direct Detection of Fe(II) in Extracellular Polymeric Substances (EPS) at the Mineral-Microbe Interface in Bacterial Pyrite Leaching 
Microbes and Environments  2016;31(1):63-69.
We herein investigated the mechanisms underlying the contact leaching process in pyrite bioleaching by Acidithiobacillus ferrooxidans using scanning transmission X-ray microscopy (STXM)-based C and Fe near edge X-ray absorption fine structure (NEXAFS) analyses. The C NEXAFS analysis directly showed that attached A. ferrooxidans produces polysaccharide-abundant extracellular polymeric substances (EPS) at the cell-pyrite interface. Furthermore, by combining the C and Fe NEXAFS results, we detected significant amounts of Fe(II), in addition to Fe(III), in the interfacial EPS at the cell-pyrite interface. A probable explanation for the Fe(II) in detected EPS is the leaching of Fe(II) from the pyrite. The detection of Fe(II) also indicates that Fe(III) resulting from pyrite oxidation may effectively function as an oxidizing agent for pyrite at the cell-pyrite interface. Thus, our results imply that a key role of Fe(III) in EPS, in addition to its previously described role in the electrostatic attachment of the cell to pyrite, is enhancing pyrite dissolution.
doi:10.1264/jsme2.ME15137
PMCID: PMC4791118  PMID: 26947441
Bacterial mineral leaching; pyrite; chemical speciation; X-ray microscopy
14.  A Probe-Based Method for Confirmation of Methicillin-Resistant Staphylococcus Aureus and Detection of Panton-Valentine Leukocidin and TST Virulence Genes 
Probe-based detection of mecA, lukS/F-PV (Panton-Valentine leukocidin) and tst virulence genes in 435 isolates of Staphylococcus aureus had comparable sensitivity and specificity to end point polymerase chain reaction as a reference standard.
doi:10.1016/j.diagmicrobio.2011.04.005
PMCID: PMC4719149  PMID: 21658873
15.  Immuno-Northern Blotting: Detection of RNA Modifications by Using Antibodies against Modified Nucleosides 
PLoS ONE  2015;10(11):e0143756.
The biological roles of RNA modifications are still largely not understood. Thus, developing a method for detecting RNA modifications is important for further clarification. We developed a method for detecting RNA modifications called immuno-northern blotting (INB) analysis and herein introduce its various capabilities. This method involves the separation of RNAs using either polyacrylamide or agarose gel electrophoresis, followed by transfer onto a nylon membrane and subsequent immunoblotting using antibodies against modified nucleosides for the detection of specific modifications. We confirmed that INB with the antibodies for 1-methyladenosine (m1A), N6-methyladenosine (m6A), pseudouridine, and 5-methylcytidine (m5C) showed different modifications in a variety of RNAs from various species and organelles. INB with the anti-m5C antibody revealed that the antibody cross-reacted with another modification on DNA, suggesting the application of this method for characterization of the antibody for modified nucleosides. Additionally, using INB with the antibody for m1A, which is a highly specific modification in eukaryotic tRNA, we detected tRNA-derived fragments known as tiRNAs under the cellular stress response, suggesting the application for tracking target RNA containing specific modifications. INB with the anti-m6A antibody confirmed the demethylation of m6A by the specific demethylases fat mass and obesity-associated protein (FTO) and ALKBH5, suggesting its application for quantifying target modifications in separated RNAs. Furthermore, INB demonstrated that the knockdown of FTO and ALKBH5 increased the m6A modification in small RNAs as well as in mRNA. The INB method has high specificity, sensitivity, and quantitative capability, and it can be employed with conventional experimental apparatus. Therefore, this method would be useful for research on RNA modifications and metabolism.
doi:10.1371/journal.pone.0143756
PMCID: PMC4659547  PMID: 26606401
16.  Role of Glycosaminoglycans in Infectious Disease 
Glycosaminoglycans (GAGs) have been shown to bind to a wide variety of microbial pathogens, including viruses, bacteria, parasites, and fungi in vitro. GAGs are thought to promote pathogenesis by facilitating pathogen attachment, invasion, or evasion of host defense mechanisms. However, the role of GAGs in infectious disease has not been extensively studied in vivo and therefore their pathophysiological significance and functions are largely unknown. Here we describe methods to directly investigate the role of GAGs in infections in vivo using mouse models of bacterial lung and corneal infection. The overall experimental strategy is to establish the importance and specificity of GAGs, define the essential structural features of GAGs, and identify a biological activity of GAGs that promotes pathogenesis.
doi:10.1007/978-1-4939-1714-3_45
PMCID: PMC4624626  PMID: 25325982
Heparan sulfate; Chondroitin sulfate; Proteoglycan; Syndecan; Pneumonia; Keratitis; Cathelicidin; Antimicrobial peptide; Host defense
17.  Incidence of floating toe and its association with the physique and foot morphology of Japanese children 
Journal of Physical Therapy Science  2015;27(10):3159-3162.
[Purpose] Physical development, foot morphology, and toe contact of children aged 3 to 5 years were assessed in order to investigate the relationships between body and foot morphology and the incidence of the condition known as “floating toe”. [Subjects] A total of 198 children, aged 3 to 5 years old, participated in this study. [Methods] Height and weight were measured for body morphology, and foot length and width were measured for foot morphology. Footprint images were taken to calculate the number of floating toes. Information about the children’s height and weight at birth, and the time of starting to walk was obtained from their guardians. [Results] At least one floating toe was observed in 87.7–98.7% of the children depending on their ages. The fifth toe was most commonly affected, occurring in 74.2% of the study population. Among the body and foot morphology parameters, only weight at birth showed a significant but very weak correlation with the number of floating toes. [Conclusion] There was a high incidence of floating toe among the children, with the fifth toe most commonly affected. Floating toe weakly but significantly correlated with weight at birth, but did not correlated with other measures of physique at birth, physical development, or the time of starting to walk.
doi:10.1589/jpts.27.3159
PMCID: PMC4668156  PMID: 26644665
Foot morphology; Physical development; Floating toe
18.  Retrospective Data Analysis and Proposal of a Practical Acceptance Criterion for Inter-laboratory Cross-validation of Bioanalytical Methods Using Liquid Chromatography/Tandem Mass Spectrometry 
The AAPS Journal  2014;16(6):1226-1236.
The purpose of this study is to conduct a retrospective data analysis for inter-laboratory cross-validation studies to set a reasonable and practical acceptance criterion based on a number of cross-validation results. From the results of cross-validation studies for 16 compounds and their metabolites, analytical bias and variation were evaluated. The accuracy of cross-validation samples was compared with that of quality control (QC) samples with statistical comparison of the analytical variation. An acceptance criterion was derived with a confidential interval approach. As the results, while a larger bias was observed for the cross-validation samples, the bias was not fully caused by analytical variation or bias attributable to the analytical methods. The direction of the deviation between the cross-validation samples and QC samples was random and not concentration-dependent, suggesting that inter-laboratory variability such as preparation errors could be a source of bias. A derived acceptance criterion corresponds to one prescribed in the Guideline on bioanalytical method validation from the Ministry of Health, Labour and Welfare in Japan and is a little wider than one in the European Medical Agency. In conclusion, thorough retrospective data analysis revealed potential causes of larger analytical bias in inter-laboratory cross-validation studies. A derived acceptance criterion would be practical and reasonable for the inter-laboratory cross-validation study.
doi:10.1208/s12248-014-9653-0
PMCID: PMC4389744  PMID: 25124547
acceptance criterion; cross-validation; Guideline on bioanalytical method validation (BMV); inter-laboratory reliability; regulated bioanalysis
19.  Preparation of Inactivated Human Skin Using High Hydrostatic Pressurization for Full-Thickness Skin Reconstruction 
PLoS ONE  2015;10(7):e0133979.
We have reported that high-hydrostatic-pressure (HHP) technology is safe and useful for producing various kinds of decellularized tissue. However, the preparation of decellularized or inactivated skin using HHP has not been reported. The objective of this study was thus to prepare inactivated skin from human skin using HHP, and to explore the appropriate conditions of pressurization to inactivate skin that can be used for skin reconstruction. Human skin samples of 8 mm in diameter were packed in bags filled with normal saline solution (NSS) or distilled water (DW), and then pressurized at 0, 100, 150, 200 and 1000 MPa for 10 minutes. The viability of skin after HHP was evaluated using WST-8 assay. Outgrowth cells from pressurized skin and the viability of pressurized skin after cultivation for 14 days were also evaluated. The pressurized skin was subjected to histological evaluation using hematoxylin and eosin staining, scanning electron microscopy (SEM), immunohistochemical staining of type IV collagen for the basement membrane of epidermis and capillaries, and immunohistochemical staining of von Willebrand factor (vWF) for capillaries. Then, human cultured epidermis (CE) was applied on the pressurized skin and implanted into the subcutis of nude mice; specimens were subsequently obtained 14 days after implantation. Skin samples pressurized at more than 200 MPa were inactivated in both NSS and DW. The basement membrane and capillaries remained intact in all groups according to histological and immunohistological evaluations, and collagen fibers showed no apparent damage by SEM. CE took on skin pressurized at 150 and 200 MPa after implantation, whereas it did not take on skin pressurized at 1000 MPa. These results indicate that human skin could be inactivated after pressurization at more than 200 MPa, but skin pressurized at 1000 MPa had some damage to the dermis that prevented the taking of CE. Therefore, pressurization at 200 MPa is optimal for preparing inactivated skin that can be used for skin reconstruction.
doi:10.1371/journal.pone.0133979
PMCID: PMC4520601  PMID: 26226373
20.  Different study conditions between dental students in China and Japan 
Background: The purpose of this study was to compare the study conditions of dental students towards dental education in China and Japan. Methods: 60 students from the Stomatology School of China Medical University and 51 students from the Dental Faculty of Kyushu University, Japan, participated in this study. Information was derived from a self-answered questionnaire consisting of 10 items. Results: More Japanese students (60%) compared to Chinese students (28%) were satisfied with their lives in dental school. For the main reason of discontent, 23.5% of the Japanese students attributed to busy study and lacking of spare time, while 38.3% of the Chinese students indicated small campus lacking of infrastructure. Conclusions: Both students of two countries think they were in big pressure. The main stressor of Japanese students was the examination, but that of Chinese students was anxiety of their future and obtains employment. The main source of tuition and maintenance was family in the both countries, but more Japanese students (25.5%) were dependent on scholarship compared with Chinese students (3.3%). Clinical Implications: The findings from this study enhance our understanding of study conditions among dental students and help to define strategies to improve student management in both Japan and China.
PMCID: PMC4565338  PMID: 26379955
Study condition; pressure; scholarship; Japan; China
21.  Printable elastic conductors with a high conductivity for electronic textile applications 
Nature Communications  2015;6:7461.
The development of advanced flexible large-area electronics such as flexible displays and sensors will thrive on engineered functional ink formulations for printed electronics where the spontaneous arrangement of molecules aids the printing processes. Here we report a printable elastic conductor with a high initial conductivity of 738 S cm−1 and a record high conductivity of 182 S cm−1 when stretched to 215% strain. The elastic conductor ink is comprised of Ag flakes, a fluorine rubber and a fluorine surfactant. The fluorine surfactant constitutes a key component which directs the formation of surface-localized conductive networks in the printed elastic conductor, leading to a high conductivity and stretchability. We demonstrate the feasibility of our inks by fabricating a stretchable organic transistor active matrix on a rubbery stretchability-gradient substrate with unimpaired functionality when stretched to 110%, and a wearable electromyogram sensor printed onto a textile garment.
Printable electronics is highly desirable for high throughput device manufacture. Here, Matsuhisa et al. report an electric ink, made of a self-assembled network of sliver flakes on the surface of a fluorine rubber matrix, which exhibits high conductivity and mechanical durability to achieve this goal.
doi:10.1038/ncomms8461
PMCID: PMC4491189  PMID: 26109453
22.  Ivy Cells: A Population of Nitric-Oxide-Producing, Slow-Spiking GABAergic Neurons and Their Involvement in Hippocampal Network Activity 
Neuron  2008;57(6):917-929.
SUMMARY
In the cerebral cortex, GABAergic interneurons are often regarded as fast-spiking cells. We have identified a type of slow-spiking interneuron that offers distinct contributions to network activity. “Ivy” cells, named after their dense and fine axons innervating mostly basal and oblique pyramidal cell dendrites, are more numerous than the parvalbumin-expressing basket, bistratified, or axo-axonic cells. Ivy cells express nitric oxide synthase, neuropeptide Y, and high levels of GABAA receptor α1 subunit; they discharge at a low frequency with wide spikes in vivo, yet are distinctively phase-locked to behaviorally relevant network rhythms including theta, gamma, and ripple oscillations. Paired recordings in vitro showed that Ivy cells receive depressing EPSPs from pyramidal cells, which in turn receive slowly rising and decaying inhibitory input from Ivy cells. In contrast to fast-spiking interneurons operating with millisecond precision, the highly abundant Ivy cells express presynaptically acting neuromodulators and regulate the excitability of pyramidal cell dendrites through slowly rising and decaying GABAergic inputs.
doi:10.1016/j.neuron.2008.01.034
PMCID: PMC4487557  PMID: 18367092
23.  Fibroblast growth factor deficiencies impact anxiety-like behavior and the serotonergic system 
Behavioural brain research  2014;264:74-81.
Serotonergic neurons in the dorsal raphe nucleus (DR) are organized in anatomically distinct subregions that form connections with specific brain structures to modulate diverse behaviors, including anxiety-like behavior. It is unclear if the functional heterogeneity of these neurons is coupled to their developmental heterogeneity, and if abnormal development of specific DR serotonergic subregions can permanently impact anxiety circuits and behavior. The goal of this study was to examine if deficiencies in different components of fibroblast growth factor (Fgf) signaling could preferentially impact the development of specific populations of DR serotonergic neurons to alter anxiety-like behavior in adulthood. Wild-type and heterozygous male mice globally hypomorphic for Fgf8, Fgfr1, or both (Fgfr1/Fgf8) were tested in an anxiety-related behavioral battery. Both Fgf8- and Fgfr1/Fgf8-deficient mice display increased anxiety-like behavior as measured in the elevated plus-maze and the open-field tests. Immunohistochemical staining of a serotonergic marker, tryptophan hydroxylase (Tph), revealed reductions in specific populations of serotonergic neurons in the ventral, interfascicular, and ventrolateral/ventrolateral periaqueductal gray subregions of the DR in all Fgf-deficient mice, suggesting a neuroanatomical basis for increased anxiety-like behavior. Overall, this study suggests Fgf signaling selectively modulates the development of different serotonergic neuron subpopulations. Further, it suggests anxiety-like behavior may stem from developmental disruption of these neurons, and individuals with inactivating mutations in Fgf signaling genes may be predisposed to anxiety disorders.
doi:10.1016/j.bbr.2014.01.053
PMCID: PMC4007771  PMID: 24512770
Fibroblast growth factor; Serotonin; Dorsal raphe nucleus; Anxiety
24.  Comparison of oncological safety between nipple sparing mastectomy and total mastectomy using propensity score matching 
Introdcution
Although nipple sparing mastectomy (NSM) has attracted increased recognition as an alternative to traditional mastectomy approaches, its oncological safety is unclear. The purpose of this study was to compare the local recurrence rate between NSM and total mastectomy (TM).
Methods
Between 2003 and 2013, 121 and 557 patients with stage 0–III breast cancer underwent NSM and TM respectively. Multivariate Cox regression and propensity score models were used to compare the two groups.
Results
There was no significant difference in the five-year local recurrence rate between the NSM and TM groups (7.6% vs 4.9%, p=0.398). In multivariate analysis, NSM was not a risk factor for local recurrence (hazard ratio: 1.653, 95% confidence interval: 0.586–4.663, p=0.343). Propensity score matching found similar five-year local recurrence free survival rates between the two groups (92.3% vs 93.7%, p=0.655).
Conclusions
Our results suggest that NSM may provide oncological safety comparable with mastectomy for carefully selected patients.
doi:10.1308/003588415X14181254788881
PMCID: PMC4473868  PMID: 26263938
Breast cancer; Nipple sparing mastectomy; Propensity score matching
25.  The Rapid Inactivation of Porcine Skin by Applying High Hydrostatic Pressure without Damaging the Extracellular Matrix 
BioMed Research International  2015;2015:587247.
We previously reported that high hydrostatic pressure (HHP) of 200 MPa for 10 minutes could induce cell killing. In this study, we explored whether HHP at 200 MPa or HHP at lower pressure, in combination with hyposmotic distilled water (DW), could inactivate the skin, as well as cultured cells. We investigated the inactivation of porcine skin samples 4 mm in diameter. They were immersed in either a normal saline solution (NSS) or DW, and then were pressurized at 100 and 200 MPa for 5, 10, 30, or 60 min. Next, we explored the inactivation of specimens punched out from the pressurized skin 10 × 2 cm in size. The viability was evaluated using a WST-8 assay and an outgrowth culture. The histology of specimens was analyzed histologically. The mitochondrial activity was inactivated after the pressurization at 200 MPa in both experiments, and no outgrowth was observed after the pressurization at 200 MPa. The arrangement and proportion of the dermal collagen fibers or the elastin fibers were not adversely affected after the pressurization at 200 MPa for up to 60 minutes. This study showed that a HHP at 200 MPa for 10 min could inactivate the skin without damaging the dermal matrix.
doi:10.1155/2015/587247
PMCID: PMC4387949  PMID: 25879028

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