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Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family consists of deaminases. Some isozymes of APOBEC3 are induced upon human papillomavirus infection or development of psoriasis skin lesions. However, the involvement of APOBEC3 in keratinocyte differentiation has not been addressed. We herein sought to evaluate the roles of APOBECs in mouse primary keratinocyte differentiation. We found that expression levels of APOBEC1 and APOBEC3 were increased during calcium-induced keratinocyte differentiation. Unexpectedly, however, the expression levels of keratinocyte differentiation markers keratin 1/10, involucrin, loricrin and filaggrin were higher in keratinocytes treated with APOBEC3 siRNAs than in those treated with control RNAs. In addition, the treatment of keratinocytes with APOBEC3 siRNAs increased the gene expression levels of Notch3, a master regulator of keratinocyte differentiation. Moreover, calcium-induced increase in Notch3 expression and keratinocyte differentiation were impaired by transfection with an APOBEC3 expression plasmid. Furthermore, co-treatment with Notch3 siRNAs reduced the APOBEC3 siRNA-mediated upregulation of Notch3 expression and in part attenuated the increased expression levels of keratinocyte differentiation markers. These results suggest that APOBEC3 is induced upon keratinocyte differentiation and negatively regulates the keratinocyte differentiation in part by its inhibitory role for Notch3 expression.

Purpose To determine, in the setting of locally advanced pancreatic cancer, the maximum tolerated dose of carbon ion radiation therapy (C-ion RT) and gemcitabine dose delivered concurrently and to estimate local effect and survival. Methods and Materials Eligibility included pathologic confirmation of pancreatic invasive ductal carcinomas and radiographically unresectable disease without metastasis. Concurrent gemcitabine was administered on days 1, 8, and 15, and the dose levels were escalated from 400 to 1000 mg/m2 under the starting dose level (43.2 GyE) of C-ion RT. The dose levels of C-ion RT were escalated from 43.2 to 55.2 GyE at 12 fractions under the fixed recommended gemcitabine dose determined. Results Seventy-six patients were enrolled. Among the 72 treated patients, dose-limiting toxicity was observed in 3 patients: grade 3 infection in 1 patient and grade 4 neutropenia in 2 patients. Only 1 patient experienced a late grade 3 gastric ulcer and bleeding 10 months after C-ion RT. The recommended dose of gemcitabine with C-ion RT was found to be 1000 mg/m2. The dose of C-ion RT with the full dose of gemcitabine (1000 mg/m2) was safely increased to 55.2 GyE. The freedom from local progression rate was 83% at 2 years using the Response Evaluation Criteria in Solid Tumors. The 2-year overall survival rates in all patients and in the high-dose group with stage III (≥45.6 GyE) were 35% and 48%, respectively. Conclusions Carbon ion RT with concurrent full-dose gemcitabine was well tolerated and effective in patients with unresectable locally advanced pancreatic cancer.

The objective of this study was to develop a two-layer cloth filtration system to remove standard plate count (SPC) bacteria from surface water having low turbidity (

A 65-year-old woman underwent high anterior resection for sigmoid colon cancer in 2011. The histopathological diagnosis was type 2, 25×27 mm, tub2, SE, N2, ly2, v1, and Stage Ⅲb. Her treatment was completed after 6months of adjuvant chemotherapy with UFT plus UZEL followed by a 5-year follow-up study, without recurrence. However, 6years after the initial operation, a routine chest and abdominal CT scan showed a 24mm local recurrence involving the left urinary tract and bilateral lung lesions. Eight courses of systemic chemotherapy using FOLFOX plus panitumumab regimen was administered immediately. CT scan after chemotherapy showed that all masses were downsized and no new lesions were identified. We resected the recurrent tumor after considering it feasible by left hemicolectomy with left nephrectomy. Histopathological examination of the recurrent tumor revealed adenocarcinoma, consistent with that of the previous primary sigmoid colon cancer. She is currently undergoing systemic chemotherapy using the FOLFOX regimen. There has been no change in the lung lesions and no new lesions have developed. This is a very rare case of recurrence more than 5 years after curative resection of Stage Ⅲ colon cancer. This paper presents the case considering that keeping the patient under surveillance for more than 5 years enabled the disclosure of recurrence without subjective symptoms.

Neoadjuvant chemotherapy (NAC) with anthracyclines followed by taxane chemotherapy has become the standard treatment for patients with locally advanced, operable breast cancer. Recently, the efficacy of nanoparticle albumin-bound paclitaxel (nab-PTX) for metastatic breast cancer was reported. However, there are still few studies of a neoadjuvant regimen including nab-PTX. Thus, the present phase II study evaluated the efficacy and safety of 5-fluorouracil, epirubicin and cyclophosphamide (FEC regimen) followed by nab-PTX as neoadjuvant treatment for operable human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Women with operable HER2-negative breast cancer (clinical stage T1a-4N1-3) received 4 cycles of FEC (5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 every 21 days), followed by 4 cycles of nab-PTX at 260 mg/m2 every 21 days. The patients then underwent mastectomy or breast-conserving surgery (BCS). The primary endpoint was pathological complete response (pCR) rate. The secondary endpoints included clinical response rate, pathological response rate, BCS rate and safety. A total of 16 patients were evaluated and 3 patients (18%) achieved pCR (1 patient with estrogen receptor-positive cancer and 2 with estrogen receptor-negative cancer). The pCR rate was 12 and 25% in patients with estrogen receptor-positive and -negative cancers, respectively. The clinical response rate was 100% (clinical complete and partial response in 6 and 10 patients, respectively). The BCS rate was 31.25%. Three patients experienced grade 3 neutropenia during FEC therapy, and no grade 3/4 events occurred during nab-PTX therapy. Thus, neoadjuvant therapy with FEC followed by nab-PTX for operable HER2-negative breast cancer was found to be a safe and effective option.

Histone H3 lysine 9 trimethylation (H3K9me3) is associated with transcriptional repression and regulated by histone lysine methyltransferases such as SUV39H1 and ESET. However, the functional roles of these enzymes in hepatocellular carcinoma (HCC) remain uncertain. In this study, we conducted loss-of-function assays for HCC cells. SUV39H1 knockdown but not ESET knockdown reduced H3K9me3 levels and impaired HCC cell growth and sphere formation. The pharmacological inhibition of SUV39H1 by chaetocin resulted in cell growth inhibition and inducing cellular apoptosis in culture and xenograft subcutaneous tumors. Real-time polymerase chain reaction analysis indicated high levels of SUV39H1 expression in 24 of 42 (57.1%) HCC surgical samples compared with corresponding nontumor tissues. Immunohistochemistry identified high levels of H3K9me3 and ESET proteins in 23 (54.8%) and 29 (69.0%) tumor tissues, respectively. However, these proteins' expressions were only observed in biliary epithelial cells and periportal hepatocytes of nontumor tissues. Expression levels of SUV39H1 but not those of ESET were significantly correlated with H3K9me3 levels. The cumulative HCC recurrence rate was significantly higher for patients with elevated SUV39H1 expression and H3K9me3 levels. In conclusion, our data indicate that elevated SUV39H1 expression and high levels of H3K9me3 have important roles in HCC development and progression. Therefore, the pharmacological inhibition of SUV39H1 may be a promising therapeutic approach for HCC treatment.

We investigated the usefulness of dual-phase F-18 fluorodeoxyglucose positron emission tomography with computed tomography (FDG-PET/CT) to differentiate benign from malignant intraductal papillary mucinous neoplasms (IPMNs) and to evaluate branch-duct IPMNs.We used FDG-PET/CT to evaluate IPMNs in 48 consecutive patients who underwent surgical resection from May 2004 to March 2012. IPMNs were classified as benign (n = 16) or malignant (n = 32) on the basis of histology analysis. The ability of FDG-PET/CT to identify branch-duct IPMNs was compared with that of the International Consensus Guidelines.The maximum standardized uptake value (SUVmax) was higher for early-phase malignant IPMNs than that for benign IPMNs (3.5 ± 2.2 vs 1.5 ± 0.4, P.001). When the SUVmax cutoff value was set at 2.0, early-phase malignant IPMNs were identified with 88% sensitivity, specificity, and accuracy. The retention index values for malignant and benign IPMNs were 19.6 ± 17.8 and -2.6 ± 12.9, respectively. When the SUVmax cutoff was set to 2.0 and the retention index value to -10.0, early-phase malignant IPMNs were identified with 88% sensitivity, 94% specificity, and 90% accuracy. In identification of branch-duct IPMNs, when the SUVmax cutoff was set to 2.0, the sensitivity, specificity, and accuracy values were 79%, 92%, and 84%, respectively. By using a maximum main pancreatic duct diameter ≥7 mm, the Guidelines identified branch-duct IPMNs with greater specificity than FDG-PET/CT. The Guidelines criteria of maximum cyst size ≥30 mm and the presence of intramural nodules identified branch-duct IPMNs with almost equal sensitivity to FDG-PET/CT.Dual-phase FDG-PET/CT is useful for preoperative identification of malignant IPMN and for evaluating branch-duct IPMN.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. To improve its outcome, reliable biomarkers are urgently needed. In this study, we aimed to elucidate the key molecules involved in PDAC progression using proteomics approaches. First, we undertook 2-D electrophoresis to identify the proteins overexpressed in PDAC tissues. Following the analysis of agarose gel spots, cofilin-1 was identified and verified as a candidate protein commonly upregulated in PDAC tissues. In immunohistochemistry, cofilin-1 was strongly expressed in the cytoplasm of PDAC cells. Samples were divided into two groups based on the level of cofilin-1 expression. The high expression group showed significantly higher incidence of hematogenous dissemination in relapsed patients than the low expression group (P = 0.0083). In in vitro experiments, knockdown of cofilin-1 significantly decreased chemotaxis in PDAC cell lines. After we confirmed that cofilin-1 was secreted from PDAC cells, we established a detection system for the immune-complex of cofilin-1 in sera. Using this system, we measured the IC levels of cofilin-1 in sera and observed that the IC levels of cofilin-1 in PDAC patients were higher than those in healthy volunteers and patients with pancreatitis (PDAC vs. healthy volunteers, P < 0.0001; PDAC vs. patients with pancreatitis, P < 0.026). Notably, the IC levels of cofilin-1 showed a stepwise increase during PDAC progression (P = 0.0034), and high IC levels of cofilin-1 indicated poor prognosis of patients after surgery (P = 0.039). These results suggest that the IC of cofilin-1 in sera is a potentially attractive serum biomarker for the prognosis of PDAC.

// Masayuki Yokoyama 1, * , Tetsuhiro Chiba 1, * , Yoh Zen 2 , Motohiko Oshima 3 , Yuko Kusakabe 1 , Yoshiko Noguchi 1 , Kaori Yuki 1, 3 , Shuhei Koide 3 , Shiro Tara 3 , Atsunori Saraya 3 , Kazumasa Aoyama 3 , Naoya Mimura 3 , Satoru Miyagi 3 , Masanori Inoue 1 , Toru Wakamatsu 1 , Tomoko Saito 1 , Sadahisa Ogasawara 1 , Eiichiro Suzuki 1 , Yoshihiko Ooka 1 , Akinobu Tawada 1 , Masayuki Otsuka 4 , Masaru Miyazaki 4 , Osamu Yokosuka 1 , Atsushi Iwama 3 1 Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan 2 Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan 3 Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 4 Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan * These authors contributed equally to this work Correspondence to: Tetsuhiro Chiba, email: techiba@faculty.chiba-u.jp Keywords: epigenetics, hepatocellular carcinoma, G9a, BIX-01294, epithelial mesenchymal transition Received: May 22, 2016 Accepted: January 27, 2017 Published: February 20, 2017 ABSTRACT Histone H3 lysine 9 dimethylation (H3K9me2) is mainly regulated by the histone lysine methyltransferase G9a and is associated with the repression of transcription. However, both the role of G9a and the significance of H3K9me2 in hepatocellular carcinoma (HCC) cells remain unclear. In this study, we conducted loss-of-function assay of G9a using short-hairpin RNA and pharmacological interference. Knockdown of G9a reduced H3K9me2 levels and impaired both HCC cell growth and sphere formation. However, transforming growth factor β1-induced epithelial mesenchymal transition (EMT) was not suppressed by G9a knockdown. Combined analyses of chromatin immunoprecipitation followed by sequencing and RNA-sequencing led to successful identification of 96 candidate epigenetic targets of G9a. Pharmacological inhibition of G9a by BIX-01294 resulted in both cell growth inhibition and induction of apoptosis in HCC cells. Intraperitoneal administration of BIX-01294 suppressed the growth of xenograft tumors generated by implantation of HCC cells in non-obese diabetic/severe combined immunodeficient mice. Immunohistochemical analyses revealed high levels of G9a and H3K9me2 in 36 (66.7%) and 35 (64.8%) primary HCC tissues, respectively. G9a expression levels were significantly positively correlated with H3K9me2 levels in tumor tissues. In contrast, in non-tumor tissues, G9a and H3K9me2 were only observed in biliary epithelial cells and periportal hepatocytes. In conclusion, G9a inhibition impairs anchorage-dependent and -independent cell growth, but not EMT in HCC cells. Our data indicate that pharmacological interference of G9a might be a novel epigenetic approach for the treatment of HCC.

膵神経内分泌腫瘍（pancreatic neuroendocrine tumor;PNET）は稀な疾患と考えられてきたが近年増加傾向にある．PNETは典型例では多血性で内部均一な充実性腫瘍であるが，非典型的な画像所見を呈した非機能性PNETの1切除例を経験した．症例は40歳，男性．検診の腹部超音波検査で30mm大の膵腫瘍を指摘された．腫瘍は乏血性で嚢胞成分や石灰化を伴い，FDG-PETにて集積を認め，solid-pseudopapillary neoplasm（SPN）もしくは非機能性PNETの診断で，脾温存膵体尾部切除術を施行した．病理組織学的に非機能性PNETの診断で，腫瘍が乏血性を呈した原因は不明であったが，嚢胞に関しては腫瘍内の出血によるものと考えられた．

In medical institutions including hospitals, it is an essential examination procedure to collect data of outputs and flow rates of patients' urine for ensuring correct health management and diagnosis. This study proposes a method for testing the performance of a toilet with an uroflowmeter, which is developed for this very purpose, when the toilet is installed to a stack system, and examines how effective the method may be according to the results, with the intention of clarifying the variation of pipe pressure allowable when the toilet is installed to a drainage ventilation system. To be more specific, this study discusses the following points: 1. the examination of how effective the abovementioned method may be for testing the performance of the toilet by applying the previously proposed method for testing the combined drainage performance of the house drain; 2. the examination of the influence of pipe pressure variations, which are caused by applying drainage loads using the aforementioned test method, on the accuracy of performance indicators, such as urine outputs, the maximum urine flow rate, urine flow curves; and finally, on the basis of the results acquired, the range of variation of pipe pressure allowable in the design of drainage and ventilation pipework is clarified.

The present study is aimed to propose the establishment of the plan of the drainage and vent system of the low-rise house and the design method and testing method of flow capacity. It is necessary to attempt the accumulation of the test data that shows a necessary drainage performance to propose the examination method. A concrete research method is as follows. 1) The condition at the edge of the stack vent pipe where it influences the flow capacity for drainage system most is presented. 2) The drainage system influence on the drain load condition is understood. It reports on the result of experimenting on these examining it.

This report presents an experimental study with the aim of developing a horizontal fixture drainage branch system to facilitate liberal drainage planning for apartment housing while intending to verify system performance and discuss design techniques. Partly, the report verifies the performance of the combined drainage system, which is applied to the infill of long-lasting SI houses, and discusses the system design. To be more specific, first, the relation between carrying performance decline in the sewage system and the characteristics of drainage from sanitary fixtures, i.e. the biggest cause of drainage problems, was examined through experiments in the laboratory. Next, the abovementioned system was used on the actual super high-rise apartment building to carry out item-to-item system performance evaluation, using both simple and detailed methods which were explained in the previous report. The system design was also discussed.

A 69-year-old woman was referred to our hospital for investigation of tarry stools. Abdominal computed tomography (CT) showed a slightly enhanced heterogeneous mass in the first to second part of the duodenum, adjacent to the gallbladder and head of the pancreas. Endoscopy showed a huge protruding tumor with ulceration in the first part of the duodenum. The preoperative histopathological diagnosis was neuroendocrine carcinoma with expression of synaptophysin. Thus, we performed pancreaticoduodenectomy with gallbladder bed resection. Histopathologically, the tumor was a large-cell neuroendocrine carcinoma (LCNEC) of the duodenum. To our knowledge, this is the first report of duodenal LCNEC arising outside the ampulla of Vater. The patient has been disease-free for 24 months since her operation, without additional therapy. Immunohistochemically, the tumor cells revealed positive expression to NeuroD and faint expression to mASH1 (hASH1): both essential transcriptional factors for normal neural development. The expression patterns of NeuroD and mASH1 suggest a favorable prognosis.

This study discusses the evaluation of influences on the drainage capacity of a drainage stack system with an air admittance valve by means of the drainage capacity prediction method, which was previously proposed by the author, while looking into the effectiveness of the method. The study also aims to propose a method to reduce labour and cost incurred by drainage capacity experiments. To be more specific, through this study, the following two points have been clarified: (1) Vent characteristics of five commonly available air admittance valves were identified using a simple experimental apparatus and the relationship between the airflow rate and the air flow resistance coefficient was acquired; (2) The results acquired from (1) were applied to the previously proposed drainage capacity prediction method and subsequently, it was found that the discrepancy between the estimated value and the actual value remained within ±10%, demonstrating that the method is effective in practical application.

Household disposers and kitchen garbage-processing machines have become commercialized. This paper gives an estimate of the change in CO2 emissions since the introduction of these machines. Compared with the rate before introduction, CO2 emissions increased by 2.1% with the introduction of direct-discharge disposers, which discharge wastewater directly into the sewerage system. By comparison, it leapt by 31.1% when kitchen garbage-processing machines were introduced. CO2 emissions of small-sized houses at the time of disposer wastewater treatment system introduction have a tendency to increase. Therefore, the rate for detached small-sized houses has increased sharply by 51.9%.

Water-closet system equipped with uroflowmetry analyzer to measure out urine flow rate and volume was developed, to improve the medical treatment environment. This is an experimental study to evaluate the performance of the watercloset system, setting up in drainage stack and horizontal fixture branch piping system. As a result of examinations, allowable measurement accuracy with uroflowmetry and the reliability of system are confirmed quantitatively, under the pipe pressure fluctuations which is given by actual drainage load. The Watercloset system can be available for 2-pipe vertical drainage stacks equipped with loop-vent pipes, under the condition of permissible pipe pressure within ±100Pa.

The roof replanting system is excellent as the technology, which eases the global warming. Especially, Tokyo Metropolitan Government and Ministry of Land, Infrastructure and Transport Japan positively promote this system. In the meantime, next fact is necessary so that these may spread further. That is to say, the first is the security of the water source necessary for the plant. Then, the second are hygienic safety of the storage water quality in the roof, etc.In this study, the water quality deterioration by the storage in making rainwater to be water source was measured, and the proper management technique was examined. To begin with, the Legionella was detected in 104CFU/100mL order as a result of storing the rainwater for 4 months. From this result, disinfection examination by chlorination, ultraviolet disinfection method and ultraviolet ray and chlorination-combined use was carried out for the water quality of the storage tank. The disinfection examination result showed appropriate disinfection method of the Legionella done the survival in the water quality of the storage tank.

Enhancement of regulatory T cell (Treg cell) frequency and function is the goal of many therapeutic strategies aimed at treating type 1 diabetes (T1D). The interleukin-2 (IL-2) pathway, which has been strongly implicated in T1D susceptibility in both humans and mice, is a master regulator of Treg cell homeostasis and function. We investigated how IL-2 pathway defects impact Treg cells in T1D-susceptible nonobese diabetic (NOD) mice in comparison with protected C57BL/6 and NOD congenic mice. NOD Treg cells were reduced in frequency specifically in the lymph nodes and expressed lower levels of CD25 and CD39/CD73 immunosuppressive molecules. In the spleen and blood, Treg cell frequency was preserved through expansion of CD25(low), effector phenotype Treg cells. Reduced CD25 expression led to decreased IL-2 signaling in NOD Treg cells. In vivo, treatment with IL-2-anti-IL-2 antibody complexes led to effective upregulation of suppressive molecules on NOD Treg cells in the spleen and blood, but had reduced efficacy on lymph node Treg cells. In contrast, NOD CD8(+) and CD4(+) effector T cells were not impaired in their response to IL-2 therapy. We conclude that NOD Treg cells have an impaired responsiveness to IL-2 that reduces their ability to compete for a limited supply of IL-2.

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas often contains multifocal lesions, and total pancreatectomy is sometimes needed for curative resection. We report here our experience with a case of IPMN with multiple invasive carcinoma foci that was successfully treated with total pancreatectomy. A 66-year-old man had jaundice, and a computed tomography (CT) scan revealed a hypovascular mass in the pancreas head in conjunction with calcification and dilation of the entire main pancreatic duct. He was diagnosed with pancreas head cancer and chronic pancreatitis, and a pancreaticoduodenectomy was planned. Intraoperative pathological examination revealed papillary growth of high grade dysplasia in the main and branch duct epithelium and perineural invasion of the atypical glands. After 2 additional resections, we performed a total pancreatectomy. Pathological findings showed that the pancreas head tumor was an invasive carcinoma derived from main-duct IPMN of the pancreas. It was a mucinous carcinoma with calcification. Moreover, we found other multiple, discontinuous invasive foci in the body and tail of the pancreas which were undetectable by preoperative imaging. This case was highly suggestive for preoperative diagnosis for pancreas tumor and developmental pattern of main-duct IPMN.

This paper proposes an account of Right Node Raising (RNR) within the framework of Dynamic Syntax (DS). The problematic properties of this construction are shown to emerge naturally from a theory that defines natural language syntax as the direct reflection of how Logical Forms are built up in time as the words of a string are processed. Within this framework, all syntactic processes, including lexical actions, are defined in terms of how partial logical structures are updated. An asymmetric account of coordination is given using the concept of linked structures, whereby the (partial) analysis of a tree representing the propositional content of one clause forms the context within which another is constructed. This approach, together with the same mechanism that is used to analyze right dislocated expressions such as subject inversion in pro-drop languages, is shown to provide an analysis of Right Node Raising, under the additional assumption that the distinctive intonation pattern of the construction licenses the postulation of segmentally empty, pronominal-like elements. The identification of the content of these is established through the analysis of the right dislocated expression where crucially the update that this provides is sensitive to the properties of the second conjunct only.

Regarding drainage piping systems with food disposers in actual super high-rise apartment houses with a height 100m, results were acquired from the experiments for the initial performance evaluation before habitation as well as the running performance evaluation by drainage load prediction after habitation. The knowledge, which contributed to a performance test, was also acquired. Before habitation, the maximum number of 6 simultaneous units of garbage wastewater, bowl flushing water, etc. was loaded. The maximum and minimum air pressure values in pipes were checked in line with the performance criteria of SHASE-S, and the safety of the initial performance was also verified. After habitation, the maximum number of simultaneous drainages was predicted and it was found that the figure recorded at the time of the initial performance verification was satisfactory. Moreover, the running pressure values in 99% of the occurrence probability were acquired, and the safety of running performance was also verified. Furthermore, the relation between the house drain′s water level as a drainage load index and the pressure was determined, and as a result of comparison of pre-habitation and post-habitation, it was confirmed that there was no significant performance deterioration caused by long-term use.

OBJECTIVE. Splenectomy is the standard surgical treatment for hereditary spherocytosis, but partial splenic embolization is another potential option. We retrospectively studied the therapeutic effects of partial splenic embolization as a treatment for hereditary spherocytosis.CONCLUSION. Partial splenic embolization is a safe and effective alternative to splenectomy or partial splenectomy in the treatment of hereditary spherocytosis.