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Aneurysm formation is a potential complication of granulomatosis with polyangiitis (GPA), previously known as Wegener’s granulomatosis. It is a very rare complication, but immediate diagnosis and therapy should be performed because an aneurysm can be life-threatening if it ruptures. An accessory left gastric artery (ALGA) is also a rare variant gastric artery that may obtain its blood supply from the left hepatic artery and left gastric artery. We herein describe a 57-year-old Japanese man who was diagnosed with GPA complicated by aneurysm rupture in an ALGA. Emergency surgery was performed after failure of arterial coil embolization to interrupt blood flow in the ALGA. The patient underwent partial resection of the lesser omentum, which contained all aneurysms. During partial resection of the lesser omentum, both the left gastric artery and ALGA were ligated because they were thought to be feeders of the aneurysms. Postoperative recovery was uneventful; no bleeding or recurrence of the aneurysms occurred. Immediate diagnosis and therapy should be performed for patients with GPA with symptoms of vascular ischemia or aortitis. Endovascular intervention is the first-choice therapy especially for hemodynamically stable patients with ruptured aneurysms or aneurysms located on variant arteries, which may have multiple blood supplies. In the present case, although endovascular treatment failed, the approach described herein was helpful during open surgery.

818 Background: Opioid-induced constipation (OIC) is the most common side effect of opioid therapy. Laxatives are usually used as a first-line treatment for OIC. Treatment options for OIC are switching to other opioids associated with less frequent OIC, such as Fentanyl. Naldemedine is an orally active peripherally acting µ-opioid receptor antagonists that was approved in Japan from 2017 for management of cancer-related OIC. The aim of this study is to investigate the relationship between Naldemedine administration and the maximum dose of oral Oxycodone which is the most frequently used oral opioids at our hospital. Methods: During June 2017 and December 2018, a total of 217 patients with cancer-related pain received Oxycodone at our institution. The first group of the patients concurrently received Naldemedine 0.2 mg daily (group A, n = 101), and the second group didn’t receive it (group B, n = 116) for cancer-related OIC reduction. We compared the maximum Oxycodone dose between two groups by medical record retrospectively. Results: The median age of group A was 69 y.o. (range 20-87 y.o.), and the median age of group B was 67 y.o. (range 27-88y.o.). There was no significant difference in common patient background between group A and B. The median dose of maximum Oxycodone dose of group A was 40 mg/day (range 10-480 mg/day), and that of group B was 20 mg/day (range 10-320 mg/day). There was a significant difference in the median dose of maximum Oxycodone between group A and B (Mann-Whitney U test, P < 0.0001). In Group A, the administration was started in 31 patient Naldemedine and Oxycodone at the same time. As for 70 remaining patients, the administration was started when they had constipation after oxycodone was administrated. In those patients, the median days was 19 days from the Oxycodone administration starting date to the Naldemedine administration starting date. Conclusions: Naldemedine administration in patients with cancer-related OIC may increase the maximum dose of oral Oxycodone.

Despite recent intensive research efforts in functional genomics, the functions of only a limited number of Arabidopsis (Arabidopsis thaliana) genes have been determined experimentally, and improving gene annotation remains a major challenge in plant science. As metabolite profiling can characterize the metabolomic phenotype of a genetic perturbation in the plant metabolism, it provides clues to the function(s) of genes of interest. We chose 50 Arabidopsis mutants, including a set of characterized and uncharacterized mutants, that resemble wild-type plants. We performed metabolite profiling of the plants using gas chromatography-mass spectrometry. To make the data set available as an efficient public functional genomics tool for hypothesis generation, we developed the Metabolite Profiling Database for Knock-Out Mutants in Arabidopsis (MeKO). It allows the evaluation of whether a mutation affects metabolism during normal plant growth and contains images of mutants, data on differences in metabolite accumulation, and interactive analysis tools. Nonprocessed data, including chromatograms, mass spectra, and experimental metadata, follow the guidelines set by the Metabolomics Standards Initiative and are freely downloadable. Proof-of-concept analysis suggests that MeKO is highly useful for the generation of hypotheses for genes of interest and for improving gene annotation. MeKO is publicly available at http://prime.psc.riken.jp/meko/.

Background Patients with sensitive gene mutations could achieve better overall survival by taking targeted drugs. Many trials have shown that non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EFGR) mutation responded to PD-1/PD-L1 inhibitors worse than EGFR wild-type. And subgroups of trials have also reported the efficacy of PD-1/PD-L1 inhibitors in the treatment of NSCLC patients with other sensitive gene mutations. So, we conducted a complementary systematic review and meta-analysis to compare efficacy of PD-1/PD-L1 inhibitors for NSCLC patients with sensitive gene mutations. Methods PubMed, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials (Central) databases were searched for all clinical trials in NSCLC until 5th of January 2019. Eligible studies included randomized controlled trials (RCTs) comparing PD-1/PD-L1 inhibitors with chemotherapy in NSCLC patients with sensitive gene mutations. The hazard ratio (HR) and 95% confidence intervals (CIs) of overall survival (OS) or progression-free survival (PFS) were used. Results We analyzed 193 patients in this study. Among cumulative total of 210 patients, 197 were treated with PD-1 or PD-L1 inhibitors. Another 8 and 5 patients were treated with CTLA-4 inhibitor alone and combination with PD-1 inhibitor, respectively. This study included non-small cell lung cancer (n = 106; 50.5%), kidney (n = 23; 10.9%), melanoma (n = 30; 14.3%), gastric (n = 19; 9.0%), Hodgkin lymphoma (n = 11; 5.2%), urothelial carcinoma (n = 10; 4.8%) and others (n = 10; 4.8%). Any grade of irAEs occurred in 73 (34.8%) cumulative patients, and among them, 28 (13.3%) were classified as grade 3-5. The most common irAEs in any grade were skin disorders (n = 29) and endocrine disorders including thyroid dysfunction and adrenal insufficiency (n = 28). Eosinophilia occurred in 57 cumulative patients (27.1%), and 21 patients out of them had eosinophilia from baseline. Among the clinical and laboratory factors, only eosinophilia was significantly associated with the occurrence of any grade of irAEs in both univariate (p = 0.010) and multivariate (p = 0.0463) analyses. Notably, endocrine irAEs were significantly related to eosinophilia (p = 0.0287). Conclusions Eosinophilia after the initiation of treatment with ICIs predicts succeeding onset of irAEs. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure Y. Miura: Honoraria (self): Ono; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): Chugai. T. Takano: Honoraria (self): Daiichi Sankyo; Honoraria (self): Kyowa Hakko Kirin; Honoraria (self): Eisai; Research grant / Funding (self): MSD; Research grant / Funding (self): Ono; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Taiho; Research grant / Funding (self): Novartis; Research grant / Funding (self): Chugai. All other authors have declared no conflicts of interest.

Background The aim of this study was to evaluate the efficacy and safety of CAPOX with planned oxaliplatin stop-and-go strategy compared to continuous use of oxaliplatin as an adjuvant setting for colon cancer. Methods Patients with curative resection of colon cancerwere randomly assigned to receive eitherCAPOX with continuous use of oxaliplatin (8 cycles of CAPOX; continuous arm) or CAPOX intermittentuse of oxaliplatin (2 cycles of CAPOX – 4 cycles of capecitabine – 2 cycles of CAPOX; intermittentarm).The primary endpoints were frequency of peripheral sensory neuropathy (PSN) at 1-year after surgery and disease-free survival rate at 3-year after surgery. The secondary end points included overall survival (OS), compliance and safety. Results A total of 200 patients were enrolled. The intent-to-treat and safety population comprised 100 and 99 patients in the continuous arm,and 100 and 98 patients in the intermittentarm. Compliance: The overall treatment completion rate and relative dose intensity of oxaliplatin were 64% and 71% in the continuous arm vs.92% and 95% in the intermittentarm(p = 0.21 and 0.12, respectively). Efficacy: The 3-year DFS was 81.6% in the continuous arm vs.82.4% in the intermittentarm(HR, 0.82; 95% CI, 0.48-1.18). Safety: The incidence of PSN (>grade 2) was 33%in the continuous arm vs.15% in the intermittentarm (p Conclusions CAPOX withplanned oxaliplatin stop-and-go strategy could be equally effectiveas an adjuvant setting for colon cancer, and substantially reduce long-term PSN and potential improve patient quality of life. Clinical trial identification 000012535 (09/December/2013). Legal entity responsible for the study Yasuhiro Kodera (Chubu Clinical Oncology Group, Japan). Funding Chubu Clinical Oncology Group. Disclosure All authors have declared no conflicts of interest.

Background According to the results of the randomized phase III study, G-SOX, the combination of S-1 and oxaliplatin (SOX) is as effective as the combination of S-1 and cisplatin for the treatment of HER2-negative advanced gastric cancer (AGC), and also has a favorable safety profile. In this trial, the dose of oxaliplatin tested was 100 mg/m2; however, the dose of 130 mg/m2 is covered by insurance in Japan, based on the results of the pivotal global study. Therefore, the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m2 (SOX130) remains to be elucidated. In this study, we conducted the final analysis of the survival outcomes in a phase II trial to assess the efficacy and safety of SOX130 in HER2-negative AGC. Methods Patients with HER2-negative AGC or recurrent gastric cancer received 80 mg/m2 S-1 per day orally on days 1-14, and 130 mg/m2 oxaliplatin intravenously, on day 1 of each 21-day cycle, until criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AE) were recorded according to CTCAE version 4.0. Results In this study, 71 patients were enrolled from June 2015 to November 2016, but 8 patients were excluded owing to ineligibility. Therefore, the efficacy and safety analyses were finally conducted among 63 patients. The confirmed RR, assessed by an independent review committee, was 46.0% (95% confidence interval [CI]: 34.3-58.2), and the disease control rate was 77.8% (95% CI: 66.1-86.3). The median PFS and OS were 4.9 months (95% CI: 4.2-7.1) and 14.8 months (95% CI: 11.1-18.9), respectively. The incidence rates of grade 3 or 4 AE were as follows: neutropenia, 9.5%; thrombocytopenia, 11.1%; anemia, 6.3%; sensory neuropathy, 12.7%; anorexia, 19.0%; and diarrhea, 6.3%. Conclusions SOX130 showed favorable survival outcomes and an acceptable safety profile in the treatment of HER2-negative AGC.

3D printing technology holds promise for application to personalized pharmaceuticals. Mold fabrication is a common technique in industrial 3D printing to produce objects with complex structures and could be used in new applications in pharmaceutical production. The aim of the current study is the fabrication of unique suppository shell molds composed of a water-soluble polymer (polyvinylalcohol) using a fused deposition modeling-type 3D printer so that hospital pharmacists can prepare tailored suppository formulations containing progesterone (a model drug for vaginal suppository formulations) in future clinical settings. Suppository formulations with holes in the shells were prepared. The drug release profiles related well to the positions of the holes (upper, middle, lower), the number of holes (0–2 holes), and the diameters of the holes (0–5 mm) in the suppositories. Matryoshka-type suppository formulations composed of 3D-printed multilayered shells were then prepared. The drug release profiles showed pulsed release, and the volumes of the inner/outer spaces in the suppository shells (1/1, 1/3) and the drug concentration (3/1, 1/1) were reflected in the observed drug release profiles. Our study indicates that a 3D printer can produce not only unique and complex suppository formulations, but also provides flexibility and expands possible applications for the development of tailored medicine.

FcγRII and FcγRIII are low-affinity Fcγ receptors that are encoded by the FCGR2A and FCGR3A genes, respectively. These genes contain functional single-nucleotide polymorphisms (SNPs), which alter the binding affinities of these receptors for the γ chain of the Fc fragment of immunoglobulin G. The known SNPs in FCGR2A and FCGR3A are rs1801274 (A>G; H131R) and rs396991 (T>G; F158V), respectively. It is also known that there are copy number variations (CNVs) in the genetic locus (1q23) where FCGR2A and FCGR3A are located. However, the frequencies of these SNPs and CNVs have not been determined in the Japanese population. The aim of this study was to investigate SNPs and CNVs in FCGR2A and FCGR3A among 113 healthy individuals. The SNPs and CNVs in FCGR2A and FCGR3A were determined using the TaqMan® SNP Genotyping and the TaqMan® Copy Number assays. Our results revealed that the incidence of FCGR2A (rs1801274) genotypes were as follows: A/A, 69.9%; A/G, 29.2%; and G/G, 0.9%. The incidence of the FCGR3A (rs396991) genotypes were as follows: T/T, 56.7%; T/G, 38.9%; and G/G, 4.4%). No CNVs were detected for FCGR2A. To the best of our knowledge, this finding has not been previously reported in the Japanese population. By contrast, CNVs were observed in FCGR3A (3 subjects were found to harbour a gene deletion and 5 subjects had 3 copies of the gene). Using simple commercially available assays we were able to confirm previous findings regarding FCGR2A and FCGR3A alleles and CNVs. These assays may provide a basis for the investigation of the role of these genes in the efficacy of antibody-based drugs, such as trastuzumab and rituximab, in Japanese subjects.

Effective dog training involves reinforcement of the dog's correct actions in response to specific cues given by the trainer. Food is usually selected as the primary reinforcer (reward), although this selection does not necessarily account for the learning preferences of individual dogs. We evaluated the relationship between reward and learning efficiency. Fifteen dogs were allocated to 3 different reward groups (food, stroking, and praise) and trained by an identical process. The food reward was the only one that shortened the time taken for the response to the command to be completed. However, this difference occurred only in the early training stages and not later in the training process.

A fixed-dose formula that combines Ombitasvir (OBV), Paritaprevir (PTV) and Ritonavir (RTV) has been launched into the field of anti-HCV therapy in Japan for patients infected with HCV genotypes 1 and 2 in 2015. However, little is yet known as to the efficacy and safety of this novel therapy in patients on maintenance haemodialysis (HD). The present report describes a preliminary experience in 10 patients (five males and five females) who underwent maintenance HD. All of them had HCV genotype 1b, without having the resistance-associated variants at Y93 or L31 in the nonstructural proteins 5A (NS5A) region. After the treatment, eight patients successfully achieved virus eradication and sustained a virological response at 12 weeks (SVR12). In addition, mac-2 binding protein glycosylation isomer (M2BPGi), a biomarker for liver fibrosis, was reduced after the therapy. Two patients withdrew from the therapy due to the development of erythema multiforme and a strong drowsiness, respectively. These results suggest that triple therapy combining OBV, PTV and RTV is effective in achieving SVR12 in most of the HCV-infected patients on HD. In addition, this combination therapy contributed to retard the progression of liver fibrosis. However, we suggest that further trial will be required to establish its clinical efficacy and safety.

Because of ever-increasing environmental deterioration it is likely that the influx of UV-B radiation (280-320 nm) will increase as a result of the depletion of stratospheric ozone. Given this fact it is essential that we better understand both the rapid and the adaptive responses of plants to UV-B stress. Here, we compare the metabolic responses of wild-type Arabidopsis with that of mutants impaired in flavonoid (transparent testa 4, tt4; transparent testa 5, tt5) or sinapoyl-malate (sinapoylglucose accumulator 1, sng1) biosynthesis, exposed to a short 24-h or a longer 96-h exposure to this photo-oxidative stress. In control experiments we subjected the genotypes to long-day conditions as well as to 24- and 96-h treatments of continuous light. Following these treatments we evaluated the dynamic response of metabolites including flavonoids, sinapoyl-malate precursors and ascorbate, which are well known to play a role in cellular protection from UV-B stress, as well as a broader range of primary metabolites, in an attempt to more fully comprehend the metabolic shift following the cellular perception of this stress. Our data reveals that short-term responses occur only at the level of primary metabolites, suggesting that these effectively prime the cell to facilitate the later production of UV-B-absorbing secondary metabolites. The combined results of these studies together with transcript profiles using samples irradiated by 24-h UV-B light are discussed in the context of current models concerning the metabolic response of plants to the stress imposed by excessive UV-B irradiation.

611 Background: Adjuvant chemotherapy (ACT) has been recommended for stage III colon cancer patients in NCCN guidelines. However, the benefit of ACT is still controversial in elderly patients. Methods: We retrospectively included stage III colon cancer patients with aged over 70 that were operated between 2008 and 2015 in Tosei general hospital from Japan. We calculated 3 years recurrence rate and performed a multivariate analysis to estimate the risk of recurrence. The model was adjusted by including the following 7 confounders: Age, ECOG-PS (0-1 or ≥ 2), tumor site (right or left), T stage (T1-3 or T4 ), N stage (N1 or N2), pathological type (por-sig or other), and complete ACT (yes or no). No complete ACT was defined as discontinuation ACT and surgery alone. Results: 182 patients were identified (87 patients aged < 70 and 95 patients aged ≥ 70). ACT was performed in 58 patients (61.1%) and complete rate was 67.2% in elderly patients. The median follow up was 36.0 months. 29 patients (30.0%) had relapse. 3 years recurrence rate was 24.3% and 37.8% with complete ACT or no complete ACT (p = 0.29). In multivariate analysis, N2 was only the risk of recurrence (HR 6.95, p < 0.01). In further analysis, addition of oxaliplatin was significant risk factor of recurrence in elderly patients (HR 10.4, p < 0.01). On the other hand, in young patients, no complete ACT was only risk of recurrence (p = 0.01). 3 years survival rate was 89.1% and 81.0% with complete ACT or no complete ACT (p = 0.27). Conclusions: The multivariate analysis showed that ACT did not reduce the risk of recurrence in elderly patients. Moreover, addition of oxaliplatin suggested not only futile but harmful in those patients. These results support the previous reports (MOSAIC study and PETACC-8 trial) that microsatellite instability and RAS status may affect the effect of oxaliplatin.

Rice plants grown in paddy fields preferentially use ammonium as a source of inorganic nitrogen. Glutamine synthetase (GS) catalyses the conversion of ammonium to glutamine. Of the three genes encoding cytosolic GS in rice, OsGS1;1 is critical for normal growth and grain filling. However, the basis of its physiological function that may alter the rate of nitrogen assimilation and carbon metabolism within the context of metabolic networks remains unclear. To address this issue, we carried out quantitative comparative analyses between the metabolite profiles of a rice mutant lacking OsGS1;1 and its background wild type (WT). The mutant plants exhibited severe retardation of shoot growth in the presence of ammonium compared with the WT. Overaccumulation of free ammonium in the leaf sheath and roots of the mutant indicated the importance of OsGS1;1 for ammonium assimilation in both organs. The metabolite profiles of the mutant line revealed: (i) an imbalance in levels of sugars, amino acids and metabolites in the tricarboxylic acid cycle, and (ii) overaccumulation of secondary metabolites, particularly in the roots under a continuous supply of ammonium. Metabolite-to-metabolite correlation analysis revealed the presence of mutant-specific networks between tryptamine and other primary metabolites in the roots. These results demonstrated a crucial function of OsGS1;1 in coordinating the global metabolic network in rice plants grown using ammonium as the nitrogen source.

Plant metabolomics developed as a powerful tool to examine gene functions and to gain deeper insight into the physiology of the plant cell. In this study, we screened Arabidopsis lines overexpressing rice full-length (FL) cDNAs (rice FOX Arabidopsis lines) using a gas chromatography-time-of-flight mass spectrometry (GC-TOF/MS)-based technique to identify rice genes that caused metabolic changes. This screening system allows fast and reliable identification of candidate lines showing altered metabolite profiles. We performed metabolomic and transcriptomic analysis of a rice FOX Arabidopsis line that harbored the FL cDNA of the rice ortholog of the Lateral Organ Boundaries (LOB) Domain (LBD)/Asymmetric Leaves2-like (ASL) gene of Arabidopsis, At-LBD37/ASL39. The investigated rice FOX Arabidopsis line showed prominent changes in the levels of metabolites related to nitrogen metabolism. The transcriptomic data as well as the results from the metabolite analysis of the Arabidopsis At-LBD37/ASL39-overexpressor plants were consistent with these findings. Furthermore, the metabolomic and transcriptomic analysis of the Os-LBD37/ASL39-overexpressing rice plants indicated that Os-LBD37/ASL39 is associated with processes related to nitrogen metabolism in rice. Thus, the combination of a metabolomics-based screening method and a gain-of-function approach is useful for rapid characterization of novel genes in both Arabidopsis and rice.

症例は59歳，男性．肝嚢胞出血の診断で内科通院中であった．出血を繰り返したため精査したところ，肝細胞癌が疑われ当科紹介となった．腹部ダイナミックCTでは，動脈相・門脈相ともに肝実質より低吸収域を示し，S5，6には造影剤の漏出を認めた．腹部MRIでは，T1強調で不均一低信号，T2強調で不均一高信号を示した．腹部血管造影検査では，腫瘍濃染像はなく，動脈・門脈圧排像もみられなかった．腫瘍マーカーは，PIVKA-ECが11,206mAU/mlと上昇していた．乏血性肝細胞癌を疑い，肝右葉切除術を行った．開腹所見では，肝腫瘍が破裂し，血性腹水を認めた．病理組織学的診断は，中分化型肝細胞癌で，腫瘍内にはCD34染色検査陽性の毛細血管が多数みられた．多血性肝細胞癌と比較して差はなく，腫瘍内血管密度と腫瘍造影効果の直接的な関連はないと考えられた．

症例は38歳，男性．腹痛を主訴に当院救急外来を受診した．腹部全体に圧痛あり，腹壁は板状硬であった．血清アミラーゼ高値であり．高度の代謝性アシドーシスを認めた．腹部造影CTで膵腫大，上腸間膜動脈本幹の狭細化，門脈内ガス像を認め，腸管壁の造影効果が不良であった．急性膵炎に伴った腸管壊死を疑い，緊急手術を施行した．下部小腸より右側結腸の血流障害を認め，同部を切除した．病理組織学的には，非閉塞性腸管虚血症（nonocclusive mesenteric ischemia:以下NOMI）と診断された．本邦におけるNOMIあるいは腸管壊死を合併した急性膵炎の報告は検索した限りでは5例と少ない．文献的考察を加えて報告する．

症例は49歳，女性．再発盲腸癌に対し，Bevacizumab+mFOLFOX6療法が行われていた．最終投与日から30日目に腹痛を訴え当院を受診した．腹部単純CTでfree airを認め，消化管穿孔の診断で開腹手術を行った．開腹所見では，Treitz靱帯より50cmの空腸が小腸間膜のリンパ節再発の全層浸潤により穿孔をきたしていた．再発リンパ節を含め約50cmの空腸を部分切除し，一期的に吻合した．術後は合併症なく，第30病日退院となった．

症例は60歳，女性．全身倦怠感と腹部膨満を主訴に近医を受診した．上部消化管造影で胃の圧排像を認め，精査目的のため当院紹介となった．腹部CTで巨大脾嚢胞性病変と腫大した虫垂，大量の腹水を認め，腹膜偽粘液腫，脾転移の診断で開腹手術が施行された．開腹所見では虫垂は穿孔し，腹腔内に粘液貯留を認めた．脾臓は小児頭大に腫大し，内部には粘液が貯留していた．回盲部切除，脾臓摘出術を行い，炭酸水素ナトリウム溶液で十分に腹腔内を洗浄した．病理組織学的診断は虫垂mucinous cystic tumorで悪性像は認めず，脾病変は脾転移と診断された．

The tobacco N protein recognizes the helicase domain (p50) of the Tobacco mosaic virus (TMV) replicase as an elicitor and mediates hypersensitive response (HR). We obtained two cDNA clones encoding novel N-like (NL) proteins NL-C26 and NL-B69 from Nicotiana tabacum cv. Samsun NN. NL-C26 and NL-B69 had a Toll-interleukin-1 receptor/nucleotide-binding site/leucine-rich repeat (TIR–NBS–LRR) structure and showed 78% and 73% identities to N, respectively. The NL-C26 and NL-B69 genes were also expressed in N. tabacum cv. Samsun nn, which lacks the N gene. Unlike N, NL-C26 and NL-B69, when coexpressed with p50, failed to induce HR on the sites of agroinfiltration in Samsun nn leaves. However, the elicitor-dependent HR in Samsun nn was induced efficiently by chimeric N proteins with the continuous TIR–NBS domains of NL-C26 and NL-B69. On the other hand, the efficiency of HR induction varied significantly among chimeric N proteins with either of the TIR and NBS domains of the NL proteins. In contrast, chimeras carrying the LRR domains of the NL proteins did not induce HR. Thus, the TIR–NBS domains of NL-C26 and NL-B69 could functionally adapt to the LRR domain of N, which may determine the specificity for the elicitor. We speculate that the NL genes are potential HR-inducing resistance genes for undetermined pathogens other than TMV.

Low skeletal muscle density (SMD) and low skeletal muscle index (SMI) are associated with poor overall survival (OS) in patients with various types of cancer. We retrospectively studied SMD and SMI using computed tomographic (CT) scans in patients with gastric cancer receiving chemotherapy to evaluate its prognostic significance. SMD and SMI were obtained from CT-based analysis using Slice-O-Matic® medical imaging software in patients who received S-1 plus cisplatin chemotherapy for metastatic gastric cancer. The CT images taken within 1 month before starting chemotherapy were used. The cut-off values for determining low SMD [

Opioid-induced constipation (OIC) is a very troublesome, difficult to manage and a nearly universal complication of chronic opioid use to control pain associated with advanced illness. Some studies have reported that OIC is so intolerable in some patients that they skip their opioid medications and bear pain instead of OIC. Laxatives have commonly been used as a prophylaxis and treatment of OIC but they are frequently ineffective because the commonly available laxatives do not target the underlying mechanism of OIC, which is the blockade of peripheral mu-receptors. Recently, there have been a number of advances in the treatment of OIC, which any physician involved with opioid-prescribing discipline should be aware of. This review will update the new options and strategies available for treating OIC along with the relevant clinical trials. Finally, this review also provides a recommendation on the preferred way to approach a patient with OIC in the modern era as well as highlight on the importance of doctor-patient communication in this setting.

Intercalation of proton-type layered titanium(IV) oxides, H2Ti5O11·xH2O (H-TiO2(A)) and H0.7Ti1.825O4·xH2O (H-TiO2(B)), with n-alkylamines were examined for carbon numbers nc = 3–18 in a benzene so...

Uptake of external sulfate from the environment and use of internal vacuolar sulfate pools are two important aspects of the acquisition of sulfur for metabolism. In this study, we demonstrated that the vacuolar SULTR4-type sulfate transporter facilitates the efflux of sulfate from the vacuoles and plays critical roles in optimizing the internal distribution of sulfate in Arabidopsis thaliana. SULTR4;1-green fluorescent protein (GFP) and SULTR4;2-GFP fusion proteins were expressed under the control of their own promoters in transgenic Arabidopsis. The fusion proteins were accumulated specifically in the tonoplast membranes and were localized predominantly in the pericycle and xylem parenchyma cells of roots and hypocotyls. In roots, SULTR4;1 was constantly accumulated regardless of the changes of sulfur conditions, whereas SULTR4;2 became abundant by sulfur limitation. In shoots, both transporters were accumulated by sulfur limitation. Vacuoles isolated from callus of the sultr4;1 sultr4;2 double knockout showed excess accumulation of sulfate, which was substantially decreased by overexpression of SULTR4;1-GFP. In seedlings, the supplied [(35)S]sulfate was retained in the root tissue of the sultr4;1 sultr4;2 double knockout mutant. Comparison of the double and single knockouts suggested that SULTR4;1 plays a major role and SULTR4;2 has a supplementary function. Overexpression of SULTR4;1-GFP significantly decreased accumulation of [(35)S]sulfate in the root tissue, complementing the phenotype of the double mutant. These results suggested that SULTR4-type transporters, particularly SULTR4;1, actively mediate the efflux of sulfate from the vacuole lumen into the cytoplasm and influence the capacity for vacuolar storage of sulfate in the root tissue. The efflux function will promote rapid turnover of sulfate from the vacuoles particularly in the vasculature under conditions of low-sulfur supply, which will optimize the symplastic (cytoplasmic) flux of sulfate channeled toward the xylem vessels.

Flow cytometric analysis of CD4+ and CD8+ T cells specific to human cytomegalovirus (CMV) was undertaken in seven patients with congenital CMV infection, six healthy infants who had acquired infection, and six CMV-seropositive adults. Intracellular cytokine assays showed that 0.03–2.23% of CD4+ T cells in the healthy infants and adults produced interferon-γ (IFN-γ) in response to CMV antigens. In contrast, such CD4+ T cells were almost undetectable in patients with congenital CMV infection who were younger than 2 years of age. Tetrameric major histocompatibility complex/peptide complex analysis demonstrated HLA*A2402-restricted phosphoprotein 65-specific CD8+ T cells to be present in most healthy infants and adults tested, but almost absent in the patients. Interestingly, CMV-specific CD4+ T-cell responses were observed in two patients with congenital infection beyond the age of 5 years. The present study points to impairment of CMV-specific cellular immunity in patients in single-cell levels with congenital CMV infection during the infant period and possible restoration in later childhood. J. Med. Virol. 71:251–258, 2003. © 2003 Wiley-Liss, Inc.

We determined cytotoxic T lymphocyte (CTL) epitopes through screening with a computer-assisted algorithm and an enzyme-linked immunospot (ELISPOT) assay using in vitro–reactivated polyclonal Epstein-Barr virus (EBV)–specific CD8+ T cells as responders. In addition, to confirm that the epitopes were generated after endogenous processing and presentation of the EBV proteins, a novel T-cell receptor (TCR) down-regulation assay was introduced, in which a fluorescent tetrameric major histocompatibility complex (MHC)/peptide complex was employed for detecting TCR down-regulation after stimulation with the epitope presented on antigen-presenting cells. Through such screening, 3 HLA A*2402–restricted epitopes were identified: IYVLVMLVL, TYPVLEEMF, and DYNFVKQLF, derived from LMP2, BRLF1, and BMLF1 proteins, respectively. TCR down-regulation assays disclosed that, in contrast to the other 2 epitopes, IYVLVMLVL was not presented on HLA A24–positive fibroblast cells infected with recombinant vaccinia viruses expressing LMP2. Furthermore, ELISPOT assays with an epitope-specific CTL clone demonstrated that the presentation was partially restored by pretreatment of the fibroblast cells with interferon-γ. The epitope was presented on transporters associated with antigen processing (TAP)–negative T2 cells transfected with plasmids encoding HLA A*2402 and the minimal epitope, indicating that the presentation is TAP independent. In conclusion, the 3 epitopes thus defined could be useful for studying EBV-specific CD8+ T-cell responses among populations positive for HLA A*2402.

e21665 Background: The oral transmucosal fentanyl disintegrating tablet, Abstral, is a formulation by which fentanyl can be rapidly absorbed across the oral mucosa producing rapid onset analgesia, and which may be effective for breakthrough cancer pain. It can be administered for the patients who cannot take the oral medicine. It has been marketed since 2014 in Japan. Methods: We selected patients who were administered Abstral for breakthrough cancer pain between 2014 and 2016 at Toyama University Hospital in Japan. We retrospectively investigated administration reasons based on medical record of those patients. Results: There were 111 patients who were administered Abstral. Primary lesions of lung/Gastrointestin/others were 43/52/16, respectively. ECOG PS 0-2/3-4 were 27/84, respectively. The median age was 66 y.o. (range 35-91 y.o.). Regularly using opioid were fentanyl patch prescribed for all patients. Median dose of fentanyl patch was 25mcg/hr (range 12.5-250mcg/hr). 90 patients (81%) had difficulties in the administration of oral medicine, which was the main reason of Abstral administration. Four patients (4%) were to reduce constipation and vomiting as side effects of oxycodone. Seven patients (6%) were to start a fentanyl patch. Three patients (3%) were assessed poor effect for short-acting opioid. Only seven patients (6%) were expected of rapid onset of analgesia effect. Abstral was administered in 27 patients (24%) during aggressive treatment such as chemotherapy administration and in 84 patients (76%) after aggressive treatment. Conclusions: The oral transmucosal fentanyl was administered for the patients who cannot take the oral medicine in Japan while it is expected to be administered to those who want to relieve breakthrough pain fast. Affirming a common understanding of the efficacy of the oral transmucosal fentanyl and breakthrough cancer pain is necessary in Japan.

Antigenic peptides recognized by virus-specific cytotoxic T lymphocytes (CTLs) are useful tools for studying the CTL responses exclusively among those who own the major histocompatibility complex (MHC) class I molecules that present the peptides. For widening the application, an efficient strategy to determine such epitopes in the context of a given MHC is highly desirable. A rapid and efficient strategy is presented for the determination of CTL epitopes in the context of given MHC molecules of interest through multiple screenings consisting of a computer-assisted algorithm and MHC stabilization and enzyme-linked immunospot assays. A major cytomegalovirus (CMV)–specific CTL epitope, QYDPVAALF, in the amino acid sequence of its lower matrix 65 kd phosphoprotein (pp65) presented by HLA-A*2402 molecules was identified from 83 candidate peptides. The results indicate that the CMV-specific CTL response is highly focused to pp65 in the context of HLA-A*2402. Endogenous processing and presentation was confirmed using a peptide-specific CD8+ T-cell clone as the effectors and autologous fibroblast cells infected with recombinant vaccinia virus expressing pp65 gene or CMV as antigen-presenting cells. Flow cytometric analysis of intracellular interferon-γ production revealed 0.04% to 0.27% of CD8+ T cells in peripheral blood of HLA-A24+ and CMV-seropositive donors to be specific for the peptide. The tetrameric MHC-peptide complexes specifically bound to the reactive T-cell clone and 0.79% of CD8+ T cells in peripheral blood from a seropositive donor. The peptide could be a useful reagent to study CTL responses to CMV among populations positive for HLA-A*2402.

Although hepatitis is a common feature of primary Epstein-Barr virus (EBV) infection, severe liver injury is rare and its pathogenesis is unclear. A previously healthy girl developed severe hepatitis with prolonged jaundice. Serologic examination showed that she had primary infection with EBV. An extremely high Epstein-Barr viral load was observed in her peripheral blood. The viral load decreased in parallel with symptomatic improvement. Histologic examinations showed spotty necrosis of the liver parenchyma and infiltration by CD8(+) T cells. The CD8(+) T cells, not hepatocytes, were positive for EBV. Possible mechanisms of viral hepatitis without infection of hepatocytes are discussed.

A criticality accident occurred at nuclear fuel processing facility of JCO Company Ltd. at 10:35 local time on September 30, 1999. In this accident, the doses to few workers were evaluated directly with individual dosimeters. Japan Nuclear Cycle Development Institute (JNC) estimated the dose to the JCO workers in cooperation with the Criticality Accident Investigation Committee. JNC carried out the dose evaluation using the following methods.(1) Dose evaluation based on 24Na activities produced in the human body due to neutron capture reaction, which were measured with whole body counter.(2) Dose evaluation by the calculation from the change of the radiation dose rate which is estimated by the area monitors, and the behavior of the employee at the criticality accident.To validate the results of the dose evaluation, dose calculation was carried out to several workers whose dose had been measured with individual dosimeters or a whole body counter. As the result, the dose calculation technique was almost applicable for the dose estimation of JCO workers.

24Na in the human body, activated by neutrons emitted at the JCO criticality accident, was observed for 62 subjects, where 148 subjects were measured by the whole body counter of JNC Tokai Works. The 148 subjects, including JCO employees and the contractors, residents neighboring the site and emergency service officers, were measured by the whole-body counter. The neutron-energy spectrum around the facility was calculated using neutron transport codes (ANISN and MCNP), and the relation between an amount of activated sodium in human body and neutron dose was evaluated from the calculated neutron energy spectrum and theoretical neutron capture probability by the human body. The maximum 24Na activity in the body was 7.7 kBq (83 Bq(24Na)/g(23Na)) and the relevant effective dose equivalent was 47 mSv.

Subacute sclerosing panencephalitis (SSPE) is a degenerative disease of the central nervous system that leads to death within a few years. Recently, it has been reported that combination therapy with intraparenchymal interferon-alpha (INF-alpha) and intraventricular ribavirin is effective. An 11-year-old SSPE patient whose clinical symptoms progressed rapidly, was treated first with intraventricular INF-alpha and then with combined intraventricular INF-alpha and ribavirin therapy. To monitor viral load over the course of the therapy, measles virus RNA was quantified using a real-time polymerase chain reaction assay. Measles virus RNA decreased rapidly after the INF-alpha therapy was started, paralleling the decrease in the measles antibody titer in the cerebrospinal fluid and the improvement in the neurological disability. After intraventricular ribavirin was combined with INF-alpha therapy, no further improvement was observed. The neurological disability gradually progressed, although the amount of virus RNA remained low.

A radioanalytical method for low level samarium-151 ( 151 Sm) and promethium-147 ( 147 Pm) in environmental samples has been studied for the environmental assessment around nuclear facilities. In this study, we use the separation method with high performance liquid chromatography (HPLC) to determine 151 Sm and 147 Pm in environmental samples such as sea sediments and marine organisms. Samarium-151 and 147 Pm in environmental samples are coprecipitated with other lanthanoids alter adding neodymium (Nd). These nuclides are purified by anion exchange methods in methanol-mineral acid media. After the purification, 151 Sm and 147 Pm are separated with HPLC in lactic acid-sodium hydroxide media, and determined with liquid scintillation counting, respectively. The Nd is determined by inductively coupled plasma atomic emission spectrometry (ICP-AES) to correct chemical recoveries of these nuclides. The detection limits for 151 Sm and 147 Pm in this method are about 0.01 Bq/sample

In higher plants, the circadian clock controls a wide range of cellular processes such as photosynthesis and stress responses. Understanding metabolic changes in arrhythmic plants and determining output-related function of clock genes would help in elucidating circadian-clock mechanisms underlying plant growth and development. In this work, we investigated physiological relevance of PSEUDO-RESPONSE REGULATORS (PRR 9, 7, and 5) in Arabidopsis thaliana by transcriptomic and metabolomic analyses. Metabolite profiling using gas chromatography–time-of-flight mass spectrometry demonstrated well-differentiated metabolite phenotypes of seven mutants, including two arrhythmic plants with similar morphology, a PRR 9 , 7 , and 5 triple mutant and a CIRCADIAN CLOCK-ASSOCIATED 1 ( CCA1 )-overexpressor line. Despite different light and time conditions, the triple mutant exhibited a dramatic increase in intermediates in the tricarboxylic acid cycle. This suggests that proteins PRR 9, 7, and 5 are involved in maintaining mitochondrial homeostasis. Integrated analysis of transcriptomics and metabolomics revealed that PRR 9, 7, and 5 negatively regulate the biosynthetic pathways of chlorophyll, carotenoid and abscisic acid, and α-tocopherol, highlighting them as additional outputs of pseudo-response regulators. These findings indicated that mitochondrial functions are coupled with the circadian system in plants.

We have developed a comprehensive method combining analytical techniques of one-dimensional (1D) and two-dimensional (GC x GC) gas chromatography-time-of-flight (TOF)-mass spectrometry. This method was applied to the metabolic phenotyping of natural variants in rice for the 68 world rice core collection (WRC) and two other varieties. Ten metabolites were selected as metabolite representatives, and the selected ion current of each metabolite peak obtained from both techniques were statistically compared. Our method of combining 1D- and GC x GC-TOF/MS is useful for the metabolic phenotyping of natural variants in rice for further studies in breeding programs.

Xylem transport of sulfate regulates distribution of sulfur in vascular plants. Here, we describe SULTR3;5 as an essential component of the sulfate transport system that facilitates the root-to-shoot transport of sulfate in the vasculature. In Arabidopsis (Arabidopsis thaliana), SULTR3;5 was colocalized with the SULTR2;1 low-affinity sulfate transporter in xylem parenchyma and pericycle cells in roots. In a yeast (Saccharomyces cerevisiae) expression system, sulfate uptake was hardly detectable with SULTR3;5 expression alone; however, cells coexpressing both SULTR3;5 and SULTR2;1 showed substantial uptake activity that was considerably higher than with SULTR2;1 expression alone. The Vmax value of sulfate uptake activity with SULTR3;5-SULTR2;1 coexpression was approximately 3 times higher than with SULTR2;1 alone. In Arabidopsis, the root-to-shoot transport of sulfate was restricted in the sultr3;5 mutants, under conditions of high SULTR2;1 expression in the roots after sulfur limitation. These results suggested that SULTR3;5 is constitutively expressed in the root vasculature, but its function to reinforce the capacity of the SULTR2;1 low-affinity transporter is only essential when SULTR2;1 mRNA is induced by sulfur limitation. Consequently, coexpression of SULTR3;5 and SULTR2;1 provides maximum capacity of sulfate transport activity, which facilitates retrieval of apoplastic sulfate to the xylem parenchyma cells in the vasculature of Arabidopsis roots and may contribute to the root-to-shoot transport of sulfate.

428 Background: The aim of this study was to evaluate the association of early tumor response to the first-line bevacizumab (BEV) combination therapy with efficacy of the subsequent therapies and survival during the BEV beyond progression (BBP) strategy for metastatic colorectal cancer (mCRC) patients. Methods: We analyzed a pooled data set from the previous phase II studies of mCRC, testing BBP strategy with the first-line mFOLFOX plus BEV (N=47) and the second-line FOLFIRI plus BEV (N=31). Patients were classified into either responders (R group, n=29) with tumor shrinkage (complete response [CR] + partial response [PR]), sub-responders (SR group, n=11) with stable disease (SD) and non-responders (NR group, n=5) with disease progression (PD) at the point of initial three months of the first-line therapy. The tumor response and PFS in the subsequent therapies and OS were evaluated. Results: In the first-line FOLFOX+BEV therapy, further tumor shrinkage was not achieved after the initial three months. PFS was 15.0 months for the R group, 8.9 months for the SR group and 2.9 months for the NR group, respectively, and there was statistical significance favoring the R group (p=0.001). In the second-line FOLFIRI+BEV, RR and DCR were 39 and 78% in the R group, 14 and 57% in the SR group, and 0 and 0% in the NR group, respectively. No additional response to the first-line therapy was observed in all groups, except for only one patient in the SR group. PFS was 8.8 months for the R group, 6.0 months for SR group and 1.4 months for NR group, respectively, and the R group was significant predictor for prolonged PFS in the second-line setting. OS were 30.8 months for the R group, 24.7 months for the SR group, and 11.1 months for the NR group, respectively. Early disease control (R+SR) was significant predictor for OS (hazard ratio [HR]: 8.48, p

631 Background: This study was designed to evaluate the influence of dose reduction and schedule modification on outcomes in patients with metastatic colorectal cancer (mCRC). Methods: Pooled datasets from two previous phase II trials of FOLFIRI (CCOG-0502; n = 36) and mFOLFOX6 (CCOG-0704; n = 30) in patients with mCRC were analyzed retrospectively. The RDIs of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). To assess the effects of dose reduction and time delay, we defined ‘dose index (DI)’ as the ratio of the actual delivered total dose to the planned total dose and ‘time index (TI)’ as the ratio of the planned duration to the actual duration of therapy. Relative dose intensity (RDI) was computed by multiplying DI by TI. DI and TI of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR) and progression-free survival (PFS). Results: In patients receiving FOLFIRI therapy, the median DI and TI of irinotecan were 0.92 and 0.90, respectively. RRs were 59% vs. 12% in the higher vs. lower DI groups (p < 0.01), and 35% vs. 35% in the higher vs. lower TI groups (p = 1.00), respectively. Median PFS was 10.2 vs. 5.0 months in the higher vs. lower DI groups (p < 0.01), and 6.1 vs. 6.7 months in the higher vs. lower TI groups (p = 0.48), respectively. In mFOLFOX6 therapy, the median DI and TI of oxaliplatin were 0.97 and 0.82, respectively. RRs were 44% vs. 36% in the higher vs. lower DI groups (p = 0.65), and 44% vs. 36% in the higher vs. lower TI groups (p = 0.65), respectively. Median PFS was 7.7 vs. 6.7 months in the higher vs. lower DI groups (p = 0.13), and 8.5 vs. 5.9 months in the higher vs. lower TI groups (p = 0.02), respectively. Multivariate analyses showed that DI of irinotecan (HR 8.48; 95% CI, 2.94-24.51, p < 0.01) and TI of oxaliplatin (HR 2.74; 95% CI, 1.02-7.33, p = 0.04) were the independent prognostic factors for PFS. Conclusions: Dose reductions in irinotecan and time delays in oxaliplatin could have significant impact on PFS in patients receiving FOLFIRI and FOLFOX6, respectively.

e14614 Background: We reported that relative dose intensity (RDI) of key cytotoxic agents, irinotecan (IRI) and oxaliplatin (OX), is a significant predictor of disease control in patients with metastatic colorectal cancer (mCRC). However, in concomitant therapy with bevacizumab (BEV), the influence of adding BEV on the relation between RDI of cytotoxic agents and outcomes are unclear. In this study, we evaluate the impact of BEV on RDI of IRI and OX-based chemotherapy on the outcome of mCRC. Methods: A retrospective analysis of mCRC patients entered into three prospective clinical trials, testing FOLFIRI (CCOG-0502), mFOLFOX6 (CCOG-0704), FOLFIRI plus BEV and mFOLFOX6 plus BEV (CCOG-0801), was performed. RDI was calculated as the delivered dose intensity divided by standard dose intensity calculated for each regimen and compared to response rate (RR), disease control rate (DCR) and progression-free survival (PFS). Results: In FOLFIRI therapy, higher RDI (IRI, >median: 80%) group achieved significant better RR, DCR and PFS than lower RDI (median: 79%) group achieved better disease control than lower RDI group (RR: 47 vs. 33% [p=0.456], DCR: 100 vs. 73% [p=0.032] and PFS: 8.5 vs. 6.2 months [p=0.064]). In addition of BEV, there were no difference between higher and lower RDI (OX, median: 76%) group in any outcomes (RR: 54 vs. 74% [p=0.159], DCR: 88 vs. 91% [p=0.672] and PFS: 11.6 vs. 11.7 months [p=0.797]). Conclusions: RDI of key cytotoxic agents is a significant predictor of disease control, especially in IRI-based regimen. Nevertheless, in concomitant therapy with BEV, there were no relations between RDI of cytotoxic agents and outcomes. These results suggest that BEV could have ‘covering effect’ to reduce the influence of dose modification of cytotoxic agents in mCRC patients.