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Supplemental files for "Phase 1 Study of P-cadherin-Targeted Radioimmunotherapy with 90Y-FF-21101 Monoclonal Antibody in Solid Tumors" Subbiah V et al.

Background Management of infectious complications in pregnant women receiving immunosuppressive therapy for systemic lupus erythematosus (SLE) is important. Maternal infection with cytomegalovirus (CMV) often causes congenital CMV infection in the foetus. Thus far, there are only few reports on congenital CMV infection after maternal reactivation in patients with SLE. We report the first case of congenital CMV infection after maternal primary infection in a patient with SLE. Case presentation A 19-year-old Japanese primigravida with SLE received treatment with prednisolone 3 mg/day and azathioprine 75 mg/day at conception. At 7 weeks of gestation, she suddenly developed fever and had decreased white blood cell and platelet counts and elevated aspartate aminotransferase and alanine aminotransferase levels. These clinical findings led to a diagnosis of SLE exacerbation. The prednisolone dose was increased to 15 mg/day, and hydroxychloroquine (200 mg/day) was administered. Consequently, all clinical findings normalised at 12 weeks. At 19 weeks, foetal ultrasound findings revealed oligohydramnios, brain hypoplasia, ventriculomegaly and hyperechogenic bowel. Maternal serological test results indicated increased CMV-specific IgG and IgM levels, low IgG avidity (26%), and positive CMV antigenemia. The foetus was diagnosed with symptomatic congenital CMV infection transmitted from the maternal primary infection. After counselling about the severe prognosis of the foetus, the mother decided to terminate her pregnancy and underwent artificial abortion at 21 weeks. Discussion The foetus of a mother with SLE who is receiving immunosuppressive therapy may be at increased risk of transmission and aggravation of congenital CMV infection; thus, preventive management and screening for congenital CMV infection during pregnancy are recommended for such patients. Maternal CMV infection shows clinical findings similar to those of SLE exacerbation, and careful differential diagnosis by maternal serological evaluation and foetal ultrasound scans is required.

This study aimed to obtain information on the transport form and pathway from the intestine to the peripheral tissues and on the intestinal absorption and metabolism properties of oleamide (

There has been a growing recognition that a systems thinking approach, which pays attention to the entire dynamic system, its constituent parts and the interactions among those parts, is an effective approach for tackling complex issues that exhibit nonlinear behaviour and involve multiple stakeholders. To understand a complex system, a systems thinking approach must identify the leverage points, which are non-intuitive and difficult to identify. This paper proposes a design tool called System Design Canvas, which supports the identification of system variables and leverage points from technological sensing data and human data while understanding stakeholders' mental model. The present case study confirms that System Design Canvas can identify system variables and leverage points that are required for the current agricultural system in Cambodia.

Deficiency of polyunsaturated fatty acids (PUFAs) is known to induce hepatic steatosis. However, it is not clearly understood which type of PUFA is responsible for the worsening of steatosis. This study observed a marked accumulation of hepatic triacylglycerol and cholesterol in fatty acid desaturase 2 knockout (FADS2-/- ) mice lacking both C18 and ≥ C20 PUFAs that were fed a PUFA-depleted diet. Hepatic triacylglycerol accumulation was associated with enhanced sterol regulatory element-binding protein (SREBP)-1-dependent lipogenesis and decreased triacylglycerol secretion into the plasma via very-low-density lipoprotein (VLDL). Furthermore, upregulation of cholesterol synthesis contributed to increased hepatic cholesterol content in FADS2-/- mice. These results suggest that ≥ C20 PUFAs synthesized by FADS2 are important in regulating hepatic triacylglycerol and cholesterol accumulation during PUFA deficiency.

Purpose Since a case of hydrocephalus in humans considered to be caused by ciliary dysfunction was first reported by Greenstone et al. in 1984, numerous papers on the correlation between ciliary function and hydrocephalus have been published. Methods We reviewed the published literature on primary ciliary dyskinesia in humans causing hydrocephalus, focusing on articles specifically examining the relation between ciliary function and hydrocephalus and its treatment. In addition, the authors’ experience is briefly discussed. Results Full texts of 16 articles reporting cases of human hydrocephalus (including ventriculomegaly) due to defects in ependymal ciliary function or primary ciliary dyskinesia observed in clinical practice were extracted. In recent years, studies on animal models, especially employing knockout mice, have revealed genetic mutations that cause hydrocephalus via ciliary dysfunction. However, a few reports on the onset of hydrocephalus in human patients with primary ciliary dyskinesia have confirmed that the incidence of this condition was extremely low compared to that in animal models. Conclusion In humans, it is rare for hydrocephalus to develop solely because of abnormalities in the cilia, and it is highly likely that other factors are also involved along with ciliary dysfunction.

Background This study aimed to clarify predictors of preterm birth in pregnancy of women with systemic lupus erythematosus (SLE). We investigated the predictors of preterm birth before pregnancy from the perspective of the importance of preconception care. Methods We analysed fetal outcomes of 108 pregnancies in 74 SLE patients in a retrospective study. We compared pre-pregnancy clinical characteristics and disease activity in these women between the preterm birth and full-term birth groups to select predictive factors for preterm birth before pregnancy. Results Eighty-three of 108 pregnancies resulted in live births, of which 27 (25.0%) were preterm births. Pre-pregnancy serum complement 3 (C3) level was significantly lower in the preterm birth group (77.0 mg/dl) than the full-term birth group (87.5 mg/dl) (P = 0.029). Multivariate analysis identified history of lupus nephritis (odds ratio: 5.734, 95% CI 1.568–21.010, P = 0.008) and low C3 level (< 85 mg/dl) at pre-pregnancy (odds ratio 4.498, 95% CI 1.296–15.616, P = 0.018) as risk factors for preterm birth. The greater the number of these risk factors, the higher was the preterm birth rate (P = 0.0007). In the case of SLEDAI score ≤ 4, the preterm birth rate was higher in the pre-pregnancy low C3 group (< 85 mg/dl) (42.1%) than in the high C3 group (C3 ≥ 85 mg/dl) (14.7%) (P = 0.018). Conclusion For patients with a history of LN, treatment management focusing on pre-pregnancy serum complement levels is very important.

Purpose: 90Y-FF-21101 is an Yttrium-90–conjugated, chimeric mAb that is highly specific for binding to human placental (P)-cadherin, a cell-to-cell adhesion molecule overexpressed and associated with cancer invasion and metastatic dissemination in many cancer types. We report the clinical activity of 90Y-FF-21101 in a first-in-human phase I study in patients with advanced solid tumors. Patients and Methods: The safety and efficacy of 90Y-FF-21101 were evaluated in a phase I 3+3 dose-escalation study in patients with advanced solid tumors (n = 15) over a dose range of 5–25 mCi/m2. Dosimetry using 111In-FF-21101 was performed 1 week prior to assess radiation doses to critical organs. Patients who demonstrated clinical benefit received repeated 90Y-FF-21101 administration every 4 months. Results: 111In-FF-21101 uptake was observed primarily in the spleen, kidneys, testes, lungs, and liver, with tumor uptake observed in the majority of patients. Organ dose estimates for all patients were below applicable limits. P-cadherin expression H-scores ranged from 0 to 242 with 40% of samples exhibiting scores ≥100. FF-21101 protein pharmacokinetics were linear with increasing antibody dose, and the mean half-life was 69.7 (±12.1) hours. Radioactivity clearance paralleled antibody clearance. A complete clinical response was observed in a patient with clear cell ovarian carcinoma, correlating with a high tumor P-cadherin expression. Stable disease was observed in a variety of other tumor types, without dose-limiting toxicity. Conclusions: The favorable safety profile and initial antitumor activity observed for 90Y-FF-21101 warrant further evaluation of this radioimmunotherapeutic (RIT) approach and provide initial clinical data supporting P-cadherin as a potential target for cancer treatment.

Leukotriene B4 (LTB4) receptor 1 (BLT1) is a chemotactic G protein-coupled receptor expressed by leukocytes, such as granulocytes, macrophages, and activated T cells. Although there is growing evidence that BLT1 plays crucial roles in immune responses, its role in dendritic cells remains largely unknown. Here, we identified novel DC subsets defined by the expression of BLT1, namely, BLT1hi and BLT1lo DCs. We also found that BLT1hi and BLT1lo DCs differentially migrated toward LTB4 and CCL21, a lymph node-homing chemoattractant, respectively. By generating LTB4-producing enzyme LTA4H knockout mice and CD11c promoter-driven Cre recombinase-expressing BLT1 conditional knockout (BLT1 cKO) mice, we showed that the migration of BLT1hi DCs exacerbated allergic contact dermatitis. Comprehensive transcriptome analysis revealed that BLT1hi DCs preferentially induced Th1 differentiation by upregulating IL-12p35 expression, whereas BLT1lo DCs accelerated T cell proliferation by producing IL-2. Collectively, the data reveal an unexpected role for BLT1 as a novel DC subset marker and provide novel insights into the role of the LTB4-BLT1 axis in the spatiotemporal regulation of distinct DC subsets.

Visual Abstract, P-cadherin is overexpressed in various cancers and can be a target for radioimmunotherapy. We investigated the preclinical pharmacokinetics and pharmacology of FF-21101, an 111In- or 90Y-conjugated monoclonal antibody against P-cadherin, to evaluate its clinical applications. Methods: The radiochemical purity, binding affinity, and in vitro serum stability of 111In or 90Y-labeled FF-21101 were evaluated. The pharmacokinetics of 111In or 90Y-FF-21101 were compared in normal mice. Tumor accumulation after 111In-FF-21101 administration was investigated in mice bearing subcutaneous tumors with high (NCI-H1373), moderate (EBC-1), or no (A549) P-cadherin expression. The tumor suppression effect after a single intravenous injection of 90Y-FF-21101 was assessed in NCI-H1373 and EBC-1 mouse xenograft models. The relationship between antibody dose and tumor accumulation was investigated in the NCI-H1373 mouse xenograft model. The absorbed radiation dose in humans after injection of 90Y-FF-21101 was estimated using γ-camera images of cynomolgus monkeys. Results: The radiochemical purities of 111In- and 90Y-FF-21101 were 98.2% ± 2.5% (n = 9) and 99.3% ± 0.6% (n = 5), respectively. The dissociation constants were 1.083 nM for 111In-FF-21101 and 1.367 nM for 90Y-FF-21101. Both 111In- and 90Y-FF-21101 were stable in human serum after 96 h of incubation and exhibited similar pharmacokinetics in normal mice. The tumor accumulation of 111In-FF-21101 was closely related to the intensity of P-cadherin expression in the cells. 90Y-FF-21101 showed significant tumor growth inhibition, indicating that NCI-H1373 and EBC-1 recurrence was not observed after intravenous administration of 3.7 and 7.4 MBq, respectively of 90Y-FF-21101 per animal. Tumor uptake in the mouse xenograft model and estimated absorbed radiation doses in the spleen of monkeys decreased with increasing antibody doses of 111In-FF-21101. Conversely, the estimated absorbed radiation dose in the red marrow increased with increasing antibody dose. An antibody dose of 4.8 mg/m2 was considered appropriate for humans, on the basis of efficacy and safety. The maximum tolerated administered activity of 90Y-FF-21101 was estimated to be 2,886 MBq/human. Conclusion: FF-21101 radioimmunotherapy exhibited high antitumor affinity and antitumor efficacy in mouse xenograft models. Extrapolation of the pharmacokinetics in monkeys to humans suggests the potential for clinical application of FF-21101 for treating P-cadherin–expressing tumor.

Objectives This study investigated postpartum bone mineral density (BMD) in patients with systemic lupus erythematosus (SLE) receiving long-term glucocorticoid (GC) therapy, assessed risk factors for decreased postpartum BMD, and evaluated change of BMD after postpartum initiation or restarting of osteoporosis drugs. Methods We retrospectively examined 30 SLE patients who gave birth and 31 non-pregnant SLE patients. In the postpartum SLE patients, BMD was measured after delivery and 1 year later. Multivariate analyses were performed to assess risk factors for decreased BMD in postpartum SLE patients. Results Patient age at pregnancy was 34.5 ± 4.5 years, and SLE duration was 9.7 ± 6.0 years. The mean prednisolone dose was 9.7 ± 3.2 mg/day. Body mass index (BMI) was 21.6 ± 2.2 kg/m2, with 13 women (43%) experiencing their first delivery. Postpartum BMD was 1.080 ± 0.120 g/cm2 in the lumbar spine and 0.834 ± 0.109 g/cm2 in the total hip. Bone loss occurred in six patients (21%) in the lumbar spine and 11 patients (37%) in the total hip. Postpartum lumbar spine BMD was significantly reduced compared to that in the non-pregnant group (1.143 ± 0.120 g/cm2, p = 0.048). Multivariate analysis identified gestational age and low BMI before pregnancy as risk factors for hip bone loss. Conclusion Postpartum BMD significantly decrease in SLE patients receiving long-term GC, and low BMI before pregnancy was a risk factor for the decrease. Preconception care to prevent osteoporosis and that regularly monitors BMD after delivery are needed.

BackgroundCongenital hydrocephalus occurs with some inheritable characteristics, but the mechanisms of its development remain poorly understood. Animal models provide the opportunity to identify potential genetic causes in this condition. The Hydrocephalus-Texas (H-Tx) rat strain is one of the most studied animal models for investigating the causative genetic alterations and analyzing downstream pathogenetic mechanisms of congenital hydrocephalus.MethodsComparative genomic hybridization (CGH) array on non-hydrocephalic and hydrocephalic H-Tx rats was used to identify causative genes of hydrocephalus. Targeted gene knockout mice were generated by CRISPR/Cas9 to study the role of this gene in hydrocephalus. ResultsCGH array revealed a copy number loss in chromosome 16p16 region in hydrocephalic H-Tx rats, encompassing the Ptpn20 gene, without change in most non-hydrocephalic H-Tx rats. Ptpn20-knockout (Ptpn20-/-) mice were generated and found to develop ventriculomegaly. Furthermore, high expression of phosphorylated Na-K-Cl cotransporter 1 (pNKCC1) was identified in the choroid plexus (CP) epithelium of mice lacking Ptpn20. ConclusionsThe high level of pNKCC1 in CP epithelium may cause the overproduction of cerebrospinal fluid and contribute to the formation of hydrocephalus in Ptpn20-/- mice. Ptpn20 may be a potential therapeutic target in the treatment of hydrocephalus.

Naturally occurring fungi have been used in the traditional production of dried bonito, Katsuobushi, in Japan. In this study, we analyzed the fungal population present during Katsuobushi production. Amplicon sequence analysis of ITS1 indicated that Aspergillus spp. are predominant throughout the production process. In addition, culture-dependent analyzes identified three species Aspergillus chevalieri, Aspergillus montevidensis, and Aspergillus sydowii, based on sequencing of benA, caM, and rpb2 genes. A. chevalieri isolates were classified into teleomorphic and anamorphic strains based on morphological analysis. A. chevarieri was the dominant species throughout the production process, whereas A. montevidensis increased and A. sydowii decreased in abundance during Katsuobushi production. Our study will enhance the understanding of fungal species involved in traditional Katsuobushi production.

Hematopoietic stem cells (HSCs) and HSC-independent progenitors are generated from hemogenic endothelium. Yokomizo et al. show that Hlf expression distinguishes nascent HSCs from HSC-independent progenitors. HSC specification, regulated by the Evi-1/Hlf axis, is activated only within Hlf+ nascent hematopoietic clusters., Before the emergence of hematopoietic stem cells (HSCs), lineage-restricted progenitors, such as erythro-myeloid progenitors (EMPs), are detected in the embryo or in pluripotent stem cell cultures in vitro. Although both HSCs and EMPs are derived from hemogenic endothelium, it remains unclear how and when these two developmental programs are segregated during ontogeny. Here, we show that hepatic leukemia factor (Hlf) expression specifically marks a developmental continuum between HSC precursors and HSCs. Using the Hlf-tdTomato reporter mouse, we found that Hlf is expressed in intra-aortic hematopoietic clusters and fetal liver HSCs. In contrast, EMPs and yolk sac hematopoietic clusters before embryonic day 9.5 do not express Hlf. HSC specification, regulated by the Evi-1/Hlf axis, is activated only within Hlf+ nascent hematopoietic clusters. These results strongly suggest that HSCs and EMPs are generated from distinct cohorts of hemogenic endothelium. Selective induction of the Hlf+ lineage pathway may lead to the in vitro generation of HSCs from pluripotent stem cells.

Similar to other modern Western nations, Japan experienced a state of total war during the twentieth century, expanding state intervention in the economy, scientific community, and the bodies of th...

Background. This study aimed to clarify predictors of preterm birth in pregnancy of women with systemic lupus erythematosus (SLE). We investigated the predictors of preterm birth before pregnancy from the perspective of the importance of preconception care.Methods. We analysed foetal outcomes of 108 pregnancies in 74 SLE patients. We compared pre-pregnancy clinical characteristics and disease activity in these women between the preterm birth and full-term birth groups to select predictive factors for preterm birth before pregnancy.Results. Eighty-three of 108 pregnancies resulted in live births, of which 27 (25.0%) were preterm births. Pre-pregnancy serum complement 3 (C3) level was significantly lower in the preterm birth group (77.0 mg/dl) than the full-term birth group (87.5 mg/dl) (P = 0.029). Multivariate analysis identified history of lupus nephritis (odds ratio: 5.734, 95% CI: 1.568-21.010, P = 0.008) and low C3 level (

Summary Although pluripotent stem cells can generate various types of differentiated cells, it is unclear why lineage-committed stem/progenitor cells derived from pluripotent stem cells are decelerated and why the differentiation-resistant propensity of embryonic stem cell (ESC)/induced pluripotent stem cell (iPSC)-derived cells is predominant compared with the in vivo equivalents derived from embryonic/adult tissues. In this study, we demonstrated that iPSCs reprogrammed and maintained with three chemical inhibitors of the fibroblast growth factor 4-mitogen-activated protein kinase cascade and GSK3β (3i) could be differentiated into all three germ layers more efficiently than the iPSCs reprogrammed without the 3i chemicals, even though they were maintained with 3i chemicals once they were reprogrammed. Although the iPSCs reprogrammed with 3i had increased numbers of Zscan4-positive cells, the Zscan4-positive cells among iPSCs that were reprogrammed without 3i did not have an accelerated differentiation ability. These observations suggest that 3i exposure during the reprogramming period determines the accelerated differentiation/maturation potentials of iPSCs that are stably maintained at the distinct state., Graphical Abstract, Highlights • iPSCs reprogrammed and maintained with 3i have accelerated differentiation potential • iPSC colonies reprogrammed with 3i contain increased number of Zscan4 (+) cells, Mouse iPSCs reprogrammed and maintained with three chemical inhibitors of the FGF4-MAPK cascade and GSK3β (3i; PD184352, CHIR99021, and SU5402) could be differentiated into all three germ layers efficiently and contain increased numbers of Zscan4, a 2-cell stage marker, positive cells.

Citrate exporter CexA plays a key role in the production of citric acid in fungi; however, its role in intracellular metabolism has remained unclear. In this study, we comparably characterized homologous cexA genes in the white koji fungus Aspergillus luchuensis mut. kawachii and the yellow koji fungus Aspergillus oryzae, which exhibit high and low abilities, respectively, to produce citric acid. Disruption of cexA caused a significant decline of both extracellular and intracellular citric acid accumulation in Aspergillus kawachii, while overexpression of the A. kawachii cexA gene (AkcexA) into A. oryzae significantly enhanced both extracellular and intracellular citric acid accumulation in A. oryzae to a level comparable to that of A. kawachii. In addition, overexpression of two intrinsic cexA homologs (AocexA and AocexB) in A. oryzae also enhanced its extracellular and intracellular citric acid accumulation. Comprehensive analysis of intracellular metabolites from an AkcexA-overexpressing strain of A. oryzae compared with its control strain identified metabolic changes associated with intracellular citric acid accumulation via the glycolytic pathway, pentose phosphate pathway, and tricarboxylic acid cycle. Our results indicate that citric acid export enhances not only extracellular citric acid accumulation but also intracellular metabolic fluxes to generate citric acid.

Aim: The Japan Diet nutritional education program effects on serum fatty acid compositions for prevention of atherosclerotic cardiovascular disease in middle-aged men brought up in the westernized dietary environment of modern Japan were examined. Methods: Thirty-three men, 30–49 years of age, attended a nutrition education class and were recommended to consume Japan Diet volumes (more fish, soybeans and soy products, vegetables, seaweed, konjak, mushrooms, and unrefined cereals and less animal fat, meat and poultry with fat, sweets, desserts and snacks, and alcoholic drinks) for 6 weeks. Three-day weighted dietary records were kept, and fatty acid intakes were calculated. Serum phospholipid fatty acid compositions were examined. Results: During the 6 weeks, fish, soy, and seaweed and/or mushrooms and/or konjak were consumed 1.0, 1.1, and 1.0 times daily on average, whereas daily fatty meat and poultry and sweet consumptions were 0.3 and 0.3, respectively. These changes were attributed to increased intake of n-3 polyunsaturated fatty acids (PUFAs) such as C20:5(n-3), C22:6(n-3), C18:4(n-3), and C20:4(n-3) and decreased intakes of all saturated fatty acids and unsaturated fatty acids such as C18:1 and C18:2(n-6). As to the phospholipid fatty acid composition, C18:0 decreased, whereas C15:0, C17:0, and C20:0 increased. Marked increases in C20:5(n-3) and C22:6(n-3) raised total n-3 PUFA from 10.30% to 13.20% along with n-6 PUFA decreasing from 33.92% to 31.16%. Despite decreases in C20:4(n-6) and C20:3(n-6), the C20:4(n-6)/C20:3(n-6) ratio used as an estimate of delta-5 desaturase activities increased and correlated positively with fish intake at completion of the intervention. Conclusions: The Japan Diet is effective for changing the fatty acids to an anti-atherosclerotic profile. The clinical trial registration number: UMIN000020639.

Colon vaginoplasty (CV) is often performed for cloacal malformation (CM). We used mice to study the vitality of spermatozoa after contact with colonic mucosa as a factor contributing to infertility. Spermatozoa isolated from the epididymides of C57BL/6J male mice (n = 23) were syringed directly into the vaginas (Vag-group) or colons (Colo-group) of female mice (n = 45). Vitality was determined by assessing motility using computer-assisted sperm analysis, viability by staining with SYBR-14 and propidium iodide, and fertility by in vitro fertilization, prior to deposition, and at 5, 10, 30, and 60 min after deposition. Motility was significantly decreased in Colo only at 10 and 60 min. Viability of Colo spermatozoa was significant at all assessment times, except at 10 min. Normal fertilization was observed with all Vag spermatozoa, but with Colo, there was arrest of embryo development with spermatozoa collected at 5 and 10 min, and no fertilization with spermatozoa collected at 30 and 60 min. The vitality of spermatozoa is compromised by contact with colonic mucosa which could contribute to infertility in CM after CV, because their ovaries and fallopian tubes are considered to be normal.

We explore the impact of temporary transfer of managers on the transaction costs among unbundled business units and the important factors to consider while initiating transfers, through a case study of five Japanese railway corporations organized under a holding company structure. Our results suggest that there are very few conflicts and, thus, low transaction costs in the system, as the transferring managers engage in informal communications to align the related business units before the conflicts are actualised. However, there are cases in which other management characteristics such as human resource development programmes and organisational structures, can substitute for managerial transfers.

This paper investigates the effect of demand response on households’ electricity consumption under the existence of the reference price effect. The reference price effect is observed in peak and shoulder hours. Consistent with reference price theory predictions, our results show that the reduction of electricity consumption is greater in the case where the current price is higher than the previous price than in the case where the current price is lower than the previous price.

By using empirical methodology, this paper investigates to what extent the public interest and the private interest theories, respectively, explain the actual regulatory process. Our estimation findings are as follows: First, on average (whole industry basis), the explanation power of the public interest theory is about 46– 78%, while that of the private interest theory is about 22–54%. Second, the explanatory power of the public interest theory is higher in non-public utility industries, while that of the private interest theory is higher in public utility industries. This suggests that regulations on non-public utility industry are constructed largely with social welfare in mind, as assumed in conventional neoclassical welfare economics, but that those in the public utility industry tend to be captured largely by private groups, as assumed in private interest theory.

The putative methyltransferase LaeA is a global regulator of metabolic and development processes in filamentous fungi. We characterized the homologous laeA genes of the white koji fungus Aspergillus luchuensis mut. kawachii (A. kawachii) to determine their role in citric acid hyperproduction. The ΔlaeA strain exhibited a significant reduction in citric acid production. Cap-analysis gene expression (CAGE) revealed that laeA is required for the gene expression of a putative citrate exporter encoding cexA, which is critical for citric acid production. Deficient citric acid production by the ΔlaeA strain was rescued by the overexpression of cexA to a level comparable with that of the cexA-overexpressing ΔcexA strain. In addition, chromatin immunoprecipitation coupled with quantitative PCR (ChIP-qPCR) analysis indicated that LaeA regulates the expression of cexA via methylation levels of the histones H3K4 and H3K9. These results indicate that LaeA is involved in citric acid production through epigenetic regulation of cexA in A. kawachii. IMPORTANCEA. kawachii has been traditionally used for production of the distilled spirit shochu in Japan. Citric acid produced by A. kawachii plays an important role in preventing microbial contamination during the shochu fermentation process. This study characterized homologous laeA genes; using CAGE, complementation test, and ChIP-qPCR, it was found that laeA is required for citric acid production through the regulation of cexA in A. kawachii. The epigenetic regulation of citric acid production elucidated in this study will be useful for controlling the fermentation processes of shochu.

SUMMARYInterleukin (IL)-11 is a member of the IL-6 family of cytokines and involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generated Il11 reporter mice. IL-11+ cells appeared in the colon of three murine tumor models, and a murine acute colitis model. Il11ra1 or Il11 deletion attenuated the development of colitis-associated colorectal cancer. IL-11+ cells expressed fibroblast markers, and genes associated with cell proliferation and tissue repair. IL-11 induced STAT3 phosphorylation in colonic fibroblasts, suggesting the activation of IL-11+ fibroblasts. Analysis using the human cancer database revealed that genes enriched in IL-11+ fibroblasts were elevated in human colorectal cancer, and correlated with reduced disease-free survival. Together, our results suggested that tumor cells induced IL-11+ fibroblasts, and that a feed-forward loop between IL-11 and IL-11+ fibroblasts might contribute to tumor development.

The safety and efficacy ofThe favorable safety profile and initial antitumor activity observed for

Objectives We explored rheumatoid arthritis (RA) disease activity before, during, and after pregnancy in patients treated with tight control and investigated the association between disease activity in the postpartum period and those before and during pregnancy. Methods We retrospectively reviewed disease activity and medications of 27 patients before pregnancy, at every trimester, and in the postpartum period. Results Prednisolone was administered to 33% of patients with a median dose of 0 (0-2.5) mg/day and biologic agents was 78% in the third trimester. The median remission rates during all periods were the Disease Activity Score-28-C-reactive Protein assessed with three variables (DAS28-CRP-3) 85%, Simplified Disease Activity Index (SDAI) 55%, and Clinical Disease Activity Index (CDAI) 54%. Although SDAI and CDAI decreased significantly from before pregnancy to the first trimester and increased from the third trimester to the postpartum period, DAS28-CRP-3 did not change during all periods. Although SDAI and CDAI before and during pregnancy were significantly correlated with those in the postpartum period, DAS28-CRP-3 was not. Conclusions Tight control before pregnancy suppressed RA disease activity during pregnancy and in the postpartum period. SDAI/CDAI before and during pregnancy were predictive for disease activity in the postpartum period.

This chapter examines the effect of the division of labor from a Bayesian viewpoint. While organizational reforms are crucial for cost reduction in the Japanese water supply industry, the effect of labor division in intra-organizational units on total costs has, to the best of our knowledge, not been examined empirically. Fortunately, a one-time survey of 79 Japanese water suppliers conducted in 2010 enables us to examine the effect. To examine this problem, a cost stochastic frontier model with endogenous regressors is considered in a cross-sectional setting, because the cost and the division of labor are regarded as simultaneously determined factors. From the empirical analysis, we obtain the following results: (1) total costs rise when the level of labor division becomes high; (2) ignoring the endogeneity leads to the underestimation of the impact of labor division on total costs; and (3) the estimation bias on inefficiency can be mitigated for relatively efficient organizations by including the labor division variable in the model, while the bias for relatively inefficient organizations needs to be controlled by considering its endogeneity. In summary, our results indicate that integration of internal sections is better than specialization in terms of costs for Japanese water supply organizations.

The putative methyltransferase LaeA is a global regulator of metabolic and development processes in filamentous fungi. We characterized the homologouslaeAgenes of the white koji fungusAspergillus luchuensismut.kawachii(A. kawachii) to determine their role in the hyperproduction of citric acid. The ΔlaeAstrain exhibited a significant reduction in citric acid productivity. Cap-analysis gene expression (CAGE) revealed thatlaeAis required for the gene expression of a putative citrate exporter encodingcexA, which is critical for citric acid production. The deficit in the productivity of citric acid by the ΔlaeAstrain was rescued by the overexpression ofcexAto a level comparable with that of thecexA-overexpressing ΔcexAstrain. In addition, chromatin immunoprecipitation coupled with quantitative PCR (ChIP-qPCR) analysis indicated that LaeA regulates the expression ofcexAvia methylation levels of the histones H3K4 and H3K9. These results indicate that LaeA is involved in citric acid production through epigenetic regulation ofcexAinA. kawachii.IMPORTANCEA. kawachiihas been traditionally used for production of the distilled spirit shochu in Japan. Citric acid produced byA. kawachiiplays an important role in preventing microbial contamination during the shochu fermentation process. This study characterized homologouslaeAgenes; using CAGE, complementation test, and ChIP-qPCR, it was found thatlaeAis required for citric acid production though regulation ofcexAinA. kawachii. The epigenetic regulation of citrate production elucidated in this study will be useful for controlling the fermentation processes of shochu.