The relationship between observation interval and prognosis in pancreatic cancer concomitant with intraductal papillary mucinous neoplasia.

BACKGROUND: Intraductal papillary mucinous neoplasia (IPMN) is a risk factor for pancreatic cancer (PC). PC concomitant with IPMN shows rapid progression similar to de novo PC, therefore, the appropriate observation interval (OI) is not yet clear. PATIENTS AND METHOD: This was a multicenter retrospective observational study, and patients with PC concomitant with IPMN were analyzed. OI was defined as the interval between the date of imaging at PC diagnosis and just before the diagnosis. Clinical factors of PC and prognosis were assessed according to OI. RESULTS: From January 2010 to December 2018, 73 patients from 11 institutions were enrolled. The images performed just before PC diagnosis were contrast-enhanced CT/magnetic resonance imaging/endoscopic ultrasonography in 44/27/2 patients, respectively. The median cyst size was 14.0 mm, and the median main pancreatic duct diameter was 3.0 mm. The median OI was 6.8 months. In OI 6 months or less (OI ≤ 6 M)/OI more than 6 months (OI > 6 M), the mean tumor size, the frequencies of metastatic PC, resectable PC and early-stage PC were 20.1/21.5 mm (P = 0.91), 12.1 %/32.5 % (P = 0.05), 72.7 %/52.5 % (P = 0.09) and 27.3 %/25.0 % (P = 1.00), respectively. The median overall survival was 35.5 months in OI ≤ 6 M and 16.2 months in OI > 6 M (P = 0.05). CONCLUSION: In OI 6 months or less, the rate of resectable PC was high, however, the rate of early PC was almost the same as that of OI more than 6 months. Approximately 10 % of cases found in the advanced stage with metastasis even if OI 6 months or less.

[An anatomical case of obstructive jaundice due to the rapid enlargement of hepatic peribiliary cysts in end-stage alcoholic liver cirrhosis].

A man in his 60s had end-stage alcoholic cirrhosis. About six months before his death, hepatic peribiliary cysts (HPBC) rapidly increased, and he developed jaundice and liver failure. The pathological autopsy performed after his death revealed that his intrahepatic bile duct was pressured due to multiple cysts caused by HPBC, which resulted in liver failure. Some cases of HPBC have been associated with alcoholic cirrhosis;however, no other cases of increased HPBC in a short period of time have been reported. Although identifying the cause of increased HPBC in a short time is difficult in this case, it may be have been caused by continuous alcohol drinking after the onset of HPBC. Most patients with HPBC have liver cirrhosis and obstructive jaundice that may promote liver failure as in this case. Therefore, patients with HPBC should not only be instructed for abstinence but also promptly consider effective treatments in the event of obstructive jaundice to prevent liver dysfunction.

Exploring the Evolvability of Plant Specialized Metabolism: Uniqueness Out Of Uniformity and Uniqueness Behind Uniformity.

The huge structural diversity exhibited by plant specialized metabolites has primarily been considered to result from the catalytic specificity of their biosynthetic enzymes. Accordingly, enzyme gene multiplication and functional differentiation through spontaneous mutations have been established as the molecular mechanisms that drive metabolic evolution. Nevertheless, how plants have assembled and maintained such metabolic enzyme genes and the typical clusters that are observed in plant genomes, as well as why identical specialized metabolites often exist in phylogenetically remote lineages, is currently only poorly explained by a concept known as convergent evolution. Here, we compile recent knowledge on the co-presence of metabolic modules that are common in the plant kingdom but have evolved under specific historical and contextual constraints defined by the physicochemical properties of each plant specialized metabolite and the genetic presets of the biosynthetic genes. Furthermore, we discuss a common manner to generate uncommon metabolites (uniqueness out of uniformity) and an uncommon manner to generate common metabolites (uniqueness behind uniformity). This review describes the emerging aspects of the evolvability of plant specialized metabolism that underlie the vast structural diversity of plant specialized metabolites in nature.

Effect of the Sway Bed on Autonomic Response, Emotional Responses, and Muscle Hardness in Children with Severe Motor and Intellectual Disabilities: A Pilot Study.

This cross-sectional study aimed to examine the effects of being swayed in a sway bed on children with severe motor and intellectual difficulties by examining potential differences in their autonomic and emotional responses, as well as their muscle hardness, and by comparing them with "a control condition without any stimulation". Children's heart rate variability, rectus femoris hardness, and passive hip abduction range of motion (ROM) were measured in two experimental conditions, differentiated by the presence of a 5-min sway stimulus. In each condition, the children's faces were video-recorded and retrospectively rated subjectively by their homeroom teacher concerning the visible expression of eight emotions. Significant intervention-related effects were observed on the heart rate variability and the "Relax" item of the emotional response indicators but not on muscle hardness or hip ROM. Our findings provide evidence that using a motorized sway bed can promote relaxation in children with severe motor and intellectual disabilities by influencing their autonomic response.

Bacterial Volatile Isovaleric Acid Triggers Growth Alteration of Arabidopsis Seedlings.

Bacterial volatile organic compounds (BVOCs) released from selected soil microbes have been shown to trigger the alteration of plant growth. However, the substances responsible for such bioactivity and the mechanism of how plants interpret and respond to BVOCs remain largely elusive. Here, we established a model bioassay system using Arabidopsis and Bacillus spp. and found that Bacillus BVOCs interfere with the normal growth of Arabidopsis seedlings. Moreover, through a bioassay-guided purification, we identified isovaleric acid (IVA) as a volatile compound that exhibits inhibitory growth activity towards Arabidopsis seedlings. Our data provide novel molecular insights into how short-chain fatty acids released from soil microbes can affect plant growth through interkingdom signals.

Type IV collagen reduces MUC5AC secretion in the lungs of ovalbumin-sensitized mice.

Mucin 5AC (MUC5AC) is excessively secreted in the respiratory tract of patients with asthma. Suppressing this secretion is important for improving the air passages, which facilitates easy breathing. We have previously reported that the addition of type IV collagen, a typical extracellular matrix (ECM) protein, to the culture medium for human cell lines and primary cells reduced MUC5AC secretion. In this report, we further investigated the effect of type IV collagen on MUC5AC secretion in vivo. We employed ovalbumin (OVA)-sensitized mice to model of asthma and exposed them to type IV collagen to verify the reducing effect of MUC5AC in vivo. The amount of MUC5AC in bronchoalveolar lavage fluid was examined after nebulization of type IV collagen. Hypersecretion of MUC5AC of the OVA-sensitized mice was suppressed by type IV collagen exposure in a time- and dose-dependent manner. Furthermore, type IV collagen exposure to OVA-sensitized mice decreased integrin α2 and ß1 expression in the lungs and increased the levels of Akt and extracellular signal-regulated kinase (ERK) phosphorylation in the trachea. These results suggest that type IV collagen suppresses MUC5AC hypersecretion via modulating integrin expression and Akt/ERK phosphorylation in the respiratory tract of the OVA-sensitized mice.

Transgenic Forsythia plants expressing sesame cytochrome P450 produce beneficial lignans.

Lignans are widely distributed plant secondary metabolites that have received attention for their benefits to human health. Sesamin is a furofran lignan that is conventionally extracted from Sesamum seeds and shows anti-oxidant and anti-inflammatory activities in the human liver. Sesamin is biosynthesized by the Sesamum-specific enzyme CYP81Q1, and the natural sources of sesamin are annual plants that are at risk from climate change. In contrast, Forsythia species are widely distributed perennial woody plants that highly accumulate the precursor lignan pinoresinol. To sustainably supply sesamin, we developed a transformation method for Forsythia leaf explants and generated transgenic Forsythia plants that heterologously expressed the CYP81Q1 gene. High-performance liquid chromatography (HPLC) and LC-mass spectrometry analyses detected sesamin and its intermediate piperitol in the leaves of two independent transgenic lines of F. intermedia and F. koreana. We also detected the accumulation of sesamin and piperitol in their vegetatively propagated descendants, demonstrating the stable and efficient production of these lignans. These results indicate that CYP81Q1-transgenic Forsythia plants are promising prototypes to produce diverse lignans and provide an important strategy for the cost-effective and scalable production of lignans.

Relationship between Sensitivity Tendency and Psychological Stress Reactivity in Healthy Students.

This study examined the relationship between sensory processing sensitivity and psychological stress reactivity in 69 healthy Japanese university students. The Japanese version of the Highly Sensitive Person Scale and the Japanese version of the Adolescent/Adult Sensory Profile were used for subjective assessment. The Galvanic skin response was measured as an objective measure of stress responses while the participants were completing the Stroop task. The Wilcoxon signed-rank test, the Spearman rank correlation coefficient, and the Mann−Whitney U test were conducted for data analysis. The results demonstrated that there was no significant correlation between the Japanese version of the Highly Sensitive Person Scale and Galvanic skin response. However, there was a marginal trend toward significance between low registration in the Japanese version of the Adolescent/Adult Sensory Profile and Galvanic skin response (rs = 0.231, p < 0.10; rs = 0.219, p < 0.10), suggesting that self-rated sensitivity was not necessarily associated with objective measures. These results indicate that sensory processing sensitivity analyses require the consideration of the traits and characteristics of the participants and multifaceted evaluations using a sensitivity assessment scale other than the Japanese version of the Highly Sensitive Person Scale.

Integrin ß1 subunit regulates cellular and secreted MUC5AC and MUC5B production in NCI-H292 human lung epithelial cells.

The surface of the human respiratory tract is covered with a mucus layer containing mucin 5AC (MUC5AC) and mucin 5B (MUC5B) as the main components. This layer contributes to biological defense by eliminating irritants, but excessive MUC5AC secretion by the airway epithelial cells exacerbates asthma. Therefore, regulating mucin production is important for asthma treatment. In this study, the effects of integrin ß1 subunit on MUC5AC and MUC5B production were examined in NCI-H292 human lung cancer epithelial cells. When integrin ß1 was overexpressed, cellular and secreted MUC5AC levels were decreased, whereas cellular MUC5B production was increased. Conversely, integrin ß1 depletion using siRNA increased cellular and secreted MUC5AC production, but decreased cellular MUC5B production. Further, the activity of extracellular signal-regulated kinase (ERK), which promotes MUC5AC production, was decreased by integrin ß1 overexpression and increased by its depletion. These results suggest that integrin ß1 suppresses MUC5AC production and promotes MUC5B production by downregulating ERK.

Vascular endothelial growth factor-A is an Immunohistochemical biomarker for the efficacy of bevacizumab-containing chemotherapy for duodenal and jejunal adenocarcinoma.

BACKGROUND: The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. METHODS: This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, ß-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. RESULTS: A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30-0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. CONCLUSION: Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

Muscarinic receptor M3 contributes to intestinal stem cell maintenance via EphB/ephrin-B signaling.

Acetylcholine (ACh) signaling through activation of nicotinic and muscarinic ACh receptors regulates expression of specific genes that mediate and sustain proliferation, differentiation, and homeostasis in the intestinal crypts. This signaling plays a pivotal role in the regulation of intestinal stem cell function, but the details have not been clarified. Here, we performed experiments using type 3 muscarinic acetylcholine receptor (M3) knockout mice and their intestinal organoids and report that endogenous ACh affects the size of the intestinal stem niche via M3 signaling. RNA sequencing of crypts identified up-regulation of the EphB/ephrin-B signaling pathway. Furthermore, using an MEK inhibitor (U0126), we found that mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling, which is downstream of EphB/ephrin-B signaling, is activated in M3-deficient crypts. Collectively, M3, EphB/ephrin-B, and the MAPK/ERK signaling cascade work together to maintain the homeostasis of intestinal epithelial cell growth and differentiation following modifications of the cholinergic intestinal niche.

Age-Related Changes in the Response of Finger Skin Blood Flow during a Braille Character Discrimination Task.

We hypothesized that age-related changes in sensory function might be reflected by a modulation of the blood flow response associated with tactile sensation. The aim of the present study was to clarify how the blood flow response of the fingers during concentrated finger perception is affected by aging. We measured the tactile-pressure threshold of the distal palmar pad of the index finger and skin blood flow in the finger (SBF) during Braille reading performed under blind conditions in young (n = 27) and older (n = 37) subjects. As a result, the tactile-pressure threshold was higher in older subjects (2.99 ± 0.37 log10 0.1 mg) than in young subjects (2.76 ± 0.24 log10 0.1 mg) (p < 0.01). On the other hand, the SBF response was markedly smaller in older subjects (-4.9 ± 7.0%) than in young subjects (-25.8 ± 15.4%) (p < 0.01). Moreover, the peak response arrival times to Braille reading in older and young subjects were 12.5 ± 3.1 s and 8.8 ± 3.6 s, respectively (p < 0.01). A decline in tactile sensitivity occurs with aging. Blood flow responses associated with tactile sensation are also affected by aging, as represented by a decrease in blood flow and a delay in the reaction time.

(+)-Sesamin-oxidising CYP92B14 shapes specialised lignan metabolism in sesame.

Sesamum spp. (sesame) are known to accumulate a variety of lignans in a lineage-specific manner. In cultivated sesame (Sesamum indicum), (+)-sesamin, (+)-sesamolin and (+)-sesaminol triglucoside are the three major lignans found richly in the seeds. A recent study demonstrated that SiCYP92B14 is a pivotal enzyme that allocates the substrate (+)-sesamin to two products, (+)-sesamolin and (+)-sesaminol, through multiple reaction schemes including oxidative rearrangement of α-oxy-substituted aryl groups (ORA). In contrast, it remains unclear whether (+)-sesamin in wild sesame undergoes oxidation reactions as in S. indicum and how, if at all, the ratio of the co-products is tailored at the molecular level. Here, we functionally characterised SrCYP92B14 as a SiCYP92B14 orthologue from a wild sesame, Sesamum radiatum, in which we revealed accumulation of the (+)-sesaminol derivatives (+)-sesangolin and its novel structural isomer (+)-7´-episesantalin. Intriguingly, SrCYP92B14 predominantly produced (+)-sesaminol either through ORA or direct oxidation on the aromatic ring, while a relatively low but detectable level of (+)-sesamolin was produced. Amino acid substitution analysis suggested that residues in the putative distal helix and the neighbouring heme propionate of CYP92B14 affect the ratios of its co-products. These data collectively show that the bimodal oxidation mechanism of (+)-sesamin might be widespread across Sesamum spp., and that CYP92B14 is likely to be a key enzyme in shaping the ratio of (+)-sesaminol- and (+)-sesamolin-derived lignans from the biochemical and evolutionary perspectives.

Bridge to surgery using a self-expandable metallic stent for stages II-III obstructive colorectal cancer.

BACKGROUND: Bridge to surgery (BTS) using a self-expandable metallic stent (SEMS) for the treatment of obstructive colorectal cancer improves the patient's quality of life. This study aimed to examine prognostic factors of obstructive colorectal cancer. METHODS: We analyzed stage II-III resectable colon cancer cases (Cur A) retrospectively registered between January 2005 and December 2017. Overall, 117 patients with Cur A obstructive colorectal cancer were evaluated: 67 of them underwent emergency surgery (ES Group) and 50 of them after BTS with SEMS placement (BTS group). We compared surgical results and prognoses between the two groups. RESULTS: A total of 50 patients underwent endoscopic SEMS placement, which technical success of 96% and morbidity rate of 18%. Primary anastomosis rates were 77.6% in ES and 95.7% in BTS (p <  0.001); postoperative complication, 46.3% in ES and 10.5% in BTS (p <  0.001); pathological findings of lymphatic invasion, 66.7% in ES and 100% in BTS (p <  0.001); venous invasion were 66.8% in ES and 92% in BTS (p = 0.04); and recurrence of 25.4% in ES and 39.1% in BTS. The 3-year overall survival was significantly different between two groups (ES, 86.8%:BTS, 58.8%), BTS is worse than ES (log-rank test; p <  0.001). Venous invasion independently predicted worsened recurrence-free and overall survival. CONCLUSIONS: The vascular invasiveness was correlated with tumor progression after SEMS placement, and the survival rate was lower in BTS. SEMS potentially worsens prognostic outcomes in stage II-III obstructive colorectal cancer.

Author Correction: Identification of a binding protein for sesamin and characterization of its roles in plant growth.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: Identification of a binding protein for sesamin and characterization of its roles in plant growth.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The attenuating effect of a dynamic cushion on the development of leg edema in wheelchair users with spinal cord injuries.

BACKGROUND: Prolonged wheelchair sitting is known to lead to venous stasis and results in leg edema. OBJECTIVE: To clarify how a dynamic cushion affects leg edema in people with spinal cord injuries (SCI) evoked by wheelchair sitting, we measured the changes in leg volume induced during wheelchair sitting with a dynamic air cushion or a static cushion. METHODS: Seven wheelchair users with SCI participated in this study. Leg edema during wheelchair sitting was evaluated with strain gauge plethysmography (the gauge was placed 10 cm proximally from the medial malleolus). Following a period of rest, the subjects sat on a reclining wheelchair containing a dynamic cushion for 15 min. Then, the protocol was repeated with a static cushion. The above two procedures were performed in a random order. These data were statistically compared between the two procedures. RESULTS: The change in leg volume observed during sitting on the dynamic cushion (-0.02 ± 0.21 ml/100 ml) was smaller than that observed during sitting on the static cushion (0.18 ± 0.28 ml/100 ml) (P< 0.05). CONCLUSIONS: These results suggested that the dynamic air cushion relieved leg edema induced by wheelchair sitting in individuals with SCI.

Concurrent Validity of the ABC Dementia Scale with Other Standard Scales: A New Comprehensive Instrument for Assessing Dementia in Japan.

BACKGROUND/AIMS: The ABC Dementia Scale (ABC-DS), a new tool for evaluating dementia, was developed in Japan. The ABC-DS is a comprehensive instrument that can simultaneously evaluate activities of daily living (ADLs), behavioral and psychological symptoms of dementia (BPSD), and cognitive function. The ABC-DS can be administered easily and quickly and can clarify the severity of dementia and its changes over time. While the ABC-DS has been reported to be useful in Alzheimer disease (AD)-type dementia, it has not yet been studied in other types of dementia. The purpose of this study was to reevaluate the standard validity of ABC-DS separately for various dementia types and severities. METHODS: We evaluated the ABC-DS in outpatients at 1 hospital in Nagasaki Prefecture and patients who use the facility. Domain A, corresponding to ADLs, correlated with Disability Assessment for Dementia (DAD); domain B, corresponding to BPSD, correlated with the Neuropsychiatric Inventory (NPI); domain C, corresponding to cognitive functions, correlated with Mini-Mental State Examination (MMSE); and the total score of the ABC-DS correlated with the Clinical Dementia Rating (CDR). RESULTS: 102 patients, comprising 38 males and 64 females with an average age of 80.7 ± 8.6 years, were enrolled. AD-type dementia was present in 38 cases, vascular dementia (VaD) in 23, mixed dementia in 23, dementia with Lewy bodies in 6, argyrophilic grain dementia in 9, and mild cognitive impairment in 3. A strong correlation was found between ABC-DS domain scores and their respective reference neuropsychological instruments (domain A and the DAD, domain B and the NPI, domain C and the MMSE, and total score and CDR). The correlation of each ABC-DS domain score with the corresponding standard scale depended on the type and severity of dementia, and we observed moderate or high correlations in AD and VaD patients with moderate and severe dementia. DISCUSSION: Although the ABC-DS targets AD, it can be used in VaD based on the results of this study. In other types of dementia, the results differed depending on the domain; in some conditions, the ABC-DS may not show sufficient concurrent validity with other standard scales. Also, the ABC-DS is more beneficial for moderate-to-severe dementia, as reported in previous studies. It is highly useful in clinical practice in Japan since there more than half of all patients have moderate-to-severe dementia.

Glycoside-specific glycosyltransferases catalyze regio-selective sequential glucosylations for a sesame lignan, sesaminol triglucoside.

Sesame (Sesamum indicum) seeds contain a large number of lignans, phenylpropanoid-related plant specialized metabolites. (+)-Sesamin and (+)-sesamolin are major hydrophobic lignans, whereas (+)-sesaminol primarily accumulates as a water-soluble sesaminol triglucoside (STG) with a sugar chain branched via ß1→2 and ß1→6-O-glucosidic linkages [i.e. (+)-sesaminol 2-O-ß-d-glucosyl-(1→2)-O-ß-d-glucoside-(1→6)-O-ß-d-glucoside]. We previously reported that the 2-O-glucosylation of (+)-sesaminol aglycon and ß1→6-O-glucosylation of (+)-sesaminol 2-O-ß-d-glucoside (SMG) are mediated by UDP-sugar-dependent glucosyltransferases (UGT), UGT71A9 and UGT94D1, respectively. Here we identified a distinct UGT, UGT94AG1, that specifically catalyzes the ß1→2-O-glucosylation of SMG and (+)-sesaminol 2-O-ß-d-glucosyl-(1→6)-O-ß-d-glucoside [termed SDG(ß1→6)]. UGT94AG1 was phylogenetically related to glycoside-specific glycosyltransferases (GGTs) and co-ordinately expressed with UGT71A9 and UGT94D1 in the seeds. The role of UGT94AG1 in STG biosynthesis was further confirmed by identification of a STG-deficient sesame mutant that predominantly accumulates SDG(ß1→6) due to a destructive insertion in the coding sequence of UGT94AG1. We also identified UGT94AA2 as an alternative UGT potentially involved in sugar-sugar ß1→6-O-glucosylation, in addition to UGT94D1, during STG biosynthesis. Yeast two-hybrid assays showed that UGT71A9, UGT94AG1, and UGT94AA2 were found to interact with a membrane-associated P450 enzyme, CYP81Q1 (piperitol/sesamin synthase), suggesting that these UGTs are components of a membrane-bound metabolon for STG biosynthesis. A comparison of kinetic parameters of these UGTs further suggested that the main ß-O-glucosylation sequence of STG biosynthesis is ß1→2-O-glucosylation of SMG by UGT94AG1 followed by UGT94AA2-mediated ß1→6-O-glucosylation. These findings together establish the complete biosynthetic pathway of STG and shed light on the evolvability of regio-selectivity of sequential glucosylations catalyzed by GGTs.