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A disintegrin and metalloprotease like decysin (ADAMDEC1) is a highly conserved secreted metalloprotease that belongs to a family of A disintegrin and metalloprotease (ADAMs). It is expressed exclusively in the gastrointestinal tract of animals and is known to possess a very rare zinc-binding motif (HEXXHXXGXXD) within the metalloprotease domain. The biological function of ADAMDEC1 as well as its true biological substrates remains unknown although its characteristic features reported to date suggest it plays a fundamental role in the physiology of mammals. Historically its expression, in healthy state, was believed to be limited to the monocyte-derived macrophages (MDMs) and dendritic cells within the gastrointestinal tract; however, the recent development of single-cell sequencing has provided evidence supporting its expression in a wider range of cell types. There is an increasing body of evidence linking the alterations in ADAMDEC1 expression and various inflammatory diseases and cancers. Although a detailed mechanistic role of ADAMDEC1 in these conditions remains elusive. In this review, we aim to summarise the characteristic features of this unique metalloprotease, discuss the associations with various human diseases and define the potential mechanistic role of ADAMDEC1 in mammalian physiology.

(1) Background: Malnutrition in cancer patients impacts quality of life (QoL) and performance status (PS). When oral/enteral nutrition is not possible and patients develop intestinal failure, parenteral nutrition (PN) is indicated. Our aim was to assess nutritional status, QoL, and PS in hospitalised cancer patients recently initiated on PN for intestinal failure. (2) Methods: The design was a cross-sectional observational study. The following information was captured: demographic, anthropometric, biochemical and medical information, as well as nutritional screening tool (NST), patient-generated subjective global assessment (PG-SGA), functional assessment of cancer therapy-general (FACT-G), and Karnofsky PS (KPS) data. (3) Results: Among 85 PN referrals, 30 oncology patients (56.2 years, 56.7% male) were identified. Mean weight (60.3 &plusmn, 16.6 kg) corresponded to normal body mass index values (21.0 &plusmn, 5.1 kg/m2). However, weight loss was significant in patients with gastrointestinal tumours (p &lt, 0.01). A high malnutrition risk was present in 53.3&ndash, 56.7% of patients, depending on the screening tool. Patients had impaired QoL (FACT-G: 26.6 &plusmn, 9.8) but PS indicated above average capability with independent daily activities (KPS: 60 &plusmn, 10). (4) Conclusions: Future research should assess the impact of impaired NS and QoL on clinical outcomes such as survival, with a view to encompassing nutritional and QoL assessment in the management pathway of this patient group.

(1) Background: Intestinal failure-associated liver disease (IFALD) in adults is characterized by steatosis with variable progression to fibrosis/cirrhosis. Reference standard liver biopsy is not feasible for all patients, but non-invasive serological and quantitative MRI markers for diagnosis/monitoring have not been previously validated. Here, we examine the potential of serum scores and feasibility of quantitative MRI used in non-IFALD liver diseases for the diagnosis of IFALD steatosis, (2) Methods: Clinical and biochemical parameters were used to calculate serum scores in patients on home parenteral nutrition (HPN) with/without IFALD steatosis. A sub-group underwent multiparameter quantitative MRI measurements of liver fat fraction, iron content, tissue T1, liver blood flow and small bowel motility, (3) Results: Compared to non-IFALD (n = 12), patients with IFALD steatosis (n = 8) demonstrated serum score elevations in Enhanced Liver Fibrosis (p = 0.032), Aspartate transaminase-to-Platelet Ratio Index (p &lt, 0.001), Fibrosis-4 Index (p = 0.010), Forns Index (p = 0.001), Gamma-glutamyl transferase-to-Platelet Ratio Index (p = 0.002) and Fibrosis Index (p = 0.001). Quantitative MRI scanning was feasible in all 10 sub-group patients. Median liver fat fraction was higher in IFALD steatosis patients (10.9% vs 2.1%, p = 0.032), other parameter differences were non-significant, (4) Conclusion: Serum scores used for non-IFALD liver diseases may be useful in IFALD steatosis. Multiparameter MRI is feasible in patients on HPN.

Radiotherapy has played a major role in both the curative and palliative treatment of cancer patients for decades. However, its toxic effect to the surrounding normal healthy tissue remains a major drawback. In cases of intra-abdominal and/or pelvic malignancy, healthy bowel is inevitably included in the radiation field, causing undesirable consequences that subsequently manifest as radiation-induced bowel injury, which is associated with significant morbidity and mortality. The pathophysiology of radiation-induced bowel injury is poorly understood, although we now know that it derives from a complex interplay of epithelial injury and alterations in the enteric immune, nervous, and vascular systems in genetically predisposed individuals. Furthermore, evidence supporting a pivotal role for the gut microbiota in the development of radiation-induced bowel injury has been growing. In this review, we aim to appraise our current understanding of radiation-induced bowel injury and the role of the microbiome in its pathogenesis as well as prevention and treatment. Greater understanding of the relationship between the disease mechanism of radiation-induced bowel injury and gut microbiome might shed light on potential future prevention and treatment strategies through the modification of a patient’s gut microbiome.

BACKGROUND: Development of fibrosis and subsequent stricture formation in Crohn's disease (CD) increases morbidity and rates of surgery and reduces patients' quality of life. There are currently no biomarkers of intestinal fibrosis that might allow earlier identification and better management of patients at increased risk of stricture formation. METHODS: MicroRNA profiling of serum from CD patients was used to identify microRNAs associated with stricture formation. Differential expression of miR-19a-3p and miR-19b-3p was validated by quantitative PCR in independent CD cohort of stricturing and nonstricturing patients (n = 46 and n = 62, respectively). Levels of miR-19a-3p and miR-19b-3p were also quantified in baseline serum samples, and expression compared between CD patients who subsequently developed stricture and those who did not (n = 11 and n = 44, respectively). RESULTS: Serum levels of miR-19a-3p and miR-19b-3p in the array were lower in CD patients with a stricturing phenotype than in control CD patients (P = 0.007 and 0.008, respectively). The reduction in miR-19a-3p and 19b-3p was verified in a second cohort (P = 0.002). The association of miR-19-3p with stricturing CD was independent of potential confounding clinical variables, including disease duration, disease activity, site, gender, and age. Serum analyses in patients with 4 years of follow-up support the hypothesis that reduced miR-19a-3p and miR-19b-3p predate stricture development with a trend toward significance (P = 0.077 and P = 0.060, respectively). CONCLUSIONS: These data identify miR-19-3p as a potential circulating marker of stricturing CD. Our data show that microRNAs have utility as noninvasive biomarkers of stricturing CD. Further longitudinal studies are required to determine the prognostic value of miR-19-3p at diagnosis.

Inflammation often precedes fibrosis and stricture formation in patients with Crohn's disease. Established medical therapies reduce inflammation, but there are currently no specific therapies to prevent fibrosis or treat established fibrosis. Our understanding of the pathogenic processes underpinning fibrogenesis is limited compared with our knowledge of the events initiating and propagating inflammation. There are several biomarkers for intestinal inflammation, but there are none that reflect the development of fibrosis. MicroRNAs (miRNAs) are regulators of cellular activities including inflammation and fibrosis and may serve as biomarkers of disease processes. Differential serum and mucosal miRNA expression profiles have been identified between patients with inflammatory bowel disease with active and inactive inflammatory disease. In contrast, studies in patients with fibrotic phenotypes are comparatively few, although specific miRNAs have defined roles in the development of fibrosis in other organ systems. Here, we discuss the most recent research on miRNA and fibrogenesis with a particular emphasis on Crohn's disease. We also anticipate the potential of miRNAs in fulfilling current unmet translational needs in this patient group by focusing on the role of miRNAs as modulators of fibrogenesis and on their potential value as serum biomarkers and therapeutic targets in the management of fibrosis.

Background Colorectal cancer (CRC) is a life-threatening complication of ulcerative colitis (UC), and patients are routinely screened for the development of precancerous lesions (dysplasia). However, rates of CRC development in patients with confirmed low-grade dysplasia vary widely between studies, suggesting a large degree of heterogeneity between these lesions that is not detectable macroscopically. A better understanding of the underlying molecular changes that occur in dysplasia will help to identify lesions at higher risk of malignancy. MicroRNAs (miRNAs) post-transcriptionally regulate protein expression and cell-signalling networks. Aberrant miRNA expression is a feature of sporadic CRC but much less is known about the changes that occur in dysplasia and in UC. Methods Comprehensive microRNA profiling was performed on RNA extracted from UC dysplastic lesions (n = 7) and UC controls (n = 10). The expression of miRNAs in UC post inflammatory polyps (n = 7) was also assessed. Candidate miRNAs were further validated by qPCR, and miRNA in situ hybridization. Serum levels of miRNAs were also assessed with a view to identification of non-invasive biomarkers of dysplasia. Results UC dysplasia was associated with a shift in miRNA expression profiles that was not seen in inflammatory polyps. In particular, levels of miR-200b-3p were increased in dysplasia, and this miRNA was localised to epithelial cells in dysplastic lesions and in UC cancers. No changes in miRNA levels were detected in the serum. Conclusion UC-Dysplasia is linked to altered miRNA expression in the mucosa and elevated miR-200b-3p levels.

The epithelial monolayer of the intestine is a selective barrier permitting nutrient and electrolyte absorption yet acting to protect the underlying tissue compartments and cellular components from attack and infiltration by antigens, bacteria and bacterial products present in the lumen. Disruption of this barrier has been associated with inflammatory bowel disease (IBD). The adherens junction (AJ), together with tight junctions (TJ) and desmosomes, form an apical junction complex that controls epithelial cell-to-cell adherence and barrier function as well as regulation of the actin cytoskeleton, intracellular signalling pathways and transcriptional regulation. Numerous studies and reviews highlight the responses of TJs to physiological and pathological stimuli. By comparison, the response of AJ proteins, and the subsequent consequences for barrier function, when exposed to the IBD inflammatory milieu, is less well studied. In this review, we will highlight the roles and responses of the AJ proteins in IBD and provide suggestions for future studies. We will also consider recently proposed therapeutic strategies to preserve or restore epithelial barrier functions to prevent and treat IBD.

目的 : koilocyte と判定できない空胞を有する細胞に対して HPV 感染の有無を調べ, 特徴的な空胞所見により HPV 感染を推定することが可能か検討した.方法 : 対象は ASC-US (atypical squamous cells of undetermined significance) 151 例, LSIL (low grade-squamous intraepithelial lesion) 11 例, NILM (negative for intraepithelial lesion or malignancy) 140 例の細胞浮遊液である. HPV 同定には L1-PCR 法, HPV 感染細胞の同定には in situ PCR 法を用いた. なお空胞細胞は核に対する空胞の局在性で A∼D に分類して検討した.成績 : ASC-US の 90.7%, LSIL の 100%, NILM の 21.4%で HPV 感染が認められた. in situ PCR 法で HPV を検出した結果, HPV 陽性率は空胞細胞 A : 86.1%, B : 7.8%, C : 44.4%, D : 9.3%であり, 空胞細胞 A と HPV 感染に有意な関係が認められ, 相対危険度は 29.4 であった. また NILM, ASC-US 例において空胞細胞 A は HPV の検出特異度が 90%以上であった.結論 : 氷河的空胞細胞 (glacial vacuole cell, GV) と名づけた空胞細胞 A の存在は HPV 感染を強く疑う新たな所見であり, 細胞診検査で GV を検出することによって, HPV の検出感度向上に貢献できると考えられた.

目的 : 意義不明な異型扁平上皮細胞 (atypical squamous cells of undetermined significance : ASC-US) 症例におけるハイリスク型 HPV 感染細胞の特徴を明らかにし, HPV-DNA 検査に頼らずに軽度扁平上皮内病変 (low-grade sqaumous intraepithelial lesion : LSIL) 相当の指導方針を導き出すことができないか検討した.方法 : 対象は ASC-US と判定された 151 例の細胞浮遊液である. HPV の同定には L1-PCR 法, HPV 感染細胞の同定には in situ PCR 法を用いた.成績 : ASC-US 症例のハイリスク型 HPV の感染率は 86.8%であった. HPV 感染を疑う所見 7 項目とハイリスク型 HPV 検出の感度, 特異度を調べたところ, 感度 40%以上, かつ特異度 90%以上を示したのは二核細胞 (圧排+) と核肥大細胞 (クロマチン不均等分布) であった. in situ PCR 法でハイリスク型 HPV を検出した結果, 二核細胞 (圧排+) では 100%, 核肥大細胞 (クロマチン不均等分布) では 81.9%でハイリスク型 HPV が検出され, 両者ともにハイリスク型 HPV 感染と有意な関係が認められた (p

Met-overaccumulating mutants provide a powerful genetic tool for examining both the regulation of the Met biosynthetic pathway and in vivo developmental responses of gene expression to altered Met levels. We have previously reported the identification of two Arabidopsis thaliana Met over-accumulation (mto) mutants, mto1-1 and mto2-1, that carry mutations in the genes encoding cystathionine gamma-synthase (CGS) and threonine synthase (TS), respectively. A third mutant, mto3-1, has recently been reported to carry a mutation in the gene encoding S-adenosylmethionine synthetase 3 (SAMS3). Here, we report the isolation of a new ethionine-resistant A. thaliana mutant that over-accumulates soluble Met approximately 20-fold in young rosettes. The causal mutation was determined to be a single, recessive mutation that was mapped to chromosome 3. Sequence analysis identified a single nucleotide change in the gene encoding SAMS3 that was distinct from the mto3-1 mutation and altered the amino acid sequence of the enzyme active site. This mutation was therefore referred to as mto3-2. Although Met over-accumulation in the mto3-2 mutant was similar to that in the mto2-1 mutant, CGS mRNA levels did not respond to the mto3-2 mutation and were similar to that in equivalent wild-type plants.

We have recently demonstrated that cyclic ADP-ribose (cADPR) serves as a second messenger for glucose-induced insulin secretion [ Takasawa et al. (1993a) Science 259, 370–373] and that CD38 has both ADP-ribosyl cyclase (ADRC) and cADPR hydrolase activities [ Takasawa et al. (1993b) J. Biol. Chem. 268, 26052–26054]. In this study, we determined the structure of the human CD38 gene, and showed that two mRNA forms originated by alternative splicing from the CD38 gene. The human CD38 gene consists of 8 exons that extend more than 77 kb on the human genome. Exon 1 encoded the 5′-untranslated region of the mRNA, the N-terminal end of CD38 and the putative transmembrane domain, and exon 2–8 encoded the remainder of CD38: the exon-intron organization of the human CD38 gene is similar to that of the Aplysia ADRC gene [ Nata et al. (1995) Gene 158, 213–218]. This structural conservation between human and Aplysia genes suggests that both genes may have evolved from a common ancestral gene.

Reg (regenerating gene), first isolated from a rat regenerating islet cDNA library, is expressed in regenerating islet β-cells. Recently, it has been revealed that Reg and Reg-related genes constitute a multigene family, Reg family, which consists of three subtypes (type I, II, III) based on the primary structures of the encoded proteins of the genes. In mouse, type I and type II Reg genes (i.e. RegI and RegII gene) have so far been isolated. In the present study, the complete nucleotide (nt) sequences of the cDNAs and genes encoding murine type III Reg (regenerating gene product), RegIIIα, RegIIIβ and RegIIIγ were determined. RegIIIα, RegIIIβ and RegIIIγ encode 175-, 175- and 174-amino acid (aa) proteins, respectively, with 60–70% homology. All three genes are composed of six exons and five introns spanning approx. 3 kb, and exhibit distinctive structural features unique for members of the Reg gene family. All the mouse Reg genes, RegIIIα, RegIIIβ, RegIIIγ, RegI and RegII, are assigned to the adjacent site of chromosome 6C by fluorescence in situ hybridization (FISH). RegIIIα, RegIIIβ and RegIIIγ were expressed weakly in pancreas, strongly in intestinal tract, but not in hyperplastic islets, whereas both RegI and RegII were expressed in hyperplastic islets. These results suggest that genes of the mouse Reg family are derived from a common ancestor gene by several gene duplications, and have obtained divergency in expression and function in the process of genetic evolution.

Object: In the present study, we compared the positive cytodiagnostic test rates with discrepancies using self-collection devices for cervical cancer screening. We made this survey to examine whether or not our selfsmear preparation method using the Kato self-collection device contributed to an improved rate of detecting atypical cells compared with existing recommended preparation methods. Methods: Specimens were collected at 14 facilities handling self-collection methods, and samples were collected by a physician in 2 facilities. The chisquared test was performed using the SPSS ver. 20 statistical software to determine the relationships between the positive cytodiagnostic rate, specimen preparation methods, and self-collection devices. Results: Collecting cells using the Kato self-collection device and preparing liquid-based specimens, we obtained a significantly higher rate of positive cytodiagnosis and our results were equal to those obtained with the direct method. Conclusions: Taking into consideration increased needs for screening using the self-collection method in future, with even more improved test accuracy, a screening test that is acceptable to society needs to be established.

The incidence of pulmonary thromboembolism (PTE) is lower in Japanese than in Caucasians. The basis for the different incidence has not been clarified. A poor anticoagulant response to activated protein C based on a single point mutation of the factor V gene (Arg506Gln) was found to be a pathogenetic factor for venous thrombosis and PTE in North America and Europe. We investigated whether the Arg506Gln mutation of factor V is responsible for the occurrence of PTE among Japanese. We analyzed genomic DNA prepared from fresh peripheral blood of 25 patients with PTE of unknown etiology (12 of acute type and 13 of chronic type) and that of 110 controls without respiratory or circulatory disorders. To detect the Arg506Gln mutation, 267 bp DNA fragments of the factor V gene including the Arg506Gln region were amplified by PCR, digested by MnlI and electrophoresed. After digestion of PCR products with MnlI, DNA fragments of 163 bp length, but not DNA fragments of 200 bp length, were identified in all samples, indicating the absence of the Arg506Gln mutation in the patients with PTE and control subjects. These results suggest that the Arg506Gln mutation is absent or very rare and not an important pathogenetic factor for PTE in Japanese.