Anti-integrin αvß6 autoantibodies are a potential biomarker for ulcerative colitis-like immune checkpoint inhibitor-induced colitis.

BACKGROUND: No specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvß6 autoantibodies in >90% of patients with ulcerative colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis. METHODS: Serum anti-integrin αvß6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvß6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients. RESULTS: Anti-integrin αvß6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvß6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvß6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvß6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvß6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.

Single Nucleotide Polymorphisms of the MEFV Gene E148Q Are Highly Associated With Disease Phenotype in Crohn's Disease.

BACKGROUND: Single nucleotide polymorphisms (SNPs) of the MEFV gene may modify inflammatory bowel disease (IBD) activity. The prevalence of MEFV gene SNPs in IBD patients and their involvement in IBD pathophysiology remains unclear. METHODS: We analyzed 12 MEFV gene SNPs in peripheral leukocytes of Japanese IBD patients (Crohn's disease [CD]: 69 patients, ulcerative colitis: 32 patients) by polymerase chain reaction using next-generation DNA sequencing and evaluated their prevalence and association with the disease characteristics. Inflammasome activity and mature interleukin (IL)-1ß and IL-18 production were evaluated in peripheral blood mononuclear cells obtained from CD patients stimulated with lipopolysaccharides and adenosine triphosphate, and compared between those with and without the E148Q SNP. COL1A1 and HSP47 gene expression was analyzed in CCD-18Co cells costimulated with IL-1ß and other inflammatory cytokines. RESULTS: The prevalence of MEFV gene SNPs in IBD patients was similar to that in the human gene database. E148Q was the most common SNP. Compared with CD patients without E148Q, those with E148Q had a significantly greater frequency of the stricture phenotype, and their peripheral blood mononuclear cells exhibited significantly higher IL-1ß and IL-18 levels and higher caspase-1 activity. IL-1ß and IL-17A synergistically increased COL1A1 and HSP47 gene expression. CONCLUSIONS: MEFV gene SNPs, including E148Q, modify the behavior of CD. IL-1ß and IL-18 are produced through enhanced caspase-1 activity in monocytes of CD patients with E148Q. IL-1ß promotes gene expression of fibrosis-related genes by cooperating with IL-17A in myofibroblasts. Therefore, E148Q might be a disease-modifying gene associated with the fibrostenosis phenotype in CD patients.

MEFV gene single nucleotide polymorphisms, including E148Q, modify the behavior of Crohn's disease to form stenosis. Interleukin-1ß is produced through enhanced caspase-1 activity in monocytes of Crohn's disease patients with E148Q, and promotes gene expression of fibrosis-related genes by cooperating with interleukin-17A in myofibroblasts.

Trajectory analyses to identify persistently low responders to COVID-19 vaccination in patients with inflammatory bowel disease: a prospective multicentre controlled study, J-COMBAT.

BACKGROUND: The degree of immune response to COVID-19 vaccination in inflammatory bowel disease (IBD) patients based on actual changes in anti-SARS-CoV-2 antibody titres over time is unknown. METHODS: Data were prospectively acquired at four predetermined time points before and after two vaccine doses in a multicentre observational controlled study. The primary outcome was humoral immune response and vaccination safety in IBD patients. We performed trajectory analysis to identify the degree of immune response and associated factors in IBD patients compared with controls. RESULTS: Overall, 645 IBD patients and 199 control participants were analysed. At 3 months after the second vaccination, the seronegative proportions were 20.3% (combination of anti-tumour necrosis factor [TNF]α and thiopurine) and 70.0% (triple combination including steroids), despite that 80.0% receiving the triple combination therapy were seropositive at 4 weeks after the second vaccination. Trajectory analyses indicated three degrees of change in immune response over time in IBD patients: high (57.7%), medium (35.6%), and persistently low (6.7%). In the control group, there was only one degree, which corresponded with IBD high responders. Older age, combined anti-TNFα and thiopurine (odds ratio [OR], 37.68; 95% confidence interval [CI], 5.64-251.54), steroids (OR, 21.47; 95%CI, 5.47-84.26), and tofacitinib (OR, 10.66; 95%CI, 1.49-76.31) were factors associated with persistently low response. Allergy history (OR, 0.17; 95%CI, 0.04-0.68) was a negatively associated factor. Adverse reactions after the second vaccination were significantly fewer in IBD than controls (31.0% vs 59.8%; p < 0.001). CONCLUSIONS: Most IBD patients showed a sufficient immune response to COVID-19 vaccination regardless of clinical factors. Assessment of changes over time is essential to optimize COVID-19 vaccination, especially in persistently low responders.

PECT1, a rate-limiting enzyme in phosphatidylethanolamine biosynthesis, is involved in the regulation of stomatal movement in Arabidopsis.

An Arabidopsis mutant displaying impaired stomatal responses to CO2 , cdi4, was isolated by a leaf thermal imaging screening. The mutated gene PECT1 encodes CTP:phosphorylethanolamine cytidylyltransferase. The cdi4 exhibited a decrease in phosphatidylethanolamine levels and a defect in light-induced stomatal opening as well as low-CO2 -induced stomatal opening. We created RNAi lines in which PECT1 was specifically repressed in guard cells. These lines are impaired in their stomatal responses to low-CO2 concentrations or light. Fungal toxin fusicoccin (FC) promotes stomatal opening by activating plasma membrane H+ -ATPases in guard cells via phosphorylation. Arabidopsis H+ -ATPase1 (AHA1) has been reported to be highly expressed in guard cells, and its activation by FC induces stomatal opening. The cdi4 and PECT1 RNAi lines displayed a reduced stomatal opening response to FC. However, similar to in the wild-type, cdi4 maintained normal levels of phosphorylation and activation of the stomatal H+ -ATPases after FC treatment. Furthermore, the cdi4 displayed normal localization of GFP-AHA1 fusion protein and normal levels of AHA1 transcripts. Based on these results, we discuss how PECT1 could regulate CO2 - and light-induced stomatal movements in guard cells in a manner that is independent and downstream of the activation of H+ -ATPases. [Correction added on 15 May 2023, after first online publication: The third sentence is revised in this version.].

Visual discrimination of optical material properties: A large-scale study.

Complex visual processing involved in perceiving the object materials can be better elucidated by taking a variety of research approaches. Sharing stimulus and response data is an effective strategy to make the results of different studies directly comparable and can assist researchers with different backgrounds to jump into the field. Here, we constructed a database containing several sets of material images annotated with visual discrimination performance. We created the material images using physically based computer graphics techniques and conducted psychophysical experiments with them in both laboratory and crowdsourcing settings. The observer's task was to discriminate materials on one of six dimensions (gloss contrast, gloss distinctness of image, translucent vs. opaque, metal vs. plastic, metal vs. glass, and glossy vs. painted). The illumination consistency and object geometry were also varied. We used a nonverbal procedure (an oddity task) applicable for diverse use cases, such as cross-cultural, cross-species, clinical, or developmental studies. Results showed that the material discrimination depended on the illuminations and geometries and that the ability to discriminate the spatial consistency of specular highlights in glossiness perception showed larger individual differences than in other tasks. In addition, analysis of visual features showed that the parameters of higher order color texture statistics can partially, but not completely, explain task performance. The results obtained through crowdsourcing were highly correlated with those obtained in the laboratory, suggesting that our database can be used even when the experimental conditions are not strictly controlled in the laboratory. Several projects using our dataset are underway.

A rare case of intestinal lymphangiectasia induced by pazopanib.

A 62-year-old man underwent left radical nephrectomy for left renal cell carcinoma at our hospital in 1999. At the age of 79 years, he was diagnosed with intra-abdominal disseminations, lung metastases, pancreas metastases, and bilateral femoral muscle metastases during a routine follow-up computed tomography scan. The patient began treatment with pazopanib. Four years later, at the age of 83 years, he developed fever, abdominal pain, and general malaise. Blood samples showed liver dysfunction, hypoalbuminemia, and anemia. Contrast-enhanced computed tomography showed thickening of the small bowel wall with marked edema of the submucosa from the third part of the duodenum to the jejunum, suggesting intestinal lymphangiectasia. The diagnosis of intestinal lymphangiectasia was confirmed by small bowel endoscopy and histological examination. The patient's general condition improved after discontinuation of pazopanib without the need for any active therapeutic interventions. The possibility of intestinal lymphangiectasia should be considered in patients with hypoalbuminemia and general malaise during treatment with multikinase inhibitors.

Interactive Video Completion.

We propose an interactive video completion method aiming for practical use in a digital production workplace. The results of earlier automatic solutions often require a considerable amount of manual modifications to make them usable in practice. To reduce such a laborious task, our method offers an efficient editing tool. Our iterative algorithm estimates the flow fields and colors in space-time holes in the video. As in earlier approaches, our algorithm uses an $L^1$L1 data term to estimate flow fields. However, we employ a novel $L^2$L2 data term to estimate temporally coherent color transitions. Our graphics processing unit implementation enables the user to interactively complete a video by drawing holes and immediately removes objects from the video. In addition, our method successfully interpolates sparse modifications initialized by the designer. According to our subjective evaluation, the videos completed with our method look significantly better than those with other state-of-the-art approaches.

Serum S100A8/A9 as a Potentially Sensitive Biomarker for Inflammatory Bowel Disease.

BACKGROUND: The clinical significance of human S100A8/A9 (h-S100A8/A9) in patients with inflammatory bowel disease (IBD) is poorly understood. OBJECTIVE: To clarify whether serum S100A8/A9 is a sensitive biomarker for IBD. METHODS: Serum specimens from outpatients with IBD (n = 101) and healthy volunteers (HVs) (n = 101) were used in this study. Enzyme-linked immunosorbent assays for h-S100A8/A9 and inflammatory cytokines were performed using these specimens. Further, correlation analysis was performed to investigate the significance of h-S100A8/A9 fluctuation in patients with IBD. RESULTS: The average of serum h-S100A8/A9 concentration in outpatients with IBD was significantly higher than that in HVs. The concentration of h-S100A8/A9 in patients with IBD was barely correlated with that of CRP and inflammatory cytokines. Despite that finding, the serum level of h-S100A8/A9 in patients with ulcerative colitis (UC) was correlated with the severity of IBD, compared with other inflammatory proteins. CONCLUSION: Serum h-S100A8/A9 is superior to CRP as a sensitive biomarker for IBD.

[CT enterography with polyethylene glycol electrolyte solution for diagnosis of Crohn's disease].

This study aimed to assess the diagnostic usefulness of CT enterography (CTE) in Crohn's disease in Japanese patients. A total of 32 cases with bowel symptoms underwent CT enterography with polyethylene glycol electrolyte solution as oral contrast medium, among which 18 were clinically diagnosed as Crohn's disease and 14 were not: ulcerative colitis 1, Beçhet disease 1, simple ulcer 1, inflammatory bowel disease without definite diagnosis 5 and bowel symptoms of unknown origin 6. The incidence of bowel wall thickening, mural hyperenhancement, "the comb sign", mesenteric lymph nodes swelling, and stenosis were significantly higher in Crohn's disease than in other disease. Moreover, uneven bowel wall thickening and unilateral mural hyperenhancement on CTE were characteristic features of Crohn's disease, which our original quantitative evaluation with imaging analysis could support. Consequently, CTE is useful in Japanese patients with Crohn's disease.

Electronegative oligothiophenes based on difluorodioxocyclopentene-annelated thiophenes: synthesis, properties, and n-type FET performances.

A series of oligothiophenes containing difluorodioxocyclopentene-annelated thiophene units was synthesized, and their electronic properties and structures were investigated by spectroscopic and electrochemical measurements and X-ray analyses. The oligothiophenes having the terminal difluorodioxocyclopentene annelations showed n-type semiconducting behavior on FET devices, and the quaterthiophene revealed field-effect electron mobility as high as 1.3 x 10(-2) cm2 V(-1) s(-1).

Nifedipine enhances the cardioprotective effect of an angiotensin-II receptor blocker in an experimental animal model of heart failure.

This study was designed to examine the hypothesis that a calcium channel blocker nifedipine (CCB) could enhance the cardioprotective effect of an angiotensin-ll receptor blocker candesartan (ARB) in the treatment for heart failure. Isoproterenol (ISP) was injected into male rats at 300 mg/kg to produce progressive heart failure. Three months later, the rats were divided into 4 groups and treated for 4 weeks with 1) vehicle (n = 20), 2) ARB at 0.2 mg/kg/day (n = 6), 3) CCB at 10 mg/kg/day (n = 6), or 4) both drugs (n = 8). Rats injected with saline served as controls (n = 13). ISP caused severe myocardial degeneration and decreased the capillary density (D(cap)) of the left ventricular (LV) myocardium (mean +/- SD: 2,197 +/- 627 vs. 2,847 +/- 298 N/mm2 for normal controls), while increasing plasma thiobarbituric acid-reactive substances (TBARS; 3.6 +/- 1.1 vs. 1.9 +/- 0.5 nmol/ml). Although ARB therapy preserved cardiac morphology, it had little effect on D(cap) or oxidative stress. On the other hand, CCB decreased plasma TBARS and 4-hydroxy-2-nonenal protein expression in LV myocardium. Furthermore, the combination of CCB and ARB increased D(cap) and preserved the ultrastructure of LV myocardium, so this combination may be a useful option for the treatment of heart failure.