Cancer‐associated fibroblasts contribute to cancer progression that is caused by epithelial–mesenchymal transition (EMT). Recently, mesenchymal stem cells (MSCs) were found to be the major candidate ...involved in the development of tumor‐promoting cancer stroma. Here we report that α‐smooth muscle actin‐positive myofibroblast‐like cells originating from MSCs contribute to inducing EMT in side population cells of pancreatic cancer. More importantly, MSC‐derived myofibroblasts function to maintain tumor‐initiating stem cell‐like characteristics, including augmenting expression levels of various stemness‐associated genes, enhancing sphere‐ forming activity, promoting tumor formation in a mouse xenograft model, and showing resistance to anticancer drugs. Furthermore, both γ‐secretase inhibitor and siRNA directed against Jagged‐1 attenuated MSC‐associated E‐cadherin suppression and sphere formation in pancreatic cancer side population cells. Thus, our results suggest that MSC‐derived myofibroblasts play important roles in regulating EMT and tumor‐initiating stem cell‐like properties of pancreatic cancer cells through an intermediating Notch signal.
Introduction: Mirikizumab (miri) treatment improved quality of life in patients with moderately-to-severely active Crohn’s disease (CD) through Week 52 (W52) as assessed by Medical Outcomes 36-Item ...Short Form Health Survey (SF-36) scores in the Phase 2 randomized, double-blind, parallel, placebo (PBO)-controlled study (SERENITY/NCT02891226). SF-36 Physical (PCS) and Mental (MCS) Component Summary, and 8 domain scores (physical functioning, role-physical, role-emotional, bodily pain, vitality, social functioning, mental and general health) were evaluated up to W104 and summarized by randomized treatment (i.e. pooled all IV and all SC) from W12-52 among endoscopic improvers at W12 who were rerandomized into maintenance and went onto the extension period. Conclusion: Treatment with miri is associated with a sustained improvement in quality of life as measured by SF-36 from W52 to W104 in patients with moderately-to-severely active CD.Table 1 Observed mean CFBL, (SD) Week 12 Endoscopic Improvers a Week 52 Week 104 Week 52 Week 104 Miri IV-C N=35 Miri IV-C N=29 Miri SC N=41 Miri SC N=38 PCS 10.47 (8.72) 11.68 (6.60) 10.70 (7.88) 9.96 (8.17) MCS 8.49 (11.30) 9.32 (12.35) 11.45 (11.42) 10.43 (11.59) Domain Scores Physical functioning 17.29 (18.48) 19.14 (17.17) 22.93 (22.30) 22.37 (22.83) Role-physical 30.89 (24.95) 32.33 (20.87) 32.01 (28.24) 26.64 (29.27) Role-emotional 13.10 (25.59) 16.95 (26.12) 22.36 (21.36) 19.96 (22.39) Bodily pain 27.20 (29.04) 35.28 (23.86) 34.61 (25.30) 31.00 (27.87) Vitality 28.04 (27.39) 26.72 (29.41) 30.79 (26.16) 29.11 (26.17) Social functioning 29.29 (29.85) 31.90 (24.91) 31.10 (24.71) 25.99 (30.26) Mental health 15.57 (20.39) 17.76 (23.59) 21.83 (23.63) 20.79 (22.74) General health 23.91 (20.38) 26.28 (21.70) 21.02 (18.31) 22.55 (18.38) aEndoscopic improvement: ≥1 point improvement in SES-CD at Week 12.
Although the precise etiologies of inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) remain obscure, several reports have indicated that dysfunction of the mucosal immune ...system plays an important role in its pathogenesis. Recent progress with genome-wide association studies has identified many IBD susceptibility genes. In individuals with genetic risk, abnormal interactions between the host immune system and gut flora, and dysregulation of cellular responses such as autophagy and ER stress, induce an abnormal host immune response in the gut resulting in intestinal inflammation. Research progress animal models in IBD, and in human IBD, has identified several key molecules in IBD pathogenesis such as TNFα and adhesion molecules, and molecular targeting therapies based on these molecules have been developed. Here, we review immunological aspects in IBD pathogenesis and the development of immunoregulatory therapy.
Inflammatory bowel disease (IBD) has increased in incidence and prevalence in Asian countries since the end of the 20th century. Moreover, differences in the cause, phenotypes, and natural history of ...IBD between the East and West have been recognized. Therefore, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have established recommendations on medical management of IBD in Asia. Initially, the committee members drafted 40 recommendations, which were then assessed according to Grading of Recommendations Assessment, Development and Evaluation. Eight statements were rejected as this indicated that consensus had not been reached. The recommendations encompass pretreatment evaluation; medical management of active IBD; medical management of IBD in remission; management of IBD during the periconception period and pregnancy; surveillance strategies for colitis‐associated cancer; monitoring side effects of thiopurines and methotrexate; and infections in IBD.
Risankizumab for Crohn's disease Hibi, Toshifumi
The Lancet (British edition),
05/2022, Letnik:
399, Številka:
10340
Journal Article
Recenzirano
Odprti dostop
In The Lancet, two new studies report randomised controlled trials of risankizumab for Crohn's disease.1,2 In the first, Geert D’Haens and colleagues share the findings of the ADVANCE and MOTIVATE ...phase 3 trials comparing the efficacy and safety of risankizumab with placebo in the induction period.1 The intention-to-treat population included 850 patients (390 46% women, 460 54% men; median age 37·5 years IQR 13·3) for ADVANCE and 569 patients (276 49% women, 293 51% men; median age 39·6 years 13·3) for MOTIVATE in hospital academic medical centres, clinical research units, and private practices. IL-23 has attracted attention as the next therapeutic target.3 The concept of IL-23 inhibition is based on the fact that raised concentrations of IL-23 are present in the mucosa of patients with Crohn's disease and genome-wide association studies have shown a correlation between gene polymorphisms of the IL-23 receptor and the development of Crohn's disease.4,5 Pathophysiological studies have also identified IL-23 as a key cytokine in chronic intestinal inflammation.5,6 Ustekinumab, a monoclonal antibody specific for IL-12B (a subunit common to IL-12 and IL-23), has already shown efficacy and safety for the treatment of patients with Crohn's disease in UNITI-1, UNITI-2, and IM-UNITI phase 3 trials.7 Ustekinumab is widely used for patients with Crohn's disease or ulcerative colitis. ...evidence accumulation, including real-world experience by using balloon-assisted endoscopy or magnetic resonance enterography, will be warranted. Because patients might respond differently to biologics with different modes of action, a subanalysis of the characteristics for good responders and poor responders in this trial would be of interest.
The impact of inflammatory bowel disease (IBD) on disability remains poorly understood. The World Health Organization's integrative model of human functioning and disability in the International ...Classification of Functioning, Disability and Health (ICF) makes disability assessment possible. The ICF is a hierarchical coding system with four levels of details that includes over 1400 categories. The aim of this study was to develop the first disability index for IBD by selecting most relevant ICF categories that are affected by IBD.
Relevant ICF categories were identified through four preparatory studies (systematic literature review, qualitative study, expert survey and cross-sectional study), which were presented at a consensus conference. Based on the identified ICF categories, a questionnaire to be filled in by clinicians, called the 'IBD disability index', was developed.
The four preparatory studies identified 138 second-level categories: 75 for systematic literature review (153 studies), 38 for qualitative studies (six focus groups; 27 patients), 108 for expert survey (125 experts; 37 countries; seven occupations) and 98 for cross-sectional study (192 patients; three centres). The consensus conference (20 experts; 17 countries) led to the selection of 19 ICF core set categories that were used to develop the IBD disability index: seven on body functions, two on body structures, five on activities and participation and five on environmental factors.
The IBD disability index is now available. It will be used in studies to evaluate the long-term effect of IBD on patient functional status and will serve as a new endpoint in disease-modification trials.
Background
Adherence to medications is important to maintain disease under control and to prevent complications in pregnant patients with ulcerative colitis (UC). To evaluate the incidence of ...non-adherence during pregnancy and its effect on relapse and pregnancy outcomes, we conducted a multicenter prospective study using a patient self-reporting system without physician interference.
Methods
Sixty-eight pregnant UC women were recruited from 17 institutions between 2013 and 2019. During the course of pregnancy, questionnaires were collected separately from patients and physicians, to investigate the true adherence to medications, disease activity, and birth outcomes. Multivariable logistic regression analysis was performed to identify the risk factors for the relapse or adverse pregnancy outcomes.
Results
Of 68 pregnancy, 15 adverse pregnancy outcomes occurred in 13 patients. The rate of self-reported non-adherence was the greatest to mesalamines in the first trimester, which was significantly higher than physicians’ estimate (
p
= 0.0116), and discontinuation was observed in 42.1% of non-adherent group. Logistic regression analysis revealed non-adherence as an independent risk factor for relapse odds ratio (OR) 7.659, 95% CI 1.928–30.427,
p
= 0.038, and possibly for adverse pregnancy outcome (OR 8.378, 95% CI 1.350–51.994,
p
= 0.023). Among the subgroup of patients treated with oral mesalamine alone, the non-adherence was confirmed to be an independent risk factor for relapse (
p
= 0.002).
Conclusion
Non-adherence to mesalamine was underestimated by physicians in pregnant UC patients and contributed to disease relapse and possibly on pregnancy outcomes. Preconceptional education regarding safety of medications and risk of self-discontinuation is warranted.
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