A Systematic Review of Self-Management Interventions for Patients with Inflammatory Bowel Disease.

Introduction: Previous studies have reported the effectiveness of inflammatory bowel disease (IBD) self-management. However, it is unclear which types of self-management interventions are effective. We conducted a systematic literature review to clarify the status and efficacy of self-management interventions for IBD. Methods: Searches were performed in databases including Embase, Medline, and Cochrane Library. Randomized, controlled studies of interventions in adult human participants with IBD involving a self-management component published in English from 2000 to 2020 were included. Studies were stratified based on study design, baseline demographic characteristics, methodological quality, and how outcomes were measured and analyzed for statistically significant improvements in outcomes, such as psychological health, quality of life, and healthcare resource usage. Results: Among 50 studies included, 31 considered patients with IBD and 14 and 5 focused on patients with ulcerative colitis and Crohn's disease, respectively. Improvements in an outcome were reported in 33 (66%) studies. Most of the interventions that significantly improved an outcome index were based on symptom management and many of these were also delivered in combination with provision of information. We also note that among effective interventions, many were conducted with individualized and patient-participatory activities, and multidisciplinary healthcare practitioners were responsible for delivery of the interventions. Conclusion: Ongoing interventions that focus on symptom management with provision of information may support self-management behavior in patients with IBD. A participatory intervention targeting individuals was suggested to be an effective intervention method.

Performing colonoscopy before steroid induction is associated with shorter steroid use in patients with ulcerative colitis.

BACKGROUND/AIMS: Risks of long-term steroid use in patients with ulcerative colitis (UC) outweigh the benefits, thus dosing should be tapered once a response is achieved. Colonoscopy is a key technique for assessing disease severity and optimizing treatment involving steroids. This retrospective longitudinal cohort study of patients with UC explored factors associated with the duration of systemic steroid use. METHODS: The Japan Medical Data Center database, an employer-based insurance claims database, was used to select individuals initiating prednisolone, with a prescription issued between January 1, 2010, and January 31, 2018. The study included adults with a confirmed diagnosis of UC, who had received ≥1 year of continuous treatment with 5-aminosalicylic acid, biologics, or thiopurine. Factors associated with prednisolone duration were assessed using a multivariate regression model. RESULTS: Median duration of prednisolone treatment was 98 days, and colonoscopy was performed ≤1 month before or at the first prescription of prednisolone (index date) in 32.8% of patients (607/1,853). Shorter durations of prednisolone treatment were associated with colonoscopy ≤1 month before or at the index date and higher prednisolone dose at index date, with incidence rate ratios (IRRs) of 0.776 (95% confidence interval [CI], 0.682-0.884; P<0.001) and 0.998 (95% CI, 0.996-1.000; P=0.018), respectively. Charlson Comorbidity Index scores of 1 and ≥2 predicted longer prednisolone treatment (IRR, 1.332; 95% CI, 1.174-1.511; P<0.001 and IRR, 1.599; 95% CI, 1.357-1.885; P<0.001, respectively). CONCLUSIONS: Performing colonoscopy before or at the time of initiating steroid was associated with a shorter duration of steroid use in patients with UC.

Increased glucose metabolism in Arid5b-/- skeletal muscle is associated with the down-regulation of TBC1 domain family member 1 (TBC1D1).

BACKGROUND: Skeletal muscle has an important role in regulating whole-body energy homeostasis, and energy production depends on the efficient function of mitochondria. We demonstrated previously that AT-rich interactive domain 5b (Arid5b) knockout (Arid5b-/-) mice were lean and resistant to high-fat diet (HFD)-induced obesity. While a potential role of Arid5b in energy metabolism has been suggested in adipocytes and hepatocytes, the role of Arid5b in skeletal muscle metabolism has not been studied. Therefore, we investigated whether energy metabolism is altered in Arid5b-/- skeletal muscle. RESULTS: Arid5b-/- skeletal muscles showed increased basal glucose uptake, glycogen content, glucose oxidation and ATP content. Additionally, glucose clearance and oxygen consumption were upregulated in Arid5b-/- mice. The expression of glucose transporter 1 (GLUT1) and 4 (GLUT4) in the gastrocnemius (GC) muscle remained unchanged. Intriguingly, the expression of TBC domain family member 1 (TBC1D1), which negatively regulates GLUT4 translocation to the plasma membrane, was suppressed in Arid5b-/- skeletal muscle. Coimmunofluorescence staining of the GC muscle sections for GLUT4 and dystrophin revealed increased GLUT4 localization at the plasma membrane in Arid5b-/- muscle. CONCLUSIONS: The current study showed that the knockout of Arid5b enhanced glucose metabolism through the downregulation of TBC1D1 and increased GLUT4 membrane translocation in skeletal muscle.

A pilot study to establish human T-cell leukemia virus type 1 (HTLV-1) carrier model using common marmoset (Callithrix jacchus).

BACKGROUND: For the diagnosis and treatment of adult T-cell leukemia/lymphoma (ATLL) caused by human T-lymphotropic virus type 1 (HTLV-1) are required therapeutic modalities urgently. Non-human primate models for ATLL would provide a valuable information for clinical studies. We did a pilot study to establish an ATLL non-human primate model using common marmosets (Callithrix jacchus). METHODS: We inoculated HTLV-1-producing MT-2 cells into 9-month-old marmosets, either intraperitoneally or intravenously. We next administrated MT-2 cells into 13-month-old marmosets under cyclosporine A (CsA) treatment to promote infection. HTLV-1 infection was determined by measuring HTLV-1 antibody titer in the common marmosets. RESULTS: The HTLV-1 antibody titer increased in the intraperitoneally inoculated marmoset with or without CsA treatment, and it kept over five 5 years though proviral copy number (proviral load, PVL) remained low throughout the study. CONCLUSION: We obtained HTLV-1 asymptomatic carriers of common marmosets by inoculating MT-2 cells.

Extremely Low Organ Toxicity and Strong Antitumor Activity of miR-34-Regulated Oncolytic Coxsackievirus B3.

Oncolytic virotherapies have emerged as new modalities for cancer treatment. We previously reported that coxsackievirus B3 (CVB3) is a novel oncolytic virus (OV) with a strong ability to lyse human non-small cell lung cancer cells; however, its non-specific toxicity against normal cells remains to be resolved. To improve its safety profile, microRNA target sequences complementary to miR-34a/c, which is expressed preferentially in normal cells, were inserted into the 5' UTR or 3' UTR of the CVB3 genome. In the presence of miR-34a/c, the gene-modified CVB3 could not replicate in normal cells. We also found that the pathogenicity of CVB3 was reduced to a greater extent by targeting miR-34a than miR-34c; in addition, it was more effective to insert the target sequences into the 3' UTR rather than the 5' UTR of the viral genome. Ultimately, we developed a double-miR-34a targeting virus (53a-CVB) by inserting miR-34a targets in both the 5' UTR and 3' UTR of the virus. 53a-CVB was minimally toxic to cells in normal tissue, but maintained nearly its full oncolytic activity in mice xenografted with human lung cancer. 53a-CVB is the first miR-34-regulated OV and represents a promising platform for the development of safe and effective anti-cancer therapies.

KLF1 mutation E325K induces cell cycle arrest in erythroid cells differentiated from congenital dyserythropoietic anemia patient-specific induced pluripotent stem cells.

Krüppel-like factor 1 (KLF1), a transcription factor controlling definitive erythropoiesis, is involved in sequential control of terminal cell division and enucleation via fine regulation of key cell cycle regulator gene expression in erythroid lineage cells. Type IV congenital dyserythropoietic anemia (CDA) is caused by a monoallelic mutation at the second zinc finger of KLF1 (c.973G>A, p.E325K). We recently diagnosed a female patient with type IV CDA with the identical missense mutation. To understand the mechanism underlying the dyserythropoiesis caused by the mutation, we generated induced pluripotent stem cells (iPSCs) from the CDA patient (CDA-iPSCs). The erythroid cells that differentiated from CDA-iPSCs (CDA-erythroid cells) displayed multinucleated morphology, absence of CD44, and dysregulation of the KLF1 target gene expression. In addition, uptake of bromodeoxyuridine by CDA-erythroid cells was significantly decreased at the CD235a+/CD71+ stage, and microarray analysis revealed that cell cycle regulator genes were dysregulated, with increased expression of negative regulators such as CDKN2C and CDKN2A. Furthermore, inducible expression of the KLF1 E325K, but not the wild-type KLF1, caused a cell cycle arrest at the G1 phase in CDA-erythroid cells. Microarray analysis of CDA-erythroid cells and real-time polymerase chain reaction analysis of the KLF1 E325K inducible expression system also revealed altered expression of several KLF1 target genes including erythrocyte membrane protein band 4.1 (EPB41), EPB42, glutathione disulfide reductase (GSR), glucose phosphate isomerase (GPI), and ATPase phospholipid transporting 8A1 (ATP8A1). Our data indicate that the E325K mutation in KLF1 is associated with disruption of transcriptional control of cell cycle regulators in association with erythroid membrane or enzyme abnormalities, leading to dyserythropoiesis.

Pathway-Based Drug Repositioning for Cancers: Computational Prediction and Experimental Validation.

Developing drugs with anticancer activity and low toxic side-effects at low costs is a challenging issue for cancer chemotherapy. In this work, we propose to use molecular pathways as the therapeutic targets and develop a novel computational approach for drug repositioning for cancer treatment. We analyzed chemically induced gene expression data of 1112 drugs on 66 human cell lines and searched for drugs that inactivate pathways involved in the growth of cancer cells (cell cycle) and activate pathways that contribute to the death of cancer cells (e.g., apoptosis and p53 signaling). Finally, we performed a large-scale prediction of potential anticancer effects for all the drugs and experimentally validated the prediction results via three in vitro cellular assays that evaluate cell viability, cytotoxicity, and apoptosis induction. Using this strategy, we successfully identified several potential anticancer drugs. The proposed pathway-based method has great potential to improve drug repositioning research for cancer treatment.

Changes in inflammatory mediators following eccentric exercise of the elbow flexors.

The aims of this study were to examine the plasma concentrations of inflammatory mediators including cytokines induced by a single bout of eccentric exercise and again 4 weeks later by a second bout of eccentric exercise of the same muscle group. Ten untrained male subjects performed two bouts of the eccentric exercise involving the elbow flexors (6 sets of 5 repetitions) separated by four weeks. Changes in muscle soreness, swelling, and function following exercise were compared between the bouts. Blood was sampled before, immediately after, 1 h, 3 h, 6 h, 24 h (1 d), 48 h (2 d), 72 h (3 d), 96 h (4 d) following exercise bout to measure plasma creatine kinase (CK) activity, plasma concentrations of myoglobin (Mb), interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1ra), IL-4, IL-6, IL-8, IL-10, IL-12p40, tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), myeloperoxidase (MPO), prostaglandin E2 (PGE2), heat shock protein (HSP) 60 and 70. After the first bout, muscle soreness increased significantly, and there was also significant increase in upper arm circumference; muscle function decreased and plasma CK activity and Mb concentration increased significantly. These changes were significantly smaller after the second bout compared to the first bout, indicating muscle adaptation to the repeated bouts of the eccentric exercise. Despite the evidence of greater muscle damage after the first bout, the changes in cytokines and other inflammatory mediators were quite minor, and considerably smaller than that following endurance exercise. These results suggest that eccentric exercise-induced muscle damage is not associated with the significant release of cytokines into the systemic circulation. After the first bout, plasma G-CSF concentration showed a small but significant increase, whereas TNF-alpha and IL-8 showed significant decreases compared to the pre-exercise values. After the second bout, there was a significant increase in IL-10, and a significant decrease in IL-8. In conclusion, although there was evidence of severe muscle damage after the eccentric exercise, this muscle damage was not accompanied by any large changes in plasma cytokine concentrations. The minor changes in systemic cytokine concentration found in this study might reflect more rapid clearance from the circulation, or a lack of any significant metabolic or oxidative demands during this particular mode of exercise. In relation to the adaptation to the muscle damage, the anti-inflammatory cytokine IL-10 might work as one of the underlying mechanisms of action.