| 1. |
- Lopez-Posadas, R., et al.
(författare)
-
Inhibiting PGGT1B Disrupts Function of RHOA, Resulting in T-cell Expression of Integrin alpha 4 beta 7 and Development of Colitis in Mice
- 2019
-
Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085. ; 157:5, s. 1293-1309
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: It is not clear how regulation of T-cell function is altered during development of inflammatory bowel diseases (IBD). We studied the mechanisms by which geranylgeranyltransferase-mediated prenylation controls T-cell localization to the intestine and chronic inflammation. METHODS: We generated mice with T-cell-specific disruption of the geranylgeranyltransferase type I, beta subunit gene (Pggt1b), called Pggt1b(Delta CD4) mice, or the ras homolog family member A gene (Rhoa), called Rhoa(Delta CD4) mice. We also studied mice with knockout of CDC42 or RAC1 and wild-type mice (controls). Intestinal tissues were analyzed by histology, multiphoton and confocal microscopy, and real-time polymerase chain reaction. Activation of CDC42, RAC1, and RHOA were measured with G-LISA, cell fractionation, and immunoblots. T cells and lamina propria mononuclear cells from mice were analyzed by flow cytometry or transferred to Rag1(-/-) mice. Mice were given injections of antibodies against integrin alpha4beta7 or gavaged with the RORC antagonist GSK805. We obtained peripheral blood and intestinal tissue samples from patients with and without IBD and analyzed them by flow cytometry. RESULTS: Pggt1b(Delta CD4) mice developed spontaneous colitis, characterized by thickening of the intestinal wall, edema, fibrosis, accumulation of T cells in the colon, and increased expression of inflammatory cytokines. Compared with control CD4+ T cells, PGGT1B-deficient CD4+ T cells expressed significantly higher levels of integrin alpha4beta7, which regulates their localization to the intestine. Inflammation induced by transfer of PGGT1B-deficient CD4+ T cells to Rag1(-/-) mice was blocked by injection of an antibody against integrin alpha4beta7. Lamina propria of Pggt1b(Delta CD4) mice had increased numbers of CD4+ T cells that expressed RORC and higher levels of cytokines produced by T-helper 17 cells (granulocyte-macrophage colony-stimulating factor, interleukin [IL]17A, IL17F, IL22, and tumor necrosis factor [TNF]). The RORC inverse agonist GSK805, but not antibodies against IL17A or IL17F, prevented colitis in Pggt1b(Delta CD4) mice. PGGT1B-deficient CD4+ T cells had decreased activation of RHOA. RhoA(Delta CD4) mice had a similar phenotype to Pggt1b(Delta CD4) mice, including development of colitis, increased numbers of CD4+ T cells in colon, increased expression of integrin alpha4beta7 by CD4+ T cells, and increased levels of IL17A and other inflammatory cytokines in lamina propria. T cells isolated from intestinal tissues from patients with IBD had significantly lower levels of PGGT1B than tissues from individuals without IBD. CONCLUSION: Loss of PGGT1B from T cells in mice impairs RHOA function, increasing CD4+ T-cell expression of integrin alpha4beta7 and localization to colon, resulting in increased expression of inflammatory cytokines and colitis. T cells isolated from gut tissues from patients with IBD have lower levels of PGGT1B than tissues from patients without IBD.
|
|
| 2. |
|
|
| 3. |
- Lopez-Posadas, R., et al.
(författare)
-
Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation
- 2016
-
Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 126:2, s. 611-626
-
Tidskriftsartikel (refereegranskat)abstract
- Although defects in intestinal barrier function are a key pathogenic factor in patients with inflammatory bowel diseases (IBDs), the molecular pathways driving disease-specific alterations of intestinal epithelial cells (IECs) are largely unknown. Here, we addressed this issue by characterizing the transcriptome of IECs from IBD patients using a genome-wide approach. We observed disease-specific alterations in IECs with markedly impaired Rho-A signaling in active IBD patients. Localization of epithelial Rho-A was shifted to the cytosol in IBDs, and inflammation was associated with suppressed Rho-A activation due to reduced expression of the Rho-A prenylation enzyme geranylgeranyltransferase-I (GGTase-l). Functionally, we found that mice with conditional loss of Rhoa or the gene encoding GGTase-1, Pggtlb, in IECs exhibit spontaneous chronic intestinal inflammation with accumulation of granulocytes and CD4(+) T cells. This phenotype was associated with cytoskeleton rearrangement and aberrant cell shedding, ultimately leading to loss of epithelial integrity and subsequent inflammation. These findings uncover deficient prenylation of Rho-A as a key player in the pathogenesis of IBDs. As therapeutic triggering of Rho-A signaling suppressed intestinal inflammation in mice with GGTase-l-deficient IECs, our findings suggest new avenues for treatment of epithelial injury and mucosal inflammation in IBD patients.
|
|
| 4. |
|
|
| 5. |
- Philipp, P., et al.
(författare)
-
Significant Enhancement of Negative Secondary Ion Yields by Cluster Ion Bombardment Combined with Cesium Flooding
- 2015
-
Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 87:19, s. 10025-10032
-
Tidskriftsartikel (refereegranskat)abstract
- In secondary ion mass spectrometry (SIMS), the beneficial effect of cesium implantation or flooding on the enhancement of negative secondary ion yields has been investigated in detail for various semiconductor and metal samples. All results have been obtained for monatomic ion bombardment. Recent progress in SIMS is based to a large extent on the development and use of cluster primary ions. In this work we show that the enhancement of negative secondary ions induced by the combination of ion bombardment with simultaneous cesium flooding is valid not only for monatomic ion bombardment but also for cluster primary ions. Experiments carried out using C60+ and Ar4000+ bombardment on silicon show that yields of negative secondary silicon ions can be optimized in the same way as by Ga+ and Cs+ bombardment. Both for monatomic and cluster ion bombardment, the optimization does not depend on the primary ion species. Hence, it can be assumed that the silicon results are also valid for other cluster primary ions and that results obtained for monatomic ion bombardment on other semiconductor and metal samples are also valid for cluster ion bombardment. In SIMS, cluster primary ions are also largely used for the analysis of organic matter. For polycarbonate, our results show that Ar4000+ bombardment combined with cesium flooding enhances secondary ion signals by a factor of 6. This can be attributed to the removal of charging effects and/or reduced fragmentation, but no major influence on ionization processes can be observed. The use of cesium flooding for the imaging of cells was also investigated and a significant enhancement of secondary ion yields was observed. Hence, cesium flooding has also a vast potential for SIMS analyses with cluster ion bombardment.
|
|
| 6. |
- Weis, J., et al.
(författare)
-
Sensitivity to change of the EORTC quality of life module measuring cancer-related fatigue (EORTC QlQ-Fa12): Results from the international psychometric validation
- 2019
-
Ingår i: Psycho-Oncology. - : Wiley. - 1057-9249 .- 1099-1611. ; 28, s. 1753-1761
-
Tidskriftsartikel (refereegranskat)abstract
- Objective The European Organisation for Research and Treatment of Cancer Quality of Life Group (EORTC QLG) has developed a multidimensional instrument measuring cancer-related fatigue, the EORTC QLQ-FA12. The analysis of sensitivity to change is an essential part of psychometric validation. With this study, we investigated the EORTC QLQ-FA12's sensitivity to change. Methods The methodology follows the EORTC guidelines of EORTC QLG for phase IV validation of modules. We included cancer patients undergoing curative and palliative treatment at t1 and followed them up prospectively over the course of their treatment (t2) and 4 weeks after completion of treatment (t3). Data were collected prospectively at 17 sites in 11 countries. Sensitivity to change was investigated using analysis of variance. Results A total sample of 533 patients was enrolled with various tumour types, different stages of cancer, and receiving either curative treatment (n=311) or palliative treatment (n=222). Over time all fatigue scores were significantly higher in the palliative treatment group compared with the curative group (p < .001). Physical fatigue increased with medium effect size over the course of treatment in the curative group (standardized response mean [SRM] (t1,t2) = 0.44]. After treatment physical [SRM (t2,t3) = 0.39], emotional [SRM (t2,t3)= 0.28] and cognitive fatigue (SRM [t2,t3] = 0.22) declined significantly in the curative group. In the palliative group, emotional (SRM [t2,t3] = 0.18) as well as cognitive [SRM [t2,t3] = 0.26) fatigue increases significantly. Conclusions The EORTC-QLQ-FA12 proved to identify clinically significant changes in fatigue in the course of curative and palliative cancer treatment.
|
|
| 7. |
- Wirtz, Andrea L, et al.
(författare)
-
Feasibility of a Combination HIV Prevention Program for Men Who Have Sex With Men in Blantyre, Malawi.
- 2015
-
Ingår i: Journal of Acquired Immune Deficiency Syndromes. - 1525-4135 .- 1944-7884. ; 70:2, s. 155-62
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The use of combination HIV prevention interventions (CHPI) now represent the standard of care to minimize HIV acquisition risks among men who have sex with men (MSM). There has been limited evaluation of these approaches in generalized HIV epidemics and/or where MSM are stigmatized. A peer-based CHPI program to target individual, social, and structural risks for HIV was developed for MSM in Blantyre, Malawi.METHODS: To test the feasibility of CHPI, adult MSM were followed prospectively from January 2012 to May 2013. Participants (N = 103) completed sociobehavioral surveys and HIV testing at each of the 3 follow-up study visits.RESULTS: Approximately 90% of participants attended each study visit and 93.2% (n = 96) completed the final visit. Participants met with peer educators a median of 3 times (range: 1-10) in the follow-up visits 2 and 3. Condom use at last sex improved from baseline through follow-up visit 3 with main (baseline: 62.5%, follow-up 3: 77.0%; P = 0.02) and casual male partners (baseline: 70.7%, follow-up 3: 86.3%; P = 0.01). Disclosure of sexual behaviors/orientation to family increased from 25% in follow-up 1 to 55% in follow-up 3 (P < 0.01).DISCUSSION: Participants maintained a high level of retention in the study highlighting the feasibility of leveraging community-based organizations to recruit and retain MSM in HIV prevention and treatment interventions in stigmatizing settings. Group-level changes in sexual behavior and disclosure in safe settings for MSM were noted. CHPI may represent a useful model to providing access to other HIV prevention for MSM and aiding retention in care and treatment services for MSM living with HIV in challenging environments.
|
|
