| 61. |
- Huuhtanen, Jani, et al.
(författare)
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IFN-alfa with dasatinib broadens the immune repertoire in patients with chronic-phase chronic myeloid leukemia
- 2022
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Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 132:17
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Tidskriftsartikel (refereegranskat)abstract
- In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-alpha is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-alpha in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCR beta sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8(+) recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-alpha reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-alpha had costimulatory effects on TCR signaling. Our work supports the combination of IFN-alpha with TKI therapy, as IFN-alpha broadens the immune repertoire and restores immunological function.
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| 62. |
- Hällgren, R, et al.
(författare)
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Accumulation of hyaluronan (hyaluronic acid) in myocardial interstitial tissue parallels development of transplantation edema in heart allografts in rats.
- 1990
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 85:3, s. 668-73
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Tidskriftsartikel (refereegranskat)abstract
- By using biotin-labeled proteoglycan core protein, hyaluronan (hyaluronic acid; HA) was visualized in rat heart grafts at different times (2, 4, and 6 d) after transplantation. In normal, nontransplanted hearts HA was present in the adventitia of arteries and veins and in the myocardial interstitial tissue. An increased accumulation of HA was evident in the edematous interstitial tissue, infiltrated with lymphocytes, on day 4 after allogeneic transplantation, and was even more pronounced by day 6. No apparent increase in HA was seen in syngeneic grafts. Biochemical assay of HA in heart tissue demonstrated that the myocardial content of HA had increased 60% by day 2 after transplantation in allogeneic as well as syngeneic grafts, indicating that surgical trauma may induce some HA accumulation in heart grafts. The extractable amount of HA declined during the following days in the syngeneic grafts, but increased progressively during the development of rejection in the allogeneic grafts, and increased on average three times by day 6. The relative water content also increased progressively during rejection of allogeneic grafts and correlated with the HA accumulation. The interstitial accumulation of HA, a glycosaminoglycan with unique water-binding qualities, is presumably implicated in the development of interstitial edema during rejection of heart grafts.
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| 63. |
- Iglesias, José, et al.
(författare)
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PPARβ/δ affects pancreatic β cell mass and insulin secretion in mice
- 2012
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 122:11, s. 4105-4117
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Tidskriftsartikel (refereegranskat)abstract
- PPARβ/δ protects against obesity by reducing dyslipidemia and insulin resistance via effects in muscle, adipose tissue, and liver. However, its function in pancreas remains ill defined. To gain insight into its hypothesized role in β cell function, we specifically deleted Pparb/d in the epithelial compartment of the mouse pancreas. Mutant animals presented increased numbers of islets and, more importantly, enhanced insulin secretion, causing hyperinsulinemia. Gene expression profiling of pancreatic β cells indicated a broad repressive function of PPARβ/δ affecting the vesicular and granular compartment as well as the actin cytoskeleton. Analyses of insulin release from isolated PPARβ/δ-deficient islets revealed an accelerated second phase of glucose-stimulated insulin secretion. These effects in PPARβ/δ-deficient islets correlated with increased filamentous actin (F-actin) disassembly and an elevation in protein kinase D activity that altered Golgi organization. Taken together, these results provide evidence for a repressive role for PPARβ/δ in β cell mass and insulin exocytosis, and shed a new light on PPARβ/δ metabolic action.
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| 64. |
- Iovino, Federico, et al.
(författare)
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Pneumococcal meningitis is promoted by single cocci expressing pilus adhesin RrgA
- 2016
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 126:8, s. 2821-2826
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pneumoniae (pneumococcus) is the primary cause of bacterial meningitis. Pneumococcal bacteria penetrates the blood-brain barrier (BBB), but the bacterial factors that enable this process are not known. Here, we determined that expression of pneumococcal pilus-1, which includes the pilus adhesin RrgA, promotes bacterial penetration through the BBB in a mouse model. S. pneumoniae that colonized the respiratory epithelium and grew in the bloodstream were chains of variable lengths; however, the pneumococci that entered the brain were division-competent, spherical, single cocci that expressed adhesive RrgA–containing pili. The cell division protein DivIVA, which is required for an ovoid shape, was localized at the poles and septum of pneumococcal chains of ovoid, nonseparated bacteria, but was absent in spherical, single cocci. In the bloodstream, a small percentage of pneumococci appeared as piliated, RrgA-expressing, DivIVA-negative single cocci, suggesting that only a minority of S. pneumoniae are poised to cross the BBB. Together, our data indicate that small bacterial cell size, which is signified by the absence of DivIVA, and the presence of an adhesive RrgA-containing pilus-1 mediate pneumococcal passage from the bloodstream through the BBB into the brain to cause lethal meningitis.
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| 65. |
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| 66. |
- Jeansson, Marie, et al.
(författare)
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Angiopoietin-1 is essential in mouse vasculature during development and in response to injury
- 2011
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 121:6, s. 2278-2289
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Tidskriftsartikel (refereegranskat)abstract
- Angiopoietin-1/Tek signaling is a critical regulator of blood vessel development, with conventional knockout of angiopoietin-1 or Tek in mice being embryonically lethal due to vascular defects. In addition, angiopoietin-1 is thought to be required for the stability of mature vessels. Using a Cre-Lox conditional gene targeting approach, we have studied the role of angiopoietin-1 in embryonic and adult vasculature. We report here that angiopoietin-1 is critical for regulating both the number and diameter of developing vessels but is not required for pericyte recruitment. Cardiac-specific knockout of angiopoietin-1 reproduced the phenotype of the conventional knockout, demonstrating that the early vascular abnormalities arise from flow-dependent defects. Strikingly, deletion in the entire embryo after day E13.5 produced no immediate vascular phenotype. However, when combined with injury or microvascular stress, angiopoietin-1 deficiency resulted in profound organ damage, accelerated angiogenesis, and fibrosis. These findings redefine our understanding of the biological roles of angiopoietin-1: it is dispensable in quiescent vessels but has a powerful ability to modulate the vascular response after injury.
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| 67. |
- Johansson, MEV, et al.
(författare)
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Goblet cells need some stress
- 2022
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 132:17
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The intestinal tract is protected by epithelium-covering mucus, which is constantly renewed by goblet cells, a specialized type of epithelial cell. Mucus is largely composed of MUC2 mucin, an enormous molecule that poses a high demand on the endoplasmic reticulum (ER) for proper folding and protein assembly, creating a challenge for the secretory machinery in goblet cells. In this issue of the JCI, Grey et al. reveal that the ER resident protein and folding sensor ERN2 (also known as IRE1β) was instrumental for goblet cells to produce sufficient amounts of mucus to form a protective mucus layer. In the absence of ERN2, mucus production was reduced, impairing the mucus barrier, which allowed bacteria to penetrate and cause an epithelial cell stress response. This study emphasizes the importance of a controlled unfolded protein response (UPR) for goblet cell secretion.
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| 68. |
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| 69. |
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| 70. |
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