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- Fessé, Per, et al.
(författare)
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Human cutaneous interfollicular melanocytes differentiate temporarily under genotoxic stress
- 2022
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Ingår i: Iscience. - : Elsevier BV. - 2589-0042. ; 25:10
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Tidskriftsartikel (refereegranskat)abstract
- DNA-damage response of cutaneous interfollicular melanocytes to fractionated radiotherapy was investigated by immunostaining of tissue sections from punch biopsies collected before, during, and after the treatment of patients for breast cancer. Our clinical assay with sterilized hair follicles, excluded the migration of immature melanocytes from the bulge, and highlighted interfollicular melanocytes as an autonomous self-renewing population. About thirty percent are immature. Surrounding keratinocytes induced and maintained melanocyte differentiation as long as treatment was ongoing. Concomitant with differentiation, melanocytes were protected from apoptosis by transient upregulation of Bcl-2 and CXCR2. CXCR2 upregulation also indicated the instigation of premature senescence, preventing proliferation. The stem cell factor BMI1 was constitutively expressed exclusively in interfollicular melanocytes and further upregulated upon irradiation. BMI1 prevents apoptosis, terminal differentiation, and premature senescence, allowing dedifferentiation post-treatment, by suppressing the p53/p21-and p16-mediated response and upregulating CXCR2 to genotoxic damage. The pre-treatment immature subset of interfollicular melanocytes was restored after the exposure ended.
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- Hedström, Gustaf, et al.
(författare)
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Mast cell infiltration is a favourable prognostic factor in diffuse large B-cell lymphoma
- 2007
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 138:1, s. 68-71
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies indicate that the inflammatory response in diffuse large B-cell lymphomas (DLBCL) is important for the clinical outcome. Mast cells are key regulators in this response; we investigated whether the number of tryptase-positive mast cells is correlated with clinical outcome. Patients with many mast cells had a significantly better event-free survival (EFS) compared to those with few mast cells (P < 0.03 in both germinal centre (GC) and non-GC DLBCL. This supports the idea that the infiltration of mast cells is a reflection of the host inflammatory response and is related to a favourable outcome.
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- Matsumoto, Taro, et al.
(författare)
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p38 MAP kinase negatively regulates endothelial cell survival,proliferation, and differentiation in FGF-2-stimulated angiogenesis
- 2002
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Ingår i: Journal of Cell Biology. - 0021-9525 .- 1540-8140. ; 156:1, s. 149-160
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Tidskriftsartikel (refereegranskat)abstract
- The p38 mitogen-activated protein kinase (p38) is activated in response to environmental stress and inflammatory cytokines. Although several growth factors, including fibroblast growth factor (FGF)-2, mediate activation of p38, the consequences for growth factor-dependent cellular functions have not been well defined. We investigated the role of p38 activation in FGF-2-induced angiogenesis. In collagen gel cultures, bovine capillary endothelial cells formed tubular growth-arrested structures in response to FGF-2. In these collagen gel cultures, p38 activation was induced more potently by FGF-2 treatment compared with that in proliferating cultures. Treatment with the p38 inhibitor SB202190 enhanced FGF-2-induced tubular morphogenesis by decreasing apoptosis, increasing DNA synthesis and cell proliferation, and enhancing the kinetics of cell differentiation including increased expression of the Notch ligand Jagged1. Overexpression of dominant negative mutants of the p38-activating kinases MKK3 and MKK6 also supported FGF-2-induced tubular morphogenesis. Sustained activation of p38 by FGF-2 was identified in vascular endothelial cells in vivo in the chick chorioallantoic membrane (CAM). SB202190 treatment enhanced FGF-2-induced neovascularization in the CAM, but the vessels displayed abnormal features indicative of hyperplasia of endothelial cells. These results implicate p38 in organization of new vessels and suggest that p38 is an essential regulator of FGF-2-driven angiogenesis.
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- Simonsson, Martin, et al.
(författare)
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Epidermal keratinocyte loss in response to daily 2 Gy fractions for 5 weeks of radiotherapy is associated with DSB-foci, growth arrest, apoptosis and lack of accelerated repopulation
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background and purpose: Tissue-sparing due to repopulation is expected to occur in epithelial cell populations during a course of fractionated radiotherapy (RT). Recently, we established, in the clinical setting of RT, the dose response relationship of subtherapeutic doses in terms of epidermal keratinocyte loss in the basal layer throughout 7 weeks of RT. Surprisingly, in the case of daily dose fractions of 1.10Gy, the keratinocyte loss per dose unit increases over the last 4 weeks of the treatment period rather than being constant or decreasing. The aim of the present study is to elaborate on the issue of germinal keratinocyte response to daily dose fractions of 2.0Gy for 5 weeks. Here, we present assessments of keratinocyte loss, DSB foci, growth arrest, mitosis and apoptosis using methods earlier described by us. Materials and Methods: In total 240 skin punch biopsies, collected from 31 breast cancer patients, before, during and after postmastectomy radiotherapy given to the thoracic wall with daily 2.0Gy fractions for 5 weeks, were investigated. The dose response for basal keratinocyte density of the interfollicular epidermis was determined. The DNA damage response of keratinocytes was studied by immunostaining for molecular markers of DNA DSBs, growth arrest, mitosis and cell death using 53BP1, p21, phospho-H3 and γH2AX (apoptosis), respectively. The stainings of keratinocytes were counted manually or by digital image analysis. Results: The dose-response relationship for the loss of basal keratinocytes over 5 weeks of RT revealed a biphasic shape. An initial radioresistant phase was followed by an increase in radiosensitivity in the second part of RT. The rate of keratinocyte loss reflected the significant changes determined by 53BP1 and γH2AX foci 30 minutes after dose fractions over the treatment period. The highest induction of DSB foci per cell was observed towards the end of treatment. The increase in the fraction of p21 stained cells was also more prominent during the second half of the treatment as compared to the first period of RT. The apoptotic frequency was generally low but increased dramatically towards the end of RT. The mitotic cell number was significantly suppressed over 5 weeks, and did not recover during the weekend treatment-gaps. Notably, the mitotic rate increased more than threefold compared to unexposed skin, 2 weeks after the end of RT, followed by a rapid decline one week later. Conclusion: The dose response for germinal keratinocyte loss as a result of daily dose fractions of 2.0Gy over 5 weeks treatment deviates significantly from an exponential curve fit. The effectiveness of each dose fraction was less in the first half of the treatment when compared with the second half. No accelerated repopulation could be revealed over the 5 weeks, but was evident after completion of radiotherapy. The changes in keratinocyte response were associated with changes in induction of DSB foci and p21 protein expression, as well as apoptotic events over the treatment period. In particular, we highlight the existence of pre-mitotic apoptosis, which increased significantly towards the end of 5 weeks RT. These findings suggest that it is necessary to reconsider the current conceptions regarding DNA repair, cell-cycle redistribution and repopulation of normal epithelial cells to a long-lasting courses of fractionated radiotherapy.
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- Turesson, Ingela, et al.
(författare)
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A low-dose hypersensitive keratinocyte loss in response to fractionated radiotherapy is associated with growth arrest and apoptosis.
- 2010
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Ingår i: Radiotherapy and oncology. - : Elsevier BV. - 1879-0887 .- 0167-8140. ; 94:1, s. 90-101
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: The existence of a hypersensitive radiation response to doses below 0.5Gy is well established for many normal and tumour cell lines. There is also evidence for hypersensitive tissue responses in acute skin damage and kidney function in mice. Recently, we have identified that a hypersensitive gammaH2AX response exists in human epidermis. The aim of this study was to investigate the dose-response of basal clonogenic keratinocytes in normal skin to fractionated radiotherapy with low dose fractions. MATERIALS: Skin punch biopsies were taken before and during radiotherapy from prostate cancer patients undergoing radiotherapy with a curative intent. Areas of epidermis receiving daily fractions of approximately 0.1, 0.2, 0.45 and 1.1Gy were biopsied on the same occasion to determine dose-response for each individual patient. In total, 89 cases were assessed either at 1, 2.5, 3, 4, 5 or 6.5 weeks in the treatment course. Biopsy sampling of another 25 patients was performed from areas receiving 0.45 and 1.1Gy per fraction at regular intervals throughout the 7-week treatment period. The number of basal keratinocytes per mm of the interfollicular epidermis was determined. The DNA damage response of the basal keratinocytes was investigated by immunohistochemical staining for molecular markers of growth arrest, mitosis and cell death, using p21, phospho-H3 and gammaH2AX, respectively. The number of stained keratinocytes in the basal layer was counted manually. The p21 staining was also quantified by digital image analysis. RESULTS: The individual dose-response relationships revealed a low-dose hypersensitivity for reduction of basal keratinocytes throughout 7 weeks of radiotherapy (p<0.01). Growth arrest and cell proliferation assessed at 1 week and 6.5 weeks showed, in both cases, hypersensitive increase of p21 (p<0.01) and hypersensitive depression of mitosis (p<0.01). Manual counting and digital image analysis of p21 showed good agreement. Cell death was infrequent but increased significantly between 1 and 6.5 weeks and displayed a hypersensitive dose-response at the end of the treatment period. CONCLUSIONS: A low-dose hypersensitivity in basal skin keratinocyte reduction is present throughout 7 weeks of radiotherapy. A persistent hypersensitive growth arrest response and cell killing mediate this effect.
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