| 1. |
- Ahlstedt, Jonas, et al.
(författare)
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Biodistribution and pharmacokinetics of recombinant α1-microglobulin and its potential use in radioprotection of kidneys.
- 2015
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Ingår i: American journal of nuclear medicine and molecular imaging. - 2160-8407. ; 5:4, s. 333-347
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Tidskriftsartikel (refereegranskat)abstract
- Peptide-receptor radionuclide therapy (PRRT) is a systemically administrated molecular targeted radiation therapy for treatment of neuroendocrine tumors. Fifteen years of clinical use show that renal toxicity, due to glomerular filtration of the peptides followed by local generation of highly reactive free radicals, is the main side-effect that limits the maximum activity that can be administrated for efficient therapy. α1-microglobulin (A1M) is an endogenous radical scavenger shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. An important feature of A1M is that, following distribution to the blood, it is equilibrated to the extravascular compartments and filtrated in the kidneys. Aiming at developing renal protection against toxic side-effects of PRRT, we have characterized the pharmacokinetics and biodistribution of intravenously (i.v.) injected (125)I- and non-labelled recombinant human A1M and the (111)In- and fluorescence-labelled somatostatin analogue octreotide. Both molecules were predominantly localized to the kidneys, displaying a prevailing distribution in the cortex. A maximum of 76% of the injected A1M and 46% of the injected octreotide were present per gram kidney tissue at 10 to 20 minutes, respectively, after i.v. injection. Immunohistochemistry and fluorescence microscopy revealed a dominating co-existence of the two substances in proximal tubules, with a cellular co-localization in the epithelial cells. Importantly, analysis of kidney extracts displayed an intact, full-length A1M at least up to 60 minutes post-injection (p.i.). In summary, the results show a highly similar pharmacokinetics and biodistribution of A1M and octreotide, thus enabling the use of A1M to protect the kidneys tissue during PRRT.
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| 2. |
- Kristiansson, Amanda, et al.
(författare)
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Protection of Kidney Function with Human Antioxidation Protein α 1 -Microglobulin in a Mouse 177 Lu-DOTATATE Radiation Therapy Model
- 2019
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Ingår i: Antioxidants and Redox Signaling. - : Mary Ann Liebert Inc. - 1523-0864 .- 1557-7716. ; 30:14, s. 1746-1759
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Peptide receptor radionuclide therapy (PRRT) is in clinical use today to treat metastatic neuroendocrine tumors. Infused, radiolabeled, somatostatin analog peptides target tumors that are killed by irradiation damage. The peptides, however, are also retained in kidneys due to glomerular filtration, and the administered doses must be limited to avoid kidney damage. The human radical scavenger and antioxidant, α 1 -microglobulin (A1M), has previously been shown to protect bystander tissue against irradiation damage and has pharmacokinetic and biodistribution properties similar to somatostatin analogs. In this study, we have investigated if A1M can be used as a renal protective agent in PRRT. Results: We describe nephroprotective effects of human recombinant A1M on the short- and long-term renal damage observed following lutetium 177 ( 177 Lu)-DOTATATE (150 MBq) exposure in BALB/c mice. After 1, 4, and 8 days (short term), 177 Lu-DOTATATE injections resulted in increased formation of DNA double-strand breaks in the renal cortex, upregulated expression of apoptosis and stress response-related genes, and proteinuria (albumin in urine), all of which were significantly suppressed by coadministration of A1M (7 mg/kg). After 6, 12, and 24 weeks (long term), 177 Lu-DOTATATE injections resulted in increased animal death, kidney lesions, glomerular loss, upregulation of stress genes, proteinuria, and plasma markers of reduced kidney function, all of which were suppressed by coadministration of A1M. Innovation and Conclusion: This study demonstrates that A1M effectively inhibits radiation-induced renal damage. The findings suggest that A1M may be used as a radioprotector during clinical PRRT, potentially facilitating improved tumor control and enabling more patients to receive treatment. © Amanda Kristiansson et al. 2018; Published by Mary Ann Liebert, Inc.
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| 3. |
- Romantsik, Olga, et al.
(författare)
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The heme and radical scavenger α1-microglobulin (A1M) confers early protection of the immature brain following preterm intraventricular hemorrhage
- 2019
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Germinal matrix intraventricular hemorrhage (GM-IVH) is associated with cerebro-cerebellar damage in very preterm infants, leading to neurodevelopmental impairment. Penetration, from the intraventricular space, of extravasated red blood cells and extracellular hemoglobin (Hb), to the periventricular parenchyma and the cerebellum has been shown to be causal in the development of brain injury following GM-IVH. Furthermore, the damage has been described to be associated with the cytotoxic nature of extracellular Hb-metabolites. To date, there is no therapy available to prevent infants from developing either hydrocephalus or serious neurological disability. Mechanisms previously described to cause brain damage following GM-IVH, i.e., oxidative stress and Hb-metabolite toxicity, suggest that the free radical and heme scavenger α1-microglobulin (A1M) may constitute a potential neuroprotective intervention. Methods: Using a preterm rabbit pup model of IVH, where IVH was induced shortly after birth in pups delivered by cesarean section at E29 (3 days prior to term), we investigated the brain distribution of recombinant A1M (rA1M) following intracerebroventricular (i.c.v.) administration at 24 h post-IVH induction. Further, short-term functional protection of i.c.v.-administered human A1M (hA1M) following IVH in the preterm rabbit pup model was evaluated. Results: Following i.c.v. administration, rA1M was distributed in periventricular white matter regions, throughout the fore- and midbrain and extending to the cerebellum. The regional distribution of rA1M was accompanied by a high co-existence of positive staining for extracellular Hb. Administration of i.c.v.-injected hA1M was associated with decreased structural tissue and mitochondrial damage and with reduced mRNA expression for proinflammatory and inflammatory signaling-related genes induced by IVH in periventricular brain tissue. Conclusions: The results of this study indicate that rA1M/hA1M is a potential candidate for neuroprotective treatment following preterm IVH.
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| 4. |
- Ekström, Claes, et al.
(författare)
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THE INSULIN-LIKE GROWTH FACTOR 1 (IGF-1) SYSTEM IN THE PRETERM RABBIT PUP : A CHARACTERIZATION OF THE IGF-1 MRNA EXPRESSION IN LIVER, IGF-1 PROTEIN LEVELS IN SERUM AND BRAIN DISTRIBUTION OF IGF-1 RECEPTORS
- 2019
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Konferensbidrag (refereegranskat)abstract
- IGF-1 is an essential regulator of fetal growth and brain development. Preterm birth in the human is followed by a rapid decrease in serum levels of IGF-1 and decreased levels of IGF-1 have been associated with development of severemorbidity. A recent clinical trial indicated that supplementation with IGF-1 prevented development of severe intraventricular hemorrhage (IVH) in extremely preterm infants. In order to better understand possible mechanisms involved in IGF-1-induced IVH prevention, we evaluated important aspects of the endogenous IGF-1 system; IGF-I mRNA expression in the liver and associated serum protein levels and brain IGF-1 receptor (IGFR) distribution in the preterm rabbit.Rabbit pups were delivered by cesarean section at E29 (preterm) or by vaginal delivery (term = E32), housed in a controlled environment and fed twice daily with bovine colostrum via a gastric tube. Serum concentrations of IGF-1protein and liver expression of IGF-1 mRNA were determined at 0, 2, 6, 12, 24, 48 and 72 h of age in preterm pups. Paraffin brain sections from perfusion fixed untreated animals (preterm pups at 20 h and term pups at 5-7 h and 96 h) were prepared for immunohistochemistry against IGF1R, by labeling with primary antibodies against IGF1R, and processed for chromogen visualization and density/quantitation analysis with confocal microscopy. Mean (SD) serum concentrations of IGF-1 decreased from 166 (33) ng/ml at birth (E29) to 28 (9) ng/ml at day 3 (P0). Hepatic expression of IGF-1 mRNA did not vary over time. The IGF1R was widely distributed in multiple brain regions in both preterm and term pups (Fig). The most abundant density of IGF1R was observed in the choroid plexus, the subfornical organ, the meninges, major fiber tracts, the cortex and sub-ependymal germinal zones. The IGF1R, was mainly localized on outer cell membranes, on cell bodies and along nerve fibers. Quantitative analysis of IGF1R immunoreactivity showed similar IGF1R densities in preterm and term pups of corresponding ages. IGF1R density decreased with increasing postnatal age in term pups.In line with what is observed in the preterm human infant, serum protein levels of IGF-1 in the preterm rabbit pup decrease rapidly following birth. The IGF1R is widely expressed in the brain following birth, with high expressions in regions and structures relevant for vessel rupture in IVH. The preterm rabbit thus presents a well-suited model for characterization and evaluation of mechanisms involved in IGF-1 induced prevention of IVH.
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| 5. |
- Hurley, Sinead M., et al.
(författare)
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The dynamics of platelet activation during the progression of streptococcal sepsis
- 2016
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- Platelets contribute to inflammation however, the role of platelet activation during the pathophysiological response to invasive bacterial infection and sepsis is not clear. Herein, we have investigated platelet activation in a mouse model of invasive Streptococcus pyogenes infection at 5,12, and 18 hours post infection and correlated this to parameters of infection. The platelet population in ex-vivo blood samples showed no increased integrin activation or surface presentation of CD62P, however platelet-neutrophil complex formation and plasma levels of CD62P were increased during bacterial dissemination and the progression of sepsis, indicating that platelet activation had occurred in vivo. Platelet-neutrophil complex formation was the most discriminatory marker of platelet activation. Platelet-neutrophil complexes were increased above baseline levels during early sepsis but decreased to significantly lower levels than baseline during late sepsis. The removal of these complexes from the circulation coincided with a significant increase in organ damage and the accumulation of platelets in the liver sinusoids, suggesting that platelet activation in the circulation precedes accumulation of platelets in damaged organs. The results demonstrate that monitoring platelet activation using complementary methods may provide prognostic information during the pathogenesis of invasive S. pyogenes infection.
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| 6. |
- Isfoss, Björn Logi, et al.
(författare)
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Stellate cells and mesenchymal stem cells in benign mammary stroma are associated with risk factors for breast cancer - an observational study
- 2018
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is not known whether stromal cells in benign breast tissue can mediate risk of breast cancer. We recently described aldehyde dehydrogenase 1 A1 (ALDH1) positive (+) cells in morphologically normal breast stroma of premenopausal women, and the data indicated that their distribution is associated with clinical risk factors for breast cancer. The aim of the present study was to define the identities of these cells using histologic and immunohistologic methods, and to investigate associations between those cells and hormonal and genetic risk factors in pre- and postmenopausal women. Methods: Stroma of morphologically normal tissue was analyzed in samples from 101 well-characterized women whose breasts had been operated. Morphology and immunolabeling were applied to determine cell identities based on the putative stem cell markers ALDH1 and stage-specific embryonic antigen-3 (SSEA3), and immunophenotypes indicating mast cells or stellate cells. The results were compared with the patients' risk factors using regression analysis (two-tailed). Results: ALDH1+ round/oval cells were associated with low parity in BRCA1/2 carriers (p=0.022), while in non-BRCA1/2-carriers they were negatively associated with nulliparity (p=0.057). In premenopausal women ALDH1+ round/oval cells were associated with family history (p=0.058). SSEA3+ round/oval cells were morphologically and immunohistologically consistent with multilineage stress-enduring (Muse) cells, and these cells were independently associated with the breast cancer risk factors low parity (p=0.015), family history (p=0.021), and hormone use after menopause (p=0.032). ALDH1+ spindle-shaped/polygonal cells were immunohistologically consistent with stellate cells, and were negatively associated with family history of breast cancer (p=0.001). Conclusion: This study identified novel stromal cell types in benign breast tissue that have a potential for stratifying women for breast cancer risk.
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| 7. |
- Isfoss, Björn Logi, et al.
(författare)
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The absence of aldehyde dehydrogenase 1 A1-positive cells in benign mammary stroma is associated with risk factors for breast cancer
- 2016
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Ingår i: Breast Cancer: Targets and Therapy. - 1179-1314. ; 8, s. 117-124
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Tidskriftsartikel (refereegranskat)abstract
- In this study, aldehyde dehydrogenase 1 (ALDH1)-expressing cells in stroma of histologically normal breast tissue from premenopausal women were investigated in situ regarding cellular morphology, cell distribution, and relation to the additional stem cell markers, CD44 (+) and CD24 (-). These results were correlated with hormonal and genetic risk factors for breast cancer. Triple immunofluorescence labeling was performed on tissues from premenopausal women with a family history of breast cancer, and breast reduction specimens from premenopausal women with no family history of breast cancer were used as a control group. The majority of ALDH1-immunoreactive cells in stroma were spindle-shaped or polygonal, and such cells that were CD44- and CD24- were absent in the breast stroma of a significantly larger number of nulliparous than parous women. A less common morphological type of ALDH1-positive cells in stroma was round or oval in shape, and such cells that were CD44+ and CD24- were absent in a significant number of women with a family history of breast cancer. The CD44+/CD24- immunophenotype is consistent with stem cells, and the round/oval morphology suggests mesenchymal cells. This study demonstrates that there are two morphologically distinct types of ALDH1-positive cells in histologically benign mammary stroma, and the absence of these cells is correlated with clinical risk factors for breast cancer in premenopausal women.
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| 8. |
- Krochak, Paul J., et al.
(författare)
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Headbox induced sheet variability
- 2017
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Ingår i: PaperCon 2017. ; , s. 673-680
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 9. |
- Ley, David, et al.
(författare)
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High presence of extracellular hemoglobin in the periventricular white matter following preterm intraventricular hemorrhage
- 2016
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 7:AUG
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Tidskriftsartikel (refereegranskat)abstract
- Severe cerebral intraventricular hemorrhage (IVH) in preterm infants continues to be a major clinical problem, occurring in about 15-20% of very preterm infants. In contrast to other brain lesions the incidence of IVH has not been reduced over the last decade, but actually slightly increased. Currently over 50% of surviving infants develop post-hemorrhagic ventricular dilatation and about 35% develop severe neurological impairment, mainly cerebral palsy and intellectual disability. To date there is no therapy available to prevent infants from developing either hydrocephalus or serious neurological disability. It is known that blood rapidly accumulates within the ventricles following IVH and this leads to disruption of normal anatomy and increased local pressure. However, the molecular mechanisms causing brain injury following IVH are incompletely understood. We propose that extracellular hemoglobin is central in the pathophysiology of periventricular white matter damage following IVH. Using a preterm rabbit pup model of IVH the distribution of extracellular hemoglobin was characterized at 72 h following hemorrhage. Evaluation of histology, histochemistry, hemoglobin immunolabeling and scanning electron microscopy revealed presence of extensive amounts of extracellular hemoglobin, i.e., not retained within erythrocytes, in the periventricular white matter, widely distributed throughout the brain. Furthermore, double immunolabeling together with the migration and differentiation markers polysialic acid neural cell adhesion molecule (PSA-NCAM) demonstrates that a significant proportion of the extracellular hemoglobin is distributed in areas of the periventricular white matter with high extracellular plasticity. In conclusion, these findings support that extracellular hemoglobin may contribute to the pathophysiological processes that cause irreversible damage to the immature brain following IVH.
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| 10. |
- Thorén, Matilda Munksgaard, et al.
(författare)
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Integrin α10, a novel therapeutic target in glioblastoma, regulates cell migration, proliferation, and survival
- 2019
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 11:4
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Tidskriftsartikel (refereegranskat)abstract
- New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10Β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10Β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody-drug conjugate (ADC), an integrin a10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10Β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10Β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.
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