| 1. |
- Alkharusi, Amira, et al.
(författare)
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Stimulation of prolactin receptor induces STAT-5 phosphorylation and cellular invasion in glioblastoma multiforme
- 2016
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Ingår i: Oncotarget. - : Impact Journals LLC. - 1949-2553. ; 7:48, s. 79558-79569
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in humans and is characterized with poor outcome. In this study, we investigated components of prolactin (Prl) system in cell models of GBM and in histological tissue sections obtained from GBM patients. Expression of Prolactin receptor (PrlR) was detected at high levels in U251-MG, at low levels in U87-MG and barely detectable in U373 cell lines and in 66% of brain tumor tissues from 32 GBM patients by immunohistochemical technique. In addition, stimulation of U251-MG and U87-MG cells but not U373 with Prl resulted in increased STAT5 phosphorylation and only in U251-MG cells with increased cellular invasion. Furthermore, STAT5 phosphorylation and cellular invasion induced in Prl stimulated cells were significantly reduced by using a Prl receptor antagonist that consists of Prl with four amino acid replacements. We conclude that Prl receptor is expressed at different levels in the majority of GBM tumors and that blocking of PrlR in U251-MG cells significantly reduce cellular invasion.
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| 2. |
- Almazan, Nerea Martin, et al.
(författare)
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Influenza-A mediated pre-existing immunity levels to SARS-CoV-2 could predict early COVID-19 outbreak dynamics
- 2023
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Ingår i: iScience. - : CELL PRESS. - 2589-0042. ; 26:12
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Tidskriftsartikel (refereegranskat)abstract
- Susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is highly variable and could be mediated by a cross-protective pre-immunity. We identified 14 cross-reactive peptides between SARS-CoV-2 and influenza A H1N1, H3N2, and human herpesvirus (HHV)-6A/B with potential relevance. The H1N1 peptide NGVEGF was identical to a peptide in the most critical receptor binding motif in SARS-CoV-2 spike protein that interacts with the angiotensin converting enzyme 2 receptor. About 62%-73% of COVID-19-negative blood donors in Stockholm had antibodies to this peptide in the early pre-vaccination phase of the pandemic. Seasonal flu vaccination enhanced neutralizing capacity to SARS-CoV-2 and T cell immunity to this peptide. Mathematical modeling taking the estimated pre -immunity levels to flu into account could fully predict pre-Omicron SARS-CoV-2 outbreaks in Stockholm and India. This cross-immunity provides mechanistic explanations to the epidemiological observation that influenza vaccination protected people against early SARS-CoV-2 infections and implies that flu-mediated cross-protective immunity significantly dampened the first SARS-CoV-2 outbreaks.
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| 3. |
- Baryawno, Ninib, et al.
(författare)
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Detection of human cytomegalovirus in medulloblastomas reveals a potential therapeutic target
- 2011
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 121:10, s. 4043-4055
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Tidskriftsartikel (refereegranskat)abstract
- Medulloblastomas are the most common malignant brain tumors in children. They express high levels of COX-2 and produce PGE(2), which stimulates tumor cell proliferation. Human cytomegalovirus (HCMV) is prevalent in the human population and encodes proteins that provide immune evasion strategies and promote oncogenic transformation and oncomodulation. In particular, HCMV induces COX-2 expression; STAT3 phosphorylation; production of PGE2, vascular endothelial growth factor, and IL-6; and tumor formation in vivo. Here, we show that a large proportion of primary medulloblastomas and medulloblastoma cell lines are infected with HCMV and that COX-2 expression, along with PGE2 levels, in tumors is directly modulated by the virus. Our analysis indicated that both HCMV immediate-early proteins and late proteins are expressed in the majority of primary medulloblastomas. Remarkably, all of the human medulloblastoma cell lines that we analyzed contained HCMV DNA and RNA and expressed HCMV proteins at various levels in vitro. When engrafted into immunocompromised mice, human medulloblastoma cells induced expression of HCMV proteins. HCMV and COX-2 expression correlated in primary tumors, cell lines, and medulloblastoma xenografts. The antiviral drug valganciclovir and the specific COX-2 inhibitor celecoxib prevented HCMV replication in vitro and inhibited PGE2 production and reduced medulloblastoma tumor cell growth both in vitro and in vivo. Ganciclovir did riot affect the growth of HCMV-negative tumor cell lines. These findings imply an important role for HCMV in medulloblastoma and suggest HCMV as a novel therapeutic target for this tumor.
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| 4. |
- Dzabic, Mensur, et al.
(författare)
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Intragraft Cytomegalovirus Protein Expression Is Associated With Reduced Renal Allograft Survival
- 2011
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 53:10, s. 969-976
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cytomegalovirus (CMV) infection is a risk factor for acute and chronic rejection of transplanted organs and is thought to mediate rejection indirectly. Methods: In this retrospective observational cohort study, early- and end-stage biopsies from renal allografts lost because of chronic allograft dysfunction (n = 29) were examined for CMV antigens and DNA using immunohistochemistry, in situ hybridization, and real-time polymerase chain reaction. Results: CMV immediate-early and late proteins were present in 27 (93%) of 29 of the end-stage chronic allograft dysfunction biopsies and in 64% of the corresponding early biopsies but not in pretransplant biopsies from CMV-seronegative donors (n = 3). Graft survival time was reduced in patients with moderate or high CMV levels in the graft soon after transplantation compared with that in patients with no or low CMV levels in the graft. No significant difference was observed in serum creatinine obtained at the time of early biopsies. Conclusions: We provide evidence that intragraft CMV protein expression is associated with end-stage chronic renal allograft dysfunction, that intragraft CMV levels increase as graft function deteriorates, and that CMV protein expression in the grafts soon after transplant is associated with reduced graft survival. Thus, CMV may have a pathological role in chronic renal allograft dysfunction.
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| 5. |
- Gredmark-Russ, Sara, et al.
(författare)
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Active cytomegalovirus infection in aortic smooth muscle cells from patients with abdominal aortic aneurysm
- 2009
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Ingår i: Journal of Molecular Medicine. - : Springer Science and Business Media LLC. - 0946-2716 .- 1432-1440. ; 87:4, s. 347-356
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Tidskriftsartikel (refereegranskat)abstract
- Cytomegalovirus (CMV) is associated with atherosclerosis and transplant vascular sclerosis. The aim of this study was to explore the hypothesis that active CMV infection in the vessel wall could be associated with abdominal aortic aneurysm (AAA). We examined the prevalence of CMV in AAA specimens from 22 patients undergoing surgery and, in five cases, characterized the function of smooth muscle cells (SMCs) from the aneurysm in vitro. Twenty-one (95%) of the 22 AAA specimens were CMV positive by a polymerase chain reaction assay, in situ hybridization, or a highly sensitive immunohistochemical staining technique. No positive cells were found in aortas from three CMV-seronegative organ donor cadavers. CMV immediate-early and late antigens were expressed in SMCs in the lesions and were associated with 5-lipoxygenase (5-LO) expression. CMV-positive intimal SMCs migrated 6.6 +/- 1.5 times more efficiently than CMV-negative medial SMCs (p < 0.05). In vitro CMV infection of medial SMCs resulted in a 3.2 +/- 1.2 times increase in migration (p < 0.05). The intimal migration was significantly inhibited by antibodies against basic fibroblast growth factor (bFGF; p < 0.05) in a dose-dependent fashion. Antibodies against platelet-derived growth factor (PDGF)-AB, insulin-like growth factor 1, vascular endothelial growth factor (VEGF), RANTES, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha, or interleukin-1beta did not significantly affect intimal SMC migration. However, intimal and medial SMCs secreted similar amounts of bFGF, MCP-1, MIP-1alpha, RANTES, PDGF-AB, PDGF-BB, epidermal growth factor, and VEGF. CMV infection in vitro of intimal and medial cells did not result in significant changes of bFGF or MCP-1 secretion. Since CMV infection can affect several functional parameters in SMCs, including several key factors in infected SMCs, our findings provide support for the hypothesis that CMV contributes to the pathogenesis of abdominal aortic aneurysm.
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| 6. |
- Omarsdottir, Soley, et al.
(författare)
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High prevalence of cytomegalovirus infection in surgical intestinal specimens from infants with necrotizing enterocolitis and spontaneous intestinal perforation : A retrospective observational study
- 2017
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Ingår i: Journal of Clinical Virology. - : Elsevier BV. - 1386-6532 .- 1873-5967. ; 93, s. 57-64
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Tidskriftsartikel (refereegranskat)abstract
- Background: Necrotizing enterocolitis (NEC) is a severe, often fatal gastrointestinal emergency that predominantly affects preterm infants, and there is evidence that neonatal cytomegalovirus (CMV) infection may in some cases contribute to its pathogenesis.Objectives: This study aimed to evaluate the prevalence of CMV in infants with NEC.Study design: Seventy intestinal specimens from 61 infants with NEC, spontaneous intestinal perforation (SIP), or related surgical complications were collected at Karolinska University Hospital and Uppsala University Hospital, Sweden. Ten specimens from autopsied infants without bowel disease served as controls. Samples were analyzed for CMV immediate-early antigen (IEA), CMV late antigen (LA), 5-lipoxigenase (5LO) and CMV-DNA by immunohistochemistry (IHC) and in situ hybridization (ISH), respectively. In 10 index samples, CMV DNA was analyzed with Taqman PCR after laser capture microdissection (LCM) of cells positive for CMV IEA by IHC.Results: CMV IEA was detected by IHC in 57 (81%) and CMV LA in 45 (64%) of 70 intestinal specimens from index cases; 2 (20%) of 10 control specimens were positive for both antigens. 5LO was detected in intestinal tissue section obtained from all examined index and controls. CMV DNA was detected in 4 of 10 samples (40%) after LCM. By ISH, all 13 IHC-IEA-positive samples were positive for CMV DNA; however, 3 of 5 IHC-IEAnegative samples (60%) were also positive.Conclusions: CMV-specific antigens and CMV DNA were highly prevalent in intestinal specimens from infants with NEC, SIP, and related surgical complications. Our findings provide further evidence that neonatal CMV infection contributes to the pathogenesis of these diseases and may affect patient outcome.
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| 7. |
- Rahbar, Afsar
(författare)
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Human cytomegalovirus (HCMV) infection in patients with inflammatory bowel diseases (IBD) : role in pathogenesis and autoimmunity
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human cytomegalovirus (HCMV) is one of eight members of the herpesvirus family that infects humans. Like other herpes viruses, HCMV establishes a latent infection after the primary infection, and reactivation may occur later in life. HCMV disease of the gastrointestinal (GI) tract is a major cause of morbidity and mortality in immunocompromised patients. The Inflammatory Bowel Diseases (IBD); ulcerative colitis (UC) and Crohn's disease (CD) are believed to have many etiologies and a number of risk factors have been implied in the pathogenesis of IBD. An initial environmental insult most likely leads to damage to the intestinal mucosal barrier and results in an inflammatory response that leads to the development of HID in genetically susceptible individuals. However, the nature of the infectious or environmental agent that may trigger and perpetuate the intestinal inflammation in UC and CD remains unknown. In the last four decades, 33 reports have described HCMV colitis as a complication of IBD. This diagnosis is not frequently considered and, if not made, leads to a high rate of colectomy (67%) and mortality (33%). Appropriate antiviral therapy appears to eliminate the virus found as a complication of the disease. The current view is that peripheral blood monocytes constitute a major site of viral latency and that differentiation of such cells into tissue macrophages upon stimulation by proinflammatory cytokines can reactivate a latent HCMV infection. In this study, we have detected an active HCMV infection in 85% of patients with UC and in 100% of patients with CD. Cells double stained for HCMV and IL-6 were detected i n intestinal tissue sections in 77% of patients with UC and in 100% of patients with CD. These observations suggest that an active HCMV infection in the intestine is very frequent in patients with IBD, and that the virus may contribute to the inflammatory process through increased production of IL-6. Furthermore, previous studies have also suggested an association between active HCMV infection and production of auto-antibodies against CD13. Here, we found cytotoxic autoantibodies specific for CD13 OBS 3 in 66% and 58% of patients with UC and CD, respectively. These observations suggest that auto-antibodies recognizing CD13 may for example, interfere with cell function, possibly thereby contributing to the chronic inflammation in the bowel of IBD patients. HCMV may also contribute to the development of different complications in IBD patients. Increased platelet numbers, activation and aggregation are wellrecognized indicators of disease activity in IBD and the virus may interfere with such processes. Here, we observed platelet aggregation and adhesion to HCMV infected endothelial cells in vitro, which could be significantly reduced by blocking of von Willebrand factor (vWF) with monoclonal antibodies. We detected high levels of vWF expression on HCMV infected endothelial cells. The increased thrombogenicity observed was dependent on active virus replication and could be inhibited by foscarnet and ganciclovir, which suggest that a late viral gene may be mediating the phenomenon. We speculate that the increased thrombogenicity by HCMV may contribute to the development of thromboembolic diseases that occur in IBD patients as well as in patients with atherosclerosis. Furthermore, it is well known that active episodes of IBD are histologically characterized by extravasation and infiltration of a large numbers of active neutrophils. We therefore examined whether HCMV could affect neutrophil functions. Our results suggest that HCMV infected neutrophils become over-reactive and that inhibition of apoptosis may cause the neutrophils to remain in the system for prolonged periods of time. Increased survival of these cells in inflamed tissues and increased release of reactive oxygen species may lead to damaging of the surrounding tissues resulting in further aggravation in diseases such as IBD and possibly also in other chronic inflammatory diseases. In conclusion, we provide evidence that an active HCMV infection is very frequent in IBD patients with severe symptoms, and that the virus may contribute to the inflammatory process and long term complications. Since antiviral drugs against HCMV are available, some IBD patients may in the future benefit from antiviral treatment and may avoid surgical treatment.
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| 8. |
- Wahlin, Bengt, et al.
(författare)
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Atherosclerosis in rheumatoid arthritis : associations between anti-cytomegalovirus IgG antibodies, CD4+CD28null T-cells, CD8+CD28null T-cells and intima-media thickness
- 2021
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Ingår i: Clinical and Experimental Rheumatology. - : Clinical and Experimental Rheumatology S.A.S.. - 0392-856X .- 1593-098X. ; 39:3, s. 578-586
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Patients with rheumatoid arthritis (RA) have an accelerated progression of atherosclerosis. The aims of this study were to study the associations between subsets of T-cells, subclinical atherosclerosis assessed by intima-media thickness (IMT) and serological status for CMV in patients with RA.Methods: Patients with new-onset RA (n=79), aged ≤60 years at diagnosis, were included in a prospective study of atherosclerosis. Controls matched for age and sex were also included (n=44). Ultrasound measurement of IMT in the common carotid artery was undertaken at inclusion (T0), after 1.5 years (T1.5) and after 11 years (T11). At T11, flow-cytometry analysis was undertaken to investigate subsets of T-cells. Serological analysis for CMV was undertaken from samples collected at T0.Results: At T0, 66% of the patients and controls were CMV immunoglobulin G-positive. CMV-IgG positive patients had a significantly more rapid increase in IMT at T1.5, compared with controls and CMV-IgG negative patients. CMV-IgG positive patients had a significantly higher percentage of T-cells lacking CD28 (both CD4+CD28null and CD8+CD28null T-cells) than CMV-IgG negative patients. Increased levels of CD4+CD28null and CD8+CD28null T-cells were significantly associated with IMT at T11, adjusted for systolic blood pressure. CX3CR1 was expressed in CD4+ and CD8+ CD28null T-cells, but CX3CR1 per se was not associated with increased IMT.Conclusions: Presence of CMV IgG-antibodies in patients with RA is associated with altered T-cell-populations and an increased burden of atherosclerosis. A possible protective effect of antiviral treatment in CMV-positive patients with new-onset RA should be considered.
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