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- Merchut-Maya, Joanna Maria, et al.
(författare)
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Human cytomegalovirus hijacks host stress response fueling replication stress and genome instability
- 2022
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Ingår i: Cell Death and Differentiation. - : Springer Science and Business Media LLC. - 1350-9047 .- 1476-5403. ; 29:8, s. 1639-1653
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Tidskriftsartikel (refereegranskat)abstract
- Viral infections enhance cancer risk and threaten host genome integrity. Although human cytomegalovirus (HCMV) proteins have been detected in a wide spectrum of human malignancies and HCMV infections have been implicated in tumorigenesis, the underlying mechanisms remain poorly understood. Here, we employed a range of experimental approaches, including single-molecule DNA fiber analysis, and showed that infection by any of the four commonly used HCMV strains: AD169, Towne, TB40E or VR1814 induced replication stress (RS), as documented by host-cell replication fork asymmetry and formation of 53BP1 foci. The HCMV-evoked RS triggered an ensuing host DNA damage response (DDR) and chromosomal instability in both permissive and non-permissive human cells, the latter being particularly relevant in the context of tumorigenesis, as such cells can survive and proliferate after HCMV infection. The viral major immediate early enhancer and promoter (MIEP) that controls expression of the viral genes IE72 (IE-1) and IE86 (IE-2), contains transcription-factor binding sites shared by promoters of cellular stress-response genes. We found that DNA damaging insults, including those relevant for cancer therapy, enhanced IE72/86 expression. Thus, MIEP has been evolutionary shaped to exploit host DDR. Ectopically expressed IE72 and IE86 also induced RS and increased genomic instability. Of clinical relevance, we show that undergoing standard-of-care genotoxic radio-chemotherapy in patients with HCMV-positive glioblastomas correlated with elevated HCMV protein markers after tumor recurrence. Collectively, these results are consistent with our proposed concept of HCMV hijacking transcription-factor binding sites shared with host stress-response genes. We present a model to explain the potential oncomodulatory effects of HCMV infections through enhanced replication stress, subverted DNA damage response and induced genomic instability.
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- Thurin, Erik, et al.
(författare)
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Return to work following meningioma surgery : a Swedish nationwide registry-based matched cohort study
- 2020
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Ingår i: Neuro-Oncology Practice. - : Oxford University Press (OUP). - 2054-2577 .- 2054-2585. ; 7:3, s. 320-328
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Tidskriftsartikel (refereegranskat)abstract
- Background: Meningioma is the most common primary intracranial tumor. It is usually slow growing and benign, and surgery is the main treatment modality. There are limited data on return to work following meningioma surgery. The objective of this study was to determine the patterns of sick-leave rate prior to surgery, and up to 2 years after, in patients compared to matched controls.Methods: Data on patients ages 18 to 60 years with histologically verified intracranial meningioma between 2009 and 2015 were identified in the Swedish Brain Tumor Registry (SBTR) and linked to 3 national registries after 5 matched controls were assigned to each patient.Results: We analyzed 956 patients and 4765 controls. One year prior to surgery, 79% of meningioma patients and 86% of controls were working (P < .001). The proportion of patients at work 2 years after surgery was 57%, in contrast to 84% of controls (P < .001). Statistically significant negative predictors for return to work in patients 2 years after surgery were high (vs low) tumor grade, previous history of depression, amount of sick leave in the year preceding surgery, and surgically acquired neurological deficits.Conclusion: There is a considerable risk for long term sick leave 2 years after meningioma surgery. Neurological impairment following surgery was a modifiable risk factor increasing the risk for long-term sick leave. More effective treatment of depression may facilitate return to work in this patient group.
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