| 1. |
- Schmidt, Linnéa, et al.
(author)
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Case-specific potentiation of glioblastoma drugs by pterostilbene
- 2016
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:45, s. 73200-73215
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Journal article (peer-reviewed)abstract
- Glioblastoma multiforme (GBM, astrocytoma grade IV) is the most common malignant primary brain tumor in adults. Addressing the shortage of effective treatment options for this cancer, we explored repurposing of existing drugs into combinations with potent activity against GBM cells. We report that the phytoalexin pterostilbene is a potentiator of two drugs with previously reported anti-GBM activity, the EGFR inhibitor gefitinib and the antidepressant sertraline. Combinations of either of these two compounds with pterostilbene suppress cell growth, viability, sphere formation and inhibit migration in tumor GBM cell (GC) cultures. The potentiating effect of pterostilbene was observed to a varying degree across a panel of 41 patient-derived GCs, and correlated in a case specific manner with the presence of missense mutation of EGFR and PIK3CA and a focal deletion of the chromosomal region 1p32. We identify pterostilbene-induced cell cycle arrest, synergistic inhibition of MAPK activity and induction of Thioredoxin interacting protein (TXNIP) as possible mechanisms behind pterostilbene's effect. Our results highlight a nontoxic stilbenoid compound as a modulator of anticancer drug response, and indicate that pterostilbene might be used to modulate two anticancer compounds in well-defined sets of GBM patients.
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| 2. |
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| 3. |
- Bergman, Lina, et al.
(author)
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Investigating Maternal Brain Alterations in Preeclampsia : the Need for a Multidisciplinary Effort
- 2019
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In: Current Hypertension Reports. - : Springer Science and Business Media LLC. - 1522-6417 .- 1534-3111. ; 21:9
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Journal article (peer-reviewed)abstract
- PURPOSE OF REVIEW: To provide insight into the mechanisms underlying cerebral pathophysiology and to highlight possible methods for evaluation, screening, and surveillance of cerebral complications in preeclampsia.RECENT FINDINGS: The pathophysiology of eclampsia remains enigmatic. Animal studies show that the cerebral circulation in pregnancy and preeclampsia might be affected with increased permeability over the blood-brain barrier and altered cerebral blood flow due to impaired cerebral autoregulation. The increased blood pressure cannot be the only underlying cause of eclampsia and cerebral edema, since some cases of eclampsia arise without simultaneous hypertension. Findings from animal studies need to be confirmed in human tissues. Evaluation of brain alterations in preeclampsia and eclampsia is challenging and demands a multidisciplinary collaboration, since no single method can accurately and fully describe how preeclampsia affects the brain. Cerebral complications of preeclampsia are significant factors in maternal morbidity and mortality worldwide. No single method can accurately describe the full picture of how preeclampsia affects the brain vasculature and parenchyma. We recommend an international and multidisciplinary effort not only to overcome the issue of limited sample availability but also to optimize the quality of research.
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| 4. |
- Bergman, Lina, et al.
(author)
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Preeclampsia and Increased Permeability Over the Blood–Brain Barrier : A Role of Vascular Endothelial Growth Receptor 2
- 2021
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In: American Journal of Hypertension. - : Oxford University Press. - 0895-7061 .- 1941-7225. ; 34:1, s. 73-81
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Journal article (peer-reviewed)abstract
- BACKGROUND: Cerebral complications in preeclampsia are leading causes of maternal mortality worldwide but the underlying pathophysiology is largely unknown and a challenge to study. Using an in vitro model of the human blood brain barrier (BBB), we explored the role of vascular endothelial growth factor receptor 2 (VEGFR2) in preeclampsia.METHODS: The human brain endothelial cell line (hCMEC/D3) cultured on Tranwells insert were exposed (12 h) to plasma from women with preeclampsia (n=28), normal pregnancy (n=28) and non-pregnant (n=16) controls. Transendothelial electrical resistance (TEER) and permeability to 70 kDa FITC-dextran were measured for assessment of BBB integrity. We explored possible underlying mechanisms, with focus on expression of tight junction proteins and phosphorylation of two tyrosine residues of VEGFR2, associated with vascular permeability and migration (pY951) and cell proliferation (pY1175). Plasma concentrations of soluble FMS like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) were measured in order to establish correlations with in vitro results.RESULTS: hCMEC/D3 exposed to plasma from women with preeclampsia exhibited reduced TEER and increased permeability to 70 kDa FITC-dextran. Further, these cells up-regulated the mRNA levels of VEGFR2, as well as pY951-VEGFR2; but reduced pY1175-VEGFR2 (p&0.05 in all cases). No difference in mRNA expression of tight junction protein was observed between gruops. There was no correlation between angiogenic biomarkers and BBB permeability.CONCLUSION: We present a promising in vitro model of the BBB in preeclampsia. Selective tyrosine phosphorylation of VEGFR2 may participate in the increased BBB permeability in preeclampsia irrespective of plasma concentrations of angiogenic biomarkers.
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| 5. |
- Fedele, Vita, et al.
(author)
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Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression
- 2017
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In: Molecular Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1541-7786 .- 1557-3125. ; 15:8, s. 998-1011
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Journal article (peer-reviewed)abstract
- Glioblastoma (GBM) comprises distinct subtypes characterized by their molecular profile. Mesenchymal identity in GBM has been associated with a comparatively unfavorable prognosis, primarily due to inherent resistance of these tumors to current therapies. The identification of molecular determinants of mesenchymal transformation could potentially allow for the discovery of new therapeutic targets. Zinc Finger and BTB Domain Containing 18 (ZBTB18/ZNF238/RP58) is a zinc finger transcriptional repressor with a crucial role in brain development and neuronal differentiation. Here, ZBTB18 is primarily silenced in the mesenchymal subtype of GBM through aberrant promoter methylation. Loss of ZBTB18 contributes to the aggressive phenotype of glioblastoma through regulation of poor prognosis-associated signatures. Restitution of ZBTB18 expression reverses the phenotype and impairs tumor-forming ability. These results indicate that ZBTB18 functions as a tumor suppressor in GBM through the regulation of genes associated with phenotypically aggressive properties.
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| 6. |
- Friis, Therese, et al.
(author)
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Cerebral Biomarkers and Blood-Brain Barrier Integrity in Preeclampsia
- 2022
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In: Cells. - : MDPI AG. - 2073-4409. ; 11:5
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Journal article (peer-reviewed)abstract
- Cerebral complications in preeclampsia contribute substantially to maternal mortality and morbidity. There is a lack of reliable and accessible predictors for preeclampsia-related cerebral complications. In this study, plasma from women with preeclampsia (n = 28), women with normal pregnancies (n = 28) and non-pregnant women (n = 16) was analyzed for concentrations of the cerebral biomarkers neurofilament light (NfL), tau, neuron-specific enolase (NSE) and S100B. Then, an in vitro blood-brain barrier (BBB) model, based on the human cerebral microvascular endothelial cell line (hCMEC/D3), was employed to assess the effect of plasma from the three study groups. Transendothelial electrical resistance (TEER) was used as an estimation of BBB integrity. NfL and tau are proteins expressed in axons, NSE in neurons and S100B in glial cells and are used as biomarkers for neurological injury in other diseases such as dementia, traumatic brain injury and hypoxic brain injury. Plasma concentrations of NfL, tau, NSE and S100B were all higher in women with preeclampsia compared with women with normal pregnancies (8.85 vs. 5.25 ng/L, p < 0.001; 2.90 vs. 2.40 ng/L, p < 0.05; 3.50 vs. 2.37 mu g/L, p < 0.001 and 0.08 vs. 0.05 mu g/L, p < 0.01, respectively). Plasma concentrations of NfL were also higher in women with preeclampsia compared with non-pregnant women (p < 0.001). Higher plasma concentrations of the cerebral biomarker NfL were associated with decreased TEER (p = 0.002) in an in vitro model of the BBB, a finding which indicates that NfL could be a promising biomarker for BBB alterations in preeclampsia.
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| 7. |
- Heiland, Dieter H., et al.
(author)
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c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas
- 2017
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:4, s. 6940-6954
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Journal article (peer-reviewed)abstract
- High-grade gliomas (HGG) are the most common brain tumors, with an average survival time of 14 months. A glioma-CpG island methylator phenotype (G-CIMP), associated with better clinical outcome, has been described in low and high-grade gliomas. Mutation of IDH1 is known to drive the G-CIMP status. In some cases, however, the hypermethylation phenotype is independent of IDH1 mutation, suggesting the involvement of other mechanisms. Here, we demonstrate that DNMT1 expression is higher in low-grade gliomas compared to glioblastomas and correlates with phosphorylated c-Jun. We show that phospho-c-Jun binds to the DNMT1 promoter and causes DNA hypermethylation. Phospho-c-Jun activation by Anisomycin treatment in primary glioblastoma-derived cells attenuates the aggressive features of mesenchymal glioblastomas and leads to promoter methylation and downregulation of key mesenchymal genes (CD44, MMP9 and CHI3L1). Our findings suggest that phospho-c-Jun activates an important regulatory mechanism to control DNMT1 expression and regulate global DNA methylation in Glioblastoma.
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| 8. |
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| 9. |
- Johansson, Patrik, et al.
(author)
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A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma
- 2020
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 32:2
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Journal article (peer-reviewed)abstract
- Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells, We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.
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| 10. |
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| 11. |
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| 12. |
- Marques, Carolina, et al.
(author)
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NF1 regulates mesenchymal gliblastoma plasticity and aggressiveness through the AP-1 transcription factor FOSL1
- 2021
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In: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 10
-
Journal article (peer-reviewed)abstract
- The molecular basis underlying glioblastoma (GBM) heterogeneity and plasticity is not fully understood. Using transcriptomic data of human patient-derived brain tumor stem cell lines (BTSCs), classified based on GBM-intrinsic signatures, we identify the AP-1 transcription factor FOSL1 as a key regulator of the mesenchymal (MES) subtype. We provide a mechanistic basis to the role of the neurofibromatosis type 1 gene (NF1), a negative regulator of the RAS/MAPK pathway, in GBM mesenchymal transformation through the modulation of FOSL1 expression. Depletion of FOSL1 in NF1-mutant human BTSCs and Kras-mutant mouse neural stem cells results in loss of the mesenchymal gene signature and reduction in stem cell properties and in vivo tumorigenic potential. Our data demonstrate that FOSL1 controls GBM plasticity and aggressiveness in response to NF1 alterations.
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| 13. |
- Matuszewski, Damian J., et al.
(author)
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Image-Based Detection of Patient-Specific Drug-Induced Cell-Cycle Effects in Glioblastoma
- 2018
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In: SLAS Discovery. - : Elsevier BV. - 2472-5560 .- 2472-5552. ; 23:10, s. 1030-1039
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Journal article (peer-reviewed)abstract
- Image-based analysis is an increasingly important tool to characterize the effect of drugs in large-scale chemical screens. Herein, we present image and data analysis methods to investigate population cell-cycle dynamics in patient-derived brain tumor cells. Images of glioblastoma cells grown in multiwell plates were used to extract per-cell descriptors, including nuclear DNA content. We reduced the DNA content data from per-cell descriptors to per-well frequency distributions, which were used to identify compounds affecting cell-cycle phase distribution. We analyzed cells from 15 patient cases representing multiple subtypes of glioblastoma and searched for clusters of cell-cycle phase distributions characterizing similarities in response to 249 compounds at 11 doses. We show that this approach applied in a blind analysis with unlabeled substances identified drugs that are commonly used for treating solid tumors as well as other compounds that are well known for inducing cell-cycle arrest. Redistribution of nuclear DNA content signals is thus a robust metric of cell-cycle arrest in patient-derived glioblastoma cells.
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| 14. |
- Nelander, Maria, et al.
(author)
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Assessment of cerebral perfusion and edema in preeclampsia with intravoxel incoherent motion MRI
- 2018
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In: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 0001-6349 .- 1600-0412. ; 97:10, s. 1212-1218
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Journal article (peer-reviewed)abstract
- BackgroundCerebral complications are the main reasons for morbidity and mortality in preeclampsia and eclampsia. Still we do not know if the pathophysiology entails hypo- or hyperperfusion of the brain, or how and when edema emerges, due to the difficulty to examine the cerebral circulation.Material and methodsWe have used a non-invasive diffusion weighted magnetic resonance imaging (MRI) technique, intravoxel incoherent motion, to study cerebral perfusion on the capillary level and cerebral edema in women with preeclampsia (n=30), normal pregnancy (n=32) and non-pregnant women (n=16). Estimates of cerebral blood volume, blood flow and edema were measured in five different regions. These points were chosen to represent blood supply areas of both the carotid and vertebrobasilar arteries, and to include both white and grey matter.ResultsExcept for the caudate nucleus, we did not detect any differences in cerebral perfusion measures on a group level. In the caudate nucleus we found lower cerebral blood volume and lower blood flow in preeclampsia compared to both normal pregnancy (p=0.01 and p=0.03, respectively) and non-pregnant women (both p=0.02). No differences in edema were detected between study groups.ConclusionThe cerebral perfusion measures were comparable between the study groups, except for a portion of the basal ganglia where hypoperfusion was detected in preeclampsia compared to normal pregnancy and non-pregnant women.
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| 15. |
- Nelander, Maria, et al.
(author)
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Cerebral Magnesium Levels in Preeclampsia; A Phosphorus Magnetic Resonance Spectroscopy Study
- 2017
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In: American Journal of Hypertension. - : Oxford University Press (OUP). - 0895-7061 .- 1941-7225. ; 30:7, s. 667-672
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Journal article (peer-reviewed)abstract
- BACKGROUND: Magnesium sulfate (MgSO4) is used as a prophylaxis for eclamptic seizures. The exact mechanism of action is not fully established. We used phosphorus magnetic resonance spectroscopy (31P-MRS) to investigate if cerebral magnesium (Mg2+) levels differ between women with preeclampsia, normal pregnant, and nonpregnant women.METHODS: This cross-sectional study comprised 28 women with preeclampsia, 30 women with normal pregnancies in corresponding gestational week (range: 23-41 weeks) and 11 nonpregnant healthy controls. All women underwent 31P-MRS from the parieto-occipital region of the brain and were interviewed about cerebral symptoms. Differences between groups were assessed by analysis of variance and Tukey's post-hoc test. Correlations between Mg2+ levels and specific neurological symptoms were estimated with Spearman's rank test.RESULTS: Mean maternal cerebral Mg2+ levels were lower in women with preeclampsia (0.12 mM ± 0.02) compared to normal pregnant controls (0.14 mM ± 0.03) (P = 0.04). Nonpregnant and normal pregnant women did not differ in Mg2+ levels. Among women with preeclampsia, lower Mg2+ levels correlated with presence of visual disturbances (P = 0.04). Plasma levels of Mg2+ did not differ between preeclampsia and normal pregnancy.CONCLUSIONS: Women with preeclampsia have reduced cerebral Mg2+ levels, which could explain the potent antiseizure prophylactic properties of MgSO4. Within the preeclampsia group, women with visual disturbances have lower levels of Mg2+ than those without such symptoms.
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| 16. |
- Nelander, Maria, 1974-, et al.
(author)
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Cerebral osmolytes and plasma osmolality in pregnancy and preeclampsia : a proton magnetic resonance spectroscopy study
- 2018
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In: American Journal of Hypertension. - : Oxford University Press (OUP). - 0895-7061 .- 1941-7225. ; 31:7, s. 847-853
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Journal article (peer-reviewed)abstract
- Background: Cerebral complications contribute substantially to mortality in preeclampsia. Pregnancy calls for extensive maternal adaptations, some associated with increased propensity for seizures, but the pathophysiology behind the eclamptic seizures is not fully understood. Plasma osmolality and sodium levels are lowered in pregnancy. This could result in extrusion of cerebral organic osmolytes, including the excitatory neurotransmitter glutamate, but this remains to be determined. The hypothesis of this study was that cerebral levels of organic osmolytes are decreased during pregnancy, and that this decrease is even more pronounced in women with preeclampsia.Method: We used proton magnetic resonance spectroscopy to compare levels of cerebral organic osmolytes, in women with preeclampsia (n=30), normal pregnancy (n=32) and non-pregnant controls (n=16). Cerebral levels organic osmolytes were further correlated to plasma osmolality, and plasma levels of glutamate and sodium.Results: Compared to non-pregnant women, women with normal pregnancy and preeclampsia had lower levels of the cerebral osmolytes myo-inositol, choline and creatine (p=0.001 or less), and all these metabolites correlated with each other (p<0.05). Women with normal pregnancies and preeclampsia had similar levels of osmolytes, except for glutamate, which was significantly lower in preeclampsia. Cerebral and plasma glutamate levels were negatively correlated with each other (p<0.008), and cerebral myo-inositol, choline and creatine levels were all positively correlated with both plasma osmolality and sodium levels (p<0.05).Conclusion: Our results indicate that pregnancy is associated with extrusion of cerebral organic osmolytes. This includes the excitatory neurotransmitter glutamate, which may be involved in the pathophysiology of seizures in preeclampsia.
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| 17. |
- Nelander, Maria, 1974-
(author)
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Preeclampsia and the Brain : Epidemiological and Magnetic Resonance Studies
- 2018
-
Doctoral thesis (other academic/artistic)abstract
- Preeclampsia is a pregnancy specific syndrome that causes substantial maternal and fetal morbidity and mortality. One major contributor to maternal deaths is eclampsia, i.e. when seizures arise in the context of preeclampsia. The pathophysiology of eclampsia is still incompletely chartered and the long-term cerebral consequences of preeclampsia are also largely unknown.This thesis consists of a register based cohort study (n=3232, study I), and a cross-sectional neuroimaging study of pregnant women with and without preeclampsia (n=78, studies II-IV).In paper I, we compared the incidence of dementia and cardiovascular disease (CVD) between women ≥65 years with a self-reported history of hypertensive pregnancy, and women with a normotensive pregnancy. No difference was found regarding dementia, but an increased risk of CVD persisted among these elderly women.In paper II, we used phosphorus magnetic resonance spectroscopy to measure cerebral magnesium levels (Mg2+). We found lower levels of Mg2+ in women with preeclampsia than in women with normal pregnancy and non-pregnant women. Further, which was novel, we showed that lower cerebral Mg2+levels correlated with visual disturbances. The findings are interesting, since magnesium sulfate is the most effective treatment and prophylaxis for eclampsia, but with a largely unknown mechanism of action.In paper III, we measured cerebral organic osmolytes with proton magnetic resonance spectroscopy and found lower levels of osmolytes in pregnancy. Cerebral osmolytes were positively correlated with a decreased plasma osmolality, indicating that there is a joint biological mechanism. The only osmolyte that differed between women with preeclampsia and healthy pregnant women was glutamate. Glutamate is an excitatory neurotransmitter, which also functions as an osmolyte. Thus, lower cerebral glutamate levels could have implications on the pathophysiology of seizures.In paper IV, cerebral perfusion and edema were assessed with magnetic resonance imaging using intravoxel incoherent motion technique. A reduced perfusion fraction was found in a part of the basal ganglia in women with preeclampsia. No difference in edema was detected.Our findings indicate Mg2+ metabolism, plasma hypoosmolality and possibly cerebral hypoperfusion to be involved in the pathophysiology of cerebral affection in preeclampsia.
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| 18. |
- Nelander, Maria, et al.
(author)
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Pregnancy hypertensive disease and risk of dementia and cardiovascular disease in women aged 65 years or older : a cohort study
- 2016
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In: BMJ Open. - : BMJ. - 2044-6055. ; 6:1
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: The primary aim was to study pregnancy hypertensive disease and subsequent risk of dementia. The second aim was to study if the increased risks of cardiovascular disease (CVD) and stroke after pregnancy hypertensive disease persist in an elderly population.DESIGN: Cohort study.SETTING: Sweden.POPULATION OR SAMPLE: 3232 women 65 years or older (mean 71 years) at inclusion.METHODS: Cox proportional hazards regression analyses were used to calculate risks of dementia, CVD and/or stroke for women exposed to pregnancy hypertensive disease. Exposure data were collected from an interview at inclusion during the years 1998-2002. Outcome data were collected from the National Patient Register and Cause of Death Register from the year of inclusion until the end of 2010. Age at inclusion was set as a time-dependent variable, and adjustments were made for body mass index, education and smoking.MAIN OUTCOME MEASURES: Dementia, CVD, stroke.RESULTS: During the years of follow-up, 7.6% of the women exposed to pregnancy hypertensive disease received a diagnosis of dementia, compared with 7.4% among unexposed women (HR 1.19; 95% CI 0.79 to 1.73). The corresponding rates for CVD were 22.9% for exposed women and 19.0% for unexposed women (HR 1.29; 95% CI 1.02 to 1.61), and for stroke 13.4% for exposed women and 10.7% for unexposed women (HR 1.36; 95% CI 1.00 to 1.81).CONCLUSIONS: There was no increased risk of dementia after self-reported pregnancy hypertensive disease in our cohort. We found that the previously reported increased risk of CVD and stroke after pregnancy hypertensive disease persists in an older population.
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| 19. |
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| 20. |
- Savchenko, Julia, et al.
(author)
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Key outcomes in childbirth : Development of a perinatal core outcome set for management of labor and delivery at or near term
- 2023
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In: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley-Blackwell. - 0001-6349 .- 1600-0412. ; 102:6, s. 728-734
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Journal article (peer-reviewed)abstract
- Introduction: Consistency and relevance of perinatal outcome measures are necessary basics for obstetric research, audit, and clinical counseling. Still, there is an unwarranted variation in reported perinatal outcomes, which impairs research synthesis, validity, and implementation, as well as clinical benchmarking and longitudinal comparisons. The aim of this study was to develop a short-term perinatal (fetal and neonatal) Core Outcome Set to be used in research and quality assurance of management of labor and delivery at or near term.Material and methods: The methods were guided by the Core Outcome Measures in Effectiveness Trials Initiative Handbook. The project was prospectively registered on July 2, 2020 in the Core Outcome Measures in Effectiveness Trials (COMET) data base (reference number 1593). A list of potential outcomes was created based on a systematic review of studies evaluating interventions for peripartum management at or near term (>= 34 weeks of gestation), including decisions regarding timing and type of onset of labor, intrapartum care, and mode of delivery. The list was entered into a two-round Delphi survey with predefined consensus criteria. Participants (n = 67) included clinicians, researchers, lay persons with experience of childbirth (patient representatives), and other stakeholders. A consensus meeting was held to reach a final agreement.Results: Response rates were 82.1% (55/67) and 92.7% (51/55) for the first and second Delphi rounds, respectively. In total, 17 outcomes were included in the final core outcome set, reflecting mortality, health or morbidity, including asphyxia, central nervous system status, infection, neonatal resuscitation and admission, breastfeeding and mother-infant interaction, operative delivery due to fetal distress, as well as birthweight and gestational age. Two of these outcomes were suggested by patient representatives.Conclusions: The Swedish Perinatal Core Outcome Set (SPeCOS) study involved a broad circle of relevant stakeholders and reached consensus on a minimal set of perinatal outcomes that should be collected and reported in a standardized way in all future studies on management of labor and delivery at or near term, regardless of the specific population or condition studied. This could improve obstetric research, evidence synthesis, uptake, implementation, and adherence, as well as clinical practice, audit, and comparisons in childbirth care.
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| 21. |
- Schmidt, L., et al.
(author)
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Comparative drug pair screening across multiple glioblastoma cell lines reveals novel drug-drug interactions
- 2013
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In: Neuro-Oncology. - : Oxford University Press (OUP). - 1522-8517 .- 1523-5866. ; 15:11, s. 1469-1478
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Journal article (peer-reviewed)abstract
- Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults, and despite state-of-the-art treatment, survival remains poor and novel therapeutics are sorely needed. The aim of the present study was to identify new synergistic drug pairs for GBM. In addition, we aimed to explore differences in drug-drug interactions across multiple GBM-derived cell cultures and predict such differences by use of transcriptional biomarkers. We performed a screen in which we quantified drug-drug interactions for 465 drug pairs in each of the 5 GBM cell lines U87MG, U343MG, U373MG, A172, and T98G. Selected interactions were further tested using isobole-based analysis and validated in 5 glioma-initiating cell cultures. Furthermore, drug interactions were predicted using microarray-based transcriptional profiling in combination with statistical modeling. Of the 5 465 drug pairs, we could define a subset of drug pairs with strong interaction in both standard cell lines and glioma-initiating cell cultures. In particular, a subset of pairs involving the pharmaceutical compounds rimcazole, sertraline, pterostilbene, and gefitinib showed a strong interaction in a majority of the cell cultures tested. Statistical modeling of microarray and interaction data using sparse canonical correlation analysis revealed several predictive biomarkers, which we propose could be of importance in regulating drug pair responses. We identify novel candidate drug pairs for GBM and suggest possibilities to prospectively use transcriptional biomarkers to predict drug interactions in individual cases.
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| 22. |
- Schwartz, David A., et al.
(author)
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Placental Tissue Destruction and Insufficiency From COVID-19 Causes Stillbirth and Neonatal Death From Hypoxic-Ischemic Injury
- 2022
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In: Archives of Pathology & Laboratory Medicine. - : COLL AMER PATHOLOGISTS. - 0003-9985 .- 1543-2165. ; 146:6, s. 660-676
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Journal article (peer-reviewed)abstract
- Context.-Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear. Objective.-To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Design.-Case-based retrospective clinicopathologic analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19. Results.-Of the 3 findings constituting SARS-CoV-2 placentitis, all 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25 of 68) and chronic villitis (32%; 22 of 68). The majority (19; 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs. Conclusions.-The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.
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| 23. |
- Schwartz, David A., et al.
(author)
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Placental Tissue Destruction and Insufficiency From COVID-19 Causes Stillbirth and Neonatal Death From Hypoxic-Ischemic Injury : A Study of 68 Cases With SARS-CoV-2 Placentitis From 12 Countries
- 2022
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In: Archives of Pathology & Laboratory Medicine. - : Archives of Pathology and Laboratory Medicine. - 0003-9985 .- 1543-2165. ; 146:6, s. 660-676
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Journal article (peer-reviewed)abstract
- Context: Perinatal death is an increasingly important problem as the coronavirus disease 2019 (COVID-19) pandemic continues, but the mechanism of death has been unclear.Objective: To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Design: Case-based retrospective clinicopathologic analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19.Results: Of the 3 findings constituting SARS-CoV-2 placentitis, all 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25 of 68) and chronic villitis (32%; 22 of 68). The majority (19; 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs.Conclusions: The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.
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| 24. |
- Wee, Shimei, et al.
(author)
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Selective Calcium Sensitivity in Immature Glioma Cancer Stem Cells
- 2014
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:12
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Journal article (peer-reviewed)abstract
- Tumor-initiating cells are a subpopulation in aggressive cancers that exhibit traits shared with stem cells, including the ability to self-renew and differentiate, commonly referred to as stemness. In addition, such cells are resistant to chemo- and radiation therapy posing a therapeutic challenge. To uncover stemness-associated functions in glioma-initiating cells (GICs), transcriptome profiles were compared to neural stem cells (NSCs) and gene ontology analysis identified an enrichment of Ca2+ signaling genes in NSCs and the more stem-like (NSC-proximal) GICs. Functional analysis in a set of different GIC lines regarding sensitivity to disturbed homeostasis using A23187 and Thapsigargin, revealed that NSC-proximal GICs were more sensitive, corroborating the transcriptome data. Furthermore, Ca2+ drug sensitivity was reduced in GICs after differentiation, with most potent effect in the NSC-proximal GIC, supporting a stemness-associated Ca2+ sensitivity. NSCs and the NSC-proximal GIC line expressed a larger number of ion channels permeable to potassium, sodium and Ca2+. Conversely, a higher number of and higher expression levels of Ca2+ binding genes that may buffer Ca2+, were expressed in NSC-distal GICs. In particular, expression of the AMPA glutamate receptor subunit GRIA1, was found to associate with Ca2+ sensitive NSC-proximal GICs, and decreased as GICs differentiated along with reduced Ca2+ drug sensitivity. The correlation between high expression of Ca2+ channels (such as GRIA1) and sensitivity to Ca2+ drugs was confirmed in an additional nine novel GIC lines. Calcium drug sensitivity also correlated with expression of the NSC markers nestin (NES) and FABP7 (BLBP, brain lipid-binding protein) in this extended analysis. In summary, NSC-associated NES+/FABP7(+)/GRIA1(+) GICs were selectively sensitive to disturbances in Ca2+ homeostasis, providing a potential target mechanism for eradication of an immature population of malignant cells.
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| 25. |
- Wikström, Anna-Karin, et al.
(author)
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Prehypertension in Pregnancy and Risks of Small for Gestational Age Infant and Stillbirth
- 2016
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In: Hypertension. - 0194-911X .- 1524-4563. ; 67:3, s. 640-646
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Journal article (peer-reviewed)abstract
- It is not fully known whether maternal prehypertension is associated with increased risk of adverse fetal outcomes, and it is debated whether increases in blood pressure during pregnancy influence adverse fetal outcomes. We performed a population-based cohort study in nonhypertensive women with term (37 weeks) singleton births (n=157446). Using normotensive (diastolic blood pressure [DBP] <80 mmHg) women as reference, we calculated adjusted odds ratios with 95% confidence intervals between prehypertension (DBP 80-89 mmHg) at 36 gestational weeks (late pregnancy) and risks of a small-for-gestational-age (SGA) birth or stillbirth. We further estimated whether an increase in DBP from early to late pregnancy affected these risks. We found that 11% of the study population had prehypertension in late pregnancy. Prehypertension was associated with increased risks of both SGA birth and stillbirth; adjusted odds ratios (95% confidence intervals) were 1.69 (1.51-1.90) and 1.70 (1.16-2.49), respectively. Risks of SGA birth in term pregnancy increased by 2.0% (95% confidence intervals 1.5-2.8) per each mmHg rise in DBP from early to late pregnancy, whereas risk of stillbirth was not affected by rise in DBP during pregnancy. We conclude that prehypertension in late pregnancy is associated with increased risks of SGA birth and stillbirth. Risk of SGA birth was also affected by rise in DBT during pregnancy. Our findings provide new insight to the relationship between maternal blood pressure and fetal well-being and suggest that impaired maternal perfusion of the placenta contribute to SGA birth and stillbirth.
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| 26. |
- Yamamoto, Shinji, et al.
(author)
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Ectopic pregnancy in simultaneous pancreas-kidney transplantation : A case report
- 2016
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In: International Journal of Surgery Case Reports. - : Elsevier BV. - 2210-2612. ; 28, s. 152-154
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Journal article (peer-reviewed)abstract
- INTRODUCTION: We present a case report of ectopic pregnancy (EP) after simultaneous pancreas-kidney transplantation (SKPTx). PRESENTATION OF CASE: A 33-year-old female status post SKPTx suddenly got abdominal pain in the lower level. She had high human chorionic Gonadotropin test. Ultrasonography revealed that there was no fetus in the uterus but a dilated right fallopian tube, which strongly suggested ectopic pregnancy. An emergency operation was performed and a dilated right side uterine tube was found with adhesions to her transplant. Salpingectomy was performed and no visible injury to the pancreas was found by the procedure. Pathological evaluation showed ectopic pregnant fetus, and no pancreas dysfunction was observed after the operation. DISCUSSION: This is the first case and operation report of EP after SKPTx. We should consider various causes of acute abdomen as well as several pathological condition in the transplanted pancreas such as pancreatitis, abscess, and thrombosis in vessels in the organ. Moreover, transplanted pancreas in abdomen is easily misrecognized as adipose tissue and there is high risk that the organ to get injured surgically. CONCLUSION: EP should be included in the different diagnosis in SKPTx female patients who get acute abdominal pain. It is highly desirable that transplant surgeon is included in the operation team for EP of these patients. (C) 2016 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.
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| 27. |
- Zaigham, Mehreen, et al.
(author)
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Clinical-pathological features in placentas of pregnancies with SARS-CoV-2 infection and adverse outcome: case series with and without congenital transmission
- 2022
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In: BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY. - : Wiley. - 1470-0328 .- 1471-0528. ; 129:8, s. 1361-1374
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Journal article (peer-reviewed)abstract
- Objective To correlate clinical outcomes to pathology in SARS-CoV-2 infected placentas in stillborn and live-born infants presenting with fetal distress. Design Retrospective, observational. Setting Nationwide. Population Five stillborn and nine live-born infants from 13 pregnant women infected with SARS-CoV-2 seeking care at seven different maternity units in Sweden. Methods Clinical outcomes and placental pathology were studied in 14 cases (one twin pregnancy) of maternal SARS-CoV-2 infection with impaired fetal outcome. Outcomes were correlated to placental pathology in order to investigate the impact of virus-related pathology on the villous capillary endothelium, trophoblast and other cells. Main outcome measures Maternal and fetal clinical outcomes and placental pathology in stillborn and live-born infants. Results Reduced fetal movements were reported (77%) and time from onset of maternal COVID-19 symptoms to signs of fetal distress among live-born infants was 6 (3-12) days and to diagnosis of stillbirth 11 (2-25) days. Two of the live-born infants died during the postnatal period. Signs of fetal distress led to emergency caesarean section in all live-born infants with umbilical cord blood gases and low Apgar scores confirming intrauterine hypoxia. Five stillborn and one live-born neonate had confirmed congenital transmission. Massive perivillous fibrinoid deposition, intervillositis and trophoblast necrosis were associated with SARS-CoV-2 placental infection and congenital transmission. Conclusions SARS-CoV-2 can cause rapid placental dysfunction with subsequent acute fetal hypoxia leading to intrauterine fetal compromise. Associated placental pathology included massive perivillous fibrinoid deposition, intervillositis and trophoblast degeneration.
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