Refine
Document Type
- Article (8)
Language
- English (8)
Has Fulltext
- yes (8)
Is part of the Bibliography
- no (8)
Keywords
- glioblastoma (3)
- anti-angiogenic therapy (2)
- glioma (2)
- ASA404 (1)
- Bipolar seesaw (1)
- Brazil Current (1)
- DMXAA (1)
- DNA methylation (1)
- Heinrich Event 1 (1)
- IDH mutation (1)
Institute
- Medizin (5)
- Geowissenschaften (2)
- Geowissenschaften / Geographie (1)
Precipitation extremes with devastating socioeconomic consequences within the South American Monsoon System (SAMS) are expected to become more frequent in the near future. The complexity in SAMS behavior, however, poses severe challenges for reliable future projections. Thus, robust paleomonsoon records are needed to constrain the high spatiotemporal variability in the response of SAMS rainfall to different climatic drivers. This study uses Ti/Ca ratios from X‐ray fluorescence scanning of a sediment core retrieved off eastern Brazilian to trace precipitation changes over the past 322 Kyr. The results indicate that despite the spatiotemporal complexity of the SAMS, insolation forcing is the primary pacemaker of variations in the monsoonal system. Additional modulation by atmospheric pCO2 suggests that SAMS intensity over eastern Brazil will be suppressed by rising CO2 emissions in the future. Lastly, our record reveals an unprecedented strong and persistent wet period during Marine Isotope Stage 6 driven by anomalously strong trade winds.
Role of the tropical atlantic for the interhemispheric heat transport during the last deglaciation
(2021)
Abstract
During the last deglaciation abrupt millennial-scale perturbations of the Atlantic Meridional Overturning Circulation massively altered the interhemispheric heat distribution affecting, for example, continental ice volume and hydroclimate. If and how the related cross-equatorial heat transport was controlled by the interplay between the southward-flowing Brazil Current (BC) and northward-flowing North Brazil Current (NBC) remains controversial. To assess the role of tropical heat transport during the last deglaciation, we obtained a high-resolution foraminiferal Mg/Ca-based sea surface temperature (SST) record from the BC domain at 21.5°S. The data reveal a yet undocumented warming of at least 4.6°C of the BC during Heinrich Stadial 1 at ∼16 ka indicating massive oceanic heat accumulation in the tropical South Atlantic. Simultaneously, a strongly diminished NBC prevented the release of this excess heat into the northern tropics. The observed magnitude of heat accumulation substantially exceeds numerical model simulations, stressing the need to further scrutinize atmospheric and oceanic heat transport during extreme climatic events.
Plain Language Summary
The Atlantic overturning circulation underwent abrupt millennial-scale perturbations. Such phases of sluggish oceanic circulation resulted in a substantial reduction of northward heat transport. As a consequence, substantial cooling occurred in the Northern Hemisphere and warming occurred in the Southern Hemisphere with severe effects on tropical precipitation. The distribution of heat within the western tropical Atlantic is accomplished by the southward-flowing BC and the northward-flowing NBC. By reconstructing SSTs for the interval between 20,000 and 10,000 yr before present, we assess the role of both currents in the interhemispheric heat transport during weak Atlantic overturning. We found that a sluggish overturning circulation resulted in anomalous southward heat transport by the BC in concert with a weak NBC, which lead to a yet undocumented warming of at least 4.6°C in the western tropical South Atlantic. This warming significantly exceeds reconstructions based on numerical simulations. This points to the need to further improve our understanding of changes in the cross-equatorial oceanic and atmospheric heat transport in response to rapid changes in ocean circulation, in particular as a significant weakening of the Atlantic overturning circulation is predicted in the wake of anthropogenic climate change.
The modern precipitation balance in southeastern (SE) Brazil is regulated by the South American summer Monsoon and threatened by global climate change. On glacial-interglacial timescales, monsoon intensity was strongly controlled by precession-forced changes in insolation. To date, relatively little is known about the spatiotemporal distribution of tropical precipitation in SE Brazil and the resulting variability of fluvial discharge on glacial-interglacial timescales. Here, we present X-ray diffraction-derived mineralogical data for the 150–70 ka period (marine isotope stage (MIS) 6 to MIS 5) from the Doce River basin. This area was sensitive to changes in monsoonal precipitation intensity due to its proximity to the South Atlantic Convergence Zone. The data, obtained from a marine sediment core (M125-55–7) close to the Doce river mouth (20°S), show pronounced changes in the Doce River suspension load’s mineralogical composition on glacial-interglacial and precessional timescales. While the ratio of silicates to carbonates displays precession-paced changes, the mineralogical composition of the carbonate-free fraction discriminates between two assemblages which strongly vary between glacial and interglacial time scales, with precession-forced variability only visible in MIS 5. The first assemblage, dominated by high contents of kaolinite and gibbsite, indicates intensified lowland erosion of mature tropical soils. The second one, characterized by higher contents of the well-ordered illite, quartz and albite, points to intensified erosion of immature soils in the upper Doce Basin. High kaolinite contents in the silicate fraction prevailed in late MIS 6 and indicate pronounced lowland soil erosion along a steepened topographic gradient. The illite-rich mineral assemblage was more abundant in MIS 5, particularly during times of high austral summer insolation, indicating strong monsoonal rainfall and intense physical erosion in the upper catchment. When the summer monsoon weakened in times of lower insolation, the mineral assemblage was dominated by kaolinite again, indicative of lower precipitation and runoff in the upper catchment and dominant lowland erosion.
Hypoxia enhances the antiglioma cytotoxicity of b10, a glycosylated derivative of betulinic acid
(2014)
B10 is a glycosylated derivative of betulinic acid with promising activity against glioma cells. Lysosomal cell death pathways appear to be essential for its cytotoxicity. We investigated the influence of hypoxia, nutrient deprivation and current standard therapies on B10 cytotoxicity. The human glioma cell lines LN-308 and LNT-229 were exposed to B10 alone or together with irradiation, temozolomide, nutrient deprivation or hypoxia. Cell growth and viability were evaluated by crystal violet staining, clonogenicity assays, propidium iodide uptake and LDH release assays. Cell death was examined using an inhibitor of lysosomal acidification (bafilomycin A1), a cathepsin inhibitor (CA074-Me) and a short-hairpin RNA targeting cathepsin B. Hypoxia substantially enhanced B10-induced cell death. This effect was sensitive to bafilomycin A1 and thus dependent on hypoxia-induced lysosomal acidification. Cathepsin B appeared to mediate cell death because either the inhibitor CA074-Me or cathepsin B gene silencing rescued glioma cells from B10 toxicity under hypoxia. B10 is a novel antitumor agent with substantially enhanced cytotoxicity under hypoxia conferred by increased lysosomal cell death pathway activation. Given the importance of hypoxia for therapy resistance, malignant progression, and as a result of antiangiogenic therapies, B10 might be a promising strategy for hypoxic tumors like malignant glioma.
Malignant brain tumors, including gliomas, brain metastases and anaplastic meningiomas, are associated with poor prognosis, and represent an unmet medical need. ASA404 (DMXAA), a vascular disrupting agent, has demonstrated promising results in several preclinical tumor models and early phase clinical trials. However, two phase III trials in non-small cell lung cancer reported insufficient results. The aim of the present study was to determine the effects of ASA404 on brain tumors. The effects of ASA404 were evaluated in vitro and in vivo using subcutaneous, and orthotopical models for malignant glioma (U-87, LN-229, U-251, LN-308 and Tu-2449), brain metastasis (HT-29) and malignant meningioma (IOMM-Lee). The acute effects of ASA404 on tumor tissue were analyzed using conventional and immunohistochemical staining techniques [hematoxylin and eosin, MIB-1 antibody/proliferation maker protein Ki-67, cleaved caspase-8, stimulator of interferon genes (STING), ionized calcium-binding adapter molecule 1]. Furthermore, the sizes of subcutaneous tumors were measured and the symptom-free survival rates of animals with intracranial tumors receiving ASA404 treatment were analyzed. ASA404 demonstrated low toxicity in vitro, but exhibited strong effects on subcutaneous tumors 24 h following a single dose of ASA404 (25 mg/kg). ASA404 induced necrosis, hemorrhages and inhibited the proliferation, and growth of tumors in the subcutaneous glioma models. However, ASA404 failed to demonstrate comparable effects in any of the intracranial tumor models examined and did not result in a prolongation of survival. Expression of STING, the molecular target of ASA404, and infiltration of macrophages, the cells mediating ASA404 activity, did not differ between subcutaneous and intracranial tumors. In conclusion, ASA404 demonstrates clear efficacy in subcutaneous tumor models, but has no relevant activity in orthotopic brain tumor models. The expression of STING and infiltration with macrophages were not determined to be involved in the differential activity observed among tumor models. It is possible that the low penetration of ASA-404 into the brain prevents concentrations sufficient enough reaching the tumor in order to exhibit acute effects in vivo.
Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.
Linking epigenetic signature and metabolic phenotype in IDH mutant and IDH wildtype diffuse glioma
(2020)
Aims: Changes in metabolism are known to contribute to tumour phenotypes. If and how metabolic alterations in brain tumours contribute to patient outcome is still poorly understood. Epigenetics impact metabolism and mitochondrial function. The aim of this study is a characterisation of metabolic features in molecular subgroups of isocitrate dehydrogenase mutant (IDHmut) and isocitrate dehydrogenase wildtype (IDHwt) gliomas. Methods: We employed DNA methylation pattern analyses with a special focus on metabolic genes, large-scale metabolism panel immunohistochemistry (IHC), qPCR-based determination of mitochondrial DNA copy number and immune cell content using IHC and deconvolution of DNA methylation data. We analysed molecularly characterised gliomas (n = 57) for in depth DNA methylation, a cohort of primary and recurrent gliomas (n = 22) for mitochondrial copy number and validated these results in a large glioma cohort (n = 293). Finally, we investigated the potential of metabolic markers in Bevacizumab (Bev)-treated gliomas (n = 29). Results: DNA methylation patterns of metabolic genes successfully distinguished the molecular subtypes of IDHmut and IDHwt gliomas. Promoter methylation of lactate dehydrogenase A negatively correlated with protein expression and was associated with IDHmut gliomas. Mitochondrial DNA copy number was increased in IDHmut tumours and did not change in recurrent tumours. Hierarchical clustering based on metabolism panel IHC revealed distinct subclasses of IDHmut and IDHwt gliomas with an impact on patient outcome. Further quantification of these markers allowed for the prediction of survival under anti-angiogenic therapy. Conclusion: A mitochondrial signature was associated with increased survival in all analyses, which could indicate tumour subgroups with specific metabolic vulnerabilities.
Bevacizumab for patients with recurrent gliomas presenting with a gliomatosis cerebri growth pattern
(2017)
Bevacizumab has been shown to improve progression-free survival and neurologic function, but failed to improve overall survival in newly diagnosed glioblastoma and at first recurrence. Nonetheless, bevacizumab is widely used in patients with recurrent glioma. However, its use in patients with gliomas showing a gliomatosis cerebri growth pattern is contentious. Due to the marked diffuse and infiltrative growth with less angiogenic tumor growth, it may appear questionable whether bevacizumab can have a therapeutic effect in those patients. However, the development of nodular, necrotic, and/or contrast-enhancing lesions in patients with a gliomatosis cerebri growth pattern is not uncommon and may indicate focal neo-angiogenesis. Therefore, control of growth of these lesions as well as control of edema and reduction of steroid use may be regarded as rationales for the use of bevacizumab in these patients. In this retrospective patient series, we report on 17 patients with primary brain tumors displaying a gliomatosis cerebri growth pattern (including seven glioblastomas, two anaplastic astrocytomas, one anaplastic oligodendroglioma, and seven diffuse astrocytomas). Patients have been treated with bevacizumab alone or in combination with lomustine or irinotecan. Seventeen matched patients treated with bevacizumab for gliomas with a classical growth pattern served as a control cohort. Response rate, progression-free survival, and overall survival were similar in both groups. Based on these results, anti-angiogenic therapy with bevacizumab should also be considered in patients suffering from gliomas with a mainly infiltrative phenotype.