TAMI-39. INTEGRATION OF SPATIALLY RESOLVED TRANSCRIPTOMICS AND METABOLOMICS UNCOVERS HYPOXIA-DRIVEN ACCUMULATION OF GENOMIC INSTABILITIES IN HUMAN GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi206-vi206
Author(s):  
Jan Kückelhaus ◽  
Paulina Will ◽  
Franz Ricklefs ◽  
Jasim Kada Benotmane ◽  
Kevin Joseph ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Developmental Stages ◽  
Recurrent Glioblastoma ◽  
S Phase ◽  
Dynamic Regulation ◽  
Hypoxia Response ◽  
Spatial Gradients ◽  
Spatially Resolved ◽  
Highly Correlated

Abstract High-dimensional technologies have provided insights into transcriptional heterogeneity and dynamic plasticity which are hallmarks of brain tumors. Although scRNA-seq recovers the diversity of transcriptional states, their spatial context within the neuronal environment has remained unexplored. Here, we integrated spatially resolved transcriptomics and metabolomics to characterize the glioma landscape at multiple molecular levels. We integrated spatial transcriptomics (10X Visium, n= 28) and metabolomics (MALDI, n= 6) from primary and recurrent glioblastoma patients. Unsupervised cluster analysis and pattern recognition uncovered 5 spatially distinct transcriptional programs, shared across patients. These included three cell-specific developmental stages largely reflecting those that are part of recently suggested models. By integrating metabolome data, we identified an additional program encompassing reactive responses to hypoxia. Areas of hypoxic response were negatively correlated with proliferation (R2= -0.34, p< 0.001) and significantly enriched for gene expression signatures from the S-phase (p< 0.001). Modeling of transient spatial gradients using vector field predictions showed opposing vector directions of hypoxia response and migratory capacity, underpinning the “go-or-growth” theory, where cells either proliferate or migrate. Inferred copy-number alterations (CNA) revealed a significant increase in genomic instability, highly correlated to hypoxia response (R2= 0.78, p< 0.001). Near necrotic areas, we observed a significant accumulation of CNAs while proliferation was inhibited, and cells remained in the S-phase. We validated this hypothesis of hypoxia-driven accumulation of CNAs by chronic hypoxia cultures of primary patient-derived cell lines. A gain of chromosomal instability after long-term hypoxia was observed, suggesting that hypoxic areas in glioblastoma function as bioreactors for genomic instability. Our findings elucidate the evolution of resistant subclones in glioblastoma. They provide novel insights into the dynamic regulation and interaction between host and tumor and cast a new light on hypoxic and necrotic areas, which may represent the source of the heterogeneous and resistant nature of glioblastomas.

Long-term outcomes in children with glioblastoma

2010 ◽  
Vol 6 (2) ◽  
pp. 145-149 ◽  
Author(s):  
Kyung Sun Song ◽  
Ji Hoon Phi ◽  
Byung-Kyu Cho ◽  
Kyu-Chang Wang ◽  
Ji Yeoun Lee ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Progression Free Survival ◽  
Radical Resection ◽  
Tumor Location ◽  
Recurrent Glioblastoma ◽  
Subtotal Resection ◽  
Long Term Outcomes ◽  
Term Outcome ◽  
Long Term Outcome

Object Glioblastoma is the most common primary malignant brain tumor; however, glioblastoma in children is less common than in adults, and little is known about its clinical outcome in children. The authors evaluated the long-term outcome of glioblastoma in children. Methods Twenty-seven children were confirmed to have harbored a glioblastoma between 1985 and 2007. The clinical features and treatment outcomes were reviewed retrospectively. All patients underwent resection; complete resection was performed in 12 patients (44%), subtotal resection in 12 patients (44%), and biopsy in 3 patients (11%). Twenty-four patients (89%) had radiation therapy, and 14 (52%) patients received chemotherapy plus radiation therapy. Among the latter, 5 patients had radiation therapy concurrent with temozolomide chemotherapy. Four patients with small-size recurrent glioblastoma received stereotactic radiosurgery. Results The median overall survival (OS) was 43 months, and the median progression-free survival was 12 months. The OS rate was 67% at 1 year, 52% at 2 years, and 40% at 5 years. The median OS was significantly associated with tumor location (52 months for superficially located tumors vs 7 months for deeply located tumors; p = 0.017) and extent of removal (106 months for completely resected tumors vs 11 months for incompletely resected tumors; p < 0.0001). Conclusions The prognosis of glioblastoma is better in children than in adults. Radical resection followed by concurrent chemoradiation therapy may be the initial treatment of choice.

scholarly journals Multiple Evidence for Climate Patterns Influencing Ecosystem Productivity across Spatial Gradients in the Venice Lagoon

2021 ◽  
Vol 9 (4) ◽  
pp. 363
Author(s):  
Camilla Bertolini ◽  
Edouard Royer ◽  
Roberto Pastres
Keyword(s):  
Time Series ◽  
Primary Productivity ◽  
Clustering Analysis ◽  
Venice Lagoon ◽  
Spatial Effects ◽  
Spatial Gradients ◽  
Climate Forecasting ◽  
Oxygen Production Rate ◽  
Temporal And Spatial

Effects of climatic changes in transitional ecosystems are often not linear, with some areas likely experiencing faster or more intense responses, which something important to consider in the perspective of climate forecasting. In this study of the Venice lagoon, time series of the past decade were used, and primary productivity was estimated from hourly oxygen data using a published model. Temporal and spatial patterns of water temperature, salinity and productivity time series were identified by applying clustering analysis. Phytoplankton and nutrient data from long-term surveys were correlated to primary productivity model outputs. pmax, the maximum oxygen production rate in a given day, was found to positively correlate with plankton variables measured in surveys. Clustering analysis showed the occurrence of summer heatwaves in 2008, 2013, 2015 and 2018 and three warm prolonged summers (2012, 2017, 2019) coincided with lower summer pmax values. Spatial effects in terms of temperature were found with segregation between confined and open areas, although the patterns varied from year to year. Production and respiration differences showed that the lagoon, despite seasonality, was overall heterotrophic, with internal water bodies having greater values of heterotrophy. Warm, dry years with high salinity had lower degrees of summer autotrophy.

scholarly journals S-phase Fraction as an Independent Prognostic Factor in Invasive Breast Carcinoma -A Study of Long-term Follow-up

2007 ◽  
Vol 10 (1) ◽  
pp. 36
Author(s):  
Jin Hae Bae ◽  
Jeong Won Bae ◽  
Sang Uk Woo ◽  
Chul Whan Kim ◽  
Jae Bok Lee ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Breast Carcinoma ◽  
S Phase ◽  
Independent Prognostic Factor ◽  
Invasive Breast Carcinoma ◽  
Phase Fraction ◽  
Long Term Follow Up

scholarly journals Direct biologically based biosensing of dynamic physiological function

2001 ◽  
Vol 280 (5) ◽  
pp. H2006-H2010 ◽  
Author(s):  
David J. Christini ◽  
Jeff Walden ◽  
Jay M. Edelberg
Keyword(s):  
Real Time ◽  
Cardiac Tissue ◽  
Physiological Function ◽  
Physiological Activity ◽  
Functional Integration ◽  
Dynamic Regulation ◽  
Excitable Tissue ◽  
Alternative Approach

Dynamic regulation of biological systems requires real-time assessment of relevant physiological needs. Biosensors, which transduce biological actions or reactions into signals amenable to processing, are well suited for such monitoring. Typically, in vivo biosensors approximate physiological function via the measurement of surrogate signals. The alternative approach presented here would be to use biologically based biosensors for the direct measurement of physiological activity via functional integration of relevant governing inputs. We show that an implanted excitable-tissue biosensor (excitable cardiac tissue) can be used as a real-time, integrated bioprocessor to analyze the complex inputs regulating a dynamic physiological variable (heart rate). This approach offers the potential for long-term biologically tuned quantification of endogenous physiological function.

AMPA Silencing Is a Prerequisite for Developmental Long-Term Potentiation in the Hippocampal CA1 Region

2008 ◽  
Vol 100 (5) ◽  
pp. 2605-2614 ◽  
Author(s):  
Therése Abrahamsson ◽  
Bengt Gustafsson ◽  
Eric Hanse
Keyword(s):  
Developmental Stages ◽  
Long Term Potentiation ◽  
Synaptic Strength ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Silent Synapses ◽  
Term Potentiation ◽  
Hippocampal Ca1 ◽  
Hippocampal Ca3

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) unsilencing is an often proposed expression mechanism both for developmental long-term potentiation (LTP), involved in circuitry refinement during brain development, and for mature LTP, involved in learning and memory. In the hippocampal CA3–CA1 connection naïve (nonstimulated) synapses are AMPA signaling and AMPA-silent synapses are created from naïve AMPA-signaling (AMPA-labile) synapses by test-pulse synaptic activation (AMPA silencing). To investigate to what extent LTPs at different developmental stages are explained by AMPA unsilencing, the amount of LTP obtained at these different developmental stages was related to the amount of AMPA silencing that preceded the induction of LTP. When examined in the second postnatal week Hebbian induction was found to produce no more stable potentiation than that causing a return to the naïve synaptic strength existing prior to the AMPA silencing. Moreover, in the absence of a preceding AMPA silencing Hebbian induction produced no stable potentiation above the naïve synaptic strength. Thus this early, or developmental, LTP is nothing more than an unsilencing (dedepression) and stabilization of the AMPA signaling that was lost by the prior AMPA silencing. This dedepression and stabilization of AMPA signaling was mimicked by the presence of the protein kinase A activator forskolin. As the relative degree of AMPA silencing decreased with development, LTP manifested itself more and more as a “genuine” potentiation (as opposed to a dedepression) not explained by unsilencing and stabilization of AMPA-labile synapses. This “genuine,” or mature, LTP rose from close to nothing of total LTP prior to postnatal day (P)13, to about 70% of total LTP at P16, and to about 90% of total LTP at P30. Developmental LTP, by stabilization of AMPA-labile synapses, thus seems adapted to select synaptic connections to the growing synaptic network. Mature LTP, by instead strengthening existing stable connections between cells, may then create functionally tightly connected cell assemblies within this network.

Developmental Timing of Stress Effects on the Brain

2018 ◽  
pp. 560-584
Author(s):  
Keira B. Leneman ◽  
Megan R. Gunnar
Keyword(s):  
Developmental Stages ◽  
Physiological Stress ◽  
Emotional Health ◽  
Rapid Change ◽  
Negative Consequences ◽  
Stress Effects ◽  
Physiological Stress Response ◽  
Infancy And Early Childhood ◽  
The Brain

The physiological stress response integrates endocrine, autonomic, and neural structures and pathways to respond and adapt to an organism’s environment. This integration is dynamic throughout development, with certain periods of rapid change for each system. With the introduction of chronic stress, physiological responses that may be adaptive in the immediate context can have long-term consequences for physical and emotional health, influencing systems differently depending upon developmental status at the time of stress exposure. From the nonhuman literature, prenatal, infancy, and adolescence are developmental stages that seem especially sensitive to major stress exposures. Human studies are less conclusive. Although much work has been done on prenatal stress and certain stressors (e.g., deprivation) during infancy and early childhood, more work is needed that addresses the challenges of isolating periods of environmental insults as well as carefully considering how prior developmental and subsequent experiences moderate exposure to major stress conditions at different points in development. Information on the transition from childhood to adolescence is especially sparse. A more comprehensive understanding of these developmental processes will enable a more targeted approach to ameliorating negative consequences of stress with both prevention and intervention.

scholarly journals Antioxidative and antimicrobial potentials of Parmelia saxatilis and Pseudoevernia furfuracea

2016 ◽  
pp. 9-18
Author(s):  
Jasmina Cilerdzic ◽  
Mirjana Stajic ◽  
Jelena Vukojevic
Keyword(s):  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Side Effects ◽  
Klebsiella Pneumoniae ◽  
Bacterial Species ◽  
Phenol Content ◽  
Negative Side Effects ◽  
Highly Correlated ◽  
Ethanol Extracts

Even though numerous lichen species possess significant medical potentials they are still unexplored, and particularly species and strains originating from Serbia. Therefore, the aim of this study was to evaluate the antioxidative and antimicrobial potential of ethanol extracts of Parmelia saxatilis and Pseudoevernia furfuracea collected in Serbia. The tested extracts were good scavengers of DPPH radicals, with capacities ranging from 14.76% to 79.76% in P. saxatilis and from 21.39% to 90.04% in P. furfuracea. In P. saxatilis level of DPPH? neutralisation was highly correlated with phenol content (r2 = 0.9981) and in P. furfuracea with amount of total flavonoides (r2 = 0.9641). The extract of P. furfuracea inhibited the growth of all tested microorganisms with exception of Aspergillus flavus, while P. saxatilis extract affected only growth of bacterial species. Among tested microorganisms, Staphylococcus aureus and Klebsiella pneumoniae were the most sensitive, while Enterococcus faecalis, Pseudomonas aeruginosa as well as micromycetes were the least sensitive to tested extracts. Because of these potentials and the fact that their long term usage does not have any negative side effects on organism and development of microbial resistance, the extracts could be included in conventional therapy.

scholarly journals Cyclin Kinase-independent role of p21CDKN1A in the promotion of nascent DNA elongation in unstressed cells

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Sabrina F Mansilla ◽  
Agustina P Bertolin ◽  
Valérie Bergoglio ◽  
Marie-Jeanne Pillaire ◽  
Marina A González Besteiro ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Genomic Stability ◽  
S Phase ◽  
Fragile Sites ◽  
Dna Lesions ◽  
Cdk Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Independent Manner ◽  
Genomic Regions

The levels of the cyclin-dependent kinase (CDK) inhibitor p21 are low in S phase and insufficient to inhibit CDKs. We show here that endogenous p21, instead of being residual, it is functional and necessary to preserve the genomic stability of unstressed cells. p21depletion slows down nascent DNA elongation, triggers permanent replication defects and promotes the instability of hard-to-replicate genomic regions, namely common fragile sites (CFS). The p21’s PCNA interacting region (PIR), and not its CDK binding domain, is needed to prevent the replication defects and the genomic instability caused by p21 depletion. The alternative polymerase kappa is accountable for such defects as they were not observed after simultaneous depletion of both p21 and polymerase kappa. Hence, in CDK-independent manner, endogenous p21 prevents a type of genomic instability which is not triggered by endogenous DNA lesions but by a dysregulation in the DNA polymerase choice during genomic DNA synthesis.

scholarly journals Snowpack variability and trends at long-term stations in northern Colorado, USA

2015 ◽  
Vol 371 ◽  
pp. 131-136 ◽  
Author(s):  
S. R. Fassnacht ◽  
M. Hultstrand
Keyword(s):  
Snow Depth ◽  
Snow Water Equivalent ◽  
Entire Period ◽  
Northern Colorado ◽  
Snow Water ◽  
Highly Correlated ◽  
The Individual

Abstract. The individual measurements from snowcourse stations were digitized for six stations across northern Colorado that had up to 79 years of record (1936 to 2014). These manual measurements are collected at the first of the month from February through May, with additional measurements in January and June. This dataset was used to evaluate the variability in snow depth and snow water equivalent (SWE) across a snowcourse, as well as trends in snowpack patterns across the entire period of record and over two halves of the record (up to 1975 and from 1976). Snowpack variability is correlated to depth and SWE. The snow depth variability is shown to be highly correlated with average April snow depth and day of year. Depth and SWE were found to be significantly decreasing over the entire period of record at two stations, while at another station the significant trends were an increase over the first half of the record and a decrease over the second half. Variability tended to decrease with time, when significant.

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