scholarly journals A mathematical dissection of the adaptation of cell populations to fluctuating oxygen levels

2019 ◽  
Author(s):  
Aleksandra Ardaševa ◽  
Robert A Gatenby ◽  
Alexander R A Anderson ◽  
Helen M Byrne ◽  
Philip K Maini ◽  
...  
Keyword(s):  
Competitive Advantage ◽  
Phenotypic Variation ◽  
Evolutionary Dynamics ◽  
Chronic Hypoxia ◽  
Evolutionary Strategies ◽  
Metabolic Phenotype ◽  
Cell Populations ◽  
Low Oxygen ◽  
Oxygen Levels ◽  
Hypoxic Conditions

AbstractThe disordered network of blood vessels that arises from tumour angiogenesis results in variations in the delivery of oxygen into the tumour tissue. This brings about regions of chronic hypoxia (i.e. sustained low oxygen levels) and regions with alternating phases of low and relatively higher oxygen levels within vascularised tumours, and makes it necessary for cancer cells to adapt to fluctuating environmental conditions. We use a phenotype-structured model to dissect the evolutionary dynamics of cell populations exposed to fluctuating oxygen levels. In this model, the phenotypic state of every cell is described by a continuous variable that provides a simple representation of its metabolic phenotype, ranging from fully oxidative to fully glycolytic, and cells are grouped into two competing populations that undergo heritable, spontaneous phenotypic variations at different rates. Model simulations indicate that, depending on the rate at which oxygen is consumed by the cells, nonlinear dynamic interactions between cells and oxygen can stimulate chronic hypoxia and cycling hypoxia. Moreover, the model supports the idea that under chronic-hypoxic conditions lower rates of phenotypic variation lead to a competitive advantage, whereas higher rates of phenotypic variation can confer a competitive advantage under cycling-hypoxic conditions. In the latter case, the numerical results obtained show that bet-hedging evolutionary strategies, whereby cells switch between oxidative and glycolytic phenotypes, can spontaneously emerge. We explain how these results can shed light on the evolutionary process that may underpin the emergence of phenotypic heterogeneity in vascularised tumours.

scholarly journals The effects of acute oxygen changes on heart rate in the freshwater crab Poppiana dentata (Randall, 1840)

2020 ◽  
Vol 48 (3) ◽  
pp. 480-487
Author(s):  
Delezia Shivani Singh ◽  
Mary Alkins-Koo ◽  
Luke Victor Rostant ◽  
Azad Mohammed
Keyword(s):  
Heart Rate ◽  
Invasive Technique ◽  
Cardiac Physiology ◽  
Low Oxygen ◽  
Heart Rates ◽  
Oxygen Levels ◽  
Non Invasive ◽  
Hypoxic Conditions ◽  
Cardiac Responses ◽  
Insight Into

Heart rate is a key physiological feature that can be used to assess the response of organisms to changing environmental conditions in aquatic habitats, such as acute fluctuations in oxygen levels and hypoxic conditions. This experiment, therefore, investigated cardiac responses in a freshwater brachyuran species, Poppiana dentata, exposed to low oxygen levels. Heart rate was derived from beats per minute (bpm) signals (n = 576) using an infrared, non-invasive technique over a 96 h period, under different dissolved oxygen (DO) conditions. These involved three regimes: normoxic (6.8 ± 0.1 mg L-1), decreasing DO to hypoxic levels (6.2 to 1.7 mg L-1), and recovery with normoxic levels (6.3 ± 0.1 mg L-1). Changes in heart rates among the three regimes were significant (P < 0.05); reflecting the shift in heart rate during different conditions of oxygen availability, normoxic (59 to 61 bpm), declining DO (54 to 62 bpm) and recovery DO (53 to 64 bpm). Additionally, the normal rhythmicity of heart rates under the normoxic condition was not maintained throughout most of the declining DO and recovery periods. P. dentata has demonstrated cardiac compensations in heart rate during low oxygen levels, providing insight into the species cardiac physiology.

scholarly journals Low oxygen levels caused by Noctiluca scintillans bloom kills corals in Gulf of Mannar, India

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
K. Diraviya Raj ◽  
G. Mathews ◽  
David O. Obura ◽  
R. L. Laju ◽  
M. Selva Bharath ◽  
...  
Keyword(s):  
Coral Reefs ◽  
Algal Blooms ◽  
Global Climate ◽  
Disease Outbreaks ◽  
Gulf Of Mannar ◽  
Coral Mortality ◽  
Low Oxygen ◽  
Noctiluca Scintillans ◽  
Oxygen Levels ◽  
Hypoxic Conditions

AbstractCoral reefs around the world are undergoing severe decline in the past few decades. Mass coral mortalities have predominantly been reported to be caused by coral bleaching or disease outbreaks. Temporary hypoxic conditions caused by algal blooms can trigger mass coral mortalities though are reported rarely. In this study in Gulf of Mannar (GoM), southeast India, we report a significant coral mortality caused by a bloom of the ciguatoxic dinoflagellate Noctiluca scintillans during September–October 2019. Dissolved oxygen levels declined below 2 mg l−1 during the bloom causing temporary hypoxia and mortality (up to 71.23%) in the fast growing coral genera Acropora, Montipora and Pocillopora. Due to global climate change, more frequent and larger algal blooms are likely in the future. Hence, it is likely that shallow water coral reefs will be affected more frequently by episodic hypoxic conditions driven by algal blooms. More studies are, however, required to understand the mechanism of coral mortality due to algal blooms, impacts on community composition and the potential for subsequent recovery.

Adaptation of Human CD4+ T Cells to Pathophysiological Hypoxia: A Transcriptome Analysis

2009 ◽  
Vol 36 (12) ◽  
pp. 2655-2669 ◽  
Author(s):  
TIMO GABER ◽  
THOMAS HÄUPL ◽  
GRIT SANDIG ◽  
KAROLINA TYKWINSKA ◽  
MONIQUE FANGRADT ◽  
...  
Keyword(s):  
T Cells ◽  
Synovial Tissue ◽  
Cd4 T Cells ◽  
Protein Modification ◽  
Quantitative Polymerase Chain Reaction ◽  
Low Oxygen ◽  
Rheumatoid Synovium ◽  
Tissue Samples ◽  
Oxygen Levels ◽  
Hypoxic Conditions

Objective.Inflamed tissues are usually characterized by low oxygen levels. We investigated whether pathophysiological hypoxia (pO2 < 1%) as found in the rheumatoid synovium modulates the transcriptome of human CD4+ T cells.Methods.We analyzed the extent to which hypoxia influences the transcriptome in the rheumatoid synovium according to a gene cluster reflecting adaptation to low oxygen levels. Hypoxia-inducible factor-1α (HIF-1α) was detected in the rheumatoid synovium using immunohistochemistry. Isolated human CD4+ T cells were exposed to hypoxia and analyzed using microarray analysis, quantitative polymerase chain reaction, and immunoblot detection.Results.In rheumatoid arthritis (RA) synovial tissue samples, hypoxia modulates the transcription profile. This profile is similar, but not identical, to that found in isolated CD4+ T cells incubated under hypoxic conditions. We show that HIF-1α is expressed in synovial tissue samples and in hypoxic CD4+ cells; and that hypoxia directly affects differential gene expression in human T cells with up to 4.8% modulation of the transcriptome. Functional genome analysis revealed substantial effects of hypoxia on immune response, transcriptional regulation, protein modification, cell growth and proliferation, and cell metabolism.Conclusion.Severe hypoxia, a feature of joint inflammation, considerably modulates the transcriptome of cells found in the rheumatoid synovium. Human CD4+ T cells adapt to hypoxic conditions mainly by HIF-1-driven effects on the transcriptome reflecting a profound influence on immune functions. Thus, hypoxia must be taken into account when therapeutically targeting inflammation.

Chronic Hypoxia as a Potential Factor in Human Life-threatening Diseases

2017 ◽  
Vol 10 (4) ◽  
pp. 3759-3762
Author(s):  
Sandhya MNVS ◽  
Vanitha K ◽  
Ramesh A
Keyword(s):  
Chronic Hypoxia ◽  
Atmospheric Oxygen ◽  
Human Life ◽  
The Body ◽  
Cellular Damage ◽  
Otto Warburg ◽  
Regular Treatment ◽  
Breathing Exercises ◽  
Hypoxic Conditions ◽  
Cancerous Cell

The review article focuses on the importance of adequate oxygen levels in the body as cure and therapy for many ailments. It is known that hypoxia is the cause for cellular damage and if it can be applied to major patho-physiology’s, it can be observed that slow and chronic hypoxic conditions are the cause for most of the diseases. On the contrary, providing each cell of the body with proper oxygen may be helpful in maintaining the immunity of the body and therefore treating many disease conditions. This theory, if tested may show positive results in heart related diseases, neuronal disorders, stresses, digestive disorders and the unresolved cancer too. Slow decrease in the levels of atmospheric oxygen could be a reason to induce chronic hypoxia. According to Dr. Otto Warburg, a Noble laurate, a normal cell when deprived of oxygen, may get converted to a cancerous cell, whereas a cancerous cell cannot survive in aerobic conditions. If this part of his research be concentrated on, there could be fruitful results in the treatment of cancer. To maintain adequate levels of oxygen in the body, simple yogic breathing practices are helpful. And to maintain the adequate atmospheric oxygen, trees and plants which cleanse the atmospheric air are useful. Clinical surveys on volunteers who have been practicing regular breathing exercises can prove the fact that proper and concentrated respiration could prevent many diseases. Thus, supplementing breathing exercises along with the regular treatment for cancer patients could be helpful in alleviating cancer and other diseases.

scholarly journals Discrete and continuum phenotype-structured models for the evolution of cancer cell populations under chemotherapy

2020 ◽  
Vol 15 ◽  
pp. 14 ◽  
Author(s):  
Rebecca E.A. Stace ◽  
Thomas Stiehl ◽  
Mark A.J. Chaplain ◽  
Anna Marciniak-Czochra ◽  
Tommaso Lorenzi
Keyword(s):  
Cancer Cell ◽  
Cell Population ◽  
Evolutionary Dynamics ◽  
Analytical Description ◽  
Chemotherapeutic Agents ◽  
Cell Populations ◽  
Theoretical Ground ◽  
Individual Based Model ◽  
Nonlocal Parabolic Equation ◽  
Epigenetic Drug

We present a stochastic individual-based model for the phenotypic evolution of cancer cell populations under chemotherapy. In particular, we consider the case of combination cancer therapy whereby a chemotherapeutic agent is administered as the primary treatment and an epigenetic drug is used as an adjuvant treatment. The cell population is structured by the expression level of a gene that controls cell proliferation and chemoresistance. In order to obtain an analytical description of evolutionary dynamics, we formally derive a deterministic continuum counterpart of this discrete model, which is given by a nonlocal parabolic equation for the cell population density function. Integrating computational simulations of the individual-based model with analysis of the corresponding continuum model, we perform a complete exploration of the model parameter space. We show that harsher environmental conditions and higher probabilities of spontaneous epimutation can lead to more effective chemotherapy, and we demonstrate the existence of an inverse relationship between the efficacy of the epigenetic drug and the probability of spontaneous epimutation. Taken together, the outcomes of the model provide theoretical ground for the development of anticancer protocols that use lower concentrations of chemotherapeutic agents in combination with epigenetic drugs capable of promoting the re-expression of epigenetically regulated genes.

scholarly journals Connectivity Map Analysis Indicates PI3K/Akt/mTOR Inhibitors as Potential Anti-Hypoxia Drugs in Neuroblastoma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2809
Author(s):  
Paolo Uva ◽  
Maria Carla Bosco ◽  
Alessandra Eva ◽  
Massimo Conte ◽  
Alberto Garaventa ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Drug Repurposing ◽  
Enrichment Analysis ◽  
Mtor Inhibitors ◽  
Gene Set Enrichment Analysis ◽  
Low Oxygen ◽  
Connectivity Map ◽  
Hypoxic Conditions ◽  
Connectivity Score

Neuroblastoma (NB) is one of the deadliest pediatric cancers, accounting for 15% of deaths in childhood. Hypoxia is a condition of low oxygen tension occurring in solid tumors and has an unfavorable prognostic factor for NB. In the present study, we aimed to identify novel promising drugs for NB treatment. Connectivity Map (CMap), an online resource for drug repurposing, was used to identify connections between hypoxia-modulated genes in NB tumors and compounds. Two sets of 34 and 21 genes up- and down-regulated between hypoxic and normoxic primary NB tumors, respectively, were analyzed with CMap. The analysis reported a significant negative connectivity score across nine cell lines for 19 compounds mainly belonging to the class of PI3K/Akt/mTOR inhibitors. The gene expression profiles of NB cells cultured under hypoxic conditions and treated with the mTORC complex inhibitor PP242, referred to as the Mohlin dataset, was used to validate the CMap findings. A heat map representation of hypoxia-modulated genes in the Mohlin dataset and the gene set enrichment analysis (GSEA) showed an opposite regulation of these genes in the set of NB cells treated with the mTORC inhibitor PP242. In conclusion, our analysis identified inhibitors of the PI3K/Akt/mTOR signaling pathway as novel candidate compounds to treat NB patients with hypoxic tumors and a poor prognosis.

scholarly journals Increased nitrite reductase activity of fetal versus adult ovine hemoglobin

2009 ◽  
Vol 296 (2) ◽  
pp. H237-H246 ◽  
Author(s):  
Arlin B. Blood ◽  
Mauro Tiso ◽  
Shilpa T. Verma ◽  
Jennifer Lo ◽  
Mahesh S. Joshi ◽  
...  
Keyword(s):  
Nitrite Reductase ◽  
Chronic Hypoxia ◽  
Reductase Activity ◽  
Fetal Hemoglobin ◽  
Nitrite Reduction ◽  
No Production ◽  
Low Oxygen ◽  
Nitrite Reductase Activity ◽  
Adult Hemoglobin ◽  
Severe Ischemia

Growing evidence indicates that nitrite, NO2−, serves as a circulating reservoir of nitric oxide (NO) bioactivity that is activated during physiological and pathological hypoxia. One of the intravascular mechanisms for nitrite conversion to NO is a chemical nitrite reductase activity of deoxyhemoglobin. The rate of NO production from this reaction is increased when hemoglobin is in the R conformation. Because the mammalian fetus exists in a low-oxygen environment compared with the adult and is exposed to episodes of severe ischemia during the normal birthing process, and because fetal hemoglobin assumes the R conformation more readily than adult hemoglobin, we hypothesized that nitrite reduction to NO may be enhanced in the fetal circulation. We found that the reaction was faster for fetal than maternal hemoglobin or blood and that the reactions were fastest at 50–80% oxygen saturation, consistent with an R-state catalysis that is predominant for fetal hemoglobin. Nitrite concentrations were similar in blood taken from chronically instrumented normoxic ewes and their fetuses but were elevated in response to chronic hypoxia. The findings suggest an augmented nitrite reductase activity of fetal hemoglobin and that the production of nitrite may participate in the regulation of vascular NO homeostasis in the fetus.

scholarly journals Cyclic Hypoxia: An Update on Its Characteristics, Methods to Measure It and Biological Implications in Cancer

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 23
Author(s):  
Samuel B. Bader ◽  
Mark W. Dewhirst ◽  
Ester M. Hammond
Keyword(s):  
Vascular Remodeling ◽  
Intermittent Hypoxia ◽  
Chronic Hypoxia ◽  
Tumor Hypoxia ◽  
Biological Response ◽  
Therapy Response ◽  
Static Condition ◽  
Oxygen Species ◽  
Oxygen Levels ◽  
Poor Patient

Regions of hypoxia occur in most if not all solid cancers. Although the presence of tumor hypoxia is a common occurrence, the levels of hypoxia and proportion of the tumor that are hypoxic vary significantly. Importantly, even within tumors, oxygen levels fluctuate due to changes in red blood cell flux, vascular remodeling and thermoregulation. Together, this leads to cyclic or intermittent hypoxia. Tumor hypoxia predicts for poor patient outcome, in part due to increased resistance to all standard therapies. However, it is less clear how cyclic hypoxia impacts therapy response. Here, we discuss the causes of cyclic hypoxia and, importantly, which imaging modalities are best suited to detecting cyclic vs. chronic hypoxia. In addition, we provide a comparison of the biological response to chronic and cyclic hypoxia, including how the levels of reactive oxygen species and HIF-1 are likely impacted. Together, we highlight the importance of remembering that tumor hypoxia is not a static condition and that the fluctuations in oxygen levels have significant biological consequences.

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