Owen2011OxygenBasedCellCycleModel.cpp

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#include "Owen2011OxygenBasedCellCycleModel.hpp"
#include "WildTypeCellMutationState.hpp"
#include "CancerCellMutationState.hpp"
#include "QuiescentCancerCellMutationState.hpp"
#include "ApoptoticCellProperty.hpp"
#include "TipCellMutationState.hpp"
#include "StalkCellMutationState.hpp"
#include "CellPropertyRegistry.hpp"
#include "CellLabel.hpp"
#include "Exception.hpp"
#include "SimulationTime.hpp"
#include "CellCycleModelOdeHandler.hpp"
#include "CvodeAdaptor.hpp"
#include "RandomNumberGenerator.hpp"
#include "AbstractPhaseBasedCellCycleModel.hpp"
#include "Secomb04Parameters.hpp"
#include "GenericParameters.hpp"
#include "Owen11Parameters.hpp"
#include "BaseUnits.hpp"

Owen2011OxygenBasedCellCycleModel::Owen2011OxygenBasedCellCycleModel(boost::shared_ptr<AbstractCellCycleModelOdeSolver> pOdeSolver)
: AbstractOdeBasedPhaseBasedCellCycleModel(SimulationTime::Instance()->GetTime(), pOdeSolver),
  mOdeIntegrationTimeStep(30.0*unit::minutes),
  sOnset(0.4),
  g2Onset(0.6),
  mOnset(0.9),
  mReferenceTimeScale(BaseUnits::Instance()->GetReferenceTimeScale()),
  mReferenceConcentrationScale(BaseUnits::Instance()->GetReferenceConcentrationScale()),
  mMaxRandInitialPhase(0.99),
  mCurrentQuiescentDuration(0.0*unit::seconds),
  mCurrentQuiescenceOnsetTime(0.0*unit::seconds),
  mEnterQuiescenceOxygenConcentration(Owen11Parameters::mpOxygenPartialPressureAtQuiescence->GetValue("Owen2011OxygenBasedCellCycleModel")),
  mLeaveQuiescenceOxygenConcentration(Owen11Parameters::mpOxygenPartialPressureLeaveQuiescence->GetValue("Owen2011OxygenBasedCellCycleModel")),
  mCriticalQuiescentDuration(Owen11Parameters::mpTimeToDeathDueToQuiescence->GetValue("Owen2011OxygenBasedCellCycleModel")),
  mp53ThresholdForApoptosisOfNormalCellsInHealthyMicroenvironment(0.8),
  mp53ThresholdForApoptosisOfNormalCellsInTumourMicroenvironment(0.08),
  mthresholdFractionOfNormalCellNeighbours(0.75)
{
    if (!mpOdeSolver)
    {
        mpOdeSolver = CellCycleModelOdeSolver<Owen2011OxygenBasedCellCycleModel, CvodeAdaptor>::Instance();
        mpOdeSolver->Initialise();
    }

    SetDt(mOdeIntegrationTimeStep/mReferenceTimeScale);

    mReferenceSolubility =
            Secomb04Parameters::mpOxygenVolumetricSolubility->GetValue("Owen2011OxygenBasedCellCycleOdeSystem") *
            GenericParameters::mpGasConcentrationAtStp->GetValue("Owen2011OxygenBasedCellCycleOdeSystem");
}

void Owen2011OxygenBasedCellCycleModel::AdjustOdeParameters(double currentTime)
{
    // Pass this time step's oxygen concentration into the solver as a constant over this timestep
    mpOdeSystem->rGetStateVariables()[3] = mpCell->GetCellData()->GetItem("oxygen");

    // Use the cell's current mutation status as another input
    static_cast<Owen2011OxygenBasedCellCycleOdeSystem*>(mpOdeSystem)->SetMutationState(mpCell->GetMutationState());
}

void Owen2011OxygenBasedCellCycleModel::CheckAndLabelCell()
{
    assert(mpCell->GetMutationState()->IsType<CancerCellMutationState>() || mpCell->GetMutationState()->IsType<WildTypeCellMutationState>());

    // Get cell's oxygen concentration
    units::quantity<unit::concentration> oxygen_concentration = mpCell->GetCellData()->GetItem("oxygen")*mReferenceConcentrationScale;
    if (mpCell->GetMutationState()->IsType<CancerCellMutationState>())
    {
        if(oxygen_concentration/mReferenceSolubility <= mEnterQuiescenceOxygenConcentration)
        {
            mpCell->SetMutationState(CellPropertyRegistry::Instance()->Get<QuiescentCancerCellMutationState>());
            assert(mpCell->GetMutationState()->IsType<QuiescentCancerCellMutationState>());
            assert(!(mpCell->GetMutationState()->IsType<CancerCellMutationState>()));
            mCurrentQuiescenceOnsetTime = SimulationTime::Instance()->GetTime()*mReferenceTimeScale;
            mCurrentCellCyclePhase = G_ZERO_PHASE;
        }
    }
    else
    {
        double p53_concentration = mpCell->GetCellData()->GetItem("p53");
        double p53threshold = 0.0;
        unsigned number_of_normal_neighbours = mpCell->GetCellData()->GetItem("Number_of_normal_neighbours");
        unsigned number_of_cancerous_neighbours = mpCell->GetCellData()->GetItem("Number_of_cancerous_neighbours");
        double normal_neighbour_fraction = double(number_of_normal_neighbours)/double(number_of_cancerous_neighbours+number_of_normal_neighbours);
        if (normal_neighbour_fraction > mthresholdFractionOfNormalCellNeighbours)
        {
            p53threshold = mp53ThresholdForApoptosisOfNormalCellsInHealthyMicroenvironment;
        }
        else
        {
            p53threshold = mp53ThresholdForApoptosisOfNormalCellsInTumourMicroenvironment;
        }
        if(p53_concentration > p53threshold)
        {
            assert(mpCell->GetMutationState()->IsType<WildTypeCellMutationState>());
            mpCell->AddCellProperty(CellPropertyRegistry::Instance()->Get<ApoptoticCellProperty>());
        }
    }
}

AbstractCellCycleModel* Owen2011OxygenBasedCellCycleModel::CreateCellCycleModel()
{
    // Create a new cell-cycle model
    Owen2011OxygenBasedCellCycleModel* p_model = new Owen2011OxygenBasedCellCycleModel(mpOdeSolver);
    /*
     * Set each member variable of the new cell-cycle model that inherits
     * its value from the parent.
     *
     * Note 1: some of the new cell-cycle model's member variables (namely
     * mBirthTime, mCurrentCellCyclePhase, mReadyToDivide, mDt, mpOdeSolver)
     * will already have been correctly initialized in its constructor.
     *
     * Note 2: one or more of the new cell-cycle model's member variables
     * may be set/overwritten as soon as InitialiseDaughterCell() is called on
     * the new cell-cycle model.
     */
    p_model->SetBirthTime(mBirthTime);
    p_model->SetDimension(mDimension);
    p_model->SetMinimumGapDuration(mMinimumGapDuration);
    p_model->SetStemCellG1Duration(mStemCellG1Duration);
    p_model->SetTransitCellG1Duration(mTransitCellG1Duration);
    p_model->SetSDuration(mSDuration);
    p_model->SetG2Duration(mG2Duration);
    p_model->SetMDuration(mMDuration);
    p_model->SetLastTime(mLastTime);
    p_model->SetEnterQuiescenceOxygenConcentration(mEnterQuiescenceOxygenConcentration);
    p_model->SetLeaveQuiescenceOxygenConcentration(mLeaveQuiescenceOxygenConcentration);
    p_model->SetCriticalQuiescentDuration(mCriticalQuiescentDuration);
    p_model->SetCurrentQuiescenceOnsetTime(mCurrentQuiescenceOnsetTime);
    p_model->SetReferenceTimeScale(mReferenceTimeScale);
    p_model->SetReferenceConcentrationScale(mReferenceConcentrationScale);

    /*
     * Create the new cell-cycle model's ODE system and use the current values
     * of the state variables in mpOdeSystem as an initial condition.
     */
    assert(mpOdeSystem);
    // note should the second argument here not be a flag ...
    p_model->SetOdeSystem(new Owen2011OxygenBasedCellCycleOdeSystem(mpCell->GetCellData()->GetItem("oxygen")*mReferenceConcentrationScale,
                                                                    mpCell->GetMutationState()));
    p_model->SetStateVariables(mpOdeSystem->rGetStateVariables());

    return p_model;
}

double Owen2011OxygenBasedCellCycleModel::GetSDuration() const
{
    return 0.0;
}

double Owen2011OxygenBasedCellCycleModel::GetG2Duration() const
{
    return 0.0;
}

double Owen2011OxygenBasedCellCycleModel::GetMDuration() const
{
    return 0.0;
}

double Owen2011OxygenBasedCellCycleModel::GetPhi()
{
    assert(mpOdeSystem != NULL);
    double phi = mpOdeSystem->rGetStateVariables()[0];
    return phi;
}

double Owen2011OxygenBasedCellCycleModel::GetVEGF()
{
    assert(mpOdeSystem != NULL);
    double VEGF = mpOdeSystem->rGetStateVariables()[2];
    return VEGF;
}

double Owen2011OxygenBasedCellCycleModel::GetP53()
{
    assert(mpOdeSystem != NULL);
    double p53 = mpOdeSystem->rGetStateVariables()[1];
    return p53;
}

units::quantity<unit::time> Owen2011OxygenBasedCellCycleModel::GetCurrentQuiescentDuration()
{
    return mCurrentQuiescentDuration;
}

units::quantity<unit::time> Owen2011OxygenBasedCellCycleModel::GetCurrentQuiescenceOnsetTime()
{
    return mCurrentQuiescenceOnsetTime;
}

units::quantity<unit::pressure> Owen2011OxygenBasedCellCycleModel::GetEnterQuiescenceOxygenConcentration()
{
    return mEnterQuiescenceOxygenConcentration;
}

units::quantity<unit::pressure> Owen2011OxygenBasedCellCycleModel::GetLeaveQuiescenceOxygenConcentration()
{
    return mLeaveQuiescenceOxygenConcentration;
}

units::quantity<unit::time> Owen2011OxygenBasedCellCycleModel::GetCriticalQuiescentDuration()
{
    return mCriticalQuiescentDuration;
}

void Owen2011OxygenBasedCellCycleModel::Initialise()
{
    assert(mpOdeSystem == NULL);
    assert(mpCell != NULL);

    mpOdeSystem = new Owen2011OxygenBasedCellCycleOdeSystem(mpCell->GetCellData()->GetItem("oxygen")*mReferenceConcentrationScale,
                                                            mpCell->GetMutationState());

    mpCell->SetBirthTime(SimulationTime::Instance()->GetTime());
    std::vector<double> init_conds = mpOdeSystem->GetInitialConditions();
    init_conds[0] = mMaxRandInitialPhase*RandomNumberGenerator::Instance()->ranf(); // phi is random initially
    init_conds[3] = mpCell->GetCellData()->GetItem("oxygen");

    mpOdeSystem->SetStateVariables(init_conds);
}

void Owen2011OxygenBasedCellCycleModel::InitialiseDaughterCell()
{
    mpOdeSystem->rGetStateVariables()[0] = mpOdeSystem->GetInitialConditions()[0];
    mCurrentCellCyclePhase = G_ONE_PHASE;
}

void Owen2011OxygenBasedCellCycleModel::OutputCellCycleModelParameters(out_stream& rParamsFile)
{
    *rParamsFile << "\t\t\t<EnterQuiescenceOxygenConcentration>" << mEnterQuiescenceOxygenConcentration << "</EnterQuiescenceOxygenConcentration>\n";
    *rParamsFile << "\t\t\t<LeaveQuiescenceOxygenConcentration>" << mLeaveQuiescenceOxygenConcentration << "</LeaveQuiescenceOxygenConcentration>\n";
    *rParamsFile << "\t\t\t<CriticalQuiescentDuration>" << mCriticalQuiescentDuration << "</CriticalQuiescentDuration>\n";

    // Call method on direct parent class
    AbstractOdeBasedPhaseBasedCellCycleModel::OutputCellCycleModelParameters(rParamsFile);
}

void Owen2011OxygenBasedCellCycleModel::ResetForDivision()
{
    assert(mpOdeSystem != NULL);
    assert(mFinishedRunningOdes);
    assert(mReadyToDivide);
    mReadyToDivide = false;
    mFinishedRunningOdes = false;

    // Keep the oxygen concentration the same but reset everything else
    mpOdeSystem->rGetStateVariables()[0] = mpOdeSystem->GetInitialConditions()[0];
    mpOdeSystem->rGetStateVariables()[1] = mpOdeSystem->GetInitialConditions()[1];
    mpOdeSystem->rGetStateVariables()[2] = mpOdeSystem->GetInitialConditions()[2];

    assert(!mpCell->GetMutationState()->IsType<QuiescentCancerCellMutationState>());
    mpCell->SetMutationState(mpCell->GetMutationState());
    mCurrentCellCyclePhase = G_ONE_PHASE;
}

bool Owen2011OxygenBasedCellCycleModel::ReadyToDivide()
{
    if (mpCell->GetMutationState()->IsType<TipCellMutationState>() || mpCell->GetMutationState()->IsType<StalkCellMutationState>())
    {
        mReadyToDivide = false;
    }
    else
    {
        if(!mpCell->HasApoptosisBegun() && !mpCell->IsDead())
        {
            UpdateCellCyclePhase();
            if(mFinishedRunningOdes)
            {
                mReadyToDivide = true;
            }
            else
            {
                mReadyToDivide = false;
            }
        }
        else
        {
            mReadyToDivide = false;
        }
    }
    return mReadyToDivide;
}

void Owen2011OxygenBasedCellCycleModel::SetSOnset(units::quantity<unit::dimensionless> value)
{
    sOnset = value;
}

void Owen2011OxygenBasedCellCycleModel::SetG2Onset(units::quantity<unit::dimensionless> value)
{
    g2Onset = value;
}

void Owen2011OxygenBasedCellCycleModel::SetMOnset(units::quantity<unit::dimensionless> value)
{
    mOnset = value;
}

void Owen2011OxygenBasedCellCycleModel::SetOdeSolverTimeStep(units::quantity<unit::time> timeStep)
{
    mOdeIntegrationTimeStep = timeStep;
    SetDt(mOdeIntegrationTimeStep/mReferenceTimeScale);
}

void Owen2011OxygenBasedCellCycleModel::SetReferenceTimeScale(units::quantity<unit::time> referenceTimeScale)
{
    mReferenceTimeScale = referenceTimeScale;
}

void Owen2011OxygenBasedCellCycleModel::SetReferenceConcentrationScale(units::quantity<unit::concentration> referenceConcentrationScale)
{
    mReferenceConcentrationScale = referenceConcentrationScale;
}

void Owen2011OxygenBasedCellCycleModel::SetMaxRandInitialPhase(units::quantity<unit::dimensionless> rand_max_phase)
{
    assert(rand_max_phase >= 0.0);
    mMaxRandInitialPhase = rand_max_phase;
}

void Owen2011OxygenBasedCellCycleModel::SetEnterQuiescenceOxygenConcentration(units::quantity<unit::pressure> enterQuiescenceOxygenConcentration)
{
    assert(enterQuiescenceOxygenConcentration>=0.0*unit::pascals);
    mEnterQuiescenceOxygenConcentration = enterQuiescenceOxygenConcentration;
}

void Owen2011OxygenBasedCellCycleModel::SetLeaveQuiescenceOxygenConcentration(units::quantity<unit::pressure> leaveQuiescenceOxygenConcentration)
{
    assert(leaveQuiescenceOxygenConcentration >= 0.0*unit::pascals);
    mLeaveQuiescenceOxygenConcentration = leaveQuiescenceOxygenConcentration;
}

void Owen2011OxygenBasedCellCycleModel::SetCriticalQuiescentDuration(units::quantity<unit::time> criticalQuiescentDuration)
{
    assert(criticalQuiescentDuration >= 0.0*unit::seconds);
    mCriticalQuiescentDuration = criticalQuiescentDuration;
}

void Owen2011OxygenBasedCellCycleModel::SetCurrentQuiescenceOnsetTime(units::quantity<unit::time> currentQuiescenceOnsetTime)
{
    assert(currentQuiescenceOnsetTime >= 0.0*unit::seconds);
    mCurrentQuiescenceOnsetTime = currentQuiescenceOnsetTime;
}

void Owen2011OxygenBasedCellCycleModel::SetThresholdFractionOfNormalCellNeighbours(double value)
{
    mthresholdFractionOfNormalCellNeighbours = value;
}

void Owen2011OxygenBasedCellCycleModel::UpdateCellCyclePhase()
{
    assert(!mpCell->HasApoptosisBegun());
    assert(!mpCell->IsDead());

    // if cell is still marked for division then the cell has failed to divide and we need to reset the cell here
    // most notably this happens in on-lattice simulations where there is no space available for a cell to divide
    if(mReadyToDivide)
    {
        ResetForDivision();
    }

    if(mpCell->GetMutationState()->IsType<CancerCellMutationState>() || mpCell->GetMutationState()->IsType<WildTypeCellMutationState>())
    {
        CheckAndLabelCell();
    }

    if(mpCell->GetMutationState()->IsType<QuiescentCancerCellMutationState>())
    {
        UpdateQuiescentDuration();
    }

    // must do this because we are using CVode and by
    // default stopping events are not found
    mpOdeSolver->CheckForStoppingEvents();

    assert(mpOdeSystem != NULL);
    double current_time = SimulationTime::Instance()->GetTime();

    // adjust ode parameters is called in here ... updates mutation state and oxygen concentration
    mFinishedRunningOdes = SolveOdeToTime(current_time);

    // Check no concentrations have gone negative
    for (unsigned i=0; i<mpOdeSystem->GetNumberOfStateVariables(); i++)
    {
        if (mpOdeSystem->rGetStateVariables()[i] < -DBL_EPSILON)
        {
            EXCEPTION("A protein concentration " << i << " has gone negative (" << mpOdeSystem->rGetStateVariables()[i] << ")\n"
                    << "A CellCycleModel numerical method is probably unstable.");
        }
    }

    if(mCurrentCellCyclePhase != G_ZERO_PHASE)
    {
        if(mpOdeSystem->rGetStateVariables()[0]<sOnset)
        {
            mCurrentCellCyclePhase = G_ONE_PHASE;
        }
        else if(mpOdeSystem->rGetStateVariables()[0]<g2Onset)
        {
            mCurrentCellCyclePhase = S_PHASE;
        }
        else if(mpOdeSystem->rGetStateVariables()[0]<mOnset)
        {
            mCurrentCellCyclePhase = G_TWO_PHASE;
        }
        else
        {
            mCurrentCellCyclePhase = M_PHASE;
        }
    }
}

void Owen2011OxygenBasedCellCycleModel::UpdateQuiescentDuration()
{
    assert(mpCell->GetMutationState()->IsType<QuiescentCancerCellMutationState>());
    assert(!(mpCell->HasCellProperty<ApoptoticCellProperty>()));
    assert(!mpCell->HasApoptosisBegun());

    // Get cell's oxygen concentration
    units::quantity<unit::concentration> oxygen_concentration = mpCell->GetCellData()->GetItem("oxygen")*mReferenceConcentrationScale;
    if (oxygen_concentration/mReferenceSolubility <= mLeaveQuiescenceOxygenConcentration)
    {
        // Update the duration of the current period of hypoxia
        mCurrentQuiescentDuration = SimulationTime::Instance()->GetTime()*mReferenceTimeScale - mCurrentQuiescenceOnsetTime;
        if (mCurrentQuiescentDuration >= mCriticalQuiescentDuration)
        {
            mpCell->AddCellProperty(CellPropertyRegistry::Instance()->Get<ApoptoticCellProperty>());
        }
    }
    else
    {
        // Reset the cell's quiescent duration.
        mCurrentQuiescentDuration = 0.0 * unit::seconds;
        mCurrentQuiescenceOnsetTime = 0.0 * unit::seconds;
        mCurrentCellCyclePhase = G_ONE_PHASE;
        mpCell->SetMutationState(CellPropertyRegistry::Instance()->Get<CancerCellMutationState>());
    }
}

// Serialization for Boost >= 1.36
#include "SerializationExportWrapperForCpp.hpp"
CHASTE_CLASS_EXPORT(Owen2011OxygenBasedCellCycleModel)
#include "CellCycleModelOdeSolverExportWrapper.hpp"
EXPORT_CELL_CYCLE_MODEL_ODE_SOLVER(Owen2011OxygenBasedCellCycleModel)