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<?xml version="1.0" encoding="UTF-8"?>
<sbml xmlns="http://www.sbml.org/sbml/level3/version1/core" xmlns:layout="http://www.sbml.org/sbml/level3/version1/layout/version1" xmlns:render="http://www.sbml.org/sbml/level3/version1/render/version1" level="3" version="1" layout:required="false" render:required="false">
<model metaid="COPASI0" id="New_Model" name="Greene2019 - Differentiate Spontaneous and Induced Evolution to Drug Resistance During Cancer Treatment" substanceUnits="substance" timeUnits="time" volumeUnits="volume" areaUnits="area" lengthUnits="length" extentUnits="substance">
<listOfUnitDefinitions>
<unitDefinition id="length" name="length">
<listOfUnits>
<unit kind="metre" exponent="1" scale="0" multiplier="1"/>
</listOfUnits>
</unitDefinition>
<unitDefinition id="area" name="area">
<listOfUnits>
<unit kind="metre" exponent="2" scale="0" multiplier="1"/>
</listOfUnits>
</unitDefinition>
<unitDefinition id="volume" name="volume">
<listOfUnits>
<unit kind="litre" exponent="1" scale="-3" multiplier="1"/>
</listOfUnits>
</unitDefinition>
<unitDefinition id="time" name="time">
<listOfUnits>
<unit kind="second" exponent="1" scale="0" multiplier="1"/>
</listOfUnits>
</unitDefinition>
<unitDefinition id="substance" name="substance">
<listOfUnits>
<unit kind="mole" exponent="1" scale="-3" multiplier="1"/>
</listOfUnits>
</unitDefinition>
</listOfUnitDefinitions>
<listOfCompartments>
<compartment metaid="COPASI1" id="compartment" name="compartment" spatialDimensions="3" size="1" units="volume" constant="true"/>
</listOfCompartments>
<listOfSpecies>
<species metaid="COPASI2" id="Resistant_tumor_R" name="Resistant tumor R" compartment="compartment" initialConcentration="0" substanceUnits="substance" hasOnlySubstanceUnits="false" boundaryCondition="false" constant="false"/>
<species metaid="COPASI3" id="Sensitive_tumor_S" name="Sensitive tumor S" compartment="compartment" initialConcentration="0.01" substanceUnits="substance" hasOnlySubstanceUnits="false" boundaryCondition="false" constant="false"/>
<species metaid="COPASI4" id="Tumor_Volume_V" name="Tumor Volume V" compartment="compartment" initialConcentration="0.01" substanceUnits="substance" hasOnlySubstanceUnits="false" boundaryCondition="true" constant="false"/>
</listOfSpecies>
<listOfParameters>
<parameter metaid="COPASI5" id="S_0" name="S_0" value="0.01" constant="true"/>
<parameter metaid="COPASI6" id="R_0" name="R_0" value="0" constant="true"/>
<parameter metaid="COPASI7" id="V_d" name="V_d" value="0.1" constant="true"/>
<parameter metaid="COPASI8" id="V_c" name="V_c" value="0.9" constant="true"/>
<parameter metaid="COPASI9" id="epsilon" name="epsilon" value="1e-06" constant="true"/>
<parameter metaid="COPASI10" id="d" name="d" value="1" constant="true"/>
<parameter metaid="COPASI11" id="p_r" name="p_r" value="0.2" constant="true"/>
<parameter metaid="COPASI12" id="u_on" name="u_on" value="1.5" constant="true"/>
<parameter metaid="COPASI13" id="delta_ton" name="delta_ton" value="1" constant="true"/>
<parameter metaid="COPASI14" id="delta_toff" name="delta_toff" value="3" constant="true"/>
<parameter metaid="COPASI15" id="u" name="u" value="0" constant="false"/>
<parameter metaid="COPASI16" id="alpha" name="alpha" value="0.01" constant="true"/>
</listOfParameters>
<listOfInitialAssignments>
<initialAssignment symbol="Sensitive_tumor_S">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<ci> S_0 </ci>
</math>
</initialAssignment>
</listOfInitialAssignments>
<listOfRules>
<assignmentRule variable="Tumor_Volume_V">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<plus/>
<ci> Resistant_tumor_R </ci>
<ci> Sensitive_tumor_S </ci>
</apply>
</math>
</assignmentRule>
</listOfRules>
<listOfReactions>
<reaction metaid="COPASI18" id="Transition_to_resistance" name="Transition to resistance" reversible="false" fast="false">
<listOfReactants>
<speciesReference species="Sensitive_tumor_S" stoichiometry="1" constant="true"/>
</listOfReactants>
<listOfProducts>
<speciesReference species="Resistant_tumor_R" stoichiometry="1" constant="true"/>
</listOfProducts>
<kineticLaw>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<times/>
<ci> compartment </ci>
<apply>
<plus/>
<ci> epsilon </ci>
<apply>
<times/>
<ci> alpha </ci>
<ci> u </ci>
</apply>
</apply>
<ci> Sensitive_tumor_S </ci>
</apply>
</math>
</kineticLaw>
</reaction>
<reaction metaid="COPASI19" id="growth_of_sensitive_tumor" name="growth of sensitive tumor" reversible="false" fast="false">
<listOfProducts>
<speciesReference species="Sensitive_tumor_S" stoichiometry="1" constant="true"/>
</listOfProducts>
<listOfModifiers>
<modifierSpeciesReference species="Resistant_tumor_R"/>
</listOfModifiers>
<kineticLaw>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<times/>
<ci> compartment </ci>
<apply>
<minus/>
<cn> 1 </cn>
<apply>
<plus/>
<ci> Sensitive_tumor_S </ci>
<ci> Resistant_tumor_R </ci>
</apply>
</apply>
<ci> Sensitive_tumor_S </ci>
</apply>
</math>
</kineticLaw>
</reaction>
<reaction metaid="COPASI20" id="growth_of_resistant_tumor" name="growth of resistant tumor" reversible="false" fast="false">
<listOfProducts>
<speciesReference species="Resistant_tumor_R" stoichiometry="1" constant="true"/>
</listOfProducts>
<listOfModifiers>
<modifierSpeciesReference species="Sensitive_tumor_S"/>
</listOfModifiers>
<kineticLaw>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<times/>
<ci> compartment </ci>
<ci> p_r </ci>
<apply>
<minus/>
<cn> 1 </cn>
<apply>
<plus/>
<ci> Sensitive_tumor_S </ci>
<ci> Resistant_tumor_R </ci>
</apply>
</apply>
<ci> Resistant_tumor_R </ci>
</apply>
</math>
</kineticLaw>
</reaction>
<reaction metaid="COPASI21" id="drug_induced_death" name="drug-induced death" reversible="false" fast="false">
<listOfReactants>
<speciesReference species="Sensitive_tumor_S" stoichiometry="1" constant="true"/>
</listOfReactants>
<kineticLaw>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<times/>
<ci> compartment </ci>
<ci> d </ci>
<ci> u </ci>
<ci> Sensitive_tumor_S </ci>
</apply>
</math>
</kineticLaw>
</reaction>
</listOfReactions>
<listOfEvents>
<event metaid="COPASI17" id="treatment" name="treatment" useValuesFromTriggerTime="true">
<trigger initialValue="false" persistent="true">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<and/>
<apply>
<gt/>
<ci> Tumor_Volume_V </ci>
<ci> V_d </ci>
</apply>
<apply>
<eq/>
<ci> u </ci>
<cn> 0 </cn>
</apply>
</apply>
</math>
</trigger>
<listOfEventAssignments>
<eventAssignment variable="u">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<plus/>
<ci> u </ci>
<ci> u_on </ci>
</apply>
</math>
</eventAssignment>
</listOfEventAssignments>
</event>
</listOfEvents>
</model>
</sbml>
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