Mathematical modelling of stem and progenitor cell dynamics during ruxolitinib treatment of patients with myeloproliferative neoplasms.

Introduction: The Philadelphia chromosome-negative myeloproliferative neoplasms are a group of slowly progressing haematological malignancies primarily characterised by an overproduction of myeloid blood cells. Patients are treated with various drugs, including the JAK1/2 inhibitor ruxolitinib. Mathematical modelling can help propose and test hypotheses of how the treatment works.

Neutrophil-to-lymphocyte ratio and all-cause mortality with and without myeloproliferative neoplasms-a Danish longitudinal study.

The neutrophil-to-lymphocyte ratio(NLR) is increased in chronic inflammation and myeloproliferative neoplasms (MPN). We hypothesize that NLR is associated with all-cause mortality and mortality by comorbidity burden in the general population and individuals with MPN. We included 835,430 individuals from The Danish General Suburban Population Study, general practitioners, and outpatient clinics.

Aging, Inflammation, and Comorbidity in Cancers-A General In Silico Study Exemplified by Myeloproliferative Malignancies.

(1) Background: We consider dormant, pre-cancerous states prevented from developing into cancer by the immune system. Inflammatory morbidity may compromise the immune system and cause the pre-cancer to escape into an actual cancerous development. The immune deficiency described is general, but the results may vary across specific cancers due to different variances (2) Methods: We formulate a general conceptual model to perform rigorous in silico consequence analysis.

Therapeutic cancer vaccination against mutant calreticulin in myeloproliferative neoplasms induces expansion of specific T cells in the periphery but specific T cells fail to enrich in the bone marrow.

Background: Therapeutic cancer vaccination against mutant calreticulin () in patients with -mutant (mut) myeloproliferative neoplasms (MPN) induces strong T-cell responses against mutant CALR yet fails to demonstrate clinical activity. Infiltration of tumor specific T cells into the tumor microenvironment is needed to attain a clinical response to therapeutic cancer vaccination.

Aim: Determine if CALRmut specific T cells isolated from vaccinated patients enrich in the bone marrow upon completion of vaccination and explore possible explanations for the lack of enrichment.

Case Report: First longitudinal study of a patient with CALR positive clonal hematopoiesis of indeterminate potential developing into pre-fibrotic myelofibrosis.

Initial diagnosis of overt myeloproliferative neoplasms (MPNs) represents the juncture during clonal evolution when symptoms or complications prompt an afflicted individual to seek medical attention. In 30-40% of the MPN subgroups essential thrombocythemia (ET) and myelofibrosis (MF), somatic mutations in the calreticulin gene () are drivers of the disease resulting in constitutive activation of the thrombopoietin receptor (MPL). In the current study, we describe a healthy mutated individual during a 12 year follow-up from initial identification of clonal hematopoiesis of indeterminate potential (CHIP) to the diagnosis of pre-MF.

Toward an optimal contraception dosing strategy.

Anovulation refers to a menstrual cycle characterized by the absence of ovulation. Exogenous hormones such as synthetic progesterone and estrogen have been used to attain this state to achieve contraception. However, large doses are associated with adverse effects such as increased risk for thrombosis and myocardial infarction.

Mechanistic-mathematical modeling of intracranial pressure (ICP) profiles over a single heart cycle. The fundament of the ICP curve form.

The intracranial pressure (ICP) curve with its different peaks has been comprehensively studied, but the exact physiological mechanisms behind its morphology has not been revealed. If the pathophysiology behind deviations from the normal ICP curve form could be identified, it could be vital information to diagnose and treat each single patient. A mathematical model of the hydrodynamics in the intracranial cavity over single heart cycles was developed.

Bayesian parameter estimation for phosphate dynamics during hemodialysis.

Hyperphosphatemia in patients with renal failure is associated with increased vascular calcification and mortality. Hemodialysis is a conventional treatment for patients with hyperphosphatemia. Phosphate kinetics during hemodialysis may be described by a diffusion process and modeled by ordinary differential equations.

HSC Niche Dynamics in Regeneration, Pre-malignancy, and Cancer: Insights From Mathematical Modeling.

The hematopoietic stem cell (HSC) niche is a crucial driver of regeneration and malignancy. Its interaction with hematopoietic and malignant stem cells is highly complex and direct experimental observations are challenging. We here develop a mathematical model which helps relate processes in the niche to measurable changes of stem and non-stem cell counts.

A novel integrated biomarker index for the assessment of hematological responses in MPNs during treatment with hydroxyurea and interferon-alpha2.

Background: Conventional cytoreductive therapy for patients with chronic Philadelphia-negative myeloproliferative neoplasms (MPNs) includes hydroxyurea (HU), interferon-alpha2 (IFN), and anagrelide. HU is worldwide the most used cytoreductive agent, which lowers elevated blood cell counts within days in the large majority of patients. However, some patients may experience rebound cytosis when HU is reduced due to cytopenia, thereby potentially giving rise to fluctuating cell counts during therapy.

Clonal haematopoiesis of indeterminate potential and impaired kidney function-A Danish general population study with 11 years follow-up.

The myeloproliferative neoplasms are associated with chronic kidney disease but whether clonal haematopoiesis of indeterminate potential (CHIP) is associated with impaired kidney function is unknown. In the Danish General Suburban Population Study (N = 19 958) from 2010 to 2013, 645 individuals were positive for JAK2V617F (N = 613) or CALR (N = 32) mutations. Mutation-positive individuals without haematological malignancy were defined as having CHIP (N = 629).

Postural orthostatic tachycardia syndrome explained using a baroreflex response model.

Patients with postural orthostatic tachycardia syndrome (POTS) experience an excessive increase in heart rate (HR) and low-frequency (∼0.1 Hz) blood pressure (BP) and HR oscillations upon head-up tilt (HUT). These responses are attributed to increased baroreflex (BR) responses modulating sympathetic and parasympathetic signalling.

Data-driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis.

Background: Hydroxyurea (HU) treatment of patients with essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) (MPNs) normalizes elevated blood cell counts within weeks in the large majority of patients. Studies on the impact of HU upon the kinetics of the JAK2V617F allele burden, leukocyte, and platelet counts over time are scarce.

Purpose: Using data-driven analysis as a novel tool to model the kinetics of the JAK2V617F allele burden and blood cell counts over time during treatment with HU.

Potential of Immunotherapies in Treating Hematological Cancer-Infection Comorbidities-A Mathematical Modelling Approach.

Background: The immune system attacks threats like an emerging cancer or infections like COVID-19 but it also plays a role in dealing with autoimmune disease, e.g., inflammatory bowel diseases, and aging.

Patient-specific parameter estimation: Coupling a heart model and experimental data.

This study develops a hemodynamic model involving the atrium, ventricle, veins, and arteries that can be calibrated to experimental results. It is a Windkessel model that incorporates an unsteady Bernoulli effect in the blood flow to the atrium. The model is represented by ordinary differential equations in terms of blood volumes in the compartments as state variables and it demonstrates the use of conductance instead of resistance to capture the effect of a non-leaking heart valve.

Mathematical modelling of the hematopoietic stem cell-niche system: Clonal dominance based on stem cell fitness.

Human blood cell production is maintained by hematopoietic stem cells (HSC) which give rise to all types of mature blood cells. Experimental observation of HSC in their physiologic bone-marrow microenvironment, the so-called stem cell niche, is challenging. Therefore, the details of HSC dynamics and the cellular interactions in the stem cell niche remain elusive.

Dynamics of competing heterogeneous clones in blood cancers explains multiple observations - a mathematical modeling approach.

Heterogeneity of stem cell clones provide a key ingredient in altered hematopoiesis and is of main interest in the study of predisease states as well as in the development of blood cancers such as chronic myeloid leukemia (CML) and the Philadelphia-negative myeloprofilerative neoplasms (MPNs). A mathematical model based on biological mechanisms and basic cell descriptors such as proliferation rates and apoptosis rates is suggested, connecting stem cell dynamics with mature blood cells and immune mediated feedback. The flexible approach allows for arbitrary numbers of mutated stem cell clones with perturbed properties.

Mathematical Modeling of MPNs Offers Understanding and Decision Support for Personalized Treatment.

(1) Background: myeloproliferative neoplasms (MPNs) are slowly developing hematological cancers characterized by few driver mutations, with V617F being the most prevalent. (2) Methods: using mechanism-based mathematical modeling (MM) of hematopoietic stem cells, mutated hematopoietic stem cells, differentiated blood cells, and immune response along with longitudinal data from the randomized Danish DALIAH trial, we investigate the effect of the treatment of MPNs with interferon-α2 on disease progression. (3) Results: At the population level, the V617F allele burden is halved every 25 months.

Global dynamics of healthy and cancer cells competing in the hematopoietic system.

Stem cells in the bone marrow differentiate to ultimately become mature, functioning blood cells through a tightly regulated process (hematopoiesis) including a stem cell niche interaction and feedback through the immune system. Mutations in a hematopoietic stem cell can create a cancer stem cell leading to a less controlled production of malfunctioning cells in the hematopoietic system. This was mathematically modelled by Andersen et al.

Data-driven analysis of JAK2V617F kinetics during interferon-alpha2 treatment of patients with polycythemia vera and related neoplasms.

Treatment with PEGylated interferon-alpha2 (IFN) of patients with essential thrombocythemia and polycythemia vera induces major molecular remissions with a reduction in the JAK2V617F allele burden to undetectable levels in a subset of patients. A favorable response to IFN has been argued to depend upon the tumor burden, implying that institution of treatment with IFN should be as early as possible after the diagnosis. However, evidence for this statement is not available.

Mathematical analysis of the Cancitis model and the role of inflammation in blood cancer progression.

Recently, a tight coupling has been observed between inflammation and blood cancer such as the Myeloproliferative Neoplasms (MPNs). A mechanism based six-dimensional model-the Cancitis model-describing the progression of blood cancer coupled to the inflammatory system is analyzed. An analytical investigation provides criteria for the existence of physiological steady states, trivial, hematopoietic, malignant and co-existing steady states.

Validation of a mathematical model for understanding intracranial pressure curve morphology.

The physiology underlying the intracranial pressure (ICP) curve morphology is not fully understood. Recent research has suggested that the morphology could be dependent on arterial cerebral inflow and the physiological and pathophysiological properties of the intracranial cavity. If understood, the ICP curve could provide information about the patient's cerebrovascular state important in individualizing treatment in neuro intensive care patients.

Increased Intracranial Pressure Attenuates the Pulsating Component of Cerebral Venous Outflow.

Background: The underlying physiology of the intracranial pressure (ICP) curve morphology is still poorly understood. If this physiology is explained it could be possible to extract clinically relevant information from the ICP curve. The venous outflow from the cranial cavity is pulsatile, and in theory the pulsatile component of venous outflow from the cranial cavity should be attenuated with increasing ICP.

Cardiovascular dynamics during head-up tilt assessed via pulsatile and non-pulsatile models.

This study develops non-pulsatile and pulsatile models for the prediction of blood flow and pressure during head-up tilt. This test is used to diagnose potential pathologies within the autonomic control system, which acts to keep the cardiovascular system at homeostasis. We show that mathematical modeling can be used to predict changes in cardiac contractility, vascular resistance, and arterial compliance, quantities that cannot be measured but are useful to assess the system's state.