11,728 research outputs found
Combined population dynamics and entropy modelling supports patient stratification in chronic myeloid leukemia
Modelling the parameters of multistep carcinogenesis is key for a better understanding of cancer
progression, biomarker identification and the design of individualized therapies. Using chronic
myeloid leukemia (CML) as a paradigm for hierarchical disease evolution we show that combined
population dynamic modelling and CML patient biopsy genomic analysis enables patient stratification
at unprecedented resolution. Linking CD34+ similarity as a disease progression marker to patientderived
gene expression entropy separated established CML progression stages and uncovered
additional heterogeneity within disease stages. Importantly, our patient data informed model enables
quantitative approximation of individual patients’ disease history within chronic phase (CP) and
significantly separates “early” from “late” CP. Our findings provide a novel rationale for personalized
and genome-informed disease progression risk assessment that is independent and complementary to
conventional measures of CML disease burden and prognosis
Advocating the need of a systems biology approach for personalised prognosis and treatment of B-CLL patients
The clinical course of B-CLL is heterogeneous. This heterogeneity leads to a clinical dilemma: can we identify those patients who will benefit from early treatment and predict the survival? In recent years, mathematical modelling has contributed significantly in understanding the complexity of diseases. In order to build a mathematical model for determining prognosis of B-CLL one has to identify, characterise and quantify key molecules involved in the disease. Here we discuss the need and role of mathematical modelling in predicting B-CLL disease pathogenesis and suggest a new systems biology approach for a personalised therapy of B-CLL patients
Memory NK cell features exploitable in anticancer immunotherapy
Besides their innate ability to rapidly produce effector cytokines and kill virus-infected or transformed cells, natural killer (NK) cells display a strong capability to adapt to environmental modifications and to differentiate into long-lived, hyperfunctional populations, dubbed memory or memory-like NK cells. Despite significant progress in the field of NK cell-based immunotherapies, some factors including their short life span and the occurrence of a tumor-dependent functional exhaustion have limited their clinical efficacy so that strategies aimed at overcoming these limitations represent one of the main current challenges in the field. In this scenario, the exploitation of NK cell memory may have a considerable potential. This article summarizes recent evidence in the literature on the peculiar features that render memory NK cells an attractive tool for antitumor immunotherapy, including their long-term survival and in vivo persistence, the resistance to tumor-dependent immunosuppressive microenvironment, the amplified functional responses to IgG-opsonized tumor cells, and in vitro expansion capability. Along with highlighting these issues, we speculate that memory NK cell-based adoptive immunotherapy settings would greatly take advantage from the combination with tumor-targeting therapeutic antibodies (mAbs), as a strategy to fully unleash their clinical efficacy
Mathematical modeling to elucidate brain tumor abrogation by immunotherapy with T11 target structure
T11 Target structure (T11TS), a membrane glycoprotein isolated from sheep
erythrocytes, reverses the immune suppressed state of brain tumor induced
animals by boosting the functional status of the immune cells. This study aims
at aiding in the design of more efficacious brain tumor therapies with T11
target structure. We propose a mathematical model for brain tumor (glioma) and
the immune system interactions, which aims in designing efficacious brain tumor
therapy. The model encompasses considerations of the interactive dynamics of
macrophages, cytotoxic T lymphocytes, glioma cells, TGF-, IFN-
and the T11TS. The system undergoes sensitivity analysis, that determines which
state variables are sensitive to the given parameters and the parameters are
estimated from the published data. Computer simulations were used for model
verification and validation, which highlight the importance of T11 target
structure in brain tumor therapy
Stem Cell Transplantation As A Dynamical System: Are Clinical Outcomes Deterministic?
Outcomes in stem cell transplantation (SCT) are modeled using probability
theory. However the clinical course following SCT appears to demonstrate many
characteristics of dynamical systems, especially when outcomes are considered
in the context of immune reconstitution. Dynamical systems tend to evolve over
time according to mathematically determined rules. Characteristically, the
future states of the system are predicated on the states preceding them, and
there is sensitivity to initial conditions. In SCT, the interaction between
donor T cells and the recipient may be considered as such a system in which,
graft source, conditioning and early immunosuppression profoundly influence
immune reconstitution over time. This eventually determines clinical outcomes,
either the emergence of tolerance or the development of graft versus host
disease. In this paper parallels between SCT and dynamical systems are explored
and a conceptual framework for developing mathematical models to understand
disparate transplant outcomes is proposed.Comment: 23 pages, 4 figures. Updated version with additional data, 2 new
figures and editorial revisions. New authors adde
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