Застосування зворотних залежностей у математичних моделях складних об’єктів та систем

Представлено метод побудови апроксимуючих поліноміальних функцій багатьох змінних, який засновано на використанні в поліномах від’ємних степенів та застосуванні до поліномів обмеження на сумарну величину ступеня добутку змінних. Запропоновано використання штрафної функції на кількість членів полінома. Експериментальним шляхом отримано оптимальну величину коефіцієнта запропонованої штрафної функції.Представлен метод построения аппроксимирующих полиномиальных функций многих переменных, основанный на использовании в полиномах отрицательных степеней и применении к полиномам ограничения на суммарную величину степени произведения переменных. Предложено использование штрафной функции на количество членов полинома. Экспериментальным путем получена оптимальная величина коэффициента предложенной штрафной функции.A method of constructing approximating polynomials functions of many variables, based on the use of the negative degrees in polynomials and the application of the limitation on the total value of the product variable to polynoms is presented. The usage of the penalty function for the number of polynomial members is suggested. The optimum value of the proposed penalty functions coefficient is experimentally obtained

Systemic and Tissue Inflammation in Juvenile Dermatomyositis: From Pathogenesis to the Quest for Monitoring Tools

Juvenile Dermatomyositis (JDM) is a systemic immune-mediated disease of childhood, characterized by muscle weakness, and a typical skin rash. Other organ systems and tissues such as the lungs, heart, and intestines can be involved, but may be under-evaluated. The inflammatory process in JDM is characterized by an interferon signature and infiltration of immune cells such as T cells and plasmacytoid dendritic cells into the affected tissues. Vasculopathy due to loss and dysfunction of endothelial cells as a result of the inflammation is thought to underlie the symptoms in most organs and tissues. JDM is a heterogeneous disease, and several disease phenotypes, each with a varying combination of affected tissues and organs, are linked to the presence of myositis autoantibodies. These autoantibodies have therefore been extensively studied as biomarkers for the disease phenotype and its associated prognosis. Next to identifying the JDM phenotype, monitoring of disease activity and disease-inflicted damage not only in muscle and skin, but also in other organs and tissues, is an important part of clinical follow-up, as these are key determinants for the long-term outcomes of patients. Various monitoring tools are currently available, among which clinical assessment, histopathological investigation of muscle and skin biopsies, and laboratory testing of blood for specific biomarkers. These investigations also give novel insights into the underlying immunological processes that drive inflammation in JDM and suggest a strong link between the interferon signature and vasculopathy. New tools are being developed in the quest for minimally invasive, but sensitive and specific diagnostic methods that correlate well with clinical symptoms or reflect local, low-grade inflammation. In this review we will discuss the types of (extra)muscular tissue inflammation in JDM and their relation to vasculopathic changes, critically assess the available diagnostic methods including myositis autoantibodies and newly identified biomarkers, and reflect on the immunopathogenic implications of identified markers

Endothelial and Inflammation Biomarker Profiles at Diagnosis Reflecting Clinical Heterogeneity and Serving as a Prognostic Tool For Treatment Response in Two Independent Cohorts of Patients With Juvenile Dermatomyositis

Objective: Juvenile dermatomyositis (DM) is a heterogeneous systemic immune-mediated vasculopathy. This study was undertaken to 1) identify inflammation/endothelial dysfunction–related biomarker profiles reflecting disease severity at diagnosis, and 2) establish whether such biomarker profiles could be used for predicting the response to treatment in patients with juvenile DM. Methods: In total, 39 biomarkers related to activation of endothelial

Galectin-9 is an easy to measure biomarker for the interferon signature in systemic lupus erythematosus and antiphospholipid syndrome

The interferon (IFN) signature is related to disease activity and vascular disease in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) and represents a promising therapeutic target. Quantification of the IFN signature is currently performed by gene expression analysis, limiting its current applicability in clinical practice. Therefore, the objective of this study was to establish an easy to measure biomarker for the IFN signature

Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy

Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. As novel and improved immunotherapies may fill this need, we dissected the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 25 tumors (10 pre- and 15 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas were infiltrated by NK, T and B cells, and immunosuppressive myeloid populations. NK cells showed reduced cytotoxicity and T cells had a dysfunctional profile. Interaction analysis revealed a vast immunoregulatory network and identified NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduced neuroblastoma growth, with complete responses in vivo. Moreover, addition of TIGIT blockade to standard relapse treatment in a chemotherapy-resistant Th-ALKF1174L/MYCN 129/SvJ syngeneic model significantly improved survival. Concluding, our integrative analysis of neuroblastoma’s vast immunoregulatory network provides novel targets and a rationale for immunotherapeutic combination strategies

Local and systemic profiles of inflammation, adaptation and regulation at the interface between tissue and immunity : Juvenile Dermatomyositis and beyond

Inflammation is the body’s natural reaction to fight infections. During inflammation, cells of the immune system, like T cells, move from the bloodstream into inflamed tissues. Specific signaling molecules are released there. The amount and combination of signaling molecules reflects the type and intensity of inflammation. These molecules can thereby serve as a source of information (biomarker) about inflammation. In part 1 of this thesis we investigated how biomarkers in blood could aid to improve the treatment of children with a rare inflammatory disease of muscle and skin, juvenile dermatomyositis (JDM). We demonstrated that specific biomarkers reliably reflect the severity and activity of the disease, and may predict response to treatment. These biomarkers have now been implemented into patient care and can thereby contribute to “precision medicine”: treatment tailored to individual needs of patients. Next to biomarker-focused research, we investigated in part 2 how T cells adapt to tissue environments. We found that the process of leaving the bloodstream could play an important role in preparing them for tissue environments. Moreover, we showed that during pregnancy, T cells at the interface between mother and child in the uterus, behave in a peculiar manner. Especially regulatory T cells, whose job it is to keep immune responses in check, were very active at this site. Their strong inhibitory function may warrant the prevention of an immune response against the child, which is an important prerequisite for a successful pregnancy. Finally, during preeclampsia, the balance between essential signaling molecules proved to be disturbed

The immune landscape of neuroblastoma: Challenges and opportunities for novel therapeutic strategies in pediatric oncology

Immunotherapy holds great promise for the treatment of pediatric cancers. In neuroblastoma, the recent implementation of anti-GD2 antibody Dinutuximab into the standard of care has improved patient outcomes substantially. However, 5-year survival rates are still below 50% in patients with high-risk neuroblastoma, which has sparked investigations into novel immunotherapeutic approaches. T cell-engaging therapies such as immune checkpoint blockade, antibody-mediated therapy and adoptive T cell therapy have proven remarkably successful in a range of adult cancers but still meet challenges in pediatric oncology. In neuroblastoma, their limited success may be due to several factors. Neuroblastoma displays low immunogenicity due to its low mutational load and lack of MHC-I expression. Tumour infiltration by T and NK cells is especially low in high-risk neuroblastoma and is prognostic for survival. Only a small fraction of tumour-infiltrating lymphocytes shows tumour reactivity. Moreover, neuroblastoma tumours employ a variety of immune evasion strategies, including expression of immune checkpoint molecules, induction of immunosuppressive myeloid and stromal cells, as well as secretion of immunoregulatory mediators, which reduce infiltration and reactivity of immune cells. Overcoming these challenges will be key to the successful implementation of novel immunotherapeutic interventions. Combining different immunotherapies, as well as personalised strategies, may be promising approaches. We will discuss the composition, function and prognostic value of tumour-infiltrating lymphocytes (TIL) in neuroblastoma, reflect on challenges for immunotherapy, including a lack of TIL reactivity and tumour immune evasion strategies, and highlight opportunities for immunotherapy and future perspectives with regard to state-of-the-art developments in the tumour immunology space

Trajectories of cardiorespiratory fitness in patients with juvenile dermatomyositis

Objectives: Previous research demonstrated decreased cardiorespiratory fitness (CRF) in patients with JDM during active disease and remission. However, longitudinal data regarding trajectories of CRF are currently lacking. The objective of this study was to determine trajectories of CRF in patients with both monocyclic and chronic JDM, and to identify potential predictors of these trajectories. Methods: Thirty-six patients with JDM [median age (interquartile range) at diagnosis: 8.3 (6.3-15.4) years] treated in our paediatric rheumatology outpatient clinic were included. All patients performed multiple cardiopulmonary exercise tests between 2003 and 2016. Relevant CRF parameters were analysed, including peak oxygen uptake, maximal workload, mechanical efficacy and oxygen uptake at ventilatory anaerobic threshold. We analysed trajectories up to 10 years after diagnosis and determined predictors of CRF outcome parameters by multilevel analyses. Results: Trajectories demonstrated significant declines in CRF during the active phase of the disease with subsequent improvement in CRF during the initial years after diagnosis. However, hereafter no further improvements, and even a decrease, in CRF were observed over time in both monocyclic and chronic subtypes of JDM. We found that a longer disease duration, younger age of onset and higher prednisone dose negatively influence CRF. Conclusion: Patients with both monocyclic and chronic JDM show decreases in long-term CRF trajectories. Longer disease duration, younger age of onset and higher prednisone dose negatively influence CRF. This study stresses the need for regular evaluation of CRF and implementation of (exercise) interventions to improve CRF in patients with JDM, even in monocyclic patients

The immune landscape of neuroblastoma: Challenges and opportunities for novel therapeutic strategies in pediatric oncology

Immunotherapy holds great promise for the treatment of pediatric cancers. In neuroblastoma, the recent implementation of anti-GD2 antibody Dinutuximab into the standard of care has improved patient outcomes substantially. However, 5-year survival rates are still below 50% in patients with high-risk neuroblastoma, which has sparked investigations into novel immunotherapeutic approaches. T cell-engaging therapies such as immune checkpoint blockade, antibody-mediated therapy and adoptive T cell therapy have proven remarkably successful in a range of adult cancers but still meet challenges in pediatric oncology. In neuroblastoma, their limited success may be due to several factors. Neuroblastoma displays low immunogenicity due to its low mutational load and lack of MHC-I expression. Tumour infiltration by T and NK cells is especially low in high-risk neuroblastoma and is prognostic for survival. Only a small fraction of tumour-infiltrating lymphocytes shows tumour reactivity. Moreover, neuroblastoma tumours employ a variety of immune evasion strategies, including expression of immune checkpoint molecules, induction of immunosuppressive myeloid and stromal cells, as well as secretion of immunoregulatory mediators, which reduce infiltration and reactivity of immune cells. Overcoming these challenges will be key to the successful implementation of novel immunotherapeutic interventions. Combining different immunotherapies, as well as personalised strategies, may be promising approaches. We will discuss the composition, function and prognostic value of tumour-infiltrating lymphocytes (TIL) in neuroblastoma, reflect on challenges for immunotherapy, including a lack of TIL reactivity and tumour immune evasion strategies, and highlight opportunities for immunotherapy and future perspectives with regard to state-of-the-art developments in the tumour immunology space