Clinical Features of Cutaneous Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cells Transplantation in Children with Hemato-Oncological Diseases

The graft-versus-host disease (GvHD) is frequent complication, it occurs in 50% of patients after allogeneic hematopoietic stem cell transplantation (HSCT) and it is one of the major causes of mortality not associated with disease recurrence. Skin lesion in the symptom complex of acute GvHD develops within the first 100 days after HSCT, and it is complicated diagnostic and therapeutic problem. Significant immunosuppressive status of children during the posttransplant period enhances and changes the course of dermatoses, infections, drug toxicity. Finally, it can lead to immunoallergic processes with possible development to generalized life-threatening diseases of the skin and mucous membranes. Meanwhile, toxic, allergic and infectious skin lesions can be present simultaneously or develop sequentially. The description of the clinical picture of skin lesions in acute GvHD is really crucial and has scientific and practical significance due to relatively small frequency of HSCT in children with oncology diseases. The article summarizes data on etiology, pathogenesis, clinical forms, diagnostic and treatment methods of cutaneous complications of the early post-transplantation period after HSCT

Perspectives for the Use of Fucoidans in Clinical Oncology

Fucoidans are natural sulfated polysaccharides that have a wide range of biological functions and are regarded as promising antitumor agents. The activity of various fucoidans and their derivatives has been demonstrated in vitro on tumor cells of different histogenesis and in experiments on mice with grafted tumors. However, these experimental models showed low levels of antitumor activity and clinical trials did not prove that this class of compounds could serve as antitumor drugs. Nevertheless, the anti-inflammatory, antiangiogenic, immunostimulating, and anticoagulant properties of fucoidans, as well as their ability to stimulate hematopoiesis during cytostatic-based antitumor therapy, suggest that effective fucoidan-based drugs could be designed for the supportive care and symptomatic therapy of cancer patients. The use of fucoidans in cancer patients after chemotherapy and radiation therapy might promote the rapid improvement of hematopoiesis, while their anti-inflammatory, immunomodulatory, and anticoagulant effects have the potential to improve the quality of life of patients with advanced cancer

Антилейкемические эффекты глюкокортикоидов при лечении острого лимфобластного лейкоза

Glucocorticoids (GC) are used as anti-inflammatory, immunosupressive and anti-tumor agents for several decades due to their ability to cell cycle inhibition and apoptosis induction but mechanism of action is not fully explored. Glucocorticoids play one of the key roles in acute lymphoblastic leukaemia treatment and are at the forefront in induction and reinduction phases. The response of tumor clone to GC determines a risk group and prognosis. A number of mechanisms of antileukemic action and resistance factors will be describe in this article.Глюкокортикоиды (ГК) на протяжении нескольких десятилетий используются в клинической медицине в качестве противовоспалительных, иммуносупрессивных и противоопухолевых агентов благодаря их свойству ингибировать клеточный цикл и индуцировать апоптоз, однако точный механизм их действия не изучен до конца. Ключевую роль препараты ГК играют в лечении острого лимфобластного лейкоза, занимая одну из базовых позиций на этапе индукции и реиндукции ремиссии. Ответ опухолевого клона на ГК детерминирует группу риска и прогноз заболевания. Ряд механизмов антилейкемического действия ГК и факторов резистентности к ним будут рассмотрены в настоящей статье

VDJtools: Unifying Post-analysis of T Cell Receptor Repertoires

<div><p>Despite the growing number of immune repertoire sequencing studies, the field still lacks software for analysis and comprehension of this high-dimensional data. Here we report VDJtools, a complementary software suite that solves a wide range of T cell receptor (TCR) repertoires post-analysis tasks, provides a detailed tabular output and publication-ready graphics, and is built on top of a flexible API. Using TCR datasets for a large cohort of unrelated healthy donors, twins, and multiple sclerosis patients we demonstrate that VDJtools greatly facilitates the analysis and leads to sound biological conclusions. VDJtools software and documentation are available at <a href="https://github.com/mikessh/vdjtools" target="_blank">https://github.com/mikessh/vdjtools</a>.</p></div

Overlap and clustering of TCR repertoires.

<p><b>A.</b> Hierarchical clustering of healthy donor and multiple sclerosis (MS) patient samples using F pairwise similarity metric (the geometric mean of the total frequency of overlapping clonotypes in first and second sample in pair). <b>B.</b> Multi-dimensional scaling (MDS) plot. Samples were projected onto two-dimensional plane based on pairwise similarities (F metric). <b>C.</b> Permutation testing for closeness of samples coming from the same group based on MDS plot. The plot shows observed (dashed red lines) and permuted (histograms) average within-group sample distance. In contrast to control group, MS group displays highly dissimilar T-cell repertoires. N = 10,000 permutations of group labels were performed. <b>D.</b> Hierarchical clustering of samples based on the Euclidean distance between Variable segment frequency vectors. Note that the clustering provides a nice separation between sample groups (Control and MS, P = 0.013, Fisher’s exact test).</p

Estimation of repertoire diversity using multinomial model.

<p><b>A.</b> Rarefaction analysis of repertoire samples from healthy donors and multiple sclerosis patients. The number of unique clonotypes in a sub-sample plotted against its size (number of T-cell receptor cDNA molecules, TRBM). Solid and dashed lines are diversity estimates computed by interpolating and extrapolating using a multinomial model respectively [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004503#pcbi.1004503.ref029" target="_blank">29</a>]. Note that generally rarefaction curves for MS samples go below those of control donors. Post-HSCT sample (MS8-HSCT) displays the lowest diversity. <b>B.</b> Comparison of repertoire diversity using normalized Chao1 estimate. Normalization is performed by down-sampling datasets to the size of smallest dataset and computing the estimate for resulting datasets (mean estimate value from n = 3 re-samples is used). MS8-HSCT sample is discarded from calculations. *—P = 0.022, two-tailed T-test; effect size estimated by Cohen’s d is 0.98.</p

Overview of VDJtools software package.

<p>VDJtools analysis routines can be grouped into 6 modules and are applicable to results produced by commonly used immune repertoire sequencing processing software. Basic statistics and segment usage module include general statistics (clonotype and read count, number and frequency of non-coding clonotypes, convergent recombination of CDR3 amino acid sequences, insert size statistics, etc), spectratyping (distribution of clonotype frequency by CDR3 length), Variable and Joining segment usage profiles and their pairing frequency in re-arranged receptor junction sequences. Repertoire overlap module includes routines for computing sets of overlapping clonotypes and their characteristics, and scatter plots of clonotype frequencies. Diversity analysis includes routines for visualizing clonotype frequency distribution, computing repertoire diversity estimates and rarefaction plots. The fourth set of routines can be used to create clonotype abundance profiles and track clonotypes in time course of vaccination, myeloablation and blood cell transplant. Sample clustering is implemented based on computed repertoire similarity measures and could be used to distinguish various biological conditions, cell subsets and tissues. Auxiliary routines provide means for clonotype table filtering (e.g. by segment usage or non-coding CDR3 sequence) as well as annotation with custom or pre-built pathogen-specific clonotype database. VDJtools can be incorporated in Java programming language-based pipelines as demonstrated by VDJviz clonotype browser.</p

CDR3 junction features.

<p>MS patient-derived repertoire is enriched for TCR sequences with long VJ insert, partially due to high abundance of specific Variable segment regions. <b>A</b>. Length of Variable and Joining segment germline parts within CDR3 (V-germ and J-germ) and of VJ insert (VJ-junc) compared between MS donors and healthy controls. <b>B</b>. Average length of VJ junctions among all and selected V-segments (TRBV5-6,5–1,5–8,7–6 and 20–1, shown to be over-expressed in MS patients compared to controls, see main text) according to TCR sequences from repertoires of healthy donors. <b>C</b>. Comparison of VJ insert lengths between control and MS donors for clonotypes with TRBV5-6,5–1,5–8,7–6 and 20–1 segments. P-values computed using two-tailed unpaired T-test (A, C) and paired T-test (B).</p

Analysis of autologous HSCT-driven changes in T-cell repertoire.

<p><b>A.</b> Stacked clonotype frequency plot highlighting the details of overlap between sample MS8 (before autologous HSCT) and MS8-HSCT (post HSCT). Top 100 clonotypes based on their average frequency in those samples are shown, while other clonotypes that were observed in both samples are marked as “Not shown”. The frequency of remaining clonotypes is marked as “Not in overlap”. <b>B.</b> Changes in Variable-Joining segment pairing in CDR3 junctions changes induced by HSCT. Chord diagram is used for visualization, ribbons connecting segment pairs are scaled by corresponding V-J pair frequency. “TRB” prefix is stripped from segment names for simplicity.</p

Дерматологическая токсичность высоких доз тиотепы у детей. Описание клинического случая

Hematopoietic stem cell transplantation (HSCT) is a treatment modality for a number of severe malignant and non-neoplastic diseases. Autologous hematopoietic stem cell transplantation (auto-HSCT) improves outcomes in patients with solid and hematological malignancies. Skin lesions at the auto-HSCT stage are quite common and represent an important diagnostic and therapeutic problem. The most significant causes of skin lesions in auto-HSCT are drug toxicity, infectious and viral lesions. Each of the complications can manifest itself to varying degrees as well as combine with others, having a significant negative on the patient’s condition, posing a threat to the patient’s life in severe cases.Трансплантация гемопоэтических стволовых клеток (ТГСК) является методом терапии ряда тяжелых злокачественных и неопухолевых заболеваний. Аутологичная трансплантация гемопоэтических стволовых клеток (ауто-ТГСК) улучшает исходы у пациентов со злокачественными новообразованиями солидной и гематологической природы. Поражения кожи на этапе ауто-ТГСК встречаются достаточно часто и представляют собой важную диагностическую и терапевтическую проблему. Наиболее значимыми причинами поражений кожи при ауто-ТГСК являются медикаментозная токсичность, инфекционные и вирусные поражения. Каждое из осложнений может проявляться в различной степени, а также сочетаться с другими, оказывая значимое отрицательное влияние на состояние пациента, в тяжелых случаях представляя угрозу для жизни пациента