T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy originating from T-cell precursors. The genetic landscape of T-ALL has been largely characterized by next-generation ...sequencing. Yet, the transcriptome of miRNAs (miRNome) of T-ALL has been less extensively studied. Using small RNA sequencing, we characterized the miRNome of 34 pediatric T-ALL samples, including the expression of isomiRs and the identification of candidate novel miRNAs (not previously annotated in miRBase). For the first time, we show that immunophenotypic subtypes of T-ALL present different miRNA expression profiles. To extend miRNome characteristics in T-ALL (to 82 T-ALL cases), we combined our small RNA-seq results with data available in Gene Expression Omnibus. We report on miRNAs most abundantly expressed in pediatric T-ALL and miRNAs differentially expressed in T-ALL versus normal mature T-lymphocytes and thymocytes, representing candidate oncogenic and tumor suppressor miRNAs. Using eight target prediction algorithms and pathway enrichment analysis, we identified differentially expressed miRNAs and their predicted targets implicated in processes (defined in Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) of potential importance in pathogenesis of T-ALL, including interleukin-6–mediated signaling, mTOR signaling, and regulation of apoptosis. We finally focused on hsa-mir-106a-363 cluster and functionally validated direct interactions of hsa-miR-20b-5p and hsa-miR-363-3p with 3′ untranslated regions of their predicted targets (PTEN, SOS1, LATS2), overrepresented in regulation of apoptosis. hsa-mir-106a-363 is a paralogue of prototypic oncogenic hsa-mir-17-92 cluster with yet unestablished role in the pathogenesis of T-ALL. Our study provides a firm basis and data resource for functional analyses on the role of miRNA-mRNA interactions in T-ALL.
Optimal discrimination between leukemic blasts and normal B-cell precursors (BCP) is critical for treatment monitoring in BCP acute lymphoblastic leukemia (ALL); thus identification of markers ...differentially expressed on normal BCP and leukemic blasts is required.
Multicenter analysis of CD73, CD86 and CD304 expression levels was performed in 282 pediatric BCP-ALL patients vs. normal bone marrow BCP, using normalized median fluorescence intensity (nMFI) values.
CD73 was expressed at abnormally higher levels (vs. pooled normal BCP) at diagnosis in 71/108 BCP-ALL patients (66%), whereas CD304 and CD86 in 119/202 (59%) and 58/100 (58%) patients, respectively. Expression of CD304 was detected at similar percentages in common-ALL and pre-B-ALL, while found at significantly lower frequencies in pro-B-ALL. A significant association (p = 0.009) was found between CD304 expression and the presence of the ETV6-RUNX1 fusion gene. In contrast, CD304 showed an inverse association with MLL gene rearrangements (p = 0.01). The expression levels of CD73, CD86 and CD304 at day 15 after starting therapy (MRD15) were stable or higher than at diagnosis in 35/37 (95%), 40/56 (71%) and 19/41 (46%) cases investigated, respectively. This was also associated with an increased mean nMFI at MRD15 vs. diagnosis of +24 and +3 nMFI units for CD73 and CD86, respectively. In addition, gain of expression of CD73 and CD86 at MRD15 for cases that were originally negative for these markers at diagnosis was observed in 16% and 18% of cases, respectively. Of note, CD304 remained aberrantly positive in 63% of patients, despite its levels of expression decreased at follow-up in 54% of cases.
Here we show that CD73, CD86 and CD304 are aberrantly (over)expressed in a substantial percentage of BCP-ALL patients and that their expression profile remains relatively stable early after starting therapy, supporting their potential contribution to improved MRD analysis by flow cytometry.
•An original method of determination of antigen expression was used.•Increased expression of CD304 is associated with specific subtypes of BCP-ALL.•The utility of CD73, CD86 and CD304 markers for MRD monitoring in BCP-ALL was confirmed.•Of the 3 markers evaluated, CD73 was the most stable at early follow-up time points.
The article concerns the problem of lateral stabilization of a tricycle with variable front wheel track. The vehicle can operate in two modes: with the front wheels folded out and connected. A ...bicycle designed for people with special needs. The element that requires elaboration is the stabilization while driving with the front wheels unfolded. In this mode, a metastable state is created. When the lateral angle of the slope exceeds the limit value, the lateral force causes the lateral tilt. This phenomenon should be treated as a disadvantage as it makes it difficult to smoothly tilt the bicycle, which can lead to disorientation of the rider and difficulty in maintaining balance. The article presents mathematical simulations that allow for the analysis of factors influencing the discussed phenomenon.
GATA-binding protein 2 (
GATA2
) is a transcription factor responsible for the regulation of blood cell proliferation, differentiation, and maintenance in hematopoietic stem cells. Here, we describe ...successful bone marrow transplantation in a carrier of a novel GATA2 pathogenic variant who was diagnosed with immunodeficiency a few years after completion of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treatment. At the age of 4 years, the patient was diagnosed with and treated for BCP-ALL. Antileukemic therapy was complicated by pulmonary cryptococcosis. Two years after completion of the maintenance therapy, the child was consulted by an immunologist because of recurrent respiratory tract infections and an episode of sepsis. Flow cytometry revealed deep monocytopenia, lymphopenia, absence of B lymphocytes, considerably reduced NK cells, poor thymic T lymphocyte production, minor defects in T cell maturation, and absence of TCRγδ+ T cells. The presence of the likely pathogenic, heterozygous missense variant within exon 5 of
GATA2
(NM_032638.5: c.1047T>G, Cys349Trp) was identified in the proband and confirmed in the father of the patient, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from a matched unrelated donor due to myelodysplastic syndrome with excess blasts at the age of 22 years. An allogeneic hematopoietic stem cell transplantation with a reduced toxicity conditioning protocol was performed using a matched sibling donor. Pre-transplant conditioning included fludarabine (5 × 30 mg/m2), treosulfan (3 × 14 g/m2), and thiotepa (10 mg/kg). Complete donor chimerism was achieved on post-transplant day 17. During the 12 months of the posttransplant observation period, she remained free from symptoms of acute or chronic graft-versus-host disease, and immunosuppressive treatment was therefore stopped. This is the second reported case of BCP-ALL in a patient with
GATA2
deficiency, and the first successfully treated with a reduced-toxicity conditioning HSCT protocol. The co-occurrence of lymphoid malignancies and primary immunodeficiencies points to the role of genetic counseling and family screening for possible cancer predisposition syndromes prior to the selection of related HSCT donors.
This study concerns the creep impact on strength parameters of the selected very cohesive soils (PI = 30–70%). The analysis refers to Neogene clays characterized by a complex structure, resulting ...directly from a complicated load history in the geological time scale and identified glacitectonic deformations. In the process of samples’ preparation for strength tests as well as during the interpretation of the post-failure state, particular attention was paid to the soil structure. The imaging methods (X-ray densitometry and computer microtomography) enabled the comparison of the soil structure and the selection of samples with similar characteristics. The completed program of strength tests consisted of two series of tests in the triaxial stress state, differentiated by the occurrence of the initial creep stage, preceding the typical strength test scheme under undrained conditions. This study allowed to obtain a quantitative assessment of the influence of the creep process on the strength parameters of tested soils. Constant stress lower than 60% of the shear stress deviator leads to the deceleration creep course (
parameter 0.64–0.89). As a result, higher values of internal friction angle (20% increase comparing to triaxial tests without creep stage) and cohesion reduction are obtained from triaxial creep tests. Creep parameter
is found to be a valuable indicator for differentiation of landslide activity trend. The tests proved low values of axial strains (1–5%) at failure, which was associated with lithogenesis. By the implementation of obtained strength parameters into the 3D finite element model of the slope, the potential influence of the creep process on the stability of an exemplary cross section of the Warsaw slope could be determined.
Infant acute lymphoblastic leukemia (ALL) is characterized by
(
) gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study ...groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stem-cell transplantation (SCT), and which factors had independent prognostic value.
Three risk groups were defined: low risk (LR):
germline; high risk (HR):
-rearranged and older than 6 months with WBC count 300 × 10
/L or more or a poor prednisone response; and medium risk (MR): all other
-rearranged cases. Patients in the MR and HR groups were randomly assigned to receive the lymphoid course low-dose cytosine arabinoside araC, 6-mercaptopurine, cyclophosphamide (IB) or experimental myeloid courses, namely araC, daunorubicin, etoposide (ADE) and mitoxantrone, araC, etoposide (MAE).
A total of 651 infants were included, with 6-year event-free survival (EFS) and overall survival of 46.1% (SE, 2.1) and 58.2% (SE, 2.0). In West European/North American groups, 6-year EFS and overall survival were 49.4% (SE, 2.5) and 62.1% (SE, 2.4), which were 10% to 12% higher than in other countries. The 6-year probability of disease-free survival was comparable for the randomized arms (ADE+MAE 39.3% SE 4.0; n = 169
IB 36.8% SE, 3.9; n = 161; log-rank
= .47). The 6-year EFS rate of patients in the HR group was 20.9% (SE, 3.4) with the intention to undergo SCT; only 46% of them received SCT, because many had early events.
rearrangement was the strongest prognostic factor for EFS, followed by age, WBC count, and prednisone response.
Early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant ALL compared with the lymphoid-type course IB. Outcome for infant ALL in Interfant-06 did not improve compared with that in Interfant-99.
Preterm births affect around 15 million children a year worldwide. Current medical efforts focus on mitigating the effects of prematurity, not on preventing it. Diagnostic methods are based on parent ...traits and transvaginal ultrasound, during which the length of the cervix is examined. Approximately 30% of preterm births are not correctly predicted due to the complexity of this process and its subjective assessment. Based on recent research, there is hope that machine learning can be a helpful tool to support the diagnosis of preterm births. The objective of this study is to present various machine learning algorithms applied to preterm birth prediction. The wide spectrum of analysed data sets is the advantage of this survey. They range from electrohysterogram signals through electronic health records to transvaginal ultrasounds. Reviews of works on preterm birth already exist; however, this is the first review that includes works that are based on a transvaginal ultrasound examination. In this work, we present a critical appraisal of popular methods that have employed machine learning methods for preterm birth prediction. Moreover, we summarise the most common challenges incurred and discuss their possible application in the future.
Introduction
Myeloid sarcoma (MS) is an extramedullary malignant tumor composed of immature myeloid cells. It occurs in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or ...chronic myeloid leukemia (CML). MS may coincide with disease diagnosis or precede bone marrow involvement by months or even years; it can also represent the extramedullary manifestation of a relapse (
1
,
2
).
Aim
The aim of this study is to describe clinical characteristics of children diagnosed with MS in Poland as well as to analyze diagnostic methods, treatment, and outcomes including overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS). The study also attempted to identify factors determining treatment outcomes.
Patients
The study group comprised 43 patients (F=18, M=25) aged 0-18 years (median age, 10.0 years; mean age, 8.8 years) diagnosed with MS based on tumor biopsy and immunohistochemistry or identification of underlying bone marrow disease and extramedullary tumor according to imaging findings.
Methods
The clinical data and diagnostic and therapeutic methods used in the study group were analyzed. A statistical analysis of the treatment outcomes was conducted with STATISTICA v. 13 (StatSoft, Inc., Tulsa, OK, USA) and analysis of survival curves was conducted with MedCalc 11.5.1 (MedCalc Software, Ostend, Belgium). Statistical significance was considered at p<0.05.
Results
In the study group, MS was most frequently accompanied by AML. The most common site of involvement was skin, followed by orbital region. Skin manifestation of MS was more common in the age group <10 years. The most frequent genetic abnormality was the t(8;21)(q22;q22) translocation. The 5-year OS probability (pOS), 5-year RFS probability (pRFS), and 5-year EFS probability (pEFS) were 0.67 ± 0.08, 0.79 ± 0.07, and 0.65 ± 0.08, respectively. In patients with isolated MS and those with concurrent bone marrow involvement by AML/MDS, pOS values were 0.56 ± 0.12 and 0.84 ± 0.09 (p=0.0251), respectively, and pEFS values were 0.56 ± 0.12 and 0.82 ± 0.08 (p=0.0247), respectively. In patients with and without the t(8;21)(q22;q22) translocation, pEFS values were 0.90 ± 0.09 and 0.51 ± 0.14 (p=0.0490), respectively.
Conclusions
MS is a disease with a highly variable clinical course. Worse treatment outcomes were observed in patients with isolated MS compared to those with concurrent bone marrow involvement by AML/MDS. Patients with the t(8;21)(q22;q22) translocation were found to have significantly higher pEFS. MS location, age group, chemotherapy regimen, surgery, and/or radiotherapy did not have a significant influence on treatment outcomes. Further exploration of prognostic factors in children with MS is indicated.
Hemolytic uremic syndrome (HUS) is defined by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). Atypical HUS (aHUS), distinguished by its etiology, is ...caused by uncontrolled overactivation of the alternative complement pathway. The correct diagnosis of aHUS is complex and involves various gene mutations. Severe combined immunodeficiency (SCID), characterized by severe T-cell lymphocytopenia and a lack of antigen-specific T-cell and B-cell immune responses, is of seldom occurrence. In 10–15% of pediatric patients, SCID is caused by adenosine deaminase (ADA) deficiency. The authors describe the case of a boy who suffered from both aHUS and ADA-deficient SCID. At the age of 9 months, the patient presented acute kidney injury with anuria and coagulopathy. The diagnosis of aHUS was established on the basis of alternative complement pathway deregulation and disease-associated gene mutations. Further examination revealed immune system failure and, at the age of 13 months, the ADA deficiency was confirmed by genetic tests and the boy was diagnosed with ADA-SCID. ADA SCID has recently been described as a possible triggering factor of aHUS development and progression. However, more research is required in this field. Nevertheless, it is crucial in clinical practice to be aware of these two co-existing life-threatening diseases.
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