The aim of this study was to explore the relationship of iron and zinc deficiencies and anemia in children aged under 5 years living in malaria endemic area of South Kivu/DRC. We conducted a ...cross-sectional study in the health zone of Miti Murhesa in South Kivu/DRC. A total of 1088 children in good general health were included in this study. Almost 40% of children were anemic. The prevalence of iron deficiency (ID) was found in 34.9% and 49.1% children based on ferritin or free erythrocyte protoporphyrin (FEP), respectively. If anemia is present, we found iron deficiency anemia (IDA) according to the WHO-criteria (ferritin) in 31%, and according to FEP in 66% of children. The overall prevalence of zinc deficiency was 17.6%. If anemia is present, zinc deficiency was found in 24.4% of children. Inflammation/infection, based upon CRP, was present in 39.7% children. The independent factors associated with anemia were recent illness, middle upper arm circumference, weight-for-height, ID according to FEP, zinc deficiency, and submicroscopic
Plasmodium
infection. A high prevalence of ID was observed in children in South Kivu according to FEP. Ferritin as acute phase protein was less suited in this population due to a high frequency of infection/inflammation. Iron and zinc deficiencies were found to be significantly associated with anemia in this population.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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TARP as antigen in cancer immunotherapy Vanhooren, Jolien; Derpoorter, Charlotte; Depreter, Barbara ...
Cancer Immunology, Immunotherapy,
11/2021, Volume:
70, Issue:
11
Journal Article
Peer reviewed
Open access
In recent decades, immunotherapy has become a pivotal element in cancer treatment. A remaining challenge is the identification of cancer-associated antigens suitable as targets for immunotherapeutics ...with potent on-target and few off-tumor effects. The T-cell receptor gamma (TCR
γ
) chain alternate reading frame protein (TARP) was first discovered in the human prostate and androgen-sensitive prostate cancer. Thereafter, TARP was also identified in breast and endometrial cancers, salivary gland tumors, and pediatric and adult acute myeloid leukemia. Interestingly, TARP promotes tumor cell proliferation and migration, which is reflected in an association with worse survival. TARP expression in malignant cells, its role in oncogenesis, and its limited expression in normal tissues raised interest in its potential utility as a therapeutic target, and led to development of immunotherapeutic targeting strategies. In this review, we provide an overview of TARP expression, its role in different cancer types, and currently investigated TARP-directed immunotherapeutic options.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Light microscopy and antigen-based rapid diagnostic tests are the primary diagnostic tools for detecting malaria, although being labour-intensive and frequently challenged by lack of personnel's ...experience and low levels of parasite density. The latter being especially important in non-endemic settings. Novel molecular techniques aim to overcome this drawback. The objective of this study was to assess the diagnostic performance of the illumigene malaria assay
(Meridian Bioscience) compared to microscopy, RDT and real-time PCR. This loop-mediated isothermal amplification (LAMP) assay is a qualitative in vitro diagnostic test for the direct detection of Plasmodium spp. DNA in human venous whole blood samples.
The illumigene assay was assessed on a retrospective panel of stored blood samples (n = 103) from returned travellers and external quality control samples (n = 12). Additionally the assay was prospectively assessed on 30 fresh routine samples with a request for malaria diagnosis. The illumigene assay was compared to microscopy, RDT and Plasmodium species specific real-time PCR.
In the retrospective evaluation, the illumigene assay showed 100% agreement with the real-time PCR, RDT and microscopy yielding a sensitivity and specificity of 100% (95% CI 95.1-100% and 89.7-100%, respectively). Seven samples from patients recently treated for Plasmodium falciparum infection that were RDT positive and microscopy negative yielded positive test results. The performance of the illumigene assay equals that of microscopy combined with RDT in the prospective panel with three false negative RDT results and one false negative microscopy result. Excellent concordance with PCR was observed. The limit of detection of the assay approached 0.5 parasites/µL for both P. falciparum and Plasmodium vivax.
In non-endemic regions where the diagnostic process for malaria infections is questioned by lack of experience and low levels of parasite densities, the illumigene assay can be of value. Due to its high sensitivity, the LAMP assay may be considered as primary diagnostic test. The results of this study indicate that negative screen results do not need further confirmation. However, before implementation, this approach needs to be confirmed in larger, prospective studies. A shortcoming of this assay is that no species identification nor determination of parasite density are possible.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Juvenile myelomonocytic leukemia (JMML) treatment primarily relies on hematopoietic stem cell transplantation and results in long-term overall survival of 50-60%, demonstrating a need to develop ...novel treatments. Dysregulation of the non-coding RNA transcriptome has been demonstrated before in this rare and unique disorder of early childhood. In this study, we investigated the therapeutic potential of targeting overexpressed long non-coding RNAs (lncRNAs) in JMML. Total RNA sequencing of bone marrow and peripheral blood mononuclear cell preparations from 19 untreated JMML patients and three healthy children revealed 185 differentially expressed lncRNA genes (131 up- and 54 downregulated). LNA GapmeRs were designed for 10 overexpressed and validated lncRNAs. Molecular knockdown (≥ 70% compared to mock control) after 24 h of incubation was observed with two or more independent GapmeRs in 6 of them. For three lncRNAs (lnc-THADA-4, lnc-ACOT9-1 and NRIR) knockdown resulted in a significant decrease of cell viability after 72 h of incubation in primary cultures of JMML mononuclear cells, respectively. Importantly, the extent of cellular damage correlated with the expression level of the lncRNA of interest. In conclusion, we demonstrated in primary JMML cell cultures that knockdown of overexpressed lncRNAs such as lnc-THADA-4, lnc-ACOT9-1 and NRIR may be a feasible therapeutic strategy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Still 30-40% of pediatric acute myeloid leukemia (pedAML) patients relapse. Delineation of the transcriptomic profile of leukemic subpopulations could aid in a better understanding of molecular ...biology and provide novel biomarkers.
Using microarray profiling and quantitative PCR validation, transcript expression was measured in leukemic stem cells (LSC, n = 24) and leukemic blasts (L-blast, n = 25) from pedAML patients in comparison to hematopoietic stem cells (HSCs, n = 19) and control myeloblasts (C-blast, n = 20) sorted from healthy subjects. Gene set enrichment analysis was performed to identify relevant gene set enrichment signatures, and functional protein associations were identified by STRING analysis.
Highly significantly overexpressed genes in LSC and L-blast were identified with a vast majority not studied in AML. CDKN1A, CFP, and CFD (LSC) and HOMER3, CTSA, and GADD45B (L-blast) represent potentially interesting biomarkers and therapeutic targets. Eleven LSC downregulated targets were identified that potentially qualify as tumor suppressor genes, with MYCT1, PBX1, and PTPRD of highest interest. Inflammatory and immune dysregulation appeared to be perturbed biological networks in LSC, whereas dysregulated metabolic profiles were observed in L-blast.
Our study illustrates the power of taking into account cell population heterogeneity and reveals novel targets eligible for functional evaluation and therapy in pedAML.
Novel transcriptional targets were discovered showing a significant differential expression in LSCs and blasts from pedAML patients compared to their normal counterparts from healthy controls. Deregulated pathways, including immune and metabolic dysregulation, were addressed for the first time in children, offering a deeper understanding of the molecular pathogenesis. These novel targets have the potential of acting as biomarkers for risk stratification, follow-up, and targeted therapy. Multiple LSC-downregulated targets endow tumor suppressor roles in other cancer entities, and further investigation whether hypomethylating therapy could result into LSC eradication in pedAML is warranted.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary The clinical course of individual CLL patients is highly variable, with life expectancies ranging from months to decades. Importantly, a significant subset of patients presents with low grade ...CLL, but will nevertheless develop a more aggressive and life-threatening disease. As these patients may potentially benefit from early treatment, it is crucial to assess patients’ prognosis at diagnosis, allowing individual risk-adapted therapy. Reliable predictions of prognosis in an early stage of the disease have long been lacking in the clinical workup of CLL patients. During the last decades many efforts have been made to identify prognostic markers in CLL, resulting in a plethora of reports describing the predictive value of different parameters with regard to overall survival, disease progression and response to therapy. In this review, we attempt to provide an overview of the literature and we discuss the most important prognostic markers in CLL, from clinical staging systems and serum markers over proliferation markers and cytogenetics to more recent markers like the IgVH mutation status and its possible surrogate markers. Particular attention is paid to the advantages and drawbacks of all different markers, both from a clinical and from a technical point-of-view, highlighting the accomplishments as well as the remaining challenges in this rapidly evolving area of CLL research. Although the great majority of prognostic markers is not included in current international treatment guidelines, several of these markers deserve to be evaluated in prospective clinical trials and may eventually contribute to an improved clinical management of CLL patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive stem cell disease of early childhood. RAS activation constitutes the core component of oncogenic signaling. In addition, leukemic ...blasts in one-fourth of JMML patients present with monosomy 7, and more than half of patients show elevated age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care and results in an event-free survival rate of 50% to 60%, indicating that novel molecular-driven therapeutic options are urgently needed. Using gene expression profiling in a series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. LIN28B overexpression was significantly correlated with higher HbF levels, whereas patients with monosomy 7 seldom showed enhanced LIN28B expression. This finding gives a biological explanation of why patients with monosomy 7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Lastly, high LIN28B expression was associated with poor clinical outcome in our JMML patient series but was not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified elevated LIN28B expression as a hallmark of a novel fetal-like subgroup in JMML.
•LIN28B is overexpressed in about half of juvenile myelomonocytic leukemia patients and defines a novel fetal-like disease subgroup.•LIN28B expression is correlated with high fetal hemoglobin levels and the absence of monosomy 7.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Guidelines for screening for primary immunodeficiencies (PID) are well-defined and several consensus diagnostic strategies have been proposed. These consensus proposals have only partially been ...implemented due to lack of standardization in laboratory procedures, particularly in flow cytometry. The main objectives of the EuroFlow Consortium were to innovate and thoroughly standardize the flowcytometric techniques and strategies for reliable and reproducible diagnosis and classification of PID of the lymphoid system. The proposed EuroFlow antibody panels comprise one orientation tube and seven classification tubes and corresponding databases of normal and PID samples. The 8-color 12-antibody PID Orientation tube (PIDOT) aims at identification and enumeration of the main lymphocyte and leukocyte subsets; this includes naïve pre-germinal center (GC) and antigen-experienced post-GC memory B-cells and plasmablasts. The seven additional 8(-12)-color tubes can be used according to the EuroFlow PID algorithm in parallel or subsequently to the PIDOT for more detailed analysis of B-cell and T-cell subsets to further classify PID of the lymphoid system. The Pre-GC, Post-GC, and immunoglobulin heavy chain (IgH)-isotype B-cell tubes aim at identification and enumeration of B-cell subsets for evaluation of B-cell maturation blocks and specific defects in IgH-subclass production. The severe combined immunodeficiency (SCID) tube and T-cell memory/effector subset tube aim at identification and enumeration of T-cell subsets for assessment of T-cell defects, such as SCID. In case of suspicion of antibody deficiency, PIDOT is preferably directly combined with the IgH isotype tube(s) and in case of SCID suspicion (e.g., in newborn screening programs) the PIDOT is preferably directly combined with the SCID T-cell tube. The proposed ≥8-color antibody panels and corresponding reference databases combined with the EuroFlow PID algorithm are designed to provide fast, sensitive and cost-effective flowcytometric diagnosis of PID of the lymphoid system, easily applicable in multicenter diagnostic settings world-wide.
Diagnostic criteria for juvenile myelomonocytic leukemia (JMML) are currently well defined, however in some patients diagnosis still remains a challenge. Flow cytometry is a well established tool for ...diagnosis and follow-up of hematological malignancies, nevertheless it is not routinely used for JMML diagnosis. Herewith, we characterized the CD34+ hematopoietic precursor cells collected from 31 children with JMML using a combination of standardized EuroFlow antibody panels to assess the ability to discriminate JMML cells from normal/reactive bone marrow cell as controls (n=29) or from cells of children with other hematological diseases mimicking JMML (n=9). CD34+ precursors in JMML showed markedly reduced B-cell and erythroid-committed precursors compared to controls, whereas monocytic and CD7+ lymphoid precursors were significantly expanded. Moreover, aberrant immunophenotypes were consistently present in CD34+ precursors in JMML, while they were virtually absent in controls. Multivariate logistic regression analysis showed that combined assessment of the number of CD34+CD7+ lymphoid precursors and CD34+ aberrant precursors or erythroid precursors had a great potential in discriminating JMMLs versus controls. Importantly our scoring model allowed highly efficient discrimination of truly JMML versus patients with JMML-like diseases. In conclusion, we show for the first time that CD34+ precursors from JMML patients display a unique immunophenotypic profile which might contribute to a fast and accurate diagnosis of JMML worldwide by applying an easy to standardize single eight-color antibody combination.
One of the most important problems in controlling malaria is the limited access to effective and accurate diagnosis of malaria parasitemia. In the Democratic Republic of Congo (DRC), malaria is one ...of the leading causes of morbidity and mortality. The purpose of this study was to assess the prevalence of anemia and the relationship with asymptomatic submicroscopic
infection. A cross-sectional study was carried out among 1,088 apparently healthy children aged between 6 and 59 months selected at random in the health zone of Miti Murhesa in South Kivu/DRC. Capillary blood was obtained for hemoglobin (Hb) concentration measurement by Hemocue
Hb 301. Malaria detection was performed by microscopy and the loop-mediated isothermal amplification (LAMP) assay. Anemia was defined as Hb < 11g/dL. We applied the chi-square test for comparisons, and multiple logistic regression was used to identify the risk factors for anemia and submicroscopic
infection. The prevalence of anemia was 39.6%, and the prevalence of parasitemia was 15.9% and 34.0% using microscopy and LAMP test, respectively. Submicroscopic
infection was found in 22.3% of the children. The independent risk factors for anemia are
infection, children younger than 24 months, low middle-upper arm circumference, and history of illness two weeks before. Otherwise, children with submicroscopic malaria infection have a significantly increased risk for anemia, with a need of transfusion. The prevalence of malaria infection was underestimated, when microscopy was used to diagnose malaria. Children with low parasitemia detected by LAMP but not by microscopy showed a significantly increased prevalence of anemia.
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