Risk Management in the Water Industry Zuzana Zemanova; Sarka Krocova; Patrik Sirotiak
Engineering proceedings,
12/2023, Letnik:
57, Številka:
1
Journal Article
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Extraordinary events have always threatened us. The continuity of drinking water supplies cannot be exposed to such risks. When dimensioning water supply systems, it is necessary to consider the use ...of preventive measures, which include risk management. The following article is the basic scope of this issue and presents risk management procedures in the water industry.
Because cytogenetic data are essential for risk stratification of childhood acute myeloid leukemia (AML), the impact of chromosomal aberrations is crucial.
Data of a large group of patients younger ...than 18 years treated according to study AML-Berlin-Frankfurt-Münster (BFM) 98 (n = 454), including their cytogenetics, were analyzed.
The favorable outcome in the subgroups of patients with t(8;21), inv(16), and t(15;17), with an overall survival of 91% (SE, 4%), 92% (SE, 6%), and 87% (SE, 5%), respectively, was confirmed. Within this group, the 5-year probability of event-free survival (pEFS) of all 17 children with t(8;21) and additional aberrations apart from del(9q) or -X/-Y was 100%. As expected, the cytogenetic finding of a complex karyotype (n = 35; pEFS, 33%; SE, 8%) or a monosomy 7 (n = 12; pEFS, 17%; SE, 11%) was associated with a poor outcome. Compared with remaining patients with cytogenetic data (pEFS, 48%; SE, 2%), prognosis in patients with an MLL rearrangement (n = 91) was inferior (pEFS, 34%; SE, 5%; P = .0005). Particularly, children with t(9;11) and additional aberrations (n = 13; pEFS, 31%; SE, 14%) and MLL rearrangements other than t(9;11) and t(11;19) (n = 41; pEFS, 24%; SE, 7%) had an unfavorable outcome. Nine patients with aberrations in 12p showed an adverse prognosis (pEFS, 11%; SE, 10%). The outcome of patients with aberrations of chromosome 5 (n = 13) was better than expected (pEFS, 50%; SE, 13%).
Because the prognostic value of rare recurrent chromosomal aberrations still has to be elucidated, these data will contribute to future risk stratification for the treatment of pediatric AML.
Mantle cell lymphoma (MCL) is a subtype of B-cell lymphoma with a large number of recurrent cytogenetic/molecular aberrations. Approximately 5-10% of patients do not respond to frontline ...immunochemotherapy. Despite many useful prognostic indexes, a reliable marker of chemoresistance is not available. We evaluated the prognostic impact of seven recurrent gene aberrations including tumor suppressor protein P53 (
) and cyclin dependent kinase inhibitor 2A (
) in the cohort of 126 newly diagnosed consecutive MCL patients with bone marrow involvement ≥5% using fluorescent in-situ hybridization (FISH) and next-generation sequencing (NGS). In contrast to
, no pathologic mutations of
were detected by NGS.
deletions were found exclusively in the context of other gene aberrations suggesting it represents a later event (after translocation t(11;14) and aberrations of
or ataxia telangiectasia mutated (
)). Concurrent deletion of
and aberration of
(deletion and/or mutation) represented the most significant predictor of short EFS (median 3 months) and OS (median 10 months). Concurrent aberration of
and
is a new, simple, and relevant index of chemoresistance in MCL. Patients with concurrent aberration of
and
should be offered innovative anti-lymphoma therapy and upfront consolidation with allogeneic stem cell transplantation.
Fibroblast activation protein (FAP) is a membrane-bound protease that is upregulated in a wide range of tumours and viewed as a marker of tumour-promoting stroma. Previously, we demonstrated ...increased FAP expression in glioblastomas and described its localisation in cancer and stromal cells. In this study, we show that FAP+ stromal cells are mostly localised in the vicinity of activated CD105+ endothelial cells and their quantity positively correlates with glioblastoma vascularisation. FAP+ mesenchymal cells derived from human glioblastomas are non-tumorigenic and mostly lack the cytogenetic aberrations characteristic of glioblastomas. Conditioned media from these cells induce angiogenic sprouting and chemotaxis of endothelial cells and promote migration and growth of glioma cells. In a chorioallantoic membrane assay, co-application of FAP+ mesenchymal cells with glioma cells was associated with enhanced abnormal angiogenesis, as evidenced by an increased number of erythrocytes in vessel-like structures and higher occurrence of haemorrhages. FAP+ mesenchymal cells express proangiogenic factors, but in comparison to normal pericytes exhibit decreased levels of antiangiogenic molecules and an increased Angiopoietin 2/1 ratio. Our results show that FAP+ mesenchymal cells promote angiogenesis and glioma cell migration and growth by paracrine communication and in this manner, they may thus contribute to glioblastoma progression.
T-cell acute lymphoblastic leukemia (T-ALL) represents a rare and clinically and genetically heterogeneous disease that constitutes 10-15% of newly diagnosed pediatric ALL cases. Despite improved ...outcomes of these children, the survival rate after relapse is extremely poor. Moreover, the survivors must also endure the acute and long-term effects of intensive therapy. Although recent studies have identified a number of recurrent genomic aberrations in pediatric T-ALL, none of the changes is known to have prognostic significance. The aim of our study was to analyze the cytogenomic changes and their various combinations in bone marrow cells of children with T-ALL and to correlate our findings with the clinical features of the subjects and their treatment responses.
We performed a retrospective and prospective comprehensive cytogenomic analysis of consecutive cohort of 66 children (46 boys and 20 girls) with T-ALL treated according to BFM-based protocols and centrally investigated cytogenetics and immunophenotypes. Using combinations of cytogenomic methods (conventional cytogenetics, FISH, mFISH/mBAND, arrayCGH/SNP and MLPA), we identified chromosomal aberrations in vast majority of patients (91%). The most frequent findings involved the deletion of CDKN2A/CDKN2B genes (71%), T-cell receptor (TCR) loci translocations (27%), and TLX3 gene rearrangements (23%). All chromosomal changes occurred in various combinations and were rarely found as a single abnormality. Children with aberrations of TCR loci had a significantly better event free (p = 0.0034) and overall survival (p = 0.0074), all these patients are living in the first complete remission. None of the abnormalities was an independent predictor of an increased risk of relapse.
We identified a subgroup of patients with TCR aberrations (both TRA/TRD and TRB), who had an excellent prognosis in our cohort with 5-year EFS and OS of 100%, regardless of the presence of other abnormality or the translocation partner. Our data suggest that escalation of treatment intensity, which may be considered in subsets of T-ALL is not needed for nonHR (non-high risk) patients with TCR aberrations.
Mutations in the Sterile alpha motif domain containing 9 (
) gene have been described in patients with severe multisystem disorder, MIRAGE syndrome, but also in patients with bone marrow (BM) failure ...in the absence of other systemic symptoms. The role of hematopoietic stem cell transplantation (HSCT) in the management of the disease is still unclear. Here, we present a patient with a novel mutation in
(c.2471 G>A, p.R824Q), manifesting with prominent gastrointestinal tract involvement and immunodeficiency, but without any sign of adrenal insufficiency typical for MIRAGE syndrome. He suffered from severe CMV (cytomegalovirus) infection at 3 months of age, with a delayed development of T lymphocyte functional response against CMV, profound T cell activation, significantly reduced B lymphocyte counts and impaired lymphocyte proliferative response. Cultured T cells displayed slightly lower calcium flux and decreased survival. At the age of 6 months, he developed severe neutropenia requiring G-CSF administration, and despite only mild morphological and immunophenotypical disturbances in the BM, 78% of the BM cells showed monosomy 7 at the age of 18 months. Surprisingly, T cell proliferation after CD3 stimulation and apoptosis of the cells normalized during the follow-up, possibly reflecting the gradual development of monosomy 7. Among other prominent symptoms, he had difficulty swallowing, requiring percutaneous endoscopic gastrostomy (PEG), frequent gastrointestinal infections, and perianal erosions. He suffered from repeated infections and periodic recurring fevers with the elevation of inflammatory markers. At 26 months of age, he underwent HSCT that significantly improved hematological and immunological laboratory parameters. Nevertheless, he continued to suffer from other conditions, and subsequently, he died at day 440 post-transplant due to sepsis. Pathogenicity of this novel
mutation was confirmed experimentally. Expression of mutant
caused a significant decrease in proliferation and increase in cell death of the transfected cells.
We describe a novel
mutation in a patient with prominent gastrointestinal and immunological symptoms but without adrenal hypoplasia. Thus, SAMD9 mutations should be considered as cause of enteropathy in pediatric patients. The insufficient therapeutic outcome of transplantation further questions the role of HSCT in the management of patients with
mutations and multisystem involvement.
Mixed phenotype acute leukemia (MPAL) represents a diagnostic and therapeutic dilemma. The European Group for the Immunological Classification of Leukemias (EGIL) scoring system unambiguously defines ...MPAL expressing aberrant lineage markers. Discussions surrounding it have focused on scoring details, and information is limited regarding its biological, clinical and prognostic significance. The recent World Health Organization classification is simpler and could replace the EGIL scoring system after transformation into unambiguous guidelines.
Simple immunophenotypic criteria were used to classify all cases of childhood acute leukemia in order to provide therapy directed against acute lymphoblastic leukemia or acute myeloid leukemia. Prognosis, genotype and immunoglobulin/T-cell receptor gene rearrangement status were analyzed.
The incidences of MPAL were 28/582 and 4/107 for children treated with acute lymphoblastic leukemia and acute myeloid leukemia regimens, respectively. In immunophenotypic principal component analysis, MPAL treated as T-cell acute lymphoblastic leukemia clustered between cases of non-mixed T-cell acute lymphoblastic leukemia and acute myeloid leukemia, while other MPAL cases were included in the respective non-mixed B-cell progenitor acute lymphoblastic leukemia or acute myeloid leukemia clusters. Analogously, immunoglobulin/T-cell receptor gene rearrangements followed the expected pattern in patients treated as having acute myeloid leukemia (non-rearranged, 4/4) or as having B-cell progenitor acute lymphoblastic leukemia (rearranged, 20/20), but were missing in 3/5 analyzed cases of MPAL treated as having T-cell acute lymphobastic leukemia. In patients who received acute lymphoblastic leukemia treatment, the 5-year event-free survival of the MPAL cases was worse than that of the non-mixed cases (53+/-10% and 76+/-2% at 5 years, respectively, P=0.0075), with a more pronounced difference among B lineage cases. The small numbers of MPAL cases treated as T-cell acute lymphoblastic leukemia or as acute myeloid leukemia hampered separate statistics. We compared prognosis of all subsets with the prognosis of previously published cohorts.
Simple immunophenotypic criteria are useful for therapy decisions in MPAL. In B lineage leukemia, MPAL confers poorer prognosis. However, our data do not justify a preferential use of current acute myeloid leukemia-based therapy in MPAL.
Most high‐risk neuroblastomas develop resistance to cytostatics and therefore there is a need to develop new drugs. In previous studies, we found that ellipticine induces apoptosis in human ...neuroblastoma cells. We also investigated whether ellipticine was able to induce resistance in the UKF‐NB‐4 neuroblastoma line and concluded that it may be possible after long‐term treatment with increasing concentrations of ellipticine. The aim of the present study was to investigate the mechanisms responsible for ellipticine resistance. To elucidate the mechanisms involved, we used the ellipticine‐resistant subline UKF‐NB‐4ELLI and performed comparative genomic hybridization, multicolor and interphase FISH, expression microarray, real‐time RT‐PCR, flow cytometry and western blotting analysis of proteins. On the basis of our results, it appears that ellipticine resistance in neuroblastoma is caused by a combination of overexpression of Bcl‐2, efflux or degradation of the drug and downregulation of topoisomerases. Other mechanisms, such as upregulation of enzymes involved in oxidative phosphorylation, cellular respiration, V‐ATPases, aerobic respiration or spermine synthetase, as well as reduced growth rate, may also be involved. Some changes are expressed at the DNA level, including gains, amplifications or deletions. The present study demonstrates that resistance to ellipticine is caused by a combination of mechanisms. (Cancer Sci 2012; 103: 334–341)
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