The formation of SCEs as an effect of occupational exposure to formaldehyde

Formaldehyde (FA) is a ubiquitous toxic chemical employed worldwide due to its disinfectant and preservative properties. Despite being classified as a human carcinogen, FA is still employed as formalin in pathology wards as standard fixative. We evaluated its relationship with the formation of sister-chromatid exchanges (SCEs) in cultured peripheral blood lymphocytes on 57 pathologists and 48 controls and the risk/protective role played by several genetic polymorphisms. All subjects were assessed for SCEs and genotyped for the most common cancer-associated gene polymorphisms: CYP1A1 exon 7 (A > G), CYP1A1*2A (T > C), CYP2C19*2 (G > A), GSTT1 (presence/absence), GSTM1 (presence/absence), GSTP1 (A > G), XRCC1 (G399A), XRCC1 (C194T), XRCC1 (A280G), XPC exon 15 (A939C), XPC exon 9 (C499T), TNFα − 308 G > A), IL10 − 1082 (G > A), and IL6 − 174 (G > C). Air-FA concentration was assessed through passive personal samplers. Pathologists, exposed to 55.2 μg/m(3) of air-FA, showed a significantly higher SCEs frequency than controls, exposed, respectively, to 18.4 μg/m(3). Air-FA was directly correlated with SCEs frequency and inversely with the replication index (RI). Regression models showed FA exposure as a significant predictor in developing SCEs, while did not highlight any role of the selected polymorphisms. Our study confirms the role of low air-FA levels as genotoxicity inductor, highlighting the importance to define exposure limits that could be safer for exposed workers. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-022-03238-w

Assessing the inhaled dose of nanomaterials by nanoparticle tracking analysis (NTA) of exhaled breath condensate (EBC) and its relationship with lung inflammatory biomarkers.

The widespread and increasing use of nanomaterials has resulted in a higher likelihood of exposure by inhalation for nanotechnology workers. However, tracking the internal dose of nanoparticles deposited at the airways level, is still challenging. To assess the suitability of particle number concentration determination as biomarker of internal dose, we carried out a cross sectional investigation involving 80 workers handling nanomaterials. External exposure was characterized by portable counters of particles DISCminiTM (Testo, DE), allowing to categorize 51 workers as exposed and 29 as non-exposed (NE) to nanoparticles. Each subject filled in a questionnaire reporting working practices and health status. Exhaled breath condensate was collected and analysed for the number of particles/ml as well as for inflammatory biomarkers. A clear-cut relationship between the number of airborne particles in the nano-size range determined by the particle counters and the particle concentration in exhaled breath condensate (EBC) was apparent. Moreover, inflammatory cytokines (IL-1β, IL-10, and TNF-α) measured in EBC, were significantly higher in the exposed subjects as compared to not exposed. Finally, significant correlations were found between external exposure, the number concentration of particles measured by the nanoparticle tracking analysis (NTA) and inflammatory cytokines. As a whole, the present study, suggests that NTA can be regarded as a reliable tool to assess the inhaled dose of particles and that this dose can effectively elicit inflammatory effects

ETV6::ABL1-Positive Myeloid Neoplasm: A Case of a Durable Response to Imatinib Mesylate without Additional or Previous Treatment

ETV6::ABL1 rearranged neoplasms are rare hematological diseases. To date, about 80 cases have been reported, including myeloid and lymphoid leukemias. The ETV6 gene codes for an ETS family transcription factor and several fusion partners have been described. When translocated, ETV6 causes the constitutive activation of the partner genes. Here, we report the case of a 54-year-old woman with a cryptic insertion of the 3′ region of ABL1 in the ETV6 gene. The patient was first diagnosed with idiopathic hypereosinophilic syndrome, according to the clinical history, conventional cytogenetics, standard molecular analyses and pathologist description. Next generation sequencing of diagnosis samples unexpectedly detected both ETV6::ABL1 type A and B fusion transcripts, which were then confirmed by FISH. The diagnosis was Myeloid/Lymphoid neoplasm with ETV6::ABL1 fusion, and the patient received imatinib mesylate treatment. In a follow-up after more than one year, the patient still maintained the molecular and complete hematological responses. This case highlights the importance of timely and proper diagnostics and prompt tyrosine kinase inhibitor treatment

Chromothripsis in acute myeloid leukemia: Biological features and impact on survival

Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study defines incidence of chromothripsis in 395 newly diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix\uae) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients. Patients harboring chromothripsis had higher age (p = 0.002), ELN high risk (HR) (p < 0.001), lower white blood cell (WBC) count (p = 0.040), TP53 loss, and/or mutations (p < 0.001) while FLT3 (p = 0.025), and NPM1 (p = 0.032) mutations were mutually exclusive with chromothripsis. Chromothripsis-positive patients showed a worse overall survival (OS) (p < 0.001) compared with HR patients (p = 0.011) and a poor prognosis in a COX-HR optimal regression model. Chromothripsis presented the hallmarks of chromosome instability [i.e., TP53 alteration, 5q deletion, higher mean of copy number alteration (CNA), complex karyotype, alterations in DNA repair, and cell cycle] and focal deletions on chromosomes 4, 7, 12, 16, and 17. CBA. FISH showed that chromothripsis is associated with marker, derivative, and ring chromosomes. In conclusion, chromothripsis frequently occurs in AML (6.6%) and influences patient prognosis and disease biology

Mitochondrial complex I and cell death: a semi-automatic shotgun model

Mitochondrial dysfunction often leads to cell death and disease. We can now draw correlations between the dysfunction of one of the most important mitochondrial enzymes, NADH:ubiquinone reductase or complex I, and its structural organization thanks to the recent advances in the X-ray structure of its bacterial homologs. The new structural information on bacterial complex I provide essential clues to finally understand how complex I may work. However, the same information remains difficult to interpret for many scientists working on mitochondrial complex I from different angles, especially in the field of cell death. Here, we present a novel way of interpreting the bacterial structural information in accessible terms. On the basis of the analogy to semi-automatic shotguns, we propose a novel functional model that incorporates recent structural information with previous evidence derived from studies on mitochondrial diseases, as well as functional bioenergetics