11 results on '"Casadei S"'
Search Results
2. Diesel exhaust particulate emissions and in vitro toxicity from Euro 3 and Euro 6 vehicles
- Author
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Zerboni, A, Rossi, T, Bengalli, R, Catelani, T, Rizzi, C, Priola, M, Casadei, S, Mantecca, P, Zerboni, Alessandra, Rossi, Tommaso, Bengalli, Rossella, Catelani, Tiziano, Rizzi, Cristiana, Priola, Marco, Casadei, Simone, Mantecca, Paride, Zerboni, A, Rossi, T, Bengalli, R, Catelani, T, Rizzi, C, Priola, M, Casadei, S, Mantecca, P, Zerboni, Alessandra, Rossi, Tommaso, Bengalli, Rossella, Catelani, Tiziano, Rizzi, Cristiana, Priola, Marco, Casadei, Simone, and Mantecca, Paride
- Abstract
Incomplete combustion processes in diesel engines produce particulate matter (PM) that significantly contributes to air pollution. Currently, there remains a knowledge gap in relation to the physical and chemical characteristics and also the biological reactivity of the PM emitted from old- and new-generation diesel vehicles. In this study, the emissions from a Euro 3 diesel vehicle were compared to those from a Euro 6 car during the regeneration of a diesel particulate filter (DPF). Different driving cycles were used to collect two types of diesel exhaust particles (DEPs). The particle size distribution was monitored using an engine exhaust particle sizer spectrometer and an electrical low-pressure impactor. Although the Euro 6 vehicle emitted particulates only during DPF regeneration that primarily occurs for a few minutes at high speeds, such emissions are characterized by a higher number of ultrafine particles (<0.1 mu m) compared to those from the Euro 3 diesel vehicle. The emitted particles possess different characteristics. For example, Euro 6 DEPs exhibit a lower PAH content than do Euro 3 samples; however, they are enriched in metals that were poorly detected or undetected in Euro 3 emissions. The biological effects of the two DEPs were investigated in human bronchial BEAS-2B cells exposed to 50 mu g/mL of PM (corresponding to 5.2 mu g/cm(2)), and the results revealed that Euro 3 DEPs activated the typical inflammatory and procarcinogenic pathways induced by combustion-derived particles, while Euro 6 DEPs were less effective in regard to activating such biological responses. Although further investigations are required, it is evident that the different in vitro effects elicited by Euro 3 and Euro 6 DEPs can be correlated with the variable chemical compositions (metals and PAHs) of the emitted particles that play a pivotal role in the inflammatory and carcinogenic potential of airborne PM.
- Published
- 2022
3. Laboratory and on-road tests assessment of fine and ultrafine particle emission factors for EURO6 LPG passenger cars
- Author
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Lonati, G., Bellin, T., Rossi, T., and Casadei, S.
- Published
- 2022
4. Diesel exhaust particulate emissions and in vitro toxicity from Euro 3 and Euro 6 vehicles
- Author
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Alessandra Zerboni, Tommaso Rossi, Rossella Bengalli, Tiziano Catelani, Cristiana Rizzi, Marco Priola, Simone Casadei, Paride Mantecca, Zerboni, A, Rossi, T, Bengalli, R, Catelani, T, Rizzi, C, Priola, M, Casadei, S, and Mantecca, P
- Subjects
Diesel particulate filter ,Air Pollutants ,Air Pollution ,Health, Toxicology and Mutagenesis ,Humans ,Particulate Matter ,Inhalation toxicology ,General Medicine ,Polycyclic Aromatic Hydrocarbons ,Bronchial-cell ,Toxicology ,Pollution ,Vehicle Emissions - Abstract
Incomplete combustion processes in diesel engines produce particulate matter (PM) that significantly contributes to air pollution. Currently, there remains a knowledge gap in relation to the physical and chemical characteristics and also the biological reactivity of the PM emitted from old- and new-generation diesel vehicles. In this study, the emissions from a Euro 3 diesel vehicle were compared to those from a Euro 6 car during the regeneration of a diesel particulate filter (DPF). Different driving cycles were used to collect two types of diesel exhaust particles (DEPs). The particle size distribution was monitored using an engine exhaust particle sizer spectrometer and an electrical low-pressure impactor. Although the Euro 6 vehicle emitted particulates only during DPF regeneration that primarily occurs for a few minutes at high speeds, such emissions are characterized by a higher number of ultrafine particles (
- Published
- 2022
5. The proteomic landscape and temporal dynamics of mammalian gastruloid development.
- Author
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Garge RK, Lynch V, Fields R, Casadei S, Best S, Stone J, Snyder M, McGann CD, Shendure J, Starita LM, Hamazaki N, and Schweppe DK
- Abstract
Gastrulation is the highly coordinated process by which the early embryo breaks symmetry, establishes germ layers and a body plan, and sets the stage for organogenesis. As early mammalian development is challenging to study in vivo, stem cell-derived models have emerged as powerful surrogates, e.g. human and mouse gastruloids. However, although single cell RNA-seq (scRNA-seq) and high-resolution imaging have been extensively applied to characterize such in vitro embryo models, a paucity of measurements of protein dynamics and regulation leaves a major gap in our understanding. Here, we sought to address this by applying quantitative proteomics to human and mouse gastruloids at four key stages of their differentiation (naïve ESCs, primed ESCs, early gastruloids, late gastruloids). To the resulting data, we perform network analysis to map the dynamics of expression of macromolecular protein complexes and biochemical pathways, including identifying cooperative proteins that associate with them. With matched RNA-seq and phosphosite data from these same stages, we investigate pathway-, stage- and species-specific aspects of translational and post-translational regulation, e.g. finding peri-gastrulation stages of human and mice to be discordant with respect to the mitochondrial transcriptome vs. proteome, and nominating novel kinase-substrate relationships based on phosphosite dynamics. Finally, we leverage correlated dynamics to identify conserved protein networks centered around congenital disease genes. Altogether, our data (https://gastruloid.brotmanbaty.org/) and analyses showcase the potential of intersecting in vitro embryo models and proteomics to advance our understanding of early mammalian development in ways not possible through transcriptomics alone.
- Published
- 2024
- Full Text
- View/download PDF
6. BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance.
- Author
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Nesic K, Krais JJ, Wang Y, Vandenberg CJ, Patel P, Cai KQ, Kwan T, Lieschke E, Ho GY, Barker HE, Bedo J, Casadei S, Farrell A, Radke M, Shield-Artin K, Penington JS, Geissler F, Kyran E, Betsch R, Xu L, Zhang F, Dobrovic A, Olesen I, Kristeleit R, Oza A, McNeish I, Ratnayake G, Traficante N, DeFazio A, Bowtell DDL, Harding TC, Lin K, Swisher EM, Kondrashova O, Scott CL, Johnson N, and Wakefield MJ
- Subjects
- Humans, Female, Animals, Mice, Mutation, Breast Neoplasms genetics, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Xenograft Model Antitumor Assays, Cell Line, Tumor, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Exons, Drug Resistance, Neoplasm genetics, BRCA1 Protein genetics, Ovarian Neoplasms genetics, Ovarian Neoplasms drug therapy, Ovarian Neoplasms pathology, RNA Splice Sites
- Abstract
PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood.We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials.Few PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene's reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which in turn promote PARPi resistance. Thus, BRCA1 SSMs can and should be clinically monitored, along with frame-restoring secondary mutations., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
7. Evaluation of the point sampling method and inter-comparison of remote emission sensing systems for screening real-world car emissions.
- Author
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Knoll M, Penz M, Schmidt C, Pöhler D, Rossi T, Casadei S, Bernard Y, Hallquist ǺM, Sjödin Ǻ, and Bergmann A
- Abstract
Emissions from internal combustion vehicles are currently not properly monitored throughout their life cycle. Remote emission sensing (RES) is a technology that can measure emissions under real driving conditions without contact. Current light extinction based RES systems are capable of providing emission factors for various gases, but lack accuracy for particulate matter (PM). Point Sampling (PS) is an extraction-based RES technique that can measure gases as well as various particle metrics such as black carbon or particle number. In this work, we evaluated the performance of a recently developed PS system and the state-of-the-art light extinction based remote sensing devices EDAR (HEAT) and ORSD (OPUS RSE) during co-location measurements. Validation measurements with portable emission measurement systems and emissions screening of several thousand cars in three European cities provide detailed insights into system's performance. Meteorological evaluations showed that the PS capture rate is strongly influenced by wind, but no other weather influences were found. Both light extinction based systems are unable to measure during rain. We found that all three systems tested were capable of screening NO
x emissions from pre-Euro 6 diesel cars. Measurement results show the ability of the PS system to quantify high and low PM emitters equally well. The open-path RES systems (EDAR, ORSD) are capable of estimating PM emissions from pre-Euro 5 diesel cars. However, deficiencies of open-path RES systems are evident in the quantification of PM emissions from newer engine technologies (diesel Euro 5 and beyond) and from petrol cars. The PS system has a 2 to 5 times lower capture rate than open-path RES systems, but the PS measurement results are more accurate (more than 5 times for PM and more than 1.35 times for NOx ). The good accuracy of individual measurements makes PS a powerful tool for reliable high emitter identification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
8. BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance.
- Author
-
Nesic K, Krais JJ, Vandenberg CJ, Wang Y, Patel P, Cai KQ, Kwan T, Lieschke E, Ho GY, Barker HE, Bedo J, Casadei S, Farrell A, Radke M, Shield-Artin K, Penington JS, Geissler F, Kyran E, Zhang F, Dobrovic A, Olesen I, Kristeleit R, Oza A, Ratnayake G, Traficante N, DeFazio A, Bowtell DDL, Harding TC, Lin K, Swisher EM, Kondrashova O, Scott CL, Johnson N, and Wakefield MJ
- Abstract
BRCA1 splice isoforms Δ11 and Δ11q can contribute to PARP inhibitor (PARPi) resistance by splicing-out the mutation-containing exon, producing truncated, partially-functional proteins. However, the clinical impact and underlying drivers of BRCA1 exon skipping remain undetermined. We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs), predicted in silico to drive exon skipping. Predictions were confirmed using qRT-PCR, RNA sequencing, western blots and BRCA1 minigene modelling. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials. We demonstrate that SSMs drive BRCA1 exon 11 skipping and PARPi resistance, and should be clinically monitored, along with frame-restoring secondary mutations.
- Published
- 2023
- Full Text
- View/download PDF
9. Diesel exhaust particulate emissions and in vitro toxicity from Euro 3 and Euro 6 vehicles.
- Author
-
Zerboni A, Rossi T, Bengalli R, Catelani T, Rizzi C, Priola M, Casadei S, and Mantecca P
- Subjects
- Humans, Particulate Matter analysis, Particulate Matter toxicity, Vehicle Emissions analysis, Vehicle Emissions toxicity, Air Pollutants analysis, Air Pollutants toxicity, Air Pollution analysis, Polycyclic Aromatic Hydrocarbons analysis
- Abstract
Incomplete combustion processes in diesel engines produce particulate matter (PM) that significantly contributes to air pollution. Currently, there remains a knowledge gap in relation to the physical and chemical characteristics and also the biological reactivity of the PM emitted from old- and new-generation diesel vehicles. In this study, the emissions from a Euro 3 diesel vehicle were compared to those from a Euro 6 car during the regeneration of a diesel particulate filter (DPF). Different driving cycles were used to collect two types of diesel exhaust particles (DEPs). The particle size distribution was monitored using an engine exhaust particle sizer spectrometer and an electrical low-pressure impactor. Although the Euro 6 vehicle emitted particulates only during DPF regeneration that primarily occurs for a few minutes at high speeds, such emissions are characterized by a higher number of ultrafine particles (<0.1 μm) compared to those from the Euro 3 diesel vehicle. The emitted particles possess different characteristics. For example, Euro 6 DEPs exhibit a lower PAH content than do Euro 3 samples; however, they are enriched in metals that were poorly detected or undetected in Euro 3 emissions. The biological effects of the two DEPs were investigated in human bronchial BEAS-2B cells exposed to 50 μg/mL of PM (corresponding to 5.2 μg/cm
2 ), and the results revealed that Euro 3 DEPs activated the typical inflammatory and pro-carcinogenic pathways induced by combustion-derived particles, while Euro 6 DEPs were less effective in regard to activating such biological responses. Although further investigations are required, it is evident that the different in vitro effects elicited by Euro 3 and Euro 6 DEPs can be correlated with the variable chemical compositions (metals and PAHs) of the emitted particles that play a pivotal role in the inflammatory and carcinogenic potential of airborne PM., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
10. Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy, and enteropathy, and implications for clinical management.
- Author
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Baxter SK, Walsh T, Casadei S, Eckert MM, Allenspach EJ, Hagin D, Segundo G, Lee MK, Gulsuner S, Shirts BH, Sullivan KE, Keller MD, Torgerson TR, and King MC
- Subjects
- Adolescent, Child, Child, Preschool, Diabetes Mellitus, Type 1 diagnosis, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 therapy, Diarrhea diagnosis, Diarrhea therapy, Female, Gene Expression, Genetic Diseases, X-Linked diagnosis, Genetic Diseases, X-Linked therapy, Hematopoietic Stem Cell Transplantation, Humans, Immune System Diseases diagnosis, Immune System Diseases genetics, Immune System Diseases therapy, Infant, Infant, Newborn, Male, Mutation, Diabetes Mellitus, Type 1 congenital, Diarrhea genetics, Genetic Diseases, X-Linked genetics, Immune System Diseases congenital
- Abstract
Background: Most patients with childhood-onset immune dysregulation, polyendocrinopathy, and enteropathy have no genetic diagnosis for their illness. These patients may undergo empirical immunosuppressive treatment with highly variable outcomes., Objective: We sought to determine the genetic basis of disease in patients referred with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like (IPEX-like) disease, but with no mutation in FOXP3; then to assess consequences of genetic diagnoses for clinical management., Methods: Genomic DNA was sequenced using a panel of 462 genes implicated in inborn errors of immunity. Candidate mutations were characterized by genomic, transcriptional, and (for some) protein analysis., Results: Of 123 patients with FOXP3-negative IPEX-like disease, 48 (39%) carried damaging germline mutations in 1 of the following 27 genes: AIRE, BACH2, BCL11B, CARD11, CARD14, CTLA4, IRF2BP2, ITCH, JAK1, KMT2D, LRBA, MYO5B, NFKB1, NLRC4, POLA1, POMP, RAG1, SH2D1A, SKIV2L, STAT1, STAT3, TNFAIP3, TNFRSF6/FAS, TNRSF13B/TACI, TOM1, TTC37, and XIAP. Many of these genes had not been previously associated with an IPEX-like diagnosis. For 42 of the 48 patients with genetic diagnoses, knowing the critical gene could have altered therapeutic management, including recommendations for targeted treatments and for or against hematopoietic cell transplantation., Conclusions: Many childhood disorders now bundled as "IPEX-like" disease are caused by individually rare, severe mutations in immune regulation genes. Most genetic diagnoses of these conditions yield clinically actionable findings. Barriers are lack of testing or lack of repeat testing if older technologies failed to provide a diagnosis., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
11. CRISPR-Cas9/long-read sequencing approach to identify cryptic mutations in BRCA1 and other tumour suppressor genes.
- Author
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Walsh T, Casadei S, Munson KM, Eng M, Mandell JB, Gulsuner S, and King MC
- Subjects
- BRCA2 Protein genetics, Breast Neoplasms genetics, Exons genetics, Family Health, Female, Germ-Line Mutation, Humans, Introns genetics, Mutagenesis, Insertional, Promoter Regions, Genetic genetics, Regulatory Sequences, Nucleic Acid genetics, Reproducibility of Results, Retroelements genetics, BRCA1 Protein genetics, CRISPR-Cas Systems, Genes, Tumor Suppressor, Mutation, Sequence Analysis, DNA methods
- Abstract
Current clinical approaches for mutation discovery are based on short sequence reads (100-300 bp) of exons and flanking splice sites targeted by multigene panels or whole exomes. Short-read sequencing is highly accurate for detection of single nucleotide variants, small indels and simple copy number differences but is of limited use for identifying complex insertions and deletions and other structural rearrangements. We used CRISPR-Cas9 to excise complete BRCA1 and BRCA2 genomic regions from lymphoblast cells of patients with breast cancer, then sequenced these regions with long reads (>10 000 bp) to fully characterise all non-coding regions for structural variation. In a family severely affected with early-onset bilateral breast cancer and with negative (normal) results by gene panel and exome sequencing, we identified an intronic SINE-VNTR-Alu retrotransposon insertion that led to the creation of a pseudoexon in the BRCA1 message and introduced a premature truncation. This combination of CRISPR-Cas9 excision and long-read sequencing reveals a class of complex, damaging and otherwise cryptic mutations that may be particularly frequent in tumour suppressor genes replete with intronic repeats., Competing Interests: Competing interests: TW discloses consulting fees from Color Genomics outside the submitted work. M-CK is an American Cancer Society Research Professor., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2021
- Full Text
- View/download PDF
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