2022
|
Fabre, Margarete A; Almeida, José Guilherme; Fiorillo, Edoardo; Mitchell, Emily; Damaskou, Aristi; Rak, Justyna; Orr`u, Valeria; Marongiu, Michele; Chapman, Michael Spencer; Vijayabaskar, M S; Baxter, Joanna; Hardy, Claire; Abascal, Federico; Williams, Nicholas; Nangalia, Jyoti; nigo Martincorena, I; Campbell, Peter J; McKinney, Eoin F; Cucca, Francesco; Gerstung, Moritz; Vassiliou, George S: The longitudinal dynamics and natural history of clonal haematopoiesis. In: Nature, 606 (7913), pp. 335–342, 2022. @article{Fabre2022-znb,
title = {The longitudinal dynamics and natural history of clonal haematopoiesis},
author = {Margarete A Fabre and José Guilherme Almeida and Edoardo Fiorillo and Emily Mitchell and Aristi Damaskou and Justyna Rak and Valeria Orr`u and Michele Marongiu and Michael Spencer Chapman and M S Vijayabaskar and Joanna Baxter and Claire Hardy and Federico Abascal and Nicholas Williams and Jyoti Nangalia and I nigo Martincorena and Peter J Campbell and Eoin F McKinney and Francesco Cucca and Moritz Gerstung and George S Vassiliou},
doi = {10.1038/s41586-022-04785-z},
year = {2022},
date = {2022-06-01},
urldate = {2022-06-01},
journal = {Nature},
volume = {606},
number = {7913},
pages = {335--342},
publisher = {Springer Science and Business Media LLC},
abstract = {Clonal expansions driven by somatic mutations become pervasive
across human tissues with age, including in the haematopoietic
system, where the phenomenon is termed clonal haematopoiesis1-4.
The understanding of how and when clonal haematopoiesis
develops, the factors that govern its behaviour, how it
interacts with ageing and how these variables relate to
malignant progression remains limited5,6. Here we track 697
clonal haematopoiesis clones from 385 individuals 55 years of
age or older over a median of 13 years. We find that 92.4% of
clones expanded at a stable exponential rate over the study
period, with different mutations driving substantially different
growth rates, ranging from 5% (DNMT3A and TP53) to more than
50% per year (SRSF2P95H). Growth rates of clones with the same
mutation differed by approximately $pm$5% per year,
proportionately affecting slow drivers more substantially. By
combining our time-series data with phylogenetic analysis of
1,731 whole-genome sequences of haematopoietic colonies from 7
individuals from an older age group, we reveal distinct patterns
of lifelong clonal behaviour. DNMT3A-mutant clones
preferentially expanded early in life and displayed slower
growth in old age, in the context of an increasingly competitive
oligoclonal landscape. By contrast, splicing gene mutations
drove expansion only later in life, whereas TET2-mutant clones
emerged across all ages. Finally, we show that mutations driving
faster clonal growth carry a higher risk of malignant
progression. Our findings characterize the lifelong natural
history of clonal haematopoiesis and give fundamental insights
into the interactions between somatic mutation, ageing and
clonal selection.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Clonal expansions driven by somatic mutations become pervasive
across human tissues with age, including in the haematopoietic
system, where the phenomenon is termed clonal haematopoiesis1-4.
The understanding of how and when clonal haematopoiesis
develops, the factors that govern its behaviour, how it
interacts with ageing and how these variables relate to
malignant progression remains limited5,6. Here we track 697
clonal haematopoiesis clones from 385 individuals 55 years of
age or older over a median of 13 years. We find that 92.4% of
clones expanded at a stable exponential rate over the study
period, with different mutations driving substantially different
growth rates, ranging from 5% (DNMT3A and TP53) to more than
50% per year (SRSF2P95H). Growth rates of clones with the same
mutation differed by approximately $pm$5% per year,
proportionately affecting slow drivers more substantially. By
combining our time-series data with phylogenetic analysis of
1,731 whole-genome sequences of haematopoietic colonies from 7
individuals from an older age group, we reveal distinct patterns
of lifelong clonal behaviour. DNMT3A-mutant clones
preferentially expanded early in life and displayed slower
growth in old age, in the context of an increasingly competitive
oligoclonal landscape. By contrast, splicing gene mutations
drove expansion only later in life, whereas TET2-mutant clones
emerged across all ages. Finally, we show that mutations driving
faster clonal growth carry a higher risk of malignant
progression. Our findings characterize the lifelong natural
history of clonal haematopoiesis and give fundamental insights
into the interactions between somatic mutation, ageing and
clonal selection. |
Fabre, Margarete A; Almeida, José Guilherme; Fiorillo, Edoardo; Mitchell, Emily; Damaskou, Aristi; Rak, Justyna; Orr`u, Valeria; Marongiu, Michele; Chapman, Michael Spencer; Vijayabaskar, M S; Baxter, Joanna; Hardy, Claire; Abascal, Federico; Williams, Nicholas; Nangalia, Jyoti; nigo Martincorena, I; Campbell, Peter J; McKinney, Eoin F; Cucca, Francesco; Gerstung, Moritz; Vassiliou, George S: The longitudinal dynamics and natural history of clonal
haematopoiesis. In: Nature, 606 (7913), pp. 335–342, 2022. @article{Fabre2022-znc,
title = {The longitudinal dynamics and natural history of clonal
haematopoiesis},
author = {Margarete A Fabre and José Guilherme Almeida and Edoardo Fiorillo and Emily Mitchell and Aristi Damaskou and Justyna Rak and Valeria Orr`u and Michele Marongiu and Michael Spencer Chapman and M S Vijayabaskar and Joanna Baxter and Claire Hardy and Federico Abascal and Nicholas Williams and Jyoti Nangalia and I nigo Martincorena and Peter J Campbell and Eoin F McKinney and Francesco Cucca and Moritz Gerstung and George S Vassiliou},
year = {2022},
date = {2022-06-01},
journal = {Nature},
volume = {606},
number = {7913},
pages = {335--342},
publisher = {Springer Science and Business Media LLC},
abstract = {Clonal expansions driven by somatic mutations become pervasive
across human tissues with age, including in the haematopoietic
system, where the phenomenon is termed clonal haematopoiesis1-4.
The understanding of how and when clonal haematopoiesis
develops, the factors that govern its behaviour, how it
interacts with ageing and how these variables relate to
malignant progression remains limited5,6. Here we track 697
clonal haematopoiesis clones from 385 individuals 55 years of
age or older over a median of 13 years. We find that 92.4% of
clones expanded at a stable exponential rate over the study
period, with different mutations driving substantially different
growth rates, ranging from 5% (DNMT3A and TP53) to more than
50% per year (SRSF2P95H). Growth rates of clones with the same
mutation differed by approximately $pm$5% per year,
proportionately affecting slow drivers more substantially. By
combining our time-series data with phylogenetic analysis of
1,731 whole-genome sequences of haematopoietic colonies from 7
individuals from an older age group, we reveal distinct patterns
of lifelong clonal behaviour. DNMT3A-mutant clones
preferentially expanded early in life and displayed slower
growth in old age, in the context of an increasingly competitive
oligoclonal landscape. By contrast, splicing gene mutations
drove expansion only later in life, whereas TET2-mutant clones
emerged across all ages. Finally, we show that mutations driving
faster clonal growth carry a higher risk of malignant
progression. Our findings characterize the lifelong natural
history of clonal haematopoiesis and give fundamental insights
into the interactions between somatic mutation, ageing and
clonal selection.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Clonal expansions driven by somatic mutations become pervasive
across human tissues with age, including in the haematopoietic
system, where the phenomenon is termed clonal haematopoiesis1-4.
The understanding of how and when clonal haematopoiesis
develops, the factors that govern its behaviour, how it
interacts with ageing and how these variables relate to
malignant progression remains limited5,6. Here we track 697
clonal haematopoiesis clones from 385 individuals 55 years of
age or older over a median of 13 years. We find that 92.4% of
clones expanded at a stable exponential rate over the study
period, with different mutations driving substantially different
growth rates, ranging from 5% (DNMT3A and TP53) to more than
50% per year (SRSF2P95H). Growth rates of clones with the same
mutation differed by approximately $pm$5% per year,
proportionately affecting slow drivers more substantially. By
combining our time-series data with phylogenetic analysis of
1,731 whole-genome sequences of haematopoietic colonies from 7
individuals from an older age group, we reveal distinct patterns
of lifelong clonal behaviour. DNMT3A-mutant clones
preferentially expanded early in life and displayed slower
growth in old age, in the context of an increasingly competitive
oligoclonal landscape. By contrast, splicing gene mutations
drove expansion only later in life, whereas TET2-mutant clones
emerged across all ages. Finally, we show that mutations driving
faster clonal growth carry a higher risk of malignant
progression. Our findings characterize the lifelong natural
history of clonal haematopoiesis and give fundamental insights
into the interactions between somatic mutation, ageing and
clonal selection. |
Fabre, Margarete A; Almeida, José Guilherme; Fiorillo, Edoardo; Mitchell, Emily; Damaskou, Aristi; Rak, Justyna; Orr`u, Valeria; Marongiu, Michele; Chapman, Michael Spencer; Vijayabaskar, M S; Baxter, Joanna; Hardy, Claire; Abascal, Federico; Williams, Nicholas; Nangalia, Jyoti; nigo Martincorena, I; Campbell, Peter J; McKinney, Eoin F; Cucca, Francesco; Gerstung, Moritz; Vassiliou, George S: The longitudinal dynamics and natural history of clonal
haematopoiesis. In: Nature, 606 (7913), pp. 335–342, 2022. @article{Fabre2022-znd,
title = {The longitudinal dynamics and natural history of clonal
haematopoiesis},
author = {Margarete A Fabre and José Guilherme Almeida and Edoardo Fiorillo and Emily Mitchell and Aristi Damaskou and Justyna Rak and Valeria Orr`u and Michele Marongiu and Michael Spencer Chapman and M S Vijayabaskar and Joanna Baxter and Claire Hardy and Federico Abascal and Nicholas Williams and Jyoti Nangalia and I nigo Martincorena and Peter J Campbell and Eoin F McKinney and Francesco Cucca and Moritz Gerstung and George S Vassiliou},
year = {2022},
date = {2022-06-01},
journal = {Nature},
volume = {606},
number = {7913},
pages = {335--342},
publisher = {Springer Science and Business Media LLC},
abstract = {Clonal expansions driven by somatic mutations become pervasive
across human tissues with age, including in the haematopoietic
system, where the phenomenon is termed clonal haematopoiesis1-4.
The understanding of how and when clonal haematopoiesis
develops, the factors that govern its behaviour, how it
interacts with ageing and how these variables relate to
malignant progression remains limited5,6. Here we track 697
clonal haematopoiesis clones from 385 individuals 55 years of
age or older over a median of 13 years. We find that 92.4% of
clones expanded at a stable exponential rate over the study
period, with different mutations driving substantially different
growth rates, ranging from 5% (DNMT3A and TP53) to more than
50% per year (SRSF2P95H). Growth rates of clones with the same
mutation differed by approximately $pm$5% per year,
proportionately affecting slow drivers more substantially. By
combining our time-series data with phylogenetic analysis of
1,731 whole-genome sequences of haematopoietic colonies from 7
individuals from an older age group, we reveal distinct patterns
of lifelong clonal behaviour. DNMT3A-mutant clones
preferentially expanded early in life and displayed slower
growth in old age, in the context of an increasingly competitive
oligoclonal landscape. By contrast, splicing gene mutations
drove expansion only later in life, whereas TET2-mutant clones
emerged across all ages. Finally, we show that mutations driving
faster clonal growth carry a higher risk of malignant
progression. Our findings characterize the lifelong natural
history of clonal haematopoiesis and give fundamental insights
into the interactions between somatic mutation, ageing and
clonal selection.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Clonal expansions driven by somatic mutations become pervasive
across human tissues with age, including in the haematopoietic
system, where the phenomenon is termed clonal haematopoiesis1-4.
The understanding of how and when clonal haematopoiesis
develops, the factors that govern its behaviour, how it
interacts with ageing and how these variables relate to
malignant progression remains limited5,6. Here we track 697
clonal haematopoiesis clones from 385 individuals 55 years of
age or older over a median of 13 years. We find that 92.4% of
clones expanded at a stable exponential rate over the study
period, with different mutations driving substantially different
growth rates, ranging from 5% (DNMT3A and TP53) to more than
50% per year (SRSF2P95H). Growth rates of clones with the same
mutation differed by approximately $pm$5% per year,
proportionately affecting slow drivers more substantially. By
combining our time-series data with phylogenetic analysis of
1,731 whole-genome sequences of haematopoietic colonies from 7
individuals from an older age group, we reveal distinct patterns
of lifelong clonal behaviour. DNMT3A-mutant clones
preferentially expanded early in life and displayed slower
growth in old age, in the context of an increasingly competitive
oligoclonal landscape. By contrast, splicing gene mutations
drove expansion only later in life, whereas TET2-mutant clones
emerged across all ages. Finally, we show that mutations driving
faster clonal growth carry a higher risk of malignant
progression. Our findings characterize the lifelong natural
history of clonal haematopoiesis and give fundamental insights
into the interactions between somatic mutation, ageing and
clonal selection. |
Andrea, Anichini; Alessandra, Molla; Gabriella, Nicolini; Eleonora, Perotti Valentina; Francesco, Sgambelluri; Alessia, Covre; Carolina, Fazio; Fortunata, Lofiego Maria; Maria, Di Giacomo Anna; Sandra, Coral; Antonella, Manca; Cristina, Sini Maria; Marina, Pisano; Teresa, Noviello; Francesca, Caruso; Silvia, Brich; Giancarlo, Pruneri; Andrea, Maurichi; Mario, Santinami; Michele, Ceccarelli; Giuseppe, Palmieri; Michele, Maio; Roberta, Mortarini: Landscape of immune-related signatures induced by targeting of different epigenetic regulators in melanoma: implications for immunotherapy. In: JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 41 (325), 2022. @article{nokey,
title = {Landscape of immune-related signatures induced by targeting of different epigenetic regulators in melanoma: implications for immunotherapy},
author = {Anichini Andrea and Molla Alessandra and Nicolini Gabriella and Perotti Valentina Eleonora and Sgambelluri Francesco and Covre Alessia and Fazio Carolina and Lofiego Maria Fortunata and Di Giacomo Anna Maria and Coral Sandra and Manca Antonella and Sini Maria Cristina and Pisano Marina and Noviello Teresa and Caruso Francesca and Brich Silvia and Pruneri Giancarlo and Maurichi Andrea and Santinami Mario and Ceccarelli Michele and Palmieri Giuseppe and Maio Michele and Mortarini Roberta},
url = {https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02529-5},
year = {2022},
date = {2022-05-10},
urldate = {2022-05-10},
journal = {JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH},
volume = {41},
number = {325},
abstract = {Background: Improvement of efficacy of immune checkpoint blockade (ICB) remains a major clinical goal. Association of ICB with immunomodulatory epigenetic drugs is an option. However epigenetic inhibitors show a heterogeneous landscape of activities. Analysis of transcriptional programs induced in neoplastic cells by distinct classes of epigenetic drugs may foster identification of the most promising agents.Methods: Melanoma cell lines characterized for mutational and differentiation profile were treated with inhibitors of DNA methyltransferases (guadecitabine) histone deacetylases (givinostat) BET proteins (JQ1 and OTX-015) and enhancer of zeste homolog 2 (GSK126). Modulatory effects of epigenetic drugs were evaluated at the gene and protein levels. Master molecules explaining changes in gene expression were identified by Upstream Regulator (UR) analysis. Gene set enrichment and IPA were used respectively to test modulation of guadecitabine-specific gene and UR signatures in baseline and on-treatment tumor biopsies from melanoma patients in the Phase Ib NIBIT-M4 Guadecitabine + Ipilimumab Trial. Prognostic significance of drug-specific immune-related genes was tested with Timer 2.0 in TCGA tumor datasets.Results: Epigenetic drugs induced different profiles of gene expression in melanoma cell lines. Immune-related genes were frequently upregulated by guadecitabine irrespective of the mutational and differentiation profiles of the melanoma cell lines to a lesser extent by givinostat but mostly downregulated by JQ1 and OTX-015. GSK126 was the least active drug. Quantitative western blot analysis confirmed drug-specific modulatory profiles. Most of the guadecitabine-specific signature genes were upregulated in on-treatment NIBIT-M4 tumor biopsies but not in on-treatment lesions of patients treated only with ipilimumab. A guadecitabine-specific UR signature containing activated molecules of the TLR NF-kB and IFN innate immunity pathways was induced in drug-treated melanoma mesothelioma and hepatocarcinoma cell lines and in a human melanoma xenograft model. Activation of guadecitabine-specific UR signature molecules in on-treatment tumor biopsies discriminated responding from non-responding NIBIT-M4 patients. Sixty-five % of the immune-related genes upregulated by guadecitabine were prognostically significant and conferred a reduced risk in the TCGA cutaneous melanoma dataset.Conclusions: The DNMT inhibitor guadecitabine emerged as the most promising immunomodulatory agent among those tested supporting the rationale for usage of this class of epigenetic drugs in combinatorial immunotherapy approaches.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background: Improvement of efficacy of immune checkpoint blockade (ICB) remains a major clinical goal. Association of ICB with immunomodulatory epigenetic drugs is an option. However epigenetic inhibitors show a heterogeneous landscape of activities. Analysis of transcriptional programs induced in neoplastic cells by distinct classes of epigenetic drugs may foster identification of the most promising agents.Methods: Melanoma cell lines characterized for mutational and differentiation profile were treated with inhibitors of DNA methyltransferases (guadecitabine) histone deacetylases (givinostat) BET proteins (JQ1 and OTX-015) and enhancer of zeste homolog 2 (GSK126). Modulatory effects of epigenetic drugs were evaluated at the gene and protein levels. Master molecules explaining changes in gene expression were identified by Upstream Regulator (UR) analysis. Gene set enrichment and IPA were used respectively to test modulation of guadecitabine-specific gene and UR signatures in baseline and on-treatment tumor biopsies from melanoma patients in the Phase Ib NIBIT-M4 Guadecitabine + Ipilimumab Trial. Prognostic significance of drug-specific immune-related genes was tested with Timer 2.0 in TCGA tumor datasets.Results: Epigenetic drugs induced different profiles of gene expression in melanoma cell lines. Immune-related genes were frequently upregulated by guadecitabine irrespective of the mutational and differentiation profiles of the melanoma cell lines to a lesser extent by givinostat but mostly downregulated by JQ1 and OTX-015. GSK126 was the least active drug. Quantitative western blot analysis confirmed drug-specific modulatory profiles. Most of the guadecitabine-specific signature genes were upregulated in on-treatment NIBIT-M4 tumor biopsies but not in on-treatment lesions of patients treated only with ipilimumab. A guadecitabine-specific UR signature containing activated molecules of the TLR NF-kB and IFN innate immunity pathways was induced in drug-treated melanoma mesothelioma and hepatocarcinoma cell lines and in a human melanoma xenograft model. Activation of guadecitabine-specific UR signature molecules in on-treatment tumor biopsies discriminated responding from non-responding NIBIT-M4 patients. Sixty-five % of the immune-related genes upregulated by guadecitabine were prognostically significant and conferred a reduced risk in the TCGA cutaneous melanoma dataset.Conclusions: The DNMT inhibitor guadecitabine emerged as the most promising immunomodulatory agent among those tested supporting the rationale for usage of this class of epigenetic drugs in combinatorial immunotherapy approaches. |
Fadda, Giovanni M.; Lobrano, Renato; Casula, Milena; Pisano, Marina; Pazzola, Antonio; Cossu, Antonio; Palmieri, Giuseppe; Paliogiannis, Panagiotis: Liquid Biopsy in the Oncological Management of a Histologically Undiagnosed Lung Carcinoma: A Case Report. In: Journal of Personalized Medicine , 12 (1874 ), 2022. @article{nokey,
title = {Liquid Biopsy in the Oncological Management of a Histologically Undiagnosed Lung Carcinoma: A Case Report},
author = {Giovanni M. Fadda and Renato Lobrano and Milena Casula and Marina Pisano and Antonio Pazzola and Antonio Cossu and Giuseppe Palmieri and Panagiotis Paliogiannis},
year = {2022},
date = {2022-05-10},
urldate = {2022-05-10},
journal = {Journal of Personalized Medicine },
volume = {12},
number = {1874 },
abstract = {Lung cancer is one of the most common and lethal cancers worldwide. Numerous medications targeting specific molecular alterations in non-small cell lung cancer have been introduced in the last decade and have revolutionized the clinical management of the disease. Their use has brought to a parallel evolution of molecular testing techniques to identify alterations in druggable molecular targets within the genetic material of the tumors. To perform molecular testing biopsy or surgery tissue specimens are needed which in addition allow the histological characterization of the tumors. Unfortunately in real-life practice not all the patients are suitable for biopsy or surgery procedures. The use of liquid biopsy for blood extracted tumoral DNA analysis is a promising approach in unbiopsied cases but it is also weighted by several methodological and technical limitations. We report here a case of histologically undiagnosed lung cancer managed with a liquid biopsy and subsequently with anti-EGFR treatment. Our report highlights that the use of liquid biopsy molecular testing in specific clinical situations can offer treatment opportunities for fragile patients affected by lung cancer.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Lung cancer is one of the most common and lethal cancers worldwide. Numerous medications targeting specific molecular alterations in non-small cell lung cancer have been introduced in the last decade and have revolutionized the clinical management of the disease. Their use has brought to a parallel evolution of molecular testing techniques to identify alterations in druggable molecular targets within the genetic material of the tumors. To perform molecular testing biopsy or surgery tissue specimens are needed which in addition allow the histological characterization of the tumors. Unfortunately in real-life practice not all the patients are suitable for biopsy or surgery procedures. The use of liquid biopsy for blood extracted tumoral DNA analysis is a promising approach in unbiopsied cases but it is also weighted by several methodological and technical limitations. We report here a case of histologically undiagnosed lung cancer managed with a liquid biopsy and subsequently with anti-EGFR treatment. Our report highlights that the use of liquid biopsy molecular testing in specific clinical situations can offer treatment opportunities for fragile patients affected by lung cancer. |
Serra, Valentina; Orr`u, Valeria; Lai, Sandra; Lobina, Monia; Steri, Maristella; Cucca, Francesco; Fiorillo, Edoardo: Comparison of whole blood cryopreservation methods for extensive flow cytometry immunophenotyping. In: Cells, 11 (9), pp. 1527, 2022. @article{Serra2022-nw,
title = {Comparison of whole blood cryopreservation methods for extensive flow cytometry immunophenotyping},
author = {Valentina Serra and Valeria Orr`u and Sandra Lai and Monia Lobina and Maristella Steri and Francesco Cucca and Edoardo Fiorillo},
doi = {10.3390/cells11091527},
year = {2022},
date = {2022-05-01},
urldate = {2022-05-01},
journal = {Cells},
volume = {11},
number = {9},
pages = {1527},
publisher = {MDPI AG},
abstract = {Fresh blood immunophenotyping by flow cytometry, based on the
reliable simultaneous detection of several markers in a cell, is
the method of choice to study the circulating human immune
system. Especially in large and multicenter studies, high sample
quality is difficult to achieve, and adequate collection and
storage of samples with fine-tuned whole blood cryopreservation
is mandatory. Here, we compared the quality of immunophenotypic
data obtained from fresh blood with those obtained after five
cryopreservation methods by quantifying the levels of 41 immune
cell populations. They comprised B and T lymphocyte subsets and
their maturation stages, as well as monocytes and granulocytes.
Three methods used fixative solutions and two other methods used
dimethyl sulfoxide solutions to preserve cell viability. The
fixative methods prevented detection of markers critical for
identification of B and T cell subsets, including CD27, CXCR3,
and CCR6. The other two methods permitted reliable
discrimination of most immune-cell populations in thawed
samples, though some cell frequencies varied compared to the
corresponding fresh sample. Of those two methods, the one
preserving blood in media containing dimethyl sulfoxide produced
results that were most similar to those with fresh samples.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Fresh blood immunophenotyping by flow cytometry, based on the
reliable simultaneous detection of several markers in a cell, is
the method of choice to study the circulating human immune
system. Especially in large and multicenter studies, high sample
quality is difficult to achieve, and adequate collection and
storage of samples with fine-tuned whole blood cryopreservation
is mandatory. Here, we compared the quality of immunophenotypic
data obtained from fresh blood with those obtained after five
cryopreservation methods by quantifying the levels of 41 immune
cell populations. They comprised B and T lymphocyte subsets and
their maturation stages, as well as monocytes and granulocytes.
Three methods used fixative solutions and two other methods used
dimethyl sulfoxide solutions to preserve cell viability. The
fixative methods prevented detection of markers critical for
identification of B and T cell subsets, including CD27, CXCR3,
and CCR6. The other two methods permitted reliable
discrimination of most immune-cell populations in thawed
samples, though some cell frequencies varied compared to the
corresponding fresh sample. Of those two methods, the one
preserving blood in media containing dimethyl sulfoxide produced
results that were most similar to those with fresh samples. |
Mariani, Stefano; Puzzoni, Marco; Giampieri, Riccardo; Ziranu, Pina; Pusceddu, Valeria; Donisi, Clelia; Persano, Mara; Pinna, Giovanna; Cimbro, Erika; Parrino, Alissa; Spanu, Dario; Pretta, Andrea; Lai, Eleonora; Liscia, Nicole; Lupi, Alessio; Giglio, Enrica; Palomba, Grazia; Casula, Milena; Pisano, Marina; Palmieri, Giuseppe; Scartozzi, Mario: Liquid Biopsy-Driven Cetuximab Rechallenge Strategy in Molecularly Selected Metastatic Colorectal Cancer Patients. In: Frontiers in Oncology, 12 (852583), 2022. @article{nokey,
title = {Liquid Biopsy-Driven Cetuximab Rechallenge Strategy in Molecularly Selected Metastatic Colorectal Cancer Patients},
author = {Stefano Mariani and Marco Puzzoni and Riccardo Giampieri and Pina Ziranu and Valeria Pusceddu and Clelia Donisi and Mara Persano and Giovanna Pinna and Erika Cimbro and Alissa Parrino and Dario Spanu and Andrea Pretta and Eleonora Lai and Nicole Liscia and Alessio Lupi and Enrica Giglio and Grazia Palomba and Milena Casula and Marina Pisano and Giuseppe Palmieri and Mario Scartozzi},
year = {2022},
date = {2022-04-21},
urldate = {2022-04-21},
journal = {Frontiers in Oncology},
volume = {12},
number = {852583},
abstract = {Background: Rechallenge with EGFR inhibitors represents a promising strategy for patients with RAS wild type (WT) colorectal cancer (CRC) but definitive selection criteria are lacking. Recently the RAS WT status on circulating tumor DNA (ct-DNA) emerged as a potential watershed for this strategy. Our study explored the liquid biopsy-driven cetuximab rechallenge in a RAS and BRAF WT selected population. Methods: CRC patients with RAS and BRAF WT both on tumor tissue and on ct-DNA at baseline receiving rechallenge with cetuximab were eligible for our analysis. Ct-DNA was analyzed for RAS-BRAF mutations with pyro-sequencing and nucleotide sequencing assays. Real-time PCR and droplet digital PCR were performed to confirm the RAS-BRAF mutational status. Results: A total of 26 patients were included in our analysis. In the global population RR was 25.0% median overall survival (mOS) was 5.0 months and median progression-free survival (mPFS) was 3.5 months. Previous response to anti-EGFR was associated with improved mPFS (5.0 vs. 2.0 months HR: 0.26 p = 0.048) and anti-EGFR free interval > 14 months and anti-EGFR free interval > 16 months were associated with improved mPFS (respectively 7.0 vs. 3.0 months HR: 0.27 p = 0.013 and not reached vs. 3.0 months HR: 0.20 p = 0.002) and with improved mOS (respectively 13.0 vs. 5.0 months HR: 0.27 p = 0.013 and 13.0 vs. 5.0 months HR: 0.20 p = 0.002). Previous lines >2 were correlated with improved mPFS (4.0 vs. 1.0 month HR: 0.05 p = 0.041) and with improved mOS (7.0 vs. 1.0 month HR: 0.045 p = 0.034). In a multiple logistic regression model only the anti-EGFR free interval was confirmed to be a significant predictor for mOS and mPFS. Conclusions: Liquid biopsy-driven cetuximab rechallenge was confirmed to be effective. The clinical outcome was consistent with available results from phase II studies. In addition to the molecular selection through the analysis of ct-DNA for RAS the long anti-EGFR free interval is confirmed as a prospective selection criterion for this therapeutic option.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background: Rechallenge with EGFR inhibitors represents a promising strategy for patients with RAS wild type (WT) colorectal cancer (CRC) but definitive selection criteria are lacking. Recently the RAS WT status on circulating tumor DNA (ct-DNA) emerged as a potential watershed for this strategy. Our study explored the liquid biopsy-driven cetuximab rechallenge in a RAS and BRAF WT selected population. Methods: CRC patients with RAS and BRAF WT both on tumor tissue and on ct-DNA at baseline receiving rechallenge with cetuximab were eligible for our analysis. Ct-DNA was analyzed for RAS-BRAF mutations with pyro-sequencing and nucleotide sequencing assays. Real-time PCR and droplet digital PCR were performed to confirm the RAS-BRAF mutational status. Results: A total of 26 patients were included in our analysis. In the global population RR was 25.0% median overall survival (mOS) was 5.0 months and median progression-free survival (mPFS) was 3.5 months. Previous response to anti-EGFR was associated with improved mPFS (5.0 vs. 2.0 months HR: 0.26 p = 0.048) and anti-EGFR free interval > 14 months and anti-EGFR free interval > 16 months were associated with improved mPFS (respectively 7.0 vs. 3.0 months HR: 0.27 p = 0.013 and not reached vs. 3.0 months HR: 0.20 p = 0.002) and with improved mOS (respectively 13.0 vs. 5.0 months HR: 0.27 p = 0.013 and 13.0 vs. 5.0 months HR: 0.20 p = 0.002). Previous lines >2 were correlated with improved mPFS (4.0 vs. 1.0 month HR: 0.05 p = 0.041) and with improved mOS (7.0 vs. 1.0 month HR: 0.045 p = 0.034). In a multiple logistic regression model only the anti-EGFR free interval was confirmed to be a significant predictor for mOS and mPFS. Conclusions: Liquid biopsy-driven cetuximab rechallenge was confirmed to be effective. The clinical outcome was consistent with available results from phase II studies. In addition to the molecular selection through the analysis of ct-DNA for RAS the long anti-EGFR free interval is confirmed as a prospective selection criterion for this therapeutic option. |
Testori, A.; Vaksman, Z.; Diskin, S. J.; Hakonarson, H.; Capasso, M.; Iolascon, A.; Maris, J. M.; Devoto, M.: Genetic Analysis in African American Children Supports Ancestry-Specific Neuroblastoma Susceptibility. In: Cancer Epidemiol Biomarkers Prev, 31 (4), pp. 870–875, 2022. @article{pmid35131881,
title = {Genetic Analysis in African American Children Supports Ancestry-Specific Neuroblastoma Susceptibility},
author = {A. Testori and Z. Vaksman and S. J. Diskin and H. Hakonarson and M. Capasso and A. Iolascon and J. M. Maris and M. Devoto},
year = {2022},
date = {2022-04-01},
journal = {Cancer Epidemiol Biomarkers Prev},
volume = {31},
number = {4},
pages = {870--875},
abstract = {Neuroblastoma is rarer in African American (AA) children compared with American children of European descent. AA children affected with neuroblastoma, however, more frequently develop the high-risk form of the disease. We have genotyped an AA cohort of 629 neuroblastoma cases (254 high-risk) and 2,990 controls to investigate genetic susceptibility to neuroblastoma in AAs. 10-6 in the EA GWAS, and explained 2% of neuroblastoma risk variance. The significance of the polygenic score dropped rapidly with inclusion of additional SNPs. These findings suggest that several common variants contribute to risk of neuroblastoma in an ancestry-specific fashion. This work supports the need for GWAS to be performed in populations of all races and ethnicities.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Neuroblastoma is rarer in African American (AA) children compared with American children of European descent. AA children affected with neuroblastoma, however, more frequently develop the high-risk form of the disease. We have genotyped an AA cohort of 629 neuroblastoma cases (254 high-risk) and 2,990 controls to investigate genetic susceptibility to neuroblastoma in AAs. 10-6 in the EA GWAS, and explained 2% of neuroblastoma risk variance. The significance of the polygenic score dropped rapidly with inclusion of additional SNPs. These findings suggest that several common variants contribute to risk of neuroblastoma in an ancestry-specific fashion. This work supports the need for GWAS to be performed in populations of all races and ethnicities. |
Cardinale, A.; Cantalupo, S.; Lasorsa, V. A.; Montella, A.; Cimmino, F.; Succoio, M.; Vermeulen, M.; Baltissen, M. P.; Esposito, M.; Avitabile, M.; Formicola, D.; Testori, A.; Bonfiglio, F.; Ghiorzo, P.; Scalvenzi, M.; Ayala, F.; Zambrano, N.; Iles, M. M.; Xu, M.; Law, M. H.; Brown, K. M.; Iolascon, A.; Capasso, M.: Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation of OBFC1. In: Hum Mol Genet, 31 (6), pp. 863–874, 2022. @article{pmid34605909,
title = {Functional annotation and investigation of the 10q24.33 melanoma risk locus identifies a common variant that influences transcriptional regulation of OBFC1},
author = {A. Cardinale and S. Cantalupo and V. A. Lasorsa and A. Montella and F. Cimmino and M. Succoio and M. Vermeulen and M. P. Baltissen and M. Esposito and M. Avitabile and D. Formicola and A. Testori and F. Bonfiglio and P. Ghiorzo and M. Scalvenzi and F. Ayala and N. Zambrano and M. M. Iles and M. Xu and M. H. Law and K. M. Brown and A. Iolascon and M. Capasso},
year = {2022},
date = {2022-03-01},
journal = {Hum Mol Genet},
volume = {31},
number = {6},
pages = {863--874},
abstract = {The 10q24.33 locus is known to be associated with susceptibility to cutaneous malignant melanoma (CMM), but the mechanisms underlying this association have been not extensively investigated. We carried out an integrative genomic analysis of 10q24.33 using epigenomic annotations and in vitro reporter gene assays to identify regulatory variants. We found two putative functional single nucleotide polymorphisms (SNPs) in an enhancer and in the promoter of OBFC1, respectively, in neural crest and CMM cells, one, rs2995264, altering enhancer activity. The minor allele G of rs2995264 correlated with lower OBFC1 expression in 470 CMM tumors and was confirmed to increase the CMM risk in a cohort of 484 CMM cases and 1801 controls of Italian origin. Hi-C and chromosome conformation capture (3C) experiments showed the interaction between the enhancer-SNP region and the promoter of OBFC1 and an isogenic model characterized by CRISPR-Cas9 deletion of the enhancer-SNP region confirmed the potential regulatory effect of rs2995264 on OBFC1 transcription. Moreover, the presence of G-rs2995264 risk allele reduced the binding affinity of the transcription factor MEOX2. Biologic investigations showed significant cell viability upon depletion of OBFC1, specifically in CMM cells that were homozygous for the protective allele. Clinically, high levels of OBFC1 expression associated with histologically favorable CMM tumors. Finally, preliminary results suggested the potential effect of decreased OBFC1 expression on telomerase activity in tumorigenic conditions. Our results support the hypothesis that reduced expression of OBFC1 gene through functional heritable DNA variation can contribute to malignant transformation of normal melanocytes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The 10q24.33 locus is known to be associated with susceptibility to cutaneous malignant melanoma (CMM), but the mechanisms underlying this association have been not extensively investigated. We carried out an integrative genomic analysis of 10q24.33 using epigenomic annotations and in vitro reporter gene assays to identify regulatory variants. We found two putative functional single nucleotide polymorphisms (SNPs) in an enhancer and in the promoter of OBFC1, respectively, in neural crest and CMM cells, one, rs2995264, altering enhancer activity. The minor allele G of rs2995264 correlated with lower OBFC1 expression in 470 CMM tumors and was confirmed to increase the CMM risk in a cohort of 484 CMM cases and 1801 controls of Italian origin. Hi-C and chromosome conformation capture (3C) experiments showed the interaction between the enhancer-SNP region and the promoter of OBFC1 and an isogenic model characterized by CRISPR-Cas9 deletion of the enhancer-SNP region confirmed the potential regulatory effect of rs2995264 on OBFC1 transcription. Moreover, the presence of G-rs2995264 risk allele reduced the binding affinity of the transcription factor MEOX2. Biologic investigations showed significant cell viability upon depletion of OBFC1, specifically in CMM cells that were homozygous for the protective allele. Clinically, high levels of OBFC1 expression associated with histologically favorable CMM tumors. Finally, preliminary results suggested the potential effect of decreased OBFC1 expression on telomerase activity in tumorigenic conditions. Our results support the hypothesis that reduced expression of OBFC1 gene through functional heritable DNA variation can contribute to malignant transformation of normal melanocytes. |
Serra, Valentina; Orr`u, Valeria; Steri, Maristella; Fiorillo, Edoardo; Cucca, Francesco; Zoledziewska, Magdalena: Genetic variant within CDK6 regulates immune response to palbociclib treatment. In: Clin. Immunol., 235 (108777), pp. 108777, 2022. @article{Serra2022-br,
title = {Genetic variant within CDK6 regulates immune response to palbociclib treatment},
author = {Valentina Serra and Valeria Orr`u and Maristella Steri and Edoardo Fiorillo and Francesco Cucca and Magdalena Zoledziewska},
doi = {10.1016/j.clim.2021.108777},
year = {2022},
date = {2022-02-01},
urldate = {2022-02-01},
journal = {Clin. Immunol.},
volume = {235},
number = {108777},
pages = {108777},
publisher = {Elsevier BV},
abstract = {Everyone carries a set of genetic variants that contribute to
regulation of the levels of blood cells, with unknown clinical
impact. One of them, rs445 within the cell-cycle checkpoint gene
CDK6, reduces the levels of myeloid cell types including
granulocytes. We treated CD3+ T cells and whole blood with
palbociclib in 41 individuals, who were stratified by genotype
for analyses. In T cells we assessed cell cycle and apoptosis,
whereas in whole blood, apoptosis in activated (CD11b+),
unactivated (CD11b-) granulocytes, cytotoxic (CD8 + CD4-), and
helper (CD8-CD4+) T cells. We find that rs445 modulates the
immune response of CD8+ T cells. It also increases the level of
apoptotic CD11b + activated granulocytes after palbociclib
treatment, which, in synergy with neutropenia, may affect drug
related adverse events. These results suggest that the effect of
palbociclib treatment may depend on underlying genetically
encoded individual immune response as well as the direct
response to the drug.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Everyone carries a set of genetic variants that contribute to
regulation of the levels of blood cells, with unknown clinical
impact. One of them, rs445 within the cell-cycle checkpoint gene
CDK6, reduces the levels of myeloid cell types including
granulocytes. We treated CD3+ T cells and whole blood with
palbociclib in 41 individuals, who were stratified by genotype
for analyses. In T cells we assessed cell cycle and apoptosis,
whereas in whole blood, apoptosis in activated (CD11b+),
unactivated (CD11b-) granulocytes, cytotoxic (CD8 + CD4-), and
helper (CD8-CD4+) T cells. We find that rs445 modulates the
immune response of CD8+ T cells. It also increases the level of
apoptotic CD11b + activated granulocytes after palbociclib
treatment, which, in synergy with neutropenia, may affect drug
related adverse events. These results suggest that the effect of
palbociclib treatment may depend on underlying genetically
encoded individual immune response as well as the direct
response to the drug. |
Paliogiannis, Panagiotis; Colombino, Maria; Sini, Maria Cristina; Manca, Antonella; Casula, Milena; Palomba, Grazia; Pisano, Marina; Doneddu, Valentina; Zinellu, Angelo; Santeufemia, Davide; and Giovanni Sotgiu,; Cossu, Antonio; Palmieri, Giuseppe: Global prognostic impact of driver genetic alterations in patients with lung adenocarcinoma: a real-life study. In: BMC Pulm Med, 22 (1), pp. 32, 2022, ISSN: 1471-2466. @article{pmid35012520,
title = {Global prognostic impact of driver genetic alterations in patients with lung adenocarcinoma: a real-life study},
author = {Panagiotis Paliogiannis and Maria Colombino and Maria Cristina Sini and Antonella Manca and Milena Casula and Grazia Palomba and Marina Pisano and Valentina Doneddu and Angelo Zinellu and Davide Santeufemia and and Giovanni Sotgiu and Antonio Cossu and Giuseppe Palmieri},
doi = {10.1186/s12890-021-01803-0},
issn = {1471-2466},
year = {2022},
date = {2022-01-10},
journal = {BMC Pulm Med},
volume = {22},
number = {1},
pages = {32},
abstract = {BACKGROUND: Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. The aim of this study was to evaluate the global survival in a real-life cohort of patients with LAC harboring driver genetic alterations.
METHODS: A series of 1282 consecutive Sardinian LAC patients who underwent genetic testing from January 2011 through July 2016 was collected. Molecular tests were based on the clinical needs of each single case (EGFR-exon18/19/21, ALK, and, more recently, BRAF-exon15), and the availability of tissue (KRAS, MET, and presence of low-frequency EGFR-T790M mutated alleles at baseline).
RESULTS: The mean follow-up time of the patients was 46 months. EGFR, KRAS, and BRAF mutations were detected in 13.7%, 21.3%, and 3% of tested cases, respectively; ALK rearrangements and MET amplifications were found respectively in 4.7% and 2% of tested cases. As expected, cases with mutations in exons 18-21 of EGFR, sensitizing to anti-EGFR tyrosine kinase inhibitors (TKIs) agents, had a significantly longer survival in comparison to those without (p < 0.0001); conversely, KRAS mutations were associated with a significantly lower survival (p = 0.0058). Among LAC patients with additional tissue section available for next-generation sequencing (NGS)-based analysis, 26/193 (13.5%) patients found positive for even low-rate EGFR-T790M mutated alleles at baseline were associated with a highly significant lower survival in comparison to those without (8.7 vs. 47.4 months, p < 0.0001).
CONCLUSIONS: In addition to its predictive value for addressing targeted therapy approaches, the assessment of as more inclusive mutation analysis at baseline may provide clues about factors significantly impacting on global survival in advanced LAC patients.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. The aim of this study was to evaluate the global survival in a real-life cohort of patients with LAC harboring driver genetic alterations.
METHODS: A series of 1282 consecutive Sardinian LAC patients who underwent genetic testing from January 2011 through July 2016 was collected. Molecular tests were based on the clinical needs of each single case (EGFR-exon18/19/21, ALK, and, more recently, BRAF-exon15), and the availability of tissue (KRAS, MET, and presence of low-frequency EGFR-T790M mutated alleles at baseline).
RESULTS: The mean follow-up time of the patients was 46 months. EGFR, KRAS, and BRAF mutations were detected in 13.7%, 21.3%, and 3% of tested cases, respectively; ALK rearrangements and MET amplifications were found respectively in 4.7% and 2% of tested cases. As expected, cases with mutations in exons 18-21 of EGFR, sensitizing to anti-EGFR tyrosine kinase inhibitors (TKIs) agents, had a significantly longer survival in comparison to those without (p < 0.0001); conversely, KRAS mutations were associated with a significantly lower survival (p = 0.0058). Among LAC patients with additional tissue section available for next-generation sequencing (NGS)-based analysis, 26/193 (13.5%) patients found positive for even low-rate EGFR-T790M mutated alleles at baseline were associated with a highly significant lower survival in comparison to those without (8.7 vs. 47.4 months, p < 0.0001).
CONCLUSIONS: In addition to its predictive value for addressing targeted therapy approaches, the assessment of as more inclusive mutation analysis at baseline may provide clues about factors significantly impacting on global survival in advanced LAC patients. |
Dallocchio, Roberto; Dessì, Alessandro; Sechi, Barbara; Chankvetadze, Bezhan; Cossu, Sergio; Mamane, Victor; Aubert, Emmanuel; Rozzo, Carla; Palmieri, Giuseppe; Spissu, Ylenia; Peluso., Paola: Exploring interaction modes between polysaccharide-based selectors and biologically active 4,4 ′ -bipyridines by experimental and computational analysis. . In: Journal of Chromatography Open, 2 (100030), pp. 1-10, 2022, ISSN: 2772-3917. @article{nokey,
title = {Exploring interaction modes between polysaccharide-based selectors and biologically active 4,4 ′ -bipyridines by experimental and computational analysis. },
author = {Roberto Dallocchio and Alessandro Dessì and Barbara Sechi and Bezhan Chankvetadze and Sergio Cossu and Victor Mamane and Emmanuel Aubert and Carla Rozzo and Giuseppe Palmieri and Ylenia Spissu and Paola Peluso. },
url = {https://irgb.cnr.it/wp-content/uploads/2024/05/Dallocchio-et-al-2022.pdf},
doi = {10.1016/j.jcoa.2022.100030},
issn = {2772-3917},
year = {2022},
date = {2022-01-06},
urldate = {2022-01-06},
journal = {Journal of Chromatography Open},
volume = {2},
number = {100030},
pages = {1-10},
abstract = {In the last few years, chiral 4,4 ′ -bipyridine derivatives have been developed for different applications in catalysis, enantioseparation science, supramolecular and theoretical chemistry by modulating the activity of the molecu- lar system through the introduction of specific substituents in the heteroaromatic scaffold. More recently, the biological activity of 2 ′ -substituted-3,3 ′ ,5,5 ′ -tetrachloro-2-iodo-4,4 ′ -bipyridines has been explored in the field of transthyretin (TTR) fibrillogenesis inhibition, and the anticancer cytotoxicity of some derivatives is currently under systematic investigation. In this frame, the high-performance liquid chromatography (HPLC) enantiosepa- ration of four atropisomeric 2,2 ′ -disubstituted-4,4 ′ -bipyridines (R, R’ = Ar, I), which contain multiple interaction sites, such as hydrogen bonding (HB) donors and acceptors, halogen bond (XB) donors, and 𝜋-extended electronic clouds, was explored by using n -hexane (Hex)/2-propanol (2-PrOH) 90:10 v/v as a mobile phase (MP), and eight chiral columns with coated and immobilized amylose- and cellulose-based selectors. The impact of subtle struc- tural variations of analytes and selectors on their mutual intermolecular interactivity was evaluated in terms of retention ( k ) and selectivity ( 𝛼) factors. On this basis, chromatographic analysis based on systematic screening of analytes and selectors was integrated with electrostatic potential ( V ) analysis and molecular dynamics (MD) sim- ulations as computational techniques. The effect of temperature on retention, selectivity, and enantiomer elution order (EEO) of the analytes with coated and immobilized amylose tris (3,5-dimethylphenylcarbamate) was also considered by comparing the variation of the thermodynamic profile associated with each enantioseparation. Chromatographic responses proved to be strictly dependent on specific regions within the analyte, and functions of different interactions sites of the analytes as the structure of the chiral selector changes were significantly disclosed.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In the last few years, chiral 4,4 ′ -bipyridine derivatives have been developed for different applications in catalysis, enantioseparation science, supramolecular and theoretical chemistry by modulating the activity of the molecu- lar system through the introduction of specific substituents in the heteroaromatic scaffold. More recently, the biological activity of 2 ′ -substituted-3,3 ′ ,5,5 ′ -tetrachloro-2-iodo-4,4 ′ -bipyridines has been explored in the field of transthyretin (TTR) fibrillogenesis inhibition, and the anticancer cytotoxicity of some derivatives is currently under systematic investigation. In this frame, the high-performance liquid chromatography (HPLC) enantiosepa- ration of four atropisomeric 2,2 ′ -disubstituted-4,4 ′ -bipyridines (R, R’ = Ar, I), which contain multiple interaction sites, such as hydrogen bonding (HB) donors and acceptors, halogen bond (XB) donors, and 𝜋-extended electronic clouds, was explored by using n -hexane (Hex)/2-propanol (2-PrOH) 90:10 v/v as a mobile phase (MP), and eight chiral columns with coated and immobilized amylose- and cellulose-based selectors. The impact of subtle struc- tural variations of analytes and selectors on their mutual intermolecular interactivity was evaluated in terms of retention ( k ) and selectivity ( 𝛼) factors. On this basis, chromatographic analysis based on systematic screening of analytes and selectors was integrated with electrostatic potential ( V ) analysis and molecular dynamics (MD) sim- ulations as computational techniques. The effect of temperature on retention, selectivity, and enantiomer elution order (EEO) of the analytes with coated and immobilized amylose tris (3,5-dimethylphenylcarbamate) was also considered by comparing the variation of the thermodynamic profile associated with each enantioseparation. Chromatographic responses proved to be strictly dependent on specific regions within the analyte, and functions of different interactions sites of the analytes as the structure of the chiral selector changes were significantly disclosed. |
Lopera-Maya, E. A.; Kurilshikov, A.; Graaf, A.; Hu, S.; Andreu-Sánchez, S.; Chen, L.; Vila, A. V.; Gacesa, R.; Sinha, T.; Collij, V.; Klaassen, M. A. Y.; Bolte, L. A.; Gois, M. F. B.; Neerincx, P. B. T.; Swertz, M. A.; Harmsen, H. J. M.; Wijmenga, C.; Fu, J.; Weersma, R. K.; Zhernakova, A.; Sanna, S.; Aguirre-Gamboa, R.; Deelen, P.; Franke, L.; Kuivenhoven, J. A.; Lopera-Maya, E. A.; Nolte, I. M.; Sanna, S.; Snieder, H.; Swertz, M. A.; Vonk, J. M.; Wijmenga, C.: Effect of host genetics on the gut microbiome in 7,738 participants of the Đutch Microbiome Project. In: Nat Genet, 54 (2), pp. 143–151, 2022. @article{pmid35115690,
title = {Effect of host genetics on the gut microbiome in 7,738 participants of the Đutch Microbiome Project},
author = {E. A. Lopera-Maya and A. Kurilshikov and A. Graaf and S. Hu and S. Andreu-Sánchez and L. Chen and A. V. Vila and R. Gacesa and T. Sinha and V. Collij and M. A. Y. Klaassen and L. A. Bolte and M. F. B. Gois and P. B. T. Neerincx and M. A. Swertz and H. J. M. Harmsen and C. Wijmenga and J. Fu and R. K. Weersma and A. Zhernakova and S. Sanna and R. Aguirre-Gamboa and P. Deelen and L. Franke and J. A. Kuivenhoven and E. A. Lopera-Maya and I. M. Nolte and S. Sanna and H. Snieder and M. A. Swertz and J. M. Vonk and C. Wijmenga},
url = {https://www.nature.com/articles/s41588-021-00992-y},
year = {2022},
date = {2022-01-01},
urldate = {2022-01-01},
journal = {Nat Genet},
volume = {54},
number = {2},
pages = {143--151},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Sanna, S.; Kurilshikov, A.; Graaf, A.; Fu, J.; Zhernakova, A.: Challenges and future directions for studying effects of host genetics on the gut microbiome. In: Nat Genet, 54 (2), pp. 100–106, 2022, ([DOI:hrefhttps://dx.doi.org/10.1038/s41588-021-00983-z10.1038/s41588-021-00983-z] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/3278393532783935]). @article{pmid35115688b,
title = {Challenges and future directions for studying effects of host genetics on the gut microbiome},
author = {S. Sanna and A. Kurilshikov and A. Graaf and J. Fu and A. Zhernakova},
url = {https://www.nature.com/articles/s41588-021-00983-z},
year = {2022},
date = {2022-01-01},
urldate = {2022-01-01},
journal = {Nat Genet},
volume = {54},
number = {2},
pages = {100--106},
abstract = {1,000 participants have been published, yet only a few genetic loci have been consistently confirmed across multiple studies. Here we discuss the state of the art for mbGWAS, focusing on current challenges such as the heterogeneity of microbiome measurements and power issues, and we elaborate on potential future directions for genetic analysis of the microbiome.},
note = {[DOI:hrefhttps://dx.doi.org/10.1038/s41588-021-00983-z10.1038/s41588-021-00983-z] [PubMed:hrefhttps://www.ncbi.nlm.nih.gov/pubmed/3278393532783935]},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
1,000 participants have been published, yet only a few genetic loci have been consistently confirmed across multiple studies. Here we discuss the state of the art for mbGWAS, focusing on current challenges such as the heterogeneity of microbiome measurements and power issues, and we elaborate on potential future directions for genetic analysis of the microbiome. |
Boulad, Farid; Maggio, Aurelio; Wang, Xiuyan; Moi, Paolo; Acuto, Santina; Kogel, Friederike; Takpradit, Chayamon; Prockop, Susan; Mansilla-Soto, Jorge; Cabriolu, Annalisa; Odak, Ashlesha; Qu, Jinrong; Thummar, Keyur; Du, Fang; Shen, Lingbo; Raso, Simona; Barone, Rita; Maggio, Rosario Di; Pitrolo, Lorella; Giambona, Antonino; Mingoia, Maura; Everett, John K; Hokama, Pascha; Roche, Aoife M; Cantu, Vito Adrian; Adhikari, Hriju; Reddy, Shantan; Bouhassira, Eric; Mohandas, Narla; Bushman, Frederic D; Rivi`ere, Isabelle; Sadelain, Michel: Lentiviral globin gene therapy with reduced-intensity conditioning in adults with $beta$-thalassemia: a phase 1 trial. In: Nat. Med., 28 (1), pp. 63–70, 2022. @article{Boulad2022-ka,
title = {Lentiviral globin gene therapy with reduced-intensity conditioning in adults with $beta$-thalassemia: a phase 1 trial},
author = {Farid Boulad and Aurelio Maggio and Xiuyan Wang and Paolo Moi and Santina Acuto and Friederike Kogel and Chayamon Takpradit and Susan Prockop and Jorge Mansilla-Soto and Annalisa Cabriolu and Ashlesha Odak and Jinrong Qu and Keyur Thummar and Fang Du and Lingbo Shen and Simona Raso and Rita Barone and Rosario Di Maggio and Lorella Pitrolo and Antonino Giambona and Maura Mingoia and John K Everett and Pascha Hokama and Aoife M Roche and Vito Adrian Cantu and Hriju Adhikari and Shantan Reddy and Eric Bouhassira and Narla Mohandas and Frederic D Bushman and Isabelle Rivi`ere and Michel Sadelain},
year = {2022},
date = {2022-01-01},
urldate = {2022-01-01},
journal = {Nat. Med.},
volume = {28},
number = {1},
pages = {63--70},
publisher = {Springer Science and Business Media LLC},
abstract = {$beta$-Thalassemias are inherited anemias that are caused by
the absent or insufficient production of the $beta$ chain of
hemoglobin. Here we report 6-8-year follow-up of four adult
patients with transfusion-dependent $beta$-thalassemia who were
infused with autologous CD34+ cells transduced with the
TNS9.3.55 lentiviral globin vector after reduced-intensity
conditioning (RIC) in a phase 1 clinical trial ( NCT01639690) .
Patients were monitored for insertional mutagenesis and the
generation of a replication-competent lentivirus (safety and
tolerability of the infusion product after RIC-primary endpoint)
and engraftment of genetically modified autologous CD34+ cells,
expression of the transduced $beta$-globin gene and
post-transplant transfusion requirements (efficacy-secondary
endpoint). No unexpected safety issues occurred during
conditioning and cell product infusion. Hematopoietic gene
marking was very stable but low, reducing transfusion
requirements in two patients, albeit not achieving transfusion
independence. Our findings suggest that non-myeloablative
conditioning can achieve durable stem cell engraftment but
underscore a minimum CD34+ cell transduction requirement for
effective therapy. Moderate clonal expansions were associated
with integrations near cancer-related genes, suggestive of
non-erythroid activity of globin vectors in stem/progenitor
cells. These correlative findings highlight the necessity of
cautiously monitoring patients harboring globin vectors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
$beta$-Thalassemias are inherited anemias that are caused by
the absent or insufficient production of the $beta$ chain of
hemoglobin. Here we report 6-8-year follow-up of four adult
patients with transfusion-dependent $beta$-thalassemia who were
infused with autologous CD34+ cells transduced with the
TNS9.3.55 lentiviral globin vector after reduced-intensity
conditioning (RIC) in a phase 1 clinical trial ( NCT01639690) .
Patients were monitored for insertional mutagenesis and the
generation of a replication-competent lentivirus (safety and
tolerability of the infusion product after RIC-primary endpoint)
and engraftment of genetically modified autologous CD34+ cells,
expression of the transduced $beta$-globin gene and
post-transplant transfusion requirements (efficacy-secondary
endpoint). No unexpected safety issues occurred during
conditioning and cell product infusion. Hematopoietic gene
marking was very stable but low, reducing transfusion
requirements in two patients, albeit not achieving transfusion
independence. Our findings suggest that non-myeloablative
conditioning can achieve durable stem cell engraftment but
underscore a minimum CD34+ cell transduction requirement for
effective therapy. Moderate clonal expansions were associated
with integrations near cancer-related genes, suggestive of
non-erythroid activity of globin vectors in stem/progenitor
cells. These correlative findings highlight the necessity of
cautiously monitoring patients harboring globin vectors. |
2021
|
Lind, L.; Zanetti, D.; Ingelsson, M.; Gustafsson, S.; v, J.; Assimes, T. L.: Large-Scale Plasma Protein Profiling of Incident Myocardial Infarction, Ischemic Stroke, and Ħeart Failure. In: J Am Heart Assoc, 10 (23), pp. e023330, 2021. @article{pmid34845919,
title = {Large-Scale Plasma Protein Profiling of Incident Myocardial Infarction, Ischemic Stroke, and Ħeart Failure},
author = {L. Lind and D. Zanetti and M. Ingelsson and S. Gustafsson and J. v and T. L. Assimes},
year = {2021},
date = {2021-12-01},
journal = {J Am Heart Assoc},
volume = {10},
number = {23},
pages = {e023330},
abstract = {=0.0038). Conclusions Large-scale proteomics seem useful for the discovery of new risk markers for CVD and to improve risk prediction in an elderly population of men. Further studies are needed to replicate the findings in independent samples of both men and women of different ages.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
=0.0038). Conclusions Large-scale proteomics seem useful for the discovery of new risk markers for CVD and to improve risk prediction in an elderly population of men. Further studies are needed to replicate the findings in independent samples of both men and women of different ages. |
Olla, S.; Steri, M.; Formato, A.; Whalen, M. B.; Corbisiero, S.; Agresti, C.: Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Đrug Repositioning. In: Pharmaceutics, 13 (12), 2021. @article{pmid34959343,
title = {Combining Human Genetics of Multiple Sclerosis with Oxidative Stress Phenotype for Đrug Repositioning},
author = {S. Olla and M. Steri and A. Formato and M. B. Whalen and S. Corbisiero and C. Agresti},
year = {2021},
date = {2021-12-01},
urldate = {2021-12-01},
journal = {Pharmaceutics},
volume = {13},
number = {12},
abstract = {In multiple sclerosis (MS), oxidative stress (OS) is implicated in the neurodegenerative processes that occur from the beginning of the disease. Unchecked OS initiates a vicious circle caused by its crosstalk with inflammation, leading to demyelination, axonal damage and neuronal loss. The failure of MS antioxidant therapies relying on the use of endogenous and natural compounds drives the application of novel approaches to assess target relevance to the disease prior to preclinical testing of new drug candidates. To identify drugs that can act as regulators of intracellular oxidative homeostasis, we applied an in silico approach that links genome-wide MS associations and molecular quantitative trait loci (QTLs) to proteins of the OS pathway. We found 10 drugs with both central nervous system and oral bioavailability, targeting five out of the 21 top-scoring hits, including arginine methyltransferase (CARM1), which was first linked to MS. In particular, the direction of brain expression QTLs for CARM1 and protein kinase MAPK1 enabled us to select BIIB021 and PEITC drugs with the required target modulation. Our study highlights OS-related molecules regulated by functional MS variants that could be targeted by existing drugs as a supplement to the approved disease-modifying treatments.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
In multiple sclerosis (MS), oxidative stress (OS) is implicated in the neurodegenerative processes that occur from the beginning of the disease. Unchecked OS initiates a vicious circle caused by its crosstalk with inflammation, leading to demyelination, axonal damage and neuronal loss. The failure of MS antioxidant therapies relying on the use of endogenous and natural compounds drives the application of novel approaches to assess target relevance to the disease prior to preclinical testing of new drug candidates. To identify drugs that can act as regulators of intracellular oxidative homeostasis, we applied an in silico approach that links genome-wide MS associations and molecular quantitative trait loci (QTLs) to proteins of the OS pathway. We found 10 drugs with both central nervous system and oral bioavailability, targeting five out of the 21 top-scoring hits, including arginine methyltransferase (CARM1), which was first linked to MS. In particular, the direction of brain expression QTLs for CARM1 and protein kinase MAPK1 enabled us to select BIIB021 and PEITC drugs with the required target modulation. Our study highlights OS-related molecules regulated by functional MS variants that could be targeted by existing drugs as a supplement to the approved disease-modifying treatments. |
Palmieri, Giuseppe; Rozzo, Carla Maria; Colombino, Maria; Casula, Milena; Sini, Maria Cristina; Manca, Antonella; Pisano, Marina; Doneddu, Valentina; Paliogiannis, Panagiotis; Cossu., Antonio: Are Molecular Alterations Linked to Genetic Instability Worth to Be Included as Biomarkers for Directing or Excluding Melanoma Patients to Immunotherapy? . In: Frontiers in Oncology, 11 (666624), pp. 1-11, 2021, ISSN: 2234-943X. @article{nokey,
title = {Are Molecular Alterations Linked to Genetic Instability Worth to Be Included as Biomarkers for Directing or Excluding Melanoma Patients to Immunotherapy? },
author = {Giuseppe Palmieri and Carla Maria Rozzo and Maria Colombino and Milena Casula and Maria Cristina Sini and Antonella Manca and Marina Pisano and Valentina Doneddu and Panagiotis Paliogiannis and Antonio Cossu. },
url = {https://irgb.cnr.it/wp-content/uploads/2024/05/Palmieri-et-al-2021-1.pdf},
doi = {doi: 10.3389/fonc.2021.666624},
issn = {2234-943X},
year = {2021},
date = {2021-05-05},
urldate = {2021-05-05},
journal = {Frontiers in Oncology},
volume = {11},
number = {666624},
pages = {1-11},
abstract = {The improvement of the immunotherapeutic potential in most human cancers, including melanoma, requires the identification of increasingly detailed molecular features underlying the tumor immune responsiveness and acting as disease-associated biomarkers. In recent past years, the complexity of the immune landscape in cancer tissues is being steadily unveiled with a progressive better understanding of the plethora of actors playing in such a scenario, resulting in histopathology diversification, distinct molecular subtypes, and biological heterogeneity. Actually, it is widely recognized that the intracellular patterns of alterations in driver genes and loci may also concur to interfere with the homeostasis of the tumor microenvironment components, deeply affecting the immune response against the tumor. Among others, the different events linked to genetic instability—aneuploidy/somatic copy number alteration (SCNA) or microsatellite instability (MSI)—may exhibit opposite behaviors in terms of immune exclusion or responsiveness.
In this review, we focused on both prevalence and impact of such different types of genetic instability in melanoma in order to evaluate whether their use as biomarkers in an integrated analysis of the molecular profile of such a malignancy may allow defining any potential predictive value for response/resistance to immunotherapy.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The improvement of the immunotherapeutic potential in most human cancers, including melanoma, requires the identification of increasingly detailed molecular features underlying the tumor immune responsiveness and acting as disease-associated biomarkers. In recent past years, the complexity of the immune landscape in cancer tissues is being steadily unveiled with a progressive better understanding of the plethora of actors playing in such a scenario, resulting in histopathology diversification, distinct molecular subtypes, and biological heterogeneity. Actually, it is widely recognized that the intracellular patterns of alterations in driver genes and loci may also concur to interfere with the homeostasis of the tumor microenvironment components, deeply affecting the immune response against the tumor. Among others, the different events linked to genetic instability—aneuploidy/somatic copy number alteration (SCNA) or microsatellite instability (MSI)—may exhibit opposite behaviors in terms of immune exclusion or responsiveness.
In this review, we focused on both prevalence and impact of such different types of genetic instability in melanoma in order to evaluate whether their use as biomarkers in an integrated analysis of the molecular profile of such a malignancy may allow defining any potential predictive value for response/resistance to immunotherapy. |
Manca, Antonella; Sini, Maria Cristina; Cesinaro, Anna Maria; Portelli, Francesca; Urso, Carmelo; Lentini, Maria; Cardia, Roberta; Alos, Llucia; Cook, Martin; Simi, Sara; Paliogiannis, Panagiotis; Giorgi, Vincenzo De; Cossu, Antonio; Palmieri, Giuseppe; Massi, Daniela: NGS-Based Analysis of Atypical Deep Penetrating Nevi. In: Cancers (Basel), 13 (12), 2021, ISSN: 2072-6694. @article{pmid34205480,
title = {NGS-Based Analysis of Atypical Deep Penetrating Nevi},
author = {Antonella Manca and Maria Cristina Sini and Anna Maria Cesinaro and Francesca Portelli and Carmelo Urso and Maria Lentini and Roberta Cardia and Llucia Alos and Martin Cook and Sara Simi and Panagiotis Paliogiannis and Vincenzo De Giorgi and Antonio Cossu and Giuseppe Palmieri and Daniela Massi},
doi = {10.3390/cancers13123066},
issn = {2072-6694},
year = {2021},
date = {2021-05-04},
journal = {Cancers (Basel)},
volume = {13},
number = {12},
abstract = {Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or epithelioid melanocytes with a distinctive wedge-shaped configuration showing activation of the WNT pathway, with unusual cyto-architectural features. It is unclear whether they show a distinct genomic profile associated with a diverse metastatic potential. We describe herein a cohort of 21 atypical DPNs analyzed by next-generation sequencing using the Ion AmpliSeq™ Comprehensive Cancer Panel. We found that β-catenin exon 3 was mutated in 95% and MAP kinase pathway genes in 71% of the cases. Less frequent mutations were observed in HRAS (19%) and MAP2K1 (24%). Isocitrate dehydrogenases 1 (IDH1) mutations, including R132C, V178I, and S278L, were identified in 38% of cases and co-existed with BRAF/HRAS mutations. The only case with progressive nodal disease carried alterations in the β-catenin pathway and mutations in IDH1 and NRAS (codon 61). By a comprehensive mutation analysis, we found low genetic heterogeneity and a lack of significant associations between specific gene mutations and histopathological features, despite atypical features. Whether the acquisition of an NRAS or IDH1 mutation in an atypical DPN may represent a molecular evolution implying a pathway to melanoma progression should be confirmed in a larger series.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Deep penetrating nevi (DPNs) are rare melanocytic neoplasms consisting of pigmented spindled or epithelioid melanocytes with a distinctive wedge-shaped configuration showing activation of the WNT pathway, with unusual cyto-architectural features. It is unclear whether they show a distinct genomic profile associated with a diverse metastatic potential. We describe herein a cohort of 21 atypical DPNs analyzed by next-generation sequencing using the Ion AmpliSeq™ Comprehensive Cancer Panel. We found that β-catenin exon 3 was mutated in 95% and MAP kinase pathway genes in 71% of the cases. Less frequent mutations were observed in HRAS (19%) and MAP2K1 (24%). Isocitrate dehydrogenases 1 (IDH1) mutations, including R132C, V178I, and S278L, were identified in 38% of cases and co-existed with BRAF/HRAS mutations. The only case with progressive nodal disease carried alterations in the β-catenin pathway and mutations in IDH1 and NRAS (codon 61). By a comprehensive mutation analysis, we found low genetic heterogeneity and a lack of significant associations between specific gene mutations and histopathological features, despite atypical features. Whether the acquisition of an NRAS or IDH1 mutation in an atypical DPN may represent a molecular evolution implying a pathway to melanoma progression should be confirmed in a larger series. |
Pisano, Marina; Dettori, Maria Antonietta; Fabbri, Davide; Delogu, Giovanna; Palmieri, Giuseppe; Rozzo., Carla: Anticancer activity of two novel hydroxylated biphenyl compounds toward malignant melanoma cells.. In: International Journal of Molecular Sciences, 22 (5636), pp. 1-18, 2021, ISSN: 1422-0067. @article{nokey,
title = {Anticancer activity of two novel hydroxylated biphenyl compounds toward malignant melanoma cells.},
author = {Marina Pisano and Maria Antonietta Dettori and Davide Fabbri and Giovanna Delogu and Giuseppe Palmieri and Carla Rozzo. },
url = {https://irgb.cnr.it/wp-content/uploads/2024/05/Pisano-et-al-2021-reprint.pdf},
doi = {10.3390/ijms22115636},
issn = {1422-0067},
year = {2021},
date = {2021-03-26},
urldate = {2021-03-26},
journal = {International Journal of Molecular Sciences},
volume = {22},
number = {5636},
pages = {1-18},
abstract = {Melanoma, the deadliest form of skin cancer, is still one of the most difficult cancers to treat despite recent advances in targeted and immune therapies. About 50% of advanced melanoma do not benefit of such therapies, and novel treatments are requested. Curcumin and its analogs have shown good anticancer properties and are being considered for use in combination with or sequence to recent therapies to improve patient outcomes. Our group previously published the synthesis and anticancer activity characterization of a novel curcumin-related compound against melanoma and neuroblastoma cells (D6). Here, two hydroxylated biphenyl compounds—namely, compounds 11 and 12—were selected among a small collection of previously screened C2-symmetric hydroxylated biphenyls structurally related to D6 and curcumin, showing the best antitumor potentiality against melanoma cells (IC50 values of 1.7 uM 0.5 uM for 11 and 2.0 uM 0.7 uM for 12) and no toxicity of normal fibroblasts up to 32 uM. Their antiproliferative activity was deeply characterized on five melanoma cell lines by performing dose-response and clonal growth inhibition assays, which revealed longlasting and irreversible effects for both compounds. Apoptosis induction was ascertained by the annexin V and TUNEL assays, whereas Western blotting showed caspase activation and PARP cleavage. A cell cycle analysis, following cell treatments with either compound 11 or 12, highlighted an arrest in the G2/M transition. Taking all this evidence together, 11 and 12 were shown to be good candidates as lead compounds to develop new anticancer drugs against malignant melanoma.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Melanoma, the deadliest form of skin cancer, is still one of the most difficult cancers to treat despite recent advances in targeted and immune therapies. About 50% of advanced melanoma do not benefit of such therapies, and novel treatments are requested. Curcumin and its analogs have shown good anticancer properties and are being considered for use in combination with or sequence to recent therapies to improve patient outcomes. Our group previously published the synthesis and anticancer activity characterization of a novel curcumin-related compound against melanoma and neuroblastoma cells (D6). Here, two hydroxylated biphenyl compounds—namely, compounds 11 and 12—were selected among a small collection of previously screened C2-symmetric hydroxylated biphenyls structurally related to D6 and curcumin, showing the best antitumor potentiality against melanoma cells (IC50 values of 1.7 uM 0.5 uM for 11 and 2.0 uM 0.7 uM for 12) and no toxicity of normal fibroblasts up to 32 uM. Their antiproliferative activity was deeply characterized on five melanoma cell lines by performing dose-response and clonal growth inhibition assays, which revealed longlasting and irreversible effects for both compounds. Apoptosis induction was ascertained by the annexin V and TUNEL assays, whereas Western blotting showed caspase activation and PARP cleavage. A cell cycle analysis, following cell treatments with either compound 11 or 12, highlighted an arrest in the G2/M transition. Taking all this evidence together, 11 and 12 were shown to be good candidates as lead compounds to develop new anticancer drugs against malignant melanoma. |
Zanni, E Di; Palagano, E; Lagostena, L; Strina, D; Rehman, A; Abinun, M; Somer, L De; Martire, B; Brown, J; Kariminejad, A; Balasubramaniam, S; Baynam, G; Gurrieri, F; Pisanti, M A; Maggio, I De; Abboud, M R; Chiesa, R; Burren, C P; Villa, A; Sobacchi, C; Picollo, A: Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Đerived From Structural and Functional Analysis of 14 ClC-7 Mutants. In: J Bone Miner Res, 36 (3), pp. 531–545, 2021. @article{pmid33125761,
title = {Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Đerived From Structural and Functional Analysis of 14 ClC-7 Mutants},
author = {E Di Zanni and E Palagano and L Lagostena and D Strina and A Rehman and M Abinun and L De Somer and B Martire and J Brown and A Kariminejad and S Balasubramaniam and G Baynam and F Gurrieri and M A Pisanti and I De Maggio and M R Abboud and R Chiesa and C P Burren and A Villa and C Sobacchi and A Picollo},
year = {2021},
date = {2021-03-01},
journal = {J Bone Miner Res},
volume = {36},
number = {3},
pages = {531--545},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Vavassori, V; Mercuri, E; Marcovecchio, G E; Castiello, M C; Schiroli, G; Albano, L; Margulies, C; Buquicchio, F; Fontana, E; Beretta, S; Merelli, I; Cappelleri, A; Rancoita, P M; Lougaris, V; Plebani, A; Kanariou, M; Lankester, A; Ferrua, F; Scanziani, E; Cotta-Ramusino, C; Villa, A; Naldini, L; Genovese, P: Modeling, optimization, and comparable efficacy of Ŧ cell and hematopoietic stem cell gene editing for treating hyper-IgM syndrome. In: EMBO Mol Med, 13 (3), pp. e13545, 2021. @article{pmid33475257,
title = {Modeling, optimization, and comparable efficacy of Ŧ cell and hematopoietic stem cell gene editing for treating hyper-IgM syndrome},
author = {V Vavassori and E Mercuri and G E Marcovecchio and M C Castiello and G Schiroli and L Albano and C Margulies and F Buquicchio and E Fontana and S Beretta and I Merelli and A Cappelleri and P M Rancoita and V Lougaris and A Plebani and M Kanariou and A Lankester and F Ferrua and E Scanziani and C Cotta-Ramusino and A Villa and L Naldini and P Genovese},
year = {2021},
date = {2021-03-01},
journal = {EMBO Mol Med},
volume = {13},
number = {3},
pages = {e13545},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Barbato, A; Iuliano, A; Volpe, M; DÁlterio, R; Brillante, S; Massa, F; Cegli, R De; Carrella, S; Salati, M; Russo, A; Russo, G; Riccardo, S; Cacchiarelli, D; Capone, M; Madonna, G; Ascierto, P A; Franco, B; Indrieri, A; Carotenuto, P: Integrated Genomics Identifies miR-181/ŦFAM Pathway as a Critical Đriver of Đrug Resistance in Melanoma. In: Int J Mol Sci, 22 (4), 2021. @article{pmid33670365,
title = {Integrated Genomics Identifies miR-181/ŦFAM Pathway as a Critical Đriver of Đrug Resistance in Melanoma},
author = {A Barbato and A Iuliano and M Volpe and R DÁlterio and S Brillante and F Massa and R De Cegli and S Carrella and M Salati and A Russo and G Russo and S Riccardo and D Cacchiarelli and M Capone and G Madonna and P A Ascierto and B Franco and A Indrieri and P Carotenuto},
year = {2021},
date = {2021-02-01},
journal = {Int J Mol Sci},
volume = {22},
number = {4},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Ferrando, Maria Laura; Gussak, Alex; Mentink, Saskia; Gutierrez, Marcela Fernandez; Baarlen, Peter; Wells, Jerry Mark: Active human and porcine serum induce competence for genetic transformation in the emerging zoonotic pathogen Streptococcus suis. In: Pathogens, 10 (2), pp. 156, 2021. @article{Ferrando2021-ga,
title = {Active human and porcine serum induce competence for genetic transformation in the emerging zoonotic pathogen Streptococcus suis},
author = {Maria Laura Ferrando and Alex Gussak and Saskia Mentink and Marcela Fernandez Gutierrez and Peter Baarlen and Jerry Mark Wells},
year = {2021},
date = {2021-02-01},
urldate = {2021-02-01},
journal = {Pathogens},
volume = {10},
number = {2},
pages = {156},
publisher = {MDPI AG},
abstract = {The acquisition of novel genetic traits through natural
competence is a strategy used by bacteria in microbe-rich
environments where microbial competition, antibiotics, and host
immune defenses threaten their survival. Here, we show that
virulent strains of Streptococcus suis, an important zoonotic
agent and porcine pathogen, become competent for genetic
transformation with plasmid or linear DNA when cultured in
active porcine and human serum. Competence was not induced in
active fetal bovine serum, which contains less complement
factors and immunoglobulins than adult serum and was strongly
reduced in heat-treated or low-molecular weight fractions of
active porcine serum. Late competence genes, encoding the uptake
machinery for environmental DNA, were upregulated in the active
serum. Competence development was independent of the early
competence regulatory switch involving XIP and ComR, as well as
sigma factor ComX, suggesting the presence of an alternative
stress-induced pathway for regulation of the late competence
genes required for DNA uptake.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The acquisition of novel genetic traits through natural
competence is a strategy used by bacteria in microbe-rich
environments where microbial competition, antibiotics, and host
immune defenses threaten their survival. Here, we show that
virulent strains of Streptococcus suis, an important zoonotic
agent and porcine pathogen, become competent for genetic
transformation with plasmid or linear DNA when cultured in
active porcine and human serum. Competence was not induced in
active fetal bovine serum, which contains less complement
factors and immunoglobulins than adult serum and was strongly
reduced in heat-treated or low-molecular weight fractions of
active porcine serum. Late competence genes, encoding the uptake
machinery for environmental DNA, were upregulated in the active
serum. Competence development was independent of the early
competence regulatory switch involving XIP and ComR, as well as
sigma factor ComX, suggesting the presence of an alternative
stress-induced pathway for regulation of the late competence
genes required for DNA uptake. |
Ängius, Andrea; Scanu, Antonio Mario; Arru, Caterina; Muroni, Maria Rosaria; Rallo, Vincenzo; Deiana, Giulia; Ninniri, Maria Chiara; Carru, Ciriaco; Porcu, Alberto; Pira, Giovanna; Uva, Paolo; Cossu-Rocca, Paolo; Miglio, Maria Rosaria" De: Portrait of cancer stem cells on colorectal cancer: Molecular
biomarkers, signaling pathways and miRNAome. In: Int. J. Mol. Sci., 22 (4), pp. 1603, 2021. @article{Angius2021-bx,
title = {Portrait of cancer stem cells on colorectal cancer: Molecular
biomarkers, signaling pathways and miRNAome},
author = {Andrea Ängius and Antonio Mario Scanu and Caterina Arru and Maria Rosaria Muroni and Vincenzo Rallo and Giulia Deiana and Maria Chiara Ninniri and Ciriaco Carru and Alberto Porcu and Giovanna Pira and Paolo Uva and Paolo Cossu-Rocca and Maria Rosaria" De Miglio},
year = {2021},
date = {2021-02-01},
journal = {Int. J. Mol. Sci.},
volume = {22},
number = {4},
pages = {1603},
publisher = {MDPI AG},
abstract = {Colorectal cancer (CRC) is a leading cause of cancer death
worldwide, and about 20% is metastatic at diagnosis and
untreatable. Increasing evidence suggests that the heterogeneous
nature of CRC is related to colorectal cancer stem cells
(CCSCs), a small cells population with stemness behaviors and
responsible for tumor progression, recurrence, and therapy
resistance. Growing knowledge of stem cells (SCs) biology has
rapidly improved uncovering the molecular mechanisms and
possible crosstalk/feedback loops between signaling pathways
that directly influence intestinal homeostasis and
tumorigenesis. The generation of CCSCs is probably connected to
genetic changes in members of signaling pathways, which control
self-renewal and pluripotency in SCs and then establish function
and phenotype of CCSCs. Particularly, various deregulated
CCSC-related miRNAs have been reported to modulate stemness
features, controlling CCSCs functions such as regulation of cell
cycle genes expression, epithelial-mesenchymal transition,
metastasization, and drug-resistance mechanisms. Primarily,
CCSC-related miRNAs work by regulating mainly signal pathways
known to be involved in CCSCs biology. This review intends to
summarize the epigenetic findings linked to miRNAome in the
maintenance and regulation of CCSCs, including their
relationships with different signaling pathways, which should
help to identify specific diagnostic, prognostic, and predictive
biomarkers for CRC, but also develop innovative CCSCs-targeted
therapies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Colorectal cancer (CRC) is a leading cause of cancer death
worldwide, and about 20% is metastatic at diagnosis and
untreatable. Increasing evidence suggests that the heterogeneous
nature of CRC is related to colorectal cancer stem cells
(CCSCs), a small cells population with stemness behaviors and
responsible for tumor progression, recurrence, and therapy
resistance. Growing knowledge of stem cells (SCs) biology has
rapidly improved uncovering the molecular mechanisms and
possible crosstalk/feedback loops between signaling pathways
that directly influence intestinal homeostasis and
tumorigenesis. The generation of CCSCs is probably connected to
genetic changes in members of signaling pathways, which control
self-renewal and pluripotency in SCs and then establish function
and phenotype of CCSCs. Particularly, various deregulated
CCSC-related miRNAs have been reported to modulate stemness
features, controlling CCSCs functions such as regulation of cell
cycle genes expression, epithelial-mesenchymal transition,
metastasization, and drug-resistance mechanisms. Primarily,
CCSC-related miRNAs work by regulating mainly signal pathways
known to be involved in CCSCs biology. This review intends to
summarize the epigenetic findings linked to miRNAome in the
maintenance and regulation of CCSCs, including their
relationships with different signaling pathways, which should
help to identify specific diagnostic, prognostic, and predictive
biomarkers for CRC, but also develop innovative CCSCs-targeted
therapies. |
Palomba, Grazia; Paliogiannis, Panagiotis; Sini, Maria C; Colombino, Maria; Casula, Milena; Manca, Antonella; Pisano, Marina; Sotgiu, Giovanni; Doneddu, Valentina; Palmieri, Giuseppe; Cossu, Antonio: KIT and PDGFRa mutational patterns in Sardinian patients with gastrointestinal stromal tumors. In: Eur J Cancer Prev, 30 (1), pp. 53–58, 2021, ISSN: 1473-5709. @article{pmid32091431,
title = {KIT and PDGFRa mutational patterns in Sardinian patients with gastrointestinal stromal tumors},
author = {Grazia Palomba and Panagiotis Paliogiannis and Maria C Sini and Maria Colombino and Milena Casula and Antonella Manca and Marina Pisano and Giovanni Sotgiu and Valentina Doneddu and Giuseppe Palmieri and Antonio Cossu},
doi = {10.1097/CEJ.0000000000000581},
issn = {1473-5709},
year = {2021},
date = {2021-01-30},
journal = {Eur J Cancer Prev},
volume = {30},
number = {1},
pages = {53--58},
abstract = {Gastrointestinal stromal tumor (GIST) is the most common mesenchymal malignancy of the gastrointestinal tract. We provide in the present article the molecular characterization of a series of primary GISTs in a cohort of Sardinian patients (Italy), with the aim to describe the patterns of KIT and PDGFRa mutations and the corresponding clinical features. Ninety-nine Sardinian patients with histologically-proven diagnosis of GIST were included in the study. Medical records and pathology reports were used to assess the demographic and clinical features of the patients and the disease at the time of the diagnosis. Formalin-fixed, paraffin-embedded tissue samples were retrieved for each case, and mutation analysis of the KIT and PDGFRa genes was performed. KIT and PDGFRa mutations were detected in 81.8% and 5% of the cases, respectively. The most common KIT mutation was W557_K558del in exon 11, while D842V in exon 18 was the most common PDGFRa genetic alteration; V561D was the only PDGFRa mutation found in exon 12. The global "wild-type" cases, with no mutations in either the KIT or PDGFRa genes, were 13 (13.1%). The mean survival of those patients was approximately 46.9 (±43.9) months. Globally, 86.9% of Sardinian patients with GIST had a KIT or PDGFRa mutation; the former were more frequent in comparison with other Italian cohorts, while PDGFRa mutations were rare. No statistical differences in survival between mutated and wild-type cases, and between KIT and PDGFRa mutated cases were detected in our study.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal malignancy of the gastrointestinal tract. We provide in the present article the molecular characterization of a series of primary GISTs in a cohort of Sardinian patients (Italy), with the aim to describe the patterns of KIT and PDGFRa mutations and the corresponding clinical features. Ninety-nine Sardinian patients with histologically-proven diagnosis of GIST were included in the study. Medical records and pathology reports were used to assess the demographic and clinical features of the patients and the disease at the time of the diagnosis. Formalin-fixed, paraffin-embedded tissue samples were retrieved for each case, and mutation analysis of the KIT and PDGFRa genes was performed. KIT and PDGFRa mutations were detected in 81.8% and 5% of the cases, respectively. The most common KIT mutation was W557_K558del in exon 11, while D842V in exon 18 was the most common PDGFRa genetic alteration; V561D was the only PDGFRa mutation found in exon 12. The global "wild-type" cases, with no mutations in either the KIT or PDGFRa genes, were 13 (13.1%). The mean survival of those patients was approximately 46.9 (±43.9) months. Globally, 86.9% of Sardinian patients with GIST had a KIT or PDGFRa mutation; the former were more frequent in comparison with other Italian cohorts, while PDGFRa mutations were rare. No statistical differences in survival between mutated and wild-type cases, and between KIT and PDGFRa mutated cases were detected in our study. |
Dettori, Maria Antonietta; Fabbri, Davide; Pisano, Marina; Rozzo, Carla; Delogu, Giovanna: Synthesis of Hydroxylated Biphenyls Derivatives Bearing an α,β-Unsaturated Ketone as Lead Structure for the Development of New Drug Candidates Against Malignant Melanoma. In: ChemMedChem, 16 , pp. 1022-1033, 2021. @article{pmid33274847,
title = {Synthesis of Hydroxylated Biphenyls Derivatives Bearing an α,β-Unsaturated Ketone as Lead Structure for the Development of New Drug Candidates Against Malignant Melanoma},
author = {Maria Antonietta Dettori and Davide Fabbri and Marina Pisano and Carla Rozzo and Giovanna Delogu },
url = {https://irgb.cnr.it/wp-content/uploads/2024/05/reprint-1.pdf},
doi = {doi.org/10.1002/cmdc.202000709},
year = {2021},
date = {2021-01-21},
urldate = {2021-01-21},
journal = {ChemMedChem},
volume = {16},
pages = {1022-1033},
abstract = {A small collection of C 2 -symmetry hydroxylated biphenyls derivatives featured with a α,β-unsaturated ketone as lead structure was prepared and the capability of such compounds to act as antiproliferative agents against four human malignant melanoma cell lines was assayed. The prodrug approach was applied in order to improve delivery of compounds into the cell by modulation of the phenolic-OH protective group. The hydroxylated biphenyl structure bearing an α,β-unsaturated ketone and a phenolic- O -prenylated chain would facilitated the delivery of the molecule and interactions with the biological targets. Four compounds showed antiproliferative activity resulting in IC 50 value in the range 1.2 - 2.8 µM..},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
A small collection of C 2 -symmetry hydroxylated biphenyls derivatives featured with a α,β-unsaturated ketone as lead structure was prepared and the capability of such compounds to act as antiproliferative agents against four human malignant melanoma cell lines was assayed. The prodrug approach was applied in order to improve delivery of compounds into the cell by modulation of the phenolic-OH protective group. The hydroxylated biphenyl structure bearing an α,β-unsaturated ketone and a phenolic- O -prenylated chain would facilitated the delivery of the molecule and interactions with the biological targets. Four compounds showed antiproliferative activity resulting in IC 50 value in the range 1.2 - 2.8 µM.. |
Mingoia, M; Caria, C A; Ye, L; Asunis, I; Marongiu, M F; Manunza, L; Sollaino, M C; Wang, J; Cabriolu, A; Kurita, R; Nakamura, Y; Cucca, F; Kan, Y W; Marini, M G; Moi, P: Induction of therapeutic levels of HbF in genome-edited primary β0 39-thalassaemia haematopoietic stem and progenitor cells. In: Br J Haematol, 192 (2), pp. 395–404, 2021. @article{pmid33216968,
title = {Induction of therapeutic levels of HbF in genome-edited primary β0 39-thalassaemia haematopoietic stem and progenitor cells},
author = {M Mingoia and C A Caria and L Ye and I Asunis and M F Marongiu and L Manunza and M C Sollaino and J Wang and A Cabriolu and R Kurita and Y Nakamura and F Cucca and Y W Kan and M G Marini and P Moi},
year = {2021},
date = {2021-01-01},
journal = {Br J Haematol},
volume = {192},
number = {2},
pages = {395--404},
abstract = {Hereditary persistence of fetal haemoglobin (HPFH) is the major modifier of the clinical severity of β-thalassaemia. The homozygous mutation c.-196 C>T in the Aγ-globin (HBG1) promoter, which causes Sardinian δβ0 -thalassaemia, is able to completely rescue the β-major thalassaemia phenotype caused by the β0 39-thalassaemia mutation, ensuring high levels of fetal haemoglobin synthesis during adulthood. Here, we describe a CRISPR/Cas9 genome-editing approach, combined with the non-homologous end joining (NHEJ) pathway repair, aimed at reproducing the effects of this naturally occurring HPFH mutation in both HBG promoters. After selecting the most efficient guide RNA in K562 cells, we edited the HBG promoters in human umbilical cord blood-derived erythroid progenitor 2 cells (HUDEP-2) and in haematopoietic stem and progenitor cells (HSPCs) from β0 -thalassaemia patients to assess the therapeutic potential of HbF induction. Our results indicate that small deletions targeting the -196-promoter region restore high levels of fetal haemoglobin (HbF) synthesis in all cell types tested. In pools of HSPCs derived from homozygous β0 39-thalassaemia patients, a 20% editing determined a parallel 20% increase of HbF compared to unedited pools. These results suggest that editing the region of HBG promoters around the -196 position has the potential to induce therapeutic levels of HbF in patients with most types of β-thalassaemia irrespective of the β-globin gene (HBB) mutations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hereditary persistence of fetal haemoglobin (HPFH) is the major modifier of the clinical severity of β-thalassaemia. The homozygous mutation c.-196 C>T in the Aγ-globin (HBG1) promoter, which causes Sardinian δβ0 -thalassaemia, is able to completely rescue the β-major thalassaemia phenotype caused by the β0 39-thalassaemia mutation, ensuring high levels of fetal haemoglobin synthesis during adulthood. Here, we describe a CRISPR/Cas9 genome-editing approach, combined with the non-homologous end joining (NHEJ) pathway repair, aimed at reproducing the effects of this naturally occurring HPFH mutation in both HBG promoters. After selecting the most efficient guide RNA in K562 cells, we edited the HBG promoters in human umbilical cord blood-derived erythroid progenitor 2 cells (HUDEP-2) and in haematopoietic stem and progenitor cells (HSPCs) from β0 -thalassaemia patients to assess the therapeutic potential of HbF induction. Our results indicate that small deletions targeting the -196-promoter region restore high levels of fetal haemoglobin (HbF) synthesis in all cell types tested. In pools of HSPCs derived from homozygous β0 39-thalassaemia patients, a 20% editing determined a parallel 20% increase of HbF compared to unedited pools. These results suggest that editing the region of HBG promoters around the -196 position has the potential to induce therapeutic levels of HbF in patients with most types of β-thalassaemia irrespective of the β-globin gene (HBB) mutations. |
Brunetta, E; Folci, M; Bottazzi, B; Santis, M De; Gritti, G; Protti, A; Mapelli, S N; Bonovas, S; Piovani, D; Leone, R; My, I; Zanon, V; Spata, G; Bacci, M; Supino, D; Carnevale, S; Sironi, M; Davoudian, S; Peano, C; Landi, F; Marco, F Di; Raimondi, F; Gianatti, A; Angelini, C; Rambaldi, A; Garlanda, C; Ciccarelli, M; Cecconi, M; Mantovani, A: Macrophage expression and prognostic significance of the long pentraxin PŦX3 in COVIĐ-19. In: Nat Immunol, 22 (1), pp. 19–24, 2021. @article{pmid33208929,
title = {Macrophage expression and prognostic significance of the long pentraxin PŦX3 in COVIĐ-19},
author = {E Brunetta and M Folci and B Bottazzi and M De Santis and G Gritti and A Protti and S N Mapelli and S Bonovas and D Piovani and R Leone and I My and V Zanon and G Spata and M Bacci and D Supino and S Carnevale and M Sironi and S Davoudian and C Peano and F Landi and F Di Marco and F Raimondi and A Gianatti and C Angelini and A Rambaldi and C Garlanda and M Ciccarelli and M Cecconi and A Mantovani},
year = {2021},
date = {2021-01-01},
journal = {Nat Immunol},
volume = {22},
number = {1},
pages = {19--24},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Baragetti, A; Severgnini, M; Olmastroni, E; Dioguardi, C C; Mattavelli, E; Angius, A; Rotta, L; Cibella, J; Caredda, G; Consolandi, C; Grigore, L; Pellegatta, F; Giavarini, F; Caruso, D; Norata, G D; Catapano, A L; Peano, C: Gut Microbiota Functional Đysbiosis Relates to Individual Điet in Subclinical Carotid Atherosclerosis. In: Nutrients, 13 (2), 2021. @article{pmid33494335,
title = {Gut Microbiota Functional Đysbiosis Relates to Individual Điet in Subclinical Carotid Atherosclerosis},
author = {A Baragetti and M Severgnini and E Olmastroni and C C Dioguardi and E Mattavelli and A Angius and L Rotta and J Cibella and G Caredda and C Consolandi and L Grigore and F Pellegatta and F Giavarini and D Caruso and G D Norata and A L Catapano and C Peano},
year = {2021},
date = {2021-01-01},
journal = {Nutrients},
volume = {13},
number = {2},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Castiello, M C; Bosticardo, M; Sacchetti, N; Calzoni, E; Fontana, E; Yamazaki, Y; Draghici, E; Corsino, C; Bortolomai, I; Sereni, L; Yu, H H; Uva, P; Palchaudhuri, R; Scadden, D T; Villa, A; Notarangelo, L D: Efficacy and safety of anti-CD45-saporin as conditioning agent for RAG deficiency. In: J Allergy Clin Immunol, 147 (1), pp. 309–320, 2021. @article{pmid32387109,
title = {Efficacy and safety of anti-CD45-saporin as conditioning agent for RAG deficiency},
author = {M C Castiello and M Bosticardo and N Sacchetti and E Calzoni and E Fontana and Y Yamazaki and E Draghici and C Corsino and I Bortolomai and L Sereni and H H Yu and P Uva and R Palchaudhuri and D T Scadden and A Villa and L D Notarangelo},
year = {2021},
date = {2021-01-01},
journal = {J Allergy Clin Immunol},
volume = {147},
number = {1},
pages = {309--320},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Capo, V; Penna, S; Merelli, I; Barcella, M; Scala, S; Basso-Ricci, L; Draghici, E; Palagano, E; Zonari, E; Desantis, G; Uva, P; Cusano, R; Sergi, L Sergi; Crisafulli, L; Moshous, D; Stepensky, P; Drabko, K; Kaya, Z; Unal, E; Gezdirici, A; Menna, G; Serafini, M; Aiuti, A; Locatelli, S L; Carlo-Stella, C; Schulz, A S; Ficara, F; Sobacchi, C; Gentner, B; Villa, A: Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of ŦCIRG1 osteopetrosis. In: Haematologica, 106 (1), pp. 74–86, 2021. @article{pmid31949009,
title = {Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of ŦCIRG1 osteopetrosis},
author = {V Capo and S Penna and I Merelli and M Barcella and S Scala and L Basso-Ricci and E Draghici and E Palagano and E Zonari and G Desantis and P Uva and R Cusano and L Sergi Sergi and L Crisafulli and D Moshous and P Stepensky and K Drabko and Z Kaya and E Unal and A Gezdirici and G Menna and M Serafini and A Aiuti and S L Locatelli and C Carlo-Stella and A S Schulz and F Ficara and C Sobacchi and B Gentner and A Villa},
year = {2021},
date = {2021-01-01},
journal = {Haematologica},
volume = {106},
number = {1},
pages = {74--86},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Mingoia, Maura; Caria, Cristian A; Ye, Lin; Asunis, Isadora; Marongiu, M Franca; Manunza, Laura; Sollaino, M Carla; Wang, Jiaming; Cabriolu, Annalisa; Kurita, Ryo; Nakamura, Yukio; Cucca, Francesco; Kan, Yuet W; Marini, M Giuseppina; Moi, Paolo: Induction of therapeutic levels of HbF in genome-edited
primary $beta$0 39-thalassaemia haematopoietic stem and
progenitor cells. In: Br. J. Haematol., 192 (2), pp. 395–404, 2021. @article{Mingoia2021-hv,
title = {Induction of therapeutic levels of HbF in genome-edited
primary $beta$0 39-thalassaemia haematopoietic stem and
progenitor cells},
author = {Maura Mingoia and Cristian A Caria and Lin Ye and Isadora Asunis and M Franca Marongiu and Laura Manunza and M Carla Sollaino and Jiaming Wang and Annalisa Cabriolu and Ryo Kurita and Yukio Nakamura and Francesco Cucca and Yuet W Kan and M Giuseppina Marini and Paolo Moi},
year = {2021},
date = {2021-01-01},
journal = {Br. J. Haematol.},
volume = {192},
number = {2},
pages = {395--404},
publisher = {Wiley},
abstract = {Hereditary persistence of fetal haemoglobin (HPFH) is the major
modifier of the clinical severity of $beta$-thalassaemia. The
homozygous mutation c.-196 C>T in the A$gamma$-globin (HBG1)
promoter, which causes Sardinian $delta$$beta$0 -thalassaemia,
is able to completely rescue the $beta$-major thalassaemia
phenotype caused by the $beta$0 39-thalassaemia mutation,
ensuring high levels of fetal haemoglobin synthesis during
adulthood. Here, we describe a CRISPR/Cas9 genome-editing
approach, combined with the non-homologous end joining (NHEJ)
pathway repair, aimed at reproducing the effects of this
naturally occurring HPFH mutation in both HBG promoters. After
selecting the most efficient guide RNA in K562 cells, we edited
the HBG promoters in human umbilical cord blood-derived
erythroid progenitor 2 cells (HUDEP-2) and in haematopoietic
stem and progenitor cells (HSPCs) from $beta$0 -thalassaemia
patients to assess the therapeutic potential of HbF induction.
Our results indicate that small deletions targeting the
-196-promoter region restore high levels of fetal haemoglobin
(HbF) synthesis in all cell types tested. In pools of HSPCs
derived from homozygous $beta$0 39-thalassaemia patients, a
20% editing determined a parallel 20% increase of HbF compared
to unedited pools. These results suggest that editing the region
of HBG promoters around the -196 position has the potential to
induce therapeutic levels of HbF in patients with most types of
$beta$-thalassaemia irrespective of the $beta$-globin gene
(HBB) mutations.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hereditary persistence of fetal haemoglobin (HPFH) is the major
modifier of the clinical severity of $beta$-thalassaemia. The
homozygous mutation c.-196 C>T in the A$gamma$-globin (HBG1)
promoter, which causes Sardinian $delta$$beta$0 -thalassaemia,
is able to completely rescue the $beta$-major thalassaemia
phenotype caused by the $beta$0 39-thalassaemia mutation,
ensuring high levels of fetal haemoglobin synthesis during
adulthood. Here, we describe a CRISPR/Cas9 genome-editing
approach, combined with the non-homologous end joining (NHEJ)
pathway repair, aimed at reproducing the effects of this
naturally occurring HPFH mutation in both HBG promoters. After
selecting the most efficient guide RNA in K562 cells, we edited
the HBG promoters in human umbilical cord blood-derived
erythroid progenitor 2 cells (HUDEP-2) and in haematopoietic
stem and progenitor cells (HSPCs) from $beta$0 -thalassaemia
patients to assess the therapeutic potential of HbF induction.
Our results indicate that small deletions targeting the
-196-promoter region restore high levels of fetal haemoglobin
(HbF) synthesis in all cell types tested. In pools of HSPCs
derived from homozygous $beta$0 39-thalassaemia patients, a
20% editing determined a parallel 20% increase of HbF compared
to unedited pools. These results suggest that editing the region
of HBG promoters around the -196 position has the potential to
induce therapeutic levels of HbF in patients with most types of
$beta$-thalassaemia irrespective of the $beta$-globin gene
(HBB) mutations. |
2020
|
Zanetti, D.; Gustafsson, S.; Assimes, T. L.; Ingelsson, E.: Comprehensive Investigation of Circulating Biomarkers and Ŧheir Causal Role in Atherosclerosis-Related Risk Factors and Clinical Events. In: Circ Genom Precis Med, 13 (6), pp. e002996, 2020. @article{pmid33125266,
title = {Comprehensive Investigation of Circulating Biomarkers and Ŧheir Causal Role in Atherosclerosis-Related Risk Factors and Clinical Events},
author = {D. Zanetti and S. Gustafsson and T. L. Assimes and E. Ingelsson},
year = {2020},
date = {2020-12-01},
journal = {Circ Genom Precis Med},
volume = {13},
number = {6},
pages = {e002996},
abstract = {Circulating biomarkers have been previously associated with atherosclerosis-related risk factors, but the nature of these associations is incompletely understood. 933 participants of the UK Biobank. ). Our results suggest that it is unlikely that CRP (C-reactive protein) and vitamin D play causal roles of any meaningful magnitude in development of cardiometabolic disease. We confirmed and extended known associations and reported several novel causal associations providing important insights about the cause of these diseases, which can help accelerate new prevention strategies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Circulating biomarkers have been previously associated with atherosclerosis-related risk factors, but the nature of these associations is incompletely understood. 933 participants of the UK Biobank. ). Our results suggest that it is unlikely that CRP (C-reactive protein) and vitamin D play causal roles of any meaningful magnitude in development of cardiometabolic disease. We confirmed and extended known associations and reported several novel causal associations providing important insights about the cause of these diseases, which can help accelerate new prevention strategies. |
Busonero, F.; Steri, M.; Orrù, V.; Sole, G.; Olla, S.; Marongiu, M.; Maschio, A.; Sidore, C.; Lai, S.; Mulas, A.; Zoledziewska, M.; Floris, M.; Pala, M.; Forabosco, P.; Asunis, I.; Pitzalis, M.; Deidda, F.; Masala, M.; Caria, C. A.; Barella, S.; Abecasis, G. R.; Schlessinger, D.; Sanna, S.; Fiorillo, E.; Cucca, F.: A Sardinian founder mutation in glycoprotein Ib platelet subunit beta(GP1BB) that impacts thrombocytopenia. In: Br J Haematol, 2020. @article{pmid33216977,
title = {A Sardinian founder mutation in glycoprotein Ib platelet subunit beta(GP1BB) that impacts thrombocytopenia},
author = { F. Busonero and M. Steri and V. Orrù and G. Sole and S. Olla and M. Marongiu and A. Maschio and C. Sidore and S. Lai and A. Mulas and M. Zoledziewska and M. Floris and M. Pala and P. Forabosco and I. Asunis and M. Pitzalis and F. Deidda and M. Masala and C. A. Caria and S. Barella and G. R. Abecasis and D. Schlessinger and S. Sanna and E. Fiorillo and F. Cucca},
year = {2020},
date = {2020-11-01},
journal = {Br J Haematol},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
: Modulatory Role of microRNAs in Triple Negative Breast Cancer with Basal-Like Phenotype. In: Cancers (Basel), 12 (11), 2020. @article{pmid33171872,
title = {Modulatory Role of microRNAs in Triple Negative Breast Cancer with Basal-Like Phenotype},
author = { },
year = {2020},
date = {2020-11-01},
journal = {Cancers (Basel)},
volume = {12},
number = {11},
abstract = {Development of new research, classification, and therapeutic options are urgently required due to the fact that TNBC is a heterogeneous malignancy. The expression of high molecular weight cytokeratins identifies a biologically and clinically distinct subgroup of TNBCs with a basal-like phenotype, representing about 75% of TNBCs, while the remaining 25% includes all other intrinsic subtypes. The triple negative phenotype in basal-like breast cancer (BLBC) makes it unresponsive to endocrine therapy, i.e., tamoxifen, aromatase inhibitors, and/or anti-HER2-targeted therapies; for this reason, only chemotherapy can be considered an approach available for systemic treatment even if it shows poor prognosis. Therefore, treatment for these subgroups of patients is a strong challenge for oncologists due to disease heterogeneity and the absence of unambiguous molecular targets. Dysregulation of the cellular miRNAome has been related to huge cellular process deregulations underlying human malignancy. Consequently, epigenetics is a field of great promise in cancer research. Increasing evidence suggests that specific miRNA clusters/signatures might be of clinical utility in TNBCs with basal-like phenotype. The epigenetic mechanisms behind tumorigenesis enable progress in the treatment, diagnosis, and prevention of cancer. This review intends to summarize the epigenetic findings related to miRNAome in TNBCs with basal-like phenotype.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Development of new research, classification, and therapeutic options are urgently required due to the fact that TNBC is a heterogeneous malignancy. The expression of high molecular weight cytokeratins identifies a biologically and clinically distinct subgroup of TNBCs with a basal-like phenotype, representing about 75% of TNBCs, while the remaining 25% includes all other intrinsic subtypes. The triple negative phenotype in basal-like breast cancer (BLBC) makes it unresponsive to endocrine therapy, i.e., tamoxifen, aromatase inhibitors, and/or anti-HER2-targeted therapies; for this reason, only chemotherapy can be considered an approach available for systemic treatment even if it shows poor prognosis. Therefore, treatment for these subgroups of patients is a strong challenge for oncologists due to disease heterogeneity and the absence of unambiguous molecular targets. Dysregulation of the cellular miRNAome has been related to huge cellular process deregulations underlying human malignancy. Consequently, epigenetics is a field of great promise in cancer research. Increasing evidence suggests that specific miRNA clusters/signatures might be of clinical utility in TNBCs with basal-like phenotype. The epigenetic mechanisms behind tumorigenesis enable progress in the treatment, diagnosis, and prevention of cancer. This review intends to summarize the epigenetic findings related to miRNAome in TNBCs with basal-like phenotype. |
Donadon, M; Torzilli, G; Cortese, N; Soldani, C; Tommaso, L Di; Franceschini, B; Carriero, R; Barbagallo, M; Rigamonti, A; Anselmo, A; Colombo, F S; Maggi, G; Lleo, A; Cibella, J; Peano, C; Kunderfranco, P; Roncalli, M; Mantovani, A; Marchesi, F: Macrophage morphology correlates with single-cell diversity and prognosis in colorectal liver metastasis. In: J Exp Med, 217 (11), 2020. @article{pmid32785653,
title = {Macrophage morphology correlates with single-cell diversity and prognosis in colorectal liver metastasis},
author = {M Donadon and G Torzilli and N Cortese and C Soldani and L Di Tommaso and B Franceschini and R Carriero and M Barbagallo and A Rigamonti and A Anselmo and F S Colombo and G Maggi and A Lleo and J Cibella and C Peano and P Kunderfranco and M Roncalli and A Mantovani and F Marchesi},
year = {2020},
date = {2020-11-01},
journal = {J Exp Med},
volume = {217},
number = {11},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Rigoni, R; Fontana, E; Dobbs, K; Marrella, V; Taverniti, V; Maina, V; Facoetti, A; DÁmico, G; Al-Herz, W; Cruz-Munoz, M E; Schuetz, C; Gennery, A R; Garabedian, E K; Giliani, S; Draper, D; Dbaibo, G; Geha, R S; Meyts, I; Tousseyn, T; Neven, B; Moshous, D; Fischer, A; Schulz, A; Finocchi, A; Kuhns, D B; Fink, D L; Lionakis, M S; Swamydas, M; Guglielmetti, S; Alejo, J; Myles, I A; Pittaluga, S; Notarangelo, L D; Villa, A; Cassani, B: Cutaneous barrier leakage and gut inflammation drive skin disease in Omenn syndrome. In: J Allergy Clin Immunol, 146 (5), pp. 1165–1179, 2020. @article{pmid32311393,
title = {Cutaneous barrier leakage and gut inflammation drive skin disease in Omenn syndrome},
author = {R Rigoni and E Fontana and K Dobbs and V Marrella and V Taverniti and V Maina and A Facoetti and G DÁmico and W Al-Herz and M E Cruz-Munoz and C Schuetz and A R Gennery and E K Garabedian and S Giliani and D Draper and G Dbaibo and R S Geha and I Meyts and T Tousseyn and B Neven and D Moshous and A Fischer and A Schulz and A Finocchi and D B Kuhns and D L Fink and M S Lionakis and M Swamydas and S Guglielmetti and J Alejo and I A Myles and S Pittaluga and L D Notarangelo and A Villa and B Cassani},
year = {2020},
date = {2020-11-01},
journal = {J Allergy Clin Immunol},
volume = {146},
number = {5},
pages = {1165--1179},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Örr`u, Valeria; Steri, Maristella; Sidore, Carlo; Marongiu, Michele; Serra, Valentina; Olla, Stefania; Sole, Gabriella; Lai, Sandra; Dei, Mariano; Mulas, Antonella; Virdis, Francesca; Piras, Maria Grazia; Lobina, Monia; Marongiu, Mara; Pitzalis, Maristella; Deidda, Francesca; Loizedda, Annalisa; Onano, Stefano; Zoledziewska, Magdalena; Sawcer, Stephen; Devoto, Marcella; Gorospe, Myriam; calo R Abecasis, Gonc; Floris, Matteo; Pala, Mauro; Schlessinger, David; Fiorillo, Edoardo; Cucca, Francesco": Complex genetic signatures in immune cells underlie autoimmunity
and inform therapy. In: Nat. Genet., 52 (10), pp. 1036–1045, 2020. @article{Orru2020-xo,
title = {Complex genetic signatures in immune cells underlie autoimmunity
and inform therapy},
author = {Valeria Örr`u and Maristella Steri and Carlo Sidore and Michele Marongiu and Valentina Serra and Stefania Olla and Gabriella Sole and Sandra Lai and Mariano Dei and Antonella Mulas and Francesca Virdis and Maria Grazia Piras and Monia Lobina and Mara Marongiu and Maristella Pitzalis and Francesca Deidda and Annalisa Loizedda and Stefano Onano and Magdalena Zoledziewska and Stephen Sawcer and Marcella Devoto and Myriam Gorospe and Gonc calo R Abecasis and Matteo Floris and Mauro Pala and David Schlessinger and Edoardo Fiorillo and Francesco" Cucca},
year = {2020},
date = {2020-10-01},
journal = {Nat. Genet.},
volume = {52},
number = {10},
pages = {1036--1045},
publisher = {Springer Science and Business Media LLC},
abstract = {We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases. |
Örr`u, Valeria; Steri, Maristella; Sidore, Carlo; Marongiu, Michele; Serra, Valentina; Olla, Stefania; Sole, Gabriella; Lai, Sandra; Dei, Mariano; Mulas, Antonella; Virdis, Francesca; Piras, Maria Grazia; Lobina, Monia; Marongiu, Mara; Pitzalis, Maristella; Deidda, Francesca; Loizedda, Annalisa; Onano, Stefano; Zoledziewska, Magdalena; Sawcer, Stephen; Devoto, Marcella; Gorospe, Myriam; calo R Abecasis, Gonc; Floris, Matteo; Pala, Mauro; Schlessinger, David; Fiorillo, Edoardo; Cucca, Francesco": Complex genetic signatures in immune cells underlie autoimmunity
and inform therapy. In: Nat. Genet., 52 (10), pp. 1036–1045, 2020. @article{Orru2020-ku,
title = {Complex genetic signatures in immune cells underlie autoimmunity
and inform therapy},
author = {Valeria Örr`u and Maristella Steri and Carlo Sidore and Michele Marongiu and Valentina Serra and Stefania Olla and Gabriella Sole and Sandra Lai and Mariano Dei and Antonella Mulas and Francesca Virdis and Maria Grazia Piras and Monia Lobina and Mara Marongiu and Maristella Pitzalis and Francesca Deidda and Annalisa Loizedda and Stefano Onano and Magdalena Zoledziewska and Stephen Sawcer and Marcella Devoto and Myriam Gorospe and Gonc calo R Abecasis and Matteo Floris and Mauro Pala and David Schlessinger and Edoardo Fiorillo and Francesco" Cucca},
year = {2020},
date = {2020-10-01},
journal = {Nat. Genet.},
volume = {52},
number = {10},
pages = {1036--1045},
publisher = {Springer Science and Business Media LLC},
abstract = {We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases. |
Örr`u, Valeria; Steri, Maristella; Sidore, Carlo; Marongiu, Michele; Serra, Valentina; Olla, Stefania; Sole, Gabriella; Lai, Sandra; Dei, Mariano; Mulas, Antonella; Virdis, Francesca; Piras, Maria Grazia; Lobina, Monia; Marongiu, Mara; Pitzalis, Maristella; Deidda, Francesca; Loizedda, Annalisa; Onano, Stefano; Zoledziewska, Magdalena; Sawcer, Stephen; Devoto, Marcella; Gorospe, Myriam; calo R Abecasis, Gonc; Floris, Matteo; Pala, Mauro; Schlessinger, David; Fiorillo, Edoardo; Cucca, Francesco": Complex genetic signatures in immune cells underlie autoimmunity
and inform therapy. In: Nat. Genet., 52 (10), pp. 1036–1045, 2020. @article{Orru2020-mz,
title = {Complex genetic signatures in immune cells underlie autoimmunity
and inform therapy},
author = {Valeria Örr`u and Maristella Steri and Carlo Sidore and Michele Marongiu and Valentina Serra and Stefania Olla and Gabriella Sole and Sandra Lai and Mariano Dei and Antonella Mulas and Francesca Virdis and Maria Grazia Piras and Monia Lobina and Mara Marongiu and Maristella Pitzalis and Francesca Deidda and Annalisa Loizedda and Stefano Onano and Magdalena Zoledziewska and Stephen Sawcer and Marcella Devoto and Myriam Gorospe and Gonc calo R Abecasis and Matteo Floris and Mauro Pala and David Schlessinger and Edoardo Fiorillo and Francesco" Cucca},
year = {2020},
date = {2020-10-01},
journal = {Nat. Genet.},
volume = {52},
number = {10},
pages = {1036--1045},
publisher = {Springer Science and Business Media LLC},
abstract = {We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases. |
Örr`u, Valeria; Steri, Maristella; Sidore, Carlo; Marongiu, Michele; Serra, Valentina; Olla, Stefania; Sole, Gabriella; Lai, Sandra; Dei, Mariano; Mulas, Antonella; Virdis, Francesca; Piras, Maria Grazia; Lobina, Monia; Marongiu, Mara; Pitzalis, Maristella; Deidda, Francesca; Loizedda, Annalisa; Onano, Stefano; Zoledziewska, Magdalena; Sawcer, Stephen; Devoto, Marcella; Gorospe, Myriam; calo R Abecasis, Gonc; Floris, Matteo; Pala, Mauro; Schlessinger, David; Fiorillo, Edoardo; Cucca, Francesco": Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. In: Nat. Genet., 52 (10), pp. 1036–1045, 2020. @article{Orru2020-va,
title = {Complex genetic signatures in immune cells underlie autoimmunity and inform therapy},
author = {Valeria Örr`u and Maristella Steri and Carlo Sidore and Michele Marongiu and Valentina Serra and Stefania Olla and Gabriella Sole and Sandra Lai and Mariano Dei and Antonella Mulas and Francesca Virdis and Maria Grazia Piras and Monia Lobina and Mara Marongiu and Maristella Pitzalis and Francesca Deidda and Annalisa Loizedda and Stefano Onano and Magdalena Zoledziewska and Stephen Sawcer and Marcella Devoto and Myriam Gorospe and Gonc calo R Abecasis and Matteo Floris and Mauro Pala and David Schlessinger and Edoardo Fiorillo and Francesco" Cucca},
url = {https://www.nature.com/articles/s41588-020-0684-4},
year = {2020},
date = {2020-10-01},
urldate = {2020-10-01},
journal = {Nat. Genet.},
volume = {52},
number = {10},
pages = {1036--1045},
publisher = {Springer Science and Business Media LLC},
abstract = {We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases. |
Örr`u, Valeria; Steri, Maristella; Sidore, Carlo; Marongiu, Michele; Serra, Valentina; Olla, Stefania; Sole, Gabriella; Lai, Sandra; Dei, Mariano; Mulas, Antonella; Virdis, Francesca; Piras, Maria Grazia; Lobina, Monia; Marongiu, Mara; Pitzalis, Maristella; Deidda, Francesca; Loizedda, Annalisa; Onano, Stefano; Zoledziewska, Magdalena; Sawcer, Stephen; Devoto, Marcella; Gorospe, Myriam; calo R Abecasis, Gonc; Floris, Matteo; Pala, Mauro; Schlessinger, David; Fiorillo, Edoardo; Cucca, Francesco": Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. In: Nat. Genet., 52 (10), pp. 1036–1045, 2020. @article{Orru2020-vab,
title = {Complex genetic signatures in immune cells underlie autoimmunity and inform therapy},
author = {Valeria Örr`u and Maristella Steri and Carlo Sidore and Michele Marongiu and Valentina Serra and Stefania Olla and Gabriella Sole and Sandra Lai and Mariano Dei and Antonella Mulas and Francesca Virdis and Maria Grazia Piras and Monia Lobina and Mara Marongiu and Maristella Pitzalis and Francesca Deidda and Annalisa Loizedda and Stefano Onano and Magdalena Zoledziewska and Stephen Sawcer and Marcella Devoto and Myriam Gorospe and Gonc calo R Abecasis and Matteo Floris and Mauro Pala and David Schlessinger and Edoardo Fiorillo and Francesco" Cucca},
doi = {10.1038/s41588-020-0684-4},
year = {2020},
date = {2020-10-01},
urldate = {2020-10-01},
journal = {Nat. Genet.},
volume = {52},
number = {10},
pages = {1036--1045},
publisher = {Springer Science and Business Media LLC},
abstract = {We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases. |
Örr`u, Valeria; Steri, Maristella; Sidore, Carlo; Marongiu, Michele; Serra, Valentina; Olla, Stefania; Sole, Gabriella; Lai, Sandra; Dei, Mariano; Mulas, Antonella; Virdis, Francesca; Piras, Maria Grazia; Lobina, Monia; Marongiu, Mara; Pitzalis, Maristella; Deidda, Francesca; Loizedda, Annalisa; Onano, Stefano; Zoledziewska, Magdalena; Sawcer, Stephen; Devoto, Marcella; Gorospe, Myriam; calo R Abecasis, Gonc; Floris, Matteo; Pala, Mauro; Schlessinger, David; Fiorillo, Edoardo; Cucca, Francesco": Complex genetic signatures in immune cells underlie autoimmunity
and inform therapy. In: Nat. Genet., 52 (10), pp. 1036–1045, 2020. @article{Orru2020-vac,
title = {Complex genetic signatures in immune cells underlie autoimmunity
and inform therapy},
author = {Valeria Örr`u and Maristella Steri and Carlo Sidore and Michele Marongiu and Valentina Serra and Stefania Olla and Gabriella Sole and Sandra Lai and Mariano Dei and Antonella Mulas and Francesca Virdis and Maria Grazia Piras and Monia Lobina and Mara Marongiu and Maristella Pitzalis and Francesca Deidda and Annalisa Loizedda and Stefano Onano and Magdalena Zoledziewska and Stephen Sawcer and Marcella Devoto and Myriam Gorospe and Gonc calo R Abecasis and Matteo Floris and Mauro Pala and David Schlessinger and Edoardo Fiorillo and Francesco" Cucca},
year = {2020},
date = {2020-10-01},
journal = {Nat. Genet.},
volume = {52},
number = {10},
pages = {1036--1045},
publisher = {Springer Science and Business Media LLC},
abstract = {We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases. |
Örr`u, Valeria; Steri, Maristella; Sidore, Carlo; Marongiu, Michele; Serra, Valentina; Olla, Stefania; Sole, Gabriella; Lai, Sandra; Dei, Mariano; Mulas, Antonella; Virdis, Francesca; Piras, Maria Grazia; Lobina, Monia; Marongiu, Mara; Pitzalis, Maristella; Deidda, Francesca; Loizedda, Annalisa; Onano, Stefano; Zoledziewska, Magdalena; Sawcer, Stephen; Devoto, Marcella; Gorospe, Myriam; calo R Abecasis, Gonc; Floris, Matteo; Pala, Mauro; Schlessinger, David; Fiorillo, Edoardo; Cucca, Francesco": Complex genetic signatures in immune cells underlie autoimmunity
and inform therapy. In: Nat. Genet., 52 (10), pp. 1036–1045, 2020. @article{Orru2020-vad,
title = {Complex genetic signatures in immune cells underlie autoimmunity
and inform therapy},
author = {Valeria Örr`u and Maristella Steri and Carlo Sidore and Michele Marongiu and Valentina Serra and Stefania Olla and Gabriella Sole and Sandra Lai and Mariano Dei and Antonella Mulas and Francesca Virdis and Maria Grazia Piras and Monia Lobina and Mara Marongiu and Maristella Pitzalis and Francesca Deidda and Annalisa Loizedda and Stefano Onano and Magdalena Zoledziewska and Stephen Sawcer and Marcella Devoto and Myriam Gorospe and Gonc calo R Abecasis and Matteo Floris and Mauro Pala and David Schlessinger and Edoardo Fiorillo and Francesco" Cucca},
year = {2020},
date = {2020-10-01},
journal = {Nat. Genet.},
volume = {52},
number = {10},
pages = {1036--1045},
publisher = {Springer Science and Business Media LLC},
abstract = {We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases. |
Örr`u, Valeria; Steri, Maristella; Sidore, Carlo; Marongiu, Michele; Serra, Valentina; Olla, Stefania; Sole, Gabriella; Lai, Sandra; Dei, Mariano; Mulas, Antonella; Virdis, Francesca; Piras, Maria Grazia; Lobina, Monia; Marongiu, Mara; Pitzalis, Maristella; Deidda, Francesca; Loizedda, Annalisa; Onano, Stefano; Zoledziewska, Magdalena; Sawcer, Stephen; Devoto, Marcella; Gorospe, Myriam; calo R Abecasis, Gonc; Floris, Matteo; Pala, Mauro; Schlessinger, David; Fiorillo, Edoardo; Cucca, Francesco": Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. In: Nat. Genet., 52 (10), pp. 1036–1045, 2020. @article{Orru2020-ce,
title = {Complex genetic signatures in immune cells underlie autoimmunity and inform therapy},
author = {Valeria Örr`u and Maristella Steri and Carlo Sidore and Michele Marongiu and Valentina Serra and Stefania Olla and Gabriella Sole and Sandra Lai and Mariano Dei and Antonella Mulas and Francesca Virdis and Maria Grazia Piras and Monia Lobina and Mara Marongiu and Maristella Pitzalis and Francesca Deidda and Annalisa Loizedda and Stefano Onano and Magdalena Zoledziewska and Stephen Sawcer and Marcella Devoto and Myriam Gorospe and Gonc calo R Abecasis and Matteo Floris and Mauro Pala and David Schlessinger and Edoardo Fiorillo and Francesco" Cucca},
doi = {10.1038/s41588-020-0684-4},
year = {2020},
date = {2020-10-01},
urldate = {2020-10-01},
journal = {Nat. Genet.},
volume = {52},
number = {10},
pages = {1036--1045},
publisher = {Springer Science and Business Media LLC},
abstract = {We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases. |
Örr`u, Valeria; Steri, Maristella; Sidore, Carlo; Marongiu, Michele; Serra, Valentina; Olla, Stefania; Sole, Gabriella; Lai, Sandra; Dei, Mariano; Mulas, Antonella; Virdis, Francesca; Piras, Maria Grazia; Lobina, Monia; Marongiu, Mara; Pitzalis, Maristella; Deidda, Francesca; Loizedda, Annalisa; Onano, Stefano; Zoledziewska, Magdalena; Sawcer, Stephen; Devoto, Marcella; Gorospe, Myriam; calo R Abecasis, Gonc; Floris, Matteo; Pala, Mauro; Schlessinger, David; Fiorillo, Edoardo; Cucca, Francesco": Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. In: Nat. Genet., 52 (10), pp. 1036–1045, 2020. @article{Orru2020-uk,
title = {Complex genetic signatures in immune cells underlie autoimmunity and inform therapy},
author = {Valeria Örr`u and Maristella Steri and Carlo Sidore and Michele Marongiu and Valentina Serra and Stefania Olla and Gabriella Sole and Sandra Lai and Mariano Dei and Antonella Mulas and Francesca Virdis and Maria Grazia Piras and Monia Lobina and Mara Marongiu and Maristella Pitzalis and Francesca Deidda and Annalisa Loizedda and Stefano Onano and Magdalena Zoledziewska and Stephen Sawcer and Marcella Devoto and Myriam Gorospe and Gonc calo R Abecasis and Matteo Floris and Mauro Pala and David Schlessinger and Edoardo Fiorillo and Francesco" Cucca},
doi = {10.1038/s41588-020-0684-4},
year = {2020},
date = {2020-10-01},
urldate = {2020-10-01},
journal = {Nat. Genet.},
volume = {52},
number = {10},
pages = {1036--1045},
publisher = {Springer Science and Business Media LLC},
abstract = {We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
We report on the influence of ~22 million variants on 731 immune
cell traits in a cohort of 3,757 Sardinians. We detected 122
significant (P < 1.28 $times$ 10-11) independent association
signals for 459 cell traits at 70 loci (53 of them novel)
identifying several molecules and mechanisms involved in cell
regulation. Furthermore, 53 signals at 36 loci overlapped with
previously reported disease-associated signals, predominantly
for autoimmune disorders, highlighting intermediate phenotypes
in pathogenesis. Collectively, our findings illustrate complex
genetic regulation of immune cells with highly selective effects
on autoimmune disease risk at the cell-subtype level. These
results identify drug-targetable pathways informing the design
of more specific treatments for autoimmune diseases. |
Marcozzi, C; Frattini, A; Borgese, M; Rossi, F; Barone, L; Solari, E; Valli, R; Gornati, R: Paracrine effect of human adipose-derived stem cells on lymphatic endothelial cells. In: Regen Med, 15 (9), pp. 2085–2098, 2020. @article{pmid33201769,
title = {Paracrine effect of human adipose-derived stem cells on lymphatic endothelial cells},
author = {C Marcozzi and A Frattini and M Borgese and F Rossi and L Barone and E Solari and R Valli and R Gornati},
year = {2020},
date = {2020-09-01},
journal = {Regen Med},
volume = {15},
number = {9},
pages = {2085--2098},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Gambardella, G; Staiano, L; Moretti, M N; Cegli, R De; Fagnocchi, L; Tullio, G Di; Polletti, S; Braccia, C; Armirotti, A; Zippo, A; Ballabio, A; Matteis, M A De; di Bernardo, D: GAĐĐ34 is a modulator of autophagy during starvation. In: Sci Adv, 6 (39), 2020. @article{pmid32978159,
title = {GAĐĐ34 is a modulator of autophagy during starvation},
author = {G Gambardella and L Staiano and M N Moretti and R De Cegli and L Fagnocchi and G Di Tullio and S Polletti and C Braccia and A Armirotti and A Zippo and A Ballabio and M A De Matteis and D di Bernardo},
year = {2020},
date = {2020-09-01},
journal = {Sci Adv},
volume = {6},
number = {39},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Colombino, M.; Rozzo, C.; Paliogiannis, P.; Casula, M.; Manca, A.; Doneddu, V.; Fedeli, M. A.; Sini, M. C.; Palomba, G.; Pisano, M.; Ascierto, P. A.; Caracò, C.; Lissia, A.; Cossu, A.; Palmieri, G.: Comparison of BRAF Mutation Screening Strategies in a Large Real-Life Series of Advanced Melanoma Patients. In: J Clin Med, 9 (8), 2020. @article{pmid32751423,
title = {Comparison of BRAF Mutation Screening Strategies in a Large Real-Life Series of Advanced Melanoma Patients},
author = {Colombino, M. and Rozzo, C. and Paliogiannis, P. and Casula, M. and Manca, A. and Doneddu, V. and Fedeli, M. A. and Sini, M. C. and Palomba, G. and Pisano, M. and Ascierto, P. A. and Caracò, C. and Lissia, A. and Cossu, A. and Palmieri, G.},
year = {2020},
date = {2020-07-01},
urldate = {2020-07-01},
journal = {J Clin Med},
volume = {9},
number = {8},
abstract = {Malignant melanoma (MM) is one of the deadliest skin cancers. BRAF mutation status plays a predominant role in the management of MM patients. The aim of this study was to compare BRAF mutational testing performed by conventional nucleotide sequencing approaches with either real-time polymerase chain reaction (rtPCR) or next-generation sequencing (NGS) assays in a real-life, hospital-based series of advanced MM patients. Consecutive patients with AJCC (American Joint Committee on Cancer) stage IIIC and IV MM from Sardinia, Italy, who were referred for molecular testing, were enrolled into the study. Initial screening was performed to assess the mutational status of the BRAF and NRAS genes, using the conventional methodologies recognized by the nationwide guidelines, at the time of the molecular classification, required by clinicians: at the beginning, Sanger-based sequencing (SS) and, after, pyrosequencing. The present study was then focused on BRAF mutation detecting approaches only. BRAF wild-type cases with available tissue and adequate DNA were further tested with rtPCR (Idyllaâ„¢) and NGS assays. Globally, 319 patients were included in the study; pathogenic BRAF mutations were found in 144 (45.1%) cases examined with initial screening. The rtPCR detected 11 (16.2%) and 3 (4.8%) additional BRAF mutations after SS and pyrosequencing, respectively. NGS detected one additional BRAF-mutated case (2.1%) among 48 wild-type cases previously tested with pyrosequencing and rtPCR. Our study evidenced that rtPCR and NGS were able to detect additional BRAF mutant cases in comparison with conventional sequencing methods; therefore, we argue for the preferential utilization of the aforementioned assays (NGS and rtPCR) in clinical practice, to eradicate false-negative cases and improve the accuracy of BRAF detection.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Malignant melanoma (MM) is one of the deadliest skin cancers. BRAF mutation status plays a predominant role in the management of MM patients. The aim of this study was to compare BRAF mutational testing performed by conventional nucleotide sequencing approaches with either real-time polymerase chain reaction (rtPCR) or next-generation sequencing (NGS) assays in a real-life, hospital-based series of advanced MM patients. Consecutive patients with AJCC (American Joint Committee on Cancer) stage IIIC and IV MM from Sardinia, Italy, who were referred for molecular testing, were enrolled into the study. Initial screening was performed to assess the mutational status of the BRAF and NRAS genes, using the conventional methodologies recognized by the nationwide guidelines, at the time of the molecular classification, required by clinicians: at the beginning, Sanger-based sequencing (SS) and, after, pyrosequencing. The present study was then focused on BRAF mutation detecting approaches only. BRAF wild-type cases with available tissue and adequate DNA were further tested with rtPCR (Idyllaâ„¢) and NGS assays. Globally, 319 patients were included in the study; pathogenic BRAF mutations were found in 144 (45.1%) cases examined with initial screening. The rtPCR detected 11 (16.2%) and 3 (4.8%) additional BRAF mutations after SS and pyrosequencing, respectively. NGS detected one additional BRAF-mutated case (2.1%) among 48 wild-type cases previously tested with pyrosequencing and rtPCR. Our study evidenced that rtPCR and NGS were able to detect additional BRAF mutant cases in comparison with conventional sequencing methods; therefore, we argue for the preferential utilization of the aforementioned assays (NGS and rtPCR) in clinical practice, to eradicate false-negative cases and improve the accuracy of BRAF detection. |
