Paolo Vezzoni | Consiglio Nazionale delle Ricerche (CNR) (original) (raw)

Papers by Paolo Vezzoni

Research paper thumbnail of Chromosome Transplantation: Opportunities and Limitations

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Aspectos científicos y éticos del Proyecto Genoma Humano en Italia

Research paper thumbnail of Equivoci e illusioni su identitŕ e modernizzazione

Sociologia e ricerca sociale, Oct 1, 2012

The theme of identity as a source of representations of self and social relations is at the cente... more The theme of identity as a source of representations of self and social relations is at the center of the contemporary sociological debate on dilemmas of modernization and has often been considered as the analytical framework within which such unresolved issues could be caught in their most emblematic profiling. Some of these controversial issues will be taken into account in the present essay through a comparison between the social sciences and the biomolecular sciences perspectives, both increasingly involved in the clarification of the most common misconceptions regarding the immutability of this set of signs and its progressive dissolution.

Research paper thumbnail of Adenocarcinoma of the Large Intestine in Young Adults

Tumori Journal, Nov 1, 1977

Twenty-eight cases of adenocarcinoma of the large intestine in patients under 30 years of age, ad... more Twenty-eight cases of adenocarcinoma of the large intestine in patients under 30 years of age, admitted to the National Cancer Institute of Milan from 1955 to 1975, are reported. Fourteen patients underwent radical surgery: of these, 8 are alive, and the survival times range from 8 months to 17 years. The 14 patients who received palliative therapy only aU died within 15 months. The degree of infiltration of the intestinal wall seemed to be the most significant prognostic factor. The worse prognosis for the neoplasia in young adults with respect to older people, already reported in the literature and confirmed by our data, seems to be correlated, more than with the histologic type or biologic behavior of the tumor, with the diagnostic delay, which results in more advanced forms, with respect to those seen in older patients, being observed at clinical examination. Although adenocarcinoma of the large intestine is prevalently found in older patients, numerous cases have been described in patients under 30 years of age (4, 8, 10, 12-20, 22). Of 17,875 deaths due to neoplasias of the colon and rectum recorded in Italy in 1966 and 1967, 187 (about 1 %) were in patients under 30 years of age (21). The frequency of adenocarcinoma of the large intestine in younger adults reported in the literature varies from 0.86 % (16) to 2.1 % (3) for patients under 30 years of age; from 0.45 % (17) to 1.1 % (22) for those under 20 to 25 years of age; and from 1.85 % (19) to 6.9 % (9) for those under 35 to 40 years of age. Here we report the case material of adenocarcinoma of the large intestine of the Istituto Nazionale Tumori of Milan from 1955 to 1975. On the basis of this data, compared and discussed in relation to those reported in the literature, we have attempted to determine the reason for the particularly severe prognosis that is usually associated with these neoplasias in young adults. CASE MATERIAL The case material consisted of 28 patients admitted to the Istituto Nazionale Tumori of Milan from 1955 to 1975 with a diagnosis of adenocarcinoma of the large intestine (table 1). Eight of the patients had previously undergone treatment Acknowledgments: The authors thank Ms. B. Johnston for preparation of the manuscript.

Research paper thumbnail of Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications

Blood, Aug 2, 2012

Omenn syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity ... more Omenn syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity because of activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre-T-cell receptor complex in immature thymocytes, which is crucial for an efficient development of the thymic epithelial component. Anti-CD3 monoclonal antibody (mAb) treatment in RAG2 ؊/؊ mice was previously shown to mimic pre-TCR signaling promoting thymic expansion. Here we show the effect of anti-CD3 mAb administration in the RAG2 R229Q mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator, displayed a significant amelioration in thymic epithelial compartment and an important reduction of peripheral T-cell activation and tissue infiltration. Furthermore, by injecting a high number of RAG2 R229Q progenitors into RAG2 ؊/؊ animals previously conditioned with anti-CD3 mAb, we detected autoimmune regulator expression together with the absence of peripheral immunopathology. These observations indicate that improving epithelial thymic function might ameliorate the detrimental behavior of the cell-autonomous RAG defect. Our data provide important therapeutic proof of concept for future clinical applications of anti-CD3 mAb treatment in severe combined immunodeficiency forms characterized by poor thymus function and autoimmunity. (Blood.

Research paper thumbnail of 3073 – PBX1 Genetic Ablation Inhibits Tumor Growth in a Mouse Model of Myeloproliferative Neoplasm

Experimental Hematology, Aug 1, 2020

Pre B cell leukemia homeobox 1 (Pbx1) regulates the balance between self-renewal and differentiat... more Pre B cell leukemia homeobox 1 (Pbx1) regulates the balance between self-renewal and differentiation of hematopoietic stem cells, and maintains proto-oncogenic transcriptional pathways implicated in several tumors. Its aberrant expression was found in a subset of myeloproliferative neoplasms (MPN) patients bearing the JAK2V617F mutation. To investigate if Pbx1 contributes to MPN, and to explore its potential as therapeutic target, we generated a new mouse strain, that we called JP, by crossing a known JAK2V617F inducible knock-in MPN model with a Pbx1 conditional-ko. In JP mice we can simultaneously activate the human JAK2 mutation and delete Pbx1. Typical MPN features, such as thrombocytemia and granulocytosis, did not develop in the absence of Pbx1. Erythrocytosis, initially displayed by JP mice, gradually resolved over time. Moreover, splenic myeloid metaplasia and in vitro cytokine independent growth were rescued by Pbx1 inactivation. Through RNA-Sequencing we analyzed molecular pathways downstream of Pbx1 and involved in MPN maintenance in stem and progenitor cells. The aberrant transcriptome in the MPN model compared to wild-type was rescued by the absence of Pbx1. Our results demonstrate that inhibition of the Pbx1-driven transcriptional program is beneficial in MPN. Modulation of Pbx1 activity by direct targeting or by targeting its downstream mediators might thus represent a novel therapeutic approach.

Research paper thumbnail of Valutazione clinica ed auxolcgica in pazienti con diagnosi molecolare di diabete insipido nefrogenico ad ereditarietà legata al cromosoma X

Rivista Italiana di Pediatria, 2000

Research paper thumbnail of Generation of 3 clones of induced pluripotent stem cells (iPSCs) from a patient affected by Autosomal Recessive Osteopetrosis due to mutations in TCIRG1 gene

Stem Cell Research, 2020

Autosomal recessive osteopetrosis (ARO) is a rare inherited disorder leading to increased bone de... more Autosomal recessive osteopetrosis (ARO) is a rare inherited disorder leading to increased bone density with impairment in bone resorption. Among the genes responsible for ARO, the TCIRG1 gene, coding for the a3 subunit of the osteoclast proton pump, is mutated in more than 50% of the cases, increasing the importance of TCIRG1-iPSCs as disease model. We generated 3 iPSC clones derived from Peripheral Blood Mononuclear Cells (PBMCs) of a patient carrying the heterozygous mutations p.Y512X and c.2236 + 1G > A. A Sendai virus-based vector was used and the iPSCs were characterized for genetic identity to parental cells, genomic integrity, pluripotency, and differentiation ability.

Research paper thumbnail of Molecular strategies in genetic diagnosis of transthyretin‐related hereditary amyloidosis

The FASEB Journal, Jul 1, 1992

Transthyretin-related hereditary (TTR) amyloidoses represent a clinically heterogeneous group of ... more Transthyretin-related hereditary (TTR) amyloidoses represent a clinically heterogeneous group of diseases associated with various point mutations of the TTR gene. We propose a molecular strategy for the diagnosis of this group of disorders.

Research paper thumbnail of Gene expression profiles of epithelial cells microscopically isolated from a breast-invasive ductal carcinoma and a nodal metastasis

Proceedings of the National Academy of Sciences of the United States of America, Dec 17, 2004

Research paper thumbnail of X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations

Nature Genetics, Apr 9, 2006

Cornelia de Lange syndrome is a multisystem developmental disorder characterized by facial dysmor... more Cornelia de Lange syndrome is a multisystem developmental disorder characterized by facial dysmorphisms, upper limb abnormalities, growth delay and cognitive retardation. Mutations in the NIPBL gene, a component of the cohesin complex, account for approximately half of the affected individuals. We report here that mutations in SMC1L1 (also known as SMC1), which encodes a different subunit of the cohesin complex, are responsible for CdLS in three male members of an affected family and in one sporadic case. Cornelia de Lange Syndrome (CdLS, MIM 122470) is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems. Although classical severe cases of CdLS are easily identified clinically, mild phenotypes are also frequent. Recently, the gene responsible for about half of CdLS cases was identified by two groups 1,2. This gene, NIPBL (homologous to Scc2 in yeast), codes for a protein that is implicated in chromosome cohesion. The core of the cohesin complex, first identified as responsible for chromatid cohesion, includes a heterodimer composed of SMC1 and SMC3, encoded by two members of the 'structural maintenance of chromosomes' gene family, and two non-SMC subunits, Scc1 (in humans, hSCC1 or hRAD21) and Scc3 (in humans, SA1 and SA2). Recent work suggests that these molecules assemble in a tripartite ring-shaped structure that interacts with DNA chains 3. In particular, in this recently proposed model, the two SMC subunits assume a rod-shaped conformation self-folded by antiparallel coiled-coil interaction and associate with each other through a 'hinge' domain positioned at one end of the rod, resulting in a V-shaped dimer. At the opposite end, each SMC molecule has a 'head' domain, whose engagement could 'close' or 'open' the ring: this region is also the site of interaction with Scc1 and Scc3 (ref. 4). However, at least three other

Research paper thumbnail of Riprogrammare cellule umane

Research paper thumbnail of Establishment and characterization of new mammary adenocarcinoma cell lines derived from double transgenic mice expressing GFP and neu oncogene

Cell Proliferation, Dec 1, 2006

A new murine cell line, named GFPneu, was established from a mammary adenocarcinoma arising in do... more A new murine cell line, named GFPneu, was established from a mammary adenocarcinoma arising in double transgenic MMTVneu × CMV-GFP mice. Breast tumours develop in 100% of females after 2 months latency, as a result of the overexpression of the activated rat neu oncogene in the mammary glands. All tissues, and in particular the breast tumours, express the GFP protein. This cell line was tumorigenic when inoculated into nude mice and the derived tumours showed the same histological features as the primaries from which they were isolated. Their histopathology reproduces many characteristics of human breast adenocarcinomas, in particular their ability to metastasize. The GFP marker allows us to visualize the presence of lung metastases in fresh tissues immediately, to confirm the histopathology. From a lung metastatic fluorescent nodule, we derived a further cell line, named MTP-GFP, which we also characterized. These two cell lines could be useful to study the role played by the neu oncogene in the maintenance of the transformed phenotype, in the metastatic process, to test novel therapeutic strategies to inhibit primary tumour growth and to observe the generation of distant metastases.

Research paper thumbnail of The contribution of molecular biology in the diagnosis of human lymphomas

PubMed, 1986

The relationship between T cell receptor (TCR) beta and gene immunoglobulin heavy chain locus was... more The relationship between T cell receptor (TCR) beta and gene immunoglobulin heavy chain locus was investigated in 25 cases of unselected human lymphomas as well as in normal and non-neoplastic lymphoid tissues. Hybridizing our blots with Jurkat 2, a clone specific for the beta chain gene of TCR, did not demonstrate extra bands in non-neoplastic tissues composed of 50-95% T-cells. On the contrary, rearranged bands were detected in six out of six cases of T-cell lymphomas. No TCR beta gene rearrangements were detected in 11 B-cell lymphomas, which in turn presented modification of the immunoglobulin heavy chain gene germline configuration. Our results suggest that TCR beta chain gene rearrangements are a good marker for human T-cell neoplasias in humans and complement the analysis with immunoglobulin genes probes. Eighth samples were devoid of any rearrangements: this group comprises cases of Hodgkin's disease T-lymphoblastic lymphomas in clinical remission and malignancies of unknown origin, as discussed in the text. We conclude that the analysis using DNA probes specific for TCR beta and IgH genes can be of aid to the pathologist in the diagnosis and classification of human lymphomas.

Research paper thumbnail of Chromosomes, genes, and cancer breakpoints

Cancer genetics and cytogenetics, Dec 1, 2002

Research paper thumbnail of Estrogen Receptors and MPA Treatment in Metastatic Renal Carcinoma. A Preliminary Report

Tumori Journal, Dec 1, 1980

Ten previously untreated patients with metastatic renal carcinoma underwent transperitoneal radic... more Ten previously untreated patients with metastatic renal carcinoma underwent transperitoneal radical nephrectomy followed by high dosage MPA treatment. Estrogen receptors were determined in the specimen of all cases by the dextran-coated charcoal method: both the neoplastic tissue and the healthy parenchyma were tested. The disease progressed in 8 cases, and 2 patients are alive without any evidence of progressive disease 12 and 27 months after the operation. Very low receptor levels were detected in these 2 cases and one of them could be defined as borderline with our threshold criterion. However, receptors were undetectable in the neoplastic tissue from 4 of 8 patients who progressed. These questionable results justified the start of a prospective multicentric trial to study in a large number of cases both hormone receptors and clinical response to hormone therapy in human renal cancer.

Research paper thumbnail of Cell fusion in the liver, revisited

World Journal of Hepatology, Feb 27, 2018

There is wide agreement that cell fusion is a physiological process in cells in mammalian bone, m... more There is wide agreement that cell fusion is a physiological process in cells in mammalian bone, muscle and placenta. In other organs, such as the cerebellum, cell fusion is controversial. The liver contains a considerable number of polyploid cells: They are commonly believed to originate by genome endoreplication, although the contribution of cell fusion to polyploidization has not been excluded. Here, we address the topic of cell fusion in the liver from a historical point of view. We discuss experimental evidence clearly supporting the hypothesis that cell fusion occurs in the liver, specifically when bone marrow cells were injected into mice and shown to rescue genetic hepatic degenerative defects. Those experiments-carried out in the latter half of the last century-were initially interpreted to show "transdifferentiation", but are now believed to demonstrate fusion between donor macrophages and host hepatocytes, raising the possibility that physiologically polyploid cells, such as hepatocytes, could originate, at least partially, through homotypic cell fusion. In support of the homotypic cell fusion hypothesis, we present new data generated using a chimera-based model, a much simpler model than those previously used. Cell fusion as a road to polyploidization in the liver has not been extensively investigated, and its contribution to a variety of conditions, such as viral

Research paper thumbnail of Recapitulation of the Roberts syndrome cellular phenotype by inhibition of INCENP, ZWINT-1 and ZW10 genes

Gene, Apr 1, 2004

Roberts syndrome is an autosomal recessive disorder characterised primarily by symmetric reductio... more Roberts syndrome is an autosomal recessive disorder characterised primarily by symmetric reduction of all limbs and growth retardation. Patients have been reported to have premature separation of heterochromatin regions of many chromosomes and abnormalities in cell cycle. Given the rarity of the syndrome, the linkage analysis approach is not suitable to identify the responsible gene. In this work, a cell line derived from a patient affected by Roberts syndrome was characterized by cell biology and molecular cytogenetics, including comparative genomic hybridization and spectral karyotype. No recurrent chromosomal rearrangements were identified. Thereafter, based on the fact that premature chromatide separation is a reliable marker of the disease, we used antisense oligonucleotide technologies to inhibit six genes involved in various steps of the correct chromosome segregation, such as chromosome cohesion, kinetochore assembling, spindle checkpoint and spindle formation. We found that the inhibition of INCENP, ZWINT-1, ZW10 genes results in the appearance of mitotic cells characterised by centromere separation, chromosome aneuploidy and micronuclei formation. In addition, INCENP, ZWINT-1, ZW10 antisense-treated chromosome morphology was very similar to that of Roberts chromosome when analysed by atomic force microscopy. We concluded that INCENP, ZWINT-1, ZW10 gene inhibition results in cellular phenocopies of Roberts syndrome. Taken together, these findings support a possible role of these genes in the pathogenesis of Roberts syndrome.

Research paper thumbnail of Fetal Liver Cells Transplanted in Utero Rescue the Osteopetrotic Phenotype in the oc/oc Mouse

American Journal of Pathology, Mar 1, 2009

Research paper thumbnail of The rat gene homologous to the human gene 9–27 is involved in the development of the mammary gland

Proceedings of the National Academy of Sciences of the United States of America, Feb 3, 1998

We have developed a model system for studying differentiation in the mammary gland, by using two ... more We have developed a model system for studying differentiation in the mammary gland, by using two clonal cultures deriving from a rat breast adenocarcinoma. They differ in the ability to form domes, structures the significance of which is unknown. By using the subtractive cDNA library approach, we isolated a cDNA that is highly expressed in the dome-forming cells, and identical to the rat8 gene and highly homologous to the human 9-27 gene. Antisense treatment of the dome-forming cells specifically and reproducibly abolishes dome formation, while forced expression of the gene in non-dome-forming cells causes morphological changes suggestive of ''f lat'' domes. In situ hybridization on rat tissues shows that the gene is expressed in epithelia, especially in those forming tubular structures, suggesting a relatedness between these structures and domes. Cytokeratin 8 and E cadherin are strongly expressed in the domes but not outside them, suggesting that the rat8 gene triggers the cells to express molecules that tighten the lateral connections between the cells; the process is likely to parallel that occurring during the differentiation of the mammary gland. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ''advertisement'' in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Research paper thumbnail of Chromosome Transplantation: Opportunities and Limitations

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Aspectos científicos y éticos del Proyecto Genoma Humano en Italia

Research paper thumbnail of Equivoci e illusioni su identitŕ e modernizzazione

Sociologia e ricerca sociale, Oct 1, 2012

The theme of identity as a source of representations of self and social relations is at the cente... more The theme of identity as a source of representations of self and social relations is at the center of the contemporary sociological debate on dilemmas of modernization and has often been considered as the analytical framework within which such unresolved issues could be caught in their most emblematic profiling. Some of these controversial issues will be taken into account in the present essay through a comparison between the social sciences and the biomolecular sciences perspectives, both increasingly involved in the clarification of the most common misconceptions regarding the immutability of this set of signs and its progressive dissolution.

Research paper thumbnail of Adenocarcinoma of the Large Intestine in Young Adults

Tumori Journal, Nov 1, 1977

Twenty-eight cases of adenocarcinoma of the large intestine in patients under 30 years of age, ad... more Twenty-eight cases of adenocarcinoma of the large intestine in patients under 30 years of age, admitted to the National Cancer Institute of Milan from 1955 to 1975, are reported. Fourteen patients underwent radical surgery: of these, 8 are alive, and the survival times range from 8 months to 17 years. The 14 patients who received palliative therapy only aU died within 15 months. The degree of infiltration of the intestinal wall seemed to be the most significant prognostic factor. The worse prognosis for the neoplasia in young adults with respect to older people, already reported in the literature and confirmed by our data, seems to be correlated, more than with the histologic type or biologic behavior of the tumor, with the diagnostic delay, which results in more advanced forms, with respect to those seen in older patients, being observed at clinical examination. Although adenocarcinoma of the large intestine is prevalently found in older patients, numerous cases have been described in patients under 30 years of age (4, 8, 10, 12-20, 22). Of 17,875 deaths due to neoplasias of the colon and rectum recorded in Italy in 1966 and 1967, 187 (about 1 %) were in patients under 30 years of age (21). The frequency of adenocarcinoma of the large intestine in younger adults reported in the literature varies from 0.86 % (16) to 2.1 % (3) for patients under 30 years of age; from 0.45 % (17) to 1.1 % (22) for those under 20 to 25 years of age; and from 1.85 % (19) to 6.9 % (9) for those under 35 to 40 years of age. Here we report the case material of adenocarcinoma of the large intestine of the Istituto Nazionale Tumori of Milan from 1955 to 1975. On the basis of this data, compared and discussed in relation to those reported in the literature, we have attempted to determine the reason for the particularly severe prognosis that is usually associated with these neoplasias in young adults. CASE MATERIAL The case material consisted of 28 patients admitted to the Istituto Nazionale Tumori of Milan from 1955 to 1975 with a diagnosis of adenocarcinoma of the large intestine (table 1). Eight of the patients had previously undergone treatment Acknowledgments: The authors thank Ms. B. Johnston for preparation of the manuscript.

Research paper thumbnail of Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications

Blood, Aug 2, 2012

Omenn syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity ... more Omenn syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity because of activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre-T-cell receptor complex in immature thymocytes, which is crucial for an efficient development of the thymic epithelial component. Anti-CD3 monoclonal antibody (mAb) treatment in RAG2 ؊/؊ mice was previously shown to mimic pre-TCR signaling promoting thymic expansion. Here we show the effect of anti-CD3 mAb administration in the RAG2 R229Q mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator, displayed a significant amelioration in thymic epithelial compartment and an important reduction of peripheral T-cell activation and tissue infiltration. Furthermore, by injecting a high number of RAG2 R229Q progenitors into RAG2 ؊/؊ animals previously conditioned with anti-CD3 mAb, we detected autoimmune regulator expression together with the absence of peripheral immunopathology. These observations indicate that improving epithelial thymic function might ameliorate the detrimental behavior of the cell-autonomous RAG defect. Our data provide important therapeutic proof of concept for future clinical applications of anti-CD3 mAb treatment in severe combined immunodeficiency forms characterized by poor thymus function and autoimmunity. (Blood.

Research paper thumbnail of 3073 – PBX1 Genetic Ablation Inhibits Tumor Growth in a Mouse Model of Myeloproliferative Neoplasm

Experimental Hematology, Aug 1, 2020

Pre B cell leukemia homeobox 1 (Pbx1) regulates the balance between self-renewal and differentiat... more Pre B cell leukemia homeobox 1 (Pbx1) regulates the balance between self-renewal and differentiation of hematopoietic stem cells, and maintains proto-oncogenic transcriptional pathways implicated in several tumors. Its aberrant expression was found in a subset of myeloproliferative neoplasms (MPN) patients bearing the JAK2V617F mutation. To investigate if Pbx1 contributes to MPN, and to explore its potential as therapeutic target, we generated a new mouse strain, that we called JP, by crossing a known JAK2V617F inducible knock-in MPN model with a Pbx1 conditional-ko. In JP mice we can simultaneously activate the human JAK2 mutation and delete Pbx1. Typical MPN features, such as thrombocytemia and granulocytosis, did not develop in the absence of Pbx1. Erythrocytosis, initially displayed by JP mice, gradually resolved over time. Moreover, splenic myeloid metaplasia and in vitro cytokine independent growth were rescued by Pbx1 inactivation. Through RNA-Sequencing we analyzed molecular pathways downstream of Pbx1 and involved in MPN maintenance in stem and progenitor cells. The aberrant transcriptome in the MPN model compared to wild-type was rescued by the absence of Pbx1. Our results demonstrate that inhibition of the Pbx1-driven transcriptional program is beneficial in MPN. Modulation of Pbx1 activity by direct targeting or by targeting its downstream mediators might thus represent a novel therapeutic approach.

Research paper thumbnail of Valutazione clinica ed auxolcgica in pazienti con diagnosi molecolare di diabete insipido nefrogenico ad ereditarietà legata al cromosoma X

Rivista Italiana di Pediatria, 2000

Research paper thumbnail of Generation of 3 clones of induced pluripotent stem cells (iPSCs) from a patient affected by Autosomal Recessive Osteopetrosis due to mutations in TCIRG1 gene

Stem Cell Research, 2020

Autosomal recessive osteopetrosis (ARO) is a rare inherited disorder leading to increased bone de... more Autosomal recessive osteopetrosis (ARO) is a rare inherited disorder leading to increased bone density with impairment in bone resorption. Among the genes responsible for ARO, the TCIRG1 gene, coding for the a3 subunit of the osteoclast proton pump, is mutated in more than 50% of the cases, increasing the importance of TCIRG1-iPSCs as disease model. We generated 3 iPSC clones derived from Peripheral Blood Mononuclear Cells (PBMCs) of a patient carrying the heterozygous mutations p.Y512X and c.2236 + 1G > A. A Sendai virus-based vector was used and the iPSCs were characterized for genetic identity to parental cells, genomic integrity, pluripotency, and differentiation ability.

Research paper thumbnail of Molecular strategies in genetic diagnosis of transthyretin‐related hereditary amyloidosis

The FASEB Journal, Jul 1, 1992

Transthyretin-related hereditary (TTR) amyloidoses represent a clinically heterogeneous group of ... more Transthyretin-related hereditary (TTR) amyloidoses represent a clinically heterogeneous group of diseases associated with various point mutations of the TTR gene. We propose a molecular strategy for the diagnosis of this group of disorders.

Research paper thumbnail of Gene expression profiles of epithelial cells microscopically isolated from a breast-invasive ductal carcinoma and a nodal metastasis

Proceedings of the National Academy of Sciences of the United States of America, Dec 17, 2004

Research paper thumbnail of X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations

Nature Genetics, Apr 9, 2006

Cornelia de Lange syndrome is a multisystem developmental disorder characterized by facial dysmor... more Cornelia de Lange syndrome is a multisystem developmental disorder characterized by facial dysmorphisms, upper limb abnormalities, growth delay and cognitive retardation. Mutations in the NIPBL gene, a component of the cohesin complex, account for approximately half of the affected individuals. We report here that mutations in SMC1L1 (also known as SMC1), which encodes a different subunit of the cohesin complex, are responsible for CdLS in three male members of an affected family and in one sporadic case. Cornelia de Lange Syndrome (CdLS, MIM 122470) is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems. Although classical severe cases of CdLS are easily identified clinically, mild phenotypes are also frequent. Recently, the gene responsible for about half of CdLS cases was identified by two groups 1,2. This gene, NIPBL (homologous to Scc2 in yeast), codes for a protein that is implicated in chromosome cohesion. The core of the cohesin complex, first identified as responsible for chromatid cohesion, includes a heterodimer composed of SMC1 and SMC3, encoded by two members of the 'structural maintenance of chromosomes' gene family, and two non-SMC subunits, Scc1 (in humans, hSCC1 or hRAD21) and Scc3 (in humans, SA1 and SA2). Recent work suggests that these molecules assemble in a tripartite ring-shaped structure that interacts with DNA chains 3. In particular, in this recently proposed model, the two SMC subunits assume a rod-shaped conformation self-folded by antiparallel coiled-coil interaction and associate with each other through a 'hinge' domain positioned at one end of the rod, resulting in a V-shaped dimer. At the opposite end, each SMC molecule has a 'head' domain, whose engagement could 'close' or 'open' the ring: this region is also the site of interaction with Scc1 and Scc3 (ref. 4). However, at least three other

Research paper thumbnail of Riprogrammare cellule umane

Research paper thumbnail of Establishment and characterization of new mammary adenocarcinoma cell lines derived from double transgenic mice expressing GFP and neu oncogene

Cell Proliferation, Dec 1, 2006

A new murine cell line, named GFPneu, was established from a mammary adenocarcinoma arising in do... more A new murine cell line, named GFPneu, was established from a mammary adenocarcinoma arising in double transgenic MMTVneu × CMV-GFP mice. Breast tumours develop in 100% of females after 2 months latency, as a result of the overexpression of the activated rat neu oncogene in the mammary glands. All tissues, and in particular the breast tumours, express the GFP protein. This cell line was tumorigenic when inoculated into nude mice and the derived tumours showed the same histological features as the primaries from which they were isolated. Their histopathology reproduces many characteristics of human breast adenocarcinomas, in particular their ability to metastasize. The GFP marker allows us to visualize the presence of lung metastases in fresh tissues immediately, to confirm the histopathology. From a lung metastatic fluorescent nodule, we derived a further cell line, named MTP-GFP, which we also characterized. These two cell lines could be useful to study the role played by the neu oncogene in the maintenance of the transformed phenotype, in the metastatic process, to test novel therapeutic strategies to inhibit primary tumour growth and to observe the generation of distant metastases.

Research paper thumbnail of The contribution of molecular biology in the diagnosis of human lymphomas

PubMed, 1986

The relationship between T cell receptor (TCR) beta and gene immunoglobulin heavy chain locus was... more The relationship between T cell receptor (TCR) beta and gene immunoglobulin heavy chain locus was investigated in 25 cases of unselected human lymphomas as well as in normal and non-neoplastic lymphoid tissues. Hybridizing our blots with Jurkat 2, a clone specific for the beta chain gene of TCR, did not demonstrate extra bands in non-neoplastic tissues composed of 50-95% T-cells. On the contrary, rearranged bands were detected in six out of six cases of T-cell lymphomas. No TCR beta gene rearrangements were detected in 11 B-cell lymphomas, which in turn presented modification of the immunoglobulin heavy chain gene germline configuration. Our results suggest that TCR beta chain gene rearrangements are a good marker for human T-cell neoplasias in humans and complement the analysis with immunoglobulin genes probes. Eighth samples were devoid of any rearrangements: this group comprises cases of Hodgkin's disease T-lymphoblastic lymphomas in clinical remission and malignancies of unknown origin, as discussed in the text. We conclude that the analysis using DNA probes specific for TCR beta and IgH genes can be of aid to the pathologist in the diagnosis and classification of human lymphomas.

Research paper thumbnail of Chromosomes, genes, and cancer breakpoints

Cancer genetics and cytogenetics, Dec 1, 2002

Research paper thumbnail of Estrogen Receptors and MPA Treatment in Metastatic Renal Carcinoma. A Preliminary Report

Tumori Journal, Dec 1, 1980

Ten previously untreated patients with metastatic renal carcinoma underwent transperitoneal radic... more Ten previously untreated patients with metastatic renal carcinoma underwent transperitoneal radical nephrectomy followed by high dosage MPA treatment. Estrogen receptors were determined in the specimen of all cases by the dextran-coated charcoal method: both the neoplastic tissue and the healthy parenchyma were tested. The disease progressed in 8 cases, and 2 patients are alive without any evidence of progressive disease 12 and 27 months after the operation. Very low receptor levels were detected in these 2 cases and one of them could be defined as borderline with our threshold criterion. However, receptors were undetectable in the neoplastic tissue from 4 of 8 patients who progressed. These questionable results justified the start of a prospective multicentric trial to study in a large number of cases both hormone receptors and clinical response to hormone therapy in human renal cancer.

Research paper thumbnail of Cell fusion in the liver, revisited

World Journal of Hepatology, Feb 27, 2018

There is wide agreement that cell fusion is a physiological process in cells in mammalian bone, m... more There is wide agreement that cell fusion is a physiological process in cells in mammalian bone, muscle and placenta. In other organs, such as the cerebellum, cell fusion is controversial. The liver contains a considerable number of polyploid cells: They are commonly believed to originate by genome endoreplication, although the contribution of cell fusion to polyploidization has not been excluded. Here, we address the topic of cell fusion in the liver from a historical point of view. We discuss experimental evidence clearly supporting the hypothesis that cell fusion occurs in the liver, specifically when bone marrow cells were injected into mice and shown to rescue genetic hepatic degenerative defects. Those experiments-carried out in the latter half of the last century-were initially interpreted to show "transdifferentiation", but are now believed to demonstrate fusion between donor macrophages and host hepatocytes, raising the possibility that physiologically polyploid cells, such as hepatocytes, could originate, at least partially, through homotypic cell fusion. In support of the homotypic cell fusion hypothesis, we present new data generated using a chimera-based model, a much simpler model than those previously used. Cell fusion as a road to polyploidization in the liver has not been extensively investigated, and its contribution to a variety of conditions, such as viral

Research paper thumbnail of Recapitulation of the Roberts syndrome cellular phenotype by inhibition of INCENP, ZWINT-1 and ZW10 genes

Gene, Apr 1, 2004

Roberts syndrome is an autosomal recessive disorder characterised primarily by symmetric reductio... more Roberts syndrome is an autosomal recessive disorder characterised primarily by symmetric reduction of all limbs and growth retardation. Patients have been reported to have premature separation of heterochromatin regions of many chromosomes and abnormalities in cell cycle. Given the rarity of the syndrome, the linkage analysis approach is not suitable to identify the responsible gene. In this work, a cell line derived from a patient affected by Roberts syndrome was characterized by cell biology and molecular cytogenetics, including comparative genomic hybridization and spectral karyotype. No recurrent chromosomal rearrangements were identified. Thereafter, based on the fact that premature chromatide separation is a reliable marker of the disease, we used antisense oligonucleotide technologies to inhibit six genes involved in various steps of the correct chromosome segregation, such as chromosome cohesion, kinetochore assembling, spindle checkpoint and spindle formation. We found that the inhibition of INCENP, ZWINT-1, ZW10 genes results in the appearance of mitotic cells characterised by centromere separation, chromosome aneuploidy and micronuclei formation. In addition, INCENP, ZWINT-1, ZW10 antisense-treated chromosome morphology was very similar to that of Roberts chromosome when analysed by atomic force microscopy. We concluded that INCENP, ZWINT-1, ZW10 gene inhibition results in cellular phenocopies of Roberts syndrome. Taken together, these findings support a possible role of these genes in the pathogenesis of Roberts syndrome.

Research paper thumbnail of Fetal Liver Cells Transplanted in Utero Rescue the Osteopetrotic Phenotype in the oc/oc Mouse

American Journal of Pathology, Mar 1, 2009

Research paper thumbnail of The rat gene homologous to the human gene 9–27 is involved in the development of the mammary gland

Proceedings of the National Academy of Sciences of the United States of America, Feb 3, 1998

We have developed a model system for studying differentiation in the mammary gland, by using two ... more We have developed a model system for studying differentiation in the mammary gland, by using two clonal cultures deriving from a rat breast adenocarcinoma. They differ in the ability to form domes, structures the significance of which is unknown. By using the subtractive cDNA library approach, we isolated a cDNA that is highly expressed in the dome-forming cells, and identical to the rat8 gene and highly homologous to the human 9-27 gene. Antisense treatment of the dome-forming cells specifically and reproducibly abolishes dome formation, while forced expression of the gene in non-dome-forming cells causes morphological changes suggestive of ''f lat'' domes. In situ hybridization on rat tissues shows that the gene is expressed in epithelia, especially in those forming tubular structures, suggesting a relatedness between these structures and domes. Cytokeratin 8 and E cadherin are strongly expressed in the domes but not outside them, suggesting that the rat8 gene triggers the cells to express molecules that tighten the lateral connections between the cells; the process is likely to parallel that occurring during the differentiation of the mammary gland. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked ''advertisement'' in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Research paper thumbnail of Chromosome Transplantation: Opportunities and Limitations

Cells, 2024

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Research paper thumbnail of Minima Christiana.  Terza versione 12.9. Prefazione Ennio Brovedani

Per poter studiare i rapporti tra la cultura moderna basata sulla Ragione e il Cristianesimo è ne... more Per poter studiare i rapporti tra la cultura moderna basata sulla Ragione e il Cristianesimo è necessario da un lato definire valori e limiti del procedimento razionale, dall’altro definire un insieme minimo di proposizioni che caratterizzano il Cristianesimo. Solo allora si potrà effettuare un confronto proficuo che ci liberi da presunzioni e antropomorfismi.

In breve: quali sono le proposizioni veramente essenziali del Cristianesimo? Ed esse reggono il confronto con la scienza moderna e la ragione?

Research paper thumbnail of SI PUO' CLONARE UN ESSERE UMANO?

Si può clonare un essere umano?, 2003

ORIGINARIAMENTE PUBBLICATO DA LATERZA. Con l'aggiunta di una breve postilla per coprire il peri... more ORIGINARIAMENTE PUBBLICATO DA LATERZA.
Con l'aggiunta di una breve postilla per coprire il periodo 2003-2023.
Chiunque può riprodurre parti o l'intero libro liberamente.

Il libro nella prima parte ripercorre la storia e le fasi salienti del processo di clonazione animale e ne illustra gli aspetti tecnici. Nella seconda parte discute gli aspetti etici e sociali del dibattito, cercando di elencare le varie argomentazioni, senza schierarsi né a favore né contro, ma semplicemente tentando di favorire la comprensione filosofica e scientifica della problematica, così che ognuno possa formarsi una sua idea personale.

Research paper thumbnail of IL FUTURO E IL PASSATO DELL'UOMO

Bruno Mondadori, 2006

Capitolo primo:Introduzione Capitolo secondo: Evoluzione e visioni del mondo Capitolo terzo: L'ev... more Capitolo primo:Introduzione Capitolo secondo: Evoluzione e visioni del mondo Capitolo terzo: L'evoluzione continua Capitolo quarto: Possiamo modificarci? Capitolo quinto: Il determinismo genetico Capitolo sesto: E' giusto modificarci? Capitolo settimo: Ginevra, 1816 Capitolo ottavo: Newton e Leibniz Appendice Avvertenza E' possibile parlare di evoluzione, genoma, ereditarietà senza parlare di nucleotidi, basi azotate, legami chimici e così via e nello steso tempo consentire di discutere tutte le implicazioni sociali etiche e filosofiche che la moderna genetica solleva? E' possibile che una persona comprenda quello che sta succedendo in biologia ed in particolare nella biologia umana senza conoscere nulla di chimica e poco di biologia? Certamente sì. Un conto infatti è fare ricerca in genetica o usare la genetica per scopi medici, cose per le quali tutte queste nozioni sono indispensabili, e un altro è comprendere cosa ci aspetta in un futuro in parte lontano e in parte assai vicino. Cercherò di farlo in questo volume, dove mostrerò come sia possibile seguire il dibattito sulla genetica moderna semplicemente usando termini cui ormai tutti sono abituati, e cioè quello di programma e di istruzione. In effetti, questa analogia è estremamente utile per comprendere come i genomi funzionino, anche se questo non sta ad indicare necessariamente che i genomi funzionino come i computer: nei secoli, gli scienziati hanno utilizzato i settori più moderni della scienza per tentare di descrivere ciò che non conoscevano né erano in grado di spiegare. All'epoca di Cartesio la meccanica e l'idraulica erano scienze avanzate ed ecco che con pulegge, tiranti e vasi comunicanti si spiegava tutta la macchina umana: alcune di queste spiegazioni, ad esempio la contrazione di un muscolo, conservano ancor oggi una loro validità. In altri settori, invece, oggi compatiamo quegli scienziati che le usavano per spiegare fenomeni che neanche adesso sappiamo da che parte prendere. Così, paragonare computer e cervello fra qualche decennio o qualche secolo sembrerà probabilmente ridicolo, ma usare il concetto di programma e istruzione per parlare di genetica potrebbe non essere così fuorviante. Anzi, si è cominciato a comprendere l'ereditarietà quando si è introdotto il concetto di programma. Un tempo infatti gli scienziati litigavano tra loro, sostenendo gli uni (preformisti) che per spiegare come da un uomo nascesse un uomo e non una pecora era necessario postulare che esistesse dentro ad ogni uomo una piccola copia umana (homunculus), ritenendo al contrario gli altri che la copia umana si organizzasse ad ogni nuova generazione da un misto di sostanze presenti nelle cellule germinali umane (epigenetisti). Gli uni dovevano risolvere il piccolo problema che originava dal fatto che in ogni homunculus ce ne dovesse stare uno più piccolo ad infinitum, mentre gli altri non riuscivano a spiegare come da una miscela informe di sostanze potesse derivare una copia nel complesso fedele all'originale. Solamente la percezione che in ogni embrione vi fosse un programma poté risolvere questo dilemma. Per programma e istruzione intendo qui ciò che tutti gli ignoranti di computer come me intendono. E' presumibile che chi è esperto possa considerare quanto dirò assolutamente impreciso. Qui, un programma verrà considerato un complesso di istruzioni che permette di eseguire un certo compito, che può essere astratto o concreto. Per noi, la sequenza di istruzioni che consente di montare un modellino è un programma, come lo sono le istruzioni che ci consentono di calcolare l'IRPEF che dobbiamo pagare. Un programma ha un grande vantaggio: è assai maneggevole. Si può lasciare fermo per tanti anni e poi ad un certo punto tirarlo fuori dal cassetto; se ne possono fare tante copie e distribuirle per Email; può essere piccolo ma dirigere la produzione di un qualcosa di molto grande e così via. Tutte queste proprietà del programma sono state sfruttate nei 3-4 miliardi di anni in cui la vita è comparsa sulla terra: una spora può rimanere anni immobile e poi riprendere a riprodursi quando le condizioni sono favorevoli; miliardi di spermatozoi possono venir prodotti e utilizzati; da una cellula grossa meno di un millimetro può derivare un elefante; e così via. Utilizzare concetti con cui tutti hanno familiarità (seppur vagamente, perché in realtà la maggior parte di noi non sa assolutamente come si costruisce un programma) è utile per spiegare molti aspetti della realtà, nel nostro caso, della genetica. Ma vi è una preoccupazione: non è che questo approccio possa essere superficiale e che in realtà alla gente vengano propinate nozioni imprecise o persino fasulle? Non so se questo può accadere in settori della fisica o in altri, ma credo proprio che non sia il caso della genetica. I concetti generali della genetica si possono comunicare facilmente, senza essere imprecisi: non è che alla fine si sappia tutta la genetica, si sa solo quella parte che consente di dare un giudizio su di essa, che in realtà è quello che conta.

Research paper thumbnail of LA BELLEZZA DELLA GENETICA

Queste brevi note vogliono introdurre alla bellezza della scienza della Genetica giovani studenti... more Queste brevi note vogliono introdurre alla bellezza della scienza della Genetica giovani studenti o persone comunque interessate alle novità di questa magnifica disciplina

Research paper thumbnail of Intersezioni. Questioni biologiche di rilevanza filosofica.

Mc Graw Hill , 2000

Affermare che la Filosofia sia un sottoinsieme della Scienza, o più precisamente che l’insieme de... more Affermare che la Filosofia sia un sottoinsieme della Scienza, o più precisamente che l’insieme delle proposizioni filosofiche debba essere compreso all’interno dell’insieme delle proposizioni scientifiche, cioè ancorate alla realtà empirica, potrebbe apparire eretico sia ai filosofi che agli scienziati. Tuttavia questo è quanto il presente libro sostiene con due diversi tipi di argomentazioni.
Il primo consiste nell’adottare un’accezione ampia di Scienza del tipo di quella in vigore presso gli antichi Greci (scienza come conoscenza, senza ulteriori distinzioni) e nel definire come Filosofia l’insieme delle proposizioni di interesse “vitale” per l’uomo.
Il secondo è di mostrare di fatto quante di queste proposizioni vitali per l’uomo siano presenti nel settore della Scienza che va sotto il nome di Biologia. L’autore esamina tutto ciò che la Biologia ci dice sui fenomeni viventi e su come si sono formati nel corso dell’evoluzione, sulla relazione tra geni e personalità, sulla coscienza, il linguaggio e gli altri aspetti che hanno a che fare con la specificità della natura umana.
In tal modo, secondo l’autore, le motivazioni di due grandi movimenti filosofici del XX secolo, quello neopositivista e quello esistenzialista, trovano una certa conciliazione. Le esigenze dell’esistenzialismo sono la radice del bisogno dell’uomo a far filosofia, mentre l’aderenza alla realtà empirica richiesta dal neopositivismo costituisce il prerequisito con cui le problematiche filosofiche vanno affrontate.

Questi temi sono stati successivamente discussi dall'autore nel libro
MINIMA CHRISTIANA
https://www.academia.edu/106531254/Minima_Christiana_Terza_versione_12_9_Prefazione_Ennio_Brovedani