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Featured researches published by Daniela Medicina.


American Journal of Pathology | 2000

Fibrinogen Brescia : Hepatic Endoplasmic Reticulum Storage and Hypofibrinogenemia Because of a γ284 Gly→Arg Mutation

Stephen O. Brennan; Jane Wyatt; Daniela Medicina; Francesco Callea; Peter M. George

The proposita suffered from liver cirrhosis and biopsy showed type 1 membrane-bound fiberglass inclusions. The hepatic inclusion bodies were weakly periodic acid-Schiff diastase-positive, and on immunoperoxidase staining reacted specifically with anti-fibrinogen antisera. Coagulation investigations revealed low functional and antigenic fibrinogen together with a prolonged thrombin time of 37 seconds (normal, 17 to 22 seconds) suggestive of a hypodysfibrinogenemia. DNA sequencing of all three fibrinogen genes showed a single heterozygous mutation of GGG (Gly)-->CGG (Arg) at codon 284 of the gamma-chain gene. However, examination of purified fibrinogen chains by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, reverse-phase high-performance liquid chromatography, ion-exchange high-performance liquid chromatography, and isoelectric focusing, failed to show any evidence of the mutant gamma(Br) chain in plasma fibrinogen. This finding was substantiated by electrospray ionization mass spectrometry, which showed only a normal gamma (and Bbeta) chain mass, but a large increase in the portion of their disialo isoforms. We speculate that misfolding of the variant protein causes hepatic retention and the subsequent hypofibrinogenemia, and that the functional defect (dysfibrinogenemia) results from hypersialylation of otherwise normal Bbeta and gamma chains consequent to the liver cirrhosis. These conclusions were supported by studies on six other family members with hypofibrinogenemia, and essentially normal clotting times, who were heterozygous for the gamma284 Gly-->Arg mutation.


Head and Neck-journal for The Sciences and Specialties of The Head and Neck | 2013

Sinonasal mucosal melanoma: Molecular profile and therapeutic implications from a series of 32 cases

Mario Turri-Zanoni; Daniela Medicina; Davide Lombardi; Marco Ungari; Piera Balzarini; Cristina Rossini; Wilma Pellegrini; Paolo Battaglia; Carlo Capella; Paolo Castelnuovo; Gabriele Palmedo; Fabio Facchetti; Heinz Kutzner; Piero Nicolai; William Vermi

Primary sinonasal mucosal melanomas are aggressive tumors with a poor clinical control by current treatments, raising the urgent need of novel strategies.


Neuro-oncology | 2013

Glutamine synthetase expression as a valuable marker of epilepsy and longer survival in newly diagnosed glioblastoma multiforme

Anna Rosati; Pietro Luigi Poliani; Alice Todeschini; Manuela Cominelli; Daniela Medicina; Marco Cenzato; Edda Simoncini; Stefano Maria Magrini; Michela Buglione; Salvatore Grisanti; Alessandro Padovani

BACKGROUND Glutamine synthetase (GS) is an astrocytic enzyme catalyzing the conversion of glutamate and ammonia to glutamine. Its up-regulation has been related to higher tumor proliferation and poor prognosis in extra-cerebral tumors. We have previously reported a GS deficiency in patients with glioblastoma multiforme (GBM) who also developed epilepsy, which is a favorable prognostic factor in glioma. Here, we investigated the prognostic value of GS expression in patients with GBM with or without epilepsy and its correlation with survival. METHODS We conducted a clinical and histopathological study on 83 (52 males) consecutive patients with newly diagnosed GBM. Immunohistochemical expression of GS was scored semi-quantitatively on the basis of cell number, staining intensity, and distribution of immunoreactive cells. Several clinical and neuropathological variables were analyzed in relation to survival and GS expression. RESULTS Median age at diagnosis was 62 years. At the last evaluation, with a median follow-up of 11.5 months (range, 1.5-58 months), 5 patients (6%) were still alive and 78 (94%) were dead. GS expression patterns in neoplastic cells were inversely correlated to the presence of epilepsy (P < .0001 for intensity and P < .009 for homogeneity of GS distribution, respectively). Univariate analysis showed that RPA score, epilepsy, O6-methylguanine-DNA methyltransferase (MGM)T status, application of Stupp protocol, and GS intensity pattern had a significant impact on survival. Absent/low intensity of GS expression was significantly associated with a longer survival in both uni- (19 vs 8 months; P < .0005) and multivariate (P = .003) analyses. CONCLUSIONS Absent/low-intensity GS expression pattern represents a valuable biomarker of both epilepsy and overall survival in GBM.


European Neurology | 2002

Alpha-1-Antitrypsin Deficiency-Associated Cervical Artery Dissection: Report of Three Cases

Alessandro Pezzini; Mauro Magoni; Luciano Corda; Lara Pini; Daniela Medicina; Mario Crispino; Marco Pavia; Alessandro Padovani; Vittorio Grassi

The pathogenesis of cervical artery dissection is poorly understood. Deficiency of the elastase inhibitor alpha-1-antitrypsin may represent a predisposing condition. Biochemical and genetic analyses in a series of 12 consecutive patients with spontaneous dissection of the neck vessels showed 3 cases associated to alpha-1-antitrypsin deficiency, in combination with transient precipitating factors. A disequilibrium between proteolytic enzymes and protease inhibitors may contribute to the pathogenesis of cervical artery dissection leading to structural abnormalities of the extracellular matrix and increasing the susceptibility of the vessel wall to additional short-lived trigger mechanisms.


The Journal of Allergy and Clinical Immunology | 2010

Revertant T lymphocytes in a patient with Wiskott-Aldrich syndrome: Analysis of function and distribution in lymphoid organs

Sara Trifari; Samantha Scaramuzza; Marco Catucci; Maurilio Ponzoni; Luca Mollica; Robert Chiesa; Federica Cattaneo; Fanny Lafouresse; Ronan Calvez; William Vermi; Daniela Medicina; Maria Carmina Castiello; Francesco Marangoni; Marita Bosticardo; Claudio Doglioni; Maurizio Caniglia; Alessandro Aiuti; Anna Villa; Maria Grazia Roncarolo; Loïc Dupré

BACKGROUND The Wiskott-Aldrich syndrome (WAS) is a rare genetic disease characterized by thrombocytopenia, immunodeficiency, autoimmunity, and hematologic malignancies. Secondary mutations leading to re-expression of WAS protein (WASP) are relatively frequent in patients with WAS. OBJECTIVE The tissue distribution and function of revertant cells were investigated in a novel case of WAS gene secondary mutation. METHODS A vast combination of approaches was used to characterize the second-site mutation, to investigate revertant cell function, and to track their distribution over a 18-year clinical follow-up. RESULTS The WAS gene secondary mutation was a 4-nucleotide insertion, 4 nucleotides downstream of the original deletion. This somatic mutation allowed the T-cell-restricted expression of a stable, full-length WASP with a 3-amino acid change compared with the wild-type protein. WASP(+) T cells appeared early in the spleen (age 10 years) and were highly enriched in a mesenteric lymph node at a later time (age 23 years). Revertant T cells had a diversified T-cell-receptor repertoire and displayed in vitro and in vivo selective advantage. They proliferated and produced cytokines normally on T-cell-receptor stimulation. Consistently, the revertant WASP correctly localized to the immunologic synapse and to the leading edge of migrating T cells. CONCLUSION Despite the high proportion of functional revertant T cells, the patient still has severe infections and autoimmune disorders, suggesting that re-expression of WASP in T cells is not sufficient to normalize immune functions fully in patients with WAS.


PLOS ONE | 2012

Three New Alpha1-Antitrypsin Deficiency Variants Help to Define a C-Terminal Region Regulating Conformational Change and Polymerization

Anna M. Fra; Bibek Gooptu; Ilaria Ferrarotti; Elena Miranda; Roberta Scabini; Riccardo Ronzoni; Federica Benini; Luciano Corda; Daniela Medicina; Maurizio Luisetti; Luisa Schiaffonati

Alpha1-antitrypsin (AAT) deficiency is a hereditary disorder associated with reduced AAT plasma levels, predisposing adults to pulmonary emphysema. The most common genetic AAT variants found in patients are the mildly deficient S and the severely deficient Z alleles, but several other pathogenic rare alleles have been reported. While the plasma AAT deficiency is a common trait of the disease, only a few AAT variants, including the prototypic Z AAT and some rare variants, form cytotoxic polymers in the endoplasmic reticulum of hepatocytes and predispose to liver disease. Here we report the identification of three new rare AAT variants associated to reduced plasma levels and characterize their molecular behaviour in cellular models. The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AAT, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening ‘latch’ interactions constraining the AAT reactive loop and through effects on core packing. In conclusion, the new AAT deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant. The new mutations cluster structurally, thus defining a region of the AAT molecule critical for regulating its conformational state.


Annals of the New York Academy of Sciences | 2006

Genetic and Immunological Characterization of Fibrinogen Inclusion Bodies in Patients with Hepatic Fibrinogen Storage and Liver Disease

Daniela Medicina; Giovanna Fabbretti; Stephen O. Brennan; Peter M. George; Bo Kudryk; Francesco Callea

Abstract: Fibrinogen storage in liver cells can occur under three different morphological inclusions. Type I contain all three fibrinogen chains (Aα, Bβ, and γ) as well as D and E fragments, whereas type II and III lack Bβ as well as D and E fragments. Patients with type I inclusions carry a point mutation (γ284 Gly‐Arg). The mutation is not present in patients with type II and III inclusions. These results appear to suggest that the three various phenotypic expressions (i.e., morphological variants) reflect different genetical abnormalities of fibrinogen.


Journal of the National Cancer Institute | 2015

EGFR Amplified and Overexpressing Glioblastomas and Association With Better Response to Adjuvant Metronomic Temozolomide

Manuela Cominelli; Salvatore Grisanti; Stefania Mazzoleni; Caterina Branca; Luciano Buttolo; Daniela Furlan; Barbara Liserre; Maria Fausta Bonetti; Daniela Medicina; Vilma Pellegrini; Michela Buglione; Roberto Liserre; Serena Pellegatta; Gaetano Finocchiaro; Piero Dalerba; Fabio Facchetti; Marina Pizzi; Rossella Galli; Pietro Luigi Poliani

BACKGROUND Lack of robust predictive biomarkers, other than MGMT promoter methylation, makes temozolomide responsiveness in newly diagnosed glioblastoma (GBM) patients difficult to predict. However, we identified patients with long-term survival (≥35 months) within a group of newly diagnosed GBM patients treated with standard or metronomic adjuvant temozolomide schedules. We thus investigated possible molecular profiles associated with longer survival following temozolomide treatment. METHODS We investigated the association of molecular features with progression-free (PFS) and overall survival (OS). Human-derived GBM cancer stem cells (CSCs) were used to investigate in vitro molecular mechanisms associated with temozolomide responsiveness. Surgically removed recurrences allowed investigation of molecular changes occurring during therapy in vivo. Statistical analyses included one- and two-way analysis of variance, Students t test, Cox proportional hazards, and the Kaplan-Meier method. All statistical tests were two-sided. RESULTS No association was found between survival and gene classifiers associated with different molecular GBM subtypes in the standard-treated group, while in metronomic-treated patients robust association was found between EGFR amplification/overexpression and PFS and OS (OS, EGFR-high vs low: hazard ratiodeath = 0.22, 95% confidence interval = 0.09 to 0.55, P = .001). The result for OS remained statistically significant after Bonferroni correction (P interaction < .0005). Long-term survival following metronomic temozolomide was independent from MGMT and EGFRvIII status and was more pronounced in EGFR-overexpressing GBM patients with PTEN loss. In vitro findings confirmed a selective dose- and time-dependent decrease in survival of temozolomide-treated EGFR+ human-derived glioblastoma CSCs, which occurred through inhibition of NF-κB transcriptional activity. In addition, reduction in EGFR-amplified cells, along with a statistically significant decrease in NF-κB/p65 expression, were observed in specimens from recurrent metronomic-treated EGFR-overexpressing GBM patients. CONCLUSIONS EGFR-amplified/overexpressing glioblastomas strongly benefit from metronomic temozolomide-based therapies.


Human Mutation | 2009

Molecular characterization of the new defective Pbrescia alpha1-antitrypsin allele†

Daniela Medicina; Nadia Montani; Anna M. Fra; Laura Tiberio; Luciano Corda; Elena Miranda; Alessandro Pezzini; Fausta Bonetti; Rosaria Ingrassia; Roberta Scabini; Fabio Facchetti; Luisa Schiaffonati

Alpha1‐antitrypsin (α1AT) deficiency is a hereditary disorder associated with reduced α1AT serum level, predisposing adults to pulmonary emphysema. Among the known mutations of the α1AT gene (SERPINA1) causing α1AT deficiency, a few alleles, particularly the Z allele, may also predispose adults to liver disease. We have characterized a new defective α1AT allele (c.745G>C) coding for a mutant α1AT (Gly225Arg), named Pbrescia. The Pbrescia α1AT allele was first identified in combination with the rare defective Mwürzburg allele in an 11‐year‐old boy showing significantly reduced serum α1AT level. Subsequently, the Pbrescia allele was found in the heterozygous state with the normal M or the defective Z allele in nine and three adults respectively. In cellular models of the disease, we show that the Pbrescia mutant is retained in the endoplasmic reticulum as ordered polymers and is secreted more slowly than the normal M α1AT. This behaviour recapitulates the abnormal cellular handling and fate of the Z α1AT and suggests that the mutation present in the Pbrescia α1AT causes a conformational change of the protein which, by favouring polymer formation, is etiologic to both severe α1AT deficiency in the plasma and toxic protein‐overload in the liver.


Human Molecular Genetics | 2016

Aberrant disulphide bonding contributes to the ER retention of alpha1-antitrypsin deficiency variants

Riccardo Ronzoni; Romina Berardelli; Daniela Medicina; Roberto Sitia; Bibek Gooptu; Anna M. Fra

Mutations in alpha1-antitrypsin (AAT) can cause the protein to polymerise and be retained in the endoplasmic reticulum (ER) of hepatocytes. The ensuing systemic AAT deficiency leads to pulmonary emphysema, while intracellular polymers are toxic and cause chronic liver disease. The severity of this process varies considerably between individuals, suggesting the involvement of mechanistic co-factors and potential for therapeutically beneficial interventions. We show in Hepa1.6 cells that the mildly polymerogenic I (Arg39Cys) AAT mutant forms aberrant inter- and intra-molecular disulphide bonds involving the acquired Cys39 and the only cysteine residue in the wild-type (M) sequence (Cys232). Substitution of Cys39 to serine partially restores secretion, showing that disulphide bonding contributes to the intracellular retention of I AAT. Covalent homodimers mediated by inter-Cys232 bonding alone are also observed in cells expressing the common Z and other polymerising AAT variants where conformational behaviour is abnormal, but not in those expressing M AAT. Prevention of such disulphide linkage through the introduction of the Cys232Ser mutation or by treatment of cells with reducing agents increases Z AAT secretion. Our results reveal that disulphide interactions enhance intracellular accumulation of AAT mutants and implicate the oxidative ER state as a pathogenic co-factor. Redox modulation, e.g. by anti-oxidant strategies, may therefore be beneficial in AAT deficiency-associated liver disease.

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Francesco Callea

Boston Children's Hospital

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Claudio Doglioni

Vita-Salute San Raffaele University

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Paola Francalanci

Boston Children's Hospital

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