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Biomedical subjects

S Ferrari

Publications and source records attributed to S Ferrari.

At least 19 recordsLinked to original sources
PubMed2007

Transcriptional profiles in melanocytes from clinically unaffected skin distinguish the neoplastic growth pattern in patients with melanoma.

BACKGROUND: It is generally accepted that sunlight may contribute to the development of melanoma. OBJECTIVES: To analyse gene expression of melanocytes obtained from clinically unaffected skin of patients with melanoma and healthy controls before and after exposure to ultraviolet B radiation. METHODS: Using GeneChip array technology, the gene expression of melanocytes obtained from the two donor groups was profiled, in order to identify transcriptional differences affecting susceptibility to melanoma. RESULTS: The data collected did not show any difference between the expression profiles of melanocytes purified from normal donors and from patients with melanoma that was able to give a statistically significant class separation. However, by means of unsupervised clustering our data could be divided into two main classes. The first class included the transcriptome profiles of melanocytes obtained from skin samples of patients with a vertical growth phase (VGP) melanoma, while the second class included the transcriptome profiles of melanocytes obtained from skin samples of patients with a radial growth phase (RGP) melanoma. CONCLUSIONS: These data suggest that melanocytes in patients with VGP and RGP melanomas show significant differences in gene expression profiles, which allow us to classify patients with melanoma also from clinically unaffected skin.

Adult↗
PubMed2006

Identification of a molecular signature for leukemic promyelocytes and their normal counterparts: Focus on DNA repair genes.

Acute promyelocytic leukemia (APL) is a clonal expansion of hematopoietic precursors blocked at the promyelocytic stage. Gene expression profiles of APL cells obtained from 16 patients were compared to eight samples of CD34+-derived normal promyelocytes. Malignant promyelocytes showed widespread changes in transcription in comparison to their normal counterpart and 1020 differentially expressed genes were identified. Discriminating genes include transcriptional regulators (FOS, JUN and HOX genes) and genes involved in cell cycle and DNA repair. The strong upregulation in APL of some transcripts (FLT3, CD33, CD44 and HGF) was also confirmed at protein level. Interestingly, a trend toward a transcriptional repression of genes involved in different DNA repair pathways was found in APL and confirmed by real-time polymerase chain reactor (PCR) in a new set of nine APLs. Our results suggest that both inefficient base excision repair and recombinational repair might play a role in APLs development. To investigate the expression pathways underlying the development of APL occurring as a second malignancy (sAPL), we included in our study eight cases of sAPL. Although both secondary and de novo APL were characterized by a strong homogeneity in expression profiling, we identified a small set of differentially expressed genes that discriminate sAPL from de novo cases.

Adult↗
PubMed2006

Identification of a molecular signature predictive of sensitivity to differentiation induction in acute myeloid leukemia.

Acute myeloid leukemia (AML) blasts are immature committed myeloid cells unable to spontaneously undergo terminal maturation, and characterized by heterogeneous sensitivity to natural differentiation inducers. Here, we show a molecular signature predicting the resistance or sensitivity of six myeloid cell lines to differentiation induced in vitro with retinoic acid or vitamin D. The identified signature was further validated by TaqMan assay for the prediction of response to an in vitro differentiation assay performed on 28 freshly isolated AML blast populations. The TaqMan assay successfully predicts the in vitro resistance or responsiveness of AML blasts to differentiation inducers. Furthermore, performing a meta-analysis of publicly available microarray data sets, we also show the accuracy of our prediction on known phenotypes and suggest that our signature could become useful for the identification of patients eligible for new therapeutic strategies.

Acute Disease↗
PubMed2006

Diffusion reaction of oxygen in HfO2/SiO2/Si stacks.

We study the oxidation mechanism of silicon in the presence of a thin HfO2 layer. We performed a set of annealing in 18O2 atmosphere on HfO2/SiO2/Si stacks observing the 18O distribution in the SiO2 layer with time-of-flight secondary ion mass spectrometry (ToF-SIMS). The 18O distribution in HfO2/SiO2/Si stacks upon 18O2 annealing suggests that what is responsible for SiO2 growth is the molecular O2, whereas no contribution is found of the atomic oxygen to the oxidation. By studying the dependence of the oxidation velocity from oxygen partial pressure and annealing temperature, we demonstrate that the rate-determining step of the oxidation is the oxygen exchange at the HfO2/SiO2 interface. When moisture is chemisorbed in HfO2 films, the oxidation of the underlying silicon substrate becomes extremely fast and its kinetics can be described as a wet silicon oxidation process. The silicon oxidation during O2 annealing of the atomic layer deposited HfO2/Si is fast in its early stage due to chemisorbed moisture and becomes slow after the first 10 s.

Journal Article↗
PubMed2006

Using magnetic forces to enhance non-viral gene transfer to airway epithelium in vivo.

We have assessed whether magnetic forces (magnetofection) can enhance non-viral gene transfer to the airways. TransMAG(PEI), a superparamagnetic particle was coupled to Lipofectamine 2000 or cationic lipid 67 (GL67)/plasmid DNA (pDNA) liposome complexes. In vitro transfection with these formulations resulted in approximately 300- and 30-fold increase in reporter gene expression, respectively, after exposure to a magnetic field, but only at suboptimal pDNA concentrations. Because GL67 has been formulated for in vivo use, we next assessed TransMAG(PEI) in the murine nasal epithelium in vivo, and compared this to naked pDNA. At the concentrations required for in vivo experiments, precipitation of magnetic complexes was seen. After extensive optimization, addition of non-precipitated magnetic particles resulted in approximately seven- and 90-fold decrease in gene expression for naked pDNA and GL67/pDNA liposome complexes, respectively, compared to non-magnetic particles. Thus, whereas exposure to a magnetic field improved in vitro transfection efficiency, translation to the in vivo setting remains difficult.

Animals↗
PubMed2006

Targeted education improves the very low recognition of vertebral fractures and osteoporosis management by general internists.

INTRODUCTION: Vertebral fractures in older persons are strong predictors of subsequent fracture risk but remain largely under-recognized. To evaluate the impact of an educational intervention on the recognition of vertebral fractures and the prescription of anti-osteoporosis treatment among general internists, we conducted a prospective study in a service of general internal medicine of a large university teaching hospital in Geneva, Switzerland. During a 3.5-month observation period (phase 1), all lateral spinal or chest radiographs performed on consecutive inpatients over 60 years were reviewed by two independent investigators, and vertebral fractures were graded according to their severity. METHODS: Results were compared with radiology reports and general internists' discharge summaries. During the following 2-month intervention period (phase 2), internists were actively educated about vertebral fracture identification by means of lectures, posters and flyers. Radiologists did not receive this educational strategy and served as controls. RESULTS: Among 292 consecutive patients (54% men; range: 60-97 years) included in phase 1, 85 (29%) were identified by investigators as having at least one vertebral fracture; radiologists detected 29 (34%), and internists detected 19 (22%). During the intervention phase, 58 (34%) of 172 patients were identified with vertebral fractures by investigators; radiologists detected 13 patients (22%) whereas among internists the detection rate almost doubled (25/58 patients, 43%; p=0.008 compared to phase 1). The percentage of patients with vertebral fracture who benefitted from an osteoporosis medical management increased from 11% (phase 1) to 40% (phase 2, p<0.03). CONCLUSIONS: Our findings confirm the large under-recognition of vertebral fractures, irrespective of their severity, and demonstrate that a simple educational strategy can significantly improve their detection on routine radiographs and, consequently, improve osteoporosis management.

Aged↗
PubMed2006

Pattern of relapse in 290 patients with nonmetastatic Ewing's sarcoma family tumors treated at a single institution with adjuvant and neoadjuvant chemotherapy between 1972 and 1999.

AIMS: Evaluation of pattern of recurrences of 290 patients with an Ewing's sarcoma family tumor (ESFT), who relapsed after adjuvant or neoadjuvant chemotherapy. METHODS: Retrospective analysis at a median follow-up of 16.6 years (range: 5-32) from the primary therapy. RESULTS: There were 378 recurrences, treated by surgery, and/or chemotherapy, radiotherapy, or only palliative treatments. At the last control 18 patients were alive and free of disease 2.5 to 20 years (median 12.1 year) from the last treatment, 4 were alive with uncontrolled disease, 2 died of second line chemotherapy-related toxicity, and 266 died of the tumor 4 months to 20.5 years from the first relapse (median 3.2 years). The 5-year event free survival after the last relapse and overall survival were 5.1 and 7.9%, respectively, and resulted significantly correlated with the time of first relapse, the site of first metastases, the treatment performed after relapse (all patients presently free of disease had been treated by surgery alone or combined with a second line chemotherapy) and for patients treated with neoadjuvant chemotherapy and locally by surgery, with the histologic response to preoperative chemotherapy. CONCLUSIONS: We confirm that the post-relapse outcome of patients with ESFT who relapse after conventional treatment is very poor. Nonetheless specific subgroups of patients may be cured even after 2 or 3 relapses: patients who relapse 2 or more years after primary treatment, patients who relapse with only lung metastases, and patients whose recurrences can be surgically treated.

Adolescent↗
PubMed2006

Virally mediated MafB transduction induces the monocyte commitment of human CD34+ hematopoietic stem/progenitor cells.

Upregulation of specific transcription factors is a generally accepted mechanism to explain the commitment of hematopoietic stem cells along precise maturation lineages. Based on this premise, transduction of primary hematopoietic stem/progenitor cells with viral vectors containing the investigated transcription factors appears as a suitable experimental model to identify such regulators. Although MafB transcription factor is believed to play a role in the regulation of monocytic commitment, no demonstration is, to date, available supporting this function in normal human hematopoiesis. To address this issue, we retrovirally transduced cord blood CD34+ hematopoietic progenitors with a MafB cDNA. Immunophenotypic and morphological analysis of transduced cells demonstrated the induction of a remarkable monomacrophage differentiation. Microarray analysis confirmed these findings and disclosed the upregulation of macrophage-related transcription factors belonging to the AP-1, MAF, PPAR and MiT families. Altogether our data allow to conclude that MafB is a key regulator of human monocytopoiesis.

Antigens, CD34↗
PubMed2006

Inhibition of Aurora A in response to DNA damage.

Mitotic kinases are the ultimate target of pathways sensing genotoxic damage and impinging on the cell cycle machinery. Here, we provide evidence that Aurora A (AurA) was inhibited upon generation of double-strand breaks in DNA. We demonstrate that AurA was not downstream of CDK1 and that inhibition of AurA and CDK1 by DNA damage occurred independently. Using a cell line functionally deficient in Chk2, a selective Chk1 inhibitor and siRNA to Chk1, we show that DNA-damage signals were delivered to AurA through a Chk1-dependent pathway. With regard to the molecular mechanism of AurA inhibition, we found that the point mutation Ser(342)>Ala rendered AurA resistant to inhibition by DNA damage. By means of two distinct approaches we examined the impact of reconstitution of AurA activity in DNA-damaged cells: (i) transient expression of wild-type and Ser(342)>Ala mutant, but not kinase-dead, AurA led to bypass of the DNA damage block; (ii) direct transduction of highly active wt-AurA into G2 arrested cells precisely after induction of DNA damage resulted in mitotic entry. We show that the mechanism through which AurA allowed entry into mitosis was reactivation of CDK1, thus indicating that AurA plays a key role upstream of CDK1. A model depicting the possible role of AurA at the onset of mitosis and upon DNA damage is presented.

Aurora Kinases↗
PubMed2006

Protein kinases controlling the onset of mitosis.

This review article focuses on protein kinases regulating the onset and transition through mitosis. The essay begins by introducing the structural features of the protein kinase catalytic domain and emphasizing the mechanism of enzymatic activation of this class of proteins. Next follows a short historical perspective on cell division and a description of our current understanding of mitosis. In the central part of the review I examine the four major kinases that set the stage for mitosis, which consist of Cdk1, Polo-like 1, Nek2 and Aurora kinases. For each entry dealt with, I focus particularly on studies that have linked DNA damage response pathways to inhibition of kinase activity, and I evaluate the conclusions drawn. Finally, I examine protein kinases initially described in the context of different cell cycle transitions and only later proposed to be involved in the control of mitosis.

Animals↗
PubMed2006

Hyperpyrexia-triggered relapses in an unusual case of ataxic chronic inflammatory demyelinating polyradiculoneuropathy.

The ataxic form of chronic inflammatory demyelinating polyradiculoneuropathy (ataxic-CIDP) has been recently described as a subtype of chronic ataxic neuropathy, distinguished by steroid responsiveness and relative preservation of myelinated fibres at sural nerve biopsy. We report on a case of progressive, predominantly sensory, steroid-responsive neuropathy with clinical, laboratory, electrophysiological and pathological features of this uncommon form of CIDP. Moreover, the present case displays peculiar hyperpyrexia-triggered relapses leading to transitory severe tetraparesis, bilateral facial drooping, dysphonia, dysphagia and dyspnoea, which leave clinicians with some unresolved questions.

Anti-Inflammatory Agents↗
PubMed2006

Effect of tolerance induction to immunodominant T-cell epitopes of Sendai virus on gene expression following repeat administration to lung.

Sendai virus (SeV) is able to transfect airway epithelial cells efficiently in vivo. However, as with other viral vectors, repeated administration leads to reduced gene expression. We have investigated the impact of inducing immunological tolerance to immunodominant T-cell epitopes on gene expression following repeated administration. Immunodominant CD4 and CD8 T-cell peptide epitopes of SeV were administered to C57BL/6 mice intranasally 10 days before the first virus administration with transmission-incompetent F-protein-deleted DeltaF/SeV-GFP. At 21 days after the first virus administration, mice were again transfected with DeltaF/SeV. To avoid interference of anti-GFP antibodies, the second transfection was carried out with DeltaF/SeV-lacZ. At 2 days after the final transfection lung beta-galactosidase expression, T-cell proliferation and antibody responses were measured. A state of 'split tolerance' was achieved with reduced T-cell proliferation, but no impact on antiviral antibody production. There was no enhancement of expression on repeat administration; instead, T-cell tolerance was, paradoxically, associated with a more profound extinction of viral expression. Multiple immune mechanisms operate to eradicate viruses from the lung, and these findings indicate that impeding the adaptive T-cell response to the immunodominant viral epitope is not sufficient to prevent the process.

Animals↗
PubMed2006

[Laparoscopic treatment of adnexal cystic masses].

Operative laparoscopy has become the gold standard for the surgical treatment of numerous gynecological benign conditions. In the case of ovarian cysts, however, the use of the laparoscopic approach has been debated due to the possibility of encountering an unexpected ovarian malignancy at the time of surgery. This would upstage a IA or IB ovarian malignancy to IC. In this review, the authors evaluate the preoperative parameters that could help in the selection of the patients who are candidate to a laparoscopic approach. In particular, the authors consider the age related risk of the patients, the use of sonography and color-Doppler velocimetry, the use of CA 125, and as a last diagnostic step, the findings at laparoscopy. In a personal series of 1.584 cysts in patients under 40 years of age, the first author encountered 7 unexpected borderline tumors and 1 mucinous G1 adenocarcinoma, while no malignancy was found in a group of strictly selected postmenopausal patients. These data have been compared with those found in scientific literature. There is no sound evidence that the stripping procedure determines a reduction of the ovarian reserve when performed with strict microsurgical principles. Recent evidence in the literature suggests that the decreased ovarian responsiveness reported by some authors following ovarian cystectomy may not be a consequence of surgery. The concern of a possible reduction of the ovarian reserve needs to be balanced with the benefits obtained with surgery. Finally, it should always be kept in mind the risk of an unexpected malignancy, even in cysts apparently benign, malignancy that can only be diagnosed through surgery obtaining a specimen for pathology.

Female↗
PubMed2005

PCBs and PAHs in sea-surface microlayer and sub-surface water samples of the Venice Lagoon (Italy).

Polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs) are two classes of micropollutants intensively monitored and regulated due to their toxicity, persistency and wide diffusion. Their concentrations have been investigated in sea-microlayer (SML) and sub-surface water (SSW) samples collected at two sites of the Venice Lagoon, a fragile ecosystem highly influenced by industrial and anthropogenic emissions. The total sigmaPCB concentration varies from 0.45 ng/l to 2.1 ng/l in SSW while a clear enrichment is observed in the SML, where it ranges from 1.2 ng/l to 10.5 ng/l. The total sigmaPAH concentration shows marked differences between the two stations and varies from 12.4 ng/l to 266.8 ng/l in SSW; in SML it is more uniform and ranges from 19.6 ng/l to 178.9 ng/l. The enrichment factors are not larger than 1 for both pollutants in the 'dissolved' phase, while they are most significant for the 'particulate' phase (sigmaPCB: 5-9; sigmaPAH: 4-14).

Environmental Monitoring↗
PubMed2005

[Bisphosphonates and combined treatments osteoporosis].

Bisphosphonates are inhibitors of bone resorption, which reduce vertebral and non-vertebral fracture risk. Their efficacity has been shown in controlled trials up to 5 years, and their safety up to ten years. There is no proven benefit of combining two bone resorption inhibitors.

Bone Resorption↗
PubMed2005

[Parathyroid hormone for osteroporsis: why and who to treat?].

Osteoporosis treatment with anti-catabolic agents, such as bisphosphonates and SERMS, inhibits bone remodeling, resulting in increased bone mineral density and preservation of bone micro-architecture. On another side, daily subcutaneous injections of parathyroid hormone (and PTH(1-34), teriparatide) stimulate osteoblastic functions and bone remodeling, resulting in new bone formation, increased bone mineral density and improved microarchitecture, thereby reducing fracture risk. However, the effects on PTH on cortical bone structure and its use in the context of anticatabolic treatments for osteoporosis remain complex.

Bone Density↗