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Biomedical subjects

A Greco

Publications and source records attributed to A Greco.

At least 19 recordsLinked to original sources
PubMed2006

Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets.

Medulloblastoma (MB) results from aberrant development of cerebellar neurons in which altered hedgehog (Hh) signalling plays a major role. We investigated the possible influence of Hh signalling on ErbB-receptor expression in MB, in particular that of the ErbB-4 CYT-1 and CYT-2 isoforms generated by alternative splicing of the cytoplasmic domain. ErbB-4 expression was downregulated in Hh-induced MBs from Patched-1(+/-) mice. Hh signalling (reflected by enhanced expression of the Gli1 transcription factor) inhibited ErbB-4 expression in mouse cerebellar granule progenitors and human MB cells. Analysis of 26 human primary MBs revealed a subset of 11 tumors characterized by low Gli1 levels, upregulated ErbB-4 expression and increased CYT-1:CYT-2 ratios. Interestingly, CYT-1 and Gli1 levels were inversely correlated. ErbB-4 CYT-1 and CYT-2 had different phenotypic effects in cultured MB cells: in response to neuregulin treatment, CYT-2 overexpression inhibited proliferation whereas CYT-1, which includes a phosphatidylinositol 3-kinase (PI3K)-binding site that is missing in CYT-2, enhanced resistance to starvation- and etoposide-induced apoptosis by activating PI3K/Akt signalling. CYT-1:CYT-2 ratios displayed correlation with tumor histotype and ErbB-2 levels, which are established prognostic indices for MB. These findings demonstrate that low-level Hh signalling in human MB is associated with the selective maintenance of high ErbB-4 CYT-1 expression, an alteration that exerts tumor-promoting effects.

Alternative Splicing↗
PubMed2006

Coronary flow, VO2 peak and anaerobic threshold in patients with dilated cardiomyopathy.

BACKGROUND: Coronary flow is influenced by several determinants and may change according to external stimuli. In patients with dilated cardiomyopathy (DC), adaptive mechanisms could induce alterations in coronary flow, possibly related to oxygen consumption. METHODS: In 67 consecutive patients with DC (mean age 52.06+/-13.84, 52 male gender, left ventricle ejection fraction (LVEF) 29.49%+/-8.68) and normal coronary angiography findings, coronary flow in left anterior descending (LAD), right coronary artery (RC) and left circumflex (LCx) was reported as TIMI frame count (TFC). All patients underwent a cardiopulmonary test with VO2 peak and anaerobic threshold (AT) measurement, New York Heart Association (NYHA) class stratification, two-dimensional echocardiographic evaluation including LVEF and left ventricle end-diastolic diameter (LVEDD) assessment. All patients were receiving optimal medical treatment. RESULTS: In a multivariate analysis, a statistically significant correlation was found between VO2 peak and TFC (B 7.61, p<0.001, R2 0.61 for LAD; B 3.42, p<0.001, R2 0.33 for RC); an inverse correlation was found between AT and TFC (B -9.77, p<0.001, R2 0.61 for LAD; B -4.26, p<0.001, R2 0.33 for RC). CONCLUSIONS: Coronary flow is related to VO2 peak and AT in patients with DC, suggesting a "compensatory" mechanism.

Anaerobic Threshold↗
PubMed2006

Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients.

Imatinib-acquired resistance related to the presence of secondary point mutations has become a frequent event in gastrointestinal stromal tumors. Here, transient transfection experiments with plasmids carrying two different KIT-acquired point mutations were performed along with immunoprecipitation of total protein extracts, derived from imatinib-treated and untreated cells. The molecular mechanics/Poisson Boltzmann surface area computational techniques were applied to study the interactions of the wild-type and mutated receptors with imatinib at the molecular level. Biochemical analyses showed KIT phosphorylation in cells transfected with vectors carrying the specific mutant genes. Imatinib treatment demonstrated that T670I was insensitive to the drug at all the applied concentrations, whereas V654A was inhibited by 6 microM of imatinib. The modeling of the mutated receptors revealed that both substitutions affect imatinib-binding site, but to a different extent: T670I substantially modifies the binding pocket, whereas V654A induces only relatively confined structural changes. We demonstrated that T670I and V654A cause indeed imatinib-acquired resistance and that the former is more resistant to imatinib than the latter. The application of molecular simulations allowed us to quantify the interactions between the mutated receptors and imatinib, and to propose a molecular rationale for this type of drug resistance.

Antineoplastic Agents↗
PubMed2006

Non-fermi liquid behavior in nearly charge ordered layered metals.

Non-Fermi liquid behavior is shown to occur in two-dimensional metals which are close to a charge ordering transition driven by the Coulomb repulsion. A linear temperature dependence of the scattering rate together with an increase of the electron effective mass occur above T*, a temperature scale much smaller than the Fermi temperature. It is shown that the anomalous temperature dependence of the optical conductivity of the quasi-two-dimensional organic metal alpha-(BEDT-TTF)2MHg(SCN)4, with M = NH4 and Rb, above T* = 50-100K, agrees qualitatively with predictions for the electronic properties of nearly charge ordered two-dimensional metals.

Journal Article↗
PubMed2006

PDGFRalpha, PDGFRbeta and KIT expression/activation in conventional chondrosarcoma.

Chondrosarcomas represent 20% of all primary bone sarcomas, and many studies have attempted to unravel molecular targets for future development of new therapies. The aim of this study was to investigate the expression/activation of PDGFRalpha, PDGFRbeta and KIT receptor tyrosine kinases (RTKs) as potential therapeutic targets in conventional central primary chondrosarcomas (CCS). The expression of PDGFRalpha, PDGFRbeta and KIT RTKs was detected in 16 CCSs using immunohistochemistry (IHC), and their level of expression and activation status were analysed by immunoprecipitation and western blot experiments. PDGFRalpha, PDGFRbeta and KIT cDNAs were screened to verify the presence of activating mutations and the presence of the cognate ligands was analysed by means of RT-PCR. RTK gene amplification was further studied by means of fluorescence in situ hybridization (FISH) analysis. The immunophenotyping and biochemical analyses showed that the CCSs co-expressed PDGFRalpha and PDGFRbeta, with the latter showing definitively greater protein expression and phosphorylation levels. PDGFRbeta was expressed but not activated in control healthy joint cartilage, in line with no PDGFB detection. Conversely, the KIT gene product did not seem to play a relevant role. These findings, in the absence of activating mutations or an abnormal genomic profile and the presence of PDGFA and PDGFB expression, are consistent with an autocrine/paracrine loop activation of the corresponding receptors. The CCS gene profile described here offers a rationale for the use of RTK inhibitors alone or in combination with chemotherapy, and supports further investigation of RTKs and their downstream signals.

Bone Neoplasms↗
PubMed2006

Simvastatin protection against acute immune-mediated glomerulonephritis in mice.

In addition to cholesterol lowering, 3-hydroxy-3-nethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors limit inflammatory changes associated with atherosclerosis. There is also support for their use as inhibitors of progression in chronic renal disease, irrespective of cause. In this study, their capacity to limit acute renal inflammation was evaluated. For this purpose, mice were treated with Simvastatin either prior to, at the time of, or shortly after induction of nephrotoxic nephritis. The severity of disease was determined by evaluation of blood urea nitrogen (BUN), proteinuria, and renal histologic changes. The reversibility of benefit was evaluated by the administration of mevalonic acid along with nephrotoxic serum (NTS) and Simvastatin The severity of the acute nephritis, including proteinuria, elevated BUN, and histologic changes, was ameliorated in a dose-dependent manner, when Simvastatin was administered either prior to NTS injection or at the time of NTS injection. By contrast, Simvastatin did not alter the course of established nephritis. Coadministration of mevalonic acid, the immediate substrate following HMG-CoA reductase, abolished Simvastatin's renoprotective effect, indicating that the benefit is, at least in part, due to interference with HMG-CoA reductase and biosynthetic substrates downstream from the enzyme. These findings provide the rationale for the evaluation of the efficacy of HMG-CoA reductase inhibitors in patients with recurrent forms of renal inflammation, to limit the severity of acute exacerbations of disease, prevent renal scarring and slow the rate of progression.

Acute Disease↗
PubMed2005

Quality control of automatically defined cancer cases by the automated registration system of the Venetian Tumour Registry. Quality control of cancer cases automatically registered.

BACKGROUND: In the Venetian Tumour Registry a substantial quota of cases (55%) is accepted using an algorithm that automatically evaluates diagnostic evidence: this study aims at assessing the reliability of the information produced in this way. METHODS: A reabstraction study was conducted, which put a stratified sample of 1539 automatically accepted cases through a double-blind manual revision. RESULTS: A significantly higher proportion of prevalent cases were found among breast, prostate and larynx cancer cases without microscopic confirmation, while there is a clear strong inverse relationship between the number of concordant diagnostic sources and the proportions of discordant diagnoses: cases based only on a single cytology record are particularly unreliable. A small number of multiple cancers are not detected because of one of the rules applied. CONCLUSION: The overall proportion of incorrect decisions is not high and similar to those reported by other registries, but errors are correlated to the diagnostic evidence pattern. As a further check, we decided to revise clinical cases for the three sites mentioned manually, in order to reduce the numbers proportion of both prevalent cases, and all cytology-based diagnoses, so as to reduce the number of 'false positives'. Coverage of hospital discharge source has been extended in order to decrease the proportion of cases based only on pathology records.

Algorithms↗
PubMed2005

Prevalence of hypercalcemia in hospitalised patients: effects of "correction" for serum albumin values.

Hypercalcemia is ideally detected by the measurement of serum ionised calcium. Because this is not widely available, in common clinical practice "albumin-corrected" calcium values are often utilized. Our study investigated whether the method used to measure serum albumin concentration may significantly interfere in the derived serum calcium values and, consequently, in the identification of hypercalcemic patients. In 170 consecutive patients admitted to our Department of Internal Medicine we measured serum total calcium, total protein, and albumin by colorimetric method; albumin concentration was also derived by electrophoresis assessment. After correcting serum calcium for colorimetrically (CA) and electrophoretically (EA) measured albumin values, the detected frequencies of hypercalcemia were compared, utilizing different cut-off limits (i.e. 11.0, 10.4 and 10.2 mg/dl). In our patients, the CA values were significantly lower than EA levels. As a consequence, EA-corrected calcium, as well as total calcium concentration were significantly lower than CA-corrected values. This may also account for the very different prevalence of hypercalcemic patients identified by serum total, EA-corrected and CA-corrected calcium values. Our data therefore indicate the importance of the method of albumin measurement in the determination of "corrected" calcium concentration.

Aged↗
PubMed2005

Influence of cognitive impairment and comorbidity on disability in hospitalized elderly patients.

BACKGROUND: The effects of cognitive impairment and comorbidity on the prevalence of disability in elderly patients who are hospitalized in acute wards are not well defined. OBJECTIVES: To evaluate the role of comorbidity and cognitive impairment on the prevalence of disability in a cohort of hospitalized older patients. PATIENTS AND METHODS: This study included 179 patients aged 65 years and over admitted to the Geriatric Unit of the Casa Sollievo della Sofferenza Hospital, in Italy. Cognitive status was evaluated by means of the Mini Mental State Examination (MMSE) and Clinical Dementia Rating Scale (CDR); the functional status was evaluated according to the Activity of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) indices. Comorbidity was identified using the Cumulative Illness Rating Scale (CIRS index). RESULTS: Of the 179 patients enrolled 73 patients were diagnosed with dementia [Alzheimers' Disease (AD) = 49 patients, Vascular Dementia (VD) = 24 patients], 35 patients with Mild Cognitive Impairment (MCI) and 71 patients had no cognitive impairment. The severity of disability was significantly higher in patients with dementia (ADL = 3.1 +/- 2.1, IADL = 1.5 +/- 2.0) than patients with MCI (ADL = 5.1 +/- 1.4, IADL = 5.2 +/- 2.2) (p < 0.0001) and patients without cognitive impairment (ADL = 5.5 +/- 0.9, IADL = 6.4 +/- 1.9) (p < 0.0001). No significant differences in CIRS index were observed between patients with dementia and MCI and no cognitive impairment patients (Dementia = 2.4 +/- 1.4 vs MCI = 2.9 +/- 1.4 vs No cognitive impairment = 2.7 +/- 1.2; p = 0.1). Moreover, a significant correlation between cognitive impairment and functional status (MMSE/ADL: r = 0.45, p = 0.0001, MMSE/IADL: r = 0.54, p = 0.0001) but not between comorbidity and functional status (CIRS/ADL: r = 0.0007, CIRS/IADL: r = 0.040) was observed. Separating patients with dementia by diagnosis of AD or VD, no significant differences in MMSE (AD = 12.2 +/- 6.7 vs VD = 13.2 +/- 6.5, p = 0.6), CDR (AD = 2.2 +/- 0.8 vs VD = 2.1 +/- 0.7, p = 0.6), ADL (AD = 3.1 +/- 2.1 vs VD = 3.0 +/- 2.1, p = 0.8), IADL (AD = 1.3 +/- 1.9 vs VD = 2.0 +/- 2.2, p = 0.1) or CIRS (AD = 2.2 +/- 1.5 vs VD = 2.8 +/- 1.3, p = 0.06) scores were observed. CONCLUSIONS: Cognitive impairment and not comorbidity, was significantly associated with disability in hospitalized older patients.

Activities of Daily Living↗
PubMed2004

What's in the pipeline about bladder reconstructive surgery? Some remarks on the state of the art.

The fusion of engineering with cell biology and advances in biomaterials may lead to de novo construction of implantable organs. Engineering of neobladder from autologous urothelial and smooth muscle cells cultured on biocompatible, either synthetic or naturally-derived substrates, is now feasible in preclinical studies and may have clinical applicability in the near future. The development of a bioartificial bladder would warrant the prevention of both the metabolic and neoplastic shortcomings of the intestinal neobladder. Two tissue-engineering techniques for bladder reconstruction have been tested on animals: 1) the in vivo technique involves the use of naturally-derived biomaterials for functional native bladder regeneration 2) the in vitro technique involves the establishment of autologous urothelial and smooth muscle cell culture from the host's urinary tract, after which the cells are seeded on the biodegradable matrix-scaffold to create a composite graft that is implanted into the same host for complete histotectonic regeneration. Waiting for the creation of a complete tissue-engineered bladder with a trigone-shaped base, we suggest, in surgical oncology after radical cystectomy, the realization of conduit or continent pouch using tissue-engineered material.

Animals↗
PubMed2004

Actinomycosis of submandibular gland: an unusual presentation.

An unusual presentation of oro-facial actinomycosis, mimicking the clinical appearance of a malignant lesion is reported. The patient, a 74-year-old female, presented with a right submandibular mass, which slowly grew in size over a period of about 2 months, and a modest dysphagia. A painless cervical mass was palpable over the submandibular region. The rhino-pharyngo-laryngeal region, explored by flexible fiberoptic examination, was normal. At ultrasonography, a 2x2 cm infiltrating dyshomogeneous mass, involving the right submandibular gland, was visible. No connection with adjacent organs was found. There was no associated cervical lymphoadenopathy. Ultrasound-guided fine-needle aspiration cytology, performed on lesion, revealed no evidence of malignancy. The presence of characteristic colonies of actinomyces infection was found. The patient was treated initially with tetracycline chloridrate 100 mg: 1 tablet every 12 hours for 7 weeks, but a repeat ultrasonography showed no resolution. A further fine-needle aspiration cytology showed no actinomyces infection in the specimen. The patient was treated with methylprednisolone, 20 mg every 24 hours, for 5 days. After steroid treatment, the patient has been well and, upon repeat ultrasonography, total resolution of the submandibular lesion was confirmed. In conclusion, the clinical presentation of cervicofacial actinomycosis is variable and may mimic a malignant lesion or chronic granulomatous infections. Diagnostic and therapeutic findings are discussed.

Actinomycosis↗
PubMed2002

Influence of collective effects and the d charge-density wave on electronic raman scattering in high-T(c) superconductors.

Electronic Raman scattering in high-T(c) superconductors is studied within the t-J model. It is shown that the A(1g) and B(1g) spectra are dominated by amplitude fluctuations of the superconducting and the d charge-density-wave order parameters, respectively. The B(2g) spectrum contains no collective effects and its broad peak reflects vaguely the doping dependence of T(c), similarly to the pronounced peak in the A(1g) spectrum. The agreement of our theory with the experiment supports the picture of two different, competing order parameters in the underdoped regime of high-T(c) superconductors.

Journal Article↗
PubMed2002

Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc.

The thyroid TRK-T3 oncogene, produced by a chromosomal translocation, is a chimeric, constitutively activated version of the NTRK1/NGF receptor and it is able to transform NIH3T3 cells and differentiate PC12 cells. TRK-T3 oncoprotein triggers multiple signal transduction pathways. Among others, TRK-T3 binds and phosphorylates the Shc and SNT1/FRS2 adaptor proteins both involved in coupling the receptor tyrosine kinase to the mitogen-activated protein kinase pathway by recruiting Grb2/SOS. We were interested in defining the role of Shc in the oncogenesis by TRK-T3. The mutation of TRK-T3 tyrosine 291, docking site for both Shc and FRS2, abrogates the oncogene biological activity. To directly explore the role of Shc we used the ShcY317F mutant, which carries the mutation of a tyrosine residue involved in Grb2 recruitment. We demonstrated that the ShcY317F mutant exerts an inhibitory effect on TRK-T3 transforming activity. Such effect can be modulated by the amount of ShcY317F protein and affects the viability of cells expressing TRK-T3 by means of a mechanism involving apoptosis. Our results indicate a definitive role of the adaptor protein Shc in TRK-T3 transforming activity.

3T3 Cells↗
PubMed2002

Increased CSF levels of prostaglandin E(2) in variant Creutzfeldt-Jakob disease.

The concentration of the cyclooxygenase product prostaglandin E(2) was sixfold higher in CSF samples from 18 cases of variant Creutzfeldt-Jakob disease (CJD) than in a group of eight subjects with other noninflammatory neurologic diseases, and comparable to those found in a group of six patients affected by diseases with a known inflammatory component. This finding suggests that cyclooxygenase activity may have a role in variant CJD pathogenesis, as previously reported in sporadic CJD.

Adult↗
PubMed2002

Ear involvement in acute promyelocytic leukemia at relapse: a disease-associated 'sanctuary'?

Extramedullary (EM) involvement occurs infrequently in acute promyelocytic leukemia (APL) and usually involves skin and CNS. We describe seven patients (four observed at a single institution) who relapsed in various sites of the auditory apparatus, including the external canal and middle ear (temporal bone). Front-line treatment included ATRA and chemotherapy (six patients) or chemotherapy alone (one patient). Three patients had concomitant hematologic relapse, two had molecular relapse and two were in hematologic and molecular remission when ear localization was documented. Local symptoms that stimulated further diagnostic studies included ear bleeding/discharge in the first patient, but were mild in the others (hypoacusia, five patients; earache, two patients). Ear involvement by leukemia was documented by histological and/or molecular studies after local surgery in five cases, and by CT scan or NMR in the remaining patients. We suggest that the ear might represent a specific sanctuary for disease involvement in APL.

Adolescent↗
PubMed2002

In vivo activation of N-methyl-D-aspartate receptors in the rat hippocampus increases prostaglandin E(2) extracellular levels and triggers lipid peroxidation through cyclooxygenase-mediated mechanisms.

Cyclooxygenases (COX) are a family of enzymes involved in the biosynthesis of prostaglandin (PG) and thromboxanes. The inducible enzyme cyclooxygenase-2 (COX-2) is the major isoform found in normal brain, where it is constitutively expressed in neurons and is further up-regulated during several pathological events, including seizures and ischaemia. Emerging evidence suggests that COX-2 is implicated in excitotoxic neurodegenerative phenomena. It remains unclear whether PGs or other products associated to COX activity take part in these processes. Indeed, it has been suggested that reactive oxygen species, produced by COX, could mediate neuronal damage. In order to obtain direct evidence of free radical production during COX activity, we undertook an in vivo microdialysis study to monitor the levels of PGE(2) and 8-epi-PGF(2alpha) following infusion of N-methyl-D-aspartate (NMDA). A 20-min application of 1 mm NMDA caused an immediate, MK-801-sensitive increase of both PGE(2) and 8-epi-PGF(2alpha) basal levels. These effects were largely prevented by the specific cytosolic phospholipase A(2) (cPLA(2) ) inhibitor arachidonyl trifluoromethyl ketone (ATK), by non- selective COX inhibitors indomethacin and flurbiprofen or by the COX-2 selective inhibitor NS-398, suggesting that the NMDA-evoked prostaglandin synthesis and free radical-mediated lipid peroxidation are largely dependent on COX-2 activity. As several lines of evidence suggest that prostaglandins may be potentially neuroprotective, our findings support the hypothesis that free radicals, rather than prostaglandins, mediate the toxicity associated to COX-2 activity.

Animals↗