Biomedical subjects

Andrea Ciarmiello

Publications and source records attributed to Andrea Ciarmiello.

9 recordsLinked to original sources

PubMed2006

HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity.

HMGA2 gene amplification and overexpression in human prolactinomas and the development of pituitary adenomas in HMGA2 transgenic mice showed that HMGA2 plays a crucial role in pituitary tumorigenesis. We have explored the pRB/E2F1 pathway to investigate the mechanism by which HMGA2 acts. Here we show that HMGA2 interacts with pRB and induces E2F1 activity in mouse pituitary adenomas by displacing HDAC1 from the pRB/E2F1 complex-a process that results in E2F1 acetylation. We found that loss of E2F1 function (obtained by mating HMGA2 and E2F1(-/-) mice) suppressed pituitary tumorigenesis in HMGA2 mice. Thus, HMGA2-mediated E2F1 activation is a crucial event in the onset of these tumors in transgenic mice and probably also in human prolactinomas.

Acetylation↗

PubMed2006

Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington's disease.

UNLABELLED: We studied the anatomic and functional changes in various brain areas during the course of Huntington's disease (HD) in a large cohort of mutation-positive individuals (n = 71) encompassing the complete range of disability (presymptomatic through stage V), and in healthy controls, for the purpose of defining both degenerative and dysfunctional brain changes in the same subjects. METHODS: We used an MRI and unsupervised multiparametric segmentation procedure based on a relaxometric approach to measure in vivo brain volumes in 71 subjects with presymptomatic to advanced HD. The same population was evaluated by 18F-FDG PET to assess variations in brain glucose metabolism. To predict age at onset in unaffected mutation carriers, we considered the estimated number of years from each subject's age to manifested HD symptoms, for a given expanded triplet number. RESULTS: Age-adjusted analyses confirmed that the 71 subjects as a group, as well as the subgroup of 24 unaffected presymptomatic subjects at risk for HD, had significantly smaller gray-matter and white-matter volumes and larger cerebrospinal fluid volumes than did controls (P < 0.0001). In the 24 presymptomatic subjects, we observed a significant inverse linear correlation between white-matter volume reduction and the estimated time to symptom onset (r2= 0.39; P = 0.0011). Both clinically unaffected subjects at risk for HD and symptomatic patients had significantly decreased glucose uptake in the cortex (frontal and temporal lobes) and striatum (caudate and putamen). HD subjects who were followed up longitudinally showed progressive white-matter reduction in the preclinical subjects (n = 10) and decreased glucose uptake in the cortex and striatum in affected (n = 21) and preclinical (n = 10) subjects. CONCLUSION: White-matter volume loss may precede gray-matter atrophy and may be associated with neuronal dysfunction in early disease.

Adult↗

PubMed2005

Juvenile Huntington's disease: does a dosage-effect pathogenic mechanism differ from the classical adult disease?

Huntington's disease (HD) is caused by a CAG repeat mutation translating as a polyglutamine (poly(Q)) expansion in the huntingtin protein, whose main pathogenic mechanism is a gain of toxic function. In the case of large expansions beyond 60 repeats onset may result in juvenile HD (JHD, onset before 20 years of age). However, the triplet number does not represent the only onset modifier even in case of large expansions, mechanisms other than the size of the mutation contribute to the phenotype. In this review we discuss the possibility that some of the pathogenic mechanisms contributing to age at onset and progression may differ in the early onset HD compared with the classical adult pathology.

Adolescent↗

PubMed2005

Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas.

Overexpression of HMGA1 proteins is a constant feature of human carcinomas. Moreover, rearrangements of this gene have been detected in several human benign tumors of mesenchymal origin. To define the role of these proteins in cell transformation in vivo, we have generated transgenic mice overexpressing ubiquitously the HMGA1 gene. These mice developed mixed growth hormone/prolactin cell pituitary adenomas and natural killer (NK)-T/NK cell lymphomas. The HMGA1-induced expression of IL-2 and IL-15 proteins and their receptors may account for the onset of these lymphomas. At odds with mice overexpressing a wild-type or a truncated HMGA2 protein, adrenal medullar hyperplasia and pancreatic islet cell hyperplasia frequently occurred and no increase in body size and weight was observed in HMGA1 mice. Taken together, these data indicate an oncogenic role of the HMGA1 gene also in vivo.

Adrenal Medulla↗

PubMed2003

Inhibition of early 99mTc-MIBI uptake by Bcl-2 anti-apoptotic protein overexpression in untreated breast carcinoma.

Lack of technetium-99m methoxyisobutylisonitrile ((99m)Tc-MIBI) uptake is consistently reported to predict poor response to subsequent chemotherapy in a variety of human malignant tumours. Since (99m)Tc-MIBI accumulates within mitochondria, which also play a central role in apoptosis through the integration of death signals by Bcl-2 family members, we tested whether early (99m)Tc-MIBI uptake is affected by alterations of the apoptotic pathway. Forty-two breast cancer patients were intravenously injected with 740 MBq of (99m)Tc-MIBI and planar images were obtained 10 min post injection with the patients in the prone lateral position. Ten carcinomas failed to accumulate (99m)Tc-MIBI and could not be visualised on scintigraphic images despite being larger than 1.8 cm (MIBI negative). Thirty-two of the 42 breast carcinomas showed focal uptake of (99m)Tc-MIBI (MIBI positive), and 10 min tumour-to-background ratios (T/B) varied between 1.14 and 6.93. The apoptotic index, the rate of proliferation, and the expression of the anti-apoptotic Bcl-2 protein and pro-apoptotic Bax protein were assessed in surgically excised tumours. All MIBI-negative carcinomas showed a dramatic and statistically significant reduction in the apoptotic index as compared with MIBI-positive lesions (mean+/-SD, 0.14+/-0.15 vs 1.28+/-0.83, P<0.0001) independently of rate of proliferation, tumour size and P-glycoprotein expression. Significantly higher levels of Bcl-2 were also found in MIBI-negative as compared with MIBI-positive carcinomas. In MIBI-positive lesions, an inverse significant correlation was found between T/B ratios and Bcl-2 levels ( r=-0.50, P<0.01). Our findings indicate that early uptake of (99m)Tc-MIBI in breast carcinomas is affected by alterations of apoptotic pathway. High levels of Bcl-2, despite the stabilisation of mitochondrial membrane potentials, prevent accumulation of (99m)Tc-MIBI in tumour cells. In conclusion, absent or reduced early (99m)Tc-MIBI uptake in large tumours may indicate a Bcl-2-mediated resistance to chemo- and radiotherapy.

Adult↗

PubMed2003

Brain tissue volume changes in relapsing-remitting multiple sclerosis: correlation with lesion load.

The aim of this study was to simultaneously measure in vivo volumes of gray matter (GM), normal white matter (WM), abnormal white matter (aWM), and cerebro-spinal fluid (CSF), and to assess their relationship in 50 patients with relapsing-remitting multiple sclerosis (RR-MS) (age range, 21-59; mean EDSS, 2.5; mean disease duration, 9.9 years), using an unsupervised multiparametric segmentation procedure applied to brain MR studies. Tissue volumes were normalized to total intracranial volume providing corresponding fractional volumes (fGM, faWM, fWM, and fCSF), subsequently corrected for aWM-related segmentation inaccuracies and adjusted to mean patients' age according to age-related changes measured in 54 normal volunteers (NV) (age range 16-70). In MS patients aWM was 23.8 +/- 29.8 ml (range 0.4-138.8). A significant decrease in fGM was present in MS patients as compared to NV (49.5 +/- 3.2% vs 53.3 +/- 2.1%; P < 0.0001), with a corresponding increase in fCSF (13.0 +/- 3.8% vs 9.1 +/- 2.4%; P < 0.0001). No difference could be detected between the two groups for fWM (37.5 +/- 2.6% vs 37.6 +/- 2.2%). faWM correlated inversely with fGM (R = -0.434, P < 0.001 at regression analysis), and directly with fCSF (R = 0.473, P < 0.001), but not with fWM. There was a significant correlation between disease duration and EDSS, while no relationship was found between EDSS or disease duration and fractional volumes. Brain atrophy in RR-MS is mainly related to GM loss, which correlates with faWM. Both measures do not appear to significantly affect EDSS, which correlates to disease duration.

Adult↗

PubMed2002

Dynamic coupling of 99mTc-MIBI efflux and apoptotic pathway activation in untreated breast cancer patients.

Our previous studies showed that the efflux rate of technetium-99m methoxyisobutylisonitrile (MIBI) is directly correlated to P-glycoprotein (Pgp) levels in breast carcinoma. The aim of this study was to test whether the Pgp-dependent efflux of 99mTc-MIBI is related to the apoptotic pathway activation in breast carcinoma. Thirty-three untreated non-consecutive patients were intravenously injected with 740 MBq 99mTc-MIBI and serial images were obtained up to 4 h. The rate of efflux was determined by mono-exponential fitting of decay-corrected time-activity curves. Tumour specimens were then obtained at surgery and processed for the determination of the apoptotic index by in situ end-labelling of DNA fragments (Tunel). The rate of tumour cell proliferation was also determined using Ki67 monoclonal antibody. All breast carcinomas showed focal uptake of 99mTc-MIBI and the time to half clearance varied between 85 and 574 min. The apoptotic index ranged between 0.3% and 4.2%, whereas the rate of proliferation varied between 13% and 40%. We found a positive and significant correlation between the apoptotic index and the rate of proliferation (r=0.79, P<0.0001). The efflux rate of 99mTc-MIBI was directly and significantly correlated with the apoptotic index (r=0.74, P<0.0001) and with the rate of proliferation (r=0.58, P<0.001). After partial correlation analysis, only the apoptotic index showed a significant correlation with the efflux rate of 99mTc-MIBI (r=0.57, P<0.001). Our findings indicate that enhanced transport activity of Pgp is associated with increased activation of the apoptotic pathway, suggesting that inhibition of Pgp function with specific modulators may be effective in these patients. Furthermore, since mitochondria are central executioners of apoptosis and intracellular sites of 99mTc-MIBI sequestration, a model for the dynamic coupling of Pgp-dependent 99mTc-MIBI efflux and apoptotic pathway activation may be derived.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Stereotaxy-based regional brain volumetry applied to segmented MRI: validation and results in deficit and nondeficit schizophrenia.

A method for postprocessing of segmented routine brain MRI studies providing automated definition of major structures (frontal, parietal, occipital, and temporal lobes; cerebellar hemispheres; and lateral ventricles) according to the Talairach atlas is presented. The method was applied to MRI studies from 25 normal subjects (NV), 14 patients with deficit schizophrenia (DS), and 14 with nondeficit schizophrenia (NDS), to evaluate their gray matter and CSF regional volumes. The two patient groups did not differ in mean age at illness onset, duration of illness, severity of psychotic symptoms, or disorganization; DS had more severe avolition and worse social functioning than NDS. For validation purposes, brain structures were manually outlined on original MR images in 10 studies, thus obtaining reference measures. Manual and automated measures were repeated 1 month apart to measure reproducibilities of both methods. The automated method required less than 1 min/operator per study vs more than 30 min for manual assessment. Mean absolute difference per structure between the two techniques was 4.8 ml. Overall reproducibility did not significantly differ between the two methods. In subjects with schizophrenia, a significant decrease in GM and increase in CSF were found. GM loss was confined to frontal and temporal lobes. Lateral ventricles were significantly larger bilaterally in NDS compared to NV and only on the right in NDS compared to DS. The finding of greater structural brain abnormalities in NDS adds to the evidence that deficit schizophrenia does not represent just the more severe end of the schizophrenia continuum.

Adolescent↗

PubMedDate not supplied

Similar TIAs and corresponding alterations in regional cerebral perfusion in Caucasian monozygotic twins with moyamoya disease.

We previously reported the first Caucasian monozygotic twins with moyamoya disease (MMD). In both patients, hyperventilation induced similar transient onset of left arm and hand paresthesias. Cerebral single photon emission computerized tomography (SPECT) showed overlapping perfusion abnormalities in the left parietal areas. Similarly, EEG showed high amplitude, bilateral, anterior, slow wave activity in the delta range during hyperventilation and rebuild-up phenomenon in both twins. Similar clinical symptoms mirrored alterations in regional cerebral perfusion by SPECT and EEG in our Caucasian monozygotic twins with MMD.

Adult↗