A study of the toxic effects of six dibenzofuranes in mitochondria from rat liver

The interactions of five dibenzofurans with the mitochondria from rat liver have been investigated. Results indicate that at low doses all dibenzofurans induce inhibition of ATP synthesis. The efficiency of ATP synthesis is measured from the ratio (R ) between the ADP-stimulated respiratory rate (State 3) and basal respiration (State 4). When R = 1, no ATP synthesis occurs. A comparison between the R values for all investigated dibenzofurans (PCDF) shows that the R values are in the same order of magnitude

An in vitro study on the toxic effects of nonylphenols (NP) in mitochondria

This paper is focused on alkylphenols, compounds which are formed by the biodegradation of polyethoxilatedalkylphenols detergents. Our experiments show that alkylphenols act not only as detergents, butalsoasuncouplersoftheoxidativephosphorylation. Thiseff~ot,canbeobservedatverylowdoses,thus suggesting that the preferential target ofnonylphenols in living organisms are mitochondria

Pemetrexed single agent chemotherapy in previously treated patients with locally advanced or metastatic non-small cell lung cancer

<p>Abstract</p> <p>Background</p> <p>The main objective of this study was to evaluate the safety of second-line pemetrexed in Stage IIIB or IV NSCLC.</p> <p>Methods</p> <p>Overall, 95 patients received pemetrexed 500 mg/m²i.v. over Day 1 of a 21-day cycle. Patients also received oral dexamethasone, oral folic acid and i.m. vitamin B12 supplementation to reduce toxicity. NCI CTC 2.0 was used to rate toxicity. All the adverse events were graded in terms of severity and relation to study treatment. Dose was reduced in case of toxicity and treatment was delayed for up to 42 days from Day 1 of any cycle to allow recovering from study drug-related toxicities. Tumor response was measured using the RECIST criteria.</p> <p>Results</p> <p>Patients received a median number of 4 cycles and 97.8% of the planned dose. Overall, 75 patients (78.9% of treated) reported at least one adverse event: 34 (35.8%) had grade 3 as worst grade and only 5 (5.2%) had grade 4. Drug-related events occurred in 57.9% of patients. Neutropenia (8.4%) and leukopenia (6.3 %) were the most common grade 3/4 hematological toxicities. Grade 3 anemia and thrombocytopenia were reported in 3.2% and 2.1% of patients, respectively. Diarrhea (6.3%), fatigue (3.2%) and dyspnea (3.2%) were the most common grade 3/4 non-hematological toxicities. The most common drug-related toxicities (any grade) were pyrexia (11.6%), vomiting, nausea, diarrhea and asthenia (9.5%) and fatigue (8.4%). Tumor Response Rate (CR/PR) in treated patients was 9.2%. The survival at 4.5 months (median follow-up) was 79% and the median PFS was 3.1 months. Twenty patients (21.1%) died mainly because of disease progression.</p> <p>Conclusion</p> <p>Patients with locally advanced or metastatic NSCLC could benefit from second-line pemetrexed, with a low incidence of hematological and non-hematological toxicities.</p

The Italian National Register of infants with congenital hypothyroidism: twenty years of surveillance and study of congenital hypothyroidism

All the Italian Centres in charge of screening, diagnosis, and follow-up of infants with congenital hypothyroidism participate in the Italian National Registry of affected infants, which performs the nationwide surveillance of the disease. It was established in 1987 as a program of the Health Ministry and is coordinated by the Istituto Superiore di Sanità. The early diagnosis performed by the nationwide newborn screening programme, the prompt treatment and the appropriate clinical management of the patients carried out by the Follow-up Centres, and the surveillance of the disease performed by the National Register of infants with congenital hypothyroidism are the components of an integrated approach to the disease which has been successfully established in our country

Coordinated Sumoylation and Ubiquitination Modulate EGF Induced EGR1 Expression and Stability

Abstract: Background: Human early growth response-1 (EGR1) is a member of the zing-finger family of transcription factors induced by a range of molecular and environmental stimuli including epidermal growth factor (EGF). In a recently published paper we demonstrated that integrin/EGFR cross-talk was required for Egr1 expression through activation of the Erk1/2 and PI3K/Akt/Forkhead pathways. EGR1 activity and stability can be influenced by many different post-translational modifications such as acetylation, phosphorylation, ubiquitination and the recently discovered sumoylation. The aim of this work was to assess the influence of sumoylation on EGF induced Egr1 expression and/or stability. Methods: We modulated the expression of proteins involved in the sumoylation process in ECV304 cells by transient transfection and evaluated Egr1 expression in response to EGF treatment at mRNA and protein levels. Results: We demonstrated that in ECV304 cells Egr1 was transiently induced upon EGF treatment and a fraction of the endogenous protein was sumoylated. Moreover, SUMO-1/Ubc9 over-expression stabilized EGF induced ERK1/2 phosphorylation and increased Egr1 gene transcription. Conversely, in SUMO-1/Ubc9 transfected cells, EGR1 protein levels were strongly reduced. Data obtained from protein expression and ubiquitination analysis, in the presence of the proteasome inhibitor MG132, suggested that upon EGF stimuli EGR1 sumoylation enhanced its turnover, increasing ubiquitination and proteasome mediated degradation. Conclusions: Here we demonstrate that SUMO-1 modification improving EGR1 ubiquitination is involved in the modulation of its stability upon EGF mediated induction

Structural and functional magnetic resonance imaging (MRI) in the prediction and characterization of mild cognitive impairment (MCI) and Alzheimer's disease (AD)

The aim of the research presented in this thesis was to improve the characterisation of the changes in brain structure and function that occur at different stages of Alzheimer’s disease (AD) progression, from pre-symptomatic AD, to mild cognitive impairment (MCI), to clinically evident dementia, using magnetic resonance imaging (MRI) techniques. Baseline structural MRI data from a cohort of healthy older adults who were followed prospectively for ten years, during which time some developed MCI and some AD, were analysed. It was found that structural MRI could detect volume loss in medial-temporal lobes up to 7-10 years before clinical symptoms of AD appear. In addition, volumetric variability of medial-temporal regions detected by structural MRI across cognitively healthy older adults correlated with their performance on a task of visuospatial associative memory, and functional activation of the same regions occurred during successful performance of the same task on functional MRI (fMRI). Three groups of participants - cognitively healthy controls, people with MCI, and patients with probable AD - were then recruited and underwent a multimodal MRI protocol, which included functional sequences acquired at rest and during the execution of two different cognitive tasks (visuospatial associative memory and self-appraisal). Cross-sectional comparisons showed: (i) that successful visuospatial associative memory performance was associated with increased functional activity (measured with task fMRI) in lateral prefrontal regions in AD patients relative to controls and (ii) that increased functional activity overlapped with frontal brain networks showing increased functional connectivity (measured with resting fMRI) in the same AD patients. Further, by demonstrating group- and condition-specific decreased frontal activity in AD patients relative to controls during a self-appraisal fMRI task, it was shown the specific utility of fMRI to unravel cognitive mechanisms underlying specific neuropsychological symptoms such as unawareness of cognitive impairment (anosognosia) in MCI and AD. In conclusion, structural MRI can detect morphological changes in the preclinical stage of AD, possibly earlier than previously described, and these reliably match cognitive functioning in older adults. In the MCI and AD stages, once symptoms of cognitive impairment are clinically evident and measurable, task-related and resting functional MRI can inform on residual brain function detectable over and above the known changes in brain morphology and cognitive performance that have already occurred at these stages, emerging as a sensitive marker of residual ability that could potentially be used to measure the effect of new treatments.EThOS - Electronic Theses Online ServiceGBUnited Kingdo