A mechanistic study on the cardiotoxicity of 5-fluorouracil in vitro and clinical and occupational perspectives

AbstractFluoropyrimidines are key agents for the treatment of gastrointestinal tract adenocarcinomas. The possible cardiotoxic effects in patients and occupationally exposed workers are multifactorial and remain a puzzle to solve for investigators. In the present study, we study what cell death pathways and what doses can determine direct cardiotoxic effects of 5-fluorouracil (5-FU) and doxorubicin (DOXO) on rat cardiocytes (H9c2) and a human colon adenocarcinoma (HT-29) cell line, already reported to be sensitive to 5-FU. We have found that 5-FU induced 50% growth inhibition (IC:50) at 72h with concentrations of 400μM and 4μM on H9c2 and HT-29, respectively. Moreover, we have found that the addition of Levofolinic Acid (LF) to 5-FU potentiated the growth inhibition induced by 5-FU. The growth inhibition induced by 5-FU alone or in combination with LF in cardiocytes was paralleled by an increase of thiobarbituric acid-reactive species (Tbars) and end products of nitric oxide (NO) suggesting the increase of the oxidative stress status in cardiocytes. Interestingly, these effects were strongly potentiated by the addition of LF, a biochemical modulator of 5-FU activity.Our data suggest that agents such as 5-FU different from anthracyclines, conventionally related to the induction of cardiotoxic effects, can also induce cardiocyte damage paralleled by oxidative stress. The strategies based upon the use of scavengers could be used in order to prevent this effect

Role of DNA repair machinery and p53 in the testicular germ cell cancer: a review

Notwithstanding the peculiar sensitivity to cisplatin-based treatment, resulting in a very high percentage of cures even in advanced stages of the disease, still we do not know the biological mechanisms that make Testicular Germ Cell Tumor (TGCT) "unique" in the oncology scene. p53 and MDM2 seem to play a pivotal role, according to several in vitro observations, but no correlation has been found between their mutational or expression status in tissue samples and patients clinical outcome. Furthermore, other players seem to be on stage: DNA Damage Repair Machinery (DDR) , especially Homologous Recombination (HR) proteins, above all Ataxia Telangiectasia Mutated (ATM), cooperates with p53 in response to DNA damage, activating apoptotic cascade and contributing to cell "fate". Homologous Recombination deficiency has been assumed to be a Germ Cell Tumor characteristic underlying platinum-sensitivity, whereby Poly(ADP-ribose) polymerase (PARP), an enzyme involved in HR DNA repair, is an intriguing target: PARP inhibitors have already entered in clinical practice of other malignancies and trials are recruiting TGCT patients in order to validate their role in this disease. This paper aims to summarize evidence, trying to outline an overview of DDR implications not only in TGCT curability, but also in resistance to chemotherapy

An Integrated Methodology of Subjective Investigation for a Sustainable Indoor Built Environment. The Case Study of a University Campus in Italy

Indoor built environments’ design and management require a holistic approach inspired by ergonomic principles and sustainability criteria. This is especially in case of renovation of existing buildings where any kind of intervention requires the direct feedback of occupants. This work deals with two aspects of these issues, often studied separately: the quality of interior spaces, in terms of Indoor Environmental Quality (IEQ), and the quality of the architecture in terms of orientation and wayfinding. A methodology focused on the subjective evaluation of the IEQ giving relevance to users and their fruition needs is also proposed. Main findings from a specific subjective investigation carried out at the Fisciano Campus of the University of Salerno (Italy) demonstrate that the subjective approach is a valuable tool to make more sustainable intervention strategies. In this way, all multidisciplinary skills can be synergically involved in improving the livability of a complex reality as University Campuses are

Attentional processing in sporadic amyotrophic lateral sclerosis: the role of ERPs

Background: Amyotrophic Lateral Sclerosis (ALS) was traditionally believed to spare cognitive functions, but subtle executive deficits have been recently reported in patients with sporadic ALS. Aims: To investigate the attentional processing related to both the involuntary attention and the sustained attention with executive control in ALS using Event-related Potentials (ERPs). Methods: 33 non-demented patients with sporadic ALS (22 spinal-onset, 11 bulbar-onset) and 32 age and sex-matched controls underwent an EEG recording. Mismatch Negativity (MMN) and Contingent Negative Variation (CNV) components were obtained. MMN latency, CNV amplitude (measured as total area and as three temporal windows of interest) were evaluated. Reaction times in the CNV paradigm were also obtained. Results: No differences emerged between ALS patients and controls as regards MMN latency and CNV characteristics. Total CNV area (Fz p<0.01) and W1-CNV area were significantly reduced (Fz p=0.07 – Cz p<0.05 – Pz p<0,05) in bALS vs controls, while no differences were found between sALS and controls. Discussion: The normal MMN latency, even when the two clinical subtypes are analyzed individually, may indicate that the disease process does not interfere with the automatic pre-attentive processing of the stimuli. However, b-ALS patients showed a difficulty in giving start and sustaining attention during a complex task of associative learning, suggesting the assumption of an abnormal integration of associative functions, as demonstrated by the decreased amplitude of CNV in frontal area and in early orienting windows. These results are in line with the hypothesis of a degeneration of the attentional networks probably due to the interneuronal pathological involvement. Conclusions: ALS patients with bulbar onset presented selective cognitive dysfunction with difficulty in sustained attention. The involuntary attention, instead, seems to be preserved, irrespective of the disease subtype

Involuntary attention in essential tremor: a MMN study

Background: Essential Tremor (ET) is one of the most common neurological disorders and the most common pathologic tremor in humans. Indeed, as has been observed in several other progressive movement disorders, the motor disturbances appear to be accompanied by cognitive deficits. Aims: To investigate the involuntary attention in patients with essential tremor using the Mismatch Negativity (MMN). Methods: seventeen non-demented patients with ET and seventeen age- and sex-matched healthy controls underwent an EEG recording. MMN was evoked in a classical auditory MMN paradigm: 1000 Hz standard stimuli, occasionally interrupted by 1100HZ deviant stimuli that occurred with a probability of 0.2, were administered while subjects were watching a silent movie. ISI was set at 1 s. MMN latency and amplitude were evaluated. Results: MMN latency was prolonged in patients with elderly-onset ET (>65 years) (p<0.005), while no differences emerged either in latency or in amplitude between younger-onset ET and controls. Discussion: Elderly onset ET patients displayed a difficulty in the automatic involuntary processing of the stimuli, as demonstrated by the prolonged MMN latency. MMN is generated from auditory cortices bilaterally, possibly with an additional downstream component in the frontal cortex, the latter being a selective index of attentional orienting. Cerebellum, which is thought to play a major role in the pathophysiology of ET, may interfere with cognitive functioning, due to its strong and bidirectional frontal connectivity particularly to the prefrontal cortex. The differences between elderly-onset and younger-onset ET patients indicate that ET may represent a heterogeneous family of diseases united by tremor, but heterogeneous in other characteristics, as regarding cognitive functioning and in particular the automatic pre-attentive orienting. Conclusion: Our psychophysiological data shed light on the involvement of the attentional frontal network in ET, revealing a picture of the pathological process underlying this disease that is more complex than traditionally believed

Attention in essential tremor: evidence from event-related potentials

Clinically subtle executive dysfunctions have recently been described in essential tremor (ET), though the presence of attentional deficits is still unclear. We investigated the psychophysiological aspects of attention in ET, using event-related potentials (ERPs). Twenty-one non-demented patients with ET and 21 age- and sex-matched healthy controls underwent a psychophysiological evaluation. P300 components and the Contingent Negative Variation (CNV) were recorded. The latencies and amplitudes of the P3a and P3b subcomponents and CNV areas were evaluated. Possible correlations between clinical parameters and ERP data were investigated. P3a latency was significantly longer in the ET group (p < 0.05), while no differences emerged between patients and controls in P3b latency. No differences were observed between the two groups in the CNV parameters. ET patients display a difficulty in the response to novelty and in the recruitment of prefrontal attentive circuits, while the memory context-updating process appears to be spared. This selective cognitive dysfunction does not appear to interfere with the attentional set linked to the expectancy evaluated during a complex choice-reaction time task, which is preserved in ET. This multitask psychophysiological approach reveals the presence of a peculiar attentional deficit in patients with ET, thus expanding the clinical features of this disease

Attentional processing in bulbar- and spinal-onset amyotrophic lateral sclerosis: Insights from event-related potentials

Our objective was to evaluate attentional processing with respect to the clinical-onset subtype in amyotrophic lateral sclerosis (ALS) using event-related potentials (ERPs). Thirty-three non-demented ALS patients (22 spinal onset, 11 bulbar onset) and 32 age- and gender-matched controls underwent a psychophysiological evaluation. Mismatch Negativity (MMN), P300 components and Contingent Negative Variation (CNV) were obtained. Latencies and amplitudes of the MMN, P3a and P3b waves and CNV amplitude were then evaluated. Clinical parameters were correlated with ERP data. No differences emerged between ALS patients and controls with regard to the MMN and P3b components. N1-P3a inter-peak latency (Fz, p = 0.003; Cz, p = 0.001; Pz, p = 0.002) was longer in ALS-b than in ALS-s. Total CNV area (Cz, p = 0.01) and W1-CNV area were significantly reduced (Cz, p = 0.05; Pz, p = 0.03) in ALS-b with respect to the one of the controls, while no differences were found between ALS-s patients and controls. In conclusion, automatic pre-attentive processing of stimuli seems to be preserved in ALS. However, a significant delay in the time-course of selective attentive processing and a difficulty in initiating and sustaining attention may be present in ALS-b, which points to a possible dysfunction in the frontal neural network that responds to novelty and to abnormal integration of associative functions. This attentional impairment should be taken in account while developing alternative communicative strategies in ALS patients. © 2014 Informa Healthcare