Plasma miRNA-based signatures in CRC screening programs

Colorectal cancer (CRC) screening programs help diagnose cancer precursors and early cancers and help reduce CRC mortality. However, currently recommended tests, the fecal immunochemical test (FIT) and colonoscopy, have low uptake. There is therefore a pressing need for screening strategies that are minimally invasive and consequently more acceptable to patients, most likely blood based, to increase early CRC identification. MicroRNAs (miRNAs) released from cancer cells are detectable in plasma in a remarkably stable form, making them ideal cancer biomarkers. Using plasma samples from FIT-positive (FIT+) subjects in an Italian CRC screening program, we aimed to identify plasma circulating miRNAs that detect early CRC. miRNAs were initially investigated by quantitative real-time PCR in plasma from 60 FIT+ subjects undergoing colonoscopy at Fondazione IRCCS Istituto Nazionale dei Tumori, then tested on an internal validation cohort (IVC, 201 cases) and finally in a large multicenter prospective series (external validation cohort [EVC], 1121 cases). For each endoscopic lesion (low-grade adenoma [LgA], high-grade adenoma [HgA], cancer lesion [CL]), specific signatures were identified in the IVC and confirmed on the EVC. A two-miRNA-based signature for CL and six-miRNA signatures for LgA and HgA were selected. In a multivariate analysis including sex and age at blood collection, the areas under the receiver operating characteristic curve (95% confidence interval) of the signatures were 0.644 (0.607–0.682), 0.670 (0.626–0.714) and 0.682 (0.580–0.785) for LgA, HgA and CL, respectively. A miRNA-based test could be introduced into the FIT+ workflow of CRC screening programs so as to schedule colonoscopies only for subjects likely to benefit most.     

MEMRI and tumors: a method for the evaluation of the contribution of Mn(II) ions in the extracellular compartment

The purpose of the work was to set‐up a simple method to evaluate the contribution of Mn²⁺ ions in the intra‐ and extracellular tumor compartments in a MEMRI experiment. This task has been tackled by “silencing” the relaxation enhancement arising from Mn²⁺ ions in the extracellular space. In vitro relaxometric measurements allowed assessment of the sequestering activity of DO2A (1,4,7,10‐tetraazacyclododecane‐1,7‐diacetic acid) towards Mn²⁺ ions, as the addition of Ca‐DO2A to a solution of MnCl₂ causes a drop of relaxivity upon the formation of the highly stable and low‐relaxivity Mn‐DO2A. It has been proved that the sequestering ability of DO2A towards Mn²⁺ ions is also fully effective in the presence of serum albumin. Moreover, it has been shown that Mn‐DO2A does not enter cell membranes, nor does the presence of Ca‐DO2A in the extracellular space prompt migration of Mn ions from the intracellular compartment. On this basis the in vivo, instantaneous, drop in SE% (percent signal enhancement) in T₁‐weighted images is taken as evidence of the sequestration of extracellular Mn²⁺ ions upon addition of Ca‐DO2A. By applying the method to B16F10 tumor bearing mice, T₁ decrease is readily detected in the tumor region, whereas a negligible change in SE% is observed in kidneys, liver and muscle. The relaxometric MRI results have been validated by ICP‐MS measurements. Copyright © 2015 John Wiley & Sons, Ltd.     

A nationally representative survey of hospital malnutrition: the Italian PIMAI (Project: Iatrogenic MAlnutrition in Italy) study

Aim and methods  Nutrition, unhealthy lifestyles and cancer appear to be strictly related, but few authors have analysed the interest in dietary information of cancer patients and their families. This survey was conducted in the Veneto area (Italy) to investigate the concern of cancer patients and their family members about diet as a health tool before and after diagnosis of cancer. Results  Seven hundred and four questionnaires were collected: 380 from cancer patients and 324 from family members of cancer subjects. Breast cancer (BC) was the most frequent disease for patients (61.8%) as well as families (26.5%). Generally, the importance of having precise diet information after diagnosis is recognised by 40.3% of patients, with significant differences between the various types of cancer: gastric and colon/rectum cancer (GCC) patients were more concerned than BC women about precise information concerning a diet to follow immediately after diagnosis (p = 0.000, ODs = 3.10, CI 1.68–5.71) or during treatments (p = 0.001, ODs = 2.67, CI 1.46–4.89). The nutritional information is supplied to patients in 34% of cases and to relatives in 30.3%, often from non-medical sources. In total healthcare workers (family doctor, oncologist, surgeon, dietician) represented the exclusive source of dietary information for 24.9% of patients and 22.9% of family members. Diet after diagnosis changes in 69.1% of GCC patients and in 39.2% of BC women. Relatives, particularly women, report difficulties preparing patients’ meals in 30.7% of cases, changes in the eating habits of the entire family in 29.9% and discontent connected with patients diet in 13.9%. The concern about proper nutrition after diagnosis increases more in GCC subjects (p < 0.025) when compared to BC subjects and in patients with more recent diagnosis (p < 0.041) when compared with patients with diagnosis >5 years ago, while in family members the interest in diet after diagnosis increases more in women than in men (p < 0.030) without other differences regarding the degree of relationship, type of cancer or diagnosis time. Relatives (92.7%) have more interest in nutritional education than patients (74.9%). Cancer patients <65 years were more interested in educational initiatives concerning nutrition (p = 0.000, ODs = 4.46, CI 2.6–7.4) than older patients (>65 years) and female subjects were more concerned than male patients (p = 0.008, ODs = 2.11, CI 1.2–3.6). Conclusions  The interest in the dietary knowledge and in educational initiatives concerning nutrition is high in cancer patients and their relatives, although it decreases with the age. The poor attention paid to nutrition of cancer patients by various healthcare workers deserves consideration, since the psychophysical wellbeing and perhaps also survival of cancer patients can be improved by correct dietary management, as well as, naturally, by the principal treatments themselves.     

Contribution of ambulatory EEG recording (Medilog 9000) in a population of epileptics

Thirty-four epileptic patients, aged 9 to 36, were submitted to A/EEG between May 1987 and July 1988. All patients had a thorough clinical and EEG work-up including long-term conventional EEG, afternoon polygraphic sleep recording and, in some cases, full-night EEG and video monitoring. Patients were divided into 2 groups: group I included 19 patients (18 with symptomatic partial epilepsy (SPE) and 1 with idiopathic generalized epilepsy (IGE) in whom no seizure had ever been recorded in spite of EEG recordings averaging a total of 16 hrs 10 min, awake and asleep); group II included 15 subjects (6 with SPE, 5 with IGE, 3 with symptomatic GE and 1 with undetermined epilepsy) in whom one or several seizures had been recorded. A/EEG was performed in order to: 1) obtain better clinical and EEG characterization of seizures, 2) study the circadian distribution of seizures, 3) verify the efficacy of drug treatment and, 4) establish the epileptic or non-epileptic nature of some ictal events. The results of A/EEG were considered positive in 52.63% of group I patients and in 93.33% of group II patients. The authors discuss the specific advantages of A/EEG vs conventional EEG: recording of seizures with random occurrence, of seizures accompanied by falls, checking the remission of seizures.     

Genetics of epilepsy: epilepsy research foundation workshop report.

The Sixth Epilepsy Research Foundation workshop, held in Oxford in March 2006, brought together basic scientists, geneticists, epidemiologists, statisticians, pharmacologists and clinicians to consider progress, issues and strategies for harnessing genetics to improve the understanding and treatment of the epilepsies. General principles were considered, including the fundamental importance of clear study design, adequate patient numbers, defi ned phenotypes, robust statistical data handling, and follow-up of genetic discoveries. Topics where some progress had been made were considered including chromosomal abnormalities, neurodevelopment, hippocampal sclerosis, juvenile myoclonic epilepsy, focal cortical dysplasia and pharmacogenetics. The ethical aspects of epilepsy genetics were reviewed. Principles and limitations of collaboration were discussed. Presentations and their matched discussions are produced here. There was optimism that further genetic research in epilepsy was not only feasible, but might lead to improvements in the lives of people with epilepsy.     

Potent relaxant effect of a Celastrus paniculatus extract in the rat and human ileum

Ethnopharmacological importance

Celastrus paniculatus Willd. (Celastraceae) is an Ayurvedic remedy used for the treatment of a number of diseases, including bowel spasms.

Aim of the study

To investigate the mode of the relaxing action of a methanolic extract prepared from the seeds of Celastrus paniculatus (CPE, 0.0001–10 μg/mL) in the rat ileum and to try to confirm on human tissues the intestinal pharmacological activity of the extract.

Materials and methods

The relaxant effect of CPE was studied in vitro by evaluating its effect on the spontaneous contractions of the isolated ileum.

Results

CPE exerted a tetrodotoxin- and ω-conotoxin-resistant inhibitory effect on rat ileum motility (IC₅₀: 0.24 ± 0.02 μg/mL; E_max: 99.0 ± 0.60%). The inhibitory effect was reduced by nifedipine but not by cyclopiazonic acid. Experiments with specific antagonists enabled us to exclude the involvement of the main endogenous spasmogenic (i.e. acetylcholine and tachykinins) and relaxing (noradrenaline, nitric oxide, ATP) compounds. CPE also relaxed the isolated human ileum (IC₅₀: 0.26 ± 0.02 μg/mL; E_max: 99.1 ± 0.46%).

Conclusion

It is concluded that (i) CPE exerted a powerful myogenic and L-type Ca²⁺-dependent relaxing effect in the isolated rat ileum and that (ii) the human ileum is sensitive to the inhibitory effect of CPE. If confirmed in vivo, our data could explain the traditional use of this herb in the treatment of intestinal spasms.     

Antiplatelet and antithrombotic activities of essential oil from wild Ocotea quixos (Lam.) Kosterm. (Lauraceae) calices from Amazonian Ecuador.

Ocotea quixos essential oil was shown to possess significant inhibitory activity of platelet aggregation and clot retraction in rodent plasma. This study is aimed at fully characterizing the antiplatelet activity of the whole essential oil and its main components trans-cinnamaldehyde and methyl cinnamate also in human plasma, at investigating the mechanism underlying such activity and at evaluating the potential antithrombotic activity of subacute treatment of mice with Ocotea essential oil. In vitro Ocotea essential oil and trans-cinnamaldehyde inhibited arachidonic acid-, U46619-, ADP-, phorbol12-myristate13-alcetate-, collagen-induced platelet aggregation and thrombin-induced clot retraction in human and rodent plasma; Ocotea oil and trans-cinnamaldehyde competitively antagonized contractions induced by thromboxane A2 receptor agonist U46619 in rat isolated aortic ring (K(B) = 18 and 3.2 microg ml(-1), respectively). In vivo Ocotea oil, orally administered in a subacute treatment (30-100 mg kg(-1) day(-1) for 5 days) to mice, prevented acute thrombosis induced by collagen-epinephrine intravenous injection. This antithrombotic activity was not accompanied by pro-haemorragic side effect, as detected by the inactivity in bleeding test, thus showing a favourable safety profile compared to the conventional antiplatelet agent, acetylsalicylic acid. Present findings indicate that Ocotea essential oil possesses potent and safe antithrombotic activity attributable to its antiplatelet and vasorelaxant effects. The main constituent trans-cinnamaldehyde seems to be the primary responsible for this activity through a putative mechanism involving the inhibition of thromboxane A2 receptors.     

Recognition Impairment Correlated with Short Bisynchronous Epileptic Discharges

The occurrence of transitory cognitive impairment during diffuse subclinical electroencephalographic (EEG) discharges has been widely documented but the role of the parameters influencing the cognitive performance and the involvement of motor or verbal response in the tasks used is still under debate. Fifteen patients suffering from primary generalized epilepsy with frequent bisynchronous EEG epileptic bursts underwent a shape recognition task during EEG monitoring. The test sequence was as follows: memorandum, pause, and multiple choice set. After pressing the response button, the patient was asked to confirm the choice verbally. The following parameters were considered: geometrical complexity of the shape, chronological position of the burst occurring during the single test, and the duration of discharge ranging from 1 to 3 s. Results showed a significant increase in incorrect responses during the test when discharges occurred, with more errors occurring for difficult than for easy shapes. Neither the discharge position nor the duration of the epileptic burst influenced the performance. Diffuse epileptic activity of short duration produced selective effects on the cognitive process regardless of the motor component of the response.