Molecular Pathogenesis of Cholangiocarcinoma

Epidemiological data from the last years show an increasing trend of incidence and mortality of cholangiocarcinoma (CC) worldwide. Many pathophysiologic aspects of this neoplasia are still unknown and need to be fully discovered. However, several progresses were recently made in order to establish the molecular mechanisms involved in the transformation and growth of malignant cholangiocytes. The principal concept that at least seems to be established is that cholangiocarcinogenesis is a multistep cellular process evolving from a normal condition of the epithelial biliary cells through a chronic inflammation status ending with malignant transformation. The bad prognosis related to CC justifies why a better identification of the molecular mechanisms involved in the growth and progression of this cancer is required for the development of effective preventive measures and valid treatment regimens. This Paper describes the scientific progresses made in the last years in defining the molecular pathways implicated in the generation of this devastating disease

Temporal integration for amplitude modulation in childhood: Interaction between internal noise and memory

It is still unclear whether the gradual improvement in amplitude-modulation (AM) sensitivity typically found in children up to 10 years of age reflects an improvement in “processing efficiency” (the central ability to use information extracted by sensory mechanisms). This hypothesis was tested by evaluating temporal integration for AM, a capacity relying on memory and decision factors. This was achieved by measuring the effect of increasing the number of AM cycles (2 vs 8) on AM-detection thresholds for three groups of children aged from 5 to 11 years and a group of young adults. AM-detection thresholds were measured using a forced-choice procedure and sinusoidal AM (4 or 32 Hz rate) applied to a 1024-Hz pure-tone carrier. All age groups demonstrated temporal integration for AM at both rates; that is, significant improvements in AM sensitivity with a higher number of AM cycles. However, an effect of age is observed as both 5–6 year olds and adults exhibited more temporal integration compared to 7–8 and 10–11 year olds at both rates. This difference is due to: (i) the 5–6 year olds displaying the worst thresholds with 2 AM cycles, but similar thresholds with 8 cycles compared to the 7–8 and 10–11 year olds, and, (ii) adults showing the best thresholds with 8 AM cycles but similar thresholds with 2 cycles compared to the 7–8 and 10–11 year olds. Computational modelling indicated that higher levels of internal noise combined with poorer short-term memory capacities in children accounted for the developmental trends. Improvement in processing efficiency may therefore account for the development of AM detection in childhood

Dietary Nitrate: Effects on the health of weaning pigs and Antimicrobial activity on seven probiotic Bifidobacterium spp. strains

The potential role of nitrite as an antimicrobial substance in the stomach may be of some importance in the ecology of the gastrointestinal tract and in host physiology. It has been shown that nitrite, under the acidic conditions of the stomach, may kill gut pathogens like Salmonella enteritidis, Escherichia coli, Salmonella typhimurium, and Yersinia enterocolitica, whereas acid alone has only a bacteriostatic effect. An in vivo study was conducted in order to assess the effects of dietary nitrate on microbiota and on the health of the gut (particularly in the stomach and small intestine). 96 weaning pigs were fed a diet containing high nitrate levels (15 mg and 150 mg) and then challenged with Salmonella enterica serovar typhimurium. Differences in composition of the gut microbiota were assessed by analysing samples from the pigs: To date analysis of 48 pigs has been completed.. Preliminary results demonstrated no effect on the population densities of microbial groups either from the challenge or from nitrate intake. However, increasing the time from challenge decreased either the counts of LAB in the stomach and jejunum or of clostridia in the stomach. Bifidobacteria also decreased in the stomach contents as nitrate supplementation increased. Supplementing the feedstuff with high dietary nitrate intake and then challenging with Salmonella did not affect the gastric pH or the degree of ulceration in the pigs. The synergistic bactericidal effects of pH, nitrite and thiocyanate on seven probiotic Bifidobacterium spp. strains were also investigated in an in vitro study. The results of the in vitro study demonstrated that an inhibitory effect exists on the seven probiotic bifidobacteria investigated with an exposure longer than 2 hours and pH values < 5.0. Addition of thiocyanate also increased the susceptibility of the tested strains. In this in vitro study, the most resistant strains at all conditions were B. animalis subsp. lactis Ra 18 and P32 and B. choerinum Su 877, Su 837 and Su 891

FIRI - a Far-Infrared Interferometer

Half of the energy ever emitted by stars and accreting objects comes to us in the FIR waveband and has yet to be properly explored. We propose a powerful Far-InfraRed Interferometer mission, FIRI, to carry out high-resolution imaging spectroscopy in the FIR. This key observational capability is essential to reveal how gas and dust evolve into stars and planets, how the first luminous objects in the Universe ignited, how galaxies formed, and when super-massive black holes grew. FIRI will disentangle the cosmic histories of star formation and accretion onto black holes and will trace the assembly and evolution of quiescent galaxies like our Milky Way. Perhaps most importantly, FIRI will observe all stages of planetary system formation and recognise Earth-like planets that may harbour life, via its ability to image the dust structures in planetary systems. It will thus address directly questions fundamental to our understanding of how the Universe has developed and evolved - the very questions posed by ESA's Cosmic Vision.Comment: Proposal developed by a large team of astronomers from Europe, USA and Canada and submitted to the European Space Agency as part of "Cosmic Vision 2015-2025

Testing the Equivalence Principle in an Einstein Elevator: Detector Dynamics and Gravity Perturbations

We discuss specific, recent advances in the analysis of an experiment to test the Equivalence Principle (EP) in free fall. A differential accelerometer detector with two proof masses of different materials free falls inside an evacuated capsule previously released from a stratospheric balloon. The detector spins slowly about its horizontal axis during the fall. An EP violation signal (if present) will manifest itself at the rotational frequency of the detector. The detector operates in a quiet environment as it slowly moves with respect to the co-moving capsule. There are, however, gravitational and dynamical noise contributions that need to be evaluated in order to define key requirements for this experiment. Specifically, higher-order mass moments of the capsule contribute errors to the differential acceleration output with components at the spin frequency which need to be minimized. The dynamics of the free falling detector (in its present design) has been simulated in order to estimate the tolerable errors at release which, in turn, define the release mechanism requirements. Moreover, the study of the higher-order mass moments for a worst-case position of the detector package relative to the cryostat has led to the definition of requirements on the shape and size of the proof masses

GERENCIAMENTO DO CUIDADO EM ENFERMAGEM: QUESTIONANDO ESTRATÉGIAS

O gerenciamento em enfermagem é uma das mais significativas áreas de abrangência da enfermagem. Suas estratégias no provimento do cuidado no contexto hospitalar são desveladas neste estudo exploratório. O enfermeiro gerente se mostra como um exímio controlador do sistema de cuidados de enfermagem, detentor do poder e da autoridade, e com poucos momentos de participação da equipe. Apresenta-se os resultados das entrevistas agrupadas em o que é gerenciamento, organização do processo de cuidado, estratégias de gerenciamento, relação grupo de trabalho e gerente, são diferenças entre turnos e dias da semana. Há necessidade preemente de pensar e repensar as estratégias de gerenciamento do cuidado gerente as atitudes, papéis ou práticas orientadas pelos atuais fundamentos teóricofilosóficos do gerenciamento em administração.Nursing care management is one of the most significant areas within the scope of nursing profession. In this exploratory study, strategies for providing care in a hospital setting are unveiled. The nurse managers show themselves as controlers of the nursing care system, holding power and authority, and having few moments of team members participation in the decision making process. The results of the interviews are grouped in the following categories: what is management, organization of the caring process, management, strategies, team work and manager relationships, differences in shifts and days of the week. There is an urgent need to re-think strategies for nursing care management in regards to attitudes, roles and practices based on theorical - philosophical aspects of management in administration

TEPEE/GReAT (General Relativity Accuracy Test in an Einstein Elevator): Ready to start

TEPEE/GReAT is an experiment aimed at testing the principle of equivalence at a level of accuracy equal to 5 parts in 1015 by means of a differential acceleration detector free falling inside a co-moving, cryogenic, evacuated capsule, released from a stratospheric balloon. The detector is spun about a horizontal axis during the fall in order to modulate the equivalence principle violation signal at the spin frequency. Thanks to the recent funding of the Italian side, the project is ready to enter its second phase. The main activities related to detector prototype (both non-cryogenic and cryogenic versions) development and testing, free-fall tests, signal extraction from noise (in particular related to the common-mode rejection factor) and flight model requirements are discussed

Adding pieces to the puzzle of differentiated-to-anaplastic thyroid cancer evolution: the oncogene E2F7

Anaplastic Thyroid Cancer (ATC) is the most aggressive and de-differentiated subtype of thyroid cancer. Many studies hypothesized that ATC derives from Differentiated Thyroid Carcinoma (DTC) through a de-differentiation process triggered by specific molecular events still largely unknown. E2F7 is an atypical member of the E2F family. Known as cell cycle inhibitor and keeper of genomic stability, in specific contexts its function is oncogenic, guiding cancer progression. We performed a meta-analysis on 279 gene expression profiles, from 8 Gene Expression Omnibus patient samples datasets, to explore the causal relationship between DTC and ATC. We defined 3 specific gene signatures describing the evolution from normal thyroid tissue to DTC and ATC and validated them in a cohort of human surgically resected ATCs collected in our Institution. We identified E2F7 as a key player in the DTC-ATC transition and showed in vitro that its down-regulation reduced ATC cells’ aggressiveness features. RNA-seq and ChIP-seq profiling allowed the identification of the E2F7 specific gene program, which is mainly related to cell cycle progression and DNA repair ability. Overall, this study identified a signature describing DTC de-differentiation toward ATC subtype and unveiled an E2F7-dependent transcriptional program supporting this process

Drug-drug interactions between palbociclib and proton pump inhibitors may significantly affect clinical outcome of metastatic breast cancer patients

BACKGROUND: Proton-pump-inhibitors (PPIs) are frequently prescribed for the management of anticancer drug-related gastrointestinal symptoms. Palbociclib is a weak base with pH-dependent solubility and potential drug-drug interaction at the absorption level may affect clinical pharmacokinetics. The current study was aimed at investigating the effect of co-administration of PPIs and palbociclib on progression-free survival (PFS) in metastatic breast cancer (mBC) patients. PATIENTS AND METHODS: Patients affected by estrogen receptor-positive, human epidermal growth factor receptor 2-negative mBC, who were candidates for first-line treatment with palbociclib, were enrolled in this retrospective observational study. Patients were defined as ‘no concomitant PPIs’ if no PPIs were administered during palbociclib treatment, and as ‘concomitant PPIs’ if the administration of PPIs covered the entire or not less than two-thirds of treatment with palbociclib. All clinical interventions were made according to clinical practice. RESULTS: A total of 112 patients were enrolled in the study; 56 belonged to the ‘no concomitant PPIs’ group and 56 to the ‘concomitant PPIs’ group. Seventy-one patients were endocrine-sensitive and received palbociclib and letrozole, and 43 were endocrine-resistant and were treated with palbociclib and fulvestrant. The most prescribed PPI was lansoprazole. Patients taking PPIs had a shorter PFS than those taking palbociclib and endocrine therapy alone (14.0 versus 37.9 months, P 2 hematological toxicities [Common Terminology Criteria for Adverse Events (CTCAE) scale]. CONCLUSIONS: The present study demonstrates that concomitant use of PPIs in mBC patients treated with palbociclib has a detrimental effect on PFS. Therefore, it is recommended to prescribe PPIs with caution in these patients, strictly adhering to the indications in the summary of product characteristics (RCP)