Apoptosis: a relevant tool for anticancer therapy.

Apoptosis is a form of cell death that permits the removal of damaged, senescent or unwanted cells in multicellular organisms, without damage to the cellular microenvironment. Defective apoptosis represents a major causative factor in the development and progression of cancer. The majority of chemotherapeutic agents, as well as radiation, utilize the apoptotic pathway to induce cancer cell death. Resistance to standard chemotherapeutic strategies also seems to be due to alterations in the apoptotic pathway of cancer cells. Recent knowledge on apoptosis has provided the basis for novel targeted therapies that exploit apoptosis to treat cancer. These new target include those acting in the extrinsic/intrinsic pathway, proteins that control the apoptosis machinery such as the p53 and proteosome pathway. Most of these forms of therapy are still in preclinical development because of their low specifity and susceptibility to drug resistance, but several of them have shown promising results. In particular, this review specifically aims at providing an update of certain molecular players that are already in use in order to target apoptosis (such as bortezomib) or which are still being clinically evaluated (such ONYX-015, survivin and exisulind/aptosyn) or which, following preclinical studies, might have the necessary requirements for becoming part of the anticancer drug programs (such as TRAIL/Apo2L, apoptin/VP3)

Prognostic and predictive factors in colorectal cancer: Kirsten Ras in CRC (RASCAL) and TP53CRC collaborative studies.

Mutations in the Ki-ras and TP53 genes are the most frequently observed genetic alterations in colorectal cancer (CRC). Ki-ras mutations are mostly found in codons 12 and 13, and less in codon 61. The majority of the TP53 mutations occur in the core domain which contains the sequence-specific DNA binding activity of the protein, and they results in loss of DNA binding. Few centres have sufficient patients to collect detailed information in the large numbers required to determine the impact of individual ki-ras and TP53 genotypes on outcome. Moreover, it has been reported that specific genetic alterations, and not any mutation, might play a different biological role in cancer progression. For these principal reasons, two collaborative studies have been conducted (the RASCAL and the TP53-CRC Collaborative Studies) with the aim of investigating the prognostic role of any, and specific, Ki-ras and TP53 mutations in CRC progression. The results obtained from the RASCAL studies suggest that Ki-ras mutations might have an effect on the survival rate of CRC patients, and that the specific codon 12 glycine/valine mutation might play a role in the progression of this neoplasia. The results of the TP53-CRC International Collaborative Study demonstrate the importance of primary tumor site when analyzing the prognostic value of TP53 mutations in CRC. In addition, different types of TP53 mutation might play a pivotal role in determining the biological behavior of CRC from different sites and hence the prognosis of patients. This meta-analysis produced evidence for interesting tumor site differences in the predictive value of TP53 mutation for survival benefit from 5FU chemotherapy

Simboli e significati nella cultura locale di una periferia urbana: uno studio di caso

Una ricerca psicologico-clinica esplora la Cultura Locale (i significati emozionali condivisi da chi partecipa a un contesto, atti a mantenere stabilità e coesione, a regolare e l’emozionalità dei processi di convivenza) di un quartiere della periferia romana nel momento della pianificazione di servizi per la comunità. La ricerca è fondata sulla analisi del testo computer assistita (Analisi Emozionale del Testo) di interviste somministrate a 8 figure chiave, e sulla analisi delle corrispondenze multiple di 314 questionari sulla percezione soggettiva della qualità di vita e sulla anticipazione dei rapporti sociali, somministrati a cittadini del quartiere. I risultati della analisi di interviste e questionari hanno messo in luce la qualità di vita come soggettivamente percepita dagli abitanti e le caratteristiche della cultura locale del territorio oggetto dello studio. Vengono fornite indicazioni pragmatiche sulla attivazione di servizi coerenti con la cultura locale del territorio esaminato. Viene messo in evidenza il possibile contributo della psicologia clinica alle discipline geografiche, urbanistiche, ambientali.This clinical-psychological research explores the Local Culture (emotional meanings shared by people in a given context aimed at maintaining stability and unity as well as regulating emotions affecting cohabitation) of a suburban neighborhood in Rome in the phase of community service planning. The inquiry is based on a computer-assisted text analysis (Emotional Text Analysis) of interviews of 8 key figures, and on the multiple correspondence analysis of questionnaires on the subjective perception of the quality of life and on the expectation of social relationships. The questionnaires have been administered to 314 inhabitants. The results of the analysis of interviews and questionnaires highlighted the quality of life in terms of subjective perception and the specific features of the local culture of the territory considered for this study. Practical solutions are indicated based on the Local Culture of the neighborhood in question. The possible contribution of clinical psychology to geographic, urban, and environmental disciplines is also highlighted. © 2019 The Author(s

La progettazione personalizzata nelle nuove misure di contrasto alla povert\ue0 (RES-REI) in Emilia-Romagna: Ottanta studi di caso

The paper deals with the implementation of the new measures of minimum income in a Northern Region in Italy (Emilia-Romagna). The Inclusion income (Rei) and the Solidarity income (Res) both provide a cash transfer conditioned to the agreement on a project to activate their recipients. Focusing on 80 case studies, this paper underscores interesting clues on the effects of these projects on work and social inclusion status of recipients

The activation of Mucolipin TRP channel 1 (TRPML1) protects motor neurons from L-BMAA neurotoxicity by promoting autophagic clearance

Cellular clearance mechanisms including the autophagy-lysosome pathway are impaired in amyotrophic lateral sclerosis (ALS). One of the most important proteins involved in the regulation of autophagy is the lysosomal Ca2+ channel Mucolipin TRP channel 1 (TRPML1). Therefore, we investigated the role of TRPML1 in a neuronal model of ALS/Parkinson-dementia complex reproduced by the exposure of motor neurons to the cyanobacterial neurotoxin beta-methylamino-L-alanine (L-BMAA). Under these conditions, L-BMAA induces a dysfunction of the endoplasmic reticulum (ER) leading to ER stress and cell death. Therefore we hypothesized a dysfunctional coupling between lysosomes and ER in L-BMAA-treated motor neurons. Here, we showed that in motor neuronal cells TRPML1 as well as the lysosomal protein LAMP1 co-localized with ER. In addition, TRPML1 co-immunoprecipitated with the ER Ca2+ sensor STIM1. Functionally, the TRPML1 agonist ML-SA1 induced lysosomal Ca2+ release in a dose-dependent way in motor neuronal cells. The SERCA inhibitor thapsigargin increased the fluorescent signal associated with lysosomal Ca2+ efflux in the cells transfected with the genetically encoded Ca2+ indicator GCaMP3-ML1, thus suggesting an interplay between the two organelles. Moreover, chronic exposure to L-BMAA reduced TRPML1 protein expression and produced an impairment of both lysosomal and ER Ca2+ homeostasis in primary motor neurons. Interestingly, the preincubation of ML-SA1, by an early activation of AMPK and beclin 1, rescued motor neurons from L-BMAA-induced cell death and reduced the expression of the ER stress marker GRP78. Finally, ML-SA1 reduced the accumulation of the autophagy-related proteins p62/SQSTM1 and LC3-II in L-BMAA-treated motor neurons. Collectively, we propose that the pharmacological stimulation of TRPML1 can rescue motor neurons from L-BMAA-induced toxicity by boosting autophagy and reducing ER stress

Farmaci oppioidi e Cannabis nella terapia del dolore

[English]:“Opioid and Cannabis in Pain Control” is the result of studies performed by the Pharmacy Department and the “Centro Interdipartimentale di Ricerca in Farmacoeconomia e Farmacoutilizzazione” (CIRFF) of the University of Naples, “Federico II”. This book is aimed to those who work in a pharmacy and who, scholars, teachers or students, are interested in delve into the issue. The text analyzes different topics with an interdisciplinary approach. A large part is devoted to the chemical and pharmacological aspects related to this topic. Subsequently, the text focuses the theme, still very debated, of using opioids and Cannabis in therapy through an exhaustive analysis of the entire existing legislation: from the first laws promulgated by the Kingdom of Italy until the last ministerial circulars by Italian republic. Finally yet importantly, an important part of the book focuses on medical and therapeutic interpretation with regard to the effects on pain control, where opioids and Cannabis are not only a fruitful frontier of research, but also a consolidated and effective tool to counteract some types of pain / [Italiano]: “Farmaci oppioidi e Cannabis nella terapia del dolore” rappresenta il frutto di alcuni studi, condotti per almeno tre lustri nel Dipartimento di Farmacia e nel Centro Interdipartimentale di Ricerca in Farmacoeconomia e Farmacoutilizzazione (CIRFF) della Federico II, e si rivolge sia a chi presta servizio ogni giorno in una farmacia, sia a chi, studioso, docente o studente, è interessato ad approfondire l’argomento. Il testo, utilizzando un approccio interdisciplinare, si muove su piani euristici differenti. Naturalmente, ampio spazio è stato dedicato alla parte farmaceutica, analizzando tutti gli aspetti chimici e farmacologici connessi a questo tema. Un secondo punto di rilievo riguarda la problematica normativa legata alla dibattuta questione dell’utilizzo in terapia degli oppioidi e della Cannabis. In tal senso, si è cercato di offrire una prospettiva chiara ed esauriente del complesso quadro legislativo vigente: a partire dalle prime leggi promulgate dal Regno d’Italia, fino ad arrivare alle ultime circolari ministeriali in materia, è stata rivista ed esaminata l’intera normativa sulle sostanze stupefacenti, spiegandone anche i passaggi più delicati e controversi. Infine, soprattutto per ciò che concerne le ricadute sulla terapia del dolore, una parte significativa del libro si è concentrata sull’interpretazione medica e terapeutica, dove i farmaci oppioidi e la Cannabis costituiscono non solo una feconda frontiera di ricerca, ma anche un consolidato ed efficace strumento per contrastare alcune tipologie di dolore

Patterns of genomic instability in gastric cancer: clinical implications and perspectives.

In gastric cancer (GC) the loss of genomic stability represents a key molecular step that occurs early in the carcinogenesis process and creates a permissive environment for the accumulation of genetic and epigenetic alterations in tumor suppressor genes and oncogenes. It is widely accepted that GC can follow at least two major genomic instability pathways, microsatellite instability (MSI) and chromosome instability (CIN). MSI is responsible for a well-defined subset of GCs. CIN represents a more common pathway comprising heterogeneous subsets of GC. In addition to MSI and CIN, the CpG islands methylator phenotype (CIMP) plays an important role in gastric carcinogenesis. CIMP may lead to the transcriptional silencing of various genes in gastric carcinogenesis. Intriguingly, more recently in addition to CpG island hypermethylation, a global DNA demethylation, that precedes genomic damage, has been observed in GC. Thus, epigenetic alterations may play a relevant role in gastric carcinogenesis as alternative mechanisms. Evidence suggests that although MSI, CIN and CIMP phenotypes can be distinguished from one another, there might be some degree of overlap. This review describes our current knowledge of the instability pathways in gastric carcinogenesis and the potential clinical applications for different forms of genomic instability in GC

Climate Change and Childhood Respiratory Health: A Call to Action for Paediatricians

Climate change (CC) is one of the main contributors to health emergencies worldwide. CC appears to be closely interrelated with air pollution, as some pollutants like carbon dioxide (CO2), nitrogen oxides (NOx) and black carbon are naturally occurring greenhouse gases. Air pollution may enhance the allergenicity of some plants and, also, has an adverse effect on respiratory health. Children are a uniquely vulnerable group that suffers disproportionately from CC burden. The increasing global warming related to CC has a big impact on plants' lifecycles, with earlier and longer pollen seasons, as well as higher pollen production, putting children affected by asthma and allergic rhinitis at risk for exacerbations. Extreme weather events may play a role too, not only in the exacerbations of allergic respiratory diseases but, also, in favouring respiratory infections. Even though paediatricians are already seeing the impacts of CC on their patients, their knowledge about CC-related health outcomes with specific regards to children's respiratory health is incomplete. This advocates for paediatricians' increased awareness and a better understanding of the CC impact on children's respiratory health. Having a special responsibility for children, paediatricians should actively be involved in policies aimed to protect the next generation from CC-related adverse health effects. Hence, there is an urgent need for them to take action and successfully educate families about CC issues. This paper aims at reviewing the evidence of CC-related environmental factors such as temperature, humidity, rainfall and extreme events on respiratory allergic diseases and respiratory infections in children and proposing specific actionable items for paediatricians to deal with CC-related health issues in their clinical practice