Controlling secretion to limit chemoresistance

The tumor microenvironment influences cancer progression and therapy outcome by mechanisms not yet fully understood. In this issue, Bent et al. (2016) show how chemotherapy causes endothelial senescence. Interestingly, senescent endothelial cells do not mount a typical senescence-associated secretory phenotype but instead acutely secrete IL-6, promoting chemoresistance. This study unveils a physiological switch involving PI3K/AKT/mTOR signaling that restrains the senescence secretory responses to limit the detrimental consequences of persistent inflammation

A genetic screen identifies novel regulators of the senescence-associated secretory phenotype

Cellular senescence is a stable cell-cycle arrest induced by ageing or many stresses such as oncogene activation. Oncogene-Induced Senescence (OIS) is an intrinsic tumour suppressive mechanism but also has numerous extrinsic functions mediated by the senescence-associated secretory phenotype (SASP). Although the SASP attracts the immune system to clear damaged cells it can also promote cancer growth and age-associated systemic inflammation. Consequently, the SASP has been considered a potential therapeutic target. However, a better understanding of the molecular pathways regulating the complex secretome of senescent cells is necessary before designing therapeutic interventions. In this work, we set up and carried out an siRNA screen for genes regulating the SASP during OIS. By screening siRNAs targeting 8,352 genes, 84 novel regulators of IL-8 and IL-6 were found. We further interrogated their effect on levels of p16INK4a, p21Cip1 and BrdU incorporation. 49 genes were found to specifically regulate the SASP without affecting other senescence features. Combining the siRNA screening system with global transcriptome profiling for 38 of these genes revealed common pathways with a potential role in regulating the SASP. One of the candidates was the splicing factor PTBP1. PTBP1 depletion blunted the induction of several SASP factors without affecting the senescence growth arrest. The altered SASP produced upon PTBP1 depletion had distinct properties. For example, it decreased the ability to transmit senescence but retained the ability to attract natural killer cells. Mechanistically, during senescence, PTBP1 promoted exon skipping of several mRNAs involved in intracellular protein trafficking. Future work will aim at fully understanding the role of PTBP1 during senescence. Our data so far suggest the feasibility of targeting PTBP1 to specifically manipulate the SASP while maintaining the ability of inducing cell cycle arrest as a potential strategy to target inflammation-driven tumourigenesis.Open Acces

Effect of Solvent on the Self-Assembly of Dialanine and Diphenylalanine Peptides

Diphenylalanine (FF) is a very common peptide with many potential applications, both biological and technological, due to a large number of different nanostructures which it attains. The current work concerns a detailed study of the self assembled structures of FF in two different solvents, an aqueous (H2O) and an organic (CH3OH) through simulations and experiments. Detailed atomistic Molecular Dynamics (MD) simulations of FF in both solvents have been performed, using an explicit solvent model. The self assembling propensity of FF in water is obvious while in methanol a very weak self assembling propensity is observed. We studied and compared structural properties of FF in the two different solvents and a comparison with a system of dialanine (AA) in the corresponding solvents was also performed. In addition, temperature dependence studies were carried out. Finally, the simulation predictions were compared to new experimental data, which were produced in the framework of the present work. A very good qualitative agreement between simulation and experimental observations was found

Βελτιστοποίηση της επικουρικής θεραπείας μετά από τη χειρουργική εκτομή των ηπατικών μεταστάσεων του καρκίνου του παχέος εντέρου: Συστηματική ανασκόπηση

Στόχοι Το ήπαρ είναι η συνηθέστερη εστία μεταστάσεων του καρκίνου του παχέος εντέρου. Παρόλο που η χειρουργική εκτομή των εξαιρέσιμων ηπατικών μεταστάσεων αποτελεί τον χρυσό κανόνα για τη θεραπεία των ασθενών που δύνανται να χειρουργηθούν, η μετέπειτα διαχείρισή τους παραμένει αμφιλεγόμενη. Στόχος αυτής της συστηματικής ανασκόπησης είναι να αντιπαραβάλει τα διαθέσιμα δεδομένα αναφορικά με τα θεραπευτικά σχήματα που χρησιμοποιούνται ως επικουρική θεραπεία, ούτως ώστε να αποσαφηνιστεί ποια είναι η βέλτιστη θεραπευτική προσέγγιση. Υλικά και Μέθοδοι Η βιβλιογραφική αναζήτηση έγινε στις βάσεις δεδομένων Pubmed/Medline και Cochrane library. Οι μελέτες που συμπεριλήφθηκαν εξέταζαν την αποτελεσματικότητα, την ανοχή από τους ασθενείς και το προφίλ ασφαλείας των διάφορων θεραπευτικών σχημάτων που χρησιμοποιήθηκαν ως επικουρική θεραπεία μετά την χειρουργική επέμβαση. Τα υπό μελέτη καταληκτικά σημεία ήταν η επιβίωση ελεύθερη υποτροπής της νόσου (RFS), η επιβίωση ελεύθερη νόσου (DFS), η ολική επιβίωση (OS) και οι σοβαρού βαθμού τοξικότητες. Αποτελέσματα Από τα 543 αποτελέσματα της αρχικής αναζήτησης, τελικά συμπεριλήφθηκαν 29 μελέτες με συνολικά 7028 ασθενείς. Σύμφωνα με τα αποτελέσματά τους, η επικουρική θεραπεία μετά τη μεταστασεκτομή συνέβαλε εν γένει στη βελτίωση της επιβίωσης ελεύθερης υποτροπής της νόσου και της επιβίωσης ελεύθερης νόσου, χωρίς ωστόσο να σημειωθεί στατιστικά σημαντική επιμήκυνση της ολικής επιβίωσης. Μάλιστα αυτή η παρατήρηση δεν φάνηκε να επηρεάζεται από το αν η επικουρική θεραπεία ήταν συστηματική ή περιοχική ή αν υπήρξε συνδυασμός των δύο αυτών μεθόδων. Εντούτοις, η ερμηνεία αυτών των αποτελεσμάτων θα πρέπει να είναι προσεκτική, καθότι οι περισσότερες μελέτες αξιολογήθηκαν ως χαμηλής ή μέτριας ποιότητας. Συμπεράσματα Με βάση τα διαθέσιμα βιβλιογραφικά δεδομένα, κρίνεται απαραίτητη η περαιτέρω διεξαγωγή άρτια σχεδιασμένων κλινικών δοκιμών που θα εστιάσουν στις σύγχρονες θεραπείες σε συγκεκριμένους υποπληθυσμούς, ούτως ώστε να περιοριστεί η ετερογένεια εντός και μεταξύ των εκάστοτε μελετών. Με αυτόν τον τρόπο, είναι δυνατόν και να διαλευκανθεί ποιες ομάδες ασθενών πρόκειται να επωφεληθούν από την επικουρική θεραπεία μετά την εκτομή των ηπατικών μεταστάσεων του καρκίνου του παχέος εντέρου.Objectives Liver is the most common site of colorectal cancer metastatic spread. Although metastasectomy is the gold standard for fit patients with resectable colorectal cancer liver metastases (CRLM), their management after surgical treatment remains controversial. The objective of this systematic review was to collate the currently available data of the agents used in the adjuvant setting in order to define the most optimal therapeutic strategy. Methods and materials A systematic review of literature was conducted by searching Pubmed/Medline and Cohrane library databases. We included studies that evaluated the efficacy, the tolerability and the safety profile of various chemotherapeutic agents that are used as adjuvant treatment after surgical resection of CRLM. The outcomes of interest were regression-free survival (RFS), disease-free survival (DFS), overall survival (OS) and severe toxicities. Results From 543 initial articles, 29 publications with 7028 patients were finally included. In general, the results of the eligible studies indicated that the adjuvant therapy after resection of CRLM led to improved RFS/DFS rates, but this benefit did not contribute to a statistically significant prolongation of OS. Moreover, the choice of the therapeutic strategy, namely systematic or regional chemotherapy or the combination of both, did not seem to have a differential impact on patient outcomes. However, these results should be interpeted with caution since the majority of the chosen studies are of low or moderate quality. Conclusions In this context, further high-quality clinical trials conducted on patient sub-populations with modern therapies are required in order to reduce in-study and between-study heterogeneity and determine which patients are expected to derive the maximum benefit from adjuvant therapy after surgery for CRLM

The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells

Contains fulltext : 4487.pdf (publisher's version ) (Open Access

Novel regulation of PLCζ activity via its XY-linker

The XY-linker region of somatic cell PLC (phospholipase)-β, -γ, -δ and -ϵ isoforms confers potent catalytic inhibition, suggesting a common auto-regulatory role. Surprisingly, the sperm PLCζ XY-linker does not mediate auto-inhibition. Unlike for somatic PLCs, the absence of the PLCζ XY-linker significantly diminishes both in vitro PIP2 (phosphatidylinositol 4,5-bisphosphate) hydrolysis and in vivo Ca2+-oscillation-inducing activity, revealing evidence for a novel PLCζ enzymatic mechanism

mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype

Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses

Refining the Design of Diblock Elastin-Like Polypeptides for Self-Assembly into Nanoparticles

Diblock copolymers based-on elastin-like polypeptide (ELP) have the potential to undergo specific phase transitions when thermally stimulated. This ability is especially suitable to form carriers, micellar structures for instance, for delivering active cargo molecules. Here, we report the design and study of an ELP diblock library based on ELP-[M1V3-i]-[I-j]. First, ELP-[M1V3-i]-[I-j] (i = 20, 40, 60; j = 20, 90) that showed a similar self-assembly propensity (unimer-to-aggregate transition) as their related monoblocks ELP-[M1V3-i] and ELP-[I-j]. By selectively oxidizing methionines of ELP-[M1V3-i] within the different diblocks structures, we have been able to access a thermal phase transition with three distinct regimes (unimers, micelles, aggregates) characteristic of well-defined ELP diblocks.Nanomedicine: an integrative approac

Effect of Neonatal Treatment With the NMDA Receptor Antagonist, MK-801, During Different Temporal Windows of Postnatal Period in Adult Prefrontal Cortical and Hippocampal Function

The neonatal MK-801 model of schizophrenia has been developed based on the neurodevelopmental and NMDA receptor hypofunction hypotheses of schizophrenia. This animal model is generated with the use of the NMDA receptor antagonist, MK-801, during different temporal windows of postnatal life of rodents leading to behavioral defects in adulthood. However, no studies have examined the role of specific postnatal time periods in the neonatal MK-801 (nMK-801) rodent model and the resulting behavioral and neurobiological effects. Thus, the goal of this study is to systematically investigate the role of NMDA hypofunction, during specific temporal windows in postnatal life on different cognitive and social behavioral paradigms, as well as various neurobiological effects during adulthood. Both female and male mice were injected intraperitoneally (i.p.) with MK-801 during postnatal days 7–14 (p7–14) or 11–15 (p11–15). Control mice were injected with saline during the respective time period. In adulthood, mice were tested in various cognitive and social behavioral tasks. Mice nMK-801-treated on p7–14 show impaired performance in the novel object, object-to-place, and temporal order object recognition (TOR) tasks, the sociability test, and contextual fear extinction. Mice nMK-801-treated on p11–15 only affects performance in the TOR task, the social memory test, and contextual fear extinction. No differences were identified in the expression of NMDA receptor subunits, the synapsin or PSD-95 proteins, either in the prefrontal cortex (PFC) or the hippocampus (HPC), brain regions significantly affected in schizophrenia. The number of parvalbumin (PV)-expressing cells is significantly reduced in the PFC, but not in the HPC, of nMK-801-treated mice on p7–14 compared to their controls. No differences in PV-expressing cells (PFC or HPC) were identified in nMK-801-treated mice on p11–15. We further examined PFC function by recording spontaneous activity in a solution that allows up state generation. We find that the frequency of up states is significantly reduced in both nMK-801-treated mice on p7–14 and p11–15 compared to saline-treated mice. Furthermore, we find adaptations in the gamma and high gamma activity in nMK-801-treated mice. In conclusion, our results show that MK-801 treatment during specific postnatal temporal windows has differential effects on cognitive and social behaviors, as well as on underlying neurobiological substrates