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Serena Scarpelli,1,2 Chiara Bartolacci,1 Aurora D’Atri,1,3 Milena Camaioni,1 Ludovica Annarumma,1 Maurizio Gorgoni,1 Chiara Cloos,1 Michele Ferrara,3 Luigi De Gennaro1,2 1Department of Psychology, Sapienza University of Rome, Rome 00185, Italy; 2IRCCS Fondazione Santa Lucia, Rome, Italy; 3Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Coppito, L’Aquila 67100, ItalyCorrespondence: Luigi De GennaroDepartment of Psychology, Sapienza University of Rome, Via Dei Marsi, 78, Rome 00185, ItalyTel +39-06-49917647Fax +39-06-49917711Email luigi.degennaro@uniroma1.itPurpose: In the current study, we aimed to investigate the EEG correlates of dream recall (DR) monitoring both the homeostatic and state-trait like factors. We assessed the influence of the time of night on the EEG correlates of DR from REM sleep. Specifically, we tested the continuity-hypothesis (on the theta EEG band) and the activation-hypothesis (on the delta and beta bands).Methods: Twenty-seven subjects underwent polysomnography with multiple provoked awakenings during REM sleep. Only the subjects showing combinations of dream recall (REC) and non-REC (NREC) conditions in both first (1st– 2nd sleep cycle) and second (3rd– 4th sleep cycle) part of the night were included in the analyses. The final sample was composed of 10 subjects (mean age 24± 0.70). EEG power spectra of the 5-min of REM sleep preceding each awakening were computed by a fast Fourier transform. The following frequency bands were considered: delta (0.50– 4.75 Hz), theta (5.00– 7.75 Hz), and beta (16.00– 24.75 Hz). We also calculated the delta/beta power ratio as an integrated EEG index of activation.Results: The 2× 2 within-subjects ANOVA recall × time revealed: a) no significant effect for time and no interaction; b) significant differences over the occipital area in the beta band; c) significant differences over the parietal area for the activation index values. Overall, the results indicated that DR is associated with higher activation regardless of homeostatic pressure across the night of sleep.Conclusion: In line with recent findings, we have shown that DR is predicted by desynchronized EEG activity during REM sleep, providing clear evidence in favor of the activation-hypothesis. We have also confirmed that the EEG pattern of DR can be ascribed to state-like factors. Further studies should assess whether homeostatic modulation may interact with some dream features and the related EEG predictors.Keywords: dream recall, REM sleep, EEG, activation hypothesis, multiple awakenings, sleep homeostasis

Anastasia Mangiaruga, Serena Scarpelli, Chiara Bartolacci, Luigi De Gennaro Department of Psychology, University of Rome “Sapienza”, Rome, Italy Abstract: Brain and sleep maturation covary across different stages of life. At the same time, dream generation and dream recall are intrinsically dependent on the development of neural systems. The aim of this paper is to review the existing studies about dreaming in infancy, adulthood, and the elderly stage of life, assessing whether dream mentation may reflect changes of the underlying cerebral activity and cognitive processes. It should be mentioned that some evidence from childhood investigations, albeit still weak and contrasting, revealed a certain correlation between cognitive skills and specific features of dream reports. In this respect, infantile amnesia, confabulatory reports, dream-reality discerning, and limitation in language production and emotional comprehension should be considered as important confounding factors. Differently, growing evidence in adults suggests that the neurophysiological mechanisms underlying the encoding and retrieval of episodic memories may remain the same across different states of consciousness. More directly, some studies on adults point to shared neural mechanisms between waking cognition and corresponding dream features. A general decline in the dream recall frequency is commonly reported in the elderly, and it is explained in terms of a diminished interest in dreaming and in its emotional salience. Although empirical evidence is not yet available, an alternative hypothesis associates this reduction to an age-related cognitive decline. The state of the art of the existing knowledge is partially due to the variety of methods used to investigate dream experience. Very few studies in elderly and no investigations in childhood have been performed to understand whether dream recall is related to specific electrophysiological pattern at different ages. Most of all, the lack of longitudinal psychophysiological studies seems to be the main issue. As a main message, we suggest that future longitudinal studies should collect dream reports upon awakening from different sleep states and include neurobiological measures with cognitive performances. Keywords: dreaming, sleep mentation, development, sleep, continuity hypothesis, aging

We report experimental and theoretical investigations on the presence and the detrimental effect of neodymium clusters on the three-level transition at near 930 nm in aluminosilicate double-clad fibers. A series of fibers with a W-type refractive index core profile to filter out the competing strong transition at 1060 nm were fabricated to study the impact of clusters on laser efficiency at near 930 nm using different core compositions. Percentage of clustered Nd ions have been evaluated using two methods based either on the saturation of the pump absorption or on laser efficiencies. Laser characterizations and numerical modeling have shown that clustering effect has a strong impact on the laser efficiency at 930 nm and fractions of clustered ions higher than 50% have been found in the most doped fiber. [ABSTRACT FROM AUTHOR]

Significance: The work establishes a requirement for glucose-dependent coordination between energy production and redox homeostasis, which is fundamental for the survival of cancer cells that accumulate Cu and contributes to tumor growth., (©2024 The Authors; Published by the American Association for Cancer Research.)

Lung cancer is a leading cause of cancer-related death worldwide that needs updated therapies to contrast both the serious side effects and the occurrence of drug resistance. A panel of non-small cell lung cancer (NSCLC) cells were herein employed as cancer models. Eight structurally related gold(I) and gold(III) complexes with NHC and halides or triphenylphosphane ligands were investigated as lung cancer cell growth inhibitors. As expected, gold compounds with PPh 3 were found to be more cytotoxic than homoleptic [(NHC) 2 -Au(I)]X or heteroleptic NHC-Au(I)X or NHC-Au(III)X 3 complexes. Mixed ligand gold(I) compounds exhibiting the linear NHC-AuPPh 3 (compound 7 ) or the trigonal NHC-Au(Cl)PPh 3 (compound 8 ) arrangements at the central metal were found to be the best lung cancer cytotoxic compounds. Analysis of the TrxR residual activity of the treated cells revealed that these compounds efficiently inhibit the most accredited molecular target for gold compounds, the TrxR, with compound 8 reaching more than 80% activity reduction in lung cells. Some of the current cancer lung therapy protocols consist of specific lung cancer cell cytotoxic agents combined with antifolate drugs; interestingly, the herein gold compounds are both TrxR and antifolate inhibitors. The human DHFR was inhibited with IC 50 ranging between 10-21 µM, depending on substrate concentrations, proceeding by a likely allosteric mechanism only for compound 8 .

Copper (Cu) is an essential trace element required for mitochondrial respiration. Late-stage clear cell renal cell carcinoma (ccRCC) accumulates Cu and allocates it to mitochondrial cytochrome c oxidase. We show that Cu drives coordinated metabolic remodeling of bioenergy, biosynthesis and redox homeostasis, promoting tumor growth and progression of ccRCC. Specifically, Cu induces TCA cycle-dependent oxidation of glucose and its utilization for glutathione biosynthesis to protect against H 2 O 2 generated during mitochondrial respiration, therefore coordinating bioenergy production with redox protection. scRNA-seq determined that ccRCC progression involves increased expression of subunits of respiratory complexes, genes in glutathione and Cu metabolism, and NRF2 targets, alongside a decrease in HIF activity, a hallmark of ccRCC. Spatial transcriptomics identified that proliferating cancer cells are embedded in clusters of cells with oxidative metabolism supporting effects of metabolic states on ccRCC progression. Our work establishes novel vulnerabilities with potential for therapeutic interventions in ccRCC. Accumulation of copper is associated with progression and relapse of ccRCC and drives tumor growth.Cu accumulation and allocation to cytochrome c oxidase (CuCOX) remodels metabolism coupling energy production and nucleotide biosynthesis with maintenance of redox homeostasis.Cu induces oxidative phosphorylation via alterations in the mitochondrial proteome and lipidome necessary for the formation of the respiratory supercomplexes. Cu stimulates glutathione biosynthesis and glutathione derived specifically from glucose is necessary for survival of Cu Hi cells. Biosynthesis of glucose-derived glutathione requires activity of glutamyl pyruvate transaminase 2, entry of glucose-derived pyruvate to mitochondria via alanine, and the glutamate exporter, SLC25A22. Glutathione derived from glucose maintains redox homeostasis in Cu-treated cells, reducing Cu-H 2 O 2 Fenton-like reaction mediated cell death. Progression of human ccRCC is associated with gene expression signature characterized by induction of ETC/OxPhos/GSH/Cu-related genes and decrease in HIF/glycolytic genes in subpopulations of cancer cells. Enhanced, concordant expression of genes related to ETC/OxPhos, GSH, and Cu characterizes metabolically active subpopulations of ccRCC cells in regions adjacent to proliferative subpopulations of ccRCC cells, implicating oxidative metabolism in supporting tumor growth.

The histone deacetylase sirtuin 6 (SIRT6) has been endowed with anti-cancer capabilities in many tumor types. Here, we investigate the impact of SIRT6-overexpression (SIRT6-OE) in Delta16HER2 mice, which are a bona fide model of HER2-positive breast cancer. After an initial delay in the tumor onset, SIRT6-OE induces a more aggressive phenotype of Delta16HER2 tumors promoting the formation of higher number of tumor foci and metastases than controls. This phenotype of SIRT6-OE tumors is associated with cancer stem cell (CSC)-like features and tumor dormancy, and low senescence and oxidative DNA damage. Accordingly, a sub-set of HER2-positive breast cancer patients with concurrent SIRT6-OE has a significant poorer relapse-free survival (RFS) probability than patients with low expression of SIRT6. ChIP-seq, RNA-seq and RT-PCR experiments indicate that SIRT6-OE represses the expression of the T-box transcription factor 3 (Tbx3) by deacetylation of H3K9ac. Accordingly, loss-of-function mutations of TBX3 or low TBX3 expression levels are predictive of poor prognosis in HER2-positive breast cancer patients. Our work indicates that high levels of SIRT6 are indicative of poor prognosis and high risk of metastasis in HER2-positive breast cancer and suggests further investigation of TBX3 as a downstream target of SIRT6 and co-marker of poor-prognosis. Our results point to a breast cancer subtype-specific effect of SIRT6 and warrant future studies dissecting the mechanisms of SIRT6 regulation in different breast cancer subtypes., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The advent of trastuzumab has significantly improved the prognosis of HER2-positive (HER2+) breast cancer patients; nevertheless, drug resistance limits its clinical benefit. Anti-HER2 active immunotherapy represents an attractive alternative strategy, but effective immunization needs to overcome the patient's immune tolerance against the self-HER2. Phage display technology, taking advantage of phage intrinsic immunogenicity, permits one to generate effective cancer vaccines able to break immune tolerance to self-antigens. In this study, we demonstrate that both preventive and therapeutic vaccination with M13 bacteriophages, displaying the extracellular (EC) and transmembrane (TM) domains of human HER2 or its Δ16HER2 splice variant on their surface (ECTM and Δ16ECTM phages), delayed mammary tumor onset and reduced tumor growth rate and multiplicity in ∆16HER2 transgenic mice, which are tolerant to human ∆16HER2. This antitumor protection correlated with anti-HER2 antibody production. The molecular mechanisms underlying the anticancer effect of vaccine-elicited anti-HER2 antibodies were analyzed in vitro against BT-474 human breast cancer cells, sensitive or resistant to trastuzumab. Immunoglobulins (IgG) purified from immune sera reduced cell viability mainly by impairing ERK phosphorylation and reactivating retinoblastoma protein function in both trastuzumab-sensitive and -resistant BT-474 cells. In conclusion, we demonstrated that phage-based HER2 vaccines impair mammary cancer onset and progression, opening new perspectives for HER2+ breast cancer treatment.

Mutant KRAS (KM), the most common oncogene in lung cancer (LC), regulates fatty acid (FA) metabolism. However, the role of FA in LC tumorigenesis is still not sufficiently characterized. Here, we show that KMLC has a specific lipid profile, with high triacylglycerides and phosphatidylcholines (PC). We demonstrate that FASN, the rate-limiting enzyme in FA synthesis, while being dispensable in EGFR-mutant or wild-type KRAS LC, is required for the viability of KMLC cells. Integrating lipidomic, transcriptomic and functional analyses, we demonstrate that FASN provides saturated and monounsaturated FA to the Lands cycle, the process remodeling oxidized phospholipids, such as PC. Accordingly, blocking either FASN or the Lands cycle in KMLC, promotes ferroptosis, a reactive oxygen species (ROS)- and iron-dependent cell death, characterized by the intracellular accumulation of oxidation-prone PC. Our work indicates that KM dictates a dependency on newly synthesized FA to escape ferroptosis, establishing a targetable vulnerability in KMLC., (© 2022. The Author(s).)

Ferroptosis has emerged as a new type of programmed cell death that can be harnessed for cancer therapy. The concept of ferroptosis was for the first time proposed in in the early 2000s, as an iron-dependent mode of regulated cell death caused by unrestricted lipid peroxidation (LPO) and subsequent plasma membrane rupture. Since the discovery and characterization of ferroptosis, a wealth of research has improved our understanding of the main pathways regulating this process, leading to both the repurposing and the development of small molecules. However, ferroptosis is still little understood and several aspects remain to be investigated. For instance, it is unclear whether specific oncogenes, cells of origin or tumor niches impose specific susceptibility/resistance to ferroptosis or if there are some ferroptosis-related genes that may be used as bona fide pan-cancer targetable dependencies. In this context, even though RAS-driven cancer cell lines seemed to be selectively sensitive to ferroptosis inducers, subsequent studies have questioned these results, indicating that in some cases mutant RAS is necessary, but not sufficient to induce ferroptosis. In this perspective, based on publicly available genomic screening data and the literature, we discuss the relationship between RAS-mutation and ferroptosis susceptibility in cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Andreani, Bartolacci and Scaglioni.)

Glioblastoma (GBM) is highly resistant to chemotherapies, immune-based therapies, and targeted inhibitors. To identify novel drug targets, we screened orthotopically implanted, patient-derived glioblastoma sphere-forming cells using an RNAi library to probe essential tumor cell metabolic programs. This identified high dependence on mitochondrial fatty acid metabolism. We focused on medium-chain acyl-CoA dehydrogenase (MCAD), which oxidizes medium-chain fatty acids (MCFA), due to its consistently high score and high expression among models and upregulation in GBM compared with normal brain. Beyond the expected energetics impairment, MCAD depletion in primary GBM models induced an irreversible cascade of detrimental metabolic effects characterized by accumulation of unmetabolized MCFAs, which induced lipid peroxidation and oxidative stress, irreversible mitochondrial damage, and apoptosis. Our data uncover a novel protective role for MCAD to clear lipid molecules that may cause lethal cell damage, suggesting that therapeutic targeting of MCFA catabolism may exploit a key metabolic feature of GBM. SIGNIFICANCE: MCAD exerts a protective role to prevent accumulation of toxic metabolic by-products in glioma cells, actively catabolizing lipid species that would otherwise affect mitochondrial integrity and induce cell death. This work represents a first demonstration of a nonenergetic role for dependence on fatty acid metabolism in cancer. This article is highlighted in the In This Issue feature, p. 2659 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

HRAS , NRAS and KRAS , collectively referred to as oncogenic RAS, are the most frequently mutated driver proto-oncogenes in cancer. Oncogenic RAS aberrantly rewires metabolic pathways promoting the generation of intracellular reactive oxygen species (ROS). In particular, lipids have gained increasing attention serving critical biological roles as building blocks for cellular membranes, moieties for post-translational protein modifications, signaling molecules and substrates for ß-oxidation. However, thus far, the understanding of lipid metabolism in cancer has been hampered by the lack of sensitive analytical platforms able to identify and quantify such complex molecules and to assess their metabolic flux in vitro and, even more so, in primary tumors. Similarly, the role of ROS in RAS-driven cancer cells has remained elusive. On the one hand, ROS are beneficial to the development and progression of precancerous lesions, by upregulating survival and growth factor signaling, on the other, they promote accumulation of oxidative by-products that decrease the threshold of cancer cells to undergo ferroptosis. Here, we overview the recent advances in the study of the relation between RAS and lipid metabolism, in the context of different cancer types. In particular, we will focus our attention on how lipids and oxidative stress can either promote or sensitize to ferroptosis RAS driven cancers. Finally, we will explore whether this fine balance could be modulated for therapeutic gain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bartolacci, Andreani, El-Gammal and Scaglioni.)

Several findings support the activation hypothesis, positing that cortical arousal promotes dream recall (DR). However, most studies have been carried out on young participants, while the electrophysiological (EEG) correlates of DR in older people are still mostly unknown. We aimed to test the activation hypothesis on 20 elders, focusing on the Non-Rapid Eye Movement (NREM) sleep stage. All the subjects underwent polysomnography, and a dream report was collected upon their awakening from NREM sleep. Nine subjects were recallers (RECs) and 11 were non-RECs (NRECs). The delta and beta EEG activity of the last 5 min and the total NREM sleep was calculated by Fast Fourier Transform. Statistical comparisons (RECs vs. NRECs) revealed no differences in the last 5 min of sleep. Significant differences were found in the total NREM sleep: the RECs showed lower delta power over the parietal areas than the NRECs. Consistently, statistical comparisons on the activation index (delta/beta power) revealed that RECs showed a higher level of arousal in the fronto-temporal and parieto-occipital regions than NRECs. Both visual vividness and dream length are positively related to the level of activation. Overall, our results are consistent with the view that dreaming and the storage of oneiric contents depend on the level of arousal during sleep, highlighting a crucial role of the temporo-parietal-occipital zone.

Background : Driving performance is strongly vulnerable to drowsiness and vigilance fluctuations. Excessive sleepiness may alter concentration, alertness, and reaction times. As people age, sleep undergoes some changes, becoming fragmented and less deep. However, the effects of these modifications on daily life have not been sufficiently investigated. Recently, the assessment of sleepiness became mandatory in Europe for people at risk who need the driving license release. Moreover, considering the expectation that people around the world are rapidly aging, it is necessary to investigate the relationships between senescence sleep changes, vigilance levels, and driving-related cognitive skills. Method : 80 healthy subjects (40 young adults and 40 elders) participated in the study. Sleep quality, sleepiness, and vigilance levels were assessed through the Pittsburgh Sleep Quality Index, the Karolinska Sleepiness Scale, the Epworth Sleepiness Scale, and the Psychomotor Vigilance Task (PVT). Driving-related cognitive abilities were assessed through Vienna Test System TRAFFIC, investigating selective attention, tachistoscopic perception, and risk assumption. Results : 2 × 2 between-subject ANOVAs showed less habitual sleep efficiency and worse performances in PVT in the older group. Unexpectedly, younger subjects show higher self-rated sleepiness. Moreover, older adults have lower performance in attention and perception tests, but they appear to be more cautious in situations involving traffic. Finally, the multiple regressions show age to be the only robust predictor of cognitive driving-related abilities. Conclusions : This is the first study that investigates the relationships among sleepiness/vigilance and specific driving-related cognitive skills on a sufficiently large sample. Nevertheless, the study should be considered preliminary and does not allow us to understand how specific changes in sleep architecture impact performances in the elders' everyday life and, specifically, on driving skills.

Sleep significantly changes across the lifespan, and several studies underline its crucial role in cognitive functioning. Similarly, mental activity during sleep tends to covary with age. This review aims to analyze the characteristics of dreaming and disturbing dreams at different age brackets. On the one hand, dreams may be considered an expression of brain maturation and cognitive development, showing relations with memory and visuo-spatial abilities. Some investigations reveal that specific electrophysiological patterns, such as frontal theta oscillations, underlie dreams during sleep, as well as episodic memories in the waking state, both in young and older adults. On the other hand, considering the role of dreaming in emotional processing and regulation, the available literature suggests that mental sleep activity could have a beneficial role when stressful events occur at different age ranges. We highlight that nightmares and bad dreams might represent an attempt to cope the adverse events, and the degrees of cognitive-brain maturation could impact on these mechanisms across the lifespan. Future investigations are necessary to clarify these relations. Clinical protocols could be designed to improve cognitive functioning and emotional regulation by modifying the dream contents or the ability to recall/non-recall them.

Several findings underlined that the electrophysiological (EEG) background of the last segment of sleep before awakenings may predict the presence/absence of dream recall (DR) in young subjects. However, little is known about the EEG correlates of DR in elderly people. Only an investigation found differences between recall and non-recall conditions during NREM sleep EEG in older adults, while-surprisingly-no EEG predictor of DR was found for what concerns REM sleep. Considering REM sleep as a privileged scenario to produce mental sleep activity related to cognitive processes, our study aimed to investigate whether specific EEG topography and frequency changes during REM sleep in elderly people may predict a subsequent recall of mental sleep activity. Twenty-one healthy older volunteers (mean age 69.2 ± 6.07 SD) and 20 young adults (mean age 23.4 ± 2.76 SD) were recorded for one night from 19 scalp derivations. Dreams were collected upon morning awakenings from REM sleep. EEG signals of the last 5 min were analyzed by the Better OSCillation algorithm to detect the peaks of oscillatory activity in both groups. Statistical comparisons revealed that older as well as young individuals recall their dream experience when the last segment of REM sleep is characterized by frontal theta oscillations. No Recall (Recall vs. Non-Recall) × Age (Young vs. Older) interaction was found. This result replicated the previous evidence in healthy young subjects, as shown in within- and between-subjects design. The findings are completely original for older individuals, demonstrating that theta oscillations are crucial for the retrieval of dreaming also in this population. Furthermore, our results did not confirm a greater presence of the theta activity in healthy aging. Conversely, we found a greater amount of rhythmic theta and alpha activity in young than older participants. It is worth noting that the theta oscillations detected are related to cognitive functioning. We emphasize the notion that the oscillatory theta activity should be distinguished from the non-rhythmic theta activity identified in relation to other phenomena such as (a) sleepiness and hypoarousal conditions during the waking state and (b) cortical slowing, considered as an EEG alteration in clinical samples., (Copyright © 2019 Scarpelli, D'Atri, Bartolacci, Mangiaruga, Gorgoni and De Gennaro.)

During the sleep onset (SO) process, the human electroencephalogram (EEG) is characterized by an orchestrated pattern of spatiotemporal changes. Sleep deprivation (SD) strongly affects both wake and sleep EEG, but a description of the topographical EEG power spectra and oscillatory activity during the wake-sleep transition after a period of prolonged wakefulness is still missing. The increased homeostatic sleep pressure should induce an earlier onset of sleep-related EEG oscillations. The aim of the present study was to assess the spatiotemporal EEG pattern at SO following SD. A dataset of a previous study was analyzed. We assessed the spatiotemporal EEG changes (19 cortical derivations) during the SO (5 min before vs. 5 min after the first epoch of Stage 2) of a recovery night after 40 h of SD in 39 healthy subjects, analyzing the EEG power spectra (fast Fourier transform) and the oscillatory activity [better oscillation (BOSC) detection method]. The spatiotemporal pattern of the EEG power spectra mostly confirmed the changes previously observed during the wake-sleep transition at baseline. The comparison between baseline and recovery showed a wide increase of the post- vs. pre-SO ratio during the recovery night in the frequency bins ≤10 Hz. We found a predominant alpha oscillatory rhythm in the pre-SO period, while after SO the theta oscillatory activity was prevalent. The oscillatory peaks showed a generalized increase in all frequency bands from delta to sigma with different predominance, while beta activity increased only in the fronto-central midline derivations. Overall, the analysis of the EEG power replicated the topographical pattern observed during a baseline night of sleep but with a stronger intensity of the SO-induced changes in the frequencies ≤10 Hz, and the detection of the rhythmic activity showed the rise of several oscillations at SO after SD that was not observed during the wake-sleep transition at baseline (e.g., alpha and frontal theta in correspondence of their frequency peaks). Beyond confirming the local nature of the EEG pattern at SO, our results show that SD has an impact on the spatiotemporal modulation of cortical activity during the falling-asleep process, inducing the earlier emergence of sleep-related EEG oscillations.

Dream experience (DE) represents a fascinating condition linked to emotional processes and the human inner world. Although the overlap between REM sleep and dreaming has been overcome, several studies point out that emotional and perceptually vivid contents are more frequent when reported upon awakenings from this sleep stage. Actually, it is well-known that REM sleep plays a pivotal role in the processing of salient and emotional waking-life experiences, strongly contributing to the emotional memory consolidation. In this vein, we highlighted that, to some extent, neuroimaging studies showed that the processes that regulate dreaming and emotional salience in sleep mentation share similar neural substrates of those controlling emotions during wakefulness. Furthermore, the research on EEG correlates of the presence/absence of DE and the results on EEG pattern related to the incorporated memories converged to assign a crucial role of REM theta oscillations in emotional re-processing. In particular, the theta activity is involved in memory processes during REM sleep as well as during the waking state, in line with the continuity hypothesis. Also, the gamma activity seems to be related to emotional processes and dream recall as well as to lucid dreams. Interestingly, similar EEG correlates of DE have been found in clinical samples when nightmares or dreams occur. Research on clinical samples revealed that promoting the rehearsal of frightening contents aimed to change them is a promising method to treat nightmares, and that lucid dreams are associated with an attenuation of nightmares. In this view, DE can defuse emotional traumatic memories when the emotional regulation and the fear extinction mechanisms are compromised by traumatic and frightening events. Finally, dreams could represent a sort of simulation of reality, providing the possibility to create a new scenario with emotional mastery elements to cope with dysphoric items included in nightmares. In addition, it could be hypothesized that the insertion of bizarre items besides traumatic memories might be functional to "impoverish" the negative charge of the experiences.

Δ16HER2 is a splice variant of HER2 and defined as the transforming isoform in HER2-positive breast cancer. It has been shown that Δ16HER2 promotes breast cancer aggressiveness and drug resistance. In the present work, we used in silico modeling to identify structural differences between Δ16HER2 and the wild-type HER2 proteins. We then developed DNA vaccines specifically against the Δ16HER2 isoform and showed that these immunotherapies hampered carcinogenesis in a breast cancer transplantable model. However, the vaccines failed to elicit immune protection in Δ16HER2 transgenic mice because of tolerogenic mechanisms toward the human HER2 self-antigen, a scenario commonly seen in HER2 + patients. Thus, we engineered bacteriophages with immunogenic epitopes of Δ16HER2 exposed on their coat for use as anticancer vaccines. These phage-based vaccines were able to break immune tolerance, triggering a protective anti-Δ16HER2 humoral response. These findings provide a rationale for the use of phage-based anti-HER2/Δ16HER2 vaccination as a safe and efficacious immunotherapy against HER2-positive breast cancers., (©2018 American Association for Cancer Research.)

Aging skeletal muscles are characterized by a progressive decline in muscle mass and muscular strength. Such muscular dysfunctions are usually associated with structural and functional alterations of skeletal muscle mitochondria. The senescence-accelerated mouse-prone 8 (SAMP8) model, characterized by premature aging and high degree of oxidative stress, was used to investigate whether a combined intervention with mild physical exercise and ubiquinol supplementation was able to improve mitochondrial function and preserve skeletal muscle health during aging. 5-month-old SAMP8 mice, in a presarcopenia phase, have been randomly divided into 4 groups ( n = 10): untreated controls and mice treated for two months with either physical exercise (0.5 km/h, on a 5% inclination, for 30 min, 5/7 days per week), ubiquinol 10 (500 mg/kg/day), or a combination of exercise and ubiquinol. Two months of physical exercise significantly increased mitochondrial damage in the muscles of exercised mice when compared to controls. On the contrary, ubiquinol and physical exercise combination significantly improved the overall status of the skeletal muscle, preserving mitochondrial ultrastructure and limiting mitochondrial depolarization induced by physical exercise alone. Accordingly, combination treatment while promoting mitochondrial biogenesis lowered autophagy and caspase 3-dependent apoptosis. In conclusion, the present study shows that ubiquinol supplementation counteracts the deleterious effects of physical exercise-derived ROS improving mitochondrial functionality in an oxidative stress model, such as SAMP8 in the presarcopenia phase.

Basal like breast cancer (BLBC) is a very aggressive subtype of breast cancer giving few chances of survival, against which cisplatin based therapy is a compromise among the anticancer activity, the resistance development and the severe side effects. With the aim of finding new anticancer agents alternative to cisplatin, seven gold(I) azolate/phosphane compounds were evaluated in vitro by MTT tests in human MDA-MB-231, human mammary epithelial HMLE cells overexpressing FoxQ1, and murine A17 cells as models of BLBC. Two compounds, (4,5-dichloro-1H-imidazolate-1-yl)-(triphenylphosphane)-gold(I) 1 and (4,5-dicyano-1H-imidazolate-1-yl)-(triphenylphosphane)-gold(I) 2 were found very active and chosen for an in vivo study in A17 tumors transplanted in syngeneic mice. The compounds resulted to be more active than cisplatin, less nephrotoxic and generally more tolerated by the mice. This study also provides evidence that both gold(I) complexes inhibited the 19 S proteasome-associated deubiquitinase USP14 and induced apoptosis, while compound 1's mechanism of action depends also on its ability to down-regulate key molecules governing cancer growth and progression, such as STAT3 and Cox-2., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

It is an acknowledged fact that health benefits are derived from fruit- and vegetables-enriched diets. In particular, polyphenols, compounds bearing one or more hydroxyl groups attached to an aromatic ring, are ascribed for most of such beneficial effects. Among them, resveratrol, a phytoalexin found in numerous plant species, and more notably in grapes, has widely piqued the interest of the scientific community by virtue of its anti-aging, anti-inflammatory and anti-oxidant properties. Moreover, evidence claiming resveratrol ability to hinder processes underlying all the three steps of carcinogenesis (tumor initiation, progression and metastasization) has propelled an incredibly massive number of studies aimed at enquiring its eventual clinical potential in the fight against cancer. However, despite a large body of data pointing to the advantages of dietary resveratrol intake in respect of certain disease conditions, and cancer inter alia, its real position still remains quite ambiguous. In this uncertain scenario, the present review focuses its attention on the highly entangled relationship between resveratrol and breast cancer, attempting to shape the plethora of controversial results stemming from studies carried out on several in vitro and in vivo breast cancer models. Coping with such a tricky matter, there are so many variabilities concerning both resveratrol itself (dosage, administration, bioavailabilty, among others) and the unique molecular traits of each specific breast cancer subtype that must be taken into account when facing the dilemma: "might resveratrol be protective against breast cancer or does it rather fuel it?"., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The phytoestrogen resveratrol has been reported to possess cancer chemo-preventive activity on the basis of its effects on tumor cell lines and xenograft or carcinogen-inducible in vivo models. Here we investigated the effects of resveratrol on spontaneous mammary carcinogenesis using Δ16HER2 mice as HER2+/ERα+ breast cancer model. Instead of inhibiting tumor growth, resveratrol treatment (0.0001% in drinking water; daily intake of 4μg/mouse) shortened tumor latency and enhanced tumor multiplicity in Δ16HER2 mice. This in vivo tumor-promoting effect of resveratrol was associated with up-regulation of Δ16HER2 and down-regulation of ERα protein levels and was recapitulated in vitro by murine (CAM6) and human (BT474) tumor cell lines. Our results demonstrate that resveratrol, acting as a proteasome inhibitor, leads to Δ16HER2 accumulation which favors the formation of Δ16HER2/HER3 heterodimers. The consequential activation of downstream mTORC1/p70S6K/4EBP1 pathway triggers cancer growth and proliferation. This study provides evidence that resveratrol mechanism of action (and hence its effects) depends on the intrinsic molecular properties of the cancer model under investigation, exerting a tumor-promoting effect in luminal B breast cancer subtype models.

To date, efficiency upon non-viral DNA delivery remains low and this implies the existence of unidentified transfection barriers. Here we explore the mechanisms of action of multicomponent (MC) cationic liposome/DNA complexes (lipoplexes) by a combination of reporter technologies, dynamic light scattering (DLS), synchrotron small angle X-ray scattering (SAXS), fluorescence activated cell sorting (FACS) analysis and laser scanning confocal microscopy (LSCM) in live cells. Lipofectamine - the gold standard among transfection reagents - was used as a reference. On the basis of our results, we suggest that an additional transfection barrier impairs transfection efficiency, that is: low lipoplex concentration at the cell surface. Based on the acquired knowledge we propose an optimized transfection protocol that allowed us to efficiently transfect DND41, JURKAT, MOLT3, P12-ICHIKAWA, ALL-SILL, TALL-1 human T-cell acute lymphoblastic leukemia (T-ALL) cell lines known to be difficult-to-transfect by using non-viral vectors and where LFN-based technologies fail to give satisfactory results., (Copyright © 2016 Elsevier Inc. All rights reserved.)

HER2 tyrosine kinase receptor is a validated target in breast cancer therapy. However, increasing evidence points to a major role of Δ16HER2 splice variant commonly coexpressed with HER2 and identified as a clinically important HER2 molecular alteration promoting aggressive metastatic breast cancer. Consistently, mice transgenic for the human Δ16HER2 isoform (Δ16HER2 mice) develop invasive mammary carcinomas with early onset and 100% penetrance. The present study provides preclinical evidence that Δ16HER2 expression confers de novo resistance to standard anti-HER2-therapies such as Lapatinib and acquired resistance to the selective Src inhibitor Saracatinib in breast cancer. Of note, Dacomitinib, an irreversible small molecule pan-HER inhibitor, was able to completely suppress Δ16HER2-driven breast carcinogenesis. Thus, only Dacomitinib may offer benefit in this molecularly defined patient subset by irreversibly inhibiting Δ16HER2 activation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Basal-like breast cancer (BLBC) remains a great challenge because of its clinically aggressive nature and lack of effective targeted therapy. We analyzed the potential anti-neoplastic effects of sanguinarine, a natural benzophenanthridine alkaloid, against BLBC cells. Sanguinarine treatment resulted in a reduction of cell migration, in a dose-dependent inhibition of cell viability and in the induction of cell death by apoptosis in both human (MDA-MB-231 cells) and mouse (A17 cells) in vitro models of BLBC. In vivo experiments demonstrated that oral administration of sanguinarine reduced the development and growth of A17 transplantable tumors in FVB syngeneic mice. Western blotting analysis revealed that suppression of BLBC growth by sanguinarine was correlated with a concurrent upregulation of p27 and downregulation of cyclin D1 and with the inhibition of STAT3 activation. In addition, we identified sanguinarine as a potent inhibitor of dihydrofolate reductase (DHFR), able to impair enzyme activity even in methotrexate resistant MDA-MB-231 cells. These results provide evidence that sanguinarine is a promising anticancer drug for the treatment of BLBC., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Increasing evidence supports the theory that tumor growth, homeostasis, and recurrence are dependent on a small subset of cells with stem cell properties, redefined cancer initiating cells (CICs) or cancer stem cells. Bone morphogenetic proteins (BMPs) are involved in cell-fate specification during embryogenesis, in the maintenance of developmental potency in adult stem cells and may contribute to sustain CIC populations in breast carcinoma. Using the mouse A17 cell model previously related to mesenchymal cancer stem cells and displaying properties of CICs, we investigated the role of BMPs in the control of breast cancer cell plasticity. We showed that an autocrine activation of BMP signaling is crucial for the maintenance of mesenchymal stem cell phenotype and tumorigenic potential of A17 cells. Pharmacological inhibition of BMP signaling cascade by Dorsomorphin resulted in the acquisition of epithelial-like traits by A17 cells, including expression of Citokeratin-18 and E-cadherin, through downregulation of Snail and Slug transcriptional factors and Cyclooxygenase-2 (COX2) expression, and in the loss of their stem-features and self-renewal ability. This phenotypic switch compromised A17 cell motility, invasiveness and in vitro tumor growth. These results reveal that BMPs are key molecules at the crossroad between stemness and cancer., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We demonstrate 308 mW of single-mode laser emission at 464 nm from a frequency doubled picosecond fiber based Master Oscillator Power Amplifier (MOPA). The laser system consisted of a gain-switched and spectrally narrowed Fabry-Perot laser diode emitting at 928 nm, which was amplified in a two-stage amplifier based on W-type double-clad Nd-doped fibers. Output pulses with a duration of 90 ps at a repetition rate of 41 MHz were frequency-doubled in a periodically poled MgO-doped Congruent Lithium Niobate. A conversion efficiency of 14.8% was achieved in single-pass configuration.

We describe an all-fiberized coherent detection system at 1.55 microm using heterodyne self-mixing modulation in a distributed-feedback fiber laser. Frequency shifting of the optical feedback is based on serrodyne phase modulation with an integrated electro-optic modulator, which is a significant advance in the simplification of the self-mixing detection scheme for class B lasers. Accurate measurement of the optical phase difference between the laser electric field and the backscattered electric field demonstrates nanometric displacement detection on noncooperative targets.