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Previous studies have reported that larger visual stimuli are perceived as lasting longer than smaller ones. However, this effect disappears when participants provide a qualitative judgment, by stating whether two stimuli have the "same or different" duration, instead of providing an explicit quantitative judgment (which stimulus lasts longer). Here, we extended these observations to the interaction between the numerosity of visual stimuli, i.e. clouds of dots, and their duration. With "longer vs shorter" responses, participants judged larger numerosities as lasting longer than smaller ones, both when the responses were related to the order (Experiment 1) or color (Experiment 4) of stimuli. In contrast, no similar effect was found with "same vs different" responses (Experiment 2) and in a time motor reproduction task (Experiment 3). The numerosity–time interference in Experiment 1 and Experiment 4 was not due to task difficulty, as sensory precision was equivalent to that of Experiment 2. We conclude that in humans the functional interaction between numerosity and time is not guided, in the main, by a shared bottom-up mechanism of magnitude coding. Rather, high-level and top-down processes involved in decision-making and guided by the use of "magnitude-related" response codes play a crucial role in triggering interference among different magnitude domains. [ABSTRACT FROM AUTHOR]

Mental health and wellbeing are increasingly threatened in the current post-pandemic times, with stress, especially in students, reaching preoccupying levels. In addition, while many educational programs are unidimensional (i.e., lacking integration between physical, emotional and cognitive elements), there are ways to promote physical, social and mental health in children and adolescents. In this opinion paper, we will discuss the importance of an integrative approach for health development and examine relevant factors, such as awareness and emotional intelligence. We will highlight evidence ranging from behavioral to electrophysiological, structural and molecular, and report several recent studies supporting the effectiveness of a holistic approach in supporting wellbeing and creativity in children and adults, and detailing a specific paradigm named the Quadrato Motor Training (QMT). QMT is a specifically structured movement meditation, involving cognitive, motor and affective components. Finally, we will support a holistic view on education, integrating motion, emotion and cognition to develop a person-centered, or in this case student-centered, approach to wellbeing and health. [ABSTRACT FROM AUTHOR]

Stilbenoids, a group of phytoalexin polyphenols produced by plants as a defence mechanism in response to stress conditions, are known for their anti-inflammatory potential. Pinosylvin, a naturally occurring molecule traditionally found in pinus trees, was here identified in Pinus nigra subsp. laricio var. calabrica from Southern Italy through HPLC analysis. Both this molecule and its well-known analogue resveratrol, the most famous wine polyphenol, were compared for their in vitro potential anti-inflammatory activity. Pinosylvin significantly inhibited the release of pro-inflammatory cytokines (TNF-α and IL-6) and NO mediator in LPS-stimulated RAW 264.7 cells. Moreover, its ability to inhibit the JAK/STAT signaling pathway was assessed: Western blot analyses showed a downregulation of both phosphorylated JAK2 and STAT3 proteins. Finally, in order to verify whether this biological activity could be attributed to a direct interaction of pinosylvin with JAK2, a molecular docking study was performed, confirming the capability of pinosylvin to bind the active site of the protein. [ABSTRACT FROM AUTHOR]

Among the prognostic and predictive biomarkers of breast cancer (BC), the role of estrogen receptor (ER)α wild‐type has been acknowledged, although the action of certain ERα splice variants has not been elucidated. Insulin/insulin receptor (IR) axis has also been involved in the progression and metastasis of BC. For instance, hyperinsulinemia, which is often associated with obesity and type 2 diabetes, may be a risk factor for BC. Similarly, an aberrant expression of IR or its hyperactivation may correlate with aggressive BC phenotypes. In the present study, we have shown that a novel naturally immortalized BC cell line (named BCAHC‐1) is characterized by a unique expression of 46 kDa ERα splice variant (ERα46) along with IR. Moreover, we have shown that a multifaceted crosstalk between ERα46 and IR occurs in BCAHC‐1 cells upon estrogen and insulin exposure for growth and pulmonary metastasis. Through high‐throughput RNA sequencing analysis, we have also found that the cytokine interleukin‐11 (IL11) is the main factor linking BCAHC‐1 cells to breast cancer‐associated fibroblasts (CAFs). In particular, we have found that IL11 induced by estrogens and insulin in BCAHC‐1 cells regulates pro‐tumorigenic genes of the "extracellular matrix organization" signaling pathway, such as ICAM‐1 and ITGA5, and promotes both migratory and invasive features in breast CAFs. Overall, our results may open a new scientific avenue to identify additional prognostic and therapeutic targets in BC. [ABSTRACT FROM AUTHOR]

It is debated whether the representation of numbers is endowed with a directional-spatial component so that perceiving small-magnitude numbers triggers leftward shifts of attention and perceiving large-magnitude numbers rightward shifts. Contrary to initial findings, recent investigations have demonstrated that centrally presented small-magnitude and large-magnitude Arabic numbers do not cause leftward and rightward shifts of attention, respectively. Here we verified whether perceiving small or large non-symbolic numerosities (i.e., clouds of dots) drives attention to the left or the right side of space, respectively. In experiment 1, participants were presented with central small (1, 2) vs large-numerosity (8, 9) clouds of dots followed by an imperative target in the left or right side of space. In experiment 2, a central cloud of dots (i.e., five dots) was followed by the simultaneous presentation of two identical dot-clouds, one on the left and one on the right side of space. Lateral clouds were both lower (1, 2) or higher in numerosity (8, 9) than the central cloud. After a variable delay, one of the two lateral clouds turned red and participants had to signal the colour change through a unimanual response. We found that (a) in Experiment 1, the small vs large numerosity of the central cloud of dots did not speed up the detection of left vs right targets, respectively, (b) in Experiment 2, the detection of colour change was not faster in the left side of space when lateral clouds were smaller in numerosity than the central reference and in the right side when clouds were larger in numerosity. These findings show that perceiving non-symbolic numerosity does not cause automatic shifts of spatial attention and suggests no inherent association between the representation of numerosity and that of directional space. [ABSTRACT FROM AUTHOR]

Orienting of attention produces a "sensory gain" in the processing of visual targets at attended locations and an increase in the amplitude of target-related P1 and N1 ERPs. P1 marks gain reduction at unattended locations; N1 marks gain enhancement at attended ones. Lateral targets that are preceded by valid cues also evoke a larger P1 over the hemisphere contralateral to the no-target side, which reflects inhibition of this side of space [Slagter, H. A., Prinssen, S., Reteig, L. C., & Mazaheri, A. Facilitation and inhibition in attention: Functional dissociation of pre-stimulus alpha activity, P1, and N1 components. Neuroimage, 125, 25–35, 2016]. To clarify the relationships among cue predictiveness, sensory gain, and the inhibitory P1 response, we compared cue- and target-related ERPs among valid, neutral, and invalid trials with predictive (80% valid/20% invalid) or nonpredictive (50% valid/50% invalid) directional cues. Preparatory facilitation over the visual cortex contralateral to the cued side of space (lateral directing attention positivity component) was reduced during nonpredictive cueing. With predictive cues, the target-related inhibitory P1 was larger over the hemisphere contralateral to the no-target side not only in response to valid but also in response to neutral and invalid targets: This result highlights a default inhibitory hemispheric asymmetry that is independent from cued orienting of attention. With nonpredictive cues, valid targets reduced the amplitude of the inhibitory P1 over the hemisphere contralateral to the no-target side whereas invalid targets enhanced the amplitude of the same inhibitory component. Enhanced inhibition was matched with speeded reorienting to invalid targets and drop in attentional costs. These findings show that reorienting of attention is modulated by the combination of cue-related facilitatory and target-related inhibitory activity. [ABSTRACT FROM AUTHOR]

The Attentional-SNARC effect (Att-SNARC) originally described by Fischer et al. (Nat Neurosci 6(6):555, 2003), consists of faster RTs to visual targets in the left side of space when these are preceded by small-magnitude Arabic cues at central fixation and by faster RTs to targets in the right side of space when these are preceded by large-magnitude cues. Verifying the consistency and reliability of this effect is important, because the effect would suggest an inherent association between the representation of space and that of number magnitude, while a number of recent studies provided no positive evidence in favour of the Att-SNARC and the inherency of this association (van Dijck et al. in Q J Exp Psychol 67(8):1500–1513, 2014; Zanolie and Pecher in Front Psychol 5:987, 2014; Fattorini et al. in Cortex 73:298–316, 2015; Pinto et al. in Cortex, DOI:10.1016/j.cortex.2017.12.015, 2018). Here, we re-analysed Att-SNARC data that we have collected in 174 participants over different studies run in our laboratory. Most important, in a subsample of 79 participants, we also verified whether the strength and reliability of the Att-SNARC is eventually linked inter-individual variations in finger counting style, imagery vividness, and verbal/visual learning style. We found no evidence for the Att-SNARC effect or for the influence of finger counting style, imagery vividness, and learning style on its direction or consistency. These results confirm no inherent link between orienting of spatial attention and representation of number magnitudes. We propose that this link is rather determined by the joint use of spatial and number magnitude or parity codes in the performance of the numerical task at hand. [ABSTRACT FROM AUTHOR]

In a series of five experiments with unimanual Go/No-Go tasks and intermixed Arabic numerical, i.e. numbers lower or higher than 5, and directional targets, i.e. arrows pointing to the left or to the right, we explored whether spatial codes used in isolation inherently evoke the left-to-right representation of number magnitudes, i.e. Space-to-Number congruency effect, and, vice-versa, whether number-magnitude codes used in isolation inherently evoke the conceptual activation of left/right spatial codes, i.e. Number-to-Space congruency effect. In Experiment 1 Go responses were provided based on instructions that activated only magnitude codes, e.g. "push only if the number is lower than 5 and whenever an arrow appears", or only spatial codes, e.g. "push only when an arrow points to the left and whenever a number appears". In Experiments 2-4, the same instructions were combined with the request of responding only to arrows in a specific colour. No fixed association was present between a specific arrow colour and a specific arrow direction. In Experiment 3, the direction of arrow-targets was kept fixed to favour the processing of arrow direction. In Experiment 4, an additional class of No-Go visual stimuli was included to heighten the focus of attention on numerical and directional arrow-targets and, in addition, only numbers 1, 2, 8 and 9 were used to force the contrast between small and large magnitude codes. The results of Experiments 1-4 highlighted no significant or reliable Space-to-Number congruency effect, e.g. faster RTs to numbers lower than 5 when participants attend to arrows pointing to the left, or Number-to-Space congruency effect, e.g. faster RTs to arrows pointing to the left when participants attend to numbers lower than 5. In Experiment 5 we confirmed that when spatial and number magnitude codes are used in conjunction, e.g. " push only when an arrow points left and when a number is lower than 5", a significant Space-to-Number congruency effect is found and we expanded this evidence to Number-to-Space congruency. Split-half testing showed that in Experiment 5 congruency effects were reliable and null-hypothesis significance testing showed that they were different from those found in all other experiments. We conclude that neither space codes used in isolation can elicit a spatial representation of number magnitudes nor number-magnitude codes used in isolation can trigger the activation of spatial codes. Thus, spatial and numerical codes must be used jointly to evoke reliable spatially organised mental number lines. [ABSTRACT FROM AUTHOR]

A series of unknown 3-(alkyl(dialkyl)amino)benzofuro[2,3- f ]quinazolin-1(2 H )-ones 4–17 has been synthesized as new ellipticine analogs, in which the carbazole moiety and the pyridine ring were replaced by a dibenzofuran residue and a pyrimidine ring, respectively. The synthesis of these benzofuroquinazolinones 4–17 was performed in a simple one-pot reaction using 3-aminodibenzofuran or its 2-methoxy derivative, as starting materials. From 3-(dipropylamino)-5-methoxybenzofuro[2,3- f ] quinazolin-1(2 H )-one ( 13 ), we prepared 3-(dipropylamino)-5-hydroxybenzofuro[2,3- f ]quinazolin-1(2 H )-one ( 18 ), referred to as DPA-HBFQ-1 . The cytotoxic activities of all the synthesized compounds, tested in different human breast cancer cell lines, revealed that DPA-HBFQ-1 was the most active compound. In particular, the latter was able to inhibit anchorage-dependent and -independent cell growth and to induce apoptosis in estrogen receptor alpha (ERα)-positive and -negative breast cancer cells. It did not affect proliferation and apoptotic responses in MCF-10A normal breast epithelial cells. The observed effects have been ascribed to an enhanced p21 Cip1/WAF1 expression in a p53-dependent manner of tumor suppressor and to a selective inhibition of human topoisomerase II. In addition, DPA-HBFQ-1 exerted growth inhibitory effects also in other cancer cell lines, even though with a lower cytotoxic activity. Our results indicate DPA-HBFQ-1 as a good candidate to be useful as cancer therapeutic agent, particularly for breast cancer. [ABSTRACT FROM AUTHOR]

Left-to-right readers classify faster past events with motor responses on the left side of space and future events with responses on the right side. This suggests a left-to-right spatial organization in the mental representation of time. Here, we show that the significance and reliability of this representation are linked to the joint use of temporal and spatial codes in the task at hand. In a first unimanual Go/No-Go Implicit Association Test (IAT), attending selectively to "past" or to "future" words did not activate corresponding "left" or "right" spatial concepts and vice versa. In a second IAT, attending to both temporal (i.e., "past" and "future") words and spatial targets (i.e., "left" and "right") pointing arrows produced faster responses for congruent rather than incongruent combinations of temporal and spatial concepts in task instructions (e.g., congruent = "Go with past words and left-pointing arrows"; incongruent = "Go with past words and right-pointing arrows"). This effect increased markedly in a STEARC task where spatial codes defined the selection between "left-side" and "right-side" button presses that were associated with "past" and "future" words. Two control experiments showed only partial or unreliable space–time congruency effects when (a) participants attended to superordinate semantic codes that included both spatial "left"/"right" or temporal "past/future" subordinate codes; (b) a primary speeded response was assigned to one dimension (e.g., "past vs. future") and a nonspeeded one to the other dimension (e.g., "left" vs. "right"). These results help to define the conditions that trigger a stable and reliable spatial representation of time-related concepts. [ABSTRACT FROM AUTHOR]

Obesity is a risk factor for breast cancer, largely due to altered expression of various adipocytokines. As it concerns adiponectin, there are not univocal results regarding its role in breast cancer occurrence and progression. Here, we demonstrate that in animals injected with human estrogen receptor (ER)-a-negative MDA-MB-231 cells pretreated with adiponectin (1 and 5µg/ml), a significant reduction (60 and 40%, respectively) in tumor volume is observed,whereas an increased tumor growth (54 and 109%, respectively) is evidenced in the animals receiving human ER-α-positive MCF-7 cells. Moreover, cyclin D1 (CD1) mRNA and protein levels are decreased in MDA-MB-231 cells, whereas they are upregulated in ER-α-positive cells by adiponectin. These findings fit with the opposite effects of adiponectin on CD1 promoter: 0.44- and 0.34-fold decrease in MDA-MB- 231 cells and 0.63- and 0.95-fold increase in MCF-7 cells, treated with 1 and 5 µg/ml, respectively. Functional studies indicate that these effects are mediated by the specific protein 1 motif located in the CD1 promoter. In the absence of ER-α, the adiponectin-mediated down-regulation of CD1 involves the recruitment of corepressors. In the presence of ER-α, the adiponectin-induced expression of CD1 requires the involvement of an activator complex. In conclusion, we propose that a possible mechanism through which adiponectin differently affects breast cancer growth is the opposite modulation of CD1 levels accordingly to ER-α expression. [ABSTRACT FROM AUTHOR]

Biological responses to estrogens in normal and malignant tissues are mainly mediated by the estrogen receptors ERα and ERβ, which function as ligand-activated transcription factors. In addition, the G protein-coupled receptor GPR30 (GPER) mediates estrogenic signaling in breast cancer cells and cancer-associated fibroblasts (CAF) that contribute to cancer progression. In this study, we evaluated the role elicited by GPER in the estrogen-regulated expression and function of vascular endothelial growth factor (VEGF) in ER-negative breast cancer cells and CAF. We demonstrated that 17β-estradiol (E2) and the GPER-selective ligand G-1 triggered a GPER/EGFR/ERK/c-fos signaling pathway that leads to increased VEGF via upregulation of HIF1α. In further extending the mechanisms involved in E2-supported angiogenesis, we also showed that conditioned medium from CAF treated with E2 and G-1 promoted human endothelial tube formation in a GPER-dependent manner. In vivo, ligand-activated GPER was sufficient to enhance tumor growth and the expression of HIF1α, VEGF, and the endothelial marker CD34 in a mouse xenograft model of breast cancer. Our findings offer important new insights into the ability of estrogenic GPER signaling to trigger HIF1α-dependent VEGF expression that supports angiogenesis and progression in breast cancer. [ABSTRACT FROM AUTHOR]

More than 80 million people worldwide have been infected with the human immunodeficiency virus (HIV). There are now approximately 39 million individuals living with HIV/acquired immunodeficiency syndrome (AIDS). Although treatments against HIV infection are available, AIDS remains a serious disease. Combination antiretroviral therapy (cART), also known as highly active antiretroviral therapy (HAART), consists of treatment with a combination of several antiretroviral drugs that block multiple stages in the virus replication cycle. However, the increasing usage of cART is inevitably associated with the emergence of HIV drug resistance. In addition, the development of persistent cellular reservoirs of latent HIV is a critical obstacle to viral eradication since viral rebound takes place once anti-retroviral therapy (ART) is interrupted. Thus, several efforts are being applied to new generations of drugs, vaccines and new types of cART. In this review, we summarize the antiviral therapies used for the treatment of HIV/AIDS, both as individual agents and as combination therapies, and highlight the role of both macrophages and HIV cellular reservoirs and the most recent clinical studies related to this disease. [ABSTRACT FROM AUTHOR]

Takenouchi–Kosaki syndrome (TKS) is a rare congenital disease caused by a de novo mutation in the Cell Division Cycle 42 (CDC42) gene. Patients with TKS present facial and body dysmorphisms, hematologic and immune dysregulation, intellectual disability, neurodevelopmental delay and hearing loss. The aim of this study is to review the literature, focusing on hearing and language abilities in children with TKS. A systematic search on PubMed, Scopus and Web of Science databases was performed, including twelve studies for a total of 13 patients. Hearing loss (HL) occurs in a great percentage of patients (84.6%); nonetheless, auditory threshold, severity of HL and language abilities were reported in a few cases. In two studies, auditory rehabilitation strategies were described. Although several studies have investigated the hematological features of TKS, still only a few authors have focused on the audiological and language abilities of these children. Given the fact that HL has a significant impact on behaviors, communications skills, and quality of life, it is important to adequately assess and rehabilitate patients early with this syndrome. Further studies are needed to improve the knowledge about this topic and improve the quality of life of patients with TKS. [ABSTRACT FROM AUTHOR]

Whether the semantic representation of numbers is endowed with an intrinsic spatial component, so that smaller numbers are inherently represented to the left of larger ones on a Mental Number Line (MNL), is a central matter of debate in numerical cognition. To gain an insight into this issue, we investigated the performance of right brain damaged patients with left spatial neglect (N+) in a bimanual Magnitude Comparison SNARC task and in a uni-manual Magnitude Comparison Go/No-Go task (i.e. "is the number smaller or larger than 5?"). While the first task requires the use of contrasting left/right spatial codes for response selection, the second task does not require the use of these codes. In line with previous evidence, in the SNARC task N+ patients displayed a significant asymmetry in Reaction Times (RTs), with slower RTs to number "4", that was immediately precedent to the numerical reference "5", with respect to the number "6", that immediately followed the same reference. This RTs asymmetry was correlated with lesion of white matter tracts, i.e. Fronto-Occipital-Fasciculus, that allows prefrontal Ba 8 and 46 to regulate the distribution of attention on sensory and memory traces in posterior occipital, temporal and parietal areas. In contrast, no similar RTs asymmetry was found in the Go/No-Go task. These findings suggest that while in the SNARC task numbers get mentally organised from left-to-right as a function of their increasing magnitude, so that N+ patients display a delay in the processing of number-magnitudes that are immediately smaller than a given numerical reference, in the Go/No-Go task no left-to-right organization is activated. These results support the idea that it is the use of contrasting left/right spatial codes, whether motor or conceptual, that triggers the generation of a spatially left-to-right organised MNL and that the representation of number magnitude is not endowed with an inherent spatial component. • Left-to-right readers mentally arrange smaller numbers to the left of larger ones • Is this arrangement linked to the use of left/right spatial response codes (L/R)? • Patients with left spatial neglect are slower with small numbers when using L/R • The same patients are not slower with small numbers in a Go/No-Go task without L/R • The left-to-right mental arrangement is not inherent to number magnitudes [ABSTRACT FROM AUTHOR]

Background: Resistance to endocrine treatments is a major clinical challenge in the management of estrogen receptor positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of this subgroup of patients demands additional studies. Methods: FoxO3a involvement in the acquisition and reversion of tamoxifen resistance was assessed in vitro in three parental ER+ breast cancer cells, MCF-7, T47D and ZR-75-1, in the deriving Tamoxifen resistant models (TamR) and in Tet-inducible TamR/FoxO3a stable cell lines, by growth curves, PLA, siRNA, RT-PCR, Western blot, Immunofluorescence, Transmission Electron Microscopy, TUNEL, cell cycle, proteomics analyses and animal models. FoxO3a clinical relevance was validated in silico by Kaplan–Meier survival curves. Results: Here, we show that tamoxifen resistant breast cancer cells (TamR) express low FoxO3a levels. The hyperactive growth factors signaling, characterizing these cells, leads to FoxO3a hyper-phosphorylation and subsequent proteasomal degradation. FoxO3a re-expression by using TamR tetracycline inducible cells or by treating TamR with the anticonvulsant lamotrigine (LTG), restored the sensitivity to the antiestrogen and strongly reduced tumor mass in TamR-derived mouse xenografts. Proteomics data unveiled novel potential mediators of FoxO3a anti-proliferative and pro-apoptotic activity, while the Kaplan–Meier analysis showed that FoxO3a is predictive of a positive response to tamoxifen therapy in Luminal A breast cancer patients. Conclusions: Altogether, our data indicate that FoxO3a is a key target to be exploited in endocrine-resistant tumors. In this context, LTG, being able to induce FoxO3a, might represent a valid candidate in combination therapy to prevent resistance to tamoxifen in patients at risk. [ABSTRACT FROM AUTHOR]

The SNARC effect consists of faster reaction times to small numerical magnitudes when manual responses are delivered in the left-side of space and to large magnitudes when responses are delivered in the right-side. This spatial compatibility effect points at the interaction between the representations of space and that of numbers. Several studies have highlighted that an important determinant for the production of the SNARC is the use of contrasting left/right spatial codes in the selection of motor responses. In these studies, one spatial code for response selection, e.g. "left", is usually associated with one number feature, e.g. "lower than 5", while the contrasting spatial code, e.g. "right", is associated with the contrasting number feature, e.g. "higher than 5". Using a task with intermixed number and letter targets, here we show that significant and reliable SNARC effects are also produced when: a) one spatial response is associated with the intra-categorical discrimination of a number feature (i.e. magnitude or parity) and the contrasting response with the simple detection of letter targets; b) or when one spatial response is associated with the intra-categorical discrimination of the position of a letter in the alphabet (i.e. before or after "m") and the contrasting spatial response with the simple detection of numerical targets (Experiments 1 and 2). In contrast, no reliable SNARC is found when no intra-categorical number or letter discrimination is required and contrasting left/right spatial response codes are simply associated with the discrimination between numbers and letters, e.g. "push left if the target is a number/push right if it is a letter" (Experiment 3). In a final control test (Experiment 4), we found no SNARC when the magnitude or parity classification of Arabic digits presented at central fixation was made unimanually with a left side or a right side-key and no left/right contrast was present in response selection. These results show that the use of contrasting left/right spatial response codes elicits reliable SNARC effects independently of their assignment to contrasting number features and confirm the important role played by the use of spatial codes in the genesis of the number-space interaction. • Left/Right Spatial Response Codes (SRC) play an important role in the genesis of the SNARC and the number-space interaction • The SNARC is found when left/right SRC are assigned to contrasting small/large or odd/even numerical features • We show that the SNARC is found when one SRC is assigned to a number feature and the other to the detection of letters • Therefore, contrasting left/right SRC must not be necessarily assigned to contrasting numerical features to get the SNARC. [ABSTRACT FROM AUTHOR]

In the developed world, pediatric obesity (PO) has been a major health concern since the last century, and this condition may lead to detrimental life-long physical and mental comorbidities. Currently, its prevalence has increased in low- and middle-income countries and in many high-income countries. Thus, the provision of effective and tailored care for children and their families has become vital. The social consequences of the COVID-19 pandemic are known everywhere, and among these, it has been argued that the COVID-19 pandemic has had a major impact on PO. Overall, the growth of PO over the last decade has been enhanced by the pandemic. During the COVID-19 pandemic, children, adolescents and young adults gained weight as the pediatric population dealt with sedentary lifestyles and changes in food habits. In this review, we want to highlight the impact that the COVID-19 pandemic had on PO. [ABSTRACT FROM AUTHOR]

N-heterocyclic carbene (NHC) silver(I) and gold(I) complexes have found different applications in various research fields, as in medicinal chemistry for their antiproliferative, anticancer, and antibacterial activity, and in chemistry as innovative and effective catalysts. The possibility of modulating the physicochemical properties, by acting on their ligands and substituents, makes them versatile tools for the development of novel metal-based compounds, mostly as anticancer compounds. As it is known, chemotherapy is commonly adopted for the clinical treatment of different cancers, even though its efficacy is hampered by several factors. Thus, the development of more effective and less toxic drugs is still an urgent need. Herein, we reported the synthesis and characterization of new silver(I) and gold(I) complexes stabilized by caffeine-derived NHC ligands, together with their biological and catalytic activities. Our data highlight the interesting properties of this series as effective catalysts in A3-coupling and hydroamination reactions and as promising anticancer, anti-inflammatory, and antioxidant agents. The ability of these complexes in regulating different pathological aspects, and often co-promoting causes, of cancer makes them ideal leads to be further structurally functionalized and investigated. [ABSTRACT FROM AUTHOR]

Picking-up and exploiting spatial and temporal regularities in the occurrence of sensory events is important for goal-directed behaviour. According to the "Predictive Coding Hypothesis" (Friston Philosophical Trans R Soc B 360(1456):815–836, 2005), these regularities are used to generate top-down predictions that are constantly compared with actual sensory events. In a previous study with the Attentional Blink (AB) paradigm, we showed that the temporal and probabilistic uncertainty of T2s that are presented outside the Attentional Blink period, i.e. at least 400 ms after T1, improves the conscious report of T2 that are presented inside the AB. The study of ERP correlated showed that this improvement was associated with a prolonged storage of pre-conscious T2 traces in extra-striate areas (Lasaponara et al. Cortex 71:15–33, 2015). Here, we tested whether variations in the probabilistic cueing of the position of a primary T1 visual target in a 4 × 4 letter array, modulate the retention of memory traces evoked by secondary letter targets (T2) that were presented in other positions of the array. Most important, in each trial, the identity of T2 was specified to participants upon disappearance of the array. We show that high probabilistic cueing facilitates T1 detection and improves the corresponding sensitivity index (d′). In contrast, retention and conscious report of secondary targets (T2) improves when the probabilistic cueing of T1 position is poor. These results suggest that uncertainty in the upcoming position of primary targets boosts the strength of memory traces evoked by secondary targets and improves the possibility that traces of secondary targets gain full access to conscious processing. [ABSTRACT FROM AUTHOR]

Background: Janus kinase (JAK) inhibitors, including upadacitinib, have been recently approved for the treatment of moderate-severe atopic dermatitis (AD) and real-world data on upadacitinib effectiveness and safety are limited. This interim analysis aimed to assess effectiveness and safety of upadacitinib throughout 48 weeks of observation in a real-world adult AD population. Methods: This prospective study collected data on adult patients affected by moderate-to-severe AD and treated with upadacitinib at the dosage of either 15 mg or 30 mg daily based on the physician decision. Upadacitinib was prescribed in the context of a national compassionate use programme. In this interim analysis, within patient comparisons of continuous scores of different scales (namely Eczema Area and Severity Index [EASI], body surface area [BSA], Dermatology Life Quality Index [DLQI], Patient Oriented Eczema Measure [POEM], Numeric Rating Scale [NRS] subtests) were performed. The percentage of patients achieving EASI 75, EASI 90 and EASI 100 at Week 16, 32 and 48 was also evaluated. Results: One hundred and forty-six patients were included in the analysis. Upadacitinib 15 mg or 30 mg daily was prescribed as monotherapy in most cases (127/146, 87.0%). Upadacitinib was initially prescribed at the dosage of 30 mg daily in 118 of 146 (80.8%) patients and 15 mg daily in 28/146 (19.2%) patients. A significant improvement in the clinical signs and symptoms of AD was detected by Week 16 and throughout the study period. EASI 75, EASI 90 and EASI 100 responses were achieved by 87.6%, 69.1% and 44.3% at Week 48, associated with a sustained reduction in the mean values of all physician-reported (EASI and BSA) and patient-reported (Itch- Sleep- and Pain-NRS, DLQI, and POEM) disease severity outcomes, up to 48 weeks of treatment. Treatment response observed in 15 mg upadacitinib-treated patients was comparable with that detected in 30 mg upadacitinib-treated patients, revealing no statistical difference between the two patient sub-cohorts. Through the observation period, dose reduction or escalation was observed in 38/146 (26%) of treated cases. Overall, 26 of 146 (17.8%) patients experienced at least one adverse event (AE) during the treatment period. In total, 29 AEs were recorded and most of them were evaluated as mild to moderate, while in 4 cases the occurrence of AE led to drug discontinuation, for a total of 7/146 (4.8%) dropouts. Conclusion: This study provides strong evidence of a sustained response obtained by upadacitinib in AD patients, who had failed to respond to conventional or biological systemic agents, through 48 weeks of observation. Upadacitinib was also demonstrated to be advantageous in terms of flexibility in dose reduction or escalation as upadacitinib dose was shaped on clinical needs that, in a real-world setting, might frequently change. [ABSTRACT FROM AUTHOR]

• High resolution LA-ICP-MS elemental analysis of medieval glasses from Byzantine Bari. • Byzantine and early Islamic glasses imported to southern Italy in the late first millennium CE. • Typological characteristics suggest the import of finished objects from the eastern Mediterranean. • Local secondary production dependent on the recycling of strongly coloured and opacified glass. The transition from the Roman natron-based glass industry to the medieval ash-based tradition in Italy in the latter part of the first millennium CE is still poorly documented. The compositional data of eighteen glass fragments excavated from the Byzantine praetorium in Bari suggest that the development in the southern part of the Peninsula differs from that in the north. Analyses by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) identified the first significant group of glasses in Italy that were produced in and imported from the eastern Mediterranean during the last two centuries of the first millennium CE. Some samples exhibit the characteristics of early Islamic natron and plant-ash glasses, while two specimens are similar in major and trace element composition to post-Roman glasses most likely manufactured in Byzantine Asia Minor. These represent the only known vessels made from the Byzantine high lithium, high boron glass found so far in the western Mediterranean. The analytical results thus show that being under Byzantine hegemony was advantageous for trade connections in the medieval Mediterranean. [ABSTRACT FROM AUTHOR]

Antibacterial resistance is a renewed public health plague in modern times, and the COVID-19 pandemic has rekindled this problem. Changes in antibiotic prescribing behavior, misinformation, financial hardship, environmental impact, and governance gaps have generally enhanced the misuse and improper access to antibiotics during the COVID-19 pandemic. These determinants, intersected with antibacterial resistance in the current pandemic, may amplify the potential for a future antibacterial resistance pandemic. The occurrence of infections with multidrug-resistant (MDR), extensively drug-resistant (XDR), difficult-to-treat drug-resistant (DTR), carbapenem-resistant (CR), and pan-drug-resistant (PDR) bacteria is still increasing. The aim of this review is to highlight the state of the art of antibacterial resistance worldwide, focusing on the most important pathogens, namely Enterobacterales, Acinetobacter baumannii, and Klebsiella pneumoniae, and their resistance to the most common antibiotics. [ABSTRACT FROM AUTHOR]

Background: The efficacy and safety of upadacitinib in atopic dermatitis (AD) have been defined in clinical trials, but no real-world data are currently available. We aimed to assess the safety and effectiveness of upadacitinib in a real-world AD patient cohort that mostly included patients who failed the available systemic therapies, including dupilumab. Methods: Prospective cohort study collecting data on upadacitinib-treated AD adult patients completing at least 16 weeks of therapy. Results: Forty-three patients showed rapid and marked response to upadacitinib with significant reduction of all disease severity scores since the first follow-up visit. At week 16, Eczema Area and Severity Index (EASI) 75, EASI 90, and EASI 100 response was observed in 97.5%, 82.1%, and 69.2% of patients, respectively. EASI 90 response reflected the achievement of a clear or almost clear condition (POEM 0-2), self-evaluated by 79.5% of patients. Patients' quality of life improved as suggested by the achievement of DLQI 0/1 by 38.5% of patients at week 4, and by 76.9% at week 16. Conclusion: Elevated effectiveness and favorable safety of upadacitinib were confirmed in patients unresponsive to dupilumab, who were not included in upadacitinib trials. [ABSTRACT FROM AUTHOR]

The nbUVB phototherapy 311 nm is also effective in mild-to-moderate psoriasis, but its exact mechanism of action on psoriatic skin is yet to be fully elucidated. Keywords: nbUVB phototherapy; plaque psoriasis; human skin cultures; 11 -HSD1 EN nbUVB phototherapy plaque psoriasis human skin cultures 11 -HSD1 391 394 4 07/18/22 20220701 NES 220701 ACKNOWLEDGMENTS Open Access Funding provided by Universita degli Studi di Siena within the CRUI-CARE Agreement. Plaque psoriasis, nbUVB phototherapy, human skin cultures, 11 -HSD1. [Extracted from the article]

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a member of the Coronavirus family which caused the worldwide pandemic of human respiratory illness coronavirus disease 2019 (COVID-19). Presumably emerging at the end of 2019, it poses a severe threat to public health and safety, with a high incidence of transmission, predominately through aerosols and/or direct contact with infected surfaces. In 2020, the search for vaccines began, leading to the obtaining of, to date, about twenty COVID-19 vaccines approved for use in at least one country. However, COVID-19 continues to spread and new genetic mutations and variants have been discovered, requiring pharmacological treatments. The most common therapies for COVID-19 are represented by antiviral and antimalarial agents, antibiotics, immunomodulators, angiotensin II receptor blockers, bradykinin B2 receptor antagonists and corticosteroids. In addition, nutraceuticals, vitamins D and C, omega-3 fatty acids and probiotics are under study. Finally, drug repositioning, which concerns the investigation of existing drugs for new therapeutic target indications, has been widely proposed in the literature for COVID-19 therapies. Considering the importance of this ongoing global public health emergency, this review aims to offer a synthetic up-to-date overview regarding diagnoses, variants and vaccines for COVID-19, with particular attention paid to the adopted treatments. [ABSTRACT FROM AUTHOR]

Introduction: Patent ductus arteriosus (PDA) is a common complication in preterm infants. While two-dimensional echocardiography is the method of choice for diagnosing a PDA, clinical signs are known to be of limited value. Study design: Haemodynamically significant PDA (hs-PDA) was defined as a ductal left-to-right shunt with elevated left atrial/aortic root ratio (>1.6:1), a ductal diameter >2 mm, retrograde diastolic flow exceeding 30% of the anterograde flow and anterograde peak diastolic flow velocity in left pulmonary artery >50 cm/s. A hs-PDA may affect the cerebral circulation and skin color is known to be related to local perfusion. In this study, we tested the value of a caudal-to-cephalic skin reflectance differential in detecting preterm infants with hs-PDA. The study was blinded and prospective. Subjects: Fifteen infants with a hs-PDA (M: 8, F: 7; gestational age: 28.0±2.0 weeks, birth weight: 880±130 g) and 15 gender- and gestational age-matched infants without a haemodynamically significant PDA (M: 8, F: 7; gestational age: 28.2±2.3 weeks, birth weight: 885±135 g) participated to the study. Outcome measure: Skin reflectance measurements were performed using a reflectance spectrophotometer (CM-2600d/2500d, Minolta, Osaka, Japan). Sole (“postductal” site) to forehead (“preductal” site) skin reflectance ratio (caudal-to-cephalic ratio). Results: hs-PDA infants showed significantly lower forehead light reflectance values on for the whole visible spectrum (p≤0.043) with the exception of 580–590 nm (p=0.058), whereas no statistically significant differences were observed for the sole skin reflectance between the two groups in the examined visible spectrum. Consequently, hs-PDA infants showed a significantly higher caudal to cephalic ratio in the 410–430 nm (p≤0.042), 460–530 nm (p≤0.027) and 590–700 nm (p≤0.011) wavelength ranges. Conclusions: These findings may provide a previously unrecognised clinical marker for haemodynamically significant PDA in preterm infants, thus predicting those preterm infants who may require intervention for PDA. [Copyright &y& Elsevier]

A correction notice related to the article "Long‑term Efectiveness and Safety of Upadacitinib for Atopic Dermatitis in a Real‑world Setting: An Interim Analysis Through 48 Weeks of Observation" is presented, which appeared in the previous issue of the periodical.

• The encapsulant formulation influences the reliability of the PV module. • POE and TPO are alternative encapsulants to EVA. • Chemical formulation, UV degradation and lifetime of encapsulants are linked. • The kind and amount of the additives play a role on the encapsulant efficiency. • Encapsulant UV resistance improves by adding additives in its formulation. This work aims to investigate the change in chemical and physical properties of different polymeric materials, potentially usable for photovoltaic modules encapsulation, caused by UV aging. Three classes of polymeric materials have been examined: ethylene-vinyl-acetate (EVA), thermoplastic polyolefins (TPO) and polyolefin elastomers (POE). EVA is currently the most used encapsulant in the photovoltaic field; TPO and POE are new materials, alternative to EVA, which can allow to overcome some of the reliability problems of photovoltaic modules linked to the degradation of EVA properties. Of each of these three material classes, different commercially available encapsulating polymer films, with different chemical formulations, have been examined. Stressful environmental conditions have been simulated in a climatic chamber and the associated changes in optical, thermal and chemical properties of the different encapsulants have been analysed and compared before and after UV aging. The link between the chemical structure, formulation and degradation of the encapsulants with their lifetime under simulated conditions of UV stress has been investigated by the assessment of the changes in thermal stability, optical transmittance, crystallinity, yellowness index and chemical degradation. This study helps to better understand the causes of the module performance reduction due to the degradation of the encapsulant material and is a guide for the selection of encapsulant films with improved characteristics, for the manufacture of more durable PV modules. [ABSTRACT FROM AUTHOR]

Summary Side-effects associated with levofloxacin treatment include phototoxicity, hypersensitivity and skin disorders. Purpuric eruptions have rarely been reported. We describe the case of a 75-year-old woman who was prescribed a 15-day course of levofloxacin (500 mg twice a day) for hemorrhagic cystitis. On exposure to sunlight, the patient developed a pruritic purpuric eruption on the lower extremities. The acute reaction differed from a classical sunburn, manifesting as confluent petechiae limited to sun-exposed areas and accompanied by pruritus. This was a rare case of solar capillaritis. Purpuric eruptions on photoexposed skin should be considered another unusual side effect of levofloxacin. [ABSTRACT FROM AUTHOR]

We have recently demonstrated that when endogenous orienting of spatial attention is guided by central directional cues that reliably predict the position of lateral targets. Pupil Dilation (PDil) is higher as compared with directional cues that do not predict target position. These findings were interpreted as reflecting different levels of Locus Coeruleus‐Noradrenergic activity during endogenous orienting. In contrast to this, we were not able to highlight reliable differences between PDil responses to infrequent invalid targets that are associated with predictive cues and frequent invalid targets that are associated with non‐predictive ones. These null findings might have been due to the spurious influence of transitory changes in luminance at the moment of target presentation or to the short time window used for the analysis of target‐related changes in PDil. Here, we re‐explored cue‐ and target‐related changes in PDil using cue and target stimuli that were kept isoluminant to their background and long lasting cue and target periods for data recording and analysis. We fully replicate our previous cue‐related results and, in addition, we demonstrate that infrequent invalid targets in the predictive experimental condition evoke larger PDil as compared with frequent ones. Analyses with Linear Mixed Models highlighted that both during the cue and target period, higher levels of PDil were associated with slower reaction times. These findings confirm that PDil is a reliable marker of the expectancy components of endogenous cue‐related and exogenous target‐related orienting of spatial attention. [ABSTRACT FROM AUTHOR]

On January 30, 2020, World Health Organization (WHO) stated that a new coronavirus disease outbreak [COronaVIrus Disease - 19 (COVID-19)] was an international public health emergency. Many news, often fake ones, about the derived pandemic rapidly spread along the media, thus leading many dermatological patients to identify as "risk category" and sometimes discontinue treatments by themselves. The Dermatology Units in Grosseto and Pordenone simultaneously carried out a data collection by remote-conducted visits, evaluating the incidence of COVID-19 in psoriatic patients. Only 1 patient (close contact of a case) as part of the psoriasis analyzed group was tested and turned out to be positive for SARS-CoV-2, developing no symptoms during the observation period. The collected information may suggest that psoriasis, biotechnologically treated or not, cannot promote or aggravate the clinical trend of the SARS-CoV-2 infection, hence stopping systemic therapy in negative or clinically free SARS-CoV-2 patients is not recommended in general. [ABSTRACT FROM AUTHOR]

Adipose tissue is a metabolic and endocrine organ that secretes bioactive molecules called adipocytokines. Among these, adiponectin has a crucial role in obesity-associated breast cancer. The key molecule of adiponectin signaling is AMPK, which is mainly activated by liver kinase B1 (LKB1). Here, we demonstrated that estrogen receptor-a (ERa)/LKB1 interaction may negatively interfere with the LKB1 capability to phosphorylate AMPK and inhibit its downstream signaling TSC2/mTOR/p70S6k. In adiponectin-treated MCF-7 cells, AMPK signaling was not working, resulting in its downstream target acetyl-CoA carboxylase (ACC) being still active. In contrast, in MDA-MB-231 cells, AMPK and ACC phosphorylation was enhanced by adiponectin, inhibiting lipogenesis and cell growth. Upon adiponectin, ERa signaling switched the energy balance of breast cancer cells toward a lipogenic phenotype. Therefore, adiponectin played an inhibitory role on ERa-negative cell growth and progression in vitro and in vivo. In contrast, low adiponectin levels, similar to those circulating in obese patients, acted on ERa-positive cells as a growth factor, stimulating proliferation. The latter effect was blunted in vivo by high adiponectin concentration. All this may have translational relevance, addressing how the handling of adiponectin, as a therapeutic tool in breast cancer treatment, needs to be carefully considered in ERa-positive obese patients, where circulating levels of this adipocytokine are relatively low. In other words, in ERa-positive breast cancer obese patients, higher adiponectin doses should be administered with respect to ERa-negative breast cancer, also opportunely combined with antiestrogen therapy. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic and relapsing inflammatory skin disease, clinically characterized by erythematous and scaly plaques. Treatment approach is mainly driven by disease severity, though several factors should be considered in order to identify the optimal therapeutic choice. Mild psoriasis may be treated with a wide array of topical agents including corticosteroids, vitamin D analogs, keratolytics, and calcipotriol/betamethasone propionate compound. Because guidelines may not provide practical indications regarding the therapeutic approach, the use of topical agents in psoriasis is more individually tailored. In order to homogenize the standard of care, at least in a local setting, we collected the real-life-based recommendations for the use of topical therapies from an expert panel, the Tuscany Consensus Group on Psoriasis, representing all leading centers for psoriasis established in Tuscany. With this document, this consensus group sought to define principles guiding the selection of therapeutic agents with straightforward recommendations derived from a real-life setting. [ABSTRACT FROM AUTHOR]

Leptin (lep) appears to play a crucial role in mammary carcinogenesis. Here, we explored whether lep can affect primary tumor mass either in vivo in MCF-7 cell tumor xenograft or in vitro in MCF-7 three-dimensional (3D) cultures. Xenograft tumors, obtained only in animals with E2 pellet implants, doubled control value after 13 weeks of lep exposure. In 3D cultures lep and/or E2 enhanced cell-cell adhesion. This increased aggregation appears to be dependent on E-cadherin (E-cad). Indeed, lep-enhanced homotypic cell adhesion in MCF-7 3D cultures was completely abrogated in the presence of function-blocking E-cadherin antibody or EGTA, a calcium-chelating agent. In 3D cultures lep and/or E2 treatment significantly increased cell growth, which was abrogated when E-cad function was blocked. These findings well correlated with an increase of mRNA and protein content of E-cad induced by lep and/or E2 in both 3D cultures and xenografts. In MCF-7 cells both hormones were able to activate E-cad promoter. Mutagenesis studies, EMSA and ChIP assays revealed that CREB and Sp1 motifs, present on E-cadherin promoter, were important for the upregulatory effects induced by both hormones on E-cadherin expression. Thus, distinct from its role as a tumor suppressor, E-cad may function as tumor enhancer in the development of primary breast cancer, particularly in obese women. [ABSTRACT FROM AUTHOR]

Agents to counteract acquired resistance to hormonal therapy for breast cancer would substantially enhance the long-term benefits of hormonal therapy. In the present study, we demonstrate how resveratrol (Res) inhibits human breast cancer cell proliferation, including MCF-7 tamoxifen-resistant cells (IC50 values for viability were in the 30-45 µM range). We show that Res, through p38MAPK phosphorylation, causes induction of p53, which recruits at the estrogen receptor α (ERα) proximal promoter, leading to an inhibition of ERα expression in terms of mRNA and protein content. These events appear specifically p53 dependent, since they are drastically abrogated with p53-targeting siRNA. Coimmunoprecipitation assay showed specific interaction between p53, the Sin3A corepressor, and histone deacetylase 1 (HDAC1), which was phosphorylated. The enhancement of the tripartite complex p53/Sin3A/HDAC1, together with NF-Y on Res treatment, was confirmed by chromatin immunoprecipitation analyses, with a concomitant release of Sp1 and RNA polymerase II, thereby inhibiting the cell transcriptional machinery. The persistence of such effects in MCF-7 tamoxifen-resistant cells at a higher extent than parental MCF-7 cells addresses how Res may be considered a useful pharmacological tool to be exploited in the adjuvant settings for treatment of breast cancer developing hormonal resistance. [ABSTRACT FROM AUTHOR]

Cell-mediated immunity is considered to be normal in Darier's Disease (DD), an inherited skin disorder complicated by skin infections. To date, there are no investigations on the local inflammatory infiltrate in DD skin lesions. In this immunohistochemical study we characterized and quantified it, making comparisons with two other inflammatory skin disorders, that is, pemphigus vulgaris (PV) and lichen ruber planus (LRP), and with the normal skin (NSk).We found a significant (P<.05) decrease of CD1a+ Langerhans cells (LCs) in DD, compared to PV, LRP, and NSk, and of CD123+ plasmacytoid dendritic cells (pDCs), compared to PV and LRP. We hypothesize that the genetic damage of keratinocytes might result in a loss of some subsets of dendritic cells and, consequently, in an impaired local immune response, which might worsen the infections that inevitably occur in this disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Tamoxifen is a mainstay of adjuvant treatment for estrogen receptor α-positive (ERα+) breast tumors, which account for over 70% of all the diagnosed breast malignancies. Unfortunately, ~30% of patients initially responding to the therapy will eventually relapse with an endocrine-resistant disease. Here, we show that the transcription factor FoxO3a can overcome tamoxifen resistance by inhibiting cell motility and invasiveness, the main features of tumor progression. The underlying mechanism could be ascribed to FoxO3a-dependent transcriptional up-regulation of the integrin α5 subunit of the α5β1 fibronectin receptor, a well-known membrane heterodimer controlling cell adhesion. Indeed, FoxO3a and integrin α5 expression is significantly correlated in ERα+ tumors, and FoxO3a protective effects are lost in cells with reduced levels of integrin α5. Therefore, a pharmacological increase in FoxO3a levels could represent an effective approach to be exploited in combination with tamoxifen treatment in order to restore the sensitivity to the therapy in refractory tumors. Resistance to endocrine therapy is still a major clinical challenge in the management of estrogen receptor α-positive (ERα+) breast cancer (BC). Here, the role of the Forkhead box class O (FoxO)3a transcription factor in tumor progression has been evaluated in tamoxifen-resistant BC cells (TamR), expressing lower levels of FoxO3a compared to sensitive ones. FoxO3a re-expression reduces TamR motility (wound-healing and transmigration assays) and invasiveness (matrigel transwell invasion assays) through the mRNA (qRT-PCR) and protein (Western blot) induction of the integrin α5 subunit of the α5β1 fibronectin receptor, a well-known membrane heterodimer controlling cell adhesion and signaling. The induction occurs through FoxO3a binding to a specific Forkhead responsive core sequence located on the integrin α5 promoter (cloning, luciferase, and ChIP assays). Moreover, FoxO3a failed to inhibit migration and invasion in integrin α5 silenced (siRNA) cells, demonstrating integrin α5 involvement in both processes. Finally, using large-scale gene expression data sets, a strong positive correlation between FoxO3a and integrin α5 in ERα+, but not in ER-negative (ERα−), BC patients emerged. Altogether, our data show how the oncosuppressor FoxO3a, by increasing the expression of its novel transcriptional target integrin α5, reverts the phenotype of endocrine-resistant BC toward a lower aggressiveness. [ABSTRACT FROM AUTHOR]

The insulin receptor isoform A (IR-A) plays an increasingly recognized role in fetal growth and tumor biology in response to circulating insulin and/or locally produced IGF2. This role seems not to be shared by the IR isoform B (IR-B). We aimed to dissect the specific impact of IR isoforms in modulating insulin signaling in triple negative breast cancer (TNBC) cells. We generated murine 4T1 TNBC cells deleted from the endogenous insulin receptor (INSR) gene and expressing comparable levels of either human IR-A or IR-B. We then measured IR isoform-specific in vitro and in vivo biological effects and transcriptome in response to insulin. Overall, the IR-A was more potent than the IR-B in mediating cell migration, invasion, and in vivo tumor growth. Transcriptome analysis showed that approximately 89% of insulin-stimulated transcripts depended solely on the expression of the specific isoform. Notably, in cells overexpressing IR-A, insulin strongly induced genes involved in tumor progression and immune evasion including chemokines and genes related to innate immunity. Conversely, in IR-B overexpressing cells, insulin predominantly induced the expression of genes primarily involved in the regulation of metabolic pathways and, to a lesser extent, tumor growth and angiogenesis. [ABSTRACT FROM AUTHOR]

The testis is an immunologically privileged site of the body where Sertoli cells work on to favor local immune tolerance by testicular autoantigens segregation and immunosuppressive factors secretion. Fas/Fas Ligand (FasL) system, expressed prevalently in Sertoli cells, has been considered to be one of the central mechanisms in testis immunological homeostasis. In different cell lines it has been reported that the proapoptotic protein FasL is regulated by 17-β estradiol (E2). Thus, using as experimental model mouse Sertoli cells TM4, which conserve a large spectrum of functional features present in native Sertoli cells, like aromatase activity, we investigated if estradiol “in situ” production may influence FasL expression. Our results demonstrate that an aromatizable androgen like androst-4-ene-3,17-dione (Δ4) enhanced FasL mRNA, protein content and promoter activity in TM4 cells. The treatment with N6,2′-O-dibutyryladenosine-3′-5′-cyclic monophosphate [(Bu)2cAMP] (simulating FSH action), that is well known to stimulate aromatase activity in Sertoli cells, amplified Δ4 induced FasL expression. Functional studies of mutagenesis, electrophoretic mobility shift (EMSA) and chromatin immunoprecipitation (ChIP) assays revealed that the Sp-1 motif on FasL promoter was required for E2 enhanced FasL expression in TM4 cells. These data let us to recruit FasL among those genes whose expression is up-regulated by E2 through a direct interaction of ERα with Sp-1 protein. Finally, evidence that an aromatizable androgen is able to increase FasL expression suggests that E2 production by aromatase activity may contribute to maintain the immunoprivilege status of Sertoli cells. J. Cell. Physiol. 211: 448–456, 2007. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The peroxisome proliferation-activated receptor gamma (PPARγ) is mainly expressed in the adipose tissue and integrates the control of energy, lipid, and glucose homeostasis. The present study, by means of RT-PCR, Western blot, and immunofluorescence techniques, demonstrates that human sperm express the PPARγ. The functionality of the receptor was evidenced by 15-deoxy-12,14-prostaglandin J2 (PGJ2) and rosiglitazone (BRL) PPARγ-agonists that were tested on capacitation, acrosome reaction, and motility. Both treatments also increase AKT phosphorylations and influence glucose and lipid metabolism in sperm. The specificity of PGJ2 and BRL effects through PPARγ on human sperm was confirmed by an irreversible PPARγ antagonist, GW9662. Our findings provide evidence that human sperm express a functional PPARγ whose activation influences sperm physiology. In conclusion, the presence of PPARγ in male gamete broadens the field of action of this nuclear receptor, bringing us to look towards sperm as an endocrine mobile unit independent of the systemic regulation. J. Cell. Physiol. 209: 977–986, 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: In the present study, we evidence how in breast cancer cells low doses of Taxol for 18h determined the upregulation of p53 and p21 waf expression concomitantly with a decrease of the anti-apoptotic Bcl-2. P53 and its gene product, the mdm2 protein, in treated cells exhibits a prevalent nuclear compartmentalization, thus potentiating p53 transactivatory properties. Indeed, the most important finding of this study consists with the evidence that Taxol at lower concentrations is able to produce the activation of p21 promoter via p53. Prolonged exposure of MCF-7 cells to Taxol (48h) resulted in an increased co-association between p21 and PCNA compared to control and this well fits with the simultaneous block of cell cycle into the G2/M phase. [Copyright &y& Elsevier]

• Group EEG studies in stroke patients do not capture interindividual variability. • We used multivariate EEG analysis to profile individual orienting of attention. • We tested right-brain damaged patients with and without neglect and controls. • We decoded individual EEG correlates of left and right orienting of attention. • These results show that reliable individual EEG profile can be obtained in neglect. Electrophysiological group studies in brain-damaged patients can be run to capture the EEG correlates of specific cognitive impairments. Nonetheless, this procedure is not adequate to characterize the inter-individual variability present in major neuropsychological syndromes. We tested the possibility of getting a reliable individual EEG characterization of deficits of endogenous orienting of spatial attention in right-brain damaged (RBD) patients with left spatial neglect (N+). We used a single-trial topographical analysis (STTA; [39] of individual scalp EEG topographies recorded during leftward and rightward orienting of attention with central cues in RBD patients with and without (N−) neglect and in healthy controls (HC). We found that the STTA successfully decoded EEG signals related to leftward and rightward orienting in five out of the six N+, five out of the six N− patients and in all the six HC. In agreement with findings from conventional average-group studies, successful classifications of EEG signals in N+ were observed during the 400–800 ms period post-cue-onset, which reflects preserved voluntary engagement of attention resources (ADAN component). These results suggest the possibility of acquiring reliable individual EEG profiles of neglect patients. [ABSTRACT FROM AUTHOR]

L5333 --> Resistance to endocrine therapy is still a major clinical challenge in the management of estrogen receptor positive (ER+) breast cancer (BC) patients, whose poor outcome demands additional studies. Forkhead box class O (FoxO)3a transcription factor, a bona fide oncosuppressor, has been involved in BC metastasis as well as in antiestrogen resistance. Here we demonstrate that the α5 subunit of the integrin α5β1, a well‐known membrane heterodimer controlling cell surface adhesion and signaling, is a novel FoxO3a transcriptional target. FoxO3a re‐expression reduces motility (wound healing and transmigration assays) of different Tamoxifen resistant BC cell lines, through the induction of α5 mRNA (qRT‐PCR) and protein (Western blot) levels. FoxO3a transcriptionally regulates α5 expression by binding to specific Forkhead responsive elements located on the α5 promoter (Luciferase and ChIP assays). Accordingly, using a large‐scale BC gene expression datasets from The Cancer Genome Atlas (TCGA) database, a strong positive correlation between FoxO3a and α5 in ER+ BC patients emerged. Altogether, our data unveil an additional mechanism through which FoxO3a activation/induction, by increasing α5 expression, restores a less aggressive phenotype in BC refractory to endocrine therapy. [ABSTRACT FROM AUTHOR]

The aim of this work is the design, preparation and characterization of membranes based on cyclosporine A (CsA) and chitosan carboxylate (CC) to be used as an implantable subcutaneous medical device for a prolonged therapeutic effect in the treatment of breast cancer. The choice to use CsA is due to literature data that have demonstrated its possible antitumor activity on different types of neoplastic cells. To this end, CsA was bound to CC through an amidation reaction to obtain a prodrug to be dispersed in a chitosan-based polymeric membrane. The reaction intermediates and the final product were characterized by Fourier transform infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance (1H-NMR). Membranes were analyzed by differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The data obtained showed the effective formation of the amide bond between CsA and CC and the complete dispersion of CsA inside the polymeric membrane. Furthermore, preliminary tests, conducted on MDA-MB-231, a type of breast cancer cell line, have shown a high reduction in the proliferation of cancer cells. These results indicate the possibility of using the obtained membranes as an interesting strategy for the release of cyclosporin-A in breast cancer patients. [ABSTRACT FROM AUTHOR]

Right Brain Damaged patients with left spatial neglect (N+), are characterised by poor allocation of attention in the contralesional left side of space. In a recent study (Lasaponara et al., 2018) we showed during orienting of spatial attention with endogenous central cues, both the EEG markers reflecting the early phases of orienting (Early Directing Attention Negativity) and those reflecting the late setting-up of sensory facilitation in the visual cortex (Late Directing Attention Positivity) are disturbed in N+ when these patients attend the left side of space. In the healthy brain, endogenous cues also elicit EEG activity related to the preparation of manual responses to upcoming spatial targets. Here, we wished to expand on our previous findings and investigate the EEG correlates of cue-related response preparation in N+ patients. To this aim we investigated the Contingent Negative Variation (CNV) response and the pre-motor Beta-oscillatory activity evoked by spatially informative central cues during the performance of a Posner task. Due to concomitant contralesional motor impairments, N+ an N- patients performed the task only with the ipsilesional right-hand. Compared to healthy controls and patients without neglect, N+ displayed a pathological suppression of CNV component that was independent of cue direction. In addition, the amplitude of the CNV in response to right-pointing cues was positively correlated with neglect severity in line bisection. N+ also displayed a pathological enhancement of pre-motor Beta oscillations over the left hemisphere during the time period that preceded manual responses to targets in the left side of space, particularly to invalidly cued ones. Synchronization in the Beta-band (ERS) was also correlated with lower detection rate and slower RTs to Invalid targets in the left side of space. These results provide new insights on the premotor components of the spatial orienting deficits suffered by patients with left spatial neglect and can help improving its diagnosis and rehabilitation. • Right Brain Damage (RBD) can produce left spatial neglect. • Endogenous spatial cues evoke EEG activity related to response preparation. • We tested cue-related CNV and Beta EEG-activity in RBD patients with neglect (N+). • N+ show pathological suppression of the CNV. • N+ show synchronization of Beta to invalid targets in the left side of space. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is the second most common hematological malignancy and, despite the great advances made in its management, the development of novel therapeutic strategies are still needed in order to extend patients' survival and to improve their quality of life. Here we show the striking ability of a mesoporous silica-based device to selectively deliver the antineoplastic drug bortezomib to Folate Receptor (FR) overexpressing MM cells, without causing injury nor perturbing the metabolic homeostasis of FR-negative healthy cells. Our data highlight the high efficacy and extraordinary safety of the tested nanodevice, paving the way for its future exploitation in the treatment of MM. A mesoporous silica-based nanodevice bearing the antineoplastic drug bortezomib (BTZ), whose release is triggered in acidic environment and grafted with folic acid (FOL) as a targeting function (FOL-MSN-BTZ) was tested on folate receptor overexpressing (FR+) multiple myeloma (MM) cells and on FR negative (FR−) normal cells. FOL-MSN-BTZ efficacy studies were conducted by means of growth experiments, TEM, TUNEL assay and Western Blotting analysis (WB). Metabolic investigations were performed to assess cells metabolic response to MSNs treatments. FOL-MSN-BTZ exclusively killed FR+ MM cells, leading to an apoptotic rate that was comparable to that induced by free BTZ, and the effect was accompanied by metabolic dysfunction and oxidative stress. Importantly, FOL-MSN-BTZ treated FR− normal cells did not show any significant sign of injury or metabolic perturbation, while free BTZ was still highly toxic. Notably, the vehicle alone (MSN-FOL) did not affect any biological process in both tested cell models. These data show the striking specificity of FOL-MSN-BTZ toward FR+ tumor cells and the outstanding safety of the MSN-FOL vehicle, paving the way for a future exploitation of FOL-MSN-BTZ in MM target therapy. [ABSTRACT FROM AUTHOR]