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Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined the small molecule selective kappa antagonist CERC-501 in rat models of alcohol-related behaviors, with the objective to evaluate its potential as a candidate therapeutic for alcohol use disorders. We first tested the effect of CERC-501 on acute alcohol withdrawal-induced anxiety-like behavior. CERC-501 was then tested on basal as well as escalated alcohol self-administration induced by 20% alcohol intermittent access. Finally, we determined the effects of CERC-501 on relapse to alcohol seeking triggered by both stress and alcohol-associated cues. Control experiments were performed to confirm the specificity of CERC-501 effects on alcohol-related behaviors. CERC-501 reversed anxiety-like behavior induced by alcohol withdrawal. It did not affect basal alcohol self-administration but did dose-dependently suppress self-administration that had escalated following long-term intermittent access to alcohol. CERC-501 blocked relapse to alcohol seeking induced by stress, but not when relapse-like behavior was triggered by alcohol-associated cues. The effects of CERC-501 were observed in the absence of sedative side effects and were not due to effects on alcohol metabolism. Thus, in a broad battery of preclinical alcohol models, CERC-501 has an activity profile characteristic of anti-stress compounds. Combined with its demonstrated preclinical and clinical safety profile, these data support clinical development of CERC-501 for alcohol use disorders, in particular for patients with negatively reinforced, stress-driven alcohol seeking and use.

“Only” about 10 to 15% of people exposed to alcohol develop alcohol-related problems. The behavioral repertoire of people confronted with opportunities to consume alcohol involves numerous choices between this drug reward and healthy alternatives. Augier et al. established a choice procedure that begins to address alcohol addiction in rats (see the Perspective by Spanagel). They found that a minority of outbred rats continued to self-administer alcohol even when a high-value alternative (such as sugar) was available. That minority displayed a remarkable constellation of behavioral traits resembling the human clinical condition, including a high motivation to obtain alcohol and continued use despite adverse consequences. The cause was impaired GABA (γ-aminobutyric acid) clearance in the central amygdala. Postmortem tissue analysis supported the possibility of a similar pathology in human alcoholism. Science , this issue p. 1321 ; see also p. 1298 Impaired GABA clearance within the central amygdala provides a molecular mechanism behind preferentially choosing alcohol. Alcohol addiction leads to increased choice of alcohol over healthy rewards. We established an exclusive choice procedure in which ~15% of outbred rats chose alcohol over a high-value reward. These animals displayed addiction-like traits, including high motivation to obtain alcohol and pursuit of this drug despite adverse consequences. Expression of the γ-aminobutyric acid (GABA) transporter GAT-3 was selectively decreased within the amygdala of alcohol-choosing rats, whereas a knockdown of this transcript reversed choice preference of rats that originally chose a sweet solution over alcohol. GAT-3 expression was selectively decreased in the central amygdala of alcohol-dependent people compared to those who died of unrelated causes. Impaired GABA clearance within the amygdala contributes to alcohol addiction, appears to translate between species, and may offer targets for new pharmacotherapies for treating this disorder.

Breast cancer (BC) is a complex disease with primary or acquired incurability characteristics in a significant part of patients. Immunotherapeutical agents represent an emerging option for breast cancer treatment, including the human epidermal growth factor 2 positive (HER2+) subtype. The immune system holds the ability to spontaneously implement a defensive response against HER2+ BC cells through complex mechanisms which can be exploited to modulate this response for obtaining a clinical benefit. Initial immune system modulating strategies consisted mostly in vaccine therapies, which are still being investigated and improved. However, the entrance of trastuzumab into the scenery of HER2+ BC treatment was the real game changing event, which embodied a dominant immune-mediated mechanism. More recently, the advent of the immune checkpoint inhibitors has caused a new paradigm shift for immuno-oncology, with promising initial results also for HER2+ BC. Breast cancer has been traditionally considered poorly immunogenic, being characterized by relatively low tumor mutation burden (TMB). Nevertheless, recent evidence has revealed high tumor infiltrating lymphocytes (TILs) and programmed cell death-ligand 1 (PD-L1) expression in a considerable proportion of HER2+ BC patients. This may translate into a higher potential to elicit anti-cancer response and, therefore, wider possibilities for the use and implementation of immunotherapy in this subset of BC patients. We are herein presenting and critically discussing the most representative evidence concerning immunotherapy in HER2+ BC cancer, both singularly and in combination with therapeutic agents acting throughout HER2-block, immune checkpoint inhibition and anti-cancer vaccines. The reader will be also provided with hints concerning potential future projection of the most promising immutherapeutic agents and approaches for the disease of interest.

A 2D-continuum model describing finite deformations in plane of discrete bi-pantographic fabrics has been recently obtained by applying an asymptotic procedure based on a set of local generalized coordinates. Rectangular bi-pantographic prototypes were additively manufactured by selective laser sintering using polyamide as raw material. Displacement-controlled bias extension tests were performed on such specimens for total elastic deformations up to ca. 25%. Experimental force measurements, complemented by discrete displacement measurements obtained by local digital image correlation, were used to fit the continuum model. In the present paper, a global and minimal set of generalized coordinates, alternative to the one used for the homogenization, is introduced for the discrete model. The mechanical constitutive parameters appearing in the discrete model are then found by means of collected experimental data. Finally, a comparison between experiments, the discrete and the continuum model is presented. It is concluded that (a) the discrete model and the experimental data are in excellent agreement, and that (b) the continuum retains the relevant phenomenology of the discrete system even for a rather low number of cells.

In the last decade, the exotic properties of pantographic metamaterials have been investigated and different mathematical models (both discrete or continuous) have been introduced. In a previous publication, a large part of the already existing literature about pantographic metamaterials has been presented. In this paper, we give some details about the next generation of research in this field. We present an organic scheme of the whole process of design, fabrication, experiments, models and image analyses.

Purpose We compared the risk factors, the diagnostic tools and the outcome of filamentous fungal infections (FFIs) in hematological patients (HAEs) and non-hematological patients (non-HAEs). Methods Prospective surveillance (2009–2011) of proven and probable FFIs was implemented in 23 Italian hospitals. Results Out of 232 FFIs, 113 occurred in HAEs and 119 in non-HAEs. The most frequent infection was invasive aspergillosis (76.1 % for HAEs, 56.3 % for non-HAEs), and the localization was principally pulmonary (83.2 % for HAEs, 74.8 % for non-HAEs). Neutropenia was a risk factor for 89.4 % HAEs; the main underlying condition was corticosteroid treatment (52.9 %) for non-HAEs. The distribution of proven and probable FFIs was different in the two groups: proven FFIs occurred more frequently in non-HAEs, whereas probable FFIs were correlated with the HAEs. The sensitivity of the galactomannan assay was higher for HAEs than for non-HAEs (95.3 vs. 48.1 %). The overall mortality rate was 44.2 % among the HAEs and 35.3 % among the non-HAEs. The etiology influenced the patient outcomes: mucormycosis was associated with a high mortality rate (57.1 % for HAEs, 77.8 % for non-HAEs). Conclusions The epidemiological and clinical data for FFIs were not identical in the HAEs and non-HAEs. The differences should be considered to improve the management of FFIs according to the patients’ setting.

The increasing usage of social media for conversations, together with the availability of its data to researchers, provides an opportunity to study human conversations on a large scale. Twitter, which allows its users to post messages of up to a limit of 140 characters, is one such social media. Previous studies of utterances in books, movies and Twitter have shown that most of these utterances, when transcribed, are much shorter than 140 characters. Furthermore, the median length of Twitter messages was found to vary across US states. Here, we investigate whether the length of Twitter messages varies across different regions in the UK. We find that the median message length, depending on grouping, can differ by up to 2 characters.

A case of systemic infection due to Saprochaete capitata in a patient with chronic lymphocytic leukemia is described. A review of the literature was conducted to identify all reported cases of this infection described between 1977 and August 2013. One hundred and four cases (included the present one) were identified. The median age of the patients was 56 years and 56 % were males. Comorbidities included acute myeloid leukemia (52 %), acute lymphoid leukemia (22 %), other hematological malignancies (13 %) and non-hematological diseases (9 %). At the time of the infection, 82 % of the patients were neutropenic. In 75 % of the cases, the yeast was isolated from blood culture, in 25 % from other sterile sites. Empirical treatment was done in 36 % of the cases. Fifty-eight percent of the individual cases were treated with a combination or a sequential antifungal therapy. Amphotericin B was the antifungal drug most commonly used, followed by voriconazole and itraconazole. The overall crude mortality was 60 %. Saprochaete capitata causes life-threatening infections in neutropenic patients. This comprehensive literature review may help the clinician to optimize the management of this rare infection.

We present a particular approach and the associated results allowing the nanostructuration of a thin photosensitive polymer film. This approach based on a scanning near-field optical microscopy configuration uses the field-enhancement (FE) effect, a so-called lightning-rod effect appearing at the extremity of a metallic tip when illuminated with an incident light polarized along the tip axis. The local enhancement of the electromagnetic field straight below the tip'sapex is observed directly through a photoisomerization reaction, inducing the growth of a topographical nanodot characterized in situ by atomic-force microscopy using the same probe. From a survey of the literature, we first review the different experimental approaches offered to nanostructure materials by near-field optical techniques. We describe more particularly the FE effect approach. An overview of the theoretical approach of this effect is then given before presenting some experimental results so as theoretical results using the finite-element method. These results show the influence on the nanostructuration of the polymer of a few experimental parameters such as the polarization state, the illumination mode and the tip'sgeometry. Finally, the potentiality of this technique for some applications in the field of lithography and high-density data storage is shown via the fabrication of nano-patterns.