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The concept of textbook outcome (TO) has been proposed for analyzing quality of surgical care. This study assessed the incidence of TO among patients undergoing curative gastric cancer resection, predictors for TO achievement, and the association of TO with survival. All patients with gastric and gastroesophageal junction cancers undergoing curative gastrectomy between January 2014–December 2017 were identified from a population-based database (Spanish EURECCA Registry). TO included: macroscopically complete resection at the time of operation, R0 resection, ≥15 lymph nodes removed and examined, no serious postoperative complications (Clavien-Dindo ≥II), no re-intervention, hospital stay ≤14 days, no 30-day readmissions and no 90-day mortality. Logistic regression was used to assess the adjusted achievement of TO. Cox survival regression was used to compare conditional adjusted survival across groups. In total, 1293 patients were included, and TO was achieved in 541 patients (41.1%). Among the criteria, "macroscopically complete resection" had the highest compliance (96.5%) while "no serious complications" had the lowest compliance (63.7%). Age (OR 0.53 for the 65–74 years and OR 0.34 for the ≥75 years age group), Charlson comorbidity index ≥3 (OR 0.53, 95%CI 0.34–0.82), neoadjuvant chemoradiotherapy (OR 0.24, 95%CI 0.08–0.70), multivisceral resection (OR 0.55, 95%CI 0.33–0.91), and surgery performed in a community hospital (OR 0.65, CI95% 0.46–0.91) were independently associated with not achieving TO. TO was independently associated with conditional survival (HR 0.67, 95%CI 0.55–0.83). TO was achieved in 41.1% of patients who underwent gastric cancer resection with curative intent and was associated with longer survival. [ABSTRACT FROM AUTHOR]

Although the number of nationwide clinical registries in upper gastrointestinal cancer is increasing, few of them perform regular clinical audits. The Spanish EURECCA Esophagogastric Cancer Registry (SEEGCR) was launched in 2013. The aim of this study was to assess the reliability of the data in terms of completeness and accuracy. Patients who were registered (2014–2017) in the online SEEGCR and underwent esophagectomy or gastrectomy with curative intent were selected for auditing. Independent teams of surgeons visited each center between July 2018 and December 2019 and checked the reliability of data entered into the registry. Completeness was established by comparing the cases reported in the registry with those provided by the Medical Documentation Service of each center. Twenty percent of randomly selected cases per hospital were checked during on-site visits for testing the accuracy of data (27 items per patient file). Correlation between the quality of the data and the hospital volume was also assessed. Some 1839 patients from 19 centers were included in the registry. The mean completeness rate in the whole series was 97.8% (range 82.8–100%). For the accuracy, 462 (25.1%) cases were checked. Out of 12,312 items, 10,905 were available for verification, resulting in a perfect agreement of 95% (87.1–98.7%). There were 509 (4.7%) incorrect and 35 (0.3%) missing entries. No correlation between hospital volume and the rate of completeness and accuracy was observed. Our results indicate that the SEEGCR contains reliable data. [ABSTRACT FROM AUTHOR]

Aim Real-life analysis of overall survival (OS) trends among metastatic breast cancer (MBC) patients may help define medical needs and evaluate the impact of public health investments. The present study aimed to evaluate the independent impact of the year of MBC diagnosis on OS in the Epidemio-Strategy-Medical-Economical (ESME)-MBC cohort. Methods ESME-MBC (NCT03275311) is a French, national, multicentre, observational cohort including 16,702 consecutive newly diagnosed MBC patients (01 January 2008–31 December 2014). Of 16,680 eligible patients, 15,085 had full immunohistochemistry data, allowing classification as hormone receptor–positive and HER2-negative (HR+/HER2–, N = 9907), HER2-positive (HER2+, N = 2861) or triple-negative (HR–/HER2–, N = 2317) subcohorts. Multivariate analyses of OS were conducted among the full ESME cohort and subcohorts. Results Median OS of the whole cohort was 37.22 months (95% confidence interval [CI], 36.3–38.04). Year of diagnosis was an independent predictor of OS (hazard ratio 0.98 [95% CI, 0.97–1.00], P = .01) together with age, subtype, disease-free interval, visceral metastases and number of organs involved. Median OS of HR+/HER2–, HER2+ and HR–/HER2– subcohorts was, respectively, 42.12 (95% CI, 40.90–43.10), 44.91 (95% CI, 42.51–47.90) and 14.52 (95% CI, 13.70–15.24) months. Year of diagnosis was a strong independent predictor of OS in HER2+ subcohort (hazard ratio 0.91 [95% CI, 0.88–0.94], P < .001), but not in HR+/HER2– nor HR–/HER2– subcohorts (hazard ratio 1.00 [95% CI, 0.98–1.01], P = .80 and 1.00 [95% CI, 0.97–1.02], P = .90, respectively). Conclusions The OS of MBC patients has slightly improved over the past decade. However, this effect is confined to HER2+ cases, highlighting the need of new strategies in the other subtypes. [ABSTRACT FROM AUTHOR]

Objectives Molecular profiling of advanced non-small-cell lung cancer (NSCLC) is recommended according to European and Italian guidelines. However, molecular routine assessment remains still heterogeneous. This observational study aimed to take a picture of the real clinical practice in molecular testing and therapeutic choices in advanced Italian NSCLCs. Materials and methods This study prospectively enrolled newly diagnosed advanced or recurrent NSCLCs referred to 38 Italian centres, from November 2014 to November 2015. Information regarding molecular profiling and treatment choices were collected. Description of patients’ outcome included overall survival (OS), progression-free survival in first (PFS1) and second-line (PFS2). Results and conclusion Among 1787 patients enrolled, 1388 (78%) performed at least one molecular analysis during the history of disease: 76% were tested for EGFR , 53% for ALK , 27% for KRAS , 16% for ROS1 , 14% for BRAF , 5% for HER2 , 4% for MET and 1% for FGFR . The remaining 399 patients (22.3%) did not receive any molecular test. Among patients receiving at least one molecular analysis, 583 (42%) presented a molecular alteration. Considering EGFR mutated and/or ALK rearranged patients (402), for which target agents were routinely reimbursed at time of study in Italy, the 86% received a personalized treatment as first and/or second line: the 90% (286) of EGFR mutants received an EGFR tyrosine kinase inhibitor, mostly gefitinib (41.1%) or afatinib (36.4%) while 74% (62) of ALK translocated patients received an ALK inhibitor, mostly crizotinib (64%). Median OS was 9.34 months (95% CI 8.62–10.0), median PFS1 was 4.61 months (95%CI 4.31–4.84) and median PFS2 was 2.76 months (95%CI 2.57–3.19). In the Italian clinical practice, routine molecular assessment was largely applied in NSCLC patients, according to national guidelines, but a low level of ALK test was reached. Most of EGFR mutants an ALK rearranged patients received a personalized treatment as first and/or second line. [ABSTRACT FROM AUTHOR]

Highlights: [•] We review the roles of the evolutionarily conserved checkpoint kinases ATM/Tel1 and ATR/Mec1 in the response to DNA double-strand breaks (DSBs). [•] We give a summary of the current literature on DSB processing. [•] We discuss how ATM/Tel1 and ATR/Mec1 are activated by DNA double-strand breaks. [•] We discuss the interplays between ATM/Tel1 and ATR/Mec1 signaling activities at DNA ends. [ABSTRACT FROM AUTHOR]

Abstract: We report the synthesis and biological properties of novel analogues of Istaroxime acting as positive inotropic compounds through the inhibition of the Na+,K+-ATPase. We explored the chemical space around the position 6 of the steroidal scaffold by changing the functional groups at that position and maintaining a basic oximic chain in position 3. Some compounds showed inhibitory potencies of the Na+,K+-ATPase higher than Istaroxime and many of the compounds tested in vivo were safer than digoxin, the classic digitalis compound currently used for the treatment of congestive heart failure as inotropic agent. The 3D-QSAR analyses using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods have been successfully applied to a set of 63 androstane derivatives as Na+,K+-ATPase inhibitors. The contour plots provide many useful insights into relationships between structural features and inhibitory potency. [Copyright &y& Elsevier]

Abstract: Social Phobia (SP) is a marked and persistent fear of social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Faces of others are perceived as threatening by social phobic patients (SPP). To investigate how face processing is altered in the distributed neural system for face perception in Social Phobia, we designed an event-related fMRI study in which Healthy Controls (HC) and SPP were presented with angry, fearful, disgusted, happy and neutral faces and scrambled pictures (visual baseline). As compared to HC, SPP showed increased neural activity not only in regions involved in emotional processing including left amygdala and insula, as expected from previous reports, but also in the bilateral superior temporal sulcus (STS), a part of the core system for face perception that is involved in the evaluation of expression and personal traits. In addition SPP showed a significantly weaker activation in the left fusiform gyrus, left dorsolateral prefrontal cortex, and bilateral intraparietal sulcus as compared to HC. These effects were found not only in response to emotional faces but also to neutral faces as compared to scrambled pictures. Thus, SPP showed enhanced activity in brain areas related to processing of information about emotional expression and personality traits. In contrast, brain activity was decreased in areas for attention and for processing other information from the face, perhaps as a result of a feeling of wariness. These results indicate a differential modulation of neural activity throughout the different parts of the distributed neural system for face perception in SPP as compared to HC. [Copyright &y& Elsevier]

Abstract: Immediate access to information about people that we encounter is an essential requirement for effective social interactions. In this manuscript we briefly review our work and work of others on familiar face recognition and propose a modified version of our model of neural systems for face perception with a special emphasis on processes associated with recognition of familiar faces. We argue that visual appearance is only one component of successful recognition of familiar individuals. Other fundamental aspects include the retrieval of “person knowledge” – the representation of the personal traits, intentions, and outlook of someone we know – and the emotional response we experience when seeing a familiar individual. Specifically, we hypothesize that the “theory of mind” areas, that have been implicated in social and cognitive functions other than face perception, play an essential role in the spontaneous activation of person knowledge associated with the recognition of familiar individuals. The amygdala and the insula, structures that are involved in the representation of emotion, also are part of the distributed network of areas that are modulated by familiarity, reflecting the role of emotion in face recognition. [Copyright &y& Elsevier]

Abstract: In a functional magnetic resonance imaging experiment, we explored whether affective person knowledge based on memories formed from minimal information is spontaneously retrieved in face perception. In the first stage of the experiment, participants were presented with 120 unfamiliar faces. Each face was presented with a description of one of four types of behaviors: aggressive, disgusting, neutral, and nice. In the second stage, participants were scanned while engaged in a one-back recognition task in which they saw the faces that were associated with behaviors and 30 novel faces. Although this task is a simple perceptual task that neither demands person evaluation nor retrieval of person knowledge, neural responses to faces differed as a function of the behaviors. Faces associated with behaviors evoked stronger activity than did novel faces in regions implicated in social cognition—anterior paracingulate cortex and superior temporal sulcus. Explicit memory for the behaviors enhanced the neural response in these regions. Faces associated with disgusting behaviors evoked stronger activity in left anterior insula than did faces associated with aggressive behaviors. This effect was equally strong for faces associated with explicitly recalled behaviors and faces associated with non-recalled behaviors. The findings suggest that affective person knowledge acquired from minimal information is spontaneously retrieved in face perception, engaging neural systems for analysis of social cognition and emotions. [Copyright &y& Elsevier]

Abstract: Recognizing personally familiar faces is the result of a spatially distributed process that involves visual perceptual areas and areas that play a role in other cognitive and social functions, such as the anterior paracingulate cortex, the precuneus and the amygdala [M.I. Gobbini, E. Leibenluft, N. Santiago, J.V. Haxby, Social and emotional attachment in the neural representation of faces, Neuroimage 22 (2004) 1628–1635; M.I. Gobbini, J.V. Haxby, Neural systems for recognition of familiar faces, Neuropsychologia, in press; E. Leibenluft, M.I. Gobbini, T. Harrison, J.V. Haxby, Mothers’ neural activation in response to pictures of their, and other, children, Biol. Psychiatry 56 (2004) 225–232]. In order to isolate the role of visual familiarity in face recognition, we used fMRI to measure the response to faces characterized by experimentally induced visual familiarity that carried no biographical information or emotional content. The fMRI results showed a stronger response in the precuneus to the visually familiar faces consistent with studies that implicate this region in the retrieval of information from long-term memory and imagery. Moreover, this finding supports the hypothesis of a key role for the precuneus in the acquisition of familiarity with faces [H. Kosaka, M. Omori, T. Iidaka, T. Murata, T. Shimoyama, T. Okada, N. Sadato, Y. Yonekura, Y. Wada, Neural substrates participating in acquisition of facial familiarity: an fMRI study, Neuroimage 20 (2003) 1734–1742]. By contrast, the visually familiar faces evoked a weaker response in the fusiform gyrus, which may reflect the development of a sparser encoding or a reduced attentional load when processing stimuli that are familiar. The visually familiar faces also evoked a weaker response in the amygdala, supporting the proposed role of this structure in mediating the guarded attitude when meeting someone new. [Copyright &y& Elsevier]

Considerable literature has focused on neural responses evoked by face viewing. We extend that literature and explore the neural correlates of maternal attachment with an fMRI study in which mothers view photographs of their own children.Seven mothers performed a one-back repetition detection task while viewing photographs of their own child, friends of their child, unfamiliar children, and unfamiliar adults.Viewing one''s own child versus a familiar child was associated with activation in the amygdala, insula, anterior paracingulate cortex, and posterior superior temporal sulcus (STS). Viewing familiar versus unfamiliar children elicited increased activation in regions associated with familiarity in adults. Viewing unfamiliar children versus unfamiliar adults was associated with activation in the fusiform gyrus, intraparietal sulcus, precuneus, and posterior STS.The sight of one''s own child versus that of a familiar child activates regions that mediate emotional responses (amygdala, insula) and are associated with theory of mind functions (anterior paracingulate cortex, posterior superior temporal sulcus). These activations may reflect the intense attachment, vigilant protectiveness, and empathy that characterize normal maternal attachment. The sight of an unfamiliar child''s face compared with that of an unfamiliar adult engages areas associated with attention as well as face perception. [Copyright &y& Elsevier]

Anaplastic lymphoma kinase (ALK) fusions identify a limited subset of non–small cell lung cancer (NSCLC) patients, whose therapeutic approach have been radically changed in recent years. However, diagnostic procedures and clinical-radiological responses to specific targeted therapies remain heterogeneous and intrinsically resistant or poor responder patients exist. A total of 290 patients with advanced NSCLC defined as ALK+ by immunohistochemistry (IHC) and/or fluorescent in situ hybridisation (FISH) test and treated with single or sequential multiple ALK inhibitors (ALKi) from 2011 to 2017 have been retrospectively retrieved from a multicentre Italian cancer network database. In 55 patients with enough leftover tumour tissue, specimens were analysed with both targeted and customised next generation sequencing panels. Identified fusion variants have been correlated with clinical outcomes. Of the 55 patients, 24 received crizotinib as first-line therapy, 1 received ceritinib, while 30 received chemotherapy. Most of the patients (64%) received ALKi in sequence. An ALK fusion variant was identified in 73% of the cases, being V3 variant (E6A20) the most frequent, followed by V1 (E13A20) and more rare ones (e.g. E6A19). In three specimens, four new EML4-ALK fusion breakpoints have been reported. Neither fusion variants nor brain metastases were significantly associated with overall survival (OS), while it was predictably longer in patients receiving a sequence of ALKi. The presence of V1 variant was associated with progression-free survival (PFS) improvement when crizotinib was used (p = 0.0073), while it did not affect cumulative PFS to multiple ALKi. Outcomes to sequential ALKi administration were not influenced by fusion variants. Nevertheless, in V1+ patients a prolonged clinical benefit was observed. Fusion variant identification by NGS technology may add relevant information about rare chromosomal events that could be potentially correlated to worse outcomes. • NGS platforms add relevant information to refine diagnosis of ALK+ NSCLC patients. • RNA-based technologies allow the identification of rare/unknown EML4-ALK fusions. • Fusion variants correlate with clinical outcomes to single/sequential ALKi. • Molecular stratification of ALK+ patients may inform clinical strategies. [ABSTRACT FROM AUTHOR]

The Mre11-Rad50-Xrs2 (MRX) complex detects and processes DNA double-strand breaks (DSBs). Its DNA binding and processing activities are regulated by transitions between an ATP-bound state and a post-hydrolysis cutting state that is nucleolytically active. Mre11 endonuclease activity is stimulated by Sae2, whose lack increases MRX persistence at DSBs and checkpoint activation. Here we show that the Rif2 protein inhibits Mre11 endonuclease activity and is responsible for the increased MRX retention at DSBs in sae2 Δ cells. We identify a Rad50 residue that is important for Rad50-Rif2 interaction and Rif2 inhibition of Mre11 nuclease. This residue is located near a Rad50 surface that binds Sae2 and is important in stabilizing the Mre11-Rad50 (MR) interaction in the cutting state. We propose that Sae2 stimulates Mre11 endonuclease activity by stabilizing a post-hydrolysis MR conformation that is competent for DNA cleavage, whereas Rif2 antagonizes this Sae2 function and stabilizes an endonuclease inactive MR conformation. [Display omitted] • Sae2 stimulates Mre11 endonuclease activity by stabilizing the MRX cutting state • Rif2 inhibits Sae2-mediated stimulation of Mre11 endonuclease activity • The rad50-N18S mutation escapes Rif2-mediated inhibition of Mre11 nuclease • Rif2 stabilizes an endonuclease inactive MR conformation that persistently binds DSBs Phosphorylated Sae2 interacts with Rad50 and stimulates Mre11 endonuclease activity through an unknown mechanism. Marsella et al. show that Sae2 binding to the Rad50-Mre11 interface stabilizes a post-hydrolysis, endonuclease-active Mre11-Rad50 conformation. Rif2 interferes with the adoption of this conformation and inhibits Mre11 endonuclease activity. [ABSTRACT FROM AUTHOR]

Chang and Tsao recently reported that the monkey face patch system encodes facial identity in a space of facial features as opposed to exemplars. Here, we discuss how such coding might contribute to face recognition, emphasizing the critical role of learning and interactions with other brain areas for optimizing the recognition of familiar faces. [ABSTRACT FROM AUTHOR]

Abstract: The Default Mode Network (DMN) is a constellation of brain areas that decrease their activity during a wide number of different goal-oriented tasks as compared to passive “rest” tasks. DMN can be modulated by different factors such as emotional states, cognitive load of the task and psychopathology, including anxiety. Moreover, DMN seems to play a pivotal role in social cognition. For example, the ability to predict another person''s behaviour taking his or her perspective modulates the activity of the DMN. Recent data from autistic patients support a role of DMN in social cognition as well. Social Phobia (SP) is an anxiety disorder characterized by an abnormal distress in situations that require social interaction. To date, no study has assessed DMN in Social Phobia. To determine potential differences in DMN activity between Social Phobia patients (SPP) and healthy control (HC) subjects we examined functional magnetic resonance imaging (fMRI) data obtained during a face perception study with emotional and neutral stimuli. As compared to HC, SPP showed a lower deactivation in the precuneus and posterior cingulate regions (PCun/PCC) during task conditions. These regions are part of the so-called “Theory of Mind” circuit and in particular they are involved in the evaluation of one''s own emotional state. Because of the role of the PCun/PCC in self-state perception and attribution and, more in general, the role of the DMN in social cognition, we suggest that its impairment in the DMN network in SPP might be relevant in the development of the feeling of wariness of others’ judgment and may be related to the so-called self-focused attention. Self-focused attention is the awareness of self-referent information, and is present in many emotional disorders and may additionally prevent individuals from observing external information that could disconfirm their own fears. Moreover, the abnormal modulation of activity in the DMN may reflect persistent rumination or anxiety-related thoughts that are not modulated by the switch from rest to task. [Copyright &y& Elsevier]

Face perception is mediated by a distributed neural system in humans that consists of multiple, bilateral regions. The functional organization of this system embodies a distinction between the representation of invariant aspects of faces, which is the basis for recognizing individuals, and the representation of changeable aspects, such as eye gaze, expression, and lip movement, which underlies the perception of information that facilitates social communication. The system also has a hierarchical organization. A core system, consisting of occipitotemporal regions in extrastriate visual cortex, mediates the visual analysis of faces. An extended system consists of regions from neural systems for other cognitive functions that can act in concert with the core system to extract meaning from faces. Of regions in the extended system for face perception, the amygdala plays a central role in processing the social relevance of information gleaned from faces, particularly when that information may signal a potential threat. [ABSTRACT FROM AUTHOR]

In order to adequately respond to stressful stimuli, glucocorticoids (GCs) target almost every tissue of the body. By exerting a negative feedback loop in the hypothalamic–pituitary–adrenal (HPA) axis GCs inhibit their own synthesis and restore homeostasis. GCs actions are mostly mediated by the GC receptor (GR), a member of the nuclear receptor superfamily. Alterations of the GR activity have been associated to different diseases including mood disorders and can lead to severe complication. Therefore, understanding the molecular complexity of GR modulation is mandatory for the development of new and effective drugs for treating GR-associated disorders. FKBP51 is a GR chaperone that has gained much attention because it is a strong inhibitor of GR activity and has a crucial role in psychiatric diseases. Both GR and FKBP51 activity are regulated by SUMOylation, a posttranslational (PTM). In this review, we focus on the impact of SUMO-conjugation as a regulator of this pathway. [ABSTRACT FROM AUTHOR]