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DNA is exposed to both endogenous and exogenous DNA damaging agents that chemically modify it. To counteract the deleterious effects exerted by DNA lesions, eukaryotic cells have evolved a network of cellular pathways, termed DNA damage response (DDR). The DDR comprises both mechanisms devoted to repair DNA lesions and signal transduction pathways that sense DNA damage and transduce this information to specific cellular targets. These targets, in turn, impact a wide range of cellular processes including DNA replication, DNA repair and cell cycle transitions. The importance of the DDR is highlighted by the fact that DDR inactivation is commonly found in cancer and causes many different human diseases. The protein kinases ATM and ATR, as well as their budding yeast orthologs Tel1 and Mec1, act as master regulators of the DDR. The initiating events in the DDR entail both DNA lesion recognition and assembly of protein complexes at the damaged DNA sites. Here, we review what is known about the early steps of the DDR.

Background To describe the incidence and the clinical characteristics of oligometastatic non-small cell lung cancer (NSCLC) patients. Oligometastatic NSCLC is gaining recognition as a clinical condition with a different prognosis compared to multi metastatic disease. Usually, four different scenarios of oligometastatic disease can be described but not epidemiological data are available. To date, it is difficult to delineate an exhaustive epidemiological scenario because no uniform or shared definition of oligometastatic status exists, even though a recent consensus defined synchronous oligometastatic disease as having a maximum of 5 metastases in 3 different organs. Methods A systematic review and a pooled analysis of literature were performed. Article selection was based on the following characteristics: focus on lung cancers; dealing with oligometastatic settings and providing a definition of oligometastatic disease; number of metastatic lesions with or without the number of organs involved; providing some incidence or clinical characteristics of oligometastatic NSCLC patients. Series focusing on a specific single metastatic organ were excluded. The research was launched in MEDLINE (OvidSP) in March 2020. Full articles were individually and collectively read by the authors according to the previous criteria. Each author inspected the reference list included in the eligible articles. If the selection criteria were recognized, the article was reviewed by all authors and then included. Data on patient clinical features were pooled together from 31 articles selected. Results A total number of 31 articles have been selected for the analysis. The following variables were extracted from the publications: (I) number of metastases, (II) number of organs involved, (III) number of patients, (IV) number and percentage of males and females, (V) number and percentage of squamous and non-squamous histology, (VI) T and N status and/or stage of primary disease for oligometastatic setting. The data collected have been analyzed according to the oligometastatic setting. Conclusions Oligometastatic status is globally identified as a different clinical condition from multi metastatic NSCLC, although the clinical characteristics were consistent in the general metastatic population, even with a lower-than-expected TN status. The brain and bones were the most frequent organs involved. Lacking consensus definition, these results must be interpreted cautiously and a prospective evaluation is urgently needed.

Significance Our brain processes faces of close others differently than faces of visually familiar individuals. While both types of faces activate similar visual areas, faces of close others activate areas involved in processing social and semantic information. Here, we used between-subject linear classifiers trained on hyperaligned brain data to investigate the neural code for visual and semantic information about familiar others. The identity of both visually and personally familiar faces could be decoded across participants from brain activity in visual areas. Instead, only the identity of personally familiar faces could be decoded in areas involved in social cognition. Our results suggest that individually distinctive information associated with familiar faces is embedded in a neural code that is shared across brains., Processes evoked by seeing a personally familiar face encompass recognition of visual appearance and activation of social and person knowledge. Whereas visual appearance is the same for all viewers, social and person knowledge may be more idiosyncratic. Using between-subject multivariate decoding of hyperaligned functional magnetic resonance imaging data, we investigated whether representations of personally familiar faces in different parts of the distributed neural system for face perception are shared across individuals who know the same people. We found that the identities of both personally familiar and merely visually familiar faces were decoded accurately across brains in the core system for visual processing, but only the identities of personally familiar faces could be decoded across brains in the extended system for processing nonvisual information associated with faces. Our results show that personal interactions with the same individuals lead to shared neural representations of both the seen and unseen features that distinguish their identities.

Here we investigated the role of racial attitudes in trait inferences from facial appearance. In two separate experiments we measured implicit racial attitudes using the race Implicit Association Test (IAT), as well as judgments of several traits after brief exposure to strangers’ faces. Results from the first experiment (n=67) suggested that judgement of attractiveness is biased by implicit skin tone preference. The second experiment (n=104) extended this finding by testing four additional personality traits (attractiveness, aggression, competence, likeability, and trustworthiness). In both experiments, implicit racial attitudes predicted differential trait ratings of White and Black faces. Additionally, we found that implicit bias measured with the IAT predicted bias in trait inferences between White and Asian, but not between Black and Asian faces. These findings suggest that an implicit racial attitude could be motivated by a more general tendency to judge White faces differently from non-White faces.

preprint of the paper

Quantifying how brain functional architecture differs from person to person is a key challenge in human neuroscience. Current individualized models of brain functional organization are based on brain regions and networks, limiting their use in studying fine-grained vertex-level differences. In this work, we present the Individualized Neural Tuning (INT) model, a fine-grained individualized model of brain functional organization. The INT model is designed to have vertex-level granularity, to capture both representational and topographic differences, and to model stimulus-general neural tuning. Through a series of analyses, we demonstrate that (a) our INT model provides a reliable individualized measure of fine-grained brain functional organization, (b) it accurately predicts individualized brain response patterns to new stimuli, and (c) it requires only 10–20 minutes of data for good performance. The high reliability, specificity, precision, and generalizability of our INT model affords new opportunities for building brain-based biomarkers based on naturalistic neuroimaging paradigms.

Background: 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. Method: 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. Results: 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). Conclusion: TO was achieved in 41.1% of patients who underwent gastric cancer resection with curative intent and was associated with longer survival. © 2021 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology

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.

To understand how a protective immune response against SARS-CoV-2 develops over time, we integrated phenotypic, transcriptional and repertoire analyses on PBMCs from mild and severe COVID-19 patients during and after infection, and compared them to healthy donors (HD). A type I IFN-response signature marked all the immune populations from severe patients during the infection. Humoral immunity was dominated by IgG production primarily against the RBD and N proteins, with neutralizing antibody titers increasing post infection and with disease severity. Memory B cells, including an atypical FCRL5+ T-BET+ memory subset, increased during the infection, especially in patients with mild disease. A significant reduction of effector memory, CD8+T cells frequency characterized patients with severe disease. Despite such impairment, we observed robust clonal expansion of CD8+T lymphocytes, while CD4+T cells were less expanded and skewed toward TCMand TH2-like phenotypes. MAIT cells were also expanded, but only in patients with mild disease. Terminally differentiated CD8+GZMB+effector cells were clonally expanded both during the infection and post-infection, while CD8+GZMK+lymphocytes were more expanded post-infection and represented bona fide memory precursor effector cells. TCR repertoire analysis revealed that only highly proliferating T cell clonotypes, which included SARS-CoV-2-specific cells, were maintained post-infection and shared between the CD8+GZMB+and GZMK+subsets. Overall, this study describes the development of immunity against SARS-CoV-2 and identifies an effector CD8+T cell population with memory precursor-like features.

Deep convolutional neural networks (DCNNs) trained for face identification can rival and even exceed human-level performance. The relationships between internal representations learned by DCNNs and those of the primate face processing system are not well understood, especially in naturalistic settings. We developed the largest naturalistic dynamic face stimulus set in human neuroimaging research (700+ naturalistic video clips of unfamiliar faces) and used representational similarity analysis to investigate how well the representations learned by high-performing DCNNs match human brain representations across the entire distributed face processing system. DCNN representational geometries were strikingly consistent across diverse architectures and captured meaningful variance among faces. Similarly, representational geometries throughout the human face network were highly consistent across subjects. Nonetheless, correlations between DCNN and neural representations were very weak overall--DCNNs captured 3% of variance in the neural representational geometries at best. Intermediate DCNN layers better matched visual and face-selective cortices than the final fully-connected layers. Behavioral ratings of face similarity were highly correlated with intermediate layers of DCNNs, but also failed to capture representational geometry in the human brain. Our results suggest that the correspondence between intermediate DCNN layers and neural representations of naturalistic human face processing is weak at best, and diverges even further in the later fully-connected layers. This poor correspondence can be attributed, at least in part, to the dynamic and cognitive information that plays an essential role in human face processing but is not modeled by DCNNs. These mismatches indicate that current DCNNs have limited validity as in silico models of dynamic, naturalistic face processing in humans.

Shared information content is represented across brains in idiosyncratic functional topographies. Hyperalignment addresses these idiosyncrasies by using neural responses to project individuals’ brain data into a common model space while maintaining the geometric relationships between distinct activity patterns. The dimensions of this common model can encode any kind of functional profiles shared across individuals, such as cortical response profiles collected during a common time-locked stimulus presentation (e.g. movie viewing) or functional connectivity profiles. Performing hyperalignment with either response-based or connectivity-based input data derives transformations to project individuals’ neural data from anatomical space into the common model such that functional information is optimally aligned across brains. Previously, only response or connectivity profiles were used in the derivation of these transformations. In this study, we used three separate data sets collected while participants watched feature films to derive transformations representing both response-based and connectivity-based information with a single algorithm. Our new method, hybrid hyperalignment, aligns response-based information as well as or better than response hyperalignment while simultaneously aligning connectivity-based information better than connectivity hyperalignment, all in one information space. These results suggest that a single common information space could encode both shared cortical response and functional connectivity profiles across individuals.

Naturalistic, dynamic movies evoke strong, consistent, and information-rich patterns of activity over a broad expanse of cortex and engage multiple perceptual and cognitive systems in parallel. The use of naturalistic stimuli enables functional brain imaging research to explore cognitive domains that are poorly sampled in highly-controlled experiments. These domains include perception and understanding of agentic action, which plays a larger role in visual representation than was appreciated from experiments using static, controlled stimuli.

Naturalistic stimuli evoke strong, consistent, and information-rich patterns of brain activity, and engage large extents of the human brain. They allow researchers to compare highly similar brain responses across subjects, and to study how complex representations are encoded in brain activity. Here, we describe and share a dataset where 25 subjects watched part of the feature film “The Grand Budapest Hotel” by Wes Anderson. The movie has a large cast with many famous actors. Throughout the story, the camera shots highlight faces and expressions, which are fundamental to understand the complex narrative of the movie. This movie was chosen to sample brain activity specifically related to social interactions and face processing. This dataset provides researchers with fMRI data that can be used to explore social cognitive processes and face processing, adding to the existing neuroimaging datasets that sample brain activity with naturalistic movies., Measurement(s) functional brain measurement Technology Type(s) functional magnetic resonance imaging Sample Characteristic - Organism Homo sapiens Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.12980924