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Abstract Background Cell cycle regulators have gain attention as potential targets for anticancer therapy. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which coordinate the G1-S transition. Palbociclib is currently approved for the treatment of hormone receptor positive, HER2-negative advanced breast cancer (BC) in association with letrozole or fulvestrant. In contrast, its efficacy in triple negative BC (TNBC), either alone or in combined therapies, has not been fully investigated to date. Methods Here we evaluated the potential of combining palbociclib with PI3K/mTOR inhibitors in Rb-proficient TNBC cells comparing different schedules of treatment: simultaneous, sequential, or sequential combined treatment (pre-incubation with palbociclib followed by exposure to both palbociclib and PI3K/mTOR inhibitors). We assessed the effects on cell proliferation, cell death, and cell cycle distribution, and looked at the impact of such treatments on glucose metabolism. Results Palbociclib exerted cytostatic effects in Rb-positive TNBC cells, inducing a reversible blockade in G0/G1 cell cycle phase associated with down-regulation of CDK6, Rb, and c-myc expression and/or activity. Palbociclib treatment induced AKT signaling, providing a rationale for its combination with PI3K/mTOR inhibitors. The simultaneous or sequential treatment resulted in an additive inhibition of cell proliferation. On the other hand, the sequential combined treatment in which palbociclib was maintained also during exposure to PI3K/mTOR inhibitors gave rise to synergistic anti-proliferative and pro-apoptotic effects, by inhibiting both CDK4/6/Rb/myc and PI3K/mTOR signaling. Interestingly, the inhibition of the Rb/E2F/myc axis mediated by palbociclib resulted in a significant down-regulation of glucose metabolism; most importantly, these inhibitory effects were enhanced by the combination of palbociclib with BYL719 (specific inhibitor of the p110α PI3K-subunit), which promoted a stronger inhibition of GLUT-1 glucose transporter expression, glucose uptake and consumption in comparison with individual treatments, under both normoxic and hypoxic conditions. Conclusions Combination of palbociclib with PI3K/mTOR inhibitors may represent a promising therapeutic option for the treatment of Rb-proficient TNBC, with the sequential combined schedule showing a superior efficacy over the other schedules. In addition our results demonstrate that the impairment of glucose metabolism may contribute to the anti-tumor activity of such drug combinations.

The importance of the immune system as a potent anti-tumor defense has been consolidated in recent times, and novel immune-related therapies are today demonstrating a strong clinical benefit in the setting of several solid neoplasms. Tumor-infiltrating lymphocytes reflect the attempt of the host to eradicate malignancies, and during the last decades, they have been shown to possess an interesting prognostic utility for breast cancer, especially in case of HER2 positive and triple-negative molecular subtypes. In parallel, the clinical evaluation of tumor-infiltrating lymphocytes has been shown to effectively predict treatment outcomes in both neoadjuvant and adjuvant settings. Currently, tumor-infiltrating lymphocytes are promising further predictive utility in view of novel immune-related therapeutic strategies which are coming into the clinical setting launching a solid rationale for the future next-generation treatment options. In this scenario, tumor-infiltrating lymphocytes might represent an important resource for the selection of the most appropriate therapeutic strategy, as well as further evaluations of the molecular mechanisms underlying tumor-infiltrating lymphocytes and the immunoediting process would eventually provide new insights to augment therapeutic success. Considering these perspectives, we review the potential utility of tumor-infiltrating lymphocytes in the definition of breast cancer prognosis and in the prediction of treatment outcomes, along with the new promising molecular-based therapeutic discoveries.

Concreteness is a fundamental dimension of word semantic representation that has attracted more and more interest to become one of the most studied variables in the psycholinguistic and cognitive neuroscience literature in the last decade. Concreteness effects have been found at both the brain and the behavioral levels, but they may vary depending on the constraints of the context and task demands. In this study, we collected concreteness norms for English and Italian words presented in different context sentences to allow better control and manipulation of concreteness in future psycholinguistic research. First, we observed high split-half correlations and Cronbach’s alpha coefficients, suggesting that our ratings were highly reliable and can be used in Italian- and English-speaking populations. Second, our data indicate that the concreteness ratings are related to the lexical density and accessibility of the sentence in both English and Italian. We also found that the concreteness of words in isolation was highly correlated with that of words in context. Finally, we analyzed differences between nouns and verbs in concreteness ratings without significant effects. Our new concreteness norms of words in context are a valuable source of information for future research in both the English and Italian language. The complete database is available on the Open Science Framework (doi: 10.17605/OSF.IO/U3PC4 ).

Iconicity, defined as the potential of linguistic signs to resemble properties or features of their referents, is increasingly recognized as a general property of language. One common approach for quantifying iconicity is to collect iconicity ratings. Although iconicity datasets have been developed for several languages, no comprehensive dataset of iconicity ratings is currently available for Italian. The current study presents IconicITA, the first dataset of Italian iconicity ratings for the 1,121 words of the Italian adaptation of Affective Norms for English Words (ANEW). Ratings were collected from both Italian native speakers (L1) and English native speakers with Italian as a second language (L2). Including L2 participants allowed us to contribute to the debate on whether iconicity ratings genuinely measure form-meaning resemblance, rather than exclusively reflecting semantic properties. We showed that L1 Italian iconicity ratings are positively associated with perceptual strength in the auditory and haptic modalities, and with specificity ratings. Conversely, we found a negative correlation between iconicity and concreteness, age of acquisition, word frequency, and letter frequency. In general, the relationship between Italian iconicity norms and various psycholinguistic variables largely replicated previous findings in the literature on iconicity. Considering L2 data, the ratings provided by L2 speakers correlated more strongly with the Italian L1 data compared to the translation-equivalent English L1 data. This finding suggests that participants' judgments were influenced not only by the semantic information of the words but also by language-specific form-level properties. We take this result as evidence of the validity of iconicity ratings to operationalize the degree of resemblance between words' form and meaning.

This paper presents a vector representation and a clustering of action concepts based on lexical features extracted from IMAGACT, a multilingual and multimodal ontology of actions in which concepts are represented through video prototypes. We computed vectors for 1,010 action concepts, where the dimensions correspond to verbs in 10 languages. Finally, an unsupervised clustering method has been applied on these data in order to discover action classes based on typological closeness. Those clusters are not language-specific or language-biased, and thus constitute an inter-linguistic classification of action domain.

IntroductionLanguage is usually considered the social vehicle of thought in intersubjective communications. However, the relationship between language and high-order cognition seems to evade this canonical and unidirectional description (ie, the notion of language as a simple means of thought communication). In recent years, clinical high at-risk mental state (CHARMS) criteria (evolved from the Ultra-High-Risk paradigm) and the introduction of the Clinical Staging system have been proposed to address the dynamicity of early psychopathology. At the same time, natural language processing (NLP) techniques have greatly evolved and have been successfully applied to investigate different neuropsychiatric conditions. The combination of at-risk mental state paradigm, clinical staging system and automated NLP methods, the latter applied on spoken language transcripts, could represent a useful and convenient approach to the problem of early psychopathological distress within a transdiagnostic risk paradigm.Methods and analysisHelp-seeking young people presenting psychological distress (CHARMS+/− and Clinical Stage 1a or 1b; target sample size for both groups n=90) will be assessed through several psychometric tools and multiple speech analyses during an observational period of 1-year, in the context of an Italian multicentric study. Subjects will be enrolled in different contexts: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa—IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Mental Health Department—territorial mental services (ASL 3—Genoa), Genoa, Italy; and Mental Health Department—territorial mental services (AUSL—Piacenza), Piacenza, Italy. The conversion rate to full-blown psychopathology (CS 2) will be evaluated over 2 years of clinical observation, to further confirm the predictive and discriminative value of CHARMS criteria and to verify the possibility of enriching them with several linguistic features, derived from a fine-grained automated linguistic analysis of speech.Ethics and disseminationThe methodology described in this study adheres to ethical principles as formulated in the Declaration of Helsinki and is compatible with International Conference on Harmonization (ICH)-good clinical practice. The research protocol was reviewed and approved by two different ethics committees (CER Liguria approval code: 591/2020—id.10993; Comitato Etico dell’Area Vasta Emilia Nord approval code: 2022/0071963). Participants will provide their written informed consent prior to study enrolment and parental consent will be needed in the case of participants aged less than 18 years old. Experimental results will be carefully shared through publication in peer-reviewed journals, to ensure proper data reproducibility.Trial registration numberDOI:10.17605/OSF.IO/BQZTN.

A dataset of specificity ratings for English words is hereby presented, analyzed and discussed in relation with other collections of speaker-generated ratings, including concreteness. Both, specificity and concreteness are analyzed in their ability to explain decision latencies in lexical and semantic tasks, showing important individual contributions. Specificity ratings are collected through best–worst scaling method on the words included in the ANEW dataset (Bradley and Lang in Affective norms for English words (ANEW): instruction manual and affective ratings (Tech. Rep.). Technical report C-1, the center for research in psychophysiology, 1999), chosen for its compatibility with many other collections of rating resources, and for its comparability with Italian specificity data (Bolognesi and Caselli in Behav Res Methods 55(7):3531–3548, 2023), allowing for cross-linguistic comparisons. Results suggest that specificity plays an important role in word processing and the importance of taking specificity into consideration when investigating concreteness effects.

As of today, the level of individualization of cancer therapies has reached a level that 20 years ago would be considered visionary. However, most of the diagnostic, prognostic, and therapy-predictive procedures which aim to improve the overall level of personalization are based on the evaluation of tumor tissue samples, therefore requiring surgical operations with consequent low compliance for patients and high costs for the hospital. Hence, the research of a panel of circulating indicators which may serve as source of information about tumor characteristics and which may be obtainable by a simple withdrawal of peripheral blood today represents a growing field of interest. This review aims to objectively summarize the characteristics of the currently available breast cancer circulating biomarkers, also providing an overview about the multitude of novel potential soluble predictors which are still under evaluation. Specifically, the usefulness of a so-called “liquid biopsy” will be discussed in terms of improvements of diagnosis, prognosis, and therapy-prediction, but an overview will be given also on the potentiality of the molecular characterization arising from the isolation of circulating biomarkers and cells. Although this review will focus on the specific case of the breast, in the future liquid biopsies will hopefully be available for virtually any type of neoplasms.