CONcreTEXT norms: Concreteness ratings for Italian and English words in context.

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).

Linguistic profile automated characterisation in pluripotential clinical high-risk mental state (CHARMS) conditions: methodology of a multicentre observational study.

INTRODUCTION: Language 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 ANALYSIS: Help-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 DISSEMINATION: The 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 NUMBER: DOI:10.17605/OSF.IO/BQZTN.

Health professionals' perception of appropriateness of care: a qualitative study in Italian pediatric hospices.

BACKGROUND: Appropriateness is particularly relevant in palliative care, an area in which it is essential to question the real need for treatments. Few studies explored the perception of appropriateness by professionals in pediatric palliative care, revealing the conflict sometimes faced when confronted with the uncertainty of prognosis and end-of-life decisions. AIMS: The objective of this study is firstly to investigate the perception that doctors, nurses and psychologists, operating in Italian pediatric hospices, have of the appropriateness of the care they provide. Secondly, to understand what repercussions the perception of non-appropriateness has at individual and team level. METHODS: A qualitative study was conducted between 2019 and 2020 through semi-structured interviews with a convenience sample of 17 professionals working it Italian pediatric hospices. RESULTS: The interviewees do not refer to a common concept of appropriateness, but compare the latter to: the quality of life, the global care of the assisted person, the proportionality of care, the early recognition of the need for palliative care. The discussion within the team emerges as a privileged place to manage the discomfort of individual professionals in the face of treatment choices in conflict with their own values. CONCLUSION: the non-referring to a univocal conception of appropriateness deprives professionals of an objective criterion to resolve the most difficult decisions. However, it allows them to establish what from time to time seems to be the most appropriate care pathway for a given patient, at a given time and context, preserving the goal of personalized care.

First enantioselective synthesis of gingesulfonic acids and unequivocal determination of their absolute stereochemistry.

Herein we report the first organocatalysed enantioselective synthesis of gingesulfonic acids and shogasulfonic acids via a mild and convenient aminothiourea-catalysed conjugate addition of bisulfite to the olefin moiety of α,ß-unsaturated carbonyls-a technology previously reported by us. A series of optically active naturally occurring sulfonic acids are prepared in their natural and unnatural configurations, and their absolute configurations are unequivocally confirmed by single crystal X-ray diffractometry.

Enhanced efficacy of AKT and FAK kinase combined inhibition in squamous cell lung carcinomas with stable reduction in PTEN.

Squamous cell lung carcinoma (SCC) accounts for 30% of patients with NSCLC and to date, no molecular targeted agents are approved for this type of tumor. However, recent studies have revealed several oncogenic mutations in SCC patients, including an alteration of the PI3K/AKT pathway, i.e. PI3K point mutations and amplification, AKT mutations and loss or reduced PTEN expression. Prompted by our observation of a correlation between PTEN loss and FAK phosphorylation in a cohort of patients with stage IV SCC, we evaluated the relevance of PTEN loss in cancer progression as well as the efficacy of a new combined treatment with the pan PI3K inhibitor buparlisip and the FAK inhibitor defactinib. An increase in AKT and FAK phosphorylation, associated with increased proliferation and invasiveness, paralleled by the acquisition of mesenchymal markers, and overexpression of the oncomir miR-21 were observed in SKMES-1-derived cell clones with a stable reduction of PTEN. Notably, the combined treatment induced a synergistic inhibition of cell proliferation, and a significant reduction in cell migration and invasion only in cells with reduced PTEN. The molecular mechanisms underlying these findings were unraveled using a specific RTK array that showed a reduction in phosphorylation of key kinases such as JNK, GSK-3 α/ß, and AMPK-α2, due to the concomitant decrease in AKT and FAK activation. In conclusion, the combination of buparlisib and defactinib was effective against cells with reduced PTEN and warrants further studies as a novel therapeutic strategy for stage IV SCC patients with loss of PTEN expression.

Combined Inhibition of CDK4/6 and PI3K/AKT/mTOR Pathways Induces a Synergistic Anti-Tumor Effect in Malignant Pleural Mesothelioma Cells.

Malignant pleural mesothelioma (MPM) is a progressive malignancy associated to the exposure of asbestos fibers. The most frequently inactivated tumor suppressor gene in MPM is CDKN2A/ARF, encoding for the cell cycle inhibitors p16INK4a and p14ARF, deleted in about 70% of MPM cases. Considering the high frequency of alterations of this gene, we tested in MPM cells the efficacy of palbociclib (PD-0332991), a highly selective inhibitor of cyclin-dependent kinase (CDK) 4/6. The analyses were performed on a panel of MPM cell lines and on two primary culture cells from pleural effusion of patients with MPM. All the MPM cell lines, as well as the primary cultures, were sensitive to palbociclib with a significant blockade in G0/G1 phase of the cell cycle and with the acquisition of a senescent phenotype. Palbociclib reduced the phosphorylation levels of CDK6 and Rb, the expression of myc with a concomitant increased phosphorylation of AKT. Based on these results, we tested the efficacy of the combination of palbociclib with the PI3K inhibitors NVP-BEZ235 or NVP-BYL719. After palbociclib treatment, the sequential association with PI3K inhibitors synergistically hampered cell proliferation and strongly increased the percentage of senescent cells. In addition, AKT activation was repressed while p53 and p21 were up-regulated. Interestingly, two cycles of sequential drug administration produced irreversible growth arrest and senescent phenotype that were maintained even after drug withdrawal. These findings suggest that the sequential association of palbociclib with PI3K inhibitors may represent a valuable therapeutic option for the treatment of MPM.

Tumor-infiltrating lymphocytes and breast cancer: Beyond the prognostic and predictive utility.

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.

CDK4/6 inhibitors in HER2-positive breast cancer.

Notwithstanding the continuous progress made in cancer treatment in the last 20 years, and the availability of new targeted therapies, metastatic Breast Cancer (BC) is still incurable. Targeting the cell cycle machinery has emerged as an attractive strategy to tackle cancer progression, showing very promising results in the preclinical and clinical settings. The first selective inhibitors of CDK4/6 received breakthrough status and FDA approval in combination with letrozole (February 2015) and fulvestrant (February 2016) as first-line therapy in ER-positive advanced and metastatic BC. Considering the success of this family of compounds in hormone-positive BC, new possible applications are being investigated in other molecular subtypes. This review summarizes the latest findings on the use of CDK4/6 inhibitors in HER2 positive BC.

Targeting the androgenic pathway in elderly patients with castration-resistant prostate cancer: A meta-analysis of randomized trials.

BACKGROUND: The novel hormonal drugs have recently entered in the armamentarium of therapies for treatment of metastatic castration-resistant prostate cancer (CRPC). First reports are available for their use in elderly men with CRPC. METHOD: A meta-analysis of randomized controlled trials (RCTs) has been performed. PubMed, the Cochrane Library, and American Society of Clinical Oncology (ASCO) University Meeting were searched for data on the use of new hormonal treatment in elderly patients with CRPC. RESULTS: Nine studies for a total of 3512 elderly patients were available for meta-analysis. Six studies reported outcomes of patients aged >75 years old while 2 studies reported on patients aged >70 years old. The pooled analysis of the androgen synthesis inhibitors revealed significantly increased overall survival (OS) due to antiandrogen agents compared with placebo or placebo and prednisone (hazard ratio (HR) for death: HR = 0.74, 95% CI: 0.67-0.82; P < 0.00001). Moreover, the new antiandrogenic therapy significantly improved the progression-free survival (HR = 0.45, 95% CI: 0.31-0.65; P < 0.0001). The incidence of any grade ≥3 adverse effect was only moderately higher during with the antiandrogenic therapy as compared to the control arms (response rate = 1.03, 95% CI: 0.88-1.20; P = 0.72). CONCLUSION: This study confirmed that agents targeting the androgen axis (i.e., enzalutamide, abiraterone) significantly prolonged OS in elderly men with CRPC.

Apatinib for the treatment of gastric cancer.

INTRODUCTION: Apatinib, a small-molecule inhibitor of vascular endothelial growth factor receptor 2, has demonstrated encouraging anti-cancer activity in gastric cancer within both in vitro and in vivo models. AREAS COVERED: Apatinib's efficacy, tolerability and safety have been evaluated in one Phase II and one Phase III study in metastatic/advanced gastric cancer. In this review, we focus on the mechanism of action of apatinib, its pharmacokinetic profile and its clinical activity in the treatment of advanced/metastatic gastric cancer. Expert commentary: Unfortunately, as yet, there is no definitive biomarker data for apatinib in gastric cancer.

A Phase II study of olaparib in breast cancer patients: biological evaluation from a 'window of opportunity' trial.

The OLTRE trial (ClinicalTrials.gov number: NCT02681562) is an open-label, 'window of opportunity' Phase II controlled trial to evaluate the biological activity of olaparib in locally advanced triple-negative breast cancer compared with other subtypes of locally advanced breast cancer patients carrying germinal BRCA mutation receiving olaparib with the same treatment approach. The primary end point is to investigate the correlation between baseline gene and protein expression profile in order to identify possible predictive markers of response to olaparib. The OLTRE trial is expected to identify the surrogate markers of the biological activity of olaparib in the treatment of patients with triple-negative breast cancer.

Apatinib: A novel receptor tyrosine kinase inhibitor for the treatment of gastric cancer.

Metastatic gastric cancer is a lethal disease characterized by a very short overall survival, underlining a critical need of new therapeutic options. Unfortunately, although several molecular targets have been investigated, only very few recently approved agents, such as trastuzumab in the HER2-positive setting and ramucirumab, led to a clinical improvement in the outcome of metastatic gastric cancer patients. VEGF (vascular endothelial growth factor) is one of the most potent angiogenic factors and is a signalling molecule secreted by many solid tumours. Since high VEGF expression is one of the characteristic features of gastric carcinomas, targeting VEGF is therefore considered as a promising therapeutic strategy for gastric cancer. In the scenario of possible new target therapies with particular regard to angiogenesis, apatinib is a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2. It is an orally-bioavailable agent currently being studied in several solid tumour types showing a promising activity in gastric cancer. Due to the recent positive results as a third line of treatment for metastatic gastric cancer patients, apatinib may be an interesting and novel type of targeted treatment for metastatic gastric cancer in several lines of therapy. In this review, we summarize the available data of apatinib, mainly focused on the clinical aspect, in advanced/metastatic gastric cancer.

High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation as Adjuvant Treatment in High-Risk Breast Cancer: Data from the European Group for Blood and Marrow Transplantation Registry.

The aim of this retrospective study was to assess toxicity and efficacy of adjuvant high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (AHSCT) in 583 high-risk breast cancer (BC) patients (>3 positive nodes) who were transplanted between 1995 and 2005 in Europe. All patients received surgery before transplant, and 55 patients (9.5%) received neoadjuvant treatment before surgery. Median age was 47.1 years, 57.3% of patients were premenopausal at treatment, 56.5% had endocrine-responsive tumors, 19.5% had a human epidermal growth factor receptor 2 (HER2)-negative tumor, and 72.4% had ≥10 positive lymph nodes at surgery. Seventy-nine percent received a single HDC procedure. Overall transplant-related mortality was 1.9%, at .9% between 2001 and 2005, whereas secondary tumor-related mortality was .9%. With a median follow-up of 120 months, overall survival and disease-free survival rates at 5 and 10 years in the whole population were 75% and 64% and 58% and 44%, respectively. Subgroup analysis demonstrated that rates of overall survival were significantly better in patients with endocrine-responsive tumors, <10 positive lymph nodes, and smaller tumor size. HER2 status did not affect survival probability. Adjuvant HDC with AHSCT has a low mortality rate and provides impressive long-term survival rates in patients with high-risk BC. Our results suggest that this treatment modality should be considered in selected high-risk BC patients and further investigated in clinical trials.

Monoclonal antibodies-based treatment in gastric cancer: current status and future perspectives.

Gastric cancer (GC) is the second leading cause of cancer-related death, and despite having improved treatment modalities over the last decade, for most patients, only modest improvements have been seen in overall survival. Recent progress in understanding the molecular biology of GC and the related signaling pathways offers, from the clinical point of view, promising advances for selected groups of patients. In the past, targeted therapies have significantly impacted the treatment strategy of several common solid tumors such as breast, colorectal, and lung cancers. Unfortunately, translational and clinical research shows fewer encouraging targeted treatments with regards to the GC. To date, only two monoclonal antibodies (mAb), named trastuzumab and ramucirumab, are approved for the treatment of advanced GC, suggesting that in GC, maybe more than in other cancers, effective targeted therapy requires patient selection based on precise predictive molecular biomarkers. The aim of this review is to summarize the available data on the clinical advantages offered by the use of mAbs in the treatment of advanced/metastatic GC. Future perspective is also discussed.

Breast cancer circulating biomarkers: advantages, drawbacks, and new insights.

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.

Ibrutinib: from bench side to clinical implications.

The activation of the B cell receptor (BCR) is nowadays known to play a primary role in the etiopathogenesis of a multitude of B cell malignancies, being one of the main factors responsible for the enhanced proliferation and survival of transformed cells. Thanks to the characterization and continuous discovery of the pathways driving B cell proliferation in consequence to BCR activation, it has been possible to develop a small molecule inhibitor specifically antagonizing the Bruton's tyrosine kinase (BTK), an enzyme located in an early strategic position within the whole pathway. Ibrutinib, formerly PCI-32765, is a first in class, potent, specific, irreversible and relatively safe BTK inhibitor, demonstrating so far an impressive efficacy in the treatment of chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma (MCL), Waldenström macroglobulinemia and multiple myeloma. This review will summarize the most important pharmacological evidences available as of today and will take in consideration the latest findings regarding the mechanism of action of ibrutinib.

International Expert Consensus on Primary Systemic Therapy in the Management of Early Breast Cancer: Highlights of the Fifth Symposium on Primary Systemic Therapy in the Management of Operable Breast Cancer, Cremona, Italy (2013).

Expert consensus-based recommendations regarding key issues in the use of primary (or neoadjuvant) systemic treatment (PST) in patients with early breast cancer are a valuable resource for practising oncologists. PST remains a valuable therapeutic approach for the assessment of biological antitumor activity and clinical efficacy of new treatments in clinical trials. Neoadjuvant trials provide endpoints, such as pathological complete response (pCR) to treatment, that potentially translate into meaningful improvements in overall survival and disease-free survival. Neoadjuvant trials need fewer patients and are less expensive than adjuvant trial, and the endpoint of pCR is achieved in months, rather than years. For these reasons, the neoadjuvant setting is ideal for testing emerging targeted therapies in early breast cancer. Although pCR is an early clinical endpoint, its role as a surrogate for long-term outcomes is the key issue. New and better predictors of treatment efficacy are needed to improve treatment and outcomes. After PST, accurate management of post-treatment residual disease is mandatory. The surgery of the sentinel lymph-node could be an acceptable option to spare the axillary dissection in case of clinical negativity (N0) of the axilla at the diagnosis and/or after PST. No data exists yet to support the modulation of the extent of locoregional radiation therapy on the basis of the response attained after PST although trials are underway.

Immune-related strategies driving immunotherapy in breast cancer treatment: a real clinical opportunity.

Because its original use as a treatment for hematologic disease, more recently immunotherapy has emerged as a novel effective therapeutic strategy for solid malignancies, such as melanoma and prostate carcinoma. For breast carcinoma, an immunologic therapeutic approach has not been well evaluated, even though there is evidence to suggest it would be a successful novel strategy, especially taking into account the high mortality rate of the most aggressive variants of this heterogeneous disease. Here, we briefly describe the most recently awarded immune-based therapies with a consolidated or potential implication for the treatment of solid malignancies. We focus on immune checkpoints and on the clinical potential of their abrogation, with a further overview of novel vaccine-based approaches and the most relevant immunotherapeutic techniques. We aim to provide an exhaustive review of the most promising immune-therapeutic agents that may have implications for breast cancer treatment.