The non-coding RNA landscape of plasma cell dyscrasias

Despite substantial advancements have been done in the understanding of the pathogenesis of plasma cell (PC) disorders, these malignancies remain hard-to-treat. The discovery and subsequent characterization of non-coding transcripts, which include several members with diverse length and mode of action, has unraveled novel mechanisms of gene expression regulation often malfunctioning in cancer. Increasing evidence indicates that such non-coding molecules also feature in the pathobiology of PC dyscrasias, where they are endowed with strong therapeutic and/or prognostic potential. In this review, we aim to summarize the most relevant findings on the biological and clinical features of the non-coding RNA landscape of malignant PCs, with major focus on multiple myeloma. The most relevant classes of non-coding RNAs will be examined, along with the mechanisms accounting for their dysregulation and the recent strategies used for their targeting in PC dyscrasias. It is hoped these insights may lead to clinical applications of non-coding RNA molecules as biomarkers or therapeutic targets/agents in the near future

Ecological factors affecting Alpine chamois population recruitment: remote sensing can support adaptive management

The analysis of ecological factors able to affect the life history traits of ungulates is important to reveal key information on population dynamics of wild herbivores. As regard to bovids, it is often crucial for juveniles and yearlings to gain quickly body size and mass, as such growths primarily increase chance to reach re- productive maturity (i.e., an increase in the survival probability). Accordingly, we modeled a set of ecological factors accounting for the variation of Alpine chamois (Rupicapra rupicapra) population recruitment through three indexes: i) the ratio kids/adult females (NK/NF), ii) the ratio yearlings/adult females (NY/NF), and iii) the yearlings eviscerated body mass (YBM). These indexes were derived respectively from block count census and from hunting records in the last 45 years in different ecological contexts in the South-West Trento province. These indexes were associated to forage quality/quantity, winter harshness, and local chamois density. In detail, we considered NDVI (Normalized Difference Vegetation Index) as a proxy for the quality of Alpine meadows used by chamois in spring and summer and snow cover data belonging to the National Aeronautics and Space Ad- ministration (NASA) remote sensing dataset (TERRA-MODIS). The reproductive success of these populations was strongly influenced both by the quality of meadows during births period (May) and by the space-time pattern of growth and maturation of Alpine pastures in spring and summer periods. Even winter harshness played an important role in this process. In particular, i) the NK/NF was positively influenced by the average quality of the grazing season previous to the births period and by the maximum NDVI value recorded in May (i.e., births period); ii) the NY/NF was negatively affected by the extent of snow cover in the first winter of kids and positively related to the average quality of the pasture in the subsequent spring and summer (i.e., the feed intake period in which individuals had to recover weight loss derived from previous winter); and iii) the YBM revealed a negative trend during the study period suggesting a difficult adaptation to climate and environmental changes taking place. Contrary to our expectations, local density was not able to influence these variables. This result may suggest that local density are not exceedingly high in the study area and therefore are not able to promote density dependent phenomena. In conclusion, these results contribute to increase the knowledge of the mechanisms underlying Alpine chamois population dynamics and give insights to plan adaptive management and conservation of this species

Communicating Europe:A computational analysis of the evolution of the European Commission’s communication on Twitter

Social media is an important means of communication for political agencies, which makes it possible to engage with large sectors of the public. For institutions which are not directly elected by voters, such as the European Commission (EC), social media can be a strategic tool for increasing perceived legitimacy and citizen engagement, especially in contexts of high politicization. In this paper, we use natural language processing techniques to provide a comprehensive overview of how EC communication on Twitter has evolved between 2010 and 2022, with respect to both its topics and its style. Our analyses show that, over time, the focus of EC communication has shifted substantially from economy-, finance- and governance-related topics, towards social policy, digital and environmental policy, and identity. These changes have progressively differentiated the EC’s profile from that of other institutions (especially more technocratic ones) and contributed to better alignment with engagement patterns of its social media audience. In addition, EC communication has become less neutral (in favor of more positive sentiment), simpler, and more readable, all features which are associated with more accessible and engaging messaging. Yet, while the EC currently scores better than most other reference agencies on several descriptors of accessibility, its style is still lexically more complex, less concrete and less action-oriented than that of other institutions. Alongside providing novel insights on how the EC’s online communication and projected political identity have changed over time, this study lays the foundations for future experimental and hypothesis-driven work combining social media data with external data sources

Identification of G-quadruplex DNA/RNA binders: Structure-based virtual screening and biophysical characterization

Background Recent findings demonstrated that, in mammalian cells, telomere DNA (Tel) is transcribed into telomeric repeat-containing RNA (TERRA), which is involved in fundamental biological processes, thus representing a promising anticancer target. For this reason, the discovery of dual (as well as selective) Tel/TERRA G-quadruplex (G4) binders could represent an innovative strategy to enhance telomerase inhibition. Methods Initially, docking simulations of known Tel and TERRA active ligands were performed on the 3D coordinates of bimolecular G4 Tel DNA (Tel2) and TERRA (TERRA2). Structure-based pharmacophore models were generated on the best complexes and employed for the virtual screening of ~ 257,000 natural compounds. The 20 best candidates were submitted to biophysical assays, which included circular dichroism and mass spectrometry at different K+ concentrations. Results Three hits were here identified and characterized by biophysical assays. Compound 7 acts as dual Tel2/TERRA2 G4-ligand at physiological KCl concentration, while hits 15 and 17 show preferential thermal stabilization for Tel2 DNA. The different molecular recognition against the two targets was also discussed. Conclusions Our successful results pave the way to further lead optimization to achieve both increased selectivity and stabilizing effect against TERRA and Tel DNA G4s. General significance The current study combines for the first time molecular modelling and biophysical assays applied to bimolecular DNA and RNA G4s, leading to the identification of innovative ligand chemical scaffolds with a promising anticancer profile. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio

Language beyond the language system:Dorsal visuospatial pathways support processing of demonstratives and spatial language during naturalistic fast fMRI

Spatial demonstratives are powerful linguistic tools used to establish joint attention. Identifying the meaning of semantically underspecified expressions like “this one” hinges on the integration of linguistic and visual cues, attentional orienting and pragmatic inference. This synergy between language and extralinguistic cognition is pivotal to language comprehension in general, but especially prominent in demonstratives. In this study, we aimed to elucidate which neural architectures enable this intertwining between language and extralinguistic cognition using a naturalistic fMRI paradigm. In our experiment, 28 participants listened to a specially crafted dialogical narrative with a controlled number of spatial demonstratives. A fast multiband-EPI acquisition sequence (TR = 388 m s) combined with finite impulse response (FIR) modelling of the hemodynamic response was used to capture signal changes at word-level resolution. We found that spatial demonstratives bilaterally engage a network of parietal areas, including the supramarginal gyrus, the angular gyrus, and precuneus, implicated in information integration and visuospatial processing. Moreover, demonstratives recruit frontal regions, including the right FEF, implicated in attentional orienting and reference frames shifts. Finally, using multivariate similarity analyses, we provide evidence for a general involvement of the dorsal (“where”) stream in the processing of spatial expressions, as opposed to ventral pathways encoding object semantics. Overall, our results suggest that language processing relies on a distributed architecture, recruiting neural resources for perception, attention, and extra-linguistic aspects of cognition in a dynamic and context-dependent fashion

Impressive long-term response with chemo-endocrine therapy in a premenopausal patient with metastatic breast cancer. A case report

Rationale: Patients with, or who develop, metastatic breast cancer have a 5-year relative survival of about 25%. Endocrine therapy clearly improves outcomes in patients with estrogen receptor-positive breast cancer. In the metastatic setting, the primary goal of treatment is to maintain long-term disease control with good quality of life. Rarely, exceptional responders achieve durable disease control, and potential cures cannot be ruled out.Patient Concerns: We report the case of a 39-year-old woman with primary breast cancer and associated synchronous bone metastases, who experienced a disease response of 12 years with hormonal therapy as maintenance after first line chemotherapy, with a good toxicity profile.Diagnosis: The patient was diagnosed with estrogen receptor + human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer with synchronous bone metastases.Interventions: This patient was treated with chemotherapy for 6 cycles as a first-line therapy following by endocrine treatment given as a maintenance therapy.Outcomes: Our patient experienced a progression-free survival >12 years with an exceptionally good quality of life.Lessons: Our anecdotal experience highlights the existence of exceptional responders among patients with hormone receptor-positive metastatic breast cancer, who achieve clinical remission and durable disease control with endocrine therapy. Being able to identify these patients could help in the selection of the best treatment option among the many available

Can cyclin-dependent kinase 4/6 inhibitors convert inoperable breast cancer relapse to operability? A case report

BACKGROUND Pathological complete response (pCR) is rare in hormone receptor-positive (HR+) HER2-negative breast cancer (BC) treated with either endocrine therapy (ET) or chemotherapy. Radical resection of locoregional relapse, although potentially curative in some cases, is challenging when the tumor invades critical structures. The oral cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with ET has obtained a significant increase in objective response rates and progression-free survival in patients with advanced BC and is now being evaluated in the neoadjuvant setting. We present a clinical case of a patient with an inoperable locoregional relapse of HR+ HER2-negative BC who experienced pCR after treatment with palbociclib.CASE SUMMARY We report the clinical case of a 60-year-old patient who presented with an inoperable locoregional relapse of HR+, HER2-negative BC 10 years after the diagnosis of the primary tumor. During a routine follow-up visit, breast magnetic resonance imaging and positron emission tomography/computed tomography revealed a 4-cm lesion in the right subclavicular region, infiltrating the chest wall and extending to the subclavian vessels, but without bone or visceral involvement. Treatment was begun with palbociclib plus letrozole, converting the disease to operability over a period of 6 mo. Surgery was performed and a pCR achieved. Of note, during treatment the patient experienced a very uncommon toxicity characterized by burning tongue and glossodynia associated with dysgeusia, paresthesia, dysesthesia, and xerostomia. A reduction in the dose of palbociclib did not provide relief and treatment with the inhibitor was thus discontinued, resolving the tongue symptoms. Laboratory exams were unremarkable. Given that this was a late relapse, the tumor was classified as endocrine-sensitive, a condition associated with high sensitivity to palbociclib.CONCLUSION This case highlights the potential of the cyclin-dependent kinase 4/6 inhibitor plus ET combination to achieve pCR in locoregional relapse of BC, enabling surgical resection of a lesion initially considered inoperable

Array and spectral ratio techniques applied to seismic noise to investigate the Campi Flegrei (Italy) subsoil structure at different scales

Abstract. The purpose of this work is to study the subsoil structure of the Campi Flegrei area using both spectral ratios and array techniques applied to seismic noise. We have estimated the dispersion curves of Rayleigh waves by applying the Frequency–Wavenumber (f–k hereinafter) and Modified Spatial Autocorrelation (MSPAC) techniques to the seismic noise recorded by the underground short period seismic Array "ARF", by the broadband stations of the UNREST experiment and by the broadband stations of the seismic monitoring network of INGV – Osservatorio Vesuviano. We have performed the inversion of a dispersion curve (obtained averaging the f–k and MSPAC dispersion curves of seismic noise and single phase velocity values of coherent transient signals) jointly with the H∕V spectral ratio of the broadband station CELG, to obtain a shear wave velocity model up to 2000 m depth. The best-fit model obtained is in a good agreement with the stratigraphic information available in the area coming from shallow boreholes and deep wells drilled for geothermal exploration. In active volcanic areas, such as Campi Flegrei, the definition of the velocity model is a crucial issue to characterize the physical parameters of the medium. Generally, a high quality characterization of the medium properties helps to separate the contributions of the volcanic source, path and site in the geophysical observables. Therefore, monitoring possible variations in time of such properties in general can help to recognize anomalies due to the volcano dynamics, i.e. fluid migration connected to the volcanic activity

Cell-Free DNA Variant Sequencing Using CTC-Depleted Blood for Comprehensive Liquid Biopsy Testing in Metastatic Breast Cancer

Keup and colleagues provide liquid biopsy preliminary results by sequencing variants in circulating tumor cells (CTCs) and cell-free deoxyribonucleic acid (cfDNA) "all from one tube" format, in order to use the same blood sample under the same isolation conditions of both analytes to reach an unbiased comparability and consistency. We appreciated the attempt of the authors to improve technical procedures in liquid biopsy research area, but we wanted to raise several issues related to cfDNA detection, reporting our research experience. This is a feasibility study as the authors analyzed only one sample from a small case series at an advanced line of treatment. In the clinical practice to monitor the disease and predict the treatment response, the analysis should be done at multiple time points. We have previously demonstrated that the quantity and the integrity of the cfDNA are not useful to determine the evolution of early breast cancer (bc), maybe due to the fact that cfDNA is not strictly related to cancer but also to an inflammatory status. Given that a high content of cfDNA could reflect inflammatory processes, we decided to investigate the role of stimulator of interferon gene (STING), an important regulator of cancer cell growth and senescence, in bc tissue in relation to cfDNA. STING biomarker analyzed by immunohistochemistry on tumor tissue could reflect a circulating inflammatory status and needs to be further investigated, not only on CTCs but also on cfDNA. One of the major issues of cfDNA is to decide what to analyze on it, in terms of type of cells and genetic alterations. Considering that multiple tests could be done to study gene copy number alterations, mutations, and variant fusions, the proper molecular test should be chosen, on the basis of the clinical need, starting from the treatment choice to disease monitoring

Dissecting Molecular Heterogeneity of Circulating Tumor Cells (CTCs) from Metastatic Breast Cancer Patients through Copy Number Aberration (CNA) and Single Nucleotide Variant (SNV) Single Cell Analysis

Circulating tumor cells' (CTCs) heterogeneity contributes to counteract their introduction in clinical practice. Through single-cell sequencing we aim at exploring CTC heterogeneity in metastatic breast cancer (MBC) patients. Single CTCs were isolated using DEPArray NxT. After whole genome amplification, libraries were prepared for copy number aberration (CNA) and single nucleotide variant (SNV) analysis and sequenced using Ion GeneStudio S5 and Illumina MiSeq, respectively. CTCs demonstrate distinctive mutational signatures but retain molecular traces of their common origin. CNA profiling identifies frequent aberrations involving critical genes in pathogenesis: gains of 1q (CCND1) and 11q (WNT3A), loss of 22q (CHEK2). The longitudinal single-CTC analysis allows tracking of clonal selection and the emergence of resistance-associated aberrations, such as gain of a region in 12q (CDK4). A group composed of CTCs from different patients sharing common traits emerges. Further analyses identify losses of 15q and enrichment of terms associated with pseudopodium formation as frequent and exclusive events. CTCs from MBC patients are heterogeneous, especially concerning their mutational status. The single-cell analysis allows the identification of aberrations associated with resistance, and is a candidate tool to better address treatment strategy. The translational significance of the group populated by similar CTCs should be elucidated