T-cell repertoire diversity: friend or foe for protective antitumor response?

: Profiling the T-Cell Receptor (TCR) repertoire is establishing as a potent approach to investigate autologous and treatment-induced antitumor immune response. Technical and computational breakthroughs, including high throughput next-generation sequencing (NGS) approaches and spatial transcriptomics, are providing unprecedented insight into the mechanisms underlying antitumor immunity. A precise spatiotemporal variation of T-cell repertoire, which dynamically mirrors the functional state of the evolving host-cancer interaction, allows the tracking of the T-cell populations at play, and may identify the key cells responsible for tumor eradication, the evaluation of minimal residual disease and the identification of biomarkers of response to immunotherapy. In this review we will discuss the relationship between global metrics characterizing the TCR repertoire such as T-cell clonality and diversity and the resultant functional responses. In particular, we will explore how specific TCR repertoires in cancer patients can be predictive of prognosis or response to therapy and in particular how a given TCR re-arrangement, following immunotherapy, can predict a specific clinical outcome. Finally, we will examine current improvements in terms of T-cell sequencing, discussing advantages and challenges of current methodologies

The epigenetic factor BORIS/CTCFL regulates the NOTCH3 gene expression in cancer cells.

Aberrant upregulation of NOTCH3 gene plays a critical role in cancer pathogenesis. However, the underlying mechanisms are still unknown. We tested here the hypothesis that aberrant epigenetic modifications in the NOTCH3 promoter region might account for its upregulation in cancer cells. We compared DNA and histone methylation status of NOTCH3 promoter region in human normal blood cells and T cell acute lymphoblastic leukemia (T-ALL) cell lines, differentially expressing NOTCH3. We found that histone methylation, rather than DNA hypomethylation, contributes towards establishing an active chromatin status of NOTCH3 promoter in NOTCH3 overexpressing cancer cells. We discovered that the chromatin regulator protein BORIS/CTCFL plays an important role in regulating NOTCH3 gene expression. We observed that BORIS is present in T-ALL cell lines as well as in cell lines derived from several solid tumors overexpressing NOTCH3. Moreover, BORIS targets NOTCH3 promoter in cancer cells and it is able to induce and to maintain a permissive/active chromatin conformation. Importantly, the association between NOTCH3 overexpression and BORIS presence was confirmed in primary T-ALL samples from patients at the onset of the disease. Overall, our results provide novel insights into the determinants of NOTCH3 overexpression in cancer cells, by revealing a key role for BORIS as the main mediator of transcriptional deregulation of NOTCH3. Copyright © 2014 Elsevier B.V. All rights reserved

The archaeal eIF2 homologue: functional properties of an ancient translation initiation factor

The eukaryotic translation initiation factor 2 (eIF2) is pivotal for delivery of the initiator tRNA (tRNAi) to the ribosome. Here, we report the functional characterization of the archaeal homologue, a/eIF2. We have cloned the genes encoding the three subunits of a/eIF2 from the thermophilic archaeon Sulfolobus solfataricus, and have assayed the activities of the purified recombinant proteins in vitro. We demonstrate that the trimeric factor reconstituted from the recombinant polypeptides has properties similar to those of its eukaryal homologue: it interacts with GTP and Met-tRNAi, and stimulates binding of the latter to the small ribosomal subunit. However, the archaeal protein differs in some functional aspects from its eukaryal counterpart. In contrast to eIF2, a/eIF2 has similar affinities for GDP and GTP, and the β-subunit does not contribute to tRNAi binding. The detailed analysis of the complete trimer and of its isolated subunits is discussed in light of the evolutionary history of the eIF2-like proteins

Epistemological obstacles in the learning process of Numeral Systems

This study has two main research objectives. Its main one is to analyze the origin of a systematic error, made by first year students of the Computer Sciences Degree at the National University of Salta. The systematic error arises when the students are dealing with Numeral Systems. From there, a second objective is to develop teaching procedures leading to recreate the error in a conceptual reconstruction process, within a playful environment. The theoretical framework used is the Brousseaunian concept of epistemological obstacles in the learning process. We use a sample of 152 students. In this article, we propose a strategy that allows real processes of error reconstruction and construction, in order to enable real epistemological progress. Resources within a virtual environment are presented as play and interactive alternatives with the aim of reinforcing the concepts studied in the classroom: videos, educational software and a computer game specifically developed for Numeral Systems.XI Workshop tecnología informática aplicada en educaciónRed de Universidades con Carreras en Informática (RedUNCI

Epistemological obstacles in the learning process of Numeral Systems

This study has two main research objectives. Its main one is to analyze the origin of a systematic error, made by first year students of the Computer Sciences Degree at the National University of Salta. The systematic error arises when the students are dealing with Numeral Systems. From there, a second objective is to develop teaching procedures leading to recreate the error in a conceptual reconstruction process, within a playful environment. The theoretical framework used is the Brousseaunian concept of epistemological obstacles in the learning process. We use a sample of 152 students. In this article, we propose a strategy that allows real processes of error reconstruction and construction, in order to enable real epistemological progress. Resources within a virtual environment are presented as play and interactive alternatives with the aim of reinforcing the concepts studied in the classroom: videos, educational software and a computer game specifically developed for Numeral Systems.XI Workshop tecnología informática aplicada en educaciónRed de Universidades con Carreras en Informática (RedUNCI

Prevalence and predictors of left ventricular hypertrophy in patients with hypertension and normal electrocardiogram

Background: Electrocardiography (ECG) has low sensitivity for detecting left ventricular hypertrophy (LVH), while echocardiography cannot be routinely performed. Design/methods: In this study we evaluate the prevalence of LVH and diastolic dysfunction in hypertensive patients with normal ECG. We excluded patients with cardiovascular (CV) diseases, diabetes, chronic kidney disease, or presenting ECG-LVH or other ECG anomalies. The enrolled 440 hypertensive patients underwent echocardiographic examination (Acuson Sequoia 512); LV mass was indexed by body surface area (LVMI) and LVH was defined as LVMI >125 g/m2 in men and >110 g/m2 in women. Diastolic function was evaluated by mitral inflow and tissue Doppler imaging (TDI). Results: The prevalence of LVH was 8.18% (95% confidence interval [CI] 5.97–11.1%). Multiple regression analysis showed that the only variable independently associated with LVH was duration of hypertension (p<0.001). The receiver operating characteristic (ROC) curve showed that duration of hypertension was a powerful predictor of LVH, with an area under the curve (AUC) of 0.878 and p<0.0001. Further, in patients with LVH the mean difference of LVMI from the cut-off value for LVH was 12.3 9.19 g/m2. Diastolic dysfunction, defined as early diastolic myocardial velocity (Em) <0.08 m/s, was detected only in 3.2% of patients. Conclusions: The prevalence of LVH among hypertensive patients with normal ECG, free of diabetes and of CV diseases is low; moreover, patients with echocardiographic LVH presented LVMI values that identified mild LVH. Few cases of impaired diastolic function were registered. We suggest that in hypertensive patients with such characteristics the echocardiographic examination should be reserved to those who present with higher duration of hypertension

Women outperform men in remembering to remember

The study of gender differences in prospective memory (i.e., remembering to remember) has received modest attention in the literature. The few reported studies investigating either subjective or objective evaluations of prospective memory have shown inconsistent data. In this study, we aimed to verify the presence of gender differences during the performance of an objective prospective memory test by considering the weight of specific variables such as length of delay, type of response, and type of cue. We submitted a sample of 100 healthy Italian participants (50 men and 50 women) to a test expressly developed to assess prospective memory: The Memory for Intentions Screening Test. Women performed better than men in remembering to do an event-based task (i.e., prompted by an external event) and when the task required a physical response modality. We discuss the behavioural differences that emerged by considering the possible role of sociological, biological, neuroanatomical, and methodological variables

Identification of a public CDR3 motif and a biased utilization of T-cell receptor V beta and J beta chains in HLA-A2/Melan-A-specific T-cell clonotypes of melanoma patients

<p>Abstract</p> <p>Background</p> <p>Assessment of T-cell diversity, besides giving insights about the molecular basis of tumor antigen recognition, has clinical implications since it provides criteria for evaluating antigen-specific T cells clinically relevant for spontaneous and vaccine-induced anti-tumor activity. Melan-A is one of the melanoma antigens most frequently recognized by peripheral and tumor-infiltrating lymphocytes in HLA-A2+ melanoma patients. Many clinical trials involving anti-tumor vaccination have been conducted using modified versions of this peptide.</p> <p>Methods</p> <p>We conducted an in-depth characterization of 210 T-cell receptor beta chain (TRB) clonotypes derived from T cells of HLA-A2+ melanoma patients displaying cytotoxic activity against natural and A27L-modified Melan-A peptides. One hundred and thirteen Melan-A-specific clonotypes from melanoma-free subjects, 199 clonotypes from T-cell clones from melanoma patients specific for melanoma antigens other than Melan-A, and 305 clonotypes derived from T cells of HLA-A2+ individuals showing unrelated specificities, were used as control. After sequence analysis, performed according to the IMGT definitions, TRBV and TRBJ usage, CDR3 length and amino acid composition were compared in the four groups of clonotypes.</p> <p>Results</p> <p>TRB sequences of Melan-A-specific clonotypes obtained from melanoma patients were highly heterogeneous, but displayed a preferential usage of few TRBV and TRBJ segments. Furthermore, they included a recurrent "public" amino acid motif (Glycine-Leucine-Glycine at positions 110-112-113 of the CDR3) rearranged with dominant TRBV and TRBJ segments and, in one case, associated with a full conservation of the entire TRB sequence.</p> <p>Conclusion</p> <p>Contrary to what observed for public anti-Melan-A T-cell receptor alpha motifs, which had been identified in several clonotypes of both melanoma patients and healthy controls, the unexpectedly high contribution of a public TRB motif in the recognition of a dominant melanoma epitope in melanoma patients may provide important information about the biology of anti-tumor T-cell responses and improve monitoring strategies of anti-tumor vaccines.</p

Where Am I? Searching for the Tangle in the Developmental Topographical Disorientation

The Developmental Topographical Disorientation (DTD) is a pathological condition that impairs an individual's ability to orient in space, even in the most familiar environments. It is a lifelong selective condition in individuals without brain damage or without impaired general cognitive functions. Here, we aimed at characterizing 54 individuals with DTD identified in a previous study, aged between 18 and 35 years and assessed through a 4-year-long online survey. To this purpose, we compared them with 54 matched healthy participants. We described the demographics, sense of direction, town knowledge, navigational strategies, left-right confusion as well as agnosic disorders (for landmarks, faces and objects). This novel study attempts to characterize the phenotype of DTD, providing an important contribution to the worldwide definition of a condition that was first described only 13 years ago, but which, considering the growing number of cases complaining of the disorder, deserves continuous and increasing attention

Enhanced performance of longitudinally post-tensioned long-span LVL beams

The scope of this paper is to highlight the advantages of using longitudinally post-tensioning for long-span timber beams compared to traditional glulam or LVL solutions. The analysis is limited to serviceability limit states for gravity loads. An analtycal iterative procedure which takes into account tendon elongation within beam deflecting has been implemented and validated through experimental tests carried out at the University of Canterbury.In particular, two different static configurations have been studied and different tendon profile configurations (straight and draped) internal and external to the beam section have been investigated and compared with traditional solid timber beams. The experimental results confirm the enhanced performance in terms of deflections at serviceability limit state of the longitudinally post-tensioned solutions with respect to traditional timber beams, especially if external draped tendons are adopted