Loss of the candidate tumor suppressor ZEB1 (TCF8, ZFHX1A) in Sézary syndrome

Cutaneous T-cell lymphoma is a group of incurable extranodal non-Hodgkin lymphomas that develop from the skin-homing CD4+ T cell. Mycosis fungoides and Sézary syndrome are the most common histological subtypes. Although next-generation sequencing data provided significant advances in the comprehension of the genetic basis of this lymphoma, there is not uniform consensus on the identity and prevalence of putative driver genes for this heterogeneous group of tumors. Additional studies may increase the knowledge about the complex genetic etiology characterizing this lymphoma. We used SNP6 arrays and GISTIC algorithm to prioritize a list of focal somatic copy-number alterations in a dataset of multiple sequential samples from 21 Sézary syndrome patients. Our results confirmed a prevalence of significant focal deletions over amplifications: single well-known tumor suppressors, such as TP53, PTEN, and RB1, are targeted by these aberrations. In our cohort, ZEB1 (TCF8, ZFHX1A) spans a deletion having the highest level of significance. In a larger group of 43 patients, we found that ZEB1 is affected by deletions and somatic inactivating mutations in 46.5% of cases; also, we found potentially relevant ZEB1 germline variants. The survival analysis shows a worse clinical course for patients with ZEB1 biallelic inactivation. Multiple abnormal expression signatures were found associated with ZEB1 depletion in Sézary patients we verified that ZEB1 exerts a role in oxidative response of Sézary cells. Our data confirm the importance of deletions in the pathogenesis of cutaneous T-cell lymphoma. The characterization of ZEB1 abnormalities in Sézary syndrome fulfils the criteria of a canonical tumor suppressor gene. Although additional confirmations are needed, our findings suggest, for the first time, that ZEB1 germline variants might contribute to the risk of developing this disease. Also, we provide evidence that ZEB1 activity in Sézary cells, influencing the reactive oxygen species production, affects cell viability and apoptosis

Modelling battery packs of real-world electric vehicles from data sheet information

Lithium-ion batteries have emerged as the leading enabling technology in developing Electric Vehicles (EVs), But, large-scale publicly available EV data are extremely difficult to find. So it becomes difficult to research and disseminate new methods for monitoring the battery pack of an EV. In this work, we propose a Simulink-based approach to define a virtual-EV model that simulates EV battery pack signals starting from input driving sessions. The battery pack module within the virtual-EV has been fine-tuned using data gathered from real-world EV data sheets. Moreover, the battery pack module includes thermal and aging models, impacting on the output signals, considering the temperature of the surrounding environment and the initial State of Health (SOH) of the battery pack. The virtual-EV generates time series of vehicle's speed, and battery pack's current, State of Charge (SOC), voltage, and average internal temperature according to the input driving cycle. We defined two Simulink EV models emulating two distinct real-world-EVs. Then, we assessed the performances of the simulators comparing the simulated data and real EV data signals collected by the same real-world-EV models, and we obtain, for both simulated EV models, R2 values higher than 0.70 and an RMSE of at most 7V and 8% for the voltage and SOC of the battery pack, respectively

Comparative Analysis of Electric Vehicle Simulator for Accurate Battery Pack Internal Signal Generation

The definition of accurate electric vehicle (EV) simulators can help mitigate the lack of large-scale public battery pack datasets in literature. This work compares two developed Simulink-based EV simulators that generate realistic EV battery pack signals from input driving sessions. The two EV simulators, referred to as simplified and advanced respectively, share the same architecture. However, they are equipped with internal blocks characterized by different complexity and precision. Both simulators generate time series of the vehicle’s speed, and battery pack’s current, state of charge (SOC), voltage, and internal temperature. Additionally, the simulators incorporate thermal and aging models, allowing for the emulation of a wide range of environmental conditions and aging statuses of the battery pack. A subset of inner parameters has been set, sourcing from online technical data sheets, to enable both virtual-EVs to mimic the same 2017 Volkswagen eGolf EV model. Indeed, given the availability of an acquired and ample real dataset specific to the same EV model, it is possible to perform an extensive and thorough validation of the simulated data. Both virtual-EVs prove to be accurate at simulating a battery pack under different aging conditions, although the comparison highlights the benefits of more sophisticated design choices, demonstrating the higher accuracy of the advanced virtual-EV over the simplified one. Indeed, the advanced virtual-EV achieves overall RMSE and R2 values, for current, voltage, and SOC of 43.34 A, 4.07 V, 4.84% and 0.28, 0.93, and 0.96, respectively. The main design differences between the two virtual-EVs are presented, and, upon examining their computational burden, distinct utilization scenarios are proposed based on the user’s needs

Blood and skin-derived Sezary cells: differences in proliferation-index, activation of PI3K/AKT/mTORC1 pathway and its prognostic relevance

Sézary syndrome (SS) is a rare and aggressive variant of Cutaneous T-Cell Lymphoma characterized by neoplastic distribution mainly involving blood, skin, and lymph-node. Although a role of the skin microenvironment in SS pathogenesis has long been hypothesized, its function in vivo is poorly characterized. To deepen this aspect, here we compared skin to blood-derived SS cells concurrently obtained from SS patients highlighting a greater proliferation-index and a PI3K/AKT/mTORC1 pathway activation level, particularly of mTOR protein, in skin-derived-SS cells. We proved that SDF-1 and CCL21 chemokines, both overexpressed in SS tissues, induce mTORC1 signaling activation, cell proliferation and Ki67 up-regulation in a SS-derived cell line and primary-SS cells. In a cohort of 43 SS cases, we observed recurrent copy number variations (CNV) of members belonging to this cascade, namely: loss of LKB1 (48%), PTEN (39%) and PDCD4 (35%) and gains of P70S6K (30%). These alterations represent druggable targets unraveling new therapeutic treatments as metformin here evaluated in vitro. Moreover, CNV of PTEN, PDCD4, and P70S6K, evaluated individually or in combination, are associated with reduced survival of SS patients. These data shed light on effects in vivo of skin-SS cells interaction underlying the prognostic and therapeutic relevance of mTORC1 pathway in SS

Paraneoplastic epidermolysis bullosa acquisita associated with thyroid carcinoma

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Role of Neutrophil-to-Lymphocyte Ratio (NLR) in Patients with Mycosis Fungoides

background: the neutrophil/lymphocyte ratio (NLR) at baseline has been demonstrated to correlate with higher stages of disease and to be a prognostic factor in numerous cancers. however, its function as a prognostic factor for mycosis fungoides (MF) has not been yet clarified. objective: our work aimed to assess the association of the NLR with different stages of MF and to outline whether higher values of this marker are related to a more aggressive MF.methods: we retrospectively calculated the NLRs in 302 MF patients at the moment of diagnosis. the NLR was obtained using the complete blood count values.results: the median NLR among patients with early stage disease (low-grade IA-IB-IIA) was 1.88, while the median NLR for patients with high-grade MF (IIB-IIIA-IIIB) was 2.64. statistical analysis showed positive associations of advanced MF stages with NLRs higher than 2.3. conclusions: our analysis demonstrates that the NLR represents a cheap and easily available parameter functioning as a marker for advanced MF. this might guide physicians in recognizing patients with advanced stages of disease requiring a strict follow-up or an early treatment

Automatic Learning Path Design: development and implementation.

This paper will describe the development and implementation of an Adaptive System Prototype with the aim to manage an automated and customized learning experience. After the first in-depth study on the usefulness and effectiveness of personalized learning approach, the research team intended to fill the gap between the theory of personalized learning environments and its practice trough the development of an adaptive learning plugin implemented on mostly used, Open Source, Learning Management Systems. The developed technology, follow the goal to identify any end user of the LMS, create a customized user profile with their starting skills and learning preferences in order to automatically tailor a personalized learning path. The main purpose is to maximize student’s performance. This paper describes the main steps for the implementation of the prototype of this Adaptive Learning System named iO3 (intelligent Open Cube), as it will be an intelligent, Open Source, Open Knowledge, Open Plugin system

Automatic Learning Path Design: development and implementation

This paper will describe the development and implementation of an Adaptive System Prototype with the aim to manage an automated and customized learning experience. After the first in-depth study on the usefulness and effectiveness of personalized learning approach, the research team intended to fill the gap between the theory of personalized learning environments and its practice trough the development of an adaptive learning plugin implemented on mostly used, Open Source, Learning Management Systems. The developed technology, follow the goal to identify any end user of the LMS, create a customized user profile with their starting skills and learning preferences in order to automatically tailor a personalized learning path. The main purpose is to maximize student’s performance. This paper describes the main steps for the implementation of the prototype of this Adaptive Learning System named iO3 (intelligent Open Cube), as it will be an intelligent, Open Source, Open Knowledge, Open Plugin system

Preclinical Evidence for Targeting PI3K/mTOR Signaling with Dual-Inhibitors as a Therapeutic Strategy against Cutaneous T-Cell Lymphoma

The phosphoinositide 3-kinase(PI3K)/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway is hyperactivated in many tumors, as well as in cutaneous T-cell lymphoma (CTCL), which includes the mycosis fungoides and the aggressive variant known as Sezary syndrome (SS). TORC1 signaling is activated in SS cells by cytokines and chemokines, which are overexpressed in SS tissues. Furthermore, the recurrent copy number variation of genes belonging to this cascade, such as PTEN, LKB1, and P70S6K, contributes to the hyperactivation of the pathway. The aim of this study was to investigate the therapeutic potential of mTOR inhibitors in CTCL. We compared the efficacy of three rapalogs (rapamycin, temsirolimus, and everolimus) and the dual-mTOR/PI3K inhibitor PF-04691502 (hereinafter PF-502) in four CTCL cell lines. PF-502 was revealed to be the most effective inhibitor of cell growth. Interestingly, PF-502 also exerted its antitumor activity in patient-derived CTCL cells and in a xenograft mouse model, where it induced significant apoptosis and increased survival of treated mice. Furthermore, we found an inverse correlation between PTEN gene expression and the ability of PF-502 to induce apoptosis in SS cells. Our data strongly support the therapeutic potential of dual PI3K/mTOR inhibitors in CTCL

Protein corona affects the relaxivity and MRI contrast efficiency of magnetic nanoparticles

Item does not contain fulltextMagnetic nanoparticles (NPs) are increasingly being considered for use in biomedical applications such as biosensors, imaging contrast agents and drug delivery vehicles. In a biological fluid, proteins associate in a preferential manner with NPs. The small sizes and high curvature angles of NPs influence the types and amounts of proteins present on their surfaces. This differential display of proteins bound to the surface of NPs can influence the tissue distribution, cellular uptake and biological effects of NPs. To date, the effects of adsorption of a protein corona (PC) on the magnetic properties of NPs have not been considered, despite the fact that some of their potential applications require their use in human blood. Here, to investigate the effects of a PC (using fetal bovine serum) on the MRI contrast efficiency of superparamagnetic iron oxide NPs (SPIONs), we have synthesized two series of SPIONs with variation in the thickness and functional groups (i.e. surface charges) of the dextran surface coating. We have observed that different physico-chemical characteristics of the dextran coatings on the SPIONs lead to the formation of PCs of different compositions. (1)H relaxometry was used to obtain the longitudinal, r1, and transverse, r2, relaxivities of the SPIONs without and with a PC, as a function of the Larmor frequency. The transverse relaxivity, which determines the efficiency of negative contrast agents (CAs), is very much dependent on the functional group and the surface charge of the SPIONs' coating. The presence of the PC did not alter the relaxivity of plain SPIONs, while it slightly increased the relaxivity of the negatively charged SPIONs and dramatically decreased the relaxivity of the positively charged ones, which was coupled with particle agglomeration in the presence of the proteins. To confirm the effect of the PC on the MRI contrast efficiency, in vitro MRI experiments at nu = 8.5 MHz were performed using a low-field MRI scanner. The MRI contrasts, produced by different samples, were fully in agreement with the relaxometry findings