MYCOSIS FUNGOIDES: NOVEL THERAPEUTIC APPROACHES TARGETING THE CUTANEOUS LYMPHOCYTE ANTIGEN (CLA)

Background Mycosis fungoides (MF) is the most common form of cutaneous T cell lymphoma. There are currently few effective therapies for the treatment of MF. Treatments for the early stages generally consist of a skin-directed therapy, and treatments for the late stages are generally systemic, and often combined. Although the initial stages of mycosis fungoides have a moderate clinical course, 30% of patients relapse or prove to be refractory to currently used treatments and are destined to progress to advanced stages of the disease for which, in fact, there is not a curative treatment. Therefore, the development of new therapeutic strategies is fundamental. While the Cutaneous Lymphocyte Antigen (CLA) is strongly expressed by MF tumor cells, it could be a specific molecular target for the treatment of MF. The aim of the whole PhD project was to investigate novel therapeutic approaches targeting CLA for the treatment of MF. The first specific aim was to investigate the antitumor effect of a CLA-targeted Near‐infrared photoimmunotherapy (NIR-PIT) on MF cells and the second specific aim was to investigate the antitumor effect of an antibody-drug conjugate (ADC) consisting of an anti-CLA monoclonal antibody and monomethyl auristatin E (MMAE). Methods In vitro validation of anti-CLA monoclonal antibody-based approaches were performed using a MF cell line called Myla CD4+ cell line. In vivo studies are ongoing on zebrafish embryo model of MF created by the injection of Myla CD4+ cells into the yolk sac at 2 days post fertilization. Results Treatment with anti-CLA monoclonal antibody alone or near infrared light irradiation alone exhibited very modest pro-death effects, while the combination of the two induced a substantial increase in death in the MF cell line showing that CLA-targeted NIR PIT has a marked anti-tumor effect in vitro. Conversely, the anti-CLA-MMAE antibody drug conjugate exhibited in vitro lower cytotoxic activity compared to anti-CLA monoclonal antibody or MMAE alone. In vivo validation phases studies are ongoing to investigate the efficacy of these anti-CLA monoclonal antibody-based approaches. Preliminary data are encouraging but are still under evaluation. Discussion An anti-CLA monoclonal antibody-based approach may represent a novel and highly selective treatment for this disease. While CLA-targeted NIR-PIT shows a marked anti-tumor effect on MF cells in vitro, it is an attractive candidate for in vivo studies and ultimately for clinical trials. The anti-CLA-MMAE ADC shows low cytotoxicity activity in vitro which could be explained by the lack of internalization of the ADC into the cells. However, it has recently been demonstrated that in vivo non-internalizing antibodies may have potent anti-cancer activity thanks to proteolytic release of MMAE in the subendothelial extracellular matrix. Thus, anti-CLA-MMAE ADC may be effective in vivo. The xenotransplantation experiments performed to evaluate the proliferation of MF cells in zebrafish embryos have given very positive and extremely encouraging results, confirming the possible use of this animal species as a model for the study of this pathology.Background Mycosis fungoides (MF) is the most common form of cutaneous T cell lymphoma. There are currently few effective therapies for the treatment of MF. Treatments for the early stages generally consist of a skin-directed therapy, and treatments for the late stages are generally systemic, and often combined. Although the initial stages of mycosis fungoides have a moderate clinical course, 30% of patients relapse or prove to be refractory to currently used treatments and are destined to progress to advanced stages of the disease for which, in fact, there is not a curative treatment. Therefore, the development of new therapeutic strategies is fundamental. While the Cutaneous Lymphocyte Antigen (CLA) is strongly expressed by MF tumor cells, it could be a specific molecular target for the treatment of MF. The aim of the whole PhD project was to investigate novel therapeutic approaches targeting CLA for the treatment of MF. The first specific aim was to investigate the antitumor effect of a CLA-targeted Near‐infrared photoimmunotherapy (NIR-PIT) on MF cells and the second specific aim was to investigate the antitumor effect of an antibody-drug conjugate (ADC) consisting of an anti-CLA monoclonal antibody and monomethyl auristatin E (MMAE). Methods In vitro validation of anti-CLA monoclonal antibody-based approaches were performed using a MF cell line called Myla CD4+ cell line. In vivo studies are ongoing on zebrafish embryo model of MF created by the injection of Myla CD4+ cells into the yolk sac at 2 days post fertilization. Results Treatment with anti-CLA monoclonal antibody alone or near infrared light irradiation alone exhibited very modest pro-death effects, while the combination of the two induced a substantial increase in death in the MF cell line showing that CLA-targeted NIR PIT has a marked anti-tumor effect in vitro. Conversely, the anti-CLA-MMAE antibody drug conjugate exhibited in vitro lower cytotoxic activity compared to anti-CLA monoclonal antibody or MMAE alone. In vivo validation phases studies are ongoing to investigate the efficacy of these anti-CLA monoclonal antibody-based approaches. Preliminary data are encouraging but are still under evaluation. Discussion An anti-CLA monoclonal antibody-based approach may represent a novel and highly selective treatment for this disease. While CLA-targeted NIR-PIT shows a marked anti-tumor effect on MF cells in vitro, it is an attractive candidate for in vivo studies and ultimately for clinical trials. The anti-CLA-MMAE ADC shows low cytotoxicity activity in vitro which could be explained by the lack of internalization of the ADC into the cells. However, it has recently been demonstrated that in vivo non-internalizing antibodies may have potent anti-cancer activity thanks to proteolytic release of MMAE in the subendothelial extracellular matrix. Thus, anti-CLA-MMAE ADC may be effective in vivo. The xenotransplantation experiments performed to evaluate the proliferation of MF cells in zebrafish embryos have given very positive and extremely encouraging results, confirming the possible use of this animal species as a model for the study of this pathology

Cross-Dictionary Linking at Sense Level with a Double-Layer Classifier

We present a system for linking dictionaries at the sense level, which is part of a wider programme aiming to extend current lexical resources and to create new ones by automatic means. One of the main challenges of the sense linking task is the existence of non one-to-one mappings among senses. Our system handles this issue by addressing the task as a binary classification problem using standard Machine Learning methods, where each sense pair is classified independently from the others. In addition, it implements a second, statistically-based classification layer to also model the dependence existing among sense pairs, namely, the fact that a sense in one dictionary that is already linked to a sense in the other dictionary has a lower probability of being linked to a further sense. The resulting double-layer classifier achieves global Precision and Recall scores of 0.91 and 0.80, respectively

Recognizing deverbal events in context

Abstract. Event detection is a key task in order to access informa- tion through content. This paper focuses on events realized by deverbal nouns in Italian. Deverbal nouns obtained through transpositional suf- fixes (such as -zione; -mento, -tura and -aggio) are commonly known as nouns of action, i.e. nouns which denote the process/action described by the corresponding verbs. However, this class of nouns is also known for a specific polysemous alternation: they may denote the result of the process/action of the corresponding verb. This paper describes a sta- tistically based analysis that helps to develop a classifier for automatic identification of deverbal nouns denoting events in context by exploit- ing rules obtained from syntagmatic and collocational cues identified by linguists

archer at SemEval-2021 Task 1: Contextualising Lexical Complexity.

Evaluating the complexity of a target word in a sentential context is the aim of the Lexical Complexity Prediction task at SemEval-2021. This paper presents the system created to assess single words lexical complexity, combining linguistic and psycholinguistic variables in a set of experiments involving random forest and XGboost regressors. Beyond encoding out-of-context information about the lemma, we implemented features based on pre-trained language models to model the target word's in-context complexity

Isolated Third Cranial Nerve Palsy Leading to the Diagnosis of Disseminated Burkitt Lymphoma: A Case Report and Literature Review

Dysfunction of the third cranial nerve can result from lesions anywhere along its course between the midbrain and the orbit. Lymphoma is a rare cause of isolated oculomotor nerve palsy (OMP), with only 19 cases reported in the literature. We describe a case of an isolated OMP leading to the diagnosis of disseminated Burkitt lymphoma (BL)

A survey on efficient vision transformers: algorithms, techniques, and performance benchmarking

Vision Transformer (ViT) architectures are becoming increasingly popular and widely employed to tackle computer vision applications. Their main feature is the capacity to extract global information through the self-attention mechanism, outperforming earlier convolutional neural networks. However, ViT deployment and performance have grown steadily with their size, number of trainable parameters, and operations. Furthermore, self-attention's computational and memory cost quadratically increases with the image resolution. Generally speaking, it is challenging to employ these architectures in real-world applications due to many hardware and environmental restrictions, such as processing and computational capabilities. Therefore, this survey investigates the most efficient methodologies to ensure sub-optimal estimation performances. More in detail, four efficient categories will be analyzed: compact architecture, pruning, knowledge distillation, and quantization strategies. Moreover, a new metric called Efficient Error Rate has been introduced in order to normalize and compare models' features that affect hardware devices at inference time, such as the number of parameters, bits, FLOPs, and model size. Summarizing, this paper firstly mathematically defines the strategies used to make Vision Transformer efficient, describes and discusses state-of-the-art methodologies, and analyzes their performances over different application scenarios. Toward the end of this paper, we also discuss open challenges and promising research directions

High serum osteopontin levels are associated with prevalent fractures and worse lipid profile in post-menopausal women with type 2 diabetes

Purpose: Patients with type 2 diabetes (T2DM) have increased fracture risk. Osteopontin (OPN) is a protein involved in bone remodeling and inflammation. The aim of this study was to evaluate the association of OPN with fracture prevalence and with metabolic parameters in post-menopausal women with T2DM. Methods: Sixty-four post-menopausal women with T2DM (age 67.0 ± 7.8 years, diabetes duration 8.9 ± 6.7 years), enrolled in a previous study, were followed up (3.6 ± 0.9 years). Previous fragility fractures were recorded. The FRAX score (without BMD) was calculated and biochemical parameters (plasma glucose, HbA1c, lipid profile and renal function) were assessed. Serum 25OH-vitamin D, calcium, PTH and OPN were evaluated at baseline. The association between OPN and fracture prevalence at baseline was evaluated by a logistic model. Results: OPN levels were higher in patients with previous fractures (n.25) than in patients without previous fractures at baseline (n.39) (p = 0.006). The odds of having fractures at baseline increased by 6.7 (1.9–31.4, 95% CI, p = 0.007) for each increase of 1 ng/ml in OPN levels, after adjustment for vitamin D and HbA1c levels. Fracture incidence was 4.7%. Higher OPN associated with a decrease in HDL-cholesterol (p = 0.048), after adjustment for age, basal HDL-cholesterol, basal and follow-up HbA1c and follow-up duration. 25OH-vitamin D associated with an increase in FRAX-estimated probability of hip fracture at follow-up (p = 0.029), after adjustment for age, 25OH-vitamin D and time. Conclusions: In post-menopausal women with T2DM, OPN might be a useful marker of fracture and worse lipid profile

Group-based Early Start Denver Model: un modello educativo per alunni con Disturbo dello Spettro Autistico nelle scuole dell’infanzia italiane

Research on the implementation of evidence-based-practices in education has increasingly focusedon identifying models for children with autism spectrum disorder (ASD) that can be adaptable inpreschools. This article outlines the main features of the Group-based Early Start Denver Model(G-ESDM), an intervention for children with ASD that has gained prominence in recent years (Vivanti,Duncan, Dawson, Rogers, 2017). Based on the philosophy, principles and strategies of theEarly Start Denver Model (ESDM), the G-ESDM is a manualized evidence-based early interventionthat includes a set of strategies to adapt to the physical and social learning environment in orderto support pupil participation in classroom activities and the school community at large.While the presence of students with Autism Spectrum Disorder (ASD) in Italian school settings representsa challenge for both special education scholars and teachers which has endorsed the paradigmof full inclusion, some reflections on the possibility of promoting the adoption of theG-ESDM in Italian preschools are required. This article outlines the main features of the G-ESDMmodels and concludes by illustrating a possible research itinerary for its implementation in theItalian educational system

Otolaryngologic symptoms in multiple sclerosis: a review

Many symptoms of multiple sclerosis may affect the ear, nose and throat. The most common otolaryngologic symptoms of multiple sclerosis are speech disorders, followed by sleep disorders, vertigo and disequilibrium, dysphagia, smell alterations, and hearing loss. Less common symptoms include sialorrhea, facial palsy, taste alterations, trigeminal neuralgia and tinnitus. The origin of otolaryngologic symptoms in multiple sclerosis is mainly central, although increasing evidence also suggests a peripheral involvement. Otolaryngologic symptoms in multiple sclerosis may have different clinical presentations; they can appear in different stages of the pathology, in some cases they can be the presenting symptoms and their worsening may be correlated with reactivation of the disease. Many of these symptoms significantly affect the quality of life or patients and lead to increased morbidity and mortality. Otolaryngologic symptoms are common in multiple sclerosis; however, they are often overlooked. In many cases, they follow the relapsing-remitting phases of the disease, and may spontaneously disappear, leading to a delay in multiple sclerosis diagnosis. Clinicians should be aware of otolaryngologic symptoms of multiple sclerosis, especially when they are associated to neurologic symptoms, as they may be early signs of a still undiagnosed multiple sclerosis or could help monitor disease progression in already diagnosed patients

Different duplex/quadruplex junctions determine the properties of anti-thrombin aptamers with mixed folding.

Mixed duplex/quadruplex oligonucleotides have attracted great interest as therapeutic targets as well as effective biomedical aptamers. In the case of thrombin-binding aptamer (TBA), the addition of a duplex motif to the G-quadruplex module improves the aptamer resistance to biodegradation and the affinity for thrombin. In particular, the mixed oligonucleotide RE31 is significantly more effective than TBA in anticoagulation experiments and shows a slower disappearance rate in human plasma and blood. In the crystal structure of the complex with thrombin, RE31 adopts an elongated structure in which the duplex and quadruplex regions are perfectly stacked on top of each other, firmly connected by a well-structured junction. The lock-and-key shape complementarity between the TT loops of the G-quadruplex and the protein exosite I gives rise to the basic interaction that stabilizes the complex. However, our data suggest that the duplex motif may have an active role in determining the greater anti-thrombin activity in biological fluids with respect to TBA. This work gives new information on mixed oligonucleotides and highlights the importance of structural data on duplex/quadruplex junctions, which appear to be varied, unpredictable, and fundamental in determining the aptamer functional properties