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1.
Urology ; 146: e12-e13, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32827537

RESUMO

Kidneys with more than 3 arteries are very rare and decision to use or not these organs can be difficult, because there is an increased risk of post-transplant vascular complications, with a higher risk of worse outcome. Here we report a case of a successful transplant a deceased donor left kidney with 5 arteries, using 2 separate wide patches containing 3 and 2 arteries, respectively. These kidneys should be considered as a source for maximize the number of organs available, but a careful selection of the recipient is also crucial for minimize the risk of complications.

2.
Front Immunol ; 11: 1215, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32695101

RESUMO

Mutation-derived neoantigens are taking central stage as a determinant in eliciting effective antitumor immune responses following adoptive T-cell therapies. These mutations are patient-specific, and their targeting calls for highly personalized pipelines. The promising clinical outcomes of tumor-infiltrating lymphocyte (TIL) therapy have spurred interest in generating T-cell infusion products that have been selectively enriched in neoantigen (or autologous tumor) reactivity. The implementation of an isolation step, prior to T-cell in vitro expansion and reinfusion, may provide a way to improve the overall response rates achieved to date by adoptive T-cell therapies in metastatic cancer patients. Here we provide an overview of the main technologies [i.e., peptide major histocompatibility complex (pMHC) multimers, cytokine capture, and activation markers] to enrich infiltrating or circulating T-cells in predefined neoantigen specificities (or tumor reactivity). The unique technical and regulatory challenges faced by such highly specialized and patient-specific manufacturing T-cell platforms are also discussed.

3.
Sensors (Basel) ; 20(7)2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32260240

RESUMO

Nowadays, analytical techniques are moving towards the development of smart biosensing strategies for the point-of-care accurate screening of disease biomarkers, such as human epididymis protein 4 (HE4), a recently discovered serum marker for early ovarian cancer diagnosis. In this context, the present work represents the first implementation of a competitive enzyme-labelled magneto-immunoassay exploiting a homemade IoT Wi-Fi cloud-based portable potentiostat for differential pulse voltammetry readout. The electrochemical device was specifically designed to be capable of autonomous calibration and data processing, switching between calibration, and measurement modes: in particular, firstly, a baseline estimation algorithm is applied for correct peak computation, then calibration function is built by interpolating data with a four-parameter logistic function. The calibration function parameters are stored on the cloud for inverse prediction to determine the concentration of unknown samples. Interpolation function calibration and concentration evaluation are performed directly on-board, thus reducing the power consumption. The analytical device was validated in human serum, demonstrating good sensing performance for analysis of HE4 with detection and quantitation limits in human serum of 3.5 and 29.2 pM, respectively, reaching the sensitivity that is required for diagnostic purposes, with high potential for applications as portable and smart diagnostic tool for point-of-care testing.

4.
Sensors (Basel) ; 20(5)2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32131395

RESUMO

Recent research in wearable sensors have led to the development of an advanced platform capable of embedding complex algorithms such as machine learning algorithms, which are known to usually be resource-demanding. To address the need for high computational power, one solution is to design custom hardware platforms dedicated to the specific application by exploiting, for example, Field Programmable Gate Array (FPGA). Recently, model-based techniques and automatic code generation have been introduced in FPGA design. In this paper, a new model-based floating-point accumulation circuit is presented. The architecture is based on the state-of-the-art delayed buffering algorithm. This circuit was conceived to be exploited in order to compute the kernel function of a support vector machine. The implementation of the proposed model was carried out in Simulink, and simulation results showed that it had better performance in terms of speed and occupied area when compared to other solutions. To better evaluate its figure, a practical case of a polynomial kernel function was considered. Simulink and VHDL post-implementation timing simulations and measurements on FPGA confirmed the good results of the stand-alone accumulator.

5.
Neurol Sci ; 41(6): 1489-1496, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31953702

RESUMO

Cognitive impairment is common in multiple sclerosis (MS), and research has emphasized the crucial role of cognitive assessment in disease monitoring. The minimal neuropsychological assessment of MS (MACFIMS) represents one of the neuropsychological batteries most widely used throughout the world. To date, a complete validation, as well as normative values of an alternative form, is lacking in the Italian population, limiting the use of this tool in longitudinal assessment. A total of 200 healthy subjects (127 females and 73 males) were recruited from the community in 8 Italian cities and were evaluated with the MACFIMS at baseline and reassessed with an alternate form of the same battery after 12 months. Regression-based norms that account for demographic influences on test performance were calculated at each time point (baseline and follow-up). The study provides, for the first time, normative values of two forms of the MACFIMS battery for the Italian population. Data application allows clinicians to monitor the performance of cognitive functions over time and to better understand the efficacy of both pharmacological and non-pharmacological interventions in clinical practice and research.

6.
J Nephrol ; 33(2): 371-381, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31583535

RESUMO

INTRODUCTION: We assessed the effect of recipient body mass index (BMI) on the outcomes of renal transplantation and the management of obese patients with end-stage renal disease across the UK. METHODS: We analyzed data of 25539 adult renal transplants (2007-2016) from the UK Transplant Registry. Patients were divided in BMI groups [underweight: < 18.5, normal: 18.5-24.9 (reference group), overweight: 25-29.9, class I obese: 30-34.9, class II/III obese: ≥ 35]. We also conducted a national survey of all UK renal transplant centers on the influence of BMI on decisions regarding management of renal transplant candidates. RESULTS: BMI ≥ 25 was an independent risk factor for delayed graft function and primary non-function (p ≤ 0.001). Underweight (p = 0.001), class I obese (p = 0.017) and class II/III obese recipients (p < 0.001) had poorer graft survival, however, 5- and 10-year graft survival rates were good. Patient survival was shorter for underweight recipients (p < 0.001) and longer for overweight (p = 0.028) and class I obese recipients (p = 0.013). The national survey revealed significant variability among transplant centers in BMI threshold for listing patients on transplant waiting list and limited support with conservative or surgical procedures for weight control. CONCLUSIONS: Obesity alone should not be a barrier for renal transplantation. A national strategy is required to give all patients equal chances in transplantation.

7.
Front Immunol ; 10: 319, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930889

RESUMO

Recent immunotherapeutic approaches using adoptive cell therapy, or checkpoint blockade, have demonstrated the powerful anti-cancer potential of CD8 cytotoxic T-lymphocytes (CTL). While these approaches have shown great promise, they are only effective in some patients with some cancers. The potential power, and relative ease, of therapeutic vaccination against tumour associated antigens (TAA) present in different cancers has been a long sought-after approach for harnessing the discriminating sensitivity of CTL to treat cancer and has seen recent renewed interest following cancer vaccination successes using unique tumour neoantigens. Unfortunately, results with TAA-targeted "universal" cancer vaccines (UCV) have been largely disappointing. Infectious disease models have demonstrated that T-cell clonotypes that recognise the same antigen should not be viewed as being equally effective. Extrapolation of this notion to UCV would suggest that the quality of response in terms of the T-cell receptor (TCR) clonotypes induced might be more important than the quantity of the response. Unfortunately, there is little opportunity to assess the effectiveness of individual T-cell clonotypes in vivo. Here, we identified effective, persistent T-cell clonotypes in an HLA A2+ patient following successful tumour infiltrating lymphocyte (TIL) therapy. One such T-cell clone was used to generate super-agonist altered peptide ligands (APLs). Further refinement produced an APL that was capable of inducing T-cells in greater magnitude, and with improved effectiveness, from the blood of all 14 healthy donors tested. Importantly, this APL also induced T-cells from melanoma patient blood that exhibited superior recognition of the patient's own tumour compared to those induced by the natural antigen sequence. These results suggest that use of APL to skew the clonotypic quality of T-cells induced by cancer vaccination could provide a promising avenue in the hunt for the UCV "magic bullet."


Assuntos
Linfócitos T CD8-Positivos/imunologia , Melanoma/imunologia , Peptídeos/imunologia , Linfócitos T Citotóxicos/imunologia , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Antígeno HLA-A2/imunologia , Humanos , Imunoterapia Adotiva/métodos , Linfócitos do Interstício Tumoral/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
8.
J Heart Lung Transplant ; 38(6): 658-667, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30846234

RESUMO

BACKGROUND: We systematically analyzed the synergistic effect of: (i) cytokine-mediated inflammatory activation of endothelial cells (ECs) with and (ii) shear-mediated platelet activation (SMPA) as a potential contributory mechanism to intraventricular thrombus formation in the setting of left ventricular assist device (LVAD) support. METHODS: Intact and shear-activated human platelets were exposed to non-activated and cytokine-activated ECs. To modulate the level of LVAD-related shear activation, platelets were exposed to shear stress patterns of varying magnitude (30, 50, and 70 dynes/cm2, 10 minutes) via a hemodynamic shearing device. ECs were activated via exposure to inflammatory tumor necrosis factor-α (TNF-α 10 and 100 ng/ml, 24 hours), consistent with inflammatory activation recorded in patients on LVAD circulatory support. RESULTS: Adhesivity of shear-activated platelets to ECs was significantly higher than that of intact/unactivated platelets, regardless of the initial activation level (70 dynes/cm2 shear-activated platelets vs intact platelets: +80%, p < 0.001). Importantly, inflammatory activation of ECs amplified platelet prothrombinase activity progressively with increasing shear stress magnitude and TNF-α concentration: thrombin generation of 70 dynes/cm2 shear-activated platelets was 2.6-fold higher after exposure and adhesion to 100 ng/ml TNF-α‒activated ECs (p < 0.0001). CONCLUSIONS: We demonstrated synergistic effect of SMPA and cytokine-mediated EC inflammatory activation to enhance EC‒platelet adhesion and platelet prothrombotic function. These mechanisms may contribute to intraventricular thrombosis in the setting of mechanical circulatory support.


Assuntos
Células Endoteliais/fisiologia , Coração Auxiliar , Ativação Plaquetária/fisiologia , Trombose/etiologia , Fator de Necrose Tumoral alfa/farmacologia , Técnicas de Cultura de Células , Células Endoteliais/efeitos dos fármacos , Humanos , Ativação Plaquetária/efeitos dos fármacos , Resistência ao Cisalhamento , Estresse Mecânico
9.
Front Immunol ; 9: 674, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29696015

RESUMO

T-cell immunity is controlled by T cell receptor (TCR) binding to peptide major histocompatibility complexes (pMHCs). The nature of the interaction between these two proteins has been the subject of many investigations because of its central role in immunity against pathogens, cancer, in autoimmunity, and during organ transplant rejection. Crystal structures comparing unbound and pMHC-bound TCRs have revealed flexibility at the interaction interface, particularly from the perspective of the TCR. However, crystal structures represent only a snapshot of protein conformation that could be influenced through biologically irrelevant crystal lattice contacts and other factors. Here, we solved the structures of three unbound TCRs from multiple crystals. Superposition of identical TCR structures from different crystals revealed some conformation differences of up to 5 Å in individual complementarity determining region (CDR) loops that are similar to those that have previously been attributed to antigen engagement. We then used a combination of rigidity analysis and simulations of protein motion to reveal the theoretical potential of TCR CDR loop flexibility in unbound state. These simulations of protein motion support the notion that crystal structures may only offer an artifactual indication of TCR flexibility, influenced by crystallization conditions and crystal packing that is inconsistent with the theoretical potential of intrinsic TCR motions.


Assuntos
Regiões Determinantes de Complementaridade , Receptores de Antígenos de Linfócitos T/química , Simulação por Computador , Cristalização , Cristalografia por Raios X , Conformação Proteica
10.
Nat Commun ; 9(1): 1092, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29545564

RESUMO

Immunotherapy directed against private tumor neo-antigens derived from non-synonymous somatic mutations is a promising strategy of personalized cancer immunotherapy. However, feasibility in low mutational load tumor types remains unknown. Comprehensive and deep analysis of circulating and tumor-infiltrating lymphocytes (TILs) for neo-epitope specific CD8+ T cells has allowed prompt identification of oligoclonal and polyfunctional such cells from most immunotherapy-naive patients with advanced epithelial ovarian cancer studied. Neo-epitope recognition is discordant between circulating T cells and TILs, and is more likely to be found among TILs, which display higher functional avidity and unique TCRs with higher predicted affinity than their blood counterparts. Our results imply that identification of neo-epitope specific CD8+ T cells is achievable even in tumors with relatively low number of somatic mutations, and neo-epitope validation in TILs extends opportunities for mutanome-based personalized immunotherapies to such tumors.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Epitopos de Linfócito T/imunologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/terapia , Antígenos de Neoplasias/imunologia , Epitopos de Linfócito T/metabolismo , Feminino , Humanos , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias Ovarianas/imunologia , Receptores de Antígenos de Linfócitos T/genética
11.
J Immunol ; 200(7): 2263-2279, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29483360

RESUMO

Peptide-MHC (pMHC) multimers, usually used as streptavidin-based tetramers, have transformed the study of Ag-specific T cells by allowing direct detection, phenotyping, and enumeration within polyclonal T cell populations. These reagents are now a standard part of the immunology toolkit and have been used in many thousands of published studies. Unfortunately, the TCR-affinity threshold required for staining with standard pMHC multimer protocols is higher than that required for efficient T cell activation. This discrepancy makes it possible for pMHC multimer staining to miss fully functional T cells, especially where low-affinity TCRs predominate, such as in MHC class II-restricted responses or those directed against self-antigens. Several recent, somewhat alarming, reports indicate that pMHC staining might fail to detect the majority of functional T cells and have prompted suggestions that T cell immunology has become biased toward the type of cells amenable to detection with multimeric pMHC. We use several viral- and tumor-specific pMHC reagents to compare populations of human T cells stained by standard pMHC protocols and optimized protocols that we have developed. Our results confirm that optimized protocols recover greater populations of T cells that include fully functional T cell clonotypes that cannot be stained by regular pMHC-staining protocols. These results highlight the importance of using optimized procedures that include the use of protein kinase inhibitor and Ab cross-linking during staining to maximize the recovery of Ag-specific T cells and serve to further highlight that many previous quantifications of T cell responses with pMHC reagents are likely to have considerably underestimated the size of the relevant populations.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígeno HLA-A2/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Coloração e Rotulagem/métodos , Citomegalovirus/imunologia , Herpesvirus Humano 4/imunologia , Humanos , Ativação Linfocitária/imunologia , Melanoma/imunologia , Orthomyxoviridae/imunologia , Ligação Proteica/imunologia , Inibidores de Proteínas Quinases/metabolismo , Proteínas de Ligação a RNA/imunologia , Células Tumorais Cultivadas
12.
Clin Cancer Res ; 23(19): 5779-5788, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28679768

RESUMO

Purpose: Infusion of highly heterogeneous populations of autologous tumor-infiltrating lymphocytes (TIL) can result in tumor regression of exceptional duration. Initial tumor regression has been associated with persistence of tumor-specific TILs 1 month after infusion, but mechanisms leading to long-lived memory responses are currently unknown. Here, we studied the dynamics of bulk tumor-reactive CD8+ T-cell populations in patients with metastatic melanoma following treatment with TILs.Experimental Design: We analyzed the function and phenotype of tumor-reactive CD8+ T cells contained in serial blood samples of 16 patients treated with TILs.Results: Polyfunctional tumor-reactive CD8+ T cells accumulated over time in the peripheral lymphocyte pool. Combinatorial analysis of multiple surface markers (CD57, CD27, CD45RO, PD-1, and LAG-3) showed a unique differentiation pattern of polyfunctional tumor-reactive CD8+ T cells, with highly specific PD-1 upregulation early after infusion. The differentiation and functional status appeared largely stable for up to 1 year after infusion. Despite some degree of clonal diversification occurring in vivo within the bulk tumor-reactive CD8+ T cells, further analyses showed that CD8+ T cells specific for defined tumor antigens had similar differentiation status.Conclusions: We demonstrated that tumor-reactive CD8+ T-cell subsets that persist after TIL therapy are mostly polyfunctional, display a stable partially differentiated phenotype, and express high levels of PD-1. These partially differentiated PD-1+ polyfunctional TILs have a high capacity for persistence and may be susceptible to PD-L1/PD-L2-mediated inhibition. Clin Cancer Res; 23(19); 5779-88. ©2017 AACR.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Linfócitos do Interstício Tumoral/imunologia , Melanoma/terapia , Receptor de Morte Celular Programada 1/imunologia , Adulto , Idoso , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunoterapia Adotiva , Ativação Linfocitária/imunologia , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Proteína 2 Ligante de Morte Celular Programada 1/antagonistas & inibidores , Proteína 2 Ligante de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T
13.
J Vis Exp ; (120)2017 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-28287509

RESUMO

Human CD8+ cytotoxic T lymphocytes (CTLs) are known to play an important role in tumor control. In order to carry out this function, the cell surface-expressed T-cell receptor (TCR) must functionally recognize human leukocyte antigen (HLA)-restricted tumor-derived peptides (pHLA). However, we and others have shown that most TCRs bind sub-optimally to tumor antigens. Uncovering the molecular mechanisms that define this poor recognition could aid in the development of new targeted therapies that circumnavigate these shortcomings. Indeed, present therapies that lack this molecular understanding have not been universally effective. Here, we describe methods that we commonly employ in the laboratory to determine how the nature of the interaction between TCRs and pHLA governs T-cell functionality. These methods include the generation of soluble TCRs and pHLA and the use of these reagents for X-ray crystallography, biophysical analysis, and antigen-specific T-cell staining with pHLA multimers. Using these approaches and guided by structural analysis, it is possible to modify the interaction between TCRs and pHLA and to then test how these modifications impact T-cell antigen recognition. These findings have already helped to clarify the mechanism of T-cell recognition of a number of cancer antigens and could direct the development of altered peptides and modified TCRs for new cancer therapies.


Assuntos
Antígenos de Neoplasias/análise , Biofísica/métodos , Cristalografia por Raios X/métodos , Imunidade Celular , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Humanos , Neoplasias/diagnóstico
14.
Eur Child Adolesc Psychiatry ; 26(5): 549-557, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27844161

RESUMO

Researchers' interest have recently moved toward the identification of recurrent psychopathological profiles characterized by concurrent elevations on different behavioural and emotional traits. This new strategy turned to be useful in terms of diagnosis and outcome prediction. We used a person-centred statistical approach to examine whether different groups could be identified in a referred sample and in a general-population sample of children and adolescents, and we investigated their relation to DSM-IV diagnoses. A latent class analysis (LCA) was performed on the Child Behaviour Checklist (CBCL) syndrome scales of the referred sample (N = 1225), of the general-population sample (N = 3418), and of the total sample. Models estimating 1-class through 5-class solutions were compared and agreement in the classification of subjects was evaluated. Chi square analyses, a logistic regression, and a multinomial logistic regression analysis were used to investigate the relations between classes and diagnoses. In the two samples and in the total sample, the best-fitting models were 4-class solutions. The identified classes were Internalizing Problems (15.68%), Severe Dysregulated (7.82%), Attention/Hyperactivity (10.19%), and Low Problems (66.32%). Subsequent analyses indicated a significant relationship between diagnoses and classes as well as a main association between the severe dysregulated class and comorbidity. Our data suggested the presence of four different psychopathological profiles related to different outcomes in terms of psychopathological diagnoses. In particular, our results underline the presence of a profile characterized by severe emotional and behavioural dysregulation that is mostly associated with the presence of multiple diagnosis.


Assuntos
Sintomas Afetivos/diagnóstico , Transtornos do Comportamento Infantil/diagnóstico , Manual Diagnóstico e Estatístico de Transtornos Mentais , Comportamento Problema , Adolescente , Sintomas Afetivos/epidemiologia , Lista de Checagem , Criança , Transtornos do Comportamento Infantil/psicologia , Emoções , Feminino , Humanos , Modelos Logísticos , Masculino , Escalas de Graduação Psiquiátrica , Psicopatologia
15.
Radiology ; 280(1): 202-11, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26953867

RESUMO

Purpose To investigate thalamic connectivity changes after use of a video game-based cognitive rehabilitation program, as thalamic damage and alterations in thalamocortical functional connectivity (FC) are important factors in cognitive dysfunction in patients with multiple sclerosis (MS). Materials and Methods This prospective study was approved by the local ethical committee. Twenty-four patients with MS and cognitive impairment were randomly assigned to either an intervention or a wait-list group. Patients were evaluated with cognitive tests and 3-T resting-state functional magnetic resonance (MR) imaging at baseline and after an 8-week period. In addition, 11 healthy subjects underwent baseline resting-state functional MR imaging. Patients in the intervention group performed the video game-based cognitive rehabilitation program, while those in the wait-list group served as control subjects. Repeated measures analysis of variance was used to test efficacy of the intervention. The thalamic resting-state network was identified with a seed-based method; both first-level and high-level analyses were performed by using software tools. Results Patients showed lower baseline FC compared with healthy subjects. A significant improvement was seen in results of the Paced Auditory Serial Addition Test and the Stroop Test after 8 weeks of cognitive rehabilitation (F = 6.616, [P = .018] and F = 5.325 [P = .030], respectively). At follow-up, the intervention group had an increased FC in the cingulum, precuneus, and bilateral parietal cortex and a lower FC in the cerebellum and in left prefrontal cortex compared with the wait-list group (P < .05, family-wise error corrected); correlations were found between FC changes in these regions and cognitive improvement (P < .05, family-wise error corrected). Conclusion The results of this study show the relevance of thalamic regulation of the brain networks involved in cognition and suggest that changes in thalamic resting-state network connectivity may represent a functional substrate for cognitive improvement associated with a video game-based cognitive rehabilitation program. (©) RSNA, 2016.


Assuntos
Transtornos Cognitivos/complicações , Transtornos Cognitivos/reabilitação , Imagem por Ressonância Magnética/métodos , Esclerose Múltipla/complicações , Tálamo/diagnóstico por imagem , Jogos de Vídeo , Adulto , Transtornos Cognitivos/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/reabilitação , Testes Neuropsicológicos , Estudos Prospectivos , Descanso , Tálamo/fisiopatologia , Resultado do Tratamento
16.
Mult Scler ; 22(13): 1741-1749, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26869527

RESUMO

BACKGROUND: The study of cognitive reserve (CR) in relationship with cognitive impairment (CI) in pediatric-onset multiple sclerosis (POMS) may provide cues to identifying subjects at higher risk of impairment and scope for therapeutic strategies. OBJECTIVES: To assess the potential impact of CR on cognition in a cohort of POMS patients. METHODS: In all, 48 POMS patients were followed up for 4.7 ± 0.4 years. CI was defined as the failure of ⩾3 tests on an extensive neuropsychological battery. Change of neuropsychological performance was assessed through the Reliable Change Index (RCI) method. At baseline, CR was estimated by measuring the intelligence quotient (IQ). The relationships were assessed through multivariable regression analyses. RESULTS: At baseline, CI was detected in 14/48 (29.2%) patients. Two out of 57 healthy control (HC; 3.5%) met the same criteria of CI (p < 0.001). A deteriorating cognitive performance using the RCI method was observed in 18/48 patients (37.6%). Among the 34 cases who were cognitively preserved at baseline, a higher reserve predicted stable/improving performance (odds ratio (OR) = 1.11; 95% confidence interval (CI): 1.03-1.20; p = 0.006). CONCLUSION: Our results suggest that higher CR in POMS patients may protect from CI, particularly in subjects with initial cognitive preservation, providing relevant implications for counseling and rehabilitation strategies.


Assuntos
Disfunção Cognitiva/fisiopatologia , Reserva Cognitiva/fisiologia , Esclerose Múltipla/fisiopatologia , Adolescente , Idade de Início , Criança , Disfunção Cognitiva/etiologia , Feminino , Seguimentos , Humanos , Masculino , Esclerose Múltipla/complicações
17.
J Biol Chem ; 291(17): 8951-9, 2016 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-26917722

RESUMO

Human CD8(+) cytotoxic T lymphocytes can mediate tumor regression in melanoma through the specific recognition of HLA-restricted peptides. Because of the relatively weak affinity of most anti-cancer T-cell receptors (TCRs), there is growing emphasis on immunizing melanoma patients with altered peptide ligands in order to induce strong anti-tumor immunity capable of breaking tolerance toward these self-antigens. However, previous studies have shown that these immunogenic designer peptides are not always effective. The melanocyte differentiation protein, glycoprotein 100 (gp100), encodes a naturally processed epitope that is an attractive target for melanoma immunotherapies, in particular peptide-based vaccines. Previous studies have shown that substitutions at peptide residue Glu(3) have a broad negative impact on polyclonal T-cell responses. Here, we describe the first atomic structure of a natural cognate TCR in complex with this gp100 epitope and highlight the relatively high affinity of the interaction. Alanine scan mutagenesis performed across the gp100(280-288) peptide showed that Glu(3) was critically important for TCR binding. Unexpectedly, structural analysis demonstrated that the Glu(3) → Ala substitution resulted in a molecular switch that was transmitted to adjacent residues, abrogating TCR binding and T-cell recognition. These findings help to clarify the mechanism of T-cell recognition of gp100 during melanoma responses and could direct the development of altered peptides for vaccination.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Melanoma/imunologia , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/imunologia , Antígeno gp100 de Melanoma/química , Antígeno gp100 de Melanoma/imunologia , Linfócitos T CD8-Positivos/patologia , Humanos , Melanoma/genética , Melanoma/patologia , Estrutura Quaternária de Proteína , Receptores de Antígenos de Linfócitos T/genética , Antígeno gp100 de Melanoma/genética
18.
J Affect Disord ; 190: 576-584, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26583347

RESUMO

BACKGROUND: Two different polymorphisms (TPH2 G-703T and 5-HTTLPR) involved in the serotonergic pathway have been reported to play a role, both alone and in interaction with the environment, in early and adult emotion regulation. As most of these studies are cross-sectional, we know little about the impact of these polymorphisms over time, particularly during adolescence. METHODS: Because we were interested in the effects of these polymorphisms and environment (i.e., family structure) at different time-points on the emotional dysregulation profile, we performed a path analysis model in a general adolescent population sample of a five-year follow-up study. RESULTS: We found a high stability of Dysregulation Profile problems independently from the examined allelic variants. We also found that early family structure directly influences the levels of dysregulation problems in early adolescence, both alone and in interaction with TPH2, suggesting the presence of a gene-environment interaction effect. Furthermore, we found that in adolescents homozygous for the TPH2 G allele, the effect of the early family structure remains active during late adolescence, albeit mediated by earlier emotional problems. LIMITATIONS: The high attrition rate, the use of only one source on behavioral problems of adolescents, and the focus on a single polymorphism in the investigated genes could limit the generalizability of the present results. CONCLUSIONS: These results suggest that early family structure could play a significant role in the development and maintenance of emotional and behavioral problems not only in early adolescence but also in late-adolescence, although this effect was mediated and moderated by behavioral and genetic variables.


Assuntos
Sintomas Afetivos/genética , Relações Familiares/psicologia , Interação Gene-Ambiente , Triptofano Hidroxilase/genética , Adolescente , Alelos , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto Jovem
19.
Stud Health Technol Inform ; 217: 282-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26294485

RESUMO

As the average age of the EU population increases, ICT solutions are going to play a key role in order to find answers to the new challenges the demographic change is carrying on. At the University of Parma an AAL (Ambient Assisted Living) system named CARDEA has been developed during the last 10 years. Within CARDEA, behavioral analysis is carried out, based on environmental sensors. If multiple users live in the same environment, however, data coming from sensors need to be properly tagged: in this paper, a simple technique for such tagging is proposed, which exploits the same wireless transmission used for transmitting data, thus not requiring additional hardware components and avoiding more complex and expensive (radio)localization techniques. Preliminary results are shown, featuring a satisfactory accuracy.


Assuntos
Atividades Cotidianas , Moradias Assistidas , Atividades Cotidianas/psicologia , Comportamento , Meio Ambiente , Planejamento Ambiental , Habitação para Idosos , Humanos , Equipamentos de Autoajuda , Tecnologia sem Fio
20.
Immunology ; 146(1): 11-22, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26076649

RESUMO

Analysis of antigen-specific T-cell populations by flow cytometry with peptide-MHC (pMHC) multimers is now commonplace. These reagents allow the tracking and phenotyping of T cells during infection, autoimmunity and cancer, and can be particularly revealing when used for monitoring therapeutic interventions. In 2009, we reviewed a number of 'tricks' that could be used to improve this powerful technology. More recent advances have demonstrated the potential benefits of using higher order multimers and of 'boosting' staining by inclusion of an antibody against the pMHC multimer. These developments now allow staining of T cells where the interaction between the pMHC and the T-cell receptor is over 20-fold weaker (K(D) > 1 mm) than could previously be achieved. Such improvements are particularly relevant when using pMHC multimers to stain anti-cancer or autoimmune T-cell populations, which tend to bear lower affinity T-cell receptors. Here, we update our previous work to include discussion of newer tricks that can produce substantially brighter staining even when using log-fold lower concentrations of pMHC multimer. We further provide a practical guide to using pMHC multimers that includes a description of several common pitfalls and how to circumvent them.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Coloração e Rotulagem/métodos , Anticorpos/imunologia , Linfócitos T CD8-Positivos/citologia , Citometria de Fluxo/métodos , Corantes Fluorescentes , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Peptídeos/imunologia , Multimerização Proteica
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