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Cysteine-altering missense variants (NOTCH3cys) in one of the 34 epidermal growth-factor-like repeat (EGFr) domains of the NOTCH3 protein are the cause of NOTCH3-associated small vessel disease (NOTCH3-SVD). NOTCH3-SVD is highly variable, ranging from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) at the severe end of the spectrum to non-penetrance. The strongest known NOTCH3-SVD modifier is NOTCH3cys variant position: NOTCH3cys variants located in EGFr domains 1-6 are associated with a more severe phenotype than NOTCH3cys variants located in EGFr domains 7-34. The objective of this study was to further improve NOTCH3-SVD genotype-based risk prediction by using relative differences in NOTCH3cys variant frequencies between large CADASIL and population cohorts as a starting point. Scientific CADASIL literature, cohorts and population databases were queried for NOTCH3cys variants. For each EGFr domain, the relative difference in NOTCH3cys variant frequency (NVFOR) was calculated using genotypes of 2574 CADASIL patients and 1647 individuals from population databases. Based on NVFOR cut-off values, EGFr domains were classified as either low (LR-EGFr), medium (MR-EGFr) or high risk (HR-EGFr). The clinical relevance of this new three-tiered EGFr risk classification was cross-sectionally validated by comparing SVD imaging markers and clinical outcomes between EGFr risk categories using a genotype-phenotype data set of 434 CADASIL patients and 1003 NOTCH3cys positive community-dwelling individuals. CADASIL patients and community-dwelling individuals harboured 379 unique NOTCH3cys variants. Nine EGFr domains were classified as an HR-EGFr, which included EGFr domains 1-6, but additionally also EGFr domains 8, 11 and 26. Ten EGFr domains were classified as MR-EGFr and 11 as LR-EGFr. In the population genotype-phenotype data set, HR-EGFr individuals had the highest risk of stroke [odds ratio (OR) = 10.81, 95% confidence interval (CI): 5.46-21.37], followed by MR-EGFr individuals (OR = 1.81, 95% CI: 0.84-3.88) and LR-EGFr individuals (OR = 1 [reference]). MR-EGFr individuals had a significantly higher normalized white matter hyperintensity volume (nWMHv; P = 0.005) and peak width of skeletonized mean diffusivity (PSMD; P = 0.035) than LR-EGFr individuals. In the CADASIL genotype-phenotype data set, HR-EGFr domains 8, 11 and 26 patients had a significantly higher risk of stroke (P = 0.002), disability (P = 0.041), nWMHv (P = 1.8 × 10-8), PSMD (P = 2.6 × 10-8) and lacune volume (P = 0.006) than MR-EGFr patients. SVD imaging marker load and clinical outcomes were similar between HR-EGFr 1-6 patients and HR-EGFr 8, 11 and 26 patients. NVFOR was significantly associated with vascular NOTCH3 aggregation load (P = 0.006), but not with NOTCH3 signalling activity (P = 0.88). In conclusion, we identified three clinically distinct NOTCH3-SVD EGFr risk categories based on NFVOR cut-off values, and identified three additional HR-EGFr domains located outside of EGFr domains 1-6. This EGFr risk classification will provide an important key to individualized NOTCH3-SVD disease prediction.
Assuntos
CADASIL , Acidente Vascular Cerebral , Humanos , Receptor Notch3/genética , CADASIL/diagnóstico por imagem , CADASIL/genética , Fator de Crescimento Epidérmico/genética , Imageamento por Ressonância Magnética , Acidente Vascular Cerebral/genética , Medição de Risco , Receptores Notch/genética , Receptores Notch/metabolismo , Mutação/genéticaRESUMO
Despite the growing interest in gender medicine, the influence of sex and gender on human diseases, including stroke, continues to be underestimated and understudied. The COVID-19 pandemic has overall impacted not only the occurrence and management of stroke but has also exacerbated sex and gender disparities among both patients and healthcare providers. This paper aims to provide an updated overview on the influence of sex and gender in stroke pathophysiology and care during COVID-19 pandemic, through biological, clinical, psychosocial and research perspectives. Gender equity and awareness of the importance of sexual differences are sorely needed, especially in times of health crisis but have not yet been achieved to date. To this purpose, the sudden yet worldwide diffusion of COVID-19 represents a unique learning experience that highlights critical unmet needs also in gender medicine. The failures of this recent past should be kept as food for thought to inspire proper strategies reducing inequalities and to address women's health and wellbeing issues, particularly in case of future pandemics.
RESUMO
Dysfunctions of lipid metabolism are associated with tumor progression and treatment resistance of cutaneous melanoma. BRAF/MEK inhibitor resistance is linked to alterations of melanoma lipid pathways. We evaluated whether a specific lipid pattern characterizes plasma from melanoma patients and their response to therapy. Plasma samples from patients and controls were analyzed for FASN and DHCR24 levels and lipidomic profiles. FASN and DHCR24 expression resulted in association with disease condition and related to plasma cholesterol and triglycerides in patients at different disease stages (n = 144) as compared to controls (n = 115). Untargeted lipidomics in plasma (n = 40) from advanced disease patients and controls revealed altered levels of different lipids, including fatty acid derivatives and sphingolipids. Targeted lipidomics identified higher levels of dihydroceramides, ceramides, sphingomyelins, ganglioside GM3, sphingosine, sphingosine-1-phosphate, and dihydrosphingosine, saturated and unsaturated fatty acids. When melanoma patients were stratified based on a long/short-term clinical response to kinase inhibitors, differences in plasma levels were shown for saturated fatty acids (FA 16:0, FA18:0) and oleic acid (FA18:1). Our results associated altered levels of selected lipid species in plasma of melanoma patients with a more favorable prognosis. Although obtained in a small cohort, these results pave the way to lipidomic profiling for melanoma patient stratification.
Assuntos
Melanoma , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Ácidos Graxos/metabolismo , Esfingolipídeos , TriglicerídeosRESUMO
Stroke is among the most prevalent causes of disability and is the second leading cause of death worldwide in Western countries [...].
Assuntos
Pessoas com Deficiência , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/terapia , Previsões , Saúde GlobalRESUMO
Stroke remains a major cause of death and disability worldwide. Identifying new circulating biomarkers able to distinguish and monitor common and rare cerebrovascular diseases that lead to stroke is of great importance. Biomarkers provide complementary information that may improve diagnosis, prognosis and prediction of progression as well. Furthermore, biomarkers can contribute to filling the gap in knowledge concerning the underlying disease mechanisms by pointing out novel potential therapeutic targets for personalized medicine. If many "conventional" lipid biomarkers are already known to exert a relevant role in cerebrovascular diseases, the aim of our study is to review novel "unconventional" lipid biomarkers that have been recently identified in common and rare cerebrovascular disorders using novel, cutting-edge lipidomic approaches.
Assuntos
Transtornos Cerebrovasculares , Acidente Vascular Cerebral , Humanos , Lipidômica , Transtornos Cerebrovasculares/diagnóstico , Biomarcadores , Doenças Raras , LipídeosRESUMO
Moyamoya arteriopathy (MMA) is a rare cerebrovascular disorder that causes recurrent ischemic and hemorrhagic strokes, leading young patients to severe neurological deficits. The pathogenesis of MMA is still unknown. The disease onset in a wide number of pediatric cases raises the question of the role of genetic factors in the disease's pathogenesis. In these patients, MMA's clinical course, or progression, is largely unclear. By performing a comprehensive molecular and cellular profile in the plasma and CSF, respectively, of MMA pediatric patients, our study is aimed at assessing the levels of circulating endothelial progenitor cells (cEPC) and the release of selected proteins at an early disease stage to clarify MMA pathogenesis and progression. We employed cytofluorimetric methods and immunoassays in pediatric MMA patients and matched control subjects by age and sex. We detected increased levels of cEPC in peripheral blood and an upregulation of angiogenic markers in CSF (i.e., angiopoietin-2 and VEGF-A). This finding is probably associated with deregulated angiogenesis, as stated by the moderate severity of collateral vessel network development (Suzuki III-IV). The absence of significant modulation of neurofilament light in CSF led us to rule out the presence of substantial neuronal injury in MMA children. Despite the limited cohort of pediatric patients, we found some peculiar cellular and molecular characteristics in their blood and CSF samples. Our findings may be confirmed by wider and perspective studies to identify predictive or prognostic circulating biomarkers and potential therapeutic targets for personalized care of MMA pediatric patients.
Assuntos
Células Progenitoras Endoteliais , Acidente Vascular Cerebral Hemorrágico , Doença de Moyamoya , Humanos , Criança , Células Progenitoras Endoteliais/patologia , Doença de Moyamoya/patologiaRESUMO
Moyamoya angiopathy (MMA) is an uncommon cerebrovascular disease characterized by a progressive steno-occlusive lesion of the internal carotid artery and the compensatory development of an unstable network of collateral vessels. These vascular hallmarks are responsible for recurrent ischemic/hemorrhagic strokes. Surgical treatment represents the preferred procedure for MMA patients, and indirect revascularization may induce a spontaneous angiogenesis between the brain surface and dura mater (DM), whose function remains rather unknown. A better understanding of MMA pathogenesis is expected from the molecular characterization of DM. We performed a comprehensive, label-free, quantitative mass spectrometry-based proteomic characterization of DM. The 30 most abundant identified proteins were located in the extracellular region or exosomes and were involved in extracellular matrix organization. Gene ontology analysis revealed that most proteins were involved in binding functions and hydrolase activity. Among the 30 most abundant proteins, Filamin A is particularly relevant because considering its well-known biochemical functions and molecular features, it could be a possible second hit gene with a potential role in MMA pathogenesis. The current explorative study could pave the way for further analyses aimed at better understanding such uncommon and disabling intracranial vasculopathy.
Assuntos
Transtornos Cerebrovasculares , Doença de Moyamoya , Humanos , Proteoma , Proteômica , Doença de Moyamoya/genética , Transtornos Cerebrovasculares/complicações , Dura-MáterRESUMO
The aim of this Special Issue was to update readers regarding state-of-the-art research into lipid metabolism and signaling in tumors and cerebrovascular diseases [...].
Assuntos
Transtornos Cerebrovasculares , Neoplasias , Humanos , Metabolismo dos Lipídeos , Transdução de SinaisRESUMO
Ring Finger Protein 213 (RNF213), also known as Mysterin, is the major susceptibility factor for Moyamoya Arteriopathy (MA), a progressive cerebrovascular disorder that often leads to brain stroke in adults and children. Although several rare RNF213 polymorphisms have been reported, no major susceptibility variant has been identified to date in Caucasian patients, thus frustrating the attempts to identify putative therapeutic targets for MA treatment. For these reasons, the investigation of novel biochemical functions, substrates and unknown partners of RNF213 will help to unravel the pathogenic mechanisms of MA and will facilitate variant interpretations in a diagnostic context in the future. The aim of the present review is to discuss novel perspectives regarding emerging RNF213 roles in light of recent literature updates and dissect their relevance for understanding MA and for the design of future research studies. Since its identification, RNF213 involvement in angiogenesis and vasculogenesis has strengthened, together with its role in inflammatory signals and proliferation pathways. Most recent studies have been increasingly focused on its relevance in antimicrobial activity and lipid metabolism, highlighting new intriguing perspectives. The last area could suggest the main role of RNF213 in the proteasome pathway, thus reinforcing the hypotheses already previously formulated that depict the protein as an important regulator of the stability of client proteins involved in angiogenesis. We believe that the novel evidence reviewed here may contribute to untangling the complex and still obscure pathogenesis of MA that is reflected in the lack of therapies able to slow down or halt disease progression and severity.
Assuntos
Adenosina Trifosfatases , Doença de Moyamoya , Adenosina Trifosfatases/metabolismo , Adulto , Criança , Predisposição Genética para Doença , Humanos , Doença de Moyamoya/patologia , Fatores de Transcrição , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Peripheral nerve sheath tumors (PNSTs) include schwannomas, neurofibromas (NFs), and plexiform neurofibromas (PNFs), among others. While they are benign tumors, according to their biological behavior, some have the potential for malignant degeneration, mainly PNFs. The specific factors contributing to the more aggressive behavior of some PNSTs compared to others are not precisely known. Considering that lipid homeostasis plays a crucial role in fibrotic/inflammatory processes and in several cancers, we hypothesized that the lipid asset was also unbalanced in this group of nerve tumors. Through untargeted lipidomics, NFs presented a significant increase in ceramide, phosphatidylcholine, and Vitamin A ester. PNFs displayed a marked decrease in 34 out of 50 lipid class analyzed. An increased level of ether- and oxidized-triacylglycerols was observed; phosphatidylcholines were reduced. After sphingolipidomic analysis, we observed six sphingolipid classes. Ceramide and dihydroceramides were statistically increased in NFs. All the glycosylated species appeared reduced in NFs, but increased in PNFs. Our findings suggested that different subtypes of PNSTs presented a specific modulation in the lipidic profile. The untargeted and targeted lipidomic approaches, which were not applied until now, contribute to better clarifying bioactive lipid roles in PNS natural history to highlight disease molecular features and pathogenesis.
Assuntos
Lipídeos/fisiologia , Neoplasias de Bainha Neural/metabolismo , Neoplasias de Bainha Neural/patologia , Adulto , Idoso , Feminino , Homeostase/fisiologia , Humanos , Lipidômica/métodos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Moyamoya arteriopathy (MA) is a rare cerebrovascular disorder characterized by ischemic/hemorrhagic strokes. The pathophysiology is unknown. A deregulation of vasculogenic/angiogenic/inflammatory pathways has been hypothesized as a possible pathophysiological mechanism. Since lipids are implicated in modulating neo-vascularization/angiogenesis and inflammation, their deregulation is potentially involved in MA. Our aim is to evaluate angiogenic/vasculogenic/inflammatory proteins and lipid profile in plasma of MA patients and control subjects (healthy donors HD or subjects with atherosclerotic cerebrovascular disease ACVD). Angiogenic and inflammatory protein levels were measured by ELISA and a complete lipidomic analysis was performed on plasma by mass spectrometry. ELISA showed a significant decrease for MMP-9 released in plasma of MA. The untargeted lipidomic analysis showed a cumulative depletion of lipid asset in plasma of MA as compared to HD. Specifically, a decrease in membrane complex glycosphingolipids peripherally circulating in MA plasma with respect to HD was observed, likely suggestive of cerebral cellular recruitment. The quantitative targeted approach demonstrated an increase in free sphingoid bases, likely associated with a deregulated angiogenesis. Our findings indicate that lipid signature could play a central role in MA and that a detailed biomarker profile may contribute to untangle the complex, and still obscure, pathogenesis of MA.
Assuntos
Lipídeos/sangue , Doença de Moyamoya/sangue , Doenças Vasculares/sangue , Biomarcadores/sangue , Feminino , Humanos , Inflamação/sangue , Arteriosclerose Intracraniana/sangue , Lipidômica/métodos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/sangueRESUMO
Cerebral amyloid angiopathy (CAA) is one of the major types of cerebral small vessel disease, and a leading cause of spontaneous intracerebral hemorrhage and cognitive decline in elderly patients. Although increasingly detected, a number of aspects including the pathophysiology, the clinical and neuroradiological phenotype, and the disease course are still under investigation. The incomplete knowledge of the disease limits the implementation of evidence-based guidelines on patient's clinical management and the development of treatments able to prevent or reduce disease progression. The SENECA (SEarchiNg biomarkErs of Cerebral Angiopathy) project is the first Italian multicenter cohort study aimed at better defining the disease natural history and identifying clinical and neuroradiological markers of disease progression. By a multidisciplinary approach and the collection of a large and well-phenotyped series and biorepository of CAA patients, the study is ultimately expected to improve the diagnosis and the knowledge of CAA pathophysiological mechanisms.
Assuntos
Angiopatia Amiloide Cerebral , Idoso , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/terapia , Hemorragia Cerebral , Estudos de Coortes , Humanos , Itália , Imageamento por Ressonância Magnética , FenótipoRESUMO
Cerebral amyloid angiopathy (CAA), one of the main types of cerebral small vessel disease, is a major cause of spontaneous intracerebral haemorrhage and an important contributor to cognitive decline in elderly patients. Despite the number of experimental in vitro studies and animal models, the pathophysiology of CAA is still largely unknown. Although several pathogenic mechanisms including an unbalance between production and clearance of amyloid beta (Aß) protein as well as 'the prion hypothesis' have been invoked as possible disease triggers, they do not explain completely the disease pathogenesis. This incomplete disease knowledge limits the implementation of treatments able to prevent or halt the clinical progression. The continuous increase of CAA patients makes imperative the development of suitable experimental in vitro or animal models to identify disease biomarkers and new pharmacological treatments that could be administered in the early disease stages to prevent irreversible changes and disease progression.
Assuntos
Peptídeos beta-Amiloides/genética , Angiopatia Amiloide Cerebral/genética , Doenças de Pequenos Vasos Cerebrais/genética , Disfunção Cognitiva/genética , Animais , Biomarcadores/sangue , Angiopatia Amiloide Cerebral/sangue , Angiopatia Amiloide Cerebral/patologia , Hemorragia Cerebral/genética , Hemorragia Cerebral/patologia , Doenças de Pequenos Vasos Cerebrais/sangue , Doenças de Pequenos Vasos Cerebrais/patologia , Disfunção Cognitiva/sangue , Disfunção Cognitiva/patologia , Progressão da Doença , Humanos , Modelos Animais , Proteínas Priônicas/genéticaRESUMO
The pathophysiological mechanisms of Moyamoya angiopathy (MA), which is a rare cerebrovascular condition characterized by recurrent ischemic/hemorrhagic strokes, are still largely unknown. An imbalance of vasculogenic/angiogenic mechanisms has been proposed as one possible disease aspect. Circulating endothelial progenitor cells (cEPCs) have been hypothesized to contribute to vascular remodeling of MA, but it remains unclear whether they might be considered a disease effect or have a role in disease pathogenesis. The aim of the present study was to provide a morphological, phenotypical, and functional characterization of the cEPCs from MA patients to uncover their role in the disease pathophysiology. cEPCs were identified from whole blood as CD45dimCD34+CD133+ mononuclear cells. Morphological, biochemical, and functional assays were performed to characterize cEPCs. A significant reduced level of cEPCs was found in blood samples collected from a homogeneous group of adult (mean age 46.86 ± 11.7; 86.36% females), Caucasian, non-operated MA patients with respect to healthy donors (HD; p = 0.032). Since no difference in cEPC characteristics and functionality was observed between MA patients and HD, a defective recruitment mechanism could be involved in the disease pathophysiology. Collectively, our results suggest that cEPC level more than endothelial progenitor cell (EPC) functionality seems to be a potential marker of MA. The validation of our results on a larger population and the correlation with clinical data as well as the use of more complex cellular model could help our understanding of EPC role in MA pathophysiology.
Assuntos
Células Endoteliais/patologia , Leucócitos Mononucleares/patologia , Doença de Moyamoya/fisiopatologia , Remodelação Vascular , Adulto , Biomarcadores/sangue , Contagem de Células , Criança , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Doença de Moyamoya/sangue , Doença de Moyamoya/genética , Neovascularização Fisiológica , Comunicação Parácrina , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Remodelação Vascular/genéticaRESUMO
Functional connectivity during cooperative actions is an important topic in social neuroscience that has yet to be answered. Here, we examined the effects of administration of (fictitious) negative social feedback in relation to cooperative capabilities. Cognitive performance and neural activation underlying the execution of joint actions was recorded with functional near-infrared spectroscopy (fNIRS) on prefrontal regions during a task where pairs of participants received negative feedback after their joint action. Performance (error rates (ERs) and response times (RTs)) and intra- and inter-brain connectivity indices were computed, along with the ConIndex (inter-brain/intra-brain connectivity). Finally, correlational measures were considered to assess the relation between these different measures. Results showed that the negative feedback was able to modulate participants' responses for both behavioral and neural components. Cognitive performance was decreased after the feedback. Moreover, decreased inter-brain connectivity and increased intra-brain connectivity was induced by the feedback, whereas the cooperative task pre-feedback condition was able to increase the brain-to-brain coupling, mainly localized within the dorsolateral prefrontal cortex (DLPFC). Finally, the presence of significant correlations between RTs and inter-brain connectivity revealed that ineffective joint action produces the worst cognitive performance and a more 'individual strategy' for brain activity, limiting the inter-brain connectivity. The present study provides a significant contribution to the identification of patterns of intra- and inter-brain functional connectivity when negative social reinforcement is provided in relation to cooperative actions.
Assuntos
Encéfalo/fisiologia , Comportamento Cooperativo , Adulto , Atenção/fisiologia , Mapeamento Encefálico/métodos , Feminino , Humanos , Relações Interpessoais , Masculino , Tempo de Reação/fisiologia , Espectroscopia de Luz Próxima ao Infravermelho , Adulto JovemRESUMO
Cooperation behavior is a core question of study on social neuroscience. In the present study, inter-brain functional connectivity and cognitive performance were considered during joint which was failing. The cognitive performance and the EEG (brain oscillations from delta to beta) underlying the execution of joint-actions were recorded when dyads of participants executed synchronicity game and received reinforcing negative feedbacks A pre-feedback condition (cooperation) and a control condition (individual task, T0) were provided as well as a check for possible learning effect (time series analysis). Finally, correlation analysis was considered to assess the relation between behavioral and physiological levels. Results showed that the external feedback was able to modulate participants' responses in both behavioral and neural components with increased RTs and ERs after the negative reinforcement. Similarly, a reduced inter-brain connectivity was found, mainly localized within the superior frontal regions, and for low-frequency bands (delta and theta). In contrast pre-feedback condition showed the best performance in terms of both behavioral and brain-to-brain coupling activity. Moreover, the presence of significant correlations between RTs and inter-brain connectivity revealed that the failing cooperation induces significant negative effects on the cognitive and brain strategy in comparison with cooperative (pre-feedback) and individual (control) condition. The present study provides significant contribution to the identification of patterns of cognitive behavior and functional connectivity when social reinforcement is provided within dyads of participants by using a hyperscanning approach.
Assuntos
Atenção/fisiologia , Mapeamento Encefálico/métodos , Ondas Encefálicas/fisiologia , Córtex Cerebral/fisiologia , Comportamento Cooperativo , Eletroencefalografia/métodos , Retroalimentação Psicológica/fisiologia , Desempenho Psicomotor/fisiologia , Percepção Visual/fisiologia , Adulto , Feminino , Humanos , Masculino , Tempo de Reação/fisiologia , Reforço Psicológico , Adulto JovemRESUMO
PURPOSE: Human life is connoted by sophisticated interactions that involve not only single individuals, but larger social groups composed by members interacting each other. Cooperation secures a benefit to all the people engaged as well as important behaviors like helping, sharing, and acting prosocially. But what happens when the joint actions are not effective? MATERIALS AND METHOD: In the present study, we asked 24 participants paired in 12 dyads to cooperate during an attentional task in a way to synchronize their responses and obtain better outcomes. In addition we tested inter-brain and cognitive strategy similarities between subjects. Then, we frustrated their strategies by providing false feedbacks signalling the incapacity to create a synergy, which was reinforced by a general negative evaluation halfway through the task. The effects of the feedback inmodulating subjects behavioural performance and brain responsiveness were explored by means of functional near-infrared spectroscopy (fNIRS). RESULTS: Results showed a worsen performance after the negative feedback in the form of longer reaction times and a specifc pattern of brain activation involving th dorsolateral prefrontal cortex (DLPFC) and the superior frontal gyrus. The DLPFC showed increased O2Hb (oxy-haemoglobin) level after the feedback, compatible with the need for higher cognitive effort. In addition, fNIRS measures revealed a decreased inter-brain synchronicity in post-feedback condition for the dyad. Also, the representation of negative emotions in response to failing interactions was signalled by a right-lateralized effect. CONCLUSIONS: Results were interpreted at light of available knowledge on perceived self-efficacy and the implementation of common goals and strategies.
Assuntos
Encéfalo/diagnóstico por imagem , Comportamento Cooperativo , Frustração , Relações Interpessoais , Adulto , Mapeamento Encefálico , Feminino , Humanos , Masculino , Tempo de Reação/fisiologia , Autoeficácia , Espectroscopia de Luz Próxima ao Infravermelho , Adulto JovemRESUMO
Previous work showed that, when we interact with other people, an alignment of psychophysiological measures occur as a clue about the intensity of the social interaction. Available evidence highlighted increase autonomic synchrony, known as physiological linkage, during intense dyadic situations, like conflictual conversations within romantic couples, friends, or therapeutic settings. Starting from the idea that higher physiological linkage could support better performance and be correlated with approach attitudes (Behavioral Activation System, BAS), in the present study a conflictual situation was proposed by making subjects compete during an attentional task and stressing the importance to win as a measure of future professional success. Autonomic activity (electrodermal: skin conductance level and response: SCL, SCR; and cardiovascular indices: heart rate: HR) was recorded during the task, where subjects received trial-related feedbacks on their performance, and an average score halfway which (fictitiously) assessed their position in terms of accuracy and reaction times with respect to the opponent. In parallel, behavioral inhibition and activation have been assessed by means of the Behavioral Inhibition/Activation System Questionnaire (BIS/BAS). 32 subjects coupled in 16 dyads were recruited. Intra-subject analyses revealed that, after the general evaluation assessing a winning condition, the behavioral performance improved and the electrodermal response increased. Also, correlational analyses showed a relation between BAS, and specifically BAS reward, with SCR. Inter-subject analyses showed higher synchrony in SCR and HR after the feedback. Such results confirm the increased synchronic effect after a highly conflictual condition, and the presence of a relation between subjective performance, approach-related motivations, and physiological linkage.
Assuntos
Atenção/fisiologia , Resposta Galvânica da Pele/fisiologia , Frequência Cardíaca/fisiologia , Tempo de Reação/fisiologia , Adulto , Feminino , Humanos , Relações Interpessoais , Itália , Masculino , Motivação , Psicofisiologia , Inquéritos e Questionários , Adulto JovemRESUMO
The occurrence of drug resistance limits the efficacy of platinum compounds in the cure of ovarian carcinoma. Since microRNAs (miRNAs) may contribute to this phenomenon by regulating different aspects of tumor cell response, the aim of this study was to exploit the analysis of expression of miRNAs in platinum sensitive/resistant cells in an attempt to identify potential regulators of drug response. MiR-483-3p, which may participate in apoptosis and cell proliferation regulation, was found up-regulated in 4 platinum resistant variants, particularly in the IGROV-1/Pt1 subline, versus parental cells. Transfection of a synthetic precursor of miR-483-3p in IGROV-1 parental cells elicited a marked up-regulation of the miRNA levels. Growth-inhibition and colony-forming assays indicated that miR-483-3p over-expression reduced cell growth and conferred mild levels of cisplatin resistance in IGROV-1 cells, by interference with their proliferative potential. Predicted targets of miR-483-3p included PRKCA (encoding PKC-alpha), previously reported to be associated to platinum-resistance in ovarian carcinoma. We found that miR-483-3p directly targeted PRKCA in IGROV-1 cells. In keeping with this finding, cisplatin sensitivity of IGROV-1 cells decreased upon molecular/pharmacological inhibition of PKC-alpha. Overall, our results suggest that overexpression of miR-483-3p by ovarian carcinoma platinum-resistant cells may interfere with their proliferation, thus protecting them from DNA damage induced by platinum compounds and ultimately representing a drug-resistance mechanism. The impairment of cell growth may account for low levels of drug resistance that could be relevant in the clinical setting.
Assuntos
MicroRNAs/genética , Neoplasias Ovarianas/tratamento farmacológico , Compostos de Platina/uso terapêutico , Proteína Quinase C-alfa/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Neoplasias Ovarianas/genéticaRESUMO
Platinum drugs have been widely used for the treatment of several solid tumors. Although DNA has been recognized as the primary cellular target for these agents, there are unresolved issues concerning their effects and the molecular mechanisms underlying the antitumor efficacy. These cytotoxic agents interact with sub-cellular compartments other than the nucleus. Here, we review how such emerging phenomena contribute to the pharmacologic activity as well as to drug resistance phenotypes. DNA-unrelated effects of platinum drugs involve alterations at the plasma membrane and in endo-lysosomal compartments. A direct interaction with the mitochondria also appears to be implicated in drug-induced cell death. Moreover, the pioneering work of a few groups has shown that platinum drugs can act on the tumor microenvironment as well, and potentiate antitumor activity of the immune system. These poorly understood aspects of platinum drug activity sites may be harnessed to enhance their antitumor efficacy. A complete understanding of DNA-unrelated effects of platinum compounds might reveal new aspects of drug resistance allowing the implementation of the antitumor therapeutic efficacy of platinum compound-based regimens and minimization of their toxic side effects.