RESUMO
BACKGROUND: Electrotactile systems are compact interfaces that can be used to convey information through the skin by producing a range of haptic sensations. In many applications, however, the user needs to perceive and interpret haptic stimulation while being engaged in parallel activities. Developing methods that ensure reliable recognition of electrotactile messages despite additional cognitive load is, therefore, an important step for the practical application of electrotactile displays. METHODS: This study investigated if a simple strategy of repeating electrotactile messages can improve message identification during multitasking. Ten participants identified 36 spatiotemporal electrotactile messages delivered through a 3 × 2 pad-matrix electrode placed on the torso while performing a concomitant cognitive task in three conditions: the messages were presented once (No-REP), and each message was repeated three (REP3) and five (REP5) times. The main outcome measure was the success rate (SR) of message identification. RESULTS: During multitasking, in the No-REP condition, the SR (median (IQR)) dropped to 56.25% (22.62%), demonstrating that the cognitive task decreased performance. However, the SR significantly improved with message repetitions, reaching 72.92% (21.87%) and 81.25% (18.66%) in REP3 and REP5 conditions respectively, without a statistically significant difference between REP3 and REP5. CONCLUSIONS: Multitasking affected the efficacy of haptic communication, but message repetition was shown to be an effective strategy for improving performance. Additionally, only three repetitions were enough, as an additional increase in the duration of message transmission (5 repetitions) did not lead to further improvement. This study is an important step toward delivering electrotactile communication that can cope with the demands of real-world applications.
Assuntos
Cognição , Eletrodos , Tato , Humanos , Masculino , Cognição/fisiologia , Feminino , Tato/fisiologia , Adulto Jovem , Adulto , Desenho de EquipamentoRESUMO
BACKGROUND: Tactile stimulation can be used to convey information to a user in different scenarios while avoiding overloading other senses. Tactile messages can be transmitted as spatial patterns, potentially allowing for a high information throughput. The aim of the present study was to design and test different encoding schemes to determine the best approach for conveying spatial patterns. METHODS: Encoding schemes with simultaneous (SIM) and sequential pad activation (SEQ) were evaluated, including four SEQ variants designed to potentially facilitate the recognition. In SEQ-col and SEQ-row, the column and row of the activated pad were signified using different frequencies, while SEQ-all and SEQ-all-fast included the activation of all pads where those belonging to the pattern were indicated by changes in frequency (ON pads). The success rate (SR) of the pattern identification and the response time were quantified in 15 participants who recognized 20 patterns delivered through a 3 × 2 pad matrix placed on the lateral torso. RESULTS: SIM was not a feasible method to present the patterns (median, 15%; IQR, 5%). The SR improved with SEQ (median, 60%; IQR, 20%) and further increased with additional cues, particularly with SEQ-row (median, 78.3%; IQR, 23.3%) and SEQ-all (median, 96.7%; IQR, 5%). Importantly, the stimulation time of SEQ-all could be decreased without a substantial drop in accuracy (SEQ-all-fast: median, 89.2%; IQR, 19.2%). CONCLUSIONS: The spatiotemporal stimulation with sequential activation of all pads (SEQ-all) seems to be the method of choice when conveying tactile messages as spatial patterns. This is an important outcome for increasing the information bandwidth of communication through the tactile channel.
Assuntos
Percepção do Tato , Tato , Estimulação Elétrica , Eletrodos , Humanos , Pele , Tronco , Tato/fisiologia , Percepção do Tato/fisiologiaRESUMO
Electrotactile stimulation is a technology that reproducibly elicits tactile sensations and can be used as an alternative channel to communicate information to the user. The presented work is a part of an effort to develop this technology into an unobtrusive communication tool for first responders. In this study, the aim was to compare the success rate (SR) between discriminating stimulation at six spatial locations (static encoding) and recognizing six spatio-temporal patterns where pads are activated sequentially in a predetermined order (dynamic encoding). Additionally, a procedure for a fast amplitude calibration, that includes a semi-automated initialization and an optional manual adjustment, was employed and evaluated. Twenty subjects, including twelve first responders, participated in the study. The electrode comprising the 3 × 2 matrix of pads was placed on the lateral torso. The results showed that high SRs could be achieved for both types of message encoding after a short learning phase; however, the dynamic approach led to a statistically significant improvement in messages recognition (SR of 93.3%), compared to static stimulation (SR of 83.3%). The proposed calibration procedure was also effective since in 83.8% of the cases the subjects did not need to adjust the stimulation amplitude manually.
Assuntos
Tronco , Tato , Calibragem , Comunicação , Estimulação Elétrica/métodos , Eletrodos , Humanos , Tato/fisiologiaRESUMO
Galectin-1 (Gal-1) has been implicated in the progression of chronic lymphocytic leukemia (CLL) but also the development of immunodeficiency, which commonly accompany this malignancy. In this in vitro study, we investigated the effects of Gal-1 inhibition in the sera of immunocompromised CLL patients on immunomodulating properties of dendritic cells (DCs). DCs derived from peripheral blood mononuclear cells were treated with a healthy serum, CLL serum as well as the combination of CLL serum and Gal-1 inhibitor (OTX008). Following the treatment, the expression levels of DC maturation markers (CD80, CD83, CD86 and IDO-1) were determined as well as their cytokine profile and the ability to polarize the immune response in co-cultures with CD4+ T cells. After treatment with CLL serum, an increase in interleukin (IL)-10 production was observed in both DC cultures and co-cultures with CD4+ T cells. OTX008 caused a reduction in IL-10 production as well as IL-2, but no significant alteration in the expression of DC maturation markers or T regulatory cell (Treg) frequency was observed. The results of our study suggest that Gal-1 from CLL serum give rise to a specific IL-10+ CD4+ T cell phenotype, other than Treg, that could mediate immunodeficiency development in CLL patients.
RESUMO
Our study aimed to evaluate the effects of Gal-1 in dose depending manner on maturation and immunomodulatory properties of monocyte-derived (Mo) DCs in-vitro. The effects were analyzed by monitoring their phenotypic characteristics, cytokine profile, and the ability to direct the immune response in the co-culture with allogeneic CD4+T cells. Gal-1 reduced the expression of CD80 and CD86 molecules on MoDCs compared to untreated MoDCs. Gal-1 at concentrations of 1 and 6 µg/mL significantly reduced IL-12 production, while the concentration of 3 µg/mL led to its significant increase. Gal-1 in all concentrations induced a significant increase in the production of IL-10. Treatment of MoDCs with 3 and 6 µg/mL of Gal-1 stimulated the production of IL-2 and IFN-γ in the co-culture with CD4+T lymphocytes. This study demonstrated a dual immunomodulatory effect of Gal-1 on MoDCs in terms of immune stimulation and immune suppression, depending on the applied concentration.
Assuntos
Galectina 1/metabolismo , Monócitos , Diferenciação Celular , Células Cultivadas , Citocinas , Células Dendríticas , Humanos , ImunidadeRESUMO
Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts due to enhanced platelet clearance and compromised production. Traditionally, ITP was regarded a B cell mediated disorder as anti-platelet antibodies are detected in most patients. The very nature of self-antigens, evident processes of isotype switching and the affinity maturation of anti-platelet antibodies indicate that B cells in order to mount anti-platelet immune response require assistance of auto-reactive CD4+ T cells. For a long time, ITP pathogenesis has been exclusively reviewed through the prism of the disturbed balance between Th1 and Th2 subsets of CD4+ T cells, however, more recently new subsets of these cells have been described including Th17, Th9, Th22, T follicular helper and regulatory T cells. In this paper, we review the current understanding of the role and immunological mechanisms by which CD4+ T cells contribute to the pathogenesis of ITP.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Púrpura Trombocitopênica Idiopática/imunologia , Subpopulações de Linfócitos T/imunologia , Humanos , FenótipoRESUMO
BACKGROUND Identifying caries predictors in the subpopulation at risk is one of the preconditions for developing effective caries prevention measures. The present exploratory study aimed to examine the significance of socio-demographic characteristics, dietary-hygiene habits, salivary pH, and salivary antimicrobial HNP-1, hBD-2, and LL-37 peptides as potential caries risk predictors in children ages 11-13 years. MATERIAL AND METHODS This prospective 1-year study enrolled 213 children ages 11-13 years. The subjects underwent a dental examination and their mothers were interviewed. Unstimulated saliva was collected from the subjects to determine its pH value, as well as the salivary levels of HNP-1, hBD-2, and LL-37 peptides in 85 of the subjects. After 12 months, the 1-year caries incidence rate was recorded. Logistic regression analysis was used to estimate the ability of selected variables to predict caries risk. RESULTS The univariable logistic regression analysis determined that the most significant independent caries risk predictors were: sex (female) (OR=2.132, p=0.007), mothers' education (OR=1.986, p=0.020), salivary pH (OR=0.270, p=0.043), oral hygiene index (OR=1.886, p=0.015), and daily tooth brushing frequency (OR=0.565, p=0.042). The multivariable model showed that sex and oral hygiene-related variables were the most important caries predictors. CONCLUSIONS Salivary HNP-1, hBD-2, and LL-37 peptides were not found to have a significant predictive value. Therefore, socio-demographic and oral hygiene variables remain important caries predictors in early adolescents, suggesting the importance of the mechanical control of biofilm as the key measure for preventing caries. However, there is still a need for effective caries risk biomarkers, and additional research is needed in this area of caries risk prediction.
Assuntos
Biomarcadores/análise , Cárie Dentária/diagnóstico , Saliva/química , Adolescente , Catelicidinas/análise , Criança , Estudos Transversais , Cárie Dentária/metabolismo , Cárie Dentária/prevenção & controle , Comportamento Alimentar , Feminino , Humanos , Incidência , Masculino , Higiene Bucal/métodos , Fragmentos de Peptídeos/análise , Prognóstico , Estudos Prospectivos , Fatores de Risco , Inquéritos e Questionários , Escovação Dentária/métodos , alfa-Defensinas/análise , beta-Defensinas/análiseRESUMO
In this study, co-precipitation synthesis of the mesoporous triple-metal nanosorbent from Fe, Cu, Ni layered double hydroxide (FeCuNi-LDH), on the basis of the data obtained from the TG analysis was carried out. The FTIR spectroscopy and XRD results confirm the formation of CuO, NiO and Fe2O3 nanoparticles, while the EDX analysis does not show significant variations on the surface in elemental composition. BET analysis shows that FeCuNi-280 (FeCuNi-LDH calcinated at 280⯰C) with mesoporous structure, has larger surface area compared to FeCuNi-LDH and FeCuNi-550 (FeCuNi-LDH calcinated at 550⯰C). The value of pHPZC of FeCuNi-280 is found to be 8.66. Obtained FeCuNi-280 material showed the ability for efficient removal of dye Reactive Blue 19 (RB19) from water, with a very high sorption capacity of 480.79â¯mg/g at optimal conditions: the sorbent dose of 0.6â¯g/dm3, stirring speed of 280â¯rpm and pH 2. The kinetics results of the sorption process were well fitted by pseudo-second order and Chrastil model, and the sorption isotherm was well described by Sips, Langmuir and Brouers-Sotolongo model. FeCuNi-280 was easily regenerated with aqueous solution of NaOH, and reutilization was successfully done in five sorption cycles. The present study show that easy-to-prepare, relatively inexpensive nanosorbent FeCuNi-280 is among the best sorbents for the removal of RB19 dye from water solution and wastewater from textile industry in wide range of pH.
Assuntos
Corantes , Nanopartículas Metálicas , Águas Residuárias/química , Poluentes Químicos da Água , Purificação da Água/métodos , Adsorção , Antraquinonas , Cobre , Compostos Férricos , Hidróxidos , Cinética , Nanopartículas Metálicas/química , Nanopartículas Metálicas/ultraestrutura , NíquelRESUMO
A new photocatalyst bismuth oxo citrate was synthesized by facile precipitation process with calcination at 200 °C. The photocatalyst was characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier-transform infrared (FTIR) spectroscopy, N2 sorptometry, and elemental analysis. Morphologically, it is composed of polyhedral particles with different, irregular shapes and sizes. The specific surface area (SSA) of the photocatalyst was 8.92 m2 g-1. It showed very good photocatalytic performance and reusability. Total decolorization of Reactive Blue 19 (RB19) was achieved in less than 10 minutes, which is much faster in comparison with TiO2 P25. Also, bismuth oxo citrate showed higher photocatalytic activity than other photocatalysts based on bismuth compounds reported by other authors. Optimal photocatalysis parameters were pH 2 and photocatalyst dose of 250 mg dm-3. The decolorization rate was found to decrease as initial dye concentration increased. The photocatalytic data best fitted to L-H kinetic model with pseudo-first order reaction rate. Chrastil diffusion model showed that diffusion has not influence on the process.
Assuntos
Bismuto/química , Processos Fotoquímicos , Antraquinonas/química , Catálise , Concentração de Íons de Hidrogênio , Microscopia Eletrônica de Varredura , Propriedades de Superfície , Fatores de TempoRESUMO
PURPOSE: The purpose of this study was to determinate disease-free interval (DFI) and overall survival (OS) in HER2-positive breast cancer patients who received adjuvant trastuzumab at the University Clinic of Nis, Serbia, and to investigate the influence of clinicopathological and biological characteristics of the tumor on prognosis. The second aim was to determinate the most frequent cause for the treatment discontinuation, recurrence rate, as well as the site of most common localization of the first recurrence of disease. METHODS: This research was conducted as a retrospective study at the University Oncology Clinic, Clinical Centre in Nis. The study included 238 patients who were operated and treated for HER2-positive breast cancer between January 1st, 2007 to September 30th, 2012 and followed up until December 31st, 2016. Trastuzumab was administered concurrently with taxanes, if administered, or after the completed anthracycline-based chemotherapy. RESULTS: After a median follow up of 69 months the 5-year DFI was 65.9% and 5-year OS was 81.8% and, as expected, significantly longer in the group of patients with smaller tumors, a smaller number of positive axillary lymph nodes, as well as a lower stage of disease (p<0.0001). Patients older than 65 years had a longer DFI compared to the 45-65 and under 45 age groups of patients (p=0.01). No statistical significance was found in the length of DFI in relation to the histological tumor subtype, tumor grade, or the status of hormone receptors. Unlike DFI, a longer OS was recorded in the group of patients with lower tumor grade (p=0.03) and there was no statistically significant difference in survival regarding the age of patients (p=0.07). Recurrence occurred in approximately one third of the patients (38.23%), mostly in the form of local recurrence. Adjuvant therapy with trastuzumab was not completely carried out in 18.49% of the patients, the most common reason being the progression of disease. CONCLUSIONS: A long median follow up period of 69 months indicated that anti-HER2 monoclonal antibody trastuzumab, after anthracycline-based chemotherapy or concurrently with taxanes, is efficient and safe in treating early breast cancer.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Recidiva Local de Neoplasia/tratamento farmacológico , Trastuzumab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Receptor ErbB-2/genética , Estudos Retrospectivos , Sérvia/epidemiologia , Taxoides/uso terapêuticoRESUMO
The goal of this study was to investigate surface motor activation zones and their temporal variability using an advanced multi-pad functional electrical stimulation system. With this system motor responses are elicited through concurrent activation of electrode matrix pads collectively termed "virtual electrodes" (VEs) with appropriate stimulation parameters. We observed VEs used to produce selective wrist, finger, and thumb extension movements in 20 therapy sessions of 12 hemiplegic stroke patients. The VEs which produce these three selective movements were created manually on the ergonomic multi-pad electrode by experienced clinicians based on visual inspection of the muscle responses. Individual results indicated that changes in VE configuration were required each session for all patients and that overlap in joint movements was evident between some VEs. However, by analyzing group data, we defined the probability distribution over the electrode surface for the three VEs of interest. Furthermore, through Bayesian logic we obtained preferred stimulation zones that are in accordance with our previously reported heuristically obtained results. We have also analyzed the number of active pads and stimulation amplitudes for these three VEs. Presented results provide a basis for an automated electrode calibration algorithm built on a priori knowledge or the starting point for manual selection of stimulation points.
Assuntos
Terapia por Estimulação Elétrica/métodos , Dedos/inervação , Hemiplegia/reabilitação , Atividade Motora , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/terapia , Polegar/inervação , Punho/inervação , Adulto , Idoso , Algoritmos , Teorema de Bayes , Fenômenos Biomecânicos , Terapia por Estimulação Elétrica/instrumentação , Desenho de Equipamento , Feminino , Hemiplegia/diagnóstico , Hemiplegia/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Contração Muscular , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/fisiopatologia , Reabilitação do Acidente Vascular Cerebral/instrumentação , Fatores de Tempo , Resultado do TratamentoRESUMO
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder of central nervous system, in which myelin specific CD4(+) T cells have a central role in orchestrating pathological events involved in disease pathogenesis. There is compelling evidence that Th1, Th9 and Th17 cells, separately or in cooperation, could mediate deleterious autoimmune response in MS. However, the phenotype differences between Th cell subpopulations initially employed in MS pathogenesis are mainly reflected in the different patterns of inflammation introduction, which results in the development of characteristic pathological features (blood-brain barrier disruption, demyelination and neurodegeneration), clinically presented with MS symptoms. Although, autoimmunity was traditionally seen as deleterious, some studies indicated that autoimmunity mediated by Th2 cells and T regulatory cells could be protective by nature. The concept of protective autoimmunity in MS pathogenesis is still poorly understood, but could be of great importance in better understanding of MS immunology and therefore, creating better therapeutic strategies.
Assuntos
Autoimunidade , Sistema Nervoso Central/imunologia , Encefalomielite Autoimune Experimental/imunologia , Esclerose Múltipla/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Animais , Barreira Hematoencefálica/imunologia , Barreira Hematoencefálica/patologia , Sistema Nervoso Central/patologia , Citocinas/imunologia , Encefalomielite Autoimune Experimental/patologia , Humanos , Camundongos , Esclerose Múltipla/patologia , Bainha de Mielina/imunologia , Bainha de Mielina/patologia , Linfócitos T Reguladores/patologia , Células Th1/imunologia , Células Th1/patologia , Células Th17/imunologia , Células Th17/patologia , Células Th2/patologiaRESUMO
A new biosorbent, abbreviated as LVB-ZrO2, was synthesized by chemically modifying Lagenaria vulgaris shell with ZrO2. The removal of textile dye RB19 from aqueous solution by LVB-ZrO2was studied. Characterization by SEM, FTIR and XRD confirmed the chemical modification of the biomaterial, which showed significant improvement of removal efficiency compared with unmodified Lagenaria vulgaris shell. LVB-ZrO2point of zero charge is 5.49. The biosorption process is highly pH dependent and the optimal pH is 2.0, at which complete dye removal was attained. The results are the best by a pseudo-second order kinetic model. The optimal adsorbent dosage is 4 mg/dm³.The RB19 biosorption follows the Langmuir isotherm model (R² = 0.9978), with the maximum sorption capacity of 75.12 mg/g. LVB-ZrO2is a mechanically stable, easy to synthesize, cost-effective, biocompatible and environmentally-friendly biosorbent with the high potential for the removal of RB19 from aqueous solution.
Assuntos
Corantes/química , Cucurbitaceae/química , Resíduos Industriais/análise , Poluentes Químicos da Água/química , Zircônio/química , Animais , Microscopia Eletrônica de Varredura , Indústria Têxtil , Eliminação de Resíduos Líquidos/métodosRESUMO
PURPOSE: The aim of this study was to investigate the influence of clinicopathological and biological characteristics on prognosis, disease free survival (DFS) and overall survival (OS), of very young patients (≤35 years of age) with breast cancer. METHODS: We retrospectively collected information of 150 women diagnosed with breast cancer, aged ≤35 years, who were operated and treated at two University Hospitals in Serbia between January 2009 and February 2011. RESULTS: After a median follow up of 44 months patients ≤30 had shorter DFS and OS compared to patients aged 31-35 years (p=0.004 and p=0.037, respectively). The differences in DFS and OS were significant with decreased survival associated with higher tumor grade (p=0.005 and p=0.0001, respectively). Tumor size and number of positive nodes were predictors of outcome with decreased survival associated with higher tumor size (p=0.0019 for DFS and p<0.0001 for OS) and increasing number of nodes (p<0.0001 for both). HER 2 receptor did not seem to have a prognostic influence while patients with hormonal receptors (HRs) positive tumors had a better DFS (p=0.034) and OS (p=0.046) than those with HRs negative tumors. In univariate survival analysis, a significant difference in DFS (p=0.0003) and OS (p=0.0003) was found between patients with vs without lymphovascular invasion (LVI). CONCLUSION: Diagnosis of breast cancer at very young age (<30) was associated with increased risk of death and shorter DFS than women aged 31-35. Negative impact on survival was seen in patients with presence of LVI, negative HRs and higher grade and stage at the time of presentation.
Assuntos
Neoplasias da Mama/patologia , Adulto , Fatores Etários , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Estadiamento de NeoplasiasRESUMO
Glutamate is an excitatory neurotransmitter of the central nervous system, which has a central role in a complex communication network established between neurons, astrocytes, oligodendrocytes, and microglia. Multiple abnormal triggers such as energy deficiency, oxidative stress, mitochondrial dysfunction, and calcium overload can lead to abnormalities in glutamate signaling. Thus, the disturbance of glutamate homeostasis could affect practically all physiological functions and interactions of brain cells, leading to excitotoxicity. Excitotoxicity is the pathological process by which nerve cells are damaged or killed by excessive stimulation by glutamate. Although neuron degeneration and death are the ultimate consequences of multiple sclerosis (MS), it is now widely accepted that alterations in the function of surrounding glial cells are key features in the progression of the disease. The present knowledge raise the possibility that the modulation of glutamate release and transport, as well as receptors blockade or glutamate metabolism modulation, might be relevant targets for the development of future therapeutic interventions in MS.
Assuntos
Ácido Glutâmico/metabolismo , Esclerose Múltipla/fisiopatologia , Receptores de Glutamato/metabolismo , Animais , Humanos , Neuroimunomodulação/fisiologiaRESUMO
PURPOSE: To evaluate the clinical benefits of cetuximab (CTX) and the prognostic value of CTX-related skin toxicity in metastatic colorectal cancer (mCRC) patients. METHODS: Sixty patients were tested for KRAS mutation at the Department of Oncology, Clinical Centre Nis. We assessed 34 wild-type KRAS mCRC patients treated with CTX. All of them were refractory to prior fluoropyrimidine, oxaliplatin and irinotecan-based regimens. The maximum grade skin toxicity according to treatment cycle was analyzed. Skin toxicity was grouped into clinically non-relevant skin toxicity (grade 0-1: Group 1) and clinically relevant skin toxicity (grade 2-4: Group 2). RESULTS: Ten out of 33 patients (30.30%) achieved partial response (PR). Eight additional patients (24.24%) showed stable disease (SD), whereas 15 (45.45%) had disease progression (PD). No patient achieved complete response (CR). Overall response rate (ORR) was 30.30%, whereas the disease control rate (DCR) was 54.54%.The median progression free survival (PFS) was 14 weeks. Some degree of skin toxicity was observed in 79.41% (27/34) of the patients. Clinically non-relevant skin toxicity was observed in 50% (17/34), and clinically relevant in 50 % (17/34) of the patients. Grade 4 skin toxicity was documented in 1 patient. The mean PFS in Group 1 was 12.65±5.59 weeks and in Group 2 22.82±12.16 (p<0.05). The results showed that grade 2-4 skin toxicity was associated with significantly better response to treatment than skin toxicity grade 0-1, with regard to ORR (80.00 vs 20.00%; p<0.05) and DCR ( 66.66 vs 33.33%; p<0.05). CONCLUSION: Cetuximab has clinical benefit when given alone or in combination with irinotecan in patients with irinotecan-refractory CRC. Skin toxicity was one of the predictors of response and it was in line with what was expected.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Anormalidades da Pele/patologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Cetuximab , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Anormalidades da Pele/induzido quimicamente , Proteínas ras/genéticaRESUMO
The precise temporal and spatial activity patterns of neurons in cortical networks are organized by different state-dependent types of network oscillations. GABAergic inhibition plays a key role in the underlying mechanisms of such oscillations and it has been suggested that the duration of widely distributed phasic inhibitory postsynaptic potentials (IPSPs) determines the frequency of the resulting network oscillation. Here, we test this hypothesis in an in vitro model of sharp wave-ripple (SPW-R) complexes, a particularly fast pattern of network oscillations at â¼200 Hz which is involved in memory consolidation. We recorded SPW-R in mouse hippocampal slices in the absence and presence of NCC-711, an inhibitor of GABA uptake. The resulting prolongation of IPSP resulted in reduced occurrence of SPW-R, whereas the superimposed fast oscillations as well as the precision of rhythmic cell synchronization remained stable. Application of Diazepam which is a positive modulator of the GABAA receptor led to consistent results. We conclude that phasic inhibition is a major regulator of network excitability in CA3 (where SPW-Rs are generated), but does not set the frequency of hippocampal ripples.
Assuntos
Potenciais Evocados/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Hipocampo/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Ácidos Nipecóticos/farmacologia , Oximas/farmacologia , 2-Amino-5-fosfonovalerato/farmacologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Diazepam/farmacologia , Estimulação Elétrica , Antagonistas de Aminoácidos Excitatórios/farmacologia , Análise de Fourier , Moduladores GABAérgicos/farmacologia , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/efeitos dos fármacos , Condução Nervosa/efeitos dos fármacos , Fatores de TempoRESUMO
The previous understanding of multiple sclerosis was solely related to neuroinflammation and its harmful effects; however, countless data indicate the importance of some inflammation-independent, neurodegenerative mechanisms associated with mitochondria malfunction, iron deposition and oxidative stress. Recently, it has been postulated that glutamate excitotoxicity, a phenomenon that takes place when an excessive amount of glutamate overactivates its cellular receptors and induces cell death, could be a missing link between inflammatory and neurodegenerative processes evident in multiple sclerosis. Glutamate is the major excitatory neurotransmitter of the central nervous system, which has been proven to have a central role in a complex communication network established between all residential brain cells, including neurons, astrocytes, oligodendrocytes and microglia. Thus, the disturbance of glutamate homeostasis could affect practically all physiological functions and interactions of brain cells, leading to heterogeneity of pathological events. The understanding of glutamate excitotoxicity as a valid mechanism of central nervous system damage in multiple sclerosis, requires the revision of the current knowledge about a source of elevated extracellular glutamate, glutamate receptor alterations, alterations of glutamate transporters and metabolizing enzymes, as well as molecular mechanism of excitotoxic damage.
Assuntos
Sistema Nervoso Central , Ácido Glutâmico/toxicidade , Esclerose Múltipla/patologia , Doenças Neurodegenerativas/induzido quimicamente , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiopatologia , Ácido Glutâmico/metabolismo , Humanos , Esclerose Múltipla/complicações , Doenças Neurodegenerativas/metabolismo , Receptores de Glutamato/metabolismoRESUMO
Due to an increased need for new immunomodulatory agents, many previously known molecules have been structurally modified in order to obtain new drugs, preserving at the same time some of the benevolent characteristics of the parent molecule. This study aimed to evaluate the immunomodulatory potential of a selected library of bile acid derivatives (BAD) using a broad spectrum of assays, evaluating rat peritoneal macrophages viability, cell membrane damage, lysosomal and adhesion function, and nitric oxide and cytokine production as a response to lipopolysaccharide stimulation. Also, in silico studies on two bile acid-activated receptors were conducted and the results were related to the observed in vitro effects. All tested BAD exerted significant toxicity in concentrations higher than 10 µM, which was determined based on mitochondria and cell membrane damage in a panel of assays. On the other hand, at lower concentrations, the tested BAD proved to be immunomodulatory since they affected lysosomal function, cell adhesion capacities and the ability to produce inflammatory cytokines in response to a stimulus. One of the compounds proved to exhibit significant toxicity toward macrophages, but also caused a concentration-dependent decrease in nitric oxide levels and was identified as a potential farnesoid X receptor agonist.
Assuntos
Macrófagos , Óxido Nítrico , Animais , Ratos , Macrófagos Peritoneais , Membrana Celular , Ácidos e Sais BiliaresRESUMO
Copy number variants (CNVs) that delete or duplicate 30 genes within the 16p11.2 genomic region give rise to a range of neurodevelopmental phenotypes with high penetrance in humans. Despite the identification of this small region, the mechanisms by which 16p11.2 CNVs lead to disease are unclear. Relevant models, such as human cortical organoids (hCOs), are needed to understand the human-specific mechanisms of neurodevelopmental disease. We generated hCOs from 17 patients and controls, profiling 167,958 cells with single-cell RNA-sequencing analysis, which revealed neuronal-specific differential expression of genes outside the 16p11.2 region that are related to cell-cell adhesion, neuronal projection growth, and neurodevelopmental disorders. Furthermore, 16p11.2 deletion syndrome organoids exhibited reduced mRNA and protein levels of RBFOX1, a gene that can also harbor CNVs linked to neurodevelopmental phenotypes. We found that the genes previously shown to be regulated by RBFOX1 are also perturbed in organoids from patients with the 16p11.2 deletion syndrome and thus identified a novel link between independent CNVs associated with neuronal development and autism. Overall, this work suggests convergent signaling, which indicates the possibility of a common therapeutic mechanism across multiple rare neuronal diseases.