RESUMO
Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n = 480,282). We estimated that autozygosity due to consanguinity accounts for 5%-18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity.
Assuntos
Consanguinidade , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/genética , Homozigoto , Fenótipo , Polimorfismo de Nucleotídeo Único , Bancos de Espécimes Biológicos , Genoma Humano , Predisposição Genética para Doença , Reino UnidoRESUMO
The act of recalling memories can paradoxically lead to the forgetting of other associated memories, a phenomenon known as retrieval-induced forgetting (RIF). Inhibitory control mechanisms, primarily mediated by the prefrontal cortex, are thought to contribute to RIF. In this study, we examined whether stimulating the medial prefrontal cortex (mPFC) with transcranial direct current stimulation modulates RIF and investigated the associated electrophysiological correlates. In a randomized study, fifty participants (27 males and 23 females) received either real or sham stimulation before performing retrieval practice on target memories. After retrieval practice, a final memory test to assess RIF was administered. We found that stimulation selectively increased the retrieval accuracy of competing memories, thereby decreasing RIF, while the retrieval accuracy of target memories remained unchanged. The reduction in RIF was associated with a more pronounced beta desynchronization within the left dorsolateral prefrontal cortex (left-DLPFC), in an early time window (<500 msec) after cue onset during retrieval practice. This led to a stronger beta desynchronization within the parietal cortex in a later time window, an established marker for successful memory retrieval. Together, our results establish the causal involvement of the mPFC in actively suppressing competing memories and demonstrate that while forgetting arises as a consequence of retrieving specific memories, these two processes are functionally independent. Our findings suggest that stimulation potentially disrupted inhibitory control processes, as evidenced by reduced RIF and stronger beta desynchronization in fronto-parietal brain regions during memory retrieval, although further research is needed to elucidate the specific mechanisms underlying this effect.Significance statement Retrieval can induce forgetting of competing memories, a phenomenon known as Retrieval Induced Forgetting (RIF). Inhibitory control mechanisms, primarily mediated by the frontal cortex, are thought to contribute to RIF. In this study, we modulated a key region (medial prefrontal cortex (mPFC)) involved in this process using brain stimulation to investigate its influence on RIF and its electrophysiological correlates. Stimulation of mPFC lead to an increased retrieval of non-target memories and reduced RIF. The reduction in RIF was accompanied by stronger beta desynchronization in the frontoparietal brain regions, with beta desynchronization in the left-dorsolateral prefrontal cortex predicting the extent of reduction in RIF.
RESUMO
Background There are varying reports about United Kingdom medical students' exposure and teaching methods regarding plastic and reconstructive surgery. To date, no systematic review has been done looking at this topic. Methods Three databases (PubMed, Embase, and Medline) were searched from January 1, 2011 to July 20, 2023 for studies that assessed United Kingdom medical students' exposure to plastic surgery and suggested recommendations to improve teaching. Three authors performed data extraction and screening, as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results Fifteen studies were included. Medical students' average current exposure to plastic surgery was 29.44%, but this was highly variable across the studies. The most common method of currently teaching plastic surgery was through lectures (34% of studies), and the most common suggested method of teaching was through courses (40% of studies). Many of the studies (12/15) were deemed as being at high risk of bias. Conclusion More recent studies need to be performed to assess current levels of teaching of plastic surgery in the United Kingdom medical school curriculum. Greater exposure to plastic surgery through lectures and integrated clinical placements is needed to ensure equitable access for all medical students to plastic surgery as a profession.
RESUMO
Advancements in technology and awareness of energy conservation and environmental protection have increased the adoption rate of electric vehicles (EVs). The rapidly increasing adoption of EVs may affect grid operation adversely. However, the increased integration of EVs, if managed appropriately, can positively impact the performance of the electrical network in terms of power losses, voltage deviations and transformer overloads. This paper presents a two-stage multi-agent-based scheme for the coordinated charging scheduling of EVs. The first stage uses particle swarm optimization (PSO) at the distribution network operator (DNO) level to determine the optimal power allocation among the participating EV aggregator agents to minimize power losses and voltage deviations, whereas the second stage at the EV aggregator agents level employs a genetic algorithm (GA) to align the charging activities to achieve customers' charging satisfaction in terms of minimum charging cost and waiting time. The proposed method is implemented on the IEEE-33 bus network connected with low-voltage nodes. The coordinated charging plan is executed with the time of use (ToU) and real-time pricing (RTP) schemes, considering EVs' random arrival and departure with two penetration levels. The simulations show promising results in terms of network performance and overall customer charging satisfaction.
RESUMO
Human activity recognition (HAR) using wearable sensors enables continuous monitoring for healthcare applications. However, the conventional centralised training of deep learning models on sensor data poses challenges related to privacy, communication costs, and on-device efficiency. This paper proposes a federated learning framework integrating spiking neural networks (SNNs) with long short-term memory (LSTM) networks for energy-efficient and privacy-preserving HAR. The hybrid spiking-LSTM (S-LSTM) model synergistically combines the event-driven efficiency of SNNs and the sequence modelling capability of LSTMs. The model is trained using surrogate gradient learning and backpropagation through time, enabling fully supervised end-to-end learning. Extensive evaluations of two public datasets demonstrate that the proposed approach outperforms LSTM, CNN, and S-CNN models in accuracy and energy efficiency. For instance, the proposed S-LSTM achieved an accuracy of 97.36% and 89.69% for indoor and outdoor scenarios, respectively. Furthermore, the results also showed a significant improvement in energy efficiency of 32.30%, compared to simple LSTM. Additionally, we highlight the significance of personalisation in HAR, where fine-tuning with local data enhances model accuracy by up to 9% for individual users.
Assuntos
Conscientização , Privacidade , Humanos , Fenômenos Físicos , Comunicação , Atividades HumanasRESUMO
Increased demand for fast edge computation and privacy concerns have shifted researchers' focus towards a type of distributed learning known as federated learning (FL). Recently, much research has been carried out on FL; however, a major challenge is the need to tackle the high diversity in different clients. Our research shows that using highly diverse data sets in FL can lead to low accuracy of some local models, which can be categorised as anomalous behaviour. In this paper, we present FedBranched, a clustering-based framework that uses probabilistic methods to create branches of clients and assigns their respective global models. Branching is performed using hidden Markov model clustering (HMM), and a round of branching depends on the diversity of the data. Clustering is performed on Euclidean distances of mean absolute percentage errors (MAPE) obtained from each client at the end of pre-defined communication rounds. The proposed framework was implemented on substation-level energy data with nine clients for short-term load forecasting using an artificial neural network (ANN). FedBranched took two clustering rounds and resulted in two different branches having individual global models. The results show a substantial increase in the average MAPE of all clients; the biggest improvement of 11.36% was observed in one client.
RESUMO
Skull base chrodomas are slow growing neoplasms usually located along the midline. They display a locally invasive nature with possibilities of extracranial metastasis. Presentation is usually late and depends upon the location and extent of the tumour. Management aims at gross total resection via open microsurgical or endoscopic approach followed by adjuvant radiotherapy. Prognosis may be good for the classical and chondroid subtypes but remains poor for de-differentiated type.
Assuntos
Cordoma , Neoplasias de Cabeça e Pescoço , Neoplasias da Base do Crânio , Humanos , Cordoma/cirurgia , Prognóstico , Radioterapia Adjuvante , Neoplasias da Base do Crânio/diagnóstico por imagem , Neoplasias da Base do Crânio/cirurgia , Base do Crânio , Resultado do TratamentoRESUMO
OBJECTIVE: Several therapeutic agents have been assessed for the treatment of COVID-19, but few approaches have been proven efficacious. Because leukotriene receptor antagonists, such as montelukast have been shown to reduce both cytokine release and lung inflammation in preclinical models of viral influenza and acute respiratory distress syndrome, we hypothesized that therapy with montelukast could be used to treat COVID-19. The objective of this study was to determine if montelukast treatment would reduce the rate of clinical deterioration as measured by the COVID-19 Ordinal Scale. METHODS: We performed a retrospective analysis of COVID-19 confirmed hospitalized patients treated with or without montelukast. We used "clinical deterioration" as the primary endpoint, a binary outcome defined as any increase in the Ordinal Scale value from Day 1 to Day 3 of the hospital stay, as these data were uniformly available for all admitted patients before hospital discharge. Rates of clinical deterioration between the montelukast and non-montelukast groups were compared using the Fisher's exact test. Univariate logistic regression was also used to assess the association between montelukast use and clinical deterioration. A total of 92 patients were analyzed, 30 who received montelukast at the discretion of the treating physician and 62 patients who did not receive montelukast. RESULTS: Patients receiving montelukast experienced significantly fewer events of clinical deterioration compared with patients not receiving montelukast (10% vs 32%, p = 0.022). Our findings suggest that montelukast associates with a reduction in clinical deterioration for COVID-19 confirmed patients as measured on the COVID-19 Ordinal Scale. CONCLUSIONS: Hospitalized COVID-19 patients treated with montelukast had fewer events of clinical deterioration, indicating that this treatment may have clinical activity. While this retrospective study highlights a potential pathway for COVID-19 treatment, this hypothesis requires further study by prospective studies.
Assuntos
Asma , Tratamento Farmacológico da COVID-19 , Deterioração Clínica , Quinolinas , Acetatos/uso terapêutico , Asma/tratamento farmacológico , Ciclopropanos , Humanos , Antagonistas de Leucotrienos/uso terapêutico , Estudos Prospectivos , Quinolinas/uso terapêutico , Estudos Retrospectivos , SARS-CoV-2 , Sulfetos , Resultado do TratamentoRESUMO
OBJECTIVE: To examine the effect of distance travelled for brain tumour surgery on patient outcomes in an LMIC. METHODS: Data were collected as part of the Pakistan Brain Tumour Epidemiology Study (PBTES) for brain tumour patients who underwent surgery in 2019. Mapping software was used to calculate the distance travelled by each patient from their primary address to the hospital. This was analysed in correlation with outcomes (change in KPS score, current status) and demographic variables. RESULTS: Of 2366 patients, the median distance travelled across the country was 104 km (IQR: 9.07 - 304). Only 970 (41%) patients had access to brain tumour surgical care within 50 km of their primary address. A total of 372 (15.7%) patients requiring brain tumour surgery had to travel more than 500 km to reach their primary care hospital. Patients travelling more than 50 km for brain tumour surgery had better pre- and post-surgery Karnofsky performance scores (p<0.001) than those travelling less than 50 km. The overall survival for these patients was also better (82.4% vs 75.7%, p= 0.002) compared to patients travelling less than 50 km. CONCLUSIONS: The distance to a hospital dictates a patient's access to continuity of care through adjuvant chemoradiotherapy and regular follow-ups. Less than half of brain tumour patients in Pakistan had access to brain tumour surgery care within 50 km of their homes. Overall outcomes were significantly better in patients travelling more than 50km for neurosurgical care - suggesting a distance bias effect.
Assuntos
Neoplasias Encefálicas , Países em Desenvolvimento , Humanos , Acessibilidade aos Serviços de Saúde , Viagem , Renda , Neoplasias Encefálicas/cirurgiaRESUMO
OBJECTIVE: To build a comprehensive brain tumour database that will allow us to analyse in detail the prevalence, demographics, and outcomes of the disease in paediatric, adolescent, and young adult age groups. Method: A national cross-sectional study was conducted at 32 centres, and data regarding patient demographics and brain tumours were collected. This data was then stratified based on age groups, healthcare sectors, socioeconomic status, tumour types, and surgical outcomes. RESULTS: Most of the patients who were diagnosed with brain tumours belonged to a lower socioeconomic background and went to public sector hospitals. More males were diagnosed with and treated for brain tumours in the paediatric, adolescent, and young adult populations. The most common tumour in the paediatric population was medulloblastoma (23.7%) and the most common tumour in the adolescent (27.8%) and young adult population (34.7%) was glioma. Significant improvement in KPS scores were seen for: craniopharyngioma (p = 0.001), meningioma (p < 0.0005) and pituitary adenoma (p < 0.0005). CONCLUSIONS: This study shows that in all three age groups, there was a greater prevalence in males. Most of the patients belonged to a lower-middle-income class background and most patients presented to public sector hospitals. Greater knowledge of these parameters unique to each age group is the key to understanding and alleviating the burden of disease. Cancer registries, specifically brain tumour registries that keep up-to-date records of these patients, are essential to identify and keep track of these unique parameters to advance medical research and treatment strategies, ultimately lowering the disease burden.
Assuntos
Neoplasias Encefálicas , Neoplasias Meníngeas , Neoplasias Hipofisárias , Masculino , Criança , Humanos , Adolescente , Adulto Jovem , Paquistão/epidemiologia , Estudos Transversais , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/patologiaRESUMO
BACKGROUND: Atrial fibrillation (AF) and hypertension are independently associated with impaired autonomic function determined using heart rate variability (HRV). As these conditions frequently co-exist, we sought to determine whether AF would worsen HRV in hypertensive patients. DESIGN: We studied HRV in AF (and hypertension) (n = 61) and hypertension control group (n = 33). The AF (and hypertension) group was subdivided into permanent AF (n = 30) and paroxysmal AF (n = 31) and re-studied. Time-domain, frequency-domain and nonlinear measures of HRV were determined. Permanent AF group (n = 30) was followed up after 8 weeks following optimisation of their heart rate and blood pressure (BP). RESULTS: Time-domain and nonlinear indices of HRV were higher in AF (and hypertension) group compared to hypertensive controls (P ≤ .01). Time-domain and nonlinear indices of HRV were higher in permanent AF group compared to paroxysmal AF (P ≤ .001). Permanent AF was an independent predictor of HRV on multivariable analysis (P = .006). Optimisation of heart rate and BP had no significant impact on HRV in permanent AF. CONCLUSIONS: AF, independent of hypertension, is characterised with marked HRV and is possibly related to vagal tone. HRV is higher in permanent AF compared to paroxysmal AF suggesting evident autonomic influence in the pathophysiology of permanent AF. Modulation of autonomic influence on cardiovascular system should be explored in future studies.
Assuntos
Fibrilação Atrial/fisiopatologia , Sistema Nervoso Autônomo/fisiopatologia , Frequência Cardíaca/fisiologia , Hipertensão/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/complicações , Estudos de Casos e Controles , Feminino , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: Menstrual-related migraine (MRM) results in moderate to severe intensity headaches accompanied by physical and emotional disability over time in women. Neuroimaging methodologies have advanced our understanding of migraine; however, the neural mechanisms of MRM are not clearly understood. METHODS: In this study, fourteen MRM patients in the interictal phase and fifteen age- and education-matched healthy control females were recruited. Resting-state functional magnetic resonance imaging (fMRI) and pulsed arterial spin labeling (PASL) MRI were collected for both the subject groups outside of their menstrual periods. Eigenvector centrality mapping (ECM) was performed on resting-state fMRI, and the relative cerebral blood flow (relCBF) was assessed using PASL-MRI. RESULTS: MRM patients showed a significantly increased eigenvector centrality in the right medial frontal gyrus compared to healthy controls. Seed-based ECM analysis revealed that increased centrality was associated with the right medial frontal gyrus's hyperconnectivity with the left insula and the right supplementary motor area. The perfusion MRI revealed significantly increased relCBF in the hyperconnected regions. Furthermore, the hyperconnection positively correlated with the attack frequency, while the hyperperfusion showed a positive correlation with the disease duration. CONCLUSION: The results suggest that menstrual-related migraine is associated with cerebral hyperconnection and hyperperfusion in critical pain-processing brain regions. Furthermore, this elevated cerebral activity is correlated with different aspects of functional impairment in MRM patients suggesting that perfusion analysis, along with whole-brain connectivity analysis, can provide a comprehensive understanding of neural mechanisms of MRM.
Assuntos
Encéfalo , Transtornos de Enxaqueca , Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular , Feminino , Humanos , Imageamento por Ressonância Magnética , Transtornos de Enxaqueca/diagnóstico por imagem , NeuroimagemRESUMO
Stroke is a leading cause of motor disability worldwide, and robot-assisted therapies have been increasingly applied to facilitate the recovery process. However, the underlying mechanism and induced neuroplasticity change remain partially understood, and few studies have investigated this from a multimodality neuroimaging perspective. The current study adopted BCI-guided robot hand therapy as the training intervention and combined multiple neuroimaging modalities to comprehensively understand the potential association between motor function alteration and various neural correlates. We adopted EEG-informed fMRI technique to understand the functional regions sensitive to training intervention. Additionally, correlation analysis among training effects, nonlinear property change quantified by fractal dimension (FD), and integrity of M1-M1 (M1: primary motor cortex) anatomical connection were performed. EEG-informed fMRI analysis indicated that for iM1 (iM1: ipsilesional M1) regressors, regions with significantly increased partial correlation were mainly located in contralesional parietal, prefrontal, and sensorimotor areas and regions with significantly decreased partial correlation were mainly observed in the ipsilesional supramarginal gyrus and superior temporal gyrus. Pearson's correlations revealed that the interhemispheric asymmetry change significantly correlated with the training effect as well as the integrity of M1-M1 anatomical connection. In summary, our study suggested that multiple functional brain regions not limited to motor areas were involved during the recovery process from multimodality perspective. The correlation analyses suggested the essential role of interhemispheric interaction in motor rehabilitation. Besides, the underlying structural substrate of the bilateral M1-M1 connection might relate to the interhemispheric change. This study might give some insights in understanding the neuroplasticity induced by the integrated BCI-guided robot hand training intervention and further facilitate the design of therapies for chronic stroke patients.
Assuntos
Eletroencefalografia , Imageamento por Ressonância Magnética , Atividade Motora , Imagem Multimodal/métodos , Neuroimagem/métodos , Reabilitação do Acidente Vascular Cerebral/métodos , Adulto , Idoso , Doença Crônica , Dominância Cerebral , Feminino , Mãos/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , RobóticaRESUMO
BACKGROUND: Patient-Reported Outcomes Measurement Information System (PROMIS) is a well-validated tool used to measure health-related quality of life for children and adolescents with chronic medical conditions. The current study evaluates PROMIS scores in 3 domains for children with Ponseti-treated idiopathic clubfoot. METHODS: This is a retrospective cohort study of 77 children, ages 5 to 16 years, treated by Ponseti protocol for idiopathic clubfoot. Three pediatric PROMIS domains (Mobility, Pain Interference, and Peer Relationships) were administered between April 2017 and June 2018. One-way analysis of variance with Bonferroni post hoc and independent sample t tests were performed to explore differences across PROMIS domain scores by sex, age, initial Dimeglio score, laterality, bracing duration, and whether the child underwent tibialis anterior transfer. RESULTS: In the self-reported group (ages 8 to 16), mean T-scores for all 3 domains in both unilaterally and bilaterally affected groups were within the normal range, with respect to the general reference pediatric population. However, children with unilateral clubfoot had a significantly higher mean Mobility T-score (54.77) than children with bilateral clubfoot (47.81, P=0.005). Children with unilateral clubfoot also had significantly lower mean pain scores (39.16) than their bilateral counterparts (46.56, P=0.005). Children who had braced >36 months had a significantly higher mean Mobility T-score (53.68) than children who braced ≤36 months (46.28, P=0.004).In the proxy group (ages 5 to 7), mean T-scores for all 3 domains in both laterality groups were within the normal range, with respect to the reference population. Children who had braced >36 months had a significantly higher mean Mobility T-score (52.75 vs. 49.15, P=0.014) and lower Pain Interference score (43.04 vs. 49.15, P=0.020) than children who braced ≤36 months. CONCLUSIONS: Children treated by Ponseti protocol for idiopathic clubfoot yielded PROMIS scores for Mobility, Pain Interference, and Peer Relationships domains similar to the reference population. Bracing duration >36 months and unilaterality were associated with less mobility impairment than their counterparts. These findings may help guide parent recommendations. LEVEL OF EVIDENCE: Level III.
Assuntos
Braquetes/estatística & dados numéricos , Pé Torto Equinovaro , Dor , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Adolescente , Criança , Pé Torto Equinovaro/complicações , Pé Torto Equinovaro/psicologia , Pé Torto Equinovaro/terapia , Feminino , Humanos , Masculino , Limitação da Mobilidade , Dor/etiologia , Dor/psicologia , Preferência do Paciente , Estudos Retrospectivos , Interação SocialRESUMO
BACKGROUND: Atrial fibrillation (AF) is the commonest abnormal heart rhythm with significant related morbidity and mortality. Several pathophysiologic mechanisms have been advocated to explain the onset of AF. There has been increasing evidence that abnormalities of the autonomic nervous system (ANS) that includes sympathetic, parasympathetic and intrinsic neural network are involved in the pathogenesis of AF. This review will consider the anatomical and pathophysiological concepts of the cardiac neuronal network and discuss how it can be investigated. DESIGN: Relevant articles for this review were selected primarily from Ovid Medline and Embase databases (see appendix). We searched for key terms "atrial fibrillation," "AF," "autonomic dysfunction," "autonomic nervous system," "heart rate variability" and "HRV" to gather relevant studies. Duplicate papers were excluded. RESULTS: Heart is richly innervated by autonomic nerves. Both sympathetic and parasympathetic systems interact in developing AF along with cardiac ganglionated plexi (GP). Thus autonomic dysfunction is present in AF. There are methods including selective ablation that reduce autonomic innervation and show to reduce the incidence of spontaneous or induced atrial arrhythmias. Heart rate variability (HRV) is a useful tool to assess sympathetic and parasympathetic influences on disease states. HRV can be improved following intervention and is thus a useful application in assessing autonomic dysfunction in patients with AF. CONCLUSION: ANS plays a crucial role in the development, propagation and complexity of AF. Assessment of the autonomic involvement in the propagation of AF may help in explaining why certain patients with AF do not benefit from cardioversion or ablation.
Assuntos
Fibrilação Atrial/fisiopatologia , Frequência Cardíaca/fisiologia , Coração/inervação , Sistema Nervoso Parassimpático/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Humanos , Sistema Nervoso Parassimpático/fisiologia , Sistema Nervoso Simpático/fisiologiaRESUMO
Glioblastoma multiforme (GBM) is the most lethal brain malignancy which involves multi-gene abnormality. Unfortunately, effective therapy against GBM remains lacking. Previously, we found that NRP-1 and its downstream NRP-1/GIPC1 pathway played an important role in GBM. In our study, we further investigated the upstream signaling of NRP-1 to understand how it is regulated. First, we identified that hsa-miR-124-3p was miRNA differentially expressed in GBM and in normal brain tissues by high-throughput sequencing. Then, by dual luciferase reporter gene, we found miR-124-3p can specially bind to the 3'UTR region of the NRP-1 thus suppresses its expression. Moreover, miR-124-3p overexpression significantly inhibited GBM cell proliferation, migration and tumor angiogenesis which resulted in GBM apoptosis and cell cycle arrest, putatively via NRP-1 mediated PI3K/Akt/NFκB pathways activation in GBM cells. Meanwhile, miR-124-3p overexpression also suppressed tumor growth and reduced tumor angiogenesis when targeted by NRP-1 in a PDX model. Furthermore, NRP-1 mAb exerted synergistic inhibitory effects with miR-124-3p overexpression in GBM. Thus, we discovered that miR-124-3p acts as the upstream suppressor of NRP-1 which promotes GBM cell development and growth by PI3K/Akt/NFκB pathway. The miR-124-3p/NRP-1/GIPC1 pathway as a new pathway has a vital role in GBM, and it could be considered as the potential target for malignant gliomas in future.
Assuntos
Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Neovascularização Patológica/genética , Neuropilina-1/genética , Interferência de RNA , Regiões 3' não Traduzidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/genética , Encéfalo/metabolismo , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Perfilação da Expressão Gênica , Glioblastoma/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , TranscriptomaRESUMO
BACKGROUND: The optimal management of thyroid nodules that undergo fine-needle aspiration (FNA) with findings of atypia of undetermined significance (AUS) is unclear. Categorizing nodules by AUS subtype and ultrasound characteristics may improve risk stratification. Therefore, the purpose of this study is to evaluate the association between AUS subtype and ultrasound features on risk of malignancy (ROM). METHODS: We performed a review of all patients with a thyroid nodule who underwent an FNA at our institution between January 2010 and November 2015. Patients with AUS were divided into groups with (1) nuclear atypia, (2) architectural atypia, or (3) Hurthle cell atypia. Their ultrasound features were assessed using the American Thyroid Association (ATA) thyroid nodule sonographic patterns. We conducted a univariate and multivariable analysis to determine the association between AUS subtype and other variables of interest with ROM. RESULTS: Of the 3428 thyroid nodules that underwent FNA, 237 (6.9%) had AUS. Of the 97 surgically resected nodules, 67 (69%) were benign and 30 (31%) were malignant. On univariate analysis nuclear atypia (p < 0.01) was associated with a thyroid malignancy. On multivariable analysis, both ATA high-risk ultrasound features (p = 0.04, odds ratio [OR] 3.68) and nuclear atypia (p < 0.01, OR 11.8) were independently associated with a final diagnosis of thyroid carcinoma. CONCLUSIONS: Nuclear atypia and ATA high-risk ultrasound features are useful in identifying patients with AUS that are at a higher risk of thyroid malignancy. Surgeons should take these factors into consideration when evaluating patients with AUS.
Assuntos
Núcleo Celular/patologia , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/patologia , Nódulo da Glândula Tireoide/diagnóstico por imagem , Nódulo da Glândula Tireoide/patologia , Biópsia por Agulha Fina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células Oxífilas/patologia , Câncer Papilífero da Tireoide/cirurgia , Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/cirurgia , Tireoidectomia , UltrassonografiaRESUMO
A new series of benzimidazole linked pyrazole derivatives were synthesized by cyclocondensation reaction through one-pot multicomponent reaction in absolute ethanol. All the synthesized compounds were tested for their in vitro anticancer activities on five human cancer cell lines including MCF-7, HaCaT, MDA-MB231, A549 and HepG2. EGFR receptor inhibitory activities were carried out for all the compounds. Majority of the compounds showed potent antiproliferative activity against the tested cancer cell lines. Compound 5a showed the most effective activity against the lungs cancer cell lines (IC50 = 2.2⯵M) and EGFR binding (IC50 = 0.97⯵M) affinity as compared to other members of the series. Compound 5a inhibited growth of A549 cancer cells by inducing a strong G2/M phase arrest. In addition, same compound inhibited growth of A549 cancer cells by inducing apoptosis. In molecular docking studies compound 5a was bound to the active pocket of the EGFR (PDB 1M17) with five key hydrogen bonds and two π-π interaction with binding energies ΔG = -34.581â¯Kcal/mol.
Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Benzimidazóis/síntese química , Benzimidazóis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirazóis/síntese química , Pirazóis/química , Ratos , Relação Estrutura-AtividadeRESUMO
New N3-benzylidene (substituted)-2-phenyl-N4-(thiazol-2-yl)-quinazoline-3,4-(4H)-diamine derivatives were design and synthesized by a sequence of reactions starting from appropriate 6-methyl anthranilic acid. The title compounds were screened for in vitro dipeptidyl peptidase IV (DPP-4) inhibitory activity and diphenyl-2-picryl-hydrazyl (DPPH) assay and results showed significant to good activity in compared to Linagliptin for antidiabetic activity and Ascorbic acid for antioxidant activity. Compound 7g (IC50=0.76nM) exhibited most promising DPP-4 inhibitory activity and also showed good antioxid and result. Docking study was also performed to provide an insight about the binding mode into binding sites of DPP-4 enzyme. Hopefully in future, compound 7g could be used as a lead compound for developing new antidiabetic agent with good antioxidant property.
Assuntos
Antioxidantes/química , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/química , Desenho de Fármacos , Hipoglicemiantes/química , Quinazolinas/química , Animais , Antioxidantes/síntese química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Compostos de Bifenilo/antagonistas & inibidores , Diabetes Mellitus Experimental/enzimologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Radicais Livres/antagonistas & inibidores , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Simulação de Acoplamento Molecular , Picratos/antagonistas & inibidores , Quinazolinas/síntese química , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Ratos Wistar , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/uso terapêuticoRESUMO
A novel series of quinazoline clubbed thiazoline derivatives was rationally designed and synthesized. The newly synthesized compounds were evaluated for in vitro dipeptidyl peptidase IV (DPP-4) inhibitory activity. Compounds that showed good to moderate activity were compared using linagliptin as standard. Compound 4x (IC50 = 1.12 nM) exhibited the most promising results. The special chemical feature of compound 4x also imparts good inhibition selectivity for DPP-4 over DPP-8/9. Moreover, docking of compound 4x into the active site of DPP-4 illustrates its possible binding interactions.