RESUMO
Background: Thyroid nodules, increasingly prevalent globally, pose a risk of malignant transformation. Early screening is crucial for management, yet current models focus mainly on ultrasound features. This study explores machine learning for screening using demographic and biochemical indicators. Methods: Analyzing data from 6,102 individuals and 61 variables, we identified 17 key variables to construct models using six machine learning classifiers: Logistic Regression, SVM, Multilayer Perceptron, Random Forest, XGBoost, and LightGBM. Performance was evaluated by accuracy, precision, recall, F1 score, specificity, kappa statistic, and AUC, with internal and external validations assessing generalizability. Shapley values determined feature importance, and Decision Curve Analysis evaluated clinical benefits. Results: Random Forest showed the highest internal validation accuracy (78.3%) and AUC (89.1%). LightGBM demonstrated robust external validation performance. Key factors included age, gender, and urinary iodine levels, with significant clinical benefits at various thresholds. Clinical benefits were observed across various risk thresholds, particularly in ensemble models. Conclusion: Machine learning, particularly ensemble methods, accurately predicts thyroid nodule presence using demographic and biochemical data. This cost-effective strategy offers valuable insights for thyroid health management, aiding in early detection and potentially improving clinical outcomes. These findings enhance our understanding of the key predictors of thyroid nodules and underscore the potential of machine learning in public health applications for early disease screening and prevention.
Assuntos
Aprendizado de Máquina , Nódulo da Glândula Tireoide , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/epidemiologia , Nódulo da Glândula Tireoide/diagnóstico por imagem , Humanos , Feminino , Masculino , China/epidemiologia , Estudos Transversais , Pessoa de Meia-Idade , Adulto , Detecção Precoce de Câncer/métodos , Idoso , Programas de Rastreamento/métodos , Ultrassonografia/métodosRESUMO
Chronic postsurgical pain (CPSP) affects postoperative rehabilitation and quality of life in patients, but its mechanisms are still poorly understood. Hyperbaric oxygen (HBO) attenuates neuropathic pain in animal and human studies, but its efficacy for CPSP treatment and its underlying mechanism have not been elucidated. This study aimed to investigate the analgesic effect of HBO in a CPSP rat model and the role of spinal cord adenosine circulation in HBO-induced analgesia. A skin/muscle incision and retraction (SMIR) rat model was used to mimic CPSP, and HBO treatment (2.5 atmospheric absolute, 60 minutes) was administered once daily for 5 consecutive days beginning 3 days after surgery. The role of spinal cord adenosine circulation in HBO-induced analgesia was investigated using ß-methylene ADP (a CD73 inhibitor), 8-cyclopentyl-1,3-dipropylxanthine (an A1R antagonist), or an intrathecal injection of adenosine. The mechanical paw withdrawal threshold was determined at different timepoints before and after surgery. The spinal cord adenosine and adenosine triphosphate (ATP) contents were analyzed using high-performance liquid chromatography, and the spinal cord expression of adenosine-1 receptor (A1R), extracellular 5'-nucleotidase (CD73), and adenosine kinase (ADK) was examined by Western blotting and immunofluorescence staining. The results showed that the mechanical paw withdrawal threshold of the ipsilateral hind paw and the adenosine content decreased, and the spinal cord expression of A1R, CD73, and ADK and ATP content increased within 14 days after surgery. HBO treatment alleviated mechanical allodynia, reduced ATP content, and increased adenosine content by activating CD73 but downregulated the spinal cord expression of A1R, CD73, and ADK. Intrathecal adenosine alleviated mechanical allodynia after SMIR and downregulated the spinal cord expression of A1R and CD73, and intrathecal ß-methylene ADP or 8-cyclopentyl-1,3-dipropylxanthine attenuated the analgesic effect of HBO treatment on SMIR-induced CPSP. PERSPECTIVE: Spinal cord adenosine is involved in the occurrence and development of CPSP, and HBO treatment alleviates CPSP by regulating adenosine production/metabolism in the spinal cord. Thus, HBO may be employed for the treatment of CPSP with favorable efficacy.
RESUMO
Substituting hydrogen with deuterium in drug molecules is an appealing bioisosteric strategy for the generation of novel chemical entities in drug development. Optimizing lead compounds through deuteration has proven to be challenging and unpredictable, particularly for compounds with multiple metabolic sites. This study presents the pioneering achievement of substituting up to 19 hydrogen atoms with deuterium on 1,4-benzodiazepine-2,5-dione derivatives, shedding light on the structure-metabolism relationship and the impact of multiple deuterations on drug-like properties. Notably, the deuterated compound 3f exhibited remarkable antitumor activity in vivo and demonstrated favorable drug-like properties as a drug candidate.
Assuntos
Antineoplásicos , Deutério , Deutério/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Humanos , Relação Estrutura-Atividade , Linhagem Celular Tumoral , Camundongos , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Benzodiazepinas/síntese químicaRESUMO
Targeting dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been verified to regulate the progression of tau pathology as a promising treatment for Alzheimer's disease (AD), while the research progress on DYRK1A inhibitors seemed to be in a bottleneck period. In this work, we identified 32 (ZJCK-6-46) as the most potential DYRK1A inhibitor (IC50 = 0.68 nM) through rational design, systematic structural optimization, and comprehensive evaluation. Compound 32 exhibited acceptable in vitro absorption, distribution, metabolism, and excretion (ADME) properties and significantly reduced the expression of p-Tau Thr212 in Tau (P301L) 293T cells and SH-SY5Y cells. Moreover, compound 32 showed favorable bioavailability, blood-brain barrier (BBB) permeability, and the potential of ameliorating cognitive dysfunction by obviously reducing the expression of phosphorylated tau and neuronal loss in vivo, which was deserved as a valuable molecular tool to reveal the role of DYRK1A in the pathogenesis of AD and to further promote the development of anti-AD drugs.
Assuntos
Doença de Alzheimer , Quinases Dyrk , Inibidores de Proteínas Quinases , Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases , Proteínas tau , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Humanos , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Proteínas tau/metabolismo , Proteínas tau/antagonistas & inibidores , Relação Estrutura-Atividade , Administração Oral , Masculino , Ratos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Células HEK293 , Camundongos , Descoberta de Drogas , Fosforilação/efeitos dos fármacos , Simulação de Acoplamento Molecular , Ratos Sprague-DawleyRESUMO
INTRODUCTION: We aimed to compare early postoperative patient-reported outcomes between multiportal robotic-assisted thoracoscopic surgery (M-RATS) and uniportal video-assisted thoracoscopic surgery (U-VATS) for non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Symptom severity and functional status were measured using the Perioperative Symptom Assessment for Lung Surgery at pre-surgery, during postoperative hospitalisation, and within 4 weeks of discharge. A propensity score-matched (PSM) analysis of patients with NSCLC who were treated with M-RATS and U-VATS was performed. The symptom severity and daily functional status presented as proportion of moderate-to-severe scores on a 0-10-point scale, were compared using a generalised estimation equation model. RESULTS: We enrolled 762 patients with NSCLC from a prospective cohort (CN-PRO-Lung 3), including 151 and 611 who underwent M-RATS and U-VATS, respectively, before PSM analysis. After 1:1 PSM, two groups of 148 patients each were created. Pain severity (P = 0.019) and activity limitation (P = 0.001) during hospitalisation were higher in the M-RATS group. However, no significant differences existed post-discharge in pain (P = 0.383), cough (P = 0.677), shortness of breath (P = 0.526), disturbed sleep (P = 0.525), drowsiness (P = 0.304), fatigue (P = 0.153), distress (P = 0.893), walking difficulty (P = 0.242), or activity limitation (P = 0.513). M-RATS caused less intraoperative blood loss (P = 0.013), more stations of dissected lymph nodes (P = 0.001), more numbers of dissected lymph nodes (P = 0.001), and less tube drainage on the first postoperative day (P = 0.003) than U-VATS. CONCLUSION: M-RATS and U-VATS achieved comparable symptom burden and functional impairment after discharge. However, compared to U-VATS, M-RATS was associated with more severe pain and activity limitation in the short postoperative period. TRIAL REGISTRATION NUMBER: ChiCTR2000033016.
RESUMO
The development of selective modulators of cyclin-dependent kinases (CDKs), a kinase family with numerous members and functional variations, is a significant preclinical challenge. Recent advancements in crystallography have revealed subtle differences in the highly conserved CDK pockets. Exploiting these differences has proven to be an effective strategy for achieving excellent drug selectivity. While previous reports briefly discussed the structural features that lead to selectivity in individual CDK members, attaining inhibitor selectivity requires consideration of not only the specific structures of the target CDK but also the features of off-target members. In this review, we summarize the structure-activity relationships (SARs) that influence selectivity in CDK drug development and analyze the pocket features that lead to selectivity using molecular-protein binding models. In addition, in recent years, novel CDK modulators have been developed, providing more avenues for achieving selectivity. These cases were also included. We hope that these efforts will assist in the development of novel CDK drugs.
Assuntos
Quinases Ciclina-Dependentes , Inibidores de Proteínas Quinases , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Animais , Modelos MolecularesRESUMO
BACKGROUND: The relationship between monocyte-to-lymphocyte ratio (MLR) and prognosis in patients with chronic kidney disease (CKD) remains unclear. The aim of this study was to investigate the association between MLR and both all-cause mortality and cardiovascular disease (CVD) mortality in patients with CKD. METHODS: This study analyzed data from National Health and Nutrition Examination Survey 2003-2010. This study included 11262 eligible subjects, and 3015 of them were with CKD. We first compared the differences in clinical characteristics between individuals with and without CKD, and then grouped the CKD population based on quartiles of MLR. The partial correlation analysis was conducted to assess the relationships between MLR and some important clinical features. Cox proportional hazards models were used to investigate the associations between MLR and mortality from all-cause and cardiovascular disease. Restricted cubic spline (RCS) was used to investigate the dose-response relationship between MLR and mortality, the receiver operating characteristic (ROC) curves is used to compare the efficacy of MLR with different clinical biological indicators in assessing the risk of death. RESULTS: During a median follow-up of 10.3 years in CKD population, 1398 (43%) all-cause deaths and 526 (16%) CVD deaths occurred. It has been found that individuals with CKD have higher MLR level. The partial correlation analysis results showed that even after adjusting for age, sex, and race, MLR is still correlated with blood glucose, lipid levels, and kidney function indicators. The results of the cox proportional hazards regression model and Kaplan-Meier curve shown after adjusting for covariates, higher MLR was significantly associated with an increased risk of mortality. Consistent results were also observed when MLR was examined as categorical variable (quartiles). The RCS demonstrated a positive association between MLR and the risk of all-cause mortality and cardiovascular mortality. The ROC results indicate that the predictive efficacy of MLR for all-cause mortality risk is comparable to eGFR, higher than NLR and CRP. The predictive efficacy of MLR for cardiovascular mortality risk is higher than these three indicators. CONCLUSION: Compared to non-CKD population, the CKD population has higher levels of MLR. In the CKD population, MLR is positively correlated with the risk of death. Furthermore, the predictive efficacy of MLR for mortality risk is higher than other clinical indicators. This suggests that MLR can serve as a simple and effective clinical indicator for predicting mortality risk in CKD patients.
Assuntos
Doenças Cardiovasculares , Monócitos , Inquéritos Nutricionais , Insuficiência Renal Crônica , Humanos , Masculino , Feminino , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Pessoa de Meia-Idade , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/sangue , Adulto , Prognóstico , Idoso , Linfócitos , Modelos de Riscos Proporcionais , Curva ROC , Causas de Morte , Estados Unidos/epidemiologia , Fatores de Risco , Contagem de Linfócitos , Taxa de Filtração GlomerularRESUMO
BACKGROUND: Analysis of patient-reported outcomes (PROs) offers valuable insights into distinguishing the effects of closely related medical procedures from the patient's perspective. In this study we compared symptom burden in patients undergoing uniportal thoracoscopic segmentectomy and wedge resection for peripheral small-sized non-small cell lung cancer (NSCLC). METHODS: This study included patients with peripheral NSCLC from an ongoing longitudinal prospective cohort study (CN-PRO-Lung 3) who underwent segmentectomy or wedge resection with tumor diameter ≤ 2 cm and consolidation tumor ratio (CTR) ≤ 0.5. PROs data were collected using the Perioperative Symptom Assessment for Lung Surgery questionnaire pre-operatively, daily post-surgery up to the fourth hospitalization day, and weekly post-discharge up to the fourth week. Propensity score matching and a generalized estimation equation model were employed to compare symptom severity. In addition, short-term clinical outcomes were compared. RESULTS: In total, data of 286 patients (82.4%) undergoing segmentectomy and 61 patients (17.6%) undergoing wedge resection were extracted from the cohort. No statistically significant differences were found in the proportion of moderate-to-severe symptoms and mean scores for pain, cough, shortness of breath, disturbed sleep, fatigue, drowsiness, and distress during the 4-day postoperative hospitalization or the 4-week post-discharge period before or after matching (all p > 0.05). Compared with segmentectomy, wedge resection showed better short-term clinical outcomes, including shorter operative time (p = 0.001), less intraoperative bleeding (p = 0.046), and lower total hospital costs (p = 0.002). CONCLUSIONS: The study findings indicate that uniportal thoracoscopic segmentectomy and wedge resection exert similar early postoperative symptom burden in patients with peripheral NSCLC (tumor diameter ≤ 2 cm and CTR ≤ 0.5). CLINICAL TRIAL REGISTRATION: Not applicable.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Assistência ao Convalescente , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Alta do Paciente , Pneumonectomia/métodos , Estudos ProspectivosRESUMO
BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is a rare and highly malignant type of non-small cell lung cancer (NSCLC), for which the treatment of choice is surgery. For peripheral PSC growing outward and invading the chest wall, a complete resection of the affected lung lobes and the invaded chest wall can improve long-term prognosis. However, when the extent of the resected chest wall is large, reconstruction is often required to reduce the risk of postoperative complications. Here, we present a case of PSC invading the chest wall treated with successful extended radical resection for lung cancer and chest wall reconstruction. CASE PRESENTATION: A 58-year-old male patient with a nodule in the right upper lobe that had been identified on physical examination 2 years before presentation presented to our hospital with a recent cough, expectoration, and chest pain. Imaging revealed a mass in the right upper lobe that had invaded the chest wall. Preoperative puncture pathology revealed poorly differentiated NSCLC. We performed extended radical resection for lung cancer under open surgery and reconstructed the chest wall using stainless steel wire and polypropylene meshes. The procedure was uneventful, and the patient was discharged 7 days postoperatively. Furthermore, the final pathology revealed PSC. CONCLUSIONS: This case underscores the feasibility of surgical R0 resection in patients with PSC with chest wall invasion and no lymph node metastasis, potentially enhancing long-term outcomes. The novel aspect of this case lies in the individualized chest wall reconstruction for a large defect, using cost-effective materials that offered satisfactory structural support and postoperative recovery, thereby providing a valuable reference for similar future surgical interventions.
Assuntos
Laparoscopia , Neoplasias Gástricas , Humanos , Duodeno/cirurgia , Gastrectomia , Neoplasias Gástricas/cirurgiaRESUMO
BACKGROUND: The association of visceral adiposity with mortality in older adults is conflicting. Whether age influences the predicting ability of visceral adiposity (VAI) for mortality remains unknown. This study uncovered the relationship between age-adjusted visceral adiposity index and mortality through the data of NHANES 2011-2014. METHODS: This study obtained data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014. The age-adjusted visceral adiposity index (AVAI) scores were expressed as quartiles. Receiver operating characteristics (ROC) curve analysis was also applied to compare the predictive ability for mortality. Multivariate weighted Cox regression models were constructed to explore the association between AVAI and mortality. Kaplan-Meier survival curves were conducted for survival analyses. Smooth curve fittings and two-piecewise linear models were applied to explore the relationships between AVAI and mortality. RESULTS: This study recruited 4281 subjects aged ≥ 18 years from the NHANES 2011-2014. The AUCs of AVAI were 0.82 (0.79, 0.86) and 0.89 (0.85, 0.92) for predicting all-cause mortality and cardiovascular mortality, which were superior to BMI, WC and VAI (all p < 0.05). AVAI is still an independent predictor for mortality adjusted for confounders. The associations of AVAI with all-cause and cardiovascular mortalities were dose-responsive, with higher AVAI scores indicating higher mortality risks. CONCLUSION: Age significantly improves the ability of VAI for predicting all-cause and cardiovascular mortality. Age-adjusted VAI is independently associated with mortality risk, and thus could be considered a reliable parameter for assessing mortality risk.
Assuntos
Adiposidade , Doenças Cardiovasculares , Humanos , Idoso , Inquéritos Nutricionais , Índice de Massa Corporal , Obesidade Abdominal/complicações , Doenças Cardiovasculares/etiologia , Fatores de RiscoRESUMO
A 60-year-old male patient suffered from frequent episodes of atrial tachycardia (AT), after the index procedure of catheter ablation for paroxysmal atrial fibrillation. During the repeat procedure, the activation map showed that the earliest activation site was located at the roof of left atrium. Multiple ablations at the earliest activation site on the roof failed to terminate the AT; however, ablation within the pulmonary artery at an adjacent anatomical site successfully eliminated the AT, even without recording distinct near-field potential.
RESUMO
Although lithium-sulfur batteries (LSBs) are considered as the promising next rechargeable storage system ascribing to their decent specific capacity of inorganic sulfur, the development is partially impeded by inferior electronic conductivity, severe shuttle effect, and large volume variation. To tackle the issues above, a great deal of effort is made on sulfur-containing polymer (SCP) that shows better electrochemical performance. Nevertheless, sluggish conversion of lithium polysulfides (LiPSs) obstructs battery performance yet. Herein, electrocatalytic LiPSs with full conversion by tailoring the interfacial electric field are discovered based on gold nanoparticles (AuNPs) anchored on sulfurized polyaniline (SPANI). A downhill path of Gibbs free energy from organosulfur polymer to intermediate product means more spontaneously and favorable for full conversion, as the significant enhancement of electron density of state in the vicinity of the HOMO level for the AuNPs increase the electron transition probability rate. This composite delivers satisfactory electrochemical performance, especially increased rate capacity of >300 mAh g-1. Furthermore, catalyst mechanism on molecule level is proposed that AuNPsdominate chemical enhancement and higher electron delocalizablility betweenAuNPs and LiPSs molecules. These results can erect a promising strategy for enhancing lithium polysulfides full conversion.
RESUMO
The power conversion efficiency of metal halide perovskite solar cells (PSCs) has increased dramatically in recent years, but there are still major bottlenecks in the commercial application of such materials, including intrinsic instability caused by external stimuli such as water, oxygen, and radiation, as well as local stress generated inside the perovskite and external stress caused by poor interlayer contact. However, some crucial sources of instability cannot be overcome by conventional encapsulation engineering. Among them, the tensile strain can weaken the chemical bonds in the perovskite lattice, thereby reducing the defects formation energy and activation energy of ion migration and accelerating the degradation rate of the perovskite crystal. This review expounds the latest in-depth understanding of microstrain in perovskite film from the thermodynamic sources and influences on the perovskite physicochemical structure and photoelectric performance. Furthermore, it also summarizes the effective strategies for strain regulation and interlayer contact performance improvement, which are conducive to the improvement of photovoltaic performance and internal stability of PSCs. Finally, we present a prospective outlook on how to achieve more stable and higher efficiency PSCs through strain engineering.
RESUMO
BACKGROUND: While the role of low-dose computed tomography (CT) in lung cancer screening is established, its limitations in detailing pulmonary vascular variations are less emphasized. Three-dimensional reconstruction technology allows surgeons to reconstruct a patient's bronchial and pulmonary vascular structures using CT scan results. However, low-dose CT may not provide the same level of clarity as enhanced CT in displaying pulmonary vascular details. This limitation can be unfavorable for preoperative detection of potential pulmonary vascular variations, especially in cases involving planned segmentectomy. CASE PRESENTATION: We report a case of a 58-year-old female with lung cancer, initially planned for Da Vinci robot-assisted thoracoscopic segmentectomy. Unexpectedly, during surgery, a pulmonary vein variation in the right upper lobe was discovered, leading to a change in the surgical method to a lobectomy. The patient had four variant right upper lobe veins draining into the superior vena cava and one into the left atrium. The surgery was complicated by significant bleeding and postoperative pulmonary congestion. Postoperative pathology confirmed adenocarcinoma. CONCLUSIONS: This case highlights the importance of meticulous intraoperative exploration, particularly in cases involving planned segmentectomy, as unexpected pulmonary vein variations can significantly affect surgical decision-making. While three-dimensional reconstruction based on preoperative CT data is a valuable tool, it may not capture the full complexity of the anatomical variations. We discuss potential preoperative imaging techniques, including contrast-enhanced CT and CT angiography, as methods to better identify these variations. The enhanced visualization provided by robot-assisted surgery plays a crucial role in identifying and adapting to these variations, underscoring the advantages of this surgical approach. Our report contributes to the existing literature by providing a detailed account of how these principles were applied in a real-world scenario, reinforcing the need for surgical adaptability and awareness of the limitations of low-dose CT in complex cases.
Assuntos
Neoplasias Pulmonares , Veias Pulmonares , Procedimentos Cirúrgicos Robóticos , Malformações Vasculares , Feminino , Humanos , Pessoa de Meia-Idade , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/cirurgia , Veias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/patologia , Veia Cava Superior/patologia , Detecção Precoce de Câncer , Pneumonectomia/métodos , Cirurgia Torácica Vídeoassistida/métodos , Malformações Vasculares/cirurgiaRESUMO
Carbon-based hole transport layer-free perovskite solar cells (PSCs) based on methylammonium lead triiodide (MAPbI3 ) have become one of the research focus due to low cost, easy preparation, and good optoelectronic properties. However, instability of perovskite under vacancy defects and stress-strain makes it difficult to achieve high-efficiency and stable power output. Here, a soft-structured long-chain 2D pentanamine iodide (abbreviated as "PI") is used to improve perovskite quality and interfacial mechanical compatibility. PI containing CH3 (CH2 )4 NH3 + and I- ions not only passivate defects at grain boundaries, but also effectively alleviate residual stress during high temperature annealing via decreasing Young's modulus of perovskite film. Most importantly, PI effectively increases matching degree of Young's modulus between MAPbI3 (47.1 GPa) and carbon (6.7 GPa), and strengthens adhesive fracture energy (Gc ) between perovskite and carbon, which is helpful for outward release of nascent interfacial stress generated under service conditions. Consequently, photoelectric conversion efficiency (PCE) of optimal device is enhanced from 10.85% to 13.76% and operational stability is also significantly improved. 83.1% output is maintained after aging for 720 h at room temperature and 25-60% relative humidity (RH). This strategy of regulation from chemistry and physics provides a strategy for efficient and stable carbon-based PSCs.
RESUMO
Multitarget-directed ligands (MTDLs) have recently attracted significant interest due to their superior effectiveness in multifactorial Alzheimer's disease (AD). Combined inhibition of two important AD targets, glycogen synthase kinase-3ß (GSK-3ß) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), may be a breakthrough in the treatment of AD. Based on our previous work, we have designed and synthesized a series of novel harmine derivatives, investigated their inhibition of GSK-3ß and DYRK1A, and evaluated a variety of biological activities. The results of the experiments showed that most of these compounds exhibited good activity against GSK-3ß and DYRK1A in vitro. ZLQH-5 was selected as the best compound due to the most potent inhibitory effect against GSK-3ß and DYRK1A. Molecular docking studies demonstrated that ZLQH-5 could form stable interactions with the ATP binding pocket of GSK-3ß and DYRK1A. In addition, ZLQH-5 showed low cytotoxicity against SH-SY5Y and HL-7702, good blood-brain barrier permeability, and favorable pharmacokinetic properties. More importantly, ZLQH-5 also attenuated the tau hyperphosphorylation in the okadaic acid SH-SY5Y cell model. These results indicated that ZLQH-5 could be a promising dual-target drug candidate for the treatment of AD.
Assuntos
Doença de Alzheimer , Neuroblastoma , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Glicogênio Sintase Quinase 3 beta , Harmina/farmacologia , Harmina/uso terapêutico , Proteínas tau/metabolismo , Proteínas tau/uso terapêutico , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , FosforilaçãoRESUMO
Background: Ischemic stroke is a significant global health issue, imposing substantial social and economic burdens. Carotid artery plaques (CAP) serve as an important risk factor for stroke, and early screening can effectively reduce stroke incidence. However, China lacks nationwide data on carotid artery plaques. Machine learning (ML) can offer an economically efficient screening method. This study aimed to develop ML models using routine health examinations and blood markers to predict the occurrence of carotid artery plaques. Methods: This study included data from 5,211 participants aged 18-70, encompassing health check-ups and biochemical indicators. Among them, 1,164 participants were diagnosed with carotid artery plaques through carotid ultrasound. We constructed six ML models by employing feature selection with elastic net regression, selecting 13 indicators. Model performance was evaluated using accuracy, sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV), F1 score, kappa value, and Area Under the Curve (AUC) value. Feature importance was assessed by calculating the root mean square error (RMSE) loss after permutations for each variable in every model. Results: Among all six ML models, LightGBM achieved the highest accuracy at 91.8%. Feature importance analysis revealed that age, Low-Density Lipoprotein Cholesterol (LDL-c), and systolic blood pressure were important predictive factors in the models. Conclusion: LightGBM can effectively predict the occurrence of carotid artery plaques using demographic information, physical examination data and biochemistry data.
RESUMO
Melatonin, a neurohormone secreted by the pineal gland and regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus, is synthesized and directly released into the cerebrospinal fluid (CSF) of the third ventricle (3rdv), where it undergoes rapid absorption by surrounding tissues to exert its physiological function. The hippocampus, a vital structure in the limbic system adjacent to the ventricles, plays a pivotal role in emotional response and memory formation. Melatonin MT1 and MT2 receptors are G protein-coupled receptors (GPCRs) that primarily mediate melatonin's receptor-dependent effects. In comparison to the MT1 receptor, the widely expressed MT2 receptor is crucial for mediating melatonin's biological functions within the hippocampus. Specifically, MT2 receptor is implicated in hippocampal synaptic plasticity and memory processes, as well as neurogenesis and axogenesis. Numerous studies have demonstrated the involvement of MT2 receptors in the pathophysiology and pharmacology of Alzheimer's disease, depression, and epilepsy. This review focuses on the anatomical localization of MT2 receptor in the hippocampus, their physiological function in this region, and their signal transduction and pharmacological roles in neurological disorders. Additionally, we conducted a comprehensive review of MT2 receptor ligands used in psychopharmacology and other MT2-selective ligands over recent years. Ultimately, we provide an outlook on future research for selective MT2 receptor drug candidates.
Assuntos
Doença de Alzheimer , Melatonina , Humanos , Hipocampo/metabolismo , Receptor MT2 de Melatonina/metabolismo , Receptor MT1 de Melatonina/metabolismoRESUMO
BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is a unique receptor expressed by macrophages in atherosclerotic plaque and is involved in the progression of atherosclerosis. Whether serum soluble TREM2 (sTREM2) levels has a relationship with coronary heart disease (CHD) remains unclear. METHODS: The cross-sectional study included 86 patients with CHD and 86 controls matched with age and sex. Demographic information, medication history, and laboratory data were collected. sTREM2 concentrations were detected by enzyme-linked immunosorbent assay. We compared the sTREM2 levels in two groups and constructed stepwise linear regression analysis for factors related to the sTREM2 level in patients with CHD; we further used the logistic regression model to evaluate the relationship between sTREM2 and CHD. The diagnostic value of sTREM2 and other biomarkers in CHD was evaluated by the receiver operating characteristic curve (ROC). RESULTS: The serum level of sTREM2 in CHD patients is higher than that in controls. In CHD patients, the stepwise linear regression analysis found that sTREM2 levels were correlated with triglyceride (TG), high-density lipoprotein cholesterols (HDL-C), apolipoprotein B (ApoB) and smoking status. Logistic regression models showed that sTREM2 was associated independently with CHD after adjusted confounders. The ROC curve showed a sensitivity of 59.3% and specificity of 81.4% with an area under the curve of 0.781 (95% CI: 0.711-0.852) for the diagnosis of CHD with serum sTREM2 at a cut-off value of > 1104.894 pg/ml, indicating a higher diagnostic value than high sensitivity C reaction protein (hs-CRP) and apolipoprotein B (ApoB). CONCLUSION: In this study, we provide evidence that sTREM2 levels are elevated in CHD patients and are associated with various cardiovascular risk factors. Additionally, sTREM2 demonstrates better diagnostic performance compared to traditional indicators in identifying CHD. These findings suggest that sTREM2 may serve as a potential biomarker for coronary heart disease.