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1.
Front Endocrinol (Lausanne) ; 15: 1378968, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38601205

RESUMO

Background: Currently, the primary treatment modalities for colorectal neuroendocrine tumors (CRNET) with a diameter between 10mm and 20mm are surgical resection (SR) and endoscopic resection (ER). However, it remains unclear which surgical approach yields the greatest survival benefit for patients. Methods: This study included data from patients diagnosed with CRNET with tumor diameters ranging from 10mm to 20mm between the years 2004 and 2019, obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were categorized into ER and SR groups based on the respective surgical approaches. Inverse probability weighting (IPTW) was employed to mitigate selection bias. Kaplan-Meier analysis and log-rank tests were utilized to estimate overall survival (OS) and cancer-specific survival (CSS). Cox regression analysis (univariate and multivariate) was performed to evaluate potential factors influencing survival. Results: A total of 292 CRNET patients were included in this study (ER group: 108 individuals, SR group: 184 individuals). Prior to IPTW adjustment, Kaplan-Meier analysis and Cox proportional hazard regression analysis demonstrated that the OS and CSS of the SR group were inferior to those of the ER group. However, after IPTW adjustment, no statistically significant differences in prognosis were observed between the two groups. Subgroup analyses revealed that patients with muscular invasion, positive lymph nodes, or distant metastasis derived greater survival benefits from SR. Significant differences in OS and CSS between the two groups were also observed across different age groups. Conclusion: For patients with mucosal-limited lesions and without local lymph node or distant metastasis, ER is the preferred surgical approach. However, for patients with muscular invasion or positive lymph nodes/distant metastasis, SR offers a better prognosis. The choice of surgical approach should be based on the specific clinical characteristics of patients within different subgroups.


Assuntos
Neoplasias Colorretais , Tumores Neuroendócrinos , Humanos , Tumores Neuroendócrinos/patologia , Prognóstico , Linfonodos/patologia , Neoplasias Colorretais/cirurgia , Neoplasias Colorretais/patologia , Probabilidade
2.
Heliyon ; 10(8): e29650, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38660242

RESUMO

Introduction: The mechanism of thymoma-associated myasthenia gravis (TAMG) is currently unknown, although patients with TAMG experience more severe myasthenic symptoms and have worse prognoses compared to regular thymoma patients. The objective of this research is to create a transcriptome map of TAMG using genes linked to disulfidptosis, detect possible biomarkers, and examine the disparities in the tumor immune microenvironment (TIME) among different thymoma patients. The findings will offer valuable knowledge for personalized treatment alternatives. Methods: Thymoma samples' RNA-seq data, along with their corresponding clinical data, were acquired from the TCGA database using methods. Next, genes and disulfidptosis-related lncRNAs(DRLs) were chosen through correlation analysis. Then, a prediction model of TAMG was established by LASSO regression. Subsequent to that, an analysis of the mutation data, the tumor mutational burden (TMB), and the assessment of immune and stromal elements within the tumor microenvironment were conducted. Results: A total of 87 patients diagnosed with thymoma were included in the study, with 29 of them having TAMG. We discovered a group of 325 lncRNAs in this sample that showed significant associations with genes related to disulfidptosis, with 25 of them displaying significantly altered expression. Moreover, utilizing LASSO regression, we constructed a predictive model incorporating 11 DRLs. The analysis revealed an area under the curve (AUC) of 0.934 (CI 0.879-0.989), a cut-off value of 0.797, along with a sensitivity of 82.8 % and specificity of 93.1 %. Furthermore, we examined the TIME in both the high-risk and low-risk groups, and observed noteworthy disparities in B cells, T cells, and APC among the two groups (p < 0.05). Conclusion: This research offers the initial examination of genes associated with disulfidptosis and TAMG through genomic and transcriptomic analysis. Furthermore, a strong risk forecasting model was created and the significance of TIME in TAMG was also clarified. The discoveries offer significant understanding into the molecular processes of TAMG and present possible indicators for categorizing risk.

3.
Eur Respir J ; 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38514095

RESUMO

INTRODUCTION: Patients with allergic bronchopulmonary aspergillosis (ABPA) suffer from repeated exacerbations. However, the involvement of T cell subsets remains unclear. METHODS: We enrolled ABPA patients, asthma patients and healthy controls. Th1, Th2, Th17, Treg and IL-21+CD4+T cells in total or sorted subsets of peripheral blood mononuclear cells (PBMCs) and ABPA Bronchoalveolar Lavage fluid (BALF) were analyzed by flow cytometry. RNA sequencing of subsets of CD4+T cells were done in exacerbated ABPA patients and healthy controls. Antibodies of T-B cell co-cultures in vitro were measured. RESULTS: ABPA patients had increased Th2 cells, similar Treg cells and decreased circulating Th1 and Th17 cells. IL-5+IL-13+IL-21+CD4+T cells was rarely detected in healthy controls but significantly elevated in the blood of ABPA patients, especially the exacerbated ones. We found that IL-5+IL-13+IL-21+CD4+T cells were mainly peripheral T helper (Tph) cells (PD-1+CXCR5-), which also presented in the BALF of ABPA patients. The proportions of circulating Tph were similar among ABPA patients, asthma patients and healthy controls, while IL-5+IL-13+IL-21+ Tph cells significantly increased in ABPA patients. Transcriptome data showed that Tph cells of ABPA patients were Th2-skewed and exhibited signatures of follicular T helper (Tfh) cells. When co-cultured in vitro, Tph cells of ABPA patients induced the differentiation of autologous B cells into plasmablasts and significantly enhanced the production of IgE. CONCLUSION: We identified a distinctly elevated population of circulating Th2-skewed Tph cells that induced the production of IgE in ABPA patients. It may be a biomarker and therapeutic target for ABPA.

4.
Cardiovasc Diabetol ; 23(1): 95, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38486275

RESUMO

OBJECTIVE: The association of the triglyceride-glucose (TyG) index with intracranial atherosclerotic stenosis (ICAS) and extracranial atherosclerotic stenosis (ECAS) is unclear. This study aimed to investigate the relationship of TyG index with the distribution and severity of ICAS and ECAS. METHOD: Patients who underwent digital subtraction angiography (DSA) for evaluating ICAS/ECAS in Zhongnan Hospital of Wuhan University from January 2017 to October 2021 were retrospectively enrolled in our study. Clinical characteristics, DSA data, blood routine, lipid profile and fasting glucose were recorded. The association of TyG index and ICAS/ECAS status were investigated in four aspects: location and distribution of stenosis, stenosis severity and whether stenosis is symptomatic. Logistic regression models were used to evaluate the association. Restricted cubic splines were constructed to model the non-linear relationship between the TyG index and different arterial stenosis status. RESULTS: Among 1129 included patients, the median age was 62 (IQR 55-68) years, and 71.3% were male. The median TyG index was 8.81 (8.40, 9.21). Elevated TyG index was significantly associated with ICAS, combined ICAS/ECAS, anterior circulation stenosis, posterior circulation stenosis, combined anterior/posterior circulation stenosis, severe stenosis, both asymptomatic and symptomatic stenosis. This association was maintained after adjusting for age, sex, smoking, drinking, medical history of hypertension and stroke, platelet, total cholesterol, high-density lipoprotein, and low-density lipoprotein. Multivariable-adjusted spline regression models showed that a progressively increasing risk of arterial stenosis was related to an elevated TyG index. CONCLUSION: Elevated TyG index was associated with ICAS/ECAS. TyG index might be a useful indicator of ICAS and severe stenosis.


Assuntos
Glucose , Lipoproteínas HDL , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Triglicerídeos , Estudos Retrospectivos , Constrição Patológica
5.
Immun Ageing ; 21(1): 14, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317229

RESUMO

The gradual aging of the global population has led to a surge in age-related diseases, which seriously threaten human health. Researchers are dedicated to understanding and coping with the complexities of aging, constantly uncovering the substances and mechanism related to aging like chronic low-grade inflammation. The NOD-like receptor protein 3 (NLRP3), a key regulator of the innate immune response, recognizes molecular patterns associated with pathogens and injury, initiating an intrinsic inflammatory immune response. Dysfunctional NLRP3 is linked to the onset of related diseases, particularly in the context of aging. Therefore, a profound comprehension of the regulatory mechanisms of the NLRP3 inflammasome in aging-related diseases holds the potential to enhance treatment strategies for these conditions. In this article, we review the significance of the NLRP3 inflammasome in the initiation and progression of diverse aging-related diseases. Furthermore, we explore preventive and therapeutic strategies for aging and related diseases by manipulating the NLRP3 inflammasome, along with its upstream and downstream mechanisms.

6.
Nat Rev Nephrol ; 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38409369

RESUMO

Kidney disease affects more than 10% of the global population and is associated with considerable morbidity and mortality, highlighting a need for new therapeutic options. Engineered nanoparticles for the treatment of kidney diseases (renal nanomedicines) represent one such option, enabling the delivery of targeted therapeutics to specific regions of the kidney. Although they are underdeveloped compared with nanomedicines for diseases such as cancer, findings from preclinical studies suggest that renal nanomedicines may hold promise. However, the physiological principles that govern the in vivo transport and interactions of renal nanomedicines differ from those of cancer nanomedicines, and thus a comprehensive understanding of these principles is needed to design nanomedicines that effectively and specifically target the kidney while ensuring biosafety in their future clinical translation. Herein, we summarize the current understanding of factors that influence the glomerular filtration, tubular uptake, tubular secretion and extrusion of nanoparticles, including size and charge dependency, and the role of specific transporters and processes such as endocytosis. We also describe how the transport and uptake of nanoparticles is altered by kidney disease and discuss strategic approaches by which nanoparticles may be harnessed for the detection and treatment of a variety of kidney diseases.

7.
Environ Sci Pollut Res Int ; 31(11): 17417-17425, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38337116

RESUMO

Wastewater treatment plants (WWTPs) are one of the most important sources and sinks for per- and polyfluoroalkyl substances (PFAS). However, limited studies have evaluated short-term temporal variability of PFAS in WWTPs, particularly for their intra-day variations. For this purpose, a time-composite sampling campaign was carried out at a WWTP influent from South China for 1 week. Five out of ten PFAS were found in the influent, i.e., perfluoroheptanoic acid (PFHpA), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorobutane sulfonic acid (PFBS), and perfluorooctanesulfonic acid (PFOS). PFOA was the most domain PFAS whereas PFOS was detected occasionally, which might be associated with the prohibition of PFOS use in China. For the first time, we observed significant intra-day fluctuations in mass fluxes for PFOS. Different from a morning peak of pharmaceuticals reported previously, PFOS mass loads fluctuated sharply at noon and night on the weekdays. Furthermore, the mass fluxes of PFOA on the weekend were significantly elevated. For the other PFAS detected, no significant diurnal variations in mass loads were identified. Correlation analysis indicated that domestic activities (e.g., home cleaning) are likely to be the major source of these perfluorocarboxylic acids especially PFOA. In addition, flow fluxes had little effects on these PFAS mass load. These results can aid in future sampling campaigns and optimizing removal strategies for PFAS in wastewater.


Assuntos
Ácidos Alcanossulfônicos , Caprilatos , Fluorocarbonos , Purificação da Água , Águas Residuárias , Fluorocarbonos/análise , China
8.
J Exp Clin Cancer Res ; 43(1): 5, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38163866

RESUMO

BACKGROUND: Tumor-associated inflammation suggests that anti-inflammatory medication could be beneficial in cancer therapy. Loratadine, an antihistamine, has demonstrated improved survival in certain cancers. However, the anticancer mechanisms of loratadine in lung cancer remain unclear. OBJECTIVE: This study investigates the anticancer mechanisms of loratadine in lung cancer. METHODS: A retrospective cohort of 4,522 lung cancer patients from 2006 to 2018 was analyzed to identify noncancer drug exposures associated with prognosis. Cellular experiments, animal models, and RNA-seq data analysis were employed to validate the findings and explore the antitumor effects of loratadine. RESULTS: This retrospective study revealed a positive association between loratadine administration and ameliorated survival outcomes in lung cancer patients, exhibiting dose dependency. Rigorous in vitro and in vivo assays demonstrated that apoptosis induction and epithelial-mesenchymal transition (EMT) reduction were stimulated by moderate loratadine concentrations, whereas pyroptosis was triggered by elevated dosages. Intriguingly, loratadine was found to augment PPARγ levels, which acted as a gasdermin D transcription promoter and caspase-8 activation enhancer. Consequently, loratadine might incite a sophisticated interplay between apoptosis and pyroptosis, facilitated by the pivotal role of caspase-8. CONCLUSION: Loratadine use is linked to enhanced survival in lung cancer patients, potentially due to its role in modulating the interplay between apoptosis and pyroptosis via caspase-8.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Animais , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Loratadina/farmacologia , Loratadina/uso terapêutico , Estudos Retrospectivos , Caspase 8 , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Prognóstico
9.
Nano Lett ; 24(5): 1570-1578, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38287297

RESUMO

Glioblastoma (GBM) is the most complex and lethal primary brain cancer. Adequate drug diffusion and penetration are essential for treating GBM, but how the spatial heterogeneity in GBM impacts drug diffusion and transport is poorly understood. Herein, we report a new method, photoactivation of plasmonic nanovesicles (PANO), to measure molecular diffusion in the extracellular space of GBM. By examining three genetically engineered GBM mouse models that recapitulate key clinical features including the angiogenic core and diffuse infiltration, we found that the tumor margin has the lowest diffusion coefficient (highest tortuosity) compared with the tumor core and surrounding brain tissue. Analysis of the cellular composition shows that tortuosity in the GBM is strongly correlated with neuronal loss and astrocyte activation. Our all-optical measurement reveals the heterogeneous GBM microenvironment and highlights the tumor margin as a diffusion barrier for drug transport in the brain, with implications for therapeutic delivery.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Camundongos , Animais , Glioblastoma/patologia , Neoplasias Encefálicas/tratamento farmacológico , Encéfalo/patologia , Linhagem Celular Tumoral , Espaço Extracelular , Microambiente Tumoral
10.
Bio Protoc ; 14(2): e4920, 2024 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-38268976

RESUMO

The blood-brain barrier (BBB) is a major obstacle to the diagnostics and treatment of many central nervous system (CNS) diseases. A prime example of this challenge is seen in glioblastoma (GBM), the most aggressive and malignant primary brain tumor. The BBB in brain tumors, or the blood-brain-tumor barrier (BBTB), prevents the efficient delivery of most therapeutics to brain tumors. Current strategies to overcome the BBB for therapeutic delivery, such as using hyperosmotic agents (mannitol), have impeded progress in clinical translation limited by the lack of spatial resolution, high incidences of complications, and potential for toxicity. Focused ultrasound combined with intravenously administered microbubbles enables the transient disruption of the BBB and has progressed to early-phase clinical trials. However, the poor survival with currently approved treatments for GBM highlights the compelling need to develop and validate treatment strategies as well as the screening for more potent anticancer drugs. In this protocol, we introduce an optical method to open the BBTB (OptoBBTB) for therapeutic delivery via ultrashort pulse laser stimulation of vascular targeting plasmonic gold nanoparticles (AuNPs). Specifically, the protocol includes the synthesis and characterization of vascular-targeting AuNPs and a detailed procedure of optoBBTB. We also report the downstream characterization of the drug delivery and tumor treatment efficacy after BBB modulation. Compared with other barrier modulation methods, our optical approach has advantages in high spatial resolution and minimally invasive access to tissues. Overall, optoBBTB allows for the delivery of a variety of therapeutics into the brain and will accelerate drug delivery and screening for CNS disease treatment. Key features • Pulsed laser excitation of vascular-targeting gold nanoparticles non-invasively and reversibly modulates the blood-brain barrier permeability. • OptoBBTB enhances drug delivery in clinically relevant glioblastoma models. • OptoBBTB has the potential for drug screening and evaluation for superficial brain tumor treatment.

11.
World J Gastrointest Oncol ; 16(1): 214-233, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38292844

RESUMO

BACKGROUND: The effectiveness of neoadjuvant therapy in esophageal cancer (EC) treatment is still a subject of debate. AIM: To compare the clinical efficacy and toxic side effects between neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant chemotherapy (nCT) for locally advanced EC (LAEC). METHODS: A comprehensive search was conducted using multiple databases, including PubMed, EMBASE, MEDLINE, Science Direct, The Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, Chinese Science and Technology Journal Database, and Chinese Biomedical Literature Database Article. Studies up to December 2022 comparing nCRT and nCT in patients with EC were selected. RESULTS: The analysis revealed significant differences between nCRT and nCT in terms of disease-free survival. The results indicated that nCRT provided better outcomes in terms of the 3-year overall survival rate (OSR) [odds ratio (OR) = 0.95], complete response rate (OR = 3.15), and R0 clearance rate (CR) (OR = 2.25). However, nCT demonstrated a better 5-year OSR (OR = 1.02) than nCRT. Moreover, when compared to nCRT, nCT showed reduced risks of cardiac complications (OR = 1.15) and pulmonary complications (OR = 1.30). CONCLUSION: Overall, both nCRT and nCT were effective in terms of survival outcomes for LAEC. However, nCT exhibited better performance in terms of postoperative complications.

12.
Small Methods ; 8(1): e2301117, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37922523

RESUMO

Live imaging of the brain extracellular matrix (ECM) provides vital insights into changes that occur in neurological disorders. Current techniques such as second or third-harmonic generation offer limited contrast for live imaging of the brain ECM. Here, a new method, pan-ECM via chemical labeling of extracellular proteins, is introduced for live brain ECM imaging. pan-ECM labels all major ECM components in live tissue including the interstitial matrix, basement membrane, and perineuronal nets. pan-ECM enables in vivo observation of the ECM heterogeneity between the glioma core and margin, as well as the assessment of ECM deterioration under stroke condition, without ECM shrinkage from tissue fixation. These findings indicate that the pan-ECM approach is a novel way to image the entire brain ECM in live brain tissue with optical resolution. pan-ECM has the potential to advance the understanding of ECM in brain function and neurological diseases.


Assuntos
Doenças do Sistema Nervoso , Acidente Vascular Cerebral , Humanos , Matriz Extracelular/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Acidente Vascular Cerebral/metabolismo , Doenças do Sistema Nervoso/diagnóstico por imagem , Doenças do Sistema Nervoso/metabolismo , Membrana Basal
13.
Interdiscip Sci ; 16(1): 104-122, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37976024

RESUMO

Vascular disease is one of the major causes of death worldwide. Endothelial cells are important components of the vascular structure. A better understanding of the endothelial cell changes in the development of vascular disease may provide new targets for clinical treatment strategies. Single-cell RNA sequencing can serve as a powerful tool to explore transcription patterns, as well as cell type identity. Our current study is based on comprehensive scRNA-seq data of several types of human vascular disease datasets with deep-learning-based algorithm. A gene set scoring system, created based on cell clustering, may help to identify the relative stage of the development of vascular disease. Metabolic preference patterns were estimated using a graphic neural network model. Overall, our study may provide potential treatment targets for retaining normal endothelial function under pathological situations.


Assuntos
Perfilação da Expressão Gênica , Doenças Vasculares , Humanos , Células Endoteliais , Análise de Sequência de RNA , Análise da Expressão Gênica de Célula Única , Algoritmos , Artérias , Análise por Conglomerados
14.
Chem Biol Interact ; 387: 110795, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-37956922

RESUMO

In order to search for novel antitumor drugs with high efficiency and low toxicity, the anti-lung cancer activity of phytosphingosine was studied. Phytosphingosine is widely distributed in fungi, plants, animals, and has several biological activities, including anti-inflammation and anti-tumor. However, its anti-lung cancer activity needs to be further investigated. The effects and pharmacological mechanisms of phytosphingosine on lung cancer treatment were investigated both in vitro and in vivo. The results showed that phytosphingosine inhibited the growth of lung cancer cell lines. Phytosphingosine induced apoptosis through a mitochondria-mediated pathway, phytosphingosine arrested the cell cycle at the G2/M phase and induced apoptosis in a dose-dependent manner by increasing Bax/Bcl-2 ratio, which caused the decrease of mitochondrial membrane potential to promote the release of cytochrome C, caspase 9 and 3, and degrade PARP in A549 cells. The results showed that phytosphingosine could damage the mitochondrial functions, increase ROS levels, and arrest the cell cycle at the G2/M stages. Finally, phytosphingosine also inhibited the growth of tumor in mice. Taken together, phytosphingosine suppressed the growth of lung cancer cells both in vitro and in vivo and had potential application in the research and development of antitumor drugs. The aim of the present study was to explain the theoretical basis of phytosphingosine therapy for lung cancer and providing new possibilities for lung cancer treatment.


Assuntos
Adenocarcinoma de Pulmão , Antineoplásicos , Neoplasias Pulmonares , Animais , Camundongos , Apoptose , Morte Celular , Mitocôndrias , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Mitose , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral
15.
Front Neurol ; 14: 1257795, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37928162

RESUMO

Background: White matter lesion (WML) is an age-related disorder associated with stroke and cognitive impairment. This study aimed to investigate the risk factors and build a predictive model of WML in young- and middle-aged people. Methods: We performed a second analysis of the data from the Dryad Digital Repository. We selected those people who are <60 years old and randomly divided them into the training group and the validation group. We investigated the risk factors of WML in the training group with logistic regression analysis and built a prediction nomogram based on multivariate logistic regression analysis; finally, the performance of the prediction nomogram was evaluated for discrimination, accuracy, and clinical utility. Results: There were 308 people in the training group and 723 people in the validation group. Multivariate regression analysis showed that the age (OR = 1.49, 95% CI: 1.31-1.70), diastolic blood pressure (OR = 1.02, 95% CI: 1.00-1.03), carotid plaque score (OR = 1.31, 95% CI: 1.14-1.50), female gender (OR = 2.27, 95% CI: 1.56-3.30), and metabolic syndrome (OR = 2.12, 95% CI: 1.22-3.70) were significantly associated with white matter lesions. The area under the curve value (AUC) of the receiver operating curve (ROC) was 0.734 for the training group and 0.642 for the validation group. The calibration curve and clinical impact curve showed that the prediction nomogram has good accuracy and clinical application value. Conclusion: Age, diastolic blood pressure, carotid plaque score, female gender, and metabolic syndrome were risk factors in young- and middle-aged people <60 years old with WML, and the nomogram based on these risk factors showed good discrimination, accuracy, and clinical utility.

16.
Clin Exp Hypertens ; 45(1): 2278205, 2023 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-37970663

RESUMO

Pulmonary arterial hypertension (PAH) is a disease with a high mortality and few treatment options to prevent the development of pulmonary vessel remodeling, pulmonary vascular resistance, and right ventricular failure. Canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is originally used in diabetes patients which could assist the glucose excretion and decrease blood glucose. Recently, a few studies have reported the protective effect of SGLT2 inhibitor on monocrotaline-induced PAH. However, the effects of canagliflozin on hypobaric hypoxia-induced PAH as well as its mechanism still unclear. In this study, we used hypobaric hypoxia-induced PAH mice model to demonstrate if canagliflozin could alleviate PAH and prevent pulmonary vessel remodeling. We found that daily canagliflozin administration significantly improved survival in mice with hypobaric hypoxia-induced PAH compared to vehicle control. Canagliflozin treatment significantly reduced right ventricular systolic pressure and increased pulmonary acceleration time determined by hemodynamic assessments. Canagliflozin significantly reduced medial wall thickening and decreased muscularization of pulmonary arterioles compared to vehicle treated mice. In addition, canagliflozin inhibited the proliferation and migration of pulmonary arterial smooth muscle cells through suppressing glycolysis and reactivating AMP-activated protein kinase signaling pathway under hypoxia condition. In summary, our findings suggest that canagliflozin is sufficient to inhibit pulmonary arterial remodeling which is a potential therapeutic strategy for PAH treatment.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Humanos , Camundongos , Animais , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Canagliflozina/efeitos adversos , Artéria Pulmonar , Hipóxia/complicações , Hipóxia/metabolismo , Miócitos de Músculo Liso/metabolismo , Proliferação de Células , Glucose/farmacologia , Remodelação Vascular , Monocrotalina/farmacologia
17.
bioRxiv ; 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37961149

RESUMO

Glioblastoma (GBM) is the most complex and lethal adult primary brain cancer. Adequate drug diffusion and penetration are essential for treating GBM, but how the spatial heterogeneity in GBM impacts drug diffusion and transport is poorly understood. Herein, we report a new method, photoactivation of plasmonic nanovesicles (PANO), to measure molecular diffusion in the extracellular space of GBM. By examining three genetically engineered GBM mouse models that recapitulate key clinical features including angiogenic core and diffuse infiltration, we found that the tumor margin has the lowest diffusion coefficient (highest tortuosity) compared with the tumor core and surrounding brain tissue. Analysis of the cellular composition shows that the tortuosity in the GBM is strongly correlated with neuronal loss and astrocyte activation. Our all-optical measurement reveals the heterogeneous GBM microenvironment and highlights the tumor margin as a diffusion barrier for drug transport in the brain, with implications for therapeutic delivery.

18.
Transl Neurosci ; 14(1): 20220324, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-38035150

RESUMO

Background: Endovascular therapy (EVT) was the standard treatment for acute ischemic stroke with large vessel occlusion. Prognosis after EVT is always a major concern. Here, we aimed to explore a predictive model for patients after EVT. Method: A total of 156 patients were retrospectively enrolled. The primary outcome was functional dependence (defined as a 90-day modified Rankin Scale score ≤ 2). Least absolute shrinkage and selection operator and univariate logistic regression were used to select predictive factors. Various machine learning algorithms, including multivariate logistic regression, linear discriminant analysis, support vector machine, k-nearest neighbors, and decision tree algorithms, were applied to construct prognostic models. Result: Six predictive factors were selected, namely, age, baseline National Institute of Health Stroke Scale (NIHSS) score, Alberta Stroke Program Early CT (ASPECT) score, modified thrombolysis in cerebral infarction score, symptomatic intracerebral hemorrhage (sICH), and complications (pulmonary infection, gastrointestinal bleeding, and cardiovascular events). Based on these variables, various models were constructed and showed good discrimination. Finally, a nomogram was constructed by multivariate logistic regression and showed a good performance. Conclusion: Our nomogram, which was composed of age, baseline NIHSS score, ASPECT score, recanalization status, sICH, and complications, showed a very good performance in predicting outcome after EVT.

19.
Platelets ; 34(1): 2287064, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38031975

RESUMO

The hybrid-channel platelet counting method (PLT-H) is a new platelet counting technique proposed by Mindray of China. In this study, we aimed to evaluate the accuracy of this technique in various situations and its reliability in platelet transfusion decision-making. A total of 378 venous blood samples were tested. Using the immunological PLT counting method recommended by the International Council for Standardization in Hematology as the reference method (PLT-IRM), Passing-Bablok regression and Bland-Altman analysis were performed on the PLT-H results. The anti-interference performance of PLT-H under different interference levels was explored using intergroup comparisons, and confusion matrices were analyzed at various transfusion cutoff values. In the absence of interference, there was a strong correlation between PLT-H and PLT-IRM (r = 0.993, 95% CI: 0.990-0.996). Under various interference conditions, the correlation between PLT-H and PLT-IRM was between 0.963 and 0.992, with an average deviation of -14.56 to -2.02. The performance of PLT-H against interference did not change significantly with increasing levels of small RBCs, large PLTs, and RBC fragments (P = .5704, 0.0832, 0.9893). In low-value samples (PLT <100 × 109/L), the coefficient of variation (CV) for PLT-H was less than 7.6%, regardless of the presence or absence of interfering substances. In addition, there was a high agreement between PLT-H and PLT-IRM (ICC = 0.972). Confusion matrice analysis at each medical decision level showed similarity to methods using the fluorescence channel (PLT-O) and superiority to the impedance channel (PLT-I). Compared with PLT-I, PLT-H has higher accuracy in PLT counting, stronger anti-interference ability, better performance in low-value samples at no extra economic cost and can be more useful for platelet transfusion decision-making. PLT-H is a novel method for platelet counting that offers higher accuracy, providing physicians with the ability to make better medical decisions, particularly in cases where values are low, or interference is present. As it does not require additional reagents, it is highly likely to replace PLT-I and become the mainstream method for platelet counting in the future.


Assuntos
Plaquetas , Transfusão de Plaquetas , Humanos , Reprodutibilidade dos Testes , Contagem de Plaquetas/métodos
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