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1.
Biostatistics ; 24(3): 760-775, 2023 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35166342

RESUMO

Leveraging large-scale electronic health record (EHR) data to estimate survival curves for clinical events can enable more powerful risk estimation and comparative effectiveness research. However, use of EHR data is hindered by a lack of direct event time observations. Occurrence times of relevant diagnostic codes or target disease mentions in clinical notes are at best a good approximation of the true disease onset time. On the other hand, extracting precise information on the exact event time requires laborious manual chart review and is sometimes altogether infeasible due to a lack of detailed documentation. Current status labels-binary indicators of phenotype status during follow-up-are significantly more efficient and feasible to compile, enabling more precise survival curve estimation given limited resources. Existing survival analysis methods using current status labels focus almost entirely on supervised estimation, and naive incorporation of unlabeled data into these methods may lead to biased estimates. In this article, we propose Semisupervised Calibration of Risk with Noisy Event Times (SCORNET), which yields a consistent and efficient survival function estimator by leveraging a small set of current status labels and a large set of informative features. In addition to providing theoretical justification of SCORNET, we demonstrate in both simulation and real-world EHR settings that SCORNET achieves efficiency akin to the parametric Weibull regression model, while also exhibiting semi-nonparametric flexibility and relatively low empirical bias in a variety of generative settings.


Assuntos
Registros Eletrônicos de Saúde , Humanos , Calibragem , Viés , Simulação por Computador
2.
Neuroradiology ; 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39014270

RESUMO

PURPOSE: To evaluate nnU-net's performance in automatically segmenting and volumetrically measuring ocular adnexal lymphoma (OAL) on multi-sequence MRI. METHODS: We collected T1-weighted (T1), T2-weighted and T1-weighted contrast-enhanced images with/without fat saturation (T2_FS/T2_nFS, T1c_FS/T1c_nFS) of OAL from four institutions. Two radiologists manually annotated lesions as the ground truth using ITK-SNAP. A deep learning framework, nnU-net, was developed and trained using two models. Model 1 was trained on T1, T2, and T1c, while Model 2 was trained exclusively on T1 and T2. A 5-fold cross-validation was utilized in the training process. Segmentation performance was evaluated using the Dice similarity coefficient (DSC), sensitivity, and positive prediction value (PPV). Volumetric assessment was performed using Bland-Altman plots and Lin's concordance correlation coefficient (CCC). RESULTS: A total of 147 patients from one center were selected as training set and 33 patients from three centers were regarded as test set. For both Model 1 and 2, nnU-net demonstrated outstanding segmentation performance on T2_FS with DSC of 0.80-0.82, PPV of 84.5-86.1%, and sensitivity of 77.6-81.2%, respectively. Model 2 failed to detect 19 cases of T1c, whereas the DSC, PPV, and sensitivity for T1_nFS were 0.59, 91.2%, and 51.4%, respectively. Bland-Altman plots revealed minor tumor volume differences with 0.22-1.24 cm3 between nnU-net prediction and ground truth on T2_FS. The CCC were 0.96 and 0.93 in Model 1 and 2 for T2_FS images, respectively. CONCLUSION: The nnU-net offered excellent performance in automated segmentation and volumetric assessment in MRI of OAL, particularly on T2_FS images.

3.
Small ; 19(37): e2301420, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37154213

RESUMO

The current immunotherapy strategies for triple negative breast cancer (TNBC) are greatly limited due to the immunosuppressive tumor microenvironment (TME). Immunization with cancer vaccines composed of tumor cell lysates (TCL) can induce an effective antitumor immune response. However, this approach also has the disadvantages of inefficient antigen delivery to the tumor tissues and the limited immune response elicited by single-antigen vaccines. To overcome these limitations, a pH-sensitive nanocalcium carbonate (CaCO3 ) carrier loaded with TCL and immune adjuvant CpG (CpG oligodeoxynucleotide 1826) is herein constructed for TNBC immunotherapy. This tailor-made nanovaccine, termed CaCO3 @TCL/CpG, not only neutralizes the acidic TME through the consumption of lactate by CaCO3 , which increases the proportion of the M1/M2 macrophages and promotes infiltration of effector immune cells but also activates the dendritic cells in the tumor tissues and recruits cytotoxic T cells to further kill the tumor cells. In vivo fluorescence imaging study shows that the pegylated nanovaccine could stay longer in the blood circulation and extravasate preferentially into tumor site. Besides, the nanovaccine exhibits high cytotoxicity in 4T1 cells and significantly inhibits tumor growth of tumor-bearing mice. Overall, this pH-sensitive nanovaccine is a promising nanoplatform for enhanced immunotherapy of TNBC.


Assuntos
Vacinas Anticâncer , Nanopartículas , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/terapia , Neoplasias de Mama Triplo Negativas/patologia , Imunoterapia/métodos , Adjuvantes Imunológicos , Linfócitos T Citotóxicos , Concentração de Íons de Hidrogênio , Microambiente Tumoral
4.
Circ Res ; 127(4): 486-501, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32349646

RESUMO

RATIONALE: Maintaining iron homeostasis is essential for proper cardiac function. Both iron deficiency and iron overload are associated with cardiomyopathy and heart failure via complex mechanisms. Although ferritin plays a central role in iron metabolism by storing excess cellular iron, the molecular function of ferritin in cardiomyocytes remains unknown. OBJECTIVE: To characterize the functional role of Fth (ferritin H) in mediating cardiac iron homeostasis and heart disease. METHODS AND RESULTS: Mice expressing a conditional Fth knockout allele were crossed with 2 distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack Fth expression specifically in myocytes (MCK-Cre) or cardiomyocytes (Myh6-Cre). Mice lacking Fth in cardiomyocytes had decreased cardiac iron levels and increased oxidative stress, resulting in mild cardiac injury upon aging. However, feeding these mice a high-iron diet caused severe cardiac injury and hypertrophic cardiomyopathy, with molecular features typical of ferroptosis, including reduced glutathione (GSH) levels and increased lipid peroxidation. Ferrostatin-1, a specific inhibitor of ferroptosis, rescued this phenotype, supporting the notion that ferroptosis plays a pathophysiological role in the heart. Finally, we found that Fth-deficient cardiomyocytes have reduced expression of the ferroptosis regulator Slc7a11, and overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis. CONCLUSIONS: Our findings provide compelling evidence that ferritin plays a major role in protecting against cardiac ferroptosis and subsequent heart failure, thereby providing a possible new therapeutic target for patients at risk of developing cardiomyopathy.


Assuntos
Sistema y+ de Transporte de Aminoácidos/metabolismo , Apoferritinas/deficiência , Cardiomiopatias/etiologia , Ferroptose/fisiologia , Ferro/metabolismo , Miocárdio/metabolismo , Envelhecimento , Alelos , Animais , Apoferritinas/efeitos adversos , Apoferritinas/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/prevenção & controle , Cardiomiopatia Hipertrófica/etiologia , Cardiomiopatia Hipertrófica/prevenção & controle , Cruzamentos Genéticos , Cicloexilaminas/administração & dosagem , Glutationa/metabolismo , Insuficiência Cardíaca/etiologia , Homeostase , Hipertrofia Ventricular Esquerda/etiologia , Deficiências de Ferro , Sobrecarga de Ferro , Ferro da Dieta/efeitos adversos , Peroxidação de Lipídeos , Masculino , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Fenilenodiaminas/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo
5.
Rheumatology (Oxford) ; 59(12): 3759-3766, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32413107

RESUMO

OBJECTIVE: The objective of this study was to compare the performance of an RA algorithm developed and trained in 2010 utilizing natural language processing and machine learning, using updated data containing ICD10, new RA treatments, and a new electronic medical records (EMR) system. METHODS: We extracted data from subjects with ≥1 RA International Classification of Diseases (ICD) codes from the EMR of two large academic centres to create a data mart. Gold standard RA cases were identified from reviewing a random 200 subjects from the data mart, and a random 100 subjects who only have RA ICD10 codes. We compared the performance of the following algorithms using the original 2010 data with updated data: (i) a published 2010 RA algorithm; (ii) updated algorithm, incorporating ICD10 RA codes and new DMARDs; and (iii) published algorithm using ICD codes only, ICD RA code ≥3. RESULTS: The gold standard RA cases had mean age 65.5 years, 78.7% female, 74.1% RF or antibodies to cyclic citrullinated peptide (anti-CCP) positive. The positive predictive value (PPV) for ≥3 RA ICD was 54%, compared with 56% in 2010. At a specificity of 95%, the PPV of the 2010 algorithm and the updated version were both 91%, compared with 94% (95% CI: 91, 96%) in 2010. In subjects with ICD10 data only, the PPV for the updated 2010 RA algorithm was 93%. CONCLUSION: The 2010 RA algorithm validated with the updated data with similar performance characteristics as the 2010 data. While the 2010 algorithm continued to perform better than the rule-based approach, the PPV of the latter also remained stable over time.


Assuntos
Artrite Reumatoide , Classificação Internacional de Doenças , Algoritmos , Registros Eletrônicos de Saúde , Humanos
7.
J Transl Med ; 15(1): 176, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28810875

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide owing to its high rates of metastasis and recurrence. The oncogene IQ motif-containing GTPase activating protein 3 (IQGAP3) is ubiquitously overexpressed in several human cancers, including liver, ovary, lung, large intestine, gastric, bone marrow, and breast malignancies and is involved in the invasion and metastasis of cancer cells. Therefore, we aimed to determine the biological role and molecular mechanism of IQGAP3 in HCC. METHODS: We used 120 archived clinical HCC samples, 9 snap-frozen HCC tumor tissues, and 4 normal liver tissues. Expression of IQGAP3 mRNA and protein in HCC cell lines (Hep3B, SMMC-7721, HCCC-9810, HepG2, BEL-7404, HCCLM3, QGY-7701, Huh7, and MHCC97H) and normal liver epithelial cells LO2 was examined by western blot, quantitative polymerase chain reaction, and immunohistochemistry. In addition, wound-healing and transwell matrix penetration assays were used to assess the migratory and invasive abilities of HCC cells, respectively. RESULTS: Expression of the IQGAP3 was robustly upregulated in HCC cells and tissues. High expression of IQGAP3 in HCC correlated with aggressive clinicopathological features and was an independent poor prognostic factor for overall survival. Furthermore, ectopic expression of IQGAP3 markedly enhanced HCC cell migration, invasion, and epithelial-to-mesenchymal transition (EMT) in vitro and promoted metastasis of orthotopic hepatic tumors in nude mice. Conversely, silencing endogenous IQGAP3 showed an opposite effect. Mechanistically, IQGAP3 promoted EMT and metastasis by activating TGF-ß signaling. CONCLUSIONS: IQGAP3 functions as an important regulator of metastasis and EMT by constitutively activating the TGF-ß signaling pathway in HCC. Our findings present new evidence of the role of IQGAP3 in EMT and metastasis, indicating its potential as a prognostic biomarker candidate and a therapeutic target against HCC.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Transição Epitelial-Mesenquimal , Proteínas Ativadoras de GTPase/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Proteínas Ativadoras de GTPase/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Metástase Neoplásica , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/genética , Estatísticas não Paramétricas , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima/genética
8.
J Sci Food Agric ; 95(2): 253-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24771525

RESUMO

BACKGROUND: A SYBR Green I-based quantitative loop-mediated isothermal amplification (LAMP) assay was developed for the rapid detection of genetically modified maize MON863. A set of primers was designed based on the integration region of the Cry3Bb1 and tahsp17 genes. RESULTS: The qualitative and quantitative reaction conditions (dNTPs, betaine, primers, Mg(2+), Bst polymerase, temperature, reaction time) were optimized. The concentrations of Mg(2+) and betaine were found to be important to the LAMP assay. The detection limits of both qualitative and quantitative LAMP for MON863 were as low as 4 haploid genomic DNA, and the LAMP reactions can be completed within 1 h at an isothermal temperature of 65 °C. CONCLUSION: The results of this study demonstrate that this new SYBR Green I-based quantitative LAMP assay system is reliable, sensitive and accurate.


Assuntos
DNA de Plantas/análise , Análise de Alimentos/métodos , Alimentos Geneticamente Modificados , Genes de Plantas , Técnicas de Amplificação de Ácido Nucleico/métodos , Plantas Geneticamente Modificadas , Zea mays/genética , Betaína/análise , Primers do DNA , Genoma de Planta , Haploidia , Humanos , Magnésio/análise , Plantas Geneticamente Modificadas/química , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes , Temperatura , Zea mays/química
9.
Carcinogenesis ; 35(12): 2748-55, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25280563

RESUMO

A growing amount of evidence supports that microRNA (miRNA) dysregulation is involved in cancer progression by directly downregulating multiple targets. Elucidating the underlying mechanism of miRNA in carcinogenesis may improve diagnostic and therapeutic strategies for malignancy. In the current study, we found that miR-105 expression was markedly downregulated in both hepatocellular carcinoma (HCC) cell lines and clinical HCC tissues, compared with normal human hepatocyte and adjacent non-cancerous tissues, respectively. Ectopic miR-105 expression suppressed, whereas inhibiting miR-105 promoted the proliferation and tumorigenicity of HCC cells both in vitro and in vivo. Furthermore, we demonstrated that miR-105 could deactivated the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway by downregulating insulin receptor substrate-1, 3-phosphoinositide-dependent protein kinase-1 and AKT1 directly, resulting in increasing cyclin-dependent kinase inhibitors 1A and 1B (p21(Cip1) and p27(Kip1)) and decreasing cyclin D1 expression in HCC. Therefore, our results suggest that miR-105 functions as a potential tumor suppressor by inhibiting the PI3K/AKT signaling pathway and might represent a potential therapeutic target for HCC patients.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proliferação de Células , MicroRNAs/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose , Western Blotting , Carcinoma Hepatocelular/metabolismo , Adesão Celular , Células Cultivadas , Citometria de Fluxo , Humanos , Técnicas Imunoenzimáticas , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ensaios Antitumorais Modelo de Xenoenxerto
10.
IEEE Open J Eng Med Biol ; 5: 330-338, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38899025

RESUMO

Goal: To establish Pulse2AI as a reproducible data preprocessing framework for pulsatile signals that generate high-quality machine-learning-ready datasets from raw wearable recordings. Methods: We proposed an end-to-end data preprocessing framework that adapts multiple pulsatile signal modalities and generates machine-learning-ready datasets agnostic to downstream medical tasks. Results: a dataset preprocessed by Pulse2AI improved systolic blood pressure estimation by 29.58%, from 11.41 to 8.03 mmHg in root-mean-square-error (RMSE) and its diastolic counterpart by 26.01%, from 7.93 to 5.87 mmHg in RMSE. For respiration rate (RR) estimation, Pulse2AI boosted performance by 19.69%, from 1.47 to 1.18 breaths per minute (BrPM) in mean-absolute-error (MAE). Conclusion: Pulse2AI turns pulsatile signals into machine learning (ML) ready datasets for arbitrary remote health monitoring tasks. We tested Pulse2AI on multiple pulsatile modalities and demonstrated its efficacy in two medical applications. This work bridges valuable assets in remote sensing and internet of medical things to ML-ready datasets for medical modeling.

11.
Biochim Biophys Acta Rev Cancer ; 1879(5): 189142, 2024 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-38914240

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) presents a significant therapeutic challenge as it is frequently diagnosed at advanced inoperable stages. Therefore, the development of a reliable screening tool for PDAC is crucial for effective prevention and treatment. Extracellular vesicles (EVs), characterized by their cup-shaped lipid bilayer structure and ubiquitous release from various cell types, offer notable advantages as an emerging liquid biopsy technique that is rapid, minimally invasive, easily sampled, and cost-effective. While EVs play a substantial role in cancer progression, EV proteins serve as direct mediators of diverse cellular behaviors and have immense potential as biomarkers for PDAC diagnosis and prognostication. This review provides an overview of EV proteins regarding PDAC diagnosis and prognostic implications as well as disease progression.

12.
medRxiv ; 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38585929

RESUMO

Randomized clinical trials (RCTs) are essential to guide medical practice; however, their generalizability to a given population is often uncertain. We developed a statistically informed Generative Adversarial Network (GAN) model, RCT-Twin-GAN, that leverages relationships between covariates and outcomes and generates a digital twin of an RCT (RCT-Twin) conditioned on covariate distributions from a second patient population. We used RCT-Twin-GAN to reproduce treatment effect outcomes of the Systolic Blood Pressure Intervention Trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure Trial, which tested the same intervention but had different treatment effect results. To demonstrate treatment effect estimates of each RCT conditioned on the other RCT patient population, we evaluated the cardiovascular event-free survival of SPRINT digital twins conditioned on the ACCORD cohort and vice versa (SPRINT-conditioned ACCORD twins). The conditioned digital twins were balanced by the intervention arm (mean absolute standardized mean difference (MASMD) of covariates between treatment arms 0.019 (SD 0.018), and the conditioned covariates of the SPRINT-Twin on ACCORD were more similar to ACCORD than a sprint (MASMD 0.0082 SD 0.016 vs. 0.46 SD 0.20). Most importantly, across iterations, SPRINT conditioned ACCORD-Twin datasets reproduced the overall non-significant effect size seen in ACCORD (5-year cardiovascular outcome hazard ratio (95% confidence interval) of 0.88 (0.73-1.06) in ACCORD vs median 0.87 (0.68-1.13) in the SPRINT conditioned ACCORD-Twin), while the ACCORD conditioned SPRINT-Twins reproduced the significant effect size seen in SPRINT (0.75 (0.64-0.89) vs median 0.79 (0.72-0.86)) in ACCORD conditioned SPRINT-Twin). Finally, we describe the translation of this approach to real-world populations by conditioning the trials on an electronic health record population. Therefore, RCT-Twin-GAN simulates the direct translation of RCT-derived treatment effects across various patient populations with varying covariate distributions.

13.
Acta Biomater ; 176: 344-355, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38244662

RESUMO

Nowadays, effective immunotherapy against triple-negative breast cancer (TNBC) remains challenging due to the immunosuppressive tumor microenvironment. Immune checkpoint inhibitor is mostly employed to restore the activity of tumor-specific immune cells, which however brings little therapeutic outcome owing to the limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue. Aiming to solve these problems, we herein constructed a tailor-made dissolving microneedle co-encapsulating the TLR7/8 agonist R848 and the immune checkpoint inhibitor aPD-1, termed αNP-RNP@DMN, and fabricated it as a transdermal drug delivery system. This well-designed microneedle patch, endowed with efficient tumor drug delivery ability, was able to mature tumor-infiltrating dendritic cells (TIDCs) and further promote the infiltration of CD8+ T cells into the tumor tissue with the aid of R848. Moreover, the introduction of aPD-1 blocked the programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1) immune checkpoints, synergistically reversing the immunosuppressive microenvironment of TNBC. In vivo therapeutic results demonstrated that αNP-RNP@DMN not only significantly prolonged the survival time of 4T1 tumor-bearing mice, but also inhibited tumor recurrence and lung metastasis after surgery, implying the great potential of this effective drug delivery system for enhanced immunotherapy of superficial tumors. STATEMENT OF SIGNIFICANCE: The limited number of tumor-infiltrating CD8+ T cells and the inefficient delivery of immune drugs to the tumor tissue hinder the effective immunotherapy of triple-negative breast cancer (TNBC). Herein, a dissolving microneedle co-encapsulating TLR7/8 agonist R848 and immune checkpoint inhibitor aPD-1 was developed and fabricated as a transdermal drug delivery system. This tailor-made microneedle patch not only promoted drug accumulation in tumor sites in a safe and painless manner, but also lifted the immune-suppressive state of tumor-infiltrating dendritic cells (TIDCs). The activated TIDCs further enhanced T-cell infiltration into the tumor tissue, thus successfully boosting the therapeutic efficacy of aPD-1. This study demonstrated that this well-designed microneedle patch could be served as an effective drug delivery system for enhanced immunotherapy of TNBC.


Assuntos
Nanopartículas , Neoplasias de Mama Triplo Negativas , Humanos , Animais , Camundongos , Neoplasias de Mama Triplo Negativas/patologia , Linfócitos T CD8-Positivos , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptor 7 Toll-Like , Recidiva Local de Neoplasia/tratamento farmacológico , Imunoterapia/métodos , Microambiente Tumoral
14.
Adv Sci (Weinh) ; 11(28): e2401845, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38757623

RESUMO

The limited success of current targeted therapies for pancreatic cancer underscores an urgent demand for novel treatment modalities. The challenge in mitigating this malignancy can be attributed to the digestive organ expansion factor (DEF), a pivotal yet underexplored factor in pancreatic tumorigenesis. The study uses a blend of in vitro and in vivo approaches, complemented by the theoretical analyses, to propose DEF as a promising anti-tumor target. Analysis of clinical samples reveals that high expression of DEF is correlated with diminished survival in pancreatic cancer patients. Crucially, the depletion of DEF significantly impedes tumor growth. The study further discovers that DEF binds to p65, shielding it from degradation mediated by the ubiquitin-proteasome pathway in cancer cells. Based on these findings and computational approaches, the study formulates a DEF-mimicking peptide, peptide-031, designed to disrupt the DEF-p65 interaction. The effectiveness of peptide-031 in inhibiting tumor proliferation has been demonstrated both in vitro and in vivo. This study unveils the oncogenic role of DEF while highlighting its prognostic value and therapeutic potential in pancreatic cancer. In addition, peptide-031 is a promising therapeutic agent with potent anti-tumor effects.


Assuntos
Proliferação de Células , Neoplasias Pancreáticas , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Humanos , Camundongos , Animais , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Camundongos Nus , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelA/genética
15.
Adv Sci (Weinh) ; : e2401731, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38981028

RESUMO

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder leading to cognitive decline. Excessive cytosolic calcium (Ca2+) accumulation plays a critical role in the pathogenesis of AD since it activates the NOD-like receptor family, pyrin domain containing 3 (NLRP3), switches the endoplasmic reticulum (ER) unfolded protein response (UPR) toward proapoptotic signaling and promotes Aß seeding. Herein, a liposomal nanodrug (felodipine@LND) is developed incorporating a calcium channel antagonist felodipine for Alzheimer's disease treatment through a low-intensity pulse ultrasound (LIPUS) irradiation-assisted blood brain barrier (BBB)-crossing drug delivery. The multifunctional felodipine@LND is effectively delivered to diseased brain through applying a LIPUS irradiation to the skull, which resulted in a series of positive effects against AD. Markedly, the nanodrug treatment switched the ER UPR toward antioxidant signaling, prevented the surface translocation of ER calreticulin (CALR) in microglia, and inhibited the NLRP3 activation and Aß seeding. In addition, it promoted the degradation of damaged mitochondria via mitophagy, thereby inhibiting the neuronal apoptosis. Therefore, the anxiety-like behavior and cognitive impairment of 5xFAD mice with AD is significantly ameliorated, which manifested the potential of LIPUS - assisted BBB-crossing delivery of felodipine@LND to serve as a paradigm for AD therapy based on the well-recognized clinically available felodipine.

16.
J Am Heart Assoc ; 13(9): e030387, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38686879

RESUMO

BACKGROUND: Coronary microvascular dysfunction as measured by myocardial flow reserve (MFR) is associated with increased cardiovascular risk in rheumatoid arthritis (RA). The objective of this study was to determine the association between reducing inflammation with MFR and other measures of cardiovascular risk. METHODS AND RESULTS: Patients with RA with active disease about to initiate a tumor necrosis factor inhibitor were enrolled (NCT02714881). All subjects underwent a cardiac perfusion positron emission tomography scan to quantify MFR at baseline before tumor necrosis factor inhibitor initiation, and after tumor necrosis factor inhibitor initiation at 24 weeks. MFR <2.5 in the absence of obstructive coronary artery disease was defined as coronary microvascular dysfunction. Blood samples at baseline and 24 weeks were measured for inflammatory markers (eg, high-sensitivity C-reactive protein [hsCRP], interleukin-1b, and high-sensitivity cardiac troponin T [hs-cTnT]). The primary outcome was mean MFR before and after tumor necrosis factor inhibitor initiation, with Δhs-cTnT as the secondary outcome. Secondary and exploratory analyses included the correlation between ΔhsCRP and other inflammatory markers with MFR and hs-cTnT. We studied 66 subjects, 82% of which were women, mean RA duration 7.4 years. The median atherosclerotic cardiovascular disease risk was 2.5%; 47% had coronary microvascular dysfunction and 23% had detectable hs-cTnT. We observed no change in mean MFR before (2.65) and after treatment (2.64, P=0.6) or hs-cTnT. A correlation was observed between a reduction in hsCRP and interleukin-1b with a reduction in hs-cTnT. CONCLUSIONS: In this RA cohort with low prevalence of cardiovascular risk factors, nearly 50% of subjects had coronary microvascular dysfunction at baseline. A reduction in inflammation was not associated with improved MFR. However, a modest reduction in interleukin-1b and no other inflammatory pathways was correlated with a reduction in subclinical myocardial injury. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02714881.


Assuntos
Artrite Reumatoide , Biomarcadores , Circulação Coronária , Inflamação , Microcirculação , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antirreumáticos/uso terapêutico , Artrite Reumatoide/fisiopatologia , Artrite Reumatoide/complicações , Artrite Reumatoide/sangue , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Circulação Coronária/fisiologia , Vasos Coronários/fisiopatologia , Vasos Coronários/diagnóstico por imagem , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Fatores de Risco de Doenças Cardíacas , Inflamação/sangue , Inflamação/fisiopatologia , Mediadores da Inflamação/sangue , Interleucina-1beta/sangue , Imagem de Perfusão do Miocárdio/métodos , Tomografia por Emissão de Pósitrons , Resultado do Tratamento , Troponina T/sangue , Inibidores do Fator de Necrose Tumoral/uso terapêutico
17.
J Oncol ; 2023: 3538928, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36761433

RESUMO

Background: The prognosis is poor for hepatocellular carcinoma (HCC), a tumor and cancer associated with inflammation that is common. New data showed that significant levels of KIAA1522 were expressed in HCC tissues and cell lines, suggesting that KIAA1522 may be a highly useful prognostic marker for HCC. However, its biochemical processes and impacts on the immune system go deeper. Objective: To verify the significance of KIAA1522 in HCC and investigate its related carcinogenic mechanisms. Methods: Studies examining the relationship between KIAA1522 expression and clinical-pathologic characteristics in HCC have been checked in the Cancer Genome Atlas (TCGA) database. A receiver operating characteristic (ROC) curve was used to assess the diagnostic efficacy of KIAA1522 in HCC. Western blot analysis was used to find the presence of the KIAA1522 protein in the tumor and paraneoplastic tissues of eight randomly chosen HCC patients. The GSVA program in R language was used to evaluate the relationship between KIAA1522 and immune cell infiltration in HCC. We searched the Search Tool for the Retrieval of Interacting Genes (STRING) database for interacting proteins connected to the expression of KIAA1522. Pathways were involved in the enrichment analysis of KIAA1522 to anticipate potential mechanisms through which KIAA1522 may affect immunological infiltration. Results: Our study found that KIAA1522 was commonly elevated in HCC tumor tissues and that it also signaled a bad outcome. We found an inverse link between KIAA1522 and cytotoxic cells and an inverse relationship between KIAA1522 and Th2 cell infiltration. In STRING analysis, the top 5 coexpressed proteins of KIAA1522 were BAIAP2, NCK2, TSNAXIP1, POGK, and KLHL31. The effect of KIAA1522 on HCC may entail cell cycle alteration, an immunological response, and suppression of the PPAR signaling pathway. Conclusion: High expression of KIAA1522 was linked to HCC immune cell infiltration, disease progression, and a poor prognosis.

18.
Quant Imaging Med Surg ; 13(10): 6482-6492, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37869313

RESUMO

Background: Epicardial adipose tissue (EAT) is a key aspect in the investigation of cardiac pathophysiology. We sought to develop a deep learning (DL) model for fully automatic extraction and quantification of EAT through pulmonary computed tomography venography (PCTV) images. Methods: In this retrospective study, we included 128 patients with atrial fibrillation and PCTV from 2 hospitals. A DL model for automated EAT segmentation was developed from a training set of 51 patients and a validation set of 13 patients from hospital A. The algorithm was further validated using an internal test set of 16 patients from hospital A and an external test set of 48 patients from hospital B. The consistency and measurement agreement of EAT quantification were compared between the DL model and the conventional manual protocol using the Dice score coefficient (DSC), Hausdorff distance (HD95), Pearson correlation coefficient, and Bland-Altman plot. Results: In the internal and external test set, automated segmentation with DL was successful in all cases. The total analysis time was shorter for DL than for manual reconstruction (5.43±2.52 vs. 106.20±15.90 min; P<0.001). The EAT segmented with the DL model had good consistency with manual segmentation (the DSC of the internal and external test sets were 0.92±0.02 and 0.88±0.03, respectively). The quantification of EAT evaluated with the 2 methods showed excellent correlation (all correlation coefficients >0.9; all P values <0.001) and minimal measurement difference. Conclusions: The proposed DL model achieved fully automatic quantification of EAT from PCTV images. The yielded results were highly consistent with those of manual quantification.

19.
Arthritis Care Res (Hoboken) ; 75(5): 1036-1045, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-34623035

RESUMO

OBJECTIVE: In rheumatoid arthritis (RA), there are limited data on risk factors for the clinical heart failure (HF) subtypes of HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). This study examined the association between inflammation and incident HF subtypes in RA. Because inflammation changes over time with disease activity, we hypothesized that the effect of inflammation may be stronger at the 5-year follow-up than at the standard 10-year follow-up from general population studies of cardiovascular risk. METHODS: We studied an electronic health record (EHR)-based RA cohort with data pre- and post-RA incidence. We applied a validated approach to identify HF and extract ejection fraction to classify HFrEF and HFpEF. Follow-up started from the RA incidence date (index date) to the earliest occurrence of incident HF, death, last EHR encounter, or 10 years. Baseline inflammation was assessed using erythrocyte sedimentation rate or C-reactive protein values. Covariates included demographic characteristics, established HF risk factors, and RA-related factors. We tested the association between baseline inflammation with incident HF and its subtypes using Cox proportional hazards models. RESULTS: We studied 9,087 patients with RA; 8.2% developed HF during 10 years of follow-up. Elevated inflammation was associated with increased risk for HF at both 5- and 10-year follow-ups (hazard ratio [HR] 1.66, 95% confidence interval [95% CI] 1.12-2.46 and HR 1.46, 95% CI 1.13-1.90, respectively), which is also seen for HFpEF at 5 years (HR 1.72, 95% CI 1.09-2.70) and 10 years (HR 1.45, 95% CI 1.07-1.94). HFrEF was not associated with inflammation for either follow-up time. CONCLUSION: Elevated inflammation early in RA diagnosis was associated with HF; this association was driven by HFpEF and not HFrEF, suggesting a window of opportunity for prevention of HFpEF in RA.


Assuntos
Artrite Reumatoide , Insuficiência Cardíaca , Humanos , Volume Sistólico , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Fatores de Risco , Inflamação , Prognóstico
20.
Adv Sci (Weinh) ; 10(17): e2205345, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37068188

RESUMO

The role of zinc in hematopoiesis is currently unclear. Here, SLC39A10 (ZIP10) is identified as a key zinc transporter in hematopoiesis. The results show that in zebrafish, Slc39a10 is a key regulator of the response to zinc deficiency. Surprisingly, both slc39a10 mutant zebrafish and hematopoietic Slc39a10-deficient mice develop a more severe form of impaired hematopoiesis than animals lacking transferrin receptor 1, a well-characterized iron gatekeeper, indicating that zinc plays a larger role than iron in hematopoiesis, at least in early hematopoietic stem cells (HSCs). Furthermore, it is shown that loss of Slc39a10 causes zinc deficiency in fetal HSCs, which in turn leads to DNA damage, apoptosis, and G1 cell cycle arrest. Notably, zinc supplementation largely restores colony formation in HSCs derived from hematopoietic Slc39a10-deficient mice. In addition, inhibiting necroptosis partially restores hematopoiesis in mouse HSCs, providing mechanistic insights into the requirement for zinc in mediating hematopoiesis. Together, these findings indicate that SLC39A10 safeguards hematopoiesis by protecting against zinc deficiency-induced necroptosis, thus providing compelling evidence that SLC39A10 and zinc homeostasis promote the development of fetal HSCs. Moreover, these results suggest that SLC39A10 may serve as a novel therapeutic target for treating anemia and zinc deficiency-related disorders.


Assuntos
Hematopoese , Peixe-Zebra , Camundongos , Animais , Peixe-Zebra/metabolismo , Zinco/metabolismo , Ferro
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