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Ocular inflammation-associated diseases are leading causes of global visual impairment, with limited treatment options. Adiponectin, a hormone primarily secreted by adipose tissue, binds to its receptors, which are widely distributed throughout the body, exerting powerful physiological regulatory effects. The protective role of adiponectin in various inflammatory diseases has gained increasing attention in recent years. Previous studies have confirmed the presence of adiponectin and its receptors in the eyes. Furthermore, adiponectin and its analogs have shown potential as novel drugs for the treatment of inflammatory eye diseases. This article summarizes the evidence for the interplay between adiponectin and inflammatory eye diseases and provides new perspectives on the diagnostic and therapeutic possibilities of adiponectin.
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Adiponectina , Inflamação , Receptores de Adiponectina , Transdução de Sinais , Humanos , Adiponectina/metabolismo , Receptores de Adiponectina/metabolismo , Animais , Inflamação/metabolismo , Oftalmopatias/metabolismo , Oftalmopatias/tratamento farmacológicoRESUMO
Histone deacetylase expression and activity are often dysregulated in central nervous system (CNS) tumors, providing a rationale for investigating histone deacetylase inhibitors (HDACIs) in selected brain tumor patients. Although many HDACIs have shown potential in in vitro studies, they have had modest efficacy in vivo This lack of activity could be due to insufficient CNS exposure to the unbound drug. In this study, we investigated the systemic pharmacokinetics and subsequent CNS distribution of two potent HDACIs, vorinostat and quisinostat, in the murine model. Both compounds undergo in vitro degradation in mouse plasma, requiring precautions during sample processing. They also have short half-lives in vivo, in both plasma and CNS, which may lead to diminished efficacy. Transgenic transporter-deficient mouse models show that the CNS delivery of vorinostat was not limited by the two major blood-brain barrier efflux transporters, p-glycoprotein and breast-cancer-resistance protein. Vorinostat had an unbound CNS tissue-to-plasma partition coefficient of 0.06 {plus minus} 0.02. Conversely, the exposure of unbound quisinostat in the brain was only 0.02 {plus minus} 0.001 of that in the plasma, and the CNS distribution of quisinostat was limited by the activity of p-glycoprotein. To gain further context for these findings, the CNS distributional kinetics for vorinostat and quisinostat were compared to another hydroxamic acid HDACI, panobinostat. A comprehensive understanding of the CNS target exposure to unbound HDACI, along with known potencies from in vitro testing, can inform the prediction of a therapeutic window for HDACIs that have limited CNS exposure to unbound drug and guide targeted dosing strategies. Significance Statement This study indicates that quisinostat and vorinostat are susceptible to enzymatic degradation in the plasma, and to a lesser degree, in the target CNS tissues. Employing techniques that minimize the post-sampling degradation in plasma, brain and spinal cord, accurate CNS distributional kinetic parameters for these potentially useful compounds were determined. A knowledge of CNS exposure (Kp,uu), time to peak, and duration can inform dosing strategies in preclinical and clinical trials in selected CNS tumors.
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Panobinostat is a potent pan-HDAC inhibitor that has been tested in multiple studies for the treatment of brain tumors. There have been contrasting views surrounding its efficacy for the treatment of tumors in the CNS following systemic administration when examined in different models or species. We conducted experiments using three different mouse strains or genotypes to have a more comprehensive understanding of the systemic as well as the CNS distributional kinetics of panobinostat. Our study found that panobinostat experienced rapid degradation in vitro in FVB mouse matrices and a faster degradation rate was observed at 37{degree sign}C compared with room temperature and 4{degree sign}C, suggesting that the in vitro instability of panobinostat was due to enzymatic metabolism. Panobinostat also showed inter-strain and inter-species differences in the in vitro plasma stability; and was stable in human plasma. The objective of this study was to examine the in vitro metabolic stability of panobinostat in different matrices and assess the influence of that metabolic stability on the in vivo pharmacokinetics and CNS delivery of panobinostat. Importantly, the plasma stability in various mouse strains was not reflected in the in vivo systemic pharmacokinetic behavior of panobinostat. Several hypotheses arise from this finding, including: the binding of panobinostat to red blood cells, the existence of competing endogenous compounds to enzyme(s), the distribution into tissues with a lower level of enzymatic activity or the metabolism occurring in the plasma is a small fraction of the total metabolism in vivo Significance Statement Panobinostat showed different in vitro degradation in plasma from different mouse strains and genotypes. However, despite the differences surrounding in vitro plasma stability, panobinostat showed similar in vivo pharmacokinetic behavior in different mouse models. This suggests that the inter-strain difference in enzymatic activity did not affect the in vivo pharmacokinetic behavior of panobinostat and its CNS distribution in mice. This lack of translation between in vitro metabolism assays and in vivo disposition can confound drug development.
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Radiation therapy, a standard treatment option for many cancer patients, induces DNA double-strand breaks (DSBs), leading to cell death. Ataxia telangiectasia mutated (ATM) kinase is a key regulator of DSB repair, and ATM inhibitors are being explored as radiosensitizers for various tumors, including primary and metastatic brain tumors. Efficacy of radiosensitizers for brain tumors may be influenced by a lack of effective drug delivery across the blood-brain barrier. The objective of this study was to evaluate the systemic pharmacokinetics and mechanisms that influence the central nervous system (CNS) distribution of WSD0628, a novel and potent ATM inhibitor, in the mouse. Further, we have used these observations to form the basis of predicting effective exposures for clinical application. We observed a greater than dose proportional increase in exposure, likely due to saturation of clearance processes. Our results show that WSD0628 is orally bioavailable and CNS penetrant, with unbound partitioning in CNS (i.e., unbound tissue partition coefficient) between 0.15 and 0.3. CNS distribution is not limited by the efflux transporters P-glycoprotein and breast cancer resistant protein. WSD0628 is distributed uniformly among different brain regions. Thus, WSD0628 has favorable pharmacokinetic properties and potential for further exploration to determine the pharmacodynamics-pharmacokinetics efficacy relationship in CNS tumors. This approach will provide critical insights for the clinical translation of WSD0628 for the treatment of primary and secondary brain tumors. SIGNIFICANCE STATEMENT: This study evaluates the preclinical systemic pharmacokinetics, dose proportionality, and mechanisms influencing CNS distribution of WSD0628, a novel ATM inhibitor for the treatment of brain tumors. Results indicate that WSD0628 is orally bioavailable and CNS penetrant without efflux transporter liability. We also observed a greater than dose proportional increase in exposure in both the plasma and brain. These favorable pharmacokinetic properties indicate WSD0628 has potential for further exploration for use as a radiosensitizer in the treatment of brain tumors.
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Proteínas Mutadas de Ataxia Telangiectasia , Neoplasias Encefálicas , Radiossensibilizantes , Animais , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Camundongos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/radioterapia , Radiossensibilizantes/farmacocinética , Radiossensibilizantes/administração & dosagem , Masculino , Feminino , Relação Dose-Resposta a Droga , Distribuição Tecidual , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATPRESUMO
Achieving adequate exposure of the free therapeutic agent at the target is a critical determinant of efficacious chemotherapy. With this in mind, a major challenge in developing therapies for central nervous system (CNS) tumors is to overcome barriers to delivery, including the blood-brain barrier (BBB). Panobinostat is a nonselective pan-histone deacetylase inhibitor that is being tested in preclinical and clinical studies, including for the treatment of pediatric medulloblastoma, which has a propensity for leptomeningeal spread and diffuse midline glioma, which can infiltrate into supratentorial brain regions. In this study, we examined the rate, extent, and spatial heterogeneity of panobinostat CNS distribution in mice. Transporter-deficient mouse studies show that panobinostat is a dual substrate of P-glycoprotein (P-gp) and breast cancer resistant protein (Bcrp), which are major efflux transporters expressed at the BBB. The CNS delivery of panobinostat was moderately limited by P-gp and Bcrp, and the unbound tissue-to-plasma partition coefficient of panobinostat was 0.32 and 0.21 in the brain and spinal cord in wild-type mice. In addition, following intravenous administration, panobinostat demonstrated heterogeneous distribution among brain regions, indicating that its efficacy would be influenced by tumor location or the presence and extent of leptomeningeal spread. Simulation using a compartmental BBB model suggests inadequate exposure of free panobinostat in the brain following a recommended oral dosing regimen in patients. Therefore, alternative approaches to CNS delivery may be necessary to have adequate exposure of free panobinostat for the treatment of a broad range of pediatric brain tumors. SIGNIFICANCE STATEMENT: This study shows that the central nervous system (CNS) penetration of panobinostat is limited by P-gp and Bcrp, and its efficacy may be limited by inadequate distribution to the tumor. Panobinostat has heterogeneous distribution into various brain regions, indicating that its efficacy might depend on the anatomical location of the tumors. These distributional parameters in the mouse CNS can inform both preclinical and clinical trial study design and may guide treatment for these devastating brain tumors in children.
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Transportadores de Cassetes de Ligação de ATP , Neoplasias Encefálicas , Criança , Humanos , Animais , Camundongos , Panobinostat/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Neoplasias/metabolismo , Sistema Nervoso Central/metabolismo , Encéfalo/metabolismo , Barreira Hematoencefálica/metabolismo , Neoplasias Encefálicas/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Proteínas de Membrana Transportadoras/metabolismoRESUMO
BACKGROUND: Irinotecan (CPT-11) is a classic chemotherapeutic agent that plays an important role in the clinical treatment of metastatic colon cancer and other malignant tumors. We previously designed a series of novel irinotecan derivatives. In this study, we select one representative, ZBH-01, to investigate its sophisticated antitumor mechanism in colon tumor cells. METHODS: The cytotoxic activity of ZBH-01 on colon cancer cells was evaluate by MTT or Cell Counting Kit-8 (CCK8) assay, 3D and xenograft model. The inhibitory effect of ZBH-01 on TOP1 was detected by DNA relaxation assay and Immuno Complex of Ezyme (ICE) bioassay. The molecular mechanism of ZBH-01 was explored by Next-Generation Sequencing (NGS), bioinformatics analyses, flow cytometry, qRT-PCR, and western blot etc. RESULTS: ZBH-01 can induce obvious DNA damage and has superior antitumor activity against colon cancer cells compared to CPT-11 and SN38 (7-Ethyl-10-hydroxy camptothecin, the in vivo active form of CPT-11) both in vivo and in vitro. Its inhibitory effect on topoisomerase I (TOP1) was also comparable with these two control drugs. There are a much larger number of 842 downregulated and 927 upregulated mRNAs in ZBH-01 treatment group than that in the controls. The most significantly enriched KEGG pathways for these dysregulated mRNAs were DNA replication, the p53 signaling pathway, and the cell cycle. After constructing a protein-protein interaction (PPI) network and screening out a prominent cluster, 14 involved in the cell cycle process was identified. Consistently, ZBH-01 induced G0/G1 phase arrest in colon cancer cells, while CPT-11/SN38 caused S phase arrest. The initiation of apoptosis by ZBH-01 was also superior to CPT-11/SN38, followed by the increased expression of Bax, active caspase 3, and cleaved-PARP, and decreased expression of Bcl-2. Additionally, CCNA2 (cyclin A2), CDK2 (cyclin-dependent kinase 2), and MYBL2 (MYB proto-oncogene like 2) might be involved in the G0/G1 cell cycle arrest induced by ZBH-01. CONCLUSIONS: ZBH-01 can be an antitumor candidate drug for preclinical study in the future.
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Camptotecina , Neoplasias do Colo , Humanos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Ciclo Celular , Divisão Celular , Neoplasias do Colo/tratamento farmacológicoRESUMO
The lack of effective chemotherapeutic agents for the treatment of brain tumors is a serious unmet medical need. This can be attributed, in part, to inadequate delivery through the blood-brain barrier (BBB) and the tumor-cell barrier, both of which have active efflux transporters that can restrict the transport of many potentially effective agents for both primary and metastatic brain tumors. This review briefly summarizes the components and function of the normal BBB with respect to drug penetration into the brain and the alterations in the BBB due to brain tumor that could influence drug delivery. Depending on what is rate-limiting a compound's distribution, the limited permeability across the BBB and the subsequent delivery into the tumor cell can be greatly influenced by efflux transporters and these are discussed in some detail. Given these complexities, it is necessary to quantify the extent of brain distribution of the active (unbound) drug to compare across compounds and to inform potential for use against brain tumors. In this regard, the metric, Kp,uu, a brain-to-plasma unbound partition coefficient, is examined and its current use is discussed. However, the extent of active drug delivery is not the only determinant of effective therapy. In addition to Kp,uu, drug potency is an important parameter that should be considered alongside drug delivery in drug discovery and development processes. In other words, to answer the question - How much is enough? - one must consider how much can be delivered with how much needs to be delivered.
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Neoplasias Encefálicas , Encéfalo , Humanos , Barreira Hematoencefálica , Proteínas de Membrana Transportadoras , Neoplasias Encefálicas/tratamento farmacológico , Transporte Biológico , Preparações FarmacêuticasRESUMO
BACKGROUND: Increased hemoglobin F (HbF) expression in individuals with ß-thalassemia contributes to the alleviation of pathological phenomena and the reduction of mortality. We have investigated the correlation between six single nucleotide polymorphisms (SNPs) in BCL11A, XmnI-HBG2, HBS1L-MYB, and ANTXR1 and the levels of HbF in ß-thalassemia carriers. METHODS: Samples were collected from 330 cases of ß-thalassemia carriers. The genotypes of the rs4671393, rs-7482144, rs28384513, rs4895441, rs9399137, and rs4527238 were determined using Sanger sequencing. RESULTS: The results both of quantitative and qualitative analysis showed that rs4671393 (BCL11A), rs7482144 (Xmn1-HBG2), and rs9399137 (HBS1L-MYB) in ß-thalassemia carriers correlated with the levels of HbF (p < 0.05), only rs28384513 (HBS1L-MYB) and rs4527238 (ANTXR1) were associated with HbF expression in ß-thalassemia minor (p < 0.05). CONCLUSIONS: These results indicate that the SNP rs4527238 in the ANTXR1 gene was found likely to play a role as a modulator of HbF levels in ß-thalassemia carriers for the first time.
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Talassemia beta , Humanos , Talassemia beta/genética , Polimorfismo de Nucleotídeo Único , Testes Hematológicos , Genótipo , Fatores de Transcrição , Proteínas dos Microfilamentos , Receptores de Superfície CelularRESUMO
PURPOSE: Recent studies have found that children with convergence insufficiency experience higher frequencies of performance-related symptoms (e.g., losing concentration), but data on performance-related symptoms among adults with accommodative dysfunctions (ADs) and/or binocular dysfunctions (BDs) are lacking, which might cause misdiagnosis, diagnostic confusion, or exacerbation of attention deficits. We aimed to describe frequencies and symptom patterns in adults with ADs and/or BDs who were treated at optometric clinics and explore any correlations between visual symptoms and clinical findings. METHODS: This cross-sectional study divided 235 participants (age: 23.7 ± 2.9 years) into three groups: ADs, BDs, and normal binocular vision (NBV) groups. Convergence Insufficiency Symptom Survey (CISS), refractive examinations, and binocular tests were administered to all participants. After 1-to-1 propensity score matching, outcomes were assessed using MannâWhitney U test and Pearson's correlation analysis among three groups. RESULTS: In this sample, the number (frequency) of individuals with ADs and/or BDs was 117 (49.8%). ADs and BDs groups experienced significantly more performance-related symptoms (feeling sleepy, losing concentration, trouble remembering, reading slowly, losing place, and having to re-read; all P < 0.05) than the NBV group. Significant correlations were observed between performance-related symptoms and clinical findings, including accommodative amplitude (r = - 0.294), accommodative facility (r = - 0.452), near phoria (r = - 0.261), near point of convergence (r = 0.482), and positive fusional vergence (r = - 0.331) (all P < 0.001). CONCLUSION: ADs and/or BDs are commonly present in adults treated at optometric clinics, and adults diagnosed with ADs and/or BDs exhibit more performance-related symptoms than participants with NBV.
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População do Leste Asiático , Transtornos da Motilidade Ocular , Adulto , Humanos , Adulto Jovem , Acomodação Ocular , Convergência Ocular , Estudos Transversais , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/epidemiologia , Visão BinocularRESUMO
Brain tumours have a poor prognosis and lack effective treatments. The blood-brain barrier (BBB) represents a major hurdle to drug delivery to brain tumours. In some locations in the tumour, the BBB may be disrupted to form the blood-brain tumour barrier (BBTB). This leaky BBTB enables diagnosis of brain tumours by contrast enhanced magnetic resonance imaging; however, this disruption is heterogeneous throughout the tumour. Thus, relying on the disrupted BBTB for achieving effective drug concentrations in brain tumours has met with little clinical success. Because of this, it would be beneficial to design drugs and drug delivery strategies to overcome the 'normal' BBB to effectively treat the brain tumours. In this review, we discuss the role of BBB/BBTB in brain tumour diagnosis and treatment highlighting the heterogeneity of the BBTB. We also discuss various strategies to improve drug delivery across the BBB/BBTB to treat both primary and metastatic brain tumours. Recognizing that the BBB represents a critical determinant of drug efficacy in central nervous system tumours will allow a more rapid translation from basic science to clinical application. A more complete understanding of the factors, such as BBB-limited drug delivery, that have hindered progress in treating both primary and metastatic brain tumours, is necessary to develop more effective therapies.
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Barreira Hematoencefálica , Neoplasias Encefálicas , Barreira Hematoencefálica/patologia , Encéfalo/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Sistemas de Liberação de Medicamentos/métodos , HumanosRESUMO
BACKGROUND: Intellectual disability (ID) represents a neurodevelopmental disorder, which is characterized by marked defects in the intellectual function and adaptive behavior, with an onset during the developmental period. ID is mainly caused by genetic factors, and it is extremely genetically heterogeneous. This study aims to identify the genetic cause of ID using trio-WES analysis. METHODS: We recruited four pediatric patients with unexplained ID from non-consanguineous families, who presented at the Department of Pediatrics, Guizhou Provincial People's Hospital. Whole-exome sequencing (WES) and Sanger sequencing validation were performed in the patients and their unaffected parents. Furthermore, conservative analysis and protein structural and functional prediction were performed on the identified pathogenic variants. RESULTS: We identified five novel de novo mutations from four known ID-causing genes in the four included patients, namely COL4A1 (c.2786T>A, p.V929D and c.2797G>A, p.G933S), TBR1 (c.1639_1640insCCCGCAGTCC, p.Y553Sfs*124), CHD7 (c.7013A>T, p.Q2338L), and TUBA1A (c.1350del, p.E450Dfs*34). These mutations were all predicted to be deleterious and were located at highly conserved domains that might affect the structure and function of these proteins. CONCLUSION: Our findings contribute to expanding the mutational spectrum of ID-related genes and help to deepen the understanding of the genetic causes and heterogeneity of ID.
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Deficiência Intelectual , Criança , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mutação/genética , Sequenciamento do ExomaRESUMO
SARI (Suppressor of AP-1, regulated by IFN-ß) is known to play an important role in some systemic disease processes such an inflammatory conditions and cancer. We hypothesize that SARI may also play a role in ocular diseases involving inflammation and neovascularization. To explore our hypothesis, further, we investigated an endotoxin-induced uveitis (EIU) and experimental argon laser-induced choroidal neovascularization (CNV) model in SARI wild-type (SARIWT ) and SARI-deficient (SARI-/- ) mice. Through imaging, morphological and immunohistochemical (IHC) studies, we found that SARI deficiency exacerbated the growth of CNV. More VEGF-positive cells were presented in the retina of SARI-/- mice with CNV. Compared to SARIWT mice, more inflammatory cells infiltrated the ocular anterior segment and posterior segments in SARI-/- mice with EIU. Collectively, the results point to a potential dual functional role of SARI in inflammatory ocular diseases, suggesting that SARI could be a potential therapy target for ocular inflammation and neovascularization.
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Fatores de Transcrição de Zíper de Leucina Básica/genética , Neovascularização de Coroide/genética , Inflamação/genética , Retina/metabolismo , Uveíte/genética , Animais , Neovascularização de Coroide/patologia , Citocinas/genética , Modelos Animais de Doenças , Endotoxinas/toxicidade , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Lasers de Gás/efeitos adversos , Camundongos , Camundongos Knockout , Retina/patologia , Retina/efeitos da radiação , Uveíte/induzido quimicamente , Uveíte/patologia , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
Activated natural killer (NK) cells can kill malignant tumor cells via granule exocytosis and secretion of IFN-γ, a key regulator of the TH1 response. Thus, mobilization of NK cells can augment cancer immunotherapy, particularly when mediated through antibody-dependent cellular cytotoxicity (ADCC). Stimulation of toll-like receptor (TLR)7/8 activity in dendritic cells promotes pro-inflammatory cytokine secretion and costimulatory molecule upregulation, both of which can potentiate NK cell activation. However, currently available TLR7/8 agonists exhibit unfavorable pharmacokinetics, limiting their in vivo efficacy. To enable efficient delivery to antigen-presenting cells, we encapsulated a novel imidazoquinoline-based TLR7/8 agonist in pH-responsive polymeric NPs. Enhanced costimulatory molecule expression on dendritic cells and a stronger pro-inflammatory cytokine response were observed with a NP-encapsulated agonist, compared to that with the soluble form. Treatment with NP-encapsulated agonists resulted in stronger in vivo cytotoxicity and prolonged activation of NK cells compared to that with a soluble agonist. In addition, TLR7/8 agonist-loaded NPs potentiated stronger NK cell degranulation, which resulted in enhanced in vitro and in vivo ADCC mediated by the epidermal growth factor receptor-targeting antibody cetuximab. TLR7/8 agonist-loaded NP treatment significantly enhanced the antitumor efficacy of cetuximab and an anti-HER2/neu antibody in mouse tumor models. Collectively, our data show that a pH-responsive NP-encapsulating TLR7/8 agonist could be used as a potent immunostimulatory adjuvant for antibody-based cancer immunotherapy by promoting NK cell activation.
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Imunoterapia/métodos , Células Matadoras Naturais/metabolismo , Nanopartículas/química , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Células A549 , Animais , Células Dendríticas/metabolismo , Citometria de Fluxo , Humanos , Imiquimode/química , Células Matadoras Naturais/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanomedicina/métodosRESUMO
Cancer vaccines composed of tumor-associated antigens (TAAs) and toll-like receptor (TLR) agonists have shown promising antitumor efficacy in preclinical studies by generating antigen-specific CD8 T cells, but translation of cancer vaccines to the clinic has been limited due to variables responses and development of resistance. The tumor microenvironment deploys various immune escape mechanisms that neutralize CD8 T cell-mediated tumor rejection. Therefore, we hypothesized that modulation of the tumor microenvironment can augment CD8 T cell activation and enhance therapeutic efficacy of cancer vaccines. To accomplish this, we aimed to eliminate immune suppressive cells and block their inhibitory signaling. Combination of the tyrosine kinase inhibitor (TKI) sunitinib with a nanoparticle-based cancer vaccine (nanovaccine) resulted in the reduction of immune-suppressive myeloid-derived suppressive cells (MDSCs) and regulatory T cells (Tregs). Blockade of programmed death-ligand 1 (PD-L1) using anti-PD-L1 antibody was used to reduce CD8 T cell exhaustion. Combination of nanovaccine+sunitinib+PD-L1 antibody treatment reduced PD-L1high M2 macrophages and MDSCs and upregulated activation of CD8 T cells in the tumor. Nanovaccine+sunitinib+PD-L1 antibody treatment also stimulated antigen-specific CD8 T cell response, which led to improved therapeutic efficacy in MB49 and B16F10 murine tumor models. These results suggest that modulation of tumor microenvironment using sunitinib and PD-L1 blockade can significantly enhance the antitumor efficacy of cancer nanovaccine.
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Anticorpos/uso terapêutico , Antígeno B7-H1/imunologia , Vacinas Anticâncer/uso terapêutico , Glicoproteínas de Membrana/agonistas , Neoplasias/terapia , Sunitinibe/uso terapêutico , Receptor 7 Toll-Like/agonistas , Receptor 8 Toll-Like/agonistas , Animais , Antígenos de Neoplasias/imunologia , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Feminino , Interleucina-10/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Linfócitos T Reguladores/imunologia , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , VacinaçãoRESUMO
MDM2-p53 inhibition may be effective in glioblastoma (GBM). This study evaluates the pharmacokinetics/pharmacodynamics of BI-907828, a potent antagonist of MDM2, in GBM, and demonstrates a translational paradigm with a focus on a unified "Delivery - Potency - Efficacy" relationship in drug development for central nervous system(CNS) tumors. BI-907828 was tested for cytotoxicity and MDM2-p53 pathway inhibition. Systemic pharmacokinetics and transport mechanisms controlling CNS distribution were evaluated in mice. BI-907828 free fractions in cell media, mouse and human specimens were measured to determine "active" unbound concentrations. Efficacy measures, including overall survival and target expression were assessed in mouse orthotopic GBM xenografts. BI-907828 exhibited potent inhibition of MDM2-p53 pathway and promoted cell death in GBM TP53 wild-type cells. MDM2-amplified cells are highly sensitive to BI-907828, with an effective unbound concentration of 0.1 nmol/L. The CNS distribution of BI-907828 is limited by blood-brain barrier (BBB) efflux mediated by P-gp, resulting in a Kp,uu_brain of 0.002. Despite this seemingly "poor" BBB penetration, weekly administration of 10 mg/kg BI-907828 extended median survival of orthotopic GBM108 xenografts from 28 to 218 days (P < 0.0001). This excellent efficacy can be attributed to high potency, resulting in a limited, yet effective, exposure in the CNS. These studies show that efficacy of BI-907828 in orthotopic models is related to high potency even though its CNS distribution is limited by BBB efflux. Therefore, a comprehensive understanding of all aspects of the "Delivery - Potency - Efficacy" relationship is warranted in drug discovery and development, especially for treatment of CNS tumors.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Camundongos , Animais , Glioblastoma/patologia , Barreira Hematoencefálica/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Encefálicas/patologia , Proteínas Proto-Oncogênicas c-mdm2 , Linhagem Celular TumoralRESUMO
As the most common type of refractive error, myopia has become one of the leading causes of visual impairment. With the increasing prevalence of myopia, there is a growing need to better understand the factors involved in its development. Inflammation, one of the most fundamental pathophysiological processes in humans, is a rapid response triggered by harmful stimuli and conditions. Although controlled inflammatory responses are necessary, over-activated inflammation is the common soil for many diseases. The impact of inflammation on myopia has received rising attention in recent years. Elevated inflammation may contribute to myopia progression either directly or indirectly by inducing scleral remodeling, and myopia development may also increase ocular inflammation. This article provides a comprehensive review of the interplay between inflammation and myopia and the potential biological mechanisms, which may present new targets for understanding the pathology of myopia and developing myopia therapies.
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Miopia , Humanos , Miopia/etiologia , Miopia/patologia , PrevalênciaRESUMO
The decline of visual plasticity restricts the recovery of visual functions in adult amblyopia. Repetitive transcranial magnetic stimulation (rTMS) has been shown to be effective in treating adult amblyopia. However, the underlying mechanisms of rTMS on visual cortex plasticity remain unclear. In this study, we found that low-frequency rTMS reinstated the amplitude of visual evoked potentials, but did not influence the impaired depth perception of amblyopic rats. Furthermore, the expression of synaptic plasticity genes and the number of dendritic spines were significantly higher in amblyopic rats which received rTMS when compared with amblyopic rats which received sham stimulation, with reduced level of inhibition and perineuronal nets in visual cortex, as observed via molecular and histological investigations. The results provide further evidence that rTMS enhances functional recovery and visual plasticity in an adult amblyopic animal model.
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Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the NAD salvage pathway of mammalian cells and is overexpressed in numerous types of cancers. These include breast cancer, ovarian cancer, prostate cancer, gastric cancer, colorectal cancer, glioma, and b-cell lymphoma. NAMPT is also known to impact the NAD and NADPH pool. Research has demonstrated that NAMPT can be inhibited. NAMPT inhibitors are diverse anticancer medicines with significant anti-tumor efficacy in ex vivo tumor models. A few notable NAMPT specific inhibitors which have been produced include FK866, CHS828, and OT-82. Despite encouraging preclinical evidence of the potential utility of NAMPT inhibitors in cancer models, early clinical trials have yielded only modest results, necessitating the adaptation of additional tactics to boost efficacy. This paper examines a number of cancer treatment methods which target NAMPT, including the usage of individual inhibitors, pharmacological combinations, dual inhibitors, and ADCs, all of which have demonstrated promising experimental or clinical results. We intend to contribute further ideas regarding the usage and development of NAMPT inhibitors in clinical therapy to advance the field of research on this intriguing target.
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PURPOSE: To identify disease associated mutations in a male infant with congenital heart defects and heterochromia. METHODS: A detailed clinical examination and routine laboratory tests were performed on the patient. We applied whole exome sequencing to identify the causal mutation on the proband and other family members. RESULTS: The patient presented with severe congenital heart disease, strabismus, and pigment disturbances of the iris. We identified a deletion of 1.99 megabase [arr[hg19]22q12.3-13.1 (chr22:36656004-38643920) *1], including SOX10 and 13 RefSeq genes on this patient, which was associated with atypical Waardenburg syndrome. CONCLUSION: Our results suggest that a deletion of 1.99 megabase (including SOX10) acts as a dominant pathogenic variant on the clinical presentations of this patient with atypical Waardenburg syndrome.
Assuntos
Síndrome de Waardenburg , Cromossomos Humanos Par 22 , Humanos , Lactente , Iris , Masculino , Mutação , Linhagem , Fatores de Transcrição SOXE/genética , Síndrome de Waardenburg/genética , Sequenciamento do ExomaRESUMO
There is a significant interest in designing therapeutic agents that can enhance ADCC and thereby improve clinical responses with approved antibodies. We recently reported the combination of an imidazoquinoline-based TLR7/8 agonist (522) with a monoclonal antibody improved ADCC in vitro and in vivo. In the present study, we tested several new small molecule TLR7/8 agonists that induce significantly higher cytokines compared to both the FDA-approved TLR7 agonist, imiquimod, and 522. We evaluated these agonists in combination with monoclonal antibody therapy, with the main goal of enhancing ADCC. Our studies show these TLR7/8 agonists induce robust pro-inflammatory cytokine secretion and activate NK cells. Specifically, we found the agonists 574 and 558 significantly enhanced NK cell-mediated ADCC in vitro as well as enhanced the anti-cancer efficacy of monoclonal antibodies in two different in vivo mouse models. Additionally, we found the agonists were able to stimulate CD8 T cells, likely indicative of an early adaptive immune response.