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Boron neutron capture therapy (BNCT) targets invasive, radioresistant cancers but requires a selective and high B-10 loading boron drug. This manuscript investigates boron-rich poly(ethylene glycol)-block-(poly(4-vinylphenyl boronate ester)) polymer micelles synthesized via atom transfer radical polymerization for their potential application in BNCT. Transmission electron microscopy (TEM) revealed spherical micelles with a uniform size of 43 ± 10 nm, ideal for drug delivery. Additionally, probe sonication proved effective in maintaining the micelles' size and morphology postlyophilization and reconstitution. In vitro studies with B16-F10 melanoma cells demonstrated a 38-fold increase in boron accumulation compared to the borophenylalanine drug for BNCT. In vivo studies in a B16-F10 tumor-bearing mouse model confirmed enhanced tumor selectivity and accumulation, with a tumor-to-blood (T/B) ratio of 2.5, surpassing BPA's T/B ratio of 1.8. As a result, mice treated with these micelles experienced a significant delay in tumor growth, highlighting their potential for BNCT and warranting further research.
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Terapia por Captura de Nêutron de Boro , Micelas , Terapia por Captura de Nêutron de Boro/métodos , Animais , Camundongos , Melanoma Experimental/patologia , Melanoma Experimental/tratamento farmacológico , Ácidos Borônicos/química , Linhagem Celular Tumoral , Polietilenoglicóis/química , Polímeros/química , Camundongos Endogâmicos C57BL , Ésteres/química , Ésteres/farmacologia , Compostos de Boro/química , Compostos de Boro/farmacologiaRESUMO
Anxiety disorders are debilitating psychiatric diseases that affect â¼16% of the world's population. Although it has been proposed that the central nucleus of the amygdala (CeA) plays a role in anxiety, the molecular and circuit mechanisms through which CeA neurons modulate anxiety-related behaviors are largely uncharacterized. Soluble epoxide hydrolase (sEH) is a key enzyme in the metabolism of polyunsaturated fatty acids (PUFAs), and has been shown to play a role in psychiatric disorders. Here, we reported that sEH was enriched in neurons in the CeA and regulated anxiety-related behaviors in adult male mice. Deletion of sEH in CeA neurons but not astrocytes induced anxiety-like behaviors. Mechanistic studies indicated that sEH was required for maintaining the the excitability of sEH positive neurons (sEHCeA neurons) in the CeA. Using chemogenetic manipulations, we found that sEHCeA neurons bidirectionally regulated anxiety-related behaviors. Notably, we identified that sEHCeA neurons directly projected to the bed nucleus of the stria terminalis (BNST; sEHCeA-BNST). Optogenetic activation and inhibition of the sEHCeA-BNST pathway produced anxiolytic and anxiogenic effects, respectively. In summary, our studies reveal a set of molecular and circuit mechanisms of sEHCeA neurons underlying anxiety.SIGNIFICANCE STATEMENT Soluble epoxide hydrolase (sEH), a key enzyme that catalyzes the degradation of EETs, is shown to play a key role in mood disorders. It is well known that sEH is mostly localized in astrocytes in the prefrontal cortex and regulates depressive-like behaviors. Notably, sEH is also expressed in central nucleus of the amygdala (CeA) neurons. While the CeA has been studied for its role in the regulation of anxiety, the molecular and circuit mechanism is quite complex. In the present study, we explored a previously unknown cellular and circuitry mechanism that guides sEHCeA neurons response to anxiety. Our findings reveal a critical role of sEH in the CeA, sEHCeA neurons and CeA-bed nucleus of the stria terminalis (BNST) pathway in regulation of anxiety-related behaviors.
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Núcleo Central da Amígdala , Núcleos Septais , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/psicologia , Núcleo Central da Amígdala/metabolismo , Núcleos Cerebelares/metabolismo , Epóxido Hidrolases , Humanos , Masculino , Camundongos , Núcleos Septais/fisiologiaRESUMO
This study aims to build a radiological model based on standard MR sequences for detecting methylguanine methyltransferase (MGMT) methylation in gliomas using texture analysis. A retrospective cross-sectional study was undertaken in a cohort of 53 glioma patients who underwent standard preoperative magnetic resonance (MR) imaging. Conventional visual radiographic features and clinical factors were compared between MGMT promoter methylated and unmethylated groups. Texture analysis extracted the top five most powerful texture features of MR images in each sequence quantitatively for detecting the MGMT promoter methylation status. The radiomic signature (Radscore) was generated by a linear combination of the five features and estimates in each sequence. The combined model based on each Radscore was established using multivariate logistic regression analysis. A receiver operating characteristic (ROC) curve, nomogram, calibration, and decision curve analysis (DCA) were used to evaluate the performance of the model. No significant differences were observed in any of the visual radiographic features or clinical factors between different MGMT methylated statuses. The top five most powerful features were selected from a total of 396 texture features of T1, contrast-enhanced T1, T2, and T2 FLAIR. Each sequence's Radscore can distinguish MGMT methylated status. A combined model based on Radscores showed differentiation between methylated MGMT and unmethylated MGMT both in the glioblastoma (GBM) dataset as well as the dataset for all other gliomas. The area under the ROC curve values for the combined model was 0.818, with 90.5% sensitivity and 72.7% specificity, in the GBM dataset, and 0.833, with 70.2% sensitivity and 90.6% specificity, in the overall gliomas dataset. Nomogram, calibration, and DCA also validated the performance of the combined model. The combined model based on texture features could be considered as a noninvasive imaging marker for detecting MGMT methylation status in glioma.
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Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/enzimologia , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Glioma/diagnóstico por imagem , Glioma/enzimologia , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Neoplasias Encefálicas/patologia , Meios de Contraste , Estudos Transversais , Metilação de DNA , Reparo do DNA , Técnicas de Apoio para a Decisão , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/enzimologia , Glioblastoma/patologia , Glioma/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Nomogramas , Curva ROC , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto JovemRESUMO
OBJECTIVE: To investigate the value of radiomics analyses based on different magnetic resonance (MR) sequences in the noninvasive evaluation of glioma characteristics for the differentiation of low-grade glioma versus high-grade glioma, isocitrate dehydrogenase (IDH)1 mutation versus IDH1 wild-type, and mutation status and 6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (+) versus MGMT promoter methylation (-) glioma. METHODS: Fifty-nine patients with untreated glioma who underwent a standard 3T-MR tumor protocol were included in the study. A total of 396 radiomics features were extracted from the MR images, with the manually delineated tumor as the volume of interest. Clinical imaging diagnostic features (tumor location, necrosis/cyst change, crossing midline, and the degree of enhancement or peritumoral edema) were analyzed by univariate logistic regression to select independent clinical factors. Radiomics and combined clinical-radiomics models were established for grading and molecular genomic typing of glioma by multiple logistic regression and cross-validation. The performance of the models based on different sequences was evaluated by using receiver operating characteristic curves, nomograms, and decision curves. RESULTS: The radiomics model based on T1-CE performed better than models based on other sequences in predicting the tumor grade and the IDH1 status of the glioma. The radiomics model based on T2 performed better than models based on other sequences in predicting the MGMT methylation status of glioma. Only the T1 combined clinical-radiomics model showed improved prediction performance in predicting tumor grade and the IDH1 status. CONCLUSIONS: The results demonstrate that state-of-the-art radiomics analysis methods based on multiparametric MR image data and radiomics features can significantly contribute to pretreatment glioma grading and molecular subtype classification.
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Neoplasias Encefálicas/diagnóstico por imagem , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/diagnóstico por imagem , Isocitrato Desidrogenase/genética , Imageamento por Ressonância Magnética/métodos , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Metilação de DNA , Feminino , Glioma/genética , Glioma/patologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Regiões Promotoras Genéticas , Adulto JovemRESUMO
BACKGROUND: Melioidosis is a tropical disease caused by Burkholderia pseudomallei (B. pseudomallei). It can infect any organ system and lead to multiple abscesses. A few studies reported that central nervous system (CNS) is also involved. We present a diabetic patient with multi-systemic melioidosis that affected the CNS, thorax, and spleen. The aim was to study the clinical and radiological features of melioidosis and enhance understanding of the disease. CASE PRESENTATION: A 38-year-old male presented with cough and expectoration mixed with blood for several days. Chest computed tomography (CT) showed a patchy opacity in his left lung, and multiple low-density lesions in his spleen. After 10 days of antibiotics treatment, his clinical symptoms improved and he was discharged from the hospital. But 8 months later, the patient experienced sudden onset of left limb weakness and seizure and was re-admitted to the hospital. Brain CT indicated a low-density lesion over the right frontal lobe, and magnetic resonance imaging (MRI) indicated a well-enhanced lobulated lesion with multiple diffusion restriction areas in the lesion. He had a neuronavigation-guided open surgery but no malignancy was found. B. pseudomallei was cultured from the operative samples. After 4 months of systemic and intraventricular antibiotic administration treatment, he recovered complete consciousness with left hemiparesis. CONCLUSIONS: Multi-systemic melioidosis may present atypical clinical, neurological, and radiological manifestations. It is extremely important to accurately diagnose before treatment is selected. CNS melioidosis in early stage manifests similar symptoms to malignancy or stroke. It might mislead to a false diagnose. Diffusion weighted imaging (DWI) can help in differentiate abscesses from cystic tumours.
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Infecções Bacterianas do Sistema Nervoso Central/diagnóstico , Complicações do Diabetes/diagnóstico , Melioidose/diagnóstico , Abscesso/diagnóstico , Abscesso/tratamento farmacológico , Abscesso/microbiologia , Adulto , Antibacterianos/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/microbiologia , Encéfalo/patologia , Burkholderia pseudomallei/isolamento & purificação , Infecções Bacterianas do Sistema Nervoso Central/complicações , Infecções Bacterianas do Sistema Nervoso Central/tratamento farmacológico , Infecções Bacterianas do Sistema Nervoso Central/patologia , China , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/patologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Melioidose/tratamento farmacológico , Melioidose/patologia , Radiografia , Radiografia Torácica , Baço/diagnóstico por imagem , Baço/microbiologia , Baço/patologia , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: Our purpose was to evaluate the diagnostic performance of diffusion-weighted imaging, the relative minimum apparent diffusion coefficient (rADCmin) in differentiating primary central nervous system lymphomas (PCNSLs) from glioblastomas (GBMs) and inflammatory demyelinating pseudotumors (IDPs). MATERIALS AND METHODS: Magnetic resonance images were reviewed retrospectively in 82 patients including 39 PCNSLs, 35 GBMs, and 8 IDPs. Regions of interest were drawn around the tumor on contrast-enhanced axial images; these images were transferred onto coregistered ADC maps to obtain the ADCmin, and the normalized ADCmin ratios (rADCmin) were calculated using the formula rADCmin = ADCmin of the lesion / ADCmin of the normal white matter. The rADCmin values were compared between PCNSLs, GBMs, and IDPs using the analysis of variance test. Receiver operating characteristic curves were constructed to evaluate the diagnostic performance of rADCmin values and to determine the optimum thresholds. Simple logistic regression was analyzed to evaluate the relationship between ADCs and tumor cellularity. RESULTS: The rADCmin value was significantly lower in PCNSLs (0.675 ± 0.113) than GBMs (0.765 ± 0.059) and IDPs (0.834 ± 0.067) (PCNSL vs GBM, P < 0.001; PCNSL vs IDP, P < 0.001). Relative ADCmin was a significant assessor for differentiating PCNSLs from non-PCNCLs (P < 0.001). The optimal cutoff value was 0.722 (sensitivity, 74.5%; specificity, 74.1%; area under the curve, 0.803) on receiver operating characteristic analysis. A stronger negative correlation (r = -0.755, P = 0.000) was obtained between the cytoplasm and rADCmin. CONCLUSIONS: Relative ADCmin value is helpful in differentiating PCNSL from GBM and IDP. Thus, ADC values may provide a useful supplement to the information obtained from conventional contrast-enhanced magnetic resonance imaging and assist in future treatment planning.
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Encefalopatias/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Doenças Desmielinizantes/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Glioblastoma/diagnóstico por imagem , Granuloma de Células Plasmáticas/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Adulto , Idoso , Doenças Desmielinizantes/complicações , Diagnóstico Diferencial , Feminino , Granuloma de Células Plasmáticas/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND AND PURPOSE: Reperfusion-associated hemorrhagic transformation (HT) is an important complication of recanalization therapy. A method to identify stroke victims that may undergo HT will improve the patient selection and safety of this treatment. In this study, we determined the relationship between timing of reperfusion and the frequency and severity of HT, and whether very early dynamic contrast-enhanced (DCE) imaging predicts the occurrence of reperfusion-associated HT in a model of experimental stroke. METHODS: Intraluminal suture occlusion of the middle cerebral artery was used to produce transient ischemia in male Sprague Dawley rats (n = 50). Reperfusion was performed by withdrawal of the occluding filament after 3 (n = 10), 4 (n = 10), 5 (n = 10), 6 (n = 10), or 7 (n = 10) hours. Magnetic resonance imaging studies were performed before reperfusion using DCE, susceptibility-weighted imaging, diffusion-weighted imaging, and T2- and T1-weighted imaging. Follow-up magnetic resonance imaging and histological studies were performed at 24 hours. RESULTS: Hemorrhagic transformation occurred by 24 hours after injury in 8 of 50 animals. The HT rate increased with prolonged ischemic duration. All animals exhibiting acute blood-brain barrier (BBB) perturbation subsequently developed HT by 24 hours. Statistically significant differences in the BBB permeability parameters (P < 0.05) between the HT group and non-HT group were detected by DCE imaging. There were also statistically significant differences (P < 0.05) between the HT area and adjacent HT area. Among the permeability parameters, subcortex rK was the most sensitive and specific predictor of HT. CONCLUSIONS: The results suggest that the use of quantitative BBB measurements may further improve early prediction and identification of HT. The DCE parameters were the sensitive early independent predictor of reperfusion-associated HT.
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Hemorragia Cerebral/patologia , Imageamento por Ressonância Magnética , Traumatismo por Reperfusão/patologia , Acidente Vascular Cerebral/patologia , Animais , Hemorragia Cerebral/complicações , Meios de Contraste , Modelos Animais de Doenças , Aumento da Imagem , Masculino , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral/complicaçõesRESUMO
In most social species, the attainment of social dominance is strongly affected by personality traits. Dominant individuals show better cognitive abilities, however, whether an individual's cognition can determine its social status has remained inconclusive. We found that mice show better cognitive abilities tend to possess a higher social rank after cohousing. The dynamic release of acetylcholine (ACh) in the prelimbic cortex (PL) is correlated with mouse dominance behavior. ACh enhanced the excitability of the PL neurons via acetylcholine muscarinic M1 receptors (M1). Inhibition of M1 impaired mice cognitive performance and induced losing in social competition. Mice with M1 deficiency in the PL performed worse on cognitive behavioral tests, and exhibited lower status when re-grouped with others. Elevating ACh level in the PL of subordinate mice induced winning. These results provide direct evidence for the involvement of M1 in social hierarchy and suggest that social rank can be tuned by altering cognition through cholinergic system.
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Acetilcolina , Cognição , Hierarquia Social , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal , Receptor Muscarínico M1 , Animais , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Receptor Muscarínico M1/metabolismo , Acetilcolina/metabolismo , Masculino , Cognição/fisiologia , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Neurônios/fisiologiaRESUMO
Malignant cancers, known for their pronounced heterogeneity, pose substantial challenges to monotherapeutic strategies and contribute to the risk of metastasis. Addressing this, our study explores the synergistic potential of combining boron neutron capture therapy (BNCT) with immune checkpoint blockade to enhance cancer treatment efficacy. We synthesized boron-rich block copolymer micelles as a novel boron drug for BNCT. Characterization was conducted using nuclear magnetic resonance, gel-permeation chromatography, transmission electron microscopy, and dynamic light scattering. These micelles, with an optimal size of 91.3 nm and a polydispersity index of 0.18, are suitable for drug delivery applications. In vitro assessments on B16-F10 melanoma cells showed a 13-fold increase in boron uptake with the micelles compared to borophenyl alanine (BPA), the conventional boron drug for BNCT. This resulted in a substantial increase in BNCT efficacy, reducing cell viability to 77% post-irradiation in micelle-treated cells, in contrast to 90% in BPA-treated cells. In vivo, melanoma-bearing mice treated with these micelles exhibited an 8-fold increase in boron accumulation in tumor tissues versus those treated with BPA, leading to prolonged tumor growth delay (5.4 days with micelles versus 3.3 days with BPA). Moreover, combining BNCT with anti-PD-L1 immunotherapy further extended the tumor growth delay to 6.6 days, and enhanced T-cell infiltration and activation at tumor sites, thereby indicating a boosted immune response. This combination demonstrates a promising approach by enhancing cytotoxic T-cell priming and mitigating the immunosuppressive effects of melanoma tumors.
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Low specificity and hypoxia-induced drug resistance are significant challenges in traditional cancer treatment. To enhance the anticancer efficacy, an injectable hydrogel system is developed through the formation of dynamic covalent bonds in hyaluronic acid, allowing for localized controlled release of drugs. This system also utilizes double-stranded DNA sequences for the intercalation delivery of the chemotherapeutic drug, enabling a multifaceted approach to therapy. Cisplatin not only serves as a chemotherapy drug but also acts as a catalyst for chemodynamic therapy (CDT) to initiate CDT cascades by creating hydrogen peroxide for the Fenton reaction. Hemoglobin, enclosed in PLGA nanoparticles, provides ferrous ions that react with hydrogen peroxide in an acidic environment, yielding hydroxyl radicals that induce cancer cell death. Additionally, oxygen released from hemoglobin mitigates hypoxia-induced chemoresistance, bolstering overall anticancer efficacy. Results demonstrate the shear-thinning properties and injectability of the hydrogel. Cisplatin elevates intracellular hydrogen peroxide levels in tumor cells, while hemoglobin efficiently releases ferrous ions and generates reactive oxygen species (ROS) in the presence of hydrogen peroxide. In in vitro and in vivo study, the combinational use of chemo- and chemodynamic therapies achieves a synergistic anticancer effect on combating glioblastoma. In summary, our CDT-based hydrogel, activated by endogenous cues and mediated by chemo drugs, spontaneously produces ROS and ameliorates the adverse tumor microenvironment with rational and selective antitumor strategies.
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Antineoplásicos , Cisplatino , Hemoglobinas , Hidrogéis , Hidrogéis/química , Hemoglobinas/metabolismo , Hemoglobinas/farmacologia , Animais , Cisplatino/farmacologia , Cisplatino/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Humanos , Linhagem Celular Tumoral , Peróxido de Hidrogênio/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Nanopartículas/química , Camundongos Nus , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto , InjeçõesRESUMO
Current synthetic grafts for ligament rupture repair often fail to integrate well with the surrounding biological tissue, leading to complications such as graft wear, fatigue, and subsequent re-rupture. To address this medical challenge, this study aims at advancing the development of a biological ligament through the integration of physiologically-inspired principles and tissue engineering strategies. In this study, interfacial polyelectrolyte complexation (IPC) spinning technique, along with a custom-designed collection system, to fabricate a hierarchical scaffold mimicking native ligament structure, is utilized. To emulate the bone-ligament interface and alleviate stress concentration, a hydroxyapatite (HAp) mineral gradient is strategically introduced near both ends of the scaffold to enhance interface integration and diminish the risk of avulsion rupture. Biomimetic viscoelasticity is successfully displayed to provide similar mechanical support to native ligamentous tissue under physiological conditions. By introducing the connective tissue growth factor (CTGF) and conducting mesenchymal stem cells transplantation, the regenerative potential of the synthetic ligament is significantly amplified. This pioneering study offers a multifaceted solution combining biomimetic materials, regenerative therapies, and advanced techniques to potentially transform ligament rupture treatment.
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Materiais Biomiméticos , Ligamentos , Polieletrólitos , Regeneração , Alicerces Teciduais , Ligamentos/química , Ligamentos/fisiologia , Alicerces Teciduais/química , Polieletrólitos/química , Materiais Biomiméticos/química , Animais , Durapatita/química , Engenharia Tecidual/métodos , Células-Tronco Mesenquimais/citologia , HumanosRESUMO
Multidrug resistance (MDR) has been considered as a major adversary in oncologic chemotherapy. To simultaneously overcome drug resistance and inhibit tumor growth, it is essential to develop a drug delivery system that can carry and release multiple therapeutic agents with spatiotemporal control. In this study, we developed a hydrogel containing an enzyme-cleavable peptide motif, with a network structure formed by 4-armed polyethylene glycol (PEG) crosslinked by complementary nucleic acid sequences. Hydrogen bond formation between nucleobase pairing allows the hydrogel to be injectable, and the peptide motif grants deliberate control over hydrogel degradation and the responsive drug release. Moreover, MDR-targeted siRNAs are complexed with stearyl-octaarginine (STR-R8), while doxorubicin (Dox) is intercalated with DNA and nanoclay structures in this hydrogel to enhance therapeutic efficacy and overcome MDR. The results show a successful configuration of a hydrogel network with in situ gelation property, injectability, and degradability in the presence of tumor-associated enzyme, MMP-2. The synergistic effect by combining MDR-targeted siRNAs and Dox manifests with the enhanced anti-cancer effect on drug resistant breast cancer cells in both in vitro and in vivo tumor models. We suggest that with the tailor-designed hydrogel system, multidrug resistance in tumor cells can be significantly inhibited by the co-delivery of multiple therapeutics with spatial-temporal control release.
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Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Hidrogéis , Neoplasias , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Hidrogéis/farmacologia , Neoplasias/tratamento farmacológico , RNA Interferente Pequeno , HumanosRESUMO
Triple-negative breast cancer (TNBC) is characterized by highly proliferative cancer cells and is the only subtype of breast cancer that lacks a targeted therapy. Boron neutron capture therapy (BNCT) is an approach that combines chemotherapy with radiotherapy and can potentially offer beneficial targeted treatment for TNBC patients owing to its unique ability to eradicate cancer cells selectively while minimizing damage to the surrounding healthy cells. Since BNCT relies on specific delivery of a high loading of B10 to the tumor site, there is growing research interest to develop more potent boron-based drugs for BNCT that can overcome the limitations of small-molecule boron compounds. In this study, polyethylene-glycol-coated boron carbon oxynitride nanoparticles (PEG@BCNO) of size 134.2±23.6nm were prepared as a promising drug for BNCT owing to their high boron content and enhanced biocompatibility. The therapeutic efficiency of PEG@BCNO was compared with a state-of-the-art 10BPA boron drug in mice bearing MDA-MB-231 tumor. In the orthotopic mouse model, PEG@BCNO showed higher B10 accumulation in the tumor tissues (6 µg 10B/g tissue compared to 3 µg 10B/g tissue in mice administered B10-enriched 10BPA drug) despite using the naturally occurring 11B/10B boron precursor in the preparation of the BCNO nanoparticles. The in vivo biodistribution of PEG@BCNO in mice bearing MDA-MB-231 showed a tumor/blood ratio of ~3.5, which is comparable to that of the state-of-the-art 10BPA-fructose drug. We further demonstrated that upon neutron irradiation, the mice bearing MDA-MB-231 tumor cells treated with PEG@BCNO and 10BPA showed tumor growth delay times of 9 days and 1 day, respectively, compared to mice in the control group after BNCT. The doubling times (DTs) for mice treated with PEG@BCNO and 10BPA as well as mice in the control group were calculated to be 31.5, 19.8, and 17.7 days, respectively. Immunohistochemical staining for the p53 and caspase-3 antibodies revealed that mice treated with PEG@BCNO showed lower probability of cancer recurrence and greater level of cellular apoptosis than mice treated with 10BPA and mice in the control group. Our study thus demonstrates the potential of pegylated BCNO nanoparticles in effectively inhibiting the growth of TNBC tumors compared to the state-of-the-art boron drug 10BPA.
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Terapia por Captura de Nêutron de Boro , Nanopartículas , Neoplasias de Mama Triplo Negativas , Camundongos , Humanos , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/radioterapia , Boro/farmacologia , Distribuição Tecidual , Nanopartículas/uso terapêuticoRESUMO
To establish a multidimensional nomogram model for predicting progression-free survival (PFS) and risk stratification in patients with advanced nasopharyngeal carcinoma (NPC). This retrospective cross-sectional study included 156 patients with advanced NPC who underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Radiomic features were extracted from the efflux rate constant (Ktrans ) and extracellular extravascular volume (Ve ) mapping derived from DCE-MRI. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied for feature selection. The Radscore was constructed using the selected features with their respective weights in the LASSO Cox regression analysis. A nomogram model combining the Radscore and clinical factors was built using multivariate Cox regression analysis. The C-index was used to assess the discrimination power of the Radscore and nomogram. The Kaplan-Meier method was used for survival analysis. Of the 360 radiomic features, 28 were selected (7, 6, and 15 features extracted from Ktrans , Ve, and Ktrans +Ve images, respectively). The combined Radscore k trans +Ve (C-index, 0.703, 95% confidence interval [CI]: 0.571-0.836) showed higher efficacy in predicting the prognosis of advanced NPC than Radscore k trans (C-index, 0.693; 95% CI, 0.560-0.826) and Radscore Ve (C-index, 0.614; 95% CI, 0.481-0.746) did. Multivariable Cox regression analysis revealed clinical stage, T stage, and treatment with nimotuzumab as risk factors for PFS. The nomogram established by Radscore k trans +Ve and risk factors (C-index, 0.732; 95% CI: 0.599-0.864) was better than Radscore k trans +Ve in predicting PFS in patients with advanced NPC. A lower Radscore k trans +Ve (HR 3.5584, 95% CI 2.1341-5.933), lower clinical stage (hazard ratio [HR] 1.5982, 95% CI 0.5262-4.854), lower T stage (HR 1.4365, 95% CI 0.6745-3.060), and nimotuzumab (NTZ) treatment (HR 0.7879, 95% CI 0.4899-1.267) were associated with longer PFS. Kaplan-Meier analysis showed a lower PFS in the high-risk group than in the low-risk group (p<0.0001). The nomogram based on combined pretreatment DCE-MRI radiomics features, NTZ, and clinicopathological risk factors may be considered as a noninvasive imaging marker for predicting individual PFS in patients with advanced NPC.
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Neural stem cells (NSCs) represent significant potential and promise in the treatment of neurodegenerative diseases and nerve injuries. An efficient methodology or platform that can help in specifically directing the stem cell fate is important and highly desirable for future clinical therapy. In this study, a biodegradable electrical conductive film composed of an oxidative polymerized carboxyl-capped aniline pentamer (CCAP) and ring-opening polymerized tetra poly(d,l-lactide) (4a-PLA) was designed with the addition of the dopant, namely chondroitin sulfate. This conductive film acts as a biological substrate for the exogenous/endogenous electric field transmission in tissue, resulting in the control of NSC fate, as well as improvement in neural tissue regeneration. The results show that CCAP is successfully synthesized and then conjugated onto 4a-PLA to form a network structure with electrical conductivity, cell adhesion capacity, and biodegradability. The neuronal differentiation of NSCs can be induced on 4a-PLAAP, and the neuronal maturation process can be facilitated by the manipulation of the electrical field. This biocompatible and electroactive material can serve as a platform to determine the cell fate of NSCs and be employed in neural regeneration. For future perspectives, its promising performance shows potential in applications, such as electrode-tissue integration interfaces, coatings on neuroprosthetics devices and neural probes, and smart drug delivery system in neurological systems.
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Compostos de Anilina/metabolismo , Materiais Biocompatíveis/metabolismo , Células-Tronco Neurais/metabolismo , Células 3T3 , Compostos de Anilina/química , Compostos de Anilina/farmacologia , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Condutividade Elétrica , Técnicas Eletroquímicas , Teste de Materiais , Camundongos , Estrutura Molecular , Células-Tronco Neurais/efeitos dos fármacosRESUMO
During nervous system development, an extracellular matrix (ECM) plays a pivotal role through surface topography and microenvironment signals in neurons and neurites maturation. Topography and microenvironment signals act as physical and chemical guiding cues, respectively, for neural tissue formation and reconstruction. Imposed surface topography can affect neural stem cells by promoting adhesion, spreading, alignment, morphological changes, and specific gene expression. Therefore, fabrication of a biomimetic construct or scaffold to support neurite outgrowth and axon extension is a crucial and common strategy for neural tissue regeneration. Here, we review recent developments in biomaterials modification for simulating the microenvironment to promote neural cell adhesion and growth. The subtopics include those of potential cellular mechanisms of topographical response, topography on cellular organization and function, contact guidance in neurite outgrowth and axon growth, ECM microenvironment as regulatory cues, as well as challenges and future perspectives of nerve conduits that are now in clinical trials and usage.
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Materiais Biocompatíveis/química , Matriz Extracelular/química , Neurônios/química , Engenharia Tecidual , Animais , Materiais Biocompatíveis/síntese química , Adesão Celular , Proliferação de Células , Humanos , Neurônios/citologia , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
Purpose: To determine whether the early assessment of temporal lobe microstructural changes using diffusion kurtosis imaging (DKI) can predict late delayed neurocognitive decline after radiotherapy in nasopharyngeal carcinoma (NPC) patients. Methods and Materials: Fifty-four NPC patients undergoing intensity-modulated radiotherapy (IMRT) participated in a prospective DKI magnetic resonance (MR) imaging study. MR imaging was acquired prior to IMRT (-0), 1 month (-1), and 3 (-3) months after IMRT. Kurtosis (Kmean, Kax, Krad) and Diffusivity (Dmean, Dax, Drad) variables in the temporal lobe gray and white matter were computed. Neurocognitive function tests (MoCA) were administered pre-radiotherapy and at 2 years post-IMRT follow-up. All the patients were divided into neurocognitive function decline (NFD group) and neurocognitive function non-decline groups (NFND group) according to whether the MoCA score declined ≥3 2 years after IMRT. All the DKI metrics were compared between the two groups, and the best imaging marker was chosen for predicting a late delayed neurocognitive decline. Results: Kurtosis (Kmean-1, Kmean-3, Kax-1, Kax-3, Krad-1, and Krad-3) and Diffusivity (Dmean-1 and Dmean-3) of white matter were significantly different between the two groups (p<0.05). Axial Kurtosis (Kax-1, Kax-3) of gray matter was significantly different between the two groups (p<0.05). By receiver operating characteristic (ROC) curves, Kmean-1 of white matter performed best in predicting of MoCA scores delayed decline (p<0.05). The radiation dose was also significantly different between NFD and NFND group (p=0.031). Conclusions: Temporal lobe white matter is more vulnerable to microstructural changes and injury following IMRT in NPC. Metrics derived from DKI should be considered as imaging markers for predicting a late delayed neurocognitive decline. Both temporal lobe white and gray matter show microstructural changes detectable by DKI. The Kmean early after radiotherapy has the best prediction performance.
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PURPOSE: To investigate temporal lobe microstructural abnormalities and neurocognitive function impairment after concurrent chemoradiotherapy (CCRT) in patients with nasopharyngeal carcinoma (NPC). METHODS: NPC patients who underwent CCRT were enrolled. High-resolution diffusion-weighted imaging (DWI) magnetic resonance imaging (MRI) and diffusion-kurtosis imaging (DKI) MRI, were performed 5 times per patient (once pre-CCRT, 1 week post-CCRT, 3 months post-CCRT, 6 months post-CCRT, and 12 months post-CCRT). Neurocognitive function was evaluated by Montreal Neurocognitive Assessment (MoCA) twice per patient, once pre-CCRT, and once 12-months after CCRT. RESULTS: Of 111 patients, 56 completed the entire protocol. The MRI derived apparent diffusion coefficient (ADC), mean of diffusion coefficient (Dmean) and fractional anisotropy (FA) values were significantly decreased (p < 0.05) over the 0-3 month period following CCRT and significantly increased (p < 0.05) over the 3-12 month period following CCRT. The mean of kurtosis coefficient (Kmean) continued to decline over a year post-CCRT. All parameters reveal more pronounced changes in white matter (WM) than in grey matter (GM). MoCA also declined after CCRT (p < 0.001). MoCA showed significant positive correlation with Kmean-WM-6 m, Kmean-WM-12 m and ΔKmean-WM. CONCLUSIONS: High-resolution DWI and DKI should be considered as a promising method for the investigation of temporal lobe microstructural change in NPC patients after CCRT.
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The aim of the study is to verify the effect of hyperglycemia on ischemia-reperfusion injury and to explore the feasibility of noninvasive observation of ischemic-reperfusion injury in hyperglycemic ischemic stroke by MRI technique. According to the duration of ischemia and blood glucose levels, 40 rats were divided into hyperglycemic ischemic 2-hr (H-I2h), hyperglycemic ischemic 6-hr (H-I6h), non- hyperglycemic ischemic 2-hr (NH-I2h), and non- hyperglycemic ischemic 6-hr (NH-I6h) groups. T2W imaging, DW imaging, T2 mapping, T2* mapping, DCE, and T1 mapping after enhancement sequences were acquired before reperfusion and approximately 3-hr after reperfusion. ADC, T1, T2, T2*, and Ktrans values of ischemic lesion were obtained in different groups. After reperfusion, the variation of ADC values showed no significant difference between groups with diabetes and groups without diabetes and between different recanalization time-points (2-hr vs 6-hr). After reperfusion, T2, T2*, and Ktrans values increased in different degrees in all four groups. Only the T1 value decreased in all groups. The change of all parameters in groups with hyperglycemia was more obvious than that in groups without hyperglycemia and was more obvious in groups with H-I6h versus those with H-I2h. This study confirms that hyperglycemia aggravates ischemia-reperfusion injury and may be an important risk factor for the prognosis of ischemic stroke. The Ktrans values should be noninvasive imaging indicators to monitor blood brain barrier permeability and ischemic-reperfusion injury in ischemic stroke.
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Barreira Hematoencefálica/diagnóstico por imagem , Hiperglicemia , Imageamento por Ressonância Magnética , Traumatismo por Reperfusão , Acidente Vascular Cerebral , Animais , Modelos Animais de Doenças , Hiperglicemia/complicações , Hiperglicemia/diagnóstico por imagem , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/diagnóstico por imagem , Traumatismo por Reperfusão/etiologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagemRESUMO
In this article, smoke suppression of Si-Al mesoporous structure on medium density fiberboard (MDF) was investigated by cone calorimeter test (CCT), scanning electron microscopy (SEM), thermal gravimetric analysis (TGA), and fourier transform infrared spectrometry (FTIR). The CCT results show that the Si-Al mesoporous structure can effectively decrease heat release rate (HRR), total heat release (THR), smoke production rate (SPR), total smoke production (TSP), smoke rate (SR), CO and CO2 concentration, etc. Particularly, the SR curves of MDF present that Si-Al mesoporous structure are considered to be a filter, which can net the solid particles and volatile flammable components in the smoke and fix onto wood fiber. Remarkably, the CO and CO2 concentration curves of MDF indicate that the Si-Al mesoporous structure has an excellent adsorption property, which can rapidly absorb CO and CO2 that generated in wood combustion process. On the other hand, the FTIR and TGA results reveal that the Si-Al mesoporous structure can significantly improve the structure of char residue.