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Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) is difficult to treat with radioactive iodine because of the absence of the sodium iodide transporter in the basement membrane of thyroid follicular cells for iodine uptake. This is usually due to the mutation or rearrangement of genes and the aberrant activation of signal pathways, which result in abnormal expression of thyroid-specific genes, leading to resistance of differentiated thyroid cancer cells to radioiodine therapy. Therefore, inhibiting the proliferation and growth of RAIR-DTC with multikinase inhibitors and other drugs or restoring its differentiation and then carrying out radioiodine therapy have become the first-line treatment strategies and main research directions. The drugs that regulate these kinases or signaling pathways have been studied in clinical and preclinical settings. In this review, we summarized the major gene mutations, gene rearrangements and abnormal activation of signaling pathways that led to radioiodine resistance of RAIR-DTC, as well as the medicine that have been tested in clinical and preclinical trials.
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Neoplasias de la Tiroides , Humanos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/radioterapia , Radioisótopos de Yodo/uso terapéutico , Transducción de SeñalRESUMEN
Olfactory tests are used for the evaluation of ability to detect and identify common odors in humans psychophysically. Olfactory tests are currently administered by professionals with a set of given odorants. Manual administration of such tests can be labor and cost intensive and data collected as such are confounded with experimental variables, which adds personnel costs and introduces potential errors and data variability. For large-scale and longitudinal studies, manually recorded data must be collected and compiled from multiple sites. It is difficult to standardize the way data are collected and recorded. There is a need for a computerized smell test system for psychophysical and clinical applications. A mobile digital olfactory testing system (DOTS) was developed, consisting of an odor delivery system (DOTS-ODD) and a mobile application program (DOTS-APP) connected wirelessly. The University of Pennsylvania Smell Identification Test was implemented in DOTS and compared to its commercial product on a cohort of 80 normosmic subjects and a clinical cohort of 12 Parkinson's disease patients. A test-retest was conducted on 29 subjects of the normal cohort. The smell identification scores obtained from the DOTS and standard UPSIT commercial test are highly correlated (râ =â 0.714, Pâ <â 0.001), and test-retest reliability coefficient was 0.807 (râ =â 0.807, Pâ <â 0.001). The DOTS is customizable and mobile compatible, which allows for the implementation of standardized olfactory tests and the customization of investigators' experimental paradigms. The DOTS-APP on mobile devices offers capabilities for a broad range of on-site, online, or remote clinical and scientific chemosensory applications.
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Aplicaciones Móviles , Trastornos del Olfato , Humanos , Olfato , Trastornos del Olfato/diagnóstico , Reproducibilidad de los Resultados , OdorantesRESUMEN
BACKGROUND: Pancreatic cancer is one of the most lethal cancers worldwide. The IAPs function as E3 ubiquitin ligases and contribute to pancreatic cancer initiation, progression, and metastasis. Although IAP-targeted therapies have been developed and shown anticancer efficacy in preclinical settings, none of them has been approved yet. METHODS: Transcriptome data from public datasets were used to analyze the correlation of IAPs and E2s, and the biological function of E2 UbcH5c in pancreatic cancer. A structure-based virtual screen was used to identify UbcH5c inhibitor, and surface plasmon resonance analysis and cellular thermal shift assays were employed to evaluate the binding affinity. The anticancer activities were demonstrated through in vitro and in vivo assays, while the related mechanisms were explored through transcriptomic and proteomic analyses and confirmed by western blot, immunofluorescence, and qRT-PCR. RESULTS: UbcH5c is positively correlated with the expression of IAPs in pancreatic cancer. We further found that UbcH5c is overexpressed and associated with a poor prognosis in pancreatic cancer. We identified a small-molecule UbcH5c inhibitor, termed DHPO, which directly bound to UbcH5c protein. DHPO inhibited cell viability and colony formation, induced apoptosis, and suppressed migration and invasion of pancreatic cancer cells in vitro. The compound inhibited UbcH5c-mediated IκBα degradation and NF-κB activation, which is critical for its anticancer activity. Furthermore, DHPO suppressed the tumor growth and metastasis in two orthotopic pancreatic tumor mouse models. CONCLUSIONS: These results indicated that inhibiting UbcH5c is a novel and effective strategy for treating pancreatic cancer and DHPO represents a new class of UbcH5c inhibitor and may be further developed as an anti-pancreatic cancer therapeutic agent.
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Neoplasias Pancreáticas , Enzimas Ubiquitina-Conjugadoras , Animales , Línea Celular Tumoral , Humanos , Ratones , FN-kappa B/metabolismo , Neoplasias Pancreáticas/patología , Proteómica , Enzimas Ubiquitina-Conjugadoras/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Neoplasias PancreáticasRESUMEN
BACKGROUND: Cervical cancer microenvironment is involved in the regulation of the behavior, morphology, and mechanical properties of the cervical cancer cells. Integrins expressed on the cell membrane combine with the factors of the microenvironment to determine cervical cancer cells' properties. The mechanical properties of integrin-extracellular matrix (ECM) interactions are important for the mechanotransduction of cervical cancer cells. However, the quantified study on the adhesion force and binding probabilities between collagen and integrins on cervical cancer cells grown on different stiffness substrates have not been reported. METHODS: Polyacrylamide (PA) gel was used as substrate to mimic the mechanical microenvironment of cancer cells. ImageJ software was used to measure the perimeter and area of the cells. SiHa cells were stained with FITC phalloidine to observe the cytoskeleton. Atomic force microscopy (AFM) was used to measure the cell mechanical properties. RESULT: The perimeters of SiHa cells grown on different stiffness substrates were 63.4 ± 1.3, 102.8 ± 4.0, and 152.6 ± 4.1 µm, for soft, intermediate, and stiff substrates, respectively. These areas were 277.2 ± 13.3, 428.9 ± 26.0, and 1166.0 ± 63.2 µm2, for soft, intermediate, and stiff substrates, respectively. The Young's modulus of SiHa cells grown on stiff substrates (3.0 ± 0.02 kPa) was higher compared with those on soft substrates (0.6 ± 0.01 kPa) or intermediate substrates (bimodal distribution, 1.36 and 1.67 kPa). The adhesion force between the functionalized probe and SiHa cells grown on glass (55.65 ± 0.78 pN) was significantly greater than that on stiff (47.03 ± 0.85 pN), intermediate (34.07 ± 0.58 pN) and soft (27.94 ± 0.47 pN) substrates. The binding probabilities of the collagen-integrin of the four rigid substrates were significantly differed. CONCLUSION: The changes in substrate stiffness can obviously regulate SiHa cells' mechanical properties, such as the Young's modulus. The adhesion force and binding probabilities of SiHa cells both increased with increasing substrate strength.
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Mecanotransducción Celular , Neoplasias del Cuello Uterino , Colágeno/química , Módulo de Elasticidad/fisiología , Femenino , Humanos , Integrinas , Microscopía de Fuerza Atómica , Microambiente TumoralRESUMEN
BACKGROUND: Reducing neuroinflammatory damage is an effective strategy for treating white-matter damage (WMD) in premature infants. Caffeine can ameliorate hypoxia-ischemia-induced brain WMD; however, its neuroprotective effect and mechanism against hypoxic-ischemic WMD remain unclear. METHODS: We used 3-day-old Sprague-Dawley rats to establish a model of cerebral hypoxia-ischemia-induced brain WMD after unilateral common carotid artery ligation and hypoxia exposure (8% O2 + 92% N2) for 2.5 h. Mechanism experiments were conducted to detect M1/M2 polarization and activation of microglia and NLRP3 inflammasome. RESULTS: Caffeine inhibited NLRP3 inflammasome activation, reduced microglial Iba-1 activation, inhibited microglia M1 polarization, and promoted microglia M2 polarization by downregulating CD86 and iNOS protein expression, inhibiting the transcription of the proinflammatory TNF-α and IL-1ß, upregulating CD206 and Arg-1 expression, and promoting the transcription of the anti-inflammatory factors IL-10 and TGF-ß. Importantly, we found that these caffeine-mediated effects could be reversed after inhibiting A2aR activity. CONCLUSIONS: Caffeine improved long-term cognitive function in neonatal rats with hypoxic-ischemic WMD via A2aR-mediated inhibition of NLRP3 inflammasome activation, reduction of microglial activation, regulation of the phenotypic polarization of microglia and the release of inflammatory factors, and improvement of myelination development. IMPACT: The direct protective effect of caffeine on hypoxic-ischemic white-matter damage (WMD) and its mechanism remains unclear. This study elucidated this mechanism using neonatal rats as an animal model of hypoxia-ischemia-induced cerebral WMD. The findings demonstrated caffeine as a promising therapeutic tool against immature WMD to protect neonatal cognitive function. We found that caffeine pretreatment reduced WMD in immature brains via regulation of microglial activation and polarization by adenosine A2a receptor, thereby, providing a scientific basis for future clinical application of caffeine.
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Hipoxia-Isquemia Encefálica , Inflamasomas , Ratas , Animales , Animales Recién Nacidos , Ratas Sprague-Dawley , Inflamasomas/metabolismo , Microglía/metabolismo , Cafeína/farmacología , Cafeína/uso terapéutico , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Hipoxia-Isquemia Encefálica/tratamiento farmacológico , Hipoxia-Isquemia Encefálica/metabolismo , IsquemiaRESUMEN
Engineering pharmaceutical formulations is governed by a number of variables, and the finding of the optimal preparation is intricately linked to the exploration of a multiparametric space through a variety of optimization tasks. As a result, making such optimization activities simpler is a significant undertaking. For the purposes of this study, we suggested a prediction model that was based on least square support vector machine (LSSVM) and whose parameters were optimized using the particle swarm optimization algorithm (PSO-LSSVM model). Other in silico optimization methods were used and compared, including the LSSVM and the back propagation (BP) neural networks algorithm. PSO-LSSVM demonstrated the highest performance on the test dataset, with the lowest mean square error. In addition, two dosage forms, quercetin solid dispersion and apigenin nanoparticles, were selected as model formulations due to the wide range of formulation compositions and manufacturing factors used in their production. Three different models were used to predict the ideal formulations of two different dosage forms, and in real world, the Taguchi orthogonal design arrays were used to optimize the formulations of each dosage form. It is clear that the predicted performance of two formulations using PSO-LSSVM was both consistent with the outcomes of the Taguchi orthogonal planned experiment, demonstrating the model's good reliability and high usefulness. Together, our PSO-LSSVM prediction model has the potential to accurately predict the best possible formulations, reduce the reliance on experimental effort, accelerate the process of formulation design, and provide a low-cost solution to drug preparation optimization.
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Redes Neurales de la Computación , Máquina de Vectores de Soporte , Composición de Medicamentos , Análisis de los Mínimos Cuadrados , Reproducibilidad de los ResultadosRESUMEN
The dielectric properties of normal and tumor human tissues have been widely reported in recent years. However, the dielectric properties of intrathoracic lymph nodes (LNs) have not been reported. In this communication, we measured the dielectric properties (i.e., permittivity and conductivity) of ex vivo intrathoracic LNs obtained from lung cancer surgeries. Results show that the permittivity and conductivity of metastatic LNs are higher than those of normal LNs over the frequency range of 1 MHz-4 GHz. Statistically significant differences are observed at single specific frequencies (64, 128, 298, 433, and 915 MHz and 2.45 GHz). Our study provides the basic data to support future-related research and fills the research gap on the dielectric properties of LNs in the lungs. Bioelectromagnetics. 2020;41:148-155. © 2020 Bioelectromagnetics Society.
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Neoplasias Pulmonares/patología , Ganglios Linfáticos/química , Ganglios Linfáticos/patología , Adulto , Anciano , Conductividad Eléctrica , Humanos , Neoplasias Pulmonares/cirugía , Metástasis Linfática/patología , Persona de Mediana EdadRESUMEN
Accurate heading perception relies on visual information integrated across a wide field, that is, optic flow. Numerous computational studies have speculated how local visual information might be pooled by the brain to compute heading, but these hypotheses lack direct neurophysiological support. In the current study, we instructed human and monkey subjects to judge heading directions based on global optic flow. We showed that a local perturbation cue applied within only a small part of the visual field could bias the subjects' heading judgments, and shift the neuronal tuning in the macaque middle temporal (MT) area at the same time. Electrical microstimulation in MT significantly biased the animals' heading judgments predictable from the tuning of the stimulated neurons. Masking the visual stimuli within these neurons' receptive fields could not remove the stimulation effect, indicating a sufficient role of the MT signals pooled by downstream neurons for global heading estimation. Interestingly, this pooling is not homogeneous because stimulating neurons with excitatory surrounds produced relatively larger effects than stimulating neurons with inhibitory surrounds. Thus our data not only provide direct causal evidence, but also new insights into the neural mechanisms of pooling local motion information for global heading estimation.
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Movimientos Oculares/fisiología , Percepción de Movimiento/fisiología , Estimulación Luminosa/métodos , Lóbulo Temporal/fisiología , Animales , Estimulación Eléctrica/métodos , Humanos , Macaca mulatta , MicroelectrodosRESUMEN
Two spatial reference systems, i.e., the observer-centered (egocentric) and object-centered (allocentric) references, are most commonly used to locate the position of the external objects in space. Although we sense the world as a unified entity, visual processing is asymmetric between upper and lower visual fields (VFs). For example, the goal-directed reaching responses are more efficient in the lower VF. Such asymmetry suggests that the visual space might be composed of different realms regarding perception and action. Since the peripersonal realm includes the space that one can reach, mostly in the lower VF, it is highly likely that the peripersonal realm might mainly be represented in the egocentric reference for visuomotor operation. In contrast, the extrapersonal realm takes place away from the observer and is mostly observed in the upper VF, which is presumably represented in the allocentric reference for orientation in topographically defined space. This theory, however, has not been thoroughly tested experimentally. In the present study, we assessed the contributions of the egocentric and allocentric reference systems on visual discrimination in the upper and lower VFs through measuring the manual reaction times (RTs) of human subjects. We found that: (a) the influence of a target's egocentric location on visual discrimination was stronger in the lower VF; and (b) the influence of a target's allocentric location on visual discrimination was stronger in the upper VF. These results support the hypothesis that the upper and lower VFs are primarily represented in the allocentric and egocentric references, respectively.
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Orientación/fisiología , Tiempo de Reacción/fisiología , Percepción Espacial/fisiología , Campos Visuales/fisiología , Adulto , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
In our research on novel secondary metabolites from micro-organisms, two new (1-2) and four known dihydroisocoumarins (3-6) were derived from soil fungus Hypoxylon sp. Their structures were determined with extensive NMR data analysis and ECD calculation comparing with those of experimental CD spectra. Interestingly, compounds 1 and 2 possessed the same planar structure and very similar NMR data, suggesting 1 and 2 were a pair of epimers at either C-3 or at C-4, confirmed by the totally opposite cotton effect around 250 nm in the CD spectra of 1 and 2. Moreover, for the first time, we revealed that the CD absorption peak at 250 nm was dominated by C-3 orientation, rather than the orientation of C-3 substituents, by intensive ECD investigations.
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Medicamentos Herbarios Chinos/aislamiento & purificación , Isocumarinas/aislamiento & purificación , Xylariales/química , Medicamentos Herbarios Chinos/química , Isocumarinas/química , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Microbiología del Suelo , EstereoisomerismoRESUMEN
In order to solve the problem of high cytotoxicity in vitro of nano-silver antibacterial gel,and the problem of large nano-silver particle size and size distribution,this study prepared nano-silver antibacterial gel with better biocompatibility and good antibacterial effect by using physical cross-linking method and using poloxamer as dispersant when prepared nano-silver.In this study,nano-silver was prepared by photo-initiator method and by adding poloxamer as a dispersant,and then UV-visible absorption spectrum test and scanning electron microscopy(SEM)test were carried out using prepared nano-silver mixture and particles after drying respectively.The gel was prepared through adjusting its pH value by using sodium bicarbonate,and then pH value test,SEM test for cross-section of gel,swelling ratio test,viscosity test,inhibition zone test and in vitro cytotoxicity test were carried out.The test results showed that the maximum absorption wavelength of prepared nano-silver,using poloxamer as dispersant and ultra-pure water as solvent,was 414 nm,and the average nano-silver size was about 60 nm.The prepared nano-silver using poloxamer as dispersant had smaller particle diameter and narrower particle size distribution than those using PVP as dispersant.Similarly,the prepared nano-silver using ultra-pure water as solvent also had smaller particle diameter and narrower particle size distribution than those using distilled water as solvent.The pH value of the prepared gel was between 5.8~6.1.The dried gel section had many holes.The water absorption of gel was fine and the viscosity of gel was fit to coat on the gauze.In addition,the prepared gel with nano-silver had greater ability to inhibit Escherichia coli and Staphyloccocus aureus at the concentrations of 24,18 and 12µg/mL.And the biocompatibility of the prepared gel with nano-silver was good when the concentration below 24µg/mL.Based on the above features,the nano-silver antibacterial gel could be used in the treatment of burn or other wounds.
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Antibacterianos/química , Vendajes , Quitosano/química , Hidrogeles/química , Nanopartículas del Metal/química , Plata/química , Quemaduras , Escherichia coli/efectos de los fármacos , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Poloxámero/química , Espectrofotometría Ultravioleta , Staphylococcus aureus/efectos de los fármacosRESUMEN
Luteolin, a natural flavonoid, is gaining growing attention for its potential in the treatment of gastric cancer. However, its clinical application is limited by factors such as poor aqueous solubility. This study aimed to develop a novel gastroretentive drug delivery system (GRDDS) to both enhance the oral bioavailability of luteolin and prolong its release and in vivo circulation time. Out of 10 luteolin-loaded PLA-based shape memory films prepared in this study, the LPC-PLA/PEG(7/3) formulation incorporated with PEG, HPMC, and NaHCO3 exhibited optimal properties in terms of drug release and inhibitory activity against SGC-7901 cells. Moreover, small-animal imaging revealed that LPC-PLA/PEG(7/3) exhibited a prolonged gastric retention time of approximately 8 h. Furthermore, the pharmacokinetic studies indicated a 354 % increase in the oral bioavailability of LPC-PLA/PEG(7/3) in rats compared to luteolin. In sum, a novel GRDDS was developed to enhance the relative bioavailability of luteolin, offering a potential strategy for practical oral administration.
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Sistemas de Liberación de Medicamentos , Luteolina , Ratas , Animales , Luteolina/farmacocinética , Luteolina/uso terapéutico , Solubilidad , Liberación de Fármacos , Poliésteres , Portadores de FármacosRESUMEN
Background: Currently, there is few literature comprehensively analyzing landscape of cuproptosis-related genes (CRGs) in liver hepatocellular carcinoma (LIHC) with multiple omics approaches. Aims: Using comprehensive analysis, we aim to find out how CRGs works on LIHC. Method: With data from The Cancer Genome Atlas (TCGA) database, we constructed a prognostic prediction model for CGRs using LASSO regression analysis and performed immune infiltration analysis using the same dataset. To validate findings, we utilized RNA expression data from the International Cancer Genome Consortium (ICGC). Furthermore, we analyzed the enrichment and features of CRGs in epithelial cells using single-cell RNA sequencing (scRNA-seq) data. To validate the reliability of findings, we performed several experiments including RT-PCR, cloning formation assay, scratch assay, and Transwell assay. Result: We have constructed a high-precision risk scoring model composed of CRGs for predicting prognosis in TCGA-LIHC. Reliability of the risk prognosis model was confirmed through Kaplan-Meier curve analysis, time-dependent ROC analysis, and multivariate regression analysis. Furthermore, we found knocking down PDSS1 increased sensitivity of LIHC cells to copper ions, and both proliferation and migration abilities were significantly reduced. Finally, we comprehensively characterized the features of CRGs in LIHC through scRNA-seq. Conclusion: In this study, we introduce PDSS1 as a novel CRG in HCC. Utilizing scRNA-seq, we provide a comprehensive landscape of cuproptosis across various cell subtypes within the HCC tumor microenvironment. Furthermore, we detailed the characteristics of high PDSS1-expressing tumor cells, including their distinctive transcription factors, metabolic profiles, and interactions with different subtypes within the tumor microenvironment. This work not only elucidated the role of PDSS1 in HCC but also enhanced our understanding of cuproptosis dynamics during tumor progression.
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Bacillus sp. CDB3 isolated from an arsenic contaminated cattle dip site possesses an uncommon arsenic resistance (ars) operon bearing eight genes in the order of arsRYCDATorf7orf8. We investigated the functions of arsA, arsT, orf7 and orf8 in arsenic resistance using a plasmid-based gene knockout approach in the ars gene deficient Escherichia coli strain AW3110. The CDB3 arsA gene was shown to play a significant role in resistance, suggesting that the encoded ArsA may couple with the arsenite transporter, forming an ArsAY complex that can enhance arsenite extrusion efficiency. The disruption of either arsTor orf7 was not observed to affect arsenic resistance in the heterologous E. coli host, but their involvement in arsenic resistance can not be excluded. The orf8 gene is predicted to encode a putative dual-specificity protein phosphatase which also shares certain homology to arsenate reductases. The function loss of orf8 resulted in a remarkable decrease in resistance to arsenate, though not arsenite. To examine if this effect was due to the reduction of arsenate by orf8, the arsC gene within the 8-gene operon was disrupted. The resulting abolishment of arsenate resistance suggests that the involvement of orf8 in arsenic resistance is not via reductase activity.
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Arseniatos/toxicidad , Arsenitos/toxicidad , Bacillus/genética , Proteínas Bacterianas/genética , Resistencia a Medicamentos/genética , Escherichia coli/efectos de los fármacos , Compuestos de Sodio/toxicidad , Contaminantes Ambientales/toxicidad , Escherichia coli/genética , Escherichia coli/crecimiento & desarrollo , Genes Bacterianos/genéticaRESUMEN
Open-ended coaxial probe method is one of the most common modalities in measuring dielectric properties (DPs) of biological tissues. Due to the significant differences between the tumors and normal tissues in DPs, the technique can be used to detect skin cancer in the early stage. Although various studies have been reported, systematic assessment is in urgent need to advance it to clinical applications, for its parameters interactions and detecting limitations remained unclear. In this study, we aim to provide a comprehensive examination of this method, including the minimum detectable tumor size by using a three-layer skin model via simulation and demonstrated that open-ended coaxial probe method can be used for detection of early-stage skin cancer. The smallest detecting size are subject to different subtypes: for BCC, inside the skin is 0.5 mm radius × 0.1 mm height; for SCC, inside the skin is 1.4 mm × 1.3 mm in radius and height; the smallest distinguishing size of BCC is 0.6 mm × 0.7 mm in radius and height; for SCC is 1.0 mm × 1.0 mm in radius and height; for MM is 0.7 mm × 0.4 mm in radius and height. The experiment results showed that sensitivity was affected by tumor dimension, probe size, skin height, and cancer subtype. The probe is more sensitive to cylinder tumor radius than height growing on the surface of the skin while the smallest size probe is the most sensitive among the working probes. We provide a detailed systematic evaluation of the parameters employed in the method for further applications.
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Neoplasias Cutáneas , Piel , Humanos , Piel/diagnóstico por imagen , Neoplasias Cutáneas/diagnóstico por imagen , Simulación por ComputadorRESUMEN
The current research in tumor immunotherapy indicates that blocking the protein-protein interaction (PPI) between PD-1 and its ligand, PD-L1, may be one of the most effective treatments for cancer patients. The α-helix is a common elements of protein secondary structure and is often involved in protein interaction. Thus, α-helix-based peptides could mimic proteins involved in such interactions and are also capable of modulating PPI in vivo. In this study, starting from a potential α-helix-rich protein, we designed a series of α-helix-based peptide candidates to block PD-1/PD-L1 interaction. These candidates were first screened using molecular docking and molecular dynamics simulations, and then their capacities to inhibit PD-1/PD-L1 interactions and to restore antitumor immune activities were investigated using the HTRF assay, SPR assay, cellular co-culture experiments and animal model experiments. Two peptides exhibited the best anti-tumor effects and the strong ability to restore the immunity of tumor-infiltrating T-cells. Further D-amino acid substitution was employed to improve the serum stability of peptide candidate, making the intravenous administration easier while maintaining the therapeutic efficacy. The resultant peptides showed promise as checkpoint inhibitors for application in tumor immunotherapy. These findings suggested that our strategy for developing peptides starting from an α-helical structure could be used in the design of bioactive inhibitors to potential block protein-protein interactions.
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Neoplasias , Receptor de Muerte Celular Programada 1 , Animales , Humanos , Simulación del Acoplamiento Molecular , Receptor de Muerte Celular Programada 1/metabolismo , Conformación Proteica en Hélice alfa , Antígeno B7-H1/metabolismo , Péptidos/farmacología , Péptidos/químicaRESUMEN
Tissue-mimicking dielectric phantoms are widely used to mimic the relative permittivity and conductivity of human tissues in various medical applications. The artificial material combinations determine the characterization of dialectic phantoms. However, a method that reliably determined the composition of artificial materials with designed values of dielectric properties and frequency is still lacking. In this work, we propose a method that easily determine the compositions of phantom to mimic the human tissues from 16 MHz to 3 GHz.
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Fantasmas de Imagen , Humanos , Conductividad EléctricaRESUMEN
White matter damage (WMD) is a primary cause of cerebral palsy and cognitive impairment in preterm infants, and no effective treatments are available. Microglia are a major component of the innate immune system. When activated, they form typical pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes and regulate myelin development and synapse formation. Therefore, they may play a pivotal role in hypoxic-ischemic (HI) WMD. Herein, we investigated neural inflammation and long-term microglia phenotypic polarization in a neonatal rat model of hypoxia-ischemia-induced WMD and elucidated the underlying pathophysiological processes. We exposed 3-day-old (P3) Sprague-Dawley rats to hypoxia (8% oxygen) for 2.5 hr after unilateral common carotid artery ligation. The activation of NLRP3 inflammatory bodies, microglia M1/M2 polarization, myelination, and synaptic development in our model were monitored 7, 14, and 21 days after birth. In addition, the Morris water maze test was performed on postnatal Day 28. We confirmed myelination disturbance in the periventricular white matter, abnormal synaptic development, and behavioral changes in the periventricular area during the development of HI WMD. In addition, we found an association between the occurrence and development of HI WMD and activation of the NLRP3 inflammasome, microglial M1/M2 polarization, and the release of inflammatory factors. NLRP3 inhibition can play an anti-inflammatory role by inhibiting the differentiation of microglia into the M1 phenotype, thereby improving myelination and synapse formation. In conclusion, microglia are key mediators of the inflammatory response and exhibit continuous phenotypic polarization 7-21 days after HI-induced WMD. This finding can potentially lead to a new treatment regimen targeting the phenotypic polarization of microglia early after HI-induced brain injury.
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Nacimiento Prematuro , Sustancia Blanca , Animales , Femenino , Ratas , Hipoxia , Inflamasomas , Isquemia , Microglía , Enfermedades Neuroinflamatorias , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas Sprague-Dawley , Animales Recién NacidosRESUMEN
Restoring sodium iodide symporter (NIS) expression and function remains a major challenge for radioiodine therapy in anaplastic thyroid cancer (ATC). For more efficient delivery of messenger RNA (mRNA) to manipulate protein expression, a lipid-peptide-mRNA (LPm) nanoparticle (NP) is developed. The LPm NP is prepared by using amphiphilic peptides to assemble a peptide core and which is then coated with cationic lipids. An amphiphilic chimeric peptide, consisting of nine arginine and hydrophobic segments (6 histidine, C18 or cholesterol), is synthesized for adsorption of mRNA encoding NIS in RNase-free conditions. In vitro studies show that LP(R9H6) m NP is most efficient at delivering mRNA and can increase NIS expression in ATC cells by more than 10-fold. After intratumoral injection of NIS mRNA formulated in optimized LPm NP, NIS expression in subcutaneous ATC tumor tissue increases significantly in nude mice, resulting in more iodine 131 (131 I) accumulation in the tumor, thereby significantly inhibiting tumor growth. Overall, this work designs three arginine-rich peptide nanoparticles, contributing to the choice of liposome cores for gene delivery. LPm NP can serve as a promising adjunctive therapy for patients with ATC by restoring iodine affinity and enhancing the therapeutic efficacy of radioactive iodine.
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Yodo , Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Animales , Ratones , Línea Celular Tumoral , Radioisótopos de Yodo/uso terapéutico , Lípidos , Liposomas , Ratones Desnudos , Péptidos , ARN Mensajero , Carcinoma Anaplásico de Tiroides/terapia , Carcinoma Anaplásico de Tiroides/genética , Carcinoma Anaplásico de Tiroides/metabolismo , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/genética , HumanosRESUMEN
Repetitive electrical nerve stimulation can induce a long-lasting perturbation of the axon's membrane potential, resulting in unstable stimulus-response relationships. Despite being observed in electrophysiology, the precise mechanism underlying electrical stimulation-dependent (ES-dependent) instability is still an open question. This study proposes a model to reveal a facet of this problem: how threshold fluctuation affects electrical nerve stimulations. This study proposes a new method based on a Circuit-Probability theory (C-P theory) to reveal the interlinkages between the subthreshold oscillation induced by neurons' resonance and ES-dependent instability of neural response. Supported by in-vivo studies, this new model predicts several key characteristics of ES-dependent instability and proposes a stimulation method to minimize the instability. This model provides a powerful tool to improve our understanding of the interaction between the external electric field and the complexity of the biophysical characteristics of axons.