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Current-induced spin-orbit torque (SOT) offers substantial promise for the development of low-power, nonvolatile magnetic memory. Recently, a single-phase material concurrently exhibiting magnetism and the spin Hall effect has emerged as a scientifically and technologically interesting platform for realizing efficient and compact SOT systems. Here, we demonstrate external-magnetic-field-free switching of perpendicular magnetization in a single-phase ferromagnetic and spin Hall oxide SrRuO3. We delicately altered the local lattices of the top and bottom surface layers of SrRuO3, while retaining a quasi-homogeneous, single-crystalline nature of the SrRuO3 bulk. This leads to unbalanced spin Hall effects between the top and bottom layers, enabling net SOT performance within single-layer ferromagnetic SrRuO3. Notably, our SrRuO3 exhibits the highest SOT efficiency and lowest power consumption among all known single-layer systems under field-free conditions. Our method of artificially manipulating the local atomic structures will pave the way for advances in spin-orbitronics and the exploration of new SOT materials.
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BACKGROUND: Endocrine therapy resistance in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) is a significant clinical challenge that poses several unmet needs in the management of the disease. This study aimed to investigate the prognostic value of c-MET-positive circulating tumor cells (cMET+ CTCs), ESR1/PIK3CA mutations, and cell-free DNA (cfDNA) concentrations in patients with hormone receptor-positive (HR+) metastatic breast cancer (mBC). METHODS: Ninety-seven patients with HR+ mBC were prospectively enrolled during standard treatment at Samsung Medical Center. CTCs were isolated from blood using GenoCTC® and EpCAM or c-MET CTC isolation kits. PIK3CA and ESR1 hotspot mutations were analyzed using droplet digital PCR. CfDNA concentrations were calculated using internal control copies from the ESR1 mutation test. Immunocytochemistry was performed to compare c-MET overexpression between primary and metastatic sites. RESULTS: The proportion of c-MET overexpression was significantly higher in metastatic sites than in primary sites (p = 0.00002). Survival analysis showed that c-MET+ CTC, cfDNA concentration, and ESR1 mutations were significantly associated with poor prognosis (p = 0.0026, 0.0021, and 0.0064, respectively) in HR+/HER2- mBC. By contrast, EpCAM-positive CTC (EpCAM+ CTC) and PIK3CA mutations were not associated with progression-free survival (PFS) in HR+/HER2- mBC. Multivariate analyses revealed that c-MET+ CTCs and cfDNA concentration were independent predictors of PFS in HR+/HER2- mBC. CONCLUSIONS: Monitoring c-MET+ CTC, rather than assessing c-MET expression in the primary BC site, could provide valuable information for predicting disease progression, as c-MET expression can change during treatment. The c-MET+ CTC count and cfDNA concentration could provide complementary information on disease progression in HR+ /HER2- mBC, highlighting the importance of integrated liquid biopsy.
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Neoplasias de la Mama , Ácidos Nucleicos Libres de Células , Células Neoplásicas Circulantes , Humanos , Femenino , Neoplasias de la Mama/patología , Células Neoplásicas Circulantes/patología , Ácidos Nucleicos Libres de Células/uso terapéutico , Pronóstico , Molécula de Adhesión Celular Epitelial/genética , Biomarcadores de Tumor/genética , Progresión de la Enfermedad , Fosfatidilinositol 3-Quinasa Clase I/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMEN
PURPOSE: Although leukemic retinopathy accounts for 80% of ocular complications in acute leukemia, its pathogenesis remains unclear. To evaluate changes in retinal and choroicapillaris and structural parameters in patients with acute leukemia, we analyzed the correlation between vascular perfusion metrics and laboratory parameters and assessed the changes after hematopoietic stem cell transplantation (HSCT). METHODS: Herein, 104 eyes of 52 patients aged 18 and above with acute leukemia were enrolled. 80 eyes of 40 healthy patients were recruited as control participants. All participants underwent optical coherence tomography (OCT) and OCT angiography (OCTA) at baseline. RESULTS: Patients with acute leukemia had a significantly thicker ganglion cell-inner plexiform layer (GCIPL) and lower circularity index than the control participants. Post-HSCT perfusion metrics did not differ significantly, but parafoveal thickness decreased significantly. During the active phase of acute leukemia, lower platelet levels were associated with significant GCIPL thickening and increased foveal avascular zone and perimeter. D-dimer levels positively correlated with GCIPL thickness. CONCLUSION: Patients with acute leukemia had subclinical retinal microvascular deficits on OCTA and GCIPL thickening on OCT, possibly associated with bone marrow function. GCIPL thickness may indicate acute ischemia in such patients. Further studies must elucidate their clinical and prognostic significance.
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As in type 1 diabetes, the loss of pancreatic ß-cells leads to insulin deficiency and the subsequent development of hyperglycemia. Exercise has been proposed as a viable remedy for hyperglycemia. Lithium, which has been used as a treatment for bipolar disorder, has also been shown to improve glucose homeostasis under the conditions of obesity and type 2 diabetes by enhancing the effects of exercise on the skeletal muscles. In this study, we demonstrated that unlike in obesity and type 2 diabetic conditions, under the condition of insulin-deficient type 1 diabetes, lithium administration attenuated pancreatic a-cell mass without altering insulin-secreting ß-cell mass, implying a selective impact on glucagon production. Additionally, we also documented that lithium downregulated the hepatic gluconeogenic program by decreasing G6Pase protein levels and upregulating AMPK activity. These findings suggest that lithium's effect on glucose metabolism in type 1 diabetes is mediated through a different mechanism than those associated with exerciseinduced metabolic changes in the muscle. Therefore, our research presents the novel therapeutic potential of lithium in the treatment of type 1 diabetes, which can be utilized along with insulin and independently of exercise.
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Pancreatic ß-cell dysfunction and eventual loss are key steps in the progression of type 2 diabetes (T2D). Endoplasmic reticulum (ER) stress responses, especially those mediated by the protein kinase RNA-like ER kinase and activating transcription factor 4 (PERK-ATF4) pathway, have been implicated in promoting these ß-cell pathologies. However, the exact molecular events surrounding the role of the PERK-ATF4 pathway in ß-cell dysfunction remain unknown. Here, we report our discovery that ATF4 promotes the expression of PDE4D, which disrupts ß-cell function via a downregulation of cAMP signaling. We found that ß-cell-specific transgenic expression of ATF4 led to early ß-cell dysfunction and loss, a phenotype that resembles accelerated T2D. Expression of ATF4, rather than C/EBP homologous protein (CHOP), promoted PDE4D expression, reduced cAMP signaling, and attenuated responses to incretins and elevated glucose. Furthermore, we found that ß-cells of leptin receptor-deficient diabetic (db/db) mice had elevated nuclear localization of ATF4 and PDE4D expression, accompanied by impaired ß-cell function. Accordingly, pharmacological inhibition of the ATF4 pathway attenuated PDE4D expression in the islets and promoted incretin-simulated glucose tolerance and insulin secretion in db/db mice. Finally, we found that inhibiting PDE4 activity with selective pharmacological inhibitors improved ß-cell function in both db/db mice and ß-cell-specific ATF4 transgenic mice. In summary, our results indicate that ER stress causes ß-cell failure via ATF4-mediated PDE4D production, suggesting the ATF4-PDE4D pathway could be a therapeutic target for protecting ß-cell function during the progression of T2D.NEW & NOTEWORTHY Endoplasmic reticulum stress has been implied to cause multiple ß-cell pathologies during the progression of type 2 diabetes (T2D). However, the precise molecular events underlying this remain unknown. Here, we discovered that elevated ATF4 activity, which was seen in T2D ß cells, attenuated ß-cell proliferation and impaired insulin secretion via PDE4D-mediated downregulation of cAMP signaling. Additionally, we demonstrated that pharmacological inhibition of the ATF4 pathway or PDE4D activity alleviated ß-cell dysfunction, suggesting its therapeutic usefulness against T2D.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Ratones , Animales , Apoptosis , Incretinas/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Secretoras de Insulina/metabolismo , Estrés del Retículo Endoplásmico/genética , Glucosa/metabolismo , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , eIF-2 Quinasa/metabolismoRESUMEN
MOTIVATION: Multi-omic profiling data, such as The Cancer Genome Atlas and pharmacogenomic data, facilitate research into cancer mechanisms and drug development. However, it is not easy for researchers to connect, integrate and analyze huge and heterogeneous data, which is a major obstacle to the utilization of cancer genomic data. RESULTS: We developed Cancer Genome Viewer (CGV), a user-friendly web service that provides functions to integrate and visualize cancer genome data and pharmacogenomic data. Users can easily select and customize the samples to be analyzed with the pre-defined selection options for patients' clinic-pathological features from multiple datasets. Using the customized dataset, users can perform subsequent data analyses comprehensively, including gene set analysis, clustering or survival analysis. CGV also provides pre-calculated drug response scores from pharmacogenomic data, which may facilitate the discovery of new cancer targets and therapeutics. AVAILABILITY AND IMPLEMENTATION: CGV web service is implemented with the R Shiny application at http://cgv.sysmed.kr and the source code is freely available at https://git.sysmed.kr/sysmed_public/cgv. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Neoplasias , Farmacogenética , Humanos , Análisis de Datos , Programas Informáticos , Genoma , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
A π-extended, diaza-triphenylene embedded, mono-anionic corrole analogue and its NiII complex were synthesized from a diaza-triphenylene precursor, which was obtained from a double one-carbon insertion into a naphthobipyrrole diester. Following conversion to the corresponding activated diol and acid-catalyzed condensation with pyrrole, subsequent reaction with pentafluorobenzaldehyde afforded mono-anionic, π-extended bipyricorrole-like macrocycle. Attempted NiII insertion with Ni(OAc)2 â 4H2 O resulted an ESR active, NiII bipyricorrole radical complex, which was converted to a stable cationic NiII complex upon treatment with [(Et3 O)+ (SbCl6 )- ]. Both complexes were characterized by 1 H and 13 Câ NMR, UV/Vis spectroscopy and single crystal X-ray diffraction analysis. The NiII bipyricorrole radical complex is converted to a cationic NiII complex by single-electron reduction using cobaltocene. Both the cationic NiII complex and the radical NiII complex exhibited ligand-centered redox behavior, whereas the NiII remains in the +2 oxidation state.
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Inflammation is an important immune response to pathogen invasion, but excessive inflammation leads to tissue injury and even cytokine storm. Therefore, proper response is needed depending on the intensity of the infection. Ras guanine nucleotide releasing protein 3 (RasGRP3) is a regulator of the TLR-mediated response. In low-intensity inflammation, it negatively regulates production of pro-inflammatory cytokines, especially IL-6. Citri Reticulatae Pericarpium, the peel of Citrus reticulata Blanco, is a major medicinal herb in Korean medicine. The present study aims to investigate whether the Citri Reticulatae Pericarpium extract (CRE) has immunomodulatory activity using the Raw264.7 macrophage. Also, we investigated the effect of CRE on RasGRP3 expression. In the present study, CRE reduced IL-6 production in the low-LPS environment (1 ng/mL) and did not in the high-LPS environment (100 ng/mL). The suppression of IL-6 production in the low-LPS environment (1 ng/mL) was abolished after the pretreatment of RasGRP3 siRNA. The reduced RasGRP3 protein content by 100 ng/mL LPS treatment was increased by CRE treatment. Additionally, nobiletin, a major component of CRE showed a suppressive effect on IL-6 production in the low-LPS environment (1 ng/mL). The present results suggest that CRE alleviates inflammatory response via activating RasGRP3 expression in low-intensity inflammation.
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Citrus , Medicamentos Herbarios Chinos , Receptor Toll-Like 4 , Interleucina-6 , Lipopolisacáridos/farmacología , Macrófagos , Inflamación/tratamiento farmacológicoRESUMEN
The reduction in esters, nitriles, and imines requires harsh conditions (highly reactive reagents, high temperatures, and pressures) or complex metal-ligand catalytic systems. Catalysts comprising earth-abundant and less toxic elements are desirable from the perspective of green chemistry. In this study, we developed a green hydroboration protocol for the reduction in esters, nitriles, and imines at room temperature (25 °C) using pinacolborane as the reducing agent and a commercially available Grignard reagent as the catalyst. Screening of various alkyl magnesium halides revealed MeMgCl as the optimal catalyst for the reduction. The hydroboration and subsequent hydrolysis of various esters yielded corresponding alcohols over a short reaction time (~0.5 h). The hydroboration of nitriles and imines produced various primary and secondary amines in excellent yields. Chemoselective reduction and density functional theory calculations are also performed. The proposed green hydroboration protocol eliminates the requirements for complex ligand systems and elevated temperatures, providing an effective method for the reduction in esters, nitriles, and imines at room temperature.
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BACKGROUND: Canine cloning technology based on somatic cell nuclear transfer (SCNT) combined with genome-editing tools such as CRISPR-Cas9 can be used to correct pathogenic mutations in purebred dogs or to generate animal models of disease. RESULTS: We constructed a CRISPR-Cas9 vector targeting canine DJ-1. Genome-edited canine fibroblasts were established using vector transfection and antibiotic selection. We performed canine SCNT using genome-edited fibroblasts and successfully generated two genome-edited dogs. Both genome-edited dogs had insertion-deletion mutations at the target locus, and DJ-1 expression was either downregulated or completely repressed. CONCLUSION: SCNT successfully produced genome-edited dogs by using the CRISPR-Cas9 system for the first time.
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Sistemas CRISPR-Cas , Técnicas de Transferencia Nuclear , Animales , Animales Modificados Genéticamente , Sistemas CRISPR-Cas/genética , Clonación de Organismos , Perros , Edición GénicaRESUMEN
Flexoelectricity-based mechanical switching of ferroelectric polarization has recently emerged as a fascinating alternative to conventional polarization switching using electric fields. Here, we demonstrate hyperefficient mechanical switching of polarization exploiting metastable ferroelectricity that inherently holds a unique mechanical response. We theoretically predict that mechanical forces markedly reduce the coercivity of metastable ferroelectricity, thus greatly bolstering flexoelectricity-driven mechanical polarization switching. As predicted, we experimentally confirm the mechanical polarization switching via an unusually low mechanical force (100 nN) in metastable ferroelectric CaTiO_{3}. Furthermore, the use of low mechanical forces narrows the width of mechanically writable nanodomains to sub-10 nm, suggesting an ultrahigh data storage density of ≥1 Tbit cm^{-2}. This Letter sheds light on the mechanical switching of ferroelectric polarization as a viable key element for next-generation efficient nanoelectronics and nanoelectromechanics.
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An increased life span and accompanying nutritional affluency have led to a rapid increase in diseases associated with aging, such as obesity and type 2 diabetes, imposing a tremendous economic and health burden on society. Pancreatic ß-cells are crucial for controlling glucose homeostasis by properly producing and secreting the glucose-lowering hormone insulin, and the dysfunction of ß-cells determines the outcomes for both type 1 and type 2 diabetes. As the native structure of insulin is formed within the endoplasmic reticulum (ER), ER homeostasis should be appropriately maintained to allow for the proper metabolic homeostasis and functioning of ß-cells. Recent studies have found that cellular senescence is critically linked with cellular stresses, including ER stress, oxidative stress, and mitochondrial stress. These studies implied that ß-cell senescence is caused by ER stress and other cellular stresses and contributes to ß-cells' dysfunction and the impairment of glucose homeostasis. This review documents and discusses the current understanding of cellular senescence, ß-cell function, ER stress, its associated signaling mechanism (unfolded protein response), and the effect of ER stress on ß-cell senescence and dysfunction.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Diabetes Mellitus Tipo 2/metabolismo , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismoRESUMEN
Cumulative studies have indicated that high-dose vitamin C has antitumor effects against a variety of cancers. However, the molecular mechanisms underlying these inhibitory effects against tumorigenesis and metastasis, particularly in relation to pancreatic cancer, are unclear. Here, we report that vitamin C at high concentrations impairs the growth and survival of pancreatic ductal adenocarcinoma (PDAC) cells by inhibiting glucose metabolism. Vitamin C was also found to trigger apoptosis in a caspase-independent manner. We further demonstrate that it suppresses the invasion and metastasis of PDAC cells by inhibiting the Wnt/ß-catenin-mediated epithelial-mesenchymal transition (EMT). Taken together, our results suggest that vitamin C has therapeutic effects against pancreatic cancer.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Vía de Señalización Wnt , beta Catenina/metabolismo , Ácido Ascórbico/farmacología , Proliferación Celular , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Transición Epitelial-Mesenquimal , Carcinogénesis , Caspasas/metabolismo , Glucosa/farmacología , Línea Celular Tumoral , Movimiento Celular , Neoplasias PancreáticasRESUMEN
Due to their commendable biocompatibility, regenerated silk fibroin (RSF) films have attracted considerable research interest. However, the poor mechanical properties of RSF films have limited their use in various biomedical applications. In this study, a novel, highly crystalline silk fibril was successfully extracted from silk by combining degumming with ultrasonication. Ultrasonication accelerated the development of silk nanofibrils measuring 130-200 nm on the surface of the over-degummed silk fibers, which was confirmed via scanning electron microscopy. Additionally, the crystallinity index of silk fibril was found to be significantly higher (~68%) than that of conventionally degummed silk (~54%), as confirmed by the Fourier-transform infrared (FTIR) spectroscopy results. Furthermore, the breaking strength and elongation of the RSF film were increased 1.6 fold and 3.4 fold, respectively, following the addition of 15% silk nanofibrils. Thus, the mechanical properties of the RSF film were remarkably improved by the addition of the silk nanofibrils, implying that it can be used as an excellent reinforcing material for RSF films.
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Fibroínas , Seda , Fibroínas/química , Seda/química , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
The development of nerve conduits with a three-dimensional porous structure has attracted great attention as they closely mimic the major features of the natural extracellular matrix of the nerve tissue. As low levels of reactive oxygen species (ROS) function as signaling molecules to promote cell proliferation and growth, this study aimed to fabricate protoporphyrin IX (PpIX)-immobilized cellulose (CEPP) monoliths as a means to both guide and stimulate nerve regeneration. CEPP monoliths can be fabricated via a simple thermally induced phase separation method and surface modification. The improved nerve tissue regeneration of CEPP monoliths was achieved by the activation of mitogen-activated protein kinases, such as extracellular signal-regulated kinases (ERKs). The resulting CEPP monoliths exhibited interconnected microporous structures and uniform morphology. The results of in vitro bioactivity assays demonstrated that the CEPP monoliths with under 0.54 ± 0.07 µmol/g PpIX exhibited enhanced photodynamic activity on Schwann cells via the generation of low levels of ROS. This photodynamic activation of the CEPP monoliths is a cell-safe process to stimulate cell proliferation without cytotoxic side effects. In addition, the protein expression of phospho-ERK increased considerably after the laser irradiation on the CEPP monoliths with low content of PpIX. Therefore, the CEPP monoliths have a potential application in nerve tissue regeneration as new nerve conduits.
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Celulosa/química , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Protoporfirinas/farmacología , Células de Schwann/citología , Animales , Línea Celular , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de la radiación , Terapia por Luz de Baja Intensidad , Regeneración Nerviosa , Tejido Nervioso/química , Fosforilación , Protoporfirinas/química , Ratas , Especies Reactivas de Oxígeno/metabolismo , Células de Schwann/efectos de los fármacos , Células de Schwann/metabolismo , Células de Schwann/efectos de la radiaciónRESUMEN
This study aimed to assess the relationship between the histopathological and textural features of perigastric adipose tissue (AT) on 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) and to evaluate the prognostic significance of perigastric AT textural features in predicting recurrence-free survival (RFS) in patients with gastric cancer. Sixty-nine patients with gastric cancer who underwent staging [18F]FDG PET/CT and subsequent curative surgery were retrospectively reviewed. Textural features of perigastric AT were extracted from PET images. On histopathological analysis, CD4, CD8, and CD163 cell infiltration and matrix metalloproteinase-11 and interleukin-6 (IL-6) expression in perigastric AT were graded. The degree of CD163 cell infiltration in perigastric AT was significantly correlated with the mean standardized uptake value (SUV), SUV histogram entropy, grey-level co-occurrence matrix (GLCM) energy, and GLCM entropy of perigastric AT. The degree of IL-6 expression in the perigastric AT was significantly correlated with the mean and median SUVs of perigastric AT. In multivariate survival analysis, GLCM entropy, GLCM dissimilarity, and GLCM homogeneity of perigastric AT were significant predictors of RFS. The textural features of perigastric AT on [18F]FDG PET/CT significantly correlated with inflammatory response in perigastric AT and were significant prognostic factors for predicting RFS in patients with gastric cancer.
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Fluorodesoxiglucosa F18 , Neoplasias Gástricas , Tejido Adiposo/diagnóstico por imagen , Tejido Adiposo/metabolismo , Fluorodesoxiglucosa F18/metabolismo , Glucosa , Humanos , Interleucina-6 , Metaloproteinasas de la Matriz , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Estudios RetrospectivosRESUMEN
Background and Objectives: In patients with severe aortic stenosis (sAS), it is crucial to maintain hemodynamic stability during the induction and maintenance of general anesthesia for transcatheter aortic valve implantation (TAVI). In this study, we assessed the efficacy and safety of remimazolam in maintaining hemodynamic stability during anesthetic induction and maintenance. Cases: TAVI was performed on seven patients with sAS, and remimazolam was administered for total intravenous anesthesia (TIVA) of general anesthesia with induction (3.0 mg/kg/h) and maintenance (1.0 mg/kg/h). All patients underwent TAVI without major hemodynamic concerns and later recovered. Conclusions: Remimazolam can be safely used for induction and maintenance of general anesthesia in patients with sAS when performing TAVI.
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Estenosis de la Válvula Aórtica , Reemplazo de la Válvula Aórtica Transcatéter , Humanos , Anestesia Intravenosa , Válvula Aórtica/cirugía , Resultado del Tratamiento , Estenosis de la Válvula Aórtica/cirugía , Anestesia GeneralRESUMEN
Introduction IMC-001 is a fully human IgG1 monoclonal antibody that binds to human PD-L1 (programmed death-ligand 1). This study evaluated the safety, pharmacokinetics, and pharmacodynamics of IMC-001 in patients with advanced solid tumors. Materials and Methods This open-labeled phase I study used a standard 3 + 3 dose-escalation design, with doses ranging from 2 to 20 mg/kg. IMC-001 was administered intravenously every 2 weeks until disease progression or unacceptable toxicity. The dose-limiting toxicity window was defined as 21 days from the first dose. Results Fifteen subjects were included in 5 dose-escalation cohorts. No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. The most common adverse events (AEs) were general weakness, decreased appetite, fever, and cough. No grade 4 or 5 treatment emergent AEs were reported during the study. One subject in the 2 mg/kg cohort showed grade 2 immune-induced thyroiditis and diabetes mellitus suspected to be related to IMC-001. Over the dose range of 2-20 mg/kg IMC-001, the AUC0-14d, AUC0-∞, and Cmax generally increased in a dose-proportional manner for each step of dose escalation. Of the 15 enrolled patients, 1 subject with rectal cancer showed a partial response, and the disease control rate was 33.3%. Conclusions IMC-001 demonstrated a favorable safety profile up to 20 mg/kg administered intravenously every 2 weeks and showed preliminary efficacy in patients with advanced solid tumors. Based on pharmacokinetic and pharmacodynamic data, 20 mg/kg was selected as the recommended phase II dose. Clinical trial identification NCT03644056 (date of registration: August 23, 2018).
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Anticuerpos Monoclonales Humanizados , Antineoplásicos , Neoplasias , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Área Bajo la Curva , Antígeno B7-H1/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Dosis Máxima Tolerada , Metástasis de la Neoplasia , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinéticaRESUMEN
This study aimed to investigate whether the Protaetia brevitarsis seulensis (PB)' water extract (PBWE) ameliorates trimethyltin (TMT)-induced seizures and hippocampal neurodegeneration. To investigate the potential neuroprotective effect of the PBWE in vitro, a lactate dehydrogenase (LDH) assay was conducted in TMT-treated primary cultures of mouse hippocampal neurons. In TMT-treated adult C57BL/6 mice, behavioral and histopathological changes were evaluated by seizure scoring and Fluoro-Jade C staining, respectively. In our in vitro assay, we observed that pretreating mice hippocampal neuron cultures with the PBWE reduced TMT-induced cytotoxicity, as indicated by the decreased LDH release. Furthermore, pretreatment with the PBWE alleviated seizures and hippocampal neurodegeneration in TMT-treated mice. The antioxidant activity of the PBWE increased in a dose-dependent manner; moreover, pretreatment with the PBWE mitigated the TMT-induced Nrf2 stimulation. In addition, six major compounds, including adenine, hypoxanthine, uridine, adenosine, inosine, and benzoic acid, were isolated from the PBWE, and among them, inosine and benzoic acid have been confirmed to have an essential antioxidative activity. In conclusion, the PBWE ameliorated TMT-induced toxicity in hippocampal neurons in both in vitro and in vivo assays, through a potential antioxidative effect. Our findings suggest that the PBWE may have pharmacotherapeutic potential in neurodegenerative diseases such as seizures or epilepsy.
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Productos Biológicos/química , Productos Biológicos/farmacología , Escarabajos/química , Hipocampo/efectos de los fármacos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Animales , Productos Biológicos/aislamiento & purificación , Biomarcadores , Cromatografía Líquida de Alta Presión , Escarabajos/anatomía & histología , Escarabajos/clasificación , Escarabajos/genética , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Genes de Insecto , Pruebas Genéticas , Hipocampo/metabolismo , Hipocampo/patología , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/etiología , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/aislamiento & purificación , Estrés Oxidativo , Fenotipo , Convulsiones/tratamiento farmacológico , Convulsiones/etiología , Compuestos de Trimetilestaño/efectos adversosRESUMEN
The photophysical properties of closo-ortho-carboranyl-based donor-acceptor dyads are known to be affected by the electronic environment of the carborane cage but the influence of the electronic environment of the donor moiety remains unclear. Herein, four 9-phenyl-9H-carbazole-based closo-ortho-carboranyl compounds (1F, 2P, 3M, and 4T), in which an o-carborane cage was appended at the C3-position of a 9-phenyl-9H-carbazole moiety bearing various functional groups, were synthesized and fully characterized using multinuclear nuclear magnetic resonance spectroscopy and elemental analysis. Furthermore, the solid-state molecular structures of 1F and 4T were determined by X-ray diffraction crystallography. For all the compounds, the lowest-energy absorption band exhibited a tail extending to 350 nm, attributable to the spin-allowed π-π* transition of the 9-phenyl-9H-carbazole moiety and weak intramolecular charge transfer (ICT) between the o-carborane and the carbazole group. These compounds showed intense yellowish emission (λem = ~540 nm) in rigid states (in tetrahydrofuran (THF) at 77 K and in films), whereas considerably weak emission was observed in THF at 298 K. Theoretical calculations on the first excited states (S1) of the compounds suggested that the strong emission bands can be assigned to the ICT transition involving the o-carborane. Furthermore, photoluminescence experiments in THFâwater mixtures demonstrated that aggregation-induced emission was responsible for the emission in rigid states. Intriguingly, the quantum yields and radiative decay constants in the film state were gradually enhanced with the increasing electron-donating ability of the substituent on the 9-phenyl group (âF for 1F < âH for 2P < âCH3 for 3M < âC(CH3)3 for 4T). These features indicate that the ICT-based radiative decay process in rigid states is affected by the electronic environment of the 9-phenyl-9H-carbazole group. Consequently, the efficient ICT-based radiative decay of o-carboranyl compounds can be achieved by appending the o-carborane cage with electron-rich aromatic systems.