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The dorsal root ganglion (DRG) is the primary neuron responsible for transmitting peripheral pain signals to the central nervous system and plays a crucial role in pain transduction. Modulation of DRG excitability is considered a viable approach for pain management. Neuronal excitability is intricately linked to the ion channels on the neurons. The small and medium-sized DRG neurons are chiefly engaged in pain conduction and have high levels of TTX-S sodium channels, with Nav1.7 accounting for approximately 80% of the current. Voltage-gated sodium channel (VGSC or Nav) blockers are vital targets for the management of central nervous system diseases, particularly chronic pain. VGSCs play a key role in controlling cellular excitability. Clinical research has shown that Nav1.7 plays a crucial role in pain sensation, and there is strong genetic evidence linking Nav1.7 and its encoding gene SCN9A gene to painful disorders in humans. Many studies have shown that Nav1.7 plays an important role in pain management. The role of Nav1.7 in pain signaling pathways makes it an attractive target for the potential development of new pain drugs. Meanwhile, understanding the architecture of Nav1.7 may help to develop the next generation of painkillers. This review provides updates on the recently reported molecular inhibitors targeting the Nav1.7 pathway, summarizes their structure-activity relationships (SARs), and discusses their therapeutic effects on painful diseases. Pharmaceutical chemists are working to improve the therapeutic index of Nav1.7 inhibitors, achieve better analgesic effects, and reduce side effects. We hope that this review will contribute to the development of novel Nav1.7 inhibitors as potential drugs.
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Canal de Sódio Disparado por Voltagem NAV1.7 , Bloqueadores do Canal de Sódio Disparado por Voltagem , Humanos , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Dor do Câncer/tratamento farmacológico , Dor do Câncer/metabolismo , Analgésicos/química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Relação Estrutura-Atividade , Manejo da Dor/métodos , Estrutura Molecular , Neoplasias/tratamento farmacológico , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/uso terapêuticoRESUMO
BACKGROUND: ATPase activity and the antioxidant function of intestinal tissue can reflect intestinal cell metabolic activity and oxidative damage, which might be related to intestinal function. However, the specific influence of intestinal ATPase activity and antioxidant function on growth performance, feed conversion efficiency, and the intestinal microbiota in sheep remains unclear. RESULTS: This study analyzed the correlation between ATPase activity and antioxidant function in the jejunum of 92 Hu sheep and their growth performance and feed conversion efficiency. Additionally, individuals with the highest (H group) and lowest (L group) jejunum MDA content and Na+ K+-ATPase activity were further screened, and the effects of jejunum ATPase activity and MDA content on the morphology and microbial community of sheep intestines were analyzed. There was a significant correlation between jejunum ATPase and SOD activity and the initial weight of Hu sheep (P < 0.01). The H-MDA group exhibited significantly higher average daily gain (ADG) from 0 to 80 days old and higher body weight (BW) after 80 days. ATPase and SOD activities, and MDA levels correlated significantly and positively with heart weight. The jejunum crypt depth and circular muscle thickness in the H-ATP group were significantly higher than in the L-ATP group, and the villus length, crypt depth, and longitudinal muscle thickness in the H-MDA group were significantly higher than in the L-MDA group (P < 0.01). High ATPase activity and MDA content significantly reduced the jejunum microbial diversity, as indicated by the Chao1 index and observed species, and affected the relative abundance of specific taxa. Among species, the relative abundance of Olsenella umbonata was significantly higher in the H-MDA group than in the L-MDA group (P < 0.05), while Methanobrevibacter ruminantium abundance was significantly lower than in the L-MDA group (P < 0.05). In vitro culture experiments confirmed that MDA promoted the proliferation of Olsenella umbonata. Thus, ATPase and SOD activities in the jejunum tissues of Hu sheep are predominantly influenced by congenital factors, and lambs with higher birth weights exhibit lower Na+ K+-ATPase, Ca2+ Mg2+-ATPase, and SOD activities. CONCLUSIONS: The ATPase activity and antioxidant performance of intestinal tissue are closely related to growth performance, heart development, and intestinal tissue morphology. High ATPase activity and MDA content reduced the microbial diversity of intestinal tissue and affect the relative abundance of specific taxa, representing a potential interaction between the host and its intestinal microbiota.
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Adenosina Trifosfatases , Antioxidantes , Microbioma Gastrointestinal , Jejuno , Animais , Jejuno/microbiologia , Jejuno/enzimologia , Antioxidantes/metabolismo , Microbioma Gastrointestinal/fisiologia , Adenosina Trifosfatases/metabolismo , Ovinos , Masculino , Malondialdeído/metabolismo , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND: Polyunsaturated fatty acids (PUFAs) have demonstrated significant therapeutic potential across a wide range of disease. The aim of this study was to investigate the potential impact of PUFA intake on the prevalence of erectile dysfunction (ED). METHODS: The study included a total of 3730 participants from the National Health and Nutrition Examination Survey (NHANES) 2001-2004. Univariate analysis, multivariate regression analysis, subgroup analysis and machine learning were utilized to explore the relationship of variables to ED. Dose response curves were constructed to observe the linear or nonlinear relationship between PUFA intake and the prevalence of ED. Propensity score matching (PSM) was used for sensitivity analysis. Finally, the potential mechanistic link between PUFA intake and ED was explored. RESULTS: Through univariate and multivariate regression analysis results before and after PSM and XGBoost algorithm model results, arachidonic acid (AA) was chosen as the main research object. The consumption of AA was found to be associated with a decreased prevalence of ED under the fully adjusted model [OR = 0.33 (0.20, 0.56), P < 0.001]. The interaction between AA and education was found in the subgroup analysis. Dose-response curves indicated a linear negative correlation between AA intake and the prevalence of ED. The above results were confirmed in the data analysis after 1:1 PSM. In addition, AA intake was associated with a decrease in inflammatory biomarkers and homocysteine. CONCLUSIONS: The results suggest that AA intake is negatively correlated with the prevalence of ED. Further, anti-inflammatory and anti-endothelial damage may play a role in this.
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Disfunção Erétil , Masculino , Humanos , Disfunção Erétil/epidemiologia , Inquéritos Nutricionais , Estudos Transversais , Prevalência , Ácidos Graxos Insaturados , Ácido AraquidônicoRESUMO
Both feature representation and classifier performance are important factors that determine the performance of computer-aided diagnosis (CAD) systems. In order to improve the performance of ultrasound-based CAD for breast cancers, a novel multiple empirical kernel mapping (MEKM) exclusivity regularized machine (ERM) ensemble classifier algorithm based on self-paced learning (SPL) is proposed, which simultaneously promotes the performance of both feature representation and the classifier. The proposed algorithm first generates multiple groups of features by MEKM to enhance the ability of feature representation, which also work as the kernel transform in multiple support vector machines embedded in ERM. The SPL strategy is then adopted to adaptively select samples from easy to hard so as to gradually train the ERM classifier model with improved performance. This algorithm is verified on a B-mode ultrasound dataset and an elastography ultrasound dataset, respectively. The results show that the classification accuracy, sensitivity and specificity on B-mode ultrasound are (86.36±6.45)%, (88.15±7.12)%, and (84.52±9.38)%, respectively, and the classification accuracy, sensitivity and specificity on elastography ultrasound are (85.97±3.75)%, (85.93±6.09)%, and (86.03±5.88)%, respectively. It indicates that the proposed algorithm can effectively improve the performance of ultrasound-based CAD for breast cancers with the potential for application.
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Neoplasias da Mama , Algoritmos , Neoplasias da Mama/diagnóstico por imagem , Computadores , Diagnóstico por Computador , Humanos , Máquina de Vetores de Suporte , UltrassonografiaRESUMO
BACKGOUND: Although Myeloid-derived suppressor cells (MDSCs) have a prominent ability to suppress the immune responses of T lymphocytes and propel tumor immune escape, a lack of profound systemic immunesuppression in tumor-bearing mice and tumor patients. The underlying mechanism of these remains unclear. METHODS: For this purpose, renal cancer-derived exosomes (RDEs) were first labeled with PKH67 and been observed the internalization by MDSCs. Flow cytometry analysis showed the proportion and activity change of MDSCs in spleen and bone marrow induced by RDEs. Further, western blot experiments were used to verify triggered mechanism of MDSCs by RDEs. Finally, proliferation and cytotoxicity of cytotoxic T lymphocytes (CTLs) co-cultured with MDSCs in vitro and a series of experiments in vivo were performed to demonstrate the specific inhibitory effect of RDEs-induced MDSCs. RESULTS: This study suggested that RDEs crucially contributed to presenting antigenic information, activating and driving specific immunosuppressive effect to MDSCs. HSP70, which is highly expressed in RDEs, initiate this process in a toll like receptor 2 (TLR2)-dependent manner. Importantly, RDEs-induced MDSCs could exert an antigen-specific immunosuppression effect on CTL and specific promote renal tumors-growth and immune escape in consequence. CONCLUSION: The immunosuppression mediated by MDSCs which is induced by RDEs is antigen-specific. HSP70, which is highly expressed in RDEs, plays a pivotal role in this process. Targeted abrogating the function of MDSCs, or eliminating the expression of HSP70 in exosomes, or blocking the crosstalk between them provides a new direction and theoretical support for future immunotherapy. Video abstract.
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Antígenos de Neoplasias/metabolismo , Exossomos/metabolismo , Tolerância Imunológica , Terapia de Imunossupressão , Neoplasias Renais/imunologia , Neoplasias Renais/metabolismo , Células Supressoras Mieloides/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Células Dendríticas/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Camundongos Endogâmicos BALB C , Linfócitos T/imunologia , Receptor 2 Toll-Like/metabolismoRESUMO
Long Wavelength Near InfraRed (LW-NIR) spectrometer has wide applications. Miniaturization and low-cost are two major goals of the development of LW-NIR spectrometer in the industrial or research community. Under the background that having a trend of spectrometer miniaturization and integration, method and main problems involved in miniaturization of LW-NIR spectrometer through MEMS scanning mirror, such as the design strategy of the light-splitting optical system, selection considerations of the MEMS scanning mirror, design method of the preamplifier circuit, etc, have been presented in detail. A prototype of miniaturized LW-NIR spectrometer, with the spectrum range of detection of 900-2,055 nm, is designed and implemented using MEMS scanning mirror, InGaAs single detector unit with high sensitivity. Littrow optical layout is used for its light-splitting optical system, and the spectral resolution is between 9.4-16 nm at 1,000-1,965 nm detection wavelength range. The prototype is successfully applied in LW-NIR spectrum measurement on pure water and ethanol aqueous solution, and a forecast analysis on ethanol aqueous solution concentration is also demonstrated. Through adopting MEMS scanning mirror into the spectrometer system, the complexity of the mechanical scanning fixtures and its controlling mechanism is greatly reduced therefore the size of the spectrometer is reduced. Furthermore, due to MEMS scanning mirror technology, LW-NIR spectrometer with single InGaAs detector is achieved, thus the cost reduction of the NIR spectrometer system is also realized because the expensive InGaAs arrays are avoided.
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In vitro T-cell differentiation from pluripotent stem cells (PSCs) could potentially provide an unlimited source of T cells for cancer immunotherapy, which, however is still hindered by the inefficient obtaining functionally-matured, terminally-differentiated T cells. Here, we established a fluorescence reporter human induced pluripotent stem cell (iPSC) line termed TCF7mCherryRUNX1GFP, in which the endogenous expression of RUNX1 and TCF7 are illustrated by the GFP and mCherry fluorescence, respectively. Utilizing TCF7mCherryRUNX1GFP, we defined that the feeder cells incorporating CXCL12-expressing OP9 cells with DL4-expressing OP9 cells at a 1:3 ratio (OP9-C1D3) significantly enhanced efficiency of CD8+ T cell differentiation from PSCs. Additionally, we engineered a chimeric antigen receptor (CAR) targeting EGFR into iPSCs. The CAR-T cells differentiated from these iPSCs using OP9-C1D3 feeders demonstrated effective cytotoxicity toward lung cancer cells. We anticipate this platform will help the in vitro HSPC and T cell differentiation optimization, serving the clinical demands of these cells.
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OBJECTIVES: Rheumatoid arthritis (RA) seriously affects the daily life of people. The whole plant of Artemisia ordosica Krasch. (AOK) has been used in folk medicine. This study aimed to investigate the in vivo anti-RA effects of AOK extract (AOKE) on collagen-induced arthritis in rats. METHODS: AOKE (400, 200, or 100 mg/kg) was administered orally to animals for 30 days. Body weight, paw swelling, arthritis index, thymus, and spleen indices, and pathological changes were assessed for effects of AOKE on RA. Furthermore, the inflammatory cytokines in rat serum were detected. In addition, the expressions of STAT3, Caspase-3, Galectin-3, and S100A9 in synovial tissue were researched using immunohistochemistry. KEY FINDINGS: The AOKE significantly reduced the arthritis indices, paw swelling, spleen, and thymus indices. Meanwhile, AOKE (400 mg/kg) decreased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-17A, and increased the level of IL-10 in rat serum. Histopathological examination showed that AOKE reduced inflammatory cell infiltration and cartilage erosion. Then, AOKE decreased the expressions of STAT3, Galectin-3, S100A9, and increased the expression of Caspase-3. CONCLUSION: AOKE had interesting anti-RA activity in rats, which deserved further research for the development and clinical use of this medicinal resource.
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SLFN11 is abnormally expressed and associated with survival outcomes in various human cancers. However, the role of SLFN11 in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to investigate the clinical value and potential functions of SLFN11 in ccRCC. Comprehensive bioinformatics analyses were performed using online databases. Quantitative real-time PCR (qPCR) and western blotting were used to validate the expression data. CCK8, flow cytometry analysis, and EdU staining were performed to determine the level of cell proliferation. Flow cytometry analysis was also used to detect cell apoptosis. Wound-healing assay and Transwell assays were performed to assess cell migration and invasion capability, respectively. SLFN11 was overexpressed and was an independent prognostic factor in ccRCC. SLFN11 knockdown inhibited cell proliferation, migration, and invasion and promoted apoptosis. Functional and pathway enrichment analyses suggested that SLFN11 may have an impact on tumorigenesis in ccRCC through regulation of the inflammatory response, the PI3K/AKT signaling pathway and other effectors. Furthermore, SLFN11 knockdown inhibited the phosphorylation of the PI3K/AKT signaling pathway and could be activated by 740 Y-P. Finally, we demonstrated that miR-183 may specifically target SLFN11, and miR-183 expression was correlated with predicted survival. SLFN11 may play a critical role in ccRCC progression and may serve as a novel prognostic biomarker in ccRCC.
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Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , MicroRNAs , Humanos , Carcinoma de Células Renais/genética , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Neoplasias Renais/genética , Transdução de Sinais , MicroRNAs/genética , Proteínas NuclearesRESUMO
Phosphodiesterase 9A (PDE9A) plays a crucial role in activating the cGMP-dependent signaling pathway and may have important effects on the growth and development of the gastrointestinal tract in Hu sheep. In this study, we analyzed the single nucleotide polymorphisms of PDE9A in 988 Hu sheep and their correlation with growth performance, feed efficiency, and gastrointestinal development. Additionally, we examined the expression level of different PDE9A genotypes in the gastrointestinal tract of Hu sheep by using fluorescence quantitative PCR. The results revealed a moderate level of polymorphism (0.25 < PIC < 0.50) at the g.286248617 T > C mutation site located in the first intron of PDE9A in Hu sheep, with three genotypes: CC, CT, and TT. The weights of the omasum, colon, and cecum were significantly greater in the CC genotype than in the TT genotype (P < 0.05), and the expression level of PDE9A in the tissues of the rumen, ileum, cecum, and colon was notably lower in the CC genotype individuals (P < 0.05). These findings suggest that the polymorphism of PDE9A affects the weight of the stomach, colon, and cecum in Hu sheep through expression regulation. Overall, the results of this study suggest that the g.286248617 T > C mutation site in the first intron of PDE9A can serve as a potential molecular marker for breeding practices related to the gastrointestinal weight of Hu sheep.
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Cruzamento , Polimorfismo de Nucleotídeo Único , Animais , 3',5'-AMP Cíclico Fosfodiesterases/genética , Trato Gastrointestinal , Genótipo , Ovinos/genéticaRESUMO
On 6 February 2023, two large earthquakes (moment magnitude 7.8 and 7.6) shocked a vast area of southeastern Türkiye and northern Syria, leading to heavy casualties and economic loss. To investigate the rupture process over multiple fault segments, we performed a comprehensive analysis of local seismic and geodetic data and determined supershear ruptures on the initial branch and the Pazarcik and Erkenek segments and subshear ruptures on the Amanos segment of event 1. The bilateral rupture of event 2 also presents distinct sub- and supershear velocities. The dynamic stress of the branch fault rupture triggered the Pazarcik segment initial rupture at a point 9 kilometers west of the junction of these two faults, boosting the supershear rupture of the Pazarcik segment of the main fault. The geometry and prestress level of multiple segments controlled the rupture behaviors and influenced the ground shaking intensity.
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Sensory quality deterioration of chicken seasoning was investigated using physicochemical properties, gas chromatography-mass spectrometry (GC-MS) and descriptive sensory analysis to approach an evaluation of the chicken seasoning deterioration. It was found that both peroxide value (POV) and total oxidation value (TOTOX) increased with the chicken seasoning deterioration, suggesting a dominant of the lipid oxidation in the sensory quality deterioration of chicken seasoning. Moreover, a continuously decreasing linoleic acid and contradictory increasing in volatile aldehydes (specifically for hexanal) indicated as characteristic oxidation indicators to evaluate the sensory quality deterioration. PLSR results further elucidated that the evolution of aldehydes was highly correlated with sensory quality deterioration. These results suggest the POV, TOTOX and hexanal as valuable indicators and provide a novel approach to quality and rapidly evaluate the sensory quality deterioration of chicken seasoning.
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To explore the wind flow turbulence and smoke flow diffusion law during the mine downward ventilation fire, two similar experimental platforms of a inclined single pipe test device and a loop system multiple pipe test device were built. The change data of the air flow in the pipeline during the fire period under different air volumes were measured. The evolution process of downward ventilation fire in the whole roadway network domain in Dayan Mine was simulated, and the emergency plan was put forward. The results show that in the experiment, the combustion intensity of the fire source is positively correlated with the ventilation power, and the fire wind pressure increases with the increase of the inclination angle of the pipeline. The throttling effect of the fire area and the combustion of the fire source together make the air volume in the pipeline change rapidly. The critical wind speed that makes the downward ventilation flow fire wind pressure equal to the fan power is 1.8 m s-1. The stronger the fan capacity, the stronger the ability of the main air path to overcome the resistance of the fire zone and maintain the original state. In the simulation, the most dangerous place when the downward ventilation fire smoke is reversed is the area (weak flow area) in the mine tunnel network where the ventilation power is weaker than the fire wind power. This study can provide a theoretical basis for the formulation of emergency plans for mine fire accidents.
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Aim: Pancreatic cancer (PC) is a devastating malignancy characterized by its aggressive nature and poor prognosis. However, the relationship of PC with peripheral metabolites remains not fully investigated. The study aimed to explore the causal linkage between PC and peripheral metabolite profiles. Methods: Employing publicly accessible genome-wide association studies (GWAS) data, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. The primary analysis employed the inverse-variance weighted (IVW) method. To address potential concerns about horizontal pleiotropy, we also employed supplementary methods such as maximum likelihood, weighted median, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO). Results: We ascertained 20 genetically determined peripheral metabolites with causal linkages to PC while high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL) particles accounted for the vast majority. Specifically, HDL particles exhibited an elevated PC risk while VLDL particles displayed an opposing pattern. The converse MR analysis underscored a notable alteration in 17 peripheral metabolites due to PC, including branch chain amino acids and derivatives of glycerophospholipid. Cross-referencing the bidirectional MR results revealed a reciprocal causation of PC and X-02269 which might form a self-perpetuating loop in PC development. Additionally, 1-arachidonoylglycerophosphocholine indicated a reduced PC risk and an increase under PC influence, possibly serving as a negative feedback regulator. Conclusion: Our findings suggest a complex interplay between pancreatic cancer and peripheral metabolites, with potential implications for understanding the etiology of pancreatic cancer and identifying novel early diagnosis and therapeutic targets. Moreover, X-02269 may hold a pivotal role in PC onset and progression.
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The small intestine serves as the first channel of dietary Vitamin A (VA) and the unique organ of VA absorption and metabolism. However, there have not been extensive investigations on the exact mechanisms within VA-related changes in intestinal metabolic disorders. This research is designed to analyze whether and how VA affects intestinal metabolic phenotypes. Male C57BL/6 mice after weaning were randomly fed a VA control diet (VAC) or a VA-deficient diet (VAD) during the entire pregnancy and lactation process. After a total of 11 weeks, cohorts of VA deprived were next fed to a VA control diet (VAD-C) for another 8 weeks. The concentration of retinol was measured by a high-performance liquid chromatography system. The 16S gene sequencing was used to evaluate the intestinal microbiota changes. Through the use of histological staining, western blots, quantitative PCR, and enzyme-linked immunosorbent assays, the intestinal morphology, inflammatory factors, and intestinal permeability were all evaluated. Following the decrease of the tissue VA levels, VAD mice show a decrease in tissue VA levels, community differences, and the richness and diversity of intestinal microbiota. VAD diet-driven changes occur in intestinal microbiota, accompanied by a higher mRNA expression of intestinal inflammatory cytokines and an increase in intestinal permeability. As dietary VA is reintroduced into VAD diet-fed mice, the tissue VA levels, inflammatory response, and intestinal homeostasis profiles are all restored, which are similar to those found after the occurrence of VA-controlled changes within intestinal microbiota. VA deficiency caused the imbalance of intestinal metabolic phenotypes through a mechanism involving changes in intestinal microbiota. It is thought that intestinal microbiota metabolic influences represent a new salient and additional mechanism, which can be used as a new method to achieve the onset and treatment of the effect of VAD on intestinal homeostasis impairment.
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BACKGROUND: Though the efficacy of anti C-type lectin-like molecule-1 (CLL1) CAR T-cells in refractory/relapsed acute myeloid leukemia (R/R-AML) have been occasionally reported, the influence of co-stimulatory domain CAR T-cells is not investigated so far. METHOD: Seven R/R-AML children treated with anti-CLL1 CAR T-cells were enrolled onto this preliminary comparison study. Among these seven patients, four received CD28/CD27-based CAR T-cells therapy, and three received 4-1BB-based CAR T-cells therapy. RESULT: The overall response rates were 75% and 66.7% in CD28/CD27 and 4-1BB group respectively. All patients experienced grade 1 to 2 cytokine release syndrome, with only one patient experiencing grade 2 immune effector cell-associated neurotoxicity syndrome. The maximum CAR T-cells durations were 156 and 274 days for CD28/CD27 group and 4-1BB group respectively. The 1-yr overall survival rate was 57.1%. CONCLUSIONS: A preliminary similar efficacy/safety index was observed in anti-CLL1-based CAR T-cells with 4-1BB or CD28/CD27 co-stimulatory elements in treating pediatric R/R-AML.
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Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Humanos , Criança , Antígenos CD28 , Linfócitos T , Leucemia Mieloide Aguda/terapia , Imunoterapia Adotiva/efeitos adversosRESUMO
Haematopoietic stem cell transplantation (HSCT) is widely used in regenerative medicine. HSCT can be used not only to treat certain types of blood cancer and immune disorders but also to induce immune tolerance in organ transplantation. However, the inadequacy of HSCs available for transplantation is still a major hurdle for clinical applications. Here, we established a novel inducible haematopoietic cell-depleting mouse model and tested the feasibility of using chimeric complementation to regenerate HSCs and their progeny cells. Large populations of syngeneic and major histocompatibility-mismatched haematopoietic cells were successfully regenerated by this model. The stable allogeneic chimeric mice maintained a substantial population of donor HSCs and Tregs, which indicated that the donor allogeneic HSCs successfully repopulated the recipient blood system, and the regenerated donor Tregs played essential roles in establishing immune tolerance in the allogeneic recipients. In addition, rat blood cells were detected in this model after xenotransplantation of rat whole bone marrow (BM) or Lin- BM cells. This mouse model holds promise for regenerating xenogeneic blood cells, including human haematopoietic cells.
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Transplante de Células-Tronco Hematopoéticas , Humanos , Camundongos , Ratos , Animais , Transplante de Medula Óssea , Células-Tronco Hematopoéticas , Células da Medula Óssea , Células Sanguíneas , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
Although early feeding strategies influence intestinal development, the effects of milk replacer (MR) feeding level on intestinal structure and functional development and underlying regulatory mechanisms remain unclear. In this study, 14 male Hu lambs were fed MR at 2% or 4% of their average body weight and weaned at 35 days of age. The MR was produced by the Institute of Feed Research of the Chinese Academy of Agricultural Sciences, and it contains 96.91% dry matter, 23.22% protein, and 13.20% fat. Jejunal tissues were assessed by RNA-seq for differences in the gene expression of lambs at 49 days of age; regulatory pathways and mechanisms of the effects of early nutrition on intestinal function and development were analyzed, along with growth performance, feed intake, jejunal histomorphology, and digestive enzyme activities. Increasing MR- feeding levels increased dry matter intake and daily gain before weaning, as well as lactase, amylase, lipase, trypsin, and chymotrypsin activities and intestinal villus length and muscular thickness. Overall, 1179 differentially expressed genes were identified, which were enriched in nutrient metabolism, coagulation cascades, and other pathways. Further, intensive MR feeding affected insulin sensitivity to reduce excessive glucose interception by intestinal tissues to ensure adequate absorbed glucose release into the portal circulation and promoted lipid and protein degradation in intestinal tissues to meet the energy demand of intestinal cells by regulating AHSG, IGFBP1, MGAT2, ITIH, and CYP2E1 expression.
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Despite extensive characterization of the state and function of haematopoietic stem cells (HSCs), the use of transcription factors to define the HSC population is still limited. We show here that the HSC population in mouse bone marrow can be defined by the distinct expression levels of Spi1 and Gata1. By using a double fluorescence knock-in mouse model, PGdKI, in which the expression levels of PU.1 and GATA-1 are indicated by the expression of GFP and mCherry, respectively, we uncover that the HSCs with lymphoid and myeloid repopulating activity are specifically enriched in a Lin- PU.1dim GATA-1- (LPG) cell subset. In vivo competitive repopulation assays demonstrate that bone marrow cells gated by LPG exhibit haematopoietic reconstitution activity which is comparable to that of classical Lin- Sca1+ c-kit+ (LSK). The integrated analysis of single-cell RNA sequence data from LPG and LSK-gated cells reveals that a transcriptional network governed by core TFs contributes to regulation of HSC multipotency. These discoveries provide new clues for HSC characterization and functional study.
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Células-Tronco Hematopoéticas , Receptores Proteína Tirosina Quinases , Camundongos , Animais , Linhagem da Célula , Células-Tronco Hematopoéticas/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Células da Medula Óssea/metabolismo , Camundongos Endogâmicos C57BLRESUMO
The WHY family is a group of plant-specific transcription factors, that can bind to single-stranded DNA molecules and play a variety of functions in plant nuclei and organelles, participating in the regulation of plant leaf senescence. It has been identified and analyzed in many species, however, the systematic identification and analysis of the WHY genes family have not yet been reported in alfalfa (Medicago sativa L.). Therefore, to explore the function of alfalfa the WHY genes, and 10 MsWHY genes were identified and further characterized their evolutionary relationship and expression patterns by analyzing the recently published genome of alfalfa. Comprehensive analysis of the chromosome location, physicochemical properties of the protein, evolutionary relationship, conserved motifs, and responses to abiotic stresses of the WHY gene family in alfalfa using bioinformatics methods. The results showed that 10 MsWHY genes were distributed on 10 chromosomes, and collinearity analysis showed that many MsWHYs might be derived from segmental duplications, and these genes are under purifying selection. Based on phylogenetic analyses, the WHY gene family of alfalfa can be divided into four subfamilies: I-IV subfamily, and approximately all the WHY genes within the same subfamily share similar gene structures. The 10 MsWHY gene family members contained 10 motifs, of which motif 2 and motif 4 are the conserved motifs shared by these genes. Furthermore, the analysis of cis-regulatory elements indicated that regulatory elements related to transcription, cell cycle, development, hormone, and stress response are abundant in the promoter sequence of the MsWHY genes. Real-time quantitative PCR demonstrated that MsWHYs gene expression is induced by drought, salt, and methyl jasmonate. The present study serves as a basic foundation for future functional studies on the alfalfa WHY family.