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The reduction in lung cancer mortality rates over the past decade can be partially ascribed to advancements in immunotherapy. Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape for advanced non-small cell lung cancer (NSCLC) and have recently been evaluated in multiple clinical trials to confirm their safety and efficacy in the neoadjuvant, adjuvant and perioperative settings for patients with resectable NSCLC. The Food and Drug Administration (FDA) has granted approval for adjuvant atezolizumab following platinum-doublet chemotherapy, neoadjuvant nivolumab and platinum-doublet chemotherapy, adjuvant pembrolizumab after platinum-doublet chemotherapy, and neoadjuvant/adjuvant pembrolizumab for resectable NSCLC, with potential forthcoming approvals for additional agents or indications. Novel data, approvals, and emerging research findings are dramatically shifting the accepted standards of care over just a few years. Despite these advances, the optimal application of these treatments is not entirely straightforward. This article summarizes the biological rationale for immunotherapy and the important clinical trials regarding perioperative ICIs. We also further outline the controversies and future directions to better guide the individualized treatment of NSCLC patients.
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To reveal the potential mechanism of the effect of Chinese Herbal Medicine Fuzi on Aplastic anaemia (AA) according to the network pharmacology approach and molecular docking. According to Ultra High Performance Liquid Chromatography Mass Spectrometry (UHPLC-MS/MS), 146 chemical ingredients of Fuzi were obtained. By SwissADME online system analysis, a total of 55 compounds such as Magnoflorine, Scutellarein, Luteolin and Gingerol may be the main active components of Fuzi and 145 common targets related to AA were predicted. 17 targets such as MAPK1, AKT1 and GRB2 were considered as hub targets. KEGG and GO enrichment analysis obtained 122 signalling pathways and 950 remarkable results. These results suggested that Fuzi exerted pharmacological effects on AA mainly by regulating PI3K-Akt, MAPK and JAK-STAT signalling pathways and epithelial cell proliferation, cell differentiation, regulate energy production and other biological processes. Meanwhile, molecular docking results showed that the hub targets had good binding ability with the main active ingredients.
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AlGaInP-based red light emitting diodes (LEDs) are considered as promising light sources in future full-color displays. At present, vertical chip configuration is still the mainstream device structure of AlGaInP-based red LEDs. However, current crowding around p-electrode severely hinders an efficient improvement. Here, we propose a Schottky-contact current blocking layer (SCBL) to enhance current spreading and to improve light extraction efficiency of AlGaInP-based red vertical miniaturized LEDs (mini-LEDs). By utilizing the Schottky contact between ITO and p-GaP, the SCBL can hinder current crowding around the p-electrode. The current is forced to inject into an active region through a p-GaP+ ohmic contact layer, avoiding light absorption by p-electrode. Through the transfer length method, the Schottky contact characteristics between the ITO and p-GaP as well as the ohmic contact characteristics between ITO and p-GaP+ are demonstrated. Benefiting from superior current spreading and improved light extraction, a mini-LED with SCBL realizes an enhancement of 31.8% in external quantum efficiency (EQE) at 20â mA in comparison with a mini-LED without SCBL.
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Emerging data have revealed that damage to tubular epithelial cell is a driving force in the progression of diabetic kidney disease (DKD). However, the specific mechanisms by which lipotoxicity contributes to the injury of these cells, thereby influencing the development of DKD, are yet to be fully understood. Here, we analyzed the GSE 30529 microarray datasets of human tubulointerstitial tissue samples from the Gene Expression Omnibus database (GEO). Concurrently, we conducted RNA-sequencing on palmitic acid (PA)-treated human renal proximal tubule epithelial cells (HK2 cells). After normalization, the differentially expressed genes (DEGs) were screened by R software and gene ontology (GO) enrichment analysis was conducted, and lysosomal-associated protein transmembrane 5 (LAPTM5) was finally selected. Our findings indicate that the expression of LAPTM5 was obviously increased in DKD patients, and the correlation between LAPTM5, and other clinical parameters of DKD was analyzed using the Spearman correlation analysis. The potential of LAPTM5 as a prognostic biomarker for DKD was further consolidated through receiver operating characteristic (ROC) analysis. To further verify the function of LAPTM5, we established mouse or in vitro systems mimicking DKD. The results showed that a consistent upregulation of LAPTM5, which was also found to be linked with inflammatory mediators within the context of DKD. Additionally, LAPTM5 silencing significantly downregulated mRNA expression of inflammatory factors in PA-treated HK2 cells. These results indicate that LAPTM5 is a potential biomarker and therapeutic treatment target for DKD. This discovery paves the way for future research and development of targeted interventions aimed at mitigating the progression of this prevalent condition.
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Biologia Computacional , Nefropatias Diabéticas , Proteínas de Membrana , Animais , Humanos , Masculino , Camundongos , Biomarcadores/metabolismo , Linhagem Celular , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Ácido Palmítico/metabolismo , Regulação para CimaRESUMO
Patients with pituitary neuroendocrine tumors (PitNETs) often experience neuropsychiatric disorders due to factors such as hormonal imbalances, and inadequate management of medications, surgeries, and radiation therapies. Commonly observed disorders include depression, anxiety, and cognitive dysfunction, which significantly impact patients' quality of life and prognosis. PitNETs have a significant presence of immune cells within the tumor microenvironment (TME), predominantly macrophages and T lymphocytes. These immune cells secrete a variety of cytokines, growth factors, and chemokines, which regulate the biological behaviors of PitNETs, including tumor initiation, proliferation, migration, invasion, and angiogenesis. In addition, this review provides a pioneering summary of the close relationships between the aberrant secretion of proinflammatory cytokines within the TME of PitNETs and the occurrence of neuropsychiatric disorders, along with their potential underlying mechanisms. The cytokines produced as a result of TME dysregulation may affect various aspects of the central nervous system, including neurotransmitter metabolism, neuroendocrine function, and neurovascular plasticity, thereby leading to a higher susceptibility to neurobehavioral disorders in PitNET patients.
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Cytogenetic karyotypes such as t(4; 14), del(17p), t(14; 16), t(14; 20), and TP53 mutations are associated with high-risk multiple-myeloma (MM) and indicate poor prognosis. Therefore, cytogenetic testing is extremely important for determining prognosis of MM. However, the aberrant karyotypes reported in the current literature are incomplete. The cytogenetic karyotype 17p gain has not received widespread attention, and its relationship with MM prognosis is unknown; additionally, the prognosis of 17p gain associated with t(4; 14) has not been studied in depth. Therefore, we introduce a special case in which a patient had both 17p gain and t(4; 14). An 81-year-old woman was admitted to the Affiliated Hospital of Shandong University of Traditional Chinese Medicine for stomach discomfort. The patient had no relevant medical history. Laboratory tests, immunophenotyping, and haematological results suggested MM, and cytogenetic tests indicated 17p gain and t(4; 14) with no other abnormalities. She was treated with two different chemotherapeutic regimens and achieved very good partial response, but eventually experienced biochemical relapses after discontinuing therapy. However, she eventually achieved good disease control with a bortezomib, lenalidomide, and dexamethasone-based regimen; she has survived longer than 5 years, much longer than the 1 year reported for MM patients with t(4:14), and been progression-free more than 3 years. We use this case to explore the possible relationship between the 17p gain and prognosis of patients with MM, as well as the treatment of MM with high-risk cytogenetic karyotypes. This case enriches the clinical application of cytogenetic analysis and adds important indicators for the prognosis of MM patients.
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III-nitride materials are of great importance in the development of modern optoelectronics, but they have been limited over years by low light utilization rate and high dislocation densities in heteroepitaxial films grown on foreign substrate with limited refractive index contrast and large lattice mismatches. Here, we demonstrate a paradigm of high-throughput manufacturing bioinspired microstructures on warped substrates by flexible nanoimprint lithography for promoting the light extraction capability. We design a flexible nanoimprinting mold of copolymer and a two-step etching process that enable high-efficiency fabrication of nanoimprinted compound-eye-like Al2O3 microstructure (NCAM) and nanoimprinted compound-eye-like SiO2 microstructure (NCSM) template, achieving a 6.4-fold increase in throughput and 25% savings in economic costs over stepper projection lithography. Compared to NCAM template, we find that the NCSM template can not only improve the light extraction capability, but also modulate the morphology of AlN nucleation layer and reduce the formation of misoriented GaN grains on the inclined sidewall of microstructures, which suppresses the dislocations generated during coalescence, resulting in 40% reduction in dislocation density. This study provides a low-cost, high-quality, and high-throughput solution for manufacturing microstructures on warped surfaces of III-nitride optoelectronic devices.
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AlGaInP-based light-emitting diodes (LEDs) suffer from a low external quantum efficiency (EQE), which is mainly restrained by the poor light extraction efficiency. Here, we demonstrate AlGaInP-based vertical miniaturized-LEDs (mini-LEDs) with a porous n-AlGaInP surface using a wet etching process to boost light extraction. We investigated the effects of etching time on the surface morphology of the porous n-AlGaInP surface. We found that as the etching time is prolonged, the density of pores increases initially and decreases subsequently. In comparison with the vertical mini-LED with a smooth n-AlGaInP surface, the vertical mini-LEDs with the porous n-AlGaInP surface reveal improvement in light output power and EQE, meanwhile, without the deterioration of electrical performance. The highest improvement of 38.9% in EQE measured at 20â mA is observed from the vertical mini-LED with the maximum density of the pores. Utilizing a three-dimensional finite-difference time-domain method, we reveal the underlying mechanisms of improved performance, which are associated with suppressed total internal reflection and efficient light scattering effect of the pores.
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BACKGROUND: The incidence of diabetic kidney disease (DKD) continues to rapidly increase, with limited available treatment options. One of the hallmarks of DKD is persistent inflammation, but the underlying molecular mechanisms of early diabetic kidney injury remain poorly understood. C-X-C chemokine receptor 2 (CXCR2), plays an important role in the progression of inflammation-related vascular diseases and may bridge between glomerular endothelium and persistent inflammation in DKD. METHODS: Multiple methods were employed to assess the expression levels of CXCR2 and its ligands, as well as renal inflammatory response and endothelial glycocalyx shedding in patients with DKD. The effects of CXCR2 on glycocalyx shedding, and persistent renal inflammation was examined in a type 2 diabetic mouse model with Cxcr2 knockout specifically in endothelial cells (DKD-Cxcr2 eCKO mice), as well as in glomerular endothelial cells (GECs), cultured in high glucose conditions. RESULTS: CXCR2 was associated with early renal decline in DKD patients, and endothelial-specific knockout of CXCR2 significantly improved renal function in DKD mice, reduced inflammatory cell infiltration, and simultaneously decreased the expression of proinflammatory factors and chemokines in renal tissue. In DKD conditions, glycocalyx shedding was suppressed in endothelial Cxcr2 knockout mice compared to Cxcr2 L/L mice. Modulating CXCR2 expression also affected high glucose-induced inflammation and glycocalyx shedding in GECs. Mechanistically, CXCR2 deficiency inhibited the activation of NF-κB signaling, thereby regulating inflammation, restoring the endothelial glycocalyx, and alleviating DKD. CONCLUSIONS: Taken together, under DKD conditions, activation of CXCR2 exacerbates inflammation through regulation of the NF-κB pathway, leading to endothelial glycocalyx shedding and deteriorating renal function. Endothelial CXCR2 deficiency has a protective role in inflammation and glycocalyx dysfunction, suggesting its potential as a promising therapeutic target for DKD treatment.
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Nefropatias Diabéticas , NF-kappa B , Receptores de Interleucina-8B , Animais , Humanos , Camundongos , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Células Endoteliais/metabolismo , Endotélio/metabolismo , Glucose , Glicocálix/metabolismo , Inflamação/metabolismo , Camundongos Knockout , NF-kappa B/metabolismo , Receptores de Quimiocinas/uso terapêutico , Receptores de Interleucina-8B/genética , Receptores de Interleucina-8B/metabolismo , Complicações do Diabetes/genética , Complicações do Diabetes/metabolismoRESUMO
Metabolic syndrome (MetS) is closely associated with an increased risk of dementia and cognitive impairment, and a complex interaction of genetic and environmental dietary factors may be implicated. Free fatty acid receptor 4 (Ffar4) may bridge the genetic and dietary aspects of MetS development. However, the role of Ffar4 in MetS-related cognitive dysfunction is unclear. In this study, we found that Ffar4 expression is down-regulated in MetS mice and MetS patients with cognitive impairment. Conventional and microglial conditional knockout of Ffar4 exacerbated high-fat diet (HFD)-induced cognitive dysfunction and anxiety, whereas microglial Ffar4 overexpression improved HFD-induced cognitive dysfunction and anxiety. Mechanistically, we found that microglial Ffar4 regulated microglial activation through type I interferon signaling. Microglial depletion and NF-κB inhibition partially reversed cognitive dysfunction and anxiety in microglia-specific Ffar4 knockout MetS mice. Together, these findings uncover a previously unappreciated role of Ffar4 in negatively regulating the NF-κB-IFN-ß signaling and provide an attractive therapeutic target for delaying MetS-associated cognitive decline.
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Disfunção Cognitiva , Síndrome Metabólica , Receptores Acoplados a Proteínas G , Animais , Humanos , Camundongos , Disfunção Cognitiva/genética , Disfunção Cognitiva/complicações , Síndrome Metabólica/complicações , Síndrome Metabólica/genética , Camundongos Knockout , Microglia/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Receptores Acoplados a Proteínas G/metabolismoRESUMO
BACKGROUND: FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated gene in acute myeloid leukemia. As a receptor tyrosine kinase (RTK), FLT3 plays a role in the proliferation and differentiation of hematopoietic stem cells. As the most frequent molecular alteration in AML, FLT3 has drawn the attention of many researchers, and a lot of small molecule inhibitors targeting FLT3 have been intensively investigated as potential drugs for AML therapy. METHODS: In this paper, PubMed and SciFinder® were used as a tool; the publications about "FLT3 inhibitor" and "Acute myeloid leukemia" were surveyed from 2014 to the present with an exclusion of those published as patents. RESULTS: In this study, the structural characterization and biological activities of representative FLT3 inhibitors were summarized. The major challenges and future directions for further research are discussed. CONCLUSION: Recently, numerous FLT3 inhibitors have been discovered and employed in FLT3-mutated AML treatment. In order to overcome the drug resistance caused by FLT3 mutations, screening multitargets FLT3 inhibitors has become the main research direction. In addition, the emergence of irreversible FLT3 inhibitors also provides new ideas for discovering new FLT3 inhibitors.
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Antineoplásicos , Leucemia Mieloide Aguda , Inibidores de Proteínas Quinases , Tirosina Quinase 3 Semelhante a fms , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Desenvolvimento de MedicamentosRESUMO
Multiple myeloma (MM) is a malignant clonal proliferative plasma cell tumor. Zinc oxide nanoparticles (ZnO NPs) are used for antibacterial and antitumor applications in the biomedical field. This study investigated the autophagy-induced effects of ZnO NPs on the MM cell line RPMI8226 and the underlying mechanism. After RPMI8226 cells were exposed to various concentrations of ZnO NPs, the cell survival rate, morphological changes, lactate dehydrogenase (LDH) levels, cell cycle arrest, and autophagic vacuoles were monitored. Moreover, we investigated the expression of Beclin 1 (Becn1), autophagy-related gene 5 (Atg5), and Atg12 at the mRNA and protein levels, as well as the level of light chain 3 (LC3). The results showed that ZnO NPs could effectively inhibit the proliferation and promote the death of RPMI8226 cells in vitro in a dose- and time-dependent manner. ZnO NPs increased LDH levels, enhanced monodansylcadaverine (MDC) fluorescence intensity, and induced cell cycle arrest at the G2/M phases in RPMI8226 cells. Moreover, ZnO NPs significantly increased the expression of Becn1, Atg5, and Atg12 at the mRNA and protein levels and stimulated the production of LC3. We further validated the results using the autophagy inhibitor 3-methyladenine (3MA). Overall, we observed that ZnO NPs can trigger autophagy signaling in RPMI8226 cells, which may be a potential therapeutic approach for MM.
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Mieloma Múltiplo , Nanopartículas , Óxido de Zinco , Humanos , Óxido de Zinco/farmacologia , Linhagem Celular Tumoral , Mieloma Múltiplo/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Autofagia , RNA MensageiroRESUMO
IMPORTANCE: Alterations in the intestinal environment are associated with various diseases, and FFAR4 is abundantly enriched in the intestine, where it has been shown to have the ability to regulate intestinal hormone secretion and intestinal microbiota; here, we confirmed previous reports. Meanwhile, we found that intestinal FFAR4 regulates glucagon-like peptide 1 secretion by decreasing Akkermansia muciniphila abundance and show that such change is associated with the level of glucose utilization at ZT12 in mice. Intestinal FFAR4 deficiency leads to severely impaired glucose tolerance at the ZT12 moment in mice, and Akkermansia muciniphila supplementation ameliorates the abnormal glucose utilization at the ZT12 moment caused by FFAR4 deficiency, which is very similar to the dawn phenomenon in diabetic patients. Collectively, our data suggest that intestinal Ffar4 deteriorates glucose tolerance at the daily light to dark transition by affecting Akkermansia muciniphila.
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Microbioma Gastrointestinal , Intolerância à Glucose , Verrucomicrobia , Animais , Humanos , Camundongos , Suplementos Nutricionais , Glucose/metabolismo , Intestinos , Camundongos Knockout , Verrucomicrobia/química , Verrucomicrobia/metabolismo , Luz , Escuridão , Receptores Acoplados a Proteínas G/metabolismo , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismoRESUMO
Several investigations have examined the involvement of free fatty acid receptor 4 (FFAR4) in metabolic disorders, but its action remains controversial. To investigate whether endogenous fibroblast growth factor 21 (FGF21)-mediated signaling controls the metabolic status in FFAR4-deficient mice, we generated FFAR4/FGF21 double knockout (DKO) mice. We also evaluated the role of FGF21 on glucose and lipid metabolism in FFAR4 KO mice fed a high-fat diet. Levels of FGF21 were significantly increased in FFAR4-deficient mice and double deletion of FGF21 and FFAR4 led to severe metabolic disorders. Additionally, FFAR4/FGF21 DKO mice displayed metabolic abnormalities that may be caused by decreased energy expenditure. Collectively, this study characterized the effects of endogenous FGF21, which acts as a master feedback regulator in the absence of FFAR4.
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Fatores de Crescimento de Fibroblastos , Doenças Metabólicas , Animais , Camundongos , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Metabolismo Energético/genética , Glucose/metabolismo , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Fígado/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BLRESUMO
Here, we propose nanoimprinted patterned sapphire with a silica array (PSSA) with the aim to promote the efficiency of InGaN-based green (â¼520â nm) mini-LEDs. According to x-ray diffraction measurements, the threading dislocation density of GaN epitaxial layers grown on nanoimprinted PSSA demonstrates a pronounced reduction compared with the epilayers on the conventional patterned sapphire substrate (PSS). Consequently, a mini-LED on PSSA exhibits a significantly boosted light output power (LOP) in comparison to a mini-LED on PSS. At 10â mA, the LOP of the mini-LED on PSS is 6.0â mW, and this is further improved to 6.8â mW for the mini-LED on PSSA. Moreover, the peak external quantum efficiencies of the mini-LEDs on PSS and PSSA are 41% and 47%, respectively. A three-dimensional (3D) finite-difference time-domain simulation demonstrates that the PSSA contributes enhanced light extraction for photons emitted from the active region. It is also highly feasible to use this nanoimprinted PSSA technology in red and blue mini-LEDs for the realization of full-color displays.
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Mitochondria is one of the most important organelles of eukaryotic cells, which is closely related to cell proliferation, apoptosis, autophagy and other life processes. Mitochondrias in biological cells are actually in a highly dynamic state. The fusion and division of mitochondria and their secondary effects play an important role in the regulation of cell life. As a malignant disease of hematopoietic system, leukemia is characterized by excessive proliferation, limited apoptosis, abnormal autophagy and other abnormal cell regulation. Therefore, abnormal mitochondrial dynamics regulation may play a key role in the pathogenesis of leukemia, refractory and drug resistance of leukemia. The article reviews the role of mitochondrial dynamics and abnormal regulation in the pathogenesis and development of leukemia, and provides a theoretical basis for the research on the regulation of mitochondrial dynamics in leukemia.
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The telomerase RNA component (TERC) gene plays an important role in telomerase-dependent extension and maintenance of the telomeres. In the event of TERC haploinsufficiency, telomere length is often affected; this, in turn, can result in the development of progeria-related diseases such as aplastic anemia (AA) and congenital keratosis. Cell reprogramming can reverse the differentiation process and can, therefore, transform cells into pluripotent stem cells with stronger differentiation and self-renewal abilities; further, cell reprograming can also extend the telomere length of these cells, which may be crucial in the diagnosis and treatment of telomere depletion diseases such as AA. In this study, we summarized the effects of TERC haploid cell reprogramming on telomere length and the correlation between this alteration and the pathogenesis of AA; by investigating the role of cell reprogramming in AA, we aimed to identify novel diagnostic indicators and therapeutic strategies for patients with AA.
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Anemia Aplástica , Telomerase , Humanos , Telomerase/genética , Telomerase/metabolismo , Anemia Aplástica/genética , Anemia Aplástica/terapia , Reprogramação Celular/genética , HaploidiaRESUMO
Acute myeloid leukaemia (AML) is one of the most lethal cancers of the haematopoietic system with a poorly understood aetiology. Recent studies have shown that aberrant alternative splicing (AS) and a (RBP) regulators are highly associated with the pathogenesis of AML. This study presents an overview of the abnormal AS and differential expression of RNA-binding proteins (RBPs) in AML and further highlights their close relation to the remodelling of the immune microenvironment in AML patients. An in-depth understanding of the regulatory mechanism underlying AML will contribute to the future development of strategies for the prevention, diagnosis and therapy of AML and thus improve the overall survival of patients with AML.
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Processamento Alternativo , Leucemia Mieloide Aguda , Humanos , Processamento Alternativo/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Leucemia Mieloide Aguda/patologia , Microambiente Tumoral/genéticaRESUMO
Hematopoietic stem cells (HSCs) are the common and essential precursors of all blood cells, including immune cells, and they are responsible for the lifelong maintenance and damage repair of blood tissue homeostasis. The vast majority (> 95%) of HSCs are in a resting state under physiological conditions and are only activated to play a functional role under stress conditions. This resting state affects their long-term survival and is also closely related to the lifelong maintenance of hematopoietic function; however, abnormal changes may also be an important factor leading to the decline of immune function in the body and the occurrence of diseases in various systems. While the importance of resting HSCs has attracted increasing research attention, our current understanding of this topic remains insufficient, and the direction of clinical targeted treatments is unclear. Here, we describe the functions of HSCs, analyze the regulatory mechanisms that affect their resting state, and discuss the relationship between resting HSCs and different diseases, with a view to providing guidance for the future clinical implementation of related targeted treatments.