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BACKGROUND & AIMS: Anti-tumor necrosis factor (anti-TNF) therapies are commonly prescribed treatments for Crohn's Disease (CD) and Ulcerative Colitis (UC). Many patients treated with anti-TNF therapy eventually develop anti-drug antibodies (ADA). Understanding the factors associated with immunogenicity in anti-TNF treated patients can help guide treatment. The Humira SERENE studies were phase 3 trials studying adalimumab induction regimens in CD and UC patients. METHODS: We imputed alleles for 7 HLA genes in 1100 patients from the SERENE CD and SERENE UC trials. We tested these alleles for association with time to immunogenicity. We then tested loci significantly associated with immunogenicity for association with patients that had consistently low drug-serum concentrations. RESULTS: This study replicated the association of HLA-DQA1*05 with time to immunogenicity (Hazard Ratio (HR) 1.42, P=2.22E-06). Specifically, HLA-DQA1*05:05 was strongly associated (HR 1.76, P=2.02E-10) and we detected a novel association represented by HLA-DRB1*01:02 (HR 3.16, P=2.92E-07). Carriage of HLA-DQA1*05:05 and HLA-DRB1*01:02 were both associated with patients who experienced consistently low adalimumab trough concentrations (HLA-DQA1*05:05 OR 1.98, P=0.0049; HLA DRB1*01:02 OR 7.06, P=7.44E-05). CONCLUSIONS: We found a significant association between alleles at genes in the human HLA locus and the formation of adalimumab immunogenicity and low adalimumab drug-serum concentrations in large clinical studies of CD and UC patients. This work extends previous results in Crohn's disease to ulcerative colitis and directly shows a genetic association in patients with low drug concentrations. This work builds on existing literature to suggest genetic screening as a useful tool for clinicians concerned with patient anti-TNF immunogenicity.
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SNP-based imputation approaches for human leukocyte antigen (HLA) typing take advantage of the haplotype structure within the major histocompatibility complex (MHC) region. These methods predict HLA classical alleles using dense SNP genotypes, commonly found on array-based platforms used in genome-wide association studies (GWAS). The analysis of HLA classical alleles can be conducted on current SNP datasets at no additional cost. Here, we describe the workflow of HIBAG, an imputation method with attribute bagging, to infer a sample's HLA classical alleles using SNP data. Two examples are offered to demonstrate the functionality using public HLA and SNP data from the latest release of the 1000 Genomes project: genotype imputation using pre-built classifiers in a GWAS, and model training to create a new prediction model. The GPU implementation facilitates model building, making it hundreds of times faster compared to the single-threaded implementation.
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Alelos , Estudo de Associação Genômica Ampla , Antígenos HLA , Teste de Histocompatibilidade , Polimorfismo de Nucleotídeo Único , Software , Humanos , Estudo de Associação Genômica Ampla/métodos , Teste de Histocompatibilidade/métodos , Antígenos HLA/genética , Genótipo , Haplótipos/genética , Algoritmos , Biologia Computacional/métodosRESUMO
The design of multifunctional nanomedicine through the combination of multimodal treatments to achieve the optimal antitumor effect is essential for cancer therapy. Herein, we design and develop a multifunctional theranostic nanoplatform using an iron ion-doxorubicin (DOX) nanoscale coordination polymer (Fe/DOX NCP) as a shell coating on the surface of polyvinyl pyrrolidone (PVP) stabilized copper-diethyldithiocarbamate nanoparticles (Cu(DDC)2 NPs) for combined tumor chemo-/photothermal/chemodynamic therapy. The obtained Cu(DDC)2@Fe/DOX NPs display pH/laser dual-responsive degradation behavior and also exhibit favorable photothermal performance. Under 808 nm laser irradiation, Cu(DDC)2@Fe/DOX NPs can convert light into heat, which not only kills tumor cells via hyperthermia in photothermal therapy (PTT), but also accelerates the degradation of Fe/DOX NCPs to release Fe3+ and DOX. The liberated Fe3+ can be used to catalyze hydrogen peroxide via the Fenton reaction to produce highly toxic hydroxyl radicals (ËOH) in chemodynamic therapy (CDT). The released DOX and the exposed Cu(DDC)2 can cause significant cell death in combined chemotherapy via a superimposed effect. In vitro and in vivo results prove that Cu(DDC)2@Fe/DOX NPs with laser irradiation present remarkable anticancer performances in hyperthermia-enhanced chemo-/CDT. Therefore, this study provides a new strategy for highly efficient synergistic cancer therapy.
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Hipertermia Induzida , Neoplasias , Humanos , Cobre/farmacologia , Fototerapia/métodos , Terapia Fototérmica , Nanomedicina , Hipertermia Induzida/métodos , Doxorrubicina/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologiaRESUMO
A proven and promising method to improve the catalytic performance of single-atom catalysts through the interaction between bimetallic atoms to change the active surface sites or adjust the catalytic sites of reactants is reported. In this work, we used an iron-platinum bimetallic reagent as the metal source to precisely synthesise covalent organic framework-derived diatomic catalysts (FePt-DAC/NC). Benefiting from the coordination between the two metal atoms, the presence of Pt single atoms can successfully regulate Fe-N3 activity. FePt-DAC/NC exhibited a stronger ability to catalyze H2O2 to produce toxic hydroxyl radicals than Fe single-atom catalysts (Fe-SA/NC) to achieve chemodynamic therapy of tumors (the catalytic efficiency improved by 186.4%). At the same time, under the irradiation of an 808 nm laser, FePt-DAC/NC exhibited efficient photothermal conversion efficiency to achieve photothermal therapy of tumors. Both in vitro and in vivo results indicate that FePt-DAC/NC can efficiently suppress tumor cell growth by a synergistic therapeutic effect with photothermally augmented nanocatalytic therapy. This novel bimetallic dual active-site monodisperse catalyst provides an important example for the application of single-atom catalysts in the biomedical field, highlighting its promising clinical potential.
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Peróxido de Hidrogênio , Neoplasias , Humanos , Domínio Catalítico , Catálise , Ciclo Celular , Proliferação de CélulasRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Alpinia officinarum Hance is a perennial natural medicine herbivorous plant, has been used in the management of treat stomach pain and diabetes, it is abundantly cultivated in Qiongzhong, Baisha and other places. P. cablin (Blanco) Benth, one of the most important traditional Chinese plants, which plays functions in antioxidant and gastrointestinal regulation, has been extensively planted in Hainan, Guangdong and other regions. AIM OF THE STUDY: In this study, we investigated the role and underlying molecular mechanism of AP on diabetic gastroparesis (DGP) in vitro and in vivo. MATERIALS AND METHODS: In this study, using ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS) to identify active compounds in A. officinarum Hance-P. cablin (Blanco) Benth drug pair (AP). Molecular docking were utilized to explore the potential mechanism of AP treatment of DGP. In in vitro assays, gastric smooth muscle cells (GSMCs) were treated with 35 mM glucose to promote apoptosis and construct the DGP model, which was treated with different concentrations of AP. Furthermore, transfection technology was used to overexpress RAGE in GSMCs and elucidate the underlying mechanisms of alleviation of DGP by AP. RESULTS: Using UPLC-MS/MS analysis, nine components of AP were identified. We found that AP effectively blocked the increase in apoptosis, oxidative stress, and intracellular Ca2+ concentrations. For in vivo experiments, mice were fed with a high-fat irregular diet to construct DGP model, and AP was co-administered via oral gavage daily to prevent the development of DGP. Compared with DGP mice, AP significantly decreased fasting blood glucose levels and increased gastric emptying levels. Consistent with in vitro experiments, AP also considerably decreased the increase in oxidative stress in DGP mice. Mechanistically, AP alleviates apoptosis and DGP by decreasing oxidative stress and intracellular Ca2+ concentrations via the inhibition of the AGE/RAGE axis. CONCLUSIONS: Collectively, this study has established that AP can improve DGP, and the mechanism may be related to the inhibition the AGE/RAGE axis to mitigate apoptosis and DGP. To summarize, this study provides a novel supplementary strategy for DGP treatment.
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Diabetes Mellitus , Neuropatias Diabéticas , Gastroparesia , Ratos , Camundongos , Animais , Gastroparesia/tratamento farmacológico , Cromatografia Líquida , Simulação de Acoplamento Molecular , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Apoptose , Estresse OxidativoRESUMO
Nanomedicine has significantly advanced precise tumor therapy, providing essential technical blessing for active drug accumulation, targeted consignment, and mitigation of noxious side effects. To enhance anti-tumor efficacy, the integration of multiple therapeutic modalities has garnered significant attention. Here, we designed an innovative CoFeSe2 @DMSA@FA nanocatalyst with Se vacancies (abbreviated as CFSDF), which exhibits synergistic chemodynamic therapy (CDT) and photothermal therapy (PTT), leading to amplified tumor oxidative stress and enhanced photothermal effects. The multifunctional CFSDF nanocatalyst exhibits the remarkable ability to catalyze the Fenton reaction within the acidic tumor microenvironment, efficiently converting hydrogen peroxide (H2 O2 ) into highly harmful hydroxyl radicals (â OH). Moreover, the nanocatalyst effectively diminishes GSH levels and ameliorates intracellular oxidative stress. The incorporation of FA modification enables CFSDF to evade immune detection and selectively target tumor tissues. Numerous inâ vitro and inâ vivo investigations have consistently demonstrated that CFSDF optimizes its individual advantages and significantly enhances therapeutic efficiency through synergistic effects of multiple therapeutic modalities, offering a valuable and effective approach to cancer treatment.
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Nanopartículas , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Catálise , Peróxido de Hidrogênio , Estresse Oxidativo , Succímero , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Diabetic gastroparesis (DGP) is a common complication of type 2 diabetes mellitus (T2DM). Alpinia officinarum Hance (AOH) is one of the most commonly used both as a food and folk medicines, which is rich in diarylheptanoids and flavonoids. The gastroprotection and hypoglycemic effect make AOH has great potential in developing of anti-DGP complementary medicine. However, the molecular mechanisms of AOH that act against DGP are yet to be elucidated. In this study, we evaluated the therapeutic effects, the potential molecular mechanism, and the changes of gut microbiota of AOH in DGP. The 5 components of the AOH were analyzed, and the potential signaling pathway of AOH improving DGP was predicted by molecular docking. Subsequently, DGP rat model was constructed using high-fat-irregular-diet, AOH intervention significantly reduced blood glucose levels, increased gastrointestinal propulsion rate, and improved gastric histological morphology in DGP rats. Meanwhile, AOH has been shown to regulate the SCF/c-kit signaling pathway and rebalance the gut microbiota, which may be closely related to its role in improving DGP. Taken together, AOH may play a protective role on DGP through multiple mechanisms, which might pave the road for development and utilization of AOH.
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Alpinia , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Gastroparesia , Ratos , Animais , Gastroparesia/tratamento farmacológico , Gastroparesia/etiologia , Gastroparesia/metabolismo , Ratos Sprague-Dawley , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Simulação de Acoplamento Molecular , Estrutura Molecular , Transdução de SinaisRESUMO
BACKGROUND: Alpinia officinarum Hance (AOH) has a long history in China as a Chinese medicine and exerts the pharmacological effects of antidiabetic and gastrointestinal protection. In traditional Chinese medicine theory, AOH is often combined with other Chinese medicines for the treatment of diabetic gastroparesis (DGP). However, the molecular mechanisms, potential targets, and bioactive ingredients of AOH that act against DGP are yet to be elucidated. In this study, network pharmacology, molecular docking, and experimental study were used to predict the therapeutic effects and the potential molecular mechanism of AOH in DGP. METHODS: Network pharmacology analysis was performed to acquire information on the active chemical ingredients, DGP-related target proteins in AOH, and potential signaling pathway. In addition, molecular docking approach was used to simulate the binding of drugs and targets. Finally, DGP-mice model was used for experimental verification in vivo. Results: Through the network pharmacological research, AKT1 was found to be the core protein in AOH for the treatment of DGP and was mainly involved in the PI3K-AKT signaling pathway. Additionally, the interactions between bioactive compounds and target proteins (PIK3CA and AKT1) were analyzed using molecular docking, which verified the results of network pharmacology. Further in vivo studies indicated that AOH could reduce fasting blood glucose levels, improve gastric emptying rate, and ameliorate biochemical indicators in DGP mice. Moreover, AOH could increase the expressions and phosphorylation levels of PI3K and AKT in the stomach to regulate oxidative stress. CONCLUSIONS: The study has shown that AOH may play a protective role on DGP through mediation of the PI3K-AKT signaling pathway to regulate oxidative stress.
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Alpinia , Diabetes Mellitus , Gastroparesia , Animais , Camundongos , Gastroparesia/tratamento farmacológico , Simulação de Acoplamento Molecular , Farmacologia em Rede , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-aktRESUMO
Objective: We used network pharmacology, molecular docking, and cellular analysis to explore the pharmacodynamic components and action mechanism of Alpinia officinarum Hance (A. officinarum) in improving type 2 diabetes mellitus (T2DM). Methods: The protein-protein interaction (PPI) network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict the potential targets and mechanism of A. officinarum toward improving T2DM. The first 9 core targets and potential active compounds were docked using Discovery Studio 2019. Finally, IR-HepG2 cells and qPCR were applied to determine the mRNA expression of the top 6 core targets of the PPI network. Results: A total of 29 active ingredients and 607 targets of A. officinarum were obtained. T2DM-related targets overlapped with 176 targets. The core targets of the PPI network were identified as AKT serine/threonine kinase 1 (AKT1), an activator of transcription 3 (STAT3), tumor necrosis factor (TNF), tumor protein p53 (TP53), SRC proto-oncogene, nonreceptor tyrosine kinase (SRC), epidermal growth factor receptor (EGFR), albumin (ALB), mitogen-activated protein kinase 1 (MAPK1), and peroxisome proliferator-activated receptor gamma (PPARG). A. officinarum performs an antidiabetic role via the AGE-RAGE signaling pathway, the HIF-1 signaling pathway, the PI3K-AKT signaling pathway, and others, according to GO and KEGG enrichment analyses. Molecular docking revealed that the binding ability of diarylheptanoid active components in A. officinarum to core target protein was higher than that of flavonoids. The cell experiments confirmed that the A. officinarum extracts improved the glucose uptake of IR-HepG2 cells and AKT expression while inhibiting the STAT3, TNF, TP53, SRC, and EGFR mRNA expression. Conclusion: A. officinarum Hance improves T2DM by acting on numerous components, multiple targets, and several pathways. Our results lay the groundwork for the subsequent research and broaden the clinical application of A. officinarum Hance.
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Atomically dispersed metal clusters are considered as promising nanocatalysts due to their excellent physicochemical properties. Here, we report a novel strategy for precisely designing Fex (x = 1-2) cluster nanocatalysts (Fe1-N-C and Fe2-N-C) with dual catalytic activity, which can catalyze H2O2 into reactive oxygen species (ROS) and oxidize glutathione (GSH) into glutathione disulfide simultaneously. The adsorption energies of Fe-N sites in Fe2-N-C for GSH and H2O2 intermediates were well controlled due to the orbital modulation of adjacent Fe sites, contributing to the higher dual catalytic activity compared to Fe1-N-C. Additionally, tamoxifen (TAM) was loaded into Fe2-N-C (Fe2@TDF NEs) to down-regulate the intracellular pH for higher Fenton-like catalytic efficiency and ROS production. The generated ROS could induce apoptosis and lipid peroxidation, triggering ferroptosis. Meanwhile, upregulation of ROS and lipid peroxidation, along with GSH depletion and GPX4 downregulation could promote the apoptosis and ferroptosis of tumor cells. In addition, the lactic acid accumulation effect of TAM and the high photothermal conversion ability of Fe2@TDF NEs could further enhance the catalytic activity to achieve synergistic antitumor effects. As a result, this work highlights the critical role of adjacent metal sites at the atomic-level and provides a rational guidance for the design and application of nanocatalytic antitumor systems.
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Hipertermia Induzida , Neoplasias , Humanos , Apoptose , Linhagem Celular Tumoral , Glutationa , Peróxido de Hidrogênio/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fototerapia , Espécies Reativas de Oxigênio/farmacologia , Ferro/química , Catálise , NanoestruturasRESUMO
Large biobank-scale whole genome sequencing (WGS) studies are rapidly identifying a multitude of coding and non-coding variants. They provide an unprecedented resource for illuminating the genetic basis of human diseases. Variant functional annotations play a critical role in WGS analysis, result interpretation, and prioritization of disease- or trait-associated causal variants. Existing functional annotation databases have limited scope to perform online queries and functionally annotate the genotype data of large biobank-scale WGS studies. We develop the Functional Annotation of Variants Online Resources (FAVOR) to meet these pressing needs. FAVOR provides a comprehensive multi-faceted variant functional annotation online portal that summarizes and visualizes findings of all possible nine billion single nucleotide variants (SNVs) across the genome. It allows for rapid variant-, gene- and region-level queries of variant functional annotations. FAVOR integrates variant functional information from multiple sources to describe the functional characteristics of variants and facilitates prioritizing plausible causal variants influencing human phenotypes. Furthermore, we provide a scalable annotation tool, FAVORannotator, to functionally annotate large-scale WGS studies and efficiently store the genotype and their variant functional annotation data in a single file using the annotated Genomic Data Structure (aGDS) format, making downstream analysis more convenient. FAVOR and FAVORannotator are available at https://favor.genohub.org.
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Genoma Humano , Software , Humanos , Anotação de Sequência Molecular , Genômica , Genótipo , Variação GenéticaRESUMO
The combination of various therapeutic modalities has received considerable attention for improving antitumor performance. Herein, an innovative nanohybrid, namely CaO2@FePt-DOX@PDA@CM (CFDPM), was developed for synergistic chemotherapy/chemodynamic therapy/Ca2+ overloading-mediated amplification of tumor oxidative stress and photothermal enhanced cancer therapy. Camouflage of the 4T1 cell membrane enabled CFDPM to escape the immune surveillance and accumulate in the tumor tissue. Ca2+, released from CaO2, could lead to mitochondrial dysfunction and facilitate the production of reactive oxygen species to amplify intracellular oxidative stress. Meanwhile, the increase of H2O2 concentration could enhance the efficiency of the chemodynamic therapy (CDT). Moreover, the hypoxic condition could be alleviated remarkably, which is attributed to the sufficient O2 supply by CaO2, resulting in the suppression of drug resistance and promotion of the chemotherapeutic effect. The nanohybrids involving Ca2+ overloading/CDT/chemotherapy could synergistically amplify the tumor oxidative stresses and remarkably aggravate the death of cancer cells. Significantly, the excellent photothermal conversion performance of CFDPM could further promote the tumoricidal effect. The in vitro and in vivo studies revealed that CFDPM could effectively advance the therapeutic efficiency via the cooperation of various therapeutic modalities to optimize their individual virtue, which would open a valuable avenue for effective cancer treatment.
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Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Doxorrubicina/uso terapêutico , Humanos , Peróxido de Hidrogênio/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Estresse Oxidativo , Células Oxífilas/metabolismo , Células Oxífilas/patologia , Fototerapia/métodosRESUMO
Recently, disulfiram (DSF), approved by the FDA as an anti-alcoholic drug, has been proved as an effective antitumor drug after chelating with Cu2+. To overcome the shortage of intracellular Cu2+, we have constructed a dual gate-controlled intelligent nanoreactor (HA-DSF@HCuS@FePtMn, HDHF) via the ingenious combination of hollow copper sulfide (HCuS) nanoparticles, DSF and FePtMn nanocrystals. HDHF has a NIR-actuated gate and enzyme-actuated gate that could be opened in the hyaluronidase-abundant tumor microenvironment with NIR laser irradiation to trigger drug (DSF/FePtMn) release and synergistic therapy. Moreover, the FePtMn nanocrystals could continuously release Fe2+, which could catalyze H2O2 into highly cytotoxic hydroxyl radicals (ËOH), triggering chemodynamic therapy (CDT). When exposed to NIR laser, HCuS could collapse and release Cu2+, which could immediately chelate with DSF, forming the effective anticancer drug (Cu(DTC)2) and enabling DSF-based chemotherapy. More importantly, the efficient photothermal therapy (PTT) effect of HCuS could accelerate the FePtMn-based CDT and the release of Cu2+/DSF, improving tumor treatment efficiency. Thus, this study represents a distinctive paradigm of a dual gate-controlled intelligent nanoreactor enabled PTT-augmented DSF-based chemotherapy and FePtMn-based CDT for cancer nanotherapy.
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Antineoplásicos , Neoplasias , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Cobre/química , Cobre/farmacologia , Dissulfiram/farmacologia , Humanos , Hialuronoglucosaminidase , Peróxido de Hidrogênio , Nanotecnologia , Neoplasias/tratamento farmacológico , Sulfetos , Microambiente TumoralRESUMO
To enhance the utilization efficiency of visible light and reduce the recombination of photogenerated electrons and holes, spindle-shaped TiO2 photocatalysts with different Ti3+ concentrations were fabricated by a simple solvothermal strategy using low-cost, environmentally friendly TiH2 and H2O2 as raw materials and triethanolamine-aqueous as the medium. The photocatalytic activities of the obtained photocatalysts were investigated in the presence of visible light. X-ray diffraction (XRD), Raman spectra, transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared (FT-IR) spectra were applied to characterize the structure, morphologies, and chemical compositions of as-fabricated Ti3+ self-doped TiO2. The concentration of triethanolamine in the mixed solvent plays a significant role on the crystallinity, morphologies, and photocatalytic activities. The electron-hole separation efficiency was found to increase with the increase in the aspect ratio of as-fabricated Ti3+ self-doped TiO2, which was proved by transient photocurrent response and electrochemical impedance spectroscopy.
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With the advancement and development of nanomedicine, tumor precision therapy provides technical support for effective accumulation and targeted drug delivery, and reduces toxic side effects. In cancer cells, breaking the redox balance could induce cancer cell death. Herein, a novel iron-containing intelligent hydrogel nanobot (FeSe2-Ce6/MOF@HA/PEI/CpG@HHPA NPs, abbreviated as FSMH) is proposed to break the intracellular redox balance and trigger the immune response. The as-fabricated multifunctional FSMH could not only exert Fenton reactions in the acidic tumor microenvironment, converting hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (ËOH), but also effectively consume GSH to attenuate the intracellular oxidative stress. The negative charge of the FSMH nanohydrogel system guarantees its superexcellent stabilization in blood circulation and optimal tumor collection. Subsequently, the surface charge of the endocytosed FSMH was transformed to a positive charge after exposure to the acidic tumor environment, further improving its tumor collection and locally releasing Fe ions and immune adjuvants. Furthermore, Ce6 was released in a pH-responsive manner in the acidic microenvironment. In the presence of near-infrared light, singlet oxygen was produced by the FSMH nanohydrogel system, to ablate tumors and promote the maturation of dendritic cells, achieving the precision-combined strategies effect of CDT, PDT, and immunotherapy.
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Ferroptose , Neoplasias , Linhagem Celular Tumoral , Humanos , Hidrogéis/farmacologia , Hidrogéis/uso terapêutico , Peróxido de Hidrogênio/uso terapêutico , Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Oxirredução , Microambiente TumoralRESUMO
Recently, extending single-atom catalysts from mono- to binary sites has been proved to be a promising way to realize more efficient chemical catalytic processes. In this work, atomically dispersed Fe, Pt dinuclear catalysts ((Fe, Pt)SA-N-C) with an ca. 2.38 Å distance for Fe1 (Fe-N3) and Pt1 (Pt-N4) could be precisely controlled via a novel secondary-doping strategy. In response to tumor microenvironments, the Fe-N3/Pt-N4 moieties exhibited synergistic catalytic performance for tumor catalytic therapy. Due to its beneficial microstructure and abundant active sites, the Fe-N3 moiety effectively initiated the intratumoral Fenton-like reaction to release a large amount of toxic hydroxyl radicals (â¢OH), which further induced tumor cell apoptosis. Meanwhile, the bonded Pt-N4 moiety could also enhance the Fenton-like activity of the Fe-N3 moiety up to 128.8% by modulating the 3d electronic orbitals of isolated Fe-N3 sites. In addition, the existence of amorphous carbon revealed high photothermal conversion efficiency when exposed to an 808 nm laser, which synergistically achieved an effective oncotherapy outcome. Therefore, the as-obtained (Fe, Pt)SA-N-C-FA-PEG has promising potential in the bio-nanomedicine field for inhibiting tumor cell growth in vitro and in vivo.
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Radical Hidroxila , Nanomedicina , Catálise , LuzRESUMO
Genome-wide association studies have successfully discovered thousands of common variants associated with human diseases and traits, but the landscape of rare variations in human disease has not been explored at scale. Exome-sequencing studies of population biobanks provide an opportunity to systematically evaluate the impact of rare coding variations across a wide range of phenotypes to discover genes and allelic series relevant to human health and disease. Here, we present results from systematic association analyses of 4,529 phenotypes using single-variant and gene tests of 394,841 individuals in the UK Biobank with exome-sequence data. We find that the discovery of genetic associations is tightly linked to frequency and is correlated with metrics of deleteriousness and natural selection. We highlight biological findings elucidated by these data and release the dataset as a public resource alongside the Genebass browser for rapidly exploring rare-variant association results.
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The rapid development and wide application of nanomaterial-involved theranostic agents have drawn surging attention for improving the living standard of humankind and healthcare conditions. In this review, recent developments in the design, synthesis, biocompatibility evaluation and potential nanomedicine applications of FePt-involved nano-systems are summarized, especially for cancer theranostic and biological molecule detection. The in vivo multi-model imaging capability is discussed in detail, including magnetic resonance imaging and computed tomography. Furthermore, we highlight the significant achievements of various FePt-involved nanotherapeutics for cancer treatment, such as drug delivery, chemodynamic therapy, photodynamic therapy, radiotherapy and immunotherapy. In addition, a series of FePt-involved nanocomposites are also applied for biological molecule detection, such as H2O2, glucose and naked-eye detection of cancer cells. Ultimately, we also summarize the challenges and prospects of FePt-involved nano-systems in nanocatalytic medicine. This review is expected to give a general pattern for the development of FePt-involved nano-systems in the field of nanocatalytic medicine and analytical determination.
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Antineoplásicos/uso terapêutico , Portadores de Fármacos/uso terapêutico , Nanocompostos/uso terapêutico , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Catálise , Linhagem Celular Tumoral , Portadores de Fármacos/química , Humanos , Peróxido de Hidrogênio/análise , Ferro/química , Nanopartículas Metálicas/química , Nanopartículas Metálicas/uso terapêutico , Nanocompostos/química , Platina/química , Medicina de PrecisãoRESUMO
Minor histocompatibility antigens (mHAg) composed of peptides presented by HLA molecules can cause immune responses involved in graft-versus-host disease (GVHD) and graft-versus-leukemia effects after allogeneic hematopoietic cell transplantation (HCT). The current study was designed to identify individual graft-versus-host genomic mismatches associated with altered risks of acute or chronic GVHD or relapse after HCT between HLA-genotypically identical siblings. Our results demonstrate that in allogeneic HCT between a pair of HLA-identical siblings, a mHAg manifests as a set of peptides originating from annotated proteins and non-annotated open reading frames, which i) are encoded by a group of highly associated recipient genomic mismatches, ii) bind to HLA allotypes in the recipient, and iii) evoke a donor immune response. Attribution of the immune response and consequent clinical outcomes to individual peptide components within this set will likely differ from patient to patient according to their HLA types.
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Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Menor/imunologia , Imunologia de Transplantes , Adolescente , Adulto , Idoso , Alelos , Criança , Pré-Escolar , Suscetibilidade a Doenças/imunologia , Feminino , Predisposição Genética para Doença , Variação Genética , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Incidência , Lactente , Recém-Nascido , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor/genética , Peptídeos/genética , Peptídeos/imunologia , Transplante Homólogo , Adulto JovemRESUMO
Despite asthma has a considerable genetic component, an important proportion of genetic risks remain unknown, especially for non-European populations. Canary Islanders have the largest African genetic ancestry observed among Southwestern Europeans and the highest asthma prevalence in Spain. Here we examined broad chromosomal regions previously associated with an excess of African genetic ancestry in Canary Islanders, with the aim of identifying novel risk variants associated with asthma susceptibility. In a two-stage cases-control study, we revealed a variant within HLA-DQB1 significantly associated with asthma risk (rs1049213, meta-analysis p = 1.30 × 10-7, OR [95% CI] = 1.74 [1.41-2.13]) previously associated with asthma and broad allergic phenotype. Subsequent fine-mapping analyses of classical HLA alleles revealed a novel allele significantly associated with asthma protection (HLA-DQA1*01:02, meta-analysis p = 3.98 × 10-4, OR [95% CI] = 0.64 [0.50-0.82]) that had been linked to infectious and autoimmune diseases, and peanut allergy. HLA haplotype analyses revealed a novel haplotype DQA1*01:02-DQB1*06:04 conferring asthma protection (meta-analysis p = 4.71 × 10-4, OR [95% CI] = 0.47 [0.29- 0.73]).