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DNA has not been utilized to record temporal information, although DNA has been used to record biological information and to compute mathematical problems. Here, we found that indel generation by Cas9 and guide RNA can occur at steady rates, in contrast to typical dynamic biological reactions, and the accumulated indel frequency can be a function of time. By measuring indel frequencies, we developed a method for recording and measuring absolute time periods over hours to weeks in mammalian cells. These time-recordings were conducted in several cell types, with different promoters and delivery vectors for Cas9, and in both cultured cells and cells of living mice. As applications, we recorded the duration of chemical exposure and the lengths of elapsed time since the onset of biological events (e.g., heat exposure and inflammation). We propose that our systems could serve as synthetic "DNA clocks."
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Proteína 9 Associada à CRISPR/metabolismo , Animais , Sequência de Bases , Microambiente Celular , Simulação por Computador , Células HEK293 , Meia-Vida , Humanos , Mutação INDEL/genética , Inflamação/patologia , Integrases/metabolismo , Masculino , Camundongos Nus , Regiões Promotoras Genéticas/genética , RNA Guia de Cinetoplastídeos/genética , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
CD4+ T cell responses are exquisitely antigen specific and directed toward peptide epitopes displayed by human leukocyte antigen class II (HLA-II) on antigen-presenting cells. Underrepresentation of diverse alleles in ligand databases and an incomplete understanding of factors affecting antigen presentation in vivo have limited progress in defining principles of peptide immunogenicity. Here, we employed monoallelic immunopeptidomics to identify 358,024 HLA-II binders, with a particular focus on HLA-DQ and HLA-DP. We uncovered peptide-binding patterns across a spectrum of binding affinities and enrichment of structural antigen features. These aspects underpinned the development of context-aware predictor of T cell antigens (CAPTAn), a deep learning model that predicts peptide antigens based on their affinity to HLA-II and full sequence of their source proteins. CAPTAn was instrumental in discovering prevalent T cell epitopes from bacteria in the human microbiome and a pan-variant epitope from SARS-CoV-2. Together CAPTAn and associated datasets present a resource for antigen discovery and the unraveling genetic associations of HLA alleles with immunopathologies.
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COVID-19 , Aprendizado Profundo , Humanos , Captana , SARS-CoV-2 , Antígenos HLA , Epitopos de Linfócito T , PeptídeosRESUMO
The determination of molecular features that mediate clinically aggressive phenotypes in prostate cancer remains a major biological and clinical challenge1,2. Recent advances in interpretability of machine learning models as applied to biomedical problems may enable discovery and prediction in clinical cancer genomics3-5. Here we developed P-NET-a biologically informed deep learning model-to stratify patients with prostate cancer by treatment-resistance state and evaluate molecular drivers of treatment resistance for therapeutic targeting through complete model interpretability. We demonstrate that P-NET can predict cancer state using molecular data with a performance that is superior to other modelling approaches. Moreover, the biological interpretability within P-NET revealed established and novel molecularly altered candidates, such as MDM4 and FGFR1, which were implicated in predicting advanced disease and validated in vitro. Broadly, biologically informed fully interpretable neural networks enable preclinical discovery and clinical prediction in prostate cancer and may have general applicability across cancer types.
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Aprendizado Profundo , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/tratamento farmacológico , Proteínas de Ciclo Celular/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Masculino , Neoplasias da Próstata/genética , Proteínas Proto-Oncogênicas/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptores Androgênicos/genética , Reprodutibilidade dos Testes , Proteína Supressora de Tumor p53/genéticaRESUMO
The number of meiotic crossovers is tightly controlled and most depend on pro-crossover ZMM proteins, such as the E3 ligase HEI10. Despite the importance of HEI10 dosage for crossover formation, how HEI10 transcription is controlled remains unexplored. In a forward genetic screen using a fluorescent crossover reporter in Arabidopsis thaliana, we identify heat shock factor binding protein (HSBP) as a repressor of HEI10 transcription and crossover numbers. Using genome-wide crossover mapping and cytogenetics, we show that hsbp mutations or meiotic HSBP knockdowns increase ZMM-dependent crossovers toward the telomeres, mirroring the effects of HEI10 overexpression. Through RNA sequencing, DNA methylome, and chromatin immunoprecipitation analysis, we reveal that HSBP is required to repress HEI10 transcription by binding with heat shock factors (HSFs) at the HEI10 promoter and maintaining DNA methylation over the HEI10 5' untranslated region. Our findings provide insights into how the temperature response regulator HSBP restricts meiotic HEI10 transcription and crossover number by attenuating HSF activity.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas Cromossômicas não Histona/genética , Troca Genética , Proteínas de Choque Térmico/metabolismo , Resposta ao Choque Térmico/genética , Meiose/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
ConspectusPhotocatalytic energy conversion is a pivotal process for harnessing solar energy to produce chemicals and presents a sustainable alternative to fossil fuels. Key strategies to enhance photocatalytic efficiency include facilitating mass transport and reactant adsorption, improving light absorption, and promoting electron and hole separation to suppress electron-hole recombination. This Account delves into the potential advantages of electrically conductive metal-organic frameworks (EC-MOFs) in photocatalytic energy conversion and examines how manipulating electronic structures and controlling morphology and defects affect their unique properties, potentially impacting photocatalytic efficiency and selectivity. Moreover, with a proof-of-concept study of photocatalytic hydrogen peroxide production by manipulating the EC-MOF's electronic structure, we highlight the potential of the strategies outlined in this Account.EC-MOFs not only possess porosity and surface areas like conventional MOFs, but exhibit electronic conductivity through d-p conjugation between ligands and metal nodes, enabling effective charge transport. Their narrow band gaps also allow for visible light absorption, making them promising candidates for efficient photocatalysts. In EC-MOFs, the modular design of metal nodes and ligands allows fine-tuning of both the electronic structure and physical properties, including controlling the particle morphology, which is essential for optimizing band positions and improving charge transport to achieve efficient and selective photocatalytic energy conversion.Despite their potential as photocatalysts, modulating the electronic structure or controlling the morphology of EC-MOFs is nontrivial, as their fast growth kinetics make them prone to defect formation, impacting mass and charge transport. To fully leverage the photocatalytic potential of EC-MOFs, we discuss our group's efforts to manipulate their electronic structures and develop effective synthetic strategies for morphology control and defect healing. For tuning electronic structures, diversifying the combinations of metals and linkers available for EC-MOF synthesis has been explored. Next, we suggest that synthesizing ligand-based solid solutions will enable continuous tuning of the band positions, demonstrating the potential to distinguish between photocatalytic reactions with similar redox potentials. Lastly, we present incorporating a donor-acceptor system in an EC-MOF to spatially separate photogenerated carriers, which could suppress electron-hole recombination. As a synthetic strategy for morphology control, we demonstrated that electrosynthesis can modify particle morphology, enhancing electrochemical surface area, which will be beneficial for reactant adsorption. Finally, we suggest a defect healing strategy that will enhance charge transport by reducing charge traps on defects, potentially improving the photocatalytic efficiency.Our vision in this Account is to introduce EC-MOFs as an efficient platform for photocatalytic energy conversion. Although EC-MOFs are a new class of semiconductor materials and have not been extensively studied for photocatalytic energy conversion, their inherent light absorption and electron transport properties indicate significant photocatalytic potential. We envision that employing modular molecular design to control electronic structures and applying effective synthetic strategies to customize morphology and defect repair can promote charge separation, electron transfer to potential reactants, and mass transport to realize high selectivity and efficiency in EC-MOF-based photocatalysts. This effort not only lays the foundation for the rational design and synthesis of EC-MOFs, but has the potential to advance their use in photocatalytic energy conversion.
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ConspectusElectrically conductive metal-organic frameworks (EC-MOFs) have emerged as a compelling class of materials, drawing increasing attention due to their unique properties facilitating charge transport within porous structures. The synergy between electrical conductivity and porosity has opened a wide range of applications, including electrocatalysis, energy storage, chemiresistive sensing, and electronic devices that have been underexplored for their insulating counterparts. Despite these promising prospects, a prevalent challenge arises from the predominant adoption of two-dimensional (2D) structures by most EC-MOFs. These 2D frameworks often show modest surface areas and short interlayer distances, hindering molecular accessibility, which deviates from the inherent characteristics of conventional MOFs. Furthermore, the quest for efficient charge transport imposes design constraints, leading to a restricted selection of functional building blocks. Additionally, there is a lack of established functionalization methods within EC-MOFs, limiting their functional diversity. Thus, these challenges have impeded EC-MOFs from reaching their full potential.In this Account, we summarize and discuss our group's efforts aimed at enhancing molecular accessibility and deploying the functional diversity of EC-MOFs. Our focus on enhancing molecular accessibility involves several strategies. First, we employed macrocyclic ligands with intrinsic pockets as the building blocks for EC-MOFs. The integrated intrinsic pockets in the frameworks supplement surface areas and additional pores to enhance molecular accessibility. The resulting macrocyclic ligand-based EC-MOFs exhibit exceptionally high surface areas and confer advantages in electrochemical performances. Second, our efforts extend to addressing the structural limitations, frequently associated with EC-MOFs' 2D structures. Through the pillar insertion strategy, we transformed a 2D EC-MOF platform into a three-dimensional (3D) structure, thereby achieving higher porosity and enhanced molecular accessibility. In pursuing functional diversity, we have delved into molecular-level tuning of EC-MOF building blocks. We demonstrated that electron-rich alkyne-based pockets in the macrocyclic ligands can host transition metals and alkali ions, enabling ion selectivity and showcasing diverse use of EC-MOFs. We utilized a postsynthetic approach to further functionalize metal nodes on the molecular level within an EC-MOF framework, introducing a proton-conducting pathway while preserving its electrical conductivity.We aspire for this Account to provide practical insights and strategies to surmount structural and functional diversity limitations in the realm of EC-MOFs. By integrating enhanced molecular accessibility and diverse functionality, our endeavor to propel the utility of these materials will inspire further rational development for future EC-MOFs and unlock their full potential.
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Hydrogen peroxide (H2O2) holds significance as a vital chemical with the potential to serve as an energy carrier. Compared with the conventional anthraquinone process, photocatalytic H2O2 production has emerged as an appealing alternative because of its energy efficiency and environmental sustainability. However, the existing photocatalysts suffer from low catalytic efficiency, limited tunability of optical properties, and reliance on sacrificial agents due to high energy loss caused by inefficient charge separation. Therefore, developing catalysts with tunable optical properties and efficient charge separation is desirable. In this work, we introduce postsynthetic functionalization into an electrically conductive metal-organic framework, namely, DPT-MOF. Leveraging DPT (3,6-di(4-pyridyl)-1,2,4,5-tetrazine) as a pillar ligand, we exploited click-type chemistry to manipulate band position and charge separation efficiency, allowing for photocatalytic nonsacrificial H2O2 production. Notably, the fluorine-functionalized MOF exhibited the highest H2O2 production rate of 1676 µmol g-1 h-1 under visible light in O2-saturated water among our other samples. This high production rate is attributed to the tuned electronic structure and prolonged charge lifetime facilitated by the fluorine groups. This work highlights the effectiveness of postsynthetic methodology in tuning optical properties, opening a promising avenue for advancing the field of semiconductive MOF-based photocatalysis.
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Eruca sativa is a commonly used edible plant in Italian cuisine. E. sativa 70% ethanol extract (ES) was fractionated with five organic solvents, including n-hexane (EHex), chloroform (ECHCl3), ethyl acetate (EEA), n-butyl alcohol (EBuOH), and water (EDW). Ethyl acetate fraction (EEA) had the highest antioxidant activity, which was correlated with the total polyphenol and flavonoid content. ES and EEA acted as PPAR-α ligands by PPAR-α competitive binding assay. EEA significantly increased cornified envelope formation as a keratinocyte terminal differentiation marker in HaCaT cells. Further, it significantly reduced nitric oxide and pro-inflammatory cytokines (IL-6 and TNF-α) in lipopolysaccharide-stimulated RAW 264.7 cells. The main flavonol forms detected in high amounts from EEA are mono-and di-glycoside of each aglycone. The main flavonol form of EEA is the mono-glycoside of each aglycone detected, and the most abundant flavonol mono-glycoside is kaempferol 3-glucoside 7.4%, followed by quercetin-3-glucoside 2.3% and isorhamnetin 3-glucoside 1.4%. Flavonol mono-glycosides were shown to be a potent PPAR-α ligand using molecular docking simulation and showed the inhibition of nitric oxide. These results suggest that the flavonol composition of E. sativa is suitable for use in improving skin barrier function and inflammation in skin disorders, such as atopic dermatitis.
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This paper introduces catheter-directed intravascular casting hydrogels for transarterial chemo/starvation/chemodynamic embolization (TACSCE) therapy of hepatocellular carcinoma (HCC). Comprising Mn ion-crosslinked hyaluronic acid-dopamine (HD) with glucose oxidase (for glucose decomposition to H2O2 in starvation therapy), doxorubicin (for chemotherapy), and iopamidol (for X-ray imaging), these hydrogels are fabricated for transarterial embolization therapy guided by X-ray fluoroscopy. Mn4+ (from MnO2) demonstrates strong coordination with the catechol group of HD, providing hypoxia relief through O2 generation and cellular glutathione (GSH) consumption, compared to the OH radical generation potential of Mn2+. The gelation time-controlled, catheter-injectable, and rheologically tuned multitherapeutic/embolic gel system effectively reaches distal arterioles, ensuring complete intravascular casting with fewer complications related to organic solvents. Glucose deprivation, cascade reactive oxygen species (ROS) generation, GSH depletion, and sustained release profiles of multiple drug cargos from the hydrogel system are also achieved. The combined chemo/starvation/chemodynamic efficacies of these designed hydrogel systems are confirmed in HCC cell cultures and HCC-bearing animal models. The developed radiopaque/injectable/embolic/sol-to-gel transformable systems for TACSCE therapy may offer enhanced therapeutic efficacies compared to typical transarterial embolization and transarterial chemoembolization procedures for HCC.
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Azobenzene, while relevant, has faced constraints in biological system applications due to its suboptimal quantum yield and short-wavelength emission. This study presents a pioneering strategy for fabricating organic microdots by coupling foldamer-linked azobenzene, resulting in robust fluorescence intensity and stability, especially in aggregated states, thereby showing promise for bioimaging applications. Comprehensive experimental and computational examinations elucidate the mechanisms underpinning enhanced photostability and fluorescence efficacy. In vitro and in vivo evaluations disclose that the external layer of cis-azo-foldamer microdots performs a self-sacrificial function during photo-bleaching. Consequently, these red-fluorescent microdots demonstrate extraordinary structural and photochemical stabilities over extended periods. The conjugation of a ß-peptide foldamer to the azobenzene chromophore through a glycine linker instigates a blue-shifted and amplified π*-n transition. Molecular dynamics simulations reveal that the aggregated state of cis-azo-foldamers fortifies the stability of cis isomers, thereby augmenting fluorescence efficiency. This investigation furnishes crucial insights into conceptualizing novel, biologically inspired materials, promising stable and enduring imaging applications, and carries implications for diverse arenas such as medical diagnostics, drug delivery, and sensing technologies.
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Recently, the pathomechanisms of keloids have been extensively researched using transcriptomic analysis, but most studies did not consider the activity of keloids. We aimed to profile the transcriptomics of keloids according to their clinical activity and location within the keloid lesion, compared with normal and mature scars. Tissue samples were collected (keloid based on its activity (active and inactive), mature scar from keloid patients and normal scar (NS) from non-keloid patients). To reduce possible bias, all keloids assessed in this study had no treatment history and their location was limited to the upper chest or back. Multiomics assessment was performed by using single-cell RNA sequencing and multiplex immunofluorescence. Increased mesenchymal fibroblasts (FBs) was the main feature in keloid patients. Noticeably, the proportion of pro-inflammatory FBs was significantly increased in active keloids compared to inactive ones. To explore the nature of proinflammatory FBs, trajectory analysis was conducted and CCN family associated with mechanical stretch exhibited higher expression in active keloids. For vascular endothelial cells (VECs), the proportion of tip and immature cells increased in keloids compared to NS, especially at the periphery of active keloids. Also, keloid VECs highly expressed genes with characteristics of mesenchymal activation compared to NS, especially those from the active keloid center. Multiomics analysis demonstrated the distinct expression profile of active keloids. Clinically, these findings may provide the future appropriate directions for development of treatment modalities of keloids. Prevention of keloids could be possible by the suppression of mesenchymal activation between FBs and VECs and modulation of proinflammatory FBs may be the key to the control of active keloids.
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Fibroblastos , Queloide , Queloide/patologia , Queloide/metabolismo , Humanos , Fibroblastos/metabolismo , Transcriptoma , Células Endoteliais/metabolismo , Feminino , Adulto , Masculino , Perfilação da Expressão Gênica , Análise de Célula ÚnicaRESUMO
BACKGROUND AND AIM: Although age at disease onset is considered to be a significant factor in the prognosis of Crohn's disease, little is known about its influence on the long-term prognosis of those with intestinal Behçet's disease (BD). This study aimed to evaluate the long-term clinical outcomes of patients with intestinal BD according to age of disease onset. METHODS: Patients diagnosed with intestinal BD at < 18, 18-60, and > 60 years of age were classified into early-onset, adult-onset, and late-onset groups, respectively. The influence of disease onset time on clinical prognosis, including specific medical requirements, BD-related intestinal surgery, hospitalization, and emergency room visits, was compared using the log-rank test in a large cohort of patients with intestinal BD. RESULTS: Among 780 patients, 21 (2.7%), 672 (86.2%), and 87 (11.1%) comprised the early-onset, adult-onset, and late-onset groups, respectively. Patients in the early-onset group were more likely to require immunosuppressants than those in the adult-onset group (P = 0.048). Nine (42.9%), 158 (23.5%), and 18 (20.7%) patients in the early-onset, adult-onset, and late-onset groups, respectively, underwent intestinal resection. The early-onset group exhibited a higher risk for intestinal resection than the late-onset (P = 0.043) and adult-onset (P = 0.030) groups. The late-onset group exhibited a higher risk for BD-related hospitalization than the adult-onset group (P = 0.023). CONCLUSIONS: Age at diagnosis affected the clinical course of intestinal BD, including intestinal surgery, hospitalization, and specific medical requirements. Different treatment strategies should be established according to age at diagnosis.
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Síndrome de Behçet , Enteropatias , Adulto , Humanos , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/terapia , Prognóstico , Imunossupressores/uso terapêutico , Intestinos , Enteropatias/diagnóstico , Enteropatias/etiologia , Enteropatias/terapiaRESUMO
PURPOSE: To describe, compare similarity of pharmacokinetic (PK), pharmacodynamic (PD) and efficacy of SB12 and reference eculizumab (ECU) and find clinically significant covariate relationships. METHODS: The PK, PD (terminal complement activity) and efficacy (LDH) data of SB12 and ECU were obtained from 289 subjects from phase I and phase III studies. One- and two-compartment PK models with first-order elimination were evaluated for SB12 and ECU. For PD and efficacy, both direct and indirect models were tested. The impact of covariates on PK, PD and efficacy parameters was assessed. Relationship between PK/PD and PD/efficacy was characterized. This modeling was performed using NONMEM version 7.4 (Icon Development Solutions, Ellicott City, MD, USA). RESULTS: The two-compartment model adequately described the PK of SB12 and ECU, and the subject's weight was chosen as a clinically significant covariate affecting drugs' clearance and central volume of distribution. Treatment group was not a significant covariate affecting clearance. The direct response model using inhibitory sigmoid Emax and sigmoid Emax relationship well described the PK/PD relationship and PD/efficacy relationship of SB12 and ECU, respectively. Through this modeling, the relationships between PK, PD and efficacy were characterized. There were no differences in PK, PD and efficacy parameters between SB12 and ECU in pooled populations of healthy subjects and paroxysmal nocturnal haemoglobinuria (PNH) patients. CONCLUSION: The population modeling showed PK, PD and efficacy similarities between SB12 and ECU in pooled population of healthy subjects and PNH patients, supporting the totality of evidence on biosimilarity for SB12.
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Anticorpos Monoclonais Humanizados , Medicamentos Biossimilares , Modelos Biológicos , Humanos , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Medicamentos Biossimilares/farmacocinética , Medicamentos Biossimilares/farmacologia , Adulto Jovem , Hemoglobinúria Paroxística/tratamento farmacológico , Adolescente , IdosoRESUMO
The terms "onychofibroblast" (nail-specific fibroblast) and onychodermis (nail-specific dermis) were first introduced in 2006 and 2012, respectively, based on distinctive histologic and immunohistochemical features from the dermis of the surrounding skin and have been demonstrated in multiple studies. Recently, based on molecular research, the definition of onychodermis containing onychofibroblasts has been expanded to encompass the area located between the nail matrix and bed epithelium and periosteum. Single-cell RNA sequencing and in situ hybridization demonstrated that onychofibroblasts within the onychodermis express the genes including RSPO4, MSX1, WIF-1, and BMP5, which are implicated in nail formation and/or in disorders with nail phenotype. A mutation in RSPO4, a component of the Wnt signaling pathway, causes anonychia congenita. Nail matrix onychodermis and nail bed onychodermis share many similar characteristics which differ from the surrounding normal dermis of the skin. Comparative spatial transcriptomic and single-cell analyses of human nail units and hair follicles suggest that onychodermis is the counterpart of follicular dermal papilla, which plays a key role in hair follicle growth and morphogenesis. Onychomatricoma, as a nail-specific tumor, has been demonstrated to be a mesenchymal tumor that originates from onychofibroblasts and is associated with the upregulation of Wnt signaling. Collectively, the onychodermis and onychofibroblasts play crucial roles in nail development and these specialized nail mesenchymal elements are key components in the pathogenesis of onychomatricoma. The concept of onychodermis containing onychofibroblasts is very important for nail biology and pathology.
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BACKGROUND: Methotrexate (MTX) combination therapy with biological agents has gained increasing interest. Here, we assessed the efficacy and tolerability of the MTX combination therapy in patients with Crohn's disease (CD). METHODS: We performed a multicenter observational study with 185 patients with CD with MTX and biologics combination therapy; the patients were recruited from three IBD Clinics in Korea. We evaluated the outcomes of the MTX combination therapy and examined the predictive factors of clinical and endoscopic remission. RESULTS: MTX was administered orally to 62.7% of patients; the mean dose was 15.5 mg per week, and the mean treatment duration was 36 months. Of the 169 patients treated with MTX combination therapy for over 6 months, the steroid-free clinical remission rates were 34.3%, 26.0%, 29.8%, and 32.7% at 4, 12, 18, and 24 months, respectively. Previous thiopurine use was a significant negatively associated independent factor (p < 0.001), and a higher dose of MTX (≥ 15 mg/week) was a positively associated independent factor of steroid-free clinical remission (p = 0.035). Ninety-six patients underwent follow-up endoscopy after 28 months, and 36 (37.5%) achieved endoscopic remission. Longer disease duration (p = 0.006), ileocolonic type of Montreal location (p = 0.036), and baseline C-reactive protein (CRP) level of more than 5 mg/L (p = 0.035) were significant negatively associated independent factors and a higher dose of MTX (≥ 15 mg/week) was a positively associated independent factor of endoscopic remission (p = 0.037). CONCLUSIONS: MTX combination therapy with biologics was effective and tolerable in patients with CD.
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Produtos Biológicos , Doença de Crohn , Humanos , Produtos Biológicos/uso terapêutico , Doença de Crohn/diagnóstico , Doença de Crohn/tratamento farmacológico , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Indução de Remissão , Resultado do TratamentoRESUMO
BACKGROUND AND AIMS: Little is known about the risk factors of bleeding after colonoscopic polypectomy in patients with end-stage renal disease (ESRD). This study investigated the incidence and risk factors of post-polypectomy bleeding (PPB), including immediate and delayed bleeding, in patients with ESRD. METHODS: Ninety-two patients with ESRD who underwent colonoscopic polypectomy between September 2005 and June 2020 at a single tertiary referral center were included. The patients' medical records were retrospectively reviewed. Patient- and polyp-related factors associated with immediate PPB (IPPB) were analyzed using logistic regression analysis. Additionally, the optimal cutoff polyp size related to a significant increase in the risk of IPPB was determined by performing receiver operating characteristic (ROC) analysis and calculating the area under the ROC curve (AUC). RESULTS: In total, 286 polyps were removed. IPPB occurred in 24 (26.1%) patients and 46 (16.1%) polyps and delayed PPB occurred in 2 (2.2%) patients. According to multivariate analysis, the polyp size (> 7 mm), old age (> 70), and endoscopic mucosal resection (EMR) as the polypectomy method (EMR versus non-EMR) were found to be independent risk factors for IPPB. According to the Youden index method, the optimal cutoff polyp size to identify high-risk polyps for IPPB was 7 mm (AUC = 0.755; sensitivity, 76.1%; specificity, 69.6%). CONCLUSIONS: Colonoscopic polypectomy should be performed with caution in patients with ESRD, especially in those with the following risk factors: advanced age (> 70 years), polyp size > 7 mm, and EMR as the polypectomy method.
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Pólipos do Colo , Falência Renal Crônica , Humanos , Idoso , Pólipos do Colo/cirurgia , Pólipos do Colo/complicações , Colonoscopia/métodos , Estudos Retrospectivos , Hemorragia Pós-Operatória/epidemiologia , Hemorragia Pós-Operatória/etiologia , Fatores de Risco , Pólipos Intestinais , Falência Renal Crônica/complicaçõesRESUMO
The Faurot frailty index (FFI) is a validated algorithm that uses enrollment and International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)-based billing information from Medicare claims data as a proxy for frailty. In October 2015, the US health-care system transitioned from the ICD-9-CM to the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). Applying the Centers for Medicare and Medicaid Services General Equivalence Mappings, we translated diagnosis-based frailty indicator codes from the ICD-9-CM to the ICD-10-CM, followed by manual review. We used interrupted time-series analysis of Medicare data to assess the comparability of the pre- and posttransition FFI scores. In cohorts of beneficiaries enrolled in January 2015-2017 with 8-month frailty look-back periods, we estimated associations between the FFI and 1-year risk of aging-related outcomes (mortality, hospitalization, and admission to a skilled nursing facility). Updated indicators had similar prevalences as pretransition definitions. The median FFI scores and interquartile ranges (IQRs) for the predicted probability of frailty were similar before and after the International Classification of Diseases transition (pretransition: median, 0.034 (IQR, 0.02-0.07); posttransition: median, 0.038 (IQR, 0.02-0.09)). The updated FFI was associated with increased risks of mortality, hospitalization, and skilled nursing facility admission, similar to findings from the ICD-9-CM era. Studies of medical interventions in older adults using administrative claims should use validated indices, like the FFI, to mitigate confounding or assess effect-measure modification by frailty.
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Fragilidade , Classificação Internacional de Doenças , Humanos , Idoso , Estados Unidos/epidemiologia , Fragilidade/epidemiologia , Medicare , Fatores de Risco , HospitalizaçãoRESUMO
Herein, the synthesis of Cu3 (HAB)x (TATHB)2-x (HAB: hexaaminobenzene, TATHB: triaminotrihydroxybenzene) is reported. Synthetic improvement of Cu3 (TATHB)2 leads to a more crystalline framework with higher electrical conductivity value than previously reported. The improved crystallinity and analogous structure between TATHB and HAB enable the synthesis of Cu3 (HAB)x (TATHB)2-x with ligand compositions precisely controlled by precursor ratios. The electrical conductivity is tuned from 4.2 × 10-8 to 2.9 × 10-5 S cm-1 by simply increasing the nitrogen content in the crystal lattice. Furthermore, computational calculation supports that the solid solution facilitates the band structure tuning. It is envisioned that the findings not only shed light on the ligand-dependent structure-property relationship but create new prospects in synthesizing multicomponent electrically conductive metal-organic frameworks (MOFs) for tailoring optoelectronic device applications.
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Cascade hydroxyl radical generating hydrogel reactor structures including a chemotherapeutic agent are invented for multiple treatment of breast cancer. Glucose oxidase (GOx) and cupric sulfate (Cu) are introduced for transforming accumulated glucose (in cancer cells) to hydroxyl radicals for starvation/chemodynamic therapy. Cu may also suppress cancer cell growth via cuproptosis-mediated cell death. Berberine hydrochloride (BER) is engaged as a chemotherapeutic agent in the hydrogel reactor for combining with starvation/chemodynamic/cuproptosis therapeutic modalities. Moreover, Cu is participated as a gel crosslinker by coordinating with catechol groups in hyaluronic acid-dopamine (HD) polymer. Controlling viscoelasticity of hydrogel reactor can extend the retention time following local injection and provide sustained drug release patterns. Low biodegradation rate of designed HD/BER/GOx/Cu hydrogel can reduce dosing frequency in local cancer therapy and avoid invasiveness-related inconveniences. Especially, it is anticipated that HD/BER/GOx/Cu hydrogel system can be applied for reducing size of breast cancer prior to surgery as well as tumor growth suppression in clinical application.
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Apoptose , Neoplasias da Mama , Neoplasias , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Catálise , Linhagem Celular Tumoral , Glucose Oxidase/metabolismo , Hidrogéis , Peróxido de Hidrogênio/química , Radical Hidroxila/química , Neoplasias/terapia , CobreRESUMO
PURPOSE: Radiation therapy (RT) has been associated with decreased health-related quality of life (HRQOL) in clinical trials of early-stage endometrial cancer (EC), but few studies have examined the association in real-world settings. We assessed HRQOL associated with adjuvant RT for older women with early-stage EC within a large U.S. population-based registry resource. METHODS: The Surveillance Epidemiology and End Results and the Medicare Health Outcomes Survey linkage (1998-2017) was used to identify women with early-stage EC aged ≥ 65 years at survey who received surgery and were diagnosed ≥ 1-year prior (n = 1,140). HRQOL was evaluated with the 36-item Short-Form Health Survey (SF-36) until 2006 and the Veterans RAND 12-Item Health Survey (VR-12) post 2006. Ordinary least squares regression was used to estimate mean difference (MD) in T scores and 95% confidence intervals (CIs) comparing treatment groups (surgery alone, adjuvant external beam radiation therapy [EBRT], or adjuvant vaginal brachytherapy [VBT]) after accounting for confounders using propensity score weighting. RESULTS: Overall, RT was not associated with physical health (MD = 0.97; 95% CI = - 1.13, 3.07) or mental health (MD = - 0.78; 95% CI = - 2.60, 1.05) relative to surgery alone. In analyses by RT type, adjuvant VBT was associated with better general health on the SF-36/VR-12 subscale (MD = 3.59; 95% CI = 0.56, 6.62) relative to surgery alone. No statistically significant associations were observed for adjuvant VBT and physical or mental health, or for adjuvant EBRT and any HRQOL domain. CONCLUSION: Older women with early-stage EC treated with adjuvant RT did not report worse physical and mental HRQOL scores compared to those treated with surgery alone, though relevant symptoms should be evaluated further to fully understand the disease and treatment specific aspects of the HRQOL.