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Cell membranes are primarily composed of lipids, membrane proteins, and carbohydrates, and the related studies of membrane components and structures at different stages of disease development, especially membrane proteins, are of great significance. Here, we investigate the chemical signature profiles of cell membranes as biomarkers for cancer cells via label-free surface-enhanced Raman scattering (SERS). A magnetic plasmonic nanoprobe was proposed by decorating magnetic beads with silver nanoparticles, allowing self-driven cell membrane-targeted accumulation within 5 min. SERS profiles of three types of breast cells were achieved under the plasmon enhancement effect of these nanoprobes. Membrane fingerprint spectra from breast cell lines were further classified with the convolutional neural network model, which perfectly distinguished between two breast cancer subtypes. We further tested various clinical samples using this method and obtained fingerprint spectra from primary cells and frozen slices. This study presents a practical, user-friendly approach for label-free and in situ analysis of cell membranes, which can work for early tumor screening and treatment assessment for tumors reliant on the Molecular profiles of cell membranes. Additionally, this method can be applied universally to explore cell membrane components of other cells, thus assisting Human Cell Atlas.
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Despite the pivotal role of stannum doping in achieving ultrahigh piezoelectric performance in barium titanate-based ceramics, the fundamental mechanisms underlying this enhancement remain elusive. Here, we introduce a single variable nonstoichiometric stannum strategy in lead-free barium titanate-based ceramics with giant piezoelectricity, revealing that stannum doping contributes intrinsically and extrinsically to enhance piezoelectricity. Density functional theory calculations elucidate the intrinsic enhancement of polarization arising from lattice distortion and increased space for titanium-oxygen bonds induced by optimal stannum doping, which is corroborated by Rayleigh analysis. A phase transition from ferroelectric multiphase coexistence to paraelectric phase is observed, alongside a rapid miniaturized and eventually disappeared domains with increasing stannum doping. This evolution in phase structure and domain configuration induces a nearly vanishing polarization anisotropy and low domain wall energy, facilitating easy polarization rotation and domain wall motion, thereby significantly contributing to the extrinsic piezoelectric response. Consequently, the origins of ultrahigh performance can be attributed to the synergistic effect of stannum-induced intrinsic and extrinsic contributions in barium titanate-based ceramics. This study provides fundamental insights into the role of doping elements and offers guidance for the design of high-performance piezoelectrics.
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OBJECTIVES: To determine the difference between orthodontic camouflage and orthodontic-orthognathic surgery using the traditional cephalometric measurement IMPA and the newly proposed IA/PAMD, the angle between the long axis of the lower incisor (IA) and the principal axis of the mandibular alveolus (PAMD). MATERIALS AND METHODS: This study included 40 cases each in the orthodontic camouflage group (OG) and orthodontic-orthognathic surgery group (SG). The differences between the IMPA and IA/PAMD before and after treatment were compared between the two groups. T0 lateral cephalometric images of the 10 cases with the highest and lowest increase in the IA/PAMD were analyzed to identify characteristics associated with a higher risk of overdecompensation of the lower incisors during presurgical orthodontic treatment. RESULTS: Both the OG and SG showed a significant improvement in hard- and soft-tissue measurements. However, in the OG, there was significant lingual inclination of the lower incisor but only a small change in the IA/PAMD. In the surgical group, the IMPA was close to 90° after treatment, but the IA/PAMD significantly increased. CONCLUSIONS: In orthodontic camouflage, the lower anterior teeth were significantly moved lingually with a better root-bone relationship. However, this relationship deteriorated in some surgical patients. Therefore, it is important to conduct cephalometric or cone-beam computed tomography examinations during preoperative orthodontics to identify and prevent possible periodontal risks.
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Cefalometría , Incisivo , Maloclusión de Angle Clase III , Procedimientos Quirúrgicos Ortognáticos , Humanos , Incisivo/diagnóstico por imagen , Cefalometría/métodos , Maloclusión de Angle Clase III/cirugía , Maloclusión de Angle Clase III/terapia , Maloclusión de Angle Clase III/diagnóstico por imagen , Femenino , Masculino , Procedimientos Quirúrgicos Ortognáticos/métodos , Mandíbula/cirugía , Mandíbula/diagnóstico por imagen , Adolescente , Adulto Joven , Ortodoncia Correctiva/métodos , AdultoRESUMEN
Histidine kinases (HKs) are important sensor proteins in fungi and play an essential role in environmental adaptation. However, the mechanisms by which fungi sense and respond to fungivores attack via HKs are not fully understood. In this study, we utilized Neurospora crassa to investigate the involvement of HKs in responding to fungivores attack. We found that the 11 HKs in N. crassa not only affected the growth and development, but also led to fluctuations in antioxidant production. Ten mutants in the genes encoding HKs (except ∆phy1) showed increased production of reactive oxygen species (ROS), especially upon Sinella curviseta attack. The ROS burst triggered changes in conidia and perithecial beaks formation, as well as accumulation of ß-glucan, ergothioneine, ergosterol, and carotenoids. ß-glucan was increased in ∆hk9, ∆os1, ∆hcp1, ∆nik2, ∆sln1, ∆phy1 and ∆phy2 mutants compared to the wild-type strain. In parallel, ergothioneine accumulation was improved in ∆phy1 and ∆hk16 mutants and further increased upon attack, except in ∆os1 and ∆hk16 mutants. Additionally, fungivores attack stimulated ergosterol and dehydroergosterol production in ∆hk9 and ∆os1 mutants. Furthermore, deletion of these genes altered carotenoid accumulation, with wild-type strain, ∆hk9, ∆os1, ∆hcp1, ∆sln1, ∆phy2, and ∆dcc1mutants showing an increase in carotenoids upon attack. Taken together, HKs are involved in regulating the production of conidia and antioxidants. Thus, HKs may act as sensors of fungivores attack and effectively improve the adaptive capacity of fungi to environmental stimuli.
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Histidina Quinasa , Neurospora crassa , Especies Reactivas de Oxígeno , Neurospora crassa/genética , Neurospora crassa/metabolismo , Histidina Quinasa/genética , Histidina Quinasa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Esporas Fúngicas/genética , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Animales , Regulación Fúngica de la Expresión Génica , Artrópodos/genética , Artrópodos/microbiología , Mutación , Adaptación Fisiológica/genética , Ergosterol/metabolismo , beta-Glucanos/metabolismo , Antioxidantes/metabolismo , Carotenoides/metabolismo , ErgotioneínaRESUMEN
Faced with worldwide mercury (Hg) contamination in groundwater, efficient in situ remediation technologies are urgently needed. Carboxymethyl cellulose (CMC) stabilized iron sulfide (CMC-FeS) nanoparticles have been found effective for immobilizing mercury in water and soil. Yet, the potential use of the nanoparticles for creating an in situ reactive zone (ISRZ) in porous geo-media has not been explored. This study assessed the transport and deliverability of CMC-FeS in sand media towards creating an ISRZ. The nanoparticles were deliverable through the saturated sand bed and the particle breakthrough/deposition profiles depended on the injection pore velocity, initial CMC-FeS concentration, and ionic strength. The transport data were well interpreted using an advection-dispersion transport model combined with the classical filtration theory. The resulting ISRZ effectively removed mercury from contaminated groundwater under typical subsurface conditions. While the operating conditions are yet to be optimized, the Hg breakthrough time can be affected by groundwater velocity, influent mercury concentration, dissolved organic matter, and co-existing metals/metalloids. The one-dimensional advection-dispersion equation well simulated the Hg breakthrough data. CMC-FeS-laden ISRZ effectively converted the more easily available Hg species to stable species. These findings reveal the potential of creating an ISRZ using CMC-FeS for in situ remediation of Hg contaminated soil and groundwater.
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Caveolin is a monotopic integral membrane protein, widely expressed in metazoa and responsible for constructing enigmatic membrane invaginations known as caveolae. Recently, the high-resolution structure of a purified human caveolin assembly, the CAV1-8S complex, revealed a unique organization of 11 protomers arranged in a tightly packed, radially symmetric spiral disc. One face and the outer rim of this disc are highly hydrophobic, suggesting that the complex incorporates into membranes by displacing hundreds of lipids from one leaflet. The feasibility of this unique molecular architecture and its biophysical and functional consequences are currently unknown. Using Langmuir film balance measurements, we find that CAV1-8S is highly surface active and intercalates into lipid monolayers. Molecular simulations of biomimetic bilayers support this 'leaflet replacement' model and reveal that while CAV1-8S effectively displaces phospholipids from one bilayer leaflet, it accumulates 40-70 cholesterol molecules into a disordered monolayer between the complex and its distal lipid leaflet. We find that CAV1-8S preferentially associates with positively curved membrane surfaces due to its influence on the conformations of distal leaflet lipids, and that these effects laterally sort lipids of the distal leaflet. Large-scale simulations of multiple caveolin assemblies confirmed their association with large, positively curved membrane morphologies, consistent with the shape of caveolae. Further, association with curved membranes regulates the exposure of caveolin residues implicated in protein-protein interactions. Altogether, the unique structure of CAV1-8S imparts unusual modes of membrane interaction with implications for membrane organization, morphology, and physiology. STATEMENT OF SIGNIFICANCE: Caveolae are membrane invaginations heavily implicated in cellular physiology and disease; however, how their unique shape and function are produced remains enigmatic. Here, following on recent characterization of the unusual structure of the CAV1-8S oligomer, we examine the molecular details of its interactions with its solvating lipid membrane. We describe a novel mode of membrane interaction-which we term 'leaflet replacement'-for the CAV1-8S complex that has not previously been observed for any other protein. The biophysical consequences of this unique molecular organization provide mechanistic insights into the functions and organization of caveolae in cells.
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Aim: To investigate the association of DNA methylation, genetic polymorphisms and mRNA level of aminolevulinate synthase 1 (ALAS1) with antituberculosis drug-induced liver injury (AT-DILI) risk.Methods: Based on a 1:1 matched case-control study with 182 cases and 182 controls, one CpG island and three single nucleotide polymorphisms (SNPs) were detected. ALAS1 mRNA level was detected in 34 samples.Results: Patients with methylation status were at high risk of AT-DILI (odds ratio: 1.567, 95% CI: 1.015-2.421, p = 0.043) and SNP rs352169 was associated with AT-DILI risk (GA vs. GG, odds ratio: 1.770, 95% CI: 1.101-2.847, p = 0.019). ALAS1 mRNA level in the cases was significantly lower than that in the controls (0.75 ± 0.34 vs. 1.00 ± 0.42, p = 0.021).Conclusion: The methylation status and SNP rs352169 of ALAS1 were associated with AT-DILI risk.
[Box: see text].
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BACKGROUND: Renal denervation (RDN) can lower blood pressure (BP) in patients with hypertension in both the presence and absence of medication. This is the first sham-controlled trial investigating the safety and efficacy of RDN in China. METHODS: This prospective, multicenter, randomized, patient- and outcome-assessor-blinded, sham-controlled trial investigated radiofrequency RDN in patients with hypertension on standardized triple antihypertensive therapy. Eligible patients were randomized 1:1 to undergo RDN using a multi-electrode radiofrequency catheter (Iberis; AngioCare, Shanghai, China) or a sham procedure. The primary efficacy outcome was the between-group difference in baseline-adjusted change in mean 24-hour ambulatory systolic BP from randomization to 6 months. RESULTS: Of 217 randomized patients (mean age, 45.3±10.2 years; 21% female), 107 were randomized to RDN and 110 were randomized to sham control. At 6 months, there was a greater reduction in 24-hour systolic BP in the RDN (-13.0±12.1 mm Hg) compared with the sham control group (-3.0±13.0 mm Hg; baseline-adjusted between-group difference, -9.4 mm Hg [95% CI, -12.8 to -5.9]; P<0.001). Compared with sham, 24-hour diastolic BP was lowered by -5.0 mm Hg ([95% CI, -7.5 to -2.4]; P<0.001) 6 months after RDN, and office systolic and diastolic BP was lowered by -6.4 mm Hg ([95% CI, -10.5 to -2.3]; P=0.003) and -5.1 mm Hg ([95% CI, -8.2 to -2.0]; P=0.001), respectively. One patient in the RDN group experienced an access site complication (hematoma), which resolved without sequelae. No other major device- or procedure-related safety events occurred through follow-up. CONCLUSIONS: In this trial of Chinese patients with uncontrolled hypertension on a standardized triple pharmacotherapy, RDN was safe and reduced ambulatory and office BP at 6 months compared with sham. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02901704.
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OBJECTIVE: The purpose was to investigate the risk factors for delayed upper gastrointestinal transit (DUGT) in small bowel capsule endoscopy (SBCE) and to improve the efficacy of SBCE. METHODS: The medical records of patients who underwent SBCE in Renji hospital between January 2015 and January 2023 were retrospectively reviewed. Data collection included patient demographics and potential risk factors for DUGT such as indications for the examination, underlying diseases, hospitalization status, anemia, inflammation. Risk factors were analyzed using univariable and multivariable logistic regression models. DUGT was defined as failure of a capsule to pass through the pylorus within 1 h. RESULTS: A total of 1459 patients who underwent SBCE were included in the study. 306 Cases (21%) experienced DUGT and all received conservative observation, medication treatment, endoscopic intervention, and other measures based on specific circumstances. The overall completion rate (CR) of the examination was 95.5% (1394/1459). Logistic regression analysis showed that hospitalization status (p = 0.030), diarrhea (p = 0.017), diabetes (p = 0.027) and cerebrovascular disease (p = 0.038) were significant risk factors for DUGT. CONCLUSIONS: In our study, DUGT of SBCE was associated with hospitalization status, diarrhea, diabetes and cerebrovascular disease. Therefore, for the patients with the above risk factors, we should closely check the capsule status during the examination process, in order to take appropriate intervention measures as soon as possible.
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Drought is a major abiotic stress affecting crop yields. Mapping quantitative trait loci (QTLs) and mining genes for drought tolerance in rice are important for identifying gene functions and targets for molecular breeding. Here, we performed linkage analysis of drought tolerance using a recombinant inbred line population derived from Jileng 1 (drought sensitive) and Milyang 23 (drought tolerant). An ultra-high-density genetic map, previously constructed by our research team using genotype data from whole-genome sequencing, was used in combination with phenotypic data for rice grown under drought stress conditions in the field in 2017-2019. Thirty-nine QTLs related to leaf rolling index and leaf withering degree were identified, and QTLs were found on all chromosomes except chromosomes 6, 10, and 11. qLWD4-1 was detected after 32 days and 46 days of drought stress in 2017 and explained 7.07-8.19% of the phenotypic variation. Two loci, qLRI2-2 and qLWD4-2, were identified after 29, 42, and 57 days of drought stress in 2018. These loci explained 10.59-17.04% and 5.14-5.71% of the phenotypic variation, respectively. There were 281 genes within the QTL interval. Through gene functional annotation and expression analysis, two candidate genes, Os04g0574600 and OsCHR731, were found. Quantitative reverse transcription PCR analysis showed that the expression levels of these genes were significantly higher under drought stress than under normal conditions, indicating positive regulation. Notably, Os04g0574600 was a newly discovered drought tolerance gene. Haplotype analysis showed that the RIL population carried two haplotypes (Hap1 and Hap2) of both genes. Lines carrying Hap2 exhibited significantly or extremely stronger drought tolerance than those carrying Hap1, indicating that Hap2 is an excellent haplotype. Among rice germplasm resources, there were two and three haplotypes of Os04g0574600 and OsCHR731, respectively. A high proportion of local rice resources in Sichuan, Yunnan, Anhui, Guangdong and Fujian provinces had Hap of both genes. In wild rice, 50% of accessions contained Hap1 of Os04g0574600 and 50% carried Hap4; 13.51%, 59.46% and 27.03% of wild rice accessions contained Hap1, Hap2, and Hap3, respectively. Hap2 of Os04g0574600 was found in more indica rice resources than in japonica rice. Therefore, Hap2 has more potential for utilization in future drought tolerance breeding of japonica rice.
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With the gradual rise of the supply chain financial model and the expansion of scale, credit risk and contagion effects are gradually strengthened as business and financial links between upstream and downstream enterprises in the supply chain. The traditional credit risk contagion assessment model based on the financial status of an enterprise and the pledging of fixed assets has been unable to meet the basic needs of modern supply chain companies and financial institutions for risk control. Therefore, this paper introduces the Cox-Copula model to comprehensively assess a company's financial situation and the business health of upstream and downstream companies in the supply chain from the perspective of actual transactions between companies and fixed asset pledges. The study found that credit risk has a contagion effect in supply chain enterprises, and this contagion effect of credit risk has certain dynamic characteristics. At the same time, it was found that the impacts of macroeconomic factors and microfinance factors on credit risk contagion of supply chain finance have differences in the two dimensions of degree and direction of action.
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Comercio , Modelos Económicos , Comercio/economía , Administración Financiera , HumanosRESUMEN
Advanced periodontitis poses a significant threat to oral health, causing extensive damage and loss of both hard and soft periodontal tissues. While traditional therapies such as scaling and root planing can effectively halt the disease's progression, they often fail to fully restore the original architecture and function of periodontal tissues due to the limited capacity for spontaneous regeneration. To address this challenge, periodontal tissue engineering has emerged as a promising approach. This technology centers on the utilization of biomaterial scaffolds, which function as three-dimensional (3D) templates or frameworks, supporting and guiding the regeneration of periodontal tissues, including the periodontal ligament, cementum, alveolar bone, and gingival tissue. These scaffolds mimic the extracellular matrix (ECM) of native periodontal tissues, aiming to foster cell attachment, proliferation, differentiation, and, ultimately, the formation of new, functional periodontal structures. Despite the inherent challenges associated with preclinical testing, the intensification of research on biomaterial scaffolds, coupled with the continuous advancement of fabrication technology, leads us to anticipate a significant expansion in their application for periodontal tissue regeneration. This review comprehensively covers the recent advancements in biomaterial scaffolds engineered specifically for periodontal tissue regeneration, aiming to provide insights into the current state of the field and potential directions for future research.
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Eltrombopag combined with immunosuppressive therapy (IST) was superior to IST alone for severe aplastic anemia (SAA) in the previous studies. But in China, horse antithymocyte globulin (hATG) is not available, instead, we use rabbit ATG (rATG). Here, we compared the efficacy and safety of IST (rATG combined with cyclosporine) combined with or without eltrombopag for the first-line treatment of SAA and very severe aplastic anemia (VSAA). A total of 371 patients in ten institutions in China from April 1, 2017 to December 1, 2022 were enrolled. The overall response (OR) rate at 3 months (54.2% vs. 41%; P = 0.046), the complete response (CR) (31.3% vs. 19.4%; P = 0.041) and OR (78.3% vs. 51.1%; P < 0.0001) rates at 6 months were significantly higher with IST combined with eltrombopag than with IST alone in SAA patients. While in VSAA patients, the addition of eltrombopag to IST only increased the CR rate at 6 months (29.8% vs. 9.43%; P = 0.010). Liver injury increased significantly in groups treated with IST combined with eltrombopag (P < 0.05). Serious treatment-related toxicities were similar (P > 0.05). In patients with SAA, 3-year failure-free survival (FFS) of eltrombopag combined with IST group was significantly higher than that of IST group (70.7 ± 5.3% vs. 50.3 ± 3.9%; P = 0.007). In patients with VSAA, the addition of eltrombopag significantly improved 3-year overall survival (OS) (82.2 ± 5.7% vs. 57.3 ± 7.2%; P = 0.020). Our findings suggested that IST combined with eltrombopag could improve the hematological recovery of newly diagnosed SAA without increasing severe toxicities. But in VSAA, the addition of eltrombopag seemed to show no other improvement to efficacy except the CR rate at 6 months.
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Anemia Aplásica , Suero Antilinfocítico , Benzoatos , Hidrazinas , Inmunosupresores , Pirazoles , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/mortalidad , Benzoatos/uso terapéutico , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Humanos , Hidrazinas/uso terapéutico , Hidrazinas/administración & dosificación , Hidrazinas/efectos adversos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Adolescente , Inmunosupresores/uso terapéutico , Suero Antilinfocítico/uso terapéutico , Suero Antilinfocítico/administración & dosificación , Adulto Joven , Anciano , Estudios Retrospectivos , Quimioterapia Combinada , Niño , Resultado del Tratamiento , Índice de Severidad de la Enfermedad , Preescolar , Ciclosporina/uso terapéutico , Ciclosporina/administración & dosificación , China/epidemiología , Tasa de SupervivenciaRESUMEN
BACKGROUND: The determining effect of facial hard tissues on soft tissue morphology in orthodontic patients has yet to be explained. The aim of this study was to clarify the hard-soft tissue relationships of the lower 1/3 of the face in skeletal Class II-hyperdivergent patients compared with those in Class I-normodivergent patients using network analysis. METHODS: Fifty-two adult patients (42 females, 10 males; age, 26.58 ± 5.80 years) were divided into two groups: Group 1, 25 subjects, skeletal Class I normodivergent pattern with straight profile; Group 2, 27 subjects, skeletal Class II hyperdivergent pattern with convex profile. Pretreatment cone-beam computed tomography and three-dimensional facial scans were taken and superimposed, on which landmarks were identified manually, and their coordinate values were used for network analysis. RESULTS: (1) In sagittal direction, Group 2 correlations were generally weaker than Group 1. In both the vertical and sagittal directions of Group 1, the most influential hard tissue landmarks to soft tissues were located between the level of cemento-enamel junction of upper teeth and root apex of lower teeth. In Group 2, the hard tissue landmarks with the greatest influence in vertical direction were distributed more forward and downward than in Group 1. (2) In Group 1, all the correlations for vertical-hard tissue to sagittal-soft tissue position and sagittal-hard tissue to vertical-soft tissue position were positive. However, Group 2 correlations between vertical-hard tissue and sagittal-soft tissue positions were mostly negative. Between sagittal-hard tissue and vertical-soft tissue positions, Group 2 correlations were negative for mandible, and were positive for maxilla and teeth. CONCLUSION: Compared with Class I normodivergent patients with straight profile, Class II hyperdivergent patients with convex profile had more variations in soft tissue morphology in sagittal direction. In vertical direction, the most relevant hard tissue landmarks on which soft tissue predictions should be based were distributed more forward and downward in Class II hyperdivergent patients with convex profile. Class II hyperdivergent pattern with convex profile was an imbalanced phenotype concerning sagittal and vertical positions of maxillofacial hard and soft tissues.
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Puntos Anatómicos de Referencia , Cefalometría , Tomografía Computarizada de Haz Cónico , Cara , Imagenología Tridimensional , Maloclusión Clase II de Angle , Maloclusión Clase I de Angle , Mandíbula , Humanos , Masculino , Femenino , Adulto , Maloclusión Clase II de Angle/diagnóstico por imagen , Maloclusión Clase II de Angle/patología , Cefalometría/métodos , Imagenología Tridimensional/métodos , Cara/anatomía & histología , Cara/diagnóstico por imagen , Maloclusión Clase I de Angle/diagnóstico por imagen , Maloclusión Clase I de Angle/patología , Mandíbula/diagnóstico por imagen , Mandíbula/patología , Adulto Joven , Maxilar/diagnóstico por imagen , Maxilar/patología , Mentón/diagnóstico por imagen , Mentón/anatomía & histología , Mentón/patología , Incisivo/diagnóstico por imagen , Incisivo/anatomía & histología , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
Microsporidia are intracellular eukaryotic pathogens that pose a substantial threat to immunocompromised hosts. The way these pathogens manipulate host cells during infection remains poorly understood. Using a proximity biotinylation strategy we established that microsporidian EnP1 is a nucleus-targeted effector that modifies the host cell environment. EnP1's translocation to the host nucleus is meditated by nuclear localization signals (NLSs). In the nucleus, EnP1 interacts with host histone H2B. This interaction disrupts H2B monoubiquitination (H2Bub), subsequently impacting p53 expression. Crucially, this inhibition of p53 weakens its control over the downstream target gene SLC7A11, enhancing the host cell's resilience against ferroptosis during microsporidian infection. This favorable condition promotes the proliferation of microsporidia within the host cell. These findings shed light on the molecular mechanisms by which microsporidia modify their host cells to facilitate their survival.
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Ferroptosis , Histonas , Microsporidios , Ubiquitinación , Microsporidios/metabolismo , Microsporidios/genética , Histonas/metabolismo , Humanos , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Interacciones Huésped-Patógeno , Animales , Núcleo Celular/metabolismo , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Microsporidiosis/metabolismoRESUMEN
BACKGROUND: Food insecurity and HIV-related stigma negatively affect HIV outcomes. Few studies have examined how food security interventions affect HIV-related stigma and social support. SETTING: Two HIV clinics in the Dominican Republic. METHODS: A pilot cluster randomized controlled trial of an urban gardens and peer nutritional counseling intervention was conducted to examine outcomes of HIV-related stigmas and social support. Adult patients (≥18 years of age) with moderate or severe household food insecurity and evidence of suboptimal ART adherence and/or a detectable viral load were enrolled; standard measures of internalized and experienced stigmas and social support were collected at baseline and at 6 and 12 months. Intervention clinic participants received training and materials from agronomists for a home garden, 3-4 sessions of nutritional counseling from the clinic's peer counselor, and a garden produce cooking workshop facilitated by professional nutritionists. RESULTS: Of 109 study participants (46 intervention and 63 control), 103 (94%) completed 12-month follow-up. Difference-in-differences multivariate longitudinal linear regressions adjusting for sociodemographic factors found that intervention participants had reduced internalized stigma by 3.04 points (scale 0-32) at 12 months (P = 0.002); reduced probability of experiencing HIV-related stigma or discrimination in the past 6 months (20 percentage points at 6 months, P = 0.05 and 25 percentage points at 12 months, P = 0.02); and modestly improved social support at 12 months (1.85 points on 30-pt scale, P = 0.093). CONCLUSION: A fully powered, larger trial is needed to establish the efficacy of the intervention and assess pathways by which the intervention may improve HIV stigma and social support.
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Consejo , Inseguridad Alimentaria , Infecciones por VIH , Estigma Social , Apoyo Social , Humanos , Infecciones por VIH/psicología , Infecciones por VIH/prevención & control , Masculino , Femenino , República Dominicana , Adulto , Persona de Mediana Edad , Jardines , Grupo Paritario , Población Urbana , Proyectos PilotoRESUMEN
The precise assessment of vascular heterogeneity in brain tumors is vital for diagnosing, grading, predicting progression, and guiding treatment decisions. However, currently, there is a significant shortage of high-resolution imaging approaches. Herein, we propose a contrast-enhanced susceptibility-weighted imaging (CE-SWI) utilizing the minimalist dextran-modified Fe3O4 nanoparticles (Dextran@Fe3O4 NPs) for ultrahigh-resolution mapping of vasculature in brain tumors. The Dextran@Fe3O4 NPs are prepared via a facile coprecipitation method under room temperature, and exhibit small hydrodynamic size (28 nm), good solubility, excellent biocompatibility, and high transverse relaxivity (r2*, 159.7 mM-1 s-1) under 9.4 T magnetic field. The Dextran@Fe3O4 NPs-enhanced SWI can increase the contrast-to-noise ratio (CNR) of cerebral vessels to 2.5 times that before injection and achieves ultrahigh-spatial-resolution visualization of microvessels as small as 0.1 mm in diameter. This advanced imaging capability not only allows for the detailed mapping of both enlarged peritumoral drainage vessels and the intratumoral microvessels, but also facilitates the sensitive imaging detection of vascular permeability deterioration in a C6 cells-bearing rat glioblastoma model. Our proposed Dextran@Fe3O4 NPs-enhanced SWI provides a powerful imaging technique with great clinical translation potential for the precise theranostics of brain tumors.
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Neoplasias Encefálicas , Dextranos , Imagen por Resonancia Magnética , Nanopartículas de Magnetita , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Animales , Imagen por Resonancia Magnética/métodos , Nanopartículas de Magnetita/química , Dextranos/química , Ratas , Medios de Contraste/química , Humanos , Línea Celular Tumoral , Tamaño de la PartículaRESUMEN
Histone lysine methyltransferase 2D (KMT2D) is the most frequently mutated epigenetic modifier in head and neck squamous cell carcinoma (HNSCC). However, the role of KMT2D in HNSCC tumorigenesis and whether its mutations confer any therapeutic vulnerabilities remain unknown. Here we show that KMT2D deficiency promotes HNSCC growth through increasing glycolysis. Additionally, KMT2D loss decreases the expression of Fanconi Anemia (FA)/BRCA pathway genes under glycolytic inhibition. Mechanistically, glycolytic inhibition facilitates the occupancy of KMT2D to the promoter/enhancer regions of FA genes. KMT2D loss reprograms the epigenomic landscapes of FA genes by transiting their promoter/enhancer states from active to inactive under glycolytic inhibition. Therefore, combining the glycolysis inhibitor 2-DG with DNA crosslinking agents or poly (ADP-ribose) polymerase (PARP) inhibitors preferentially inhibits tumor growth of KMT2D-deficient mouse HNSCC and patient-derived xenografts (PDXs) harboring KMT2D-inactivating mutations. These findings provide an epigenomic basis for developing targeted therapies for HNSCC patients with KMT2D-inactivating mutations.
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Glucólisis , Carcinoma de Células Escamosas de Cabeza y Cuello , Animales , Humanos , Ratones , Glucólisis/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteína BRCA1/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/deficiencia , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Proteína BRCA2/deficiencia , N-Metiltransferasa de Histona-Lisina/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Regulación Neoplásica de la Expresión Génica , Ensayos Antitumor por Modelo de Xenoinjerto , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Femenino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transducción de Señal , Regiones Promotoras Genéticas/genética , Proteína de la Leucemia Mieloide-LinfoideRESUMEN
BACKGROUND: Medication-related osteonecrosis of the Jaw (MRONJ) is a rare but severe side effect in patients treated with medications such as Bisphosphonates (BPs). Its pathophysiological mechanism needs to be more precise. Establishing preventive measures and treatment standards is necessary. This study aimed to develop a composite hydrogel scaffold constituted by methacrylated gelatin (GelMA), methacrylated heparin (HepMA) and PRF, and investigate its potential application value in the prevention of MRONJ. METHODS: GelMA, HepMA, and PRF were prepared using specific ratios for hydrogel scaffolds. Through mechanical properties and biocompatibility analysis, the release rate of growth factors and the ability to promote bone differentiation in vitro were evaluated. To explore the healing-enhancing effects of hydrogels in vivo, the composite hydrogel scaffold was implanted to the MRONJ rat model. Micro-computed tomography (Micro-CT) and histological examination were conducted to evaluate the bone morphology and tissue regeneration. RESULTS: The Hep/GelMA-PRF hydrogel improved the degradation rate and swelling rate. It was also used to control the release rate of growth factors effectively. In vitro, the Hep/GelMA-PRF hydrogel was biocompatible and capable of reversing the inhibitory effect of zoledronic acid (ZOL) on the osteogenic differentiation of MC3T3-E1s. In vivo, the micro-CT analysis and histological evaluation demonstrated that the Hep/GelMA-PRF group exhibited the best tissue reconstruction. Moreover, compared to the ZOL group, the expression of osteogenesis proteins, including osteocalcin (OCN), type collagen I (Col I), and bone morphogenetic protein-2 (BMP-2) in the Hep/GelMA-PRF group were all significantly upregulated (P < 0.05). CONCLUSIONS: The Hep/GelMA-PRF hydrogel scaffold could effectively control the release rate of growth factors, induce osteogenic differentiation, reduce inflammation, and keep a stable microenvironment for tissue repair. It has potential application value in the prevention of MRONJ.
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Osteonecrosis de los Maxilares Asociada a Difosfonatos , Gelatina , Heparina , Hidrogeles , Andamios del Tejido , Animales , Hidrogeles/uso terapéutico , Ratas , Osteonecrosis de los Maxilares Asociada a Difosfonatos/prevención & control , Fibrina Rica en Plaquetas , Microtomografía por Rayos X , Metacrilatos/química , Ratones , Ratas Sprague-Dawley , Diferenciación Celular/efectos de los fármacos , Masculino , Regeneración Ósea/efectos de los fármacos , Ácido Zoledrónico/uso terapéutico , Osteogénesis/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
Propylthiouracil (PTU) and methimazole (MMI), two classical antithyroid agents possess risk of drug-induced liver injury (DILI) with unknown mechanism of action. This study aimed to examine and compare their hepatic toxicity using a quantitative system toxicology approach. The impact of PTU and MMI on hepatocyte survival, oxidative stress, mitochondrial function and bile acid transporters were assessed in vitro. The physiologically based pharmacokinetic (PBPK) models of PTU and MMI were constructed while their risk of DILI was calculated by DILIsym, a quantitative systems toxicology (QST) model by integrating the results from in vitro toxicological studies and PBPK models. The simulated DILI (ALT >2 × ULN) incidence for PTU (300 mg/d) was 21.2%, which was within the range observed in clinical practice. Moreover, a threshold dose of 200 mg/d was predicted with oxidative stress proposed as an important toxic mechanism. However, DILIsym predicted a 0% incidence of hepatoxicity caused by MMI (30 mg/d), suggesting that the toxicity of MMI was not mediated through mechanism incorporated into DILIsym. In conclusion, DILIsym appears to be a practical tool to unveil hepatoxicity mechanism and predict clinical risk of DILI.