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Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP10-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP10-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP10-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.
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Inibidores de Checkpoint Imunológico/uso terapêutico , Imunidade , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Nanotecnologia , Acetilmuramil-Alanil-Isoglutamina/metabolismo , Animais , Comportamento Animal , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Proliferação de Células/efeitos dos fármacos , Colesterol/metabolismo , Feminino , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Imunidade/efeitos dos fármacos , Imunoterapia , Lipoproteínas HDL/metabolismo , Camundongos Endogâmicos C57BL , Primatas , Distribuição Tecidual/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacosRESUMO
ConspectusElectrides make up a fascinating group of materials with unique physical and chemical properties. In these materials, excess electrons do not behave like normal electrons in metals or form any chemical bonds with atoms. Instead, they "float" freely in the gaps within the material's structure, acting like negatively charged particles called anions (see the graph). Recently, there has been a surge of interest in van der Waals (vdW) electrides or electrenes in two dimensions. A typical example is layered lanthanum bromide (LaBr2), which can be taken as [La3+(Br1-)2]+â¢(e-). Each excess free electron is trapped within a hexagonal pore, forming dense dots of electron density. These anionic electrons are loosely bound, giving vdW electrides some unique properties such as ferromagnetism, superconductivity, topological features, and Dirac plasmons. The high density of the free electron makes electrides very promising for applications in thermionic emission, organic light-emitting diodes, and high-performance catalysts.In this Account, we first discuss the discovery of numerous vdW electrides through high-throughput computational screening of over 67,000 known inorganic crystals in Materials Project. A dozen of them have been newly discovered and have not been reported before. Importantly, they possess completely different structural prototypes and properties of anionic electrons compared to widely studied electrides such as Ca2N. Finding these new vdW electrides expands the variety of electrides that can be made in the experiment and opens up new possibilities for studying their unique properties and applications.Then, based on the screened vdW electrides, we delve into their various emerging properties. For example, we developed a new magnetic mechanism specific to atomic-orbital-free ferromagnetism in electrides. We uncover the dual localized and extended nature of the anionic electrons in such electrides and demonstrate the formation of the local moment by the localized feature and the ferromagnetic interaction by the direct overlapping of their extended states. We further show the effective tuning of the magnetic properties of vdW electrides by engineering their structural, electronic, and compositional properties. Besides, we show that the complex interaction between the multiple quantum orderings in vdW electrides leads to many interesting properties including valley polarization, charge density waves, a topological property, a superconducting property, and a thermoelectrical property.Moreover, we discuss strategies to leverage the unique intrinsic properties of vdW electrides for practical applications. We show that these properties make vdW electrides potential candidates for advanced applications such as spin-orbit torque memory devices, valleytronic devices, K-ion batteries, and thermoelectricity. Finally, we discuss the current challenges and future perspectives for research using these emerging materials.
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Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer, and the early detection and diagnosis of this disease are crucial in reducing mortality rates. The timely diagnosis of LUAD is essential for controlling tumour development and enabling early surgical treatment. GPR56 is a vital G protein-coupled receptor and its role in T lymphocytes has received considerable attention. However, its function in B cells remains unclear. This study aimed to investigate the significance of GPR56 in LUAD. We found that GPR56 exhibited a significant increase in circulating plasmablasts and a decrease in new memory B cells. GPR56 expression in B cells was significantly reduced after LPS stimulation and the proportion of HLA-DR+ and CD40+ proportions were also decreased in GPR56+ B cells after stimulation. Additionally, GPR56 exhibited significant down-regulation in circulating B cell subsets of early-stage LUAD patients, and there were significant correlations between GPR56+ B cell subsets and tumour markers. In conclusion, GPR56 could reflect the hypoactivation state of B cells and the decreased proportion of GPR56+ B cell subset in LUAD patients can signify the active humoral immunity in vivo. The expression of GPR56 in B cells could potentially hold value in the early diagnosis of LUAD.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Receptores Acoplados a Proteínas G , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Ativação Linfocitária , Regulação para Baixo , Estadiamento de Neoplasias , Imunidade Humoral , Biomarcadores Tumorais/metabolismoRESUMO
Rechargeable aqueous zinc-ion batteries are practically plagued by the short lifespan and low Coulombic efficiency (CE) of Zn anodes resulting from random dendrite deposition and parasitic reactions. Herein, the host-guest chemistry of cucurbituril additive with Zn2+ to achieve longstanding Zn anodes is manipulated. The macrocyclic molecule of cucurbit[5]uril (CB[5]) is delicately designed to reconstruct both the CB[5]-adsorbed electric-double layer (EDL) structure at the Zn interface and the hydrated sheath of Zn2+ ions. Especially benefiting from the desirable carbonyl rims and suitable hydrophobic cavities, the CB[5] has a strong host-guest interaction with Zn2+ ions, which exclusively permits rapid Zn2+ flux across the EDL interface but retards the H2O radicals and SO4 2-. Accordingly, such a unique particle redistributor warrants long-lasting dendrite-free deposition by homogenizing Zn nucleation/growth and significantly improved CE by inhibiting side reactions. The Zn anode can deliver superior reversibility in CB[5]-containing electrolyte with a ninefold increase of cycle lifetime and an elevated CE of 99.7% under harsh test conditions (10 mA cm-2/10 mA h cm-2). The work opens a new avenue from the perspective of host-guest chemistry to propel the development of rechargeable Zn metal batteries and beyond.
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Given the insidious and high-fatality nature of cardiovascular diseases (CVDs), the emergence of fluoride as a newly identified risk factor demands serious consideration alongside traditional risk factors. While vascular smooth muscle cells (VSMCs) play a pivotal role in the progression of CVDs, the toxicological impact of fluoride on VSMCs remains largely uncharted. In this study, we constructed fluorosis model in SD rats and A7R5 aortic smooth muscle cell lines to confirm fluoride impaired VSMCs. Fluoride aggravated the pathological damage of rat aorta in vivo. Then A7R5 were exposed to fluoride with concentration ranging from 0 to 1200 µmol/L over a 24-h period, revealing a dose-dependent inhibition of cell proliferation and migration. The further metabolomic analysis showed alterations in metabolite profiles induced by fluoride exposure, notably decreasing organic acids and lipid molecules level. Additionally, gene network analysis underscored the frequency of fluoride's interference with amino acids metabolism, potentially impacting the tricarboxylic acid (TCA) cycle. Our results also highlighted the ATP-binding cassette (ABC) transporters pathway as a central element in VSMC impairment. Moreover, we observed a dose-dependent increase in osteopontin (OPN) and α-smooth muscle actin (α-SMA) mRNA level and a dose-dependent decrease in ABC subfamily C member 1 (ABCC1) and bestrophin 1 (BEST1) mRNA level. These findings advance our understanding of fluoride as a CVD risk factor and its influence on VSMCs and metabolic pathways, warranting further investigation into this emerging risk factor.
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Aminoácidos , Proliferação de Células , Fluoretos , Músculo Liso Vascular , Ratos Sprague-Dawley , Animais , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/efeitos dos fármacos , Fluoretos/farmacologia , Linhagem Celular , Aminoácidos/metabolismo , Proliferação de Células/efeitos dos fármacos , Ratos , Movimento Celular/efeitos dos fármacos , Masculino , Aorta/patologia , Aorta/efeitos dos fármacos , Aorta/metabolismo , Metabolômica , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Redes Reguladoras de Genes/efeitos dos fármacosRESUMO
BACKGROUND: Postpartum women often experience stress urinary incontinence (SUI) and vaginal microbial dysbiosis, which seriously affect women's physical and mental health. Understanding the relationship between SUI and vaginal microbiota composition may help to prevent vaginal diseases, but research on the potential association between these conditions is limited. RESULTS: This study employed 16S rRNA gene sequencing to explore the association between SUI and vaginal dysbiosis. In terms of the vaginal microbiota, both species richness and evenness were significantly higher in the SUI group. Additionally, the results of NMDS and species composition indicated that there were differences in the composition of the vaginal microbiota between the two groups. Specifically, compared to postpartum women without SUI (Non-SUI), the relative abundance of bacteria associated with bacterial dysbiosis, such as Streptococcus, Prevotella, Dialister, and Veillonella, showed an increase, while the relative abundance of Lactobacillus decreased in SUI patients. Furthermore, the vaginal microbial co-occurrence network of SUI patients displayed higher connectivity, complexity, and clustering. CONCLUSION: The study highlights the role of Lactobacillus in maintaining vaginal microbial homeostasis. It found a correlation between SUI and vaginal microbiota, indicating an increased risk of vaginal dysbiosis. The findings could enhance our understanding of the relationship between SUI and vaginal dysbiosis in postpartum women, providing valuable insights for preventing bacterial vaginal diseases and improving women's health.
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Microbiota , Incontinência Urinária por Estresse , Doenças Vaginais , Feminino , Humanos , Incontinência Urinária por Estresse/etiologia , Disbiose/microbiologia , RNA Ribossômico 16S/genética , Vagina/microbiologia , Microbiota/genética , Lactobacillus/genética , Bactérias/genética , Doenças Vaginais/complicaçõesRESUMO
The implementation of microstructured optical fibers (MOFs) with novel micro-structures and perfect performance is challenging due to the complex fabrication processes. Physics-informed neural networks (PINNs) offer what we believe to be a new approach to solving complex partial differential equations within the virtual fabrication model of MOFs. This study, for what appears to be the first time, integrates the complex partial differential equations and boundary conditions describing the fiber drawing process into the loss function of a neural network. To more accurately solve the free boundary of the fiber's inner and outer diameters, we additionally construct a neural network to describe the free boundary conditions. This model not only captures the evolution of the fiber's inner and outer diameters but also provides the velocity distribution and pressure distribution within the molten glass, thus laying the foundation for a quantitative analysis of capillary collapse. Furthermore, results indicate that the trends in the effects of temperature, feed speed, and draw speed on the fiber drawing process align with actual fabrication conditions, validating the feasibility of the model. The methodology proposed in this study offers what we believe to be a novel approach to simulating the fiber drawing process and holds promise for advancing the practical applications of MOFs.
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Sleep and related disorders could lead to changes in various brain networks, but little is known about the role of amyloid ß (Aß) burden-a key Alzheimer's disease (AD) biomarker-in the relationship between sleep disturbance and altered resting state functional connectivity (rsFC) in older adults. This cross-sectional study examined the association between sleep disturbance, Aß burden, and rsFC using a large-scale dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sample included 489 individuals (53.6% cognitively normal, 32.5% mild cognitive impairment, and 13.9% AD) who had completed sleep measures (Neuropsychiatric Inventory), PET Aß data, and resting-state fMRI scans at baseline. Within and between rsFC of the Salience (SN), the Default Mode (DMN) and the Frontal Parietal network (FPN) were compared between participants with sleep disturbance versus without sleep disturbance. The interaction between Aß positivity and sleep disturbance was evaluated using the linear regressions, controlling for age, diagnosis status, gender, sedatives and hypnotics use, and hypertension. Although no significant main effect of sleep disturbance was found on rsFC, a significant interaction term emerged between sleep disturbance and Aß burden on rsFC of SN (ß = 0.11, P = 0.006). Specifically, sleep disturbance was associated with SN hyperconnectivity, only with the presence of Aß burden. Sleep disturbance may lead to altered connectivity in the SN when Aß is accumulated in the brain. Individuals with AD pathology may be at increased risk for sleep-related aberrant rsFC; therefore, identifying and treating sleep problems in these individuals may help prevent further disease progression.
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Doença de Alzheimer , Transtornos do Sono-Vigília , Humanos , Idoso , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Estudos Transversais , Encéfalo/metabolismo , Imageamento por Ressonância Magnética , SonoRESUMO
Metal-organic frameworks (MOFs) based on tin (Sn) have shown great potential as materials for lithium storage, thanks to their ability to alleviate volume expansion due to the homogeneous distribution of Sn in a porous matrix framework. However, the weak mechanical strength of the porous Sn-MOF structure has been a major challenge, leading to pulverization during the discharging/charging process. To overcome this issue, we have developed a feasible strategy to strengthen the Sn-MOF mechanical properties by incorporating SiO2/GeO2 nanoparticles during the synthesis process. The resulting composites of Sn-Si and Sn-Ge exhibited high energy density and long-term cycle stability, thanks to their synergistic effect in alloying and conversion reactions. Our density functional theory (DFT) calculations have revealed that the rigid SiO2/GeO2 nanoparticles enhance the Sn-MOF mechanical properties, including Young's and shear moduli, which contribute to the long-term cycle stability of these composites.
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OBJECTIVE: This study aimed to investigate the expression of GPR56 in the T cells of early-stage lung adenocarcinoma (LUAD) patients and clarify its diagnostic significance. METHODS: Blood samples were collected from 32 patients with stage IA LUAD and 31 healthy controls. GPR56 and perforin were analysed in circulating T-cell subsets by flow cytometry. In addition, a correlation between perforin and GPR56 expression was detected. Changes in GPR56+ cells in early LUAD patients were analysed, and the diagnostic significance of GPR56+ T cells for early LUAD was studied by receiver operating characteristic (ROC) curve analysis. RESULTS: The expression of GPR56 in CD8+ T cells from early-stage LUAD patients was significantly greater than that in CD4+ T cells. The percentage of perforin-positive GPR56+ cells in early-stage LUAD patients was high. GPR56 levels in the T cells of LUAD patients were significantly lower than those in healthy controls. ROC analysis revealed that the area under the curve for the percentage of GPR56-positive CD8+ TEMRA cells to distinguish early-stage LUAD patients from healthy individuals- reached 0.7978. CONCLUSION: The decreased expression of GPR56 in the peripheral blood of early-stage LUAD patients correlated with perforin levels, reflecting compromised antitumor immunity and aiding early-stage LUAD screening.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Estadiamento de Neoplasias , Receptores Acoplados a Proteínas G , Humanos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Masculino , Feminino , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Pessoa de Meia-Idade , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Idoso , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Perforina/metabolismo , Perforina/genética , Curva ROC , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Biomarcadores Tumorais/metabolismo , AdultoRESUMO
OBJECTIVES: To develop a sensitive point-of-care testing (POCT) aqueous vascular endothelial growth factor (VEGF) detection system, and assess its role for predicting the response to anti-VEGF treatment in macular edema secondary to retinal vein occlusion (RVO-ME) patients. METHODS: An automatic point-of-care aqueous humor Magnetic Particle Chemiluminescence Enzyme Immuno-Assay (MPCLEIA) VEGF detection system was developed. The predictive values of aqueous cytokine levels, in combination with imaging parameters, on anatomical treatment response (ATR, the relative central macular thickness change [ΔCMT/bl-CMT]) were analyzed. RESULTS: The automatic MPCLEIA system was able to provide results in 45â¯min with only 20⯵L sample. Among the 57 eyes with available pre- and post-treatment evaluation, ATR significantly correlated with levels of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and VEGF measured by Luminex xMAP platform, and VEGF measured by MPCLEIA. Optimal cut-off values for these biomarkers were 13.26â¯ng/L, 23.57â¯ng/L, 1,110.12â¯ng/L, 105.52â¯ng/L, and 85.39â¯ng/L, respectively. Univariate analysis showed significant associations between ATR category (good response if ATR≤-25â¯% or poor response otherwise) and IL-6, IL-8, MCP-1, VEGF-xMAP, and VEGF-MPCLEIA (p<0.05). Multivariate logistic regression revealed that ATR category was significantly associated with aqueous VEGF-MPCLEIA (p=0.006) and baseline(bl)-CMT (p=0.008). Receiver operating characteristics analysis yielded an AUC of 0.959 for the regression model combining VEGF-MPCLEIA and bl-CMT, for predicting ATR category. CONCLUSIONS: Our novel MPCLEIA-based automatic VEGF detection system enables accurate POCT of aqueous VEGF, which shows promise in predicting the treatment response of RVO-ME to anti-VEGF agents when combined with bl-CMT.
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Edema Macular , Fator A de Crescimento do Endotélio Vascular , Humanos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Sistemas Automatizados de Assistência Junto ao Leito , Interleucina-8 , Edema Macular/diagnóstico , Edema Macular/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo , Interleucina-6 , Humor Aquoso/metabolismoRESUMO
Endothelial cell senescence is involved in endothelial dysfunction and aging-related vascular diseases. The D1-like dopamine receptor (DR1), a number of G-protein-coupled receptors, is currently under consideration as a potential therapeutic target for the prevention of atherosclerosis. However, the role of DR1 in regulating ox-LDL-stimulated endothelial cell senescence remains unknown. Here, we found that the elevated Prx hyperoxidation and reactive oxygen species (ROS) levels in ox-LDL-treated Human umbilical vein endothelial cells (HUVECs) were observed, suppressed by DR1 agonist SKF38393. Increased proportion of senescence-associated ß-galactosidase (SA-ß-gal) positive staining cells and activated p16/p21/p53 pathway in ox-LDL-treated HUVECs were significantly abolished by DR1 activation. In addition, SKF38393 increased the phosphorylation of cAMP response element-binding protein (CREB) at serine-133, nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and expression of HO-1 in HUVECs. In contrast, adding H-89, a PKA inhibitor, diminished the effects of DR1 activation. Further studies performed with DR1 siRNA confirmed that DR1 was involved in CREB/Nrf2 pathway. Taken together, DR1 activation reduces ROS production and cell senescence by upregulating CREB/Nrf2 antioxidant signaling in ox-LDL-induced endothelial cells. Thus, DR1 could be a potential molecular target to counteract oxidative stress-induced cellular senescence.
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Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Fator 2 Relacionado a NF-E2 , Humanos , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Senescência Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Lipoproteínas LDL/farmacologia , Lipoproteínas LDL/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Dopamina D1/metabolismoRESUMO
Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.
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Fibrose , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Animais , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Camundongos , Masculino , Proteínas de Sinalização YAP/metabolismo , Fibroblastos/metabolismo , Citidina/análogos & derivados , Citidina/farmacologia , Camundongos Knockout , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Acetiltransferase N-Terminal E/metabolismo , Via de Sinalização Hippo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Células Cultivadas , Transdução de Sinais , Acetiltransferases N-Terminal/metabolismo , Miocárdio/patologia , Miocárdio/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismoRESUMO
BACKGROUND: Age-related blepharoptosis, or ptosis, affects vision and appearance. Associations with age, gender, BMI, and diabetes have been explored, but the link to blood lipids remains unclear. The impact on refraction also lacks consensus. This study addresses gaps by investigating ptosis prevalence and factors in a representative Chinese population, aiming for a comprehensive understanding. METHODS: A cross-sectional study was conducted among individuals aged 50 and above who were willing to participate in comprehensive systemic check-ups, behavioral questionnaires, and ophthalmic examinations at Yaoxi Community Health Center in Wenzhou City, Zhejiang Province. RESULTS: The prevalence of blepharoptosis among the elderly participants at this health center was 27.16%. Individuals with blepharoptosis tended to be older, male, exhibited slightly higher body mass index, wider waist circumference, engaged in lower exercise frequency, and had a higher prevalence of hypertension, diabetes, and with-the-rule astigmatism compared to their counterparts without these conditions. Adjusting for all other confounding variables, older age, being male, higher fasting plasma glucose (FPG), and lower exercise frequency displayed statistically significant relationships with blepharoptosis. After examining the distribution of blepharoptosis degrees within relevant factor subgroups, we noted a higher prevalence of severe ptosis in subgroups associated with older age, male gender, higher FPG, and against-the-rule astigmatism. CONCLUSION: The notable associations with age, gender, FPG, and exercise level suggest a multifactorial etiology for blepharoptosis. The observed link between with-the-rule astigmatism and blepharoptosis implies a potential contributory role in the refractive aspect of blepharoptosis. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
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Povo Asiático , Blefaroptose , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Etários , Povo Asiático/estatística & dados numéricos , Blefaroptose/epidemiologia , China/epidemiologia , Estudos Transversais , Prevalência , Medição de Risco , Fatores de RiscoRESUMO
Lung adenocarcinoma (LUAD) is the most widespread cancer in the world, and its development is associated with complex biological mechanisms that are poorly understood. Here, we revealed a marked upregulation in the mRNA level of C1orf131 in LUAD samples compared to non-tumor tissue samples in The Cancer Genome Atlas (TCGA). Depletion of C1orf131 suppressed cell proliferation and growth, whereas it stimulated apoptosis in LUAD cells. Mechanistic investigations revealed that C1orf131 knockdown induced cell cycle dysregulation via the AKT and p53/p21 signalling pathways. Additionally, C1orf131 knockdown blocked cell migration through the modulation of epithelial-mesenchymal transition (EMT) in lung adenocarcinoma. Notably, we identified the C1orf131 protein nucleolar localization sequence, which included amino acid residues 137-142 (KKRKLT) and 240-245 (KKKRKG). Collectively, C1orf131 has potential as a novel therapeutic marker for patients in the future, as it plays a vital role in the progression of lung adenocarcinoma.
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Adenocarcinoma de Pulmão , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Humanos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Proliferação de Células/genética , Movimento Celular/genética , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Apoptose/genética , Progressão da Doença , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Células A549RESUMO
BACKGROUND: The oral cavity is home to various ecological niches, each with its own unique microbial composition. Understanding the microbial communities and gene composition in different ecological niches within the oral cavity of oral cancer (OC) patients is crucial for determining how these microbial populations contribute to disease progression. METHODS: In this study, saliva and dental plaque samples were collected from patients with OC. Metagenomic sequencing was employed to analyze the microbial community classification and functional composition of the different sample groups. RESULTS: The results of the study revealed significant differences in both the function and classification of microbial communities between saliva and dental plaque samples. The diversity of microbial species in saliva was found to be higher compared to that in plaque samples. Notably, Actinobacteria were enriched in the dental plaque of OC patients. Furthermore, the study identified several inter-group differential marker species, including Prevotella intermedia, Haemophilus parahaemolyticus, Actinomyces radius, Corynebacterium matruchitii, and Veillonella atypica. Additionally, 1,353 differential genes were annotated into 23 functional pathways. Interestingly, a significant correlation was observed between differentially labeled species and Herpes simplex virus 1 (HSV-1) infection, which may be related to the occurrence and development of cancer. CONCLUSIONS: Significant differences in the microbial and genetic composition of saliva and dental plaque samples were observed in OC patients. Furthermore, pathogenic bacteria associated with oral diseases were predominantly enriched in saliva. The identification of inter-group differential biomarkers and pathways provide insights into the relationship between oral microbiota and the occurrence and development of OC.
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Placa Dentária , Neoplasias Bucais , Humanos , Saliva/microbiologia , Placa Dentária/microbiologia , Bactérias/genética , RNA Ribossômico 16S/genéticaRESUMO
OBJECTIVE: To assess the efficacy and safety of intentional watch and wait (W&W) and organ preservation surgery following neoadjuvant chemoradiotherapy plus consolidation CAPEOX in magnetic resonance imaging (MRI)-defined low-risk rectal cancer. BACKGROUND: Clinical T2/early T3 rectal cancers can achieve high yield pathological complete response (ypCR) rates after chemoradiotherapy; thus, an intentional W&W or organ preservation strategy for good clinical responders in these subgroups can be further tested. METHODS: This prospective, single-arm, phase 2 trial enrolled patients with low-risk MRI prestaged rectal cancers, who concurrently received chemoradiation, followed by four 3-weekly cycles of CAPEOX regimen. Following reassessment, clinical complete response (cCR) or near-cCR patients underwent W&W/organ preservation surgery; the primary endpoint was a 3-year organ preservation rate. RESULTS: Of the 64 participants, 58 completed treatment, with 6.4% and 33.9% grade 3 to 4 toxicities in the radiotherapy and consolidation CAPEOX phases, respectively, during a median 39.5-month follow-up. Initial cCR, and non-cCR occurred in 33, 13, and 18 patients, respectively. Of the 31 cCR and 7 near-cCR cases managed by W&W, local regrowth occurred in 7; of these, 6 received salvage surgery. The estimated 2-year local regrowth rates were 12.9% [95% confidence interval (CI): 1.1%-24.7%] in cCR and 42.9% (95% CI: 6.2%-79.6%) in near-cCR cases, respectively. Eight patients received local excision, including 2 with regrowth salvage. Lung metastases occurred in 3 patients and multiple metastasis occurred in 1 patient; no local recurrence occurred. The estimated 3-year organ preservation rate was 67.2% (95% CI: 55.6%-78.8%). The estimated 3-year cancer-specific survival, non-regrowth disease-free survival, and stoma-free survival were 96.6% (95% CI: 92.1%-100%), 92.2% (95% CI: 85.5%-98.9%), and 82.7% (95% CI: 73.5%-91.9%), respectively. CONCLUSIONS: Chemoradiotherapy plus consolidation CAPEOX for MRI-defined low-risk rectal cancer can lead to high rates of organ preservation through intentional W&W or local excision. The oncologic safety of this strategy should be further tested.
Assuntos
Terapia Neoadjuvante , Neoplasias Retais , Humanos , Preservação de Órgãos , Estudos Prospectivos , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/terapia , Quimiorradioterapia/métodos , Imageamento por Ressonância Magnética , Conduta Expectante , Recidiva Local de Neoplasia , Resultado do TratamentoRESUMO
A novel metal-organic framework (MOF)-on-MOF dual enzyme-mimic nanozyme was designed as enhanced cascade signal amplification for the colorimetric and chemiluminescent (CL) dual-mode aptasensing. The MOF-on-MOF hybrid is composed of MOF-818 with catechol oxidase-like activity and iron porphyrin MOF [PMOF(Fe)] with peroxidase-like activity, called MOF-818@PMOF(Fe). MOF-818 can catalyze the 3,5-di-tert-butylcatechol substrate and produce H2O2 in situ. Subsequently, PMOF(Fe) catalyzes H2O2 to produce reactive oxygen species, which oxidize 3,3',5,5'-tetramethylbenzidine or luminol to produce color or luminescence. Thanks to the nano-proximity effect and the confinement effect, the efficiency of the biomimetic cascade catalysis is greatly improved, which in turn generates enhanced colorimetric and CL signals. Taking the detection of chlopyrifos as an example, the prepared dual enzyme-mimic MOF nanozyme is combined with the aptamer with specific recognition ability to develop a colorimetric/CL dual-mode aptasensor for highly sensitive and selective detection of chlorpyrifos. The proposed MOF-on-MOF dual nanozyme-enhanced cascade system may provide a new pathway for the further development of a biomimetic cascade sensing platform.
Assuntos
Estruturas Metalorgânicas , Colorimetria , Peróxido de Hidrogênio , Peroxidases/metabolismo , CatáliseRESUMO
As the Human Microbiome Project (HMP) progresses, the relationship between microbes and human health has been receiving increasing attention. A growing number of reports support the correlation between cancer and microbes. However, most studies have focused on bacteria, rather than fungal communities. In this study, we studied the alteration in lung mycobiome in patients with non-small-cell lung cancer (NSCLC) using metagenomic sequencing and qPCR. The higher fungal diversity and more complex network were observed in the patients with NSCLC. In addition, Alternaria arborescens was found as the most relevant fungus to NSCLC, and the enrichment of it in cancerous tissue was also detected. This study proposes that the changes in fungal communities may be closely related to lung cancer, and provides insights into further exploration the relationship between lung cancer and fungi.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Micobioma , Humanos , Fungos/genética , PulmãoRESUMO
Recombinant LL-37 Lactococcus lactis (Oral LL-37) was designed to prevent progression of COVID-19 by targeting virus envelope, however, effectiveness and safety of Oral LL-37 in clinical application was unclear. A total of 238 adult inpatients, open-labelled, randomized, placebo-controlled, single-center study was conducted to investigate the primary end points, including negative conversion time (NCT) of SARS-CoV-2 RNA and adverse events (AEs). As early as intervened on 6th day of case confirmed, Oral LL-37 could significantly shorten NCT (LL-37 9.80 ± 2.67 vs. placebo 14.04 ± 5.89, p < 0.01). For Oral LL-37, as early as treated in 6 days, the adjusted hazard ratio (HR) for a primary event of nucleic acid negative outcome was 6.27-fold higher than 7-day-later (HR: 6.276, 95% confidence interval [CI]: 3.631-10.848, p < 0.0001), and the adjusted HR of Oral LL-37 within 6 days is higher than placebo (HR: 2.427 95% CI: 1.239-4.751, p = 0.0097). No severe AEs were observed during hospitalization and follow-up investigation. This study shows that early intervention of Oral LL-37 incredibly reduces NCT implying a potential for clearance of Omicron BA.5.1.3 without evident safety concerns.