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Airway hillocks are stratified epithelial structures of unknown function1. Hillocks persist for months and have a unique population of basal stem cells that express genes associated with barrier function and cell adhesion. Hillock basal stem cells continually replenish overlying squamous barrier cells. They exhibit dramatically higher turnover than the abundant, largely quiescent classic pseudostratified airway epithelium. Hillocks resist a remarkably broad spectrum of injuries, including toxins, infection, acid and physical injury because hillock squamous cells shield underlying hillock basal stem cells from injury. Hillock basal stem cells are capable of massive clonal expansion that is sufficient to resurface denuded airway, and eventually regenerate normal airway epithelium with each of its six component cell types. Hillock basal stem cells preferentially stratify and keratinize in the setting of retinoic acid signalling inhibition, a known cause of squamous metaplasia2,3. Here we show that mouse hillock expansion is the cause of vitamin A deficiency-induced squamous metaplasia. Finally, we identify human hillocks whose basal stem cells generate functional squamous barrier structures in culture. The existence of hillocks reframes our understanding of airway epithelial regeneration. Furthermore, we show that hillocks are one origin of 'squamous metaplasia', which is long thought to be a precursor of lung cancer.
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Plasticidade Celular , Células Epiteliais , Regeneração , Mucosa Respiratória , Células-Tronco , Animais , Feminino , Humanos , Masculino , Camundongos , Células Epiteliais/citologia , Células Epiteliais/patologia , Metaplasia/etiologia , Metaplasia/patologia , Mucosa Respiratória/citologia , Mucosa Respiratória/lesões , Mucosa Respiratória/patologia , Células-Tronco/citologia , Tretinoína/metabolismo , Tretinoína/farmacologia , Vitamina A/metabolismo , Vitamina A/farmacologia , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos C57BLRESUMO
As crucial epigenetic regulators, long noncoding RNAs (lncRNAs) play critical functions in development processes and various diseases. However, the regulatory mechanism of lncRNAs in early heart development is still limited. In this study, we identified cardiac mesoderm-related lncRNA (LncCMRR). Knockout (KO) of LncCMRR decreased the formation potential of cardiac mesoderm and cardiomyocytes during embryoid body differentiation of mouse embryonic stem (ES) cells. Mechanistic analyses showed that LncCMRR functionally interacted with the transcription suppressor PURB and inhibited its binding potential at the promoter region of Flk1, which safeguarded the transcription of Flk1 during cardiac mesoderm formation. We also carried out gene ontology term and signaling pathway enrichment analyses for the differentially expressed genes after KO of LncCMRR, and found significant correlation of LncCMRR with cardiac muscle contraction, dilated cardiomyopathy, and hypertrophic cardiomyopathy. Consistently, the expression level of Flk1 at E7.75 and the thickness of myocardium at E17.5 were significantly decreased after KO of LncCMRR, and the survival rate and heart function index of LncCMRR-KO mice were also significantly decreased as compared with the wild-type group. These findings indicated that the defects in early heart development led to functional abnormalities in adulthood heart of LncCMRR-KO mice. Conclusively, our findings elucidate the main function and regulatory mechanism of LncCMRR in cardiac mesoderm formation, and provide new insights into lncRNA-mediated regulatory network of mouse ES cell differentiation.
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RNA Longo não Codificante , Animais , Camundongos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Camundongos Knockout , Diferenciação Celular/genética , Miocárdio , Miócitos Cardíacos , Mesoderma/metabolismoRESUMO
Long noncoding RNAs (lncRNAs) are abundantly expressed in the nervous system, but their regulatory roles in neuronal differentiation are poorly understood. Using a human embryonic stem cell (hESC)-based 2D neural differentiation approach and a 3D cerebral organoid system, we show that SOX1-OT variant 1 (SOX1-OT V1), a SOX1 overlapping noncoding RNA, plays essential roles in both dorsal cortical neuron differentiation and ventral GABAergic neuron differentiation by facilitating SOX1 expression. SOX1-OT V1 physically interacts with HDAC10 through its 5' region, acts as a decoy to block HDAC10 binding to the SOX1 promoter, and thus maintains histone acetylation levels at the SOX1 promoter. SOX1 in turn activates ASCL1 expression and promotes neuronal differentiation. Taken together, we identify a SOX1-OT V1/HDAC10-SOX1-ASCL1 axis, which promotes neurogenesis, highlighting a role for lncRNAs in hESC neuronal differentiation.
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Células-Tronco Embrionárias Humanas , Neurônios/citologia , RNA Longo não Codificante , Fatores de Transcrição SOXB1 , Diferenciação Celular/genética , Histona Desacetilases/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Humanos , Neurônios/metabolismo , RNA Longo não Codificante/genética , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismoRESUMO
Modal parameter estimation is crucial in vibration-based damage detection and deserves increased attention and investigation. Concrete arch dams are prone to damage during severe seismic events, leading to alterations in their structural dynamic characteristics and modal parameters, which exhibit specific time-varying properties. This highlights the significance of investigating the evolution of their modal parameters and ensuring their accurate identification. To effectively accomplish the recursive estimation of modal parameters for arch dams, an adaptive recursive subspace (ARS) method with variable forgetting factors was proposed in this study. In the ARS method, the variable forgetting factors were adaptively updated by assessing the change rate of the spatial Euclidean distance of adjacent modal frequency identification values. A numerical simulation of a concrete arch dam under seismic loading was conducted by using ABAQUS software, in which a concrete damaged plasticity (CDP) model was used to simulate the dam body's constitutive relation, allowing for the assessment of damage development under seismic loading. Utilizing the dynamic responses obtained from the numerical simulation, the ARS method was implemented for the modal parameter recursive estimation of the arch dam. The identification results revealed a decreasing trend in the frequencies of the four initial modes of the arch dam: from an undamaged state characterized by frequencies of 0.910, 1.166, 1.871, and 2.161 Hz to values of 0.895, 1.134, 1.842, and 2.134 Hz, respectively. Concurrently, increases in the damping ratios of these modes were observed, transitioning from 4.44%, 4.28%, 5.42%, and 5.56% to 4.98%, 4.91%, 6.61%, and 6.85%%, respectively. The correlation of the identification results with damage progression validated the effectiveness of the ARS method. This study's outcomes have substantial theoretical and practical importance, facilitating the immediate comprehension of the dynamic characteristics and operational states of concrete arch dam structures.
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Investigating the dynamic response patterns and failure modes of concrete gravity dams subjected to strong earthquakes is a pivotal area of research for addressing seismic safety concerns associated with gravity dam structures. Dynamic shaking table testing has proven to be a robust methodology for exploring the dynamic characteristics and failure modes of gravity dams. This paper details the dynamic test conducted on a gravity dam model on a shaking table. The emulation concrete material, featuring high density, low dynamic elastic modulus, and appropriate strength, was meticulously designed and fabricated. Integrating the shaking table conditions with the model material, a comprehensive gravity dam shaking table model test was devised to capture the dynamic response of the model under various dynamic loads. Multiple operational conditions were carefully selected for in-depth analysis. Leveraging the dynamic strain responses, the progression of damage in the gravity dam model under these diverse conditions was thoroughly examined. Subsequently, the recorded acceleration responses were utilized for identifying dynamic characteristic parameters, including the acceleration amplification factor in the time domain, acceleration response spectrum characteristics in the frequency domain, and modal parameters reflecting the inherent characteristics of the structure. To gain a comprehensive understanding, a comparative analysis was performed by aligning the observed damage development with the identified dynamic characteristic parameters, and the sensitivity of these identified parameters to different levels of damage was discussed. The findings of this study not only offer valuable insights for conducting and scrutinizing shaking table experiments on gravity dams but also serve as crucial supporting material for identifying structural dynamic characteristic parameters and validating damage diagnosis methods for gravity dam structures.
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Chlorophyll fluorescence is the long-wave light released by the residual energy absorbed by vegetation after photosynthesis and dissipation, which can directly and non-destructively reflect the photosynthetic state of plants from the perspective of the mechanism of photosynthetic process. Moso bamboo has a substantial carbon sequestration ability, and leaf-expansion stage is an important phenological period for carbon sequestration. Gross primary production (GPP) is a key parameter reflecting vegetation carbon sequestration process. However, the ability of chlorophyll fluorescence in moso bamboo to explain GPP changes is unclear. The research area of this study is located in the bamboo forest near the flux station of Anji County, Zhejiang Province, where an observation tower is built to monitor the carbon flux and meteorological change of bamboo forest. The chlorophyll fluorescence physiological parameters (Fp) and fluorescence yield (Fy) indices were measured and calculated for the leaves of newborn moso bamboo (I Du bamboo) and the old leaves of 4- to 5-year-old moso bamboo (â ¢ Du bamboo) during the leaf-expansion stage. The chlorophyll fluorescence in response to the environment and its effect on carbon flux were analyzed. The results showed that: Fv/Fm, Y(II) and α of â Du bamboo gradually increased, while â ¢ Du bamboo gradually decreased, and FYint and FY687/FY738 of â Du bamboo were higher than those of â ¢ Du bamboo; moso bamboo was sensitive to changes in air temperature(Ta), relative humidity(RH), water vapor pressure(E), soil temperature(ST) and soil water content (SWC), the Fy indices of the upper, middle and lower layers were significantly correlated with Ta, E and ST; single or multiple vegetation indices were able to estimate the fluorescence yield indices well (all with R2 greater than 0.77); chlorophyll fluorescence (Fp and Fy indices) of â Du bamboo and â ¢ Du bamboo could explain 74.4% and 72.7% of the GPP variation, respectively; chlorophyll fluorescence and normalized differential vegetation index of the canopy (NDVIc) could estimate GPP well using random forest (â Du bamboo: r = 0.929, RMSE = 0.069 g C·m-2; â ¢ Du bamboo: r = 0.899, RMSE = 0.134 g C·m-2). The results of this study show that chlorophyll fluorescence can provide a basis for judging the response of moso bamboo to environmental changes and can well explain GPP. This study has important scientific significance for evaluating the potential mechanisms of growth, stress feedback and photosynthetic carbon sequestration of bamboo.
Assuntos
Clorofila , Fotossíntese , Folhas de Planta , Clorofila/metabolismo , Folhas de Planta/metabolismo , Fluorescência , Poaceae/metabolismo , Poaceae/crescimento & desenvolvimento , Sequestro de Carbono , Carbono/metabolismoRESUMO
PURPOSE: This study evaluated the relationship between refractive outcomes and postoperative anterior chamber depth (ACD, measured from corneal epithelium to lens) measured by swept-source optical coherence tomography (SS-OCT), optical low-coherence reflectometry (OLCR), and Scheimpflug devices under the undilated pupil. METHODS: Patients undergoing cataract phacoemulsification with intraocular lens (IOL) implantation in a hospital setting were enrolled. Postoperative ACD (postACD) was performed with an SS-OCT device, an OLCR device, and a Scheimpflug device at least 1 month after cataract surgery. After adjusting the mean predicted error to 0, differences in refractive outcomes were calculated with the Olsen formula using actual postACD measured from 3 devices and predicted value. RESULTS: Overall, this comparative case study included 69 eyes of 69 patients, and postACD measurements were successfully taken using all 3 devices. The postACD measured with the SS-OCT, OLCR, and Scheimpflug devices was 4.59 ± 0.30, 4.50 ± 0.30, and 4.54 ± 0.32 mm, respectively. Statistically significant differences in postACD were found among 3 devices (P < 0.001), with intraclass correlation coefficients (ICCs) and Bland-Altman showing good agreement. No significant difference in median absolute error was found with the Olsen formula using actual postACD obtained with 3 devices. Percentage prediction errors were within ± 0.50 D in 65% (OLCR), 70% (Scheimpflug), and 67% (SS-OCT) calculated by actual postACD versus 64% by predicted value. CONCLUSION: Substantial agreement was found in postACD measurements obtained from the SS-OCT, OLCR, and Scheimpflug devices, with a trend toward comparable refractive outcomes in the Olsen formula. Meanwhile, postACD measurements may be potentially superior for the additional enhancement of refractive outcomes.
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Catarata , Cristalino , Lentes Intraoculares , Humanos , Câmara Anterior/diagnóstico por imagem , Comprimento Axial do Olho , Refração Ocular , Catarata/diagnóstico , Tomografia de Coerência Óptica/métodos , Biometria/métodos , Reprodutibilidade dos TestesRESUMO
During neocortical development, neural stem cells (NSCs) divide symmetrically to self-renew at the early stage and then divide asymmetrically to generate post-mitotic neurons. The molecular mechanisms regulating the balance between NSC self-renewal and neurogenesis are not fully understood. Using mouse in utero electroporation (IUE) technique and in vitro human NSC differentiation models including cerebral organoids (hCOs), we show here that regulator of cell cycle (RGCC) modulates NSC self-renewal and neuronal differentiation by affecting cell cycle regulation and spindle orientation. RGCC deficiency hampers normal cell cycle process and dysregulates the mitotic spindle, thus driving more cells to divide asymmetrically. These modulations diminish the NSC population and cause NSC pre-differentiation that eventually leads to brain developmental malformation in hCOs. We further show that RGCC might regulate NSC spindle orientation by affecting the organization of centrosome and microtubules. Our results demonstrate that RGCC is essential to maintain the NSC pool during cortical development and suggest that RGCC defects could have etiological roles in human brain malformations.
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Neocórtex , Células-Tronco Neurais , Animais , Diferenciação Celular , Camundongos , Neurogênese , NeurôniosRESUMO
Glaucoma, a blinding neurodegenerative disease, whose risk factors include elevated intraocular pressure (IOP), age, and genetics, is characterized by accelerated and progressive retinal ganglion cell (RGC) death. Despite decades of research, the mechanism of RGC death in glaucoma is still unknown. Here, we demonstrate that the genetic effect of the SIX6 risk variant (rs33912345, His141Asn) is enhanced by another major POAG risk gene, p16INK4a (cyclin-dependent kinase inhibitor 2A, isoform INK4a). We further show that the upregulation of homozygous SIX6 risk alleles (CC) leads to an increase in p16INK4a expression, with subsequent cellular senescence, as evidenced in a mouse model of elevated IOP and in human POAG eyes. Our data indicate that SIX6 and/or IOP promotes POAG by directly increasing p16INK4a expression, leading to RGC senescence in adult human retinas. Our study provides important insights linking genetic susceptibility to the underlying mechanism of RGC death and provides a unified theory of glaucoma pathogenesis.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Glaucoma de Ângulo Aberto/metabolismo , Proteínas de Homeodomínio/fisiologia , Células Ganglionares da Retina/fisiologia , Transativadores/fisiologia , Sequência de Aminoácidos , Animais , Estudos de Casos e Controles , Morte Celular , Linhagem Celular , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Glaucoma de Ângulo Aberto/genética , Glaucoma de Ângulo Aberto/patologia , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Regulação para CimaRESUMO
Long noncoding RNAs (lncRNAs) play a wide range of roles in the epigenetic regulation of crucial biological processes, but the functions of lncRNAs in cortical development are poorly understood. Using human embryonic stem cell (hESC)-based 2D neural differentiation approach and 3D cerebral organoid system, we identified that the lncRNA PAUPAR, which is adjacent to PAX6, plays essential roles in cortical differentiation by interacting with PAX6 to regulate the expression of a large number of neural genes. Mechanistic studies showed that PAUPAR confers PAX6 proper binding sites on the target neural genes by directly binding the genomic regions of these genes. Moreover, PAX6 recruits the histone methyltransferase NSD1 through its C-terminal PST enrichment domain, then regulate H3K36 methylation and the expression of target genes. Collectively, our data reveal that the PAUPAR/PAX6/NSD1 complex plays a critical role in the epigenetic regulation of hESC cortical differentiation and highlight the importance of PAUPAR as an intrinsic regulator of cortical differentiation.
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Córtex Cerebral/metabolismo , Células-Tronco Embrionárias/metabolismo , Regulação da Expressão Gênica , Fator de Transcrição PAX6/metabolismo , RNA Longo não Codificante/metabolismo , Sítios de Ligação , Diferenciação Celular/genética , Células Cultivadas , Células-Tronco Embrionárias/citologia , Deleção de Genes , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Metilação , Organoides , RNA Longo não Codificante/genéticaRESUMO
The repair and regeneration of tissues using endogenous stem cells represents an ultimate goal in regenerative medicine. To our knowledge, human lens regeneration has not yet been demonstrated. Currently, the only treatment for cataracts, the leading cause of blindness worldwide, is to extract the cataractous lens and implant an artificial intraocular lens. However, this procedure poses notable risks of complications. Here we isolate lens epithelial stem/progenitor cells (LECs) in mammals and show that Pax6 and Bmi1 are required for LEC renewal. We design a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Our method differs conceptually from current practice, as it preserves endogenous LECs and their natural environment maximally, and regenerates lenses with visual function. Our approach demonstrates a novel treatment strategy for cataracts and provides a new paradigm for tissue regeneration using endogenous stem cells.
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Catarata/terapia , Cristalino/citologia , Cristalino/fisiologia , Recuperação de Função Fisiológica , Regeneração/fisiologia , Células-Tronco/citologia , Visão Ocular/fisiologia , Animais , Catarata/congênito , Catarata/patologia , Catarata/fisiopatologia , Extração de Catarata , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Proteínas do Olho/metabolismo , Proteínas de Homeodomínio/metabolismo , Homeostase , Humanos , Macaca , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/metabolismo , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Repressoras/metabolismo , Células-Tronco/metabolismoRESUMO
BACKGROUND: To investigate the refractive outcomes of second-eye adjustment (SEA) methods in different intraocular lens (IOL) power calculation formulas for second eye following bilateral sequential cataract surgery. METHODS: This retrospective consecutive case-series study included 234 eyes from 234 patients who underwent bilateral sequential phacoemulsification and implantation of enVista MX60 in a hospital setting. Postoperative refraction outcomes calculated by standard formulas (SRK/T and Barrett Universal II, BUII) with SEA method were compared with those calculated by an artificial intelligence-based IOL power calculation formula (PEARL DGS) under second eye enhancement (SEE) method. The median absolute error (MedAE), mean absolute error (MAE) and percentage prediction errors (PE) of eyes within ±0.25 diopters (D), ±0.50 D, ±0.75 D and ± 1.00 D were determined. RESULTS: Overall, the improvement in MedAE after SEA was significant for PEARL DGS (p < 0.01), SRK/T (p < 0.001) and BUII (p = 0.031), which increased from 74.36, 71.37, and 77.78% to 83.33, 80.34, and 79.49% of eyes within a PE of ±0.50 D, respectively. For first eyes with a medium axial length (22-26 mm), PEARL DGS with SEE had the lowest MedAE (0.21 D). For a first-eye MAE over 0.50 D, SEA method led to significant improvement in the second eye (p < 0.01). Interocular axis length differences exceeding 0.3 mm were associated with weaker effects using SEA in the studied formulas (p > 0.05). CONCLUSIONS: Either SEA method with SRK/T and BUII formulas or second-eye enhancement method based on the PEARL DGS formula can improve postoperative refractive outcomes in second eye.
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Inteligência Artificial , Lentes Intraoculares , Comprimento Axial do Olho , Biometria , Humanos , Implante de Lente Intraocular , Óptica e Fotônica , Estudos Retrospectivos , Acuidade VisualRESUMO
PURPOSE: To evaluate the accuracy of wavefront-derived objective refraction in pseudophakic eyes. METHODS: Retrospective case series. A total of 356 eyes (356 patients) that underwent phacoemulsification and posterior chamber intraocular lens implantation were included. Noncycloplegic subjective manifest refraction (MR) and objective refraction results from the wavefront aberrometer were obtained and compared. Subgroup analysis of objective refraction at 2.6-mm zone was performed based on axial length (AL) and average keratometry. RESULTS: The biases (at the 2.6-mm, 3-mm, and 4-mm zones) were - 0.29 ± 0.37 D, - 0.53 ± 0.41 D, and - 0.51 ± 0.60 D for sphere; - 0.27 ± 0.36 D, - 0.52 ± 0.38 D, and - 0.53 ± 0.51 D for spherical equivalent (SE); 0.03 ± 0.20 D, 0.03 ± 0.22 D, and 0.04 ± 0.27 D for J0; and 0.01 ± 0.16 D, 0.03 ± 0.22 D, and 0.01 ± 0.22 D for J45, respectively. Objective refraction for sphere, SE, and J0 (at 2.6 mm, 3 mm, and 4 mm) was significantly different from MR (P < 0.05), while J45 values were equal. The objective refraction at 2.6 mm was the most accurate in short eyes (≤ 22.5 mm) with a minimum bias for SE (- 0.15 ± 0.28 D) and highest percentage of SE within ± 0.25 to ± 0.75 D of MR. However, there was no difference between the keratometry subgroups. CONCLUSIONS: The wavefront aberrometer achieved the best accuracy at 2.6 mm in pseudophakic eyes with short AL. It still needs modification to be used as a substitute for MR in such patients.
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Facoemulsificação , Testes Visuais , Córnea , Humanos , Refração Ocular , Estudos RetrospectivosRESUMO
Aspidosperma alkaloids, a subclass of monoterpenoid indole alkaloids rich in the Apocynaceae plants, possess remarkable antitumor activities, but the underlying mechanisms have rarely been reported. In the current project, 11-methoxytabersonine (11-MT), an aspidosperma-type alkaloid isolated from Tabernaemontana bovina, significantly inhibited the viability of two human lung cancer cell lines A549 and H157, and the molecular mechanisms were thus investigated. The results showed that 11-MT killed lung cancer cells via induction of necroptosis in an apoptosis-independent manner. In addition, 11-MT strongly induced autophagy in the two cell lines, which played a protective role against 11-MT-induced necroptosis. Finally, the autophagy caused by 11-MT was found to be via activation of the AMP activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) and the c-Jun N-terminal kinase (JNK) signaling pathways in both cells. Taken together, 11-MT exhibited an antitumor mechanism different from that of previously reported analogues and could have the potential to serve as a lead compound for the development of new chemotherapy for lung cancer.
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Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Monoterpenos/farmacologia , Necroptose/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Tabernaemontana/química , Células A549 , Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/isolamento & purificação , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Monoterpenos/isolamento & purificação , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismoRESUMO
An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumour DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive 'liquid biopsy' for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1,098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P < 0.001) and was highly correlated with tumour burden, treatment response, and stage. Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P < 0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.
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Biomarcadores Tumorais , Carcinoma Hepatocelular , DNA Tumoral Circulante , Metilação de DNA , Neoplasias Hepáticas , Modelos Biológicos , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Masculino , PrognósticoRESUMO
Lysosomes are intracellular digestive organelles that participate in various physiological and pathological processes, including the regulation of immune checkpoint molecules, immune cell function in the tumor microenvironment, antigen presentation, metabolism, and autophagy. Abnormalities or dysfunction of lysosomes are associated with the occurrence, development, and drug resistance of tumors. Lysosomes play a crucial role and have potential applications in tumor immunotherapy. Targeting lysosomes or harnessing their properties is an effective strategy for tumor immunotherapy. However, the mechanisms and approaches related to lysosomes in tumor immunotherapy are not fully understood at present, and further basic and clinical research is needed to provide better treatment options for cancer patients. This review focuses on the research progress related to lysosomes and tumor immunotherapy in these.
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Neoplasias , Humanos , Apresentação de Antígeno , Lisossomos/metabolismo , Imunoterapia , Autofagia , Microambiente TumoralRESUMO
Background: Few studies have investigated near vision loss (NVL) in China. To address this gap, we aimed to explore trends in the prevalence and disease burden of NVL from 1990 to 2019 and to predict trends over the next decade. Methods: Using data from the Global Burden of Disease 2019 study, we calculated the age-standardised prevalence rate (ASPR), age-specific disability-adjusted life years (DALYs), and annual percentage change (EAPC) in China and different regions. We then used the Bayesian age-period-cohort (BAPC) predictive model to predict the prevalence trends from 2020 to 2030 in both contexts. Results: At the global level, ASPRs increased from 5613.27 in 1990 to 5937.81 per 100 000 population in 2019, with an EAPC of 0.06. The ASPR in China specifically decreased from 7538.14 in 1990 to 7392.86 per 100 000 population in 2019 (EAPC = -0.02). The age-standardised DALY rate was higher in women than in men, both globally and in China. The NVL burden was relatively higher in low-income regions, low sociodemographic index regions, and the South-East Asia Region compared to other regions. The predictive model indicated that the ASR trend for NVL slowly increased at a global level after 2020, yet decreased in China. Conclusions: Despite a decline in the age-standardised prevalence of NVL in China over the next decade, the current burden remains substantial. To alleviate this burden, decision-makers should adopt inclusive approaches by involving all stakeholders.
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Teorema de Bayes , Humanos , China/epidemiologia , Prevalência , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Estudos de Coortes , Carga Global da Doença/tendências , Saúde Global/estatística & dados numéricos , Adulto Jovem , Adolescente , Efeitos Psicossociais da Doença , Anos de Vida Ajustados por Deficiência/tendências , Idoso de 80 Anos ou mais , Previsões , Anos de Vida Ajustados por Qualidade de VidaRESUMO
Limiting artifacts during sample preparation can significantly increase data quality in single-cell proteomics experiments. Towards this goal, we characterize the impact of protein leakage by analyzing thousands of primary single cells that were prepared either fresh immediately after dissociation or cryopreserved and prepared at a later date. We directly identify permeabilized cells and use the data to define a signature for protein leakage. We use this signature to build a classifier for identifying damaged cells that performs accurately across cell types and species.
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BACKGROUND: Gamma-aminobutyric acid (GABA), a common neurotransmitter, has been found in various cancers but its origin and its role in the tumor immune microenvironment remains unclear. METHODS: Here, we reported the expression of glutamate decarboxylase 1 (GAD1, converting glutamate into GABA) in lung cancer tissues based on the publicly available database, and explored the effects and underlying mechanism of GABA on lung cancer progression. RESULTS: Compared with normal tissues, GAD1 was aberrantly overexpressed in lung adenocarcinoma (LUAD) based on TCGA database. Furthermore, the LUAD patients' overall survival was negatively correlated with the GAD1 expression levels. Our work found that a GABAa receptor inhibitor had a therapeutic effect on mouse tumors and significantly reduced tumor size and weight. Further experiments showed that GABA derived from tumor cells promoted tumor progression not by directly affecting cancer cells but by affecting macrophages polarization in the tumor microenvironment. We found that GABA inhibited the NF-κB pathway and STAT3 pathway to prevent macrophages from polarizing towards M1 type, while promoting macrophage M2 polarization by activating the STAT6 pathway. GABA was also found to promote tumor neovascularization by increasing the expression of FGF2 in macrophages. CONCLUSIONS: These results suggest that GABA affects tumor progression by regulating macrophage polarization, and targeting GABA and its signaling pathway may represent a potential therapy for lung cancer.