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CRISPR-Cas9-mediated genome editing depends on PAM recognition to initiate DNA unwinding. PAM mutations can abolish Cas9 binding and prohibit editing. Here, we identified a Cas9 from the thermophile Alicyclobacillus tengchongensis for which the PAM interaction can be robustly regulated by DNA topology. AtCas9 has a relaxed PAM of N4CNNN and N4RNNA (R = A/G) and is able to bind but not cleave targets with mutated PAMs. When PAM-mutated DNA was in underwound topology, AtCas9 exhibited enhanced binding affinity and high cleavage activity. Mechanistically, AtCas9 has a unique loop motif, which docked into the DNA major groove, and this interaction can be regulated by DNA topology. More importantly, AtCas9 showed near-PAMless editing of supercoiled plasmid in E. coli. In mammalian cells, AtCas9 exhibited broad PAM preference to edit plasmid with up to 72% efficiency and effective base editing at four endogenous loci, representing a potentially powerful tool for near-PAMless editing.
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Sistemas CRISPR-Cas , Escherichia coli , Animales , Escherichia coli/genética , Escherichia coli/metabolismo , Edición Génica , ADN/genética , Plásmidos , Mamíferos/metabolismoRESUMEN
Diverse ß-carboline (ßC) alkaloids are produced by microbes, plants, and animals with myriad bioactivities and drug potentials. However, the biosynthetic mechanism of ßCs remains largely elusive, especially regarding the hydroxyl and glucosyl modifications of ßCs. Here, we report the presence of the bacterial-like Pictet-Spenglerase gene Fcs1 in the entomopathogenic Beauveria fungi that can catalyze the biosynthesis of the ßC skeleton. The overexpression of Fcs1 in Beauveria bassiana led to the identification of six ßC methyl glycosides, termed bassicarbosides (BCSs) A-F. We verified that the cytochrome P450 (CYP) genes adjacent to Fcs1 cannot oxidize ßCs. Alternatively, the separated CYP684B2 family gene Fcs2 was identified to catalyze ßC hydroxylation together with its cofactor gene Fcs3. The functional homologue of Fcs2 is only present in the Fcs1-containing fungi and highly similar to the Fcs1-connected yet nonfunctional CYP. Both evolved quicker than those from fungi without Fcs1 homologues. Finally, the paired methyl/glucosyl transferase genes were verified to mediate the production of BCSs from hydroxy-ßCs. All these functionally verified genes are located on different chromosomes of Beauveria, which is in contrast to the typical content-clustered feature of fungal biosynthetic gene clusters (BGCs). We also found that the production of BCSs selectively contributed to fungal infection of different insect species. Our findings shed light on the biosynthetic mechanism of ßC glycosides, including the identification of a ßC hydroxylase. The results of this study also propose an evolving process of fungal BGC formation following the horizontal transfer of a bacterial gene to fungi.
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Alcaloides , Beauveria , Animales , Carbolinas , Sistema Enzimático del Citocromo P-450/genética , Familia de Multigenes , Hongos/genética , Beauveria/genéticaRESUMEN
Gastric cancer metastasis is a major cause of poor prognosis. Our previous research showed that methionine restriction (MR) lowers the invasiveness and motility of gastric carcinoma. In this study, we investigated the particular mechanisms of MR on gastric carcinoma metastasis. In vitro, gastric carcinoma cells (AGS, SNU-5, MKN7, KATO III, SNU-1, and MKN45) were grown in an MR medium for 24 h. In vivo, BALB/c mice were given a methionine-free (Met-) diet. Transwell assays were used to investigate cell invasion and migration. The amounts of Krüppel like factor 10 (KLF10) and cystathionine ß-synthase (CBS) were determined using quantitative real-time PCR and Western blot. To determine the relationship between KLF10 and CBS, chromatin immunoprecipitation and a dual-luciferase reporter experiment were used. Hematoxylin-eosin staining was used to detect lung metastasis. Liquid chromatography-mass spectrometry was used to determine cystathionine content. MR therapy had varying effects on the invasion and migration of gastric carcinoma cells AGS, SNU-5, MKN7, KATO III, SNU-1, and MKN45. KLF10 was highly expressed in AGS cells but poorly expressed in KATO III cells. KLF10 improved MR's ability to prevent gastric carcinoma cell invasion and migration. In addition, KLF10 may interact with CBS, facilitating transcription. Further detection revealed that inhibiting the KLF10/CBS-mediated trans-sulfur pathway lowered Met-'s inhibitory effect on lung metastasis development. KLF10 transcription activated CBS, accelerated the trans-sulfur pathway, and increased gastric carcinoma cells' susceptibility to MR.
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Carcinoma , Neoplasias Pulmonares , Neoplasias Gástricas , Ratones , Animales , Metionina/metabolismo , Cistationina betasintasa/genética , Cistationina betasintasa/metabolismo , Neoplasias Gástricas/patología , Racemetionina , Azufre , Neoplasias Pulmonares/genética , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de la Respuesta de Crecimiento Precoz/metabolismoRESUMEN
The prevention and treatment of gastric cancer has been the focus and difficulty of medical research. We aimed to explore the mechanism of inhibiting migration and invasion of gastric cancer cells by methionine restriction (MR). The human gastric cancer cell lines AGS and MKN45 cultured with complete medium (CM) or medium without methionine were used for in vitro experiments. MKN45 cells were injected tail vein into BALB/c nude mice and then fed with normal diet or methionine diet for in vivo experiments. MR treatment decreased cell migration and invasion, increased E-cadherin expression, decreased N-cadherin and p-p65 expressions, and inhibited nuclear p65 translocation of AGS and MKN45 cells when compared with CM group. MR treatment increased IκBα protein expression and protein stability, and decreased IκBα protein ubiquitination level and TRIM47 expression. TRIM47 interacted with IκBα protein, and overexpression of TRIM47 reversed the regulatory effects of MR. TRIM47 promoted lung metastasis formation and partially attenuated the effect of MR on metastasis formation in vivo compared to normal diet group mice. MR reduces TRIM47 expression, leads to the degradation of IκBα, and then inhibits the translocation of nuclear p65 and the migration and invasion of gastric cancer cells.
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Neoplasias Gástricas , Animales , Humanos , Ratones , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Metionina/metabolismo , Metionina/farmacología , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Inhibidor NF-kappaB alfa/metabolismo , Inhibidor NF-kappaB alfa/farmacología , Proteínas Nucleares/metabolismo , Racemetionina/metabolismo , Racemetionina/farmacología , Neoplasias Gástricas/metabolismo , Proteínas de Motivos Tripartitos/metabolismoRESUMEN
An independent correlation between pre-RDW and 1-year mortality after surgery in elderly hip fracture can be used to predict mortality in elderly hip fracture patients and has predictive significance in anemia patients. With further research, a treatment algorithm can be developed to potentially identify patients at high risk of preoperative mortality. INTRODUCTION: Red blood cell distribution width (RDW) is an independent predictor of various disease states in elderly individuals, but its association with the prognosis of elderly hip fracture patients is controversial. This study aimed to evaluate the prognostic value of RDW in such patients, construct a prediction model containing RDW using random survival forest (RSF) and Cox regression analysis, and compare RDW in patients with and without anemia. METHODS: We retrospectively analyzed the data of elderly patients who underwent hip fracture surgery, selected the best variables using RSF, stratified the independent variables by Cox regression analysis, constructed a 1-year mortality prediction model of elderly hip fracture with RDW, and conducted internal validation and external validation. RESULTS: Two thousand one hundred six patients were included in this study. The RSF algorithm selects 12 important influencing factors, and Cox regression analysis showed that eight variables including preoperative RDW (pre-RDW) were independent risk factors for death within 1-year after hip fracture surgery in elderly patients. Stratified analysis showed that pre-RDW was still independently associated with 1-year mortality in the non-anemia group and not in the anemia group. The nomogram prediction model had high differentiation and fit, and the prediction model constructed by the total cohort of patients was also used for validation of patients in the anemia patients and obtained good clinical benefits. CONCLUSION: An independent correlation between pre-RDW and 1-year mortality after surgery in elderly hip fracture can be used to predict mortality in elderly hip fracture patients and has predictive significance in anemia patients.
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Anemia , Fracturas de Cadera , Humanos , Anciano , Índices de Eritrocitos , Estudios Retrospectivos , Oportunidad Relativa , Anemia/complicaciones , PronósticoRESUMEN
BACKGROUND: The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients <3 years of age remains controversial. Data on haploidentical donor (HID) transplants in this age group is limited. PATIENTS AND METHODS: We retrospectively analyzed the prognosis of 97 patients with acute leukemia aged <3 years who underwent HID transplantation at our institute. RESULTS: With a median follow-up of 45 months, the 3-year disease-free survival (DFS), overall survival (OS), and 3-year cumulative incidence rate of treatment-related mortality were 69.3% (95% confidence interval (CI): 59.9%-78.7%), 74.2% (95% CI: 65.2%-83.2%), and 3.6% (95% CI: 0.9%-9.7%) in all 97 patients, respectively. The 3-year DFS and OS rate in patients diagnosed <1 year and patients diagnosed ≥1 year were comparable: 77.8% (95% CI: 62.2%-93.4%) versus 66.3% (95% CI: 55.0%-77.6%, p = .253) and 82.5% (95% CI: 66.3-98.7%) versus 72.8% (95% CI: 61.9%-83.7%, p = .153), respectively. At the last follow-up, 23 patients had died, and 20 had died of relapse. Multivariate analysis revealed that positive pre-HSCT flow cytometric minimal residual disease (hazard ratio 5.605, p = .000) and AML-M7 expression (hazard ratio 2.906, p = .014) were independent adverse prognostic variables for relapse. CONCLUSIONS: HID transplantation is potent and safe for infants and young patients with acute leukemia. Relapse is the primary cause of treatment failure.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Preescolar , Estudios Retrospectivos , Trasplante Homólogo , Leucemia Mieloide Aguda/terapia , Pronóstico , Enfermedad Aguda , Enfermedad Crónica , RecurrenciaRESUMEN
PURPOSE: Achieving a pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (NCRT) remains a challenge for most patients with rectal cancer. Exploring the potential of combining NCRT with immunotherapy or targeted therapy for those achieving a partial response (PR) offers a promising avenue to enhance treatment efficacy. This study investigated the impact of NCRT on the tumor microenvironment in locally advanced rectal cancer (LARC) patients who exhibited a PR. METHODS: This was a retrospective, observational study. Five patients demonstrating a PR after neoadjuvant treatment for LARC were enrolled in the study. Biopsy samples before treatment and resected specimens after treatment were stained with a panel of 26 antibodies targeting various immune and tumor-related markers, each labeled with distinct metal tags. The labeled samples were then analyzed using the Hyperion imaging system. RESULTS: Heterogeneity within the tumor microenvironment was observed both before and after NCRT. Notably, tumor-associated macrophages, CD4 + T cells, CD8 + T cells, CD56 + natural killer cells, tumor-associated neutrophils, cytokeratin, and E-cadherin exhibited slight increase in abundance within the tumor microenvironment following treatment (change ratios = 0.78, 0.2, 0.27, 0.32, 0.17, 0.46, 0.32, respectively). Conversely, the number of CD14 + monocytes, CD19 + B cells, CD45 + CD4 + T cells, collagen I, α-smooth muscle actin, vimentin, and ß-catenin proteins displayed significant decreases post-treatment (change ratios = 1.73, 1.92, 1.52, 1.25, 1.52, 1.12, 2.66, respectively). Meanwhile, Foxp3 + regulatory cells demonstrated no significant change (change ratio = 0.001). CONCLUSIONS: NCRT has diverse effects on various components of the tumor microenvironment in LARC patients who achieve a PR after treatment. Leveraging combination therapies may optimize treatment outcomes in this patient population.
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Terapia Neoadyuvante , Neoplasias del Recto , Microambiente Tumoral , Humanos , Neoplasias del Recto/terapia , Neoplasias del Recto/patología , Neoplasias del Recto/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Quimioradioterapia , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
In recent years, the stroke incidence has been increasing year by year, and the related sequelae after stroke, such as cognitive impairment, motor dysfunction, and post-stroke depression, seriously affect the patient's rehabilitation and daily activities. Repetitive transcranial magnetic stimulation (rTMS), as a safe, non-invasive, and effective new rehabilitation method, has been widely recognized in clinical practice. This article reviews the application and research progress of rTMS in treating different functional impairments (cognitive impairment, motor dysfunction, unilateral spatial neglect, depression) after stroke in recent years, and preliminary summarized the possible mechanisms. It has been found that the key parameters that determine the effectiveness of rTMS in improving post-stroke functional impairments include pulse number, stimulated brain areas, stimulation intensity and frequency, as well as duration. Generally, high-frequency stimulation is used to excite the ipsilateral cerebral cortex, while low-frequency stimulation is used to inhibit the contralateral cerebral cortex, thus achieving a balance of excitability between the two hemispheres. However, the specific mechanisms and the optimal stimulation mode for different functional impairments have not yet reached a consistent conclusion, and more research is needed to explore and clarify the best way to use rTMS. Furthermore, we will identify the issues and challenges in the current research, explore possible mechanisms to deepen understanding of rTMS, propose future research directions, and offer insightful insights for better clinical applications.
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Agnosia , Rehabilitación de Accidente Cerebrovascular , Accidente Cerebrovascular , Humanos , Estimulación Magnética Transcraneal , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/terapia , Encéfalo , Corteza CerebralRESUMEN
Edible bird's nest (EBN), a most highly priced and valuable foodstuff, contains high percentage of proteins and carbohydrates. However, proteins adhering to these carbohydrates make the EBN hard and tough, which need to be boiled as the bird's nest soup to make the Chinese cuisine. To overcome the hard and tough texture of EBN and improve the digestion degrees, the present study screened and identified a probiotic strain Bacillus amyloliquefaciens YZW02 from 5-year stored EBN sample completely solubilizing EBN for the first time. The 24-h B. amyloliquefaciens fermented EBN contained 20.30-21.48 mg/mL of the soluble protein contents with a recovery rate of 98-100%, DPPH radical scavenging rate of 84.76% and ABTS radical scavenging capacity of 41.05%. The mixed fermentation of B. amyloliquefaciens YZW02 and Bacillus natto BN1 were further applied to improve the low-MW peptide percentages and antioxidant activities. The mixed-fermentation of B. natto BN1 with 4-h cultured B. amyloliquefaciens YZW02 had the lowest percentage (82.23%) of >12-kDa proteins/peptides and highest percentages of 3-12 kDa, 1-3 kDa and 0.1-1 kDa peptides of 8.6% ± 0.08, 7.57% ± 0.09, 1.77% ± 0.05 and 0.73% ± 0.05, with the highest DPPH, ABTS and â¢OH scavenging capacity of 90.23%, 46.45% and 49.12%, respectively. These findings would provide an efficient strategy for improving the solubility and antioxidant activities of EBNs.
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Antioxidantes , Bacillus amyloliquefaciens , Aves , Fermentación , Probióticos , Solubilidad , Bacillus amyloliquefaciens/química , Bacillus amyloliquefaciens/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Animales , Probióticos/química , Probióticos/metabolismo , Aves/microbiologíaRESUMEN
PURPOSE: The adverse health consequences of premarital sex and childhood sexual abuse (CSA) are both global public health problems. Based on a random sample of college students from a Chinese city, this study investigated the relationship between CSA severity and premarital sex among students, focusing on sex differences. METHODS: A total of 2722 college students from 4 schools in Luzhou were recruited by multistage random sampling. Self-administered questionnaires were used to measure CSA experiences and premarital sex. Binary logistic regression analyses were conducted to analyse the relationship between CSA and premarital sex. RESULTS: The prevalence of CSA was 9.39%, and that of mild, moderate and severe CSA was 4.04%, 2.90% and 2.46%, respectively. The premarital sex reporting rate was 22.42%. After adjusting for confounding variables, CSA was positively associated with premarital sex. Notably, a cumulative effect of CSA on premarital sex was observed among students. Further stratification analyses showed that males who experienced CSA had a higher premarital sex rate than females, and this sex difference was also observed among students with different CSA severities. CONCLUSION: CSA and its severity were associated with premarital sex among college students. Furthermore, this association was stronger for males than females. Therefore, it is important to emphasize CSA prevention, especially for boys. These findings can promote understanding of the effects of CSA on premarital sex, and CSA prevention and intervention strategies should consider CSA severity and sex differences.
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Abuso Sexual Infantil , Caracteres Sexuales , Conducta Sexual , Femenino , Humanos , Masculino , China/epidemiología , Estudiantes , Pueblos del Este de AsiaRESUMEN
Invasion and metastasis are the leading causes of death in individuals with malignant tumors, including gastric cancer. In this study, we aim to explore the effect and related mechanisms of methionine restriction (MR) on gastric carcinoma metastasis. In the MR cell model, gastric carcinoma cells are cultured in the MR medium, and in the animal model, BALB/c nude rodents are administered with a methionine-free diet after receiving injections of MKN45 cells into the caudal vein. Transwell assay is used to detect cell invasion and migration. Chromatin immunoprecipitation is performed to investigate the levels of H3K9me2, H3K27Ac, and H3K27me3 in the E-cadherin promoter. The results show that MR inhibits gastric carcinoma cell migration, invasion, and lung metastasis. MR increases E-cadherin while reducing the H3K27me3 level in the E-cadherin promoter. E-cadherin expression in gastric carcinoma cells is adversely regulated by HDAC2. Overexpressing HDAC2 reduces the H3K27Ac level in the E-cadherin promoter, while interfering with HDAC2 increases the H3K27Ac level. HDAC2 interference under MR conditions further upregulates E-cadherin expression and inhibits gastric carcinoma cell migration, invasion, and lung metastasis. MR combined with HDAC2 interference promotes E-cadherin expression by mediating the methylation and acetylation of E-cadherin, thus inhibiting the invasion, migration, and lung metastasis of gastric carcinoma cells. Our study provides a new theoretical basis for the inhibitory effect of MR on gastric cancer.
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Carcinoma , Neoplasias Pulmonares , Neoplasias Gástricas , Animales , Neoplasias Gástricas/patología , Regulación hacia Arriba , Histonas/metabolismo , Metionina/metabolismo , Cadherinas/genética , Cadherinas/metabolismo , Neoplasias Pulmonares/genética , Racemetionina/metabolismo , Línea Celular Tumoral , Movimiento Celular , Invasividad Neoplásica/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
The propensity to metastasize is the most important prognostic indicator for solid cancers. New insights into the mechanisms of early carcinogenesis have revealed micrometastases are generated far earlier than previously thought. Evidence supports a synergistic relationship between vascular and lymphatic seeding which can occur before there is clinical evidence of a primary tumour. Early vascular seeding prepares distal sites for colonisation while regional lymphatics are co-opted to promote facilitative cancer cell mutations. In response, the host mounts a global inflammatory and immunomodulatory response towards these cells supporting the concept that cancer is a systemic disease. Cancer staging systems should be refined to better reflect cancer cell loads in various tissue compartments while clinical perspectives should be broadened to encompass this view when approaching high-risk cancers. Measured adjunctive therapies implemented earlier for low-volume, in-transit cancer offers the prospect of preventing advanced disease and the need for heroic therapeutic interventions. This review seeks to re-appraise how we view the metastatic process for solid cancers. It will explore in-transit metastasis in the context of high-risk skin cancer and how it dictates disease progression. It will also discuss how these implications will influence our current staging systems and its consequences on management.
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Micrometástasis de Neoplasia , Neoplasias Cutáneas , Humanos , Metástasis Linfática , Micrometástasis de Neoplasia/patología , Neoplasias Cutáneas/patología , Pronóstico , Piel/patología , Biopsia del Ganglio Linfático Centinela , Estadificación de NeoplasiasRESUMEN
Breast cancer is the most common malignancy in the world and one of the leading causes of cancer death, which is a heterogeneous disease involving genetic and environmental factors. Breast cancer stem cells (BCSCs) are the main players in the aggressiveness of different tumors, at the same time, these cells are the main challenge for cancer treatment. There are multiple treatment options for breast cancer (BC) patients and the lack of understanding of prognostic and predictive biomarkers for breast cancer is a potential research direction for us to develop better treatments in the future. In this paper, we conducted a correlation analysis between SIK2 and clinical traits by searching numerous BRCA datasets in the GEO database. The model was constructed and validated by incorporating tumor samples from the TCGA-BRCA cohort. Surprisingly, we found differential expression of SIK2 gene in individual tumor samples from the UCSC database. Subsequently, we found significantly high expression of SIK2 in epithelial cells by comparing the differential expression of SIK2 in different cell subpopulations and performed subsequent immune infiltration and pathway correlation analysis. Differential genes in SIK2+ epithelial cells, which may be potential therapeutic targets for breast cancer. In conclusion, our results suggest that SIK2 may be a potential prognostic and predictive biomarker that could serve as an oncogenic messenger for breast cancer. This discovery of SIK2 may provide more valuable references for potential therapeutic tools for breast cancer.
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Neoplasias de la Mama , Neoplasias Mamarias Animales , Femenino , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Células Epiteliales/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
With the rapid development of fully automatic operation (FAO) and location-based services, the evaluation criteria of average localization accuracy can no longer meet our demands, in favor of deterministic localization. However, most localization researches modeled localization performance function and enhanced it by minimizing average localization root mean square error (RMSE). The performance degradation in a small region was not considered. In this paper, we present a survey of deterministic localization and analyze the relationship between accuracy and certainty. In this paper, two common solutions of localization enhancement are presented and their localization certainties are discussed. Furthermore, we carry out related localization enhancement experiments in rail transit line and analyze their improvement on deterministic localization. The experimental results show that the overall localization performance is improved, while the deterministic localization requires the stricter solution to promote.
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The phenylpyrazole derivative 5-amino-3-[1-cyano-2-(3-phenyl-1H-pyrazol-4-yl) vinyl]-1-phenyl-1H-pyrazole-4-carbonitrile (LN002), which was screened out through high-throughput molecular docking for the AOX target, exhibits promising efficacy against Cryptosporidium. However, its poor water solubility limits its oral bioavailability and therapeutic utility. In this study, solid dispersion agents were prepared by using HP-ß-CD and Soluplus® and characterized through differential scanning calorimetry, Fourier transform infrared, powder X-ray diffraction, and scanning electron microscopy. Physical and chemical characterization showed that the crystal morphology of LN002 transformed into an amorphous state, thus forming a solid dispersion of LN002. The solid dispersion prepared with an LN002/HP-ß-CD/Soluplus® mass ratio of 1:3:9 (w/w/w) exhibited significantly increased solubility and cumulative dissolution. Meanwhile, LN002 SDs showed good preservation stability under accelerated conditions of 25 °C and 75% relative humidity. The complexation of LN002 with HP-ß-CD and Soluplus® significantly improved water solubility, pharmacological properties, absorption, and bioavailability.
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Disponibilidad Biológica , Cryptosporidium parvum , Solubilidad , Cryptosporidium parvum/efectos de los fármacos , Animales , Administración Oral , Polietilenglicoles/química , Pirazoles/química , Pirazoles/farmacocinética , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Simulación del Acoplamiento Molecular , Polivinilos/química , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos X , Rastreo Diferencial de Calorimetría , Ratas , Masculino , 2-Hidroxipropil-beta-Ciclodextrina/químicaRESUMEN
BACKGROUND: The treatment of gastric cancer remains a challenge. METHODS: We divided gastric cancer into three subtypes based on 14 cancer functional states. We investigated differences between subtypes through multi-omics data, especially at the single-cell level, which allowed us to analyze differences from the perspective of each type of cell rather than the whole. RESULTS: The cluster 1 is characterized by high levels of tumor progression-related cancer functional status, worst survival outcomes, low metabolic level, high infiltration of immunosuppressive cells, high copy number variations (CNV), and low tumor mutational burden (TMB). The cluster 2 is characterized by low levels of tumor progression-related cancer functional status, favorable prognosis, moderate metabolic level, low immune cell infiltration, high CNV, and moderate TMB. Then, the cluster 3 is characterized by the high level of all cancer functional status, high metabolic level, low CNV, high TMB, high infiltration of immune cells with high cytotoxicity, and better response to immunotherapy. We also established a prognostic model based on cancer functional status and validated its robustness. CONCLUSIONS: Collectively, our study identified gastric cancer subtypes and provided new insights into the clinical treatment of gastric cancer.
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Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Variaciones en el Número de Copia de ADN/genética , Inmunosupresores , Inmunoterapia , Multiómica , Pronóstico , Microambiente TumoralRESUMEN
We generate spin squeezed ground states in an atomic spin-1 Bose-Einstein condensate tuned near the quantum-critical point separating the different spin phases of the interacting ensemble using a novel nonadiabatic technique. In contrast to typical nonequilibrium methods for preparing atomic squeezed states by quenching through a quantum phase transition, squeezed ground states are time stationary with a constant quadrature squeezing angle. A squeezed ground state with 6-8 dB of squeezing and a constant squeezing angle is demonstrated. The long-term evolution of the squeezed ground state is measured and shows gradual decrease in the degree of squeezing over 2 s that is well modeled by a slow tuning of the Hamiltonian due to the loss of atomic density. Interestingly, modeling the gradual decrease does not require additional spin decoherence models despite a loss of 75% of the atoms.
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This study explores the role of the long noncoding RNA (LncRNA) CRNDE in cisplatin (CDDP) resistance of gastric cancer (GC) cells. Here, we show that LncRNA CRNDE is upregulated in carcinoma tissues and tumor-associated macrophages (TAMs) of GC patients. In vitro experiments show that CRNDE is enriched in M2-polarized macrophage-derived exosomes (M2-exo) and is transferred from M2 macrophages to GC cells via exosomes. Silencing CRNDE in M2-exo reverses the promotional effect of M2-exo on cell proliferation in CDDP-treated GC cells and homograft tumor growth in CDDP-treated nude mice. Mechanistically, CRNDE facilitates neural precursor cell expressed developmentally downregulated protein 4-1 (NEDD4-1)-mediated phosphatase and tensin homolog (PTEN) ubiquitination. Silencing CRNDE in M2-exo enhances the CDDP sensitivity of GC cells treated with M2-exo, which is reduced by PTEN knockdown. Collectively, these data reveal a vital role for CRNDE in CDDP resistance of GC cells and suggest that the upregulation of CRNDE in GC cells may be attributed to the transfer of TAM-derived exosomes.
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Exosomas , MicroARNs , ARN Largo no Codificante , Neoplasias Gástricas , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Cisplatino/metabolismo , Cisplatino/farmacología , Cisplatino/uso terapéutico , Exosomas/genética , Exosomas/metabolismo , Exosomas/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Ratones Desnudos , MicroARNs/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMEN
BACKGROUND: The development of new-onset atrial fibrillation (NOAF) after acute myocardial infarction (AMI) is a clinical complication that requires a better understanding of the causative risk factors. This study aimed to explore the risk factors and the expression and function of miR-1 and miR-133a in new atrial fibrillation after AMI. METHODS: We collected clinical data from 172 patients with AMI treated with emergency percutaneous coronary intervention (PCI) between October 2021 and October 2022. Independent predictors of NOAF were determined using binary logistic univariate and multivariate regression analyses. The predictive value of NOAF was assessed using the area under the receiver operating characteristic (ROC) curve for related risk factors. In total, 172 venous blood samples were collected preoperatively and on the first day postoperatively; the expression levels of miR-1 and miR-133a were determined using the polymerase chain reaction. The clinical significance of miR-1 and miR-133a expression levels was determined by Spearman correlation analysis. RESULTS: The Glasgow prognostic score, left atrial diameter, and infarct area were significant independent risk factors for NOAF after AMI. We observed that the expression levels of miR-1 and miR-133a were significantly higher in the NOAF group than in the non-NOAF group. On postoperative day 1, strong associations were found between miR-133a expression levels and the neutrophil ratio and between miR-1 expression levels and an increased left atrial diameter. CONCLUSIONS: Our findings indicate that the mechanism of NOAF after AMI may include an inflammatory response associated with an increased miR-1-related mechanism. Conversely, miR-133a could play a protective role in this clinical condition.
Asunto(s)
Apéndice Atrial , Fibrilación Atrial , MicroARNs , Infarto del Miocardio , Intervención Coronaria Percutánea , Humanos , Fibrilación Atrial/etiología , Fibrilación Atrial/genética , MicroARNs/genética , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/genética , Intervención Coronaria Percutánea/efectos adversosRESUMEN
BACKGROUND: Polarization of microglia, the resident retinal immune cells, plays important roles in mediating both injury and repair responses post-retinal ischemia-reperfusion (I/R) injury, which is one of the main pathological mechanisms behind ganglion cell apoptosis. Aging could perturb microglial balances, resulting in lowered post-I/R retinal repair. Young bone marrow (BM) stem cell antigen 1-positive (Sca-1+) cells have been demonstrated to have higher reparative capabilities post-I/R retinal injury when transplanted into old mice, where they were able to home and differentiate into retinal microglia. METHODS: Exosomes were enriched from young Sca-1+ or Sca-1- cells, and injected into the vitreous humor of old mice post-retinal I/R. Bioinformatics analyses, including miRNA sequencing, was used to analyze exosome contents, which was confirmed by RT-qPCR. Western blot was then performed to examine expression levels of inflammatory factors and underlying signaling pathway proteins, while immunofluorescence staining was used to examine the extent of pro-inflammatory M1 microglial polarization. Fluoro-Gold labelling was then utilized to identify viable ganglion cells, while H&E staining was used to examine retinal morphology post-I/R and exosome treatment. RESULTS: Sca-1+ exosome-injected mice yielded better visual functional preservation and lowered inflammatory factors, compared to Sca-1-, at days 1, 3, and 7 days post-I/R. miRNA sequencing found that Sca-1+ exosomes had higher miR-150-5p levels, compared to Sca-1- exosomes, which was confirmed by RT-qPCR. Mechanistic analysis found that miR-150-5p from Sca-1+ exosomes repressed the mitogen-activated protein kinase kinase kinase 3 (MEKK3)/JNK/c-Jun axis, leading to IL-6 and TNF-α downregulation, and subsequently reduced microglial polarization, all of which contributes to reduced ganglion cell apoptosis and preservation of proper retinal morphology. CONCLUSION: This study elucidates a potential new therapeutic approach for neuroprotection against I/R injury, via delivering miR-150-5p-enriched Sca-1+ exosomes, which targets the miR-150-5p/MEKK3/JNK/c-Jun axis, thereby serving as a cell-free remedy for treating retinal I/R injury and preserving visual functioning.