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1.
Nat Cancer ; 2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39242942

RESUMEN

Prostate cancer (PCa) exhibits significant geoethnic disparities as reflected by distinct variations in the cancer genome and disease progression. Here, we perform a comprehensive proteogenomic characterization of localized high-risk PCa utilizing paired tumors and nearby tissues from 125 Chinese male patients, with the primary objectives of identifying potential biomarkers, unraveling critical oncogenic events and delineating molecular subtypes with poor prognosis. Our integrated analysis highlights the utility of GOLM1 as a noninvasive serum biomarker. Phosphoproteomics analysis reveals the crucial role of Ser331 phosphorylation on FOXA1 in regulating FOXA1-AR-dependent cistrome. Notably, our proteomic profiling identifies three distinct subtypes, with metabolic immune-desert tumors (S-III) emerging as a particularly aggressive subtype linked to poor prognosis and BCAT2 catabolism-driven PCa progression. In summary, our study provides a comprehensive resource detailing the unique proteomic and phosphoproteomic characteristics of PCa molecular pathogenesis and offering valuable insights for the development of diagnostic and therapeutic strategies.

2.
Chem Sci ; 2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39246341

RESUMEN

The linking chemistry between molecular catalysts and substrates is a crucial challenge for enhancing electrocatalytic performance. Herein, we elucidate the influence of various immobilization methods of amino-substituted Ni phthalocyanine catalysts on their electrocatalytic CO2 reduction reaction (eCO2RR) activity. A graphite-conjugated Ni phthalocyanine, Ni(NH2)8Pc-GC, demonstrates remarkable electrocatalytic performance both in H-type and flow cells. In situ infrared spectroscopy and theoretical calculations reveal that the graphite conjugation, through strong electronic coupling, increases the electron density of the active site, reduces the adsorption energy barrier of *COOH, and enhances the catalytic performance. As the cathode catalyst, Ni(NH2)8Pc-GC also displays remarkable charge-discharge cycle stability of over 50 hours in a Zn-CO2 battery. These findings underscore the significance of immobilization methods and highlight the potential for further advancements in eCO2RR.

3.
Sci Rep ; 14(1): 20199, 2024 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-39215105

RESUMEN

Temozolomide (TMZ) resistance is a major challenge in the treatment of glioblastoma (GBM). Tumour reproductive cells (TRCs) have been implicated in the development of chemotherapy resistance. By culturing DBTRG cells in three-dimensional soft fibrin gels to enrich GBM TRCs and performing RNA-seq analysis, the expression of stanniocalcin-1 (STC), a gene encoding a secreted glycoprotein, was found to be upregulated in TRCs. Meanwhile, the viability of TMZ-treated TRC cells was significantly higher than that of TMZ-treated 2D cells. Analysis of clinical data from CGGA (Chinese Glioma Genome Atlas) database showed that high expression of STC1 was closely associated with poor prognosis, glioma grade and resistance to TMZ treatment, suggesting that STC1 may be involved in TMZ drug resistance. The expression of STC1 in tissues and cells was examined, as well as the effect of STC1 on GBM cell proliferation and TMZ-induced DNA damage. The results showed that overexpression of STC1 promoted and knockdown of STC1 inhibited TMZ-induced DNA damage. These results were validated in an intracranial tumour model. These data revealed that STC1 exerts regulatory functions on MGMT expression in GBM, and provides a rationale for targeting STC1 to overcome TMZ resistance.


Asunto(s)
Neoplasias Encefálicas , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Glioblastoma , Glicoproteínas , Temozolomida , Animales , Femenino , Humanos , Masculino , Ratones , Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Daño del ADN , Metilasas de Modificación del ADN/metabolismo , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Enzimas Reparadoras del ADN/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Glicoproteínas/metabolismo , Glicoproteínas/genética , Temozolomida/farmacología , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo
4.
J Clin Invest ; 134(18)2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39146021

RESUMEN

Strategies beyond hormone-related therapy need to be developed to improve prostate cancer mortality. Here, we show that FUBP1 and its methylation were essential for prostate cancer progression, and a competitive peptide interfering with FUBP1 methylation suppressed the development of prostate cancer. FUBP1 accelerated prostate cancer development in various preclinical models. PRMT5-mediated FUBP1 methylation, regulated by BRD4, was crucial for its oncogenic effect and correlated with earlier biochemical recurrence in our patient cohort. Suppressed prostate cancer progression was observed in various genetic mouse models expressing the FUBP1 mutant deficient in PRMT5-mediated methylation. A competitive peptide, which was delivered through nanocomplexes, disrupted the interaction of FUBP1 with PRMT5, blocked FUBP1 methylation, and inhibited prostate cancer development in various preclinical models. Overall, our findings suggest that targeting FUBP1 methylation provides a potential therapeutic strategy for prostate cancer management.


Asunto(s)
ADN Helicasas , Proteínas de Unión al ADN , Neoplasias de la Próstata , Proteína-Arginina N-Metiltransferasas , Proteínas de Unión al ARN , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Humanos , Animales , Ratones , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Metilación , ADN Helicasas/genética , ADN Helicasas/metabolismo , Progresión de la Enfermedad , Línea Celular Tumoral , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
5.
Theor Appl Genet ; 137(9): 211, 2024 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-39210238

RESUMEN

Soybean, a source of plant-derived lipids, contains an array of fatty acids essential for health. A comprehensive understanding of the fatty acid profiles in soybean is crucial for enhancing soybean cultivars and augmenting their qualitative attributes. Here, 180 F10 generation recombinant inbred lines (RILs), derived from the cross-breeding of the cultivated soybean variety 'Jidou 12' and the wild soybean 'Y9,' were used as primary experimental subjects. Using inclusive composite interval mapping (ICIM), this study undertook a quantitative trait locus (QTL) analysis on five distinct fatty acid components in the RIL population from 2019 to 2021. Concurrently, a genome-wide association study (GWAS) was conducted on 290 samples from a genetically diverse natural population to scrutinize the five fatty acid components during the same timeframe, thereby aiming to identify loci closely associated with fatty acid profiles. In addition, haplotype analysis and the Kyoto Encyclopedia of Genes and Genomes pathway analysis were performed to predict candidate genes. The QTL analysis elucidated 23 stable QTLs intricately associated with the five fatty acid components, exhibiting phenotypic contribution rates ranging from 2.78% to 25.37%. In addition, GWAS of the natural population unveiled 102 significant loci associated with these fatty acid components. The haplotype analysis of the colocalized loci revealed that Glyma.06G221400 on chromosome 6 exhibited a significant correlation with stearic acid content, with Hap1 showing a markedly elevated stearic acid level compared with Hap2 and Hap3. Similarly, Glyma.12G075100 on chromosome 12 was significantly associated with the contents of oleic, linoleic, and linolenic acids, suggesting its involvement in fatty acid biosynthesis. In the natural population, candidate genes associated with the contents of palmitic and linolenic acids were predominantly from the fatty acid metabolic pathway, indicating their potential role as pivotal genes in the critical steps of fatty acid metabolism. Furthermore, genomic selection (GS) for fatty acid components was conducted using ridge regression best linear unbiased prediction based on both random single nucleotide polymorphisms (SNPs) and SNPs significantly associated with fatty acid components identified by GWAS. GS accuracy was contingent upon the SNP set used. Notably, GS efficiency was enhanced when using SNPs derived from QTL mapping analysis and GWAS compared with random SNPs, and reached a plateau when the number of SNP markers exceeded 3,000. This study thus indicates that Glyma.06G221400 and Glyma.12G075100 are genes integral to the synthesis and regulatory mechanisms of fatty acids. It provides insights into the complex biosynthesis and regulation of fatty acids, with significant implications for the directed improvement of soybean oil quality and the selection of superior soybean varieties. The SNP markers delineated in this study can be instrumental in establishing an efficacious pipeline for marker-assisted selection and GS aimed at improving soybean fatty acid components.


Asunto(s)
Mapeo Cromosómico , Ácidos Grasos , Glycine max , Sitios de Carácter Cuantitativo , Glycine max/genética , Glycine max/metabolismo , Ácidos Grasos/metabolismo , Mapeo Cromosómico/métodos , Fenotipo , Polimorfismo de Nucleótido Simple , Haplotipos , Fitomejoramiento , Genes de Plantas , Estudios de Asociación Genética , Estudio de Asociación del Genoma Completo
6.
Sci Total Environ ; 949: 175181, 2024 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-39094660

RESUMEN

The impacts of various drought types on autumn phenology have yet to be extensively explored. We address the influence of pre-season agricultural and meteorological droughts on autumn phenology in the Northern Hemisphere. To this end, enhanced autumn phenology models incorporating drought factors was developed, contributing to a deeper understanding of these complex interactions. The study reveals that there was no significant trend of advancement or delay in the End of Season (EOS) across the Northern Hemisphere based on SIF estimates from 2001 to 2020. The cumulative and delayed impacts of pre-season agricultural drought on EOS were found to be more pronounced than those associated with meteorological drought. The analysis of various evaluation indexes shows that the performance of the Cooling Degree Days (CDD) model incorporating the Standardized Soil Moisture Drought Index (CDDSSMI) in simulating EOS in the Northern Hemisphere is >14 % higher than that of the standard CDD model. Additionally, the performance of the CDD model with the Standardized Precipitation Index (CDDSPI) in simulating EOS in the Northern Hemisphere is improved by >5.6 % compared to the standard CDD model. A comparison of future EOS projections across various models reveals that the CDD model significantly overestimates EOS in different scenarios (SSP245 and SSP585). The CDDSSMI model projects EOS approximately 7 days earlier than the CDD model, and the CDDSPI model projects EOS approximately 5 days earlier than the CDD model. This study highlights the diverse impacts of drought types on plant autumn phenology and underscores the significance of parameterizing drought impacts in autumn phenology models.


Asunto(s)
Agricultura , Sequías , Estaciones del Año , Agricultura/métodos , Modelos Teóricos , Cambio Climático , Monitoreo del Ambiente/métodos
7.
BMC Genomics ; 25(1): 783, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39138389

RESUMEN

Soybean represents a vital source of premium plant-based proteins for human nutrition. Importantly, the level of water-soluble protein (WSP) is crucial for determining the overall quality and nutritional value of such crops. Enhancing WSP levels in soybean plants is a high-priority goal in crop improvement. This study aimed to elucidate the genetic basis of WSP content in soybean seeds by identifying quantitative trait loci (QTLs) and set the foundation for subsequent gene cloning and functional analysis. Using 180 F10 recombinant inbred lines generated by crossing the high-protein soybean cultivar JiDou 12 with the wild variety Ye 9, our researcher team mapped the QTLs influencing protein levels, integrating Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and gene expression profiling to identify candidate genes. During the 2020 and 2022 growing seasons, a standard bell-shaped distribution of protein content trait data was observed in these soybean lines. Eight QTLs affecting protein content were found across eight chromosomes, with LOD scores ranging from 2.59 to 7.30, explaining 4.15-11.74% of the phenotypic variance. Notably, two QTLs were newly discovered, one with a elite allele at qWSPC-15 from Ye 9. The major QTL, qWSPC-19, on chromosome 19 was stable across conditions and contained genes involved in nitrogen metabolism, amino acid biosynthesis, and signaling. Two genes from this QTL, Glyma.19G185700 and Glyma.19G186000, exhibited distinct expression patterns at maturity, highlighting the influence of these genes on protein content. This research revealed eight QTLs for WSP content in soybean seeds and proposed a gene for the key QTL qWSPC-19, laying groundwork for gene isolation and enhanced soybean breeding through the use of molecular markers. These insights are instrumental for developing protein-rich soybean cultivars.


Asunto(s)
Mapeo Cromosómico , Glycine max , Sitios de Carácter Cuantitativo , Semillas , Glycine max/genética , Glycine max/metabolismo , Semillas/genética , Semillas/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Agua/metabolismo , Solubilidad , Fenotipo
8.
FEBS J ; 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39136063

RESUMEN

Renal fibrosis is the common outcome of practically all progressive forms of chronic kidney disease (CKD), a significant societal health concern. Glutamate dehydrogenase (GDH) 1 is one of key enzymes in glutamine metabolism to catalyze the reversible conversion of glutamate to α-ketoglutarate and ammonia. However, its function in renal fibrosis has not yet been proven. In this study, GDH1 expression was significantly downregulated in kidney tissues of both children with kidney disease and animal models of CKD. In vivo, the use of R162 (a GDH1 inhibitor) significantly improved renal fibrosis, as indicated by Sirius red and Masson trichrome staining. These findings are consistent with the impaired expression of fibrosis indicators in kidneys from both the unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (5/6 Nx) models. In vitro, silencing GDH1 or pretreatment with R162 inhibited the induction of fibrosis indicators in tissue kidney proximal tubular cells (TKPTS) treated with Transforming growth factor Beta 1 (TGF-ß1), whereas activating GDH1 worsened TGF-ß1's induction impact. Using RNA-sequence, luciferase reporter assays and Biacore analysis, we demonstrated that GDH1 interacts with Peroxisome proliferator-activated receptor gamma (PPARγ) and blocks its transcriptional activity, independent of the protein's expression. Additionally, R162 treatment boosted PPARγ transcriptional activity, and blocking of this signaling pathway reversed R162's protective effect. Finally, we discovered that R162 treatment or silencing GDH1 greatly lowered reactive oxygen species (ROS) and lipid accumulation. These findings concluded that suppressing GDH1 or R162 treatment could prevent renal fibrosis by augmenting PPARγ transcriptional activity to control lipid accumulation and redox balance.

9.
Phytopathology ; 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39145683

RESUMEN

Verticillium dahliae is a soilborne phytopathogenic fungus causing Verticillium wilt on hundreds of plant species. Several sequenced genomes of V. dahliae are available, but functional characterization of most genes has just begun. Based on our previous comparison of the transcriptome from the wild-type and ΔVdCf2 strains, a significant upregulation of the gene cassette, Vd276-280, in the ΔVdCf2 strain was observed. In this study, the functional characterization of the Vd276-280 gene cassette was performed. Agrobacterium-mediated knockout of this gene cassette in V. dahliae significantly inhibited conidiation, melanized microsclerotium formation in the mutant strains, and their virulence towards cotton. Furthermore, deletion of individual genes in the Vd276-280 gene cassette identified that the disruption of VDAG_07276 and VDAG_07280 delayed microsclerotium formation, inhibited conidiation, and reduced virulence towards cotton. Our data suggest that VDAG_07276 and VDAG_07280 in the Vd276-280 gene cassette mainly act as positive regulators of development and virulence in V. dahliae.

10.
Adv Sci (Weinh) ; : e2407063, 2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-39099335

RESUMEN

Transition metal-nitrogen-carbon (M-N-C) catalysts have emerged as promising candidates for electrocatalytic CO2 reduction reaction (CO2RR) due to their uniform active sites and high atomic utilization rate. However, poor efficiency at low overpotentials and unclear reaction mechanisms limit the application of M-N-C catalysts. In this study, Fe-N-C catalysts are developed by incorporating S atoms onto ordered hierarchical porous carbon substrates with a molecular iron thiophenoporphyrin. The well-prepared FeSNC catalyst exhibits superior CO2RR activity and stability, attributes to an optimized electronic environment, and enhances the adsorption of reaction intermediates. It displays the highest CO selectivity of 94.0% at -0.58 V (versus the reversible hydrogen electrode (RHE)) and achieves the highest partial current density of 13.64 mA cm-2 at -0.88 V. Furthermore, when employed as the cathode in a Zn-CO2 battery, FeSNC achieves a high-power density of 1.19 mW cm-2 and stable charge-discharge cycles. Density functional theory calculations demonstrate that the incorporation of S atoms into the hierarchical porous carbon substrate led to the iron center becoming more electron-rich, consequently improving the adsorption of the crucial reaction intermediate *COOH. This study underscores the significance of hierarchical porous structures and heteroatom doping for advancing electrocatalytic CO2RR and energy storage technologies.

11.
Small ; : e2405533, 2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39212632

RESUMEN

Photocatalysis is a most important approach to addressing global energy shortages and environmental issues due to its environmentally friendly and sustainable properties. The key to realizing efficient photocatalysis relies on developing appropriate catalysts with high efficiency and chemical stability. Among various photocatalysts, Metal-organic frameworks (MOFs)-derived hollow-structured materials have drawn increased attention in photocatalysis based on advantages like more active sites, strong light absorption, efficient transfer of pho-induced charges, excellent stability, high electrical conductivity, and better biocompatibility. Specifically, MOFs-derived hollow-structured materials are widely utilized in photocatalytic CO2 reduction (CO2RR), hydrogen evolution (HER), nitrogen fixation (NRR), degradation, and other reactions. This review starts with the development story of MOFs, the commonly adopted synthesis strategies of MOFs-derived hollow materials, and the latest research progress in various photocatalytic applications are also introduced in detail. Ultimately, the challenges of MOFs-derived hollow-structured materials in practical photocatalytic applications are also prospected. This review holds great potential for developing more applicable and efficient MOFs-derived hollow-structured photocatalysts.

12.
Molecules ; 29(16)2024 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-39202989

RESUMEN

Phosphogypsum is a solid waste with great environmental stockpile pressure produced by the wet production of phosphoric acid. Although there are various methods to purify and utilize phosphogypsum, the means for environmentally friendly, low energy consumption, and high value-added utilization still need to be further explored. Here, CaSO4·2H2O crystal was directly purified and regulated from phosphogypsum by using the anti-solvent method. The antisolvent can be adsorbed in the c-axis direction of the crystal and further inhibit the growth rate in this direction, resulting in a change in the morphology of the crystal. By adjusting the polarity and chain length of the anti-solvent, the morphology of CaSO4·2H2O crystal can change from butterfly-like flake crystals to hexagonal prism-like crystals. When n-propanol with long chain was used as the anti-solvent, the morphology of the CaSO4·2H2O crystal showed a hexagonal prism with a specific surface area of 19.98 m2/g and a Cu2+ loading efficiency of 52.67%. The encouraging results open up new possibilities for the application of phosphogypsum.

13.
PLoS One ; 19(8): e0305772, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39208277

RESUMEN

The task of question matching/retrieval focuses on determining whether two questions are semantically equivalent. It has garnered significant attention in the field of natural language processing (NLP) due to its commercial value. While neural network models have made great strides and achieved human-level accuracy, they still face challenges when handling complex scenarios. In this paper, we delve into the utilization of different specializations encoded in different layers of large-scale pre-trained language models (PTMs). We propose a novel attention-based model called ERNIE-ATT that effectively integrates the diverse levels of semantics acquired by PTMs, thereby enhancing robustness. Experimental evaluations on two challenging datasets showcase the superior performance of our proposed model. It outperforms not only traditional models that do not use PTMs but also exhibits a significant improvement over strong PTM-based models. These findings demonstrate the effectiveness of our approach in enhancing the robustness of question matching/retrieval systems.


Asunto(s)
Procesamiento de Lenguaje Natural , Semántica , Humanos , Redes Neurales de la Computación , Atención/fisiología
14.
Oncogene ; 43(34): 2595-2610, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39068217

RESUMEN

Castration-resistant prostate cancer (CRPC) nearly inevitably develops after long-term treatment with androgen deprivation therapy (ADT), leading to significant mortality. Investigating the mechanisms driving CRPC development is imperative. Here, we determined that the pioneer transcription factor GATA2, which is frequently amplified in CRPC patients, inhibits interferon (IFN)-ß-mediated antitumor immunity, thereby promoting CRPC progression. Employing a genetically engineered mouse model (GEMM), we demonstrated that GATA2 overexpression hindered castration-induced cell apoptosis and tumor shrinkage, facilitating tumor metastasis and CRPC development. Notably, GATA2 drives castration resistance predominantly via repressing castration-induced activation of IFN-ß signaling and CD8+ T-cell infiltration. This finding aligns with the negative correlation between GATA2 expression and IFNB1 expression, as well as CD8+ T-cell infiltration in CRPC patients. Mechanistically, GATA2 recruited PIAS1 as corepressor, and reprogramed the cistrome of IRF3, a key transcription factor of the IFN-ß axis, in an androgen-independent manner. Furthermore, we identified a novel silencer element that facilitated the function of GATA2 and PIAS1 through looping to the IFNB1 promoter. Importantly, depletion of GATA2 augmented antitumor immunity and attenuated CRPC development. Consequently, our findings elucidate a novel mechanism wherein GATA2 promotes CRPC progression by suppressing IFN-ß axis-mediated antitumor immunity, underscoring GATA2 as a promising therapeutic target for CRPC.


Asunto(s)
Factor de Transcripción GATA2 , Interferón beta , Neoplasias de la Próstata Resistentes a la Castración , Animales , Humanos , Masculino , Ratones , Línea Celular Tumoral , Factor de Transcripción GATA2/genética , Factor de Transcripción GATA2/metabolismo , Regulación Neoplásica de la Expresión Génica , Interferón beta/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Transducción de Señal
15.
Artículo en Inglés | MEDLINE | ID: mdl-38961535

RESUMEN

Small cell lung cancer (SCLC) is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models. Here, we analyzed formalin-fixed, paraffin-embedded (FFPE) samples of surgical resections by proteomic profiling, and stratified SCLC into three proteomic subtypes (S-I, S-II, and S-III) with distinct clinical outcomes and chemotherapy responses. The proteomic subtyping was an independent prognostic factor and performed better than current tumor-node-metastasis or Veterans Administration Lung Study Group staging methods. The subtyping results could be further validated using FFPE biopsy samples from an independent cohort, extending the analysis to both surgical and biopsy samples. The signatures of the S-II subtype in particular suggested potential benefits from immunotherapy. Differentially overexpressed proteins in S-III, the worst prognostic subtype, allowed us to nominate potential therapeutic targets, indicating that patient selection may bring new hope for previously failed clinical trials. Finally, analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line immunotherapy. Collectively, our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.


Asunto(s)
Neoplasias Pulmonares , Proteómica , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Carcinoma Pulmonar de Células Pequeñas/terapia , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Proteómica/métodos , Pronóstico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Inmunoterapia , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proteoma
16.
J Pathol ; 264(1): 68-79, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39022843

RESUMEN

Metastasis is the primary culprit behind cancer-related fatalities in multiple cancer types, including prostate cancer. Despite great advances, the precise mechanisms underlying prostate cancer metastasis are far from complete. By using a transgenic mouse prostate cancer model (TRAMP) with and without Phf8 knockout, we have identified a crucial role of PHF8 in prostate cancer metastasis. By complexing with E2F1, PHF8 transcriptionally upregulates SNAI1 in a demethylation-dependent manner. The upregulated SNAI1 subsequently enhances epithelial-to-mesenchymal transition (EMT) and metastasis. Given the role of the abnormally activated PHF8/E2F1-SNAI1 axis in prostate cancer metastasis and poor prognosis, the levels of PHF8 or the activity of this axis could serve as biomarkers for prostate cancer metastasis. Moreover, targeting this axis could become a potential therapeutic strategy for prostate cancer treatment. © 2024 The Pathological Society of Great Britain and Ireland.


Asunto(s)
Factor de Transcripción E2F1 , Transición Epitelial-Mesenquimal , Histona Demetilasas , Neoplasias de la Próstata , Factores de Transcripción de la Familia Snail , Factores de Transcripción , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/enzimología , Animales , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción de la Familia Snail/genética , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factor de Transcripción E2F1/metabolismo , Factor de Transcripción E2F1/genética , Ratones , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Ratones Noqueados , Transducción de Señal , Metástasis de la Neoplasia , Ratones Transgénicos , Movimiento Celular
17.
Int J Clin Pharmacol Ther ; 62(9): 412-422, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39037109

RESUMEN

OBJECTIVES: This study aimed to understand the pharmacokinetics of ticagrelor in Chinese patients with acute coronary syndrome (ACS), identify influencing factors, and inform ticagrelor treatment optimization. MATERIALS AND METHODS: Data from 195 ACS patients, including 491 plasma ticagrelor concentration timepoints and clinical information, were analyzed using NONMEN for pharmacokinetic (PK) parameter factors. The model underwent internal validation with bootstrap methodology. RESULTS: The PK curve of ticagrelor was well delineated using a one disposition compartment model with first-order absorption rate constant, 0.67/h. When the direct bilirubin levels and white plasma cell counts increased, female patients showed decreased glomerular filtration rate, decreased ticagrelor clearance rate, and increased exposure. When the direct bilirubin levels increased and body weight and hemoglobin decreased, rs6787801 was GG compared with AA and GA, the ticagrelor metabolite clearance rate decreased and exposure increased. CONCLUSION: The study offers key insights into ticagrelor's dose-exposure relationship post-percutaneous coronary intervention in ACS patients, highlighting factors critical for personalized treatment strategies.


Asunto(s)
Síndrome Coronario Agudo , Intervención Coronaria Percutánea , Ticagrelor , Humanos , Ticagrelor/farmacocinética , Ticagrelor/uso terapéutico , Síndrome Coronario Agudo/terapia , Síndrome Coronario Agudo/tratamiento farmacológico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Pueblo Asiatico , China , Inhibidores de Agregación Plaquetaria/farmacocinética , Inhibidores de Agregación Plaquetaria/uso terapéutico , Modelos Biológicos , Antagonistas del Receptor Purinérgico P2Y/farmacocinética , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacocinética , Adulto , Pueblos del Este de Asia
18.
J Cancer ; 15(14): 4477-4489, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39006069

RESUMEN

Background: Glioblastoma multiforme (GBM) is the most common malignant form of glioma, but the molecular mechanisms underlying the progression of GBM in hypoxic microenvironment remain elusive. This study aims to explore the pathological functions of hypoxia-responsive genes on GBM progression and its downstream signaling pathways. Methods: RNA-seq was performed in normoxic and hypoxic U87 cells to identify the differentially expressed genes (DEGs) under hypoxia. The mRNA expression levels of hypoxia-responsive gene F3 in glioma clinical samples were analyzed according to the transcriptional information from CGGA, TCGA and Rembrandt databases. EdU, transwell and wound-healing assays were conducted to evaluate the pathological functions of F3 on GBM proliferation and migration under hypoxia. RNA-seq and gene set enrichment analysis were conducted to analyze the enriched pathways in LN229 cells overexpressed F3 compared to controls. GBM cells were treated with NF-κB inhibitor PDTC, and cell experiments were performed to evaluate the effects of PDTC on OE-F3-LN229 and OE-F3-U87 cells. Western blot was performed to validate the downstream pathways. Results: F3 was identified as a hypoxia responsive gene in GBM cells. The mRNA expression level of F3 was negatively correlated with the overall survival of glioma patients, and significantly increased in grade IV and GBM than lower grade or other histology of glioma. Overexpression of F3 enhanced the proliferation and migration of hypoxic U87 and LN229 cells, while knockdown inhibited them. In OE-F3-LN229 cells, the NF-κB pathway was activated, with an increased level of phosphorylated p65. PDTC treatment effectively rescued the enhanced proliferation and migration of OE-F3-LN229 cells under hypoxia, indicating that the effect of F3 on GBM progression is probably dependent on the NF-κB pathway. Conclusion: Hypoxia-induced F3 activates NF-κB pathway through upregulation of the phosphorylated p65, thus promoting the proliferation and migration of GBM cells under hypoxia, which might be a potential therapeutic target for GBM treatment.

19.
World Neurosurg ; 2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38897401

RESUMEN

OBJECTIVE: To investigate the long-term clinical outcomes of staged surgical resection in giant Pituitary Neuroendocrine Tumors(pitNET).Method We performed a retrospective analysis of the clinical data of 16 patients who underwent surgery. The patients were diagnosed and underwent surgery at the Department of Neurosurgery of Shiyan Taihe Hospital from January 2013 to March 2021. Among the cases, 12 patients underwent primarily transsphenoidal surgery followed by secondary transcranial surgery, while 4 patients underwent primarily transsphenoidal surgery followed by secondary transsphenoidal surgery. Before the surgery, all patients underwent a pituitary MRI scan, pituitary hormone level examination, visual acuity, and visual field examination. A pituitary MRI was rechecked within 1 week after the operation. A tumor resection rate of 100% on MRI was considered as a total resection, between 90% to 100% as a subtotal resection, and lower than 90% as a partial resection. After the surgery, regular clinical visits and telephone or internet platform follow-ups were conducted. Outcome In our clinical investigation, after staged surgery 10 patients had a total resection, 5 had a subtotal resection, and 1 had a partial resection depending on the tumor size and invasion. The clinical outcomes showed that 1 case suffered from postoperative intracranial infection, 1 case had decreased visual acuity, and 6 cases experienced decreased pituitary function after surgery.Postoperative complications were cured after symptomatic treatment, except for 1 patient who experienced decreased vision and 1 patient sufferred hypopituitarism required long-term oral levothyroxine tablet treatment. No cases of intracranial hemorrhage or death were caused by intentionally staged resection surgery. Conclusion Staged surgery for giant pitNET is a safe and effective clinical surgery strategy.

20.
Spine Surg Relat Res ; 8(3): 235-242, 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38868799

RESUMEN

The major symptoms of lumbar disc herniation (LDH) are low back pain, radiative lower extremity pain, and lower limb movement disorder. Patients with LDH suffer from great distress in their daily life accompanied by severe economic hardship and difficulty in self-care, with an increasing tendency in the aging population. PubMed and the Cochrane Central Register of Controlled Trials were searched for relevant studies of spontaneous resorption or regression in LDH after conservative treatment and for other potential studies, which included those from inception to June 30, 2023. The objective of this narrative review is to summarize previous literatures about spontaneous resorption in LDH and to discuss the mechanisms and influencing factors in order to assess the probability of spontaneous resorption by conservative treatment. Spontaneous resorption without surgical treatment is influenced by the types and sizes of the LDH, inflammatory responses, and therapeutic factors. If the lumbar disc herniated tissue comprises a higher percentage of cartilage or modic changes have been shown on magnetic resonance imaging (MRI), resorption in LDH is prevented. The bull's eye sign on enhanced MRI, which is a ring enhancement around a protruding disc, is a vital indicator for easy reabsorption. In addition, the type of extrusion and sequestration in LDH could forecast the higher feasibility of natural reabsorption. Moreover, the higher the proportion of protrusion on the intervertebral disc tissue within the spinal canal, the greater the likelihood of reabsorption. Therefore, which illustrates the feasibility of conservative treatments for LDH. Nonsurgical management of LDH with clinical symptoms is recommended by the authors.

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