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1.
Cancer Immunol Immunother ; 73(2): 37, 2024 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-38281198

RESUMEN

BACKGROUND: Numerous studies have highlighted the crucial value of the heavy chain of ferritin (FTH1) as a key regulator of iron metabolism and a suppressor of ferroptosis, intimately tied to the tumor immune microenvironment (TIME). Nevertheless, the precise impact of FTH1 on cancer immunotherapy remains vague. Our study aims to systematically explore the prognostic significance and immune role of FTH1 in pan-cancers immunotherapy. METHODS: Our study delves into the potential of FTH1 as an immunotherapeutic target within the TIME of various solid cancers. The immune landscape and underlying mechanisms of FTH1 in the TIME were investigated by multiple algorithms and bioinformatics methods. Single-cell sequencing analysis and multiplex immunofluorescence staining techniques are applied to observe FTH1 co-expression on both tumor and immune cells. RESULTS: FTH1 exhibited aberrant expression patterns across multiple cancers, which is strongly correlated with immunotherapy resistance. Patients with high FTH1 expression levels tended to derive less benefit from immunotherapies. Moreover, FTH1 demonstrated a significant correlation with TIME infiltration, immune checkpoint molecules, and immune-related pathways. Notably, FTH1 showed a positive association with macrophage infiltrations, its expression was particularly noteworthy in malignant cells and macrophages. Inhibiting FTH1-related signaling pathways appeared to be a potential strategy to counteract tumor immunotherapy resistance. CONCLUSION: Our comprehensive analyses may offer valuable insights into the role of FTH1 in tumor immunotherapy. The observed correlations pave the way for further functional experiments, fostering an enhanced understanding that could shape future research endeavors.


Asunto(s)
Neoplasias , Humanos , Pronóstico , Neoplasias/terapia , Algoritmos , Biología Computacional , Inmunoterapia , Microambiente Tumoral , Ferritinas , Oxidorreductasas
2.
BMC Med ; 20(1): 187, 2022 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-35550592

RESUMEN

BACKGROUND: Cytokines have been reported to alter the response to immune checkpoint inhibitors (ICIs) in patients with the tumor in accordance with their plasma concentrations. Here, we aimed to identify the key cytokines which influenced the responses and stimulated resistance to ICIs and tried to improve immunological response and develop novel clinical treatments in non-small cell lung cancer (NSCLC). METHODS: The promising predictive cytokines were analyzed via the multi-analyte flow assay. Next, we explored the correlation baseline level of plasma cytokines and clinical outcomes in 45 NSCLC patients treated with ICIs. The mechanism of the potential candidate cytokine in predicting response and inducing resistance to ICIs was then investigated. RESULTS: We found NSCLC with a low baseline concentration of IL-6 in plasma specimens or tumor tissues could derive more benefit from ICIs based on the patient cohort. Further analyses revealed that a favorable relationship between PD-L1 and IL-6 expression was seen in NSCLC specimens. Results in vitro showed that PD-L1 expression in the tumor was enhanced by IL-6 via the JAK1/Stat3 pathway, which induced immune evasion. Notably, an adverse correlation was found between IL-6 levels and CD8+ T cells. And a positive association between IL-6 levels and myeloid-derived suppressor cells, M2 macrophages and regulator T cells was also seen in tumor samples, which may result in an inferior response to ICIs. Results of murine models of NSCLC suggested that the dual blockade of IL-6 and PD-L1 attenuated tumor growth. Further analyses detected that the inhibitor of IL-6 stimulated the infiltration of CD8+ T cells and yielded the inflammatory phenotype. CONCLUSIONS: This study elucidated the role of baseline IL-6 levels in predicting the responses and promoting resistance to immunotherapy in patients with NSCLC. Our results indicated that the treatment targeting IL-6 may be beneficial for ICIs in NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Antígeno B7-H1 , Biomarcadores , Linfocitos T CD8-positivos/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Inmunoterapia/métodos , Interleucina-6 , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Ratones
3.
Future Oncol ; 18(19): 2433-2443, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35440164

RESUMEN

The success of sotorasib (AMG-510) and adagrasib (MRTX-849) has resolved the problem of non-availability of drugs for patients with KRASG12C-mutated non-small-cell lung cancer. However, more research is required before these drugs can be introduced as a first-line treatment for those patients, and there are no available drugs for other non-G12C-mutated patients so far; therefore, immunotherapy remains the optimal first-line treatment in this situation. The role of KRAS in affecting the response to immunotherapy in non-small-cell lung cancer has not been fully elucidated. The purpose of this review was to summarize the impact of KRAS mutations, a highly heterogeneous group, on immunotherapy to provide clinicians and researchers with relevant information that can help guide decision-making.


Sotorasib (AMG-510) and adagrasib (MRTX-849) have changed the problem of non-availability of targeted drugs for patients with KRAS-mutated lung cancer. However, thus far, immunotherapy remains the optimal treatment for lung cancer patients with KRAS mutations who have not received previous treatment. The role of KRAS in affecting the response to immunotherapy in non-small-cell lung cancer has not been fully elucidated. The purpose of this review was to summarize the impact of KRAS mutations, a highly heterogeneous group, on immunotherapy to provide clinicians and researchers with relevant information that can help guide decision-making.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Acetonitrilos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Humanos , Factores Inmunológicos/uso terapéutico , Inmunoterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/terapia , Mutación , Piperazinas , Proteínas Proto-Oncogénicas p21(ras)/genética , Pirimidinas
4.
Cancer Sci ; 111(6): 1876-1886, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32187778

RESUMEN

The tumor microenvironment (TME) is a vital component of tumor tissue. Increasing evidence suggests their significance in predicting outcomes and guiding therapies. However, no studies have reported a systematic analysis of the clinicopathologic significance of TME in lung adenocarcinoma (LUAD). Here, we inferred tumor stromal cells in 1184 LUAD patients using computational algorithms based on bulk tumor expression data, and evaluated the clinicopathologic significance of stromal cells. We found LUAD patients showed heterogeneous abundance in stromal cells. Infiltration of stromal cells was influenced by clinicopathologic features, such as age, gender, smoking, and TNM stage. By clustering stromal cells, we identified 2 clinically and molecularly distinct LUAD subtypes with immune active and immune repressed features. The immune active subtype is characterized by repressed metabolism and repressed proliferation of tumor cells, while the immune repressed subtype is characterized by active metabolism and active proliferation of tumor cells. Differentially expressed gene analysis of the two LUAD subtypes identified an immune activation signature. To diagnose TME subtypes practically, we constructed a TME score using principal component analysis based on the immune activation signature. The TME score predicted TME subtypes effectively in 3 independent datasets with areas under the receiver operating characteristic curves of 0.960, 0.812, and 0.819, respectively. In conclusion, we proposed 2 clinically and molecularly distinct LUAD subtypes based on tumor microenvironment that could be valuable in predicting clinical outcome and guiding immunotherapy.


Asunto(s)
Adenocarcinoma del Pulmón/clasificación , Neoplasias Pulmonares/clasificación , Microambiente Tumoral/fisiología , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/metabolismo , Algoritmos , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Sensibilidad y Especificidad
5.
Carcinogenesis ; 40(1): 121-130, 2019 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-30304323

RESUMEN

Alternative splicing (AS), a major mechanism for the enhancement of transcriptome and proteome diversity, has been widely demonstrated to be involved in the full spectrum of oncogenic processes. High-throughput sequencing technology and the rapid accumulation of clinical data sets have provided an opportunity to systemically analyze the association between messenger RNA AS variants and patient clinical outcomes. Here, we compared differentially spliced AS transcripts between esophageal carcinoma (ESCA) and non-tumor tissues, profiled genome-wide survival-associated AS events in 87 patients with esophageal adenocarcinoma (EAC) and 79 patients with esophageal squamous cell carcinoma (ESCC) using The Cancer Genome Atlas (TCGA) RNA-seq data set, and constructed predictive models as well as splicing regulation networks by integrated bioinformatic analysis. A total of 2326 AS events in 1738 genes and 1812 AS events in 1360 genes were determined to be significantly associated with overall survival (OS) of patients in the EAC and ESCC cohorts, respectively, including some essential participants in the oncogenic process. The predictive model of each splice type performed reasonably well in distinguishing good and poor outcomes of patients with esophageal cancer, and values for the area under curve reached 0.942 and 0.815 in the EAC exon skip predictive model and the ESCC alternate acceptor site predictive model, respectively. The splicing regulation networks revealed an interesting correlation between survival-associated splicing factors and prognostic AS genes. In summary, we created prognostic models for patients with esophageal cancer based on AS signatures and constructed novel splicing correlation networks.


Asunto(s)
Adenocarcinoma/genética , Empalme Alternativo , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/genética , Neoplasias Esofágicas/mortalidad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Pronóstico
6.
BMC Genomics ; 20(1): 126, 2019 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-30744552

RESUMEN

BACKGROUND: Longan (Dimocarpus longan Lour.) is an important fruit tree in the subtropical regions of Southeast Asia and Australia. Among the factors affecting D. longan fruit yield, the difficulty and instability of blossoming is one of the most challenging issues. Perpetual flowering (PF) is a crucial trait for fruit trees and is directly linked to production potential. Therefore, studying the molecular regulatory mechanism of longan PF traits is crucial for understanding and solving problems related to flowering. In this study, comparative transcriptome analysis was performed using two longan cultivars that display opposite flowering phenotypes during floral induction. RESULTS: We obtained 853.72 M clean reads comprising 125.08 Gb. After comparing these data with the longan genome, 27,266 known genes and 1913 new genes were detected. Significant differences in gene expression were observed between the two genotypes, with 6150 and 6202 differentially expressed genes (DEGs) for 'SJ' and 'SX', respectively. The transcriptional landscape of floral transition at the early stage was very different in these two longan genotypes with respect to key hormones, circadian rhythm, sugar metabolism, and transcription factors. Almost all flowering-related DEGs identified are involved in photoperiod and circadian clock pathways, such as CONSTANS-like (COL), two-component response regulator-like (APRRs), gigantea (GI), and early flowering (EFL). In addition, the leafy (LFY) gene, which is the central floral meristem identity gene, may inhibit PF formation in 'SJ'. CONCLUSION: This study provides a platform for understanding the molecular mechanisms responsible for changes between PF and seasonal flowering (SF) longan genotypes and may benefit studies on PF trait mechanisms of evergreen fruit trees.


Asunto(s)
Flores/crecimiento & desarrollo , Perfilación de la Expresión Génica , Sapindaceae/crecimiento & desarrollo , Sapindaceae/genética , Reguladores del Crecimiento de las Plantas/metabolismo , Sapindaceae/citología , Sapindaceae/metabolismo , Transducción de Señal/genética , Almidón/metabolismo , Sacarosa/metabolismo , Factores de Transcripción/metabolismo
8.
J Transl Med ; 17(1): 430, 2019 12 30.
Artículo en Inglés | MEDLINE | ID: mdl-31888670

RESUMEN

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide, and the timely and serial assessment of low-dose computed tomography (LDCT) in high-risk populations remains a challenge. Furthermore, testing a single biomarker for the diagnosis of lung cancers is of relatively low effectiveness. Thus, a stronger diagnostic combination of blood biomarkers is needed to improve the diagnosis of non-small cell lung cancer (NSCLC). METHODS: The blood levels of individual biomarkers [IDH1, DNA methylation of short stature homeobox 2 gene (SHOX2), and prostaglandin E receptor 4 gene (PTGER4)] were measured and statistically analyzed in samples from healthy controls and patients with lung cancer. In total, 221 candidates were enrolled and randomly assigned into two groups for the training and validation of a diagnostic panel. Additionally, a subgroup analysis was performed in the whole cohort. RESULTS: A newly combined 3-marker diagnostic model for lung cancers was established and validated with area under the receiver operating characteristic (ROC) curve (AUC) values ranging from 0.835 to 0.905 in independent groups showing significantly stronger diagnostic value compared with a single tested biomarker. The sensitivity of the diagnostic model was as high as 86.1% and 80.0% in the training and validation sets, respectively. Although no apparent differences were found between the 3-marker and 2-marker models, the high clinical T-stage and histological type specificity of IDH1 and two other methylated DNA biomarkers were demonstrated in the subgroup analysis. CONCLUSIONS: The combination of single biomarkers with high stage-specificity and histological type specificity (SHOX2 and PTGER4 DNA methylation and IDH1) showed better diagnostic performance in the detection of lung cancers compared with single marker assessment. A greater clinical utility of the panel may be developed by adding demographic/epidemiologic characteristics.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Metilación de ADN/genética , Isocitrato Deshidrogenasa/metabolismo , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patología , Investigación Biomédica Traslacional , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Curva ROC , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
9.
Int J Mol Sci ; 19(8)2018 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-30044387

RESUMEN

Longan is an important fruit tree in the subtropical region of Southeast Asia and Australia. However, its blooming and its yield are susceptible to stresses such as droughts, high salinity, and high and low temperature. To date, the molecular mechanisms of abiotic stress tolerance and flower induction in longan have not been elucidated. WRKY transcription factors (TFs), which have been studied in various plant species, play important regulatory roles in plant growth, development, and responses to stresses. However, there is no report about WRKYs in longan. In this study, we identified 55 WRKY genes with the conserved WRKY domain and zinc finger motif in the longan genome. Based on the structural features of WRKY proteins and topology of the phylogenetic tree, the longan WRKY (DlWRKY) family was classified into three major groups (I⁻III) and five subgroups (IIa⁻IIe) in group II. Tissue expression analysis showed that 25 DlWRKYs were highly expressed in almost all organs, suggesting that these genes may be important for plant growth and organ development in longan. Comparative RNA-seq and qRT-PCR-based gene expression analysis revealed that 18 DlWRKY genes showed a specific expression during three stages of flower induction in "Sijimi" ("SJ"), which exhibited the "perpetual flowering" (PF) habit, indicating that these 18 DlWRKY genes may be involved in the flower induction and the genetic control of the perpetual flowering trait in longan. Furthermore, the RT-qPCR analysis illustrated the significant variation of 27, 18, 15, 17, 27, and 23 DlWRKY genes under SA (Salicylic acid), MeJA (Methyl Jasmonate), heat, cold, drought, or high salinity treatment, respectively, implicating that they might be stress- or hormone-responsive genes. In summary, we systematically and comprehensively analyzed the structure, evolution, and expression pattern of the DlWRKY genes. The results presented here increase our understanding of the WRKY family in fruit trees and provide a basis for the further elucidation of the biological function of DlWRKY genes in longan.


Asunto(s)
Flores/crecimiento & desarrollo , Proteínas de Plantas/genética , Sapindaceae/genética , Estrés Fisiológico/genética , Frío , Sequías , Perfilación de la Expresión Génica , Genoma de Planta/genética , Estudio de Asociación del Genoma Completo , Familia de Multigenes , Filogenia , Proteínas de Plantas/metabolismo , Alineación de Secuencia , Análisis de Secuencia de ARN , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Dedos de Zinc/genética
10.
Molecules ; 23(3)2018 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-29543725

RESUMEN

Ubiquitin-conjugating enzymes (E2s or UBC enzymes) play vital roles in plant development and combat various biotic and abiotic stresses. Longan (Dimocarpus longan Lour.) is an important fruit tree in the subtropical region of Southeast Asia and Australia; however the characteristics of the UBC gene family in longan remain unknown. In this study, 40 D. longan UBC genes (DlUBCs), which were classified into 15 groups, were identified in the longan genome. An RNA-seq based analysis showed that DlUBCs showed distinct expression in nine longan tissues. Genome-wide RNA-seq and qRT-PCR based gene expression analysis revealed that 11 DlUBCs were up- or down-regualted in the cultivar "Sijimi" (SJ), suggesting that these genes may be important for flower induction. Finally, qRT-PCR analysis showed that the mRNA levels of 13 DlUBCs under SA (salicylic acid) treatment, seven under methyl jasmonate (MeJA) treatment, 27 under heat treatment, and 16 under cold treatment were up- or down-regulated, respectively. These results indicated that the DlUBCs may play important roles in responses to abiotic stresses. Taken together, our results provide a comprehensive insight into the organization, phylogeny, and expression patterns of the longan UBC genes, and therefore contribute to the greater understanding of their biological roles in longan.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Sapindaceae/crecimiento & desarrollo , Análisis de Secuencia de ARN/métodos , Enzimas Ubiquitina-Conjugadoras/genética , Frío , Flores/genética , Flores/crecimiento & desarrollo , Flores/metabolismo , Regulación del Desarrollo de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Genoma de Planta , Familia de Multigenes , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Sapindaceae/enzimología , Sapindaceae/genética , Estrés Fisiológico , Enzimas Ubiquitina-Conjugadoras/metabolismo
12.
Neural Netw ; 176: 106331, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38701599

RESUMEN

Adversarial attack reveals a potential imperfection in deep models that they are susceptible to being tricked by imperceptible perturbations added to images. Recent deep multi-object trackers combine the functionalities of detection and association, rendering attacks on either the detector or the association component an effective means of deception. Existing attacks focus on increasing the frequency of ID switching, which greatly damages tracking stability, but is not enough to make the tracker completely ineffective. To fully explore the potential of adversarial attacks, we propose Blind-Blur Attack (BBA), a novel attack method based on spatio-temporal motion information to fool multi-object trackers. Specifically, a simple but efficient perturbation generator is trained with the blind-blur loss, simultaneously making the target invisible to the tracker and letting the background be regarded as moving targets. We take TraDeS as our main research tracker, and verify our attack method on other excellent algorithms (i.e., CenterTrack, FairMOT, and ByteTrack) on MOT-Challenge benchmark datasets (i.e., MOT16, MOT17, and MOT20). BBA attack reduced the MOTA of TraDeS and ByteTrack from 69.1 and 80.3 to -238.1 and -357.0, respectively, indicating that it is an efficient method with a high degrees of transferability.


Asunto(s)
Algoritmos , Redes Neurales de la Computación , Humanos , Aprendizaje Profundo , Procesamiento de Imagen Asistido por Computador/métodos , Seguridad Computacional
13.
Sci Data ; 11(1): 913, 2024 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-39179570

RESUMEN

The testis serves as the primary site for spermatogenesis in mammals and is a crucial organ for the secretion of male hormones. Heat stress (HS) can have adverse effects on the seminiferous tubules, sperm quality, and sperm fertilization capability within the testis. Despite numerous previous studies describing various time points after heat stress in mice, a systematic and comprehensive dataset on heat stress and recovery in mice has been lacking. This study aimed to explore the gene expression changes in the recovery of multiple seminiferous epithelial cycles and spermatogenic cycles in mouse testicles after heat stress. We obtained high-throughput bulk RNA-seq data from testicular tissue of 4 NC mice and 32 HS mice (divided into 9 groups: NC, 30 min, 2 h, 6 h, 24 h, 3d, 8d, 24d, 47d, and 95d) and illustrated the dynamic changes in differential genes. This data set provides valuable insights into the detailed dynamic changes of one or more spermatogenic cycles after heat stress in mouse testicles, as well as the molecular mechanisms involved.


Asunto(s)
Respuesta al Choque Térmico , RNA-Seq , Espermatogénesis , Testículo , Animales , Masculino , Ratones , Testículo/metabolismo , Espermatogénesis/genética
14.
EBioMedicine ; 101: 105019, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38364701

RESUMEN

BACKGROUND: In recent years, a growing number of patients with multiple primary lung cancer (MPLC) are being diagnosed, and a subset of these patients is found to have a large number of lesions at the time of diagnosis, which are referred to as 'super MPLC'. METHODS: Here, we perform whole exome sequencing (WES) and immunohistochemistry (IHC) analysis of PD-L1 and CD8 on 212 tumor samples from 42 patients with super MPLC. FINDINGS: We report the genomic alteration landscape of super MPLC. EGFR, RBM10 and TP53 mutation and TERT amplification are important molecular events in the evolution of super MPLC. We propose the conception of early intrapulmonary metastasis, which exhibits different clinical features from conventional metastasis. The IHC analyses of PD-L1 and CD8 reveal a less inflamed microenvironment of super MPLC than that of traditional non-small cell lung cancer (NSCLC). We identify the potentially susceptible germline mutations for super MPLC. INTERPRETATION: Our study depicts the genomic characteristics and immune landscape, providing insights into the pathogenesis and possible therapeutic guidance of super MPLC. FUNDING: A full list of funding bodies that supported this study can be found in the Acknowledgements section.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neoplasias Primarias Múltiples , Humanos , Neoplasias Pulmonares/patología , Antígeno B7-H1/genética , Mutación , Genómica , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/genética , Microambiente Tumoral/genética , Proteínas de Unión al ARN/genética
15.
Cancer Cell ; 42(6): 1106-1125.e8, 2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38788718

RESUMEN

Neuroendocrine carcinomas (NECs) are extremely lethal malignancies that can arise at almost any anatomic site. Characterization of NECs is hindered by their rarity and significant inter- and intra-tissue heterogeneity. Herein, through an integrative analysis of over 1,000 NECs originating from 31 various tissues, we reveal their tissue-independent convergence and further unveil molecular divergence driven by distinct transcriptional regulators. Pan-tissue NECs are therefore categorized into five intrinsic subtypes defined by ASCL1, NEUROD1, HNF4A, POU2F3, and YAP1. A comprehensive portrait of these subtypes is depicted, highlighting subtype-specific transcriptional programs, genomic alterations, evolution trajectories, therapeutic vulnerabilities, and clinicopathological presentations. Notably, the newly discovered HNF4A-dominated subtype-H exhibits a gastrointestinal-like signature, wild-type RB1, unique neuroendocrine differentiation, poor chemotherapeutic response, and prevalent large-cell morphology. The proposal of uniform classification paradigm illuminates transcriptional basis of NEC heterogeneity and bridges the gap across different lineages and cytomorphological variants, in which context-dependent prevalence of subtypes underlies their phenotypic disparities.


Asunto(s)
Carcinoma Neuroendocrino , Regulación Neoplásica de la Expresión Génica , Humanos , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Carcinoma Neuroendocrino/clasificación , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas Señalizadoras YAP , Factor Nuclear 4 del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo
16.
Thorac Cancer ; 14(15): 1368-1382, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37021520

RESUMEN

OBJECTIVE: Advanced lung cancers carrying Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation remain a group that lacks effective treatments. Receptor activator of nuclear factorκB ligand (RANKL) has been demonstrated to drive malignant phenotypes in lung cancer; however, its role in KRAS-mutant (mt) lung adenocarcinoma (LUAD) is not yet fully elucidated. MATERIALS AND METHODS: The data used to explore expression and prognosis were obtained from The Cancer Genome Atlas, Genotype-Tissue Expression databases, and from our hospital. The proliferation, invasion, and migration capacities of KRAS-mt LUAD cells were evaluated. The prediction model was established via Lasso regression method. RESULTS: RANKL is strongly expressed in advanced KRAS-mt LUAD, and significantly distinct association exists between high RANKL expression and poor survival. The enriched expression of RANKL in advanced KRAS-mt LUAD was confirmed by specimens from our hospital. Further, although not statistically significant, our clinical cohort (n = 57) revealed a longer median progression-free survival in advanced KRAS-mt LUAD patients treated with RANKL inhibitor than those without (300 vs. 133 days, p = 0.210), but not in KRAS-wt ones (208 vs. 250 days, p = 0.334). Decrease of KRAS-mt LUAD cells' capacity for proliferation, invasion, and migration was observed when RANKL was knocked down. Enrichment analysis suggested distinct roles of RANKL between KRAS-mt and KRAS-wt LUAD, with adhesion-related pathways and molecules significantly downregulated in the KRAS-mt RANKL-high tumors. Finally, a model for predicting overall survival of KRAS-wt LUAD was established according to four related key genes (BCAM, ICAM5, ITGA3, and LAMA3), which had good performance in prediction concordance. CONCLUSIONS: RANKL acts as an unfavorable prognostic biomarker for patients with advanced KRAS-mt LUAD. Inhibition of RANKL may be a feasible strategy for this subset of patients.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Pronóstico , Ligandos , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Biomarcadores
17.
Biotechnol Genet Eng Rev ; : 1-24, 2023 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-36772792

RESUMEN

This study was to conduct a meta-analysis to explore the impact of gross total resection (GTR) and subtotal resection (STR) on survival outcomes in glioma patients. Relevant studies were searched in multiple databases from the available date of inception through 30 December 2021. The weighted mean differences (WMDs), relative risks (RRs), or hazard ratios (HRs) with 95% confidence intervals (CIs) were used to access the effect of GTR versus STR treatments on the outcomes. The histology (low-grade or high-grade) and study population (children and adults) were used for subgroup analysis. Sensitivity analysis was performed for all outcomes. Begg's test and trim-and-fill method were used for publication bias. Totally 100 studies enrolling 62,129 patients were selected in this meta-analysis. The summary results showed that GTR was superior in improving 1-, 2-, 3-, 5-, 10-, 15-year overall survival (OS), OS time, 1-, 3-, 5-year progression-free survival (PFS), recurrence, local control and seizure control among glioma patients. In addition, high-grade patients who underwent GTR had improvements in 1-, 2- and 3-year OS, OS time, and 1-year PFS, while low-grade patients receiving GTR had improvements in 2-, 5- and 15-year OS, recurrence, seizure control, and tumor progression compared with those receiving STR. GTR was likely to be more effective on survival outcomes than STR among patients with gliomas.

18.
Biomedicines ; 11(4)2023 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-37189759

RESUMEN

The emergence of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) revolutionized the treatment of advanced-stage non-small cell lung cancer (NSCLC). Detected in more than 50% of late-stage lung adenocarcinoma in Asian patients, the EGFR mutation was regarded as a golden mutation for Asians. However, resistance to TKIs seems inevitable and severely hinders patients from getting further benefits from treatment. Even though resistance caused by EGFR T790M could be effectively managed by third-generation EGFR-TKIs currently, resistance to third-generation EGFR-TKIs is still a troublesome issue faced by both clinicians and patients. Various efforts have been made to maximize the benefits of patients from EGFR-TKIs therapy. Thus, new requirements and challenges have been posed to clinicians of this era. In this review, we summarized the clinical evidence on the efficacy of third-generation EGFR-TKIs in patients with EGFR-mutated NSCLC. Then, we discussed advancements in sequential treatment aiming to delay the onset of resistance. Moreover, the resistance mechanisms and features were depicted to help us better understand our enemies. Lastly, we put forward future strategies, including recent approaches involving the utilization of antibody drug conjugates against resistance and research directions about shaping the evolution of NSCLC as a core idea in the management of NSCLC.

19.
Front Microbiol ; 14: 1209389, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37608954

RESUMEN

Gut microbiota play an important role in the gut ecology and development of pigs, which is always regulated by nutrients. This study investigated the effect of L-Citrulline on growth performance, carcass characteristics, and its potential regulatory mechanism. The results showed that 1% dietary L-Citrulline supplementation for 52 days significantly increased final weight, liveweight gain, carcass weight, and average backfat and markedly decreased drip loss (p < 0.05) of finishing pigs compared with the control group. Microbial analysis of fecal samples revealed a marked increase in α-diversity and significantly altered composition of gut microbiota in finishing pigs in response to L-Citrulline. In particular, these altered gut microbiota at the phylum and genus level may be mainly involved in the metabolic process of carbohydrate, energy, and amino acid, and exhibited a significant association with final weight, carcass weight, and backfat thickness. Taken together, our data revealed the potential role of L-Citrulline in the modulation of growth performance, carcass characteristics, and the meat quality of finishing pigs, which is most likely associated with gut microbiota.

20.
Front Microbiol ; 14: 1266042, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37840732

RESUMEN

Choline is an essential nutrient for pig development and plays a role in the animal's growth performance, carcass characteristics, and reproduction aspects in weaned pigs and sows. However, the effect of choline on finishing pigs and its potential regulatory mechanism remains unclear. Here, we feed finishing pigs with 1% of the hydrochloride salt of choline, such as choline chloride (CHC), under a basic diet condition for a short period of time (14 days). A 14-day supplementation of CHC significantly increased final weight and carcass weight while having no effect on carcass length, average backfat, or eye muscle area compared with control pigs. Mechanically, CHC resulted in a significant alteration of gut microbiota composition in finishing pigs and a remarkably increased relative abundance of bacteria contributing to growth performance and health, including Prevotella, Ruminococcaceae, and Eubacterium. In addition, untargeted metabolomics analysis identified 84 differently abundant metabolites in the liver between CHC pigs and control pigs, of which most metabolites were mainly enriched in signaling pathways related to the improvement of growth, development, and health. Notably, there was no significant difference in the ability of oxidative stress resistance between the two groups, although increased bacteria and metabolites keeping balance in reactive oxygen species showed in finishing pigs after CHC supplementation. Taken together, our results suggest that a short-term supplementation of CHC contributes to increased body weight gain and carcass weight of finishing pigs, which may be involved in the regulation of gut microbiota and alterations of liver metabolism, providing new insights into the potential of choline-mediated gut microbiota/metabolites in improving growth performance, carcass characteristics, and health.

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