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Mutations or abnormal expression of oncogenes and tumor suppressor genes are known to cause cancer. Recent studies have shown that epigenetic modifications are key drivers of cancer development and progression. Nevertheless, the mechanistic role of epigenetic dysregulation in the tumor microenvironment is not fully understood. Here, we reviewed the role of epigenetic modifications of cancer cells and non-cancer cells in the tumor microenvironment and recent research advances in cancer epigenetic drugs. In addition, we discussed the great potential of epigenetic combination therapies in the clinical treatment of cancer. However, there are still some challenges in the field of cancer epigenetics, such as epigenetic tumor heterogeneity, epigenetic drug heterogeneity, and crosstalk between epigenetics, proteomics, metabolomics, and other omics, which may be the focus and difficulty of cancer treatment in the future. In conclusion, epigenetic modifications in the tumor microenvironment are essential for future epigenetic drug development and the comprehensive treatment of cancer. Epigenetic combination therapy may be a novel strategy for the future clinical treatment of cancer.
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Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.
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PURPOSE: A potential association between breast (BC) and thyroid cancer (TC) has been observed. We investigated if the relationship between BC and TC is causal using bidirectional Mendelian randomization (MR) in Asian and European populations. METHODS: BC-linked single nucleotide polymorphisms (SNPs) were acquired from a genome-wide association study (GWAS) conducted by the Breast Cancer Association Consortium and Biobank Japan. The most recent TC GWAS data were obtained from the FinnGen Project and National Biobank of Korea. We assessed the potential causal relationship between BC and TC using various MR methods, including inverse-variance-weighting (IVW). Sensitivity, heterogeneity, and pleiotropic tests were performed to assess reliability. RESULTS: We found a bidirectional causal association between BC and TC within Europeans (IVW, TC on BC: odds ratio [OR] 1.090, 95% confidence interval [CI]: 1.012-1.173, P = 0.023; BC on TC: OR 1.265, 95% CI: 1.158-1.381, P < 0.001). A one-way causal relationship between BC susceptibility and TC risk was found in Asians (IVW BC on TC: OR 2.274, 95% CI: 2.089-2.475, P < 0.001). Subsequently, we identified a noteworthy bidirectional causal relationship between estrogen receptor (ER)-positive BC and TC (IVW, TC on ER-positive BC: OR 1.104, 95% CI: 1.001-1.212, P = 0.038; ER-positive BC on TC: OR 1.223, 95%CI: 1.072-1.395, P = 0.003), but not ER-negative BC and TC in Europeans. CONCLUSION: We revealed a reciprocal causal association between ER-positive BC and TC. These findings establish a theoretical framework for the simultaneous surveillance and treatment of BC and TC.
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Regulatory T cell (Treg) deficiency leads to immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, which is a CD4+ T cell-driven autoimmune disease in both humans and mice. Despite understanding the molecular and cellular characteristics of IPEX syndrome, new treatment options have remained elusive. Here, we hypothesized that salvianolic acid B (Sal B), one of the main active ingredients of Salvia miltiorrhiza, can protect against immune disorders induced by Treg deficiency. To examine whether Sal B can inhibit Treg deficiency-induced autoimmunity, Treg-deficient scurfy (SF) mice with a mutation in forkhead box protein 3 were treated with different doses of Sal B. Immune cells, inflammatory cell infiltration, and cytokines were evaluated by flow cytometry, hematoxylin and eosin staining and enzyme-linked immunosorbent assay Kits, respectively. Moreover, RNA sequencing, western blot, and real-time PCR were adopted to investigate the molecular mechanisms of action of Sal B. Sal B prolonged lifespan and reduced inflammation in the liver and lung of SF mice. Moreover, Sal B decreased plasma levels of several inflammatory cytokines, such as IL-2, IFN-γ, IL-4, TNF-α, and IL-6, in SF mice. By analyzing the transcriptomics of livers, we determined the signaling pathways, especially the IL-2-signal transducer and activator of transcription 5 (STAT5) signaling pathway, which were associated with Treg deficiency-induced autoimmunity. Remarkably, Sal B reversed the expression of gene signatures related to the IL-2-STAT5 signaling pathway in vitro and in vivo. Sal B prolongs survival and inhibits lethal inflammation in SF mice through the IL-2-STAT5 axis. Our findings may inspire novel drug discovery efforts aimed at treating IPEX syndrome.
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Autoinmunidad , Benzofuranos , Interleucina-2 , Factor de Transcripción STAT5 , Transducción de Señal , Linfocitos T Reguladores , Animales , Factor de Transcripción STAT5/metabolismo , Ratones , Linfocitos T Reguladores/efectos de los fármacos , Benzofuranos/farmacología , Transducción de Señal/efectos de los fármacos , Interleucina-2/metabolismo , Autoinmunidad/efectos de los fármacos , Ratones Endogámicos C57BL , Citocinas/metabolismo , Masculino , Enfermedades Genéticas Ligadas al Cromosoma X , Diabetes Mellitus Tipo 1/congénito , Diarrea , Enfermedades del Sistema Inmune/congénito , DepsidosRESUMEN
PURPOSE: The potential efficacy of metformin in breast cancer (BC) has been hotly discussed but never conclusive. This genetics-based study aimed to evaluate the relationships between metformin targets and BC risk. METHODS: Metformin targets from DrugBank and genome-wide association study (GWAS) data from IEU OpenGWAS and FinnGen were used to investigate the breast cancer (BC)-metformin causal link with various Mendelian Randomization (MR) methods (e.g., inverse-variance-weighting). The genetic association between type 2 diabetes (T2D) and the drug target of metformin was also analyzed as a positive control. Sensitivity and pleiotropic tests ensured reliability. RESULTS: The primary targets of metformin are PRKAB1, ETFDH and GPD1L. We found a causal association between PRKAB1 and T2D (odds ratio [OR] 0.959, P = 0.002), but no causal relationship was observed between metformin targets and overall BC risk (PRKAB1: OR 0.990, P = 0.530; ETFDH: OR 0.986, P = 0.592; GPD1L: OR 1.002, P = 0.806). A noteworthy causal relationship was observed between ETFDH and estrogen receptor (ER)-positive BC (OR 0.867, P = 0.018), and between GPD1L and human epidermal growth factor receptor 2 (HER2)-negative BC (OR 0.966, P = 0.040). Other group analyses did not yield positive results. CONCLUSION: The star target of metformin, PRKAB1, does not exhibit a substantial causal association with the risk of BC. Conversely, metformin, acting as an inhibitor of ETFDH and GPD1L, may potentially elevate the likelihood of developing ER-positive BC and HER2-negative BC. Consequently, it is not advisable to employ metformin as a standard supplementary therapy for BC patients without T2D.
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Neoplasias de la Mama , Diabetes Mellitus Tipo 2 , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Metformina , Humanos , Metformina/uso terapéutico , Metformina/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicaciones , Quimioterapia Adyuvante/métodos , Hipoglucemiantes/uso terapéutico , Polimorfismo de Nucleótido SimpleRESUMEN
ß-arrestin2 is a versatile protein for signaling transduction in brain physiology and pathology. Herein, we investigated the involvement of ß-arrestin2 in pharmacological effects of fluoxetine for depression. A chronic mild stress (CMS) model was established using wild-type (WT) and ß-arrestin2-/- mice. Behavioral results demonstrated that CMS mice showed increased immobility time in the tail suspension test and forced swimming test, elevated concentrations of pro-inflammatory factors in peripheral blood, increased expression of pyroptosis-related proteins, and increased co-labeling of glial fibrillary acidic protein and Caspase1 p10 in the hippocampus compared to the CON group. Treatment with fluoxetine (FLX) ameliorated these conditions. However, compared with the ß-arrestin2-/- CMS group, these results of the ß-arrestin2-/- CMS + FLX group showed no significant changes. These results suggested that the above effects of FLX could be eliminated by knocking out ß-arrestin2. Mass spectrometry implying that FLX promoted the binding of ß-arrestin2 to the NLRP2 inflammasome of depressed mice. Subsequently, the results of the cellular experiments suggested that the 5HT2B receptor antagonist may attenuate L-kynurenine + ATP-induced cell pyroptosis by attenuating NLRP2 binding to ß-arrestin2. We further found that the lack of ß-arrestin2 eliminated the anti-pyroptosis effect of fluoxetine. In conclusion, ß-arrestin2 is an essential protein for fluoxetine to alleviate pyroptosis in the hippocampal astrocytes of CMS mice. Mechanistically, we found that the 5-HT2BR-ß-arrestin2-NLRP2 axis is vital for maintaining the antidepressant effects of fluoxetine.
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Antidepresivos , Astrocitos , Depresión , Modelos Animales de Enfermedad , Fluoxetina , Piroptosis , Estrés Psicológico , Arrestina beta 2 , Animales , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Piroptosis/efectos de los fármacos , Arrestina beta 2/metabolismo , Ratones , Depresión/tratamiento farmacológico , Depresión/metabolismo , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Masculino , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Ratones Endogámicos C57BL , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones Noqueados , Conducta Animal/efectos de los fármacos , Inflamasomas/metabolismo , Enfermedad CrónicaRESUMEN
Advances in chromatin mapping have exposed the complex chromatin hierarchical organization in mammals, including topologically associating domains (TADs) and their substructures, yet the functional implications of this hierarchy in gene regulation and disease progression are not fully elucidated. Our study delves into the phenomenon of shared TAD boundaries, which are pivotal in maintaining the hierarchical chromatin structure and regulating gene activity. By integrating high-resolution Hi-C data, chromatin accessibility, and DNA double-strand breaks (DSBs) data from various cell lines, we systematically explore the complex regulatory landscape at high-level TAD boundaries. Our findings indicate that these boundaries are not only key architectural elements but also vibrant hubs, enriched with functionally crucial genes and complex transcription factor binding site-clustered regions. Moreover, they exhibit a pronounced enrichment of DSBs, suggesting a nuanced interplay between transcriptional regulation and genomic stability. Our research provides novel insights into the intricate relationship between the 3D genome structure, gene regulation, and DNA repair mechanisms, highlighting the role of shared TAD boundaries in maintaining genomic integrity and resilience against perturbations. The implications of our findings extend to understanding the complexities of genomic diseases and open new avenues for therapeutic interventions targeting the structural and functional integrity of TAD boundaries.
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Cromatina , Roturas del ADN de Doble Cadena , Reparación del ADN , Regulación de la Expresión Génica , Humanos , Cromatina/metabolismo , Cromatina/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Animales , Genómica/métodos , Inestabilidad Genómica , Ensamble y Desensamble de CromatinaRESUMEN
Topologically associating domains (TADs), megabase-scale features of chromatin spatial architecture, are organized in a domain-within-domain TAD hierarchy. Within TADs, the inner and smaller subTADs not only manifest cell-to-cell variability, but also precisely regulate transcription and differentiation. Although over 20 TAD callers are able to detect TAD, their usability in biomedicine is confined by a disagreement of outputs and a limit in understanding TAD hierarchy. We compare 13 computational tools across various conditions and develop a metric to evaluate the similarity of TAD hierarchy. Although outputs of TAD hierarchy at each level vary among callers, data resolutions, sequencing depths, and matrices normalization, they are more consistent when they have a higher similarity of larger TADs. We present comprehensive benchmarking of TAD hierarchy callers and operational guidance to researchers of life science researchers. Moreover, by simulating the mixing of different types of cells, we confirm that TAD hierarchy is generated not simply from stacking Hi-C heatmaps of heterogeneous cells. Finally, we propose an air conditioner model to decipher the role of TAD hierarchy in transcription.
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Benchmarking , Cromatina , Cromatina/química , Humanos , Biología Computacional/métodos , Programas Informáticos , Ensamble y Desensamble de CromatinaRESUMEN
Cognitive impairment, as a prevalent symptom of nervous system disorders, poses one of the most challenging aspects in the management of brain diseases. Lipids present in the cell membranes of all neurons within the brain and dietary lipids can regulate the cognition and memory function. In recent years, the advancements in gut microbiome research have enabled the exploration of dietary lipids targeting the gut-brain axis as a strategy for regulating cognition. This present review provides an in-depth overview of how lipids modulate cognition via the gut-brain axis depending on metabolic, immune, neural and endocrine pathways. It also comprehensively analyzes the effects of diverse lipids on the gut microbiota and intestinal barrier function, thereby affecting the central nervous system and cognitive capacity. Moreover, comparative analysis of the positive and negative effects is presented between beneficial and detrimental lipids. The former encompass monounsaturated fatty acids, short-chain fatty acids, omega-3 polyunsaturated fatty acids, phospholipids, phytosterols, fungal sterols and bioactive lipid-soluble vitamins, as well as lipid-derived gut metabolites, whereas the latter (detrimental lipids) include medium- or long-chain fatty acids, excessive proportions of n-6 polyunsaturated fatty acids, industrial trans fatty acids, and zoosterols. To sum up, the focus of this review is on how gut-brain communication mediates the impact of dietary lipids on cognitive capacity, providing a novel theoretical foundation for promoting brain cognitive health and scientific lipid consumption patterns.
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Grasas de la Dieta , Ácidos Grasos Omega-3 , Grasas de la Dieta/metabolismo , Ácidos Grasos/metabolismo , Encéfalo/metabolismo , Ácidos Grasos Omega-3/metabolismo , CogniciónRESUMEN
A salt-tolerant strain, Pseudomonas mendocina A4, was isolated from brackish-water ponds showing simultaneous heterotrophic nitrification-aerobic denitrification and phosphorus removal capability. The optimal conditions for nitrogen and phosphate removal of strain A4 were pH 7-8, carbon/nitrogen ratio 10, phosphorus/nitrogen ratio 0.2, temperature 30 °C, and salinity range of 0-5 % using sodium succinate as the carbon source. The nitrogen and phosphate removal efficiencies were 96-100 % and 88-96 % within 24 h, respectively. The nitrogen and phosphate removal processes were matched with the modified Gompertz model, and the underlying mechanisms were confirmed by the activities of key metabolic enzymes. Under 10 % salinity, the immobilization technology was employed to enhance the nitrogen and phosphate removal efficiencies of strain A4, achieving 87 % and 76 %, respectively. These findings highlight the potential application of strain A4 in both freshwater and marine culture wastewater treatment.
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Desnitrificación , Radioisótopos de Nitrógeno , Pseudomonas mendocina , Fosfatos , Pseudomonas mendocina/metabolismo , Nitrógeno/metabolismo , Aerobiosis , Nitrificación , Fósforo , Procesos Heterotróficos , Carbono , Nitritos/químicaRESUMEN
BACKGROUND: We aimed to assess differences in intestinal microflora between patients with operable hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) with microvascular invasion (MVI) and those without MVI. Additionally, we investigated the potential of the microbiome as a non-invasive biomarker for patients with MVI. METHODS: We analyzed the preoperative gut microbiomes (GMs) of two groups, the MVI (n = 46) and non-MVI (n = 56) groups, using 16S ribosomal RNA gene sequencing data. At the operational taxonomic unit level, we employed random forest models to predict MVI risk and validated the results in independent validation cohorts [MVI group (n = 17) and non-MVI group (n = 15)]. RESULTS: ß diversity analysis, utilizing weighted UniFrac distances, revealed a significant difference between the MVI and non-MVI groups, as indicated by non-metric multidimensional scaling and principal coordinate analysis. We also observed a significant correlation between the characteristic intestinal microbial communities at the genus level and their main functions. Nine optimal microbial markers were identified, with an area under the curve of 79.76% between 46 MVI and 56 non-MVI samples and 79.80% in the independent verification group. CONCLUSION: This pioneering analysis of the GM in patients with operable HBV-HCC with and without MVI opens new avenues for treating HBV-HCC with MVI. We successfully established a diagnostic model and independently verified microbial markers for patients with MVI. As preoperative targeted biomarkers, GM holds potential as a non-invasive tool for patients with HBV-HCC with MVI.
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Carcinoma Hepatocelular , Microbioma Gastrointestinal , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/patología , Virus de la Hepatitis B/genética , Neoplasias Hepáticas/cirugía , Microbioma Gastrointestinal/genética , Estudios Retrospectivos , Invasividad Neoplásica , BiomarcadoresRESUMEN
The sorghum-sudangrass hybrid is the main high-quality forage grass in Southwest China, but, in recent years, it has suffered from leaf spot disease, with a prevalence of 88% in Bazhong, Sichuan, China, seriously affecting yield and quality. The causal agents were obtained from symptomatic leaves by tissue isolation and verified by pathogenicity assays. A combination of morphological characterization and sequence analysis revealed that strains SCBZSL1, SCBZSX5, and SCBZSW6 were Nigrospora sphaerica, Colletotrichum boninense, and Didymella corylicola, respectively, and the latter two were the first instance to be reported on sorghum-sudangrass hybrids in the world. SCBZSX5 significantly affected the growth of the plants, which can reduce plant height by 25%. The biological characteristics of SCBZSX5 were found to be less sensitive to the change in light and pH, and its most suitable culture medium was Potato Dextrose Agar (PDA), with the optimal temperature of 25 °C and lethal temperature of 35 °C. To clarify the interactions between the pathogen SCBZSX5 and plants, metabolomics analyses revealed that 211 differential metabolites were mainly enriched in amino acid metabolism and flavonoid metabolism. C. boninense disrupted the osmotic balance of the plant by decreasing the content of acetyl proline and caffeic acid in the plant, resulting in disease occurrence, whereas the sorghum-sudangrass hybrids improved tolerance and antioxidant properties through the accumulation of tyrosine, tryptophan, glutamic acid, leucine, glycitein, naringenin, and apigetrin to resist the damage caused by C. boninense. This study revealed the mutualistic relationship between sorghum-sudangrass hybrids and C. boninense, which provided a reference for the control of the disease.
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Cancer therapy resistance (CTR) is the development of cancer resistance to multiple therapeutic strategies, which severely affects clinical response and leads to cancer progression, recurrence, and metastasis. N6-methyladenosine (m6A) has been identified as the most common, abundant, and conserved internal transcriptional alterations of RNA modifications, regulating RNA splicing, translation, stabilization, degradation, and gene expression, and is involved in the development and progression of a variety of diseases, including cancer. Recent studies have shown that m6A modifications play a critical role in both cancer development and progression, especially in reversing CTR. Although m6A modifications have great potential in CTR, the specific molecular mechanisms are not fully elucidated. In this review, we summarize the potential molecular mechanisms of m6A modification in CTR. In addition, we update recent advances in natural products from Traditional Chinese Medicines (TCM) and small-molecule lead compounds targeting m6A modifications, and discuss the great potential and clinical implications of these inhibitors targeting m6A regulators and combinations with other therapies to improve clinical efficacy and overcome CTR.
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Productos Biológicos , Neoplasias , Humanos , Resistencia a Antineoplásicos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , AdenosinaRESUMEN
BACKGROUND AND AIMS: Extrahepatic recurrence (EHR) is one of the major reasons for the poor prognosis of hepatocellular carcinoma (HCC). The present study aimed to develop and assess the performance of predictive models by using a combination of presurgical circulating tumor cell (CTCs) data and clinicopathological features to screen patients at high risk of EHR to achieve precise decision-making. PATIENTS AND METHODS: A total of 227 patients with recurrent HCC and preoperative CTC data from January 2014 to August 2019 were enrolled. All patients were randomly assigned to one of two cohorts: development or validation. Two preoperative and postoperative nomogram models for EHR prediction were developed and multi-dimensionally validated. RESULTS: Patients with EHR had generally lower recurrence-free survival (p < 0.001), and overall survival (p < 0.001), and significantly higher CTC counts (epithelial CTCs, epithelial/mesenchymal hybrid CTCs, and mesenchymal CTCs count, all p < 0.05) than those without EHR. Univariate and multivariate analyses revealed that EHR was associated with four risk factors in the development cohort: total CTC count (p = 0.014), tumor size (p = 0.028), node number (p = 0.045), and microvascular invasion (p = 0.035). These factors were incorporated into two nomogram models (preoperative and postoperative), which reliably predicted EHR through multidimensional verification (e.g., calibration plot, receiver operating characteristic analysis, decision curve analysis, and clinical impact curve analysis) in the development and validation cohorts, respectively. With threshold of scores of 100.3 and 176.8 before and after surgery respectively, both nomograms were able to stratify patients into two distinct prognostic subgroups (all p < 0.05). CONCLUSION: The present study proposed two nomogram models integrating presurgical CTC counts and clinicopathological risks and showed relatively good predictive performance of EHR, which may be beneficial to the clinical practice of HCC recurrence. Further multicenter studies are needed to assess its general applicability.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Neoplásicas Circulantes , Humanos , Carcinoma Hepatocelular/patología , Nomogramas , Neoplasias Hepáticas/patología , Hepatectomía , Pronóstico , Recurrencia Local de Neoplasia/patología , Estudios RetrospectivosRESUMEN
PURPOSE: The purpose of this study was to estimate the clinical efficacy and identify the best beneficiaries of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 749 HCC patients who underwent surgical resection (380 underwent PA-TACE, 369 had resection only) with a high risk of recurrence were reviewed retrospectively. Patients receiving PA-TACE were randomly split into development and validation cohorts. Univariate and multivariate analyses were performed in the development cohort. A novel model for PA-TACE-insensitivity prediction was built based on univariate and multivariate analysis and was multi-dimensionally validated in the validation set and all samples. RESULTS: After propensity score matching (PSM), in the early-recurrence group, no significant improvement in RFS was achieved with PA-TACE compared to radical hepatic resection alone. PA-TACE insensitive patients were considered as the PA-TACE non-benefit population and were associated with six clinicopathological factors: AFP, node number, tumor capsule, Ki-67 index, MVI, and complications in the development cohort. These factors were incorporated into a nomogram model, which reliably predicted PA-TACE insensitivity, with concordance indices of 0.874 and 0.897 for the development and validation cohort, respectively. In the overall sample, PA-TACE did not significantly improve patients' RFS and OS in the high-score group, while the low-score group had statistical significance. Recurrence pattern diversity was also found to be a factor leading to PA-TACE insensitivity. CONCLUSION: We constructed a new PA-TACE-insensitivity prediction model with potential clinical value. The good predictive performance and availability would allow this model to effectively screen PA-TACE beneficiaries.KEY MESSAGESThe independent influencing factors of PA-TACE insensitivity in patients who received PA-TACE were analyzed to construct a predictive model and its clinical application performance was verified with multi-dimensional methods.PA-TACE treatment should be avoided for patients with high scores according to this model, while it should be cautiously recommended for patients with low scores after multiple considerations.Compared with other related models, this model has obvious advantages in versatility and effectiveness. It can effectively screen the best benefit population of PA-TACE and provide a reliable reference for the selection of precise treatment plans for patients after radical resection of hepatocellular carcinoma.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/patología , Nomogramas , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Pronóstico , Estudios Retrospectivos , Quimioembolización Terapéutica/métodos , Adyuvantes InmunológicosRESUMEN
Autopolyploidization has driven the successful invasion of Solidago canadensis in East Asia. However, it was believed that only diploid S. canadensis invaded Europe, whereas polyploids never did. Here, molecular identification, ploidy level, and morphological traits of ten S. canadensis populations collected in Europe were compared with previously identified S. canadensis populations from other continents and S. altissima populations. Furthermore, the ploidy-driven geographical differentiation pattern of S. canadensis in different continents was investigated. All ten European populations were identified as S. canadensis with five diploid and five hexaploid populations. Significant differences in morphological traits existed among diploids and polyploids (tetraploids and hexaploids), rather than between polyploids from different introduced ranges and between S. altissima and polyploidy S. canadensis. The invasive hexaploids and diploids had few differences in latitudinal distributions in Europe, which was similar to the native range but different from a distinct climate-niche differentiation in Asia. This may be attributed to the bigger difference in climate between Asia and Europe and North America. The morphological and molecular evidences proved the invasion of polyploid S. canadensis in Europe and suggest that S. altissima may be merged into a complex of S. canadensis species. Our study may be concluded that geographical and ecological niche differentiation of an invasive plant driven by ploidy depends on the degree of difference in the environmental factors between the introduced and native range, which provides new insight into the invasive mechanism.
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BACKGROUND: Type 2 diabetes mellitus (T2DM) is an independent risk factor for colorectal cancer (CRC), and the patients with CRC and T2DM have worse survival. The human gut microbiota (GM) is linked to the development of CRC and T2DM, respectively. However, the GM characteristics in patients with CRC and T2DM remain unclear. METHODS: We performed fecal metagenomic and targeted metabolomics studies on 36 samples from CRC patients with T2DM (DCRC group, n = 12), CRC patients without diabetes (CRC group, n = 12), and healthy controls (Health group, n = 12). We analyzed the fecal microbiomes, characterized the composition and function based on the metagenomics of DCRC patients, and detected the short-chain fatty acids (SCFAs) and bile acids (BAs) levels in all fecal samples. Finally, we performed a correlation analysis of the differential bacteria and metabolites between different groups. RESULTS: Compared with the CRC group, LefSe analysis showed that there is a specific GM community in DCRC group, including an increased abundance of Eggerthella , Hungatella , Peptostreptococcus , and Parvimonas , and decreased Butyricicoccus , Lactobacillus , and Paraprevotella . The metabolomics analysis results revealed that the butyric acid level was lower but the deoxycholic acid and 12-keto-lithocholic acid levels were higher in the DCRC group than other groups ( P < 0.05). The correlation analysis showed that the dominant bacterial abundance in the DCRC group ( Parvimonas , Desulfurispora , Sebaldella , and Veillonellales , among others) was negatively correlated with butyric acid, hyodeoxycholic acid, ursodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, cholic acid and glycocholate. However, the abundance of mostly inferior bacteria was positively correlated with these metabolic acid levels, including Faecalibacterium , Thermococci , and Cellulophaga . CONCLUSIONS: Unique fecal microbiome signatures exist in CRC patients with T2DM compared to those with non-diabetic CRC. Alterations in GM composition and SCFAs and secondary BAs levels may promote CRC development.
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Neoplasias Colorrectales , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Microbiota , Humanos , Microbioma Gastrointestinal/genética , Bacterias/genética , Ácidos Grasos Volátiles , Neoplasias Colorrectales/metabolismo , Butiratos , Heces/microbiologíaRESUMEN
PURPOSE: Myopic scleral pit (MSP) is a rare physical sign of pathological myopia (PM). The aim of this study was to summarize the clinical characteristics of MSP and analyze its correlation with PM. METHODS: Eight cases with PM and MSP were enrolled in this study. Comprehensive ophthalmic examinations, including subjective refraction, slit-lamp biomicroscope, intraocular pressure, fundus photographs, A- and B-scan ultrasonography and spectral-domain optical coherence tomography, were performed. RESULTS: All the patients had a long history of PM with visual impairment, long axial length, and myopia-related fundus degeneration. Mean axial length was 31.48 ± 2.17 mm. Mean size of MSP was 0.69 ± 0.29 optic disc diameter (PD). Mean logMAR BCVA was 1.21 ± 0.88 logMAR. Spearman correlation analysis showed that the logMAR BCVA had no correlation with the size of pits (P = 0.34). Fundus examination revealed a focal pale concave located in the sclera exposed area of retinal choroid atrophy was found in all cases. OCT showed a deep scleral pit where the retinal choroid was thin or absent, without retinal sensory detachment or sensory defect. CONCLUSIONS: This study identified a rare scleral lesion in all eight individuals with PM, which was termed "myopic scleral pit". This phenomenon is different from focal choroidal excavation and posterior staphyloma.
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Miopía Degenerativa , Desprendimiento de Retina , Enfermedades de la Esclerótica , Humanos , Miopía Degenerativa/complicaciones , Miopía Degenerativa/diagnóstico , Miopía Degenerativa/patología , Esclerótica/diagnóstico por imagen , Esclerótica/patología , Agudeza Visual , Enfermedades de la Esclerótica/diagnóstico , Enfermedades de la Esclerótica/etiología , Enfermedades de la Esclerótica/patología , Coroides/patología , Tomografía de Coherencia Óptica/métodos , Desprendimiento de Retina/diagnóstico , Desprendimiento de Retina/etiología , Desprendimiento de Retina/patologíaRESUMEN
Gastric cancer (GC) ranks fifth among all malignant tumors globally, especially in East Asia, and has attracted extensive attention and research. MicroRNA (miRNA) modulation during genomic instability (GI) may be associated with the development and metastasis of malignant tumors. We aimed to identify GI-related miRNA signatures for the prediction of GC prognosis. We constructed a GI-related miRNA signature (GIMiSig) scheme based on The Cancer Genome Atlas (TCGA) training set (n = 389), which was later verified based on the TCGA test set (n = 194). GI-related miRNAs were identified by analyzing somatic mutation profiles and miRNA expression. A GI-related miRNA-gene co-expression network was also constructed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were analyzed to reveal possible biological pathways associated with GI-related miRNAs. The correlation of the GIMiSig with clinical factors of the TCGA dataset was analyzed. MiRNA mimics and inhibitors were used to evaluate the biological functions of miR-100-5p and miR-145-3p in GC cell lines AGS and MKN-45. This study identified a GI-related 12-miRNA signature for the prediction of GC prognosis. GIMiSig scores, similar to tumor stages, showed significant correlations with overall survival (OS, p < 0.05). GIMiSig showed high accuracy in predicting GC prognosis. MiR-100-5p and miR-145-3p promoted cell growth, invasion, and migration but inhibited apoptosis in GC cells. We report a reliable GI-related 12-miRNA signature for predicting GC prognosis. Furthermore, miR-100-5p and miR-145-3p may promote GC cell growth, invasion, and migration.
Asunto(s)
MicroARNs , Neoplasias Gástricas , Humanos , MicroARNs/genética , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Postoperative transarterial chemoembolization (PA-TACE) is an effective adjuvant therapy for preventing early postoperative recurrence of hepatocellular carcinoma (HCC); however, many patients are insensitive to it. Therefore, the present study aimed to explore the in-depth reasons for PA-TACE resistance and provide a reliable basis for selecting patients who will benefit the most from PA-TACE. METHODS: The unique gene expression profiles of primary tumors from PA-TACE-sensitive or -insensitive patients were analyzed using microarray data. Combined differential expression analysis, gene set enrichment analysis (GSEA), and weighted correlation network analysis (WGCNA) were used to screen for potential drivers of PA-TACE insensitivity. The expression of ALDOB was silenced or overexpressed in hepatoma cell lines, and changes in glycolytic activity, cycle, apoptosis, and malignant biological phenotypes were observed under normoxia and hypoxia. Finally, an animal model was constructed to verify the effects of ALDOB dysregulation on the tumorigenic ability of HCC cells in vivo. RESULTS: The inhibition of ALDOB promoted the up-regulation of Ki67 expression, and glycolytic activity was significantly enhanced. Moreover, the proliferation, invasion, and migration capabilities were increased in HCC cells and even worse in hypoxia. This advantage of malignant behavior was also validated using in vivo models. CONCLUSION: Down-regulation of ALDOB may underlie the metabolic reprogramming observed in HCC by promoting the malignant behavior of HCC cells. Hypoxia and ALDOB down-regulation acted additively, which was closely related to PA-TACE insensitivity. The use of ALDOB and Ki67 as a combined marker has the potential to identify the 'PA-TACE beneficiary population'.