RESUMEN
Island vertebrates have evolved a number of morphological, physiological, and life history characteristics that set them apart from their mainland relatives. However, to date, the evolution of metabolism and its impact on the vulnerability to extinction of insular vertebrates remains poorly understood. This study used metabolic data from 2813 species of tetrapod vertebrates, including 695 ectothermic and 2118 endothermic species, to reveal that island mammals and birds evolved convergent metabolic strategies toward a slow pace of life. Insularity was associated with shifts toward slower metabolic rates and greater generation lengths in endotherms, while insularity just drove the evolution of longer generation lengths in ectotherms. Notably, a slow pace of life has exacerbated the extinction of insular endemic species in the face of anthropogenic threats. These findings have important implications for understanding physiological adaptations associated with the island syndrome and formulating conservation strategies across taxonomic groups with different metabolic modes.
Asunto(s)
Evolución Biológica , Extinción Biológica , Islas , Animales , Aves/fisiología , Mamíferos , Filogenia , Efectos AntropogénicosRESUMEN
Robust, sensitive, and rapid molecular detection tools are essential prerequisites for disease diagnosis and epidemiological control. However, the current mainstream tests necessitate expensive equipment and specialized operators, impeding the advancement of molecular diagnostics. The CRISPR-Cas system is an integral component of the bacterial adaptive immune system, wherein Cas proteins recognize PAM sequences by binding to CRISPR RNA, subsequently triggering DNA or RNA cleavage. The discovery of the CRISPR-Cas system has invigorated molecular diagnostics. With further in-depth research on this system, its application in molecular diagnosis is flourishing. In this review, we provide a comprehensive overview of recent research progress on the CRISPR-Cas system, specifically focusing on its application in molecular diagnosis.
Asunto(s)
Sistemas CRISPR-Cas , Sistemas CRISPR-Cas/genética , Humanos , Patología Molecular/métodos , Técnicas de Diagnóstico MolecularRESUMEN
Wild rhesus macaques are a potential source of zoonotic parasites for humans, and Entamoeba spp. are common intestinal parasites. To investigate the prevalence of Entamoeba in wild rhesus macaques in China and explore the genetic differentiation of the potentially pathogenic species Entamoeba nuttalli, a total of 276 fecal samples from five populations at high altitudes (HAG, 2,800-4,100 m above sea level) and four populations at low altitudes (LAG, 5-1,000 m above sea level) were collected. PCR methods based on the ssrRNA gene were used to detect Entamoeba infection. Genotyping of E. nuttalli was performed based on six tRNA-linked short tandem repeat (STR) loci for further genetic analyses. The results revealed that Entamoeba infection (69.2%) was common in wild rhesus macaques in China, especially in LAG which had a significantly higher prevalence rate than that in HAG (P < 0.001). Three zoonotic species were identified: Entamoeba chattoni (60.9%) was the most prevalent species and distributed in all the populations, followed by Entamoeba coli (33.3%) and Entamoeba nuttalli (17.4%). In addition, a novel Entamoeba ribosomal lineage named RL13 (22.8%) was identified, and phylogenetic analysis revealed a close genetic relationship between RL13 and Entamoeba. hartmanni. Genotyping of E. nuttalli obtained 24 genotypes from five populations and further analysis showed E. nuttalli had a high degree of genetic differentiation (FST > 0.25, Nm < 1) between the host populations. The result of analysis of molecular variance (AMOVA) revealed that observed genetic differences mainly originate from differences among populations (FST = 0.91). Meanwhile, the phylogenetic tree showed that these genotypes of E. nuttalli were clustered according to geographical populations, indicating a significant phylogeographic distribution pattern. Considering the potential pathogenicity of E. nuttalli, attention should be paid to its risk of zoonotic transmission.
Asunto(s)
Entamoeba , Entamebiasis , Heces , Genotipo , Macaca mulatta , Filogenia , Animales , Entamoeba/genética , Entamoeba/clasificación , Entamoeba/aislamiento & purificación , China/epidemiología , Entamebiasis/epidemiología , Entamebiasis/parasitología , Entamebiasis/veterinaria , Heces/parasitología , Enfermedades de los Monos/parasitología , Enfermedades de los Monos/epidemiología , Prevalencia , Variación Genética , Repeticiones de Microsatélite , ADN Protozoario/genéticaRESUMEN
Objective: Based on real-world research, we aimed to evaluate the effectiveness and economy of recombinant human thrombopoietin (rhTPO) and recombinant human interleukin 11 (rhIL-11) in the treatment of cancer therapy induced thrombocytopenia (CTIT). Methods: We retrospectively collected clinical data of patients with CTIT who were treated with rhTPO or rhIL-11 in a single cancer hospital from January 2020 to December 2021. Propensity score matching (PSM) was applied to eliminate confounding factors. The measurements of effectiveness analysis were the platelet compliance rate, days of medication, days of compliance, highest platelet count after medication, platelet count elevation before and after medication, and the lowest platelet count after next-cycle cancer therapy. The economic evaluation was performed according to the results of the effectiveness evaluation. At the same time, patients were stratified according to type of tumor and grade of thrombocytopenia for subgroup analysis. Results: A total of 262 patients were collected and 174 patients were enrolled after PSM, 87 in the rhTPO group and 87 in the rhIL-11 group. In all patients, there were no significant differences in the platelet compliance rate, mean days of medication, median days of compliance, median highest platelet count after medication, and the median platelet count elevation before and after medication between the two groups (p > 0.05), but the median lowest platelet count after next-cycle cancer therapy in the rhTPO group was lower than that in the rhIL-11 group (p = 0.014). The subgroup analysis showed that the rhTPO group had longer mean days of medication than the rhIL-11 group in patients with hematological malignancies (p = 0.042), and a lower median lowest platelet count after next-cycle cancer therapy in patients with grade I/II thrombocytopenia than rhIL-11 group (p = 0.022), with no significant difference in other outcome indicators (p > 0.05). As there was no statistically significant difference in platelet compliance rate between the two groups, the cost-minimization analysis showed that the rhIL-11 group had lower treatment costs than the rhTPO group. Conclusion: RhTPO and rhIL-11 showed similar effectiveness in the treatment of CTIT, but rhIL-11 was more advantageous in economic cost.
RESUMEN
Whether the heat and cold tolerance of endotherms evolve independently or correlatively remains unresolved. Both physiological trade-offs and natural selection can contribute to a coevolutionary pattern of heat and cold tolerance in endotherms. Using a published database, we tested the correlation between upper and lower thermal limits across endothermic species with multi-response generalized linear mixed models incorporating phylogenies. We found a positive correlation between upper and lower thermal limits, which suggested a coevolutionary pattern of heat and cold tolerance. Specifically, this relationship between heat and cold tolerance is phylogenetically constrained for tropical endotherms but not for temperate endotherms. The correlated evolution between heat and cold tolerance may have a significant influence on endotherms' evolution and ecology and needs to be further investigated.
Asunto(s)
Ecología , Calor , Filogenia , FríoRESUMEN
Drug resistance remains a major challenge in cancer treatment, necessitating the development of novel strategies to overcome it. Protein arginine methyltransferases (PRMTs) are enzymes responsible for epigenetic arginine methylation, which regulates various biological and pathological processes, as a result, they are attractive therapeutic targets for overcoming anti-cancer drug resistance. The ongoing development of small molecules targeting PRMTs has resulted in the generation of chemical probes for modulating most PRMTs and facilitated clinical treatment for the most advanced oncology targets, including PRMT1 and PRMT5. In this review, we summarize various mechanisms underlying protein arginine methylation and the roles of specific PRMTs in driving cancer drug resistance. Furthermore, we highlight the potential clinical implications of PRMT inhibitors in decreasing cancer drug resistance. PRMTs promote the formation and maintenance of drug-tolerant cells via several mechanisms, including altered drug efflux transporters, autophagy, DNA damage repair, cancer stem cell-related function, epithelial-mesenchymal transition, and disordered tumor microenvironment. Multiple preclinical and ongoing clinical trials have demonstrated that PRMT inhibitors, particularly PRMT5 inhibitors, can sensitize cancer cells to various anti-cancer drugs, including chemotherapeutic, targeted therapeutic, and immunotherapeutic agents. Combining PRMT inhibitors with existing anti-cancer strategies will be a promising approach for overcoming anti-cancer drug resistance. Furthermore, enhanced knowledge of the complex functions of arginine methylation and PRMTs in drug resistance will guide the future development of PRMT inhibitors and may help identify new clinical indications.
Asunto(s)
Antineoplásicos , Neoplasias , Humanos , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteína-Arginina N-Metiltransferasas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Arginina/metabolismo , Arginina/uso terapéutico , Microambiente Tumoral , Proteínas Represoras/uso terapéuticoRESUMEN
CRISPR technology has been used to revolutionize various facets of life sciences because of its potent gene editing capabilities. In particular, CRISPR technology is anticipated to be used to cure congenital disorders, and malignant cancers brought on by gene mutation. In this article, we introduce a Split-Cas9 system, in which Cas9 protein is split into two or more parts and recombined in cells to function specific induction circumstances. Split-Cas9 system can improve the therapeutic index of CRISPR technology by splitting Cas9 proteins into small fragments, thus enhancing their compatibility with virus vectors and precise temporal and spatial control. This article examined the combination mode of Split-Cas9 system, contrasted the differences in its split sites and activity efficiency, and discussed the use and clinical transformation in vivo and in vitro.
Asunto(s)
Sistemas CRISPR-Cas , Edición Génica , Proteína 9 Asociada a CRISPR/genética , Vectores Genéticos/genética , Recombinación GenéticaRESUMEN
Diet and feeding behavior data are crucial to a deep understanding of the behavioral response and adaptation of primates to a high-altitude environment. From August 2019 to June 2021, we collected data on the feeding behavior of a high-altitude rhesus macaque Macaca mulatta group from Yajiang County, Western Sichuan Plateau, which has an altitude of over 3,500 m. The results showed that feeding (33.0 ± 1.8%) and moving (28.3 ± 2.6%) were the dominant behavior of rhesus macaques. Macaques ate 193 food items, comprising 11 food categories from 90 species. Our study found that plant roots (30.9 ± 30.1%) and young leaves (28.0 ± 33.1%) were the main foods eaten by macaques. The preferred foods of rhesus macaques were young leaves, fruits, and seeds, and the consumption of these items was positively correlated with its food availability. When the availability of preferred foods was low, macaques took plant roots, barks, and fallen leaves as fallback foods. In particular, roots were a dominant food item in winter, and this way of feeding became a key survival strategy. Our results suggest that, facing the relative scarcity and strong seasonal fluctuations of food resources in high-altitude habitat, macaques adopt active foraging strategies, relying on a variety of food species and adjusting flexibly their food choices based on food availability, which may help to maximize the energy efficiency of high-altitude macaques.
RESUMEN
Base editing technology, developed from the CRISPR/Cas9 system, is able to efficiently implement single-base substitutions at specific DNA or RNA sites without generating double-strand breaks with precision and efficiency. Point mutations account for 58% of disease-causing genetic mutations in humans, and single nucleotide variants are an important cause of tumorigenesis, and the advent of base editors offers new hope for the study or treatment of such diseases. Although it has some limitations, base editors have been continuously improved in terms of editing efficiency, specificity, and product purity since their development. In this review, we examine the main base editing technologies and discuss their applications and prospects in tumor research and therapy, as well as elaborate on their mode of delivery.
Asunto(s)
Sistemas CRISPR-Cas , Edición Génica , Humanos , ADN/genéticaRESUMEN
Less is known about the role of gut microbiota in overwintering environmental adaptation in migratory birds. Here, we performed metagenomic sequencing on fresh fecal samples (n = 24) collected during 4 periods of overwintering (Dec: early; Jan: middle I; Feb: middle II; Mar: late) to characterize gut microbial taxonomic and functional characteristics of black-necked crane (Grus nigricollis). The results demonstrated no significant change in microbial diversity among overwintering periods. Analysis of compositions of microbiomes with bias correction (ANCOM-BC) determined 15 Proteobacteria species enriched in late overwintering period. Based on previous reports, these species are associated with degradation of chitin, cellulose, and lipids. Meanwhile, fatty acid degradation and betalain biosynthesis pathways are enriched in late overwintering period. Furthermore, metagenomic binning obtained 91 high-quality bins (completeness >70% and contamination <10%), 5 of which enriched in late overwintering period. Carnobacterium maltaromaticum, unknown Enterobacteriaceae, and Yersinia frederiksenii have genes for chitin and cellulose degradation, acetate, and glutamate production. Unknown Enterobacteriaceae and Y. frederiksenii hold genes for synthesis of 10 essential amino acids required by birds, and the latter has genes for γ-aminobutyrate production. C. maltaromaticum has genes for pyridoxal synthesis. These results implied the gut microbiota is adapted to the host diet and may help black-necked cranes in pre-migratory energy accumulation by degrading the complex polysaccharide in their diet, supplying essential amino acids and vitamin pyridoxal, and producing acetate, glutamate, and γ-aminobutyrate that could stimulate host feeding. Additionally, enriched Proteobacteria also encoded more carbohydrate-active enzymes (CAZymes) and antibiotic resistance genes (ARGs) in late overwintering period. KEY POINTS: ⢠Differences in gut microbiota function during overwintering period of black-necked cranes depend mainly on changes in core microbiota abundance ⢠Gut microbiota of black-necked crane adapted to the diet during overwintering period ⢠Gut microbiota could help black-necked cranes to accumulate more energy in the late overwintering period.
Asunto(s)
Microbioma Gastrointestinal , Microbiota , Animales , Microbioma Gastrointestinal/genética , Proteobacteria , Aves/genética , Aves/microbiología , CelulosaRESUMEN
There have been many reports on the genetic mechanism in rhesus macaques (RMs) for environmental adaptation to high altitudes, but the synergistic involvement of gut microbiota in this adaptation remains unclear. Here we performed fecal metagenomic and metabolomic studies on samples from high- and low-altitude populations to assess the synergistic role of gut microbiota in the adaptation of RMs to high-altitude environments. Microbiota taxonomic annotation yielded 7471 microbiota species. There were 37 bacterial species whose abundance was significantly enriched in the high-altitude populations, 16 of which were previously reported to be related to the host's dietary digestion and energy metabolism. Further functional gene enrichment found a stronger potential for gut microbiota to synthesize energy substrate acetyl-CoA using CO2 and energy substrate pyruvate using oxaloacetate, as well as a stronger potential to transform acetyl-CoA to energy substrate acetate in high-altitude populations. Interestingly, there were no apparent differences between low-altitude and high-altitude populations in terms of genes enriched in the main pathways by which the microbiota consumed the three energy substrates, and none of the three energy substrates were detected in the fecal metabolites. These results strongly suggest that gut microbiota plays an important energy compensatory role that helps RMs to adapt to high-altitude environments. Further functional enrichment after metabolite source analysis indicated the abundance of metabolites related to the degradation of exogenous toxins was also significantly higher in high-altitude populations, which suggested a contributory role of gut microbiota to the degradation of exogenous toxins in wild RMs adapted to high-altitude environments.
Asunto(s)
Microbioma Gastrointestinal , Animales , Microbioma Gastrointestinal/genética , Macaca mulatta/genética , Macaca mulatta/microbiología , Metagenoma , Altitud , Acetilcoenzima A/genética , MetabolomaRESUMEN
The incidence and mortality rate of malignant melanoma are increasing worldwide. Metastasis reduces the efficacy of current melanoma therapies and leads to poor prognosis for patients. EZH2 is a methyltransferase that promotes the proliferation, metastasis, and drug resistance of tumor cells by regulating transcriptional activity. EZH2 inhibitors could be effective in melanoma therapies. Herein, we aimed to investigate whether the pharmacological inhibition of EZH2 by ZLD1039, a potent and selective S-adenosyl-l-methionine-EZH2 inhibitor, suppresses tumor growth and pulmonary metastasis in melanoma cells. Results showed that ZLD1039 selectively reduced H3K27 methylation in melanoma cells by inhibiting EZH2 methyltransferase activity. Additionally, ZLD1039 exerted excellent antiproliferative effects on melanoma cells in 2D and 3D culture systems. Administration of ZLD1039 (100 mg/kg) by oral gavage caused antitumor effects in the A375 subcutaneous xenograft mouse model. RNA sequencing and GSEA revealed that the ZLD1039-treated tumors exhibited changes in the gene sets enriched from the "Cell Cycle" and "Oxidative Phosphorylation", whereas the "ECM receptor interaction" gene set had a negative enrichment score. Mechanistically, ZLD1039 induced G0/G1 phase arrest by upregulating p16 and p27 and inhibiting the functions of the cyclin D1/CDK6 and cyclin E/CDK2 complexes. Moreover, ZLD1039 induced apoptosis in melanoma cells via the mitochondrial reactive oxygen species apoptotic pathway, consistent with the changes in transcriptional signatures. ZLD1039 also exhibited excellent antimetastatic effects on melanoma cells in vitro and in vivo. Our data highlight that ZLD1039 may be effective against melanoma growth and pulmonary metastasis and thus could serve as a therapeutic agent for melanoma.
Asunto(s)
Neoplasias Pulmonares , Melanoma , Neoplasias Cutáneas , Humanos , Animales , Ratones , Proliferación Celular , Melanoma/genética , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Metiltransferasas , Línea Celular Tumoral , Apoptosis , Proteína Potenciadora del Homólogo Zeste 2/metabolismoRESUMEN
BACKGROUND: Blastocystis is a common intestinal protist with a wide range of hosts. Thus far, 38 subtypes have been identified. In recent years, wild animals have been confronted with habitat fragmentation as well as an increasing risk of zoonotic disease transmission due to human disturbance. Only limited data are available on Blastocystis infection and subtype distribution in wild rhesus macaques in China. The aim of the present study was to investigate the prevalence and genetic diversity of Blastocystis in nine wild rhesus macaque populations in China. METHODS: A total of 276 faecal samples were collected from five high-altitude populations (high-altitude group [HAG]; 2800-4100 m a.s.l.) and four low-altitude populations (low-altitude group [LAG]; 5-1000 m a.s.l) of rhesus macaques. PCR-based analysis, using a new primer pair for the amplification of a 1690-bp sequence of the small subunit ribosomal RNA (SSU rRNA) gene, was used for prevalence and genetic diversity analysis. RESULT: Analysis of faecal samples revealed that Blastocystis infection was common in rhesus macaques, with an infection positivity rate of 80.1% (n = 221/276 samples). There was no significant difference (P = 0.121) in positivity rate between the LAG (84.3%) and HAG (76.8%). Overall, 33 haplotypes were obtained and classified into four subtypes (STs), of which three were potentially zoonotic subtypes (ST1, 29.7%; ST2, 16.7%; ST3, 31.9%) and one that was first identified in this study and named ST39 (12.0%). The STs were distributed differently among the rhesus macaque populations, except for ST3, which was found in all populations. Phylogenetic analyses revealed two major divergent clades of ST3 for the HAG and LAG. Genetic diversity analysis showed a high genetic diversity of ST3 (haplotype diversity: 0.846; nucleotide diversity: 0.014) in the rhesus macaques, but a high genetic differentiation (FST > 0.25) and a low gene flow (Nm = 0.09) between the HAG and LAG. CONCLUSION: Our study, which is the first investigation on Blastocystis infection in multiple wild rhesus macaque populations in China, indicates a potential risk of zoonotic transmission of Blastocystis in the study areas. Blastocystis ST3 showed high genetic diversity in wild rhesus macaques and significant genetic differentiation between the HAG and LAG. Our results provide fundamental information on the genetic diversity and prevalence of Blastocystis in wild rhesus macaque populations.
Asunto(s)
Infecciones por Blastocystis , Blastocystis , Animales , Humanos , Blastocystis/genética , Infecciones por Blastocystis/epidemiología , Infecciones por Blastocystis/veterinaria , Macaca mulatta , Variación Genética , Prevalencia , Filogenia , Altitud , China/epidemiología , HecesRESUMEN
Animal gut microbiota plays an indispensable role in host adaptation to different altitude environments. At present, little is known about the mechanism of animal gut microbiota in host adaptation to high altitude environments. Here, we selected wild macaques, humans, and dogs with different levels of kinship and intimate relationships in high altitude and low altitude environments, and analyzed the response of their gut microbiota to the host diet and altitude environments. Alpha diversity analysis found that at high altitude, the gut microbiota diversity of wild macaques with more complex diet in the wild environments is much higher than that of humans and dogs with simpler diet (p < 0.05), and beta diversity analysis found that the UniFrac distance between humans and dogs was significantly lower than between humans and macaques (p < 0.05), indicating that diet strongly drive the convergence of gut microbiota among species. Meanwhile, alpha diversity analysis found that among three subjects, the gut microbiota diversity of high altitude population is higher than that of low altitude population (ACE index in three species, Shannon index in dog and macaque and Simpson index in dog, p < 0.05), and beta diversity analysis found that the UniFrac distances among the three subjects in the high altitude environments were significantly lower than in the low altitude environments (p < 0.05). Additionally, core shared ASVs analysis found that among three subjects, the number of core microbiota in high altitude environments is higher than in low altitude environments, up to 5.34 times (1,105/207), and the proportion and relative abundance of the core bacteria types in each species were significantly higher in high altitude environments than in low altitude environments (p < 0.05). The results showed that high altitude environments played an important role in driving the convergence of gut microbiota among species. Furthermore, the neutral community model trial found that the gut microbiota of the three subjects was dispersed much more at high altitude than at low altitude, implying that the gut microbiota convergence of animals at high altitudes may be partly due to the microbial transmission between hosts mediated by human activities.
RESUMEN
Enhancer of zeste homologue 2 (EZH2) is the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2), which plays an important role in post-translational modifications of histones. In this study, we designed and synthesized a new series EZH2 covalent inhibitors that have rarely been reported. Biochemical studies and mass spectrometry provide information that SKLB-03220 could covalently bind to the S-adenosylmethionine (SAM) pocket of EZH2. Besides, SKLB-03220 was highly potent for EZH2MUT, while exhibiting weak activities against other tested histone methyltransferases (HMTs) and kinases. Moreover, SKLB-03220 displayed noteworthy potency against ovarian cancer cell lines and continuously abolished H3K27me3 after washing out. Furthermore, oral administration of SKLB-03220 significantly inhibited tumor growth in PA-1 xenograft model without obvious adverse effects. Taken together, SKLB-03220 is a potent, selective EZH2 covalent inhibitor with noteworthy anticancer efficacy both in vitro and in vivo.
Asunto(s)
Proteína Potenciadora del Homólogo Zeste 2 , Neoplasias Ováricas , Femenino , Humanos , Línea Celular Tumoral , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Histonas/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Complejo Represivo Polycomb 2/metabolismo , Piridonas/farmacología , Piridonas/uso terapéutico , Piridonas/químicaRESUMEN
The importance of the "gut-liver axis" in the pathogenesis of liver diseases has been revealed recently; which promotes the process of developing preventive and therapeutic strategies. However, considering that there are still many challenges in the medical treatment of liver diseases, potential preventive dietary intervention may be a good alternative choice. Plant-based foods have received much attention due to their reported health-promoting effects in targeting multiple pathways involved in the pathogenesis of liver diseases as well as the relative safety for general use. Based on the PubMed and Web of Science databases, this review emphatically summarizes the plant-based foods and their chemical constituents with reported effects to impact the LPS/TLR4 signaling pathway of gut-liver axis of various liver diseases, reflecting their health benefits in preventing/alleviating liver diseases. Moreover, some plant-based foods with potential gut-liver effects are specifically analyzed from the reported studies and conclusions. This review intends to provide readers an overview of the current progress in the field of this research topic. We expect to see more hepatoprotective measures for alleviating the current prevalence of liver diseases.
Asunto(s)
Microbioma Gastrointestinal , Hepatopatías , Humanos , Estudios Prospectivos , Hígado , Hepatopatías/prevención & controlRESUMEN
BACKGROUND: Imatinib mesylate (IM) is highly effective in the treatment of gastrointestinal stromal tumors (GISTs). However, the most of GISTs patients develop secondary drug resistance after 1-3 years of IM treatment. The aim of this study was to explore the IM-resistance mechanism via the multi-scope combined with plasma concentration of IM, genetic polymorphisms and plasma sensitive metabolites. METHODS: This study included a total of 40 GISTs patients who had been regularly treated and not treated with IM. The plasma samples were divided into three experiments, containing therapeutic drug monitoring (TDM), OCT1 genetic polymorphisms and non-targeted metabolomics. According to the data of above three experiments, the IM-resistant cell line, GIST-T1/IMR cells, was constructed for verification the IM-resistance mechanism. RESULTS: The results of non-targeted metabolomics analysis suggested that the sphingophospholipid metabolic pathway including the SPK1/S1P axis was inferred in IM-insensitive patients with GISTs. A GIST cell line (GIST-T1) was immediately induced as an IM resistance cell model (GIST-T1/IMR) and we found that blocking the signal pathway of SPK1/S1P in the GIST-T1/IMR could sensitize treatment of IM and reverse the IM-resistance. CONCLUSIONS: Our findings suggest that IM secondary resistance is associated with the elevation of S1P, and blockage the signaling pathway of SPK1/S1P warrants evaluation as a potential therapeutic strategy in IM-resistant GISTs. The design of this study from blood management, group information collection, IM plasma concentration with different elements, identification of sphingolipid metabolism and lastly verification the function of SPK1/S1P in the IM-resistance GISTs cells.
Asunto(s)
Antineoplásicos , Neoplasias Gastrointestinales , Tumores del Estroma Gastrointestinal , Neoplasias Gástricas , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/patología , Resistencia a Antineoplásicos , Neoplasias Gástricas/tratamiento farmacológico , Transducción de Señal , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/genética , Neoplasias Gastrointestinales/tratamiento farmacológico , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patologíaRESUMEN
Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are two of the most fatal respiratory diseases, seriously threatening human health and imposing a heavy burden on families and society. Although COPD is a significant independent risk factor for LC, it is still unclear how COPD affects the prognosis of LC patients, especially when LC patients with COPD receive immunotherapy. With the development of immune checkpoint inhibition (ICI) therapy, an increasing number of inhibitors of programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) have been applied to the treatment of LC. Recent studies suggest that LC patients with COPD may benefit more from immunotherapy. In this review, we systematically summarized the outcomes of LC patients with COPD after anti-PD-1/PD-L1 treatment and discussed the tumor immune microenvironment (TIME) regulated by COPD in LC immunotherapy, which provides novel insights for the clinical treatment of LC patients with COPD.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptor de Muerte Celular Programada 1 , Neoplasias Pulmonares/patología , Microambiente TumoralRESUMEN
The response to neoadjuvant chemotherapy (NAC) is highly correlated with survival in breast cancer (BC) patients. The early prediction of the response to NAC could facilitate treatment adjustments on a patient-by-patient basis, which would improve patient outcomes and survival. Conventional techniques used for detecting circulating microRNAs (miRNAs), which act as biomarkers for the early prediction of NAC efficacy in BC patients, are associated with limitations such as low sensitivity and specificity. We designed a highly sensitive graphene oxide (GO)-based qRT-PCR method for detecting miRNAs associated with the chemotherapeutic response in BC patients. The results showed that miRNA levels at both the baseline and end of the first NAC cycle could help distinguish NAC responders from NAC nonresponders; BC patients with lower plasma miRNA levels were more likely to achieve pathological complete remission. Thus, GO-based qRT-PCR could facilitate early prediction of NAC efficacy in BC patients.
Asunto(s)
Neoplasias de la Mama , MicroARN Circulante , MicroARNs , Humanos , Femenino , Terapia Neoadyuvante/métodos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , MicroARNs/genéticaRESUMEN
Triclocarban (TCC), an antimicrobial ingredient in personal care products, is associated with immunosuppression and physiological dysfunctions of aquatic organisms. The aim of this study was to investigate whether TCC can induce common carp NETosis (neutrophil death by neutrophil extracellular trap (NET) release) and then to attempt to identify the potential molecular mechanisms. Herein, scanning electron microscopy and flow cytometric assays showed that revealed that TCC triggers DNA-containing web-like structures and increases extracellular DNA content. In the proteomic analysis, we observed that NET-related proteins, extracellular regulated protein kinase (Mapk1, Mapk14, Jak2) and apoptotic protein (caspase3) were significantly increased, and defender against cell death 1 (Dad1) was significantly decreased after TCC treatments. Meanwhile, we confirmed that TCC stress can trigger NETosis in common carp by activating the reactive oxygen species (ROS)/ERK1/2/p38 signaling. We think that the upregulated NDUFS1 expression is closely related to oxidative stress induced by TCC. Importantly, we discovered that SIRT3 expression was significantly decreased in the process of TCC-induced NETs. Importantly, pretreatment with the SIRT3 agonist honokiol (HKL) effectively suppressed TCC-induced NET release. In contrast, the SIRT3 antagonist 3-TYP escalated TCC-induced NET formation. Mechanistically, SIRT3 degradation serves as a potential mediator for regulating oxidative stress crosstalk between ERK1/2/p38 signals in the process of TCC-induced NET formation. These findings unveil new insights into the TCC-evoked health risk of fish and other aquatic organisms and suggest that SIRT3 is a potential pharmacological intervention target to alleviate TCC-induced common carp NETosis.