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Primary amines are privileged molecules in drug development. Yet, there is a noticeable scarcity of methods for directly introducing a primary amine group into the ubiquitous C(sp3)-H bonds within organic compounds. Here, we report an iron-based catalytic system that enables direct primary amination of C(sp3)-H bonds under aqueous conditions and air. Various types of C(sp3)-H bonds, including benzylic, allylic, and aliphatic ones, can be readily functionalized with high selectivity and efficiency. The broad utility of this method has been further verified by late-stage amination of 11 complex bioactive molecules. Mechanistic studies unveil a protonated iron-nitrene complex as the key intermediate for the C-H bond activation. This work extends the toolbox for direct C(sp3)-H functionalizations, opening up new opportunities for late-stage modifications of organic molecules.
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Background: The immune system appears to play a crucial role in how breast cancer responds to chemotherapy. In this study, we investigated a peripheral marker of immune and inflammation named the neutrophil to albumin ratio (NAR) to explore its potential relationship with pathological complete response (pCR) in locally advanced breast cancer patients who underwent neoadjuvant chemotherapy (NAC). Methods: We conducted a retrospective analysis of 212 consecutive breast cancer patients who received NAC. The NAR was calculated by examining the complete blood cell count and albumin level in peripheral blood before starting NAC. Through ROC curve analysis, we determined the optimal cutoff value for NAR as 0.0877. We used Pearson's chi-square test or Fisher's exact test to evaluate the relationship between NAR and pCR, as well as other clinical and pathological characteristics. Logistic regression models were employed for univariate and multivariate analyses. Results: The results of both univariate and multivariate logistic regression analyses showed that NAR was associated with tumor pathological regression. The NAR high group had a higher pCR rate compared to the NAR low group (OR 3.127 [95% CI 1.545-6.328]; p = 0.002). Conclusion: According to this study, it was observed that patients with breast cancer who had high levels of NAR were more likely to achieve pCR when undergoing NAC.
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The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling is activated by infections of bacteria, fungi, viruses and parasites and mediated cellular and humoral immune responses. In the pea aphid Acyrthosiphon pisum little is known about the function of JAK/STAT signaling in its immune system. In this study, we first showed that expression of genes in the JAK/STAT signaling, including the receptors Domeless1/2, Janus kinase (JAK) and transcriptional factor Stat92E, is up-regulated upon bacteria Escherichia coli and Staphylococcus aureus and fungus Beauveria bassiana infections. After knockdown of expression of these genes by means of dsRNA injection, the aphids harbored more bacteria and suffered more death after infected with E. coli and S. aureus, but showed no significant change after B. bassiana infection. Our study suggests the JAK/STAT signaling contributes to the defense against bacterial infection in the pea aphid.
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Afídeos , Janus Quinases , Fatores de Transcrição STAT , Transdução de Sinais , Animais , Janus Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Staphylococcus aureus/fisiologia , Escherichia coli , Proteínas de Insetos/metabolismo , Proteínas de Insetos/genética , Beauveria/fisiologiaRESUMO
The longhorned beetles are key players for the maintenance of biodiversity in the terrestrial ecosystem. As xylophagous cerambycid insects in Coleoptera, the beetles have evolved specialized olfactory and gustatory systems to recognize chemical cues in the surrounding habitats. Despite over 36,000 described species in the Cerambycidae family including a wood-boring pest Pharsalia antennata, only a limited number of them (<1 %) have been characterized regarding their chemical ecology at the molecular level. Here, we surveyed four membrane protein gene families in P. antennata related to chemoreception through transcriptomics, phylogenetics and expression profiling analyses. In total, 144 genes encoding 72 odorant receptors (ORs), 33 gustatory receptors (GRs), 23 ionotropic receptors (IRs), four sensory neuron membrane proteins (SNMPs) and 12 ionotropic glutamate receptors (iGluRs) were harvested from the transcriptome of multiple tissues including antennae and legs of both sexes. The lineage-specific expansion of PantORs possibly implied a diverse range of host plants in this beetle, supporting this correlation between the host range and olfactory receptor repertoire sizes across cerambycid species. Further phylogenetic analysis revealed that Group 2 was contributed mainly to the large OR gene repertoire in P. antennata, representing 18 genes in Group 2A and eight in Group 2B. On the other hand, some key chemosensory genes were identified by applying a phylogenetics approach, such as PantOR21 close to the 2-phenylethanol receptor in Megacyllene caryae, three carbon dioxide GRs and seven Antennal IRs (A-IRs) clades. We also determined sex- and tissue-specific expression profiles of 69 chemosensory genes, revealing the high expression of most PantORs in antennae. Noticeably, 10 sex-biased genes (six PantORs, three PantIRs and PantSNMP1a) were presented in antennae, five sex-biased PantGRs in legs and 39 sex-biased genes (15 PantORs, 13 PantGRs, eight PantIRs and three PantSNMPs) in abdomens. These findings have greatly enhanced our knowledge about the chemical ecology of P. antennata and identify candidate molecular targets for mediating smell and taste of this beetle.
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Besouros , Proteínas de Insetos , Filogenia , Animais , Besouros/genética , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Receptores Odorantes/genética , Receptores Odorantes/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Feminino , Transcriptoma , Receptores Ionotrópicos de Glutamato/genética , Receptores Ionotrópicos de Glutamato/metabolismo , Família Multigênica , Antenas de Artrópodes/metabolismoRESUMO
BACKGROUND: Radiofrequency ablation has been applied for the treatment of hypertrophic obstructive cardiomyopathy (HOCM). The two known procedures are percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) and endocardial radiofrequency septal ablation (ERSA). METHODS: This study presents a retrospective analysis of the PIMSRA and ERSA procedures in patients with drug-refractory HOCM. A total of 28 patients participated in the study, with 12 receiving PIMSRA and 16 receiving ERSA. The objective of our study was to compare the short-term effects of these two radiofrequency ablation procedures. RESULTS: At the 30-day follow-up, the PIMSRA group demonstrated a greater reduction in left ventricular outflow tract peak gradient at rest compared to the ERSA group (22.25 [16.72] mmHg versus 47.75 [21.94] mmHg) (p < .01). The values for the PIMSRA group decreased from 99.33 (32.00) mmHg to 22.25 (16.72) mmHg (p < .01), while the ERSA group decreased from 97.75 (30.24) mmHg to 47.75 (21.94) mmHg (p < .01). Only the PIMSRA group exhibited a decrease in mitral regurgitation (MR). The area of MR decreased from 10.13 (4.12) mm2 to 3.65 (2.80) mm2 in the PIMSRA group (p < .01). Additionally, the PIMSRA group experienced reductions in left atrial diameter (LAD) and left ventricular ejection fraction (LVEF)%. The values for LAD changed from 43.58 (7.53) mm to 37.08 (6.92) mm (p = .03), and the values for LVEF% decreased from 65.75 (6.12) pg/mL to 60.83 (4.06) pg/mL (p = .03). CONCLUSION: In terms of the two types of radiofrequency ablation methods used in HOCM, it has been observed that PIMSRA demonstrates a more favorable early treatment effect compared to ERSA.
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Apêndice Atrial , Cardiomiopatia Hipertrófica , Insuficiência da Valva Mitral , Ablação por Radiofrequência , Humanos , Estudos Retrospectivos , Volume Sistólico , Função Ventricular Esquerda , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/cirurgiaRESUMO
Telomerase (TE) is a promising diagnostic and prognostic biomarker for many cancers. Quantification of TE activity in living cells is of great significance in biomedical and clinical research. Conventional fluorescence-based sensors for quantification of intracellular TE may suffer from problems of fast photobleaching and auto-fluorescence of some endogenous molecules, and hence are liable to produce false negative or positive results. To address this issue, a fluorescence-SERS dual-signal nano-system for real-time imaging of intracellular TE was designed by functionalizing a bimetallic Au@Ag nanostructure with 4-p-mercaptobenzoic acid (internal standard SERS tag) and a DNA hybrid complex consisted of a telomerase primer strand and its partially complimentary strand modified with Rhodamine 6G. The bimetallic Au@Ag nanostructure serves as an excellent SERS-enhancing and fluorescence-quenching substrate. Intracellular TE will trigger the extension of the primer strand and cause the shedding of Rhodamine 6G-modified complimentary strand from the nano-system through intramolecular DNA strand displacement, resulting in the recovery of the fluorescence of Rhodamine 6G and decrease in its SERS signal. Both the fluorescence of R6G and the ratio between the SERS signals of 4-p-mercaptobenzoic acid and Rhodamine 6G can be used for in situ imaging of intracellular TE. Experimental results showed that the proposed nano-system was featured with low background, excellent cell internalization efficiency, good biocompatibility, high sensitivity, good selectivity, and robustness to false positive results. It can be used to distinguish cancer cells from normal ones, identify different types of cancer cells, as well as perform absolute quantification of intracellular TE, which endows it with great potential in clinical diagnosis, target therapy and prognosis of cancer patients.
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Nanoestruturas , Telomerase , Humanos , Fluorescência , Telomerase/metabolismo , DNARESUMO
BACKGROUND: Left atrial appendage closure (LAAC) is a safe and effective method for preventing embolic events in patients with non-valvular atrial fibrillation. However, peri-device leaks (PDLs) are sometimes unavoidable. Controversy exists regarding whether PDLs lead to embolic events. OBJECTIVES: This study aimed to explore the association between PDLs and embolic events, including ischaemic stroke, transient ischaemic attacks (TIAs), and systemic embolism (SE). METHODS: We conducted a systematic search of the PubMed, Web of Science, MEDLINE, and Cochrane Library databases for studies published up to September 25, 2022, to compare the rate of ischaemic stroke/TIA/SE between the PDL group and the non-PDL group after LAAC. RESULTS: Thirteen studies comprising 54,405 patients were included in the meta-analysis. The PDL group detected by transoesophageal echocardiography (TEE) had a significantly higher rate of ischaemic stroke/TIA/SE than the non-PDL group (OR: 1.20, 95% CI: 1.08-1.33, p = 0.0009). However, no difference in ischaemic stroke/TIA/SE was found between the PDL and non-PDL subgroups of the cardiac computed tomography angiography (CCTA) group (OR: 1.12, 95% CI: 0.51-2.50, p = 0.77). CCTA and TEE showed different rates of PDL detection, with the CCTA group having a higher rate of PDL detection (p < 0.0001), especially for trivial leaks. CONCLUSIONS: PDL detected by TEE increases the risk of embolic events after LAAC. However, no association was found between PDL and ischaemic stroke/TIA/SE in the CCTA group, which showed a higher rate of PDL detection than TEE, particularly for trivial leaks. In the future, CCTA may be used to explore the relationship between PDL size and ischaemic stroke/TIA/SE.
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Apêndice Atrial , Fibrilação Atrial , Isquemia Encefálica , Embolia , Ataque Isquêmico Transitório , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Ataque Isquêmico Transitório/etiologia , Oclusão do Apêndice Atrial Esquerdo , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Isquemia Encefálica/etiologia , Fibrilação Atrial/etiologia , AVC Isquêmico/etiologia , Embolia/etiologia , Embolia/prevenção & controle , Apêndice Atrial/diagnóstico por imagem , Apêndice Atrial/cirurgia , Resultado do Tratamento , Ecocardiografia Transesofagiana , Cateterismo Cardíaco/efeitos adversosRESUMO
Telomerase (TE) is recognized as a potential biomarker for early diagnosis, monitoring and treatment of cancer. At present, most of the methods for TE detection are only applicable to in vitro assays, and unsuitable for in vivo applications. Though a few intracellular probes have been reported to have good specificity for TE, they do not involve signal amplification, which hinders their applicability in scenarios requiring high sensitivity. It is rather challenging to develop highly sensitive biosensors for intracellular TE detection due to the difficulty in design TE probes with both high specificity and compatibility with signal amplification in living cells. Herein, a highly sensitive and selective three-dimensional DNAzyme motor for monitoring of TE activity in living cells was developed by innovatively integrating TE-mediated chain replacement reaction with a three-dimensional DNA walker. Specifically, the DNAzyme motor was constructed by assembling both DNAzyme substrates and swing arms made up of a hairpin-structured DNAzyme and a telomeric primer onto gold nanoparticles. TE in cells can activate the DNAzyme motor to carry out continuous chain replacement and substrate cutting reactions, and hence realize signal amplification in living cells. The DNAzyme motor was successfully utilized to monitor the dynamic changes of TE activity in four types of cells. Due to the advantages of simple synthesis, good biocompatibility and high sensitivity and specificity for TE, the proposed DNAzyme motor is expected to have great application potential in the early diagnosis of cancer.
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A versatile triple cascade amplification strategy was developed for ultrasensitive simultaneous detection of multiple cancer biomarkers using single particle inductively coupled plasma mass spectrometry (spICP-MS). The triple cascade amplification strategy consisted of an enhanced RecJf exonuclease-assisted target recycling amplification module, a hybridization chain reaction amplification module, and a signal amplification module based on DNA-templated multiple metal nanoclusters. In the enhanced RecJf exonuclease-assisted target recycling amplification module, the DNA bases at the 5' ends of aptamers for specific recognition of biomarkers were deliberately replaced by the corresponding RNA bases to enhance amplification efficiency. The signal amplification module based on DNA-templated multiple metal nanoclusters was innovatively used to amplify the signals measured by spICP-MS and at the same time effectively suppress possible background interferences. The proposed spICP-MS platform achieved satisfactory quantitative results for both carcinoembryonic antigen (CEA) and a-fetoprotein (AFP) in human serum samples with accuracy comparable to that of the commercial ELISA kits. Moreover, it has wide dynamic ranges for both CEA (0.01-100 ng/mL) and AFP (0.01-200 ng/mL). The limit of detection for CEA and AFP was 0.6 and 0.5 pg/mL, respectively. Compared with conventional biomarkers detection methods, the proposed spICP-MS platform has the advantages of operational simplicity, ultra-high sensitivity, wide dynamic range, and low background. Therefore, it is reasonable to expect that the proposed spICP-MS platform can be further developed to be a promising alternative tool for biomarker detection in fields of clinical diagnosis and biomedical research.
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Técnicas Biossensoriais , Neoplasias , Humanos , Antígeno Carcinoembrionário/análise , Técnicas Biossensoriais/métodos , Biomarcadores Tumorais , alfa-Fetoproteínas , DNA/química , Exonucleases , Espectrometria de Massas , Neoplasias/diagnósticoRESUMO
The wood-boring beetles, including the majority of Cerambycidae, have developed the ability to metabolize a variety of toxic compounds derived from host plants and the surrounding environment. However, detoxification mechanisms underlying the evolutionary adaptation of a cerambycid beetle Pharsalia antennata to hosts and habitats are largely unexplored. Here, we characterized three key gene families in relation to detoxification (cytochrome P450 monooxygenases: P450s, carboxylesterases: COEs and glutathione-S-transferases: GSTs), by combinations of transcriptomics, gene identification, phylogenetics and expression profiles. Illumina sequencing generated 668,701,566 filtered reads in 12 tissues of P. antennata, summing to 100.28 gigabases data. From the transcriptome, 215 genes encoding 106 P450s, 77 COEs and 32 GSTs were identified, of which 107 relatives were differentially expressed genes. Of the identified 215 genes, a number of relatives showed the orthology to those in Anoplophora glabripennis, revealing 1:1 relationships in 94 phylogenetic clades. In the trees, P. antennata detoxification genes mainly clustered into one or two subfamilies, including 64 P450s in the CYP3 clan, 33 COEs in clade A, and 20 GSTs in Delta and Epsilon subclasses. Combining transcriptomic data and PCR approaches, the numbers of detoxification genes expressed in abdomens, antennae and legs were 188, 148 and 141, respectively. Notably, some genes exhibited significantly sex-biased levels in antennae or legs of both sexes. The findings provide valuable reference resources for further exploring xenobiotics metabolism and odorant detection in P. antennata.
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Plant invasions profoundly impact both natural and managed ecosystems, and removal of the invasive plants addresses only part of the problem of restoring impacted areas. The rehabilitation of diverse communities and their ecosystem functions following removal of invasive plants is an important goal of ecological restoration. Arthropod assemblages and trophic interactions are important indicators of the success of restoration, but they have largely been overlooked in saltmarshes. We determined how arthropod assemblages and trophic interactions changed with the invasion of the exotic plant Spartina alterniflora and with the restoration of the native plant Phragmites australis following Spartina removal in a Chinese saltmarsh. We investigated multiple biotic and abiotic variables to gain insight into the factors underlying the changes in arthropod assemblages and trophic structure. We found that although Spartina invasion had changed arthropod diversity, community structure, feeding-guild composition, and the diets of arthropod natural enemies in the saltmarsh, these changes could be reversed by the restoration of native Phragmites vegetation following removal of the invader. The variation in arthropod assemblages and trophic structure were critically associated with four biotic and abiotic variables (aboveground biomass, plant density, leaf N, and soil salinity). Our findings demonstrate the positive effects of controlling invasive plants on biodiversity and nutrient cycling and provide a foundation for assessing the efficacy of ecological restoration projects in saltmarshes.
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Contemporary pharmacological studies have reported that freshwater clam (Corbicula fluminea) can provide a broad spectrum of bioactivities, including antioxidant, anticancer, antihypertensive, hepatoprotective, and hypocholesterolemic effects. The aim of this study was to evaluate the gastroprotective effects of water extract of freshwater clam (WEC) on indomethacin (IND)-induced gastric mucosal cell damage in vitro and gastric ulcer in vivo. The cell viability of rat gastric mucosa RGM-1 cells was markedly decreased by 0.8 mM of IND treatment, and pre-treated with various concentration of WEC significantly restored IND-induced cell damage in a dose-dependent manner. WEC also significantly attenuated the elevated reactive oxygen species (ROS) levels, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, and nuclear factor-κB (NF-κB) p65 nuclear translocation induced by IND. In the in vivo study, IND caused severe gastric ulcer in Wistar rats, while WEC pretreatment effectively reduced the ulcer area and edema in the submucosa. We found that WEC significantly restored glutathione (GSH) content in gastric mucosa in a dose-dependent manner (p < 0.05). The reduction of prostaglandin E2 (PGE2) caused by IND was also improved with higher doses of WEC administration. Moreover, the overexpression of COX-2, iNOS, and tumor necrosis factor-α (TNF-α) proteins in gastric mucosa was downregulated by administration of WEC. Consequently, WEC can be used as a potential nutritional supplement to improve NSAIDs-caused gastric mucosal lesions.
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Objective To investigate the patterns of perioperative blood transfusion in patients with blood loss during major cardiac surgery,so as to provide data reference for rational and standardized blood use.Methods The adult patients(aged 18 years or above)who underwent vascular surgery,coronary artery bypass grafting surgery,heart valve surgery or surgery for congenital heart disease in a national multicenter(four large hospitals)survey in China,2015-2016 were included in this study.We described their baseline characteristics,postoperative outcomes,and in particular,bleeding and patterns of perioperative blood transfusion(autologous and allogeneic,the latter including red blood cells,plasma,and platelet,or a combination of these components).Results Autologous blood transfusion in operation accounted for the highest proportion(58.84%)in patients undergoing heart valve surgery.The patients undergoing vascular surgery had the largest autologous blood transfusion volume(722 ml)and the highest intraoperative transfusion proportion of allogeneic blood(53.28%),especially that of platelet(39.34%).Compared with the transfusion of red blood cells,the transfusion of other blood components showed concentrated time distribution,and the proportion of plasma transfusion was the highest one day post operation.With the increase in bleeding volume,combined transfusion presented increased proportion and became the dominant transfusion pattern.Conclusions The blood transfusion patterns varied significantly depending on different types of cardiac surgery,different perioperative stages,and different bleeding volumes.It is necessary to formulate the targeted transfusion practice scheme on the basis of understanding the current situation,so as to make better use of blood resources and improve the safety of transfusion.
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Transfusão de Componentes Sanguíneos , Procedimentos Cirúrgicos Cardíacos , Adulto , Humanos , Plasma , Transfusão de Sangue/métodos , Procedimentos Cirúrgicos Cardíacos/métodos , Perda Sanguínea CirúrgicaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Danhong injection (DHI)ï¼which is extracted from Salviae miltiorrhizae and Flos carthamiï¼has been widely prescribed to patients with unstable angina pectoris (UAP) in China. However, a high quality clinical trial is needed. AIM OF THE STUDY: To determine whether DHI can relieve symptoms of transient myocardial ischemia in patients with unstable angina pectoris. MATERIALS AND METHODS: A double-blind, placebo-controlled, randomized clinical trial was conducted in nine hospitals in China. Inpatients with UAP with blood stasis syndrome (BSS) were randomized 1:1 to receive DHI or placebo. The primary outcome was improvement rate in the quantification score of angina pectoris. Secondary outcomes included blood stasis syndrome scale, nitrates use, electrocardiogram recordings, PCI procedures, Seattle Angina Questionnaire (SAQ) and biochemical indexes. RESULTS: 160 participants were enrolled and 159 were analyzed. There was no signiï¬cant diï¬erence in primary outcome as compared with control group at the end of 7-day treatment, but significant difference at 28-day follow up (70.53% [95% CI, 59.97-81.09%] and 54.34% [95% CI, 42.68-65.99%]; P = 0.0423). The BSS score was significantly lower in the DHI group than that in the control group at day 28 (6.49 [6.96] vs 10.53 [9.07], P = 0.0034). In addition, DHI was signiï¬cantly superior to placebo in the angina stability score of SAQ (91.10 [17.37] versus 78.21 [22.08], P < 0.001). There were no significant differences in other secondary outcome measures. CONCLUSIONS: A small decrease in the total effective rate and an increase in the angina stability score were observed 28 days after implementation of DHI in UAP with a total blood stasis syndrome score decrease, but the efficacy was not observed at day 7. The findings support that DHI may potentially relieve clinical symptoms and can benefit angina stability. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02007187.
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Angina Instável/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Fitoterapia , Adulto , Idoso , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/uso terapêutico , Método Duplo-Cego , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Elevated expression of eukaryotic initiation factor 3c (eIF3C) was recently uncovered to promote several types of cancer progression by inducing cell proliferation. Here, we aimed to assess the expression and prognostic value of eIF3C in intrahepatic cholangiocarcinoma (ICC) patients. METHODS: Expression of eIF3C was analyzed by immunohistochemistry in tissue microarrays (TMAs) containing 138 ICC and paired peritumoral tissues from ICC patients. Then, the roles of eIF3C in ICC cells were investigated by RNA interference, and the relationship between the eIF3C and KI67 expression was explored in ICC cells and tissues. Finally, the relation between the eIF3C level and clinicopathologic features of ICC was probed, and Kaplan-Meier and Cox's analyses were performed to assess the prognostic merit of eIF3C and KI67 in ICC patients. RESULTS: The expression of eIF3C was elevated in ICC tissues compared to paired peritumoral tissues, which was consistent with the result from the GEPIA database. The downregulation of eIF3C in ICC cells impaired the cellular invasion, metastasis, colony formation, and proliferation. Moreover, we further found a positive relationship between the eIF3C and KI67 expression in ICC cells and tissues. The expression of eIF3C in ICC tissues was positively correlated with lymphatic metastasis (p = 0.049), and the high level of KI67 was frequently found in ICC patients with the large tumor (p = 0.028), high serum AFP (p = 0.019), or lymphatic metastasis (p = 0.039). Notably, patients with the eIF3C or KI67 overexpression had shorter overall survival and higher disease-free survival rates than those with low expression of eIF3C or KI67, and the combination of eIF3C or KI67 expression was an independent parameter for predicting the prognosis and recurrence of ICC patients. CONCLUSIONS: Elevated eIF3C expression promotes ICC development, and combination of eIF3C and KI67 is a valuable predictor of the survival and recurrence of ICC patient.
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Neoplasias dos Ductos Biliares/genética , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/genética , Fator de Iniciação 3 em Eucariotos/genética , Antígeno Ki-67/metabolismo , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Proliferação de Células/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Fator de Iniciação 3 em Eucariotos/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Carga TumoralRESUMO
How two subgenomes in allo-tetraploids adapt to coexistence and coordinate through structure and expression evolution requires extensive studies. In the present study, we report an improved genome assembly of allo-tetraploid common carp, an updated genome annotation of allo-tetraploid goldfish and the chromosome-scale assemblies of a progenitor-like diploid Puntius tetrazona and an outgroup diploid Paracanthobrama guichenoti. Parallel subgenome structure evolution in the allo-tetraploids was featured with equivalent chromosome components, higher protein identities, similar transposon divergence and contents, homoeologous exchanges, better synteny level, strong sequence compensation and symmetric purifying selection. Furthermore, we observed subgenome expression divergence processes in the allo-tetraploids, including inter-/intrasubgenome trans-splicing events, expression dominance, decreased expression levels, dosage compensation, stronger expression correlation, dynamic functionalization and balancing of differential expression. The potential disorders introduced by different progenitors in the allo-tetraploids were hypothesized to be alleviated by increasing structural homogeneity and performing versatile expression processes. Resequencing three common carp strains revealed two major ecotypes and uncovered candidate genes relevant to growth and survival rate.
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Carpas/genética , Evolução Molecular , Regulação da Expressão Gênica , Genoma , Carpa Dourada/genética , Tetraploidia , Processamento Alternativo/genética , Animais , Sequência de Bases , Variação Genética , Cariótipo , Funções Verossimilhança , Anotação de Sequência Molecular , Filogenia , Seleção Genética , Especificidade da Espécie , Sintenia/genéticaRESUMO
BACKGROUND: Accumulating evidence indicates that circRNAs may serve as essential regulators in the progression of several human cancers, but the function and mechanism of circRNAs in intrahepatic cholangiocarcinoma (ICC) are largely unknown. METHODS: RNA-seq was used to assess differentially expressed circRNAs between 4 ICC and peritumor tissues. Quantitative RT-PCR and in situ hybridization were used to determine the circHMGCS1-016 expression in ICC tissues. The function and mechanism of circHMGCS1-016 were further identified via in vivo experiments. The clinical characteristics and prognostic significance of circHMGCS1-016 were analyzed by a retrospective study. The functions of circHMGCS1-016 were assessed via modifying circRNA expression in ICC cells. Moreover, the molecular mechanisms of circHMGCS1-016 in ICC cells were explored by circRNA precipitation, miRNA immunoprecipitation, SILAC and luciferase reporter assays. RESULTS: We identified that compared with peritumor tissues, ICC tissues expressed hsa_circ_0008621 (circHMGCS1-016) high by RNA-seq, which was further identified by qRT-PCR and in situ hybridization. Moreover, the expression of circHMGCS1-016 was revealed to be associated with survival and recurrence of ICC patients. By regulating circHMGCS1-016 expression, we found that elevated circHMGCS1-016 promoted ICC development both in vitro and in vivo. By SILAC and circRNA-pull down, we demonstrated that circHMGCS1-016 induced ICC cell invasion and reshaped the tumor immune microenvironment via the miR-1236-3p/CD73 and GAL-8 axis. In ICC tissues, we uncovered that a high level of circHMGCS1-016 was positively associated with CD73 and GAL-8 expression and negatively related to the CD8+ T cells infiltration, which was further validated by establishing a humanized mouse tumor model. Importantly, we displayed that ICC patients with high levels of circHMGCS1-016 in tumor tissues benefited less from anti-PD1 treatment compared to those with low levels of circHMGCS1-016. CONCLUSIONS: CircHMGCS1-016 is a forceful contributor in ICC development and immune tolerance via miR-1236-3p/CD73 and GAL-8 axis. CircHMGCS1-016 can be explored as a new potential biomarker and therapeutic target for PD1-resistant ICC.
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5'-Nucleotidase/genética , Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/genética , Galectinas/genética , Hidroximetilglutaril-CoA Sintase/genética , MicroRNAs/genética , RNA Circular , Microambiente Tumoral/genética , Animais , Neoplasias dos Ductos Biliares/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/patologia , Modelos Animais de Doenças , Progressão da Doença , Imunofluorescência , Proteínas Ligadas por GPI/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Imunomodulação/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Interferência de RNA , Microambiente Tumoral/imunologiaRESUMO
Background: Despite recent improvements in the diagnosis and therapy of intrahepatic cholangiocarcinoma (ICC), the prognosis for ICC patients remains poor. Therefore, it is needed to identify new biological indicators for ICC progression. Methods: Immunohistochemistry was engaged to inspect the ecto-5'-nucleotidase (CD73) and CD8 expressions in tissue microarrays including tissues from 140 ICC patients. Then, the association between the level of CD73/CD8 and clinicopathologic characteristics of ICC was analysed. Finally, the prognostic value of CD73 and CD8 levels in ICC patients was assessed by Kaplan-Meier and multivariate and univariate analyses. Results: The CD73 expression was evidently upregulated in ICC tissues compared to the corresponding peritumoral tissues. The elevated CD73 expression was positively related to the lymphatic metastasis (p=0.049). While the level of tumour-infiltrating CD8 T+ cells in tumour tissues was negatively associated with serum AFP (p=0.019), tumor size (p=0.028), and lymphatic metastasis (p=0.039). Additionally, patients with elevated CD73 expression or low tumour-infiltrating CD8+ T cells exhibited shorter overall survival (OS) and higher disease-free survival (DFS) rates than patients with low CD73 expression and/or high tumour-infiltrating CD8+ T cells. Notably, the overexpression of CD73 or low tumour-infiltrating CD8+ T cells was an independent indicator for predicting the OS and DFS of ICC patients. Conclusions: We revealed that CD73 expression and low tumour-infiltrating CD8+T cells are valuable predictors of survival and recurrence in patients with ICC.
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BACKGROUND: Teleost scale not only provides a protective layer resisting penetration and pathogens but also participate in coloration. It is interesting to study the mechanism of teleost scale formation. Furthermore, whether there existed consensus genes between scale coloration and skin coloration has not been examined yet. METHODS AND RESULTS: We analyzed the transcriptome profiles of red scale, white scale, red skin, and white skin of common carp (Cyprinus carpio). Pair-wise comparison identified 3391 differentially expressed genes (DEGs) between scale and skin, respectively. The 1765 up-regulated genes (UEGs) in scale, as the down-regulated genes in skin, preferred mineralization and other scale development-related processes. The 1626 skin UEGs were enriched in the morphogenesis of skin and appendages. We also identified 195 UEGs in white scale and 223 UEGs in red scale. The white scale UEGs primarily participated in regulation of growth and cell migration. The UEGs in red scale preferred pigment cell differentiation and retinoid metabolic process. A total of 22 DEGs had consensus expression patterns in skin and scale of the same coloration. The expression levels of these DEGs clearly grouped skin and scale of the same coloration together with principle component analysis and correlation analysis. Eleven consensus DEGs were homologous to the orthologs of Poropuntius huangchuchieni, 82% of which were under strong purifying selection. Eight processes including lipid storage and lipid catabolism were shared in both scale pigmentation and skin pigmentation. CONCLUSIONS: We identified consensus DEGs and biological processes in scale and skin pigmentation. Our transcriptome analysis will contribute to further elucidation of mechanisms of teleost scale formation and coloration.
Assuntos
Carpas/genética , Análise de Sequência de RNA , Pigmentação da Pele/genética , Transcriptoma/genética , Escamas de Animais/metabolismo , Animais , Sequência Conservada/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genoma , Especificidade de Órgãos/genética , Pele/metabolismoRESUMO
BACKGROUND: Liver metastasis is an indicator of unfavorable responses to immunotherapy in colorectal cancer patients. However, the difference of immune microenvironment between primary tumors and liver metastases has not been well understood. PATIENTS AND METHODS: Fifty-four colon cancer with liver metastasis patients who received resection of both primary and metastasis lesions have been analyzed. The immune score is based on the density of infiltrating immune cells (CD3+ cell, CD8+ cell, CD11b+ cell, CD11c+ cell, and CD33+ cell) in the center and margin of the tumor. The expression of immune markers between the primary tumor and hepatic metastases was analyzed using Wilcoxon's signed rank test. RESULTS: All the five markers had higher expression in tumor margins than center tumor in both primary tumor and hepatic metastases lesions. The expression of CD11c and CD11b had no difference between metastatic lesions and primary tumor. In tumor margins, except CD11b, all the other 4 markers expressed significantly higher in hepatic metastases than in primary tumor. Intra-tumor, CD3 had higher expression in primary tumor than in hepatic metastases, while CD33 had higher expression in hepatic metastases than in primary tumor. CD8+ CD3+ cells of the total CD8+ cell population in primary tumor was significantly higher than in hepatic metastases (36.42% vs. 24.88%, p = 0.0069). CONCLUSIONS: The immune microenvironment between primary tumor and hepatic metastasis is different. More immunosuppressing cells in liver may partially explain why immunotherapy in colon cancer is less effective with liver metastatic disease.