RESUMO
Predicting therapeutic responses in cancer patients is a major challenge in the field of precision medicine due to high inter- and intra-tumor heterogeneity. Most drug response models need to be improved in terms of accuracy, and there is limited research to assess therapeutic responses of particular tumor types. Here, we developed a novel method DROEG (Drug Response based on Omics and Essential Genes) for prediction of drug response in tumor cell lines by integrating genomic, transcriptomic and methylomic data along with CRISPR essential genes, and revealed that the incorporation of tumor proliferation essential genes can improve drug sensitivity prediction. Concisely, DROEG integrates literature-based and statistics-based methods to select features and uses Support Vector Regression for model construction. We demonstrate that DROEG outperforms most state-of-the-art algorithms by both qualitative (prediction accuracy for drug-sensitive/resistant) and quantitative (Pearson correlation coefficient between the predicted and actual IC50) evaluation in Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopedia datasets. In addition, DROEG is further applied to the pan-gastrointestinal tumor with high prevalence and mortality as a case study at both cell line and clinical levels to evaluate the model efficacy and discover potential prognostic biomarkers in Cisplatin and Epirubicin treatment. Interestingly, the CRISPR essential gene information is found to be the most important contributor to enhance the accuracy of the DROEG model. To our knowledge, this is the first study to integrate essential genes with multi-omics data to improve cancer drug response prediction and provide insights into personalized precision treatment.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Genes Essenciais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Genômica/métodos , Medicina de Precisão/métodosRESUMO
BACKGROUND: Infiltration of CD8 + T cells in the tumor microenvironment is correlated with better prognosis in various malignancies. Our study aimed to investigate vital genes correlated with CD8 + T cell infiltration in stomach adenocarcinoma (STAD) and develop a new prognostic model. METHODS: Using the STAD dataset, differentially expressed genes (DEGs) were analyzed, and co-expression networks were constructed. Combined with the CIBERSORT algorithm, the most relevant module of WGCNA with CD8 + T cell infiltration was selected for subsequent analysis. The vital genes were screened out by univariate regression analysis to establish the risk score model. The expression of the viral genes was verified by lasso regression analysis and in vitro experiments. RESULTS: Four CD8 + T cell infiltration-related genes (CIDEC, EPS8L3, MUC13, and PLEKHS1) were correlated with the prognosis of STAD. Based on these genes, a risk score model was established. We found that the risk score could well predict the prognosis of STAD, and the risk score was positively correlated with CD8 + T cell infiltration. The validation results of the gene expression were consistent with TCGA. Furthermore, the risk score was significantly higher in tumor tissues. The high-risk group had poorer overall survival (OS) in each subgroup. CONCLUSIONS: Our study constructed a new risk score model for STAD prognosis, which may provide a new perspective to explore the tumor immune microenvironment mechanism in STAD.
Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Prognóstico , Adenocarcinoma/genética , Neoplasias Gástricas/genética , Linfócitos T CD8-Positivos , Microambiente Tumoral/genética , Biomarcadores , Proteínas Adaptadoras de Transdução de SinalRESUMO
BACKGROUND: Stomach adenocarcinoma (STAD) is the most common histological type of gastric cancer (GC). Macrophages are an essential part of the tumor microenvironment. We attempted to search for potential molecular markers associated with macrophages, which might be helpful for STAD diagnosis and treatment. METHODS: Firstly, exosome in macrophages was extracted for RNA sequencing to identify differentially expressed microRNAs (miRNAs) (DEmiRNAs). Then, DEmiRNAs and differentially expressed mRNAs (DEmRNAs) were screened in the Cancer Genome Atlas (TCGA) database. The miRNAs related to macrophage M2 polarization were obtained by intersecting the DEmiRNAs obtained from the sequencing data and TCGA data. Using the Pearson correlation coefficient method, the mRNAs significantly related to macrophage M2 were screened out, followed by construction of the macrophage M2-miRNA-mRNA network. Subsequently, real-time-polymerase chain reaction (RT-PCR) and online datasets were applied to validate the expression of DEmiRNAs and DEmRNAs. RESULTS: A total of 6 DEmiRNAs were identified in RNA sequencing; 59 DEmiRNAs and 1838 DEmRNAs were identified in TCGA database. Among which, a common miRNA (hsa-miR-133a-3p) associated with the M2 polarization of macrophages was identified. Fifteen common mRNAs were obtained between DEmRNAs and mRNAs targeted by DEmiRNAs. Eventually, a core macrophage M2-1 down-regulated miRNA-7 and up-regulated mRNAs network was constructed, including hsa-miR-133a-3p, SLC39A1, TTYH3, HAVCR2, TPM3, XPO1, POU2F1, and MMP14. The expression of miRNA and mRNAs was in line with the validation results of RT-PCR and online datasets. CONCLUSION: In this study, the screening of biomarkers in exosome of macrophage M2 may contribute to the prognosis of STAD patients.
Assuntos
Adenocarcinoma , Exossomos , MicroRNAs , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , RNA Mensageiro/genética , Exossomos/genética , Transcriptoma , Redes Reguladoras de Genes , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Microambiente TumoralRESUMO
Understanding the dynamic behavior of a nanostructure translocating through a nanopore is important for various applications. In this paper, the characteristics in ion current traces of tetrahedral DNA nanostructures (TDN) translocating through a solid-state nanopore are examined, by combined experimental and theoretical simulations. The results of finite element analysis reveal the correlation between orientation of TDN and the conductance blockade. The experimentally measured fluctuations in the conductance blockade, expressed as voltage-dependent histogram profiles, are consistent with the simulation, revealing the nature of a random distribution in orientation and weak influence of electrostatic and viscous torques. The step changes in orientation of a TDN during translocation are further explained by the collision with the nanopore, while the gradual changes in orientation illustrate the impact of a weak torque field in the nano-fluidic channel. The results demonstrate a general method and basic understanding in the dynamic behavior of nanostructures translocating through solid-state nanopores.
Assuntos
Nanoporos , Nanoestruturas , Simulação por Computador , DNA/química , Transporte de Íons , Nanoestruturas/químicaRESUMO
Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease with systemic involvement, and its pathophysiology remains unclear. Genome-wide association studies (GWAS) in the Chinese population have revealed an association between AOSD and the major histocompatibility complex (MHC) locus; however, causal variants in the MHC remain undetermined. In the present study, we identified independent amino-acid polymorphisms in human leukocyte antigen (HLA) molecules that are associated with Han Chinese patients with AOSD by fine-mapping the MHC locus. Through conditional analyses, we identified position 34 in HLA-DQα1 (p = 1.44 × 10-14) and Asn in HLA-DRß1 position 37 (p = 5.12 × 10-11) as the major determinants for AOSD. Moreover, we identified the associations for three main HLA class II alleles: HLA-DQB1*06:02 (OR = 2.70, p = 3.02 × 10-14), HLA-DRB1*15:01 (OR = 2.44, p = 3.66 × 10-13), and HLA-DQA1*01:02 (OR = 1.97, p = 1.09 × 10-9). This study reveals the relationship between functional variations in the class II HLA region and AOSD, implicating the MHC locus in the pathogenesis of AOSD.
Assuntos
Aminoácidos/genética , Predisposição Genética para Doença/genética , Cadeias alfa de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Polimorfismo de Nucleotídeo Único , Doença de Still de Início Tardio/genética , Adulto , Alelos , Povo Asiático/genética , China , Frequência do Gene , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla/métodos , Genótipo , Cadeias alfa de HLA-DQ/química , Cadeias HLA-DRB1/química , Haplótipos , Humanos , Desequilíbrio de Ligação , Modelos Moleculares , Conformação Proteica , Doença de Still de Início Tardio/etnologiaRESUMO
BACKGROUND: Next-generation sequencing technology is developing rapidly and target capture sequencing has become an important technique. Several different platforms for library preparation and target capture with different bait types respectively are commercially available. Here we compare the performance of the four platforms with different bait types to find out their advantages and limitations. The purpose of this study is to help investigators and clinicians select the appropriate platform for their particular application and lay the foundation for the development of a better target capture platform for next-generation sequencing. RESULTS: We formulate capture efficiency as a novel parameter that can be used to better evaluations of specificity and coverage depth among the different capture platforms. Target coverage, capture efficiency, GC bias, AT Dropout, sensitivity in single nucleotide polymorphisms, small insertions and deletions detection, and the feature of each platform were compared for low input samples. In general, all platforms perform well and small differences among them are revealed. In our results, RNA baits have stronger binding power than DNA baits, and with ultra deep sequencing, double stranded RNA baits perform better than single stranded RNA baits in all aspects. DNA baits got better performance in the region with high GC content and RNA baits got lower AT dropout suggesting that the binding power is different between DNA and RNA baits to genome regions with different characteristics. CONCLUSIONS: The platforms with double stranded RNA baits have the most balanced capture performance. Our results show the key differences in performance among the four updated platforms with four different bait types. The better performance of double stranded RNA bait with ultra deep sequencing suggests that it may improve the sensitivity of ultra low frequent mutation detection. In addition, we further propose that the mixed baits of double stranded RNA and single stranded DNA may improve target capture performance.
Assuntos
DNA/genética , Sequenciamento do Exoma/métodos , Exoma , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Composição de Bases , Humanos , Mutação INDEL , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Short tandem repeats (STRs) are important polymorphism makers for human identification and kinship analyses in forensic science. With the continuous development of massively parallel sequencing (MPS), more laboratories have utilized this technology for forensic applications. Existing STR genotyping tools, mostly developed for whole-genome sequencing data, are not effective for MPS data. More importantly, their backward compatibility with the conventional capillary electrophoresis (CE) technology has not been evaluated and guaranteed. RESULTS: In this study, we developed a new end-to-end pipeline called STRsearch for STR-MPS data analysis. The STRsearch can not only determine the allele by counting repeat patterns and INDELs that are actually in the STR region, but it also translates MPS results into standard STR nomenclature (numbers and letters). We evaluated the performance of STRsearch in two forensic sequencing datasets, and the concordance with CE genotypes was 75.73 and 75.75%, increasing 12.32 and 9.05% than the existing tool named STRScan, respectively. Additionally, we trained a base classifier using sequence properties and used it to predict the probability of correct genotyping at a given locus, resulting in the highest accuracy of 96.13%. CONCLUSIONS: All these results demonstrated that STRsearch was a better tool to protect the backward compatibility with CE for the targeted STR profiling in MPS data. STRsearch is available as open-source software at https://github.com/AnJingwd/STRsearch.
Assuntos
Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Repetições de Microssatélites , DNA/genética , Conjuntos de Dados como Assunto , Eletroforese Capilar/métodos , Reação em Cadeia da Polimerase/métodos , Reprodutibilidade dos TestesRESUMO
The ACTN3 gene locates on 11q13-q14 and encodes the α-actinin-3 protein, which is only expressed in human skeletal muscle and influenced muscle function and metabolism. The previous studies reported that SNP rs1815739 is associated with elite power athletes' performance. In this study, we investigated the association between five SNPs within the ACTN3 gene and Chinese children physical fitness. We recruited 2244 Han Chinese children participants, and measured their 25-m run, stand broad jump, 10-m shuttle run, handgrip, BMI (calculated by weight and height) data. SNPs rs1671064, rs2275998, rs2290463, rs10791881, and rs1815739 of ACTN3 gene were genotyped and analyzed in five physical fitness data. QTL analysis on genotype and physical fitness data was carried out in all samples. Furthermore, a dichotomous division of samples into an overweight group (543) and a normal group (1701) was used for an association study of overweight. In the QTL analysis, we found rs2290463 was significantly associated with stand broad jump (corrected P value = 0.009, beta = 2.692). After added age and gender as covariates in the regression test, the association became more significant (P value = 5.80 × 10- 5, corrected P value = 4.06 × 10- 4); when we used BMI as a covariate, the association still existed (P value = 4.65 × 10- 4, corrected P value = 0.001). In the association study of overweight, rs2275998 was found to be significant (OR, 95% CI = 0.733 [0.6-0.895]; Pallele = 0.011, Pgenotype = 0.024) after the Bonferroni correction, and the association did not change much after a further correction for gender, age, and stand broad jump performance. Our results showed that common variants in ACTN3 are significantly associated with both stand broad jump performance and overweight in Han Chinese children.
Assuntos
Actinina/genética , Povo Asiático/etnologia , Sobrepeso/genética , Aptidão Física , Polimorfismo de Nucleotídeo Único , Povo Asiático/genética , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Genótipo , Força da Mão , Humanos , Masculino , Locos de Características QuantitativasRESUMO
BACKGROUND: Athletic performances are complex traits with heritability of ~66%. Dynamic balance is one of the most important athletic performances, and there has been little studies for it in sports genomics. The candidate PPARD gene was reported to be able to affect muscle development for balance predisposition and influence the athletic performance including skiing triumph in the Caucasian population. This study aims to investigate whether the PPARD gene is a susceptibility gene for dynamic balance performance in Han Chinese children. RESULTS: A total 2244 children were recruited and their balance beam performances were measured. Five polymorphisms in the PPARD gene were genotyped through the MassARRAY Sequenom platform. Rs2016520 exerted significant association with dynamic balance performance (minor allele C, P = 0.015, Pcorrected < 0.05) and was affirmed in a meta-analysis by combining previously reported Caucasian cohorts (OR = 1.57, 95% CI = [1.30, 1.91], P < 10 -5) . Another polymorphism, rs2267668, was also significantly associated with dynamic balance performance (minor allele G, P = 0.015, Pcorrected < 0.05). In the dichotomous study, 321 cases (61% boys and 39% girls) and 370 controls (49% boys and 51% girls) in our samples were selected as representatives, and the thresholds were the mean velocity (0.737 m/s) ± standard deviation (0.264 m/s), in which rs2016520-C and rs2267668-G still remained significant (CI =1.41 [1.11~1.79], P = 0.004, Pcorrected < 0.016; CI =1.45 [1.14~1.86], P = 0.002, Pcorrected < 0.016). In different genders, consistent OR direction was observed for each variant. CONCLUSIONS: Our results suggested that the PPARD gene is associated with dynamic balance performance of human being, and further studies to reveal its etiology is strongly suggested.
Assuntos
Genótipo , PPAR delta/genética , Polimorfismo de Nucleotídeo Único , Equilíbrio Postural/genética , Alelos , Povo Asiático/genética , Criança , China , Feminino , Frequência do Gene , Estudos de Associação Genética , Ligação Genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Razão de Chances , Locos de Características QuantitativasRESUMO
BACKGROUND/AIMS: Gastric cancer (GC) is the most common gastrointestinal malignancy, causing cancer-related deaths in East Asia. MicroRNAs (miRNAs) are small non-coding RNAs aberrantly expressed in human tumors. In this study, we aim to investigate the roles of miR-204 in the epithelial to mesenchymal transition (EMT)-associated chemosensitivity. METHODS: The expression of miR-204 was detected in clinical tumor samples and GC cell lines by real time PCR. Tumor cell's growth, invasion, and migration were measured by MTT assay, wound healing assay, and transwell invasion assay, respectively. Western blot method was used to detect the protein levels of indicated genes. Luciferase reporter assay was performed to validate the target gene of miR-204. The in vivo role of miR-204 was measured using a xenograft mouse model of GC. RESULTS: By comparing the expressions of miR-204 in human gastric tumors and their adjacent normal tissues, it was disclosed that miR-204 was significantly downregulated in gastric tumors. Moreover, miR-204 was downregulated in multiple GC cell lines compared with normal gastric epithelial cells. Overexpression of miR-204 suppressed GC cells' proliferation, invasion, and migration. It is noteworthy that 5-FU treatments induced miR-204 expression and suppressed TGF-ß pathway. By establishment of 5-FU resistant GC cell line, it was revealed that miR-204 was significantly downregulated in 5-FU resistant GC cells, representing mesenchymal features with downregulation of epithelial marker, while mesenchymal markers were upregulated. We identified TGFBR2 as a direct target of miR-204 by Western blot method and luciferase assay in GC cells and tumor samples as well. In addition, overexpression of miR-204 sensitized GC cells to 5-FU in vitro. Xenograft experiments demonstrated that the combination of miR-204 and 5-FU efficiently inhibited tumor growth and improved survival rate of mice as well. Eventually, we illustrated the restoration of TGFBR2 in miR-204 overexpression GC cells, which recovered resistance to 5-FU treatments compared with miR-204 overexpression GC cells. CONCLUSION: This study describes a miRNA-based therapeutic strategy against 5-FU resistance in GC, contributing to the development of anti-chemoresistance therapeutic agents.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Fluoruracila/farmacologia , MicroRNAs , Proteínas de Neoplasias , Proteínas Serina-Treonina Quinases , RNA Neoplásico , Receptores de Fatores de Crescimento Transformadores beta , Neoplasias Gástricas , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The hepatitis B virus (HBV) genotyping may profoundly affect the accurate diagnosis and antiviral treatment of viral hepatitis. Existing genotyping methods such as serological, immunological, or molecular testing are still suffered from substandard specificity and low sensitivity in laboratory or clinical application. In a previous study, a set of high-efficiency hybridizable DNA origami-based shape ID probes to target the templates through which genetic variation could be determined in an ultrahigh resolution of atomic force microscopy (AFM) nanomechanical imaging are established. Here, as a further confirmatory research to explore the sensitivity and applicability of this assay, differentially predesigned DNA origami shape ID probes are also developed for precisely HBV genotyping. Through the specific identification of visualized DNA origami nanostructure with clinical HBV DNA samples, the genetic variation information of genotypes can be directly identified under AFM. As a proof-of-concept, five genotype B and six genotype C are detected in 11 HBV-infected patients' blood DNA samples of Han Chinese population in the single-blinded test. The AFM image-based DNA origami shape ID genotyping approach shows high specificity and sensitivity, which could be promising for virus infection diagnosis and precision medicine in the future.
Assuntos
DNA Viral/sangue , DNA Viral/genética , Genes Virais , Genótipo , Vírus da Hepatite B/genética , China , DNA Viral/química , Etnicidade , Humanos , Microscopia de Força Atômica , Conformação de Ácido Nucleico , Estudo de Prova de ConceitoRESUMO
BACKGROUND: Renal hypouricemia (RHUC) is a heterogeneous genetic disorder that is characterized by decreased serum uric acid concentration and increased fractional excretion of uric acid. Previous reports have revealed many functional mutations in two urate transporter genes, SLC22A12 and/or SLC2A9, to be the causative genetic factors of this disorder. However, there are still unresolved patients, suggesting the existence of other causal genes or new mutations. Here, we report an RHUC patient with novel compound heterozygous mutations in the SLC22A12 gene. CASE PRESENTATION: A 27-year-old female presenting with recurrent hypouricemia during routine checkups was referred to our hospital. After obtaining the patient's consent, both the patient and her healthy parents were analyzed using whole-exome sequencing (WES) and Sanger sequencing to discover and validate causal mutations, respectively. The prioritization protocol of WES screened out two mutations of c.269G > A/p.R90H and c.1289_1290insGG/p.M430fsX466, which are both located in the SLC22A12 gene, in the patient. Sanger sequencing further confirmed that the patient's heterozygous c.269G > A/p.R90H mutation, which has been reported previously, derived from her mother, and the heterozygous c.1289_1290insGG/p.M430fsX466 mutation, which was found for the first time, derived from her father. p.R90H, which is highly conserved among different species, may decrease the stability of this domain and was considered to be almost damaging in silicon analysis. p.M430fsX466 lacks the last three transmembrane domains, including the tripeptide motif (S/T)XΦ (X = any amino acid and Φ = hydrophobic residue), at the C-terminal, which interact with scaffolding protein PDZK1 and thus will possibly lead to weak functioning of urate transport through the disruption of the "transporter complex" that is formed by URAT1 and PDZK1. CONCLUSIONS: We report a Chinese patient with RHUC, which was caused by compound heterozygous mutations of the SLC22A12 gene, using WES and Sanger sequencing for the first time. Mutation-induced structural instability or malfunction of the urate transporter complex may be the main mechanisms for this hereditary disorder.
Assuntos
Mutação/genética , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Erros Inatos do Transporte Tubular Renal/genética , Cálculos Urinários/genética , Adulto , Povo Asiático/genética , Feminino , Heterozigoto , Humanos , Masculino , Erros Inatos do Transporte Tubular Renal/metabolismo , Ácido Úrico/metabolismo , Cálculos Urinários/metabolismoRESUMO
Autophagy is an intracellular degradation pathway that delivers organelles or protein to the lysosome and has been recently implicated in the resistance of gastric cancer to chemotherapy. This study aimed to investigate whether blocking autophagy is a new approach for the treatment of chemoresistant gastric cancer. SGC-7901 gastric cancer cell line was treated with 5-fluorouracil (5-FU) or/and autophagy inhibitor bafilomycin A1. Cell viability and growth were evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and clonogenic assay. Apoptosis was evaluated by flow cytometry. Cell migratory and invasive ability were evaluated by migration and invasion assays. Autophagy was evaluated by scanning electron microscopic, acridine orange staining, and Western blot analysis. We observed that 5-FU induced autophagy in SGC-7901 cells. Bafilomycin A1 decreased the viability and clone formation, inhibited the invasive and migratory ability, and increased the apoptosis of SGC-7901 cells. Taken together, our data suggest that chemotherapy-induced autophagy contributes to gastric cancer chemoresistance, and the inhibition of autophagy is a promising strategy for gastric cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/farmacologia , Macrolídeos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células , Sobrevivência Celular , Fluoruracila/farmacologia , Humanos , Neoplasias GástricasRESUMO
BACKGROUND For patients with stage IV gastric cancer, it is unclear whether splenectomy combined with palliative surgery is needed to reduce tumor load and relieve symptoms. The objective of the present study was to investigate the effect of splenectomy combined with palliative resection for stage IV gastric carcinoma on immunological dysfunction and patient prognosis. MATERIAL AND METHODS We retrospectively analyzed medical records of 106 stage IV gastric cancer patients who underwent palliative surgery; of these, 49 patients were treated with palliative resection for gastric carcinoma combined with splenectomy, while the other 57 patients retained their spleens. The immunologic function and prognosis in these 2 groups were examined and compared. RESULTS The immune function of patients in the group that retained their spleens was better later in the postoperative course than in the resection group. The groups did not show statistically significant differences in postoperative infectious complications, median survival time, and survival rate; however, the average postoperative hospitalization time of patients in the retained group was significantly shorter. CONCLUSIONS Splenectomy combined with gastric cancer resection did not improve the prognosis of the patients; patients who retained their spleens had faster recovery and improved immune function. However, whether retaining the spleen is an independent factor improving the prognosis needs further investigation.
Assuntos
Esplenectomia , Neoplasias Gástricas/cirurgia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Prognóstico , Esplenectomia/efeitos adversos , Neoplasias Gástricas/imunologiaAssuntos
Genes MHC da Classe II/genética , Genes MHC Classe I/genética , Doença de Still de Início Tardio/genética , Adulto , Povo Asiático/genética , China , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo ÚnicoRESUMO
A novel hydrogen peroxide (H2O2) and nitric oxide (NO) biosensor was fabricated by immobilizing hemoglobin (Hb) on a gold nanoparticle-decorated MoS2 nanosheet (AuNPs@MoS2) nanocomposite film modified glass carbon electrode. The AuNPs@MoS2 nanocomposite not only made the immobilized Hb keep its native biological activity but also facilitated the electron transfer between electrode and the electroactive center of Hb due to its excellent conductivity and biocompatibility. The direct electrochemistry and bioelectrocatalytic activity of Hb were investigated by cyclic voltammetry (CV). The modified electrode showed good electrocatalytic ability toward the reduction of H2O2 and NO. Under optimal conditions, the current response was linear with the concentration of H2O2 and NO in the range from 10 to 300 µM and 10 to 1100 µM with a detection limit of 4 and 5 µM, respectively. This MoS2-based biosensor was sensitive, reproducible and stable, indicating that AuNPs@MoS2 nanocomposite maybe a promising platform to construct electrochemical sensors for chemical and biological molecules detection.
Assuntos
Técnicas Biossensoriais/métodos , Dissulfetos/química , Técnicas Eletroquímicas/métodos , Hemoglobinas/química , Proteínas Imobilizadas/química , Molibdênio/química , Animais , Bovinos , Ouro/química , Peróxido de Hidrogênio , Nanopartículas Metálicas/química , Nanocompostos/química , Óxido NítricoRESUMO
γ-Glutamyltranspeptidase (GGT) is a tumor biomarker that selectively catalyzes the cleavage of glutamate overexpressed on the plasma membrane of tumor cells. Here, we developed two novel fluorescent inâ situ targeting (FIST) probes that specifically target GGT in tumor cells, which comprise 1)â a GGT-specific substrate unit (GSH), and 2)â a boron-dipyrromethene (BODIPY) moiety for fluorescent signalling. In the presence of GGT, sulfur-substituted BODIPY was converted to amino-substituted BODIPY, resulting in dramatic fluorescence variations. By exploiting this enzyme-triggered photophysical property, we employed these FIST probes to monitor the GGT activity in living cells, which showed remarkable differentiation between ovarian cancer cells and normal cells. These probes represent two first-generation chemodosimeters featuring enzyme-mediated rapid, irreversible aromatic hydrocarbon transfer between the sulfur and nitrogen atoms accompanied by switching of photophysical properties.
Assuntos
Compostos de Boro/química , Corantes Fluorescentes/química , Imagem Óptica/métodos , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/enzimologia , Porfobilinogênio/análogos & derivados , gama-Glutamiltransferase/análise , Compostos de Boro/metabolismo , Linhagem Celular Tumoral , Ensaios Enzimáticos/métodos , Feminino , Corantes Fluorescentes/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Microscopia Confocal/métodos , Ovário/enzimologia , Porfobilinogênio/química , Porfobilinogênio/metabolismo , gama-Glutamiltransferase/metabolismoRESUMO
BACKGROUND: Gastric adenocarcinoma (GAC) is a malignant tumor with the highest incidence in the digestive system. Macrophages have been proven to play important roles in tumor microenvironment. METHODS: Herein, single-cell RNA sequencing (scRNA-seq) profiles from the Gene Expression Omnibus (GEO) and bulk RNA-seq data from the Cancer Genome Atlas (TCGA) database were utilized to construct a macrophage marker gene signature (MMGS) to predict the prognosis of GAC patients. Subsequently, a risk score model based on the MMGS was built to predict the prognosis of GAC patients; further, this was validated in the GEO cohort. The risk score categorized patients into the high- and low-risk groups. A nomogram model based on the risk score and clinic-pathological characteristics was developed. RESULTS: Seven genes, ABCA1, CTHRC1, GADD45B, NPC2, PLTP, PRSS23, and RNASE1, were included in the risk score model. Patients with a low-risk score showed a better prognosis. The MMGS had good sensitivity and specificity for predicting the prognosis inGAC patients. The risk score was an independent prognostic factor. The constructed nomogram exhibited favorable predictability and reliability for predicting GAC prognosis. CONCLUSION: In conclusion, the risk score model based on the seven MMGSs performed well in the predicting prognosis of GAC patients. Our study may provide new insights into clinical decision-making for the personalized treatment of patients with gastric cancer (GC).
Assuntos
Adenocarcinoma , Biomarcadores Tumorais , Biologia Computacional , Nomogramas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Prognóstico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Biologia Computacional/métodos , Biomarcadores Tumorais/genética , Masculino , Feminino , Regulação Neoplásica da Expressão Gênica , Macrófagos/metabolismo , Microambiente Tumoral/genética , Pessoa de Meia-Idade , Transcriptoma , Perfilação da Expressão Gênica/métodos , IdosoRESUMO
BACKGROUND: Mosaic chromosomal alterations are implicated in neuropsychiatric disorders, but the contribution to schizophrenia (SCZ) risk for somatic copy number variations (sCNVs) emerging in early developmental stages has not been fully established. METHODS: We analyzed blood-derived genotype arrays from 9715 patients with SCZ and 28,822 control participants of Chinese descent using a computational tool (MoChA) based on long-range chromosomal information to detect mosaic chromosomal alterations. We focused on probable early developmental sCNVs through stringent filtering. We assessed the burden of sCNVs across varying cell fraction cutoffs, as well as the frequency with which genes were involved in sCNVs. We integrated this data with the PGC (Psychiatric Genomics Consortium) dataset, which comprises 12,834 SCZ cases and 11,648 controls of European descent, and complemented it with genotyping data from postmortem brain tissue of 936 participants (449 cases and 487 controls). RESULTS: Patients with SCZ had a significantly higher somatic losses detection rate than control participants (1.00% vs. 0.52%; odds ratio = 1.91; 95% CI, 1.47-2.49; two-sided Fisher's exact test, p = 1.49 × 10-6). Further analysis indicated that the odds ratios escalated proportionately (from 1.91 to 2.78) with the increment in cell fraction cutoffs. Recurrent sCNVs associated with SCZ (odds ratio > 8; Fisher's exact test, p < .05) were identified, including notable regions at 10q21.1 (ZWINT), 3q26.1 (SLITRK3), 1q31.1 (BRINP3) and 12q21.31-21.32 (MGAT4C and NTS) in the Chinese cohort, and some regions were validated with PGC data. Cross-tissue validation pinpointed somatic losses at loci like 1p35.3-35.2 and 19p13.3-13.2. CONCLUSIONS: The study highlights the significant impact of mosaic chromosomal alterations on SCZ, suggesting their pivotal role in the disorder's genetic etiology.