Effect of low skeletal muscle mass on NK cells in patients with acute myeloid leukemia and its correlation with prognosis.

The objective of this study was to analyze the correlation between skeletal muscle mass and the distribution of peripheral blood lymphocytes and natural killer (NK) cells, as well as their impact on prognosis in patients with acute myeloid leukemia (AML). A retrospective analysis was conducted on 211 newly diagnosed AML patients, evaluating skeletal muscle index (SMI), NK cell proportion, and absolute value, along with relevant clinical data. Linear regression and Spearman's correlation coefficient were used to assess the relationship between various indicators and SMI, followed by multiple linear regression for further modeling. Univariate and multivariate Cox proportional hazards regression models were used to identify independent predictors for overall survival (OS). Among the 211 AML patients, 38 cases (18.0%) were diagnosed with sarcopenia. Multiple linear regression analysis included weight, fat mass, ECOG score, body mass index, and peripheral blood NK cell proportion, constructing a correlation model for SMI (R2 = 0.745). Univariate analysis identified higher NK cell count (> 9.53 × 106/L) as a poor predictor for OS. Multivariate Cox proportional hazards regression model indicated that age ≥ 60 years, PLT < 100 × 109/L, ELN high risk, sarcopenia, and B cell count > 94.6 × 106/L were independent adverse prognostic factors for AML patients. Low skeletal muscle mass may negatively impact the count and function of NK cells, thereby affecting the prognosis of AML. However, further basic and clinical research is needed to explore the specific mechanisms underlying the relationship between NK cells and SMI in AML.

Peptides for diagnosis and treatment of ovarian cancer.

Ovarian cancer is the most deadly gynecologic malignancy, and its incidence is gradually increasing. Despite improvements after treatment, the results are unsatisfactory and survival rates are relatively low. Therefore, early diagnosis and effective treatment remain two major challenges. Peptides have received significant attention in the search for new diagnostic and therapeutic approaches. Radiolabeled peptides specifically bind to cancer cell surface receptors for diagnostic purposes, while differential peptides in bodily fluids can also be used as new diagnostic markers. In terms of treatment, peptides can exert cytotoxic effects directly or act as ligands for targeted drug delivery. Peptide-based vaccines are an effective approach for tumor immunotherapy and have achieved clinical benefit. In addition, several advantages of peptides, such as specific targeting, low immunogenicity, ease of synthesis and high biosafety, make peptides attractive alternative tools for the diagnosis and treatment of cancer, particularly ovarian cancer. In this review, we focus on the recent research progress regarding peptides in the diagnosis and treatment of ovarian cancer, and their potential applications in the clinical setting.

Network pharmacology study of the mechanism underlying the therapeutic effect of Zhujing pill and its main component oleanolic acid against diabetic retinopathy.

Diabetic retinopathy (DR) is the leading cause of blindness in the working population worldwide, with few effective drugs available for its treatment in the early stages. The Zhujing pill (ZJP) is well-established to enhance the early symptoms of DR, but the mechanism underlying its therapeutic effect remains unclear. In the present study, we used systems biology and multidirectional pharmacology to screen the main active ingredients of ZJP and retrieved DrugBank and Genecards databases to obtain 'drug-disease' common targets. Using bioinformatics analysis, we obtained the core targets, and potential mechanisms of action of ZJP and its main components for the treatment of DR. Molecular docking was used to predict the binding sites and the binding affinity of the main active ingredients to the core targets. The predicted mechanism was verified in animal experiments. We found that the main active ingredient of ZJP was oleanolic acid, and 63 common 'drug-disease' targets were identified. Topological analysis and cluster analysis based on the protein-protein interaction network of the Metascape database screened the core targets as PRKCA, etc. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that these core targets were significantly enriched in the pro-angiogenic pathway of the VEGF signaling pathway. Molecular docking and surface plasmon resonance revealed that ZJP and its main active component, oleanolic acid had the highest binding affinity with PKC-α, the core target of the VEGF signaling pathway. Animal experiments validated that ZJP and oleanolic acid could improve DR.

Design, Synthesis, and Biological Activity of Novel Laccase Inhibitors as Fungicides against Rice Blast.

Laccase is a potential target for novel agricultural fungicide discovery. PMDD-5Y was the first agent reported with high activity against laccase to control phytopathogenic fungi. Thirty-two novel agents containing cinnamaldehyde thiosemicarbazide were synthesized with PMDD-5Y as the lead compound, with most of the target compounds exhibiting excellent activity in vitro. Compound a2 (EC50 = 9.71 µg/mL) exhibited greater potency against Magnaporthe oryzae than the commercial fungicide isoprothiolane (EC50 = 18.62 µg/mL). The curative and protective effects of a2 against M. oryzae on rice were more than those of PMDD-5Y. Scanning electron microscopy indicated that a2 could cause mycelial growth atrophy and malformation. Furthermore, a2 (IC50 = 0.18 mmol/L) showed higher activity against laccase than PMDD-5Y (IC50 = 0.33 mmol/L) and cysteine (IC50 = 0.30 mmol/L). Molecular docking analysis revealed the nature of interaction between these compounds and laccase. This research identified a novel laccase inhibitor a2 as a fungicide candidate to control rice blast in agriculture.

Symmetric subgenomes and balanced homoeolog expression stabilize the establishment of allopolyploidy in cyprinid fish.

BACKGROUND: Interspecific postzygotic reproduction isolation results from large genetic divergence between the subgenomes of established hybrids. Polyploidization immediately after hybridization may reset patterns of homologous chromosome pairing and ameliorate deleterious genomic incompatibility between the subgenomes of distinct parental species in plants and animals. However, the observation that polyploidy is less common in vertebrates raises the question of which factors restrict its emergence. Here, we perform analyses of the genome, epigenome, and gene expression in the nascent allotetraploid lineage (2.95 Gb) derived from the intergeneric hybridization of female goldfish (Carassius auratus, 1.49 Gb) and male common carp (Cyprinus carpio, 1.42 Gb), to shed light on the changes leading to the stabilization of hybrids. RESULTS: We firstly identify the two subgenomes derived from the parental lineages of goldfish and common carp. We find variable unequal homoeologous recombination in somatic and germ cells of the intergeneric F1 and allotetraploid (F22 and F24) populations, reflecting high plasticity between the subgenomes, and rapidly varying copy numbers between the homoeolog genes. We also find dynamic changes in transposable elements accompanied by genome merger and duplication in the allotetraploid lineage. Finally, we observe the gradual decreases in cis-regulatory effects and increases in trans-regulatory effects along with the allotetraploidization, which contribute to increases in the symmetrical homoeologous expression in different tissues and developmental stages, especially in early embryogenesis. CONCLUSIONS: Our results reveal a series of changes in transposable elements, unequal homoeologous recombination, cis- and trans-regulations (e.g. DNA methylation), and homoeologous expression, suggesting their potential roles in mediating adaptive stabilization of regulatory systems of the nascent allotetraploid lineage. The symmetrical subgenomes and homoeologous expression provide a novel way of balancing genetic incompatibilities, providing a new insight into the early stages of allopolyploidization in vertebrate evolution.

The Prognostic Value of Sarcopenia in Acute Myeloid Leukemia Patients and the Development and Validation of a Novel Nomogram for Predicting Survival.

BACKGROUND: Acute myeloid leukemia (AML) occurs frequently in the elderly, of whom the prognosis is dismal. Sarcopenia is a progressive and generalized skeletal muscle disorder associated with an increased possibility of adverse outcomes. This study aims to explore the prognostic value of sarcopenia in AML patients and develop a novel prognostic model. METHODS: A total of 227 AML patients were enrolled. Body composition was assessed by bioelectrical impedance analysis before treatment. Sarcopenia was diagnosed by low muscle quantity. Cox proportional hazard regression model were applied to verify prognostic variables for overall survival (OS) and disease-free survival (DFS). A novel prognostic model of nomogram was developed and validated by 'R'. RESULTS: Forty-one (18.1%) patients were defined as sarcopenia. The median age of the sarcopenic group was significantly greater than the non-sarcopenic group (median 70 vs. 64 years, P = 0.001). Sarcopenic patients showed significantly less height (P = 0.002), weight (P <0.001), Body Mass Index (P <0.001), Fat Mass (P = 0.017), Fat-free Mass (P <0.001), Appendicular Skeletal Muscle Mass (P <0.001), Skeletal Muscle Index (P <0.001), Fat-free Mass Index (P <0.001), and hemoglobin level (P = 0.025) than the non-sarcopenic ones. Patients in the sarcopenic group also showed a statistically shorter OS and DFS (median OS: 13.7 vs. 55.6 months, P = 0.003; median DFS: 12.5 months vs. not reached, P = 0.026). ELN high risk [Hazard Ratio (HR): 1.904, 95% Confidence Interval (CI): 1.018-3.562, P = 0.044), sarcopenia (HR: 1.887, 95% CI: 1.071-3.324, P = 0.028), and reduced-intensity regimens (HR: 3.765, 95% CI: 1.092-12.980, P = 0.036) were independent predictors for OS in multivariate analysis. A nomogram for predicting OS was constructed using the above three factors. The c index, calibration plots and decision curve analyses (DCA) showed better discrimination, calibration, and net benefits of the nomogram than the ELN model. CONCLUSION: Sarcopenia was common and had an inferior prognosis in AML and needs more attention in clinical practice.

Can Circulating Cell-Free DNA or Circulating Tumor DNA Be a Promising Marker in Ovarian Cancer?

In recent years, the studies on ovarian cancer have made great progress, but the morbidity and mortality of patients with ovarian cancer are still very high. Due to the lack of effective early screening and detecting tools, 70% of ovarian cancer patients are diagnosed at an advanced stage. The overall survival rate of ovarian cancer patients treated with surgical combined with chemotherapy has not been significantly improved, and they usually relapse or resist chemotherapy. Therefore, a novel tumor marker is beneficial for the diagnosis and prognosis of patients with ovarian cancer. As the index of "liquid biopsy," circulating cell-free DNA/circulating tumor DNA (cfDNA/ctDNA) has attracted a lot of attention. It has more remarkable advantages than traditional methods and gives a wide range of clinical applications in kinds of solid tumors. This review attempts to illuminate the important value of cfDNA/ctDNA in ovarian cancer, including diagnosis, monitoring, and prognosis. Meanwhile, we will present future directions and challenges for detection of cfDNA/ctDNA.

Combined effects of dosage compensation and incomplete dominance on gene expression in triploid cyprinids.

Hybridization and polyploidy are pervasive evolutionary features of flowering plants and frequent among some animal groups, such as fish. These processes always lead to novel genotypes and various phenotypes, including growth heterosis. However, its genetic basis in lower vertebrate is still poorly understood. Here, we conducted transcriptome-level analyses of the allopolyploid complex of Carassius auratus red var. (R) (♀) × Cyprinus carpio L. (C) (♂), including the allodiploid and allotetraploid with symmetric subgenomes, and the two allotriploids with asymmetric subgenomes. The gradual changes of gene silencing and novel gene expression suggested the weakening of the constraint of polymorphic expression in genotypic changes. Then, analyses of the direction and magnitude of homoeolog expression exhibited various asymmetric expression patterns, which supported that R incomplete dominance and dosage compensation were co-regulated in the two triploids. Under these effects, various magnitudes of R-homoeolog expression bias were observed in growth-regulated genes, suggesting that they might contribute to growth heterosis in the two triploids. The determination of R incomplete dominance and dosage compensation, which might be led by asymmetric subgenomes and multiple sets of homologous chromosomes, explained why various expression patterns were shaped and their potential contribution to growth heterosis in the two triploids.

Comparative analysis of testis transcriptomes associated with male infertility in triploid cyprinid fish.

Spermatogenesis involves a series of cellular transformations and thousands of regulated genes. Previously, we showed that the triploid fish (3nBY) cannot produce mature spermatozoa. In the present study, evaluation of the testis microstructure revealed that germ cells of 3nBY could develop into round spermatids, but then degenerated, resulting in male infertility. In this study we comparatively analysed the testis transcriptomes from 3nBY and its diploid parent YB and identified a series of differentially expressed genes (DEGs) that were enriched in the Wnt signalling pathway and the apoptotic and ubiquitin-mediated proteolysis processes in 3nBY. Gene ontology functional analyses revealed that some DEGs in 3nBY were directly associated with the process of gamete generation, development and sperm flagellum assembly. In addition, the expression of a number of genes related to meiosis (Inhibitor Of DNA Binding 2 (ID2), Ovo Like Transcriptional Repressor 1 (OVOL1)), mitochondria (ATP1b (ATPase Na+/K+ Transporting Subunit Beta 1), ATP2a (ATPase, Ca++ Transporting, Cardiac Muscle, Slow Twitch 2), ATP5a (ATP Synthase F1 Subunit Alpha), Mitochondrially Encoded Cytochrome C Oxidase I (COX1), NADH Dehydrogenase Subunit 4 (ND4)) and chromatin structure (Histone 1 (H1), Histone 2a (H2A), Histone 2b (H2B), Histone 3 (H3), Histone 4 (H4)) was lower in the testes of 3nBY, whereas the expression of genes encoding ubiquitin (Ubiquitin Conjugating Enzymes (UBEs), Ring Finger Proteins (RNFs)) and apoptosis (CASPs (Caspase 3, Caspase 7,Caspase 8), BCLs (B-Cell Lymphoma 3, B-Cell CLL/Lymphoma 2, B Cell CLL/Lymphoma 10)) proteins involved in spermatid degeneration was higher. These data suggest that the disrupted expression of genes associated with spermatogenesis and the increased expression of mitochondrial ubiquitin, which initiates cell apoptosis, may result in spermatid degeneration in male 3nBY. This study provides information regarding the potential molecular regulatory mechanisms underlying male infertility in polyploid fish.

Comparison of diploid and triploid Carassius auratus provides insights into adaptation to environmental change.

Focusing on adaptation of aquatic organisms, especially fish, can help elucidate complex dynamics in freshwater ecology. The differences in genetic and epigenetic regulation between diploid and triploid Carassius auratus affect survival under eutrophication. To identify the underlying mechanisms that lead to better adaption of triploids than diploids, we compared mRNA and microRNA (miRNA) expressions in liver tissue of diploid and triploid individuals obtained from the Dongting lake water system in central China. Differential expression analysis revealed that 566 transcripts were significantly up-regulated, whereas 758 were down-regulated in triploids; of these differentially expressed transcripts, 33 transcripts including cacna1d, nfkb2, hspa1 and fgfr4 were involved in the MAPK signaling pathway, and eight transcripts were determined to be regulated by seven miRNAs. Additionally, four of 25 differential expressed (DE) transcripts (mhc1, irf7, nfkb2 and pik3c) involving the viral carcinogenesis pathway were regulated by four miRNAs. Furthermore, genetic polymorphisms analysis showed that more heterozygous mutations were detected in triploids than diploids. The dN/dS results revealed that 21 genes were under positive selection (dN/dS>1) in C. auratus complex. We hypothesize that these changes related to genetic and epigenetic regulation may be caused by abiotic stresses, and facilitate adaptation to environmental changes.

Asymmetric expression patterns reveal a strong maternal effect and dosage compensation in polyploid hybrid fish.

BACKGROUND: Hybridization and polyploidization are regarded as the major driving forces in plant speciation, diversification, and ecological adaptation. Our knowledge regarding the mechanisms of duplicated-gene regulation following genomic merging or doubling is primarily derived from plants and is sparse for vertebrates. RESULTS: We successfully obtained an F1 generation (including allodiploid hybrids and triploid hybrids) from female Megalobrama amblycephala Yih (BSB, 2n = 48) × male Xenocypri davidi Bleeker (YB, 2n = 48). The duplicated-gene expression patterns of the two types of hybrids were explored using RNA-Seq data. In total, 5.44 × 108 (69.32 GB) clean reads and 499,631 assembled unigenes were obtained from the testis transcriptomes. The sequence similarity analysis of 4265 orthologs revealed that the merged genomes were dominantly expressed in different ploidy hybrids. The differentially expressed genes in the two types of hybrids were asymmetric compared with those in both parents. Furthermore, the genome-wide expression level dominance (ELD) was biased toward the maternal BSB genome in both the allodiploid and triploid hybrids. In addition, the dosage-compensation mechanisms that reduced the triploid expression levels to the diploid state were determined in the triploid hybrids. CONCLUSIONS: Our results indicate that divergent genomes undergo strong interactions and domination in allopolyploid offspring. Genomic merger has a greater effect on the gene-expression patterns than genomic doubling. The various expression mechanisms (including maternal effect and dosage compensation) in different ploidy hybrids suggest that the initial genomic merger and doubling play important roles in polyploidy adaptation and evolution.

Analyzing homoeolog expression provides insights into the rediploidization event in gynogenetic hybrids of Carassius auratus red var. × Cyprinus carpio.

Rediploidization is considered to be a part of the evolutionary history of allotetraploids, and resulted in the emergence of novel epigenetic regulatory activities. To study the changing patterns of gene expression following the reduction of a genome by 50%, we used RNA-seq and quantitative real-time PCR (qPCR) to investigate total gene expression and homoeolog expression in three hybrids of a C. auratus red var. (2n = 100, ♀) (R) and C. carpio (2n = 100, ♂) (C) (i.e., F1, F18, and G4) and their original parents. A comparison of homoeolog expression between G4 and F18 identified 7 genes (0.22%) that exhibited novel R/C homoeolog expression patterns in G4, while 4 genes (0.12%) were affected by R/C homoeolog silencing. We determined the direction and extent of the homoeolog expression bias (HEB). The C-HEB genes (i.e., nrp1a and igf1) and R-HEB genes (i.e., fgf23 and esm1) provided insights into the effects of the dominance of one parental homoeolog expression on growth regulation. This dominance may contribute to the rapid growth of G4 fish. Our findings may be relevant for clarifying the relationship between growth heterosis and differences in homoeolog expression patterns.

Determination of dosage compensation and comparison of gene expression in a triploid hybrid fish.

BACKGROUND: Polyploidy and hybridization are both recognized as major forces in evolution. Most of our current knowledge about differences in gene regulation in polyploid hybrids comes from plant studies. The gene expression of diverged genomes and regulatory interactions are still unclear in lower vertebrates. RESULTS: We generated 229 million cleaned reads (42.23 Gbp) from triploid of maternal grass carp (Ctenopharyngodon idellus, Cyprininae, 2n = 48) × paternal blunt snout bream (Megalobrama amblycephala, Cultrinae, 2n = 48) and their diploid parents using next-generation sequencing. In total, 157,878 contigs were assembled and 15,444 genes were annotated. We examined gene expression level changes among the parents and their triploid offspring. The mechanisms of dosage compensation that reduced triploid expression levels to the diploid state were determined in triploid fish. In this situation, novel gene expression and gene silencing were observed. Then, we established a model to determine the extent and direction of expression level dominance (ELD) and homoeolog expression bias (HEB) based on the relative expression level among the parents and their triploid offspring. CONCLUSIONS: Our results showed that the genome-wide ELD was biased toward maternal genome in triploid. Extensive alterations in homoeolog expression suggested a combination of regulatory and epigenetic interactions through the transcriptome network. Additionally, the expression patterns of growth genes provided insights into the relationship between the characteristics of growth and underlying mechanisms in triploids. Regulation patterns of triploid state suggest that various expression levels from the initial genomic merger have important roles in adaptation.

Id1 enhances human ovarian cancer endothelial progenitor cell angiogenesis via PI3K/Akt and NF-κB/MMP-2 signaling pathways.

BACKGROUND: Endothelial progenitor cells (EPCs) contribute to tumor angiogenesis and growth. We previously reported that over-expression of an inhibitor of DNA binding/differentiation 1 (Id1) in EPCs can enhance EPC proliferation, migration, and adhesion. In this study, we investigated the role of Id1 in EPC angiogenesis in patients with ovarian cancer and the underlying signaling pathway. METHODS: Circulating EPCs from 22 patients with ovarian cancer and 15 healthy control subjects were cultured. Id1 and matrix metalloproteinase-2 (MMP-2) expression were analyzed by real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blot. EPC angiogenesis was detected by tube formation assays. Double-stranded DNA containing the interference sequences was synthesized according to the structure of a pGCSIL-GFP viral vector and then inserted into a linearized vector. Positive clones were identified as lentiviral vectors that expressed human Id1 short hairpin RNA (shRNA). RESULTS: Id1 and MMP-2 expression were increased in EPCs freshly isolated from ovarian cancer patients compared to those obtained from healthy subjects. shRNA-mediated Id1 down-regulation substantially reduced EPC angiogenesis and MMP-2 expression. Importantly, transfection of EPCs with Id1 in vitro induced phosphorylation of Akt (p-Akt) via phosphoinositide 3-kinase and increased the expression of MMP-2 via NF-κB. Blockage of both pathways by specific inhibitors (LY294002 and PDTC, respectively) abrogated Id1-enhanced EPC angiogenesis. CONCLUSIONS: Id1 can enhance EPC angiogenesis in ovarian cancer, which is mainly mediated by the PI3K/Akt and NF-κB/MMP-2 signaling pathways. Id1 and its downstream effectors are potential targets for treatment of ovarian cancer because of their contribution to angiogenesis.