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Background. Breast and ovarian cancers are common malignancies among women, contributing to a significant disease burden, and are characterized by a high level of genomic instability, owing to the failure of homologous recombination repair (HRR). Pharmacological inhibition of poly(ADP-ribose) polymerase (PARP) could elicit the synthetic lethal effect of tumor cells in patients with homologous recombination deficiency, ultimately achieving a favorable clinical benefit. However, primary and acquired resistance remain the greatest hurdle, limiting the efficacy of PARP inhibitors; thus, strategies conferring or augmenting tumor cell sensitivity to PARP inhibitors are urgently required. Methods. Our RNA-seq data of niraparib-treated and -untreated tumor cells were analyzed by R language. Gene Set Enrichment Analysis (GSEA) was applied to assess the biological functions of GTP cyclohydrolase 1 (GCH1). Quantitative real-time PCR, Western blotting, and immunofluorescence were applied to confirm the upregulation of GCH1 upon niraparib treatment at transcriptional and translational levels. Immunohistochemistry of patient-derived xenograft (PDX)-derived tissue sections further validated that niraparib increased GCH1 expression. Tumor cell apoptosis was detected by flow cytometry, while the superiority of the combination strategy was confirmed in the PDX model. Results. The expression of GCH1 was aberrantly enriched in breast and ovarian cancers and increased after niraparib treatment via JAK-STAT signaling. GCH1 was also demonstrated to be associated with the HRR pathway. Subsequently, the enhancement of the tumor-killing effect of PARP inhibitors induced by GCH1 suppression using siRNA and GCH1 inhibitor was validated by flow cytometry in vitro. Finally, using the PDX model, we further demonstrated that GCH1 inhibitors markedly potentiated PARP inhibitors' antitumor efficacy in vivo. Conclusion. Our results illustrated that PARP inhibitors promote GCH1 expression via the JAK-STAT pathway. We also elucidated the potential relationship between GCH1 and the homologous recombination repair pathway and proposed a combination regimen of GCH1 suppression with PARP inhibitors in breast and ovarian cancers. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a manifestation of hepatic metabolic syndrome that varies in severity. Hepatocellular carcinoma progresses from NAFLD when there is heterogeneity in the infiltration of immune cells and molecules. A precise molecular classification of NAFLD remains lacking, allowing further exploration of the link between NAFLD and hepatocellular carcinoma. In this work, a weighted gene coexpression network analysis was used to identify two coexpression modules based on multiple omics data used to differentiate NAFLD subtypes. Additionally, key genes in the process of glucose metabolism and NAFLD were used to construct a prognostic model in a cohort of patients with hepatocellular carcinoma. Furthermore, the specific expression of signature genes in hepatocellular carcinoma cells was analyzed using a single-cell RNA sequencing approach. A total of 19 liver tissues of NAFLD patients were obtained from the GEO database, and 81 glucose metabolism-related genes were downloaded from the CTD database. In addition, based on nine signature genes, we constructed a prognostic model to divide the HCC cohort into high and low-risk groups. We also demonstrated a significant correlation between prognostic models and clinical phenotypes. Furthermore, we integrated single-cell RNA-sequencing data and immunology data to assess potential relationships between different molecular subtypes and hepatocellular carcinoma. Finally, our study discovered that the glucose metabolism pathway may play an important role in the process of NAFLD-hepatocellular carcinoma. In addition, three glucose metabolism-related genes (SERPINE1, VCAN, and TFPI2) may be the potential targets for the immunotherapy of patients with NAFLD-hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

To investigate the mechanism of the effect of process parameters on bubble flow behavior during automated fiber placement (AFP) and the relationship between the bubble and voids, mechanical properties of laminates, this paper analyzes the multiphase flow coupling behavior of the bubble and fiber formation using computational fluid dynamics (CFD) and finite element (FE) method under different AFP process parameters. The effects of AFP process parameters on bubble characteristics and fiber deformation are then discussed, respectively, including bubble displacement, maximum cross-sectional area, the lowest internal temperature of the bubble, bubble breakup, and maximum deformation of the fiber. Furthermore, the AFP and corresponding test experiments are performed to investigate the relationships between different bubble characteristics and void content, mechanical properties, mainly interlaminar shear strength (ILSS) and flexural strength (FS). The results show that the maximum cross-sectional area of bubbles is closely related to the AFP process parameters. The FS and ILSS are positively correlated with the maximum cross-sectional area. With the increase of bubble displacement and fiber maximum deformation, FS and ILSS are first increased and then decreased. [ABSTRACT FROM AUTHOR]

Given that myc was known to be a cancer-causing gene in several cancers including kidney renal clear cell carcinoma (KIRC). We aimed to construct myc-regulated genes (MRGs)-based prognostic signature. We obtained the mRNA expression and clinical data of KIRC from The Cancer Genome Atlas (TCGA) database and MRGs from the Molecular Signature Database (MSigDB). Then, a prognostic signature consisting of 8 MRGs (IRF9, UBE2C, YBX3, CDKN2B, CKAP2L, CYFIP2, FBLN5, and PDLIM7) was developed by differential expression analysis, cox regression analysis, and least absolute shrinkage and selection operator (lasso) analysis. Patients with KIRC were divided into high- and low-risk groups based on risk scores of MRGs-based signatures. Patients in the high-risk group showed inferior clinical characteristics and survival. In addition, the risk score was an independent prognostic factor for KIRC, and the risk score=based nomogram displayed satisfactory performance to predict the survival of KIRC. The MRGs-based signature is also correlated with immune cell infiltration and the mRNA expression of important immune checkpoints (IDO2, PDCD1, LAG3, FOXP3, and TIGIT). The tumor mutation burden (TMB) landscape between the high- and low-risk groups showed higher levels of TMB in the high-risk group than in the low-risk group and that higher levels of TMB predicted a poorer prognosis in KIRC. Furthermore, patients with KIRC in the high-risk group are more likely to experience immune escape. At last, we found patients with KIRC in the high-risk group were more sensitive to several chemotherapy drugs such as sunitinib, gefitinib, nilotinib, and rapamycin than patients with KIRC in the low-risk group. Our study successfully constructed and validated an MRGs-based signature that can predict clinical characteristics, prognosis, level of immune infiltration, and responsiveness to immunotherapy and chemotherapy drugs in patients with KIRC. [ABSTRACT FROM AUTHOR]

Background. GRAM structural domain-containing protein 1A (GRAMD1A) is upregulated in a variety of human cancer tissues and is closely associated with tumourigenesis and progression. Methods. Patient RNA-sequencing data and clinicopathological information were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. The expression of GRAMD1A in kidney cancer cell lines and KIRC patients was analysed by quantitative polymerase chain reaction (qPCR). Receiver Operator Characteristic (ROC) curves, nomograms, Kaplan-Meier analysis, forest plots, and COX analysis were used to assess the diagnostic and prognostic value of GRAMD1A in KIRC, and gene set enrichment analysis (GSEA) was used to explore its potential signalling pathways. In addition, the Sangerbox website, Kaplan-Meier plotter database, and TISIDB and TIMER databases were used to further analyse the correlation of GRAMD1A with microsatellite instability (MSI), tumour mutational burden (TMB), immune checkpoint genes, and tumour-infiltrating lymphocytes (TILs). Results. GRAMD1A was significantly highly expressed in KIRC and associated with shorter overall survival and relapse-free survival (P < 0.05). The AUC value of the ROC curve to identify KIRC and normal renal tissues was 0.942. Forest plot and COX analysis visualized that GRAMD1A could be an independent prognostic factor in KIRC patients (P < 0.01), and nomograms to determine the overall survival (OS) of KIRC patients also showed good efficacy (C-index: 0.776). Moreover, Spearman correlation analysis showed a positive correlation between GRAMD1A and MSI, TMB (P < 0.01). On the other hand, GRAMD1A was also found to be closely associated with immune checkpoint genes. Meanwhile, patients with KIRC with high GRAMD1A expression had a relatively low hazard ratio (HR) of death when B lymphocytes, natural killer T cells, CD4+ T lymphocytes, CD8+ T lymphocytes, and macrophages were enriched in the tumour microenvironment (TME), and a greater HR of death when regulatory T lymphocytes with tumour-specific immunosuppressive effects were significantly enriched. Last, GSEA shows that GRAMD1A is closely associated with the regulation of energy metabolism in KIRC. Conclusions. GRAMD1A is a promising diagnostic and prognostic biomarker for patients with KIRC, and its biological function correlates to some extent with immune infiltration in TME. [ABSTRACT FROM AUTHOR]

The silty clay in the lower reaches of the Yellow River is characterized by loose structure, low strength, and strong capillary effect. Based on the technology of ancient glutinous rice mortar and microbial-induced calcium carbonate precipitation (MICP), experiments on optimal mass ratio of cementitious liquid to bacterial liquid and optimal concentration of cementitious liquid for MICP and improved MICP technology were carried out by measuring the production of CaCO3, and direct shear test and unconfined compressive strength test of plain silt, glutinous mixing silt, and improved silt with MICP and modified MICP were conducted. The microstructure of the reaction products of MICP and improved MICP technology were also evaluated based on scanning electron microscopy (SEM). Research results showed that the mechanical properties of silt with glutinous rice slurry were effectively improved. With the increase in the concentration of glutinous rice slurry, the strength and internal friction angle of soil samples first increased and then decreased, and the cohesion presented a linear increasing trend. When the concentration of cementitious liquid was 0.5 M and the mass ratio of cementitious liquid to bacterial liquid was 2 : 1, the amount of CaCO3 formed was the most, and the conversion rate of Ca2+ was more than 80%. The improved MICP could increase the conversion rate of Ca2+ (93.44%). An improved MICP showed that glutinous rice slurry could improve bacterial activity, increase the urease content in the bacterial solution, and promote the production of CaCO3. Silt cohesion and internal friction angle of the silt were improved by the improved MICP technology, and the strengthening effect of mechanical properties of modified MICP-reinforced soil is better than that of the MICP-reinforced soil; conventional MICP technology could also improve the soil cohesion, but the improvement in the internal friction angle was not obvious. The SEM results indicated that compared with the reaction product of MICP technology, the structure of the product of improved MICP technology is more compact, resulting in a marked reinforcement of MICP performance with glutinous rice slurry. This study provides new insights into enhancing the mechanical behaviour of MICP-treated silt in the Yellow River Basin with glutinous rice slurry. [ABSTRACT FROM AUTHOR]

Human Parainfluenza Virus Type 3 (HPIV3) is one of the main pathogens that cause acute lower respiratory tract infections in infants and young children. However, there are currently no effective antiviral drugs and vaccines. Herein, we found that a natural compound, curcumin, inhibits HPIV3 infection and has antiviral effects on entry and replication of the virus life cycle. Immunofluorescence and western blotting experiments revealed that curcumin disrupts F-actin and inhibits viral inclusion body (IB) formation, thus inhibiting virus replication. Curcumin can also downregulate cellular PI4KB and interrupt its colocalization in viral IBs. This study verified the antiviral ability of curcumin on HPIV3 infection and preliminarily elucidated its influence on viral replication, providing a theoretical basis for antiviral drug development of HPIV3 and other parainfluenza viruses. [ABSTRACT FROM AUTHOR]