Discovery of 2,4-diarylaminopyrimidine derivatives bearing sulfonamide moiety as novel FAK inhibitors.

Two series of 2,4-diarylaminopyrimidine derivatives containing sulfonamide moiety were designed and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most compounds significantly inhibited the enzymatic activities of FAK, and the best compound was 7b (IC50 = 0.27 nM). A majority of aminoethyl sulfonamide derivatives could effectively inhibit the proliferation of human cancer cell lines (HCT116, A549, MDA-MB-231 and Hela) expressing high levels of FAK. Particularly, compounds 7b, 7c, and 7o exhibited more significant efficacy against all of four cancer cell lines within concentrations of 1.5 µM. Furthermore, these three compounds displayed higher selectivity of cancer cells over normal cells (SI value > 14), compared to the positive control TAE226 (SI value = 1.63). Interestingly, introduction of dithiocarbamate moiety to the aminoethyl sulfonamide derivatives can indeed improve the antiproliferative activities against A549 cells. Especially, compound 8d demonstrated most significant cytotoxicity activity against A549 cells with an IC50 value of 0.08 µM, which is 20-fold superior to parent compound 7k. Additionally, compound 7b, which display the best anti-FAK potency, can inhibit the clone formation and migration of HCT-116 cells, and cause cell cycle arrest at G2/M phase, inducing apoptosis by promoting ROS production. Overall, these results suggest that 7b is a valuable FAK inhibitor that deserves further optimization to improve its druggability.

Ultrafast vibrational energy redistribution in cyclotrimethylene trinitramine (RDX).

The microscopic mechanism of the energy transfer in cyclotrimethylene trinitramine (RDX) is of particular importance for the study of the energy release process in high-energy materials. In this work, an effective vibrational Hamiltonian based on normal modes (NMs) has been introduced to study the energy transfer process of RDX. The results suggest that the energy redistribution in RDX can be characterized as an ultrafast process with a time scale of 25 fs, during which the energy can be rapidly localized to the -NNO2 twisting mode (vNNO2), the N-N stretching mode (vN-N), and the C-H stretching mode (vC-H). Here, the vNNO2 and vN-N modes are directly related to the cleavage and dissociation of the N-N bond in RDX and, therefore, can be referred to as "active modes." More importantly, we found that the energy can be rapidly transferred from the vC-H mode to the vNNO2 mode due to their strong coupling. From this perspective, the vC-H mode can be regarded as an "energy collector" that plays a pivotal role in supplying energy to the "active modes." In addition, the bond order analysis shows that the dissociation of the N-N bonds of RDX follows a combined twisting and stretching path along the N-N bond. This could be an illustration of the further exothermic decomposition triggered by the accumulation of vibrational energy. The present study reveals the microscopic mechanism for the vibrational energy redistribution process of RDX, which is important for further investigation of the energy transfer process in high-energy materials.

Evaluation of Small Molecules in Blank EDTA Plasma Tubes and Optimization of Metabolomic Workflow for Biomarker Studies Using Plasma Samples.

As the first step of metabolomic analysis in biomarker identification studies, various types of blood collection tubes are used in clinical practice. However, little attention is paid to potential contamination caused by the blank tube itself. Here, we evaluated small molecules in blank EDTA plasma tubes through LC-MS-based untargeted metabolomic analysis and identified small molecules with markedly varied levels among different production batches or specifications. Our data demonstrate possible contamination and data interference caused by blank EDTA plasma tubes when employing large clinical cohorts for biomarker identification. Therefore, we propose a workflow of filtering metabolites in blank tubes prior to statistical analysis to improve the fidelity of biomarker identification.

Identification of diagnostic markers and lipid dysregulation in oesophageal squamous cell carcinoma through lipidomic analysis and machine learning.

BACKGROUND: Oesophageal cancer (EC) ranks high in both morbidity and mortality. A non-invasive and high-sensitivity diagnostic approach is necessary to improve the prognosis of EC patients. METHODS: A total of 525 serum samples were subjected to lipidomic analysis. We combined serum lipidomics and machine-learning algorithms to select important metabolite features for the detection of oesophageal squamous cell carcinoma (ESCC), the major subtype of EC in developing countries. A diagnostic model using a panel of selected features was developed and evaluated. Integrative analyses of tissue transcriptome and serum lipidome were conducted to reveal the underlying mechanism of lipid dysregulation. RESULTS: Our optimised diagnostic model with a panel of 12 lipid biomarkers together with age and gender reaches a sensitivity of 90.7%, 91.3% and 90.7% and an area under receiver-operating characteristic curve of 0.958, 0.966 and 0.818 in detecting ESCC for the training cohort, validation cohort and independent validation cohort, respectively. Integrative analysis revealed matched variation trend of genes encoding key enzymes in lipid metabolism. CONCLUSIONS: We have identified a panel of 12 lipid biomarkers for diagnostic modelling and potential mechanisms of lipid dysregulation in the serum of ESCC patients. This is a reliable, rapid and non-invasive tumour-diagnostic approach for clinical application.

Long Noncoding RNA NHEG1 Drives ß-Catenin Transactivation and Neuroblastoma Progression through Interacting with DDX5.

Recent studies suggest that long noncoding RNAs (lncRNAs) play essential roles in tumor progression. However, the functional roles and underlying mechanisms of lncRNAs in neuroblastoma (NB), the most common malignant solid tumor in pediatric population, still remain elusive. Herein, through integrating analysis of a public RNA sequencing dataset, neuroblastoma highly expressed 1 (NHEG1) was identified as a risk-associated lncRNA, contributing to an unfavorable outcome of NB. Depletion of NHEG1 led to facilitated differentiation and decreased growth and aggressiveness of NB cells. Mechanistically, NHEG1 bound to and stabilized DEAD-box helicase 5 (DDX5) protein through repressing proteasome-mediated degradation, resulting in ß-catenin transactivation that altered target gene expression associated with NB progression. We further determined a lymphoid enhancer binding factor 1 (LEF1)/transcription factor 7-like 2 (TCF7L2)/NHEG1/DDX5/ß-catenin axis with a positive feedback loop and demonstrated that NHEG1 harbored oncogenic properties via its interplay with DDX5. Administration of small interfering RNAs against NHEG1 or DDX5 reduced tumor growth and prolonged survival of nude mice bearing xenografts. High NHEG1 or DDX5 expression was associated with poor survival of NB patients. These results indicate that lncRNA NHEG1 exhibits oncogenic activity that affects NB progression via stabilizing the DDX5 protein, which might serve as a potential therapeutic target for NB.

Risk-Associated Long Noncoding RNA FOXD3-AS1 Inhibits Neuroblastoma Progression by Repressing PARP1-Mediated Activation of CTCF.

Neuroblastoma (NB) is the most common extracranial tumor in childhood. Recent studies have implicated the emerging roles of long noncoding RNAs (lncRNAs) in tumorigenesis and aggressiveness. However, the functions and targets of risk-associated lncRNAs in NB progression still remain to be determined. Herein, through mining of public microarray datasets, we identify lncRNA forkhead box D3 antisense RNA 1 (FOXD3-AS1) as an independent prognostic marker for favorable outcome of NB patients. FOXD3-AS1 is downregulated in NB tissues and cell lines, and ectopic expression of FOXD3-AS1 induces neuronal differentiation and decreases the aggressiveness of NB cells in vitro and in vivo. Mechanistically, as a nuclear lncRNA, FOXD3-AS1 interacts with poly(ADP-ribose) polymerase 1 (PARP1) to inhibit the poly(ADP-ribosyl)ation and activation of CCCTC-binding factor (CTCF), resulting in derepressed expression of downstream tumor-suppressive genes. Rescue experiments indicate that FOXD3-AS1 harbors tumor-suppressive properties by inhibiting the oncogenic roles of PARP1 or CTCF and plays crucial roles in all-trans-retinoic-acid-mediated therapeutic effects on NB. Administration of FOXD3-AS1 construct or siRNAs against PARP1 or CTCF reduces the tumor growth and prolongs the survival of nude mice. These findings suggest that as a risk-associated lncRNA, FOXD3-AS1 inhibits the progression of NB through repressing PARP1-mediated CTCF activation.

Tracking Intramolecular Vibrational Redistribution in Polyatomic Small-Molecule Liquids by Ultrafast Time-Frequency-Resolved CARS.

Selective excitation of C-H stretching vibrational modes, detection of intramolecular vibrational energy redistribution (IVR), and vibrational modes coupling in the electronic ground state of benzene are performed by using femtosecond time- and frequency-resolved coherent anti-Stokes Raman scattering (CARS) spectroscopy. Both of the parent modes in the Raman-active bands are coherently excited by an ultrafast stimulated Raman pump, giving initial excitations of 3056 cm-1 (A1g) and 3074 cm-1 (E2g) and subsequent IVR from the parent modes to daughter modes of 1181 and 992 cm-1, and the coherent vibrational coupling of the relevant modes is tracked. The directionality and selectivity of IVR and coherent coupling among all of the relevant vibrational modes are discussed in the view of molecular symmetry.

miRNA-584-5p exerts tumor suppressive functions in human neuroblastoma through repressing transcription of matrix metalloproteinase 14.

Matrix metalloproteinase 14 (MMP-14) is a membrane-anchored MMP crucial for tumorigenesis and aggressiveness, and is highly expressed in neuroblastoma (NB), the most common extracranial solid tumor in childhood. Recent evidence shows the emerging roles of endogenous promoter-targeting microRNAs (miRNAs) in regulating gene transcription. However, the roles of miRNAs in the transcription of MMP-14 still remain largely unknown. In this study, through mining computational algorithm program and Argonaute-chromosome interaction dataset, we identified one binding site of miRNA-584-5p (miR-584-5p) within the MMP-14 promoter. In NB tissues, miR-584-5p was under-expressed and inversely correlated with MMP-14 expression, and was an independent prognostic factor for favorable outcome of patients. miR-584-5p precursor attenuated the expression of MMP-14 in a Dicer-dependent manner, resulting in decreased levels of vascular endothelial growth factor, in cultured NB cell lines. In addition, miR-584-5p suppressed the promoter activity of MMP-14, and mutation of miR-584-5p binding site abolished these effects. Mechanistically, miR-584-5p recruited Argonaute 2 to facilitate the enrichment of enhancer of zeste homolog 2, histone H3 lysine 27 trimethylation, and histone H3 lysine 9 dimethylation on MMP-14 promoter in NB cells, which was abolished by repressing the miR-584-5p-promoter interaction. Gain- and loss-of-function studies demonstrated that miR-584-5p suppressed the growth, invasion, metastasis, and angiogenesis of NB cells in vitro and in vivo. Moreover, restoration of MMP-14 expression rescued the NB cells from changes in these biological features. Taken together, these results indicate that promoter-targeting miR-584-5p exerts tumor suppressive functions in NB through repressing the transcription of MMP-14.

Hot spot formation and chemical reaction initiation in shocked HMX crystals with nanovoids: a large-scale reactive molecular dynamics study.

We report million-atom reactive molecular dynamic simulations of shock initiation of ß-cyclotetramethylene tetranitramine (ß-HMX) single crystals containing nanometer-scale spherical voids. Shock induced void collapse and subsequent hot spot formation as well as chemical reaction initiation are observed which depend on the void size and impact strength. For an impact velocity of 1 km s(-1) and a void radius of 4 nm, the void collapse process includes three stages; the dominant mechanism is the convergence of upstream molecules toward the centerline and the downstream surface of the void forming flowing molecules. Hot spot formation also undergoes three stages, and the principal mechanism is kinetic energy transforming to thermal energy due to the collision of flowing molecules on the downstream surface. The high temperature of the hot spot initiates a local chemical reaction, and the breakage of the N-NO2 bond plays the key role in the initial reaction mechanism. The impact strength and void size have noticeable effects on the shock dynamical process, resulting in a variation of the predominant mechanisms leading to void collapse and hot spot formation. Larger voids or stronger shocks result in more intense hot spots and, thus, more violent chemical reactions, promoting more reaction channels and generating more reaction products in a shorter duration. The reaction products are mainly concentrated in the developed hot spot, indicating that the chemical reactivity of the hmx crystal is greatly enhanced by void collapse. The detailed information derived from this study can aid a thorough understanding of the role of void collapse in hot spot formation and the chemical reaction initiation of explosives.

Anisotropic shock sensitivity in a single crystal δ-cyclotetramethylene tetranitramine: a reactive molecular dynamics study.

The anisotropic shock sensitivity in a single crystal δ-cyclotetramethylene tetranitramine (δ-HMX) was investigated using the compress-shear reactive dynamics (CS-RD) computational protocol. Significant anisotropies in the thermo-mechanical and chemical responses were found by measuring the shear stress, energy, temperature, and chemical reactions during the dynamical process for the shock directions perpendicular to the (100), (010), (001), (110), (101), (011), and (111) planes. We predict that δ-HMX is sensitive for the shocks perpendicular to the (111), (011), (110), and (101) planes, which is intermediate to the (100) and (010) plane and is insensitive to the (001) plane. The internal energy accumulated within the duration of the surmounting shear stress barrier is a useful criterion to distinguish the sensitive directions from the less sensitive ones. The molecular origin of the anisotropic sensitivity is suggested to be the intermolecular steric arrangements across a slip plane induced by shock compression. The shear deformation induced by the shock along the sensitive direction encounters strong intermolecular contacts and has small intermolecular free space for geometry relaxation when the molecules collide, leading to high shear stress barriers and energy accumulation, which benefits the temperature increase and initial chemical bond breaking that trigger further reactions.

Shock initiated thermal and chemical responses of HMX crystal from ReaxFF molecular dynamics simulation.

To gain an atomistic-level understanding of the thermal and chemical responses of condensed energetic materials under thermal shock, we developed a thermal shock reactive dynamics (TS-RD) computational protocol using molecular dynamics simulation coupled with ReaxFF force field. ß-Octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX) was selected as a a target explosive due to its wide usage in the military and industry. The results show that a thermal shock initiated by a large temperature gradient between the "hot" region and the "cold" region results in thermal expansion of the particles and induces a thermal-mechanical wave propagating back and forth in the system with an averaged velocity of 3.32 km s(-1). Heat propagating along the direction of thermal shock leads to a temperature increment of the system and thus chemical reaction initiation. Applying a continuum reactive heat conduction model combined with the temperature distribution obtained from the RD simulation, a heat conduction coefficient is derived as 0.80 W m(-1) K(-1). The chemical reaction mechanisms during thermal shock were analyzed, showing that the reaction is triggered by N-NO2 bond breaking followed by HONO elimination and ring fission. The propagation rates of the reaction front and reaction center are obtained to be 0.069 and 0.038 km s(-1), based on the time and spatial distribution of NO2. The pressure effect on the thermal shock was also investigated by employing uniaxial compression before the thermal shock. We find that compression significantly accelerates thermal-mechanical wave propagation and heat conduction, resulting in higher temperature and more excited molecules and thus earlier initiation and faster propagation of chemical reactions.

PLCL1 suppresses tumour progression by regulating AMPK/mTOR-mediated autophagy in renal cell carcinoma.

Autophagy has been increasingly recognized as a critical regulatory mechanism in the maintenance of cellular homeostasis. A previous study showed that phospholipase C-like protein 1 (PLCL1) is associated with lipid metabolism in renal cell carcinoma (RCC). However, it is unclear whether PLCL1 regulates autophagy, thereby influencing the progression of RCC. Bioinformatics analysis of five microarray datasets revealed that expression of PLCL1 is decreased in tumours and is positively correlated with prognosis in RCC patients. Three independent public datasets, clinical RCC tissues and RCC cell lines, were validated using real-time qPCR, western blotting and immunohistochemistry. Using wound healing and transwell assays, we observed that elevated PLCL1 levels decreased the migratory distance and the invasive number of 786-O and ACHN cells, but PLCL1 knockdown reversed these changes in 769P cell lines compared to those in controls. The results of flow cytometry analysis indicated that PLCL1 promotes apoptosis. Moreover, transcriptional analysis based on stable overexpression of PLCL1 in 786-O cells revealed that PLCL1 is related to autophagy, and western blotting and autophagic experimental results further verified these findings. Mechanistic investigations confirmed that PLCL1 activates the AMPK/mTOR pathway and interacts with decidual protein induced by progesterone (DEPP). Collectively, our data suggest that PLCL1 functions as a suppressor of RCC progression by activating the AMPK/mTOR pathway, interacting with DEPP, initiating autophagy and inducing apoptosis. PLCL1 may be a promising therapeutic target for the diagnosis and treatment of ccRCC patients.

The Influence of Hydrogen Bonds on the Roaming Reaction.

Roaming bypasses the conventional transition state and is a significant reaction pathway due to the unusual energy distributions of its products; however, its reaction pathway under external environmental interactions remains unclear. Herein, we report for the first time the roaming process of nitrobenzene, which is influenced by the hydrogen bonds (H-bonds) between nitro- and phenyl radicals and water molecules in the gas phase. Notably, despite the fact that the single water structure produces a higher but narrower barrier, whereas the double water structure leads to a lower but wider barrier, the roaming reaction still occurs. The underlying mechanism responsible for these influences of H-bonds is ascribed to the dramatically changed polarization and correlation interactions between the roaming radicals. The reaction rates and thermal perturbation probabilities are also remarkably influenced due to the presence of the H-bonds, by approximately 2 orders of magnitude. It is anticipated that this work will encourage the promising feasibility of introducing environmental molecules to modulate the roaming reaction.

Integrative analysis of deoxyribonuclease 1-like 3 as a potential biomarker in renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma (RCC), is insensitive to radiotherapy and chemotherapy after surgery. Deoxyribonuclease 1-like 3 (DNASE1L3), an endonuclease that cleaves both membrane-encapsulated single- and double-stranded DNA, suppresses cell cycle progression, proliferation and metabolism in hepatocellular carcinoma cells. There is currently no established link between DNASE1L3 and RCC inhibition. We are gonging to explored the mechanism underlying the relationship between DNASEL1L3 and RCC. Methods: RNA sequencing data for RCC tissue and peritumoral tissue were downloaded from The Cancer Genome Atlas database and analyzed. The expression levels of DNASE1L3 in RCC and normal samples were verified using the Gene Expression Omnibus (GEO) database, Human Protein Atlas database and western blotting. The role and potential mechanism of DNASE1L3 were investigated by analysis of immune-related databases and wound healing, invasion, cell counting kit 8 and immunofluorescence assays. Results: We revealed that DNASE1L3 expression was downregulated in RCC group compared with control group [The Cancer Genome Atlas (TCGA): 7.98 vs. 10.87, P<0.001]. Meanwhile, DNASE1L3 expression correlated with the clinical characteristics of patients. Patients with low DNASE1L3 expression had worse survival (P<0.001) and larger (r=-0.32, P<0.001) and heavier tumors (r=-0.17, P<0.001). DNASE1L3 overexpression inhibited the proliferation (786-O: 0.135±0.014 vs. 0.322±0.027, P<0.001) and invasion (786-O: 1,479±134 vs. 832±67, P<0.05) of RCC cells. The expression of DNASE1L3 was significantly correlated with the tumor immune microenvironment and drug sensitivity in ccRCC. Moreover, the level of the key phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway protein P-AKT was decreased in the group of cells transfected with DNASE1L3. Conclusions: This study strongly suggest that DNASE1L3 may be a promising potential biomarker for the diagnosis and treatment of ccRCC patients.

Metabolic detection of malignant brain gliomas through plasma lipidomic analysis and support vector machine-based machine learning.

BACKGROUND: Most malignant brain gliomas (MBGs) are associated with dismal outcomes, mainly due to their late diagnosis. Current diagnostic methods for MBGs are based on imaging and histological examination, which limits their early detection. Here, we aimed to identify reliable plasma lipid biomarkers for non-invasive diagnosis for MBGs. METHODS: Untargeted lipidomic analysis was firstly performed using a discovery cohort (n=107). The data were processed by a support vector machine (SVM)-based discriminating model to retrieve a panel of candidate biomarkers. Then, a targeted quantification method was developed, and the SVM-based diagnostic model was constructed using a training cohort (n=750) and tested using a test cohort (n=225). Finally, the performance of the diagnostic model was further evaluated in an independent validation cohort (n=920) enrolled from multiple medical centers. FINDINGS: A panel of 11 plasma lipids was identified as candidate biomarkers with an accuracy of 0.999. The diagnostic model developed achieved a high performance in distinguishing MBGs patients from normal controls with an area under the receiver-operating characteristic curve (AUC) of 0.9877 and 0.9869 in the training and test cohorts, respectively. In the validation cohort, the 11 lipid panel still achieved an accuracy of 0.9641 and an AUC of 0.9866. INTERPRETATION: The present study demonstrates the applicability and robustness of utilizing a machine learning algorithm to analyze lipidomic data for efficient and reliable biomarker screening. The 11 lipid biomarkers show great potential for the non-invasive diagnosis of MBGs with high throughput. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgments section.

HNF4A-AS1-encoded small peptide promotes self-renewal and aggressiveness of neuroblastoma stem cells via eEF1A1-repressed SMAD4 transactivation.

Cancer stem cells play crucial roles in tumorigenesis and aggressiveness, while regulatory mechanisms in neuroblastoma (NB), a pediatric extracranial malignancy with highest incidence, are still unknown. Herein, a small 51-amino acid peptide (sPEP1) encoded by hepatocyte nuclear factor 4 alpha antisense RNA 1 (HNF4A-AS1) was identified in tumor tissues and cells, which facilitated self-renewal and aggressiveness of NB stem cells. MiRNA-409-5p interacted with HNF4A-AS1 to facilitate sPEP1 translation via recruiting eukaryotic translation initiation factor 3 subunit G, while sPEP1 repressed serum deprivation-induced senescence and promoted sphere formation, growth, or metastasis of NB stem cells. Mechanistically, sPEP1 directly interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1A1) to facilitate its binding to SMAD family member 4 (SMAD4), resulting in repression of SMAD4 transactivation and transcriptional upregulation of stem cell genes associated with tumor progression. Rescue experiments revealed that sPEP1 exerted oncogenic roles via facilitating physical interaction between eEF1A1 and SMAD4. Notably, knockdown of sPEP1 significantly repressed the self-renewal and metastasis of NB stem cells in vivo. High sPEP1 or eEF1A1 levels in clinical NB tissues were linked to poor patients' survival. These findings suggest that HNF4A-AS1-encoded sPEP1 promotes self-renewal and aggressive features of NB stem cells by eEF1A1-repressed SMAD4 transactivation.

Genetic basis analysis of key Loci in 23 Yannong series wheat cultivars/lines.

Fungal diseases, drought, pre-harvest sprouting (PHS) and other biotic and abiotic stresses have seriously affected the quality and yield in wheat production. Identifying related genes/loci in released cultivars/lines can provide reference information and theoretical basis for wheat improvement. Yannong series wheat cultivars/lines have distinctive characteristics in wheat cultivars and play an important role in genetic improvement and production of Chinese wheat production system. To dissect their genetic basis of the stress-resistant traits, in this study, 23 representative Yannong series wheat cultivars/lines were tested by 58 molecular markers for 40 genes related to adaptability, disease resistance and stress tolerance to clarify the genetic composition of the key loci. The results showed that most of the tested wheat accessions carried dwarfing genes RhtB1b/RhtD1b/Rht8 and recessive vernalization genes vrn-A1/vrn-B1/vrn-D1/vrn-B3. It was also consistent with the phenotypic traits of tested Yannong series wheat which were dwarf and winter or semi winter wheat. In addition, the overall level of seedling powdery mildew resistance in 23 Yannong wheat cultivars/lines was moderate or inadequate. Eleven accessions carried none of the tested Pm genes and twelve accessions carried Pm2, Pm6, Pm42 and Pm52 singly or in combination. Then, 23 wheat cultivars/lines were also tested by 17 diagnostic markers for 14 Yr genes. The results showed that 16 wheat cultivars/lines were likely to carry one or more of tested Yr genes, whereas Yannong 15, Yannong 17, Yannong 23, Yannong 24, Yannong 377, Yannong 572 and Yannong 999 carried none of the tested Yr genes. Moreover, in our study, nine markers for four genes related to drought tolerance and PHS were used to evaluate the stress tolerance of the 23 wheat cultivars/lines. The results indicated that all 23 wheat cultivars/lines carried drought resistance genes Ta-Dreb1/TaCRT-D, indicating that they had the drought resistance to the extent. Except for Yannong 30, Yannong 377, Yannong 390, Yannong 745 and Yannong 1766, other wheat cultivars/lines carried one to three elite PHS-resistant alleles Vp-1Bc/Vp-1Bf/TaAFP-1Bb.

Metabolic detection and systems analyses of pancreatic ductal adenocarcinoma through machine learning, lipidomics, and multi-omics.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, characterized by rapid progression, metastasis, and difficulty in diagnosis. However, there are no effective liquid-based testing methods available for PDAC detection. Here we introduce a minimally invasive approach that uses machine learning (ML) and lipidomics to detect PDAC. Through greedy algorithm and mass spectrum feature selection, we optimized 17 characteristic metabolites as detection features and developed a liquid chromatography-mass spectrometry-based targeted assay. In this study, 1033 patients with PDAC at various stages were examined. This approach has achieved 86.74% accuracy with an area under curve (AUC) of 0.9351 in the large external validation cohort and 85.00% accuracy with 0.9389 AUC in the prospective clinical cohort. Accordingly, single-cell sequencing, proteomics, and mass spectrometry imaging were applied and revealed notable alterations of selected lipids in PDAC tissues. We propose that the ML-aided lipidomics approach be used for early detection of PDAC.

HNF4A-AS1/hnRNPU/CTCF axis as a therapeutic target for aerobic glycolysis and neuroblastoma progression.

BACKGROUND: Aerobic glycolysis is a hallmark of metabolic reprogramming that contributes to tumor progression. However, the mechanisms regulating expression of glycolytic genes in neuroblastoma (NB), the most common extracranial solid tumor in childhood, still remain elusive. METHODS: Crucial transcriptional regulators and their downstream glycolytic genes were identified by integrative analysis of a publicly available expression profiling dataset. In vitro and in vivo assays were undertaken to explore the biological effects and underlying mechanisms of transcriptional regulators in NB cells. Survival analysis was performed by using Kaplan-Meier method and log-rank test. RESULTS: Hepatocyte nuclear factor 4 alpha (HNF4A) and its derived long noncoding RNA (HNF4A-AS1) promoted aerobic glycolysis and NB progression. Gain- and loss-of-function studies indicated that HNF4A and HNF4A-AS1 facilitated the glycolysis process, glucose uptake, lactate production, and ATP levels of NB cells. Mechanistically, transcription factor HNF4A increased the expression of hexokinase 2 (HK2) and solute carrier family 2 member 1 (SLC2A1), while HNF4A-AS1 bound to heterogeneous nuclear ribonucleoprotein U (hnRNPU) to facilitate its interaction with CCCTC-binding factor (CTCF), resulting in transactivation of CTCF and transcriptional alteration of HNF4A and other genes associated with tumor progression. Administration of a small peptide blocking HNF4A-AS1-hnRNPU interaction or lentivirus-mediated short hairpin RNA targeting HNF4A-AS1 significantly suppressed aerobic glycolysis, tumorigenesis, and aggressiveness of NB cells. In clinical NB cases, high expression of HNF4A-AS1, hnRNPU, CTCF, or HNF4A was associated with poor survival of patients. CONCLUSIONS: These findings suggest that therapeutic targeting of HNF4A-AS1/hnRNPU/CTCF axis inhibits aerobic glycolysis and NB progression.