Discovery of a Novel and Potent Cyclin-Dependent Kinase 8/19 (CDK8/19) Inhibitor for the Treatment of Cancer.

The mediator kinases CDK8 and CDK19 control the dynamic transcription of selected genes in response to various signals and have been shown to be hijacked to sustain hyperproliferation by various solid and liquid tumors. CDK8/19 is emerging as a promising anticancer therapeutic target. Here, we report the discovery of compound 12, a novel small molecule CDK8/19 inhibitor. This molecule demonstrated not only decent enzymatic and cellular activities but also remarkable selectivity in CDK and kinome panels. Besides, compound 12 also displayed favorable ADME profiles including low CYP1A2 inhibition, acceptable clearance, and high oral bioavailability in multiple preclinical species. Robust in vivo PD and efficacy studies in mice models further demonstrated its potential use as mono- and combination therapy for the treatment of cancers.

Long non-coding RNA CCAT1 acts as an oncogene to promote radiation resistance in lung adenocarcinoma: an epigenomics-based investigation.

Long non-coding RNAs (lncRNAs) appear to be the crucial modulators in various processes and critically influence the oncogenesis. As one of the LncRNAs, LncRNA CCAT1 has been reported to be closely associated with the progression multiple cancers, but its role in modulating the radioresistance of lung adenocarcinoma (LUAD) remains unclear. In our present study, we screened the potential radioresistance related LncRNAs in LUAD based on the data from The Cancer Genome Atlas (TCGA) database. Data suggested that CCAT1 was abundantly expressed in LUAD and CCAT1 was significantly associated with poor prognosis and radioresistance. Moreover, our in vitro experiments showed that radiation treatment could trigger elevated expression of CCAT1 in the human LUAD cell lines. Further loss/gain-of-function investigations indicated that CCAT1 knockdown significantly inhibited cell proliferation, migration and promoted cell apoptosis in NCI-H1299 cells under irradiation, whereas CCAT1 overexpression in A549 cells yield the opposite effects. In summary, we identified the promoting role of CCAT1 in radioresistance of LUAD, which may provide a theoretical basis for radiotherapy sensitization of LUAD.

Discovery of Novel and Potent Prolyl Hydroxylase Domain-Containing Protein (PHD) Inhibitors for The Treatment of Anemia.

Stabilization of hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase domain enzymes (PHDs) represents a breakthrough in treating anemia associated with chronic kidney disease. Here, we identified a novel scaffold for noncarboxylic PHD inhibitors by utilizing structure-based drug design (SBDD) and generative models. Iterative optimization of potency and solubility resulted in compound 15 which potently inhibits PHD thus stabilizing HIF-α in vitro. X-ray cocrystal structure confirmed the binding model was distinct from previously reported carboxylic acid PHD inhibitors by pushing away the R383 and Y303 residues resulting in a larger inner subpocket. Furthermore, compound 15 demonstrated a favorable in vitro/in vivo absorption, distribution, metabolism, and excretion (ADME) profile, low drug-drug interaction risk, and clean early safety profiling. Functionally, oral administration of compound 15 at 10 mg/kg every day (QD) mitigated anemia in a 5/6 nephrectomy rat disease model.

Predicting the prognosis of lung cancer patients treated with intensity-modulated radiotherapy based on radiomic features.

AIMS: This study aimed to develop a method for predicting short-term outcomes of lung cancer patients treated with intensity-modulated radiotherapy (IMRT) using radiomic features detected through computed tomography images. METHOD: A prediction model was developed based on a dataset of radiomic features obtained from 132 patients with lung cancer receiving IMRT. Dimension reduction was performed for the features using the maximum-relevance and minimum-redundancy (mRMR) algorithm, and the least absolute shrinkage and selection operator (LASSO) regression model was utilized to optimize feature selection for the IMRT-sensitivity prediction model. The model was constructed using binary logistic regression analysis and was evaluated using the concordance index (C-index), calibration plots, receiver operating characteristic curve, and decision curve analysis. RESULTS: Fifty features were selected from 1348 radiomic features using the mRMR method. Of these, three radiomic features were selected by LASSO logistic regression to construct the radiomics nomogram. The C-index of the model was 0.776 (95% confidence interval: 0.689-0.862) and 0.791 (95% confidence interval: 0.607-0.974) in the training and validation cohorts, respectively. Decision curve analysis showed that the radiomics nomogram was clinically useful. CONCLUSION: Radiomic features have the potential to be applied to predict the short-term efficacy of IMRT in patients with inoperable lung cancer.

Conductive silk fibroin hydrogel with semi-interpenetrating network with high toughness and fast self-recovery for strain sensors.

Regenerated silk fibroin (RSF) hydrogels have been extensively studied in the fields of biomedicine and wearable devices in recent years due to their outstanding biocompatibility. However, the pure RSF hydrogels usually exhibited frangibility and low ductility, limiting their application in many aspects severely. Herein, we demonstrate a tough RSF/poly (N, N-dimethylallylamine) hydrogel with semi-interpenetrating network, which possesses good mechanical properties with high stretchability (εb = 900%), tensile strength (σb = 101.7 kPa), toughness (Wf = 516.7 kJ/m3) and tearing fracture energy (T = 407.3 J/m2). Besides, the gels show low residual strain in the cyclic tests and rapid self-recovery (80% toughness recovery within 5 min with the maximum strain of 400%). Moreover, the gels also show high ionic conductivity due to the incorporation of the NaCl and the hydrogel can act as an ideal candidate for strain sensor with high sensitivity (GF = 1.84), admirable linearity, and good durability (1000 cycles with the strain of 100%). When used as a wearable strain sensor for monitoring human movements, it also can detect small and large deformations with high sensitivity. It is expected that this work can provide a new strategy for the fabrication of smart RSF-based hydrogels and expand their application in multiple scenarios.

Genome-Wide Identification of the AP2/ERF Gene Family and Functional Analysis of GmAP2/ERF144 for Drought Tolerance in Soybean.

Drought is a major environmental constraint that causes substantial reductions in plant growth and yield. Expression of stress-related genes is largely regulated by transcription factors (TFs), including in soybean [Glycine max (L.) Merr.]. In this study, 301 GmAP2/ERF genes that encode TFs were identified in the soybean genome. The TFs were divided into five categories according to their homology. Results of previous studies were then used to select the target gene GmAP2/ERF144 from among those up-regulated by drought and salt stress in the transcriptome. According to respective tissue expression analysis and subcellular determination, the gene was highly expressed in leaves and encoded a nuclear-localized protein. To validate the function of GmAP2/ERF144, the gene was overexpressed in soybean using Agrobacterium-mediated transformation. Compared with wild-type soybean, drought resistance of overexpression lines increased significantly. Under drought treatment, leaf relative water content was significantly higher in overexpressed lines than in the wild-type genotype, whereas malondialdehyde content and electrical conductivity were significantly lower than those in the wild type. Thus, drought resistance of transgenic soybean increased with overexpression of GmAP2/ERF144. To understand overall function of the gene, network analysis was used to predict the genes that interacted with GmAP2/ERF144. Reverse-transcription quantitative PCR showed that expression of those interacting genes in two transgenic lines was 3 to 30 times higher than that in the wild type. Therefore, GmAP2/ERF144 likely interacted with those genes; however, that conclusion needs to be verified in further specific experiments.

Key Soybean Seedlings Drought-Responsive Genes and Pathways Revealed by Comparative Transcriptome Analyses of Two Cultivars.

Seedling drought stress is one of the most important constraints affecting soybean yield and quality. To unravel the molecular mechanisms under soybean drought tolerance, we conducted comprehensive comparative transcriptome analyses of drought-tolerant genotype Jindou 21 (JD) and drought-sensitive genotype Tianlong No.1 (N1) seedlings that had been exposed to drought treatment. A total of 6038 and 4112 differentially expressed genes (DEGs) were identified in drought-tolerant JD and drought-sensitive N1, respectively. Subsequent KEGG pathway analyses showed that numerous DEGs in JD are predominately involved in signal transduction pathways, including plant hormone signaling pathway, calcium signaling pathway, and MAPK signaling pathway. Interestingly, JA and BR plant hormone signal transduction pathways were found specifically participating in drought-tolerant JD. Meanwhile, the differentially expressed CPKs, CIPKs, MAPKs, and MAP3Ks of calcium and MAPK signaling pathway were only identified in JD. The number of DEGs involved in transcription factors (TFs) is larger in JD than that of in N1. Moreover, some differently expressed transcriptional factor genes were only identified in drought-tolerant JD, including FAR1, RAV, LSD1, EIL, and HB-PHD. In addition, this study suggested that JD could respond to drought stress by regulating the cell wall remodeling and stress-related protein genes such as EXPs, CALSs, CBPs, BBXs, and RD22s. JD is more drought tolerant than N1 owing to more DEGs being involved in multiple signal transduction pathways (JA, BR, calcium, MAPK signaling pathway), stress-related TFs, and proteins. The above valuable genes and pathways will deepen the understanding of the molecular mechanisms under drought stress in soybean.

The prospective multiple-centre randomized controlled clinical study of high-dose amoxicillin-proton pump inhibitor dual therapy for H. pylori infection in Sichuan areas.

OBJECTIVES: To evaluate the safety and efficacy of high-dose amoxicillin-proton pump inhibitor dual therapy, and to provide a new eradication regimen as a first-line option for patients with H. pylori infection. METHODS: A total of 971 H. pylori positive patients who received initial treatment were recruited from March to August 2020, and randomly divided into treatment group and control group. The treatment group received of 20 mg esomeprazole four times daily and 750 mg amoxicillin four times daily for 14 days. Control group received of 220 mg bismuth potassium citrate twice daily, 20 mg esomeprazole twice daily, 1000 mg amoxicillin twice daily and 250 mg clarithromycin capsule twice daily for 14 days. Four weeks after the end of treatment, the urea breath test was reviewed to detect whether H. pylori was eradicated. RESULTS: There were no statistical differences in age, gender, the total clinical symptom scores before and after initial treatment, the compliance, and the degree of remission of symptoms before and after initial treatment between the two groups. The eradication rates of H. pylori between dual therapy and quadruple therapy were 88.31% and 85.26% (p=.158) by intention-to-treat (ITT) analysis, 88.66% and 85.44% (p=.186) by modified intention-to-treat (mITT) analysis, and 91.63% and 90.60% (p=.116) by PP analysis, respectively. Adverse events in dual therapy group were significantly lower than quadruple therapy group (13.3% vs. 28.2% (p<.01)). CONCLUSIONS: For the initial treatment of H. pylori infection, the high-dose dual therapy regimen has the same efficacy as the bismuth-containing quadruple therapy regimen, good compliance, less adverse reactions and high safety, so it can be recommended as the empirical first-line treatment regimen for the eradication of H. pylori (KY2019173).

Clinical Significance and Biological Function of miR-1274a in Non-small Cell Lung Cancer.

Since the discovery of microRNAs (miRNAs) as a class of important regulatory molecules, miRNAs are involved in the occurrence and development of tumors. In this paper, we aimed to identify the role of miR-1274a in non-small cell lung cancer (NSCLC). The miR-1274a expression levels in four NSCLC cells and tissues from 125 patients were determined by qRT-PCR assays. Kaplan-Meier survival curves and Cox regression analysis were used to examine the prognostic significance of miR-1274a in NSCLC patients. The CCK-8 and Transwell assays were performed to evaluate the cell proliferation, invasion, and migration ability of NSCLC cells. The miR-1274a expression levels were significantly higher in NSCLC tissues than in adjacent normal tissues, and overexpression of miR-1274a had a poor prognosis in NSCLC patients. Functional studies in two NSCLC cell lines have shown that overexpression of miR-1274a could promote cell proliferation, migration, and invasion. miR-1274a expression levels are upregulated in NSCLC tissues, and a high expression is associated with a poor prognosis in patients with NSCLC. Moreover, miR-1274a promotes cell proliferation, migration, and invasion. Based on our findings, miR-1274a may act as a tumor miRNA in the occurrence and development of NSCLC.

Dissection of Alkylpyridinium Structures to Understand Deamination Reactions.

Via conversion to Katritzky pyridinium salts, alkyl amines can now be used as alkyl radical precursors for a range of deaminative functionalization reactions. The key step of all these methods is single electron reduction of the pyridinium ring, which triggers C-N bond cleavage. However, little has been done to understand how the precise nature of the pyridinium influences these events. Using a combination of synthesis, computation, and electrochemistry, this study delineates the steric and electronic effects that substituents have on the canonical steps and the overall process. Depending on the approach taken, consideration of both the reduction and the subsequent radical dissociation may be necessary. Whereas the electronic effects on these steps work in opposition to each other, the steric effects are synergistic, with larger substituents favoring both steps. This understanding provides a framework for future design of pyridinium salts to match the mode of catalysis or activation.

Nickel-Catalyzed Deaminative Cyanation: Nitriles and One-Carbon Homologation from Alkyl Amines.

A nickel-catalyzed deaminative cyanation of Katritzky pyridinium salts has been developed. When it is coupled with formation of the pyridinium salt from primary amines, this method enables alkyl amines to be converted to alkyl nitriles. A less toxic cyanide reagent, Zn(CN)2, is utilized, and diverse functional groups and heterocycles are tolerated. The method also enables a one-carbon homologation of alkyl amines via reduction of the nitrile products, in addition to many other potential transformations of the versatile nitrile group.

Overcoming the Naphthyl Requirement in Stereospecific Cross-Couplings to Form Quaternary Stereocenters.

The use of a simple stilbene ligand has enabled a stereospecific Suzuki-Miyaura cross-coupling of tertiary benzylic carboxylates, including those lacking naphthyl substituents. This method installs challenging all-carbon diaryl quaternary stereocenters in good yield and ee and represents an important breakthrough in the "naphthyl requirement" that pervades stereospecific cross-couplings involving enantioenriched electrophiles.

LncRNA HCP5 promotes malignant cell behaviors in esophageal squamous cell carcinoma via the PI3K/AKT/mTOR signaling.

The role of lncRNA HCP5 in esophageal squamous cell carcinoma (ESCC) remains unknown despite its involvement in different malignancies. MTT assay, EdU assay, TUNEL assay, transwell assay, and sphere formation assay were conducted to reveal ESCC cell viability, proliferation, apoptosis, migration, invasion, and stemness characteristics. FISH and subcellular fraction assays were performed to reveal the subcellular location of HCP5 in ESCC cells. Luciferase reporter assay and RIP assay were conducted to explore the downstream axis of HCP5. Our findings revealed that HCP5 expression was at a higher level in ESCC tissues and cells compared to that in control tissues and cells. Additionally, HCP5 promoted ESCC cellular activities by promoting proliferation, migration, invasion ability and stemness characteristics of ESCC cells as well as suppressing cell apoptosis. Furthermore, we found that HCP5 bound with miR-139-5p to upregulate PDE4A via the competing endogenous RNA network in ESCC cells. Importantly, HCP5 was discovered to stimulate the PI3K/AKT/mTOR signaling by regulating the downstream target genes. Finally, rescue assays indicated that HCP5 promoted ESCC cell growth by activating the PDE4A-medaited PI3K/AKT/mTOR pathway. HCP5 promotes ESCC cellular development by modulating the miR-139-5p/PDE4A pathway and stimulating the PI3K/AKT/mTOR signaling pathway, which may be conducive for the improvement of ESCC treatment.

Nickel-Catalyzed, Stereospecific C-C and C-B Cross-Couplings via C-N and C-O Bond Activation.

Highly enantioenriched benzylic and allylic amines and alcohols are readily available via asymmetric synthesis and in complex natural products. The development of mild, nickel-catalyzed cross-couplings of their derivatives has advanced the tools available for the preparation of a range of highly enantioenriched products, including those with quaternary stereocenters. This perspective focuses on cross-couplings with convenient and functional group-tolerant organoboron reagents and highlights the discoveries of activating groups and conditions that have led to high-yielding and highly stereospecific reactions. Emphasis is placed on mechanistic understanding, particularly with regards to controlling inversion vs. retention pathways. Limitations and opportunities for future developments are also highlighted.

Hydrolyzed Hydrogels with Super Stretchability, High Strength, and Fast Self-Recovery for Flexible Sensors.

Polyacrylamide is widely employed in constructing functional hydrogels. However, the volume expansion of this hydrogel in water weakens its mechanical properties and restricts its application. Herein, we report a strategy to convert the swollen and weak polyacrylamide/carboxymethyl chitosan hydrogel into a strong and tough one by hydrolysis in acid solution with an elevated temperature. The obtained hydrolyzed hydrogels possess a high strength, toughness, and tearing fracture energy of 5.9 MPa, 22 MJ/m3 and 7517 J/m2, which are 254, 535 and 186 times higher than those of the original swollen one, respectively. In addition, the gels demonstrate low residual strain and rapid self-recovery abilities. Moreover, the gels have good shape memory behavior controlled by temperature. Furthermore, the gels can be worked as strain sensors with a broad strain window, high sensitivity, excellent linear response, and great durability in monitoring human motions after immersing treatment in a normal saline solution. This work provides a new method for preparing the stretchable and tough polyacrylamide-based hydrogels used in the areas of soft actuators and flexible electronics.

The lncRNA ALMS1-IT1 may promote malignant progression of lung adenocarcinoma via AVL9-mediated activation of the cyclin-dependent kinase pathway.

Lung adenocarcinoma (LUAD) is the primary epithelial tumor of the lung. The lack of clinical symptoms and specific molecular diagnostic indicators during the early stages of LUAD mean that the disease may not be detected until late stages, and the 5-year survival rate is only approximately 15%. Long non-coding RNA ALMS1 intronic script 1 (ALMS1-IT1) was previously reported to be correlated with the poor prognosis of head and neck squamous cell carcinoma patients. Here, we investigated whether ALMS1-IT1 has prognostic potential for LUAD. Bioinformatics analyses were performed to examine the expression and prognostic value of ALMS1 and AVL9 (for which gene expression is positively correlated with ALMS1-IT1 expression in LUAD) in LUAD based on TCGA and Oncomine databases. We report that ALMS1-IT1 and AVL9 were both highly expressed in LUAD and correlated with poor outcomes in LUAD patients. Of note, the prognosis of LUAD patients with low expression of both ALMS1-IT1 and AVL9 was superior to that of other patients. Furthermore, the proliferation, migration and invasion of LUAD cells were decreased in cells lacking ALMS1-IT1, and this decrease could be almost completely reversed through overexpression of AVL9. Gene set enrichment analysis revealed that expression of genes related to the cell cycle pathway is closely related to both the high expression of ALMS1-IT1 and AVL9 in LUAD. Finally, up-regulation of ALMS1-IT1 can activate the cyclin-dependent kinase pathway, whereas absence of AVL9 can reverse this activation, as shown by western blotting. In summary, ALMS1-IT1/AVL9 may promote the malignant progression of LUAD, at least in part by regulating the cyclin-dependent kinase pathway.

Printable and Recyclable Conductive Ink Based on a Liquid Metal with Excellent Surface Wettability for Flexible Electronics.

Flexible electronics greatly facilitate human life due to their convenience and comfortable utilization. Liquid metals are an ideal candidate for flexible devices; however, the high surface tension and poor surface wettability restrict their application on diverse substrates. Herein, a printable and recyclable ink composed of poly(vinyl alcohol) and a liquid metal (PVA-LM) was developed to resolve these problems. The materials were designed considering the compatibility between PVA and the liquid metal, and the composite theory was applied to determine the component proportion. The developed composites improved the surface wettability of the liquid metal on diverse substrates, and three-dimensional (3D) printing technology was chosen to maximize the use of this material. Moreover, the PVA-LM ink showed excellent conductivity of about 1.3 × 105 S/m after being turned on, which favored the designing of alarm systems and object locators. The flexible sensors produced with this ink have broad application, high sensitivity, and superstable signal generation even after 200 cycles. When acting as strain sensors, the constructed composites had high sensitivity for monitoring the human movements. Furthermore, liquid metals in printed products can be recycled under alkaline conditions. This study opens a new direction for the next generation of environmentally friendly flexible devices.

High-Throughput Metabolomics Method for Discovering Metabolic Biomarkers and Pathways to Reveal Effects and Molecular Mechanism of Ethanol Extract From Epimedium Against Osteoporosis.

Metabolomics is an effective strategy to explore the molecular mechanism of herbal medicine. Epimedium, a traditional Chinese herb from the Epimedium brevicornu Maxim., has a therapeutic effect on osteoporosis (OP), however the molecular mechanism of the anti-OP effect is uncle\ar. Therefore, we investigated the pharmacological effect and action mechanism of ethanol extract of epimedium (Ext-epi) onOP rat model. The serum of OP rats was analyzed utilized UPLC-Q-TOF/MS metabolomics, and the potential biomarkers were screened and identified using multivariate data analysis systems and network databases. To further appraise the influence of Ext-epi on biological markers and metabolic pathways, and reveal the potential mechanism of Ext-epi on OP treatment. The results showed that 46 potential biomarkers were screened out and after intervention with Ext-epi extracts solution, 16 potential biomarkers were significantly recalled. Further pathway experiments showed that key pathway analysis include sarachidonic acid metabolism, glycerolphospholipid metabolism as potential targets which is related with the efficacy of Ext-epi protect against OP. These results explain the correlation between metabolites and molecular mechanisms, which is of great significance for understanding the intervention of Ext-epi on OP. In short, based on UPLC-Q-TOF/MS metabolomics may provide effective strategies for understanding the pathogenesis of diseases and evaluating the intervention effect of natural products.

SOD1 Promotes Cell Proliferation and Metastasis in Non-small Cell Lung Cancer via an miR-409-3p/SOD1/SETDB1 Epigenetic Regulatory Feedforward Loop.

Superoxide dismutase 1(SOD1) is a major antioxidant with oncogenic effects in many human cancers. Although SOD1 is overexpressed in various cancers, the clinical significance and functions of SOD1 in non-small cell lung cancer (NSCLC), particularly the epigenetic regulation of SOD1 in NSCLC carcinogenesis and progression have been less well investigated. In this study, we found that SOD1 expression was upregulated in NSCLC cell lines and tissues. Further, elevated SOD1 expression could promote NSCLC cell proliferation, invasion and migration. While inhibition of SOD1 expression induced NSCLC G1-phase cell cycle arrest and promoted apoptosis. In addition, miR-409-3p could repress SOD1 expression and significantly counteract its oncogenic activities. Bioinformatics analysis indicated that SET domain bifurcated histone lysine methyltransferase1 (SETDB1) was involved in the epigenetic regulation of miR-409-3p and SOD1 expression and functions in NSCLC cells. Identification of this miR-409-3p/SOD1/SETDB1 epigenetic regulatory feedforward loop may provide new insights into further understanding of NSCLC tumorigenesis and progression. Additionally, our results incicate that SOD1 may be a potential new therapeutic target for NSCLC treatment.