Discovery of a Long Half-Life AURKA Inhibitor to Treat MYC-Amplified Solid Tumors as a Monotherapy and in Combination with Everolimus.

Aurora kinase inhibitors, such as alisertib, can destabilize MYC-family oncoproteins and have demonstrated compelling antitumor efficacy. In this study, we report 6K465, a novel pyrimidine-based Aurora A inhibitor, that reduces levels of c-MYC and N-MYC oncoproteins more potently than alisertib. In an analysis of the antiproliferative effect of 6K465, the sensitivities of small cell lung cancer (SCLC) and breast cancer cell lines to 6K465 were strongly associated with the protein levels of c-MYC and/or N-MYC.

Analysis of structure-activity relationship of indol-3-yl-N-phenylcarbamic amides as potent STING inhibitors.

A structure-activity relationship (SAR) study of stimulator of interferon gene (STING) inhibition was performed using a series of indol-3-yl-N-phenylcarbamic amides and indol-2-yl-N-phenylcarbamic amides. Among these analogs, compounds 10, 13, 15, 19, and 21 inhibited the phosphorylation of STING and interferon regulatory factor 3 (IRF3) to a greater extent than the reference compound, H-151. All five analogs showed stronger STING inhibition than H-151 on the 2',3'-cyclic GMP-AMP-induced expression of interferon regulatory factors (IRFs) in a STING knock-in THP-1 reporter cell line.

Dissolved Oxygen and Water Temperature Drive Vertical Spatiotemporal Variation of Phytoplankton Community: Evidence from the Largest Diversion Water Source Area.

In order to study the vertical distribution characteristics of phytoplankton in the Danjiangkou Reservoir, the water source of the Middle Route Project of the South-North Water Diversion, seven sampling sites were set up in the Reservoir for quarterly sampling from 2017 to 2019, and water environment surveys were conducted simultaneously. The results showed that 157 species (including varieties) were identified, belonging to 9 phyla and 88 genera. In terms of species richness, Chlorophyta had the largest number of species, accounting for 39.

Influence of Atmospheric Phosphorus and Nitrogen Sedimentation on Water Quality in the Middle Route Project of the South-to-North Water Diversion in Henan Province.

In order to understand the potential effects of atmospheric nitrogen and phosphorus deposition on the water quality of the Middle Route Project of the South-to-North Water Diversion Project, samples of dry and wet deposition of atmospheric nitrogen and phosphorus, meteorological factors, and water quality factors were analyzed out to investigate in the Middle Route Project of the South-to-North Water Diversion in Henan Province from October 2018 to October 2020. The variation characteristics of atmospheric nitrogen and phosphorus deposition with time in the Henan section of the main canal are revealed, and the influence of atmospheric dry and wet deposition on the water quality of the middle line is discussed. It was found that the total nitrogen (TN) sedimentation flux has obvious seasonal variation, which was consistent with the variation trend of rainfall, and increased with the increase of rainfall.

MOF-templated synthesis of photoluminescent MoS QDs.

Fabricating MoS QDs using porous metal-organic frameworks (MOFs) as templates remains a great challenge, because the MOF structure is prone to collapse during solvothermal reactions, resulting in a loss of the function of the template. In the present work, the production of homogeneous photoluminescent MoS QDs was achieved by using the structurally stable MOF MIL-101 as limited nanoreactors. The process developed opens up a new route for fabricating other photoluminescent QDs and their derived nanomaterials.

The Drosha-Independent MicroRNA6778-5p/GSK3 Axis Mediates the Proliferation of Gastric Cancer Cells.

Background: Gastric cancer (GC) is a primary cause of cancer death around the world. Previous studies have found that Drosha plays a significant role in the development of tumor cells. Soon after, we unexpectedly found that the expression of microRNA6778-5p (miR6778-5p) is unconventionally high in the gastric cancer cells low-expressing Drosha.

AKT phosphorylation as a predictive biomarker for PI3K/mTOR dual inhibition-induced proteolytic cleavage of mTOR companion proteins in small cell lung cancer.

Background: Constitutive activation of PI3K signaling has been well recognized in a subset of small cell lung cancer (SCLC), the cancer type which has the most aggressive clinical course amongst pulmonary tumors. Whereas cancers that acquire a mutation/copy gain in PIK3CA or loss of PTEN have been implicated in enhanced sensitivity to inhibitors targeting the PI3K/AKT/mTOR pathway, the complexities of the pathway and corresponding feedback loops hamper clear predictions as to the response of tumors presenting these genomic features.

Methods: The correlation between the expression profile of proteins involved in the PI3K/AKT/mTOR signaling and cell viability in response to treatment with small molecule inhibitors targeting isoform-specific PI3Ks, AKT, and mTOR was assessed in 13 SCLC cancer cell lines.

Fabrication and Characterization of a Self-Powered n-BiSe/p-Si Nanowire Bulk Heterojunction Broadband Photodetector.

In the present study, vacuum evaporation method is used to deposit BiSe film onto Si nanowires (NWs) to form bulk heterojunction for the first time. Its photodetector is self-powered, its detection wavelength ranges from 390 nm to 1700 nm and its responsivity reaches its highest value of 84.3 mA/W at 390 nm.

Deformation of the nucleus by TGFβ1 via the remodeling of nuclear envelope and histone isoforms.

The cause of nuclear shape abnormalities which are often seen in pre-neoplastic and malignant tissues is not clear. In this study we report that deformation of the nucleus can be induced by TGFβ1 stimulation in several cell lines including Huh7. In our results, the upregulated histone H3.

Association of ERBB4 genetic polymorphism with the risk and prognosis of non-small cell lung cancer in Chinese Han population: A population-based case-control study.

The aim of this study was to explore the association of rs1836724 single-nucleotide polymorphism (SNP) of ERBB4 with risk and prognosis of non-small cell lung cancer (NSCLC) in the Chinese Han population.The genotype of rs1836724 SNP of ERBB4 from 258 patients with NSCLC and 200 noncancer controls were detected the TaqMan-MGB probes real-time fluorescence polymerase chain reaction. The distribution of genotype and alleles between the 2 groups was compared, and the association between clinicopathological characteristic and rs1836724 SNP was analyzed.

Discovery and Synthesis of a Pyrimidine-Based Aurora Kinase Inhibitor to Reduce Levels of MYC Oncoproteins.

The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound was identified, which potently (IC < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines.

Transcriptionomic Study on Apoptosis of SKOV-3 Cells Induced by Phycoerythrin from Gracilaria lemaneiformis.

Objective: To investigate the effects of Phycoerythrin (PE) on the human ovarian cancer cell line SKOV-3 and its antitumor mechanisms from a transcriptional point of view.

Methods: SKOV-3 cells were exposed to different concentrations of phycoerythrin. The efficiency of this treatment was evaluated through cell growth inhibition, changes in cell morphology, apoptosis and intracellular ROS levels.

[Application of transcranial Doppler in prognosis assessment of nerve function in patients with acute cerebral infarction after intracranial mechanical thrombectomy].

Objective: To investigate the application value of transcranial Doppler (TCD) in the prognosis assessment of nerve function in patients with acute cerebral infarction (ACI) after intracranial mechanical thrombectomy.

Methods: A retrospective analysis was conducted. The clinical data of 43 patients with acute anterior circulation cerebral infarction who received intra-arterial mechanical thrombotomy for recanalization admitted to Taizhou Central Hospital from January 2018 to December 2019 were analyzed.

Clinical features related to hospital expenses for non-cystic fibrosis bronchiectasis in China.

Objective: Bronchiectasis is a common chronic airway disease. We investigated the economic burden and associated factors of bronchiectasis in China.

Methods: In this multicenter retrospective cohort study, we reviewed medical records of patients admitted to 18 tertiary hospitals during 2010 to 2014 with a bronchiectasis-related diagnosis.

Progerin in muscle leads to thermogenic and metabolic defects via impaired calcium homeostasis.

Mutations in lamin A (LMNA) are responsible for a variety of human dystrophic and metabolic diseases. Here, we created a mouse model in which progerin, the lamin A mutant protein that causes Hutchinson-Gilford progeria syndrome (HGPS), can be inducibly overexpressed. Muscle-specific overexpression of progerin was sufficient to induce muscular dystrophy and alter whole-body energy expenditure, leading to premature death.

Sun1 Mediates Interkinetic Nuclear Migration and Notch Signaling in the Neurogenesis of Zebrafish.

Interkinetic nuclear migration (INM) is a process by which nuclei oscillate between the basal and apical surfaces of epithelial cells in coordination with the cell cycle. The cytoskeletal machinery including microtubules and actin has been reported to drive apical INM; however, the role of nuclear proteins in this process has yet to be fully elucidated. Here, we investigated the function of a SUN-domain protein, Sun1, in zebrafish.

Determining the number of chemical species in nuclear magnetic resonance data matrix by taking advantage of collinearity and noise.

The number of chemical species is crucial in analyzing pulsed field gradient nuclear magnetic resonance spectral data. Any method to determine the number must handle the obstacles of collinearity and noise. Collinearity in pulsed field gradient NMR data poses a serious challenge to and fails many existing methods.

Therapeutic effect evaluation of reteplase on acute pulmonary embolism.

Thrombolysis is the main therapeutic method of acute pulmonary embolism (APE). In order to investigate the efficacy of reteplase on APE and the changes of cytokines in the progression of APE, 72 patients with APE were randomized into reteplase group and urokinase group which received reteplase thrombolysis and urokinase thrombolysis, respectively. The clinical symptoms, blood pressure, heart rate (HR), blood gas index and cytokines of patients were observed before and after therapy for assessing the thrombolysis effect of each group; blood level of high sensitive C-reactive protein (hs-CRP), TNF-α, IL-1β, IL-6 and IL-10 was detected at 0h, 2h, 6h, 12h and 24h after thrombolysis.

Design and synthesis of BPR1K653 derivatives targeting the back pocket of Aurora kinases for selective isoform inhibition.

Twenty five novel chemical analogs of the previously reported Aurora kinase inhibitor BPR1K653 (1-(4-(2-((5-chloro-6-phenylfuro[2,3-d]pyrimidin-4-yl)amino)ethyl)phenyl)-3-(2-((dimethylamino)methyl)phenyl)urea) have been designed, synthesized, and evaluated by Aurora-A and Aurora-B enzymatic kinase activity assays. Similar to BPR1K653, analogs 3b-3h bear alkyl or tertiary amino group at the ortho position of the phenylurea, and showed equal or better inhibition activity for Aurora-B over Aurora-A. Conversely, preferential Aurora-A inhibition activity was observed when the same functional group was moved to the meta position of the phenylurea.

Highly oxygenated and structurally diverse diterpenoids from Euphorbia helioscopia.

A phytochemical investigation on the aerial part of Euphorbia helioscopia (Euphorbiaceae) led to the isolation of 22 highly oxygenated diterpenoids with structural types of ent-abietane, ent-kaurane, lathyrane, ent-atisane and ingenane. 17 of them, named euphelionolides A - N, 16-epi-18-hydroxy-abbeokutone, as well as eupheliotriols A and B, were identified to be previously undescribed compounds by extensive analysis of spectroscopic data. The stereostructures of euphelionolides A - K were determined by single crystal X-ray diffraction combined with analysis of substituent effects and comparison of optical characteristics.

Sun1 deficiency leads to cerebellar ataxia in mice.

Migration and organization of the nucleus are essential for the proliferation and differentiation of cells, including neurons. However, the relationship between the positioning of the nucleus and cellular morphogenesis remains poorly understood. Inherited recessive cerebellar ataxia has been attributed to mutations in SYNE1, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex.

Analysis of the discriminative methods for diagnosis of benign and malignant solitary pulmonary nodules based on serum markers.

Background: Screening indexes of tumor serum markers for benign and malignant solitary pulmonary nodules (SPNs) were analyzed to find the optimum method for diagnosis.

Methods: Enzyme-linked immunosorbent assays, an automatic immune analyzer and radioimmunoassay methods were used to examine the levels of 8 serum markers in 164 SPN patients, and the sensitivity for differential diagnosis of malignant or benign SPN was compared for detection using a single plasma marker or a combination of markers. The results for serological indicators that closely relate to benign and malignant SPNs were screened using the Fisher discriminant analysis and a non-conditional logistic regression analysis method, respectively.

H3K9 histone methyltransferase, KMT1E/SETDB1, cooperates with the SMAD2/3 pathway to suppress lung cancer metastasis.

Aberrant histone methylation is a frequent event during tumor development and progression. KMT1E (also known as SETDB1) is a histone H3K9 methyltransferase that contributes to epigenetic silencing of both oncogenes and tumor suppressor genes in cancer cells. In this report, we demonstrate that KMT1E acts as a metastasis suppressor that is strongly downregulated in highly metastatic lung cancer cells.

Dysregulated interactions between lamin A and SUN1 induce abnormalities in the nuclear envelope and endoplasmic reticulum in progeric laminopathies.

Hutchinson-Gilford progeria syndrome (HGPS) is a human progeroid disease caused by a point mutation on the LMNA gene. We reported previously that the accumulation of the nuclear envelope protein SUN1 contributes to HGPS nuclear aberrancies. However, the mechanism by which interactions between mutant lamin A (also known as progerin or LAΔ50) and SUN1 produce HGPS cellular phenotypes requires further elucidation.