Discovery of a novel CDK4/6 and HDAC dual-targeting agent for the treatment of hepatocellular carcinoma.

The down-regulation of p21 after long-term CDK4/6 inhibition represents a key mechanism causing resistance to CDK4/6 inhibitors in some tumor cells, while the HDAC inhibitor could upregulate the level of p21. Herein, a series of novel CDK4/6 and HDAC dual-targeting inhibitors based on the moiety of palbociclib were designed and synthesized. Among them, compound N14 potently inhibited CDK4/6 and HDAC1/6 at nanomolar levels and induced cell apoptosis and G/G phase arrest through HDAC-p21-CDK signaling pathway in HuH-7 cell line.

Combined Multi-Atlas and Multi-Layer Perception for Alzheimer's Disease Classification.

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. To distinguish the stage of the disease, AD classification technology challenge has been proposed in Pattern Recognition and Computer Vision 2021 (PRCV 2021) which provides the gray volume and average cortical thickness data extracted in multiple atlases from magnetic resonance imaging (MRI). Traditional methods either train with convolutional neural network (CNN) by MRI data to adapt the spatial features of images or train with recurrent neural network (RNN) by temporal features to predict the next stage.

The amyloid structure of mouse RIPK3 (receptor interacting protein kinase 3) in cell necroptosis.

RIPK3 amyloid complex plays crucial roles during TNF-induced necroptosis and in response to immune defense in both human and mouse. Here, we have structurally characterized mouse RIPK3 homogeneous self-assembly using solid-state NMR, revealing a well-ordered N-shaped amyloid core structure featured with 3 parallel in-register β-sheets. This structure differs from previously published human RIPK1/RIPK3 hetero-amyloid complex structure, which adopted a serpentine fold.

ICP6 Prevents RIP1 Activation to Hinder Necroptosis Signaling.

Necroptosis is a type of programmed necrosis which depends on the activation of receptor-interacting protein kinase 3 (RIP3). Herpes simplex virus type 1 (HSV-1) is known to block necroptosis by the viral protein ICP6 in human cells, but its specific inhibitory mechanism is not fully understood. Here we reported that ICP6 could promote rather than suppress the formation of necrosome, the necroptosis signaling complex containing RIP3 and upstream regulator receptor-interacting protein kinase 1 (RIP1), but blocked RIP3 activation.

RIP3-mediated necroptosis is regulated by inter-filament assembly of RIP homotypic interaction motif.

Necroptosis is mediated by signaling complexes called necrosomes, which contain receptor-interacting protein 3 (RIP3) and upstream effectors, such as RIP1. In necrosomes, the RIP homotypic interaction motif (RHIM) of RIP3 and RIP1 forms amyloidal complex. But how the amyloidal necrosomes control RIP3 activation and cell necroptosis has not been determined.

NADPH-Cytochrome P450 Reductase Ccr1 Is a Target of Tamoxifen and Participates in Its Antifungal Activity via Regulating Cell Wall Integrity in Fission Yeast.

Invasive fungal diseases are a leading cause of mortality among immunocompromised populations. Treatment is notoriously difficult due to the limited number of antifungal drugs as well as the emergence of drug resistance. Tamoxifen (TAM), a selective estrogen receptor modulator frequently used for the treatment of breast cancer, has been found to have antifungal activities and may be a useful addition to the agents used to treat fungal infectious diseases.

Quantitative oil spill risk from offshore fields in the Bohai Sea, China.

The oil spill risk in the environments surrounding the Bohai Sea is aggravated by increasing marine petroleum exploitation. There is a growing need to assess the risk of oil pollution in sensitive marine areas and coastlines. Both the recurrence frequency of spill accidents and the duration of exposure in marine areas and coastal shorelines are considered in our statistical model, which consists of a probabilistic oil spill model used to simulate various oil spill scenarios at twenty oil fields in the Bohai Sea based on high-resolution oceanographic, meteorological, and geomorphological data.

Numerical modelling of temporal and spatial patterns of petroleum hydrocarbons concentration in the Bohai Sea.

The discharge of petroleum hydrocarbons (PHs; ~10,000tons annually) into the Bohai Sea, a shallow inland sea in China, presents a serious threat to the marine environment. To evaluate the effects of PHs pollution and estimate the corresponding environmental capacity, we have developed a genetic algorithm-based coupled hydrodynamic/transport for simulating PHs concentration evolution and distribution from July 2006 to October 2007, with the predicted values being in good agreement with monitoring results. Importantly, the mean PHs concentrations and seasonal concentration variations were primarily determined by external loading, i.

[Association between left ventricular twist/untwist and diastolic dysfunction of high cardiovascular risk population in the community].

Objective: To assess the association between left ventricular (LV) twist and untwist with the severity of diastolic dysfunction of high cardiovascular risk population in the community.

Methods: This cross-sectional survey was performed in high cardiovascular risk people with normal left ventricular (LV) ejection fraction in an urban community of Beijing (n = 620). Normal LV diastolic function was defined in 305 subjects, mild diastolic dysfunction in 266 subjects and moderate/severe diastolic dysfunction in 49 subjects.

Undifferentiated embryonal sarcoma of liver in an old female: case report and review of the literature.

The clinical characteristics of undifferentiated (embryonal) sarcoma of the liver (UESL) were investigated and the best treatment modalities were recommended. Both histology and immuno-histochemistry demonstrated the cellular features of this peculiar tumor. The tumor size was 12 cm multiply 9 cm multiply 8 cm in the right liver lobe.

Oligonucleotide chip, real-time PCR and sequencing for genotyping of hepatitis B virus.

Aim: To compare the oligonucleotide chip, real-time PCR and sequencing for genotyping of hepatitis B virus in Chinese patients with chronic hepatitis B.

Methods: Mixture of samples with different genotypes and clinical serum samples from 126 chronic hepatitis B patients was tested for hepatitis B virus genotypes by oligonucleotide chip, real-time PCR and sequencing of PCR products, respectively. Clinical performances, time required and costs of the three assays were evaluated.

[Clinical significance of AFP-L3 variants determined by micro centrifugal column].

Objective: To evaluate the clinical significance of AFP-L3 in patients with hepatocellular carcinoma.

Methods: Serum AFP-L3 variants were separated by micro centrifugal column, and detected by chemiluminescence.

Results: AFP and AFP-L3 levels were higher in patients with hepatocellular carcinoma than those in patients with chronic hepatitis (P<0.

Functional disruption of the prion protein gene in cloned goats.

The cellular prion protein (PrPC), a membrane glycoprotein anchored to the outer surface of neurons, lymphocytes and other cells, is associated directly with the pathogenesis of the transmissible spongiform encephalopathies (TSEs) occurring mainly in humans, cattle, sheep and goats. Although mice lacking PrPC develop and reproduce normally and are resistant to scrapie infection, large animals lacking PrPC, especially those species in which TSE occurs naturally, are currently not available. Here, five live PRNP+/- goats cloned by gene targeting are reported.

[Expression of goat beta-casein gene targeting vector in mammary gland cell].

The study of mammary gland bioreactor is in the ascendant. In order to generate transgenic goats of well-controlled expression of exogenic genes, we constructed a human lactoferrin (hLF) gene targeting vector containing promoter, exon 1, intron1 and some of exon 2 (about 6.1 kb fragment) and exon 6 approximately 9 (about 3.

Transfer of an expression YAC into goat fetal fibroblasts by cell fusion for mammary gland bioreactor.

Yeast artificial chromosomes (YACs) as transgenes in transgenic animals are likely to ensure optimal expression levels. Microinjection of YACs is the exclusive technique used to produce YACs transgenic livestock so far. However, low efficiency and high cost are its critical restrictive factors.

[Flow cytometric detection and significance of four cyclins in esophageal cancer].

Objective: To study the expression and significance of cyclin E, cyclin D1, CDK4 and p27 protein in esophageal squamous cell cancer (ESCC) and their correlation with tumor differentiation and lymph node metastasis.

Methods: Expressions of cyclin E, cyclin D1, CDK4 and p27 protein in 65 patients with ESCC were quantitatively detected by flow cytometry.

Results: The expressions of cyclin E, cyclin D1, CDK4 in poorly-differentiated ESCC were higher than those in well-differentiated ESCC (P = 0.