Palbociclib and Michael-acceptor hybrid compounds as CDK4/6 covalent inhibitors: Improved potency, broad anticancer spectrum and overcoming drug resistance.

To search for potent CDK4/6 covalent inhibitors, total 14 compounds have been designed and synthesized by connecting different Michael-acceptor to the piperazine moiety of palbociclib. All the compounds displayed good antiproliferative activity against human hepatoma cell (HepG2), non-small cell lung cancer (A549), and breast cancer (MDA-MB-231 and MCF-7) cell lines. In particular, compound A4 showed the highest inhibitory activity to MDA-MB-231 and MCF-7 cells with IC50 values of 0.51 µM and 0.48 µM, respectively. More importantly, A4 also showed strong inhibition against MDA-MB-231/palbociclib cells, indicating that A4 could effectively avoid the resistance of palbociclib. In the enzyme test, A4 showed selective inhibitory activity against CDK4/6, with the IC50 value of 18 nM and 13 nM, respectively. It was also found that A4 could efficiently induce apoptosis and arrest the cell cycle at G0/G1 phase. Moreover, A4 could significantly decrease the phosphorylation level of CDK4 and CDK6. HPLC and molecular modeling studies suggested that A4 could form a covalent bond with the target protein.

Aerobic C-C Bond Cleavage of Allylic Alcohols via Co-Catalyzed Hydrogen Atom Transfer.

A simple, efficient method has been developed for the CoIII-H-catalyzed aerobic C-C bond cleavage of tertiary allylic alcohols to access ketones. This novel approach presents excellent chemoselectivity, good functional group compatibility, and high yields. This reaction occurs through a HAT-initiated peroxide intermediate, and an adjacent glycol-type diradical fragmentation process is recommended.

Is Orthokeratology Treatment Zone Decentration Effective and Safe in Controlling Myopic Progression?

OBJECTIVE: To compare the myopia control efficacy and safety of decentered versus centered positioning of orthokeratology. METHODS: This is a retrospective intrasubject study, including 46 children with myopia (25 boys, 21 girls; age 11.12±0.33 years) treated for 1 year with OK decentration in one eye (group D) and central location in the other (Group C). Axial length was measured before and at 6 months and 12 months after the initial lens wear, respectively. Corneal topography was measured at baseline and at 1-month after lens wear. The corneal topography obtained from the 1-month visit was used to quantify treatment zone decentration (TZD) for each subject. Cycloplegic refraction was required for all children before fitting the orthokeratology lenses. RESULTS: No differences were found between the groups in the biological ocular parameters ( P ≥0.05 for all). The axial elongation in group D and group C differed after 6 and 12 months ( P <0.001 for all). Similar corneal staining rates ( P =0.06) were noted during follow-up in groups D (n=20; 7.24%) and C (n=10; 3.62%), all of grade I. The uncorrected visual acuity (UCVA) in group D and C differed after 1, 6, and 12 months ( P =0.002, 0.010, 0.044), except 3 months ( P =0.146). Group D (n=32; 17.39%) was more likely to have glare or ghosting (chi-squared test, P <0.001) than group C (n=12; 6.52%) during follow-up visits. Axial elongation was significantly associated with baseline spherical equivalent (SE) in group C ( P =0.019). In group D, axial elongation was significantly associated with SE and TZD ( P <0.05 for all). CONCLUSIONS: This intrasubject study showed that when the UCVA was acceptable and there were no apparent complications, orthokeratology decentration may be beneficial in controlling the progression of myopia. Axial elongation became slower in children with a higher SE and a larger TZD, because TZD ranged from 0.5 mm to 1.5 mm.

Alien species invasion of deep-sea bacteria into mouse gut microbiota.

INTRODUCTION: Deep sea has numerous bacteria which dominate in the biomass of deep-sea sediments. Some deep-sea bacteria may possess the capacity to destroy mammal health by the alteration of gut microbiota, acting as potential pathogens. OBJECTIVES: Pathogenic bacteria are great threats to human health. However, the ultimate origin of pathogenic bacteria has not been intensively explored. In this study, therefore, the influence of deep-sea bacteria on the gut microbiota was evaluated on a global scale. METHODS: The bacteria isolated from each of 106 deep-sea sediment samples were transplanted into mice in our study to assess the infectiousness of deep-sea bacteria. RESULTS: The results showed that some bacteria from deep sea, an area that has existed since the earth was formed, could proliferate in mouse gut. Based on the infectious evaluation of the bacteria from each of 106 deep-sea sediments, the bacteria isolated from 13 sediments invaded the gut bacterial communities of mice, leading to the significant alteration of mouse gut microbiota. Among the 13 deep-sea sediments, the bacteria isolated from 9 sediments could destroy mouse health by inducing glucose metabolism deterioration, liver damage and inflammatory symptom. As an example, a bacterium was isolated from deep-sea sediment DP040, which was identified to be Bacillus cereus (termed as Bacillus cereus DP040). Bacillus cereus DP040 could invade the gut microbiota of mice to change the gut microbial structure, leading to inflammatory symptom of mice. The deep-sea sediments containing the bacteria destroying the health of mice were distributed in hydrothermal vent, mid-ocean ridge and hadal trench of the Indian Ocean, the Atlantic Ocean and the Pacific Ocean. CONCLUSION: Our findings demonstrate that deep sea is an important origin of potential pathogenic bacteria and provide the first biosecurity insight into the alien species invasion of deep-sea bacteria into mammal gut microbiota.

Curved Film Microstructure Arrays Fabricated via Mechanical Stretching.

We report on curved film microstructure arrays fabricated through polydimethylsiloxane (PDMS) film buckling induced by mechanical stretching. In the process of the microstructure preparation, a PDMA film is glued on a bidirectionally prestretched PDMS sheet that has a square distributed hole array on its surface. After releasing the prestrain, the film microstructure array is created spontaneously. The fabricated microstructures possess a spherical surface and demonstrate very good uniformity. The film microstructure arrays can serve as microlens arrays with a focal length of 1010 µm. The microstructure formation mechanism is investigated via theoretical analysis and numerical simulation. The simulation results agree well with the experimental results. The prestrain applied by mechanical stretching during the fabrication has an important effect on the shape of the resulting film microstructures. The microstructure geometry can be easily tuned through controlling the applied prestrain.

Cobalt-Catalyzed Deprotection of Allyl Carboxylic Esters Induced by Hydrogen Atom Transfer.

A brief, efficient method has been developed for the removal of the allyl protecting group from allyl carboxylic esters using a Co(II)/TBHP/(Me2SiH)2O catalytic system. This facile strategy displays excellent chemoselectivity, functional group tolerance, and high yields. This transformation probably occurs through the hydrogen atom transfer process, and a Co(III)-six-membered cyclic intermediate is recommended.

Requirement of splicing factor hnRNP A2B1 for tumorigenesis of melanoma stem cells.

BACKGROUND: Cancer stem cells play essential roles in tumorigenesis, thus forming an important target for tumor therapy. The hnRNP family proteins are important splicing factors that have been found to be associated with tumor progression. However, the influence of hnRNPs on cancer stem cells has not been extensively explored. METHODS: Quantitative real-time PCR and Western blot were used to examine gene expressions. RNA immunoprecipitation assays were conducted to identify the RNAs interacted with hnRNP A2B1. The in vivo assays were performed in nude mice. RESULTS: In this study, the results showed that out of 19 evaluated hnRNPs, hnRNP A2B1 was significantly upregulated in melanoma stem cells compared with non-stem cells, suggesting an important role of hnRNP A2B1 in cancer stem cells. Silencing of hnRNP A2B1 triggered cell cycle arrest in G2 phase, leading to apoptosis of melanoma stem cells. The results also revealed that hnRNP A2B1 could bind to the precursor mRNAs of pro-apoptosis genes (DAPK1, SYT7, and RNF128) and anti-apoptosis genes (EIF3H, TPPP3, and DOCK2) to regulate the splicing of these 6 genes, thus promoting the expressions of anti-apoptosis genes and suppressing the expressions of pro-apoptosis genes. The in vivo data indicated that hnRNP A2B1 was required for tumorigenesis by affecting the splicing of TPPP3, DOCK2, EIF3H, RNF128, DAPK1, and SYT7, thus suppressing apoptosis of melanoma stem cells. CONCLUSION: Our findings showed the requirement of hnRNP A2B1 for tumorigenesis, thus presenting novel molecular insights into the role of hnRNPs in cancer stem cells.

Origin of Magnetically Induced Optical Transmission of Magnetic Nanocomposite Films.

Herein, we present an investigation on the origin of the magnetically induced optical transmission of composite films comprised of polydimethylsiloxane and magnetic nanofillers via experiment and simulation. Structured and unstructured films were used in the study, which were fabricated with and without magnetic fields, respectively. Altered optical transmittance was observed from both types of films when they were subjected to an external magnetic field. Numerical analyses were performed to investigate the effect of the particle movement under magnetic field and the film magnetostriction on the film optical transmittance. The simulation results show that the changed light transmission under magnetic field is mainly due to a variation in the film thickness resulting from the film magnetostriction. The ellipsometric analysis results confirm the altered film thickness in response to the external magnetic field, and the measurements of the film magnetostrictive stresses validate that there is magnetostriction in the magnetic composite films. Additionally, it is indicated that there might be some relationship between the magnetically induced optical transmission and the film magnetostrictive stress under certain conditions.