Discovery of a nitroaromatic nannocystin with potent in vivo anticancer activity against colorectal cancer by targeting AKT1.

The development of targeted chemotherapeutic agents against colorectal cancer (CRC), one of the most common cancers with a high mortality rate, is in a constant need. Nannocystins are a family of myxobacterial secondary metabolites featuring a 21-membered depsipeptide ring. The in vitro anti-CRC activity of natural and synthetic nannocystins was well documented, but little is known about their in vivo efficacy and if positive, the underlying mechanism of action. In this study we synthesized a nitroaromatic nannocystin through improved preparation of a key fragment, and characterized its in vitro activity and in vivo efficacy against CRC. We first described the total synthesis of compounds 2-4 featuring Heck macrocyclization to forge their 21-membered macrocycle. In a panel of 7 cancer cell lines from different tissues, compound 4 inhibited the cell viability with IC values of 1-6 nM. In particular, compound 4 (1, 2, 4 nM) inhibited the proliferation of CRC cell lines (HCT8, HCT116 and LoVo) in both concentration and time dependent manners. Furthermore, compound 4 concentration-dependently inhibited the colony formation and migration of CRC cell lines. Moreover, compound 4 induced cell cycle arrest at sub-G1 phase, apoptosis and cellular senescence in CRC cell lines. In three patient-derived CRC organoids, compound 4 inhibited the PDO with IC values of 3.68, 28.93 and 11.81 nM, respectively. In a patient-derived xenograft mouse model, injection of compound 4 (4, 8 mg/kg, i.p.) every other day for 12 times dose-dependently inhibited the tumor growth without significant change in body weight. We conducted RNA-sequencing, molecular docking and cellular thermal shift assay to elucidate the anti-CRC mechanisms of compound 4, and revealed that it exerted its anti-CRC effect at least in part by targeting AKT1.

Artificial Neural Network: A Method for Prediction of Surgery-Related Pressure Injury in Cardiovascular Surgical Patients.

PURPOSE: The aim of this study was to build an artificial neural network (ANN) model for predicting surgery-related pressure injury (SRPI) in cardiovascular surgical patients. DESIGN: Prospective cohort study. SUBJECTS AND SETTING: One hundred forty-nine patients who had cardiovascular surgery were included in the study. This study was conducted in a 1000-bed teaching hospital in Eastern China where 250 to 350 cardiac surgeries are performed each year. METHODS: We performed a prospective cohort study among consecutive patients undergoing cardiovascular surgery between January and December 2015. The ANN model was built based on possible SRPI risk factors. The model performance was tested by a receiver operating characteristic curve and the C-index. A C-index from 0.5 to 0.7 is classified as having low accuracy, 0.7 to 0.9 as having moderate accuracy, and 0.9 to 1.0 as having high accuracy. We also compared the actual SRPI incidences based on the ANN stratification. RESULTS: Thirty-seven of 147 patients developed SRPIs, yielding an incidence rate of 24.8% (95% CI, 18.1-32.6). The C-index was 0.815, which showed the ANN model had a moderate prediction value for SRPI. According to the ANN model, the SRPI predicting incidence ranged from 6.4% to 67.7%. Surgery-related pressure injury incidences were significantly different among 3 risk groups stratified by the ANN (P < .05). CONCLUSION: We established an ANN model that provides moderate prediction of SRPI in patients undergoing cardiovascular surgical procedures. Identification and additional associated factors should be incorporated into the ANN model to increase its predictive ability.

Beyond Clusters: Supramolecular Networks Self-Assembled from Nanosized Silver Clusters and Inorganic Anions.

Assembly of small clusters into rigid bodies with precise shape and symmetry has been witnessed by the significant advances in cluster-based metal-organic frameworks (MOFs), however, nanosized silver cluster based MOFs remain largely unexplored. Herein, two anion-templated silver clusters, CO3 @Ag20 and SO4 @Ag22 , were ingeniously incorporated into a 2D sql lattice (1, [CO3 @Ag20 (iPrS)10 (NO3 )8 (DMF)2 ]n ) and an unprecedented 3D two-fold interpenetrated dia network (2, [SO4 @Ag22 (iPrS)12 (NO3 )6 ⋅2 NO3 ]n ), respectively, under mild solvothermal conditions. Their atomically precise structures were confirmed by single-crystal X-ray diffraction analysis and further consolidated by IR spectroscopy, thermogravimetric analysis (TGA), and elemental analysis. Each drum-like CO3 @Ag20 cluster is extended by twelve NO3 (-) ions to form the 2D sql lattice of 1, whereas each ball-shaped SO4 @Ag22 cluster with a twisted truncated tetrahedral geometry is pillared by four [Ag6 (NO3 )3 ] triangular prisms to form the 3D interpenetrated dia network of 2. Notably, 2 is the first interpenetrated 3D MOF constructed from silver clusters. These results demonstrate the dual role of the anions, which not only internally act as anion templates to induce the formation of silver thiolate clusters but also externally extend the cluster units into the rigid networks. The photoluminescent and electrochemical properties of 2 are discussed in detail.

Single-Crystal to Single-Crystal Phase Transition and Segmented Thermochromic Luminescence in a Dynamic 3D Interpenetrated Ag(I) Coordination Network.

A new 3D Ag(I)-based coordination network, [Ag2(pz)(bdc)·H2O]n (1; pz = pyrazine and H2bdc = benzene-1,3-dicarboxylic acid), was constructed by one-pot assembly and structurally established by single-crystal X-ray diffraction at different temperatures. Upon cooling from 298 to 93 K, 1 undergo an interesting single-crystal to single-crystal phase transition from orthorhombic Ibca (Z = 16) to Pccn (Z = 32) at around 148 K. Both phases show a rare 2-fold-interpenetrated 4-connected lvt network but incorporate different [Ag2(COO)2] dimeric secondary building units. It is worth mentioning that complex 1 shows red- and blue-shifted luminescences in the 290-170 and 140-80 K temperature ranges, respectively. The variable-temperature single-crystal X-ray crystallographic studies suggest that the argentophilic interactions and rigidity of the structure dominated the luminescence chromism trends at the respective temperature ranges. Upon being mechanically ground, 1 exhibits a slight mechanoluminescence red shift from 589 to 604 nm at 298 K.

Curcumin enhances anti­cancer efficacy of either gemcitabine or docetaxel on pancreatic cancer cells.

Curcumin is a natural compound extracted from turmeric (Curcuma longa), which has been reported to be a promising anti­cancer drug in various human cancers. However, the effects of combination treatment of curcumin with gemcitabine or docetaxel on pancreatic cancer remains elusive. In the present study, the combinatory effects of curcumin with either gemcitabine or docetaxel on the proliferation, apoptosis, migration as well as invasion of PC cells were investigated. Calcusyn software was used to determine whether curcumin has is synergistic with gemcitabine or docetaxel. Combination index values from combinational use were all lower than 1, indicating the synergism of curcumin with gemcitabine or docetaxel on PC cells in vitro. EdU assay showed that curcumin could enhance the ability of gemcitabine or docetaxel to inhibit the proliferation of PC cells. Furthermore, the results from transmission electron microscope, DAPI staining experiments and western blot analysis revealed that curcumin may trigger apoptosis of PC cells via PARP/caspase­3 signaling pathway and reinforced pro­apoptotic ability of either gemcitabine or docetaxel. In addition, curcumin exhibited marked suppressive ability on metastasis of PC cells by wound healing and matrigel­transwell assay. Mechanistically, upregulation of TIMP1/TIMP2 with concomitant downregulation of MMP2/MMP9/N­cadherin proteins may be involved in this process. In conclusion, curcumin showed synergistic anti­cancer effects with either gemcitabine or docetaxel on PC cells.