Design, synthesis, and biological evaluation of phenylcyclopropylamine-entinostat conjugates that selectively target cancer cells.

Small molecule-based selective cancer cell-targeting can be a desirable anticancer therapeutic strategy. Aiming to discover such small molecules, we previously developed phenylcyclopropylamine (PCPA)-drug conjugates (PDCs) that selectively release anticancer agents in cancer cells where lysine-specific demethylase 1 (LSD1) is overexpressed. In this work, we designed PCPA-entinostat conjugates for selective cancer cell targeting. PCPA-entinostat conjugate 12 with a 4-oxybenzyl group linker released entinostat in the presence of LSD1 in in vitro assays and selectively inhibited the growth of cancer cells in preference to normal cells, suggesting the potential of PCPA-entinostat conjugates as novel anticancer drug delivery small molecules.

Directed Disulfide Pairing and Folding of Peptides for the De Novo Development of Multicyclic Peptide Libraries.

Disulfide-rich peptides (DRPs) have been an emerging frontier for drug discovery. There have been two DRPs approved as drugs (i.e., Ziconotide and Linaclotide), and many others are undergoing preclinical studies or in clinical trials. All of these DRPs are of nature origin or derived from natural peptides. It is still a challenge to design new DRPs without recourse to natural scaffolds due to the difficulty in handling the disulfide pairing. Here we developed a simple and robust strategy for directing the disulfide pairing and folding of peptides with up to six cysteine residues. Our strategy exploits the dimeric pairing of CPPC (cysteine-proline-proline-cysteine) motifs for directing disulfide formation, and DRPs with different multicyclic topologies were designed and synthesized by regulating the patterns of CPPC motifs and cysteine residues in peptides. As neither sequence manipulations nor unnatural amino acids are involved, the designed DRPs can be used as templates for the de novo development of biosynthetic multicyclic peptide libraries, enabling selection of DRPs with new functions directly from fully randomized sequences. We believe that this work represents as an important step toward the discovery and design of new multicyclic peptide ligands and therapeutics with structures not derived from natural scaffolds.

Cancer-Cell-Selective Targeting by Arylcyclopropylamine-Vorinostat Conjugates.

Anticancer drug delivery by small molecules offers a number of advantages over conventional macromolecular drug delivery systems. We previously developed phenylcyclopropylamine (PCPA)-drug conjugates (PDCs) as small-molecule-based drug delivery vehicles for targeting lysine-specific demethylase 1 (LSD1)-overexpressing cancers. In this study, we applied this PDC strategy to the HDAC-inhibitory anticancer agent vorinostat. Among three synthesized PCPA or arylcyclopropylamine (ACPA)-vorinostat conjugates 1, 9, and 32, conjugate 32 with a 4-oxybenzyl linker showed sufficient stability in buffer solutions, potent LSD1 inhibition, efficient LSD1-dependent vorinostat release, and potent and selective antiproliferative activity toward LSD1-expressing human breast cancer and small-cell lung cancer cell lines. These results indicate that the conjugate selectively releases vorinostat in cancer cells. A similar strategy may be applicable to other anticancer drugs.

Retraction Note: The diagnostic nomogram of platelet-based score models for hepatic alveolar echinococcosis and atypical liver cancer.

Editor's Note: this Article has been retracted; the Retraction Note is available at https://www.nature.com/articles/s41598-020-73758-x.

Relationship between platelet-based models and the prognosis of patients with malignant hepatic tumors.

Platelets (PLTs) are involved in tumor growth, metabolism and vascular activation. PLT-based models have been reported to have significant value on the recurrence of malignant hepatic tumors. The present study aimed to investigate the effect of PLT count and 18 PLT-based models on the prognosis of patients with malignant hepatic tumors. The clinical data from 189 patients with malignant hepatic tumors were retrospectively analyzed and used to calculate the scores of the 18 PLT-based models. Receiver operating characteristic curve was used to determine the suitable cut-off values of mortality and recurrence in patients with malignant hepatic tumors. The overall survival and cumulative recurrence rates of patients were calculated using Kaplan-Meier survival curves and the difference was analyzed using log-rank test. Multivariate analysis was performed to determine the independent risk factors of recurrence-free survival and overall survival. In the present study, 11 models were considered as predictors of mortality (P<0.05) and six models were considered as predictors of recurrence (P<0.05). The results from multivariate analysis demonstrated that vascular cancer embolus, uric acid >231 µmol/l, hemoglobin >144 g/l and the Lok index model >0.695 were considered as independent risk factors of mortality (P<0.05). Furthermore, vascular cancer embolus, PLT to lymphocyte ratio (PLR) >175 and fibrosis-4 (FIB-4) >4.82 were independent factors of recurrence (P<0.05). In addition, the results from this study indicated that the Lok-index could be considered as a predictor of the overall survival rate. In conclusion, the FIB-4 and PLR model may be valuable for predicting the recurrence-free rate of patients with malignant hepatic tumors.

The diagnostic nomogram of platelet-based score models for hepatic alveolar echinococcosis and atypical liver cancer.

Hepatic alveolar echinococcosis (HAE) and liver cancer had similarities in imaging results, clinical characteristics, and so on. And it is difficult for clinicians to distinguish them before operation. The aim of our study was to build a differential diagnosis nomogram based on platelet (PLT) score model and use internal validation to check the model. The predicting model was constructed by the retrospective database that included in 153 patients with HAE (66 cases) or liver cancer (87 cases), and all cases was confirmed by clinicopathology and collected from November 2011 to December 2018. Lasso regression analysis model was used to construct data dimensionality reduction, elements selection, and building prediction model based on the 9 PLT-based scores. A multi-factor regression analysis was performed to construct a simplified prediction model, and we added the selected PLT-based scores and relevant clinicopathologic features into the nomogram. Identification capability, calibration, and clinical serviceability of the simplified model were evaluated by the Harrell's concordance index (C-index), calibration plot, receiver operating characteristic curve (ROC), and decision curve. An internal validation was also evaluated by the bootstrap resampling. The simplified model, including in 4 selected factors, was significantly associated with differential diagnosis of HAE and liver cancer. Predictors of the simplified diagnosis nomogram consisted of the API index, the FIB-4 index, fibro-quotent (FibroQ), and fibrosis index constructed by King's College Hospital (King's score). The model presented a perfect identification capability, with a high C-index of 0.929 (0.919 through internal validation), and good calibration. The area under the curve (AUC) values of this simplified prediction nomogram was 0.929, and the result of ROC indicated that this nomogram had a good predictive value. Decision curve analysis showed that our differential diagnosis nomogram had clinically identification capability. In conclusion, the differential diagnosis nomogram could be feasibly performed to verify the preoperative individualized diagnosis of HAE and liver cancer.

Improvement of cerium on photosynthesis of maize seedlings under a combination of potassium deficiency and salt stress.

Added Ce(3+) can partly substitute for Ca(2+) or Mg(2+) and improve photosynthesis under the deficiency of these elements, but very few studies focused on photosynthetic improvement in maize seedlings caused by K(+) deficiency, salt stress, especially a combination of K(+) deficiency and salt stress. In the present study, the effects of Ce(3+) on the photosynthesis of maize seedlings under the three different stresses were investigated. The results showed that added Ce(3+) under various stresses increased the ratios of free water/bound water and of K(+)/Na(+), the pigment contents, the values of Fv/Fm, Y(II), ETR(II), Y(NPQ), Qp, qL, NPQ, and qN of photosystem II (PSII), the values of Y(I) and ETR(I) of photosystem I (PSI) and the expression levels of LhcII cab1 and rbcL, and decreased the values of Y(NO) and Y(NA). This implied that added Ce(3+) depressed ion toxicity, photodamage of PSII, and acceptor side constraints of PSI, and enhanced adjustable energy dissipation, the responses of photochemistry, and carbon assimilation caused by K(+) deficiency, salt stress, and the combination of K(+) deficiency and salt stress. However, Ce(3+) mitigation of photosynthetic inhibition in maize seedlings caused by the combined stresses was greater than that of salt stress, and Ce(3+) mitigation under salt stress was greater than that under K(+) deficiency. In addition, the results also showed that Ce(3+) cannot improve photosynthesis and growth of maize seedlings under K(+) deficiency by substituting for K(+).