Coassembly of Linear Diblock Copolymer Chains and Homopolymer Brushes on Silica Particles: A Combined Computer Simulation and Experimental Study

A combined computer simulation and experimental study on coassembly of poly­(2-(dimethylamino)­ethyl methacrylate)-<i>block</i>-polystyrene (PDMAEMA-<i>b</i>-PS) block copolymers and PS brushes on silica particles was performed. PS brushes on silica particles at two different grafting densities were prepared by the “grafting to” approach, and PDMAEMA-<i>b</i>-PS block copolymers with different molecular weights and compositions were synthesized by reversible addition–fragmentation chain transfer polymerization. In THF/methanol mixtures, block copolymer chains and PS brushes coassemble into surface micelles (s-micelles), with collapsed PS cores and PDMAEMA coronae. Meanwhile, block copolymer chains are able to self-assemble into block copolymer micelles (b-micelles). Computer simulation results and experimental results indicate that block copolymer concentration, PS and PDMAEMA block lengths, and PS grafting density exert significant influences on the coassembly process. In low BCP concentration regime, the average size of s-micelles increases with BCP concentration and keeps unchanged at high concentration. The PS block length has a significant influence on the size of s-micelles. The average size increases with an increase in PS block length. For a BCP with long solvophilic PDMAEMA block, it is energy favorable to self-assemble into b-micelles, but to coassemble into s-micelles. With an increase in PDMAEMA block length, the morphology of the s-micelles changes from wormlike/spherical structures to spherical structures and to smaller spherical structures. The average size of the s-micelles coassembled by PS brushes at a lower grafting density is smaller than those coassembled by PS brushes at a higher grafting density

Genetic association study of <i>TERT</i> gene variants with chronic kidney disease susceptibility in the Chinese population

The incidence and mortality of chronic kidney disease (CKD) are increasing globally. Studies have demonstrated the significance of genetic risk factors in the progression of CKD. Telomerase reverse transcriptase (TERT) may be implicated in the development of CKD. This study aimed to investigate the correlation between TERT gene variants and susceptibility to CKD in the Chinese population. A total of 507 patients with CKD and 510 healthy controls were recruited for this case-control study. Four candidate loci were identified using the MassARRAY platform. Logistic regression analysis was employed to assess the association between TERT gene variants and the risk of CKD. The false positive reporting probability (FPRP) method was utilized to evaluate the validity of statistically significant associations. The multifactorial dimensionality reduction (MDR) method was used to evaluate the interaction between SNPs and the risk of CKD. Furthermore, discrepancies in the clinical features of subjects with diverse genotypes were evaluated using one-way analysis of variance (ANOVA). Our findings revealed a correlation between rs2735940 and rs4635969 and an increased risk of CKD. Stratification analysis indicated that rs4635969 was related to an increased risk of CKD in different subgroups (age ≤ 50 years and male). MDR analysis indicated that the two-site model (rs2735940 and rs4635969) was the best prediction model. Furthermore, the rs2735940 GG genotype was found to be linked to an increased level of microalbuminuria (MAU) in patients with CKD. Our study is the first to reveal a connection between TERT gene variants and susceptibility to CKD, providing new insights into the field of nephrology.</p

Small Molecular TRAIL Inducer ONC201 Induces Death in Lung Cancer Cells: A Preclinical Study

<div><p>Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively targets cancer cells. The present preclinical study investigated the anti-cancer efficiency of ONC201, a first-in-class small molecule TRAIL inducer, in lung cancer cells. We showed that ONC201 was cytotoxic and anti-proliferative in both established (A549 and H460 lines) and primary human lung cancer cells. It was yet non-cytotoxic to normal lung epithelial cells. Further, ONC201 induced exogenous apoptosis activation in lung cancer cells, which was evidenced by TRAIL/death receptor-5 (DR5) induction and caspase-8 activation. The caspase-8 inhibitor or TRAIL/DR5 siRNA knockdown alleviated ONC201’s cytotoxicity against lung cancer cells. Molecularly, ONC201 in-activated Akt-S6K1 and Erk signalings in lung cancer cells, causing Foxo3a nuclear translocation. For the <i>in vivo</i> studies, intraperitoneal injection of ONC201 at well-tolerated doses significantly inhibited xenografted A549 tumor growth in severe combined immunodeficient (SCID) mice. Further, ONC201 administration induced TRAIL/DR5 expression, yet inactivated Akt-S6K1 and Erk in tumor tissues. These results of the study demonstrates the potent anti-lung cancer activity by ONC201.</p></div

Inhibition of extrinsic apoptosis activation attenuates ONC201’s cytotoxicity in human lung cancer cells.

<p>A549 cells transfected with scramble control siRNA (SCR-siRNA), TRAIL siRNA or DR5 siRNA (100 nM each) were treated with ONC201 (10 μM) for applied time, TRAIL/DR5 mRNA and protein expressions were shown (A, GAPDH was tested as the control); Cell viability and apoptosis were examined by MTT assay (B) and ssDNA apoptosis ELISA assay (C), respectively. A549 cells were pre-treated with z-IETD-fmk (40 μM) or z-VAD-fmk (40 μM) for 1 hour, followed by ONC201 (10 μM) treatment for indicated time, cell viability and apoptosis were examined by MTT assay (D) and Sub G1 FACS assay (E), respectively. H460 cells or primary human lung cancer cells (“Pat-2”), pretreated with z-IETD-fmk (40 μM, 1 hour) or TRAIL plus DR5 siRNA (100 nM each, 36 hours), were treated with ONC201 (10 μM) for 72 hours, cell viability was tested by MTT assay (F). The results presented were representative of three independent experiments. The values were expressed as the means ± SD. “C” stands for untreated control group. “Veh” stands for 0.2% DMSO (D and E). *<b><i>p</i></b><0.05 vs “No siRNA” group (A). *<b><i>p</i></b><0.05 vs “SCR siRNA” group (B and C). *<b><i>p</i></b><0.05 vs “Veh” group (D and E). *<b><i>p</i></b><0.05 vs ONC201 only group (F).</p

Intraperitoneal injection of ONC201 inhibits A549 xenograft tumor growth in SCID mice.

<p>SCID mice bearing A549 tumors (n = 10) were administrated with vehicle control (“Saline”), or ONC201 (10/50 mg/kg, <i>i</i>.<i>p</i>.), tumor volumes (in mm³, A) and mice body weights (in grams, C) were recorded every week for a total of 5 weeks. The estimated daily tumor growth (in mm³ per day, B) was also presented. The signaling molecule in the xenografted tumor tissues (3 days post initial ONC201 treatment) were tested by Western blot assay (D) and IHC staining (E, for p-Akt). * <b><i>p</i></b> < 0.05 vs. group of Vehicle control. ** <b><i>p</i></b> < 0.05 vs. group of ONC201 at 10 mg/kg. The above xenograft experiments were repeated twice, and similar results were obtained. Bar = 100 μm (E).</p

ONC201 provokes apoptosis in human lung cancer cells.

<p>A549 (A-F), H460 (G-I) or primary human lung cancer cells (“Pat-1/-2”) (G-I), as well as the lung epithelial BEAS-2B cells (G-I) were treated with applied concentration of ONC201 for indicated time, TRAIL and DR5 expressions were tested by real-time PCR assay (A, B, G and H) or Western blot assay (B, Upper panel); Relative caspase-8/-3 activity was also presented (C and D); Cell apoptosis was tested by ssDNA ELISA assay (E) and Sub-G1 FACS assay (F and I). The results presented were representative of three independent experiments. The values were expressed as the means ± SD. “C” stands for untreated control group. *<b><i>p</i></b><0.05 vs “C” group.</p

ONC201 induces death in human lung cancer cells.

<p>A549 (A-C), H460 (D) or primary human lung cancer cells (“Pat-1/-2”) (D), as well as the lung epithelial BEAS-2B cells (D) and human HL-7702 hepatocytes (E) were treated with applied concentration of ONC201 for indicated time, cells were subjected to MTT assay (A, D and E), colony formation assay (B) and LDH release assay (C). The results presented were representative of three independent experiments. The values were expressed as the means ± SD. “C” stands for untreated control group. *<b><i>p</i></b><0.05 vs “C” group.</p

Image_1_LASSO-derived prognostic model predicts cancer-specific survival in advanced pancreatic ductal adenocarcinoma over 50 years of age: a retrospective study of SEER database research.tif

BackgroundThis study aimed to develop a prognostic model for patients with advanced ductal adenocarcinoma aged ≥50 years.MethodsPatient information was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed to screen the model variables. Cases from Nanchang Central Hospital were collected for external validation. The new nomogram and the American Joint Committee on Cancer (AJCC) criteria were evaluated using integrated discrimination improvement (IDI) and net reclassification index (NRI) indicators. Survival curves presented the prognosis of the new classification system and AJCC criteria.ResultsIn total, 17,621 eligible patients were included. Lasso Cox regression selected 4 variables including age, chemotherapy, radiotherapy and AJCC stage. The C-index of the training cohort was 0.721. The C-index value of the validation cohort was 0.729. The AUCs for the training cohorts at 1, 2, and 3 years were 0.749, 0.729, and 0.715, respectively. The calibration curves showed that the predicted and actual probabilities at 1, 2, and 3 years matched. External validation confirmed the model’s outstanding predictive power. Decision curve analysis indicated that the clinical benefit of the nomogram was higher than that of the AJCC staging system. The model evaluation indices preceded the AJCC staging with NRI (1-year: 0.88, 2-year: 0.94, 3-year: 0.72) and IDI (1-year: 0.24, 2-year: 0.23, 3-year: 0.22). The Kaplan–Meier curves implied that the new classification system was more capable of distinguishing between patients at different risks.ConclusionsThis study established a prognostic nomogram and risk classification system for advanced pancreatic cancer in patients aged ≥50 years to provide a practical tool for the clinical management of patients with pancreatic ductal adenocarcinoma.</p

Table_1_Histological, microecological and transcriptomic physiological responses underlying hypoxia and reoxygenation adaptation in yellowtail kingfish (Seriola lalandi).docx

Yellowtail kingfish has emerged as one of the most promising marine fishes for aquaculture in China because it is tasty, fast growing, and has high economic value. To investigate the tolerance and adaptability to hypoxia of farmed yellowtail kingfish, juveniles were exposed to hypoxia (3.0 ± 0.5 mg/L) for 5 days and then returned to normoxia (7.5 ± 0.5 mg/L) for another 5 days. Using tissue sections and high-throughput sequencing technology, we investigated the histological, microecological, transcriptomic, and physiological adaptation mechanisms of yellowtail kingfish. The results showed that hypoxia increased the gill lamellae length and spacing, which were reversible post-reoxygenation. At the genus level, the relative abundances of Prevotella, Bacteroides, Roseburia, and Blautia in the gastrointestinal tract increased under hypoxia and were maintained post-reoxygenation. The liver transcriptome revealed that, compared with normoxia group, the different expression genes (DEGs) were mainly enriched in Steroid biosynthesis and PPAR signaling pathways in hypoxia group. Compared with normoxia group, the DEGs were mainly enriched in Ribosome biogenesis in eukaryotes, Steroid biosynthesis, Fatty acid biosynthesis, and PPAR signaling pathways in reoxygenation group. Furthermore, compared with hypoxia group, the DEGs were mainly enriched in Ribosome biogenesis in eukaryotes and Ribosome pathways in reoxygenation group. In contrast to normoxia, of the key genes of the PPAR signaling pathway, FABP4 was significantly downregulated, and SCD-1 and FATP were significantly upregulated. These findings indicated reduced lipid deposition and increased lipid decomposition in liver under hypoxia. The genes including PPARα, SCD-1, ANGPTL4, and FASN were significantly upregulated in lipid metabolism-related pathways, which indicated that lipid metabolism activity was more vigorous during reoxygenation. In contrast to the hypoxia group, almost all of the genes involved in Ribosome biogenesis in eukaryotes and Ribosome pathways for protein processing were significantly upregulated during reoxygenation; this is probably related to the clearance of misfolded proteins and the folding of the new proteins repairing there is damage to the body. The present results shed light on the possible synergetic function of lipid metabolism, protein repairment and synthesis, and gastrointestinal microbiota in resistance and homeostasis maintenance of yellowtail kingfish coping with hypoxic stress in aquaculture.</p

Comparison of the Watson formula and bioimpedance spectroscopy for measuring body volume and calculating kt/V in patients with peritoneal dialysis

Background: Ascertaining the total body water (V), usually obtained by the Watson formula or bioimpedance spectroscopy (BIS), is crucial for the calculation of Kt/V in patients with peritoneal dialysis (PD). The aim of our study was to compare two different methods of determining V and explore which one is suitable for clinical application. Methods: This was a retrospective observational study. V was determined using the Watson formula (Vwat) and BIS (Vbis). The differences between Vbis and Vwat and between Kt/Vbis and Kt/Vwat were assessed. The patients were allocated to different groups according to the Kt/Vwat and Kt/Vbis values. Clinical parameters were compared between these groups to investigate which method of obtaining the Kt/V value was more suitable. Results: 150 patients on PD were included. Vwat was significantly higher than Vbis, apart from in female patients with volume overload. Consequently, weekly Kt/Vwat was lower than Kt/Vbis in these patients. A significant negative correlation between mean Vwat-Vbis and overhydration values was also found. Moreover, through uniform manifold approximation and projection analysis, a clustering tendency between patients in the adequate group with both Kt/Vwat and Kt/Vbis > =1.7 and patients in the inconsistent group with Kt/Vwat  =1.7 was identified, suggesting that their clinical features were similar. There were significant differences between Vwat and Vbis and between Kt/Vwat and Kt/Vbis. Kt/Vwat may underestimate small-solute dialysis adequacy in most cases. Kt/Vbis instead of Kt/Vwat could be accounted for in creating individualized dialysis prescriptions if the patient has no obvious clinical symptoms.</p