Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment ...remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.
We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in ...such patients.
In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes.
The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval CI, 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.
LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.).
MicroRNAs have been shown to play an important role in normal hematopoisis and leukemogenesis. Here, we report function and mechanisms of miR-181 family in myeloid differentiation and acute myeloid ...leukemia (AML). The aberrant overexpression of all the miR-181 family members (miR-181a/b/c/d) was detected in French-American-British M1, M2 and M3 subtypes of adult AML patients. By conducting gain- and loss-of-function experiments, we demonstrated that miR-181a inhibits granulocytic and macrophage-like differentiation of HL-60 cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) by directly targeting and downregulating the expression of PRKCD (which then affected the PRKCD-P38-C/EBPα pathway), CTDSPL (which then affected the phosphorylation of retinoblastoma protein) and CAMKK1. The three genes were also demonstrated to be the targets of miR-181b, miR-181c and miR-181d, respectively. Significantly decreases in the expression levels of the target proteins were detected in AML patients. Inhibition of the expression of miR-181 family members owing to Lenti-miRZip-181a infection in bone marrow blasts of AML patients increased target protein expression levels and partially reversed myeloid differentiation blockage. In the mice implanted with AML CD34+ HSPCs, expression inhibition of the miR-181 family by Lenti-miRZip-181a injection improved myeloid differentiation, inhibited engraftment and infiltration of the leukemic CD34+ cells into the bone marrow and spleen, and released leukemic symptoms. In conclusion, our findings revealed new mechanism of miR-181 family in normal hematopoiesis and AML development, and suggested that expression inhibition of the miR-181 family could provide a new strategy for AML therapy.
This study aimed to explore the role of alanine aminotransferase (ALT) in the effects of urinary caffeine and its primary metabolites on cognitive function in elderly people.
In this investigation, ...we meticulously curated a cohort from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) database. Animal fluency emerged as the pivotal metric for assessing cognitive function within our study population. In order to navigate the intricacies of mixture analysis and circumvent potential complexities, we harnessed the power of Bayesian kernel machine regression (BKMR) models. This method allowed us to dissect the nuanced impacts of caffeine and its primary urinary metabolites on cognitive function. While accounting for caffeine and its metabolites, we analyzed the relationship between ALT and cognitive function through non-linear dynamics. Lastly, employing structural equation modeling, we probed the intriguing question of whether ALT mediates the influence of 3,7-dimethylxanthine on cognitive function. This comprehensive approach has unveiled a deeper understanding of the multifaceted interplay among these variables, offering invaluable insights into the determinants of cognitive function within our cohort.
After meticulous adjustment for various covariates, our linear regression analysis unveiled a noteworthy finding: 3,7-dimethylxanthine demonstrated a significant positive correlation with cognitive function (p < 0.05). Importantly, within the BKMR model employed, 3,7-dimethylxanthine emerged as the most influential factor within the compound, with posterior inclusion probabilities of 0.995 and 0.939. Furthermore, our single-exposure effect model confirmed its presence at the 25th, 50th, and 75th percentile concentrations of other components within the compound. Interestingly, bivariate concentration curves indicated no interaction within the compound, underscoring the prominent impact of 3,7-dimethylxanthine on cognitive function. Subsequently, through a test of Restricted Cubic Splines (RCS), we revealed a non-linear relationship between ALT and cognitive function at the 10th, 50th, and 90th percentiles (p < 0.05), indicating a heightened risk of diminished cognitive function in the low ALT group. Employing structural equation modeling, we meticulously examined the mediating role of ALT in relation to 3,7-dimethylxanthine and cognitive function. However, our study results did not yield significant evidence of a mediating effect. This comprehensive analysis elucidates the intricate interplay between these variables, unveiling the subtle mechanisms governing cognitive function.
In this study, a noteworthy positive correlation was observed between 3,7-dimethylxanthine and cognitive function. Additionally, a non-linear relationship was identified between ALT and cognitive function, with lower levels of ALT associated with a decline in cognitive function. The RCS trend suggested that higher levels of ALT may similarly lead to diminished cognitive performance. However, in our pursuit to ascertain potential mediation, we regrettably found no significant evidence supporting mediation among these factors involving ALT. This underscores the need for more comprehensive investigations and expanded clinical explorations into the intricate associations among these three pivotal elements.
We report the extraordinary toughness, hysteresis, self-recovery, and persistent fatigue resistance of an anisotropic hydrogel with single-domain lamellar structure, consisting of periodical stacking ...of several thousands of rigid, hydrophobic bilayers in the ductile, hydrophilic polymer matrix. The stratified lamellar bilayers not only diffract light to exhibit magnificent structural color but also serve as reversible sacrificial bonds that dissociate upon deformation, exhibiting large hysteresis as an energy dissipation mechanism. Both the molecular dissociation and lipid-like mobile nature of bilayers dramatically enhance the resistance to crack propagation by suppressing the stress concentration at the crack tip with the formation of extraordinary crack blunting. This unique toughening phenomenon could allow deep insight into the toughening mechanism of the hydrogel-like soft materials such as biological soft tissues.
The thermoelectric performance of materials relies substantially on the band structures that determine the electronic and phononic transports, while the transport behaviors compete and counter-act ...for the power factor PF and figure-of-merit ZT. These issues make a full-scale computation of the whole set of thermoelectric parameters particularly attractive, while a calculation scheme of the electronic and phononic contributions to thermal conductivity remains yet challenging. In this work, we present a full-scale computation scheme based on the first-principles calculations by choosing a set of doped half-Heusler compounds as examples for illustration. The electronic structure is computed using the WIEN2k code and the carrier relaxation times for electrons and holes are calculated using the Bardeen and Shockley's deformation potential (DP) theory. The finite-temperature electronic transport is evaluated within the framework of Boltzmann transport theory. In sequence, the density functional perturbation combined with the quasi-harmonic approximation and the Klemens' equation is implemented for calculating the lattice thermal conductivity of carrier-doped thermoelectric materials such as Ti-doped NbFeSb compounds without losing a generality. The calculated results show good agreement with experimental data. The present methodology represents an effective and powerful approach to calculate the whole set of thermoelectric properties for thermoelectric materials.
Wolbachia influence the fitness of their invertebrate hosts. They have effects on reproductive incompatibility and egg production. Although the former are well characterized, the mechanistic basis of ...the latter is unclear. Here, we investigate whether apoptosis, which has been implicated in fecundity in model insects, influences the interaction between fecundity and Wolbachia in the planthopper Laodelphax striatellus. Wolbachia‐infected females produced about 30% more eggs than uninfected females. We used the terminal deoxyribonucleotidyl transferase (TDT)‐mediated dUTP‐digoxigenin nick end labeling staining to visualize apoptosis. Microscopic observations indicated that the Wolbachia strain wStri increased the number of ovarioles that contained apoptotic nurse cells in both young and aged adult females. The frequency of apoptosis was much higher in the infected females. The increased fecundity appeared to be a result of apoptosis of nurse cells, which provide nutrients to the growing oocytes. In addition, cell apoptosis inhibition by caspase messenger RNA interference in Wolbachia‐infected L. striatellus markedly decreased egg numbers. Together, these data suggest that wStri might enhance fecundity by increasing the number of apoptotic cells in the ovaries in a caspase‐dependent manner. Our findings establish a link between Wolbachia‐induced apoptosis and egg production effects mediated by Wolbachia, although the way in which the endosymbiont influences caspase levels remains to be determined.
The energy loss functions (ELFs) of Fe and Ni have been derived from measured reflection electron energy loss spectroscopy (REELS) spectra by a reverse Monte Carlo analysis in our previous work. In ...this work, we present further improvements of ELFs for these metals. For Fe, we have updated ELFs at primary electron energies of 2 keV and 3 keV in a wider photon energy region (0-180 eV) with a better accuracy, which is verified by sum rules. Regarding to Ni, we supplement the ELF at primary energy of 5 keV and we also improve the data accuracy at 3 keV. Applying these new and more accurate ELFs we present the optical constants and dielectric functions for the two metals. The improvements were highlighted by comparing our present results with the previous data.
Metastasis is responsible for the rapid recurrence and poor survival of malignancies. Epithelial-mesenchymal transition (EMT) has a critical role in metastasis. Increasing evidence indicates that EMT ...can be regulated by microRNAs (miRNAs). miR-148a is a liver-abundant miRNA. However, the role of miR-148a in the development of liver cancer remains largely unknown. In this study, we found that, compared with normal livers, miR-148a was significantly decreased in hepatocellular carcinoma (HCC) tissues, especially in those with the portal vein tumor thrombus. An in vitro transwell assay and an in vivo orthotopic liver xenograft model showed that the restoration of miR-148a expression significantly repressed the migration and pulmonary metastasis of hepatoma cells. Linear regression analysis revealed a positive correlation between the expression of miR-148a and the mRNA level of E-cadherin gene in human HCC tissues. Both gain- and loss-of-function studies disclosed that miR-148a promoted the expression of epithelial marker (E-cadherin) and reduced the levels of mesenchymal markers (N-cadherin, fibronectin or vimentin) in hepatoma cells. These data suggest that miR-148a may suppress EMT and cancer metastasis. Further mechanistic investigations showed that miR-148a directly inhibited Met expression by binding to its 3'-UTR. Moreover, the reintroduction of miR-148a attenuated the downstream signaling of Met, like activated phosphorylation of AKT-Ser473 and inhibitory phosphorylation of GSK-3β-Ser9, and consequently reduced the nuclear accumulation of Snail, a transcription factor that promotes EMT. Taken together, miR-148a may negatively regulate Met/Snail signaling and therefore inhibit the EMT and metastasis of hepatoma cells. These findings highlight the significance of miR-148a downregulation in tumor progression and implicate miR-148a as an attractive candidate for cancer therapy.
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