Multiple myeloma (MM) is the second most common hematologic neoplasms and an appropriate in vivo environment for myeloma cells has potential implications for initiation, progression, and metastasis of MM. Exosomes, entities carrying microRNAs (miRNAs) to target locations, participate in the cross-talk between myeloma cells and nonmalignant components of the in vivo environment. This study disclosed the emerging roles of circulating exosome-associated miRNAs in drug resistance (DR) of MM. To this end, the medical records of consecutively hospitalized MM patients, who received novel agents-based therapies, were analyzed. Then, an optimized procedure was established for exosome isolation and exosomal RNA analysis. The exosome-associated miRNA expression patterns for predicting bortezomib (Bz) resistance of MM were further examined using a microarray. In total, 204 patients were enrolled with DR rates of 36.5%, 73.1% and 81.8% in the bortezomib (Bz), thalidomide and lenalidomide containing groups. The serum total light chain ratio ≥ 100, CRP ≥ 20 mg/L, and the second-line usage increased risks of acquired Bz-resistance. Among 68 cases having genetic tests, a high risk factor for predicting de novo DR was 1q21 amplification, which also correlated with lower levels of cholesterol and LDL-C. Moreover, nano-sized exosomes were isolated with significantly increasing internal RNAs and down-regulation of exosomal miR-16-5p, miR-15a-5p and miR-20a-5p, miR-17-5p was revealed in the patients resistant to Bz. The routine workup of MM hardly suggested a value for DR prediction. The circulating exosomes carrying miRNAs provided a window that permits a better understanding of the in vivo intercellular crosstalk in MM patients.

SUMMARYNeuroblasts generate neurons with different functions by asymmetric cell division, cell cycle exit and differentiation. The underlying transcriptional regulatory pathways remain elusive. Here, we performed genetic screens in C. elegans and identified three evolutionarily conserved transcription factors (TFs) essential for Q neuroblast lineage progression. Through live cell imaging and genetic analysis, we showed that the storkhead TF HAM-1 regulates spindle positioning and myosin polarization during asymmetric cell division and that the PAR-1-like kinase PIG-1 is a transcriptional regulatory target of HAM-1. The TEAD TF EGL-44, in a physical association with the zinc-finger TF EGL-46, instructs cell cycle exit after the terminal division. Finally, the Sox domain TF EGL-13 is necessary and sufficient to establish the correct neuronal fate. Genetic analysis further demonstrated that HAM-1, EGL-44/EGL-46 and EGL-13 form three transcriptional regulatory pathways. We have thus identified TFs that function at distinct developmental stages to ensure appropriate neuroblast lineage progression and suggest that their vertebrate homologs might similarly regulate neural development.

Neuronal migration and neurite growth are essential events in neural development, but it remains unclear how guidance cues are transduced through receptors to the actin cytoskeleton, which powers these processes. We report that a cytokinetic scaffold protein, Anillin, is redistributed to the leading edge of the C. elegans Q neuroblast during cell migration and neurite growth. To bypass the requirement for Anillin in cytokinesis, we used the somatic CRISPR-Cas9 technique to generate conditional mutations in Anillin. We demonstrate that Anillin regulates cell migration and growth cone extension by stabilizing the F-actin network at the leading edge. Our biochemical analysis shows that the actin-binding domain of Anillin is sufficient to stabilize F-actin by antagonizing the F-actin severing activity of Cofilin. We further uncover that the active form of RhoG/MIG-2 directly binds to Anillin and recruits it to the leading edge. Our results reveal a novel pathway in which Anillin transduces the RhoG signal to the actin cytoskeleton during neuronal migration and neurite growth.

Independent of their role in apoptosis, cell engulfment proteins are essential for midbody internalization and degradation after cell division.

Autophagy genes are not only essential for exposing the engulfment signal on apoptotic cells but also function in phagocytes to promote apoptotic cell removal.

Background: We compared the effectiveness of self-expanding metal stent alone vs. radioactive stent embedded with 125 I seeds implantation insertion in patients of inoperable esophageal squamous cell cancer combined with malignant esophageal stenosis. Methods: We studied two groups of patients with stenosis attribute to inoperable esophageal squamous cell carcinoma. Group A had placed self-expanding metal stent alone insertion; group B encountered radioactive stent embedded with

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Emerging evidence highlights the role of gut microbiota in regulating the pathogenesis of coronary heart disease. Here, we performed 16S rRNA gene sequencing and UPLC-Q-TOF/MS-based metabolomics to investigate the gut microbiome and metabolomes of cecal contents in the isoproterenol (ISO)-induced acute myocardial ischemia (AMI) rats. As expected, considerable gut microbiota alterations were observed in the AMI rats compared with the control rats, paralleling with intestinal inflammation and apoptosis. At phylum level, the abundance of Firmicutes was significantly decreased, whereas the abundance of Bacteroidetes and Spirochaetae was strikingly enriched in the AMI group. At genus level, the significant alteration of genera Treponema 2 , Rikenellaceae RC9 gut group , Prevotellaceae UCG-003 , and Bacteroides may contribute to the pathogenesis of AMI. These altered microbiota might influence the intestinal permeability and subsequently impair intestinal barrier and stimulate gut inflammation. Consistently, significantly metabolic differences of cecal contents between the AMI and control groups were revealed, and threonic acid, L-urobilin and L-urobilinogen were considered the most associated cecal metabolites with AMI. These strikingly altered metabolites were mainly related to energy metabolism and oxidative stress which could lead to apoptosis and further affect gut barrier. Ultimately, we revealed the potential link of these altered gut microbiota/metabolomes and intestinal inflammatory factors and apoptotic proteins and further confirmed their intimate connections with intestinal inflammation and gut barrier. Our findings depict uncovered potential relationship among the gut microbiome, cecal metabolomes and AMI.