In silico evidence of high frequency of miRNA-related SNPs in Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) is the dominant histological type of esophageal cancer significantly reported in developing nations. There is an increasing evidence suggesting that single nucleotide polymorphisms (SNPs) in the untranslated regions of genes (3′-UTRs) targeted by microRNAs (miRNAs) can change the target gene's expression and thereby affect the individual's cancer risk. Thus, in support of the role of SNPs occurring in miRNA target sites (miR-TS-SNPs) in the cancer, we analyzed the next generation sequencing data of 10 ESCC patients. In each patient, about 3,000 SNPs in 3′-UTRs were obtained in their whole-exome sequencing profiles. We applied two separate methods, manual and computational in silico approaches, to predict the miR-TS-SNPs with more effects on the miRNA–target interactions. dbSNP, 1000G, ExAC, Iranome, miRandb, miRCancer, TargetScan, Human, miRNASNP2 and miRBase databases were used for positive selection of miR-TS-SNPs and DIANA-miRPath v3.0 for pathway analysis. We identified six rare germline miR-TS-SNPs and two other ones with unknown miR-TS-SNPs. We interestingly observed all of these variants in only one patient, which can be evidence of the relationship between miR-TS-SNPs and cancer incidence. The study of cancer genetics including miR-TS-SNPs reveals miRNAs and their related pathways, which will be greatly useful in cancer research from noninvasive biomarkers to new treatments.     

Spontaneous Immunity Against the Receptor Tyrosine Kinase ROR1 in Patients with Chronic Lymphocytic Leukemia

Background

ROR1 is a receptor tyrosine kinase expressed in chronic lymphocytic leukemia (CLL) and several other malignancies but absent in most adult normal tissues. ROR1 is considered an onco-fetal antigen. In the present study we analysed spontaneous humoral and cellular immunity against ROR1 in CLL patients.

Materials and Methods

Antibodies against ROR1 were analysed in 23 patients and 20 healthy donors by ELISA and Western blot. Purified serum IgG from patients was tested for cytotoxicity against CLL cells using the MTT viability assay. A cellular immune response against ROR1 derived HLA-A2 restricted 9 aa and 16 aa long peptides were analysed using peptide loaded dendritic cells co-cultured with autologous T cells from CLL patients (n = 9) and healthy donors (n = 6). IFN-γ, IL-5 and IL-17A-secreting T cells were assessed by ELISPOT and a proliferative response using a H3-thymidine incorporation assay.

Results

The majority of CLL patients had antibodies against ROR1. Significantly higher titers of anti-ROR1 antibodies were noted in patients with non-progressive as compared to progressive disease. The extracellular membrane-close ROR1 KNG domain seemed to be an immunodominant epitope. Ten patients with high titers of anti-ROR1 binding antibodies were tested for cytotoxicity. Five of those had cytotoxic anti-ROR1 antibodies against CLL cells. ROR1-specific IFN-γ and IL-17A producing T cells could be detected in CLL patients, preferentially in non-progressive as compared to patients with progressive disease (p<0.05).

Conclusion

ROR1 seemed to spontaneously induce a humoral as well as a T cell response in CLL patients. The data support the notion that ROR1 might be a specific neo-antigen and may serve as a target for immunotherapy.     

Modeling the adsorptive selectivity of carbon nanotubes for effective separation of CO2/N2 mixtures

Canonical Monte Carlo (CMC) simulations were carried out to investigate the behavior of CO₂ and N₂ mixtures upon adsorption on single walled carbon nanotubes (CNTs). In the simulation, all the particle–particle interactions between CO₂, N and C were modeled using Lennard-Jones (LJ) potential. To provide deep insight into the effect of pore width, temperature, pressure and bulk composition on the adsorption behavior of CO₂ /N₂ mixtures, five different CNTs [(6,6), (7,7), (8,8) (9,9) and (10,10) CNT] with diameters ranging from 0.807 to 1.35 nm, three temperatures (300 323 and 343 K), six pressures (0.15, 2, 4, 6, 8 and 10 MPa), and three bulk mole compositions of carbon dioxide (0.3 0.5 and 0.7) were tested. The results from all the simulation conditions investigated in this work show that CNTs preferentially adsorb carbon dioxide relative to nitrogen in a binary mixture. The results are consistent with the hypothesis that stronger interaction of one component with the nanotube surface results in a higher adsorption capacity compared to the other component. An optimized pore size of D = 8.07 nm corresponding to (6, 6) CNT, at T = 300 K and P = 0.15 MPa at a bulk mole composition of y_CO2 =0.3 was identified in which carbon nanotubes demonstrate the greatest selectivity for separation of carbon dioxide relative to nitrogen. In addition, it is worth pointing out that, under similar simulation conditions, CNTs exhibit higher selectivity compared to other carbon-based materials [carbon membrane polyimide (PI) and PI/multi-wall carbon nanotubes (MWCNTs)] for CO₂ adsorption. As a prototype, the selectivity of an equimolar mixture of CO₂ /N₂ for adsorption on (6, 6) CNTs at 300 K and 0.15 MPa reaches 9.68, which is considerably larger than that reported in carbon membrane. Therefore, it can be concluded that carbon nanotubes can act as a capable adsorbent for adsorption/desorption of CO₂ in comparison with other carbon-based materials in the literature.     

The adult mouse and human pancreas contain rare multipotent stem cells that express insulin

The search for putative precursor cells within the pancreas has been the focus of extensive research. Previously, we identified rare pancreas-derived multipotent precursor (PMP) cells in the mouse with the intriguing capacity to generate progeny in the pancreatic and neural lineages. Here, we establish the embryonic pancreas as the developmental source of PMPs through lineage-labeling experiments. We also show that PMPs express insulin and can contribute to multiple pancreatic and neural cell types in vivo. In addition, we have isolated PMPs from adult human islet tissue that are also capable of extensive proliferation, self-renewal, and generation of multiple differentiated pancreatic and neural cell types. Finally, both mouse and human PMP-derived cells ameliorated diabetes in transplanted mice. These findings demonstrate that the adult mammalian pancreas contains a population of insulin(+) multipotent stem cells and suggest that these cells may provide a promising line of investigation toward potential therapeutic benefit.     

Mitogen-activated protein kinase phosphorylates and targets inducible cAMP early repressor to ubiquitin-mediated destruction

Inducible cAMP early repressor (ICER) is an important mediator of cAMP antiproliferative activity that acts as a putative tumor suppressor gene product. In this study, we examined the regulation of ICER protein by phosphorylation and ubiquitination in human choriocarcinoma JEG-3 and mouse pituitary AtT20 cells. We found that cAMP stabilized ICER protein by inhibiting the mitogen-activated protein kinase (MAPK) cascade. Activation of the MAPK pathway increased ICER phosphorylation. ICER phosphorylation was abrogated by inhibition of the MAPK pathway either by cAMP or directly by the MAPK inhibitor PD098059. The MAPKs extracellular signal-regulated kinases 1 and 2 physically interact with ICER and mediated the phosphorylation of ICER on a critical serine residue (Ser-41). A mutant form of ICER in which Ser-41 was substituted by alanine had a half-life 4-5 h longer than its wild-type counterpart. This alteration in stability was due to the inability of the Ser-41-mutant ICER to be efficiently ubiquitinated and degraded via the ubiquitin-proteasome pathway. These results present a novel cell signaling cross-talk mechanism at the cell nucleus between the MAPK and cAMP pathways, whereby MAPK targets a repressor of the cAMP-dependent gene expression for ubiquitination and proteasomal degradation.     

Dentin regeneration based on tooth tissue engineering: A review

Missing or damaged teeth due to caries, genetic disorders, oral cancer, or infection may contribute to physical and mental impairment that reduces the quality of life. Despite major progress in dental tissue repair and those replacing missing teeth with prostheses, clinical treatments are not yet entirely satisfactory, as they do not regenerate tissues with natural teeth features. Therefore, much of the focus has centered on tissue engineering (TE) based on dental stem/progenitor cells to create bioengineered dental tissues. Many in vitro and in vivo studies have shown the use of cells in regenerating sections of a tooth or a whole tooth. Tooth tissue engineering (TTE), as a promising method for dental tissue regeneration, can form durable biological substitutes for soft and mineralized dental tissues. The cell-based TE approach, which directly seeds cells and bioactive components onto the biodegradable scaffolds, is currently the most potential method. Three essential components of this strategy are cells, scaffolds, and growth factors (GFs). This study investigates dentin regeneration after an injury such as caries using TE and stem/progenitor cell-based strategies. We begin by discussing about the biological structure of a dentin and dentinogenesis. The engineering of teeth requires knowledge of the processes that underlie the growth of an organ or tissue. Then, the three fundamental requirements for dentin regeneration, namely cell sources, GFs, and scaffolds are covered in the current study, which may ultimately lead to new insights in this field.     

Aqua mediated synthesis of substituted 2-amino-4H-chromenes catalyzed by green and reusable Preyssler heteropolyacid

A simple, clean and environmentally benign route to the synthesis of 2-amino-4H-chromenes is described using Preyssler type heteropolyacid, H(14)[NaP(5)W(30)O(110)], as a green and reusable catalyst in water. The products were obtained in very good yields.