Residence of cancer-propagating cells (CPCs) within preferential microenvironmental niches has a major part in evading therapy. However, the nature of niches involved and the mechanisms protecting CPCs remain largely unknown. We addressed these issues in mouse transplantation models of acute lymphoblastic leukemia (ALL). When the engrafted leukemic cells substantially damaged adjacent microenvironment in the bone marrow (BM), after chemotherapy small foci of CPCs were retained, surrounded by sheaths of supporting cells that comprise a protective niche. We investigated patients' BM biopsies and found evidence of a similar process in patients receiving induction therapy. The efficacy of chemotherapy was enhanced by interfering with the niche formation or function. We therefore identified a therapy-induced niche that protects CPCs.
Recently, intriguing new roles for some small nucleolar RNA host genes (SNHGs) in cancer have emerged. In the present study, a panel of SNHGs was profiled to detect aberrantly expressed SNHGs in gastric cancer (GC). The expression of SNHG5 was significantly downregulated in GC and was significantly associated with the formation of a tumor embolus and with the tumor, node and metastasis stage. SNHG5 was a long non-coding RNA, which was a class of non-coding RNA transcripts longer than 200 nucleotides. SNHG5 suppressed GC cell proliferation and metastasis in vitro and in vivo. Furthermore, SNHG5 exerted its function through interacting with MTA2, preventing the translocation of MTA2 from the cytoplasm into the nucleus. SNHG5 overexpression led to significant increases in the acetylation levels of histone H3 and p53, indicating that SNHG5 might affect acetylation by trapping MTA2 in the cytosol, thereby interfering with the formation of the nucleosome remodeling and histone deacetylation complex. This study is the first to demonstrate that SNHG5 is a critical and powerful regulator that is involved in GC progression through trapping MTA2 in the cytosol. These results imply that SNHG5 may be a novel therapeutic target for the treatment of GC.
IntroductionAcquired aplastic anemia (AA), characterized by pancytopenia in peripheral blood (PB) and bone marrow (BM) hypoplasia, is a bone marrow failure syndrome attacked by autologous T cells, such as CD8 ϩ cytotoxic T cells, CD4 ϩ Th1 cells, and Th17 cells, on BM hematopoietic progenitors. [1][2][3][4] Hematopoiesis recovery after successful immunosuppressive treatment provided powerful evidence for the core role of the immune-mediated destruction of hematopoietic progenitor/stem cells. Mechanisms of immunemediated destruction of hematopoiesis include Th1 polarization response conferring immoderate production of inhibitory cytokines such as interferon-␥ (IFN-␥), tumor necrosis factor-␣ (TNF-␣), and interleukin-2 (IL-2), direct toxicity to autologous CD34 ϩ cells by T-cell populations, and Th17 immune response. [4][5][6][7] In that sense, AA is a specific autoimmune disease because of aberrant T-cell immune homeostasis and BM is the main target organ.It is now well established that CD4 ϩ T-cell subpopulations constitutively expressing the surface protein CD25 and the transcription factor FoxP3 are indispensable for the maintenance of immunologic self-tolerance and immunosuppression. [8][9][10][11] There is also accumulating evidence that impaired function of CD4 ϩ CD25 ϩ regulatory T cells (Tregs) has been implicated in the development of several common autoimmune diseases, 8,10 myelodysplastic syndromes, 12 and AA. 13 Until now, the only report of Treg abnormality in AA has shown that the numbers of circulating Tregs decreased in most patients. Meanwhile, almost all patients had low levels of nuclear factor of activated T cells, cytoplasmic 2 (NFAT1/ NFATc2) which could explain decreased FoxP3 expression in Tregs from AA patients. 13 But little is known regarding the function of Tregs in AA.Physiologically, induction of immune tolerance and suppression of autoreactive effector T-cell proliferation were the critical function of CD4 ϩ CD25 ϩ Tregs through cell contact-inhibition mechanisms and/or production of inhibitory cytokine. Furthermore, BM is a reservoir for CD4 ϩ CD25 ϩ Tregs that home to and are retained in BM through the stromal-derived factor-1␣ (SDF-1␣)/ CXCR4 signal. 14 Previous data demonstrated that the only way for Tregs homing to BM was via the SDF-1␣/CXCR4 signal. 14,15 It was believed that CXCR4 was the only receptor of SDF-1␣ for years. However, several reports recently provided evidence that SDF-1␣ also bound to another 7 transmembrane span receptor CXCR7. 16,17 Thus, the role of the SDF-1␣/CXCR4 axis in regulating Treg trafficking between BM and PB becomes more complex. Combined with the fact that BM is the target organ attacked by autoreactive effector T cells leading to hematopoiesis destruction, we hypothesized that Tregs in AA might have impaired homing potential to BM so as to be less efficient to suppress the effector T-cell proliferation and Th1-type cytokine production. We also hypothesized that Tregs in AA had intrinsic deficiencies of immunosuppression for autologous effector T...
Scanning tunneling microscopy ͑STM͒, atomic force microscopy ͑AFM͒, and near-edge x-ray absorption fine structure ͑NEXAFS͒ have been used to study the structure of tetracene films on hydrogen-passivated Si͑001͒. STM imaging of the films with nominal thickness of three monolayers ͑3 ML͒ exhibits the characteristic "herringbone" molecular packing known from the bulk crystalline tetracene, showing standing molecules on the ab plane. The dimensions and orientation of the herringbone lattice indicate a commensurate structural relationship between the lattice and the crystalline substrate. The corresponding AFM images illustrate that at and above the third layer of the films, the islands are anisotropic, in contrast with the submonolayer fractals, with two preferred growth directions appearing orthogonal to each other. The polarization dependent NEXAFS measurements indicate that the average molecular tilting angle with respect to the surface first increases with the film thickness up to 3 ML, then stabilizes at a value close to the bulk tetracene case afterwards. The combined results indicate a distinct growth morphological change that occurs around a few monolayers of thickness.
Reprogramming human adult blood mononuclear cells (MNCs) cells by transient plasmid expression is becoming increasingly popular as an attractive method for generating induced pluripotent stem (iPS) cells without the genomic alteration caused by genome-inserting vectors. However, its efficiency is relatively low with adult MNCs compared with cord blood MNCs and other fetal cells and is highly variable among different adult individuals. We report highly efficient iPS cell derivation under clinically compliant conditions via three major improvements. First, we revised a combination of three EBNA1/OriP episomal vectors expressing five transgenes, which increased reprogramming efficiency by ‡10-50-fold from our previous vectors. Second, human recombinant vitronectin proteins were used as cell culture substrates, alleviating the need for feeder cells or animal-sourced proteins. Finally, we eliminated the previously critical step of manually picking individual iPS cell clones by pooling newly emerged iPS cell colonies. Pooled cultures were then purified based on the presence of the TRA-1-60 pluripotency surface antigen, resulting in the ability to rapidly expand iPS cells for subsequent applications. These new improvements permit a consistent and reliable method to generate human iPS cells with minimal clonal variations from blood MNCs, including previously difficult samples such as those from patients with paroxysmal nocturnal hemoglobinuria. In addition, this method of efficiently generating iPS cells under feeder-free and xeno-free conditions allows for the establishment of clinically compliant iPS cell lines for future therapeutic applications. STEM CELLS
Till now, little is known about the effects of chemotherapy on the immunity of cancer patients and the ideal timing ("window" period) for immunotherapy combined with chemotherapy. In this study, we addressed the immunogenicity of apoptotic ovarian cancer cells induced by paclitaxel and carboplatin, the immunologic aspects in ovarian cancer patients under chemotherapy, and the CTL response when CD8(+) T cells were stimulated with tumor antigen in the "window" period. The immunogenicity of apoptotic ovarian cancer cells was detected first. Then, blood samples from each ovarian cancer patient were obtained before (S(0)) and at days 5-7 (S(1)), days 12-14 (S(2)) and days 25-28 (S(3)) after chemotherapy. The proportions of immunocyte subsets and the function of NK cells were studied. We found that apoptotic ovarian cancer cells elicited a powerful CTL response with antitumor activity in vitro. The proportions of CD3(+) T cells, CD4(+) T cells and the ratio of CD4(+) to CD8(+) cells did not change significantly on S(1), S(2) and S(3), compared to S(0), whereas the percentage of Treg cells decreased remarkably on S(2). The proportions of Th1, Tc1, CD45RO memory T, NKT cells and the ratio of Tc1 to Tc2 cells increased significantly on S(2). IFN-gamma secreting CD8(+) T cells also increased remarkably on S(2), especially when CD8(+) T cells were stimulated with autologous tumor antigen. From our point of view, chemotherapy induces temporary immune reconstitution and augments anti-tumor immune response. It is probable that the "window" period of days 12-14 after chemotherapy provides the best opportunity for immunotherapy.
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