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Showing 100 Latest Publications
TitleDate Created
Evaluation of Somatosensory Evoked Potential and Pain Rating Index in a Patient with Spinal Cord Injury Accepted Cell Therapy.Thursday, May 26, 2016
Hua R, Li P, Wang X, Yang J, Zheng P, Niu X, Li Y, An Y,
Pain physician. May-2016
Spinal cord, neuropathic pain, somatosensory evoked potential, umbilical cord mesenchymal stem cells.
Eicosapentaenoic acid attenuates dexamethasome-induced apoptosis by inducing adaptive autophagy via GPR120 in murine bone marrow-derived mesenchymal stem cells.Thursday, May 26, 2016
Gao B, Han YH, Wang L, Lin YJ, Sun Z, Lu WG, Hu YQ, Li JQ, Lin XS, Liu BH, Jie Q, Yang L, Luo ZJ,
Cell death & disease. 27-5-2016
Long-term use of glucocorticoids is a widespread clinical problem, which currently has no effective solution other than discontinuing the use. Eicosapentaenoic acid (EPA), an omega-3 long chain polyunsaturated fatty acid (n-3 PUFA), which is largely contained in fish or fish oil, has been reported to promote cell viability and improve bone metabolism. However, little is known about the effects of EPA on dexamethasome (Dex)-induced cell apoptosis. In this study, we showed that EPA-induced autophagy of murine bone marrow-derived mesenchymal stem cells (mBMMSCs). Meanwhile, EPA, but not arachidonic acid (AA), markedly inhibited Dex-induced apoptosis and promoted the viability of mBMMSCs. We also observed that EPA-induced autophagy was modulated by GPR120, but not GPR40. Further experiments showed that the mechanism of EPA-induced autophagy associated with GPR120 modulation involved an increase in the active form of AMP-activated protein kinase and a decrease in the activity of mammalian target of RAPA. The protective effect of EPA on Dex-induced apoptosis via GPR120-meditated induction of adaptive autophagy was supported by in vivo experiments. In summary, our findings may have important implications in developing future strategies to use EPA in the prevention and therapy of the side effects induced by long-term Dex-abuse.
Biologics and Cell Therapy Tissue Engineering Approaches for the Management of the Edentulous Maxilla: A Systematic Review.Thursday, May 26, 2016
Avila-Ortiz G, Bartold PM, Giannobile W, Katagiri W, Nares S, Rios H, Spagnoli D, Wikesjö UM,
The International journal of oral & maxillofacial implants. 26-5-2016
Clinical success has been demonstrated with the application of different TERM modalities for implant site development in the edentulous atrophic maxilla. However, indications are narrow and further study is needed. Clinical trials assessing meaningful outcomes, involving larger populations, and with longer follow-up are warranted to discern the effectiveness of the achieved results compared with a valid control.
Banking Umbilical Cord Blood (UCB) Stem Cells: Awareness, Attitude and Expectations of Potential Donors from One of the Largest Potential Repository (India).Thursday, May 26, 2016
Pandey D, Kaur S, Kamath A,
PloS one. 27-5-2016
Obstetricians should play a more active role in explaining the patients regarding pros and cons of UCB banking.
The Effect of Combined Pulsed Wave Low-Level Laser Therapy and Human Bone Marrow Mesenchymal Stem Cell-Conditioned Medium on Open Skin Wound Healing in Diabetic Rats.Thursday, May 26, 2016
Pouriran R, Piryaei A, Mostafavinia A, Zandpazandi S, Hendudari F, Amini A, Bayat M,
Photomedicine and laser surgery. 26-May-2016
It was magnificently attained that PWLLLT significantly accelerated the wound healing process in the experimental model for STZ-induced type I DM rats.
Comparison between Stromal Vascular Fraction and Adipose Mesenchymal Stem Cells in Remodeling Hypertrophic Scars.Thursday, May 26, 2016
Domergue S, Bony C, Maumus M, Toupet K, Frouin E, Rigau V, Vozenin MC, Magalon G, Jorgensen C, Noël D,
PloS one. 26-5-2016
Hypertrophic scars (HTS) are characterized by excessive amount of collagen deposition and principally occur following burn injuries or surgeries. In absence of effective treatments, the use of mesenchymal stem/stromal cells, which have been shown to attenuate fibrosis in various applications, seems of interest. The objectives of the present study were therefore to evaluate the effect of human adipose tissue-derived mesenchymal stem cells (hASC) on a pre-existing HTS in a humanized skin graft model in Nude mice and to compare the efficacy of hASCs versus stromal vascular fraction (SVF). We found that injection of SVF or hASCs resulted in an attenuation of HTS as noticed after clinical evaluation of skin thickness, which was associated with lower total collagen contents in the skins of treated mice and a reduced dermis thickness after histological analysis. Although both SVF and hASCs were able to significantly reduce the clinical and histological parameters of HTS, hASCs appeared to be more efficient than SVF. The therapeutic effect of hASCs was attributed to higher expression of TGFβ3 and HGF, which are important anti-fibrotic mediators, and to higher levels of MMP-2 and MMP-2/TIMP-2 ratio, which reflect the remodelling activity responsible for fibrosis resorption. These results demonstrated the therapeutic potential of hASCs for clinical applications of hypertrophic scarring.
Stem/Progenitor Cells in Liver Regeneration.Thursday, May 26, 2016
Itoh T,
Hepatology (Baltimore, Md.). 26-May-2016
In severely or chronically injured livers where the proliferative capacity of hepatocytes is compromised, putative stem/progenitor cells are supposed to be activated. These cells are generally characterized as biliary epithelial cell marker-positive cells that emerge ectopically in the parenchymal region of the liver, as determined by histo-pathological examination of various liver diseases in humans and animal models. Whereas the biliary system indeed harbors cells with stem/progenitor activity that can be defined ex vivo, genetic lineage tracing studies in mice have casted doubt on their exact contribution as the genuine stem/progenitor cell population that differentiates in situ into hepatocytes. Here, I briefly review recent advances in the characterization and certification of the stem/progenitor cells in the adult liver and discuss the on-going and future challenges to further our understanding of the cellular basis of liver regeneration. This article is protected by copyright. All rights reserved.
Lack of Phenotypical and Morphological Evidences of Endothelial to Hematopoietic Transition in the Murine Embryonic Head during Hematopoietic Stem Cell Emergence.Thursday, May 26, 2016
Iizuka K, Yokomizo T, Watanabe N, Tanaka Y, Osato M, Takaku T, Komatsu N,
PloS one. 26-5-2016
During mouse ontogeny, hematopoietic cells arise from specialized endothelial cells, i.e., the hemogenic endothelium, and form clusters in the lumen of arterial vessels. Hemogenic endothelial cells have been observed in several embryonic tissues, such as the dorsal aorta, the placenta and the yolk sac. Recent work suggests that the mouse embryonic head also produces hematopoietic stem cells (HSCs)/progenitors. However, a histological basis for HSC generation in the head has not yet been determined because the hematopoietic clusters and hemogenic endothelium in the head region have not been well characterized. In this study, we used whole-mount immunostaining and 3D confocal reconstruction techniques to analyze both c-Kit+ hematopoietic clusters and Runx1+ hemogenic endothelium in the whole-head vasculature. The number of c-Kit+ hematopoietic cells was 20-fold less in the head arteries than in the dorsal aorta. In addition, apparent nascent hematopoietic cells, which are characterized by a "budding" structure and a Runx1+ hemogenic endothelium, were not observed in the head. These results suggest that head HSCs may not be or are rarely generated from the endothelium in the same manner as aortic HSCs.
Deferoxamine released from PLGA promotes healing of osteoporotic bone defect via enhanced angiogenesis and osteogenesis.Thursday, May 26, 2016
Jia P, Chen H, Kang H, Qi J, Zhao P, Jiang M, Guo L, Zhou Q, Qian ND, Bing Zhou H, Xu YJ, Deng LF,
Journal of biomedical materials research. Part A. 26-May-2016
The regeneration capacity of osteoporotic bones is generally lower than that of normal bones. Current methods of osteoporotic bone defect treatment are not always satisfactory. Recent studies demonstrate that activation of the hypoxia inducible factor-1α (HIF-1α) pathway, by genetic methods or hypoxia-mimicking agents, could accelerate bone regeneration. However, little is known as to whether modulating the HIF-1α pathway promotes osteoporotic defect healing. To address this problem in the present study, we first demonstrated that HIF-1α and vascular endothelial growth factor (VEGF) expression levels are lower in osteoporotic bones than in normal bones. Second, we loaded poly(Lactic-co-glycolic acid) (PLGA) with the hypoxia-mimetic agent deferoxamine (DFO). Deferoxamine released from PLGA had no significant effect on the proliferation of mesenchymal stem cells (MSCs);however, DFO did enhance the osteogenic differentiation of MSCs. In addition, DFO upregulated the mRNA expression levels of angiogenic factors in MSCs. Endothelial tubule formation assays demonstrate that DFO promoted angiogenesis in human umbilical vein endothelial cells (HUVEC). Third, untreated PLGA scaffolds (PLGA group) or DFO-containing PLGA (PLGA+DFO group) were implanted into critically sized osteoporotic femur defects in ovariectomized (OVX) rats. After treatment periods of 14 or 28 days, micro-CT, histological, CD31 immunohistochemical, and dynamic bone histomorphometric analyses showed that DFO dramatically stimulated bone formation and angiogenesis in a critically sized osteoporotic femur defect model. Our in vitro and in vivo results demonstrate that DFO may promote the healing of osteoporotic bone defects due to enhanced angiogenesis and osteogenesis. This article is protected by copyright. All rights reserved.
Mechanoresponsiveness of human umbilical cord mesenchymal stem cells in invitro chondrogenesis- a comparative study with growth factor induction.Thursday, May 26, 2016
N S R, Nair PD,
Journal of biomedical materials research. Part A. 26-May-2016
Fetal derived mesenchymal stem cells especially human umbilical cord matrix mesenchymal stem cells (hUCMSCs), with their ease of availability, pluripotency and high expansion potential have emerged as an alternative solution for stem cell based cartilage therapies. An attempt to elucidate the effect of dynamic mechanical compression in modulating the chondrogenic differentiation of hUCMSCs is done in this study to add on to the knowledge of optimizing chondrogenic signals necessary for the effective differentiation of these stem cells and subsequent integration to the surrounding tissues. hUCMSCs were seeded in porous Poly (vinyl alcohol)-Poly (caprolactone) (PVA-PCL) scaffolds and cultured in chondrogenic medium with/without TGF-β3 and were subjected to a dynamic compression of 10% strain, 1Hz for 1/4h for 7 days. The results on various analysis shows that the extent of dynamic compression is an important factor affecting cell viability. Mechanical stimulation in the form of dynamic compression stimulates expression of chondrogenic genes even in the absence of chondrogenic growth factors and also augments growth factor induced chondrogenic potential of hUCMSC. This article is protected by copyright. All rights reserved.
Growth-Factor Nanocapsules That Enable Tunable Controlled Release for Bone Regeneration.Thursday, May 26, 2016
Tian H, Du J, Wen J, Liu Y, Montgomery SR, Scott TP, Aghdasi B, Xiong C, Suzuki A, Hayashi T, Ruangchainikom M, Phan K, Weintraub G, Raed A, Murray SS, Daubs MD, Yang X, Yuan XB, Wang JC, Lu Y,
ACS nano. 26-May-2016
Growth factors are of great potential in regenerative medicine. However, the short half-lives of growth factors in vivo and a strict requirement of their therapeutic window make their use in clinical settings challenging. Thus, sophisticated drug delivery systems that protect the growth factor from degradation and enable controlled delivery are required for the successful translation of growth factors as viable clinical therapies in regenerative medicine. In this research, a nanoscale controlled release system (degradable protein nanocapsule) is established via in-situ polymerization on growth factor. Engineering the surface polymer composition readily adjusts the release rate. Improved therapeutic outcomes can be achieved with growth factor nanocapsules, as illustrated in spinal cord fusion mediated by bone morphogenetic protein-2 (BMP-2) nanocapsules.
Roughness gradients on zirconia for rapid screening of cell-surface interactions: Fabrication, characterization and application.Thursday, May 26, 2016
Flamant Q, Stanciuc AM, Pavailler H, Martin Sprecher C, Alini M, Peroglio M, Anglada M,
Journal of biomedical materials research. Part A. 26-May-2016
Roughness is one of the key parameters for successful osseointegration of dental implants. The understanding of how roughness affects cell response is thus crucial to improve implant performance. Surface gradients, which allow rapid and systematic investigations of cell-surface interactions, have the potential to facilitate this task. In this study, a novel method aiming to produce roughness gradients at the surface of zirconia using hydrofluoric acid etching was implemented. The topography was exhaustively characterized at the micro- and nano-scale by white light interferometry and atomic force microscopy, including the analysis of amplitude, spatial, hybrid, functional and fractal parameters. A rapid screening of the influence of roughness on human mesenchymal stem cell morphology was conducted and potential correlations between roughness parameters and cell morphology were investigated. The roughness gradient induced significant changes in cell area (p<0.001), aspect ratio (p=0.01) and solidity (p=0.026). Nano-roughness parameters were linearly correlated to cell solidity (p<0.005), while micro-roughness parameters appeared non-linearly correlated to cell area, highlighting the importance of multiscale optimization of implant topography to induce the desired cell response. The gradient method proposed here drastically reduces the efforts and resources necessary to study cell-surface interactions and provides results directly transferable to industry. This article is protected by copyright. All rights reserved.
Leukemia Inhibitory Factor Enhances Endogenous Cardiomyocyte Regeneration after Myocardial Infarction.Thursday, May 26, 2016
Kanda M, Nagai T, Takahashi T, Liu ML, Kondou N, Naito AT, Akazawa H, Sashida G, Iwama A, Komuro I, Kobayashi Y,
PloS one. 26-5-2016
Cardiac stem cells or precursor cells regenerate cardiomyocytes; however, the mechanism underlying this effect remains unclear. We generated CreLacZ mice in which more than 99.9% of the cardiomyocytes in the left ventricular field were positive for 5-bromo-4-chloro-3-indolyl-β-d-galactoside (X-gal) staining immediately after tamoxifen injection. Three months after myocardial infarction (MI), the MI mice had more X-gal-negative (newly generated) cells than the control mice (3.04 ± 0.38/mm2, MI; 0.47 ± 0.16/mm2, sham; p < 0.05). The cardiac side population (CSP) cell fraction contained label-retaining cells, which differentiated into X-gal-negative cardiomyocytes after MI. We injected a leukemia inhibitory factor (LIF)-expression construct at the time of MI and identified a significant functional improvement in the LIF-treated group. At 1 month after MI, in the MI border and scar area, the LIF-injected mice had 31.41 ± 5.83 X-gal-negative cardiomyocytes/mm2, whereas the control mice had 12.34 ± 2.56 X-gal-negative cardiomyocytes/mm2 (p < 0.05). Using 5-ethynyl-2'-deoxyurinide (EdU) administration after MI, the percentages of EdU-positive CSP cells in the LIF-treated and control mice were 29.4 ± 2.7% and 10.6 ± 3.7%, respectively, which suggests that LIF influenced CSP proliferation. Moreover, LIF activated the Janus kinase (JAK)signal transducer and activator of transcription (STAT), mitogen-activated protein kinase/extracellular signal-regulated (MEK)extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)-AKT pathways in CSPs in vivo and in vitro. The enhanced green fluorescent protein (EGFP)-bone marrow-chimeric CreLacZ mouse results indicated that LIF did not stimulate cardiogenesis via circulating bone marrow-derived cells during the 4 weeks following MI. Thus, LIF stimulates, in part, stem cell-derived cardiomyocyte regeneration by activating cardiac stem or precursor cells. This approach may represent a novel therapeutic strategy for cardiogenesis.
Pericytes of the neurovascular unit: key functions and signaling pathways.Thursday, May 26, 2016
Sweeney MD, Ayyadurai S, Zlokovic BV,
Nature neuroscience. 26-May-2016
Pericytes are vascular mural cells embedded in the basement membrane of blood microvessels. They extend their processes along capillaries, pre-capillary arterioles and post-capillary venules. CNS pericytes are uniquely positioned in the neurovascular unit between endothelial cells, astrocytes and neurons. They integrate, coordinate and process signals from their neighboring cells to generate diverse functional responses that are critical for CNS functions in health and disease, including regulation of the blood-brain barrier permeability, angiogenesis, clearance of toxic metabolites, capillary hemodynamic responses, neuroinflammation and stem cell activity. Here we examine the key signaling pathways between pericytes and their neighboring endothelial cells, astrocytes and neurons that control neurovascular functions. We also review the role of pericytes in CNS disorders including rare monogenic diseases and complex neurological disorders such as Alzheimer's disease and brain tumors. Finally, we discuss directions for future studies.
Correction to: Weng Z, et al. Stem Cells Dev 2014 Jul 15;23:1704-1716.Thursday, May 26, 2016
Stem cells and development. 1-Jun-2016
High prevalence of side population in human cancer cell lines.Thursday, May 26, 2016
Boesch M, Zeimet AG, Fiegl H, Wolf B, Huber J, Klocker H, Gastl G, Sopper S, Wolf D,
Oncoscience. 2016
Cancer cell lines are essential platforms for performing cancer research on human cells. We here demonstrate that, across tumor entities, human cancer cell lines harbor minority populations of putative stem-like cells, molecularly defined by dye extrusion resulting in the side population phenotype. These findings establish a heterogeneous nature of human cancer cell lines and argue for their stem cell origin. This should be considered when interpreting research involving these model systems.
Single-particle tracking uncovers dynamics of glutamate-induced retrograde transport of NF-κB p65 in living neurons.Thursday, May 26, 2016
Widera D, Klenke C, Nair D, Heidbreder M, Malkusch S, Sibarita JB, Choquet D, Kaltschmidt B, Heilemann M, Kaltschmidt C,
Neurophotonics. Oct-2016
Retrograde transport of NF-κB from the synapse to the nucleus in neurons is mediated by the dynein/dynactin motor complex and can be triggered by synaptic activation. The caliber of axons is highly variable ranging down to 100 nm, aggravating the investigation of transport processes in neurites of living neurons using conventional light microscopy. We quantified for the first time the transport of the NF-κB subunit p65 using high-density single-particle tracking in combination with photoactivatable fluorescent proteins in living mouse hippocampal neurons. We detected an increase of the mean diffusion coefficient ([Formula: see text]) in neurites from [Formula: see text] to [Formula: see text] after stimulation with glutamate. We further observed that the relative amount of retrogradely transported p65 molecules is increased after stimulation. Glutamate treatment resulted in an increase of the mean retrograde velocity from [Formula: see text] to [Formula: see text], whereas a velocity increase from [Formula: see text] to [Formula: see text] was observed for anterogradely transported p65. This study demonstrates for the first time that glutamate stimulation leads to an increased mobility of single NF-κB p65 molecules in neurites of living hippocampal neurons.
MicroRNA-regulated viral vectors for gene therapy.Thursday, May 26, 2016
Geisler A, Fechner H,
World journal of experimental medicine. 20-May-2016
Safe and effective gene therapy approaches require targeted tissue-specific transfer of a therapeutic transgene. Besides traditional approaches, such as transcriptional and transductional targeting, microRNA-dependent post-transcriptional suppression of transgene expression has been emerging as powerful new technology to increase the specificity of vector-mediated transgene expression. MicroRNAs are small non-coding RNAs and often expressed in a tissue-, lineage-, activation- or differentiation-specific pattern. They typically regulate gene expression by binding to imperfectly complementary sequences in the 3' untranslated region (UTR) of the mRNA. To control exogenous transgene expression, tandem repeats of artificial microRNA target sites are usually incorporated into the 3' UTR of the transgene expression cassette, leading to subsequent degradation of transgene mRNA in cells expressing the corresponding microRNA. This targeting strategy, first shown for lentiviral vectors in antigen presenting cells, has now been used for tissue-specific expression of vector-encoded therapeutic transgenes, to reduce immune response against the transgene, to control virus tropism for oncolytic virotherapy, to increase safety of live attenuated virus vaccines and to identify and select cell subsets for pluripotent stem cell therapies, respectively. This review provides an introduction into the technical mechanism underlying microRNA-regulation, highlights new developments in this field and gives an overview of applications of microRNA-regulated viral vectors for cardiac, suicide gene cancer and hematopoietic stem cell therapy, as well as for treatment of neurological and eye diseases.
Endocytosis and serpentine filopodia drive blebbishield-mediated resurrection of apoptotic cancer stem cells.Thursday, May 26, 2016
Jinesh GG, Kamat AM,
Cell death discovery. 20-05-2016
The blebbishield emergency program helps to resurrect apoptotic cancer stem cells (CSCs) themselves. Understanding the mechanisms behind this program is essential to block resurrection of CSCs during cancer therapy. Here we demonstrate that endocytosis drives serpentine filopodia to construct blebbishields from apoptotic bodies and that a VEGF-VEGFR2-endocytosis-p70S6K axis governs subsequent transformation. Disengagement of RalGDS from E-cadherin initiates endocytosis of RalGDS and its novel interaction partners cdc42, VEGFR2, cleaved β-catenin, and PKC-ζ as well as its known interaction partner K-Ras. We also report novel interactions of p45S6K (cleaved p70S6K) and PKM-ζ with PAK-1 filopodia-forming machinery specifically in blebbishields. Thus, a RalGDS-endocytosis-filopodia-VEGFR2-K-Ras-p70S6K axis drives the blebbishield emergency program, and therapeutic targeting of this axis might prevent resurrection of CSCs during cancer therapy.
Evaluation of tendon healing using fibroblast like synoviocytes in rabbits: A biomechanical study.Thursday, May 26, 2016
Azad-Tirgan M, Sarrafzadeh-Rezaei F, Malekinejad H, Hobbenaghi R, Heshmatian B,
Veterinary research forum : an international quarterly journal. 2016
Tendon never restores the complete biological and mechanical properties after healing. Several techniques are available for tissue-engineered biological augmentation for tendon healing like stem cells. Recently, synovium has been investigated as a source of cells for tissue engineering. In the present study, we investigated potentials of fibroblast like synoviocytes (FLSs) in tendon healing. Sixteen rabbits were divided randomly into control and treatment groups. One rabbit was used as a donor of synovial membrane (synovium). The injury model was unilateral complete transection through the middle one third of deep digital flexor tendon (DDFT). Subsequently, the tendon stumps were sutured with 3/0 nylon. In treatment group, 0.1 mL phosphate-buffered saline (PBS) solution containing 1 × 10(6) nucleated cells of FLSs was injected intratendinously at both tendon stumps just next to incision line. In control group, 0.1 mL PBS without FLSs was used for intratendinous injection. Model animals were euthanized at eight weeks, DDFTs were harvested and prepared for biomechanical study. Results of study showed that, there was no significant differences in biomechanical parameters values between FLSs treated and control groups. In conclusion, intratendinous injection of FLSs did not improve biomechanical properties during eight weeks in rabbit.
Insulin-secreting β cells require a post-genomic concept.Thursday, May 26, 2016
Jiang FX, Morahan G,
World journal of diabetes. 25-May-2016
Pancreatic insulin-secreting β cells are essential in maintaining normal glucose homeostasis accomplished by highly specialized transcription of insulin gene, of which occupies up to 40% their transcriptome. Deficiency of these cells causes diabetes mellitus, a global public health problem. Although tremendous endeavors have been made to generate insulin-secreting cells from human pluripotent stem cells (i.e., primitive cells capable of giving rise to all cell types in the body), a regenerative therapy to diabetes has not yet been established. Furthermore, the nomenclature of β cells has become inconsistent, confusing and controversial due to the lack of standardized positive controls of developmental stage-matched in vivo cells. In order to minimize this negative impact and facilitate critical research in this field, a post-genomic concept of pancreatic β cells might be helpful. In this review article, we will briefly describe how β cells were discovered and islet lineage is developed that may help understand the cause of nomenclatural controversy, suggest a post-genomic definition and finally provide a conclusive remark on future research of this pivotal cell.
Natural Killer Cells for Therapy of Leukemia.Thursday, May 26, 2016
Suck G, Linn YC, Tonn T,
Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur̈ Transfusionsmedizin und Immunham̈atologie. Mar-2016
Clinical application of natural killer (NK) cells against leukemia is an area of intense investigation. In human leukocyte antigen-mismatched allogeneic hematopoietic stem cell transplantations (HSCT), alloreactive NK cells exert powerful anti-leukemic activity in preventing relapse in the absence of graft-versus-host disease, particularly in acute myeloid leukemia patients. Adoptive transfer of donor NK cells post-HSCT or in non-transplant scenarios may be superior to the currently widely used unmanipulated donor lymphocyte infusion. This concept could be further improved through transfusion of activated NK cells. Significant progress has been made in good manufacturing practice (GMP)-compliant large-scale production of stimulated effectors. However, inherent limitations remain. These include differing yields and compositions of the end-product due to donor variability and inefficient means for cryopreservation. Moreover, the impact of the various novel activation strategies on NK cell biology and in vivo behavior are barely understood. In contrast, reproduction of the third-party NK-92 drug from a cryostored GMP-compliant master cell bank is straightforward and efficient. Safety for the application of this highly cytotoxic cell line was demonstrated in first clinical trials. This novel 'off-the-shelf' product could become a treatment option for a broad patient population. For specific tumor targeting chimeric-antigen-receptor-engineered NK-92 cells have been designed.
OCT4 Remodels the Phenotype and Promotes Angiogenesis of HUVECs by Changing the Gene Expression Profile.Thursday, May 26, 2016
Mou Y, Yue Z, Wang X, Li W, Zhang H, Wang Y, Li R, Sun X,
International journal of medical sciences. 2016
It has been shown that forced expression of four mouse stem cell factors (OCT4, Sox2, Klf4, and c-Myc) changed the phenotype of rat endothelial cells to vascular progenitor cells. The present study aimed to explore whether the expression of OCT4 alone might change the phenotype of human umbilical vein endothelial cells (HUVECs) to endothelial progenitor cells and, if so, to examine the possible mechanism involved. A Matrigel-based in vitro angiogenesis assay was used to evaluate the angiogenesis of the cells; the gene expression profile was analyzed by an oligonucleotide probe-based gene array chip and validated by RT-QPCR. The cellular functions of the mRNAs altered by OCT4 were analyzed with Gene Ontology. We found that induced ectopic expression of mouse OCT4 in HUVECs significantly enhanced angiogenesis of the cells, broadly changed the gene expression profile and particularly increased the expression of CD133, CD34, and VEGFR2 (KDR) which are characteristic marker molecules for endothelial progenitor cells (EPCs). Furthermore by analyzing the cellular functions that were targeted by the mRNAs altered by OCT4 we found that stem cell maintenance and cell differentiation were among the top functional response targeted by up-regulated and down-regulated mRNAs upon forced expression of OCT4. These results support the argument that OCT4 remodels the phenotype of HUVECs from endothelial cells to EPCs by up-regulating the genes responsible for stem cell maintenance and down-regulating the genes for cell differentiation.
Oncolytic viruses as immunotherapy: progress and remaining challenges.Thursday, May 26, 2016
Aurelian L,
OncoTargets and therapy. 2016
Oncolytic viruses (OVs) comprise an emerging cancer therapeutic modality whose activity involves both direct tumor cell lysis and the induction of immunogenic cell death (ICD). Cellular proteins released from the OV-lysed tumor cells, known as damage-associated molecular patterns and tumor-associated antigens, activate dendritic cells and elicit adaptive antitumor immunity. Interaction with the innate immune system and the development of long-lasting immune memory also contribute to OV-induced cell death. The degree to which the ICD component contributes to the clinical efficacy of OV therapy is still unclear. Modulation of a range of immune interactions may be beneficial or detrimental in nature and the interactions depend on the specific tumor, the site and extent of the disease, the immunosuppressive tumor microenvironment, the OV platform, the dose, time, and delivery conditions, as well as individual patient responses. To enhance the contribution of ICD, OVs have been engineered to express immunostimulatory genes and strategies have been developed to combine OV therapy with chemo- and immune-based therapeutic regimens. However, these approaches carry the risk that they may also be tolerogenic depending on their levels and the presence of other cytokines, their direct antiviral effects, and the timing and conditions of their expression. The contribution of autophagy to adaptive immunity, the ability of the OVs to kill cancer stem cells, and the patient's baseline immune status are additional considerations. This review focuses on the complex and as yet poorly understood balancing act that dictates the outcome of OV therapy. We summarize current understanding of the OVs' function in eliciting antitumor immunity and its relationship to therapeutic efficacy. Also discussed are the criteria involved in restraining antiviral immune responses and minimizing pathology while promoting antitumor immunity to override immune tolerance.
Synthesis, toxicity, biocompatibility, and biomedical applications of graphene and graphene-related materials.Thursday, May 26, 2016
Gurunathan S, Kim JH,
International journal of nanomedicine. 2016
Graphene is a two-dimensional atomic crystal, and since its development it has been applied in many novel ways in both research and industry. Graphene possesses unique properties, and it has been used in many applications including sensors, batteries, fuel cells, supercapacitors, transistors, components of high-strength machinery, and display screens in mobile devices. In the past decade, the biomedical applications of graphene have attracted much interest. Graphene has been reported to have antibacterial, antiplatelet, and anticancer activities. Several salient features of graphene make it a potential candidate for biological and biomedical applications. The synthesis, toxicity, biocompatibility, and biomedical applications of graphene are fundamental issues that require thorough investigation in any kind of applications related to human welfare. Therefore, this review addresses the various methods available for the synthesis of graphene, with special reference to biological synthesis, and highlights the biological applications of graphene with a focus on cancer therapy, drug delivery, bio-imaging, and tissue engineering, together with a brief discussion of the challenges and future perspectives of graphene. We hope to provide a comprehensive review of the latest progress in research on graphene, from synthesis to applications.
Human 343delT HSPB5 Chaperone associated with Early-onset Skeletal Myopathy causes Defects in Protein Solubility.Thursday, May 26, 2016
Mitzelfelt KA, Limphong P, Choi MJ, Kondrat FD, Lai S, Kolander KD, Kwok WM, Dai Q, Grzybowski MN, Zhang H, Taylor GM, Lui Q, Thao MT, Hudson JA, Barresi R, Bushby K, Jungbluth H, Wraige E, Geurts AM, Benesch JL, Riedel M, Christians ES, Minella AC, Benjamin IJ,
The Journal of biological chemistry. 19-May-2016
Mutations of HSPB5 (also known as CRYAB or αB-crystallin), a bona fide heat shock protein and molecular chaperone encoded by the HSPB5 (crystallin, alpha B) gene, are linked to various multisystem disorders featuring variable combinations of cataracts, cardiomyopathy, and skeletal myopathy. This study aims at investigating the pathological mechanisms involved in an early onset myofibrillar myopathy manifesting in a child harboring a homozygous recessive mutation in HSPB5, 343delT. To study HSPB5 343delT protein dynamics, we utilize model cell culture systems including induced pluripotent stem cells (iPSCs) derived from the 343delT patient (343delT/343delT) along with isogenic, heterozygous, gene-corrected control cells (WT KI/343delT), and BHK21 cells, a cell line lacking endogenous HSPB5 expression. 343delT/343delT and WT KI/343delT iPSC-derived skeletal myotubes (iSKMs) and cardiomyocytes (iCMs) did not express detectable levels of 343delT protein, contributable to extreme insolubility of the mutant protein. Overexpression of HSPB5 343delT resulted in insoluble mutant protein aggregates and induction of a cellular stress response. Co-expression of 343delT with WT prevented visible aggregation of 343delT and improved its solubility. Additionally, in vitro refolding of 343delT in the presence of WT rescued its solubility. We demonstrate an interaction between WT and 343delT both in vitro and within cells. These data support a loss of function model for the myopathy observed in the patient, as the insoluble mutant would be unavailable to perform normal functions of HSPB5, though additional gain-of-function effects of the mutant protein cannot be excluded. Additionally, our data highlights the solubilization of 343delT by WT, concordant with the recessive inheritance of the disease and absence of symptoms in carrier individuals.
Activation of PPARγ and CD36 expression--the dual pathophysiological roles of progesterone.Thursday, May 26, 2016
Yang X, Zhang W, Chen Y, Li Y, Sun L, Liu Y, Liu M, Yu M, Li X, Han J, Duan Y,
The Journal of biological chemistry. 12-May-2016
Progesterone or its analog, one of components of the hormone replacement therapy (HRT), may attenuate the cardioprotective effects of estrogen. However, the underlying mechanisms have not been fully elucidated. Expression of CD36, a receptor for oxidized low-density lipoprotein (oxLDL) to enhance macrophage/foam cell formation, is activated by the transcription factor of peroxisome proliferator-activated receptor γ (PPARγ). CD36 also functions as a fatty acid transporter to influence fatty acid metabolism and pathophysiological status of several diseases. In this study, we determined that progesterone induced macrophage CD36 expression which is related to progesterone receptor (PR) activity. Progesterone enhanced cellular oxLDL uptake in a CD36-dependent manner. Mechanistically, progesterone increased PPARγ expression, PPARγ promoter activity in a PR-dependent manner, and the binding of PR with the progesterone response element (PRE) in the PPARγ promoter. Specific deletion of macrophage PPARγ (MφPPARγ KO) expression in mice abolished progesterone-induced macrophage CD36 expression and cellular oxLDL accumulation. Meanwhile, we determined that associated with gestation and increased serum progesterone levels, CD36 and PPARγ expression in mouse adipose tissue, skeletal muscle and peritoneal macrophages were substantially activated. Taken together, our study demonstrates that progesterone can play the dual pathophysiological roles by activating PPARγ expression in which progesterone increases macrophage CD36 expression and oxLDL accumulation, a negative effect on atherosclerosis; and enhances PPARγ-CD36 pathway in adipose tissue and skeletal muscle, a protective effect on pregnancy.
Dynamic Heterogeneity of Brachyury in Mouse Epiblast Stem Cells Mediates Distinct Respond to Extrinsic BMP Signaling.Thursday, May 26, 2016
Song L, Chen J, Peng G, Tang K, Jing N,
The Journal of biological chemistry. 16-May-2016
Mouse pluripotent cells such as embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs) provide excellent in vitro systems to study imperative pre- and post-implantation events of in vivo mammalian development. It is known that mouse ESCs are dynamic heterogeneous populations. However, it remains largely unclear whether and how EpiSCs possess similar heterogeneity and plasticity as ESCs. Here, we show that EpiSCs are discriminated by the expression of a specific marker T (Brachyury) into two populations. The T positive (T+) and the T negative (T-) populations can be interconverted within the same culture condition. In addition, the two populations display distinct responses to BMP signaling and different developmental potentials. The T- EpiSCs are preferentially differentiated into ectoderm lineages; whereas T+ EpiSCs have a biased potential for mesendoderm fates. Mechanistic studies reveal that T+ EpiSCs have an earlier and faster responses to BMP4 stimulation than T- EpiSCs. Id1 mediates the commitment of T- EpiSC to epidermal lineage during BMP4 treatment. On the other hand, Snail modulates the conversion of T+ EpiSC to mesendoderm fates with the presence of BMP4. Furthermore, T expression is essential for epithelia-mesenchymal-transition during EpiSCs differentiation. Our findings suggest that the dynamic heterogeneity of T+/T- sub-population primes EpiSCs toward particular cell lineages, providing important insights into the dynamic development of the early mouse embryo.
Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer.Thursday, May 26, 2016
Lilenbaum RA, Horn LA,
Journal of the National Comprehensive Cancer Network : JNCCN. May-2016
For appropriate treatment selection, the updated NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) recommend broad molecular profiling for all patients with nonsquamous disease. Three different tyrosine kinase inhibitors (TKIs) are recommended as first-line treatment of EGFR mutation-positive NSCLC: gefitinib, erlotinib, and afatinib. Most patients whose disease responds will still experience progression, and the type of disease progression drives management. Systemic progression requires switching TKI treatment, whereas patients with oligoprogression and central nervous system progression may have their new lesions treated but continue on their TKI. A new third-generation TKI has been approved and others are currently under development, and new combinations of these drugs with a VEGFR inhibitor offer promise to improve outcomes.
Macrophage-mediated trogocytosis leads to death of antibody-opsonized tumor cells.Thursday, May 26, 2016
Velmurugan R, Challa DK, Ram S, Ober RJ, Ward ES,
Molecular cancer therapeutics. 25-May-2016
Understanding the complex behavior of effector cells such as monocytes or macrophages in regulating cancerous growth is of central importance for cancer immunotherapy. Earlier studies using CD20-specific antibodies have demonstrated that the Fcγ receptor (FcγR)-mediated transfer of the targeted receptors from tumor cells to these effector cells through trogocytosis can enable escape from antibody therapy, leading to the viewpoint that this process is pro-tumorigenic. In the current study we demonstrate that persistent trogocytic attack results in the killing of HER2-overexpressing breast cancer cells. Further, antibody engineering to increase FcγR interactions enhances this tumoricidal activity. These studies extend the complex repertoire of activities of macrophages to trogocytic-mediated cell death of HER2-overexpressing target cells and have implications for the development of effective antibody-based therapies.
The Dorsoventral Patterning of Human Forebrain Follows an Activation/Transformation Model.Thursday, May 26, 2016
Chi L, Fan B, Feng D, Chen Z, Liu Z, Hui Y, Xu X, Ma L, Fang Y, Zhang Q, Jin G, Liu L, Guan F, Zhang X,
Cerebral cortex (New York, N.Y. : 1991). 25-May-2016
The anteroposterior patterning of the central nervous system follows an activation/transformation model, which proposes that a prospective telencephalic fate will be activated by default during the neural induction stage, while this anterior fate could be transformed posteriorly according to caudalization morphogens. Although both extrinsic signals and intrinsic transcription factors have been implicated in dorsoventral (DV) specification of vertebrate telencephalon, the DV patterning model remains elusive. This is especially true in human considering its evolutionary trait and uniqueness of gene regulatory networks during neural induction. Here, we point to a model that human forebrain DV patterning also follows an activation/transformation paradigm. Human neuroectoderm (NE) will activate a forebrain dorsal fate automatically and this default anterior dorsal fate does not depend on Wnts activation or Pax6 expression. Forced expression of Pax6 in human NE hinders its ventralization even under sonic hedgehog (Shh) treatment, suggesting that the ventral fate is repressed by dorsal genes. Genetic manipulation of Nkx2.1, a key gene for forebrain ventral progenitors, shows that Nkx2.1 is neither necessary nor sufficient for Shh-driven ventralization. We thus propose that Shh represses dorsal genes of human NE and subsequently transforms the primitively activated dorsal fate ventrally in a repression release manner.
Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies.Thursday, May 26, 2016
Sabatino M, Hu J, Sommariva M, Gautam S, Fellowes V, Hocker JD, Dougherty S, Qin H, Klebanoff CA, Fry TJ, Gress RE, Kochenderfer JN, Stroncek DF, Ji Y, Gattinoni L,
Blood. 25-May-2016
Long-lived, self-renewing, multipotent T memory stem cells (TSCM) can trigger profound and sustained tumor regression but their rareness poses a major hurdle to their clinical application. Presently, clinically compliant procedures to generate relevant numbers of this T cell population are undefined. Here, we provide a strategy for deriving large numbers of clinical-grade tumor-redirected TSCM starting from naïve precursors. CD8(+)CD62L(+)CD45RA(+) naïve T cells enriched by streptamer-based serial positive selection were activated by CD3/CD28 engagement in the presence of IL-7, IL-21 and the glycogen synthase-3β inhibitor TWS119, and genetically engineered to express a CD19-specific chimeric antigen receptor (CD19-CAR). These conditions enabled the generation of CD19-CAR modified CD8(+) TSCM that were phenotypically, functionally, and transcriptomically equivalent to their naturally occurring counterpart. Compared with CD8(+) T cells generated with clinical protocols currently under investigation, CD19-CAR modified CD8(+) TSCM exhibited enhanced metabolic fitness and mediated robust, long-lasting antitumor responses against systemic acute lymphoblastic leukemia xenografts. This clinical-grade platform provides the basis for a phase 1 trial evaluating the activity of CD19-CAR modified CD8(+) TSCM in patients with B-cell malignancies refractory to prior allogeneic hematopoietic stem cell transplantation.
Complex karyotypes, KRAS and POT1 mutations impact outcome in CLL after chlorambucil based chemo- or chemoimmunotherapy.Thursday, May 26, 2016
Herling CD, Klaumünzer M, Krings Rocha C, Altmüller J, Thiele H, Bahlo J, Kluth S, Crispatzu G, Herling M, Schiller J, Engelke A, Tausch E, Döhner H, Fischer K, Goede V, Nürnberg P, Reinhardt HC, Stilgenbauer S, Hallek M, Kreuzer KA,
Blood. 25-May-2016
Genetic instability is a feature of chronic lymphocytic leukemia (CLL) with adverse prognosis. We hypothesized that chromosomal translocations or complex karyotypes, and distinct somatic mutations may impact outcome after first-line chemoimmunotherapy of CLL patients. We performed metaphase karyotyping and next generation sequencing (NGS) of 85 genes in pretreatment blood samples obtained from 161 patients registered for CLL11, a three-arm phase-III trial comparing frontline chlorambucil (Clb) versus Clb plus rituximab (Clb-R), or Clb plus obinutuzumab (Clb-G) in CLL patients with significant comorbidity. Chromosomal aberrations as assessed by karyotyping were observed in 68.8% of 154 patients, 31.2% carried translocations, 19.5% showed complex karyotypes. NGS revealed 198 missense/nonsense mutations and 76 small indels in 76.4% of patients. The most frequently mutated genes were NOTCH1, SF3B1, ATM, TP53, BIRC3, POT1, XPO1, and KRAS Sole chemotherapy, treatment with Clb-R, or genetic lesions in TP53 (9.9% of patients) and KRAS (6.2% of patients) were significantly associated with non-response to study therapy. In multivariate models, complex karyotypes and POT1 mutations (8.1% of patients) represented significant prognostic factors for an unfavorable survival, independently of IGHV mutation status, Binet stage, and serum beta-2-microglobuline. Patients with co-presence of complex karyotypes and deletions/mutations involving TP53 demonstrated a particularly short survival. In summary, this is the first prospective, controlled study in CLL patients that shows a role of complex karyotype aberrations as an independent prognostic factor for survival after front-line therapy. Moreover, the study identifies mutations in KRAS and POT1 as novel determinants of outcome after chemoimmunotherapy using chlorambucil and anti-CD20 treatment.
Pbx1 is required for adult SVZ neurogenesis.Thursday, May 26, 2016
Grebbin BM, Hau AC, Groß A, Anders-Maurer M, Schramm J, Koss M, Wille C, Mittelbronn M, Selleri L, Schulte D,
Development (Cambridge, England). 25-May-2016
TALE-homeodomain proteins function as part of heteromeric complexes that contain one member each of the PBC- and MEIS/PREP-subclasses. As we have recently shown, MEIS2 cooperates with the neurogenic transcription factor PAX6 in the control of adult subventricular zone (SVZ) neurogenesis in rodents. Expression of the PBC-protein Pbx1 in the SVZ has been reported but its functional role(s) had not yet been investigated. Using a genetic loss-of-function model, we now show that Pbx1 is an early regulator of SVZ neurogenesis. Targeted deletion of Pbx1 by retroviral transduction of Cre recombinase into Pbx2-deficient SVZ stem- and progenitor cells carrying floxed alleles of Pbx1 significantly reduced the production of neurons and increased the generation of oligodendrocytes. Loss of Pbx1-expression in neuronally committed neuroblasts in the rostral migratory stream in a Pbx2 null (Pbx2(-)/(-)) background, by contrast, severely compromised cell survival. By chromatin immunoprecipitation from endogenous tissues or isolated cells, we further detect PBX1 binding to known regulatory regions of the neuron-specific genes DCX and TH days or even weeks before the respective genes are expressed during the normal program of SVZ neurogenesis, suggesting that PBX1 may act as priming factor to mark these genes for subsequent activation. Collectively, our results establish that PBX1 regulates adult neural cell fate determination in a way that goes beyond the that of its heterodimerization partner MEIS2.
Growth hormone is permissive for neoplastic colon growth.Thursday, May 26, 2016
Chesnokova V, Zonis S, Zhou C, Recouvreux MV, Ben-Shlomo A, Araki T, Barrett R, Workman M, Wawrowsky K, Ljubimov VA, Uhart M, Melmed S,
Proceedings of the National Academy of Sciences of the United States of America. 25-May-2016
Growth hormone (GH) excess in acromegaly is associated with increased precancerous colon polyps and soft tissue adenomas, whereas short-stature humans harboring an inactivating GH receptor mutation do not develop cancer. We show that locally expressed colon GH is abundant in conditions predisposing to colon cancer and in colon adenocarcinoma-associated stromal fibroblasts. Administration of a GH receptor (GHR) blocker in acromegaly patients induced colon p53 and adenomatous polyposis coli (APC), reversing progrowth GH signals. p53 was also induced in skin fibroblasts derived from short-statured humans with mutant GHR. GH-deficient prophet of pituitary-specific positive transcription factor 1 (Prop1)(-/-) mice exhibited induced colon p53 levels, and cross-breeding them with Apc(min+/-) mice that normally develop intestinal and colon tumors resulted in GH-deficient double mutants with markedly decreased tumor number and size. We also demonstrate that GH suppresses p53 and reduces apoptosis in human colon cell lines as well as in induced human pluripotent stem cell-derived intestinal organoids, and confirm in vivo that GH suppresses colon mucosal p53/p21. GH excess leads to decreased colon cell phosphatase and tensin homolog deleted on chromosome 10 (PTEN), increased cell survival with down-regulated APC, nuclear β-catenin accumulation, and increased epithelial-mesenchymal transition factors and colon cell motility. We propose that GH is a molecular component of the "field change" milieu permissive for neoplastic colon growth.
Unveiling the Differences of Secretome of Human Bone Marrow Mesenchymal Stem Cells, Adipose Tissue derived Stem Cells and Human Umbilical Cord Perivascular Cells: A Proteomic Analysis.Thursday, May 26, 2016
Pires A, Pinheiro B, Teixeira FG, Anjo S, Samy S, Gomes E, Serra S, Silva NA, Manadas B, Sousa N, Salgado AJ,
Stem cells and development. 25-May-2016
The use of human mesenchymal stem cells (hMSCs) has emerged as a possible therapeutic strategy for CNS related conditions. Research in the last decade, strongly suggests that MSC-mediated benefits are closely related with their secretome. Studies published in recent years have shown the secretome of hMSCs isolated from different tissue sources may present significant variation. With this in mind, the present work performed a comparative proteomic-based analysis through mass spectrometry on the secretome of hMSCs derived from bone marrow (BMSCs), adipose tissue (ASCs) and human umbilical cord perivascular cells (HUCPVCs). The results revealed that BMSCs, ASCs and HUCPVCs differed in their secretion of neurotrophic, neurogenic, axon guidance, axon growth and neurodifferentiative proteins, as well as, proteins with neuroprotective actions against oxidative stress, apoptosis and excitotoxicity, which have been shown to be involved in several CNS disorders/injuries processes. Although important changes were observed within the secretome of the cell populations that were analysed, all cell populations shared the capability of secreting important neuro-regulatory molecules. The difference in their secretion pattern may indicate that their secretome is specific to a condition(s) of the CNS. Nevertheless, the confirmation that the secretome of MSCs isolated from different tissue sources is rich in neuro-regulatory molecules represents an important asset not only for the development of future neuro-regenerative strategies, as well as for their use as a therapeutic option for human clinical trials.
The role of Klotho protein in chronic kidney disease: studies in animals and humans.Thursday, May 26, 2016
Gołembiewska E, Stępniewska J, Kabat-Koperska J, Kędzierska K, Domański M, Ciechanowski K,
Current protein & peptide science. 26-May-2016
The identification of Klotho gene was a major discovery as the gene encodes a protein regulating multiple functions. A defect in Klotho gene expression in mice results in a phenotype of premature aging including shortened life span, growth retardation, hypogonadism, skin and muscle atrophies, vascular calcification, cognition impairment, motor neuron degeneration and others. This phenotype is associated with phosphate balance disorders and underlines the major function of Klotho in mineral metabolism. As another 2 related paralogs were discovered (beta-Klotho, which is involved in bile acid and energy metabolism, and gamma-Klotho, with a yet to be defined function), this led to the revised naming of Klotho as alpha-Klotho. Two forms of alpha-Klotho protein have been reported: a membrane-bound and a soluble one. Membrane Klotho forms a complex with fibroblast growth factor (FGF) receptors and functions as an obligate co-receptor for the FGF-23 phosphatonin in distal tubules. The soluble form of Klotho seems to function as a humoral factor and regulates glycoproteins on the cell surface including ion channels and growth factors. There is data suggesting that soluble Klotho exerts phosphaturic effects independently of FGF-23. Circulating soluble Klotho is produced either by proteolytic cleavage of the extracellular domain of the transmembrane form by two membrane-anchored proteases (ADAM10 and ADAM17) or by alternative mRNA splicing. In animal models Klotho has been shown to exert pleiotropic actions, including cytoprotection, anti-oxidation, anti-apoptosis, protection of vasculature, promotion of angiogenesis and vascularization, inhibition of fibrogenesis and preservation of stem cells. The exact diagnostic and therapeutic role of Klotho in humans is not fully known yet. The article presents the role of Klotho in physiology and different stages of chronic kidney disease (CKD).
Involvement of P2 receptors in regulation of glomerular permeability to albumin by extracellular nucleotides of intra-/extra-glomerular origins.Thursday, May 26, 2016
Kasztan M, Jankowski M,
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. Apr-2016
Plasma filtration through glomerular filtration barrier (GFB) is a key process to maintain fluid and electrolyte homeostasis. GFB consisting of endothelial cells, podocytes and basement membrane restricts passage of albumin but is permeable for smaller plasma molecules. Various biological agents, such as extracellular nucleotides influence activity of cells, which in turn affects permeability of GFB. Nucleotides are released from cells outside and within the glomeruli that activate the purinoceptors - P2Rs classified into ATP-gated non-selective ion channels, P2X receptors (P2XRs), and G-protein-coupled metabotropic P2Y receptors (P2YRs). P2Rs are expressed on cellular components of GFB. P2Rs activation triggers intracellular calcium concentration and calcium-dependent metabolism with subsequent affect on glomerular permeability to albumin. Purinergic-dependent glomerular cell activation also affects the biophysical properties of acelluar glomerular basement membrane (GMB). Finally, P2Rs stimulation may lead to increased proteins excretion in urine. The involvement of P2Rs in increased GFB permeability to albumin may be expected under pathophysiological conditions characterized by increased albumin excretion in urine.
Author response: use of bioartificial dermal regeneration template for skin restoration in combat casualty injuries.Thursday, May 26, 2016
Valerio I, Tintle S,
Regenerative medicine. 26-May-2016
Response to: Leclère FM & Casoli V. Use of bioartificial dermal regeneration template for skin restoration in combat casualty injuries. Regen. Med. doi:10.2217/rme-2016-0044 (2016).
A Genetic Mosaic Screen Reveals Ecdysone-Responsive Genes Regulating Drosophila Oogenesis.Thursday, May 26, 2016
Ables ET, Hwang GH, Finger DS, Hinnant TD, Drummond-Barbosa D,
G3 (Bethesda, Md.). 25-May-2016
Multiple aspects of Drosophila oogenesis, including germline stem cell activity, germ cell differentiation, and follicle survival are regulated by the steroid hormone ecdysone. While the transcriptional targets of ecdysone signaling have been studied extensively during development, targets in the ovary remain largely unknown. Early studies of salivary gland polytene chromosomes led to the model that ecdysone stimulates a hierarchical transcriptional cascade, wherein a core group of ecdysone-sensitive transcription factors induce tissue-specific responses by activating secondary branches of transcriptional targets. More recently, genome-wide approaches have identified hundreds of putative ecdysone-responsive targets. Determining whether these putative targets represent bona fide targets in vivo, however, requires that they be tested via traditional mutant analysis in a cell-type specific fashion. To investigate the molecular mechanisms whereby ecdysone signaling regulates oogenesis, we used genetic mosaic analysis to screen putative ecdysone-responsive genes for novel roles in the control of the earliest steps of oogenesis. We identified a cohort of genes required for stem cell maintenance, stem and progenitor cell proliferation, and follicle encapsulation, growth, and survival. These genes encode transcription factors, chromatin modulators, and factors required for RNA transport, stability, and ribosome biogenesis, suggesting that ecdysone might control a wide range of molecular processes during oogenesis. Our results suggest that although ecdysone target genes are known to have cell type-specific roles, many ecdysone response genes that control larval or pupal cell types at developmental transitions are reiteratively used in the adult ovary. These results provide novel insight into the molecular mechanisms by which ecdysone signaling controls oogenesis, laying new ground for future studies.
Stem cells: The cancer's gone, but did chemotherapy damage your heart?Thursday, May 26, 2016
Bellin M, Mummery CL,
Nature reviews. Cardiology. 26-May-2016
Human Lymphoid Tissues Harbor a Distinct CD69+CXCR6+ NK Cell Population.Thursday, May 26, 2016
Lugthart G, Melsen JE, Vervat C, van Ostaijen-Ten Dam MM, Corver WE, Roelen DL, van Bergen J, van Tol MJ, Lankester AC, Schilham MW,
Journal of immunology (Baltimore, Md. : 1950). 25-May-2016
Knowledge of human NK cells is based primarily on conventional CD56(bright) and CD56(dim) NK cells from blood. However, most cellular immune interactions occur in lymphoid organs. Based on the coexpression of CD69 and CXCR6, we identified a third major NK cell subset in lymphoid tissues. This population represents 30-60% of NK cells in marrow, spleen, and lymph node but is absent from blood. CD69(+)CXCR6(+) lymphoid tissue NK cells have an intermediate expression of CD56 and high expression of NKp46 and ICAM-1. In contrast to circulating NK cells, they have a bimodal expression of the activating receptor DNAX accessory molecule 1. CD69(+)CXCR6(+) NK cells do not express the early markers c-kit and IL-7Rα, nor killer cell Ig-like receptors or other late-differentiation markers. After cytokine stimulation, CD69(+)CXCR6(+) NK cells produce IFN-γ at levels comparable to CD56(dim) NK cells. They constitutively express perforin but require preactivation to express granzyme B and exert cytotoxicity. After hematopoietic stem cell transplantation, CD69(+)CXCR6(+) lymphoid tissue NK cells do not exhibit the hyperexpansion observed for both conventional NK cell populations. CD69(+)CXCR6(+) NK cells constitute a separate NK cell population with a distinct phenotype and function. The identification of this NK cell population in lymphoid tissues provides tools to further evaluate the cellular interactions and role of NK cells in human immunity.
Prions: Beyond a Single Protein.Thursday, May 26, 2016
Das AS, Zou WQ,
Clinical microbiology reviews. Jul-2016
Since the term protein was first coined in 1838 and protein was discovered to be the essential component of fibrin and albumin, all cellular proteins were presumed to play beneficial roles in plants and mammals. However, in 1967, Griffith proposed that proteins could be infectious pathogens and postulated their involvement in scrapie, a universally fatal transmissible spongiform encephalopathy in goats and sheep. Nevertheless, this novel hypothesis had not been evidenced until 1982, when Prusiner and coworkers purified infectious particles from scrapie-infected hamster brains and demonstrated that they consisted of a specific protein that he called a "prion." Unprecedentedly, the infectious prion pathogen is actually derived from its endogenous cellular form in the central nervous system. Unlike other infectious agents, such as bacteria, viruses, and fungi, prions do not contain genetic materials such as DNA or RNA. The unique traits and genetic information of prions are believed to be encoded within the conformational structure and posttranslational modifications of the proteins. Remarkably, prion-like behavior has been recently observed in other cellular proteins-not only in pathogenic roles but also serving physiological functions. The significance of these fascinating developments in prion biology is far beyond the scope of a single cellular protein and its related disease.
Controlled Release of Collagen-Binding SDF-1α Improves Cardiac Function after Myocardial Infarction by Recruiting Endogenous Stem Cells.Thursday, May 26, 2016
Sun J, Zhao Y, Li Q, Chen B, Hou X, Xiao Z, Dai J,
Scientific reports. 2016
Stromal cell-derived factor-1α (SDF-1α) is a well-characterized chemokine that mobilizes stem cells homing to the ischemic heart, which is beneficial for cardiac regeneration. However, clinically administered native SDF-1α diffuses quickly, thus decreasing its local concentration, and results in side effects. Thus, a controlled release system for SDF-1α is required to produce an effective local concentration in the ischemic heart. In this study, we developed a recombinant chemokine, consisting of SDF-1α and a collagen-binding domain, which retains both the SDF-1α and collagen-binding activity (CBD-SDF-1α). In an in vitro assay, CBD-SDF-1α could specifically bind to a collagen gel and achieve sustained release. An intramyocardial injection of CBD-SDF-1α after acute myocardial infarction demonstrated that the protein was largely tethered in the ischemic area and that controlled release had been achieved. Furthermore, CBD-SDF-1α enhanced the recruitment of c-kit positive (c-kit(+)) stem cells, increased capillary density and improved cardiac function, whereas NAT-SDF-1α had no such beneficial effects. Our findings demonstrate that CBD-SDF-1α can specifically bind to collagen and achieve controlled release both in vitro and in vivo. Local delivery of this protein could mobilize endogenous stem cells homing to the ischemic heart and improve cardiac function after myocardial infarction.
Corporate profile: Sangamo BioSciences, Inc.Thursday, May 26, 2016
Wolffe E,
Regenerative medicine. 26-May-2016
Sangamo BioSciences, Inc., (CA, USA) is the pioneer and leader in the next phase of molecular medicine; genome editing. The company's proprietary platform is based on a human DNA-binding motif, the zinc finger DNA-binding protein (ZFP). Sangamo engineers ZFPs to bind to virtually any DNA sequence with exquisite specificity, making the platform uniquely suitable for therapeutic applications. Zinc finger nucleases can be designed to enable therapeutic genome editing, to knockout a gene or add a DNA sequence to an investigator-chosen site in the genome. The company is focused on developing novel ZFP Therapeutics(®) as potentially curative therapies for genetic and infectious diseases, including hemophilia, lysosomal storage disorders, hemoglobinopathies and HIV/AIDS. Sangamo is the only company with human clinical trials of this novel technology.
Generation of equine induced pluripotent stem cells and analysis of their therapeutic potential for muscle injuries.Thursday, May 26, 2016
Lee EM, Kim AY, Lee EJ, Park JK, Park SI, Cho SG, Kim HK, Kim SY, Jeong KS,
Cell transplantation. 25-May-2016
Horse health has become a major concern with the expansion of horse-related industries and sports; the importance of healthy muscles for horse performance and daily activities is undisputed. Here, we generated equine induced pluripotent stem cells (E-iPSCs) by reprogramming equine adipose-derived stem cells into iPSCs using a polycistronic lentiviral vector encoding four transcription factors (i.e., Oct4, Sox2, Klf4, and c-Myc) and then examined their pluripotent characteristics. Subsequently, established E-iPSCs were transplanted into muscle-injured Rag/mdx mice. The histopathology results showed that E-iPSC-transplanted mice exhibited enhanced muscle regeneration compared to controls. In addition, E-iPSC-derived myofibers were observed in the injured muscles. In conclusion, we show that E-iPSCs could be successfully generated from equine ASCs and transplanted into injured muscles and that E-iPSCs have the capacity to induce regeneration of injured muscles.
Cops2 promotes pluripotency maintenance by Stabilizing Nanog Protein and Repressing Transcription.Thursday, May 26, 2016
Zhang W, Ni P, Mou C, Zhang Y, Guo H, Zhao T, Loh YH, Chen L,
Scientific reports. 2016
The COP9 signalosome has been implicated in pluripotency maintenance of human embryonic stem cells. Yet, the mechanism for the COP9 signalosome to regulate pluripotency remains elusive. Through knocking down individual COP9 subunits, we demonstrate that Cops2, but not the whole COP9 signalosome, is essential for pluripotency maintenance in mouse embryonic stem cells. Down-regulation of Cops2 leads to reduced expression of pluripotency genes, slower proliferation rate, G2/M cell cycle arrest, and compromised embryoid differentiation of embryonic stem cells. Cops2 also facilitates somatic cell reprogramming. We further show that Cops2 binds to Nanog protein and prevent the degradation of Nanog by proteasome. Moreover, Cops2 functions as transcriptional corepressor to facilitate pluripotency maintenance. Altogether, our data reveal the essential role and novel mechanisms of Cops2 in pluripotency maintenance.
An Easily Accessible Self-Healing Transparent Film Based on a 2D Supramolecular Network of Hydrogen-Bonding Interactions between Polymeric Chains.Thursday, May 26, 2016
Roy N, Tomović Ž, Buhler E, Lehn JM,
Chemistry (Weinheim an der Bergstrasse, Germany). 25-May-2016
Self-healing polymers hold great promise for the future, enhancing in particular the longevity of polymeric materials. We describe a self-healing covalent polymer, presenting an extensive array of hydrogen-bonding sites based on the combination of urea, urethane, and bis-acyl-hydrazine units. Solvent-cast thin-films prepared by polycondensation of a commercially available dihydrazide and a diisocyanate prepolymer exhibited excellent room temperature autonomous healing with almost full recovery of mechanical properties when two parts of a cut film were overlapped and gently pressed together. This autonomous healing upon damage may be attributed to the supramolecular dynamics of multiple lateral inter-chain hydrogen-bonding interactions between the polymer chains. The solid-state structure of a model compound incorporating the same structural backbone corroborates the existence of an extensive two-dimensional supramolecular hydrogen-bonding network.
Semi-automatic Method for Ca(2+) Imaging Data Analysis of Maturing Human Embryonic Stem Cells-Derived Retinal Pigment Epithelium.Thursday, May 26, 2016
Abu Khamidakh AE, Dos Santos FC, Skottman H, Juuti-Uusitalo K, Hyttinen J,
Annals of biomedical engineering. 25-May-2016
Ca(2+) is a second messenger controlling vital cellular processes, including cell maturation. Changes in Ca(2+) signaling during maturation of human embryonic stem cell-derived retinal pigment epithelial cells (hESC-RPE) have not been assessed previously. The aim of this study was to investigate maturation-dependent changes in transient intracellular Ca(2+) ([Ca(2+)] i ) increases in hESC-RPE. For this, we developed image analysis tools to evaluate cell-specific Ca(2+) signals from the entire field of view. Spontaneous and mechanically induced transient [Ca(2+)] i increases (STIs and MITIs) were analyzed in hESC-RPEs cultured for 9 or 28 days, altogether from more than 80,000 cells. Both cultures showed STIs: the longer culture time resulted in twofold increase of amount of cells with STIs. Mechanical stimulation induced intercellular Ca(2+) waves in cells from both time points, but longer culture time reduced Ca(2+) wave spreading. Depletion of intracellular Ca(2+) stores decreased cell fraction with STIs and MITIs at both time points, and absence of extracellular Ca(2+) had similar effect on cells with STIs. To conclude, hESC-RPE cells undergo significant Ca(2+) signaling re-arrangements during a short maturation period increasing cell fraction with STIs, while decreasing coordinated cell response to mechanical stimulation. This knowledge and proposed analysis tools can be used for assessment of hESC-RPE maturation in vitro.
Absence of gliosis in a teleost model of spinal cord regeneration.Thursday, May 26, 2016
Vitalo AG, Sîrbulescu RF, Ilieş I, Zupanc GK,
Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology. 25-May-2016
Among the cellular processes that follow injury to the central nervous system, glial scar formation is thought to be one of the major factors that prevent regeneration. In regeneration-competent organisms, glial scar formation has been a matter of controversy. We addressed this issue by examining the glial population after spinal cord injury in a model of regeneration competency, the knifefish Apteronotus leptorhynchus. Analysis of spinal cord sections immunostained against the glial markers glial fibrillary acidic protein, vimentin, or chondroitin sulfate proteoglycan failed to produce any evidence for the formation of a glial scar in the area of the lesion at post-injury survival times ranging from 5 to 185 days. This result was independent of the lesion paradigm applied-amputation of the caudal part of the spinal cord or hemisection lesioning-and similar after examination of transverse and longitudinal sections. We hypothesize that the well-developed network of radial glia in both the intact and the injured spinal cord provides a support system for regeneration of tissue lost to injury. This glial network is likely also involved in the generation of new cells, as indicated by the large subset of glial fibrillary acidic protein-labeled glia that express the stem cell marker Sox2.
Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa.Thursday, May 26, 2016
Chan BK, Sistrom M, Wertz JE, Kortright KE, Narayan D, Turner PE,
Scientific reports. 2016
Increasing prevalence and severity of multi-drug-resistant (MDR) bacterial infections has necessitated novel antibacterial strategies. Ideally, new approaches would target bacterial pathogens while exerting selection for reduced pathogenesis when these bacteria inevitably evolve resistance to therapeutic intervention. As an example of such a management strategy, we isolated a lytic bacteriophage, OMKO1, (family Myoviridae) of Pseudomonas aeruginosa that utilizes the outer membrane porin M (OprM) of the multidrug efflux systems MexAB and MexXY as a receptor-binding site. Results show that phage selection produces an evolutionary trade-off in MDR P. aeruginosa, whereby the evolution of bacterial resistance to phage attack changes the efflux pump mechanism, causing increased sensitivity to drugs from several antibiotic classes. Although modern phage therapy is still in its infancy, we conclude that phages, such as OMKO1, represent a new approach to phage therapy where bacteriophages exert selection for MDR bacteria to become increasingly sensitive to traditional antibiotics. This approach, using phages as targeted antibacterials, could extend the lifetime of our current antibiotics and potentially reduce the incidence of antibiotic resistant infections.
Effects of different femoral tunnel positions on tension changes in anterolateral ligament reconstruction.Thursday, May 26, 2016
Katakura M, Koga H, Nakamura K, Sekiya I, Muneta T,
Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA. 25-May-2016
With F2-4 mm posterior and 8 mm proximal to the lateral epicondyle-the reconstructed ALL had the least tension change with only a slight increase in tension as the knee extended. This result indicates that F2 is recommended for ALL reconstruction to better control ALRI, which will help determine the optimal femoral tunnel position for ALL reconstruction.
Label-free nonlinear optical microscopy detects early markers for osteogenic differentiation of human stem cells.Thursday, May 26, 2016
Hofemeier AD, Hachmeister H, Pilger C, Schürmann M, Greiner JF, Nolte L, Sudhoff H, Kaltschmidt C, Huser T, Kaltschmidt B,
Scientific reports. 2016
Tissue engineering by stem cell differentiation is a novel treatment option for bone regeneration. Most approaches for the detection of osteogenic differentiation are invasive or destructive and not compatible with live cell analysis. Here, non-destructive and label-free approaches of Raman spectroscopy, coherent anti-Stokes Raman scattering (CARS) and second harmonic generation (SHG) microscopy were used to detect and image osteogenic differentiation of human neural crest-derived inferior turbinate stem cells (ITSCs). Combined CARS and SHG microscopy was able to detect markers of osteogenesis within 14 days after osteogenic induction. This process increased during continued differentiation. Furthermore, Raman spectroscopy showed significant increases of the PO4(3-) symmetric stretch vibrations at 959 cm(-1) assigned to calcium hydroxyapatite between days 14 and 21. Additionally, CARS microscopy was able to image calcium hydroxyapatite deposits within 14 days following osteogenic induction, which was confirmed by Alizarin Red-Staining and RT- PCR. Taken together, the multimodal label-free analysis methods Raman spectroscopy, CARS and SHG microscopy can monitor osteogenic differentiation of adult human stem cells into osteoblasts with high sensitivity and spatial resolution in three dimensions. Our findings suggest a great potential of these optical detection methods for clinical applications including in vivo observation of bone tissue-implant-interfaces or disease diagnosis.
Neogenin Promotes BMP2 Activation of YAP and Smad1 and Enhances Astrocytic Differentiation in Developing Mouse Neocortex.Thursday, May 26, 2016
Huang Z, Sun D, Hu JX, Tang FL, Lee DH, Wang Y, Hu G, Zhu XJ, Zhou J, Mei L, Xiong WC,
The Journal of neuroscience : the official journal of the Society for Neuroscience. 25-May-2016
Astrocytes, a major type of glial cells in the brain, play important roles in modulating synaptic transmission and information processing, and maintaining CNS homeostasis. The abnormal astrocytic differentiation during development contributes to dysfunctions of synaptic plasticity and neuropsychological disorders. Here we provide evidence for neogenin's function in regulation of the neocortical astrocyte differentiation during mouse brain development. We also provide evidence for the necessity of neogenin in BMP2/Smad1-induced astrocyte differentiation through YAP. Thus, our findings identify an unrecognized function of neogenin in mouse neocortical astrocyte differentiation, and suggest a signaling pathway, BMP2-neogenin-YAP-Smad1, underlying astrogliogenesis in developing mouse neocortex.
The distribution pattern of ERα expression, ESR1 genetic variation and expression of growth factor receptors: association with breast cancer prognosis in Russian patients treated with adjuvant tamoxifen.Thursday, May 26, 2016
Babyshkina N, Vtorushin S, Zavyalova M, Patalyak S, Dronova T, Litviakov N, Slonimskaya E, Kzhyshkowska J, Cherdyntseva N, Choynzonov E,
Clinical and experimental medicine. 25-May-2016
Identification of additional biomarkers associated with ER genomic and nongenomic pathways could be very useful to distinguish patients who will benefit from tamoxifen treatment. The aim of this study was to analyze the prognostic significance of the distribution pattern of ERα expression, ESR1 gene single-nucleotide polymorphisms and expression levels of growth factor receptors in Russian hormone receptor-positive breast cancer patients treated with adjuvant tamoxifen. Formalin-fixed paraffin-embedded tumor tissue samples from 97 patients were examined for the distribution pattern of ERα expression, as well as for EGFR and TGF-βR1 expression by immunohistochemistry. Genotypes for ESR1 +30T>C (rs2077647) and ESR1 2014G>A (rs2228480) were analyzed using a TaqMan assay. Progression-free survival (PFS) was used as an endpoint for the survival analyses. We found that patients with the heterogeneous distribution of ERα expression had poor prognosis on tamoxifen treatment (P = 0.021). We identified a high EGFR expression in patients who developed distant metastasis or recurrence during tamoxifen treatment (a tamoxifen-resistant group-TR) in contrast to the distant metastasis-free patients (a tamoxifen-sensitive group-TS) (80.0 vs. 41.9 %, respectively, P = 0.009). Carriers of the ESR12014A mutant allele were more prevalent among the TR patients compared to the TS patients (26.3 vs. 8.0 %, respectively, P = 0.009). EGFR expression and the distribution pattern of ERα expression were associated with the response to tamoxifen by both univariate and multivariate logistic regression analyses. The presence of these markers either alone or in combination was correlated with the worse PFS for all patients. Analysis of the distribution pattern of ERα expression and the EGFR status in tumor tissue may be valuable for patient selection for tamoxifen adjuvant therapy.
Human iPSC-derived osteoblasts and osteoclasts together promote bone regeneration in 3D biomaterials.Thursday, May 26, 2016
Jeon OH, Panicker LM, Lu Q, Chae JJ, Feldman RA, Elisseeff JH,
Scientific reports. 2016
Bone substitutes can be designed to replicate physiological structure and function by creating a microenvironment that supports crosstalk between bone and immune cells found in the native tissue, specifically osteoblasts and osteoclasts. Human induced pluripotent stem cells (hiPSC) represent a powerful tool for bone regeneration because they are a source of patient-specific cells that can differentiate into all specialized cell types residing in bone. We show that osteoblasts and osteoclasts can be differentiated from hiPSC-mesenchymal stem cells and macrophages when co-cultured on hydroxyapatite-coated poly(lactic-co-glycolic acid)/poly(L-lactic acid) (HA-PLGA/PLLA) scaffolds. Both cell types seeded on the PLGA/PLLA especially with 5% w/v HA recapitulated the tissue remodeling process of human bone via coupling signals coordinating osteoblast and osteoclast activity and finely tuned expression of inflammatory molecules, resulting in accelerated in vitro bone formation. Following subcutaneous implantation in rodents, co-cultured hiPSC-MSC/-macrophage on such scaffolds showed mature bone-like tissue formation. These findings suggest the importance of coupling matrix remodeling through osteoblastic matrix deposition and osteoclastic tissue resorption and immunomodulation for tissue development.
Proteomic analysis of mouse oocytes identifies PRMT7 as reprogramming factor that replaces SOX2 in the induction of pluripotent stem cells.Thursday, May 26, 2016
Wang B, Pfeiffer MJ, Drexler HC, Fuellen G, Boiani M,
Journal of proteome research. 26-May-2016
The reprogramming process that leads to induced pluripotent stem cells (iPSCs) may benefit from adding oocyte factors to Yamanaka's reprogramming cocktail (OCT4, SOX2, KLF4, with or without MYC; OSK(M)). We previously searched for such facilitators of reprogramming (the reprogrammome) by applying label-free LC-MS/MS analysis to mouse oocytes, producing a catalog of 28 candidates that are (i) able to robustly access the cell nucleus, and (ii) shared between mature mouse oocytes and pluripotent embryonic stem cells. In the present study we hypothesized that our 28 reprogrammome candidates would also be (iii) abundant in mature oocytes, (iv) depleted after oocyte-to-embryo transition, and (v) able to potentiate or replace the OSKM factors. Using LC-MS/MS and isotopic labeling methods, we found that the abundance profiles of the 28 proteins were below those of known oocyte-specific and housekeeping proteins. Of the 28 proteins, only arginine methyltransferase 7 (PRMT7) changed substantially during mouse embryogenesis and promoted the conversion of mouse fibroblasts into iPSCs. Specifically, PRMT7 replaced SOX2 in a factor-substitution assay, yielding iPSCs. These findings exemplify how proteomics can be used to prioritize the functional analysis of reprogrammome candidates. The LC-MS/MS data are available via ProteomeXchange with identifier PXD003093.
Resveratrol promotes differentiation of mouse embryonic stem cells to cardiomyocytes.Thursday, May 26, 2016
Ding H, Xu X, Qin X, Yang C, Feng Q,
Cardiovascular therapeutics. 26-May-2016
RV can successfully direct the differentiation of mESCs into cardiomyocytes, shedding light on its future applications to treat cardiovascular diseases. This article is protected by copyright. All rights reserved.
Efficacy and safety of regenerative cell therapy for pulmonary arterial hypertension in animal models: a preclinical systematic review protocol.Thursday, May 26, 2016
Suen CM, Zhai A, Lalu MM, Welsh C, Levac BM, Fergusson D, McIntyre L, Stewart DJ,
Systematic reviews. 2016
Canine Adipose-Derived Stem Cells: Purinergic Characterization and Neurogenic Potential for Therapeutic Applications.Thursday, May 26, 2016
Roszek K, Makowska N, Czarnecka J, Porowińska D, Dąbrowski M, Danielewska J, Nowak W,
Journal of cellular biochemistry. 25-May-2016
The presented results evidence that canine adipose-derived stem cells (ADSCs) represent the premature population of stem cells with great biological potential and properties. ADCS are easy to obtain and culture, able to differentiate into the neurogenic lineage as well as it is easy to control their proliferation rate with nucleotides and nucleosides or analogues. We report that in vitro cultured canine ADSCs response to adenosine- and ATP-mediated stimulation. Differences in canine ADSCs and human mesenchymal stem cells in ecto-nucleotidase activity have been observed. The ecto-nucleotidase activity changes during ADSCs in vitro transdifferentiation into neurogenic lineage are fast and simple to analyze. Therefore, the simple analysis of ecto-enzymes activity allows for verification of the stem cells quality: their stemness or initiation of the differentiation process. The biological potential of the cells isolated from canine fat, as well as the good quality control of this cell culture, make them a promising tool for both experimental and therapeutic usage. This article is protected by copyright. All rights reserved.
Properties of internalization factors contributing to the uptake of extracellular DNA into tumor-initiating stem cells of mouse Krebs-2 cell line.Thursday, May 26, 2016
Dolgova EV, Potter EA, Proskurina AS, Minkevich AM, Chernych ER, Ostanin AA, Efremov YR, Bayborodin SI, Nikolin VP, Popova NA, Kolchanov NA, Bogachev SS,
Stem cell research & therapy. 2016
The internalization dynamics of extracellular DNA, copy number of the plasmids taken up by the cells, and competition between different types of double-stranded DNA upon internalization into tumor-initiating stem cells of mouse ascites Krebs-2 have been comprehensively analyzed. Investigation of the extracellular DNA internalization into tumor-initiating stem cells is an important part of understanding their properties and possible destruction mechanisms. For example, a TAMRA-labeled DNA probe may serve as an instrument to develop a target for the therapy of cancer, aiming at elimination of tumor stem cells, as well as developing a straightforward test system for the quantification of poorly differentiated cells, including tumor-initiating stem cells, in the bulk tumor sample (biopsy or surgery specimen).
The impact of patient co-morbidities on the regenerative capacity of cardiac explant-derived stem cells.Thursday, May 26, 2016
Mayfield AE, Fitzpatrick ME, Latham N, Tilokee EL, Villanueva M, Mount S, Lam BK, Ruel M, Stewart DJ, Davis DR,
Stem cell research & therapy. 2016
The regenerative performance of the earliest precursor cell population cultured from human explant tissue declines with accumulating medical co-morbidities. This effect is associated with diminished production of pro-cardiogenic cytokines and exosomes while IL-6 is markedly increased. Predictors of cardiac events demonstrated a lower capacity to support angiogenesis and repair injured myocardium in a mouse model of myocardial infarction.
Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication.Thursday, May 26, 2016
Kaufhold S, Garbán H, Bonavida B,
Journal of experimental & clinical cancer research : CR. 2016
The transcription factor Yin Yang 1 (YY1) is frequently overexpressed in cancerous tissues compared to normal tissues and has regulatory roles in cell proliferation, cell viability, epithelial-mesenchymal transition, metastasis and drug/immune resistance. YY1 shares many properties with cancer stem cells (CSCs) that drive tumorigenesis, metastasis and drug resistance and are regulated by overexpression of certain transcription factors, including SOX2, OCT4 (POU5F1), BMI1 and NANOG. Based on these similarities, it was expected that YY1 expression would be associated with SOX2, OCT4, BMI1, and NANOG's expressions and activities. Data mining from the proteomic tissue-based datasets from the Human Protein Atlas were used for protein expression patterns of YY1 and the four CSC markers in 17 types of cancer, including both solid and hematological malignancies. A close association was revealed between the frequency of expressions of YY1 and SOX2 as well as SOX2 and OCT4 in all cancers analyzed. Two types of dynamics were identified based on the nature of their association, namely, inverse or direct, between YY1 and SOX2. These two dynamics define distinctive patterns of BMI1 and OCT4 expressions. The relationship between YY1 and SOX2 expressions as well as the expressions of BMI1 and OCT4 resulted in the classification of four groups of cancers with distinct molecular signatures: 1) Prostate, lung, cervical, endometrial, ovarian and glioma cancers (YY1(lo)SOX2(hi)BMI1(hi)OCT4(hi)) 2) Skin, testis and breast cancers (YY1(hi)SOX2(lo)BMI1(hi)OCT4(hi)) 3) Liver, stomach, renal, pancreatic and urothelial cancers (YY1(lo)SOX2(lo)BMI1(hi)OCT4(hi)) and 4) Colorectal cancer, lymphoma and melanoma (YY1(hi)SOX2(hi)BMI1(lo)OCT4(hi)). A regulatory loop is proposed consisting of the cross-talk between the NF-kB/PI3K/AKT pathways and the downstream inter-regulation of target gene products YY1, OCT4, SOX2 and BMI1.
Enhanced Anti-Inflammatory Efficacy Through Targeting to Macrophages: Synthesis and In Vitro Evaluation of Folate-Glycine-Celecoxib.Thursday, May 26, 2016
Li Y, Xiao Y, Yin Z,
AAPS PharmSciTech. 25-May-2016
As an effective COX-2 inhibitor, celecoxib is widely used in anti-inflammation therapy. However, it may cause cardiovascular risks and renal adverse effects. In the present study, we aimed to construct a celecoxib prodrug with enhanced anti-inflammatory efficacy and reduced adverse effects using folate in order to target activated macrophages. Folate-glycine-celecoxib was synthesized and identified by (1)H-NMR, MS, and FTIR analyses. The cytotoxicity of folate-glycine-celecoxib was tested on murine macrophage cells (RAW264.7) using thiazolyl blue tetrazolium bromide. Cellular uptake studies were employed to determine targeting ability toward folate receptors via flow cytometry and confocal microscopy. Anti-inflammatory efficacy of folate-glycine-celecoxib was investigated by measuring the concentration of LPS-induced nitric oxide (NO). Folate-glycine-celecoxib exhibited lower cytotoxicity than conventional celecoxib, and this conjugate could be targetedly transported into RAW264.7 cells through binding with folate receptors on cell surface. Through targeting to RAW264.7 cells, folate-glycine-celecoxib exhibited better effects than equimolar celecoxib in NO inhibition, suggesting greater anti-inflammatory activity. These findings demonstrated that the prodrug folate-glycine-celecoxib had potential to treat inflammatory disease with low cytotoxicity and high targeting ability.
Adipose-Derived Stromal Cells from Lipomas: Isolation, Characterisation and Review of the Literature.Thursday, May 26, 2016
Tremp M, Menzi N, Tchang L, di Summa PG, Schaefer DJ, Kalbermatten DF,
Pathobiology : journal of immunopathology, molecular and cellular biology. 26-May-2016
ADSCs from lipoma may be interesting in the application of regenerative medicine. We discuss possible molecular treatment options to regulate their activities at the source of the MSL.
Derivation and application of pluripotent stem cells for regenerative medicine.Thursday, May 26, 2016
Wang J, Zhou Q,
Science China. Life sciences. Jun-2016
Pluripotent stem cells (PSCs) are cells that can differentiate into any type of cells in the body, therefore have valuable promise in regenerative medicine of cell replacement therapies and tissue/organ engineering. PSCs can be derived either from early embryos or directly from somatic cells by epigenetic reprogramming that result in customized cells from patients. Here we summarize the methods of deriving PSCs, the various types of PSCs generated with different status, and their versatile applications in both clinical and embryonic development studies. We also discuss an intriguing potential application of PSCs in constructing tissues/organs in large animals by interspecies chimerism. All these emerging findings are likely to contribute to the breakthroughs in biological research and the prosperous prospects of regenerative medicine.
Corepressive function of nuclear receptor coactivator 2 in androgen receptor of prostate cancer cells treated with antiandrogen.Thursday, May 26, 2016
Takeda K, Hara N, Nishiyama T, Tasaki M, Ishizaki F, Tomita Y,
BMC cancer. 2016
NCOA2, which has been thought to be recruited as a coactivator, possibly plays a corepressive role in AR of prostate cancer cells when treated with antiandrogens, suggesting its potential as a therapeutic target.
Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone.Thursday, May 26, 2016
Price TT, Burness ML, Sivan A, Warner MJ, Cheng R, Lee CH, Olivere L, Comatas K, Magnani J, Kim Lyerly H, Cheng Q, McCall CM, Sipkins DA,
Science translational medicine. 25-May-2016
Breast cancer metastatic relapse can occur years after therapy, indicating that disseminated breast cancer cells (BCCs) have a prolonged dormant phase before becoming proliferative. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating BCCs to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Using real-time in vivo microscopy of bone marrow (BM) in a breast cancer xenograft model, we show that dormant and proliferating BCCs occupy distinct areas, with dormant BCCs predominantly found in E-selectin- and stromal cell-derived factor 1 (SDF-1)-rich perisinusoidal vascular regions. We use highly specific inhibitors of E-selectin and C-X-C chemokine receptor type 4 (CXCR4) (SDF-1 receptor) to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Whereas E-selectin interactions are critical for allowing BCC entry into the BM, the SDF-1/CXCR4 interaction anchors BCCs to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation. Homing studies with primary BCCs also demonstrate that E-selectin regulates their entry into bone through the sinusoidal niche, and immunohistochemical staining of patient BMs shows dormant micrometastatic disease adjacent to SDF-1(+) vasculature. These findings shed light on how BCCs traffic within the host, and suggest that simultaneous blockade of CXCR4 and E-selectin in patients could molecularly excise dormant micrometastases from the protective BM environment, preventing their emergence as relapsed disease.
Chronic Myeloid Leukemia Blood Inflicted Injury in Cord Derived Wharton's Jelly Mesenchymal Stem Cells.Thursday, May 26, 2016
Wajid N, Ali M, Javed S, Ali F, Anwar SS,
Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. May-2016
Stressed environment of CML patients' blood/plasma induced injury to WJMSCs as well as reduced their viability. Effectiveness of these cells for therapeutics of CML is, therefore, likely to be reduced.
Tracing haematopoietic stem cell formation at single-cell resolution.Thursday, May 26, 2016
Zhou F, Li X, Wang W, Zhu P, Zhou J, He W, Ding M, Xiong F, Zheng X, Li Z, Ni Y, Mu X, Wen L, Cheng T, Lan Y, Yuan W, Tang F, Liu B,
Nature. 26-May-2016
Haematopoietic stem cells (HSCs) are derived early from embryonic precursors, such as haemogenic endothelial cells and pre-haematopoietic stem cells (pre-HSCs), the molecular identity of which still remains elusive. Here we use potent surface markers to capture the nascent pre-HSCs at high purity, as rigorously validated by single-cell-initiated serial transplantation. Then we apply single-cell RNA sequencing to analyse endothelial cells, CD45(-) and CD45(+) pre-HSCs in the aorta-gonad-mesonephros region, and HSCs in fetal liver. Pre-HSCs show unique features in transcriptional machinery, arterial signature, metabolism state, signalling pathway, and transcription factor network. Functionally, activation of mechanistic targets of rapamycin (mTOR) is shown to be indispensable for the emergence of HSCs but not haematopoietic progenitors. Transcriptome data-based functional analysis reveals remarkable heterogeneity in cell-cycle status of pre-HSCs. Finally, the core molecular signature of pre-HSCs is identified. Collectively, our work paves the way for dissection of complex molecular mechanisms regulating stepwise generation of HSCs in vivo, informing future efforts to engineer HSCs for clinical applications.
The Stress Response Paradox: Fighting Degeneration at the Cost of Cancer.Thursday, May 26, 2016
Arneaud SL, Douglas PM,
The FEBS journal. 26-May-2016
In the modern research era, sequencing and high-throughput analysis have linked genetic factors with a multitude of disease states. Often times, the same cellular machinery is implicated in several different diseases and has made it challenging to drug a particular disease with minimal pleotropic consequences. It is intriguing to see how different fields of disease research can present such differing views when describing the same biological process, pathway or molecule. As observations in one field converge with research in another, we gain a more complete picture of a biological system and can accurately assess the feasibility for translational science. As an example discussed here, modulating latent stress response pathways within the cell provides exciting therapeutic potential, however, opposing views have emerged in the fields of degenerative disease and cancer. This at first glance seems logical since suppression of degenerative disease entails maintaining cell viability, while cancer aims to enhance selective senescence and cell death. Since both of these disciplines seek novel therapeutic interventions, we should not overlook how scientific biases involving one biological process may impact different disease paradigms. This article is protected by copyright. All rights reserved.
Bad Memory: CD4 T Cell Presensitization Fosters Antibody-Mediated Kidney Transplant Rejection.Thursday, May 26, 2016
Dean PG, Griffin MD,
Journal of the American Society of Nephrology : JASN. 25-May-2016
Differentiation of Rat Bone Marrow Mesenchymal Stem Cells Into Neuron-Like Cells In Vitro and Co-Cultured with Biological Scaffold as Transplantation Carrier.Thursday, May 26, 2016
Yue W, Yan F, Zhang YL, Liu SL, Hou SP, Mao GC, Liu N, Ji Y,
Medical science monitor : international medical journal of experimental and clinical research. 2016
BACKGROUND Autograft and allograft transplantation are used to prompt the regeneration of axons after nerve injury. However, the poor self-regeneration caused by the glial scar and growth inhibitory factors after neuronal necrosis limit the efficacy of these methods. The purpose of this study was to develop a new chitosan porous scaffold for cell seeding. MATERIAL AND METHODS The bone marrow mesenchymal stem cells (BMSCs) and tissue-engineered biomaterial scaffold compound were constructed and co-cultured in vitro with the differentiated BMSCs of Wistar rats and chitosan scaffold in a 3D environment. The purity of the third-generation BMSCs culture was identified using flow cytometry and assessment of induced neuronal differentiation. The scaffolds were prepared by the freeze-drying method. The internal structure of scaffolds and the change of cells' growth and morphology were observed under a scanning electron microscope. The proliferation of cells was detected with the MTT method. RESULTS On day 5 there was a significant difference in the absorbance value of the experimental group (0.549±0.0256) and the control group (0.487±0.0357) (P>0.05); but on day 7 there was no significant difference in the proliferation of the experimental group (0.751±0.011) and the control group and (0.78±0.017) (P>0.05). CONCLUSIONS Tissue engineering technology can provide a carrier for cells seeding and is expected to become an effective method for the regeneration and repair of nerve cells. Our study showed that chitosan porous scaffolds can be used for such purposes.
Innovations in interventional pain management of chronic spinal pain.Wednesday, May 25, 2016
Manchikanti L, Boswell MV, Hirsch JA,
Expert review of neurotherapeutics. 25-May-2016
Interventional pain management and interventional techniques include neural blockade, neural ablative procedures, spinal cord and peripheral nerve stimulation, intrathecal drug delivery systems, minimally invasive lumbar decompression (MILD®), percutaneous endoscopic spinal decompression, and regenerative medicine. In addition, advances are also related to the evidence synthesis of comparative effectiveness research. Expert Commentary: Multiple innovations in interventional pain management and potential innovations may reduce costs and improve care and outcomes with proper evidence synthesis and application of principles of evidence-based medicine. Innovations in interventional pain management in managing chronic low back pain depend on extensive research and appropriate evidence synthesis. Innovations should be developed in conjunction with health care policy based on principles of evidence-based medicine.
ChREBP promotes the differentiation of leukemia-initiating cells to inhibit leukemogenesis through the TXNIP/RUNX1 pathways.Wednesday, May 25, 2016
Zeng H, Gu H, Chen C, Li M, Xia F, Xie L, Liu X, Zhang F, Tong X, Wang J, Yu Z, Zheng J,
Oncotarget. 20-May-2016
Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the maintenance of stemness in LICs, although the detailed mechanisms are poorly understood. Herein, we provide intriguing evidence showing that a glucose-responsive transcription factor, carbohydrate responsive element binding protein (ChREBP), served as a tumor suppressor rather than an oncogene, as previously described, to inhibit the development of acute myeloid leukemia by promoting the differentiation of LICs. Using an MLL-AF9-induced murine leukemia model, we demonstrated that the deletion of ChREBP resulted in the blockage of the differentiation of LICs and significantly reduced survival in ChREBP-null leukemic mice. However, ChREBP was not required for the normal repopulation abilities of hematopoietic stem cells. ChREBP promoted leukemia cell differentiation through the direct inhibition of RUNX1 or the transactivation of TXNIP to downregulate the RUNX1 level and ROS generation. Moreover, knockdown of ChREBP in human leukemia THP1 cells led to markedly enhanced proliferation and decreased differentiation upon PMA treatment. Collectively, we unraveled an unexpected role of ChREBP in leukemogenesis, which may provide valuable clues for developing novel metabolic strategies for leukemia treatment.
RNAi mediated IL-6 in vitro knockdown in psoriasis skin model with topical siRNA delivery system based on liquid crystalline phase.Wednesday, May 25, 2016
Depieri LV, Borgheti-Cardoso LN, Campos PM, Otaguiri KK, Vicentini FT, Lopes LB, Fonseca MJ, Vitória Lopes Badra Bentley M,
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. 17-May-2016
Gene therapy by RNA interference (RNAi) is a post-transcriptional silencing process that can suppress the expression of a particular gene and it is a promising therapeutic approach for the treatment of many severe diseases, including cutaneous disorders. However, difficulties related to administration and body distribution limit the clinical use of small interfering RNA (siRNA) molecules. In this study, we proposed to use nanocarriers to enable siRNA application in the topical treatment of skin disorders. A siRNA nanodispersion based on liquid crystalline phase and composed of monoolein (MO), oleic acid (OA) and polyethylenimine (PEI) was developed and its physicochemical properties, efficiency of complexation and carrier/siRNA stability were assessed. Subsequently, cell viability, cellular uptake, in vitro skin irritation test using reconstructed human epidermis (RHE) and in vitro IL-6 knockdown in psoriasis skin model were evaluated. The results showed that the liquid crystalline nanodispersion is a promising topical delivery system for administration of siRNA, being able to overcome the limitations of the route of administration, as well those resulting from the characteristics of siRNA molecules. The formulation was effective at complexing the siRNA, presented high rate of cell uptake (∼ 90%), increased the skin penetration of siRNA in vitro, and did not cause skin irritation compared with Triton-X (a moderate irritant), resulting in a 4-fold higher viability of reconstructed human epidermis and a 15.5-fold lower release of IL-1α. A single treatment with the liquid crystalline nanodispersion carrying IL-6 siRNA for 6 h was able to reduce the extracellular IL-6 levels by 3.3-fold compared with control treatment in psoriasis skin model. Therefore, liquid crystalline nanodispersion is a suitable nanocarrier for siRNA with therapeutic potential to suppress skin disease-specific genes. This study also highlights the applicability of reconstructed skin models in pharmaceutical field to evaluate the performance of delivery systems without the use of animal models.
Conformal Nanoencapsulation of Allogeneic T Cells Mitigates Graft-Versus-Host Disease and Retains Graft-Versus-Leukemia Activity.Wednesday, May 25, 2016
Zhao S, Zhang L, Han J, Chu J, Wang H, Chen X, Wang Y, Tun N, Lu L, Bai XF, Martha Y, Devine S, He X, Yu J,
ACS nano. 25-May-2016
Allogeneic transplantation of hematopoietic stem cells (HSC) in combination with T cells has a curative potential for hematopoietic malignancies through graft-versus-leukemia (GVL) effects, but is often compromised by the notorious side effect of graft-versus-host disease (GVHD) resulting from alloreactivity of the donor T cells. Here, we tested if temporary immunoisolation achieved by conformally encapsulating the donor T cells within a biocompatible and biodegradable porous film (~450 nm in thickness) of chitosan and alginate, could attenuate GVHD without compromising GVL. The nanoencapsulation was found not to affect the phenotype of T cells in terms of size, viability, proliferation, cytokine secretion, and cytotoxicity against tumor cells. Moreover, the porous nature of the nanoscale film allowed the encapsulated T cells to communicate with their environment as evidenced by their intact capability of binding to antibodies. Lethally-irradiated mice transplanted with bone marrow cells (BMCs) and the conformally encapsulated allogeneic T cells exhibited significantly improved survival and reduced GVHD associated with less liver damage, a smaller CD8+ to CD4+ T cells, and a better engraftment of donor BMCs compared to the transplantation of BMCs and non-encapsulated allogeneic T cells. Moreover, the conformal nanoencapsulation did not compromise the GVL effect of the donor T cells. These data show that conformal nanoencapsulation of T cells within biocompatible and biodegradable nanoscale porous materials is a potentially safe and effective approach to improve allogeneic HSC transplantation for treating hematological malignancies and other diseases.
Bortezomib for the Prevention and Treatment of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.Wednesday, May 25, 2016
Al-Homsi AS, Feng Y, Duffner U, Al Malki MM, Goodyke A, Cole K, Muilenburg M, Abdel-Mageed A,
Experimental hematology. 17-May-2016
Allogeneic hematopoietic stem cell transplantation is the standard treatment for a variety of benign and malignant conditions. However, graft-versus-host-disease (GvHD) continues to present a major barrier to the success and wide applicability of this procedure. While current GvHD prevention and treatment regimens exclusively target T cells, bortezomib, a reversible proteasome inhibitor possesses unique immune regulatory activities that span a wide variety of cellular processes of T and dendritic cells essential for the development of GvHD. Herein, we review the current understanding of bortezomib's effects in vitro and in animal models and summarize the clinical data relevant to its use in the prevention and treatment of GvHD. We conclude with an outline of the remaining challenges and opportunities to optimize bortezomib's potential role in this setting.
The bright side of plasmonic gold nanoparticles; activation of Nrf2, the cellular protective pathway.Wednesday, May 25, 2016
Goldstein A, Soroka Y, Frušić-Zlotkin M, Lewis A, Kohen R,
Nanoscale. 25-May-2016
Plasmonic gold nanoparticles (AuNPs) are widely investigated for cancer therapy, due to their ability to strongly absorb light and convert it to heat and thus selectively destroy tumor cells. In this study we shed light on a new aspect of AuNPs and their plasmonic excitation, wherein they can provide anti-oxidant and anti-inflammatory protection by stimulating the cellular protective Nrf2 pathway. Our study was carried out on cells of the immune system, macrophages, and on skin cells, keratinocytes. A different response to AuNPs was noted in the two types of cells, explained by their distinct uptake profiles. In keratinocytes, the exposure to AuNPs, even at low concentrations, was sufficient to activate the Nrf2 pathway, without any irradiation, due to the presence of free AuNPs inside the cytosol. In contrast, in macrophages, the plasmonic excitation of the AuNPs by a low, non-lethal irradiation dose was required for their release from the constraining vesicles. The mechanism by which AuNPs activate the Nrf2 pathway was studied. Direct and indirect activation were suggested, based on the inherent ability of the AuNPs to react with thiol groups and to generate reactive oxygen species, in particular, under plasmonic excitation. The ability of AuNPs to directly activate the Nrf2 pathway renders them good candidates for treatment of disorders in which the up-regulation of Nrf2 is beneficial, specifically for topical treatment of inflammatory skin diseases.
Cardiac mitochondrial oxidative capacity is partly preserved after cryopreservation with dimethyl sulfoxide.Thursday, May 26, 2016
Meyer A, Charles AL, Singh F, Zoll J, Talha S, Enache I, Chaarloux A, Inser-Horobeti ME, Geny B,
Cryo letters. 25-5-2016
Thus, fresh samples extemporaneous analysis should be preferred when available despite the fact that cryopreservation using DMSO partly protect cardiac mitochondrial respiration and coupling. These data support the interest to further refine cryopreservation methods.
Connecting HIV-1 Integration and Transcription: a step forward towards new treatments.Wednesday, May 25, 2016
Lucic B, Lusic M,
FEBS letters. 25-May-2016
Thanks to the current combined antiretroviral therapy (cART), HIV-1 infection has become a manageable though chronic disease. The reason for this lies in the fact that long-lived cellular reservoirs persist in patients on cART. Despite numerous efforts to understand molecular mechanisms that contribute to viral latency, the important question of how and when latency is established remains unanswered. Related to this is the connection between HIV-1 integration and the capacity of the provirus to enter the latent state. In this review, we will give an overview of these nuclear events in the viral life cycle in the light of current therapeutic approaches, which aim to either reactivate the provirus or even excise the proviral DNA from the cellular genome. This article is protected by copyright. All rights reserved.
What's in the Literature?Thursday, May 26, 2016
Silvestri NJ, Wolfe GI, Bromberg M, Lacomis D,
Journal of clinical neuromuscular disease. Jun-2016
One of the first questions asked by patients and family members when a diagnosis of amyotrophic lateral sclerosis is made is "what about stem cells?" The term "stem cells" has attractiveness to it, with the assumption that stem cell treatment (stem nerve cells) can replace lost nerve cells. There are perhaps 2 types of stem cell trials, those that are vetted by the Food and Drug Administration and those that have no official oversight and whose results are infrequently published. The issue of the latter was discussed in the last edition of this column. The results of one of the formal stem cell trials now in the United States have been reported. Spinal muscular atrophy is a form of motor neuron disease affecting children and has a genetic cause, which has led to a feasibility study giving antisense oligonucleotides, and the results have also been reported. Biomarkers of amyotrophic lateral sclerosis are being sought, and the presence of neurofilaments is promising. Inflammatory neuropathies are an important group because they are treatable. Intravenous immune globulin is a commonly used agent, but a number of questions persist: one is efficacy among brands, another is the probability of a response, and a third is optimum dosing and taper schedules. A number of recent articles address these issues. The predictive value of single-fiber electromyography in determining which patients with ocular myasthenia will develop generalized disease, the risk of crisis after thymectomy, and 2 papers discussing new forms of congenital myasthenic syndrome are discussed. The risk of brain tumors, quality of life, and the assessment of trunk muscle strength in patients with type 1 myotonic dystrophy is reviewed. An article describing the discovery of mutations in SCN4A as a cause of congenital myopathy is discussed, as is one describing the occurrence of rhabdomyolysis in a group of patients subsequently discovered to have various forms of muscular dystrophy. Finally, articles describing the features of patients with inflammatory myopathies and Jo-1 and either 3-hydroxy-3-methylglutaryl-conezymea reductase or to signal recognition particle antibodies are reviewed.
Epoxyeicosatrienoic Acids Regulate Adipocyte Differentiation of Mouse 3T3 Cells, Via PGC-1α Activation, Which is Required for HO-1 Expression and Increased Mitochondrial Function.Wednesday, May 25, 2016
Waldman M, Bellner L, Vanella L, Schragenheim J, Sodhi K, Singh SP, Lin D, Lakhkar AD, Li J, Hochhauser E, Arad M, Darzynkiewicz Z, Kappas A, Abraham NG,
Stem cells and development. 25-May-2016
Epoxyeicosatrienoic acid (EET) contributes to browning of white adipose stem cells to ameliorate obesity/diabetes and insulin resistance. In the current study, we show that EET altered pre-adipocyte function, enhanced of peroxisome proliferation-activated receptor γ coactivator α (PGC-1α) expression and increased mitochondrial function in the 3T3-L1 pre-adipocyte. Cells treated with EET resulted in an increase, p<0.05, in PGC-1α and a decrease in mitochondrial-derived ROS (MitoSox), p<0.05. The EET increase in HO-1 levels is dependent on activation of PGC-1α as cells deficient in PGC-1α (PGC-1α knockout adipocyte cell) have an impaired ability to express HO-1, p<0.02. Additionally, adipocytes treated with EET exhibited an increase in mitochondrial SOD in a PGC-1α -dependent manner, p<0.05. The increase in PGC-1α was associated with an increase in β-catenin, (p<0.05), adiponectin expression, p<0.05, and lipid accumulation, p<0.02. EET decreased heme levels and mitochondrial-derived ROS (MitoSox), p<0.05, compared to adipocytes that were untreated. EET also decreased MEST mRNA and protein levels (p<0.05). An adipocyte-derived EET acting in an autocrine/paracrine manner to increase PGC-1α is required for activation of HO-1 expression. This is the first study to dissect the mechanism by which the anti-adipogenic and anti-inflammatory lipid, EET, induces the PGC-1α signaling cascade, and reprograms the adipocyte phenotype by regulating mitochondrial function and HO-1 expression, leading to an increase in healthy, i.e. small, adipocytes and a decrease in adipocyte enlargement and terminal differentiation. This is manifested by an increase in mitochondrial function and an increase in the canonical Wnt signaling cascade during adipocyte proliferation and terminal differentiation.
Low Six4 and Six5 gene dosage improves dystrophic phenotype and prolongs life span of mdx mice.Wednesday, May 25, 2016
Yajima H, Kawakami K,
Development, growth & differentiation. 25-May-2016
Muscle regeneration is an important process for skeletal muscle growth and recovery. Repair of muscle damage is exquisitely programmed by cellular mechanisms inherent in myogenic stem cells, also known as muscle satellite cells. We demonstrated previously the involvement of homeobox transcription factors, SIX1, SIX4 and SIX5, in the coordinated proliferation and differentiation of isolated satellite cells in vitro. However, their roles in adult muscle regeneration in vivo remain elusive. To investigate SIX4 and SIX5 functions during muscle regeneration, we introduced knockout alleles of Six4 and Six5 into an animal model of Duchenne Muscular Dystrophy (DMD), mdx (Dmd(mdx) /Y) mice, characterized by frequent degeneration-regeneration cycles in muscles. A lower number of small myofibers, higher number of thick ones and lower serum creatine kinase and lactate dehydrogenase activities were noted in 50-week-old Six4(+/-) 5(+/-) Dmd(mdx) /Y mice than Dmd(mdx) /Y mice, indicating improvement of dystrophic phenotypes of Dmd(mdx) /Y mice. Higher proportions of cells positive for MYOD1 and MYOG (markers of regenerating myonuclei) and SIX1 (a marker of regenerating myoblasts and newly regenerated myofibers) in 12-week-old Six4(+/-) 5(+/-) Dmd(mdx) /Y mice suggested enhanced regeneration, compared with Dmd(mdx) /Y mice. Although grip strength was comparable in Six4(+/-) 5(+/-) Dmd(mdx) /Y and Dmd(mdx) /Y mice, treadmill exercise did not induce muscle weakness in Six4(+/-) 5(+/-) Dmd(mdx) /Y mice, suggesting higher regeneration capacity. In addition, Six4(+/-) 5(+/-) Dmd(mdx) /Y mice showed 33.8% extension of life span. The results indicated that low Six4 and Six5 gene dosage improved dystrophic phenotypes of Dmd(mdx) /Y mice by enhancing muscle regeneration, and suggested that SIX4 and SIX5 are potentially useful de novo targets in therapeutic applications against muscle disorders, including DMD.
Role of Fibroblast Growth Factor-5 on the Proliferation of Human Tonsil-derived Mesenchymal Stem Cells.Wednesday, May 25, 2016
Park GC, Song JS, Park HY, Shin SC, Jang JY, Lee JC, Wang SG, Lee BJ, Jung JS,
Stem cells and development. 25-May-2016
Human mesenchymal stem cells (MSCs) are a promising tool for therapeutic applications in cell-based therapy and regenerative medicine, and MSCs from the human palatine tonsils have recently been used as a new tissue source. However, the understanding of the proliferation and differentiation capacity of T-MSCs is limited. In this study, we compared the proliferative potential of T-MSCs with BM-MSCs and adipose tissue-derived MSCs (A-MSCs). Additionally, we investigated the underlying mechanism of T-MSC function. We showed that T-MSCs proliferated faster than A-MSCs and BM-MSCs in MTT assays, cell count assays, and cell cycle distribution analyses. DNA microarray and real-time PCR analyses revealed that the expression of fibroblast growth factor-5 (FGF5) was significantly elevated in T-MSCs compared with those in A-MSCs and BM-MSCs. Cell growth curves showed a difference in cell growth between untreated cells and siFGF5-treated T-MSCs. The administration of recombinant human FGF5 (rhFGF5) to the cells transfected with siFGF5 led to a significant increase in the proliferation rates. The administration of rhFGF5 to T-MSCs led to an increase in the levels of phosphorylated ERK1/2. However, treatment with siFGF5 resulted in an overall decrease in the level of phosphorylated ERK1/2. The osteogenic differentiation of T-MSCs was reduced following siFGF5 transfection, and it recovered to near-normal levels when rhFGF5 was added. These findings indicate that T-MSCs show significantly higher proliferative potential compared with BM-MSCs and A-MSCs. FGF5 facilitates cell proliferation through ERK1/2 activation, and it influences the osteogenic differentiation of T-MSCs.
Autophagy Guarantees Stemness of Muscle Stem Cells By Maintaining Quiescence.Wednesday, May 25, 2016
Liu S, Jin Y, Shi S,
Oral diseases. 25-May-2016
Muscle regeneration relies on muscle stem cells, also known as satellite cells. Satellite cells are maintained in a quiescent state and can be activated on-demand for regeneration until they reach irreversible senescence. Recently, García-Prat et al. (2016) revealed that the transition from quiescence to senescence in satellite cells is associated with autophagy impairment, which is induced by the aging process. This article is protected by copyright. All rights reserved.
The role of microRNAs in animal cell reprograming.Wednesday, May 25, 2016
Cruz-Santos M, Aragón-Raygoza A, Espinal-Centeno A, Arteaga-Vázquez M, Bako L, Cruz-Hernández A, Cruz-Ramirez A,
Stem cells and development. 25-May-2016
Our concept of cell reprogramming and cell plasticity has evolved since John Gurdon transferred the nucleus of a completely differentiated cell into an enucleated Xenopus laevis egg thereby generating embryos which developed into tadpoles. More recently, induced expression of transcription factors, oct4, sox2, klf4 and c-myc has evidenced the plasticity of the genome to change the expression program and cell phenotype by driving differentiated cells to the pluripotent state. Beyond these milestone achievements, research in artificial cell reprogramming has been focused on other molecules different than transcription factors. Among the candidate molecules, micro-RNAs stand out due to their potential to control the levels of proteins which are involved in cellular processes such as self-renewal, proliferation and differentiation. Here, we review the role of microRNAs in the maintenance and differentiation of mesenchymal stem cells, epimorphic regeneration and somatic cell reprogramming to iPSCs.
Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging.Wednesday, May 25, 2016
Brosh RM, Bellani M, Liu Y, Seidman MM,
Ageing research reviews. 17-May-2016
Fanconi Anemia (FA) is a rare autosomal genetic disorder characterized by progressive bone marrow failure (BMF), endocrine dysfunction, cancer, and other clinical features commonly associated with normal aging. The anemia stems directly from an accelerated decline of the hematopoietic stem cell compartment. Although FA is a complex heterogeneous disease linked to mutations in 19 currently identified genes, there has been much progress in understanding the molecular pathology involved. FA is broadly considered a DNA repair disorder and the FA gene products, together with other DNA repair factors, have been implicated in interstrand cross-link (ICL) repair. However, in addition to the defective DNA damage response, altered epigenetic regulation, and telomere defects, FA is also marked by elevated levels of inflammatory mediators in circulation, a hallmark of faster decline in not only other hereditary aging disorders but also normal aging. In this review, we offer a perspective of FA as a monogenic accelerated aging disorder, citing the latest evidence for its multi-factorial deficiencies underlying its unique clinical and cellular features.
Mechanisms Involved in the Development of the Chronic Gastrointestinal Syndrome in Nonhuman Primates after Total-Body Irradiation with Bone Marrow Shielding.Wednesday, May 25, 2016
Shea-Donohue T, Fasano A, Zhao A, Notari L, Yan S, Sun R, Bohl JA, Desai N, Tudor G, Morimoto M, Booth C, Bennett A, Farese AM, MacVittie TJ,
Radiation research. 25-May-2016
In this study, nonhuman primates (NHPs) exposed to lethal doses of total body irradiation (TBI) within the gastrointestinal (GI) acute radiation syndrome range, sparing ∼5% of bone marrow (TBI-BM5), were used to evaluate the mechanisms involved in development of the chronic GI syndrome. TBI increased mucosal permeability in the jejunum (12-14 Gy) and proximal colon (13-14 Gy). TBI-BM5 also impaired mucosal barrier function at doses ranging from 10-12.5 Gy in both small intestine and colon. Timed necropsies of NHPs at 6-180 days after 10 Gy TBI-BM5 showed that changes in small intestine preceded those in the colon. Chronic GI syndrome in NHPs is characterized by continued weight loss and intermittent GI syndrome symptoms. There was a long-lasting decrease in jejunal glucose absorption coincident with reduced expression of the sodium-linked glucose transporter. The small intestine and colon showed a modest upregulation of several different pro-inflammatory mediators such as NOS-2. The persistent inflammation in the post-TBI-BM5 period was associated with a long-lasting impairment of mucosal restitution and a reduced expression of intestinal and serum levels of alkaline phosphatase (ALP). Mucosal healing in the postirradiation period is dependent on sparing of stem cell crypts and maturation of crypt cells into appropriate phenotypes. At 30 days after 10 Gy TBI-BM5, there was a significant downregulation in the gene and protein expression of the stem cell marker Lgr5 but no change in the gene expression of enterocyte or enteroendocrine lineage markers. These data indicate that even a threshold dose of 10 Gy TBI-BM5 induces a persistent impairment of both mucosal barrier function and restitution in the GI tract and that ALP may serve as a biomarker for these events. These findings have important therapeutic implications for the design of medical countermeasures.
Loss of GltB Inhibits Biofilm Formation and Biocontrol Efficiency of Bacillus subtilis Bs916 by Altering the Production of γ-Polyglutamate and Three Lipopeptides.Thursday, May 26, 2016
Zhou H, Luo C, Fang X, Xiang Y, Wang X, Zhang R, Chen Z,
PloS one. 2016
This is the first report of a key regulatory protein (GltB) that is involved in biofilm regulation and its regulation mechanism and biocontrol efficiency by B. subtilis.
The combination of Everolimus with Verapamil reduces ovarian weight and vascular permeability on ovarian hyperstimulation syndrome: a preclinical experimental randomized controlled study.Wednesday, May 25, 2016
Kitsou C, Kosmas I, Lazaros L, Tzallas C, Tinelli A, Mynbaev O, Prapas N, Prapas I, Dalkalitsis A, Georgiou I,
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 25-May-2016
The efficacy of pathways inhibition and the combined effect of Everolimus (mTOR inhibitor) and Verapamil (CYP3A inhibitor) in ovarian hyperstimulation syndrome (OHSS) need to be tested. Therefore, the impact of a leucotriene receptor antagonist, an anticoagulant, a GnRH antagonist as well as Everolimus plus Verapamil (at various doses and days of administration) on an OHSS rat model was tested. Sixty three female Wistar rats were randomly divided into seven groups. The control group received saline, while the OHSS group received rec-FSH for four consecutive days. The other five groups received rec-FSH for four days and Montelukast daily, Heparin daily, GnRH antagonist daily, Everolimus plus Verapamil in the last two days (half days group) and Everolimus plus Verapamil (half dose group) daily, respectively. All groups received also hCG at the fifth day. Significantly reduced ovarian weight was observed in the Everolimus plus Verapamil groups (half days and half-dose groups) and the Montelukast group compared to the OHSS group (p = 0.001 and p = 0.001, respectively). The vascular permeability was significantly reduced in the Everolimus plus Verapamil group (half dose group) and the GnRH antagonist group compared to the OHSS group (p < 0.001 and p = 0.011, respectively). However, estradiol and progesterone levels did not differ significantly between the groups. Studying the inhibition of different pathways, we concluded that the co-administration of Everolimus and Verapamil (at half dose) is beneficial for reducing ovarian weight and vascular permeability in an OHSS animal model.
Establishment of a multimarker qPCR panel for the molecular characterization of circulating tumor cells in blood samples of metastatic breast cancer patients during the course of palliative treatment.Wednesday, May 25, 2016
Bredemeier M, Edimiris P, Tewes M, Mach P, Aktas B, Schellbach D, Wagner J, Kimmig R, Kasimir-Bauer S,
Oncotarget. 20-May-2016
Monitoring MBC patients using a multimarker qPCR panel for the characterization of CTC might help to treat patients accordingly in the future.
Reactive oxygen species formation and bystander effects in gradient irradiation on human breast cancer cells.Wednesday, May 25, 2016
Zhang D, Zhou T, He F, Rong Y, Lee SH, Wu S, Zuo L,
Oncotarget. 20-May-2016
Ionizing radiation (IR) in cancer radiotherapy can induce damage to neighboring cells via non-targeted effects by irradiated cells. These so-called bystander effects remain an area of interest as it may provide enhanced efficacy in killing carcinomas with minimal radiation. It is well known that reactive oxygen species (ROS) are ubiquitous among most biological activities. However, the role of ROS in bystander effects has not been thoroughly elucidated. We hypothesized that gradient irradiation (GI) has enhanced therapeutic effects via the ROS-mediated bystander pathways as compared to uniform irradiation (UI). We evaluated ROS generation, viability, and apoptosis in breast cancer cells (MCF-7) exposed to UI (5 Gy) or GI (8-2 Gy) in radiation fields at 2, 24 and 48 h after IR. We found that extracellular ROS release induced by GI was higher than that by UI at both 24 h (p < 0.001) and 48 h (p < 0.001). More apoptosis and less viability were observed in GI when compared to UI at either 24 h or 48 h after irradiation. The mean effective doses (ED) of GI were ~130% (24 h) and ~48% (48 h) higher than that of UI, respectively. Our results suggest that GI is superior to UI regarding redox mechanisms, ED, and toxic dosage to surrounding tissues.
Platelet factor 4 is produced by subsets of myeloid cells in premetastatic lung and inhibits tumor metastasis.Wednesday, May 25, 2016
Jian J, Pang Y, Yan HH, Min Y, Achyut BR, Hollander MC, Lin PC, Liang X, Yang L,
Oncotarget. 19-May-2016
Bone marrow-derived myeloid cells can form a premetastatic niche and provide a tumor-promoting microenvironment. However, subsets of myeloid cells have also been reported to have anti-tumor properties. It is not clear whether there is a transition between anti- and pro- tumor function of these myeloid cells, and if so, what are the underlying molecular mechanisms. Here we report platelet factor 4 (PF4), or CXCL4, but not the other family members CXCL9, 10, and 11, was produced at higher levels in the normal lung and early stage premetastatic lungs but decreased in later stage lungs. PF4 was mostly produced by Ly6G+CD11b+ myeloid cell subset. Although the number of Ly6G+CD11b+ cells was increased in the premetastatic lungs, the expression level of PF4 in these cells was decreased during the metastatic progression. Deletion of PF4 (PF4 knockout or KO mice) led an increased metastasis suggesting an inhibitory function of PF4. There were two underlying mechanisms: decreased blood vessel integrity in the premetastatic lungs and increased production of hematopoietic stem/progenitor cells (HSCs) and myeloid derived suppressor cells (MDSCs) in tumor-bearing PF4 KO mice. In cancer patients, PF4 expression levels were negatively correlated with tumor stage and positively correlated with patient survival. Our studies suggest that PF4 is a critical anti-tumor factor in the premetastatic site. Our finding of PF4 function in the tumor host provides new insight to the mechanistic understanding of tumor metastasis.
Suppression of endogenous lipogenesis induces reversion of the malignant phenotype and normalized differentiation in breast cancer.Wednesday, May 25, 2016
Gonzalez-Guerrico AM, Espinoza I, Schroeder B, Park CH, Kvp CM, Khurana A, Corominas-Faja B, Cuyàs E, Alarcón T, Kleer C, Menendez JA, Lupu R,
Oncotarget. 18-May-2016
The correction of specific signaling defects can reverse the oncogenic phenotype of tumor cells by acting in a dominant manner over the cancer genome. Unfortunately, there have been very few successful attempts at identifying the primary cues that could redirect malignant tissues to a normal phenotype. Here we show that suppression of the lipogenic enzyme fatty acid synthase (FASN) leads to stable reversion of the malignant phenotype and normalizes differentiation in a model of breast cancer (BC) progression. FASN knockdown dramatically reduced tumorigenicity of BC cells and restored tissue architecture, which was reminiscent of normal ductal-like structures in the mammary gland. Loss of FASN signaling was sufficient to direct tumors to a reversed phenotype that was near normal when considering the development of polarized growth-arrested acinar-like structure similar to those formed by nonmalignant breast cells in a 3D reconstituted basement membrane in vitro. This process, in vivo, resulted in a low proliferation index, mesenchymal-epithelial transition, and shut-off of the angiogenic switch in FASN-depleted BC cells orthotopically implanted into mammary fat pads. The role of FASN as a negative regulator of correct breast tissue architecture and terminal epithelial cell differentiation was dominant over the malignant phenotype of tumor cells possessing multiple cancer-driving genetic lesions as it remained stable during the course of serial in vivo passage of orthotopic tumor-derived cells. Transient knockdown of FASN suppressed hallmark structural and cytosolic/secretive proteins (vimentin, N-cadherin, fibronectin) in a model of EMT-induced cancer stem cells (CSC). Indirect pharmacological inhibition of FASN promoted a phenotypic switch from basal- to luminal-like tumorsphere architectures with reduced intrasphere heterogeneity. The fact that sole correction of exacerbated lipogenesis can stably reprogram cancer cells back to normal-like tissue architectures might open a new avenue to chronically restrain BC progression by using FASN-based differentiation therapies.
Activators and Repressors: A balancing act for X-inactivation.Wednesday, May 25, 2016
Goodrich L, Panning B, Leung KN,
Seminars in cell & developmental biology. 17-May-2016
In early female embryos X-chromosome inactivation occurs concomitant with up regulation of the non-coding RNA, Xist, on the future inactive X-chromosome. Up regulation of Xist and coating of the future inactive X is sufficient to induce silencing. Therefore unlocking the mechanisms of X-chromosome inactivation requires thorough understanding of the transcriptional regulators, both activators and repressors, which control Xist. Mouse pluripotent embryonic stem cells, which have two active X chromosomes, provide a tractable ex vivo model system for studying X-chromosome inactivation, since this process is triggered by differentiation signals in these cultured cells. Yet there are significant discrepancies found between ex vivo analyses in mouse embryonic stem cells and in vivo studies of early embryos. In this review we elaborate on potential models of how Xist is up regulated on a single X chromosome in female cells and how ex vivo and in vivo analyses enlighten our understanding of the activators and repressors that control this non-coding RNA gene.
NOVA regulate Dcc alternative splicing during neuronal migration and axon guidance in the spinal cord.Wednesday, May 25, 2016
Leggere JC, Saito Y, Darnell RB, Tessier-Lavigne M, Junge HJ, Chen Z,
eLife. 25-May-2016
RNA-binding proteins (RBPs) control multiple aspects of post-transcriptional gene regulation and function during various biological processes in the nervous system. To further reveal the functional significance of RBPs during neural development, we carried out an in vivo RNAi screen in the dorsal spinal cord interneurons, including the commissural neurons. We found that the NOVA family of RBPs play a key role in neuronal migration, axon outgrowth, and axon guidance. Interestingly, Nova mutants display similar defects as the knockout of the Dcc transmembrane receptor. We show here that Nova deficiency disrupts the alternative splicing of Dcc, and that restoring Dcc splicing in Nova knockouts is able to rescue the defects. Together, our results demonstrate that the production of DCC splice variants controlled by NOVA has a crucial function during many stages of commissural neuron development.
Enhanced anti-tumor activity and cytotoxic effect on cancer stem cell population of metformin-butyrate compared with metformin HCl in breast cancer.Wednesday, May 25, 2016
Lee KM, Lee M, Lee J, Kim SW, Moon HG, Noh DY, Han W,
Oncotarget. 20-May-2016
Metformin, which is a drug commonly used to treat type 2 diabetes, has shown anti-tumor effects in numerous experimental, epidemiologic, observational, and clinical studies. Here, we report a new metformin derivative, metformin-butyrate (MFB). Compared to metformin-HCl, it more potently activates AMPK, inhibits mTOR, and impairs cell cycle progression at S and G2/M phases. Moreover, MFB inhibits the mammosphere formation of breast cancer cells and shows cytotoxic effects against CD44+CD24-/low populations in vitro and in vivo, indicating that it might have preferential effects on the cancer stem cell population. MFB showed synergistic cytotoxicity with docetaxel and cisplatin, and MFB pretreatment of breast cancer cells prior to their injection into the mammary fat pads of mice significantly decreased the obtained xenograft tumor volumes, compared with untreated or metformin-pretreated cells. Overall, MFB showed greater anti-neoplastic activity and greater efficacies in targeting the G2/M phase and breast cancer stem cell population, compared to metformin-HCl. This suggests that MFB may be a promising therapeutic agent against aggressive and resistant breast cancers.
Overexpression of EZH2 is associated with the poor prognosis in osteosarcoma and function analysis indicates a therapeutic potential.Wednesday, May 25, 2016
Sun R, Shen J, Gao Y, Zhou Y, Yu Z, Hornicek F, Kan Q, Duan Z,
Oncotarget. 20-May-2016
Osteosarcoma is a primary malignant bone tumor that has a poor prognosis due to local recurrence, metastasis, and chemotherapy resistance. Therefore, there is an urgent need to develop novel potential therapeutic targets for osteosarcoma. Enhancer of zeste homologue 2 (EZH2) is a member of the polycomb group of proteins, which has important functions in epigenetic silencing and cell cycle regulation. Overexpression of EZH2 has been found in several malignancies, however, its expression and the role of EZH2 in osteosarcoma is largely unknown. In this study, we examined EZH2 expression by immunohistochemistry in a large series of osteosarcoma tissues in association with tumor characteristics and patient outcomes. EZH2 expression was also analyzed in a microarray dataset of osteosarcoma. Results showed that higher expression of EZH2 was significantly associated with more aggressive tumor behavior and poor patient outcomes of osteosarcoma. We subsequently investigated the functional and therapeutic relevance of EZH2 as a target in osteosarcoma. Immunohistochemical analysis indicated that EZH2 expression was significantly associated with more aggressive tumor behavior and poorer patient outcomes of osteosarcoma. EZH2 silencing by siRNA inhibited osteosarcoma cell growth, proliferation, migration, and invasion. Moreover, suppression of EZH2 attenuated cancer stem cell functions. Similar results were observed in osteosarcoma cells treated with EZH2 specific inhibitor 3-deazaneplanocin A (DZNep), which exhausted cellular levels of EZH2. These results suggest that EZH2 is critical for the growth and metastasis of osteosarcoma, and an epigenetic therapy that pharmacologically targets EZH2 via specific inhibitors may constitute a novel approach to the treatment of osteosarcoma.
The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation.Wednesday, May 25, 2016
Wu Q, Madany P, Dobson JR, Schnabl JM, Sharma S, Smith TC, van Wijnen AJ, Stein JL, Lian JB, Stein GS, Muthuswami R, Imbalzano AN, Nickerson JA,
Oncotarget. 20-May-2016
Cancer cells reprogram cellular metabolism to meet the demands of growth. Identification of the regulatory machinery that regulates cancer-specific metabolic changes may open new avenues for anti-cancer therapeutics. The epigenetic regulator BRG1 is a catalytic ATPase for some mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is a well-characterized tumor suppressor in some human cancers, but is frequently overexpressed without mutation in other cancers, including breast cancer. Here we demonstrate that BRG1 upregulates de novo lipogenesis and that this is crucial for cancer cell proliferation. Knockdown of BRG1 attenuates lipid synthesis by impairing the transcription of enzymes catalyzing fatty acid and lipid synthesis. Remarkably, exogenous addition of palmitate, the key intermediate in fatty acid synthesis, rescued the cancer cell proliferation defect caused by BRG1 knockdown. Our work suggests that targeting BRG1 to reduce lipid metabolism and, thereby, to reduce proliferation, has promise for epigenetic therapy in triple negative breast cancer.
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