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Stem Cells
Retention and Functional Effect of Adipose-Derived Stromal Cells Administered in Alginate Hydrogel in a Rat Model of Acute Myocardial Infarction.
May 18, 2018   Stem Cells International
Follin B, Ghotbi AA, Clemmensen AE, Bentsen S, Juhl M, Søndergaard RH, Lund LD, Haack-Sørensen M, Hasbak P, Cohen S, Ripa RS, Kastrup J, Ekblond A, Kjær A
Retention and Functional Effect of Adipose-Derived Stromal Cells Administered in Alginate Hydrogel in a Rat Model of Acute Myocardial Infarction.
May 18, 2018
Stem Cells International
Background: Cell therapy for heart disease has been proven safe and efficacious, despite poor cell retention in the injected area. Improving cell retention is hypothesized to increase the treatment effect. In the present study, human adipose-derived stromal cells (ASCs) were delivered in an in situ forming alginate hydrogel following acute myocardial infarction (AMI) in rats. Methods: ASCs were transduced with luciferase and tested for ASC phenotype. AMI was inducted in nude rats, with subsequent injection of saline (controls), 1 × 106 ASCs in saline or 1 × 106 ASCs in 1% (w/v) alginate hydrogel. ASCs were tracked by bioluminescence and functional measurements were assessed by magnetic resonance imaging (MRI) and 82rubidium positron emission tomography (PET). Results: ASCs in both saline and alginate hydrogel significantly increased the ejection fraction (7.2% and 7.8% at 14 days and 7.2% and 8.0% at 28 days, resp.). After 28 days, there was a tendency for decreased infarct area and increased perfusion, compared to controls. No significant differences were observed between ASCs in saline or alginate hydrogel, in terms of retention and functional salvage. Conclusion: ASCs improved the myocardial function after AMI, but administration in the alginate hydrogel did not further improve retention of the cells or myocardial function.
Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma.
May 17, 2018   Science Translational Medicine
Lochmann TL, Powell KM, Ham J, Floros KV, Heisey DAR,   . . . . . .   , Gowda M, Souers AJ, Reynolds CP, Benes CH, Faber AC
Targeted inhibition of histone H3K27 demethylation is effective in high-risk neuroblastoma.
May 17, 2018
Science Translational Medicine
High-risk neuroblastoma is often distinguished by amplification of MYCN and loss of differentiation potential. We performed high-throughput drug screening of epigenetic-targeted therapies across a large and diverse tumor cell line panel and uncovered the hypersensitivity of neuroblastoma cells to GSK-J4, a small-molecule dual inhibitor of lysine 27 of histone 3 (H3K27) demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), and histone demethylase Jumonji D3 (JMJD3). Mechanistically, GSK-J4 induced neuroblastoma differentiation and endoplasmic reticulum (ER) stress, with accompanying up-regulation of p53 up-regulated modulator of apoptosis (PUMA) and induction of cell death. Retinoic acid (RA)-resistant neuroblastoma cells were sensitive to GSK-J4. In addition, GSK-J4 was effective at blocking the growth of chemorefractory and patient-derived xenograft models of high-risk neuroblastoma in vivo. Furthermore, GSK-J4 and RA combination increased differentiation and ER stress over GSK-J4 effects and limited the growth of neuroblastomas resistant to either drug alone. In MYCN-amplified neuroblastoma, PUMA induction by GSK-J4 sensitized tumors to the B cell lymphoma 2 (BCL-2) inhibitor venetoclax, demonstrating that epigenetic-targeted therapies and BCL-2 homology domain 3 mimetics can be rationally combined to treat this high-risk subset of neuroblastoma. Therefore, H3K27 demethylation inhibition is a promising therapeutic target to treat high-risk neuroblastoma, and H3K27 demethylation can be part of rational combination therapies to induce robust antineuroblastoma activity.
Lava flows, stem-cell crackdown and Ebola returns.
May 17, 2018   Nature Add nature.com free-link Cancel
Pancreas regeneration.
May 17, 2018   Nature Add nature.com free-link Cancel
Zhou Q, Melton DA
Pancreas regeneration.
May 17, 2018
Nature
The pancreas is made from two distinct components: the exocrine pancreas, a reservoir of digestive enzymes, and the endocrine islets, the source of the vital metabolic hormone insulin. Human islets possess limited regenerative ability; loss of islet β-cells in diseases such as type 1 diabetes requires therapeutic intervention. The leading strategy for restoration of β-cell mass is through the generation and transplantation of new β-cells derived from human pluripotent stem cells. Other approaches include stimulating endogenous β-cell proliferation, reprogramming non-β-cells to β-like cells, and harvesting islets from genetically engineered animals. Together these approaches form a rich pipeline of therapeutic development for pancreatic regeneration.
New approaches for brain repair-from rescue to reprogramming.
May 17, 2018   Nature Add nature.com free-link Cancel
Barker RA, Götz M, Parmar M
New approaches for brain repair-from rescue to reprogramming.
May 17, 2018
Nature
The ability to repair or promote regeneration within the adult human brain has been envisioned for decades. Until recently, such efforts mainly involved delivery of growth factors and cell transplants designed to rescue or replace a specific population of neurons, and the results have largely been disappointing. New approaches using stem-cell-derived cell products and direct cell reprogramming have opened up the possibility of reconstructing neural circuits and achieving better repair. In this Review we briefly summarize the history of neural repair and then discuss these new therapeutic approaches, especially with respect to chronic neurodegenerative disorders.
Diverse mechanisms for endogenous regeneration and repair in mammalian organs.
May 17, 2018   Nature Add nature.com free-link Cancel
Wells JM, Watt FM
Diverse mechanisms for endogenous regeneration and repair in mammalian organs.
May 17, 2018
Nature
Mammalian organs comprise an extraordinary diversity of cell and tissue types. Regenerative organs, such as the skin and gastrointestinal tract, use resident stem cells to maintain tissue function. Organs with a lower cellular turnover, such as the liver and lungs, mostly rely on proliferation of committed progenitor cells. In many organs, injury reveals the plasticity of both resident stem cells and differentiated cells. The ability of resident cells to maintain and repair organs diminishes with age, whereas, paradoxically, the risk of cancer increases. New therapeutic approaches aim to harness cell plasticity for tissue repair and regeneration while avoiding the risk of malignant transformation of cells.
Bioengineering strategies to accelerate stem cell therapeutics.
May 17, 2018   Nature Add nature.com free-link Cancel
Madl CM, Heilshorn SC, Blau HM
Bioengineering strategies to accelerate stem cell therapeutics.
May 17, 2018
Nature
Although only a few stem cell-based therapies are currently available to patients, stem cells hold tremendous regenerative potential, and several exciting clinical applications are on the horizon. Biomaterials with tuneable mechanical and biochemical properties can preserve stem cell function in culture, enhance survival of transplanted cells and guide tissue regeneration. Rapid progress with three-dimensional hydrogel culture platforms provides the opportunity to grow patient-specific organoids, and has led to the discovery of drugs that stimulate endogenous tissue-specific stem cells and enabled screens for drugs to treat disease. Therefore, bioengineering technologies are poised to overcome current bottlenecks and revolutionize the field of regenerative medicine.
Hypothermia broadens the therapeutic time window of mesenchymal stem cell transplantation for severe neonatal hypoxic ischemic encephalopathy.
May 23, 2018   Scientific Reports
Ahn SY, Chang YS, Sung DK, Sung SI, Park WS
Hypothermia broadens the therapeutic time window of mesenchymal stem cell transplantation for severe neonatal hypoxic ischemic encephalopathy.
May 23, 2018
Scientific Reports
Recently, we have demonstrated that concurrent hypothermia and mesenchymal stem cells (MSCs) transplantation synergistically improved severe neonatal hypoxic ischemic encephalopathy (HIE). The current study was designed to determine whether hypothermia could extend the therapeutic time window of MSC transplantation for severe neonatal HIE. To induce HIE, newborn rat pups were exposed to 8% oxygen for 2 h following unilateral carotid artery ligation on postnatal day (P) 7. After approving severe HIE involving >50% of the ipsilateral hemisphere volume, hypothermia (32 °C) for 2 days was started. MSCs were transplanted 2 days after HIE modeling. Follow-up brain MRI, sensorimotor function tests, assessment of inflammatory cytokines in the cerebrospinal fluid (CSF), and histological evaluation of peri-infarction area were performed. HIE induced progressively increasing brain infarction area over time, increased cell death, reactive gliosis and brain inflammation, and impaired sensorimotor function. All these damages observed in severe HIE showed better, robust improvement with a combination treatment of hypothermia and delayed MSC transplantation than with either stand-alone therapy. Hypothermia itself did not significantly reduce brain injury, but broadened the therapeutic time window of MSC transplantation for severe newborn HIE.
Conserved and non-conserved characteristics of porcine glial cell line-derived neurotrophic factor expressed in the testis.
May 22, 2018   Scientific Reports
Kakiuchi K, Taniguchi K, Kubota H
Conserved and non-conserved characteristics of porcine glial cell line-derived neurotrophic factor expressed in the testis.
May 22, 2018
Scientific Reports
Glial cell line-derived neurotrophic factor (GDNF) is essential for the self-renewal and proliferation of spermatogonial stem cells (SSCs) in mice, rats, and rabbits. Although the key extrinsic factors essential for spermatogonial proliferation in other mammals have not been determined, GDNF is one of the potential candidates. In this study, we isolated porcine GDNF (pGDNF) cDNAs from neonatal testis and generated recombinant pGDNF to investigate its biological activity on gonocytes/undifferentiated spermatogonia, including SSCs. In porcine testis, long and short forms of GDNF transcripts, the counterparts of pre-(α)pro and pre-(β)pro GDNF identified in humans and rodents, were expressed. The two transcripts encode identical mature proteins. Recombinant pGDNF supported proliferation of murine SSCs in culture, and their stem cell activity was confirmed by a transplantation assay. Subsequently, porcine gonocytes/undifferentiated spermatogonia were cultured with pGDNF; however, pGDNF did not affect their proliferation. Furthermore, GDNF expression was localised to the vascular smooth muscle cells, and its cognate receptor GFRA1 expression was negligible during spermatogonial proliferation in the testes. These results indicate that although pGDNF retains structural similarity with those of other mammals and conserves the biological activity on the self-renewal of murine SSCs, porcine SSCs likely require extrinsic factors other than GDNF for their proliferation.
Prenatal alcohol exposure increases the susceptibility to develop aggressive prolactinomas in the pituitary gland.
May 23, 2018   Scientific Reports
Jabbar S, Reuhl K, Sarkar DK
Prenatal alcohol exposure increases the susceptibility to develop aggressive prolactinomas in the pituitary gland.
May 23, 2018
Scientific Reports
Excess alcohol use is known to promote development of aggressive tumors in various tissues in human patients, but the cause of alcohol promotion of tumor aggressiveness is not clearly understood. We used an animals model of fetal alcohol exposure that is known to promote tumor development and determined if alcohol programs the pituitary to acquire aggressive prolactin-secreting tumors. Our results show that pituitaries of fetal alcohol-exposed rats produced increased levels of intra-pituitary aromatase protein and plasma estrogen, enhanced pituitary tissue growth, and upon estrogen challenge developed prolactin-secreting tumors (prolactinomas) that were hemorrhagic and often penetrated into the surrounding tissue. Pituitary tumors of fetal alcohol-exposed rats produced higher levels of hemorrhage-associated genes and proteins and multipotency genes and proteins. Cells of pituitary tumor of fetal alcohol exposed rat grew into tumor spheres in ultra-low attachment plate, expressed multipotency genes, formed an increased number of colonies, showed enhanced cell migration, and induced solid tumors following inoculation in immunodeficient mice. These data suggest that fetal alcohol exposure programs the pituitary to develop aggressive prolactinoma after estrogen treatment possibly due to increase in stem cell niche within the tumor microenvironment.
A Five-microRNA Signature for Survival Prognosis in Pancreatic Adenocarcinoma based on TCGA Data.
May 22, 2018   Scientific Reports
Shi XH, Li X, Zhang H, He RZ, Zhao Y, Zhou M, Pan ST, Zhao CL, Feng YC, Wang M, Guo XJ, Qin RY
A Five-microRNA Signature for Survival Prognosis in Pancreatic Adenocarcinoma based on TCGA Data.
May 22, 2018
Scientific Reports
Novel biomarkers for pancreatic adenocarcinoma are urgently needed because of its poor prognosis. Here, by using The Cancer Genome Atlas (TCGA) RNA-seq data, we evaluated the prognostic values of the differentially expressed miRNAs and constructed a five-miRNA signature that could effectively predict patient overall survival (OS). The Kaplan-Meier overall survival curves of two groups based on the five miRNAs were notably different, showing overall survival in 10.2% and 47.8% at five years for patients in high-risk and low-risk groups, respectively. The ROC curve analysis achieved AUC of 0.775, showing good sensitivity and specificity of the five-miRNA signature model in predicting pancreatic adenocarcinoma patient survival risk. The functional enrichment analysis suggested that the target genes of the miRNA signature may be involved in various pathways related to cancer, including PI3K-Akt, TGF-β, and pluripotent stem cell signaling pathways. Finally, we analyzed expression of the five specific miRNAs in the miRNA signature, and validated the reliability of the results in 20 newly diagnosed pancreatic adenocarcinoma patients using qRT-PCR. The expression results of qRT-PCR were consistent with the TCGA results. Taken together, these findings suggested that the five-miRNA signature (hsa-miR-203, hsa-miR-424, hsa-miR-1266 hsa-miR-1293, and hsa-miR-4772) could be used as a prognostic marker for pancreatic adenocarcinoma.
α-Synuclein stimulation of monoamine oxidase-B and legumain protease mediates the pathology of Parkinson's disease.
Jun 16, 2018   The EMBO Journal
Kang SS, Ahn EH, Zhang Z, Liu X, Manfredsson FP, Sandoval IM, Dhakal S, Iuvone PM, Cao X, Ye K
α-Synuclein stimulation of monoamine oxidase-B and legumain protease mediates the pathology of Parkinson's disease.
Jun 16, 2018
The EMBO Journal
Dopaminergic neurodegeneration in Parkinson's disease (PD) is associated with abnormal dopamine metabolism by MAO-B (monoamine oxidase-B) and intracellular α-Synuclein (α-Syn) aggregates, called the Lewy body. However, the molecular relationship between α-Syn and MAO-B remains unclear. Here, we show that α-Syn directly binds to MAO-B and stimulates its enzymatic activity, which triggers AEP (asparagine endopeptidase; legumain) activation and subsequent α-Syn cleavage at N103, leading to dopaminergic neurodegeneration. Interestingly, the dopamine metabolite, DOPAL, strongly activates AEP, and the N103 fragment of α-Syn binds and activates MAO-B. Accordingly, overexpression of AEP in SNCA transgenic mice elicits α-Syn N103 cleavage and accelerates PD pathogenesis, and inhibition of MAO-B by Rasagiline diminishes α-Syn-mediated PD pathology and motor dysfunction. Moreover, virally mediated expression of α-Syn N103 induces PD pathogenesis in wild-type, but not MAO-B-null mice. Our findings thus support that AEP-mediated cleavage of α-Syn at N103 is required for the association and activation of MAO-B, mediating PD pathogenesis.
Infusion of alloanergized donor lymphocytes after CD34-selected haploidentical myeloablative hematopoietic stem cell transplantation.
Jun 09, 2018   Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research
Davies JK, Brennan LL, Wingard J, Cogle CR, Kapoor N, Shah AJ, Dey BR, Spitzer TR, De Lima M, Cooper LJ, Thall P, Champlin RE, Nadler LM, Guinan EC
Infusion of alloanergized donor lymphocytes after CD34-selected haploidentical myeloablative hematopoietic stem cell transplantation.
Jun 09, 2018
Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research
PURPOSE: Allogeneic haematopoietic stem-cell transplantation (HSCT) is a curative treatment for many haematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T-cells is a simple approach to rebuild immunity whilst limiting GvHD after haploidentical HSCT but the optimal T-cell dose and impact on immune reconstitution remain unknown.  Experimental Design: We performed a multicentre Phase 1 trial of alloanergized donor lymphocyte infusion (aDLI) after CD34-selected myeloablative haploidentical HSCT. The primary aim was feasibility and safety with secondary aims of assessing the less frequently addressed issue of impact on immune reconstitution. RESULTS: Nineteen high-risk acute leukemia or myelodysplasia patients were enrolled. Engraftment occurred in 18/19 patients (95%). Pre-aDLI, twelve patients (63%) had bacteremia, 9/17 at-risk patients (53%) reactivated CMV and one developed acute GvHD. Sixteen patients received aDLI at dose-levels 1 (103 T-cells/kg, n=4), 2 (104, n=8), and 3 (105, n=4). Post-aDLI, 5 patients developed clinically significant acute GvHD and 4/14 at-risk patients (29%) reactivated CMV. T-cell recovery was significantly greater and functional virus- and tumor-associated antigen-specific T-cells were detectable earlier in patients receiving dose-level 2 or 3 vs dose-level 1/no aDLI. Alloanergization of donor cells expanded the CD4+ T-regulatory cell frequency within aDLI which increased further in vivo without impeding expansion of virus- and tumor-associated antigen-specific T-cells. CONCLUSIONS:  These data demonstrate safety and a potential role for aDLI in contributing to immune reconstitution and expanding tolerogenic regulatory T-cells in vivo after CD34-selected myeloablative haploidentical HSCT.
Increasing aggressiveness of patient-derived xenograft models of cervix carcinoma during serial transplantation.
May 18, 2018   Oncotarget
Wegner CS, Hauge A, Andersen LMK, Huang R, Simonsen TG, Gaustad JV, Rofstad EK
Increasing aggressiveness of patient-derived xenograft models of cervix carcinoma during serial transplantation.
May 18, 2018
Oncotarget
Four patient-derived xenograft (PDX) models (BK-12, ED-15, HL-16, LA-19) of carcinoma of the uterine cervix have been developed in our laboratory, and their stability during serial transplantation in vivo was investigated in this study. Two frozen cell stocks were established, one from xenografted tumors in passage 2 (early generation) and the other from xenografted tumors transplanted serially in mice for approximately two years (late generation), and the biology of late generation tumors was compared with that of early generation tumors. Late generation tumors showed higher incidence of lymph node metastases than early generation tumors in three models (ED-15, HL-16, LA-19), and the increased metastatic propensity was associated with increased tumor growth rate, increased microvascular density, and increased expression of angiogenesis-related and cancer stem cell-related genes. Furthermore, late generation tumors showed decreased fraction of pimonidazole-positive tissue (i.e., decreased fraction of hypoxic tissue) in two models (HL-16, LA-19) and decreased fraction of collagen-I-positive tissue (i.e., less extensive extracellular matrix) in two models (ED-15, HL-16). This study showed that serially transplanted PDXs may not necessarily mirror the donor patients' diseases, and consequently, proper use of serially transplanted PDX models in translational cancer research requires careful molecular monitoring of the models.
Treatment with specific soluble factors promotes the functional maturation of transcription factor-mediated, pancreatic transdifferentiated cells.
May 27, 2018   PloS One
Motoyama H, Kobayashi A, Yokoyama T, Shimizu A, Sakai H, Notake T, Fukushima K, Miyagawa SI
Treatment with specific soluble factors promotes the functional maturation of transcription factor-mediated, pancreatic transdifferentiated cells.
May 27, 2018
PloS One
Pancreatic lineage-specific transcription factors (TFs) display instructive roles in converting adult cells to endocrine pancreatic cells through a process known as transdifferentiation. However, little is known about potential factors capable of accelerating transdifferentiation following transduction to achieve the functional maturation of transdifferentiated cells. In this study, we demonstrated, using adult liver-derived progenitor cells, that soluble factors utilized in pancreatic differentiation protocols of pluripotent stem cells promote functional maturation of TFs-mediated transdifferentiated cells. Treatment with an N2 supplement in combination with three soluble factors (glucagon-like peptide-1 [GLP-1] receptor agonist, notch inhibitor, and transforming growth factor-β [TGF-β] inhibitor) enhanced liver-to-pancreas transdifferentiation based on the following findings: i) the incidence of c-peptide-positive cells increased by approximately 1.2-fold after the aforementioned treatment; ii) the c-peptide expression level in the treated cells increased by approximately 12-fold as compared with the level in the untreated cells; iii) the treated cells secreted insulin in a glucose-dependent manner, whereas the untreated cells did not; and iv) transplantation of treated-transdifferentiated cells into streptozotocin-induced immunodeficient diabetic mice led to the amelioration of hyperglycemia. These results suggest that treatment with specific soluble factors promotes the functional maturation of transdifferentiated cells. Our findings could facilitate the development of new modalities for cell-replacement therapy for patients with diabetes.
miRNAs that Induce Human Cardiomyocyte Proliferation Converge on the Hippo Pathway.
May 16, 2018   Cell Reports
Diez-Cuñado M, Wei K, Bushway PJ, Maurya MR, Perera R, Subramaniam S, Ruiz-Lozano P, Mercola M
miRNAs that Induce Human Cardiomyocyte Proliferation Converge on the Hippo Pathway.
May 16, 2018
Cell Reports
Understanding the mechanisms that control human cardiomyocyte proliferation might be applicable to regenerative medicine. We screened a whole genome collection of human miRNAs, identifying 96 to be capable of increasing proliferation (DNA synthesis and cytokinesis) of human iPSC-derived cardiomyocytes. Chemical screening and computational approaches indicated that most of these miRNAs (67) target different components of the Hippo pathway and that their activity depends on the nuclear translocation of the Hippo transcriptional effector YAP. 53 of the 67 miRNAs are present in human iPSC cardiomyocytes, yet anti-miRNA screening revealed that none are individually essential for basal proliferation of hiPSC cardiomyocytes despite the importance of YAP for proliferation. We propose a model in which multiple endogenous miRNAs redundantly suppress Hippo signaling to sustain the cell cycle of immature cardiomyocytes.
Defective Replication Stress Response Is Inherently Linked to the Cancer Stem Cell Phenotype.
May 16, 2018   Cell Reports
McGrail DJ, Lin CC, Dai H, Mo W, Li Y, Stephan C, Davies P, Lu Z, Mills GB, Lee JS, Lin SY
Defective Replication Stress Response Is Inherently Linked to the Cancer Stem Cell Phenotype.
May 16, 2018
Cell Reports
Extensive spontaneous DNA damage from oncogene-induced replication stress is ubiquitous in precancerous lesions. While this damage induces differentiation, senescence, or apoptosis in normal cells, defects in DNA replication stress response (RSR) allow cells to continue proliferating, ultimately leading to early tumorigenesis. Using systems-level approaches, we developed a replication stress response defect gene signature that predicted risk of cancer development from hyperplastic lesions. Intriguingly, we found that replication stress response defects rewire non-malignant cells into a cancer stem cell (CSC)-like state, and analysis of CSCs indicated that they inherently harbor replication stress response defects. High-throughput drug screening to elucidate molecules required for survival of replication stress response defective cells identified a dependence on MEK/ERK signaling. Inhibition of this signaling cascade restored oncogene-induced senescence through a p53-independent MDM2/p21 axis. Moreover, MEK/ERK inhibition also depleted CSC populations. Together, these findings provide insights into the role of replication stress response defects in CSCs and an actionable pathway for therapeutic targeting.
C. elegans Blastomeres Clear the Corpse of the Second Polar Body by LC3-Associated Phagocytosis.
May 16, 2018   Cell Reports
Fazeli G, Stetter M, Lisack JN, Wehman AM
C. elegans Blastomeres Clear the Corpse of the Second Polar Body by LC3-Associated Phagocytosis.
May 16, 2018
Cell Reports
To understand how undifferentiated pluripotent cells cope with cell corpses, we examined the clearance of polar bodies born during female meiosis. We found that polar bodies lose membrane integrity and expose phosphatidylserine in Caenorhabditis elegans. Polar body signaling recruits engulfment receptors to the plasma membrane of embryonic blastomeres using the PI3K VPS-34, RAB-5 GTPase and the sorting nexin SNX-6. The second polar body is then phagocytosed using receptor-mediated engulfment pathways dependent on the Rac1 ortholog CED-10 but undergoes non-apoptotic programmed cell death independent of engulfment. RAB-7 GTPase is required for lysosome recruitment to the polar body phagosome, while LC3 lipidation is required for degradation of the corpse membrane after lysosome fusion. The polar body phagolysosome vesiculates in an mTOR- and ARL-8-dependent manner, which assists its timely degradation. Thus, we established a genetic model to study clearance by LC3-associated phagocytosis and reveal insights into the mechanisms of phagosome maturation and degradation.
Extracellular Forms of Aβ and Tau from iPSC Models of Alzheimer's Disease Disrupt Synaptic Plasticity.
Jun 03, 2018   Cell Reports
Hu NW, Corbett GT, Moore S, Klyubin I, O'Malley TT, Walsh DM, Livesey FJ, Rowan MJ
Extracellular Forms of Aβ and Tau from iPSC Models of Alzheimer's Disease Disrupt Synaptic Plasticity.
Jun 03, 2018
Cell Reports
The early stages of Alzheimer's disease are associated with synaptic dysfunction prior to overt loss of neurons. To identify extracellular molecules that impair synaptic plasticity in the brain, we studied the secretomes of human iPSC-derived neuronal models of Alzheimer's disease. When introduced into the rat brain, secretomes from human neurons with either a presenilin-1 mutation, amyloid precursor protein duplication, or trisomy of chromosome 21 all strongly inhibit hippocampal long-term potentiation. Synaptic dysfunction caused by presenilin-1 mutant and amyloid precusor protein duplication secretomes is mediated by Aβ peptides, whereas trisomy of chromosome 21 (trisomy 21) neuronal secretomes induce dysfunction through extracellular tau. In all cases, synaptotoxicity is relieved by antibody blockade of cellular prion protein. These data indicate that human models of Alzheimer's disease generate distinct proteins that converge at the level of cellular prion protein to induce synaptic dysfunction in vivo.
Expression Profiling of Differentially Regulated Genes in Fanconi Anemia.
May 16, 2018   Methods In Molecular Biology (Clifton, N.J.)
Zipporah E B, Govarthanan K, Shyamsunder P, Verma RS
Expression Profiling of Differentially Regulated Genes in Fanconi Anemia.
May 16, 2018
Methods In Molecular Biology (Clifton, N.J.)
Gene expression analysis mainly helps to study gene quantification methods by using various downstream detection approaches like imaging, amplification, probe hybridization, or sequencing. With respect to DNA, which is less static, mRNA levels vary over time, between cell types under divergent conditions. Gene expression analysis is principally focused on determination of mRNA levels transcribed from DNA. DNA microarrays are one of the robust and powerful tools to detect changes in multiple transcripts in larger cohorts in parallel. The basic principle of DNA microarray hybridization is complementary base pairing of single-stranded nucleic-acid sequences. On a microarray platform (also called a chip), known sequences called targets are attached at fixed locations (spots) to a solid surface such as glass using robotic spotting. Since a large number of samples (variables) are used in a typical hybridization experiment, which often leads to impreciseness for example, target mRNA transcribed from the same source should be identical every time. In such cases, developing an optimized protocol for microarray platform to study the expression profiling of differentially regulated genes is a challenging task. Thus genome-wide expression array analysis yields data about candidate genes that may be involved in disease acquisition progression, and helps in better understanding the pathophysiology of the disease. In this chapter we describe in detail the microarray technique, a well-accepted method for understanding the development and progression of Fanconi anemia (FA), a genetic disorder which is characterized by progressive bone marrow failure and a predisposition to cancer.
Genetic Insights Into Frailty: Association of 9p21-23 Locus With Frailty.
May 19, 2018   Frontiers In Medicine
Sathyan S, Barzilai N, Atzmon G, Milman S, Ayers E, Verghese J
Genetic Insights Into Frailty: Association of 9p21-23 Locus With Frailty.
May 19, 2018
Frontiers In Medicine
Frailty is a complex aging phenotype associated with increased vulnerability to disability and death. Understanding the biological antecedents of frailty may provide clues to healthy aging. The genome-wide association study hotspot, 9p21-23 region, is a risk locus for a number of age-related complex disorders associated with frailty. Hence, we conducted an association study to examine whether variations in 9p21-23 locus plays a role in the pathogenesis of frailty in 637 community-dwelling Ashkenazi Jewish adults aged 65 and older enrolled in the LonGenity study. The strongest association with frailty (adjusted for age and gender) was found with the SNP rs518054 (odds ratio: 1.635, 95% CI = 1.241-2.154; p-value: 4.81 × 10-04) intergenic and located between LOC105375977 and C9orf146. The prevalence of four SNPs (rs1324192, rs7019262, rs518054, and rs571221) risk alleles haplotype in this region was significantly higher (compared with other haplotypes) in frail older adults compared with non-frail older adults (29.7 vs. 20.8%, p = 0.0005, respectively). Functional analyses using in silico approaches placed rs518054 in the CTCF binding site as well as DNase hypersensitive region. Furthermore, rs518054 was found to be in an enhancer site of NFIB gene located downstream. NFIB is a transcription factor that promotes cell differentiation during development, has antiapoptotic effect, maintains stem cell populations in adult tissues, and also acts as epigenetic regulators. Our study found novel association of SNPs in the regulatory region in the 9p21-23 region with the frailty phenotype; signifying the importance of this locus in aging.
Genomic Imprinting and the Regulation of Postnatal Neurogenesis.
May 19, 2018   Brain Plasticity (Amsterdam, Netherlands)
Lozano-Ureña A, Montalbán-Loro R, Ferguson-Smith AC, Ferrón SR
Genomic Imprinting and the Regulation of Postnatal Neurogenesis.
May 19, 2018
Brain Plasticity (Amsterdam, Netherlands)
Most genes required for mammalian development are expressed from both maternally and paternally inherited chromosomal homologues. However, there are a small number of genes known as "imprinted genes" that only express a single allele from one parent, which is repressed on the gene from the other parent. Imprinted genes are dependent on epigenetic mechanisms such as DNA methylation and post-translational modifications of the DNA-associated histone proteins to establish and maintain their parental identity. In the brain, multiple transcripts have been identified which show parental origin-specific expression biases. However, the mechanistic relationship with canonical imprinting is unknown. Recent studies on the postnatal neurogenic niches raise many intriguing questions concerning the role of genomic imprinting and gene dosage during postnatal neurogenesis, including how imprinted genes operate in concert with signalling cues to contribute to newborn neurons' formation during adulthood. Here we have gathered the current knowledge on the imprinting process in the neurogenic niches. We also review the phenotypes associated with genetic mutations at particular imprinted loci in order to consider the impact of imprinted genes in the maintenance and/or differentiation of the neural stem cell pool in vivo and during brain tumour formation.
Could a plant derived protein potentiate the anticancer effects of a stem cell in brain cancer?
May 18, 2018   Oncotarget
Bonturi CR, Motaln H, Silva MCC, Salu BR, de Brito MV, de Andrade Luz Cost L, Torquato HFV, Nunes NNDS, Paredes-Gamero EJ, Turnšek TL, Oliva MLV
Could a plant derived protein potentiate the anticancer effects of a stem cell in brain cancer?
May 18, 2018
Oncotarget
Glioblastoma is the most aggressive brain tumor with poor overall survival bellow 2 years. The natural compounds with anti-cancer properties, are thus gaining attention for possible adjuvant GBM treatment. In various cancer models Enterolobium contortisiliquum Trypsin Inhibitor (EcTI) proved to have anti-cancer effects. Here, we investigated the EcTI effects on GBM U87 cells and on mesenchymal stem cells (MSC) compared to their direct coculture (MSC/U87). MSC are present in tumor stroma, modulating GBM cells phenotype, and also represent potential drug delivery vehicle due to their tumor tropism. We showed that in p53-wild type U87 cells, metabolic activity was less affected by EcTI as in MSC monocuture, but the metabolic rate of mixed coculture was significantly reduced at lower EcTI concentration. Under coculture condition, EcTI potentiated MSC induced cell cycle arrest, possible due to highly increased p53, p21 and lower D1 expression, but there was no effect on apoptosis. Accordingly, in the coculture EcTI also enhanced Ca2+ signalling mediated via bradykinin receptor 2, being associated with nitric oxide release that highly impaired proliferation and invasion. The mechanism did not seem to involve changes in cell adhesion but rather it down-regulated the β1 integrin signaling with associated p-FAK in U87 cells, both supporting inhibition of invasion. Finally, some cytokines were down-regulated, indicating that EcTI inhibition of signalling might be mediated by cytokines. In conclusion, these results indicate that in cocultured MSC/U87 cells EcTI impairs the metabolic activity, proliferation, and reduced invasion, possibly associated with observed cytokines secretion. In this context, we confirmed that the plant derived protein potentiated the anticancer effects, induced by MSC, as represented by GBM U87 cell line.
Metabolic changes associated with metformin potentiates Bcl-2 inhibitor, Venetoclax, and CDK9 inhibitor, BAY1143572 and reduces viability of lymphoma cells.
May 18, 2018   Oncotarget
Chukkapalli V, Gordon LI, Venugopal P, Borgia JA, Karmali R
Metabolic changes associated with metformin potentiates Bcl-2 inhibitor, Venetoclax, and CDK9 inhibitor, BAY1143572 and reduces viability of lymphoma cells.
May 18, 2018
Oncotarget
Metformin exerts direct anti-tumor effects by activating AMP-activated protein kinase (AMPK), a major sensor of cellular metabolism in cancer cells. This, in turn, inhibits pro-survival mTOR signaling. Metformin has also been shown to disrupt complex 1 of the mitochondrial electron transport chain. Here, we explored the lymphoma specific anti-tumor effects of metformin using Daudi (Burkitt), SUDHL-4 (germinal center diffuse large B-cell lymphoma; GC DLBCL), Jeko-1 (Mantle-cell lymphoma; MCL) and KPUM-UH1 (double hit DLBCL) cell lines. We demonstrated that metformin as a single agent, especially at high concentrations produced significant reductions in viability and proliferation only in Daudi and SUDHL-4 cell lines with associated alterations in mitochondrial oxidative and glycolytic metabolism. As bcl-2 proteins, cyclin dependent kinases (CDK) and phosphoinositol-3- kinase (PI3K) also influence mitochondrial physiology and metabolism with clear relevance to the pathogenesis of lymphoma, we investigated the potentiating effects of metformin when combined with novel agents Venetoclax (bcl-2 inhibitor), BAY-1143572 (CDK9 inhibitor) and Idelalisib (p110δ- PI3K inhibitor). Co-treating KPUM-UH1 and SUDHL-4 cells with 10 mM of metformin resulted in 1.4 fold and 8.8 fold decreases, respectively, in IC-50 values of Venetoclax. By contrast, 3-fold and 10 fold reduction in IC-50 values of BAY-1143572 in Daudi and Jeko-1 cells respectively was seen in the presence of 10 mM of metformin. No change in IC-50 value for Idelalisib was observed across cell lines. These data suggest that although metformin is not a potent single agent, targeting cancer metabolism with similar but more effective drugs in novel combination with either bcl-2 or CDK9 inhibitors warrants further exploration.
Author Correction: A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies.
May 17, 2018   Nature Add nature.com free-link Cancel
Bahr C, von Paleske L, Uslu VV, Remeseiro S, Takayama N,   . . . . . .   , Zandstra PW, Lupien M, Dick JE, Trumpp A, Spitz F
Author Correction: A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies.
May 17, 2018
Nature
In the originally published version of this Letter, ref. 43 was erroneously provided twice. In the 'Estimation of relative cell-type-specific composition of AML samples' section in the Methods, the citation to ref. 43 after the GEO dataset GSE24759 is correct. However, in the 'Mice' section of the Methods, the citation to ref. 43 after 'TAMERE' should have been associated with a new reference1. The original Letter has been corrected online (with the new reference included as ref. 49).

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