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Showing 100 Latest Publications
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Odontoblasts: specialized hard-tissue-forming cells in the dentin-pulp complex.Saturday, April 30, 2016
Kawashima N, Okiji T,
Congenital anomalies. 30-Apr-2016
Odontoblasts are specialized cells that produce dentin and exhibit unique morphological characteristics; i.e., they extend cytoplasmic processes into dentinal tubules. While osteoblasts, which are typical hard-tissue-forming cells, are generated from mesenchymal stem cells during normal and pathological bone metabolism, the induction of odontoblasts only occurs once during tooth development, and odontoblasts survive throughout the lives of healthy teeth. During the differentiation of odontoblasts, signaling molecules from the inner enamel epithelium are considered necessary for the differentiation of odontoblast precursors, i.e., peripheral dental papilla cells. If odontoblasts are destroyed by severe external stimuli, such as deep caries, the differentiation of dental pulp stem cells into odontoblast-like cells is induced. Various bioactive molecules, such as non-collagenous proteins, might be involved in this process, although the precise mechanisms responsible for odontoblast differentiation have not been fully elucidated. Recently, our knowledge about the other functional activities of odontoblasts (apart from dentin formation) has increased. For example, it has been suggested that odontoblasts might act as nociceptive receptors, and surveillance cells that detect the invasion of exogenous pathogens. The regeneration of the dentin-pulp complex has recently gained much attention as a promising future treatment modality that could increase the longevity of pulpless teeth. Finally, congenital dentin anomalies, which are concerned with the disturbance of odontoblast functions, are summarized. This article is protected by copyright. All rights reserved.
Therapeutic approaches for treating hemophilia A using embryonic stem cells.Saturday, April 30, 2016
Kasuda S, Tatsumi K, Sakurai Y, Shima M, Hatake K,
Hematology/oncology and stem cell therapy. 22-Apr-2016
Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem (ES) cells (tet-226aa/N6-Ainv18) that secrete human factor VIII (hFVIII) by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency (SCID) mice, carbon tetrachloride (CCl4)-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future.
Effect of stem cell-based therapy for ischemic stroke treatment: A meta-analysis.Saturday, April 30, 2016
Wang Q, Duan F, Wang MX, Wang XD, Liu P, Ma LZ,
Clinical neurology and neurosurgery. 21-Apr-2016
Stroke is a major cause of death and long-term disability worldwide. Cell-based therapies improve neural functional recovery in pre-clinical studies, but clinical results require evaluation. We aimed to assess the effects of mesenchymal stem cells on ischemic stroke treatment. We searched the PubMed, Embase and Cochrane databases until July 2015 and selected the controlled trials using mesenchymal stem cells for ischemic stroke treatment compared with cell-free treatment. We assessed the results by meta-analysis using the error matrix approach, and we assessed the association of mesenchymal stem cell counts with treatment effect by dose-response meta-analysis. Seven trials were included. Manhattan plots revealed no obvious advantage of the application of stem cells to treat ischemic stroke. For the comprehensive evaluation index, stem cell treatment did not significantly reduce the mortality of ischemic stroke patients (relative risk (RR) 0.59, 95% confidence interval (CI) 0.29-1.19; ln(RR) 0.54, 95% CI -0.18 to 1.25, p=0.141). The National Institutes of Health Stroke Scale was also not significantly improved by stem cell treatment (standardized mean difference (SMD) 0.94, 95% CI -0.13 to 2.01, p=0.072). The European Stroke Scale was significantly improved using the stem cell treatment (SMD 1.15, 95% CI 0.37-1.92). The dose-response meta-analysis did not reveal a significant linear regression relationship between the number of stem cells and therapeutic effect, except regarding the National Institutes of Health Stroke Scale index. In conclusion, our assessments indicated no significant difference between stem cell and cell-free treatments. Further research is needed to discover more effective stem cell-based therapies for ischemic stroke treatment.
Atypical accessory intraparietal sutures mimicking complex fractures in a neonate.Saturday, April 30, 2016
Eklund MJ, Carver KC, Stalcup ST, Riemer EC, Taylor MA, Hill JG,
Clinical imaging. 22-Mar-2016
Partial or complete division of the parietal bones resulting in anomalous cranial sutures is a rare entity and may raise concern for fracture and potential abuse when identified on radiological examination in young children. We present a case of a 4-week-old male found to have anomalous intraparietal sutures originally interpreted as fractures during a comprehensive evaluation for nonaccidental trauma. Our goal is to raise awareness of a complex branching pattern of accessory intraparietal sutures, which has not been previously described. Additionally, we will review the characteristics that aid in the radiologic differentiation of accessory cranial sutures and fractures.
Lipid vesicles loading aluminum phthalocyanine chloride: Formulation properties and disaggregation upon intracellular delivery.Saturday, April 30, 2016
Calori IR, Tedesco AC,
Journal of photochemistry and photobiology. B, Biology. 13-Apr-2016
Aluminum phthalocyanine chloride (AlClPc) is a second-generation photodynamic therapy (PDT) photosensitizer characterized for its high hydrophobicity and self-aggregation tendency in aqueous media, which hamper its potential application. Aiming at AlClPc solubilization we proposed here the use of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) at different proportions to form mixed lipid vesicles (LVs) as a drug delivery system. LVs were prepared by ethanol injection method and formed nano-sized vesicles (about 100nm) with suitable polydispersity index, negative zeta potential, and stable in aqueous medium for at least 50days. AlClPc strongly interacts with LV (high binding constant values), especially due to aluminum-phosphate specific interactions, which gives a surface localization to AlClPc molecules as demonstrated by fluorescence quenching data. Anisotropy, static and time-resolved fluorescence measurements corroborated with these results and demonstrated that AlClPc self-aggregation occurred even in the liposomes. However, formulation uptake by oral squamous cell carcinoma (OSCC) the AlClPc was distributed in cellular organelles and suffered a disaggregation process demonstrated by fluorescence life-time imaging microscopy. This amazing behavior is new and increases the scientific knowledge about the intracellular mechanism of action of PDT photosensitizers. In addition, these results open a new perspective to the potential use of AlClPc-LV formulations for photodynamic treatment.
Nanomedicine: Application of nanoparticles in clinical therapies and diagnostics.Saturday, April 30, 2016
Kargul J, Irminger-Finger I, Laurent GJ,
The international journal of biochemistry & cell biology. 27-Apr-2016
Role for the Aryl Hydrocarbon Receptor and Diverse Ligands In Oral Squamous Cell Carcinoma Migration and Tumorigenesis.Saturday, April 30, 2016
Stanford EA, Ramirez-Cardenas A, Wang Z, Novikov O, Alamoud K, Koutrakis P, Mizgerd JP, Genco CA, Kukuruzinska M, Monti S, Bais MV, Sherr DH,
Molecular cancer research : MCR. 29-Apr-2016
This study, for the first time, demonstrates the ability of diverse AHR ligands to regulate AHR activity in oral squamous cell carcinoma cells, as well as regulate several important characteristics of oral cancer stem cells, in vivo and in vitro.
Melatonin Pretreatment Enhances the Homing of Bone Marrow-derived Mesenchymal Stem Cells Following Transplantation in a Rat Model of Liver Fibrosis.Saturday, April 30, 2016
Mortezaee K, Pasbakhsh P, Ragerdi Kashani I, Sabbaghziarani F, Omidi A, Zendedel A, Ghasemi S, Dehpour AR,
Iranian biomedical journal. 30-Apr-2016
This study indicates the improved homing potential of BMMSCs in pretreatment with melatonin. Therefore, this strategy may represent an applied approach for improving the stem cell therapy of liver fibrosis.
In vitro evolution of coenzyme-independent variants from the glmS ribozyme structural scaffold.Saturday, April 30, 2016
Lau MW, Ferré-D'Amaré AR,
Methods (San Diego, Calif.). 26-Apr-2016
Uniquely among known natural ribozymes that cleave RNA sequence-specifically, the glmS ribozyme-riboswitch employs a small molecule, glucosamine-6-phosphate (GlcN6P) as a catalytic cofactor. In vitro selection was employed to search for coenzyme-independent variants of this ribozyme. In addition to shedding light on the catalytic mechanism of the ribozyme, such variants could resemble the evolutionary ancestors of the modern, GlcN6P-regulated ribozyme-riboswitch. A mutant pool was constructed such that the secondary structure elements, which define the triply-pseudoknotted global fold of the ribozyme, was preserved. A stringent selection scheme that relies on thiol-mercury affinity chromatography for separating active and inactive sequences ultimately yielded a triple mutant with a cleavage rate exceeding 3 min(-1) that only requires divalent cations for activity. Mutational analysis demonstrated that a point reversion of the variant toward the wild-type sequence was sufficient to partially restore GlcN6P-dependence, suggesting that coenzyme dependence can be readily be acquired by RNAs that adopt the glmS ribozyme fold. The methods employed to perform this selection experiment are described in detail in this review.
Hematopoietic stem cell transplantation outcomes for 11 patients with dedicator of cytokinesis 8 deficiency.Saturday, April 30, 2016
Al-Herz W, Chu JI, van der Spek J, Raghupathy R, Massaad MJ, Keles S, Biggs CM, Cockerton L, Chou J, Dbaibo G, Elisofon SA, Hanna-Wakim R, Kim HB, Lehmann LE, McDonald DR, Notarangelo LD, Veys P, Chatila TA, Geha RS, Gaspar HB, Pai SY,
The Journal of allergy and clinical immunology. 6-Apr-2016
Allogeneic HSCT ameliorated the infectious and atopic symptoms of patients with DOCK8 deficiency. In patients with mixed chimerism, selective advantage for donor-derived T cells and switched memory B cells promoted restoration of cellular and humoral immunity and protection against opportunistic infection.
Investigation of peanut oral immunotherapy with CpG/peanut nanoparticles in a murine model of peanut allergy.Saturday, April 30, 2016
Srivastava KD, Siefert A, Fahmy TM, Caplan MJ, Li XM, Sampson HA,
The Journal of allergy and clinical immunology. 26-Apr-2016
Preclinical findings indicate that peanut oral immunotherapy with CpG/PN-NPs might be a valuable strategy for peanut-specific immunotherapy in human subjects.
Human IgE-independent systemic anaphylaxis.Saturday, April 30, 2016
Finkelman FD, Khodoun MV, Strait R,
The Journal of allergy and clinical immunology. 26-Apr-2016
Anaphylaxis is a rapidly developing, life-threatening, generalized or systemic allergic reaction that is classically elicited by antigen crosslinking of antigen-specific IgE bound to the high-affinity IgE receptor FcεRI on mast cells and basophils. This initiates signals that induce cellular degranulation with release and secretion of vasoactive mediators, enzymes, and cytokines. However, IgE-independent mechanisms of anaphylaxis have been clearly demonstrated in experimental animals. These include IgG-dependent anaphylaxis, which involves the triggering of mediator release by IgG/antigen complex crosslinking of FcγRs on macrophages, basophils, and neutrophils; anaphylaxis mediated by binding of the complement-derived peptides C3a and C5a to their receptors on mast cells, basophils, and other myeloid cells; and direct activation of mast cells by drugs that interact with receptors on these cells. Here we review the mechanisms involved in these IgE-independent forms of anaphylaxis and the clinical evidence for their human relevance. We conclude that this evidence supports the existence of all 3 IgE-independent mechanisms as important causes of human disease, although practical and ethical considerations preclude their demonstration to the degree of certainty possible with animal models. Furthermore, we cite evidence that different clinical situations can suggest different mechanisms as having a primal role in anaphylaxis and that IgE-dependent and distinct IgE-independent mechanisms can act together to increase anaphylaxis severity. As specific agents become available that can interfere with mechanisms involved in the different types of anaphylaxis, recognition of specific types of anaphylaxis is likely to become important for optimal prophylaxis and therapy.
The KCC2 Cotransporter and Human Epilepsy: Getting Excited About Inhibition.Saturday, April 30, 2016
Kahle KT, Khanna AR, Duan J, Staley KJ, Delpire E, Poduri A,
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 29-Apr-2016
The cation-Cl(-) cotransporter KCC2, encoded by SLC12A5, is required for the emergence and maintenance of GABAergic fast synaptic inhibition in organisms across evolution. These findings have suggested that KCC2 deficiency might play a role in the pathogenesis human epilepsy, but this has only recently been substantiated by two lines of genetic evidence. The first is the discovery of heterozygous missense polymorphisms in SLC12A5, causing decreased KCC2-dependent Cl(-) extrusion capacity, in an Australian family with inherited febrile seizures and in a French-Canadian cohort with severe genetic generalized epilepsy (GGE). The second is the discovery of recessive loss-of-function mutations in SLC12A5 in patients with a severe, early-onset Mendelian disease termed "epilepsy of infancy with migrating focal seizures" (EIMFS). These findings collectively support the paradigm that precisely regulated KCC2 activity is required for synaptic inhibition in humans, and that genetically encoded impairment of KCC2 function, due to effects on gene dosage, intrinsic activity, or extrinsic regulation, can influence epilepsy phenotypes in patients. Accordingly, KCC2 could be a target for a novel antiepileptic strategies that aims to restore GABA inhibition by facilitating Cl(-) extrusion. Such drugs could have relevance for pharmaco-resistant epilepsies and possibly other diseases characterized by synaptic hyperexcitability, such as the spectrum autism disorders.
Effects and mechanisms of melatonin on neural differentiation of induced pluripotent stem cells.Saturday, April 30, 2016
Shu T, Wu T, Pang M, Liu C, Wang X, Wang J, Liu B, Rong L,
Biochemical and biophysical research communications. 26-Apr-2016
Melatonin, a lipophilic molecule mainly synthesized in the pineal gland, has properties of antioxidation, anti-inflammation, and antiapoptosis to improve neuroprotective functions. Here, we investigate effects and mechanisms of melatonin on neural differentiation of induced pluripotent stem cells (iPSCs). iPSCs were induced into neural stem cells (NSCs), then further differentiated into neurons in medium with or without melatonin, melatonin receptor antagonist (Luzindole) or Phosphatidylinositide 3 kinase (PI3K) inhibitor (LY294002). Melatonin significantly promoted the number of neurospheres and cell viability. In addition, Melatonin markedly up-regulated gene and protein expression of Nestin and MAP2. However, Luzindole or LY294002 attenuated these increase. The expression of pAKT/AKT were increased by Melatonin, while Luzindole or LY294002 declined these melatonin-induced increase. These results suggest that melatonin significantly increased neural differentiation of iPSCs via activating PI3K/AKT signaling pathway through melatonin receptor.
Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain.Saturday, April 30, 2016
He S, Mansour MR, Zimmerman MW, Ki DH, Layden HM, Akahane K, Gjini E, de Groh ED, Perez-Atayde AR, Zhu S, Epstein JA, Look AT,
eLife. 27-Apr-2016
Earlier reports showed that hyperplasia of sympathoadrenal cell precursors during embryogenesis in Nf1-deficient mice is independent of Nf1's role in down-modulating RAS-MAPK signaling. We demonstrate in zebrafish that nf1 loss leads to aberrant activation of RAS signaling in MYCN-induced neuroblastomas that arise in these precursors, and that the GTPase-activating protein (GAP)-related domain (GRD) is sufficient to suppress the acceleration of neuroblastoma in nf1-deficient fish, but not the hypertrophy of sympathoadrenal cells in nf1 mutant embryos. Thus, even though neuroblastoma is a classical 'developmental tumor', NF1 relies on a very different mechanism to suppress malignant transformation than it does to modulate normal neural crest cell growth. We also show marked synergy in tumor cell killing between MEK inhibitors (trametinib) and retinoids (isotretinoin) in primary nf1a-/- zebrafish neuroblastomas. Thus, our model system has considerable translational potential for investigating new strategies to improve the treatment of very high-risk neuroblastomas with aberrant RAS-MAPK activation.
Life science experiments performed in space in the ISS/Kibo facility and future research plans.Saturday, April 30, 2016
Ohnishi T,
Journal of radiation research. 29-Apr-2016
Over the past several years, current techniques in molecular biology have been used to perform experiments in space, focusing on the nature and effects of space radiation. In the Japanese 'Kibo' facility in the International Space Station (ISS), the Japan Aerospace Exploration Agency (JAXA) has performed five life science experiments since 2009, and two additional experiments are currently in progress. The first life science experiment in space was the 'Rad Gene' project, which utilized two human cultured lymphoblastoid cell lines containing a mutated P53: gene (m P53: ) and a parental wild-type P53: gene (wt P53: ) respectively. Four parameters were examined: (i) detecting space radiation-induced DSBs by observing γH2AX foci; (ii) observing P53: -dependent gene expression during space flight; (iii) observing P53: -dependent gene expression after space flight; and (iv) observing the adaptive response in the two cell lines containing the mutated and wild type P53: genes after exposure to space radiation. These observations were completed and have been reported, and this paper is a review of these experiments. In addition, recent new information from space-based experiments involving radiation biology is presented here. These experiments involve human cultured cells, silkworm eggs, mouse embryonic stem cells and mouse eggs in various experiments designed by other principal investigators in the ISS/Kibo. The progress of Japanese science groups involved in these space experiments together with JAXA are also discussed here. The Japanese Society for Biological Sciences in Space (JSBSS), the Utilization Committee of Space Environment Science (UCSES) and the Science Council of Japan (ACJ) have supported these new projects and new experimental facilities in ISS/Kibo. Currently, these organizations are proposing new experiments for the ISS through 2024.
Emergence of undifferentiated colonies from mouse embryonic stem cells undergoing differentiation by retinoic acid treatment.Saturday, April 30, 2016
Sharova LV, Sharov AA, Piao Y, Stagg CA, Amano T, Qian Y, Dudekula D, Schlessinger D, Ko MS,
In vitro cellular & developmental biology. Animal. 29-Apr-2016
Retinoic acid (RA) is one of the most potent inducers of differentiation of mouse embryonic stem cells (ESCs). However, previous studies show that RA treatment of cells cultured in the presence of a leukemia inhibitory factor (LIF) also result in the upregulation of a gene called Zscan4, whose transient expression is a marker for undifferentiated ESCs. We explored the balance between these two seemingly antagonistic effects of RA. ESCs indeed differentiated in the presence of LIF after RA treatment, but colonies of undifferentiated ESCs eventually emerged from these differentiated cells - even in the presence of RA. These colonies, named secondary colonies, consist of three cell types: typical undifferentiated ESCs expressing pluripotency genes such as Pou5f1, Sox2, and Nanog; cells expressing Zscan4; and endodermal-like cells located at the periphery of the colony. The capacity to form secondary colonies was confirmed for all eight tested ESC lines. Cells from the secondary colonies - after transfer to the standard ESC medium - retained pluripotency, judged by their strong alkaline phosphatase (ALP) staining, typical colony morphology, gene expression profile, stable karyotype, capacity to differentiate into all three germ layers in embryoid body formation assays, and successful contribution to chimeras after injection into blastocysts. Based on flow cytometry analysis (FACS), the proportion of Zscan4-positive cells in secondary colonies was higher than in standard ESC colonies, which may explain the capacity of ESCs to resist the differentiating effects of RA and instead form secondary colonies of undifferentiated ESCs. This hypothesis is supported by cell-lineage tracing analysis, which showed that most cells in the secondary colonies were descendents of cells transiently expressing Zscan4.
Isolation and biological characterization of tendon-derived stem cells from fetal bovine.Saturday, April 30, 2016
Yang J, Zhao Q, Wang K, Liu H, Ma C, Huang H, Liu Y,
In vitro cellular & developmental biology. Animal. 29-Apr-2016
The lack of appropriate candidates of cell sources for cell transplantation has hampered efforts to develop therapies for tendon injuries, such as tendon rupture, tendonitis, and tendinopathy. Tendon-derived stem cells (TDSCs) are a type of stem cells which may be used in the treatment of tendon injuries. In this study, TDSCs were isolated from 5-mo-old Luxi Yellow fetal bovine and cultured in vitro and further analyzed for their biological characteristics using immunofluorescence and reverse transcription-polymerase chain reaction (RT-PCR) assays. It was found that primary TDSCs could be expanded for 42 passages in vitro maintaining proliferation. The expressions of stem cell marker nucleostemin and tenocyte-related markers, such as collagen I, collagen II, collagen III, and tenascin-C, were observed on different passage cells by immunofluorescence. The results from RT-PCR show that TDSCs were positive for collagen type I, CD44, tenascin-C, and collagen type III but negative for collagen type II. Meanwhile, TDSC passage 4 was successfully induced to differentiate into osteoblasts, adipocytes, and chondrocytes. Our results indicate that the fetal bovine TDSCs not only had strong self-renewal capacity but also possess the potential for multi-lineage differentiation. This study provides theoretical basis and experimental foundation for potential therapeutic application of the fetal bovine TDSCs in the treatment of tendon injuries.
Crosstalk between tumor suppressors p53 and PKCδ: Execution of the intrinsic apoptotic pathways.Saturday, April 30, 2016
Dashzeveg N, Yoshida K,
Cancer letters. 26-Apr-2016
p53 and PKCδ are tumor suppressors that execute apoptotic mechanisms in response to various cellular stresses. p53 is a transcription factor that is frequently mutated in human cancers; it regulates apoptosis in transcription-dependent and -independent ways in response to genotoxic stresses. PKCδ is a serine/threonine protein kinase and mutated in human cancers. Available evidence shows that PKCδ activates p53 by direct and/or indirect mechanisms. Moreover, PKCδ is also implicated in the transcriptional regulation of p53 in response to DNA damage. Recent findings demonstrated that p53, in turn, binds onto the PKCδ promoter and induces its expression upon DNA damage to facilitate apoptosis. Both p53 and PKCδ are associated with the apoptotic mechanisms in the mitochondria by regulating Bcl-2 family proteins to provide mitochondrial outer membrane permeabilization. This review discusses the crosstalk between p53 and PKCδ in the context of apoptotic cell death and cancer therapy.
What Can Ethobehavioral Studies Tell Us about the Brain's Fear System?Saturday, April 30, 2016
Pellman BA, Kim JJ,
Trends in neurosciences. 26-Apr-2016
Foraging-associated predation risk is a natural problem all prey must face. Fear evolved due to its protective functions, guiding and shaping behaviors that help animals adapt to various ecological challenges. Despite the breadth of risky situations in nature that demand diversity in fear behaviors, contemporary neurobiological models of fear stem largely from Pavlovian fear conditioning studies that focus on how a particular cue becomes capable of eliciting learned fear responses, thus oversimplifying the brain's fear system. Here we review fear from functional, mechanistic, and phylogenetic perspectives where environmental threats cause animals to alter their foraging strategies in terms of spatial and temporal navigation, and discuss whether the inferences we draw from fear conditioning studies operate in the natural world.
Anti-myocardial ischemia effect of Syringa pinnatifolia Hemsl. by inhibiting expression of cyclooxygenase-1 and -2 in myocardial tissues of mice.Saturday, April 30, 2016
Cao Y, Wang J, Su G, Wu Y, Bai R, Zhang Q, Gao X, Li C, Chen S, Tu P, Chai X,
Journal of ethnopharmacology. 26-Apr-2016
Ethanol extract of SP has a protective effect against myocardial ischemia via down regulation of COX-1 and COX-2 expression and by adjusting the ischemia-induced imbalance between 6-keto-PGF1α and TXB2. This study shows substantial evidence to support the clinical application of SP and indicates that such medicine has great potential for treating ischemia-induced heart disease.
Couples with non-obstructive azoospermia are interested in future treatments with artificial gametes.Saturday, April 30, 2016
Hendriks S, Hessel M, Mochtar MH, Meissner A, van der Veen F, Repping S, Dancet EA,
Human reproduction (Oxford, England). 29-Apr-2016
The authors report no financial or other conflict of interest relevant to the subject of this article.
Differentiation of human adipose stromal cells in vitro into insulin-sensitive adipocytes.Saturday, April 30, 2016
Huttala O, Mysore R, Sarkanen JR, Heinonen T, Olkkonen VM, Ylikomi T,
Cell and tissue research. 29-Apr-2016
Adipose tissue-related diseases such as obesity and type 2 diabetes are worldwide epidemics. In order to develop adipose tissue cultures in vitro that mimic more faithfully the in vivo physiology, new well-characterized and publicly accepted differentiation methods of human adipose stem cells are needed. The aims of this study are (1) to improve the existing natural adipose tissue extract (ATE)-based induction method and (2) to study the effects of a differentiation method on insulin responsiveness of the resulting adipocytes. Different induction media were applied on human adipose stromal cell (hASC) monocultures to study the differentiation capacity of the induction media and the functionality of the differentiated adipocytes. Cells were differentiated for 14 days to assess triglyceride accumulation per cell and adipocyte-specific gene expression (PPARγ, adiponectin, AP2, leptin, Glut4, Prdm16, CIDEA, PGC1-α, RIP140, UCP and ADCY5). Insulin response was studied by measuring glucose uptake and inhibition of lipolysis after incubation with 100 or 500 nM insulin. The selected differentiation method included a 3-day induction with ATE, 6 days in serum-free medium supplemented with 1.15 μM insulin and 9.06 μM Troglitazone, followed by 4 days in a defined serum- and insulin-free stimulation medium. This protocol induced prominent general adipocyte gene expression, including markers for both brown and white adipocytes and triglyceride accumulation. Moreover, the cells were sensitive to insulin as observed from increased glucose uptake and inhibition of lipolysis. This differentiation protocol provides a promising approach for the induction of hASC adipogenesis to obtain functional and mature human adipocytes.
Autologous chondrocytes as a novel source for neo-chondrogenesis in haemophiliacs.Saturday, April 30, 2016
Stocco E, Barbon S, Radossi P, Rajendran S, Dalzoppo D, Bortolami M, Bagno A, Grandi F, Gamba PG, Parnigotto PP, Tagariello G, Grandi C,
Cell and tissue research. 29-Apr-2016
Haemophilic arthropathy is the major cause of disability in patients with haemophilia and, despite prophylaxis with coagulation factor concentrates, some patients still develop articular complications. We evaluate the feasibility of a tissue engineering approach to improve current clinical strategies for cartilage regeneration in haemophiliacs by using autologous chondrocytes (haemophilic chondrocytes; HaeCs). Little is known about articular chondrocytes from haemophilic patients and no characterisation has as yet been performed. An investigation into whether blood exposure alters HaeCs should be interesting from the perspective of autologous implants. The typical morphology and expression of specific target genes and surface markers were therefore assessed by optical microscopy, reverse transcription plus the polymerase chain reaction (PCR), real-time PCR and flow-cytometry. We then considered chondrocyte behaviour on a bio-hybrid scaffold (based on polyvinyl alcohol/Wharton's jelly) as an in vitro model of articular cartilage prosthesis. Articular chondrocytes from non-haemophilic donors were used as controls. HaeC morphology and the resulting immunophenotype CD44(+)/CD49c(+)/CD49e(+)/CD151(+)/CD73(+)/CD49f(-)/CD26(-) resembled those of healthy donors. Moreover, HaeCs were active in the transcription of genes involved in the synthesis of the extracellular matrix proteins of the articular cartilage (ACAN, COL1A, COL2A, COL10A, COL9A, COMP, HAS1, SOX9), although the over-expression of COL1A1, COL10A1, COMP and HAS was observed. In parallel, the composite scaffold showed adequate mechanical and biological properties for cartilage tissue engineering, promoting chondrocyte proliferation. Our preliminary evidence contributes to the characterisation of HaeCs, highlighting the opportunity of using them for autologous cartilage implants in patients with haemophilia.
Matrigel and Activin A promote cell-cell contact and anti-apoptotic activity in cultured human retinal pigment epithelium cells.Saturday, April 30, 2016
Guo X, Zhu D, Lian R, Han Y, Guo Y, Li Z, Tang S, Chen J,
Experimental eye research. 26-Apr-2016
Age-related macular degeneration (AMD) is a leading cause of blindness among the aging population. Currently, replacement of diseased retinal pigment epithelium (RPE) cells with transplanted healthy RPE cells could be a feasible approach for AMD therapy. However, maintaining cell-cell contact and good viability of RPE cells cultured in vitro is difficult and fundamentally determines the success of RPE cell transplantation. This study was conducted to examine the role of Matrigel and Activin A (MA) in regulating cell-cell contact and anti-apoptotic activity in human RPE (hRPE) cells, as assessed by atomic force microscopy (AFM), scanning electron microscope (SEM), immunofluorescence staining, quantitative polymerase chain reaction (qPCR) analysis, Annexin V/propidium iodide (PI) analysis, mitochondrial membrane potential (△Ψ m) assays, intracellular reactive oxygen species (ROS) assays and Western blotting. hRPE cells cultured in vitro could maintain their epithelioid morphology after MA treatment over at least 4 passages. The contact of N-cadherin to the lateral cell border was promoted in hRPE cells at P2 by MA. MA treatment also enhanced the expression of tight junction-associated genes and proteins, such as Claudin-1, Claudin-3, Occludin and ZO-1, as well as polarized ZO-1 protein distribution and barrier function, in cultured hRPE cells. Moreover, MA treatment decreased apoptotic cells, ROS and Bax and increased △Ψ m and Bcl2 in hRPE cells under serum withdrawal-induced apoptosis. In addition, MA treatment elevated the protein expression levels of β-catenin and its target proteins, including Cyclin D1, c-Myc and Survivin, as well as the gene expression levels of ZO-1, β-catenin, Survivin and TCF-4, all of which could be down-regulated by the Wnt/β-catenin pathway inhibitor XAV-939. Taken together, MA treatment could effectively promote cell-cell contact and anti-apoptotic activity in hRPE cells, partly involving the Wnt/β-catenin pathway. This study will benefit the understanding of hRPE cells and future cell therapy.
Feedback mechanisms control coexistence in a stem cell model of acute myeloid leukaemia.Saturday, April 30, 2016
Crowell HL, MacLean AL, Stumpf MP,
Journal of theoretical biology. 27-Apr-2016
Haematopoietic stem cell dynamics regulate healthy blood cell production and are disrupted during leukaemia. Competition models of cellular species help to elucidate stem cell dynamics in the bone marrow microenvironment (or niche), and to determine how these dynamics impact leukaemia progression. Here we develop two models that target acute myeloid leukaemia with particular focus on the mechanisms that control proliferation via feedback signalling. It is within regions of parameter space permissive of coexistence that the effects of competition are most subtle and the clinical outcome least certain. Steady state and linear stability analyses identify parameter regions that allow for coexistence to occur, and allow us to characterise behaviour near critical points. Where analytical expressions are no longer informative, we proceed statistically and sample parameter space over a coexistence region. We find that the rates of proliferation and differentiation of healthy progenitors exert key control over coexistence. We also show that inclusion of a regulatory feedback onto progenitor cells promotes healthy haematopoiesis at the expense of leukaemia, and that - somewhat paradoxically - within the coexistence region feedback increases the sensitivity of the system to dominance by one lineage over another.
Heterogeneity in studies of mesenchymal stromal cells to treat or prevent GVHD: a scoping review of the evidence.Saturday, April 30, 2016
Rizk M, Monaghan M, Shorr R, Kekre N, Bredeson CN, Allan DS,
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 26-Apr-2016
Effective treatments are lacking for the treatment of steroid-refractory graft versus host disease (GVHD), a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Mesenchymal stromal cells (MSCs) have demonstrated promise but there is uncertainty regarding their clinical effectiveness. A systematic scoping review of the literature was performed to characterize the heterogeneity of published studies and identify opportunities for standardization. Thirty studies were identified, including 19 studies (507 patients) addressing the treatment of acute or chronic GVHD and 11 prevention studies (277 patients). Significant heterogeneity was observed in the age and diagnoses of study subjects, the intensity and specifics of the conditioning regimens, degree of HLA-matching and source of hematopoietic cells. MSCs were derived from bone marrow (83% of studies), cord blood (13%), or adipose tissue (3%) and were cryopreserved from third party allogeneic donors in the majority of studies (91% of prevention studies and 63% of treatment studies). Culture conditions and media supplements were highly variable and characterization of MSCs did not conform to all ISCT criteria in any study. MSCs were harvested from cell culture at passage 1-7 and the dosage of MSCs ranged from 1 - 10 x 10(6)/kg using varying schedules of administration. Treatment response criteria were not standardized and effectiveness in controlled treatment studies (5 studies) was unconvincing. Details of actively recruiting trials suggest heterogeneity still persists with only 53% of registered trials describing the use of standard GVHD response criteria and few detailing methods of MSC manufacturing. Future studies will need to make substantial coordinated efforts to reduce study heterogeneity and clarify the role of MSCs in GVHD.
A Bioluminescent Assay for Measuring Glucose Uptake.Saturday, April 30, 2016
Valley MP, Karassina N, Aoyama N, Carlson C, Cali JJ, Vidugiriene J,
Analytical biochemistry. 26-Apr-2016
Identifying activators and inhibitors of glucose uptake are critical for both diabetes management and anticancer therapy. To facilitate such studies, easy-to-use nonradioactive assays are desired. Here we describe a bioluminescent glucose uptake assay for measuring glucose transport in cells. The assay is based on the uptake of 2-deoxyglucose and the enzymatic detection of the 2-deoxyglucose-6-phosphate that accumulates. Uptake can be measured from a variety of cell types, it can be inhibited by known glucose transporter inhibitors, and the bioluminescent assay yields similar results when compared with the radioactive method. With HCT 116 cells, glucose uptake can be detected in as low as 5,000 cells and remains linear up to 50,000 cells with signal-to-background values ranging from 5 to 45. The assay can be used to screen for glucose transporter inhibitors, or by multiplexing with viability readouts, changes in glucose uptake can be differentiated from overall effects on cell health. The assay also can provide a relevant end point for measuring insulin sensitivity. With adipocytes and myotubes, insulin-dependent increases in glucose uptake have been measured with 10- and 2-fold assay windows, respectively. Significant assay signals of 2-fold or more have also been measured with human iPSC-derived cardiomyocytes and skeletal myoblasts.
Lower relapse rates with good post-transplant outcome in alcoholic liver disease: Experience from a living donor liver transplant center.Saturday, April 30, 2016
Saigal S, Choudhary NS, Yadav SK, Saraf N, Kumar N, Rai R, Mehrotra S, Rastogi V, Rastogi A, Goja S, Bhangui P, Ramachandra SK, Raut V, Gautam D, Soin AS,
Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology. 29-Apr-2016
Good results can be obtained following LDLT for ALD, with significantly lower relapse rates in our setup as compared to the West.
Schizophrenia susceptibility gene product dysbindin-1 regulates the homeostasis of cyclin D1.Saturday, April 30, 2016
Ito H, Morishita R, Nagata KI,
Biochimica et biophysica acta. 27-Apr-2016
Dysbindin-1 (dystrobrevin binding protein-1, DTNBP1) is now widely accepted as a potential schizophrenia susceptibility gene and accumulating evidence indicates its functions in the neural development. In this study, we tried to identify new binding partners for dysbindin-1 to clarify the novel function of this molecule. When consulted with BioGRID protein interaction database, cyclin D3 was found to be a possible binding partner for dysbindin-1. We then examined the interaction between various dysbindin-1 isoforms (dysbindin-1A, -1B and -1C) and all three D-type cyclins (cyclin D1, D2, and D3) by immunoprecipitation with the COS7 cell expression system, and found that dysbindin-1A preferentially interacts with cyclin D1. The mode of interaction between these molecules was considered as direct binding since recombinant dysbindin-1A and cyclin D1 formed a complex in vitro. Mapping analyses revealed that the C-terminal region of dysbindin-1A binds to the C-terminal of cyclin D1. Consistent with the results of the biochemical analyses, endogenous dysbindin-1was partially colocalized with cyclin D1 in NIH3T3 fibroblast cells and in neuronal stem and/or progenitor cells in embryonic mouse brain. While co-expression of dysbindin-1A with cyclin D1 changed the localization of the latter from the nucleus to cytosol, cyclin D1-binding partner CDK4 inhibited the dysbindin-cyclin D1 interaction. Meanwhile, depletion of endogenous dysbindin-1A increased cyclin D1 expression. These results indicate that dysbindin-1A may control the cyclin D1 function spatiotemporally and might contribute to better understanding of the pathophysiology of dysbindin-1-associated disorders.
Investigation of salicylate hepatic responses in comparison with chemical analogues of the drug.Saturday, April 30, 2016
Cameron AR, Logie L, Patel K, Bacon S, Forteath C, Harthill J, Roberts A, Sutherland C, Stewart D, Viollet B, Sakamoto K, McDougall G, Foretz M, Rena G,
Biochimica et biophysica acta. 26-Apr-2016
Antihyperglycaemic effects of the hydroxybenzoic acid salicylate might stem from effects of the drug on mitochondrial uncoupling, activation of AMP-activated protein kinase and inhibition of NF-κB signalling. Here, we have gauged the contribution of these effects to control of hepatocyte glucose production, comparing salicylate with inactive hydroxybenzoic acid analogues of the drug. In rat H4IIE hepatoma cells, salicylate was the only drug tested that activated AMPK. Salicylate also reduced mTOR signalling but this property was observed widely amongst the analogues. In a sub-panel of analogues, salicylate alone reduced promoter activity of the key gluconeogenic enzyme glucose 6-phosphatase and suppressed basal glucose production in mouse primary hepatocytes. Both salicylate and 2,6 dihydroxybenzoic acid suppressed TNFα-induced IκB degradation and in genetic knockout experiments we found the effect of salicylate on IκB degradation was AMPK-independent. Previous data also identified AMPK-independent regulation of glucose production but we found that direct inhibition of neither NF-κB nor mTOR signalling suppressed glucose production, suggesting that other factors besides these cell signalling pathways may need to be considered to account for this response to salicylate. We found for example that H4IIE cells were exquisitely sensitive to uncoupling with modest doses of salicylate, which occurred on a similar time course to another antihyperglycaemic uncoupling agent 2,4-dinitrophenol, whilst there was no discernible effect at all of two salicylate analogues which are not anti-hyperglycaemic. This finding supports much earlier literature suggesting that salicylates exert anti-hyperglycaemic effects at least in part through uncoupling.
Mechanisms of cellular plasticity in cerebral perivascular region.Saturday, April 30, 2016
Egawa N, Lok J, Arai K,
Progress in brain research. 2016
Brain vasculature acts in synergism with neurons to maintain brain function. This neurovascular coupling, or trophic coupling between cerebral endothelium and neuron, is now well accepted as a marker for mapping brain activity. Neurovascular coupling is most active in the perivascular region, in which there are ample opportunities for cell-cell interactions within the neurovascular unit. This trophic coupling between cells maintains neurovascular function and cellular plasticity. Recent studies have revealed that even adult brains contain multiple stem cells of various lineages, which may provide cellular plasticity through the process of differentiation among these stem cell populations. In this chapter, we provide an overview of the process by which neurovascular components contribute to cellular plasticity in the cerebral perivascular regions, focusing on mechanisms of cell-cell interaction in adult brain.
Trim33/Tif1γ is involved in late stages of granulomonopoiesis in mice.Saturday, April 30, 2016
Chrétien ML, Legouge C, Martin RZ, Hammann A, Trad M, Aucagne R, Largeot A, Bastie JN, Delva L, Quéré R,
Experimental hematology. 26-Apr-2016
Trim33/Tif1γ (Trim33) is a member of the tripartite motif family. We previously showed by using a conditional hematopoietic specific Trim33 knock out (Trim33(Δ/Δ)) mouse that Trim33 deficiency in hematopoietic stem cells led to severe defects in hematopoiesis, resembling the main features of human chronic myelomonocytic leukemia. We also demonstrated that Trim33 is involved in hematopoietic aging through the TGFβ signaling. Nevertheless, how Trim33 contributes to the terminal stages of myeloid differentiation still remains to be clarified. We reveal here the crucial role of Trim33 expression in the control of mature granulomonocytic differentiation. An important component of Trim33-deficient mice is the alteration of myeloid differentiation, as characterized by dysplastic features, abnormal granulocyte and monocyte maturation and the expansion of CD11b(+)Ly6G(high)Ly6C(low) myeloid cells, which share some features with polymorphonuclear-myeloid derived suppressor cells (PMN-MDSCs). Moreover, in Trim33(Δ/Δ) mice, we observed, in association with the lack of Csf-1 receptor, the alteration of CSF-1-mediated macrophage differentiation. Altogether, these results indicate that Trim33 deficiency leads to the expansion of a subset of myeloid cells characterizing the myelodysplastic/myeloproliferative neoplasm.
The zinc finger transcription factor PW1/PEG3 restrains murine beta cell cycling.Saturday, April 30, 2016
Sojoodi M, Stradiot L, Tanaka K, Heremans Y, Leuckx G, Besson V, Staels W, Van de Casteele M, Marazzi G, Sassoon D, Heimberg H, Bonfanti P,
Diabetologia. 29-Apr-2016
These results indicate that PW1 is a co-regulator of the beta cell cycle and can thus be considered a novel therapeutic target in diabetes.
An effectiveness-implementation hybrid trial study protocol targeting posttraumatic stress disorder and comorbidity.Saturday, April 30, 2016
Zatzick DF, Russo J, Darnell D, Chambers DA, Palinkas L, Van Eaton E, Wang J, Ingraham LM, Guiney R, Heagerty P, Comstock B, Whiteside LK, Jurkovich G,
Implementation science : IS. 29-4-2016 NCT02655354 . Registered 27 July 2015.
Mechanical Stretching Promotes Skin Tissue Regeneration via Enhancing Mesenchymal Stem Cell Homing and Transdifferentiation.Saturday, April 30, 2016
Liang X, Huang X, Zhou Y, Jin R, Li Q,
Stem cells translational medicine. 29-Apr-2016
Skin tissue expansion is a clinical procedure for skin regeneration to cover cutaneous defects that can be accompanied by severe complications. The transplantation of mesenchymal stem cells (MSCs) has been proven effective in promoting skin expansion and ameliorating complications. This study, which sought to provide a systematic understanding of the mechanism, determined that mechanical stretching could upregulate MSC expression of genes related to hypoxia, vascularization, and cell proliferation; enhance transplanted MSC homing to the expanded skin tissue; and promote their transdifferentiation into epidermal basal cells and endothelial cells.
Concise Review: Bridging the Gap: Novel Neuroregenerative and Neuroprotective Strategies in Spinal Cord Injury.Saturday, April 30, 2016
Ahuja CS, Fehlings M,
Stem cells translational medicine. 29-Apr-2016
Spinal cord injuries (SCIs) result in devastating, lifelong disability for patients and their families. This article discusses important neuroprotective interventions currently applied in clinical practice, including surgical decompression, blood pressure augmentation, and i.v. methylprednisolone. Translational therapies on the horizon are discussed, such as riluzole, minocycline, fibroblast growth factor, magnesium, and hypothermia. The key neuroregenerative strategies of the next decade are summarized, including glial scar degradation, Rho-ROCK inhibition, cell-based therapies, and novel bioengineered adjuncts. The need for combinatorial approaches to this multifactorial problem is emphasized, relevant studies at the forefront of translation are discussed, and perspectives on the future direction of SCI research are presented.
Human Cartilage-Derived Progenitor Cells From Committed Chondrocytes for Efficient Cartilage Repair and Regeneration.Saturday, April 30, 2016
Jiang Y, Cai Y, Zhang W, Yin Z, Hu C, Tong T, Lu P, Zhang S, Neculai D, Tuan RS, Ouyang HW,
Stem cells translational medicine. 29-Apr-2016
Injury of cartilage, a non-self-repairing tissue, often progresses to pathogenesis of degenerative joint diseases, such as osteoarthritis. Although tissue-derived stem cells have been shown to contribute to tissue renewal and homeostasis, the derivation, biological function, and application potential of stem/progenitor cells found in adult human articular cartilage are incompletely understood. This study reports the derivation of a population of cartilage stem/progenitor cells from fully differentiated chondrocytes under specific culture conditions, which have the potential to reassume their chondrocytic phenotype for efficient cartilage regeneration. These findings support the possibility of using in vitro amplified chondrocyte-derived progenitor cells for joint cartilage repair.
Comparison and evaluation of biomechanical, electrical, and biological methods for assessment of damage to tissue collagen.Saturday, April 30, 2016
Hepfer RG, Brockbank KG, Chen Z, Greene ED, Campbell LH, Wright GJ, Linthurst-Jones A, Yao H,
Cell and tissue banking. 29-Apr-2016
In regard to evaluating tissue banking methods used to preserve or otherwise treat (process) soft allograft tissue, current tests may not be sufficiently sensitive to detect potential damage inflicted before, during, and after processing. Using controlled parameters, we aim to examine the sensitivity of specific biomechanical, electrical, and biological tests in detecting mild damage to collagen. Fresh porcine pulmonary heart valves were treated with an enzyme, collagenase, and incubated using various times. Controls received no incubation. All valves were cryopreserved and stored at -135 °C until being rewarmed for evaluation using biomechanical, permeability, and cell viability tests. Statistically significant time dependent changes in leaflet ultimate stress, (p = 0.006), permeability (p = 0.01), and viability (p ≤ 0.02, four different days of culture) were found between heart valves subjected to 0-15 min of collagenase treatment (ANOVA). However, no statistical significance was found between the tensile modulus of treated and untreated valves (p = 0.07). Furthermore, the trends of decreasing and increasing ultimate stress and viability, respectively, were somewhat inconsistent across treatment times. These results suggest that permeability tests may offer a sensitive, quantitative assay to complement traditional biomechanical and viability tests in evaluating processing methods used for soft tissue allografts, or when making changes to current validated methods. Multiple test evaluation may also offer insight into the mechanism of potential tissue damage such as, as is the case here, reduced collagen content and increased tissue porosity.
Monocyte/macrophage lineage commitment and distribution are affected by the lack of regulatory T cells in scurfy mice.Saturday, April 30, 2016
Skuljec J, Cabanski M, Surdziel E, Lachmann N, Brennig S, Pul R, Jirmo AC, Habener A, Visic J, Dalüge K, Hennig C, Moritz T, Happle C, Hansen G,
European journal of immunology. 30-Apr-2016
Foxp3(+) regulatory T (Treg) cells play a pivotal role in maintaining immunological tolerance. Loss-of-function mutations in the Foxp3 gene result in multi-organ inflammation known as IPEX syndrome in humans and scurfy (Sf) disease in mice. While the impact of missing Treg cells on adaptive immune cells is well documented, their role in regulation of myeloid cells remains unclear. Here we report that Sf mice exhibit an altered composition of stem and progenitor cells, characterized by increased numbers of myeloid precursors and higher efficiency of macrophage generation ex vivo. The proportion of monocytes/macrophages in the bone marrow, blood and spleen was significantly elevated in Sf mice, which was accompanied with tissue-specific monocyte expression of homing receptor and phagocytic activity. Sf mice displayed high levels of M-CSF and other inflammatory cytokines, including monocyte-recruiting chemokines. Adoptive transfer of wild type CD4(+) cells and in vivo neutralization of M-CSF normalized frequencies of monocyte subsets and their progenitors and reduced high levels of monocyte-related cytokines in Sf mice, while Treg cell transfer to RAG2(-/-) mice had no effect on myelopoiesis and monocyte/macrophage counts. Our findings illustrate that deregulated myelopoiesis in Sf mice is mainly caused by the inflammatory reaction resulting from the lack of Treg cells. This article is protected by copyright. All rights reserved.
Three-dimensional ex vivo co-culture models of the leukaemic bone marrow niche for functional drug testing.Saturday, April 30, 2016
Dhami SP, Kappala SS, Thompson A, Szegezdi E,
Drug discovery today. 26-Apr-2016
Acute myeloid leukaemia (AML) is a hierarchically structured malignancy in which aberrant leukaemic stem cells drive the production of leukaemic blast cell clones. AML cells strictly depend on the bone marrow microenvironment (BMM) in which they reside. Classical AML cell cultures fail to mimic the BMM and, therefore, drug discovery studies are dominated by in vivo models. However, animal models are time consuming, labour intensive, provide limited mechanistic insight, and are unsuited for high-throughput studies, necessitating the development of novel AML models. The evolving ex vivo BMM-mimicking culture systems aim to fill this gap, with increasing success. Here, we discuss how AML-microenvironment co-culture models advance our understanding of this disease, and highlight their future potential for translational AML research.
Androgen control of lipid metabolism in prostate cancer: novel insights and future applications.Saturday, April 30, 2016
Butler LM, Centenera MM, Swinnen JV,
Endocrine-related cancer. 29-Apr-2016
One of the most typical hallmarks of prostate cancer cells is their exquisite dependence on androgens, which is the basis of the widely applied androgen deprivation therapy. Among the variety of key cellular processes and functions that are regulated by androgens, lipid metabolism stands out by its complex regulation and its many intricate links with cancer cell biology. Here we review our current knowledge on the links between androgens and lipid metabolism in prostate cancer, and highlight recent developments and insights into the links between key oncogenic stimuli and altered lipid synthesis and/or uptake that may hold significant potential for biomarker development and provide new vulnerabilities for therapeutic intervention.
Expression of the prospective mesoderm genes twist, snail, and mef2 in penaeid shrimp.Saturday, April 30, 2016
Wei J, Glaves RS, Sellars MJ, Xiang J, Hertzler PL,
Development genes and evolution. 29-Apr-2016
In penaeid shrimp, mesoderm forms from two sources: naupliar mesoderm founder cells, which invaginate during gastrulation, and posterior mesodermal stem cells called mesoteloblasts, which undergo characteristic teloblastic divisions. The primordial mesoteloblast descends from the ventral mesendoblast, which arrests in cell division at the 32-cell stage and ingresses with its sister dorsal mesendoblast prior to naupliar mesoderm invagination. The naupliar mesoderm forms the muscles of the naupliar appendages (first and second antennae and mandibles), while the mesoteloblasts form the mesoderm, including the muscles, of subsequently formed posterior segments. To better understand the mechanism of mesoderm and muscle formation in penaeid shrimp, twist, snail, and mef2 cDNAs were identified from transcriptomes of Penaeus vannamei, P. japonicus, P. chinensis, and P. monodon. A single Twist ortholog was found, with strong inferred amino acid conservation across all three species. Multiple Snail protein variants were detected, which clustered in a phylogenetic tree with other decapod crustacean Snail sequences. Two closely-related mef2 variants were found in P. vannamei. The developmental mRNA expression of these genes was studied by qPCR in P. vannamei embryos, larvae, and postlarvae. Expression of Pv-twist and Pv-snail began during the limb bud stage and continued through larval stages to the postlarva. Surprisingly, Pv-mef2 expression was found in all stages from the zygote to the postlarva, with the highest expression in the limb bud and protozoeal stages. The results add comparative data on the development of anterior and posterior mesoderm in malacostracan crustaceans, and should stimulate further studies on mesoderm and muscle development in penaeid shrimp.
Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells.Saturday, April 30, 2016
Chawla A, Alatrash G, Philips AV, Qiao N, Sukhumalchandra P, Kerros C, Diaconu I, Gall V, Neal S, Peters HL, Clise-Dwyer K, Molldrem JJ, Mittendorf EA,
Cancer immunology, immunotherapy : CII. 29-Apr-2016
Neutrophil elastase (NE) is an innate immune cell-derived inflammatory mediator that we have shown increases the presentation of tumor-associated peptide antigens in breast cancer. In this study, we extend these observations to show that NE uptake has a broad effect on enhancing antigen presentation by breast cancer cells. We show that NE increases human leukocyte antigen (HLA) class I expression on the surface of breast cancer cells in a concentration and time-dependent manner. HLA class I upregulation requires internalization of enzymatically active NE. Western blots of NE-treated breast cancer cells confirm that the expression of total HLA class I as well as the antigen-processing machinery proteins TAP1, LMP2, and calnexin does not change following NE treatment. This suggests that NE does not increase the efficiency of antigen processing; rather, it mediates the upregulation of HLA class I by stabilizing and reducing membrane recycling of HLA class I molecules. Furthermore, the effects of NE extend beyond breast cancer since the uptake of NE by EBV-LCL increases the presentation of HLA class I-restricted viral peptides, as shown by their increased sensitivity to lysis by EBV-specific CD8+ T cells. Together, our results show that NE uptake increases the responsiveness of breast cancer cells to adaptive immunity by broad upregulation of membrane HLA class I and support the conclusion that the innate inflammatory mediator NE enhances tumor cell recognition and increases tumor sensitivity to the host adaptive immune response.
Tenogenic modulating insider factor: Systematic assessment on the functions of TNMD gene.Saturday, April 30, 2016
Dex S, Lin D, Shukunami C, Docheva D,
Gene. 26-Apr-2016
Tenomodulin (TNMD, Tnmd) is a gene highly expressed in tendon known to be important for tendon maturation with key implications for the residing tendon stem/progenitor cells as well as for the regulation of endothelial cell migration in chordae tendineae cordis in the heart and in experimental tumour models. This review aims at providing an encompassing overview of this gene and its protein. In addition, its known expression pattern as well as putative signalling pathways will be described. A chronological overview of the discovered functions of this gene in tendon and other tissues and cells is provided as well as its use as a tendon and ligament lineage marker is assessed in detail and discussed. Last, information about the possible connections between TNMD genomic mutations and mRNA expression to various diseases is delivered. Taken together this review offers a solid synopsis on the up-to-date information available about TNMD and aids at directing and focusing the future research to fully uncover the roles and implications of this interesting gene.
The hepatocyte growth factor-expressing character is required for mesenchymal stem cells to protect the lung injured by lipopolysaccharide in vivo.Saturday, April 30, 2016
Hu S, Li J, Xu X, Liu A, He H, Xu J, Chen Q, Liu S, Liu L, Qiu H, Yang Y,
Stem cell research & therapy. 26-4-2016
MSC restores lung permeability and lung injury in part by maintaining HGF levels in the lung and the HGF-expressing character is required for MSC to protect the injured lung.
A global look into human T cell subsets before and after cryopreservation using multiparametric flow cytometry and two-dimensional visualization analysis.Saturday, April 30, 2016
Lemieux J, Jobin C, Simard C, Néron S,
Journal of immunological methods. 26-Apr-2016
The cryopreservation of human lymphocytes is an essential step for the achievement of several cellular therapies. Besides, T cells are considered as promising actors in cancer therapy for their cytotoxic and regulatory properties. Consequently, the development of tools to monitor the impact of freezing and thawing processes on their fine distribution may be an asset to achieve quality control in cellular therapy. In this study, the phenotypes of freshly isolated human mononuclear cells were compared to those observed following one cycle of cryopreservation and rest periods 0h, 1h and 24h after thawing but before staining. T cells were scrutinized for their distribution according to naive, memory effector, regulatory and helper subsets. Flow cytometry analyses were done using eight-color antibody panels as proposed by the Human Immunophenotyping Consortium. Data were further analyzed by using conventional directed gating and clustering software, namely SPADE and viSNE. Overall, SPADE and viSNE tools were very efficient to monitor the outcome of PBMC populations and T cell subsets. T cells were more sensitive to cryopreservation than other cells. Our results indicated that submitting the thawed cells to a 1h rest period improved the detection of some cell markers when compared to fresh samples. In contrast, cells submitted to a 24h rest period, or to none, were less representative of fresh sample distribution. The heterogeneity of PBMC, as well as the effects of freeze-thaw cycle on their distribution, can be easily monitored by using SPADE and viSNE.
Forkhead Box Q1 Is A Novel Target of Breast Cancer Stem Cell Inhibition by Diallyl Trisulfide.Saturday, April 30, 2016
Kim SH, Kaschula CH, Priedigkeit N, Lee AV, Singh SV,
The Journal of biological chemistry. 29-Apr-2016
Diallyl trisulfide (DATS), a metabolic byproduct of garlic, is known to inhibit growth of breast cancer cells in vitro and in vivo. The present study demonstrates that DATS targets breast cancer stem cells (bCSC). Exposure of MCF-7 and SUM159 human breast cancer cells to pharmacological concentrations of DATS (2.5 and 5 μM) resulted in dose-dependent inhibition of bCSC as evidenced by mammosphere assay and flow cytometric analysis of aldehyde dehydrogenase 1 (ALDH1) activity and CD44high/CD24low/epithelial specific antigen-positive fraction. DATS-mediated inhibition of bCSC was associated with a decrease in protein level of FoxQ1. Overexpression of FoxQ1 in MCF-7 and SUM159 cells increased ALDH1 activity and CD49f+/CD24- fraction. Inhibition of ALDH1 activity and/or mammosphere formation upon DATS treatment was significantly attenuated by overexpression of FoxQ1. In agreement with these results, stable knockdown of FoxQ1 using small hairpin RNA augmented bCSC inhibition by DATS. Expression profiling for cancer stem cell-related genes suggested that FoxQ1 may negatively regulate expression of Dachshund homolog 1 (DACH1), whose expression is lost in invasive breast cancer. Chromatin immunoprecipitation confirmed recruitment of FoxQ1 at the DACH1 promoter. Moreover, inducible expression of DACH1 augmented DATS-mediated inhibition of bCSC. Expression of FoxQ1 protein was significantly higher in triple-negative breast cancer cases compared with normal mammary tissues. Moreover, an inverse association was observed between FoxQ1 and DACH1 gene expression in breast cancer cell lines and tumors. DATS administration inhibited ALDH1 activity in vivo in SUM159 xenografts. These results indicate that FoxQ1 is a novel target of bCSC inhibition by DATS.
Cofactors of LIM Domains Associate with Estrogen Receptor alpha to Regulate the Expression of Noncoding RNA H19 and Corneal Epithelial Progenitor Cell Function.Saturday, April 30, 2016
Klein RH, Stephens DN, Ho H, Chen JK, Salmans ML, Wang W, Yu Z, Andersen B,
The Journal of biological chemistry. 29-Apr-2016
Cofactors of LIM domain proteins, CLIM1 and CLIM2, are widely expressed transcriptional cofactors that are recruited to gene regulatory regions by DNA-binding proteins, including LIM domain transcription factors. In the cornea, epithelial specific expression of a dominant negative (DN) CLIM under the Keratin 14 (K14) promoter causes blistering, wounding, inflammation, epithelial hyperplasia and neovascularization, followed by epithelial thinning and subsequent epidermal-like differentiation of the corneal epithelium. The defects in corneal epithelial differentiation and cell fate determination suggest that CLIM may regulate corneal progenitor cells and the transition to differentiation. Consistent with this notion, the K14-DN-Clim corneal epithelium first exhibits increased proliferation followed by fewer progenitor cells with decreased proliferative potential. In vivo ChIP-Seq experiments with corneal epithelium show that CLIM binds to and regulates numerous genes involved in cell adhesion and proliferation, including limbally enriched genes. Intriguingly, CLIM associates primarily with non-LHX motifs in corneal epithelial cells, including that of estrogen receptor alpha (ERα). Among CLIM targets is the noncoding RNA H19 whose deregulation is associated with Silver-Russell and Beckwith-Wiedermann syndromes. We demonstrate here that H19 negatively regulates corneal epithelial proliferation. In addition to cell cycle regulators, H19 affects the expression of multiple cell adhesion genes. CLIM interacts with ERα at the H19 locus, potentially explaining the higher expression of H19 in female than male corneas. Together, our results demonstrate an important role for CLIM in regulating the proliferative potential of corneal epithelial progenitors and identify CLIM downstream target H19 as a regulator of corneal epithelial proliferation and adhesion.
Use of serial rigid bronchoscopy in the treatment of plastic bronchitis in children.Saturday, April 30, 2016
Soyer T, Yalcin Ş, Emiralioğlu N, Yilmaz EA, Soyer O, Orhan D, Doğru D, Sekerel BE, Tanyel FC,
Journal of pediatric surgery. 12-Apr-2016
BC are tenacious mucus plugs which are firmly wedged to the tracheobronchial tree. The use of optical forceps with rigid suction provides adequate removal of BC during RB. Because of underlying disease, it is difficult to cure cast formation. Therefore, most of the patients require serial RB when they become unresponsive to standard therapy or develop partial or complete airway obstruction.
Hydroxyapatite doped alginate beads as scaffolds for the osteoblastic differentiation of mesenchymal stem cells.Saturday, April 30, 2016
Wang MO, Bracagalia L, Thompson JA, Fisher JP,
Journal of biomedical materials research. Part A. 30-Apr-2016
This work investigates the role of an osteoblastic matrix component, hydroxyapatite (HA), in modular alginate scaffolds to support osteoblastic differentiation of human mesenchymal stem cells for the purpose of tissue engineered bone constructs. This system is first evaluated in a tubular perfusion bioreactor, which has been shown to improve osteoblastic differentiation over static culture conditions. HMSCs in alginate scaffolds that contain HA show increased osteoblastic gene expression compared to cells in pure alginate scaffolds, as well as significantly more matrix production and mineralization. The differentiated hMSCs and cell-laid matrix are ultimately evaluated in an in vivo site specific model. Implantation of these scaffolds with preformed matrix into the rat femoral condyle defects results in abundant bone growth and significant incorporation of the scaffold into the surrounding tissue. The developed mineralized matrix, induced in part by the HA component in the scaffold, could lead to increased tissue development in critically sized defects, and should be included in future implant strategies. This article is protected by copyright. All rights reserved.
Decellularized ovine arteries as biomatrix scaffold support endothelial of mesenchymal stem cells.Saturday, April 30, 2016
Zhang W, Huo Y, Wang X, Jia Y, Su L, Wang C, Li Y, Yang Y, Liu Y,
Heart and vessels. 29-Apr-2016
The differentiation rate of adipose-derived mesenchymal stem cells (Ad-MSCs) into endothelial cells is always lower under normal condition, which limits further clinical application of Ad-MSCs for angiogenesis regenerative medicine and needs to be enhanced. In the present study, the tissue-specific-derived decellularized ovine arteries matrix (DCS) was used as scaffold to investigate the pro-endothelial differentiation ability of decellularized ovine arteries matrix as well as the underlying mechanisms. The prepared decellularized ovine arteries matrix by the combination of enzymatic and chemical decellularization approaches preserved macroscopic 3D architecture, native composition and ultrastructure of natural ovine arteries. The RT-PCR, histopathological and immunofluorescence assay results suggested that DCS could increase the proliferation ability of MSC. What's more, the DCS could also induce the endothelial differentiation of MSC, which was further enhanced by adding VEGF. Our results showed that natural 3D matrix from decellularized ovine arteries could induce the endothelial differentiation of AD-MSCs alone or with the combination of VEGF. Our results indicated that the decellularized ovine arteries matrix would serve as an efficient culture system for promoting endothelial differentiation of Ad-MSCs.
Attenuation of Oxidative and Nitrosative Stress in Cortical Area Associates with Antidepressant-like Effects of Tropisetron in Male Mice following Social Isolation Stress.Saturday, April 30, 2016
Haj-Mirzaian A, Amiri S, Amini-Khoei H, Rahimi-Balaei M, Kordjazy N, Olson CO, Rastegar M, Naserzadeh P, Marzban H, Dehpour AR, Hosseini MJ, Mehr SE,
Brain research bulletin. 26-Apr-2016
Tropisetron, a 5-HT3 receptor antagonist widely used as an antiemetic, has been reported to have positive effects on mood disorders. Adolescence is a critical period during the development of brain, where exposure to chronic stress during this time is highly associated with the development of depression. In this study, we showed that 4 weeks of juvenile social isolation stress (SIS) provoked depressive-like behaviors in male mice, which was associated with disruption of mitochondrial function and nitric oxide overproduction in the cortical areas. In this study, Tropisetron (5mg/kg) reversed the negative behavioral effects of SIS in male mice. We found that the effects of Tropisetron were mediated through mitigating the negative activity of inducible nitric oxide synthase (iNOS) on mitochondrial activity. Administration of aminoguanidine (specific iNOS inhibitor, 20mg/kg) augmented the protective effects of Tropisetron (1mg/kg) on SIS. Furthermore, L-arginine (nitric oxide precursor, 100mg/kg) abolished the positive effects of Tropisetron. These results have increased our knowledge on the pivotal role of mitochondrial function in the pathophysiology of depression, and highlighted the role of 5-HT3 receptors in psychosocial stress response during adolescence. Finally, we observed that Tropisetron alleviated the mitochondrial dysfunction through decreased nitrergic system activity in the cerebral cortex.
The effects of creatine supplementation on striatal neural progenitor cells depend on developmental stage.Saturday, April 30, 2016
Andres RH, Ducray AD, Andereggen L, Hohl T, Schlattner U, Wallimann T, Widmer HR,
Amino acids. 29-Apr-2016
Transplantation of neural progenitor cells (NPCs) is a promising experimental therapy for Huntington's disease (HD). The variables responsible for the success of this approach, including selection of the optimal developmental stage of the grafted cells, are however largely unknown. Supporting cellular energy metabolism by creatine (Cr) supplementation is a clinically translatable method for improving cell transplantation strategies. The present study aims at investigating differences between early (E14) and late (E18) developmental stages of rat striatal NPCs in vitro. NPCs were isolated from E14 and E18 embryos and cultured for 7 days with or without Cr [5 mM]. Chronic treatment significantly increased the percentage of GABA-immunoreactive neurons as compared to untreated controls, both in the E14 (170.4 ± 4.7 %) and the E18 groups (129.3 ± 9.3 %). This effect was greater in E14 cultures (p < 0.05). Similarly, short-term treatment for 24 h resulted in increased induction (p < 0.05) of the GABA-ergic phenotype in E14 (163.0 ± 10.4 %), compared to E18 cultures (133.3 ± 9.5 %). Total neuronal cell numbers and general viability were not affected by Cr (p > 0.05). Protective effects of Cr against a metabolic insult were equal in E14 and E18 NPCs (p > 0.05). Cr exposure promoted morphological differentiation of GABA-ergic neurons, including neurite length in both groups (p < 0.05), but the number of branching points was increased only in the E18 group (p < 0.05). Our results demonstrate that the role of Cr as a GABA-ergic differentiation factor depends on the developmental stage of striatal NPCs, while Cr-mediated neuroprotection is not significantly influenced. These findings have potential implications for optimizing future cell replacement strategies in HD.
Machine Perfusion of Donor Livers for Transplantation: A Proposal for Standardized Nomenclature and Reporting Guidelines.Saturday, April 30, 2016
Karangwa SA, Dutkowski P, Fontes P, Friend PJ, Guarrera JV, Markmann JF, Mergental H, Minor T, Quintini C, Selzner M, Uygun K, Watson CJ, Porte RJ,
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 29-Apr-2016
With increasing demand for donor organs for transplantation, machine perfusion promises to be a beneficial alternative preservation method for donor livers; particularly those considered to be of sub-optimal quality, also known as extended criteria donor livers. Over the last decade, numerous studies researching MP of donor livers have been published and incredible advances have been made both in experimental and clinical research in this area. With numerous research groups working on MP, various techniques are being explored, often applying different nomenclature. The objective of this review is to catalog the differences observed in the nomenclature used in the current literature to denote various MP techniques and in the manner in which methodology is reported. From this analysis, we propose a standardization of nomenclature on liver MP to maximize consistency, enable reliable comparison and meta-analyses of studies. In addition, we propose a standardized set of guidelines for the reporting of methodology of future studies on liver MP which will facilitate comparison as well as clinical implementation of liver MP procedures. This article is protected by copyright. All rights reserved.
Conservation of spermatogonial stem cell marker expression in undifferentiated felid spermatogonia.Saturday, April 30, 2016
Vansandt LM, Livesay JL, Dickson MJ, Li L, Pukazhenthi BS, Keefer CL,
Theriogenology. 1-Apr-2016
Spermatogonial stem cells (SSCs) are distinct in their ability to self-renew, transmit genetic information, and persist throughout the life of an individual. These characteristics make SSCs a useful tool for addressing diverse challenges such as efficient transgenic production in nonrodent, biomedical animal models, or preservation of the male genome for species in which survival of frozen-thawed sperm is low. A requisite first step to access this technology in felids is the establishment of molecular markers. This study was designed to evaluate, in the domestic cat (Felis catus), the expression both in situ and following enrichment in vitro of six genes (GFRA1, GPR125, ZBTB16, POU5F1, THY1, and UCHL1) that had been previously identified as SSC markers in other species. Antibodies for surface markers glial cell line-derived neurotrophic factor family receptor alpha 1, G protein-coupled receptor 125, and thymus cell antigen 1 could not be validated, whereas Western blot analysis of prepubertal, peripubertal, and adult cat testis confirmed protein expression for the intracellular markers ubiquitin carboxy-terminal hydrolase 1, zinc finger and BTB domain-containing protein 16, and POU domain, class 5, transcription factor 1. Colocalization of the markers by immunohistochemistry revealed that several cells within the subpopulation adjacent to the basement membrane of the seminiferous tubules and identified morphologically as spermatogonia, expressed all three intracellular markers. Studies performed on cheetah (Acinonyx jubatus) and Amur leopard (Panthera pardus orientalis) testis exhibited a conserved expression pattern in protein molecular weights, relative abundance, and localization of positive cells within the testis. The expression of the three intracellular SSC marker proteins in domestic and wild cat testes confirms conservation of these markers in felids. Enrichment of marker transcripts after differential plating was also observed. These markers will facilitate further studies in cell enrichment and IVC of felid SSCs enabling both production of transgenic domestic cats and preservation of the male genome from rare and endangered felids.
Comparison of two high-throughput semiconductor chip sequencing platforms in noninvasive prenatal testing for Down syndrome in early pregnancy.Saturday, April 30, 2016
Kim S, Jung H, Han SH, Lee S, Kwon J, Kim MG, Chu H, Chen H, Han K, Kwak H, Park S, Joo HJ, Kim BC, Bhak J,
BMC medical genomics. 1-4-2016
These results suggested that, using two different sequencers, NIPT to detect fetal trisomy 21 in early pregnancy is accurate and platform-independent. The data suggested that the amount of sequencing and the application of common, simple, and robust statistical analyses are more important than sequencing chemistry and platform types. This result has practical implications in countries where PGM is approved for NIPT but the Proton system is not.
One-Step Cartilage Repair Technique as a Next Generation of Cell Therapy for Cartilage Defects: Biological Characteristics, Preclinical Application, Surgical Techniques, and Clinical Developments.Saturday, April 30, 2016
Zhang C, Cai YZ, Lin XJ,
Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association. 27-Apr-2016
Level IV, systematic review of Level II and IV studies.
Development and Characterization of a 3D Printed, Keratin-Based Hydrogel.Saturday, April 30, 2016
Placone JK, Navarro J, Laslo GW, Lerman MJ, Gabard AR, Herendeen GJ, Falco EE, Tomblyn S, Burnett L, Fisher JP,
Annals of biomedical engineering. 29-Apr-2016
Keratin, a naturally-derived polymer derived from human hair, is physiologically biodegradable, provides adequate cell support, and can self-assemble or be crosslinked to form hydrogels. Nevertheless, it has had limited use in tissue engineering and has been mainly used as casted scaffolds for drug or growth factor delivery applications. Here, we present and assess a novel method for the printed, sequential production of 3D keratin scaffolds. Using a riboflavin-SPS-hydroquinone (initiator-catalyst-inhibitor) photosensitive solution we produced 3D keratin constructs via UV crosslinking in a lithography-based 3D printer. The hydrogels obtained have adequate printing resolution and result in compressive and dynamic mechanical properties, uptake and swelling capacities, cytotoxicity, and microstructural characteristics that are comparable or superior to those of casted keratin scaffolds previously reported. The novel keratin-based printing resin and printing methodology presented have the potential to impact future research by providing an avenue to rapidly and reproducibly manufacture patient-specific hydrogels for tissue engineering and regenerative medicine applications.
Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency.Saturday, April 30, 2016
Cicalese MP, Ferrua F, Castagnaro L, Pajno R, Barzaghi F, Giannelli S, Dionisio F, Brigida I, Bonopane M, Casiraghi M, Tabucchi A, Carlucci F, Grunebaum E, Adeli M, Bredius RG, Puck JM, Stepensky P, Tezcan I, Rolfe K, De Boever E, Reinhardt RR, Appleby J, Ciceri F, Roncarolo MG, Aiuti A,
Blood. 29-Apr-2016
Adenosine deaminase (ADA) deficiency is a rare, autosomal recessive systemic metabolic disease characterized by severe combined immunodeficiency (SCID). The treatment of choice for ADA-deficient SCID (ADA-SCID) is hematopoietic stem cell transplant (SCT) from a human leukocyte antigen (HLA)-matched sibling donor, although fewer than 25% of patients have such a donor available. Enzyme replacement therapy (ERT) partially and temporarily relieves immunodeficiency. We investigated the medium-term outcome of gene therapy (GT) in 18 patients with ADA-SCID for whom an HLA-identical family donor was not available; most were not responding well to ERT. Patients were treated with an autologous CD34(+) enriched cell fraction that contained CD34(+) cells transduced with a retroviral vector encoding the human ADA cDNA sequence (GSK2696273) as part of single-arm, open-label studies or compassionate use programs. Overall survival was 100% over 2.3 to 13.4 years (median: 6.9 years). Gene-modified cells were stably present in multiple lineages throughout follow up. GT resulted in a sustained reduction in the severe infection rate from 1.17 events per person-year to 0.17 events per person-year (n=17, Patient 1 data not available). Immune reconstitution was demonstrated by normalization of T cell subsets (CD3(+), CD4(+), and CD8(+)), evidence of thymopoiesis, and sustained T cell proliferative capacity. B cell function was evidenced by immunoglobulin production, decreased intravenous immunoglobulin use, and antibody response after vaccination. All 18 patients reported infections as adverse events; infections of respiratory and gastrointestinal tracts were reported most frequently. No events indicative of leukemic transformation were reported. Trial details are registered at as #NCT00598481.
Epidermal stem cells (ESCs) accelerate diabetic wound healing via the Notch signaling pathway.Friday, April 29, 2016
Yang RH, Qi SH, Shu B, Ruan SB, Lin ZP, Lin Y, Shen R, Zhang FG, Chen XD, Xie JL,
Bioscience reports. 22-Apr-2016
Chronic, non-healing wounds are a major complication of diabetes. Recently, various cell therapies have been reported for promotion of diabetic wound healing. Epidermal stem cells (ESCs) are considered a powerful tool for tissue therapy. However, the effect and the mechanism of the therapeutic properties of ESCs in the diabetic wound healing are unclear. Herein, to determine the ability of ESCs to diabetic wound healing, a dorsal skin defect in a streptozotocin-induced diabetes mellitus mouse model was used. ESCs were isolated from mouse skin. We found that both the mRNA and protein levels of a Notch ligand Jagged1 (Jag1), Notch1 and Notch target gene Hes1 were significantly increased at the wound margins. In addition, we observed that Jag1 was high expressed in ESCs. Overexpression of Jag1 promotes ESCs migration, while knockdown Jag1 resulted in a significant reduction in ESCs migration in vitro Importantly, Jag1 overexpression improves diabetic wound healing in vivo These results provide evidence that ESCs accelerate diabetic wound healing via the Notch signaling pathway, and provide a promising potential for activation of the Notch pathway for the treatment of diabetic wound.
EVI1 interferes with myeloid maturation via transcriptional repression of Cebpa, via binding to two far downstream regulatory elements.Friday, April 29, 2016
Wilson M, Tsakraklides V, Tran M, Xiao YY, Zhang Y, Perkins AS,
The Journal of biological chemistry. 21-Apr-2016
One mechanism by which oncoproteins work is through perturbation of cellular maturation; understanding the mechanisms by which this occurs can lead to the development of targeted therapies. EVI1 is a zinc-finger oncoprotein involved in the development of acute myeloid leukemia; previous work has shown it to interfere with the maturation of granulocytes from immature precursors. Here we investigate the mechanism by which that occurs, using an immortalized hematopoietic progenitor cell line, EML-C1, as a model system. We document that overexpression of EVI1 abrogates retinoic acid-induced maturation of EML cells into committed myeloid cells, a process that can be documented by the downregulation of stem cell antigen-1 and acquisition of responsiveness to granulocyte-macrophage colony-stimulating factor. We show this requires DNA binding capacity of EVI1, suggesting downstream target genes are involved. We identify the myeloid regulator Cebpa as a target gene, and identify two EVI1 binding regions within evolutionarily conserved enhancer elements at +35 kb at +37 kb relative to the gene. EVI1 can strongly suppress Cebpa transcription, and add-back of Cebpa into EVI1-expressing EML cells partially corrects the block in maturation. We identify the DNA sequences to which EVI1 binds at +35 kb and +37 kb, and show that mutation of one of these releases Cebpa from EVI1-induced suppression. We observe a more complex picture in primary bone marrow cells, where EVI1 suppresses Cebpa in stem cells but not in more committed progenitors. Our data thus identify a regulatory node by which EVI1 contributes to leukemia, and this represents a possible therapeutic target for treatment of EVI1-expressing leukemia.
1,8-cineole potentiates IRF3-mediated antiviral response in human stem cells and an ex vivo model of rhinosinusitis.Friday, April 29, 2016
Müller J, Greiner JF, Zeuner M, Brotzmann V, Schäfermann J, Wieters F, Widera D, Sudhoff H, Kaltschmidt B, Kaltschmidt C,
Clinical science (London, England : 1979). 25-Apr-2016
Common cold is one of the most frequent human inflammatory diseases caused by viruses and can facilitate bacterial super-infections resulting in sinusitis or pneumonia. The active ingredient of the drug Soledum, 1,8-cineole, is commonly applied for treating inflammatory diseases of the respiratory tract. However, the potential of 1,8-cineole for treating primary viral infections of the respiratory tract remains unclear.In the present study, we demonstrate for the first time that 1,8-cineole potentiates Poly(I:C)-induced activity of the anti-viral transcription factor Interferon Regulatory Factor 3, while simultaneously reducing pro-inflammatory NF-κB-activity in human cell lines, inferior turbinate stem cells (ITSCs) and ex vivo cultivated human nasal mucosa. Co-treatment of cell lines with Poly(I:C) and 1,8-cineole resulted in significantly increased IRF3 reporter gene activity compared to Poly(I:C) alone, whereas NF-κB-activity was reduced. Accordingly, 1,8-cineole- and Poly(I:C)-treatment led to increased nuclear translocation of IRF3 in ITSCs and a human ex vivo model of rhinosinusitis compared to the Poly(I:C)-treated approach. Nuclear translocation of IRF3 was significantly increased in ITSCs and slice cultures treated with LPS and 1,8-cineole compared to the LPS-treated cells mimicking bacterial infection.Our findings strongly suggest that 1,8-cineole potentiates the antiviral activity of IRF3 in addition to its inhibitory effect on pro-inflammatory NF-κB-signalling and may thus broaden its field of application.
Enhanced autophagy in colorectal cancer stem cells does not contribute to radio-resistance.Friday, April 29, 2016
Yan C, Luo L, Goto S, Urata Y, Guo CY, Doi H, Kitazato K, Li TS,
Oncotarget. 25-Apr-2016
Autophagy, an essential catabolic pathway of degrading cellular components within the lysosome, has been found to benefit the growth and therapeutic resistance of cancer cells. In this study, we investigated the role of autophagy in the radio-sensitivity of cancer stem cells. By separating CD44+/CD133+ cancer stem cells from parental HCT8 human colorectal cancer cells, we found a significantly higher level of autophagy in the CD44+/CD133+ cells than in the parental cells. Exposure to 5 Gy of f-ray significantly damaged both CD44+/CD133+ cells and parental cells, but the radiation-induced damage did not differ between the groups. Unexpectedly, autophagy was not significantly induced by radiation exposure in the CD44+/CD133+ cells and parental cells. The inhibition of autophagy by the silencing of ATG7, a factor required for autophagy at the stage of autophagosome precursor synthesis, did not significantly change the growth and radiation-induced damage in both CD44+/CD133+ cells and parental cells. Although an enhanced basic level of autophagy was found in the CD44+/CD133+ cancer stem cells, our data suggest that the canonical autophagy in cancer cells plays few roles, if any, in radio-sensitivity.
Emblica officinalis extract downregulates pro-angiogenic molecules via upregulation of cellular and exosomal miR-375 in human ovarian cancer cells.Friday, April 29, 2016
De A, Powers B, De A, Zhou J, Sharma S, Van Veldhuizen P, Bansal A, Sharma R, Sharma M,
Oncotarget. 25-Apr-2016
Ovarian cancer (OC) is highly resistant to current treatment strategies based on a combination of surgery, chemotherapy and radiation therapy. We have recently demonstrated the anti-neoplastic effect of Amla extract (Emblica officinalis, AE) on OC cells in vitro and in vivo. We hypothesized that AE attenuates growth of OC through microRNA (miR)-regulated mechanism(s). The inhibitory effect of AE on proliferation, migration and invasiveness (P≤0.001) of SKOV3 cells and >90% attenuation of tumor growth in a xenograft mouse model suggested multiple targets. RT-qPCR analysis of microRNAs associated with OC showed a >2,000-fold increase in the expression of miR-375 in AE-treated SKOV3 cells that was blocked by an exogenous miR-375 inhibitor (P≤0.001). AE also decreased the gene and protein expression of IGF1R, a target of miR-375 (P≤0.001), and SNAIL1 (P≤0.002), an EMT-associated transcription factor that represses E-cadherin expression (P≤0.003). AE increased E-cadherin expression (P≤0.001). Treatment of SKOV3 cells with AE resulted in increased miR-375 in exosomes in the medium (P≤0.01). Finally, AE significantly decreased the expression of IGF1R and SNAIL1 proteins during attenuation of SKOV3-derived xenograft tumor. Together, these results show that AE modulates cancer cells and the tumor microenvironment via activation of miR-375 and by targeting IGF1R and SNAIL1 in OC cells.
Benzyl butyl phthalate promotes breast cancer stem cell expansion via SPHK1/S1P/S1PR3 signaling.Friday, April 29, 2016
Wang YC, Tsai CF, Chuang HL, Chang YC, Chen HS, Lee JN, Tsai EM,
Oncotarget. 26-Apr-2016
Understanding the regulatory mechanisms unique to breast cancer stem cells (BCSCs) is required to control breast cancer metastasis. We found that phthalates promote BCSCs in human breast cancer cell cultures and xenograft tumors. A toxic phthalate, benzyl butyl phthalate (BBP), activated aryl hydrocarbon receptor in breast cancer cells to stimulate sphingosine kinase 1 (SPHK1)/sphingosine 1-phosphate (S1P)/sphingosine-1-phosphate receptor 3 (S1PR3) signaling and enhance formation of metastasis-initiating BCSCs. BBP induced histone modifications in S1PR3 in side population (SP) cells, but not in non-SP cells. SPHK1 or S1PR3 knockdown in breast cancer cells effectively reduced tumor growth and lung metastasis in vivo. Our findings suggest S1PR3 is a determinant of phthalate-driven breast cancer metastasis and a possible therapeutic target for regulating BCSC populations. Furthermore, the association between breast carcinogenesis and environmental pollutants has important implications for public health.
Bone marrow mesenchymal stem cells participate in prostate carcinogenesis and promote growth of prostate cancer by cell fusion in vivo.Friday, April 29, 2016
Luo F, Liu T, Wang J, Li J, Ma P, Ding H, Feng G, Lin D, Xu Y, Yang K,
Oncotarget. 27-Apr-2016
The tumor microenvironment is comprised of diverse stromal cells that contribute towards tumor progression. As a result, there has been a growing interest in the role of bone marrow derived cells (BMDCs) in cancer progression. However, the role of BMDCs in prostate cancer (PCa) progression still remains unclear. In this study, we established GFP bone marrow transplanted TRAMP and MUN-induced prostate cancer models, in order to investigate the role of BMDCs in prostate cancer progression. By tracing GFP positive cells, we observed that BMDCS were recruited into mouse prostate tissues during tumorigenesis. GFP+/Sca-1+/CD45- BMDCs were significantly increased in the MNU-induced PCa group, as compared to the citrated-treated control group (2.67 ± 0.25% vs 0.67 ± 0.31%, p = 0.006). However, there were no significant differences found in GFP+/Sca-1+/CD45+ cell populations between the two groups (0.27 ± 0.15% vs 0.10 ± 0.10%, p = 0.334). Moreover, co-grafting of bone marrow mesenchymal stem cells (BMMSCs) and RM1 cells were found to promote RM1 tumor growth in vivo, and cell fusion was observed in RM-1+BMMSCs xenografts. Therefore, the data suggests that BMDCs can be recruited to the prostate during carcinogenesis, and that BMMSCs may promote the growth of PCa.
Human umbilical cord matrix-derived stem cells expressing interferon-β gene inhibit breast cancer cells via apoptosis.Friday, April 29, 2016
Shen CJ, Chan TF, Chen CC, Hsu YC, Long CY, Lai CS,
Oncotarget. 26-Apr-2016
Human umbilical cord mesenchymal stem cells (hUCMSCs) derived from the umbilical cord matrix have been reported to be used as anti-tumor gene carrier for attenuation of tumor growth, which extends the half-life and lowers the unexpected cytotoxicity of the gene in vivo. Interferon-β (IFNβ) is known to possess robust anti-tumor effects on different types of cancer cell lines in vitro. The present study was aimed to investigate the anti-tumor effect of IFNβ gene-transfected hUCMSCs (IFNβ-hUCMSCs) on breast cancer cells with emphasis on triple negative breast carcinoma. Our findings revealed that the co-culture of IFNβ-hUCMSCs with the human triple negative breast carcinoma cell lines MDA-MB-231 or Hs578T significantly inhibited growth of both carcinoma cells. In addition, the culture medium conditioned by these cells also significantly suppressed the growth and induced apoptosis of both carcinoma cells. Further investigation showed that the suppressed growth and the apoptosis induced by co-culture of IFNβ-hUCMSCs or conditioned medium were abolished by pretreating anti-IFNβ neutralizing antibody. These findings indicate that IFNβ-hUCMSCs triggered cell death of breast carcinoma cells through IFN-β production, thereby induced apoptosis and suppressed tumor cell growth. In conclusion, we demonstrated that IFNβ-hUCMSCs inhibited the growth of breast cancer cells through apoptosis. with potent anti-cancer activity, it represents as an anti-cancer cytotherapeutic modality against breast cancer.
Repurposing cephalosporin antibiotics as pro-senescent radiosensitizers.Friday, April 29, 2016
Labay E, Mauceri HJ, Efimova EV, Flor AC, Sutton HG, Kron SJ, Weichselbaum RR,
Oncotarget. 25-Apr-2016
Radiation therapy remains a significant therapeutic modality in the treatment of cancer. An attractive strategy would be to enhance the benefits of ionizing radiation (IR)with radiosensitizers. A high-content drug repurposing screen of approved and investigational agents, natural products and other small molecules has identified multiple candidates that blocked repair of IR damage in vitro. Here, we validated a subset of these hits in vitro and then examined effects on tumor growth after IR in a murine tumor model. Based on robust radiosensitization in vivo and other favorable properties of cephalexin, we conducted additional studies with other beta-lactam antibiotics. When combined with IR, each cephalosporin tested increased DNA damage and slowed tumor growth without affecting normal tissue toxicity. Our data implicate reactive oxygen species in the mechanism by which cephalosporins augment the effects of IR. This work provides a rationale for using commonly prescribed beta-lactam antibiotics as non-toxic radiosensitizers to enhance the therapeutic ratio of radiotherapy.
Tacrolimus Modulates TGF-β Signaling to Induce Epithelial-Mesenchymal Transition in Human Renal Proximal Tubule Epithelial Cells.Saturday, April 30, 2016
Bennett J, Cassidy H, Slattery C, Ryan MP, McMorrow T,
Journal of clinical medicine. 2016
Epithelial-mesenchymal transition (EMT), a process which describes the trans-differentiation of epithelial cells into motile mesenchymal cells, is pivotal in stem cell behavior, development and wound healing, as well as contributing to disease processes including fibrosis and cancer progression. Maintenance immunosuppression with calcineurin inhibitors (CNIs) has become routine management for renal transplant patient, but unfortunately the nephrotoxicity of these drugs has been well documented. HK-2 cells were exposed to Tacrolimus (FK506) and EMT markers were assessed by RT PCR and western blot. FK506 effects on TGF-β mRNA were assessed by RT PCR and TGF-β secretion was measured by ELISA. The impact of increased TGF-β secretion on Smad signaling pathways was investigated. The impact of inhibition of TGF-β signaling on EMT processes was assessed by scratch-wound assay. The results presented in this study suggest that FK506 initiates EMT processes in the HK-2 cell line, with altered expression of epithelial and myofibroblast markers evident. Additionally, the study demonstrates that FK506 activation of the TGF-β/ SMAD pathways is an essential step in the EMT process. Overall the results demonstrate that EMT is heavily involved in renal fibrosis associated with CNI nephrotoxicity.
Enhanced snoMEN Vectors Facilitate Establishment of GFP-HIF-1α Protein Replacement Human Cell Lines.Friday, April 29, 2016
Ono M, Yamada K, Bensaddek D, Afzal V, Biddlestone J, Ortmann B, Mudie S, Boivin V, Scott MS, Rocha S, Lamond AI,
PloS one. 26-04-2016
The snoMEN (snoRNA Modulator of gene ExpressioN) vector technology was developed from a human box C/D snoRNA, HBII-180C, which contains an internal sequence that can be manipulated to make it complementary to RNA targets, allowing knock-down of targeted genes. Here we have screened additional human nucleolar snoRNAs and assessed their application for gene specific knock-downs to improve the efficiency of snoMEN vectors. We identify and characterise a new snoMEN vector, termed 47snoMEN, that is derived from box C/D snoRNA U47, demonstrating its use for knock-down of both endogenous cellular proteins and G/YFP-fusion proteins. Using multiplex 47snoMEM vectors that co-express multiple 47snoMEN in a single transcript, each of which can target different sites in the same mRNA, we document >3-fold increase in knock-down efficiency when compared with the original HBII-180C based snoMEN. The multiplex 47snoMEM vector allowed the construction of human protein replacement cell lines with improved efficiency, including the establishment of novel GFP-HIF-1α replacement cells. Quantitative mass spectrometry analysis confirmed the enhanced efficiency and specificity of protein replacement using the 47snoMEN-PR vectors. The 47snoMEN vectors expand the potential applications for snoMEN technology in gene expression studies, target validation and gene therapy.
β-Arrestin-2 modulates radiation-induced intestinal crypt progenitor/stem cell injury.Friday, April 29, 2016
Liu Z, Tian H, Jiang J, Yang Y, Tan S, Lin X, Liu H, Wu B,
Cell death and differentiation. 29-Apr-2016
Intestinal crypt progenitor/stem (ICPS) cell apoptosis and vascular endothelial cell apoptosis are responsible for the initiation and development of ionizing radiation (IR)-evoked gastrointestinal syndrome. The signaling mechanisms underlying IR-induced ICPS cell apoptosis remain largely unclear. Our findings provide evidence that β-arrestin-2 (βarr2)-mediated ICPS cell apoptosis is crucial for IR-stimulated intestinal injury. βArr2-deficient mice exhibited decreased ICPS cell and intestinal Lgr5(+) (leucine-rich repeat-containing G-protein-coupled receptor 5-positive) stem cell apoptosis, promoted crypt proliferation and reproduction, and protracted survival following lethal doses of radiation. Radioprotection in the ICPS cells isolated from βarr2-deficient mice depended on prolonged nuclear factor-κB (NF-κB) activation via direct interaction of βarr2 with IκBα and subsequent inhibition of p53-upregulated modulator of apoptosis (PUMA)-mediated mitochondrial dysfunction. Unexpectedly, βarr2 deficiency had little effect on IR-induced intestinal vascular endothelial cell apoptosis in mice. Consistently, βarr2 knockdown also provided significant radioresistance by manipulating NF-κB/PUMA signaling in Lgr5(+) cells in vitro. Collectively, these observations show that targeting the βarr2/NF-κB/PUMA novel pathway is a potential radiomitigator for limiting the damaging effect of radiotherapy on the gastrointestinal system. Significance statement: acute injury to the intestinal mucosa is a major dose-limiting complication of abdominal radiotherapy. The issue of whether the critical factor for the initiation of radiation-induced intestinal injury is intestinal stem cell apoptosis or endothelial cell apoptosis remains unresolved. βArrs have recently been found to be multifunctional adaptor of apoptosis. Here, we found that β-arrestin-2 (βarr2) deficiency was associated with decreased radiation-induced ICPS cell apoptosis, which prolonged survival in abdominally irradiated mice. Moreover, βarr2 deficiency-mediated intestinal progenitor/stem cell radioprotection relied on protracted NF-κB activation and subsequent suppression of PUMA induction. Our results suggest that ICPS cell apoptosis is the factor involved in the initiation and development of radiation-induced gastrointestinal syndrome. βArr2 is a potential target for lessening radiation-induced ICPS cell apoptosis.Cell Death and Differentiation advance online publication, 29 April 2016; doi:10.1038/cdd.2016.38.
Nicotinate-Curcumin Impedes Foam Cell Formation from THP-1 Cells through Restoring Autophagy Flux.Friday, April 29, 2016
Gu HF, Li HZ, Tang YL, Tang XQ, Zheng XL, Liao DF,
PloS one. 29-4-2016
Our previous studies have indicated that a novel curcumin derivate nicotinate-curcumin (NC) has beneficial effects on the prevention of atherosclerosis, but the precise mechanisms are not fully understood. Given that autophagy regulates lipid metabolism, the present study was designed to investigate whether NC decreases foam cell formation through restoring autophagy flux in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 cells. Our results showed that ox-LDL (100 μg/ml) was accumulated in THP-1 cells and impaired autophagy flux. Ox-LDL-induced impairment of autophagy was enhanced by treatment with the autophagy inhibitor chloroquine (CQ) and rescued by the autophagy inducer rapamycin. The aggregation of ox-LDL was increased by CQ, but decreased by rapamycin. In addition, colocalization of lipid droplets with LC3-II was remarkably reduced in ox-LDL group. In contrast, NC (10 μM) rescued the impaired autophagy flux by significantly increasing level of LC3-II, the number of autophagolysosomes, and the degradation of p62 in ox-LDL-treated THP-1 cells. Inhibition of the PI3K-Akt-mTOR signaling was required for NC-rescued autophagy flux. Notably, our results showed that NC remarkably promoted the colocalization of lipid droplets with autophagolysosomes, increased efflux of cholesterol, and reduced ox-LDL accumulation in THP-1 cells. However, treatment with 3-methyladenine (3-MA) or CQ reduced the protective effects of NC on lipid accumulation. Collectively, the findings suggest that NC decreases lipid accumulation in THP-1 cells through restoring autophagy flux, and further implicate that NC may be a potential therapeutic reagent to reverse atherosclerosis.
Toxicity testing and drug screening using iPSC-derived hepatocytes, cardiomyocytes, and neural cells.Friday, April 29, 2016
Csöbönyeiová M, Polák Š, Danišovič L,
Canadian journal of physiology and pharmacology. 1-Feb-2016
Unexpected toxicity in areas such as cardiotoxicity, hepatotoxicity, and neurotoxicity is a serious complication of clinical therapy and one of the key causes for failure of promising drug candidates in development. Animal studies have been widely used for toxicology research to provide preclinical security evaluation of various therapeutic agents under development. Species differences in drug penetration of the blood-brain barrier, drug metabolism, and related toxicity contribute to failure of drug trials from animal models to human. The existing system for drug discovery has relied on immortalized cell lines, animal models of human disease, and clinical trials in humans. Moreover, drug candidates that are passed as being safe in the preclinical stage often show toxic effects during the clinical stage. Only around 16% drugs are approved for human use. Research on induced pluripotent stem cells (iPSCs) promises to enhance drug discovery and development by providing simple, reproducible, and economically effective tools for drug toxicity screening under development and, on the other hand, for studying the disease mechanism and pathways. In this review, we provide an overview of basic information about iPSCs, and discuss efforts aimed at the use of iPSC-derived hepatocytes, cardiomyocytes, and neural cells in drug discovery and toxicity testing.
Practical Points in Gastric Pathology.Saturday, April 30, 2016
Ahn S, Park do Y,
Archives of pathology & laboratory medicine. May-2016
-Our literature review revealed that clear cell changes and micropapillary carcinoma components in gastric carcinomas are associated with poor clinical outcomes and should hence be included in pathologic reports. Moreover, we suggest a stepwise biopsy-endoscopic resection modality for the diagnosis of borderline neoplasia-nonneoplasia cases.
Identification of Serum miR-146a and miR-155 as Novel Noninvasive Complementary Biomarkers for Ankylosing Spondylitis.Saturday, April 30, 2016
Qian BP, Ji ML, Qiu Y, Wang B, Yu Y, Shi W, Luo YF,
Spine. May-2016
Highly Hybridizable Spherical Nucleic Acids by Tandem Glutathione Treatment and Polythymine Spacing.Friday, April 29, 2016
Sun J, Curry DE, Yuan Q, Zhang X, Liang H,
ACS applied materials & interfaces. 29-Apr-2016
Gold nanoparticle (AuNP) - templated spherical nucleic acids (SNAs) have been demonstrated as an important functional material in bionanotechnology. Fabrication of SNAs having high hybridization capacity to their complementary sequences is critical to ensure their applicability in areas such as antisense gene therapy and cellular sensing. The traditional salt-aging procedure is effective but tedious, requiring 1-3 days to complete. The rapid low-pH assisted protocol is efficient, but causes concerns related to nonspecific DNA adsorption to the AuNP core. To address these issue, we systematically compared the SNAs prepared by these two methods (salt-aging method and low-pH protocol). In terms of the number of complementary DNA that each SNA can bind and the average binding affinity of each thiolated DNA probe to its complementary strand, both methods yielded comparable hybridizability, although higher loading capacity was witnessed with SNAs made using the low-pH method. Additionally, it was found that the nonspecific DNA binding could be eliminated almost completely by a simple glutathione (GSH) treatment of SNAs.Compared to conventional methods using toxic mercapto-hexanol or alkanethiols to remove nonspecific DNA adsorption, glutathione is mild, cost-effective, and technically easy to use. In addition, GSH-passivated SNAs minimize the toxicity concerns related to AuNP-induced GSH depletion and therefore offer a more biocompatible alternative to previously reported SNAs. Moreover, rational design of probe sequences through inclusion of a poly-thymine spacer into the DNA sequences resulted in enhanced DNA loading capacity and stability against salt-induced aggregation. This work provides not only efficient and simple technical solutions to the issue of nonspecific DNA adsorption, but also new insights into the hybridizability of SNAs.
Extracellular Nicotinamide Phosphoribosyltrasferase (eNAMPT), A New Cancer Metabokine.Friday, April 29, 2016
Grolla AA, Travelli C, Genazzani AA, Sethi JK,
British journal of pharmacology. 29-Apr-2016
In this review, we focus on the secreted form of nicotinamide phosphoribosyltrasferase, eNAMPT/PBEF/Visfatin. Although intracellular NAMPT is a key enzyme in controlling NAD metabolism, eNAMPT has been reported to function as a cytokine, with multiple roles in physiology and pathology. Circulating eNAMPT has been associated with several metabolic and inflammatory disorders, including cancer. Since cytokines produced in the tumour microenvironment play an important role in cancer pathogenesis, in part by reprogramming cellular metabolism, future improvements in cancer immune-therapy will require a better understanding of the crosstalk between cytokine action and tumour biology. In this review the knowledge of eNAMPT in cancer will be discussed, focusing on its immune-metabolic function as a "metabokine", its secretion, its mechanism of action and possible roles in the cancer microenvironment. This article is protected by copyright. All rights reserved.
S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide.Friday, April 29, 2016
Stewart RL, Carpenter BL, West DS, Knifley T, Liu L, Wang C, Weiss HL, Gal TS, Durbin EB, Arnold SM, O'Connor KL, Chen M,
Oncotarget. 25-Apr-2016
S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular invasion and decreased overall survival. In addition, depletion of S100A4 by shRNA inhibits NF-κB activity and decreases TNFα-induced MMP9 expression. Furthermore, inhibition of the NF-κB/MMP9 axis decreases lung carcinoma invasive potential. Niclosamide, a reported inhibitor of S100A4, blocks expression and function of S100A4 with a reduction in proliferation, invasion and NF-κB-mediated MMP9 expression. Collectively, this study highlights the importance of the S100A4/NF-κB/MMP9 axis in lung cancer invasion and provides a rationale for targeting S100A4 to combat lung cancer.
Cell-in-Shell Hybrids: Chemical Nanoencapsulation of Individual Cells.Friday, April 29, 2016
Park JH, Hong D, Lee J, Choi IS,
Accounts of chemical research. 29-Apr-2016
Nature has developed a fascinating strategy of cryptobiosis ("secret life") for counteracting the stressful, and often lethal, environmental conditions that fluctuate sporadically over time. For example, certain bacteria sporulate to transform from a metabolically active, vegetative state to an ametabolic endospore state. The bacterial endospores, encased within tough biomolecular shells, withstand the extremes of harmful stressors, such as radiation, desiccation, and malnutrition, for extended periods of time and return to a vegetative state by breaking their protective shells apart when their environment becomes hospitable for living. Certain ciliates and even higher organisms, for example, tardigrades, and others are also found to adopt a cryptobiotic strategy for survival. A common feature of cryptobiosis is the structural presence of tough sheaths on cellular structures. However, most cells and cellular assemblies are not "spore-forming" and are vulnerable to the outside threats. In particular, mammalian cells, enclosed with labile lipid bilayers, are highly susceptible to in vitro conditions in the laboratory and daily life settings, making manipulation and preservation difficult outside of specialized conditions. The instability of living cells has been a main bottleneck to the advanced development of cell-based applications, such as cell therapy and cell-based sensors. A judicious question arises: can cellular tolerance against harmful stresses be enhanced by simply forming cell-in-shell hybrid structures? Experimental results suggest that the answer is yes. A micrometer-sized "Iron Man" can be generated by chemically forming an ultrathin (<100 nm) but durable shell on a "non-spore-forming" cell. Since the report on silica nanoencapsulation of yeast cells, in which cytoprotective yeast-in-silica hybrids were formed, several synthetic strategies have been developed to encapsulate individual cells in a cytocompatible fashion, mimicking the cryptobiotic cell-in-shell structures found in nature, for example, bacterial endospores. Bioinspired silicification and phenolics-based coatings are, so far, the main approaches to the formation of cytoprotective cell-in-shell hybrids, because they ensure cell viability during encapsulations and also generate durable nanoshells on cell surfaces. The resulting cell-in-shell hybrids extrinsically possess enhanced resistance to external aggressors, and more intriguingly, the encapsulation alters their metabolic activity, exemplified by retarded or suppressed cell cycle progression. In addition, recent developments in the field have further advanced the synthetic tools available to the stage of chemical sporulation and germination of mammalian cells, where cytoprotective shells are formed on labile mammalian cells and broken apart on demand. For example, individual HeLa cells are coated with a metal-organic complex of ferric ion and tannic acid, and cellular adherence and proliferation are controlled by the programmed shell formation and degradation. Based on these demonstrations, the (degradable) cell-in-shell hybrids are anticipated to find their applications in various biomedical and bionanotechnological areas, such as cytotherapeutics, high-throughput screening, sensors, and biocatalysis, as well as providing a versatile research platform for single-cell biology.
Effect of Opioid on Adult Hippocampal Neurogenesis.Friday, April 29, 2016
Zhang Y, Loh HH, Law PY,
TheScientificWorldJournal. 2016
During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs' effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opiate drugs in general cause a loss of newly born neural progenitors in the subgranular zone of dentate gyrus, by either modulating proliferation or interfering with differentiation and maturation. We also discuss the consequent impact of regulation of adult neurogenesis in animal's opioid addiction behavior. We further look into the future directions in studying the convergence between the adult neurogenesis field and opioid addiction field, since the adult-born granular cells were shown to play a role in neuroplasticity and may help to reduce the vulnerability to drug craving and relapse.
Kinetics of Langerhans cell chimerism in the skin of dogs following 2 Gy TBI allogeneic hematopoietic stem cell transplantation.Friday, April 29, 2016
Peters S, Junghanss C, Knueppel A, Murua Escobar H, Roolf C, Knuebel G, Sekora A, Lindner I, Jonas L, Freund M, Lange S,
BMC hematology. 2016
Our study indicates that LC donor chimerism correlates with chimerism development in the peripheral blood but occurs delayed following NM-HSCT.
Survey of the Antibiofilm and Antimicrobial Effects of Zingiber officinale (in Vitro Study).Friday, April 29, 2016
Aghazadeh M, Zahedi Bialvaei A, Aghazadeh M, Kabiri F, Saliani N, Yousefi M, Eslami H, Samadi Kafil H,
Jundishapur journal of microbiology. Feb-2016
The findings of the present study indicate that ginger extract has good antifungal and antibiofilm formation by fungi against C. albicans and C. Krusei. Concentrations between 0.625 mg/mL and 5 mg/mL had the highest antibiofilm and antifungal effects. Perhaps, the use of herbal extracts such as ginger represents a new era for antimicrobial therapy after developing antibiotic resistance in microbes.
ROS-Mediated NLRP3 Inflammasome Activation in Brain, Heart, Kidney, and Testis Ischemia/Reperfusion Injury.Friday, April 29, 2016
Minutoli L, Puzzolo D, Rinaldi M, Irrera N, Marini H, Arcoraci V, Bitto A, Crea G, Pisani A, Squadrito F, Trichilo V, Bruschetta D, Micali A, Altavilla D,
Oxidative medicine and cellular longevity. 2016
Ischemia and reperfusion (I/R) causes a reduction in arterial blood supply to tissues, followed by the restoration of perfusion and consequent reoxygenation. The reestablishment of blood flow triggers further damage to the ischemic tissue through reactive oxygen species (ROS) accumulation, interference with cellular ion homeostasis, and inflammatory responses to cell death. In normal conditions, ROS mediate important beneficial responses. When their production is prolonged or elevated, harmful events are observed with peculiar cellular changes. In particular, during I/R, ROS stimulate tissue inflammation and induce NLRP3 inflammasome activation. The mechanisms underlying the activation of NLRP3 are several and not completely elucidated. It was recently shown that NLRP3 might sense directly the presence of ROS produced by normal or malfunctioning mitochondria or indirectly by other activators of NLRP3. Aim of the present review is to describe the current knowledge on the role of NLRP3 in some organs (brain, heart, kidney, and testis) after I/R injury, with particular regard to the role played by ROS in its activation. Furthermore, as no specific therapy for the prevention or treatment of the high mortality and morbidity associated with I/R is available, the state of the art of the development of novel therapeutic approaches is illustrated.
Leukemia Stem Cell-Released Microvesicles Promote the Survival and Migration of Myeloid Leukemia Cells and These Effects Can Be Inhibited by MicroRNA34a Overexpression.Friday, April 29, 2016
Wang Y, Cheng Q, Liu J, Dong M,
Stem cells international. 2016
Leukemia stem cells (LSCs) play the major role in relapse of acute myeloid leukemia (AML). Recent evidence indicates that microvesicles (MVs) released from cancer stem cells can promote tumor growth and invasion. In this study, we investigated whether LSCs-released MVs (LMVs) can regulate the malignance of AML cells and whether overexpression of tumor suppressive microRNA (miR), miR34a, is able to interrupt this process. LSCs were transfected with miRNA control (miRCtrl) or miR34a mimic for producing LMVs, respectively, defined as LMVs(miRCtrl) and LMVs(miR34a). The effect of miR34a transfection on LSC proliferation and the effects of LMVs(miRCtrl) or LMVs(miR34a) on the proliferation, migration, and apoptosis of AML cells (after LSC depletion) were determined. The levels of miR34a targets, caspase-3 and T cell immunoglobulin mucin-3 (Tim-3), were analyzed. Results showed that (1) LMVs(miRCtrl) promoted proliferation and migration and inhibited apoptosis of AML cells, which were associated with miR34a deficit; (2) transfection of miR34a mimic inhibited LSC proliferation and increased miR34a level in LMVs(miR34a); (3) LMVs(miR34a) produced opposite effects as compared with LMVs(miRCtrl), which were associated with the changes of caspase-3 and Tim-3 levels. In summary, LMVs support AML cell malignance and modulating miR34a could offer a new approach for the management of AML.
Human Liver Stem Cells Suppress T-Cell Proliferation, NK Activity, and Dendritic Cell Differentiation.Friday, April 29, 2016
Bruno S, Grange C, Tapparo M, Pasquino C, Romagnoli R, Dametto E, Amoroso A, Tetta C, Camussi G,
Stem cells international. 2016
Human liver stem cells (HLSCs) are a mesenchymal stromal cell-like population resident in the adult liver. Preclinical studies indicate that HLSCs could be a good candidate for cell therapy. The aim of the present study was to evaluate the immunogenicity and the immunomodulatory properties of HLSCs on T-lymphocytes, natural killer cells (NKs), and dendritic cells (DCs) in allogeneic experimental settings. We found that HLSCs inhibited T-cell proliferation by a mechanism independent of cell contact and dependent on the release of prostaglandin E2 (PGE2) and on indoleamine 2,3-dioxygenase activity. When compared with mesenchymal stromal cells (MSCs), HLSCs were more efficient in inhibiting T-cell proliferation. At variance with MSCs, HLSCs did not elicit NK degranulation. Moreover, HLSCs inhibited NK degranulation against K562, a NK-sensitive target, by a mechanism dependent on HLA-G release. When tested on DC generation from monocytes, HLSCs were found to impair DC differentiation and DCs ability to induce T-cell proliferation through PGE2. This study shows that HLSCs have immunomodulatory properties similar to MSCs, but, at variance with MSCs, they do not elicit a NK response.
Magnetic Nanoparticles for Targeting and Imaging of Stem Cells in Myocardial Infarction.Friday, April 29, 2016
Santoso MR, Yang PC,
Stem cells international. 2016
Stem cell therapy has broad applications in regenerative medicine and increasingly within cardiovascular disease. Stem cells have emerged as a leading therapeutic option for many diseases and have broad applications in regenerative medicine. Injuries to the heart are often permanent due to the limited proliferation and self-healing capability of cardiomyocytes; as such, stem cell therapy has become increasingly important in the treatment of cardiovascular diseases. Despite extensive efforts to optimize cardiac stem cell therapy, challenges remain in the delivery and monitoring of cells injected into the myocardium. Other fields have successively used nanoscience and nanotechnology for a multitude of biomedical applications, including drug delivery, targeted imaging, hyperthermia, and tissue repair. In particular, superparamagnetic iron oxide nanoparticles (SPIONs) have been widely employed for molecular and cellular imaging. In this mini-review, we focus on the application of superparamagnetic iron oxide nanoparticles in targeting and monitoring of stem cells for the treatment of myocardial infarctions.
Organotypic Cultures as a Model to Study Adult Neurogenesis in CNS Disorders.Friday, April 29, 2016
Cavaliere F, Benito-Muñoz M, Matute C,
Stem cells international. 2016
Neural regeneration resides in certain specific regions of adult CNS. Adult neurogenesis occurs throughout life, especially from the subgranular zone of hippocampus and the subventricular zone, and can be modulated in physiological and pathological conditions. Numerous techniques and animal models have been developed to demonstrate and observe neural regeneration but, in order to study the molecular and cellular mechanisms and to characterize multiple types of cell populations involved in the activation of neurogenesis and gliogenesis, investigators have to turn to in vitro models. Organotypic cultures best recapitulate the 3D organization of the CNS and can be explored taking advantage of many techniques. Here, we review the use of organotypic cultures as a reliable and well defined method to study the mechanisms of neurogenesis under normal and pathological conditions. As an example, we will focus on the possibilities these cultures offer to study the pathophysiology of diseases like Alzheimer disease, Parkinson's disease, and cerebral ischemia.
XPC Promotes Pluripotency of Human Dental Pulp Cells through Regulation of Oct-4/Sox2/c-Myc.Friday, April 29, 2016
Liu L, Peng Z, Xu Z, Wei X,
Stem cells international. 2016
Introduction. Xeroderma pigmentosum group C (XPC), essential component of multisubunit stem cell coactivator complex (SCC), functions as the critical factor modulating pluripotency and genome integrity through interaction with Oct-4/Sox2. However, its specific role in regulating pluripotency and multilineage differentiation of human dental pulp cells (DPCs) remains unknown. Methods. To elucidate the functional role XPC played in pluripotency and multilineage differentiation of DPCs, expressions of XPC in DPCs with long-term culture were examined by real-time PCR and western blot. DPCs were transfected with lentiviral-mediated human XPC gene; then transfection rate was investigated by real-time PCR and western blot. Cell cycle, apoptosis, proliferation, senescence, multilineage differentiation, and expression of Oct-4/Sox2/c-Myc in transfected DPCs were examined. Results. XPC, Oct-4, Sox2, and c-Myc were downregulated at P7 compared with P3 in DPCs with long-term culture. XPC genes were upregulated in DPCs at P2 after transfection and maintained high expression level at P3 and P7. Cell proliferation, PI value, and telomerase activity were enhanced, whereas apoptosis was suppressed in transfected DPCs. Oct-4/Sox2/c-Myc were significantly upregulated, and multilineage differentiation in DPCs with XPC overexpression was enhanced after transfection. Conclusions. XPC plays an essential role in the modulation of pluripotency and multilineage differentiation of DPCs through regulation of Oct-4/Sox2/c-Myc.
Harnessing the Angiogenic Potential of Stem Cell-Derived Exosomes for Vascular Regeneration.Friday, April 29, 2016
Alcayaga-Miranda F, Varas-Godoy M, Khoury M,
Stem cells international. 2016
Mesenchymal stem cells (MSCs) are known to display important regenerative properties through the secretion of proangiogenic factors. Recent evidence pointed at the key role played by exosomes released from MSCs in this paracrine mechanism. Exosomes are key mediators of intercellular communication and contain a cargo that includes a modifiable content of microRNA (miRNA), mRNA, and proteins. Since the biogenesis of the MSCs-derived exosomes is regulated by the cross talk between MSCs and their niche, the content of the exosomes and consequently their biological function are dependent on the cell of origin and the physiologic or pathologic status of their microenvironment. Recent preclinical studies revealed that MSCs-derived exosomes have a critical implication in the angiogenic process since the use of exosomes-depleted conditioned medium impaired the MSCs angiogenesis response. In this review, we discuss the current knowledge related to the angiogenic potential of MSCs-exosomes and methods to enhance their biological activities for improved vascular regeneration. The current gain of insight in exosomes studies highlights the power of combining cell based therapies and their secreted products in therapeutic angiogenesis.
Substance P combined with epidermal stem cells promotes wound healing and nerve regeneration in diabetes mellitus.Friday, April 29, 2016
Zhu FB, Fang XJ, Liu DW, Shao Y, Zhang HY, Peng Y, Zhong QL, Li YT, Liu DM,
Neural regeneration research. Mar-2016
Exogenous substance P accelerates wound healing in diabetes, but the mechanism remains poorly understood. Here, we established a rat model by intraperitoneally injecting streptozotocin. Four wounds (1.8 cm diameter) were drilled using a self-made punch onto the back, bilateral to the vertebral column, and then treated using amniotic membrane with epidermal stem cells and/or substance P around and in the middle of the wounds. With the combined treatment the wound-healing rate was 100% at 14 days. With prolonged time, type I collagen content gradually increased, yet type III collagen content gradually diminished. Abundant protein gene product 9.5- and substance P-immunoreactive nerve fibers regenerated. Partial nerve fiber endings extended to the epidermis. The therapeutic effects of combined substance P and epidermal stem cells were better than with amniotic membrane and either factor alone. Our results suggest that the combination of substance P and epidermal stem cells effectively contributes to nerve regeneration and wound healing in diabetic rats.
Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR.Friday, April 29, 2016
Maiese K,
Neural regeneration research. Mar-2016
Throughout the globe, diabetes mellitus (DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder. DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy. The mechanistic target of rapamycin (mTOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM. mTOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis, insulin resistance, insulin secretion, stem cell proliferation and differentiation, pancreatic β-cell function, and programmed cell death with apoptosis and autophagy. mTOR is central element for the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1 (WISP1), and growth factors. As a result, mTOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease. Future studies directed to elucidate the delicate balance mTOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.
Deconstructing brain-derived neurotrophic factor actions in adult brain circuits to bridge an existing informational gap in neuro-cell biology.Friday, April 29, 2016
Bowling H, Bhattacharya A, Klann E, Chao MV,
Neural regeneration research. Mar-2016
Brain-derived neurotrophic factor (BDNF) plays an important role in neurodevelopment, synaptic plasticity, learning and memory, and in preventing neurodegeneration. Despite decades of investigations into downstream signaling cascades and changes in cellular processes, the mechanisms of how BDNF reshapes circuits in vivo remain unclear. This informational gap partly arises from the fact that the bulk of studies into the molecular actions of BDNF have been performed in dissociated neuronal cultures, while the majority of studies on synaptic plasticity, learning and memory were performed in acute brain slices or in vivo. A recent study by Bowling-Bhattacharya et al., measured the proteomic changes in acute adult hippocampal slices following treatment and reported changes in proteins of neuronal and non-neuronal origin that may in concert modulate synaptic release and secretion in the slice. In this paper, we place these findings into the context of existing literature and discuss how they impact our understanding of how BDNF can reshape the brain.
Endothelial Mesenchymal Transition: Comparative Analysis of Different Induction Methods.Friday, April 29, 2016
Pinto MT, Covas DT, Kashima S, Rodrigues CO,
Biological procedures online. 2016
Our work suggests that the response of endothelial cells to TGF-β is intrinsic to the dose, cell type and environment. Optimization of induction conditions may be essential, as pathways triggering EndMT may vary during development and pathological conditions. Therefore, caution is needed regarding indiscriminate use of TGF-β to induce EndMT for mechanistic studies.
Predictors of English Health Literacy among U.S. Hispanic Immigrants: The importance of language, bilingualism and sociolinguistic environment.Friday, April 29, 2016
Jacobson HE, Hund L, Soto Mas F,
Literacy & numeracy studies : an international journal in the education and training of adults. 27-04-2016
In the United States, data confirm that Spanish-speaking immigrants are particularly affected by the negative health outcomes associated with low health literacy. Although the literature points to variables such as age, educational background and language, only a few studies have investigated the factors that may influence health literacy in this group. Similarly, the role that bilingualism and/or multilingualism play in health literacy assessment continues to be an issue in need of further research. The purpose of this study was to examine the predictors of English health literacy among adult Hispanic immigrants whose self-reported primary language is Spanish, but who live and function in a bilingual community. It also explored issues related to the language of the instrument. An analysis of data collected through a randomized controlled study was conducted. Results identified English proficiency as the strongest predictor of health literacy (p < 0.001). The results further point to the importance of primary and secondary language in the assessment of heath literacy level. This study raises many questions in need of further investigation to clarify how language proficiency and sociolinguistic environment affect health literacy in language minority adults; proposes language approaches that may be more appropriate for measuring health literacy in these populations; and recommends further place-based research to determine whether the connection between language proficiency and health is generalizable to border communities.
Lung-On-A-Chip Technologies for Disease Modeling and Drug Development.Friday, April 29, 2016
Konar D, Devarasetty M, Yildiz DV, Atala A, Murphy SV,
Biomedical engineering and computational biology. 2016
Animal and two-dimensional cell culture models have had a profound impact on not only lung research but also medical research at large, despite inherent flaws and differences when compared with in vivo and clinical observations. Three-dimensional (3D) tissue models are a natural progression and extension of existing techniques that seek to plug the gaps and mitigate the drawbacks of two-dimensional and animal technologies. In this review, we describe the transition of historic models to contemporary 3D cell and organoid models, the varieties of current 3D cell and tissue culture modalities, the common methods for imaging these models, and finally, the applications of these models and imaging techniques to lung research.
Combining Multi-atlas Segmentation with Brain Surface Estimation.Friday, April 29, 2016
Huo Y, Carass A, Resnick SM, Pham DL, Prince JL, Landman BA,
Proceedings of SPIE--the International Society for Optical Engineering. 27-Feb-2016
Whole brain segmentation (with comprehensive cortical and subcortical labels) and cortical surface reconstruction are two essential techniques for investigating the human brain. The two tasks are typically conducted independently, however, which leads to spatial inconsistencies and hinders further integrated cortical analyses. To obtain self-consistent whole brain segmentations and surfaces, FreeSurfer segregates the subcortical and cortical segmentations before and after the cortical surface reconstruction. However, this "segmentation to surface to parcellation" strategy has shown limitations in various situations. In this work, we propose a novel "multi-atlas segmentation to surface" method called Multi-atlas CRUISE (MaCRUISE), which achieves self-consistent whole brain segmentations and cortical surfaces by combining multi-atlas segmentation with the cortical reconstruction method CRUISE. To our knowledge, this is the first work that achieves the reliability of state-of-the-art multi-atlas segmentation and labeling methods together with accurate and consistent cortical surface reconstruction. Compared with previous methods, MaCRUISE has three features: (1) MaCRUISE obtains 132 cortical/subcortical labels simultaneously from a single multi-atlas segmentation before reconstructing volume consistent surfaces; (2) Fuzzy tissue memberships are combined with multi-atlas segmentations to address partial volume effects; (3) MaCRUISE reconstructs topologically consistent cortical surfaces by using the sulci locations from multi-atlas segmentation. Two data sets, one consisting of five subjects with expertly traced landmarks and the other consisting of 100 volumes from elderly subjects are used for validation. Compared with CRUISE, MaCRUISE achieves self-consistent whole brain segmentation and cortical reconstruction without compromising on surface accuracy. MaCRUISE is comparably accurate to FreeSurfer while achieving greater robustness across an elderly population.
Conversion of human fibroblasts into functional cardiomyocytes by small molecules.Saturday, April 30, 2016
Cao N, Huang Y, Zheng J, Spencer CI, Zhang Y, Fu JD, Nie B, Xie M, Zhang M, Wang H, Ma T, Xu T, Shi G, Srivastava D, Ding S,
Science (New York, N.Y.). 28-Apr-2016
Reprogramming somatic fibroblasts into alternative lineages would provide a promising source of cells for regenerative therapy. However, transdifferentiating human cells to specific homogeneous, functional cell types is challenging. Here we show that cardiomyocyte-like cells can be generated by treating human fibroblasts with a combination of nine compounds (9C). The chemically induced cardiomyocyte-like cells (ciCMs) uniformly contracted and resembled human cardiomyocytes in their transcriptome, epigenetic, and electrophysiological properties. 9C treatment of human fibroblasts resulted in a more open-chromatin conformation at key heart developmental genes, enabling their promoters/enhancers to bind effectors of major cardiogenic signals. When transplanted into infarcted mouse hearts, 9C-treated fibroblasts were efficiently converted to ciCMs. This pharmacological approach for lineage-specific reprogramming may have many important therapeutic implications after further optimization to generate mature cardiac cells.
NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice.Friday, April 29, 2016
Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D'Amico D, Ropelle ER, Lutolf MP, Aebersold R, Schoonjans K, Menzies KJ, Auwerx J,
Science (New York, N.Y.). 28-Apr-2016
Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of cellular nicotinamide adenine dinucleotide (NAD(+)) and its impact on mitochondrial activity as a pivotal switch to modulate muscle SC (MuSC) senescence. Treatment with the NAD(+) precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response (UPR(mt)) and synthesis of prohibitin proteins, and this rejuvenated MuSCs in aged mice. NR also prevented MuSC senescence in the Mdx mouse model of muscular dystrophy. We furthermore demonstrate that NR delays senescence of neural SCs (NSCs) and melanocyte SCs (McSCs), and increased mouse lifespan. Strategies that conserve cellular NAD(+) may reprogram dysfunctional SCs and improve lifespan in mammals.
Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation.Friday, April 29, 2016
Rialdi A, Campisi L, Zhao N, Lagda AC, Pietzsch C, Ho JS, Martinez-Gil L, Fenouil R, Chen X, Edwards M, Metreveli G, Jordan S, Peralta Z, Munoz-Fontela C, Bouvier N, Merad M, Jin J, Weirauch M, Heinz S, Benner C, van Bakel H, Basler C, García-Sastre A, Bukreyev A, Marazzi I,
Science (New York, N.Y.). 28-Apr-2016
The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of diseases associated with exacerbated inflammation. Here, we identify Topoisomerase 1 (Top1) as a positive regulator of RNA polymerase II (RNAPII) transcriptional activity at pathogen-induced genes. Depletion or chemical inhibition of Top1 suppresses the host response against Influenza and Ebola viruses as well as bacterial products. As a result, therapeutic pharmacological inhibition of Top1 protects mice from death in experimental models of lethal inflammation. Our results indicate that Top1 inhibition could be used as therapy against life threatening infections characterized by an acutely exacerbated immune response.
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