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Replicating viruses for gynecologic cancer therapy.Wednesday, June 29, 2016
Park JW, Kim M,
European journal of gynaecological oncology. 2016
Despite advanced therapeutic treatments, gynecologic malignancies such as cervical and ovarian cancers are still the top ten leading cause of cancer death among women in South Korea. Thus a novel and innovative approach is urgently needed. Naturally occurring viruses are live, replication-proficient viruses that specifically infect human cancer cells while sparing normal cell counterparts. Since the serendipitous discovery of the naturally oncotropic virus targeting gynecologic cancer in 1920s, various replicating viruses have shown various degrees of safety and efficacy in preclinical or clinical applications for gynecologic cancer therapy. Cellular oncogenes and tumor suppressor genes, which are frequently dysregulated in gynecologic malignancies, play an important role in determining viral oncotropism. Published articles describing replicating, oncolytic viruses for gynecologic cancers are thoroughly reviewed. This review outlines the discovery of replication-proficient virus strains for targeting gynecologic malignancies, recent progresses elucidating molecular connections between oncogene/tumor suppressor gene abnormalities and viral oncotropism, and the associated preclinical/clinical implications. The authors would also like to propose future directions in the utility of the replicating viruses for gynecologic cancer therapy.
Liver Graft versus Host Disease after Allogeneic Peripheral Stem Cell Transplantation: Update on Etiopathogenesis and Diagnosis.Wednesday, June 29, 2016
Mihăilă RG,
Romanian journal of internal medicine = Revue roumaine de médecine interne. Jun-2016
Graft versus host disease (GVHD) is the main complication of allogeneic hematopoietic cell transplantation and is more frequent after peripheral stem cell transplants. Graft versus leukemia or lymphoma component of them is beneficial to eradicate residual tumor mass after previous treatment and conditioning regimen. A severe GVHD may endanger the patient's life. The most important liver manifestations of GVHD are increased serum alkaline phosphatase and bilirubin values. The last allows to estimate the GVHD severity. Sometimes, an increase of aminotransferases can mimic an acute hepatitis. Donor-derived hematopoietic cells appeared to turn in mesenchymal liver cells. Activated CD4(+) T cells, humoral and complement activation, a large number of cytokines and cytokine receptors are involved in GVHD development. Correct and early recognition of GVHD and its differentiation from the other liver diseases are essential for the medical practice.
A standardized procedure to obtain mesenchymal stem/stromal cells from minimally manipulated dental pulp and Wharton's jelly samples.Wednesday, June 29, 2016
Ducret M, Fabre H, Degoult O, Atzeni G, McGuckin C, Forraz N, Mallein-Gerrin F, Perrier-Groult E, Fargues JC,
Bulletin du Groupèment international pour la recherche scientifique en stomatologie & odontologie. 2016
Transplantation of mesenchymal stem/stromalcells (MSCs) has emerged as an effectivemethod to treat diseased or damagedorgans and tissues, and hundreds of clinicaltrials using MSCs are currently under way todemonstrate the validity of such a therapeuticapproach. However, most MSCs used for clinicaltrials are prepared in research laboratorieswith insufficient manufacturing quality control.In particular, laboratories lack standardizedprocedures for in vitro isolation of MSCs fromtissue samples, resulting in heterogeneouspopulations of cells and variable experimentaland clinical results.MSCs are now referred to as Human CellularTissue-based Products or Advanced TherapyMedicinal Products, and guidelines fromthe American Code of Federal Regulation ofthe Food and Drug Administration (21 CFRPart 1271) and from the European MedicinesAgency (European Directive 1394/2007) definerequirements for appropriate production ofthese cells. These guidelines, commonly called"Good Manufacturing Practices" (GMP),include recommendations about laboratorycell culture procedures to ensure optimal reproducibility,efficacy and safety of the finalmedicinal product. In particular, the Food andDrug Administration divides ex vivo culturedcells into "minimally" and "more than minimally"manipulated samples, in function of theuse or not of procedures "that might alter thebiological features of the cells". Today, minimalmanipulation conditions have not beendefined for the collection and isolation ofMSCs (Torre et al. 2015)(Ducret et al. 2015).Most if not all culture protocols that have beenreported so far are unsatisfactory, becauseof the use of xeno- or allogeneic cell culturemedia, enzymatic treatment and long-termcell amplification that are known to alter thequality of MSCs.The aim of this study was to describe a standardizedprocedure for recovering MSCs withminimal handling from two promising sources,the dental pulp (DP) and the Wharton's jelly(WJ) of the umbilical cord. The quality and homogeneityof the expanded cell populationswere assessed by using flow cytometry withcriteria that go beyond the International Societyof Cellular Therapy (ISCT) guidelines forMSC characterization.
A Study on the Mechanism of Low-Expressed Cancer Stem Cell Marker Lgr5 in Inhibition of the Proliferation and Invasion of Colorectal Carcinoma.Wednesday, June 29, 2016
Jia H, Xiang L, Wang Z, Zhou Q,
Cell biochemistry and biophysics. Nov-2015
The present study intends to explore the influence of Lgr5 as a marker of tumor stem cells after siRNA interference on the proliferation and invasion of colorectal carcinoma (CRC) and its mechanism. The tissue samples were taken for biopsy from 32 cases of patients and 32 cases of normal subjects by colonoscopy. Real-time quantitative PCR was used to detect the differential expression of Lgr5. After siRNA interference of Lgr5 in CRC cell line CT-26 cells, RT-PCR method was used to detect the mRNA expression level of Lgr5 after interference of CT-26 cells. CCK8 method was used to observe the influence of Lgr5 interference on the proliferation, colony formation, and invasion of CT-26 cells. RT-PCR and Western blot were used to detect the E-cadherin mRNA and protein levels in CT-26 cells. Lgr5 expression level in CRC tissue was significantly higher than that in the corresponding para-carcinoma tissue and the control group, and the differences were statistically significant (P < 0.05). Lgr5 mRNA expression level in tissue with lymph node metastasis was significantly higher than that in the tissue without lymph node metastasis, and the difference was statistically significant (P < 0.05). Compared with the control group, CT-26 cell proliferation, colony formation, and migration capability after Lgr5 siRNA transfection were all significantly reduced, and the differences were statistically significant (P < 0.05). CT-26 cells after Lgr5 interference were found with significantly reduced E-cadherin mRNA and protein levels. Lgr5 facilitates the cell proliferation, colony formation, and migration of colorectal carcinoma, which may be closely related to the expression level of E-cadherin.
Experimental Research on Differentiation-Inducing Growth of Nerve Lateral Bud by HUC-MSCs Chitosan Composite Conduit.Wednesday, June 29, 2016
Xiao Q, Zhang X, Wu Y,
Cell biochemistry and biophysics. Nov-2015
This study is intended to explore the role of human umbilical-cord-derived mesenchymal stem cells (HUC-MSCs) in nerve end-to-side anastomosis, as well as in the induction and promotion of growth of nerve lateral bud. The chitosan nerve conduit was prepared based on the biological characteristics of chitosan, and the nerve conduit was filled with HUC-MSCs, and was used to bridge the nerve end-to-side anastomotic stoma. The experimental animals were randomly assigned into three groups (10 in each group), and the nerve end-to-side anastomosis was conducted: (1) group A (control group): traditional tibial nerve-common peroneal nerve end-to-side anastomosis; (2) group B (experimental group 1): tibial nerve-common peroneal nerve end-to-side anastomotic stoma bridged with chitosan nerve conduit; (3) group C (experimental group 2): tibial nerve-common peroneal nerve end-to-side anastomotic stoma bridged by chitosan nerve conduit filled with HUC-MSCs. General morphological observation, nerve electrophysiology, and anti-S-100 immunohistochemistry were performed. All experimental animals survived, and no infections were found at operative incisions. The nerve continuity was in good condition through visual observation when sampling, which is mild adhesion to the surrounding tissue and easy to be separated. 12 W HUC-MSCs chitosan composite nerve conduits were degraded completely after operation. Electrophysiological test showed that the nerve conduction velocity (NCV) in group C was significantly higher than that in group A or group B (p < 0.01). There were no significant differences between NCVs of group A and group B. Toluidine blue staining and transmission electron microscope showed that the number of the medullated fibers and the myelin sheath thickness in group C were larger than those in group A or B. There were no significant differences between the numbers of the medullated fibers and between the myelin sheath thicknesses of groups A and B. By means of anti-S-100 immunohistochemistry, the arrangement of a large number of brown-red proliferating schwann cells around the regenerated nerve fibers in group C could be found, while fewer and sparse brown-red matters and very poor growth of schwann cells could be observed in groups A and B. Slightly more favorable situation could be observed in group B compared with group A. HUC-MSCs play obviously an important role in promoting nerve regeneration during the nerve end-to-side anastomosis, which induces the growth of axis bud, accelerates the growth velocity of regenerated fiber, and promotes the growth and maturity of schwann cells.
Paraneoplastic pemphigus as a presentation of acute myeloid leukemia: Early diagnosis and remission.Tuesday, June 28, 2016
Siddiqui S, Bilal M, Otaibi Z, Bilimoria F, Patel N, Rossetti J,
Hematology/oncology and stem cell therapy. 23-Jun-2016
Skin lesions are frequently encountered in clinical practice which can be a presentation of systemic diseases not excluding an occult malignancy. Commonly reported paraneoplastic dermatologic manifestations include acanthosis nigricans, dermatomyositis, erythroderma, hypertrophic osteoarthropathy, Sweet syndrome, and paraneoplastic pemphigus (PNP). PNP is a rare autoimmune mucocutaneous disease characterized by severe stomatitis, polymorphic skin eruptions, and associated underlying neoplasms most commonly non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and Castleman disease. PNP is characterized on histopathology as dyskeratotic epithelial cells with acantholysis with a typical immunofluorescence staining pattern of direct and/or indirect staining of intercellular, basement membrane, and dermoepidermal junction with immunoglobulin-G and C3. PNP has been described to have poor prognosis with a mortality range of 75-90% and a mean survival of less than 1year. We describe a previously unreported case of PNP associated with acute myeloid leukemia (AML) where the patient presented with a nonhealing ulcer and hemorrhagic crusting on the face that did not respond to antimicrobials and steroids. Investigations revealed leukocytosis with peripherally circulating blasts. Skin biopsy revealed an evolving PNP and bone marrow biopsy confirmed evidence of AML. The patient underwent induction, consolidation, and then successful allogenic bone marrow transplantation with complete remission. The skin lesion, which was initially refractory to treatments, surprisingly resolved within 7days of starting induction chemotherapy. In this case, the skin lesion was a key factor in early diagnosis and instituting treatment for the underlying AML. Early intervention gave our patient a better outcome with an ongoing survival of 18months since diagnosis, maintaining complete remission.
Pulsed DC Electric Field-Induced Differentiation of Cortical Neural Precursor Cells.Wednesday, June 29, 2016
Chang HF, Lee YS, Tang TK, Cheng JY,
PloS one. 2016
We report the differentiation of neural stem and progenitor cells solely induced by direct current (DC) pulses stimulation. Neural stem and progenitor cells in the adult mammalian brain are promising candidates for the development of therapeutic neuroregeneration strategies. The differentiation of neural stem and progenitor cells depends on various in vivo environmental factors, such as nerve growth factor and endogenous EF. In this study, we demonstrated that the morphologic and phenotypic changes of mouse neural stem and progenitor cells (mNPCs) could be induced solely by exposure to square-wave DC pulses (magnitude 300 mV/mm at frequency of 100-Hz). The DC pulse stimulation was conducted for 48 h, and the morphologic changes of mNPCs were monitored continuously. The length of primary processes and the amount of branching significantly increased after stimulation by DC pulses for 48 h. After DC pulse treatment, the mNPCs differentiated into neurons, astrocytes, and oligodendrocytes simultaneously in stem cell maintenance medium. Our results suggest that simple DC pulse treatment could control the fate of NPCs. With further studies, DC pulses may be applied to manipulate NPC differentiation and may be used for the development of therapeutic strategies that employ NPCs to treat nervous system disorders.
Bioengineered Colorectal Cancer Drugs: Orally Delivered Anti-Inflammatory Agents.Wednesday, June 29, 2016
Urbanska AM, Zhang X, Prakash S,
Cell biochemistry and biophysics. Jul-2015
Intestinal inflammation is one of the major factors that increase colorectal cancer (CRC) incidence worldwide. Inflammation in the gastrointestinal tract is directly linked to tumor development at the early stages of the disease, thus a key issue toward the prevention and the treatment of colonic neoplasia. Thus, the use of anti-inflammatory drugs has emerged first as a strategy to reduce chronic inflammation in case of many inflammatory bowel diseases (IBD), but it has proven its efficacy by reducing the risk of colonic neoplasia. This comprehensive review highlights the role of chronic inflammation, mainly in IBD, in the development of CRC including molecular and immune mechanisms that have tumorigenic effects. Multiple lines of evidence indicate that several bioactive and phytochemical compounds used as anti-inflammatory drugs have also antitumoral attributes. The uses of orally delivered cytokines and small molecules, as well as key dietary supplementation as anti-inflammatory therapeutics are discussed. In addition, comprehensive knowledge about CRC and intestinal inflammation, and the importance of the intestinal mucosal wall as a mucosal immunological barrier that comes into play during interactions with gut microbiota (pathogens and commensal), luminal secretions (bile acids, and bacterial and epithelial metabolites), and ingested chemicals (food components, high fat content, heterocyclic amines, and low intake of dietary fiber) are underscored. The multifunctionality of several anti-inflammatory drugs opens a line for their application in the treatment and prevention not only in IBD but also in CRC. Current bioengineering approaches for oral delivery of anti-inflammatory agents including cytokines, genetically modified bacteria, or small molecule inhibitors of inflammation directly contribute to the early management of CRC. Limitations of the current therapeutics, which stem from the lack of complete understanding of the complex molecular interactions between the intestinal microbiota, colonic epithelial barrier, and host immune system, are also discussed.
Gata6-Dependent GLI3 Repressor Function is Essential in Anterior Limb Progenitor Cells for Proper Limb Development.Wednesday, June 29, 2016
Hayashi S, Akiyama R, Wong J, Tahara N, Kawakami H, Kawakami Y,
PLoS genetics. Jun-2016
Gli3 is a major regulator of Hedgehog signaling during limb development. In the anterior mesenchyme, GLI3 is proteolytically processed into GLI3R, a truncated repressor form that inhibits Hedgehog signaling. Although numerous studies have identified mechanisms that regulate Gli3 function in vitro, it is not completely understood how Gli3 function is regulated in vivo. In this study, we show a novel mechanism of regulation of GLI3R activities in limb buds by Gata6, a member of the GATA transcription factor family. We show that conditional inactivation of Gata6 prior to limb outgrowth by the Tcre deleter causes preaxial polydactyly, the formation of an anterior extra digit, in hindlimbs. A recent study suggested that Gata6 represses Shh transcription in hindlimb buds. However, we found that ectopic Hedgehog signaling precedes ectopic Shh expression. In conjunction, we observed Gata6 and Gli3 genetically interact, and compound heterozygous mutants develop preaxial polydactyly without ectopic Shh expression, indicating an additional prior mechanism to prevent polydactyly. These results support the idea that Gata6 possesses dual roles during limb development: enhancement of Gli3 repressor function to repress Hedgehog signaling in the anterior limb bud, and negative regulation of Shh expression. Our in vitro and in vivo studies identified that GATA6 physically interacts with GLI3R to facilitate nuclear localization of GLI3R and repressor activities of GLI3R. Both the genetic and biochemical data elucidates a novel mechanism by Gata6 to regulate GLI3R activities in the anterior limb progenitor cells to prevent polydactyly and attain proper development of the mammalian autopod.
CD34 Promotes Pathological Epi-Retinal Neovascularization in a Mouse Model of Oxygen-Induced Retinopathy.Wednesday, June 29, 2016
Siemerink MJ, Hughes MR, Dallinga MG, Gora T, Cait J, Vogels IM, Yetin-Arik B, Van Noorden CJ, Klaassen I, McNagny KM, Schlingemann RO,
PloS one. 2016
The sialomucins CD34 and podocalyxin (PODXL) are anti-adhesive molecules expressed at the luminal membrane of endothelial cells of small blood vessels and facilitate vascular lumen formation in the developing mouse aorta. CD34 transcript and protein levels are increased during human angiogenesis, its expression is particularly enriched on endothelial tip cell filopodia and CD34 is a marker for tip cells in vitro. Here, we investigated whether CD34 merely marks endothelial tip cells or has a functional role in tip cells and angiogenesis. We assessed that silencing CD34 in human microvascular endothelial cells has little effect on endothelial cell migration or invasion, but has a significant effect on vascular-endothelial growth factor-induced angiogenic sprouting activity in vitro. In vivo, the absence of CD34 reduced the density of filopodia on retinal endothelial tip cells in neonatal mice, but did not influence the overall architecture of the retinal vascular network. In oxygen-induced retinopathy, Cd34-/- mice showed normal intra-retinal regenerative angiogenesis but the number of pathological epi-retinal neovascular tufts were reduced. We conclude that CD34 is not essential for developmental vascularization in the retina, but its expression promotes the formation of pathological, invasive vessels during neovascularization.
Variation in the Calculation of Allostatic Load Score: 21 Examples from NHANES.Tuesday, June 28, 2016
Duong MT, Bingham BA, Aldana PC, Chung ST, Sumner AE,
Journal of racial and ethnic health disparities. 28-Jun-2016
After decades of resistance, there is now a genuine consensus that disease cannot be prevented or even successfully treated unless the role of stress is addressed alongside traditionally recognized factors such as genes and the environment. Measurement of allostatic load, which is quantified by the allostatic load score (ALS), is one of the most frequently used methods to assess the physiologic response to stress. Even though there is universal agreement that in the calculation of ALS, biomarkers from three categories should be included (cardiovascular, metabolic and immune), enormous variation exists in how ALS is calculated. Specifically, there is no consensus on which biomarkers to include or the method which should be used to determine whether the value of a biomarker represents high risk. In this perspective, we outline the approach taken in 21 different NHANES studies.
Effects of agitation rate on aggregation during beads-to-beads subcultivation of microcarrier culture of human mesenchymal stem cells.Tuesday, June 28, 2016
Takahashi I, Sato K, Mera H, Wakitani S, Takagi M,
Cytotechnology. 28-Jun-2016
With the aim to utilize human mesenchymal stem cells (hMSCs) grown in large scale for regenerative medicine, effects of agitation rate on aggregation during beads-to-beads subcultivation of microcarrier culture of hMSCs were studied. hMSCs could attach and grew on surface-type microcarriers of Cytodex 1, whereas almost no cell elongation and growth were observed on porous type microcarriers of Cytopores. The percentages of aggregated Cytodex 1 microcarriers at an agitation rate of 60 and 90 rpm were lower than that at 30 rpm, which was the lowest agitation rate necessary for the suspension of Cytodex 1 microcarriers, and the cells grew fastest at 60 rpm. hMSC could be subcultivated on Cytodex 1 by the beads-to-beads method at both 30 and 60 rpm without trypsinization. However, agitation at 60 rpm resulted in a markedly lower percentage of aggregated microcarriers not only before but also after subcultivation. The percentages of CD90- and CD166-positive cells among cells grown on Cytodex 1 at 60 rpm (91.5 and 87.6 %) were comparable to those of cells grown in the pre-culture on dishes. In conclusion, hMSCs could be subcultivated on Cytodex 1 by beads-to-beads method maintaining the expressions of the cell surface antigens CD90 and CD166, while adjusting agitation rate could decrease the microcarrier aggregation.
The Neural Cell Adhesion Molecule-Derived (NCAM)-Peptide FG Loop (FGL) Mobilizes Endogenous Neural Stem Cells and Promotes Endogenous Regenerative Capacity after Stroke.Tuesday, June 28, 2016
Klein R, Mahlberg N, Ohren M, Ladwig A, Neumaier B, Graf R, Hoehn M, Albrechtsen M, Rees S, Fink GR, Rueger MA, Schroeter M,
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology. 28-Jun-2016
The neural cell adhesion molecule (NCAM)-derived peptide FG loop (FGL) modulates synaptogenesis, neurogenesis, and stem cell proliferation, enhances cognitive capacities, and conveys neuroprotection after stroke. Here we investigated the effect of subcutaneously injected FGL on cellular compartments affected by degeneration and regeneration after stroke due to middle cerebral artery occlusion (MCAO), namely endogenous neural stem cells (NSC), oligodendrocytes, and microglia. In addition to immunohistochemistry, we used non-invasive positron emission tomography (PET) imaging with the tracer [(18)F]-fluoro-L-thymidine ([(18)F]FLT) to visualize endogenous NSC in vivo. FGL significantly increased endogenous NSC mobilization in the neurogenic niches as evidenced by in vivo and ex vivo methods, and it induced remyelination. Moreover, FGL affected neuroinflammation. Extending previous in vitro results, our data show that the NCAM mimetic peptide FGL mobilizes endogenous NSC after focal ischemia and enhances regeneration by amplifying remyelination and modulating neuroinflammation via affecting microglia. Results suggest FGL as a promising candidate to promote recovery after stroke.
A tunable hydrogel system for long-term release of cell-secreted cytokines and bioprinted in situ wound cell delivery.Tuesday, June 28, 2016
Skardal A, Murphy SV, Crowell K, Mack D, Atala A, Soker S,
Journal of biomedical materials research. Part B, Applied biomaterials. 28-Jun-2016
For many cellular therapies being evaluated in preclinical and clinical trials, the mechanisms behind their therapeutic effects appear to be the secretion of growth factors and cytokines, also known as paracrine activity. Often, delivered cells are transient, and half-lives of the growth factors that they secrete are short, limiting their long-term effectiveness. The goal of this study was to optimize a hydrogel system capable of in situ cell delivery that could sequester and release growth factors secreted from those cells after the cells were no longer present. Here, we demonstrate the use of a fast photocross-linkable heparin-conjugated hyaluronic acid (HA-HP) hydrogel as a cell delivery vehicle for sustained growth factor release, which extends paracrine activity. The hydrogel could be modulated through cross-linking geometries and heparinization to support sustained release proteins and heparin-binding growth factors. To test the hydrogel in vivo, we used it to deliver amniotic fluid-derived stem (AFS) cells, which are known to secrete cytokines and growth factors, in full thickness skin wounds in a nu/nu murine model. Despite transience of the AFS cells in vivo, the HA-HP hydrogel with AFS cells improved wound closure and reepithelialization and increased vascularization and production of extracellular matrix in vivo. These results suggest that HA-HP hydrogel has the potential to prolong the paracrine activity of cells, thereby increasing their therapeutic effectiveness in wound healing. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2016.
Receipt of mammography recommendations among White and non-White women before and after the 2009 United States Preventive Services Task Force recommendation change.Tuesday, June 28, 2016
Gonzales FA, Taplin SH, Yu M, Breen N, Cronin KA,
Cancer causes & control : CCC. 28-Jun-2016
Recommendations to reduce screening may be differentially implemented across racial/ethnic groups. Changes in reports of mammography recommendation from a clinician after the USPSTF breast cancer screening recommendation change were observed only among non-White women without a recent history of mammography. It is unclear whether these differences are due to the clinician, the women, or both.
Hypomegakaryocytic thrombocytopenia (HMT): an immune-mediated bone marrow failure characterized by an increased number of PNH-phenotype cells and high plasma thrombopoietin levels.Tuesday, June 28, 2016
Saito C, Ishiyama K, Yamazaki H, Zaimoku Y, Nakao S,
British journal of haematology. 28-Jun-2016
Patients with mild hypomegakaryocytic thrombocytopenia (HMT) that does not meet the diagnostic criteria for a definite disease entity may potentially progress to aplastic anaemia (AA) that is refractory to therapy. To clarify the clinical picture of HMT, we prospectively followed 25 HMT patients with white blood cell count >3·0 × 10(9) /l, haemoglobin level >100 g/l and platelet count of <100·0 × 10(9) /l in the absence of morphological and karyotypic abnormalities in the bone marrow. Glycosylphosphatidylinositol-anchored protein-deficient blood cells [paroxysmal nocturnal haemoglobinuria (PNH)-type cells] were detected in 7 of the 25 (28%) patients and elevated plasma thrombopoietin (TPO, also termed THPO) levels (>320 pg/ml) were observed in 11 (44%) patients. Five (four PNH+ and one PNH-) of six TPO(high) patients who were treated with ciclosporin (CsA) showed improvement. Among the 21 patients who were followed without treatment, thrombocytopenia progressed in four of ten TPO(low) patients and four of 11 TPO(high) patients. The 3-year failure-free survival rate of the CsA-treated TPO(high) patients (100%) was significantly higher than that of the untreated TPO(high) patients (20%). These results suggest that a significant population of HMT patients has an immune pathophysiology that is similar to AA and may be improved by early therapeutic intervention with CsA.
Health-Related Quality of Life and Burden of Fatigue in Patients with Primary Immune Thrombocytopenia by Phase of Disease.Tuesday, June 28, 2016
Efficace F, Mandelli F, Fazi P, Santoro C, Gaidano G, Cottone F, Borchiellini A, Carpenedo M, Pina Simula M, Di Giacomo V, Bergamaschi M, Donatella Vincelli I, Rodeghiero F, Ruggeri M, Scaramucci L, Rambaldi A, Cascavilla N, Forghieri F, Petrungaro A, Ditonno P, Caocci G, Cirrincione S, Gabriella Mazzucconi M,
American journal of hematology. 28-Jun-2016
The main objective of this study was to compare health-related quality of life (HRQOL) of primary immune thrombocytopenia (pITP) patients with that of general population, overall, and by patient group (i.e., newly diagnosed, persistent, and chronic patients). Fatigue was also investigated as a secondary objective. Overall, 424 adult patients were enrolled in a multicenter observational study and the control group consisted of a representative sample from the general population. Propensity score matching plus further multivariate linear regression adjustment was used to compare HRQOL outcomes between pITP patients and general population. Mean age of patients was 54 years. Of those with HRQOL assessment, 99 patients (23.6%) were newly diagnosed, 53 (12.6%) were persistent, and 268 (63.8%) were chronic pITP patients. Comparison by patient group versus their respective peers in the general population revealed greater impairments in persistent pITP patients. Persistent pITP patients reported clinically meaningful impairments in physical functioning (-15; 95% CI, -24.1 to -5.8; P = 0.002), social functioning (-15.3; 95% CI, -25.5 to -5.1; P = 0.004), role physical (-28.4; 95% CI, -43.1 to -13.7; P < 0.001), role emotional (-23.9; 95% CI, -40.1 to -7.7; P = 0.004), and mental health scales (-11.3; 95% CI, -21.2 to -1.4; P = 0.026) of the SF-36 questionnaire. Higher fatigue severity was associated with lower physical and mental HRQOL outcomes. Our findings suggest that the burden of the disease and treatment might depend on the disease phase and that persistent pITP patients are the most vulnerable subgroup. This article is protected by copyright. All rights reserved.
Myc and Fgf Are Required for Zebrafish Neuromast Hair Cell Regeneration.Wednesday, June 29, 2016
Lee SG, Huang M, Obholzer ND, Sun S, Li W, Petrillo M, Dai P, Zhou Y, Cotanche DA, Megason SG, Li H, Chen ZY,
PloS one. 2016
Unlike mammals, the non-mammalian vertebrate inner ear can regenerate the sensory cells, hair cells, either spontaneously or through induction after hair cell loss, leading to hearing recovery. The mechanisms underlying the regeneration are poorly understood. By microarray analysis on a chick model, we show that chick hair cell regeneration involves the activation of proliferation genes and downregulation of differentiation genes. Both MYC and FGF are activated in chick hair cell regeneration. Using a zebrafish lateral line neuromast hair cell regeneration model, we show that the specific inhibition of Myc or Fgf suppresses hair cell regeneration, demonstrating that both pathways are essential to the process. Rapid upregulation of Myc and delayed Fgf activation during regeneration suggest a role of Myc in proliferation and Fgf in differentiation. The dorsal-ventral pattern of fgfr1a in the neuromasts overlaps with the distribution of hair cell precursors. By laser ablation, we show that the fgfr1a-positive supporting cells are likely the hair cell precursors that directly give rise to new hair cells; whereas the anterior-posterior fgfr1a-negative supporting cells have heightened proliferation capacity, likely to serve as more primitive progenitor cells to replenish lost precursors after hair cell loss. Thus fgfr1a is likely to mark compartmentalized supporting cell subtypes with different capacities in renewal proliferation and hair cell regeneration. Manipulation of c-MYC and FGF pathways could be explored for mammalian hair cell regeneration.
Cloning and Characterization of a Nanog Pseudogene in Sika Deer (Cervus nippon).Tuesday, June 28, 2016
Wang D, Guo Q, Ba H, Li C,
DNA and cell biology. 28-Jun-2016
Nanog plays a crucial role in the maintenance of stem cell pluripotency. Annual full regeneration of deer antlers has been shown to be a stem cell-based process, and antler stem cells (ASCs) reportedly express Nanog. In the present study, we found that Nanog RNA expressed by ASCs was a pseudogene (Nanog-ps). The coding sequence of Nanog-ps was 93.1% homologous to that of bovine Nanog, but with two missing nucleotides after position 391. Deletion of the two nucleotides in Nanog-ps resulted in a frame-shift mutation, suggesting that Nanog-ps would not encode a normal Nanog protein. Overexpression of Nanog-ps failed to affect downstream genes of Nanog or to enhance cell proliferation in the ASCs. However, this pseudogene was transcribed in the ASCs and encoded a nuclear protein; the expression levels of Nanog-ps were also related to the degree of stemness in antler cells. Here, we reported this pseudogene, because it could serve as a useful marker for identifying ASCs and evaluating the degree of their stemness.
Maternal CD4+ microchimerism in HIV-exposed newborns after spontaneous vaginal delivery or caesarean section.Tuesday, June 28, 2016
Buxmann H, Reitter A, Bapistella S, Stürmer M, Königs C, Ackermann H, Louwen F, Bader P, Schlößer RL, Willasch AM,
Early human development. 25-Jun-2016
In this small cohort, spontaneous vaginal delivery in HIV-infected women with normal MTCT risk was associated with lower maternal CD4+ cell transfer to newborns compared to planned caesarean section.
Effect of Different Times of Intraperitoneal Injections of Human Bone Marrow Mesenchymal Stem Cell Conditioned Medium on Gentamicin-Induced Acute Kidney Injury.Wednesday, June 29, 2016
Abedi A, Azarnia M, Jamali Zahvarehy M, Foroutan T, Golestani S,
Urology journal. 2016
Secretory factors of human mesenchymal stem cells can be partly protective against gentamicin-induced nephrotoxicity. .
Overexpression of the oncostatin-M receptor in cervical squamous cell carcinoma is associated with epithelial-mesenchymal transition and poor overall survival.Tuesday, June 28, 2016
Kucia-Tran JA, Tulkki V, Smith S, Scarpini CG, Hughes K, Araujo AM, Yan KY, Botthof J, Pérez-Gómez E, Quintanilla M, Cuschieri K, Caffarel MM, Coleman N,
British journal of cancer. 28-Jun-2016
OSM:OSMR interactions are able to induce EMT, increased cancer stem cell-like properties and enhanced lung colonisation in SCC cells. These changes are likely to contribute to the highly significant adverse outcome associated with OSMR overexpression in cervical SCCs.British Journal of Cancer advance online publication 28 June 2016; doi:10.1038/bjc.2016.199
Transplantation of Human Amniotic Mesenchymal Stem Cells Promotes Functional Recovery in a Rat Model of Traumatic Spinal Cord Injury.Tuesday, June 28, 2016
Zhou HL, Zhang XJ, Zhang MY, Yan ZJ, Xu ZM, Xu RX,
Neurochemical research. 28-Jun-2016
Human amniotic membrane mesenchymal stem cells (hAMSCs) are considered ideal candidate stem cells for cell-based therapy. In this study, we assessed whether hAMSCs transplantation promotes neurological functional recovery in rats after traumatic spinal cord injury (SCI). In addition, the potential mechanisms underlying the possible benefits of this therapy were investigated. Female Sprague-Dawley rats were subjected to SCI using a weight drop device and then hAMSCs, or phosphate-buffered saline (PBS) were immediately injected into the contused dorsal spinal cord at 2 mm rostral and 2 mm caudal to the injury site. Our results indicated that transplanted hAMSCs migrated in the host spinal cord without differentiating into neuronal or glial cells. Compared with the control group, hAMSCs transplantation significantly decreased the numbers of ED1(+) macrophages/microglia and caspase-3(+) cells. In addition, hAMSCs transplantation significantly increased the levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in the injured spinal cord, and promoted both angiogenesis and axonal regeneration. These effects were associated with significantly improved neurobehavioral recovery in the hAMSCs transplantation group. These results show that transplantation of hAMSCs provides neuroprotective effects in rats after SCI, and could be candidate stem cells for the treatment of SCI.
Co-expression of Foxa.a, Foxd and Fgf9/16/20 defines a transient mesendoderm regulatory state in ascidian embryos.Wednesday, June 29, 2016
Hudson C, Sirour C, Yasuo H,
eLife. 28-Jun-2016
In many bilaterian embryos nuclear β-catenin (nβ-catenin) promotes mesendoderm over ectoderm lineages. Although this is likely to represent an evolutionary ancient developmental process, the regulatory architecture of nβ-catenin-induced mesendoderm remains elusive in the majority of animals. Here, we show that, in ascidian embryos, three nβ-catenin transcriptional targets, Foxa.a, Foxd and Foxa.a, Foxd and Fgf9/16/20, are each required for the correct initiation of both the mesoderm and endoderm gene regulatory networks. Conversely, these three factors are sufficient, in combination, to produce a mesendoderm ground state that can be further programmed into mesoderm or endoderm lineages. Importantly, we show that the combinatorial activity of these three factors is sufficient to reprogramme developing ectoderm cells to mesendoderm. We conclude that in ascidian embryos the transient mesendoderm regulatory state is defined by co-expression of Foxa.a, Foxd and Fgf9/16/20.
PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells.Tuesday, June 28, 2016
Pérez Millán MI, Brinkmeier ML, Mortensen AH, Camper SA,
eLife. 28-Jun-2016
Mutations in PROP1 are the most common cause of hypopituitarism in humans; therefore, unraveling its mechanism of action is highly relevant from a therapeutic perspective. Our current understanding of the role of PROP1 in the pituitary gland is limited to the repression and activation of the pituitary transcription factor genes Hesx1 and Pou1f1, respectively. To elucidate the comprehensive PROP1-dependent gene regulatory network, we conducted genome wide analysis of PROP1 DNA binding and effects on gene expression in mutant mice, mouse isolated stem cells and engineered mouse cell lines. We determined that PROP1 is essential for stimulating stem cells to undergo an epithelial to mesenchymal transition-like process necessary for cell migration and differentiation. Genomic profiling reveals that PROP1 binds to genes expressed in epithelial cells like Claudin 23, and to EMT inducer genes like Zeb2, Notch2 and Gli2. Zeb2 activation appears to be a key step in the EMT process. Our findings identify PROP1 as a central transcriptional component of pituitary stem cell differentiation.
Genetics in Keratoconus: where are we?Tuesday, June 28, 2016
Bykhovskaya Y, Margines B, Rabinowitz YS,
Eye and vision (London, England). 2016
Keratoconus (KC) is a non-inflammatory thinning and protrusion of the cornea in which the cornea assumes a conical shape. Complex etiology of this condition at present remains an enigma. Although environmental factors have been involved in KC pathogenesis, strong underlining genetic susceptibility has been proven. The lack of consistent findings among early genetic studies suggested a heterogeneity and complex nature of the genetic contribution to the development of KC. Recently, genome-wide linkage studies (GWLS) and genome-wide association studies (GWAS) were undertaken. Next-generation sequencing (NGS)-based genomic screens are also currently being carried out. Application of these recently developed comprehensive genetic tools led to a much greater success and increased reproducibility of genetic findings in KC. Involvement of the LOX gene identified through GWLS has been confirmed in multiple cohorts of KC patients around the world. KC susceptibility region located at the 2q21.3 chromosomal region near the RAB3GAP1 gene identified through GWAS was independently replicated. Rare variants in the ZNF469 gene (mutated in corneal dystrophy Brittle Cornea Syndrome) and in the TGFBI gene (mutated in multiple corneal epithelial-stromal TGFBI dystrophies) have been repeatedly identified in familial and sporadic KC patients of different ethnicities. Additional comprehensive strategies using quantitative endophenotypes have been successfully employed to bring further understanding to the genetics of KC. Additional genetic determinants including the COL5A1 gene have been identified in the GWAS of KC-related trait central corneal thickness. These recent discoveries confirmed the importance of the endophenotype approach for studying complex genetic diseases such as KC and showed that different connective tissue disorders may have the same genetic determinants.
Effects of Granulocyte Colony-Stimulating Factor on Patients with Liver Failure: a Meta-Analysis.Tuesday, June 28, 2016
Yang Q, Yang Y, Shi Y, Lv F, He J, Chen Z,
Journal of clinical and translational hepatology. 28-Jun-2016
The results of this meta-analysis indicate that G-CSF treatment in patients with LF significantly improved liver function, reduced the incidence of sepsis, and prolonged short-term survival.
Changes in the health care system of India have effects on management of human immunodeficiency virus infection and acquired immune deficiency syndrome epidemic.Tuesday, June 28, 2016
Nar AS, Andrioti D, Ganatra P,
Indian journal of public health. 15-06-2016
Electrospun silk fibroin mat enhances tendon-bone healing in a rabbit extra-articular model.Tuesday, June 28, 2016
Zhi Y, Liu W, Zhang P, Jiang J, Chen S,
Biotechnology letters. 27-Jun-2016
The electrospun SF mat wrapping could enhance tendon-bone healing of soft tissue graft.
TRIM28 is an Epigenetic Barrier to Induced Pluripotent Stem Cell Reprogramming.Tuesday, June 28, 2016
Miles DC, de Vries NA, Gisler S, Lieftink C, Akhtar W, Gogola E, Pawlitzky I, Hulsman D, Tanger E, Koppens M, Beijersbergen RL, van Lohuizen M,
Stem cells (Dayton, Ohio). 28-Jun-2016
Since the discovery of induced pluripotent stem cells there has been intense interest in understanding the mechanisms that allow a somatic cell to be reprogrammed back to a pluripotent state. Several groups have studied the alterations in gene expression that occur as somatic cells modify their genome to that of an embryonic stem cell. Underpinning many of the gene expression changes are modifications to the epigenetic profile of the associated chromatin. We have used a large-scale shRNA screen to identify epigenetic modifiers that act as barriers to reprogramming. We have uncovered an important role for TRIM28 in cells resisting transition between somatic and pluripotent states. TRIM28 achieves this by maintaining the H3K9me3 repressed state and keeping endogenous retroviruses silenced. We propose that knockdown of TRIM28 during reprogramming results in more plastic H3K9me3 domains, dysregulation of genes nearby H3K9me3 marks, and up regulation of endogenous retroviruses, thus facilitating the transition through reprogramming. This article is protected by copyright. All rights reserved.
Functional roles of glycoconjugates in the maintenance of stemness and differentiation process of neural stem cells.Tuesday, June 28, 2016
Yagi H, Kato K,
Glycoconjugate journal. 27-Jun-2016
Neural stem cells (NSCs) possess a high proliferative potential and capacity for self-renewal with retention of multipotency to differentiate into brain-forming cells. NSCs have gained a considerable attention because of their potential application in treatment strategies on the basis of transplantation for neurodegenerative disorders and nerve injuries. Although several signaling pathways have been reportedly involved in the fate determination process of NSCs, the molecular mechanisms underlying the maintenance of neural cell stemness and differentiation process remain largely unknown. Glycoconjugates expressed in the NSC niche in the brain offer markers of NSCs; moreover, they serve as cell regulators, which are actively involved in the modulation of signal transduction. The glycans function on NCS surfaces by recruiting growth factor receptors to specific microdomains as components of glycolipids, thereby mediating the ligand-receptor interactions both indirectly and directly as components of proteoglycans and interacting with specific lectin-type receptors as components of ligand glycoproteins. In this review, we outline current knowledge of the possible functional mechanisms of glycoconjugates to determine cell fates, which are associated with their expression pattern and structural characteristic features.
NANOG reverses the Myogenic Differentiation Potential of Senescent Stem Cells by Restoring ACTIN Filamentous Organization and SRF-Dependent Gene Expression.Tuesday, June 28, 2016
Mistriotis P, Bajpai VK, Wang X, Rong N, Shahini A, Asmani M, Liang MS, Wang J, Lei P, Liu S, Zhao R, Andreadis ST,
Stem cells (Dayton, Ohio). 28-Jun-2016
Cellular senescence as a result of organismal aging or progeroid diseases leads to stem cell pool exhaustion hindering tissue regeneration and contributing to the progression of age-related disorders. Here we discovered that ectopic expression of the pluripotent factor NANOG in senescent or progeroid myogenic progenitors reversed cellular aging and restored completely the ability to generate contractile force. To elicit its effects, NANOG enabled reactivation of the ROCK and TGF-β pathways - both of which were impaired in senescent cells - leading to ACTIN polymerization, MRTF-A translocation into the nucleus and SRF-dependent myogenic gene expression. Collectively our data reveal that cellular senescence can be reversed and provide a novel strategy to regain the lost function of aged stem cells without reprogramming to the pluripotent state. This article is protected by copyright. All rights reserved.
miR-93 regulates Msk2-mediated chromatin remodelling in diabetic nephropathy.Tuesday, June 28, 2016
Badal SS, Wang Y, Long J, Corcoran DL, Chang BH, Truong LD, Kanwar YS, Overbeek PA, Danesh FR,
Nature communications. 2016
How the kidney responds to the metabolic cues from the environment remains a central question in kidney research. This question is particularly relevant to the pathogenesis of diabetic nephropathy (DN) in which evidence suggests that metabolic events in podocytes regulate chromatin structure. Here, we show that miR-93 is a critical metabolic/epigenetic switch in the diabetic milieu linking the metabolic state to chromatin remodelling. Mice with inducible overexpression of a miR-93 transgene exclusively in podocytes exhibit significant improvements in key features of DN. We identify miR-93 as a regulator of nucleosomal dynamics in podocytes. miR-93 has a critical role in chromatin reorganization and progression of DN by modulating its target Msk2, a histone kinase, and its substrate H3S10. These findings implicate a central role for miR-93 in high glucose-induced chromatin remodelling in the kidney, and provide evidence for a previously unrecognized role for Msk2 as a target for DN therapy.
Angiopellosis as an Alternative Mechanism of Cell Extravasation.Tuesday, June 28, 2016
Allen TA, Gracieux D, Talib M, Tokarz DA, Hensley MT, Cores J, Vandergriff A, Tang J, de Andrade JB, Dinh PU, Yoder JA, Cheng K,
Stem cells (Dayton, Ohio). 28-Jun-2016
Stem cells possess the ability to home in and travel to damaged tissue when injected intravenously. For the cells to exert their therapeutic effect, they must cross the blood vessel wall and enter the surrounding tissues. The mechanism of extravasation injected stem cells employ for exit has yet to be characterized. Using intravital microscopy and a transgenic zebrafish line Tg(fli1a:egpf) with GFP-expressing vasculature, we documented the detailed extravasation processes in vivo for injected stem cells in comparison to white blood cells (WBCs). While WBCs left the blood vessels by the standard diapedesis process, injected cardiac and mesenchymal stem cells underwent a distinct method of extravasation that was markedly different from diapedesis. Here, the vascular wall undergoes an extensive remodeling to allow the cell to exit the lumen, while the injected cell remains distinctively passive in activity. We termed this process Angio-pello-sis, which represents an alternative mechanism of cell extravasation to the prevailing theory of diapedesis. This article is protected by copyright. All rights reserved.
High Glucose Causes Human Cardiac Progenitor Cell Dysfunction by Promoting Mitochondrial Fission: Role of a GLUT1 Blocker.Tuesday, June 28, 2016
Choi HY, Park JH, Jang WB, Ji ST, Jung SY, Kim da Y, Kang S, Kim YJ, Yun J, Kim JH, Baek SH, Kwon SM,
Biomolecules & therapeutics. 1-Jul-2016
Cardiovascular disease is the most common cause of death in diabetic patients. Hyperglycemia is the primary characteristic of diabetes and is associated with many complications. The role of hyperglycemia in the dysfunction of human cardiac progenitor cells that can regenerate damaged cardiac tissue has been investigated, but the exact mechanism underlying this association is not clear. Thus, we examined whether hyperglycemia could regulate mitochondrial dynamics and lead to cardiac progenitor cell dysfunction, and whether blocking glucose uptake could rescue this dysfunction. High glucose in cardiac progenitor cells results in reduced cell viability and decreased expression of cell cycle-related molecules, including CDK2 and cyclin E. A tube formation assay revealed that hyperglycemia led to a significant decrease in the tube-forming ability of cardiac progenitor cells. Fluorescent labeling of cardiac progenitor cell mitochondria revealed that hyperglycemia alters mitochondrial dynamics and increases expression of fission-related proteins, including Fis1 and Drp1. Moreover, we showed that specific blockage of GLUT1 improved cell viability, tube formation, and regulation of mitochondrial dynamics in cardiac progenitor cells. To our knowledge, this study is the first to demonstrate that high glucose leads to cardiac progenitor cell dysfunction through an increase in mitochondrial fission, and that a GLUT1 blocker can rescue cardiac progenitor cell dysfunction and downregulation of mitochondrial fission. Combined therapy with cardiac progenitor cells and a GLUT1 blocker may provide a novel strategy for cardiac progenitor cell therapy in cardiovascular disease patients with diabetes.
Novel role of ASC as a regulator of metastatic phenotype.Tuesday, June 28, 2016
Okada N, Fujii C, Matsumura T, Kitazawa M, Okuyama R, Taniguchi S, Hida S,
Cancer medicine. 28-Jun-2016
Disorders of cytoskeletal remodeling and signal transduction are frequently involved in cancer progression. In particular, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) has been reported a proapoptotic molecule that is epigenetically silenced in several human cancers. ASC is a well-characterized adaptor protein involved in the formation of multiprotein oligomers, called inflammasomes, and plays a crucial role in the activation and secretion of interleukin-1β and interleukin-18 in innate immune cells. However, the function of ASC in the regulation of tumor progression remains elusive. The present investigation examined the involvement of ASC in cancer progression and the acquisition of metastatic ability. To determine the effect of ASC depletion in in vitro and in vivo model systems, ASC was stably knocked down in B16 murine melanoma cell lines using retroviral transduction of shRNA. ASC suppression increased the motility of B16BL6 cells in scratch assays and augmented invasiveness as assessed by a Matrigel-coated transwell system. Invadopodia formation and Src phosphorylation level were markedly enhanced in ASC-knockdown cells as well. Since caspase-8 has been reported to enhance cellular migration by Tyr380 phosphorylation via Src, we examined Tyr380 phosphorylation of caspase-8 in ASC-knockdown cells and found it to be elevated in ASC-knockdown cells but attenuated by z-VAD-fmk or z-IETD-fmk. Moreover, ASC ablation increased pulmonary metastasis in mice after intravenous injection of B16BL6 cells. Our cumulative findings indicate that ASC suppresses cancer metastasis and progression via the modulation of cytoskeletal remodeling and the Src-caspase-8 signaling pathway.
Human Embryonic Stem Cells - What Have We Done? What Are We Doing? Where Are We Going?Tuesday, June 28, 2016
Ilic D, Ogilvie C,
Stem cells (Dayton, Ohio). 28-Jun-2016
Human pluripotent stem cells possess remarkable proliferative and developmental capacity, and thus have great potential for advancement of cellular therapy, disease modelling and drug discovery. Twelve years have passed since the first reported isolation of human embryonic stem cell lines (hESC), followed in October 2010 by the first treatment of a patient with hESC-based cellular therapy at the Shepherd Center in Atlanta. Despite seemingly insurmountable challenges and obstacles in the early days, hESC clinical potential reached application in an extraordinarily short time. Eight currently ongoing clinical trials are yielding encouraging results and these are likely to lead to new trials for other diseases. However, with the discovery of induced pluripotent stem cells (iPSC), disease-specific hESC lines derived from patients undergoing preimplantation genetic diagnosis (PGD) for single gene disorders fell short of expectations. Lack of ethical controversy made human iPSC (hiPSC) with specific genotypes/phenotypes more appealing than hESC for drug discovery and toxicology-related studies, and in time, lines from HLA-homologous hiPSC banks are likely to take over from hESC in clinical applications. Currently, hESC are indispensable; the results of hESC-based clinical trials will set a gold standard for future iPSC-based cellular therapy. This article is protected by copyright. All rights reserved.
NFATc1 regulates cell proliferation, migration, and invasion of ovarian cancer SKOV3 cells in vitro and in vivo.Tuesday, June 28, 2016
Li L, Duan Z, Yu J, Dang HX,
Oncology reports. 23-Jun-2016
NFATc1 (nuclear factor of activated T‑cells c1) is associated with malignancy in several cancer models. However, the expression and function of NFATc1 in ovarian cancer remain elusive. In the present study, we investigated the role of NFATc1 in human epithelial ovarian cancer (EOC) using human ovarian adenocarcinoma SKOV3 cells and patient characteristics. NFATc1 expression was silenced by siRNA in the SKOV3 ovarian cancer cell line and in human ovarian cancer nude mouse xenografts. Real‑time PCR, western blotting, immunohistochemical staining, MTT, flow cytometry, transwell, erasion trace and mouse assays were used to detect NFATc1 expression, cell proliferation, apoptosis, cell invasion and migration, tumor growth and angiogenesis. Survival analysis was performed to assess the correlation between NFATc1 expression and survival. NFATc1 was overexpressed in the SKOV3 ovarian cancer cell line and in human serous/mucinous ovarian cancer tissues. The silencing of NFATc1 expression by siRNA reduced cell proliferation and migration and promoted apoptosis in vitro and decreased the ovarian cancer cell tumorigenesis in vivo in nude mice. NFATc1 overexpression in high‑grade serous ovarian carcinomas was an independent prognostic factor of poor overall survival and of early relapse (P<0.01) in a univariate analysis. Our present data provide evidence that NFATc1 is overexpressed in human serous/mucinous ovarian cancer and is associated with a poor prognosis. NFATc1 silencing regulates the cell cycle, apoptosis, invasion and migration. NFATc1 thus has the potential to be a therapeutic target and to be used in EOC diagnosis and prognosis.
Tunicamycin-induced endoplasmic reticulum stress reduces in vitro subpopulation and invasion of CD44+/CD24- phenotype breast cancer stem cells.Tuesday, June 28, 2016
Nami B, Donmez H, Kocak N,
Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie. 24-Jun-2016
Tunicamycin is an inhibitor of glycosylation that disturbs protein folding machinery in eukaryotic cells. Tunicamycin causes accumulation of unfolded proteins in cell endoplasmic reticulum (ER) and induces ER stress. ER stress is an essential mechanism for cellular homeostasis has role in cell death via reprogramming of protein processing, regulation of autophagy and apoptosis. In this study we show effect of tunicamycin on subpopulation and invasion of CD44+/CD24- MCF7 breast cancer stem cells. CD44+/CD24- cells were isolated from MCF7 cell line by fluorescence activated cell sorting (FACS) and treated with tunicamycin. ER stress was monitored by evaluation of X-box binding protein 1(XBP-1) mRNA splicing, cleaved activating transcription factor 6 (ATF6) nuclear translocation and CCAAT/enhancer-binding protein homologous protein (CHOP) expression. CD44+/CD24- subpopulation was analyzed using flow cytometry. Invasion was investigated by scratch assay, trypan blue staining, 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) proliferation and in vitro migration assays. Increased level of spliced XBP-1, ATF6 nuclear translocation and CHOP protein expression were detected in CD44+/CD24- and original MCF7 cells treated with tunicamycin. Also, a significant decline in CD44+/CD24- cell subpopulation was determined in the cells treated with tunicamycin. The results also showed inhibited invasion, increased cell death, suppressed proliferation and reduced migration in the CD44+/CD24- and CD44+/CD24- rich MCF7 cell culture, under effect of tunicamycin. Our results indicate that CD44+/CD24- phenotype MCF7 cells are susceptible to tunicamycin. The results showed that tunicamycin-induced ER stress suppresses CD44+/CD24- phenotype cell subpopulation and in vitro invasion and accelerates tumorosphore formation. These results suggest that tunicamycin-induced ER stress inhibits CD44+/CD24- phenotype MCF7 breast cancer stem cells. We conclude that using ER-targeting chemicals like tunicamycin is an interesting approach to target breast cancer stem cells inside tumor.
[Inhibitory effect of total saponins of Panax notoginseng on rat bone marrow mesenchymal stem cell apoptosis].Tuesday, June 28, 2016
Ou YF, Fu XK, Mei XS, Zheng HZ,
Sheng li xue bao : [Acta physiologica Sinica]. 25-Jun-2016
The study was aimed to investigate the effects of total saponins of Panax notoginseng (tPNS) on cobalt chloride (CoCl2)-induced apoptosis of rat bone marrow mesenchymal stem cells (rBMSCs) and the underlying mechanism. rBMSCs were isolated by density gradient centrifugation from Sprague Dawley (SD) rats. After being incubated with different concentrations of tPNS (1, 10, 100 μg/mL) for 48 h, the rBMSCs were stained with EdU and PI for proliferation and cell cycle assay, respectively. CoCl2 group was treated with 300 μmol CoCl2 for 24 h, and different concentrations tPNS groups were treated with 300 μmol CoCl2 plus 1, 10 or 100 μg/mL tPNS. After Annexin V-FITC/PI staining, flow cytometry was applied to measure the cell apoptosis. For mitochondrial membrane potential assay, rhodamine123 and Hoechst33342 staining were used. qRT-PCR was applied to analyze gene expression of Bcl-2 family. The results showed that the proliferation rates of the three concentrations tPNS groups were all higher than that of the control group (all P < 0.05). Compared with control group, only 100 μg/mL tPNS group exhibited increased cell percentage of S and G2 phase. Compared with that in control group (without CoCl2), the apoptotic rate was increased by 14.2% in CoCl2 group. And the apoptotic rates were reduced by 14.4%, 12.8% and 13.9% in three concentrations tPNS groups, compared with that in CoCl2 group (all P < 0.01). CoCl2 could decrease the mitochondrial membrane potential, while different concentrations of tPNS reversed the inhibitory effect of CoCl2. Bcl-2 and Bcl-xl mRNA expressions in all tPNS groups were higher than those in CoCl2 group (all P < 0.05). Moreover, 10 and 100 μg/mL tPNS groups showed lower ratios of Bax/Bcl-2, compared with CoCl2 group. The results suggest that tPNS protects the rBMSCs against CoCl2-induced apoptosis through improving the cell mitochondrial membrane potential, up-regulating the expressions of anti-apoptosis genes Bcl-2 and Bcl-xl, and reducing the Bax/Bcl-2 gene expression ratio.
Transcription Factor GLIS3: a New and Critical Regulator of Postnatal Stages of Mouse Spermatogenesis.Tuesday, June 28, 2016
Kang HS, Chen LY, Lichti-Kaiser K, Liao G, Gerrish K, Bortner CD, Yao HH, Eddy EM, Jetten AM,
Stem cells (Dayton, Ohio). 28-Jun-2016
In this study, we identify a novel and essential role for the Krüppel-like zinc finger transcription factor GLIS3 in the regulation of postnatal spermatogenesis. We show that GLIS3 is expressed in gonocytes, spermatogonial stem cells (SSCs) and spermatogonial progenitors (SPCs), but not in differentiated spermatogonia and later stages of spermatogenesis or in somatic cells. Spermatogenesis is greatly impaired in GLIS3 knockout mice. Loss of GLIS3 function causes a moderate reduction in the number of gonocytes, but greatly affects the generation of SSCs/SPCs, and as a consequence the development of spermatocytes. Gene expression profiling demonstrated that the expression of genes associated with undifferentiated spermatogonia was dramatically decreased in GLIS3-deficient mice and that the cytoplasmic-to-nuclear translocation of FOXO1, which marks the gonocyte-to-SSC transition and is necessary for SSC self-renewal, is inhibited. These observations suggest that GLIS3 promotes the gonocyte-to-SSC transition and is a critical regulator of the dynamics of early postnatal spermatogenesis. This article is protected by copyright. All rights reserved.
Prolonged Culture of Aligned Skeletal Myotubes on Micromolded Gelatin Hydrogels.Tuesday, June 28, 2016
Bettadapur A, Suh GC, Geisse NA, Wang ER, Hua C, Huber HA, Viscio AA, Kim JY, Strickland JB, McCain ML,
Scientific reports. 2016
In vitro models of skeletal muscle are critically needed to elucidate disease mechanisms, identify therapeutic targets, and test drugs pre-clinically. However, culturing skeletal muscle has been challenging due to myotube delamination from synthetic culture substrates approximately one week after initiating differentiation from myoblasts. In this study, we successfully maintained aligned skeletal myotubes differentiated from C2C12 mouse skeletal myoblasts for three weeks by utilizing micromolded (μmolded) gelatin hydrogels as culture substrates, which we thoroughly characterized using atomic force microscopy (AFM). Compared to polydimethylsiloxane (PDMS) microcontact printed (μprinted) with fibronectin (FN), cell adhesion on gelatin hydrogel constructs was significantly higher one week and three weeks after initiating differentiation. Delamination from FN-μprinted PDMS precluded robust detection of myotubes. Compared to a softer blend of PDMS μprinted with FN, myogenic index, myotube width, and myotube length on μmolded gelatin hydrogels was similar one week after initiating differentiation. However, three weeks after initiating differentiation, these parameters were significantly higher on μmolded gelatin hydrogels compared to FN-μprinted soft PDMS constructs. Similar results were observed on isotropic versions of each substrate, suggesting that these findings are independent of substrate patterning. Our platform enables novel studies into skeletal muscle development and disease and chronic drug testing in vitro.
Endocrine pancreas engineered using porcine islets and partial pancreatic scaffolds.Tuesday, June 28, 2016
Katsuki Y, Yagi H, Okitsu T, Kitago M, Tajima K, Kadota Y, Hibi T, Abe Y, Shinoda M, Itano O, Takeuchi S, Kitagawa Y,
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. 19-Jun-2016
This scaffold from a large animal maintained islet survival and function in the short-term, retaining the cells as a solid organ in the parenchymal space after infusion through the pancreatic duct. These results suggest that this scaffold is suitable for further fabrication of fully functional bioengineered endocrine pancreases when implanted in vivo. Therefore, it may represent a key improvement in the field of beta-cell replacement therapy. Nonetheless, the facilitation of longer-term islet survival and studies of implantation in vivo is required for successful clinical translation.
EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells.Tuesday, June 28, 2016
Krusche B, Ottone C, Clements MP, Johnstone ER, Goetsch K, Lieven H, Mota SG, Singh P, Khadayate S, Ashraf A, Davies T, Pollard SM, De Paola V, Roncaroli F, Martinez-Torrecuadrada J, Bertone P, Parrinello S,
eLife. 2016
Glioblastomas (GBM) are aggressive and therapy-resistant brain tumours, which contain a subpopulation of tumour-propagating glioblastoma stem-like cells (GSC) thought to drive progression and recurrence. Diffuse invasion of the brain parenchyma, including along preexisting blood vessels, is a leading cause of therapeutic resistance, but the mechanisms remain unclear. Here, we show that ephrin-B2 mediates GSC perivascular invasion. Intravital imaging, coupled with mechanistic studies in murine GBM models and patient-derived GSC, revealed that endothelial ephrin-B2 compartmentalises non-tumourigenic cells. In contrast, upregulation of the same ephrin-B2 ligand in GSC enabled perivascular migration through homotypic forward signalling. Surprisingly, ephrin-B2 reverse signalling also promoted tumourigenesis cell-autonomously, by mediating anchorage-independent cytokinesis via RhoA. In human GSC-derived orthotopic xenografts, EFNB2 knock-down blocked tumour initiation and treatment of established tumours with ephrin-B2-blocking antibodies suppressed progression. Thus, our results indicate that targeting ephrin-B2 may be an effective strategy for the simultaneous inhibition of invasion and proliferation in GBM.
Human Mesenchymal Stem Cell-Derived Microvesicles Prevent the Rupture of Intracranial Aneurysm in Part by Suppression of Mast Cell Activation via a PGE2-Dependent Mechanism.Tuesday, June 28, 2016
Liu J, Kuwabara A, Kamio Y, Hu S, Park J, Hashimoto T, Lee JW,
Stem cells (Dayton, Ohio). 28-Jun-2016
Human MSC-derived MVs prevented the rupture of intracranial aneurysm, in part due to their anti-inflammatory effect on mast cells, which was mediated by PGE2 production and EP4 activation. This article is protected by copyright. All rights reserved.
Inactivated mesenchymal stem cells maintain immunomodulatory capacity.Tuesday, June 28, 2016
Luk F, de Witte S, Korevaar SS, Roemeling-van Rhijn M, Franquesa M, Strini T, van den Engel S, Gargesha M, Roy D, Dor FJ, Horwitz EM, de Bruin RW, Betjes MG, Baan CC, Hoogduijn MJ,
Stem cells and development. 27-Jun-2016
Mesenchymal stem cells (MSC) are studied as a cell therapeutic agent for treatment of various immune diseases. However, therapy with living culture-expanded cells comes with safety concerns. Furthermore, development of effective MSC immunotherapy is hampered by lack of knowledge of the mechanisms of action and the therapeutic components of MSC. Such knowledge allows better identification of diseases that are responsive to MSC treatment, optimization of the MSC product, and development of therapy based on functional components of MSC. To close in on the components that carry the therapeutic immunomodulatory activity of MSC, we generated MSC that were unable to respond to inflammatory signals or secrete immunomodulatory factors but preserved their cellular integrity (HI-MSC). Secretome-deficient HI-MSC and control MSC showed the same bio-distribution and persistence after infusion in mice with ischemic kidney injury. Both control and HI-MSC induced mild inflammatory responses in healthy mice and induced dramatic increases in IL-10 and reductions in IFN-γ levels in sepsis mice. In vitro experiments showed that opposite to control MSC, HI-MSC lacked the capability to suppress T cell proliferation or induce regulatory B cell formation. However, both HI-MSC and control MSC modulated monocyte function in response to LPS. The results of this study demonstrate that, in particular disease models, the immunomodulatory effect of MSC does not depend on their secretome or active cross-talk with immune cells but on recognition of MSC by monocytic cells. These findings provide a new view on MSC-induced immunomodulation and help identify key components of the therapeutic effects of MSC.
From dioxin toxicity of human Ah receptor to putative physiologic functions in homeostasis of stem/progenitor cells.Tuesday, June 28, 2016
Bock KW,
Biochemical pharmacology. 24-Jun-2016
Despite decades of intensive research physiologic Ah receptor (AHR) functions are not yet elucidated. Challenges include marked species differences and dependence of AHR function on the cell type and cellular context. Hints to physiologic functions may be derived (i) from feedback loops between endogenous ligands and substrates of major target enzymes such as CYP1A1 and UGT1A1, and (ii) from dioxin toxicity in human individuals. For example, dioxin-mediated chloracne is probably due to dysregulated homeostasis of sebocyte stem/progenitor cells. Dioxin-mediated inflammatory responses may be due to complex dysregulation of hematopoiesis. Comparison of AHR functions with those of PXR and its target enzyme CYP3A4 may be helpful to emphasize AHR functions in spezialized cells: PXR is known to be mainly involved in regulation of systemic metabolism of endo- and xenobiotics. However, AHR may be mostly controlling local homeostasis of signals in specialized cells such as stem/progenitor cells. Accumulating evidence suggests that knowledge about physiologic AHR functions may stimulate drug development.
Transcriptomic Analyses of Adipocyte Differentiation from Human Mesenchymal Stromal-Cells (MSC).Tuesday, June 28, 2016
Casado-Díaz A, Anter J, Müller S, Winter P, Quesada-Gómez JM, Dorado G,
Journal of cellular physiology. 28-Jun-2016
Adipogenesis is a physiological process required for fat-tissue development, mainly involved in regulating the organism energetic-state. Abnormal distribution-changes and dysfunctions in such tissue are associated to different pathologies. Adipocytes are generated from progenitor cells, via a complex differentiating process not yet well understood. Therefore, we investigated differential mRNA and miRNA expression patterns of human mesenchymal stromal-cells (MSC) induced and not induced to differentiate into adipocytes by next (second)-generation sequencing. A total of 2,866 differentially-expressed genes (101 encoding miRNA) were identified, with 705 (46 encoding miRNA) being upregulated in adipogenesis. They were related to different pathways, including PPARG, lipid, carbohydrate and energy metabolism, redox, membrane-organelle biosynthesis and endocrine system. Downregulated genes were related to extracellular matrix and cell migration, proliferation and differentiation. Analyses of mRNA-miRNA interaction showed that repressed miRNA-encoding genes can act downregulating PPARG-related genes; mostly the PPARG activator (PPARGC1A). Induced miRNA-encoding genes regulate downregulated genes related to TGFB1. These results shed new light to understand adipose-tissue differentiation and physiology, increasing our knowledge about pathologies like obesity, type-2 diabetes and osteoporosis. This article is protected by copyright. All rights reserved.
Hematopoietic, Mesenchymal and Immune Cells are More Enhanced in Bone Marrow Than in Peripheral Blood From G-CSF Primed Healthy Donors.Tuesday, June 28, 2016
De Felice L, Agostini F, Suriano C, Fraboni D, Gregorj C, Tirindelli MC, Picardi A, Santarone S, Di Piazza F, Di Bartolomeo P, Arcese W,
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 24-Jun-2016
The use of granulocyte colony-stimulating factor (G-CSF) primed bone marrow (G-BM) has been recently considered as an alternative to mobilized hematopoietic stem cells from peripheral blood (G-PB) especially in haploidentical transplant setting. The purpose of this study was to compare the effect of in vivo G-CSF priming on BM and PB hematopoietic, mesenchymal (MSC) and immune cells. Forty healthy donors undergoing BM harvest for haploidentical transplant were given subcutaneous rhG-CSF for seven days. BM and PB samples were harvested on days -7 and 0. The hematopoietic stem/progenitor cells increased significantly after G-CSF priming in both BM and PB with a selective rise of BM CD34+CD38- cell subset. A striking enhancement of the mesenchymal progenitors was detected in G-BM. CD3+, CD4+, CD8+, CD19+ cell fractions, the naïve CD4+ and CD8+ subpopulations, NK cells and Treg cells increased in G-BM, while only slight changes were detected in PB. Myeloid dendritic cells (DC1) were significantly up regulated in both G-BM and G-PB, while DC2 increased only in G-BM. In conclusion, our results show substantial differences in the biological effects exerted by G-CSF at BM and PB levels on hematopoietic cells and immune cell fractions. Furthermore, the impressive rise of MSC progenitors in G-BM might also be relevant to provide MSCs for several clinical use.
Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy.Tuesday, June 28, 2016
Deguise MO, Boyer JG, McFall ER, Yazdani A, De Repentigny Y, Kothary R,
Scientific reports. 2016
Motor neuron loss and neurogenic atrophy are hallmarks of spinal muscular atrophy (SMA), a leading genetic cause of infant deaths. Previous studies have focused on deciphering disease pathogenesis in motor neurons. However, a systematic evaluation of atrophy pathways in muscles is lacking. Here, we show that these pathways are differentially activated depending on severity of disease in two different SMA model mice. Although proteasomal degradation is induced in skeletal muscle of both models, autophagosomal degradation is present only in Smn(2B/-) mice but not in the more severe Smn(-/-); SMN2 mice. Expression of FoxO transcription factors, which regulate both proteasomal and autophagosomal degradation, is elevated in Smn(2B/-) muscle. Remarkably, administration of trichostatin A reversed all molecular changes associated with atrophy. Cardiac muscle also exhibits differential induction of atrophy between Smn(2B/-) and Smn(-/-); SMN2 mice, albeit in the opposite direction to that of skeletal muscle. Altogether, our work highlights the importance of cautious analysis of different mouse models of SMA as distinct patterns of atrophy induction are at play depending on disease severity. We also revealed that one of the beneficial impacts of trichostatin A on SMA model mice is via attenuation of muscle atrophy through reduction of FoxO expression to normal levels.
Insight into the relationship between the cell culture model, cell trafficking and siRNA silencing efficiency.Tuesday, June 28, 2016
Capel V, Vllasaliu D, Watts P, Stolnik S,
Biochemical and biophysical research communications. 24-Jun-2016
Despite research efforts, cell uptake processes determining siRNA silencing efficiency remain unclear. Here, we examine the relationship between in vitro cell culture models, cellular trafficking and siRNA silencing efficiency to provide a mechanistic insight on siRNA delivery system design. Model siRNA-polyplexes, based on chitosan as a 'classical' condensing agent, were applied to a panel of lung epithelial cell lines, H1299, A549 and Calu-3 and cell internalization levels, trafficking pathways and gene silencing assessed on exposure to pharmacological inhibitors. The data reveal striking differences in the internalization behaviour and gene silencing efficiency in the tested cell lines, despite their common lung epithelial origins. The model system's silencing was lower where clathrin internalization pathway predominated in Calu-3, relative to silencing in H1299 cells where a non-clathrin internalization appears dominant. Increased silencing on endosomal disruption was apparent in Calu-3 cells, but absent when cellular internalization was not predominantly clathrin-mediated in A549 cells. This highlights that identifying cell trafficking pathways before incorporation of functional components to siRNA delivery systems (e.g. endosomolytic compounds) is crucial. The study hence stresses the importance of selection of appropriate cell culture model, relevant to in vivo target, to assess the gene silencing efficiency and decide which functionalities the 'stratified siRNA silencing vector' requires.
Overexpression of PRAS40(T246A) in the Proliferative Compartment Suppresses mTORC1 Signaling, Keratinocyte Migration and Skin Tumor Development.Tuesday, June 28, 2016
Rho O, Srivastava J, Cho J, DiGiovanni J,
The Journal of investigative dermatology. 24-Jun-2016
The proline-rich Akt substrate of 40 kDa (PRAS40), an inhibitory component of the mTORC1 complex, was identified as an Akt substrate through phosphorylation at Thr246. Phosphorylation at this site releases PRAS40 from the mTORC1 complex allowing increased activity. Targeted expression of a mutant form of PRAS40 (PRAS40(T246A)) in basal keratinocytes of mouse epidermis (BK5.PRAS40(T246A) mice) has allowed further examination of mTORC1 specific signaling in epithelial carcinogenesis. BK5.PRAS40(T246A) mice were resistant to TPA-induced epidermal hyperproliferation and skin tumor development. In transgenic mice, PRAS40(T246A) remained bound to raptor in keratinocytes even after treatment with TPA, consistent with reduced mTORC1 signaling and altered levels of cell cycle proteins. BK5.PRAS40(T246A) mice also displayed attenuated skin inflammation in response to TPA. Inhibition of mTORC1 in keratinocytes significantly inhibited their migration in vitro and, in addition, inhibited TPA-induced proliferation and migration of bulge-region stem cells in vivo. Furthermore, targeted inhibition of mTORC1 in BK5.PRAS40(T246A) mice resulted in delayed wound healing. Decreased keratinocyte migration and impaired wound healing correlated with altered expression of EMT markers and reduced smad signaling. Collectively, the current data using this unique mouse model provide further evidence that mTORC1 signaling in keratinocytes regulates key events in keratinocyte function and epithelial cancer development.
[Pneumocystosis during HIV infection].Tuesday, June 28, 2016
El Fane M, Sodqi M, Oulad Lahsen A, Chakib A, Marih L, Marhoum El Filali K,
Revue de pneumologie clinique. 24-Jun-2016
Pneumocystosis is an opportunistic disease caused by invasion of unicellular fungus Pneumocystic jirovecii which is responsible for febrile pneumonia among patients with cellular immunodeficiency especially those HIV infected. Despite the decreasing of its incidence due to the introduction of antiretroviral therapy, as well as anti-Pneumocystis prophylaxis among these patients, Pneumocystis pneumonia remains the first AIDS-defining event and a leading cause of mortality among HIV-infected patients. The usual radiological presentation is that of diffuse interstitial pneumonia. The diagnosis is confirmed by the detection of trophozoides and/or cysts P. jirovecii in bronchoalveolar lavage (BAL) samples using several staining techniques. The use of polymerase chain reaction in the BAL samples in conjunction with standard immunofluorescent or colorimetric tests have allowed for more has allowed for more rapid and accurate diagnosis. The standard regimen of treatment is the association of trimethoprim-sulfamethoxazole which has been utilized as an effective treatment with a favourable recovery. Early HIV diagnosis and antiretroviral therapy should reduce the incidence of this dreaded disease.
JAK-STAT signaling in cancer: From cytokines to non-coding genome.Tuesday, June 28, 2016
Pencik J, Pham HT, Schmoellerl J, Javaheri T, Schlederer M, Culig Z, Merkel O, Moriggl R, Grebien F, Kenner L,
Cytokine. 24-Jun-2016
In the past decades, studies of the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) signaling have uncovered highly conserved programs linking cytokine signaling to the regulation of essential cellular mechanisms such as proliferation, invasion, survival, inflammation and immunity. Inhibitors of the JAK/STAT pathway are used for treatment of autoimmune diseases, such as rheumatoid arthritis or psoriasis. Aberrant JAK/STAT signaling has been identified to contribute to cancer progression and metastatic development. Targeting of JAK/STAT pathway is currently one of the most promising therapeutic strategies in prostate cancer (PCa), hematopoietic malignancies and sarcomas. Notably, newly identified regulators of JAK/STAT signaling, the non-coding RNAs transcripts and their role as important targets and potential clinical biomarkers are highlighted in this review. In addition to the established role of the JAK/STAT signaling pathway in traditional cytokine signaling the non-coding RNAs add yet another layer of hidden regulation and function. Understanding the crosstalk of non-coding RNA with JAK/STAT signaling in cancer is of critical importance and may result in better patient stratification not only in terms of prognosis but also in the context of therapy.
Selenocysteine containing analogues of Atx1-based peptides protect cells from copper ion toxicity.Tuesday, June 28, 2016
Shoshan MS, Lehman Y, Goch W, Bal W, Tshuva EY, Metanis N,
Organic & biomolecular chemistry. 28-Jun-2016
Seleno-substituted model peptides of copper metallochaperone proteins were analyzed for the metal affinity and in vitro anti-oxidative reactivity. An acyclic MTCXXC (X is any amino acid) reference peptide previously analyzed as a potent inhibitor of ROS production underwent substitution of the cysteine residues with selenocysteine to give two singly substituted derivatives C3U and C6U and the doubly substituted analogue C3U/C6U. Presumably due to the softer nature of Se vs. S, all selenocysteine containing peptides demonstrated high affinity to Cu(i), higher than that of the reference peptide, and in the same order of magnitude as that measured for the native protein, Atox1. A stronger impact of residue 3 confirmed previous findings on its more dominant role in metal coordination. In vitro studies on the HT-29 human colon cancer cell line, MEF mice embryonic fibroblasts, and MEF with the knocked-out Atox1 gene (Atox1 -/-) consistently identified C3U/C6U as the most potent inhibitor of ROS cellular production based on the 2',7'-dichlorodihydrofluorescin diacetate (H2DCF-DA) assay, also in comparison with known drugs employed in the clinic for Wilson's disease. The selenocysteine containing peptides are thus promising drug candidates for chelation therapy of Wilson's disease and related conditions relevant to excessive copper levels.
Neuronal regeneration after acute spinal cord injury in adult rats.Tuesday, June 28, 2016
B H, G N,
The spine journal : official journal of the North American Spine Society. 24-Jun-2016
To our knowledge, this is the first study to demonstrate that neurons are regenerated 3-5 mm away from the injured site, and no neurons are regenerated at the injured site in this SCI model, which suggests a novel train of thought regarding SCI treatment.
Chondroitinase administration and pcDNA3.1-BDNF-BMSC transplantation promote motor functional recovery associated with NGF expression in spinal cord-transected rat.Tuesday, June 28, 2016
Xiong LL, Li Y, Shang FF, Chen SW, Chen H, Ju SM, Zou Y, Tian HL, Wang TH, Luo CZ, Wang XY,
Spinal cord. 28-Jun-2016
Co-treated strategy could effectively promote motor functional recovery and axonal regeneration in SCT rats associated with NGF upregulation.Spinal Cord advance online publication, 28 June 2016; doi:10.1038/sc.2016.55.
Progestin-mediated activation of MAPK and AKT in nuclear progesterone receptor negative breast epithelial cells: The role of membrane progesterone receptors.Tuesday, June 28, 2016
Salazar M, Lerma-Ortiz A, Hooks GM, Ashley AK, Ashley RL,
Gene. 24-Jun-2016
Progesterone (P4), a steroid produced during estrous cycles and gestation for maintenance of pregnancy, also plays key roles in breast development to allow lactation post-parturition. Progestins (P4 and related steroids) are also implicated in breast cancer etiology. Hormone replacement therapy containing both estrogen and progestins increases breast cancer incidence while estrogen hormone therapy lowers breast cancer risk. P4 signaling via nuclear P4 receptors (PRs) has been extensively studied in breast cancer, however, progestin signaling via non-classical membrane bound progestin receptors (MPRs and PGRMC1) remains unclear. Moreover, P4 metabolites and synthetic progestins may bind membrane progestin receptors. We hypothesized that PR-negative breast epithelial cells express non-classical progestin receptors, which activate intracellular signaling pathways differently depending on nature of progestin. Therefore, our objectives for the current study were to determine expression of MPRs and PGRMC1 in two PR-negative non-tumorigenic breast epithelial cell lines, assess progestin-mediated signaling and biological functions. We determined five MPR isoforms and PGRMC1 were present in MCF10A cells and all progestin receptors but MPRβ in MCF12A cells. MCF10A and MCF12A cells were treated with P4, select P4 metabolites (5αP and 3αHP), medroxyprogesterone acetate (MPA), or a specific MPR-Agonist (MPR-Ag) and phosphorylation of ERK, p38, JNK, and AKT was characterized following treatment. To our knowledge this is the first report of ERK and JNK activation in MCF10A and MCF12A cells with P4, P4 metabolites, MPA, and MPR-Ag. Activation of ERK and JNK in cells treated with MPR-Ag implicates MPRs may serve as the receptors responsible for their activation. In contrast, p38 activation varied with cell type and with progestin treatment. P4 and MPA promoted AKT phosphorylation in the MCF12A cell line only whereas no activation was observed in MCF10A cells. Interestingly, cellular proliferation increased in MCF10A cells treated with MPA or 5αP, while MPR-Ag tended to slightly decrease proliferation. Collectively, our data highlights the importance of investigating the effects of synthetic progestins in breast cancer biology. Our results add to the understanding that various progestins have on breast epithelial cells and underscores the importance of considering both membrane bound receptors and progestin type in breast cancer development.
Statins and Alkylphospholipids as New Anticancer Agents Targeting Lipid Metabolism.Tuesday, June 28, 2016
Apostolova S, Toshkova R, Momchilova A, Tzoneva R,
Anti-cancer agents in medicinal chemistry. 23-Jun-2016
The partial efficacy and high toxicity of the current anticancer chemotherapeutics as well as the development of multiple drug resistance are major problems in cancer therapy. Therefore, there is an emergency need for the development of novel well-tolerated anticancer agents with different mode of action that could be successfully used in combination with other drugs as an adjuvant therapy. The inhibition of intracellular signaling pathways associated with cancer growth and invasiveness is a main therapeutic approach in cancer treatment. It is well known that lipid metabolism is involved in the regulation of key cellular processes such as proliferation, differentiation and apoptosis. Statins and alkylphospholipids are both relatively new synthetic agents with considerable anticancer properties that disturb lipid metabolism and subsequently modulate proliferation and cell survival signaling pathways, leading to apoptosis. Numerous in vitro and in vivo studies have shown promising results for the use of statins and alkylphospholipids as potential therapeutic agents in the treatment of various human malignancies. However, more investigations and clinical trials are needed to assess their optimal safe dose and maximal efficacy and better understand the molecular mechanisms underlying the antitumor effects of these drugs.
Midgut epithelium in molting silkworm: A fine balance among cell growth, differentiation, and survival.Tuesday, June 28, 2016
Franzetti E, Casartelli M, D'Antona P, Montali A, Romanelli D, Cappellozza S, Caccia S, Grimaldi A, de Eguileor M, Tettamanti G,
Arthropod structure & development. 24-Jun-2016
The midgut of insects has attracted great attention as a system for studying intestinal stem cells (ISCs) as well as cell death-related processes, such as apoptosis and autophagy. Among insects, Lepidoptera represent a good model to analyze these structures and processes. In particular, larva-larva molting is an interesting developmental phase since the larva must deal with nutrient starvation and its organs are subjected to rearrangements due to proliferation and differentiation events. Several studies have analyzed ISCs in vitro and characterized key factors involved in their division and differentiation during molt. However, in vivo studies performed during larva-larva transition on these cells, and on the whole midgut epithelium, are fragmentary. In the present study, we analyzed the larval midgut epithelium of the silkworm, Bombyx mori, during larva-larva molting, focusing our attention on ISCs. Moreover, we investigated the metabolic changes that occur in the epithelium and evaluated the intervention of autophagy. Our data on ISCs proliferation and differentiation, autophagy activation, and metabolic and functional activities of the midgut cells shed light on the complexity of this organ during the molting phase.
Efficient elimination of pancreatic cancer stem cells by hedgehog/GLI inhibitor GANT61 in combination with mTOR inhibition.Tuesday, June 28, 2016
Miyazaki Y, Matsubara S, Ding Q, Tsukasa K, Yoshimitsu M, Kosai K, Takao S,
Molecular cancer. 2016
Thus, this novel combination treatment could be useful for the control of pancreatic cancer by targeting pancreatic CSCs. This is the first report of the efficient elimination of pancreatic cancer stem-like cells by the double blockage of Hh/GLI and mTOR signaling.
Erratum to: CXCL14 and MCP1 are potent trophic factors associated with cell migration and angiogenesis leading to higher regenerative potential of dental pulp side population cells.Tuesday, June 28, 2016
Hayashi Y, Murakami M, Kawamura R, Ishizaka R, Fukuta O, Nakashima M,
Stem cell research & therapy. 27-06-2016
NEK2 regulates stem-like properties and predicts poor prognosis in hepatocellular carcinoma.Tuesday, June 28, 2016
Lin S, Zhou S, Jiang S, Liu X, Wang Y, Zheng X, Zhou H, Li X, Cai X,
Oncology reports. 22-Jun-2016
NEK2 has been estimated to play an important role in cancer progression. However, its relevance in hepatocellular carcinoma (HCC) has not yet been explored. Immunohistochemistry revealed NEK2 expression was upregulated in HCC. NEK2-positive hepatocellular carcinoma patients were associated with poor prognosis after surgery compared with NEK2-negative patients based on Kaplan-Meier curves. Deletion of NEK2 reduced self-renewal properties and chemotherapeutic resistance, and decreased the stemness associated genes in cell lines. NEK2 was associated with unfavorable outcomes in HCC patients, and was revealed to regulate self-renewal property by means of Wnt/β-catenin signaling, and chemotherapeutic resistance by preferential regulation of the expression of ABCG2 and ALDH1A1 in HCC cells.
Urinary tract obstruction: Stem cells hinder stricture formation.Tuesday, June 28, 2016
Thoma C,
Nature reviews. Urology. 28-Jun-2016
Risk Factors for Extubation Failure in Extremely Low Birth Weight Infants.Tuesday, June 28, 2016
Wang SH, Liou JY, Chen CY, Chou HC, Hsieh WS, Tsao PN,
Pediatrics and neonatology. 7-Jun-2016
This study shows that nearly half of ELBW infants do not require intubation. Among ELBW infants who require invasive ventilator support, those who have lower postextubation arterial pH and bicarbonate levels are at high risk of extubation failure.
Discriminating the Independent Influence of Cell Adhesion and Spreading Area on Stem Cell Fate Determination Using Micropatterned Surfaces.Tuesday, June 28, 2016
Wang X, Hu X, Dulińska-Molak I, Kawazoe N, Yang Y, Chen G,
Scientific reports. 2016
Adhesion and spreading are essential processes of anchorage dependent cells involved in regulation of cell functions. Cells interact with their extracellular matrix (ECM) resulting in different degree of adhesion and spreading. However, it is not clear whether cell adhesion or cell spreading is more important for cell functions. In this study, 10 types of isotropical micropatterns that were composed of 2 μm microdots were prepared to precisely control the adhesion area and spreading area of human mesenchymal stem cells (MSCs). The respective influence of adhesion and spreading areas on stem cell functions was investigated. Adhesion area showed more significant influences on the focal adhesion formation, binding of myosin to actin fibers, cytoskeletal organization, cellular Young's modulus, accumulation of YAP/TAZ in nuclei, osteogenic and adipogenic differentiation of MSCs than did the spreading area. The results indicated that adhesion area rather than spreading area played more important roles in regulating cell functions. This study should provide new insight of the influence of cell adhesion and spreading on cell functions and inspire the design of biomaterials to process in an effective manner for manipulation of cell functions.
Requirement of IP3 Receptor 3 (IP3R3) in Nitric Oxide induced Cardiomyocyte Differentiation of Mouse Embryonic Stem Cells.Tuesday, June 28, 2016
Wei W, Huang W, Yue J,
Experimental cell research. 24-Jun-2016
Nitric oxide (NO) markedly induces cardiomyocyte (CM) differentiation of embryonic stem (ES) cells. Here we examined the role of the Ca(2+) signaling in the NO-induced CM differentiation of mouse ES cells. We found that NO induced intracellular Ca(2+) increases in ES cells in a dose-dependent manner, and application of IP3 pathway antagonists not only significantly inhibited this induced Ca(2+) increase but also abolished NO-induced CM differentiation of ES cells. Subsequently, all 3 types of inositol 1, 4, 5-trisphosphate (IP3) receptors (IP3Rs) in mouse ES cells were individually or triply knocked down. Interestingly, only knockdown of type 3 IP3R (IP3R3) or triple-knockdown of three types of IP3Rs significantly inhibited the NO-induced Ca(2+) increases. Consistently, IP3R3 knockdown blocked the NO-induced CM differentiation of ES cells. CMs derived from IP3R3 knockdown ES cells also showed both structural and functional defects. In summary, our results indicate that the IP3R3-Ca(2+) pathway is required for NO-induced CM differentiation of ES cells.
Long Non-coding RNA H19 Inhibits Adipocyte Differentiation of Bone Marrow Mesenchymal Stem Cells through Epigenetic Modulation of Histone Deacetylases.Tuesday, June 28, 2016
Huang Y, Zheng Y, Jin C, Li X, Jia L, Li W,
Scientific reports. 2016
Bone marrow mesenchymal stem cells (BMSCs) exhibit an increased propensity toward adipocyte differentiation accompanied by a reduction in osteogenesis in osteoporotic bone marrow. However, limited knowledge is available concerning the role of long non-coding RNAs (lncRNAs) in the differentiation of BMSCs into adipocytes. In this study, we demonstrated that lncRNA H19 and microRNA-675 (miR-675) derived from H19 were significantly downregulated in BMSCs that were differentiating into adipocytes. Overexpression of H19 and miR-675 inhibited adipogenesis, while knockdown of their endogenous expression accelerated adipogenic differentiation. Mechanistically, we found that miR-675 targeted the 3' untranslated regions of the histone deacetylase (HDAC) 4-6 transcripts and resulted in deregulation of HDACs 4-6, essential molecules in adipogenesis. In turn, trichostatin A, an HDAC inhibitor, significantly reduced CCCTC-binding factor (CTCF) occupancy in the imprinting control region upstream of the H19 gene locus and subsequently downregulated the expression of H19. These results show that the CTCF/H19/miR-675/HDAC regulatory pathway plays an important role in the commitment of BMSCs into adipocytes.
Clinical Benefits of Stem Cells for Chronic Symptomatic Systolic Heart Failure A Systematic Review of the Existing Data and Ongoing Trials.Tuesday, June 28, 2016
Poulin MF, Deka A, Mohamedali B, Schaer GL,
Cell transplantation. 27-Jun-2016
The benefits of stem cell therapy for patients with chronic symptomatic systolic heart failure due to ischemic (ICM) and non-ischemic cardiomyopathy (NICM) are unclear. We performed a systematic review of major published and ongoing trials of stem cell therapy for systolic heart failure and compared measured clinical outcomes for both types of cardiomyopathy. The majority of the 29 published studies demonstrated clinical benefits of autologous bone marrow derived stem cells. Left ventricular ejection fraction (LVEF) was improved in the majority of trials after therapy. Cell delivery combined with coronary artery bypass grafting was associated with the greatest improvement in LVEF. Left ventricular end-systolic volume (or diameter), New York Heart Association functional classification, quality of life, and exercise capacity were also improved in most studies after cell therapy. Most ICM trials demonstrated a significant improvement in perfusion defects, infarct size and myocardial viability. Several larger clinical trials are in progress that employ alternative delivery modes, cell types and longer follow-up periods. Stem cells are a promising therapeutic modality for patients with heart failure due to ICM or NICM. More data is required from larger blinded trials to determine which combination of cell type and delivery mode will yield the most benefit with avoidance of harm in these patient populations.
Novel Therapeutic Effects of Non-thermal atmospheric pressure plasma for Muscle Regeneration and Differentiation.Tuesday, June 28, 2016
Choi JW, Kang SU, Kim YE, Park JK, Yang SS, Kim YS, Lee YS, Lee Y, Kim CH,
Scientific reports. 2016
Skeletal muscle can repair muscle tissue damage, but significant loss of muscle tissue or its long-lasting chronic degeneration makes injured skeletal muscle tissue difficult to restore. It has been demonstrated that non-thermal atmospheric pressure plasma (NTP) can be used in many biological areas including regenerative medicine. Therefore, we determined whether NTP, as a non-contact biological external stimulator that generates biological catalyzers, can induce regeneration of injured muscle without biomaterials. Treatment with NTP in the defected muscle of a Sprague Dawley (SD) rat increased the number of proliferating muscle cells 7 days after plasma treatment (dapt) and rapidly induced formation of muscle tissue and muscle cell differentiation at 14 dapt. In addition, in vitro experiments also showed that NTP could induce muscle cell proliferation and differentiation of human muscle cells. Taken together, our results demonstrated that NTP promotes restoration of muscle defects through control of cell proliferation and differentiation without biological or structural supporters, suggesting that NTP has the potential for use in muscle tissue engineering and regenerative therapies.
The Social Framework Surrounding the Development of Regenerative Medicine in Japan.Tuesday, June 28, 2016
Nakazawa E, Takimoto Y, Akabayashi A,
Cambridge quarterly of healthcare ethics : CQ : the international journal of healthcare ethics committees. Jul-2016
In 2014, the Japanese government amended the laws concerning regenerative medicine. This reform aimed to contribute to the appropriate promotion of regenerative medicine and new drug discovery for intractable diseases using stem cells. It also helped restrict stem cell tourism, that is, provision of stem cell therapy of unclear efficacy and safety to tourists from abroad, and its relaxed regulations may even lead to the resolution of the drug lag problem. Stem cell medicine is positioned as a part of a national growth strategy that requires cooperation among the industry, government, healthcare field, and academia. It can be characterized as a "mesoscopic strategy," in that it aims to achieve high-level technological developments that would allow results from human-induced pluripotent stem cell and traditional stem cell research to contribute to regenerative medicine and drug development for intractable diseases, while attempting to strike a balance with commercialization and improved access of citizens to cutting-edge medical care.
Stem cell transplantation outcomes in lymphoblastic lymphoma.Monday, June 27, 2016
Brammer JE, Khouri I, Marin D, Ledesma C, Rondon G, Ciurea SO, Nieto Y, Champlin RE, Hosing C, Kebriaei P,
Leukemia & lymphoma. 27-Jun-2016
Lymphoblastic lymphoma (LBL) is an aggressive lymphoma pathologically similar to lymphoblastic leukemia, but primarily presents with nodal or extra-medullary involvement. The aim of this study is to describe outcomes of patients undergoing stem cell transplantation (SCT) for LBL compared to historical data. Thirty-nine patients, of which 54% lacked complete remission (CR), received SCT for LBL between 1990 and 2015; 31 allogeneic and eight autologous. Overall survival (OS) and progression free survival (PFS) at three years for the entire cohort was 41%, the cumulative incidence (CI) of non-relapse mortality (NRM) was 18% at one year, and CI relapse mortality was 28% at one-year and 36% at three years; results similar to historical reports. On multivariate analysis, the use of total-body irradiation (TBI) based conditioning and transplantation in CR were independently predictive of OS and PFS. For patients requiring SCT for LBL, CR and TBI-based conditioning prior to allogeneic SCT may provide improved disease control.
Peripheral Motor and Sensory Nerve Conduction following Transplantation of Undifferentiated Autologous Adipose Tissue-Derived Stem Cells in a Biodegradable U.S. Food and Drug Administration-Approved Nerve Conduit.Tuesday, June 28, 2016
Klein SM, Vykoukal J, Li DP, Pan HL, Zeitler K, Alt E, Geis S, Felthaus O, Prantl L,
Plastic and reconstructive surgery. Jul-2016
Therapeutic, V.
Enhanced sensitivity of cancer stem cells to chemotherapy using functionalized mesoporous silica nanoparticles.Monday, June 27, 2016
Chen Z, Zhu P, Zhang Y, Liu Y, He Y, Zhang L, Gao YF,
Molecular pharmaceutics. 27-Jun-2016
Cancer stem cells (CSCs) are responsible for cancer drug resistance with high expression of ABCG2, which pumps the internalized chemotherapeutic out to escape drug-induced cytotoxicity. Here, we established a functionalized mesoporous silica nanoparticle (MSN) system to deliver shABCG2 and doxorubicin (Dox) synergistically. With excellent cell uptake and endosomal escape capacities, the dual-delivery carriers internalized shABCG2 and Dox into CSCs efficiently. ABCG2 depletion increased intracellular and intranuclear Dox enrichment, drove vigorous Dox-induced cell death, and impaired the self-renewal of CSCs. Additionally, the nanoparticles eliminated tumors efficiently and reduced tumor initiation by CSCs in vivo, with negligible side effects. Our findings suggest that well-designed delivery systems for conventional chemotherapeutic agents are promising for CSCs therapy.
Impact of fluorescent silicon nanoparticles on circulating hemolymph and hematopoiesis in an invertebrate model organism.Monday, June 27, 2016
Xing R, Li KL, Zhou YF, Su YY, Yan SQ, Zhang KL, Wu SC, Sima YH, Zhang KQ, He Y, Xu SQ,
Chemosphere. 24-Jun-2016
Silicon nanoparticles (SiNPs) have attractive potential applications in biological and medical fields, and yet their impact on animals is still controversial, and there have been no reports of their effects on hematopoiesis. In this study, the effects of SiNPs on hemocytes and hematopoiesis were investigated by administering SiNPs via a vascular injection into an invertebrate model, the silkworm. Our results show that the ability of SiNPs to enter different types of circulating hemocytes and their impact on those hemocytes differed significantly. Rapid accumulation of SiNPs was observed in granulocytes, oenocytoids, and spherulocytes, which have immune functions in the circulating hemolymph, whereas SiNPs did not easily enter prohemocytes, which can differentiate into granulocytes, oenocytoids, and spherulocytes and replenish them. The SiNPs that entered the hemocytes initiated autophagy and apoptosis via the lysosomal/mitochondrial pathway. High-dose SiNPs weakly stimulated lysosomal activity in hematopoietic organs, but did not lead to a significant increase in reactive oxygen species or severe autophagy or apoptosis in the organ tissues. We suggest that the damage caused by high-dose SiNPs to hematopoiesis is self-healing, because few SiNPs entered the hematopoietic stem cells in the circulating hemolymph, so the damage to the hematopoietic tissues was limited.
Effects of heterocyclic-based head group modifications on the structure-activity relationship of tocopherol-based lipids for non-viral gene delivery.Monday, June 27, 2016
Gosangi M, Mujahid TY, Gopal V, Patri SV,
Organic & biomolecular chemistry. 27-Jun-2016
Gene therapy, a promising strategy for the delivery of therapeutic nucleic acids, is greatly dependent on the development of efficient vectors. In this study, we designed and synthesized several tocopherol-based lipids varying in the head group region. Here, we present the structure-activity relationship of stable aqueous suspensions of lipids that were synthetically prepared and formulated with 1,2-dioleoyl phosphatidyl ethanolamine (DOPE) as the co-lipid. The physicochemical properties such as the hydrodynamic size, zeta potential, stability and morphology of these formulations were investigated. Interaction with plasmid DNA was clearly demonstrated through gel binding and EtBr displacement assays. Further, the transfection potential was examined in mouse neuroblastoma Neuro-2a, hepatocarcinoma HepG2, human embryonic kidney and Chinese hamster ovarian cell lines, all of different origins. Cell-uptake assays with N-methylpiperidinium, N-methylmorpholinium, N-methylimidazolium and N,N-dimethylaminopyridinium head group containing formulations evidently depicted efficient cell uptake as observed by particulate cytoplasmic fluorescence. Trafficking of lipoplexes using an endocytic marker and rhodamine-labeled phospholipid DHPE indicated that the lipoplexes were not sequestered in the lysosomes. Importantly, lipoplexes were non-toxic and mediated good transfection efficiency as analyzed by β-Gal and GFP reporter gene expression assays which established the superior activity of lipids whose structures correlate strongly with the transfection efficiency.
Unusual magnetic resonance imaging presentation of post-BMT cerebral toxoplasmosis masquerading as meningoencephalitis and ventriculitis.Monday, June 27, 2016
Helton KJ, Maron G, Mamcarz E, Leventaki V, Patay Z, Sadighi Z,
Bone marrow transplantation. 27-Jun-2016
Paneth Cell-Rich Regions Separated by a Cluster of Lgr5+ Cells Initiate Crypt Fission in the Intestinal Stem Cell Niche.Tuesday, June 28, 2016
Langlands AJ, Almet AA, Appleton PL, Newton IP, Osborne JM, Näthke IS,
PLoS biology. Jun-2016
The crypts of the intestinal epithelium house the stem cells that ensure the continual renewal of the epithelial cells that line the intestinal tract. Crypt number increases by a process called crypt fission, the division of a single crypt into two daughter crypts. Fission drives normal tissue growth and maintenance. Correspondingly, it becomes less frequent in adulthood. Importantly, fission is reactivated to drive adenoma growth. The mechanisms governing fission are poorly understood. However, only by knowing how normal fission operates can cancer-associated changes be elucidated. We studied normal fission in tissue in three dimensions using high-resolution imaging and used intestinal organoids to identify underlying mechanisms. We discovered that both the number and relative position of Paneth cells and Lgr5+ cells are important for fission. Furthermore, the higher stiffness and increased adhesion of Paneth cells are involved in determining the site of fission. Formation of a cluster of Lgr5+ cells between at least two Paneth-cell-rich domains establishes the site for the upward invagination that initiates fission.
Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense.Monday, June 27, 2016
Garaude J, Acín-Pérez R, Martínez-Cano S, Enamorado M, Ugolini M, Nistal-Villán E, Hervás-Stubbs S, Pelegrín P, Sander LE, Enríquez JA, Sancho D,
Nature immunology. 27-Jun-2016
Macrophages tightly scale their core metabolism after being activated, but the precise regulation of the mitochondrial electron-transport chain (ETC) and its functional implications are currently unknown. Here we found that recognition of live bacteria by macrophages transiently decreased assembly of the ETC complex I (CI) and CI-containing super-complexes and switched the relative contributions of CI and CII to mitochondrial respiration. This was mediated by phagosomal NADPH oxidase and the reactive oxygen species (ROS)-dependent tyrosine kinase Fgr. It required Toll-like receptor signaling and the NLRP3 inflammasome, which were both connected to bacterial viability-specific immune responses. Inhibition of CII during infection with Escherichia coli normalized serum concentrations of interleukin 1β (IL-1β) and IL-10 to those in mice treated with dead bacteria and impaired control of bacteria. We have thus identified ETC adaptations as an early immunological-metabolic checkpoint that adjusts innate immune responses to bacterial infection.
Targeting Colorectal Cancer Stem-Like Cells with Anti-CD133 Antibody-Conjugated SN-38 Nanoparticles.Monday, June 27, 2016
Ning ST, Lee SY, Wei MF, Peng CL, Lin SY, Tsai MH, Lee PC, Shih YH, Lin CY, Luo TY, Shieh MJ,
ACS applied materials & interfaces. 27-Jun-2016
Cancer stem-like cells play a key role in tumor development, and these cells are relevant to the failure of conventional chemotherapy. To achieve favorable therapy for colorectal cancer, PEG-PCL-based nanoparticles, which possess good biological compatibility, were fabricated as nanocarriers for the topoisomerase inhibitor, SN-38. For cancer stem cell therapy, CD133 (prominin-1) is a theoretical cancer stem-like cell (CSLC) marker for colorectal cancer and is a proposed therapeutic target. Cells with CD133 overexpression have demonstrated enhanced tumor-initiating ability and tumor relapse probability. To resolve the problem of chemotherapy failure, SN-38-loaded nanoparticles were conjugated with anti-CD133 antibody to target CD133- positive (CD133+) cells. In this study, anti-CD133 antibody-conjugated SN-38-loaded nanoparticles (CD133Ab-NPs-SN-38) efficiently bound to HCT116 cells, which overexpress CD133 glycoprotein. The cytotoxic effect of CD133Ab-NPs-SN-38 was greater than that of non- targeted nanoparticles (NPs-SN-38) in HCT116 cells. Furthermore, CD133Ab-NPs-SN-38 could target CD133+ cells and inhibit colony formation compared with NPs-SN-38. In vivo studies in an HCT116 xenograft model revealed that CD133Ab-NPs-SN-38 suppressed tumor growth and retarded recurrence. A reduction in CD133 expression in HCT116 cells treated with CD133Ab- NPs-SN-38 was also observed in immunohistochemistry results. Therefore, this CD133-targeting nanoparticle delivery system could eliminate CD133-positive cells and is a potential cancer stem cell targeted therapy.
Development of Causative Treatment Strategies for Lacrimal Gland Insufficiency by Tissue Engineering and Cell Therapy. Part 2: Reconstruction of Lacrimal Gland Tissue: What Has Been Achieved So Far and What Are the Remaining Challenges?Monday, June 27, 2016
Massie I, Dietrich J, Roth M, Geerling G, Mertsch S, Schrader S,
Current eye research. 27-Jun-2016
The lacrimal gland is located in the upper temporal compartment of the orbita, and along with the ocular surface, eye lids, and sensory and motor nerves forms the lacrimal functional unit (LFU). The LFU is responsible for producing, distributing, and maintaining the tear film in order to maintain a smooth, moist, and regular ocular surface epithelium such that appropriate refractive properties are achieved and the eyeball is protected against dust, debris, and pathogens. If the main lacrimal gland is impaired (due to either disease or injury), this balance is disrupted, and severe quantitative dry eye syndrome (DES) can develop. DES treatments remain palliative, with the most commonly used therapies being based on tear substitution, tear retention, and control of inflammation on the ocular surface. Causative treatments such as salivary gland transplantation have shown to reduce symptoms in very severe cases, however can cause problems on the ocular surface due to different properties of saliva and tears. Therefore, causative approaches for treating DES by regeneration or reconstruction of lacrimal gland tissue depending on disease severity seem highly appealing. This article reviews current approaches for in vitro reconstruction of lacrimal gland tissue. Finally, the limitations that must be overcome before a new, tissue-engineered therapy may be delivered to clinic will be discussed.
Fibrin-based stem cell containing scaffold improves the dynamics of burn wound healing.Monday, June 27, 2016
Chung E, Rybalko VY, Hsieh PL, Leal SL, Samano MA, Willauer AN, Stowers RS, Natesan S, Zamora DO, Christy RJ, Suggs LJ,
Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society. 27-Jun-2016
For severe burn injuries, successful medical intervention is accomplished by rapidly and safely providing physical barriers that can cover damaged skin tissues, thereby preventing critical danger of extensive bleeding and infection. Despite availability of a large assortment of wound coverage options, the etiology of wound healing is rather complex leading to significant defects in skin repair. The use of cell-mediated treatment approaches in combination with bioengineered wound coverage constructs may provide the missing tool to improve wound healing outcomes. In this study, we have used an engineered 3D PEGylated fibrin (P-fibrin) gel as a scaffold for adipose derived stem cells (ASCs) delivery into the burn injury model. We were able to confirm the presence of ASCs in the wound site two weeks after the initial injury. Delivery of ASCs-containing gels was associated with improved vascularization of the injured area at early time points accompanied by an increased abundance of mannose receptor expressing cells. Moreover, the application of P-fibrin biomaterial exhibited positive effects on early mononuclear cell recruitment and granulation tissue formation without negatively affecting wound closure kinetics or extent of connective tissue deposition. Collectively, our data support the feasibility of using P-fibrin gels in wound dressing applications requiring controlled delivery of viable cells. This article is protected by copyright. All rights reserved.
The Clock mutant mouse is a novel experimental model for nocturia and nocturnal polyuria.Monday, June 27, 2016
Ihara T, Mitsui T, Nakamura Y, Kira S, Miyamoto T, Nakagomi H, Sawada N, Hirayama Y, Shibata K, Shigetomi E, Shinozaki Y, Yoshiyama M, Andersson KE, Nakao A, Takeda M, Koizumi S,
Neurourology and urodynamics. 27-Jun-2016
We demonstrated that Clock(Δ19/Δ19) mice showed the phenotype of NOC/NP. The Clock(Δ19/Δ19) mouse may be used as an animal model of NOC and NP. Neurourol. Urodynam. © 2016 Wiley Periodicals, Inc.
Stem Cell Activation in Adult Organisms.Tuesday, June 28, 2016
Bloch W,
International journal of molecular sciences. 2016
Stem cells are responsible for the organ and tissue development, growth and maintenance from embryonic stage up to late adult life.[...].
Site-Specific Genome Engineering in Human Pluripotent Stem Cells.Tuesday, June 28, 2016
Merkert S, Martin U,
International journal of molecular sciences. 2016
The possibility to generate patient-specific induced pluripotent stem cells (iPSCs) offers an unprecedented potential of applications in clinical therapy and medical research. Human iPSCs and their differentiated derivatives are tools for diseases modelling, drug discovery, safety pharmacology, and toxicology. Moreover, they allow for the engineering of bioartificial tissue and are promising candidates for cellular therapies. For many of these applications, the ability to genetically modify pluripotent stem cells (PSCs) is indispensable, but efficient site-specific and safe technologies for genetic engineering of PSCs were developed only recently. By now, customized engineered nucleases provide excellent tools for targeted genome editing, opening new perspectives for biomedical research and cellular therapies.
Three-dimensional mapping and regulation of action potential propagation in nanoelectronics-innervated tissues.Monday, June 27, 2016
Dai X, Zhou W, Gao T, Liu J, Lieber CM,
Nature nanotechnology. 27-Jun-2016
Real-time mapping and manipulation of electrophysiology in three-dimensional (3D) tissues could have important impacts on fundamental scientific and clinical studies, yet realization is hampered by a lack of effective methods. Here we introduce tissue-scaffold-mimicking 3D nanoelectronic arrays consisting of 64 addressable devices with subcellular dimensions and a submillisecond temporal resolution. Real-time extracellular action potential (AP) recordings reveal quantitative maps of AP propagation in 3D cardiac tissues, enable in situ tracing of the evolving topology of 3D conducting pathways in developing cardiac tissues and probe the dynamics of AP conduction characteristics in a transient arrhythmia disease model and subsequent tissue self-adaptation. We further demonstrate simultaneous multisite stimulation and mapping to actively manipulate the frequency and direction of AP propagation. These results establish new methodologies for 3D spatiotemporal tissue recording and control, and demonstrate the potential to impact regenerative medicine, pharmacology and electronic therapeutics.
Assessment of regeneration in meniscal lesions by use of mesenchymal stem cells derived from equine bone marrow and adipose tissue.Tuesday, June 28, 2016
González-Fernández ML, Pérez-Castrillo S, Sánchez-Lázaro JA, Prieto-Fernández JG, López-González ME, Lobato-Pérez S, Colaço BJ, Olivera ER, Villar-Suárez V,
American journal of veterinary research. Jul-2016
OBJECTIVE To assess the ability to regenerate an equine meniscus by use of a collagen repair patch (scaffold) seeded with mesenchymal stem cells (MSCs) derived from bone marrow (BM) or adipose tissue (AT). SAMPLE 6 female Hispano-Breton horses between 4 and 7 years of age; MSCs from BM and AT were obtained for the in vitro experiment, and the horses were subsequently used for the in vivo experiment. PROCEDURES Similarities and differences between MSCs derived from BM or AT were investigated in vitro by use of cell culture. In vivo assessment involved use of a meniscus defect and implantation on a scaffold. Horses were allocated into 2 groups. In one group, defects in the medial meniscus were treated with MSCs derived from BM, whereas in the other group, defects were treated with MSCs derived from AT. Defects were created in the contralateral stifle joint but were not treated (control samples). RESULTS Both types of MSCs had universal stem cell characteristics. For in vivo testing, at 12 months after treatment, treated defects were regenerated with fibrocartilaginous tissue, whereas untreated defects were partially repaired or not repaired. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that MSCs derived from AT could be a good alternative to MSCs derived from BM for use in regenerative treatments. Results also were promising for a stem cell-based implant for use in regeneration in meniscal lesions. IMPACT FOR HUMAN MEDICINE Because of similarities in joint disease between horses and humans, these results could have applications in humans.
Telomerase and estrogen-sensing activities are essential for continued mammary growth in vivo but dispensable for "reprogramming" neural stem cells.Monday, June 27, 2016
George AL, Boulanger CA, Smith GH,
Aging. 24-Jun-2016
It has been proposed that the erosion of telomere length is a limiting factor in replicative capacity and important in cell senescence. To determine if this activity was essential in the mouse mammary gland in vivo, we serially transplanted mammary fragments from wild type (TER+/+), heterozygous (TER+/-), and homozygous (TER-/-) mammary tissues into the cleared mammary fat pads of immune-compromised nude mice. Individual implants from both homozygous and heterozygous TER null outgrowths showed growth senescence beginning at transplant generation two, earlier than implants from TER+/+ mammary glands which continued to show growth. This result suggests that either mammary epithelial stem cells maintain their telomere length in order to self renew, or that the absence or reduction of telomerase template results in more frequent death/extinction of stem cells during symmetric divisions. A third possibility is the inability of signaling cells in the niche to replicate resulting in reduction of the maintenance signals necessary for stem cell renewal. Consistent with this, examination of senescent outgrowths revealed the absence of estrogen receptor alpha (ERα+) epithelium although progesterone receptor (PR+) cells were abundant. Despite their inability to establish mammary growth in vivo, TER+/- cells were able to direct neural stem cells to mammary cell fates.
Clinical manufacturing of CAR T cells: foundation of a promising therapy.Monday, June 27, 2016
Wang X, Rivière I,
Molecular therapy oncolytics. 2016
The treatment of cancer patients with autologous T cells expressing a chimeric antigen receptor (CAR) is one of the most promising adoptive cellular therapy approaches. Reproducible manufacturing of high-quality, clinical-grade CAR-T cell products is a prerequisite for the wide application of this technology. Product quality needs to be built-in within every step of the manufacturing process. We summarize herein the requirements and logistics to be considered, as well as the state of the art manufacturing platforms available. CAR-T cell therapy may be on the verge of becoming standard of care for a few clinical indications. Yet, many challenges pertaining to manufacturing standardization and product characterization remain to be overcome in order to achieve broad usage and eventual commercialization of this therapeutic modality.
Oncolytic herpes simplex virus kills stem-like tumor-initiating colon cancer cells.Monday, June 27, 2016
Warner SG, Haddad D, Au J, Carson JS, O'Leary MP, Lewis C, Monette S, Fong Y,
Molecular therapy oncolytics. 2016
Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection.
Role of Chondrocytes in Cartilage Formation, Progression of Osteoarthritis and Cartilage Regeneration.Monday, June 27, 2016
Akkiraju H, Nohe A,
Journal of developmental biology. Dec-2015
Articular cartilage (AC) covers the diarthrodial joints and is responsible for the mechanical distribution of loads across the joints. The majority of its structure and function is controlled by chondrocytes that regulate Extracellular Matrix (ECM) turnover and maintain tissue homeostasis. Imbalance in their function leads to degenerative diseases like Osteoarthritis (OA). OA is characterized by cartilage degradation, osteophyte formation and stiffening of joints. Cartilage degeneration is a consequence of chondrocyte hypertrophy along with the expression of proteolytic enzymes. Matrix Metalloproteinases (MMPs) and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) are an example of these enzymes that degrade the ECM. Signaling cascades involved in limb patterning and cartilage repair play a role in OA progression. However, the regulation of these remains to be elucidated. Further the role of stem cells and mature chondrocytes in OA progression is unclear. The progress in cell based therapies that utilize Mesenchymal Stem Cell (MSC) infusion for cartilage repair may lead to new therapeutics in the long term. However, many questions are unanswered such as the efficacy of MSCs usage in therapy. This review focuses on the role of chondrocytes in cartilage formation and the progression of OA. Moreover, it summarizes possible alternative therapeutic approaches using MSC infusion for cartilage restoration.
Exosome-mediated transfer from the tumor microenvironment increases TGFβ signaling in squamous cell carcinoma.Monday, June 27, 2016
Languino LR, Singh A, Prisco M, Inman GJ, Luginbuhl A, Curry JM, South AP,
American journal of translational research. 2016
Transforming growth factor-beta (TGFβ) signaling in cancer is context dependent and acts either as a tumor suppressor or a tumor promoter. Loss of function mutation in TGFβ type II receptor (TβRII) is a frequent event in oral cavity squamous cell carcinoma (SCC). Recently, heterogeneity of TGFβ response has been described at the leading edge of SCC and this heterogeneity has been shown to influence stem cell renewal and drug resistance. Because exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways we investigated whether exosomes contain components of the TGFβ signaling pathway and whether exosome transfer between stromal fibroblasts and tumor cells can influence TGFβ signaling in SCC. We demonstrate that exosomes purified from stromal fibroblasts isolated from patients with oral SCC contains TβRII. We also demonstrate that transfer of fibroblast exosomes increases TGFβ signaling in SCC keratinocytes devoid of TβRII which remain non-responsive to TGFβ ligand in the absence of exosome transfer. Overall our data show that stromal communication with tumor cells can direct TGFβ signaling in SCC.
Autologous preconditioned mesenchymal stem cell sheets improve left ventricular function in a rabbit old myocardial infarction model.Monday, June 27, 2016
Tanaka Y, Shirasawa B, Takeuchi Y, Kawamura D, Nakamura T, Samura M, Nishimoto A, Ueno K, Morikage N, Hosoyama T, Hamano K,
American journal of translational research. 2016
Mesenchymal stem cells (MSCs) constitute one of the most powerful tools for therapeutic angiogenesis in infarcted hearts. However, conventional MSC transplantation approaches result in insufficient therapeutic effects due to poor retention of graft cells in severe ischemic diseases. Cell sheet technology has been developed as a new method to prolong graft cell retention even in ischemic tissue. Recently, we demonstrated that hypoxic pretreatment enhances the therapeutic efficacy of cell sheet implantation in infarcted mouse hearts. In this study, we investigated whether hypoxic pretreatment activates the therapeutic functions of bone marrow-derived MSC (BM-MSC) sheets and improves cardiac function in rabbit infarcted hearts following autologous transplantation. Production of vascular endothelial growth factor (VEGF) was increased in BM-MSC monolayer sheets and it peaked at 48 h under hypoxic culture conditions (2% O2). To examine in vivo effects, preconditioned autologous BM-MSC sheets were implanted into a rabbit old myocardial infarction model. Implantation of preconditioned BM-MSC sheets accelerated angiogenesis in the peri-infarcted area and decreased the infarcted area, leading to improvement of the left ventricular function of the infarcted heart. Importantly, the therapeutic efficacy of the preconditioned BM-MSC sheets was higher than that of standardly cultured sheets. Thus, implantation of autologous preconditioned BM-MSC sheets is a feasible approach for enhancing therapeutic angiogenesis in chronically infarcted hearts.
Modulation of mesenchymal stem cells with miR-375 to improve their therapeutic outcome during scar formation.Monday, June 27, 2016
Sheng W, Feng Z, Song Q, Niu H, Miao G,
American journal of translational research. 2016
Understanding of the mechanism of cutaneous scar formation with the goal of developing potential therapies to promote scar-less wound healing appears to be extremely critical. Mesenchymal stem cells (MSCs) have a demonstrate role in promoting scar-less wound healing. However, recent studies have shown that the function of MSCs may be attenuated due to insufficient activation in vivo. Here, we aimed to increase the activity and functions of MSCs to improve their effects during scar formation. We found that overexpression of microRNA-375 (miR-375) in MSCs significantly decreased the levels of tissue inhibitor of metalloproteinases 1 (TIMP-1) protein, but not mRNA. Mechanistically, miR-375 inhibited TIMP-1 protein translation through binding to the 3'-UTR of the TIMP-1 mRNA in MSCs. Transplantation of miR-375-expressing MSCs significantly reduced the fibrosis in the scar region of the mice, possibly through reduction of reactive oxygen species (ROS), suppression of transition of myofibroblasts from fibroblasts, and increases in hepatic growth factor (HGF). Together, these data suggest that overexpression of miR-375 in MSCs may substantially improve the effects of MSCs on reduction of scar during wound healing. Our study sheds new light on a scar-less wound healing.
Rat adipose-derived stem cells express low level of α-Gal and are dependent on CD59 for protection from human xenoantibody and complement-mediated lysis.Monday, June 27, 2016
Jia Y, Zhao Y, Wang L, Xiang Y, Chen S, Ming CS, Wang CY, Chen G,
American journal of translational research. 2016
Since increasing evidence has indicated that adipose-derived stem cells (ASCs) can function across the species barrier, the use of xenogeneic ASCs may be a practical alternative to the autotransplantation and allotransplantation. Before animal ASCs can be used clinically, evidence needs to be provided to indicate whether they will survive in a human host. In the present study, we investigated whether rat ASCs (rASCs) could resist human xenoantibody and complement-mediated lysis as well as investigated the possible mechanisms involved. We found that rASCs could significantly resist human natural antibody and complement-mediated cytotoxicity when incubated with 20% or 50% normal human serum (NHS) in vitro, as compared with rat lymphocytes (rLCs). Mechanistically, rASCs expressed lower level of xenoantigen Galα1-3Galβ1-4GlcNAc (α-Gal), which was correlated with decreased binding of human xenoreactive IgG and IgM and reduced deposition of complement C3c and C4c. More interestingly, rASCs had minimal deposition of human membrane attack complex (C5b-9). When the expression of CD55 and CD59 was analyzed by flow cytometry, we found that rASCs expressed very weak CD55 but expressed much higher level of CD59 than rLCs. Moreover, the knockdown of CD59 expression by siRNA largely reversed the resistance of rASCs to the human serum-mediated lysis. Taken together, these data have demonstrated for the first time that rat ASCs are capable to protect themselves from human xenoantibody and complement-mediated lysis, which is dependent on CD59 and is correlated with low expression of α-Gal. Xenogenic ASCs may have the potential to treat patients in the future.
Concerted changes in transcriptional regulation of genes involved in DNA methylation, demethylation, and folate-mediated one-carbon metabolism pathways in the NCI-60 cancer cell line panel in response to cancer drug treatment.Monday, June 27, 2016
Krushkal J, Zhao Y, Hose C, Monks A, Doroshow JH, Simon R,
Clinical epigenetics. 2016
These transcriptional changes are likely to influence vital cellular functions of DNA methylation and demethylation, cellular growth, DNA biosynthesis, and DNA repair, and some of them may contribute to cytotoxic and apoptotic action of the drugs. This concerted molecular response was observed in a time-dependent manner, which may provide future guidelines for temporal selection of genetic drug targets for combination drug therapy treatment regimens.
Resistance of papillary thyroid cancer stem cells to chemotherapy.Monday, June 27, 2016
Giuffrida R, Adamo L, Iannolo G, Vicari L, Giuffrida D, Eramo A, Gulisano M, Memeo L, Conticello C,
Oncology letters. Jul-2016
Thyroid carcinoma is the most common endocrine neoplasm, with the highest mortality rate of all the endocrine cancers. Among the endocrine malignancies, ~80% are papillary thyroid carcinomas (PTCs). In the initiation and progression of this tumor, genetic alterations in the mitogen-associated protein kinase pathway, including RAS point mutations, RET/PTC oncogene rearrangements and BRAF point mutations, play an important role, particularly in deciding targeted therapy. In the present study, a small population of thyroid tumor cells, known as tumor spheres, were isolated and characterized from PTC surgical samples. These spheres can be expanded indefinitely in vitro and give rise to differentiated adherent cells when cultivated in differentiative conditions. The present study showed by reverse transcription-polymerase chain reaction and flow cytometric analysis that the undifferentiated PTC cells exhibited a characteristic antigen expression profile of adult progenitor/stem cells. The cells were more resistant to chemotherapeutics, including bortezomib, taxol, cisplatin, etoposide, doxorubicin and vincristine, than differentiated PTC cells and the majority possessed a quiescent status, as revealed by the various cell cycle characteristics and anti-apoptotic protein expression. Such advances in cancer thyroid stem cell biology may provide relevant information for future targeted therapies.
Bone mesenchymal stem cells differentiate into myofibroblasts in the tumor microenvironment.Monday, June 27, 2016
Zhang J, Sun D, Fu Q, Cao Q, Zhang H, Zhang K,
Oncology letters. Jul-2016
The aim of the present study was to investigate the tropism of mesenchymal stem cells (MSCs) to the tumor microenvironment, and to evaluate the feasibility of bone marrow mesenchymal stem cells differentiating into myofibroblasts in vitro. A total of 1 ml bone marrow was extracted from the greater trochanter of one male New Zealand rabbit, and MSCs were obtained by density gradient centrifugation and cultured routinely. The surface markers were analyzed by flow cytometry. A VX2 tumor was aseptically excised from another male New Zealand rabbit and primary cultured. The tropism of MSCs for 30% and 50% VX2 conditioned medium was determined by using Transwell migration assays. MSCs were incubated in 30% VX2 conditioned medium for 7 or 14 days. The messenger (m)RNA levels and protein expression of α-smooth muscle actin (α-SMA) and vimentin were measured by reverse transcription-polymerase chain reaction and western blotting. MSCs were observed to have a spindle shape. The cultured MSCs were cluster of differentiation (CD)44(+), CD105(+), CD106(+) and CD34(-). VX2 cells demonstrated a spindle or polygon shape. In the Transwell assay, it was observed that the migrated cells appeared more frequently in the 30% VX2 conditioned medium group compared with the other groups when microscopically examined, which was additionally confirmed by the results of a colorimetric assay. The mRNA levels and protein expression of α-SMA and vimentin significantly increased in the test group compared with the control group at 7 days (P<0.01), and further increased in the test group at 14 days (P<0.01). The results of the present study demonstrated that MSCs have tropism for the tumor microenvironment and furthermore, may differentiate into myofibroblasts in the tumor microenvironment in vitro. The present study suggested that MSCs may migrate to the tumor and subsequently differentiate into myofibroblasts due to the tumor microenvironment, which may lead to promotion of the growth of the tumor. The present study additionally suggested that MSCs may be the precursors of tumor/carcinoma-associated myofibroblasts.
Power of PTEN/AKT: Molecular switch between tumor suppressors and oncogenes.Monday, June 27, 2016
Xie Y, Naizabekov S, Chen Z, Tokay T,
Oncology letters. Jul-2016
An increasing amount of evidence has shown that tumor suppressors can become oncogenes, or vice versa, but the mechanism behind this is unclear. Recent findings have suggested that phosphatase and tensin homolog (PTEN) is one of the powerful switches for the conversion between tumor suppressors and oncogenes. PTEN regulates a number of cellular processes, including cell death and proliferation, through the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Furthermore, a number of studies have suggested that PTEN deletions may alter various functions of certain tumor suppressor and oncogenic proteins. The aim of the present review was to analyze specific cases driven by PTEN loss/AKT activation, including aberrant signaling pathways and novel drug targets for clinical application in personalized medicine. The findings illustrate how PTEN loss and/or AKT activation switches MDM2-dependent p53 downregulation, and induces conversion between oncogene and tumor suppressor in enhancer of zeste homolog 2, BTB domain-containing 7A, alternative reading frame 2, p27 and breast cancer 1, early onset, through multiple mechanisms. This review highlights the genetic basis of complex drug targets and provides insights into the rationale of precision cancer therapy.
Hypoxia regulates the expression of tissue factor pathway signaling elements in a rat glioma model.Monday, June 27, 2016
Monteiro RQ, Lima LG, Gonçalves NP, DE Souza MR, Leal AC, Demasi MA, Sogayar MC, Carneiro-Lobo TC,
Oncology letters. Jul-2016
Hypoxia and necrosis are fundamental features of glioma, and their emergence is critical for the rapid biological progression of this fatal tumor. The presence of vaso-occlusive thrombus is higher in grade IV tumors [glioblastoma multiforme (GBM)] compared with lower grade tumors, suggesting that the procoagulant properties of the tumor contribute to its aggressive behavior, as well as the establishment of tumor hypoxia and necrosis. Tissue factor (TF), the primary cellular initiator of coagulation, is overexpressed in GBMs and likely favors a thrombotic microenvironment. Phosphatase and tensin homolog (PTEN) loss and hypoxia are two common alterations observed in glioma that may be responsible for TF upregulation. In the present study, ST1 and P7 rat glioma lines, with different levels of aggressiveness, were comparatively analyzed with the aim of identifying differences in procoagulant mechanisms. The results indicated that P7 cells display potent procoagulant activity compared with ST1 cells. Flow cytometric analysis showed less pronounced levels of TF in ST1 cells compared with P7 cells. Notably, P7 cells supported factor X (FX) activation via factor VIIa, whereas no significant FXa generation was observed in ST1 cells. Furthermore, the exposure of phosphatidylserine on the surface of P7 and ST1 cells was investigated. The results supported the assembly of prothrombinase complexes, accounting for the production of thrombin. Furthermore, reverse transcription-quantitative polymerase chain reaction showed that CoCl2 (known to induce a hypoxic-like stress) led to an upregulation of TF levels in P7 and ST1 cells. Therefore, increased TF expression in P7 cells was accompanied by increased TF procoagulant activity. In addition, hypoxia increased the shedding of procoagulant TF-bearing microvesicles in both cell lines. Finally, hypoxic stress induced by treatment with CoCl2 upregulated the expression of the PAR1 receptor in both P7 and ST1 cells. In addition to PAR1, P7, but not ST1 cells, expressed higher levels of PAR2 under hypoxic stress. Thus, modulating these molecular interactions may provide additional insights for the development of more efficient therapeutic strategies against aggressive glioma.
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