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Stem Cells
A gene network regulated by FGF signalling during ear development
Jul 22, 2017   Scientific Reports
Anwar M, Tambalo M, Ranganathan R, Grocott T, Streit A
A gene network regulated by FGF signalling during ear development
Jul 22, 2017
Scientific Reports
During development cell commitment is regulated by inductive signals that are tightly controlled in time and space. In response, cells activate specific programmes, but the transcriptional circuits that maintain cell identity in a changing signalling environment are often poorly understood. Specification of inner ear progenitors is initiated by FGF signalling. Here, we establish the genetic hierarchy downstream of FGF by systematic analysis of many ear factors combined with a network inference approach. We show that FGF rapidly activates a small circuit of transcription factors forming positive feedback loops to stabilise otic progenitor identity. Our predictive network suggests that subsequently, transcriptional repressors ensure the transition of progenitors to mature otic cells, while simultaneously repressing alternative fates. Thus, we reveal the regulatory logic that initiates ear formation and highlight the hierarchical organisation of the otic gene network.
Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study
Jul 24, 2017   The Lancet. Oncology
Wolthers BO, Frandsen TL, Baruchel A, Attarbaschi A, Barzilai S,   . . . . . .   , Vrooman LM, Yano M, Zapotocka E, Schmiegelow K, Ponte di Legno Toxicity Working Group
Asparaginase-associated pancreatitis in childhood acute lymphoblastic leukaemia: an observational Ponte di Legno Toxicity Working Group study
Jul 24, 2017
The Lancet. Oncology
Survival for childhood acute lymphoblastic leukaemia surpasses 90% with contemporary therapy; however, patients remain burdened by the severe toxic effects of treatment, including asparaginase-associated pancreatitis. To investigate the risk of complications and risk of re-exposing patients with asparaginase-associated pancreatitis to asparaginase, 18 acute lymphoblastic leukaemia trial groups merged data for this observational study. Patient files from 26 trials run by 18 trial groups were reviewed on children (aged 1·0-17·9 years) diagnosed with t(9;22)-negative acute lymphoblastic leukaemia between June 1, 1996, and Jan 1, 2016, who within 50 days of asparaginase exposure developed asparaginase-associated pancreatitis. Asparaginase-associated pancreatitis was defined by at least two criteria: abdominal pain, pancreatic enzymes at least three times the upper limit of normal (ULN), and imaging compatible with pancreatitis. Patients without sufficient data for diagnostic criteria were excluded. Primary outcomes were defined as acute and persisting complications of asparaginase-associated pancreatitis and risk of re-exposing patients who suffered an episode of asparaginase-associated pancreatitis to asparaginase. Data were collected from Feb 2, 2015, to June 30, 2016, and analysed and stored in a common database at Rigshospitalet, Copenhagen, Denmark. Of 465 patients with asparaginase-associated pancreatitis, 33 (8%) of 424 with available data needed mechanical ventilation, 109 (26%) of 422 developed pseudocysts, acute insulin therapy was needed in 81 (21%) of 393, and seven (2%) of 458 patients died. Risk of assisted mechanical ventilation, need for insulin, pseudocysts, or death was associated with older age (median age for patients with complications 10·5 years [IQR 6·4-13·8] vs without complications 6·1 years [IQR 3·6-12·2], p
Haploidentical transplantation compared with matched sibling and unrelated donor transplantation for adults with standard-risk acute lymphoblastic leukaemia in first complete remission
Jul 24, 2017   British Journal Of Haematology
Han LJ, Wang Y, Fan ZP, Huang F, Zhou J, Fu YW, Qu H, Xuan L, Xu N, Ye JY, Bian ZL, Song YP, Huang XJ, Liu QF
Haploidentical transplantation compared with matched sibling and unrelated donor transplantation for adults with standard-risk acute lymphoblastic leukaemia in first complete remission
Jul 24, 2017
British Journal Of Haematology
We retrospectively investigated outcomes of haploidentical donor (HID) transplant for adults with standard-risk acute lymphoblastic leukaemia (ALL) in first complete remission (CR1) compared with human leucocyte antigen (HLA)-matched sibling donor (MSD) and HLA-matched unrelated donor (MUD) transplants. A total of 348 adult patients were enrolled, including 127 HID, 144 MSD and 77 MUD recipients. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 39·5%, 24·0% and 40·3% for HID, MSD and MUD, respectively (P = 0·020). However, there was no difference in grade III-IV aGVHD (11·4%, 7·7%, 13·5%, respectively, P = 0·468). The 5-year cumulative transplant-related mortality was 16·4%, 11·6% and 19·6% (P = 0·162), the 5-year relapse rate post-transplantation was 14·8%, 21·1% and 16·7% (P = 0·231), the 5-year overall survival was 70·1%, 73·7% and 69·8% (P = 0·525), and the 5-year disease-free survival was 68·7%, 67·3% and 63·7%, respectively (P = 0·606). Furthermore, the 3-year GVHD-free, relapse-free survival was not different (50·8%, 54·9% and 52·2%, respectively, P = 0·847). Our results indicate that the outcomes of HID transplants are equivalent to those of MSD and MUD, and that HID transplantation is a valid alternative for standard-risk adults with ALL in CR1 who lack matched donors. © 2017 John Wiley & Sons Ltd.
Controlled Exposure of Bioactive Growth Factor in 3D Amyloid Hydrogel for Stem Cells Differentiation
Jul 24, 2017   Advanced Healthcare Materials
Das S, Kumar R, Jha NN, Maji SK
Controlled Exposure of Bioactive Growth Factor in 3D Amyloid Hydrogel for Stem Cells Differentiation
Jul 24, 2017
Advanced Healthcare Materials
Amyloid based hydrogels can mimic the extracellular matrix and serve as matrices for tissue engineering both in vitro and in vivo. A pH responsive self-assembled amyloid hydrogel system is used to encapsulate various growth factors for driving stem cell differentiation toward neuronal lineage. Diffusion studies with fluorescence recovery after photobleaching and bulk release with the model protein fluorescein isothiocyanate-bovine serum albumin show that encapsulated protein molecules can be released in a sustained fashion from the hydrogel over a considerable period of time (30 d). Moreover, by modulating the porosity of the hydrogel by the simple addition of salt, the encapsulated protein molecules can be retained for a longer period of time within the hydrogel. Mesenchymal stem cells, when cultured in 3D amyloid hydrogels with growth factors fibroblast growth factor 8 and sonic hedgehog, show more neuron specific differentiation as compared to hydrogel alone. This higher differentiation potential of growth factor encapsulated amyloid hydrogels can be due to concomitant exposure of cells to biomechanical as well as biochemical cues during the course of differentiation. The present study suggests that amyloid based hydrogel can be exploited for controlled growth factor delivery as well as directed stem cell differentiation to neuron. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
The clinical significance of monitoring the expression of the SIL-TAL1 fusion gene in T-cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation
Jul 24, 2017   International Journal Of Laboratory Hematology
Zhao X, Hong Y, Qin Y, Xu Y, Chang Y, Wang Y, Zhang X, Xu L, Huang X
The clinical significance of monitoring the expression of the SIL-TAL1 fusion gene in T-cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation
Jul 24, 2017
International Journal Of Laboratory Hematology
SIL-TAL1 rearrangement is common in T-cell acute lymphoblastic leukemia (T-ALL). However, whether this fusion gene might be used as a reliable marker of minimal residual disease (MRD) following allogeneic stem cell transplantation (allo-HSCT) remains unknown METHODS: The clinical data of consecutive 29 patients with T-ALL who received allo-HSCT were collected. Their MRD were evaluated by SIL-TAL1, Wilms' tumor 1 (WT1) expression, and the leukemia-associated immunophenotype (LAIP) . The median follow-up was 354 days (71-2111 days). Of the enrolled patients, 14 (87.5%) patients died of leukemia relapse. A total of 15 (51.7%) patients experienced relapse at a median of 90 days (60-540 days) after transplantation. The SIL-TAL1 expression of 16 patients converted from negative prior to transplantation to positive at 77 days (30-281 days) following transplantation; furthermore, 15 (93.8%) of them eventually experienced relapse. In the 15 relapsed patients, 13 (86.7%) had increased SIL-TAL1 expression levels 30 days (11-220 days) earlier than the hematological relapse and the detection of abnormal WT1 and LAIP. We are the first to demonstrate the reliability of the SIL-TAL1 fusion gene as a good MRD marker for patients with T-ALL after allo-HSCT. © 2017 John Wiley & Sons Ltd.
Decellularization of Human Internal Mammary Artery: Biomechanical Properties and Histopathological Evaluation
Jul 24, 2017   BioResearch Open Access
Kajbafzadeh AM, Khorramirouz R, Kameli SM, Hashemi J, Bagheri A
Decellularization of Human Internal Mammary Artery: Biomechanical Properties and Histopathological Evaluation
Jul 24, 2017
BioResearch Open Access
This study undertook to create small-diameter vascular grafts and assess their structure and mechanical properties to withstand arterial implantation. Twenty samples of intact human internal mammary arteries (IMAs) were collected and decellularized using detergent-based methods. To evaluate residual cellular and extracellular matrix (ECM) components, histological analysis was performed. Moreover, collagen typing and ECM structure were analyzed by Picrosirius red and Movat's pentachrome staining. Scanning electron microscopy was also applied to assess microarchitecture of both endothelial and adventitial surfaces of native and decellularized arterial samples. Furthermore, mechanical tests were performed to evaluate the rigidity and suture strength of the arteries. Human IMAs were completely decellularized in all three segments (proximal, middle, and distal). ECM proteins such as collagen and elastic fibers were efficiently preserved and no structural distortion in intima, media, and adventitial surfaces was observed. The parameters of the mechanical tests revealed no significant differences in the mechanical properties of decellularized arteries in comparison to native arteries with considerable strength, suture retention, and stress relaxation (Young's modulus [MPa] = 0.22 ± 0.023 [native] and 0.22 ± 0.015 [acellular]; and suture strength 0.56 ± 0.19 [native] vs. 0.56 ± 0.12 [acellular], respectively). Decellularized IMA represents a potential arterial scaffold as an alternative to autologous grafts for future arterial bypass surgeries. By this technique, microarchitecture and mechanical integrity of decellularized arteries were considerably similar to native arteries. The goal of this study was to introduce an efficient method for complete decellularization of human IMA and evaluate the ECM and biomechanical properties.
Label-free photoacoustic imaging of the cardio-cerebrovascular development in the embryonic zebrafish
Jul 24, 2017   Biomedical Optics Express
Chen Q, Jin T, Qi W, Mo X, Xi L
Label-free photoacoustic imaging of the cardio-cerebrovascular development in the embryonic zebrafish
Jul 24, 2017
Biomedical Optics Express
Zebrafish play an important role in biology, pharmacology, toxicology, and medicine. The cardio-cerebrovascular development of zebrafish is particularly critical to understand both brain disorders and cardiovascular diseases in human. In this paper, we applied optical resolution photoacoustic microscopy (ORPAM) to image the whole-body vasculature of the embryonic zebrafish with a special focus on the development of the cardio-cerebrovascular system. Using the intrinsic optical absorption contrast of the embryo, we successfully visualized the formation of the cardio-cerebrovascular network in high-resolution using a 10 × objective, and monitored the whole-body vascular development using a 4 × objective. In addition, we evaluated the impact of the eggshell and pigment inhibitor on the image quality. Our results suggest that ORPAM is capable of studying the cardio-cerebrovascular development of zebrafish in the embryonic stage, and thus has the potential to investigate the cardiovascular and cerebrovascular diseases of human in the future.
Pleomorphism and drug resistant cancer stem cells are characteristic of aggressive primary meningioma cell lines
Jul 24, 2017   Cancer Cell International
Khan I, Baeesa S, Bangash M, Schulten HJ, Alghamdi F,   . . . . . .   , Damanhouri G, Saini K, Chaudhary A, Abuzenadah A, Hussein D
Pleomorphism and drug resistant cancer stem cells are characteristic of aggressive primary meningioma cell lines
Jul 24, 2017
Cancer Cell International
Meningioma tumors arise in arachnoid membranes, and are the most reported central nervous system (CNS) tumors worldwide. Up to 20% of grade I meningioma tumors reoccur and currently predictive cancer stem cells (CSCs) markers for aggressive and drug resistant meningiomas are scarce. Meningioma tissues and primary cell lines were investigated using whole transcriptome microarray analysis, immunofluorescence staining of CSCs markers (including CD133, Sox2, Nestin, and Frizzled 9), and drug treatment with cisplatin or etoposide. Unsupervised hierarchical clustering of six meningioma samples separated tissues into two groups. Analysis identified stem cells related pathways to be differential between the two groups and indicated the de-regulation of the stem cell associated genes Reelin (RELN), Calbindin 1 (CALB1) and Anterior Gradient 2 Homolog (AGR2). Immunofluorescence staining for four tissues confirmed stemness variation in situ. Biological characterization of fifteen meningioma primary cell lines concordantly separated cells into two functionally distinct sub-groups. Pleomorphic cell lines (NG type) grew significantly faster than monomorphic cell lines (G type), had a higher number of cells that express Ki67, and were able to migrate aggressively in vitro. In addition, NG type cell lines had a lower expression of nuclear Caspase-3, and had a significantly higher number of CSCs co-positive for CD133+ Sox2+ or AGR2+ BMI1+. Importantly, these cells were more tolerant to cisplatin and etoposide treatment, showed a lower level of nuclear Caspase-3 in treated cells and harbored drug resistant CSCs. Collectively, analyses of tissues and primary cell lines revealed stem cell associated genes as potential targets for aggressive and drug resistant meningiomas.
Digital Multiplex Ligation-Dependent Probe Amplification for Detection of Key Copy Number Alterations in T- and B-Cell Lymphoblastic Leukemia
Jul 24, 2017   The Journal Of Molecular Diagnostics : JMD
Benard-Slagter A, Zondervan I, de Groot K, Ghazavi F, Sarhadi V, Van Vlierberghe P, De Moerloose B, Schwab C, Vettenranta K, Harrison CJ, Knuutila S, Schouten J, Lammens T, Savola S
Digital Multiplex Ligation-Dependent Probe Amplification for Detection of Key Copy Number Alterations in T- and B-Cell Lymphoblastic Leukemia
Jul 24, 2017
The Journal Of Molecular Diagnostics : JMD
Recurrent and clonal genetic alterations are characteristic of different subtypes of T- and B-cell lymphoblastic leukemia (ALL), and several subtypes are strong independent predictors of patient outcome. A next-generation sequencing-based multiplex ligation-dependent probe amplification variant (digitalMLPA) has been developed enabling simultaneous detection of copy number alterations (CNAs) of up to 1000 target sequences. This novel digitalMLPA assay was designed and optimized to detect CNAs of 56 key target genes and regions in ALL. In addition, a set of digital karyotyping probes has been included for the detection of gross ploidy changes (high hyperdiploidy or hypodiploidy), to determine the extent of CNAs, while also serving as reference probes for data normalization. Sixty-seven ALL patient samples (including both B-cell and T-cell ALL), previously characterized for genetic aberrations by standard MLPA, array comparative genomic hybridization, and/or single-nucleotide polymorphism array, were analyzed single blinded using digitalMLPA. The digitalMLPA assay reliably identified whole chromosome losses and gains (including high hyperdiploidy), whole gene deletions or gains, intrachromosomal amplification of chromosome 21, fusion genes, and various intragenic deletions, which were confirmed by other methods. Furthermore, subclonal alterations were reliably detected if present in at least 20% to 30% of neoplastic cells. The diagnostic sensitivity of the digitalMLPA assay was 98.9%, and the specificity was 97.8%. These results merit further consideration of digitalMLPA as a valuable alternative for genetic work-up of newly diagnosed ALL patients. Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.
High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain
Jul 24, 2017   Cell Stem Cell
Zhou T, Tan L, Cederquist GY, Fan Y, Hartley BJ, Mukherjee S, Tomishima M, Brennand KJ, Zhang Q, Schwartz RE, Evans T, Studer L, Chen S
High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain
Jul 24, 2017
Cell Stem Cell
Zika virus (ZIKV) infects fetal and adult human brain and is associated with serious neurological complications. To date, no therapeutic treatment is available to treat ZIKV-infected patients. We performed a high-content chemical screen using human pluripotent stem cell-derived cortical neural progenitor cells (hNPCs) and found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ) can inhibit ZIKV infection in hNPCs. Further validation showed that HH also rescues ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ inhibit ZIKV infection in adult mouse brain in vivo. Strikingly, HH suppresses viral propagation when administered to adult mice with active ZIKV infection, highlighting its therapeutic potential. Our approach highlights the power of stem cell-based screens and validation in human forebrain organoids and mouse models in identifying drug candidates for treating ZIKV infection and related neurological complications in fetal and adult patients. Copyright © 2017 Elsevier Inc. All rights reserved.
Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness
Jul 24, 2017   Cell Stem Cell
Takizawa H, Fritsch K, Kovtonyuk LV, Saito Y, Yakkala C, Jacobs K, Ahuja AK, Lopes M, Hausmann A, Hardt WD, Gomariz Á, Nombela-Arrieta C, Manz MG
Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness
Jul 24, 2017
Cell Stem Cell
Bacterial infection leads to consumption of short-lived innate immune effector cells, which then need to be replenished from hematopoietic stem and progenitor cells (HSPCs). HSPCs express pattern recognition receptors, such as Toll-like receptors (TLRs), and ligation of these receptors induces HSPC mobilization, cytokine production, and myeloid differentiation. The underlying mechanisms involved in pathogen signal transduction in HSCs and the resulting biological consequences remain poorly defined. Here, we show that in vivo lipopolysaccharide (LPS) application induces proliferation of dormant HSCs directly via TLR4 and that sustained LPS exposure impairs HSC self-renewal and competitive repopulation activity. This process is mediated via TLR4-TRIF-ROS-p38, but not MyD88 signaling, and can be inhibited pharmacologically without preventing emergency granulopoiesis. Live Salmonella Typhimurium infection similarly induces proliferative stress in HSCs, in part via TLR4-TRIF signals. Thus, while direct TLR4 activation in HSCs might be beneficial for controlling systemic infection, prolonged TLR4 signaling has detrimental effects and may contribute to inflammation-associated HSPC dysfunction. Copyright © 2017 Elsevier Inc. All rights reserved.
Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia
Jul 24, 2017   Cell Stem Cell
Windrem MS, Osipovitch M, Liu Z, Bates J, Chandler-Militello D,   . . . . . .   , Wang S, Nedergaard M, Findling RL, Tesar PJ, Goldman SA
Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia
Jul 24, 2017
Cell Stem Cell
In this study, we investigated whether intrinsic glial dysfunction contributes to the pathogenesis of schizophrenia (SCZ). Our approach was to establish humanized glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotent stem cells derived from patients with childhood-onset SCZ. After neonatal implantation into myelin-deficient shiverer mice, SCZ GPCs showed premature migration into the cortex, leading to reduced white matter expansion and hypomyelination relative to controls. The SCZ glial chimeras also showed delayed astrocytic differentiation and abnormal astrocytic morphologies. When established in myelin wild-type hosts, SCZ glial mice showed reduced prepulse inhibition and abnormal behavior, including excessive anxiety, antisocial traits, and disturbed sleep. RNA-seq of cultured SCZ human glial progenitor cells (hGPCs) revealed disrupted glial differentiation-associated and synaptic gene expression, indicating that glial pathology was cell autonomous. Our data therefore suggest a causal role for impaired glial maturation in the development of schizophrenia and provide a humanized model for its in vivo assessment. Copyright © 2017 Elsevier Inc. All rights reserved.
An Actomyosin-Arf-GEF Negative Feedback Loop for Tissue Elongation under Stress
Jul 24, 2017   Current Biology : CB
West JJ, Zulueta-Coarasa T, Maier JA, Lee DM, Bruce AEE, Fernandez-Gonzalez R, Harris TJC
An Actomyosin-Arf-GEF Negative Feedback Loop for Tissue Elongation under Stress
Jul 24, 2017
Current Biology : CB
In response to a pulling force, a material can elongate, hold fast, or fracture. During animal development, multi-cellular contraction of one region often stretches neighboring tissue. Such local contraction occurs by induced actomyosin activity, but molecular mechanisms are unknown for regulating the physical properties of connected tissue for elongation under stress. We show that cytohesins, and their Arf small G protein guanine nucleotide exchange activity, are required for tissues to elongate under stress during both Drosophila dorsal closure (DC) and zebrafish epiboly. In Drosophila, protein localization, laser ablation, and genetic interaction studies indicate that the cytohesin Steppke reduces tissue tension by inhibiting actomyosin activity at adherens junctions. Without Steppke, embryogenesis fails, with epidermal distortions and tears resulting from myosin misregulation. Remarkably, actomyosin network assembly is necessary and sufficient for local Steppke accumulation, where live imaging shows Steppke recruitment within minutes. This rapid negative feedback loop provides a molecular mechanism for attenuating the main tension generator of animal tissues. Such attenuation relaxes tissues and allows orderly elongation under stress. Copyright © 2017 Elsevier Ltd. All rights reserved.
Increased overall cortical connectivity with syndrome specific local decreases suggested by atypical sleep-EEG synchronization in Williams syndrome
Jul 22, 2017   Scientific Reports
Gombos F, Bódizs R, Kovács I
Increased overall cortical connectivity with syndrome specific local decreases suggested by atypical sleep-EEG synchronization in Williams syndrome
Jul 22, 2017
Scientific Reports
Williams syndrome (7q11.23 microdeletion) is characterized by specific alterations in neurocognitive architecture and functioning, as well as disordered sleep. Here we analyze the region, sleep state and frequency-specific EEG synchronization of whole night sleep recordings of 21 Williams syndrome and 21 typically developing age- and gender-matched subjects by calculating weighted phase lag indexes. We found broadband increases in inter- and intrahemispheric neural connectivity for both NREM and REM sleep EEG of Williams syndrome subjects. These effects consisted of increased theta, high sigma, and beta/low gamma synchronization, whereas alpha synchronization was characterized by a peculiar Williams syndrome-specific decrease during NREM states (intra- and interhemispheric centro-temporal) and REM phases of sleep (occipital intra-area synchronization). We also found a decrease in short range, occipital connectivity of NREM sleep EEG theta activity. The striking increased overall synchronization of sleep EEG in Williams syndrome subjects is consistent with the recently reported increase in synaptic and dendritic density in stem-cell based Williams syndrome models, whereas decreased alpha and occipital connectivity might reflect and underpin the altered microarchitecture of primary visual cortex and disordered visuospatial functioning of Williams syndrome subjects.
Osteosarcoma: Molecular Pathogenesis and iPSC Modeling
Jul 24, 2017   Trends In Molecular Medicine
Lin YH, Jewell BE, Gingold J, Lu L, Zhao R, Wang LL, Lee DF
Osteosarcoma: Molecular Pathogenesis and iPSC Modeling
Jul 24, 2017
Trends In Molecular Medicine
Rare hereditary disorders provide unequivocal evidence of the importance of genes in human disease pathogenesis. Familial syndromes that predispose to osteosarcomagenesis are invaluable in understanding the underlying genetics of this malignancy. Recently, patient-derived induced pluripotent stem cells (iPSCs) have been successfully utilized to model Li-Fraumeni syndrome (LFS)-associated bone malignancy, demonstrating that iPSCs can serve as an in vitro disease model to elucidate osteosarcoma etiology. We provide here an overview of osteosarcoma predisposition syndromes and review recently established iPSC disease models for these familial syndromes. Merging molecular information gathered from these models with the current knowledge of osteosarcoma biology will help us to gain a deeper understanding of the pathological mechanisms underlying osteosarcomagenesis and will potentially aid in the development of future patient therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.
Impact of Preimplantation Genetic Screening on Donor oocyte-recipient cycles in the United States
Jul 24, 2017   American Journal Of Obstetrics And Gynecology
Barad DH, Darmon SK, Kushnir VA, Albertini DF, Gleicher N
Impact of Preimplantation Genetic Screening on Donor oocyte-recipient cycles in the United States
Jul 24, 2017
American Journal Of Obstetrics And Gynecology
Our objective was to estimate the contribution of Preimplantation genetic screening to in-vitro fertilization pregnancy outcomes in donor oocyte-recipient cycles. This is a retrospective cross-sectional study of United States national data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System between 2005-2013. Society for Assisted Reproductive Technology Clinic Outcome Reporting relies on voluntarily annual reports by over 90% of United States in-vitro fertilization centers. We evaluated pregnancy and live birth rates in donor oocyte-recipient cycles after first embryo transfer with day 5/6 embryos. Statistical models, adjusted for patient and donor ages, number of embryos transferred, race, infertility diagnosis and cycle year were created to compare live birth rates in 392 Preimplantation genetic screening and 20,616 Control cycles. Overall, pregnancy and live birth rates were significantly lower in Preimplantation genetic screening cycles than in control cycles. Adjusted odds of live birth for Preimplantation genetic screening cycles were reduced by 35% (OR 0.65, 95% CI 0.53 to 0.80; P < 0.001). Preimplantation Genetic Screening, as practiced in donor oocyte-recipient cycles over the past nine years, has not been associated with improved odds of live birth or reduction in miscarriage rates. Copyright © 2017 Elsevier Inc. All rights reserved.
AMLprofiler: A Diagnostic and Prognostic Microarray for Acute Myeloid Leukemia
Jul 23, 2017   Methods In Molecular Biology (Clifton, N.J.)
Alessandrini M, Kappala SS, Pepper MS
AMLprofiler: A Diagnostic and Prognostic Microarray for Acute Myeloid Leukemia
Jul 23, 2017
Methods In Molecular Biology (Clifton, N.J.)
Acute myeloid leukemia is characterized by the proliferation and accumulation of immature hematopoietic cells of the myeloid lineage in the bone marrow. The disease is typified by diverse genetic abnormalities and marked heterogeneity both with regard to response to treatment and survival. The AMLprofiler is a qualitative in vitro diagnostic microarray developed by SkylineDx for use with Affymetrix technology. The AMLprofiler makes use of RNA chemistry and incorporates seven separate assays based on three different technologies-cytogenetics, mutation, and expression analysis-to predict post-therapy survival rates in patients with acute myeloid leukemia. The assay has been validated for processing of bone marrow samples from which RNA is isolated within 48 h. The samples are subsequently processed using Affymetrix GeneChip reagent kits and analyzed on the Affymetrix GeneChip 3000Dx v2 system. The scanned AMLprofiler data is sent to a centralized server of SkylineDx via a secured Internet connection, and a diagnostic report is generated within 15 min. We have performed several AMLprofiler assays in our laboratory and found the data generated via this assay to be consistent with standard modalities.
Development of new ganglioside probes and unraveling of raft domain structure by single-molecule imaging
Jul 23, 2017   Biochimica Et Biophysica Acta
Suzuki KGN, Ando H, Komura N, Fujiwara T, Kiso M, Kusumi A
Development of new ganglioside probes and unraveling of raft domain structure by single-molecule imaging
Jul 23, 2017
Biochimica Et Biophysica Acta
Gangliosides are involved in a variety of biological roles and are a component of lipid rafts found in cell plasma membranes (PMs). Gangliosides are especially abundant in neuronal PMs and are essential to their physiological functions. However, the dynamic behaviors of gangliosides have not been investigated in living cells due to a lack of fluorescent probes that behave like their parental molecules. We have recently developed, using an entirely chemical method, four new ganglioside probes (GM1, GM2, GM3, and GD1b) that act similarly to their parental molecules in terms of raft partitioning and binding affinity. Using single fluorescent-molecule imaging, we have found that ganglioside probes dynamically enter and leave rafts featuring CD59, a GPI-anchored protein. This occurs both before and after stimulation. The residency time of our ganglioside probes in rafts with CD59 oligomers was 48 ms, after stimulation. The residency times in CD59 homodimer and monomer rafts were 40 ms and 12 ms, respectively. In this review, we introduce an entirely chemical-based ganglioside analog synthesis method and describe its application in single-molecule imaging and for the study of the dynamic behavior of gangliosides in cell PMs. Finally, we discuss how raft domains are formed, both before and after receptor engagement. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa. Copyright © 2017. Published by Elsevier B.V.
Molecular Imaging in stem cell-based therapies of cardiac diseases
Jul 23, 2017   Advanced Drug Delivery Reviews
Li X, Hacker M
Molecular Imaging in stem cell-based therapies of cardiac diseases
Jul 23, 2017
Advanced Drug Delivery Reviews
In the past 15years, despite regenerative medicine has shown great potential for cardiovascular diseases, the outcome and safety of stem cell transplantation has shown controversial results in the published literature. Medical imaging might be useful for monitoring and quantification transplanted cells within the heart and to serially characterize the effects of stem cell therapy of the myocardium. From the multiple available noninvasive imaging techniques, magnetic resonance imaging and nuclear imaging by positron (PET) or single photon emission computer tomography (SPECT) are the most used clinical approaches to follow the fate of transplanted stem cells in vivo. In this article, we provide a review on the role of different noninvasive imaging modalities and discuss their advantages and disadvantages. We focus on the different in-vivo labeling and reporter gene imaging strategies for stem cell tracking as well as the concept and reliability to use imaging parameters as noninvasive surrogate endpoints for the evaluation of the post-therapeutic outcome. Copyright © 2017. Published by Elsevier B.V.
Migration ability and Toll-like receptor expression of human mesenchymal stem cells improves significantly after three-dimensional culture
Jul 23, 2017   Biochemical And Biophysical Research Communications
Zhou P, Liu Z, Li X, Zhang B, Wang X, Lan J, Shi Q, Li D, Ju X
Migration ability and Toll-like receptor expression of human mesenchymal stem cells improves significantly after three-dimensional culture
Jul 23, 2017
Biochemical And Biophysical Research Communications
While the conventional two-dimensional (2D) culture protocol is well accepted for the culture of mesenchymal stem cells (MSCs), this method fails to recapitulate the in vivo native three-dimensional (3D) cellular microenvironment, and may result in phenotypic changes, and homing and migration capacity impairments. MSC preparation in 3D culture systems has been considered an attractive preparatory and delivery method recently. We seeded human umbilical cord-derived MSCs (hUCMSCs) in a 3D culture system with porcine acellular dermal matrix (PADM), and investigated the phenotypic changes, the expression changes of some important receptors, including Toll-like receptors (TLRs) and C-X-C chemokine receptor type 4 (CXCR4) when hUCMSCs were transferred from 2D to 3D systems, as well as the alterations in in vivo homing and migration potential. It was found that the percentage of CD105-positive cells decreased significantly, whereas that of CD34- and CD271-positive cells increased significantly in 3D culture, compared to that in 2D culture. The mRNA and protein expression levels of TLR2, TLR3, TLR4, TLR6, and CXCR4 in hUCMSCs were increased significantly upon culturing with PADM for 3 days, compared to the levels in 2D culture. The numbers of migratory 3D hUCMSCs in the heart, liver, spleen, and bone marrow were significantly greater than the numbers of 2D hUCMSCs, and the worst migration occurred in 3D + AMD3100 (CXCR4 antagonist) hUCMSCs. These results suggested that 3D culture of hUCMSCs with PADM could alter the phenotypic characteristics of hUCMSCs, increase their TLR and CXCR4 expression levels, and promote their migratory and homing capacity in which CXCR4 plays an important role. Copyright © 2017. Published by Elsevier Inc.
Effect of calcium phosphate nanocomposite on in vitro remineralization of human dentin lesions
Jul 23, 2017   Dental Materials : Official Publication Of The Academy Of Dental Materials
Weir MD, Ruan J, Zhang N, Chow LC, Zhang K, Chang X, Bai Y, Xu HHK
Effect of calcium phosphate nanocomposite on in vitro remineralization of human dentin lesions
Jul 23, 2017
Dental Materials : Official Publication Of The Academy Of Dental Materials
Secondary caries is a primary reason for dental restoration failures. The objective of this study was to investigate the remineralization of human dentin lesions in vitro via restorations using nanocomposites containing nanoparticles of amorphous calcium phosphate (NACP) or NACP and tetracalcium phosphate (TTCP) for the first time. NACP was synthesized by a spray-drying technique and incorporated into a resin consisting of ethoxylated bisphenol A dimethacrylate (EBPADMA) and pyromellitic glycerol dimethacrylate (PMGDM). After restoring the dentin lesions with nanocomposites as well as a non-releasing commercial composite control, the specimens were treated with cyclic demineralization (pH 4, 1h per day) and remineralization (pH 7, 23h per day) for 4 or 8 weeks. Calcium (Ca) and phosphate (P) ion releases from composites were measured. Dentin lesion remineralization was measured at 4 and 8 weeks by transverse microradiography (TMR). Lowering the pH increased ion release of NACP and NACP-TTCP composites. At 56 days, the released Ca concentration in mmol/L (mean±SD; n=3) was (13.39±0.72) at pH 4, much higher than (1.19±0.06) at pH 7 (p
Quiescent Oct4+ Neural Stem Cells (NSCs) Repopulate Ablated Glial Fibrillary Acidic Protein+ NSCs in the Adult Mouse Brain
Jul 22, 2017   Stem Cells (Dayton, Ohio)
Reeve RL, Yammine SZ, Morshead CM, van der Kooy D
Quiescent Oct4+ Neural Stem Cells (NSCs) Repopulate Ablated Glial Fibrillary Acidic Protein+ NSCs in the Adult Mouse Brain
Jul 22, 2017
Stem Cells (Dayton, Ohio)
Adult primitive neural stem cells (pNSCs) are a rare population of glial fibrillary acidic protein (GFAP)- Oct4+ cells in the mouse forebrain subependymal zone bordering the lateral ventricles that give rise to clonal neurospheres in leukemia inhibitory factor in vitro. pNSC neurospheres can be passaged to self-renew or give rise to GFAP+ NSCs that form neurospheres in epidermal growth factor and fibroblast growth factor 2, which we collectively refer to as definitive NSCs (dNSCs). Label retention experiments using doxycycline-inducible histone-2B (H2B)-green fluorescent protein (GFP) mice and several chase periods of up to 1 year quantified the adult pNSC cell cycle time as 3-5 months. We hypothesized that while pNSCs are not very proliferative at baseline, they may exist as a reserve pool of NSCs in case of injury. To test this function of pNSCs, we obtained conditional Oct4 knockout mice, Oct4fl/fl ;Sox1Cre (Oct4CKO ), which do not yield adult pNSC-derived neurospheres. When we ablated the progeny of pNSCs, namely all GFAP+ dNSCs, in these Oct4CKO mice, we found that dNSCs did not recover as they do in wild-type mice, suggesting that pNSCs are necessary for dNSC repopulation. Returning to the H2B-GFP mice, we observed that the cytosine β-d-arabinofuranoside ablation of proliferating cells including dNSCs-induced quiescent pNSCs to proliferate and significantly dilute their H2B-GFP label. In conclusion, we demonstrate that pNSCs are the most quiescent stem cells in the adult brain reported to date and that their lineage position upstream of GFAP+ dNSCs allows them to repopulate a depleted neural lineage. Stem Cells 2017. © 2017 AlphaMed Press.
Clinical impact of pre-transplant gut microbial diversity on outcomes of allogeneic hematopoietic stem cell transplantation
Jul 22, 2017   Annals Of Hematology
Doki N, Suyama M, Sasajima S, Ota J, Igarashi A,   . . . . . .   , Kakihana K, Takahashi N, Sakamaki H, Honda K, Ohashi K
Clinical impact of pre-transplant gut microbial diversity on outcomes of allogeneic hematopoietic stem cell transplantation
Jul 22, 2017
Annals Of Hematology
Post-transplant microbial diversity in the gastrointestinal tract is closely associated with clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about the impact of the fecal microbiota before allo-HSCT. We analyzed fecal samples approximately 2 weeks before conditioning among 107 allo-HSCT recipients between 2013 and 2015. Microbial analysis was performed using 16S rRNA gene sequencing. Operational taxonomic unit-based microbial diversity was estimated by calculating the Shannon index. Patients were classified into three groups based on the diversity index: low (3) diversity (18 (16.8%), 48 (44.9%), and 41 (38.3%) patients, respectively). There were no significant differences in the 20-month overall survival, cumulative incidence of relapse, and non-relapse mortality among three groups. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was similar among the three groups (low 55.6%; intermediate 35.4%; high 48.8%, p = 0.339, at day 100). Furthermore, we found no differences in the cumulative incidence of grade II to IV acute gastrointestinal GVHD among the three groups (low 38.9%; intermediate 21.3%; high 24.4%, p = 0.778, at day 100). Regarding the composition of microbiota before allo-HSCT, aGVHD patients showed a significantly higher abundance of phylum Firmicutes (p 
Steroid-Mediated Decrease in Blood Mesenchymal Stem Cells in Liver Transplant could Impact Long-Term Recovery
Jul 22, 2017   Stem Cell Reviews
Walker ND, Mourad Y, Liu K, Buxhoeveden M, Schoenberg C,   . . . . . .   , Ponzio NM, Pyrsopoulos N, Koneru B, Gubenko Y, Rameshwar P
Steroid-Mediated Decrease in Blood Mesenchymal Stem Cells in Liver Transplant could Impact Long-Term Recovery
Jul 22, 2017
Stem Cell Reviews
Orthotopic liver transplant (OLT) remains the standard of care for end stage liver disease. To circumvent allo-rejection, OLT subjects receive gluococorticoids (GC). We investigated the effects of GC on endogenous mesenchymal stem (stromal) cells (MSCs) in OLT. This question is relevant because MSCs have regenerative potential and immune suppressor function. Phenotypic analyses of blood samples from 12 OLT recipients, at pre-anhepatic, anhepatic and post-transplant (2 h, Days 1 and 5) indicated a significant decrease in MSCs after GC injection. The MSCs showed better recovery in the blood from subjects who started with relatively low MSCs as compared to those with high levels at the prehepatic phase. This drop in MSCs appeared to be linked to GC since similar change was not observed in liver resection subjects. In order to understand the effects of GC on decrease MSC migration, in vitro studies were performed in transwell cultures. Untreated MSCs could not migrate towards the GC-exposed liver tissue, despite CXCR4 expression and the production of inflammatory cytokines from the liver cells. GC-treated MSCs were inefficient with respect to migration towards CXCL12, and this correlated with retracted cytoskeleton and motility. These dysfunctions were partly explained by decreases in the CXCL12/receptor axis. GC-associated decrease in MSCs in OLT recipients recovered post-transplant, despite poor migratory ability towards GC-exposed liver. In total, the study indicated that GC usage in transplant needs to be examined to determine if this could be reduced or avoided with adjuvant cell therapy.
Multicellular Vascularized Engineered Tissues through User-Programmable Biomaterial Photodegradation
Jul 24, 2017   Advanced Materials (Deerfield Beach, Fla.)
Arakawa CK, Badeau BA, Zheng Y, DeForest CA
Multicellular Vascularized Engineered Tissues through User-Programmable Biomaterial Photodegradation
Jul 24, 2017
Advanced Materials (Deerfield Beach, Fla.)
A photodegradable material-based approach to generate endothelialized 3D vascular networks within cell-laden hydrogel biomaterials is introduced. Exploiting multiphoton lithography, microchannel networks spanning nearly all size scales of native human vasculature are readily generated with unprecedented user-defined 4D control. Intraluminal channel architectures of synthetic vessels are fully customizable, providing new opportunities for next-generation microfluidics and directed cell function. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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