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Showing 100 Latest Publications
TitleDate Created
Inhibitors of Growth 1b Suppresses Peroxisome Proliferator-Activated Receptor-β/δ Expression Through Downregulation of Hypoxia-Inducible Factor 1α in Osteoblast Differentiation.Friday, February 05, 2016
Qu B, Hong Z, Gong K, Sheng J, Wu HH, Deng SL, Huang G, Ma ZH, Pan XM,
DNA and cell biology. 5-Feb-2016
Bone formation, a highly regulated developmental process, involves osteoblast differentiation, which is controlled by different important transcription factors. Recent evidence has suggested possible negative regulation of inhibitors of growth (ING) 1b on the osteoblast marker expression. The aim of this study is to examine the detailed mechanism by which the activity of ING1b inhibits osteoblast differentiation. In the current study, we investigated the function and mechanism by which ING1b inhibits osteoblast differentiation using C3H10T1/2 mesenchymal stem cells and MC3T3-E1 preosteoblasts. Real-time polymerase chain reaction and Western blotting showed that ING1b was decreased during osteoblast differentiation and ING1b overexpression markedly decreased alkaline phosphatase (ALP) activity, runt-related transcription factor 2 (Runx2) expression, and collagen type 1 synthesis, whereas ING1b silencing significantly upregulated ALP activity, Runx2 expression, and collagen type 1 synthesis. Further studies indicated that ING1b suppressed the expression of peroxisome proliferator-activated receptor (PPAR)-β/δ in a hypoxia-inducible factor (HIF) 1α-dependent manner, while ING1b silencing significantly increased the expression of PPAR-β/δ and HIF1α. Moreover, PPAR-β/δ or HIF1α silencing significantly inhibited ALP activity, Runx2 expression, and collagen type 1 synthesis. These results demonstrated that ING1b is an important regulator of osteoblast differentiation and suppresses PPAR-β/δ. Our study may provide additional insight into osteoblast differentiation and offer a potential new molecular target for osteoporosis.
[Clinical and Epidemiological Study of Complicated Infection by Varicella-Zoster Virus in the Pediatric Age].Friday, February 05, 2016
Maia C, Fonseca J, Carvalho I, Santos H, Moreira D,
Acta medica portuguesa. 5-2-2016
Multicenter studies should be planned in order to optimize and adjust the vaccine strategies to our reality.
O-013 Defining the Basis of Epithelial Defects in Crohn's Using Intestinal Spheroid Culture.Friday, February 05, 2016
VanDussen K, Miyoshi H, Sonnek N, Ciorba M, Stappenbeck T,
Inflammatory bowel diseases. Mar-2016
We have examined a large number of intestinal spheroid lines and demonstrated that some epithelial phenotypes persist in culture whereas others do not. Inter-individual variation was evident in human spheroid lines generated from different patients in certain culture conditions. Thus, human spheroid lines are a very promising tool for understanding the basis of epithelial defects in Crohn's. Moreover, these results show that researchers will need to take care when selecting human intestinal spheroid lines for use in their studies.
O-004 Analysis of Chromatin and Transcriptional Profiles in Crohn's Disease Reveals Molecular Subclasses and Highlights Functional Regulatory Regions Implicated in Disease.Friday, February 05, 2016
Weiser M, Sheikh S, Kochar B, Gipson G, Herfarth H, Sartor R, McGovern D, Rahbar R, Sadiq T, Furey T, Koruda M, Robinson A,
Inflammatory bowel diseases. Mar-2016
We used chromatin status as a novel marker of disease in Crohn's. We identified a subset of CD patients that are characterized at the chromatin level in the colon by enrichment of enhancer marks specific to small intestine, and loss of enhancer activity specific to colon. Among individuals with enhancer activity indicative of normal colon, we integrated data from well-described transcriptional markers with novel chromatin variables to identify molecular associations and interactions that affect disease predisposition. Despite small patient numbers we were able to use chromatin profiles to identify patients that required post-operative management with anti-TNF agents.
Protein profile of basal prostate epithelial progenitor cells-stage-specific embryonal antigen 4 expressing cells have enhanced regenerative potential in vivo.Friday, February 05, 2016
Höfner T, Klein C, Eisen C, Rigo-Watermeier T, Haferkamp A, Sprick MR,
Journal of cellular and molecular medicine. 5-Feb-2016
The long-term propagation of basal prostate progenitor cells ex vivo has been very difficult in the past. The development of novel methods to expand prostate progenitor cells in vitro allows determining their cell surface phenotype in greater detail. Mouse (Lin(-) Sca-1(+) CD49f(+) Trop2(high) -phenotype) and human (Lin(-) CD49f(+) TROP2(high) ) basal prostate progenitor cells were expanded in vitro. Human and mouse cells were screened using 242 anti-human or 176 antimouse monoclonal antibodies recognizing the cell surface protein profile. Quantitative expression was evaluated at the single-cell level using flow cytometry. Differentially expressed cell surface proteins were evaluated in conjunction with the known CD49f(+) /TROP2(high) phenotype of basal prostate progenitor cells and characterized by in vivo sandwich-transplantation experiments using nude mice. The phenotype of basal prostate progenitor cells was determined as CD9(+) /CD24(+) /CD29(+) /CD44(+) /CD47(+) /CD49f(+) /CD104(+) /CD147(+) /CD326(+) /Trop2(high) of mouse as well as human origin. Our analysis revealed several proteins, such as CD13, Syndecan-1 and stage-specific embryonal antigens (SSEAs), as being differentially expressed on murine and human CD49f(+) TROP2(+) basal prostate progenitor cells. Transplantation experiments suggest that CD49f(+) TROP2(high) SSEA-4(high) human prostate basal progenitor cells to be more potent to regenerate prostate tubules in vivo as compared with CD49f(+) TROP2(high) or CD49f(+) TROP2(high) SSEA-4(low) cells. Determination of the cell surface protein profile of functionally defined murine and human basal prostate progenitor cells reveals differentially expressed proteins that may change the potency and regenerative function of epithelial progenitor cells within the prostate. SSEA-4 is a candidate cell surface marker that putatively enables a more accurate identification of the basal PESC lineage.
Duane retraction syndrome in a patient with Duchenne muscular dystrophy.Friday, February 05, 2016
Bosley TM, Salih MA, Alkhalidi H, Oystreck DT, El Khashab HY, Kondkar AA, Abu-Amero KK,
Ophthalmic genetics. 5-Feb-2016
This boy is the third patient to be reported with DRS and DMD, the second with bilateral DRS and the only one with other neurologic features. Mutated dystrophin is present in extraocular muscles and in the central nervous system (CNS) in DMD, leaving open the question of whether this co-occurrence is the result of the genetic muscle abnormality, CNS effects caused by dystrophin mutations, or chance.
Beat Rate Variability in Murine Embryonic Stem Cell-Derived Cardiomyocytes: Effect of Antiarrhythmic Drugs.Friday, February 05, 2016
Niehoff J, Matzkies M, Nguemo F, Hescheler J, Reppel M,
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 8-Feb-2016
Spontaneously beating cardiomyocytes derived from mESCs showed BRV that appears to be similar to the HRV known from humans. Antiarrhythmic drugs affected BRV parameters similar to clinical observations. Therefore, our study demonstrates that this in vitro model can contribute to a better understanding of electrophysiological properties of mESC-derived cardiomyocytes and might serve as a valuable tool for drug safety screening.
Age-Related Decline of Neutrophilic Inflammation Is Associated with Better Postoperative Prognosis in Non-eosinophilic Nasal Polyps.Friday, February 05, 2016
Kim DW, Kim DK, Jo A, Jin HR, Eun KM, Mo JH, Cho SH,
PloS one. 8-2-2016
Age-related decline in neutrophil inflammation may favorably affect postoperative results in elderly patients with NE-NP.
Cancer Stem Cells and Their Cellular Origins in Primary Liver and Biliary Tract Cancers.Friday, February 05, 2016
Oikawa T,
Hepatology (Baltimore, Md.). 5-Feb-2016
Liver and biliary tract cancers are highly aggressive, heterogeneous in their phenotypic traits, and result in clinical outcomes that are difficult to manage. Cancers have subpopulations of cells termed cancer stem cells (CSCs) that share common intrinsic signaling pathways for self-renewal and differentiation with normal stem cells. These CSCs likely have the potential to evolve over time and to give rise to new genetically and functionally diverse subclones by accumulating genetic mutations. Extrinsic signaling from the tumor microenvironment, including the CSC niche, has been implicated in tumor initiation/progression and heterogeneity through dynamic cross talk. CSCs have become recognized as pivotal sources of tumor initiation/progression, relapse/metastasis and chemo-resistance. The origins of CSCs are hypothesized to derive from the transformation of normal stem/progenitors and/or from the reprogramming of adult cells that converts them to stem/progenitor traits. However, the precise mechanisms have not yet been fully elucidated. This review focuses on the candidate normal cells of origin of liver and biliary tract cancers and the future directions of therapies targeting CSCs. This article is protected by copyright. All rights reserved.
Timeline: iPSCs-The First Decade.Friday, February 05, 2016
Chari S, Mao S,
Cell stem cell. 4-Feb-2016
Research into induced pluripotent stem cells (iPSCs) has expanded at a remarkable pace in the decade since Shinya Yamanaka and Kazutoshi Takahashi first reported their groundbreaking discovery in 2006. This Timeline highlights the key events in the development of this field, including basic insights into the production of iPSCs and how they have been applied to improve our understanding and treatment of human disease. To view this Timeline, open or download the PDF. You can also listen to the associated interview with Debbie Sweet, Editor of Cell Stem Cell, and Elena Porro, Editor of Cell. PAPERCLIP.
A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer.Friday, February 05, 2016
Bu P, Wang L, Chen KY, Srinivasan T, Murthy PK, Tung KL, Varanko AK, Chen HJ, Ai Y, King S, Lipkin SM, Shen X,
Cell stem cell. 4-Feb-2016
Emerging evidence suggests that microRNAs can initiate asymmetric division, but whether microRNA and protein cell fate determinants coordinate with each other remains unclear. Here, we show that miR-34a directly suppresses Numb in early-stage colon cancer stem cells (CCSCs), forming an incoherent feedforward loop (IFFL) targeting Notch to separate stem and non-stem cell fates robustly. Perturbation of the IFFL leads to a new intermediate cell population with plastic and ambiguous identity. Lgr5+ mouse intestinal/colon stem cells (ISCs) predominantly undergo symmetric division but turn on asymmetric division to curb the number of ISCs when proinflammatory response causes excessive proliferation. Deletion of miR-34a inhibits asymmetric division and exacerbates Lgr5+ ISC proliferation under such stress. Collectively, our data indicate that microRNA and protein cell fate determinants coordinate to enhance robustness of cell fate decision, and they provide a safeguard mechanism against stem cell proliferation induced by inflammation or oncogenic mutation.
CDX2: Linking Cell and Patient Fates in Colon Cancer.Friday, February 05, 2016
Fearon ER, Huang EH,
Cell stem cell. 4-Feb-2016
Administering adjuvant chemotherapy to stage II colon cancer patients is controversial due to limited benefit observed for this subpopulation. Recently, Dalerba et al. (2016) identified a subgroup of stage II patients that might benefit from adjuvant chemotherapy based on lack of CDX2 expression in their cancer stem cells.
Time to Relax: Mechanical Stress Release Guides Stem Cell Responses.Friday, February 05, 2016
Sommerfeld SD, Elisseeff JH,
Cell stem cell. 4-Feb-2016
Stem cells integrate spatiotemporal cues, including the mechanical properties of their microenvironment, into their fate decisions. Chaudhuri et al. (2015) show that the ability of the extracellular matrix to dissipate cell-induced forces, referred to as stress-relaxation, is a key mechanical signal influencing stem cell fate and function.
Naive versus Primed: It's Now Three-Dimensional.Friday, February 05, 2016
Wei Z, Lu W,
Cell stem cell. 4-Feb-2016
We are only beginning to understand the higher-order chromatin structure of pluripotent stem cells and its relevance to cell fate. Three recent studies used different approaches to reconstruct the 3D chromatin landscape of naive and primed pluripotent cells, unveiling common features as well as differences between these two states.
Compacting Chromatin to Ensure Muscle Satellite Cell Quiescence.Friday, February 05, 2016
Li Y, Dilworth FJ,
Cell stem cell. 4-Feb-2016
Satellite cells comprise a pool of quiescent stem cells that repair muscle damage, but the mechanisms enforcing their quiescence are poorly defined. In this issue of Cell Stem Cell, Boonsanay et al. (2016) show that the histone methyltransferase Suv4-20H1 maintains satellite cell quiescence by promoting a heterochromatic state through transcriptional repression of the myogenic master regulator MyoD.
Activated Muscle Satellite Cells Chase Ghosts.Friday, February 05, 2016
Mourikis P, Relaix F,
Cell stem cell. 4-Feb-2016
The in vivo behaviors of skeletal muscle stem cells, i.e., satellite cells, during homeostasis and after injury are poorly understood. In this issue of Cell Stem Cell, Webster et al. (2016) now perform a tour de force intravital microscopic analysis of this population, showing that "ghost fiber" remnants act as scaffolds to guide satellite cell divisions after injury.
Mom Knows Best: Imprinted Control of Hematopoietic Stem Cell Quiescence.Friday, February 05, 2016
Serrano-Lopez J, Cancelas JA,
Cell stem cell. 4-Feb-2016
The mechanisms by which imprinted loci control activity of hematopoietic stem cells (HSCs) are not known. In this issue of Cell Stem Cell, Qian et al. (2016) demonstrate that non-coding RNAs expressed by the maternal-imprinted locus Dlk1-Gtl2 maintain HSC self-renewal through the inhibition of PI3K-mTOR signaling, mitochondrial biogenesis, and metabolic activity.
HIF2α contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells.Friday, February 05, 2016
Alam MW, Persson CU, Reinbothe S, Kazi JU, Rönnstrand L, Wigerup C, Ditzel HJ, Lykkesfeldt AE, Påhlman S, Jögi A,
Oncotarget. 3-Feb-2016
The majority of breast cancers express estrogen receptor α (ERα), and most patients with ERα-positive breast cancer benefit from antiestrogen therapy. The ERα-modulator tamoxifen and ERα-downregulator fulvestrant are commonly employed antiestrogens. Antiestrogen resistance remains a clinical challenge, with few effective treatments available for patients with antiestrogen-resistant breast cancer. Hypoxia, which is intrinsic to most tumors, promotes aggressive disease, with the hypoxia-inducible transcription factors HIF1 and HIF2 regulating cellular responses to hypoxia. Here, we show that the ERα-expressing breast cancer cells MCF-7, CAMA-1, and T47D are less sensitive to antiestrogens when hypoxic. Furthermore, protein and mRNA levels of HIF2α/HIF2A were increased in a panel of antiestrogen-resistant cells, and antiestrogen-exposure further increased HIF2α expression. Ectopic expression of HIF2α in MCF-7 cells significantly decreased sensitivity to antiestrogens, further implicating HIF2α in antiestrogen resistance. EGFR is known to contribute to antiestrogen resistance: we further show that HIF2α drives hypoxic induction of EGFR and that EGFR induces HIF2α expression. Downregulation or inhibition of EGFR led to decreased HIF2α levels. This positive and bilateral HIF2-EGFR regulatory crosstalk promotes antiestrogen resistance and, where intrinsic hypoxic resistance exists, therapy itself may exacerbate the problem. Finally, inhibition of HIFs by FM19G11 restores antiestrogen sensitivity in resistant cells. Targeting HIF2 may be useful for counteracting antiestrogen resistance in the clinic.
Brother of the regulator of the imprinted site (BORIS) variant subfamily 6 is involved in cervical cancer stemness and can be a target of immunotherapy.Friday, February 05, 2016
Asano T, Hirohashi Y, Torigoe T, Mariya T, Horibe R, Kuroda T, Tabuchi Y, Saijo H, Yasuda K, Mizuuchi M, Takahashi A, Asanuma H, Hasegawa T, Saito T, Sato N,
Oncotarget. 3-Feb-2016
Cervical cancer is a major cause of cancer death in females worldwide. Cervical cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are resistant to conventional radiotherapy and chemotherapy, and CSCs/CICs are thought to be responsible for recurrence. Eradication of CSCs/CICs is thus essential to cure cervical cancer. In this study, we isolated cervical CSCs/CICs by sphere culture, and we identified a cancer testis (CT) antigen, CTCFL/BORIS, that is expressed in cervical CSCs/CICs. BORIS has 23 mRNA isoform variants classified by 6 subfamilies (sfs), and they encode 17 different BORIS peptides. BORIS sf1 and sf4 are expressed in both CSCs/CICs and non-CSCs/CICs, whereas BORIS sf6 is expressed only in CSCs/CICs. Overexpression of BORIS sf6 in cervical cancer cells increased sphere formation and tumor-initiating ability compared with those in control cells, whereas overexpression of BORIS sf1 and BORIS sf4 resulted in only slight increases. Thus, BORIS sf6 is a cervical CSC/CIC-specific subfamily and has a role in the maintenance of cervical CSCs/CICs. BORIS sf6 contains a specific c-terminal domain (C34), and we identified a human leukocyte antigen (HLA)-A2-restricted antigenic peptide, BORIS C34_24(9) encoded by BORIS sf6. A BORIS C34_24(9)-specific cytotoxic T cell (CTL) clone showed cytotoxicity for BORIS sf6-overexpressing cervical cancer cells. Furthermore, the CTL clone significantly suppressed sphere formation of CaSki cells. Taken together, the results indicate that the CT antigen BORIS sf6 is specifically expressed in cervical CSCs/CICs, that BORIS sf6 has a role in the maintenance of CSCs/CICs, and that BORIS C34_24(9) peptide is a promising candidate for cervical CSC/CIC-targeting immunotherapy.
Effects of multiwalled carbon nanotubes on electrospun poly(lactide-co-glycolide)-based nanocomposite scaffolds on neural cells proliferation.Friday, February 05, 2016
Lv ZJ, Liu Y, Miao H, Leng ZQ, Guo JH, Liu J,
Journal of biomedical materials research. Part B, Applied biomaterials. 5-Feb-2016
The repair of nerves remains a major challenge in neuron-regeneration. In this study, poly(lactic-co-glycolic acid)/multi-walled carbon nanotubes (PLGA/MWCNTs) nanofibrous scaffolds were fabricated by electrospinning method. The surface morphology, physical, and mechanical properties were characterized through scanning electron microscopy (SEM), transmission electron microscopy, and tensile tests, respectively. SEM analysis, Live/Dead staining, immunostaining assays were performed to evaluate neural cells growth. Blending PLGA with MWCNTs resulted in increase diameter and porosity of the scaffolds, and exhibited better mechanical properties. The results demonstrated that the scaffolds with higher MWCNTs concentration provided better survival for neural cells after 8 days of culture, especially for astrocytes growth. This could be useful in treating the disease like multiple sclerosis that causing central nervous system demyelination and axonal injury. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2016.
Specification and function of hemogenic endothelium during embryogenesis.Friday, February 05, 2016
Gritz E, Hirschi KK,
Cellular and molecular life sciences : CMLS. 5-Feb-2016
Hemogenic endothelium is a specialized subset of developing vascular endothelium that acquires hematopoietic potential and can give rise to multilineage hematopoietic stem and progenitor cells during a narrow developmental window in tissues such as the extraembryonic yolk sac and embryonic aorta-gonad-mesonephros. Herein, we review current knowledge about the historical and developmental origins of hemogenic endothelium, the molecular events that govern hemogenic specification of vascular endothelial cells, the generation of multilineage hematopoietic stem and progenitor cells from hemogenic endothelium, and the potential for translational applications of knowledge gained from further study of these processes.
Overcoming resistance to endocrine therapy in breast cancer; new approaches to a nagging problem.Friday, February 05, 2016
Luqmani YA, Alam-Eldin N,
Medical principles and practice : international journal of the Kuwait University, Health Science Centre. 5-Feb-2016
In the majority of women, breast cancer progresses through increased transcriptional activity due to over-expressed estrogen receptor (ER). Therapeutic strategies include a) reduction of circulating ovarian estrogen or of peripherally produced estrogen (in postmenopausal women) with aromatase inhibitors and b) application of selective estrogen receptor modulators (SERMS) for receptor blockade. Success of these interventions is limited by the variable but persistent onset of acquired resistance and by intrinsic refractiveness which manifests despite adequate levels of ER in about 50% of patients with advanced metastatic disease. Loss of functional ER leads to endocrine insensitivity, loss of cellular adhesion and polarity, and increased migratory potential due to trans-differentiation of the epithelial cancer cells into a mesenchymal-like phenotype (EMT). Multiple mechanisms contributing to therapeutic failure have been proposed: a) loss or modification in ER expression including epigenetic mechanisms b) agonistic actions of SERMS that may be enhanced through increased expression of co-activators c) attenuation of tamoxifen metabolism through expression of genetic variants of P450 cytochromes that leads to more or less active metabolites d) increased growth factor signaling particularly through epidermal growth factor receptor (EGFR/erbB2) activation of pathways involving keratinocyte growth factor (KGF) platelet-derived growth factor (PDGF/abl) and nuclear factor ƙB (NFƙB). In addition, the small non-coding microRNAs, recently recognized as critical gene regulators, exhibit differential expression in tamoxifen sensitive vs resistant cell lines. Several studies suggest the potential of using these either as targets, or as therapeutic agents, to modulate EMT regulators, as a means of reversing the aggressive metastatic phenotype by reversal of EMT, with the added benefit of re-sensitisation to anti-estrogens.
Impaired expression of DICER and some microRNAs in HBZ expressing cells from acute adult T-cell leukemia patients.Friday, February 05, 2016
Gazon H, Belrose G, Terol M, Meniane JC, Mesnard JM, Césaire R, Jr JP,
Oncotarget. 3-Feb-2016
Global dysregulation of microRNAs (miRNAs), a class of non-coding RNAs that regulate genes expression, is a common feature of human tumors. Profiling of cellular miRNAs on Adult T cell Leukemia (ATL) cells by Yamagishi et al. showed a strong decrease in expression for 96.7% of cellular miRNAs in ATL cells. However, the mechanisms that regulate the expression of miRNAs in ATL cells are still largely unknown. In this study, we compared the expression of 12 miRs previoulsy described for being overexpress by Tax and the expression of several key components of the miRNAs biogenesis pathways in different HBZ expressing cell lines as well as in primary CD4 (+) cells from acute ATL patients. We showed that the expression of miRNAs and Dicer1 were downregulated in cells lines expressing HBZ as weel as in fresh CD4 (+) cells from acute ATL patients. Using qRT-PCR, western blotting analysis and Chromatin Immunoprecipitation, we showed that dicer transcription was regulated by c-Jun and JunD, two AP-1 transcription factors. We also demonstrated that HBZ affects the expression of Dicer by removing JunD from the proximal promoter. Furthermore, we showed that at therapeutic concentration of 1mM, Valproate (VPA) an HDAC inhibitors often used in cancer treatment, rescue Dicer expression and miRNAs maturation. These results might offer a rationale for clinical studies of new combined therapy in an effort to improve the outcome of patients with acute ATL.
ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor.Friday, February 05, 2016
Divisato G, Formicola D, Esposito T, Merlotti D, Pazzaglia L, Del Fattore A, Siris E, Orcel P, Brown JP, Nuti R, Strazzullo P, Benassi MS, Cancela ML, Michou L, Rendina D, Gennari L, Gianfrancesco F,
American journal of human genetics. 4-Feb-2016
Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk.
Preparation of Cytokine-activated NK Cells for Use in Adoptive Cell Therapy in Cancer Patients: Protocol Optimization and Therapeutic Potential.Friday, February 05, 2016
van Ostaijen-Ten Dam MM, Prins HJ, Boerman GH, Vervat C, Pende D, Putter H, Lankester A, van Tol MJ, Zwaginga JJ, Schilham MW,
Journal of immunotherapy (Hagerstown, Md. : 1997). 15-9-2015
Cell-based immunotherapy using donor-derived natural killer (NK) cells after allogeneic hematopoietic stem cell transplantation may be an attractive treatment of residual leukemia. This study aimed to optimize clinical grade production of a cytokine-activated NK-cell product. NK cells were isolated either by double depletion (CD3, CD19) or by sequential depletion and enrichment (CD3, CD56) via CliniMACS from leukapheresis material and cultured in vitro with interleukin (IL)-2 or IL-15. Both NK cell isolation procedures yielded comparable recovery of NK cells and levels of T-cell contamination. After culture with cytokines, the CD3CD56 procedure resulted in NK cells of higher purity, that is, less T cells and monocytes, higher viability, and a slightly higher yield than the CD3CD19 procedure. CD69, NKp44, and NKG2A expression were higher on CD3CD56 products, whereas lysis of Daudi cells was comparable. Five days of culture led to higher expression of CD69, NKp44, and NKp30 and lysis of K562 and Daudi cell lines. Although CD69 expression and lysis of Daudi cells were slightly higher in cultures with IL-2, T-cell contamination was lower with IL-15. Therefore, further experiments were performed with CD3CD56 products cultured with IL-15. Cryopreservation of IL-15-activated NK cells resulted in a loss of cytotoxicity (>92%), whereas thawing of isolated, uncultured NK cells followed by culture with IL-15 yielded cells with about 43% of the original lytic activity. Five-day IL-15-activated NK cells lysed tumor target cell lines and primary leukemic blasts, providing the basis for NK cell-based immunotherapeutic strategies in a clinical setting.
Expansion of Tumor-reactive T Cells From Patients With Pancreatic Cancer.Friday, February 05, 2016
Meng Q, Liu Z, Rangelova E, Poiret T, Ambati A, Rane L, Xie S, Verbeke C, Dodoo E, Del Chiaro M, Löhr M, Segersvärd R, Maeurer MJ,
Journal of immunotherapy (Hagerstown, Md. : 1997). 6-2-2016
Generation of T lymphocytes with reactivity against cancer is a prerequisite for effective adoptive cellular therapies. We established a protocol for tumor-infiltrating lymphocytes (TILs) from patients with pancreatic ductal adenocarcinoma. Tumor samples from 17 pancreatic cancer specimens were cultured with cytokines (IL-2, IL-15, and IL-21) to expand TILs. After 10 days of culture, TILs were stimulated with an anti-CD3 antibody (OKT3) and irradiated allogeneic peripheral blood mononuclear cells. Reactivity of TILs against tumor-associated antigens (mesothelin, survivin, or NY-ESO-1) was detected by intracellular cytokine production by flow cytometry. Cytotoxicity was measured using a Chromium 51 release assay, and reactivity of TILs against autologous tumor cells was detected by INF-γ production (ELISA). TIL composition was tested by CD45RA, CCR7, 4-1BB, LAG-3, PD-1, TIM3, and CTLA-4 marker analysis. TCR Vβ was determined by flow cytometry and TCR clonality was gauged measuring the CDR3 region length by PCR analysis and subsequent sequencing. We could reliably obtain TILs from 17/17 patients with a majority of CD8 T cells. CD3CD8, CD3CD4, and CD3CD4CD8 [double-negative (DN) T cells] resided predominantly in central (CD45RACCR7) and effector (CD45RACCR7) memory subsets. CD8 TILs tested uniformly positive for LAG-3 (about 100%), whereas CD4 TILs showed only up to 12% LAG-3 staining and PD-1 showed a broad expression pattern in TILs from different patients. TILs from individual patients recognized strongly (up to 11.9% and 8.2% in CD8) NY-ESO-1, determined by ICS, or mesothelin, determined respectively by TNF-α and IFN-γ production. Twelve of 17 of CD8 TILs showed preferential expansion of certain TCR Vβ families (eg, 99.2% Vβ13.2 in CD8 TILs, 77% in the Vβ1, 65.9% in the Vβ22, and 63.3% in the Vβ14 family). TCR CDR3 analysis exhibited monoclonal or oligoclonal TCRs, some of them (eg, CD8 Vβ13.2) reacting strongly against autologous tumor defined by INF-γ production or by cytotoxicity. We have optimized methods for generating pancreatic cancer-specific TILs that can be used for adoptive cellular therapy of patients with pancreatic cancer.
The Immunomodulatory Potential of Mesenchymal Stromal Cells: A Story of a Regulatory Network.Friday, February 05, 2016
Najar M, Raicevic G, Crompot E, Fayyad-Kazan H, Bron D, Toungouz M, Lagneaux L,
Journal of immunotherapy (Hagerstown, Md. : 1997). 6-2-2016
Mesenchymal stromal cells (MSCs) have recently been the subject of great interest in the fields of regenerative medicine and immunotherapy due to their unique biological properties. In particular, MSCs possess immunoregulatory properties that can modulate immune as well as inflammatory responses. Although there are many studies about MSC immunomodulation, several complex and conflicting mechanisms have been reported. Herein, we aim to review these mechanisms and identify a link between these pathways. We focus on human studies in which bone marrow-derived MSCs and T cells were investigated. We propose that MSC-induced immunomodulation exists as a network where converging regulatory pathways compete to establish a tolerogenic state. As interleukin-10 seems to play a central role in this network, we also discuss the relationship between this cytokine and other regulatory factors in the context of immunomodulation.
A SCARECROW-based regulatory circuit controls Arabidopsis thaliana meristem size from the root endodermis.Friday, February 05, 2016
Moubayidin L, Salvi E, Giustini L, Terpstra I, Heidstra R, Costantino P, Sabatini S,
Planta. 5-Feb-2016
SCARECROW controls Arabidopsis root meristem size from the root endodermis tissue by regulating the DELLA protein RGA that in turn mediates the regulation of ARR1 levels at the transition zone. Coherent organ growth requires a fine balance between cell division and cell differentiation. Intriguingly, plants continuously develop organs post-embryonically thanks to the activity of meristems that allow growth and environmental plasticity. In Arabidopsis thaliana, continued root growth is assured when division of the distal stem cell and their daughters is balanced with cell differentiation at the meristematic transition zone (TZ). We have previously shown that at the TZ, the cytokinin-dependent transcription factor ARR1 controls the rate of differentiation commitment of meristematic cells and that its activities are coordinated with those of the distal stem cells by the gene SCARECROW (SCR). In the stem cell organizer (the quiescent center, QC), SCR directly suppresses ARR1 both sustaining stem cell activities and titrating non-autonomously the ARR1 transcript levels at the TZ via auxin. Here, we show that SCR also exerts a fine control on ARR1 levels at the TZ from the endodermis by sustaining gibberellin signals. From the endodermis, SCR controls the RGA REPRESSOR OF ga1-3 (RGA) DELLA protein stability throughout the root meristem, thus controlling ARR1 transcriptional activation at the TZ. This guarantees robustness and fineness to the control of ARR1 levels necessary to balance cell division to cell differentiation in sustaining coherent root growth. Therefore, this work advances the state of the art in the field of root meristem development by integrating the activity of three hormones, auxin, gibberellin, and cytokinin, under the control of different tissue-specific activities of a single root key regulator, SCR.
Mucin glycosylating enzyme GALNT2 suppresses malignancy in gastric adenocarcinoma by reducing MET phosphorylation.Friday, February 05, 2016
Liu SY, Shun CT, Hung KY, Juan HF, Hsu CL, Huang MC, Lai IR,
Oncotarget. 30-Jan-2016
Glycosylation affects malignancy in cancer. Here, we report that N- acetylgalactosaminyltransferase 2 (GALNT2), an enzyme that mediates the initial step of mucin type-O glycosylation, suppresses malignant phenotypes in gastric adenocarcinoma (GCA) by modifying MET (Hepatocyte growth factor receptor) activity. GALNT2 mRNA and protein were downregulated in GCAs, and this reduction was associated with more advanced disease stage and shorter recurrence-free survival. Suppressing GALNT2 expression in GCA cells increased cell growth, migration, and invasion in vitro, and tumor metastasis in vivo. GALNT2 knockdown enhanced phosphorylation of MET and decreased expression of the Tn antigen on MET. Inhibiting MET activity with PHA665752 decreased the malignant phenotypes caused by GALNT2 knockdown in GCA cells. Our results indicate that GALNT2 suppresses the malignant potential of GCA cells and provide novel insights into the significance of O-glycosylation in MET activity and GCA progression.
In Vitro Reconstruction of Neuronal Networks Derived from Human iPS Cells Using Microfabricated Devices.Friday, February 05, 2016
Takayama Y, Kida YS,
PloS one. 30-1-2016
Morphology and function of the nervous system is maintained via well-coordinated processes both in central and peripheral nervous tissues, which govern the homeostasis of organs/tissues. Impairments of the nervous system induce neuronal disorders such as peripheral neuropathy or cardiac arrhythmia. Although further investigation is warranted to reveal the molecular mechanisms of progression in such diseases, appropriate model systems mimicking the patient-specific communication between neurons and organs are not established yet. In this study, we reconstructed the neuronal network in vitro either between neurons of the human induced pluripotent stem (iPS) cell derived peripheral nervous system (PNS) and central nervous system (CNS), or between PNS neurons and cardiac cells in a morphologically and functionally compartmentalized manner. Networks were constructed in photolithographically microfabricated devices with two culture compartments connected by 20 microtunnels. We confirmed that PNS and CNS neurons connected via synapses and formed a network. Additionally, calcium-imaging experiments showed that the bundles originating from the PNS neurons were functionally active and responded reproducibly to external stimuli. Next, we confirmed that CNS neurons showed an increase in calcium activity during electrical stimulation of networked bundles from PNS neurons in order to demonstrate the formation of functional cell-cell interactions. We also confirmed the formation of synapses between PNS neurons and mature cardiac cells. These results indicate that compartmentalized culture devices are promising tools for reconstructing network-wide connections between PNS neurons and various organs, and might help to understand patient-specific molecular and functional mechanisms under normal and pathological conditions.
A simple and effective method for making multipotent/multilineage scaffolds with hydrophilic nature without any postmodification/treatment.Friday, February 05, 2016
Vaikkath D, Anitha R, Sumathy B, Nair PD,
Colloids and surfaces. B, Biointerfaces. 28-Dec-2015
A number of biodegradable and bioresorbable materials, as well as scaffold designs, have been experimentally and/or clinically studied for tissue engineering of diverse tissue types. Cell-material responses are strongly dependent on the properties of the scaffold material. In this study, scaffolds based on polycaprolactone (PCL) and PCL blended with a triblock copolymer, Polycaprolactone-polytetrahydrofuran-polycaprolactone (PCL-PTHF-PCL) at different ratios were fabricated by electrospinning. Blending and electrospinning of the triblock copolymer with PCL generated a super hydrophilic scaffold, the mechanical and biological properties of which varied with the concentration of the triblock copolymer. The hydrophilicity of the electrospun scaffolds was determined by measurement of water-air contact angle. Cellular response to the electrospun scaffolds was studied by seeding two types of cells, L929 fibroblast cell line and rat mesenchymal stem cells (RMSC). We observed that the super hydrophilicity of the material did not prevent cell adhesion, while the cell proliferation was low or negligible for scaffolds containing higher amount of PCL-PTHF-PCL. Chondrogenic differentiation of RMSC was found to be better on the PCL blend containing 10% (w/v) of PCL-PTHF-PCL than the bare PCL. Our studies indicate that the cellular response is dependent on the biomaterial composition and highlight the importance of tailoring the scaffold properties for applications in tissue engineering and regenerative medicine.
Stem cells and exosomes in cardiac repair.Friday, February 05, 2016
Singla DK,
Current opinion in pharmacology. 2-Feb-2016
Cardiac diseases currently lead in the number of deaths per year, giving rise an interest in transplanting embryonic and adult stem cells as a means to improve damaged tissue from conditions such as myocardial infarction and coronary artery disease. After testing these cells as a treatment option in both animal and human models, it is believed that these cells improve the damaged tissue primarily through the release of autocrine and paracrine factors. Major concerns such as teratoma formation, immune response, difficulty harvesting cells, and limited cell proliferation and differentiation, hinder the routine use of these cells as a treatment option in the clinic. The advent of stem cell-derived exosomes circumvent those concerns, while still providing the growth factors, miRNA, and additional cell protective factors that aid in repairing and regenerating the damaged tissue. These exosomes have been found to be anti-apoptotic, anti-fibrotic, pro-angiogenic, as well as enhance cardiac differentiation, all of which are key to repairing damaged tissue. As such, stem cell derived exosomes are considered to be a potential new and novel approach in the treatment of various cardiac diseases.
siRNA-Mediated Knockdown of the mTOR Inhibitor RTP801 Promotes Retinal Ganglion Cell Survival and Axon Elongation by Direct and Indirect Mechanisms.Friday, February 05, 2016
Morgan-Warren PJ, O'Neill J, de Cogan F, Spivak I, Ashush H, Kalinski H, Ahmed Z, Berry M, Feinstein E, Scott RA, Logan A,
Investigative ophthalmology & visual science. 1-Feb-2016
The RTP801 knockdown promoted RGC survival and axon elongation after ONC, without increasing de novo regenerative sprouting. The neuroprotection was predominantly direct, with mTORC1-dependent and -independent components. Enhanced neurite/axon elongation by siRTP801 required the presence of activated retinal glia and was mediated by potentiated secretion of neurotrophic factors.
FYN expression potentiates FLT3-ITD induced STAT5 signaling in acute myeloid leukemia.Friday, February 05, 2016
Chougule RA, Kazi JU, Rönnstrand L,
Oncotarget. 2-Feb-2016
FYN is a non-receptor tyrosine kinase belonging to the SRC family of kinases, which are frequently over-expressed in human cancers, and play key roles in cancer biology. SRC has long been recognized as an important oncogene, but little attention has been given to its other family members. In this report, we have studied the role of FYN in FLT3 signaling in respect to acute myeloid leukemia (AML). We observed that FYN displays a strong association with wild-type FLT3 as well as oncogenic FLT3-ITD and is dependent on the kinase activity of FLT3 and the SH2 domain of FYN. We identified multiple FYN binding sites in FLT3, which partially overlapped with SRC binding sites. To understand the role of FYN in FLT3 signaling, we generated FYN overexpressing cells. We observed that expression of FYN resulted in slightly enhanced phosphorylation of AKT, ERK1/2 and p38 in response to ligand stimulation. Furthermore, FYN expression led to a slight increase in FLT3-ITD-dependent cell proliferation, but potent enhancement of STAT5 phosphorylation as well as colony formation. We also observed that FYN expression is deregulated in AML patient samples and that higher expression of FYN, in combination with FLT3-ITD mutation, resulted in enrichment of the STAT5 signaling pathway and correlated with poor prognosis in AML. Taken together our data suggest that FYN cooperates with oncogenic FLT3-ITD in cellular transformation by selective activation of the STAT5 pathway. Therefore, inhibition of FYN, in combination with FLT3 inhibition, will most likely be beneficial for this group of AML patients.
Layer specific and general requirements for ERK/MAPK signaling in the developing neocortex.Friday, February 05, 2016
Xing L, Larsen RS, Bjorklund GR, Li X, Wu Y, Philpot BD, Snider WD, Newbern JM,
eLife. 2-2-2016
Aberrant signaling through the Raf/MEK/ERK (ERK/MAPK) pathway causes pathology in a family of neurodevelopmental disorders known as 'RASopathies' and is implicated in autism pathogenesis. Here, we have determined the functions of ERK/MAPK signaling in developing neocortical excitatory neurons. Our data reveal a critical requirement for ERK/MAPK signaling in the morphological development and survival of large Ctip2(+) neurons in layer 5. Loss of Map2k1/2 (Mek1/2) led to deficits in corticospinal tract formation and subsequent corticospinal neuron apoptosis. ERK/MAPK hyperactivation also led to reduced corticospinal axon elongation, but was associated with enhanced arborization. ERK/MAPK signaling was dispensable for axonal outgrowth of layer 2/3 callosal neurons. However, Map2k1/2 deletion led to reduced expression of Arc and enhanced intrinsic excitability in both layers 2/3 and 5, in addition to imbalanced synaptic excitation and inhibition. These data demonstrate selective requirements for ERK/MAPK signaling in layer 5 circuit development and general effects on cortical pyramidal neuron excitability.
Preclinical evaluation of a nanoformulated antihelminthic, niclosamide, in ovarian cancer.Friday, February 05, 2016
Lin CK, Bai MY, Hu TM, Wang YC, Chao TK, Weng SJ, Huang RL, Su PH, Lai HC,
Oncotarget. 1-Feb-2016
Ovarian cancer treatment remains a challenge and targeting cancer stem cells presents a promising strategy. Niclosamide is an "old" antihelminthic drug that uncouples mitochondria of intestinal parasites. Although recent studies demonstrated that niclosamide could be a potential anticancer agent, its poor water solubility needs to be overcome before further preclinical and clinical investigations can be conducted. Therefore, we evaluated a novel nanosuspension of niclosamide (nano-NI) for its effect against ovarian cancer. Nano-NI effectively inhibited the growth of ovarian cancer cells in which it induced a metabolic shift to glycolysis at a concentration of less than 3 μM in vitro and suppressed tumor growth without obvious toxicity at an oral dose of 100 mg/kg in vivo. In a pharmacokinetic study after oral administration, nano-NI showed rapid absorption (reaching the maximum plasma concentration within 5 min) and improved the bioavailability (the estimated bioavailability for oral nano-NI was 25%). In conclusion, nano-NI has the potential to be a new treatment modality for ovarian cancer and, therefore, further clinical trials are warranted.
Creating an Animal Model of Tendinopathy by Inducing Chondrogenic Differentiation with Kartogenin.Friday, February 05, 2016
Yuan T, Zhang J, Zhao G, Zhou Y, Zhang CQ, Wang JH,
PloS one. 1-2-2016
Previous animal studies have shown that long term rat treadmill running induces over-use tendinopathy, which manifests as proteoglycan accumulation and chondrocytes-like cells within the affected tendons. Creating this animal model of tendinopathy by long term treadmill running is however time-consuming, costly and may vary among animals. In this study, we used a new approach to develop an animal model of tendinopathy using kartogenin (KGN), a bio-compound that can stimulate endogenous stem/progenitor cells to differentiate into chondrocytes. KGN-beads were fabricated and implanted into rat Achilles tendons. Five weeks after implantation, chondrocytes and proteoglycan accumulation were found at the KGN implanted site. Vascularity as well as disorganization in collagen fibers were also present in the same site along with increased expression of the chondrocyte specific marker, collagen type II (Col. II). In vitro studies confirmed that KGN was released continuously from KGN-alginate in vivo beads and induced chondrogenic differentiation of tendon stem/progenitor cells (TSCs) suggesting that chondrogenesis after KGN-bead implantation into the rat tendons is likely due to the aberrant differentiation of TSCs into chondrocytes. Taken together, our results showed that KGN-alginate beads can be used to create a rat model of tendinopathy, which, at least in part, reproduces the features of over-use tendinopathy model created by long term treadmill running. This model is mechanistic (stem cell differentiation), highly reproducible and precise in creating localized tendinopathic lesions. It is expected that this model will be useful to evaluate the effects of various topical treatments such as NSAIDs and platelet-rich plasma (PRP) for the treatment of tendinopathy.
Role of the Slug Transcription Factor in Chemically-Induced Skin Cancer.Friday, February 05, 2016
von Maltzan K, Li Y, Rundhaug JE, Hudson LG, Fischer SM, Kusewitt DF,
Journal of clinical medicine. 5-2-2016
The Slug transcription factor plays an important role in ultraviolet radiation (UVR)-induced skin carcinogenesis, particularly in the epithelial-mesenchymal transition (EMT) occurring during tumor progression. In the present studies, we investigated the role of Slug in two-stage chemical skin carcinogenesis. Slug and the related transcription factor Snail were expressed at high levels in skin tumors induced by 7,12-dimethylbenz[α]anthracene application followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. TPA-induced transient elevation of Slug and Snail proteins in normal mouse epidermis and studies in Slug transgenic mice indicated that Slug modulates TPA-induced epidermal hyperplasia and cutaneous inflammation. Although Snail family factors have been linked to inflammation via interactions with the cyclooxygenase-2 (COX-2) pathway, a pathway that also plays an important role in skin carcinogenesis, transient TPA induction of Slug and Snail appeared unrelated to COX-2 expression. In cultured human keratinocytes, TPA induced Snail mRNA expression while suppressing Slug expression, and this differential regulation was due specifically to activation of the TPA receptor. These studies show that Slug and Snail exhibit similar patterns of expression during both UVR and chemical skin carcinogenesis, that Slug and Snail can be differentially regulated under some conditions and that in vitro findings may not recapitulate in vivo results.
Role of Epigenetics in Stem Cell Proliferation and Differentiation: Implications for Treating Neurodegenerative Diseases.Friday, February 05, 2016
Srinageshwar B, Maiti P, Dunbar GL, Rossignol J,
International journal of molecular sciences. 03-2-2016
The main objectives of this review are to survey the current literature on the role of epigenetics in determining the fate of stem cells and to assess how this information can be used to enhance the treatment strategies for some neurodegenerative disorders, like Huntington's disease, Parkinson's disease and Alzheimer's disease. Some of these epigenetic mechanisms include DNA methylation and histone modifications, which have a direct impact on the way that genes are expressed in stem cells and how they drive these cells into a mature lineage. Understanding how the stem cells are behaving and giving rise to mature cells can be used to inform researchers on effective ways to design stem cell-based treatments. In this review article, the way in which the basic understanding of how manipulating this process can be utilized to treat certain neurological diseases will be presented. Different genetic factors and their epigenetic changes during reprogramming of stem cells into induced pluripotent stem cells (iPSCs) have significant potential for enhancing the efficacy of cell replacement therapies.
Addition of Adipose-Derived Stem Cells to Mesenchymal Stem Cell Sheets Improves Bone Formation at an Ectopic Site.Friday, February 05, 2016
Wang Z, Li Z, Dai T, Zong C, Liu Y, Liu B,
International journal of molecular sciences. 02-2-2016
To determine the effect of adipose-derived stem cells (ADSCs) added to bone marrow-derived mesenchymal stem cell (MSC) sheets on bone formation at an ectopic site. We isolated MSCs and ADSCs from the same rabbits. We then prepared MSC sheets for implantation with or without ADSCs subcutaneously in the backs of severe combined immunodeficiency (SCID) mice. We assessed bone formation at eight weeks after implantation by micro-computed tomography and histological analysis. In osteogenic medium, MSCs grew to form multilayer sheets containing many calcium nodules. MSC sheets without ADSCs formed bone-like tissue; although neo-bone and cartilage-like tissues were sparse and unevenly distributed by eight weeks after implantation. In comparison, MSC sheets with ADSCs promoted better bone regeneration as evidenced by the greater density of bone, increased mineral deposition, obvious formation of blood vessels, large number of interconnected ossified trabeculae and woven bone structures, and greater bone volume/total volume within the composite constructs. Our results indicate that although sheets of only MSCs have the potential to form tissue engineered bone at an ectopic site, the addition of ADSCs can significantly increase the osteogenic potential of MSC sheets. Thus, the combination of MSC sheets with ADSCs may be regarded as a promising therapeutic strategy to stimulate bone regeneration.
Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine-289 phosphorylation.Friday, February 05, 2016
Jin Y, Cai Q, Shenoy AK, Lim S, Zhang Y, Charles S, Tarrash M, Fu X, Kamarajugadda S, Trevino JG, Tan M, Lu J,
Oncotarget. 3-Feb-2016
The Warburg effect, which reflects cancer cells' preference for aerobic glycolysis over glucose oxidation, contributes to tumor growth, progression and therapy resistance. The restraint on pyruvate flux into mitochondrial oxidative metabolism in cancer cells is in part attributed to the inhibition of pyruvate dehydrogenase (PDH) complex. Src is a prominent oncogenic non-receptor tyrosine kinase that promotes cancer cell proliferation, invasion, metastasis and resistance to conventional and targeted therapies. However, the potential role of Src in tumor metabolism remained unclear. Here we report that activation of Src attenuated PDH activity and generation of reactive oxygen species (ROS). Conversely, Src inhibitors activated PDH and increased cellular ROS levels. Src inactivated PDH through direct phosphorylation of tyrosine-289 of PDH E1α subunit (PDHA1). Indeed, Src was the main kinase responsible for PDHA1 tyrosine phosphorylation in cancer cells. Expression of a tyrosine-289 non-phosphorable PDHA1 mutant in Src-hyperactivated cancer cells restored PDH activity, increased mitochondrial respiration and oxidative stress, decreased experimental metastasis, and sensitized cancer cells to pro-oxidant treatment. The results suggest that Src contributes to the Warburg phenotype by inactivating PDH through tyrosine phosphorylation, and the metabolic effect of Src is essential for Src-driven malignancy and therapy resistance. Combination therapies consisting of both Src inhibitors and pro-oxidants may improve anticancer efficacy.
The Notch pathway promotes the cancer stem cell characteristics of CD90+ cells in hepatocellular carcinoma.Friday, February 05, 2016
Luo J, Wang P, Wang R, Wang J, Liu M, Xiong S, Li Y, Cheng B,
Oncotarget. 19-Dec-2015
CD90 has been identified as a marker for liver cancer stem cells (CSCs) that are responsible for tumorigenic activity, but it is not known how CD90+ cells contribute to tumor initiation and progression. Our data demonstrated that high expression of CD90 in Hepatocellular Carcinoma (HCC) tissues correlated with venous filtration in HCC patients. CD90+ cells isolated from HCC cell lines exhibited increased tumorigenicity, chemoresistance, tumor invasion and metastasis. Notch pathway was activated in CD90+ cells and we found that inhibition of Notch pathway in CD90+ CSCs decreased tumorigenicity, cell invasion, migration and expression of stem cell related genes. Activation of Notch pathway in CD90- cells induced self-renewal, invasion and migration. Furthermore, we observed that cancer stem cell features were facilitated by stimulating G1-S transition in the cell cycle phase and inhibiting apoptosis mediated by Notch pathway. Our findings suggested CD90 could be used as a potential biomarker for HCC CSCs, and that cancer stem cell activity was elevated through up activated Notch pathway in CD90+ CSCs.
Evaluating Cell Processes, Quality, and Biomarkers in Pluripotent Stem Cells Using Video Bioinformatics.Friday, February 05, 2016
Zahedi A, On V, Lin SC, Bays BC, Omaiye E, Bhanu B, Talbot P,
PloS one. 19-12-2015
There is a foundational need for quality control tools in stem cell laboratories engaged in basic research, regenerative therapies, and toxicological studies. These tools require automated methods for evaluating cell processes and quality during in vitro passaging, expansion, maintenance, and differentiation. In this paper, an unbiased, automated high-content profiling toolkit, StemCellQC, is presented that non-invasively extracts information on cell quality and cellular processes from time-lapse phase-contrast videos. Twenty four (24) morphological and dynamic features were analyzed in healthy, unhealthy, and dying human embryonic stem cell (hESC) colonies to identify those features that were affected in each group. Multiple features differed in the healthy versus unhealthy/dying groups, and these features were linked to growth, motility, and death. Biomarkers were discovered that predicted cell processes before they were detectable by manual observation. StemCellQC distinguished healthy and unhealthy/dying hESC colonies with 96% accuracy by non-invasively measuring and tracking dynamic and morphological features over 48 hours. Changes in cellular processes can be monitored by StemCellQC and predictions can be made about the quality of pluripotent stem cell colonies. This toolkit reduced the time and resources required to track multiple pluripotent stem cell colonies and eliminated handling errors and false classifications due to human bias. StemCellQC provided both user-specified and classifier-determined analysis in cases where the affected features are not intuitive or anticipated. Video analysis algorithms allowed assessment of biological phenomena using automatic detection analysis, which can aid facilities where maintaining stem cell quality and/or monitoring changes in cellular processes are essential. In the future StemCellQC can be expanded to include other features, cell types, treatments, and differentiating cells.
Phenylethyl isothiocyanate reverses cisplatin resistance in biliary tract cancer cells via glutathionylation-dependent degradation of Mcl-1.Friday, February 05, 2016
Li Q, Zhan M, Chen W, Zhao B, Yang K, Yang J, Yi J, Huang Q, Mohan M, Hou Z, Wang J,
Oncotarget. 3-Feb-2016
Biliary tract cancer (BTC) is a highly malignant cancer. BTC exhibits a low response rate to cisplatin (CDDP) treatment, and therefore, an understanding of the mechanism of CDDP resistance is urgently needed. Here, we show that BTC cells develop CDDP resistance due, in part, to upregulation of myeloid cell leukemia 1 (Mcl-1). Phenylethyl isothiocyanate (PEITC), a natural compound found in watercress, could enhance the efficacy of CDDP by degrading Mcl-1. PEITC-CDDP co-treatment also increased the rate of apoptosis of cancer stem-like side population (SP) cells and inhibited xenograft tumor growth without obvious toxic effects. In vitro, PEITC decreased reduced glutathione (GSH), which resulted in decreased GSH/oxidized glutathione (GSSG) ratio and increased glutathionylation of Mcl-1, leading to rapid proteasomal degradation of Mcl-1. Furthermore, we identified Cys16 and Cys286 as Mcl-1 glutathionylation sites, and mutating them resulted in PEITC-mediated degradation resistant Mcl-1 protein. In conclusion, we demonstrate for the first time that CDDP resistance is partially associated with Mcl-1 in BTC cells and we identify a novel mechanism that PEITC can enhance CDDP-induced apoptosis via glutathionylation-dependent degradation of Mcl-1. Hence, our results provide support that dietary intake of watercress may help reverse CDDP resistance in BTC patients.
Novel Acellular Scaffold Made from Decellularized Schwann Cell Sheets for Peripheral Nerve Regeneration.Friday, February 05, 2016
Junka R, Yu X,
Regenerative engineering and translational medicine. Dec-2015
Peripheral nerve injuries present a serious clinical need with approximately 50 % of surgical cases achieving only some restoration of function. In order to better guide regenerating nerves, supporting cells of the nerve tissue were grown into sheets and subsequently decellularized, leaving a myriad of surrounding protein as a scaffold. Constructs have been shown to support cell growth and neurite extension in vitro. Future projects will combine various cell types present in the nerve tissue as well as stem cells to fully support and reconstruct architecture of the peripheral nerves.
miR-199b, a novel tumor suppressor miRNA in acute myeloid leukemia with prognostic implications.Friday, February 05, 2016
Favreau AJ, McGlauflin RE, Duarte CW, Sathyanarayana P,
Experimental hematology & oncology. 2015
Loss of miR-199b can lead to myeloproliferation while HDAC inhibitors restore miR-199b expression and promote apoptosis. Low miR-199b in AML patients correlates with worse overall survival and has prognostic significance for FAB-M5 subtype.
Crosstalk between adipose-derived stem cells and chondrocytes: when growth factors matter.Friday, February 05, 2016
Zhong J, Guo B, Xie J, Deng S, Fu N, Lin S, Li G, Lin Y, Cai X,
Bone research. 2016
Adipose-derived stem cells (ASCs) and mesenchymal stem cells are promising for tissue repair because of their multilineage differentiation capacity. Our previous data confirmed that the implantation of mixed ASCs and chondrocytes into cartilage defects induced desirable in vivo healing outcomes. However, the paracrine action of ASCs on chondrocytes needs to be further elucidated. In this study, we established a co-culture system to achieve cell-to-cell and cell-to-tissue crosstalk and explored the soluble growth factors in both ASCs and chondrocytes supplemented with 1% fetal bovine serum to mimic the physiological microenvironment. In ASCs, we screened for growth factors by semi-quantitative PCR and quantitative real-time PCR and found that the expression of bone morphogenetic protein 2 (BMP-2), vascular endothelial growth factor B (VEGFB), hypoxia inducible factor-1α (HIF-1α), fibroblast growth factor-2 (FGF-2), and transforming growth factor-β1 significantly increased after co-culture in comparison with mono-culture. In chondrocytes, VEGFA was significantly enhanced after co-culture. Unexpectedly, the expression of collagen II and aggrecan was significantly down-regulated in the co-culture group compared with the mono-culture group. Meanwhile, among all the growth factors screened, we found that the BMP family members BMP-2, BMP-4, and BMP-5 were down-regulated and that VEGFB, HIF-1α, FGF-2, and PDGF were significantly decreased after co-culture. These results suggest that crosstalk between ASCs and chondrocytes is a pathway through the regulated growth factors that might have potential in cartilage repair and regeneration and could be useful for tissue engineering.
AAV vector encoding human VEGF165-transduced pectineus muscular flaps increase the formation of new tissue through induction of angiogenesis in an in vivo chamber for tissue engineering: A technique to enhance tissue and vessels in microsurgically engineered tissue.Friday, February 05, 2016
Moimas S, Manasseri B, Cuccia G, Stagno d'Alcontres F, Geuna S, Pattarini L, Zentilin L, Giacca M, Colonna MR,
Journal of tissue engineering. 03-02-2016
In regenerative medicine, new approaches are required for the creation of tissue substitutes, and the interplay between different research areas, such as tissue engineering, microsurgery and gene therapy, is mandatory. In this article, we report a modification of a published model of tissue engineering, based on an arterio-venous loop enveloped in a cross-linked collagen-glycosaminoglycan template, which acts as an isolated chamber for angiogenesis and new tissue formation. In order to foster tissue formation within the chamber, which entails on the development of new vessels, we wondered whether we might combine tissue engineering with a gene therapy approach. Based on the well-described tropism of adeno-associated viral vectors for post-mitotic tissues, a muscular flap was harvested from the pectineus muscle, inserted into the chamber and transduced by either AAV vector encoding human VEGF165 or AAV vector expressing the reporter gene β-galactosidase, as a control. Histological analysis of the specimens showed that muscle transduction by AAV vector encoding human VEGF165 resulted in enhanced tissue formation, with a significant increase in the number of arterioles within the chamber in comparison with the previously published model. Pectineus muscular flap, transduced by adeno-associated viral vectors, acted as a source of the proangiogenic factor vascular endothelial growth factor, thus inducing a consistent enhancement of vessel growth into the newly formed tissue within the chamber. In conclusion, our present findings combine three different research fields such as microsurgery, tissue engineering and gene therapy, suggesting and showing the feasibility of a mixed approach for regenerative medicine.
Controlled-release of tetracycline and lovastatin by poly(d,l-lactide-co-glycolide acid)-chitosan nanoparticles enhances periodontal regeneration in dogs.Friday, February 05, 2016
Lee BS, Lee CC, Wang YP, Chen HJ, Lai CH, Hsieh WL, Chen YW,
International journal of nanomedicine. 2016
Chronic periodontitis is characterized by inflammation of periodontal tissues, leading to bone resorption and tooth loss. The goal of treatment is to regenerate periodontal tissues including bone and cementum lost as a consequence of disease. The local delivery of tetracycline was proven to be effective in controlling localized periodontal infection without apparent side effects. Previous studies suggested that lovastatin has a significant role in new bone formation; however, the local delivery of lovastatin might enhance its therapeutic effects. A number of local delivery devices have been developed recently, including poly(d,l-lactide-co-glycolide acid) (PLGA) nanoparticles. The aim of this study was to develop a local delivery device, PLGA-lovastatin-chitosan-tetracycline nanoparticles, which allows the sequential release of tetracycline and lovastatin to effectively control local infection and promote bone regeneration in periodontitis. The size and microstructure of nanoparticles were examined by transmission electron microscopy, Nanoparticle Size Analyzer, and Fourier transform infrared spectroscopy. The release of tetracycline and lovastatin was quantified using a UV-Vis spectrophotometer. Furthermore, the cytotoxic effect and alkaline phosphatase activity of the nanoparticles in osteoblast cell cultures as well as antibacterial activity against periodontal pathogens were investigated. Finally, the bone regeneration potential of PLGA nanoparticles in three-walled defects in beagle dogs was investigated. The results indicated that PLGA-lovastatin-chitosan-tetracycline nanoparticles showed good biocompatibility, antibacterial activity, and increased alkaline phosphatase activity. The volumetric analysis from micro-CT revealed significantly increased new bone formation in defects filled with nanoparticles in dogs. This novel local delivery device might be useful as an adjunctive treatment in periodontal regenerative therapy.
Fullerene mediates proliferation and cardiomyogenic differentiation of adipose-derived stem cells via modulation of MAPK pathway and cardiac protein expression.Friday, February 05, 2016
Hao T, Zhou J, Lü S, Yang B, Wang Y, Fang W, Jiang X, Lin Q, Li J, Wang C,
International journal of nanomedicine. 2016
Zero-dimensional fullerenes can modulate the biological behavior of a variety of cell lines. However, the effects and molecular mechanisms of proliferation and cardiomyogenic differentiation in brown adipose-derived stem cells (BADSCs) are still unclear. In this study, we report the initial biological effects of fullerene-C60 on BADSCs at different concentrations. Results suggest that fullerene-C60 has no cytotoxic effects on BADSCs even at a concentration of 100 μg/mL. Fullerene-C60 improves the MAPK expression level and stem cell survival, proliferation, and cardiomyogenesis. Further, we found that the fullerene-C60 modulates cardiomyogenic differentiation. Fullerene-C60 improves the expression of cardiomyocyte-specific proteins (cTnT and α-sarcomeric actinin). At elevated concentration, fullerene-C60 reduces the incidence of diminished spontaneous cardiac differentiation of BADSCs with time. At the genetic level, fullerene-C60 (5 μg/mL) also improves the expression of cTnT. In addition, fullerene-C60 promotes the formation of gap junction among cells. These findings have important implications for clinical application of fullerenes in the treatment of myocardial infarction.
Protein kinase A inhibitor, H89, enhances survival and clonogenicity of dissociated human embryonic stem cells through Rho-associated coiled-coil containing protein kinase (ROCK) inhibition.Friday, February 05, 2016
Zhang L, Xu Y, Xu J, Wei Y, Xu X,
Human reproduction (Oxford, England). 3-Feb-2016
Nil.
A Telomerase-specific Doxorubicin-releasing Molecular Beacon for Cancer Theranostics.Friday, February 05, 2016
Ma Y, Wang Z, Zhang M, Han Z, Chen D, Zhu Q, Gao W, Qian Z, Gu Y,
Angewandte Chemie (International ed. in English). 5-Feb-2016
A molecular beacon-based drug delivery system was designed for both detection of telomerase activity in living cells and telomerase-triggered drug release for precise cancer treatment. This system is composed of a gold nanoparticle core densely packed with FITC-labeled hairpin DNA sequences hybridized with telomerase primers. Molecules of the anticancer drug doxorubicin were intercalated into the stem region of the DNA sequence. The presence of telomerase will elongate the primers, leading to inner chain substitution followed by the release of the FITC fluorescence and the trapped doxorubicin. This molecular beacon could specifically distinguish tumor cells and normal cells based on telomerase activity, precisely release doxorubicin in response to telomerase activity in the tumor cells, and prevent toxicity to normal organs.
Notch regulation of gastrointestinal stem cells.Friday, February 05, 2016
Demitrack ES, Samuelson LC,
The Journal of physiology. 5-Feb-2016
The gastrointestinal (GI) tract epithelium is continuously replenished by actively cycling stem and progenitor cells. These cell compartments are regulated to balance proliferation and stem cell renewal with differentiation into the various mature cell types to maintain tissue homeostasis. In this topical review we focus on the role of the Notch signaling pathway to regulate GI stem cell function in adult small intestine and stomach. We first present the current view of stem and progenitor cell populations in these tissues and then summarize the studies that have established the Notch pathway as a key regulator of gastric and intestinal stem cell function. Notch signaling has been shown to be a niche factor required for maintenance of GI stem cells in both tissues. In addition, Notch has been described to regulate epithelial cell differentiation. Recent studies have revealed key similarities and differences in how Notch regulates stem cell function in the stomach compared to intestine. We summarize the literature regarding Notch regulation of GI stem cell proliferation and differentiation, highlighting tissue specific functions to compare and contrast Notch in the stomach and intestine. This article is protected by copyright. All rights reserved.
Precision Medicine: Personalized Proteomics for the Diagnosis and Treatment of Idiopathic Inflammatory Disease.Friday, February 05, 2016
Velez G, Roybal CN, Colgan D, Tsang SH, Bassuk AG, Mahajan VB,
JAMA ophthalmology. 4-Feb-2016
The analysis identifies a common cytokine signature for posterior uveitis and guides the diagnosis of a patient with idiopathic uveitis. Personalized treatment reversed the visual loss, illustrating how proteomic tools may individualize therapy.
The effect of diabetes on the wound healing potential of adipose-tissue derived stem cells.Friday, February 05, 2016
Kim SM, Kim YH, Jun YJ, Yoo G, Rhie JW,
International wound journal. Mar-2016
To investigate whether diabetes mellitus affects the wound-healing-promoting potential of adipose tissue-derived stem cells, we designed a wound-healing model using diabetic mice. We compared the degree of wound healing between wounds treated with normal adipose tissue-derived stem cells and wounds treated with diabetic adipose tissue-derived stem cells. We evaluated the wound-healing rate, the epithelial tongue distance, the area of granulation tissue, the number of capillary and the number of Ki-67-stained cells. The wound-healing rate was significantly higher in the normal adipose tissue-derived stem cells group than in the diabetic adipose tissue-derived stem cells group; it was also significantly higher in the normal adipose tissue-derived stem cells group than in the control group. Although the diabetic adipose tissue-derived stem cells group showed a better wound-healing rate than the control group, the difference was not statistically significant. Similar trends were observed for the other parameters examined: re-epithelisation and keratinocyte proliferation; granulation tissue formation; and dermal regeneration. However, with regard to the number of capillary, diabetic adipose tissue-derived stem cells retained their ability to promote neovasculisation and angiogenesis. These results reflect the general impairment of the therapeutic potential of diabetic adipose tissue-derived stem cells in vivo.
Macrophage migration inhibitory factor induces autophagy to resist hypoxia/serum deprivation‑induced apoptosis via the AMP‑activated protein kinase/mammalian target of rapamycin signaling pathway.Friday, February 05, 2016
Xia W, Hou M,
Molecular medicine reports. 3-Feb-2016
Macrophage migration inhibitory factor (MIF) is an anti‑apoptotic agent in various cell types and protects the heart from stress‑induced injury by modulating autophagy. Autophagy, a conserved pathway for bulk degradation of intracellular proteins and organelles, helps to preserve and recycle energy and nutrients for cells to survive during starvation. The present study hypothesized that MIF protects bone marrow‑derived mesenchymal stem cells (MSCs) from apoptosis by modulating autophagy via the AMP‑activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway. MSCs were obtained from rat bone marrow and cultured. Apoptosis was induced by hypoxia/serum deprivation for 24 h and was assessed using flow cytometry. MIF protected MSCs from apoptosis by modulating autophagy via the AMPK/mTOR signaling pathway resulting in increased expression of autophagy‑associated proteins (including LC3BI/LC3BII, Beclin‑1 and autophagy protein 5), and by increased phosphorylation of AMPK and decreased phosphorylation of mTOR. The MIF anti‑apoptotic effects were blocked by autophagy inhibitor, 3‑methyladenine or AMPK inhibitor, Compound C. These results indicate that MIF exerts a permissive role in protecting MSCs from apoptosis by regulation of autophagy via the AMPK/mTOR signaling pathway.
Histone H4 acetylation and the epigenetic reader Brd4 are critical regulators of pluripotency in embryonic stem cells.Friday, February 05, 2016
Gonzales-Cope M, Sidoli S, Bhanu NV, Won KJ, Garcia BA,
BMC genomics. 2016
Together, our data demonstrate the fundamental role of Brd4 in monitoring cell differentiation through its interaction with acetylated histone marks and disruption of Brd4 may cause aberrant differentiation.
Recurrent cerebral ischaemic events in the setting of paroxysmal nocturnal haemoglobinuria.Friday, February 05, 2016
Azevedo L, Costa MR, Fonseca AC, Pinho E Melo T,
BMJ case reports. 2016
The authors present a case of a 28-year-old man with a known history of paroxysmal nocturnal haemoglobinuria (PNH), under platelet antiaggregation, admitted following recurrent transitory arterial ischaemic attacks. Concomitant thrombosis of the superior mesenteric artery and bilateral renal infarction was found. Cardioembolism, namely patent foramen ovale, was excluded and anticoagulation added, with no further events on 10-month follow-up. PNH is a rare acquired disorder of haematopoietic stem cells, characterised by haemolytic anaemia, pancytopenia and thrombotic events classically involving the venous system. Reports of cerebral artery stroke and accompanying intra-abdominal arterial thrombosis are especially rare. Complementary investigation and treatment options in these patients are discussed.
KCTD12 Regulates Colorectal Cancer Cell Stemness through the ERK Pathway.Friday, February 05, 2016
Li L, Duan T, Wang X, Zhang RH, Zhang M, Wang S, Wang F, Wu Y, Huang H, Kang T,
Scientific reports. 2016
Targeting cancer stem cells (CSCs) in colorectal cancer (CRC) remains a difficult problem, as the regulation of CSCs in CRC is poorly understood. Here we demonstrated that KCTD12, potassium channel tetramerization domain containing 12, is down-regulated in the CSC-like cells of CRC. The silencing of endogenous KCTD12 and the overexpression of ectopic KCTD12 dramatically enhances and represses CRC cell stemness, respectively, as assessed in vitro and in vivo using a colony formation assay, a spheroid formation assay and a xenograft tumor model. Mechanistically, KCTD12 suppresses CRC cell stemness markers, such as CD44, CD133 and CD29, by inhibiting the ERK pathway, as the ERK1/2 inhibitor U0126 abolishes the increase in expression of CRC cell stemness markers induced by the down-regulation of KCTD12. Indeed, a decreased level of KCTD12 is detected in CRC tissues compared with their adjacent normal tissues and is an independent prognostic factor for poor overall and disease free survival in patients with CRC (p = 0.007). Taken together, this report reveals that KCTD12 is a novel regulator of CRC cell stemness and may serve as a novel prognostic marker and therapeutic target for patients with CRC.
Intracerebral hemorrhage and deep microbleeds associated with cnm-positive Streptococcus mutans; a hospital cohort study.Friday, February 05, 2016
Tonomura S, Ihara M, Kawano T, Tanaka T, Okuno Y, Saito S, Friedland RP, Kuriyama N, Nomura R, Watanabe Y, Nakano K, Toyoda K, Nagatsuka K,
Scientific reports. 2016
Oral infectious diseases are epidemiologically associated with stroke. We previously showed that oral Streptococcus mutans with the cnm gene encoding a collagen-binding Cnm protein induced intracerebral hemorrhage (ICH) experimentally and was also associated with cerebral microbleeds (CMBs) in our population-based cohort study. We therefore investigated the roles of cnm-positive Streptococcus mutans in this single hospital-based, observational study that enrolled 100 acute stroke subjects. The cnm gene in Streptococcus mutans isolated from saliva was screened using PCR techniques and its collagen-binding activities examined. CMBs were evaluated on T2* gradient-recalled echo MRI. One subject withdrew informed consent and 99 subjects (63 males) were analyzed, consisting of 67 subjects with ischemic stroke, 5 with transient ischemic attack, and 27 with ICH. Eleven cases showed Streptococcus mutans strains positive for cnm. The presence of cnm-positive Streptococcus mutans was significantly associated with ICH [OR vs. ischemic stroke, 4.5; 95% CI, 1.17-19.1] and increased number of deep CMBs [median (IQR), 3 (2-9) vs. 0 (0-1), p = 0.0002]. In subjects positive for Streptococcus mutans, collagen binding activity was positively correlated with the number of deep CMBs (R(2) = 0.405; p < 0.0001). These results provide further evidence for the key role of oral health in stroke.
Correspondence on: "Microgravity Reduces the Differentiation and Regenerative Potential of Embryonic Stem Cells".Friday, February 05, 2016
Verhaar A, Peppelenbosch M,
Stem cells and development. 5-Feb-2016
Role of the Retinoblastoma protein, Rb, during adult neurogenesis in the olfactory bulb.Friday, February 05, 2016
Naser R, Vandenbosch R, Omais S, Hayek D, Jaafar C, Al Lafi S, Saliba A, Baghdadi M, Skaf L, Ghanem N,
Scientific reports. 2016
Adult neural stem cells (aNSCs) are relatively quiescent populations that give rise to distinct neuronal subtypes throughout life, yet, at a very low rate and restricted differentiation potential. Thus, identifying the molecular mechanisms that control their cellular expansion is critical for regeneration after brain injury. Loss of the Retinoblastoma protein, Rb, leads to several defects in cell cycle as well as neuronal differentiation and migration during brain development. Here, we investigated the role of Rb during adult neurogenesis in the olfactory bulb (OB) by inducing its temporal deletion in aNSCs and progenitors. Loss of Rb was associated with increased proliferation of adult progenitors in the subventricular zone (SVZ) and the rostral migratory stream (RMS) but did not alter self-renewal of aNSCs or neuroblasts subsequent migration and terminal differentiation. Hence, one month after their birth, Rb-null neuroblasts were able to differentiate into distinct subtypes of GABAergic OB interneurons but were gradually lost after 3 months. Similarly, Rb controlled aNSCs/progenitors proliferation in vitro without affecting their differentiation capacity. This enhanced SVZ/OB neurogenesis associated with loss of Rb was only transient and negatively affected by increased apoptosis indicating a critical requirement for Rb in the long-term survival of adult-born OB interneurons.
Silver nanoparticles disrupt germline stem cell maintenance in the Drosophila testis.Friday, February 05, 2016
Ong C, Lee QY, Cai Y, Liu X, Ding J, Yung LY, Bay BH, Baeg GH,
Scientific reports. 2016
Silver nanoparticles (AgNPs), one of the most popular nanomaterials, are commonly used in consumer products and biomedical devices, despite their potential toxicity. Recently, AgNP exposure was reported to be associated with male reproductive toxicity in mammalian models. However, there is still a limited understanding of the effects of AgNPs on spermatogenesis. The fruit fly Drosophila testis is an excellent in vivo model to elucidate the mechanisms underlying AgNP-induced defects in spermatogenesis, as germ lineages can be easily identified and imaged. In this study, we evaluated AgNP-mediated toxicity on spermatogenesis by feeding Drosophila with AgNPs at various concentrations. We first observed a dose-dependent uptake of AgNPs in vivo. Concomitantly, AgNP exposure caused a significant decrease in the viability and delay in the development of Drosophila in a dose-dependent manner. Furthermore, AgNP-treated male flies showed a reduction in fecundity, and the resulting testes contained a decreased number of germline stem cells (GSCs) compared to controls. Interestingly, testes exposed to AgNPs exhibited a dramatic increase in reactive oxygen species levels and showed precocious GSC differentiation. Taken together, our study suggests that AgNP exposure may increase ROS levels in the Drosophila testis, leading to a reduction of GSC number by promoting premature GSC differentiation.
Negative regulation of initial steps in skeletal myogenesis by mTOR and other kinases.Friday, February 05, 2016
Wilson RA, Liu J, Xu L, Annis J, Helmig S, Moore G, Timmerman C, Grandori C, Zheng Y, Skapek SX,
Scientific reports. 2016
The transition from a committed progenitor cell to one that is actively differentiating represents a process that is fundamentally important in skeletal myogenesis. Although the expression and functional activation of myogenic regulatory transcription factors (MRFs) are well known to govern lineage commitment and differentiation, exactly how the first steps in differentiation are suppressed in a proliferating myoblast is much less clear. We used cultured mammalian myoblasts and an RNA interference library targeting 571 kinases to identify those that may repress muscle differentiation in proliferating myoblasts in the presence or absence of a sensitizing agent directed toward CDK4/6, a kinase previously established to impede muscle gene expression. We identified 55 kinases whose knockdown promoted myoblast differentiation, either independently or in conjunction with the sensitizer. A number of the hit kinases could be connected to known MRFs, directly or through one interaction node. Focusing on one hit, Mtor, we validated its role to impede differentiation in proliferating myoblasts and carried out mechanistic studies to show that it acts, in part, by a rapamycin-sensitive complex that involves Raptor. Our findings inform our understanding of kinases that can block the transition from lineage commitment to a differentiating state in myoblasts and offer a useful resource for others studying myogenic differentiation.
miR-203 inhibits proliferation and self-renewal of leukemia stem cells by targeting survivin and Bmi-1.Friday, February 05, 2016
Zhang Y, Zhou SY, Yan HZ, Xu DD, Chen HX, Wang XY, Wang X, Liu YT, Zhang L, Wang S, Zhou PJ, Fu WY, Ruan BB, Ma DL, Wang Y, Liu QY, Ren Z, Liu Z, Zhang R, Wang YF,
Scientific reports. 2016
Drug resistance is one of the leading causes of failed cancer therapy in the treatment of acute myeloid leukemia. Although the mechanisms of resistance are poorly understood, they may be related to the presence of leukemia stem cells (LSCs). Down-regulation of the miR-203 reportedly contributes to oncogenesis and chemo-resistance in multiple cancers. We found that miR-203 expression was down-regulated in CD34 + AML cells as compared with CD34- cells isolated from patients as well as in LSC-enriched (CD34 + CD38-) cell lines KG-1a or MOLM13. Additionally, re-expression of miR-203 led to decreased cell proliferation, self-renewal, and sphere formation in LSCs. Moreover, miR-203 was found to directly target the 3'un-translated regions of survivin and Bmi-1 mRNAs affecting proliferation and self-renewal in LSCs. In this study, we identified a novel miR-203/survivin/Bmi-1 axis involved in the regulation of biological properties of LSCs. This axis may represent a new therapeutic target for acute myeloid leukemia and a potential prognosis/diagnostic marker for LSCs therapy.
Notch-induced expression of FZD7 requires noncanonical NOTCH3 signalling in human breast epithelial cells.Friday, February 05, 2016
Bhat V, Sun Y, Weger S, Raouf A,
Stem cells and development. 5-Feb-2016
The evolutionarily conserved Notch and Wnt signaling pathways have demonstrated roles in normal mammary gland development and in breast carcinogenesis. We previously reported that in human mammary gland, signaling through NOTCH3 alone regulates the commitment of the undifferentiated bipotential progenitors to the luminal cell fate, indicating that NOTCH3 may regulate the expression of unique genes apart from the other Notch receptors. In this study, we used gain of function and loss of function experiments and found that a Wnt signaling receptor, Frizzled7 (FZD7), is a unique and non-redundant target of NOTCH3 in human breast epithelial cells. Interestingly, neither the constitutively active forms of NOTCH1-2, 4 nor loss of expression of these receptors were able to alter expression of FZD7 in human breast epithelial cells. We further show that FZD7-expressing cells are found more frequently in the luminal progenitor-enriched subpopulation of cells obtained from breast reduction samples compared to the undifferentiated bipotent progenitors. As well, we show that NOTCH3-induced expression of FZD7 occurs in absence of CSL (CBF1-Suppressor of Hairless-Lag-1). Our data suggest that non-canonical Notch signaling through NOTCH3 could modulate Wnt signaling via FZD7 and in this way, might be involved in luminal cell differentiation.
Hoxa10 null animals exhibit reduced platelet biogenesis.Friday, February 05, 2016
Konieczna IM, DeLuca TA, Eklund EA, Miller WM,
British journal of haematology. 5-Feb-2016
The transcription factor HOXA10 is an important regulator of myelopoiesis. Engineered over-expression of Hoxa10 in mice results in a myeloproliferative disorder that progresses to acute myeloid leukaemia (AML) over time, and in humans over-expression is associated with poor outcomes in AML. Here, we report that loss of Hoxa10 expression in mice results in reduced platelet count and platelet production, but does not affect clotting efficiency. About 40% fewer platelets were found in Hoxa10 null animals in comparison to wild type littermates. We found a nearly 50% reduction in the percentage of reticulated platelets in Hoxa10 null mice, suggesting deficient platelet production. Furthermore, Hoxa10 null animals recovered less efficiently from induced thrombocytopenia, supporting our hypothesis of defective platelet production. This also correlated with reduced colony formation potential of stem and progenitor cells seeded in megakaryocyte-enhancing conditions in vitro. Together, our results indicate that HOXA10 is important for megakaryopoiesis and platelet biogenesis.
Genetic diversity and natural selection in the rhoptry-associated protein 1 (RAP-1) of recent Plasmodium knowlesi clinical isolates from Malaysia.Friday, February 05, 2016
Rawa MS, Fong MY, Lau YL,
Malaria journal. 2016
The present study found higher genetic polymorphism in the PkRAP-1 gene than the polymorphism level reported in a previous study. This observation may stem from the difference in sample size between the present (n = 30) and the previous (n = 5) study. Synonymous and non-synonymous mutation analysis indicated purifying (negative) selection of the gene. The separation of PkRAP-1haplotypes into two groups provides further evidence to the postulation of two distinct P. knowlesi types or lineages.
Molecular insights into the premature aging disease progeria.Friday, February 05, 2016
Vidak S, Foisner R,
Histochemistry and cell biology. 4-Feb-2016
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease presenting many features resembling the normal aging process. HGPS patients die before the age of 20 years due to cardiovascular problems and heart failure. HGPS is linked to mutations in the LMNA gene encoding the intermediate filament protein lamin A. Lamin A is a major component of the nuclear lamina, a scaffold structure at the nuclear envelope that defines mechanochemical properties of the nucleus and is involved in chromatin organization and epigenetic regulation. Lamin A is also present in the nuclear interior where it fulfills lamina-independent functions in cell signaling and gene regulation. The most common LMNA mutation linked to HGPS leads to mis-splicing of the LMNA mRNA and produces a mutant lamin A protein called progerin that tightly associates with the inner nuclear membrane and affects the dynamic properties of lamins. Progerin expression impairs many important cellular processes providing insight into potential disease mechanisms. These include changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence. In this review, we discuss these pathways and their potential contribution to the disease pathologies as well as therapeutic approaches used in preclinical and clinical tests.
Dermoscopy and Reflectance Confocal Microscopy for Monitoring the Treatment of Actinic Keratosis with Ingenol Mebutate Gel: Report of Two Cases.Friday, February 05, 2016
Longo C, Borsari S, Benati E, Moscarella E, Alfano R, Argenziano G,
Dermatology and therapy. 4-Feb-2016
Ingenol mebutate is a valuable therapy for the treatment of AK. This case report adds further evidence to the usefulness of dermoscopy and RCM in the assessment and monitoring of treatment outcome.
Suppression of c‑FLIPL promotes JNK activation in malignant melanoma cells.Friday, February 05, 2016
Tian F, Hu Y, Sun X, Lu G, Li Y, Yang J, Tao J,
Molecular medicine reports. 3-Feb-2016
The up‑regulation of cellular Fas‑associated death domain‑like interleukin‑1β‑converting enzyme (FLICE)‑like inhibitory protein (c‑FLIP) has been reported in various tumor types, and has been previously shown to be associated with the clinicopathological features of melanoma. To assess its potential role in cancer therapy, the present study evaluated the effects of short hairpin (sh)RNAs of different c‑FLIP isoforms on cellular proliferation and c‑Jun N‑terminal kinase (JNK) signaling. Human c‑FLIP shRNA plasmids were constructed and transfected into the A875 melanoma cell line. It was observed that c‑FLIP shRNA exhibited strong inhibitory effects against the levels of phosphorylated‑JNK and inhibited cellular proliferation in A875 cells. Thus, this indicated that c‑FLIP long form shRNA serves a specific inhibitory role in cellular proliferation through inducing the activation of the JNK pathway in A875 cells. The present study provided insight into the development of RNAi based therapies for melanoma.
IL-15 Trispecific Killer Engagers (TriKEs) Make Natural Killer Cells Specific to CD33+ Targets While Also Inducing In Vivo Expansion, and Enhanced Function.Friday, February 05, 2016
Vallera DA, Felices M, McElmurry RT, McCullar V, Zhou X, Schmohl J, Zhang B, Lenvik A, Panoskaltsis-Mortari A, Verneris MR, Tolar J, Cooley S, Weisdorf D, Blazar BR, Miller JS,
Clinical cancer research : an official journal of the American Association for Cancer Research. 4-Feb-2016
Off-the-shelf 161533 TriKE imparts antigen specificity and promotes in vivo persistence, activation, and survival of NK cells. These qualities are ideal for NK cell therapy of myeloid malignancies or targeting antigens of solid tumors.
GFI1 as a novel prognostic and therapeutic factor for AML/MDS.Friday, February 05, 2016
Hönes JM, Botezatu L, Helness A, Vadnais C, Vassen L, Robert F, Hergenhan SM, Thivakaran A, Schütte J, Al-Matary YS, Lams RF, Fraszscak J, Makishima H, Radivoyevitch T, Przychodzen B, da Conceição Castro SV, Görgens A, Giebel B, Klein-Hitpass L, Lennartz K, Heuser M, Thiede C, Ehninger G, Dührsen U, Maciejewski J, Möröy T, Khandanpour C,
Leukemia. 5-Feb-2016
Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor exerts its function by recruiting histone-deacetylases (HDACs) to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors (HATis) than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 level are involved in epigenetic regulation that could open new therapeutic approaches for AML-patients.Leukemia accepted article preview online, 05 February 2016. doi:10.1038/leu.2016.11.
Neural Stem Cell Therapy and Rehabilitation in the CNS: An Emerging Partnership.Friday, February 05, 2016
Ross HH, Ambrosio F, Trumbower RD, Reier PJ, Behrman AL, Wolf SL,
Physical therapy. 4-Feb-2016
The goal of regenerative medicine is to restore function through therapy at such levels as the gene, cell, tissue or organ. For many disorders, however, regenerative medicine approaches in isolation may not be optimally effective. Rehabilitation is a promising adjunct therapy given the beneficial impact that physical activity and other training modalities can offer. Accordingly, "regenerative rehabilitation" is an emerging concentration of study with the specific goal of improving positive functional outcomes by enhancing tissue restoration following injury. The present article focuses on one emerging example of regenerative rehabilitation-namely, the integration of clinically-based protocols with stem cell technologies following central nervous system (CNS) injury. For the purposes of this review, we summarize the state of stem cell technologies for the CNS and provide a rationale for a synergistic benefit of carefully orchestrated rehabilitation protocols in conjunction with cellular therapies. We close by overviewing practical steps to increase the involvement of physical therapy in regenerative rehabilitation research.
The Cervico-Ocular Reflex Is Increased In People With Non-Specific Neck Pain.Friday, February 05, 2016
de Vries J, Ischebeck BK, Voogt LP, Janssen M, Frens MA, Kleinrensink GJ, van der Geest JN,
Physical therapy. 4-Feb-2016
This study suggests that people with non-specific neck pain have an increased COR. The COR is an objective non-voluntary eye reflex and an unaltered VOR. This study shows that an increased COR is not restricted to traumatic neck pain patients.
Adding Psychosocial Factors Does Not Improve Predictive Models in Patients With Spinal Pain Enough to Warrant Extensive Screening for Them at Baseline.Friday, February 05, 2016
Ailliet L, Rubinstein SM, Hoekstra T, van Tulder MW, de Vet HC,
Physical therapy. 4-Feb-2016
Psychosocial variables have little added value in predicting outcome in patients presenting to the chiropractor with NP or LBP. We therefor advise chiropractors not to screen extensively for them at baseline. Identification of the small subgroup with high psychosocial scores and high risk for chronicity needs further investigation.
Test-Retest Reliability of Dual-Task Outcome Measures in People With Parkinson's Disease.Friday, February 05, 2016
Strouwen C, Molenaar EA, Keus SH, Münks L, Bloem BR, Nieuwboer A,
Physical therapy. 4-Feb-2016
In people with PD, dual-task measures proved to be reliable for use in clinical studies and look promising for use in clinical practice to assess improvements after dual-task training. Large effects, however, are needed to obtain meaningful effect sizes.
Developmental Biology and Regenerative Medicine: Addressing the Vexing Problem of Persistent Muscle Atrophy in the Chronically Torn Human Rotator Cuff.Friday, February 05, 2016
Meyer GA, Ward SR,
Physical therapy. 4-Feb-2016
Persistent muscle atrophy in the chronically torn rotator cuff is a significant obstacle for treatment and recovery. Large atrophic changes are predictive of poor surgical and non-surgical outcomes and frequently fail to resolve even following functional restoration of loading and rehabilitation. New insights into the processes of muscle atrophy and recovery gained through studies in Developmental Biology combined with the novel tools and strategies emerging in Regenerative Medicine provides new avenues to combat the vexing problem of muscle atrophy in the rotator cuff. Moving these treatment strategies forward is likely going to involve the combination of surgery, biologic/cellular agents and physical interventions, as increasing experimental evidence points to the beneficial interaction between biologic therapies and physiologic stresses. Thus, the physical therapy profession is poised to play a significant role in defining the success of these combinatorial therapies. This perspective will provide an overview of the Developmental Biology and Regenerative Medicine strategies currently under investigation to combat muscle atrophy and how they may integrate into the current and future practice of physical therapy.
Validation of the Comprehensive ICF Core Set for Vocational Rehabilitation From the Perspective of Physical Therapists: An International Delphi Survey.Friday, February 05, 2016
Kaech Moll VM, Escorpizo R, Portmann Bergamaschi R, Finger ME,
Physical therapy. 4-Feb-2016
The content validity of the ICF Core Set for VR is insufficient from a sole PT perspective. The results of this study could be used to define a PT specific set of ICF categories to develop and guide PT clinical practice in VR.
Breast Cancer MDA-MB-231 Cells Use Secreted Heat Shock Protein-90alpha (Hsp90α) to Survive a Hostile Hypoxic Environment.Friday, February 05, 2016
Dong H, Zou M, Bhatia A, Jayaprakash P, Hofman F, Ying Q, Chen M, Woodley DT, Li W,
Scientific reports. 2016
Rapidly growing tumours in vivo often outgrow their surrounding available blood supply, subjecting themselves to a severely hypoxic microenvironment. Understanding how tumour cells adapt themselves to survive hypoxia may help to develop new treatments of the tumours. Given the limited blood perfusion to the enlarging tumour, whatever factor(s) that allows the tumour cells to survive likely comes from the tumour cells themselves or its associated stromal cells. In this report, we show that HIF-1α-overexpressing breast cancer cells, MDA-MB-231, secrete heat shock protein-90alpha (Hsp90α) and use it to survive under hypoxia. Depletion of Hsp90α secretion from the tumour cells was permissive to cytotoxicity by hypoxia, whereas supplementation of Hsp90α-knockout tumour cells with recombinant Hsp90α, but not Hsp90β, protein prevented hypoxia-induced cell death via an autocrine mechanism through the LDL receptor-related protein-1 (LRP1) receptor. Finally, direct inhibition of the secreted Hsp90α with monoclonal antibody, 1G6-D7, enhanced tumour cell death under hypoxia. Therefore, secreted Hsp90α is a novel survival factor for certain tumours under hypoxia.
The Sertoli cell: one hundred fifty years of beauty and plasticity.Friday, February 05, 2016
França LR, Hess RA, Dufour JM, Hofmann MC, Griswold MD,
Andrology. 4-Feb-2016
It has been one and a half centuries since Enrico Sertoli published the seminal discovery of the testicular 'nurse cell', not only a key cell in the testis, but indeed one of the most amazing cells in the vertebrate body. In this review, we begin by examining the three phases of morphological research that have occurred in the study of Sertoli cells, because microscopic anatomy was essentially the only scientific discipline available for about the first 75 years after the discovery. Biochemistry and molecular biology then changed all of biological sciences, including our understanding of the functions of Sertoli cells. Immunology and stem cell biology were not even topics of science in 1865, but they have now become major issues in our appreciation of Sertoli cell's role in spermatogenesis. We end with the universal importance and plasticity of function by comparing Sertoli cells in fish, amphibians, and mammals. In these various classes of vertebrates, Sertoli cells have quite different modes of proliferation and epithelial maintenance, cystic vs. tubular formation, yet accomplish essentially the same function but in strikingly different ways.
Aspirin Enhances Osteogenic Potential of Periodontal Ligament Stem Cells (PDLSCs) and Modulates the Expression Profile of Growth Factor-associated Genes in PDLSCs.Friday, February 05, 2016
Abd Rahman F, Mohd Ali J, Abdullah M, Abu Kasim NH, Musa S,
Journal of periodontology. 5-Feb-2016
Aspirin modulates the expression of growth factors associated genes and enhances osteogenic potential in PDLSCs. Aspirin upregulated the expression of genes that could activate biological functions and canonical pathways related to cell proliferation, human embryonic stem cell pluripotency, tissue regeneration and differentiation. These findings suggest that aspirin enhances PDLSCs function and may be useful in regenerative dentistry applications, particularly in the areas of periodontal health and regeneration.
Approaches for characterizing threshold dose-response relationships for DNA-damage pathways involved in carcinogenicity in vivo and micronuclei formation in vitro.Friday, February 05, 2016
Clewell RA, Andersen ME,
Mutagenesis. 4-Feb-2016
Assessing the shape of dose-response curves for DNA-damage in cellular systems and for the consequences of DNA damage in intact animals remains a controversial topic. This overview looks at aspects of the pharmacokinetics (PK) and pharmacodynamics (PD) of cellular DNA-damage/repair and their role in defining the shape of dose-response curves using an in vivo example with formaldehyde and in vitro examples for micronuclei (MN) formation with several test compounds. Formaldehyde is both strongly mutagenic and an endogenous metabolite in cells. With increasing inhaled concentrations, there were transitions in gene changes, from activation of selective stress pathway genes at low concentrations, to activation of pathways for cell-cycle control, p53-DNA damage, and stem cell niche pathways at higher exposures. These gene expression changes were more consistent with dose-dependent transitions in the PD responses to formaldehyde in epithelial cells in the intact rat rather than the low-dose linear extrapolation methods currently used for carcinogens. However, more complete PD explanations of non-linear dose response for creation of fixed damage in cells require detailed examination of cellular responses in vitro using measures of DNA damage and repair that are not easily accessible in the intact animal. In the second section of the article, we illustrate an approach from our laboratory that develops fit-for-purpose, in vitro assays and evaluates the PD of DNA damage and repair through studies using prototypical DNA-damaging agents. Examination of a broad range of responses in these cells showed that transcriptional upregulation of cell cycle control and DNA repair pathways only occurred at doses higher than those causing overt damage fixed damage-measured as MN formation. Lower levels of damage appear to be handled by post-translational repair process using pre-existing proteins. In depth evaluation of the PD properties of one such post-translational process (formation of DNA repair centers; DRCs) has indicated that the formation of DRCs and their ability to complete repair before replication are consistent with threshold behaviours for mutagenesis and, by extension, with chemical carcinogenesis.
Cytotoxic effects of SMAC-mimetic compound LCL161 in head and neck cancer cell lines.Friday, February 05, 2016
Brands RC, Herbst F, Hartmann S, Seher A, Linz C, Kübler AC, Müller-Richter UD,
Clinical oral investigations. 4-Feb-2016
SMAC-mimetic compounds show promising results in the treatment of other tumor entities in vitro and might be useful drugs to improve HNSCC therapy.
Comparative transcriptomic profiling of hydrogen peroxide signaling networks in zebrafish and human keratinocytes: Implications toward conservation, migration and wound healing.Friday, February 05, 2016
Lisse TS, King BL, Rieger S,
Scientific reports. 2016
Skin wounds need to be repaired rapidly after injury to restore proper skin barrier function. Hydrogen peroxide (H2O2) is a conserved signaling factor that has been shown to promote a variety of skin wound repair processes, including immune cell migration, angiogenesis and sensory axon repair. Despite growing research on H2O2 functions in wound repair, the downstream signaling pathways activated by this reactive oxygen species in the context of injury remain largely unknown. The goal of this study was to provide a comprehensive analysis of gene expression changes in the epidermis upon exposure to H2O2 concentrations known to promote wound repair. Comparative transcriptome analysis using RNA-seq data from larval zebrafish and previously reported microarray data from a human epidermal keratinocyte line shows that H2O2 activates conserved cell migration, adhesion, cytoprotective and anti-apoptotic programs in both zebrafish and human keratinocytes. Further assessment of expression characteristics and signaling pathways revealed the activation of three major H2O2-dependent pathways, EGF, FOXO1, and IKKα. This study expands on our current understanding of the clinical potential of low-level H2O2 for the promotion of epidermal wound repair and provides potential candidates in the treatment of wound healing deficits.
Nanoquinacrine induced apoptosis in cervical cancer stem cells through the inhibition of hedgehog-GLI1 cascade: Role of GLI-1.Friday, February 05, 2016
Nayak A, Satapathy SR, Das D, Siddharth S, Tripathi N, Bharatam PV, Kundu C,
Scientific reports. 2016
To improve the pharmacokinetics and to study the anti-cervical cancer and anti-stem cells (CSCs) mechanism of Quinacrine (QC), a spherical nano particle of QC (i.e. NQC) was prepared and characterized. QC and NQC showed higher cytotoxicity in multiple cancer cells than the normal epithelial cells. NQC exhibited more toxicity in cervical cancer cells and its CSCs than QC. A dose-dependent decreased expression of Hedgehog-GLI (HH-GLI) components were noted in NQC treated HeLa cells and its CSCs. NQC increased the expressions of negatively regulated HH-GLI components (GSK3β, PTEN) and caused apoptosis in CSCs. Reduction of GLI1 at mRNA and promoter level were noted after NQC exposure. The expressions of HH-GLI components, GLI1 promoter activity and apoptosis were unaltered in NQC treated GLI1-knockdown cells. In silico, cell based and in vitro reconstitution assay revealed that NQC inhibit HH-GLI cascade by binding to the consensus sequence (5'GACCACCCA3') of GLI1 in GLI-DNA complex through destabilizing DNA-GLI1 complex. NQC reduced the tumors size and proliferation marker Ki-67 in an in vivo xenograft mice model. Thus, NQC induced apoptosis in cancers through inhibition of HH-GLI cascade by GLI1. Detail interaction of QC-DNA-GLI complex can pave path for anticancer drug design.
Cell autonomous and non-autonomous function of CUL4B in Mouse Spermatogenesis.Friday, February 05, 2016
Yin Y, Liu L, Yang C, Lin C, Veith GM, Wang C, Sutovsky P, Zhou P, Ma L,
The Journal of biological chemistry. 4-Feb-2016
CUL4B Ubiquitin ligase belongs to the cullin-RING ubiquitin ligase family. Although sharing many sequential and structural similarities, CUL4B plays distinct roles in spermatogenesis from its homologous protein CUL4A. We previously reported that genetic ablation of Cul4a in the mouse led to male infertility due to aberrant meiotic progression. In the present study, we generated Cul4b germ cell-specific conditional knockout (Cul4bVasa) as well as Cul4b-global knockout (Cul4bSox2) mouse to investigate its roles in spermatogenesis. Germ cell-specific deletion of Cul4b led to male infertility, despite normal testicular morphology and comparable numbers of spermatozoa. Notably, significantly impaired sperm mobility due to reduced mitochondrial activity and glycolysis level were observed in the majority of the mutant spermatozoa, manifested by low, if any, sperm ATP production. Furthermore, Cul4bVasa spermatozoa exhibited defective arrangement of axonemal microtubules and flagella outer dense fibers. Our mass spectrometry analysis identified INSL6 as a novel CUL4B substrate in male germ cells, evidenced by its directly poly-ubiquination and degradation by CUL4B E3 ligase. Nevertheless, Cul4b-global knockout males lost their germ cells in an age-dependent manner, implying failure of maintaining the spermatogonial stem cell niche in somatic cells. Taken together, our results show that CUL4B is indispensable to spermatogenesis, and it functions cell-autonomously in male germ cells to ensure spermatozoa motility, while functions non-cell-autonomously in somatic cells to maintain spermatogonial stemness. Thus, CUL4B links two distinct spermatogenetic processes to a single E3 ligase, highlighting the significance of ubiquitin modification during spermatogenesis.
Noninvasive In Vivo Imaging to Follow Bacteria Engaged in Cancer Therapy.Friday, February 05, 2016
Leschner S, Weiss S,
Methods in molecular biology (Clifton, N.J.). 2016
Non-invasive in vivo imaging represents a powerful tool to monitor cellular and molecular processes in the living animal. In the special case of bacteria-mediated cancer therapy using bioluminescent bacteria, it opens up the possibility to follow the course of the microorganisms into the tumor via the circulation. The mechanism by which bacteria elicit their anti-tumor potential is not completely understood. However, this knowledge is crucial to improve bacteria as an anti-cancer tool that can be introduced into the clinic. For the study of these aspects, in vivo imaging can be considered a key technology.
Tumor-Targeting Salmonella typhimurium A1-R: An Overview.Friday, February 05, 2016
Hoffman RM,
Methods in molecular biology (Clifton, N.J.). 2016
The present chapter reviews the development of the tumor-targeting amino-acid auxotrophic strain S. typhimurium A1 and the in vivo selection and characterization of the high-tumor-targeting strain S. typhimurium A1-R. Efficacy of S. typhimurium A1-R in nude-mouse models of prostate, breast, pancreatic, and ovarian cancer, as well as sarcoma and glioma in orthotopic mouse models is described. Also reviewed is efficacy of S. typhimurium A1-R targeting of primary bone tumor and lung metastasis of high-grade osteosarcoma, breast-cancer brain metastasis, and experimental breast-cancer bone metastasis in orthotopic mouse models. The efficacy of S. typhimurium A1-R on pancreatic cancer stem cells, on pancreatic cancer in combination with anti-angiogenic agents, as well as on cervical cancer, soft-tissue sarcoma, and pancreatic cancer patient-derived orthotopic xenograft (PDOX) mouse models, is also described.
Application of buccal fat pad-derived stem cells in combination with autogenous iliac bone graft in the treatment of maxillomandibular atrophy: a preliminary human study.Friday, February 05, 2016
Khojasteh A, Sadeghi N,
International journal of oral and maxillofacial surgery. 1-Feb-2016
Stem cell therapy for the treatment of bone defects is an alternative or adjunct to autologous bone grafting. This study assessed the efficacy of buccal fat pad-derived stem cells (BFPSCs) with iliac bone block grafting for the treatment of extensive human alveolar ridge defects. Eight patients with extensive jaw atrophy were selected for this study. The jaws were reconstructed with non-vascularized anterior iliac crest bone blocks. Gaps between the blocks were filled with freeze-dried bone granules and covered with a collagen membrane. In the test group (n=4), these granules were seeded with BFPSCs. Cone beam computed tomography scans were used to assess the amount of new bone formed at six sites in each patient. Trephine biopsies of 2-mm were also taken from the graft site during implant placement for histomorphometric analysis. The mean bone width change at the graft site was greater in the test group than in the control group (3.94±1.62mm vs. 3.01±0.89mm). New bone formation was 65.32% in the test group versus 49.21% in the control group. The application of BFPSCs in conjunction with iliac bone block grafts may increase the amount of new bone formation and decrease secondary bone resorption in extensively atrophic jaws.
Fusion with stem cell makes the hepatocellular carcinoma cells similar to liver tumor-initiating cells.Friday, February 05, 2016
Wang R, Chen S, Li C, Ng KT, Kong CW, Cheng J, Cheng SH, Li RA, Lo CM, Man K, Sun D,
BMC cancer. 2015
Fusion with stem cells transforms liver cancer cells into tumor initiating-like cells. Results indicate that fusion between cancer cell and stem cell may generate tumor initiating-like cells.
The Pathophysiology of Moyamoya Disease: An Update.Friday, February 05, 2016
Bang OY, Fujimura M, Kim SK,
Journal of stroke. Jan-2016
Moyamoya disease (MMD) is a unique cerebrovascular disease characterized by the progressive stenosis of large intracranial arteries and a hazy network of basal collaterals called moyamoya vessels. Because the etiology of MMD is unknown, its diagnosis is based on characteristic angiographic findings. Re-vascularization techniques (e.g., bypass surgery) are used to restore perfusion, and are the primary treatment for MMD. There is no specific treatment to prevent MMD progression. This review summarizes the recent advances in MMD pathophysiology, including the genetic and circulating factors related to disease development. Genetic and environmental factors may play important roles in the development of the vascular stenosis and aberrant angiogenesis in complex ways. These factors include the related changes in circulating endothelial/smooth muscle progenitor cells, cytokines related to vascular remodeling and angiogenesis, and endothelium, such as caveolin which is a plasma membrane protein. With a better understanding of MMD pathophysiology, nonsurgical approaches targeting MMD pathogenesis may be available to stop or slow the progression of this disease. The possible strategies include targeting growth factors, retinoic acid, caveolin-1, and stem cells.
MicroRNA-301a promotes cell proliferation via PTEN targeting in Ewing's sarcoma cells.Friday, February 05, 2016
Kawano M, Tanaka K, Itonaga I, Iwasaki T, Tsumura H,
International journal of oncology. 5-Feb-2016
MicroRNAs (miRNAs) regulate cell proliferation and differentiation by affecting gene expression at the post-transcriptional level by binding to complementary sequences within mRNAs in cancer cells, indicating that miRNAs can function as tumor suppressors or oncogenes. Recent studies showed that dysregulation of miRNA expression was associated with increased tumorigenicity and poor prognosis in several types of cancers, including Ewing's sarcoma (ES). To explore possible oncogenic factors in ES, we conducted microarray-based investigation and profiled the changes in miRNA expression and their effects on downstream mRNAs in five ES cell lines and human mesenchymal stem cells (hMSCs). miR-301a was significantly upregulated, while the phosphatase and tensin homolog (PTEN) expression was significantly downregulated in all tested ES cells as compared to hMSCs. When anti-miR-301a was transfected into ES cell lines, PTEN expression was significantly enhanced, suggesting that PTEN might be a target of miR-301a in ES cells. The expression of protein kinase B (Akt), which is inversely correlated with PTEN expression, was significantly downregulated in anti-miR-301a-transfected cells. Additionally, the transfection of anti-miR-301a inhibited ES cell proliferation and cell cycle progression. Furthermore, downregulation of miR-301a in ES cells significantly suppressed tumor growth in vivo. Our results demonstrated the novel mechanism controlling PTEN expression via miR-301a in ES cells. Given that PTEN is a pivotal phosphatase factor that regulates cell cycle progression, apoptosis, and proliferation, these results might lead to development of new ES-related therapeutic targets.
The angiogenic variation of skeletal site-specific human BMSCs from same alveolar cleft patients: a comparative study.Friday, February 05, 2016
Du Y, Jiang F, Liang Y, Wang Y, Zhou W, Pan Y, Xue M, Peng Y, Yuan H, Chen N, Jiang H,
Journal of molecular histology. 4-Feb-2016
Tissue engineering strategies hold great potential for alveolar cleft reconstruction. Bone marrow stromal cells (BMSCs) from iliac crest and craniofacial regions are candidate seeding cells with site-specific characteristics and bone-repairing properties. Craniofacial BMSCs seem to possess stronger multipotency and osteogenic capabilities than BMSCs isolated from iliac crest. However, the angiogenic capabilities of these two type cell is rarely reported. We obtained human BMSCs (hBMSCs) of maxilla (M-hBMSCs) and iliac crest (I-hBMSCs) from same alveolar cleft patients to investigate the agiogenic variations using co-culture system with human umbilical vein endothelial cells (HUVECs). From in vitro comparison, M-hBMSCs allowed HUVECs to form more tube-like structures and sprouting angiogenesis by tube formation assays and 3D fibrin vasculogenic assay, respectively. By transplantation in vivo, M-hBMSCs enhanced larger size vessel like structures distributed the entire implants compared with I-hBMSCs. Western blotting was used to assess the angiogenesis related factors including hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The results showed a significant higher expression of bFGF protein in M-hBMSCs and HUVECs co-culture system both in vitro and in vivo. As bFGF could promote migration and proliferation of endothelial cells, scratch wound healing and transwell migration assays were performed as well as MTT assays and cell cycle analysis. The data suggested the effect of M-hBMSCs on HUVECs was stronger than I-hBMSCs. Taken together, these results indicated that craniofacial BMSCs seemed to have greater angiogenesis capability than iliac crest BMSCs and this might be associated with the different levels of bFGF protein expression in co-culture system.
Murine Models Demonstrate Distinct Vasculogenic and Cardiomyogenic cKit+ Lineages in the Heart.Friday, February 05, 2016
Hatzistergos KE, Hare JM,
Circulation research. 5-Feb-2016
After 2 recent genetic studies in mice addressing the developmental origins(1) and regenerative activity of cardiac cKit(+) cells,(2) 2 additional reports by Sultana et al(3) and Liu et al(4) provide further information on the expression of cKit in the embryonic and adult hearts. Here, we synthesize the findings from the 4 distinct cKit models to gain insights into the biology of this important cell type.
Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere.Friday, February 05, 2016
Chalmers BA, Xing H, Houston S, Clark C, Ghassabian S, Kuo A, Cao B, Reitsma A, Murray CP, Stok JE, Boyle GM, Pierce CJ, Littler SW, Winkler DA, Bernhardt PV, Pasay C, De Voss JJ, McCarthy J, Parsons PG, Walter GH, Smith MT, Cooper HM, Nilsson SK, Tsanaktsidis J, Savage GP, Williams CM,
Angewandte Chemie (International ed. in English). 5-Feb-2016
Pharmaceutical and agrochemical discovery programs are under considerable pressure to meet increasing global demand and thus require constant innovation. Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market place, but an obvious omission is that of the Platonic solid cubane. Eaton, however, suggested that this molecule has the potential to act as a benzene bioisostere. Herein, we report the validation of Eaton's hypothesis with cubane derivatives of five molecules that are used clinically or as agrochemicals. Two cubane analogues showed increased bioactivity compared to their benzene counterparts whereas two further analogues displayed equal bioactivity, and the fifth one demonstrated only partial efficacy. Ramifications from this study are best realized by reflecting on the number of bioactive molecules that contain a benzene ring. Substitution with the cubane scaffold where possible could revitalize these systems, and thus expedite much needed lead candidate identification.
White matter tract integrity in treatment-resistant gambling disorder.Friday, February 05, 2016
Chamberlain SR, Derbyshire K, Daws RE, Odlaug BL, Leppink EW, Grant JE,
The British journal of psychiatry : the journal of mental science. 4-Feb-2016
BackgroundGambling disorder is a relatively common psychiatric disorder recently re-classified within the DSM-5 under the category of 'substance-related and addictive disorders'.AimsTo compare white matter integrity in patients with gambling disorder with healthy controls; to explore relationships between white matter integrity and disease severity in gambling disorder.MethodIn total, 16 participants with treatment-resistant gambling disorder and 15 healthy controls underwent magnetic resonance imaging (MRI). White matter integrity was analysed using tract-based spatial statistics.ResultsGambling disorder was associated with reduced fractional anisotropy in the corpus callosum and superior longitudinal fasciculus. Fractional anisotropy in distributed white matter tracts elsewhere correlated positively with disease severity.ConclusionsReduced corpus callosum fractional anisotropy is suggestive of disorganised/damaged tracts in patients with gambling disorder, and this may represent a trait/vulnerability marker for the disorder. Future research should explore these measures in a larger sample, ideally incorporating a range of imaging markers (for example functional MRI) and enrolling unaffected first-degree relatives of patients.
Mindfulness-based cognitive therapy v. group psychoeducation for people with generalised anxiety disorder: randomised controlled trial.Friday, February 05, 2016
Wong SY, Yip BH, Mak WW, Mercer S, Cheung EY, Ling CY, Lui WW, Tang WK, Lo HH, Wu JC, Lee TM, Gao T, Griffiths SM, Chan PH, Ma HS,
The British journal of psychiatry : the journal of mental science. 4-Feb-2016
BackgroundResearch suggests that an 8-week mindfulness-based cognitive therapy (MBCT) course may be effective for generalised anxiety disorder (GAD).AimsTo compare changes in anxiety levels among participants with GAD randomly assigned to MBCT, cognitive-behavioural therapy-based psychoeducation and usual care.MethodIn total, 182 participants with GAD were recruited (trial registration number: CUHK_CCT00267) and assigned to the three groups and followed for 5 months after baseline assessment with the two intervention groups followed for an additional 6 months. Primary outcomes were anxiety and worry levels.ResultsLinear mixed models demonstrated significant group × time interaction (F(4,148) = 5.10, P = 0.001) effects for decreased anxiety for both the intervention groups relative to usual care. Significant group × time interaction effects were observed for worry and depressive symptoms and mental health-related quality of life for the psychoeducation group only.ConclusionsThese results suggest that both of the interventions appear to be superior to usual care for the reduction of anxiety symptoms.
Chronic fatigue syndrome: comparing outcomes in White British and Black and minority ethnic patients after cognitive-behavioural therapy.Friday, February 05, 2016
Ingman T, Ali S, Bhui K, Chalder T,
The British journal of psychiatry : the journal of mental science. 4-Feb-2016
BackgroundCognitive-behavioural therapy (CBT) is one of the most promising treatments for chronic fatigue syndrome (CFS). It is unclear whether CBT is effective for Black and minority ethnic (BME) groups.AimsTo assess the effectiveness of CBT in BME patients compared with White British patients presenting to a specialist CFS service.MethodData from 67 (19.0%) BME participants and 285 (81.0%) White British participants referred to a specialist CFS service in the UK were collected at baseline and after CBT treatment.ResultsPairwise comparisons revealed that both BME participants and White British participants significantly improved on measures of fatigue severity (P < 0.001), physical functioning (P < 0.001) and work/social adjustment (P < 0.001). Independent samples t-tests showed that BME participants improved despite exhibiting significantly higher baseline damage beliefs (P = 0.009), catastrophising (P = 0.024), all-or-nothing behaviour (P = 0.036) and avoidance/resting behaviour (P = 0.001), compared with White British participants.ConclusionsTo our knowledge, this study is the first to indicate that CBT is effective for treating CFS in a group of patients from diverse BME backgrounds.
Prostate Cancer Stem Cells: Viewing Signaling Cascades at a Finer Resolution.Friday, February 05, 2016
Lin X, Farooqi AA, Qureshi MZ, Romero MA, Tabassum S, Ismail M,
Archivum immunologiae et therapiae experimentalis. 4-Feb-2016
It is becoming characteristically more understandable that within tumor cells, there lies a sub-population of tumor cells with "stem cell" like properties and remarkable ability of self-renewal. Many features of these self-renewing cells are comparable with normal stem cells and are termed as "cancer stem cells". Accumulating experimentally verified data has started to scratch the surface of spatio-temporally dysregulated intracellular signaling cascades in the biology of prostate cancer stem cells. We partition this multicomponent review into how different signaling cascades operate in cancer stem cells and how bioactive ingredients isolated from natural sources may modulate signaling network.
Source: NCBI - Disclaimer and Copyright notice
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