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Sample records for abnormal cell growth

  1. Adult T-cell leukemia cells are characterized by abnormalities of Helios expression that promote T cell growth.

    PubMed

    Asanuma, Satomi; Yamagishi, Makoto; Kawanami, Katsuaki; Nakano, Kazumi; Sato-Otsubo, Aiko; Muto, Satsuki; Sanada, Masashi; Yamochi, Tadanori; Kobayashi, Seiichiro; Utsunomiya, Atae; Iwanaga, Masako; Yamaguchi, Kazunari; Uchimaru, Kaoru; Ogawa, Seishi; Watanabe, Toshiki

    2013-08-01

    Molecular abnormalities involved in the multistep leukemogenesis of adult T-cell leukemia (ATL) remain to be clarified. Based on our integrated database, we focused on the expression patterns and levels of Ikaros family genes, Ikaros, Helios, and Aiolos, in ATL patients and HTLV-1 carriers. The results revealed profound deregulation of Helios expression, a pivotal regulator in the control of T-cell differentiation and activation. The majority of ATL samples (32/37 cases) showed abnormal splicing of Helios expression, and four cases did not express Helios. In addition, novel genomic loss in Helios locus was observed in 17/168 cases. We identified four ATL-specific short Helios isoforms and revealed their dominant-negative function. Ectopic expression of ATL-type Helios isoform as well as knockdown of normal Helios or Ikaros promoted T-cell growth. Global mRNA profiling and pathway analysis showed activation of several signaling pathways important for lymphocyte proliferation and survival. These data provide new insights into the molecular involvement of Helios function in the leukemogenesis and phenotype of ATL cells, indicating that Helios deregulation is one of the novel molecular hallmarks of ATL.

  2. Growth and differentiation of circulating hemopoietic stem cells with atomic bomb irradiation-induced chromosome abnormalities

    SciTech Connect

    Amenomori, T.; Honda, T.; Otake, M.; Tomonaga, M.; Ichimaru, M.

    1988-11-01

    The effects of atomic bomb irradiation on hemopoietic stem cells were studied cytogenetically using single colonies derived from hemopoietic progenitor cells. The subjects studied were 21 healthy atomic bomb survivors (10 males and 11 females) in the high dose exposure group (100+ rad) with a known high incidence (10% or more) of radiation-induced chromosome abnormalities in their peripheral blood lymphocytes (stimulated with phytohemagglutinin), and 11 nonexposed healthy controls (5 males and 6 females). Colony formation by circulating granulocyte-macrophage (GM-CFC) and erythroid (BFU-E) progenitor cells was made by the methylcellulose method using peripheral blood mononuclear cells. Chromosome specimens were prepared from single colonies by our micromethod. The total number of colonies analyzed in the exposed group was 131 for GM-CFC and 75 for BFU-E. Chromosome abnormalities were observed in 15 (11.5%) and 9 (12.0%) colonies, respectively. In the control group, the total number of colonies analyzed was 61 for GM-CFC and 41 for BFU-E. None of these colonies showed chromosome abnormalities. The difference in incidence of chromosome abnormalities was highly significant by an exact test; p = 0.003 for GM-CFC and 0.017 for BFU-E. The karyotypes of chromosome abnormalities obtained from the colonies in the exposed group were mostly translocations, but deletion and marker chromosomes were also observed. In two individuals, such karyotypic abnormalities as observed in the peripheral lymphocytes were also seen in the myeloid progenitor cells. This finding suggests that atomic bomb irradiation produced a chromosome aberration on multipotent hemopoietic stem cells common to myeloid and lymphoid lineages.

  3. A RAS oncogene imparts growth factor independence to myeloid cells that abnormally regulate protein kinase C: a nonautocrine transformation pathway.

    PubMed

    Boswell, H S; Nahreini, T S; Burgess, G S; Srivastava, A; Gabig, T G; Inhorn, L; Srour, E F; Harrington, M A

    1990-06-01

    The factor-dependent cell line FDC-P1 has been utilized as a model of interleukin 3 (IL-3)-dependent myeloid cell proliferation. However, it has been recently observed that active phorbol esters (e.g., phorbol 12-myristate 13-acetate) may entirely replace IL-3 to promote its proliferation. These observations reveal abnormal regulation of protein kinase C (pkC) (absence of downregulation or overexpression). This property allowed a test of the hypothesis that the T24 RAS (codon 12) oncogene acts by constitutive and persistent pkC activation, driving proliferation. FDC-P1 cells were transfected by electroporation with the T24 RAS-containing vector pAL 8, or with a control vector pSVX Zip Neo, and neomycin-resistant clones were selected. Multiple RAS-transfectant clones were categorized for their growth factor requirement and incorporation of the 6.6-kb human mutant H-RAS genome. IL-3-independent clones had incorporated multiple (more than two) copies of the entire 6.6-kb RAS genome. The incorporation of multiple 6.6-kb RAS genomes was correlated with high-level p21 RAS expression. No evidence for autostimulatory growth factor production by clones containing the RAS oncogene was observed. Thus, acquisition of growth factor independence in myeloid cells by abundant expression of a RAS oncogene is linked, in part, to abnormal regulation of pkC, which acts as a collaborating oncogene.

  4. GNG11 (G-protein γ subunit 11) suppresses cell growth with induction of reactive oxygen species and abnormal nuclear morphology in human SUSM-1 cells.

    PubMed

    Takauji, Yuki; Kudo, Ikuru; En, Atsuki; Matsuo, Ryo; Hossain, Mohammad; Nakabayashi, Kazuhiko; Miki, Kensuke; Fujii, Michihiko; Ayusawa, Dai

    2017-04-05

    Enforced expression of GNG11, G-protein γ subunit 11, induces cellular senescence in normal human diploid fibroblasts. We here examined the effect of the expression of GNG11 on the growth of immortalized human cell lines, and found that it suppressed the growth of SUSM-1 cells, but not of HeLa cells. We then compared these two cell lines to understand the molecular basis for the action of GNG11. We found that expression of GNG11 induced the generation of reactive oxygen species (ROS) and abnormal nuclear morphology in SUSM-1 cells but not in HeLa cells. Increased ROS generation by GNG11 would likely be caused by the down-regulation of the antioxidant enzymes in SUSM-1 cells. We also found that SUSM-1 cells, even under normal culture conditions, showed higher levels of ROS and higher incidence of abnormal nuclear morphology than HeLa cells, and that abnormal nuclear morphology was relevant to the increased ROS generation in SUSM-1 cells. Thus, SUSM-1 and HeLa cells showed differences in the regulation of ROS and nuclear morphology, which might account for their different responses to the expression of GNG11. Then, SUSM-1 cells may provide a unique system to study the regulatory relationship between ROS generation, nuclear morphology, and G-protein signaling.

  5. Abnormal Grain Growth Suppression in Aluminum Alloys

    NASA Technical Reports Server (NTRS)

    Hales, Stephen J. (Inventor); Claytor, Harold Dale (Inventor); Alexa, Joel A. (Inventor)

    2015-01-01

    The present invention provides a process for suppressing abnormal grain growth in friction stir welded aluminum alloys by inserting an intermediate annealing treatment ("IAT") after the welding step on the article. The IAT may be followed by a solution heat treatment (SHT) on the article under effectively high solution heat treatment conditions. In at least some embodiments, a deformation step is conducted on the article under effective spin-forming deformation conditions or under effective superplastic deformation conditions. The invention further provides a welded article having suppressed abnormal grain growth, prepared by the process above. Preferably the article is characterized with greater than about 90% reduction in area fraction abnormal grain growth in any friction-stir-welded nugget.

  6. Abnormal mandibular growth and the condylar cartilage.

    PubMed

    Pirttiniemi, Pertti; Peltomäki, Timo; Müller, Lukas; Luder, Hans U

    2009-02-01

    Deviations in the growth of the mandibular condyle can affect both the functional occlusion and the aesthetic appearance of the face. The reasons for these growth deviations are numerous and often entail complex sequences of malfunction at the cellular level. The aim of this review is to summarize recent progress in the understanding of pathological alterations occurring during childhood and adolescence that affect the temporomandibular joint (TMJ) and, hence, result in disorders of mandibular growth. Pathological conditions taken into account are subdivided into (1) congenital malformations with associated growth disorders, (2) primary growth disorders, and (3) acquired diseases or trauma with associated growth disorders. Among the congenital malformations, hemifacial microsomia (HFM) appears to be the principal syndrome entailing severe growth disturbances, whereas growth abnormalities occurring in conjunction with other craniofacial dysplasias seem far less prominent than could be anticipated based on their often disfiguring nature. Hemimandibular hyperplasia and elongation undoubtedly constitute the most obscure conditions that are associated with prominent, often unilateral, abnormalities of condylar, and mandibular growth. Finally, disturbances of mandibular growth as a result of juvenile idiopathic arthritis (JIA) and condylar fractures seem to be direct consequences of inflammatory and/or mechanical damage to the condylar cartilage.

  7. Dynamic Abnormal Grain Growth in Refractory Metals

    NASA Astrophysics Data System (ADS)

    Noell, Philip J.; Taleff, Eric M.

    2015-11-01

    High-temperature plastic deformation of the body-centered cubic (BCC) refractory metals Mo and Ta can initiate and propagate abnormal grains at significantly lower temperatures and faster rates than is possible by static annealing alone. This discovery reveals a new and potentially important aspect of abnormal grain growth (AGG) phenomena. The process of AGG during plastic deformation at elevated temperatures, termed dynamic abnormal grain growth (DAGG), was observed at homologous temperatures between 0.52 and 0.72 in both Mo and Ta sheet materials; these temperatures are much lower than those for previous observations of AGG in these materials during static annealing. DAGG was used to repeatedly grow single crystals several centimeters in length. Investigations to date have produced a basic understanding of the conditions that lead to DAGG and how DAGG is affected by microstructure in BCC refractory metals. The current state of understanding for DAGG is reviewed in this paper. Attention is given to the roles of temperature, plastic strain, boundary mobility and preexisting microstructure. DAGG is considered for its potential useful applications in solid-state crystal growth and its possibly detrimental role in creating undesired abnormal grains during thermomechanical processing.

  8. Parsing abnormal grain growth in specialty aluminas

    NASA Astrophysics Data System (ADS)

    Lawrence, Abigail Kremer

    Grain growth in alumina is strongly affected by the impurities present in the material. Certain impurity elements are known to have characteristic effects on abnormal grain growth in alumina. Specialty alumina powders contain multiple impurity species including MgO, CaO, SiO2, and Na 2O. In this work, sintered samples made from alumina powders containing various amounts of the impurities in question were characterized by their grain size and aspect ratio distributions. Multiple quantitative methods were used to characterize and classify samples with varying microstructures. The grain size distributions were used to partition the grain size population into subpopulations depending on the observed deviation from normal behavior. Using both grain size and aspect ratio a new visual representation for a microstructure was introduced called a morphology frequency map that gives a fingerprint for the material. The number of subpopulations within a sample and the shape of the distribution on the morphology map provided the basis for a classification scheme for different types of microstructures. Also using the two parameters a series of five metrics were calculated that describe the character of the abnormal grains in the sample, these were called abnormal character values. The abnormal character values describe the fraction of grains that are considered abnormal, the average magnitude of abnormality (including both grain size and aspect ratio), the average size, and variance in size. The final metric is the correlation between grain size and aspect ratio for the entire population of grains. The abnormal character values give a sense of how different from "normal" the sample is, given the assumption that a normal sample has a lognormal distribution of grain size and a Gaussian distribution of aspect ratios. In the second part of the work the quantified measures of abnormality were correlated with processing parameters such as composition and heat treatment conditions. A

  9. Abnormal grain growth in AISI 304L stainless steel

    SciTech Connect

    Shirdel, M.; Mirzadeh, H.; Parsa, M.H.

    2014-11-15

    The microstructural evolution during abnormal grain growth (secondary recrystallization) in 304L stainless steel was studied in a wide range of annealing temperatures and times. At relatively low temperatures, the grain growth mode was identified as normal. However, at homologous temperatures between 0.65 (850 °C) and 0.7 (900 °C), the observed transition in grain growth mode from normal to abnormal, which was also evident from the bimodality in grain size distribution histograms, was detected to be caused by the dissolution/coarsening of carbides. The microstructural features such as dispersed carbides were characterized by optical metallography, X-ray diffraction, scanning electron microscopy, energy dispersive X-ray analysis, and microhardness. Continued annealing to a long time led to the completion of secondary recrystallization and the subsequent reappearance of normal growth mode. Another instance of abnormal grain growth was observed at homologous temperatures higher than 0.8, which may be attributed to the grain boundary faceting/defaceting phenomenon. It was also found that when the size of abnormal grains reached a critical value, their size will not change too much and the grain growth behavior becomes practically stagnant. - Highlights: • Abnormal grain growth (secondary recrystallization) in AISI 304L stainless steel • Exaggerated grain growth due to dissolution/coarsening of carbides • The enrichment of carbide particles by titanium • Abnormal grain growth due to grain boundary faceting at very high temperatures • The stagnancy of abnormal grain growth by annealing beyond a critical time.

  10. Abnormalities of proximal femoral growth after severe Perthes' disease.

    PubMed

    Sponseller, P D; Desai, S S; Millis, M B

    1989-08-01

    We studied the pattern of proximal femoral growth after severe Perthes' disease (Catterall grade III or IV) by retrospective analysis of serial radiographs in 52 hips (46 patients). Our aim was to determine the relationship between proximal femoral growth abnormalities and metaphyseal cysts, epiphyseal extrusion, physeal narrowing, and extensive epiphyseal necrosis. The average follow-up after treatment was 9.8 years (range 4 to 16 years), and 37 of the hips were followed to skeletal maturity. Slowing of proximal femoral growth was common: symmetrical abnormality was seen in 26 hips and asymmetrical abnormality in nine. However, definite premature closure of the proximal femoral physis was seen in only three hips. Abnormality seemed to be due to altered growth velocity rather than to bar formation in most cases. Metaphyseal cysts, epiphyseal extrusion and physeal narrowing during the active stage of the disease, alone or in combination, were found to be neither sensitive nor specific predictors of the subsequent growth pattern.

  11. Defining Normal and Abnormal Fetal Growth: Promises and Challenges

    PubMed Central

    Zhang, Jun; Merialdi, Mario; Platt, Lawrence D.; Kramer, Michael S.

    2010-01-01

    Normal fetal growth is a critical component of a healthy pregnancy and influences the long-term health of the offspring. However, defining normal and abnormal fetal growth has been a long-standing challenge in clinical practice and research. The authors review various references and standards that are widely used to evaluate fetal growth, and discuss common pitfalls of current definitions of abnormal fetal growth. Pros and cons of different approaches to customize fetal growth standards are described. The authors further discuss recent advances towards an integrated definition for fetal growth restriction. Such a definition may incorporate fetal size with the status of placental health measured by maternal and fetal Doppler velocimetry and biomarkers, biophysical findings and genetics. Although the concept of an integrated definition appears promising, further development and testing are required. An improved definition of abnormal fetal growth should benefit both research and clinical practice. PMID:20074690

  12. Abnormal Grain Growth in M-252 and S-816 Alloys

    NASA Technical Reports Server (NTRS)

    Decker, R F; Rush, A I; Dano, A G; Freeman, J W

    1957-01-01

    An experimental investigation was carried out on air- and vacuum-melted M-252 and S-816 alloys to find conditions of heating and hot-working which resulted in abnormal grain growth. The experiments were mainly limited to normal conditions of heating for hot-working and heat treatment and normal temperatures of solution treatment were used to allow grain growth after susceptibility to abnormal grain growth was developed by various experimental conditions. Results indicated that small reductions of essentially strain-free metal were the basic cause of such grain growth.

  13. Kidney abnormalities in sickle cell disease.

    PubMed

    López Revuelta, K; Ricard Andrés, M P

    2011-01-01

    Patients with sickle cell disease exhibits numerous kidney structural and functional abnormalities, changes that are seen along the entire length of the nephron. Changes are most marked in patients with homozygous sickle cell anemia, but are also seen in those with compound heterozygous states and the sickle cell trait. The renal features of sickle cell disease include some of the most common reasons for referral to nephrologists, such as hematuria, proteinuria, tubular disturbances and chronic kidney disease. Therapy of these conditions requires specialized knowledge of their distinct pathogenic mechanisms. Spanish Haemathology and Hemotherapy Association has recently publicated their Clinical Practice Guidelines of SCD management. Renal chapter is reproduced in this article for Nefrología difussion.

  14. Brain growth rate abnormalities visualized in adolescents with autism.

    PubMed

    Hua, Xue; Thompson, Paul M; Leow, Alex D; Madsen, Sarah K; Caplan, Rochelle; Alger, Jeffry R; O'Neill, Joseph; Joshi, Kishori; Smalley, Susan L; Toga, Arthur W; Levitt, Jennifer G

    2013-02-01

    Autism spectrum disorder is a heterogeneous disorder of brain development with wide ranging cognitive deficits. Typically diagnosed before age 3, autism spectrum disorder is behaviorally defined but patients are thought to have protracted alterations in brain maturation. With longitudinal magnetic resonance imaging (MRI), we mapped an anomalous developmental trajectory of the brains of autistic compared with those of typically developing children and adolescents. Using tensor-based morphometry, we created 3D maps visualizing regional tissue growth rates based on longitudinal brain MRI scans of 13 autistic and seven typically developing boys (mean age/interscan interval: autism 12.0 ± 2.3 years/2.9 ± 0.9 years; control 12.3 ± 2.4/2.8 ± 0.8). The typically developing boys demonstrated strong whole brain white matter growth during this period, but the autistic boys showed abnormally slowed white matter development (P = 0.03, corrected), especially in the parietal (P = 0.008), temporal (P = 0.03), and occipital lobes (P = 0.02). We also visualized abnormal overgrowth in autism in gray matter structures such as the putamen and anterior cingulate cortex. Our findings reveal aberrant growth rates in brain regions implicated in social impairment, communication deficits and repetitive behaviors in autism, suggesting that growth rate abnormalities persist into adolescence. Tensor-based morphometry revealed persisting growth rate anomalies long after diagnosis, which has implications for evaluation of therapeutic effects.

  15. Renal abnormalities in sickle cell disease.

    PubMed

    Ataga, K I; Orringer, E P

    2000-04-01

    Sickle cell anemia and the related hemoglobinopathies are associated with a large spectrum of renal abnormalities. The patients have impaired urinary concentrating ability, defects in urinary acidification and potassium excretion, and supranormal proximal tubular function. The latter is manifest by increased secretion of creatinine and by reabsorption of phosphorus and beta(2)-microglobulin. Young patients with sickle cell disease (SCD) have supranormal renal hemodynamics with elevations in both effective renal plasma flow (ERPF) and glomerular filtration rate (GFR). These parameters decrease with age as well as following the administration of prostaglandin inhibitors. Proteinuria, a common finding in adults with sickle cell disease, may progress to the nephrotic syndrome. Proteinuria, hypertension, and increasing anemia predict end-stage renal disease (ESRD). While ESRD can be managed by dialysis and/or renal transplantation, there may be an increased rate of complications in renal transplant recipients with SCD. Hematuria is seen in individuals with all of the SCDs as well as with sickle cell trait. In most cases the etiology of the hematuria turns out to be benign. However, there does appear to be an increased association between SCD and renal medullary carcinoma. Therefore, those SCD patients who present with hematuria should initially undergo a thorough evaluation in order to exclude this aggressive neoplasm. Papillary necrosis may occur due to medullary ischemia and infarction. Erythropoietin levels are usually lower than expected for their degree of anemia and decrease further as renal function deteriorates. An abnormal balance of renal prostaglandins may be responsible for some of the changes in sickle cell nephropathy. Acute renal failure is a component of the acute multiorgan failure syndrome (MOFS). Finally, progression of sickle cell nephropathy to ESRD may be slowed by adequate control of hypertension and proteinuria. However, the prevention of the

  16. Cardiovascular Abnormalities in Sickle Cell Disease

    PubMed Central

    Gladwin, Mark T.; Sachdev, Vandana

    2013-01-01

    Sickle cell disease is characterized by recurrent episodes of ischemia-reperfusion injury to multiple vital organ systems and a chronic hemolytic anemia, both contributing to progressive organ dysfunction. The introduction of treatments that induce protective fetal hemoglobin and reduce infectious complications has greatly prolonged survival. However, with increased longevity, cardiovascular complications are increasingly evident, with the notable development of a progressive proliferative systemic vasculopathy, pulmonary hypertension (PH) and left ventricular diastolic dysfunction. Pulmonary hypertension is reported in autopsy studies and numerous clinical studies have shown that increased pulmonary pressures are an important risk marker for mortality in these patients. In epidemiological studies, the development of PH is associated with intravascular hemolysis, cutaneous leg ulceration, renal insufficiency, iron overload and liver dysfunction. Chronic anemia in sickle cell disease results in cardiac chamber dilation and a compensatory increase in left ventricular mass. This is often accompanied by left ventricular diastolic dysfunction which has also been a strong independent predictor of mortality patients with sickle cell disease. Both PH and diastolic dysfunction are associated with marked abnormalities in exercise capacity in these patients. Sudden death is an increasingly recognized problem and further cardiac investigations are necessary to recognize and treat high-risk patients. PMID:22440212

  17. Catalase and superoxide dismutase conjugated with platelet-endothelial cell adhesion molecule antibody distinctly alleviate abnormal endothelial permeability caused by exogenous reactive oxygen species and vascular endothelial growth factor.

    PubMed

    Han, Jingyan; Shuvaev, Vladimir V; Muzykantov, Vladimir R

    2011-07-01

    Reactive oxygen species (ROS) superoxide anion (O(2)()) and hydrogen peroxide (H(2)O(2)) produced by activated leukocytes and endothelial cells in sites of inflammation or ischemia cause endothelial barrier dysfunction that may lead to tissue edema. Antioxidant enzymes (AOEs) catalase and superoxide dismutase (SOD) conjugated with antibodies to platelet-endothelial cell adhesion molecule-1 (PECAM-1) specifically bind to endothelium, quench the corresponding ROS, and alleviate vascular oxidative stress and inflammation. In the present work, we studied the effects of anti-PECAM/catalase and anti-PECAM/SOD conjugates on the abnormal permeability manifested by transendothelial electrical resistance decline, increased fluorescein isothiocyanate-dextran influx, and redistribution of vascular endothelial-cadherin in human umbilical vein endothelial cell (HUVEC) monolayers. Anti-PECAM/catalase protected HUVEC monolayers against H(2)O(2)-induced endothelial barrier dysfunction. Polyethylene glycol-conjugated catalase exerted orders of magnitude lower endothelial uptake and no protective effect, similarly to IgG/catalase. Anti-PECAM/catalase, but not anti-PECAM/SOD, alleviated endothelial hyperpermeability caused by exposure to hypoxanthine/xanthine oxidase, implicating primarily H(2)O(2) in the disruption of the endothelial barrier in this model. Thrombin-induced endothelial permeability was not affected by treatment with anti-PECAM/AOEs or the NADPH oxidase inhibitor apocynin or overexpression of AOEs, indicating that the endogenous ROS play no key role in thrombin-mediated endothelial barrier dysfunction. In contrast, anti-PECAM/SOD, but not anti-PECAM/catalase, inhibited a vascular endothelial growth factor (VEGF)-induced increase in endothelial permeability, identifying a key role of endogenous O(2)() in the VEGF-mediated regulation of endothelial barrier function. Therefore, AOEs targeted to endothelial cells provide versatile molecular tools for testing the roles of

  18. Abnormal growth of ovarian antral follicles in breast cancer patients.

    PubMed

    Byskov, A G; McNatty, K P; Westergaard, L; Larsen, J K; Grinsted, J; Peters, H

    1983-07-01

    Ovarian antral follicles from patients with breast cancer were compared with follicles from healthy women. Steroid levels in the follicular fluid and the health status of the follicles were evaluated. Follicles were judged to be healthy or atretic by flow cytometric determinations of the deoxyribonucleic acid content of aspirated granulosa cell nuclei. Fifteen of the 25 follicles (60%) from the cancer patients contained unmeasurable or abnormally low steriod levels (i.e., less than 100 ng/ml) which were significantly (P less than 0.001) lower than in follicles of the same health status from healthy women (500 to 1000 ng/ml). It is speculated whether substances other than the usual follicular steriods are produced by the cancer patients, which stimulate mitotic activity of the granulosa cells.

  19. Arsenic promotes centrosome abnormalities and cell colony formation in p53 compromised human lung cells

    SciTech Connect

    Liao Weiting; Lin Pinpin; Cheng, T.-S.; Yu, H.-S.; Chang, Louis W.

    2007-12-01

    Epidemiological evidence indicated that residents, especially cigarette smokers, in arseniasis areas had significantly higher lung cancer risk than those living in non-arseniasis areas. Thus, an interaction between arsenic and cigarette smoking in lung carcinogenesis was suspected. p53 dysfunction or mutation in lung epithelial cells was frequently observed in cigarette smokers. Our present study was to explore the differential effects by arsenic on H1355 cells (human lung adenocarcinoma cell line with mutation in p53), BEAS-2B (immortalized lung epithelial cell with functional p53) and pifithrin-{alpha}-treated BEAS-2B cells (p53-inhibited cells). These cells were treated with different doses of sodium arsenite (0, 0.1, 1, 5 and 10 {mu}M) for 48 h. A greater reduction in cell viability was observed in the BEAS-2B cells vs. p53 compromised cells (H1355 or p53-inhibited BEAS-2B). Similar observation was also made on 7-day cell survival (growth) study. TUNEL analysis confirmed that there was indeed a significantly reduced arsenite-induced apoptosis found in p53-compromised cells. Centrosomal abnormality has been attributed to eventual chromosomal missegregation, aneuploidy and tumorigenesis. In our present study, reduced p21 and Gadd45a expressions and increased centrosomal abnormality (atopic and multiple centrosomes) were observed in both arsenite-treated H1355 and p53-inhibited BEAS-2B cells as compared with similarly treated BEAS-2B cells. Increased anchorage-independent growth (colony formation) of BEAS-2B cells co-treated with pifithrin-{alpha} and 5 {mu}M sodium arsenite was also observed in soft agar. Our present investigation demonstrated that arsenic would act specifically on p53 compromised cells (either with p53 dysfunction or inhibited) to induce centrosomal abnormality and colony formation. These findings provided strong evidence on the carcinogenic promotional role of arsenic, especially under the condition of p53 dysfunction.

  20. Phenomenology of Abnormal Grain Growth in Systems with Nonuniform Grain Boundary Mobility

    NASA Astrophysics Data System (ADS)

    DeCost, Brian L.; Holm, Elizabeth A.

    2016-07-01

    We have investigated the potential for nonuniform grain boundary mobility to act as a persistence mechanism for abnormal grain growth (AGG) using Monte Carlo Potts model simulations. The model system consists of a single initially large candidate grain embedded in a matrix of equiaxed grains, corresponding to the abnormal growth regime before impingement occurs. We assign a mobility advantage to grain boundaries between the candidate grain and a randomly selected subset of the matrix grains. We observe AGG in systems with physically reasonable fractions of fast boundaries; the probability of abnormal growth increases as the density of fast boundaries increases. This abnormal growth occurs by a series of fast, localized growth events that counteract the tendency of abnormally large grains to grow more slowly than the surrounding matrix grains. Resulting abnormal grains are morphologically similar to experimentally observed abnormal grains.

  1. Ring chromosome 5 associated with severe growth retardation as the sole major physical abnormality

    SciTech Connect

    Migliori, M.V.; Pettinari, A.; Cherubini, V.; Bartolotta, E.; Pecora, R.

    1994-01-01

    The authors report on a case of ring chromosome 5 in a 36-month-old girl with severe growth retardation, clinodactyly, mild psychological abnormalities, and normal facial appearance. Endocrine tests showed partial growth hormone deficiency. Cytogenetic investigation failed to demonstrate any apparent microscopic deletion of either the short or long arm of chromosome 5 as a consequence of ring formation. In 12% of cells examined, the ring was either absent or present in multiple copies. Only 3 previous cases of ring chromosome 5 have been reported in association with short stature of prenatal onset and minor anomalies, without mental retardation. 12 refs., 3 figs.

  2. Visualizing how cancer chromosome abnormalities form in living cells

    Cancer.gov

    For the first time, scientists have directly observed events that lead to the formation of a chromosome abnormality that is often found in cancer cells. The abnormality, called a translocation, occurs when part of a chromosome breaks off and becomes attac

  3. The effect of abnormal cell proportion on specimen classifier performance

    NASA Technical Reports Server (NTRS)

    Castleman, K. R.; White, B. S.

    1981-01-01

    An analysis is presented of the results obtained from a cell classifier which is confronted with an abnormal/normal cell ratio which is different from the ratio assumed in the calibration of the classifier. False negative and false positive error rates are determined in advance for classifier operation, along with the necessary sample size in order to validate the predicted distributions. Changes are demonstrated to happen only regarding the false negative rate, where reductions in the abnormal cell rate below the expected rates would cause totally unreliable data. Substantial overproduction of abnormal cells would be quickly noticeable, while production rates beyond, but close to, the expected rates would only require more extensive sampling. Classifier systems for 10% proportions of abnormal cells are concluded to be possible, but difficulties are present with much lower rates

  4. Persistent expression of Twist1 in chondrocytes causes growth plate abnormalities and dwarfism in mice.

    PubMed

    Guzzo, Rosa M; Andreeva, Viktoria; Spicer, Douglas B; Drissi, M Hicham

    2011-01-01

    Evidence from various in vitro gain and loss of function studies indicate that the bHLH transcription factor Twist1 negatively regulates chondrocyte differentiation; however limited information regarding Twist1 function in postnatal cartilage development and maintenance is available. Twist1 expression within the postnatal growth plate is restricted to immature, proliferating chondrocytes, and is significantly decreased or absent in hypertrophic chondrocytes. In order to examine the effect of maintaining the expression of Twist1 at later stages of chondocyte differentiation, we used type II collagen Cre (Col2-Cre) mice to activate a Cre-inducible Twist1 transgene specifically in chondrocytes (Col2-Twist1). At two weeks, postnatal growth was inhibited in Col2-Twist1 mice, as evidenced by limb shortening. Histological examination revealed abnormal growth plate structure, characterized by poor columnar organization of proliferating cartilaginous cells, decreased cellularity, and expansion of the hypertrophic zone. Moreover, structural defects within the growth plates of Col2-Twist1 transgenic mice included abnormal vascular invasion and focal regions of bony formation. Quantitative analysis of endochondral bone formation via micro-computed topography revealed impaired trabecular bone formation in the hindlimbs of Col2-Twist1 transgenic mice at various timepoints of postnatal development. Taken together, these findings indicate that regulated Twist1 expression contributes to growth plate organization and endochondral ossification to modulate postnatal longitudinal bone growth.

  5. Hypoxia-Induced Reactive Oxygen Species Cause Chromosomal Abnormalities in Endothelial Cells in the Tumor Microenvironment

    PubMed Central

    Hida, Yasuhiro; Maishi, Nako; Towfik, Alam Mohammad; Inoue, Nobuo; Shindoh, Masanobu; Hida, Kyoko

    2013-01-01

    There is much evidence that hypoxia in the tumor microenvironment enhances tumor progression. In an earlier study, we reported abnormal phenotypes of tumor-associated endothelial cells such as those resistant to chemotherapy and chromosomal instability. Here we investigated the role of hypoxia in the acquisition of chromosomal abnormalities in endothelial cells. Tumor-associated endothelial cells isolated from human tumor xenografts showed chromosomal abnormalities, >30% of which were aneuploidy. Aneuploidy of the tumor-associated endothelial cells was also shown by simultaneous in-situ hybridization for chromosome 17 and by immunohistochemistry with anti-CD31 antibody for endothelial staining. The aneuploid cells were surrounded by a pimonidazole-positive area, indicating hypoxia. Human microvascular endothelial cells expressed hypoxia-inducible factor 1 and vascular endothelial growth factor A in response to either hypoxia or hypoxia-reoxygenation, and in these conditions, they acquired aneuploidy in 7 days. Induction of aneuploidy was inhibited by either inhibition of vascular endothelial growth factor signaling with vascular endothelial growth factor receptor 2 inhibitor or by inhibition of reactive oxygen species by N-acetyl-L-cysteine. These results indicate that hypoxia induces chromosomal abnormalities in endothelial cells through the induction of reactive oxygen species and excess signaling of vascular endothelial growth factor in the tumor microenvironment. PMID:24260373

  6. Abnormalities of T cell signaling in systemic lupus erythematosus

    PubMed Central

    2011-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease resulting from a loss of tolerance to multiple self antigens, and characterized by autoantibody production and inflammatory cell infiltration in target organs, such as the kidneys and brain. T cells are critical players in SLE pathophysiology as they regulate B cell responses and also infiltrate target tissues, leading to tissue damage. Abnormal signaling events link to defective gene transcription and altered cytokine production, contributing to the aberrant phenotype of T cells in SLE. Study of signaling and gene transcription abnormalities in SLE T cells has led to the identification of novel targets for therapy. PMID:21457530

  7. Excimer laser phototherapy for the dissolution of abnormal growth

    DOEpatents

    Gruen, Dieter M.; Young, Charles E.; Pellin, Michael J.

    1987-01-01

    Removal of abnormal human tissue with reduced thermal damage is achieved by selecting a laser having a wavelength in the order of 290-400 nm, orienting a laser-transmitting glass member toward the abnormal tissue and directing the laser through the glass member at power densities, pulse rates, and times sufficient to cause multiphoton absorption and bond breaking by Coulomb repulsion rather than thermal destruction. The glass member may include a laser beam concentrator provided by a lens or cone at the tissue-treatment end to increase the beam energy per unit area and reduce the treatment area.

  8. Excimer laser phototherapy for the dissolution of abnormal growth

    DOEpatents

    Gruen, D.M.; Young, C.E.; Pellin, M.J.

    1985-02-19

    Removal of abnormal human tissue with reduced thermal damage is achieved by selecting a laser having a wavelength in the order of 290 to 400 nm, orienting a laser-transmitting glass member toward the abnormal tissue and directing the laser through the glass member at power densities, pulse rates, and times sufficient to cause multiphoton absorption and bond breaking by Coulomb repulsion rather than thermal destruction. The glass member may include a laser beam concentrator provided by a lens or cone at the tissue-treatment end to increase the beam energy per unit area and reduce the treatment area. 6 figs.

  9. Quantifying the abnormal hemodynamics of sickle cell anemia

    NASA Astrophysics Data System (ADS)

    Lei, Huan; Karniadakis, George

    2012-02-01

    Sickle red blood cells (SS-RBC) exhibit heterogeneous morphologies and abnormal hemodynamics in deoxygenated states. A multi-scale model for SS-RBC is developed based on the Dissipative Particle Dynamics (DPD) method. Different cell morphologies (sickle, granular, elongated shapes) typically observed in deoxygenated states are constructed and quantified by the Asphericity and Elliptical shape factors. The hemodynamics of SS-RBC suspensions is studied in both shear and pipe flow systems. The flow resistance obtained from both systems exhibits a larger value than the healthy blood flow due to the abnormal cell properties. Moreover, SS-RBCs exhibit abnormal adhesive interactions with both the vessel endothelium cells and the leukocytes. The effect of the abnormal adhesive interactions on the hemodynamics of sickle blood is investigated using the current model. It is found that both the SS-RBC - endothelium and the SS-RBC - leukocytes interactions, can potentially trigger the vicious ``sickling and entrapment'' cycles, resulting in vaso-occlusion phenomena widely observed in micro-circulation experiments.

  10. About Abnormal Grain Growth in Joints Obtained by Friction Stir Welding

    NASA Astrophysics Data System (ADS)

    Mironov, S. Yu.

    2015-05-01

    Some special features of abnormal grain growth in welded joints of aluminum alloys formed by fiction stir welding (FSW) are studied. The microstructure and the texture of the alloys are determined after welding and annealing at 400, 450 and 500°C for different times. The abnormal grain growth is shown to depend much on the macroscopic inhomogeneity of the structure inside the weld.

  11. Early recognition of growth abnormalities permitting early intervention

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Normal growth is a sign of good health. Monitoring for growth disturbances is fundamental to children's health care. Early detection and diagnosis of the causes of short stature allows management of underlying medical conditions, optimizing attainment of good health and normal adult height. This rev...

  12. Abnormal response of the proliferation and differentiation of growth plate chondrocytes to melatonin in adolescent idiopathic scoliosis.

    PubMed

    Wang, William Wei-Jun; Man, Gene Chi-Wai; Wong, Jack Ho; Ng, Tzi-Bun; Lee, Kwong-Man; Ng, Bobby Kin-Wah; Yeung, Hiu-Yan; Qiu, Yong; Cheng, Jack Chun-Yiu

    2014-09-25

    Abnormalities in the melatonin signaling pathway and the involvement of melatonin receptor MT2 have been reported in patients with adolescent idiopathic scoliosis (AIS). Whether these abnormalities were involved in the systemic abnormal skeletal growth in AIS during the peripubertal period remain unknown. In this cross-sectional case-control study, growth plate chondrocytes (GPCs) were cultured from twenty AIS and ten normal control subjects. Although the MT2 receptor was identified in GPCs from both AIS and controls, its mRNA expression was significantly lower in AIS patients than the controls. GPCs were cultured in the presence of either the vehicle or various concentrations of melatonin, with or without the selective MT2 melatonin receptor antagonist 4-P-PDOT (10 µM). Then the cell viability and the mRNA expression of collagen type X (COLX) and alkaline phosphatase (ALP) were assessed by MTT and qPCR, respectively. In the control GPCs, melatonin at the concentrations of 1, 100 nM and 10 µM significantly reduced the population of viable cells, and the mRNA level of COLX and ALP compared to the vehicle. Similar changes were not observed in the presence of 4-P-PDOT. Further, neither proliferation nor differentiation of GPCs from AIS patients was affected by the melatonin treatment. These findings support the presence of a functional abnormality of the melatonin signaling pathway in AIS GPCs, which might be associated with the abnormal endochondral ossification in AIS patients.

  13. The Effects of Grain Size and Texture on Dynamic Abnormal Grain Growth in Mo

    NASA Astrophysics Data System (ADS)

    Noell, Philip J.; Taleff, Eric M.

    2016-10-01

    This is the first report of abnormal grain morphologies specific to a Mo sheet material produced from a commercial-purity arc-melted ingot. Abnormal grains initiated and grew during plastic deformation of this material at temperatures of 1793 K and 1813 K (1520 °C and 1540 °C). This abnormal grain growth during high-temperature plastic deformation is termed dynamic abnormal grain growth, DAGG. DAGG in this material readily consumes nearly all grains near the sheet center while leaving many grains near the sheet surface unconsumed. Crystallographic texture, grain size, and other microstructural features are characterized. After recrystallization, a significant through-thickness variation in crystallographic texture exists in this material but does not appear to directly influence DAGG propagation. Instead, dynamic normal grain growth, which may be influenced by texture, preferentially occurs near the sheet surface prior to DAGG. The large grains thus produced near the sheet surface inhibit the subsequent growth of the abnormal grains produced by DAGG, which preferentially consume the finer grains near the sheet center. This produces abnormal grains that span the sheet center but leave unconsumed polycrystalline microstructure near the sheet surface. Abnormal grains are preferentially oriented with the < 110rangle approximately along the tensile axis. These results provide additional new evidence that boundary curvature is the primary driving force for DAGG in Mo.

  14. Abnormal Skeletal Growth in Adolescent Idiopathic Scoliosis Is Associated with Abnormal Quantitative Expression of Melatonin Receptor, MT2

    PubMed Central

    Yim, Annie Po-yee; Yeung, Hiu-yan; Sun, Guangquan; Lee, Kwong-man; Ng, Tzi-bun; Lam, Tsz-ping; Ng, Bobby Kin-wah; Qiu, Yong; Moreau, Alain; Cheng, Jack Chun-yiu

    2013-01-01

    The defect of the melatonin signaling pathway has been proposed to be one of the key etiopathogenic factors in adolescent idiopathic scoliosis (AIS). A previous report showed that melatonin receptor, MT2, was undetectable in some AIS girls. The present study aimed to investigate whether the abnormal MT2 expression in AIS is quantitative or qualitative. Cultured osteoblasts were obtained from 41 AIS girls and nine normal controls. Semi-quantification of protein expression by Western blot and mRNA expression by TaqMan real-time PCR for both MT1 and MT2 were performed. Anthropometric parameters were also compared and correlated with the protein expression and mRNA expression of the receptors. The results showed significantly lower protein and mRNA expression of MT2 in AIS girls compared with that in normal controls (p = 0.02 and p = 0.019, respectively). No differences were found in the expression of MT1. When dichotomizing the AIS girls according to their MT2 expression, the group with low expression was found to have a significantly longer arm span (p = 0.036). The results of this study showed for the first time a quantitative change of MT2 in AIS that was also correlated with abnormal arm span as part of abnormal systemic skeletal growth. PMID:23519105

  15. Changing pattern of epithelial cell abnormalities using revised Bethesda system

    PubMed Central

    Mufti, Shagufta T.; Altaf, Fadwa J

    2014-01-01

    Objective(s): In developing countries and worldwide cervical cancer is an important cause of female mortality. Reports describing the frequency and pattern of abnormal Pap smears in Saudi Arabia, using the revised Bethesda system (RBS) are very few. The current study was conducted to explore the changing pattern of epithelial cell abnormalities (ECA) detected in Pap smears (PS) in females of the Western region of Saudi Arabia at King Abdulaziz University Hospital, Jeddah using the RBS. Materials and Methods: A retrospective study was designed to review all the PSs from the archives of Cytopathology Department at King Abdulaziz University Hospital, starting from January 2000 to October 2012 using RBS. Cytological aspects of PSs were reviewed with age distribution. Results: Of the 15805 PS, 84 (0.53%) unsatisfactory smears were excluded. There were 2295 cases (14.52%) with ECA. In the abnormal squamous cell category the distribution of lesions was as follows: Atypical squamous cells of indeterminate significance (ASC-US) were 7.1%; atypical squamous cells, cannot exclude high squamous intraepithelial lesion (ASC-H) were 1.08%; low grade squamous intraepithelial lesion (LSIL) including human papillomavirus was 2.2%, high grade squamous intraepithelial lesion (HSIL) was 0.8% and high grade squamous intraepithelial lesion with suspicious invasion was 0.06% smears. The mean age (MA) incidence was 39,43,45,46 and 45 years respectively. Conclusion: The percentage of abnormal PS is increasing (14.52%) over the last decade. This increase is evident by different studies conducted across Saudi Arabia. Under present circumstances the need for mass screening. PMID:25729547

  16. The development of hepatic stellate cells in normal and abnormal human fetuses – an immunohistochemical study

    PubMed Central

    Loo, Christine K C; Pereira, Tamara N; Pozniak, Katarzyna N; Ramsing, Mette; Vogel, Ida; Ramm, Grant A

    2015-01-01

    The precise embryological origin and development of hepatic stellate cells is not established. Animal studies and observations on human fetuses suggest that they derive from posterior mesodermal cells that migrate via the septum transversum and developing diaphragm to form submesothelial cells beneath the liver capsule, which give rise to mesenchymal cells including hepatic stellate cells. However, it is unclear if these are similar to hepatic stellate cells in adults or if this is the only source of stellate cells. We have studied hepatic stellate cells by immunohistochemistry, in developing human liver from autopsies of fetuses with and without malformations and growth restriction, using cellular Retinol Binding Protein-1 (cRBP-1), Glial Fibrillary Acidic Protein (GFAP), and α-Smooth Muscle Actin (αSMA) antibodies, to identify factors that influence their development. We found that hepatic stellate cells expressing cRBP-1 are present from the end of the first trimester of gestation and reduce in density throughout gestation. They appear abnormally formed and variably reduced in number in fetuses with abnormal mesothelial Wilms Tumor 1 (WT1) function, diaphragmatic hernia and in ectopic liver nodules without mesothelium. Stellate cells showed similarities to intravascular cells and their presence in a fetus with diaphragm agenesis suggests they may be derived from circulating stem cells. Our observations suggest circulating stem cells as well as mesothelium can give rise to hepatic stellate cells, and that they require normal mesothelial function for their development. PMID:26265759

  17. Growth plate abnormalities in a new dwarf mouse model: tich.

    PubMed

    Brown, R A; Bird, L; Blunn, G W; Archer, J R

    1994-03-01

    Growth plate cartilage calcification has been examined in a recently described mouse mutant, tich, which is co-isogenic with the A.TL strain. Long bones were studied from 1-day-old and 1-month-old mice which carried a homozygous recessive gene mutation making them short limbed and dumpy. Specimens were studied by routine histology, scanning electron microscopy and radiography. In 1-day-old tich mice the front of calcified cartilage was recessed behind the advancing periosteum and bone. No similar recess was seen in control mice. At 1 month of age, a number of the long bone growth plates were irregularly thickened, particularly in the central area. This produced a central tongue of non-calcified cartilage (particularly prominent in the proximal tibia) which gave rise to a corresponding pit in the calcified cartilage layer, in macerated specimens. This was accompanied by poor resorption of calcified cartilage. At both ages the presence of the respective defects was radiographically confirmed. At present it is not known whether this is primarily a defect of calcification or resorption but its presence, apparently from a single mutation in a genetically defined mouse strain, makes it a potentially valuable model.

  18. The onset and evolution of fatigue-induced abnormal grain growth in nanocrystalline Ni–Fe

    DOE PAGES

    Furnish, T. A.; Mehta, A.; Van Campen, D.; ...

    2016-10-11

    Conventional structural metals suffer from fatigue-crack initiation through dislocation activity which forms persistent slip bands leading to notch-like extrusions and intrusions. Ultrafine-grained and nanocrystalline metals can potentially exhibit superior fatigue-crack initiation resistance by suppressing these cumulative dislocation activities. Prior studies on these metals have confirmed improved high-cycle fatigue performance. In the case of nano-grained metals, analyses of subsurface crack initiation sites have indicated that the crack nucleation is associated with abnormally large grains. But, these post-mortem analyses have led to only speculation about when abnormal grain growth occurs (e.g., during fatigue, after crack initiation, or during crack growth). In thismore » study, a recently developed synchrotron X-ray diffraction technique was used to detect the onset and progression of abnormal grain growth during stress-controlled fatigue loading. Our study provides the first direct evidence that the grain coarsening is cyclically induced and occurs well before final fatigue failure—our results indicate that the first half of the fatigue life was spent prior to the detectable onset of abnormal grain growth, while the second half was spent coarsening the nanocrystalline structure and cyclically deforming the abnormally large grains until crack initiation. Post-mortem fractography, coupled with cycle-dependent diffraction data, provides the first details regarding the kinetics of this abnormal grain growth process during high-cycle fatigue testing. Finally, precession electron diffraction images collected in a transmission electron microscope after the in situ fatigue experiment also confirm the X-ray evidence that the abnormally large grains contain substantial misorientation gradients and sub-grain boundaries.« less

  19. The onset and evolution of fatigue-induced abnormal grain growth in nanocrystalline Ni–Fe

    SciTech Connect

    Furnish, T. A.; Mehta, A.; Van Campen, D.; Bufford, D. C.; Hattar, K.; Boyce, B. L.

    2016-10-11

    Conventional structural metals suffer from fatigue-crack initiation through dislocation activity which forms persistent slip bands leading to notch-like extrusions and intrusions. Ultrafine-grained and nanocrystalline metals can potentially exhibit superior fatigue-crack initiation resistance by suppressing these cumulative dislocation activities. Prior studies on these metals have confirmed improved high-cycle fatigue performance. In the case of nano-grained metals, analyses of subsurface crack initiation sites have indicated that the crack nucleation is associated with abnormally large grains. But, these post-mortem analyses have led to only speculation about when abnormal grain growth occurs (e.g., during fatigue, after crack initiation, or during crack growth). In this study, a recently developed synchrotron X-ray diffraction technique was used to detect the onset and progression of abnormal grain growth during stress-controlled fatigue loading. Our study provides the first direct evidence that the grain coarsening is cyclically induced and occurs well before final fatigue failure—our results indicate that the first half of the fatigue life was spent prior to the detectable onset of abnormal grain growth, while the second half was spent coarsening the nanocrystalline structure and cyclically deforming the abnormally large grains until crack initiation. Post-mortem fractography, coupled with cycle-dependent diffraction data, provides the first details regarding the kinetics of this abnormal grain growth process during high-cycle fatigue testing. Finally, precession electron diffraction images collected in a transmission electron microscope after the in situ fatigue experiment also confirm the X-ray evidence that the abnormally large grains contain substantial misorientation gradients and sub-grain boundaries.

  20. ETOPOSIDE INDUCES CHROMOSOMAL ABNORMALITIES IN SPERMATOCYTES AND SPERMATOGONIAL STEM CELLS

    SciTech Connect

    Marchetti, F; Pearson, F S; Bishop, J B; Wyrobek, A J

    2005-07-15

    Etoposide (ET) is a chemotherapeutic agent widely used in the treatment of leukemia, lymphomas and many solid tumors, such as testicular and ovarian cancers, that affect patients in their reproductive years. The purpose of the study was to use sperm FISH analyses to characterize the long-term effects of ET on male germ cells. We used a mouse model to characterize the induction of chromosomal aberrations (partial duplications and deletions) and whole chromosomal aneuploidies in sperm of mice treated with a clinical dose of ET. Semen samples were collected at 25 and 49 days after dosing to investigate the effects of ET on meiotic pachytene cells and spermatogonial stem-cells, respectively. ET treatment resulted in major increases in the frequencies of sperm carrying chromosomal aberrations in both meiotic pachytene (27- to 578-fold) and spermatogonial stem-cells (8- to 16-fold), but aneuploid sperm were induced only after treatment of meiotic cells (27-fold) with no persistent effects in stem cells. These results demonstrate that male meiotic germ cells are considerably more sensitive to ET than spermatogonial stem-cell and that increased frequencies of sperm with structural aberrations persist after spermatogonial stem-cell treatment. These findings predict that patients who undergo chemotherapy with ET may have transient elevations in the frequencies of aneuploid sperm, but more importantly, may have persistent elevations in the frequencies of sperm with chromosomal aberrations, placing them at higher risk for abnormal reproductive outcomes long after the end of their chemotherapy.

  1. Self-correction of chromosomal abnormalities in human preimplantation embryos and embryonic stem cells.

    PubMed

    Bazrgar, Masood; Gourabi, Hamid; Valojerdi, Mojtaba Rezazadeh; Yazdi, Poopak Eftekhari; Baharvand, Hossein

    2013-09-01

    Aneuploidy is commonly seen in human preimplantation embryos, most particularly at the cleavage stage because of genome activation by third cell division. Aneuploid embryos have been used for the derivation of normal embryonic stem cell (ESC) lines and developmental modeling. This review addresses aneuploidies in human preimplantation embryos and human ESCs and the potential of self-correction of these aberrations. Diploid-aneuploid mosaicism is the most frequent abnormality observed; hence, embryos selected by preimplantation genetic diagnosis at the cleavage or blastocyst stage could be partly abnormal. Differentiation is known as the barrier for eliminating mosaic embryos by death and/or decreased division of abnormal cells. However, some mosaicisms, such as copy number variations could be compatible with live birth. Several reasons have been proposed for self-correction of aneuploidies during later stages of development, including primary misdiagnosis, allocation of the aneuploidy in the trophectoderm, cell growth advantage of diploid cells in mosaic embryos, lagging of aneuploid cell division, extrusion or duplication of an aneuploid chromosome, and the abundance of DNA repair gene products. Although more studies are needed to understand the mechanisms of self-correction as a rare phenomenon, most likely, it is related to overcoming mosaicism.

  2. Cell Growth Enhancement

    NASA Technical Reports Server (NTRS)

    1992-01-01

    Exogene Corporation uses advanced technologies to enhance production of bio-processed substances like proteins, antibiotics and amino acids. Among them are genetic modification and a genetic switch. They originated in research for Jet Propulsion Laboratory. Extensive experiments in cell growth through production of hemoglobin to improve oxygen supply to cells were performed. By improving efficiency of oxygen use by cells, major operational expenses can be reduced. Greater product yields result in decreased raw material costs and more efficient use of equipment. A broad range of applications is cited.

  3. A Pilot Study of Abnormal Growth in Autism Spectrum Disorders and Other Childhood Psychiatric Disorders

    ERIC Educational Resources Information Center

    Rommelse, Nanda N. J.; Peters, Cindy T. R.; Oosterling, Iris J.; Visser, Janne C.; Bons, Danielle; van Steijn, Daphne J.; Draaisma, Jos; van der Gaag, Rutger-Jan; Buitelaar, Jan. K.

    2011-01-01

    The aims of the current study were to examine whether early growth abnormalities are (a) comparable in autism spectrum disorders (ASD) and other childhood psychiatric disorders, and (b) specific to the brain or generalized to the whole body. Head circumference, height, and weight were measured during the first 19 months of life in 129 children…

  4. Effects of corticosteroids on the proliferation of normal and abnormal human connective tissue cells.

    PubMed

    Priestley, G C; Brown, J C

    1980-01-01

    Four corticosteroids were tested in vitro for effect on the proliferation of four strains of fibroblasts from scleroderma skin, four strains from normal adult skin and four strains of rheumatoid synovial cells. Significant effects on fibroblasts occurred only at the highest steroid concentration tested (10 microgram/ml) where the inhibitory ranking of the steriods was clobetasol propionate greater than clobetasone butyrate greater than betamethasone valerate greater than hydrocortisone. Hydrocortisone and betamethasone valerate stimulated proliferation of two normal strains, had no certain effect on the scleroderma group, and inhibited growth of synovial cells. Clobetasone butyrate and clobetasol propionate inhibited growth of all cells. All four steroids substantially reduced acid mucopolysaccharide secretion by scleroderma fibroblasts. These results suggest that fibroblasts from normal and abnormal skin show only small differences in their responses to corticosteroids in vitro, but contrast sharply with the mouse L-929 fibroblasts previously used in some assays of topical corticosteroid potency.

  5. Abnormal grain growth in Eurofer-97 steel in the ferrite phase field

    NASA Astrophysics Data System (ADS)

    Oliveira, V. B.; Sandim, H. R. Z.; Raabe, D.

    2017-03-01

    Reduced-activation ferritic-martensitic (RAFM) Eurofer-97 steel is a candidate material for structural applications in future fusion reactors. Depending on the amount of prior cold rolling strain and annealing temperature, important solid-state softening reactions such as recovery, recrystallization, and grain growth occur. Eurofer-97 steel was cold rolled up to 70, 80 and 90% reductions in thickness and annealed in the ferrite phase field (below ≈ 800 °C). Changes in microstructure, micro-, and mesotexture were followed by orientation mappings provided by electron backscatter diffraction (EBSD). Eurofer-97 steel undergoes abnormal grain growth above 650 °C and this solid-state reaction seems to be closely related to the high mobility of a few special grain boundaries that overcome pinning effects caused by fine particles. This solid-state reaction promotes important changes in the microstructure and microtexture of this steel. Abnormal grain growth kinetics for each condition was determined by means of quantitative metallography.

  6. Haemolysis and abnormal haemorheology in sickle cell anaemia.

    PubMed

    Connes, Philippe; Lamarre, Yann; Waltz, Xavier; Ballas, Samir K; Lemonne, Nathalie; Etienne-Julan, Maryse; Hue, Olivier; Hardy-Dessources, Marie-Dominique; Romana, Marc

    2014-05-01

    Although pulmonary hypertension, leg ulcers, priapism, stroke and glomerulopathy in sickle cell anaemia (SCA) result from the adverse effects of chronic haemolysis on vascular function (haemolytic phenotype), osteonecrosis, acute chest syndrome and painful vaso-occlusive crises are caused by abnormal vascular cell adhesion and increased blood viscosity (viscosity-vaso-occlusion phenotype). However, this model with two sub-phenotypes does not take into account the haemorheological dimension. We tested the relationships between the biological parameters reflecting the haemolytic rate (haemolytic component) and red blood cell (RBC) rheological characteristics in 97 adults with SCA. No significant difference in the proportion of patients with low or high haemolytic component in the low and high blood viscosity groups was observed. The RBC elongation index (i.e. deformability) was negatively correlated with the haemolytic component. The RBC aggregates strength (i.e. RBC aggregates robustness) was negatively correlated with RBC elongation index. Sickle RBCs with high density had lower elongation index and higher aggregates strength. In conclusion, (i) the 'haemolytic' phenotype is characterized by decreased RBC deformability and increased RBC aggregates strength and (ii) the viscosity-vaso-occlusive phenotype is characterized by increased RBC deformability but not always by increased blood viscosity. α-thalassaemia modulates the haemorheological properties but other factors seem to be involved.

  7. Morphological and functional platelet abnormalities in Berkeley sickle cell mice.

    PubMed

    Shet, Arun S; Hoffmann, Thomas J; Jirouskova, Marketa; Janczak, Christin A; Stevens, Jacqueline R M; Adamson, Adewole; Mohandas, Narla; Manci, Elizabeth A; Cynober, Therese; Coller, Barry S

    2008-01-01

    Berkeley sickle cell mice are used as animal models of human sickle cell disease but there are no reports of platelet studies in this model. Since humans with sickle cell disease have platelet abnormalities, we studied platelet morphology and function in Berkeley mice (SS). We observed elevated mean platelet forward angle light scatter (FSC) values (an indirect measure of platelet volume) in SS compared to wild type (WT) (37+/-3.2 vs. 27+/-1.4, mean+/-SD; p<0.001), in association with moderate thrombocytopenia (505+/-49 x 10(3)/microl vs. 1151+/-162 x 10(3)/microl; p<0.001). Despite having marked splenomegaly, SS mice had elevated levels of Howell-Jolly bodies and "pocked" erythrocytes (p<0.001 for both) suggesting splenic dysfunction. SS mice also had elevated numbers of thiazole orange positive platelets (5+/-1% vs. 1+/-1%; p<0.001), normal to low plasma thrombopoietin levels, normal plasma glycocalicin levels, normal levels of platelet recovery, and near normal platelet life spans. Platelets from SS mice bound more fibrinogen and antibody to P-selectin following activation with a threshold concentration of a protease activated receptor (PAR)-4 peptide compared to WT mice. Enlarged platelets are associated with a predisposition to arterial thrombosis in humans and some humans with SCD have been reported to have large platelets. Thus, additional studies are needed to assess whether large platelets contribute either to pulmonary hypertension or the large vessel arterial occlusion that produces stroke in some children with sickle cell disease.

  8. Maternal risk factors for abnormal placental growth: The national collaborative perinatal project

    PubMed Central

    Baptiste-Roberts, Kesha; Salafia, Carolyn M; Nicholson, Wanda K; Duggan, Anne; Wang, Nae-Yuh; Brancati, Frederick L

    2008-01-01

    Background Previous studies of maternal risk factors for abnormal placental growth have focused on placental weight and placental ratio as measures of placental growth. We sought to identify maternal risk factors for placental weight and two neglected dimensions of placental growth: placental thickness and chorionic plate area. Methods We conducted an analysis of 24,135 mother-placenta pairs enrolled in the National Collaborative Perinatal Project, a prospective cohort study of pregnancy and child health. We defined growth restriction as < 10th percentile and hypertrophy as > 90th percentile for three placental growth dimensions: placental weight, placental thickness and chorionic plate area. We constructed parallel multinomial logistic regression analyses to identify (a) predictors of restricted growth (vs. normal) and (b) predictors of hypertrophic growth (vs. normal). Results Black race was associated with an increased likelihood of growth restriction for placental weight, thickness and chorionic plate area, but was associated with a reduced likelihood of hypertrophy for these three placental growth dimensions. We observed an increased likelihood of growth restriction for placental weight and chorionic plate area among mothers with hypertensive disease at 24 weeks or beyond. Anemia was associated with a reduced likelihood of growth restriction for placental weight and chorionic plate area. Pre-pregnancy BMI and pregnancy weight gain were associated with a reduced likelihood of growth restriction and an increased likelihood of hypertrophy for all three dimensions of placental growth. Conclusion Maternal risk factors are either associated with placental growth restriction or placental hypertrophy not both. Our findings suggest that the placenta may have compensatory responses to certain maternal risk factors suggesting different underlying biological mechanisms. PMID:18811957

  9. Predicting the Probability of Abnormal Stimulated Growth Hormone Response in Children After Radiotherapy for Brain Tumors

    SciTech Connect

    Hua Chiaho; Wu Shengjie; Chemaitilly, Wassim; Lukose, Renin C.; Merchant, Thomas E.

    2012-11-15

    Purpose: To develop a mathematical model utilizing more readily available measures than stimulation tests that identifies brain tumor survivors with high likelihood of abnormal growth hormone secretion after radiotherapy (RT), to avoid late recognition and a consequent delay in growth hormone replacement therapy. Methods and Materials: We analyzed 191 prospectively collected post-RT evaluations of peak growth hormone level (arginine tolerance/levodopa stimulation test), serum insulin-like growth factor 1 (IGF-1), IGF-binding protein 3, height, weight, growth velocity, and body mass index in 106 children and adolescents treated for ependymoma (n = 72), low-grade glioma (n = 28) or craniopharyngioma (n = 6), who had normal growth hormone levels before RT. Normal level in this study was defined as the peak growth hormone response to the stimulation test {>=}7 ng/mL. Results: Independent predictor variables identified by multivariate logistic regression with high statistical significance (p < 0.0001) included IGF-1 z score, weight z score, and hypothalamic dose. The developed predictive model demonstrated a strong discriminatory power with an area under the receiver operating characteristic curve of 0.883. At a potential cutoff point of probability of 0.3 the sensitivity was 80% and specificity 78%. Conclusions: Without unpleasant and expensive frequent stimulation tests, our model provides a quantitative approach to closely follow the growth hormone secretory capacity of brain tumor survivors. It allows identification of high-risk children for subsequent confirmatory tests and in-depth workup for diagnosis of growth hormone deficiency.

  10. Raman spectroscopy of DNA packaging in individual human sperm cells distinguishes normal from abnormal cells.

    PubMed

    Huser, Thomas; Orme, Christine A; Hollars, Christopher W; Corzett, Michele H; Balhorn, Rod

    2009-05-01

    Healthy human males produce sperm cells of which about 25-40% have abnormal head shapes. Increases in the percentage of sperm exhibiting aberrant sperm head morphologies have been correlated with male infertility, and biochemical studies of pooled sperm have suggested that sperm with abnormal shape may contain DNA that has not been properly repackaged by protamine during spermatid development. We have used micro-Raman spectroscopy to obtain Raman spectra from individual human sperm cells and examined how differences in the Raman spectra of sperm chromatin correlate with cell shape. We show that Raman spectra of individual sperm cells contain vibrational marker modes that can be used to assess the efficiency of DNA-packaging for each cell. Raman spectra obtained from sperm cells with normal shape provide evidence that DNA in these sperm is very efficiently packaged. We find, however, that the relative protein content per cell and DNA packaging efficiencies are distributed over a relatively wide range for sperm cells with both normal and abnormal shape. These findings indicate that single cell Raman spectroscopy should be a valuable tool in assessing the quality of sperm cells for in-vitro fertilization.

  11. Raman Spectroscopy of DNA Packaging in Individual Human Sperm Cells distinguishes Normal from Abnormal Cells

    SciTech Connect

    Huser, T; Orme, C; Hollars, C; Corzett, M; Balhorn, R

    2009-03-09

    Healthy human males produce sperm cells of which about 25-40% have abnormal head shapes. Increases in the percentage of sperm exhibiting aberrant sperm head morphologies have been correlated with male infertility, and biochemical studies of pooled sperm have suggested that sperm with abnormal shape may contain DNA that has not been properly repackaged by protamine during spermatid development. We have used micro-Raman spectroscopy to obtain Raman spectra from individual human sperm cells and examined how differences in the Raman spectra of sperm chromatin correlate with cell shape. We show that Raman spectra of individual sperm cells contain vibrational marker modes that can be used to assess the efficiency of DNA-packaging for each cell. Raman spectra obtained from sperm cells with normal shape provide evidence that DNA in these sperm is very efficiently packaged. We find, however, that the relative protein content per cell and DNA packaging efficiencies are distributed over a relatively wide range for sperm cells with both normal and abnormal shape. These findings indicate that single cell Raman spectroscopy should be a valuable tool in assessing the quality of sperm cells for in-vitro fertilization.

  12. The Initiation and Propagation of Dynamic Abnormal Grain Growth in Molybdenum

    NASA Astrophysics Data System (ADS)

    Noell, Philip J.; Worthington, Daniel L.; Taleff, Eric M.

    2015-12-01

    Plastic straining can initiate and propagate abnormal grains at temperatures significantly lower than is possible by static annealing. This phenomenon is termed dynamic abnormal grain growth (DAGG). Experiments that produce DAGG in commercial-purity molybdenum sheet materials are used to study the initiation and propagation of abnormal grains by plastic straining at temperatures from 1673 K to 2073 K (1400° C to 1800° C). The minimum strain necessary to initiate DAGG, termed the critical strain, decreases approximately linearly with increasing temperature. The variation in critical strain values observed at a single temperature and strain rate is well described by a normal distribution. An increased fraction of grains aligned with the < 110rangle along the tensile axis, a preferred orientation for DAGG grains, appears to decrease the critical strain for DAGG initiation. DAGG grains preferentially grow into the finest-grained polycrystalline regions, which suggests that the driving force for DAGG propagation is primarily from grain-boundary curvature. No effects of local crystallographic texture variation on growth are evident in microstructures containing DAGG grains. Together, these observations support the hypothesis that plastic straining during DAGG acts primarily to increase boundary mobility, rather than to increase the driving force for boundary migration.

  13. Abnormal B-cell function in HTLV-I-tax transgenic mice.

    PubMed

    Peebles, R S; Maliszewski, C R; Sato, T A; Hanley-Hyde, J; Maroulakou, I G; Hunziker, R; Schneck, J P; Green, J E

    1995-03-16

    Transgenic mice that carry the HTLV-I Tax gene develop an exocrinopathy with some similarities to Sjoegren's syndrome. Our experiments reveal that these mice have lymphadenopathy and splenomegaly composed primarily of B lymphocytes, as well as abnormal levels of secreted immunoglobulins. To gain insight into whether the lymphadenopathy manifested by these transgenic mice was the result of induction of cytokines by Tax, we utilized cell lines from these mice to study in vitro B-cell responses. Conditioned media (CM) derived from the cell lines caused B-cells to proliferate when a second signal, surface Ig cross-linking, was provided. The CM also caused a marked enhancement of IgM secretion by spleen cells or by purified B-cells treated with supplemental cytokines. The B-cell proliferative response and enhanced IgM secretion have not been attributed to a known cytokine. These results suggest that the CM from the cell lines contain a factor(s) involved in novel pathways of B-cell growth and differentiation that may participate in the pathologic development of autoimmune disease.

  14. Partial percutaneous epiphyseodesis in patients with congenital abnormalities of the growth plates.

    PubMed

    Waseem, Mohammad; Fischer, Jochen; Paton, Robin W

    2004-01-01

    We present a rare series of a small cohort of seven patients with 12 valgus knees. This is the largest series of children with underlying growth plate disorders published so far. Prediction of remaining growth in these children is difficult as most existing methods of growth prediction focus on normal patients. These methods of growth prediction in otherwise normal children are only 86-94% accurate at best. Hence we chose to use an educated guess based on the method by Menelaus to predict the right timing for surgery in our patients. Partial percutaneous epiphyseodesis has been shown to be an effective and minimally invasive method in the treatment of angular deformities of the knee. The successful partial ablation of the physes through a percutaneous approach was achieved in all of our patients. However, due to difficulties in the accurate assessment of remaining growth the results were not ideal. The mean preoperative deformity was 23 degrees of valgus and an average correction of 18 degress was achieved. Five patients with five knees (41.6%) had overcorrection or undercorrection of 10 degrees or more. Four of them required further surgical intervention. Difficulty arose mainly with the correct prediction of growth arrest in patients with abnormal physes. We review and discuss the current literature on partial epiphyseodesis and methods for the prediction of remaining growth.

  15. Intrauterine Growth Restriction Associated with Hematologic Abnormalities: Probable Manifestations of Placental Mesenchymal Dysplasia

    PubMed Central

    Martinez-Payo, Cristina; Bernabeu, Rocio Alvarez; Villar, Isabel Salas; Goy, Enrique Iglesias

    2015-01-01

    Introduction Placental mesenchymal dysplasia is a rare vascular disease associated with intrauterine growth restriction, fetal demise as well as Beckwith–Wiedemann syndrome. Some neonates present hematologic abnormalities possibly related to consumptive coagulopathy and hemolytic anemia in the placental circulation. Case report We present a case of placental mesenchymal dysplasia in a fetus with intrauterine growth restriction and cerebellar hemorrhagic injury diagnosed in the 20th week of pregnancy. During 26th week, our patient had an intrauterine fetal demise in the context of gestational hypertension. We have detailed the ultrasound findings that made us suspect the presence of hematologic disorders during 20th week. Discussion We believe that the cerebellar hematoma could be the consequence of thrombocytopenia accompanied by anemia. If hemorrhagic damage during fetal life is found, above all associates with an anomalous placental appearance and with intrauterine growth restriction, PMD should be suspected along other etiologies. PMID:26495159

  16. Small Size at Birth or Abnormal Intrauterine Growth Trajectory: Which Matters More for Child Growth?

    PubMed

    Hutcheon, Jennifer A; Jacobsen, Geir W; Kramer, Michael S; Martinussen, Marit; Platt, Robert W

    2016-06-15

    Small size at birth is linked with lifelong adverse health implications. However, small size is only a proxy for the pathological process of interest, intrauterine growth restriction. We examined the extent to which information on intrauterine growth patterns improved prediction of childhood anthropometry, above and beyond birth weight alone. We obtained fetal weights estimated via serial ultrasound for 478 children in the Scandinavian Successive Small-for-Gestational-Age Births Study (1986-1988). Size at birth was classified using birth weight-for-gestational-age z scores and conditional fetal growth z scores (reflecting growth between 25 weeks' gestation and birth) using internal references. Conditional z scores were also expressed as residuals of birth weight z scores. Growth measures were linked with age-5-years anthropometric characteristics using linear regression. In univariable analyses, conditional fetal growth z scores were positively associated with z scores for child height, body mass index, total skinfold thickness, and head circumference (β = 0.24 (95% confidence interval (CI): 0.18, 0.31), β = 0.16 (95% CI: 0.09, 0.23), β = 0.08 (95% CI: 0.01, 0.16), and β = 0.37 (95% CI: 0.22, 0.52), respectively). However, conditional z scores were highly correlated with birth weight z scores (r = 0.9), and residuals explained minimal additional variation in anthropometric factors (null coefficients; adjusted R(2) increases < 0.01). Information on the intrauterine trajectory through which birth weight was attained provided little additional insight into child growth beyond that obtained from absolute size at birth.

  17. 46,XY/45,X mosaicism in an amniotic fluid cell culture: suppression of abnormal cell line after subcultivation.

    PubMed Central

    Hasholt, L

    1979-01-01

    An abnormal cell population, 45,X, appeared in 3 of 4 cell lines established from an amniotic fluid specimen obtained from a normal mid-trimester pregnancy. Two of the cell lines were subjected to repeated chromosome analyses until VII passage. The abnormal cells were suppressed after repeated trypsinisations; simultaneously, fibroblast-like cells outgrew the cultures, which were previously predominated by epithelial-like cells. Polyploidy was found in 0 to 12% of the cells, the highest level existing in the early passages. The question of whether chromosomally abnormal cells present in primary cultures and the early subcultures reflect the karyotype of the fetus is discussed. PMID:573801

  18. Mechanism of abnormally slow crystal growth of CuZr alloy

    SciTech Connect

    Yan, X. Q.; Lü, Y. J.

    2015-10-28

    Crystal growth of the glass-forming CuZr alloy is shown to be abnormally slow, which suggests a new method to identify the good glass-forming alloys. The crystal growth of elemental Cu, Pd and binary NiAl, CuZr alloys is systematically studied with the aid of molecular dynamics simulations. The temperature dependence of the growth velocity indicates the different growth mechanisms between the elemental and the alloy systems. The high-speed growth featuring the elemental metals is dominated by the non-activated collision between liquid-like atoms and interface, and the low-speed growth for NiAl and CuZr is determined by the diffusion across the interface. We find that, in contrast to Cu, Pd, and NiAl, a strong stress layering arisen from the density and the local order layering forms in front of the liquid-crystal interface of CuZr alloy, which causes a slow diffusion zone. The formation of the slow diffusion zone suppresses the interface moving, resulting in much small growth velocity of CuZr alloy. We provide a direct evidence of this explanation by applying the compressive stress normal to the interface. The compression is shown to boost the stress layering in CuZr significantly, correspondingly enhancing the slow diffusion zone, and eventually slowing down the crystal growth of CuZr alloy immediately. In contrast, the growth of Cu, Pd, and NiAl is increased by the compression because the low diffusion zones in them are never well developed.

  19. Effects of abnormal cell-to-cell interference on p-type floating gate and control gate NAND flash memory

    NASA Astrophysics Data System (ADS)

    Kim, Yong Jun; Kang, Jun Geun; Lee, Byungin; Cho, Gyu-Seog; Park, Sung-Kye; Choi, Woo Young

    2014-01-01

    Abnormal cell-to-cell interference occurring in NAND flash memory has been investigated. In the case of extremely downscaled NAND flash memory, cell-to-cell interference increases abnormally. The abnormal cell-to-cell interference has been observed in a p-type floating gate (FG)/control gate (CG) cells for the first time. It has been found that the depletion region variation leads to the abnormal cell-to-cell interference. The depletion region variation of FG and CG is determined by state of neighbor cells. The depletion region variation affects CG-to-FG coupling capacitance and threshold voltage variation (ΔVT). Finally, it is observed that there is a symmetrical relationship between n- and p-type FG/CG NAND flash memory in terms of cell-to-cell interference.

  20. Growth of plasmodium falciparum in human erythrocytes containing abnormal membrane proteins

    SciTech Connect

    Schulman, S. City Univ. of New York, NY ); Roth, E.F. Jr.; Cheng, B.; Rybicki, A.C.; Sussman, I.I.; Wong, M.; Nagel, R.L.; Schwartz, R.S. ); Wang, W. ); Ranney, H.M. )

    1990-09-01

    To evaluate the role of erythrocyte (RBC) membrane proteins in the invasion and maturation of Plasmodium falciparum, the authors have studied, in culture, abnormal RBCs containing quantitative or qualitative membrane protein defects. These defects included hereditary spherocytosis (HS) due to decreases in the content of spectrin (HS(Sp{sup +})), hereditary elliptocytosis (HE) due to protein 4.1 deficiency (HE(4.1{sup 0})), HE due to a spectrin {alpha}I domain structural variant that results in increased content of spectrin dimers (HE(Sp{alpha}{sup I/65})), and band 3 structural variants. Parasite invasion, measured by the initial uptake of ({sup 3}H)hypoxanthine 18 hr after inoculation with merozoites, was normal in all of the pathologic RBCs. In contrast, RBCs from six HS(Sp{sup +}) subjects showed marked growth inhibition that became apparent after the first or second growth cycle. The extent of decreased parasite growth in HS(Sp{sup +}) RBCs closely correlated with the extent of RBC spectrin deficiency. Homogeneous subpopulations of dense HS RBCs exhibited decreased parasite growth to the same extent as did HS whole blood. RBCs from four HE subjects showed marked parasite growth and development.

  1. Functional Changes after Recombinant Human Growth Hormone Replacement in Patients with Chronic Traumatic Brain Injury and Abnormal Growth Hormone Secretion.

    PubMed

    Mossberg, Kurt A; Durham, William J; Zgaljardic, Dennis J; Gilkison, Charles R; Danesi, Christopher P; Sheffield-Moore, Melinda; Masel, Brent E; Urban, Randall J

    2017-02-15

    We explored the effects of recombinant human growth hormone (rhGH) replacement on physical and cognitive functioning in subjects with a moderate-to-severe traumatic brain injury (TBI) with abnormal growth hormone (GH) secretion. Fifteen individuals who sustained a TBI at least 12 months prior to study enrollment were identified as having abnormal GH secretion by glucagon stimulation testing (maximum GH response less than 8 ng/mL). Peak cardiorespiratory capacity, body composition, and muscle force testing were assessed at baseline and one year after rhGH replacement. Additionally, standardized neuropsychological tests that assess memory, processing speed, and cognitive flexibility, as well as self-report inventories related to depression and fatigue, were administered at baseline and 1 year after rhGH replacement. Comparison tests were performed with proper post hoc analyses. All analyses were carried out at α < 0.05. Peak O2 consumption, peak oxygen pulse (estimate of cardiac stroke volume), and peak ventilation all significantly increased (p < 0.05). Maximal isometric and isokinetic force production were not altered. Skeletal muscle fatigue did not change but the perceptual rating of fatigue was reduced by ∼25% (p = 0.06). Cognitive performance did not change significantly over time, whereas self-reported symptoms related to depression and fatigue significantly improved. The observed changes suggest that rhGH replacement has a positive impact on cardiorespiratory fitness and a positive impact on perceptual fatigue in survivors of TBI with altered GH secretion.

  2. Cerebral blood flow abnormalities in children with sickle cell disease: a systematic review.

    PubMed

    Behpour, Amir M; Shah, Prakesh S; Mikulis, David J; Kassner, Andrea

    2013-03-01

    A systematic review was performed to assess whether cerebral blood flow with different imaging modalities could identify brain abnormalities in children with sickle cell disease where structural magnetic resonance imaging and transcranial Doppler velocity appeared normal. A total of 11 studies were identified which reported cerebral blood flow abnormalities alongside structural magnetic resonance imaging or transcranial Doppler velocity abnormalities in patients with sickle cell disease. Potential for bias was assessed with the quality assessment of diagnostic accuracy studies scale in addition to treatment bias. Subjects of each study were categorized into patients with and without stroke. The prevalence of abnormalities for each modality was then separately calculated in each group. The included studies had mostly moderate degrees of bias. The prevalence of blood flow abnormalities compared with structural magnetic resonance imaging abnormalities was equal to or lower in patients with stroke and equal to or greater in patients without stroke. Blood flow abnormalities were more prevalent than transcranial Doppler abnormalities in four studies of patients without stroke and in one study of patients with stroke. The studies suggest that the assessment of cerebral blood flow in sickle cell disease can be of potential value in addressing brain abnormalities at the tissue level; however, further studies are warranted.

  3. Monocarboxylate transporter 8 in neuronal cell growth.

    PubMed

    James, S R; Franklyn, J A; Reaves, B J; Smith, V E; Chan, S Y; Barrett, T G; Kilby, M D; McCabe, C J

    2009-04-01

    Thyroid hormones are essential for the normal growth and development of the fetus, and even small alterations in maternal thyroid hormone status during early pregnancy may be associated with neurodevelopmental abnormalities in childhood. Mutations in the novel and specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) have been associated with severe neurodevelopmental impairment. However, the mechanism by which MCT8 influences neural development remains poorly defined. We have therefore investigated the effect of wild-type (WT) MCT8, and the previously reported L471P mutant, on the growth and function of human neuronal precursor NT2 cells as well as MCT8-null JEG-3 cells. HA-tagged WT MCT8 correctly localized to the plasma membrane in NT2 cells and increased T(3) uptake in both cell types. In contrast, L471P MCT8 was largely retained in the endoplasmic reticulum and displayed no T(3) transport activity. Transient overexpression of WT and mutant MCT8 proteins failed to induce endoplasmic reticular stress or apoptosis. However, MCT8 overexpression significantly repressed cell proliferation in each cell type in both the presence and absence of the active thyroid hormone T(3) and in a dose-dependent manner. In contrast, L471P MCT8 showed no such influence. Finally, small interfering RNA depletion of endogenous MCT8 resulted in increased cell survival and decreased T(3) uptake. Given that T(3) stimulated proliferation in embryonic neuronal NT2 cells, whereas MCT8 repressed cell growth, these data suggest an entirely novel role for MCT8 in addition to T(3) transport, mediated through the modulation of cell proliferation in the developing brain.

  4. Zika virus infection induces mitosis abnormalities and apoptotic cell death of human neural progenitor cells

    PubMed Central

    Souza, Bruno S. F.; Sampaio, Gabriela L. A.; Pereira, Ciro S.; Campos, Gubio S.; Sardi, Silvia I.; Freitas, Luiz A. R.; Figueira, Claudio P.; Paredes, Bruno D.; Nonaka, Carolina K. V.; Azevedo, Carine M.; Rocha, Vinicius P. C.; Bandeira, Antonio C.; Mendez-Otero, Rosalia; dos Santos, Ricardo Ribeiro; Soares, Milena B. P.

    2016-01-01

    Zika virus (ZIKV) infection has been associated with severe complications both in the developing and adult nervous system. To investigate the deleterious effects of ZIKV infection, we used human neural progenitor cells (NPC), derived from induced pluripotent stem cells (iPSC). We found that NPC are highly susceptible to ZIKV and the infection results in cell death. ZIKV infection led to a marked reduction in cell proliferation, ultrastructural alterations and induction of autophagy. Induction of apoptosis of Sox2+ cells was demonstrated by activation of caspases 3/7, 8 and 9, and by ultrastructural and flow cytometry analyses. ZIKV-induced death of Sox2+ cells was prevented by incubation with the pan-caspase inhibitor, Z-VAD-FMK. By confocal microscopy analysis we found an increased number of cells with supernumerary centrosomes. Live imaging showed a significant increase in mitosis abnormalities, including multipolar spindle, chromosome laggards, micronuclei and death of progeny after cell division. FISH analysis for chromosomes 12 and 17 showed increased frequency of aneuploidy, such as monosomy, trisomy and polyploidy. Our study reinforces the link between ZIKV and abnormalities in the developing human brain, including microcephaly. PMID:28008958

  5. The grain size distribution and the detection of abnormal grain growth of austenite in an eutectoid steel containing niobium

    SciTech Connect

    Bruno, J.C. . Dept. de Engenharia Mecanica e de Materiais); Rios, P.R. . Dept. de Ciencia dos Materiais e Metalurgia)

    1995-02-15

    The abnormal grain growth of austenite was studied in a commercial steel of composition (wt%): 0.70 C, 1.36 Mn, 0.72 Si, 0.015 P, 0.027 S and 0.03 Nb. Specimens were thermocycled at various conditions and then grain size distribution determined. The grain size distribution shape did not change during normal grain growth but this distribution widened and flattened during the abnormal grain growth. The initial smaller mean size of carbonitrides and/or the highest homogeneity of niobium carbonitride size distribution of the samples submitted to thermal cycles, in comparison with the normalized samples, increased the abnormal grain growth temperature from 1,373 K to 1,473 K.

  6. Epigenetic Silencing of the Key Antioxidant Enzyme Catalase in Karyotypically Abnormal Human Pluripotent Stem Cells

    PubMed Central

    Konki, Mikko; Pasumarthy, Kalyan; Malonzo, Maia; Sainio, Annele; Valensisi, Cristina; Söderström, Mirva; Emani, Maheswara Reddy; Stubb, Aki; Närvä, Elisa; Ghimire, Bishwa; Laiho, Asta; Järveläinen, Hannu; Lahesmaa, Riitta; Lähdesmäki, Harri; Hawkins, R. David; Lund, Riikka J.

    2016-01-01

    Epigenomic regulation is likely to be important in the maintenance of genomic integrity of human pluripotent stem cells, however, the mechanisms are unknown. We explored the epigenomes and transcriptomes of human pluripotent stem cells before and after spontaneous transformation to abnormal karyotypes and in correlation to cancer cells. Our results reveal epigenetic silencing of Catalase, a key regulator of oxidative stress and DNA damage control in abnormal cells. Our findings provide novel insight into the mechanisms associated with spontaneous transformation of human pluripotent stem cells towards malignant fate. The same mechanisms may control the genomic stability of cells in somatic tissues. PMID:26911679

  7. Cell phone radiation effects on cytogenetic abnormalities of oral mucosal cells.

    PubMed

    Daroit, Natália Batista; Visioli, Fernanda; Magnusson, Alessandra Selinger; Vieira, Geila Radunz; Rados, Pantelis Varvaki

    2015-01-01

    The aim of this study was to evaluate the effects of exposure to cell phone electromagnetic radiation on the frequency of micronuclei, broken eggs cells, binucleated cells, and karyorrhexis in epithelial cells of the oral mucosa. The sample was composed of 60 cell phone users, who were non-smokers and non-drinkers, and had no clinically visible oral lesions. Cells were obtained from anatomical sites with the highest incidence of oral cancer: lower lip, border of the tongue, and floor of the mouth. The Feulgen reaction was used for quantification of nuclear anomalies in 1,000 cells/slide. A slightly increase in the number of micronucleated cells in the lower lip and in binucleated cells on the floor of the mouth was observed in individuals who used their phones > 60 minutes/week. The analysis also revealed an increased number of broken eggs in the tongue of individuals owning a cell phone for over eight years. Results suggest that exposure to electromagnetic waves emitted by cell phones can increase nuclear abnormalities in individuals who use a cell phone for more than 60 minutes per week and for over eight years. Based on the present findings, we suggest that exposure to electromagnetic radiation emitted by cell phones may interfere with the development of metanuclear anomalies. Therefore, it is demonstrated that, despite a significant increase in these anomalies, the radiation emitted by cell phones among frequent users is within acceptable physiological limits.

  8. An examination of abnormal grain growth in low strain nickel-200

    SciTech Connect

    Underwood, O.; Madison, J.; Martens, R. M.; Thompson, G. B.; Welsh, S.; Evans, J.

    2016-06-21

    Here, this study offers experimental observation of the effect of low strain conditions (ε < 10%) on abnormal grain growth (AGG) in Nickel-200. At such conditions, stored mechanical energy is low within the microstructure enabling one to observe the impact of increasing mechanical deformation on the early onset of AGG compared to a control, or nondeformed, equivalent sample. The onset of AGG was observed to occur at specific pairings of compressive strain and annealing temperature and an empirical relation describing the influence of thermal exposure and strain content was developed. The evolution of low-Σ coincident site lattice (CSL) boundaries and overall grain size distributions are quantified using electron backscatter diffraction preceding, at onset and during ensuing AGG, whereby possible mechanisms for AGG in the low strain regime are offered and discussed.

  9. An examination of abnormal grain growth in low strain nickel-200

    DOE PAGES

    Underwood, O.; Madison, J.; Martens, R. M.; ...

    2016-06-21

    Here, this study offers experimental observation of the effect of low strain conditions (ε < 10%) on abnormal grain growth (AGG) in Nickel-200. At such conditions, stored mechanical energy is low within the microstructure enabling one to observe the impact of increasing mechanical deformation on the early onset of AGG compared to a control, or nondeformed, equivalent sample. The onset of AGG was observed to occur at specific pairings of compressive strain and annealing temperature and an empirical relation describing the influence of thermal exposure and strain content was developed. The evolution of low-Σ coincident site lattice (CSL) boundaries andmore » overall grain size distributions are quantified using electron backscatter diffraction preceding, at onset and during ensuing AGG, whereby possible mechanisms for AGG in the low strain regime are offered and discussed.« less

  10. Microtubule Abnormalities Underlying Gulf War Illness in Neurons from Human-Induced Pluripotent Cells

    DTIC Science & Technology

    2016-09-01

    disease. These new human cell lines will provide a major resource for GWI researchers. What was the impact on other disciplines? ▪ Nothing to...AWARD NUMBER: W81XWH-15-1-0433 TITLE: Microtubule Abnormalities Underlying Gulf War Illness in Neurons from Human -Induced Pluripotent Cells...2015 - 31 Aug 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Microtubule Abnormalities Underlying Gulf War Illness in Neurons from Human -Induced

  11. Abnormalities in centrosome number in human embryos and embryonic stem cells.

    PubMed

    Gu, Yi-Fan; OuYang, Qi; Dai, Can; Lu, Chang-Fu; Lin, Ge; Gong, Fei; Lu, Guang-Xiu

    2016-05-01

    Chromosomal abnormalities are common in human embryos. Previous studies have suggested links between centrosome number and chromosome abnormalities, but information regarding abnormalities in centrosome number in human embryos is limited. We analyzed abnormalities in centrosome number in human embryos and embryonic stem cells (hESCs). Following normal fertilization, supernumerary centrosomes were present at rates of 7.3% in two-pronucleus (2PN)-stage zygotes and 6.5% in first-cleavage zygotes. Supernumerary centrosomes were also detected in 24.4% of blastomeres from 60% of embryos derived from 2PN zygotes. Conversely, in mono- (1PN) and tri-pronucleus (3PN) zygotes, the frequency of abnormal centrosome number increased substantially at first cleavage. Rates in blastomeres of Day-3 embryos, however, were about the same between embryos derived from 1PN and 2PN zygotes, whereas abnormalities in centrosome number were higher in those from 3PN zygotes. By comparison, the rate of abnormal centrosome numbers in hESCs was 1.5-11.2%. Thus, abnormalities in centrosome number existed in human zygotes and cleaved embryos-especially those resulting from aberrant fertilization-but the frequency of such abnormalities was lower in hESCs derived from these embryos. These findings identify a source of the chromosomal instability in human embryos and hESCs, and highlight new safety issues for human assisted reproductive technology. Mol. Reprod. Dev. 83: 392-404, 2016. © 2016 Wiley Periodicals, Inc.

  12. Abnormal mitosis triggers p53-dependent cell cycle arrest in human tetraploid cells.

    PubMed

    Kuffer, Christian; Kuznetsova, Anastasia Yurievna; Storchová, Zuzana

    2013-08-01

    Erroneously arising tetraploid mammalian cells are chromosomally instable and may facilitate cell transformation. An increasing body of evidence shows that the propagation of mammalian tetraploid cells is limited by a p53-dependent arrest. The trigger of this arrest has not been identified so far. Here we show by live cell imaging of tetraploid cells generated by an induced cytokinesis failure that most tetraploids arrest and die in a p53-dependent manner after the first tetraploid mitosis. Furthermore, we found that the main trigger is a mitotic defect, in particular, chromosome missegregation during bipolar mitosis or spindle multipolarity. Both a transient multipolar spindle followed by efficient clustering in anaphase as well as a multipolar spindle followed by multipolar mitosis inhibited subsequent proliferation to a similar degree. We found that the tetraploid cells did not accumulate double-strand breaks that could cause the cell cycle arrest after tetraploid mitosis. In contrast, tetraploid cells showed increased levels of oxidative DNA damage coinciding with the p53 activation. To further elucidate the pathways involved in the proliferation control of tetraploid cells, we knocked down specific kinases that had been previously linked to the cell cycle arrest and p53 phosphorylation. Our results suggest that the checkpoint kinase ATM phosphorylates p53 in tetraploid cells after abnormal mitosis and thus contributes to proliferation control of human aberrantly arising tetraploids.

  13. Mediators in cell growth and differentiation

    SciTech Connect

    Ford, R.J.; Maizel, A.L.

    1985-01-01

    This book contains papers divided among seven sections. The section headings are: Cell Cycle and Control of Cell Growth, Growth Factors for Nonlymphoid Cells, Colony-Stimulating Factors, Stem Cells and Hematopoiesis, Lymphoid Growth Factors, Growth Factors in Neoplasia, Interferon, and Differentiation in Normal and Neoplastic Cells.

  14. Monte Carlo study on abnormal growth of Goss grains in Fe-3%Si steel induced by second-phase particles

    NASA Astrophysics Data System (ADS)

    Xin, Dong-qun; He, Cheng-xu; Gong, Xue-hai; Wang, Hao; Meng, Li; Ma, Guang; Hou, Peng-fei; Zhang, Wen-kang

    2016-12-01

    The selective abnormal growth of Goss grains in magnetic sheets of Fe-3%Si (grade Hi-B) induced by second-phase particles (AlN and MnS) was studied using a modified Monte Carlo Potts model. The starting microstructures for the simulations were generated from electron backscatter diffraction (EBSD) orientation imaging maps of recrystallized samples. In the simulation, second-phase particles were assumed to be randomly distributed in the initial microstructures and the Zener drag effect of particles on Goss grain boundaries was assumed to be selectively invalid because of the unique properties of Goss grain boundaries. The simulation results suggest that normal growth of the matrix grains stagnates because of the pinning effect of particles on their boundaries. During the onset of abnormal grain growth, some Goss grains with concave boundaries in the initial microstructure grow fast abnormally and other Goss grains with convex boundaries shrink and eventually disappear.

  15. Mitigating Abnormal Grain Growth for Friction Stir Welded Al-Li 2195 Spun Formed Domes

    NASA Technical Reports Server (NTRS)

    Chen, Po-Shou; Russell, Carolyn

    2012-01-01

    Formability and abnormal grain growth (AGG) are the two major issues that have been encountered for Al alloy spun formed dome development using friction stir welded blanks. Material properties that have significant influence on the formability include forming range and strain hardening exponent. In this study, tensile tests were performed for two 2195 friction stir weld parameter sets at 400 F to study the effects of post weld anneal on the forming range and strain hardening exponent. It was found that the formability can be enhanced by applying a newly developed post weld anneal to heat treat the friction stir welded panels. This new post weld anneal leads to a higher forming range and much improved strain hardening exponent. AGG in the weld nugget is known to cause a significant reduction of ductility and fracture toughness. This study also investigated how AGG may be influenced by the heating rate to the solution heat treatment temperature. After post-weld annealing, friction stir welds were strained to 15% and 39% by compression at 400 F before they were subjected to SHT at 950 F for 1 hour. Salt bath SHT is very effective in reducing the grain size as it helps arrest the onset of AGG and promote normal recrystallization and grain growth. However, heat treating a 18 ft dome using a salt bath is not practical. Efforts are continuing at Marshall Space Flight Center to identify the welding parameters and heat treating parameters that can help mitigate the AGG in the friction stir welds.

  16. Ethanol alters proliferation and differentiation of normal and chromosomally abnormal human embryonic stem cell-derived neurospheres.

    PubMed

    Krishnamoorthy, Malini; Gerwe, Brian A; Scharer, Christopher D; Sahasranaman, Vanita; Eilertson, Carmen D; Nash, Rachel J; Usta, Sümeyra Naz; Kelly, Shasmine; Rose, Matthew; Peraza, Rene; Arumugham, Jagan; Stewart, Bethany; Stice, Steven L; Nash, Rodney J

    2013-06-01

    Ethanol is a powerful substance and, when consumed during pregnancy, has significant psychoactive and developmental effects on the developing fetus. These abnormalities include growth retardation, neurological deficits, and behavioral and cognitive deficiencies, commonly referred to as fetal alcohol spectrum disorder. The effect of ethanol has been reported to affect cellular development on the embryonic level, however, not much is known about mutations contributing to the influence of ethanol. The purpose of our study was to determine if mutation contribute to changes in differentiation patterning, cell-cycle regulatory gene expression, and DNA methylation in human embryonic stem cells after ethanol exposure. We exposed human embryonic stem cells (with and without know DNA mutations) to a low concentration (20 mM) of ethanol and measured neurosphere proliferation and differentiation, glial protein levels, expression of various cell-cycle genes, and DNA methylation. Ethanol altered cell-cycle gene expression between the two cell lines; however, gene methylation was not affected in ether lines.

  17. Salt-induced abnormalities on root tip mitotic cells of Allium cepa: prevention by inositol pretreatment.

    PubMed

    Chatterjee, Jolly; Majumder, Arun Lahiri

    2010-09-01

    Salt-induced growth reduction of plants is a well-known phenomenon which poses major problem in crop productivity in places where vast majority of land plants are affected by salt. In this report, studies were carried out to reveal the effect of salt injury on the cell division pattern in roots and the role of myo-inositol in preventing the salt-induced ion disequilibrium on the chromosome and DNA degradation in roots. Present study revealed induction of various chromosomal abnormalities on the root tip mitotic cells of Allium cepa by treatment with different concentrations of NaCl (0-500 mM) for 24 h as also the amelioration of such effect by prior treatment of the roots with different concentration of myo-inositol (0-300 mM). Results showed that a narrow albeit definite range of extracellular myo-inositol (100-150 mM) is effective in preventing internucleosomal fragmentation which is the early response in roots under salt stress. Transgenic tobacco plants overexpressing Oryza (OsINO1) as well as Porteresia (PcINO1) cytosolic L: -myo-inositol-1-phosphate synthase coding genes can withstand and retain their chromosomal and DNA integrity in 100 mM NaCl solution and can subsequently prevent DNA fragmentation, caused by intracellular endonuclease activity at this salt concentration.

  18. Abnormal erythroid cell proliferation and myelofibrosis in a cat.

    PubMed

    Iwanaga, Tomoko; Miura, Naoki; Miyoshi, Noriaki; Endo, Yasuyuki; Momoi, Yasuyuki

    2012-07-01

    A cat was presented with severe progressive anemia despite marked erythroblastosis. The cat was negative for feline leukemia virus antigen and feline immunodeficiency virus antibody. Bone marrow cytology revealed an excess of erythroid cells with a predominance of prorubricytes and basophilic rubricytes. No response to immunosuppressive therapy was obtained, and a tentative diagnosis of myelodysplastic syndrome was made. The cat showed a partial response to low-dose cytarabine (20 mg/m(2) subcutaneously q24) but died 51 days after the 1st admission. Histopathological examination revealed fibrosis in the bone marrow and marked infiltration of erythroid cells into other organs.

  19. Focal adhesion protein abnormalities in myelodysplastic mesenchymal stromal cells

    SciTech Connect

    Aanei, Carmen Mariana; Eloae, Florin Zugun; Flandrin-Gresta, Pascale; Tavernier, Emmanuelle; Carasevici, Eugen; Guyotat, Denis; Campos, Lydia

    2011-11-01

    Direct cell-cell contact between haematopoietic progenitor cells (HPCs) and their cellular microenvironment is essential to maintain 'stemness'. In cancer biology, focal adhesion (FA) proteins are involved in survival signal transduction in a wide variety of human tumours. To define the role of FA proteins in the haematopoietic microenvironment of myelodysplastic syndromes (MDS), CD73-positive mesenchymal stromal cells (MSCs) were immunostained for paxillin, pFAK [Y{sup 397}], and HSP90{alpha}/{beta} and p130CAS, and analysed for reactivity, intensity and cellular localisation. Immunofluorescence microscopy allowed us to identify qualitative and quantitative differences, and subcellular localisation analysis revealed that in pathological MSCs, paxillin, pFAK [Y{sup 397}], and HSP90{alpha}/{beta} formed nuclear molecular complexes. Increased expression of paxillin, pFAK [Y{sup 397}], and HSP90{alpha}/{beta} and enhanced nuclear co-localisation of these proteins correlated with a consistent proliferative advantage in MSCs from patients with refractory anaemia with excess blasts (RAEB) and negatively impacted clonogenicity of HPCs. These results suggest that signalling via FA proteins could be implicated in HPC-MSC interactions. Further, because FAK is an HSP90{alpha}/{beta} client protein, these results suggest the utility of HSP90{alpha}/{beta} inhibition as a target for adjuvant therapy for myelodysplasia.

  20. Leptin Enhances Cholangiocarcinoma Cell Growth

    PubMed Central

    Fava, Giammarco; Alpini, Gianfranco; Rychlicki, Chiara; Saccomanno, Stefania; DeMorrow, Sharon; Trozzi, Luciano; Candelaresi, Cinzia; Venter, Julie; Di Sario, Antonio; Marzioni, Marco; Bearzi, Italo; Glaser, Shannon; Alvaro, Domenico; Marucci, Luca; Francis, Heather; Svegliati-Baroni, Gianluca; Benedetti, Antonio

    2008-01-01

    Cholangiocarcinoma is a strongly aggressive malignancy with a very poor prognosis. Effective therapeutic strategies are lacking because molecular mechanisms regulating cholangiocarcinoma cell growth are unknown. Furthermore, experimental in vivo animal models useful to study the pathophysiologic mechanisms of malignant cholangiocytes are lacking. Leptin, the hormone regulating caloric homeostasis, which is increased in obese patients, stimulates the growth of several cancers, such as hepatocellular carcinoma. The aim of this study was to define if leptin stimulates cholangiocarcinoma growth. We determined the expression of leptin receptors in normal and malignant human cholangiocytes. Effects on intrahepatic cholangiocarcinoma (HuH-28) cell proliferation, migration, and apoptosis of the in vitro exposure to leptin, together with the intracellular pathways, were then studied. Moreover, cholangiocarcinoma was experimentally induced in obese fa/fa Zucker rats, a genetically established animal species with faulty leptin receptors, and in their littermates by chronic feeding with thioacetamide, a potent carcinogen. After 24 weeks, the effect of leptin on cholangiocarcinoma development and growth was assessed. Normal and malignant human cholangiocytes express leptin receptors. Leptin increased the proliferation and the metastatic potential of cholangiocarcinoma cells in vitro through a signal transducers and activators of transcription 3–dependent activation of extracellular signal-regulated kinase 1/2. Leptin increased the growth and migration, and was antiapoptotic for cholangiocarcinoma cells. Moreover, the loss of leptin function reduced the development and the growth of cholangiocarcinoma. The experimental carcinogenesis model induced by thioacetamide administration is a valid and reproducible method to study cholangiocarcinoma pathobiology. Modulation of the leptin-mediated signal could be considered a valid tool for the prevention and treatment of

  1. Human mesenchymal stem cells are sensitive to abnormal gravity and exhibit classic apoptotic features.

    PubMed

    Meng, Rui; Xu, Hui-yun; Di, Sheng-meng; Shi, Dong-yan; Qian, Ai-rong; Wang, Jin-fu; Shang, Peng

    2011-02-01

    The aim of the present study was to investigate the effects of abnormal gravity on human mesenchymal stem cells (hMSCs). Strong magnetic field and magnetic field gradient generate a magnetic force that can add to or subtract from the gravitational force. In this study, this is defined as a high-magneto-gravitational environment (HMGE). The HMGE provides three apparent gravity levels, i.e. hypogravity (μg), hypergravity (2g) and normal gravity with strong magnetic field (1g) conditions. After hMSCs were subject to HMGE for 12 h, the proliferation, morphology, structure and apoptosis were investigated. Results showed that the proliferation of hMSCs was inhibited under μg condition. The abnormal gravity induced morphologic characteristics of apoptosis cells, such as cell shrinkage, membrane blebbing, nuclear chromatin condensation and margination, decreased cell viability, and increased caspase-3/7 activity. The rate of apoptosis under μg condition is up to 56.95%. The F-actin stress fibers and microtubules were disrupted under abnormal gravity condition. Under μg-condition, the expression of p53 at mRNA and protein levels was up-regulated more than 9- and 6 folds, respectively. The Pifithrin-α, an specific inhibitor of p53, inhibited the apoptosis and prevented the disruption of cytoskeleton induced by abnormal gravity. These results implied that hMSCs were sensitive to abnormal gravity and exhibited classic apoptotic features, which might be associated with p53 signaling.

  2. [Alpha-lipoic acid triggers elimination of cells with abnormal nuclei in human carcinoma epidermoid cell line].

    PubMed

    Kisurina-Evgen'eva, O P; Onishchenko, G E

    2010-01-01

    The skin is usually exposed to adverse environmental conditions that may cause pathological cell proliferation and cellular transformations leading to the formation of malignant cells. Antioxidants may affect these processes and induce the elimination of transformed cell. The purpose of this work was to investigate the effect of alfa-lipoic acid on human carcinoma epidermoid cell line A431. Our results showed that alfa-lipoic acid induced inhibition of cell proliferation or stimulated apoptotic cell death. Cells with abnormal nuclei were eliminated by apoptosis. Electron microscopy showed that survived cells had typical for control cells shape and organization of the nuclei, organization of the cytoplasm and organelles. Thus, alfa-lipoic acid not only triggered apoptosis of carcinoma cells, but it may also activate the mechanism of elimination of cells with abnormal chromosome number.

  3. T cell abnormalities in systemic sclerosis with a focus on Th17 cells.

    PubMed

    Brembilla, Nicolò Costantino; Chizzolini, Carlo

    2012-01-01

    Systemic sclerosis (SSc) is a connective tissue disorder characterized by vascular alterations and deregulated fibroblast activation leading to fibrosis of the skin and internal organs. SSc is thought to be an autoimmune disease, owning the presence of auto-antibodies. Genetic studies lend support to the critical role exerted by the immune response in the physiopathology of the disease, since several of the SSc-associated polymorphisms have been found in genes involved in the immune response. Oligoclonal T cells, preferentially producing type 2 cytokines, are present in affected tissues and peripheral blood early in the disease course, and their soluble mediators favor the production of pro-fibrotic and pro-angiogenic factors by fibroblasts, most likely participating in the establishment of fibrosis. More recently, we and others have reported an increased expression of additional T cell subsets, including Th17 cells, and their hallmark cytokines in the peripheral blood, serum and skin of SSc individuals. Here, we will review recent data on the presence of various T helper cells in SSc, and discuss the potential role of Th17 cells in promoting inflammatory responses while keeping fibrosis in check. An understanding of the immune abnormalities characteristic of SSc and their significance, represents a critical step towards the identification of novel therapies that could modify the course of the disease.

  4. Developmental origin of abnormal dendritic growth in the mouse brain induced by in utero disruption of aryl hydrocarbon receptor signaling.

    PubMed

    Kimura, Eiki; Kubo, Ken-Ichiro; Matsuyoshi, Chieri; Benner, Seico; Hosokawa, Mayuko; Endo, Toshihiro; Ling, Wenting; Kohda, Masanobu; Yokoyama, Kazuhito; Nakajima, Kazunori; Kakeyama, Masaki; Tohyama, Chiharu

    2015-01-01

    Increased prevalence of mental disorders cannot be solely attributed to genetic factors and is considered at least partly attributable to chemical exposure. Among various environmental chemicals, in utero and lactational dioxin exposure has been extensively studied and is known to induce higher brain function abnormalities in both humans and laboratory animals. However, how the perinatal dioxin exposure affects neuromorphological alterations has remained largely unknown. Therefore, in this study, we initially studied whether and how the over-expression of aryl hydrocarbon receptor (AhR), a dioxin receptor, would affect the dendritic growth in the hippocampus of the developing brain. Transfecting a constitutively active AhR plasmid into the hippocampus via in utero electroporation on gestational day (GD) 14 induced abnormal dendritic branch growth. Further, we observed that 14-day-old mice born to dams administered with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dose: 0, 0.6, or 3.0 μg/kg) on GD 12.5 exhibited disrupted dendritic branch growth in both the hippocampus and amygdala. Finally, we observed that 16-month-old mice born to dams exposed to perinatal TCDD as described above exhibited significantly reduced spine densities. These results indicated that abnormal micromorphology observed in the developing brain may persist until adulthood and may induce abnormal higher brain function later in life.

  5. The significance of abnormal circulating cells in patients with Hodgkin's disease.

    PubMed

    Schiffer, C A; Levi, J A; Wiernik, P H

    1975-10-01

    Buffy coat preparations of peripheral blood from two patients with Stage IVB Hodgkin's disease, 33 patients with Hodgkin's disease undergoing complete staging including laparotomy, 12 normal controls and eight patients with viral upper respiratory infections were examined for the presence of abnormal cells. Primitive histiocytic cells were seen in the two patients with IVB disease and in two patients with IIIB disease all of whom proved to be refractory to chemotherapy. Reed-Sternberg cells were seen in one IVB patient. Large cells with basophilic, agranular cytoplasm and moderately convoluted nuclei often with a perinuclear halo and nucleoli were detected in 30 of 35 patients with Hodgkin's disease, five of eight patients with viral infections but in none of 12 normal controls. Other abnormal large cells with round nuclei, occasional prominent nucleoli, grey to lightly eosinophilic cytoplasm and diffuse granulation were seen almost exclusively in Hodgkin's disease. There was no correlation between histology, stage, splenic involvement, skin test positivity and response to therapy with the presence or frequency of either of these cell types. This observation suggests that these cells are more likely to be 'reactive' rather than malignant. It is unusual for abnormal histiocytic cells to circulate in Hodgkin's disease and their presence may be a poor prognostic sign. The presence of other types of large atypical cells is not indicative of either haematogenous spread of Hodgkin's disease or of poor prognosis after treatment with radiotherapy alone.

  6. Platelet-derived growth factor over-expression in retinal progenitors results in abnormal retinal vessel formation.

    PubMed

    Edqvist, Per-Henrik D; Niklasson, Mia; Vidal-Sanz, Manuel; Hallböök, Finn; Forsberg-Nilsson, Karin

    2012-01-01

    Platelet-derived growth factor (PDGF) plays an important role in development of the central nervous system, including the retina. Excessive PDGF signaling is associated with proliferative retinal disorders. We reported previously that transgenic mice in which PDGF-B was over-expressed under control of the nestin enhancer, nes/tk-PdgfB-lacZ, exhibited enhanced apoptosis in the developing corpus striatum. These animals display enlarged lateral ventricles after birth as well as behavioral aberrations as adults. Here, we report that in contrast to the relatively mild central nervous system phenotype, development of the retina is severely disturbed in nes/tk-PdgfB-lacZ mice. In transgenic retinas all nuclear layers were disorganized and photoreceptor segments failed to develop properly. Since astrocyte precursor cells did not populate the retina, retinal vascular progenitors could not form a network of vessels. With time, randomly distributed vessels resembling capillaries formed, but there were no large trunk vessels and the intraocular pressure was reduced. In addition, we observed a delayed regression of the hyaloid vasculature. The prolonged presence of this structure may contribute to the other abnormalities observed in the retina, including the defective lamination.

  7. Glycosaminoglycan-Mediated Loss of Cathepsin K Collagenolytic Activity in MPS I Contributes to Osteoclast and Growth Plate Abnormalities

    PubMed Central

    Wilson, Susan; Hashamiyan, Saadat; Clarke, Lorne; Saftig, Paul; Mort, John; Dejica, Valeria M.; Brömme, Dieter

    2009-01-01

    Mucopolysaccharidoses are a group of lysosomal storage diseases characterized by the build-up of glycosaminoglycans (GAGs) and severe skeletal abnormalities. As GAGs can regulate the collagenolytic activity of the major osteoclastic protease cathepsin K, we investigated the presence and activity of cathepsin K and its co-localization with GAGs in mucopolysaccharidosis (MPS) type I bone. The most dramatic difference between MPS I and wild-type mice was an increase in the amount of cartilage in the growth plates in MPS I bones. Though the number of cathepsin K-expressing osteoclasts was increased in MPS I mice, these mice revealed a significant reduction in cathepsin K-mediated cartilage degradation. As excess heparan and dermatan sulfates inhibit type II collagen degradation by cathepsin K and the spatial overlap between cathepsin K and heparan sulfate strongly increased in MPS I mice, the build up of subepiphyseal cartilage is speculated to be a direct consequence of cathepsin K inhibition by MPS I-associated GAGs. Moreover, isolated MPS I and Ctsk−/− osteoclasts displayed fewer actin rings and formed fewer resorption pits on dentine disks, as compared with wild-type cells. These results suggest that the accumulation of GAGs in murine MPS I bone has an inhibitory effect on cathepsin K activity, resulting in impaired osteoclast activity and decreased cartilage resorption, which may contribute to the bone pathology seen in MPS diseases. PMID:19834056

  8. [Research Progress on Gene Expression Abnormality of Hematopoietic Stem/Progenitor Cells in Myelodysplastic Syndromes].

    PubMed

    Zhang, Jing; Ma, Yan; Xu, Xiao-Ping

    2015-10-01

    Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal disease involving one or more series of hematopoietic cells. Its pathogenesis is still unclear. No effective targeted drug is available to prevent this disease progression. MDS originates in hematopoietic stem cells. Recent researches found that the complex abnormal gene expression occurred in bone marrow CD34⁺ cells plays a key role in development of MDS. Some of these genes are closely related with the patient's prognosis and survival, such as DLK1, ribosomal transcripts gene, Toll-like receptors gene, EPA-1 and interferon-stimulated genes. Due to heterogeneity of this disease, abnormal gene expression profiles in bone marrow CD34⁺ cells are closely associated with particular FAB or cytogenetic subtypes. To elucidate the pathogenesis of MDS and investigate its therapeutic target, this article reviews progress of researches on abnormal gene expression profiles of hematopoietic stem/progenitor cells in low-risk, high-risk patients and MDS patients who carry common cytogenetic abnormalities.

  9. Human 14-3-3 gamma protein results in abnormal cell proliferation in the developing eye of Drosophila melanogaster

    PubMed Central

    Hong, Sophia W; Qi, Wenqing; Brabant, Marc; Bosco, Giovanni; Martinez, Jesse D

    2008-01-01

    Background 14-3-3 proteins are a family of adaptor proteins that participate in a wide variety of cellular processes. Recent evidence indicates that the expression levels of these proteins are elevated in some human tumors providing circumstantial evidence for their involvement in human cancers. However, the mechanism through which these proteins act in tumorigenesis is uncertain. Results To determine whether elevated levels of 14-3-3 proteins may perturb cell growth we overexpressed human 14-3-3 gamma (h14-3-3 gamma) in Drosophila larvae using the heat shock promoter or the GMR-Gal4 driver and then examined the effect that this had on cell proliferation in the eye imaginal discs of third instar larvae. We found that induction of h14-3-3 gamma resulted in the abnormal appearance of replicating cells in the differentiating proneural photoreceptor cells of eye imaginal discs where h14-3-3 gamma was driven by the heat shock promoter. Similarly, we found that driving h14-3-3 gamma expression specifically in developing eye discs with the GMR-Gal4 driver resulted in increased numbers of replicative cells following the morphogenetic furrow. Interestingly, we found that the effects of overexpressing h1433 gamma on eye development were increased in a genetic background where String (cdc25) function was compromised. Conclusion Taken together our results indicate that h14-3-3 gamma can promote abnormal cell proliferation and may act through Cdc25. This has important implications for 14-3-3 gamma as an oncogene as it suggests that elevated levels of 14-3-3 may confer a growth advantage to cells that overexpress it. PMID:18194556

  10. Abnormal osteogenic and chondrogenic differentiation of human mesenchymal stem cells from patients with adolescent idiopathic scoliosis in response to melatonin

    PubMed Central

    Chen, Chong; Xu, Caixia; Zhou, Taifeng; Gao, Bo; Zhou, Hang; Chen, Changhua; Zhang, Changli; Huang, Dongsheng; Su, Peiqiang

    2016-01-01

    Abnormalities of membranous and endochondral ossification in patients with adolescent idiopathic scoliosis (AIS) remain incompletely understood. To investigate abnormalities in the melatonin signaling pathway and cellular response to melatonin in AIS, a case-control study of osteogenic and chondrogenic differentiation was performed using human mesenchymal stem cells (hMSCs). AIS was diagnosed by physical and radiographic examination. hMSCs were isolated from the bone marrow of patients with AIS and control subjects (n=12 each), and purified by density gradient centrifugation. The expression levels of melatonin receptors (MTs) 1 and 2 were detected by western blotting. Osteogenic and chondrogenic differentiation was induced by culturing hMSCs in osteogenic and chondrogenic media containing vehicle or 50 nM melatonin. Alkaline phosphatase (ALP) activity assays, quantitative glycosaminoglycan (GAG) analysis, and reverse transcription-quantitative polymerase chain reaction analysis were performed. Compared with controls, MT2 demonstrated low expression in the AIS group. Melatonin increased ALP activity, GAG synthesis and upregulated the expression of genes involved in osteogenic and chondrogenic differentiation including, ALP, osteopontin, osteocalcin, runt-related transcription factor 2, collagen type II, collagen type X, aggrecan and sex-determining region Y-box 9 in the normal control hMSCs, but did not affect the AIS groups. Thus, AIS hMSCs exhibit abnormal cellular responses to melatonin during osteogenic and chondrogenic differentiation, which may be associated with abnormal membranous and endochondral ossification, and skeletal growth. These results indicate a potential modulating role of melatonin via the MT2 receptor on abnormal osteogenic and chondrogenic differentiaation in patients with AIS. PMID:27314307

  11. Radiation-Induced Growth Retardation and Microstructural and Metabolite Abnormalities in the Hippocampus

    PubMed Central

    Zawaski, Janice A.; Sahnoune, Iman

    2016-01-01

    Cranial radiotherapy (CRT) increases survival in pediatric brain-tumor patients but can cause deleterious effects. This study evaluates the acute and long-term impact of CRT delivered during childhood/adolescence on the brain and body using a rodent model. Rats received CRT, either 4 Gy fractions × 5 d (fractionated) or a cumulative dose of 20 Gy (single dose) at 28 d of age. Animals were euthanized 1 d, 5 d, or 3.5 mo after CRT. The 3.5 mo group was imaged prior to euthanasia. At 3.5 mo, we observed significant growth retardation in irradiated animals, versus controls, and the effects of single dose on brain and body weights were more severe than fractionated. Acutely single dose significantly reduced body weight but increased brain weight, whereas fractionation significantly reduced brain but not body weights, versus controls. CRT suppressed cell proliferation in the hippocampal subgranular zone acutely. Fractional anisotropy (FA) in the fimbria was significantly lower in the single dose versus controls. Hippocampal metabolite levels were significantly altered in the single dose animals, reflecting a heightened state of inflammation that was absent in the fractionated. Our findings indicate that despite the differences in severity between the doses they both demonstrated an effect on cell proliferation and growth retardation, important factors in pediatric CRT. PMID:27242931

  12. Relationship between pulmonary and cardiac abnormalities in sickle cell disease: implications for the management of patients

    PubMed Central

    Maioli, Maria Christina Paixão; Soares, Andrea Ribeiro; Bedirian, Ricardo; Alves, Ursula David; de Lima Marinho, Cirlene; Lopes, Agnaldo José

    2015-01-01

    Objective To evaluate the association between clinical, pulmonary, and cardiovascular findings in patients with sickle cell disease and, secondarily, to compare these findings between sickle cell anemia patients and those with other sickle cell diseases. Methods Fifty-nine adults were included in this cross-sectional study; 47 had sickle cell anemia, and 12 had other sickle cell diseases. All patients underwent pulmonary function tests, chest computed tomography, and echocardiography. Results Abnormalities on computed tomography, echocardiography, and pulmonary function tests were observed in 93.5%, 75.0%; and 70.2% of patients, respectively. A higher frequency of restrictive abnormalities was observed in patients with a history of acute chest syndrome (85% vs. 21.6%; p-value < 0.0001) and among patients with increased left ventricle size (48.2% vs. 22.2%; p-value = 0.036), and a higher frequency of reduced respiratory muscle strength was observed in patients with a ground-glass pattern (33.3% vs. 4.3%; p-value = 0.016). Moreover, a higher frequency of mosaic attenuation was observed in patients with elevated tricuspid regurgitation velocity (61.1% vs. 24%; p-value = 0.014). Compared to patients with other sickle cell diseases, sickle cell anemia patients had suffered increased frequencies of acute pain episodes, and acute chest syndrome, and exhibited mosaic attenuation on computed tomography, and abnormalities on echocardiography. Conclusion A significant interrelation between abnormalities of the pulmonary and cardiovascular systems was observed in sickle cell disease patients. Furthermore, the severity of the cardiopulmonary parameters among patients with sickle cell anemia was greater than that of patients with other sickle cell diseases. PMID:26969771

  13. Increased Fetal Plasma Erythropoietin in Monochorionic Twin Pregnancies With Selective Intrauterine Growth Restriction and Abnormal Umbilical Artery Doppler.

    PubMed

    Chang, Yao-Lung; Chao, An-Shine; Peng, Hsiu-Huei; Chang, Shuenn-Dyh; Su, Sheng-Yuan; Chen, Kuan-Ju; Cheng, Po-Jen; Wang, Tzu-Hao

    2016-08-01

    Hypoxia is the primary stimulus for the production of erythropoietin (EPO) in both fetal and adult life. Here, we investigated fetal plasma EPO concentrations in monochorionic (MC) twin pregnancies with selective intrauterine growth restriction (sIUGR) and abnormal umbilical artery (UA) Doppler. We diagnosed sIUGR in presence of (1) birth-weight discordance >20% and (2) either twin with a birth weight <10th percentile. An abnormal UA Doppler was defined as a persistent absent-reverse end diastolic flow (AREDF). The intertwin EPO ratio was calculated as the plasma EPO level of the smaller (or small-for-gestational-age) twin divided by the EPO concentration of the larger (or appropriate-for-gestational-age (AGA)) twin. Thirty-two MC twin pairs were included. Of these, 17 pairs were normal twins (Group 1), seven pairs were twins with sIUGR without UA Doppler abnormalities (Group 2), and eight pairs were twins with sIUGR and UA Doppler abnormalities (Group 3). The highest EPO ratio was identified in Group 3 (p < .001) but no significant differences were observed between Groups 1 and 2. Fetal hemoglobin levels did not differ significantly in the three groups, and fetal EPO concentration did not correlate with gestational age at birth. We conclude that fetal plasma EPO concentrations are selectively increased in MC twin pregnancies with sIUGR and abnormal UA Doppler, possibly as a result of uncompensated hypoxia.

  14. T-cell abnormalities in common variable immunodeficiency: the hidden defect.

    PubMed

    Wong, Gabriel K; Huissoon, Aarnoud P

    2016-08-01

    This review discusses how the T-cell compartment in common variable immunodeficiency is marked by the premature arrest in thymic output, leading to T-cell exhaustion and immune dysregulation. Although B cells have been the main focus of the disorder, ample experimental data suggest that T-cell abnormalities can be seen in a large proportion of Freiburg Group 1a patients and those suffering from inflammatory complications. The reductions in T-cell receptor excision circles, naïve T cells, invariant NKT cells and regulatory T cells suggest a diminished thymic output, while CD8 T cells are driven towards exhaustion either via an antigen-dependent or an antigen-independent manner. The theoretical risk of anti-T-cell therapies is discussed, highlighting the need for an international effort in generating longitudinal data in addition to better-defined underlying molecular characterisation.

  15. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer.

    PubMed

    Nefedova, Yulia; Huang, Mei; Kusmartsev, Sergei; Bhattacharya, Raka; Cheng, Pingyan; Salup, Raoul; Jove, Richard; Gabrilovich, Dmitry

    2004-01-01

    Abnormal differentiation of myeloid cells is one of the hallmarks of cancer. However, the molecular mechanisms of this process remain elusive. In this study, we investigated the effect of tumor-derived factors on Janus kinase (Jak)/STAT signaling in myeloid cells during their differentiation into dendritic cells. Tumor cell conditioned medium induced activation of Jak2 and STAT3, which was associated with an accumulation of immature myeloid cells. Jak2/STAT3 activity was localized primarily in these myeloid cells, which prevented the differentiation of immature myeloid cells into mature dendritic cells. This differentiation was restored after removal of tumor-derived factors. Inhibition of STAT3 abrogated the negative effects of these factors on myeloid cell differentiation, and overexpression of STAT3 reproduced the effects of tumor-derived factors. Thus, this is a first demonstration that tumor-derived factors may affect myeloid cell differentiation in cancer via constitutive activation of Jak2/STAT3.

  16. Growth and development after hematopoietic cell transplant in children.

    PubMed

    Sanders, J E

    2008-01-01

    Hematopoietic cell transplantation (HCT) following high-dose chemotherapy or chemoradiotherapy for children with malignant or nonmalignant hematologic disorders has resulted in an increasing number of long-term disease-free survivors. The preparative regimens include high doses of alkylating agents, such as CY with or without BU, and may include TBI. These agents impact the neuroendocrine system in growing children and their subsequent growth and development. Children receiving high-dose CY or BUCY have normal thyroid function, but those who receive TBI-containing regimens may develop thyroid function abnormalities. Growth is not impacted by chemotherapy-only preparative regimens, but TBI is likely to result in growth hormone deficiency and decreased growth rates that need to be treated with synthetic growth hormone therapy. Children who receive high-dose CY-only have normal development through puberty, whereas those who receive BUCY have a high incidence of delayed pubertal development. Following fractionated TBI preparative regimens, approximately half of the patients have normal pubertal development. These data demonstrate that the growth and development problems after HCT are dependent upon the preparative regimen received. All children should be followed for years after HCT for detection of growth and development abnormalities that are treatable with appropriate hormone therapy.

  17. Peripheral blood T- and B-cell immunophenotypic abnormalities in selected women with unexplained recurrent miscarriage.

    PubMed

    Carbone, Javier; Sarmiento, Elizabeth; Gallego, Antonio; Lanio, Nallibe; Navarro, Joaquin; García, Sandra; Fernandez-Cruz, Eduardo

    2016-02-01

    We aimed to investigate if women with recurrent miscarriage disclosed abnormalities in the maturation and activation status of peripheral blood lymphocyte subsets. In a case control study, 24 women with recurrent miscarriage, 37 women with children but no history of miscarriage and 39 women without previous pregnancies were evaluated. Lymphocyte subsets were evaluated using three-colour flow-cytometry. Selected women with recurrent miscarriage had significantly higher absolute counts of central memory CD4+ T-cells, CD8+DR+ T-cells and memory non-switched B-cells than the control groups. Recurrent miscarriage may be associated with abnormalities of the maturation and activation status of peripheral blood T and B lymphocytes.

  18. An abnormal T cell repertoire in hypergammaglobulinaemic primary Sjögren's syndrome.

    PubMed Central

    Kay, R A; Hay, E M; Dyer, P A; Dennett, C; Green, L M; Bernstein, R M; Holt, P J; Pumphrey, R S; Boylston, A W; Ollier, W E

    1991-01-01

    T cell antigen specificity is determined by the products of the genes which encode the variable regions of their receptors. Of the T cell receptor (TCR) variable region gene products examined, only V beta 6.7a TCR-positive lymphocytes were reduced in primary Sjögren's syndrome patients with IgG1 hypergammaglobulinaemia compared with an age-, sex- and HLA-matched control population. The levels of V beta 6.7a T cells were also significantly reduced when these patients were compared with an age- and sex-matched but HLA-unmatched control group and non-tissue typed normal people of both sexes. Since published studies show no such abnormality in rheumatoid arthritis, systemic lupus erythematosus or other autoimmune diseases, this abnormality may reflect a pathogenic process specific to primary Sjögren's syndrome. PMID:1864006

  19. End stage renal disease serum contains a specific renal cell growth factor

    SciTech Connect

    Klotz, L.H.; Kulkarni, C.; Mills, G. )

    1991-01-01

    End stage renal disease (ESRD) kidneys display abnormal growth characterized by a continuum of cystic disease, adenoma and carcinoma. This study evaluates the hypothesis that serum of patients with ESRD contains increased amounts of a growth factor which specifically induces proliferation of renal cells. ESRD sera compared to sera from normal controls induced a two to three-fold increase in the proliferative rate of renal cell carcinoma cell lines and normal kidney explants compared to cell lines from other sites. The increased proliferative activity of ESRD sera on renal cells was paralleled by an increase in cytosolic free calcium. The growth factor activity was encoded by a polypeptide of between 15 and 30 kd. The activity of ESRD sera on renal cells was not mimicked or inhibited by epidermal growth factor, basic fibroblast growth factor and platelet derived growth factor indicating that the renal cell specific growth factor activity in ESRD is different from these factors.

  20. Gestational lead exposure induces developmental abnormalities and up-regulates apoptosis of fetal cerebellar cells in rats.

    PubMed

    Mousa, Alyaa M; Al-Fadhli, Ameera S; Rao, Muddanna S; Kilarkaje, Narayana

    2015-01-01

    Lead (Pb), a known environmental toxicant, adversely affects almost all organ systems. In this study, we investigated the effects of maternal lead exposure on fetal rat cerebellum. Female Sprague-Dawley rats were given lead nitrate in drinking water (0, 0.5, and 1%) for two weeks before conception, and during pregnancy. Fetuses were collected by caesarian section on gestational day 21 and observed for developmental abnormalities. The fetal cerebellar sections from control and 1% lead group were stained with cresyl violet. Immunohistochemical expressions of p53, Bax, Bcl-2, and caspase 3 were quantified by AnalySIS image analyzer (Life Science, Germany). Lead exposure induced developmental abnormalities of eyes, ear, limbs, neck and ventral abdominal wall; however, these abnormalities were commonly seen in the 1% lead-treated group. In addition, lead also caused fetal mortality and reduced body growth in both dose groups and reduced brain weight in the 1% lead-treated group. The fetal cerebella from the 1% lead-treated group showed unorganized cerebellar cortical layers, and degenerative changes in granule and Purkinje cells such as the formation of clumps of Nissl granules. An increase in Bax and caspase 3, and a decrease in Bcl-2 (p < 0.05), but not in p53, showed apoptosis of the neurons. In conclusion, gestational lead exposure in rats induces fetal toxicity and developmental abnormalities. The lead exposure also impairs development of cerebellar layers, induces structural changes, and apoptosis in the fetal cerebellar cortex. These results suggest that lead exposure during gestation is extremely toxic to developing cerebellum in rats.

  1. Effect of Lycium bararum polysaccharides on methylmercury-induced abnormal differentiation of hippocampal stem cells

    PubMed Central

    Tian, Jian-Ying; Chen, Wei-Wei; Cui, Jing; Wang, Hao; Chao, Ci; Lu, Zhi-Yan; Bi, Yong-Yi

    2016-01-01

    The aim of the present study was to observe the effects of a general extract of Lycium bararum polysaccharides (LBPs) on methylmercury (MeHg)-induced damage in hippocampus neural stem cells (hNSCs). The hippocampal tissues of embryonic day 16 Sprague-Dawley rats were extracted for the isolation, purification and cloning of hNSCs. Following passage and proliferation for 10 days, the cells were allocated at random into the following groups: Control, LBPs, MeHg and MeHg + LBPs. MTT and microtubule-associated protein 2 (MAP-2)/glial fibrillary acidic protein/Hoechst immunofluorescence tests were performed to detect the differentiation and growth of hNSCs in the various groups. The differentiation rate of MeHg-treated hNSCs and the perimeter of MAP-2-positive neurons were 3.632±0.63% and 62.36±5.58 µm, respectively, significantly lower compared with the control group values of 6.500±0.81% and 166±8.16 µm (P<0.05). Furthermore, the differentiation rate and the perimeter of MAP-2-positive neurons in LBPs groups cells was 7.75±0.59% and 253.3±11.21 µm, respectively, significantly higher compared with the control group (P<0.05). The same parameters in the MeHg + LBPs group were 5.92±0.98% and 111.9±6.07 µm, respectively, significantly higher than the MeHg group (P<0.05). The astrocyte differentiation rates in the MeHg and MeHg + LBPs group were 41.19±2.14 and 34.58±1.70, respectively (P<0.05). These results suggest that LBPs may promote the generation and development of new neurons and inhibit the MeHg-induced abnormal differentiation of astrocytes. Thus, LBPs may be considered to be a potential new treatment for MeHg-induced neurotoxicity in hNSCs. PMID:27446261

  2. Spectral Cytopathology of Cervical Samples: Detecting Cellular Abnormalities in Cytologically Normal Cells

    PubMed Central

    Schubert, Jennifer M.; Bird, Benjamin; Papamarkakis, Kostas; Miljković, Miloš; Bedrossian, Kristi; Laver, Nora; Diem, Max

    2010-01-01

    Aim Spectral Cytopathology (SCP) is a novel spectroscopic method for objective and unsupervised classification of individual exfoliated cells. The limitations of conventional cytopathology are well-recognized within the pathology community. In SCP, cellular differentiation is made by observing molecular changes in the nucleus and the cytoplasm, which may or may not produce morphological changes detectable by conventional cytopathology. This proof of concept study demonstrates SCP’s potential as an enhancing tool for cytopathologists by aiding in the accurate and reproducible diagnosis of cells in all states of disease. Method Infrared spectra are collected from cervical cells deposited onto reflectively coated glass slides. Each cell has a corresponding infrared spectrum that describes its unique biochemical composition. Spectral data are processed and analyzed by an unsupervised chemometric algorithm, Principal Component Analysis (PCA). Results In this blind study, cervical samples are classified by analyzing the spectra of morphologically normal looking squamous cells from normal samples and samples diagnosed by conventional cytopathology with low grade squamous intraepithelial lesions (LSIL). SCP discriminated cytopathological diagnoses amongst twelve different cervical samples with a high degree of specificity and sensitivity. SCP also correlated two samples with abnormal spectral changes: these samples had a normal cytopathological diagnosis but had a history of abnormal cervical cytology. The spectral changes observed in the morphologically normal looking cells are most likely due to an infection with human papillomavirus, HPV. HPV DNA testing was conducted on five additional samples, and SCP accurately differentiated these samples by their HPV status. Conclusions SCP tracks biochemical variations in cells that are consistent with the onset of disease. HPV has been implicated as the cause of these changes detected spectroscopically. SCP does not depend on

  3. Inhibition of expression of the circadian clock gene Period causes metabolic abnormalities including repression of glycometabolism in Bombyx mori cells

    PubMed Central

    Tao, Hui; Li, Xue; Qiu, Jian-Feng; Cui, Wen-Zhao; Sima, Yang-Hu; Xu, Shi-Qing

    2017-01-01

    Abnormalities in the circadian clock system are known to affect the body’s metabolic functions, though the molecular mechanisms responsible remain uncertain. In this study, we achieved continuous knockdown of B. mori Period (BmPer) gene expression in the B. mori ovary cell line (BmN), and generated a Per-KD B. mori model with developmental disorders including small individual cells and slow growth. We conducted cell metabolomics assays by gas chromatography/liquid chromatography-mass spectrometry and showed that knockdown of BmPer gene expression resulted in significant inhibition of glycometabolism. Amino acids that used glucose metabolites as a source were also down-regulated, while lipid metabolism and nucleotide metabolism were significantly up-regulated. Metabolite correlation analysis showed that pyruvate and lactate were closely related to glycometabolism, as well as to metabolites such as aspartate, alanine, and xanthine in other pathways. Further validation experiments showed that the activities of the key enzymes of glucose metabolism, hexokinase, phosphofructokinase, and citrate synthase, were significantly decreased and transcription of their encoding genes, as well as that of pyruvate kinase, were also significantly down-regulated. We concluded that inhibition of the circadian clock gene BmPer repressed glycometabolism, and may be associated with changes in cellular amino acid metabolism, and in cell growth and development. PMID:28393918

  4. Excess TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.

    PubMed

    Endo, Toyoshi; Kobayashi, Tetsuro

    2013-09-01

    Hypothyroidism in the young leads to irreversible growth failure. hyt/hyt Mice have a nonfunctional TSH receptor (TSHR) and are severely hypothyroid, but growth retardation was not observed in adult mice. We found that epiphysial cartilage as well as cultured chondrocytes expressed functional TSHR at levels comparable to that seen in the thyroid, and that addition of TSH to cultured chondrocytes suppressed expression of chondrocyte differentiation marker genes such as Sox-9 and type IIa collagen. Next, we compared the long bone phenotypes of two distinct mouse models of hypothyroidism: thyroidectomized (THYx) mice and hyt/hyt mice. Although both THYx and hyt/hyt mice were severely hypothyroid and had similar serum Ca(2+) and growth hormone levels, the tibia was shorter and the proliferating and hypertrophic zones in the growth plate was significantly narrower in THYx mice than in hyt/hyt mice. Supplementation of hyt/hyt mice thyroid hormone resulted in a wider growth plate compared with that of wild-type mice. Expressions of chondrocyte differentiation marker genes Sox-9 and type IIa collagen in growth plate from THYx mice were 52 and 60% lower than those of hyt/hyt mice, respectively. High serum TSH causes abnormal skeletal development in young mice with hypothyroidism via suppressive effects on the growth plate.

  5. Acentrosomal Drosophila epithelial cells exhibit abnormal cell division, leading to cell death and compensatory proliferation

    PubMed Central

    Poulton, John S; Cuningham, John C; Peifer, Mark

    2014-01-01

    Summary Mitotic spindles are critical for accurate chromosome segregation. Centrosomes, the primary microtubule nucleating centers of animal cells, play key roles in forming and orienting mitotic spindles. However, the survival of Drosophila without centrosomes suggested they are dispensable in somatic cells, challenging the canonical view. We used fly wing disc epithelia as a model to resolve these conflicting hypotheses, revealing that centrosomes play vital roles in spindle assembly, function, and orientation. Many acentrosomal cells exhibit prolonged spindle assembly, chromosome mis-segregation, DNA damage, misoriented divisions, and eventual apoptosis. We found that multiple mechanisms buffer the effects of centrosome loss, including alternative microtubule nucleation pathways and the Spindle Assembly Checkpoint. Apoptosis of acentrosomal cells is mediated by JNK signaling, which also drives compensatory proliferation to maintain tissue integrity and viability. These data reveal the importance of centrosomes in fly epithelia, but also demonstrate the robust compensatory mechanisms at the cellular and organismal level. PMID:25241934

  6. Abnormal integrity of the nucleolus associated with cell cycle arrest owing to the temperature-sensitive ubiquitin-activating enzyme E1.

    PubMed

    Sudha, T; Tsuji, H; Sameshima, M; Matsuda, Y; Kaneda, S; Nagai, Y; Yamao, F; Seno, T

    1995-03-01

    A mouse cell mutant, ts85, containing the temperature-sensitive ubiquitin-activating enzyme was arrested in G2 phase at the non-permissive temperature. In the arrested cells, azure C, a nucleolus-specific stain, revealed a U-shaped or ring-shaped arrangement of nucleolar lobes with an unstained region in the center. Silver staining of the nucleolar organizer region (NOR) and fluorescence in situ hybridization (FISH) with rDNA both gave signals in azure C-positive regions. Electron microscopic examination revealed a cloud of unidentified electron-dense particles (diameter approximately 70 nm) in the azure C-negative center space. When the arrested cells were released into M-phase, we observed the association of NOR-bearing chromosomes with a pulverization-like abnormality. FISH with rDNA and NOR silver staining demonstrated that the pulverization-like abnormality was restricted to NORs. The frequent occurrence of persistent nucleolar material in prophase and prometaphase of the stressed cells after release indicated a delayed dissociation of the nucleolus that brought about the abnormal chromosomes in M-phase. ts85 cells transfected with the mouse E1 cDNA recovered growth at the non-permissive temperature and no longer showed abnormal nucleolar morphology. It seems that the ubiquitin system plays a role in the dissolution of the nucleolus, possibly involving the NOR-bearing chromosomes.

  7. Interplay between cell growth and cell cycle in plants.

    PubMed

    Sablowski, Robert; Carnier Dornelas, Marcelo

    2014-06-01

    The growth of organs and whole plants depends on both cell growth and cell-cycle progression, but the interaction between both processes is poorly understood. In plants, the balance between growth and cell-cycle progression requires coordinated regulation of four different processes: macromolecular synthesis (cytoplasmic growth), turgor-driven cell-wall extension, mitotic cycle, and endocycle. Potential feedbacks between these processes include a cell-size checkpoint operating before DNA synthesis and a link between DNA contents and maximum cell size. In addition, key intercellular signals and growth regulatory genes appear to target at the same time cell-cycle and cell-growth functions. For example, auxin, gibberellin, and brassinosteroid all have parallel links to cell-cycle progression (through S-phase Cyclin D-CDK and the anaphase-promoting complex) and cell-wall functions (through cell-wall extensibility or microtubule dynamics). Another intercellular signal mediated by microtubule dynamics is the mechanical stress caused by growth of interconnected cells. Superimposed on developmental controls, sugar signalling through the TOR pathway has recently emerged as a central control point linking cytoplasmic growth, cell-cycle and cell-wall functions. Recent progress in quantitative imaging and computational modelling will facilitate analysis of the multiple interconnections between plant cell growth and cell cycle and ultimately will be required for the predictive manipulation of plant growth.

  8. Modeling circadian clock-cell cycle interaction effects on cell population growth rates.

    PubMed

    El Cheikh, R; Bernard, S; El Khatib, N

    2014-12-21

    The circadian clock and the cell cycle are two tightly coupled oscillators. Recent analytical studies have shown counter-intuitive effects of circadian gating of the cell cycle on growth rates of proliferating cells which cannot be explained by a molecular model or a population model alone. In this work, we present a combined molecular-population model that studies how coupling the circadian clock to the cell cycle, through the protein WEE1, affects a proliferating cell population. We show that the cell cycle can entrain to the circadian clock with different rational period ratios and characterize multiple domains of entrainment. We show that coupling increases the growth rate for autonomous periods of the cell cycle around 24 h and above 48 h. We study the effect of mutation of circadian genes on the growth rate of cells and show that disruption of the circadian clock can lead to abnormal proliferation. Particularly, we show that Cry 1, Cry 2 mutations decrease the growth rate of cells, Per 2 mutation enhances it and Bmal 1 knockout increases it for autonomous periods of the cell cycle less than 21 h and decreases it elsewhere. Combining a molecular model to a population model offers new insight on the influence of the circadian clock on the growth of a cell population. This can help chronotherapy which takes benefits of physiological rhythms to improve anti-cancer efficacy and tolerance to drugs by administering treatments at a specific time of the day.

  9. Comparison of gene expression profiles and responses to zinc chloride among inter- and intraspecific hybrids with growth abnormalities in wheat and its relatives.

    PubMed

    Takamatsu, Kiyofumi; Iehisa, Julio C M; Nishijima, Ryo; Takumi, Shigeo

    2015-07-01

    Hybrid necrosis is a well-known reproductive isolation mechanism in plant species, and an autoimmune response is generally considered to trigger hybrid necrosis through epistatic interaction between disease resistance-related genes in hybrids. In common wheat, the complementary Ne1 and Ne2 genes control hybrid necrosis, defined as type I necrosis. Two other types of hybrid necrosis (type II and type III) have been observed in interspecific hybrids between tetraploid wheat and Aegilops tauschii. Another type of hybrid necrosis, defined here as type IV necrosis, has been reported in F1 hybrids between Triticum urartu and some accessions of Triticum monococcum ssp. aegilopoides. In types I, III and IV, cell death occurs gradually starting in older tissues, whereas type II necrosis symptoms occur only under low temperature. To compare comprehensive gene expression patterns of hybrids showing growth abnormalities, transcriptome analysis of type I and type IV necrosis was performed using a wheat 38k oligo-DNA microarray. Defense-related genes including many WRKY transcription factor genes were dramatically up-regulated in plants showing type I and type IV necrosis, similarly to other known hybrid abnormalities, suggesting an association with an autoimmune response. Reactive oxygen species generation and necrotic cell death were effectively inhibited by ZnCl2 treatment in types I, III and IV necrosis, suggesting a significant association of Ca(2+) influx in upstream signaling of necrotic cell death in wheat hybrid necrosis.

  10. Role of abnormal anterior pituitary hormones-growth hormone and prolactin in active systemic lupus erythematosus

    PubMed Central

    Zhu, Xiaohua; Xu, Jinhua; Li, Shujuan; Huang, Wen; Li, Feng

    2015-01-01

    Background: The role of anterior pituitary hormones in systemic lupus erythematosus (SLE) remains controversial. Aims and Objectives: We determined the expression levels of human growth hormone (GH), prolactin (PRL), and their receptors in subjects presenting with SLE, and modulation of disease severity. Materials and methods: Forty-seven subjects and ten healthy controls were assessed for possible association between SLE disease activity and levels of serum PRL, GH and thyrotropin-releasing hormone (TRH). In peripheral blood mononuclear cells (PBMC), specific binding and mRNA expression of receptors for GH (GHR), and PRL (PRLR) were determined by receptor-ligand binding assay (RLBA) and RT-PCR. PBMC of recruited subjects were treated with hPRL and rhGH to assess IgG production and antibodies against dsDNA. Results: In active SLE subjects we found elevated PRL and GH levels. Study subject PBMCs displayed augmented GHR and PRLR protein and mRNA expression. Study subjects also showed a positive correlation in serum PRL levels and specific antibodies against dsDNA, SLE disease activity index (SLEDAI), and proteinuria. However, a negative correlation was found between serum PRL levels and complement component C3. We found a positive correlation between specific binding rates of PRLR and GHR and both SLE activity and dsDNA antibody titers. Enhanced IgG and anti-dsDNA secretion was observed in cultured PBMC stimulated by PRL or GH with/without PHA, PWM, IL-2 or IL-10. In active SLE, a close association was found between augmented PRL and GH levels, expression and specific binding activities of PRLR and GHR, and changes in the specific titer of anti-dsDNA. Conclusion: Anterior pituitary hormones play an important role in the pathogenesis of SLE. High levels of growth hormone (GH) and prolactin (PRL) play a role in pathogenesis of SLE, which is correlated with SLE disease activity and antibodies against dsDNA. The mechanism of GH and PRL in SLE was complicated and should

  11. Cerebellar cortex development in the weaver condition presents regional and age-dependent abnormalities without differences in Purkinje cells neurogenesis.

    PubMed

    Martí, Joaquín; Santa-Cruz, María C; Hervás, José P; Bayer, Shirley A; Villegas, Sandra

    2016-01-01

    Ataxias are neurological disorders associated with the degeneration of Purkinje cells (PCs). Homozygous weaver mice (wv/wv) have been proposed as a model for hereditary cerebellar ataxia because they present motor abnormalities and PC loss. To ascertain the physiopathology of the weaver condition, the development of the cerebellar cortex lobes was examined at postnatal day (P): P8, P20 and P90. Three approaches were used: 1) quantitative determination of several cerebellar features; 2) qualitative evaluation of the developmental changes occurring in the cortical lobes; and 3) autoradiographic analyses of PC generation and placement. Our results revealed a reduction in the size of the wv/wv cerebellum as a whole, confirming previous results. However, as distinguished from these reports, we observed that quantified parameters contribute differently to the abnormal growth of the wv/wv cerebellar lobes. Qualitative analysis showed anomalies in wv/wv cerebellar cytoarchitecture, depending on the age and lobe analyzed. Such abnormalities included the presence of the external granular layer after P20 and, at P90, ectopic cells located in the molecular layer following several placement patterns. Finally, we obtained autoradiographic evidence that wild-type and wv/wv PCs presented similar neurogenetic timetables, as reported. However, the innovative character of this current work lies in the fact that the neurogenetic gradients of wv/wv PCs were not modified from P8 to P90. A tendency for the accumulation of late-formed PCs in the anterior and posterior lobes was found, whereas early-generated PCs were concentrated in the central and inferior lobes. These data suggested that wv/wv PCs may migrate properly to their final destinations. The extrapolation of our results to patients affected with cerebellar ataxias suggests that all cerebellar cortex lobes are affected with several age-dependent alterations in cytoarchitectonics. We also propose that PC loss may be regionally

  12. Peripheral blood natural killer cells and mild thyroid abnormalities in women with reproductive failure.

    PubMed

    Triggianese, P; Perricone, C; Conigliaro, P; Chimenti, M S; Perricone, R; De Carolis, C

    2016-03-01

    Abnormalities in peripheral blood natural killer (NK) cells have been reported in women with primary infertility and recurrent spontaneous abortion (RSA) and several studies have been presented to define cutoff values for abnormal peripheral blood NK cell levels in this context. Elevated levels of NK cells were observed in infertile/RSA women in the presence of thyroid autoimmunity (TAI), while no studies have been carried out, to date, on NK cells in infertile/RSA women with non-autoimmune thyroid diseases. The contribution of this study is two-fold: (1) the evaluation of peripheral blood NK cell levels in a cohort of infertile/RSA women, in order to confirm related data from the literature; and (2) the assessment of NK cell levels in the presence of both TAI and subclinical hypothyroidism (SCH) in order to explore the possibility that the association between NK cells and thyroid function is not only restricted to TAI but also to SCH. In a retrospective study, 259 age-matched women (primary infertility [n = 49], primary RSA [n = 145], and secondary RSA [n = 65]) were evaluated for CD56+CD16+NK cells by flow cytometry. Women were stratified according to thyroid status: TAI, SCH, and without thyroid diseases (ET). Fertile women (n = 45) were used as controls. Infertile/RSA women showed higher mean NK cell levels than controls. The cutoff value determining the abnormal NK cell levels resulted ⩾15% in all the groups of women. Among the infertile/RSA women, SCH resulted the most frequently associated thyroid disorder while no difference resulted in the prevalence of TAI and ET women between patients and controls. A higher prevalence of women with NK cell levels ⩾15% was observed in infertile/RSA women with SCH when compared to TAI/ET women. According to our data, NK cell assessment could be used as a diagnostic tool in women with reproductive failure and we suggest that the possible association between NK cell levels and thyroid function can be described not only

  13. Effect of Process Parameters on Abnormal Grain Growth during Friction Stir Processing of a Cast Al Alloy

    SciTech Connect

    Jana, Saumyadeep; Mishra, Rajiv S.; Baumann, John A.; Grant, Glenn J.

    2010-11-25

    The effects of process parameters and friction stir processing (FSP) run configurations on the stability of nugget microstructure at elevated temperatures were evaluated. Cast plates of an Al-7Si- 0.6Mg alloy were friction stir processed using a combination of tool rotation rates and tool traverse speeds. All single pass runs showed some extent of abnormal grain growth (AGG), whereas multi-pass runs were more resistant to AGG. Additionally, higher tool rpm was found to be beneficial for controlling AGG. These effects were analyzed by comparing the result of this work with other published results and AGG models.

  14. Abnormal crystal growth in CH3NH3PbI3-xClx using a multi-cycle solution coating process

    DOE PAGES

    Dong, Qingfeng; Yuan, Yongbo; Shao, Yuchuan; ...

    2015-06-23

    Recently, the efficiency of organolead trihalide perovskite solar cells has improved greatly because of improved material qualities with longer carrier diffusion lengths. Mixing chlorine in the precursor for mixed halide films has been reported to dramatically enhance the diffusion lengths of mixed halide perovskite films, mainly as a result of a much longer carrier recombination lifetime. Here we report that adding Cl containing precursor for mixed halide perovskite formation can induce the abnormal grain growth behavior that yields well-oriented grains accompanied by the appearance of some very large size grains. The abnormal grain growth becomes prominent only after multi-cycle coatingmore » of MAI : MACl blend precursor. The large grain size is found mainly to contribute to a longer carrier charge recombination lifetime, and thus increases the device efficiency to 18.9%, but without significantly impacting the carrier transport property. As a result, the strong correlation identified between material process and morphology provides guidelines for future material optimization and device efficiency enhancement.« less

  15. Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice

    PubMed Central

    Borghesani, Paul R.; Alt, Frederick W.; Bottaro, Andrea; Davidson, Laurie; Aksoy, Saime; Rathbun, Gary A.; Roberts, Thomas M.; Swat, Wojciech; Segal, Rosalind A.; Gu, Yansong

    2000-01-01

    Motor incoordination, immune deficiencies, and an increased risk of cancer are the characteristic features of the hereditary disease ataxia–telangiectasia (A-T), which is caused by mutations in the ATM gene. Through gene targeting, we have generated a line of Atm mutant mice, Atmy/y mice. In contrast to other Atm mutant mice, Atmy/y mice show a lower incidence of thymic lymphoma and survive beyond a few months of age. Atmy/y mice exhibit deficits in motor learning indicative of cerebellar dysfunction. Even though we found no gross cerebellar degeneration in older Atmy/y animals, ectopic and abnormally differentiated Purkinje cells were apparent in mutant mice of all ages. These findings establish that some neuropathological abnormalities seen in A-T patients also are present in Atm mutant mice. In addition, we report a previously unrecognized effect of Atm deficiency on development or maintenance of CD4+8+ thymocytes. We discuss these findings in the context of the hypothesis that abnormal development of Purkinje cells and lymphocytes contributes to the pathogenesis of A-T. PMID:10716718

  16. Screening for ALK abnormalities in central nervous system metastases of non-small-cell lung cancer: ALK abnormalities in CNS metastases of NSCLC.

    PubMed

    Nicoś, Marcin; Jarosz, Bożena; Krawczyk, Paweł; Wojas-Krawczyk, Kamila; Kucharczyk, Tomasz; Sawicki, Marek; Pankowski, Juliusz; Trojanowski, Tomasz; Milanowski, Janusz

    2016-11-23

    Anaplastic lymphoma kinase (ALK) gene rearrangement was reported in 3-7% of primary non-small-cell lung cancer (NSCLC) and its presence is commonly associated with adenocarcinoma (AD) type and non-smoking history. ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, alectinib and ceritinib showed efficiency in patients with primary NSCLC harboring ALK gene rearrangement. Moreover, response to ALK TKIs was observed in central nervous system (CNS) metastatic lesions of NSCLC. However, there are no reports concerning the frequency of ALK rearrangement in CNS metastases. We assessed the frequency of ALK abnormalities in 145 formalin fixed paraffin embedded (FFPE) tissue samples from CNS metastases of NSCLC using immunohistochemical (IHC) automated staining (BenchMark GX, Ventana, USA) and fluorescence in situ hybridization (FISH) technique (Abbot Molecular, USA). The studied group was heterogeneous in terms of histopathology and smoking status. ALK abnormalities were detected in 4.8% (7/145) of CNS metastases. ALK abnormalities were observed in six AD (7.5%; 6/80) and in single patients with adenosuqamous lung carcinoma. Analysis of clinical and demographic factors indicated that expression of abnormal ALK was significantly more frequently observed (p=0.0002; χ(2) =16.783) in former-smokers. Comparison of IHC and FISH results showed some discrepancies, which were caused by unspecific staining of macrophages and glial/nerve cells, which constitute the background of CNS tissues. Our results indicate high frequency of ALK gene rearrangement in CNS metastatic sites of NSCLC that are in line with prior studies concerning evaluation of the presence of ALK abnormalities in such patients. However, we showed that assessment of ALK by IHC and FISH methods in CNS tissues require additional standardizations. This article is protected by copyright. All rights reserved.

  17. Reactivation of Lysosomal Ca2+ Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells.

    PubMed

    Zou, Jianlong; Hu, Bo; Arpag, Sezgi; Yan, Qing; Hamilton, Audra; Zeng, Yuan-Shan; Vanoye, Carlos G; Li, Jun

    2015-04-29

    Loss of function of FIG4 leads to Charcot-Marie-Tooth disease Type 4J, Yunis-Varon syndrome, or an epilepsy syndrome. FIG4 is a phosphatase with its catalytic specificity toward 5'-phosphate of phosphatidylinositol-3,5-diphosphate (PI3,5P2). However, the loss of FIG4 decreases PI3,5P2 levels likely due to FIG4's dominant effect in scaffolding a PI3,5P2 synthetic protein complex. At the cellular level, all these diseases share similar pathology with abnormal lysosomal storage and neuronal degeneration. Mice with no FIG4 expression (Fig4(-/-)) recapitulate the pathology in humans with FIG4 deficiency. Using a flow cytometry technique that rapidly quantifies lysosome sizes, we detected an impaired lysosomal fission, but normal fusion, in Fig4(-/-) cells. The fission defect was associated with a robust increase of intralysosomal Ca(2+) in Fig4(-/-) cells, including FIG4-deficient neurons. This finding was consistent with a suppressed Ca(2+) efflux of lysosomes because the endogenous ligand of lysosomal Ca(2+) channel TRPML1 is PI3,5P2 that is deficient in Fig4(-/-) cells. We reactivated the TRPML1 channels by application of TRPML1 synthetic ligand, ML-SA1. This treatment reduced the intralysosomal Ca(2+) level and rescued abnormal lysosomal storage in Fig4(-/-) culture cells and ex vivo DRGs. Furthermore, we found that the suppressed Ca(2+) efflux in Fig4(-/-) culture cells and Fig4(-/-) mouse brains profoundly downregulated the expression/activity of dynamin-1, a GTPase known to scissor organelle membranes during fission. This downregulation made dynamin-1 unavailable for lysosomal fission. Together, our study revealed a novel mechanism explaining abnormal lysosomal storage in FIG4 deficiency. Synthetic ligands of the TRPML1 may become a potential therapy against diseases with FIG4 deficiency.

  18. Alterations of growth plate and abnormal insulin-like growth factor I metabolism in growth-retarded hypokalemic rats: effect of growth hormone treatment.

    PubMed

    Gil-Peña, Helena; Garcia-Lopez, Enrique; Alvarez-Garcia, Oscar; Loredo, Vanessa; Carbajo-Perez, Eduardo; Ordoñez, Flor A; Rodriguez-Suarez, Julian; Santos, Fernando

    2009-09-01

    Hypokalemic tubular disorders may lead to growth retardation which is resistant to growth hormone (GH) treatment. The mechanism of these alterations is unknown. Weaning female rats were grouped (n = 10) in control, potassium-depleted (KD), KD treated with intraperitoneal GH at 3.3 mg x kg(-1) x day(-1) during the last week (KDGH), and control pair-fed with KD (CPF). After 2 wk, KD rats were growth retarded compared with CPF rats, the osseous front advance (+/-SD) being 67.07 +/- 10.44 and 81.56 +/- 12.70 microm/day, respectively. GH treatment did not accelerate growth rate. The tibial growth plate of KD rats had marked morphological alterations: lower heights of growth cartilage (228.26 +/- 23.58 microm), hypertrophic zone (123.68 +/- 13.49 microm), and terminal chondrocytes (20.8 +/- 2.39 microm) than normokalemic CPF (264.21 +/- 21.77, 153.18 +/- 15.80, and 24.21 +/- 5.86 microm). GH administration normalized these changes except for the distal chondrocyte height. Quantitative PCR of insulin-like growth factor I (IGF-I), IGF-I receptor, and GH receptor genes in KD growth plates showed downregulation of IGF-I and upregulation of IGF-I receptor mRNAs, without changes in their distribution as analyzed by immunohistochemistry and in situ hybridization. GH did not further modify IGF-I mRNA expression. KD rats had normal hepatic IGF-I mRNA levels and low serum IGF-I values. GH increased liver IGF-I mRNA, but circulating IGF-I levels remained reduced. This study discloses the structural and molecular alterations induced by potassium depletion on the growth plate and shows that the lack of response to GH administration is associated with persistence of the disturbed process of chondrocyte hypertrophy and depressed mRNA expression of local IGF-I in the growth plate.

  19. Egestion of asbestos fibers in Tetrahymena results in early morphological abnormalities. A step in the induction of heterogeneous cell lines?

    PubMed

    Hjelm, K K

    1989-01-01

    In Tetrahymena populations exposed to crocidolite asbestos fibers, many cells develop morphological abnormalities within 1-2 hours. The abnormalities are mainly large or small protrusions or indentations, or flattened parts of the cell surface and most often located in the posterior part of the cell. They are formed repeatedly in all cells but are also continuously repaired so that the fraction of cells affected represents an equilibrium between these two processes. Their formation is connected with egestion of the large bundles of fibers formed by phagocytosis. Such effects of egestion of fibers do not seem to have been reported previously. Egestion of a bundle of fibers is much slower than for other types of undigestible residues. In contrast to normal exocytosis occurring invariably at the cytoproct, egestion of asbestos often occurs in the posterior part of the cell outside the cytoproct. To my knowledge this is the first reported case of either very slow or extra-cytoproctal egestion in Tetrahymena. Cells with large abnormalities have a greater tendency to develop into "early heterogeneous" cells than the average abnormal cell. Some of these give rise to hereditarily stable heterogeneous cell lines of Tetrahymena. The morphological abnormalities are probably caused by mechanical action of the crocidolite fibers resulting in local damage of the cytoskeletal elements responsible for normal cell shape. The heterogenous cell lines may arise when cellular structures carrying non-genic cytotactically inherited information are modified. The relevance of these ideas to the induction of cancer by asbestos is briefly discussed.

  20. Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum.

    PubMed

    Lin, Chi-Ying; Louis, Elan D; Faust, Phyllis L; Koeppen, Arnulf H; Vonsattel, Jean-Paul G; Kuo, Sheng-Han

    2014-12-01

    Structural changes in Purkinje cells have been identified in the essential tremor cerebellum, although the mechanisms that underlie these changes remain poorly understood. Climbing fibres provide one of the major excitatory inputs to Purkinje cells, and climbing fibre-Purkinje cell connections are essential for normal cerebellar-mediated motor control. The distribution of climbing fibre-Purkinje cell synapses on Purkinje cell dendrites is dynamically regulated and may be altered in disease states. The aim of the present study was to examine the density and distribution of climbing fibre-Purkinje cell synapses using post-mortem cerebellar tissue of essential tremor cases and controls. Using vesicular glutamate transporter type 2 immunohistochemistry, we labelled climbing fibre-Purkinje cell synapses of 12 essential tremor cases and 13 age-matched controls from the New York Brain Bank. Normally, climbing fibres form synapses mainly on the thick, proximal Purkinje cell dendrites in the inner portion of the molecular layer, whereas parallel fibres form synapses on the thin, distal Purkinje cell spiny branchlets. We observed that, compared with controls, essential tremor cases had decreased climbing fibre-Purkinje cell synaptic density, more climbing fibres extending to the outer portion of the molecular layer, and more climbing fibre-Purkinje cell synapses on the thin Purkinje cell spiny branchlets. Interestingly, in essential tremor, the increased distribution of climbing fibre-Purkinje cell synapses on the thin Purkinje cell branchlets was inversely associated with clinical tremor severity, indicating a close relationship between the altered distribution of climbing fibre-Purkinje cell connections and tremor. These findings suggest that abnormal climbing fibre-Purkinje cell connections could be of importance in the pathogenesis of essential tremor.

  1. Telomere length in the two extremes of abnormal fetal growth and the programming effect of maternal arterial hypertension.

    PubMed

    Tellechea, Mariana; Gianotti, Tomas Fernandéz; Alvariñas, Jorge; González, Claudio D; Sookoian, Silvia; Pirola, Carlos J

    2015-01-19

    We tested the hypothesis that leukocyte telomere length (LTL) is associated with birth weight in both extremes of abnormal fetal growth: small (SGA) and large for gestational age newborns (LGA). Clinical and laboratory variables of the mothers and the neonates were explored; 45 newborns with appropriate weight for gestational age (AGA), 12 SGA and 12 LGA were included. Whether the differences might be explained by variation in OBFC1 (rs9419958) and CTC1 (rs3027234) genes associated with LTL was determined. A significant association between birth weight and LTL was observed; LTL was significantly shorter in LGA newborns (1.01 ± 0.12) compared with SGA (1.73 ± 0.19) p < 0.005, mean ± SE. Maternal (Spearman R = -0.6, p = 0.03) and neonatal LTL (R = -0.25, p = 0.03) were significantly and inversely correlated with maternal history of arterial hypertension in previous gestations. Neonatal LTL was not significantly associated with either rs9419950 or rs3027234, suggesting that the association between neonatal LTL and birth weight is not influenced by genetic variation in genes that modify the interindividual LTL. In conclusion, telomere biology seems to be modulated by abnormal fetal growth; modifications in telomere length might be programmed by an adverse environment in utero.

  2. Stochastic Gompertz model of tumour cell growth.

    PubMed

    Lo, C F

    2007-09-21

    In this communication, based upon the deterministic Gompertz law of cell growth, a stochastic model in tumour growth is proposed. This model takes account of both cell fission and mortality too. The corresponding density function of the size of the tumour cells obeys a functional Fokker--Planck equation which can be solved analytically. It is found that the density function exhibits an interesting "multi-peak" structure generated by cell fission as time evolves. Within this framework the action of therapy is also examined by simply incorporating a therapy term into the deterministic cell growth term.

  3. Cerebellar microfolia and other abnormalities of neuronal growth, migration, and lamination in the Pit1dw-J homozygote mutant mouse

    NASA Technical Reports Server (NTRS)

    Sekiguchi, M.; Abe, H.; Moriya, M.; Tanaka, O.; Nowakowski, R. S.

    1998-01-01

    The Snell dwarf mouse (Pit1dw-J homozygote) has a mutation in the Pit1 gene that prevents the normal formation of the anterior pituitary. In neonates and adults there is almost complete absence of growth hormone (GH), prolactin (PRL), thyroxin (T4), and thyroid-stimulating hormone (TSH). Since these hormones have been suggested to play a role in normal development of the central nervous system (CNS), we have investigated the effects of the Pit1dw-J mutation on the cerebellum and hippocampal formation. In the cerebellum, there were abnormalities of both foliation and lamination. The major foliation anomalies were 1) changes in the relative size of specific folia and also the proportional sizes of the anterior vs posterior cerebellum; and 2) the presence of between one and three microfolia per half cerebellum. The microfolia were all in the medial portion of the hemisphere in the caudal part of the cerebellum. Each microfolium was just rostral to a normal fissure and interposed between the fissure and a normal gyrus. Lamination abnormalities included an increase in the number of single ectopic granule cells in the molecular layer in both cerebellar vermis (86%) and hemisphere (40%) in comparison with the wild-type mouse. In the hippocampus of the Pit1dw-J homozygote mouse, the number of pyramidal cells was decreased, although the width of the pyramidal cell layer throughout areas CA1-CA3 appeared to be normal, but less densely populated than in the wild-type mouse. Moreover, the number of granule cells that form the granule cell layer was decreased from the wild-type mouse and some ectopic granule cells (occurring both as single cells and as small clusters) were observed in the innermost portion of the molecular layer. The abnormalities observed in the Pit1dw-J homozygote mouse seem to be caused by both direct and indirect effects of the deficiency of TSH (or T4), PRL, or GH rather than by a direct effect of the deletion of Pit1.

  4. Membrane trafficking and mitochondrial abnormalities precede subunit c deposition in a cerebellar cell model of juvenile neuronal ceroid lipofuscinosis

    PubMed Central

    Fossale, Elisa; Wolf, Pavlina; Espinola, Janice A; Lubicz-Nawrocka, Tanya; Teed, Allison M; Gao, Hanlin; Rigamonti, Dorotea; Cattaneo, Elena; MacDonald, Marcy E; Cotman, Susan L

    2004-01-01

    Background JNCL is a recessively inherited, childhood-onset neurodegenerative disease most-commonly caused by a ~1 kb CLN3 mutation. The resulting loss of battenin activity leads to deposition of mitochondrial ATP synthase, subunit c and a specific loss of CNS neurons. We previously generated Cln3Δex7/8 knock-in mice, which replicate the common JNCL mutation, express mutant battenin and display JNCL-like pathology. Results To elucidate the consequences of the common JNCL mutation in neuronal cells, we used P4 knock-in mouse cerebella to establish conditionally immortalized CbCln3 wild-type, heterozygous, and homozygous neuronal precursor cell lines, which can be differentiated into MAP-2 and NeuN-positive, neuron-like cells. Homozygous CbCln3Δex7/8 precursor cells express low levels of mutant battenin and, when aged at confluency, accumulate ATPase subunit c. Recessive phenotypes are also observed at sub-confluent growth; cathepsin D transport and processing are altered, although enzyme activity is not significantly affected, lysosomal size and distribution are altered, and endocytosis is reduced. In addition, mitochondria are abnormally elongated, cellular ATP levels are decreased, and survival following oxidative stress is reduced. Conclusions These findings reveal that battenin is required for intracellular membrane trafficking and mitochondrial function. Moreover, these deficiencies are likely to be early events in the JNCL disease process and may particularly impact neuronal survival. PMID:15588329

  5. The role of the cilium in normal and abnormal cell cycles: emphasis on renal cystic pathologies

    PubMed Central

    Pan, Junmin; Seeger-Nukpezah, Tamina; Golemis, Erica A.

    2013-01-01

    The primary cilium protrudes from the cell surface and acts as a sensor for chemical and mechanical growth cues, with receptors for a number of growth factors (PDGFα, Hedgehog, Wnt, Notch) concentrated within the ciliary membrane. In normal tissues, the cilium assembles after cells exit mitosis and is resorbed as part of cell cycle re-entry. Although regulation of the cilium by cell cycle transitions has been appreciated for over 100 years, only recently have data emerged to indicate the cilium also exerts influence on the cell cycle. The resorption/protrusion cycle, regulated by proteins including Aurora-A, VHL, and GSK-3β, influences cell responsiveness to growth cues involving cilia-linked receptors; further, resorption liberates the ciliary basal body to differentiate into the centrosome, which performs discrete functions in S-, G2-, and M-phase. Besides these roles, the cilium provides a positional cue that regulates polarity of cell division, and thus directs cells towards fates of differentiation versus proliferation. In this review, we summarize the specific mechanisms mediating the cilia-cell cycle dialog. We then emphasize the examples of polycystic kidney disease (PKD), nephronopthisis (NPHP), and VHL-linked renal cysts as cases in which defects of ciliary function influence disease pathology, and may also condition response to treatment. PMID:22782110

  6. Growth retardation, intellectual disability, facial anomalies, cataract, thoracic hypoplasia, and skeletal abnormalities: a novel phenotype.

    PubMed

    Shah, Hitesh; Bens, Susanne; Caliebe, Almuth; Graham, John M; Girisha, Katta Mohan

    2012-11-01

    We report on a 14-year-old girl with growth deficiency, microcephaly, intellectual disability, distinctive dysmorphic features (bulbous nose with wide nasal base, hypotelorism, deeply set eyes, protruding cupped ears, and thick lower lip), cataract, pigmentary retinopathy, hypoplastic thorax, kyphoscoliosis, and unusual skeletal changes but without chromosomal imbalances detected by array-CGH who probably represents a novel phenotype.

  7. Abnormal gut integrity is associated with reduced linear growth in rural Malawian children

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The aim of the present study was to investigate the relation of environmental enteropathy, as measured by the dual sugar absorption test, to linear growth faltering in 2- to 5-year-old Malawian children. Dietary quality, food insecurity, anthropometry, and site-specific sugar testing were measured i...

  8. The Impact of Abnormal Glucose Tolerance and Obesity on Fetal Growth

    PubMed Central

    Hill, David J.; Evers, Susan; Van Aarsen, Kristine; Yama, Brie; Yuan, Su; Campbell, M. Karen

    2015-01-01

    Objective. Factors linked with insulin resistance were examined for their association with large-for-gestational-age (LGA) infant birth weight and gestational diabetes. Study Design. Data came from a longitudinal cohort study of 2,305 subjects without overt diabetes, analyzed using multinomial logistic and linear regression. Results. High maternal BMI (OR = 1.53 (1.11, 2.12)), height (1.98 (1.62, 2.42)), antidepressant use (1.71 (1.20, 2.44)), pregnancy weight-gain exceeding 40 pounds (1.79 (1.25, 2.57)), and high blood sugar (2.68, (1.53, 5.27)) were all positively associated with LGA birth. Strikingly, the difference in risk from diagnosed and treated gestational diabetes compared to women with a single abnormal glucose tolerance test (but no diagnosis of gestational diabetes) was significant (OR = 0.65, p = 0.12 versus OR = 2.84, p < 0.01). When weight/length ratio was used instead, different factors were found to be significant. BMI and pregnancy weight-gain were found to influence the development of gestational diabetes, through an additive interaction. Conclusions. High prepregnancy BM, height, antidepressant use, pregnancy weight-gain exceeding 40 pounds, and high blood sugar were associated with LGA birth, but not necessarily infant weight/length ratio. An additive interaction between BMI and pregnancy weight-gain influenced gestational diabetes development. PMID:25977929

  9. Peri-Implantation Hormonal Milieu: Elucidating Mechanisms of Abnormal Placentation and Fetal Growth1

    PubMed Central

    Mainigi, Monica A.; Olalere, Devvora; Burd, Irina; Sapienza, Carmen; Bartolomei, Marisa; Coutifaris, Christos

    2013-01-01

    ABSTRACT Assisted reproductive technologies (ART) have been associated with several adverse perinatal outcomes involving placentation and fetal growth. It is critical to examine each intervention individually in order to assess its relationship to the described adverse perinatal outcomes. One intervention ubiquitously used in ART is superovulation with gonadotropins. Superovulation results in significant changes in the hormonal milieu, which persist during the peri-implantation and early placentation periods. Epidemiologic evidence suggests that the treatment-induced peri-implantation maternal environment plays a critical role in perinatal outcomes. In this study, using the mouse model, we have isolated the exposure to the peri-implantation period, and we examine the effect of superovulation on placentation and fetal growth. We report that the nonphysiologic peri-implantation maternal hormonal environment resulting from gonadotropin stimulation appears to have a direct effect on fetal growth, trophoblast differentiation, and gene expression. This appears to be mediated, at least in part, through trophoblast expansion and invasion. Although the specific molecular and cellular mechanism(s) leading to these observations remain to be elucidated, identifying this modifiable risk factor will not only allow us to improve perinatal outcomes with ART, but help us understand the pathophysiology contributing to these outcomes. PMID:24352558

  10. Review: Placental perturbations induce the developmental abnormalities often observed in bovine somatic cell nuclear transfer.

    PubMed

    Chavatte-Palmer, P; Camous, S; Jammes, H; Le Cleac'h, N; Guillomot, M; Lee, R S F

    2012-02-01

    Since the first success in cloning sheep, the production of viable animals by somatic cell nuclear transfer (SCNT) has developed significantly. Cattle are by far the most successfully cloned species but, despite this, the technique is still associated with a high incidence of pregnancy failure and accompanying placental and fetal pathologies. Pre- and early post-implantation losses can affect up to 70% of the pregnancies. In the surviving pregnancies, placentomegaly and fetal overgrowth are commonly observed, but the incidence varies widely, depending on the genotype of the nuclear donor cell and differences in SCNT procedures. In all cases, the placenta is central to the onset of the pathologies. Although cellular organisation of the SCNT placenta appears normal, placental vascularisation is modified and fetal-to-maternal tissue ratios are slightly increased in the SCNT placentomes. In terms of functionality, steroidogenesis is perturbed and abnormal estrogen production and metabolism probably play an important part in the increased gestation length and lack of preparation for parturition observed in SCNT recipients. Maternal plasma concentrations of pregnancy-associated glycoproteins are increased, mostly due to a reduction in turnover rate rather than increased placental production. Placental glucose transport and fructose synthesis appear to be modified and hyperfructosemia has been observed in neonatal SCNT calves. Gene expression analyses of the bovine SCNT placenta show that multiple pathways and functions are affected. Abnormal epigenetic re-programming appears to be a key component of the observed pathologies, as shown by studies on the expression of imprinted genes in SCNT placenta.

  11. Assessment of nuclear abnormalities in exfoliated cells from the oral epithelium of mobile phone users.

    PubMed

    Souza, Leonardo da Cunha Menezes; Cerqueira, Eneida de Moraes Marcílio; Meireles, José Roberto Cardoso

    2014-06-01

    Transmission and reception of mobile telephony signals take place through electromagnetic wave radiation, or electromagnetic radiofrequency fields, between the mobile terminal and the radio base station. Based on reports in the literature on adverse effects from exposure to this type of radiation, the objective of this study was to evaluate the genotoxic and cytotoxic potential of such exposure, by means of the micronucleus test on exfoliated cells from the oral epithelium. The sample included 45 individuals distributed in 3 groups according to the amount of time in hours per week (t) spent using mobile phones: group I, t > 5 h; group II, t > 1 h and ≤ 5 h; and group III, t ≤ 1 h. Cells from the oral mucosa were analyzed to assess the numbers of micronuclei, broken egg structures and degenerative nuclear abnormalities indicative of apoptosis (condensed chromatin, karyorrhexis and pyknosis) or necrosis (karyolysis in addition to these changes). The occurrences of micronuclei and degenerative nuclear abnormalities did not differ between the groups, but the number of broken egg (structures that may be associated with gene amplification) was significantly greater in the individuals in group I (p < 0.05).

  12. Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer.

    PubMed

    Sterner-Kock, Anja; Thorey, Irmgard S; Koli, Katri; Wempe, Frank; Otte, Jürgen; Bangsow, Thorsten; Kuhlmeier, Katharina; Kirchner, Thomas; Jin, Shenchu; Keski-Oja, Jorma; von Melchner, Harald

    2002-09-01

    Transforming growth factor-betas (TGF-betas) are multifunctional growth factors that are secreted as inactive (latent) precursors in large protein complexes. These complexes include the latency-associated propeptide (LAP) and a latent transforming growth factor-beta binding protein (LTBP). Four isoforms of LTBPs (LTBP-1-LTBP-4) have been cloned and are believed to be structural components of connective tissue microfibrils and local regulators of TGF-beta tissue deposition and signaling. By using a gene trap strategy that selects for integrations into genes induced transiently during early mouse development, we have disrupted the mouse homolog of the human LTBP-4 gene. Mice homozygous for the disrupted allele develop severe pulmonary emphysema, cardiomyopathy, and colorectal cancer. These highly tissue-specific abnormalities are associated with profound defects in the elastic fiber structure and with a reduced deposition of TGF-beta in the extracellular space. As a consequence, epithelial cells have reduced levels of phosphorylated Smad2 proteins, overexpress c-myc, and undergo uncontrolled proliferation. This phenotype supports the predicted dual role of LTBP-4 as a structural component of the extracellular matrix and as a local regulator of TGF-beta tissue deposition and signaling.

  13. Abnormal neutrophil chemotactic activity in children with congenital insensitivity to pain with anhidrosis (CIPA): the role of nerve growth factor.

    PubMed

    Beigelman, Avraham; Levy, Jacov; Hadad, Nurit; Pinsk, Vered; Haim, Alon; Fruchtman, Yariv; Levy, Rachel

    2009-03-01

    A 1926-ins-T mutation in the TrkA gene encoding the tyrosine kinase receptor for nerve growth factor (NGF) was previously documented in patients with congenital insensitivity to pain with anhidrosis (CIPA). These patients suffer from skin lacerations which often evolve into deep tissue infections. Abnormality in neutrophil functions may explain this high rate of severe infections. In this study we show that chemotaxis was significantly (P<0.001) suppressed in patients' neutrophils, compared to healthy controls. Although NGF alone did not exert a chemotactic effect, its presence enhanced both migration toward fMLP and phosphorylation of MAP kinases (ERK and JNK) in neutrophils from healthy controls, but not in neutrophils from CIPA patients. The significantly impaired chemotactic activity of neutrophils from a CIPA patient, which has been attributed to the molecular defect in the TrkA receptor, may contribute to the high rate of infection.

  14. [Ichthyosis vulgaris, growth retardation, hair dysplasia, tooth abnormalities, immunologic deficiencies, psychomotor retardation and resorption disorders. Case report of 2 siblings].

    PubMed

    Braun-Falco, O; Ring, J; Butenandt, O; Selzle, D; Landthaler, M

    1981-02-01

    Two siblings (4 and 10 years old) with ichthyosis vulgaris, growth and mental retardation, hair dysplasia, teeth abnormalities, recurrent infections and malabsorption are presented. The elder sister of the children as well as the rest of the family are unremarkable. The complex of symptoms does not fit into one of the known Ichthyosis syndromes. Microscopically the dystrophic hairs show changes in diameters, nodules, lack of the medulla, rough cuticle and splits vertical to the axis, sometimes resembling trichorrhexis nodosa. In the scanning electron-microscope there is a clear difference to Netherton's syndrome. The plasma concentrations of the vitamines A, B12 as well as of beta-carotines are low in spite of normal nutrition. During parenteral therapy with vitamin A and B12 symptoms ameliorate slightly.

  15. Itraconazole suppresses the growth of glioblastoma through induction of autophagy: involvement of abnormal cholesterol trafficking.

    PubMed

    Liu, Rui; Li, Jingyi; Zhang, Tao; Zou, Linzhi; Chen, Yi; Wang, Kui; Lei, Yunlong; Yuan, Kefei; Li, Yi; Lan, Jiang; Cheng, Lin; Xie, Na; Xiang, Rong; Nice, Edouard C; Huang, Canhua; Wei, Yuquan

    2014-07-01

    Glioblastoma is one of the most aggressive human cancers with poor prognosis, and therefore a critical need exists for novel therapeutic strategies for management of glioblastoma patients. Itraconazole, a traditional antifungal drug, has been identified as a novel potential anticancer agent due to its inhibitory effects on cell proliferation and tumor angiogenesis; however, the molecular mechanisms involved are still unclear. Here, we show that itraconazole inhibits the proliferation of glioblastoma cells both in vitro and in vivo. Notably, we demonstrate that treatment with itraconazole induces autophagic progression in glioblastoma cells, while blockage of autophagy markedly reverses the antiproliferative activities of itraconazole, suggesting an antitumor effect of autophagy in response to itraconazole treatment. Functional studies revealed that itraconazole retarded the trafficking of cholesterol from late endosomes and lysosomes to the plasma membrane by reducing the levels of SCP2, resulting in repression of AKT1-MTOR signaling, induction of autophagy, and finally inhibition of cell proliferation. Together, our studies provide new insights into the molecular mechanisms regarding the antitumor activities of itraconazole, and may further assist both the pharmacological investigation and rational use of itraconazole in potential clinical applications.

  16. Congenital Abnormalities

    MedlinePlus

    ... Listen Español Text Size Email Print Share Congenital Abnormalities Page Content Article Body About 3% to 4% ... of congenital abnormalities earlier. 5 Categories of Congenital Abnormalities Chromosome Abnormalities Chromosomes are structures that carry genetic ...

  17. Impact of genetic abnormalities on survival after allogeneic hematopoietic stem cell transplantation in multiple myeloma.

    PubMed

    Schilling, G; Hansen, T; Shimoni, A; Zabelina, T; Pérez-Simón, J-A; Simon-Perez, J-A; Gutierrez, N C; Bethge, W; Liebisch, P; Schwerdtfeger, R; Bornhäuser, M; Otterstetter, S; Penas, E M M; Dierlamm, J; Ayuk, F; Atanackovic, D; Bacher, U; Bokemeyer, C; Zander, A; San Miguel, J; Miguel, J S; Nagler, A; Kröger, N

    2008-06-01

    We analyzed the prognostic impact of the most frequent genetic abnormalities detected by fluorescence in situ hybridization in 101 patients with multiple myeloma, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after melphalan/fludarabine-based reduced conditioning. The incidences of abnormalities in the present analysis were as follows: del(13q14) (61%), t(11;14)(q13;q32) (14%), t(4;14)(p16.3;q32) (19%), MYC-gain gains (8q24) (21%), del(17p13) (16%) and t(14;16)(q32;q23) (5%). None of the patients had t(6;14)(p25;q32). The overall complete remission (CR) rate was 50% with no differences between the genetic abnormalities except for patients with del(17p13) who achieved less CR (7 vs 56%; P=0.001). Univariate analysis revealed a higher relapse rate in patients aged >50 years (P=0.002), patients with del(13q14) (P=0.006) and patients with del(17p13) (P=0.003). In multivariate analyses, only del(13q14) (HR: 2.34, P=0.03) and del(17p13) (HR: 2.24; P=0.04) significantly influenced the incidence of relapse, whereas for event-free survival, only age (HR 2.8; P=0.01) and del(17p13) (HR: 2.05; P=0.03) retained their negative prognostic value. These data show that del(17p13) is a negative prognostic factor for achieving CR as well as for event-free survival after HSCT. Translocation t(4;14) might be overcome by allogeneic HSCT, which will have implication for risk-adapted strategies.

  18. Rust fungi causing galls, witches' brooms, and other abnormal plant growths in northwestern Argentina.

    PubMed

    Hernández, José R; Hennen, Joe F

    2003-01-01

    Conspicuous galls and witches' brooms frequently are symptoms of rust infections on plant hosts in the ecologically diverse northwestern region of Argentina. These symptoms are caused by systemic or locally systemic spermogonial-aecial infections, although uredinial and telial infections also might be involved. Sixteen species of rust fungi are treated in this paper, most of which cause a plant response that results in enlarged growth. Ypsilospora tucumanensis J.R. Hern. & J.F. Hennen on Inga edulis is described as a species new to science. Puccinia cordiae Arthur is cited as a new record for Argentina. These rusts also are included: Chaconia ingae, Gerwasia imperialis, Kuehneola loeseneriana, Prospodium appendiculatum, Prospodium elegans, Prospodium perornatum, Puccinia bougainvilleae, Puccinia pampeana, Ravenelia argentinica, Ravenelia hieronymi, Ravenelia papillosa, Ravenelia spegazziniana, Uromyces cestri and Uropyxis rickiana. For some of the scientific names, lectotype specimens have been designated.

  19. Growth abnormalities in the population exposed in utero and early postnatally to polychlorinated biphenyls and dibenzofurans

    SciTech Connect

    Yueliang L. Guo; Chen-Chin Hsu; Lambert, G.H.

    1995-09-01

    This article reviews the findings in children exposed to various levels of polychlorinated biphenyls (PCBs) and related compounds in utero and early postnatally. Yu-Cheng ({open_quotes}oil-disease{close_quotes}) mothers were Taiwanese women exposed to PCBs and their heat-degradation products form the ingestion of contaminated rice oil in 1979. Children of these mothers were born growth retarded, with dysmorphic physical findings, and delayed cognitive development compared with unexposed children. In this article, findings in Yu-Cheng children born between 1978 and 1985 are summarized and compared with two other well-documented cohorts of children prenatally exposed to different levels of PCBs. Results of the investigation in Yu-Cheng children will provide important information about the toxicities, health effects, and mechanisms of PCB/PCDF exposure and demonstrate that the developing human is more sensitive than the adult to the toxic effects of these chemicals. 53 refs., 2 tabs.

  20. Abnormal intracellular calcium homeostasis associated with vulnerability in the nerve cells from heroin-dependent rat.

    PubMed

    Liu, Xiaoshan; Wang, Guangyong; Pu, Hongwei; Jing, Hualan

    2014-07-14

    The cellular mechanisms by which opiate addiction develops with repetitive use remain largely unresolved. Intercellular calcium homeostasis is one of the most critical elements to determine neuroadaptive changes and neuronal fate. Heroin, one of the most addictive opiates, may induce neurotoxicity potentially inducing brain impairment, especially for those chronic users who get an overdose. Here we examined changes in intracellular calcium concentration ([Ca2+]i) after repeated exposure to heroin using cultured cerebral cortical neurons. Dynamic changes in [Ca2+]i indicated by fluo-3-AM were monitored using confocal laser scan microscopy, followed by cytotoxicity assessments. It showed that the cells dissociated from heroin-dependent rats had a smaller depolarization-induced [Ca2+]i responses, and a higher elevation in [Ca2+]i when challenged with a high concentration of heroin (500 μM). The restoration ability to remove calcium after washout of these stimulants was impaired. Calcium channel blocker verapamil inhibited the heroin-induced [Ca2+]i elevations as well as the heroin-induced cell damage. The relative [Ca2+]i of the nerve cells closely correlated with the number of damaged cells induced by heroin. These results demonstrate that nerve cells from heroin-dependent rats manifest abnormal [Ca2+]i homeostasis, as well as vulnerability to heroin overdose, suggesting involvement of [Ca2+]i regulation mechanisms in heroin addiction and neurotoxicity.

  1. Galactosylceramidase deficiency causes sperm abnormalities in the mouse model of globoid cell leukodystrophy

    SciTech Connect

    Luddi, A.; Strazza, M.; Carbone, M.; Moretti, E.; Costantino-Ceccarini, E. . E-mail: costantino@unisi.it

    2005-03-10

    The classical recessive mouse mutant, 'the twitcher,' is one of the several animal models of the human globoid cell leukodystrophy (Krabbe disease) caused by a deficiency in the gene encoding the lysosomal enzyme galactosylceramidase (GALC). The failure to hydrolyze galactosylceramide (gal-cer) and galactosylsphingosine (psychosine) leads to degeneration of oligodendrocytes and severe demyelination. Substrate for GALC is also the galactosyl-alkyl-acyl-glycerol (GalAAG), precursor of the seminolipid, the most abundant glycolipid in spermatozoa of mammals. In this paper, we report the pathobiology of the testis and sperm in the twitcher mouse and demonstrate the importance of GALC for normal sperm maturation and function. The GALC deficit results in accumulation of GalAAG in the testis of the twitcher mouse. Morphological studies revealed that affected spermatozoa have abnormally swollen acrosomes and angulation of the flagellum mainly at midpiece-principal piece junction. Multiple folding of the principal piece was also observed. Electron microscopy analysis showed that in the twitcher sperm, acrosomal membrane is redundant, detached from the nucleus and folded over. Disorganization and abnormal arrangements of the axoneme components were also detected. These results provide in vivo evidence that GALC plays a critical role in spermiogenesis.

  2. Craniofacial bone abnormalities and malocclusion in individuals with sickle cell anemia: a critical review of the literature

    PubMed Central

    Costa, Cyrene Piazera Silva; de Carvalho, Halinna Larissa Cruz Correia; Thomaz, Erika Bárbara Abreu Fonseca; Sousa, Soraia de Fátima Carvalho

    2012-01-01

    This study aims to critically review the literature in respect to craniofacial bone abnormalities and malocclusion in sickle cell anemia individuals. The Bireme and Pubmed electronic databases were searched using the following keywords: malocclusion, maxillofacial abnormalities, and Angle Class I, Class II and lass III malocclusions combined with sickle cell anemia. The search was limited to publications in English, Spanish or Portuguese with review articles and clinical cases being excluded from this study. Ten scientific publications were identified, of which three were not included as they were review articles. There was a consistent observation of orthodontic and orthopedic variations associated with sickle cell anemia, especially maxillary protrusions. However, convenience sampling, sometimes without any control group, and the lack of estimates of association and hypotheses testing undermined the possibility of causal inferences. It was concluded that despite the high frequency of craniofacial bone abnormalities and malocclusion among patients with sickle cell anemia, there is insufficient scientific proof that this disease causes malocclusion PMID:23049386

  3. Cancer cells. 3: Growth factors and transformation

    SciTech Connect

    Feramisco, J.; Ozanne, B.; Stiles, C.

    1985-01-01

    This book contains over 50 papers. Some of the titles are: Structure of Human Epidermal Growth Factor and Expression of Normal and Variant mRNAs in Epdermoid Carcinoma Cells; Tyrosine Kinase Activity Associated with the v-erb-B Gene Product; Cloning and Characterization of Human Epidermal Growth Factor-Receptor Gene Sequences in A431 Carcinoma Cells; Anti-oncogenes and the Suppression of Tumor Formation; and Normal Human sis/PDGF-2 Gene Expression Induces Cellular Transformation.

  4. Cloned Hemoglobin Genes Enhance Growth Of Cells

    NASA Technical Reports Server (NTRS)

    Khosla, Chaitan; Bailey, James E.

    1991-01-01

    Experiments show that portable deoxyribonucleic acid (DNA) sequences incorporated into host cells make them produce hemoglobins - oxygen-binding proteins essential to function of red blood cells. Method useful in several biotechnological applications. One, enhancement of growth of cells at higher densities. Another, production of hemoglobin to enhance supplies of oxygen in cells, for use in chemical reactions requiring oxygen, as additive to serum to increase transport of oxygen, and for binding and separating oxygen from mixtures of gases.

  5. [Distribution of abnormal cell clone with deletion of chromosome 20q in marrow cell lineages and apoptosis cells in myelodysplastic syndrome].

    PubMed

    Qin, Ling; Wang, Chun; Qin, You-Wen; Xie, Kuang-Cheng; Yan, Shi-Ke; Gao, Yan-Rong; Wang, Xiao-Rui; Zhao, Chu-Xian

    2008-06-01

    This study was aimed to investigate the distribution of abnormal clone in marrow cell lineages and apoptosis cells in myelodysplastic syndrome (MDS) with deletion of chromosome 20q. Monoclonal antibodies recognizing myeloid precursors (CD15), erythroid precursors (GPA), T cells (CD3(+)CD56(-)CD16(-)), B cells (CD19), NK cells (CD3(-)CD56(+)CD16(+)) were used to sort bone marrow cells in a MDS patient with del (20q) by fluorescence activated cell sorting (FACS). Annexin V-FITC and PI were used to sort bone marrow Annexin V(+)PI(-) and Annexin V(-)PI(-) cells by FACS. The sorted positive cells were detected by interphase dual-color fluorescence in situ hybridization (D-FISH) using a LSI D20S108 probe (Spectrum Orange) and a Telvysion TM 20p probe (Spectrum Green). FACS and FISH analysis were also performed on the samples from 4 cases with normal karyotype. The results showed that the proportions of MDS clone in the myeloid and erythroid precursors were 70.50% and 93.33% respectively, in the RAEB-1 patient with del (20q) and were obviously higher than that in control group (5.39% and 6.17%). The proportions of abnormal clone in T, B and NK cells were 3.23%, 4.32% and 5.77% respectively and were less than that in control group (5.76%, 4.85%, 6.36%). The percentage of apoptotic cells in the bone marrow nucleated cells was 16.09%. The proportions of MDS clone in Annexin V(+)PI(-) and Annexin V(-)PI(-) cells were 32.48% and 70.11%, respectively. It is concluded that most myeloid and erythroid precursors are originated from the abnormal clone in MDS with del (20q). A little part of apoptotic cells are derived from the abnormal clone.

  6. Stromal influences on breast cancer cell growth.

    PubMed Central

    van Roozendaal, C. E.; van Ooijen, B.; Klijn, J. G.; Claassen, C.; Eggermont, A. M.; Henzen-Logmans, S. C.; Foekens, J. A.

    1992-01-01

    Paracrine influences from fibroblasts derived from different sources of breast tissue on epithelial breast cancer cell growth in vitro were investigated. Medium conditioned (CM) by fibroblasts derived from tumours, adjacent normal breast tissue, and normal breast tissue obtained from reduction mammoplasty or from skin tissue significantly stimulated the growth of the steroid-receptor positive cell lines MCF-7 and ZR 75.1. The proliferation index (PI) on MCF-7 cells with CM from fibroblasts derived from breast tumour tissue was significantly higher than that obtained with fibroblasts derived from adjacent normal breast tissue (2p less than 0.05, n = 8). The PI obtained with CM from normal fibroblast cultures from reduction mammoplasty tissue, like normal tissue adjacent to the tumour, fell in the lower range of values. Skin fibroblast, like tumour tissue derived fibroblast, CM caused a high range PI. MDA-MB-231 and Evsa-T, two steroid-receptor negative cell lines, showed only a minor growth stimulatory responses with some of the fibroblast CM's. Evsa-T was occasionally inhibited by CM's. In conclusion, stromal factors play a role in the growth regulation of human breast cancer cells. The effects on cancer cell growth are, however, varying depending on the source of the stroma and the characteristics of the epithelial tumour cells. PMID:1733444

  7. Autism as a sequence: from heterochronic germinal cell divisions to abnormalities of cell migration and cortical dysplasias

    PubMed Central

    Casanova, Manuel F.

    2014-01-01

    The considerable heterogeneity in the number and severity of symptoms observed in autism spectrum disorders (ASD) has been regarded as an obstacle to any future research. Some authors believe that clinical heterogeneity results from the complex interplay of the many genetic and environmental factors that themselves define a condition as multifactorial. However, it is important to note that neuropathological findings in both idiopathic and syndromic autism suggests a single pathophysiological mechanism acting during brain development: the heterochronic division of germinal cells and subsequent migrational abnormalities of daughter cells to their target fields. Multiple exogenous (e.g., viruses, drugs) and endogenous (e.g., genetic mutations) factors are known to disrupt the division of germinal cells and provide for an autism phenotype. The variety of endogenous and exogenous factors, their timing of action during brain development, and the genetic susceptibility of affected individuals (a Triple Hit hypothesis) may all account for the clinical heterogeneity of ASD. PMID:24780284

  8. Cell death associated with abnormal mitosis observed by confocal imaging in live cancer cells.

    PubMed

    Castiel, Asher; Visochek, Leonid; Mittelman, Leonid; Zilberstein, Yael; Dantzer, Francoise; Izraeli, Shai; Cohen-Armon, Malka

    2013-08-21

    Phenanthrene derivatives acting as potent PARP1 inhibitors prevented the bi-focal clustering of supernumerary centrosomes in multi-centrosomal human cancer cells in mitosis. The phenanthridine PJ-34 was the most potent molecule. Declustering of extra-centrosomes causes mitotic failure and cell death in multi-centrosomal cells. Most solid human cancers have high occurrence of extra-centrosomes. The activity of PJ-34 was documented in real-time by confocal imaging of live human breast cancer MDA-MB-231 cells transfected with vectors encoding for fluorescent γ-tubulin, which is highly abundant in the centrosomes and for fluorescent histone H2b present in the chromosomes. Aberrant chromosomes arrangements and de-clustered γ-tubulin foci representing declustered centrosomes were detected in the transfected MDA-MB-231 cells after treatment with PJ-34. Un-clustered extra-centrosomes in the two spindle poles preceded their cell death. These results linked for the first time the recently detected exclusive cytotoxic activity of PJ-34 in human cancer cells with extra-centrosomes de-clustering in mitosis, and mitotic failure leading to cell death. According to previous findings observed by confocal imaging of fixed cells, PJ-34 exclusively eradicated cancer cells with multi-centrosomes without impairing normal cells undergoing mitosis with two centrosomes and bi-focal spindles. This cytotoxic activity of PJ-34 was not shared by other potent PARP1 inhibitors, and was observed in PARP1 deficient MEF harboring extracentrosomes, suggesting its independency of PARP1 inhibition. Live confocal imaging offered a useful tool for identifying new molecules eradicating cells during mitosis.

  9. [Molecular abnormalities in lymphomas].

    PubMed

    Delsol, G

    2010-11-01

    . Gene profiling analysis shows that the expression of several genes is deregulated including PDGFRA (platelet-derived growth factor receptor) gene, encoding a receptor with tyrosine kinase activity. In angio-immunoblastic T-cell lymphomas molecular abnormalities are found in follicular helper T-cell (TFH) that express some distinctive markers such as CD10, PD-1, CXCR5 and the CXCL13 chemokine. ALK-positive anaplastic large cell lymphoma is a paradigme of T-cell lymphoma since it is associated with an X-ALK oncogenic fusion protein due to a translocation involving ALK gene at 2p23. ALK tyrosine kinase activates downstream pathways (Stat3/5b, Src kinases, PLCγ, PI3 kinase) implicated in lymphomagenesis, proliferation and protection against apoptosis. Specific ALK inhibitors are currently in clinical evaluation. Lastly several lymphomas are associated with infectious agents that play a direct (EB virus, HTLV1) or indirect role (e.g. Helicobacter pylori in MALT lymphoma) in lymphomagenesis.

  10. Insulin-like growth factor binding protein-6 transgenic mice: postnatal growth, brain development, and reproduction abnormalities.

    PubMed

    Bienvenu, Géraldine; Seurin, Danielle; Grellier, Pascale; Froment, Pascal; Baudrimont, Marielle; Monget, Philippe; Le Bouc, Yves; Babajko, Sylvie

    2004-05-01

    In biological fluids, IGFs bind to six distinct binding proteins (IGFBP-1 to -6). IGFBP-6 is of particular interest because it has been shown to inhibit proliferation in many cell types and to be synthesized in the central nervous system (CNS). It also has the strongest affinity for IGF-II among the IGFBPs. To study IGFBP-6 function in vivo, we established IGFBP-6 transgenic mice in which human IGFBP-6 (hIGFBP-6) cDNA is expressed under the control of the glial fibrillary acidic protein (GFAP) promoter. Northern and Western blot analysis revealed strong transgene expression in the CNS. With histological examination of the CNS, cerebellum size and weight proved to be reduced by about 25% and 35%, respectively, and there were smaller numbers of differentiated, GFAP-expressing astrocytes than in wild-type mice. Between birth and 1 month of age, transgenic mice had high levels of circulating hIGFBP-6 and reduced plasma IGF-I, and, as a result, body weight was significantly reduced. Reproductive physiology was also affected. Litter size was reduced by 27% when wild-type males were mated with 3-month-old transgenic females and by 66% when mated with 6-month-old transgenic females. Histological examination of ovaries of transgenic mice revealed a marked decrease in weight and in the number of corpora lutea, suggesting altered ovulation, and circulating LH levels were reduced by 50%. Our results indicate that this new model of transgenic mouse may prove to be a useful tool in elucidating the in vivo role of IGFBP-6 in the brain, especially in regard to hypothalamic control, and in reproductive physiology.

  11. Abnormal apical cell membrane in cystic fibrosis respiratory epithelium. An in vitro electrophysiologic analysis.

    PubMed Central

    Cotton, C U; Stutts, M J; Knowles, M R; Gatzy, J T; Boucher, R C

    1987-01-01

    The transepithelial chloride permeability of airway and sweat ductal epithelium has been reported to be decreased in patients with cystic fibrosis (CF). In the present study, we investigated whether the airway epithelial defect was in the cell path by characterizing the relative ion permeabilities of the apical membrane of respiratory epithelial cells from CF and normal subjects. Membrane electric potential difference (PD) and the responses to luminal Cl- replacement, isoproterenol, and amiloride were measured with intracellular microelectrodes. The PD across the apical barrier was smaller for CF (-11 mV) than normal (-29 mV) epithelia whereas the PD across the basolateral barrier was similar, (-26 and -34 mV respectively). In contrast to normal nasal epithelium, the apical membrane in CF epithelia was not Cl- permselective and was not responsive to isoproterenol. Amiloride, a selective Na+ channel blocker, induced a larger apical membrane hyperpolarization and a greater increase in transepithelial resistance in CF epithelia. Both reduced apical cell membrane Cl- conductance and increased Na+ conductance appear to contribute to the abnormal function of respiratory epithelia of CF patients. PMID:3793933

  12. Texture Analysis of Abnormal Cell Images for Predicting the Continuum of Colorectal Cancer

    PubMed Central

    Tanougast, Camel

    2017-01-01

    Abnormal cell (ABC) is a markedly heterogeneous tissue area and can be categorized into three main types: benign hyperplasia (BH), carcinoma (Ca), and intraepithelial neoplasia (IN) or precursor cancerous lesion. In this study, the goal is to determine and characterize the continuum of colorectal cancer by using a 3D-texture approach. ABC was segmented in preprocessing step using an active contour segmentation technique. Cell types were analyzed based on textural features extracted from the gray level cooccurrence matrices (GLCMs). Significant texture features were selected using an analysis of variance (ANOVA) of ABC with a p value cutoff of p < 0.01. Features selected were reduced with a principal component analysis (PCA), which accounted for 97% of the cumulative variance from significant features. The simulation results identified 158 significant features based on ANOVA from a total of 624 texture features extracted from GLCMs. Performance metrics of ABC discrimination based on significant texture features showed 92.59% classification accuracy, 100% sensitivity, and 94.44% specificity. These findings suggest that texture features extracted from GLCMs are sensitive enough to discriminate between the ABC types and offer the opportunity to predict cell characteristics of colorectal cancer. PMID:28331793

  13. Role of bentonite clays on cell growth.

    PubMed

    Cervini-Silva, Javiera; Ramírez-Apan, María Teresa; Kaufhold, Stephan; Ufer, Kristian; Palacios, Eduardo; Montoya, Ascención

    2016-04-01

    Bentonites, naturally occurring clays, are produced industrially because of their adsorbent capacity but little is known about their effects on human health. This manuscript reports on the effect of bentonites on cell growth behaviour. Bentonites collected from India (Bent-India), Hungary (Bent-Hungary), Argentina (Bent-Argentina), and Indonesia (Bent-Indonesia) were studied. All four bentonites were screened in-vitro against two human cancer cell lines [U251 (central nervous system, glioblastoma) and SKLU-1 (lung adenocarcinoma)] supplied by the National Cancer Institute (USA). Bentonites induced growth inhibition in the presence of U251 cells, and growth increment in the presence of SKLU-1 cells, showing that interactions between bentonite and cell surfaces were highly specific. The proliferation response for U251 cells was explained because clay surfaces controlled the levels of metabolic growth components, thereby inhibiting the development of high-grade gliomas, particularly primary glioblastomas. On the other hand, the proliferation response for SKLU-1 was explained by an exacerbated growth favoured by swelling, and concomitant accumulation of solutes, and their hydration and transformation via clay-surface mediated reactions.

  14. Growth control in colon epithelial cells: gadolinium enhances calcium-mediated growth regulation.

    PubMed

    Attili, Durga; Jenkins, Brian; Aslam, Muhammad Nadeem; Dame, Michael K; Varani, James

    2012-12-01

    Gadolinium, a member of the lanthanoid family of transition metals, interacts with calcium-binding sites on proteins and other biological molecules. The overall goal of the present investigation was to determine if gadolinium could enhance calcium-induced epithelial cell growth inhibition in the colon. Gadolinium at concentrations as low as 1-5 μM combined with calcium inhibits proliferation of human colonic epithelial cells more effectively than calcium alone. Gadolinium had no detectable effect on calcium-induced differentiation in the same cells based on change in cell morphology, induction of E-cadherin synthesis, and translocation of E-cadherin from the cytosol to the cell surface. When the colon epithelial cells were treated with gadolinium and then exposed to increased calcium concentrations, movement of extracellular calcium into the cell was suppressed. In contrast, gadolinium treatment had no effect on ionomycin-induced release of stored intracellular calcium into the cytoplasm. Whether these in vitro observations can be translated into an approach for reducing abnormal proliferation in the colonic mucosa (including polyp formation) is not known. These results do, however, provide an explanation for our recent findings that a multi-mineral supplement containing all of the naturally occurring lanthanoid metals including gadolinium are more effective than calcium alone in preventing colon polyp formation in mice on a high-fat diet.

  15. Micronuclei and nuclear abnormalities in buccal mucosa cells in patients with anorexia and bulimia nervosa.

    PubMed

    Torres-Bugarín, Olivia; Pacheco-Gutiérrez, Angélica Guadalupe; Vázquez-Valls, Eduardo; Ramos-Ibarra, María Luisa; Torres-Mendoza, Blanca Miriam

    2014-11-01

    The aim of this study is to assess the frequency of micronucleated cell (MNC) and nuclear abnormalities (NA) in the buccal mucosa cells of females with anorexia nervosa (AN) or bulimia nervosa (BN), compared with healthy women. Individuals with AN and BN have inadequate feeding and compensatory behaviour to avoid weight gain. These behaviours can cause extreme body stress, thereby inducing DNA damage. In a cross-sectional study, we assessed the frequency of MNC and NA in the buccal mucosa cells of female participants with AN or BN. All of these patients had been admitted to a private clinic for the treatment of eating disorders after diagnosis with AN (n = 10) or BN (n = 7) according to the DSM-IV. Age-matched healthy female participants (n = 17) composed the control group. Oral mucosa samples were collected, fixed, stained by aceto-orcein/fast green and microscopically examined. Normal cells, MNC and NAs were counted within a 2000 cell sample. The results were analyzed with the Kruskal-Wallis and Mann-Whitney tests. Differences were observed in the frequency of MNC in healthy females (1.2±0.9) versus that of patients with AN (3.4±1.5) (P < 0.0001) and BN (4.1±2.2) (P < 0.001). No differences were found among these groups in terms of NA. AN and BN are related to the loss of genetic material through chromosomal fractures and/or damage to the mitotic spindle (i.e. possibly a result of a deficiency in DNA precursors). Self-imposed compensatory behaviours in AN and BN, such as severe food restriction, potential malnutrition, vomiting, use of diuretics and laxatives and acute exhaustive exercise, are possible inducers of MNC and genotoxic damage. Of these compensatory behaviours, only vomiting has not been linked to genotoxic damage. This is the first report in women with BN, which should be studied in the future.

  16. Multiple model estimator based detection of abnormal cell overheating in a Li-ion battery string with minimum number of temperature sensors

    NASA Astrophysics Data System (ADS)

    Lystianingrum, Vita; Hredzak, Branislav; Agelidis, Vassilios G.

    2015-01-01

    This paper proposes modeling of abnormal cell overheating caused by internal short circuit in a cell of a Li-ion battery string by augmenting the cell state space model with unknown input disturbance. Furthermore, with minimum number of temperature sensors, in order to identify which of the cells in the string is experiencing the abnormal overheating, a multiple model estimator (MME) is used. Simulation results demonstrate that the proposed MME can detect the abnormally overheating cell as well as quickly detect that an abnormal overheating event occurred in the battery string.

  17. Cell metabolism: an essential link between cell growth and apoptosis

    PubMed Central

    Mason, Emily F.; Rathmell, Jeffrey C.

    2010-01-01

    Growth factor-stimulated or cancerous cells require sufficient nutrients to meet the metabolic demands of cell growth and division. If nutrients are insufficient, metabolic checkpoints are triggered that lead to cell cycle arrest and the activation of the intrinsic apoptotic cascade through a process dependent on the Bcl-2 family of proteins. Given the connections between metabolism and apoptosis, the notion of targeting metabolism to induce cell death in cancer cells has recently garnered much attention. However, the signaling pathways by which metabolic stresses induce apoptosis have not as of yet been fully elucidated. Thus, the best approach to this promising therapeutic avenue remains unclear. This review will discuss the intricate links between metabolism, growth, and intrinsic apoptosis and will consider ways in which manipulation of metabolism might be exploited to promote apoptotic cell death in cancer cells. PMID:20816705

  18. Exercise tolerance, lung function abnormalities, anemia, and cardiothoracic ratio in sickle cell patients.

    PubMed

    van Beers, Eduard J; van der Plas, Mart N; Nur, Erfan; Bogaard, Harm-Jan; van Steenwijk, Reindert P; Biemond, Bart J; Bresser, Paul

    2014-08-01

    Many patients with sickle cell disease (SCD) have a reduced exercise capacity and abnormal lung function. Cardiopulmonary exercise testing (CPET) can identify causes of exercise limitation. Forty-four consecutive SCD patients (27 HbSS, 11 HbSC, and 6 HbS-beta thalassemia) with a median age (interquartile range) of 26 (21-41) years underwent pulmonary function tests, CPET, chest x-ray, and echocardiography to further characterize exercise limitation in SCD. Peak oxygen uptake (V'O2 -peak), expressing maximum exercise capacity, was decreased in 83% of the studied patients. V'O2 -peak correlated with hemoglobin levels (R = 0.440, P = 0.005), forced vital capacity (FVC) (R = 0.717, P < 0.0001). Cardiothoracic ratio on chest x-ray inversely correlated with FVC (R = -0.637, P < 0.001). According to criteria for exercise limitation, the patients were limited in exercise capacity due to anemia (n = 17), cardiovascular dysfunction (n = 2), musculoskeletal function (n = 10), pulmonary ventilatory abnormalities (n = 1), pulmonary vascular exercise limitation (n = 1), and poor effort (n = 3). In the present study we demonstrate that anemia is the most important determinant of reduced exercise tolerance observed in SCD patients without signs of pulmonary hypertension. We found a strong correlation between various parameters of lung volume and cardiothoracic ratio and we hypothesize that cardiomegaly and relative small chest size may be important causes of the impairment in pulmonary function, that is, reduced long volumes and diffusion capacity, in SCD. Taking into account anthropomorphic differences between SCD patients and controls could help to interpret lung function studies in SCD better.

  19. Altered growth, differentiation, and responsiveness to epidermal growth factor of human embryonic mesenchymal cells of palate by persistent rubella virus infection

    SciTech Connect

    Yoneda, T.; Urade, M.; Sakuda, M.; Miyazaki, T.

    1986-05-01

    We previously demonstrated that human embryonic mesenchymal cells derived from the palate (HEMP cells) retain alkaline phosphatase (ALP) content and capacity for collagen synthesis after long-term culture, and their growth is markedly stimulated by epidermal growth factor (EGF). There was a dramatic decrease in ALP content and capacity to synthesize collagen in HEMP cells (HEMP-RV cells) persistently infected with rubella virus (RV). EGF increased ALP activity and decreased collagen synthesis in HEMP cells, whereas EGF showed no effect on these activities in HEMP-RV cells. Growth of HEMP-RV cells was slightly reduced compared with that of HEMP cells. EGF stimulated growth of HEMP cells and to a lesser extent of HEMP-RV cells. Binding of /sup 125/I-EGF to cell-surface receptors in HEMP-RV cells was, to our surprise, twice as much as that in HEMP cells. However, internalization of bound /sup 125/I-EGF in HEMP-RV cells was profoundly diminished. Thus, persistent RV infection causes not only changes in HEMP cell growth and differentiation but a decrease in or loss of HEMP cell responsiveness to EGF. The effects of persistent RV infection on palatal cell differentiation as well as growth may be responsible for the pathogenesis of congenital rubella. Furthermore, since HEMP cells appear to be closely related to osteoblasts, these results suggest a mechanism for RV-induced osseous abnormalities manifested in congenital rubella patients.

  20. Cancer Cells Hijack Gluconeogenic Enzymes to Fuel Cell Growth.

    PubMed

    Balsa-Martinez, Eduardo; Puigserver, Pere

    2015-11-19

    In this issue and the October 15th issue of Molecular Cell, studies by Montal et al. (2015) and Vincent et al. (2015) report that certain types of cancer cells utilize the gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and phosphoenolpyruvate carboxykinase 2 (PCK2) to reprogram anabolic metabolism and support cell growth.

  1. Morphological abnormalities, impaired fetal development and decrease in myostatin expression following somatic cell nuclear transfer in dogs.

    PubMed

    Hong, Il-Hwa; Jeong, Yeon-Woo; Shin, Taeyoung; Hyun, Sang-Hwan; Park, Jin-Kyu; Ki, Mi-Ran; Han, Seon-Young; Park, Se-Il; Lee, Ji-Hyun; Lee, Eun-Mi; Kim, Ah-Young; You, Sang-Young; Hwang, Woo-Suk; Jeong, Kyu-Shik

    2011-05-01

    Several mammals, including dogs, have been successfully cloned using somatic cell nuclear transfer (SCNT), but the efficiency of generating normal, live offspring is relatively low. Although the high failure rate has been attributed to incomplete reprogramming of the somatic nuclei during the cloning process, the exact cause is not fully known. To elucidate the cause of death in cloned offspring, 12 deceased offspring cloned by SCNT were necropsied. The clones were either stillborn just prior to delivery or died with dyspnea shortly after birth. On gross examination, defects in the anterior abdominal wall and increased heart and liver sizes were found. Notably, a significant increase in muscle mass and macroglossia lesions were observed in deceased SCNT-cloned dogs. Interestingly, the expression of myostatin, a negative regulator of muscle growth during embryogenesis, was down-regulated at the mRNA level in tongues and skeletal muscles of SCNT-cloned dogs compared with a normal dog. Results of the present study suggest that decreased expression of myostatin in SCNT-cloned dogs may be involved in morphological abnormalities such as increased muscle mass and macroglossia, which may contribute to impaired fetal development and poor survival rates.

  2. Membrane toxicity of abnormal prion protein in adrenal chromaffin cells of scrapie infected sheep.

    PubMed

    McGovern, Gillian; Jeffrey, Martin

    2013-01-01

    Transmissible spongiform encephalopathies (TSEs) or prion diseases are associated with accumulations of disease specific PrP (PrP(d)) in the central nervous system (CNS) and often the lymphoreticular system (LRS). Accumulations have additionally been recorded in other tissues including the peripheral nervous system and adrenal gland. Here we investigate the effect of sheep scrapie on the morphology and the accumulation of PrP(d) in the adrenal medulla of scrapie affected sheep using light and electron microscopy. Using immunogold electron microscopy, non-fibrillar forms of PrP(d) were shown to accumulate mainly in association with chromaffin cells, occasional nerve endings and macrophages. PrP(d) accumulation was associated with distinctive membrane changes of chromaffin cells including increased electron density, abnormal linearity and invaginations. Internalisation of PrP(d) from the chromaffin cell plasma membrane occurred in association with granule recycling following hormone exocytosis. PrP(d) accumulation and internalisation from membranes is similarly associated with perturbations of membrane structure and trafficking in CNS neurons and tingible body macrophages of the LRS. These data suggest that a major toxic effect of PrP(d) is at the level of plasma membranes. However, the precise nature of PrP(d)-membrane toxicity is tissue and cell specific suggesting that the normal protein may act as a multi-functional scaffolding molecule. We further suggest that the co-localisation of PrP(d) with exocytic granules of the hormone trafficking system may provide an additional source of infectivity in blood.

  3. Abnormalities in plasma and red blood cell fatty acid profiles of patients with colorectal cancer.

    PubMed Central

    Baró, L.; Hermoso, J. C.; Núñez, M. C.; Jiménez-Rios, J. A.; Gil, A.

    1998-01-01

    We evaluated total plasma fatty acid concentrations and percentages, and the fatty acid profiles for the different plasma lipid fractions and red blood cell lipids, in 17 patients with untreated colorectal cancer and 12 age-matched controls with no malignant diseases, from the same geographical area. Cancer patients had significantly lower total plasma concentrations of saturated, monounsaturated and essential fatty acids and their polyunsaturated derivatives than healthy controls; when the values were expressed as relative percentages, cancer patients had significantly higher proportions of oleic acid and lower levels of linoleic acid than controls. With regard to lipid fractions, cancer patients had higher proportions of oleic acid in plasma phospholipids, triglycerides and cholesterol esters, and lower percentages of linoleic acid and its derivatives. On the other hand, alpha-linolenic acid was significantly lower in triglycerides from cancer patients and tended to be lower in phospholipids. Its derivatives also tended to be lower in phospholipids and triglycerides from cancer patients. Our findings suggest that colorectal cancer patients present abnormalities in plasma and red blood cell fatty acid profiles characterized by lower amounts of most saturated, monounsaturated and essential fatty acids and their polyunsaturated derivatives, especially members of the n-6 series, than their healthy age-matched counterparts. These changes are probably due to metabolic changes caused by the illness per se but not to malnutrition. PMID:9667678

  4. Micronuclei Frequencies and Nuclear Abnormalities in Oral Exfoliated Cells of Nuclear Power Plant Workers

    PubMed Central

    Babannavar, Roopa; Lohra, Abhishek; Kodgi, Ashwin; Bapure, Sunil; Rao, Yogesh; J., Arun; Malghan, Manjunath

    2014-01-01

    Aim: Biomonitoring provides a useful tool to estimate the genetic risk from exposure to genotoxic agents. The aim of this study was to evaluate the frequencies of Micronuclei (MN) and other Nuclear abnormalities (NA) from exfoliated oral mucosal cells in Nuclear Power Station (NPS) workers. Materials and Methods: Micronucleus frequencies in oral exfoliated cells were done from individuals not known to be exposed to either environmental or occupational carcinogens (Group I). Similarly samples were obtained from full-time Nuclear Power Station (NPS) workers with absence of Leukemia and any malignancy (Group II) and workers diagnosed as leukemic patients and undergoing treatment (Group III). Results: There was statistically significant difference between Group I, Group II & Group III. MN and NA frequencies in Leukemic Patients were significantly higher than those in exposed workers &control groups (p < 0.05). Conclusion: MN and other NA reflect genetic changes, events associated with malignancies. Therefore, there is a need to educate those who work in NPS about the potential hazard of occupational exposure and the importance of using protective measures. PMID:25654022

  5. The pituitary growth hormone cell in space

    NASA Technical Reports Server (NTRS)

    Hymer, Wesley C.; Grindeland, R.

    1989-01-01

    Growth hormone (GH), produced and secreted from specialized cells in the pituitary gland, controls the metabolism of protein, fat, and carbohydrate. It is also probably involved in the regulation of proper function of bone, muscle and immune systems. The behavior of the GH cell system was studied by flying either isolated pituitary cells or live rats. In the latter case, pituitary GH cells are prepared on return to earth and then either transplanted into hypophysectomized rats or placed into cell culture so that function of GH cells in-vivo vs. in-vitro can be compared. The results from three flights to date (STS-8, 1983; SL-3, 1985; Cosmos 1887, 1987) established that the ability of GH cells to release hormone, on return to earth, is compromised. The mechanism(s) responsible for this attenuation response is unknown. However, the data are sufficiently positive to indicate that the nature of the secretory defect resides directly within the GH cells.

  6. Control of cell cycle and cell growth by molecular chaperones.

    PubMed

    Aldea, Martí; Garí, Eloi; Colomina, Neus

    2007-11-01

    Cells adapt their size to both intrinsic and extrinsic demands and, among them, those that stem from growth and proliferation rates are crucial for cell size homeostasis. Here we revisit mechanisms that regulate cell cycle and cell growth in budding yeast. Cyclin Cln3, the most upstream activator of Start, is retained at the endoplasmic reticulum in early G(1) and released by specific chaperones in late G(1) to initiate the cell cycle. On one hand, these chaperones are rate-limiting for release of Cln3 and cell cycle entry and, on the other hand, they are required for key biosynthetic processes. We propose a model whereby the competition for specialized chaperones between growth and cycle machineries could gauge biosynthetic rates and set a critical size threshold at Start.

  7. Complex chromosomal abnormalities in a patient with HTLV-1 positive T-cell leukemia

    SciTech Connect

    Hyde, P.; Macera, M.J.; Gogineni, S.K.

    1994-09-01

    HTLV-1 positive adult T-cell leukemia (ATL) is associated with numerous chromosomal abnormalities. The chromosomal rearrangements can be extremely complex and additional material is often present, making precise identification by routine cytogenetic techniques difficult. We report a case of ATL that was established of bone marrow cells by both QFQ and GTG banding techniques revealed a highly complex 49,XX,der(2)t(2;?)(q37;?),+5,+2mar karyotype in the dividing cells. The identical cytogenetic findings were also seen in unstimulated peripheral blood collected one week later. Using the FISH-technique, we applied spectrum green-labeled No. 1- and No. 7-specific WCP, spectrum orange-labeled No. 2- and No. 5-specific WCP (GIBCO/BRL, Gaithersburg, MD) and biotin-labeled No. 18-specific WCP (Oncor, Gaithersburg, MD) to metaphase chromosomes. The large marker chromosome was identified as an extra 1q arm, the material attached to the distal 2q was additional 7q. The presence of three No. 5 chromosomes was verified and the small marker was determined to be an extra partial 5p in Robertsonian translocation with an additional partial 18q arm. The karyotype was revised to 49,XX,+1q,der(2)t(2;7)(q37;q22),+5,+t(5;18)(p14{r_arrow}p11::q11{r_arrow}q12). Identification of the numerous chromosomal anomalies associated with the disease by molecular techniques shall lead to a better understanding of this deadly cancer.

  8. Molecular detection of chromosomal abnormalities in germ and somatic cells of aged male mice

    SciTech Connect

    Lowe, X.; Baulch, J.; Quintana, L.; Ramsey, M.; Breneman, J.; Tucker, J.; Wyrobek, A.; Collins, B.; Allen, J.; Holland, N.

    1994-12-31

    Three cytogenetic methods were applied to eight B6C3F1 male mice aged 22.5 - 30.5mo to determine if advanced age was associated with an elevated risk of producing chromosomally defective germinal and somatic cells; sperm aneuploidy analysis by multi-color fluorescence in situ hybridization for three chromosomes, spermatid micronucleus analysis with anti-kinetochore antibodies, and translocation analysis of somatic metaphases by {open_quotes}painting{close_quotes} for two chromosomes. Eight mice aged 2.4mo served as controls. Sperm aneuploidy was measured by multi-color fluorescence in situ co-hybridization with DNA probes specific for chromosomes X, Y and 8, scoring 10,000 cells per animal. The aged group showed significant 1.5 - 2.0 fold increases in the hyperhaploidy phenotypes X-X-8, Y-Y-8, 8-8-Y, and 8-8-X with the greater effects appearing in animals aged >29mo. The aged group also showed significantly increased frequencies of micronucleated spermatids (2.0 vs 0.4 per 1000; all were kinetochore negative). Analysis of metaphase chromosomes from blood by {open_quotes}painting{close_quotes} of chromosomes 2 and 8 yielded 4 translocation per 858 cell-equivalents in the aged group which was a non-significant elevation over 0/202 in controls. Although interpretation must be cautious due to the small number of animals analyzed, these findings suggest that advanced paternal age may be a risk factor for chromosomal abnormalities of reproductive and somatic importance.

  9. Defective in vitro growth of the hemopoietic progenitor cells in the acquired immunodeficiency syndrome.

    PubMed Central

    Stella, C C; Ganser, A; Hoelzer, D

    1987-01-01

    In addition to immunologic derangement, hematological abnormalities have been reported in the majority of patients with acquired immunodeficiency syndrome (AIDS). In this study 15 patients with AIDS or AIDS-related complex (ARC) were evaluated for the in vitro growth of hemopoietic progenitor cells. In all patients a significant reduction of growth (mean +/- SEM) of colony-forming unit-granulocyte, erythrocyte, macrophage, (megakaryocyte) (CFU-GEM) (1.2 +/- 0.3), burst-forming unit-erythroid (BFU-E) (17 +/- 10), CFU-megakaryocyte (CFU-Mk) (1.7 +/- 0.6), and CFU-granulocyte-macrophage (CFU-GM) (35 +/- 10) was observed in comparison with normal controls. Depletion of T cells from the bone marrow before culture led to a significant increase in colony growth, which indicated an imbalance of the normally modulating T cell subsets. This increase was reversed by readdition of autologous T cells causing a decrease in colony growth to a degree, dependent on the T4 to T8 ratio. A decreased number of hemopoietic progenitor cells and/or a defective modulation of progenitor cell growth, normally carried out by T lymphocyte subsets, might be the cause of the hematological abnormalities in AIDS patients. PMID:3497175

  10. Segmentation of cytoplasm and nuclei of abnormal cells in cervical cytology using global and local graph cuts.

    PubMed

    Zhang, Ling; Kong, Hui; Chin, Chien Ting; Liu, Shaoxiong; Chen, Zhi; Wang, Tianfu; Chen, Siping

    2014-07-01

    Automation-assisted reading (AAR) techniques have the potential to reduce errors and increase productivity in cervical cancer screening. The sensitivity of AAR relies heavily on automated segmentation of abnormal cervical cells, which is handled poorly by current segmentation algorithms. In this paper, a global and local scheme based on graph cut approach is proposed to segment cervical cells in images with a mix of healthy and abnormal cells. For cytoplasm segmentation, the multi-way graph cut is performed globally on the a* channel enhanced image, which can be effective when the image histogram presents a non-bimodal distribution. For segmentation of nuclei, especially when they are abnormal, we propose to use graph cut adaptively and locally, which allows the combination of intensity, texture, boundary and region information. Two concave points-based approaches are integrated to split the touching-nuclei. As part of an ongoing clinical trial, preliminary validation results obtained from 21 cervical cell images with non-ideal imaging condition and pathology show that our segmentation method achieved 93% accuracy for cytoplasm, and 88.4% F-measure for abnormal nuclei, outperforming state of the art methods in terms of accuracy. Our method has the potential to improve the sensitivity of AAR in screening for cervical cancer.

  11. The cell biology of bone growth.

    PubMed

    Price, J S; Oyajobi, B O; Russell, R G

    1994-02-01

    The field of bone cell biology is clearly of relevance to the problem of stunting in children, as in the final analysis the cells of the growing long bone are the ultimate 'regulators'. It is the alterations in the functions of these cells that manifests as a reduction in height. Normal longitudinal growth is achieved by the coordinated recruitment, proliferation, differentiation, maturation and eventual death of the cells of growth plate and bone. Cellular activity is closely regulated by endocrine factors acting directly or indirectly, with factors produced locally and stored within the bone and cartilage microenvironment having a critical role in intercellular communication. Disruption of any of these processes can lead to growth disturbances, since it only requires a defect in a single gene to have profound effects. Studies in recent years have shed light on the biochemical and molecular effects of cytokines and growth factors and have shown that these regulatory molecules may mediate the effects of certain hormones important in controlling growth. However, the complex interrelationship of these molecules is still not clear. Notwithstanding, understanding of the mechanisms involved in bone remodelling is increasing, as this area attracts much research because of the high incidence of metabolic bone disease in Western society. Although studies of adult bone remodelling are of relevance, there is a requirement for increased research directed specifically at the mechanisms of endochondral ossification and its regulation. Longitudinal bone growth is a challenge to the cell biologist, since it is an accelerated cycle of cellular division and differentiation, within which it is not easy to separate events temporally and spatially. In addition, different regulatory mechanisms are probably important at different stages of growth. Another difficulty impeding progress in this field is the lack of appropriate animal models for research. Much information has come from

  12. Potential uses, limitations, and basic procedures of micronuclei and nuclear abnormalities in buccal cells.

    PubMed

    Torres-Bugarín, Olivia; Zavala-Cerna, María Guadalupe; Nava, Arnulfo; Flores-García, Aurelio; Ramos-Ibarra, María Luisa

    2014-01-01

    The use of biomarkers as tools to evaluate genotoxicity is increasing recently. Methods that have been used previously to evaluate genomic instability are frequently expensive, complicated, and invasive. The micronuclei (MN) and nuclear abnormalities (NA) technique in buccal cells offers a great opportunity to evaluate in a clear and precise way the appearance of genetic damage whether it is present as a consequence of occupational or environmental risk. This technique is reliable, fast, relatively simple, cheap, and minimally invasive and causes no pain. So, it is well accepted by patients; it can also be used to assess the genotoxic effect derived from drug use or as a result of having a chronic disease. Furthermore the beneficial effects derived from changes in life style or taking additional supplements can also be evaluated. In the present paper, we aim to focus on the explanation of MN test and its usefulness as a biomarker; we further give details about procedures to perform and interpret the results of the test and review some factors that could have an influence on the results of the technique.

  13. Potential Uses, Limitations, and Basic Procedures of Micronuclei and Nuclear Abnormalities in Buccal Cells

    PubMed Central

    Torres-Bugarín, Olivia; Zavala-Cerna, María Guadalupe; Nava, Arnulfo; Flores-García, Aurelio; Ramos-Ibarra, María Luisa

    2014-01-01

    The use of biomarkers as tools to evaluate genotoxicity is increasing recently. Methods that have been used previously to evaluate genomic instability are frequently expensive, complicated, and invasive. The micronuclei (MN) and nuclear abnormalities (NA) technique in buccal cells offers a great opportunity to evaluate in a clear and precise way the appearance of genetic damage whether it is present as a consequence of occupational or environmental risk. This technique is reliable, fast, relatively simple, cheap, and minimally invasive and causes no pain. So, it is well accepted by patients; it can also be used to assess the genotoxic effect derived from drug use or as a result of having a chronic disease. Furthermore the beneficial effects derived from changes in life style or taking additional supplements can also be evaluated. In the present paper, we aim to focus on the explanation of MN test and its usefulness as a biomarker; we further give details about procedures to perform and interpret the results of the test and review some factors that could have an influence on the results of the technique. PMID:24778463

  14. Bacterial cell curvature through mechanical control of cell growth

    PubMed Central

    Cabeen, Matthew T; Charbon, Godefroid; Vollmer, Waldemar; Born, Petra; Ausmees, Nora; Weibel, Douglas B; Jacobs-Wagner, Christine

    2009-01-01

    The cytoskeleton is a key regulator of cell morphogenesis. Crescentin, a bacterial intermediate filament-like protein, is required for the curved shape of Caulobacter crescentus and localizes to the inner cell curvature. Here, we show that crescentin forms a single filamentous structure that collapses into a helix when detached from the cell membrane, suggesting that it is normally maintained in a stretched configuration. Crescentin causes an elongation rate gradient around the circumference of the sidewall, creating a longitudinal cell length differential and hence curvature. Such curvature can be produced by physical force alone when cells are grown in circular microchambers. Production of crescentin in Escherichia coli is sufficient to generate cell curvature. Our data argue for a model in which physical strain borne by the crescentin structure anisotropically alters the kinetics of cell wall insertion to produce curved growth. Our study suggests that bacteria may use the cytoskeleton for mechanical control of growth to alter morphology. PMID:19279668

  15. Cell metabolism: Growth and environment. Volume I

    SciTech Connect

    Subramanian, T.A.V.

    1986-01-01

    This book describes: Protein metabolism in relation to secondary biosynthesis; nucleic acid metabolism in relation to growth; the spatial organization of secondary metabolism in microbial and plant cells; aflatoxin bioysynthesis; role of oxygenases in the metabolism of phenolic compounds; regulation of secondary metabolism by trace metals; and index.

  16. Isoprenoid Biosynthesis Inhibitors Targeting Bacterial Cell Growth.

    PubMed

    Desai, Janish; Wang, Yang; Wang, Ke; Malwal, Satish R; Oldfield, Eric

    2016-10-06

    We synthesized potential inhibitors of farnesyl diphosphate synthase (FPPS), undecaprenyl diphosphate synthase (UPPS), or undecaprenyl diphosphate phosphatase (UPPP), and tested them in bacterial cell growth and enzyme inhibition assays. The most active compounds were found to be bisphosphonates with electron-withdrawing aryl-alkyl side chains which inhibited the growth of Gram-negative bacteria (Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa) at ∼1-4 μg mL(-1) levels. They were found to be potent inhibitors of FPPS; cell growth was partially "rescued" by the addition of farnesol or overexpression of FPPS, and there was synergistic activity with known isoprenoid biosynthesis pathway inhibitors. Lipophilic hydroxyalkyl phosphonic acids inhibited UPPS and UPPP at micromolar levels; they were active (∼2-6 μg mL(-1) ) against Gram-positive but not Gram-negative organisms, and again exhibited synergistic activity with cell wall biosynthesis inhibitors, but only indifferent effects with other inhibitors. The results are of interest because they describe novel inhibitors of FPPS, UPPS, and UPPP with cell growth inhibitory activities as low as ∼1-2 μg mL(-1) .

  17. Assessment of the abnormal growth of floating macrophytes in Winam Gulf (Kenya) by using MODIS imagery time series

    NASA Astrophysics Data System (ADS)

    Fusilli, L.; Collins, M. O.; Laneve, G.; Palombo, A.; Pignatti, S.; Santini, F.

    2013-02-01

    The objective of this research study is to assess the capability of time-series of MODIS imagery to provide information suitable for enhancing the understanding of the temporal cycles shown by the abnormal growth of the floating macrophytes in order to support monitoring and management action of Lake Victoria water resources. The proliferation of invasive plants and aquatic weeds is of growing concern. Starting from 1989, Lake Victoria has been interested by the high infestation of water hyacinth with significant socio-economic impact on riparian populations. In this paper, we describe an approach based on the time-series of MODIS to derive the temporal behaviour, the abundance and distribution of the floating macrophytes in the Winam Gulf (Kenyan portion of the Lake Victoria) and its possible links to the concentrations of the main water constituencies. To this end, we consider the NDVI values computed from the MODIS imagery time-series from 2000 to 2009 to identify the floating macrophytes cover and an appropriate bio-optical model to retrieve, by means of an inverse procedure, the concentrations of chlorophyll a, coloured dissolved organic matter and total suspended solid. The maps of the floating vegetation based on the NDVI values allow us to assess the spatial and temporal dynamics of the weeds with high time resolution. A floating vegetation index (FVI) has been introduced for describing the weeds pollution level. The results of the analysis show a consistent temporal relation between the water constituent concentrations within the Winam Gulf and the FVI, especially in the proximity of the greatest proliferation of floating vegetation in the last 10 years that occurred between the second half of 2006 and the first half of 2007.The adopted approach will be useful to implement an automatic system for monitoring and predicting the floating macrophytes proliferation in Lake Victoria.

  18. Abnormal sperm morphology in mouse germ cells after short-term exposures to acetamiprid, propineb, and their mixture.

    PubMed

    Rasgele, Pinar Göç

    2014-03-01

    Pesticides are one of the most potent environmental contaminants, which accumulate in biotic and abiotic components of ecosystems. Acetamiprid (Acm), a neonicotinoid insecticide, and Propineb (Pro), a dithiocarbamate fungicide, are widely used to control sucking insects and fungal infections on crops, respectively. The present study was undertaken to investigate the genotoxic effects of these compounds, individually and in mixtures, in mouse germ cells by using the sperm morphology assay. Mice were injected intraperitoneally with 0.625, 1.25, and 2.50 μg mL⁻¹ of Acm, 12.5, 25, and 50 μg mL⁻¹ of Pro, and their mixture at the same concentrations over 24 and 48 h. Acm did not significantly increase the percentage of abnormal sperm at any concentration. The frequency of abnormal sperm significantly increased after 24 and 48 h of exposure to 50 μg mL⁻¹ of Pro. The mixtures of 2.50 μg mL⁻¹ of Acm and 50 μg mL⁻¹ of Pro induced sperm abnormalities antagonistically both after 24 and 48 h of exposure. Results suggest that Acm was non-genotoxic for mouse germ cells, while Pro may have been a germ cell mutagen due to the observed increase in the frequency of sperm abnormalities. However, to gain better insight into the mutagenicity and DNA damaging potential of both of these pesticides, further studies at molecular level should be done.

  19. Cardiac troponin I is abnormally expressed in non-small cell lung cancer tissues and human cancer cells.

    PubMed

    Chen, Chao; Liu, Jia-Bao; Bian, Zhi-Ping; Xu, Jin-Dan; Wu, Heng-Fang; Gu, Chun-Rong; Shi, Yi; Zhang, Ji-Nan; Chen, Xiang-Jian; Yang, Di

    2014-01-01

    Cardiac troponin I (cTnI) is the only sarcomeric protein identified to date that is expressed exclusively in cardiac muscle. Its expression in cancer tissues has not been reported. Herein, we examined cTnI expression in non-small cell lung cancer (NSCLC) tissues, human adenocarcinoma cells SPCA-1 (lung) and BGC 823 (gastric) by immunohistochemistry, western blot analysis and real-time PCR. Immunopositivity for cTnI was demonstrated in 69.4% (34/49) NSCLC tissues evaluated, and was strong intensity in 35.3% (6/17) lung squamous cell carcinoma cases. The non-cancer-bearing lung tissues except tuberculosis (9/9, 100%) showed negative staining for cTnI. Seven monoclonal antibodies (mAbs) against human cTnI were applied in immunofluorescence. The result showed that the staining pattern within SPCA-1 and BGC 823 was dependent on the epitope of the cTnI mAbs. The membrane and nucleus of cancer cells were stained by mAbs against N-terminal peptides of cTnI, and cytoplasm was stained by mAbs against the middle and C-terminal peptides of cTnI. A ~25 kD band was identified by anti-cTnI mAb in SPCA-1 and BGC 823 extracts by western blot, as well as in cardiomyocyte extracts. The cTnI mRNA expressions in SPCA-1 and BGC 823 cells were about ten thousand times less than that in cardiomyocytes. Our study shows for the first time that cTnI protein and mRNA were abnormally expressed in NSCLC tissues, SPCA-1 and BGC 823 cells. These findings challenge the conventional view of cTnI as a cardiac-specific protein, enabling the potential use of cTnI as a diagnostic marker or targeted therapy for cancer.

  20. Normal and abnormal grain growth in fine-grained Nd-Fe-B sintered magnets prepared from He jet milled powders

    NASA Astrophysics Data System (ADS)

    Bittner, F.; Woodcock, T. G.; Schultz, L.; Schwöbel, C.; Gutfleisch, O.; Zickler, G. A.; Fidler, J.; Üstüner, K.; Katter, M.

    2017-03-01

    Fine-grained, heavy rare earth free Nd-Fe-B sintered magnets were prepared from He jet milled powders with an average particle size of 1.5 μm by low temperature sintering at 920 °C or 980 °C. A coercivity of >1600 kA/m was achieved for an average grain size of 1.68 μm. Transmission electron microscopy showed that the distribution and composition of intergranular and grain boundary junction phases was similar to that in conventionally processed magnets. Microstructural analysis on different length scales revealed the occurrence of abnormal grain growth, which is unexpected for sintering temperatures below 1000 °C. A larger area fraction of abnormal grains was observed in the sample sintered at 920 °C compared to that sintered at 980 °C. Microtexture investigation showed a better crystallographic alignment of the abnormal grains compared to the fine-grained matrix, which is explained by a size dependent alignment of the powder particles during magnetic field alignment prior to sintering. Slightly larger particles in the initial powder show a better alignment and will act as nucleation sites for abnormal grain growth. Magneto-optical Kerr investigations confirmed the lower switching field of the abnormal grains compared to the fine-grained matrix. The demagnetisation curve of the sample sintered at 920 °C showed reduced rectangularity and this was attributed to a cooperative effect of the larger fraction of abnormal grains with low switching field and, as a minor effect, a reduced degree of crystallographic texture in this sample compared to the material sintered at 980 °C, which did not show the reduced rectangularity of the demagnetisation curve.

  1. Triiodothyronine regulates cell growth and survival in renal cell cancer.

    PubMed

    Czarnecka, Anna M; Matak, Damian; Szymanski, Lukasz; Czarnecka, Karolina H; Lewicki, Slawomir; Zdanowski, Robert; Brzezianska-Lasota, Ewa; Szczylik, Cezary

    2016-10-01

    Triiodothyronine plays an important role in the regulation of kidney cell growth, differentiation and metabolism. Patients with renal cell cancer who develop hypothyreosis during tyrosine kinase inhibitor (TKI) treatment have statistically longer survival. In this study, we developed cell based model of triiodothyronine (T3) analysis in RCC and we show the different effects of T3 on renal cell cancer (RCC) cell growth response and expression of the thyroid hormone receptor in human renal cell cancer cell lines from primary and metastatic tumors along with human kidney cancer stem cells. Wild-type thyroid hormone receptor is ubiquitously expressed in human renal cancer cell lines, but normalized against healthy renal proximal tube cell expression its level is upregulated in Caki-2, RCC6, SKRC-42, SKRC-45 cell lines. On the contrary the mRNA level in the 769-P, ACHN, HKCSC, and HEK293 cells is significantly decreased. The TRβ protein was abundant in the cytoplasm of the 786-O, Caki-2, RCC6, and SKRC-45 cells and in the nucleus of SKRC-42, ACHN, 769-P and cancer stem cells. T3 has promoting effect on the cell proliferation of HKCSC, Caki-2, ASE, ACHN, SK-RC-42, SMKT-R2, Caki-1, 786-0, and SK-RC-45 cells. Tyrosine kinase inhibitor, sunitinib, directly inhibits proliferation of RCC cells, while thyroid hormone receptor antagonist 1-850 (CAS 251310‑57-3) has less significant inhibitory impact. T3 stimulation does not abrogate inhibitory effect of sunitinib. Renal cancer tumor cells hypostimulated with T3 may be more responsive to tyrosine kinase inhibition. Moreover, some tumors may be considered as T3-independent and present aggressive phenotype with thyroid hormone receptor activated independently from the ligand. On the contrary proliferation induced by deregulated VHL and or c-Met pathways may transgress normal T3 mediated regulation of the cell cycle.

  2. Elastic Deformations During Bacterial Cell Growth

    NASA Astrophysics Data System (ADS)

    Huang, K. C.

    2010-03-01

    The wide variety of shapes and sizes found in bacterial species is almost universally defined by the cell wall, which is a cross-linked network of the material peptidoglycan. In recent years, cell shape has been shown to play a critical role in regulating many important biological functions including attachment, dispersal, motility, polar differentiation, predation, and cellular differentiation. In previous work, we have shown that the spatial organization of the peptidoglycan network can change the mechanical equilibrium of the cell wall and result in changes in cell shape. However, experimental data on the mechanical properties of peptidoglycan is currently limited. Here, we describe a straightforward, inexpensive approach for extracting the mechanical properties of bacterial cells in gels of user-defined stiffness, using only optical microscopy to match growth kinetics to the predictions of a continuum model of cell growth. Using this simple yet general methodology, we have measured the Young's modulus for bacteria ranging across a wide variety of shapes, sizes, and cell wall thicknesses, and our method can easily be extended to other commonly studied bacteria. This method makes it possible to rapidly determine how changes in genotype and biochemistry affect the mechanical properties of the cell wall, and may be particularly relevant for studying the relationship between cell shape and structure, the genetic and molecular control of the mechanical properties of the cell wall, and the identification of antibiotics and other small molecules that affect and specifically modify the mechanical properties of the cell wall. Our work also suggests that bacteria may utilize peptidoglycan synthesis to transduce mechanosensory signals from local environment.

  3. Expanding the spectrum of phenotypes associated with germline PIGA mutations: a child with developmental delay, accelerated linear growth, facial dysmorphisms, elevated alkaline phosphatase, and progressive CNS abnormalities.

    PubMed

    van der Crabben, Saskia N; Harakalova, Magdalena; Brilstra, Eva H; van Berkestijn, Frédérique M C; Hofstede, Floris C; van Vught, Adrianus J; Cuppen, Edwin; Kloosterman, Wigard; Ploos van Amstel, Hans Kristian; van Haaften, Gijs; van Haelst, Mieke M

    2014-01-01

    Phosphatidyl inositol glycan (PIG) enzyme subclasses are involved in distinct steps of glycosyl phosphatidyl inositol anchor protein biosynthesis. Glycolsyl phosphatidyl inositol-anchored proteins have heterogeneous functions; they can function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Germline mutations in genes encoding different members of the PIG family result in diverse conditions with (severe) developmental delay, (neonatal) seizures, hypotonia, CNS abnormalities, growth abnormalities, and congenital abnormalities as hallmark features. The variability of clinical features resembles the typical diversity of other glycosylation pathway deficiencies such as the congenital disorders of glycosylation. Here, we report the first germline missense mutation in the PIGA gene associated with accelerated linear growth, obesity, central hypotonia, severe refractory epilepsy, cardiac anomalies, mild facial dysmorphic features, mildly elevated alkaline phosphatase levels, and CNS anomalies consisting of progressive cerebral atrophy, insufficient myelinization, and cortical MRI signal abnormalities. X-exome sequencing in the proband identified a c.278C>T (p.Pro93Leu) mutation in the PIGA gene. The mother and maternal grandmother were unaffected carriers and the mother showed 100% skewing of the X-chromosome harboring the mutation. These results together with the clinical similarity of the patient reported here and the previously reported patients with a germline nonsense mutation in PIGA support the determination that this mutation caused the phenotype in this family.

  4. Functional abnormalities of sinusoidal endothelial cells in rats with acute liver rejection.

    PubMed

    Yokoi, Y; Nakamura, S; Muro, H; Baba, S

    1994-01-01

    The purpose of this study was to determine the changes of hepatic sinusoidal endothelial cell (SEC) function in acute liver rejection with respect to receptor-mediated endocytosis. Orthotopic rat liver transplantation was performed in Lewis rats grafted with DA livers and in Lewis rats grafted with Lewis livers as rejectors and controls, respectively. Animals were killed at 1, 3, 5, 7, and 10 days after the operation. Fc receptors (FcRs) were histochemically stained on frozen liver sections by applying peroxidase-antiperoxidase IgG complex as a ligand, and the FcR activity, i.e., capacity of binding the ligands represented by the FcR staining intensity, was semiquantitatively analyzed as an indicator of SEC function. The serum level of hyaluronic acid, which is specifically cleared from the circulation by receptor-mediated SEC endocytosis, was also assayed, along with the total serum bilirubin. Three days after the operation, the SECs of rejectors showed a significantly weaker FcR staining intensity of about half the value of that seen in the controls (P < 0.05), and staining disappeared after 5 days (P < 0.01). The decrease of FcR staining intensity, i.e., FcR activity, showed a correlation with elevation of the serum hyaluronic acid level (r = -0.77; P < 0.001). Histological evidence of endothelialitis and a significant elevation of total serum bilirubin (P < 0.01) were also present at 3 and 5 days, respectively. These results suggest that impairment of the endocytic function of SECs occurs at an earlier phase of acute liver rejection when compared with development of abnormalities of traditional indicators. Determination of receptor-mediated SEC endocytic functions may thus provide useful information for the early diagnosis of acute rejection.

  5. Fibroblast prostaglandin E2 synthesis. Persistence of an abnormal phenotype after short-term exposure to mononuclear cell products.

    PubMed

    Korn, J H

    1983-05-01

    Acquired abnormalities of connective tissue metabolism in inflammatory diseases often persist when lesional tissue is maintained in in vitro culture. Although connective tissue cells are exposed to inflammatory cell-derived mediators in vivo and such mediators have been shown to alter connective tissue cell behavior, it is unclear whether the persistence of metabolic defects in vitro could result from remote in vivo exposure to these mediators. An in vitro model was used to test whether transient exposure of normal fibroblasts to inflammatory mediators could lead to metabolic alterations that persist during in vitro culture. Short-term exposure of human foreskin fibroblasts in vitro to supernates of mitogen-activated peripheral blood mononuclear cells led to persistent abnormalities of prostaglandin E2 (PGE2) metabolism. Fibroblasts previously exposed to mononuclear cell products synthesized more than twice as much PGE2 when stimulated compared with similarly stimulated but previously unexposed control fibroblasts of the same strain. The enhanced PGE2 synthesis persisted for as long as 20 wk and 19 cell generations after the original exposure to mononuclear cell products. Exposure of fibroblast populations to mononuclear cell products may, thus, lead to metabolite alterations that are still evident after multiple cell generations.

  6. Growth requirements of human mammary epithelial cells in culture.

    PubMed

    Taylor-Papadimitriou, J; Shearer, M; Stoker, M G

    1977-12-15

    Colony-forming epithelial cells can be separated from the non-dividing "foam cells" in human milk by differential adhesion to glass and freezing. The growth of such partially purified mammary epithelial cells is stimulated by co-culture with non-dividing feeder cells. Foam cells, mitomycin-treated mouse fibroblast lines and human mammary fibroblasts and calf lens epithelial cells are all effective in promoting mammary epithelial cell growth. Contact between epithelial cells and feeders is not required for the growth-promoting effect. The mitogenic effect of epidermal growth factor on mammary epithelial cells also requires feeder cell activity.

  7. DASAF: An R Package for Deep Sequencing-Based Detection of Fetal Autosomal Abnormalities from Maternal Cell-Free DNA

    PubMed Central

    Tang, Xiaoyan; Qiu, Feng; Tao, Chunmei; Gao, Junhui; Ma, Mengmeng; Zhong, Tingyan; Cai, JianPing; Li, Yixue

    2016-01-01

    Background. With the development of massively parallel sequencing (MPS), noninvasive prenatal diagnosis using maternal cell-free DNA is fast becoming the preferred method of fetal chromosomal abnormality detection, due to its inherent high accuracy and low risk. Typically, MPS data is parsed to calculate a risk score, which is used to predict whether a fetal chromosome is normal or not. Although there are several highly sensitive and specific MPS data-parsing algorithms, there are currently no tools that implement these methods. Results. We developed an R package, detection of autosomal abnormalities for fetus (DASAF), that implements the three most popular trisomy detection methods—the standard Z-score (STDZ) method, the GC correction Z-score (GCCZ) method, and the internal reference Z-score (IRZ) method—together with one subchromosome abnormality identification method (SCAZ). Conclusions. With the cost of DNA sequencing declining and with advances in personalized medicine, the demand for noninvasive prenatal testing will undoubtedly increase, which will in turn trigger an increase in the tools available for subsequent analysis. DASAF is a user-friendly tool, implemented in R, that supports identification of whole-chromosome as well as subchromosome abnormalities, based on maternal cell-free DNA sequencing data after genome mapping. PMID:27437397

  8. Scalable Wordline Shielding Scheme using Dummy Cell beyond 40 nm NAND Flash Memory for Eliminating Abnormal Disturb of Edge Memory Cell

    NASA Astrophysics Data System (ADS)

    Park, Ki-Tae; Lee, SeungChul; Sel, Jong-Sun; Choi, Jungdal; Kim, Kinam

    2007-04-01

    A scalable wordline shielding scheme using dummy cell in NAND flash memory is presented to eliminate abnormal disturb of edge memory cell which causes to degradation of NAND flash performance. The proposed NAND flash is also able to improve more NAND scaling compared to conventional NAND string beyond sub-40 nm technology node. By using a proposed program scheme which includes an optimized bias voltage and adjusted Vth of dummy cell, almost abnormal disturbance of edge memory cell is removed and over 58% capacitive coupling noise between select transistor and edge memory cell can be reduced from both simulation and experimental results which used 63 nm NAND flash technology. The proposed NAND flash also improves Vth distribution of memory cell by providing almost equal operation conditions for all memory cells in NAND string.

  9. Budding yeast colony growth study based on circular granular cell

    NASA Astrophysics Data System (ADS)

    Aprianti, Devi; Khotimah, S. N.; Viridi, S.

    2016-08-01

    Yeast colony growth can be modelled by using circular granular cells, which can grow and produce buds. The bud growth angle can be set to regulate cell budding pattern. Cohesion force, contact force and Stokes force were adopted to accommodate the behaviour and interactions among cells. Simulation steps are divided into two steps, the explicit step is due to cell growing and implicit step for the cell rearrangement. Only in explicit step that time change was performed. In this study, we examine the influence of cell diameter growth time and reproduction time combination toward the growth of cell number and colony formation. We find a commutative relation between the cell diameter growth time and reproduction time to the specific growth rate. The greater value of the multiplication of the parameters, the smaller specific growth rate is obtained. It also shows a linear correlation between the specific growth rate and colony diameter growth rate.

  10. Magnetic resonance angiography in children with sickle cell disease and abnormal transcranial Doppler ultrasonography findings enrolled in the STOP study.

    PubMed

    Abboud, Miguel R; Cure, Joel; Granger, Suzanne; Gallagher, Dianne; Hsu, Lewis; Wang, Winfred; Woods, Gerald; Berman, Brian; Brambilla, Don; Pegelow, Charles; Lewin, Jonathan; Zimmermann, Robert A; Adams, Robert J

    2004-04-01

    The stroke prevention study in sickle cell disease (STOP) demonstrated a 90% reduction in stroke risk with transfusion among patients with time-averaged mean cerebral blood velocity (TAMV) of 200 cm/s or more as measured by transcranial Doppler (TCD). In STOP, 232 brain magnetic resonance angiograms (MRAs) were performed on 100 patients, 47 in the transfusion arm and 53 in the standard care arm. Baseline MRA findings were interpreted as normal in 75 patients and as indicating mild stenosis in 4 patients and severe stenosis in 21 patients. Among 35 patients who underwent magnetic resonance angiography within 30 days of random assignment, the TAMV was significantly higher in 7 patients with severe stenosis compared with 28 patients with normal MRA findings or mild stenosis (276.7 +/- 34 vs 215 +/- 15.6 cm/s; P<.001). In the standard care arm, 4 of 13 patients with abnormal MRA findings had strokes compared with 5 of 40 patients with normal MRA findings (P=.03). In this arm, TAMV became normal (less than 170 cm/s) or conditional (170-199 cm/s) in 26 of 38 patients with normal or mildly abnormal baseline MRA but remained abnormal in 8 of 10 patients with severely abnormal baseline MRA. These results suggest that TCD often detects flow abnormalities indicative of stroke risk before MRA lesions become evident. Furthermore, patients with abnormal MRA findings and higher TCD velocities are at higher risk for stroke, and their cerebral TAMVs are unlikely to decrease without transfusion.

  11. Total lymphoid irradiation leads to transient depletion of the mouse thymic medulla and persistent abnormalities among medullary stromal cells

    SciTech Connect

    Adkins, B.; Gandour, D.; Strober, S.; Weissman, I.

    1988-05-15

    Mice given multiple doses of sublethal irradiation to both the thymus and the peripheral lymphoid tissues showed major transient, and some persistent disruptions in general thymic architecture and in thymic stromal components. At 2 wk after total lymphoid irradiation (TLI), the thymus lacked identifiable medullary regions by immunohistochemical analyses. Medullary stromal cells expression MHC Ag or a medullary epithelial cell Ag, as well as medullary macrophages, were undetectable. Instead, the processes of cortical epithelial cells were observed throughout the entire thymus. Strikingly, thymocyte subsets with mature phenotypes (CD4+CD8- and CD4-CD8+) were present in the apparent absence of a medulla. This early, gross effect was rapidly reversed such that by 1 to 2 mo after TLI, medullary areas with MHC Ag-positive cells were evident. However, abnormalities in a subset of medullary stromal cells appeared to be more persistent. Medullary epithelial cells, identified by the MD1 mAb, were greatly reduced in number and abnormally organized for at least 4 mo after TLI. In addition, macrophages containing endogenous peroxidase activity, normally abundant in medullary regions, were undetectable at all times examined after TLI. Therefore, this irradiation regimen induced both transient and long term effects in the thymus, primarily in medullary regions. These results suggest that TLI may be used as an experimental tool for studying the impact of selective depletion of medullary stromal cells on the development of specific T cell functions.

  12. Alveolar abnormalities

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/001093.htm Alveolar abnormalities To use the sharing features on this page, please enable JavaScript. Alveolar abnormalities are changes in the tiny air sacs in ...

  13. Nail abnormalities

    MedlinePlus

    Beau's lines; Fingernail abnormalities; Spoon nails; Onycholysis; Leukonychia; Koilonychia; Brittle nails ... 2012:chap 71. Zaiac MN, Walker A. Nail abnormalities associated with systemic pathologies. Clin Dermatol . 2013;31: ...

  14. Proepithelin Regulates Prostate Cancer Cell Biology by Promoting Cell Growth, Migration, and Anchorage-Independent Growth

    PubMed Central

    Monami, Giada; Emiliozzi, Velia; Bitto, Alessandro; Lovat, Francesca; Xu, Shi-Qiong; Goldoni, Silvia; Fassan, Matteo; Serrero, Ginette; Gomella, Leonard G.; Baffa, Raffaele; Iozzo, Renato V.; Morrione, Andrea

    2009-01-01

    The growth factor proepithelin has recently emerged as an important regulator of transformation in several physiological and pathological systems. In this study, we determined the biological roles of proepithelin in prostate cancer cells using purified human recombinant proepithelin as well as proepithelin-depletion strategies. Proepithelin promoted the migration of androgen-dependent and -independent human prostate cancer cells; androgen-independent DU145 cells were the more responsive. In these cells, proepithelin additionally stimulated wound closure, invasion, and promotion of cell growth in vitro. These effects required the activation of both the Akt and mitogen-activated protein kinase pathways. We have analyzed proepithelin expression levels in different available prostate cancer microarray studies using the Oncomine database and found a statistically significant increase in proepithelin mRNA expression levels in prostate cancers compared with nonneoplastic controls. Notably, depletion of endogenous proepithelin by siRNA and antisense strategies impaired the ability of DU145 cells to grow and migrate after serum withdrawal and inhibited anchorage-independent growth. Our results provide the first evidence for a role of proepithelin in stimulating the migration, invasion, proliferation, and anchorage-independent growth of prostate cancer cells. This study supports the hypothesis that proepithelin may play a critical role as an autocrine growth factor in the establishment and initial progression of prostate cancer. Furthermore, proepithelin may prove to be a useful clinical marker for the diagnosis of prostate tumors. PMID:19179604

  15. Metabolism, cell growth and the bacterial cell cycle

    PubMed Central

    Wang, Jue D.; Levin, Petra A.

    2010-01-01

    Adaptation to fluctuations in nutrient availability is a fact of life for single-celled organisms in the ‘wild’. A decade ago our understanding of how bacteria adjust cell cycle parameters to accommodate changes in nutrient availability stemmed almost entirely from elegant physiological studies completed in the 1960s. In this Opinion article we summarize recent groundbreaking work in this area and discuss potential mechanisms by which nutrient availability and metabolic status are coordinated with cell growth, chromosome replication and cell division. PMID:19806155

  16. Overexpression of Rac1 in leukemia patients and its role in leukemia cell migration and growth

    SciTech Connect

    Wang, Jiying; Rao, Qing; Wang, Min; Wei, Hui; Xing, Haiyan; Liu, Hang; Wang, Yanzhong; Tang, Kejing; Peng, Leiwen; Tian, Zheng; Wang, Jianxiang

    2009-09-04

    Rac1 belongs to the Rho family that act as critical mediators of signaling pathways controlling cell migration and proliferation and contributes to the interactions of hematopoietic stem cells with their microenvironment. Alteration of Rac1 might result in unbalanced interactions and ultimately lead to leukemogenesis. In this study, we analyze the expression of Rac1 protein in leukemia patients and determine its role in the abnormal behaviours of leukemic cells. Rac1 protein is overexpressed in primary acute myeloid leukemia cells as compared to normal bone marrow mononuclear cells. siRNA-mediated silencing of Rac1 in leukemia cell lines induced inhibition of cell migration, proliferation, and colony formation. Additionally, blocking Rac1 activity by an inhibitor of Rac1-GTPase, NSC23766, suppressed cell migration and growth. We conclude that overexpression of Rac1 contributes to the accelerated migration and high proliferation potential of leukemia cells, which could be implicated in leukemia development and progression.

  17. Reversal of Phenotypic Abnormalities by CRISPR/Cas9-Mediated Gene Correction in Huntington Disease Patient-Derived Induced Pluripotent Stem Cells.

    PubMed

    Xu, Xiaohong; Tay, Yilin; Sim, Bernice; Yoon, Su-In; Huang, Yihui; Ooi, Jolene; Utami, Kagistia Hana; Ziaei, Amin; Ng, Bryan; Radulescu, Carola; Low, Donovan; Ng, Alvin Yu Jin; Loh, Marie; Venkatesh, Byrappa; Ginhoux, Florent; Augustine, George J; Pouladi, Mahmoud A

    2017-02-21

    Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in HTT. Here we report correction of HD human induced pluripotent stem cells (hiPSCs) using a CRISPR-Cas9 and piggyBac transposon-based approach. We show that both HD and corrected isogenic hiPSCs can be differentiated into excitable, synaptically active forebrain neurons. We further demonstrate that phenotypic abnormalities in HD hiPSC-derived neural cells, including impaired neural rosette formation, increased susceptibility to growth factor withdrawal, and deficits in mitochondrial respiration, are rescued in isogenic controls. Importantly, using genome-wide expression analysis, we show that a number of apparent gene expression differences detected between HD and non-related healthy control lines are absent between HD and corrected lines, suggesting that these differences are likely related to genetic background rather than HD-specific effects. Our study demonstrates correction of HD hiPSCs and associated phenotypic abnormalities, and the importance of isogenic controls for disease modeling using hiPSCs.

  18. FNC efficiently inhibits mantle cell lymphoma growth.

    PubMed

    Zhang, Yan; Zhang, Rong; Ding, Xixi; Peng, Bangan; Wang, Ning; Ma, Fang; Peng, Youmei; Wang, Qingduan; Chang, Junbiao

    2017-01-01

    FNC, 2'-deoxy-2'-β-fluoro-4'-azidocytidine, is a novel cytidine analogue, that has shown strong antiproliferative activity in human lymphoma, lung adenocarcinoma and acute myeloid leukemia. In this study, we investigated the effects of FNC on mantle cell lymphoma (MCL) and the underlying mechanisms. In in vitro experiments, cell viability was detected by the CCK8 assay, and cell cycle progression and apoptosis were assessed by flow cytometry, and the expression of relative apoptosis proteins were detected by Western Blot. The in vivo antitumor effect of FNC was investigated in a SCID xenograft model. Finally, the mechanisms of action of FNC were assessed using a whole human genome expression profile chip. The data showed that FNC inhibited cell growth in a dose- and time-dependent manner, and FNC could induce apoptosis by the death recepter pathways in JeKo-1 cells and arrest the cell cycle in the G1/S or G2/M phase. Notably, FNC showed in vivo efficacy in mice bearing JeKo-1 xenograft tumors. Gene expression profile analysis revealed that the differentially expressed genes were mainly focused on the immune system process, cellular process and death. These findings implied that FNC may be a valuable therapeutic in mantle cell lymphoma and provided an experimental basis for the early clinical application of FNC.

  19. FNC efficiently inhibits mantle cell lymphoma growth

    PubMed Central

    Ding, Xixi; Peng, Bangan; Wang, Ning; Ma, Fang; Peng, Youmei; Wang, Qingduan; Chang, Junbiao

    2017-01-01

    FNC, 2'-deoxy-2'-β-fluoro-4'-azidocytidine, is a novel cytidine analogue, that has shown strong antiproliferative activity in human lymphoma, lung adenocarcinoma and acute myeloid leukemia. In this study, we investigated the effects of FNC on mantle cell lymphoma (MCL) and the underlying mechanisms. In in vitro experiments, cell viability was detected by the CCK8 assay, and cell cycle progression and apoptosis were assessed by flow cytometry, and the expression of relative apoptosis proteins were detected by Western Blot. The in vivo antitumor effect of FNC was investigated in a SCID xenograft model. Finally, the mechanisms of action of FNC were assessed using a whole human genome expression profile chip. The data showed that FNC inhibited cell growth in a dose- and time-dependent manner, and FNC could induce apoptosis by the death recepter pathways in JeKo-1 cells and arrest the cell cycle in the G1/S or G2/M phase. Notably, FNC showed in vivo efficacy in mice bearing JeKo-1 xenograft tumors. Gene expression profile analysis revealed that the differentially expressed genes were mainly focused on the immune system process, cellular process and death. These findings implied that FNC may be a valuable therapeutic in mantle cell lymphoma and provided an experimental basis for the early clinical application of FNC. PMID:28333959

  20. Hormonal and echocardiographic abnormalities in adult patients with sickle-cell anemia in Bahrain

    PubMed Central

    Garadah, Taysir S; Jaradat, Ahmed A; Alalawi, Mohammed E; Hassan, Adla B

    2016-01-01

    Background Adrenal, thyroid, and parathyroid gland hormonal changes are recognized in children with homozygous (HbSS) sickle-cell anemia (SCA), but are not clear in adult patients with SCA. Aim To assess the metabolic and endocrine abnormalities in adult patients with SCA and evaluate left ventricular (LV) systolic and diastolic functions compared with patients with no SCA and further study the relationship between serum levels of cortisol, free thyroxine (T4), and testosterone with serum ferritin. Materials and methods The study was conducted on 82 patients with adult HbSS SCA compared with a sex- and age-matched control group. The serum levels of cortisol, parathyroid hormone (PTH), testosterone, thyroid-stimulating hormone (TSH), and free T4 were compared. Blood levels of hemoglobin, reticulocyte count, lactate dehydrogenase (LDH), calcium, alkaline phosphatase (ALP), vitamin D3, and ferritin were also compared. Pulsed Doppler echo was performed to evaluate the LV mass, wall thickness, and cavity dimensions with diastolic filling velocities of early (E) and atria (A) waves. Biometric data were analyzed as mean ± standard deviation between the two groups. Multiple regression analysis was performed between serum levels of ferritin as independent variable and testosterone, cortisol, and thyroid hormones. Results A total of 82 adult patients with HbSS SCA were enrolled who had a mean age of 21±5.7 years, with 51 males (62%). Patients with SCA compared with the control group had significantly lower hemoglobin, body mass index, cortisol, vitamin D3, testosterone, and T4. Furthermore, there were significantly high levels of reticulocyte count, PTH, TSH, ferritin, LDH, ALP, and uric acid. The incidence of subclinical hypothyroidism and adrenal insufficiency was 7% and 4.8%, respectively, with hypogonadism 9.8% and vitamin D3 deficiency 61%. There were inverse relationships between ferritin as independent variable and serum levels of testosterone, T4, and cortisol

  1. Berberine slows cell growth in autosomal dominant polycystic kidney disease cells

    SciTech Connect

    Bonon, Anna; Mangolini, Alessandra; Pinton, Paolo; Senno, Laura del; Aguiari, Gianluca

    2013-11-22

    Highlights: •Berberine at appropriate doses slows cell proliferation in ADPKD cystic cells. •Reduction of cell growth by berberine occurs by inhibition of ERK and p70-S6 kinase. •Higher doses of berberine cause an overall cytotoxic effect. •Berberine overdose induces apoptotic bodies formation and DNA fragmentation. •Antiproliferative properties of this drug make it a new candidate for ADPKD therapy. -- Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary monogenic disorder characterized by development and enlargement of kidney cysts that lead to loss of renal function. It is caused by mutations in two genes (PKD1 and PKD2) encoding for polycystin-1 and polycystin-2 proteins which regulate different signals including cAMP, mTOR and EGFR pathways. Abnormal activation of these signals following PC1 or PC2 loss of function causes an increased cell proliferation which is a typical hallmark of this disease. Despite the promising findings obtained in animal models with targeted inhibitors able to reduce cystic cell growth, currently, no specific approved therapy for ADPKD is available. Therefore, the research of new more effective molecules could be crucial for the treatment of this severe pathology. In this regard, we have studied the effect of berberine, an isoquinoline quaternary alkaloid, on cell proliferation and apoptosis in human and mouse ADPKD cystic cell lines. Berberine treatment slows cell proliferation of ADPKD cystic cells in a dose-dependent manner and at high doses (100 μg/mL) it induces cell death in cystic cells as well as in normal kidney tubule cells. However, at 10 μg/mL, berberine reduces cell growth in ADPKD cystic cells only enhancing G{sub 0}/G{sub 1} phase of cell cycle and inhibiting ERK and p70-S6 kinases. Our results indicate that berberine shows a selected antiproliferative activity in cellular models for ADPKD, suggesting that this molecule and similar natural compounds could open new

  2. Mesenchymal stem cell like (MSCl) cells generated from human embryonic stem cells support pluripotent cell growth

    SciTech Connect

    Varga, Nora; Vereb, Zoltan; Rajnavoelgyi, Eva; Nemet, Katalin; Uher, Ferenc; Sarkadi, Balazs; Apati, Agota

    2011-10-28

    Highlights: Black-Right-Pointing-Pointer MSC like cells were derived from hESC by a simple and reproducible method. Black-Right-Pointing-Pointer Differentiation and immunosuppressive features of MSCl cells were similar to bmMSC. Black-Right-Pointing-Pointer MSCl cells as feeder cells support the undifferentiated growth of hESC. -- Abstract: Mesenchymal stem cell like (MSCl) cells were generated from human embryonic stem cells (hESC) through embryoid body formation, and isolated by adherence to plastic surface. MSCl cell lines could be propagated without changes in morphological or functional characteristics for more than 15 passages. These cells, as well as their fluorescent protein expressing stable derivatives, efficiently supported the growth of undifferentiated human embryonic stem cells as feeder cells. The MSCl cells did not express the embryonic (Oct4, Nanog, ABCG2, PODXL, or SSEA4), or hematopoietic (CD34, CD45, CD14, CD133, HLA-DR) stem cell markers, while were positive for the characteristic cell surface markers of MSCs (CD44, CD73, CD90, CD105). MSCl cells could be differentiated toward osteogenic, chondrogenic or adipogenic directions and exhibited significant inhibition of mitogen-activated lymphocyte proliferation, and thus presented immunosuppressive features. We suggest that cultured MSCl cells can properly model human MSCs and be applied as efficient feeders in hESC cultures.

  3. PREVENTION OF CONVERSION TO ABNORMAL TCD WITH HYDROXYUREA IN SICKLE CELL ANEMIA: A PHASE III INTERNATIONAL RANDOMIZED CLINICAL TRIAL

    PubMed Central

    Hankins, Jane S.; McCarville, M. Beth; Rankine-Mullings, Angela; Reid, Marvin E.; Lobo, Clarisse L.C.; Moura, Patricia G.; Ali, Susanna; Soares, Deanne; Aldred, Karen; Jay, Dennis W.; Aygun, Banu; Bennett, John; Kang, Guolian; Goldsmith, Jonathan C.; Smeltzer, Matthew P.; Boyett, James M.; Ware, Russell E.

    2015-01-01

    Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170-199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was an NHLBI-funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSβ0-thalassemia (1), and HbSD (1), median age 5.4 years (range, 2.7-9.8)]. Due to slow patient accrual and administrative delays, SCATE was terminated early. In an intention-to-treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI 0 to 35%) in the hydroxyurea arm and 47% (95% CI 6 to 81%) in observation arm at 15 months (p=0.16). In post-hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities, compared to observation (0% versus 50%, p=0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (−15.5 versus +10.2 cm/sec, p=0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities. PMID:26414435

  4. Prevention of conversion to abnormal transcranial Doppler with hydroxyurea in sickle cell anemia: A Phase III international randomized clinical trial.

    PubMed

    Hankins, Jane S; McCarville, Mary Beth; Rankine-Mullings, Angela; Reid, Marvin E; Lobo, Clarisse L C; Moura, Patricia G; Ali, Susanna; Soares, Deanne P; Aldred, Karen; Jay, Dennis W; Aygun, Banu; Bennett, John; Kang, Guolian; Goldsmith, Jonathan C; Smeltzer, Matthew P; Boyett, James M; Ware, Russell E

    2015-12-01

    Children with sickle cell anemia (SCA) and conditional transcranial Doppler (TCD) ultrasound velocities (170-199 cm/sec) may develop stroke. However, with limited available clinical data, the current standard of care for conditional TCD velocities is observation. The efficacy of hydroxyurea in preventing conversion from conditional to abnormal TCD (≥200 cm/sec), which confers a higher stroke risk, has not been studied prospectively in a randomized trial. Sparing Conversion to Abnormal TCD Elevation (SCATE #NCT01531387) was a National Heart, Lung, and Blood Institute-funded Phase III multicenter international clinical trial comparing alternative therapy (hydroxyurea) to standard care (observation) to prevent conversion from conditional to abnormal TCD velocity in children with SCA. SCATE enrolled 38 children from the United States, Jamaica, and Brazil [HbSS (36), HbSβ(0) -thalassemia (1), and HbSD (1), median age = 5.4 years (range, 2.7-9.8)]. Because of the slow patient accrual and administrative delays, SCATE was terminated early. In an intention-to-treat analysis, the cumulative incidence of abnormal conversion was 9% (95% CI = 0-35%) in the hydroxyurea arm and 47% (95% CI = 6-81%) in observation arm at 15 months (P = 0.16). In post hoc analysis according to treatment received, significantly fewer children on hydroxyurea converted to abnormal TCD velocities when compared with observation (0% vs. 50%, P = 0.02). After a mean of 10.1 months, a significant change in mean TCD velocity was observed with hydroxyurea treatment (-15.5 vs. +10.2 cm/sec, P = 0.02). No stroke events occurred in either arm. Hydroxyurea reduces TCD velocities in children with SCA and conditional velocities.

  5. Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death.

    PubMed

    Parker, J A; Connolly, J B; Wellington, C; Hayden, M; Dausset, J; Neri, C

    2001-11-06

    Huntington's disease (HD) is a dominant neurodegenerative disease caused by polyglutamine (polyQ) expansion in the protein huntingtin (htt). HD pathogenesis appears to involve the production of mutated N-terminal htt, cytoplasmic and nuclear aggregation of htt, and abnormal activity of htt interactor proteins essential to neuronal survival. Before cell death, neuronal dysfunction may be an important step of HD pathogenesis. To explore polyQ-mediated neuronal toxicity, we expressed the first 57 amino acids of human htt containing normal [19 Gln residues (Glns)] and expanded (88 or 128 Glns) polyQ fused to fluorescent marker proteins in the six touch receptor neurons of Caenorhabditis elegans. Expanded polyQ produced touch insensitivity in young adults. Noticeably, only 28 +/- 6% of animals with 128 Glns were touch sensitive in the tail, as mediated by the PLM neurons. Similar perinuclear deposits and faint nuclear accumulation of fusion proteins with 19, 88, and 128 Glns were observed. In contrast, significant deposits and morphological abnormalities in PLM cell axons were observed with expanded polyQ (128 Glns) and partially correlated with touch insensitivity. PLM cell death was not detected in young or old adults. These animals indicate that significant neuronal dysfunction without cell death may be induced by expanded polyQ and may correlate with axonal insults, and not cell body aggregates. These animals also provide a suitable model to perform in vivo suppression of polyQ-mediated neuronal dysfunction.

  6. Effects of ocean acidification driven by elevated CO2 on larval shell growth and abnormal rates of the venerid clam, Mactra veneriformis

    NASA Astrophysics Data System (ADS)

    Kim, Jee-Hoon; Yu, Ok Hwan; Yang, Eun Jin; Kang, Sung-Ho; Kim, Won; Choy, Eun Jung

    2016-11-01

    The venerid clam ( Mactra veneriformis Reeve 1854) is one of the main cultured bivalve species in intertidal and shallow subtidal ecosystems along the west coast of Korea. To understand the effects of ocean acidification on the early life stages of Korean clams, we investigated shell growth and abnormality rates and types in the D-shaped, umbonate veliger, and pediveliger stages of the venerid clam M. veneriformis during exposure to elevated seawater pCO2. In particular, we examined abnormal types of larval shell morphology categorized as shell deformations, shell distortions, and shell fissures. Specimens were incubated in seawater equilibrated with bubbled CO2-enriched air at (400±25)×10-6 (ambient control), (800±25)×10-6 (high pCO2), or (1 200±28)×10-6 (extremely high pCO2), the atmospheric CO2 concentrations predicted for the years 2014, 2084, and 2154 (70-year intervals; two human generations), respectively, in the Representative Concentration Pathway (RCP) 8.5 scenario. The mean shell lengths of larvae were significantly decreased in the high and extremely high pCO2 groups compared with the ambient control groups. Furthermore, under high and extremely high pCO2 conditions, the cultures exhibited significantly increased abundances of abnormal larvae and increased severity of abnormalities compared with the ambient control. In the umbonate veliger stage of the experimental larvae, the most common abnormalities were shell deformations, distortions, and fissures; on the other hand, convex hinges and mantle protuberances were absent. These results suggest that elevated CO2 exerts an additional burden on the health of M. veneriformis larvae by impairing early development.

  7. Mechanisms of Abnormal Cell-Extracellular Matrix Interactions in Human Breast Cancer

    DTIC Science & Technology

    1999-09-01

    plectin, bullous pemphigoid antigen 1 (BPAG1) and envoplakin (30). While desmoplakin and BPAG1 are constituents of desmosome and hemidesomsome...coil proteins (30). Loss of plectin function, as in the case with BPAG1, has been linked to skin diseases such as epidermolysis bullosa possibly...caused by disruption of anchorage site of keratin filaments to hemidesmosomes (37). On the other hand, abnormal expression of desmosomal proteins such as

  8. [Stem cells and growth factors in wound healing].

    PubMed

    Pikuła, Michał; Langa, Paulina; Kosikowska, Paulina; Trzonkowski, Piotr

    2015-01-02

    Wound healing is a complex process which depends on the presence of various types of cells, growth factors, cytokines and the elements of extracellular matrix. A wound is a portal of entry for numerous pathogens, therefore during the evolution wound healing process has formed very early, being critical for the survival of every individual. Stem cells, which give rise to their early descendants progenitor cells and subsequently differentiated cells, play a specific role in the process of wound healing. Among the most important cells which take part in wound healing the following cells need to be distinguished: epidermal stem cells, dermal precursor of fibroblasts, adipose-derived stem cells as well as bone marrow cells. The activity of these cells is strictly regulated by various growth factors, inter alia epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF), vascular endothelial growth factor (VEGF). Any disorders in functioning of stem cells and biological activity of growth factors may lead to the defects in wound healing, for instance delayed wound healing or creation of hypertrophic scars. Therefore, knowledge concerning the mechanisms of wound healing is extremely essential from clinical point of view. In this review the current state of the knowledge of the role of stem cells and growth factors in the process of wound healing has been presented. Moreover, some clinical aspects of wound healing as well as the possibility of the therapy based on stem cells and growth factors have included.

  9. Nanoscale Drug Delivery Platforms Overcome Platinum-Based Resistance in Cancer Cells Due to Abnormal Membrane Protein Trafficking

    PubMed Central

    Xue, Xue; Hall, Matthew D.; Zhang, Qiang; Wang, Paul C.; Gottesman, Michael M.; Liang, Xing-Jie

    2014-01-01

    The development of cellular resistance to platinum-based chemotherapies is often associated with reduced intracellular platinum concentrations. In some models, this reduction is due to abnormal membrane protein trafficking, resulting in reduced uptake by transporters at the cell surface. Given the central role of platinum drugs in the clinic, it is critical to overcome cisplatin resistance by bypassing the plasma membrane barrier to significantly increase the intracellular cisplatin concentration enough to inhibit the proliferation of cisplatin-resistant cells. Therefore, rational design of appropriate nanoscale drug delivery platforms (nDDPs) loaded with cisplatin or other platinum analogs as payloads is a possible strategy to solve this problem. This review will focus on the known mechanism of membrane trafficking in cisplatin-resistant cells, and the development and employment of nDDPs to improve cell uptake of cisplatin. PMID:24219825

  10. Nanoscale drug delivery platforms overcome platinum-based resistance in cancer cells due to abnormal membrane protein trafficking.

    PubMed

    Xue, Xue; Hall, Matthew D; Zhang, Qiang; Wang, Paul C; Gottesman, Michael M; Liang, Xing-Jie

    2013-12-23

    The development of cellular resistance to platinum-based chemotherapies is often associated with reduced intracellular platinum concentrations. In some models, this reduction is due to abnormal membrane protein trafficking, resulting in reduced uptake by transporters at the cell surface. Given the central role of platinum drugs in the clinic, it is critical to overcome cisplatin resistance by bypassing the plasma membrane barrier to significantly increase the intracellular cisplatin concentration enough to inhibit the proliferation of cisplatin-resistant cells. Therefore, rational design of appropriate nanoscale drug delivery platforms (nDDPs) loaded with cisplatin or other platinum analogues as payloads is a possible strategy to solve this problem. This review will focus on the known mechanism of membrane trafficking in cisplatin-resistant cells and the development and employment of nDDPs to improve cell uptake of cisplatin.

  11. Functional characterization of the Arabidopsis eukaryotic translation initiation factor 5A-2 that plays a crucial role in plant growth and development by regulating cell division, cell growth, and cell death.

    PubMed

    Feng, Haizhong; Chen, Qingguo; Feng, Jian; Zhang, Jian; Yang, Xiaohui; Zuo, Jianru

    2007-07-01

    The eukaryotic translation initiation factor 5A (eIF-5A) is a highly conserved protein found in all eukaryotic organisms. Although originally identified as a translation initiation factor, recent studies in mammalian and yeast (Saccharomyces cerevisiae) cells suggest that eIF-5A is mainly involved in RNA metabolism and trafficking, thereby regulating cell proliferation, cell growth, and programmed cell death. In higher plants, the physiological function of eIF-5A remains largely unknown. Here, we report the identification and characterization of an Arabidopsis (Arabidopsis thaliana) mutant fumonisin B(1)-resistant12 (fbr12). The fbr12 mutant shows an antiapoptotic phenotype and has reduced dark-induced leaf senescence. Moreover, fbr12 displays severe defects in plant growth and development. The fbr12 mutant plant is extreme dwarf with substantially reduced size and number of all adult organs. During reproductive development, fbr12 causes abnormal development of floral organs and defective sporogenesis, leading to the abortion of both female and male germline cells. Microscopic studies revealed that these developmental defects are associated with abnormal cell division and cell growth. Genetic and molecular analyses indicated that FBR12 encodes a putative eIF-5A-2 protein. When expressed in a yeast mutant strain carrying a mutation in the eIF-5A gene, FBR12 cDNA is able to rescue the lethal phenotype of the yeast mutant, indicating that FBR12 is a functional eIF-5A. We propose that FBR12/eIF-5A-2 is fundamental for plant growth and development by regulating cell division, cell growth, and cell death.

  12. Nuclear abnormalities in buccal mucosa cells of patients with type I and II diabetes treated with folic acid.

    PubMed

    Gómez-Meda, B C; Zamora-Perez, A L; Muñoz-Magallanes, T; Sánchez-Parada, M G; García Bañuelos, J J; Guerrero-Velázquez, C; Sánchez-Orozco, L V; Vera-Cruz, J M; Armendáriz-Borunda, J; Zúñiga-González, G M

    2016-02-01

    Diabetes mellitus (DM) is characterized by high blood glucose. Excessive production of free radicals may cause oxidative damage to DNA and other molecules, leading to complications of the disease. It may be possible to delay or reduce such damage by administration of antioxidants such as folic acid (FA). The objective of this study was to determine the effect of FA on nuclear abnormalities (NAs) in the oral mucosa of patients with DM. NAs (micronucleated cells, binucleated cells, pyknotic nuclei, karyorrhexis, karyolysis, abnormally condensed chromatin, and nuclear buds) were analyzed in 2000 cells from 45 healthy individuals (control group) and 55 patients with controlled or uncontrolled type I or II DM; 35 patients in the latter group were treated with FA. Samples were taken from the FA group before and after treatment. An increased rate of NAs was found in patients with DM in comparison with that of the control group (P<0.001). FA supplementation in patients with DM reduced the frequency of NAs (20.4 ± 8.0 before treatment vs. 10.5 ± 5.2 after treatment; P<0.001). The type I and type II DM and controlled and uncontrolled DM subgroups were analyzed in terms of sex, age, and smoking habit. The significantly reduced frequencies of buccal mucosa cells with micronuclei, binucleation, pyknosis, karyorrhexis, karyorrhexis+abnormally condensed chromatin, karyolysis, and nuclear buds produced by FA supplementation in DM patients (P<0.02) are consistent with the idea that free radicals are responsible for the increased frequency of NAs in DM patients.

  13. Enhanced conversion of induced neuronal cells (iN cells) from human fibroblasts: Utility in uncovering cellular deficits in mental illness-associated chromosomal abnormalities.

    PubMed

    Passeri, Eleonora; Wilson, Ashley M; Primerano, Amedeo; Kondo, Mari A; Sengupta, Srona; Srivastava, Rupali; Koga, Minori; Obie, Cassandra; Zandi, Peter P; Goes, Fernando S; Valle, David; Rapoport, Judith L; Sawa, Akira; Kano, Shin-ichi; Ishizuka, Koko

    2015-12-01

    The novel technology of induced neuronal cells (iN cells) is promising for translational neuroscience, as it allows the conversion of human fibroblasts into cells with postmitotic neuronal traits. However, a major technical barrier is the low conversion rate. To overcome this problem, we optimized the conversion media. Using our improved formulation, we studied how major mental illness-associated chromosomal abnormalities may impact the characteristics of iN cells. We demonstrated that our new iN cell culture protocol enabled us to obtain more precise measurement of neuronal cellular phenotypes than previous iN cell methods. Thus, this iN cell culture provides a platform to efficiently obtain possible cellular phenotypes caused by genetic differences, which can be more thoroughly studied in research using other human cell models such as induced pluripotent stem cells.

  14. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  15. Abnormal crystal growth in CH3NH3PbI3-xClx using a multi-cycle solution coating process

    SciTech Connect

    Dong, Qingfeng; Yuan, Yongbo; Shao, Yuchuan; Fang, Yanjun; Wang, Qi; Huang, Jinsong

    2015-06-23

    Recently, the efficiency of organolead trihalide perovskite solar cells has improved greatly because of improved material qualities with longer carrier diffusion lengths. Mixing chlorine in the precursor for mixed halide films has been reported to dramatically enhance the diffusion lengths of mixed halide perovskite films, mainly as a result of a much longer carrier recombination lifetime. Here we report that adding Cl containing precursor for mixed halide perovskite formation can induce the abnormal grain growth behavior that yields well-oriented grains accompanied by the appearance of some very large size grains. The abnormal grain growth becomes prominent only after multi-cycle coating of MAI : MACl blend precursor. The large grain size is found mainly to contribute to a longer carrier charge recombination lifetime, and thus increases the device efficiency to 18.9%, but without significantly impacting the carrier transport property. As a result, the strong correlation identified between material process and morphology provides guidelines for future material optimization and device efficiency enhancement.

  16. Abnormalities of follicular helper T-cell number and function in Wiskott-Aldrich syndrome

    PubMed Central

    Zhang, Xuan; Dai, Rongxin; Li, Wenyan; Zhao, Hongyi; Zhang, Yongjie; Zhou, Lina; Du, Hongqiang; Luo, Guangjin; Wu, Junfeng; Niu, Linlin; An, Yunfei; Zhang, Zhiyong; Ding, Yuan; Song, Wenxia; Liu, Chaohong

    2016-01-01

    Wiskott-Aldrich syndrome protein (WASp) is a hematopoietic-specific regulator of actin nucleation. Wiskott-Aldrich syndrome (WAS) patients show immunodeficiencies, most of which have been attributed to defective T-cell functions. T follicular helper (Tfh) cells are the major CD4+ T-cell subset with specialized B-cell helper capabilities. Aberrant Tfh cells activities are involved in immunopathologies such as autoimmunity, immunodeficiencies, and lymphomas. We found that in WAS patients, the number of circulating Tfh cells was significantly reduced due to reduced proliferation and increased apoptosis, and Tfh cells were Th2 and Th17 polarized. The expression of inducible costimulator (ICOS) in circulating Tfh cells was higher in WAS patients than in controls. BCL6 expression was decreased in total CD4+ T and Tfh cells of WAS patients. Mirroring the results in patients, the frequency of Tfh cells in WAS knockout (KO) mice was decreased, as was the frequency of BCL6+ Tfh cells, but the frequency of ICOS+ Tfh cells was increased. Using WAS chimera mice, we found that the number of ICOS+ Tfh cells was decreased in WAS chimera mice, indicating that the increase in ICOS+ Tfh cells in WAS KO mice was cell extrinsic. The data from in vivo CD4+ naive T-cell adoptive transfer mice as well as in vitro coculture of naive B and Tfh cells showed that the defective function of WASp-deficient Tfh cells was T-cell intrinsic. Consistent findings in both WAS patients and WAS KO mice suggested an essential role for WASp in the development and memory response of Tfh cells and that WASp deficiency causes a deficient differentiation defect in Tfh cells by downregulating the transcription level of BCL6. PMID:27170596

  17. Abnormal strong burn-in degradation of highly efficient polymer solar cells caused by spinodal donor-acceptor demixing

    NASA Astrophysics Data System (ADS)

    Li, Ning; Perea, José Darío; Kassar, Thaer; Richter, Moses; Heumueller, Thomas; Matt, Gebhard J.; Hou, Yi; Güldal, Nusret S.; Chen, Haiwei; Chen, Shi; Langner, Stefan; Berlinghof, Marvin; Unruh, Tobias; Brabec, Christoph J.

    2017-02-01

    The performance of organic solar cells is determined by the delicate, meticulously optimized bulk-heterojunction microstructure, which consists of finely mixed and relatively separated donor/acceptor regions. Here we demonstrate an abnormal strong burn-in degradation in highly efficient polymer solar cells caused by spinodal demixing of the donor and acceptor phases, which dramatically reduces charge generation and can be attributed to the inherently low miscibility of both materials. Even though the microstructure can be kinetically tuned for achieving high-performance, the inherently low miscibility of donor and acceptor leads to spontaneous phase separation in the solid state, even at room temperature and in the dark. A theoretical calculation of the molecular parameters and construction of the spinodal phase diagrams highlight molecular incompatibilities between the donor and acceptor as a dominant mechanism for burn-in degradation, which is to date the major short-time loss reducing the performance and stability of organic solar cells.

  18. Abnormal strong burn-in degradation of highly efficient polymer solar cells caused by spinodal donor-acceptor demixing

    PubMed Central

    Li, Ning; Perea, José Darío; Kassar, Thaer; Richter, Moses; Heumueller, Thomas; Matt, Gebhard J.; Hou, Yi; Güldal, Nusret S.; Chen, Haiwei; Chen, Shi; Langner, Stefan; Berlinghof, Marvin; Unruh, Tobias; Brabec, Christoph J.

    2017-01-01

    The performance of organic solar cells is determined by the delicate, meticulously optimized bulk-heterojunction microstructure, which consists of finely mixed and relatively separated donor/acceptor regions. Here we demonstrate an abnormal strong burn-in degradation in highly efficient polymer solar cells caused by spinodal demixing of the donor and acceptor phases, which dramatically reduces charge generation and can be attributed to the inherently low miscibility of both materials. Even though the microstructure can be kinetically tuned for achieving high-performance, the inherently low miscibility of donor and acceptor leads to spontaneous phase separation in the solid state, even at room temperature and in the dark. A theoretical calculation of the molecular parameters and construction of the spinodal phase diagrams highlight molecular incompatibilities between the donor and acceptor as a dominant mechanism for burn-in degradation, which is to date the major short-time loss reducing the performance and stability of organic solar cells. PMID:28224984

  19. Fluid shear stress as a regulator of gene expression in vascular cells: possible correlations with diabetic abnormalities

    NASA Technical Reports Server (NTRS)

    Papadaki, M.; Eskin, S. G.; Ruef, J.; Runge, M. S.; McIntire, L. V.

    1999-01-01

    Diabetes mellitus is associated with increased frequency, severity and more rapid progression of cardiovascular diseases. Metabolic perturbations from hyperglycemia result in disturbed endothelium-dependent relaxation, activation of coagulation pathways, depressed fibrinolysis, and other abnormalities in vascular homeostasis. Atherosclerosis is localized mainly at areas of geometric irregularity at which blood vessels branch, curve and change diameter, and where blood is subjected to sudden changes in velocity and/or direction of flow. Shear stress resulting from blood flow is a well known modulator of vascular cell function. This paper presents what is currently known regarding the molecular mechanisms responsible for signal transduction and gene regulation in vascular cells exposed to shear stress. Considering the importance of the hemodynamic environment of vascular cells might be vital to increasing our understanding of diabetes.

  20. Abnormalities in endocrine and immune cells are correlated in dextran-sulfate-sodium-induced colitis in rats

    PubMed Central

    El-Salhy, Magdy; Hatlebakk, Jan Gunnar; Gilja, Odd Helge

    2016-01-01

    The interaction between the gut hormones and the immune system has been suggested to serve an important role in the pathophysiology of inflammatory bowel disease. The aims of the present study were to elucidate the possible abnormalities in the colonic endocrine cells in rats with dextran sodium sulfate (DSS)-induced colitis, and to determine whether they are correlated with alterations in the immune cells. A total of 24 male Wistar rats were divided into two groups: Control and DSS-induced colitis. Colonic tissues were harvested via postmortem laparotomy from all of the animals at the end of the experimental period, and fixed and sectioned for histology. The colonic endocrine and immune cells in those tissue samples were immunostained and their densities quantified by computerized image analysis. The densities of chromogranin A, serotonin, peptide YY and oxyntomodulin cells were significantly higher, and those of pancreatic peptide and somatostatin cells were lower in rats with DSS-induced colitis than in the controls. The densities of mucosal leukocytes, T and B lymphocytes, macrophages/monocytes, and mast cells were significantly higher than in the controls, and these changes were closely associated with the aforementioned changes in all endocrine cell types. These observations indicate an interaction between intestinal hormones and the immune system as represented by immune cells. PMID:27959399

  1. In vivo cell-autonomous transcriptional abnormalities revealed in mice expressing mutant huntingtin in striatal but not cortical neurons.

    PubMed

    Thomas, Elizabeth A; Coppola, Giovanni; Tang, Bin; Kuhn, Alexandre; Kim, SoongHo; Geschwind, Daniel H; Brown, Timothy B; Luthi-Carter, Ruth; Ehrlich, Michelle E

    2011-03-15

    Huntington's disease (HD), caused by a CAG repeat expansion in the huntingtin (HTT) gene, is characterized by abnormal protein aggregates and motor and cognitive dysfunction. Htt protein is ubiquitously expressed, but the striatal medium spiny neuron (MSN) is most susceptible to dysfunction and death. Abnormal gene expression represents a core pathogenic feature of HD, but the relative roles of cell-autonomous and non-cell-autonomous effects on transcription remain unclear. To determine the extent of cell-autonomous dysregulation in the striatum in vivo, we examined genome-wide RNA expression in symptomatic D9-N171-98Q (a.k.a. DE5) transgenic mice in which the forebrain expression of the first 171 amino acids of human Htt with a 98Q repeat expansion is limited to MSNs. Microarray data generated from these mice were compared with those generated on the identical array platform from a pan-neuronal HD mouse model, R6/2, carrying two different CAG repeat lengths, and a relatively high degree of overlap of changes in gene expression was revealed. We further focused on known canonical pathways associated with excitotoxicity, oxidative stress, mitochondrial dysfunction, dopamine signaling and trophic support. While genes related to excitotoxicity, dopamine signaling and trophic support were altered in both DE5 and R6/2 mice, which may be either cell autonomous or non-cell autonomous, genes related to mitochondrial dysfunction, oxidative stress and the peroxisome proliferator-activated receptor are primarily affected in DE5 transgenic mice, indicating cell-autonomous mechanisms. Overall, HD-induced dysregulation of the striatal transcriptome can be largely attributed to intrinsic effects of mutant Htt, in the absence of expression in cortical neurons.

  2. Controlling mechanisms in directional growth of aggregated archaeal cells.

    PubMed

    Milkevych, Viktor; Batstone, Damien J

    2014-12-28

    Members of the family Methanosarcinaceae are important archaeal representatives due to their broad functionality, ubiquitous presence, and functionality in harsh environments. A key characteristic is their multicellular (packet) morphology represented by aggregates of spatially confined cells. This morphology is driven by directed growth of cells in confinement with sequential variation in growth direction. To further understand why spatially confined Methanosarcina cells (and in general, confined prokaryotes) change their direction of growth during consecutive growth-division stages, and how a particular cell senses its wall topology and responds to changes on it a theoretical model for stress dependent growth of aggregated archaeal cells was developed. The model utilizes a confined elastic shell representation of aggregated archaeal cell and is derived based on a work-energy principle. The growth law takes into account the fine structure of archaeal cell wall, polymeric nature of methanochondroitin layer, molecular-biochemical processes and is based on thermodynamic laws. The developed model has been applied to three typical configurations of aggregated cell in 3D. The developed model predicted a geometry response with delayed growth of aggregated archaeal cells explained from mechanistic principles, as well as continuous changes in direction of growth during the consecutive growth-division stages. This means that cell wall topology sensing and growth anisotropy can be predicted using simple cellular mechanisms without the need for dedicated cellular machinery.

  3. Prevalence and pattern of growth abnormalities in children with extrahepatic portal vein obstruction: Response to shunt surgery

    PubMed Central

    Mir, Toufeeq Ahmad; Misgar, Raiz Ahmad; Laway, Bashir Ahmad; Shah, Omar Javed; Shah, Zafar Amin; Zargar, Showkat Ali

    2016-01-01

    Objective: Growth retardation is common in children with extrahepatic portal vein obstruction (EHPVO) and growth hormone (GH) resistance may play a dominant role. The aim of this study was to ascertain growth parameters and growth-related hormones in children with EHPVO, comparing with controls and to study the response of shunt surgery on growth parameters. Materials and Methods: The auxological and growth-related hormone profile (GH; insulin-like growth factor binding protein-3 [IGFBP-3] and IGF-1) of thirty children with EHPVO were compared with controls. The effect of shunt surgery on growth parameters in 12 children was also studied. Results: The mean height standard deviation score (HSDS) of cases (−1.797 ± 1.146) was significantly lower than that of controls (−0.036 ± 0.796); the mean weight SDS of cases (−1.258 ± 0.743) was also lower than that of controls (−0.004 ± 0.533). The mean GH level of cases (5.00 ± 6.46 ng/ml) was significantly higher than that of controls (1.78 ± 2.04 ng/ml). The mean IGF-1 level of cases (100.25 ± 35.93 ng/ml) was significantly lower as compared to controls (233.53 ± 115.06 ng/ml) as was the mean IGFBP-3 level (2976.53 ± 1212.82 ng/ml in cases and 5183.28 ± 1531.28 ng/ml in controls). In 12 patients who underwent shunt surgery, growth parameters significantly improved. Conclusions: Marked decrease in weight and height SDSs associated with GH resistance is seen in children with EHPVO, which improves with shunt surgery. PMID:27867876

  4. Abnormal regulation of DNA replication and increased lethality in ataxia telangiectasia cells exposed to carcinogenic agents

    SciTech Connect

    Jaspers, N.G.; de Wit, J.; Regulski, M.R.; Bootsma, D.

    1982-01-01

    The effect of different carcinogenic agents on the rate of semiconservative DNA replication in normal and ataxia telangiectasis (AT) cells was investigated. The rate of DNA synthesis in all AT cell strains tested was depressed to a significantly lesser extent than in normal cells after exposure to X-rays under oxia or hypoxia or to bleomycin, agents to which AT cells are hypersensitive. In contrast, inhibition of DNA replication in normal human and AT cells was similar after treatment with some DNA-methylating agents or mitomycin C. Colony-forming ability of AT cells treated with these agents was not different from normal cells. Treatment with 4-nitroquinoline 1-oxide elicited a variable response in both AT and normal cell strains. In some strains, including those shown to be hypersensitive to the drug by other workers, the inhibition of DNA synthesis was more pronounced than in other cell strains, but no significant difference between AT and normal cells could be detected. The rejoining of DNA strand breaks induced by X-rays, measured by DNA elution techniques, occurred within l2 hr after treatment and could not be correlated with the difference in DNA synthesis inhibition in AT and normal cells. After low doses of X-rays, AT cells rejoined single-strand breaks slightly more slowly than did normal cells. The rate of DNA replication in X-irradiation AT and normal cells was not affected by nicotinamide, an inhibitor of poly(adenosine diphosphate ribose) synthesis. These data indicate that the diminished inhibition of DNA replication in carcinogen-treated AT cells (a) is a general characteristic of all AT cell strains, (b) correlates with AT cellular hypersensitivity, (c) is not directly caused by the bulk of the DNA strand breaks produced by carcinogenic agents, and (d) is not based on differences in the induction of poly(adenosine diphosphate ribose) synthesis between X-irradiated AT and normal cells.

  5. Facile solvothermal synthesis of abnormal growth of one-dimensional ZnO nanostructures by ring-opening reaction of polyvinylpyrrolidone

    NASA Astrophysics Data System (ADS)

    Xu, G.; Wang, X. L.; Liu, G. Z.

    2015-02-01

    Abnormal growth of one-dimensional (1-D) ZnO nanostructures (NSs) have been accomplished with the assistance of polyvinylpyrrolidone (PVP) under a super high alkaline alcoholic solvothermal condition. The products were characterized by transmission electron microscopy (TEM), thermogravimetric analysis (TGA), X-ray diffraction (XRD), Fourier transform infrared (FT-IR) and proton nuclear magnetic resonance (1H NMR) spectroscopy. The effect of synthetic conditions, such as reaction temperature and the addition of PVP, on the morphologies of ZnO products were investigated. The results show that PVP molecules had the significant role in the transformation of morphologies of ZnO NSs ranging from nanorods, nanoparticles to pyramids, as well as flower-like assembly features. The possible growth mechanism of ZnO pyramids was proposed based on ring-opening reaction of PVP.

  6. The evidence for the role of transforming growth factor-beta in the formation of abnormal scarring.

    PubMed

    Chalmers, Richard L

    2011-06-01

    The complex biological and physiological mechanisms that result in poor quality scarring are still not fully understood. This review looks at current evidence of the role of transforming growth factor-beta (TGFβ) in this pathological process.

  7. Abnormal centrosome amplification in cells through the targeting of Ran-binding protein-1 by the human T cell leukemia virus type-1 Tax oncoprotein.

    PubMed

    Peloponese, Jean-Marie; Haller, Kerstin; Miyazato, Akiko; Jeang, Kuan-Teh

    2005-12-27

    Human T cell leukemia virus type-1 (HTLV-1) is an oncogenic retrovirus etiologically causal of adult T cell leukemia. The virus encodes a Tax oncoprotein that functions in transcriptional regulation, cell cycle control, and transformation. Because adult T cell leukemia like many other human cancers is a disease of genomic instability with frequent gains and losses of chromosomes, to understand this disease it is important to comprehend how HTLV-1 engenders aneuploidy in host cells. In this regard, loss of cell cycle checkpoints permits tolerance of aneuploidy but does not explain how aneuploidy is created. We show here that HTLV-1 Tax causes abnormal centrosome fragmentation in the mitotic phase of the cell cycle. We report that Tax directly binds Ran and Ran-binding protein-1, locates to centrosomes/spindle poles, and causes supernumerary centrosomes.

  8. Hepatobiliary Ultrasonographic Abnormalities in Adult Patients with Sickle Cell Anaemia in Steady State in Ile-Ife, Nigeria

    PubMed Central

    Oguntoye, Oluwatosin O.; Ndububa, Dennis A.; Yusuf, Musah; Bolarinwa, Rahman A.; Ayoola, Oluwagbemiga O.

    2017-01-01

    Summary Background Sickle cell anaemia (SCA) is associated with structural manifestations in the hepatobiliary axis. This study aimed to investigate the hepatobiliary ultrasonographic abnormalities in adult patients with sickle cell anaemia in steady state attending the Haematology clinic of a federal tertiary health institution in Ile-Ife, Nigeria. Material/Methods Basic demographic data as well as right upper abdominal quadrant ultrasonography of 50 consecutive sickle cell anaemia patients were compared with those of 50 age- and sex-matched subjects with HbAA as controls. Results Each of the study groups (patients and controls) comprised of 21 (42%) males and 29 (58%) females. The age range of the patients was 18–45 years with a mean (±SD) of 27.6±7.607 years, while that of the controls was 21–43 years with a mean (±SD) of 28.0±5.079 years (p=0.746). Amongst the patients, 32 (64%) had hepatomegaly, 15 (30%) cholelithiasis and 3 (6%) biliary sludge. Fourteen (28%) of the patients had normal hepatobiliary ultrasound findings. In the control group, one (2%) person had cholelithiasis, one (2%) biliary sludge, one (2%) fatty liver and none hepatomegaly. Forty-seven (94%) of the controls had normal hepatobiliary ultrasound findings. There was a statistically significant difference in the prevalence of hepatomegaly and cholelithiasis between the patients and controls (p value <0.001 for both comparisons). Conclusions In this study, hepatomegaly, cholelithiasis and biliary sludge were the most common hepatobiliary ultrasound findings in patients with sickle cell anaemia. Ultrasonography is a useful tool for assessing hepatobiliary abnormalities in patients with sickle cell anaemia. PMID:28105246

  9. Abnormal tuning of saccade-related cells in pontine reticular formation of strabismic monkeys

    PubMed Central

    Mustari, Michael J.

    2015-01-01

    Strabismus is a common disorder, characterized by a chronic misalignment of the eyes and numerous visual and oculomotor abnormalities. For example, saccades are often highly disconjugate. For humans with pattern strabismus, the horizontal and vertical disconjugacies vary with eye position. In monkeys, manipulations that disturb binocular vision during the first several weeks of life result in a chronic strabismus with characteristics that closely match those in human patients. Early onset strabismus is associated with altered binocular sensitivity of neurons in visual cortex. Here we test the hypothesis that brain stem circuits specific to saccadic eye movements are abnormal. We targeted the pontine paramedian reticular formation, a structure that directly projects to the ipsilateral abducens nucleus. In normal animals, neurons in this structure are characterized by a high-frequency burst of spikes associated with ipsiversive saccades. We recorded single-unit activity from 84 neurons from four monkeys (two normal, one exotrope, and one esotrope), while they made saccades to a visual target on a tangent screen. All 24 neurons recorded from the normal animals had preferred directions within 30° of pure horizontal. For the strabismic animals, the distribution of preferred directions was normal on one side of the brain, but highly variable on the other. In fact, 12/60 neurons recorded from the strabismic animals preferred vertical saccades. Many also had unusually weak or strong bursts. These data suggest that the loss of corresponding binocular vision during infancy impairs the development of normal tuning characteristics for saccade-related neurons in brain stem. PMID:26063778

  10. Prostate cancer cell response to paclitaxel is affected by abnormally expressed securin PTTG1.

    PubMed

    Castilla, Carolina; Flores, M Luz; Medina, Rafael; Pérez-Valderrama, Begoña; Romero, Francisco; Tortolero, María; Japón, Miguel A; Sáez, Carmen

    2014-10-01

    PTTG1 protein, the human securin, has a central role in sister chromatid separation during mitosis, and its altered expression has been reported in many tumor types. Paclitaxel is a widely used chemotherapeutic drug, whose mechanism of action is related to its ability to arrest cells in mitosis and the subsequent induction of the intrinsic apoptotic pathway. By using two prostate cancer cell lines with different responses to paclitaxel treatment, we have identified two situations in which PTTG1 influences cell fate differentially. In slippage-prone PC3 cells, both PTTG1 downregulation and overexpression induce an increase in mitotic cells that is associated with diminished apoptosis after paclitaxel treatment. In LNCaP cells, however, PTTG1 downregulation prevents mitotic entry and, subsequently, inhibits mitosis-associated, paclitaxel-induced apoptosis. In contrast, PTTG1 overexpression induces an increase in mitotic cells and apoptosis after paclitaxel treatment. We have also identified a role for Mcl-1 protein in preventing apoptosis during mitosis in PC3 cells, as simultaneous PTTG1 and Mcl-1 silencing enhances mitosis-associated apoptosis after paclitaxel treatment. The finding that a more efficient mitotic arrest alone in PC3 cells is not enough to increase apoptosis was also confirmed with the observation that a selected paclitaxel-resistant PC3 cell line showed an apoptosis-resistant phenotype associated with increased mitosis upon paclitaxel treatment. These findings could contribute to identify putative responsive and nonresponsive cells and help us to approach incomplete responses to paclitaxel in the clinical setting.

  11. Expression of abnormal von Willebrand factor by endothelial cells from a patient with type IIA von Willebrand disease.

    PubMed Central

    Levene, R B; Booyse, F M; Chediak, J; Zimmerman, T S; Livingston, D M; Lynch, D C

    1987-01-01

    Studies were conducted to characterize the biosynthesis of von Willebrand factor (vWf) by cultured endothelial cells (EC) derived from the umbilical vein of a patient with type IIA von Willebrand disease. The patient's EC, compared with those from normal individuals, produced vWf that had decreased amounts of large multimers and an increase in rapidly migrating satellite species, features characteristic of plasma vWf from patients with type IIA von Willebrand disease. The type IIA EC did produce a full spectrum of vWf multimers in both cell lysates and postculture medium, although the relative amounts of the largest species were decreased. The large multimers were degraded in conjunction with the appearance of rapidly migrating satellites that contained approximately equal to 170-kDa proteolytic fragments, suggesting that this patient's functional defect is due to abnormal proteolysis and not to a primary failure of vWf subunit oligomerization. Moreover, the observed degradation appears to result from an abnormal vWf molecule and not elevated protease levels. These results suggest that this patient's von Willebrand disease phenotype is caused by increased proteolytic sensitivity of his vWf protein. Images PMID:3306682

  12. Cardiac conduction abnormalities in patients with breast cancer undergoing high-dose chemotherapy and stem cell transplantation.

    PubMed

    Ando, M; Yokozawa, T; Sawada, J; Takaue, Y; Togitani, K; Kawahigashi, N; Narabayashi, M; Takeyama, K; Tanosaki, R; Mineishi, S; Kobayashi, Y; Watanabe, T; Adachi, I; Tobinai, K

    2000-01-01

    Cardiac toxicities in 39 consecutive patients with breast cancer receiving high-dose chemotherapy (HDC) with stem cell transplantation were reviewed. All 39 patients received various anthracycline-containing regimens in adjuvant settings and/or for metastatic disease before HDC. As a cytoreductive regimen, all received cyclophosphamide 2000 mg/m2 and thiotepa 200 mg/m2 for 3 consecutive days. No immediate fatal toxicities were observed, but one patient developed chronic congestive heart failure and two had transient left ventricular dysfunction. Pericardial effusion was observed in another three patients. ST-T abnormalities during HDC were observed in two patients and arrhythmias were observed in nine, four of which occurred during stem cell infusion (SCI). There were three atrial arrhythmias, two ventricular arrhythmias, and four atrioventricular (AV)-block episodes. Two patients developed advanced and complete AV-block with an asystolic pause. Notably, three patients experienced AV-block with uncontrolled vomiting. No relationship was observed between the cumulative dose of anthracycline and cardiac toxicities during HDC. These results suggest that abnormalities in the conduction system during HDC may be more frequent than previously reported. Vagal reflex secondary to emesis may play an important role in the development of AV-block. Bone Marrow Transplantation (2000) 25, 185-189.

  13. Genomic abnormalities of Waldenström macroglobulinemia and related low-grade B-cell lymphomas.

    PubMed

    Braggio, Esteban; Fonseca, Rafael

    2013-04-01

    Waldenström macroglobulinemia (WM) is a lymphoproliferative disease characterized by a heterogeneous lymphoplasmacytic bone marrow infiltrate and monoclonal immunoglobulin M production. WM shows similarities in presentations with related B-cell malignancies, sometimes making it difficult to distinguish them. To better characterize the genetic basis of WM, we performed a comparative genomic analysis with the related entities, lymphoplasmacytic lymphomas without monoclonal immunoglobulin M protein, marginal zone lymphomas, chronic lymphocytic leukemia, and monoclonal gammopathy of undetermined significance. Overall, WM shows a very stable karyotype and shares most of the chromosomal abnormalities with most of the indolent B-cell malignancies. Trisomy 4 is unique to WM; however, no candidate genes have been identified in the chromosome. Abnormalities that affect myeloid differentiation primary response 88 (MYD88)--interleukin-1 receptor-associated kinase 4 (IRAK4) and nuclear factor kappa B (NF-κB) signaling pathways were found in a significant proportion of WM cases, which suggest their relevance in the pathogenesis of the disease and opening new avenues that may be a guide to design novel therapeutic approaches.

  14. THE TOPOGRAPHY OF TIP GROWTH IN A PLANT CELL

    PubMed Central

    Castle, Edward S.

    1958-01-01

    Tips of young Phycomyces sporangiophores were dusted with starch grains, and growth photographically recorded. Rates of longitudinal displacement from the cell tip of individual markers were determined, also corresponding rates of change of cell diameter. From these the magnitude and spatial distribution of "relative elemental growth rates" along both longitudinal and circumferential axes of the cell were obtained. Growth rates in these two directions are functions of distance from the cell apex, and have different spatial distributions. In particular, rates of growth in cell circumference are complexly patterned. Relative elemental growth rates in length and in girth are approximately equal and maximal at the cell's apex, with a value of 2.4 mm. mm.–1 hr.–1. The characteristic shape of the tip is maintained constant in the face of its changing substance and position. This shape reflects a steady state of the cell's constituent growth patterns. At every point the growing membrane simultaneously expands in the two dimensions of its surface. The degree of polarization or directional preference of growth is measured by the ratio of longitudinal to circumferential relative elemental growth rate at any point. The ratio is not constant, but changes with position along the tip. This fact does not support the idea that membrane growth is based upon a quantal "growth event." Possible causal factors in oriented membrane growth are discussed. PMID:13525674

  15. Disruption of Endothelial Cell Homeostasis Plays a Key Role in the Early Pathogenesis of Coronary Artery Abnormalities in Kawasaki Disease

    PubMed Central

    Ueno, Kentaro; Ninomiya, Yumiko; Hazeki, Daisuke; Masuda, Kiminori; Nomura, Yuichi; Kawano, Yoshifumi

    2017-01-01

    Disruption of endothelial cell homeostasis may be associated with the pathogenesis of coronary artery abnormalities (CAA) in Kawasaki disease (KD). We sought to clarify the poorly understood pathogenic role of endothelial cell survival and death in KD vasculitis. Human umbilical vein endothelial cells (HUVECs) stimulated with sera from KD patients, compared with sera from patients with bacterial infections, exhibited significant increases in cytotoxicity, high mobility group box protein 1 (HMGB-1), and caspase-3/7 and a decrease in phosphorylated Akt/Akt (pAkt/Akt) ratios. HUVECs stimulated with sera from KD patients treated with immunoglobulin (IG) showed significantly decreased cytotoxicity, HMGB-1, and caspase-3/7 levels and increased pAkt/Akt ratios, as compared with results for untreated HUVECs (P < 0.001, P = 0.008, P = 0.040, and P < 0.001, respectively). In HUVECs stimulated with sera from KD patients, the increased cytotoxicity levels and the suppression of increased pAkt/Akt ratios after subsequent IG treatment were closely related to the development of CAA (P = 0.002 and P = 0.035). Our data reveal that shifting the balance toward cell death rather than survival appears to perturb endothelial cell homeostasis and is closely related to the development of CAA. The cytoprotective effects of IG treatment appear to ameliorate endothelial cell homeostasis. PMID:28255175

  16. Abnormal ion content, hydration and granule expansion of the secretory granules from cystic fibrosis airway glandular cells

    SciTech Connect

    Baconnais, S.; Delavoie, F. |; Zahm, J.M.; Milliot, M.; Castillon, N.; Terryn, C.; Banchet, V.; Michel, J.; Danos, O.; Merten, M.; Chinet, T.; Zierold, K.; Bonnet, N.; Puchelle, E. , E-Mail: edith.puchelle@univ-reims.fr; Balossier, G.

    2005-10-01

    The absence or decreased expression of cystic fibrosis transmembrane conductance regulator (CFTR) induces increased Na{sup +} absorption and hyperabsorption of the airway surface liquid (ASL) resulting in a dehydrated and hyperviscous ASL. Although the implication of abnormal airway submucosal gland function has been suggested, the ion and water content in the Cystic Fibrosis (CF) glandular secretory granules, before exocytosis, is unknown. We analyzed, in non-CF and CF human airway glandular cell lines (MM-39 and KM4, respectively), the ion content in the secretory granules by electron probe X-ray microanalysis and the water content by quantitative dark field imaging on freeze-dried cryosections. We demonstrated that the ion content (Na{sup +}, Mg{sup 2+}, P, S and Cl{sup -}) is significantly higher and the water content significantly lower in secretory granules from the CF cell line compared to the non-CF cell line. Using videomicroscopy, we observed that the secretory granule expansion was deficient in CF glandular cells. Transfection of CF cells with CFTR cDNA or inhibition of non-CF cells with CFTR{sub inh}-172, respectively restored or decreased the water content and granule expansion, in parallel with changes in ion content. We hypothesize that the decreased water and increased ion content in glandular secretory granules may contribute to the dehydration and increased viscosity of the ASL in CF.

  17. Thiazolidinediones enhance vascular endothelial growth factor expression and induce cell growth inhibition in non-small-cell lung cancer cells

    PubMed Central

    2010-01-01

    Background It is known that thiazolidinediones are involved in regulating the expression of various genes, including the vascular endothelial growth factor (VEGF) gene via peroxisome proliferator-activated receptor γ (PPARγ); VEGF is a prognostic biomarker for non-small-cell lung cancer (NSCLC). Methods In this study, we investigated the effects of troglitazone and ciglitazone on the mRNA expression of VEGF and its receptors in human NSCLC cell lines, RERF-LC-AI, SK-MES-1, PC-14, and A549. These mRNA expressions were evaluated by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. We also studied the effect of Je-11, a VEGF inhibitor, on the growth of these cells. Results In NSCLC cells, thiazolidinediones increased the mRNA expression of VEGF and neuropilin-1, but not that of other receptors such as fms-like tyrosine kinase and kinase insert domain receptor-1. Furthermore, the PPARγ antagonist GW9662 completely reversed this thiazolidinedione-induced increase in VEGF expression. Furthermore, the addition of VEGF inhibitors into the culture medium resulted in the reversal of thiazolidinedione-induced growth inhibition. Conclusions Our results indicated that thiazolidinediones enhance VEGF and neuropilin-1 expression and induce the inhibition of cell growth. We propose the existence of a pathway for arresting cell growth that involves the interaction of thiazolidinedione-induced VEGF and neuropilin-1 in NSCLC. PMID:20214829

  18. Complex cell cycle abnormalities caused by human T-lymphotropic virus type 1 Tax.

    PubMed

    Yang, Liangpeng; Kotomura, Naoe; Ho, Yik-Khuan; Zhi, Huijun; Bixler, Sandra; Schell, Michael J; Giam, Chou-Zen

    2011-03-01

    Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL), a malignancy of CD4(+) T cells whose etiology is thought to be associated with the viral trans-activator Tax. We have shown recently that Tax can drastically upregulate the expression of p27(Kip1) and p21(CIP1/WAF1) through protein stabilization and mRNA trans-activation and stabilization, respectively. The Tax-induced surge in p21(CIP1/WAF1) and p27(Kip1) begins in S phase and results in cellular senescence. Importantly, HeLa and SupT1 T cells infected by HTLV-1 also arrest in senescence, thus challenging the notion that HTLV-1 infection causes cell proliferation. Here we use time-lapse microscopy to investigate the effect of Tax on cell cycle progression in two reporter cell lines, HeLa/18x21-EGFP and HeLa-FUCCI, that express enhanced green fluorescent protein (EGFP) under the control of 18 copies of the Tax-responsive 21-bp repeat element and fluorescent ubiquitin cell cycle indicators, respectively. Tax-expressing HeLa cells exhibit elongated or stalled cell cycle phases. Many of them bypass mitosis and become single senescent cells as evidenced by the expression of senescence-associated β-galactosidase. Such cells have twice the normal equivalent of cellular contents and hence are enlarged, with exaggerated nuclei. Interestingly, nocodazole treatment revealed a small variant population of HeLa/18x21-EGFP cells that could progress into mitosis normally with high levels of Tax expression, suggesting that genetic or epigenetic changes that prevent Tax-induced senescence can occur spontaneously at a detectable frequency.

  19. Abnormalities of quantities and functions of natural killer cells in severe aplastic anemia.

    PubMed

    Liu, Chunyan; Li, Zhishang; Sheng, Weiwei; Fu, Rong; Li, Lijuan; Zhang, Tian; Wu, Yuhong; Xing, Limin; Song, Jia; Wang, Huaquan; Shao, Zonghong

    2014-01-01

    Severe aplastic anemia (SAA) is a rare disease characterized by severe pancytopenia and bone marrow failure. Natural killer (NK) cells are large granular lymphocytes derived from hematopoietic stem cells (HSCs) or common lymphoid progenitors (CLP). They play a key role in n the innate immunity and adaptive immune. In this study, the quantitative and functional changes of natural killer (NK) cell subsets in peripheral blood of severe aplastic anemia (SAA) patients before and after immunosuppressive therapy (IST) were investigated. Results showed that the percentage of NK cells and its subsets in peripheral blood lymphocytes was decreased in SAA patients. After IST, the percentage of NK cells and their subsets increased dramatically. The median expressions of CD158a, NKG2D and NKp46 on NK cells were higher in SAA patients compared to that in normal controls, and the expressions of perforin in newly diagnosed and recovery SAA patients were higher than that in controls. Therefore, we concluded that the decrease of total NK cells, and CD56(bright), CD56(dim) NK cell subsets and the higher expressions of NKp46 and perforin on NK cells may cause the over-function of T lymphocytes and thus lead to hematopoiesis failure in SAA.

  20. Bestatin inhibits cell growth, cell division, and spore cell differentiation in Dictyostelium discoideum.

    PubMed

    Poloz, Yekaterina; Catalano, Andrew; O'Day, Danton H

    2012-04-01

    Bestatin methyl ester (BME) is an inhibitor of Zn(2+)-binding aminopeptidases that inhibits cell proliferation and induces apoptosis in normal and cancer cells. We have used Dictyostelium as a model organism to study the effects of BME. Only two Zn(2+)-binding aminopeptidases have been identified in Dictyostelium to date, puromycin-sensitive aminopeptidase A and B (PsaA and PsaB). PSA from other organisms is known to regulate cell division and differentiation. Here we show that PsaA is differentially expressed throughout growth and development of Dictyostelium, and its expression is regulated by developmental morphogens. We present evidence that BME specifically interacts with PsaA and inhibits its aminopeptidase activity. Treatment of cells with BME inhibited the rate of cell growth and the frequency of cell division in growing cells and inhibited spore cell differentiation during late development. Overexpression of PsaA-GFP (where GFP is green fluorescent protein) also inhibited spore cell differentiation but did not affect growth. Using chimeras, we have identified that nuclear versus cytoplasmic localization of PsaA affects the choice between stalk or spore cell differentiation pathway. Cells that overexpressed PsaA-GFP (primarily nuclear) differentiated into stalk cells, while cells that overexpressed PsaAΔNLS2-GFP (cytoplasmic) differentiated into spores. In conclusion, we have identified that BME inhibits cell growth, division, and differentiation in Dictyostelium likely through inhibition of PsaA.

  1. Hippocampal cell loss and propagation of abnormal discharges accompanied with the expression of tonic convulsion in the spontaneously epileptic rat.

    PubMed

    Hanaya, Ryosuke; Sasa, Masashi; Sugata, Sei; Tokudome, Mai; Serikawa, Tadao; Kurisu, Kaoru; Arita, Kazunori

    2010-04-30

    Spontaneously epileptic rats (SER) are double mutants with both tonic convulsion and absence-like seizures from the age of 8 weeks. Hippocampal CA3 neurons in SER display a long-lasting depolarizing shift accompanied by repetitive firing (attributed to abnormalities of the Ca(2+) channels) with a single stimulation of the mossy fibers. In the present investigation, we examined if the seizure discharges of SER were correlated with the hippocampal abnormality of SER using electrophysiological and histological methods. In CA1 neurons of seizure-susceptible mature SER, higher-voltage (<8-11 V) stimulations induced a long depolarization shift (in 25% of neurons) with repetitive firing (in 12.5% of neurons). However, the tremor rat, one of the parent strains of SER, did not exhibit such abnormal firing in the CA3 region of the hippocampus. The number of CA3 neurons in SER was significantly (p<0.01) lower than that in tremor rats and Wistar rats, although no significant difference was established in the hilus. Sprouting of mossy fiber was observed in the dentate of mature SER; however, negligible staining was spotted in the dentate of both mature tremor and Wistar rats. Interestingly, expression of the brain-derived neurotrophic factor was higher in the hilus, CA3, and granular cell layer of dentate gyrus in SER than normal Wistar rats. The expression levels of TUNEL, bax, and Caspase-3 did not show significant changes between the SER and Wistar rats. SER exhibited hippocampal sclerosis-like changes which did not have enough potential for epileptogenesis. Repetitive tonic seizures and vulnerable CA3 neurons of SER could be involved in the induction of sclerosis-like changes in the hippocampus.

  2. Early neurologic abnormalities associated with human T-cell lymphotropic virus type 1 infection in a cohort of Peruvian children

    PubMed Central

    Kendall, Emily A.; González, Elsa; Espinoza, Iván; Tipismana, Martín; Verdonck, Kristien; Clark, Daniel; Vermund, Sten H.; Gotuzzo, Eduardo

    2009-01-01

    Objective Because human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) may occur in some children infected with HTLV-1-infected, we sought to determine the prevalence of neurologic abnormalities and any associations with infective dermatitis in these children. Study design We enrolled 58 children infected with HTLV-1 and 42 uninfected children (ages 3-17) of mothers infected with HTLV-1 in a family study in Lima, Peru. We obtained medical and developmental histories, surveyed current neurologic symptoms, and conducted a standardized neurologic examination without prior knowledge of HTLV-1 status. Results HTLV-1 infection was associated with reported symptoms of lower extremity weakness/fatigue (OR=6.1, CI:0.7–281), lumbar pain (odds ratio [OR] = 1.7, 95% confidence interval [CI]:0.4–8), and paresthesia/dysesthesia (OR=2.6, CI:0.6–15.8). HTLV-1 infection was associated with lower-extremity hyperreflexia (OR=3.1, CI:0.8–14.2), ankle clonus (OR=5.0, CI:1.0–48.3), and extensor plantar reflex (OR undefined; p = 0.2). Among children infected HTLV-1, a history of infective dermatitis was associated with weakness (OR=2.7, CI:0.3–33), lumbar pain (OR=1.3, CI:0.2–8), paresthesia/dysesthesia (OR=2.9, CI:0.5–20), and urinary disturbances (OR=5.7, CI:0.5–290). Conclusions Abnormal neurologic findings were common in Peruvian children infected with HTLV-1, and several findings were co-prevalent with infective dermatitis. Pediatricians should monitor children infected with HTLV-1 for neurologic abnormalities. PMID:19628219

  3. Serious foetal growth restriction is associated with reduced proportions of natural killer cells in decidua basalis.

    PubMed

    Eide, Irina P; Rolfseng, Toril; Isaksen, Christina V; Mecsei, Reidun; Roald, Borghild; Lydersen, Stian; Salvesen, Kjell A; Harsem, Nina K; Austgulen, Rigmor

    2006-03-01

    Extravillous trophoblasts are major participants in placental development and remodelling of spiral arteries. Trophoblast invasion is regulated by maternal immune cells, and abnormal leucocyte subpopulation composition has been reported in implantation failure. In pre-eclampsia (PE), with or without foetal growth restriction (FGR), superficial trophoblast invasion and insufficient remodelling of spiral arteries are common findings. In the present study, we have compared spiral artery remodelling and leucocyte composition in decidual tissue from 30 cases (PE=8, FGR=5, PE + FGR=17) and 31 controls. Six histological remodelling criteria were established, and each pregnancy obtained a remodelling score. Numbers of natural killer (NK) cells (CD56+), T cells (CD3+) and activated (CD25+ or CD69+) leucocytes were determined and related to total leucocyte (CD45+) numbers in serial sections. Cases demonstrated significantly impaired spiral artery remodelling, inappropriate placental growth and reduced NK cell proportions, as compared to controls (P=0.02, P<0.001 and P=0.01, respectively). Reduced NK cell proportion was primarily found in pregnancies complicated by FGR, with or without PE, and a significant positive correlation was observed between NK cell proportion, trophoblast infiltration and placental growth. Our in vivo observations support the hypothesized association between NK cells, impaired placental development and pathogenesis of PE/FGR.

  4. Impaired proliferative potential of bone marrow mesenchymal stromal cells in patients with myelodysplastic syndromes is associated with abnormal WNT signaling pathway.

    PubMed

    Pavlaki, Konstantia; Pontikoglou, Charalampos G; Demetriadou, Anthi; Batsali, Aristea K; Damianaki, Athina; Simantirakis, Emmanouil; Kontakis, Michail; Galanopoulos, Athanasios; Kotsianidis, Ioannis; Kastrinaki, Maria-Christina; Papadaki, Helen A

    2014-07-15

    It has been shown that bone marrow mesenchymal stromal cells (MSCs) from patients with myelodysplastic syndromes (MDSs) display defective proliferative potential. We have probed the impaired replicative capacity of culture-expanded MSCs in MDS patients (n=30) compared with healthy subjects (n=32) by studying senescence characteristics and gene expression associated with WNT/transforming growth factor-β1 (TGFB1) signaling pathways. We have also explored the consequences of the impaired patient MSC proliferative potential by investigating their differentiation potential and the capacity to support normal CD34(+) cell growth under coculture conditions. Patient MSCs displayed decreased gene expression of the senescence-associated cyclin-dependent kinase inhibitors CDKN1A, CDKN2A, and CDKN2B, along with PARG1, whereas the mean telomere length was upregulated in patient MSCs. MDS-derived MSCs exhibited impaired capacity to support normal CD34(+) myeloid and erythroid colony formation. No significant changes were observed between patients and controls in gene expression related to TGFB1 pathway. Patient MSCs displayed upregulated non-canonical WNT expression, combined with downregulated canonical WNT expression and upregulated canonical WNT inhibitors. MDS-derived MSCs displayed defective osteogenic and adipogenic lineage priming under non-differentiating culture conditions. Pharmacological activation of canonical WNT signaling in patient MDSs led to an increase in cell proliferation and upregulation in the expression of early osteogenesis-related genes. This study indicates abnormal WNT signaling in MSCs of MDS patients and supports the concept of a primary MSC defect that might have a contributory effect in MDS natural history.

  5. Fibroblast growth factor 8 increases breast cancer cell growth by promoting cell cycle progression and by protecting against cell death

    SciTech Connect

    Nilsson, Emeli M.; Brokken, Leon J.S.; Haerkoenen, Pirkko L.

    2010-03-10

    Fibroblast growth factor 8 (FGF-8) is expressed in a large proportion of breast cancers, whereas its level in normal mammary gland epithelium is low. Previous studies have shown that FGF-8b stimulates breast cancer cell growth in vitro and in vivo. To explore the mechanisms by which FGF-8b promotes growth, we studied its effects on cell cycle regulatory proteins and signalling pathways in mouse S115 and human MCF-7 breast cancer cells. We also studied the effect of FGF-8b on cell survival. FGF-8b induced cell cycle progression and up-regulated particularly cyclin D1 mRNA and protein in S115 cells. Silencing cyclin D1 with siRNA inhibited most but not all FGF-8b-induced proliferation. Inhibition of the FGF-8b-activated ERK/MAPK pathway decreased FGF-8b-stimulated proliferation. Blocking the constitutively active PI3K/Akt and p38 MAPK pathways also lowered FGF-8b-induced cyclin D1 expression and proliferation. Corresponding results were obtained in MCF-7 cells. In S115 and MCF-7 mouse tumours, FGF-8b increased cyclin D1 and Ki67 levels. Moreover, FGF-8b opposed staurosporine-induced S115 cell death which effect was blocked by inhibiting the PI3K/Akt pathway but not the ERK/MAPK pathway. In conclusion, our results suggest that FGF-8b increases breast cancer cell growth both by stimulating cell cycle progression and by protecting against cell death.

  6. Annual Research Review: Growth connectomics – the organization and reorganization of brain networks during normal and abnormal development

    PubMed Central

    Vértes, Petra E; Bullmore, Edward T

    2015-01-01

    Background We first give a brief introduction to graph theoretical analysis and its application to the study of brain network topology or connectomics. Within this framework, we review the existing empirical data on developmental changes in brain network organization across a range of experimental modalities (including structural and functional MRI, diffusion tensor imaging, magnetoencephalography and electroencephalography in humans). Synthesis We discuss preliminary evidence and current hypotheses for how the emergence of network properties correlates with concomitant cognitive and behavioural changes associated with development. We highlight some of the technical and conceptual challenges to be addressed by future developments in this rapidly moving field. Given the parallels previously discovered between neural systems across species and over a range of spatial scales, we also review some recent advances in developmental network studies at the cellular scale. We highlight the opportunities presented by such studies and how they may complement neuroimaging in advancing our understanding of brain development. Finally, we note that many brain and mind disorders are thought to be neurodevelopmental in origin and that charting the trajectory of brain network changes associated with healthy development also sets the stage for understanding abnormal network development. Conclusions We therefore briefly review the clinical relevance of network metrics as potential diagnostic markers and some recent efforts in computational modelling of brain networks which might contribute to a more mechanistic understanding of neurodevelopmental disorders in future. PMID:25441756

  7. Deformation of Platonic foam cells: effect on growth rate.

    PubMed

    Evans, Myfanwy E; Zirkelbach, Johannes; Schröder-Turk, Gerd E; Kraynik, Andrew M; Mecke, Klaus

    2012-06-01

    The diffusive growth rate of a polyhedral cell in dry three-dimensional foams depends on details of shape beyond cell topology, in contrast to the situation in two dimensions, where, by von Neumann's law, the growth rate depends only on the number of cell edges. We analyze the dependence of the instantaneous growth rate on the shape of single foam cells surrounded by uniform pressure; this is accomplished by supporting the cell with films connected to a wire frame and inducing cell distortions by deforming the wire frame. We consider three foam cells with a very simple topology; these are the Platonic foam cells, which satisfy Plateau's laws and are based on the trivalent Platonic solids (tetrahedron, cube, and dodecahedron). The Surface Evolver is used to model cell deformations induced through extension, compression, shear, and torsion of the wire frames. The growth rate depends on the deformation mode and frame size and can increase or decrease with increasing cell distortion. The cells have negative growth rates, in general, but dodecahedral cells subjected to torsion in small wire frames can have positive growth rates. The deformation of cubic cells is demonstrated experimentally.

  8. Deformation of Platonic foam cells: Effect on growth rate

    NASA Astrophysics Data System (ADS)

    Evans, Myfanwy E.; Zirkelbach, Johannes; Schröder-Turk, Gerd E.; Kraynik, Andrew M.; Mecke, Klaus

    2012-06-01

    The diffusive growth rate of a polyhedral cell in dry three-dimensional foams depends on details of shape beyond cell topology, in contrast to the situation in two dimensions, where, by von Neumann's law, the growth rate depends only on the number of cell edges. We analyze the dependence of the instantaneous growth rate on the shape of single foam cells surrounded by uniform pressure; this is accomplished by supporting the cell with films connected to a wire frame and inducing cell distortions by deforming the wire frame. We consider three foam cells with a very simple topology; these are the Platonic foam cells, which satisfy Plateau's laws and are based on the trivalent Platonic solids (tetrahedron, cube, and dodecahedron). The Surface Evolver is used to model cell deformations induced through extension, compression, shear, and torsion of the wire frames. The growth rate depends on the deformation mode and frame size and can increase or decrease with increasing cell distortion. The cells have negative growth rates, in general, but dodecahedral cells subjected to torsion in small wire frames can have positive growth rates. The deformation of cubic cells is demonstrated experimentally.

  9. Effect of specific silencing of EMMPRIN on the growth and cell cycle distribution of MCF-7 breast cancer cells.

    PubMed

    Yang, X Q; Yang, J; Wang, R; Zhang, S; Tan, Q W; Lv, Q; Meng, W T; Mo, X M; Li, H J

    2015-12-02

    The extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a member of the immunoglobulin family and shows increased expression in tumor cells. We examined the effect of RNAi-mediated EMMPRIN gene silencing induced by lentiviral on the growth and cycle distribution of MCF-7 breast cancer cells. Lentiviral expressing EMMPRIN-short hairpin RNA were packaged to infect MCF-7 cells. The inhibition efficiency of EMMPRIN was validated by real-time fluorescent quantitation polymerase chain reaction and western blotting. The effect of EMMPRIN on cell proliferation ability was detected using the MTT assay and clone formation experiments. Changes in cell cycle were detected by flow cytometry. EMMPRIN-short hairpin RNA-packaged lentiviral significantly down-regulated EMMPRIN mRNA and protein expression, significantly inhibited cell proliferation and in vitro tumorigenicity, and induced cell cycle abnormalities. Cells in the G0/G1 and G2/M phases were increased, while cells in the S phase were decreased after infection of MCF-7 cells for 3 days. The EMMPRIN gene facilitates breast cancer cell malignant proliferation by regulating cell cycle distribution and may be a molecular target for breast cancer gene therapy.

  10. DNA methylation abnormalities at gene promoters are extensive and variable in the elderly and phenocopy cancer cells.

    PubMed

    Gautrey, Hannah E; van Otterdijk, Sanne D; Cordell, Heather J; Mathers, John C; Strathdee, Gordon

    2014-07-01

    Abnormal patterns of DNA methylation are one of the hallmarks of cancer cells. The process of aging has also been associated with similar, albeit less dramatic, changes in methylation patterns, leading to the hypothesis that age-related changes in DNA methylation may partially underlie the increased risk of cancer in the elderly. Here we studied 377 participants aged 85 yr from the Newcastle 85+ Study to investigate the extent of, and interindividual variation in, age-related changes in DNA methylation at specific CpG islands. Using highly quantitative pyrosequencing analysis, we found extensive and highly variable methylation of promoter-associated CpG islands with levels ranging from 4% to 35%, even at known tumor suppressor genes such as TWIST2. Furthermore, the interindividual differences in methylation seen across this elderly population phenocopies multiple features of the altered methylation patterns seen in cancer cells. Both aging- and cancer-related methylation can occur at similar sets of genes, both result in the formation of densely methylated, and likely transcriptionally repressed, alleles, and both exhibit coordinate methylation across multiple loci. In addition, high methylation levels were associated with subsequent diagnosis of leukemia or lymphoma during a 3-yr follow-up period (P=0.00008). These data suggest that the accumulation of age-related changes in promoter-associated CpG islands may contribute to the increased cancer risk seen during aging.-Gautrey, H. E., van Otterdijk, S. D., Cordell, H. J., Newcastle 85+ study core team, Mathers, J. C., Strathdee, G. DNA methylation abnormalities at gene promoters are extensive and variable in the elderly and phenocopy cancer cells.

  11. [Additional phragmoplast corrects abnormal cytokinesis in wheat x rye hybrid pollen mother cells].

    PubMed

    Gordeeva, E I; Shamina, N V; Dudka, L F; Kovtunenko, V Ia; Bolobolova, E U

    2009-01-01

    The phragmoplast dysfunction in wheat x rye hybrid F1 male meiosis has been described. The pollen mother cells (PMCs) show the phenotype where transition from central spindle fibers (forming a solid bundle) to a phragmoplast (hollow cylinder) is blocked. The blockade suppresses centrifugal movement of the phragmoplast and cell plate formation. The resulting cells occur to be binucleate. Sometimes, the two nuclei join and form one restitution nucleus. PMCs of wheat x rye F1 hybrid N D-144gp 06r. F1 (T. aestivum c. 93-60 T 9 x S. cereale c. Saratovskaya 7) showing this phenotype have an additional phragmoplast at late telophase. This happens like that in the case of immobile phragmoplast formation in meiosis in bicotyledons: the new phragmoplast arises by the aid of microtubules polymerization starting from the spindle poles. The new additional phragmoplast builds a new cell plate and accomplishes cytokinesis.

  12. ULTRASOUND INCREASES THE RATE OF BACTERIAL CELL GROWTH

    PubMed Central

    Pitt, William G.; Ross, S. Aaron

    2006-01-01

    Ultrasound was employed to increase the growth rate of bacterial cells attached to surfaces. Staphylococcus epidermidis, Pseudomonas aeruginosa and Escherichia coli cells adhered to and grew on a polyethylene surface in the presence of ultrasound. It was found that low frequency ultrasound (70 kHz) of low acoustic intensity (<2 W/cm2) increased the growth rate of the cells compared to growth without ultrasound. However, at high intensity levels, cells were partially removed from the surface. Ultrasound also enhanced planktonic growth of S. epidermidis and other planktonic bacteria. It is hypothesized that ultrasound increases the rate of transport of oxygen and nutrients to the cells and increases the rate of transport of waste products away from the cells, thus enhancing their growth. PMID:12790676

  13. Cell surface abnormality in clones of skin fibroblasts from a carrier of Duchenne muscular dystrophy.

    PubMed Central

    Hillier, J; Jones, G E; Statham, H E; Witkowski, J A; Dubowitz, V

    1985-01-01

    We have previously reported that skin fibroblasts from patients with Duchenne muscular dystrophy (DMD) have a lower intercellular adhesiveness than control cells, and that cells from carriers of DMD have normal adhesiveness instead of the expected intermediate value. We have now cloned skin fibroblasts from a carrier of DMD (subject AS) who is also heterozygous for G6PD B/G6PD Mediterranean and determined the intercellular adhesiveness and G6PD phenotypes of the clones. G6PD activity was determined using the 2d-G6P/G6P ratio method. Normal cells had a percentage utilisation of 7.31% and uncloned cells from AS a value of 25.16%. Of 16 clones, 15 had normal values (mean 8.72%) while one clone was G6PD Med with a value of 57.5%. Mean intercellular adhesiveness of normal and uncloned cells from AS were 2.95 and 2.90 respectively. Of 11 clones tested, nine had normal values of adhesiveness (mean 3.1) and all these clones were G6PD B. The single G6PD Med clone had a value of 0.88, compared with 1.39 for DMD cells. We have no explanation at present for the single clone that was G6PD B but DMD-like on aggregation. PMID:3989823

  14. Lysosome abnormalities and lipofucsin content of nerve cells of oedematous human cerebral cortex.

    PubMed

    Castejón, O J

    2004-01-01

    Lysosome alterations and lipofucsin content of nerve cells, capillary endothelial cells and pericytes were examined in the anoxic-ischaemic brain parenchyma of thirty two patients with congenital hydrocephalus, complicated brain traumatic injuries, brain tumours and vascular anomalies. Cortical biopsies of frontal, parietal and temporal cortex were processed for transmission electron microscopy. In oedematous non pyramidal and pyramidal nerve cells, lysosomes showed fragmentation of their limiting membranes and an associated dense granulation. Areas of cytoplasmic focal necrosis were observed surrounding the lysosomes. Lipofucsin granules were also observed in neonate and infant patients with congenital hydrocephalus, suggesting that lipofucsin formation is a life span process. Lysosomes coexisting with an increased amount of lipofucsin granules were observed in young and adult patients with brain trauma, tumours and vascular anomalies. Phagocytic astrocytes and activated oligodendroglial cells showed the overall spectrum of an altered endosomal/lysosomal system. Lipofucsin granules and multivesicular bodies also were distinguished in endothelial and pericyte cells. The role of released and activated lysosomal enzymes is discussed in relation with the cytoplasmatic focal necrosis of nerve cells and the genesis of moderate and severe oedema.

  15. Abnormal Cell Properties and Down-Regulated FAK-Src Complex Signaling in B Lymphoblasts of Autistic Subjects

    PubMed Central

    Wei, Hongen; Malik, Mazhar; Sheikh, Ashfaq M.; Merz, George; Ted Brown, W.; Li, Xiaohong

    2011-01-01

    Recent studies suggest that one of the major pathways to the pathogenesis of autism is reduced cell migration. Focal adhesion kinase (FAK) has an important role in neural migration, dendritic morphological characteristics, axonal branching, and synapse formation. The FAK-Src complex, activated by upstream reelin and integrin β1, can initiate a cascade of phosphorylation events to trigger multiple intracellular pathways, including mitogen-activated protein kinase–extracellular signal–regulated kinase and phosphatidylinositol 3-kinase–Akt signaling. In this study, by using B lymphoblasts as a model, we tested whether integrin β1 and FAK-Src signaling are abnormally regulated in autism and whether abnormal FAK-Src signaling leads to defects in B-lymphoblast adhesion, migration, proliferation, and IgG production. To our knowledge, for the first time, we show that protein expression levels of both integrin β1 and FAK are significantly decreased in autistic lymphoblasts and that Src protein expression and the phosphorylation of an active site (Y416) are also significantly decreased. We also found that lymphoblasts from autistic subjects exhibit significantly decreased migration, increased adhesion properties, and an impaired capacity for IgG production. The overexpression of FAK in autistic lymphoblasts countered the adhesion and migration defects. In addition, we demonstrate that FAK mediates its effect through the activation of Src, phosphatidylinositol 3-kinase–Akt, and mitogen-activated protein kinase signaling cascades and that paxillin is also likely involved in the regulation of adhesion and migration in autistic lymphoblasts. PMID:21703394

  16. Mitochondrial Abnormality Associates with Type-Specific Neuronal Loss and Cell Morphology Changes in the Pedunculopontine Nucleus in Parkinson Disease

    PubMed Central

    Pienaar, Ilse S.; Elson, Joanna L.; Racca, Claudia; Nelson, Glyn; Turnbull, Douglass M.; Morris, Christopher M.

    2014-01-01

    Cholinergic neuronal loss in the pedunculopontine nucleus (PPN) associates with abnormal functions, including certain motor and nonmotor symptoms. This realization has led to low-frequency stimulation of the PPN for treating patients with Parkinson disease (PD) who are refractory to other treatment modalities. However, the molecular mechanisms underlying PPN neuronal loss and the therapeutic substrate for the clinical benefits following PPN stimulation remain poorly characterized, hampering progress toward designing more efficient therapies aimed at restoring the PPN's normal functions during progressive parkinsonism. Here, we investigated postmortem pathological changes in the PPN of PD cases. Our study detected a loss of neurons producing gamma-aminobutyric acid (GABA) as their output and glycinergic neurons, along with the pronounced loss of cholinergic neurons. These losses were accompanied by altered somatic cell size that affected the remaining neurons of all neuronal subtypes studied here. Because studies showed that mitochondrial dysfunction exists in sporadic PD and in PD animal models, we investigated whether altered mitochondrial composition exists in the PPN. A significant up-regulation of several mitochondrial proteins was seen in GABAergic and glycinergic neurons; however, cholinergic neurons indicated down-regulation of the same proteins. Our findings suggest an imbalance in the activity of key neuronal subgroups of the PPN in PD, potentially because of abnormal inhibitory activity and altered cholinergic outflow. PMID:24099985

  17. Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass.

    PubMed

    Uc, Aliye; Olivier, Alicia K; Griffin, Michelle A; Meyerholz, David K; Yao, Jianrong; Abu-El-Haija, Maisam; Buchanan, Katherine M; Vanegas Calderón, Oriana G; Abu-El-Haija, Marwa; Pezzulo, Alejandro A; Reznikov, Leah R; Hoegger, Mark J; Rector, Michael V; Ostedgaard, Lynda S; Taft, Peter J; Gansemer, Nick D; Ludwig, Paula S; Hornick, Emma E; Stoltz, David A; Ode, Katie L; Welsh, Michael J; Engelhardt, John F; Norris, Andrew W

    2015-01-01

    Diabetes is a common and significant co-morbidity in cystic fibrosis (CF). The pathogenesis of cystic fibrosis related diabetes (CFRD) is incompletely understood. Because exocrine pancreatic disease is similar between humans and pigs with CF, the CF pig model has the potential to contribute significantly to the understanding of CFRD pathogenesis. We determined the structure of the endocrine pancreas in fetal, newborn and older CF and non-CF pigs and assessed endocrine pancreas function by intravenous glucose tolerance test (IV-GTT). In fetal pigs, pancreatic insulin and glucagon density was similar between CF and non-CF. In newborn and older pigs, the insulin and glucagon density was unchanged between CF and non-CF per total pancreatic area, but increased per remnant lobular tissue in CF reflecting exocrine pancreatic loss. Although fasting glucose levels were not different between CF and non-CF newborns, CF newborns demonstrated impaired glucose tolerance and increased glucose area under the curve during IV-GTT. Second phase insulin secretion responsiveness was impaired in CF newborn pigs and significantly lower than that observed in non-CF newborns. Older CF pigs had elevated random blood glucose levels compared with non-CF. In summary, glycaemic abnormalities and insulin secretion defects were present in newborn CF pigs and spontaneous hyperglycaemia developed over time. Functional changes in CF pig pancreas were not associated with a decline in islet cell mass. Our results suggest that functional islet abnormalities, independent of structural islet loss, contribute to the early pathogenesis of CFRD.

  18. Detection of numerical chromosomal abnormalities (chr. 1 and 18) before and after photodynamic therapy of human bladder carcinoma cells in vitro

    NASA Astrophysics Data System (ADS)

    Bachor, Ruediger; Reich, Ella D.; Kleinschmidt, Klaus; Hautmann, Richard E.

    1997-12-01

    The application of nonradioactive in situ hybridization with chromosome-specific probes for cytogenetic analysis has increased significantly in recent years. In the field of photodynamic therapy (PDT) the hypothesis is that after PDT the remaining viable malignant cells are potentially metastatic cells. Therefore, we performed in vitro experiments on human bladder carcinoma cells to evaluate numerical chromosomal abnormalities before and after PDT. The possible genotoxic effect of PDT with porphycene (AamTPPn) appears to be small based on criteria such as numerical chromosomal abnormalities for chromosome 1 and 18.

  19. Abnormal variation of the growth rate under high NH3 injected regime in the growth of GaN by NH3-source MBE

    NASA Astrophysics Data System (ADS)

    Choi, Sungkuk; Jung, Soohoon; Cho, Youngji; Lee, Sangtae; Chang, Jiho

    2017-03-01

    Unusual growth-rate variation during GaN formation using gas-source MBE has been discussed with respect to the chemical reactions occurring in the transition layer. A series of samples were prepared to confirm the assumption by verifying the growth regime and the impacts on the crystal quality of the GaN film. We found that the growth rate can be varied along with the amount of NH3 supply even under NH3-rich condition with a fixed Ga flux. Two growth conditions were investigated for their impact on the transition layer. One was the atomic force microscopy result, which revealed that the adatom migration length is closely related to the transition layer formation. The other one is the photoluminescent spectra, which revealed that the luminescence property of GaN is strongly related to the transition layer.

  20. Glycosylation abnormalities in Gdt1p/TMEM165 deficient cells result from a defect in Golgi manganese homeostasis.

    PubMed

    Potelle, Sven; Morelle, Willy; Dulary, Eudoxie; Duvet, Sandrine; Vicogne, Dorothée; Spriet, Corentin; Krzewinski-Recchi, Marie-Ange; Morsomme, Pierre; Jaeken, Jaak; Matthijs, Gert; De Bettignies, Geoffroy; Foulquier, François

    2016-04-15

    Congenital disorders of glycosylation (CDG) are severe inherited diseases in which aberrant protein glycosylation is a hallmark. From this genetically and clinically heterogenous group, a significant subgroup due to Golgi homeostasis defects is emerging. We previously identified TMEM165 as a Golgi protein involved in CDG. Extremely conserved in the eukaryotic reign, the molecular mechanism by which TMEM165 deficiencies lead to Golgi glycosylation abnormalities is enigmatic. AsGDT1 is the ortholog of TMEM165 in yeast, both gdt1Δ null mutant yeasts and TMEM165 depleted cells were used. We highlighted that the observed Golgi glycosylation defects due to Gdt1p/TMEM165 deficiency result from Golgi manganese homeostasis defect. We discovered that in both yeasts and mammalian Gdt1p/TMEM165-deficient cells, Mn(2+) supplementation could restore a normal glycosylation. We also showed that the GPP130 Mn(2+) sensitivity was altered in TMEM165 depleted cells. This study not only provides novel insights into the molecular causes of glycosylation defects observed in TMEM165-deficient cells but also suggest that TMEM165 is a key determinant for the regulation of Golgi Mn(2+) homeostasis.

  1. Leukocyte abnormalities.

    PubMed

    Gabig, T G

    1980-07-01

    Certain qualitative abnormalities in neutrophils and blood monocytes are associated with frequent, severe, and recurrent bacterial infections leading to fatal sepsis, while other qualitative defects demonstrated in vitro may have few or no clinical sequelae. These qualitative defects are discussed in terms of the specific functions of locomotion, phagocytosis, degranulation, and bacterial killing.

  2. Connecting chromosome replication with cell growth in bacteria.

    PubMed

    Murray, Heath

    2016-12-01

    For bacteria to proliferate they must duplicate their genetic material so that it can be passed to their progeny. This requires that DNA replication is coordinated with cell growth and division. In the natural environment bacterial growth is dynamic and strongly influenced by changes in nutrient availability. Recent studies have found that bacteria utilize a range of regulatory systems, many of them species-specific, to coordinate DNA replication with cell growth. This variability likely reflects the diverse lifestyles of different bacterial types.

  3. Role of Fetuin-A in Breast Tumor Cell Growth

    DTIC Science & Technology

    2009-03-01

    Growth PRINCIPAL INVESTIGATOR: Josiah Ochieng, Ph.D. CONTRACTING ORGANIZATION: Meharry Medical College Nashville, TN 37208...COVERED (From - To) 4. TITLE AND SUBTITLE Role of fetuin-A in Breast Tumor Cell Growth 5a. CONTRACT NUMBER W81XWH-07-1-0254 5b. GRANT NUMBER...hypothesis of this grant is that fetuin-A is a major serum derived growth factor for breast carcinoma cells and creates a favorable environment for the

  4. Beta2-microglobulin causes abnormal phosphatidylserine exposure in human red blood cells.

    PubMed

    Pavone, Barbara; Bucci, Sonia; Sirolli, Vittorio; Merlini, Giampaolo; Del Boccio, Piero; Di Rienzo, Marianna; Felaco, Paolo; Amoroso, Luigi; Sacchetta, Paolo; Di Ilio, Carmine; Federici, Giorgio; Urbani, Andrea; Bonomini, Mario

    2011-03-01

    The exposure of the aminophospholipid phosphatidylserine on the external leaflet of red blood cell plasma membrane can have several pathophysiological consequences with particular regard to the processes of cell phagocytosis, haemostasis and cell-cell interaction. A significant increase in phosphatidylserine-exposing erythrocytes has been reported in chronic haemodialysis patients and found to be strongly influenced by the uraemic milieu. To identify uraemic compound(s) enhancing phosphatidylserine externalization in erythrocytes, we fractionated by chromatographic methods the ultrafiltrate obtained during dialysis, and examined by flow cytometry the effect of the resulting fractions on phosphatidylserine exposure in human red cells. Chromatographic procedures disclosed a homogeneous fraction able to increase erythrocyte phosphatidylserine exposure. The inducer of such externalization was identified by monodimensional gel electrophoresis and mass spectrometry investigations as beta2-microglobulin. To confirm the beta2-microglobulin effect and to examine the influence of protein glycation (as it occurs in uraemia) on phosphatidylserine erythrocyte exposure, erythrocytes from normal subjects were incubated with recombinant beta2-microglobulin (showing no glycation sites at mass analysis), commercial beta2-microglobulin (8 glycation sites), or with in vitro glycated recombinant beta2-microglobulin (showing multiple glycation sites). Elevated concentrations of beta2-microglobulin (corresponding to plasma levels reached in dialysis patients) increased slightly but significantly the protein's ability to externalize phosphatidylserine on human erythrocytes. Such an effect was markedly enhanced by glycated forms of the protein. Beta2-microglobulin is recognized as a surrogate marker of middle-molecule uraemic toxins and represents a key component of dialysis-associated amyloidosis. Our study adds further evidence to the potential pathophysiologic consequences of beta2

  5. The prevalence of hypertension and abnormal kidney function in children with sickle cell disease –a cross sectional review

    PubMed Central

    2013-01-01

    Background Renal disease is a known contributor to mortality in adults with sickle cell disease (SCD) and renal abnormalities are evident in childhood. Hyperfiltration (evidenced by elevated glomerular filtration rate, GFR) occurs in children with SCD early in disease. However, the incidence of low GFR (<90 ml/min/1.73 m2) suggestive of chronic kidney disease (CKD), is not well established. The prevalence of hypertension is also not well known. The goal of this study was to determine the prevalence of hypertension and CKD in a cohort of children with SCD. Methods We performed a retrospective chart review of patients followed at the Rainbow Babies and Children’s Sickle Cell Disease Clinic who were seen during routine follow up visits. Inclusion criteria were all patients ages 3–18. Exclusion criteria included recent (within 2 weeks) hospitalization and/or episode of acute chest, pain crises, febrile illness or red blood cell transfusion. Data collected included serum creatinine, blood pressure and history of sickle cell complications (acute chest syndrome, stroke or stroke risk). Estimated GFR (eGFR) was calculated using the updated Schwartz creatinine-based estimating formula. Analysis examined the associations among eGFR, blood pressure and sickle cell complications. The Institutional Review Board at University Hospitals Case Medical Center approved this study. Results A total of 48 children had complete data available. Mean eGFR was 140 mL/min/1.73 m2 +/- 34.9 (range 71.9-404.2 mL/min/1.73 m2). Four patients (8.3%) had eGFRs < 90 mL/min/1.73 m2, 35 patients (72.9%) had eGFRs > 120 mL/min/1.73 m2 and 9 patients (18.8%) had eGFRs in the normal range. Eight patients (16.7%) had evidence of elevated blood pressures (pre-hypertension or hypertension). There was no correlation between eGFR and age, and no association of eGFR with acute chest or stroke risk. Conclusion In this SCD cohort, we identified abnormally low eGFR (suggestive of early CKD

  6. Can Insulin Production Suppress β Cell Growth?

    PubMed

    De Vas, Matias; Ferrer, Jorge

    2016-01-12

    While insulin has mitogenic effects in many cell types, its effects on β cells remain elusive. In this issue of Cell Metabolism, Szabat et al. (2015) genetically block insulin production in adult β cells and show that this leads to a relief of ER stress, AKT activation, and increased β cell proliferation.

  7. Ultrastructural characterization of normal and abnormal chondrogenesis in micromass rat embryo limb bud cell cultures.

    PubMed

    Renault, J Y; Caillaud, J M; Chevalier, J

    1995-02-01

    Inhibition of chondrogenesis in limb bud cell micromass cultures has been proposed as a short-term teratogen detection test. Validation studies were performed by testing large series of reference compounds and comparing their teratogenic potential with their ability to inhibit chondrogenesis; however, there are few reports describing the histological and ultrastructural changes associated with inhibition of chondrogenesis in vitro. The objective of this study was to provide a qualitative description of the histological and ultrastructural alterations induced by three chondrogenesis inhibitors: retinoic acid (RA) and 6-aminonicotinamide (6AN), two teratogens, and doxylamine succinate (DS), a nonteratogen compound. In addition, in order to have a basis for the interpretation of the morphological alterations induced by the test compounds, the histological and ultrastructural changes which occur during the time course of chondrogenesis in control cultures were described and compared with those in rat embryo limb buds. We found that RA at 0.5 micrograms/ml led to a marked decrease in the number and size of cartilaginous foci; most cells lacked morphological signs of differentiation but their ability to proliferate was unaffected. At concentrations of 2 micrograms/ml and more, 6AN delayed cell proliferation, reduced staining of the extracellular matrix, and induced the formation of endoplasmic cisternae. DS at 50 micrograms/ml affected both differentiation and proliferation; pigment deposits were observed in chondrocytes, suggesting phospholipid metabolism disorders. In conclusion, this study showed that inhibition of chondrogenesis in this simple cell culture system can be associated with different types of histological and ultrastructural alterations. Examination of these alterations can provide useful information about the teratogenic potential of tested compounds and their mechanism of action.

  8. On the growth of walled cells: From shells to vesicles.

    NASA Astrophysics Data System (ADS)

    Boudaoud, Arezki

    2003-03-01

    The growth of isolated walled cells is investigated. Examples of such cells range from bacteria to giant algae, and include cochlear hair, plant root hair, fungi and yeast cells. They are modeled as elastic shells inflated by a liquid. Cell growth is driven by fluid pressure and is similar to a plastic deformation of the wall. The requirement of mechanical equilibrium leads to two new scaling laws for cell size that are in quantitative agreement with the compiled biological data. Given these results, possible shapes for growing cells are computed by analogy with those of vesicle membranes.

  9. Growth of Walled Cells: From Shells to Vesicles

    NASA Astrophysics Data System (ADS)

    Boudaoud, Arezki

    2003-07-01

    The growth of isolated walled cells is investigated. Examples of such cells range from bacteria to giant algae, and include cochlear hair, plant root hair, fungi, and yeast cells. They are modeled as elastic shells containing a liquid. Cell growth is driven by fluid pressure and is is similar to a plastic deformation of the wall. The requirement of mechanical equilibrium leads to two new scaling laws for cell size that are in quantitative agreement with the compiled biological data. Given these results, possible shapes for growing cells are computed by analogy with those of vesicle membranes.

  10. Effects of Na(+) channel and cell coupling abnormalities on vulnerability to reentry: a simulation study.

    PubMed

    Qu, Zhilin; Karagueuzian, Hrayr S; Garfinkel, Alan; Weiss, James N

    2004-04-01

    The role of dynamic instabilities in the initiation of reentry in diseased (remodeled) hearts remains poorly explored. Using computer simulations, we studied the effects of altered Na(+) channel and cell coupling properties on the vulnerable window (VW) for reentry in simulated two-dimensional cardiac tissue with and without dynamic instabilities. We related the VW for reentry to effects on conduction velocity, action potential duration (APD), effective refractory period dispersion and restitution, and concordant and discordant APD alternans. We found the following: 1). reduced Na(+) current density and slowed recovery promoted postrepolarization refractoriness and enhanced concordant and discordant APD alternans, which increased the VW for reentry; 2). uniformly reduced cell coupling had little effect on cellular electrophysiological properties and the VW for reentry. However, randomly reduced cell coupling combined with decoupling promoted APD dispersion and alternans, which also increased the VW for reentry; 3). the combination of decreased Na(+) channel conductance, slowed Na(+) channel recovery, and cellular uncoupling synergistically increased the VW for reentry; and 4) the VW for reentry was greater when APD restitution slope was steep than when it was flat. In summary, altered Na(+) channel and cellular coupling properties increase vulnerability to reentrant arrhythmias. In remodeled hearts with altered Na(+) channel properties and cellular uncoupling, dynamic instabilities arising from electrical restitution exert important influences on the VW for reentry.

  11. Mechanisms of Abnormal Growth Regulation in Prostatic Adenocarcinoma Using Abi1/Hssh3bp1 Conditional Knockout Mouse Model

    DTIC Science & Technology

    2009-06-01

    2008). Hence library containing SH2 domains was used in the screening. These experiments were done in collaboration with Dr. Bruce Mayer and Dr...Machida (University of Connecticut Health Science Center, Farmington, CT) using the overlay method developed by Dr. Mayer laboratory (Machida et al...Shin, and B.J. Mayer . 2007. High-throughput phosphotyrosine profiling using SH2 domains. Mol Cell. 26:899-915. Macoska, J.A., J. Xu, D. Ziemnicka, T.S

  12. HMGCR positively regulated the growth and migration of glioblastoma cells.

    PubMed

    Qiu, Zhihua; Yuan, Wen; Chen, Tao; Zhou, Chenzhi; Liu, Chao; Huang, Yongkai; Han, Deqing; Huang, Qinghui

    2016-01-15

    The metabolic program of cancer cells is significant different from the normal cells, which makes it possible to develop novel strategies targeting cancer cells. Mevalonate pathway and its rate-limiting enzyme HMG-CoA reductase (HMGCR) have shown important roles in the progression of several cancer types. However, their roles in glioblastoma cells remain unknown. In this study, up-regulation of HMGCR in the clinical glioblastoma samples was observed. Forced expression of HMGCR promoted the growth and migration of U251 and U373 cells, while knocking down the expression of HMGCR inhibited the growth, migration and metastasis of glioblastoma cells. Molecular mechanism studies revealed that HMGCR positively regulated the expression of TAZ, an important mediator of Hippo pathway, and the downstream target gene connective tissue growth factor (CTGF), suggesting HMGCR might activate Hippo pathway in glioblastoma cells. Taken together, our study demonstrated the oncogenic roles of HMGCR in glioblastoma cells and HMGCR might be a promising therapeutic target.

  13. Senescent stromal-derived osteopontin promotes preneoplastic cell growth.

    PubMed

    Pazolli, Ermira; Luo, Xianmin; Brehm, Sarah; Carbery, Kelly; Chung, Jun-Jae; Prior, Julie L; Doherty, Jason; Demehri, Shadmehr; Salavaggione, Lorena; Piwnica-Worms, David; Stewart, Sheila A

    2009-02-01

    Alterations in the tissue microenvironment collaborate with cell autonomous genetic changes to contribute to neoplastic progression. The importance of the microenvironment in neoplastic progression is underscored by studies showing that fibroblasts isolated from a tumor stimulate the growth of preneoplastic and neoplastic cells in xenograft models. Similarly, senescent fibroblasts promote preneoplastic cell growth in vitro and in vivo. Because senescent cells accumulate with age, their presence is hypothesized to facilitate preneoplastic cell growth and tumor formation in older individuals. To identify senescent stromal factors directly responsible for stimulating preneoplastic cell growth, we carried out whole-genome transcriptional profiling and compared senescent fibroblasts with their younger counterparts. We identified osteopontin (OPN) as one of the most highly elevated transcripts in senescent fibroblasts. Importantly, reduction of OPN protein levels by RNA interference did not affect senescence induction in fibroblasts; however, it dramatically reduced the growth-promoting activities of senescent fibroblasts in vitro and in vivo, showing that OPN is necessary for paracrine stimulation of preneoplastic cell growth. In addition, we found that recombinant OPN was sufficient to stimulate preneoplastic cell growth. Finally, we show that OPN is expressed in senescent stroma within preneoplastic lesions that arise following 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate treatment of mice, suggesting that stromal-derived OPN-mediated signaling events affect neoplastic progression.

  14. Senescent Stromal-Derived Osteopontin Promotes Preneoplastic Cell Growth

    PubMed Central

    Pazolli, Ermira; Luo, Xianmin; Brehm, Sarah; Carbery, Kelly; Chung, Jun-Jae; Prior, Julie L.; Doherty, Jason; Demehri, Shadmehr; Salavaggione, Lorena; Piwnica-Worms, David; Stewart, Sheila A.

    2008-01-01

    Alterations in the tissue microenvironment collaborate with cell autonomous genetic changes to contribute to neoplastic progression. The importance of the microenvironment in neoplastic progression is underscored by studies demonstrating that fibroblasts isolated from a tumor stimulate the growth of preneoplastic and neoplastic cells in xenograft models. Similarly, senescent fibroblasts promote preneoplastic cell growth in vitro and in vivo. Because senescent cells accumulate with age, their presence is hypothesized to facilitate preneoplastic cell growth and tumor formation in older individuals. To identify senescent stromal factors directly responsible for stimulating preneoplastic cell growth, we carried out whole genome transcriptional profiling and compared senescent fibroblasts to their younger counterparts. We identified osteopontin (OPN) as one of the most highly elevated transcripts in senescent fibroblasts. Importantly, reduction of OPN protein levels by RNAi did not impact senescence induction in fibroblasts; however, it dramatically reduced the growth-promoting activities of senescent fibroblasts in vitro and in vivo, demonstrating that OPN is necessary for paracrine stimulation of preneoplastic cell growth. In addition, we found that recombinant OPN was sufficient to stimulate preneoplastic cell growth. Finally, we demonstrate that OPN is expressed in senescent stroma within preneoplastic lesions that arise following DMBA/TPA treatment of mice, suggesting that stromal-derived OPN-mediated signaling events impact neoplastic progression. PMID:19155301

  15. Red blood cell abnormalities and the pathogenesis of anemia in end-stage renal disease.

    PubMed

    Georgatzakou, Hara T; Antonelou, Marianna H; Papassideri, Issidora S; Kriebardis, Anastasios G

    2016-08-01

    Anemia is the most common hematologic complication in end-stage renal disease (ESRD). It is ascribed to decreased erythropoietin production, shortened red blood cell (RBC) lifespan, and inflammation. Uremic toxins severely affect RBC lifespan; however, the implicated molecular pathways are poorly understood. Moreover, current management of anemia in ESRD is controversial due to the "anemia paradox" phenomenon, which underlines the need for a more individualized approach to therapy. RBCs imprint the adverse effects of uremic, inflammatory, and oxidative stresses in a context of structural and functional deterioration that is associated with RBC removal signaling and morbidity risk. RBCs circulate in hostile plasma by raising elegant homeostatic defenses. Variability in primary defect, co-morbidity, and therapeutic approaches add complexity to the pathophysiological background of the anemic ESRD patient. Several blood components have been suggested as biomarkers of anemia-related morbidity and mortality risk in ESRD. However, a holistic view of blood cell and plasma modifications through integrated omics approaches and high-throughput studies might assist the development of new diagnostic tests and therapies that will target the underlying pathophysiologic processes of ESRD anemia.

  16. Antizyme (AZ) regulates intestinal cell growth independently of polyamines

    PubMed Central

    Ray, Ramesh M.; Bhattacharya, Sujoy; Bavaria, Mitul N.; Viar, Mary Jane; Johnson, Leonard R.

    2014-01-01

    Since antizyme (AZ) is known to inhibit cell proliferation and to increase apoptosis, the question arises as to whether these effects occur independently of polyamines. Intestinal epithelial cells (IEC-6) were grown in control medium and medium containing 5mM difluoromethylornithine (DFMO) to inhibit ODC, DFMO + 5μM spermidine (SPD), DFMO+ 5μM spermine (SPM), or DFMO+ 10 μM putrescine (PUT) for 4 days and various parameters of growth were measured along with AZ levels. Cell counts were significantly decreased and mean doubling times were significantly increased by DFMO. Putrescine restored growth in the presence of DFMO. However, both SPD and SPM when added with DFMO caused a much greater inhibition of growth than did DFMO alone, and both of these polyamines caused a dramatic increase in AZ. The addition of SPD or SPM to media containing DFMO + PUT significantly inhibited growth and caused a significant increase in AZ. IEC-6 cells transfected with AZ-siRNA grew more than twice as rapidly as either control cells or those incubated with DFMO, indicating that removal of AZ increases growth in cells in which polyamine synthesis is inhibited as well as in control cells. In a separate experiment the addition of SPD increased AZ levels and inhibited growth of cells incubated with DFMO by 50%. The addition of 10 mM asparagine (ASN) prevented the increase in AZ and restored growth to control levels. These results show that cell growth in the presence or absence of ODC activity and in the presence or absence of polyamines depends only on the levels of AZ. Therefore, the effects of AZ on cell growth are independent of polyamines. PMID:24930035

  17. Protein kinase C activators inhibit capillary endothelial cell growth

    SciTech Connect

    Doctrow, S.R.

    1986-05-01

    Phorbol 12,13-dibutyrate (PDBu) binds specifically to bovine capillary endothelial (BCE) cells (K/sub d/ = 8nM) and inhibits the proliferation (K/sub 50/ = 6 +/- 4 nM). Under similar conditions, PDBu does not inhibit the growth of bovine aortic endothelial or smooth muscle cells. PDBu markedly attenuates the response of BCE cells to purified human hepatoma-derived growth factor which, in the absence of PDBu, stimulates BCE cell growth by about 3-fold. Several observations suggest that the inhibition of BCE cell growth by PDBu is mediated by protein kinase C: (1) different phorbol compounds inhibit BCE cell growth according to the relative potencies as protein kinase C activators (12-tetradecanoylphorbol 13-acetate > PDBu >> phorbol 12,13-diacetate >>>..beta..-phorbol; ..cap alpha..-phorbol 12,13-didecanoate). (2) Specific binding of PDBu to BCE cells is displaced by sn-1,2-dioctanoylglycerol (diC/sub 8/), a protein kinase C activator and an analog of the putative second messenger activating this kinase in vivo. The weak protein kinase C activator, sn-1,2-dibutyrylglycerol, does not affect PDBu binding. (3) A cytosolic extract from BCE cells contains a Ca/sup 2 +//phosphatidylserine-dependent kinase that is activated by diC/sub 8/ and PDBu, but not by ..beta..-phorbol. These results support a role for protein kinase C in suppressing capillary endothelial cell growth and may therefore have implications in the intracellular regulation of angiogenesis.

  18. Symbiotic Cell Differentiation and Cooperative Growth in Multicellular Aggregates

    PubMed Central

    Yamagishi, Jumpei F; Saito, Nen; Kaneko, Kunihiko

    2016-01-01

    As cells grow and divide under a given environment, they become crowded and resources are limited, as seen in bacterial biofilms and multicellular aggregates. These cells often show strong interactions through exchanging chemicals, as evident in quorum sensing, to achieve mutualism and division of labor. Here, to achieve stable division of labor, three characteristics are required. First, isogenous cells differentiate into several types. Second, this aggregate of distinct cell types shows better growth than that of isolated cells without interaction and differentiation, by achieving division of labor. Third, this cell aggregate is robust with respect to the number distribution of differentiated cell types. Indeed, theoretical studies have thus far considered how such cooperation is achieved when the ability of cell differentiation is presumed. Here, we address how cells acquire the ability of cell differentiation and division of labor simultaneously, which is also connected with the robustness of a cell society. For this purpose, we developed a dynamical-systems model of cells consisting of chemical components with intracellular catalytic reaction dynamics. The reactions convert external nutrients into internal components for cellular growth, and the divided cells interact through chemical diffusion. We found that cells sharing an identical catalytic network spontaneously differentiate via induction from cell-cell interactions, and then achieve division of labor, enabling a higher growth rate than that in the unicellular case. This symbiotic differentiation emerged for a class of reaction networks under the condition of nutrient limitation and strong cell-cell interactions. Then, robustness in the cell type distribution was achieved, while instability of collective growth could emerge even among the cooperative cells when the internal reserves of products were dominant. The present mechanism is simple and general as a natural consequence of interacting cells with

  19. ABNORMAL REGULATION OF MICROVASCULAR TONE IN A MURINE MODEL OF SICKLE CELL DISEASE ASSESSED BY CONTRAST ULTRASOUND

    PubMed Central

    Wu, Melinda D.; Belcik, J. Todd; Qi, Yue; Zhao, Yan; Benner, Cameron; Pei, Hong; Linden, Joel; Lindner, Jonathan R.

    2015-01-01

    Background Microvascular dysregulation, abnormal rheology, and vaso-occlusive events play a role in the pathophysiology of sickle cell disease (SCD). We hypothesized that abnormalities in skeletal muscle perfusion in a murine model of SCD could be parametrically assessed by quantitative contrast-enhanced ultrasound (CEU) perfusion imaging. Methods We studied a murine model of moderate SCD without anemia produced by homozygous β-globin deletion replaced by human βs-globin transgene (NY1DD−/−, n=18), heterozygous transgene replacement (NY1DD+/−, n=19), and C57Bl/6 control mice (n=14). Quantitative CEU of the proximal hindlimb skeletal muscle was performed at rest and during contractile exercise (2 Hz). Time-intensity data were analyzed to measure microvascular blood volume (MBV), microvascular blood transit rate (β), and microvascular blood flow (MBF). Erythrocyte deformability was measured by elongation at various rotational shears. Results At rest, muscle MBV was similar between strains whereas β was significantly (ANOVA p=0.0015) reduced to a similar degree in NY1DD−/− and NY1DD+/− compared to wild-type mice (0.24±0.10, 0.16±0.07, and 0.34±0.14 s−1, respectively), resulting in a reduction in MBF. During contractile exercise, there were no group-wise differences in β (1.43±0.67 s−1, 1.09±0.42 s−1, 1.36±0.49 s−1; for NY1DD−/−, NY1DD+/−, and wild-type, respectively), nor for MBF or MBV. Erythrocyte deformability at high shear stress (≥5 Pa) was mildly reduced in both transgenic groups, although it did not correlate with the blood flow or β. Conclusions CEU in skeletal muscle has revealed a lower microvascular blood transit rate in the NY1DD model of SCD and sickle trait but no alterations in MBV. The abnormality in microvascular blood transit rate is likely due to vasomotor dysfunction since it abrogated by contractile exercise and at rest is only weakly related to erythrocyte deformability. PMID:26123012

  20. Shared clonal cytogenetic abnormalities in aberrant mast cells and leukemic myeloid blasts detected by single nucleotide polymorphism microarray-based whole-genome scanning.

    PubMed

    Frederiksen, John K; Shao, Lina; Bixby, Dale L; Ross, Charles W

    2016-04-01

    Systemic mastocytosis (SM) is characterized by a clonal proliferation of aberrant mast cells within extracutaneous sites. In a subset of SM cases, a second associated hematologic non-mast cell disease (AHNMD) is also present, usually of myeloid origin. Polymerase chain reaction and targeted fluorescence in situ hybridization studies have provided evidence that, in at least some cases, the aberrant mast cells are related clonally to the neoplastic cells of the AHNMD. In this work, a single nucleotide polymorphism microarray (SNP-A) was used to characterize the cytogenetics of the aberrant mast cells from a patient with acute myeloid leukemia and concomitant mast cell leukemia associated with a KIT D816A mutation. The results demonstrate the presence of shared cytogenetic abnormalities between the mast cells and myeloid blasts, as well as additional abnormalities within mast cells (copy-neutral loss of heterozygosity) not detectable by routine karyotypic analysis. To our knowledge, this work represents the first application of SNP-A whole-genome scanning to the detection of shared cytogenetic abnormalities between the two components of a case of SM-AHNMD. The findings provide additional evidence of a frequent clonal link between aberrant mast cells and cells of myeloid AHNMDs, and also highlight the importance of direct sequencing for identifying uncommon activating KIT mutations.

  1. AAV9-NPC1 significantly ameliorates Purkinje cell death and behavioral abnormalities in mouse NPC disease.

    PubMed

    Xie, Chang; Gong, Xue-Min; Luo, Jie; Li, Bo-Liang; Song, Bao-Liang

    2017-03-01

    Niemann-Pick type C (NPC) disease is a fatal inherited neurodegenerative disorder caused by loss-of-function mutations in the NPC1 or NPC2 gene. There is no effective way to treat NPC disease. In this study, we used adeno-associated virus (AAV) serotype 9 (AAV9) to deliver a functional NPC1 gene systemically into NPC1(-/-) mice at postnatal day 4. One single AAV9-NPC1 injection resulted in robust NPC1 expression in various tissues, including brain, heart, and lung. Strikingly, AAV9-mediated NPC1 delivery significantly promoted Purkinje cell survival, restored locomotor activity and coordination, and increased the lifespan of NPC1(-/-) mice. Our work suggests that AAV-based gene therapy is a promising means to treat NPC disease.

  2. Laying the groundwork for growth: Cell-cell and cell-ECM interactions in cardiovascular development.

    PubMed

    Bowers, Stephanie L K; Baudino, Troy A

    2010-03-01

    Cardiac development is reliant upon the spatial and temporal regulation of both genetic and chemical signals. Central to the communication of these signals are direct interactions between cells and their surrounding environment. The extracellular matrix (ECM) plays an integral role in cell communication and tissue growth throughout development by providing both structural support and chemical signaling factors. The present review discusses elements of cell-cell and cell-ECM interactions involved in cardiogenesis, and how disruption of these interactions can result in numerous heart defects. Examining the relationships between cells and their immediate environment has implications for novel and existing therapeutic strategies to combating congenital disorders.

  3. Microtubules Growth Rate Alteration in Human Endothelial Cells

    PubMed Central

    Alieva, Irina B.; Zemskov, Evgeny A.; Kireev, Igor I.; Gorshkov, Boris A.; Wiseman, Dean A.; Black, Stephen M.; Verin, Alexander D.

    2010-01-01

    To understand how microtubules contribute to the dynamic reorganization of the endothelial cell (EC) cytoskeleton, we established an EC model expressing EB3-GFP, a protein that marks microtubule plus-ends. Using this model, we were able to measure microtubule growth rate at the centrosome region and near the cell periphery of a single human EC and in the EC monolayer. We demonstrate that the majority of microtubules in EC are dynamic, the growth rate of their plus-ends is highest in the internal cytoplasm, in the region of the centrosome. Growth rate of microtubule plus-ends decreases from the cell center toward the periphery. Our data suggest the existing mechanism(s) of local regulation of microtubule plus-ends growth in EC. Microtubule growth rate in the internal cytoplasm of EC in the monolayer is lower than that of single EC suggesting the regulatory effect of cell-cell contacts. Centrosomal microtubule growth rate distribution in single EC indicated the presence of two subpopulations of microtubules with “normal” (similar to those in monolayer EC) and “fast” (three times as much) growth rates. Our results indicate functional interactions between cell-cell contacts and microtubules. PMID:20445745

  4. Microtubules growth rate alteration in human endothelial cells.

    PubMed

    Alieva, Irina B; Zemskov, Evgeny A; Kireev, Igor I; Gorshkov, Boris A; Wiseman, Dean A; Black, Stephen M; Verin, Alexander D

    2010-01-01

    To understand how microtubules contribute to the dynamic reorganization of the endothelial cell (EC) cytoskeleton, we established an EC model expressing EB3-GFP, a protein that marks microtubule plus-ends. Using this model, we were able to measure microtubule growth rate at the centrosome region and near the cell periphery of a single human EC and in the EC monolayer. We demonstrate that the majority of microtubules in EC are dynamic, the growth rate of their plus-ends is highest in the internal cytoplasm, in the region of the centrosome. Growth rate of microtubule plus-ends decreases from the cell center toward the periphery. Our data suggest the existing mechanism(s) of local regulation of microtubule plus-ends growth in EC. Microtubule growth rate in the internal cytoplasm of EC in the monolayer is lower than that of single EC suggesting the regulatory effect of cell-cell contacts. Centrosomal microtubule growth rate distribution in single EC indicated the presence of two subpopulations of microtubules with "normal" (similar to those in monolayer EC) and "fast" (three times as much) growth rates. Our results indicate functional interactions between cell-cell contacts and microtubules.

  5. Another brick in the cell wall: biosynthesis dependent growth model.

    PubMed

    Barbacci, Adelin; Lahaye, Marc; Magnenet, Vincent

    2013-01-01

    Expansive growth of plant cell is conditioned by the cell wall ability to extend irreversibly. This process is possible if (i) a tensile stress is developed in the cell wall due to the coupling effect between turgor pressure and the modulation of its mechanical properties through enzymatic and physicochemical reactions and if (ii) new cell wall elements can be synthesized and assembled to the existing wall. In other words, expansive growth is the result of coupling effects between mechanical, thermal and chemical energy. To have a better understanding of this process, models must describe the interplay between physical or mechanical variable with biological events. In this paper we propose a general unified and theoretical framework to model growth in function of energy forms and their coupling. This framework is based on irreversible thermodynamics. It is then applied to model growth of the internodal cell of Chara corallina modulated by changes in pressure and temperature. The results describe accurately cell growth in term of length increment but also in term of cell pectate biosynthesis and incorporation to the expanding wall. Moreover, the classical growth model based on Lockhart's equation such as the one proposed by Ortega, appears as a particular and restrictive case of the more general growth equation developed in this paper.

  6. Investigation of Abnormal Grain Growth in a Friction Stir Welded and Spin-Formed Al-Li Alloy 2195 Crew Module

    NASA Technical Reports Server (NTRS)

    Tayon, Wesley A.; Domack, Marcia S.; Hoffman, Eric K.; Hales, Stephen J.

    2013-01-01

    In order to improve manufacturing efficiency and reduce structural mass and costs in the production of launch vehicle structures, NASA is pursuing a wide-range of innovative, near-net shape manufacturing technologies. A technology that combines friction stir welding (FSW) and spin-forming has been applied to manufacture a single-piece crew module using Aluminum-Lithium (AL-Li) Alloy 2195. Plate size limitations for Al-Li alloy 2195 require that two plates be FSW together to produce a spin-forming blank of sufficient size to form the crew module. Subsequent forming of the FSW results in abnormal grain growth (AGG) within the weld region upon solution heat treatment (SHT), which detrimentally impacts strength, ductility, and fracture toughness. The current study seeks to identify microstructural factors that contribute to the development of AGG. Electron backscatter diffraction (EBSD) was used to correlate driving forces for AGG, such as stored energy, texture, and grain size distributions, with the propensity for AGG. Additionally, developmental annealing treatments prior to SHT are examined to reduce or eliminate the occurrence of AGG by promoting continuous, or uniform, grain growth

  7. Transcriptomic regulations in oligodendroglial and microglial cells related to brain damage following fetal growth restriction.

    PubMed

    Rideau Batista Novais, Aline; Pham, Hoa; Van de Looij, Yohan; Bernal, Miguel; Mairesse, Jerome; Zana-Taieb, Elodie; Colella, Marina; Jarreau, Pierre-Henri; Pansiot, Julien; Dumont, Florent; Sizonenko, Stéphane; Gressens, Pierre; Charriaut-Marlangue, Christiane; Tanter, Mickael; Demene, Charlie; Vaiman, Daniel; Baud, Olivier

    2016-12-01

    Fetal growth restriction (FGR) is a major complication of human pregnancy, frequently resulting from placental vascular diseases and prenatal malnutrition, and is associated with adverse neurocognitive outcomes throughout life. However, the mechanisms linking poor fetal growth and neurocognitive impairment are unclear. Here, we aimed to correlate changes in gene expression induced by FGR in rats and abnormal cerebral white matter maturation, brain microstructure, and cortical connectivity in vivo. We investigated a model of FGR induced by low-protein-diet malnutrition between embryonic day 0 and birth using an interdisciplinary approach combining advanced brain imaging, in vivo connectivity, microarray analysis of sorted oligodendroglial and microglial cells and histology. We show that myelination and brain function are both significantly altered in our model of FGR. These alterations, detected first in the white matter on magnetic resonance imaging significantly reduced cortical connectivity as assessed by ultrafast ultrasound imaging. Fetal growth retardation was found associated with white matter dysmaturation as shown by the immunohistochemical profiles and microarrays analyses. Strikingly, transcriptomic and gene network analyses reveal not only a myelination deficit in growth-restricted pups, but also the extensive deregulation of genes controlling neuroinflammation and the cell cycle in both oligodendrocytes and microglia. Our findings shed new light on the cellular and gene regulatory mechanisms mediating brain structural and functional defects in malnutrition-induced FGR, and suggest, for the first time, a neuroinflammatory basis for the poor neurocognitive outcome observed in growth-restricted human infants. GLIA 2016;64:2306-2320.

  8. Trivalent dimethylarsenic compound induces histone H3 phosphorylation and abnormal localization of Aurora B kinase in HepG2 cells

    SciTech Connect

    Suzuki, Toshihide; Miyazaki, Koichi; Kita, Kayoko; Ochi, Takafumi

    2009-12-15

    Trivalent dimethylarsinous acid [DMA(III)] has been shown to induce mitotic abnormalities, such as centrosome abnormality, multipolar spindles, multipolar division, and aneuploidy, in several cell lines. In order to elucidate the mechanisms underlying these mitotic abnormalities, we investigated DMA(III)-mediated changes in histone H3 phosphorylation and localization of Aurora B kinase, which is a key molecule in cell mitosis. DMA(III) caused the phosphorylation of histone H3 (ser10) and was distributed predominantly in mitotic cells, especially in prometaphase cells. By contrast, most of the phospho-histone H3 was found to be localized in interphase cells after treatment with inorganic arsenite [iAs(III)], suggesting the involvement of a different pathway in phosphorylation. DMA(III) activated Aurora B kinase and slightly activated ERK MAP kinase. Phosphorylation of histone H3 by DMA(III) was effectively reduced by ZM447439 (Aurora kinase inhibitor) and slightly reduced by U0126 (MEK inhibitor). By contrast, iAs(III)-dependent histone H3 phosphorylation was markedly reduced by U0126. Aurora B kinase is generally localized in the midbody during telophase and plays an important role in cytokinesis. However, in some cells treated with DMA(III), Aurora B was not localized in the midbody of telophase cells. These findings suggested that DMA(III) induced a spindle abnormality, thereby activating the spindle assembly checkpoint (SAC) through the Aurora B kinase pathway. In addition, cytokinesis was not completed because of the abnormal localization of Aurora B kinase by DMA(III), thereby resulting in the generation of multinucleated cells. These results provide insight into the mechanism of arsenic tumorigenesis.

  9. ANGUSTIFOLIA mediates one of the multiple SCRAMBLED signaling pathways regulating cell growth pattern in Arabidopsis thaliana.

    PubMed

    Kwak, Su-Hwan; Song, Sang-Kee; Lee, Myeong Min; Schiefelbein, John

    2015-09-25

    In Arabidopsis thaliana, an atypical leucine-rich repeat receptor-like kinase, SCRAMBLED (SCM), is required for multiple developmental processes including root epidermal cell fate determination, silique dehiscence, inflorescence growth, ovule morphogenesis, and tissue morphology. Previous work suggested that SCM regulates these multiple pathways using distinct mechanisms via interactions with specific downstream factors. ANGUSTIFOLIA (AN) is known to regulate cell and tissue morphogenesis by influencing cortical microtubule arrangement, and recently, the AN protein was reported to interact with the SCM protein. Therefore, we examined whether AN might be responsible for mediating some of the SCM-dependent phenotypes. We discovered that both scm and an mutant lines cause an abnormal spiral or twisting growth of roots, but only the scm mutant affected root epidermal patterning. The siliques of the an and scm mutants also exhibited spiral growth, as previously reported, but only the scm mutant altered silique dehiscence. Interestingly, we discovered that the spiral growth of roots and siliques of the scm mutant is rescued by a truncated SCM protein that lacks its kinase domain, and that a juxtamembrane domain of SCM was sufficient for AN binding in the yeast two-hybrid analysis. These results suggest that the AN protein is one of the critical downstream factors of SCM pathways specifically responsible for mediating its effects on cell/tissue morphogenesis through cortical microtubule arrangement.

  10. Automated identification of abnormal metaphase chromosome cells for the detection of chronic myeloid leukemia using microscopic images

    NASA Astrophysics Data System (ADS)

    Wang, Xingwei; Zheng, Bin; Li, Shibo; Mulvihill, John J.; Chen, Xiaodong; Liu, Hong

    2010-07-01

    Karyotyping is an important process to classify chromosomes into standard classes and the results are routinely used by the clinicians to diagnose cancers and genetic diseases. However, visual karyotyping using microscopic images is time-consuming and tedious, which reduces the diagnostic efficiency and accuracy. Although many efforts have been made to develop computerized schemes for automated karyotyping, no schemes can get be performed without substantial human intervention. Instead of developing a method to classify all chromosome classes, we develop an automatic scheme to detect abnormal metaphase cells by identifying a specific class of chromosomes (class 22) and prescreen for suspicious chronic myeloid leukemia (CML). The scheme includes three steps: (1) iteratively segment randomly distributed individual chromosomes, (2) process segmented chromosomes and compute image features to identify the candidates, and (3) apply an adaptive matching template to identify chromosomes of class 22. An image data set of 451 metaphase cells extracted from bone marrow specimens of 30 positive and 30 negative cases for CML is selected to test the scheme's performance. The overall case-based classification accuracy is 93.3% (100% sensitivity and 86.7% specificity). The results demonstrate the feasibility of applying an automated scheme to detect or prescreen the suspicious cancer cases.

  11. B cell hyperactivity and abnormalities in T cell markers and immunoregulatory function in a patient with nucleoside phosphorylase deficiency.

    PubMed Central

    Zabay, J M; De La Concha, E G; Ludeña, C; Lozano, C; Pascual-Salcedo, D; Bootello, A; Gonzalezporqué, P

    1982-01-01

    We describe a 2 year old girl with nucleoside phosphorylase (PNP) deficiency, who had low blood T cell numbers and T lymphocyte blastogenic response to mitogens, hypergammaglobulinaemia, high titres of antibodies to many common antigens, various autoantibodies, a monoclonal IgM-kappa protein, an increased frequency of mature Ig containing blood B cells and a high production of Ig in vitro in unstimulated cultures. E rosetting cells showed faint or no immunofluorescence staining with monoclonal antibodies directed against T cell membrane antigens. In vitro Ig production in response to pokeweed mitogen was defective, and no T cell helper or suppressor activity was observed. It is suggested that the immunoregulatory deficiency might have caused the B cell hyperactivity. PMID:6819909

  12. Cognitive and behavioral abnormalities in children after hematopoietic stem cell transplantation for severe congenital immunodeficiencies.

    PubMed

    Titman, Penny; Pink, Elizabeth; Skucek, Emily; O'Hanlon, Katherine; Cole, Tim J; Gaspar, Jane; Xu-Bayford, Jinhua; Jones, Alison; Thrasher, Adrian J; Davies, E Graham; Veys, Paul A; Gaspar, H Bobby

    2008-11-01

    Hematopoietic stem cell transplantation (HSCT) is a highly successful treatment for severe congenital immunodeficiencies. However, some studies have suggested that children may experience cognitive difficulties after HSCT. This large-scale study assessed cognitive and behavioral function for the cohort of children treated by HSCT at one center between 1979 and 2003 to determine the frequency and severity of problems and to identify risk factors. A total of 105 patients were assessed on standardized measures of cognitive and emotional and behavioral function together with a control group of unaffected siblings. The average IQ for the cohort was 85 (95% confidence interval, 81-90), significantly lower than both the population average of 100 (P < .001) and unaffected siblings. Multivariate analysis indicated that the underlying genetic defect, diagnosis of adenosine deaminase-deficient severe combined immunodeficiency, and consanguinity were associated with worse outcome but that age at transplantation and chemotherapy conditioning were not. Children treated by HSCT for severe immunodeficiency have an increased risk of long-term cognitive difficulties and associated emotional and behavioral difficulties. The specific genetic diagnosis, consanguinity, and severe clinical course are associated with poor outcome. Long-term follow-up of these patients should include screening to identify and manage these problems more effectively.

  13. Effects of strong magnetic fields on cell growth and radiation response of human T-lymphocytes in culture.

    PubMed

    Norimura, T; Imada, H; Kunugita, N; Yoshida, N; Nikaido, M

    1993-06-01

    Experiments were undertaken in order to verify whether or not a strong magnetic field would have any biological effects on the cell growth, viability and radiation response of mammalian cells. Magnetic field exposures were conducted using a superconducting magnet with freshly-isolated human peripheral blood T-lymphocytes maintained at their normal growing temperature of 37 degrees C. The static magnetic fields with intensities up to 6.3-tesla (T) exerted little influence on the cell growth and viability of actively-growing T-lymphocytes under normal cell-culture conditions. On the other hand, the T cells exposed to the magnetic fields (4 T-6.3 T) during PHA stimulation were inhibited in their cell growth when compared to controls. The effects of the magnetic fields with intensities up to 2 T on cell growth properties, however, were minimal in this system. Also, the radiosensitivity of T-lymphocytes previously exposed to the strong magnetic fields was more sensitive than that of control cells. These results suggest that exposure to a static magnetic field of 4 T or stronger might lead to physiological and growth abnormalities at the cellular level.

  14. Growth rate and cell size: a re-examination of the growth law.

    PubMed

    Vadia, Stephen; Levin, Petra Anne

    2015-04-01

    Research into the mechanisms regulating bacterial cell size has its origins in a single paper published over 50 years ago. In it Schaechter and colleagues made the observation that the chemical composition and size of a bacterial cell is a function of growth rate, independent of the medium used to achieve that growth rate, a finding that is colloquially referred to as 'the growth law'. Recent findings hint at unforeseen complexity in the growth law, and suggest that nutrients rather than growth rate are the primary arbiter of size. The emerging picture suggests that size is a complex, multifactorial phenomenon mediated through the varied impacts of central carbon metabolism on cell cycle progression and biosynthetic capacity.

  15. Fibrillarin, a nucleolar protein, is required for normal nuclear morphology and cellular growth in HeLa cells

    SciTech Connect

    Amin, Mohammed Abdullahel; Matsunaga, Sachihiro; Ma, Nan; Takata, Hideaki; Yokoyama, Masami; Uchiyama, Susumu; Fukui, Kiichi . E-mail: kfukui@bio.eng.osaka-u.ac.jp

    2007-08-24

    Fibrillarin is a key small nucleolar protein in eukaryotes, which has an important role in pre-rRNA processing during ribosomal biogenesis. Though several functions of fibrillarin are known, its function during the cell cycle is still unknown. In this study, we confirmed the dynamic localization of fibrillarin during the cell cycle of HeLa cells and also performed functional studies by using a combination of immunofluorescence microscopy and RNAi technique. We observed that depletion of fibrillarin has almost no effect on the nucleolar structure. However, fibrillarin-depleted cells showed abnormal nuclear morphology. Moreover, fibrillarin depletion resulted in the reduction of the cellular growth and modest accumulation of cells with 4n DNA content. Our data suggest that fibrillarin would play a critical role in the maintenance of nuclear shape and cellular growth.

  16. Culture of human mesenchymal stem cells at low oxygen tension improves growth and genetic stability by activating glycolysis

    PubMed Central

    Estrada, J C; Albo, C; Benguría, A; Dopazo, A; López-Romero, P; Carrera-Quintanar, L; Roche, E; Clemente, E P; Enríquez, J A; Bernad, A; Samper, E

    2012-01-01

    Expansion of human stem cells before cell therapy is typically performed at 20% O2. Growth in these pro-oxidative conditions can lead to oxidative stress and genetic instability. Here, we demonstrate that culture of human mesenchymal stem cells at lower, physiological O2 concentrations significantly increases lifespan, limiting oxidative stress, DNA damage, telomere shortening and chromosomal aberrations. Our gene expression and bioenergetic data strongly suggest that growth at reduced oxygen tensions favors a natural metabolic state of increased glycolysis and reduced oxidative phosphorylation. We propose that this balance is disturbed at 20% O2, resulting in abnormally increased levels of oxidative stress. These observations indicate that bioenergetic pathways are intertwined with the control of lifespan and decisively influence the genetic stability of human primary stem cells. We conclude that stem cells for human therapy should be grown under low oxygen conditions to increase biosafety. PMID:22139129

  17. Caenorhabditis elegans EFA-6 limits microtubule growth at the cell cortex.

    PubMed

    O'Rourke, Sean M; Christensen, Sara N; Bowerman, Bruce

    2010-12-01

    Microtubules are polymers of tubulin heterodimers that exhibit dynamic instability: periods of growth followed by periods of shrinkage. However, the molecular regulation of dynamic instability remains elusive. Here, we show that EFA-6, a cortically-localized protein, limits the growth of microtubules near the cell cortex of early embryonic cells from Caenorhabditis elegans, possibly by inducing microtubule catastrophes. Compared with wild type, embryos lacking EFA-6 had abnormally long and dense microtubules at the cell cortex, and growing microtubule plus ends resided at the cortex for up to five-fold longer. Loss of EFA-6 also caused excess centrosome separation and displacement towards the cell cortex early in mitosis, and subsequently a loss of anaphase spindle-pole oscillations and increased rates of spindle elongation. The centrosome separation phenotype was dependent on the motor protein dynein, suggesting a possible link between the modulation of microtubule dynamics at the cortex and dynein-dependent force production. EFA-6 orthologues activate ARF6-type GTPases to regulate vesicle trafficking. However, we show that only the C. elegans EFA-6 amino-terminus is both necessary and sufficient to limit microtubule growth along the cortex, and that this function is independent of ARF-6.

  18. Automated single cell microbioreactor for monitoring intracellular dynamics and cell growth in free solution†

    PubMed Central

    Johnson-Chavarria, Eric M.; Agrawal, Utsav; Tanyeri, Melikhan; Kuhlman, Thomas E.

    2014-01-01

    We report an automated microfluidic-based platform for single cell analysis that allows for cell culture in free solution with the ability to control the cell growth environment. Using this approach, cells are confined by the sole action of gentle fluid flow, thereby enabling non-perturbative analysis of cell growth away from solid boundaries. In addition, the single cell microbioreactor allows for precise and time-dependent control over cell culture media, with the combined ability to observe the dynamics of non-adherent cells over long time scales. As a proof-of-principle demonstration, we used the platform to observe dynamic cell growth, gene expression, and intracellular diffusion of repressor proteins while precisely tuning the cell growth environment. Overall, this microfluidic approach enables the direct observation of cellular dynamics with exquisite control over environmental conditions, which will be useful for quantifying the behaviour of single cells in well-defined media. PMID:24836754

  19. Using bacterial cell growth to template catalytic asymmetry.

    PubMed

    Kaehr, Bryan; Brinker, C Jeffrey

    2010-08-07

    We report an approach to position gold nanoparticle catalysts for metal reduction asymmetrically on a biological template (E. coli) by exploiting the polarity of the bacterial cell envelope undergoing growth and division.

  20. Targeting Btk with ibrutinib inhibit gastric carcinoma cells growth

    PubMed Central

    Wang, Jin Dao; Chen, Xiao Ying; Ji, Ke Wei; Tao, Feng

    2016-01-01

    Bruton’s tyrosine kinase (Btk) is a member of the Tec-family non-receptor tyrosine kinases family. It has previously been reported to be expressed in B cells and has an important role in B-cell malignancies. While the roles of Btk in the pathogenesis of certain B-cell malignancies are well established, the functions of Btk in gastric carcinoma have never been investigated. Herein, we found that Btk is over-expressed in gastric carcinoma tissues and gastric cancer cells. Knockdown of Btk expression selectively inhibits the growth of gastric cancer cells, but not that of the normal gastric mucosa epithelial cell, which express very little Btk. Inhibition of Btk by its inhibitor ibrutinib has an additive inhibitory effect on gastric cancer cell growth. Treatment of gastric cancer cells, but not immortalized breast epithelial cells with ibrutinib results in effective cell killing, accompanied by the attenuation of Btk signals. Ibrutinib also induces apoptosis in gastric carcinoma cells as well as is a chemo-sensitizer for docetaxel (DTX), a standard of care for gastric carcinoma patients. Finally, ibrutinib markedly reduces tumor growth and increases tumor cell apoptosis in the tumors formed in mice inoculated with the gastric carcinoma cells. Given these promising preclinical results for ibrutinib in gastric carcinoma, a strategy combining Btk inhibitor warrants attention in gastric cancer. PMID:27508020

  1. Purification and cultivation of human pituitary growth hormone secreting cells

    NASA Technical Reports Server (NTRS)

    Hymer, W. C.

    1984-01-01

    A multiphase study was conducted to examine the properties of growth hormone cells. Topics investigated included: (1) to determine if growth hormone (GH) cells contained within the rat pituitary gland can be separated from the other hormone producing cell types by continuous flow electrophoresis (CFE); (2) to determine what role, if any, gravity plays in the electrophoretic separation of GH cells; (3) to compare in vitro GH release from rat pituitary cells previously exposed to microgravity conditions vs release from cells not exposed to microgravity; (4) to determine if the frequency of different hormone producing pituitary cell types contained in cell suspensions can be quantitated by flow cytometry; and (5) to determine if GH contained within the human post mortem pituitary gland can be purified by CFE. Specific experimental procedures and results are included.

  2. Purification and cultivation of human pituitary growth hormone secreting cells

    NASA Technical Reports Server (NTRS)

    Hymer, W. C.

    1978-01-01

    The maintainance of actively secreting human pituitary growth hormone cells (somatotrophs) in vitro was studied. The primary approach was the testing of agents which may be expected to increase the release of the human growth hormone (hGH). A procedure for tissue procurement is described along with the methodologies used to dissociate human pituitary tissue (obtained either at autopsy or surgery) into single cell suspensions. The validity of the Biogel cell column perfusion system for studying the dynamics of GH release was developed and documented using a rat pituitary cell system.

  3. Adaptation to optimal cell growth through self-organized criticality.

    PubMed

    Furusawa, Chikara; Kaneko, Kunihiko

    2012-05-18

    A simple cell model consisting of a catalytic reaction network is studied to show that cellular states are self-organized in a critical state for achieving optimal growth; we consider the catalytic network dynamics over a wide range of environmental conditions, through the spontaneous regulation of nutrient transport into the cell. Furthermore, we find that the adaptability of cellular growth to reach a critical state depends only on the extent of environmental changes, while all chemical species in the cell exhibit correlated partial adaptation. These results are in remarkable agreement with the recent experimental observations of the present cells.

  4. TOR and paradigm change: cell growth is controlled.

    PubMed

    Hall, Michael N

    2016-09-15

    This year marks the 25th anniversary of the discovery of target of rapamycin (TOR), a highly conserved kinase and central controller of cell growth. In this Retrospective, I briefly describe the discovery of TOR and the subsequent elucidation of its cellular role. I place particular emphasis on an article by Barbet et al. from 1996, the first suggesting that TOR controls cell growth in response to nutrients.

  5. TOR and paradigm change: cell growth is controlled

    PubMed Central

    Hall, Michael N.

    2016-01-01

    This year marks the 25th anniversary of the discovery of target of rapamycin (TOR), a highly conserved kinase and central controller of cell growth. In this Retrospective, I briefly describe the discovery of TOR and the subsequent elucidation of its cellular role. I place particular emphasis on an article by Barbet et al. from 1996, the first suggesting that TOR controls cell growth in response to nutrients. PMID:27634743

  6. Poly(ADP-ribosyl)ation enhances H-RAS protein stability and causes abnormal cell cycle progression in human TK6 lymphoblastoid cells treated with hydroquinone.

    PubMed

    Liu, Linhua; Ling, Xiaoxuan; Tang, Huanwen; Chen, Jialong; Wen, Qiaosheng; Zou, Fei

    2015-08-05

    Hydroquinone (HQ), one of the most important benzene-derived metabolites, can induce aberrant cell cycle progression; however, the mechanism of this induction remains unclear. Poly(ADP-ribosyl)ation (PARylation), which is catalysed primarily by poly(ADP-ribose) polymerase-1 (PARP-1), participates in various biological processes, including cell cycle control. The results of the present study show an accumulation in G1 phase versus S phase of TK6 human lymphoblast cells treated with HQ for 48h compared with PBS-treated cells; after 72h of HQ treatment, the cells transitioned from G1 arrest to S phase arrest. We examined the expression of six genes related to the cell cycle or leukaemia to further explore the reason for this phenomenon. Among these genes, H-RAS was found to be associated with this phenomenon because its mRNA and protein expression decreased at 48h and increased at 72h. Experiments for PARP activity induction and inhibition revealed that the observed PARylation was positively associated with H-RAS expression. Moreover, in cells treated with HQ in conjunction with PARP-1 knockdown, expression of the H-RAS protein decreased and the number of cells in G1 phase increased. The degree of poly(ADP-ribosyl) modification of the H-RAS protein increased in cells treated with HQ for 72h, further supporting that changes in PARylation contributed to the rapid alteration of H-RAS protein expression, followed by abnormal progression of the cell cycle. Co-immunoprecipitation (co-IP) assays were employed to determine whether protein complexes were formed by PARP-1 and H-RAS proteins, and the direct interaction between these proteins indicated that PARylation regulated H-RAS expression. As detected by confocal microscopy, the H-RAS protein was found in the nucleus and cytoplasm. To our knowledge, this study is the first to reveal that H-RAS protein can be modified by PARylation.

  7. Effects of hepatocyte growth factor on glutathione synthesis, growth, and apoptosis is cell density-dependent

    SciTech Connect

    Yang Heping; Magilnick, Nathaniel; Xia Meng; Lu, Shelly C.

    2008-01-15

    Hepatocyte growth factor (HGF) is a potent hepatocyte mitogen that exerts opposing effects depending on cell density. Glutathione (GSH) is the main non-protein thiol in mammalian cells that modulates growth and apoptosis. We previously showed that GSH level is inversely related to cell density of hepatocytes and is positively related to growth. Our current work examined whether HGF can modulate GSH synthesis in a cell density-dependent manner and how GSH in turn influence HGF's effects. We found HGF treatment of H4IIE cells increased cell GSH levels only under subconfluent density. The increase in cell GSH under low density was due to increased transcription of GSH synthetic enzymes. This correlated with increased protein levels and nuclear binding activities of c-Jun, c-Fos, p65, p50, Nrf1 and Nrf2 to the promoter region of these genes. HGF acts as a mitogen in H4IIE cells under low cell density and protects against tumor necrosis factor {alpha} (TNF{alpha})-induced apoptosis by limiting JNK activation. However, HGF is pro-apoptotic under high cell density and exacerbates TNF{alpha}-induced apoptosis by potentiating JNK activation. The increase in cell GSH under low cell density allows HGF to exert its full mitogenic effect but is not necessary for its anti-apoptotic effect.

  8. Effector and Naturally Occurring Regulatory T Cells Display No Abnormalities in Activation Induced Cell Death in NOD Mice

    PubMed Central

    Kaminitz, Ayelet; Yolcu, Esma S.; Askenasy, Enosh M.; Stein, Jerry; Yaniv, Isaac; Shirwan, Haval; Askenasy, Nadir

    2011-01-01

    Background Disturbed peripheral negative regulation might contribute to evolution of autoimmune insulitis in type 1 diabetes. This study evaluates the sensitivity of naïve/effector (Teff) and regulatory T cells (Treg) to activation-induced cell death mediated by Fas cross-linking in NOD and wild-type mice. Principal Findings Both effector (CD25−, FoxP3−) and suppressor (CD25+, FoxP3+) CD4+ T cells are negatively regulated by Fas cross-linking in mixed splenocyte populations of NOD, wild type mice and FoxP3-GFP tranegenes. Proliferation rates and sensitivity to Fas cross-linking are dissociated in Treg cells: fast cycling induced by IL-2 and CD3/CD28 stimulation improve Treg resistance to Fas-ligand (FasL) in both strains. The effector and suppressor CD4+ subsets display balanced sensitivity to negative regulation under baseline conditions, IL-2 and CD3/CD28 stimulation, indicating that stimulation does not perturb immune homeostasis in NOD mice. Effective autocrine apoptosis of diabetogenic cells was evident from delayed onset and reduced incidence of adoptive disease transfer into NOD.SCID by CD4+CD25− T cells decorated with FasL protein. Treg resistant to Fas-mediated apoptosis retain suppressive activity in vitro. The only detectable differential response was reduced Teff proliferation and upregulation of CD25 following CD3-activation in NOD mice. Conclusion These data document negative regulation of effector and suppressor cells by Fas cross-linking and dissociation between sensitivity to apoptosis and proliferation in stimulated Treg. There is no evidence that perturbed AICD in NOD mice initiates or promotes autoimmune insulitis. PMID:21738739

  9. Induction of Embryogenesis in Brassica Napus Microspores Produces a Callosic Subintinal Layer and Abnormal Cell Walls with Altered Levels of Callose and Cellulose

    PubMed Central

    Parra-Vega, Verónica; Corral-Martínez, Patricia; Rivas-Sendra, Alba; Seguí-Simarro, Jose M.

    2015-01-01

    The induction of microspore embryogenesis produces dramatic changes in different aspects of the cell physiology and structure. Changes at the cell wall level are among the most intriguing and poorly understood. In this work, we used high pressure freezing and freeze substitution, immunolocalization, confocal, and electron microscopy to analyze the structure and composition of the first cell walls formed during conventional Brassica napus microspore embryogenesis, and in cultures treated to alter the intracellular Ca2+ levels. Our results revealed that one of the first signs of embryogenic commitment is the formation of a callose-rich, cellulose-deficient layer beneath the intine (the subintinal layer), and of irregular, incomplete cell walls. In these events, Ca2+ may have a role. We propose that abnormal cell walls are due to a massive callose synthesis and deposition of excreted cytoplasmic material, and the parallel inhibition of cellulose synthesis. These features were absent in pollen-like structures and in microspore-derived embryos, few days after the end of the heat shock, where abnormal cell walls were no longer produced. Together, our results provide an explanation to a series of relevant aspects of microspore embryogenesis including the role of Ca2+ and the occurrence of abnormal cell walls. In addition, our discovery may be the explanation to why nuclear fusions take place during microspore embryogenesis. PMID:26635844

  10. Induction of ribosomal subunits misassembly by antisense RNAs to control cell growth.

    PubMed

    Mangiarotti, G

    2000-08-25

    The assembly of ribosomal subunits starting from free ribosomal RNA and protein of Dictyostelium discoideum was induced in vitro in the presence of several oligoribonucleotides complementary to defined sequences of ribosomal RNA. The reconstituted particles had a full complement of ribosomal proteins, but did not function in an in vitro protein synthesis system and were disassembled following interaction with mRNA. The same result was obtained in vivo by fusing the oligodeossiribonucleotides coding for the selected oligoribonucleotides to the promoter of the gene coding for contact site A protein. This gene is expressed only in the first part of development. Transfected growing cells, transferred in developing buffer in the presence of pulses of cAMP, accumulated significant amounts of the oligoribonucleotides. When retransferred to the growth medium, they grew progressively more slowly, until their doubling time doubled, apparently due to the availability of a limiting amount of functional ribosomes. To avoid disassembly of misassembled subunits (G. Mangiarotti et al., 1997, J. Biol. Chem. 272, 27818-27822), two oligoribonucleotides complementary to sequences present at the 5' ends of pre-17S and pre-26S RNAs were also induced to accumulate during early development with the same technique. When transfected cells were retransferred to the growth medium, their rate of growth declined rapidly to zero and cells died, apparently because they were unable to disassemble misassembled ribosomal subunits and avoid their entry into polyribosomes. This technique to perturb protein synthesis, arrest cell growth, and cause cell suicide will be tested in abnormally growing animal cells.

  11. Transgenic sickle cell trait mice do not exhibit abnormal thermoregulatory and stress responses to heat shock exposure.

    PubMed

    Chen, Yifan; Islam, Aminul

    2016-07-01

    There remains controversy over whether individuals with sickle cell trait (SCT) are vulnerable to health risks during physical activity in high temperatures. We examined thermoregulatory and stress-related responses to heat exposure in SCT and wild-type (WT) mice. No significant differences in core temperature (Tc) were observed between SCT and WT mice during heat exposure. There was no correlation between peak Tc during heat exposure and levels of hemoglobin S in SCT mice. Basal levels of circulating inflammatory and stress-related markers were not significantly different between SCT and WT mice. Although heat exposure caused significant increases in plasma interleukins 1β and 6, and 8-isoprostane in SCT and WT mice, no differences were found between SCT and WT mice with similar thermal response profiles during heat exposure. SCT mice had significantly higher expression of heat shock protein 72 in heart, liver and gastrocnemius muscle than WT mice under control and post-heat conditions. In conclusion, there is neither thermoregulatory dysfunction nor abnormal stress-related response in SCT mice exposed to moderate heat. The hemoglobin variant in mice is associated with altered tissue stress protein homeostasis.

  12. S-Fms signalobody enhances myeloid cell growth and migration.

    PubMed

    Kawahara, Masahiro; Hitomi, Azusa; Nagamune, Teruyuki

    2014-07-01

    Since receptor tyrosine kinases (RTKs) control various cell fates in many types of cells, mimicry of RTK functions is promising for artificial control of cell fates. We have previously developed single-chain Fv (scFv)/receptor chimeras named signalobodies that can mimic receptor signaling in response to a specific antigen. While the RTK-based signalobodies enabled us to control cell growth and migration, further extension of applicability in another cell type would underlie the impact of the RTK-based signalobodies. In this study, we applied the scFv-c-Fms (S-Fms) signalobody in a murine myeloid progenitor cell line, FDC-P1. S-Fms transduced a fluorescein-conjugated BSA (BSA-FL)-dependent growth signal and activated downstream signaling molecules including MEK, ERK, Akt, and STAT3, which are major constituents of Ras/MAPK, PI3K/Akt, and JAK/STAT signaling pathways. In addition, S-Fms transduced a migration signal as demonstrated by the transwell-based migration assay. Direct real-time observation of the cells further confirmed that FDC/S-Fms cells underwent directional cell migration toward a positive gradient of BSA-FL. These results demonstrated the utility of the S-Fms signalobody for controlling growth and migration of myeloid cells. Further extension of our approach includes economical large-scale production of practically relevant blood cells as well as artificial control of cell migration for tissue regeneration and immune response.

  13. Critical telomerase activity for uncontrolled cell growth

    NASA Astrophysics Data System (ADS)

    Wesch, Neil L.; Burlock, Laura J.; Gooding, Robert J.

    2016-08-01

    The lengths of the telomere regions of chromosomes in a population of cells are modelled using a chemical master equation formalism, from which the evolution of the average number of cells of each telomere length is extracted. In particular, the role of the telomere-elongating enzyme telomerase on these dynamics is investigated. We show that for biologically relevant rates of cell birth and death, one finds a critical rate, R crit, of telomerase activity such that the total number of cells diverges. Further, R crit is similar in magnitude to the rates of mitosis and cell death. The possible relationship of this result to replicative immortality and its associated hallmark of cancer is discussed.

  14. Epitaxial silicon growth for solar cells

    NASA Technical Reports Server (NTRS)

    Daiello, R. V.; Robinson, P. H.; Richman, D.

    1979-01-01

    The epitaxial procedures, solar cell fabrication, and evaluation techniques are described. The development of baseline epitaxial solar cell structures grown on high quality conventional silicon substrates is discussed. Diagnostic layers and solar cells grown on four potentially low cost silicon substrates are considered. The crystallographic properties of such layers and the performance of epitaxially grown solar cells fabricated on these materials are described. An advanced epitaxial reactor, the rotary disc, is described along with the results of growing solar cell structures of the baseline type on low cost substrates. The add on cost for the epitaxial process is assessed and the economic advantages of the epitaxial process as they relate to silicon substrate selection are examined.

  15. Intercellular propagation of individually programmed growth bursts in FRTL-5 cells. Implications for interpreting growth factor actions

    SciTech Connect

    Derwahl, M.; Studer, H.; Huber, G.; Gerber, H.; Peter, H.J. )

    1990-11-01

    Five methods are commonly used to quantify FRTL-5 cells' and other thyrocytes' growth in vitro and the impact of growth inhibiting or stimulating maneuvers: Total cell count, mitotic index, DNA measurement, total (3H)thymidine incorporation, and the fraction of (3H)thymidine labeled cells. All of them assess cell growth as though all cells were homogeneous with an identical response to growth factors. We demonstrate here that this assumption is not valid. Rather, some intrinsically growth-prone cells appear to pass a growth signal to neighboring cells so that variably sized colonies of synchronized cells within each cluster growing from monodispersed cells are formed. This is true for FRTL-5 cells growing in vitro in monolayers and in three-dimensional, collagen embedded spheroids. The pattern is the same when cell suspensions or collagen-embedded spheroids are implanted onto nude mice. Patches with alternating high and low growth become particularly prominent in the large tumor-like organoids grown from monodispersed cells in nude mice. The pattern much reminds of similar observations in growing intact thyroids. Since there is no significant correlation between the fraction of (3H)thymidine labeled cells and the size of two- or three-dimensional clusters in any experiment, growth of signal-spreading cells is assumed to occur in leaps and bounds. Growth velocity in each subclone of a cell population depends on the mean interval between bursts of replications and on the number of cells synchronized by cell-to-cell diffusion of the growth signal emanating from one dividing cell. Thus, growth-promoting and growth-inhibiting factors may not only act on the mean interval between successive growth bursts, but they may also change cell-to-cell spreading of growth signals.

  16. Simultaneous optical measurements of cell motility and growth.

    PubMed

    Sridharan, Shamira; Mir, Mustafa; Popescu, Gabriel

    2011-10-01

    It has recently been shown that spatial light interference microscopy (SLIM) developed in our laboratory can be used to quantify the dry mass growth of single cells with femtogram sensitivity [M. Mir et al., Proc. Nat. Acad. Sci. 108, 32 (2011)]. Here we show that it is possible to measure the motility of single cells in conjunction with the dry mass measurements. Specifically the effect of poly-L-lysine substrate on the dry mass growth of Drosophila S2 cells is studied. By measuring the mean square displacement of single cells and clusters it is shown that cells that adhere better to the surface are unable to grow. Using such a technique it is possible to measure both growth and morphogenesis, two of the cornerstones of developmental biology.

  17. LncRNA SNHG12 promotes cell growth and inhibits cell apoptosis in colorectal cancer cells

    PubMed Central

    Wang, J.Z.; Xu, C.L.; Wu, H.; Shen, S.J.

    2017-01-01

    Several long non-coding RNA (lncRNA) might be correlated with the prognosis of colorectal cancer (CRC) and serve as a diagnostic and prognostic biomarker. However, the exact expression pattern of small nucleolar RNA host gene 12 (SNHG12) in colorectal cancer and its clinical significance remains unclear. The level of SNHG12 was detected by qRT-PCR in CRC tissues and CRC cells. MTT assay and colony formation assay were performed to examine the cell proliferation of CRC cells transfected with pcDNA-SNHG12 or si-SNHG12. Flow cytometry technology was used to detect cell cycle and cell apoptosis of CRC cells transfected with pcDNA-SNHG12 or si-SNHG12. The protein level of cell cycle progression-related molecules, including cyclin-dependent kinases (CDK4, CDK6), cyclin D1 (CCND1) and cell apoptosis-related molecule caspase 3 was detected by western blot. The effect of SNHG12 knockdown was examined in vivo. Increased levels of SNHG12 were observed in CRC tissues and in CRC cells. SNHG12 promoted the cell proliferation of CRC cells. In addition, SNHG12 overexpression boosted the cell cycle progression of SW480 cells transfected with pcDNA-SNHG12 and SNHG12 knockdown inhibited the cell cycle progression of HT29 cells transfected with si-SNHG12. SNHG12 also inhibited the cell apoptosis of CRC cells. We also found that SNHG12 increased the expression of cell cycle-related proteins and suppressed the expression of caspase 3. Our results suggest that SNHG12 promoted cell growth and inhibited cell apoptosis in CRC cells, indicating that SNHG12 might be a useful biomarker for colorectal cancer. PMID:28225893

  18. Pantothenate kinase-2 (Pank2) silencing causes cell growth reduction, cell-specific ferroportin upregulation and iron deregulation.

    PubMed

    Poli, Maura; Derosas, Manuela; Luscieti, Sara; Cavadini, Patrizia; Campanella, Alessandro; Verardi, Rosanna; Finazzi, Dario; Arosio, Paolo

    2010-08-01

    Pantothenate kinase 2 (Pank2) is a mitochondrial enzyme that catalyses the first regulatory step of Coenzyme A synthesis and that is responsible for a genetic movement disorder named Pank-associated neurodegeneration (PKAN). This is characterized by abnormal iron accumulation in the brain, particularly in the globus pallidus. We downregulated Pank2 in some cell lines by using specific siRNAs to study its effect on iron homeostasis. In HeLa cells this caused a reduction of cell proliferation and of aconitase activity, signs of cytosolic iron deficiency without mitochondrial iron deposition, and a 12-fold induction of ferroportin mRNA. Pank2 silencing caused a strong induction of ferroportin mRNA also in hepatoma HepG2, a modest one in neuroblastoma SH-SY5Y and none in glioma U373 cells. A reduction of cell growth was observed in all these cell types. The strong Pank2-mediated alteration of ferroportin expression in some cell types might alter iron transfer to the brain and be connected with brain iron accumulation.

  19. Molecular mobility of scaffolds' biopolymers influences cell growth.

    PubMed

    Podlipec, Rok; Gorgieva, Selestina; Jurašin, Darija; Urbančič, Iztok; Kokol, Vanja; Strancar, Janez

    2014-09-24

    Understanding biocompatibility of materials and scaffolds is one of the main challenges in the field of tissue engineering and regeneration. The complex nature of cell-biomaterial interaction requires extensive preclinical functionality testing by studying specific cell responses to different biomaterial properties, from morphology and mechanics to surface characteristics at the molecular level. Despite constant improvements, a more general picture of biocompatibility is still lacking and tailormade scaffolds are not yet available. The scope of our study was thus the investigation of the correlation of fibroblast cell growth on different gelatin scaffolds with their morphological, mechanical as well as surface molecular properties. The latter were thoroughly investigated via polymer molecular mobility studied by site-directed spin labeling and electron paramagnetic resonance spectroscopy (EPR) for the first time. Anisotropy of the rotational motion of the gelatin side chain mobility was identified as the most correlated quantity with cell growth in the first days after adhesion, while weaker correlations were found with scaffold viscoelasticity and no correlations with scaffold morphology. Namely, the scaffolds with highly mobile or unrestricted polymers identified with the cell growth being five times less efficient (N(cells) = 60 ± 25 mm(-2)) as compared to cell growth on the scaffolds with considerable part of polymers with the restricted rotational motion (N(cells) = 290 ± 25 mm(-2)). This suggests that molecular mobility of scaffold components could play an important role in cell response to medical devices, reflecting a new aspect of the biocompatibility concept.

  20. Exercise protects against obesity induced semen abnormalities via downregulating stem cell factor, upregulating Ghrelin and normalizing oxidative stress.

    PubMed

    Alhashem, Fahaid; Alkhateeb, Mahmoud; Sakr, Hussein; Alshahrani, Mesfer; Alsunaidi, Mohammad; Elrefaey, Hesham; Alessa, Riyad; Sarhan, Mohammad; Eleawa, Samy M; Khalil, Mohammad A

    2014-01-01

    Increased oxidative stress and hormonal imbalance have been hypothesized to underlie infertility in obese animals. However, recent evidence suggests that Ghrelin and Stem Cell Factor (SCF) play an important role in fertility, in lean individuals. Therefore, this study aimed at investigating whether changes in the levels of Ghrelin and SCF in rat testes underlie semen abnormal parameters observed in obese rats, and secondly, whether endurance exercise or Orlistat can protect against changes in Ghrelin, SCF, and/or semen parameters in diet induced obese rats. Obesity was modelled in male Wistar rats using High Fat Diet (HFD) 12-week protocol. Eight week-old rats (n=40) were divided into four groups, namely, Group I: fed with a standard diet (12 % of calories as fat); Group II: fed HFD (40 % of calories as fat); Group III: fed the HFD with a concomitant dose of Orlistat (200 mg/kg); and Group IV: fed the HFD and underwent 30 min daily swimming exercise. The model was validated by measuring the levels of testosterone, FSH, LH, estradiol, leptin, triglycerides, total, HDL, and LDL cholesterol, and final change in body weight. Levels were consistent with published obesity models (see Results). As predicted, the HFD group had a 76.8 % decrease in sperm count, 44.72 % decrease in sperm motility, as well as 47.09 % increase in abnormal sperm morphology. Unlike the control group, in the HFD group (i.e. obese rats) Ghrelin mRNA and protein were elevated, while SCF mRNA and protein were diminished in the testes. Furthermore, in the HFD group, SOD and GPx activities were significantly reduced, 48.5±5.8 % (P=0.0012) and 45.6±4.6 % (P=0.0019), respectively, while TBARS levels were significantly increased (112.7±8.9 %, P=0.0001). Finally, endurance exercise training and Orlistat administration individually and differentially protected semen parameters in obese rats. The mechanism includes, but is not limited to, normalizing the levels of Ghrelin, SCF, SOD, GPx and TBARS. In rat

  1. Hormonal modulation of brain tumour growth: a cell culture study.

    PubMed

    Gibelli, N; Zibera, C; Butti, G; Assietti, R; Sica, G; Scerrati, M; Iacopino, F; Roselli, R; Paoletti, P; Robustelli della Cuna, G

    1989-01-01

    Tissue samples derived from two neuroepithelial tumours and five meningiomas were obtained at surgery from seven patients and cultured in order to study the effect of dexamethasone (DEX) and testosterone acetate (TA) on cell proliferation. Glucocorticoid and androgen receptors (GR, AR) were determined both on tissue samples (7 cases) and on five out of the seven cell cultures obtained by tumours. GR and AR were present respectively in 5 and in 4 out of the tumour specimens assayed and in 4/5 and 2/3 of the tested cell cultures. DEX activity on cell growth was tested on six cell cultures. Four of them showed a significant growth inhibition at the highest drug concentration. On the contrary, a significant growth stimulation was observed in four out of the five cultures, where GR were present, using low hormone concentrations. Treatment with pharmacological doses of TA caused a significant cytotoxicity in all the tested cultures. Low TA concentrations inhibited cell growth in one out of the two cell cultures which contained AR, but were ineffective in cultures lacking AR. Our preliminary results suggest a possible role in growth regulation by DEX and TA in intracranial tumours, on the basis of the presence of specific hormone receptors.

  2. Dual control of cell growth by somatomedins and platelet-derived growth factor.

    PubMed Central

    Stiles, C D; Capone, G T; Scher, C D; Antoniades, H N; Van Wyk, J J; Pledger, W J

    1979-01-01

    Quiescent BALB/c 3T3 cells exposed briefly to a platelet-derived growth factor (PDGF) become "competent" to replicate their DNA but do not "progress" into S phase unless incubated with growth factors contained in platelet-poor plasma. Plasma from hypophysectomized rats is deficient in progression activity; it does not stimulate PDGF-treated competent cells to synthesize DNA, demonstrating that somatomedin C is required for progression. Various growth factors were tested for progression activity and competence activity by using BALB/c 3T3 tissue culture assays. Multiplication stimulating activity and other members of the somatomedin family of growth factors are (like somatomedin C) potent mediators of progression. Other mitogenic agents, such as fibroblast growth factor, are (like PDGF) potent inducers of competence. Growth factors with potent progression activity have little or no competence activity and vice versa. In contrast, simian virus 40 provides both competence and progression activity. Coordinate control of BALB/c 3T3 cell growth in vitro by competence factors and somatomedins may be a specific example of a common pattern of growth regulation in animal tissues. PMID:312500

  3. Regulation of rat ovarian cell growth and steroid secretion

    PubMed Central

    Johnson, CC; Dawson, WE; Turner, JT; Wyche, JH

    1980-01-01

    A cultured rat ovarian cell line (31 A-F(2)) was used to study the effect of growth factors (epidermal growth factor [EGF] and fibroblast growth factor [FGF]), a survival factor (ovarian growth factor [OGF]), a hormone (insulin), and an iron-binding protein (transferring) on cell proliferation and steroid production under defined culture conditions. EGF and insulin were shown to be mitogenic (half-maximal response at 0.12 nM and 0.11 muM, respectively) for 31A-F(2) cells incubated in serum-free medium. EGF induced up to three doublings in the cell population, whereas insulin induced an average of one cell population doubling. FGF, OGF, and transferrin were found not to have any prominent effect on cell division when incubated individually with 31A-F(2) cells in serum-free medium. However, a combination of EGF, OGF, insulin, and transferrin stimulated cell division to the same approximate extent as cells incubated in the presence of 5 percent fetal calf serum. EGF or insulin did not significantly affect total cell cholesterol levels (relative to cells incubated in serum-free medium) when incubated individually with 31A-F(2) cells. However, cell cholesterol levels were increased by the addition of OGF (250 percent), FGF (370 percent), or a combination of insulin and EGF (320 percent). Progesterone secretion from 31A-F(2) cells was enhanced by EGF (25 percent), FGF (80 percent), and insulin (115 percent). However, the addition of a mitogenic mixture of EGF, OGF, insulin, and transferrin suppressed progesterone secretion 150 percent) below that of control cultures. These studies have permitted us to determine that EGF and insulin are mitogenic factors that are required for the growth of 31A-F(2) cells and that OGF and transferrin are positive cofactors that enhance growth. Also, additional data suggest that cholesterol and progesterone production in 31A-F(2) cells can be regulated by peptide growth factors and the hormone insulin. PMID:6995465

  4. Oxygen modulates growth of human cells at physiologic partial pressures

    PubMed Central

    1984-01-01

    We have examined the growth of human diploid fibroblasts (WI-38 and IMR90) as a function of initial seeding density and oxygen tension. Cells at young and mid-passage levels were subcultivated in Dulbecco's modified Eagle's medium with 10% fetal bovine serum at 0.005, 0.01, 0.03, 0.1, 0.3, 1, and 2 X 10(4) cells/cm2. Flasks were equilibrated before and after seeding with 1 of 10 gas mixtures containing the desired oxygen tension (9-591 mm Hg) and placed in incubators that measure and maintain a preset oxygen tension. The partial pressure of oxygen (PO2) in media of all flasks was determined at harvest. Cells were shielded from light of wavelength less than 500 nm. Cell growth varied inversely with oxygen tension and seeding density. At 50 cells/cm2, growth was maximal at PO2 9 and 16 mm Hg. Growth was progressively inhibited as the oxygen tension was increased. The population doubling increase at 14 d was 8.6 for PO2 9 and 16 mm Hg, 5.8 for PO2 42 mm Hg, 3.8 for PO2 78 mm Hg, 3.8 for PO2 104 mm Hg, and 3 for PO2 138 mm Hg. As the seeding density was increased, the differences in growth at PO2 less than 140 mm Hg were progressively minimized, such that at seeding densities of 10(4) cells/cm2 there was little difference in the rate of exponential growth or the final saturation density of cells cultivated between PO2 9 and 96 mm Hg. At all seeding densities tested, growth was progressively inhibited when the PO2 was increased greater than 140 mm Hg. The seeding density dependence of oxygen's influence on cellular growth is not explained by oxygen consumption of higher density cultures. Oxygen acts directly on the cells and not by destroying some essential medium component. We have found that oxygen regulates the growth of human cells under pressures of oxygen physiologic to humans, and that oxygen toxicity contributes to the seeding density dependence of cellular growth commonly seen in cell culture. PMID:6736869

  5. Role of growth factors in the growth of normal and transformed cells

    SciTech Connect

    Lokeshwar, V.B.

    1989-01-01

    Growth factors play an important role in the growth of normal cells. However, their untimely and/or excess production leads to neoplastic transformation. The role of growth factors in the growth of normal cells was studied by investigating the mechanism of transmodulation of the cell surface EGF receptor number by protamine. Protamine increased the EGF stimulated mitogenic response in Swiss mouse 3T3 cells and A431 cells by increasing the number of functionally active EGF receptors. Protamine also increased EGF receptor number in plasma membranes and solubilized membranes. This was evidenced by an increase in both {sup 125}I-EGF-EGF-receptor complex and EGF stimulated phosphorylation of the EGF receptor. The solubilized EGF receptor was retained on a protamine-agarose gel indicating that protamine might increase EGF receptor number by directly activating cryptic EGF receptors in the plasma membranes. The role of growth factors in neoplastic transformation was studied by investigating the role of the oncogene v-sis in the growth of Simian sarcoma virus (SSV) transformed cells. The product of the oncogene v-sis is 94% homologous to the B chain of PDGF. This study found that (i) v-sis gene product is synthesized as a 32 kDa unglycosylated monomer which is glycosylated, dimerized and proteolytically processed into p36, p72, p68, p58, p44 and p27 mol. wt. species respectively. (ii) p36, p72, p68 and p58 are very likely formed in the endoplasmic reticulum and/or Golgi complex. A fraction of newly synthesized p72, p68 and p58 is degraded intracellularly at a fast rate. (iii) p44 is a secretory product which remains tightly associated with the cell surface. p44 is recaptured by the cells through interaction with cell surface PDGF receptors and degraded into p27. (iv) During long term cultures p44 is extracellularly cleaved into a 27 kDa product.

  6. A study of cell electrophoresis as a means of purifying growth hormone secreting cells

    NASA Technical Reports Server (NTRS)

    Plank, Lindsay D.; Hymer, W. C.; Kunze, M. Elaine; Marks, Gary M.; Lanham, J. Wayne

    1983-01-01

    Growth hormone secreting cells of the rat anterior pituitary are heavily laden with granules of growth hormone and can be partialy purified on the basis of their resulting high density. Two methods of preparative cell electrophoresis were investigated as methods of enhancing the purification of growth hormone producing cells: density gradient electrophoresis and continuous flow electrophoresis. Both methods provided a two- to four-fold enrichment in growth hormone production per cell relative to that achieved by previous methods. Measurements of electrophoretic mobilities by two analytical methods, microscopic electrophoresis and laser-tracking electrophoresis, revealed very little distinction between unpurified anterior pituitary cell suspensions and somatotroph-enriched cell suspensions. Predictions calculated on the basis of analytical electrophoretic data are consistent with the hypothesis that sedimentation plays a significant role in both types of preparative electrophoresis and the electrophoretic mobility of the growth hormone secreting subpopulation of cells remains unknown.

  7. ROS Regulation of Polar Growth in Plant Cells1[OPEN

    PubMed Central

    Mangano, Silvina; Juárez, Silvina Paola Denita

    2016-01-01

    Root hair cells and pollen tubes, like fungal hyphae, possess a typical tip or polar cell expansion with growth limited to the apical dome. Cell expansion needs to be carefully regulated to produce a correct shape and size. Polar cell growth is sustained by oscillatory feedback loops comprising three main components that together play an important role regulating this process. One of the main components are reactive oxygen species (ROS) that, together with calcium ions (Ca2+) and pH, sustain polar growth over time. Apoplastic ROS homeostasis controlled by NADPH oxidases as well as by secreted type III peroxidases has a great impact on cell wall properties during cell expansion. Polar growth needs to balance a focused secretion of new materials in an extending but still rigid cell wall in order to contain turgor pressure. In this review, we discuss the gaps in our understanding of how ROS impact on the oscillatory Ca2+ and pH signatures that, coordinately, allow root hair cells and pollen tubes to expand in a controlled manner to several hundred times their original size toward specific signals. PMID:27208283

  8. In vitro melanoma cell growth after preenucleation radiation therapy

    SciTech Connect

    Kenneally, C.Z.; Farber, M.G.; Smith, M.E.; Devineni, R.

    1988-02-01

    The in vitro efficacy of 20 Gy (2000 rad) of external beam irradiation delivered to patients with choroidal melanomas prior to enucleation was investigated in 11 patients whose tumors were grown in cell culture. Phase-contrast microscopy was used to compare growth patterns between irradiated and nonirradiated tumors. Cell types were determined by histologic stains, and electron microscopy identified intracytoplasmic melanin. Irradiated melanomas did not grow and did not attach to culture flasks, thus demonstrating that preenucleation irradiation alters the in vitro growth of melanoma cells.

  9. Effect of transforming growth factor-β1 on human intrahepatic cholangiocarcinoma cell growth

    PubMed Central

    Shimizu, Tetsuya; Yokomuro, Shigeki; Mizuguchi, Yoshiaki; Kawahigashi, Yutaka; Arima, Yasuo; Taniai, Nobuhiko; Mamada, Yasuhiro; Yoshida, Hiroshi; Akimaru, Koho; Tajiri, Takashi

    2006-01-01

    AIM: To elucidate the biological effects of transforming growth factor-β1 (TGF-β1) on intrahepatic cholan-giocarcinoma (ICC). METHODS: We investigated the effects of TGF-β1 on human ICC cell lines (HuCCT1, MEC, and HuH-28) by monitoring the influence of TGF-β1 on tumor growth and interleukin-6 (IL-6) expression in ICC cells. RESULTS: All three human ICC cell lines produced TGF-β1 and demonstrated accelerated growth in the presence of TGF-β1 with no apoptotic effect. Studies on HuCCT1 revealed a TGF-β1-induced stimulation of the expression of TGF-β1, as well as a decrease in TGF-β1 mRNA expression induced by neutralizing anti-TGF-β1 antibody. These results indicate that TGF-β1 stimulates the production and function of TGF-β1 in an autocrine fashion. Further, IL-6 secretion was observed in all three cell lines and exhibited an inhibitory response to neutralizing anti-TGF-β1 antibody. Experiments using HuCCT1 revealed a TGF-β1-induced acceleration of IL-6 protein expression and mRNA levels. These findings demonstrate a functional interaction between TGF-β1 and IL-6. All three cell lines proliferated in the presence of IL-6. In contrast, TGF-β1 induced no growth effect in HuCCT1 in the presence of small interfering RNA against a specific cell surface receptor of IL-6 and signal transducer and activator of transcription-3. CONCLUSION: ICC cells produce TGF-β1 and confer a TGF-β1-induced growth effect in an autocrine fashion. TGF-β1 activates IL-6 production, and the functional interaction between TGF-β1 and IL-6 contributes to ICC cell growth by TGF-β1. PMID:17072955

  10. The relation between growth phases, cell volume changes and metabolism of adherent cells during cultivation.

    PubMed

    Rehberg, M; Ritter, J B; Genzel, Y; Flockerzi, D; Reichl, U

    2013-04-15

    In biotechnology, mathematical models often consider changes in cell numbers as well as in metabolite conversion to describe different cell growth phases. It has been frequently observed that the cell number is only a delayed indicator of cell growth compared to the biomass, which challenges the principle structure of corresponding models. Here, we evaluate adherent cell growth phases in terms of cell number and biomass increase on the basis of detailed experimental data of three independent cultivations for Madin Darby canine kidney cells. We develop a model linking cell numbers and mean cell diameters to estimate cell volume changes during growth without the need for diameter distribution measurements. It simultaneously describes the delay between cell number and cell volume increase, cell-specific volume changes and the transition from growth to maintenance metabolism while taking different pre-culture conditions, which affect the cell diameter, into account. In addition, inspection of metabolite uptake and release rates reveals that glucose is mainly used for generation of cellular energy and glutamine is not required for cellular maintenance. Finally, we conclude that changes in cell number, cell diameter and metabolite uptake during cultivation contribute to the understanding of the time course of intracellular metabolites during the cultivation process.

  11. Pumpkin seed extract: Cell growth inhibition of hyperplastic and cancer cells, independent of steroid hormone receptors.

    PubMed

    Medjakovic, Svjetlana; Hobiger, Stefanie; Ardjomand-Woelkart, Karin; Bucar, Franz; Jungbauer, Alois

    2016-04-01

    Pumpkin seeds have been known in folk medicine as remedy for kidney, bladder and prostate disorders since centuries. Nevertheless, pumpkin research provides insufficient data to back up traditional beliefs of ethnomedical practice. The bioactivity of a hydro-ethanolic extract of pumpkin seeds from the Styrian pumpkin, Cucurbita pepo L. subsp. pepo var. styriaca, was investigated. As pumpkin seed extracts are standardized to cucurbitin, this compound was also tested. Transactivational activity was evaluated for human androgen receptor, estrogen receptor and progesterone receptor with in vitro yeast assays. Cell viability tests with prostate cancer cells, breast cancer cells, colorectal adenocarcinoma cells and a hyperplastic cell line from benign prostate hyperplasia tissue were performed. As model for non-hyperplastic cells, effects on cell viability were tested with a human dermal fibroblast cell line (HDF-5). No transactivational activity was found for human androgen receptor, estrogen receptor and progesterone receptor, for both, extract and cucurbitin. A cell growth inhibition of ~40-50% was observed for all cell lines, with the exception of HDF-5, which showed with ~20% much lower cell growth inhibition. Given the receptor status of some cell lines, a steroid-hormone receptor independent growth inhibiting effect can be assumed. The cell growth inhibition for fast growing cells together with the cell growth inhibition of prostate-, breast- and colon cancer cells corroborates the ethnomedical use of pumpkin seeds for a treatment of benign prostate hyperplasia. Moreover, due to the lack of androgenic activity, pumpkin seed applications can be regarded as safe for the prostate.

  12. Inhibition of Nb2 T-lymphoma cell growth by transforming growth factor-beta.

    PubMed Central

    Rayhel, E J; Prentice, D A; Tabor, P S; Flurkey, W H; Geib, R W; Laherty, R F; Schnitzer, S B; Chen, R; Hughes, J P

    1988-01-01

    Transforming growth factor-beta (TGF-beta) inhibits proliferation of Nb2 cells, a rat T lymphoma, in response to lactogens and interleukin-2. Prostaglandins may play an important role in the pathway through which TGF-beta exerts its inhibitory actions, because prostaglandin E2 also inhibits proliferation of Nb2 cells, and indomethacin, an inhibitor of prostaglandin synthesis, reverses the inhibitory effects of TGF-beta on Nb2 cell proliferation. PMID:3262338

  13. Modeling Intrinsic Heterogeneity and Growth of Cancer Cells

    PubMed Central

    Greene, James M.; Levy, Doron; Fung, King L.; Silva de Souza, Paloma; Gottesman, Michael M.; Lavi, Orit

    2014-01-01

    Intratumoral heterogeneity has been found to be a major cause of drug resistance. Cell-to-cell variation increases as a result of cancer-related alterations, which are acquired by stochastic events and further induced by environmental signals. However, most cellular mechanisms include natural fluctuations that are closely regulated, and thus lead to asynchronization of the cells, which causes intrinsic heterogeneity in a given population. Here, we derive two novel mathematical models, a stochastic agent-based model and an integro-differential equation model, each of which describes the growth of cancer cells as a dynamic transition between proliferative and quiescent states. These models are designed to predict variations in growth as a function of the intrinsic heterogeneity emerging from the durations of the cell-cycle and apoptosis, and also include cellular density dependencies. By examining the role all parameters play in the evolution of intrinsic tumor heterogeneity, and the sensitivity of the population growth to parameter values, we show that the cell-cycle length has the most significant effect on the growth dynamics. In addition, we demonstrate that the agent-based model can be approximated well by the more computationally efficient integro-differential equations when the number of cells is large. This essential step in cancer growth modeling will allow us to revisit the mechanisms of multi-drug resistance by examining spatiotemporal differences of cell growth while administering a drug among the different sub-populations in a single tumor, as well as the evolution of those mechanisms as a function of the resistance level. PMID:25457229

  14. Modeling intrinsic heterogeneity and growth of cancer cells.

    PubMed

    Greene, James M; Levy, Doron; Fung, King Leung; Souza, Paloma S; Gottesman, Michael M; Lavi, Orit

    2015-02-21

    Intratumoral heterogeneity has been found to be a major cause of drug resistance. Cell-to-cell variation increases as a result of cancer-related alterations, which are acquired by stochastic events and further induced by environmental signals. However, most cellular mechanisms include natural fluctuations that are closely regulated, and thus lead to asynchronization of the cells, which causes intrinsic heterogeneity in a given population. Here, we derive two novel mathematical models, a stochastic agent-based model and an integro-differential equation model, each of which describes the growth of cancer cells as a dynamic transition between proliferative and quiescent states. These models are designed to predict variations in growth as a function of the intrinsic heterogeneity emerging from the durations of the cell-cycle and apoptosis, and also include cellular density dependencies. By examining the role all parameters play in the evolution of intrinsic tumor heterogeneity, and the sensitivity of the population growth to parameter values, we show that the cell-cycle length has the most significant effect on the growth dynamics. In addition, we demonstrate that the agent-based model can be approximated well by the more computationally efficient integro-differential equations when the number of cells is large. This essential step in cancer growth modeling will allow us to revisit the mechanisms of multidrug resistance by examining spatiotemporal differences of cell growth while administering a drug among the different sub-populations in a single tumor, as well as the evolution of those mechanisms as a function of the resistance level.

  15. Low plasma adiponectin level, white blood cell count and Helicobacter pylori titre independently predict abnormal pancreatic beta-cell function.

    PubMed

    So, Wing-Yee; Tong, Peter C; Ko, Gary T; Ma, Ronald C; Ozaki, Risa; Kong, Alice P; Yang, Xilin; Ho, Chung-Shun; Lam, Christopher C; Chan, Juliana C

    2009-11-01

    Adiponectin is an adipocytokine with insulin sensitizing effect while chronic inflammation damages pancreatic beta-cells leading to reduced insulin response. We aimed to prove the hypothesis that adiponectin levels and inflammatory markers (white blood cell counts [WCC], Helicobacter pylori [HP] titers, high sensitivity C-reactive protein [hs-CRP]) may interact to affect risk of diabetes. We studied 288 Chinese men (age-median: 41.0 years, IQR: 35.3-46.0 years) being recruited from the community in Hong Kong. The mean adiponectin level was 5.39+/-2.81 microg/ml and 40.9% (n=107) had low adiponectin level (<4 microg/ml). On multiple regression analysis, adiponectin was negatively associated with diabetes, HOMA insulin resistance top quartile, plasma glucose (PG) and 2h insulin; and positively associated with HOMA insulin sensitivity index. WCC was independently associated with PG and 15' insulin, and negatively associated with HOMA insulin sensitivity top quartile. HP titre was associated with 30' PG level and diabetes. hs-CRP did not enter the multivariable model. In conclusion, adiponectin, WCC and HP titer are independent predictors for hyperglycemia and reduced insulin sensitivity in Chinese men. These findings may explain the high risk for diabetes in Chinese population despite their relatively low adiposity.

  16. Amygdalin inhibits the growth of renal cell carcinoma cells in vitro.

    PubMed

    Juengel, Eva; Thomas, Anita; Rutz, Jochen; Makarevic, Jasmina; Tsaur, Igor; Nelson, Karen; Haferkamp, Axel; Blaheta, Roman A

    2016-02-01

    Although amygdalin is used by many cancer patients as an antitumor agent, there is a lack of information on the efficacy and toxicity of this natural compound. In the present study, the inhibitory effect of amygdalin on the growth of renal cell carcinoma (RCC) cells was examined. Amygdalin (10 mg/ml) was applied to the RCC cell lines, Caki-1, KTC-26 and A498, for 24 h or 2 weeks. Untreated cells served as controls. Tumor cell growth and proliferation were determined using MTT and BrdU tests, and cell cycle phases were evaluated. Expression of the cell cycle activating proteins cdk1, cdk2, cdk4, cyclin A, cyclin B, cyclin D1 and D3 as well as of the cell cycle inhibiting proteins p19 and p27 was examined by western blot analysis. Surface expression of the differentiation markers E- and N-cadherin was also investigated. Functional blockade by siRNA was used to determine the impact of several proteins on tumor cell growth. Amygdalin treatment caused a significant reduction in RCC cell growth and proliferation. This effect was correlated with a reduced percentage of G2/M-phase RCC cells and an increased percentage of cells in the G0/1-phase (Caki-1 and A498) or cell cycle arrest in the S-phase (KTC-26). Furthermore, amygdalin induced a marked decrease in cell cycle activating proteins, in particular cdk1 and cyclin B. Functional blocking of cdk1 and cyclin B resulted in significantly diminished tumor cell growth in all three RCC cell lines. Aside from its inhibitory effects on growth, amygdalin also modulated the differentiation markers, E- and N-cadherin. Hence, exposing RCC cells to amygdalin inhibited cell cycle progression and tumor cell growth by impairing cdk1 and cyclin B expression. Moreover, we noted that amygdalin affected differentiation markers. Thus, we suggest that amygdalin exerted RCC antitumor effects in vitro.

  17. Evaluation of primers and PCR performance on HPV DNA screening in normal and low grade abnormal cervical cells.

    PubMed

    Chaiwongkot, Arkom; Pientong, Chamsai; Ekalaksananan, Tipaya; Kongyingyoes, Bunkerd; Thinkhamrop, Jadsada; Yuenyao, Pissamai; Sriamporn, Supannee

    2007-01-01

    High risk human papillomaviruses (HR-HPVs) are associated with increased risk of normal cervical cells developing to dysplasia and cervical carcinoma. Therefore, HR-HPV DNA testing can predict an endpoint of cervical carcinogenesis that is earlier than the development of cervical abnormalities. Not only the sensitivity of methods but also the amount of HPV DNA are very important and might be parameters to distinguish HPV detection. In this study, we evaluated the effects of primer sets and the polymerase chain reaction (PCR) performance with low viral load samples with normal cervical cytology (140 samples) and mild dysplasia (140 samples) using two consensus primers MY09/MY11 and GP5+/6+. The PCR was performed with single and nested PCR. Positive samples with both primer sets were then HPV genotyped by dot blot hybridization. Results showed higher sensitivity of single PCR using primer GP5+/GP6+ than primer MY09/MY11. HPV DNA was detected in 15% (21 of 140)and 20.7% (29 of 140) of normal cervical samples, respectively. For mild dysplasia samples, HPV DNA was detected in 37.1% (52 of 140) with MY09/MY11 and 50% (70 of 140) using GP5+/GP6+. In normal cervical samples, the positivity rate was increased to 38.5% (54 of 140) by nested PCR using primer GP5+/6+, but only 2 mild dysplasia samples that were negative by single GP5+/6+ were positive by auto-nested PCR. These results suggested that, in low viral load samples, the sensitivity of HPV DNA detection depends not only on primer sets but also PCR performance. HPV 16 was the most common in mild dysplasia samples (20.8%), whereas HPV type 58 was found in 11.1%. This study suggested that nested PCR might be necessary for HPV DNA detection in cervical samples of women participating in cervical cancer screening.

  18. Mass Spectrometry Identification of Potential Mediators of Progestin-only Contraceptive Induced Abnormal Uterine Bleeding in Human Endometrial Stromal Cells

    PubMed Central

    Shapiro, John P.; Basar, Murat; Kayisli, Umit A.; Guzeloglu-Kayisli, Ozlem; Huang, S. Joseph; Suarez, Adrian A.; Ozer, Hatice Gulcin; Schatz, Frederick; Lockwood, Charles J.

    2015-01-01

    Objective Thrombin and hypoxia each target human endometrial stromal cells (HESCs) to mediate long-acting progestin-only contraceptive (LAPC) induced abnormal uterine bleeding (AUB). Thus, the secretome resulting from treatment of primary cultures of HESCs with thrombin or hypoxia was screened by mass spectrometry (MS) to detect potential protein mediators that lead to AUB. Study Design Cultured HESCs were primed with estradiol ± medroxyprogesterone acetate (MPA) or etonorgestrel (ETO), the respective progestins in MPA injected and ETO implanted LAPCs, and then treated by incubation with thrombin or under hypoxia. Collected conditioned medium supernatants were used for protein identification and quantitation of potential AUB mediators by liquid chromatography combined with tandem MS analysis. Microarray analysis of parallel cultures and immunostaining of endometrial biopsies of LAPC users vs. non-users corroborated MS results. Results MS identified several proteins displaying changes in expression levels from either thrombin or hypoxia treatments that are integral to angiogenesis or extracellular matrix formation. Several MS identified proteins were confirmed by mRNA microarray analysis. Over expressed stanniocalcin-1 (STC-1) was observed in endometrium of LAPC users. Unlike controls, all LAPC users displayed endometrial tubal metaplasia (ETM). Conclusions MS analysis identified many proteins that can affect angiogenesis or vessel integrity, thereby contributing to AUB. Confirmation of STC-1 overexpression in LAPC users and microarray data supports the validity of the MS data and suggests STC-1 involvement in AUB. The discovery of ETM in LAPC users indicates that LAPC-related side effects extend beyond AUB. The results presented here demonstrate a complex biological response to LAPC use. PMID:25529278

  19. Circulating progenitor and angiogenic cell frequencies are abnormally static over pregnancy in women with preconception diabetes: A pilot study.

    PubMed

    Lima, Patricia D A; Chen, Zhilin; Tayab, Aysha; Murphy, Malia S Q; Pudwell, Jessica; Smith, Graeme N; Croy, B Anne

    2017-01-01

    Type 1 and 2 diabetes decrease the frequencies and functional capacities of circulating angiogenic cells (CAC). Diabetes also elevates gestational complications. These observations may be interrelated. We undertook pilot studies to address the hypothesis that preconception diabetes deviates known gestational increases in CACs. Cross-sectional study of type 1 diabetic, type 2 diabetic and normoglycemic pregnant women was conducted at 1st, 2nd, and 3rd trimester and compared to a 6mo postpartum surrogate baseline. Circulating progenitor cells (CPC; CD34+CD45dimSSlow) and CACs (CD34+CD45dimSSlow expressing CD133 without or with KDR) were quantified by flow cytometry and by colony assay (CFU-Hill). In pregnant normoglycemic women, CD34+CD45dimSSlow cell frequency was greater in 1st and 3rd trimester than postpartum but frequency of these cells was static over type 1 or 2 diabetic pregnancies. Type 1 and type 2 diabetic women showed CACs variance versus normal controls. Type 1 diabetic women had more total CD34+KDR+ CACs in 1st trimester and a higher ratio of CD133+KDR+ to total CD133+ cells in 1st and 2nd trimesters than control women, demonstrating an unbalance in CD133+KDR+ CACs. Type 2 diabetic women had more CD133+KDR+ CACs in 1st trimester and fewer CD133+KDR- CACs at mid-late pregnancy than normal pregnant women. Thus, pregnancy stage-specific physiological fluctuation in CPCs (CD34+) and CACs (CD133+KDR+ and CD133+KDR-) did not occur in type 1 and type 2 diabetic women. Early outgrowth colonies were stable across normal and diabetic pregnancies. Therefore, preconception diabetes blocks the normal dynamic pattern of CAC frequencies across gestation but does not alter colony growth. The differences between diabetic and typical women were seen at specific gestational stages that may be critical for initiation of the uterine vascular pathologies characterizing diabetic gestations.

  20. Circulating progenitor and angiogenic cell frequencies are abnormally static over pregnancy in women with preconception diabetes: A pilot study

    PubMed Central

    Chen, Zhilin; Tayab, Aysha; Murphy, Malia S. Q.; Pudwell, Jessica; Smith, Graeme N.; Croy, B. Anne

    2017-01-01

    Type 1 and 2 diabetes decrease the frequencies and functional capacities of circulating angiogenic cells (CAC). Diabetes also elevates gestational complications. These observations may be interrelated. We undertook pilot studies to address the hypothesis that preconception diabetes deviates known gestational increases in CACs. Cross-sectional study of type 1 diabetic, type 2 diabetic and normoglycemic pregnant women was conducted at 1st, 2nd, and 3rd trimester and compared to a 6mo postpartum surrogate baseline. Circulating progenitor cells (CPC; CD34+CD45dimSSlow) and CACs (CD34+CD45dimSSlow expressing CD133 without or with KDR) were quantified by flow cytometry and by colony assay (CFU-Hill). In pregnant normoglycemic women, CD34+CD45dimSSlow cell frequency was greater in 1st and 3rd trimester than postpartum but frequency of these cells was static over type 1 or 2 diabetic pregnancies. Type 1 and type 2 diabetic women showed CACs variance versus normal controls. Type 1 diabetic women had more total CD34+KDR+ CACs in 1st trimester and a higher ratio of CD133+KDR+ to total CD133+ cells in 1st and 2nd trimesters than control women, demonstrating an unbalance in CD133+KDR+ CACs. Type 2 diabetic women had more CD133+KDR+ CACs in 1st trimester and fewer CD133+KDR- CACs at mid-late pregnancy than normal pregnant women. Thus, pregnancy stage-specific physiological fluctuation in CPCs (CD34+) and CACs (CD133+KDR+ and CD133+KDR-) did not occur in type 1 and type 2 diabetic women. Early outgrowth colonies were stable across normal and diabetic pregnancies. Therefore, preconception diabetes blocks the normal dynamic pattern of CAC frequencies across gestation but does not alter colony growth. The differences between diabetic and typical women were seen at specific gestational stages that may be critical for initiation of the uterine vascular pathologies characterizing diabetic gestations. PMID:28278173

  1. Abnormal expression of inflammatory genes in placentas of women with sickle cell anemia and sickle hemoglobin C disease.

    PubMed

    Baptista, Letícia C; Costa, Maria Laura; Ferreira, Regiane; Albuquerque, Dulcinéia M; Lanaro, Carolina; Fertrin, Kleber Y; Surita, Fernanda G; Parpinelli, Mary A; Costa, Fernando F; Melo, Mônica Barbosa de

    2016-10-01

    Sickle cell disease (SCD) is a complex disease that is characterized by the polymerization of deoxyhemoglobin S, altered red blood cell membrane biology, endothelial activation, hemolysis, a procoagulant state, acute and chronic inflammation, and vaso-occlusion. Among the physiological changes that occur during pregnancy, oxygen is consumed by fetal growth, and pregnant women with SCD are more frequently exposed to low oxygen levels. This might lead to red blood cells sickling, and, consequently, to vaso-occlusion. The mechanisms by which SCD affects placental physiology are largely unknown, and chronic inflammation might be involved in this process. This study aimed to evaluate the gene expression profile of inflammatory response mediators in the placentas of pregnant women with sickle cell cell anemia (HbSS) and hemoglobinopathy SC (HbSC). Our results show differences in a number of these genes. For the HbSS group, when compared to the control group, the following genes showed differential expression: IL1RAP (2.76-fold), BCL6 (4.49-fold), CXCL10 (-2.12-fold), CXCR1 (-3.66-fold), and C3 (-2.0-fold). On the other hand, the HbSC group presented differential expressions of the following genes, when compared to the control group: IL1RAP (4.33-fold), CXCL1 (3.05-fold), BCL6 (4.13-fold), CXCL10 (-3.32-fold), C3 (-2.0-fold), and TLR3 (2.38-fold). Taken together, these data strongly suggest a differential expression of several inflammatory genes in both SCD (HbSS and HbSC), indicating that the placenta might become an environment with hypoxia, and increased inflammation, which could lead to improper placental development.

  2. Autocrine growth inhibition by transforming growth factor β-1 (TGFβ-1) in human neuroendocrine tumour cells

    PubMed Central

    Wimmel, A; Wiedenmann, B; Rosewicz, S

    2003-01-01

    Background and aim: The role of transforming growth factor β-1 (TGFβ-1) in neuroendocrine tumour biology is currently unknown. We therefore examined the expression and biological significance of TGFβ signalling components in neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) tract. Methods: Expression of TGFβ-1 and its receptors, Smads and Smad regulated proteins, was examined in surgically resected NET specimens and human NET cell lines by immunohistochemistry, reverse transcriptase-polymerase chain reaction, immunoblotting, and ELISA. Activation of TGFβ-1 dependent promoters was tested by transactivation assays. Growth regulation was evaluated by cell numbers, soft agar assays, and cell cycle analysis using flow cytometry. The role of endogenous TGFβ was assessed by a TGFβ neutralising antibody and stable transfection of a dominant negative TGFβR II receptor construct. Results: Coexpression of TGFβ-1 and its receptors TGFβR I and TGFβR II was detected in 67% of human NETs and in all three NET cell lines examined. NET cell lines expressed the TGFβ signal transducers Smad 2, 3, and 4. In two of the three cell lines, TGFβ-1 treatment resulted in transactivation of a TGFβ responsive reporter construct as well as inhibition of c-myc and induction of p21(WAF1) expression. TGFβ-1 inhibited anchorage dependent and independent growth in a time and dose dependent manner in TGFβ-1 responsive cell lines. TGFβ-1 mediated growth inhibition was due to G1 arrest without evidence of induction of apoptosis. Functional inactivation of endogenous TGFβ revealed the existence of an autocrine antiproliferative loop in NET cells. Conclusions: Neuroendocrine tumour cells of the gastroenteropancreatic tract are subject to paracrine and autocrine growth inhibition by TGFβ-1, which may account in part for the low proliferative index of this tumour entity. PMID:12912863

  3. [Abnormal expression of insulin-like growth factor-I receptor and inhibitory effect of its transcription intervention on nude mice xenograft tumor].

    PubMed

    Yao, M; Yan, X D; Cai, Y; Gu, J J; Yang, X L; Pan, L H; Wang, L; Yao, D F

    2016-11-20

    Objective: To investigate the expression of insulin-like growth factor-I receptor (IGF-IR) in liver cancer and the inhibitory effect of its transcription intervention on nude mice xenograft tumor. Methods: A total of 40 patients with primary liver cancer were enrolled, and 40 samples of cancer lesions, peri-cancerous tissues (with a distance of 2 cm to the margin of cancer lesion), or distal liver tissues (with a distance of 5 cm to the margin of cancer lesion), with a weight of 200 mg, were collected after surgery. Some of these samples were used for pathological examination, and the rest were stored at -85°C. A total of 18 BALB/c nude mice aged 4-6 weeks with a body weight of 18-20 g (9 male and 9 female mice) were randomly divided into control group, negative control group, and co-intervention group, with 6 mice in each group, and fed under specific pathogen-free conditions. The cell line was cultured in the dimethyl sulfoxide complete medium containing 10% fetal bovine serum in a CO2incubator at 37°C. When the cell confluence reached 90% after cell inoculation, shRNA was divided into co-intervention group, negative control group, and untreated control group and were transfected to hepatoma cells using PolyJetTM transfection reagent. Stable cell clones obtained by G418 screening and used for the in vivo study. Immunohistochemistry, Western blotting, and quantitative real-time PCR were used to analyze the expression of IGF-IR in the human hepatoma tissue and cell line. The IGF-IR shRNA eukaryotic expression plasmids were established and screened for the most effective sequence; they were transfected to PLC/PRF/5 hepatoma cells, and the CCK-8 assay was used to analyze the changes in cell proliferation. The stable cell line screened out by G418 was inoculated to establish the subcutaneous xenograft tumor in nude mice. The tumor growth curve was plotted and histological examination was performed. Graphpad Prism 5.0 and SPSS 18.0 were used for plotting and data

  4. The Populus Class III HD ZIP transcription factor POPCORONA affects cell differentiation during secondary growth of woody stems.

    PubMed

    Du, Juan; Miura, Eriko; Robischon, Marcel; Martinez, Ciera; Groover, Andrew

    2011-02-28

    The developmental mechanisms regulating cell differentiation and patterning during the secondary growth of woody tissues are poorly understood. Class III HD ZIP transcription factors are evolutionarily ancient and play fundamental roles in various aspects of plant development. Here we investigate the role of a Class III HD ZIP transcription factor, POPCORONA, during secondary growth of woody stems. Transgenic Populus (poplar) trees expressing either a miRNA-resistant POPCORONA or a synthetic miRNA targeting POPCORONA were used to infer function of POPCORONA during secondary growth. Whole plant, histological, and gene expression changes were compared for transgenic and wild-type control plants. Synthetic miRNA knock down of POPCORONA results in abnormal lignification in cells of the pith, while overexpression of a miRNA-resistant POPCORONA results in delayed lignification of xylem and phloem fibers during secondary growth. POPCORONA misexpression also results in coordinated changes in expression of genes within a previously described transcriptional network regulating cell differentiation and cell wall biosynthesis, and hormone-related genes associated with fiber differentiation. POPCORONA illustrates another function of Class III HD ZIPs: regulating cell differentiation during secondary growth.

  5. Phytoglobins Improve Hypoxic Root Growth by Alleviating Apical Meristem Cell Death1[OPEN

    PubMed Central

    Stasolla, Claudio

    2016-01-01

    Hypoxic root growth in maize (Zea mays) is influenced by the expression of phytoglobins (ZmPgbs). Relative to the wild type, suppression of ZmPgb1.1 or ZmPgb1.2 inhibits the growth of roots exposed to 4% oxygen, causing structural abnormalities in the root apical meristems. These effects were accompanied by increasing levels of reactive oxygen species (ROS), possibly through the transcriptional induction of four Respiratory Burst Oxidase Homologs. TUNEL-positive nuclei in meristematic cells indicated the involvement of programmed cell death (PCD) in the process. These cells also accumulated nitric oxide and stained heavily for ethylene biosynthetic transcripts. A sharp increase in the expression level of several 1-aminocyclopropane synthase (ZmAcs2, ZmAcs6, and ZmAcs7), 1-aminocyclopropane oxidase (Aco15, Aco20, Aco31, and Aco35), and ethylene-responsive (ZmErf2 and ZmEbf1) genes was observed in hypoxic ZmPgb-suppressing roots, which overproduced ethylene. Inhibiting ROS synthesis with diphenyleneiodonium or ethylene perception with 1-methylcyclopropene suppressed PCD, increased BAX inhibitor-1, an effective attenuator of the death programs in eukaryotes, and restored root growth. Hypoxic roots overexpressing ZmPgbs had the lowest level of ethylene and showed a reduction in ROS staining and TUNEL-positive nuclei in the meristematic cells. These roots retained functional meristems and exhibited the highest growth performance when subjected to hypoxic conditions. Collectively, these results suggest a novel function of Pgbs in protecting root apical meristems from hypoxia-induced PCD through mechanisms initiated by nitric oxide and mediated by ethylene via ROS. PMID:27702845

  6. Mechanical Behavior of Cells within a Cell-Based Model of Wheat Leaf Growth

    PubMed Central

    Zubairova, Ulyana; Nikolaev, Sergey; Penenko, Aleksey; Podkolodnyy, Nikolay; Golushko, Sergey; Afonnikov, Dmitry; Kolchanov, Nikolay

    2016-01-01

    Understanding the principles and mechanisms of cell growth coordination in plant tissue remains an outstanding challenge for modern developmental biology. Cell-based modeling is a widely used technique for studying the geometric and topological features of plant tissue morphology during growth. We developed a quasi-one-dimensional model of unidirectional growth of a tissue layer in a linear leaf blade that takes cell autonomous growth mode into account. The model allows for fitting of the visible cell length using the experimental cell length distribution along the longitudinal axis of a wheat leaf epidermis. Additionally, it describes changes in turgor and osmotic pressures for each cell in the growing tissue. Our numerical experiments show that the pressures in the cell change over the cell cycle, and in symplastically growing tissue, they vary from cell to cell and strongly depend on the leaf growing zone to which the cells belong. Therefore, we believe that the mechanical signals generated by pressures are important to consider in simulations of tissue growth as possible targets for molecular genetic regulators of individual cell growth. PMID:28018409

  7. Total triterpenoids from Ganoderma Lucidum suppresses prostate cancer cell growth by inducing growth arrest and apoptosis.

    PubMed

    Wang, Tao; Xie, Zi-ping; Huang, Zhan-sen; Li, Hao; Wei, An-yang; Di, Jin-ming; Xiao, Heng-jun; Zhang, Zhi-gang; Cai, Liu-hong; Tao, Xin; Qi, Tao; Chen, Di-ling; Chen, Jun

    2015-10-01

    In this study, one immortalized human normal prostatic epithelial cell line (BPH) and four human prostate cancer cell lines (LNCaP, 22Rv1, PC-3, and DU-145) were treated with Ganoderma Lucidum triterpenoids (GLT) at different doses and for different time periods. Cell viability, apoptosis, and cell cycle were analyzed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR and Western blotting. It was found that GLT dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. GLT-induced apoptosis was due to activation of Caspases-9 and -3 and turning on the downstream apoptotic events. GLT-induced cell cycle arrest (mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4 (CDK4) and E2F1 expression at the late time. These findings demonstrate that GLT suppresses prostate cancer cell growth by inducing growth arrest and apoptosis, which might suggest that GLT or Ganoderma Lucidum could be used as a potential therapeutic drug for prostate cancer.

  8. The cell growth suppressor, mir-126, targets IRS-1.

    PubMed

    Zhang, Jin; Du, Ying-ying; Lin, Yi-feng; Chen, Ya-ting; Yang, Lu; Wang, Hui-jun; Ma, Duan

    2008-12-05

    miRNAs are a family of approximately 22-nuleotide-long noncoding RNAs involved in the formation and progress of tumors. Since traditional methods for the detection of miRNAs expression have many disadvantages, we developed a simple method called polyA RT PCR. With this method, we detected a series of miRNAs and found that mir-126 is one of the miRNAs underexpressed in breast cancer cells. Flow cytometry analysis showed that mir-126 inhibited cell cycle progression from G1/G0 to S. Further studies revealed that mir-126 targeted IRS-1 at the translation level. Knocking down of IRS-1 suppresses cell growth in HEK293 and breast cancer cell MCF-7, which recapitulates the effects of mir-126. In conclusion, we developed a simple method for high-throughput screening of miRNAs and found that mir-126, a cell growth suppressor, targets IRS-1.

  9. The MRL proteins: adapting cell adhesion, migration and growth.

    PubMed

    Coló, Georgina P; Lafuente, Esther M; Teixidó, Joaquin

    2012-01-01

    MIG-10, RIAM and Lamellipodin (Lpd) are the founding members of the MRL family of multi-adaptor molecules. These proteins have common domain structures but display distinct functions in cell migration and adhesion, signaling, and in cell growth. The binding of RIAM with active Rap1 and with talin provides these MRL molecules with important regulatory roles on integrin-mediated cell adhesion and migration. Furthermore, RIAM and Lpd can regulate actin dynamics through their binding to actin regulatory Ena/VASP proteins. Recent data generated with the Drosophila MRL ortholog called Pico and with RIAM in melanoma cells indicate that these proteins can also regulate cell growth. As MRL proteins represent a relatively new family, many questions on their structure-function relationships remain unanswered, including regulation of their expression, post-translational modifications, new interactions, involvement in signaling and their knockout mice phenotype.

  10. Red blood cells of sickle cell disease patients exhibit abnormally high abundance of N-methyl D-aspartate receptors mediating excessive calcium uptake.

    PubMed

    Hänggi, Pascal; Makhro, Asya; Gassmann, Max; Schmugge, Markus; Goede, Jeroen S; Speer, Oliver; Bogdanova, Anna

    2014-10-01

    Recently we showed that N-methyl D-aspartate receptors (NMDARs) are expressed in erythroid precursors (EPCs) and present in the circulating red blood cells (RBCs) of healthy humans, regulating intracellular Ca(2+) in these cells. This study focuses on investigating the possible role of NMDARs in abnormally high Ca(2+) permeability in the RBCs of patients with sickle cell disease (SCD). Protein levels of the NMDAR subunits in the EPCs of SCD patients did not differ from those in EPCs of healthy humans. However, the number and activity of the NMDARs in circulating SCD-RBCs was substantially up-regulated, being particularly high during haemolytic crises. The number of active NMDARs correlated negatively with haematocrit and haemoglobin levels in the blood of SCD patients. Calcium uptake via these non-selective cation channels was induced by RBC treatment with glycine, glutamate and homocysteine and was facilitated by de-oxygenation of SCD-RBCs. Oxidative stress and RBC dehydration followed receptor stimulation and Ca(2+) uptake. Inhibition of the NMDARs with an antagonist memantine caused re-hydration and largely prevented hypoxia-induced sickling. The EPCs of SCD patients showed higher tolerance to memantine than those of healthy subjects. Consequently, NMDARs in the RBCs of SCD patients appear to be an attractive target for pharmacological intervention.

  11. Phase transitions in tumor growth: II prostate cancer cell lines

    NASA Astrophysics Data System (ADS)

    Llanos-Pérez, J. A.; Betancourt-Mar, A.; De Miguel, M. P.; Izquierdo-Kulich, E.; Royuela-García, M.; Tejera, E.; Nieto-Villar, J. M.

    2015-05-01

    We propose a mechanism for prostate cancer cell lines growth, LNCaP and PC3 based on a Gompertz dynamics. This growth exhibits a multifractal behavior and a "second order" phase transition. Finally, it was found that the cellular line PC3 exhibits a higher value of entropy production rate compared to LNCaP, which is indicative of the robustness of PC3, over to LNCaP and may be a quantitative index of metastatic potential tumors.

  12. Short-term zinc deficiency inhibits chondrocyte proliferation and induces cell apoptosis in the epiphyseal growth plate of young chickens.

    PubMed

    Wang, Xibin; Fosmire, Gary J; Gay, Carol V; Leach, Roland M

    2002-04-01

    The purpose of this study was to investigate the effect of zinc deficiency on chondrocyte proliferation, differentiation and apoptosis in the epiphyseal growth plate of juvenile chickens. Newly hatched broiler chickens were fed either a low zinc (10 mg/kg diet) or a zinc-adequate (68 mg/kg diet) soy protein-based purified diet. Cell proliferation in the growth plate was evaluated with bromodeoxyuridine (BrdU) labeling. Apoptosis was assessed using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method. Chondrocyte differentiation was evaluated with immunostaining of osteonectin as a marker of maturation. As early as d 3 of feeding, zinc deficiency significantly inhibited chondrocyte proliferation, promoted cell differentiation and induced cell apoptosis in the growth plate. These effects were manifested primarily in areas remote from the blood supply. Immunostaining for local growth factors such as insulin-like growth factor-1 (IGF-1), parathyroid hormone-related protein (PTHrP) and fibroblast growth factor-2 (FGF-2) did not reveal any differences between growth plates of zinc-deficient and zinc-adequate chickens after 3 d of feeding. By d 7, severe growth plate lesions characterized by reduced cellularity and abnormally shaped cells were formed in areas remote from blood vessels. Immunoreactive IGF-1, PTHrP and FGF-2 were all greatly reduced in the lesion. However, the growth rate and food intake of zinc-deficient chickens were not different from those of the controls during the 7-d experiment. Therefore, a direct effect of zinc deficiency on proliferation, differentiation, and apoptosis of growth plate chondrocytes was indicated.

  13. Hormonal Control of Breast Cancer Cell Growth

    DTIC Science & Technology

    1997-09-01

    the ICE/ced-3 protease necessary for mammalian apoptosis . Nature , 376: 37-43, 1995. 55. Tewari, M., Quan, L.T., O’Rourke, K., Desnoyers, S., Zeng, Z...61. Enari, M., Hug, H. and Nagata, S. Involvement of an ICE-like protease in Fas- mediated apoptosis . Nature , 375: 78-81, 1995. 62. Liebermann, D.A...inhibition is the activation of genes controlling programmed cell death (PCD), leading to apoptosis , as it has been shown in other systems (24-26,42,43

  14. Hematopoietic Stem Cell and Its Growth Factor

    DTIC Science & Technology

    1988-02-16

    that both K15 and H5 were selectively retained by mature eosinophiles but not by other granulocytes. These results were obtained by the isolation of...Platelets M143 > 90% 40-60% neg neg neg K15 neutrophils: >90% >95% neg neg neg eosinophils : + H4 weakly + >90% neg neg + + H5 5-15% >95% 10-20% neg...down a band at 130KD from platelets and a complex of 140- 150KD/90-94KD from HEL cells. Because of the unusual reactivity and the possibility that the

  15. Hydrodynamic effects on cell growth in agitated microcarrier bioreactors

    NASA Technical Reports Server (NTRS)

    Cherry, Robert S.; Papoutsakis, E. Terry

    1988-01-01

    The net growth rate of bovine embryonic kidney cells in microcarrier bioreactor is the result of a variable death rate imposed on a cell culture trying to grow at a constant intrinsic growth rate. The death rate is a function of the agitation conditions in the system, and increases at higher agitation because of increasingly energetic interactions of the cell covered microcarriers with turbulent eddies in the fluid. At very low agitation rates bead-bead bridging becomes important; the large clumps formed by bridging can interact with larger eddies than single beads, leading to a higher death rate at low agitation. The growth and death rate were correlated with a dimensionless eddy number which compares eddy forces to the buoyant force on the bead.

  16. Mesenchymal stem cell therapy for injured growth plate.

    PubMed

    Shukrimi, Awang B; Afizah, Mohd H; Schmitt, Jacqueline F; Hui, James H P

    2013-01-01

    The growth plate has a limited self-healing capacity. Fractures sustained to the growth plate of young children could cause growth disturbances like angular deformity or growth arrest. Established therapies for injured physis only address related complications. Mesenchymal stem cells (MSCs) are multipotent cells which are capable of differentiating into various cells of the musculoskeletal system. Various MSC types have been tested for physeal regeneration, through in vivo lapine, porcine and ovine models, for the duration of 4-16 weeks. The created defect sizes ranged from 7-50% of the growth plate area, to simulate clinically-encountered cases. In vitro models have also been investigated, as a means to screen potential treatments. The effects of MSCs gathered from these models have revealed its function in the prevention of bone bridge formation, with the subsequent development of organized physeal repair tissue. Possible influential factors like the number of implanted MSCs, preconditioned state, growth factors, chondrocyte-MSC interaction and scaffolds are discussed. Possible further studies to optimize physeal repair based on MSC therapy in articular cartilage are also included.

  17. HPV-16 E2 gene disruption and sequence variation in CIN 3 lesions and invasive squamous cell carcinomas of the cervix: relation to numerical chromosome abnormalities

    PubMed Central

    Graham, D A; Herrington, C S

    2000-01-01

    Aim—To test the hypothesis that, because the human papillomavirus (HPV) E2 protein represses viral early gene transcription, E2 gene sequence variation or disruption could play a part in the induction of the numerical chromosome abnormalities that have been described in squamous cervical lesions. Methods—The integrity and sequence of the E2 gene from 11 cervical intraepithelial neoplasia (CIN) grade 3 lesions and 14 invasive squamous cell carcinomas, all of which contained HPV-16, were analysed by the polymerase chain reaction (PCR). The E2 gene was amplified in three overlapping fragments and PCR products sequenced directly. Chromosome abnormalities were identified by interphase cytogenetics using chromosome specific probes for chromosomes 1, 3, 11, 17, 18, and X. Results—E2 gene disruption was present in significantly more invasive carcinomas (eight of 14) than CIN 3 lesions (one of 11) (p = 0.03). No association was found between E2 disruption and the presence of a numerical chromosome abnormality. The E2 gene from the non-disrupted isolates was sequenced and wild-type (n = 5) and variant (n = 11) sequences identified. Variant sequences belonged to European and African classes and contained from one to 15 amino acid substitutions. Although numerical chromosome abnormalities were significantly more frequent in invasive squamous cell carcinoma than CIN 3 (p = 0.04), there was no significant relation between the presence of sequence variation and either histological diagnosis or chromosome abnormality. Conclusions—These data do not support the hypothesis that E2 gene disruption or variation is important in the induction of chromosome imbalance in these lesions. However, there is a relation between E2 gene disruption and the presence of invasive disease. PMID:11040943

  18. Growth hormone induces multiplication of the slowly cycling germinal cells of the rat tibial growth plate.

    PubMed

    Ohlsson, C; Nilsson, A; Isaksson, O; Lindahl, A

    1992-10-15

    To study the effect of locally infused growth hormone (GH) or insulin-like growth factor I(IGF-I) on slowly cycling cells in the germinal cell layer of the tibial growth plate, osmotic minipumps delivering 14.3 microCi of [3H]thymidine per day were implanted s.c. into hypophysectomized rats, and GH (1 microgram) or IGF-I (10 micrograms) was injected daily through a cannula implanted in the proximal tibia. The opposite leg served as a control. After 12 days of treatment, the osmotic minipumps were removed, and three rats in each group were given GH (20 micrograms/day, s.c.) for an additional 14 days to chase the labeled cells out of the proliferative layers. Labeled cells remained in the germinal layer, in the perichondrial ring, and on the surface of the articular cartilage close to the epiphyseal plate. GH administered together with labeled thymidine significantly increased the number of labeled cells in the germinal cell layer compared to that in the control leg (ratio = 1.95 +/- 0.13), whereas IGF-I showed no stimulatory effect (ratio = 0.96 +/- 0.04). Therefore GH but not IGF-I stimulates the multiplication of the slowly cycling (label-retaining) cells in the germinal layer of the epiphyseal plate. IGF-I acts only on the proliferation of the resulting chondrocytes.

  19. Purification and cultivation of human pituitary growth hormone secreting cells

    NASA Technical Reports Server (NTRS)

    Hymer, W. C.

    1979-01-01

    Efforts were directed towards maintenance of actively secreting human pituitary growth hormone cells (somatotrophs) in vitro. The production of human growth hormone (hGH) by this means would be of benefit for the treatment of certain human hypopituitary diseases such as dwarfism. One of the primary approaches was the testing of agents which may logically be expected to increase hGH release. The progress towards this goal is summarized. Results from preliminary experiments dealing with electrophoresis of pituitary cell for the purpose of somatotroph separation are described.

  20. Replicating vesicles as models of primitive cell growth and division.

    PubMed

    Hanczyc, Martin M; Szostak, Jack W

    2004-12-01

    Primitive cells, lacking the complex bio-machinery present in modern cells, would have had to rely on the self-organizing properties of their components and on interactions with their environment to achieve basic cellular functions such as growth and division. Many bilayer-membrane vesicles, depending on their composition and environment, can exhibit complex morphological changes such as growth, fusion, fission, budding, internal vesicle assembly and vesicle-surface interactions. The rich dynamic properties of these vesicles provide interesting models of how primitive cellular replication might have occurred in response to purely physical and chemical forces.

  1. Microcrystalline silicon growth for heterojunction solar cells

    NASA Technical Reports Server (NTRS)

    Iles, P. A.; Leung, D. C.; Fang, P. H.

    1984-01-01

    A single source of evaporation with B mixed with highly doped Si is used instead of the coevaporation of separate Si and B sources to reduce possible carbon contamination. The results of both the heterojunction or heteroface structures, however, are similar when evaporation is used. The best Voc of the heterojunction is about 460mV and no improvement in Voc in the heteroface structure is observed. Slight Voc degradation occurred. A study of the p m-Si/p c-Si structure showed a negative Voc in many cases. The interface properties between the two materials are such that instead of repelling minority carriers from the substrate carrier, collection actually occurred. Another study of cells made in the part of substrates not covered by n-Si results in performance lower than the controls. This indicates possible substrate degradation in the process.

  2. Pituitary follicular cells produce basic fibroblast growth factor

    SciTech Connect

    Ferrara, N.; Schweigerer, L.; Neufeld, G.; Mitchell, R.; Gospodarowicz, D.

    1987-08-01

    Cultured monolayers of bovine pituitary follicular cells, which transport ions, contain high amounts of mitogenic activity for endothelial cells which, on the basis of gene expression analysis, heparin-Sepharose elution profile, bioassay, immunoblotting, radioimmunoassay, and radioreceptor assay, has been identified as basic fibroblast growth factor (bFGF). These data indicate that follicular cells may be a major source of bFGF in the pituitary gland. Considering that bFGF has been proposed to play a role in paracrine regulation of pituitary hormone secretion, the data also suggest that these cells may exert important local regulatory functions.

  3. Cell longevity and sustained primary growth in palm stems.

    PubMed

    Tomlinson, P Barry; Huggett, Brett A

    2012-12-01

    Longevity, or organismal life span, is determined largely by the period over which constituent cells can function metabolically. Plants, with modular organization (the ability continually to develop new organs and tissues) differ from animals, with unitary organization (a fixed body plan), and this difference is reflected in their respective life spans, potentially much longer in plants than animals. We draw attention to the observation that palm trees, as a group of monocotyledons without secondary growth comparable to that of lignophytes (plants with secondary growth from a bifacial cambium), retain by means of sustained primary growth living cells in their trunks throughout their organismal life span. Does this make palms the longest-lived trees because they can grow as individuals for several centuries? No conventional lignophyte retains living metabolically active differentiated cell types in its trunk for this length of time, even though the tree as a whole can exist for millennia. Does this contrast also imply that the long-lived cells in a palm trunk have exceptional properties, which allows this seeming immortality? We document the long-life of many tall palm species and their inherent long-lived stem cell properties, comparing such plants to conventional trees. We provide a summary of aspects of cell age and life span in animals and plants. Cell replacement is a feature of animal function, whereas conventional trees rely on active growth centers (meristems) to sustain organismal development. However, the long persistence of living cells in palm trunks is seen not as evidence for unique metabolic processes that sustain longevity, but is a consequence of unique constructional features. This conclusion suggests that the life span of plant cells is not necessarily genetically determined.

  4. Netrin-4 regulates angiogenic responses and tumor cell growth

    SciTech Connect

    Nacht, Mariana; St Martin, Thia B.; Byrne, Ann; Klinger, Katherine W.; Teicher, Beverly A.; Madden, Stephen L. Jiang, Yide

    2009-03-10

    Netrin-4 is a 628 amino acid basement membrane component that promotes neurite elongation at low concentrations but inhibits neurite extension at high concentrations. There is a growing body of literature suggesting that several molecules, including netrins, are regulators of both neuronal and vascular growth. It is believed that molecules that guide neural growth and development are also involved in regulating morphogenesis of the vascular tree. Further, netrins have recently been implicated in controlling epithelial cell branching morphogenesis in the breast, lung and pancreas. Characterization of purified netrin-4 in in vitro angiogenesis assays demonstrated that netrin-4 markedly inhibits HMVEC migration and tube formation. Moreover, netrin-4 inhibits proliferation of a variety of human tumor cells in vitro. Netrin-4 has only modest effects on proliferation of endothelial and other non-transformed cells. Netrin-4 treatment results in phosphorylation changes of proteins that are known to control cell growth. Specifically, Phospho-Akt-1, Phospho-Jnk-2, and Phospho-c-Jun are reduced in tumor cells that have been treated with netrin-4. Together, these data suggest a potential role for netrin-4 in regulating tumor growth.

  5. Altered tumor cell growth and tumorigenicity in models of microgravity

    NASA Astrophysics Data System (ADS)

    Yamauchi, K.; Taga, M.; Furian, L.; Odle, J.; Sundaresan, A.; Pellis, N.; Andrassy, R.; Kulkarni, A.

    Spaceflight environment and microgravity (MG) causes immune dysfunction and is a major health risk to humans, especially during long-term space missions. The effects of microgravity environment on tumor growth and carcinogenesis are yet unknown. Hence, we investigated the effects of simulated MG (SMG) on tumor growth and tumorigenicity using in vivo and in vitro models. B16 melanoma cells were cultured in static flask (FL) and rotating wall vessel bioreactors (BIO) to measure growth and properties, melanin production and apoptosis. BIO cultures had 50% decreased growth (p<0.01), increased doubling time and a 150% increase in melanin production (p<0.05). Flow cytometric analysis showed increased apoptosis in BIO. When BIO cultured melanoma cells were inoculated sc in mice there was a significant increase in tumorigenicity as compared to FL cells. Thus SMG may have supported &selected highly tumorigenic cells and it is pos sible that in addition to decreased immune function MG may alter tumor cell characteristics and invasiveness. Thus it is important to study effects of microgravity environment and its stressors using experimental tumors and SMG to understand and evaluate carcinogenic responses to true microgravity. Further studies on carcinogenic events and their mechanisms will allow us develop and formulate countermeasures and protect space travelers. Additional results will be presented. (Supported by NASA NCC8-168 grant, ADK)

  6. Effects of deuterium oxide on cell growth and vesicle speed in RBL-2H3 cells

    PubMed Central

    Triplett, Ashley R.

    2014-01-01

    For the first time we show the effects of deuterium oxide on cell growth and vesicle transport in rat basophilic leukemia (RBL-2H3) cells. RBL-2H3 cells cultured with 15 moles/L deuterium showed decreased cell growth which was attributed to cells not doubling their DNA content. Experimental observations also showed an increase in vesicle speed for cells cultured in deuterium oxide. This increase in vesicle speed was not observed in deuterium oxide cultures treated with a microtubule-destabilizing drug, suggesting that deuterium oxide affects microtubule-dependent vesicle transport. PMID:25237603

  7. Intercellular adhesion molecule-4 and CD36 are implicated in the abnormal adhesiveness of sickle cell SAD mouse erythrocytes to endothelium

    PubMed Central

    Trinh-Trang-Tan, Marie-Marcelle; Vilela-Lamego, Camilo; Picot, Julien; Wautier, Marie-Paule; Cartron, Jean-Pierre

    2010-01-01

    Background Abnormal adhesiveness of red blood cells to endothelium has been implicated in vaso-occlusive crisis of sickle cell disease. The present study examined whether the SAD mouse model exhibits the same abnormalities of red blood cell adhesion as those found in human sickle cell disease. Design and Methods The repertoire of adhesive molecules on murine erythrocytes and bEnd.3 microvascular endothelial cells was determined by flow cytometry using monoclonal antibodies or by western blotting. Adhesion was investigated in dynamic conditions and measured at different shear stresses. Results CD36, CD47 and intercellular adhesion molecular-4, but not Lutheran blood group antigen/basal cell adhesion molecule, are present on mouse mature erythrocytes. α4β1 are not expressed on SAD and wild type reticulocytes. Endothelial bEnd.3 cells express αVβ3, α4β1, CD47, vascular cell adhesion molecule-1, and Lutheran blood group antigen/basal cell adhesion molecule, but not CD36. Adhesion of SAD red cells is: (i) 2- to 3-fold higher than that of wild type red cells; (ii) further increased on platelet activating factor-activated endothelium; (iii) not stimulated by epinephrine; (iv) inhibited after treating the endothelium with a peptide reproducing one of the binding sequences of mouse intercellular adhesion molecular-4, or with mon-oclonal antibody against murine αv integrin; and (v) inhibited after pretreatment of red blood cells with anti-mouse CD36 monoclonal antibodies. The combination of treatments with intercellular adhesion molecular-4 peptide and anti-CD36 monoclonal antibodies eliminates excess adhesion of SAD red cells. The phosphorylation state of intercellular adhesion molecular-4 and CD36 is probably not involved in the over-adhesiveness of SAD erythrocytes. Conclusions Intercellular adhesion molecular-4/αvβ3 and CD36/thrombospondin interactions might contribute to the abnormally high adhesiveness of SAD red cells. The SAD mouse is a valuable animal model

  8. Thymic abnormalities and enhanced apoptosis of thymocytes and bone marrow cells in transgenic mice overexpressing Cu/Zn-superoxide dismutase: implications for Down syndrome.

    PubMed Central

    Peled-Kamar, M; Lotem, J; Okon, E; Sachs, L; Groner, Y

    1995-01-01

    The copper-zinc superoxide dismutase (CuZnSOD) gene resides on chromosome 21 and is overexpressed in Down syndrome (DS) patients. Transgenic CuZnSOD mice with elevated levels of CuZnSOD were used to determine whether, as in DS, overexpression of CuZnSOD was also associated with thymus and bone marrow abnormalities. Three independently derived transgenic CuZnSOD strains had abnormal thymi showing diminution of the cortex and loss of corticomedullary demarcation, resembling thymic defects in children with DS. Transgenic CuZnSOD mice were also more sensitive than control mice to in vivo injection of lipopolysaccharide (LPS), reflected by an earlier onset and enhanced apoptotic cell death in the thymus. This higher susceptibility to LPS-induced apoptosis was associated with an increased production of hydrogen peroxide and a higher degree of lipid peroxidation. When cultured under suboptimal concentrations of interleukin 3 or in the presence of tumour necrosis factor, bone marrow cells from transgenic CuZnSOD mice produced 2- to 3-fold less granulocyte and macrophage colonies than control. The results indicate that transgenic CuZnSOD mice have certain thymus and bone marrow abnormalities which are similar to those found in DS patients, and that the defects are presumably due to an increased oxidative damage resulting in enhanced cell death by apoptosis. Images PMID:7588627

  9. Monosomal karyotype predicts poor survival after allogeneic stem cell transplantation in chromosome 7 abnormal myelodysplastic syndrome and secondary acute myeloid leukemia.

    PubMed

    van Gelder, M; de Wreede, L C; Schetelig, J; van Biezen, A; Volin, L; Maertens, J; Robin, M; Petersen, E; de Witte, T; Kröger, N

    2013-04-01

    Treatment algorithms for poor cytogenetic-risk myelodysplastic syndrome (MDS), defined by chromosome 7 abnormalities or complex karyotype (CK), include allogeneic stem cell transplantation (alloSCT). We studied outcome of alloSCT in chromosome 7 abnormal MDS patients as this data are scarce in literature. We specifically focused on the impact of the extra presence of CK and monosomal karyotype (MK). The European Group for Blood and Marrow Transplantation database contained data on 277 adult MDS patients with a chromosome 7 abnormality treated with alloSCT. Median age at alloSCT was 45 years. Median follow-up of patients alive was 5 years. Five-year progression-free survival (PFS) and overall survival (OS) were 22% and 28%, respectively. In multivariate analysis, statistically significant predictors for worse PFS were higher MDS stages treated, but not in complete remission (CR) (hazards ratio (HR) 1.7), and the presence of CK (HR 1.5) or MK (HR 1.8). Negative predictive factors for OS were higher MDS stages treated, but not in CR (HR 1.8), and the presence of CK (HR 1.6) or MK (HR 1.7). By means of the cross-validated log partial likelihood, MK showed to have a better predictive value than CK. The results are relevant when considering alloSCT for higher-stage MDS patients having MK including a chromosome 7 abnormality.

  10. RF-EMF exposure at 1800 MHz did not elicit DNA damage or abnormal cellular behaviors in different neurogenic cells.

    PubMed

    Su, Liling; Wei, Xiaoxia; Xu, Zhengping; Chen, Guangdi

    2017-04-01

    Despite many years of studies, the debate on genotoxic effects of radiofrequency electromagnetic fields (RF-EMF) continues. To systematically evaluate genotoxicity of RF-EMF, this study examined effects of RF-EMF on DNA damage and cellular behavior in different neurogenic cells. Neurogenic A172, U251, and SH-SY5Y cells were intermittently (5 min on/10 min off) exposed to 1800 MHz RF-EMF at an average specific absorption rate (SAR) of 4.0 W/kg for 1, 6, or 24 h. DNA damage was evaluated by quantification of γH2AX foci, an early marker of DNA double-strand breaks. Cell cycle progression, cell proliferation, and cell viability were examined by flow cytometry, hemocytometer, and cell counting kit-8 assay, respectively. Results showed that exposure to RF-EMF at an SAR of 4.0 W/kg neither significantly induced γH2AX foci formation in A172, U251, or SH-SY5Y cells, nor resulted in abnormal cell cycle progression, cell proliferation, or cell viability. Furthermore, prolonged incubation of these cells for up to 48 h after exposure did not significantly affect cellular behavior. Our data suggest that 1800 MHz RF-EMF exposure at 4.0 W/kg is unlikely to elicit DNA damage or abnormal cellular behaviors in neurogenic cells. Bioelectromagnetics. 38:175-185, 2017. © 2016 Wiley Periodicals, Inc.

  11. Rapamycin promotes Schwann cell migration and nerve growth factor secretion

    PubMed Central

    Liu, Fang; Zhang, Haiwei; Zhang, Kaiming; Wang, Xinyu; Li, Shipu; Yin, Yixia

    2014-01-01

    Rapamycin, similar to FK506, can promote neural regeneration in vitro. We assumed that the mechanisms of action of rapamycin and FK506 in promoting peripheral nerve regeneration were similar. This study compared the effects of different concentrations of rapamycin and FK506 on Schwann cells and investigated effects and mechanisms of rapamycin on improving peripheral nerve regeneration. Results demonstrated that the lowest rapamycin concentration (1.53 nmol/L) more significantly promoted Schwann cell migration than the highest FK506 concentration (100μmol/L). Rapamycin promoted the secretion of nerve growth factors and upregulated growth-associated protein 43 expression in Schwann cells, but did not significantly affect Schwann cell proliferation. Therefore, rapamycin has potential application in peripheral nerve regeneration therapy. PMID:25206862

  12. Soliton growth-signal transduction in topologically quantized T cells

    NASA Astrophysics Data System (ADS)

    Matsson, Leif

    1993-09-01

    A model for growth-signal transduction of the T cell and its growth factor, interleukin-2, is presented. It is obtained as a generalization of the usual rate equation and is founded on the observation that a definite number of receptor occupations must take place in order to promote transition to the S phase and subsequent DNA replication. The generalized rate equation is identified as the equation of motion of a Lagrangian field theory of Ginzburg-Landau (Goldstone) type. However it is not an ad hoc model but is a microscopic theory of the interaction of interleukin-2 and its receptor. The topological quantum number of the model is related to the observed definite number of receptor occupations required to elicit growth-signal transduction. Individual receptor quanta, up to this limit, are subjected to a type of Bose condensation. This collective excitation constitutes the growth signal in the form of a topological kink soliton which is then launched by the next potential receptor occupation that makes the interaction repulsive. The model provides a possible long-absent explanation of the triggering mechanism for growth-signal transduction by means of the ambivalent interaction, which switches sign after a definite number of receptor occupations. Moreover, it offers an explanation of how Nature screens out fractional signals in the growth-signal-transduction process of T cells. Although the model is derived for assumed point-like cells and certain other restrictions, the obtained dose-response curves are in striking agreement with proliferation data from studies of both the leukemic T cell line MLA-144 from gibbon ape and normal human T cells in, and without, the presence of monoclonal anti-Tac antibodies.

  13. Occurrence of molecular abnormalities of cell cycle in L132 cells after in vitro short-term exposure to air pollution PM(2.5).

    PubMed

    Abbas, Imane; Garçon, Guillaume; Saint-Georges, Françoise; Billet, Sylvain; Verdin, Anthony; Gosset, Pierre; Mulliez, Philippe; Shirali, Pirouz

    2010-12-05

    To improve the knowledge of the underlying mechanisms implying in air pollution Particulate Matter (PM)-induced lung toxicity in humans, we were interested in the sequential occurrence of molecular abnormalities from TP53-RB gene signaling pathway activation in the L132 target human lung epithelial cell model. The most toxicologically relevant physical and chemical characteristics of air pollution PM(2.5) collected in Dunkerque, a French highly-industrialized sea-side city, were determined. L132 cells were exposed during 24, 48 and 72h to Dunkerque City's PM(2.5) (i.e. Lethal Concentration (LC)(10)=18.84μgPM/mL or 5.02μgPM/cm(2); LC(50)=75.36μgPM/mL or 20.10μgPM/cm(2)), TiO(2) and desorbed PM (i.e. dPM; EqLC(10)=15.42μg/mL or 4.11μgPM/cm(2); EqLC(50)=61.71μg/mL or 16.46μgPM/cm(2)), benzene (7μM) or Benzo[a]Pyrene (B[a]P; 1μM). Dunkerque City's PM(2.5) altered the gene expression and/or the protein concentration of several key cell cycle controllers from TP53-RB gene signaling pathway (i.e. P53; BCL2; P21; cyclin D1, cyclin-dependent kinase 1; retinoblastoma protein) in L132 cells, thereby leading to the occurrence of cell proliferation and apoptosis together. The activation of the critical cell cycle controllers under study might be related to PM-induced oxidative stress, through the possible involvement of covalent metals in redox systems, the metabolic activation of organic chemicals by enzyme-catalyzed reactions, and phagocytosis. Taken together, these results might ask the critical question whether there is a balance or, in contrast, rather an imbalance between the cell proliferation and the apoptosis occurring in PM-exposed L132 cells, with possible consequences in term of PM-induced lung tumorgenesis.

  14. Estrogens and Insulin-Like Growth Factor 1 Modulate Neoplastic Cell Growth in Human Cholangiocarcinoma

    PubMed Central

    Alvaro, Domenico; Barbaro, Barbara; Franchitto, Antonio; Onori, Paolo; Glaser, Shannon S.; Alpini, Gianfranco; Francis, Heather; Marucci, Luca; Sterpetti, Paola; Ginanni-Corradini, Stefano; Onetti Muda, Andrea; Dostal, David E.; De Santis, Adriano; Attili, Adolfo F.; Benedetti, Antonio; Gaudio, Eugenio

    2006-01-01

    We investigated the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF-1), and IGF-1R (receptor) in human cholangiocarcinoma and cholangiocarcinoma cell lines (HuH-28, TFK-1, Mz-ChA-1), evaluating the role of estrogens and IGF-1 in the modulation of neoplastic cell growth. ER-α, ER-β, IGF-1, and IGF-1R were expressed (immunohistochemistry) in all biopsies (18 of 18) of intrahepatic cholangiocarcinoma. ER-α was expressed (Western blot) only by the HuH-28 cell line (intrahepatic cholangiocarcinoma), whereas ER-β, IGF-1, and IGF-1R were expressed in the three cell lines examined. In serum-deprived HuH-28 cells, serum readmission induced stimulation of cell proliferation that was inhibited by ER and IGF-1R antagonists. 17β-Estradiol and IGF-1 stimulated proliferation of HuH-28 cells to a similar extent to that of MCF7 (breast cancer) but greater than that of TFK-1 and Mz-ChA-1, inhibiting apoptosis and exerting additive effects. These effects of 17β-estradiol and IGF-1 were associated with enhanced protein expression of ER-α, phosphorylated (p)-ERK1/2 and pAKT but with decreased expression of ER-β. Finally, transfection of IGF-1R anti-sense oligonucleotides in HuH-28 cells markedly decreased cell proliferation. In conclusion, human intrahepatic cholangiocarcinomas express receptors for estrogens and IGF-1, which cooperate in the modulation of cell growth and apoptosis. Modulation of ER and IGF-1R could represent a strategy for the management of cholangiocarcinoma. PMID:16936263

  15. Implications of Stem Cell Growth Regulation for Breast Cancer

    DTIC Science & Technology

    2007-06-01

    during development and maintenance of the gland could determine the growth potential, differentiation and senescence of the mammary epithelial cell...described the fractions of mature and stem/progenitor cells in developing and adult mammary gland, that took into account well-understood biological...aging and senescence of the mammary population. Mice with a null mutation in syndecan-1 (Sdc1) resist tumor development in a number of different

  16. FH535 inhibited migration and growth of breast cancer cells.

    PubMed

    Iida, Joji; Dorchak, Jesse; Lehman, John R; Clancy, Rebecca; Luo, Chunqing; Chen, Yaqin; Somiari, Stella; Ellsworth, Rachel E; Hu, Hai; Mural, Richard J; Shriver, Craig D

    2012-01-01

    There is substantial evidence indicating that the WNT signaling pathway is activated in various cancer cell types including breast cancer. Previous studies reported that FH535, a small molecule inhibitor of the WNT signaling pathway, decreased growth of cancer cells but not normal fibroblasts, suggesting this pathway plays a role in tumor progression and metastasis. In this study, we tested FH535 as a potential inhibitor for malignant phenotypes of breast cancer cells including migration, invasion, and growth. FH535 significantly inhibited growth, migration, and invasion of triple negative (TN) breast cancer cell lines (MDA-MB231 and HCC38) in vitro. We demonstrate that FH535 was a potent growth inhibitor for TN breast cancer cell lines (HCC38 and MDA-MB-231) but not for other, non-TN breast cancer cell lines (MCF-7, T47D or SK-Br3) when cultured in three dimensional (3D) type I collagen gels. Western blotting analyses suggest that treatment of MDA-MB-231 cells with FH535 markedly inhibited the expression of NEDD9 but not activations of FAK, Src, or downstream targets such as p38 and Erk1/2. We demonstrated that NEDD9 was specifically associated with CSPG4 but not with β1 integrin or CD44 in MDA-MB-231 cells. Analyses of gene expression profiles in breast cancer tissues suggest that CSPG4 expression is higher in Basal-type breast cancers, many of which are TN, than any other subtypes. These results suggest not only a mechanism for migration and invasion involving the canonical WNT-signaling pathways but also novel strategies for treating patients who develop TN breast cancer.

  17. Metabolic pathways promoting cancer cell survival and growth.

    PubMed

    Boroughs, Lindsey K; DeBerardinis, Ralph J

    2015-04-01

    Activation of oncogenes and loss of tumour suppressors promote metabolic reprogramming in cancer, resulting in enhanced nutrient uptake to supply energetic and biosynthetic pathways. However, nutrient limitations within solid tumours may require that malignant cells exhibit metabolic flexibility to sustain growth and survival. Here, we highlight these adaptive mechanisms and also discuss emerging approaches to probe tumour metabolism in vivo and their potential to expand the metabolic repertoire of malignant cells even further.

  18. Targeting the erythropoietin receptor on glioma cells reduces tumour growth

    SciTech Connect

    Peres, Elodie A.; Valable, Samuel; Guillamo, Jean-Sebastien; Marteau, Lena; Bernaudin, Jean-Francois; Roussel, Simon; Lechapt-Zalcman, Emmanuele; Bernaudin, Myriam; Petit, Edwige

    2011-10-01

    Hypoxia has been shown to be one of the major events involved in EPO expression. Accordingly, EPO might be expressed by cerebral neoplastic cells, especially in glioblastoma, known to be highly hypoxic tumours. The expression of EPOR has been described in glioma cells. However, data from the literature remain descriptive and controversial. On the basis of an endogenous source of EPO in the brain, we have focused on a potential role of EPOR in brain tumour growth. In the present study, with complementary approaches to target EPO/EPOR signalling, we demonstrate the presence of a functional EPO/EPOR system on glioma cells leading to the activation of the ERK pathway. This EPO/EPOR system is involved in glioma cell proliferation in vitro. In vivo, we show that the down-regulation of EPOR expression on glioma cells reduces tumour growth and enhances animal survival. Our results support the hypothesis that EPOR signalling in tumour cells is involved in the control of glioma growth.

  19. The TIP GROWTH DEFECTIVE1 S-acyl transferase regulates plant cell growth in Arabidopsis.

    PubMed

    Hemsley, Piers A; Kemp, Alison C; Grierson, Claire S

    2005-09-01

    TIP GROWTH DEFECTIVE1 (TIP1) of Arabidopsis thaliana affects cell growth throughout the plant and has a particularly strong effect on root hair growth. We have identified TIP1 by map-based cloning and complementation of the mutant phenotype. TIP1 encodes an ankyrin repeat protein with a DHHC Cys-rich domain that is expressed in roots, leaves, inflorescence stems, and floral tissue. Two homologues of TIP1 in yeast (Saccharomyces cerevisiae) and human (Homo sapiens) have been shown to have S-acyl transferase (also known as palmitoyl transferase) activity. S-acylation is a reversible hydrophobic protein modification that offers swift, flexible control of protein hydrophobicity and affects protein association with membranes, signal transduction, and vesicle trafficking within cells. We show that TIP1 binds the acyl group palmitate, that it can rescue the morphological, temperature sensitivity, and yeast casein kinase2 localization defects of the yeast S-acyl transferase mutant akr1Delta, and that inhibition of acylation in wild-type Arabidopsis roots reproduces the Tip1- mutant phenotype. Our results demonstrate that S-acylation is essential for normal plant cell growth and identify a plant S-acyl transferase, an essential research tool if we are to understand how this important, reversible lipid modification operates in plant cells.

  20. Regulation of skeletal muscle stem cells by fibroblast growth factors.

    PubMed

    Pawlikowski, Bradley; Vogler, Thomas Orion; Gadek, Katherine; Olwin, Bradley B

    2017-03-01

    Fibroblast growth factors (FGFs) are essential for self-renewal of skeletal muscle stem cells (satellite cells) and required for maintenance and repair of skeletal muscle. Satellite cells express high levels of FGF receptors 1 and 4, low levels of FGF receptor 3, and little or no detectable FGF receptor 2. Of the multiple FGFs that influence satellite cell function in culture, FGF2 and FGF6 are the only members that regulate satellite cell function in vivo by activating ERK MAPK, p38α/β MAPKs, PI3 kinase, PLCγ and STATs. Regulation of FGF signaling is complex in satellite cells, requiring Syndecan-4, a heparan sulfate proteoglycan, as well as ß1-integrin and fibronectin. During aging, reduced responsiveness to FGF diminishes satellite cell self-renewal, leading to impaired skeletal muscle regeneration and depletion of satellite cells. Mislocalization of ß1-integrin, reductions in fibronectin, and alterations in heparan sulfate content all contribute to reduced FGF responsiveness in satellite cells. How these cell surface proteins regulate satellite cell self-renewal is incompletely understood. Here we summarize the current knowledge, highlighting the role(s) for FGF signaling in skeletal muscle regeneration, satellite cell behavior, and age-induced muscle wasting. Developmental Dynamics, 2017. © 2017 Wiley Periodicals, Inc.

  1. Modeling the effect of insulin-like growth factor-1 on human cell growth.

    PubMed

    Phillips, Gemma M A; Shorten, Paul R; Wake, Graeme C; Guan, Jian

    2015-01-01

    Insulin-like growth factor-1 (IGF-1) plays a key role in human growth and development. The interactions of IGF-1 with IGF-1 receptors and IGF-1 binding proteins (IGFBPs) regulate IGF-1 function. Recent research suggests that a metabolite of IGF-1, cyclo-glycyl-proline (cGP), has a role in regulating IGF-1 homeostasis. A component of this interaction is believed to be the competitive binding of IGF-1 and cGP to IGFBPs. In this paper we describe a mathematical model of the interaction between IGF-1 and cGP on human cell growth. The model can be used to understand the interaction between IGF-1, IGFBPs, cGP and IGF-1 receptors along with the kinetics of cell growth. An explicit model of the known interactions between IGF-1, cGP, IGFBPs, IGF-1 receptors explained a large portion of the variance in cell growth (R(2) = 0.83). An implicit model of the interactions between IGF-1, cGP, IGFBPs, IGF-1 receptors that included a hypothesized feedback of cGP on IGF-1 receptors explained nonlinear features of interaction between IGF-1 and cGP not described by the explicit model (R(2) = 0.84). The model also explained the effect of IGFBP antibody on the interaction between cGP and IGF-1 (R(2) = 0.78). This demonstrates that the competitive binding of IGF-1 and cGP to IGFBPs plays a large role in the interaction between IGF-1 and cGP, but that other factors potentially play a role in the interaction between cGP and IGF-1. These models can be used to predict the complex interaction between IGF-1 and cGP on human cell growth and form a basis for further research in this field.

  2. Identifying Francisella tularensis genes required for growth in host cells.

    PubMed

    Brunton, J; Steele, S; Miller, C; Lovullo, E; Taft-Benz, S; Kawula, T

    2015-08-01

    Francisella tularensis is a highly virulent Gram-negative intracellular pathogen capable of infecting a vast diversity of hosts, ranging from amoebae to humans. A hallmark of F. tularensis virulence is its ability to quickly grow to high densities within a diverse set of host cells, including, but not limited to, macrophages and epithelial cells. We developed a luminescence reporter system to facilitate a large-scale transposon mutagenesis screen to identify genes required for growth in macrophage and epithelial cell lines. We screened 7,454 individual mutants, 269 of which exhibited reduced intracellular growth. Transposon insertions in the 269 growth-defective strains mapped to 68 different genes. FTT_0924, a gene of unknown function but highly conserved among Francisella species, was identified in this screen to be defective for intracellular growth within both macrophage and epithelial cell lines. FTT_0924 was required for full Schu S4 virulence in a murine pulmonary infection model. The ΔFTT_0924 mutant bacterial membrane is permeable when replicating in hypotonic solution and within macrophages, resulting in strongly reduced viability. The permeability and reduced viability were rescued when the mutant was grown in a hypertonic solution, indicating that FTT_0924 is required for resisting osmotic stress. The ΔFTT_0924 mutant was also significantly more sensitive to β-lactam antibiotics than Schu S4. Taken together, the data strongly suggest that FTT_0924 is required for maintaining peptidoglycan integrity and virulence.

  3. How to Foster an Understanding of Growth and Cell Division

    ERIC Educational Resources Information Center

    Kruger, Dirk; Fleige, Jennifer; Riemeier, Tanja

    2006-01-01

    The study presents the frequencies of students' conceptions of growth and cell division before and after one hour of instruction. The investigation supplements qualitative results by directing attention to those conceptions which might occur most frequently to students: teachers can then concentrate their preparation on practical requirements. A…

  4. Fluoxetine regulates cell growth inhibition of interferon-α.

    PubMed

    Lin, Yu-Min; Yu, Bu-Chin; Chiu, Wen-Tai; Sun, Hung-Yu; Chien, Yu-Chieh; Su, Hui-Chen; Yen, Shu-Yang; Lai, Hsin-Wen; Bai, Chyi-Huey; Young, Kung-Chia; Tsao, Chiung-Wen

    2016-10-01

    Fluoxetine, a well-known anti-depression agent, may act as a chemosensitizer to assist and promote cancer therapy. However, how fluoxetine regulates cellular signaling to enhance cellular responses against tumor cell growth remains unclear. In the present study, addition of fluoxetine promoted growth inhibition of interferon-alpha (IFN-α) in human bladder carcinoma cells but not in normal uroepithelial cells through lessening the IFN-α-induced apoptosis but switching to cause G1 arrest, and maintaining the IFN-α-mediated reduction in G2/M phase. Activations and signal transducer and transactivator (STAT)-1 and peroxisome proliferator-activated receptor alpha (PPAR-α) were involved in this process. Chemical inhibitions of STAT-1 or PPAR-α partially rescued bladder carcinoma cells from IFN-α-mediated growth inhibition via blockades of G1 arrest, cyclin D1 reduction, p53 downregulation and p27 upregulation in the presence of fluoxetine. However, the functions of both proteins were not involved in the control of fluoxetine over apoptosis and maintained the declined G2/M phase of IFN-α. These results indicated that activation of PPAR-α and STAT-1 participated, at least in part, in growth inhibition of IFN-α in the presence of fluoxetine.

  5. Identifying Francisella tularensis Genes Required for Growth in Host Cells

    PubMed Central

    Brunton, J.; Steele, S.; Miller, C.; Lovullo, E.; Taft-Benz, S.

    2015-01-01

    Francisella tularensis is a highly virulent Gram-negative intracellular pathogen capable of infecting a vast diversity of hosts, ranging from amoebae to humans. A hallmark of F. tularensis virulence is its ability to quickly grow to high densities within a diverse set of host cells, including, but not limited to, macrophages and epithelial cells. We developed a luminescence reporter system to facilitate a large-scale transposon mutagenesis screen to identify genes required for growth in macrophage and epithelial cell lines. We screened 7,454 individual mutants, 269 of which exhibited reduced intracellular growth. Transposon insertions in the 269 growth-defective strains mapped to 68 different genes. FTT_0924, a gene of unknown function but highly conserved among Francisella species, was identified in this screen to be defective for intracellular growth within both macrophage and epithelial cell lines. FTT_0924 was required for full Schu S4 virulence in a murine pulmonary infection model. The ΔFTT_0924 mutant bacterial membrane is permeable when replicating in hypotonic solution and within macrophages, resulting in strongly reduced viability. The permeability and reduced viability were rescued when the mutant was grown in a hypertonic solution, indicating that FTT_0924 is required for resisting osmotic stress. The ΔFTT_0924 mutant was also significantly more sensitive to β-lactam antibiotics than Schu S4. Taken together, the data strongly suggest that FTT_0924 is required for maintaining peptidoglycan integrity and virulence. PMID:25987704

  6. Monitoring of lung tumour cell growth in artificial membranes.

    PubMed

    Yang, Ying; Sulé-Suso, Josep; El Haj, Alicia J; Hoban, Paul R; Wang, Ruikang

    2004-10-15

    Morbidity of many tumour types is associated with invasion of tumour cells through the basement membrane and subsequent metastasis to vital organs. Tumour invasion is frequently detected late on as many patients present with advanced disease. The method of detecting invasion is through conventional histological staining techniques, which are time consuming and require processing of the sample. This can affect interpretation of the results. In this study, a new imaging technique, optical coherence tomography (OCT), was used to monitor lung tumour cell growth in two artificial membranes composed of either collagen type I or Matrigel. In parallel, standard histological section analysis was performed to validate the accuracy of the monitoring by OCT. Cross-sectional images from OCT revealed that lung tumour cells infiltrated only when low cell seeding density (5 x 10(5)) and low collagen concentration (1.5 mg/ml) were combined. The cells could be easily differentiated from the artificial membranes and appeared as either a brighter layer on the top of the membrane or brighter foci embedded within the darker membrane. These cell-membrane morphologies matched remarkably to the standard histological section images. Our results suggest that OCT has a great potential to become a useful tool for fast and robust imaging of cell growth in vivo and as a potential assessment of cell invasion.

  7. Electrical impedance characterization of cell growth on interdigitated microelectrode array.

    PubMed

    Lee, Gi Hyun; Pyun, Jae-Chul; Cho, Sungbo

    2014-11-01

    Electrical cell-substrate impedance sensing is a method for label-free and real-time monitoring of biological cells, which has been increasingly employed in the diagnostic and pharmaceutical industries. In this study, we fabricated an interdigitated electrode (IDE) array, which consists of 10 fingers, with a length of 1.2 mm, width of 50 μm, spacing of 50 μm, and thickness of 75 nm. The impedance spectra of the fabricated IDE were measured without or with cells in the frequency range of 100 Hz to 100 kHz using a lock-in amplifier based system and characterized by equivalent circuit modelling. Regarding the total impedance as a series resistance (R) and capacitance (C) model, R and C parameters were traced at a selected frequency during cell growth. It was able to monitor cell adherence and proliferation dependent on the behaviours and characteristics of cells on the fabricated IDE array by monitoring RC parameters. The degree of changes in RC value during cell growth was dependent on the type of cells used.

  8. Cell growth and function on calcium phosphate reinforced chitosan scaffolds.

    PubMed

    Zhang, Yong; Zhang, Miqin

    2004-03-01

    Macroporous chitosan scaffolds reinforced by calcium phosphate powders such as hydroxyapatite (HA) or calcium phosphate invert glass were fabricated using a thermally induced phase separation technique. Human osteoblast-like MG63 cells were cultured on the composite scaffolds for up to 11 days, and the cell growth and function were analyzed. The cell growth is much faster on the chitosan/HA scaffolds incorporated with the glass (CHG) than on the chitosan/HA scaffold without the glass (CH). The total protein content of cells were quantified and increased over time on both composites (CH, CHG) but was significantly higher on CHG after 7 days of culture. The cells on CHG also expressed significantly higher amount of alkaline phosphatase at days 7 and 11 and osteocalcin at day 7 than those on CH. The results suggested that the addition of glass in chitosan/hydroxyapatite composite scaffolds might enhance the proliferation and osteoblastic phenotype expression of MG63 cells. However, the chitosan-matrix scaffolds did not show higher phenotype expression of MG63 cells, in comparison with the TCPS plate, probably due to the degradation of chitosan and release of acidic byproducts. Larger amount of soluble calcium phosphate invert glasses should be added into the scaffolds to prevent chitosan from fast degradation that may affect the differentiation of osteoblast cells.

  9. Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis

    PubMed Central

    Parajuli, Keshab R; Zhang, Qiuyang; Liu, Sen; Patel, Neil K; Lu, Hua; Zeng, Shelya X; Wang, Guangdi; Zhang, Changde; You, Zongbing

    2014-01-01

    Methoxyacetic acid (MAA) is a primary metabolite of ester phthalates that are used in production of consumer products and pharmaceutical products. MAA causes embryo malformation and spermatocyte death through inhibition of histone deacetylases (HDACs). Little is known about MAA’s effects on cancer cells. In this study, two immortalized human normal prostatic epithelial cell lines (RWPE-1 and pRNS-1-1) and four human prostate cancer cell lines (LNCaP, C4-2B, PC-3, and DU-145) were treated with MAA at different doses and for different time periods. Cell viability, apoptosis, and cell cycle analysis were performed using flow cytometry and chemical assays. Gene expression and binding to DNA were assessed using real-time PCR, Western blot, and chromatin immunoprecipitation analyses. We found that MAA dose-dependently inhibited prostate cancer cell growth through induction of apoptosis and cell cycle arrest at G1 phase. MAA-induced apoptosis was due to down-regulation of the anti-apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2, also named cIAP1), leading to activation of caspases 7 and 3 and turning on the downstream apoptotic events. MAA-induced cell cycle arrest (mainly G1 arrest) was due to up-regulation of p21 expression at the early time and down-regulation of cyclin-dependent kinase 4 (CDK4) and CDK2 expression at the late time. MAA up-regulated p21 expression through inhibition of HDAC activities, independently of p53/p63/p73. These findings demonstrate that MAA suppresses prostate cancer cell growth by inducing growth arrest and apoptosis, which suggests that MAA could be used as a potential therapeutic drug for prostate cancer. PMID:25606576

  10. Targeting glutamine transport to suppress melanoma cell growth.

    PubMed

    Wang, Qian; Beaumont, Kimberley A; Otte, Nicholas J; Font, Josep; Bailey, Charles G; van Geldermalsen, Michelle; Sharp, Danae M; Tiffen, Jessamy C; Ryan, Renae M; Jormakka, Mika; Haass, Nikolas K; Rasko, John E J; Holst, Jeff

    2014-09-01

    Amino acids, especially leucine and glutamine, are important for tumor cell growth, survival and metabolism. A range of different transporters deliver each specific amino acid into cells, some of which are increased in cancer. These amino acids consequently activate the mTORC1 pathway and drive cell cycle progression. The leucine transporter LAT1/4F2hc heterodimer assembles as part of a large complex with the glutamine transporter ASCT2 to transport amino acids. In this study, we show that the expression of LAT1 and ASCT2 is significantly increased in human melanoma samples and is present in both BRAF(WT) (C8161 and WM852) and BRAF(V600E) mutant (1205Lu and 451Lu) melanoma cell lines. While inhibition of LAT1 by BCH did not suppress melanoma cell growth, the ASCT2 inhibitor BenSer significantly reduced both leucine and glutamine transport in melanoma cells, leading to inhibition of mTORC1 signaling. Cell proliferation and cell cycle progression were significantly reduced in the presence of BenSer in melanoma cells in 2D and 3D cell culture. This included reduced expression of the cell cycle regulators CDK1 and UBE2C. The importance of ASCT2 expression in melanoma was confirmed by shRNA knockdown, which inhibited glutamine uptake, mTORC1 signaling and cell proliferation. Taken together, our study demonstrates that ASCT2-mediated glutamine transport is a potential therapeutic target for both BRAF(WT) and BRAF(V600E) melanoma.

  11. Paradoxical growth of Candida albicans in the presence of caspofungin is associated with multiple cell wall rearrangements and decreased virulence.

    PubMed

    Rueda, Cristina; Cuenca-Estrella, Manuel; Zaragoza, Oscar

    2014-01-01

    In the last decade, echinocandins have emerged as an important family of antifungal drugs because of their fungicidal activity against Candida spp. Echinocandins inhibit the enzyme β-1,3-d-glucan synthase, encoded by the FKS genes, and resistance to echinocandins is associated with mutations in this gene. In addition, echinocandin exposure can produce paradoxical growth, defined as the ability to grow at high antifungal concentrations but not at intermediate concentrations. In this work, we have demonstrated that paradoxical growth of Candida albicans in the presence of caspofungin is not due to antifungal degradation or instability. Media with high caspofungin concentrations recovered from wells where C. albicans showed paradoxical growth inhibited the growth of a Candida krusei reference strain. Cells exhibiting paradoxical growth at high caspofungin concentrations showed morphological changes such as enlarged size, abnormal septa, and absence of filamentation. Chitin content increased from the MIC to high caspofungin concentrations. Despite the high chitin levels, around 23% of cells died after treatment with caspofungin, indicating that chitin is required but not sufficient to protect the cells from the fungicidal effect of caspofungin. Moreover, we found that after paradoxical growth, β-1,3-glucan was exposed at the cell wall surface. Cells grown at high caspofungin concentrations had decreased virulence in the invertebrate host Galleria mellonella. Cells grown at high caspofungin concentrations also induced a proinflammatory response in murine macrophages compared to control cells. Our work highlights important aspects about fungal adaptation to caspofungin, and although this adaptation is associated with reduced virulence, the clinical implications remain to be elucidated.

  12. Rottlerin inhibits cell growth and invasion via down-regulation of Cdc20 in glioma cells

    PubMed Central

    Wang, Lixia; Hou, Yingying; Yin, Xuyuan; Su, Jingna; Zhao, Zhe; Ye, Xiantao; Zhou, Xiuxia; Zhou, Li; Wang, Zhiwei

    2016-01-01

    Rottlerin, isolated from a medicinal plant Mallotus phillippinensis, has been demonstrated to inhibit cellular growth and induce cytoxicity in glioblastoma cell lines through inhibition of calmodulin-dependent protein kinase III. Emerging evidence suggests that rottlerin exerts its antitumor activity as a protein kinase C inhibitor. Although further studies revealed that rottlerin regulated multiple signaling pathways to suppress tumor cell growth, the exact molecular insight on rottlerin-mediated tumor inhibition is not fully elucidated. In the current study, we determine the function of rottlerin on glioma cell growth, apoptosis, cell cycle, migration and invasion. We found that rottlerin inhibited cell growth, migration, invasion, but induced apoptosis and cell cycle arrest. Mechanistically, the expression of Cdc20 oncoprotein was measured by the RT-PCR and Western blot analysis in glioma cells treated with rottlerin. We observed that rottlerin significantly inhibited the expression of Cdc20 in glioma cells, implying that Cdc20 could be a novel target of rottlerin. In line with this, over-expression of Cdc20 decreased rottlerin-induced cell growth inhibition and apoptosis, whereas down-regulation of Cdc20 by its shRNA promotes rottlerin-induced anti-tumor activity. Our findings indicted that rottlerin could exert its tumor suppressive function by inhibiting Cdc20 pathway which is constitutively active in glioma cells. Therefore, down-regulation of Cdc20 by rottlerin could be a promising therapeutic strategy for the treatment of glioma. PMID:27626499

  13. Suppressing The Growth Of Dendrites In Secondary Li Cells

    NASA Technical Reports Server (NTRS)

    Davies, Evan D.; Perrone, David E.; Shen, David H.

    1996-01-01

    Proposed technique for suppressing growth of lithium dendrites in rechargeable lithium electrochemical power cells involves periodic interruption of steady charging current with short, high-current discharge pulses. Technique applicable to lithium cells of several different types, including Li/TiS(2), Li/NbSe(3), Li/CoO(2), Li/MoS(2), Li/Vo(x), and Li/MnO(2). Cells candidates for use in spacecraft, military, communications, automotive, and other applications in which high-energy-density rechargeable batteries needed.

  14. Two-dimensional diffusion limited system for cell growth

    SciTech Connect

    Hlatky, L.

    1985-11-01

    A new cell system, the ''sandwich'' system, was developed to supplement multicellular spheroids as tumor analogues. Sandwiches allow new experimental approaches to questions of diffusion, cell cycle effects and radiation resistance in tumors. In this thesis the method for setting up sandwiches is described both theoretically and experimentally followed by its use in x-ray irradiation studies. In the sandwich system, cells are grown in a narrow gap between two glass slides. Where nutrients and waste products can move into or out of the local environment of the cells only by diffusing through the narrow gap between the slides. Due to the competition between cells, self-created gradients of nutrients and metabolic products are set up resulting in a layer of cells which resembles a living spheroid cross section. Unlike the cells of the spheroid, however, cells in all regions of the sandwich are visible. Therefore, the relative sizes of the regions and their time-dependent growth can be monitored visually without fixation or sectioning. The oxygen and nutrient gradients can be ''turned off'' at any time without disrupting the spatial arrangement of the cells by removing the top slide of the assembly and subsequently turned back on if desired. Removal of the top slide also provides access to all the cells, including those near the necrotic center, of the sandwich. The cells can then be removed for analysis outside the sandwich system. 61 refs., 17 figs.

  15. The intellectual capacity of patients with Laron syndrome (LS) differs with various molecular defects of the growth hormone receptor gene. Correlation with CNS abnormalities.

    PubMed

    Shevah, O; Kornreich, L; Galatzer, A; Laron, Z

    2005-12-01

    The correlation between the molecular defects of the GH receptor (R), psychosocial development and brain abnormalities were evaluated in 10 patients with Laron syndrome (LS), in whom all data were available. The findings revealed that the intelligence quotient (IQ) and abnormalities in the brain of the patients with LS differ with various molecular defects of the GH-receptor. The most severe mental deficits and brain pathology occurred in patients with 3, 5, 6 exon deletion. Patients with point mutations in exons 2, 4 and 7 presented various degrees of medium to mild CNS abnormalities that correlated with the IQ. Notably, the patient with the E180 splice mutation in exon 6 had a normal IQ, which fits the report on normal IQ in a large Ecuadorian cohort with the same mutation. This is the first report to support a correlation between IQ, brain abnormalities and localization of the molecular defects in the GH-R gene. As all patients with LS are IGF-I-deficient, it must be assumed that other as yet unknown factors related to the molecular defects in the GH-R are the major cause of the differences in intellect and brain abnormalities.

  16. Automated inference procedure for the determination of cell growth parameters

    NASA Astrophysics Data System (ADS)

    Harris, Edouard A.; Koh, Eun Jee; Moffat, Jason; McMillen, David R.

    2016-01-01

    The growth rate and carrying capacity of a cell population are key to the characterization of the population's viability and to the quantification of its responses to perturbations such as drug treatments. Accurate estimation of these parameters necessitates careful analysis. Here, we present a rigorous mathematical approach for the robust analysis of cell count data, in which all the experimental stages of the cell counting process are investigated in detail with the machinery of Bayesian probability theory. We advance a flexible theoretical framework that permits accurate estimates of the growth parameters of cell populations and of the logical correlations between them. Moreover, our approach naturally produces an objective metric of avoidable experimental error, which may be tracked over time in a laboratory to detect instrumentation failures or lapses in protocol. We apply our method to the analysis of cell count data in the context of a logistic growth model by means of a user-friendly computer program that automates this analysis, and present some samples of its output. Finally, we note that a traditional least squares fit can provide misleading estimates of parameter values, because it ignores available information with regard to the way in which the data have actually been collected.

  17. Human Adenomyosis Endometrium Stromal Cells Secreting More Nerve Growth Factor: Impact and Effect.

    PubMed

    Li, Yan; Zou, Shien; Xia, Xian; Zhang, Shaofen

    2015-09-01

    Abnormal expression of nerve growth factor (NGF) was found in adenomyosis (AM). We collected AM foci from patients and eutopic endometrium from non-AM controls. Endometrium stromal cells (ESCs) were cultured. Different levels of 17β-estradiol, tumor necrosis factor (TNF), CoCl2, and H2O2 were added to the culture system separately, then the expression level of NGF in ESCs was detected. After adding different levels of NGF, the proliferation and apoptosis of ESCs and aromatase expression were detected. We found that 17β-estradiol promoted NGF production in AM ESCs but not in control ESCs; TNF promoted NGF production in both AM and control ESCs; and CoCl2 inhibited NGF production in control ESCs, but had no effect in AM ESCs. Nerve growth factor promoted the proliferation and synthesis of aromatase in AM ESCs. In conclusion, locally increased estrogen levels and inflammation may cause increased NGF production in the uterus of patients with AM. Nerve growth factor stimulated the proliferation and increased aromatase expression of ESCs from AM foci, suggesting NGF might contribute to the pathology and etiology of AM.

  18. The Sur7 Protein Regulates Plasma Membrane Organization and Prevents Intracellular Cell Wall Growth in Candida albicans

    PubMed Central

    Alvarez, Francisco J.; Douglas, Lois M.; Rosebrock, Adam

    2008-01-01

    The Candida albicans plasma membrane plays important roles in cell growth and as a target for antifungal drugs. Analysis of Ca-Sur7 showed that this four transmembrane domain protein localized to stable punctate patches, similar to the plasma membrane subdomains known as eisosomes or MCC that were discovered in S. cerevisiae. The localization of Ca-Sur7 depended on sphingolipid synthesis. In contrast to S. cerevisiae, a C. albicans sur7Δ mutant displayed defects in endocytosis and morphogenesis. Septins and actin were mislocalized, and cell wall synthesis was very abnormal, including long projections of cell wall into the cytoplasm. Several phenotypes of the sur7Δ mutant are similar to the effects of inhibiting β-glucan synthase, suggesting that the abnormal cell wall synthesis is related to activation of chitin synthase activity seen under stress conditions. These results expand the roles of eisosomes by demonstrating that Sur7 is needed for proper plasma membrane organization and cell wall synthesis. A conserved Cys motif in the first extracellular loop of fungal Sur7 proteins is similar to a characteristic motif of the claudin proteins that form tight junctions in animal cells, suggesting a common role for these tetraspanning membrane proteins in forming specialized plasma membrane domains. PMID:18799621

  19. Melanin or a Melanin-Like Substance Interacts with the N-Terminal Portion of Prion Protein and Inhibits Abnormal Prion Protein Formation in Prion-Infected Cells.

    PubMed

    Hamanaka, Taichi; Nishizawa, Keiko; Sakasegawa, Yuji; Oguma, Ayumi; Teruya, Kenta; Kurahashi, Hiroshi; Hara, Hideyuki; Sakaguchi, Suehiro; Doh-Ura, Katsumi

    2017-03-15

    Prion diseases are progressive fatal neurodegenerative illnesses caused by the accumulation of transmissible abnormal prion protein (PrP). To find treatments for prion diseases, we searched for substances from natural resources that inhibit abnormal PrP formation in prion-infected cells. We found that high-molecular-weight components from insect cuticle extracts reduced abnormal PrP levels. The chemical nature of these components was consistent with that of melanin. In fact, synthetic melanin produced from tyrosine or 3-hydroxy-l-tyrosine inhibited abnormal PrP formation. Melanin did not modify cellular or cell surface PrP levels, nor did it modify lipid raft or cellular cholesterol levels. Neither did it enhance autophagy or lysosomal function. Melanin was capable of interacting with PrP at two N-terminal domains. Specifically, it strongly interacted with the PrP region of amino acids 23 to 50 including a positively charged amino acid cluster and weakly interacted with the PrP octarepeat peptide region of residues 51 to 90. However, the in vitro and in vivo data were inconsistent with those of prion-infected cells. Abnormal PrP formation in protein misfolding cyclic amplification was not inhibited by melanin. Survival after prion infection was not significantly altered in albino mice or exogenously melanin-injected mice compared with that of control mice. These data suggest that melanin, a main determinant of skin color, is not likely to modify prion disease pathogenesis, even though racial differences in the incidence of human prion diseases have been reported. Thus, the findings identify an interaction between melanin and the N terminus of PrP, but the pathophysiological roles of the PrP-melanin interaction remain unclear.IMPORTANCE The N-terminal region of PrP is reportedly important for neuroprotection, neurotoxicity, and abnormal PrP formation, as this region is bound by many factors, such as metal ions, lipids, nucleic acids, antiprion compounds, and several

  20. Haematological abnormalities in mitochondrial disorders

    PubMed Central

    Finsterer, Josef; Frank, Marlies

    2015-01-01

    INTRODUCTION This study aimed to assess the kind of haematological abnormalities that are present in patients with mitochondrial disorders (MIDs) and the frequency of their occurrence. METHODS The blood cell counts of a cohort of patients with syndromic and non-syndromic MIDs were retrospectively reviewed. MIDs were classified as ‘definite’, ‘probable’ or ‘possible’ according to clinical presentation, instrumental findings, immunohistological findings on muscle biopsy, biochemical abnormalities of the respiratory chain and/or the results of genetic studies. Patients who had medical conditions other than MID that account for the haematological abnormalities were excluded. RESULTS A total of 46 patients (‘definite’ = 5; ‘probable’ = 9; ‘possible’ = 32) had haematological abnormalities attributable to MIDs. The most frequent haematological abnormality in patients with MIDs was anaemia. 27 patients had anaemia as their sole haematological problem. Anaemia was associated with thrombopenia (n = 4), thrombocytosis (n = 2), leucopenia (n = 2), and eosinophilia (n = 1). Anaemia was hypochromic and normocytic in 27 patients, hypochromic and microcytic in six patients, hyperchromic and macrocytic in two patients, and normochromic and microcytic in one patient. Among the 46 patients with a mitochondrial haematological abnormality, 78.3% had anaemia, 13.0% had thrombopenia, 8.7% had leucopenia and 8.7% had eosinophilia, alone or in combination with other haematological abnormalities. CONCLUSION MID should be considered if a patient’s abnormal blood cell counts (particularly those associated with anaemia, thrombopenia, leucopenia or eosinophilia) cannot be explained by established causes. Abnormal blood cell counts may be the sole manifestation of MID or a collateral feature of a multisystem problem. PMID:26243978

  1. Fibroblast growth factor receptor signaling is essential for lens fiber cell differentiation.

    PubMed

    Zhao, Haotian; Yang, Tianyu; Madakashira, Bhavani P; Thiels, Cornelius A; Bechtle, Chad A; Garcia, Claudia M; Zhang, Huiming; Yu, Kai; Ornitz, David M; Beebe, David C; Robinson, Michael L

    2008-06-15

    The vertebrate lens provides an excellent model to study the mechanisms that regulate terminal differentiation. Although fibroblast growth factors (FGFs) are thought to be important for lens cell differentiation, it is unclear which FGF receptors mediate these processes during different stages of lens development. Deletion of three FGF receptors (Fgfr1-3) early in lens development demonstrated that expression of only a single allele of Fgfr2 or Fgfr3 was sufficient for grossly normal lens development, while mice possessing only a single Fgfr1 allele developed cataracts and microphthalmia. Profound defects were observed in lenses lacking all three Fgfrs. These included lack of fiber cell elongation, abnormal proliferation in prospective lens fiber cells, reduced expression of the cell cycle inhibitors p27(kip1) and p57(kip2), increased apoptosis and aberrant or reduced expression of Prox1, Pax6, c-Maf, E-cadherin and alpha-, beta- and gamma-crystallins. Therefore, while signaling by FGF receptors is essential for lens fiber differentiation, different FGF receptors function redundantly.

  2. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth muscle cell survival patterns to promote pulmonary arterial hypertension.

    PubMed

    Aghamohammadzadeh, Reza; Zhang, Ying-Yi; Stephens, Thomas E; Arons, Elena; Zaman, Paula; Polach, Kevin J; Matar, Majed; Yung, Lai-Ming; Yu, Paul B; Bowman, Frederick P; Opotowsky, Alexander R; Waxman, Aaron B; Loscalzo, Joseph; Leopold, Jane A; Maron, Bradley A

    2016-07-01

    Activation of the mammalian target of rapamycin complex 1 (mTORC1) subunit Raptor induces cell growth and is a downstream target of Akt. Elevated levels of aldosterone activate Akt, and, in pulmonary arterial hypertension (PAH), correlate with pulmonary arteriole thickening, which suggests that mTORC1 regulation by aldosterone may mediate adverse pulmonary vascular remodeling. We hypothesized that aldosterone-Raptor signaling induces abnormal pulmonary artery smooth muscle cell (PASMC) survival patterns to promote PAH. Remodeled pulmonary arterioles from SU-5416/hypoxia-PAH rats and monocrotaline-PAH rats with hyperaldosteronism expressed increased levels of the Raptor target, p70S6K, which provided a basis for investigating aldosterone-Raptor signaling in human PASMCs. Aldosterone (10(-9) to 10(-7) M) increased Akt/mTOR/Raptor to activate p70S6K and increase proliferation, viability, and apoptosis resistance in PASMCs. In PASMCs transfected with Raptor-small interfering RNA or treated with spironolactone/eplerenone, aldosterone or pulmonary arterial plasma from patients with PAH failed to increase p70S6K activation or to induce cell survival in vitro Optimal inhibition of pulmonary arteriole Raptor was achieved by treatment with Staramine-monomethoxy polyethylene glycol that was formulated with Raptor-small interfering RNA plus spironolactone in vivo, which decreased arteriole muscularization and pulmonary hypertension in 2 experimental animal models of PAH in vivo Up-regulation of mTORC1 by aldosterone is a critical pathobiologic mechanism that controls PASMC survival to promote hypertrophic vascular remodeling and PAH.-Aghamohammadzadeh, R., Zhang, Y.-Y., Stephens, T. E., Arons, E., Zaman, P., Polach, K. J., Matar, M., Yung, L.-M., Yu, P. B., Bowman, F. P., Opotowsky, A. R., Waxman, A. B., Loscalzo, J., Leopold, J. A., Maron, B. A. Up-regulation of the mammalian target of rapamycin complex 1 subunit Raptor by aldosterone induces abnormal pulmonary artery smooth

  3. Adaptation of Chinese hamster ovary cells to low culture temperature: cell growth and recombinant protein production.

    PubMed

    Yoon, Sung Kwan; Hong, Jong Kwang; Choo, Seung Ho; Song, Ji Yong; Park, Hong Woo; Lee, Gyun Min

    2006-04-20

    Recombinant Chinese hamster ovary (rCHO) cells producing erythropoietin (EPO) and rCHO cells producing follicle-stimulating hormone (FSH) showed a significant increase in specific productivity (q) when grown at 32 degrees C compared to 37 degrees C. However, low culture temperature suppressed cell growth, and therefore, did not increase volumetric productivity as much as q. In an attempt to increase the volumetric productivity through improvement of hypothermic growth, EPO producing rCHO (CHO-EPO) cells and FSH producing rCHO (CHO-FSH) cells were adapted at 32 degrees C in a repeated batch mode using spinner flasks. Cell growth of both CHO-EPO and CHO-FSH gradually improved during adaptation at 32 degrees C. Specific growth rates of CHO-EPO and CHO-FSH cells at 32 degrees C, through adaptation, were increased by 73% and 20%, respectively. During adaptation at 32 degrees C, mRNA levels of cold-inducible RNA-binding protein (CIRP) of both rCHO cell lines did not change significantly, suggesting that CIRP expression may not be the only cause for growth suppression at low culture temperature. Unlike cell growth, the recombinant protein production of both rCHO cell lines was not increased during adaptation due to decreased specific productivities. The specific EPO productivity and specific FSH productivity were decreased by 49% and 22%, respectively. Southern blot analyses showed that the decreased specific productivities were not due to the loss of foreign gene copies. Taken together, improvement of hypothermic cell growth by adaptation does not appear to be applicable for enhanced recombinant protein production, since specific productivity decreases during adaptation to the low culture temperature.

  4. CD200-expressing human basal cell carcinoma cells initiate tumor growth.

    PubMed

    Colmont, Chantal S; Benketah, Antisar; Reed, Simon H; Hawk, Nga V; Telford, William G; Ohyama, Manabu; Udey, Mark C; Yee, Carole L; Vogel, Jonathan C; Patel, Girish K

    2013-01-22

    Smoothened antagonists directly target the genetic basis of human basal cell carcinoma (BCC), the most common of all cancers. These drugs inhibit BCC growth, but they are not curative. Although BCC cells are monomorphic, immunofluorescence microscopy reveals a complex hierarchical pattern of growth with inward differentiation along hair follicle lineages. Most BCC cells express the transcription factor KLF4 and are committed to terminal differentiation. A small CD200(+) CD45(-) BCC subpopulation that represents 1.63 ± 1.11% of all BCC cells resides in small clusters at the tumor periphery. By using reproducible in vivo xenograft growth assays, we determined that tumor initiating cell frequencies approximate one per 1.5 million unsorted BCC cells. The CD200(+) CD45(-) BCC subpopulation recreated BCC tumor growth in vivo with typical histological architecture and expression of sonic hedgehog-regulated genes. Reproducible in vivo BCC growth was achieved with as few as 10,000 CD200(+) CD45(-) cells, representing ~1,500-fold enrichment. CD200(-) CD45(-) BCC cells were unable to form tumors. These findings establish a platform to study the effects of Smoothened antagonists on BCC tumor initiating cell and also suggest that currently available anti-CD200 therapy be considered, either as monotherapy or an adjunct to Smoothened antagonists, in the treatment of inoperable BCC.

  5. Ponicidin Inhibits Monocytic Leukemia Cell Growth by Induction of Apoptosis

    PubMed Central

    Liu, Jia-Jun; Zhang, Yong; Guang, Wei-Bin; Yang, Hong-Zhi; Lin, Dong-Jun; Xiao, Ruo-Zhi

    2008-01-01

    In this study two monocytic leukemia cell lines, U937 and THP-1 cells, were used to investigate the anti-proliferation effects caused by ponicidin. Cell viability was measured by an MTT assay. Cell apoptosis was assessed by flow cytometry as well as DNA fragmentation analysis. Cell morphology was observed using an inverted microscope and Hoechst 33258 staining. RT-PCR and Western blot analysis were used to detect survivin as well as Bax and Bcl-2 expressions after the cells were treated with different concentrations of ponicidin. The results revealed that ponicidin could inhibit the growth of U937 and THP-1 cells significantly by induction of apoptosis. The suppression was in both time- and dose-dependent manner. Marked morphological changes of cell apoptosis were observed clearly after the cells were treated with ponicidin for 48∼72 h. RT-PCR and Western blot analysis demonstrated that both survivin and Bcl-2 expressions were down-regulated remarkably while Bax expression remained constant before and after apoptosis occurred. We therefore conclude that ponicidin has significant anti-proliferation effects by inducing apoptosis on leukemia cells in vitro, downregulation of survivin as well as Bcl-2 expressions may be the important apoptosis inducing mechanisms. The results suggest that ponicidin may serve as potential therapeutic agent for leukemia. PMID:19330074

  6. Purification and Cultivation of Human Pituitary Growth Hormones Secreting Cells

    NASA Technical Reports Server (NTRS)

    Hymer, W. C.; Todd, P.; Grindeland, R.; Lanham, W.; Morrison, D.

    1985-01-01

    The rat and human pituitary gland contains a mixture of hormone producing cell types. The separation of cells which make growth hormone (GH) is attempted for the purpose of understanding how the hormone molecule is made within the pituitary cell; what form(s) it takes within the cell; and what form(s) GH assumes as it leaves the cell. Since GH has a number of biological targets (e.g., muscle, liver, bone), the assessment of the activities of the intracellular/extracellular GH by new and sensitive bioassays. GH cells contained in the mixture was separated by free flow electrophoresis. These experiments show that GH cells have different electrophoretic mobilities. This is relevant to NASA since a lack of GH could be a prime causative factor in muscle atrophy. Further, GH has recently been implicated in the etiology of motion sickness in space. Continous flow electrophoresis experiment on STS-8 showed that GH cells could be partially separated in microgravity. However, definitive cell culture studies could not be done due to insufficient cell recoveries.

  7. Growth of connective tissue progenitor cells on microtextured polydimethylsiloxane surfaces.

    PubMed

    Mata, Alvaro; Boehm, Cynthia; Fleischman, Aaron J; Muschler, George; Roy, Shuvo

    2002-12-15

    Growth of human connective tissue progenitor cells (CTPs) was characterized on smooth and microtextured polydimethylsiloxane (PDMS) surfaces. Human bone-marrow-derived cells were cultured for 9 days under conditions promoting osteoblastic differentiation on smooth PDMS surfaces and on PDMS post microtextures that were 6 microm high and 5, 10, 20, and 40 microm in diameter, respectively. Glass tissue-culture dishes were used as controls. The number of viable cells was determined, and an alkaline phosphatase stain was used as a marker for osteoblastic phenotype. CTPs attached, proliferated, and differentiated on all surfaces. Cells on the smooth PDMS and control surfaces spread and proliferated as colonies in proximity to other cells and migrated in random directions, with cell process lengths of up to 80 microm. In contrast, cells on the PDMS post microtextures grew as sparsely distributed networks of cells, with processes, occasionally up to 300 microm, that appeared to interact with the posts. Cell counts revealed that there were fewer (50%) CTPs on the smooth PDMS surface than were on the glass control surfaces. However, there were consistently more (>144%) CTPs on the PDMS post textures than on the controls. In particular, the 10-microm-in-diameter posts (268%) exhibited a significantly (p < 0.05) greater cell number than did the smooth PDMS.

  8. Wall relaxation and the driving forces for cell expansive growth

    NASA Technical Reports Server (NTRS)

    Cosgrove, D. J.

    1987-01-01

    When water uptake by growing cells is prevented, the turgor pressure and the tensile stress in the cell wall are reduced by continued wall loosening. This process, termed in vivo stress relaxation, provides a new way to study the dynamics of wall loosening and to measure the wall yield threshold and the physiological wall extensibility. Stress relaxation experiments indicate that wall stress supplies the mechanical driving force for wall yielding. Cell expansion also requires water absorption. The driving force for water uptake during growth is created by wall relaxation, which lowers the water potential of the expanding cells. New techniques for measuring this driving force show that it is smaller than believed previously; in elongating stems it is only 0.3 to 0.5 bar. This means that the hydraulic resistance of the water transport pathway is small and that rate of cell expansion is controlled primarily by wall loosening and yielding.

  9. Cell size and growth regulation in the Arabidopsis thaliana apical stem cell niche

    PubMed Central

    Willis, Lisa; Refahi, Yassin; Wightman, Raymond; Landrein, Benoit; Teles, José; Huang, Kerwyn Casey; Meyerowitz, Elliot M.

    2016-01-01

    Cell size and growth kinetics are fundamental cellular properties with important physiological implications. Classical studies on yeast, and recently on bacteria, have identified rules for cell size regulation in single cells, but in the more complex environment of multicellular tissues, data have been lacking. In this study, to characterize cell size and growth regulation in a multicellular context, we developed a 4D imaging pipeline and applied it to track and quantify epidermal cells over 3–4 d in Arabidopsis thaliana shoot apical meristems. We found that a cell size checkpoint is not the trigger for G2/M or cytokinesis, refuting the unexamined assumption that meristematic cells trigger cell cycle phases upon reaching a critical size. Our data also rule out models in which cells undergo G2/M at a fixed time after birth, or by adding a critical size increment between G2/M transitions. Rather, cell size regulation was intermediate between the critical size and critical increment paradigms, meaning that cell size fluctuations decay by ∼75% in one generation compared with 100% (critical size) and 50% (critical increment). Notably, this behavior was independent of local cell–cell contact topologies and of position within the tissue. Cells grew exponentially throughout the first >80% of the cell cycle, but following an asymmetrical division, the small daughter grew at a faster exponential rate than the large daughter, an observation that potentially challenges present models of growth regulation. These growth and division behaviors place strong constraints on quantitative mechanistic descriptions of the cell cycle and growth control. PMID:27930326

  10. Mxi1 regulates cell proliferation through insulin-like growth factor binding protein-3

    SciTech Connect

    Ko, Je Yeong; Yoo, Kyung Hyun; Lee, Han-Woong; Park, Jong Hoon

    2011-11-11

    Highlights: Black-Right-Pointing-Pointer Mxi1 regulates cell proliferation. Black-Right-Pointing-Pointer Expression of IGFBP-3 is regulated by Mxi1. Black-Right-Pointing-Pointer Inactivation of Mxi1 reduces IGFBP-3 expression in vitro and in vivo. -- Abstract: Mxi1, a member of the Myc-Max-Mad network, is an antagonist of the c-Myc oncogene and is associated with excessive cell proliferation. Abnormal cell proliferation and tumorigenesis are observed in organs of Mxi1-/- mice. However, the Mxi1-reltaed mechanism of proliferation is unclear. The present study utilized microarray analysis using Mxi1 mouse embryonic fibroblasts (MEFs) to identify genes associated with cell proliferation. Among these genes, insulin-like growth factor binding protein-3 (IGFBP-3) was selected as a candidate gene for real-time PCR to ascertain whether IGFBP-3 expression is regulated by Mxi1. Expression of IGFBP-3 was decreased in Mxi1-/- MEFs and Mxi1-/- mice, and the gene was regulated by Mxi1 in Mxi1 MEFs. Furthermore, proliferation pathways related to IGFBP-3 were regulated in Mxi1-/- mice compared to Mxi1+/+ mice. To determine the effect of Mxi1 inactivation on the induction of cell proliferation, a proliferation assay is performed in both Mxi1 MEFs and Mxi1 mice. Cell viability was regulated by Mxi1 in Mxi1 MEFs and number of PCNA-positive cells was increased in Mxi1-/- mice compared to Mxi1+/+ mice. Moreover, the IGFBP-3 level was decreased in proliferation defect regions in Mxi1-/- mice. The results support the suggestion that inactivation of Mxi1 has a positive effect on cell proliferation by down-regulating IGFBP-3.

  11. Autophagy contributes to gefitinib-induced glioma cell growth inhibition

    SciTech Connect

    Chang, Cheng-Yi; Kuan, Yu-Hsiang; Ou, Yen-Chuan; Li, Jian-Ri; Wu, Chih-Cheng; Pan, Pin-Ho; Chen, Wen-Ying; Huang, Hsuan-Yi; Chen, Chun-Jung

    2014-09-10

    Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, have been evaluated in patients with malignant gliomas. However, the molecular mechanisms involved in gefitinib-mediated anticancer effects against glioma are incompletely understood. In the present study, the cytostatic potential of gefitinib was demonstrated by the inhibition of glioma cell growth, long-term clonogenic survival, and xenograft tumor growth. The cytostatic consequences were accompanied by autophagy, as evidenced by monodansylcadaverine staining of acidic vesicle formation, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), degradation of p62, punctate pattern of GFP-LC3, and conversion of GFP-LC3 to cleaved-GFP. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 or Beclin 1 attenuated gefitinib-induced growth inhibition. Gefitinib-induced autophagy was not accompanied by the disruption of the Akt/mammalian target of rapamycin signaling. Instead, the activation of liver kinase-B1/AMP-activated protein kinase (AMPK) signaling correlated well with the induction of autophagy and growth inhibition caused by gefitinib. Silencing of AMPK suppressed gefitinib-induced autophagy and growth inhibition. The crucial role of AMPK activation in inducing glioma autophagy and growth inhibition was further supported by the actions of AMP mimetic AICAR. Gefitinib was shown to be capable of reducing the proliferation of glioma cells, presumably by autophagic mechanisms involving AMPK activation. - Highlights: • Gefitinib causes cytotoxic and cytostatic effect on glioma. • Gefitinib induces autophagy. • Gefitinib causes cytostatic effect through autophagy. • Gefitinib induces autophagy involving AMPK.

  12. Dopamine and T cells: dopamine receptors and potent effects on T cells, dopamine production in T cells, and abnormalities in the dopaminergic system in T cells in autoimmune, neurological and psychiatric diseases.

    PubMed

    Levite, M

    2016-01-01

    Dopamine, a principal neurotransmitter, deserves upgrading to 'NeuroImmunotransmitter' thanks to its multiple, direct and powerful effects on most/all immune cells. Dopamine by itself is a potent activator of resting effector T cells (Teffs), via two independent ways: direct Teffs activation, and indirect Teffs activation by suppression of regulatory T cells (Tregs). The review covers the following findings: (i) T cells express functional dopamine receptors (DRs) D1R-D5R, but their level and function are dynamic and context-sensitive, (ii) DR membranal protein levels do not necessarily correlate with DR mRNA levels, (iii) different T cell types/subtypes have different DR levels and composition and different responses to dopamine, (iv) autoimmune and pro-inflammatory T cells and T cell leukaemia/lymphoma also express functional DRs, (v) dopamine (~10(-8) M) activates resting/naive Teffs (CD8(+) >CD4(+) ), (vi) dopamine affects Th1/Th2/Th17 differentiation, (vii) dopamine inhibits already activated Teffs (i.e. T cells that have been already activated by either antigen, mitogen, anti-CD3 antibodies cytokines or other molecules), (viii) dopamine inhibits activated Tregs in an autocrine/paracrine manner. Thus, dopamine 'suppresses the suppressors' and releases the inhibition they exert on Teffs, (ix) dopamine affects intracellular signalling molecules and cascades in T cells (e.g. ERK, Lck, Fyn, NF-κB, KLF2), (x) T cells produce dopamine (Tregs>Teffs), can release dopamine, mainly after activation (by antigen, mitogen, anti-CD3 antibodies, PKC activators or other), uptake extracellular dopamine, and most probably need dopamine, (xi) dopamine is important for antigen-specific interactions between T cells and dendritic cells, (xii) in few autoimmune diseases (e.g. multiple sclerosis/SLE/rheumatoid arthritis), and neurological/psychiatric diseases (e.g. Parkinson disease, Alzheimer's disease, Schizophrenia and Tourette), patient's T cells seem to have abnormal DRs

  13. Modeling Bacterial Population Growth from Stochastic Single-Cell Dynamics

    PubMed Central

    Molina, Ignacio; Theodoropoulos, Constantinos

    2014-01-01

    A few bacterial cells may be sufficient to produce a food-borne illness outbreak, provided that they are capable of adapting and proliferating on a food matrix. This is why any quantitative health risk assessment policy must incorporate methods to accurately predict the growth of bacterial populations from a small number of pathogens. In this aim, mathematical models have become a powerful tool. Unfortunately, at low cell concentrations, standard deterministic models fail to predict the fate of the population, essentially because the heterogeneity between individuals becomes relevant. In this work, a stochastic differential equation (SDE) model is proposed to describe variability within single-cell growth and division and to simulate population growth from a given initial number of individuals. We provide evidence of the model ability to explain the observed distributions of times to division, including the lag time produced by the adaptation to the environment, by comparing model predictions with experiments from the literature for Escherichia coli, Listeria innocua, and Salmonella enterica. The model is shown to accurately predict experimental growth population dynamics for both small and large microbial populations. The use of stochastic models for the estimation of parameters to successfully fit experimental data is a particularly challenging problem. For instance, if Monte Carlo methods are employed to model the required distributions of times to division, the parameter estimation problem can become numerically intractable. We overcame this limitation by converting the stochastic description to a partial differential equation (backward Kolmogorov) instead, which relates to the distribution of division times. Contrary to previous stochastic formulations based on random parameters, the present model is capable of explaining the variability observed in populations that result from the growth of a small number of initial cells as well as the lack of it compared to

  14. Modeling bacterial population growth from stochastic single-cell dynamics.

    PubMed

    Alonso, Antonio A; Molina, Ignacio; Theodoropoulos, Constantinos

    2014-09-01

    A few bacterial cells may be sufficient to produce a food-borne illness outbreak, provided that they are capable of adapting and proliferating on a food matrix. This is why any quantitative health risk assessment policy must incorporate methods to accurately predict the growth of bacterial populations from a small number of pathogens. In this aim, mathematical models have become a powerful tool. Unfortunately, at low cell concentrations, standard deterministic models fail to predict the fate of the population, essentially because the heterogeneity between individuals becomes relevant. In this work, a stochastic differential equation (SDE) model is proposed to describe variability within single-cell growth and division and to simulate population growth from a given initial number of individuals. We provide evidence of the model ability to explain the observed distributions of times to division, including the lag time produced by the adaptation to the environment, by comparing model predictions with experiments from the literature for Escherichia coli, Listeria innocua, and Salmonella enterica. The model is shown to accurately predict experimental growth population dynamics for both small and large microbial populations. The use of stochastic models for the estimation of parameters to successfully fit experimental data is a particularly challenging problem. For instance, if Monte Carlo methods are employed to model the required distributions of times to division, the parameter estimation problem can become numerically intractable. We overcame this limitation by converting the stochastic description to a partial differential equation (backward Kolmogorov) instead, which relates to the distribution of division times. Contrary to previous stochastic formulations based on random parameters, the present model is capable of explaining the variability observed in populations that result from the growth of a small number of initial cells as well as the lack of it compared to

  15. Probabilistic Model of Microbial Cell Growth, Division, and Mortality ▿

    PubMed Central

    Horowitz, Joseph; Normand, Mark D.; Corradini, Maria G.; Peleg, Micha

    2010-01-01

    After a short time interval of length δt during microbial growth, an individual cell can be found to be divided with probability Pd(t)δt, dead with probability Pm(t)δt, or alive but undivided with the probability 1 − [Pd(t) + Pm(t)]δt, where t is time, Pd(t) expresses the probability of division for an individual cell per unit of time, and Pm(t) expresses the probability of mortality per unit of time. These probabilities may change with the state of the population and the habitat's properties and are therefore functions of time. This scenario translates into a model that is presented in stochastic and deterministic versions. The first, a stochastic process model, monitors the fates of individual cells and determines cell numbers. It is particularly suitable for small populations such as those that may exist in the case of casual contamination of a food by a pathogen. The second, which can be regarded as a large-population limit of the stochastic model, is a continuous mathematical expression that describes the population's size as a function of time. It is suitable for large microbial populations such as those present in unprocessed foods. Exponential or logistic growth with or without lag, inactivation with or without a “shoulder,” and transitions between growth and inactivation are all manifestations of the underlying probability structure of the model. With temperature-dependent parameters, the model can be used to simulate nonisothermal growth and inactivation patterns. The same concept applies to other factors that promote or inhibit microorganisms, such as pH and the presence of antimicrobials, etc. With Pd(t) and Pm(t) in the form of logistic functions, the model can simulate all commonly observed growth/mortality patterns. Estimates of the changing probability parameters can be obtained with both the stochastic and deterministic versions of the model, as demonstrated with simulated data. PMID:19915038

  16. Mathematical Modeling of Tumor Cell Growth and Immune System Interactions

    NASA Astrophysics Data System (ADS)

    Rihan, Fathalla A.; Safan, Muntaser; Abdeen, Mohamed A.; Abdel-Rahman, Duaa H.

    In this paper, we provide a family of ordinary and delay differential equations to describe the dynamics of tumor-growth and immunotherapy interactions. We explore the effects of adoptive cellular immunotherapy on the model and describe under what circumstances the tumor can be eliminated. The possibility of clearing the tumor, with a strategy, is based on two parameters in the model: the rate of influx of the effector cells, and the rate of influx of IL2. The critical tumor-growth rate, below which endemic tumor does not exist, has been found. One can use the model to make predictions about tumor-dormancy.

  17. Immunological abnormalities in human immunodeficiency virus (HIV)-infected asymptomatic homosexual men. HIV affects the immune system before CD4+ T helper cell depletion occurs.

    PubMed Central

    Miedema, F; Petit, A J; Terpstra, F G; Schattenkerk, J K; de Wolf, F; Al, B J; Roos, M; Lange, J M; Danner, S A; Goudsmit, J

    1988-01-01

    To investigate the effect of persistent HIV infection on the immune system, we studied leukocyte functions in 14 asymptomatic homosexual men (CDC group II/III) who were at least two years seropositive, but who still had normal numbers of circulating CD4+ T cells. Compared with age-matched heterosexual men and HIV-negative homosexual men, the CD4+ and CD8+ T cells from seropositive men showed decreased proliferation to anti-CD3 monoclonal antibody and decreased CD4+ T-helper activity on PWM-driven differentiation of normal donor B cells. Monocytes of HIV-infected homosexual men showed decreased accessory function on normal T cell proliferation induced by CD3 monoclonal antibody. The most striking defect in leukocyte functional activities was observed in the B cells of HIV-infected men. B cells of 13 out of 14 seropositive men failed to produce Ig in response to PWM in the presence of adequate allogeneic T-helper activity. These findings suggest that HIV induces severe immunological abnormalities in T cells, B cells, and antigen-presenting cells early in infection before CD4+ T cell numbers start to decline. Impaired immunological function in subclinically HIV-infected patients may have clinical implications for vaccination strategies, in particular the use of live vaccines in groups with a high prevalence of HIV seropositivity. PMID:2974045

  18. Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production.

    PubMed

    Karampetsou, Maria P; Comte, Denis; Kis-Toth, Katalin; Terhorst, Cox; Kyttaris, Vasileios C; Tsokos, George C

    2016-06-15

    T cells from patients with systemic lupus erythematosus (SLE) display a number of abnormalities, including increased early signaling events following engagement of the TCR. Signaling lymphocytic activation molecule family cell surface receptors and the X-chromosome-defined signaling lymphocytic activation molecule-associated protein (SAP) adaptor are important in the development of several immunocyte lineages and modulating the immune response. We present evidence that SAP protein levels are decreased in T cells and in their main subsets isolated from 32 women and three men with SLE, independent of disease activity. In SLE T cells, SAP protein is also subject to increased degradation by caspase-3. Forced expression of SAP in SLE T cells normalized IL-2 production, calcium (Ca(2+)) responses, and tyrosine phosphorylation of a number of proteins. Exposure of normal T cells to SLE serum IgG, known to contain anti-CD3/TCR Abs, resulted in SAP downregulation. We conclude that SLE T cells display reduced levels of the adaptor protein SAP, probably as a result of continuous T cell activation and degradation by caspase-3. Restoration of SAP levels in SLE T cells corrects the overexcitable lupus T cell phenotype.

  19. Effect on the growth and development and induction of abnormalities by a glyphosate commercial formulation and its active ingredient during two developmental stages of the South-American Creole frog, Leptodactylus latrans.

    PubMed

    Bach, Nadia Carla; Natale, Guillermo Sebastián; Somoza, Gustavo Manuel; Ronco, Alicia Estela

    2016-12-01

    We evaluated the acute lethal and sublethal effects of technical-grade glyphosate (GLY) and the GLY-based commercial formulation Roundup ULTRA MAX® (RU) on two Gosner stages (Gss) 25 and 36 of the South-American Creole frog, Leptodactylus latrans. Bioassays were performed following standardized methods within a wide range of concentrations (0.0007-9.62 mg of acid equivalents per liter-a.e./L-of RU and 3-300 mg/L of GLY). The endpoints evaluated were mortality, swimming activity, growth, development, and the presence of morphologic abnormalities, especially in the mouthparts. No lethal effects were observed on larvae exposed to GLY during either Gs-25 or Gs-36. The concentrations inducing 50 % lethality in RU-exposed larvae at different exposure times and Gss ranged from 3.26 to 9.61 mg a.e./L. Swimming activity was affected by only RU. Effects on growth and development and the induction of morphologic abnormalities-like oral abnormalities and edema-were observed after exposure to either GLY or RU. Gs-25 was the most sensitive stage to both forms of the herbicide. The commercial formulation was much more toxic than the active ingredient on all the endpoints assessed. Effects on growth, development, and the induction of morphologic abnormalities observed in the range of environmental concentrations reported for agroecosystems of Argentina constitute an alert to the potential detrimental effects of the herbicide that could be affecting the fitness and survival of anurans in agroecosystems.

  20. Growth Patterns in Children with Sickle Cell Anemia during Puberty

    PubMed Central

    Rhodes, Melissa; Akohoue, Sylvie A.; Shankar, Sadhna M.; Fleming, Irma; An, Angel; Yu, Chung; Acra, Sari; Buchowski, Maciej S.

    2009-01-01

    Background Previous studies of children with homozygous sickle cell anemia (SCA) show impaired growth and maturation. The correlation of this suboptimal growth with metabolic and hematological factors during puberty is poorly understood. Procedure We studied a group of pre-adolescent children with SCA (19 males, 14 females) and healthy controls (16 males, 15 females) matched for race, sex, body size, and pubertal development. Height, weight, body mass index (BMI), and body composition changes were longitudinally assessed over a 2-year period and compared between the groups and with Z scores based on US growth charts. These changes were correlated with hemoglobin concentration and with energy expenditure measured using indirect whole-room calorimetry. Results Children with SCA progressed through puberty slower than control children. While, after 2 years, pubertal males with SCA were shorter, their annual increases in weight were not different from controls. The mean fat free mass (FFM) increments were significantly less in males and females with SCA than in control children. In males with SCA, growth in height declined over time and was significantly slower than in matched controls (p<0.05). Conclusion Growth delays were present during puberty in children with SCA. Decreased growth velocity in children with SCA was independently associated with decreased hemoglobin concentration and increased total energy expenditure. PMID:19544390

  1. Parthenolide suppresses pancreatic cell growth by autophagy-mediated apoptosis

    PubMed Central

    Liu, Weifeng; Wang, Xinshuai; Sun, Junjun; Yang, Yanhui; Li, Wensheng; Song, Junxin

    2017-01-01

    Pancreatic cancer is an aggressive malignancy and is unresponsive to conventional chemotherapies. Parthenolide, a sesquiterpene lactone isolated from feverfew, has exhibited potent anticancer effects against various cancers. The purpose of this report was to investigate the effect and underlying mechanism of parthenolide in human pancreatic cancer Panc-1 and BxPC3 cells. The results demonstrated that parthenolide suppressed the growth and induced apoptosis of Panc-1 and BxPC3 pancreatic cancer cells with the half maximal inhibitory concentration (IC50) ranging between 7 and 9 μM after 24 h of treatment. Significant autophagy was induced by parthenolide treatment in pancreatic cancer cells. Parthenolide treatment concentration-dependently increased the percentage of autophagic cells and significantly increased the expression levels of p62/SQSTM1, Beclin 1, and LC3II in Panc-1 cells. Punctate LC3II staining confirmed autophagy. Furthermore, inhibiting autophagy by chloroquine, 3-methyladenine, or LC3II siRNA significantly blocked parthenolide-induced apoptosis, suggesting that parthenolide induced apoptosis through autophagy in this study. In conclusion, these studies established that parthenolide inhibits pancreatic cell growth by autophagy-mediated apoptosis. Data of the present study suggest that parthenolide can serve as a potential chemotherapeutic agent for pancreatic cancer. PMID:28176967

  2. Synergistic activation of cells by Epstein-Barr virus and B-cell growth factor.

    PubMed Central

    Hutt-Fletcher, L M

    1987-01-01

    Infection with Epstein-Barr virus (EBV) is initiated by virus binding to the C3dg-C3d receptor CR2. Several workers have implicated this receptor in the control of B-cell activation by examining the effects of antibodies to CR2 and isolated C3d on B-cell proliferation and differentiation. We report here on the activating effects of irradiated EBV, which retains its capacity to bind to CR2 but loses its ability to function as a T-independent B-cell activator. EBV synergized with B-cell growth factor in the induction of uptake of tritiated thymidine by T cell-depleted leukocytes from seronegative donors but did not induce secretion of immunoglobulin. Synergism could be inhibited with an anti-viral antibody that inhibited binding of EBV to CR2. No similar synergism was found between EBV and recombinant interleukin 2, interleukin 1 alpha, or gamma interferon or with the lipid A fraction of bacterial lipopolysaccharide. EBV may thus initiate B-cell activation as it binds to CR2. Infectious virus may, under normal circumstances, induce the cell to make those growth factors necessary to support B-cell proliferation; the difficulty of transforming cells with transfected EBV DNA may in part reflect the absence of an activation event provided by intact virus as it attaches to CR2. The synergism of EBV and B-cell growth factor more clearly distinguishes the effects of B-cell growth factor from those of interleukin 1 and interleukin 2 in other models of B-cell activation. Thus, this may be a useful model for further delineation of unique effects of B-cell growth factor on B-cell function. PMID:3027404

  3. Fibroblast cell interactions with human melanoma cells affect tumor cell growth as a function of tumor progression.

    PubMed Central

    Cornil, I; Theodorescu, D; Man, S; Herlyn, M; Jambrosic, J; Kerbel, R S

    1991-01-01

    It is known from a variety of experimental systems that the ability of tumor cells to grow locally and metastasize can be affected by the presence of adjacent normal tissues and cells, particularly mesenchymally derived stromal cells such as fibroblasts. However, the comparative influence of such normal cell-tumor cell interactions on tumor behavior has not been thoroughly investigated from the perspective of different stages of tumor progression. To address this question we assessed the influence of normal dermal fibroblasts on the growth of human melanoma cells obtained from different stages of tumor progression. We found that the in vitro growth of most (4 out of 5) melanoma cell lines derived from early-stage radial growth phase or vertical growth phase metastatically incompetent primary lesions is repressed by coculture with normal dermal fibroblasts, suggesting that negative homeostatic growth controls are still operative on melanoma cells from early stages of disease. On the other hand, 9 out of 11 melanoma cell lines derived from advanced metastatically competent vertical growth phase primary lesions, or from distant metastases, were found to be consistently stimulated to grow in the presence of dermal fibroblasts. Evidence was obtained to show that this discriminatory fibroblastic influence is mediated by soluble inhibitory and stimulatory growth factor(s). Taken together, these results indicate that fibroblast-derived signals can have antithetical growth effects on metastatic versus metastatically incompetent tumor subpopulations. This resultant conversion in responsiveness to host tissue environmental factors may confer upon small numbers of metastatically competent cells a growth advantage, allowing them to escape local growth constraints both in the primary tumor site and at distant ectopic tissue sites. PMID:2068080

  4. SATB2 expression increased anchorage-independent growth and cell migration in human bronchial epithelial cells

    PubMed Central

    Wu, Feng; Jordan, Ashley; Kluz, Thomas; Shen, Steven; Sun, Hong; Cartularo, Laura A; Costa, Max

    2016-01-01

    The special AT-rich sequence-binding protein 2 (SATB2) is a protein that binds to the nuclear matrix attachment region of the cell and regulates gene expression by altering chromatin structure. In our previous study, we reported that SATB2 gene expression was induced in human bronchial epithelial BEAS-2B cells transformed by arsenic, chromium, nickel and vanadium. In this study , we show that ectopic expression of SATB2 in the normal human bronchial epithelial cell-line BEAS-2B increased anchorage-independent growth and cell migration, meanwhile, shRNA – mediated knockdown of SATB2 significantly decreased anchorage-independent growth in Ni transformed BEAS-2B cells. RNA sequencing analyses of SATB2 regulated genes revealed the enrichment of those involved in cytoskeleton, cell adhesion and cell-movement pathways. Our evidence supports the hypothesis that SATB2 plays an important role in BEAS-2B cell transformation. PMID:26780400

  5. Growth dynamics and cyclin expression in cutaneous T-cell lymphoma cell lines

    PubMed Central

    Biskup, Edyta; Manfé, Valentina; Kamstrup, Maria R.; Gniadecki, Robert

    2010-01-01

    We have investigated cell growth dynamics and cyclins B1 and E expression in cell lines derived from mycosis fungoides (MyLa), Sézary syndrome (SeAx), and CD30+ lympho-proliferative diseases (Mac1, Mac2a, JK). Mac1 and Mac2a had the highest growth rate (doubling time 18–28 h, >90% cycling cells) whereas SeAx was proliferating slowly (doubling time 55 h, approximately 35% cycling cells). Expression of cyclin B1 correlated positively with doubling time whereas expression of cyclin E was unscheduled and constant across the investigated cell lines. All cell lines exhibited high expression of PCNA. Thus, we concluded that cyclin B1 could be used for rapid screening of cell proliferation in malignant lymphocytes derived from cutaneous T-cell lymphoma. PMID:25386244

  6. Teroxirone inhibited growth of human non-small cell lung cancer cells by activating p53

    SciTech Connect

    Wang, Jing-Ping; Lin, Kai-Han; Liu, Chun-Yen; Yu, Ya-Chu; Wu, Pei-Tsun; Chiu, Chien-Chih; Su, Chun-Li; Chen, Kwun-Min; Fang, Kang

    2013-11-15

    In this work, we demonstrated that the growth of human non-small-cell-lung-cancer cells H460 and A549 cells can be inhibited by low concentrations of an epoxide derivative, teroxirone, in both in vitro and in vivo models. The cytotoxicity was mediated by apoptotic cell death through DNA damage. The onset of ultimate apoptosis is dependent on the status of p53. Teroxirone caused transient elevation of p53 that activates downstream p21 and procaspase-3 cleavage. The presence of caspase-3 inhibitor reverted apoptotic phenotype. Furthermore, we showed the cytotoxicity of teroxirone in H1299 cells with stable ectopic expression of p53, but not those of mutant p53. A siRNA-mediated knockdown of p53 expression attenuated drug sensitivity. The in vivo experiments demonstrated that teroxirone suppressed growth of xenograft tumors in nude mice. Being a potential therapeutic agent by restraining cell growth through apoptotic death at low concentrations, teroxirone provides a feasible perspective in reversing tumorigenic phenotype of human lung cancer cells. - Highlights: • Teroxirone repressed tumor cell growth in nude mice of human lung cancer cells. • The apoptotic cell death reverted by caspase-3 inhibitor is related to p53 status. • Teroxirone provides a good candidate for lung cancer treatment.

  7. Yes is a central mediator of cell growth in malignant mesothelioma cells.

    PubMed

    Sato, Ayami; Sekine, Miki; Virgona, Nantiga; Ota, Masako; Yano, Tomohiro

    2012-11-01

    The constitutive activation of the Src family kinases (SFKs) has been established as a poor prognostic factor in malignant mesothelioma (MM), however, the family member(s) which contribute to the malignancy have not been defined. This study aimed to identify the SFK member(s) contributing to cell growth using RNA interference in various MM cell lines. Silencing of Yes but not of c-Src or Fyn in MM cells leads to cell growth suppression. This suppressive effect caused by Yes silencing mainly depends on G1 cell cycle arrest and partly the induction of apoptosis. Also, the knockout of Yes induces the inactivation of β-catenin signaling and subsequently decreases the levels of cyclin D necessary for G1-S transition in the cell cycle. In addition, Yes knockout has less effect on cell growth suppression in β-catenin-deficient H28 MM cells compared to other MM cells which express the catenin. Overall, we conclude that Yes is a central mediator for MM cell growth that is not shared with other SFKs such as c-Src.

  8. Genotype-driven therapies for non-small cell lung cancer: focus on EGFR, KRAS and ALK gene abnormalities.

    PubMed

    Gaughan, Elizabeth M; Costa, Daniel B

    2011-05-01

    Non-small cell lung cancers (NSCLCs) are heterogeneous cancers. In 2004, the identification of epidermal growth factor receptor (EGFR) somatic mutations provided the first glimpse of a clinically relevant NSCLC oncogene. Approximately 70% of NSCLCs with EGFR mutations (exon 19 deletions or the exon 21 L858R) attain responses to EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, with improved response rate (RR), progression-free survival (PFS) and in some reports overall survival (OS) when compared with EGFR wildtype (WT) cases. Three randomized trials of gefitinib versus chemotherapy (IPASS, WJTOG3405, NEJ002) in stage IV NSCLC have consistently demonstrated better RR and PFS (hazard ratios of 0.48 [IPASS], 0.49 [WJTOG3405] and 0.30 [NEJ002]) for EGFR-mutated NSCLCs treated with gefitinib. Novel irreversible EGFR TKIs (afatinib, XL647, PF00299804) show similar activity in EGFR-mutated patients. A translocation involving the anaplastic lymphoma kinase (ALK) gene with EML4, identified in 2007, is the most recent oncogene found in NSCLC. Crizotinib (PF02341066), an ALK TKI, has shown impressive activity against ALK translocated NSCLC in an expanded cohort of a phase I trial (NCT00585195). Over 80 patients have been treated and the RR is ∼60% with the 6-month PFS rate exceeding 70%. A registration phase III trial of crizotinib versus second-line chemotherapy (pemetrexed/docetaxel) is underway (PROFILE 1007, NCT00932893). KRAS, EGFR mutations and ALK translocations are mutually exclusive and few EGFR WT NSCLCs respond to EGFR TKIs. The promising results of EGFR and ALK TKIs in molecular subgroups of NSCLCs herald a new age of drug and clinical trial development for patients with NSCLC.

  9. AP-2α inhibits hepatocellular carcinoma cell growth and migration.

    PubMed

    Huang, Wenhuan; Chen, Cheng; Liang, Zhongheng; Qiu, Junlu; Li, Xinxin; Hu, Xiang; Xiang, Shuanglin; Ding, Xiaofeng; Zhang, Jian

    2016-03-01

    Transcription factor AP-2α is involved in many types of human cancers, but its role in hepatocellular carcinogenesis is largely unknown. In this study, we found that expression of AP-2α was low in 40% of human hepatocellular cancers compared with adjacent normal tissues by immunohistochemical analysis. Moreover, AP-2α expression was low or absent in hepatocellular cancer cell lines (HepG2, Hep3B, SMMC-7721 and MHHC 97-H). Human liver cancer cell lines SMMC-7721 and Hep3B stably overexpressing AP-2α were established by lentiviral infection and puromycin screening, and the ectopic expression of AP-2α was able to inhibit hepatocellular cancer cell growth and proliferation by cell viability, MTT assay and liquid colony formation in vitro and in vivo. Furthermore, AP-2α overexpression decreased liver cancer cell migration and invasion as assessed by wound healing and Transwell assays, increasing the sensitivity of liver cancer cells to cisplatin analyzed by MTT assays. Also AP-2α overexpression suppressed the sphere formation and renewed the ability of cancer stem cells. Finally, we found that AP-2α is epigenetically modified and modulates the levels of phosphorylated extracellular signal-regulated protein kinase (ERK), β-catenin, p53, EMT, and CD133 expression in liver cancer cell lines. These results suggested that AP-2α expression is low in human hepatocellular cancers by regulating multiple signaling to affect hepatocellular cancer cell growth and migration. Therefore, AP-2α might represent a novel potential target in human hepatocellular cancer therapy.

  10. Mutual effects of growth hormone and growth factors on avian skeletal muscle satellite cells.

    PubMed

    Hodik, V; Mett, A; Halevy, O

    1997-10-01

    Chicken growth hormone (cGH) has been shown to affect chicken skeletal muscle satellite cell proliferation and differentiation in vitro. This study describes the interactions of cGH with basic fibroblast growth factor (bFGF) and insulin-like growth factor I (IGF-I). Both cGH and bFGF induced cGH receptor (cGH-R) gene expression as well as that of the avian FGF receptor, FREK, when added at low concentrations to satellite cells. bFGF caused a rapid induction of cGH-R mRNA. Combinations of low levels of bFGF and cGH caused a further increase in receptor mRNA expression levels, relative to that caused by each peptide alone, and their effect on DNA synthesis was synergistic. However, combinations of cGH and bFGF at high concentrations decreased cGH-R and FREK mRNA levels and DNA synthesis in a dose-dependent manner. These results imply that the mutual effects of bFGF and cGH on satellite cell proliferation are receptor-mediated and that each peptide regulates both receptors gene expression. IGF-I induced DNA synthesis in satellite cells but did not affect cGH-R gene expression at any of the concentrations tested. Coincubation of 3.5 ng/ml cGH and various concentrations of IGF-I did not significantly change DNA synthesis relative to the effect of cGH alone. However, combinations with high levels of cGH abolished it. Similar time-course (up to 6 hr) induction of DNA synthesis in serum-starved cells was observed in the presence of cGH or IGF-I, suggesting that cGH affects satellite cell proliferation in an IGF-I-independent manner.

  11. Mantle cell lymphoma harboring Burkitt's-like translocations presents differential expression of aurora kinase genes compared with others 8q abnormalities.

    PubMed

    de Oliveira, Fábio Morato; Rodrigues-Alves, Ana Paula Nunes; Lucena-Araújo, Antônio Roberto; de Paula Silva, Ferdinando; da Silva, Fernanda Borges; Falcão, Roberto Passetto

    2014-05-01

    We compared the levels of AURKA and AURKB in 24 (mantle cell lymphoma) MCL patients harboring 8q abnormalities and its relationship with MYCC gene status. Two distinct subgroups were observed, in terms of MYCC expression. Except for the patients with Burkitt's-like translocation, none of the patients harboring 8q abnormalities, including balanced translocations or duplications of MYCC band, identified both by G-banding and SKY, showed differential expression levels of MYCC. These previous findings also reflected in the differential expression of AURKA and AURKB genes. We found that AURKA and AURKB mRNA were expressed at significantly higher levels in MCL patients harboring Burkitt's-like translocation, when compared to patients with 8q rearrangements. The high expression of aurora kinase genes is reported to be associated with some parameters of clinical oncologic aggressiveness, such as high histological grade, invasion and increased rates of metastasis in several types of cancers. It is possible that in MCL patients expressing abnormal levels of MYCC together with a high expression of AURKA might offer some resistant to the conventional therapy purposes. Thus, aurora kinase inhibitors may also be considered for this specific subgroup on MCL, whose aggressive clinical course resembles high-grade lymphoma.

  12. Long non-coding RNA XIST promotes cell growth by regulating miR-139-5p/PDK1/AKT axis in hepatocellular carcinoma.

    PubMed

    Mo, Yichao; Lu, Yaoyong; Wang, Peng; Huang, Simin; He, Longguang; Li, Dasheng; Li, Fuliang; Huang, Junwei; Lin, Xiaoxia; Li, Xueru; Che, Siyao; Chen, Qinshou

    2017-02-01

    Abnormal expression of long non-coding RNA often contributes to unrestricted growth of cancer cells. Long non-coding RNA XIST expression is upregulated in several cancers; however, its modulatory mechanisms have not been reported in hepatocellular carcinoma. In this study, we found that XIST expression was significantly increased in hepatocellular carcinoma tissues and cell lines. XIST promoted cell cycle progression from the G1 phase to the S phase and protected cells from apoptosis, which contributed to hepatocellular carcinoma cell growth. In addition, we revealed that there was reciprocal repression between XIST and miR-139-5p. PDK1 was identified as a direct target of miR-139-5p. We proposed that XIST was responsible for hepatocellular carcinoma cell proliferation, and XIST exerted its function through the miR-139-5p/PDK1 axis.

  13. Effects of space flight exposure on cell growth, tumorigenicity and gene expression in cancer cells

    NASA Astrophysics Data System (ADS)

    Yang, Cheng; Li, Yuehui; Zhang, Zhijie; Luo, Chen; Tong, Yongqing; Zhou, Guohua; Xie, Pingli; Hu, Jinyue; Li, Guancheng

    2008-12-01

    It is well recognized that harsh outer space environment, consisting of microgravity and radiation, poses significant health risks for human cells. To investigate potential effects of the space environment exposure on cancer cells we examined the biological changes in Caski cells carried by the "Shen Zhou IV" spaceship. After exposure for 7 days in spaceflight, 1440 survival subclonal cell lines were established and 4 cell lines were screened. 44F10 and 17E3 were selected because of their increased cell proliferation and tumorigenesis, while 48A9 and 31F2 had slower cytological events. Experiments with cell proliferation assay, flow cytometry, soft agar assay, tumorigenesis assay and DNA microarray analysis have shown that selected cell lines presented multiple biological changes in cell morphology, cell growth, tumorigenicity and gene expression. These results suggest that space environment exposure can make significant biological impact on cancer cells and provide an entry point to find the immunological target of tumorigenesis.

  14. Meiotic prophase abnormalities and metaphase cell death in MLH1-deficient mouse spermatocytes: insights into regulation of spermatogenic progress.

    PubMed

    Eaker, Shannon; Cobb, John; Pyle, April; Handel, Mary Ann

    2002-09-01

    The MLH1 protein is required for normal meiosis in mice and its absence leads to failure in maintenance of pairing between bivalent chromosomes, abnormal meiotic division, and ensuing sterility in both sexes. In this study, we investigated whether failure to develop foci of MLH1 protein on chromosomes in prophase would lead to elimination of prophase spermatocytes, and, if not, whether univalent chromosomes could align normally on the meiotic spindle and whether metaphase spermatocytes would be delayed and/or eliminated. In spite of the absence of MLH1 foci, no apoptosis of spermatocytes in prophase was detected. In fact, chromosomes of pachytene spermatocytes from Mlh1(-/-) mice were competent to condense metaphase chromosomes, both in vivo and in vitro. Most condensed chromosomes were univalents with spatially distinct FISH signals. Typical metaphase events, such as synaptonemal complex breakdown and the phosphorylation of Ser10 on histone H3, occurred in Mlh1(-/-) spermatocytes, suggesting that there is no inhibition of onset of meiotic metaphase in the face of massive chromosomal abnormalities. However, the condensed univalent chromosomes did not align correctly onto the spindle apparatus in the majority of Mlh1(-/-) spermatocytes. Most meiotic metaphase spermatocytes were characterized with bipolar spindles, but chromosomes radiated away from the microtubule-organizing centers in a prometaphase-like pattern rather than achieving a bipolar orientation. Apoptosis was not observed until after the onset of meiotic metaphase. Thus, spermatocytes are not eliminated in direct response to the initial meiotic defect, but are eliminated later. Taken together, these observations suggest that a spindle assembly checkpoint, rather than a recombination or chiasmata checkpoint, may be activated in response to meiotic errors, thereby ensuring elimination of chromosomally abnormal gamete precursors.

  15. Inferring time derivatives including cell growth rates using Gaussian processes

    PubMed Central

    Swain, Peter S.; Stevenson, Keiran; Leary, Allen; Montano-Gutierrez, Luis F.; Clark, Ivan B.N.; Vogel, Jackie; Pilizota, Teuta

    2016-01-01

    Often the time derivative of a measured variable is of as much interest as the variable itself. For a growing population of biological cells, for example, the population's growth rate is typically more important than its size. Here we introduce a non-parametric method to infer first and second time derivatives as a function of time from time-series data. Our approach is based on Gaussian processes and applies to a wide range of data. In tests, the method is at least as accurate as others, but has several advantages: it estimates errors both in the inference and in any summary statistics, such as lag times, and allows interpolation with the corresponding error estimation. As illustrations, we infer growth rates of microbial cells, the rate of assembly of an amyloid fibril and both the speed and acceleration of two separating spindle pole bodies. Our algorithm should thus be broadly applicable. PMID:27941811

  16. Inferring time derivatives including cell growth rates using Gaussian processes

    NASA Astrophysics Data System (ADS)

    Swain, Peter S.; Stevenson, Keiran; Leary, Allen; Montano-Gutierrez, Luis F.; Clark, Ivan B. N.; Vogel, Jackie; Pilizota, Teuta

    2016-12-01

    Often the time derivative of a measured variable is of as much interest as the variable itself. For a growing population of biological cells, for example, the population's growth rate is typically more important than its size. Here we introduce a non-parametric method to infer first and second time derivatives as a function of time from time-series data. Our approach is based on Gaussian processes and applies to a wide range of data. In tests, the method is at least as accurate as others, but has several advantages: it estimates errors both in the inference and in any summary statistics, such as lag times, and allows interpolation with the corresponding error estimation. As illustrations, we infer growth rates of microbial cells, the rate of assembly of an amyloid fibril and both the speed and acceleration of two separating spindle pole bodies. Our algorithm should thus be broadly applicable.

  17. Chymase-producing cells of the innate immune system are required for decidual vascular remodeling and fetal growth.

    PubMed

    Meyer, Nicole; Woidacki, Katja; Knöfler, Martin; Meinhardt, Gudrun; Nowak, Désirée; Velicky, Philipp; Pollheimer, Jürgen; Zenclussen, Ana C

    2017-03-22

    Intrauterine growth restriction (IUGR) is caused by insufficient remodeling of spiral arteries (SAs). The mechanism underlying the relevance of natural killer cells (NKs) and mast cells (MCs) for SA remodeling and its effects on pregnancy outcome are not well understood. We show that NK depletion arrested SA remodeling without affecting pregnancy. MC depletion resulted in abnormally remodeled SAs and IUGR. Combined absence of NKs and MCs substantially affected SA remodeling and impaired fetal growth. We found that α-chymase mast cell protease (Mcpt) 5 mediates apoptosis of uterine smooth muscle cells, a key feature of SA remodeling. Additionally, we report a previously unknown source for Mcpt5: uterine (u) NKs. Mice with selective deletion of Mcpt5(+) cells had un-remodeled SAs and growth-restricted progeny. The human α-chymase CMA1, phylogenetic homolog of Mcpt5, stimulated the ex vivo migration of human trophoblasts, a pre-requisite for SA remodeling. Our results show that chymases secreted by uMCs and uNKs are pivotal to the vascular changes required to support pregnancy. Understanding the mechanisms underlying pregnancy-induced vascular changes is essential for developing therapeutic options against pregnancy complications associated with poor vascular remodeling.

  18. Chymase-producing cells of the innate immune system are required for decidual vascular remodeling and fetal growth

    PubMed Central

    Meyer, Nicole; Woidacki, Katja; Knöfler, Martin; Meinhardt, Gudrun; Nowak, Désirée; Velicky, Philipp; Pollheimer, Jürgen; Zenclussen, Ana C.

    2017-01-01

    Intrauterine growth restriction (IUGR) is caused by insufficient remodeling of spiral arteries (SAs). The mechanism underlying the relevance of natural killer cells (NKs) and mast cells (MCs) for SA remodeling and its effects on pregnancy outcome are not well understood. We show that NK depletion arrested SA remodeling without affecting pregnancy. MC depletion resulted in abnormally remodeled SAs and IUGR. Combined absence of NKs and MCs substantially affected SA remodeling and impaired fetal growth. We found that α-chymase mast cell protease (Mcpt) 5 mediates apoptosis of uterine smooth muscle cells, a key feature of SA remodeling. Additionally, we report a previously unknown source for Mcpt5: uterine (u) NKs. Mice with selective deletion of Mcpt5+ cells had un-remodeled SAs and growth-restricted progeny. The human α-chymase CMA1, phylogenetic homolog of Mcpt5, stimulated the ex vivo migration of human trophoblasts, a pre-requisite for SA remodeling. Our results show that chymases secreted by uMCs and uNKs are pivotal to the vascular changes required to support pregnancy. Understanding the mechanisms underlying pregnancy-induced vascular changes is essential for developing therapeutic options against pregnancy complications associated with poor vascular remodeling. PMID:28327604

  19. Intracellular growth of Mycobacterium tuberculosis after macrophage cell death leads to serial killing of host cells.

    PubMed

    Mahamed, Deeqa; Boulle, Mikael; Ganga, Yashica; Mc Arthur, Chanelle; Skroch, Steven; Oom, Lance; Catinas, Oana; Pillay, Kelly; Naicker, Myshnee; Rampersad, Sanisha; Mathonsi, Colisile; Hunter, Jessica; Sreejit, Gopalkrishna; Pym, Alexander S; Lustig, Gila; Sigal, Alex

    2017-01-28

    A hallmark of pulmonary tuberculosis is the formation of macrophage-rich granulomas. These may restrict Mycobacterium tuberculosis (Mtb) growth, or progress to central necrosis and cavitation, facilitating pathogen growth. To determine factors leading to Mtb proliferation and host cell death, we used live cell imaging to track Mtb infection outcomes in individual primary human macrophages. Internalization of Mtb aggregates caused macrophage death, and phagocytosis of large aggregates was more cytotoxic than multiple small aggregates containing similar numbers of bacilli. Macrophage death did not result in clearance of Mtb. Rather, it led to accelerated intracellular Mtb growth regardless of prior activation or macrophage type. In contrast, bacillary replication was controlled in live phagocytes. Mtb grew as a clump in dead cells, and macrophages which internalized dead infected cells were very likely to die themselves, leading to a cell death cascade. This demonstrates how pathogen virulence can be achieved through numbers and aggregation states.

  20. AMPK Regulation of Cell Growth, Apoptosis, Autophagy, and Bioenergetics.

    PubMed

    Paz, Marina Villanueva; Cotán, David; Maraver, Juan Garrido; Oropesa-Ávila, Manuel; de la Mata, Mario; Pavón, Ana Delgado; de Lavera, Isabel; Gómez, Elizabet Alcocer; Córdoba, Mónica Álvarez; Alcázar, José A Sánchez

    2016-01-01

    In eukaryotic cells, AMP-activated protein kinase (AMPK) generally promotes catabolic pathways that produce ATP and at the same time inhibits anabolic pathways involved in different processes that consume ATP. As an energy sensor, AMPK is involved in the main cellular functions implicated in cell fate, such as cell growth and autophagy.Recently, AMPK has been connected with apoptosis regulation, although the molecular mechanism by which AMPK induces and/or inhibits cell death is not clear.This chapter reviews the essential role of AMPK in signaling pathways that respond to cellular stress and damage, highlighting the complex and reciprocal regulation between AMPK and their targets and effectors. The therapeutic implications of the role of AMPK in different pathologies such as diabetes, cancer, or mitochondrial dysfunctions are still controversial, and it is necessary to further investigate the molecular mechanisms underlying AMPK activation.

  1. Large-cell Monte Carlo renormalization of irreversible growth processes

    NASA Technical Reports Server (NTRS)

    Nakanishi, H.; Family, F.

    1985-01-01

    Monte Carlo sampling is applied to a recently formulated direct-cell renormalization method for irreversible, disorderly growth processes. Large-cell Monte Carlo renormalization is carried out for various nonequilibrium problems based on the formulation dealing with relative probabilities. Specifically, the method is demonstrated by application to the 'true' self-avoiding walk and the Eden model of growing animals for d = 2, 3, and 4 and to the invasion percolation problem for d = 2 and 3. The results are asymptotically in agreement with expectations; however, unexpected complications arise, suggesting the possibility of crossovers, and in any case, demonstrating the danger of using small cells alone, because of the very slow convergence as the cell size b is extrapolated to infinity. The difficulty of applying the present method to the diffusion-limited-aggregation model, is commented on.

  2. Bacterial actin and tubulin homologs in cell growth and division.

    PubMed

    Busiek, Kimberly K; Margolin, William

    2015-03-16

    In contrast to the elaborate cytoskeletal machines harbored by eukaryotic cells, such as mitotic spindles, cytoskeletal structures detectable by typical negative stain electron microscopy are generally absent from bacterial cells. As a result, for decades it was thought that bacteria lacked cytoskeletal machines. Revolutions in genomics and fluorescence microscopy have confirmed the existence not only of smaller-scale cytoskeletal structures in bacteria, but also of widespread functional homologs of eukaryotic cytoskeletal proteins. The presence of actin, tubulin, and intermediate filament homologs in these relatively simple cells suggests that primitive cytoskeletons first arose in bacteria. In bacteria such as Escherichia coli, homologs of tubulin and actin directly interact with each other and are crucial for coordinating cell growth and division. The function and direct interactions between these proteins will be the focus of this review.

  3. Sphingosine kinase-1 mediates androgen-induced osteoblast cell growth

    SciTech Connect

    Martin, Claire; Lafosse, Jean-Michel; Malavaud, Bernard; Cuvillier, Olivier

    2010-01-01

    Herein we report that the lipid kinase sphingosine kinase-1 (SphK1) is instrumental in mediating androgen-induced cell proliferation in osteoblasts. Dihydrotestosterone (DHT) triggered cell growth in steroid-deprived MC3T3 cells, which was associated with a rapid stimulation of SphK1 and activation of both Akt and ERK signaling pathways. This mechanism relied on functional androgen receptor/PI3K/Akt nongenotropic signaling as pharmacological antagonists could block SphK1 stimulation by DHT and its consequences. Finally, SphK1 inhibition not only abrogated DHT-induced ERK activation but also blocked cell proliferation, while ERK inhibition had no impact, suggesting that SphK1 was critical for DHT signaling yet independently of the ERK.

  4. B-cell receptor configuration and mutational analysis of patients with chronic lymphocytic leukaemia and trisomy 12 reveal recurrent molecular abnormalities.

    PubMed

    Falisi, Erika; Novella, Elisabetta; Visco, Carlo; Guercini, Nicola; Maura, Francesco; Giaretta, Ilaria; Pomponi, Fabrizio; Nichele, Ilaria; Finotto, Silvia; Montaldi, Annamaria; Neri, Antonino; Rodeghiero, Francesco

    2014-03-01

    Trisomy 12 (+12) is the third most frequent cytogenetic aberration in chronic lymphocytic leukaemia (CLL) retrievable both as the sole chromosomal abnormality or in association with additional alterations. NOTCH1 mutations are known to be more prevalent among +12 patients, whereas mutations of FBXW7, a gene involved in NOTCH1 degradation, that lead to the constitutional activation of NOTCH1 have not been investigated in this setting. We analyzed a unicentric cohort of 44 +12 patients with CLL for mutations of TP53, NOTCH1 and FBXW7 genes, and we correlated them with B-cell receptor (BCR) configurations. FBXW7, TP53 and NOTCH1 mutations were identified in 4.5%, 6.8% and 18.2% of patients, respectively. FBXW7 and NOTCH1 mutations appeared in a mutually exclusive fashion, suggesting that both aberrations might affect the same biological pathway. We found that 44.1% of +12 CLL patients had stereotyped B-cell receptors, which is significantly higher than that observed in patients with CLL and no +12 (27%, p = 0.01). Subsets #1, #8, #10, #28 and #59 were the most represented stereotyped patterns, and IGHV4-39*01 was the gene configuration most commonly used. There was a significantly higher risk for Richter's syndrome (RS) transformation in patients with NOTCH1 or FBXW7 mutations, with four of the seven (57%) patients developing RS and characterized at least by one of the two abnormalities. These observations suggest that, similarly to the aberrations of NOTCH1, FBXW7 gene mutations may also result in cell proliferation and evasion from apoptosis in patients with +12 CLL. Together with the extremely high frequency of stereotyped BCRs and RS transformation, these abnormalities appear to cluster in these CLL patients with additional chromosome 12, suggesting a connection with the prognosis of the disease.

  5. Genomic imprinting in development, growth, behavior and stem cells.

    PubMed

    Plasschaert, Robert N; Bartolomei, Marisa S

    2014-05-01

    Genes that are subject to genomic imprinting in mammals are preferentially expressed from a single parental allele. This imprinted expression of a small number of genes is crucial for normal development, as these genes often directly regulate fetal growth. Recent work has also demonstrated intricate roles for imprinted genes in the brain, with important consequences on behavior and neuronal function. Finally, new studies have revealed the importance of proper expression of specific imprinted genes in induced pluripotent stem cells and in adult stem cells. As we review here, these findings highlight the complex nature and developmental importance of imprinted genes.

  6. Induction of micronuclei and sister chromatid exchange in bone-marrow cells and abnormalities in sperm of Algerian mice (Mus spretus) exposed to cadmium, lead and zinc.

    PubMed

    Tapisso, Joaquim Torres; Marques, Carla Cristina; Mathias, Maria da Luz; Ramalhinho, Maria da Graça

    2009-08-01

    As a consequence of human activities, large amounts of cadmium, lead and zinc are released in the environment, often simultaneously. The aim of this study was to investigate under experimental conditions the DNA damage induced in Algerian mice (Mus spretus) exposed to cadmium (Cd), lead (Pb) and zinc (Zn) separately, or in selected combinations. Three cytogenetic end points were considered: the frequencies of micronucleated cells (MN) and sister chromatid exchange (SCE) in the bone marrow and the frequency of sperm abnormalities. Mice were treated by intraperitoneal (i.p.) injections with 5 or 10 doses of aqueous solutions of cadmium acetate, lead acetate and zinc acetate in concentrations corresponding to 1/10 of the LD50, respectively, 21.5, 0.46 and 1.5 mg/kg bw. The control groups were injected in the same way with distilled water. With only one exception (Cd + Zn group treated with 5 doses), the results show a significant increase of MN in all groups for both treatments (5 and 10 doses). Similarly, the results concerning the SCE revealed a statistically significant increase in all treated animals, with the exception of the Zn group treated with 5 doses. The number of sperm abnormalities was significantly higher in animals treated with 5 doses, except in the group Pb + Zn. In animals treated with 10 doses the number of sperm abnormalities was always statistically higher compared with controls. This study indicates that cadmium, lead and zinc can induce MN, SCEs and sperm abnormalities in Algerian mice and that the clastogenic potential is dependent on the time of exposure and the interaction between the three elements, confirming the environmental damage that may result from the simultaneous action of several metals. Most relevant is the toxic potential for Zn, related with the dose, which may compromise its protective effect against other metal contaminations, such as cadmium.