WorldWideScience

Sample records for proliferative activity s-phase

  1. Proliferative Activity and Neuroprotective Effect of Ligustrazene ...

    African Journals Online (AJOL)

    Proliferative Activity and Neuroprotective Effect of. Ligustrazene Derivative by Irritation of Vascular. Endothelial Growth Factor Expression in Middle Cerebral. Artery Occlusion Rats. Zhang Huazheng1, Wang Penglong2, Ren Liwei1, Wang Xiaobo2, Li Guoliang2,. Wang Mina1, Chu Fuhao2, Gong Yan2, Xu Bing2, Bi Siling1, ...

  2. Proliferative activity of stomach cancer and assessment of individual radiosensitivity

    International Nuclear Information System (INIS)

    Chissov, V.I.; Sergeeva, N.S.; Dar'yalova, S.L.; Petrov, A.N.; Repina, A.G.; Belous, T.A.; Pelevina, I.I.

    1991-01-01

    An indirect immunofluorescent method with polyclonal antibodies to thymidine was used to assess the proliferative activity (PA-percent of cells in the S-phase of the cell cycle) of 79 stomach tumors from primary cancer patients. Stomach cancer PA was shown to vary from 0.1 to 69.7%. Stomach cancer PA did not depend either on a tumor size or a degree of the involvement of regional lymph nodes. The mean PA of well-differentiated adenocarcinoma was slightly lower (14.9±4.7%) than that of low differentiated ones. Of 79 patients a tumor process was interpreted as a resectable one in 62. They were given preoperative irradiation at a total focal dose of 36 Gy followed by operation. It was shown that tumor radioresistance could be predicted in unchanged PA indices of their increase at the beginning of a course of irradiation with the probability of 95%

  3. Anti-proliferative activity of recombinant melittin expressed in ...

    African Journals Online (AJOL)

    Recombinant melittin was then successfully expressed in Escherichia coli. The activity of affinity-purified recombinant melittin was determined in human leukemic U937 cells. Results show that the recombinant melittin had the same anti-proliferative activity in human leukemic U937 cells in vitro as natural one. This shows the ...

  4. Antioxidant and Anti-proliferative Activities of Flavonoids from ...

    African Journals Online (AJOL)

    Purpose: To investigate the chemical composition of Bidens pilosa L. var. radiata. Sch Bip. (BP), as well as its antioxidant and anti-proliferative activities. Methods: The whole herb of BP was extracted with 95 % ethanol, which was then partitioned sequentially with petroleum ether, ethyl acetate and n-butyl alcohol to obtain ...

  5. Cdc7 is required throughout the yeast S phase to activate replication origins.

    Science.gov (United States)

    Donaldson, A D; Fangman, W L; Brewer, B J

    1998-02-15

    The long-standing conclusion that the Cdc7 kinase of Saccharomyces cerevisiae is required only to trigger S phase has been challenged by recent data that suggests it acts directly on individual replication origins. We tested the possibility that early- and late-activated origins have different requirements for Cdc7 activity. Cells carrying a cdc7(ts) allele were first arrested in G1 at the cdc7 block by incubation at 37 degrees C, and then were allowed to enter S phase by brief incubation at 23 degrees C. During the S phase, after return to 37 degrees C, early-firing replication origins were activated, but late origins failed to fire. Similarly, a plasmid with a late-activated origin was defective in replication. As a consequence of the origin activation defect, duplication of chromosomal sequences that are normally replicated from late origins was greatly delayed. Early-replicating regions of the genome duplicated at approximately their normal time. The requirements of early and late origins for Cdc7 appear to be temporally rather than quantitatively different, as reducing overall levels of Cdc7 by growth at semi-permissive temperature reduced activation at early and late origins approximately equally. Our results show that Cdc7 activates early and late origins separately, with late origins requiring the activity later in S phase to permit replication initiation.

  6. NLRP3 inflammasome activation is associated with proliferative diabetic retinopathy.

    Science.gov (United States)

    Loukovaara, Sirpa; Piippo, Niina; Kinnunen, Kati; Hytti, Maria; Kaarniranta, Kai; Kauppinen, Anu

    2017-12-01

    Innate immunity and dysregulation of inflammatory processes play a role in vascular diseases like atherosclerosis or diabetes. Nucleotide-binding domain and Leucine-rich repeat Receptor containing a Pyrin domain 3 (NLRP3) inflammasomes are pro-inflammatory signalling complexes that were found in 2002. In addition to pathogens and other extracellular threats, they can be activated by various endogenous danger signals. The purpose of this study was to find out whether NLRP3 activation occurs in patients with sight-threatening forms of diabetic retinopathy (DR). Inflammasome components NLRP3 and caspase-1, inflammasome-related pro-inflammatory cytokines IL-1β and IL-18, vascular endothelial growth factor (VEGF), acute-phase cytokines TNF-α and IL-6, as well as adaptive immunity-related cytokine interferon gamma (IFN-γ) were measured from the vitreous samples of 15 non-proliferative diabetic retinopathy (non-PDR) and 23 proliferative diabetic retinopathy (PDR) patients using the enzyme-linked immunosorbent assay (ELISA) method. The adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) was determined using the Western blot technique. Inflammasome components were present in the vitreous of DR patients. Along with VEGF, the levels of caspase-1 and IL-18 were significantly increased, especially in PDR eyes. Interestingly, clearly higher levels of NLRP3 were found in the PDR eyes with tractional retinal detachment (TRD) than from PDR eyes with fully attached retina. There were no significant differences in the amounts of IL-1β, TNF-α, IL-6, and IFN-γ that were detectable in the vitreous of both non-PDR and PDR patients. Our results suggest that NLRP3 inflammasome activation can be associated especially with the pathogenesis of PDR. The lack of differences in TNF-α, IL-6, and IFN-γ also alludes that acute inflammation or T-cell-mediated responses do not dominate in PDR pathogenesis. © 2017 Acta Ophthalmologica Scandinavica Foundation

  7. Proliferative activity as a prognostic factor of a human tumor radiation reactions

    International Nuclear Information System (INIS)

    Karakulov, R.K.; Pelevina, I.I.

    1986-01-01

    The following questions are considered: 1) whether cell proliferation initial parameters can serve for predicting the tumor radial reaction; 2) whether proliferative activity change can be a criterion for estimating the treatment efficiency; 3) acquisition of data on biological peculiarities of different types of tumors. Connection between proliferative activity drop and clinical reaction under tumor radiotherapy is ascertained

  8. Correlation between proliferative activity and cellular thickness of human mesenchymal stem cells

    International Nuclear Information System (INIS)

    Katsube, Yoshihiro; Hirose, Motohiro; Nakamura, Chikashi; Ohgushi, Hajime

    2008-01-01

    A cell's shape is known to be related to its proliferative activity. In particular, large and flat mammalian adult stem cells seem to show slow proliferation, however using quantitative analysis to prove the phenomenon is difficult. We measured the proliferation and cellular thickness of human mesenchymal stem cells (MSCs) by atomic force microscopy and found that MSCs with high proliferative activity were thick while those with low proliferative activity were thin, even though these MSCs were early passage cells. Further, low proliferative MSCs contained many senescence-associated β-galactosidase positive cells together with high senescence-associated gene expression. These findings suggest that the measurement of cellular thickness is useful for estimating the proliferative activity of human MSCs and is expected to be a practical tool for MSC applications in regenerative medicine

  9. Proliferative activity in oral pyogenic granuloma: A comparative immunohistochemical study

    Directory of Open Access Journals (Sweden)

    Rezvani Gita

    2010-07-01

    Full Text Available Context: Pyogenic granuloma (PG is one of the most common reactive vascular lesions in the oral mucosa, which has been divided into the lobular capillary hemangioma (LCH and the non lobular type (non-LCH as two distinct entities, on the basis of some investigations. Aims: This study aims to compare the proliferative and angiogenic activity of two histological types of PG to determine whether they have two distinct types of biological behavior. Settings and Design: In this retrospective cross-sectional study, immunostaining was performed on 10 cases of each type of PG. Materials and Methods: About 4μm sections were cut from formalin-fixed paraffin-embedded blocks and each specimen was stained with both anti-CD31 and anti-Ki-67 antibodies simultaneously. Labeling index (LI was determined for both types by counting Ki-67 and CD31 positive cells separately and simultaneously in 1000 stromal and luminal cells. Micro vessel count (MVC, the mean number of micro vessels in five areas at Χ200 magnification, was also determined for both groups. Statistical Analysis: The results were statistically compared using the Mann-Whitney U-test. Results: Ki-67 LI in LCH (5.4 ± 2.4 was higher than non-LCH (3.9 ± 3.9. The percentage of CD31 positive cells in LCH (28.5 ± 22 was lower than non-LCH (37.1 ± 20.8 and simultaneously immunostaining for both markers in LCH type (2.4 ± 2.1 was higher than non-LCH (1.2 ± 1. The MVC was approximately 77.35 ± 34.6 and 82.6 ± 42.7 in the lobular areas of LCH and central areas of non-LCH PG, respectively. These differences were not statistically significant. Conclusions: These results demonstrate a higher proliferation activity in endothelial cells of LCH PG than in non-LCH.

  10. Epithelial cell proliferative activity of Barrett's esophagus : methodology and correlation with traditional cancer risk markers

    NARCIS (Netherlands)

    Peters, FTM; Ganesh, S; Kuipers, EJ; De Jager-Krikken, A; Karrenbeld, A; Harms, Geert; Sluiter, WJ; Koudstaal, J; Klinkenberg-Knol, EC; Lamers, CBHW; Kleibeuker, JH

    Barrett's esophagus (BE) is a premalignant condition, due to chronic gastroesophageal reflux. Effective antireflux therapy may diminish cancer risk. To evaluate this option an intermediate marker is needed. We developed a methodology for measurement of epithelial cell proliferative activity of

  11. Multiple determinants controlling activation of yeast replication origins late in S phase.

    Science.gov (United States)

    Friedman, K L; Diller, J D; Ferguson, B M; Nyland, S V; Brewer, B J; Fangman, W L

    1996-07-01

    Analysis of a 131-kb segment of the left arm of yeast chromosome XIV beginning 157 kb from the telomere reveals four highly active origins of replication that initiate replication late in S phase. Previous work has shown that telomeres act as determinants for late origin activation. However, at least two of the chromosome XIV origins maintain their late activation time when located on large circular plasmids, indicating that late replication is independent of telomeres. Analysis of the replication time of plasmid derivatives containing varying amounts of chromosome XIV DNA show that a minimum of three chromosomal elements, distinct from each tested origin, contribute to late activation time. These late determinants are functionally equivalent, because duplication of one set of contributing sequences can compensate for the removal of another set. Furthermore, insertion of an origin that is normally early activated into this domain results in a shift to late activation, suggesting that the chromosome XIV origins are not unique in their ability to respond to the late determinants.

  12. Effect of С(60 fullerene on metabolic and proliferative activity of PKE cell line

    Directory of Open Access Journals (Sweden)

    I. V. Belochkina

    2014-04-01

    Full Text Available The effect of С60 fullerene aqueous colloid solution (C60FAS on activity of redox and proliferative processes in PKE (transplantable cell line of pig kidney embryo cells has been studied. In particular, it was established that the presence of С60 fullerene (127 μМ in culturing medium of PKE cells during 48 h did not change their ability to reduce non-toxic АlamarBlue redox indicator and proliferative acti­vity.

  13. [A correlation between diffusion kurtosis imaging and the proliferative activity of brain glioma].

    Science.gov (United States)

    Tonoyan, A S; Pronin, I N; Pitshelauri, D I; Shishkina, L V; Fadeeva, L M; Pogosbekyan, E L; Zakharova, N E; Shults, E I; Khachanova, N V; Kornienko, V N; Potapov, A A

    2015-01-01

    The aim of the study was to assess the capabilities of diffusion kurtosis imaging (DKI) in diagnosis of the glioma proliferative activity and to evaluate a relationship between the glioma proliferative activity index and diffusion parameters of the contralateral normal appearing white matter (CNAWM). The study included 47 patients with newly diagnosed brain gliomas (23 low grade, 13 grade III, and 11 grade IV gliomas). We determined a relationship between absolute and normalized parameters of the diffusion tensor (mean (MD), axial (AD), and radial (RD) diffusivities; fractional (FA) and relative (RA) anisotropies) and diffusion kurtosis (mean (MK), axial (AK), and radial (RK) kurtosis; kurtosis anisotropy (KA)) and the proliferative activity index in the most malignant glioma parts (pAK, and RK) and anisotropy (KA, FA, RA) values increased, and diffusivity (MD, AD, RD) values decreased as the glioma proliferative activity index increased. A strong correlation between the proliferative activity index and absolute RK (r=0,71; p=0.000001) and normalized values of MK (r=0.8; p=0.000001), AK (r=0.71; p=0.000001), RK (r=0.81; p=0.000001), and RD (r=-0.71; p=0.000001) was found. A weak, but statistically significant correlation between the glioma proliferative activity index and diffusion values RK (r=-0.36; p=0.014), KA (r=-0.39; p=0.007), RD (r=0.35; p=0.017), FA (r=-0.42; p=0.003), and RA (r=-0.41; p=0.004) of CNAWM was found. DKI has good capabilities to detect immunohistochemical changes in gliomas. DKI demonstrated a high sensitivity in detection of microstructural changes in the contralateral normal appearing white matter in patients with brain gliomas.

  14. Analysis of in situ proliferative activity in oral gingival epithelium in patients with xerostomia.

    Science.gov (United States)

    Celenligil-Nazliel, Haviye; Palali, Ali; Ayhan, Ayşe; Ruacan, Sevket

    2003-02-01

    Sjögren's syndrome is an autoimmune disease characterized by xerostomia and keratoconjunctivitis sicca. The relationship between xero-stomia and proliferative activity in human gingival epithelium is not known. Proliferating cell nuclear antigen (PCNA) is a nuclear protein associated with the cell cycle. Nuclear PCNA immunoreactivity is found in the proliferative compartment of normal tissues. The aims of this study were to evaluate PCNA expression in oral gingival epithelium of healthy and inflamed gingiva obtained from patients with Sjögren's syndrome, and to compare the results to age- and gender-matched subjects with normal salivary function. Eighteen Sjögren's syndrome patients and 28 controls (14 with chronic periodontitis and 14 with no clinical evidence of periodontal disease) were included in the study. Biopsies were obtained from both inflamed and healthy gingiva. The expression of PCNA was evaluated in formalin-fixed, paraffin-embedded gingival samples using an immunoperoxidase technique and PC10 monoclonal antibody to PCNA. PCNA expression was observed both in the basal and suprabasal layers, and was found to be more prominent in the suprabasal layers. Proliferative index (PI) in inflamed gingiva was significantly lower in the Sjögren's syndrome group. However, no significant difference was observed between the study and control groups with respect to PI in healthy gingiva. In both groups, PI was found to be increased due to inflammation. Our data indicate that proliferative activity is observed in the suprabasal layers and, less frequently, in the basal layer. Inflammation caused increased proliferative activity. However, this positive effect of inflammation on epithelial cell proliferation decreased significantly with a lack of saliva. Therefore, it appears that saliva-derived biological mediators may also contribute to increased proliferative activity observed during inflammation.

  15. Anti-proliferative activity of recombinant melittin expressed in ...

    African Journals Online (AJOL)

    kesiena

    2012-02-09

    Feb 9, 2012 ... 44 amino acid residues mediated by dipeptidylpeptidase. IV (Vlasak et al., 1983). It has been reported that the melittin exhibits antimicrobial activity and pro- ... Construction of recombinant expression vector. A pair of complementary oligonucleotides named Mel-1 (5′-GAT. CCG GAA TTG GAG CAG TTC ...

  16. Cytosol cathepsin-D content and proliferative activity of human breast cancer. The Comitato Italiano per il Controllo di Qualita del Laboratorio in Oncologia.

    Science.gov (United States)

    Paradiso, A; Mangia, A; Correale, M; Abbate, I; Ferri, G; Piffanelli, A; Catozzi, L; Amadori, D; Riccobon, A; De Lena, M

    1992-01-01

    Mitogenic properties have been demonstrated in vitro for the lysosomal acidic protease cathepsin-D (cath-D). We investigated possible relationships between cath-D cytosol cell content and tumor proliferative activity in a series of 129 operable breast cancer patients. For total cytosol cath-D evaluation, a solid phase two-site immunoradiometric assay was utilized on tumor cell cytosol obtained for hormone receptor assay (DCC method). The percentage of S-phase cells was analyzed by 3H-thymidine autoradiographic assay. Median 3H-thymidine Labeling Index (3H-Tdr-LI) of the series was 2.7%; median cath-D content resulted 57 pmol/mg of protein cytosol and was significantly higher in node-positive with respect to the node-negative subgroup (p < 0.03). When classified in low, intermediate or high tumor cath-D content and slow or fast proliferative activity (cut-off: median values of the series), no significant agreement was found between the two variables. Statistical analysis, however, showed that a significant inverse correlation existed in node positive tumors between cath-D and 3H-Tdr-LI values which was even more evident in N-positive high estrogen receptor-positive (ER+) cases (coefficient of correlation = 0.6828; p = 0.0001). Cytosol cath-D content cannot be generally proposed as a direct marker of proliferative activity for operable breast cancer.

  17. Proliferative and antioxidant activity of Symphytum officinale root extract.

    Science.gov (United States)

    Sowa, Ireneusz; Paduch, Roman; Strzemski, Maciej; Zielińska, Sylwia; Rydzik-Strzemska, Ewelina; Sawicki, Jan; Kocjan, Ryszard; Polkowski, Janusz; Matkowski, Adam; Latalski, Michał; Wójciak-Kosior, Magdalena

    2018-03-01

    The root of Symphytum officinale L. is commonly used in folk medicine to promote the wound healing, reduce the inflammation and in the treatment of broken bones. The objective of our investigation was to analyse the extract from S. officinale in term of its antioxidant activity and the effect on cell viability and proliferation of human skin fibroblast (HSF). Moreover, the quantification of main phenolics and allantoin was conducted using HPLC-DAD method. Five compounds were found: rosmarinic, p-hydroxybenzoic, caffeic, chlorogenic and p-coumaric acid. DPPH, FRAP and TPC assay showed the high antioxidant activity of the extract. MTT test proved the stimulatory effect on cell metabolism and viability of HSF cells. Moreover, no changes in cytoskeleton structure and cells shape were observed. The obtained results indicate that non-toxic extract from S. officinale root has strong antioxidant potential and a beneficial effect on human skin fibroblasts.

  18. Nuclear AP4A-binding activity of sea urchin embryos changes in relation to the initiation of S phase

    International Nuclear Information System (INIS)

    Morioka, M.; Shimada, H.

    1986-01-01

    The AP 4 A-binding activity of sea urchin embryos was studied using radioactively labelled diadenosine 5', 5'''-P 1 ,P 4 -tetraphosphate (Ap 4 A). Among various subcellular components that can bind [ 3 H]AP 4 A, nuclei alone showed the highly specific Ap 4 A-binding activity which was not influenced by the presence of AP 4 A, AP 5 A and GP 4 G. The addition of an excess amount of ATP only slightly reduced the binding of [ 3 H]AP 4 A to the nuclei. It was found that AP 4 A binds to the residual proteinaceous structure of nuclei which was resistant to the extraction with 2 M NaCl. The nuclear AP 4 A-binding activity fluctuated cyclically during each cell cycle, with at transient increase at the beginning of S phase followed by an abrupt-decrease within 10 min. When the initiation of S phase was blocked, the increase in the AP 4 A-binding activity was also prevented. It seems that the binding of AP 4 A to the nuclear structural protein is involved in the initiation of S phase

  19. Effect of postradiation bleeding on proliferative activity of cells in small intestine crypts of rats

    Energy Technology Data Exchange (ETDEWEB)

    Petrovic, N V [Institut za Nuklearne Nauke Boris Kidric, Vinca (Yugoslavia)

    1975-12-01

    The effect of postradiation bleeding on the dynamics of duodenal crypt's cell proliferation in rats was studied. The animals, females, three months old, weighing 170 or 180 g, were exposed to radiation of 800 R (115 R/min) and immediately after irradiation were bled by cardiac puncture to 50% of total blood volume. Proliferative activity of duodenal epithelium cells was monitored for a period of five days after irradiation. For control purposes normal, irradiated and only bled animals were used. The results demonstrated that although there are no significant differences in proliferative activity of duodenal epithelium cells in irradiated and bled animals and only irradiated animals, the postradiation reparative processes in irradiated and bled animals is considerably more stable. It is considered that bleeding itself by its hypoxic activity reduced the sensitivity of epithelium to the dose of radiation used. On the other hand, bleeding removed the damaging agents which appear after total body irradiation.

  20. Moxifloxacin and ciprofloxacin induces S-phase arrest and augments apoptotic effects of cisplatin in human pancreatic cancer cells via ERK activation

    International Nuclear Information System (INIS)

    Yadav, Vikas; Varshney, Pallavi; Sultana, Sarwat; Yadav, Jyoti; Saini, Neeru

    2015-01-01

    Pancreatic cancer, one of the most dreadful gastrointestinal tract malignancies, with the current chemotherapeutic drugs has posed a major impediment owing to poor prognosis and chemo-resistance thereby suggesting critical need for additional drugs as therapeutics in combating the situation. Fluoroquinolones have shown promising and significant anti-tumor effects on several carcinoma cell lines. Previously, we reported growth inhibitory effects of fourth generation fluoroquinolone Gatifloxacin, while in the current study we have investigated the anti-proliferative and apoptosis-inducing mechanism of older generation fluoroquinolones Moxifloxacin and Ciprofloxacin on the pancreatic cancer cell-lines MIA PaCa-2 and Panc-1. Cytotoxicity was measured by MTT assay. Apoptosis induction was evaluated using annexin assay, cell cycle assay and activation of caspase-3, 8, 9 were measured by western blotting and enzyme activity assay. Herein, we found that both the fluoroquinolones suppressed the proliferation of pancreatic cancer cells by causing S-phase arrest and apoptosis. Blockade in S-phase of cell cycle was associated with decrease in the levels of p27, p21, CDK2, cyclin-A and cyclin-E. Herein we also observed triggering of extrinsic as well as intrinsic mitochondrial apoptotic pathway as suggested by the activation of caspase-8, 9, 3, and Bid respectively. All this was accompanied by downregulation of antiapoptotic protein Bcl-xL and upregulation of proapoptotic protein Bak. Our results strongly suggest the role of extracellular-signal-regulated kinases (ERK1/2), but not p53, p38 and c-JUN N-terminal kinase (JNK) in fluoroquinolone induced growth inhibitory effects in both the cell lines. Additionally, we also found both the fluoroquinolones to augment the apoptotic effects of broad spectrum anticancer drug Cisplatin via ERK. The fact that these fluoroquinolones synergize the effect of cisplatin opens new insight into therapeutic index in treatment of pancreatic

  1. Proliferative activity of vervet monkey bone marrow-derived adherent cells

    International Nuclear Information System (INIS)

    Kramvis, A.; Garnett, H.M.

    1987-01-01

    Vervet monkey bone marrow-derived adherent cell population cultured in Fischer's medium supplemented with 12.5% fetal calf serum and 12.5% horse serum consists of two cell shapes: fusiform (type I) and polygonal (type II). Limiting-dilution cloning of the cells suggested that the two morphologically distinct cell types belong to the same cellular system even though they differ in their proliferative capabilities. The labeling index of type II cells, as measured by autoradiography, was found to be consistently lower than that of type I cells. It is probable that these two phenotypes represent different stages of differentiation, where progenitor type I gives rise to type II cells. The bone marrow-derived adherent cells were found to be cytokinetically at rest in vivo, using the thymidine suicide test, and relatively radioresistant with a D0 = 2.1 Gy and n = 2.36 at the time of explantation from the bone. Furthermore, in culture these cells are characterized by a relatively long cell cycle of 60 h, where the length of the S phase is 30 h, G2 is 12 h, M is 6 h, and G1 is 12 h. Thus, the vervet monkey bone marrow-derived adherent cells represent a cell population with a low turnover rate both in vivo and in vitro

  2. Proliferative activity and branching morphogenesis in the human prostate: a closer look at pre- and postnatal prostate growth

    NARCIS (Netherlands)

    Xue, Y.; Sonke, G.; Schoots, C.; Schalken, J.; Verhofstad, A.; de la Rosette, J.; Smedts, F.

    2001-01-01

    To gain further insight into the molecular cell biologic features of prostate development, we investigated the proliferative activity of prostate epithelial and stromal cells and their topographic relationship with neuroendocrine (NE) cell distribution and regional heterogeneity. Consecutive

  3. Proliferative activity and branching morphogenesis in the human prostate: a closer look at pre- and postnatal prostate growth.

    NARCIS (Netherlands)

    Xue, Y.; Sonke, G.S.; Schoots, C.; Schalken, J.A.; Verhofstad, A.A.J.; Rosette, J.J.M.H.C. de la; Smedts, F.

    2001-01-01

    BACKGROUND: To gain further insight into the molecular cell biologic features of prostate development, we investigated the proliferative activity of prostate epithelial and stromal cells and their topographic relationship with neuroendocrine (NE) cell distribution and regional heterogeneity.

  4. Evaluation of in vitro anti-proliferative and immunomodulatory activities of compounds isolated from Curcuma longa

    Science.gov (United States)

    Yue, Grace G. L.; Chan, Ben C. L.; Hon, Po-Ming; Lee, Mavis Y. H.; Fung, Kwok-Pui; Leung, Ping-Chung; Lau, Clara B. S.

    2010-01-01

    The rhizome of Curcuma longa (CL) has been commonly used in Asia as a potential candidate for the treatment of different diseases, including inflammatory disorders and cancers. The present study evaluated the anti-proliferative activities of the isolated compounds (3 curcuminoids and 2 turmerones) from CL, using human cancer cell lines HepG2, MCF-7 and MDA-MB-231. The immunomodulatory activities of turmerones (α and aromatic) isolated from CL were also examined using human peripheral blood mononuclear cells (PBMC). Our results showed that the curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin) and α-turmerone significantly inhibited proliferation of cancer cells in dose-dependent manner. The IC50 values of these compounds in cancer cells ranged from 11.0–41.8 μg/ml. Alpha-turmerone induced MDA-MB-231 cells to undergo apoptosis, which was confirmed by annexin-V & propidium iodide staining, and DNA fragmentation assay. The caspase cascade was activated as shown by a significant decrease of procaspases-3, -8 and -9 in α-turmerone treated cells. Both α-turmerone and aromatic-turmerone showed stimulatory effects on PBMC proliferation and cytokine production. The anti-proliferative effect of α-turmerone and immunomodulatory activities of ar-turmerone were shown for the first time. The findings revealed the potential use of CL crude extract (containing curcuminoids and volatile oil including turmerones) as chemopreventive agent. PMID:20438793

  5. Nongenotoxic p53 activation protects cells against S-phase-specific chemotherapy

    DEFF Research Database (Denmark)

    Kranz, Dominique; Dobbelstein, Matthias

    2006-01-01

    Mutations in the tumor suppressor gene TP53 represent the most frequent genetic difference between tumor cells and normal cells. Here, we have attempted to turn this difference into an advantage for normal cells during therapy. Using the Mdm2 antagonist nutlin-3, we first activated p53 in U2OS an...... a killer to a protector of cells, with the potential to reduce unwanted side effects of chemotherapy....

  6. Hyper-activation of Notch3 amplifies the proliferative potential of rhabdomyosarcoma cells.

    Directory of Open Access Journals (Sweden)

    Maria De Salvo

    Full Text Available Rhabdomyosarcoma (RMS is a pediatric myogenic-derived soft tissue sarcoma that includes two major histopathological subtypes: embryonal and alveolar. The majority of alveolar RMS expresses PAX3-FOXO1 fusion oncoprotein, associated with the worst prognosis. RMS cells show myogenic markers expression but are unable to terminally differentiate. The Notch signaling pathway is a master player during myogenesis, with Notch1 activation sustaining myoblast expansion and Notch3 activation inhibiting myoblast fusion and differentiation. Accordingly, Notch1 signaling is up-regulated and activated in embryonal RMS samples and supports the proliferation of tumor cells. However, it is unable to control their differentiation properties. We previously reported that Notch3 is activated in RMS cell lines, of both alveolar and embryonal subtype, and acts by inhibiting differentiation. Moreover, Notch3 depletion reduces PAX3-FOXO1 alveolar RMS tumor growth in vivo. However, whether Notch3 activation also sustains the proliferation of RMS cells remained unclear. To address this question, we forced the expression of the activated form of Notch3, Notch3IC, in the RH30 and RH41 PAX3-FOXO1-positive alveolar and in the RD embryonal RMS cell lines and studied the proliferation of these cells. We show that, in all three cell lines tested, Notch3IC over-expression stimulates in vitro cell proliferation and prevents the effects of pharmacological Notch inhibition. Furthermore, Notch3IC further increases RH30 cell growth in vivo. Interestingly, knockdown of Notch canonical ligands JAG1 or DLL1 in RMS cell lines decreases Notch3 activity and reduces cell proliferation. Finally, the expression of Notch3IC and its target gene HES1 correlates with that of the proliferative marker Ki67 in a small cohort of primary PAX-FOXO1 alveolar RMS samples. These results strongly suggest that high levels of Notch3 activation increase the proliferative potential of RMS cells.

  7. Cyclin E-induced S phase without activation of the pRb/E2F pathway

    DEFF Research Database (Denmark)

    Lukas, J; Herzinger, T; Hansen, Klaus

    1997-01-01

    In cells of higher eukaryotes, cyclin D-dependent kinases Cdk4 and Cdk6 and, possibly, cyclin E-dependent Cdk2 positively regulate the G1- to S-phase transition, by phosphorylating the retinoblastoma protein (pRb), thereby releasing E2F transcription factors that control S-phase genes. Here we...

  8. Synthesis, characterization, in vitro anti-proliferative and hemolytic activity of hydroxyapatite

    Science.gov (United States)

    Palanivelu, R.; Ruban Kumar, A.

    2014-06-01

    Hydroxyapatite (Ca10(PO4)6(OH)2, HAP) nanoparticles are widely used in several biomedical applications due to its compositional similarities to bone mineral, excellent biocompatibility and bioactivity, osteoconductivity. In this present investigation, HAP nanoparticles synthesized by precipitation technique using calcium nitrate and di-ammonium phosphate. The crystalline nature and the functional group analysis are confirmed using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and Fourier transform Raman spectroscopy (FT-Raman) respectively. The morphological observations are ascertained from field emission electron scanning electron microscope (FE-SEM) and transmission electron microscope (TEM). In vitro anti-proliferative and hemolytic activities are carried out on the synthesized HAP samples and the studies reveals that HAP have mild activity against erythrocytes.

  9. ROLE OF THE MORPHOMETRIC PARAMETERS OF INTRATUMORAL MICROVESSELS AND THE PROLIFERATIVE ACTIVITY OF TUMOR CELLS IN RENAL CELL CARCINOMA

    Directory of Open Access Journals (Sweden)

    N. A. Gorban

    2014-08-01

    Full Text Available Tumor cell proliferation and angiogenesis are essential factors for tumor growth, progression, and metastasis.Objective: to assess the relationship between the values of proliferative activity and the morphometric parameters of intratumoral microvessels in metastatic and localized carcinomas of the kidney.Materials and methods. Surgical specimens taken from 54 patients (32 men and 22 women aged 26 to 69 years (mean age 55 ± 1.5 years with the verified diagnosis of clear-cell renal cell carcinoma (RCC were studied.Conclusion. Proliferative activity and angioarchitectonics are an important biological characteristic of a tumor of unequal clinical value in RCC. Metastatic carcinoma has a higher proliferative activity and a low tumor vascularization than those of localized carcinoma.

  10. Synthesis, characterization and anti-proliferative activity of heterocyclic hypervalent organoantimony compounds.

    Science.gov (United States)

    Chen, Yi; Yu, Kun; Tan, Nian-Yuan; Qiu, Ren-Hua; Liu, Wei; Luo, Ning-Lin; Tong, Le; Au, Chak-Tong; Luo, Zi-Qiang; Yin, Shuang-Feng

    2014-05-22

    Three heterocyclic hypervalent organoantimony chlorides RN(CH2C6H4)2SbCl (2a R = t-Bu, 2b R = Cy, 2c R = Ph) and their chalcogenide derivatives [RN(CH2C6H4)2Sb]2O (3a R = t-Bu, 3b R = Cy, 3c R = Ph) were synthesized and characterized by techniques such as (1)H NMR, (13)C NMR, X-ray diffraction, and elemental analysis. It is found that the anti-proliferative activity detected over these compounds can be attributed to the coordination bond between the antimony and nitrogen atoms of these compounds. Moreover, a preliminary study on mechanistic action suggests that the inhibition effect is ascribable to cell cycle arrest and cell apoptosis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  11. PECULIARITIES OF PROLIFERATIVE ACTIVITY OF CERVICAL SQUAMOUS CANCER IN HIV INFECTION.

    Science.gov (United States)

    Lytvynenko, M; Shkolnikov, V; Bocharova, T; Sychova, L; Gargin, V

    2017-09-01

    Patients with human immunodeficiency virus (HIV) infection have a statistically significant increased risk of developing cervical cancer. The expression of the human Ki-67 protein is strictly associated with cell proliferation. The purpose of our work was detection of proliferative activity in cervical squamous cancer in women with HIV infection. We investigated 24 cases (12 patients with HIV and 12 patients without HIV infection) of cervical carcinoma, where biopsy had been performed before the treatment. According to histopathological diagnoses, well-differentiated, moderately and poorly differentiated squamous cell carcinoma (7, 13 and 4 cases respectively) was determined. Mean age of women in the group with HIV infection was 32.7 years, and 38.2 years in the group without HIV infection. Detection of protein Ki-67 expression was performed with nuclear staining in the intermediate and superficial cells. The results of this work show that proliferative activity of cervical squamous cancer in women with HIV infection is characterized by a higher level of Ki-67 with averaging level for all histological types of squamous cell carcinoma 62.5±5.6% that is one and half times higher than in group without HIV infection. Depending on a histological type, expression of Ki-67 has increased from 4.7±3.8% in well-differentiated squamous cell carcinoma up to 89.2±5.1% in poorly differentiated squamous cell carcinoma for group with HIV, and from 21.3±2.4% to 79.4±3.7 in group without HIV.

  12. In vitro anti-proliferative activity of clove extract on human gastric carcinoma

    Directory of Open Access Journals (Sweden)

    A. Karimi

    2017-10-01

    Full Text Available Background and objectives: Cancer cell resistance to common chemotherapy agents is on rise. Plants are considered valuable sources of herbal drugs for cancer therapy. The present study was conducted to investigate the in vitro antioxidant, anti-proliferative, and apoptosis-inducing properties of clove (Syzygium aromaticum L. extract in human gastric carcinoma (AGS. Methods: Crude ethanol extract of S. aromaticum dried buds was prepared and  in vitro anti-proliferative effects of the extract on AGS and normal Human dermal fibroblasts (HDF cell lines were studied by MTT assay. To examine apoptosis induction, AGS cells were incubated with IC50 concentrations of the extract, stained with propidium iodide (PI and annexin V-fluorescein isothiocyanate (FITC, and analyzed by flow cytometry. Antioxidant activity and total phenolics and flavonoids contents were evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH assay, Folin-Ciocalteu method, and aluminum chloride colorimetric method, respectively. Results: The IC50 of DPPH and total phenolics and flavonoids contents of the extract were 10.05±1.93 μg/mL, 225.6±40 mg GAE/g, and 29.30±2.35 mgRUT/g, respectively. The IC50 of the extract against HDFs was 649 µg/mL, higher than AGS cells, which was 118.7 g/mL at 48 h after treatment. Flow cytometric analysis showed that the extract induced cell apoptosis. Conclusions: Crude ethanol S. aromaticum extract had high total phenolics content, and suppressed the proliferation of human gastric cancer cells, likely due to apoptosis induction. Further studies should be conducted to determine the mechanisms of its anticancer effects.

  13. Calcium/calmodulin-dependent protein kinase II activity regulates the proliferative potential of growth plate chondrocytes.

    Science.gov (United States)

    Li, Yuwei; Ahrens, Molly J; Wu, Amy; Liu, Jennifer; Dudley, Andrew T

    2011-01-01

    For tissues that develop throughout embryogenesis and into postnatal life, the generation of differentiated cells to promote tissue growth is at odds with the requirement to maintain the stem cell/progenitor cell population to preserve future growth potential. In the growth plate cartilage, this balance is achieved in part by establishing a proliferative phase that amplifies the number of progenitor cells prior to terminal differentiation into hypertrophic chondrocytes. Here, we show that endogenous calcium/calmodulin-dependent protein kinase II (CamkII, also known as Camk2) activity is upregulated prior to hypertrophy and that loss of CamkII function substantially blocks the transition from proliferation to hypertrophy. Wnt signaling and Pthrp-induced phosphatase activity negatively regulate CamkII activity. Release of this repression results in activation of multiple effector pathways, including Runx2- and β-catenin-dependent pathways. We present an integrated model for the regulation of proliferation potential by CamkII activity that has important implications for studies of growth control and adult progenitor/stem cell populations.

  14. Roles of tissue plasminogen activator and its inhibitor in proliferative diabetic retinopathy

    Institute of Scientific and Technical Information of China (English)

    Shu-Ling; Wu; Dong-Mei; Zhan; Shu-Hong; Xi; Xiang-Lian; He

    2014-01-01

    AIM:To investigate the role of tissue plasminogen activator(t-PA) and plasminogen activator inhibitor(PAI)in proliferative diabetic retinopathy(PDR) and to discuss the correlations among t-PA, PAI and vascular endothelial growth factor(VEGF) expressions.METHODS:A total of 36 vitreous samples were collected from 36 patients with PDR(PDR group), and 17 vitreous samples from 17 patients with idiopathic macular hole were used as control. The concentrations of t-PA, PAI and VEGF in samples were determined by ELISA method. The correlations among t-PA, PAI and VEGF expressions were discussed.RESULTS:The concentrations of t-PA, PAI and VEGF in the PDR group were significantly higher than those in the control group(P <0.001). The t-PA and PAI expressions were highly correlated with the VEGF expression(P <0.001).CONCLUSION:In addition to VEGF, a variety of bioactive substances, such as t-PA and PAI, are involved in the pathogenesis involved in the angiogenesis of PDR.VEGF can activate t-PA expression, resulting in collagen tissue degradation and angiogenesis. VEGF may also activate the mechanism for endogenous anti-neovascularization.

  15. Cytological Study of Breast Carcinoma Before and After Oncotherapy with Special Reference to Morphometry and Proliferative Activity.

    Science.gov (United States)

    Koley, Sananda; Chakrabarti, Srabani; Pathak, Swapan; Manna, Asim Kumar; Basu, Siddhartha

    2015-12-01

    Our study was done to assess the cytological changes due to oncotherapy in breast carcinoma especially on morphometry and proliferative activity. Cytological aspirates were collected from a total of 32 cases of invasive ductal carcinoma both before and after oncotherapy. Morphometry was done on the stained cytological smears to assess the different morphological parameters of cell dimension by using the ocular morphometer and the software AutoCAD 2007. Staining was done with Ki-67 and proliferating cell nuclear antigen (PCNA) as proliferative markers. Different morphological parameters were compared before and after oncotherapy by unpaired Student's t test. Statistically significant differences were found in morphometric parameters, e.g., mean nuclear diameter, mean nuclear area, mean cell diameter, and mean cell area, and in the expression of proliferative markers (Ki-67 and PCNA). Statistical analysis was done by obtaining p values. There are statistically significant differences between morphological parameter of breast carcinoma cells before and after oncotherapy.

  16. Proliferative effects of apical, but not basal, matrix metalloproteinase-7 activity in polarized MDCK cells

    International Nuclear Information System (INIS)

    Harrell, Permila C.; McCawley, Lisa J.; Fingleton, Barbara; McIntyre, J. Oliver; Matrisian, Lynn M.

    2005-01-01

    Matrix metalloproteinase-7 (MMP-7) is primarily expressed in glandular epithelium. Therefore, its mechanism of action may be influenced by its regulated vectorial release to either the apical and/or basolateral compartments, where it would act on its various substrates. To gain a better understanding of where MMP-7 is released in polarized epithelium, we have analyzed its pattern of secretion in polarized MDCK cells expressing stably transfected human MMP-7 (MDCK-MMP-7), and HCA-7 and Caco2 human colon cancer cell lines. In all cell lines, latent MMP-7 was secreted to both cellular compartments, but was 1.5- to 3-fold more abundant in the basolateral compartment as compared to the apical. However, studies in the MDCK system demonstrated that MMP-7 activity was 2-fold greater in the apical compartment of MDCK-MMP-7 HIGH -polarized monolayers, which suggests the apical co-release of an MMP-7 activator. In functional assays, MMP-7 over-expression increased cell saturation density as a result of increased cell proliferation with no effect on apoptosis. Apical MMP-7 activity was shown to be responsible for the proliferative effect, which occurred, as demonstrated by media transfer experiments, through cleavage of an apical substrate and not through the generation of a soluble factor. Taken together, our findings demonstrate the importance of MMP-7 secretion in relation to its mechanism of action when expressed in a polarized epithelium

  17. Evaluation of viability and proliferative activity of human urothelial cells cultured onto xenogenic tissue-engineered extracellular matrices.

    LENUS (Irish Health Repository)

    Davis, Niall F

    2011-04-01

    To evaluate the viability and proliferative activity of human urothelial cells (HUCs) cultured on tissue-engineered extracellular matrix scaffolds and to assess the potential of extracellular matrixes to support the growth of HUCs in their expected in vivo urine environment.

  18. Effect of Enterococcus faecium EF 55 on morphometry and proliferative activity of intestinal mucosa in broilers infected with Salmonella Enteritidis

    Directory of Open Access Journals (Sweden)

    Ševčíková Zuzana

    2016-09-01

    Full Text Available Introduction: The present study aimed to investigate the effect of Enterococcus faecium EF55 on chickens, as well as its influence on proliferative activity of epithelial intestinal cells after infection with Salmonella enterica serovar Enteritidis phage type 4 (SE PT4. Moreover, the length and area of duodenal and jejunal villi of the birds were examined.

  19. Nuclear Morphometry in Ductal Breast Carcinoma with Correlation to Cell Proliferative Activity and Prognosis

    International Nuclear Information System (INIS)

    Radwan, M.M.; Amer, K.A.; Mokhtar, N.M.

    2003-01-01

    Morphometry is the quantitative description of biologic structures. This study was designed to evaluate the efficiency of morphometric measurements in diagnosis and prognosis of patients with breast carcinoma. Methods: Histological samples from 61 patients of invasive duct carcinoma (IDC) of no special type (NST), 12 cases of ductal carcinoma in situ (DCIS) and 14 control breast samples taken from fibrocystic change disease were retrospectively analyzed by computerized nuclear morphometry. All IDC patients underwent modified radical mastectomy without preoperative chemotherapy. The mean follow up was 28±19 months (range] -71). In each case, 25-50 nuclei were measured and the mean nuclear area (MNA), mean nuclear perimeter (MNP), mean maximum nuclear diameter (MMNO) and mean minimal nuclear diameter (Mmnd) were measured. The mean axis ratio (MAR), mean nuclear compactness (MNC), mean nuclear size (MNS) and mean shape factor (MSHF), were calculated mathematically. To measure the nuclear diameters, a new method was employed using the AutoCAD program. Morphometric parameters were compared with different clinico pathologic features, patient's survival and cell proliferative activity as determined by Ki-67 immunostaining which was evaluated quantitatively. Most of the morphometric parameters were significantly higher in DCIS and IDC groups than benign one. In IDC group morphometric features related to nuclear size (MNA, MNP, MMNO, Mmnd and MNS) were significantly correlated to most clinico pathologic features and cell proliferative activity assessed by Ki-67 immunostaining. However, the shape factor failed to achieve this correlation. The univariate analysis using Kaplan Meier curves indicated that short survival time was correlated with high nuclear morphometric values (MNA. MNP, MMND, Mmnd, MNS and MSHF). Moreover, the Spear man correlation analysis showed that Mmnd has the highest converse correlation with survival (r= -0.75, (ρ < 0.0001). In multivariate analysis

  20. Proliferative activity of elastin-like-peptides depends on charge and phase transition.

    Science.gov (United States)

    Yuan, Yuan; Koria, Piyush

    2016-03-01

    Elastin-like-peptides (ELPs) are stimulus-responsive protein-based polymers and are attractive biomaterials due to their biocompatibility and unique properties. This study shows that in addition to their physical properties, ELPs have biological activities that are conducive to tissue regeneration. Specifically, we found that ELPs induce fibroblast proliferation via cell surface heparan sulfate proteoglycans (HSPG). Furthermore, our data suggests that ELP based materials with differential proliferative potential can be designed by controlling the interaction of ELPs with HSPGs by incorporating either hydrophobic or positively charged residues within the ELP sequence. Fibroblast proliferation is important for granulation tissue formation which is important in chronic wounds as well as in healing of other tissues. The customizable biological activity of ELPs coupled with their unique physical properties will enable us to design novel, sustainable and cost effective therapies for different tissue regeneration applications. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 697-706, 2016. © 2015 Wiley Periodicals, Inc.

  1. Biocatalytically Oligomerized Epicatechin with Potent and Specific Anti-proliferative Activity for Human Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Ramaswamy Nagarajan

    2008-11-01

    Full Text Available Catechins, naturally occurring flavonoids derived from wine and green tea, are known to exhibit multiple health benefits. Epigallocatechin gallate (EGCG is one of the most widely investigated catechins, but its efficacy in cancer therapy is still inconsistent and limited. The poor stability of EGCG has contributed to the disparity in the reported anti-cancer activity and other beneficial properties. Here we report an innovative enzymatic strategy for the oligomerization of catechins (specifically epicatechin that yields stable, water-soluble oligomerized epicatechins with enhanced and highly specific anti-proliferative activity for human breast cancer cells. This one-pot oxidative oligomerization is carried out in ambient conditions using Horseradish Peroxidase (HRP as a catalyst yielding water-soluble oligo(epicatechins. The oligomerized epicatechins obtained exhibit excellent growth inhibitory effects against human breast cancer cells with greater specificity towards growth-inhibiting cancer cells as opposed to normal cells, achieving a high therapeutic differential. Our studies indicate that water-soluble oligomeric epicatechins surpass EGCG in stability, selectivity and efficacy at lower doses.

  2. Extraction, purification and anti-proliferative activities of polysaccharides from Lentinus edodes.

    Science.gov (United States)

    Zhao, Yong-Ming; Wang, Jin; Wu, Zhi-Gang; Yang, Jian-Ming; Li, Wei; Shen, Li-Xia

    2016-12-01

    In this study, the enzyme-assisted extraction of polysaccharides from Lentinus edodes (LEPs) was optimized by response surface methodology, and a preliminary characterization of the extracted LEPs and their anti-proliferative activities were investigated. An orthogonal assay was constructed to determine the optimal amounts of cellulase, papain and pectinase, which were 15, 20 and 15g/kg, respectively. Then effects of extraction conditions were evaluated and optimized using a Box-Behnken design. The results showed that the highest polysaccharides yield of 15.65% was achieved with an extraction temperature of 54°C, pH 5.0, enzymatic treatment time of 93min and a liquid/material ratio of 29:1mL/g, which correlated well with the predicted yield of 15.58%. Subsequently, the crude LEPs were further purified by DEAE-cellulose and Sephadex-100 chromatography to obtain two fractions, which were designated as LEP-1 and LEP-2 and their monosaccharide compositions were characterized by GC. Fourier-transform infrared spectra demonstrated that LEP-1 and LEP-2 were distinct from each other regarding their chemical structures. In addition, the LEPs exhibited inhibition of cell proliferation on HCT-116 and HeLa cells in vitro. In summary, this study provides an efficient enzyme-assisted extraction for LEPs, which can be used as natural antitumor agents in the pharmaceutical and functional food industries. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. In vitro anti-proliferative and anti-inflammatory activity of leaf and fruit extracts from Vaccinium bracteatum Thunb

    Czech Academy of Sciences Publication Activity Database

    Landa, Přemysl; Skálová, L.; Boušová, I.; Kutil, Zsófia; Langhansová, Lenka; Lou, J.D.; Vaněk, Tomáš

    2014-01-01

    Roč. 27, č. 1 (2014), s. 103-106 ISSN 1011-601X R&D Projects: GA MŠk ME08070 Institutional support: RVO:61389030 Keywords : anti-proliferative activity * anti-inflammatory activity * breast cancer Subject RIV: EI - Biotechnology ; Bionics Impact factor: 0.682, year: 2014 http://www.pjps.pk/wp-content/uploads/pdfs/27/1/Paper-15.pdf

  4. THE BIOTIC FACTOR OF TREMATOD OPISTHORHIS FELINEUS INVASION INFLUENCE ON HOST IMMUNE STATUS AND SOMATIC CELLS PROLIFERATIVE ACTIVITY

    Directory of Open Access Journals (Sweden)

    A. G. Rybka

    2016-01-01

    Full Text Available The paper confirms long-time opisthorhis invasion role as a risk factor of host immune system reconstitution as well as an important factor in holangiocarcinomas development. It was shown that opisthorhosis invasion primal stage induce host immune system reconstitution. Host immune B-cells system is activated by metacercaria antigens, while the same antigens inhibits T-cells activity. Opisthorhis metabolites stimulate proliferative mithogen-induced T-cells acti vity. Chronic opisthorchis invasion leads to immune system disbalance. It means: decrease of specific and non-speci fic natural killers activity, number of high proliferative activity T-lymphocytes and the shift of regulatory T-cells subset to suppressors prevalence. At the same time specific as well as non-specific T-suppressors functional ability is very low. It was shown T-cells helper-amplifier activation. Despite of circulating B-cells decrease the antibody produced cells number is spleen increases significantly at the same time with circulating immune complexes accumulation. Even 3–6 month after dehelmintisation the immune system disbalance decreases but lefts. In addition, chronic opisthorhis invasion leads to the proliferative processes activation in ductal epithelium, liver, lymph nodes and in other organs which leads to cancer proliferation. According to the results obtained the opisthorhis infected patients needs to be immunocorrected before as well as after dehelmintisation for holangiocancerogenesis profylaxis.

  5. [Effect of low-intensity electromagnetic fields of industrial frequency on the ultrastructure and proliferative activity of rat's thymus cells].

    Science.gov (United States)

    Zhitkevich, T I; Bokut', T B; Netukova, N I

    2001-01-01

    Effects of two types of low-intensity electromagnetic fields (EMF) of industrial frequency (50 Hz) on the fine structure and proliferative activity of thymic cells in white rats were studied. It was found that a weak EMF with a prevailing electrical component (380-480 V/m, 120-140 nT1) did not affect the DNA synthesis intensity. An EMF with a stronger magnetic induction (10-15 V/m, 800-1500 nT1) diminished the glucose-6-phosphate dehydrogenase activity and proliferative processes in cultured stimulated lymphocytes. Electron microscopic investigation of the thymus after both types of exposure revealed an accumulation of lymphocytes with pyknotic nuclei and electron-dense cytoplasm, as well as hypoplasia of the vascular endothelium. At the same time, EMF with a prevailing magnetic component produced a more marked negative effect on the ultrastructure of thymic cells, which indicated a lowered secretory activity of epitheliocytes.

  6. Evaluation of cell proliferative activity after irradiation using immunohistochemical approach and flow cytometry

    Energy Technology Data Exchange (ETDEWEB)

    Tamada, Takashi (Okayama Univ. (Japan). School of Medicine)

    1992-06-01

    To evaluate a proliferative activity of post-irradiated malignant cells, we studied the kinetics of HeLa cells using immunohistochemical approach and flow cytometry. HeLa cells were stained with two proliferation-associated monoclonal antibodies, Ki-67 and anti-DNA polymerase {alpha} antibody. Nucleoli of non-irradiated cells were granularly stained with Ki-67. After irradiation, only the center of nuclei was diffusely stained with Ki-67. One hundred forty-four hours after low-dose irradiation, the staining patterns became the same as the control. On the other hand, after high-dose irradiation, the center of nuclei was weakly stained. DNA polymerase {alpha} was diffusely labelled with nuclei of the control. It was located around the border of nuclei of low-dose irradiated cells like a ring. But after high-dose irradiation, it was granularly distributed in the periphery of nuclei. FITC conjugated Ki-67/PI two parameter analysis was done by a single laser flow cytometer. Twenty-four hours after irradiation, DNA-histograms showed the accumulation to G{sub 2}/M phase and the increase of DNA content of G{sub 2}/M cells, as exposure dose was increased. Two parameter analysis showed the increase of FITC uptake of G{sub 2}/M phase as dose increased. These changes of flow cytometry were remarkably observed after 24 hours' incubation. It was shown that the difference of Ki-67 antigen and DNA polymerase {alpha} appearance depended on the irradiation dose. These findings suggest that immunohistochemical staining with Ki-67 or anti-DNA polymerase {alpha} antibody and flow cytometry using Ki-67 are available to evaluate cell damages after irradiation. (author).

  7. Azithromycin Synergistically Enhances Anti-Proliferative Activity of Vincristine in Cervical and Gastric Cancer Cells

    International Nuclear Information System (INIS)

    Zhou, Xuezhang; Zhang, Yuyan; Li, Yong; Hao, Xiujing; Liu, Xiaoming; Wang, Yujiong

    2012-01-01

    In this study, the anti-proliferative and anticancer activity of azithromycin (AZM) was examined. In the presence of AZM, cell growth was inhibited more effectively in Hela and SGC-7901 cancer cells, relative to transformed BHK-21 cells. The respective 50% inhibition of cell growth (IC 50 ) values for Hela, SGC-7901 and BHK-21 were 15.66, 26.05 and 91.00 µg/mL at 72 h post incubation, indicative of a selective cytotoxicity against cancer cells. Cell apoptosis analysis using Hoechst nuclear staining and annexin V-FITC binding assay further demonstrated that AZM was capable of inducing apoptosis in both cancer cells and transformed cells. The apoptosis induced by AZM was partly through a caspase-dependent mechanism with an up-regulation of apoptotic protein cleavage PARP and caspase-3 products, as well as a down-regulation of anti-apoptotic proteins, Mcl-1, bcl-2 and bcl-X1. More importantly, a combination of AZM and a low dose of the common anti-cancer chemotherapeutic agent vincristine (VCR), produced a selectively synergistic effect on apoptosis of Hela and SGC-7901 cells, but not BHK-21 cells. In the presence of 12.50 μg/mL of VCR, the respective IC 50 values of Hela, SGC-7901 and BHK-21 cells to AZM were reduced to 9.47 µg/mL, 8.43 µg/mL and 40.15 µg/mL at 72 h after the incubation, suggesting that the cytotoxicity of AZM had a selective anti-cancer effect on cancer over transformed cells in vitro. These results imply that AZM may be a potential anticancer agent for use in chemotherapy regimens, and it may minimize side effects via reduction of dosage and enhancing the effectiveness common chemotherapeutic drugs

  8. Structural and functional development of rat and mouse gastric mucous cells in relation to their proliferative activity

    International Nuclear Information System (INIS)

    Wattel, W.

    1978-01-01

    An investigation has been carried out to find a relation between the differentiation and the mitotic activity of gastric mucous cells of the rat and the mouse. It is shown that the bulk mucous production is carried out by the older, non-proliferative, surface mucous cells that line the foveolae and the gastric surface. One experiment describes the renewal of mouse gastric mucous cells following fast neutron irradiation. (C.F.)

  9. Phytochemical properties and anti-proliferative activity of Olea europaea L. leaf extracts against pancreatic cancer cells.

    Science.gov (United States)

    Goldsmith, Chloe D; Vuong, Quan V; Sadeqzadeh, Elham; Stathopoulos, Costas E; Roach, Paul D; Scarlett, Christopher J

    2015-07-17

    Olea europaea L. leaves are an agricultural waste product with a high concentration of phenolic compounds; especially oleuropein. Oleuropein has been shown to exhibit anti-proliferative activity against a number of cancer types. However, they have not been tested against pancreatic cancer, the fifth leading cause of cancer related death in Western countries. Therefore, water, 50% ethanol and 50% methanol extracts of Corregiola and Frantoio variety Olea europaea L. leaves were investigated for their total phenolic compounds, total flavonoids and oleuropein content, antioxidant capacity and anti-proliferative activity against MiaPaCa-2 pancreatic cancer cells. The extracts only had slight differences in their phytochemical properties, and at 100 and 200 μg/mL, all decreased the viability of the pancreatic cancer cells relative to controls. At 50 μg/mL, the water extract from the Corregiola leaves exhibited the highest anti-proliferative activity with the effect possibly due to early eluting HPLC peaks. For this reason, olive leaf extracts warrant further investigation into their potential anti-pancreatic cancer benefits.

  10. In vitro anti-proliferative and anti-inflammatory activity of leaf and fruit extracts from Vaccinium bracteatum Thunb.

    Science.gov (United States)

    Landa, Premysl; Skalova, Lenka; Bousova, Iva; Kutil, Zsofia; Langhansova, Lenka; Lou, Ji-Dong; Vanek, Tomas

    2014-01-01

    The aim of this study was to evaluate in vitro anti-proliferative (tested on MCF-7, MDA-MB-231, and MCF-10A cell lines) and anti-inflammatory (evaluated as inhibition of prostaglandin E2 synthesis catalyzed by cyclooxygenase-2) effect of various extracts from Vaccinium bracteatum leaves and fruits. The highest anti-proliferative effect possessed leaf dichloromethane extract with IC50 values ranging from 93 to 198 μg/mL. In the case of cyclooxygenase-2 inhibition, n-hexane, dichloromethane, and ethanol fruit extracts showed the best activity with IC50 values = 2.0, 5.4, and 12.7 μg/mL, respectively. These results indicate that V. bracteatum leaves and fruits could be useful source of anti-cancer and anti-inflammatory compounds.

  11. Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells

    Directory of Open Access Journals (Sweden)

    Helson Lawrence

    2007-01-01

    Full Text Available Abstract Background With current treatment strategies, nearly half of all medulloblastoma (MB patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, over-expression of c-MYC has been shown to correlate with anaplasia and unfavorable prognosis. In neuroblastoma – an embryonal tumor with biological similarities to MB – the quassinoid NBT-272 has been demonstrated to inhibit cellular proliferation and to down-regulate c-MYC protein expression. Methods To study MB cell responses to NBT-272 and their dependence on the level of c-MYC expression, DAOY (wild-type, empty vector transfected or c-MYC transfected, D341 (c-MYC amplification and D425 (c-MYC amplification human MB cells were used. The cells were treated with different concentrations of NBT-272 and the impact on cell proliferation, apoptosis and c-MYC expression was analyzed. Results NBT-272 treatment resulted in a dose-dependent inhibition of cellular proliferation (IC50 in the range of 1.7 – 9.6 ng/ml and in a dose-dependent increase in apoptotic cell death in all human MB cell lines tested. Treatment with NBT-272 resulted in up to 90% down-regulation of c-MYC protein, as demonstrated by Western blot analysis, and in a significant inhibition of c-MYC binding activity. Anti-proliferative effects were slightly more prominent in D341 and D425 human MB cells with c-MYC amplification and slightly more pronounced in c-MYC over-expressing DAOY cells compared to DAOY wild-type cells. Moreover, treatment of synchronized cells by NBT-272 induced a marked cell arrest at the G1/S boundary. Conclusion In human MB cells, NBT-272 treatment inhibits cellular proliferation at nanomolar concentrations, blocks cell cycle progression, induces apoptosis, and down-regulates the expression of the oncogene c-MYC. Thus, NBT-272 may represent a novel drug candidate to inhibit

  12. Zebularine exerts its antiproliferative activity through S phase delay and cell death in human malignant mesothelioma cells.

    Science.gov (United States)

    Takemura, Yukitoshi; Satoh, Motohiko; Hatanaka, Kenichi; Kubota, Shunichiro

    2018-04-24

    Malignant mesothelioma is an asbestos-related aggressive tumor and current therapy remains ineffective. Zebularine as a DNA methyltransferase (DNMT) inhibitor has an anti-tumor effect in several human cancer cells. The aim of the present study was to investigate whether zebularine could induce antiproliferative effect in human malignant mesothelioma cells. Zebularine induced cell growth inhibition in a dose-dependent manner. In addition, zebularine dose-dependently decreased expression of DNMT1 in all malignant mesothelioma cells tested. Cell cycle analysis indicated that zebularine induced S phase delay. Zebularine also induced cell death in malignant mesothelioma cells. In contrast, zebularine did not induce cell growth inhibition and cell death in human normal fibroblast cells. These results suggest that zebularine has a potential for the treatment of malignant mesothelioma by inhibiting cell growth and inducing cell death.

  13. Immunohistochemical Estimates of Angiogenesis, Proliferative Activity, p53 Expression, and Multiple Drug Resistance Have No Prognostic Impact in Osteosarcoma: A Comparative Clinicopathological Investigation

    DEFF Research Database (Denmark)

    Sørensen, Flemming Brandt; Jensen, Kenneth; Vaeth, Michael

    2008-01-01

    Purpose. To investigate angiogenesis, multiple drug resistance (MDR) and proliferative activity as prognostic variables in patients suffering from osteosarcoma. Methods. Histologic biopsies from 117 patients treated in the period from 1972 through 1999 were immunohistologically investigated...

  14. Inhibition of Rac1 activity induces G1/S phase arrest through the GSK3/cyclin D1 pathway in human cancer cells.

    Science.gov (United States)

    Liu, Linna; Zhang, Hongmei; Shi, Lei; Zhang, Wenjuan; Yuan, Juanli; Chen, Xiang; Liu, Juanjuan; Zhang, Yan; Wang, Zhipeng

    2014-10-01

    Rac1 has been shown to regulate the cell cycle in cancer cells. Yet, the related mechanism remains unclear. Thus, the present study aimed to investigate the mechanism involved in the regulation of G1/S phase transition by Rac1 in cancer cells. Inhibition of Rac1 by inhibitor NSC23766 induced G1/S phase arrest and inhibited the proliferation of A431, SW480 and U2-OS cells. Suppression of GSK3 by shRNA partially rescued G1/S phase arrest and inhibition of proliferation. Incubation of cells with NSC23766 reduced p-AKT and inactivated p-GSK3α and p-GSK3β, increased p-cyclin D1 expression and decreased the level of cyclin D1 protein. Consequently, cyclin D1 targeting transcriptional factor E2F1 expression, which promotes G1 to S phase transition, was also reduced. In contrast, constitutive active Rac1 resulted in increased p-AKT and inactivated p-GSK3α and p-GSK3β, decreased p-cyclin D1 expression and enhanced levels of cyclin D1 and E2F1 expression. Moreover, suppression of GSK3 did not alter p-AKT or Rac1 activity, but decreased p-cyclin D1 and increased total cyclin D1 protein. However, neither Rac1 nor GSK3 inhibition altered cyclin D1 at the RNA level. Moreover, after inhibition of Rac1 or GSK3 following proteasome inhibitor MG132 treatment, cyclin D1 expression at the protein level remained constant, indicating that Rac1 and GSK3 may regulate cyclin D1 turnover through phosphorylation and degradation. Therefore, our findings suggest that inhibition of Rac1 induces cell cycle G1/S arrest in cancer cells by regulation of the GSK3/cyclin D1 pathway.

  15. Proliferative activity of benign human prostate, prostatic adenocarcinoma and seminal vesicle evaluated by thymidine labeling

    International Nuclear Information System (INIS)

    Meyer, J.S.; Sufrin, G.; Martin, S.A.

    1982-01-01

    The thymidine labeling index (TLI) was measured in vitro in the epithelium and stroma of benign prostate glands and seminal vesicles and in the epithelium of prostatic adenocarcinomas. The mean epithelial TLI of normal peripheral (posterior) prostatic zone was 0.12 percent, and that of the normal central (deep) zone was 0.11 percent. Mean normal stromal TLI's were 0.08 percent and 0.06 percent, respectively. The mean TLI of epithelium in nodular hyperplasia was 0.31 percent, which differs significantly from normal epithelium (p less than 0.05), and the mean stromal TLI was also increased (0.16 percent, p less than 0.1). The mean TLI of prostatic adenocarcinomas was 0.90 percent (range 0.14 to 3.90 percent) which was significantly higher than for either normal epithelium (p less than 0.001) or epithelium of nodular hyperplasia (p less than 0.05). Trends of increasing TLI with increasing histologic grades and increasing nuclear size and numbers of nucleoli were not significant. The data support participation of both epithelial and stromal proliferation in nodular hyperplasia, and indicate a low basal proliferative rate in normal prostatic glands. The low TLI's of prostatic adenocarcinomas relative to other malignancies are consistent with their frequently slowly progressive course. The very low proliferative rate of seminal vesicular epithelium (mean TLI 0.02 percent) may account for the rarity of seminal vesicular carcinomas

  16. Proliferative activity of benign human prostate, prostatic adenocarcinoma and seminal vesicle evaluated by thymidine labeling

    International Nuclear Information System (INIS)

    Meyer, J.S.; Sufrin, G.; Martin, S.A.

    1982-01-01

    The thymidine labeling index (TLI) was measured in vitro in the epithelium and stroma of benign prostate glands and seminal vesicles and in the epithelium of prostatic adenocarcinomas. The mean epithelial TLI of normal peripheral (posterior) prostatic zone was 0.12 per cent, and that of the normal central (deep) zone was 0.11 per cent. Mean normal stromal TLI's were 0.08 per cent and 0.06 per cent, respectively. The mean TLI of epithelium in nodular hyperplasia was 0.31 per cent, which differs significantly from normal epithelium, and the mean stromal TLI was also increased. The mean TLI of prostatic adenocarcinomas was 0.90 per cent (range 0.14 to 3.90 per cent) which was significantly higher than for either normal epithelium or epithelium of nodular hyperplasia. Trends of increasing TLI with increasing histologic grades and increasing nuclear size and numbers of nucleoli were not significant. The data support participation of both epithelial and stromal proliferation in nodular hyperplasia, and indicate a low basal proliferative rate in normal prostatic glands. The low TLI's of prostatic adenocarcinomas relative to other malignancies are consistent with their frequently slowly progressive course. The very low proliferative rate of seminal vesicular epithelium may account for the rarity of seminal vesicular carcinomas

  17. F-18-FDG positron emission tomography findings correlate pathological proliferative activity of oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Toyoizumi, Osamu; Oriuchi, Noboru; Miyakubo, Mitsuyuki

    2010-01-01

    It is still controversial whether fluorodeoxyglucose (FDG) uptake is correlated with cellular proliferation and prognosis of oral squamous cell carcinoma (OSC). In this study, we performed positron emission tomography (PET) study and immunohistochemical analysis to elucidate the relationship between FDG uptake and expression of cellular proliferative markers and pathological prognostic markers in patients with OSC. FDG PET and immunohistochemical staining have been carried out in sixteen patients with OSC. Tumor uptake of FDG was expressed with standardized uptake value (SUV). The expression of Ki-67, Topoisomerase IIα (Topo IIα), p53, and p63 in cancer cells was quantitatively assessed with positivity of the immunohistochemical staining. SUV was compared with the results of immunohistochemical analysis. FDG PET study revealed that SUV ranged from 3.6 to 22.1 with average of 10.4. Average positive rate of Ki-67, Topo IIα, p53, and p63 was 68.9%, 58.9%, 72.0%, and 65.2%, respectively. Pearson product-moment correlation coefficient analysis revealed that SUV was significantly correlated with Ki-67 (r=0.616, p=0.01), Topo IIα (r=0.677, p=0.004), p53 (r=0.613, p=0.01), and p63 (r=0.710, p=0.002), respectively. The present preliminary study indicated that FDG uptake was closely correlated with pathological cellular proliferative and prognostic markers in patients with OSC. (author)

  18. Daphne striata Tratt. and D. mezereum L.: a study of anti-proliferative activity towards human cancer cells and antioxidant properties.

    Science.gov (United States)

    Tundis, Rosa; Loizzo, Monica R; Bonesi, Marco; Peruzzi, Lorenzo; Efferth, Thomas

    2018-02-12

    In this study, we investigated for the first time the anti-proliferative and antioxidant properties of D. mezereum and D. striata. The aerial parts were extracted by maceration with n-hexane, dichloromethane, and methanol. MPLC, GC, and GC-MS were used for the phytochemical study. The anti-proliferative activity was tested against MCF-7, A549, LNCaP, ACHN, and C32 cancer human cells. The antioxidant activity was measured by employing β-carotene bleaching, ABTS, DPPH, and FRAP tests. The Relative Antioxidant Capacity Index (RACI) was applied from the perspective of statistics. D. mezereum dichloromethane extract showed a remarkable anti-proliferative with an IC 50 of 6.08 μg/mL against LNCaP cells. Experimental data indicate that Daphne species have interesting anti-proliferative and antioxidant properties that deserve more investigations to develop novel antineoplastic drugs.

  19. Curcumin Conjugated with PLGA Potentiates Sustainability, Anti-Proliferative Activity and Apoptosis in Human Colon Carcinoma Cells

    Science.gov (United States)

    Waghela, Bhargav N.; Sharma, Anupama; Dhumale, Suhashini; Pandey, Shashibahl M.; Pathak, Chandramani

    2015-01-01

    Curcumin, an ingredient of turmeric, exhibits a variety of biological activities such as anti-inflammatory, anti-atherosclerotic, anti-proliferative, anti-oxidant, anti-cancer and anti-metastatic. It is a highly pleiotropic molecule that inhibits cell proliferation and induces apoptosis in cancer cells. Despite its imperative biological activities, chemical instability, photo-instability and poor bioavailability limits its utilization as an effective therapeutic agent. Therefore, enhancing the bioavailability of curcumin may improve its therapeutic index for clinical setting. In the present study, we have conjugated curcumin with a biodegradable polymer Poly (D, L-lactic-co-glycolic acid) and evaluated its apoptotic potential in human colon carcinoma cells (HCT 116). The results show that curcumin-PLGA conjugate efficiently inhibits cell proliferation and cell survival in human colon carcinoma cells as compared to native curcumin. Additionally, curcumin conjugated with PLGA shows improved cellular uptake and exhibits controlled release at physiological pH as compared to native curcumin. The curcumin-PLGA conjugate efficiently activates the cascade of caspases and promotes intrinsic apoptotic signaling. Thus, the results suggest that conjugation potentiates the sustainability, anti-proliferative and apoptotic activity of curcumin. This approach could be a promising strategy to improve the therapeutic index of cancer therapy. PMID:25692854

  20. GTP depletion synergizes the anti-proliferative activity of chemotherapeutic agents in a cell type-dependent manner

    International Nuclear Information System (INIS)

    Lin, Tao; Meng, Lingjun; Tsai, Robert Y.L.

    2011-01-01

    Highlights: → Strong synergy between mycophenolic acid (MPA) and 5-FU in MDA-MB-231 cells. → Cell type-dependent synergy between MPA and anti-proliferative agents. → The synergy of MPA on 5-FU is recapitulated by RNA polymerase-I inhibition. → The synergy of MPA on 5-FU requires the expression of nucleostemin. -- Abstract: Mycophenolic acid (MPA) depletes intracellular GTP by blocking de novo guanine nucleotide synthesis. GTP is used ubiquitously for DNA/RNA synthesis and as a signaling molecule. Here, we made a surprising discovery that the anti-proliferative activity of MPA acts synergistically with specific chemotherapeutic agents in a cell type-dependent manner. In MDA-MB-231 cells, MPA shows an extremely potent synergy with 5-FU but not with doxorubicin or etoposide. The synergy between 5-FU and MPA works most effectively against the highly tumorigenic mammary tumor cells compared to the less tumorigenic ones, and does not work in the non-breast cancer cell types that we tested, with the exception of PC3 cells. On the contrary, MPA shows the highest synergy with paclitaxel but not with 5-FU in SCC-25 cells, derived from oral squamous cell carcinomas. Mechanistically, the synergistic effect of MPA on 5-FU in MDA-MB-231 cells can be recapitulated by inhibiting the RNA polymerase-I activity and requires the expression of nucleostemin. This work reveals that the synergy between MPA and anti-proliferative agents is determined by cell type-dependent factors.

  1. Chemical composition, antioxidant, anti-inflammatory and anti-proliferative activities of essential oils of plants from Burkina Faso.

    Directory of Open Access Journals (Sweden)

    Bagora Bayala

    Full Text Available This research highlights the chemical composition, antioxidant, anti-inflammatory and anti-proliferative activities of essential oils from leaves of Ocimum basilicum, Ocimum americanum, Hyptis spicigera, Lippia multiflora, Ageratum conyzoides, Eucalyptus camaldulensis and Zingiber officinale. Essential oils were analyzed by gas chromatography-mass spectrometry and gas chromatography-flame ionization detector. Major constituents were α-terpineol (59.78% and β-caryophyllene (10.54% for Ocimum basilicum; 1, 8-cineol (31.22%, camphor (12.730%, α-pinene (6.87% and trans α-bergamotene (5.32% for Ocimum americanum; β-caryophyllene (21%, α-pinene (20.11%, sabinene (10.26%, β-pinene (9.22% and α-phellandrene (7.03% for Hyptis spicigera; p-cymene (25.27%, β-caryophyllene (12.70%, thymol (11.88, γ-terpinene (9.17% and thymyle acetate (7.64% for Lippia multiflora; precocene (82.10%for Ageratum conyzoides; eucalyptol (59.55%, α-pinene (9.17% and limonene (8.76% for Eucalyptus camaldulensis; arcurcumene (16.67%, camphene (12.70%, zingiberene (8.40%, β-bisabolene (7.83% and β-sesquiphellandrène (5.34% for Zingiber officinale. Antioxidant activities were examined using 1,1-diphenyl-2-picryl-hydrazyl (DPPH and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS methods. O. basilicum and L. multiflora exhibited the highest antioxidant activity in DPPH and ABTS tests, respectively. Anti-inflammatory properties were evaluated by measuring the inhibition of lipoxygenase activity and essential oil of Z. officinale was the most active. Anti-proliferative effect was assayed by the measurement of MTT on LNCaP and PC-3 prostate cancer cell lines, and SF-763 and SF-767 glioblastoma cell lines. Essential oils from A. conyzoides and L. multiflora were the most active on LNCaP and PC-3 cell lines, respectively. The SF-767 glioblastoma cell line was the most sensitive to O. basilicum and L. multiflora EOs while essential oil of A. conyzoides showed the

  2. Two novel prenylated kaempferol derivatives from fresh bud's fur of Platanus acerifolia and their anti-proliferative activities.

    Science.gov (United States)

    Zuo, Bo; Liao, Zhi-Xin; Xu, Chen; Liu, Chao

    2016-01-06

    Two novel prenylated kaempferol derivatives (1, 2), together with seven known metabolites were isolated from ethanol extract of fresh Platanus acerifolia bud's fur by multistep chromatographic processing. Structure of compounds 1 and 2 was confirmed by 1D, 2D NMR spectra and HR-ESI-MS. In addition, compound 1 was further analysed by X-ray crystallography. Anti-proliferative activities in vitro against human breast carcinoma (MCF-7) and human hepatocellular carcinoma (Hep-G2) cell lines for compound 1, 2 and 8 were evaluated. Compound 1 exhibited cytotoxic activity towards MCF-7 and Hep-G2 cell lines with the IC 50 values 38.2 and 39.5 μM, respectively. Moreover, compound 2 showed weak cytotoxic activities against the two cell lines.

  3. Steroid hormones as regulators of the proliferative activity of normal and neoplastic intestinal epithelial cells (review).

    Science.gov (United States)

    Tutton, P J; Barkla, D H

    1988-01-01

    Glucocorticoid and mineralocorticoid receptors are present in normal epithelial cells of both the small and large intestine and there have also been contentious reports of androgen, oestrogen and progesterone receptors in the epithelium of the normal large intestine. The majority of reports suggest that stimulation of the intestinal glucocorticoid receptors results in increased proliferation of epithelial cells in the small bowel, as does stimulation of androgen receptors and possibly mineralocorticoid receptors. The proliferative response of the normal intestine to oestrogens is difficult to evaluate and that to progestigens appears not to have been reported. Epidemiological studies reveal a higher incidence of bowel cancer in premenopausal women than in men of the same age and yet there is a lower incidence of these tumors in women of higher parity. These findings have been atributted to a variety of non-epithelial gender characteristic such as differences in bile metabolism, colonic bacterial and fecal transit times. In experimental animals, androgens have also been shown to influence carcinogenesis and this could well be attributed to changes in food intake etc. However, many studies have now revealed steroid hormone receptors on colorectal tumor cells and thus a direct effect of the steroid hormones on the epithelium during and after malignant transformation must now be considered.

  4. S-phase cell distribution in the small intestine irradiated at different times of the day. I. Acute irradiation injury

    Energy Technology Data Exchange (ETDEWEB)

    Becciolini, A; Balzi, M; Cremonini, D; Fabbrica, D [Florence Univ. (Italy). Ist. di Radiologia

    1983-01-01

    The S-phase cell distribution has been analysed to evaluate the behaviour of proliferative cells in the intestinal epithelium after irradiation at different times of the day. A marked reduction of S cell frequency was observed at early intervals after abdominal irradiation; this reduction was particularly evident in the lower half of the crypts. At subsequent intervals a progressive extension of the proliferative compartment, with labelled cells also at the top of the crypt, was present. The irradiated groups generally showed a homogeneous behaviour even if a more marked reduction in S-phase cells was observed in group C. The invertase activity, a brush border enzyme synthetized during the differentiation process, presented a different behaviour at the early intervals in the irradiated groups. When the extension of the proliferative compartment occurred the invertase activity reached values close to zero. The modifications in brush border enzymes and in S-phase cell distribution, at early killing times, led to the hypothesis of an early differentiation.

  5. Inhibition of proliferative activity in tissue culture in vivo of esophagus and stomach tumour cells under preoperative irradiation

    International Nuclear Information System (INIS)

    Zinchenko, V.A.; Okulov, L.V.; Gol'dshmid, B.Ya.

    1988-01-01

    Inhibition of proliferative activity of tumor cells as a result of radiation effect. Tumor tissue taken from patiets with preoperative tumor irradiation by 30 Gy cumulative dose (5 Gy per a session) and from patients whose tumors were not subjected to irradiation (control) was used. The tumor tissue was cultivated in the diffusion chamber and then implanted to the abdominal cavity of the non-inbred male rats. On preparations in the growth area pathomorphological changes were evaluated, the share of mitotically dividing and DNA-synthesizing cells was determined. The absence of growth area around the explant, obvious reduction of mitotic activity and DNA-synthesizing function of cells in preparations of irradiated tumors in 88 % of cases testify to the inhibition of the stomach cardial section and esophagus tumor tissue repopulation after radiation effect. The investigation results confirm the advisability of preoperative irradiation of patients with tumors of the given localization

  6. Downregulation of TXNIP leads to high proliferative activity and estrogen-dependent cell growth in breast cancer.

    Science.gov (United States)

    Park, Jun Won; Lee, Su Hyung; Woo, Gye-Hyung; Kwon, Hyo-Jung; Kim, Dae-Yong

    2018-04-06

    TXNIP is a potent tumor suppressor with reduced expression in various types of human cancer. The prognostic and predictive power of TXNIP has been recognized in human breast cancer. The aim of this study is to investigate the clinical relevance and functional roles of TXNIP downregulation in breast cancer. We examined TXNIP expression at the protein level in tissue microarray (TMA)-based human breast cancers and its correlation with clinical parameters and molecular markers on immunohistochemistry (IHC). Compared with normal tissues, TXNIP expression was significantly decreased in human breast cancer tissues and animal mammary tumors, along with tumor progression. TXNIP was restored immediately after histone deacetylase inhibitor treatment in breast cancer cells, implying transcriptional regulation of TXNIP by histone modification. Decreased TXNIP protein levels were more common in tumors showing high proliferative activity, such as high Ki-67 labeling indexes and low p27 expression. TXNIP knockdown led to increased in vitro and in vivo breast cancer cell growth accompanied by p27 reduction and GLUT1 induction. Interestingly, estrogen receptor (ER)-positive breast cancer samples showed higher TXNIP expression compared to ER-negative samples. TXNIP expression decreased when ER signaling was activated by estradiol, while its expression increased under ER blockage by anti-estrogen fulvestrant. In addition, TXNIP knockdown in breast cancer cells caused significant reduction in the cell-growth inhibitory effect of anti-estrogen fulvestrant. In conclusion, our data demonstrated that TXNIP functions to suppress high proliferative activity and estrogen-dependent cell growth in breast cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Increased Stiffness in Aged Skeletal Muscle Impairs Muscle Progenitor Cell Proliferative Activity.

    Directory of Open Access Journals (Sweden)

    Grégory Lacraz

    Full Text Available Skeletal muscle aging is associated with a decreased regenerative potential due to the loss of function of endogenous stem cells or myogenic progenitor cells (MPCs. Aged skeletal muscle is characterized by the deposition of extracellular matrix (ECM, which in turn influences the biomechanical properties of myofibers by increasing their stiffness. Since the stiffness of the MPC microenvironment directly impacts MPC function, we hypothesized that the increase in muscle stiffness that occurs with aging impairs the behavior of MPCs, ultimately leading to a decrease in regenerative potential.We showed that freshly isolated individual myofibers from aged mouse muscles contain fewer MPCs overall than myofibers from adult muscles, with fewer quiescent MPCs and more proliferative and differentiating MPCs. We observed alterations in cultured MPC behavior in aged animals, where the proliferation and differentiation of MPCs were lower and higher, respectively. These alterations were not linked to the intrinsic properties of aged myofibers, as shown by the similar values for the cumulative population-doubling values and fusion indexes. However, atomic force microscopy (AFM indentation experiments revealed a nearly 4-fold increase in the stiffness of the MPC microenvironment. We further showed that the increase in stiffness is associated with alterations to muscle ECM, including the accumulation of collagen, which was correlated with higher hydroxyproline and advanced glycation end-product content. Lastly, we recapitulated the impaired MPC behavior observed in aging using a hydrogel substrate that mimics the stiffness of myofibers.These findings provide novel evidence that the low regenerative potential of aged skeletal muscle is independent of intrinsic MPC properties but is related to the increase in the stiffness of the MPC microenvironment.

  8. In vitro anti-proliferative activity on colon cancer cell line (HT-29) of Thai medicinal plants selected from Thai/Lanna medicinal plant recipe database "MANOSROI III".

    Science.gov (United States)

    Manosroi, Aranya; Akazawa, Hiroyuki; Akihisa, Toshihiro; Jantrawut, Pensak; Kitdamrongtham, Worapong; Manosroi, Worapaka; Manosroi, Jiradej

    2015-02-23

    Thai/Lanna region has its own folklore wisdoms including the traditional medicinal plant recipes. Thai/Lanna medicinal plant recipe database "MANOSROI III" has been developed by Prof. Dr. Jiradej Manosroi. It consists of over 200,000 recipes for all diseases including cancer. To investigate the anti-proliferative and apoptotic activities on human colon cancer cell line (HT-29) as well as the cancer cell selectivity of the methanolic extracts (MEs) and fractions of the 23 selected plants from the "MANOSROI III" database. The 23 selected plants were extracted with methanol under reflux and evaluated for their anti-proliferative activity by sulforhodamine B assay. The 5 plants (Gloriosa superba, Caesalpinia sappan, Fibraurea tinctoria, Ventilago denticulata and Psophocarpus tetragonolobus) with potent anti-proliferative activity were fractionated by liquid-liquid partition to give 4 fractions including each hexane (HF), methanol-water (MF), n-butanol (BF) and water (WF) fractions. They were tested for anti-proliferative activity and cancer cell selectivity. The ME and fractions of G. superba which showed potent anti-proliferative activity were further examined for morphological changes and apoptotic activities by acridine orange (AO)/ethidium bromide (EB) staining. The ME of G. superba root showed active with the highest anti-proliferative activity at 9.17 and 1.58 folds of cisplatin and doxorubicin, respectively. After liquid-liquid partition, HF of V. denticulata, MFs of F. tinctoria, V. denticulata and BF of P. tetragonolobus showed higher anti-proliferative activities than their MEs. The MF of G. superba indicated the highest anti-proliferative activity at 7.73 and 1.34 folds of cisplatin and doxorubicin, respectively, but only 0.86 fold of its ME. The ME and HF, MF and BF of G. superba and MF of F. tinctoria demonstrated high cancer cell selectivity. At 50 µg/ml, ME, HF, MF and BF of G. superba demonstrated higher apoptotic activities than the two standard drugs

  9. Proliferative and anti-proliferative effects of dietary levels of phytoestrogens in rat pituitary GH3/B6/F10 cells - the involvement of rapidly activated kinases and caspases

    International Nuclear Information System (INIS)

    Jeng, Yow-Jiun; Watson, Cheryl S

    2009-01-01

    Phytoestogens are a group of lipophillic plant compounds that can have estrogenic effects in animals; both tumorigenic and anti-tumorigenic effects have been reported. Prolactin-secreting adenomas are the most prevalent form of pituitary tumors in humans and have been linked to estrogen exposures. We examined the proliferative effects of phytoestrogens on a rat pituitary tumor cell line, GH 3 /B 6 /F 10 , originally subcloned from GH 3 cells based on its ability to express high levels of the membrane estrogen receptor-α. We measured the proliferative effects of these phytoestrogens using crystal violet staining, the activation of several mitogen-activated protein kinases (MAPKs) and their downstream targets via a quantitative plate immunoassay, and caspase enzymatic activities. Four phytoestrogens (coumestrol, daidzein, genistein, and trans-resveratrol) were studied over wide concentration ranges. Except trans-resveratrol, all phytoestrogens increased GH 3 /B 6 /F 10 cell proliferation at some concentration relevant to dietary levels. All four phytoestrogens attenuated the proliferative effects of estradiol when administered simultaneously. All phytoestrogens elicited MAPK and downstream target activations, but with time course patterns that often differed from that of estradiol and each other. Using selective antagonists, we determined that MAPKs play a role in the ability of these phytoestrogens to elicit these responses. In addition, except for trans-resveratrol, a serum removal-induced extrinsic apoptotic pathway was blocked by these phytoestrogens. Phytoestrogens can block physiological estrogen-induced tumor cell growth in vitro and can also stimulate growth at high dietary concentrations in the absence of endogenous estrogens; these actions are correlated with slightly different signaling response patterns. Consumption of these compounds should be considered in strategies to control endocrine tumor cell growth, such as in the pituitary

  10. Triterpenoid Saponins from Anemone rivularis var. Flore-Minore and Their Anti-Proliferative Activity on HSC-T6 Cells.

    Science.gov (United States)

    Wang, Xiao-Yang; Gao, Hui; Xie, Xiao-Jie; Jurhiin, Jirimubatu; Zhang, Mu-Zi-He; Zhou, Yan-Ping; Liu, Rui; Ning, Meng; Han, Jin; Tang, Hai-Feng

    2018-02-23

    Five previously undescribed triterpenoid saponins ( 1 - 5 ), along with eight known ones ( 6 - 13 ), were isolated from the whole plants of Anemone rivularis var. flore-minore . Their structures were clarified by extensive spectroscopic data and chemical evidence. For the first time, the lupane-type saponins ( 3 and 12 ) were reported from the Anemone genus. The anti-proliferative activity of all isolated saponins was evaluated on hepatic stellate cells (HSC-T6). Saponins 12 and 13 , which possess more monosaccharides than the others, displayed potent anti-proliferative activity, with IC 50 values of 18.21 and 15.56 μM, respectively.

  11. Biogenic amines as regulators of the proliferative activity of normal and neoplastic intestinal epithelial cells (review).

    Science.gov (United States)

    Tutton, P J; Barkla, D H

    1987-01-01

    embryonic origin and that cells exhibiting an admixture of endocrine and proliferative properties exist in colonic tumours, but not in the normal intestinal epithelium. Thus, it appears that in the normal intestine a clear structural and functional distinction exists between the regulating cells (i.e. the sympathetic neurones and enteroendocrine cells) and the regulated cells (i.e. the undifferentiated crypt cells): cells that have acquired a regulating role are no longer able to divide and cells which are able to divide do not take up or store amines.(ABSTRACT TRUNCATED AT 400 WORDS)

  12. Anti-proliferative and apoptosis-inducing activity of lycopene against three subtypes of human breast cancer cell lines

    Science.gov (United States)

    Takeshima, Mikako; Ono, Misaki; Higuchi, Takako; Chen, Chen; Hara, Takayuki; Nakano, Shuji

    2014-01-01

    Although lycopene, a major carotenoid component of tomatoes, has been suggested to attenuate the risk of breast cancer, the underlying preventive mechanism remains to be determined. Moreover, it is not known whether there are any differences in lycopene activity among different subtypes of human breast cancer cells. Using ER/PR positive MCF-7, HER2-positive SK-BR-3 and triple-negative MDA-MB-468 cell lines, we investigated the cellular and molecular mechanism of the anticancer activity of lycopene. Lycopene treatment for 168 consecutive hours exhibited a time-dependent and dose-dependent anti-proliferative activity against these cell lines by arresting the cell cycle at the G0/G1 phase at physiologically achievable concentrations found in human plasma. The greatest growth inhibition was observed in MDA-MB-468 where the sub-G0/G1 apoptotic population was significantly increased, with demonstrable cleavage of PARP. Lycopene induced strong and sustained activation of the ERK1/2, with concomitant cyclin D1 suppression and p21 upregulation in these three cell lines. In triple negative cells, lycopene inhibited the phosphorylation of Akt and its downstream molecule mTOR, followed by subsequent upregulation of proapoptotic Bax without affecting anti-apoptotic Bcl-xL. Taken together, these data indicate that the predominant anticancer activity of lycopene in MDA-MB-468 cells suggests a potential role of lycopene for the prevention of triple negative breast cancer. PMID:24397737

  13. TU-F-12A-02: Quantitative Characterization of Normal Bone Marrow Proliferative Activity with FLT PET/CT

    Energy Technology Data Exchange (ETDEWEB)

    Weisse, N; Jeraj, R [Department of Medical Physics, University of Wisconsin, Madison, WI (United States)

    2014-06-15

    Purpose: [F-18]FLT PET is a tool for assessing health of bone marrow by evaluating its proliferative activity. This study establishes a baseline quantitative characterization of healthy marrow proliferation to aid in diagnosis of hematological disease. Methods: 31 patients (20 male, 11 female, 41–76 years) being treated for solid cancers with no history of hematological disease, osseous metastatic disease, or radiation therapy received pre-treatment FLT PET/CT scans. Total bone marrow was isolated from whole body FLT PET images by manually removing organs and applying a standardize uptake value (SUV) threshold of 1.0. Because adult marrow is concentrated in the axial skeleton, quantitative total bone marrow analysis (QTBMA) was used to isolate marrow in the lumbar spine, thoracic spine, sacrum, and pelvis for analysis. SUVmean, SUVmax, and SUVCV were used to quantify bone marrow proliferation. Correlations were explored between SUV and patient characteristics including age, weight, height, and BMI using the Spearman coefficient (ρ). Results: The population-averaged whole-skeleton SUVmean, SUVmax, and SUVCV were 3.0±0.6, 18.4±5.7, and 0.6±0.1, respectively. Uptake values in the axial skeleton were similar to the whole-skeleton demonstrated by SUVmean in the thoracic spine (3.6±0.6), lumbar spine (3.3±0.5), sacrum (3.0±0.6), and pelvis regions (2.8±0.5). Whole-skeleton SUVmax correlated with patient weight (ρ=0.47, p<0.01) and BMI (ρ=0.60, p<0.01), suggesting marrow activity is related to the body's burden. SUV measures in the thoracic spine, lumbar spine, sacrum, and pelvis were negatively correlated with age (ρ:−0.41 to −0.46, p≤0.02). These negative correlations reflect the fact that active marrow in the adult skeleton is localized in the axial skeleton and decreases with age. Conclusions: Normal bone marrow characterizations were determined using FLT

  14. ICG-001 affects DRP1 activity and ER stress correlative with its anti-proliferative effect

    OpenAIRE

    Zinecker, Heidi; Ouaret, Djamila; Ebner, Daniel; Gaidt, Moritz M.; Taylor, Steve; Aulicino, Anna; Jagielowicz, Marta; Hornung, Veit; Simmons, Alison

    2017-01-01

    Mitochondria form a highly dynamic network driven by opposing scission and fusion events. DRP1 is an essential modulator of mitochondrial fission and dynamics within mammalian cells. Its fission activity is regulated by posttranslational modifications such as activating phosphorylation at serine 616. DRP1 activity has recently been implicated as being dysregulated in numerous human disorders such as cancer and neurodegenerative diseases. Here we describe the development of a cell-based screen...

  15. Anti-proliferative action of vitamin D in MCF7 is still active after siRNA-VDR knock-down

    NARCIS (Netherlands)

    J.L. Costa (José); P.P. Eijk (Paul); M.A. van de Wiel (Mark); D. ten Berge (Derk); F. Schmitt (Fernando); C.J. Narvaez (Carmen); J. Welsh; B. Ylstra (Bauke)

    2009-01-01

    textabstractBackground: The active form of Vitamin D, 1,25-dihydroxyvitamin D3(1,25D), has strong anti-proliferative effects, yet the molecular mechanisms underneath this effect remain unclear. In contrast, the molecular mechanism of 1,25D for the regulation of calcium homeostasis has principally

  16. The prognostic value of oncogenic antigen 519 (OA-519) expression and proliferative activity detected by antibody MIB-1 in node-negative breast cancer

    DEFF Research Database (Denmark)

    Jensen, V; Ladekarl, M; Holm-Nielsen, P

    1995-01-01

    of invasion of skin or deep fascia (= T1N0M0 and T2N0M0). The median follow-up time was 104 months (range 5-143 months). Immunohistochemical analysis of OA-519 expression was performed on formalin-fixed, paraffin-embedded tissue. The proliferative activity was estimated using a Ki-67 equivalent monoclonal...

  17. Prolonged effect of fluid flow stress on the proliferative activity of mesothelial cells after abrupt discontinuation of fluid streaming

    International Nuclear Information System (INIS)

    Aoki, Shigehisa; Ikeda, Satoshi; Takezawa, Toshiaki; Kishi, Tomoya; Makino, Junichi; Uchihashi, Kazuyoshi; Matsunobu, Aki; Noguchi, Mitsuru; Sugihara, Hajime; Toda, Shuji

    2011-01-01

    Highlights: ► Late-onset peritoneal fibrosis leading to EPS remains to be elucidated. ► Fluid streaming is a potent factor for peritoneal fibrosis in PD. ► We focused on the prolonged effect of fluid streaming on mesothelial cell kinetics. ► A history of fluid streaming exposure promoted mesothelial proliferative activity. ► We have thus identified a potent new factor for late-onset peritoneal fibrosis. -- Abstract: Encapsulating peritoneal sclerosis (EPS) often develops after transfer to hemodialysis and transplantation. Both termination of peritoneal dialysis (PD) and transplantation-related factors are risks implicated in post-PD development of EPS, but the precise mechanism of this late-onset peritoneal fibrosis remains to be elucidated. We previously demonstrated that fluid flow stress induced mesothelial proliferation and epithelial–mesenchymal transition via mitogen-activated protein kinase (MAPK) signaling. Therefore, we speculated that the prolonged bioactive effect of fluid flow stress may affect mesothelial cell kinetics after cessation of fluid streaming. To investigate how long mesothelial cells stay under the bioactive effect brought on by fluid flow stress after removal of the stress, we initially cultured mesothelial cells under fluid flow stress and then cultured the cells under static conditions. Mesothelial cells exposed to fluid flow stress for a certain time showed significantly high proliferative activity compared with static conditions after stoppage of fluid streaming. The expression levels of protein phosphatase 2A, which dephosphorylates MAPK, in mesothelial cells changed with time and showed a biphasic pattern that was dependent on the duration of exposure to fluid flow stress. There were no differences in the fluid flow stress-related bioactive effects on mesothelial cells once a certain time had passed. The present findings show that fluid flow stress exerts a prolonged bioactive effect on mesothelial cells after termination

  18. Prolifération filamenteuse en boues activées

    OpenAIRE

    Juzan, L.; Vedrenne, J.

    2010-01-01

    / Le développement excessif de bactéries filamenteuses en boues activées peut entrainer des dysfonctionnements biologiques tels qu'un foisonnement et/ou un moussage stable. Quels sont les moyens de prévention, de diagnostic et de traitement actuellement disponibles ?

  19. Preliminary in vitro evaluation of the anti-proliferative activity of guanylhydrazone derivatives.

    Science.gov (United States)

    França, Paulo H B; Da Silva-Júnior, Edeildo F; Aquino, Pedro G V; Santana, Antônio E G; Ferro, Jamylle N S; De Oliveira Barreto, Emiliano; Do Ó Pessoa, Cláudia; Meira, Assuero Silva; De Aquino, Thiago M; Alexandre-Moreira, Magna S; Schmitt, Martine; De Araújo-Júnior, João X

    2016-03-01

    Guanylhydrazones have shown promising antitumor activity in preclinical tumor models in several studies. In this study, we aimed at evaluating the cytotoxic effect of a series of synthetic guanylhydrazones. Different human tumor cell lines, by including HCT-8 (colon carcinoma), MDA-MB-435 (melanoma) and SF-295 (glioblastoma) were continuous exposed to guanylhydrazone derivatives for 72 hours and growth inhibition of tumor cell lines and macrophages J774 was measured using tetrazolium salt (MTT) assay. Compounds 7, 11, 16 and 17 showed strong cytotoxic activity with IC50 values lower than 10 μmol L(-1) against four tumor cell lines. Among them, 7 was less toxic to non-tumor cells. Finally, obtained data suggest that guanylhydrazones may be regarded as potential lead compounds for the design of novel anticancer agents.

  20. Preliminary in vitro evaluation of the anti-proliferative activity of guanylhydrazone derivatives

    Directory of Open Access Journals (Sweden)

    França Paulo H. B.

    2016-03-01

    Full Text Available Guanylhydrazones have shown promising antitumor activity in preclinical tumor models in several studies. In this study, we aimed at evaluating the cytotoxic effect of a series of synthetic guanylhydrazones. Different human tumor cell lines, by including HCT-8 (colon carcinoma, MDA-MB-435 (melanoma and SF-295 (glioblastoma were continuous exposed to guanylhydrazone derivatives for 72 hours and growth inhibition of tumor cell lines and macrophages J774 was measured using tetrazolium salt (MTT assay. Compounds 7, 11, 16 and 17 showed strong cytotoxic activity with IC50 values lower than 10 μmol L−1 against four tumor cell lines. Among them, 7 was less toxic to non-tumor cells. Finally, obtained data suggest that guanylhydrazones may be regarded as potential lead compounds for the design of novel anticancer agents.

  1. Water-soluble derivatives of 25-OCH3-PPD and their anti-proliferative activities.

    Science.gov (United States)

    Zhou, Wu-Xi; Sun, Yuan-Yuan; Yuan, Wei-Hui; Zhao, Yu-Qing

    2017-05-01

    (20R)-25-Methoxyl-dammarane-3β,12β,20-triol (25-OCH 3 -PPD, AD-1) is a dammarane-type sapogenin showing anti-tumor potential. In the search for new anti-tumor agents with higher potency than our previously identified compound 25-OCH 3 -PPD, 11 novel sulfamic acid and diacid derivatives that could improve water solubility and contribute to good drug potency and pharmacokinetic profiles were designed and synthesized. Their in vitro anti-tumor activities in MCF-7, A-549, HCT-116, and BGC-823 cell lines and one normal cell line were tested by standard MTT assay. Results showed that compared with compound 25-OCH 3 -PPD, compounds 1, 4, and 5 exhibited higher cytotoxic activity on almost all cell lines, together with lower toxicity in the normal cell. In particular, compound 1 exhibited the best anti-tumor activity in the in vitro assays. The water solubility of 25-OCH 3 -PPD and its derivatives was tested and the results showed that the solubility of 25-OCH 3 -PPD sulfamic acid and diacid derivatives were better than that of 25-OCH 3 -PPD in water, which may provide valuable data for the research and development of new anti-tumor agents. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Proliferative activity of endotheliocytes of growing capillaries of the rabbit cornea

    International Nuclear Information System (INIS)

    Gurina, O.Yu.; Mamontov, S.G.; Banin, V.V.

    1987-01-01

    The authors studied the intensity of DNA synthesis by cells of newly formed capillaries, growing in the rabbit cornea, after infliction of a silver nitrate burn and local application of colchicine. The intensity of capillary growth was investigated during stimulation and a combination of the burn with colchicine. Changes in activity of DNA synthesis by the endotheliocytes of newly formed capillaries during exposure throughout growth were also investigated. The intensity of cell proliferation was studied by measuring the incorporation of tritium-labelled thymidine into the endotheoiocyte nuclei

  3. Malignant Trigeminal Nerve Sheath Tumor and Anaplastic Astrocytoma Collision Tumor with High Proliferative Activity and Tumor Suppressor P53 Expression

    Directory of Open Access Journals (Sweden)

    Maher Kurdi

    2014-01-01

    Full Text Available Background. The synchronous development of two primary brain tumors of distinct cell of origin in close proximity or in contact with each other is extremely rare. We present the first case of collision tumor with two histological distinct tumors. Case Presentation. A 54-year-old woman presented with progressive atypical left facial pain and numbness for 8 months. MRI of the brain showed left middle cranial fossa heterogeneous mass extending into the infratemporal fossa. At surgery, a distinct but intermingled intra- and extradural tumor was demonstrated which was completely removed through left orbitozygomatic-temporal craniotomy. Histopathological examination showed that the tumor had two distinct components: malignant nerve sheath tumor of the trigeminal nerve and temporal lobe anaplastic astrocytoma. Proliferative activity and expressed tumor protein 53 (TP53 gene mutations were demonstrated in both tumors. Conclusions. We describe the first case of malignant trigeminal nerve sheath tumor (MTNST and anaplastic astrocytoma in collision and discuss the possible hypothesis of this rare occurrence. We propose that MTNST, with TP53 mutation, have participated in the formation of anaplastic astrocytoma, or vice versa.

  4. DNA Amplifications and Aneuploidy, High Proliferative Activity and Impaired Cell Cycle Control Characterize Breast Carcinomas with Poor Prognosis

    Directory of Open Access Journals (Sweden)

    Harald Blegen

    2003-01-01

    Full Text Available In order to explore whether specific cytogenetic abnormalities can be used to stratify tumors with a distinctly different clinical course, we performed comparative genomic hybridization (CGH of tumors from patients who were diagnosed with metastatic disease after an interval of less than 2 years or who remained free from distant metastases for more than 10 years. All patients presented with distant metastases after mastectomy indicating that none of the patients in this study was cured and free of remaining tumor cells. Tumors in the group of short‐term survivors showed a higher average number of chromosomal copy alterations compared to the long‐term survivors. Of note, the number of sub‐chromosomal high‐level copy number increases (amplifications was significantly increased in the group of short‐term survivors. In both short‐ and long‐term survivors recurrent chromosomal gains were mapped to chromosomes 1q, 4q, 8q, and 5p. Copy number changes that were more frequent in the group of short‐term survivors included gains of chromosome 3q, 9p, 11p and 11q and loss of 17p. Our results indicate that low‐ and high grade malignant breast adenocarcinomas are characterized by a specific pattern of chromosomal copy number changes. Furthermore, immunohistochemical evaluation of the expression levels of Ki‐67, p27KIP1, p21WAF1, p53, cyclin A and cyclin E revealed a correlation between increased proliferative activity and poor outcome.

  5. Chronic Proliferative Dermatitis in Mice: NFκB Activation Autoinflammatory Disease

    Directory of Open Access Journals (Sweden)

    Yanhua Liang

    2011-01-01

    Full Text Available Autoinflammatory diseases are a heterogeneous group of congenital diseases characterized by the presence of recurrent inflammation, in the absence of infectious agents, detectable autoantibodies or antigen-specific autoreactive T-cells. SHARPIN deficient mice presents multiorgan chronic inflammation without known autoantibodies or autoreactive T-cells, designated Sharpincpdm. Histological studies demonstrated epidermal hyperproliferation, Th-2 inflammation, and keratinocyte apoptosis in this mutant. The mutant mice have decreased behavioral mobility, slower growth, and loss of body weight. Epidermal thickness and mitotic epidermal cells increase along with disease development. K5/K14 expression is distributed through all layers of epidermis, along with K6 expression in interfollicular epidermis, suggesting epidermal hyperproliferation. K1/K10 is only detectable in outer layers of spinosum epidermis, reflecting accelerated keratinocyte migration. Alpha smooth muscle actin is overexpressed in skin blood vessels, which may release the elevated white blood cells to dermis. CD3+CD45+ cells and granulocytes, especially eosinophils and mast cells, aggregate in the mutant skin. TUNEL assay, together with Annexin-V/propidium iodide FACS analysis, confirmed the increase of apoptotic keratinocytes in skin. These data validate and provide new lines of evidence of the proliferation-inflammation-apoptosis triad in Sharpincpdm mice, an NFκB activation autoinflammatory disease.

  6. In vitro anti-proliferative and anti-inflammatory activity of leaf and fruit extracts from Vaccinium bracteatum Thunb

    OpenAIRE

    Landa, P. (Přemysl); Skálová, L.; Boušová, I.; Kutil, Z. (Zsófia); Langhansová, L. (Lenka); Lou, J.D.; Vaněk, T. (Tomáš)

    2014-01-01

    The aim of this study was to evaluate in vitro anti-proliferative (tested on MCF-7, MDA-MB-231, and MCF-10A cell lines) and anti-inflammatory (evaluated as inhibition of prostaglandin E2 synthesis catalyzed by cyclooxygenase-2) effect of various extracts from Vaccinium bracteatum leaves and fruits. The highest anti-proliferative effect possessed leaf dichloromethane extract with IC50 values ranging from 93 to 198 mug/mL. In the case of cyclooxygenase-2 inhibition, n-hexane, dichloromethane, a...

  7. Influence of constant, alternating and cyclotron low-intensity electromagnetic fields on fibroblast proliferative activity in vitro.

    Science.gov (United States)

    Afinogenov, Gennadi; Afinogenova, Anna; Kalinin, Andrey

    2009-12-16

    Available data allow assuming the presence of stimulation of reparative processes under influence of low-intensity electromagnetic field, commensurable with a magnetic field of the Earth. Research of effects of low-intensity electromagnetic fields on fibroblast proliferative activity in human lungs in cell culture was performed.The influence of a constant electromagnetic field, an alternating electromagnetic field by frequency of 50 Hz and cyclotron electromagnetic field with identical intensity for all kinds of fields - 80 mcTl - on value of cellular mass and a correlation of live and dead cells in culture is investigated in three series of experiments. We used the universal electromagnetic radiator generating all three kinds of fields and supplied by a magnetometer which allows measuring the intensity of accurate within 0.1 mcTl including taking into account the Earth's magnetic field intensity.The peak value for stimulation cellular proliferation in the present experiences was two-hour influence by any of the specified kinds of electromagnetic fields. The irradiation by cyclotron electromagnetic field conducts positive dynamics in growth of live cells (up to 206+/-22%) and decreases the number of dead cells (down to 31+/-6%). Application of cyclotron magnetic fields promoted creation of optimum conditions for proliferation. As a result of researches we observed the reliable 30% increase of nitro-tetrazolium index (in nitro-tetrazolium blue test) after irradiation by cyclotron electromagnetic field in experience that testifies to strengthening of the cell breathing of living cells.In our opinion, it is necessary to pay attention not only to a pure gain of cells, but also to reduction of number dead cells that can be criterion of creation of optimum conditions for their specific development and valuable functioning.

  8. Chromatographic analysis, anti-proliferative and radical scavenging activity of Pinus wallichina essential oil growing in high altitude areas of Kashmir, India.

    Science.gov (United States)

    Yousuf Dar, Mohd; Shah, Wajaht A; Mubashir, Sofi; Rather, Manzoor A

    2012-10-15

    To evaluate the in vitro anti-proliferative and radical scavenging properties of the essential oil and its fractions and to determine the chemo-type of P. wallichiana essential oil. Pinus wallichiana oil was extracted by hydro-distillation and fractionated by silica gel column chromatography method. The oil and its fractions were analyzed by Gas chromatography, Gas chromatography-mass spectrometry and (13)C NMR. Different concentrations of oil 12.5, 25, 50 and 100μg/ml and single concentration 50μg/ml of its fractions B(1), B(2), A(2), G(2), Uk(13) and I(2) were evaluated for its anti-proliferative activity by in vitro {3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide} assay against human monocyte, lung carcinoma, liver adenocarcinoma, prostate and ovarian carcinoma, while as the radical scavenging activity was evaluated by different in vitro DPPH assays. The analyses indicated the presence of 17 constituents with β-pinene (46.8%) and α-pinene (25.2%) as major constituents. The oil and its fractions showed significant anti-proliferative activity. The radical scavenging activity also showed good results. The oil could be used as a drug to control the diseases like cancer, cirrhosis and arteriosclerosis, caused by reactive oxygen species. Copyright © 2012 Elsevier GmbH. All rights reserved.

  9. Korean Ginseng Berry Fermented by Mycotoxin Non-producing Aspergillus niger and Aspergillus oryzae: Ginsenoside Analyses and Anti-proliferative Activities.

    Science.gov (United States)

    Li, Zhipeng; Ahn, Hyung Jin; Kim, Nam Yeon; Lee, Yu Na; Ji, Geun Eog

    2016-01-01

    To transform ginsenosides, Korean ginseng berry (KGB) was fermented by mycotoxin non-producing Aspergillus niger and Aspergillus oryzae. Changes of ginsenoside profile and anti-proliferative activities were observed. Results showed that A. niger tended to efficiently transform protopanaxadiol (PPD) type ginsenosides such as Rb1, Rb2, Rd to compound K while A. oryzae tended to efficiently transform protopanaxatriol (PPT) type ginsenoside Re to Rh1 via Rg1. Butanol extracts of fermented KGB showed high cytotoxicity on human adenocarcinoma HT-29 cell line and hepatocellular carcinoma HepG2 cell line while that of unfermented KGB showed little. The minimum effective concentration of niger-fermented KGB was less than 2.5 µg/mL while that of oryzae-fermented KGB was about 5 µg/mL. As A. niger is more inclined to transform PPD type ginsenosides, niger-fermented KGB showed stronger anti-proliferative activity than oryzae-fermented KGB.

  10. Endothelin-1 activation of ETB receptors leads to a reduced cellular proliferative rate and an increased cellular footprint

    International Nuclear Information System (INIS)

    Wilson, Jamie L.; Taylor, Linda; Polgar, Peter

    2012-01-01

    Endothelin-1 (ET-1) is a vasoactive peptide which signals through two G-protein coupled receptors, endothelin receptor A (ETA) and B (ETB). We determined that ET-1 activation of its ETB receptor in stably cDNA transfected CHO cells leads to a 55% reduction in cell number by end-point cell counting and a 35% decrease in cell growth by a real-time cell-substrate impedance-based assay after 24 h of cell growth. When CHO ETB cells were synchronized in the late G1 cell cycle phase, ET-1 delayed their S phase progression compared to control by 30% as determined by [ 3 H]-thymidine incorporation. On the other hand, no such delay was observed during late G2/M to G1 transit when cells were treated with ET-1 after release from mitotic arrest. Using the cell-substrate impedance-based assay, we observed that ET-1 induces opposing morphological changes in CHO ETA and CHO ETB cells with ETB causing an increase in the cell footprint and ETA a decrease. Likewise, in pulmonary artery smooth muscle cells, which express both ETA and ETB receptors, ET-1 induces an ETA-dependent contraction and an ETB dependent dilation. These results are shedding light on a possible beneficial role for ETB in diseases involving ET-1 dysfunction such as pulmonary hypertension. -- Highlights: ► ET- hinders cell proliferation in CHO cells transfected with ETB. ► ET-1 also decreases the rate of DNA synthesis in CHO ETB cells. ► JNK and PI3K appear to be involved in this reduction of DNA synthesis. ► ETB activation in CHO ETB cells and hSMCs leads to dilatory morphological changes. ► In CHO ETA and hSMCs, ETA activation leads to constrictive morphological changes.

  11. Endothelin-1 activation of ETB receptors leads to a reduced cellular proliferative rate and an increased cellular footprint

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, Jamie L.; Taylor, Linda; Polgar, Peter, E-mail: peterp@bu.edu

    2012-06-10

    Endothelin-1 (ET-1) is a vasoactive peptide which signals through two G-protein coupled receptors, endothelin receptor A (ETA) and B (ETB). We determined that ET-1 activation of its ETB receptor in stably cDNA transfected CHO cells leads to a 55% reduction in cell number by end-point cell counting and a 35% decrease in cell growth by a real-time cell-substrate impedance-based assay after 24 h of cell growth. When CHO ETB cells were synchronized in the late G1 cell cycle phase, ET-1 delayed their S phase progression compared to control by 30% as determined by [{sup 3}H]-thymidine incorporation. On the other hand, no such delay was observed during late G2/M to G1 transit when cells were treated with ET-1 after release from mitotic arrest. Using the cell-substrate impedance-based assay, we observed that ET-1 induces opposing morphological changes in CHO ETA and CHO ETB cells with ETB causing an increase in the cell footprint and ETA a decrease. Likewise, in pulmonary artery smooth muscle cells, which express both ETA and ETB receptors, ET-1 induces an ETA-dependent contraction and an ETB dependent dilation. These results are shedding light on a possible beneficial role for ETB in diseases involving ET-1 dysfunction such as pulmonary hypertension. -- Highlights: Black-Right-Pointing-Pointer ET- hinders cell proliferation in CHO cells transfected with ETB. Black-Right-Pointing-Pointer ET-1 also decreases the rate of DNA synthesis in CHO ETB cells. Black-Right-Pointing-Pointer JNK and PI3K appear to be involved in this reduction of DNA synthesis. Black-Right-Pointing-Pointer ETB activation in CHO ETB cells and hSMCs leads to dilatory morphological changes. Black-Right-Pointing-Pointer In CHO ETA and hSMCs, ETA activation leads to constrictive morphological changes.

  12. The prognostic value of oncogenic antigen 519 (OA-519) expression and proliferative activity detected by antibody MIB-1 in node-negative breast cancer

    DEFF Research Database (Denmark)

    Jensen, V; Ladekarl, M; Holm-Nielsen, P

    1995-01-01

    The prognostic value of oncogenic antigen 519 (OA-519) expression and tumour proliferative activity was evaluated in a retrospective series of 118 patients with low-risk breast cancer. Low risk was defined as negative axillary nodes, tumour diameter histological evidence...... analysis, both the MIB-1 index and OA-519 expression were of independent prognostic value (2p breast cancer who might benefit from adjuvant therapy....

  13. Immunoregulatory activities of human immunodeficiency virus (HIV) proteins: Effect of HIV recombinant and synthetic peptides on immunoglobulin synthesis and proliferative responses by normal lymphocytes

    International Nuclear Information System (INIS)

    Nair, M.P.N.; Pottathil, R.; Heimer, E.P.; Schwartz, S.A.

    1988-01-01

    Recombinant and synthetic peptides corresponding to envelope proteins of the human immunodeficiency virus (HIV) were examined for their effects on the activities of lymphocytes from normal donors in vitro. Although lymphocytes cultured with env-gag peptides produced significant amounts of IgG, addition of env-gag peptides to a pokeweed mitogen-induced B-cell activation system resulted in suppression of immunoglobulin synthesis by normal lymphocytes. Recombinant antigens, env-gag and env-80 dihydrofolate reductase (DHFR), produced a substantial proliferative response by peripheral blood mononuclear cells (PBMC) as determined by [ 3 H]thymidine incorporation. PBMC precultured with HIV synthetic peptide env 578-608 also manifested significant proliferative responses as compared to control cultures. CD3 + lymphocytes precultured with recombinant HIV antigens, env-gag and env-80 DHFR, and synthetic HIV peptide, env 487-511, showed moderate but significant proliferative responses. Both recombinant antigens and synthetic peptides also produced a dose-dependent stimulatory effect on proliferation by CD3 - lymphocytes. These studies demonstrate that recombinant and synthetic peptides of the HIV genome express immunoregulatory T- and B-cell epitopes. Identification of unique HIV epitopes with immunogenic and immunoregulatory activities is necessary for the development of an effective vaccine against HIV infection

  14. Changes in retinal venular oxygen saturation predict activity of proliferative diabetic retinopathy 3 months after panretinal photocoagulation.

    Science.gov (United States)

    Torp, Thomas Lee; Kawasaki, Ryo; Wong, Tien Yin; Peto, Tunde; Grauslund, Jakob

    2018-03-01

    Proliferative diabetic retinopathy (PDR) is a severe blinding condition. We investigated whether retinal metabolism, measured by retinal oximetry, may predict PDR activity after panretinal laser photocoagulation (PRP). We performed a prospective, interventional, clinical study of patients with treatment-naive PDR. Wide-field fluorescein angiography (OPTOS, Optomap) and global and focal retinal oximetry (Oxymap T1) were performed at baseline (BL), and 3 months (3M) after PRP. Angiographic findings were used to divide patients according to progression or non-progression of PDR after PRP. We evaluated differences in global and focal retinal oxygen saturation between patients with and without progression of PDR after PRP treatment. We included 45 eyes of 37 patients (median age and duration of diabetes were 51.6 and 20 years). Eyes with progression of PDR developed a higher retinal venous oxygen saturation than eyes with non-progression at 3M (global: +5.9% (95% CI -1.5 to 12.9), focal: +5.4%, (95% CI -4.1 to 14.8)). Likewise, progression of PDR was associated with a lower arteriovenular (AV) oxygen difference between BL and 3M (global: -6.1%, (95% CI -13.4 to -1.4), focal: -4.5% (95% CI -12.1 to 3.2)). In a multiple logistic regression model, increment in global retinal venular oxygen saturation (OR 1.30 per 1%-point increment, p=0.017) and decrement in AV oxygen saturation difference (OR 0.72 per 1%-point increment, p=0.016) at 3M independently predicted progression of PDR. Development of higher retinal venular and lower AV global oxygen saturation independently predicts progression of PDR despite standard PRP and might be a potential non-invasive marker of angiogenic disease activity. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  15. Anti-proliferative and mutagenic activities of aqueous and methanol extracts of leaves from Pereskia bleo (Kunth) DC (Cactaceae).

    Science.gov (United States)

    Er, Hui Meng; Cheng, En-Hsiang; Radhakrishnan, Ammu Kutty

    2007-09-25

    The anti-proliferative effects of the aqueous and methanol extracts of leaves of Pereskia bleo (Kunth) DC (Cactaceae) against a mouse mammary cancer cell line (4T1) and a normal mouse fibroblast cell line (NIH/3T3) were evaluated under an optimal (in culture medium containing 10% foetal bovine serum (FBS)) and a sub-optimal (in culture medium containing 0.5% FBS) conditions. Under the optimal condition, the aqueous extract showed a significant (pCactaceae) do not have appreciable anti-proliferative effect on the 4T1 and NIH/3T3 cells as the EC(50) values obtained are greater than 50 microg/mL when tested under optimal culture condition. Moreover, the aqueous extract may form mutagenic compound(s) upon the metabolisation by liver enzymes.

  16. S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component.

    Science.gov (United States)

    Zheng, Lei; Roeder, Robert G; Luo, Yan

    2003-07-25

    We have isolated and functionally characterized a multicomponent Oct-1 coactivator, OCA-S which is essential for S phase-dependent histone H2B transcription. The p38 component of OCA-S binds directly to Oct-1, exhibits potent transactivation potential, is selectively recruited to the H2B promoter in S phase, and is essential for S phase-specific H2B transcription in vivo and in vitro. Surprisingly, p38 represents a nuclear form of glyceraldehyde-3-phosphate dehydrogenase, and binding to Oct-1, as well as OCA-S function, is stimulated by NAD(+) but inhibited by NADH. OCA-S also interacts with NPAT, a cyclin E/cdk2 substrate that is broadly involved in histone gene transcription. These studies thus link the H2B transcriptional machinery to cell cycle regulators, and possibly to cellular metabolic state (redox status), and set the stage for studies of the underlying mechanisms and the basis for coordinated histone gene expression and coupling to DNA replication.

  17. Phenolic composition, antioxidant and anti-proliferative activities of edible and medicinal plants from the Peruvian Amazon

    Directory of Open Access Journals (Sweden)

    Jan Tauchen

    Full Text Available ABSTRACT Among 23 extracts of medicinal and edible plants tested, Mauritia flexuosa L.f., Arecaceae, showed significant antioxidant ability (DPPH and ORAC = 1062.9 and 645.9 ± 51.4 µg TE/mg extract, respectively, while Annona montana Macfad., Annonaceae, demonstrated the most promising anti-proliferative effect (IC50 for Hep-G2 and HT-29 = 2.7 and 9.0 µg/ml, respectively. However, combinatory antioxidant/anti-proliferative effect was only detected in Oenocarpus bataua Mart., Arecaceae (DPPH = 903.8 and ORAC = 1024 µg TE/mg extract; IC50 for Hep-G2 and HT-29 at 102.6 and 38.8 µg/ml, respectively and Inga edulis Mart., Fabaceae (DPPH = 337.0 and ORAC = 795.7 µg TE/mg extract; IC50 for Hep-G2 and HT-29 at 36.3 and 57.9 µg/ml, respectively. Phenolic content was positively correlated with antioxidant potential, however not with anti-proliferative effect. None of these extracts possessed toxicity towards normal foetal lung cells, suggesting their possible use in development of novel plant-based agents with preventive and/or therapeutic action against oxidative stress-related diseases.

  18. Noninvasive Evaluation of Cellular Proliferative Activity in Brain Neurogenic Regions in Rats under Depression and Treatment by Enhanced [18F]FLT-PET Imaging.

    Science.gov (United States)

    Tamura, Yasuhisa; Takahashi, Kayo; Takata, Kumi; Eguchi, Asami; Yamato, Masanori; Kume, Satoshi; Nakano, Masayuki; Watanabe, Yasuyoshi; Kataoka, Yosky

    2016-08-03

    Neural stem cells in two neurogenic regions, the subventricular zone and the subgranular zone (SGZ) of the hippocampal dentate gyrus, can divide and produce new neurons throughout life. Hippocampal neurogenesis is related to emotions, including depression/anxiety, and the therapeutic effects of antidepressants, as well as learning and memory. The establishment of in vivo imaging for proliferative activity of neural stem cells in the SGZ might be used to diagnose depression and to monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging with 3'-deoxy-3'-[(18)F]fluoro-l-thymidine ([(18)F]FLT) has been studied to allow visualization of proliferative activity in two neurogenic regions of adult mammals; however, the PET imaging has not been widely used because of lower accumulation of [(18)F]FLT, which does not allow quantitative assessment of the decline in cellular proliferative activity in the SGZ under the condition of depression. We report the establishment of an enhanced PET imaging method with [(18)F]FLT combined with probenecid, an inhibitor of drug transporters at the blood-brain barrier, which can allow the quantitative visualization of neurogenic activity in rats. Enhanced PET imaging allowed us to evaluate reduced cell proliferation in the SGZ of rats with corticosterone-induced depression, and further the recovery of proliferative activity in rats under treatment with antidepressants. This enhanced [(18)F]FLT-PET imaging technique with probenecid can be used to assess the dynamic alteration of neurogenic activity in the adult mammalian brain and may also provide a means for objective diagnosis of depression and monitoring of the therapeutic effect of antidepressant treatment. Adult hippocampal neurogenesis may play a role in major depression and antidepressant therapy. Establishment of in vivo imaging for hippocampal neurogenic activity may be useful to diagnose depression and monitor the therapeutic efficacy of

  19. Proliferative Activity of Mammary Carcinoma Cells by AgNOR Count in C3H mice Receiving Ethanol Extract of Sponge Haliclona sp

    Science.gov (United States)

    Sijabat, Lanceria; Susilaningsih, Neni; Trianto, Agus; Murwani, Retno

    2018-02-01

    Quantification of argyrophilic nucleolar organizer region (AgNORs) was considered as one of markers of proliferative activity of cancer cells. Sponge Haliclona sp extract contains anticancer bioactive compounds and our previous study showed that the extract was able to improve histological grade of induced mammary adenocarcinoma in mice. The following research was conducted to study the extract administration on the proliferative activity of the carcinoma cells represented by AgNOR count in mice. This experimental study applied post test only control group design. Twenty C3H mice were divided into four groups namely C (control), H1, H2 and H3. Each group was given 0, 0.15, 1.5, and 15 mg Haliclona sp extract respectively. After three weeks of extract administration, mice were inoculated with breast cancer cells from donor mice. The extract administration were continued for another three weeks. AgNOR count was performed on tumor sections and expressed as mean of AgNOR (mAgNOR) and percentage of AgNOR (pAgNOR). Means of mAgNOR in C, H1, H2 and H3 were 4.070, 3.195, 3.450, and 3.190 respectively. Means of pAgNOR in C, H1, H2 and H3 were 34,40, 25,40, 38,40 and 19,80 respectively. The lowest means of mAgNOR and pAgNOR which is an indication of lower proliferative activity of the cancer cells was found in H3. However no significant difference can be found among treatment groups (p>0.05). Using AgNOR count, the ethanol extract of Haliclona sp could not show significant reduction in proliferation of mammary carcinoma cells of C3H mice. This finding support the view that AgNOR alone could not be used to determine pathology of cancer cells.

  20. Uric acid stimulates proliferative pathways in vascular smooth muscle cells through the activation of p38 MAPK, p44/42 MAPK and PDGFRβ.

    Science.gov (United States)

    Kırça, M; Oğuz, N; Çetin, A; Uzuner, F; Yeşilkaya, A

    2017-04-01

    Hyperuricemia and angiotensin II (Ang II) may have a pathogenetic role in the development of hypertension and atherosclerosis as well as cardiovascular disease (CVD) and its prognosis. The purpose of this study was to investigate whether uric acid can induce proliferative pathways of vascular smooth muscle cell (VSMC) that are thought to be responsible for the development of CVD. The phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), p44/42 mitogen-activated protein kinase (p44/42 MAPK) and platelet-derived growth factor receptor β (PDGFRβ) was measured by Elisa and Western blot techniques to determine the activation of proliferative pathways in primary cultured VSMCs from rat aorta. Results demonstrated that uric acid can stimulate p38 MAPK, p44/42 MAPK and PDGFRβ phosphorylation in a time- and concentration-dependent manner. Furthermore, treatment of VSMCs with the angiotensin II type I receptor (AT1R) inhibitor losartan suppressed p38 MAPK and p44/42 MAPK induction by uric acid. The stimulatory effect of uric acid on p38 MAPK was higher compared to that of Ang II. The results of this study show for the first time that uric acid-induced PDGFRβ phosphorylation plays a crucial role in the development of CVDs and that elevated uric acid levels could be a potential therapeutical target in CVD patients.

  1. Prognostic significance of s-phase fraction detected by antithymidine antibodies in epidermoid cervix carcinomas

    International Nuclear Information System (INIS)

    Zamulaeva, Irina A.; Podgorodnichenko, Vladimir K.; Guseva, Ludmila I.; Krikunova, Ludmila I.; Saenko, Alexander S.

    1996-01-01

    Purpose: To assess the predictive value of pretreatment proliferative activity of epidermoid cervix carcinoma cells with respect to short- and long-term results of radiotherapy. Methods and Materials: The proliferative activity of 25 epidermoid cervix carcinomas was evaluated as the immunofluorescent labelling index (LI) by rabbit antithymidine antibodies reacting specifically with single-stranded DNA of replication forks in S-phase cells. The short-term clinical outcome was estimated at 3-6 months after treatment by visual and palpatory examination. Three-year follow-up data were obtained through hospital charts and correspondence with referring physicians for only 19 patients. Results: There was no statistically significant association between LI and such conventional prognostic factors as clinical stage. The LI value of cervix carcinomas was significantly associated with complete regression at 3-6 months after radiotherapy and 3-year disease-free survival. Complete regression at 3-6 months was observed in 87.5% patients with fast proliferating tumors (LI > 7.0%), and only in 41.2% patients with slowly proliferating tumors (p = 0.03). Probability of 3-year disease-free survival was 85.7% in patients with fast proliferating tumors and 50.0% in those with slowly proliferating tumors (p = 0.05). Conclusions: The immunofluorescent LI of epidermoid cervix carcinoma is able to provide prognostic information on short-term tumor response to radiotherapy and disease-free survival

  2. Anti-proliferative activity of 2,6-dichloro-9- or 7-(ethoxycarbonylmethyl)-9H- or 7H-purines against several human solid tumour cell lines.

    Science.gov (United States)

    Morales, Fátima; Ramírez, Alberto; Conejo-García, Ana; Morata, Cynthia; Marchal, Juan A; Campos, Joaquín M

    2014-04-09

    As leads we took several benzo-fused seven- and six-membered scaffolds linked to the pyrimidine or purine moieties with notable anti-proliferative activity against human breast, colon and melanoma cancerous cell lines. We then decided to maintain the double-ringed nitrogenous bases and change the other components to the ethyl acetate moiety. This way six purine and two 5-fluorouracil derivatives were obtained and evaluated against the MCF-7, HCT-116, A-375 and G-361 cancer cell lines. Two QSARs are obtained between the anti-proliferative IC₅₀ values for compounds 26-33 and the clog P against the melanoma cell lines A-375 and G-361. Our results show that two of the analogues [ethyl 2-(2,6-dichloro-9H- or 7H-purine-9- or 7-yl)acetates (30 and 33, respectively)] are potent cytotoxic agents against all the tumour cell lines assayed, showing single-digit micromolar IC₅₀ values. This exemplifies the potential of our previously reported purine compounds to qualify as lead structures for medicinal chemistry campaigns, affording simplified analogues easy to synthesize and with a noteworthy bioactivity. The selective activity of 30 and 33 against the melanoma cell line A-375, via apoptosis, supposes a great advantage for a future therapeutic use. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  3. A comparative study of proliferative activity and tumor stage of pregnancy-associated melanoma (PAM) and non-PAM in gestational age women.

    Science.gov (United States)

    Merkel, Emily A; Martini, Mary C; Amin, Sapna M; Yélamos, Oriol; Lee, Christina Y; Sholl, Lauren M; Rademaker, Alfred W; Guitart, Joan; Gerami, Pedram

    2016-01-01

    The influence of pregnancy on the development, progression, and prognosis of melanoma is controversial. We sought to compare clinical characteristics, histologic features, and proliferative activity in pregnancy-associated melanoma (PAM) and melanoma in nonpregnant women of reproductive age (non-PAM). In this retrospective cohort study, we reviewed medical records and pathology reports from women given a diagnosis of melanoma between 2006 and 2015. We also examined tumor proliferation rates using mitotic count and 2 immunohistochemical markers of proliferation, phosphohistone H3 and Ki-67. In 50 PAM and 122 non-PAM cases, a diagnosis of melanoma in situ was associated with PAM. Among invasive melanomas, there was no difference in proliferative activity between groups. Pregnancy status was also not associated with age at diagnosis, tumor site, Breslow depth, Clark level, ulceration, or overall stage. This was a retrospective study with a small sample size of mostly patients with early-stage melanoma. In our study of primarily early-stage melanoma, pregnancy did not have a significant impact on tumor proliferation. Particularly for patients given a diagnosis of stage I melanoma who are undergoing close surveillance, a history of PAM should not outweigh traditional factors, such as advanced maternal age, in planning future pregnancies. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  4. Proliferative retinopathy predicts nephropathy

    DEFF Research Database (Denmark)

    Karlberg, Charlotte; Falk, Christine; Green, Anders

    2012-01-01

    We wanted to examine proliferative retinopathy as a marker of incident nephropathy in a 25-year follow-up study of a population-based cohort of Danish type 1 diabetic patients and to examine cross-sectional associations between nephropathy and retinopathy in long-term surviving patients of the same...... cohort. All type 1 diabetic patients from Fyn County, Denmark, were identified as of 1 July 1973. One hundred and eighty four patients were examined in 1981-1982 (baseline) and in 2007-2008 (follow-up). The level of retinopathy was graded by ophthalmoscopy at baseline and nine-field digital colour fundus...... and proliferative retinopathy, respectively. In conclusion, proliferative retinopathy is an independent marker of long-term nephropathy in type 1 diabetes. Upcoming studies should examine whether these microvascular complications are also causally linked in type 1 diabetes....

  5. A peroxisome proliferator-activated receptor ligand MCC-555 imparts anti-proliferative response in pancreatic cancer cells by PPARgamma-independent up-regulation of KLF4

    Energy Technology Data Exchange (ETDEWEB)

    Min, Kyung-Won [Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996 (United States); Zhang, Xiaobo [Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996 (United States); College of Animal Science and Technology, Northwest A and F University, Yangling, Shaanxi, 712100 (China); Imchen, Temjenmongla [Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996 (United States); Baek, Seung Joon, E-mail: sbaek2@utk.edu [Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996 (United States)

    2012-09-01

    MCC-555 is a novel PPARα/γ dual ligand of the thiazolidinedione class and was recently developed as an anti-diabetic drug with unique properties. MCC-555 also has anti-proliferative activity through growth inhibition and apoptosis induction in several cancer cell types. Our group has shown that MCC-555 targets several proteins in colorectal tumorigenesis including nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1) which plays an important role in chemoprevention responsible for chemopreventive compounds. NAG-1 is a member of the TGF-β superfamily and is involved in tumor progression and development; however, NAG-1's roles in pancreatic cancer have not been studied. In this report, we found that MCC-555 alters not only NAG-1 expression, but also p21 and cyclin D1 expression. NAG-1 and p21 expression was not blocked by PPARγ-specific antagonist GW9662, suggesting that MCC-555-induced NAG-1 and p21 expression is independent of PPARγ activation. However, decreasing cyclin D1 by MCC-555 seems to be affected by PPARγ activation. Further, we found that the GC box located in the NAG-1 promoter play an important role in NAG-1 transactivation by MCC-555. Subsequently, we screened several transcription factors that may bind to the GC box region in the NAG-1 promoter and found that KLF4 potentially binds to this region. Expression of KLF4 precedes NAG-1 and p21 expression in the presence of MCC-555, whereas blocking KLF4 expression using specific KLF4 siRNA showed that both NAG-1 and p21 expression by MCC-555 was blocked. In conclusion, MCC-555's actions on anti-proliferation involve both PPARγ-dependent and -independent pathways, thereby enhancing anti-tumorigenesis in pancreatic cancer cells. -- Highlights: ► PPARα/γ ligand MCC-555 exhibits anti-proliferative activity in pancreatic cancer cells. ► MCC-555 affects KLF4 expression following by NAG-1 and p21 expression in a PPARγ independent manner. ► MCC-555 also affects cyclin D1 down

  6. A peroxisome proliferator-activated receptor ligand MCC-555 imparts anti-proliferative response in pancreatic cancer cells by PPARgamma-independent up-regulation of KLF4

    International Nuclear Information System (INIS)

    Min, Kyung-Won; Zhang, Xiaobo; Imchen, Temjenmongla; Baek, Seung Joon

    2012-01-01

    MCC-555 is a novel PPARα/γ dual ligand of the thiazolidinedione class and was recently developed as an anti-diabetic drug with unique properties. MCC-555 also has anti-proliferative activity through growth inhibition and apoptosis induction in several cancer cell types. Our group has shown that MCC-555 targets several proteins in colorectal tumorigenesis including nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1) which plays an important role in chemoprevention responsible for chemopreventive compounds. NAG-1 is a member of the TGF-β superfamily and is involved in tumor progression and development; however, NAG-1's roles in pancreatic cancer have not been studied. In this report, we found that MCC-555 alters not only NAG-1 expression, but also p21 and cyclin D1 expression. NAG-1 and p21 expression was not blocked by PPARγ-specific antagonist GW9662, suggesting that MCC-555-induced NAG-1 and p21 expression is independent of PPARγ activation. However, decreasing cyclin D1 by MCC-555 seems to be affected by PPARγ activation. Further, we found that the GC box located in the NAG-1 promoter play an important role in NAG-1 transactivation by MCC-555. Subsequently, we screened several transcription factors that may bind to the GC box region in the NAG-1 promoter and found that KLF4 potentially binds to this region. Expression of KLF4 precedes NAG-1 and p21 expression in the presence of MCC-555, whereas blocking KLF4 expression using specific KLF4 siRNA showed that both NAG-1 and p21 expression by MCC-555 was blocked. In conclusion, MCC-555's actions on anti-proliferation involve both PPARγ-dependent and -independent pathways, thereby enhancing anti-tumorigenesis in pancreatic cancer cells. -- Highlights: ► PPARα/γ ligand MCC-555 exhibits anti-proliferative activity in pancreatic cancer cells. ► MCC-555 affects KLF4 expression following by NAG-1 and p21 expression in a PPARγ independent manner. ► MCC-555 also affects cyclin D1 down

  7. Cell structure and proliferative activity of organ cultures of normal embryonic lung tissue of mice resistant (C57BL) and predisposed (A) to lung tumors

    International Nuclear Information System (INIS)

    Kolesnichenko, T.S.; Gor'kova, T.G.

    1985-01-01

    Local factors such as proliferative activity and the numerical ratio between epithelial and mesenchymal cells, and also the character of interaction between the tissue components in ontogeny may play an important role in the realization of sensitivity of mice of a particular line to the development of lung tumors. These characteristics of lung tissue in mice of lines A and C57BL are investigated under normal conditions and during induced carcinogenesis. Results are given of a comparative study of the relative numbers of epithelial and mesenchymal cells in organ cultures of embryonic lungs. 3 H-thymidine was added to the cultures on the 14th day of the experiment in a concentration of 1 microCi/m1 medium. An autoradiographic study of the cultures was performed

  8. Proliferative activity (MIB-1 index) is an independent prognostic parameter in patients with high-grade soft tissue sarcomas of subtypes other than malignant fibrous histiocytomas

    DEFF Research Database (Denmark)

    Jensen, V; Sørensen, Flemming Brandt; Bentzen, S M

    1998-01-01

    . The proliferative activity was assessed by use of the monoclonal antibody MIB-1 and evaluated in multiple, random systematic sampled fields of vision. The percentage of proliferating cells (the MIB-1 index) ranged between 1% and 85% (median 12%). A significant increase in mean MIB-1 index was seen with increasing...... histological malignancy grade. Variation in the incidence of p53 accumulation and bcl-2 positivity among different histological subtypes was observed. p53 accumulation was frequent in synovial sarcomas and leiomyo- and rhabdomyosarcomas, whereas bcl-2 preferentially was expressed in synovial sarcomas....... Univariate analysis identified patient age, tumour size, histological grade of malignancy, MIB-1 index and p53 accumulation as significant prognostic parameters. Multivariate Cox analysis, including tests for interaction terms between histological subtypes and MIB-1 index, showed independent prognostic...

  9. The differential proliferative ability of satellite cells in Lantang and Landrace pigs.

    Directory of Open Access Journals (Sweden)

    Xiu-qi Wang

    Full Text Available Here, for the first time, we evaluate the hypothesis that the proliferative abilities of satellite cells (SCs isolated from Lantang (indigenous Chinese pigs and Landrace pigs, which differ in muscle characteristics, are different. SCs were isolated from the longissimus dorsi muscle of neonatal Lantang and Landrace pigs. Proliferative ability was estimated by the count and proliferative activity of viable cells using a hemocytometer and MTT assay at different time points after seeding, respectively. Cell cycle information was detected by flow cytometry. Results showed that there was a greater (P<0.05 number of SCs in Lantang pigs compared with Landrace pigs after 72 h of culture. The percentage of cell population in S phase and G(2/M phases in Lantang pigs were higher (P<0.05, while in G(0/G(1 phase was lower (P<0.05 in comparison with the Landrace pigs. The mRNA abundances of MyoD, Myf5, myogenin and Pax7 in SCs from Lantang pigs were higher (P<0.05, while those of myostatin, Smad3 and genes in the mammalian target of rapamycin (mTOR pathway (with the exception of 4EBP1 were lower (P<0.05 than the Landrace pigs. Protein levels of MyoD, myogenin, myostatin, S6K, phosphorylated mTOR and phosphorylated eIF4E were consistent with the corresponding mRNA abundance. Collectively, these findings suggested that SCs in the two breeds present different proliferative abilities, and the proliferative potential of SCs in Lantang pigs is higher than in Landrace pigs.

  10. The truncated splice variant of peroxisome proliferator-activated receptor alpha, PPARα-tr, autonomously regulates proliferative and pro-inflammatory genes

    International Nuclear Information System (INIS)

    Thomas, Maria; Bayha, Christine; Klein, Kathrin; Müller, Simon; Weiss, Thomas S.; Schwab, Matthias; Zanger, Ulrich M.

    2015-01-01

    The peroxisome proliferator-activated receptor alpha (PPARα) controls lipid/energy homeostasis and inflammatory responses. The truncated splice variant PPARα-tr was suggested to exert a dominant negative function despite being unable to bind consensus PPARα DNA response elements. The distribution and variability factor of each PPARα variant were assessed in the well-characterized cohort of human liver samples (N = 150) on the mRNA and protein levels. Specific siRNA-mediated downregulation of each transcript as well as specific overexpression with subsequent qRT-PCR analysis of downstream genes was used for investigation of specific functional roles of PPARα-wt and PPARα-tr forms in primary human hepatocytes. Bioinformatic analyses of genome-wide liver expression profiling data suggested a possible role of PPARα-tr in downregulating proliferative and pro-inflammatory genes. Specific gene silencing of both forms in primary human hepatocytes showed that induction of metabolic PPARα-target genes by agonist WY14,643 was prevented by PPARα-wt knock-down but neither prevented nor augmented by PPARα-tr knock-down. WY14,643 treatment did not induce proliferative genes including MYC, CDK1, and PCNA, and knock-down of PPARα-wt had no effect, while PPARα-tr knock-down caused up to 3-fold induction of these genes. Similarly, induction of pro-inflammatory genes IL1B, PTGS2, and CCL2 by IL-6 was augmented by knock-down of PPARα-tr but not of PPARα-wt. In contrast to human proliferative genes, orthologous mouse genes were readily inducible by WY14,643 in PPARα-tr non-expressing AML12 mouse hepatocytes. Induction was augmented by overexpression of PPARα-wt and attenuated by overexpression of PPARα-tr. Pro-inflammatory genes including IL-1β, CCL2 and TNFα were induced by WY14,643 in mouse and human cells and both PPARα forms attenuated induction. As potential mechanism of PPARα-tr inhibitory action we suggest crosstalk with WNT/β-catenin pathway. Finally

  11. The proliferative status of intestinal epithelial clonogenic cells: sensitivity to S phase specific cytotoxic agents.

    Science.gov (United States)

    Boarder, T A; Blackett, N M

    1976-11-01

    High concentrations of tritiated thymidine and cytosine arabinoside (Ara-C) have been used to selectively kill cells in the crypts of Lieberkuhn that are synthesizing DNA. The effect of these agents on the number of regenerating microcolonies seen 3 1/2 days after a range of radiation doses indicates that a majority of the clonogenic cells are proliferating rapidly and that the slowly proliferating cells at the base of the crypt do not represent the whole clonogenic population.

  12. Proliferative capacity of murine hematopoietic stem cells

    International Nuclear Information System (INIS)

    Hellman, S.; Botnick, L.E.; Hannon, E.C.; Vigneulle, R.M.

    1978-01-01

    The present study demonstrates a decrease in self-renewal capacity with serial transfer of murine hematopoietic stem cells. Production of differentiated cell progeny is maintained longer than stem cell self-renewal. In normal animals the capacity for self-renewal is not decreased with increasing donor age. The stem cell compartment in normal animals, both young and old, appears to be proliferatively quiescent. After apparent recovery from the alkylating agent busulfan, the probability of stem cell self-renewal is decreased, there is a permanent defect in the capacity of the bone marrow for serial transplantation, and the stem cells are proliferatively active. These findings support a model of the hematopoietic stem cell compartment as a continuum of cells with decreasing capacities for self-renewal, increasing likelihood for differentiation, and increasing proliferative activity. Cells progress in the continuum in one direction and such progression is not reversible

  13. Reconstitution of active telomerase in primary human foreskin fibroblasts : effects on proliferative characteristics and response to ionizing radiation

    NARCIS (Netherlands)

    Kampinga, H.H.; Waarde-Verhagen, M.A.W.H. van; Assen-Bolt, A.J. van; Rodemann, H.P.; Prowse, K.R.; Linskens, M.H.K.

    2004-01-01

    Purpose: Telomere shortening has been proposed to trigger senescence, and since most primary cells do not express active telomerase, reactivation of telomerase activity was proposed as a safe and non-transforming way of immortalizing cells. However, to study radiation responses, it is as yet unclear

  14. Wound healing morbidity in STS patients treated with preoperative radiotherapy in relation to in vitro skin fibroblast radiosensitivity, proliferative capacity and TGF-β activity

    International Nuclear Information System (INIS)

    Akudugu, John M.; Bell, Robert S.; Catton, Charles; Davis, Aileen M.; Griffin, Anthony M.; O'Sullivan, Brian; Waldron, John N.; Ferguson, Peter C.; Wunder, Jay S.; Hill, Richard P.

    2006-01-01

    Background and purpose: In a recent study, we demonstrated that the ability of dermal fibroblasts, obtained from soft tissue sarcoma (STS) patients, to undergo initial division in vitro following radiation exposure correlated with the development of wound healing morbidity in the patients following their treatment with preoperative radiotherapy. Transforming growth factor beta (TGF-β) is thought to play an important role in fibroblast proliferation and radiosensitivity both of which may impact on wound healing. Thus, in this study we examined the interrelationship between TGF-β activity, radiosensitivity and proliferation of cultured fibroblasts and the wound healing response of STS patients after preoperative radiotherapy to provide a validation cohort for our previous study and to investigate mechanisms. Patients and methods: Skin fibroblasts were established from skin biopsies of 46 STS patients. The treatment group consisted of 28 patients who received preoperative radiotherapy. Eighteen patients constituted a control group who were either irradiated postoperatively or did not receive radiation treatment. Fibroblast cultures were subjected to the colony forming and cytokinesis-blocked binucleation assays (low dose rate: ∼0.02 Gy/min) and TGF-β assays (high dose-rate: ∼1.06 Gy/min) following γ-irradiation. Fibroblast radiosensitivity and initial proliferative ability were represented by the surviving fraction at 2.4 Gy (SF 2.4 ) and binucleation index (BNI), respectively. Active and total TGF-β levels in fibroblast cultures were determined using a biological assay. Wound healing complication (WHC), defined as the requirement for further surgery or prolonged deep wound packing, was the clinical endpoint examined. Results: Of the 28 patients treated with preoperative radiotherapy, 8 (29%) had wound healing difficulties. Fibroblasts from patients who developed WHC showed a trend to retain a significantly higher initial proliferative ability after

  15. Inhibition of H3K27me3 Histone Demethylase Activity Prevents the Proliferative Regeneration of Zebrafish Lateral Line Neuromasts

    Science.gov (United States)

    Bao, Beier; He, Yingzi; Tang, Dongmei; Li, Wenyan; Li, Huawei

    2017-01-01

    The H3K27 demethylases are involved in a variety of biological processes, including cell differentiation, proliferation, and cell death by regulating transcriptional activity. However, the function of H3K27 demethylation in the field of hearing research is poorly understood. Here, we investigated the role of H3K27me3 histone demethylase activity in hair cell regeneration using an in vivo animal model. Our data showed that pharmacologic inhibition of H3K27 demethylase activity with the specific small-molecule inhibitor GSK-J4 decreased the number of regenerated hair cells in response to neomycin damage. Furthermore, inhibition of H3K27me3 histone demethylase activity dramatically suppressed cell proliferation and activated caspase-3 levels in the regenerating neuromasts of the zebrafish lateral line. GSK-J4 administration also increased the expression of p21 and p27 in neuromast cells and inhibited the ERK signaling pathway. Collectively, our findings indicate that H3K27me3 demethylation is a key epigenetic regulator in the process of hair cell regeneration in zebrafish and suggest that H3K27me3 histone demethylase activity might be a novel therapeutic target for the treatment of hearing loss. PMID:28348517

  16. The effect of beta-hydroxy-beta-methylbutyrate (HMB) on the proliferative response of blood lymphocytes and the phagocytic activity of blood monocytes and granulocytes in calves.

    Science.gov (United States)

    Wójcik, R; Małaczewska, J; Siwicki, A K; Miciński, J; Zwierzchowski, G

    2013-01-01

    The objective of this study was to evaluate the effect of HMB on selected indicators of immunity in calves. The experiment was performed on 14 calves aged 30 +/- 2 days, divided into two equal groups of control (group I) and experimental (group II) animals. The feed administered to experimental group calves was supplemented with HMB at 40 mg/kg BW, whereas control calves were administered standard farm-made feed without supplementation. Blood was sampled from the jugular vein immediately before the experiment (day 0) and on experimental days 15, 30 and 60 to determine the following parameters of immunity: proliferative response of LPS- and ConA-stimulated lymphocytes (MTT), respiratory burst activity (RBA) and potential killing activity (PKA) of phagocytes. The results revealed a significant increase in RBA and MTT values in calves administered HMB in comparison with the control group throughout the experiment. In the group of animals receiving HMB, an increase in PKA values was noted only on day 30.

  17. Anti-Proliferative Activity of Meroditerpenoids Isolated from the Brown Alga Stypopodium flabelliforme against Several Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Patricia Valentao

    2011-05-01

    Full Text Available The sea constitutes one of the most promising sources of novel compounds with potential application in human therapeutics. In particular, algae have proved to be an interesting source of new bioactive compounds. In this work, six meroditerpenoids (epitaondiol, epitaondiol diacetate, epitaondiol monoacetate, stypotriol triacetate, 14-ketostypodiol diacetate and stypodiol isolated from the brown alga Stypopodium flabelliforme were tested for their cell proliferation inhibitory activity in five cell lines. Cell lines tested included human colon adenocarcinoma (Caco-2, human neuroblastoma (SH-SY5Y, rat basophilic leukemia (RBL-2H3, murine macrophages (RAW.267 and Chinese hamster fibroblasts (V79. Antimicrobial activity of the compounds was also evaluated against Staphylococcus aureus, Salmonella typhimurium, Proteus mirabilis, Bacillus cereus, Enterococcus faecalis and Micrococcus luteus. Overall, the compounds showed good activity against all cell lines, with SH-SY5Y and RAW.267 being the most susceptible. Antimicrobial capacity was observed for epitaondiol monoacetate, stypotriol triacetate and stypodiol, with the first being the most active. The results suggest that these molecules deserve further studies in order to evaluate their potential as therapeutic agents.

  18. The KDM5 family is required for activation of pro-proliferative cell cycle genes during adipocyte differentiation

    DEFF Research Database (Denmark)

    Brier, Ann-Sofie B; Loft, Anne; Madsen, Jesper G S

    2017-01-01

    The KDM5 family of histone demethylases removes the H3K4 tri-methylation (H3K4me3) mark frequently found at promoter regions of actively transcribed genes and is therefore generally considered to contribute to corepression. In this study, we show that knockdown (KD) of all expressed members...... of the KDM5 family in white and brown preadipocytes leads to deregulated gene expression and blocks differentiation to mature adipocytes. KDM5 KD leads to a considerable increase in H3K4me3 at promoter regions; however, these changes in H3K4me3 have a limited effect on gene expression per se. By contrast......, genome-wide analyses demonstrate that KDM5A is strongly enriched at KDM5-activated promoters, which generally have high levels of H3K4me3 and are associated with highly expressed genes. We show that KDM5-activated genes include a large set of cell cycle regulators and that the KDM5s are necessary...

  19. Transcriptional Regulation of Δ6-Desaturase by Peroxisome Proliferative-Activated Receptor δ Agonist in Human Pancreatic Cancer Cells: Role of MEK/ERK1/2 Pathway

    Directory of Open Access Journals (Sweden)

    Maryam Darabi

    2013-01-01

    Full Text Available The Δ6-desaturase (Δ6D, also known as fatty acid desaturase 2, is a regulatory enzyme in de novo fatty acid synthesis, which has been linked to obesity and diabetes. The aim of the present study was to investigate the effect of peroxisome proliferative-activated receptor δ (PPARδ agonist and MEK/ERK1/2-dependent pathway on the expression of Δ6D in human pancreatic carcinoma cell line PANC-1. PANC-1 cells cultured in RPMI-1640 were exposed to the commonly used ERK1/2 pathway inhibitor PD98059 and PPARδ agonist GW0742. Changes in mRNA and protein expression of Δ6D were then determined using real-time RT-PCR and Western blot, respectively. The expression of Δ6D (P40%, P25%, P<0.05 pretreatment. PPARδ and MEK/ERK1/2 signaling pathways affect differentially the expression of Δ6D in pancreatic cancer cells. Furthermore, there may be an inhibitory crosstalk between these two regulatory pathways on the mRNA expression of Δ6D and subsequently on Δ6D protein expression.

  20. Histogram Analysis of Diffusion Weighted Imaging at 3T is Useful for Prediction of Lymphatic Metastatic Spread, Proliferative Activity, and Cellularity in Thyroid Cancer.

    Science.gov (United States)

    Schob, Stefan; Meyer, Hans Jonas; Dieckow, Julia; Pervinder, Bhogal; Pazaitis, Nikolaos; Höhn, Anne Kathrin; Garnov, Nikita; Horvath-Rizea, Diana; Hoffmann, Karl-Titus; Surov, Alexey

    2017-04-12

    Pre-surgical diffusion weighted imaging (DWI) is increasingly important in the context of thyroid cancer for identification of the optimal treatment strategy. It has exemplarily been shown that DWI at 3T can distinguish undifferentiated from well-differentiated thyroid carcinoma, which has decisive implications for the magnitude of surgery. This study used DWI histogram analysis of whole tumor apparent diffusion coefficient (ADC) maps. The primary aim was to discriminate thyroid carcinomas which had already gained the capacity to metastasize lymphatically from those not yet being able to spread via the lymphatic system. The secondary aim was to reflect prognostically important tumor-biological features like cellularity and proliferative activity with ADC histogram analysis. Fifteen patients with follicular-cell derived thyroid cancer were enrolled. Lymph node status, extent of infiltration of surrounding tissue, and Ki-67 and p53 expression were assessed in these patients. DWI was obtained in a 3T system using b values of 0, 400, and 800 s/mm². Whole tumor ADC volumes were analyzed using a histogram-based approach. Several ADC parameters showed significant correlations with immunohistopathological parameters. Most importantly, ADC histogram skewness and ADC histogram kurtosis were able to differentiate between nodal negative and nodal positive thyroid carcinoma. histogram analysis of whole ADC tumor volumes has the potential to provide valuable information on tumor biology in thyroid carcinoma. However, further studies are warranted.

  1. Studies quantifying modulatory effects of inhaled NO2 and SO2 on tracheal mucus secretion, proliferative activity of airway epithelium and architecture of lung parenchyma

    International Nuclear Information System (INIS)

    Wagner, U.; Barth, P.J.; Bredenbroeker, D.; Haase, H.; Locher, A.; Janssen, P.; Yu, F.; Wichert, P. von

    1995-10-01

    The following studies were designed to quantify changes in tracheal mucus secretion and epithelial proliferation of peripheral airways induced by inhaled NO 2 and SO 2 . Groups of male Sprague-Dawley rats were exposed alternatively to 1, 5, 10 and 20 ppm NO 2 and SO 2 the exposure-time being 3 or 25 days (d) respectively. Studies of tracheal mucus secretion radiolabelling mucins with 35 S clearly demonstrated a concentration dependant modulation of mucus secretion. We were able to demonstrate for the first time a significant increase of mucus secretion due to submucosal application of the peptide hormone GLP-1(7-36)amide. We were able to demonstrate amylin to be a potent secretagogue, dose-dependently stimulating mucus secretion. Our morphologic data reveal the effects caused by concentrations between 4-5 ppm NO 2 to be so small, that they are hardly detectable at light microscopic level. The assessment of proliferative activity, however, clearly demonstrates an increased proliferation due to even lower concentrations indicating, that even 1 ppm is able to cause epithelial impairment with consecutive regeneration. Double-labelling techniques of proliferation markers and the 10 kD Clara cell specific antigen reveal the Clara cell to be the only source for epithelial regeneration in peripheral airways under the reported experimental conditions of this study. (orig.) [de

  2. Resveratrol prevents oxidative stress-induced senescence and proliferative dysfunction by activating the AMPK-FOXO3 cascade in cultured primary human keratinocytes.

    Directory of Open Access Journals (Sweden)

    Yasuo Ido

    Full Text Available The aging process is perceived as resulting from a combination of intrinsic factors such as changes in intracellular signaling and extrinsic factors, most notably environmental stressors. In skin, the relationship between intrinsic changes and keratinocyte function is not clearly understood. Previously, we found that increasing the activity of AMP-activated protein kinase (AMPK suppressed senescence in hydrogen peroxide (H2O2-treated human primary keratinocytes, a model of oxidative stress-induced cellular aging. Using this model in the present study, we observed that resveratrol, an agent that increases the activities of both AMPK and sirtuins, ameliorated two age-associated phenotypes: cellular senescence and proliferative dysfunction. In addition, we found that treatment of keratinocytes with Ex527, a specific inhibitor of sirtuin 1 (SIRT1, attenuated the ability of resveratrol to suppress senescence. In keeping with the latter observation, we noted that compared to non-senescent keratinocytes, senescent cells lacked SIRT1. In addition to these effects on H2O2-induced senescence, resveratrol also prevented the H2O2-induced decrease in proliferation (as indicated by 3H-thymidine incorporation in the presence of insulin. This effect was abrogated by inhibition of AMPK but not SIRT1. Compared to endothelium, we found that human keratinocytes expressed relatively high levels of Forkhead box O3 (FOXO3, a downstream target of both AMPK and SIRT1. Treatment of keratinocytes with resveratrol transactivated FOXO3 and increased the expression of its target genes including catalase. Resveratrol's effects on both senescence and proliferation disappeared when FOXO3 was knocked down. Finally, we performed an exploratory study which showed that skin from humans over 50 years old had lower AMPK activity than skin from individuals under age 20. Collectively, these findings suggest that the effects of resveratrol on keratinocyte senescence and proliferation

  3. Paracrine stimulation of P2X7 receptor by ATP activates a proliferative pathway in ovarian carcinoma cells.

    Science.gov (United States)

    Vázquez-Cuevas, Francisco G; Martínez-Ramírez, Angélica S; Robles-Martínez, Leticia; Garay, Edith; García-Carrancá, Alejandro; Pérez-Montiel, Delia; Castañeda-García, Carolina; Arellano, Rogelio O

    2014-11-01

    P2X7 is a purinergic receptor-channel; its activation by ATP elicits a broad set of cellular actions, from apoptosis to signals for survival. Here, P2X7 expression and function was studied in human ovarian carcinoma (OCA) cells, and biopsies from non-cancerous and cancer patients were analyzed by immunohistochemistry. Ovarian surface epithelium in healthy tissue expressed P2X7 at a high level that was maintained throughout the cancer. The cell lines SKOV-3 and CAOV-3 were used to investigate P2X7 functions in OCA. In SKOV-3 cells, selective stimulation of P2X7 by 2'(3')-O-(4-benzoylbenzoyl) adenosine-5'-triphosphate (BzATP) induced a dose-dependent increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) but not cell death. Instead, BzATP increased the levels of phosphorylated ERK and AKT (pERK and pAKT), with an EC(50) of 44 ± 2 and 1.27 ± 0.5 μM, respectively; 10 μM BzATP evoked a maximum effect within 15 min that lasted for 120 min. Interestingly, basal levels of pERK and pAKT were decreased in the presence of apyrase in the medium, strongly suggesting an endogenous, ATP-mediated phenomenon. Accordingly: (i) mechanically stimulated cells generated a [Ca(2+)](i) increase that was abolished by apyrase; (ii) apyrase induced a decrease in culture viability, as measured by the MTS assay for mitochondrial activity; and (iii) incubation with 10 μM AZ10606120, a specific P2X7 antagonist and transfection with the dominant negative P2X7 mutant E496A, both reduced cell viability to 70.1 ± 8.9% and to 76.5 ± 5%, respectively, of control cultures. These observations suggested that P2X7 activity was auto-induced through ATP efflux; this increased pERK and pAKT levels that generated a positive feedback on cell viability. © 2014 Wiley Periodicals, Inc.

  4. Impact of maternal diabetes type 1 on proliferative potential, differentiation and apoptotic activity in villous capillaries of term placenta.

    Science.gov (United States)

    Jirkovská, Marie; Kučera, Tomáš; Dvořáková, Veronika; Jadrníček, Martin; Moravcová, Milena; Žižka, Zdeněk; Krejčí, Vratislav

    2016-04-01

    Maternal diabetes mellitus changes morphology and impairs function of placental capillaries. Here, quantitative parameters characterizing cell proliferation using detection of Ki67, differentiation reflected by nestin expression and apoptosis in placental capillary bed with active caspase 3 as a marker were compared in normal term placentas and placentas from pregnancies complicated by Type 1 maternal diabetes mellitus. Specimens of sixteen diabetic placentas and eight control placentas were collected by systematic uniform random sampling. Immunohistochemical detections of Ki67, nestin, and active caspase 3 were performed in histological sections of five haphazardly chosen blocks per placenta. Twenty fields of view per section, i.e. one hundred fields of view per placenta, were used for analysis of proliferation as well as of apoptosis, and in approximately 70 capillary cross-sections per placenta the nestin-positive segments of their circumference were measured. The percentage of Ki67-positive cells counted in the capillary wall was significantly lower in diabetic group. The counts of Ki67-labelled nuclei per villous area unit were significantly lower in cytotrophoblast and capillary wall of terminal villi in diabetic placenta. The proportion of nestin-labeled segments of capillary circumference was significantly higher in placentas of diabetic group. No differences in the numbers of apoptotic cells were found between studied groups. The results show that the term placenta in Type 1 diabetes has lower potential to enlarge the surface area of structures involved in maternofetal transport, and that the villous capillary bed displays delayed differentiation. Those factors may participate in decreased ability of diabetic placenta to comply with fetal requirements in the final stage of pregnancy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. SGR J1550-5418 BURSTS DETECTED WITH THE FERMI GAMMA-RAY BURST MONITOR DURING ITS MOST PROLIFIC ACTIVITY

    Energy Technology Data Exchange (ETDEWEB)

    Van der Horst, A. J.; Finger, M. H. [Universities Space Research Association, NSSTC, Huntsville, AL 35805 (United States); Kouveliotou, C. [Space Science Office, VP62, NASA/Marshall Space Flight Center, Huntsville, AL 35812 (United States); Gorgone, N. M. [Connecticut College, New London, CT 06320 (United States); Kaneko, Y.; Goegues, E.; Lin, L. [Sabanc Latin-Small-Letter-Dotless-I University, Orhanl Latin-Small-Letter-Dotless-I -Tuzla, Istanbul 34956 (Turkey); Baring, M. G. [Department of Physics and Astronomy, Rice University, MS-108, P.O. Box 1892, Houston, TX 77251 (United States); Guiriec, S.; Bhat, P. N.; Chaplin, V. L.; Goldstein, A. [University of Alabama, Huntsville, CSPAR, Huntsville, AL 35805 (United States); Granot, J. [Racah Institute of Physics, Hebrew University, Jerusalem 91904 (Israel); Watts, A. L. [Astronomical Institute ' Anton Pannekoek' , University of Amsterdam, Postbus 94249, 1090 GE Amsterdam (Netherlands); Bissaldi, E.; Gruber, D. [Max Planck Institute for Extraterrestrial Physics, Giessenbachstrasse, Postfach 1312, 85748 Garching (Germany); Gehrels, N.; Harding, A. K. [NASA Goddard Space Flight Center, Greenbelt, MD 20771 (United States); Gibby, M. H.; Giles, M. M., E-mail: A.J.VanDerHorst@uva.nl [Jacobs Technology, Inc., Huntsville, AL (United States); and others

    2012-04-20

    We have performed detailed temporal and time-integrated spectral analysis of 286 bursts from SGR J1550-5418 detected with the Fermi Gamma-ray Burst Monitor (GBM) in 2009 January, resulting in the largest uniform sample of temporal and spectral properties of SGR J1550-5418 bursts. We have used the combination of broadband and high time-resolution data provided with GBM to perform statistical studies for the source properties. We determine the durations, emission times, duty cycles, and rise times for all bursts, and find that they are typical of SGR bursts. We explore various models in our spectral analysis, and conclude that the spectra of SGR J1550-5418 bursts in the 8-200 keV band are equally well described by optically thin thermal bremsstrahlung (OTTB), a power law (PL) with an exponential cutoff (Comptonized model), and two blackbody (BB) functions (BB+BB). In the spectral fits with the Comptonized model, we find a mean PL index of -0.92, close to the OTTB index of -1. We show that there is an anti-correlation between the Comptonized E{sub peak} and the burst fluence and average flux. For the BB+BB fits, we find that the fluences and emission areas of the two BB functions are correlated. The low-temperature BB has an emission area comparable to the neutron star surface area, independent of the temperature, while the high-temperature BB has a much smaller area and shows an anti-correlation between emission area and temperature. We compare the properties of these bursts with bursts observed from other SGR sources during extreme activations, and discuss the implications of our results in the context of magnetar burst models.

  6. SGR J1550-5418 Bursts Detected with the Fermi Gamma-Ray Burst Monitor during Its Most Prolific Activity

    Science.gov (United States)

    vanderHorst, A. J.; Kouveliotou, C.; Gorgone, N. M.; Kaneko, Y.; Baring, M. G.; Guiriec, S.; Gogus, E,; Granot, J.; Watts, A. L.; Lin, L.; hide

    2012-01-01

    We have performed detailed temporal and time-integrated spectral analysis of 286 bursts from SGR J1550-5418 detected with the Fermi Gamma-ray Burst Monitor (GBM) in 2009 January, resulting in the largest uniform sample of temporal and spectral properties of SGR J1550-5418 bursts. We have used the combination of broadband and high time-resolution data provided with GBM to perform statistical studies for the source properties.We determine the durations, emission times, duty cycles, and rise times for all bursts, and find that they are typical of SGR bursts. We explore various models in our spectral analysis, and conclude that the spectra of SGR J15505418 bursts in the 8-200 keV band are equally well described by optically thin thermal bremsstrahlung (OTTB), a power law (PL) with an exponential cutoff (Comptonized model), and two blackbody (BB) functions (BB+BB). In the spectral fits with the Comptonized model, we find a mean PL index of -0.92, close to the OTTB index of -1. We show that there is an anti-correlation between the Comptonized E(sub peak) and the burst fluence and average flux. For the BB+BBfits, we find that the fluences and emission areas of the two BB functions are correlated. The low-temperature BB has an emission area comparable to the neutron star surface area, independent of the temperature, while the high temperature BB has a much smaller area and shows an anti-correlation between emission area and temperature.We compare the properties of these bursts with bursts observed from other SGR sources during extreme activations, and discuss the implications of our results in the context of magnetar burst models.

  7. Immune gene expression profiling of Proliferative Kidney Disease in rainbow trout Oncorhynchus mykiss reveals a dominance of anti-inflammatory, antibody and T helper cell-like activities.

    Science.gov (United States)

    Gorgoglione, Bartolomeo; Wang, Tiehui; Secombes, Christopher J; Holland, Jason W

    2013-07-16

    The myxozoan Tetracapsuloides bryosalmonae is the causative agent of Proliferative Kidney Disease (PKD) targeting primarily the kidney of infected fish where it causes a chronic lymphoid immunopathology. Although known to be associated with suppression of some cellular aspects of innate immunity and a prominent lymphocytic hyperplasia, there remains a considerable knowledge gap in our understanding of the underlying immune mechanisms driving PKD pathogenesis. To provide further insights, the expression profiles of a panel of innate/inflammatory and adaptive immune molecules were examined in rainbow trout Oncorhynchus mykiss following a natural exposure to the parasite. Relative to controls, fish with early to advanced stages of kidney pathology exhibited up-regulation of the inflammatory cytokines interleukin (IL)-6 and IL-11, although remaining refractory towards genes indicative of macrophage activity. Antimicrobial peptides (AMPs) and anti-inflammatory markers, including cathelicidin (CATH) and IL-10 were markedly up-regulated during clinical disease. Up-regulation of adaptive immune molecules, including cell markers and antibody genes reflect the lymphocytic dominance of this disease and the likely importance of lymphocyte subsets in PKD pathogenesis. Up-regulation of T helper (TH) cell-like response genes and transcription factors implies that T. bryosalmonae may elicit a complex interplay between TH cell subsets. This work, for the first time in the study of fish-myxozoan interactions, suggests that PKD pathogenesis is shaped by an anti-inflammatory phenotype, a profound B cell/antibody response and dysregulated TH cell-like activities. A better understanding of the functional roles of fish immune cells and molecules in PKD pathogenesis may facilitate future development of control measures against this disease.

  8. Immune gene expression profiling of Proliferative Kidney Disease in rainbow trout Oncorhynchus mykiss reveals a dominance of anti-inflammatory, antibody and T helper cell-like activities

    Science.gov (United States)

    2013-01-01

    The myxozoan Tetracapsuloides bryosalmonae is the causative agent of Proliferative Kidney Disease (PKD) targeting primarily the kidney of infected fish where it causes a chronic lymphoid immunopathology. Although known to be associated with suppression of some cellular aspects of innate immunity and a prominent lymphocytic hyperplasia, there remains a considerable knowledge gap in our understanding of the underlying immune mechanisms driving PKD pathogenesis. To provide further insights, the expression profiles of a panel of innate / inflammatory and adaptive immune molecules were examined in rainbow trout Oncorhynchus mykiss following a natural exposure to the parasite. Relative to controls, fish with early to advanced stages of kidney pathology exhibited up-regulation of the inflammatory cytokines interleukin (IL)-6 and IL-11, although remaining refractory towards genes indicative of macrophage activity. Antimicrobial peptides (AMPs) and anti-inflammatory markers, including cathelicidin (CATH) and IL-10 were markedly up-regulated during clinical disease. Up-regulation of adaptive immune molecules, including cell markers and antibody genes reflect the lymphocytic dominance of this disease and the likely importance of lymphocyte subsets in PKD pathogenesis. Up-regulation of T helper (TH) cell-like response genes and transcription factors implies that T. bryosalmonae may elicit a complex interplay between TH cell subsets. This work, for the first time in the study of fish-myxozoan interactions, suggests that PKD pathogenesis is shaped by an anti-inflammatory phenotype, a profound B cell / antibody response and dysregulated TH cell-like activities. A better understanding of the functional roles of fish immune cells and molecules in PKD pathogenesis may facilitate future development of control measures against this disease. PMID:23865616

  9. Comparative Study of Green Sub- and Supercritical Processes to Obtain Carnosic Acid and Carnosol-Enriched Rosemary Extracts with in Vitro Anti-Proliferative Activity on Colon Cancer Cells

    Directory of Open Access Journals (Sweden)

    Andrea del Pilar Sánchez-Camargo

    2016-12-01

    Full Text Available In the present work, four green processes have been compared to evaluate their potential to obtain rosemary extracts with in vitro anti-proliferative activity against two colon cancer cell lines (HT-29 and HCT116. The processes, carried out under optimal conditions, were: (1 pressurized liquid extraction (PLE, using an hydroalcoholic mixture as solvent at lab-scale; (2 Single-step supercritical fluid extraction (SFE at pilot scale; (3 Intensified two-step sequential SFE at pilot scale; (4 Integrated PLE plus supercritical antisolvent fractionation (SAF at pilot scale. Although higher extraction yields were achieved by using PLE (38.46% dry weight, this extract provided the lowest anti-proliferative activity with no observed cytotoxic effects at the assayed concentrations. On the other hand, extracts obtained using the PLE + SAF process provided the most active rosemary extracts against both colon cancer cell lines, with LC50 ranging from 11.2 to 12.4 µg/mL and from 21.8 to 31.9 µg/mL for HCT116 and HT-29, respectively. In general, active rosemary extracts were characterized by containing carnosic acid (CA and carnosol (CS at concentrations above 263.7 and 33.9 mg/g extract, respectively. Some distinct compounds have been identified in the SAF extracts (rosmaridiphenol and safficinolide, suggesting their possible role as additional contributors to the observed strong anti-proliferative activity of CA and CS in SAF extracts.

  10. Structure–activity relationships of the human prothrombin kringle-2 peptide derivative NSA9: anti-proliferative activity and cellular internalization

    OpenAIRE

    Hwang, Hyun Sook; Kim, Dong Won; Kim, Soung Soo

    2006-01-01

    The human prothrombin kringle-2 protein inhibits angiogenesis and LLC (Lewis lung carcinoma) growth and metastasis in mice. Additionally, the NSA9 peptide (NSAVQLVEN) derived from human prothrombin kringle-2 has been reported to inhibit the proliferation of BCE (bovine capillary endothelial) cells and CAM (chorioallantoic membrane) angiogenesis. In the present study, we examined the structure–activity relationships of the NSA9 peptide in inhibiting the proliferation of endothelial cells lines...

  11. Ccdc85C, a causative protein for hydrocephalus and subcortical heterotopia, is expressed in the systemic epithelia with proliferative activity in rats.

    Science.gov (United States)

    Tanaka, Natsuki; Izawa, Takeshi; Takenaka, Shigeo; Yamate, Jyoji; Kuwamura, Mitsuru

    2015-07-01

    Coiled-coil domain containing 85c (Ccdc85c) is a causative gene for spontaneous mutant mouse with non-obstructive hydrocephalus and subcortical heterotopia. Detailed functions of Ccdc85C protein have not been clarified. To reveal roles of Ccdc85C, we examined the distribution and expression pattern of Ccdc85C in the systemic developing organs in rats. Ccdc85C was expressed in various simple epithelia but not stratified epithelia. In the various epithelia, Ccdc85C was localized at cell-cell junctions and its expression was strong at apical junctions. Furthermore, intense expression was seen at developing period and gradually decreased with advancing development. Distribution of Ccdc85C coincides with that of proliferating epithelial cells. These results suggest that Ccdc85C plays an important role in the proliferative property of simple epithelia.

  12. Evaluation of the effects of ethinylestradiol on sexual differentiation in the olvas-GFP/STII-YI medaka (transgenic Oryzias latipes) strain as estimated by proliferative activity of germ cells

    International Nuclear Information System (INIS)

    Hano, Takeshi; Oshima, Yuji; Kinoshita, Masato; Tanaka, Minoru; Mishima, Noriko; Wakamatsu, Yuko; Ozato, Kenjiro; Shimasaki, Yohei; Honjo, Tsuneo

    2011-01-01

    We evaluated the effects of 17(-ethinylestradiol (EE 2 ) on sexual differentiation in transgenic olvas-GFP/STII-YI medaka (Oryzias latipes) in terms of the proliferative activity of germ cells. This strain contains the green fluorescent protein (GFP) gene fused to the regulatory region of the medaka vasa gene, and germ cell-specific expression of GFP can be visualized in living (transparent) individuals. From 0 days post-hatch (0 dph) onwards, juveniles were exposed to graded concentrations of EE 2 (25.2-1710 ng/L) for 35 days. The gonads of live specimens were monitored by measuring their size and calculating their GFP-fluorescence area. GFP-fluorescent area in control females was about 10 times that in control males at 10 days posthatch (dph) whereas the gonadal size of 10 dph males that had been exposed to 158 ng/L of EE 2 significantly increased up to twice the size of control males, indicating that abnormal sexual differentiation towards female might occur in these individuals. Histological examination and identification of the sex-linked marker SL1 indicated that male to female sex reversal occurred at EE 2 exposure ≥45.1 ng/L at 35 dph. These results suggest that observation of proliferative activity of germ cells in the olvas-GFP/STII-YI strain could be applied to facilitated screening fish model to detect adverse effects on sexual differentiation as early as 10 dph juveniles.

  13. Non-Proliferative Diabetic Retinopathy Vision Simulator

    Science.gov (United States)

    ... Oncology Oculoplastics/Orbit Refractive Management/Intervention Retina/Vitreous Uveitis Focus On Pediatric Ophthalmology ... Retinopathy Diagnosis Diabetic Retinopathy Treatment Proliferative Diabetic Retinopathy Vision Simulator Non-Proliferative Diabetic ...

  14. Proliferative myositis: a case report

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Young Sook; Jeon, Ho Jong [Chosun University College of Medicine, Gwangju (Korea, Republic of)

    2002-09-01

    We report a case of proliferative myositis arising in the pectoralis major muscle of a 59-year-old man who presented with palpable mass. The initial clinical impression was a malignant tumor. Ultrasonography revealed the lesion as a spindle-shaped hypoechoic mass, and MR imaging of the left pectoralis major muscle showed hypointensity at T1-weighted imaging, hyperintensity at T2-weighted imaging, and strong enhancement at contrast-enhanced T1-weighted imaging.

  15. Proliferative myositis: a case report

    International Nuclear Information System (INIS)

    Kim, Young Sook; Jeon, Ho Jong

    2002-01-01

    We report a case of proliferative myositis arising in the pectoralis major muscle of a 59-year-old man who presented with palpable mass. The initial clinical impression was a malignant tumor. Ultrasonography revealed the lesion as a spindle-shaped hypoechoic mass, and MR imaging of the left pectoralis major muscle showed hypointensity at T1-weighted imaging, hyperintensity at T2-weighted imaging, and strong enhancement at contrast-enhanced T1-weighted imaging

  16. Lifespan extension by preserving proliferative homeostasis in Drosophila.

    Directory of Open Access Journals (Sweden)

    Benoît Biteau

    2010-10-01

    Full Text Available Regenerative processes are critical to maintain tissue homeostasis in high-turnover tissues. At the same time, proliferation of stem and progenitor cells has to be carefully controlled to prevent hyper-proliferative diseases. Mechanisms that ensure this balance, thus promoting proliferative homeostasis, are expected to be critical for longevity in metazoans. The intestinal epithelium of Drosophila provides an accessible model in which to test this prediction. In aging flies, the intestinal epithelium degenerates due to over-proliferation of intestinal stem cells (ISCs and mis-differentiation of ISC daughter cells, resulting in intestinal dysplasia. Here we show that conditions that impair tissue renewal lead to lifespan shortening, whereas genetic manipulations that improve proliferative homeostasis extend lifespan. These include reduced Insulin/IGF or Jun-N-terminal Kinase (JNK signaling activities, as well as over-expression of stress-protective genes in somatic stem cell lineages. Interestingly, proliferative activity in aging intestinal epithelia correlates with longevity over a range of genotypes, with maximal lifespan when intestinal proliferation is reduced but not completely inhibited. Our results highlight the importance of the balance between regenerative processes and strategies to prevent hyperproliferative disorders and demonstrate that promoting proliferative homeostasis in aging metazoans is a viable strategy to extend lifespan.

  17. Estrogen signaling in the proliferative endometrium: implications in endometriosis

    Directory of Open Access Journals (Sweden)

    Rita de Cássia Pereira da Costa e Silva

    2016-02-01

    Full Text Available SUMMARY Even though the physiological role of estrogen in the female reproductive cycle and endometrial proliferative phase is well established, the signaling pathways by which estrogen exerts its action in the endometrial tissue are still little known. In this regard, advancements in cell culture techniques and maintenance of endometrial cells in cultures enabled the discovery of new signaling mechanisms activated by estrogen in the normal endometrium and in endometriosis. This review aims to present the recent findings in the genomic and non-genomic estrogen signaling pathways in the proliferative human endometrium specifically associated with the pathogenesis and development of endometriosis.

  18. Evaluation of the anti-proliferative and cytotoxic potentials of ...

    African Journals Online (AJOL)

    The partitioned aqueous and chloroform fractions obtained from the methanol extract of the leaf of Cnidoscolus aconitifolius were examined for anti-proliferative (1-30 mg/mL) and cytotoxic activities (20-400 μg/mL) using the seed radicle inhibition and tadpole mortality assays over a period of 24 and 96 h respectively.

  19. An ATM-independent S-phase checkpoint response involves CHK1 pathway

    Science.gov (United States)

    Zhou, Xiang-Yang; Wang, Xiang; Hu, Baocheng; Guan, Jun; Iliakis, George; Wang, Ya

    2002-01-01

    After exposure to genotoxic stress, proliferating cells actively slow down the DNA replication through a S-phase checkpoint to provide time for repair. We report that in addition to the ataxia-telangiectasia mutated (ATM)-dependent pathway that controls the fast response, there is an ATM-independent pathway that controls the slow response to regulate the S-phase checkpoint after ionizing radiation in mammalian cells. The slow response of S-phase checkpoint, which is resistant to wortmannin, sensitive to caffeine and UCN-01, and related to cyclin-dependent kinase phosphorylation, is much stronger in CHK1 overexpressed cells, and it could be abolished by Chk1 antisense oligonucleotides. These results provide evidence that the ATM-independent slow response of S-phase checkpoint involves CHK1 pathway.

  20. Multiple functions of the S-phase checkpoint mediator.

    Science.gov (United States)

    Tanaka, Katsunori

    2010-01-01

    There is mounting evidence that replication defects are the major source of spontaneous genomic instability in cells, and that S-phase checkpoints are the principal defense against such instability. The S-phase checkpoint mediator protein Mrc1/Claspin mediates the checkpoint response to replication stress by facilitating phosphorylation of effector kinase by a sensor kinase. In this review, the multiple functions and the regulation of the S-phase checkpoint mediator are discussed.

  1. SMC1-Mediated Intra-S-Phase Arrest Facilitates Bocavirus DNA Replication

    Science.gov (United States)

    Luo, Yong; Deng, Xuefeng; Cheng, Fang; Li, Yi

    2013-01-01

    Activation of a host DNA damage response (DDR) is essential for DNA replication of minute virus of canines (MVC), a member of the genus Bocavirus of the Parvoviridae family; however, the mechanism by which DDR contributes to viral DNA replication is unknown. In the current study, we demonstrate that MVC infection triggers the intra-S-phase arrest to slow down host cellular DNA replication and to recruit cellular DNA replication factors for viral DNA replication. The intra-S-phase arrest is regulated by ATM (ataxia telangiectasia-mutated kinase) signaling in a p53-independent manner. Moreover, we demonstrate that SMC1 (structural maintenance of chromosomes 1) is the key regulator of the intra-S-phase arrest induced during infection. Either knockdown of SMC1 or complementation with a dominant negative SMC1 mutant blocks both the intra-S-phase arrest and viral DNA replication. Finally, we show that the intra-S-phase arrest induced during MVC infection was caused neither by damaged host cellular DNA nor by viral proteins but by replicating viral genomes physically associated with the DNA damage sensor, the Mre11-Rad50-Nbs1 (MRN) complex. In conclusion, the feedback loop between MVC DNA replication and the intra-S-phase arrest is mediated by ATM-SMC1 signaling and plays a critical role in MVC DNA replication. Thus, our findings unravel the mechanism underlying DDR signaling-facilitated MVC DNA replication and demonstrate a novel strategy of DNA virus-host interaction. PMID:23365434

  2. Proliferative and inflammatory factors in the vitreous of patients with proliferative diabetic retinopathy

    Directory of Open Access Journals (Sweden)

    V V Chernykh

    2015-01-01

    Full Text Available Purpose: The purpose was to measure the concentrations of various cytokines and growth factors (including vascular endothelial growth factor [VEGF] and pigment epithelium-derived factor [PEDF] in the vitreous of patients with proliferative diabetic retinopathy (PDR and to investigate interaction between inflammatory and proliferative factors in the genesis of PDR. Materials and Methods : Vitreous samples from 32 eyes with PDR and 25 eyes without diabetes mellitus and signs of DR (control were collected. Vitreous concentrations of VEGF, PEDF, monocyte chemotactic protein-1 (MCP-1, interleukin-4 (IL-4, IL-6, IL-8, IL-10, IL-17A, and secretory immunoglobulin A (sIgA were simultaneously measured using enzyme-linked immunoassay. Results : Vitreous levels of VEGF, PEDF, IL-17A, IL-6, IL-8, IL-4, and sIgA were significantly (Π < 0.05 higher in eyes with PDR compared to control. The concentration of VEGF was more than 17-times higher than in control, and the concentration of PEDF was not changed oppositely and was also higher (1.45-times compared to control, that may indicate disturbances of compensatory mechanisms in angiogenesis regulation in PDR. Significant (Π < 0.05 positive correlations were observed between vitreous concentrations of VEGF and IL-17ΐ (r = 0.45, VEGF and IL-8 (r = 0.48, VEGF and IL-4 (r = 0.51, PEDF and IL-17ΐ (r = 0.48, PEDF and IL-8 (r = 0.59, MCP-1 and PEDF (r = 0.72, MCP-1 and IL-8 (r0 = 0.45, IL-4 and IL-17ΐ (r = 0.65, IL-4 and IL-8 (r = 0.71, IL-8 and IL-17ΐ (r = 0.59. Conclusions: Significantly raised levels of inflammatory and proliferative factors and numerous positive correlations between them may demonstrate a significant role of activation of vascular proliferation and local inflammation in the pathogenesis of PDR.

  3. Cytotoxic, Anti-Proliferative and Apoptosis Activity of l-Amino Acid Oxidase from Malaysian Cryptelytrops purpureomaculatus (CP-LAAO) Venom on Human Colon Cancer Cells.

    Science.gov (United States)

    Zainal Abidin, Syafiq Asnawi; Rajadurai, Pathmanathan; Hoque Chowdhury, Md Ezharul; Othman, Iekhsan; Naidu, Rakesh

    2018-06-08

    The aim of this study is to investigate the potential anti-cancer activity of l-amino acid oxidase (CP-LAAO) purified from the venom of Cryptelytrops purpureomaculatus on SW480 and SW620 human colon cancer cells. Mass spectrometry guided purification was able to identify and purify CP-LAAO. Amino acid variations identified from the partial protein sequence of CP-LAAO may suggest novel variants of these proteins. The activity of the purified CP-LAAO was confirmed with o-phenyldiamine (OPD)-based spectrophotometric assay. CP-LAAO demonstrated time- and dose-dependent cytotoxic activity and the EC 50 value was determined at 13 µg/mL for both SW480 and SW620 cells. Significant increase of caspase-3 activity, reduction of Bcl-2 levels, as well as morphological changes consistent with apoptosis were demonstrated by CP-LAAO. Overall, these data provide evidence on the potential anti-cancer activity of CP-LAAO from the venom of Malaysian C. purpureomaculatus for therapeutic intervention of human colon cancer.

  4. Vitrectomy for proliferative diabetic retinopathy

    Directory of Open Access Journals (Sweden)

    Chao Peng

    2013-10-01

    Full Text Available AIM:To observe the clinical effect of vitrectomy for proliferative diabetic retinopathy(PDR.METHODS: The clinical data of 55 cases(65 eyes, underwent vitrectomy, membrane peeling, endolaser photocoagulation and silicone oil or C3F8 injection, were retrospectively studied. During 6 months to 1 year follow-up period, visual acuity, intraocular pressure, retinal conditions and complications were observed.RESULTS: All 65 eyes received vitrectomy, of which silicone oil was tamponaded in 32 eyes, C3F8 was injected in 8 eyes, BBS was filled in 25 eyes. Visual improvement achieved in 42 eyes. Two eyes were manually vision, form count fingers to 0.05 in 18 eyes, >0.05-0.1 in 28 eyes, >0.1-0.3 in 12 eyes and >0.3 in 5 eyes. Retinal hole was occurred in 7 eyes, limitations fibrosis membrane remained in 8 eyes, retinal detachment appeared in 5 eyes, IOP increased in 18 eyes, vitreous hemorrhage relapsed in 12 eyes, 36 eyes received supplemental photocoagulation treatment 1-3 times after operation.CONCLUSION:Vitrectomy combined endophotocoagulation is an effective treatment for PDR. Silicone oil tamponade can limit the hemorrhage.

  5. The KDM5 family is required for activation of pro-proliferative cell cycle genes during adipocyte differentiation

    DEFF Research Database (Denmark)

    Brier, Ann-Sofie B; Loft, Anne; Madsen, Jesper G S

    2017-01-01

    The KDM5 family of histone demethylases removes the H3K4 tri-methylation (H3K4me3) mark frequently found at promoter regions of actively transcribed genes and is therefore generally considered to contribute to corepression. In this study, we show that knockdown (KD) of all expressed members of th...

  6. Mik1 levels accumulate in S phase and may mediate an intrinsic link between S phase and mitosis

    DEFF Research Database (Denmark)

    Christensen, P U; Bentley, N J; Martinho, R G

    2000-01-01

    is independent of the Rad3- and Cds1-dependent checkpoint controls. In response to perturbed S phase, Rad3-Cds1 checkpoint controls are required to maintain high levels of Mik1, probably indirectly by extending the S phase period, where Mik1 is stable. In addition, we find that Mik1 protein can be moderately...

  7. Prognostic value of lymphoma-specific S-phase fraction compared with that of other cell proliferation markers

    Energy Technology Data Exchange (ETDEWEB)

    Holte, H.; Kvaloey, S. [Dept. of Oncology, Univ. of Oslo (Norway); Suo Zhenhe; Langholm, R. [Dept. of Pathology, Univ. of Oslo (Norway); Smeland, E.B. [Dept. of Immunology, Univ. of Oslo (Norway); Stokke, T. [Dept. of Biophysics, Univ. of Oslo (Norway)

    1999-11-01

    The proliferation-associated antigens Ki67 (immunohistochemistry) and proliferative cell nuclear antigen (PCNA) (immunohistochemistry and immunoblotting) were analysed together with DNA synthesis ({sup 3}H-thymidine incorporation) and cell-cycle distribution (tumour-specific S-phase fraction determined by flow cytometry) in lymph node suspensions from 63 patients with newly diagnosed B-Cell non-Hodgkin`s lymphomas. Details of clinical parameters, treatment and patient outcome were available for all patients, and retrospectively analysed. Of the proliferation-associated parameters, only high S-phase fraction (p < 0.00001) and high PCNA expression by immunoblotting (p=0.012) were predictive of a poor prognosis. Of the conventional parameters, high-grade malignancy, high International Prognostic Index (IPI) score, bulky disease and presence of B symptoms predicted a patient for poor survival. High S-phase fraction was predictive of a short survival for the low-grade lymphomas analyses separately (p < 0.00001), as well as for patients treated with an Adriamycin- and a non-Adriamycin-containing regimen (p < 0.005 for both groups). In a multivariate analysis, S-phase fraction (p=0.00006), IPI score (p=0.015) and B symptoms (p=0.017) had independent prognostic values, but not histological grade. (orig.)

  8. Prognostic value of lymphoma-specific S-phase fraction compared with that of other cell proliferation markers

    International Nuclear Information System (INIS)

    Holte, H.; Kvaloey, S.; Suo Zhenhe; Langholm, R.; Smeland, E.B.; Stokke, T.

    1999-01-01

    The proliferation-associated antigens Ki67 (immunohistochemistry) and proliferative cell nuclear antigen (PCNA) (immunohistochemistry and immunoblotting) were analysed together with DNA synthesis ( 3 H-thymidine incorporation) and cell-cycle distribution (tumour-specific S-phase fraction determined by flow cytometry) in lymph node suspensions from 63 patients with newly diagnosed B-Cell non-Hodgkin's lymphomas. Details of clinical parameters, treatment and patient outcome were available for all patients, and retrospectively analysed. Of the proliferation-associated parameters, only high S-phase fraction (p < 0.00001) and high PCNA expression by immunoblotting (p=0.012) were predictive of a poor prognosis. Of the conventional parameters, high-grade malignancy, high International Prognostic Index (IPI) score, bulky disease and presence of B symptoms predicted a patient for poor survival. High S-phase fraction was predictive of a short survival for the low-grade lymphomas analyses separately (p < 0.00001), as well as for patients treated with an Adriamycin- and a non-Adriamycin-containing regimen (p < 0.005 for both groups). In a multivariate analysis, S-phase fraction (p=0.00006), IPI score (p=0.015) and B symptoms (p=0.017) had independent prognostic values, but not histological grade. (orig.)

  9. Proliferative lifespan is conserved after nuclear transfer.

    Science.gov (United States)

    Clark, A John; Ferrier, Patricia; Aslam, Samena; Burl, Sarah; Denning, Chris; Wylie, Diana; Ross, Arlene; de Sousa, Paul; Wilmut, Ian; Cui, Wei

    2003-06-01

    Cultured primary cells exhibit a finite proliferative lifespan, termed the Hayflick limit. Cloning by nuclear transfer can reverse this cellular ageing process and can be accomplished with cultured cells nearing senescence. Here we describe nuclear transfer experiments in which donor cell lines at different ages and with different proliferative capacities were used to clone foetuses and animals from which new primary cell lines were generated. The rederived lines had the same proliferative capacity and rate of telomere shortening as the donor cell lines, suggesting that these are innate, genetically determined, properties that are conserved by nuclear transfer.

  10. Identification of compounds with anti-proliferative activity against Trypanosoma brucei brucei strain 427 by a whole cell viability based HTS campaign.

    Directory of Open Access Journals (Sweden)

    Melissa L Sykes

    Full Text Available Human African Trypanosomiasis (HAT is caused by two trypanosome sub-species, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Drugs available for the treatment of HAT have significant issues related to difficult administration regimes and limited efficacy across species and disease stages. Hence, there is considerable need to find new alternative and less toxic drugs. An approach to identify starting points for new drug candidates is high throughput screening (HTS of large compound library collections. We describe the application of an Alamar Blue based, 384-well HTS assay to screen a library of 87,296 compounds against the related trypanosome subspecies, Trypanosoma brucei brucei bloodstream form lister 427. Primary hits identified against T.b. brucei were retested and the IC(50 value compounds were estimated for T.b. brucei and a mammalian cell line HEK293, to determine a selectivity index for each compound. The screening campaign identified 205 compounds with greater than 10 times selectivity against T.b. brucei. Cluster analysis of these compounds, taking into account chemical and structural properties required for drug-like compounds, afforded a panel of eight compounds for further biological analysis. These compounds had IC(50 values ranging from 0.22 µM to 4 µM with associated selectivity indices ranging from 19 to greater than 345. Further testing against T.b. rhodesiense led to the selection of 6 compounds from 5 new chemical classes with activity against the causative species of HAT, which can be considered potential candidates for HAT early drug discovery. Structure activity relationship (SAR mining revealed components of those hit compound structures that may be important for biological activity. Four of these compounds have undergone further testing to 1 determine whether they are cidal or static in vitro at the minimum inhibitory concentration (MIC, and 2 estimate the time to kill.

  11. Anti-proliferative and differentiation-inducing activities of the green tea catechin epigallocatechin-3-gallate (EGCG) on the human eosinophilic leukemia EoL-1 cell line.

    Science.gov (United States)

    Lung, H L; Ip, W K; Wong, C K; Mak, N K; Chen, Z Y; Leung, K N

    2002-12-06

    A novel approach for the treatment of leukemia is the differentiation therapy in which immature leukemia cells are induced to attain a mature phenotype when exposed to differentiation inducers, either alone or in combinations with other chemotherapeutic or chemopreventive drugs. Over the past decade, numerous studies indicated that green tea catechins (GTC) could suppress the growth and induce apoptosis on a number of human cancer cell lines. However, the differentiation-inducing activity of GTC on human tumors remains poorly understood. In the present study, the effect of the major GTC epigallocatechin-3-gallate (EGCG) on the proliferation and differentiation of a human eosinophilc leukemic cell line, EoL-1, was examined. Our results showed that EGCG suppressed the proliferation of the EoL-1 cells in a dose-dependent manner, with an estimated IC(50) value of 31.5 microM. On the other hand, EGCG at a concentration of 40 microM could trigger the EoL-1 cells to undergo morphological differentiation into mature eosinophil-like cells. Using RT-PCR and flow cytometry, it was found that EGCG upregulated the gene and protein expression of two eosinophil-specific granule proteins, the major basic protein (MBP) and eosinophil peroxidase (EPO), in EoL-1 cells. Taken together, our findings suggest that EGCG can exhibit anti-leukemic activity on a human eosinophilic cell line EoL-1 by suppressing the proliferation and by inducing the differentiation of the leukemia cells.

  12. Identification of a novel polyprenylated acylphloroglucinol‑derived SIRT1 inhibitor with cancer‑specific anti-proliferative and invasion-suppressing activities.

    Science.gov (United States)

    Zhu, Lijia; Qi, Ji; Chiao, Christine Ya-Chi; Zhang, Qiang; Porco, John A; Faller, Douglas V; Dai, Yan

    2014-11-01

    SIRT1, a class III histone deacetylase, plays a critical role in regulating cancer cell growth, migration and invasion, which makes it a potential target for cancer therapeutics. In this study, we screened derivatives of several groups of natural products and identified a novel SIRT1 inhibitor JQ-101, a synthetic derivative of the polyprenylated acylphloroglucinol (PPAP) natural products, with an IC(50) for SIRT1 of 30 µM in vitro, with 5-fold higher activity for SIRT1 vs. SIRT2. Exposure of tumor cells to JQ-101 significantly enhanced acetylation of p53 and histone H4K16 at known sites of SIRT1 deacetylation, validating SIRT1 as its cellular target. JQ-101 suppressed cancer cell growth and survival by targeting SIRT1, and also exhibited selective cytotoxicity towards a panel of human tumor cell lines, while producing no toxicity in two normal human cell types at comparable concentrations. JQ-101 induced both apoptosis and cell senescence, and suppressed cancer cell invasion in vitro. In summary, we have identified JQ-101 as a new SIRT1 inhibitor which may have potential application in cancer treatment through its ability to induce tumor cell apoptosis and senescence and suppress cancer cell invasion.

  13. Identification of a novel polyprenylated acylphloroglucinol-derived SIRT1 inhibitor with cancer-specific anti-proliferative and invasion-suppressing activities

    Science.gov (United States)

    ZHU, LIJIA; QI, JI; CHIAO, CHRISTINE YA-CHI; ZHANG, QIANG; PORCO, JOHN A.; FALLER, DOUGLAS V.; DAI, YAN

    2014-01-01

    SIRT1, a class III histone deacetylase, plays a critical role in regulating cancer cell growth, migration and invasion, which makes it a potential target for cancer therapeutics. In this study, we screened derivatives of several groups of natural products and identified a novel SIRT1 inhibitor JQ-101, a synthetic derivative of the polyprenylated acylphloroglucinol (PPAP) natural products, with an IC50 for SIRT1 of 30 μM in vitro, with 5-fold higher activity for SIRT1 vs. SIRT2. Exposure of tumor cells to JQ-101 significantly enhanced acetylation of p53 and histone H4K16 at known sites of SIRT1 deacetylation, validating SIRT1 as its cellular target. JQ-101 suppressed cancer cell growth and survival by targeting SIRT1, and also exhibited selective cytotoxicity towards a panel of human tumor cell lines, while producing no toxicity in two normal human cell types at comparable concentrations. JQ-101 induced both apoptosis and cell senescence, and suppressed cancer cell invasion in vitro. In summary, we have identified JQ-101 as a new SIRT1 inhibitor which may have potential application in cancer treatment through its ability to induce tumor cell apoptosis and senescence and suppress cancer cell invasion. PMID:25189993

  14. Assessment of p21, p53 expression, and Ki-67 proliferative activities in the gastric mucosa of children with Helicobacter pylori gastritis.

    Science.gov (United States)

    Saf, Coskun; Gulcan, Enver Mahir; Ozkan, Ferda; Cobanoglu Saf, Seyhan Perihan; Vitrinel, Ayca

    2015-02-01

    Helicobacter pylori that is generally acquired in childhood and infects the gastric mucosa is considered to be responsible for many pathobiological changes that are linked to the pathogenesis of gastric cancer. Although the majority of studies on the subject have been carried out in adults, there are a limited number of studies on children that reflect the early period of infection and may be of greater significance. We aimed to determine the role of H. pylori infection and/or gastritis in several histopathological changes, p53, p21, and cell proliferation-associated Ki-67 antigen expression in the gastric mucosa. We studied 60 patients with a mean age of 7.5 ± 4.5 years at referral. On the basis of endoscopic appearance and the evaluation of the gastric antral specimens, the patients were divided into three groups: patients without gastritis, patients with H. pylori-positive gastritis, and patients with H. pylori-negative gastritis. To determine the expression of p53, Ki-67, and p21 in gastric biopsy specimens, immunohistochemical stains were performed. The incidence of neutrophil activity, which was one of our histopathologic parameters, was significantly higher in the H. pylori-positive gastritis group than the other two groups. The presence of lymphoid aggregate was more frequent in H. pylori ± gastritis groups than the nongastritis group. p53 expression was found to be significantly higher in the H. pylori-positive gastritis group than the nongastritis group. Ki-67 and p21 expressions were significantly more frequent in the H. pylori-positive gastritis group than the other two groups. When we evaluated the density of H. pylori, as the density of bacteria increases, we found that the expressions of p53, p21, and Ki-67 increased significantly. Expression of the studied precancerous markers in significant amounts indicates the importance of childhood H. pylori infection in the constitution of gastric cancer in adulthood.

  15. Histone H1 interphase phosphorylation becomes largely established in G1 or early S phase and differs in G1 between T-lymphoblastoid cells and normal T cells

    Directory of Open Access Journals (Sweden)

    Gréen Anna

    2011-08-01

    Full Text Available Abstract Background Histone H1 is an important constituent of chromatin, and is involved in regulation of its structure. During the cell cycle, chromatin becomes locally decondensed in S phase, highly condensed during metaphase, and again decondensed before re-entry into G1. This has been connected to increasing phosphorylation of H1 histones through the cell cycle. However, many of these experiments have been performed using cell-synchronization techniques and cell cycle-arresting drugs. In this study, we investigated the H1 subtype composition and phosphorylation pattern in the cell cycle of normal human activated T cells and Jurkat T-lymphoblastoid cells by capillary electrophoresis after sorting of exponentially growing cells into G1, S and G2/M populations. Results We found that the relative amount of H1.5 protein increased significantly after T-cell activation. Serine phosphorylation of H1 subtypes occurred to a large extent in late G1 or early S phase in both activated T cells and Jurkat cells. Furthermore, our data confirm that the H1 molecules newly synthesized during S phase achieve a similar phosphorylation pattern to the previous ones. Jurkat cells had more extended H1.5 phosphorylation in G1 compared with T cells, a difference that can be explained by faster cell growth and/or the presence of enhanced H1 kinase activity in G1 in Jurkat cells. Conclusion Our data are consistent with a model in which a major part of interphase H1 phosphorylation takes place in G1 or early S phase. This implies that H1 serine phosphorylation may be coupled to changes in chromatin structure necessary for DNA replication. In addition, the increased H1 phosphorylation of malignant cells in G1 may be affecting the G1/S transition control and enabling facilitated S-phase entry as a result of relaxed chromatin condensation. Furthermore, increased H1.5 expression may be coupled to the proliferative capacity of growth-stimulated T cells.

  16. In vitro anti-proliferative effect of interferon alpha in solid tumors: A potential predicative test

    International Nuclear Information System (INIS)

    Fuchsberger, N.; Kubes, M.; Kontsek, P.; Borecky, L.; Hornak, M.; Silvanova; Godal, A.; Svec, J.

    1993-01-01

    An in vitro test for the anti-proliferative effect of human leukocyte interferon (IFN-alpha) was performed in primary cultures of tumor cells obtained from 32 patients with either malignant melanoma (13), renal carcinoma (4) or bladder carcinoma (15). Our results demonstrated activity of IFN in all three groups of solid tumors. However, appreciable differences in sensitivity to anti-proliferative effect of IFN between individual tumors of the same type were found. The potential of this anti-proliferative test for prediction of treatment response in IFN-therapy is discussed. (author)

  17. Retinal vessel caliber as a potential marker of treatment outcome in patients with proliferative diabetic retinopathy

    DEFF Research Database (Denmark)

    Vergmann, Anna Stage; Torp, Thomas Lee; Lundberg, Kristian

    Title of abstract: Retinal vessel caliber as a potential marker of treatment outcome in patients with proliferative diabetic retinopathy Design of study: Three months prospective, interventional clinical study. Purpose: The retinal vascular tree can be measured non-invasively and summarized...... into the central retinal artery and vein equivalent (CRAE and CRVE). The purpose of this study was to evaluate retinal calibers as biomarkers for disease activity 3 months after panretinal photocoagulation (PRP) in patients with proliferative diabetic retinopathy (PDR). Methods: Fifty one eyes from 40 newly...... with proliferative diabetic retinopathy....

  18. Adult neurogenesis in the central olfactory pathway of dendrobranchiate and caridean shrimps: New insights into the evolution of the deutocerebral proliferative system in reptant decapods.

    Science.gov (United States)

    Wittfoth, Christin; Harzsch, Steffen

    2018-04-16

    Persistent neurogenesis in the central olfactory pathway characterizes many reptant decapods such as lobsters, crayfish and crabs. In these animals, the deutocerebral proliferative system generates new neurons which integrate into the neuronal network of the first order processing neuropil of the olfactory system, the deutocerebral chemosensory lobes (also called olfactory lobes). However, differences concerning the phenotype and the mechanisms that drive adult neurogenesis were reported in crayfish versus spiny lobsters. While numerous studies have focussed on these mechanisms and regulation of adult neurogenesis, investigations about the phylogenetic distribution are missing. To contribute an evolutionary perspective on adult neurogenesis in decapods, we investigated two representatives of basally diverging lineages, the dendrobranchiate Penaeus vannamei and the caridean Crangon crangon using the thymidine analogue Bromodeoxyuridine (BrdU) as marker for the S phase of cycling cells. Compared to reptant decapods, our results suggest a simpler mechanism of neurogenesis in the adult brain of dendrobranchiate and caridean shrimps. Observed differences in the rate of proliferation and spatial dimensions are suggested to correlate with the complexity of the olfactory system. We assume that a more complex and mitotically more active proliferative system in reptant decapods evolved with the emergence of another processing neuropil, the accessory lobes. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

  19. Proliferation Index and Karyometric Features of Pancreatic Intraductal Proliferative Lesions

    Directory of Open Access Journals (Sweden)

    Romana Tomaszewska

    1999-01-01

    Full Text Available The increasing frequency and poor prognosis in pancreatic cancer prompt us to search for morphological lesions being a substrate for its development. Studies of autopsy and surgically resected material as well as recent molecular studies have proved that one of the possible pathways of pancreatic neoplasia is the intraepithelial proliferation – dysplasia – cancer sequence. In the present paper we studied the proliferative activity (Ki‐67 index in pancreatic intraepithelial proliferative lesions and its correlation with geometric features of cell nuclei as signs of increasing dysplasia. The studies were carried out in a group of 35 patients operated on for pancreatic cancer, chronic pancreatitis and other conditions not associated with the pancreas. We used immunohistochemical methods and basic morphometric parameters. The results of our studies indicate that the cell proliferative activity depends both on the type of epithelial proliferation and underlying pancreatic disease. The values of Ki‐67 index are significantly different in low‐grade proliferation (flat and papillary hyperplasia and high‐grade proliferation (atypical papillary hyperplasia and carcinoma in situ. A set of karyometric features correlates with Ki‐67 index but there is no single feature which would have a diagnostic value.

  20. Endothelin-1 is associated with fibrosis in proliferative diabetic retinopathy membranes.

    Science.gov (United States)

    Chang, William; Lajko, Michelle; Fawzi, Amani A

    2018-01-01

    To characterize the relationship between endothelin-1 and fibrosis in epiretinal membranes in proliferative diabetic retinopathy and explore the role of endothelial-mesenchymal transition in these membranes. Membranes were obtained from eyes undergoing pars plana vitrectomy for complicated proliferative diabetic retinopathy or idiopathic epiretinal membrane. Through standard immunohistochemical techniques, we labeled membranes to explore the distribution of endothelin-1 and endothelin receptor B, comparing proliferative diabetic retinopathy and idiopathic epiretinal membranes. In addition, membranes were also labeled with markers for fibroblasts, endothelial, and glial cells and studied with confocal laser scanning microscopy. The intensity of endothelin-1 labeling was quantified using standard image analysis software. Fourteen membranes were included in the analysis, nine from eyes with proliferative diabetic retinopathy and five idiopathic membranes. Flatmount diabetic membranes showed co-localization of endothelin-1 with S100A4 and CD31. Immunohistochemistry and quantitative analysis of cross-sectional membranes showed significantly higher endothelin-1 labeling in proliferative diabetic retinopathy membranes compared to idiopathic membranes (pmembranes showed more elements staining positive for S100A4 compared to idiopathic membranes. Epiretinal membrane formation in proliferative diabetic retinopathy involves higher tissue levels of endothelin-1 and fibroblastic activity. Furthermore, endothelin-1, endothelial and fibroblastic staining appear to be correlated, suggestive of endothelial-to-mesenchymal transition in proliferative diabetic retinopathy.

  1. Chalepin: A Compound from Ruta angustifolia L. Pers Exhibits Cell Cycle Arrest at S phase, Suppresses Nuclear Factor-Kappa B (NF-κB) Pathway, Signal Transducer and Activation of Transcription 3 (STAT3) Phosphorylation and Extrinsic Apoptotic Pathway in Non-small Cell Lung Cancer Carcinoma (A549).

    Science.gov (United States)

    Richardson, Jaime Stella Moses; Aminudin, Norhaniza; Abd Malek, Sri Nurestri

    2017-10-01

    Plants have been a major source of inspiration in developing novel drug compounds in the treatment of various diseases that afflict human beings worldwide. Ruta angustifolia L. Pers known locally as Garuda has been conventionally used for various medicinal purposes such as in the treatment of cancer. A dihydrofuranocoumarin named chalepin, which was isolated from the chloroform extract of the plant, was tested on its ability to inhibit molecular pathways of human lung carcinoma (A549) cells. Cell cycle analysis and caspase 8 activation were conducted using a flow cytometer, and protein expressions in molecular pathways were determined using Western blot technique. Cell cycle analysis showed that cell cycle was arrested at the S phase. Further studies using Western blotting technique showed that cell cycle-related proteins such as cyclins, cyclin-dependent kinases (CDKs), and inhibitors of CDKs correspond to a cell cycle arrest at the S phase. Chalepin also showed inhibition in the expression of inhibitors of apoptosis proteins. Nuclear factor-kappa B (NF-κB) pathway, signal transducer and activation of transcription 3 (STAT-3), cyclooxygenase-2, and c-myc were also downregulated upon treatment with chalepin. Chalepin was found to induce extrinsic apoptotic pathway. Death receptors 4 and 5 showed a dramatic upregulation at 24 h. Analysis of activation of caspase 8 with the flow cytometer showed an increase in activity in a dose- and time-dependent manner. Activation of caspase 8 induced cleavage of BH3-interacting domain death agonist, which initiated a mitochondrial-dependent or -independent apoptosis. Chalepin causes S phase cell cycle arrest, NF-κB pathway inhibition, and STAT-3 inhibition, induces extrinsic apoptotic pathway, and could be an excellent chemotherapeutic agent. This study reports the capacity of an isolated bioactive compound known as chalepin to suppress the nuclear factor kappa-light-chain-enhancer of activated B cells pathway, signal

  2. Proliferative and morphologic changes in rat colon following bypass surgery.

    Science.gov (United States)

    Barkla, D H; Tutton, P J

    1985-06-01

    In this study the proliferative and morphologic changes that occur in the colon of normal and dimethylhydrazine-treated rats following surgical bypass of the middle third of the colon are reported. Proliferative changes were measured by estimating accumulated mitotic indexes following vinblastine treatment and morphologic changes were observed with the use of light microscopy and scanning electron microscopy. Data were collected on Days 0, 7, 14, 30, and 72 after surgery. The results show that surgical bypass produces contrasting effects in the segments proximal to and distal to the suture line. In the proximal segment there was morphologic evidence of hyperplasia, although proliferative activity was unchanged except for an increase at 7 days in normal rats. In the distal segment there was a long-lived increase in the mitotic index, although morphologic changes were not seen. The results for DMH-treated rats were similar to those in normal rats. Groups of isolated dysplastic epithelial cells were often seen in the submucosa adjacent to sutures up to 72 days after surgery. Increased lymphoid infiltration was seen in segments proximal to but not distal to the suture line. It is hypothesized that the different responses of the proximal and distal segments may be related to the different embryologic origins of those segments. It is also hypothesized that the seeding of the submucosa with epithelial cells during suturing may be a factor in tumor recurrence.

  3. Lupeol induces S-phase arrest and mitochondria-mediated ...

    Indian Academy of Sciences (India)

    48

    Lupeol induces S-phase arrest and mitochondria-mediated apoptosis in cervical cancer cells. Nupoor Prasad1, Akash Sabarwal2, Umesh C. S. Yadav1, Rana P. Singh2,*. 1School of Life Sciences, Central University of Gujarat, Gandhinagar, Gujarat, India. 2Cancer Biology Laboratory, School of Life Sciences, Jawaharlal ...

  4. Inhibition of autophagy enhances DNA damage-induced apoptosis by disrupting CHK1-dependent S phase arrest

    Energy Technology Data Exchange (ETDEWEB)

    Liou, Jong-Shian; Wu, Yi-Chen; Yen, Wen-Yen; Tang, Yu-Shuan [Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, ROC (China); Kakadiya, Rajesh B.; Su, Tsann-Long [Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, ROC (China); Yih, Ling-Huei, E-mail: lhyih@gate.sinica.edu.tw [Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, ROC (China)

    2014-08-01

    DNA damage has been shown to induce autophagy, but the role of autophagy in the DNA damage response and cell fate is not fully understood. BO-1012, a bifunctional alkylating derivative of 3a-aza-cyclopenta[a]indene, is a potent DNA interstrand cross-linking agent with anticancer activity. In this study, BO-1012 was found to reduce DNA synthesis, inhibit S phase progression, and induce phosphorylation of histone H2AX on serine 139 (γH2AX) exclusively in S phase cells. Both CHK1 and CHK2 were phosphorylated in response to BO-1012 treatment, but only depletion of CHK1, but not CHK2, impaired BO-1012-induced S phase arrest and facilitated the entry of γH2AX-positive cells into G2 phase. CHK1 depletion also significantly enhanced BO-1012-induced cell death and apoptosis. These results indicate that BO-1012-induced S phase arrest is a CHK1-dependent pro-survival response. BO-1012 also resulted in marked induction of acidic vesicular organelle (AVO) formation and microtubule-associated protein 1 light chain 3 (LC3) processing and redistribution, features characteristic of autophagy. Depletion of ATG7 or co-treatment of cells with BO-1012 and either 3-methyladenine or bafilomycin A1, two inhibitors of autophagy, not only reduced CHK1 phosphorylation and disrupted S phase arrest, but also increased cleavage of caspase-9 and PARP, and cell death. These results suggest that cells initiate S phase arrest and autophagy as pro-survival responses to BO-1012-induced DNA damage, and that suppression of autophagy enhances BO-1012-induced apoptosis via disruption of CHK1-dependent S phase arrest. - Highlights: • Autophagy inhibitors enhanced the cytotoxicity of a DNA alkylating agent, BO-1012. • BO-1012-induced S phase arrest was a CHK1-dependent pro-survival response. • Autophagy inhibition enhanced BO-1012 cytotoxicity via disrupting the S phase arrest.

  5. Hypersensitivity of mouse NEIL1-knockdown cells to hydrogen peroxide during S phase

    International Nuclear Information System (INIS)

    Yamamoto, Ryohei; Ohshiro, Yukari; Shimotani, Tatsuhiko; Yamamoto, Mizuki; Matsuyama, Satoshi; Ide, Hiroshi; Kubo, Kihei

    2014-01-01

    Oxidative base damage occurs spontaneously due to reactive oxygen species generated as byproducts of respiration and other pathological processes in mammalian cells. Many oxidized bases are mutagenic and/or toxic, and most are repaired through the base excision repair pathway. Human endonuclease VIII-like protein 1 (hNEIL1) is thought to play an important role during the S phase of the cell cycle by removing oxidized bases in DNA replication fork-like (bubble) structures, and the protein level of hNEIL1 is increased in S phase. Compared with hNEIL1, there is relatively little information on the properties of the mouse ortholog mNEIL1. Since mouse cell nuclei lack endonuclease III-like protein (NTH) activity, in contrast to human cell nuclei, mNEIL1 is a major DNA glycosylase for repair of oxidized pyrimidines in mouse nuclei. In this study, we made mNEIL1-knockdown cells using an shRNA expression vector and examined the cell cycle-related variation in hydrogen peroxide (H 2 O 2 ) sensitivity. Hypersensitivity to H 2 O 2 caused by mNEIL1 knockdown was more significant in S phase than in G1 phase, suggesting that mNEIL1 has an important role during S phase, similarly to hNEIL1

  6. MCM-BP regulates unloading of the MCM2–7 helicase in late S phase

    Science.gov (United States)

    Nishiyama, Atsuya; Frappier, Lori; Méchali, Marcel

    2011-01-01

    Origins of DNA replication are licensed by recruiting MCM2–7 to assemble the prereplicative complex (pre-RC). How MCM2–7 is inactivated or removed from chromatin at the end of S phase is still unclear. Here, we show that MCM-BP can disassemble the MCM2–7 complex and might function as an unloader of MCM2–7 from chromatin. In Xenopus egg extracts, MCM-BP exists in a stable complex with MCM7, but is not associated with the MCM2–7 hexameric complex. MCM-BP accumulates in nuclei in late S phase, well after the loading of MCM2–7 onto chromatin. MCM-BP immunodepletion in Xenopus egg extracts inhibits replication-dependent MCM dissociation without affecting pre-RC formation and DNA replication. When excess MCM-BP is incubated with Xenopus egg extracts or immunopurified MCM2–7, it binds to MCM proteins and promotes disassembly of the MCM2–7 complex. Recombinant MCM-BP also releases MCM2–7 from isolated late-S-phase chromatin, but this activity is abolished when DNA replication is blocked. MCM-BP silencing in human cells also delays MCM dissociation in late S phase. We propose that MCM-BP plays a key role in the mechanism by which pre-RC is cleared from replicated DNA in vertebrate cells. PMID:21196493

  7. DIAGNOSTIC CRITERIA FOR PROLIFERATIVE THYROID LESIONS IN BONY FISHES

    Science.gov (United States)

    Thyroid proliferative lesions are rather common in bony fishes but disagreement exists in the fish pathology community concerning diagnostic criteria for hyperplastic versus neoplastic lesions. To simplify the diagnosis of proliferative thyroid lesions and to reduce confusion reg...

  8. Huaier Aqueous Extract Induces Hepatocellular Carcinoma Cells Arrest in S Phase via JNK Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Chengshuo Zhang

    2015-01-01

    Full Text Available Huaier aqueous extract, the main active constituent of Huaier proteoglycan, has antihepatocarcinoma activity in experimental and clinical settings. However, the potential and associated antihepatoma mechanisms of Huaier extract are not yet fully understood. Therefore, in this study, we aimed to elucidate the inhibitory proliferation effect of Huaier extract on apoptosis and cycle of HepG2 and Bel-7402 cells. Our data demonstrated that incubation with Huaier extract resulted in a marked decrease in cell viability dose-dependently. Flow cytometric analysis showed that a 48 h treatment of Huaier extract caused cell apoptosis. Typical apoptotic nucleus alterations were observed with fluorescence microscope after Hoechst staining. Immunoblot analysis further demonstrated that Huaier extract activated caspase 3 and PARP. Additionally, Huaier extract inhibited the activity of p-ERK, p-p38, and p-JNK in terms of MAPK. Furthermore, Huaier extract induced HCC cells arrest in S phase and decreased the cycle related protein expression of β-catenin and cyclin D1. Studies with JNK specific inhibitor, SP600125, showed that Huaier extract induced S phase arrest and decreased β-catenin and cyclin D1 expression via JNK signaling pathway. In conclusion, we verify that Huaier extract causes cell apoptosis and induces hepatocellular carcinoma cells arrest in S phase via JNK pathway, which advances our understanding on the molecular mechanisms of Huaier extract in hepatocarcinoma management.

  9. Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74

    Science.gov (United States)

    Djudjaj, Sonja; Lue, Hongqi; Rong, Song; Papasotiriou, Marios; Klinkhammer, Barbara M.; Zok, Stephanie; Klaener, Ole; Braun, Gerald S.; Lindenmeyer, Maja T.; Cohen, Clemens D.; Bucala, Richard; Tittel, Andre P.; Kurts, Christian; Moeller, Marcus J.; Floege, Juergen; Ostendorf, Tammo

    2016-01-01

    Pathologic proliferation of mesangial and parietal epithelial cells (PECs) is a hallmark of various glomerulonephritides. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that mediates inflammation by engagement of a receptor complex involving the components CD74, CD44, CXCR2, and CXCR4. The proliferative effects of MIF may involve CD74 together with the coreceptor and PEC activation marker CD44. Herein, we analyzed the effects of local glomerular MIF/CD74/CD44 signaling in proliferative glomerulonephritides. MIF, CD74, and CD44 were upregulated in the glomeruli of patients and mice with proliferative glomerulonephritides. During disease, CD74 and CD44 were expressed de novo in PECs and colocalized in both PECs and mesangial cells. Stress stimuli induced MIF secretion from glomerular cells in vitro and in vivo, in particular from podocytes, and MIF stimulation induced proliferation of PECs and mesangial cells via CD74. In murine crescentic GN, Mif-deficient mice were almost completely protected from glomerular injury, the development of cellular crescents, and the activation and proliferation of PECs and mesangial cells, whereas wild-type mice were not. Bone marrow reconstitution studies showed that deficiency of both nonmyeloid and bone marrow–derived Mif reduced glomerular cell proliferation and injury. In contrast to wild-type mice, Cd74-deficient mice also were protected from glomerular injury and ensuing activation and proliferation of PECs and mesangial cells. Our data suggest a novel molecular mechanism and glomerular cell crosstalk by which local upregulation of MIF and its receptor complex CD74/CD44 mediate glomerular injury and pathologic proliferation in GN. PMID:26453615

  10. Proliferative myositis in a patient with AIDS

    Energy Technology Data Exchange (ETDEWEB)

    Wlachovska, B.; Deux, J.F.; Marsault, C.; Le Breton, C. [Department of Radiology, Hopital Tenon, 4 rue de la Chine, 75020, Paris (France); Abraham, B. [Department of Tropical and Infectious Diseases, Hopital Tenon, Paris (France); Sibony, M. [Department of Anatomy, Hopital Tenon, Paris (France)

    2004-04-01

    We report a case of proliferative myositis in the right biceps of a 56-year-old man with acquired immune deficiency syndrome (AIDS). Imaging methods included sonography, computed tomography and magnetic resonance imaging. The diagnosis was made by a core-cut biopsy and fine needle aspiration biopsy with immunohistochemical analysis. The lesion disappeared after 2 months without treatment. It is particularly important to determine whether intramuscular masses arising in patients with AIDS are due to an infectious or malignant process. (orig.)

  11. Proliferative myositis in a patient with AIDS

    International Nuclear Information System (INIS)

    Wlachovska, B.; Deux, J.F.; Marsault, C.; Le Breton, C.; Abraham, B.; Sibony, M.

    2004-01-01

    We report a case of proliferative myositis in the right biceps of a 56-year-old man with acquired immune deficiency syndrome (AIDS). Imaging methods included sonography, computed tomography and magnetic resonance imaging. The diagnosis was made by a core-cut biopsy and fine needle aspiration biopsy with immunohistochemical analysis. The lesion disappeared after 2 months without treatment. It is particularly important to determine whether intramuscular masses arising in patients with AIDS are due to an infectious or malignant process. (orig.)

  12. COMPARISONS BETWEEN THE NON-PROLIFERATIVE AND PROLIFERATIVE THERAPY IN FIBROCYSTIC MASTOSIS.

    Science.gov (United States)

    Carauleanu, A; Socolov, R; Rugina, V; Gabia, O; Carauleanu, Daniela Mihaela; Lupascu, Ivona Anghlcelache; Socolov, Demetra

    2016-01-01

    Fibrocystic mastosis (FCM) is the most frequent benign breast lesion. Most treatments for fibrocystic mastosis are: hormonl, with beneficial results and non-hormonal, with fluctuating results. A number of 210 cases were studied, which were divided into 7 groups. The study lasted for 9 months and it was carried out on the basis of a personal examination sheet. The following were monitored: age groups, mastodynia, reducing breast nodules, a significant reduction in the volume of the mastosic cysts, reducion of the fibrous tissue, medication tolerance. Mastodynia has declined by 90% in the cases treated with Tamoxifen and Danazol, by 70% in the case of Lynestrenol and Bromocriptine, by 50% in the 15 patients who were given Utrogestan. Knowing the advantages and disadvantages of drugs (contraindications, side effects), age category, breast pain reduction, antiproliferative activity, tolerability, relapse allow us to assess the benefit-risk. Even in those circumstances that remained incompletely clarified for objective reasons, related to the inaccurate/incorrect reporting by the patients, there is a significant difference (p < 0.05) between the frequency of relapses following the treatment with Tamoxifen and the other categories of drugs who were administered. Our study shows that in the groups that were administered Logest, Utrogestan and Bromocriptine, only antalgic effects were achieved (disappearance or only decrease of mastodynia) and no anti-proliferative effects were obtained. Basically, hormone treatment should be made based on a histopathological examination.

  13. Antibacterial, antioxidant and cell proliferative properties of Coccinia grandis fruits

    Directory of Open Access Journals (Sweden)

    Prashant Sakharkar

    2017-06-01

    Full Text Available Objective: Little knowledge is available on the antimicrobial and antioxidant properties of Coccina grandis fruits and no study has reported on its cell proliferative property. The aim of this study was to examine the antimicrobial, antioxidant and cell proliferative property of fruits of C. grandis. Material and Methods: Fruits of C. grandis were extracted using water; ethanol and acetone by cold and hot Soxhlet extraction. The antibacterial activities of the extracts were tested against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Pseudomonas aeruginosa using the modified Kirby-Bauer diffusion method and compared against erythromycin. The antioxidant property was determined using Cayman's antioxidant assay; whereas cell proliferation/cytotoxic properties were evaluated using the Cell Titer 96 Aqueous One Solution Cell MTS assay with MDA-MB 321 breast cancer cells. Data were analyzed for correlation and differences using unpaired student's t-test and one-way ANOVA. A p value of Results: Both cold and hot ethanol and acetone extracts of C. grandis fruits showed some degree of bacterial growth inhibition. Acetone extracts exhibited higher antibacterial activity. Both ethanol extracts showed antioxidant property when compared with standard Trolox. In contrary to cytotoxicity, all four extracts showed cell proliferation compared to controls at different concentrations. However, acetone extracts exhibited greater cell proliferation compared to ethanol extracts and cold extracts performed better than the hot extracts. Conclusion: C. grandis fruits exhibited some degree of antimicrobial, antioxidant and cell proliferative properties. Further investigation is warranted to isolate, confirm and characterize phytochemicals that are responsible for the medicinal properties observed.

  14. Standard effective doses for proliferative tumours

    International Nuclear Information System (INIS)

    Jones, L.C.; Hoban, P.

    1999-01-01

    This study was undertaken to investigate the treatment schedules used clinically for highly proliferative tumours, particularly with reference to the effects of fraction size, fraction number and treatment duration. The linear quadratic model (with time component) is used here to compare non-standard treatment regimens (e.g. accelerated and hyperfractionated schedules), currently the focus of randomized trials, with each other and some common 'standard regimens'. To ensure easy interpretation of results, two parameters known as proliferative standard effective dose one (PSED 1 ) and proliferative standard effective dose two (PSED 2 ) have been calculated for each regimen. Graphs of PSED 1 and PSED 2 versus potential doubling time (T p ) have been generated for a range of fractionation regimens which are currently under trial in various randomized studies. From these graphs it can be seen that the highly accelerated schedules (such as CHART) only show advantages for tumours with very short potential doubling times. Calculations for most of the schedules considered showed at least equivalent tumour control expected for the trial schedule compared with the control arm used and these values agree quite well with clinical results. These calculations are in good agreement with clinical results available at present. The greater the PSED 1 or PSED 2 for the schedule considered the greater the tumour control, which can be expected. However, as has been seen with clinical trials, this higher cell kill also results in higher acute effects which have proved too great for some accelerated schedules to continue. (author)

  15. Protein tyrosine phosphatase-1B (PTP1B) helps regulate EGF-induced stimulation of S-phase entry in human corneal endothelial cells

    Science.gov (United States)

    Ishino, Yutaka; Zhu, Cheng; Harris, Deshea L.

    2008-01-01

    expression, but not EGFR expression, was elevated in HCEC from older donors, suggesting that the reduced proliferative activity of these cells in response to EGF is due, at least in part, to increased PTP1B activity. The fact that inhibition of PTP1B increased the relative number of cells entering S-phase strongly suggests that PTP1B helps negatively regulate EGF-stimulated cell cycle entry in HCEC. These results also suggest that it may be possible to increase the proliferative activity of HCEC, particularly in cells from older donors, by inhibiting the activity of this important protein tyrosine phosphatase. PMID:18253097

  16. 3,3'-Diindolylmethane, a cruciferous vegetable derived synthetic anti-proliferative compound in thyroid disease

    International Nuclear Information System (INIS)

    Tadi, Kiranmayi; Chang Yushan; Ashok, Badithe T.; Chen, Yuangen; Moscatello, Augustine; Schaefer, Steven D.; Schantz, Stimsom P.; Policastro, Anthony J.; Geliebter, Jan; Tiwari, Raj K.

    2005-01-01

    Considerable epidemiological evidence exists to link thyroid disease with differing patterns of dietary consumption, in particular, cruciferous vegetables. We have been studying the anti-thyroid cancer (TCa) activity of indole-3-carbinol (I3C) found in cruciferous vegetables and its acid catalyzed dimer, 3,3'-diindolylmethane (DIM). There are no studies as yet to elucidate the effect of these compounds on the altered proliferative patterns in goiter or thyroid neoplasia. In this study, we tested the anti-proliferative effects of I3C and DIM on four different thyroid cancer cell lines representative of papillary (B-CPAP and 8505-C) and follicular carcinoma of the thyroid (CGTH-W-1 and ML-1), and primary human goiter cells. Cell survival and IC 50 values for I3C and DIM were calculated by the XTT assay and cell cycle distribution analysis was done by flow cytometry. DIM was found to be a better anti-proliferative agent than I3C in both papillary and follicular TCa resulting in a greater cytotoxic effect at a concentration over three fold lower than predicted by the molar ratio of DIM and I3C. The anti-proliferative activity of DIM in follicular TCa was mediated by a G1 arrest followed by induction of apoptosis. DIM also inhibited the growth of primary goiter cells by 70% compared to untreated controls. Contrary to traditional belief that cruciferous vegetables are 'goitrogenic,' DIM has anti-proliferative effects in glandular thyroid proliferative disease. Our preclinical studies provide a strong rationale for the clinical exploration of DIM as an adjuvant to surgery in thyroid proliferative disease

  17. Proliferative glomerulonephritis and primary antiphospholipid syndrome

    International Nuclear Information System (INIS)

    Abdalla, H. Abdalla; Kfoury, Hala K.; Al-Khader, Abdulla A.; Al-Suleiman, M.

    2006-01-01

    Little is known regarding the association of primary antiphospholipid syndrome (APLS) and proliferative glomerulonephiritis (GN). We describe a biopsy-documented case with primary APLS and proliferative (GN) with no evidence of thrombotic microangiopathy (TMA), and in the absence of other manifestations of systematic lupus erythematosus (SLE). She presented initially with left popliteal deep venous thrombosis and nephrotic syndrome. Her first pregnancy at the age of 26 years resulted in the intra-uterine fetal death at term. Two subsequent pregnancies ended up with miscarriages at 3 and 4 months of gestation. Urinalysis revealed glomerular red blood cells of 1.0000.000/ml and granular cast; proteinuria of 13.4grams/24 hours, which was non-selective; hemoglobin 12 gm/dl, normal white blood cell and platelets; serum albumin 2.6gm/dl; anti-nuclear antibody (ANA) and anti DNA were negative and complement levels normal. Lupus anticoagulant was positive leading to a diagnosis of primary APLS. The biopsy findings were consistent with membranoproliferative GN. She continued to have steroid-resistant proteinuria, but stable renal function after a 12-year follow up period. She had 2 pregnancies during this period and was delivered at term using caesarian section. She received heparin during the pregnancies. Later she developed hypertension easily controlled by atenolol. This case provides evidence that primary APLS can be associated with proliferative GN due to immune deposits and not only TMA as previously reported, and in the complete absence of SLE. Performing more renal biopsies in this group of patients may disclose a greater prevalence of proleferative GN and may help in devising a rationale for treatment. (author)

  18. Amniocar as a proliferative medium for mesenchymal cells

    Directory of Open Access Journals (Sweden)

    V. V. Chestkov

    2014-01-01

    Full Text Available Objectives. To develop the Amniocar nutrient medium that contains fetal calf serum (FCS and growth factors cocktail for mass cultivation of human fibroblasts. To study proliferative activity of the medium on cultures of HUVEC cells of mesenchymal origin and mesenchymal stromal cells, as well as on cell culture of human amniotic fluid.Materials and methods. Determination of the rate of accumulation of the cellular mass and cell morphology in the course of cultivation of cells of various histogenesis in the Amniocar medium and nutrient medium that contains 10 % of FCS.Results. It has been demonstrated that the Amniocar medium is prevalent as compared to the standard DMEM medium with 10 % of FCS by 2 to 5 times for cultivation of skin fibroblasts, HUVEC, and mesenchymal stem cells. The Amniocar medium increased the quantity of endothelial cells that enter mitosis and maintained the culture of HUVEC cells with prolonged passaging in vitro. Clonal cultivation of human amniotic fluid cells in the Amniocar medium secured development of colonies of both fibroblast and epithelial type.Conclusions. Proliferative Amniocar medium is efficient for mass cultivation of various cells of mesenchymal origin and can be used for diagnostic purposes in medical genetics, oncology, etc.

  19. Cell cycle G2/M arrest through an S phase-dependent mechanism by HIV-1 viral protein R.

    Science.gov (United States)

    Li, Ge; Park, Hyeon U; Liang, Dong; Zhao, Richard Y

    2010-07-07

    Cell cycle G2 arrest induced by HIV-1 Vpr is thought to benefit viral proliferation by providing an optimized cellular environment for viral replication and by skipping host immune responses. Even though Vpr-induced G2 arrest has been studied extensively, how Vpr triggers G2 arrest remains elusive. To examine this initiation event, we measured the Vpr effect over a single cell cycle. We found that even though Vpr stops the cell cycle at the G2/M phase, but the initiation event actually occurs in the S phase of the cell cycle. Specifically, Vpr triggers activation of Chk1 through Ser345 phosphorylation in an S phase-dependent manner. The S phase-dependent requirement of Chk1-Ser345 phosphorylation by Vpr was confirmed by siRNA gene silencing and site-directed mutagenesis. Moreover, downregulation of DNA replication licensing factors Cdt1 by siRNA significantly reduced Vpr-induced Chk1-Ser345 phosphorylation and G2 arrest. Even though hydroxyurea (HU) and ultraviolet light (UV) also induce Chk1-Ser345 phosphorylation in S phase under the same conditions, neither HU nor UV-treated cells were able to pass through S phase, whereas vpr-expressing cells completed S phase and stopped at the G2/M boundary. Furthermore, unlike HU/UV, Vpr promotes Chk1- and proteasome-mediated protein degradations of Cdc25B/C for G2 induction; in contrast, Vpr had little or no effect on Cdc25A protein degradation normally mediated by HU/UV. These data suggest that Vpr induces cell cycle G2 arrest through a unique molecular mechanism that regulates host cell cycle regulation in an S-phase dependent fashion.

  20. Cell cycle G2/M arrest through an S phase-dependent mechanism by HIV-1 viral protein R

    Directory of Open Access Journals (Sweden)

    Liang Dong

    2010-07-01

    Full Text Available Abstract Background Cell cycle G2 arrest induced by HIV-1 Vpr is thought to benefit viral proliferation by providing an optimized cellular environment for viral replication and by skipping host immune responses. Even though Vpr-induced G2 arrest has been studied extensively, how Vpr triggers G2 arrest remains elusive. Results To examine this initiation event, we measured the Vpr effect over a single cell cycle. We found that even though Vpr stops the cell cycle at the G2/M phase, but the initiation event actually occurs in the S phase of the cell cycle. Specifically, Vpr triggers activation of Chk1 through Ser345 phosphorylation in an S phase-dependent manner. The S phase-dependent requirement of Chk1-Ser345 phosphorylation by Vpr was confirmed by siRNA gene silencing and site-directed mutagenesis. Moreover, downregulation of DNA replication licensing factors Cdt1 by siRNA significantly reduced Vpr-induced Chk1-Ser345 phosphorylation and G2 arrest. Even though hydroxyurea (HU and ultraviolet light (UV also induce Chk1-Ser345 phosphorylation in S phase under the same conditions, neither HU nor UV-treated cells were able to pass through S phase, whereas vpr-expressing cells completed S phase and stopped at the G2/M boundary. Furthermore, unlike HU/UV, Vpr promotes Chk1- and proteasome-mediated protein degradations of Cdc25B/C for G2 induction; in contrast, Vpr had little or no effect on Cdc25A protein degradation normally mediated by HU/UV. Conclusions These data suggest that Vpr induces cell cycle G2 arrest through a unique molecular mechanism that regulates host cell cycle regulation in an S-phase dependent fashion.

  1. Cetuximab-Associated Crescentic Diffuse Proliferative Glomerulonephritis

    Directory of Open Access Journals (Sweden)

    Sukesh Manthri

    2017-01-01

    Full Text Available Cetuximab-induced nephrotoxicity is very rare, occurring in less than 1% of colorectal cancer patients and not defined in other populations. We report a rare case of crescentic diffuse proliferative glomerulonephritis (GN that developed in close temporal association with cetuximab treatment. A 65-year-old female recently completed chemotherapy with cetuximab treatment for moderately differentiated oral squamous cell carcinoma. She was admitted with acute renal failure and nephrotic-range proteinuria. Laboratory data showed serum creatinine of 6.6 mg/dl and urinalysis showed proteinuria, moderate hemoglobinuria, hyaline casts (41/LPF, WBC (28/HPF, and RBC (81/HPF. Serologic studies were negative for ANA, anti-GBM, ANCA, hepatitis B, and hepatitis C. Serum C3 and C4 level were normal. Renal biopsy showed crescentic diffuse proliferative GN with focal features of thrombotic microangiopathy. Patient was started on cyclophosphamide and steroids. Her renal function did not improve on day 8 and she was started on hemodialysis. Previous reports suggest that EGFR-targeting medications can possibly trigger or exacerbate an IgA-mediated glomerular process leading to renal failure. This case suggests that cetuximab therapy may have triggered or exacerbated a severe glomerular injury with an unfavorable outcome. Treating physicians should maintain a high degree of caution and monitor renal function in patients on EGFR inhibitors.

  2. Iron(III-salophene: an organometallic compound with selective cytotoxic and anti-proliferative properties in platinum-resistant ovarian cancer cells.

    Directory of Open Access Journals (Sweden)

    Thilo S Lange

    2008-05-01

    Full Text Available In this pioneer study to the biological activity of organometallic compound Iron(III-salophene (Fe-SP the specific effects of Fe-SP on viability, morphology, proliferation, and cell-cycle progression on platinum-resistant ovarian cancer cell lines were investigated.Fe-SP displayed selective cytotoxicity against SKOV-3 and OVCAR-3 (ovarian epithelial adenocarcinoma cell lines at concentrations between 100 nM and 1 microM, while the viability of HeLa cells (epithelial cervix adenocarcinoma or primary lung or skin fibroblasts was not affected. SKOV-3 cells in contrast to fibroblasts after treatment with Fe-SP revealed apparent hallmarks of apoptosis including densely stained nuclear granular bodies within fragmented nuclei, highly condensed chromatin and chromatin fragmentation. Fe-SP treatment led to the activation of markers of the extrinsic (Caspase-8 and intrinsic (Caspase-9 pathway of apoptosis as well as of executioner Caspase-3 while PARP-1 was deactivated. Fe-SP exerted effects as an anti-proliferative agent with an IC(50 value of 300 nM and caused delayed progression of cells through S-phase phase of the cell cycle resulting in a complete S-phase arrest. When intra-peritoneally applied to rats Fe-SP did not show any systemic toxicity at concentrations that in preliminary trials were determined to be chemotherapeutic relevant doses in a rat ovarian cancer cell model.The present report suggests that Fe-SP is a potent growth-suppressing agent in vitro for cell lines derived from ovarian cancer and a potential therapeutic drug to treat such tumors in vivo.

  3. Correlation of proliferative and clonogenic tumor cells in multiple myeloma

    International Nuclear Information System (INIS)

    Karp, J.E.; Burke, P.J.; Saylor, P.L.; Humphrey, R.L.

    1984-01-01

    To expand on the findings from previous clinical trials that the growth of residual tumor is increased at a predictable time following initial drug administration, malignant plasma cells from bone marrows of patients with multiple myeloma (MM) were examined for changes in proliferation and clonogenicity induced in vivo by cyclophosphamide and in vitro by drug-induced humoral stimulatory activity. Peak plasma cell [ 3 H]thymidine labeling index (LI) occurred predictably following drug and paralleled changes in agar colony formation by marrow cells obtained during therapy. Colony-forming capacity of pretreatment MM marrow populations was enhanced when those cells were cultured with humoral stimulatory activity, similar to the increased colony formation detected in Day 9 postcyclophosphamide marrows at the time of peak plasma cell LI. To further define a relationship between proliferative plasma cells and colony-forming tumor cells, MM marrows were fractionated by sedimentation on an isokinetic gradient. Enrichment of a proliferative tumor cell cohort was achieved, evidenced by [ 3 H]thymidine LI. Colony-forming cells were also enriched by isokinetic gradient sedimentation, and agar colony formation by MM marrow cell fractions correlated with the kinetic characteristics of the isolated subpopulations. These studies of whole and fractionated human MM marrow cell populations suggest that the kinetically active cells which are induced to proliferate in vivo and in vitro are closely related to the clonogenic tumor cells which produce colonies in agar and which, like those cells measured by [ 3 H]thymidine LI, respond to growth stimulation by drug-induced humoral stimulatory activity

  4. A Predictive Model for Estimation Risk of Proliferative Lupus Nephritis

    Directory of Open Access Journals (Sweden)

    Dong-Ni Chen

    2018-01-01

    Conclusion: This study developed and validated a model including demographic and clinical indices to evaluate the probability of presenting proliferative LN to guide therapeutic decisions and outcomes.

  5. Body linear traits for identifying prolific goats

    Directory of Open Access Journals (Sweden)

    Avijit Haldar

    2014-12-01

    Full Text Available Aim: The present study was conducted on prolific goat breed to identify body linear type traits that might be associated with prolificacy trait in goats. Materials and Methods: Two-stage stratified random sample survey based data were collected from 1427 non-pregnant goats with the history of single, twin and triplet litter sizes (LZ between January 2008 to February 2011 for 3 years in 68 villages located in East and North East India. Data on sixteen body linear traits were analyzed using logistic regression model to do the step-wise selection for identifying the body linear traits that could determine LZ. An average value for each identified body linear trait was determined for classifying the goats into three categories: Goats having the history of single LZ, goats having the history of twin LZ and goats having the history of triplet LZ. Results: The LZ proportions for single, twin and triplet, were 29.50, 59.14 and 11.36%, respectively, with the prolificacy rate of 181.85% in Indian Black Bengal goats. A total of eight body linear traits that could determine LZ in prolific goats were identified. Heart girth (HG measurement (>60.90 cm, paunch girth (PG (>70.22 cm, wither height (WH (>49.75 cm, neck length (>21.45 cm, ear length (>12.80 cm and distance between trochanter major (DTM bones (>12.28 cm, pelvic triangle area (PTA (>572.25 cm2 and clearance at udder (CU (>23.16 cm showed an increase likelihood of multiple LZ when compared to single LZ. Further, HG measurement (>62.29 cm, WH (>50.54 cm, PG (>71.85 cm and ear length (>13.00 cm, neck length (>22.01 cm, PTA (>589.64 cm2, CU (>23.20 cm and DTM bones (>12.47 cm were associated with increased likelihood of triplet LZ, when compared with that of twin LZ. Conclusion: HG measurement was the best discriminating factor, while PG, neck length, DTM bones, CU, PTA, WH and ear length measurements were other important factors that could be used for identifying prolific goats to achieve economic

  6. Testing Whether Defective Chromatin Assembly in S-Phase Contributes to Breast Cancer

    National Research Council Canada - National Science Library

    Adams, Peter

    2003-01-01

    .... We used a dominant negative mutant of (chromatin assembly factor-I) CAF1, a complex that assembles newly synthesized DNA into nucleosomes, to inhibit S-phase chromatin assembly and found that this induced S-phase arrest...

  7. Testing Whether Defective Chromatin Assembly in S-Phase Contributes to Breast Cancer

    National Research Council Canada - National Science Library

    Adams, Peter

    2004-01-01

    .... We used a dominant negative mutant of (chromatin assembly factor-I) CAF1, a complex that assembles newly synthesized DNA into nucleosomes, to inhibit S-phase chromatin assembly and found that this induced S-phase arrest...

  8. 18F-FLT Positron Emission Tomography/Computed Tomography Imaging in Pancreatic Cancer: Determination of Tumor Proliferative Activity and Comparison with Glycolytic Activity as Measured by 18F-FDG Positron Emission Tomography/Computed Tomography Imaging

    Directory of Open Access Journals (Sweden)

    Senait Aknaw Debebe

    2016-02-01

    Full Text Available Objective: This phase-I imaging study examined the imaging characteristic of 3’-deoxy-3’-(18F-fluorothymidine (18F-FLT positron emission tomography (PET in patients with pancreatic cancer and comparisons were made with (18F-fluorodeoxyglucose (18F-FDG. The ultimate aim was to develop a molecular imaging tool that could better define the biologic characteristics of pancreas cancer, and to identify the patients who could potentially benefit from surgical resection who were deemed inoperable by conventional means of staging. Methods: Six patients with newly diagnosed pancreatic cancer underwent a combined FLT and FDG computed tomography (CT PET/CT imaging protocol. The FLT PET/CT scan was performed within 1 week of FDG PET/CT imaging. Tumor uptake of a tracer was determined and compared using various techniques; statistical thresholding (z score=2.5, and fixed standardized uptake value (SUV thresholds of 1.4 and 2.5, and applying a threshold of 40% of maximum SUV (SUVmax and mean SUV (SUVmean. The correlation of functional tumor volumes (FTV between 18F-FDG and 18F-FLT was assessed using linear regression analysis. Results: It was found that there is a correlation in FTV due to metabolic and proliferation activity when using a threshold of SUV 2.5 for FDG and 1.4 for FLT (r=0.698, p=ns, but a better correlation was obtained when using SUV of 2.5 for both tracers (r=0.698, p=ns. The z score thresholding (z=2.5 method showed lower correlation between the FTVs (r=0.698, p=ns of FDG and FLT PET. Conclusion: Different tumor segmentation techniques yielded varying degrees of correlation in FTV between FLT and FDGPET images. FLT imaging may have a different meaning in determining tumor biology and prognosis.

  9. The proliferative human monocyte subpopulation contains osteoclast precursors

    Science.gov (United States)

    Lari, Roya; Kitchener, Peter D; Hamilton, John A

    2009-01-01

    Introduction Immediate precursors of bone-resorbing osteoclasts are cells of the monocyte/macrophage lineage. Particularly during clinical conditions showing bone loss, it would appear that osteoclast precursors are mobilized from bone marrow into the circulation prior to entering tissues undergoing such loss. The observed heterogeneity of peripheral blood monocytes has led to the notion that different monocyte subpopulations may have special or restricted functions, including as osteoclast precursors. Methods Human peripheral blood monocytes were sorted based upon their degree of proliferation and cultured in macrophage colony-stimulating factor (M-CSF or CSF-1) and receptor activator of nuclear factor-kappa-B ligand (RANKL). Results The monocyte subpopulation that is capable of proliferation gave rise to significantly more multinucleated, bone-resorbing osteoclasts than the bulk of the monocytes. Conclusions Human peripheral blood osteoclast precursors reside in the proliferative monocyte subpopulation. PMID:19222861

  10. Avaliação da Atividade Proliferativa no Epitélio Mamário Adjacente a Fibroadenoma em Mulheres Tratadas com Tamoxifeno Evaluation of Proliferative Activity in the Mammary Epithelium Adjacent to Fibroadenoma in Women Treated with Tamoxifen

    Directory of Open Access Journals (Sweden)

    Juarez Antônio de Sousa

    2000-08-01

    Full Text Available Objetivo: estudar a atividade proliferativa do epitélio mamário normal adjacente a fibroadenoma em mulheres na fase lútea do ciclo menstrual, tratadas com tamoxifeno. Pacientes e Métodos: estudou-se por técnica imuno-histoquímica, com o uso do anticorpo monoclonal MIB-1, a atividade proliferativa no epitélio mamário adjacente a fibroadenoma. O estudo foi randomizado e duplo-cego. As 44 mulheres com fibroadenoma foram divididas em 3 grupos: A (n = 16; placebo, B (n = 15; tamoxifeno, 10 mg e C (n = 13; tamoxifeno, 20 mg. O tamoxifeno foi utilizado por 22 dias, a partir do 2º dia do ciclo menstrual, e a biópsia realizada no 23º dia. Resultados: a porcentagem média de núcleos corados por 1000 células no grupo A foi 9,2, no grupo B, 4,5, e no grupo C, 3,2. O teste de Fisher revelou que o tamoxifeno reduziu de forma significante a imunoexpressão do MIB-1 nas doses de 10 e 20 mg em comparação com o grupo placebo (pPurpose: to study the monoclonal antibody MIB-1 in the normal breast epithelium adjacent to a fibroadenoma in women in the luteal phase of the menstrual cycle treated with tamoxifen. Patients and methods: the proliferative activity of the mammary epithelium adjacent to the fibroadenoma was studied by immunohistochemistry based on immunoexpression of the monoclonal antibody MIB-1. The study was randomized and double blind and was conducted on 44 women with fibroadenomas, divided into 3 groups: A (n = 16; placebo, B (n = 15; tamoxifen, 10 mg, and C (n = 13; tamoxifen, 20 mg. Tamoxifen was administered for 22 days starting on the 2nd day of the menstrual cycle and a biopsy was taken on the 23rd day. Results: the mean percentage of stained nuclei per 1000 cells was 9.2 in group A, 4.5 in group B, and 3.2 in group C. Fisher's test revealed that tamoxifen significantly reduced the immunoexpression of MIB-1 at the doses of 10 and 20 mg compared to the placebo group (p<0.0001, with no significant differences between doses in terms of

  11. ATM regulates Cdt1 stability during the unperturbed S phase to prevent re-replication

    Science.gov (United States)

    Iwahori, Satoko; Kohmon, Daisuke; Kobayashi, Junya; Tani, Yuhei; Yugawa, Takashi; Komatsu, Kenshi; Kiyono, Tohru; Sugimoto, Nozomi; Fujita, Masatoshi

    2014-01-01

    Ataxia-telangiectasia mutated (ATM) plays crucial roles in DNA damage responses, especially with regard to DNA double-strand breaks (DSBs). However, it appears that ATM can be activated not only by DSB, but also by some changes in chromatin architecture, suggesting potential ATM function in cell cycle control. Here, we found that ATM is involved in timely degradation of Cdt1, a critical replication licensing factor, during the unperturbed S phase. At least in certain cell types, degradation of p27Kip1 was also impaired by ATM inhibition. The novel ATM function for Cdt1 regulation was dependent on its kinase activity and NBS1. Indeed, we found that ATM is moderately phosphorylated at Ser1981 during the S phase. ATM silencing induced partial reduction in levels of Skp2, a component of SCFSkp2 ubiquitin ligase that controls Cdt1 degradation. Furthermore, Skp2 silencing resulted in Cdt1 stabilization like ATM inhibition. In addition, as reported previously, ATM silencing partially prevented Akt phosphorylation at Ser473, indicative of its activation, and Akt inhibition led to modest stabilization of Cdt1. Therefore, the ATM-Akt-SCFSkp2 pathway may partly contribute to the novel ATM function. Finally, ATM inhibition rendered cells hypersensitive to induction of re-replication, indicating importance for maintenance of genome stability. PMID:24280901

  12. Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.

    Directory of Open Access Journals (Sweden)

    Bérengère Gobin

    Full Text Available Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma, a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1. Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma and POS-1 (undifferentiated osteosarcoma. Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R, appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor

  13. Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry

    DEFF Research Database (Denmark)

    Lomazzi, Marina; Moroni, M Cristina; Jensen, Michael R

    2002-01-01

    Deregulation of the retinoblastoma protein (pRB) pathway is a hallmark of cancer. In the absence of other genetic alterations, this deregulation results in lack of differentiation, hyperproliferation and apoptosis. The pRB protein acts as a transcriptional repressor by targeting the E2F...... transcription factors, whose functions are required for entry into S phase. Increased E2F activity can induce S phase in quiescent cells--this is a central element of most models for the development of cancer. We show that although E2F1 alone is not sufficient to induce S phase in diploid mouse and human...

  14. Dysregulation of T lymphocyte proliferative responses in autoimmunity.

    Directory of Open Access Journals (Sweden)

    Sydney K Elizer

    Full Text Available T cells are critically dependent on cellular proliferation in order to carry out their effector functions. Autoimmune strains are commonly thought to have uncontrolled T cell proliferation; however, in the murine model of autoimmune diabetes, hypo-proliferation of T cells leading to defective AICD was previously uncovered. We now determine whether lupus prone murine strains are similarly hyporesponsive. Upon extensive characterization of T lymphocyte activation, we have observed a common feature of CD4 T cell activation shared among three autoimmune strains-NOD, MRL, and NZBxNZW F1s. When stimulated with a polyclonal mitogen, CD4 T cells demonstrate arrested cell division and diminished dose responsiveness as compared to the non-autoimmune strain C57BL/6, a phenotype we further traced to a reliance on B cell mediated costimulation, which underscores the success of B cell directed immune therapies in preventing T cell mediated tissue injury. In turn, the diminished proliferative capacity of these CD4 T cells lead to a decreased, but activation appropriate, susceptibility to activation induced cell death. A similar decrement in stimulation response was observed in the CD8 compartment of NOD mice; NOD CD8 T cells were distinguished from lupus prone strains by a diminished dose-responsiveness to anti-CD3 mediated stimulation. This distinction may explain the differential pathogenetic pathways activated in diabetes and lupus prone murine strains.

  15. Autologous proliferative therapies in recalcitrant lateral epicondylitis.

    Science.gov (United States)

    Tetschke, Elisa; Rudolf, Margit; Lohmann, Christoph H; Stärke, Christian

    2015-09-01

    This study investigates the clinical effects of autologous conditioned plasma (ACP) injections and low-level laser application as therapy options for chronic lateral epicondylitis. A total of 52 patients with chronic lateral epicondylitis were evaluated in this study; 26 of these patients received three ACP injections and the control group, with 26 patients, received 12 laser applications, with standardized physical therapy for all patients afterward. Control examinations took place before treatment, after 2 and 6 mos, and in the 1 yr final follow-up. The control examination included the visual analog scale for pain and Disabilities of the Arm, Shoulder and Hand outcome measure scores. The analysis at final follow-up after 1 yr showed that both treatment options resulted in successful therapy outcome for the patients. In total, 63.5 % were successfully treated. Successful treatment was defined as more than 30% improvement in the visual analog score and more than 10.2 points in the Disabilities of the Arm, Shoulder and Hand score. Both groups showed a significant improvement in time response. This study demonstrates the beneficial effects of autologous proliferative therapies in the treatment of lateral epicondylitis. The data show that laser application and ACP therapy lead to a clinical improvement in epicondylopathia. Especially the new treatment with ACP can be highlighted as an alternative and as an easy-to-apply therapy option for clinical practice.

  16. Leptin: A proliferative factor for breast cancer?

    International Nuclear Information System (INIS)

    Caldefie-Chezet, F.; Damez, M.; Latour, M. de; Konska, G.; Mishellani, F.; Fusillier, C.; Guerry, M.; Penault-Llorca, F.; Guillot, J.; Vasson, M.-P.

    2005-01-01

    Mammary adipose tissue is an important source of paracrine mitogens and anti-mitogens, including insulin-like growth factor, transforming growth factors, and cytokines (especially, TNFα and IL-1β). Nevertheless, it is also an important source of the adipocytokine, leptin. Recently, leptin was reported to stimulate the proliferation of various cell types (pancreatic β cells, prostate, colorectal, lung, etc.) as a new growth factor. It was also shown to stimulate the proliferation of breast cancer cell lines. In this study, we conducted an immunohistochemical analysis of leptin expression in normal tissue and benign and malignant ductal breast cell, representing the different states of the invasion process. We determined for the first time that leptin is expressed both by ductal breast tumors and by benign lesions as atypical hyperplasia. This suggests that leptin may be taken up or synthesized by all modified ductal breast cells, and may prove a proliferative factor. Moreover, leptin is unexpressed by normal tissue in the healthy breast but is exhibited by the normal tissue in near vicinity of the malignant ductal breast lesions. We also postulated that leptin may be a prognostic or diagnostic factor for ductal breast cancer. These putative hypotheses require further study

  17. Lack of a differential radiation response for proliferative and non-proliferative rat thyroid cells (FRTL-5) in vitro

    International Nuclear Information System (INIS)

    Brosing, J.W.; Giese, W.L.; Mulcahy, R.T.

    1989-01-01

    FRTL-5 rat thyroid epithelial cells maintain normal thyroid function and morphology in vitro, exhibit an absolute requirement for thyroid stimulating hormone (TSH) for proliferation and display radiation dose response characteristics indistinguishable from those of rat thyroid epithelial cells in vivo. In TSH-free medium cells remain in a non-proliferative, yet viable, state for prolonged periods of time and respond to TSH re-stimulation by a return to exponential growth. Flow cytometric analysis using two-step acridine orange (AO) staining revealed an accumulation of cells in the G1 phase of the cell cycle accompanied by a pronounced reduction in red fluorescence (indicative of RNA content) in FRTL-5 cells cultured in the absence of TSH. The response of proliferative and non-proliferative FRTL-5 cells to single dose, split dose and fractionated radiation was compared to determine whether proliferative status was an important response determinant. The response of FRTL-5 cells was not influenced by proliferative status at the time of irradiation. Additionally, dose response was not altered by variable (12 hr-8 days) non-proliferative intervals before or after irradiation. As revealed by split dose experiments, the rate and extent of sublethal damage repair was likewise similar for proliferative and non-proliferative cells. Multifraction experiments employing three fractions separated by 6 hr intervals indicate that non-proliferative FRTL-5 cells completely repair sublethal damage between fractions. These results indicate that the radiation response of FRTL-5 cells is not influenced by the proliferative status of the cells prior to or post-irradiation

  18. Ternary CoS{sub 2}/MoS{sub 2}/RGO electrocatalyst with CoMoS phase for efficient hydrogen evolution

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yan-Ru; Shang, Xiao [State Key Laboratory of Heavy Oil Processing, China University of Petroleum (East China), Qingdao 266580 (China); Gao, Wen-Kun [State Key Laboratory of Heavy Oil Processing, China University of Petroleum (East China), Qingdao 266580 (China); College of Science, China University of Petroleum (East China), Qingdao 266580 (China); Dong, Bin, E-mail: dongbin@upc.edu.cn [State Key Laboratory of Heavy Oil Processing, China University of Petroleum (East China), Qingdao 266580 (China); College of Science, China University of Petroleum (East China), Qingdao 266580 (China); Chi, Jing-Qi; Li, Xiao; Yan, Kai-Li; Chai, Yong-Ming [State Key Laboratory of Heavy Oil Processing, China University of Petroleum (East China), Qingdao 266580 (China); Liu, Yun-Qi, E-mail: liuyq@upc.edu.cn [State Key Laboratory of Heavy Oil Processing, China University of Petroleum (East China), Qingdao 266580 (China); Liu, Chen-Guang [State Key Laboratory of Heavy Oil Processing, China University of Petroleum (East China), Qingdao 266580 (China)

    2017-08-01

    Highlights: • Ternary CoS{sub 2}/MoS{sub 2}/RGO with CoMoS phase as electrocatalyst for HER was prepared. • CoMoS phase have the metallic nature and highly intrinsic activity for HER. • RGO support ensures good distribution of CoMoS phase and enhances the conductivity. • The introduction of CoMoS and RGO may be a novel strategy for efficient HER of MoS{sub 2}. - Abstract: CoMoS phase with metallic character plays crucial role on enhancing the activity of MoS{sub 2} electrocatalysts for hydrogen evolution reaction (HER). However, only Co atoms located in the edges of MoS{sub 2} can create CoMoS phase, so it is a challenge to obtain CoMoS phase with homogeneous distribution limited by the layered MoS{sub 2} and doping method of Co. Herein, we reported a simple one-pot hydrothermal method to prepare novel ternary CoS{sub 2}/MoS{sub 2}/RGO with CoMoS phase for HER using reduced graphene oxide (RGO) as support. XPS proves the formation of CoMoS phase, implying the enhanced activity for HER. RGO support ensures the well distribution of CoMoS phase and enhances the conductivity of CoS{sub 2}/MoS{sub 2}/RGO. Compared to CoS{sub 2}/RGO, MoS{sub 2}/RGO and CoS{sub 2}/MoS{sub 2}, the obtained CoS{sub 2}/MoS{sub 2}/RGO shows superior activity for HER with an onset overpotential of −80 mV (vs. RHE), small Tafel slope of 56 mV dec{sup −1}, high exchange current density of 11.4 μA cm{sup −2} and rigid electrochemical durability. The enhanced performances for HER may be ascribed to the formation of CoMoS phase with high activity and the existence of RGO support with good electrical conductivitys in ternary CoS{sub 2}/MoS{sub 2}/RGO. Therefore, the introduction of CoMoS phase and RGO into MoS{sub 2} could effectively enhance electrocatalytic properties for HER.

  19. NEIL3 Repairs Telomere Damage during S Phase to Secure Chromosome Segregation at Mitosis

    Directory of Open Access Journals (Sweden)

    Jia Zhou

    2017-08-01

    Full Text Available Oxidative damage to telomere DNA compromises telomere integrity. We recently reported that the DNA glycosylase NEIL3 preferentially repairs oxidative lesions in telomere sequences in vitro. Here, we show that loss of NEIL3 causes anaphase DNA bridging because of telomere dysfunction. NEIL3 expression increases during S phase and reaches maximal levels in late S/G2. NEIL3 co-localizes with TRF2 and associates with telomeres during S phase, and this association increases upon oxidative stress. Mechanistic studies reveal that NEIL3 binds to single-stranded DNA via its intrinsically disordered C terminus in a telomere-sequence-independent manner. Moreover, NEIL3 is recruited to telomeres through its interaction with TRF1, and this interaction enhances the enzymatic activity of purified NEIL3. Finally, we show that NEIL3 interacts with AP Endonuclease 1 (APE1 and the long-patch base excision repair proteins PCNA and FEN1. Taken together, we propose that NEIL3 protects genome stability through targeted repair of oxidative damage in telomeres during S/G2 phase.

  20. A retinoblastoma orthologue is a major regulator of S-phase, mitotic, and developmental gene expression in Dictyostelium.

    Directory of Open Access Journals (Sweden)

    Kimchi Strasser

    Full Text Available The retinoblastoma tumour suppressor, Rb, has two major functions. First, it represses genes whose products are required for S-phase entry and progression thus stabilizing cells in G1. Second, Rb interacts with factors that induce cell-cycle exit and terminal differentiation. Dictyostelium lacks a G1 phase in its cell cycle but it has a retinoblastoma orthologue, rblA.Using microarray analysis and mRNA-Seq transcriptional profiling, we show that RblA strongly represses genes whose products are involved in S phase and mitosis. Both S-phase and mitotic genes are upregulated at a single point in late G2 and again in mid-development, near the time when cell cycling is reactivated. RblA also activates a set of genes unique to slime moulds that function in terminal differentiation.Like its mammalian counterpart Dictyostelium, RblA plays a dual role, regulating cell-cycle progression and transcriptional events leading to terminal differentiation. In the absence of a G1 phase, however, RblA functions in late G2 controlling the expression of both S-phase and mitotic genes.

  1. Modifications of S-phase cell distribution in the intestinal crypts after multiple daily fractionation

    Energy Technology Data Exchange (ETDEWEB)

    Becciolini, A; Cremonini, D; Fabbrica, D; Balzi, M [Florence Univ. (Italy). Ist. di Radiologia

    1983-01-01

    The effects obtained by multiple daily fractionation (3 Gy x2 or 3 Gy x2x2) on the distribution of S-phase cells along the crypt of the small intestine were investigated. The frequency of labelled cell distribution was reduced at early intervals; then the proliferating compartment gradually extended to the villus junctions. During recovery labelled cell frequency in the lower half of the crypts returned to control levels, while labelled cells were present in the differentiating area. With lower total dose modifications were milder and, as early as 72 h before exposure, distribution was already similar to controls. Invertase activity showed an initial increase and a higher reduction during acute damage when fractionation with higher doses was used. A lack of return to normal activity was present even 11 days after exposure when, however, the characteristic circadian pattern was observed.

  2. S-phase cell distribution in the small intestine irradiated at different times of the day. 2. Recovery phase

    Energy Technology Data Exchange (ETDEWEB)

    Becciolini, A; Balzi, M; Cremonini, D; Fabbrica, D [Florence Univ. (Italy). Ist. di Radiologia

    1983-01-01

    Modifications occurring during recovery in the small intestine of animals exposed to the same radiation dose given at different times of the day were evaluated. S-phase cell distribution along the crypts and invertase activity were evaluated to ascertain the functional capacity of epithelial cells. In animals killed between 5 and 6 days after exposure, S-phase cell distribution and functional conditions tended towards normality although recovery was not complete. Labelled cells occurred also at villus junctions, demonstrating limitation in size of the differentiating compartment. This was confirmed by reduced activity of the brush border enzymes. Animals irradiated at the end of the dark period recovered more quickly and efficiently. In this group, labelled cell distribution was almost the same as in the controls starting from 120 h, and invertase activity was also closer to the controls than in any other group.

  3. Intravitreal methotrexate infusion for proliferative vitreoretinopathy

    Directory of Open Access Journals (Sweden)

    Sadaka A

    2016-09-01

    Full Text Available Ama Sadaka,1 Robert A Sisk,1–3 James M Osher,1,3 Okan Toygar,4 Melinda K Duncan,5 Christopher D Riemann1,3 1Department of Ophthalmology, University of Cincinnati College of Medicine, 2Department of Opthalmology, Cincinnati Children’s Hospital Medical Center, 3Cincinnati Eye Institute, Cincinnati, OH, USA; 4Department of Ophthalmology, Bahcesehir University Medical Faculty, Istanbul, Turkey; 5Department of Biological Sciences, University of Delaware, Newark, DE, USA Purpose: The purpose of this study was to evaluate intravitreal methotrexate infusion (IMI during pars plana vitrectomy (PPV for retinal detachment in patients with high risk for the development of proliferative vitreoretinopathy (PVR.Methods: Patients presenting with severe recurrent PVR with tractional retinal detachment and/or a history of severe ocular inflammation were treated with IMI. Clinical outcomes were determined from a retrospective medical chart review.Results: Twenty-nine eyes presenting with either tractional retinal detachment and recurrent PVR (n=22 or a history of severe inflammation associated with high PVR risk (n=7 received IMI during PPV. Best-corrected visual acuity at 6 months was ≥20/200 in 19 of 29 eyes (66% and remained stable or improved compared with initial presentation in 24 of 29 eyes (83%. At the last follow-up examination, the retinas of 26 of 29 eyes (90% remained attached after IMI while three eyes required another reattachment procedure. Three additional eyes (10% developed recurrent limited PVR without recurrent RD and were observed. No complications attributable to IMI occurred during a mean follow-up of 27 months.Conclusion: Eyes at high risk for PVR development due to a history of prior PVR or intraocular inflammation had a low incidence of PVR following IMI at the time of PPV for RD repair. No significant safety issues from IMI were observed in this series. Keywords: tractional retinal detachment, recurrent retinal detachment, pars

  4. Proliferative and non-proliferative lesions of the rat and mouse integument.

    Science.gov (United States)

    Mecklenburg, Lars; Kusewitt, Donna; Kolly, Carine; Treumann, Silke; Adams, E Terence; Diegel, Kelly; Yamate, Jyoji; Kaufmann, Wolfgang; Müller, Susanne; Danilenko, Dimitry; Bradley, Alys

    2013-01-01

    The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) project is a joint initiative of the societies of toxicological pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP). Its aim is to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory rodents. A widely accepted international harmonization of nomenclature in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and will provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. The purpose of this publication is to provide a standardized nomenclature for classifying microscopical lesions observed in the integument of laboratory rats and mice. Example colour images are provided for most lesions. The standardized nomenclature presented in this document and additional colour images are also available electronically at http://www.goreni.org. The nomenclature presented herein is based on histopathology databases from government, academia, and industrial laboratories throughout the world, and covers lesions that develop spontaneously as well as those induced by exposure to various test materials. (DOI: 10.1293/tox.26.27S; J Toxicol Pathol 2013; 26: 27S-57S).

  5. Synchronization of S phase in Schizosaccharomyces pombe cells by transient exposure to M-factor pheromone

    DEFF Research Database (Denmark)

    Nielsen, Olaf

    2016-01-01

    A well-characterized S phase, a unicellular lifestyle, and a plethora of mutations in key components of DNA metabolism make fission yeast a particularly attractive system in which to study DNA replication. However, synchronization of passage through a normal S phase has proved challenging. This p....... This protocol describes how combining nitrogen starvation with M-factor mating pheromone treatment presents a highly effective method for synchronizing passage through an ostensibly normal S phase....

  6. Protein oxidation and degradation during proliferative senescence of human MRC-5 fibroblasts.

    Science.gov (United States)

    Sitte, N; Merker, K; von Zglinicki, T; Grune, T

    2000-03-01

    One of the highlights of age-related changes of cellular metabolism is the accumulation of oxidized proteins. The aging process on a cellular level can be treated either as the ongoing proliferation until a certain number of cell divisions is reached (the Hayflick limit) or as the aging of nondividing cells, that is, the age-related changes in cells without proliferation. The present investigation was undertaken to reveal the changes in protein turnover, proteasome activity, and protein oxidation status during proliferative senescence. We were able to demonstrate that the activity of the cytosolic proteasomal system declines dramatically during the proliferative senescence of human MRC-5 fibroblasts. Regardless of the loss in activity, it could be demonstrated that there are no changes in the transcription and translation of proteasomal subunits. This decline in proteasome activity was accompanied by an increased concentration of oxidized proteins. Cells at higher proliferation stages were no longer able to respond with increased degradation of endogenous [(35)S]-Met-radiolabeled proteins after hydrogen peroxide- or quinone-induced oxidative stress. It could be demonstrated that oxidized proteins in senescent human MRC-5 fibroblasts are not as quickly removed as they are in young cells. Therefore, our study demonstrates that the accumulation of oxidized proteins and decline in protein turnover and activity of the proteasomal system are not only a process of postmitotic aging but also occur during proliferative senescence and result in an increased half-life of oxidized proteins.

  7. Bilateral proliferative retinopathy in B-cell acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Devesh Kumawat

    2018-01-01

    Full Text Available A 4-year-old child with B-cell acute lymphoblastic leukemia presented with vitreous hemorrhage due to proliferative retinopathy in both eyes. Pars plana vitrectomy was performed in both eyes to clear nonresolving vitreous hemorrhage after systemic stabilization. Visual recovery was limited by the disc drag in the right eye and subfoveal exudation in the left eye. Etiopathogenesis and management of proliferative retinopathy in acute leukemias are discussed.

  8. Replication of each copy of the yeast 2 micron DNA plasmid occurs during the S phase.

    Science.gov (United States)

    Zakian, V A; Brewer, B J; Fangman, W L

    1979-08-01

    Saccharomyces cerevisiae contains 50-100 copies per cell of a circular plasmid called 2 micron DNA. Replication of this DNA was studied in two ways. The distribution of replication events among 2 micron DNA molecules was examined by density transfer experiments with asynchronous cultures. The data show that 2 micron DNA replication is similar to chromosomal DNA replication: essentially all 2 micron duplexes were of hybrid density at one cell doubling after the density transfer, with the majority having one fully dense strand and one fully light strand. The results show that replication of 2 micron DNA occurs by a semiconservative mechanism where each of the plasmid molecules replicates once each cell cycle. 2 micron DNA is the only known example of a multiple-copy, extrachromosomal DNA in which every molecule replicates in each cell cycle. Quantitative analysis of the data indicates that 2 micron DNA replication is limited to a fraction of the cell cycle. The period in the cell cycle when 2 micron DNA replicates was examined directly with synchronous cell cultures. Synchronization was accomplished by sequentially arresting cells in G1 phase using the yeast pheromone alpha-factor and incubating at the restrictive temperature for a cell cycle (cdc 7) mutant. Replication was monitored by adding 3H-uracil to cells previously labeled with 14C-uracil, and determining the 3H/14C ratio for purified DNA species. 2 micron DNA replication did not occur during the G1 arrest periods. However, the population of 2 micron DNA doubled during the synchronous S phase at the permissive temperature, with most of the replication occurring in the first third of S phase. Our results indicate that a mechanism exists which insures that the origin of replication of each 2 micron DNA molecule is activated each S phase. As with chromosomal DNA, further activation is prevented until the next cell cycle. We propose that the mechanism which controls the replication initiation of each 2 micron DNA

  9. Benign Proliferative Breast Lesions and Risk of Cancer

    Directory of Open Access Journals (Sweden)

    Serap Erel

    2010-06-01

    Full Text Available Benign breast lesions (BBL includes a wide variety of histologic entities, which have been broadly classified into non-proliferative lesions, proliferative lesions without atypia, and hyperplasia with atypia. With the increased use of mammography, more benign lesions are being detected, and in order to estimate the risk of breast cancer for specific histologic categories is of great importance to guide clinical management. Women with proliferative lesions without atypia are at slightly increased risk of subsequent breast cancer, whereas women with proliferative lesions with atypia have a higher risk. The risk is 1.5- 2-fold in women with proliferative lesions without atypia, 4-5-fold in women with proliferative lesions with atypia, and 8-10 fold in women with ductal carcinoma in situ. Age at diagnosis of BBL, menopausal status, family history of breast cancer in a first-degree relative, and time since BBL diagnosis on risk of breast cancer are important for risk evaluation. [Archives Medical Review Journal 2010; 19(3.000: 155-167

  10. Epstein-Barr virus BGLF4 kinase retards cellular S-phase progression and induces chromosomal abnormality.

    Directory of Open Access Journals (Sweden)

    Yu-Hsin Chang

    Full Text Available Epstein-Barr virus (EBV induces an uncoordinated S-phase-like cellular environment coupled with multiple prophase-like events in cells replicating the virus. The EBV encoded Ser/Thr kinase BGLF4 has been shown to induce premature chromosome condensation through activation of condensin and topoisomerase II and reorganization of the nuclear lamina to facilitate the nuclear egress of nucleocapsids in a pathway mimicking Cdk1. However, the observation that RB is hyperphosphorylated in the presence of BGLF4 raised the possibility that BGLF4 may have a Cdk2-like activity to promote S-phase progression. Here, we investigated the regulatory effects of BGLF4 on cell cycle progression and found that S-phase progression and DNA synthesis were interrupted by BGLF4 in mammalian cells. Expression of BGLF4 did not compensate Cdk1 defects for DNA replication in S. cerevisiae. Using time-lapse microscopy, we found the fate of individual HeLa cells was determined by the expression level of BGLF4. In addition to slight cell growth retardation, BGLF4 elicits abnormal chromosomal structure and micronucleus formation in 293 and NCP-TW01 cells. In Saos-2 cells, BGLF4 induced the hyperphosphorylation of co-transfected RB, while E2F1 was not released from RB-E2F1 complexes. The E2F1 regulated activities of the cyclin D1 and ZBRK1 promoters were suppressed by BGLF4 in a dose dependent manner. Detection with phosphoamino acid specific antibodies revealed that, in addition to Ser780, phosphorylation of the DNA damage-responsive Ser612 on RB was enhanced by BGLF4. Taken together, our study indicates that BGLF4 may directly or indirectly induce a DNA damage signal that eventually interferes with host DNA synthesis and delays S-phase progression.

  11. Vitreous vascular endothelial growth factor concentrations in proliferative diabetic retinopathy versus proliferative vitreoretinopathy.

    Science.gov (United States)

    Citirik, Mehmet; Kabatas, Emrah Utku; Batman, Cosar; Akin, Kadir Okhan; Kabatas, Naciye

    2012-01-01

    To assess vitreous vascular endothelial growth factor (VEGF) concentrations in proliferative diabetic retinopathy (PDR) in comparison to proliferative vitreoretinopathy (PVR). Vitreous samples were collected from 69 eyes of 69 patients with traumatic lens dislocation (n = 10), grade B PVR with rhegmatogenous retinal detachment (n = 13), grade C PVR with rhegmatogenous retinal detachment (n = 14), PDR with vitreous hemorrhage (n = 18), and PDR with vitreous hemorrhage and tractional retinal detachment (n = 14). Vitreous fluid samples were obtained at vitrectomy, and the levels of VEGF were measured by enzyme-linked immunosorbent assay. The mean vitreous level of VEGF was 15.14 ± 5.22 pg/ml in eyes with grade B PVR, 99.15 ± 38.58 pg/ml in eyes with grade C PVR, 4,534.01 ± 1,193.28 pg/ml in eyes with vitreous hemorrhage secondary to PDR, 5,157.29 ± 969.44 pg/ml in eyes with vitreous hemorrhage and tractional retinal detachment secondary to PDR, and 16.19 ± 5.76 pg/ml in eyes of the control group with traumatic lens dislocation. Vitreous VEGF concentrations were significantly higher in the patients with grade C PVR, PDR with vitreous hemorrhage and PDR with vitreous hemorrhage and tractional retinal detachment in comparison to the control patients (p < 0.05). A significant alteration was not observed in patients with grade B PVR (p = 0.55). Vitreous VEGF concentrations are increased in PDR and grade C PVR. The high VEGF concentrations could suggest a possible effect of VEGF on advanced PVR. Copyright © 2011 S. Karger AG, Basel.

  12. uPAR EXPRESSION IN CANINE NORMAL PROSTATE AND WITH PROLIFERATIVE DISORDERS

    Directory of Open Access Journals (Sweden)

    Mariana Rodrigues Faleiro

    2013-06-01

    Full Text Available Prostatic lesions such as prostatic intraepithelial neoplasia (PIN and proliferative inflammatory atrophy (PIA are studied in human and canine species due to their malignance potential. The plasminogen activator (PA system has been suggested to play a central role in cell adhesion, angiogenesis, inflammation, and tumor invasion. The urokinase-type plasminogen activator receptor (uPAR is a component of the PA, with a range of expression in tumor and stromal cells. In this study, uPAR expression in both canine normal prostates and with proliferative disorders (benign prostatic hyperplasia-BPH, proliferative inflammatory atrophy-PIA, prostatic intraepithelial neoplasia-PIN, and carcinoma-PC was evaluated by immunohistochemistry in a tissue microarray (TMA slide to establish the role of this enzyme in extracellular matrix (ECM remodeling and in the processes of tissue invasion. A total of 298 cores and 355 diagnoses were obtained, with 36 (10.1% normal prostates, 46 (13.0% with BPH, 128 (36.1% with PIA, 74 (20.8% with PIN and 71 (20.0% with PC. There is variation in the expression of uPAR in canine prostate according to the lesion, with lower expression in normal tissue and with BPH, and higher expression in tissue with PIA, PIN and PC. The high expression of uPAR in inflammatory and neoplastic microenvironment indicates increased proteolytic activity in canine prostates with PIA, PIN, and PC.

  13. Extracellular matrix-dependent myosin dynamics during G1-S phase cell cycle progression in hepatocytes

    International Nuclear Information System (INIS)

    Bhadriraju, Kiran; Hansen, Linda K.

    2004-01-01

    Cell spreading and proliferation are tightly coupled in anchorage-dependent cells. While adhesion-dependent proliferation signals require an intact actin cytoskeleton, and some of these signals such as ERK activation have been characterized, the role of myosin in spreading and cell cycle progression under different extracellular matrix (ECM) conditions is not known. Studies presented here examine changes in myosin activity in freshly isolated hepatocytes under ECM conditions that promote either proliferation (high fibronectin density) or growth arrest (low fibronectin density). Three different measures were obtained and related to both spreading and cell cycle progression: myosin protein levels and association with cytoskeleton, myosin light chain phosphorylation, and its ATPase activity. During the first 48 h in culture, corresponding with transit through G1 phase, there was a six-fold increase in both myosin protein levels and myosin association with actin cytoskeleton. There was also a steady increase in myosin light chain phosphorylation and ATPase activity with spreading, which did not occur in non-spread, growth-arrested cells on low density of fibronectin. Myosin-inhibiting drugs blocked ERK activation, cyclin D1 expression, and S phase entry. Overexpression of the cell cycle protein cyclin D1 overcame both ECM-dependent and actomyosin-dependent inhibition of DNA synthesis, suggesting that cyclin D1 is a key event downstream of myosin-dependent cell cycle regulation

  14. Mechanisms of Inflammation in Proliferative Vitreoretinopathy: From Bench to Bedside

    Directory of Open Access Journals (Sweden)

    Stavros N. Moysidis

    2012-01-01

    Full Text Available Proliferative vitreoretinopathy (PVR is a vision-threatening disease and a common complication of surgery to correct rhegmatogenous retinal detachment (RRD. Several models of the pathogenesis of this disease have been described with some of these models focusing on the role of inflammatory cells and other models focusing on the role of growth factors and cytokines in the vitreous which come into contact with intraretinal and retinal pigment epithelial cells. New experiments have shed light on the pathogenesis of PVR and offer promising avenues for clinical intervention before PVR develops. One such target is the indirect pathway of activation of platelet-derived growth factor receptor alpha (PDGRα, which plays an important role in PVR. Clinical trials assessing the efficacy of 5-fluorouracil (5-FU and low-molecular-weight heparin (LMWH, daunorubicin, and 13-cis-retinoic acid, among other therapies, have yielded mixed results. Here we review inflammatory and other mechanisms involved in the pathogenesis of PVR, we highlight important clinical trials, and we discuss how findings at the bench have the potential to be translated to the bedside.

  15. Cell flux through S phase in the mouse duodenal epithelium determined by cell sorting and radioautography

    International Nuclear Information System (INIS)

    Bjerknes, M.; Cheng, H.

    1982-01-01

    An accumulation of cells in early S phase was observed in normal mouse duodenal epithelium studied with flow cytometry. To determine if this accumulation of cells was the result of a lower rate of DNA synthesis, animals were given a single injection of 3 H-thymidine and the epithelium collected one hour later. The epithelium was processed for flow cytometry. Seven sort windows were established in different portions of the DNA histogram. Cells from each window were sorted onto glass slides that were then processed for radioautography. The number of silver grains over the nuclei of each sorted population was counted. It was found that cells in early S phase had significantly fewer grains over their nuclei than did mid- or late-S phase cells. We conclude that the accumulation of cells in early S phase is due, at least in part, to a lower rate of DNA synthesis in early than in mid or late S phase

  16. Multi-lobulation of the nucleus in prolonged S phase by nuclear expression of Chk tyrosine kinase.

    Science.gov (United States)

    Nakayama, Yuji; Yamaguchi, Naoto

    2005-04-01

    Chk tyrosine kinase phosphorylates Src-family tyrosine kinases and suppresses their kinase activity. We recently showed that Chk localizes to the nucleus as well as the cytoplasm and inhibits cell proliferation. To investigate the role of nuclear Chk in proliferation, various Chk mutants were constructed and expressed. Nuclear localization of Chk-induced dynamic multi-lobulation of the nucleus and prolonged S phase of the cell cycle. The N-terminal domain of Chk and a portion of its kinase domain but not the kinase activity were responsible for induction of the multi-lobulation. Cell sorting analysis revealed that nuclear multi-lobulated cells were enriched in late S phase. Multi-lobulated nuclei were surrounded with lamin B1 that was particularly concentrated in concave regions of the nuclei. Furthermore, treatment with nocodazole or taxol disrupted multi-lobulation of the nucleus. These results suggest that nuclear multi-lobulation in late S phase, which is dependent on polymerization and depolymerization of microtubules, may be involved in nuclear Chk-induced inhibition of proliferation.

  17. Multi-lobulation of the nucleus in prolonged S phase by nuclear expression of Chk tyrosine kinase

    International Nuclear Information System (INIS)

    Nakayama, Yuji; Yamaguchi, Naoto

    2005-01-01

    Chk tyrosine kinase phosphorylates Src-family tyrosine kinases and suppresses their kinase activity. We recently showed that Chk localizes to the nucleus as well as the cytoplasm and inhibits cell proliferation. To investigate the role of nuclear Chk in proliferation, various Chk mutants were constructed and expressed. Nuclear localization of Chk-induced dynamic multi-lobulation of the nucleus and prolonged S phase of the cell cycle. The N-terminal domain of Chk and a portion of its kinase domain but not the kinase activity were responsible for induction of the multi-lobulation. Cell sorting analysis revealed that nuclear multi-lobulated cells were enriched in late S phase. Multi-lobulated nuclei were surrounded with lamin B1 that was particularly concentrated in concave regions of the nuclei. Furthermore, treatment with nocodazole or taxol disrupted multi-lobulation of the nucleus. These results suggest that nuclear multi-lobulation in late S phase, which is dependent on polymerization and depolymerization of microtubules, may be involved in nuclear Chk-induced inhibition of proliferation

  18. Possible mechanisms for arsenic-induced proliferative diseases

    Energy Technology Data Exchange (ETDEWEB)

    Wetterhahn, K.E.; Dudek, E.J.; Shumilla, J.A. [Dartmouth College and Medical School, Hanover, NH (United States)] [and others

    1996-12-31

    Possible mechanisms for cardiovascular diseases and cancers which have been observed on chronic exposure to arsenic have been investigated. We tested the hypothesis that nonlethal levels of arsenic are mitogenic, cause oxidative stress, increase nuclear translocation of trans-acting factors, and increase expression of genes involved in proliferation. Cultured porcine vascular (from aorta) endothelial cells were used as a model cell system to study the effects of arsenic on the target cells for cardiovascular diseases. Treatment of postconfluent cell cultures with nonovertly toxic concentrations of arsenite increased DNA synthesis, similar to the mitogenic response observed with hydrogen peroxide. Within 1 hour of adding noncytotoxic concentrations of arsenite, cellular levels of oxidants increased relative to control levels, indicating that arsenite promotes cellular oxidations. Arsenite treatment increased nuclear translocation of NF-{kappa}B, an oxidative stress-responsive transcription factor, in a manner similar to that observed with hydrogen peroxide. Pretreatment of intact cells with the antioxidants N-acetylcysteine and dimethylfumarate prevented the arsenite-induced increases in cellular oxidant formation and NF-KB translocation. Arsenite had little or no effect on binding of NF-KB to its DNA recognition sequence in vitro, indicating that it is unlikely that arsenite directly affects NF-KB. The steady-state mRNA levels of intracellular adhesion molecule and urokinase-like plasminogen activator, genes associated with the active endothelial phenotype in arteriosclerosis and cancer metastasis, were increased by nontoxic concentrations of arsenite. These data suggest that arsenite promotes proliferative diseases like heart disease and cancer by activating oxidant-sensitive endothelial cell signaling and gene expression. It is possible that antioxidant therapy would be useful in preventing arsenic-induced cardiovascular disease and cancer.

  19. Proliferative changes in nonpalpable breast lesions detected by mammography

    International Nuclear Information System (INIS)

    Vega, A.; Delgado, A.; Ortega, E.; Garijo, F.; Mosquera, J.; Sogo, C.; Alvarez, A.

    2000-01-01

    To analyze retrospectively the radiological findings in nonpalpable breast lesions detected by mammography that lead to the performance of surgical biopsy, resulting in a histological diagnosis of proliferative breast disease with and without atypia. From two Spanish hospitals, 421 women with 429 biopsies indicative of the presence of proliferative breast disease with and without atypia were selected out of a total of 1252 surgical biopsies in nonpalpable lesions that proved to be benign. Age, personal and familial history of breast cancer, reason for requesting the mammography and radiological findings that had indicated the need for surgical biopsy were recorded for each patient. The diagnosis was proliferative breast disease (epithelial hyperplasia) in 347 women with 354 biopsies and atypical hyperplasia in the remaining 74 women with 75 biopsies, representing 28% and 6%, respectively, of the 1252 biopsies of lesions found to be benign. In 221 of the 354 cases of epithelial hyperplasia (62%) and 45 of the 75 cases of atypical hyperplasia (60%), the presence of calcifications was the most common radiological findings leading to biopsy (p<0.05). Parenchymal distortion, with or without calcifications, was the second most common radiological sign. The histological study revealed a close relationship between these proliferative events and radial scars. Calcifications are the radiological finding that most frequently indicate the need for surgical biopsy in nonpalpable lesions that results in a diagnosis of proliferative breast disease with and without atypia. (Author) 12 refs

  20. Mitogenic Activity of a Water-Soluble Adjuvant (Bu-WSA) Obtained from Bacterionema matruchotii: IV. Synergistic Effects of Bu-WSA on Concanavalin A-Induced Proliferative Response of Human Peripheral Blood Lymphocytes.

    Science.gov (United States)

    Nitta, Toshimasa; Okumura, Seiichi; Tsushi, Masao; Nakano, Masayasu

    1982-07-01

    Butanol-extracted water-soluble adjuvant (Bu-WSA) obtained from Bacterionema matruchotii was cultured with peripheral blood mononuclear cells (PBM) in the presence of sub- and/or supra-optimal mitogenic concentrations of concanavalin A (Con A). The addition of Bu-WSA resulted in increased tritiated thymidine incorporation above that produced by Con A alone. Bu-WSA by itself is not mitogenic for PBM and in fact produced a decrease in thymidine uptake compared to the control. We investigated the response of subpopulation(s) of PBM to Bu-WSA, Con A and a mixture of Bu-WSA and Con A. Separation of PBM into purified T cells, B cells and macrophages showed that cell-cell cooperation of T cells with B cells or macrophages is necessary for the observed synergistic effect of Bu-WSA with Con A. A marked increase in thymidine incorporation by the mixture of T and B cell populations occurred, while only a small amount of thymidine was incorporated when the B cell population was absent. Mitomycin treatment revealed that the response could be ascribed to the T-cell response with a B-cell helper effect. Moreover, Con A and Bu-WSA appeared to act on the same T cell population. This model may provide unique information about the activation of human peripheral blood T cells compared with the activation of these cells by other mitogens. © owned by Center for Academic Publications Japan (Publisher).

  1. Mitogenic activity of a water-soluble adjuvant (Bu-WSA) obtained from Bacterionema matruchotii. IV. Synergistic effects of Bu-WSA on Concanavalin A-induced proliferative response of human peripheral blood lymphocytes.

    Science.gov (United States)

    Nitta, T; Okumura, S; Tsushi, M; Nakano, M

    1982-01-01

    Butanol-extracted water-soluble adjuvant (Bu-WSA) obtained from Bacterionema matruchotii was cultured with peripheral blood mononuclear cells (PBM) in the presence of sub- and/or supra-optimal mitogenic concentrations of concanavalin A (Con A). The addition of Bu-WSA resulted in increased tritiated thymidine incorporation above that produced by Con A alone. Bu-WSA by itself is not mitogenic for PBM and in fact produced a decrease in thymidine uptake compared to the control. We investigated the response of subpopulation(s) of PBM to Bu-WSA, Con A and a mixture of Bu-WSA and Con A. Separation of PBM into purified T cells, B cells and macrophages showed that cell-cell cooperation of T cells with B cells or macrophages is necessary for the observed synergistic effect of Bu-WSA with Con A. A marked increase in thymidine incorporation by the mixture of T and B cell populations occurred, while only a small amount of thymidine was incorporated when the B cell population was absent. Mitomycin treatment revealed that the response could be ascribed to the T-cell response with a B-cell helper effect. Moreover, Con A and Bu-WSA appeared to act on the same T cell population. This model may provide unique information about the activation of human peripheral blood T cells compared with the activation of these cells by other mitogens.

  2. Anti-proliferative effect of RCE-4 from Reineckia carnea on human cervical cancer HeLa cells by inhibiting the PI3K/Akt/mTOR signaling pathway and NF-κB activation.

    Science.gov (United States)

    Bai, Caihong; Yang, Xiaojiao; Zou, Kun; He, Haibo; Wang, Junzhi; Qin, Huilin; Yu, Xiaoqin; Liu, Chengxiong; Zheng, Juyan; Cheng, Fan; Chen, Jianfeng

    2016-06-01

    Cervical cancer is the second leading cause of cancer deaths in women worldwide. In recent years, the studies find that inflammation is a critical component of tumor progression, and the ideal therapeutic methods should be aimed at the inflammation reaction triggers. (1β,3β,5β,25S)-spirostan-1,3-diol1-[α-L-rhamnopyranosyl-(1 → 2)-β-D-xylopyranoside] (RCE-4) was the main active composition of Reineckia carnea (Andr.) Kunth. It significantly induced apoptosis in cervical cancer Caski cells through the mitochondrial pathway in our previous studies; however, its underlying mechanism remains poorly understood. This study aimed to further evaluate the effect of RCE-4 on human cervical cancer HeLa cells. Based on this observation, we investigated the anti-cervical cancer effect of RCE-4 by modulating phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway, nuclear factor-kappa B (NF-κB) activation, and inflammation-related key factors in HeLa cells. The results indicated that the HeLa cell was the most sensitive with an IC50 of 7.01 μM; RCE-4 significantly promoted the release of cellular lactate dehydrogenase (LDH); increased DNA fragmentation and apoptosis; reduced PI3K, Akt, mTOR, and NF-κBp65 phosphorylation levels; increased the Bax and cleaved poly (ADP-ribose) polymerase (PARP) protein levels; suppressed Bcl-2 protein expression; elevated the Bax/Bcl-2 expression ratio; and decreased the interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) mRNA expressions in HeLa cells in a concentration-dependent manner. These findings suggest that RCE-4 exerted beneficially anti-cervical cancer effect on HeLa cells, mainly inhibiting PI3K/Akt/mTOR signaling pathway phosphorylation and NF-κB activation, promoting HeLa cell apoptosis. Graphical abstract Anti-tumor effect of RCE-4 on HeLa cells.

  3. Proliferative, necrotizing and crescentic immune complex-mediated glomerulonephritis in a cat

    Directory of Open Access Journals (Sweden)

    Carolyn Gross

    2015-09-01

    Full Text Available Case Summary A 5-year-old cat was examined for vomiting and anorexia of 2 days’ duration. Azotemia, hyperphosphatemia and hypoalbuminemia were the main biochemical findings. Serial analyses of the urine revealed isosthenuria, proteinuria and eventual glucosuria. Hyperechoic perirenal fat was detected surrounding the right kidney by ultrasonography. Histopathologic evaluation of ante-mortem ultrasound-guided needle biopsies of the right kidney was consistent with proliferative, necrotizing and crescentic glomerulonephritis with fibrin thrombi, proteinaceous and red blood cell casts, and moderate multifocal chronic-active interstitial nephritis. Owing to a lack of clinical improvement, the cat was eventually euthanized. Post-mortem renal biopsies were processed for light microscopy, transmission electron microscopy and immunofluorescence. This revealed severe focal proliferative and necrotizing glomerulonephritis with cellular crescent formation, podocyte injury and secondary segmental sclerosis. Ultrastructural analysis revealed scattered electron-dense deposits in the mesangium, and immunofluorescence demonstrated positive granular staining for λ light chains, consistent with immune complex-mediated glomerulonephritis. Severe diffuse acute tubular epithelial injury and numerous red blood cell casts were also seen. Relevance and novel information To our knowledge, this is the first report of naturally occurring proliferative, necrotizing and crescentic immune complex glomerulonephritis in a cat.

  4. Proliferative signaling initiated in ACTH receptors

    Directory of Open Access Journals (Sweden)

    C.F.P. Lotfi

    2000-10-01

    Full Text Available This article reviews recent results of studies aiming to elucidate modes of integrating signals initiated in ACTH receptors and FGF2 receptors, within the network system of signal transduction found in Y1 adrenocortical cells. These modes of signal integration should be central to the mechanisms underlying the regulation of the G0->G1->S transition in the adrenal cell cycle. FGF2 elicits a strong mitogenic response in G0/G1-arrested Y1 adrenocortical cells, that includes a rapid and transient activation of extracellular signal-regulated kinases-mitogen-activated protein kinases (ERK-MAPK (2 to 10 min, b transcription activation of c-fos, c-jun and c-myc genes (10 to 30 min, c induction of c-Fos and c-Myc proteins by 1 h and cyclin D1 protein by 5 h, and d onset of DNA synthesis stimulation within 8 h. ACTH, itself a weak mitogen, interacts with FGF2 in a complex manner, blocking the FGF2 mitogenic response during the early and middle G1 phase, keeping ERK-MAPK activation and c-Fos and cyclin D1 induction at maximal levels, but post-transcriptionally inhibiting c-Myc expression. c-Fos and c-Jun proteins are mediators in both the strong and the weak mitogenic responses respectively triggered by FGF2 and ACTH. Induction of c-Fos and stimulation of DNA synthesis by ACTH are independent of PKA and are inhibited by the PKC inhibitor GF109203X. In addition, ACTH is a poor activator of ERK-MAPK, but c-Fos induction and DNA synthesis stimulation by ACTH are strongly inhibited by the inhibitor of MEK1 PD98059.

  5. Esculetin exerts anti-proliferative effects against non-small-cell lung carcinoma by suppressing specificity protein 1 in vitro.

    Science.gov (United States)

    Lee, Ra H; Jeon, Young-Joo; Cho, Jin H; Jang, Jeong-Yun; Kong, Il-Keun; Kim, Seok-Ho; Kim, MinSeok S; Chung, Hak-Jae; Oh, Keon B; Park, Seon-Min; Shin, Jae-Cheon; Seo, Jae-Min; Ko, Sungho; Shim, Jung-Hyun; Chae, Jung-Il

    2017-01-01

    Esculetin, a coumarin derivative, is a phenolic compound isolated from Artemisia capillaris, Citrus limonia, and Euphorbia lathyris. Although it has been reported to have anti-inflammatory, anti-oxidant, and anti-proliferative activities in several human cancers, its anti-proliferative activity against non-small-cell lung carcinoma (NSCLC) and the molecular mechanisms involved have not been adequately elucidated. In this study, we used two NSCLC cell lines (NCI-H358 and NCI-H1299) to investigate the anti-proliferative activity and apoptotic effect of esculetin. Our data showed that esculetin-treated cells exhibited reduced proliferation and apoptotic cell morphologies. Intriguingly, the transcription factor specificity protein 1 (Sp1) was significantly suppressed by esculetin in a dose- and time-dependent manner. Furthermore, the levels of p27 and p21, two key regulators of the cell cycle, were up-regulated by the esculetin-mediated down-regulation of Sp1; the level of a third cell-cycle regulator, survivin, was decreased, resulting in caspase-dependent apoptosis. Therefore, we conclude that esculetin could be a potent anti-proliferative agent in patients with NSCLC.

  6. Anti-proliferative effect of Moringa oleifera Lam (Moringaceae) leaf ...

    African Journals Online (AJOL)

    Purpose: To investigate the in vitro anti-proliferative effect and mechanism of action of Moringa oleifera Lam. leaf extract on human colon carcinoma HCT116 cell line. Methods: M. oleifera leaves were extracted with methanol. It was fractionated by Sephadex LH-20 column chromatography. Several fractions were identified ...

  7. Treatment and prevention of porcine proliferative enteropathy with oral tiamulin.

    Science.gov (United States)

    McOrist, S; Smith, S H; Shearn, M F; Carr, M M; Miller, D J

    The effect of an oral treatment or prevention programme, incorporating the antibiotic tiamulin, on the development of proliferative enteropathy in experimentally challenged pigs was studied. Twenty weaner pigs were challenged orally with a virulent inoculum of Lawsonia intracellularis strain LR189/5/83, a British isolate of the causative agent of porcine proliferative enteropathy, and seven control pigs were dosed with a buffer solution. Seven of the 20 challenged pigs were left untreated; they gained less weight than the controls and three of them developed mild to moderate diarrhoea two weeks after the challenge. All seven developed lesions, six visible grossly, of proliferative enteropathy, and numerous intracellular L intracellularis were detected in sections of the intestines examined three weeks after the challenge. To test a 'prevention' dosing strategy for tiamulin, six of the challenged pigs were dosed orally with 50 ppm tiamulin, incorporated in a 2 per cent stabilised premix, given from two days before the challenge until they were euthanased. To test a 'treatment' strategy, the remaining group of seven challenged pigs were dosed orally with 150 ppm tiamulin given in the premix from seven days after challenge until they were euthanased. All the control pigs and the 13 pigs treated with tiamulin, either before or after challenge, remained clinically normal and had no specific lesions of proliferative enteropathy in sections of the intestines examined post mortem.

  8. Proliferative verrucous leukoplakia; a critical appraisal of the diagnostic criteria

    NARCIS (Netherlands)

    Carrard, V.C.; Brouns, E.R.E.A.; van der Waal, I.

    2013-01-01

    Since its introduction in the literature in 1985, the term proliferative verrucous leukoplakia (PVL) has been the subject of an ongoing discussion with regard to its definition. Widespread or multifocal occurrence of oral leukoplakia is not just synonymous to PVL. In the present treatise the

  9. Dutch guidelines for diagnosis and therapy of proliferative lupus nephritis

    NARCIS (Netherlands)

    van Tellingen, A.; Voskuyl, A. E.; Vervloet, M. G.; Bijl, M.; de Sevaux, R. G. L.; Berger, S. P.; Derksen, R. H. W. M.; Berden, J. H. M.

    Proliferative lupus nephritis is a strong predictor of morbidity and mortality in patients with systemic lupus erythematosus. Despite improvements in the management of lupus nephritis, a significant number of the patients do not respond to immunosuppressive therapy and progress to end-stage renal

  10. The subunits of the S-phase checkpoint complex Mrc1/Tof1/Csm3: dynamics and interdependence.

    Science.gov (United States)

    Uzunova, Sonya Dimitrova; Zarkov, Alexander Stefanov; Ivanova, Anna Marianova; Stoynov, Stoyno Stefanov; Nedelcheva-Veleva, Marina Nedelcheva

    2014-01-01

    The S-phase checkpoint aims to prevent cells from generation of extensive single-stranded DNA that predisposes to genome instability. The S. cerevisiae complex Tof1/Csm3/Mrc1 acts to restrain the replicative MCM helicase when DNA synthesis is prohibited. Keeping the replication machinery intact allows restart of the replication fork when the block is relieved. Although the subunits of the Tof1/Csm3/Mrc1 complex are well studied, the impact of every single subunit on the triple complex formation and function needs to be established. This work studies the cellular localization and the chromatin binding of GFP-tagged subunits when the complex is intact and when a subunit is missing. We demonstrate that the complex is formed in cell nucleus, not the cytoplasm, as Tof1, Csm3 and Mrc1 enter the nucleus independently from one another. Via in situ chromatin binding assay we show that a Tof1-Csm3 dimer formation and chromatin binding is required to ensure the attachment of Mrc1 to chromatin. Our study indicates that the translocation into the nucleus is not the process to regulate the timing of chromatin association of Mrc1. We also studied the nuclear behavior of Mrc1 subunit in the process of adaptation to the presence hydroxyurea. Our results indicate that after prolonged HU incubation, cells bypass the S-phase checkpoint and proceed throughout the cell cycle. This process is accompanied by Mrc1 chromatin detachment and Rad53 dephosphorylation. In S. cerevisiae the subunits of the S-phase checkpoint complex Mrc1/Tof1/Csm3 independently enter the cell nucleus, where a Tof1-Csm3 dimer is formed to ensure the chromatin binding of Mrc1 and favor DNA replication and S-phase checkpoint fork arrest. In the process of adaptation to the presence of hydroxyurea Mrc1 is detached from chromatin and Rad53 checkpoint activity is diminished in order to allow S-phase checkpoint escape and completion of the cell cycle.

  11. Phytoestrogen bakuchiol exhibits in vitro and in vivo anti-breast cancer effects by inducing S phase arrest and apoptosis

    Directory of Open Access Journals (Sweden)

    Li eLi

    2016-05-01

    Full Text Available Phytoestrogen has been proposed as an alternative to hormone replacement therapy, which has been demonstrated to promote a high risk of breast cancer. However, the effect of phytoestrogen on breast cancer development has not been fully understood. Bakuchiol is an active ingredient of a traditional Chinese herbal medicine Fructus Psoraleae, the dried ripe fruit of Psoralea corylifolia L. (Fabaceae. The in vitro and in vivo estrogenic activities and anti-breast cancer effects of bakuchiol have not been well studied. We found that bakuchiol induced the GFP expression in transgenic medaka (Oryzias melastigma, Tg, Chg:GFP dose-dependently (0-1 µg/ml, demonstrating its in vivo estrogenic activity. Low dose of bakuchiol (1 µg/ml induced the cell proliferation and ERα expression in MCF-7 cells, which could be blocked by the antiestrogen ICI 182780, suggesting the in vitro estrogenic activity of bakuchiol. Our data indicated that high doses of bakuchiol (>2 µg/ml inhibited breast cancer cell growth, with a stronger antiproliferative effect than resveratrol, a widely studied analogue of bakuchiol. High doses of bakuchiol (4 µg/ml, 7 µg/ml and 10 µg/ml were used for the further in vitro anti-breast cancer studies. Bakuchiol induced ERβ expression and suppressed ERα expression in MCF-7 cells. It also induced S phase arrest in both MCF-7 and MDA-MB-231 cells, which could be rescued by caffeine. Knock-down of p21 also marginally rescued S phase arrest in MCF-7 cells. The S phase arrest was accompanied by the upregulation of ATM, P-Cdc2 (Tyr15, Myt1, P-Wee1 (Ser642, p21 and Cyclin B1, suggesting that blocking of Cdc2 activation may play an important role in bakuchiol-induced S phase arrest. Furthermore, bakuchiol induced cell apoptosis and disturbed mitochondrial membrane potential in MCF-7 cells. The bakuchiol-induced apoptosis was associated with increased expression of Caspase family and Bcl-2 family proteins, suggesting that bakuchiol may induce

  12. In vitro Anti-proliferative and Apoptotic Activities of Eurycoma ...

    African Journals Online (AJOL)

    HP

    Results: F1 showed unremarkable growth inhibition rate while F2 and F3 ... Treatment with F2 and F3 (100 µg/ml) for 96 h increased cell death from 3.3 to 95.5 and 76.3 %, ... three decades [4]. ... [9], breast [10] and cervical cancers [11] have ... 60 was obtained from American Type Culture ... acted as a negative control.

  13. New cyclic peptides with osteoblastic proliferative activity from Dianthus superbus.

    Science.gov (United States)

    Tong, Yun; Luo, Jian-Guang; Wang, Rui; Wang, Xiao-Bing; Kong, Ling-Yi

    2012-03-01

    Two new cyclic peptides, dianthins G-H (1 and 2), together with the known dianthin E (3), were isolated from the traditional Chinese medicinal plant Dianthus superbus. The sequences of cyclic peptides 1 and 2 were elucidated as cyclo (-Gly(1)-Pro(2)-Leu(3)-Thr(4)-Leu(5)-Phe(6)-) and cyclo (-Gly(1)-Pro(2)-Val(3)-Thr(4)-Ile(5)-Phe(6)-), on the basis of ESI tandem mass fragmentation analysis, extensive 2D NMR methods and X-ray diffraction. The isolated three compounds all increase proliferation of MC3T3-E1 cells in vitro using MTT method. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Antioxidant and Anti-proliferative Activities of Flavonoids from ...

    African Journals Online (AJOL)

    significant growth inhibitory effect on RKO cells with IC50 of 39.08 μmol/L and 17.68 μmol/L, respectively ..... YJ.. Essential oil from rhizomes of Ligusticum chuanxiong induces apoptosis in hypertrophic scar ... Liu H, Mou Y, Zhao J, Wang J, Zhou L, Wang M, Wang. D, Han J, Yu Z, Yang F. Flavonoids from Halostachys.

  15. Clastogenic adaption of Vicia faba root tip meristem cells after consecutive treatments with S-phase dependent and S-phase independent agents

    International Nuclear Information System (INIS)

    Heindorff, K.; Schubert, I.; Rieger, R.; Michaelis, A.

    1987-01-01

    Pretreatment of Vicia faba root tip meristems with low doses of S-phase independent clastogens, such as X-rays or bleomycin, prior to a high (challenge) dose of S-phase dependent clastogens, such as alkylating agents (TEM, Trenimon) or the pyridazine derivative MH, led to decreased challenge treatment-induced aberration frequencies, i.e., clastogenic adaptation. Using the inverse treatment sequence bleomycin and MH proved to be able to substitute for each other in provoking clastogenic (cross) adaptation while bleomycin and alkylating agents were unable to do so. The data support the assumption of inducible cellular functions that become triggered by low clastogen doses and additionally describe some particular properties of bleomycin when used for conditioning. Bleomycin proved to be capable to exert protection independent of the agent used for challenge treatment. (author)

  16. Different proliferative capacity of lung fibroblasts obtained from control subjects and patients with emphysema

    NARCIS (Netherlands)

    Noordhoek, JA; Postma, DS; Chong, LL; Vos, JTWM; Kauffman, HF; Timens, W; van Straaten, JFM

    2003-01-01

    To characterize the possible role of a dysregulated proliferative capacity of pulmonary fibroblasts in insufficient tissue repair in lungs from patients with pulmonary emphysema, the authors undertook in vitro proliferative studies with pulmonary fibroblasts obtained from lung tissue of patients

  17. Rehabilitation effect of oral drug on the patients with proliferative diabetic retinopathy after operation

    Directory of Open Access Journals (Sweden)

    Wei Zu

    2014-08-01

    Full Text Available AIM:To observe the rehabilitation effect of oral Calcium Dobesilate Tablets and Epalrestat Tablets on the proliferative diabetic retinopathy(PDRpatients after vitrectomy.METHODS: After vitrectomy patients informed consent, they were randomly divided into intervention group and control group, and their vision and fundus were followed up and compared at 2d; 3, 6, 9, 12mo after operation.RESULTS: The recovery and sustainment of visual acuity, and subsiding of macular edema of patients in drug intervention group were significantly better than that in control group.CONCLUSION: PDR patients after vitrectomy actively orally take medicine to protect retina, which can improve vision and fundus rehabilitation.

  18. Chemical analyses of wasp-associated streptomyces bacteria reveal a prolific potential for natural products discovery

    DEFF Research Database (Denmark)

    Poulsen, Michael; Oh, Dong-Chan; Clardy, Jon

    2011-01-01

    and solitary Hymenoptera. Here we test this possibility by examining two species of solitary mud dauber wasps, Sceliphron caementarium and Chalybion californicum. We performed enrichment isolations from 33 wasps and obtained more than 200 isolates of Streptomyces Actinobacteria. Chemical analyses of 15...... and antibacterial activity. The prevalence and anti-microbial properties of Actinobacteria associated with these two solitary wasp species suggest the potential role of these Streptomyces as antibiotic-producing symbionts, potentially helping defend their wasp hosts from pathogenic microbes. Finding...... phylogenetically diverse and chemically prolific Actinobacteria from solitary wasps suggests that insect-associated Actinobacteria can provide a valuable source of novel natural products of pharmaceutical interest....

  19. DYRK1A Is a Regulator of S-Phase Entry in Hepatic Progenitor Cells.

    Science.gov (United States)

    Kruitwagen, Hedwig S; Westendorp, Bart; Viebahn, Cornelia S; Post, Krista; van Wolferen, Monique E; Oosterhoff, Loes A; Egan, David A; Delabar, Jean-Maurice; Toussaint, Mathilda J; Schotanus, Baukje A; de Bruin, Alain; Rothuizen, Jan; Penning, Louis C; Spee, Bart

    2018-01-15

    Hepatic progenitor cells (HPCs) are adult liver stem cells that act as second line of defense in liver regeneration. They are normally quiescent, but in case of severe liver damage, HPC proliferation is triggered by external activation mechanisms from their niche. Although several important proproliferative mechanisms have been described, it is not known which key intracellular regulators govern the switch between HPC quiescence and active cell cycle. We performed a high-throughput kinome small interfering RNA (siRNA) screen in HepaRG cells, a HPC-like cell line, and evaluated the effect on proliferation with a 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay. One hit increased the percentage of EdU-positive cells after knockdown: dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A). Although upon DYRK1A silencing, the percentage of EdU- and phosphorylated histone H3 (pH3)-positive cells was increased, and total cell numbers were not increased, possibly through a subsequent delay in cell cycle progression. This phenotype was confirmed with chemical inhibition of DYRK1A using harmine and with primary HPCs cultured as liver organoids. DYRK1A inhibition impaired Dimerization Partner, RB-like, E2F, and multivulva class B (DREAM) complex formation in HPCs and abolished its transcriptional repression on cell cycle progression. To further analyze DYRK1A function in HPC proliferation, liver organoid cultures were established from mBACtgDyrk1A mice, which harbor one extra copy of the murine Dyrk1a gene (Dyrk+++). Dyrk+++ organoids had both a reduced percentage of EdU-positive cells and reduced proliferation compared with wild-type organoids. This study provides evidence for an essential role of DYRK1A as balanced regulator of S-phase entry in HPCs. An exact gene dosage is crucial, as both DYRK1A deficiency and overexpression affect HPC cell cycle progression.

  20. Antimicrobial and Anti-Proliferative Effects of Skin Mucus Derived from Dasyatis pastinaca (Linnaeus, 1758

    Directory of Open Access Journals (Sweden)

    Virginia Fuochi

    2017-11-01

    Full Text Available Resistance to chemotherapy occurs in various diseases (i.e., cancer and infection, and for this reason, both are very difficult to treat. Therefore, novel antimicrobial and chemotherapic drugs are needed for effective antibiotic therapy. The aim of the present study was to assess the antimicrobial and anti-proliferative effects of skin mucus derived from Dasyatis pastinaca (Linnaeus, 1758. Our results showed that skin mucus exhibited a significant and specific antibacterial activity against Gram-negative bacteria but not against Gram-positive bacteria. Furthermore, we also observed a significant antifungal activity against some strains of Candida spp. Concerning anti-proliferative activity, we showed that fish mucus was specifically toxic for acute leukemia cells (HL60 with an inhibition of proliferation in a dose dependent manner (about 52% at 1000 μg/mL of fish skin mucous, FSM. Moreover, we did not observe effects in healthy cells, in neuroblastoma cells (SH-SY5Y, and multiple myeloma cell lines (MM1, U266. Finally, it exhibited strong expression and activity of chitinase which may be responsible, at least in part, for the aforementioned results.

  1. Transcriptional Regulation of S Phase Kinase-associated Protein 2 by NR4A Orphan Nuclear Receptor NOR1 in Vascular Smooth Muscle Cells*

    Science.gov (United States)

    Gizard, Florence; Zhao, Yue; Findeisen, Hannes M.; Qing, Hua; Cohn, Dianne; Heywood, Elizabeth B.; Jones, Karrie L.; Nomiyama, Takashi; Bruemmer, Dennis

    2011-01-01

    Members of the NR4A subgroup of the nuclear hormone receptor superfamily have emerged as key transcriptional regulators of proliferation and inflammation. NOR1 constitutes a ligand-independent transcription factor of this subgroup and induces cell proliferation; however, the transcriptional mechanisms underlying this mitogenic role remain to be defined. Here, we demonstrate that the F-box protein SKP2 (S phase kinase-associated protein 2), the substrate-specific receptor of the ubiquitin ligase responsible for the degradation of p27KIP1 through the proteasome pathway, constitutes a direct transcriptional target for NOR1. Mitogen-induced Skp2 expression is silenced in vascular smooth muscle cells (VSMC) isolated from Nor1-deficient mice or transfected with Nor1 siRNA. Conversely, adenovirus-mediated overexpression of NOR1 induces Skp2 expression in VSMC and decreases protein abundance of its target p27. Transient transfection experiments establish that NOR1 transactivates the Skp2 promoter through a nerve growth factor-induced clone B response element (NBRE). Electrophoretic mobility shift and chromatin immunoprecipitation assays further revealed that NOR1 is recruited to this NBRE site in the Skp2 promoter in response to mitogenic stimulation. In vivo Skp2 expression is increased during the proliferative response underlying neointima formation, and this transcriptional induction depends on the expression of NOR1. Finally, we demonstrate that overexpression of Skp2 rescues the proliferative arrest of Nor1-deficient VSMC. Collectively, these results characterize Skp2 as a novel NOR1-regulated target gene and detail a previously unrecognized transcriptional cascade regulating mitogen-induced VSMC proliferation. PMID:21868379

  2. The use of analogy in pro-life argumentation

    Directory of Open Access Journals (Sweden)

    Simona Mazilu

    2012-11-01

    Full Text Available The paper is concerned with how analogy is strategically used in pro-life argumentation on abortion. Pragma-dialectics (van Eemeren and Grootendorst 1992 offers a set of critical questions by means of which I will evaluate the use of the argumentation based on a relation of analogy in terms of dialectical soundness. Examining various pro-life texts, I have noticed that the analogies employed remain unexplained. Therefore, despite the apparent similarities between abortion and the German holocaust or slavery, for instance, there are essential differences which are not mentioned. I claim that these analogies mainly have a rhetorical function, to operate what has been called by Micheli (2007: 960 “a transfer of emotional consensus”.

  3. Scoring radiologic characteristics to predict proliferative potential in meningiomas

    International Nuclear Information System (INIS)

    Hashiba, Tetsuo; Hashimoto, Naoya; Maruno, Motohiko; Izumoto, Shuichi; Suzuki, Tsuyoshi; Kagawa, Naoki; Yoshimine, Toshiki

    2006-01-01

    We investigated the feasibility of using radiologic characteristics to predict the proliferative potential in meningiomas. Our statistical analysis revealed that the presence of peritumoral edema, an ambiguous brain-tumor border, and irregular tumor shape were significantly correlated with a higher MIB-1 staining index (SI) value. We developed the following scoring system for specific features in each tumor: peritumoral edema (tumor with edema=1, tumor without edema=0); brain-tumor border (tumor with any ambiguous border=1, tumor circumscribed by a distinct rim=0); and tumor shape (tumor with irregular shape=1, tumor with smooth shape=0). Using Spearman's correlation coefficient analysis, we found a significant correlation (P<0.005) between total score calculated for each patient and SI value. Our findings suggest that the proliferative potential of meningiomas can be predicted using a less invasive preoperative examination focusing on the presence of peritumoral edema, ambiguous brain-tumor border, and irregular tumor shape. (author)

  4. Proliferative verrucous leukoplakia: an aggressive form of oral leukoplakia.

    Science.gov (United States)

    Shopper, Thomas P; Brannon, Robert B; Stalker, William H

    2004-01-01

    Proliferative verrucous leukoplakia (PVL) is an aggressive form of oral leukoplakia that is persistent, often multifocal, and refractory to treatment with a high risk of recurrence and malignant transformation. This article describes the clinical aspects and histologic features of a case that demonstrated the typical behavior pattern in a long-standing, persistent lesion of PVL of the mandibular gingiva and that ultimately developed into squamous cell carcinoma. Prognosis is poor for this seemingly harmless-appearing white lesion of the oral mucosa.

  5. Prolific plant regeneration through organogenesis from scalps of ...

    African Journals Online (AJOL)

    Four types of potting media comprising of sand, peat, sand + top soil + goat dung (3:2:1 v/v) and top soil + sand (1:1 v/v) were evaluated during acclimatization of the plantlets. Prolific shoot regeneration from scalps was obtained on MS medium containing 2.5 mM BAP, at 9.61 and 40.6 shoots per explant after 4 and 8 weeks ...

  6. Panretinal photocoagulation versus intravitreal injection retreatment pain in high-risk proliferative diabetic retinopathy

    Directory of Open Access Journals (Sweden)

    Célia Regina Farias de Araújo Lucena

    2013-02-01

    Full Text Available PURPOSE: To compare pain related to intravitreal injection and panretinal photocoagulation in the management of patients with high-risk proliferative diabetic retinopathy. METHODS: Prospective study including patients with high-risk proliferative diabetic retinopathy and no prior laser treatment randomly assigned to receive panretinal photocoagulation (PRP group or panretinal photocoagulation plus intravitreal ranibizumab (PRPplus group. In all patients, panretinal photocoagulation was administered in two sessions (weeks 0 and 2, and intravitreal ranibizumab was administered at the end of the first laser session in the PRPplus group. Retreatment was performed at weeks 16 and 32 if active new vessels were detected at fluorescein angiography. Patients in the PRPplus group received intravitreal ranibizumab and patients in the PRP group received 500-µm additional spots per quadrant of active new vessels. After the end of retreatment, a 100-degree Visual Analog Scale was used for pain score estimation. The patient was asked about the intensity of pain during the whole procedure (retinal photocoagulation session or intravitreal ranibizumab injection. Statistics for pain score comparison were performed using a non-parametric test (Wilcoxon rank sums. RESULTS: Seventeen patients from PRPplus and 14 from PRP group were evaluated for pain scores. There were no significant differences between both groups regarding gender, glycosylated hemoglobin and disease duration. Mean intravitreal injection pain (±SEM was 4.7 ± 2.1 and was significantly lower (p<0.0001 than mean panretinal photocoagulation pain (60.8 ± 7.8. Twelve out of 17 patients from the PRPplus group referred intensity pain score of zero, while the minimal score found in PRP group was found in one patient with 10.5. CONCLUSION: In patients with high-risk proliferative diabetic retinopathy who needed retreatment for persistent new vessels, there was more comfort for the patient when retreatment

  7. Atypical hyperplasia, proliferative fibrocystic change, and exogenous hormone use.

    Science.gov (United States)

    Zera, R T; Danielson, D; Van Camp, J M; Schmidt-Steinbrunn, B; Hong, J; McCoy, M; Anderson, W R; Linzie, B M; Rodriguez, J L

    2001-10-01

    The association between breast cancer development and exogenous hormone use (EHU) is suggested by indirect clinical evidence. We undertook this study to better define the relationship that EHU has with proliferative fibrocystic change (PFC) and atypical hyperplasia (AH). Women diagnosed with AH without associated carcinoma from January 1990 to December 1999 were compared with control subjects who underwent breast biopsy procedures during the same interval and who were diagnosed with either a proliferative fibrocystic change (PFC) or a nonproliferative fibrocystic change (NPFC). EHU was defined as the use of estrogen or progesterone taken together or separately within 3 months of biopsy. EHU was significantly higher in patients with AH compared with women with NPFC (P =.01). This observation was also significant if all proliferative change (both AH and PFC) was compared with NPFC (P =.03); it was not significant when PFC alone was compared with NPFC. No significant difference in EHU was demonstrated between women with AH and those with PFC. There is strong association between AH and EHU. These results support the theory that a continuum exists between hyperplasia and carcinoma and that EHU may influence the transition from one to the other in an undefined subset of women. We encourage our patients with AH to discontinue EHU.

  8. How unfinished business from S-phase affects mitosis and beyond

    DEFF Research Database (Denmark)

    Mankouri, H.W.; Huttner, D.; Hickson, I.D.

    2013-01-01

    The eukaryotic cell cycle is conventionally viewed as comprising several discrete steps, each of which must be completed before the next one is initiated. However, emerging evidence suggests that incompletely replicated, or unresolved, chromosomes from S-phase can persist into mitosis, where...... they present a potential threat to the faithful segregation of sister chromatids. In this review, we provide an overview of the different classes of loci where this 'unfinished S-phase business' can lead to a variety of cytogenetically distinct DNA structures throughout the various steps of mitosis...

  9. Relação entre a quantidade de AgNORS, atividade proliferativa e o estágio de desenvolvimento placentário em equinos Relationship between the amount of AgNORs, proliferative activity and stage of placental development in horses

    Directory of Open Access Journals (Sweden)

    Ana C.F. Mançanares

    2012-12-01

    silver nitrate and are related to the activity of rRNA synthesis and to the agility and speed of cell proliferation in the tissues studied. The objective of this study was to relate the amount of AgNORs, proliferative activity and stage of pregnancy in horses, using the coloring of Silver Nitrate. The embryonic attachments were collected, fixed in 10% buffered formaldehyde, embedded in paraplast and stained by silver nitrate. The groups were determined according to the gestational age. The amount of the corium NOR found in early pregnancy indicates the onset of cell activity, and in that the pregnancy progresses, the amount of NOR increases, suggesting higher activity and increased synthesis of their importance in maintaining the fetus. Contrary to what occurs in the corium, the quantification of NORs was higher in late pregnancy than in the beginning, suggesting the stabilization of these membranes in late pregnancy. The chorionic girdle and the yolk sac were found in early pregnancy and had lots of NORs, suggesting synthesis function and proliferation in early pregnancy, since their functions is maintenance of the embryo until the complete formation of the true placenta (chorio-allantoic membranes. We conclude that the membranes that develop in a progressive manner in accordance with the growing embryo/fetal (chorion, amnion and allantoic membranes have an increased number of NORs and the membranes that involute after the formation of the embryo/fetus (yolk sac and chorionic girdle have a decrease in number, suggesting a reduction in proliferative activity in these membranes.

  10. Synergy among rat T cells in the proliferative response to alloantigen

    International Nuclear Information System (INIS)

    Wright, P.W.; Loop, S.M.; Bernstein, I.D.

    1979-01-01

    A synergistic interaction in the proliferative response to alloantigen is described for mixtures of rat thymus and lymph node cells. The optimal conditions for synergy are quantitatively defined. Regression analysis of the slope of the dose-response curve has been utilized to estimate the degree of interaction in thymus--lymph node cell mixtures. The slope of the response of cell mixtures was noted to be significantly greater than the slope for the response of lympth node cells alone. Irradiation was shown to have a differential effect on the response of thymus and lymph node cells in mixtures. Irradiated thymus cells retained the capacity for synergy in mixtures, whereas irradiated lymph node cells did not. Additional studies have demonstrated that both de novo protein synthesis and specific antigen recognition by both responding cell populations in mixtures was required for maximal synergy. These studies demonstrate that synergy cannot be explained as an artifact of altered cell density in vitro. They establish that thymus cells and lymph node cells represent distinct subsets which manifest qualitatively different functions in the proliferative response to alloantigen. Thymus cells can respond directly to alloantigen by proliferation but also have the capacity to amplify the proliferative response of lymph node cells, a capacity which is resistant to X irradiation but requires recognition of alloantigen and de novo protein synthesis. Lymph node cells may similarly respond by proliferation to alloantigen but lack the amplifier activity of thymus cells. Synergy for rat lymphoidcells, like mouse lymphoid cells, has been shown to involve an interaction of thymus-derived lymphocytes

  11. Induction of S-phase entry by E2F transcription factors depends on their nuclear localization

    DEFF Research Database (Denmark)

    Müller, H; Moroni, M C; Vigo, E

    1997-01-01

    The E2F transcription factors are essential for regulating the correct timing of activation of several genes whose products are implicated in cell proliferation and DNA replication. The E2Fs are targets for negative regulation by the retinoblastoma protein family, which includes pRB, p107, and p130......, and they are in a pathway that is frequently found altered in human cancers. There are five members of the E2F family, and they can be divided into two functional subgroups. Whereas, upon overexpression, E2F-1, -2, and -3 induce S phase in quiescent fibroblasts and override G1 arrests mediated by the p16INK4A tumor...... suppressor protein or neutralizing antibodies to cyclin D1, E2F-4 and -5 do not. Using E2F-1 and E2F-4 as representatives of the two subgroups, we showed here, by constructing a set of chimeric proteins, that the amino terminus of E2F-1 is sufficient to confer S-phase-inducing potential as well...

  12. Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase

    DEFF Research Database (Denmark)

    Beck, Halfdan; Nähse, Viola; Larsen, Marie Sofie Yoo

    2010-01-01

    are important negative regulators of CDK1 and -2. Strikingly, WEE1 depletion rapidly induced DNA damage in S phase in newly replicated DNA, which was accompanied by a marked increase in single-stranded DNA. This DNA damage is dependent on CDK1 and -2 as well as the replication proteins MCM2 and CDT1 but not CDC...

  13. Ultrastructural organization of premature condensed chromosomes at S-phase as observed by atomic force microscopy

    International Nuclear Information System (INIS)

    Fan Yihui; Zhang Xiaohong; Bai Jing; Mao Renfang; Zhang Chunyu; Lei Qingquan; Fu Songbin

    2007-01-01

    In this study, we used calyculin A to induce premature condensed chromosomes (PCC). S-phase PCC is as 'pulverized' appearance when viewed by light microscopy. Then, we applied atomic force microscopy (AFM) to investigate the ultrastructual organization of S-phase PCC. S-phase PCC shows ridges and grooves as observed by AFM. After trypsin treatment, chromosome surface roughness is increased and chromosome thickness is decreased. At high magnification, the ridges are composed of densely packed 30 nm chromatin fibers which form chromosome axis. Around the ridges, many 30 nm chromatin fibers radiate from center. Some of the 30 nm chromatin fibers are free ends. The grooves are not real 'gap', but several 30 nm chromatin fibers which connect two ridges and form 'grid' structure. There are four chromatin fibers detached from chromosome: two free straight 30 nm chromatin fibers, one loop chromatin fiber and one straight combining with loop chromatin fiber. These results suggested that the S-phase PCC was high-order organization of 30 nm chromatin fibers and the 30 nm chromatin fibers could exist as loops and free ends

  14. Synthesis and Anti-Proliferative Effects of Mono- and Bis-Purinomimetics Targeting Kinases

    Directory of Open Access Journals (Sweden)

    Andrea Bistrović

    2017-11-01

    Full Text Available A series of mono-pyrrolo[2,3-d]pyrimidines 4a–4k, unsymmetrical bis-purine isosteres 5a–5e and symmetrical bis-pyrrolo[2,3-d]pyrimidines 6a and 6b connected via di(1,2,3-triazolylphenyl linker were synthesized by click chemistry. Whereas mono- 4g and bis-pseudopurine 5e showed selective inhibitory activities on cervical carcinoma (HeLa cells, bis-pyrrolo[2,3-d]pyrimidine 6b exhibited potent and selective anti-proliferative effect in the nanomolar range on pancreatic carcinoma (CFPAC-1 cells. Among these, compound 6b induced a significant reduction in the expression level of CDK9 (cyclin-dependent kinase 9/cyclin T1 in CFPAC-1 cells concomitant with attenuation of proliferative signaling mediated by c-Raf (rapidly accelerated fibrosarcoma and p38 MAP (mitogen-activated protein kinases. Our findings encourage further development of novel structurally related analog of 6b to obtain more selective anticancer agent for treating pancreatic cancer.

  15. Variations in Mre11/Rad50/Nbs1 status and DNA damage-induced S-phase arrest in the cell lines of the NCI60 panel

    Directory of Open Access Journals (Sweden)

    Eastman Alan

    2011-05-01

    Full Text Available Abstract Background The Mre11/Rad50/Nbs1 (MRN complex is a regulator of cell cycle checkpoints and DNA repair. Defects in MRN can lead to defective S-phase arrest when cells are damaged. Such defects may elicit sensitivity to selected drugs providing a chemical synthetic lethal interaction that could be used to target therapy to tumors with these defects. The goal of this study was to identify these defects in the NCI60 panel of cell lines and identify compounds that might elicit selective cytotoxicity. Methods We screened the NCI60 panel in search of cell lines that express low levels of MRN proteins, or that fail to arrest in S-phase in response to the topisomerase I inhibitor SN38. The NCI COMPARE program was used to discover compounds that preferentially target cells with these phenotypes. Results HCT116 cells were initially identified as defective in MRN and S phase arrest. Transfection with Mre11 also elevated Rad50 and Nbs1, and rescued the defective S-phase arrest. Cells of the NCI60 panel exhibited a large range of protein expression but a strong correlation existed between Mre11, Rad50 and Nbs1 consistent with complex formation determining protein stability. Mre11 mRNA correlated best with protein level suggesting it was the primary determinant of the overall level of the complex. Three other cell lines failed to arrest in response to SN38, two of which also had low MRN. However, other cell lines with low MRN still arrested suggesting low MRN does not predict an inability to arrest. Many compounds, including a family of benzothiazoles, correlated with the failure to arrest in S phase. The activity of benzothiazoles has been attributed to metabolic activation and DNA alkylation, but we note several cell lines in which sensitivity does not correlate with metabolism. We propose that the checkpoint defect imposes an additional mechanism of sensitivity on cells. Conclusions We have identified cells with possible defects in the MRN complex

  16. Variations in Mre11/Rad50/Nbs1 status and DNA damage-induced S-phase arrest in the cell lines of the NCI60 panel

    International Nuclear Information System (INIS)

    Garner, Kristen M; Eastman, Alan

    2011-01-01

    The Mre11/Rad50/Nbs1 (MRN) complex is a regulator of cell cycle checkpoints and DNA repair. Defects in MRN can lead to defective S-phase arrest when cells are damaged. Such defects may elicit sensitivity to selected drugs providing a chemical synthetic lethal interaction that could be used to target therapy to tumors with these defects. The goal of this study was to identify these defects in the NCI60 panel of cell lines and identify compounds that might elicit selective cytotoxicity. We screened the NCI60 panel in search of cell lines that express low levels of MRN proteins, or that fail to arrest in S-phase in response to the topisomerase I inhibitor SN38. The NCI COMPARE program was used to discover compounds that preferentially target cells with these phenotypes. HCT116 cells were initially identified as defective in MRN and S phase arrest. Transfection with Mre11 also elevated Rad50 and Nbs1, and rescued the defective S-phase arrest. Cells of the NCI60 panel exhibited a large range of protein expression but a strong correlation existed between Mre11, Rad50 and Nbs1 consistent with complex formation determining protein stability. Mre11 mRNA correlated best with protein level suggesting it was the primary determinant of the overall level of the complex. Three other cell lines failed to arrest in response to SN38, two of which also had low MRN. However, other cell lines with low MRN still arrested suggesting low MRN does not predict an inability to arrest. Many compounds, including a family of benzothiazoles, correlated with the failure to arrest in S phase. The activity of benzothiazoles has been attributed to metabolic activation and DNA alkylation, but we note several cell lines in which sensitivity does not correlate with metabolism. We propose that the checkpoint defect imposes an additional mechanism of sensitivity on cells. We have identified cells with possible defects in the MRN complex and S phase arrest, and a series of compounds that may

  17. VISUAL OUTCOME FOLLOWING PANRETINAL PHOTOCOAGULATION IN PROLIFERATIVE DIABETIC RETINOPATHY

    Directory of Open Access Journals (Sweden)

    Nellaye Mani Sindhu

    2018-01-01

    Full Text Available BACKGROUND Diabetes mellitus can be called as a noninfectious pandemic and the incidence of diabetic retinopathy is also uncontrollable. This vision-threatening complication can be treated by early diagnosis and effective treatment like panretinal photocoagulation. The aim of the study is to evaluate the effect of panretinal photocoagulation on visual acuity, colour vision, contrast sensitivity and severity of visual field changes. MATERIALS AND METHODS Prospective study of visual outcome following panretinal photocoagulation in patients with proliferative diabetic retinopathy conducted in Retina Clinic, RIO, Trivandrum, during the time period one year from April 2008. Inclusion Criteria- Eyes with proliferative diabetic retinopathy, visual acuity better than or equal to 6/60, a follow up of at least 6 months after panretinal photocoagulation. Exclusion Criteria- Eyes with cataractous changes in the lens, eyes, which would be undergoing or have undergone focal photocoagulation eyes, which undergone barrage or sectoral retinal photocoagulation, patients with colour blindness, eyes with vitreous haemorrhage and macular preretinal haemorrhage, glaucomatous patients with peripheral field loss. RESULTS The mean age of the patients was 52 years. Male patients (30 outnumbered the female patients (23. Mean duration of diabetes was 14.42 years. Though, there is a statistically significant reduction in visual acuity in the first followup, which was improved and stabilised by 6 months. There is a statistically significant reduction in the contrast sensitivity, which was stabilised after 3 months. Only, 9.5% patients had peripheral constrictions of visual field and no significant change in the colour vision. CONCLUSION We recommend panretinal photocoagulation for all patients with proliferative diabetic retinopathy.

  18. Chronic proliferative synovitis of the equine metacarpophalangeal joint

    International Nuclear Information System (INIS)

    Kannegieter, N.J.

    1990-01-01

    Chronic proliferative synovitis of 27 metacarpophalangeal joints in 16 horses is described. The diagnosis was based on a history of lameness and, or, poor performance, pain on flexion of the metacarpophalangeal joint, the response to intra-articular anaesthesia, and plain and contrast radiography. Radiographic findings included concavity of the distal dorsal metacarpus proximal to the sagittal ridge, and an increase in size of the synovial tissue adjacent to the proximal, dorsal attachment of the joint capsule. Mineralisation of the synovial tissue was present in some joints, and chip fractures from the dorsal aspect of the proximal phalanx were also occasionally seen. Treatment by arthroscopic resection of the tissue gave excellent results

  19. Comments on 'Standard effective doses for proliferative tumours'

    International Nuclear Information System (INIS)

    Dasu, Iuliana Livia; Dasu, Alexandru; Denekamp, Juliana; Fowler, Jack F.

    2000-01-01

    We should like to make some comments on the paper published by Jones et al (1999). The paper presents some interesting and useful contributions on the theoretical evaluation of different fractionated schedules used now. The use of the linear quadratic equation has been very useful in focusing attention on the differences in fractionation responses of fast and slow proliferating normal tissues and tumours. Unfortunately the BED 10 or BED 3 units for (α/β ratios of 10 Gy and 3 Gy respectively) do not directly relate to anything used in routine clinical practice. The purpose of the paper by Jones et al (1999) is to covert any new schedule into the equivalent total dose as if it was given in the same size fractions as are in common use in that department. They illustrate that, if proliferation is taken into account for the altered schedule, it can be compared in two ways with the standard conventional schedule: (a) the proliferative standard effective dose one (PSED 1 ) in which the proliferation correction is applied in the altered schedule, but not in the standard schedule; (b) the proliferative standard effective dose two (PSED 2 ) in which the proliferation correction is applied to both schedules using the same proliferation parameters. This is expected to provide a better evaluation of the response of a 'real' tumour (i.e. a tumour that also proliferates during the standard treatment). However, there seem to be two errors in the paper. First, the authors quoted a wrong equation for calculating the proliferative standard effective dose two (PSED 2 ) (equations (2) and (A6) in their paper). There are also some special cases with respect to the time available for proliferation and the duration of the treatment that have been neglected in their paper and which require further specification. Therefore, we should like to give the full mathematical derivation of the correct equations for calculating the proliferative standard effective doses. We would also like to make

  20. Apoptotic and anti-proliferative effects of all-trans retinoic acid

    International Nuclear Information System (INIS)

    Zamora, Monica; Ortega, Juan Alberto; Alana, Lide; Vinas, Octavi; Mampel, Teresa

    2006-01-01

    We examined the apoptotic and anti-proliferative effects of all-trans retinoic acid (atRA) in HeLa cells. Our results demonstrated that HeLa cells were more sensitive to the anti-proliferative effects of atRA than to its apoptotic effects. Furthermore, we demonstrated that caspase inhibition attenuates cell death but does not alter the atRA-dependent reduction in cell proliferation, which suggests that atRA-induced apoptosis is independent of the arrest in cell proliferation. To check whether ANT proteins mediated these atRA effects, we transiently transfected cells with expression vectors encoding for individual ANT (adenine nucleotide translocase 1-3). Our results revealed that ANT1 and ANT3 over-expressing HeLa cells increased their atRA sensitivity. Thus, our results not only demonstrate the different functional activities of ANT isoforms, but also contribute to a better understanding of the properties of atRA as an anti-tumoral agent used in cancer therapy

  1. Arctigenin in combination with quercetin synergistically enhances the anti-proliferative effect in prostate cancer cells

    Science.gov (United States)

    Wang, Piwen; Phan, Tien; Gordon, David; Chung, Seyung; Henning, Susanne M.; Vadgama, Jaydutt V.

    2014-01-01

    Scope We investigated whether a combination of two promising chemopreventive agents arctigenin and quercetin increases the anti-carcinogenic potency at lower concentrations than necessary when used individually in prostate cancer. Methods and results Androgen-dependent LAPC-4 and LNCaP prostate cancer cells were treated with low doses of arctigenin and quercetin alone or in combination for 48h. The anti-proliferative activity of arctigenin was 10-20 fold stronger than quercetin in both cell lines. Their combination synergistically enhanced the anti-proliferative effect, with a stronger effect in androgen receptor (AR) wild-type LAPC-4 cells than in AR mutated LNCaP cells. Arctigenin demonstrated a strong ability to inhibit AR protein expression in LAPC-4 cells. The combination treatment significantly inhibited both AR and PI3K/Akt pathways compared to control. A protein array analysis revealed that the mixture targets multiple pathways particularly in LAPC-4 cells including Stat3 pathway. The mixture significantly inhibited the expression of several oncogenic microRNAs including miR-21, miR-19b, and miR-148a compared to control. The mixture also enhanced the inhibition of cell migration in both cell lines compared to individual compounds tested. Conclusion The combination of arctigenin and quercetin, that target similar pathways, at low physiological doses, provides a novel regimen with enhanced chemoprevention in prostate cancer. PMID:25380086

  2. Role of Stromal Paracrine Signals in Proliferative Diseases of the Aging Human Prostate

    Directory of Open Access Journals (Sweden)

    Kenichiro Ishii

    2018-04-01

    Full Text Available Androgens are essential for the development, differentiation, growth, and function of the prostate through epithelial–stromal interactions. However, androgen concentrations in the hypertrophic human prostate decrease significantly with age, suggesting an inverse correlation between androgen levels and proliferative diseases of the aging prostate. In elderly males, age- and/or androgen-related stromal remodeling is spontaneously induced, i.e., increased fibroblast and myofibroblast numbers, but decreased smooth muscle cell numbers in the prostatic stroma. These fibroblasts produce not only growth factors, cytokines, and extracellular matrix proteins, but also microRNAs as stromal paracrine signals that stimulate prostate epithelial cell proliferation. Surgical or chemical castration is the standard systemic therapy for patients with advanced prostate cancer. Androgen deprivation therapy induces temporary remission, but the majority of patients eventually progress to castration-resistant prostate cancer, which is associated with a high mortality rate. Androgen deprivation therapy-induced stromal remodeling may be involved in the development and progression of castration-resistant prostate cancer. In the tumor microenvironment, activated fibroblasts stimulating prostate cancer cell proliferation are called carcinoma-associated fibroblasts. In this review, we summarize the role of stromal paracrine signals in proliferative diseases of the aging human prostate and discuss the potential clinical applications of carcinoma-associated fibroblast-derived exosomal microRNAs as promising biomarkers.

  3. Analysis of the proliferative potential of odontogenic epithelial cells of pericoronal follicles.

    Science.gov (United States)

    Cimadon, Natalia; Lauxen, Isabel Silva; Carrard, Vinicius Coelho; Sant'Ana Filho, Manoel; Rados, Pantelis Varvaki; Oliveira, Márcia Gaiger

    2014-11-01

    To evaluate the proliferative potential and the cell proliferation rate of odontogenic epithelial cells. Forty-two cases of pericoronal follicles of impacted third molars were submitted to silver impregnation technique for quantification of argyrophilic nucleolar organizer regions (AgNOR) and immunohistochemical staining for EGFR and Ki-67. For AgNOR quantification, the mean number of active nucleolar organizer regions per nucleus (mAgNOR) and the percentage of cells with 1, 2, 3 and 4 or more AgNORs per nucleus (pAgNOR) were quantified. Ki-67 immunolabeling was quantified, whereas for EGFR, a descriptive analysis of staining patterns (membrane, cytoplasm or membrane + cytoplasm positivity) was performed. We evaluated the reduced epithelium of the enamel organ and/or islands of odontogenic epithelium present in the entire connective tissue. mAgNOR were 1.43 (1.0-2.42) and were significantly different among pericoronary follicles from upper and lower teeth (p = 0.041). Immunostaining of Ki-67 was negative in all cases. EGFR immunolabeling was found mainly in the cytoplasm and was more intense in islands and cords when compared to reduced epithelium of the enamel organ. Odontogenic epithelial cells of some pericoronal follicles have proliferative potential, suggesting their association with the development of odontogenic lesions. The authors suggest that nonerupted, especially of the lower teeth, should be monitored and if necessary removed.

  4. Proliferative and nonproliferative breast disease in atomic-bomb survivors

    International Nuclear Information System (INIS)

    Tokunaga, Masayoshi; Land, C.E.; Aoki, Yoichiro; Yamamoto, Tsutomu; Asano, Masahide; Sato, Eiichi; Tokuoka, Shoji; Sakamoto, Goi; Page, D.L.

    1993-10-01

    The risk of female breast cancer in association with radiation exposure is well established, on the basis of follow-up studies of the atomic-bomb survivors and other exposed populations. This association is especially strong for women exposed before age 20 yr and appears to be much weaker among women exposed after age 40 yr. In this study, breast-tissue autopsy samples from high-dose and low-dose individuals in the Radiation Effects Research Foundation Life Span Study sample were examined in detail to determine whether nonproliferative or proliferative breast lesions are associated with radiation exposure. The results suggest that proliferative disease in general and atypical hyperplasia in particular are associated with radiation exposure and that the risk is strongest for subjects who were ages 40-49 yr at the time of the bombings. It is hypothesized that this finding may be related to the age dependence of radiation-induced breast cancer, in the sense that potential cancers reflecting early-stage changes induced at these ages by radiation exposure may receive too little hormonal promotion to progress to frank cancers. (author)

  5. Neoplastic and proliferative disorders of the perinephric space

    International Nuclear Information System (INIS)

    Heller, M.T.; Haarer, K.A.; Thomas, E.; Thaete, F.L.

    2012-01-01

    The perinephric space is a well-marginated central compartment of the retroperitoneum, located between the anterior and posterior pararenal spaces. Various neoplastic and proliferative disorders can affect the perinephric space, and there is a wide array of imaging findings. Although many perinephric lesions may extend directly from the kidney and adrenal gland, other lesions occur in the perinephric space due to haematogenous spread, as part of a systemic disease, or by extension from an adjacent retroperitoneal compartment. Imaging plays a pivotal role in the diagnosis of perinephric diseases, as many of the disease processes affecting this space will not result in clinical signs or symptoms until the disease is at an advanced stage. Despite the often shared non-specific clinical and imaging findings among these disease processes, application of a categorical differential diagnosis based on the imaging characteristics will serve to narrow the differential diagnosis and direct further evaluation and treatment. In this article, the lesions have been categorized as soft-tissue rind [nephroblastomatosis, fibrosis, Erdheim–Chester disease (ECD), extramedullary haematopoiesis, lymphoma, infiltrating metastases], focal solid lesions (extension of renal or adrenal malignancies, melanoma metastases, treated lymphoma), fat-containing lesions (angiomyolipoma, liposarcoma, myelolipoma), and cystic lesions (lymphangiomas, abscesses). The aim of this article is to demonstrate and describe the key imaging features of several neoplastic and proliferative disorders that affect the perinephric space.

  6. Oral proliferative verrucous leukoplakia: A case report with an update

    Directory of Open Access Journals (Sweden)

    Rakhi Issrani

    2013-01-01

    Full Text Available White lesions both physiologic as well as pathologic are relatively frequent in the oral cavity, the most common pathology being oral leukoplakia (OL. There are many variants of OL, one of which is oral proliferative verrucous leukoplakia (OPVL. OPVL is a rare clinico-pathological entity, which is slow growing, long-term progressive lesion, but remains an enigmatic and difficult to define. The etiology of OPVL remains still unclear. Tobacco use does not seem to have a significant influence on the appearance of OPVL. These lesions may occur both in smokers and non-smokers. It is observed more frequently in women and elderly patients over 60 years at the time of diagnosis. The buccal mucosa and tongue are the most frequently involved sites. It develops initially as a white plaque of hyperkeratosis that eventually becomes a multifocal disease with confluent, exophytic and proliferative features. Various published case series have presented OPVL as a disease with aggressive biological behavior due to its high probability of recurrence and a high rate of malignant transformation. Prognosis is poor for this seemingly harmless-appearing white lesion of the oral mucosa. This article describes the clinical aspects and histologic features of an OPVL case that demonstrated the typical behavior pattern in a long-standing, persistent lesion and discusses this relatively rare entity in light of current information.

  7. The role of glutathione in lymphocyte activation and proliferation

    International Nuclear Information System (INIS)

    Messina, J.P.

    1990-01-01

    The object of this work was to establish the requirement for GSH and cystine during the activation and proliferation of human peripheral blood mononuclear cells (PBMC). In the author's initial experiments the intracellular GSH content of PBMC was altered by continuous culture or pretreatment with BSO, a specific inhibitor of GSH synthesis. His results demonstrate that, continuous culture of mitogen stimulated PBMC in the presence of BSO inhibited entry into S-phase of the cell cycle and produced a simultaneous decrease in intracellular GSH. The influence of BSO on early activation events were determined by BSO pretreatment. Extensive depletion (>90%) of the intracellular GSH level prior to mitogenic stimulation did not impair the ability of these cells to produce IL-2 and express IL-2R, indicating that GSH may not be involved in the generation and response to early activation signals. Furthermore, the removal of BSO from these cultures rapidly reversed its inhibitory effects on DNA and GSH synthesis. Cystine transport activities and metabolism by PBMC were characterized in order to examine its contributions to intracellular GSH and early activation proteins. In spite of the ability of cystine to sustain the proliferative response of PBMC, differences in the kinetics of cystine and cysteine uptake indicated that separate transport systems may be operational. Treatment with 2ME enhanced cystine uptake, but lowered the proliferative responses of these cells. Metabolic studies with [ 35 S] cystine demonstrated that mitogen stimulation of PBMC enhance cystine uptake

  8. Atypical proliferative myositis: original MR description with pathologic correlation: Case report

    Energy Technology Data Exchange (ETDEWEB)

    Jarraya, Mohamed; Guermazi, Ali [Boston University School of Medicine, Department of Radiology, Musculoskeletal Section, Boston, MA (United States); Parva, Pedram [VA Boston Healthcare System, Boston, MA (United States); Stone, Michael [Stamford Hospital, Department of Surgery, Stamford, CT (United States); Klein, Michael J. [Hospital for Special Surgery, Department of Pathology and Laboratory Medicine, New York, NY (United States)

    2014-08-15

    Proliferative myositis (PM) along with proliferative fasciitis and nodular fasciitis are a group of pseudosarcomatous myofibroblastic proliferations. Although the histologic presentation of each is almost identical, the magnetic resonance imaging (MRI) appearance of proliferative myositis is closer to that of inflammatory myopathies. We report a case of PM in which the imaging and histologic features combine typical findings of PM with unusual imaging features, suggesting of reactive (or nodular) fasciitis. (orig.)

  9. Atypical proliferative myositis: original MR description with pathologic correlation: Case report

    International Nuclear Information System (INIS)

    Jarraya, Mohamed; Guermazi, Ali; Parva, Pedram; Stone, Michael; Klein, Michael J.

    2014-01-01

    Proliferative myositis (PM) along with proliferative fasciitis and nodular fasciitis are a group of pseudosarcomatous myofibroblastic proliferations. Although the histologic presentation of each is almost identical, the magnetic resonance imaging (MRI) appearance of proliferative myositis is closer to that of inflammatory myopathies. We report a case of PM in which the imaging and histologic features combine typical findings of PM with unusual imaging features, suggesting of reactive (or nodular) fasciitis. (orig.)

  10. T-cell proliferative responses following sepsis in neonatal rats.

    Science.gov (United States)

    Dallal, Ousama; Ravindranath, Thyyar M; Choudhry, Mashkoor A; Kohn, Annamarie; Muraskas, Jonathan K; Namak, Shahla Y; Alattar, Mohammad H; Sayeed, Mohammed M

    2003-01-01

    Both experimental and clinical evidence suggest a suppression of T-cell function in burn and sepsis. The objective of the present study was to evaluate splenocyte and purified T-cell proliferative response and IL-2 production in septic neonatal rats. We also examined if alterations in T-cell proliferation and IL-2 production in neonatal sepsis is due to elevation in PGE2. PGE2 is known to play a significant role in T-cell suppression during sepsis in adults. Sepsis was induced in 15-day-old neonatal Sprague-Dawley rats by implanting 0.1 cm3 of fecal pellet impregnated with Escherichia coli (50 CFU) and Bacteroides fragilis (10(3) CFU). Animals receiving fecal pellets without the bacteria were designated as sterile. A group of septic and sterile rats were treated with PGE2 synthesis inhibitors, NS398 and resveratrol. These treatments of animals allowed us to evaluate the role of PGE2 in T-cell suppression during neonatal sepsis. Splenocytes as well as purified T cells were prepared and then proliferative response and IL-2 productive capacities were measured. A significant suppression of splenocyte proliferation and IL-2 production was noticed in both sterile and septic animals compared to the T cells from unoperated control rats. In contrast, the proliferation and IL-2 production by nylon wool purified T cells in sterile rats was not significantly different from control rats, whereas, a significant suppression in Con A-mediated T-cell proliferation and IL-2 production noticed in septic rat T cells compared to the sterile and control rat T cells. Such decrease in T-cell proliferation and IL-2 production was accompanied with 20-25% deaths in neonates implanted with septic pellets. No mortality was noted in sterile-implanted neonates. Treatment of animals with COX-1 inhibitor had no effect on T-cell proliferation response in both septic and sterile groups, whereas COX-2 inhibitor abrogated the decrease in T-cell proliferative response in the septic group. The treatment

  11. A preliminary study of thermo-mechanical stability of carbon S-phase formed in austenitic stainless steel

    Energy Technology Data Exchange (ETDEWEB)

    Li, Wei; Chiu, Yu Long; Dong, Hanshan, E-mail: wsgddf@hotmail.com [School of Metallurgy and Materials, College of Physical and Engineering Sciences, The University of Birmingham, Birmingham (United Kingdom)

    2010-07-01

    Carbon S-phase was generated in the surface of AISI316 austenitic stainless steel by plasma carburising at 500°C for 10h in a gas mixture of 1.5%CH4 and 98.5%H{sub 2}. The thermo-mechanical stability of the carbon S-phase was studied by stressing the 'dog-bone' tensile specimens in the range of 0-200MPa at temperatures ranging from 400 to 500°C for 100-150h. Post-test characterisation was conducted using XRD, SEM, TEM and micro-indentation. The experimental results demonstrate that when tested at a fix temperature the thickness of the carbon S-phase layer increased with the stress applied to the tensile specimens during the thermo-mechanical stability tests. This indicates that tensile stress promotes the diffusion of carbon in the carbon-S-phase. When stressed at 400°C the microstructure of the carbon S-phase was not affected by the stress level; however, when stressed at 450 and 500°C for 100MPa or above, the corrosion resistance of the carbon S-phase slightly deteriorated. The application of a tensile stress during annealing of S-phase layer can retard the deduction of its hardness. This is believed to be related to the early stage precipitation of carbides in the S-phase, which could be facilitated by the applied tensile stress during thermal annealing. (author)

  12. Differential S-phase progression after irradiation of p53 functional versus non-functional tumour cells

    Directory of Open Access Journals (Sweden)

    Zölzer Friedo

    2014-12-01

    Full Text Available Background. Many pathways seem to be involved in the regulation of the intra-S-phase checkpoint after exposure to ionizing radiation, but the role of p53 has proven to be rather elusive. Here we have a closer look at the progression of irradiated cells through S-phase in dependence of their p53 status.

  13. Enhancement of postreplication repair in ultraviolet-light-irradiated Chinese hamster cells by irradiation in G2 or s-phase

    International Nuclear Information System (INIS)

    D'Ambrosio, S.M.; Aebersold, P.M.; Setlow, R.B.

    1978-01-01

    Postreplication repair in synchronous Chinese hamster cells was determined after split doses of ultraviolet (uv) radiation. Repair was enhanced by irradiation of cells in G 2 or S-phase with a small dose of uv radiation at least 1.5 h before a three-fold larger dose of uv. There was significantly greater enhancement when the first dose was given in G 2 than when it was given in the S-phase 0.5 to 1.5 h before the test dose. These data indicate that enhancement of postreplication repair does not require active DNA replication and qualitatively is independent of when in the cell cycle the cells are irradiated

  14. S phase entry of neural progenitor cells correlates with increased blood flow in the young subventricular zone.

    Directory of Open Access Journals (Sweden)

    Benjamin Lacar

    Full Text Available The postnatal subventricular zone (SVZ contains proliferating neural progenitor cells in close proximity to blood vessels. Insults and drug treatments acutely stimulate cell proliferation in the SVZ, which was assessed by labeling cells entering S phase. Although G1-to-S progression is metabolically demanding on a minute-to-hour time scale, it remains unknown whether increased SVZ cell proliferation is accompanied by a local hemodynamic response. This neurovascular coupling provides energy substrates to active neuronal assemblies. Transcardial dye perfusion revealed the presence of capillaries throughout the SVZ that constrict upon applications of the thromboxane A(2 receptor agonist U-46119 in acute brain slice preparations. We then monitored in vivo blood flow using laser Doppler flowmetry via a microprobe located either in the SVZ or a mature network. U-46119 injections into the lateral ventricle decreased blood flow in the SVZ and the striatum, which are near the ventricle. A 1-hour ventricular injection of epidermal and basic fibroblast growth factor (EGF and bFGF significantly increased the percentage of Sox2 transcription factor-positive cells in S phase 1.5 hours post-injection. This increase was accompanied by a sustained rise in blood flow in the SVZ but not in the striatum. Direct growth factor injections into the cortex did not alter local blood flow, ruling out direct effects on capillaries. These findings suggest that an acute increase in the number of G1-to-S cycling SVZ cells is accompanied by neurometabolic-vascular coupling, which may provide energy and nutrient for cell cycle progression.

  15. A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)-p53 signaling

    NARCIS (Netherlands)

    Shvarts, Avi; Brummelkamp, Thijn R.; Scheeren, Ferenc; Koh, Eugene; Daley, George Q.; Spits, Hergen; Bernards, René

    2002-01-01

    Senescence limits the proliferative capacity of primary cells in culture. We describe here a genetic screen to identify genes that allow bypass of this checkpoint. Using retroviral cDNA expression libraries, we identify BCL6 as a potent inhibitor of senescence. BCL6 is frequently activated in

  16. A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19ARF-p53 signaling

    NARCIS (Netherlands)

    Shvarts, A.; Brummelkamp, T.; Koh, E.; Daley, G.Q.; Bernards, R.A.

    2002-01-01

    Senescence limits the proliferative capacity of primary cells in culture. We describe here a genetic screen to identify genes that allow bypass of this checkpoint. Using retroviral cDNA expression libraries, we identify BCL6 as a potent inhibitor of senescence. BCL6 is frequently activated in

  17. Analysis and Enhancements of a Prolific Macroscopic Model of Epilepsy

    Directory of Open Access Journals (Sweden)

    Christopher Fietkiewicz

    2016-01-01

    Full Text Available Macroscopic models of epilepsy can deliver surprisingly realistic EEG simulations. In the present study, a prolific series of models is evaluated with regard to theoretical and computational concerns, and enhancements are developed. Specifically, we analyze three aspects of the models: (1 Using dynamical systems analysis, we demonstrate and explain the presence of direct current potentials in the simulated EEG that were previously undocumented. (2 We explain how the system was not ideally formulated for numerical integration of stochastic differential equations. A reformulated system is developed to support proper methodology. (3 We explain an unreported contradiction in the published model specification regarding the use of a mathematical reduction method. We then use the method to reduce the number of equations and further improve the computational efficiency. The intent of our critique is to enhance the evolution of macroscopic modeling of epilepsy and assist others who wish to explore this exciting class of models further.

  18. Anticardiolipin antibodies in proliferative diabetic retinopathy: An additional risk factor

    International Nuclear Information System (INIS)

    Shahin, Maha; ElDiasty, Amany M; Mabed, Mohamed

    2009-01-01

    To report the prevalence of anticardiolipin antibodies in patients with proliferative diabetic retinopathy (PDR) having high-risk criteria (HRC). Diabetic patients having PDR with HRC and diabetics free of retinopathy were compared for the presence of anticardiolipin antibodies. Among the 34 patients, 6 (17.7%) of diabetics having PDR with HRC were positive for anticardiolipin antibodies. There was no significant association of aCL antibodies with sex or type of diabetes. Using Pearson's correlation test, no significant associations of aCL antibodies with duration of diabetes or age of patients were found. All patients who were positive for anticardiolipin antibodies had PDR with HRC. The difference was statistically significant. Presence of anticardiolipin antibodies may represent an additional risk factor for PDR. (author)

  19. Accounting for treatment delays when treating highly proliferative tumours

    International Nuclear Information System (INIS)

    Jones, L.; Metcalfe, P.; Hoban, P.

    1999-01-01

    This study was undertaken to investigate the possibility of increasing the dose per fraction or increasing the number of fractions to account for treatment delays occurring during radiotherapy treatments for highly proliferative tumours. The linear quadratic model with time was used to determine the difference in biological effective dose (BED) for the original schedule and the schedule including a treatment delay. Tables of extra fractions and extra dose per fraction required to account for a number of possible delays have been determined. It has been shown that for tumours with very short potential doubling times it is best to deliver the extra dose as an increase in dose per fraction rather than an increase in the number of fractions, while for tumours with moderately short potential doubling times (above 7 days) the reverse is true. The equivalent uninterrupted schedules, which would have delivered the same effects to the tumour, have also been determined. (author)

  20. Inheritance of proliferative breast disease in breast cancer kindreds

    International Nuclear Information System (INIS)

    Skolnick, M.H.; Cannon-Albright, L.A.; Goldgar, D.E.; Ward, J.H.; Marshall, C.J.; Schumann, G.B.; Hogle, H.; McWhorter, W.P.; Wright, E.C.; Tran, T.D.; Bishop, D.T.; Kushner, J.P.; Eyre, H.J.

    1990-01-01

    Previous studies have emphasized that genetic susceptibility to breast cancer is rare and is expressed primarily as premenopausal breast cancer, bilateral breast cancer, or both. Proliferative breast disease (PBD) is a significant risk factor for the development of breast cancer and appears to be a precursor lesion. PBD and breast cancer were studied in 103 women from 20 kindreds that were selected for the presence of two first degree relatives with breast cancer and in 31 control women. Physical examination, screening mammography, and four-quadrant fine-needle breast aspirates were performed. Cytologic analysis of breast aspirates revealed PBD in 35% of clinically normal female first degree relatives of breast cancer cases and in 13% of controls. Genetic analysis suggests that genetic susceptibility causes both PBD and breast cancer in these kindreds. This study supports the hypothesis that this susceptibility is responsible for a considerable portion of breast cancer, including unilateral and postmenopausal breast cancer

  1. Anti-Myeloperoxidase Antibodies Associate with Future Proliferative Lupus Nephritis

    Directory of Open Access Journals (Sweden)

    S. W. Olson

    2017-01-01

    Full Text Available Background. The subclinical pathophysiology of proliferative lupus nephritis (PLN has not been fully elucidated. Myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA is associated with PLN, but prediagnostic levels have not been reported. Methods. We performed a retrospective case-control Department of Defense Serum Repository (DoDSR study comparing MPO-ANCA levels in longitudinal prediagnostic serum samples for 23 biopsy confirmed proliferative lupus nephritis (PLN patients to DoDSR identified age, sex, race, and age of serum matched healthy and SLE without LN disease controls. We also compared the temporal relationship of MPO-ANCA to anti-double stranded DNA antibodies (dsDNAab. Results. A greater proportion of PLN patients had prediagnostic MPO-ANCA levels above ≥3 U/mL and ≥6 U/mL compared to SLE without LN (91% versus 43%, p<0.001; 57% versus 5%, p<0.001, resp.. In subgroup analysis, the MPO-ANCA threshold of ≥3 U/mL was significant at <1 year (88% versus 39%, p=0.007 and 1–4 years (87% versus 38%, p=0.009 prior to diagnosis. Statistically significant subclinical MPO-ANCA levels (≥3 U/mL occurred prior to statistically significant dsDNAab ≥ 3 IU/ml (89% versus 11%, p=0.003. Conclusions. Subclinical MPO-ANCA levels could distinguish future PLN from SLE without LN. MPO-ANCA manifests prior to clinical disease and subclinical dsDNAab to suggest that it may contribute directly to PLN pathogenicity.

  2. S phase entry causes homocysteine-induced death while ataxia telangiectasia and Rad3 related protein functions anti-apoptotically to protect neurons.

    Science.gov (United States)

    Ye, Weizhen; Blain, Stacy W

    2010-08-01

    A major phenotype seen in neurodegenerative disorders is the selective loss of neurons due to apoptotic death and evidence suggests that inappropriate re-activation of cell cycle proteins in post-mitotic neurons may be responsible. To investigate whether reactivation of the G1 cell cycle proteins and S phase entry was linked with apoptosis, we examined homocysteine-induced neuronal cell death in a rat cortical neuron tissue culture system. Hyperhomocysteinaemia is a physiological risk factor for a variety of neurodegenerative diseases, including Alzheimer's disease. We found that in response to homocysteine treatment, cyclin D1, and cyclin-dependent kinases 4 and 2 translocated to the nucleus, and p27 levels decreased. Both cyclin-dependent kinases 4 and 2 regained catalytic activity, the G1 gatekeeper retinoblastoma protein was phosphorylated and DNA synthesis was detected, suggesting transit into S phase. Double-labelling immunofluorescence showed a 95% co-localization of anti-bromodeoxyuridine labelling with apoptotic markers, demonstrating that those cells that entered S phase eventually died. Neurons could be protected from homocysteine-induced death by methods that inhibited G1 phase progression, including down-regulation of cyclin D1 expression, inhibition of cyclin-dependent kinases 4 or 2 activity by small molecule inhibitors, or use of the c-Abl kinase inhibitor, Gleevec, which blocked cyclin D and cyclin-dependent kinase 4 nuclear translocation. However, blocking cell cycle progression post G1, using DNA replication inhibitors, did not prevent apoptosis, suggesting that death was not preventable post the G1-S phase checkpoint. While homocysteine treatment caused DNA damage and activated the DNA damage response, its mechanism of action was distinct from that of more traditional DNA damaging agents, such as camptothecin, as it was p53-independent. Likewise, inhibition of the DNA damage sensors, ataxia-telangiectasia mutant and ataxia telangiectasia and Rad

  3. β2-adrenoceptor blockage induces G1/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NFκB pathway

    Directory of Open Access Journals (Sweden)

    Zhang Dong

    2011-11-01

    Full Text Available Abstract Background Smoking and stress, pancreatic cancer (PanCa risk factors, stimulate nitrosamine 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK and catecholamines production respectively. NNK and catecholamine bind the β-adrenoceptors and induce PanCa cell proliferation; and we have previously suggested that β-adrenergic antagonists may suppress proliferation and invasion and stimulate apoptosis in PanCa. To clarify the mechanism of apoptosis induced by β2-adrenergic antagonist, we hypothesize that blockage of the β2-adrenoceptor could induce G1/S phase arrest and apoptosis and Ras may be a key player in PanCa cells. Results The β1 and β2-adrenoceptor proteins were detected on the cell surface of PanCa cells from pancreatic carcinoma specimen samples by immunohistochemistry. The β2-adrenergic antagonist ICI118,551 significantly induced G1/S phase arrest and apoptosis compared with the β1-adrenergic antagonist metoprolol, which was determined by the flow cytometry assay. β2-adrenergic antagonist therapy significantly suppressed the expression of extracellular signal-regulated kinase, Akt, Bcl-2, cyclin D1, and cyclin E and induced the activation of caspase-3, caspase-9 and Bax by Western blotting. Additionally, the β2-adrenergic antagonist reduced the activation of NFκB in vitro cultured PanCa cells. Conclusions The blockage of β2-adrenoceptor markedly induced PanCa cells to arrest at G1/S phase and consequently resulted in cell death, which is possibly due to that the blockage of β2-adrenoceptor inhibited NFκB, extracellular signal-regulated kinase, and Akt pathways. Therefore, their upstream molecule Ras may be a key factor in the β2-adrenoceptor antagonist induced G1/S phase arrest and apoptosis in PanCa cells. The new pathway discovered in this study may provide an effective therapeutic strategy for PanCa.

  4. GADD45a Regulates Olaquindox-Induced DNA Damage and S-Phase Arrest in Human Hepatoma G2 Cells via JNK/p38 Pathways

    Directory of Open Access Journals (Sweden)

    Daowen Li

    2017-01-01

    Full Text Available Olaquindox, a quinoxaline 1,4-dioxide derivative, is widely used as a feed additive in many countries. The potential genotoxicity of olaquindox, hence, is of concern. However, the proper mechanism of toxicity was unclear. The aim of the present study was to investigate the effect of growth arrest and DNA damage 45 alpha (GADD45a on olaquindox-induced DNA damage and cell cycle arrest in HepG2 cells. The results showed that olaquindox could induce reactive oxygen species (ROS-mediated DNA damage and S-phase arrest, where increases of GADD45a, cyclin A, Cdk 2, p21 and p53 protein expression, decrease of cyclin D1 and the activation of phosphorylation-c-Jun N-terminal kinases (p-JNK, phosphorylation-p38 (p-p38 and phosphorylation-extracellular signal-regulated kinases (p-ERK were involved. However, GADD45a knockdown cells treated with olaquindox could significantly decrease cell viability, exacerbate DNA damage and increase S-phase arrest, associated with the marked activation of p-JNK, p-p38, but not p-ERK. Furthermore, SP600125 and SB203580 aggravated olaquindox-induced DNA damage and S-phase arrest, suppressed the expression of GADD45a. Taken together, these findings revealed that GADD45a played a protective role in olaquindox treatment and JNK/p38 pathways may partly contribute to GADD45a regulated olaquindox-induced DNA damage and S-phase arrest. Our findings increase the understanding on the molecular mechanisms of olaquindox.

  5. Temporal changes in retinal vascular parameters associated with successful panretinal photocoagulation in proliferative diabetic retinopathy

    DEFF Research Database (Denmark)

    Torp, Thomas Lee; Kawasaki, Ryo; Wong, Tien Yin

    2018-01-01

    PURPOSE: We aimed to investigate changes in retinal vascular geometry over time after panretinal photocoagulation (PRP) in patients with proliferative diabetic retinopathy (PDR). METHODS: Thirty-seven eyes with PDR were included. Wide-field fluorescein angiography (Optomap, Optos PLC., Dunfermline......, Scotland, UK) was used to diagnose PDR at baseline and to assess activity at follow-up month three and six. At each time-point, a trained grader measured retinal vessel geometry on optic disc (OD) centred images using semiautomated software (SIVA, Singapore I Vessel Assessment, National University...... of Singapore, Singapore) according to a standardized protocol. RESULTS: At baseline, the mean age and duration of diabetes were 52.8 and 22.3 years, and 65% were male. Mean HbA1c was 69.9 mmol/mol, and blood pressure was 155/84 mmHg. Of the 37 eyes with PDR, eight (22%) eyes had progression at month three...

  6. Proliferative compensation of residual radiation damage in the compartment of hematopoietic early progenitor cells of the mouse

    International Nuclear Information System (INIS)

    Huebner, G.E.; Wangenheim, K.H. von; Feinendegen, L.E.

    1984-01-01

    The rate of cell entry from the compartment of hematopoietic early progenitor cells into differentiation was determined in sublethally irradiated mice. By use of the criterion of repopulating ability, transplantation of 5-( 125 I) iodo-2'-deoxyuridine labeled bone marrow cells into fatally irradiated syngeneic recipients allows to measure the relative number of early progenitor cells lodging in the spleen and the turnover of these cells in the donors. Following 450 rad the relative number of transplantable early progenitor cells in S-phase recovers to normal within 2 weeks and stabilizes after 5 weeks. At this time, the labeled progenitors turn over with a half-time of 1.4-2.2 days; the respective times for unirradiated mice are 1.5-1.8 days. This, quantitative and qualitative residual radiation damage that is known to exist in the compartment of CFU-S, is disguised within 2-5 weeks after irradiation by proliferative compensation in the entirety of early hemopoietic precursor cells which are here defined by their capacity of selfrenewal and delivery of differentiated cells and of seeding to spleens of lethally irradiated recipients. (orig.)

  7. Isoliquiritigenin exhibits anti-proliferative properties in the pituitary independent of estrogen receptor function

    International Nuclear Information System (INIS)

    Weis, Karen E.; Raetzman, Lori T.

    2016-01-01

    The plant flavonoid isoliquiritigenin (ISL) is a botanical estrogen widely taken as an herbal supplement to ease the symptoms of menopause. ISL has been also shown to have anti-tumor properties in a number of cancer cell backgrounds. However, the effects of ISL on normal cells are less well known and virtually unstudied in the context of the pituitary gland. We have established a pituitary explant culture model to screen chemical agents for gene expression changes within the pituitary gland during a period of active proliferation and differentiation. Using this whole-organ culture system we found ISL to be weakly estrogenic based on its ability to induce Cckar mRNA expression, an estrogen receptor (ER) mediated gene. Using a range of ISL from 200 nM to 200 μM, we discovered that ISL promoted cell proliferation at a low concentration, yet potently inhibited proliferation at the highest concentration. ICI 182,780 failed to antagonize ISL's repression of pituitary cell proliferation, indicating the effect is independent of ER signaling. Coincident with a decrease in proliferating cells, we observed down-regulation of transcript for cyclin D2 and E2 and a strong induction of mRNA and protein for the cyclin dependent kinase inhibitor Cdkn1a (p21). Importantly, high dose ISL did not alter the balance of progenitor vs. differentiated cell types within the pituitary explants and they seemed otherwise healthy; however, TUNEL staining revealed an increase in apoptotic cell death in ISL treated cultures. Our results merit further examination of ISL as an anti-tumor agent in the pituitary gland. - Highlights: • Isoliquiritigenin possesses weak estrogenic activity based on induction of Cckar. • ISL can be anti-proliferative in pituitary explants without altering cell lineages. • Anti-proliferative behavior of ISL is not estrogen receptor mediated. • ISL induces p21 expression leading to cell cycle arrest and apoptosis.

  8. Isoliquiritigenin exhibits anti-proliferative properties in the pituitary independent of estrogen receptor function

    Energy Technology Data Exchange (ETDEWEB)

    Weis, Karen E.; Raetzman, Lori T., E-mail: raetzman@life.illinois.edu

    2016-12-15

    The plant flavonoid isoliquiritigenin (ISL) is a botanical estrogen widely taken as an herbal supplement to ease the symptoms of menopause. ISL has been also shown to have anti-tumor properties in a number of cancer cell backgrounds. However, the effects of ISL on normal cells are less well known and virtually unstudied in the context of the pituitary gland. We have established a pituitary explant culture model to screen chemical agents for gene expression changes within the pituitary gland during a period of active proliferation and differentiation. Using this whole-organ culture system we found ISL to be weakly estrogenic based on its ability to induce Cckar mRNA expression, an estrogen receptor (ER) mediated gene. Using a range of ISL from 200 nM to 200 μM, we discovered that ISL promoted cell proliferation at a low concentration, yet potently inhibited proliferation at the highest concentration. ICI 182,780 failed to antagonize ISL's repression of pituitary cell proliferation, indicating the effect is independent of ER signaling. Coincident with a decrease in proliferating cells, we observed down-regulation of transcript for cyclin D2 and E2 and a strong induction of mRNA and protein for the cyclin dependent kinase inhibitor Cdkn1a (p21). Importantly, high dose ISL did not alter the balance of progenitor vs. differentiated cell types within the pituitary explants and they seemed otherwise healthy; however, TUNEL staining revealed an increase in apoptotic cell death in ISL treated cultures. Our results merit further examination of ISL as an anti-tumor agent in the pituitary gland. - Highlights: • Isoliquiritigenin possesses weak estrogenic activity based on induction of Cckar. • ISL can be anti-proliferative in pituitary explants without altering cell lineages. • Anti-proliferative behavior of ISL is not estrogen receptor mediated. • ISL induces p21 expression leading to cell cycle arrest and apoptosis.

  9. Human CDT1 associates with CDC7 and recruits CDC45 to chromatin during S phase

    DEFF Research Database (Denmark)

    Ballabeni, Andrea; Zamponi, Raffaela; Caprara, Greta

    2009-01-01

    The initiation of DNA replication is a tightly controlled process that involves the formation of distinct complexes at origins of DNA replication at specific periods of the cell cycle. Pre-Replicative Complexes are formed during telophase and early G1. They rearrange at the start of S phase to form...... pre-Initiation Complexes, which are a prerequisite for DNA replication. The CDT1 protein is required for the formation of the pre-Replicative Complexes. Here we show that human CDT1 associates with the CDC7 kinase and recruits CDC45 to chromatin. Moreover, we show that the amount of CDT1 bound...

  10. Implications of S-phase exchanges for the mechanisms of radiosensitivity in trisomy 21

    International Nuclear Information System (INIS)

    Athanasiou, K.; Bartsocas, C.S.

    1982-01-01

    Human lymphocytes obtained from four patients with Down syndrome and from two normal individuals were irradiated with X-rays during their S phase and examined for chromatid type aberrations. It is suggested that the significantly increased frequency of asymmetrical chromatid interchanges found in trisomic cells is related to an altered DNA repair system. This altered repair system is probably responsible for the increased frequency of chromosome aberrations that can be induced in these cells by x-rays and the increased tendency for leukemia observed in Down syndrome as well

  11. TRF2 Recruits RTEL1 to Telomeres in S Phase to Promote T-Loop Unwinding

    OpenAIRE

    Sarek, Grzegorz; Vannier, Jean-Baptiste; Panier, Stephanie; Petrini, John?H.J.; Boulton, Simon?J.

    2015-01-01

    Summary The helicase RTEL1 promotes t-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres. An interaction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engages with the telomere to promote t-loop unwinding is unclear. Here, we establish that the shelterin protein TRF2 recruits RTEL1 to telomeres in S phase, which is required to?prevent catastrophic t-loop processing by structure-specific nucleases. We show that ...

  12. Heme oxygenase is not involved in the anti-proliferative effects of statins on pancreatic cancer cells

    International Nuclear Information System (INIS)

    Vanova, K.; Boukalova, S.; Gbelcova, H.; Muchova, L.; Neuzil, J.; Gurlich, R.; Ruml, T.; Vitek, L.

    2016-01-01

    Pancreatic cancer is recognized as one of the most fatal tumors due to its aggressiveness and resistance to therapy. Statins were previously shown to inhibit the proliferation of cancer cells via various signaling pathways. In healthy tissues, statins activate the heme oxygenase pathway, nevertheless the role of heme oxygenase in pancreatic cancer is still controversial. The aim of this study was to evaluate, whether anti-proliferative effects of statins in pancreatic cancer cells are mediated via the heme oxygenase pathway. In vitro effects of various statins and hemin, a heme oxygenase inducer, on cell proliferation were evaluated in PA-TU-8902, MiaPaCa-2 and BxPC-3 human pancreatic cancer cell lines. The effect of statins on heme oxygenase activity was assessed and heme oxygenase-silenced cells were used for pancreatic cancer cell proliferation studies. Cell death rate and reactive oxygen species production were measured in PA-TU-8902 cells, followed by evaluation of the effect of cerivastatin on GFP-K-Ras trafficking and expression of markers of invasiveness, osteopontin (SPP1) and SOX2. While simvastatin and cerivastatin displayed major anti-proliferative properties in all cell lines tested, pravastatin did not affect the cell growth at all. Strong anti-proliferative effect was observed also for hemin. Co-treatment of cerivastatin and hemin increased anti-proliferative potential of these agents, via increased production of reactive oxygen species and cell death compared to individual treatment. Heme oxygenase silencing did not prevent pancreatic cancer cells from the tumor-suppressive effect of cerivastatin or hemin. Cerivastatin, but not pravastatin, protected Ras protein from trafficking to the cell membrane and significantly reduced expressions of SPP1 (p < 0.05) and SOX2 (p < 0.01). Anti-proliferative effects of statins and hemin on human pancreatic cancer cell lines do not seem to be related to the heme oxygenase pathway. While hemin triggers reactive

  13. Fibrinolysis and proliferative endarteritis: two related processes in chronic infections? The model of the blood-borne pathogen Dirofilaria immitis.

    Directory of Open Access Journals (Sweden)

    Javier González-Miguel

    Full Text Available The interaction between blood-borne pathogens and fibrinolysis is one of the most important mechanisms that mediate invasion and the establishment of infectious agents in their hosts. However, overproduction of plasmin (final product of the route has been related in other contexts to proliferation and migration of the arterial wall cells and degradation of the extracellular matrix. We have recently identified fibrinolysis-activating antigens from Dirofilaria immitis, a blood-borne parasite whose key pathological event (proliferative endarteritis is produced by similar mechanisms to those indicated above. The objective of this work is to study how two of this antigens [actin (ACT and fructose-bisphosphate aldolase (FBAL] highly conserved in pathogens, activate fibrinolysis and to establish a relationship between this activation and the development of proliferative endarteritis during cardiopulmonary dirofilariasis. We demonstrate that both proteins bind plasminogen, enhance plasmin generation, stimulate the expression of the fibrinolytic activators tPA and uPA in endothelial cell cultures and are located on the surface of the worm in contact with the host's blood. ELISA, western blot and immunofluorescence techniques were employed for this purpose. Additionally, the implication of lysine residues in this interaction was analyzed by bioinformatics. The involvement of plasmin generated by the ACT/FBAL and plasminogen binding in cell proliferation and migration, and degradation of the extracellular matrix were shown in an "in vitro" model of endothelial and smooth muscle cells in culture. The obtained results indicate that ACT and FBAL from D. immitis activate fibrinolysis, which could be used by the parasite like a survival mechanism to avoid the clot formation. However, long-term overproduction of plasmin can trigger pathological events similar to those described in the emergence of proliferative endarteritis. Due to the high degree of

  14. The Role of MKP-1 in the Anti-Proliferative Effects of Glucocorticoids in Primary Rat Pre-Osteoblasts.

    Directory of Open Access Journals (Sweden)

    Micheline Sanderson

    Full Text Available Glucocorticoid (GC-induced osteoporosis has been attributed to a GC-induced suppression of pre-osteoblast proliferation. Our previous work identified a critical role for mitogen-activated protein kinase (MAPK phosphatase-1 (MKP-1 in mediating the anti-proliferative effects of GCs in immortalized pre-osteoblasts, but we subsequently found that MKP-1 null mice were not protected against the pathological effects of GCs on bone. In order to reconcile this discrepancy, we have assessed the effects of GCs on proliferation, activation of the MAPK ERK1/2 and MKP-1 expression in primary adipose-derived stromal cells (ADSCs and ADSC-derived pre-osteoblasts (ADSC-OBs. ADSCs were isolated by means of collagenase digestion from adipose tissue biopsies harvested from adult male Wistar rats. ADSC-OBs were prepared by treating ADSCs with osteoblast differentiation media for 7 days. The effects of increasing concentrations of the GC dexamethasone on basal and mitogen-stimulated cell proliferation were quantified by tritiated thymidine incorporation. ERK1/2 activity was measured by Western blotting, while MKP-1 expression was quantified on both RNA and protein levels, using semi-quantitative real-time PCR and Western blotting, respectively. GCs were strongly anti-proliferative in both naïve ADSCs and ADSC-OBs, but had very little effect on mitogen-induced ERK1/2 activation and did not upregulate MKP-1 protein expression. These findings suggest that the anti-proliferative effects of GCs in primary ADSCs and ADSC-OBs in vitro do not require the inhibition of ERK1/2 activation by MKP-1, which is consistent with our in vivo findings in MKP-1 null mice.

  15. Origin of the modified orientation relationship for S(S'')-phase in Al-Mg-Cu alloys

    International Nuclear Information System (INIS)

    Kovarik, L.; Miller, M.K.; Court, S.A.; Mills, M.J.

    2006-01-01

    The formation of S-phase with a modified orientation relationship (OR) has been previously observed in several Al-Cu-Mg alloys. In this paper, high-resolution transmission electron microscopy and Z-contrast imaging have been used to study the origin of the modified OR in an alloy with low Cu/Mg ratio and small Si addition. Based on the observations, and supported by ab initio simulations, the formation is governed by coherency at the (0 2 1) S //(0 1 4) Al S-phase/matrix interface, which is shown to coexist with the more commonly reported (0 0 1) S //(0 2 1) Al interface. This new (0 2 1) S //(0 1 4) Al S-phase/matrix interface explanation is compared with previously published explanations based on the invariant line concept and establishment of a different S-phase/matrix interface. Energy dispersive X-ray spectroscopy and atom probe tomography indicate that the S-phase is slightly enriched in Si. The role of Si as well as the overall alloy composition is discussed. Because of the similarities between our results and the early work of Bagaryatsky, the S''-phase notation is adopted for this early-forming, strained version of the S-phase

  16. TRF2 recruits RTEL1 to telomeres in S phase to promote t-loop unwinding.

    Science.gov (United States)

    Sarek, Grzegorz; Vannier, Jean-Baptiste; Panier, Stephanie; Petrini, John H J; Boulton, Simon J

    2015-02-19

    The helicase RTEL1 promotes t-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres. An interaction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engages with the telomere to promote t-loop unwinding is unclear. Here, we establish that the shelterin protein TRF2 recruits RTEL1 to telomeres in S phase, which is required to prevent catastrophic t-loop processing by structure-specific nucleases. We show that the TRF2-RTEL1 interaction is mediated by a metal-coordinating C4C4 motif in RTEL1, which is compromised by the Hoyeraal-Hreidarsson syndrome (HHS) mutation, RTEL1(R1264H). Conversely, we define a TRF2(I124D) substitution mutation within the TRFH domain of TRF2, which eliminates RTEL1 binding and phenocopies the RTEL1(R1264H) mutation, giving rise to aberrant t-loop excision, telomere length heterogeneity, and loss of the telomere as a circle. These results implicate TRF2 in the recruitment of RTEL1 to facilitate t-loop disassembly at telomeres in S phase. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Potent anti-proliferative effects against oral and cervical cancers of Thai medicinal plants selected from the Thai/Lanna medicinal plant recipe database "MANOSROI III".

    Science.gov (United States)

    Manosroi, Aranya; Akazawa, Hiroyuki; Pattamapun, Kassara; Kitdamrongtham, Worapong; Akihisa, Toshihiro; Manosroi, Worapaka; Manosroi, Jiradej

    2015-07-01

    Thai/Lanna medicinal plant recipes have been used for the treatment of several diseases including oral and cervical cancers. To investigate anti-proliferative activity on human cervical (HeLa) and oral (KB) cancer cell lines of medicinal plants selected from Thai/Lanna medicinal plant recipe database "MANOSROI III". Twenty-three methanolic plant crude extracts were tested for phytochemicals and anti-proliferative activity on HeLa and KB cell lines for 24 h by the sulforhodamine B (SRB) assay at the doses of 1 × 10(1)-1 × 10(-6 )mg/ml. The nine extracts with the concentrations giving 50% growth inhibition (GI50) lower than 100 µg/ml were further semi-purified by liquid/liquid partition in order to evaluate and enhance the anti-proliferative potency. All extracts contained steroids/triterpenoids, but not xanthones. The methanolic extracts of Gloriosa superba L. (Colchinaceae) root and Albizia chinensis (Osbeck) Merr. (Leguminosae-Mimosoideae) wood gave the highest anti-proliferative activity on HeLa and KB cell lines with the GI50 values of 0.91 (6.0- and 0.31-fold of cisplatin and doxorubicin) and 0.16 µg/ml (28.78- and 82.29-fold of cisplatin and doxorubicin), respectively. Hexane and methanol-water fractions of G. superba exhibited the highest anti-proliferative activity on HeLa and KB cell lines with the GI50 values of 0.15 (37- and 1.9-fold of cisplatin and doxorubicin) and 0.058 µg/ml (77.45- and 221.46-fold of cisplatin and doxorubicin), respectively. This study has demonstrated the potential of plants selected from MANOSROI III database especially G. superba and A. chinensis for further development as anti-oral and cervical cancer agents.

  18. Treatment effects of captopril on non-proliferative diabetic retinopathy

    Institute of Scientific and Technical Information of China (English)

    WANG Ning; ZHENG Zhi; JIN Hui-yi; XU Xun

    2012-01-01

    Background Diabetic retinopathy (DR) is one of the most common complications of diabetes.Angiotensin-converting enzyme inhibitor is thought to play an important role in preventing and treating retinal diseases in animal models of DR.The aim of the present study was to investigate the role of angiotensin-converting enzyme inhibitor (ACEI,captopril) in the treatment of patients with non-proliferative DR.Methods Three hundred and seventeen type 2 diabetic patients (88.05% of participants) without or with mild to moderate non-proliferative retinopathy were randomly divided into captopril group (n=202) and placebo group (n=115).All subjects received 24-month follow-up.General clinical examinations,including blood pressure and glycated hemoglobin,as well as comprehensive standardized ophthalmic examinations were performed.Color fundus photography and optical coherence tomography (OCT) were used to grade diabetic retinopathy and detect macular edema respectively.Results The levels of blood pressure and glycated hemoglobin in the two groups of patients remained within the normal range during the entire follow-up and no significant difference was found between the initial and last visits,suggesting that ACEI drugs play a protective role on the DR patients independent of its anti-blood pressure role.DR classification showed that 169 eyes (83.66%) remained unchanged and the DR grade of 33 eyes (16.34%) increased in captopril group,while 84 eyes (73.04%) remained unchanged and the grade of 31 eyes (26.96%) increased in placebo group (P=0.024).Captopril treatment improved macular edema in 55.45% eyes,which was significantly higher than the 37.39% improvement in placebo group (P=0.002).No significant difference was found in the visual acuity between the two groups (P=0.271).Conclusion Captopril can improve or delay the development of DR and macular edema,which can be used in the early treatment of DR patients with type 2 diabetic mellitus.

  19. Proliferative diabetic retinopathy after vitrectomy early factors affect IOP

    Directory of Open Access Journals (Sweden)

    Shi-Bo Liu

    2013-05-01

    Full Text Available AIM:To explore possible causes of early postoperative elevated intraocular pressure caused by proliferative diabetic retinopathy(PDRvitrectomy. METHODS:Totally 72 cases(100 eyeswhich have performed vitrectomy for proliferative diabetic retinopathy were retrospectively analyzed to observe the incidence of postoperative ocular hypertension, and the relevant factors that caused postoperative high intraocular pressure were statistically analyzed. Early postoperative ocular hypertension diagnostic criteria: any time after 2 weeks of non-contact tonometer measured IOP> 25mmHg(1mmHg=0.133kPa. RESULTS:High intraocular pressure after vitrectomy occurred in 27 eyes(27%, the incidence of male and female were 27.27%, 26.79%, the difference was not statistically significant(P>0.05. Eyes filled with balanced liquid filling incidence rate of 30.95%, 6.25%, and the difference was statistically significant(P0.05. Incidences of intraoperative panretinal photocoagulation and additional retinal photocoagulation group were 41%, 20%, and the difference was statistically significant(P<0.05. Preoperative retinopathy of four, five, six groups of incidence were 9.52%, 23.81%, 40.56%, and the groups were statistically significant(P<0.05. Unconsolidated preoperative retinal detachment and retinal detachment incidence rate of 19%, 41%, and the difference was statistically significant(P<0.05. Surgery in the united lens resection with intraoperative unfederated lens the resection group's incidence rate of 34%, 15%, the difference was statistically significant(P<0.05. Logistic regression analysis showed that retinal detachment preoperative and intraoperative intraocular filling were independent risk factors that caused early postoperative ocular hypertension after vitrectomy. CONCLUSION:Post-operative ocular hypertension after PDR vitrectomy is related to preoperative retinal detachment, intraoperative lensectomy, intraoperative intraocular filling, and intraoperative

  20. ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle.

    Science.gov (United States)

    Ray, Alo; Blevins, Chessica; Wani, Gulzar; Wani, Altaf A

    2016-01-01

    Cell cycle checkpoint is mediated by ATR and ATM kinases, as a prompt early response to a variety of DNA insults, and culminates in a highly orchestrated signal transduction cascade. Previously, we defined the regulatory role of nucleotide excision repair (NER) factors, DDB2 and XPC, in checkpoint and ATR/ATM-dependent repair pathway via ATR and ATM phosphorylation and recruitment to ultraviolet radiation (UVR)-induced damage sites. Here, we have dissected the molecular mechanisms of DDB2- and XPC- mediated regulation of ATR and ATM recruitment and activation upon UVR exposures. We show that the ATR and ATM activation and accumulation to UVR-induced damage not only depends on DDB2 and XPC, but also on the NER protein XPA, suggesting that the assembly of an active NER complex is essential for ATR and ATM recruitment. ATR and ATM localization and H2AX phosphorylation at the lesion sites occur as early as ten minutes in asynchronous as well as G1 arrested cells, showing that repair and checkpoint-mediated by ATR and ATM starts early upon UV irradiation. Moreover, our results demonstrated that ATR and ATM recruitment and H2AX phosphorylation are dependent on NER proteins in G1 phase, but not in S phase. We reasoned that in G1 the UVR-induced ssDNA gaps or processed ssDNA, and the bound NER complex promote ATR and ATM recruitment. In S phase, when the UV lesions result in stalled replication forks with long single-stranded DNA, ATR and ATM recruitment to these sites is regulated by different sets of proteins. Taken together, these results provide evidence that UVR-induced ATR and ATM recruitment and activation differ in G1 and S phases due to the existence of distinct types of DNA lesions, which promote assembly of different proteins involved in the process of DNA repair and checkpoint activation.

  1. Glomerular Damage in Experimental Proliferative Glomerulonephritis Under Glomerular Capillary Hypertension

    Directory of Open Access Journals (Sweden)

    Pei-Rong Wang

    2015-03-01

    Full Text Available Background/Aims: Immunologically and hemodynamically mediated the destruction of glomerular architecture is thought to be the major causes of end-stage renal failure. The purpose of this study is to evaluate the effect of glomerular hypertension on glomerular injury and the progression of glomerular sclerosis after Thy-1 nephritis was induced. Method: Thy-1 nephritis was induced in the stroke-prone spontaneously hypertensive rat strain (SHR-SP (group SP and in age-matched Wistar-Kyoto (WKY (group WKY rats, following unilateral nephrectomy (UNX, and a vehicle was injected alone in UNX SHR-SP as control (group SC. Result: The degree of glomerular damage in response to a single dose of anti-thy-1 antibody, and its functional consequences (eg. proteinuria, diminished GFR are more pronounced in group SP than normotensive group WKY and hypertensive group SC without mesangial cell injury. While normotensive group WKY rats recovered completely from mesangial cell injury on day 28-42, glomeruli in group SP kept on persistent macrophage infiltration, α-SMA expression on day 42-56. In addition, glomerular capillary repair with the GECs was rarely seen in pronouncedly proliferative and sclerostic areas. The incidence of glomerular sclerosis and the level of proteinuria were markedly increased by day 56 in the group SP. Conclusions: Our results demonstrate that glomerular hypertension aggravate glomerular damage and glomerulosclerosis in this model of Thy 1 nephritis.

  2. Subretinal Perfluorocarbon Liquid for Dissection of Proliferative Vitreoretinopathy

    Directory of Open Access Journals (Sweden)

    Jose Dalma-Weiszhausz

    2012-01-01

    Full Text Available Proliferative vitreoretinopathy (PVR is a frequent condition following complex retinal detachments or trauma, and subretinal PVR is a common cause of retinal redetachment. Subretinal PVR removal is challenging and may require creating multiple or large retinotomies, making manipulation of the retina difficult and sometimes hazardous. We propose a novel surgical technique that may facilitate subretinal removal of PVR. After peripheral retinotomy of 180 degrees or greater, perfluorocarbon liquid (PFCL is carefully introduced into the subretinal space as a single bubble which provides space to perform the maneuvers. The PFCL serves as a second hand which folds the retina over, thereby allowing better visualization for safer and easier subretinal PVR removal. PFCL in then removed by direct aspiration as a single bubble while still under balanced salt solution, taking advantage of its high surface tension which prevents leaving bubbles behind. The described technique allows adequate exposure of the subretinal space for proper dissection of difficult-to-reach subretinal PVR. We applied this technique in five patients with chronic retinal detachment, extensive subretinal PVR and poor visual potential. The utilization of subretinal PFCL can assist dissection of subretinal PVR and may be useful in eyes with complicated retinal detachment and poor visual prognosis.

  3. Health assessment of environmental pollutants: proliferative and degenerative diseases

    International Nuclear Information System (INIS)

    Stuart, B.O.

    1988-01-01

    In order to achieve a balanced approach to risk assessment between carcinogenic and non-carcinogenic health effects one must examine the risk of disease or death in the general population exposed to a particular air pollutant that can be related quantitatively to intensity and duration of exposures (National Academy of Sciences, 1983). Such risk assessment should be based upon careful evaluation of scientific findings of dose-response relationships in the chronically exposed population. Quantitative assessment of environmentally produced disease in man has proven to be complex and demanding. A variety of factors play important roles in this task. As an example, there are induction-latency periods for chronic diseases, including cancer, which may range from five to twenty-five years. The diseases themselves, whether proliferative or degenerative, may follow several stages of progression. There is only sparse epidemiological data on serious health effects that may be due to environmental as compared to occupational exposures. Exposures to chemical or radiological air contaminants do not occur singly but to a multiplicity of agents, and disease processes are frequently markedly affected by the interaction of a variety of factors, particularly that of cigarette smoking. There is growing recognition of potentially sensitive subpopulations, including the elderly and the very young, but adequate techniques for assessing the magnitude of increased risks to these groups have not yet been developed

  4. Subretinal Perfluorocarbon Liquid for Dissection of Proliferative Vitreoretinopathy

    Science.gov (United States)

    Dalma-Weiszhausz, Jose; Franco-Cardenas, Valentina; Dalma, Alejandro

    2012-01-01

    Proliferative vitreoretinopathy (PVR) is a frequent condition following complex retinal detachments or trauma, and subretinal PVR is a common cause of retinal redetachment. Subretinal PVR removal is challenging and may require creating multiple or large retinotomies, making manipulation of the retina difficult and sometimes hazardous. We propose a novel surgical technique that may facilitate subretinal removal of PVR. After peripheral retinotomy of 180 degrees or greater, perfluorocarbon liquid (PFCL) is carefully introduced into the subretinal space as a single bubble which provides space to perform the maneuvers. The PFCL serves as a second hand which folds the retina over, thereby allowing better visualization for safer and easier subretinal PVR removal. PFCL in then removed by direct aspiration as a single bubble while still under balanced salt solution, taking advantage of its high surface tension which prevents leaving bubbles behind. The described technique allows adequate exposure of the subretinal space for proper dissection of difficult-to-reach subretinal PVR. We applied this technique in five patients with chronic retinal detachment, extensive subretinal PVR and poor visual potential. The utilization of subretinal PFCL can assist dissection of subretinal PVR and may be useful in eyes with complicated retinal detachment and poor visual prognosis. PMID:23502847

  5. Coordination Skills during Vitrectomy in Treatment of Proliferative Diabetic Retinopathy

    Institute of Scientific and Technical Information of China (English)

    Xuehong Chen; Shanshan Luo; Yanchan Liu

    2014-01-01

    Purpose:.To discuss effective nursing and coordination skills for vitrectomy in the treatment of diabetic retinopathy. Methods: Fifty patients (51 eyes) with diabetic retinopathy required vitrectomy were enrolled in this study..Individual nursing service was delivered by strengthening preoperative preparation, providing psychological nursing, and intraopera-tive observation of the severity of diseases by circulating nurses;meticulous nursing was given postoperatively. Results:All 50 patients underwent surgery successfully..Intra-operatively,.patients had stable physical signs..Five patients had postoperative visual acuity0.3..No complicated infection was seen. Conclusion: For patients diagnosed with proliferative diabetic retinopathy requiring vitrectomy,.full preparations should be made and psychological nursing should be delivered preopera-tively, the severity of diseases and clinical reactions should be closely observed intraoperatively,.and proper processing and nursing measures should be taken postoperatively,.which col-lectively enhance surgical success rate,.decrease surgical com-plications,.and attain favorable treatment efficacy.(Eye Science 2014; 29:55-58).

  6. OM-101 Decreases the Fibrotic Response Associated with Proliferative Vitreoretinopathy

    Science.gov (United States)

    Dvashi, Zeev; Ben-Yaakov, Keren; Weinberg, Tamir; Greenwald, Yoel

    2017-01-01

    Purpose This study aimed to investigate the effect of OM-101 on the fibrotic response occurring in proliferative vitreoretinopathy (PVR) in an animal model. Methods Antifibrotic effect of OM-101 was investigated in vivo. As control, eight weeks old c57black mice underwent intravitreal injection with Hepes (group A) or dispase (0.3 units), to induce retinal detachment (RD) and PVR. The dispase-injected mice were randomly divided into two groups B and C (N = 25 mice); in group C, the eyes were treated with intravitreal injection of OM-101 (3 μl), and group B with PBS, as a control. After additional five days, mice were injected with the same initial treatment. Three days later, mice were euthanized, and the eyes were enucleated and processed for histological analysis. Results Intravitreal injection of dispase caused RD in 64% of the mice in group B, and 93% of those mice had PVR. Only 32% of mice treated with OM-101 and dispase (group C) developed RD, and only 25% of those developed PVR. Conclusions OM-101 was found effective in reducing the incidence of RD and PVR maintaining the normal architecture of the retina. This study suggests that OM-101 is a potentially effective and safe drug for the treatment of PVR patients. PMID:29109865

  7. Automated detection of neovascularization for proliferative diabetic retinopathy screening.

    Science.gov (United States)

    Roychowdhury, Sohini; Koozekanani, Dara D; Parhi, Keshab K

    2016-08-01

    Neovascularization is the primary manifestation of proliferative diabetic retinopathy (PDR) that can lead to acquired blindness. This paper presents a novel method that classifies neovascularizations in the 1-optic disc (OD) diameter region (NVD) and elsewhere (NVE) separately to achieve low false positive rates of neovascularization classification. First, the OD region and blood vessels are extracted. Next, the major blood vessel segments in the 1-OD diameter region are classified for NVD, and minor blood vessel segments elsewhere are classified for NVE. For NVD and NVE classifications, optimal region-based feature sets of 10 and 6 features, respectively, are used. The proposed method achieves classification sensitivity, specificity and accuracy for NVD and NVE of 74%, 98.2%, 87.6%, and 61%, 97.5%, 92.1%, respectively. Also, the proposed method achieves 86.4% sensitivity and 76% specificity for screening images with PDR from public and local data sets. Thus, the proposed NVD and NVE detection methods can play a key role in automated screening and prioritization of patients with diabetic retinopathy.

  8. Wingless promotes proliferative growth in a gradient-independent manner.

    Science.gov (United States)

    Baena-Lopez, Luis Alberto; Franch-Marro, Xavier; Vincent, Jean-Paul

    2009-10-06

    Morphogens form concentration gradients that organize patterns of cells and control growth. It has been suggested that, rather than the intensity of morphogen signaling, it is its gradation that is the relevant modulator of cell proliferation. According to this view, the ability of morphogens to regulate growth during development depends on their graded distributions. Here, we describe an experimental test of this model for Wingless, one of the key organizers of wing development in Drosophila. Maximal Wingless signaling suppresses cellular proliferation. In contrast, we found that moderate and uniform amounts of exogenous Wingless, even in the absence of endogenous Wingless, stimulated proliferative growth. Beyond a few cell diameters from the source, Wingless was relatively constant in abundance and thus provided a homogeneous growth-promoting signal. Although morphogen signaling may act in combination with as yet uncharacterized graded growth-promoting pathways, we suggest that the graded nature of morphogen signaling is not required for proliferation, at least in the developing Drosophila wing, during the main period of growth.

  9. Fatty acid synthase inhibition triggers apoptosis during S phase in human cancer cells.

    Science.gov (United States)

    Zhou, Weibo; Simpson, P Jeanette; McFadden, Jill M; Townsend, Craig A; Medghalchi, Susan M; Vadlamudi, Aravinda; Pinn, Michael L; Ronnett, Gabriele V; Kuhajda, Francis P

    2003-11-01

    C75, an inhibitor of fatty acid synthase (FAS), induces apoptosis in cultured human cancer cells. Its proposed mechanism of action linked high levels of malonyl-CoA after FAS inhibition to potential downstream effects including inhibition of carnitine palmitoyltransferase-1 (CPT-1) with resultant inhibition of fatty acid oxidation. Recent data has shown that C75 directly stimulates CPT-1 increasing fatty acid oxidation in MCF-7 human breast cancer cells despite inhibitory concentrations of malonyl-CoA. In light of these findings, we have studied fatty acid metabolism in MCF7 human breast cancer cells to elucidate the mechanism of action of C75. We now report that: (a) in the setting of increased fatty acid oxidation, C75 inhibits fatty acid synthesis; (b) C273, a reduced form of C75, is unable to inhibit fatty acid synthesis and is nontoxic to MCF7 cells; (c) C75 and 5-(tetradecyloxy)-2-furoic acid (TOFA), an inhibitor of acetyl-CoA carboxylase, both cause a significant reduction of fatty acid incorporation into phosphatidylcholine, the major membrane phospholipid, within 2 h; (d) pulse chase studies with [(14)C]acetate labeling of membrane lipids show that both C75 and TOFA accelerate the decay of (14)C-labeled lipid from membranes within 2 h; (e) C75 also promotes a 2-3-fold increase in oxidation of membrane lipids within 2 h; and (f) because interference with phospholipid synthesis during S phase is known to trigger apoptosis in cycling cells, we performed double-labeled terminal deoxynucleotidyltransferase-mediated nick end labeling and BrdUrd analysis with both TOFA and C75. C75 triggered apoptosis during S phase, whereas TOFA did not. Moreover, application of TOFA 2 h before C75 blocked the C75 induced apoptosis, whereas etomoxir did not. Taken together these data indicate that FAS inhibition and its downstream inhibition of phospholipid production is a necessary part of the mechanism of action of C75. CPT-1 stimulation does not likely play a role in the

  10. Proliferative Retinopathy in Type 1 Diabetes Is Associated With Cerebral Microbleeds, Which Is Part of Generalized Microangiopathy

    NARCIS (Netherlands)

    Woerdeman, J.P.; van Duinkerken, E.; Wattjes, M.P.; Barkhof, F.; Snoek, F.J.; Moll, A.C.; Klein, M.; de Boer, M.P.; IJzerman, R.G.; Serne, E.H.; Diamant, M.

    2014-01-01

    OBJECTIVE: We investigated whether proliferative diabetic retinopathy in type 1 diabetic patients can be generalized to cerebral small vessel disease and whether it is associated with impaired peripheral microvascular function. RESEARCH DESIGN AND METHODS: Thirty-three patients with proliferative

  11. Juglans mandshurica Maxim extracts exhibit antitumor activity on HeLa cells in vitro.

    Science.gov (United States)

    Xin, Nian; Hasan, Murtaza; Li, Wei; Li, Yan

    2014-04-01

    The present study examined the potential application of Juglans mandshurica Maxim extracts (HT) for cancer therapy by assessing their anti‑proliferative activity, reduction of telomerase activity, induction of apoptosis and cell cycle arrest in S phase in HeLa cells. From the perspective of using HT as a herbal medicine, photomicroscopy and florescent microscopy techniques were utilized to characterize the effect of the extracts on telomerase activity and cell morphology. Flow cytometry was employed to study apoptosis and cell cycle of HeLa cells, and DNA laddering was performed. The results showed that HT inhibited cell proliferation and telomerase activity, induced apoptosis and caused S phase arrest of HeLa cells in vitro. HT inhibited HeLa cell proliferation significantly, and the highest inhibition rate was 83.7%. A trap‑silver staining assay showed that HT was capable of markedly decreasing telomerase activity of HeLa cells and this inhibition was enhanced in a time‑ and dose‑dependent manner. Results of a Hoechst 33258 staining assay showed that HeLa cells treated by HT induced cell death. Through DNA agarose gel electrophoresis, DNA ladders of HeLa cells treated with HT were observed, indicating apoptosis. In conclusion, the present study demonstrated that HT exhibited anti‑tumor effects comprising the inhibition of growth and telomerase activity as well as apoptosis and cell cycle arrest in HeLa cells.

  12. Anti-proliferative effects of Bifidobacterium adolescentis SPM0212 extract on human colon cancer cell lines

    International Nuclear Information System (INIS)

    Lee, Do Kyung; Jang, Seok; Kim, Mi Jin; Kim, Jung Hyun; Chung, Myung Jun; Kim, Kyung Jae; Ha, Nam Joo

    2008-01-01

    Lactic acid bacteria (LAB) are beneficial probiotic organisms that contribute to improved nutrition, microbial balance, and immuno-enhancement of the intestinal tract, as well as anti-tumor activity. The aim of the present work was to study the growth inhibition of tumor cells by butanol extract of Bifidobacterium adolescentis isolated from healthy young Koreans. The anti-proliferative activity of B. adolescentis isolates was assessed by XTT assays on three human colon cancer cell lines (Caco-2, HT-29, and SW480). The effects of B. adolescentis SPM0212 butanol extract on tumor necrosis factor-α (TNF-α) and nitric oxide (NO) production were tested using the murine macrophage RAW 264.7 cell line. The butanol extract of B. adolescentis SPM0212 dose-dependently inhibited the growth of Caco-2, HT-29, and SW480 cells by 70%, 30%, and 40%, respectively, at 200 μg/mL. Additionally, the butanol extract of B. adolescentis SPM0212 induced macrophage activation and significantly increased the production of TNF-α and NO, which regulate immune modulation and are cytotoxic to tumor cells. The butanol extract of B. adolescentis SPM0212 increased activity of the host immune system and may improve human health by helping to prevent colon cancer as a biological response modifier

  13. Cytological evidence for DNA chain elongation after UV irradiation in the S phase

    International Nuclear Information System (INIS)

    Minka, D.F.; Nath, J.

    1981-01-01

    Human cells irradiated with UV light synthesize lower molecular weight DNA than unirradiated cells. This reduction in molecular weight is greater in xeroderma pigmentosum (XP) cells than in normal cells. The molecular weight of DNA is further reduced by the addition of caffeine to XP cells. By several hours after irradiation, DNA fragments are barely detectable. Cells from excision-proficient and excision-deficient XP patients were studied autoradiographically to produce cytological evidence of DNA chain elongation. Replicate cultures with and without caffeine were synchronized and irradiated with UV light during the S phase. Caffeine was removed in G2, and the cells were labeled with 3 H-thymidine. Results showed significantly increased labeling during G2 of excision-deficient XP cells. Labeling was dependent on the time of irradiation and presence of caffeine. The XP variant cells had no increase in labeling for any irradiation time

  14. Automatic Detection of P and S Phases by Support Vector Machine

    Science.gov (United States)

    Jiang, Y.; Ning, J.; Bao, T.

    2017-12-01

    Many methods in seismology rely on accurately picked phases. A well performed program on automatically phase picking will assure the application of these methods. Related researches before mostly focus on finding different characteristics between noise and phases, which are all not enough successful. We have developed a new method which mainly based on support vector machine to detect P and S phases. In it, we first input some waveform pieces into the support vector machine, then employ it to work out a hyper plane which can divide the space into two parts: respectively noise and phase. We further use the same method to find a hyper plane which can separate the phase space into P and S parts based on the three components' cross-correlation matrix. In order to further improve the ability of phase detection, we also employ array data. At last, we show that the overall effect of our method is robust by employing both synthetic and real data.

  15. Ductal carcinoma of breast: nuclear grade as a predictor of S-phase fraction.

    Science.gov (United States)

    Dabbs, D J

    1993-06-01

    Nuclear grade (NG) and S-phase fraction (SPF) are established independent prognostic variables for ductal breast carcinomas. Nuclear grade can be assigned by a pathologist in a simple fashion during histopathologic evaluation of the tumor, while SPF requires flow cytometric evaluation of tumor samples. This prospective study was undertaken to determine whether elevated SPF could be predicted from NG alone and how NG and SPF correlate with c-erbB-2 expression. Eighty-two breast carcinomas of ductal type were assigned an NG of low (grade 1 or grade 2) or high (grade 3). S-phase fraction was recorded initially from fresh-frozen tissue samples and was designated as either low SPF (below the value designated as the cutoff for elevated SPF) or high SPF (a value at or greater than the cutoff value). On fresh tissue the NG predicted the range of SPF (low or high) in 89% of cases. Four percent of the cases that did not correlate could definitely be attributed to sample error. The remaining 7% that did not correlate could have been due to sample error, specimen quality, or tumor heterogeneity, as demonstrated by reversal of SPF range as performed on paraffin blocks of tumor. Eighty-eight percent of the tumors positive for c-erbB-2 were NG 3 and 12% were NG 2. All c-erbB-2 tumors were aneuploid. This study demonstrates the importance of carefully assigning NGs on tissue and indicates the importance of reviewing flow cytometric data side by side with histopathologic parameters to detect discrepancies between these two modalities. Careful nuclear grading assignment can accurately predict the range of SPF.

  16. Neurotrophins and Neurotrophin Receptors in Proliferative Diabetic Retinopathy

    Science.gov (United States)

    Abu El-Asrar, Ahmed M.; Mohammad, Ghulam; De Hertogh, Gert; Nawaz, Mohd Imtiaz; Van Den Eynde, Kathleen; Siddiquei, Mohammad Mairaj; Struyf, Sofie; Opdenakker, Ghislain; Geboes, Karel

    2013-01-01

    Neurotrophins (NTs) are emerging as important mediators of angiogenesis and fibrosis. We investigated the expression of the NTs nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) and their receptors TrkA, TrkB, and TrkC in proliferative diabetic retinopathy (PDR). As a comparison, we examined the expression of NTs and their receptors in the retinas of diabetic rats. Vitreous samples from 16 PDR and 15 nondiabetic patients were studied by Western blot analysis and enzyme-linked immunosorbent assay (ELISA). Epiretinal membranes from 17 patients with PDR were studied by immunohistochemistry. Rats were made diabetic with a single high dose of streptozotocin and retinas of rats were examined by Western blot analysis. Western blot analysis revealed a significant increase in the expression of NT-3 and NT-4 and the shedding of receptors TrkA and TrkB in vitreous samples from PDR patients compared to nondiabetic controls, whereas NGF and BDNF and the receptor TrkC were not detected with the use of Western blot analysis and ELISA. In epiretinal membranes, vascular endothelial cells and myofibroblasts expressed NT-3 and the receptors TrkA, TrkB and TrkC in situ, whereas NT-4 was not detected. The expression levels of NT-3 and NT-4 and the receptors TrkA and TrkB, both in intact and solubilized forms, were upregulated in the retinas of diabetic rats, whereas the receptor TrkC was not detected. Co-immunoprecipitation studies revealed binding between NT-3 and the receptors TrkA and TrkB in the retinas of diabetic rats. Our findings in diabetic eyes from humans and rats suggest that the increased expression levels within the NT-3 and NT-4/Trk axis are associated with the progression of PDR. PMID:23762379

  17. The impact of octreotide in experimental proliferative vitreoretinopathy

    Directory of Open Access Journals (Sweden)

    Ozge Evren

    2013-01-01

    Full Text Available Aims: This study aims to investigate the effects of intravitreal octreotide on the growth factors, which have significant roles in the pathogenesis of proliferative vitreoretinopathy (PVR. Settings and Design: An experimental trial. Materials and Methods: 21 guinea pigs were randomly assigned to form 3 groups each including 7 animals. In group 1 (the control group, 0.2 ml saline solution was applied intravitreally in a location of 1.5 mm behind the limbus. In group 2 (the sham group, 0.07 IU dispase in 0.1 ml and 0.1 ml saline solution were applied via the same route. The guinea pigs in group 3 (the treatment group were applied 0.07 IU dispase in 0.1 ml and 1 mg octreotide in 0.1 ml via the same route. Octreotide injection was applied twice during the period of 10 weeks of the experiment. At the end of the 10 weeks, eyes were enucleated and retinal homogenates were prepared. The platelet derivated growth factor (PDGF, insulin-like growth factor (IGF 1 and transforming growth factor (TGF ß levels in homogenized retina tissue were measured by Enzyme Linked-Immuno-Sorbent Assay (ELISA method. Statistical Analysis Used: Kruskal-Wallis variance analysis and Mann-Whitney U test. Results: In the treatment group, a significant decrease was observed in retinal PDGF levels (P 0.05. Conclusions: Intravitreally applied octreotide at a dose of 1 mg has a highly strong effect on PDGF. This study suggests that intravitreal octreotide may suppress PVR development and that octreotide may merit investigation for PVR prophylaxis.

  18. Tamponade in surgery for retinal detachment associated with proliferative vitreoretinopathy.

    Science.gov (United States)

    Schwartz, Stephen G; Flynn, Harry W; Lee, Wen-Hsiang; Ssemanda, Elizabeth; Ervin, Ann-Margret

    2009-10-07

    Retinal detachment (RD) with proliferative vitreoretinopathy (PVR) often requires surgery. During surgery, a tamponade agent is needed to reduce the rate of recurrent retinal detachment. The objective of this review was to evaluate the benefits and adverse outcomes of surgery with various tamponade agents. We searched the Cochrane Controlled Register (CENTRAL), MEDLINE, EMBASE, Latin America and Carribbean Health Sciences (LILACS) and the UK Clinical Trials Gateway (UKCTG). There were no language or date restrictions in the search for trials. The electronic databases were last searched on 9 July 2009. We included randomized clinical trials comparing patients treated with various tamponade agents. Two individuals screened the search results independently. One study with two trials was eligible for inclusion in the review. One study with two trials was included in the review. The first trial randomized 151 eyes to receive either silicone oil or sulfur hexafluoride (SF(6)) gas tamponades; the second trial randomized 271 eyes to receive either silicone oil or perfluropropane (C(3)F(8)) gas tamponades. In patients with RD associated with PVR, pars plana vitrectomy and infusion of either silicone oil or perfluropropane gas appear comparable for a broad variety of cases. Sulfur hexafluoride gas was associated with worse anatomic and visual outcomes than either silicone oil or perfluropropane gas. The use of either C(3)F(8) or silicone oil appears reasonable for most patients with RD associated with PVR. Because there do not appear to be any major differences in outcomes between the two agents, the choice of a tamponade agent should be individualized for each patient.

  19. Ki67 Proliferative Index in Carcinoid Tumors Involving Ovary.

    Science.gov (United States)

    Zhang, Xiaotun; Jones, Andrea; Jenkins, Sarah M; Huang, Yajue

    2018-03-01

    Primary ovarian carcinoid tumors are rare neoplasms that constitute less than 0.1% of all ovarian carcinomas. However, carcinoid tumors metastatic to ovaries are more common. Cell proliferative rate is an important factor in the determination of neuroendocrine tumor prognosis. Limited data are available as regards Ki67 proliferation index in predicting the physiological features of carcinoid tumors involving the ovary. Pathology files of Mayo Clinic Rochester (1995-2014) were searched, and clinical information was collected from medical records. All cases were stained with an antibody against Ki67, and digital analysis was performed with digital imaging analysis. A total of 36 cases (median age 64 years, range 33-83 years), including 9 primary (median age 68 years, range 33-73 years) and 27 metastatic carcinoid cases (median age 64 years, range 36-83 years), were investigated in the current study. Seven out of nine (77.8%) primary ovarian carcinoids are associated with mature teratoma. Twenty two metastatic carcinoids (81.5%) were from the GI tract, four (14.8%) from the pancreas, and one (3.7%) from the posterior thorax location. There was significant difference of Ki67 index between primary (median 2.3%, range, 0.6-8.4%) and metastatic carcinoid tumors (median 9.7%, range, 1.3-46.7%) (p = 0.002). The survival time is much shorter among patients with metastatic carcinoid tumor (median survival 5.8 years) comparing to primary ovarian carcinoid tumor (median 14.2 years) (p = 0.0005). A strong association between Ki67 index and patient survival time was identified (Hazard ratio for 1-percentage point increase 1.11, p = 0.001). Comparing to primary ovarian carcinoid tumor, metastatic carcinoid usually exhibits a higher Ki67 index and a worse outcome.

  20. Identification of Genetic on Blood Serum Protein of Prolific Ewes

    Science.gov (United States)

    Sutiyono; Ondho, Y. S.; Setiatin, E. T.; Sutopo; Laily, A. N.; Prasetyowati, D. E.; Noviani, F.

    2018-02-01

    The aim of the research was to identify the genetic specification of blood plasma protein in ewes that are prolific. The material of study of local sheep in Bawen and Jambu Sub-district of Semarang Regency is 132 which is determined by purposive sampling that have been give lambing three times. Ewes were divided into three groups that always has a single child (L1), ever had twins (L2) and twins more than two (LM2). Blood sampling was performed using dispossible syringe in jugular vein as much as 5 ml per ewe. Blood plasma was analyzed by Polyacrylamide Gel Electrophoresis-Thin Layer (PAGETLE) method in Biochemistry Laboratory of Veterinary Faculty of Gadjah Mada University. Data analysis is using descriptive statistics and the laws of equilibrium Hardy-Weberg. The research parameters were comparison type of ewes and frequency genetic of protein of blood serum. The results showed that the parent comparisons of L1, L2 and LM2 were 66 (50.00%), 49 (37.12%) and 17 (12.88%), respectively. The frequency genes haven a high propensity to relationship of prolificacy nature parent are Pal2, AlbB, CPF, TFB, PTFS and AmlB on pointes, 67.65, 55.88, 91.17, 70.59, 79.41 and 91.18%. Conclusion the mostly LM2 ewes have genotypes Pal1Pal2, AlbBAlbC, CpFCpF, TfATfB, PtfSPtfS and AmlBAmlB whit frequency are 52.94%, 52.94%, 88.24, 47.06, 64.71 and 88.24% respectively.

  1. Identification of anti-proliferative kinase inhibitors as potential therapeutic agents to treat canine osteosarcoma.

    Science.gov (United States)

    Mauchle, Ulrike; Selvarajah, Gayathri T; Mol, Jan A; Kirpensteijn, Jolle; Verheije, Monique H

    2015-08-01

    Osteosarcoma is the most common primary bone tumour in dogs but various forms of therapy have not significantly improved clinical outcomes. As dysregulation of kinase activity is often present in tumours, kinases represent attractive molecular targets for cancer therapy. The purpose of this study was to identify novel compounds targeting kinases with the potential to induce cell death in a panel of canine osteosarcoma cell lines. The ability of 80 well-characterized kinase inhibitor compounds to inhibit the proliferation of four canine osteosarcoma cell lines was investigated in vitro. For those compounds with activity, the mechanism of action and capability to potentiate the activity of doxorubicin was further evaluated. The screening showed 22 different kinase inhibitors that induced significant anti-proliferative effects across the four canine osteosarcoma cell lines investigated. Four of these compounds (RO 31-8220, 5-iodotubercidin, BAY 11-7082 and an erbstatin analog) showed significant cell growth inhibitory effects across all cell lines in association with variable induction of apoptosis. RO 31-8220 and 5-iodotubercidin showed the highest ability to potentiate the effects of doxorubicin on cell viability. In conclusion, the present study identified several potent kinase inhibitors targeting the PKC, CK1, PKA, ErbB2, mTOR and NF-κB pathways, which may warrant further investigations for the treatment of osteosarcoma in dogs. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. An "enigmatic" L-carnosine (β-alanyl-L-histidine)? Cell proliferative activity as a fundamental property of a natural dipeptide inherent to traditional antioxidant, anti-aging biological activities: balancing and a hormonally correct agent, novel patented oral therapy dosage formulation for mobility, skeletal muscle power and functional performance, hypothalamic-pituitary- brain relationship in health, aging and stress studies.

    Science.gov (United States)

    Babizhayev, Mark A; Yegorov, Yegor E

    2015-01-01

    Hypothalamic releasing and inhibiting hormones are major neuroendocrine regulators of human body metabolism being driven directly to the anterior pituitary gland via hypothalamic-hypophyseal portal veins. The alternative physiological or therapeutic interventions utilizing the pharmaco-nutritional boost of imidazole-containing dipeptides (non-hydrolized oral form of carnosine, carcinine, N-acetylcarnosine lubricant eye drops) can maintain health, enhance physical exercise performance and prevent ageing. Carnosine (β-alanyl-L-histidine) is synthesized in mammalian skeletal muscle. There is an evidence that the release of carnosine from the skeletal muscle sarcomeres moieties during physical exercise affects autonomic neurotransmission and physiological functions. Carnosine released from skeletal muscle during exercise acts as a powerful afferent physiological signaling stimulus for hypothalamus, may be transported into the hypothalamic tuberomammillary nucleus (TMN), specifically to TMN-histamine neurons and hydrolyzed herewith via activities of carnosine-degrading enzyme (carnosinase 2) localized in situ. Through the colocalized enzymatic activity of Histidine decarboxylase in the histaminergic neurons, the resulting L-histidine may subsequently be converted into histamine, which could be responsible for the effects of carnosine on neurotransmission and physiological function. Carnosine and its imidazole-containing dipeptide derivatives are renowned for their anti-aging, antioxidant, membrane protective, metal ion chelating, buffering, anti-glycation/ transglycating activities used to prevent and treat a spectrum of age-related and metabolic diseases, such as neurodegenerative disease, sight threatening eye diseases, Diabetes mellitus and its complications, cancers and other disorders due to their wide spectrum biological activities. The precursor of carnosine (and related imidazole containing compounds) synthesis in skeletal muscles beta-alanine is used as the

  3. A synthetic cryptochrome inhibitor induces anti-proliferative effects and increases chemosensitivity in human breast cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Chun, Sung Kook [Department of Brain & Cognitive Sciences, Daegu-Gyeongbuk Institute of Science & Technology, Daegu, 711-873 (Korea, Republic of); Department of Biological Sciences, Seoul National University, Seoul, 151-747 (Korea, Republic of); Department of Brain & Cognitive Sciences, Seoul National University, Seoul, 151-747 (Korea, Republic of); Chung, Sooyoung [Department of Biological Sciences, Seoul National University, Seoul, 151-747 (Korea, Republic of); Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 136-705 (Korea, Republic of); Kim, Hee-Dae [Department of Biological Sciences, Seoul National University, Seoul, 151-747 (Korea, Republic of); Lee, Ju Hyung [Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749 (Korea, Republic of); Jang, Jaebong [College of Pharmacy, Seoul National University, Seoul, 151-742 (Korea, Republic of); Kim, Jeongah; Kim, Doyeon [Department of Brain & Cognitive Sciences, Daegu-Gyeongbuk Institute of Science & Technology, Daegu, 711-873 (Korea, Republic of); Department of Biological Sciences, Seoul National University, Seoul, 151-747 (Korea, Republic of); Department of Brain & Cognitive Sciences, Seoul National University, Seoul, 151-747 (Korea, Republic of); Son, Gi Hoon [Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 136-705 (Korea, Republic of); Oh, Young J. [Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749 (Korea, Republic of); Suh, Young-Ger [College of Pharmacy, Seoul National University, Seoul, 151-742 (Korea, Republic of); Lee, Cheol Soon [Gachon Clinical Trials Center, Gachon University, Incheon, 417-842 (Korea, Republic of); and others

    2015-11-13

    Disruption of circadian rhythm is a major cause of breast cancer in humans. Cryptochrome (CRY), a circadian transcription factor, is a risk factor for initiation of breast cancer, and it is differentially expressed between normal and breast cancer tissues. Here, we evaluated the anti-proliferative and pro-apoptotic activity of KS15, a recently discovered small-molecule inhibitor of CRY, in human breast cancer cells. First, we investigated whether KS15 treatment could promote E-box-mediated transcription by inhibiting the activity of CRY in MCF-7 human breast cancer cells. Protein and mRNA levels of regulators of cell cycle and apoptosis, as well as core clock genes, were differentially modulated in response to KS15. Next, we investigated whether KS15 could inhibit proliferation and increase sensitivity to anti-tumor drugs in MCF-7 cells. We found that KS15 decreased the speed of cell growth and increased the chemosensitivity of MCF-7 cells to doxorubicin and tamoxifen, but had no effect on MCF-10A cells. These findings suggested that pharmacological inhibition of CRY by KS15 exerts an anti-proliferative effect and increases sensitivity to anti-tumor drugs in a specific type of breast cancer. - Highlights: • Cryptochrome inhibitor (KS15) has anti-tumor activity to human breast cancer cells. • KS15 induces differential changes in cell cycle regulators and pro-apoptotic genes. • KS15 inhibits MCF-7 cell growth and enhances susceptibility to anti-tumor drugs.

  4. A synthetic cryptochrome inhibitor induces anti-proliferative effects and increases chemosensitivity in human breast cancer cells

    International Nuclear Information System (INIS)

    Chun, Sung Kook; Chung, Sooyoung; Kim, Hee-Dae; Lee, Ju Hyung; Jang, Jaebong; Kim, Jeongah; Kim, Doyeon; Son, Gi Hoon; Oh, Young J.; Suh, Young-Ger; Lee, Cheol Soon

    2015-01-01

    Disruption of circadian rhythm is a major cause of breast cancer in humans. Cryptochrome (CRY), a circadian transcription factor, is a risk factor for initiation of breast cancer, and it is differentially expressed between normal and breast cancer tissues. Here, we evaluated the anti-proliferative and pro-apoptotic activity of KS15, a recently discovered small-molecule inhibitor of CRY, in human breast cancer cells. First, we investigated whether KS15 treatment could promote E-box-mediated transcription by inhibiting the activity of CRY in MCF-7 human breast cancer cells. Protein and mRNA levels of regulators of cell cycle and apoptosis, as well as core clock genes, were differentially modulated in response to KS15. Next, we investigated whether KS15 could inhibit proliferation and increase sensitivity to anti-tumor drugs in MCF-7 cells. We found that KS15 decreased the speed of cell growth and increased the chemosensitivity of MCF-7 cells to doxorubicin and tamoxifen, but had no effect on MCF-10A cells. These findings suggested that pharmacological inhibition of CRY by KS15 exerts an anti-proliferative effect and increases sensitivity to anti-tumor drugs in a specific type of breast cancer. - Highlights: • Cryptochrome inhibitor (KS15) has anti-tumor activity to human breast cancer cells. • KS15 induces differential changes in cell cycle regulators and pro-apoptotic genes. • KS15 inhibits MCF-7 cell growth and enhances susceptibility to anti-tumor drugs.

  5. Antibacterial, antioxidant and anti-proliferative properties and zinc content of five south Portugal herbs.

    Science.gov (United States)

    Nunes, Ricardo; Pasko, Pawel; Tyszka-Czochara, Malgorzata; Szewczyk, Agnieszka; Szlosarczyk, Marek; Carvalho, Isabel S

    2017-12-01

    Crataegus monogyna L. (Rosaceae) (CM), Equisetum telmateia L. (Equisataceae) (ET), Geranium purpureum Vil. (Geraniaceae) (GP), Mentha suaveolens Ehrh. (Lamiaceae) (MS), and Lavandula stoechas L. spp. luisieri (Lamiaceae) (LS) are all medicinal. To evaluate the antioxidant, antiproliferative and antimicrobial activities of plant extracts and quantify individual phenolics and zinc. Aerial part extracts were prepared with water (W), ethanol (E) and an 80% mixture (80EW). Antioxidant activity was measured with TAA, FRAP and RP methods. Phenolics were quantified with a HPLC. Zinc was quantified using voltammetry. Antibacterial activity (after 48 h) was tested using Enterococcus faecalis, Bacillus cereus, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Listeria monocytogenes. Antiproliferative activity (after 24 h) was tested using HEP G2 cells and fibroblasts. Solvents influenced results; the best were E and 80EW. GP had the highest antioxidant activity (TAA and FRAP of 536.90 mg AAE/g dw and 783.48 mg TE/g dw, respectively). CM had the highest zinc concentration (37.21 mg/kg) and phenolic variety, with neochlorogenic acid as the most abundant (92.91 mg/100 g dw). LS was rich in rosmarinic acid (301.71 mg/100 g dw). GP and LS inhibited the most microorganisms: B. cereus, E. coli and S. aureus. GP also inhibited E. faecalis. CM had the lowest MIC: 5830 μg/mL. The antibacterial activity is explained by the phenolics present. LS and CM showed the most significant anti-proliferative activity, which is explained by their zinc content. The most promising plants for further studies are CM, LS and GP.

  6. Prevalence and 25 year incidence of proliferative retinopathy among Danish type 1 diabetic patients

    DEFF Research Database (Denmark)

    Grauslund, J; Green, A; Sjølie, A K

    2009-01-01

    AIMS/HYPOTHESIS: This study aimed to evaluate the prevalence of retinopathy in long-surviving type 1 diabetic patients. It also investigated the 25 year incidence of proliferative retinopathy and associated risk factors in a Danish population-based cohort. METHODS: A population-based cohort of 727...... type 1 diabetic patients from Fyn County, Denmark, was identified in 1973. In 1981-1982, baseline retinopathy was graded and other risk factors were assessed in 573 patients. Twenty-five years later, 308 patients were still alive. Of these, 201 (65.3%) were re-examined at follow-up in 2007......-2008. RESULTS: The median age and duration of diabetes at follow-up were 58.8 and 43 years, respectively. At follow-up, the prevalence of diabetic retinopathy was 97.0%. Non-proliferative retinopathy was found in 45.8%, and 51.2% had proliferative retinopathy. The 25 year incidence of proliferative retinopathy...

  7. Anti-proliferative therapy for HIV cure: a compound interest approach.

    Science.gov (United States)

    Reeves, Daniel B; Duke, Elizabeth R; Hughes, Sean M; Prlic, Martin; Hladik, Florian; Schiffer, Joshua T

    2017-06-21

    In the era of antiretroviral therapy (ART), HIV-1 infection is no longer tantamount to early death. Yet the benefits of treatment are available only to those who can access, afford, and tolerate taking daily pills. True cure is challenged by HIV latency, the ability of chromosomally integrated virus to persist within memory CD4 + T cells in a non-replicative state and activate when ART is discontinued. Using a mathematical model of HIV dynamics, we demonstrate that treatment strategies offering modest but continual enhancement of reservoir clearance rates result in faster cure than abrupt, one-time reductions in reservoir size. We frame this concept in terms of compounding interest: small changes in interest rate drastically improve returns over time. On ART, latent cell proliferation rates are orders of magnitude larger than activation and new infection rates. Contingent on subtypes of cells that may make up the reservoir and their respective proliferation rates, our model predicts that coupling clinically available, anti-proliferative therapies with ART could result in functional cure within 2-10 years rather than several decades on ART alone.

  8. Imaging findings in children with proliferative disorders following multivisceral transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Hryhorczuk, Anastasia L. [Tufts Medical Center, Department of Radiology, Boston, MA (United States); Kim, Heung Bae [Boston Children' s Hospital, Department of Surgery, Boston, MA (United States); Harris, Marian H.; Vargas, Sara O. [Boston Children' s Hospital, Department of Pathology, Boston, MA (United States); Zurakowski, David [Boston Children' s Hospital, Department of Biostatistics, Boston, MA (United States); Lee, Edward Y. [Boston Children' s Hospital and Harvard Medical School, Departments of Radiology and Medicine, Boston, MA (United States)

    2015-08-15

    Multivisceral transplantation represents an important treatment option for children with intestinal failure. The attendant immunosuppression can lead to a spectrum of cellular proliferations including benign and malignant smooth muscle tumors and lymphoproliferative disorders, many related to cellular dysregulation from Epstein-Barr virus infection. The purpose of this study is to investigate the rates of post-transplantation proliferative disorders among children with multivisceral transplantation and to characterize the imaging and pathological features of these disorders. We identified all consecutive children who underwent multivisceral transplant from August 2004 to October 2011 with at least 27 months of clinical and imaging follow-up. We reviewed medical records to determine the underlying causes of the multivisceral transplant, age at transplantation, onset of neoplasm development, and outcome. Two pediatric radiologists reviewed all imaging studies independently and diagnosis of disease was made by consensus interpretation. Pathological specimens were reviewed for histopathological findings of post-transplantation neoplasm in this pediatric patient population. The study population consisted of 14 consecutive pediatric patients (7 boys and 7 girls; mean age 26 months, range 4-113 months). Of these 14 children, 4 (29%) developed histologically confirmed post-transplant neoplasms at a mean time of 2.4 years after multivisceral transplantation. Types of neoplasms included post-transplant lymphoproliferative disorder (PTLD) in three (21%) and Epstein-Barr-virus-associated smooth muscle tumor in two (14%). (One child developed both neoplasms following transplantation). Both children with smooth muscle tumor associated with Epstein-Barr virus presented with characteristic hypointense solid masses with peripheral rim enhancement on cross-sectional imaging studies. The mortality rate of children who developed post-transplant neoplasms was higher than that of those

  9. Imaging findings in children with proliferative disorders following multivisceral transplantation

    International Nuclear Information System (INIS)

    Hryhorczuk, Anastasia L.; Kim, Heung Bae; Harris, Marian H.; Vargas, Sara O.; Zurakowski, David; Lee, Edward Y.

    2015-01-01

    Multivisceral transplantation represents an important treatment option for children with intestinal failure. The attendant immunosuppression can lead to a spectrum of cellular proliferations including benign and malignant smooth muscle tumors and lymphoproliferative disorders, many related to cellular dysregulation from Epstein-Barr virus infection. The purpose of this study is to investigate the rates of post-transplantation proliferative disorders among children with multivisceral transplantation and to characterize the imaging and pathological features of these disorders. We identified all consecutive children who underwent multivisceral transplant from August 2004 to October 2011 with at least 27 months of clinical and imaging follow-up. We reviewed medical records to determine the underlying causes of the multivisceral transplant, age at transplantation, onset of neoplasm development, and outcome. Two pediatric radiologists reviewed all imaging studies independently and diagnosis of disease was made by consensus interpretation. Pathological specimens were reviewed for histopathological findings of post-transplantation neoplasm in this pediatric patient population. The study population consisted of 14 consecutive pediatric patients (7 boys and 7 girls; mean age 26 months, range 4-113 months). Of these 14 children, 4 (29%) developed histologically confirmed post-transplant neoplasms at a mean time of 2.4 years after multivisceral transplantation. Types of neoplasms included post-transplant lymphoproliferative disorder (PTLD) in three (21%) and Epstein-Barr-virus-associated smooth muscle tumor in two (14%). (One child developed both neoplasms following transplantation). Both children with smooth muscle tumor associated with Epstein-Barr virus presented with characteristic hypointense solid masses with peripheral rim enhancement on cross-sectional imaging studies. The mortality rate of children who developed post-transplant neoplasms was higher than that of those

  10. Regional control of Drosophila gut stem cell proliferation: EGF establishes GSSC proliferative set point & controls emergence from quiescence.

    Science.gov (United States)

    Strand, Marie; Micchelli, Craig A

    2013-01-01

    Adult stem cells vary widely in their rates of proliferation. Some stem cells are constitutively active, while others divide only in response to injury. The mechanism controlling this differential proliferative set point is not well understood. The anterior-posterior (A/P) axis of the adult Drosophila midgut has a segmental organization, displaying physiological compartmentalization and region-specific epithelia. These distinct midgut regions are maintained by defined stem cell populations with unique division schedules, providing an excellent experimental model with which to investigate this question. Here, we focus on the quiescent gastric stem cells (GSSCs) of the acidic copper cell region (CCR), which exhibit the greatest period of latency between divisions of all characterized gut stem cells, to define the molecular basis of differential stem cell activity. Our molecular genetic analysis demonstrates that the mitogenic EGF signaling pathway is a limiting factor controlling GSSC proliferation. We find that under baseline conditions, when GSSCs are largely quiescent, the lowest levels of EGF ligands in the midgut are found in the CCR. However, acute epithelial injury by enteric pathogens leads to an increase in EGF ligand expression in the CCR and rapid expansion of the GSSC lineage. Thus, the unique proliferative set points for gut stem cells residing in physiologically distinct compartments are governed by regional control of niche signals along the A/P axis.

  11. Regional control of Drosophila gut stem cell proliferation: EGF establishes GSSC proliferative set point & controls emergence from quiescence.

    Directory of Open Access Journals (Sweden)

    Marie Strand

    Full Text Available Adult stem cells vary widely in their rates of proliferation. Some stem cells are constitutively active, while others divide only in response to injury. The mechanism controlling this differential proliferative set point is not well understood. The anterior-posterior (A/P axis of the adult Drosophila midgut has a segmental organization, displaying physiological compartmentalization and region-specific epithelia. These distinct midgut regions are maintained by defined stem cell populations with unique division schedules, providing an excellent experimental model with which to investigate this question. Here, we focus on the quiescent gastric stem cells (GSSCs of the acidic copper cell region (CCR, which exhibit the greatest period of latency between divisions of all characterized gut stem cells, to define the molecular basis of differential stem cell activity. Our molecular genetic analysis demonstrates that the mitogenic EGF signaling pathway is a limiting factor controlling GSSC proliferation. We find that under baseline conditions, when GSSCs are largely quiescent, the lowest levels of EGF ligands in the midgut are found in the CCR. However, acute epithelial injury by enteric pathogens leads to an increase in EGF ligand expression in the CCR and rapid expansion of the GSSC lineage. Thus, the unique proliferative set points for gut stem cells residing in physiologically distinct compartments are governed by regional control of niche signals along the A/P axis.

  12. Tet1 is required for Rb phosphorylation during G1/S phase transition

    International Nuclear Information System (INIS)

    Huang, Shengsong; Zhu, Ziqi; Wang, Yiqin; Wang, Yanru; Xu, Longxia; Chen, Xuemei; Xu, Qing; Zhang, Qimin; Zhao, Xin; Yu, Yi; Wu, Denglong

    2013-01-01

    Highlights: •Tet1 was required for NIT3T3 proliferation. •Tet1 depletion inhibited G1-S entry. •Cyclin D1 accumulation and Rb phosphorylation was blocked by Tet1 knockdown. -- Abstract: DNA methylation plays an important role in many biological processes, including regulation of gene expression, maintenance of chromatin conformation and genomic stability. TET-family proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which indicates that these enzymes may participate in DNA demethylation. The function of TET1 has not yet been well characterized in somatic cells. Here, we show that depletion of Tet1 in NIH3T3 cells inhibits cell growth. Furthermore, Tet1 knockdown blocks cyclin D1 accumulation in G1 phase, inhibits Rb phosphorylation and consequently delays entrance to G1/S phase. Taken together, this study demonstrates that Tet1 is required for cell proliferation and that this process is mediated through the Rb pathway

  13. JUPITER’S PHASE VARIATIONS FROM CASSINI : A TESTBED FOR FUTURE DIRECT-IMAGING MISSIONS

    International Nuclear Information System (INIS)

    Mayorga, L. C.; Jackiewicz, J.; Rages, K.; West, R. A.; Knowles, B.; Lewis, N.; Marley, M. S.

    2016-01-01

    We present empirical phase curves of Jupiter from ∼0° to 140° as measured in multiple optical bandpasses by Cassini /Imaging Science Subsystem (ISS) during the Millennium flyby of Jupiter in late 2000 to early 2001. Phase curves are of interest for studying the energy balance of Jupiter and understanding the scattering behavior of the planet as an exoplanet analog. We find that Jupiter is significantly darker at partial phases than an idealized Lambertian planet by roughly 25% and is not well fit by Jupiter-like exoplanet atmospheric models across all wavelengths. We provide analytic fits to Jupiter’s phase function in several Cassini /ISS imaging filter bandpasses. In addition, these observations show that Jupiter’s color is more variable with phase angle than predicted by models. Therefore, the color of even a near Jupiter-twin planet observed at a partial phase cannot be assumed to be comparable to that of Jupiter at full phase. We discuss how the Wide-Field Infrared Survey Telescope and other future direct-imaging missions can enhance the study of cool giants.

  14. S-phase induction by interleukin-6 followed by chemotherapy in patients with refractory multiple myeloma

    DEFF Research Database (Denmark)

    de Nully Brown, P; Jensen, P O; Diamant, M

    1998-01-01

    .0 microg/kg (n = 6) by subcutaneous injection once daily for 5 days and chemotherapy was administered on the last day of rhIL-6 injection. The effect of rhIL-6 treatment on labeling index (LI) was heterogeneous, but no statistically significant change was noted for this particular group as a whole. In two......The plasma cell labeling index (PCLI) in patients with multiple myeloma (MM) is relatively low and this has been associated with the low rate of remission following chemotherapy. Interleukin-6 (IL-6) has been demonstrated to be a major growth factor of myeloma cells. In order to increase the S......-phase proportion of myeloma cells, which might increase the sensitivity to chemotherapy, we gave rhIL-6 followed by chemotherapy to 15 myeloma patients with refractory disease. A total of 25 treatment cycles were administered since ten patients had two cycles. The rhIL-6 dose was 2.5 (n = 3), 5.0 (n = 6) and 10...

  15. Dynamic interaction of p220NPAT and CBP/p300 promotes S-phase entry

    International Nuclear Information System (INIS)

    Wang, Aiyan; Ikura, Tsuyoshi; Eto, Kazuhiro; Ota, Masato S.

    2004-01-01

    Cajal bodies contain cyclin E/cdk2 and the substrate p220 NPAT to regulate the transcription of histones, which is essential for cell proliferation, however, recent mouse knockout studies indicate that cyclin E and cdk2 are dispensable for these events. Because the CBP/p300 histone acetyltransferase are also known to be involved in cell proliferation, we examined the molecular and functional interactions of p220 NPAT with the CBP/p300 at the G1/S boundary as cell cycle regulators. The subnuclear localization of p220 NPAT and CBP/p300 proteins showed that their foci partially overlapped in a cell cycle dependent manner. Overexpression of p220 NPAT and CBP/p300 cooperatively enhanced G1/S transition and DNA synthesis even without cdk2 phosphorylation site. Finally, molecular alignment analysis indicated that p220 NPAT contains several potential substrate sites for CBP/p300. Overall, our findings demonstrate that p220 NPAT and CBP/p300 form a transient complex at the G1/S boundary to play cooperative roles to promote the S-phase entry

  16. Human Adipose Derived Stem Cells Induced Cell Apoptosis and S Phase Arrest in Bladder Tumor

    Directory of Open Access Journals (Sweden)

    Xi Yu

    2015-01-01

    Full Text Available The aim of this study was to determine the effect of human adipose derived stem cells (ADSCs on the viability and apoptosis of human bladder cancer cells. EJ and T24 cells were cocultured with ADSCs or cultured with conditioned medium of ADSCs (ADSC-CM, respectively. The cell counting and colony formation assay showed ADSCs inhibited the proliferation of EJ and T24 cells. Cell viability assessment revealed that the secretions of ADSCs, in the form of conditioned medium, were able to decrease cancer cell viability. Wound-healing assay suggested ADSC-CM suppressed migration of T24 and EJ cells. Moreover, the results of the flow cytometry indicated that ADSC-CM was capable of inducing apoptosis of T24 cells and inducing S phase cell cycle arrest. Western blot revealed ADSC-CM increased the expression of cleaved caspase-3 and cleaved PARP, indicating that ADSC-CM induced apoptosis in a caspase-dependent way. PTEN/PI3K/Akt pathway and Bcl-2 family proteins were involved in the mechanism of this reaction. Our study indicated that ADSCs may provide a promising and practicable manner for bladder tumor therapy.

  17. Anti-proliferative and pro-apoptotic activity of whole extract and isolated indicaxanthin from Opuntia ficus-indica associated with re-activation of the onco-suppressor p16{sup INK4a} gene in human colorectal carcinoma (Caco-2) cells

    Energy Technology Data Exchange (ETDEWEB)

    Naselli, Flores; Tesoriere, Luisa; Caradonna, Fabio; Bellavia, Daniele; Attanzio, Alessandro; Gentile, Carla; Livrea, Maria A., E-mail: maria.livrea@unipa.it

    2014-07-18

    Highlights: • Cactus pear fruit extract and indicaxanthin cause apoptosis of colon cancer cells. • Indicaxanthin does not cause ROS formation, but affects epigenoma in Caco-2 cells. • Indicaxanthin reverses methylation of oncosuppressor p16{sup INK4a} gene in Caco-2 cells. • Indicaxanthin reactivates retinoblastoma in Caco-2 cells. • Bioavailable indicaxanthin may have chemopreventive activity in colon cancer. - Abstract: Phytochemicals may exert chemo-preventive effects on cells of the gastro-intestinal tract by modulating epigenome-regulated gene expression. The effect of the aqueous extract from the edible fruit of Opuntia ficus-indica (OFI extract), and of its betalain pigment indicaxanthin (Ind), on proliferation of human colon cancer Caco-2 cells has been investigated. Whole extract and Ind caused a dose-dependent apoptosis of proliferating cells at nutritionally relevant amounts, with IC{sub 50} 400 ± 25 mg fresh pulp equivalents/mL, and 115 ± 15 μM (n = 9), respectively, without toxicity for post-confluent differentiated cells. Ind accounted for ∼80% of the effect of the whole extract. Ind did not cause oxidative stress in proliferating Caco-2 cells. Epigenomic activity of Ind was evident as de-methylation of the tumor suppressor p16{sup INK4a} gene promoter, reactivation of the silenced mRNA expression and accumulation of p16{sup INK4a}, a major controller of cell cycle. As a consequence, decrease of hyper-phosphorylated, in favor of the hypo-phosphorylated retinoblastoma was observed, with unaltered level of the cycline-dependent kinase CDK4. Cell cycle showed arrest in the G2/M-phase. Dietary cactus pear fruit and Ind may have chemo-preventive potential in intestinal cells.

  18. Anti-proliferative and pro-apoptotic activity of whole extract and isolated indicaxanthin from Opuntia ficus-indica associated with re-activation of the onco-suppressor p16INK4a gene in human colorectal carcinoma (Caco-2) cells

    International Nuclear Information System (INIS)

    Naselli, Flores; Tesoriere, Luisa; Caradonna, Fabio; Bellavia, Daniele; Attanzio, Alessandro; Gentile, Carla; Livrea, Maria A.

    2014-01-01

    Highlights: • Cactus pear fruit extract and indicaxanthin cause apoptosis of colon cancer cells. • Indicaxanthin does not cause ROS formation, but affects epigenoma in Caco-2 cells. • Indicaxanthin reverses methylation of oncosuppressor p16 INK4a gene in Caco-2 cells. • Indicaxanthin reactivates retinoblastoma in Caco-2 cells. • Bioavailable indicaxanthin may have chemopreventive activity in colon cancer. - Abstract: Phytochemicals may exert chemo-preventive effects on cells of the gastro-intestinal tract by modulating epigenome-regulated gene expression. The effect of the aqueous extract from the edible fruit of Opuntia ficus-indica (OFI extract), and of its betalain pigment indicaxanthin (Ind), on proliferation of human colon cancer Caco-2 cells has been investigated. Whole extract and Ind caused a dose-dependent apoptosis of proliferating cells at nutritionally relevant amounts, with IC 50 400 ± 25 mg fresh pulp equivalents/mL, and 115 ± 15 μM (n = 9), respectively, without toxicity for post-confluent differentiated cells. Ind accounted for ∼80% of the effect of the whole extract. Ind did not cause oxidative stress in proliferating Caco-2 cells. Epigenomic activity of Ind was evident as de-methylation of the tumor suppressor p16 INK4a gene promoter, reactivation of the silenced mRNA expression and accumulation of p16 INK4a , a major controller of cell cycle. As a consequence, decrease of hyper-phosphorylated, in favor of the hypo-phosphorylated retinoblastoma was observed, with unaltered level of the cycline-dependent kinase CDK4. Cell cycle showed arrest in the G2/M-phase. Dietary cactus pear fruit and Ind may have chemo-preventive potential in intestinal cells

  19. Tamponade in surgery for retinal detachment associated with proliferative vitreoretinopathy.

    Science.gov (United States)

    Schwartz, Stephen G; Flynn, Harry W; Lee, Wen-Hsiang; Wang, Xue

    2014-02-14

    Retinal detachment (RD) with proliferative vitreoretinopathy (PVR) often requires surgery to restore normal anatomy and to stabilize or improve vision. PVR usually occurs in association with recurrent RD (that is, after initial retinal re-attachment surgery) but occasionally may be associated with primary RD. Either way, a tamponade agent (gas or silicone oil) is needed during surgery to reduce the rate of postoperative recurrent RD. The objective of this review was to assess the relative safety and effectiveness of various tamponade agents used with surgery for retinal detachment (RD) complicated by proliferative vitreoretinopathy (PVR). We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 5), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to June 2013), EMBASE (January 1980 to June 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to June 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 26 June 2013. We included randomized controlled trials (RCTs) of participants undergoing surgery for RD associated with PVR that compared various tamponade agents. Two review authors screened the search results independently. We used the standard methodological procedures expected by The Cochrane Collaboration. The review included 516 participants from three RCTs. One study was conducted in the USA and consisted of two trials: the first trial randomized 151 adults to receive either silicone oil or sulfur hexafluoride (SF6) gas tamponades; and the second trial randomized 271 adults to receive either

  20. S-phase Specific Downregulation of Human O6-Methylguanine DNA Methyltransferase (MGMT and its Serendipitous Interactions with PCNA and p21cip1 Proteins in Glioma Cells

    Directory of Open Access Journals (Sweden)

    AGM Mostofa

    2018-04-01

    Full Text Available Whether the antimutagenic DNA repair protein MGMT works solo in human cells and if it has other cellular functions is not known. Here, we show that human MGMT associates with PCNA and in turn, with the cell cycle inhibitor, p21cip1 in glioblastoma and other cancer cell lines. MGMT protein was shown to harbor a nearly perfect PCNA-Interacting Protein (PIP box motif. Isogenic p53-null H1299 cells were engineered to express the p21 protein by two different procedures. Reciprocal immunoprecipitation/western blotting, Far-western blotting, and confocal microscopy confirmed the specific association of MGMT with PCNA and the ability of p21 to strongly disrupt the MGMT-PCNA complexes in tumor cells. Alkylation DNA damage resulted in a greater colocalization of MGMT and PCNA proteins, particularly in HCT116 cells deficient in p21 expression. p21 expression in isogenic cell lines directly correlated with markedly higher levels of MGMT mRNA, protein, activity and greater resistance to alkylating agents. In other experiments, four glioblastoma cell lines synchronized at the G1/S phase using either double thymidine or thymidine-mimosine blocks and subsequent cycling consistently showed a loss of MGMT protein at mid- to late S-phase, irrespective of the cell line, suggesting such a downregulation is fundamental to cell cycle control. MGMT protein was also specifically degraded in extracts from S-phase cells and evidence strongly suggested the involvement of PCNA-dependent CRL4Cdt2 ubiquitin-ligase in the reaction. Overall, these data provide the first evidence for non-repair functions of MGMT in cell cycle and highlight the involvement of PCNA in MGMT downregulation, with p21 attenuating the process.

  1. Syntheses and modulations in the chromatin contents of histones H1/sup o/ and H1 during G1 and S phases in Chinese hamsters cells

    International Nuclear Information System (INIS)

    D'Anna, J.A.; Gurley, L.R.; Tobey, R.A.

    1982-01-01

    Flow cytometry, conventional autoradiography, and autoradiography employing high concentrations of high specific activity [ 3 H]thymidine indicate that (1) treatment of Chinese hamster ovary (line CHO) cells with butyrate truly blocks cells in G 1 and (2) cells blocked in G 1 by isoleucine deprivation remain blocked in G 1 when they are released into complete medium containing butyrate. Measurements of H1/sup o/ content relative to core histones and H1/sup o/:H1 ratios indicate that H1/sup o/ is enhanced somewhat in G 1 cells arrested by isoleucine deprivation; however, (1) treatment with butyrate greatly increases the H1/sup o/ content in G 1 -blocked cells, and (2) the enhancement is very sensitive to butyrate concentration. Measurements of relative histone contents in the isolated chromatin of synchronized cultures also suggest that the acid-soluble content of histone H1 (relative to core histones) becomes greatly depleted in the isolated chromatin when synchronized cells are blocked in early S phase by sequential use of isoleucine deprivation and hydroxyurea blockade. We also have measured [ 3 H]lysine incorporation, various protein ratios, and relative rates of deposition of newly synthesized H1/sup o/, H1, and H4 onto chromatin during G 1 and S in the absence of butyrate. The results suggest a dynamic picture of chromatin organization in which (1) newly synthesized histone H1/sup o/ binds to chromatin during traverse of G 1 and S phases and (2) histone H1 dissociates from (or becomes loosely bound to) chromatin during prolonged early S-phase block with hydroxyurea

  2. Anti-proliferative and pro-apoptotic activity of whole extract and isolated indicaxanthin from Opuntia ficus-indica associated with re-activation of the onco-suppressor p16(INK4a) gene in human colorectal carcinoma (Caco-2) cells.

    Science.gov (United States)

    Naselli, Flores; Tesoriere, Luisa; Caradonna, Fabio; Bellavia, Daniele; Attanzio, Alessandro; Gentile, Carla; Livrea, Maria A

    2014-07-18

    Phytochemicals may exert chemo-preventive effects on cells of the gastro-intestinal tract by modulating epigenome-regulated gene expression. The effect of the aqueous extract from the edible fruit of Opuntia ficus-indica (OFI extract), and of its betalain pigment indicaxanthin (Ind), on proliferation of human colon cancer Caco-2 cells has been investigated. Whole extract and Ind caused a dose-dependent apoptosis of proliferating cells at nutritionally relevant amounts, with IC50 400±25 mg fresh pulp equivalents/mL, and 115±15 μM (n=9), respectively, without toxicity for post-confluent differentiated cells. Ind accounted for ∼80% of the effect of the whole extract. Ind did not cause oxidative stress in proliferating Caco-2 cells. Epigenomic activity of Ind was evident as de-methylation of the tumor suppressor p16(INK4a) gene promoter, reactivation of the silenced mRNA expression and accumulation of p16(INK4a), a major controller of cell cycle. As a consequence, decrease of hyper-phosphorylated, in favor of the hypo-phosphorylated retinoblastoma was observed, with unaltered level of the cycline-dependent kinase CDK4. Cell cycle showed arrest in the G2/M-phase. Dietary cactus pear fruit and Ind may have chemo-preventive potential in intestinal cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Immunochemical expression of proliferative cell nuclear antigen in aging cultured astrocytes

    Directory of Open Access Journals (Sweden)

    M. C. Vanzani

    2003-08-01

    Full Text Available Cell differentiation degree and mitotic activity were sequentially assessed by immunoperoxidase labeling of glial fibrillary acidic protein (GFAP and proliferative cell nuclear antigen (PCNA, respectively, in rat brain cultured astrocytes maintained up to 60 days in vitro (DIV of first subculture, or weekly passaged until their 12th subculture. Cell count was performed through a 0.01 mm2 section reticule and morphometric analysis with a stereological grid. The number of double immunoreactive cells peaked by 2 DIV to achieve its lowest value at 60 DIV. At 24 hs of cell seeding of successive passages, such values peaked by the 6th subculture to gradually decrease thereafter. Increasing cell hypertrophy was found during the long-term first subculture but not after passaging. At the end of the observation period, doubly immunolabeled astrocytes were still recorded, thus evidencing retention of proliferative potential despite aging.El grado de diferenciación celular y la actividad mitótica fueron secuencialmente determinados mediante marcación por inmunoperoxidasa de la proteína gliofibrilar ácida (GFAP y del antígeno nuclear de proliferación celular (PCNA, respectivamente, en cultivos astrocitarios obtenidos de encéfalo de rata y mantenidos hasta 60 días in vitro (DIV de su primer subcultivo, o mediante pasajes semanales hasta el 12do subcultivo. El conteo celular se realizó mediante una retícula de 0.01-mm2 de sección y el análisis morfométrico con una grilla estereológica. El número de células doblemente inmunorreactivas alcanzó valores máximos a los 2 DIV para descender a los menores a los 60 DIV. A las 24 hs de sembrado celular de los sucesivos pasajes, esos valores ascendieron hacia el 6to subcultivo para luego declinar. En cuanto a la hipertrofia celular, se observó en todo el curso del primer subcultivo, pero no durante los posteriores pasajes. Al final del período de observación, todavía se continuaban detectando

  4. Clinical and experimental study on angiopoietin-like protein 8 associated with proliferative diabetic retinopathy

    Directory of Open Access Journals (Sweden)

    Chang-Xia Dong

    2017-12-01

    Full Text Available AIM: To confirm the role of angiopoietin-like protein 8 (Angptl 8 in proliferative diabetic retinopathy (PDR. METHODS: The sera and aqueous humor of 10 PDR patients and 10 non-diabetic retinopathy (NDR patients (idiopathic macular hole patients were collected and the expression of Angptl 8 was detected by enzyme linked immune-sorbent assay (ELISA. Experimental diabetes mice model was induced with streptozotocin. The expression of glycosylated hemoglobin and Angptl 8 in sera was detected. Recombinant Angptl 8 was re-infused into wild type (WT diabetic mice and spatial frequency threshold and contrast sensitivity were measured. In vitro retinal pigment epithelium (RPE were stimulated by recombinant Angptl 8 for 24h. MMT assay were used to detect cell proliferation. At the same time, qRT-PCR and Western blot was used to measure the expression of proliferation-related factors in PRE cells. RESULTS: The expression of Angptl 8 was markedly increased in the sera and aqueous humor of PDR patients (F=99.02, P<0.0001 in sera; t=10.42, P<0.0001 in aqueous. After successfully establishing the diabetic mice model, we found that glycosylated hemoglobin and Angptl 8 expression levels were increased. Re-infusion of recombinant Angptl 8 into WT diabetic mice could further decrease spatial frequency threshold and contrast sensitivity (P<0.01. In vitro, RPE cells stimulated by recombinant Angptl 8 could increase the relative absorbance of MMT assay (1.486±0.042 vs 1.000±0.104, P<0.05 and proliferating cell nuclear antigen (PCNA expression (0.55±0.01 vs 0.29±0.03, P<0.05. The proliferative effect of Angptl 8 is mainly mediated by increasing the expression of proliferation-activating factors cyclin A1 (4.973±0.205 vs 2.720±0.197, P<0.05, cyclin F (5.690±0.219 vs 4.297±0.292, P<0.05 and E2F2 (2.297±0.102 vs 1.750±0.146, P<0.05, and reducing the expression of proliferation-inhibiting factors cdkn1 (2.370±0.074 vs 3.317±0.135, P<0.05 and cdkn2 (4.793±0

  5. T-dependence of human B lymphocyte proliferative response to mitogens.

    Science.gov (United States)

    Brochier, J; Samarut, C; Gueho, J P; Revillard, J P

    1976-01-01

    Human peripheral blood and tonsil lymphocytes were fractionated on anti-Ig-coated Sephadex columns or by centrifugation after rosetting with native sheep erythrocytes. Both methods allowed the recovery of B and T-enriched populations the purity of which was checked by fluorescein-labelled anti-Ig serum, E and EAC rosette formation, and heterologous antisera specific for B or T lymphocytes. The proliferative response of T cells to PHA, Con A, PWM, and ALS was not found different from that of unfractionated cells, whereas no response of the B cells could be observed to these mitogens providing that no contaminating T cells were present. Addition of T lymphocytes to these unresponsive B cells allowed them to respond to phytomitogens, but not to ALS. X-irradiated T cells could, to some extent, replace the diving T lymphocytes; no T-replacing factor could be found in cell-free supernatants from T cells, whether or not they had been activated by mitrogens. This model of B-T cooperation appears useful for studying the differentiation and maturation of human B lymphocytes.

  6. Chemical analyses of wasp-associated streptomyces bacteria reveal a prolific potential for natural products discovery.

    Directory of Open Access Journals (Sweden)

    Michael Poulsen

    2011-02-01

    Full Text Available Identifying new sources for small molecule discovery is necessary to help mitigate the continuous emergence of antibiotic-resistance in pathogenic microbes. Recent studies indicate that one potentially rich source of novel natural products is Actinobacterial symbionts associated with social and solitary Hymenoptera. Here we test this possibility by examining two species of solitary mud dauber wasps, Sceliphron caementarium and Chalybion californicum. We performed enrichment isolations from 33 wasps and obtained more than 200 isolates of Streptomyces Actinobacteria. Chemical analyses of 15 of these isolates identified 11 distinct and structurally diverse secondary metabolites, including a novel polyunsaturated and polyoxygenated macrocyclic lactam, which we name sceliphrolactam. By pairing the 15 Streptomyces strains against a collection of fungi and bacteria, we document their antifungal and antibacterial activity. The prevalence and anti-microbial properties of Actinobacteria associated with these two solitary wasp species suggest the potential role of these Streptomyces as antibiotic-producing symbionts, potentially helping defend their wasp hosts from pathogenic microbes. Finding phylogenetically diverse and chemically prolific Actinobacteria from solitary wasps suggests that insect-associated Actinobacteria can provide a valuable source of novel natural products of pharmaceutical interest.

  7. S-phase checkpoint elements of the E2F-1 family increase radiosensitivity in fibrosarcoma cells lacking p53

    International Nuclear Information System (INIS)

    Bodis, Stephan; Pruschy, Martin; Wirbelauer, Christiane; Glanzmann, Christoph; Krek, Wilhelm

    1997-01-01

    Purpose: Correct advance of cells through the S-phase of the mammalian cell cycle depends on the timely controlled activity of the E2F-1 transcription factor by cyclin A-cdk2. We are studying the reproductive integrity and radiosensitation of isogenic mouse fibrosarcoma cells, differing only in their p53 status, after expression of E2F-1 wildtype (wt) and specific E2F-1 mutants (mt) lacking the cyclin-A-binding domain. In this tumor model system only p53 wild-type expressing tumor cells are sensitive to ionizing radiation in vitro and in vivo. Material and Methods: Either wild-type p53 or genetically engineered p53 'null' mouse embryo fibroblasts were transfected with the oncogenes E1A and ras. These otherwise isogenic fibrosarcoma cells, with a malignant phenotype and tumorigenic in nude mice, were transfected with retroviruses containing either E2F-1 wild-type or specific E2F-1 mutants lacking the cyclin-A binding domain. Reproductive integrity after E2F-1 transfection with or without ionizing radiation (RT) was tested using the clonogenic assay. Tumor cell morphology of treated cells is analyzed for cell death mechanism. Results: E2F-1 wild-type expression in fibrosarcoma cells induced a clear p53 dependent cell death. While clonogenic survival of p53 'null' tumor cells was only slightly reduced with the expression of E2F-1 wild type (survival fraction of 0.5), the clonogenic survival of p53 wild-type fibrosarcoma tumor cells was reduced by at least one logarithm (survival fraction of 0.05). However, expression of the specific E2F-1 mutant lacking the cyclin-A binding domain reduced clonogenic survival in both the p53 'null' and the p53 wild-type fibrosarcoma cells by at least 2 logarithms (survival fraction 0.01 for p53 'null' and 0.002 for p53 wild-type). The mean values of the survival fractions after 2 and 5 Gy radiation alone in p53 'null' fibrosarcoma cells (SF 2 and SF 5) were SF 2 0.7, SF 5 = 0.15, respectively. The combination of ionizing RT in the p53

  8. Uncoupling of S phase and mitosis in cardiomyocytes and hepatocytes lacking the winged-helix transcription factor Trident

    NARCIS (Netherlands)

    Korver, W.; Schilham, M. W.; Moerer, P.; van den Hoff, M. J.; Dam, K.; Lamers, W. H.; Medema, R. H.; Clevers, H.

    1998-01-01

    In order to maintain a stable karyotype, the eukaryotic cell cycle is coordinated such that only one round of S phase precedes each mitosis, and mitosis is not initiated until DNA replication is completed. Several checkpoints and regulatory proteins have been defined in lower eukaryotes that govern

  9. S-phase Synchronization Facilitates the Early Progression of Induced-Cardiomyocyte Reprogramming through Enhanced Cell-Cycle Exit.

    Science.gov (United States)

    Bektik, Emre; Dennis, Adrienne; Pawlowski, Gary; Zhou, Chen; Maleski, Danielle; Takahashi, Satoru; Laurita, Kenneth R; Deschênes, Isabelle; Fu, Ji-Dong

    2018-05-04

    Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds a great promise for regenerative medicine and has been studied in several major directions. However, cell-cycle regulation, a fundamental biological process, has not been investigated during iCM-reprogramming. Here, our time-lapse imaging on iCMs, reprogrammed by Gata4, Mef2c, and Tbx5 (GMT) monocistronic retroviruses, revealed that iCM-reprogramming was majorly initiated at late-G1- or S-phase and nearly half of GMT-reprogrammed iCMs divided soon after reprogramming. iCMs exited cell cycle along the process of reprogramming with decreased percentage of 5-ethynyl-20-deoxyuridine (EdU)⁺/α-myosin heavy chain (αMHC)-GFP⁺ cells. S-phase synchronization post-GMT-infection could enhance cell-cycle exit of reprogrammed iCMs and yield more GFP high iCMs, which achieved an advanced reprogramming with more expression of cardiac genes than GFP low cells. However, S-phase synchronization did not enhance the reprogramming with a polycistronic-viral vector, in which cell-cycle exit had been accelerated. In conclusion, post-infection synchronization of S-phase facilitated the early progression of GMT-reprogramming through a mechanism of enhanced cell-cycle exit.

  10. MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts.

    Science.gov (United States)

    Wang, Daren; Zhang, Hui; Li, Min; Frid, Maria G; Flockton, Amanda R; McKeon, B Alexandre; Yeager, Michael E; Fini, Mehdi A; Morrell, Nicholas W; Pullamsetti, Soni S; Velegala, Sivareddy; Seeger, Werner; McKinsey, Timothy A; Sucharov, Carmen C; Stenmark, Kurt R

    2014-01-03

    Pulmonary hypertensive remodeling is characterized by excessive proliferation, migration, and proinflammatory activation of adventitial fibroblasts. In culture, fibroblasts maintain a similar activated phenotype. The mechanisms responsible for generation/maintenance of this phenotype remain unknown. We hypothesized that aberrant expression of microRNA-124 (miR-124) regulates this activated fibroblast phenotype and sought to determine the signaling pathways through which miR-124 exerts effects. We detected significant decreases in miR-124 expression in fibroblasts isolated from calves and humans with severe pulmonary hypertension. Overexpression of miR-124 by mimic transfection significantly attenuated proliferation, migration, and monocyte chemotactic protein-1 expression of hypertensive fibroblasts, whereas anti-miR-124 treatment of control fibroblasts resulted in their increased proliferation, migration, and monocyte chemotactic protein-1 expression. Furthermore, the alternative splicing factor, polypyrimidine tract-binding protein 1, was shown to be a direct target of miR-124 and to be upregulated both in vivo and in vitro in bovine and human pulmonary hypertensive fibroblasts. The effects of miR-124 on fibroblast proliferation were mediated via direct binding to the 3' untranslated region of polypyrimidine tract-binding protein 1 and subsequent regulation of Notch1/phosphatase and tensin homolog/FOXO3/p21Cip1 and p27Kip1 signaling. We showed that miR-124 directly regulates monocyte chemotactic protein-1 expression in pulmonary hypertension/idiopathic pulmonary arterial hypertension fibroblasts. Furthermore, we demonstrated that miR-124 expression is suppressed by histone deacetylases and that treatment of hypertensive fibroblasts with histone deacetylase inhibitors increased miR-124 expression and decreased proliferation and monocyte chemotactic protein-1 production. Stable decreases in miR-124 expression contribute to an epigenetically reprogrammed, highly

  11. PROSPECTIVE STUDY OF HISTOLOGICAL PROLIFERATIVE CHANGES IN ADJACENT AREAS OF BREAST CANCER

    Directory of Open Access Journals (Sweden)

    Rema Nair Sarkar

    2016-11-01

    Full Text Available BACKGROUND Breast cancer remains a global health problem with an increasing incidence. Proliferative breast diseases are recognised as one of the risk factors in the development of carcinoma. This study was undertaken to know the frequency of proliferative lesions and other lesions in association with breast carcinomas in mastectomy specimens. MATERIALS AND METHODS 100 cases of excised carcinoma breast sent to the Department of Pathology for a three-year period at tertiary care centre was thoroughly examined and changes adjacent to the tumour was recorded and tissue was subjected for histopathological examination and results tabulated. RESULTS Infiltrating duct cell carcinoma, Not Otherwise Specified (NOS type was present in 89% of cases. Among the associated lesions, nonproliferative lesions constituted 16%, proliferative breast disease without atypia 29%, proliferative breast disease with atypia 10% and others 45%. Fibrocystic disease constituted 14% of cases, epithelial hyperplasia 15%, sclerosing adenosis 12% and atypical ductal hyperplasia in 10% of cases. Other types of associated lesions were duct carcinoma in situ in 4 cases. CONCLUSION Proliferative lesions adjacent to carcinoma breast were seen in 39% of cases. Fibrocystic disease, epithelial hyperplasia, sclerosing adenosis and atypical ductal hyperplasia being the commonest lesions adjacent to carcinoma breast in the present study.

  12. Proliferative response of the murine esophageal epithelium to radiation: Modification by food consumption patterns

    International Nuclear Information System (INIS)

    Burholt, D.R.

    1985-01-01

    The single layer of proliferative epithelial cells of the murine esophagus undergoes a sequence of damage and recovery following cytotoxic insult. The modification of both damage and proliferative recovery by the alteration of animal eating patterns was investigated following thoracic field irradiation through the determination of /sup 3/H-TdR incorporation into the esophagus along with selective counting of labeled nuclei and mitotic figures. Initial radiation-induced damage, as determined by /sup 3/H-TdR incorporation suppression and mitotic delay, is under normal conditions dependent on the time of day of treatment. This circadian sensitivity may be altered by changing the eating pattern of the animal. The proliferative recovery following single dose irradiation is also dependent on food consumption patterns: fasting immediately following treatment and then refeeding 2 days later results in a more rapid proliferative recovery than observed under control eating conditions, while reduced food consumption during the period of proliferative hyperplasia reduces the extent of recovery. During multifraction radiation schedules both the damage produced by a subsequent dose and recovery capacity are influenced by the food consumption pattern between fractions

  13. The development of proliferative verrucous leukoplakia in oral lichen planus. A preliminary study

    Science.gov (United States)

    Llorente-Pendás, Santiago; González-Garcia, Manuel; García-Martín, José-Manuel

    2016-01-01

    Background Was to describe 14 cases of a proliferative verrucous leukoplakia as a clinical evolution of oral lichen planus. Material and Methods The clinical and histopathological characteristics of 14 cases of OLP that progress towards a plaque-like and verrucous form were indicated, with monitoring over a period of six to 24.3 years. Results The female/male ratio was 11/3, (78.6 and 21.4%). The mean age when the first biopsy was undertaken was 56.4 years old. None of the patients smoked during the study. As bilateral reticular was clinically diagnostic criterion, the second most frequent clinical form was the plaque form (n=10; 71.4%), followed by the atrophic (n=6; 42.8%), and erosive forms (n=4; 28.5%). Clinically it spread towards attached gingival mucosa and the hard palate. In the histopathologic study, there were a predominance of hyperkeratosis and verrucous epithelial hyperplasia. Three of the cases progressed to a squamous cell carcinoma, and one patient developed two verrucous carcinoma. Conclusions Further research is needed to demonstrate if proliferative multifocal oral lichen planus and proliferative multifocal oral leukoplakia are the same disorder but have different behaviour of malignancy for reasons of origin. Key words:Oral lichen planus, proliferative verrucous oral leukoplakia, malignant oral lichen planus, multifocal verrucous oral lichen planus, proliferative verrucous oral lichen planus. PMID:27031060

  14. Polish natural bee honeys are anti-proliferative and anti-metastatic agents in human glioblastoma multiforme U87MG cell line.

    Directory of Open Access Journals (Sweden)

    Justyna Moskwa

    Full Text Available Honey has been used as food and a traditional medicament since ancient times. However, recently many scientists have been concentrating on the anti-oxidant, anti-proliferative, anti-inflammatory and other properties of honey. In this study, we investigated for the first time an anticancer effect of different honeys from Poland on tumor cell line - glioblastoma multiforme U87MG. Anti-proliferative activity of honeys and its interferences with temozolomide were determined by a cytotoxicity test and DNA binding by [H3]-thymidine incorporation. A gelatin zymography was used to conduct an evaluation of metalloproteinases (MMP-2 and MMP-9 expression in U87MG treatment with honey samples. The honeys were previously tested qualitatively (diastase activity, total phenolic content, lead and cadmium content. The data demonstrated that the examined honeys have a potent anti-proliferative effect on U87MG cell line in a time- and dose-dependent manner, being effective at concentrations as low as 0.5% (multifloral light honey - viability 53% after 72 h of incubation. We observed that after 48 h, combining honey with temozolomide showed a significantly higher inhibitory effect than the samples of honey alone. We observed a strong inhibition of MMP-2 and MMP-9 for the tested honeys (from 20 to 56% and from 5 to 58% compared to control, respectively. Our results suggest that Polish honeys have an anti-proliferative and anti-metastatic effect on U87MG cell line. Therefore, natural bee honey can be considered as a promising adjuvant treatment for brain tumors.

  15. Diagnostic value of ductogalactography and cytology in the proliferative changes of the mammary ducts

    International Nuclear Information System (INIS)

    Sessa, M.; Cerroni, L.; Bertolotti, A.

    1991-01-01

    Three hundred and thiyrty-six patients with nipple discharge and neither physical signs at breast examination nor pathological findings at mammography, were observed from 1984 to 1988 and studied by means of ductogalactography and cytology of discharge. Of this group, 76 patients (22%) underwent surgery and histology. In 65/76 cases proliferative pathologic conditions were demonstrated: 51 single/ multiple papillomas and 14 carcinomas. Ductogalactography suggested proliferative pathologic conditions in 59 cases and cytology of discharge showed blood in 44 patients, papillary clusters in 23, and atypical cells in 15 (both as single occurrences and in association). In cancer patients discharge appeared to be mostly spontaneous, monoductal and blood-stained. In papillomas, induced discharge was almost as frequent as spontaneous discharge, and milky discharge was also present. Ductogalactography confirmed its value in the diagnosis of proliferative pathologic conditions of the mammary ducts, being especially useful to detect carcinomas without palpable tumors. Cytology of discharge had poorer diagnostic significance

  16. Proliferative diabetic retinopathy is associated with microalbuminuria in patients with type 2 diabetes

    Directory of Open Access Journals (Sweden)

    M.C. Boelter

    2006-08-01

    Full Text Available Diabetic retinopathy is one of the leading causes of blindness in working-age individuals. Diabetic patients with proteinuria or those on dialysis usually present severe forms of diabetic retinopathy, but the association of diabetic retinopathy with early stages of diabetic nephropathy has not been entirely established. A cross-sectional study was conducted on 1214 type 2 diabetic patients to determine whether microalbuminuria is associated with proliferative diabetic retinopathy in these patients. Patients were evaluated by direct and indirect ophthalmoscopy and grouped according to the presence or absence of proliferative diabetic retinopathy. The agreement of diabetic retinopathy classification performed by ophthalmoscopy and by stereoscopic color fundus photographs was 95.1% (kappa = 0.735; P < 0.001. Demographic information, smoking history, anthropometric and blood pressure measurements, glycemic and lipid profile, and urinary albumin were evaluated. On multiple regression analysis, diabetic nephropathy (OR = 5.18, 95% CI = 2.91-9.22, P < 0.001, insulin use (OR = 2.52, 95% CI = 1.47-4.31, P = 0.001 and diabetes duration (OR = 1.04, 95% CI = 1.01-1.07, P = 0.011 were positively associated with proliferative diabetic retinopathy, and body mass index (OR = 0.90, 95% CI = 0.86-0.96, P < 0.001 was negatively associated with it. When patients with macroalbuminuria and on dialysis were excluded, microalbuminuria (OR = 3.3, 95% CI = 1.56-6.98, P = 0.002 remained associated with proliferative diabetic retinopathy. Therefore, type 2 diabetic patients with proliferative diabetic retinopathy more often presented renal involvement, including urinary albumin excretion within the microalbuminuria range. Therefore, all patients with proliferative diabetic retinopathy should undergo an evaluation of renal function including urinary albumin measurements.

  17. The Relationship between Proliferative Scars and Endothelial Function in Surgically Revascularized Patients

    Directory of Open Access Journals (Sweden)

    Murat Ziyrek

    2015-12-01

    Full Text Available Background: Proliferative scars are benign fibrotic proliferations which demonstrate abnormal wound healing in response to skin injuries. As postulated in the “response to injury hypothesis”, atherosclerosis is also triggered by an endothelial injury. Keloid and atherosclerotic processes have many pathophysiological and cytological features in common. Aims: In this study, we investigated the relationship between proliferative scars and endothelial function in surgically revascularized patients. We aimed to test the hypothesis that atherosclerosis is a wound healing abnormality. Study Design: Cross-sectional study. Methods: Consecutive patients who were admitted to the cardiology outpatient clinic with a history of coronary artery bypass grafting operation were evaluated. Thirty-three patients with proliferative scars at the median sternotomy site formed the keloid group, and 36 age- and sex-matched patients with no proliferative scar at the median sternotomy site formed the control group. Endothelial function was evaluated by flow-mediated vasodilatation of the brachial artery via ultrasonograhic examination. Results: There is no signicant difference according to the demographic data, biochemical parameters, clinical parameters and number of grafts between keloid and control groups. Endothelial-dependent vasodilatory response was lower in the keloid group than the control group (9.30±3.5 and 18.68±8.2, respectively; p=0.001. Conclusion: This study showed that endothalial dysfunction, which is strongly correlated with atherosclerosis, was more prominent in patients with proliferative scars. As proliferative scars and atherosclerosis have many features in common, we might conclude that atherosclerosis is a wound healing abnormality.

  18. Different lasers and techniques for proliferative diabetic retinopathy.

    Science.gov (United States)

    Moutray, Tanya; Evans, Jennifer R; Lois, Noemi; Armstrong, David J; Peto, Tunde; Azuara-Blanco, Augusto

    2018-03-15

    Diabetic retinopathy (DR) is a chronic progressive disease of the retinal microvasculature associated with prolonged hyperglycaemia. Proliferative DR (PDR) is a sight-threatening complication of DR and is characterised by the development of abnormal new vessels in the retina, optic nerve head or anterior segment of the eye. Argon laser photocoagulation has been the gold standard for the treatment of PDR for many years, using regimens evaluated by the Early Treatment of Diabetic Retinopathy Study (ETDRS). Over the years, there have been modifications of the technique and introduction of new laser technologies. To assess the effects of different types of laser, other than argon laser, and different laser protocols, other than those established by the ETDRS, for the treatment of PDR. We compared different wavelengths; power and pulse duration; pattern, number and location of burns versus standard argon laser undertaken as specified by the ETDRS. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 5); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 8 June 2017. We included randomised controlled trials (RCTs) of pan-retinal photocoagulation (PRP) using standard argon laser for treatment of PDR compared with any other laser modality. We excluded studies of lasers that are not in common use, such as the xenon arc, ruby or Krypton laser. We followed Cochrane guidelines and graded the certainty of evidence using the GRADE approach. We identified 11 studies from Europe (6), the USA (2), the Middle East (1) and Asia (2). Five studies compared different types of laser to argon: Nd:YAG (2 studies) or diode (3 studies). Other studies compared modifications to the standard argon laser PRP technique. The studies were poorly reported and we judged all to be at high risk of bias in at least one domain. The sample size

  19. Anti-proliferative effect of Moringa oleifera Lam (Moringaceae) leaf ...

    African Journals Online (AJOL)

    Several fractions were identified by thin layer chromatography (TLC), proton ..... activity of essential oil extracted from Thai medicinal ... Soy phytochemicals and tea bioactive components synergistically inhibit androgen-sensitive human.

  20. A comparative study of proliferative nodules and lethal melanomas in congenital nevi from children.

    Science.gov (United States)

    Yélamos, Oriol; Arva, Nicoleta C; Obregon, Roxana; Yazdan, Pedram; Wagner, Annette; Guitart, Joan; Gerami, Pedram

    2015-03-01

    Differentiating proliferative nodules (PNs) from melanomas arising in congenital nevi (CN) is a considerable challenge for dermatopathologists. Most of the specimens dermatopathologists assess that deal with this differential diagnosis involve proliferations of melanocytes arising in the dermis. In this study, we compare the clinical, histologic, and molecular findings of these 2 conditions. In our database, we found 22 examples of PNs arising in the dermis of CN and 2 cases of lethal melanomas arising from the dermis/epidermis of CN of children. Importantly, we found that among dermal melanocytic proliferations arising from CN in children, PNs are far more common than lethal melanomas. Clinically, multiplicity of lesions favored a diagnosis of PNs, whereas ulceration was infrequent in PNs compared with lethal melanomas. Histologically, PNs showed several distinct patterns including expansile nodules of epithelioid melanocytes with mitotic counts lower than that seen in the melanomas (1.67 vs. 12.5 mitoses/mm), a small round blue cell pattern often highly mitotically active, neurocristic-like, blue nevus-like, a nevoid melanoma-like pattern, or an undifferentiated spindle cell pattern. The lethal melanomas both featured expansile nodules of epithelioid melanocytes with high mitotic counts (range, 5 to 20 mitoses/mm) and an ulcerated overlying epidermis. At the molecular level, the PNs showed mostly whole chromosomal copy number aberrations, which in some cases were accompanied by rare partial chromosomal aberrations, whereas both lethal melanomas showed highly elevated copy number aberrations involving 6p25 without gains of the long arm of chromosome 6.

  1. Feeding manipulation elicits different proliferative responses in the gastrointestinal tract of suckling and weanling rats

    Directory of Open Access Journals (Sweden)

    Palanch A.C.

    1998-01-01

    Full Text Available Food deprivation has been found to stimulate cell proliferation in the gastric mucosa of suckling rats, whereas the weanling period has been reported to be unresponsive in terms of proliferative activity. In the present study we analyze regional differences in the effect of milk or food deprivation on cell proliferation of the epithelia of the esophagus and of five segments of small intestine in suckling, weanling and newly weaned Wistar rats of both sexes. DNA synthesis was determined using tritiated thymidine to obtain labeling indices (LI; crypt depth and villus height were also determined. Milk deprivation decreased LI by 50% in the esophagus (from 15 to 8.35% and small intestine (from 40 to 20% of 14-day-old rats. In 18-day-old rats, milk and food deprivation decreased LI in the esophagus (from 13 to 5% and in the distal segments of the small intestine (from 36-40 to 24-32%. In contrast, the LI of the epithelia of the esophagus (5% and of all small intestine segments (around 30% of 22-day-old rats were not modified by food deprivation. Crypt depth did not change after treatment (80 to 120 µm in 14- and 22-day-old rats, respectively. Villus height decreased in some small intestine segments of unfed 14- (from 400 to 300 µm and 18-day-old rats (from 480 to 360 µm. The results show that, contrary to the stomach response, milk deprivation inhibited cell proliferation in the esophagus and small intestine of suckling rats, demonstrating the regional variability of each segment of the gastrointestinal tract in suckling rats. In newly weaned rats, food deprivation did not alter the proliferation of these epithelia, similarly to the stomach, indicating that weanling is a period marked by the insensitivity of gastrointestinal epithelia to dietary alterations

  2. Meningiomas: Objective assessment of proliferative indices by immunohistochemistry and automated counting method.

    Science.gov (United States)

    Chavali, Pooja; Uppin, Megha S; Uppin, Shantveer G; Challa, Sundaram

    2017-01-01

    The most reliable histological correlate of recurrence risk in meningiomas is increased mitotic activity. Proliferative index with Ki-67 immunostaining is a helpful adjunct to manual counting. However, both show considerable inter-observer variability. A new immunohistochemical method for counting mitotic figures, using antibody against the phosphohistone H3 (PHH3) protein was introduced. Similarly, a computer based automated counting for Ki-67 labelling index (LI) is available. To study the use of these new techniques in the objective assessment of proliferation indices in meningiomas. This was a retrospective study of intracranial meningiomas diagnosed during the year 2013.The hematoxylin and eosin (H and E) sections and immunohistochemistry (IHC) with Ki-67 were reviewed by two pathologists. Photomicrographs of the representative areas were subjected to Ki-67 analysis by Immunoratio (IR) software. Mean Ki-67 LI, both manual and by IR were calculated. IHC with PHH3 was performed. PHH3 positive nuclei were counted and mean values calculated. Data analysis was done using SPSS software. A total of 64 intracranial meningiomas were diagnosed. Evaluation on H and E, PHH3, Ki-67 LI (both manual and IR) were done in 32 cases (22 grade I and 10 grade II meningiomas). Statistically significant correlation was seen between the mitotic count in each grade and PHH3 values and also between the grade of the tumor and values of Ki-67 and PHH3. Both the techniques used in the study had advantage over, as well as, correlated well with the existing techniques and hence, can be applied to routine use.

  3. Proliferative kinetics of the haematopoietic stem cells of the mouse after several weeks of reconvalescence of an irradiation attack

    International Nuclear Information System (INIS)

    Huebner, G.

    1980-01-01

    The 125 IDU(iodo-deoxyuridine) tracer-technique was applied for investigating proliferative kinetics. The intention was to reveal a possible persistent irradiation damage in the haematopoietic stem-cells of the mouse. The three following methodically differing arrangements were made: 1. 35 days after irradiation with 450 rad no difference is found between the measured turnover of incorporated 125 IUD in the bone marrow and not irradiated mice. However, there is a splenic cell population which unambiguously transfers its activity slowlier. A dose-response relationship exists to a limited extent. 2. By four transplantations at different instants the donors were marked first, and then the turnover of the early haematopoietic precursor cells in the bone marrow was detected. It resulted that 35 days after irradiation with 450 rad the turnover takes place slightly slowlier than in not irradiated early precursor cells. Iodised water, which is administered before the tracer technique is applied, seems to have a stimulating effect, particularly on the turnover of irradiated stem cells; the marking with a specific activity of 2000 Ci/mol seems to have a slightly toxic effect. 3. A test was developed, by which the proliferation velocity of stem cells and their descendants is measured when there is a very high proliferation stimulus. Differing amounts of bone marrow cells are transfused to lethally irradiated receivers. Within the logarithmic phase of the 125 IDU incorporation the relative cellular proliferation, originating in the stem cells being in the spleen, is determined for the interval between day 3 and day 5. It results very clearly that the descendants of those stem cells irradiated with 450 rad after a reconvalescence time of 35 days present a lower degree of rapid proliferative ability than the not irradiated cells. (orig./MG) [de

  4. Overexpression of catalase delays G0/G1- to S-phase transition during cell cycle progression in mouse aortic endothelial cells.

    Science.gov (United States)

    Onumah, Ogbeyalu E; Jules, George E; Zhao, Yanfeng; Zhou, LiChun; Yang, Hong; Guo, ZhongMao

    2009-06-15

    Although it is understood that hydrogen peroxide (H(2)O(2)) promotes cellular proliferation, little is known about its role in endothelial cell cycle progression. To assess the regulatory role of endogenously produced H(2)O(2) in cell cycle progression, we studied the cell cycle progression in mouse aortic endothelial cells (MAECs) obtained from mice overexpressing a human catalase transgene (hCatTg), which destroys H(2)O(2). The hCatTg MAECs displayed a prolonged doubling time compared to wild-type controls (44.0 +/- 4.7 h versus 28.6 +/- 0.8 h, pcatalase inhibitor, prevented the observed diminished growth rate in hCatTg MAECs. Inhibition of catalase activity with aminotriazole abrogated catalase overexpression-induced antiproliferative action. Flow cytometry analysis indicated that the prolonged doubling time was principally due to an extended G(0)/G(1) phase in hCatTg MAECs compared to the wild-type cells (25.0 +/- 0.9 h versus 15.9 +/- 1.4 h, pinhibitors, p21 and p27, which inhibit the Cdk activity required for the G(0)/G(1)- to S-phase transition. Knockdown of p21 and/or p27 attenuated the antiproliferative effect of catalase overexpression in MAECs. These results, together with the fact that catalase is an H(2)O(2) scavenger, suggest that endogenously produced H(2)O(2) mediates MAEC proliferation by fostering the transition from G(0)/G(1) to S phase.

  5. Effects of 2-Deoxy-D-Glucose on Metabolic Status, Proliferative Capacity and Growth Rate of FSall Tumor: Observations made by In Vivo 31P-Nuclear Magnetic Resonance Spectroscopy and Flow Cytometry

    International Nuclear Information System (INIS)

    Chang, Hye Sook; Choi, Eun Kyung; Cho, Jeong Gill; Lim, Tae Hwan; Lee, Tae Keun; Yi, Yun; Cho, Young Joo; Kim, Gon Sup

    1991-01-01

    The effect of 2-deoxy-d-glucose (2-DDG) on C 3 H mouse fibrosarcoma (FSall) was studied. Metabolic status, especially for energy metabolism, was studied using in vivo 31 P-MRS, proliferative capacity was observed on flow cytometry (FC) and growth rate was measured after transplantation of 106 viable tumor cells in the dorsum of foot of C 3 Hf/Sed mice. One gram of 2-DDG per kg of body weight was injected intraperitoneally on 12th day of implantation. Average tumor size on 12th day of implantation was 250mm 3 . Growth rate of FSall tumor was measured by tumor doubling time between tumor age 5-12 days was 0.84 days with slope 0.828 and tumor doubling time between tumor age 13-28 days was 3.2 days with slope 0.218 in control group. After 2-DDG injection, tumor doubling time was elongated to 5.1 days with slope 0.136. The effect of 2-DDG studied in vivo 31 P-MRS suggested that the increase of phosphomonoester (PME) and inorganic phosphate (Pi) by increasing size of tumor, slowed down after 2-DDG injection. Flow cytometry showed significantly increased S-phase and G 2 +M phase fraction suggesting increased proliferative capacity of tumor cells in the presence of 2-DDG. Authors observed an interesting effect 2-DDG on FSall tumor and attempt to utilize as an adjunct for radiotherapy

  6. Protein metabolism of prolific ewes during late gestation and early lactation

    NARCIS (Netherlands)

    Sebek, L.B.J.

    2001-01-01

    Subject headings: protein / metabolism / ewes

    Introduction of prolific crossbred ewes and a new protein evaluation system for ruminants, the DVE/OEB system, necessitate a reconsideration of ewe feeding strategies. The objective of this thesis is to investigate the amount

  7. The T309G MDM2 gene polymorphism is a novel risk factor for proliferative vitreoretinopathy

    NARCIS (Netherlands)

    S. Pastor-Idoate (Salvador); I. Rodriguez-Hernández (Irene); J. Rojas (Jimena); I. Fernandez (Itziar); M.T. García-Gutierrez (María Teresa); J.M. Ruiz-Moreno (Jose María); A. Rocha-Sousa (Amandio); Y. Ramkissoon (Yashin); S. Harsum (Steven); R.E. MacLaren (Robert ); D. Charteris (David); J.C. Vanmeurs (Jan C.); R. González-Sarmiento (Rogelio); J.C. Pastor (Jose Carlos)

    2013-01-01

    textabstractProliferative vitreoretinopathy (PVR) is still the major cause of failure in retinal detachment (RD) surgery. It is believed that down-regulation in the p53 pathway could be an important key in PVR pathogenesis. The purpose was to evaluate the impact of T309G MDM2 polymorphism

  8. Automatic non-proliferative diabetic retinopathy screening system based on color fundus image.

    Science.gov (United States)

    Xiao, Zhitao; Zhang, Xinpeng; Geng, Lei; Zhang, Fang; Wu, Jun; Tong, Jun; Ogunbona, Philip O; Shan, Chunyan

    2017-10-26

    Non-proliferative diabetic retinopathy is the early stage of diabetic retinopathy. Automatic detection of non-proliferative diabetic retinopathy is significant for clinical diagnosis, early screening and course progression of patients. This paper introduces the design and implementation of an automatic system for screening non-proliferative diabetic retinopathy based on color fundus images. Firstly, the fundus structures, including blood vessels, optic disc and macula, are extracted and located, respectively. In particular, a new optic disc localization method using parabolic fitting is proposed based on the physiological structure characteristics of optic disc and blood vessels. Then, early lesions, such as microaneurysms, hemorrhages and hard exudates, are detected based on their respective characteristics. An equivalent optical model simulating human eyes is designed based on the anatomical structure of retina. Main structures and early lesions are reconstructed in the 3D space for better visualization. Finally, the severity of each image is evaluated based on the international criteria of diabetic retinopathy. The system has been tested on public databases and images from hospitals. Experimental results demonstrate that the proposed system achieves high accuracy for main structures and early lesions detection. The results of severity classification for non-proliferative diabetic retinopathy are also accurate and suitable. Our system can assist ophthalmologists for clinical diagnosis, automatic screening and course progression of patients.

  9. Detection of Lawsonia intracellularis in the tonsils of pigs with proliferative enteropathy

    DEFF Research Database (Denmark)

    Jensen, Tim Kåre; Møller, Kristian; Lindecrona, R. H.

    2000-01-01

    to necropsy but not in four pigs with moderate PE lesions. However, L. intracellularis was detected in the tonsils of 4/9 pigs with PE complicated with necroses and in 4/4 pigs with proliferative haemorrhagic enteropathy in which L. intracellularis antigen also was demonstrated in tonsillar macrophages...

  10. APPROACHES TO THE CONSTRUCTION OF THE VITRECTOMY RISK MANAGEMENT SYSTEM IN PATIENTS WITH PROLIFERATIVE DIABETIC RETINOPATHY

    Directory of Open Access Journals (Sweden)

    A. M. Ruban

    2016-08-01

    Full Text Available The article presents the some approaches to create a system support of making decision during vitrectomy in patients with diabetic proliferative retinopathy, promotes objective assessment of individual risk-management for patient and allows optimize ophthalmological care for them.

  11. Evaluation of VEGF gene polymorphisms and proliferative diabetic retinopathy in Mexican population.

    Science.gov (United States)

    Gonzalez-Salinas, Roberto; Garcia-Gutierrez, Maria C; Garcia-Aguirre, Gerardo; Morales-Canton, Virgilio; Velez-Montoya, Raul; Soberon-Ventura, Vidal R; Gonzalez, Victoria; Lechuga, Rodrigo; Garcia-Solis, Pablo; Garcia-Gutierrez, David G; Garcia-Solis, Marco Vinicio; Saenz de Viteri, Manuel; Solis-S, Juan C

    2017-01-01

    To assess if the included vascular endothelial growth factor (VEGF) polymorphisms rs3025035, rs3025021 and rs2010963 are associated to proliferative retinopathy in a Mexican population with type 2 diabetes mellitus (T2DM). A case-control study was conducted in adult individuals with T2DM associated to proliferative retinopathy or non-proliferative retinopathy from Oct. 2014 to Jun. 2015 from the Retina Department of the Asociation to Prevent Blindness in Mexico. The selected patients were adults with a diagnosis of T2DM ≥5y. All subjects had a comprehensive ocular examination and the classification of the retinopathy severity was made considering the Early Treatment Diabetic Retinopathy Study (ETDRS) standardization protocols. Genomic DNA was extracted from whole fresh blood. All samples were genotyped by qPCR for selected VEGF polymorphisms. Hardy-Weinberg equilibrium was calculated by comparing Chi-square values between the expected and the observed values for genotype counts. In total 142 individuals were enrolled, 71 individuals with T2DM and associated proliferative retinopathy and 71 individuals with non-proliferative retinopathy. One-sided Fisher's exact test was performed for rs3025021 [OR (95% CI)=0.44(0.08-2.2); P =0.25] and rs2010963 [OR (95% CI)=0.63(0.25-1.6); P =0.23]. The minor allelic frequencies obtained were 26% for rs3025021, 10% for rs3025035 and 61% for rs2010963. The pairwise linkage disequilibrium between the three SNP was assessed, and was as follows: rs3025021 vs rs3025035: D'=1.0, r 2 =0.1043, P ≤0.0001; rs3025021 vs rs2010963: D'=0.442, r 2 =0.0446, P =0.149; rs3025035 vs rs2010963: D'=0.505, r 2 =0.0214, P =0.142. This is the first analysis involving VEGF polymorphisms and proliferative diabetic retinopathy in a Mexican population. A major finding of the present study is that none of the polymorphisms studied was significantly associated with proliferative retinopathy. Based on these results, we can infer that different populations

  12. Selective AR Modulators that Distinguish Proliferative from Differentiative Gene Promoters

    Science.gov (United States)

    2017-08-01

    Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and should not be...Research and Materiel Command Fort Detrick, Maryland 21702-5012 11. SPONSOR/MONITOR’S REPORT NUMBER(S) 12. DISTRIBUTION / AVAILABILITY STATEMENT...recognition, we performed a high -throughput screen for compounds eliciting differential AR activity on cARE vs. sARE reporters. Of 10,000 compounds

  13. Role of P-glycoprotein on CD69+CD4+ cells in the pathogenesis of proliferative lupus nephritis and non-responsiveness to immunosuppressive therapy.

    Science.gov (United States)

    Tsujimura, Shizuyo; Adachi, Tomoko; Saito, Kazuyoshi; Tanaka, Yoshiya

    2017-01-01

    P-glycoprotein (P-gp) expression on activated lymphocytes in systemic lupus erythematosus (SLE) plays a role in active efflux of intracellular drugs, resulting in drug resistance. The role of P-gp-expressing lymphocytes in the pathogenesis of SLE remains unclear. The aim of this study was to determine the importance of P-gp + CD4 + cells in organ manifestations in refractory SLE. The proportion of P-gp + CD4 + cells was determined by flow cytometry in peripheral blood of patients with SLE (n=116) and healthy adults (n=10). Renal biopsy specimens were examined by immunohistochemistry for P-gp expression. CD69 is a marker of CD4 cell activation. The proportion of both P-gp-expressing CD4 + cells and CD69-expressing CD4 + cells in peripheral blood was higher in SLE than control. The proportion of P-gp + CD69 + CD4 + cells correlated with Systemic Lupus Erythematosus Disease Activity Index and was higher in poor responders to corticosteroids. Furthermore, the proportion of P-gp + CD69 + CD4 + cells was significantly higher in proliferative lupus nephritis (LN) with poor response to corticosteroids. The efficacy of immunosuppressive therapy depended on the regulation of the proportion of P-gp + CD69 + CD4 + cells. Marked accumulation of P-gp + CD4 + cells in renal interstitial tissue and high proportion of peripheral P-gp + CD69 + CD4 + cells were noted in patients with proliferative LN. The results showed high proportion of P-gp + CD69 + CD4 + cells in peripheral blood and their accumulation in renal tissue in patients with proliferative LN refractory to CS therapy, suggesting that P-gp expression on activated CD4 + T cells is a potentially useful marker for refractoriness to treatment and a novel target for treatment.

  14. O2-(6-Oxocyclohex-1-en-1-yl)methyl diazen-1-ium-1,2-diolates: a new class of nitric oxide donors activatable by GSH/GSTπ with both anti-proliferative and anti-metastatic activities against melanoma.

    Science.gov (United States)

    Bai, Chengfeng; Xue, Rongfang; Wu, Jianbing; Lv, Tian; Luo, Xiaojun; Huang, Yun; Gong, Yan; Zhang, Honghua; Zhang, Yihua; Huang, Zhangjian

    2017-05-02

    The new nitric oxide (NO) donor O 2 -(6-oxocyclohex-1-en-1-yl)methyl diazen-1-ium-1,2-diolate 3c could simultaneously liberate NO as well as an active 3-glutathionyl-2-exomethylene-cyclohexanone 2 in the presence of GSH/GSTπ; exhibit potent antiproliferative activity; repress migration, invasion, and lateral migration of metastatic B16-BL6 cells; and significantly decrease hetero-adhesion of B16-BL6 cells to human umbilical vein endothelial cells.

  15. Software Infrastructure to Enable Modeling & Simulation as a Service (M&SaaS), Phase II

    Data.gov (United States)

    National Aeronautics and Space Administration — This SBIR Phase 2 project will produce a software service infrastructure that enables most modeling and simulation (M&S) activities from code development and...

  16. Proliferative status of primitive hematopoietic progenitors from patients with acute myelogenous leukemia (AML).

    Science.gov (United States)

    Guan, Y; Hogge, D E

    2000-12-01

    One possible explanation for the competitive advantage that malignant cells in patients with acute myelogenous leukemia (AML) appear to have over normal hematopoietic elements is that leukemic progenitors proliferate more rapidly than their normal progenitor cell counterparts. To test this hypothesis, an overnight 3H-thymidine (3H-Tdr) suicide assay was used to analyze the proliferative status of malignant progenitors detected in both colony-forming cell (CFC) and long-term culture initiating cell (LTC-IC) assays from the peripheral blood of nine patients with newly diagnosed AML. Culture of AML cells in serum-free medium with 100 ng/ml Steel factor (SF), 20 ng/ml interleukin 3 (IL-3) and 20 ng/ml granulocyte colony-stimulating factor (G-CSF) for 16-24 h maintained the number of AML-CFC and LTC-IC at near input values (mean % input +/- s.d. for CFC and LTC-IC were 78 +/- 33 and 126 +/- 53, respectively). The addition of 20 muCi/ml high specific activity 3H-Tdr to these cultures reduced the numbers of both progenitor cell types from most of the patient samples substantially: mean % kill +/- s.d. for AML-CFC and LTC-IC were 64 +/- 27 and 82 +/- 16, respectively, indicating that a large proportion of both progenitor populations were actively cycling. FISH analysis of colonies from CFC and LTC-IC assays confirmed that most cytogenetically abnormal CFC and LTC-IC were actively cycling (mean % kill +/- s.d.: 68 +/- 26 and 85 +/- 13, respectively). Interestingly, in six patient samples where a significant number of cytogenetically normal LTC-ICs were detected, the % kill of these cells (74 +/- 20) was similar to that of the abnormal progenitors. These data contrast with the predominantly quiescent cell cycle status of CFC and LTC-IC previously observed in steady-state peripheral blood from normal individuals but also provide evidence that a significant proportion of primitive malignant progenitors from AML patients are quiescent and therefore may be resistant to standard

  17. The nontoxic natural compound Curcumin exerts anti-proliferative, anti-migratory, and anti-invasive properties against malignant gliomas

    International Nuclear Information System (INIS)

    Senft, Christian; Polacin, Margareth; Priester, Maike; Seifert, Volker; Kögel, Donat; Weissenberger, Jakob

    2010-01-01

    New drugs are constantly sought after to improve the survival of patients with malignant gliomas. The ideal substance would selectively target tumor cells without eliciting toxic side effects. Here, we report on the anti-proliferative, anti-migratory, and anti-invasive properties of the natural, nontoxic compound Curcumin observed in five human glioblastoma (GBM) cell lines in vitro. We used monolayer wound healing assays, modified Boyden chamber trans-well assays, and cell growth assays to quantify cell migration, invasion, and proliferation in the absence or presence of Curcumin at various concentrations. Levels of the transcription factor phospho-STAT3, a potential target of Curcumin, were determined by sandwich-ELISA. Subsequent effects on transcription of genes regulating the cell cycle were analyzed by quantitative real-time PCR. Effects on apoptosis were determined by caspase assays. Curcumin potently inhibited GBM cell proliferation as well as migration and invasion in all cell lines contingent on dose. Simultaneously, levels of the biologically active phospho-STAT3 were decreased and correlated with reduced transcription of the cell cycle regulating gene c-Myc and proliferation marking Ki-67, pointing to a potential mechanism by which Curcumin slows tumor growth. Curcumin is part of the diet of millions of people every day and is without known toxic side effects. Our data show that Curcumin bears anti-proliferative, anti-migratory, and anti-invasive properties against GBM cells in vitro. These results warrant further in vivo analyses and indicate a potential role of Curcumin in the treatment of malignant gliomas

  18. Expression of the angiogenic mediator, angiopoietin-like 4, in the eyes of patients with proliferative sickle retinopathy.

    Directory of Open Access Journals (Sweden)

    Kathleen Jee

    Full Text Available The recent success of therapies directly targeting the angiogenic mediator, vascular endothelial growth factor (VEGF, for the treatment of proliferative diabetic retinopathy has encouraged clinicians to extend the use of anti-VEGF therapies for the treatment of another ischemic retinal vascular disease, proliferative sickle cell retinopathy (PSR, the most common cause of irreversible blindness in patients with sickle cell disease. However, results from case reports evaluating anti-VEGF therapies for PSR have been mixed. This highlights the need to identify alternative therapeutic targets for the treatment of retinal neovascularization in sickle cell patients. In this regard, angiopoietin-like 4 (ANGPTL4 is a novel angiogenic factor regulated by the transcription factor, hypoxia-inducible factor 1, the master regulator of angiogenic mediators (including VEGF in ischemic retinal disease. In an effort to identify alternative targets for the treatment of sickle cell retinopathy, we have explored the expression of ANGPTL4 in the eyes of patients with PSR. To this end, we examined expression and localization of ANGPTL4 by immunohistochemistry in autopsy eyes from patients with known PSR (n = 5 patients. Complementary studies were performed using enzyme-linked immunosorbent assays in aqueous (n = 8; 7 patients, 2 samples from one eye of same patient and vitreous (n = 3 patients samples from a second group of patients with active PSR. We detected expression of ANGPTL4 in neovascular tissue and in the ischemic inner retina in PSR, but not control, eyes. We further observed elevated expression of ANGPTL4 in the aqueous and vitreous of PSR patients compared to controls. These results suggest that ANGPTL4 could contribute to the development of retinal neovascularization in sickle cell patients and could therefore be a therapeutic target for the treatment of PSR.

  19. Epigenetic mismatches with mutated transcribing genes at leukemogenic S-phase binding/start sites--potential targets for therapy with enzyme inhibitors.

    Science.gov (United States)

    Prindull, Gregor

    2012-11-01

    This review focuses on gene transcription patterns of leukemogenic S-phases in mitotic cell cycles for identification of enzymatic reactions as potential targets for epigenetics-based drug therapy. Transcription of leukemic genes is triggered by reprogrammed transcription factors (TFs) mediated by chromatin histones. Reprogrammed TFs originate from transcriptional alterations of CpG methylation patterns of mutated epigenetic genes. They preserve memory information of earlier leukemogenic exposures, even transgenerationally via the zygote, through small (e.g. pi)RNA transmitted between cells by exosomes. Normally, reprogrammed TFs are enzymatically silenced and stored as markers in heterochromatic domains. Failure of intra S-phase surveillance (IS) permits the formation and continual operation of DNA replication forks in spite of persisting genotoxic stress. Silenced TFs are re-activated by euchromatin, most likely through leakages of insulator barriers of cis-regulating chromatin modulators (CRM) that normally separate hetero- from euchromatin domains. During transport by sliding nucleosomes, reprogrammed leukemogenic TFs are misplaced at transcription factor binding-/starting-sites (TFBS /TSS) allowing them to interact with and trigger replication of mutated leukemic genes. Interactions of enzymatically reprogrammed TFs, transcribed from mutated epigenetic genes, with replicating leukemic genes at TFBS/TSSs are key driving forces in leukemogenesis. Probably, epigenetic genes, although mutated, still retain their control of replication of leukemic genes. Epigenetics-based enzyme inhibitors must target reprogrammed TFs. Prudently, therapeutic corrections should be introduced within the frame of conventional, cytoreductive treatment protocols. Alternatively, reprogrammed TFs could be replaced by cell populations with regular TF production. Clinically, classification of leukemias should be based on their epigenetic presentation.

  20. Silkworm Pupa Protein Hydrolysate Induces Mitochondria-Dependent Apoptosis and S Phase Cell Cycle Arrest in Human Gastric Cancer SGC-7901 Cells

    Directory of Open Access Journals (Sweden)

    Xiaotong Li

    2018-03-01

    Full Text Available Silkworm pupae (Bombyx mori are a high-protein nutrition source consumed in China since more than 2 thousand years ago. Recent studies revealed that silkworm pupae have therapeutic benefits to treat many diseases. However, the ability of the compounds of silkworm pupae to inhibit tumourigenesis remains to be elucidated. Here, we separated the protein of silkworm pupae and performed alcalase hydrolysis. Silkworm pupa protein hydrolysate (SPPH can specifically inhibit the proliferation and provoke abnormal morphologic features of human gastric cancer cells SGC-7901 in a dose- and time-dependent manner. Moreover, flow cytometry indicated that SPPH can induce apoptosis and arrest the cell-cycle in S phase. Furthermore, SPPH was shown to provoke accumulation of reactive oxygen species (ROS and depolarization of mitochondrial membrane potential. Western blotting analysis indicated that SPPH inhibited Bcl-2 expression and promoted Bax expression, and subsequently induced apoptosis-inducing factor and cytochrome C release, which led to the activation of initiator caspase-9 and executioner caspase-3, cleavage of poly (ADP-ribose polymerase (PARP, eventually caused cell apoptosis. Moreover, SPPH-induced S-phase arrest was mediated by up-regulating the expression of E2F1 and down-regulating those of cyclin E, CDK2 and cyclin A2. Transcriptome sequencing and gene set enrichment analysis (GSEA also revealed that SPPH treatment could affect gene expression and pathway regulation related to tumourigenesis, apoptosis and cell cycle. In summary, our results suggest that SPPH could specifically suppress cell growth of SGC-7901 through an intrinsic apoptotic pathway, ROS accumulation and cell cycle arrest, and silkworm pupae have a potential to become a source of anticancer agents in the future.

  1. THE ATM-SMC1 PATHWAY IS ESSENTIAL FOR ACTIVATION OF THE CHROMIUM[VI]-INDUCED S-PHASE CHECKPOINT

    Science.gov (United States)

    Hexavalent chromium (Cr[VI] is a common industrial waste product, an environmental pollutant, and a recognized human carcinogen. Following cellular uptake, Cr[VI] can cause DNA damage, however, the mechanisims by which mammalian cells respond to Cr-induced DNA damage remain to b...

  2. DYRK1A is a regulator of S phase entry in hepatic progenitor cells

    NARCIS (Netherlands)

    Kruitwagen, Hedwig Suzanne; Westendorp, Bart; Viebahn, Cornelia S; Post, Krista; van Wolferen, Monique E; Oosterhoff, Loes A; Egan, David A; Delabar, Jean-Maurice; Toussaint, Mathilda Jm; Schotanus, Baukje A; de Bruin, Alain; Rothuizen, Jan; Penning, Louis C; Spee, Bart

    Hepatic progenitor cells (HPCs) are adult liver stem cells that act as second line of defense in liver regeneration. They are normally quiescent, but in case of severe liver damage HPC proliferation is triggered by external activation mechanisms from their niche. Although several important

  3. Anti-proliferative effect of olmesartan on Tenon's capsule fibroblasts

    Directory of Open Access Journals (Sweden)

    Xuan Wang

    2016-05-01

    Full Text Available AIM: To evaluate the inhibitive effect of olmesartan to fibroblast proliferation and the anti-scarring effect in Tenon’s capsule, both in vitro and in vivo. METHODS: Human primary Tenon’s capsule fibroblasts were cultured in vitro, treated with up titrating concentrations of olmesartan. The rate of inhibition was tested with methyl thiazol tetrazolium (MTT method. Real-time PCR was performed to analyze changes in mRNA expressions of the fibrosis-related factors: matrix metalloproteinase-2 (MMP-2, tissue inhibitor of metalloproteinase (TIMP-1,2 and proliferating cell nuclear antigen (PCNA. Thirty rabbits were divided into 5 groups (3, 7, 14, 21, and 28d. A rabbit conjunctiva flap model was created in each eye. Olmesartan solution was injected subconjunctivally and then evaluated its anti-proliferation and anti-fibrosis effects through the histological morphology and immunohistochemistry of MMP-2 and PCNA in each group. Only the 7d group was treated with Masson’s trichrome to compare the neovascularization in the subconjunctiva area. RESULTS: In vitro, cultured Tenon's capsule human fibroblasts showed a dose dependent inhibition by olmesartan in MTT. Olmesartan reduced mRNA expressions of MMP-2 and PCNA but increased mRNA expressions of TIMP-1 and TIMP-2. In vivo, the rabbit eyes treated with olmesartan at 3rd, 7th, 14th and 21st days demonstrated a significant reduced expressions of MMP-2 and PCNA compared with control eye, no significant difference observed in 28th day group. The cellular proliferation and neovascularization was suppressed by olmesartan in Masson’s trichrome observation. CONCLUSION: By inhibiting fibroblasts in vitro and in vivo, olmesartan prevents the proliferation and activity of fibroblasts in scar tissue formation, which might benefit glaucoma filtering surgery.

  4. Temporal correlations between sensitivity to radiation-induced mitotic delay and the S phase of the sea urchin egg

    International Nuclear Information System (INIS)

    Rustad, R.C.; Viswanathan, G.; Antonellis, B.C.

    1979-01-01

    Separate samples of eggs from the sea urchin Arbacia punctulata were gamma irradiated (4kR) at different times after fertilisation and division delay measured. The results demonstrated a characteristic post-fertilisation pattern of a rise in sensitivity to radiation-induced mitotic delay, followed by a biphasic decrease in sensitivity to a refractory period. Measurements of the cumulative incorporation of 3 H-TdR showed that the first period of decreasing radiation sensitivity was closely associated with the bulk synthesis of DNA (S phase). (U.K.)

  5. Epigenetically-inherited centromere and neocentromere DNA replicates earliest in S-phase.

    Directory of Open Access Journals (Sweden)

    Amnon Koren

    2010-08-01

    Full Text Available Eukaryotic centromeres are maintained at specific chromosomal sites over many generations. In the budding yeast Saccharomyces cerevisiae, centromeres are genetic elements defined by a DNA sequence that is both necessary and sufficient for function; whereas, in most other eukaryotes, centromeres are maintained by poorly characterized epigenetic mechanisms in which DNA has a less definitive role. Here we use the pathogenic yeast Candida albicans as a model organism to study the DNA replication properties of centromeric DNA. By determining the genome-wide replication timing program of the C. albicans genome, we discovered that each centromere is associated with a replication origin that is the first to fire on its respective chromosome. Importantly, epigenetic formation of new ectopic centromeres (neocentromeres was accompanied by shifts in replication timing, such that a neocentromere became the first to replicate and became associated with origin recognition complex (ORC components. Furthermore, changing the level of the centromere-specific histone H3 isoform led to a concomitant change in levels of ORC association with centromere regions, further supporting the idea that centromere proteins determine origin activity. Finally, analysis of centromere-associated DNA revealed a replication-dependent sequence pattern characteristic of constitutively active replication origins. This strand-biased pattern is conserved, together with centromere position, among related strains and species, in a manner independent of primary DNA sequence. Thus, inheritance of centromere position is correlated with a constitutively active origin of replication that fires at a distinct early time. We suggest a model in which the distinct timing of DNA replication serves as an epigenetic mechanism for the inheritance of centromere position.

  6. Proliferative retinopathy and proteinuria predict mortality rate in type 1 diabetic patients from Fyn County, Denmark

    DEFF Research Database (Denmark)

    Grauslund, J; Green, A; Sjølie, A K

    2008-01-01

    AIMS/HYPOTHESIS: We evaluated the effect of diabetic retinopathy on 25 year survival rate among a population-based cohort of type 1 diabetic patients from Fyn County, Denmark. METHODS: In 1973 all diabetic patients from Fyn County, Denmark with onset before the age of 30 years as of 1 July 1973...... were identified (n=727). In 1981, only 627 patients were still alive and resident in Denmark. Of these, 573 (91%) participated in a clinical baseline examination, in which diabetic retinopathy was graded and other markers of diabetes measured. Mortality rate was examined in a 25 year follow....../INTERPRETATION: Proliferative retinopathy and proteinuria predict mortality rate in a population-based cohort of type 1 diabetic patients. In combination they act even more strongly. Non-proliferative diabetic retinopathy did not affect survival rate....

  7. Ocular pulse amplitude after panretinal photocoagulation in normotensive eyes with proliferative diabetic retinopathy.

    Science.gov (United States)

    Bozic, Marija M; Karadzic, Jelena B; Kovacevic, Igor M; Marjanovic, Ivan S

    2017-06-26

    To assess the effect of panretinal laser photocoagulation on ocular pulse amplitude (OPA) in normotensive eyes with proliferative diabetic retinopathy. Prospectively, we performed unilateral argon laser panretinal photocoagulation (PRP) in 30 patients with diabetes mellitus type II and previously untreated bilateral proliferative diabetic retinopathy. Before and 7 and 30 days after the treatment, OPA was measured using dynamic contour tonometer. Compared with the untreated contralateral eyes, laser photocoagulation led to a reduction of OPA. Ocular pulse amplitude did not significantly differ in photocoagulated eyes 7 days after the treatment, but there was a significant difference in OPA 30 days after the treatment. The decrease in OPA values was 15% 7 days after PRP and 40% 30 days after PRP. Ocular pulse amplitude reduction after PRP indirectly informs us about choriocapillary closure, already reported in previous studies.

  8. Easy labeling of proliferative phase and sporogonic phase of microsporidia Nosema bombycis in host cells.

    Directory of Open Access Journals (Sweden)

    Jie Chen

    Full Text Available Microsporidia are eukaryotic, unicellular parasites that have been studied for more than 150 years. These organisms are extraordinary in their ability to invade a wide range of hosts including vertebrates and invertebrates, such as human and commercially important animals. A lack of appropriate labeling methods has limited the research of the cell cycle and protein locations in intracellular stages. In this report, an easy fluorescent labeling method has been developed to mark the proliferative and sporogonic phases of microsporidia Nosema bombycis in host cells. Based on the presence of chitin, Calcofluor White M2R was used to label the sporogonic phase, while β-tubulin antibody coupled with fluorescence secondary antibody were used to label the proliferative phase by immunofluorescence. This method is simple, efficient and can be used on both infected cells and tissue slices, providing a great potential application in microsporidia research.

  9. Expression of platelet-derived growth factor and its receptors in proliferative disorders of fibroblastic origin.

    OpenAIRE

    Smits, A.; Funa, K.; Vassbotn, F. S.; Beausang-Linder, M.; af Ekenstam, F.; Heldin, C. H.; Westermark, B.; Nistér, M.

    1992-01-01

    Platelet-derived growth factor (PDGF) is known to stimulate the proliferation of connective tissue-derived cells in vitro. Less is known about its functions in vivo, and the role of PDGF in the development of human tumors has not been clarified. The authors have investigated the occurrence of PDGF and PDGF receptors in a series of proliferative disorders of fibroblastic origin using immunohistochemical and in situ hybridization techniques. High expression of PDGF beta-receptor mRNA and protei...

  10. Japan Turns Pro-Life: Recent Change in Reproductive Health Policy and Controversies over Prenatal Screening

    Directory of Open Access Journals (Sweden)

    Etsuji Okamoto

    2014-02-01

    Full Text Available Japan, known as a pro-choice country in terms of abortion, is currently facing the increase of “selective abortions” thanks to new prenatal screening. Efforts to restrict proliferation of new technology has not been successful and it is likely that Japan will turn pro-life by strictly enforcing the Maternity Protection Act (MPA, which prohibits abortions due to “fetal cause”.

  11. Japan turns pro-life: recent change in reproductive health policy and challenges by new technologies

    OpenAIRE

    Okamoto, Etsuji

    2014-01-01

    Japan, known as a pro-choice country in terms of abortion, is currently facing the increase of “selective abortions” thanks to new prenatal screening. Efforts to restrict proliferation of new technology has not been successful and it is likely that Japan will turn pro-life by strictly enforcing the Maternity Protection Act (MPA), which prohibits abortions due to “fetal cause”.

  12. Evaluation of the anti-proliferative and cytostatic effect of Citrus sinensis (orange) fruit juice.

    Science.gov (United States)

    Chinedu, Enegide; Arome, David; Ameh, Solomon F; Ameh, Gift E

    2014-09-01

    This work has been designed to evaluate the anti-proliferative and cytostatic effects of Citrus sinensis (orange) fruit juice on rapidly proliferating cells. The study was carried out on the seeds of Sorghum bicolor for 72 h. The mean radicle length (mm) of the seeds was taken at 48 and 72 h. The result showed that when compared with the control, methotrexate, the standard drug showed a significant (P < 0.001) anti-proliferative effect throughout the experiment. The inhibition of the radicle growth was more after 72 h (87.42%). At a dose of 5% (v/v), the juice showed a slightly significant (P < 0.05) effect affect after 72 h; however, there was no significant effect at 48 h. The juice at doses of 10% and 20% (v/v) showed a highly significant (P < 0.001) anti-proliferative effect throughout the experiment; however, the percentage inhibitions were higher at 72 h. At 72 h, the percentage inhibition for juice at 10% (v/v) was 72.37% and at 20% (v/v) was 91.96%. The concentrations of 40% and 60% (v/v) showed cytostatic effects as no appreciable growth of the radicles of the seeds was observed throughout the experiment. The percentage inhibition for 40% (v/v) was 100% and 99.72% for 48 and 72 h, respectively, while that for the juice concentration of 60% (v/v) was 100% throughout the study. The experiment has shown that C. sinensis fruit juice has a potential for causing both anti-proliferative and cytostatic effects on fast proliferating cells and hence cancerous cells.

  13. Erythrocyte fatty acids and risk of proliferative and nonproliferative fibrocystic disease in women in Shanghai, China.

    Science.gov (United States)

    Shannon, Jackilen; King, Irena B; Lampe, Johanna W; Gao, Dao Li; Ray, Roberta M; Lin, Ming-Gang; Stalsberg, Helge; Thomas, David B

    2009-01-01

    Although benign breast changes are more common than breast cancer, little evidence regarding risk factors for benign breast conditions is available. Omega-3 (n-3) fatty acids have antiinflammatory and antiproliferative actions and may be important in reducing the risk of benign conditions. There is a lack of research on the association of n-3 fatty acids with risk of benign fibrocystic breast changes. The objectives of the study were to evaluate the role of n-3 and other fatty acids in the development of benign proliferative fibrocystic conditions (PFCs) and nonproliferative fibrocystic conditions (NPFCs) in the breast and to evaluate the progression of fibrocystic changes in breast cancer. We conducted a case-control study to determine erythrocyte fatty acid concentrations in 155 women with NPFCs, 185 women with PFCs, 241 women with breast cancer (127 with nonproliferative and 114 with proliferative changes in the noncancerous extratumoral mammary epithelium), and 1,030 control subjects. We estimated the relative risk of NPFCs, PFCs, and breast cancer with proliferative and nonproliferative changes in extratumoral tissue compared with the risk of these changes alone. Women in the highest quartile of eicosapentaenoic acid concentrations were 67% less likely to have an NPFC alone or with breast cancer and 49% less likely to have breast cancer than were women with PFCs. gamma-Linolenic acid (18:3n-6) was positively associated with all fibrocystic and cancerous conditions. Palmitic:palmitoleic acid (n-7 saturation index) was inversely associated with risk in all comparisons. Our results support a protective effects of n-3 fatty acid intake and the n-7 saturation index against benign fibrocystic breast changes and the progression of proliferative changes to breast cancer.

  14. The induction of chromosomal aberrations by X irradiation during S-phase in cultured diploid Syrian hamster fibroblasts

    International Nuclear Information System (INIS)

    Savage, J.R.K.; Bhunya, S.P.

    1980-01-01

    The induction of chromosomal aberrations by 4.0 Gy of 250 kV X-rays in cell throughout S-phase has been investigated in untransformed diploid Syrian hamster fibroblasts. Using a method of subdividing S into catologically defined stages (on the basis of replication band patterns displayed after brome-deoxyuridine incorporation) it is shown that: (1) This dose does not perturb, measurable, the intracellular programme of synthesis at the chromosome band level, so that the cell classification criteria remain valid after radiation. (2) Mitotic delay and perturbation appears to be less for cells in very early S, but there is no evidence of a massive cell mixing of S cells. (3) S-phase is, in general, much less sensitive to aberration induction at all sub-phases than G 2 . (4) Both chromosome and chromatid-type aberrations are found in pre- S and S cells, but chromatid-types predominate in the latter at all sub-phases. (5) The frequency of chromatid-types, especially interchanges falls in eraly. (orig.)

  15. Too much of a good thing? An observational study of prolific authors.

    Science.gov (United States)

    Wager, Elizabeth; Singhvi, Sanjay; Kleinert, Sabine

    2015-01-01

    Introduction. Researchers' productivity is usually measured in terms of their publication output. A minimum number of publications is required for some medical qualifications and professional appointments. However, authoring an unfeasibly large number of publications might indicate disregard of authorship criteria or even fraud. We therefore examined publication patterns of highly prolific authors in 4 medical specialties. Methods. We analysed Medline publications from 2008-12 using bespoke software to disambiguate individual authors focusing on 4 discrete topics (to further reduce the risk of combining publications from authors with the same name and affiliation). This enabled us to assess the number and type of publications per author per year. Results. While 99% of authors were listed on fewer than 20 publications in the 5-year period, 24 authors in the chosen areas were listed on at least 25 publications in a single year (i.e., >1 publication per 10 working days). Types of publication by the prolific authors varied but included substantial numbers of original research papers (not simply editorials or letters). Conclusions. Institutions and funders should be alert to unfeasibly prolific authors when measuring and creating incentives for researcher productivity.

  16. Too much of a good thing? An observational study of prolific authors

    Directory of Open Access Journals (Sweden)

    Elizabeth Wager

    2015-08-01

    Full Text Available Introduction. Researchers’ productivity is usually measured in terms of their publication output. A minimum number of publications is required for some medical qualifications and professional appointments. However, authoring an unfeasibly large number of publications might indicate disregard of authorship criteria or even fraud. We therefore examined publication patterns of highly prolific authors in 4 medical specialties.Methods. We analysed Medline publications from 2008–12 using bespoke software to disambiguate individual authors focusing on 4 discrete topics (to further reduce the risk of combining publications from authors with the same name and affiliation. This enabled us to assess the number and type of publications per author per year.Results. While 99% of authors were listed on fewer than 20 publications in the 5-year period, 24 authors in the chosen areas were listed on at least 25 publications in a single year (i.e., >1 publication per 10 working days. Types of publication by the prolific authors varied but included substantial numbers of original research papers (not simply editorials or letters.Conclusions. Institutions and funders should be alert to unfeasibly prolific authors when measuring and creating incentives for researcher productivity.

  17. Proliferative thyroid lesions in three diplodactylid geckos: Nephrurus amyae, Nephrurus levis, and Oedura marmorata.

    Science.gov (United States)

    Hadfield, Catherine A; Clayton, Leigh A; Clancy, Meredith M; Beck, Sarah E; Mangus, Lisa M; Montali, Richard J

    2012-03-01

    Over a 5-mo period, three diplodactylid geckos housed at the National Aquarium were diagnosed with proliferative thyroid lesions: a rough knob-tail gecko (Nephrurus amyae), a smooth knob-tail gecko (Nephrurus levis), and a marbled velvet gecko (Oedura marmorata). Clinical signs included an intraoral mass or ventral throat swelling (or both), oral bleeding, and weight loss. Both of the knob-tail geckos died. The histologic diagnosis for the rough knob-tail gecko was thyroid carcinoma with metastases to the liver and lungs, and thyroid carcinoma with no metastases was reported in the smooth knob-tail gecko. A thyroidectomy was performed on the marbled velvet gecko with a histologic diagnosis of adenomatous hyperplasia. Postoperative weight loss and bradycardia resolved following oral supplementation with levothyroxine. The animal is in normal health 10 mo post-surgery. Five other diplodactylid geckos in the collection remain unaffected, giving a 38% prevalence of proliferative thyroid lesions (3/8). The etiology remains undetermined. This is the first report of a cluster of proliferative thyroid lesions in geckos.

  18. Anatomical and functional outcomes of retinectomies in retinal detachments complicated by proliferative vitreoretinopathy

    Directory of Open Access Journals (Sweden)

    Mohammad Idrees Adhi

    2017-10-01

    Full Text Available Purpose: To study anatomical and functional outcomes of retinectomies in rhegmatogenous retinal detachments complicated by proliferative vitreoretinopathy. Methods: This is a retrospective interventional consecutive case series of eyes with rhegmatogenous retinal detachments complicated by advanced proliferative vitreoretinopathy and managed by relaxing retinectomy over a period of seventeen years. Three-port pars plana vitrectomy included core vitrectomy and removal of all epi-retinal membranes. On failure to flatten, retina was cut and excised. Basal vitrectomy and removal of anterior flap of retina then followed. Silicone oil was used as temponade in majority of cases. The dependent variables were anatomical and functional outcomes. The statistical analysis was performed on SPSS 21. Results: Series included 370 eyes of 337 patients. Mean follow up was 39 months. Scleral explant was used in 90(24.39% cases. Two hundred and nine (56.49% eyes were operated with trans conjunctival sutureless vitrectomy technique. Procedure was bilateral in 33 patients (09.79%. Retina attached in 311(84.05% eyes after initial surgery. Final re-attachment after one or more surgeries was achieved in 344(92.97% eyes. Two hundred and eleven (57.02% cases achieved visual acuity of 6/60 or better. Conclusion: Relaxing retinectomies have good and encouraging anatomical and functional outcomes. This surgery can be effectively carried out with trans conjunctival sutureless vitrectomy technique. Keywords: Retinotomy and retinectomy, Proliferative vitreoretinopathy, Trans conjunctival sutureless vitrectomy, Silicone oil

  19. Eco-friendly synthesis, in vitro anti-proliferative evaluation, and 3D-QSAR analysis of a novel series of monocationic 2-aryl/heteroaryl-substituted 6-(2-imidazolinyl)benzothiazole mesylates.

    Science.gov (United States)

    Racané, Livio; Ptiček, Lucija; Sedić, Mirela; Grbčić, Petra; Kraljević Pavelić, Sandra; Bertoša, Branimir; Sović, Irena; Karminski-Zamola, Grace

    2018-04-17

    Herein, we describe the synthesis of twenty-one novel water-soluble monocationic 2-aryl/heteroaryl-substituted 6-(2-imidazolinyl)benzothiazole mesylates 3a-3u and present the results of their anti-proliferative assays. Efficient syntheses were achieved by three complementary simple two-step synthetic protocols based on the condensation reaction of aryl/heteroaryl carbaldehydes or carboxylic acid. We developed an eco-friendly synthetic protocol using glycerol as green solvent, particularly appropriate for the condensation of thermally and acid-sensitive heterocycles such as furan, benzofuran, pyrrole, and indole. Screening of anti-proliferative activity was performed on four human tumour cell lines in vitro including pancreatic cancer (CFPAC-1), metastatic colon cancer (SW620), hepatocellular carcinoma (HepG2), and cervical cancer (HeLa), as well as in normal human fibroblast cell lines. All tested compounds showed strong to moderate anti-proliferative activity on tested cell lines depending on the structure containing aryl/heteroaryl moiety coupled to 6-(2-imidazolinyl)benzothiazole moiety. The most potent cytostatic effects on all tested cell lines with [Formula: see text] values ranging from 0.1 to 3.70 [Formula: see text] were observed for benzothiazoles substituted with naphthalene-2-yl 3c, benzofuran-2-yl 3e, indole-3-yl 3j, indole-2-yl 3k, quinoline-2-yl 3s, and quinoline-3-yl 3t and derivatives substituted with phenyl 3a, naphthalene-1-yl 3b, benzothiazole-2-yl 3g, benzothiazole-6-yl 3h, N-methylindole-3-yl 3l, benzimidazole-2-yl 3n, benzimidazole-5(6)-yl 3o, and quinolone-4-yl 3u with [Formula: see text] values ranging from 1.1 to 29.1 [Formula: see text]. Based on obtained anti-proliferative activities, 3D-QSAR models for five cell lines were derived. Molecular volume, molecular surface, the sum of hydrophobic surface areas, molecular mass, and possibility of making dispersion forces were identified by QSAR analyses as molecular properties that are

  20. Cysteine-based 3-substituted 1,5-benzoxathiepin derivatives: Two new classes of anti-proliferative agents

    Directory of Open Access Journals (Sweden)

    Nawal Mahfoudh

    2018-03-01

    Full Text Available Two distinct series of the 3-amino-1,5-benzoxathiepin scaffold, derived from L-cysteine, were synthesized and evaluated for their anti-proliferative activity in the breast cancer MDA-MB-231 and MCF-7 cells, and in the ovarian carcinoma SKOV-3 cell line. (3R-Amino-3,4-dihydro-2H-1,5-benzoxathiepin [(R-10] was diversified into two forms: (a by incorporating different amino acids at its position 3, through an amide bond; and (b by construction of the purine ring to give 6-chloro-9-[2-(3,4-dihydro-2H-1,5-benzoxathiepin-(3R-yl]-9H-purine [(R-28]. Nevertheless, when the introduction of iodine was tried at position 2 of the purine ring of (R-28, 2-{[2-(6-chloro-2-iodo-9H-purin-9-ylprop-2-en-1-yl]thio}phenol (34 was obtained. Compound 34 shows activity against cancer cells. Interestingly, 34 inhibits mammosphere formation at the micromolar range, demonstrating activity against cancer stem cells. Although further studies of its targets and mechanism of action are needed, these findings support the therapeutic potential of this compound in cancer.

  1. Anti-proliferative, Cytotoxic and NF-ĸB Inhibitory Properties of Spiro(Lactone-Cyclohexanone) Compounds in Human Leukemia.

    Science.gov (United States)

    Bouhenna, Mustapha M; Orlikova, Barbora; Talhi, Oualid; Schram, Ben; Pinto, Diana C G A; Taibi, Nadia; Bachari, Khaldoun; Diederich, Marc; Silva, Artur M S; Mameri, Nabil

    2017-09-01

    NF-ĸB affects most aspects of cellular physiology. Deregulation of NF-ĸB signaling is associated with inflammatory diseases and cancer. In this study, we evaluated the cytotoxic and NF-ĸB inhibition potential of new spiro(lactone-cyclohexanone) compounds in two different human leukemia cell lines (U937 and K562). The anti-proliferative effects of the spiro(lactone-cyclohexanone) compounds on human K562 and U937 cell lines was evaluated by trypan blue staining, as well as their involvement in NF-kB regulation were analyzed by luciferase reporter gene assay, Caspase-3/7 activities were evaluated to analyze apoptosis induction. Both spiro(coumarin-cyclohexanone) 4 and spiro(6- methyllactone-cyclohexanone) 9 down-regulated cancer cell viability and proliferation. Compound 4 inhibited TNF-α-induced NF-ĸB activation in a dose-dependent manner and induced caspase-dependent apoptosis in both leukemia cell lines. Results show that compound 4 and compound 9 have potential as anti-cancer agents. In addition, compound 4 exerted NF-kB inhibition activity in leukemia cancer cells. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  2. Seismic attenuation in the African LLSVP estimated from PcS phases

    Science.gov (United States)

    Liu, Chujie; Grand, Stephen P.

    2018-05-01

    Seismic tomography models have revealed two broad regions in the lowermost mantle marked by ∼3% slower shear velocity than normal beneath the south central Pacific and southern Africa. These two regions are known as large-low-shear-velocity provinces (LLSVP). There is debate over whether the LLSVPs can be explained by purely thermal variations or whether they must be chemically distinct from normal mantle. Elastic properties alone, have been unable to distinguish the thermal from chemical interpretations. Anelastic structure, however, can help discriminate among models of the LLSVPs since intrinsic attenuation is more sensitive to temperature than to chemical variations. Here we estimate Qμ (the shear wave quality factor) in the African LLSVP using PcS waves generated from a Scotia Arc earthquake, recorded by broadband seismometers deployed in Southern Africa during the Kaapvaal experiment. The upward leg of the PcS waves sweeps from normal mantle into the African LLSVP across the array. We use the spectral ratio (SR) and instantaneous frequency matching (IFM) techniques to measure the differential attenuation (Δt*) between waves sampling the African LLSVP and the waves that sample normal lower mantle. Using both methods for estimating Δt* we find that PcS waves sampling the LLSVP are more attenuated than the waves that miss the LLSVP yielding a Δt* difference of more than 1 s. Using the Δt* measurements we estimate the average Qμ in the LLSVP to be about 110. Using a range of activation enthalpy (H*) estimates, we find an average temperature anomaly within the LLSVP ranging from +250 to +800 K. Our estimated temperature anomaly range overlaps previous isochemical geodynamic studies that explain the LLSVP as a purely thermal structure although the large uncertainties cannot rule out chemical variations as well.

  3. The G protein-coupled receptor GPR30 mediates the proliferative and invasive effects induced by hydroxytamoxifen in endometrial cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Du, Gui-Qiang; Zhou, Long; Chen, Xiao-Yue [Department of Obstetrics and Gynecology, The International Peace Maternity and Child Health Hospital of the China Welfare Institute Affiliated to Shanghai Jiao Tong University, 910, Hengshan Road, Shanghai (China); Wan, Xiao-Ping, E-mail: wanxiaoping61@126.com [Department of Obstetrics and Gynecology, The International Peace Maternity and Child Health Hospital of the China Welfare Institute Affiliated to Shanghai Jiao Tong University, 910, Hengshan Road, Shanghai (China); He, Yin-Yan [Department of Obstetrics and Gynecology, Shanghai First People' s Hospital, Shanghai Jiao Tong University, Shanghai (China)

    2012-04-06

    Highlights: Black-Right-Pointing-Pointer We assessed hydroxytamoxifen (OHT) effects in two endometrial cancer cell lines. Black-Right-Pointing-Pointer GPR30 mediates the proliferative effects induced by OHT. Black-Right-Pointing-Pointer GPR30 mediates the invasive effects induced by OHT. Black-Right-Pointing-Pointer GPR30 expression was up-regulated by OHT in endometrial cancer cell line. -- Abstract: The selective ER modulator tamoxifen (TAM) is the most widely used ER antagonist for treatment of women with hormone-dependent breast tumor. However, long-term treatment is associated with an increased risk of endometrial cancer. The aim of the present study was to demonstrate new insight into the role of G-protein coupled receptor 30 (GPR30) in the activity of TAM, which promoted endometrial cancer. In endometrial cancer cell lines ISHIKAWA and KLE, the potential of 4-hydroxytamoxifen (OHT), the active metabolite of TAM, 17{beta}-estradiol (E2) and G1, a non-steroidal GPR30-specific agonist to promote cell proliferation and invasion was evaluated. All agents above induced high proliferative and invasive effects, while the down-regulation of GPR30 or the interruption of MAPK signal pathway partly or completely prevented the action of the regent. Moreover, the RNA and protein expression of GPR30 was up-regulated by G1, E2 or OHT in both cell lines. The present study provided a new insight into the mechanism involved in the agonistic activity exerted by TAM in the uterus.

  4. A lentiviral vector with expression controlled by E2F-1: A potential tool for the study and treatment of proliferative diseases

    International Nuclear Information System (INIS)

    Strauss, Bryan E.; Patricio, Juliana Rotelli; Vieira de Carvalho, Anna Carolina; Bajgelman, Marcio C.

    2006-01-01

    We have constructed a lentiviral vector with expression limited to cells presenting active E2F-1 protein, a potential advantage for gene therapy of proliferative diseases. For the FE2FLW vector, the promoter region of the human E2F-1 gene was utilized to drive expression of luciferase cDNA, included as a reporter of viral expression. Primary, immortalized, and transformed cells were transduced with the FE2FLW vector and cell cycle alterations were induced with serum starvation/replacement, contact inhibition or drug treatment, revealing cell cycle-dependent changes in reporter activity. Forced E2F-1 expression, but not E2F-2 or E2F-3, increased reporter activity, indicating a major role for this factor in controlling expression from the FE2FLW virus. We show the utility of this vector as a reporter of E2F-1 and proliferation-dependent cellular alterations upon cytotoxic/cytostatic treatment, such as the introduction of tumor suppressor genes. We propose that the FE2FLW vector may be a starting point for the development of gene therapy strategies for proliferative diseases, such as cancer or restinosis

  5. The G protein-coupled receptor GPR30 mediates the proliferative and invasive effects induced by hydroxytamoxifen in endometrial cancer cells

    International Nuclear Information System (INIS)

    Du, Gui-Qiang; Zhou, Long; Chen, Xiao-Yue; Wan, Xiao-Ping; He, Yin-Yan

    2012-01-01

    Highlights: ► We assessed hydroxytamoxifen (OHT) effects in two endometrial cancer cell lines. ► GPR30 mediates the proliferative effects induced by OHT. ► GPR30 mediates the invasive effects induced by OHT. ► GPR30 expression was up-regulated by OHT in endometrial cancer cell line. -- Abstract: The selective ER modulator tamoxifen (TAM) is the most widely used ER antagonist for treatment of women with hormone-dependent breast tumor. However, long-term treatment is associated with an increased risk of endometrial cancer. The aim of the present study was to demonstrate new insight into the role of G-protein coupled receptor 30 (GPR30) in the activity of TAM, which promoted endometrial cancer. In endometrial cancer cell lines ISHIKAWA and KLE, the potential of 4-hydroxytamoxifen (OHT), the active metabolite of TAM, 17β-estradiol (E2) and G1, a non-steroidal GPR30-specific agonist to promote cell proliferation and invasion was evaluated. All agents above induced high proliferative and invasive effects, while the down-regulation of GPR30 or the interruption of MAPK signal pathway partly or completely prevented the action of the regent. Moreover, the RNA and protein expression of GPR30 was up-regulated by G1, E2 or OHT in both cell lines. The present study provided a new insight into the mechanism involved in the agonistic activity exerted by TAM in the uterus.

  6. Differential expression of follistatin and FLRG in human breast proliferative disorders

    Directory of Open Access Journals (Sweden)

    Amaral Vania F

    2009-09-01

    Full Text Available Abstract Background Activins are growth factors acting on cell growth and differentiation. Activins are expressed in high grade breast tumors and they display an antiproliferative effect inducing G0/G1 cell cycle arrest in breast cancer cell lines. Follistatin and follistatin- related gene (FLRG bind and neutralize activins. In order to establish if these activin binding proteins are involved in breast tumor progression, the present study evaluated follistatin and FLRG pattern of mRNA and protein expression in normal human breast tissue and in different breast proliferative diseases. Methods Paraffin embedded specimens of normal breast (NB - n = 8; florid hyperplasia without atypia (FH - n = 17; fibroadenoma (FIB - n = 17; ductal carcinoma in situ (DCIS - n = 10 and infiltrating ductal carcinoma (IDC - n = 15 were processed for follistatin and FLRG immunohistochemistry and in situ hybridization. The area and intensity of chromogen epithelial and stromal staining were analyzed semi-quantitatively. Results Follistatin and FLRG were expressed both in normal tissue and in all the breast diseases investigated. Follistatin staining was detected in the epithelial cytoplasm and nucleus in normal, benign and malignant breast tissue, with a stronger staining intensity in the peri-alveolar stromal cells of FIB at both mRNA and protein levels. Conversely, FLRG area and intensity of mRNA and protein staining were higher both in the cytoplasm and in the nucleus of IDC epithelial cells when compared to NB, while no significant changes in the stromal intensity were observed in all the proliferative diseases analyzed. Conclusion The present findings suggest a role for follistatin in breast benign disease, particularly in FIB, where its expression was increased in stromal cells. The up regulation of FLRG in IDC suggests a role for this protein in the progression of breast malignancy. As activin displays an anti-proliferative effect in human mammary cells, the

  7. Lactobacillus casei Exerts Anti-Proliferative Effects Accompanied by Apoptotic Cell Death and Up-Regulation of TRAIL in Colon Carcinoma Cells

    Science.gov (United States)

    Santarmaki, Valentina; Aindelis, Georgios; Tompoulidou, Evgenia; Lamprianidou, Eleftheria E.; Saxami, Georgia; Ypsilantis, Petros; Lampri, Evangeli S.; Simopoulos, Constantinos; Kotsianidis, Ioannis; Galanis, Alex; Kourkoutas, Yiannis; Dimitrellou, Dimitra; Chlichlia, Katerina

    2016-01-01

    Probiotic microorganisms such as lactic acid bacteria (LAB) exert a number of strain-specific health-promoting activities attributed to their immunomodulatory, anti-inflammatory and anti-carcinogenic properties. Despite recent attention, our understanding of the biological processes involved in the beneficial effects of LAB strains is still limited. To this end, the present study investigated the growth-inhibitory effects of Lactobacillus casei ATCC 393 against experimental colon cancer. Administration of live Lactobacillus casei (as well as bacterial components thereof) on murine (CT26) and human (HT29) colon carcinoma cell lines raised a significant concentration- and time-dependent anti-proliferative effect, determined by cell viability assays. Specifically, a dramatic decrease in viability of colon cancer cells co-incubated with 109 CFU/mL L. casei for 24 hours was detected (78% for HT29 and 52% for CT26 cells). In addition, live L. casei induced apoptotic cell death in both cell lines as revealed by annexin V and propidium iodide staining. The significance of the in vitro anti-proliferative effects was further confirmed in an experimental tumor model. Oral daily administration of 109 CFU live L. casei for 13 days significantly inhibited in vivo growth of colon carcinoma cells, resulting in approximately 80% reduction in tumor volume of treated mice. Tumor growth inhibition was accompanied by L. casei-driven up-regulation of the TNF-related apoptosis-inducing ligand TRAIL and down-regulation of Survivin. Taken together, these findings provide evidence for beneficial tumor-inhibitory, anti-proliferative and pro-apoptotic effects driven by this probiotic LAB strain. PMID:26849051

  8. Lactobacillus casei Exerts Anti-Proliferative Effects Accompanied by Apoptotic Cell Death and Up-Regulation of TRAIL in Colon Carcinoma Cells.

    Directory of Open Access Journals (Sweden)

    Angeliki Tiptiri-Kourpeti

    Full Text Available Probiotic microorganisms such as lactic acid bacteria (LAB exert a number of strain-specific health-promoting activities attributed to their immunomodulatory, anti-inflammatory and anti-carcinogenic properties. Despite recent attention, our understanding of the biological processes involved in the beneficial effects of LAB strains is still limited. To this end, the present study investigated the growth-inhibitory effects of Lactobacillus casei ATCC 393 against experimental colon cancer. Administration of live Lactobacillus casei (as well as bacterial components thereof on murine (CT26 and human (HT29 colon carcinoma cell lines raised a significant concentration- and time-dependent anti-proliferative effect, determined by cell viability assays. Specifically, a dramatic decrease in viability of colon cancer cells co-incubated with 10(9 CFU/mL L. casei for 24 hours was detected (78% for HT29 and 52% for CT26 cells. In addition, live L. casei induced apoptotic cell death in both cell lines as revealed by annexin V and propidium iodide staining. The significance of the in vitro anti-proliferative effects was further confirmed in an experimental tumor model. Oral daily administration of 10(9 CFU live L. casei for 13 days significantly inhibited in vivo growth of colon carcinoma cells, resulting in approximately 80% reduction in tumor volume of treated mice. Tumor growth inhibition was accompanied by L. casei-driven up-regulation of the TNF-related apoptosis-inducing ligand TRAIL and down-regulation of Survivin. Taken together, these findings provide evidence for beneficial tumor-inhibitory, anti-proliferative and pro-apoptotic effects driven by this probiotic LAB strain.

  9. Lactobacillus casei Exerts Anti-Proliferative Effects Accompanied by Apoptotic Cell Death and Up-Regulation of TRAIL in Colon Carcinoma Cells.

    Science.gov (United States)

    Tiptiri-Kourpeti, Angeliki; Spyridopoulou, Katerina; Santarmaki, Valentina; Aindelis, Georgios; Tompoulidou, Evgenia; Lamprianidou, Eleftheria E; Saxami, Georgia; Ypsilantis, Petros; Lampri, Evangeli S; Simopoulos, Constantinos; Kotsianidis, Ioannis; Galanis, Alex; Kourkoutas, Yiannis; Dimitrellou, Dimitra; Chlichlia, Katerina

    2016-01-01

    Probiotic microorganisms such as lactic acid bacteria (LAB) exert a number of strain-specific health-promoting activities attributed to their immunomodulatory, anti-inflammatory and anti-carcinogenic properties. Despite recent attention, our understanding of the biological processes involved in the beneficial effects of LAB strains is still limited. To this end, the present study investigated the growth-inhibitory effects of Lactobacillus casei ATCC 393 against experimental colon cancer. Administration of live Lactobacillus casei (as well as bacterial components thereof) on murine (CT26) and human (HT29) colon carcinoma cell lines raised a significant concentration- and time-dependent anti-proliferative effect, determined by cell viability assays. Specifically, a dramatic decrease in viability of colon cancer cells co-incubated with 10(9) CFU/mL L. casei for 24 hours was detected (78% for HT29 and 52% for CT26 cells). In addition, live L. casei induced apoptotic cell death in both cell lines as revealed by annexin V and propidium iodide staining. The significance of the in vitro anti-proliferative effects was further confirmed in an experimental tumor model. Oral daily administration of 10(9) CFU live L. casei for 13 days significantly inhibited in vivo growth of colon carcinoma cells, resulting in approximately 80% reduction in tumor volume of treated mice. Tumor growth inhibition was accompanied by L. casei-driven up-regulation of the TNF-related apoptosis-inducing ligand TRAIL and down-regulation of Survivin. Taken together, these findings provide evidence for beneficial tumor-inhibitory, anti-proliferative and pro-apoptotic effects driven by this probiotic LAB strain.

  10. Proliferative capacity of stem/progenitor-like cells in the kidney may associate with the outcome of patients with acute tubular necrosis.

    Science.gov (United States)

    Ye, Youxin; Wang, Bingyin; Jiang, Xinxin; Hu, Weiming; Feng, Jian; Li, Hua; Jin, Mei; Ying, Yingjuan; Wang, Wenjuan; Mao, Xiaoou; Jin, Kunlin

    2011-08-01

    Animal studies indicate that adult renal stem/progenitor cells can undergo rapid proliferation in response to renal injury, but whether the same is true in humans is largely unknown. To examine the profile of renal stem/progenitor cells responsible for acute tubular necrosis in human kidney, double and triple immunostaining was performed using proliferative marker and stem/progenitor protein markers on sections from 10 kidneys with acute tubular necrosis and 4 normal adult kidneys. The immunopositive cells were recorded using 2-photon confocal laser scanning microscopy. We found that dividing cells were present in the tubules of the cortex and medulla, as well as the glomerulus in normal human kidney. Proliferative cells in the parietal layer of Bowman capsule expressed CD133, and dividing cells in the tubules expressed immature cell protein markers paired box gene 2, vimentin, and nestin. After acute tubular necrosis, Ki67-positive cells in the cortex tubules significantly increased compared with normal adult kidney. These Ki67-positive cells expressed CD133 and paired box gene 2, but not the cell death marker, activated caspase-3. In addition, the number of dividing cells increased significantly in patients with acute tubular necrosis who subsequently recovered, compared with patients with acute tubular necrosis who consequently developed protracted acute tubular necrosis or died. Our data suggest that renal stem/progenitor cells may reside not only in the parietal layer of Bowman capsule but also in the cortex and medulla in normal human kidney, and the proliferative capacity of renal stem/progenitor cells after acute tubular necrosis may be an important determinant of a patient's outcome. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Phosphoinositide-3-kinases p110alpha and p110beta mediate S phase entry in astroglial cells in the marginal zone of rat neocortex

    Directory of Open Access Journals (Sweden)

    Rabea eMüller

    2013-03-01

    Full Text Available In cells cultured from neocortex of newborn rats, phosphoinositide-3-kinases of class I regulate the DNA synthesis in a subgroup of astroglial cells. We have studied the location of these cells as well as the kinase isoforms which facilitate the S phase entry. Using dominant negative isoforms as well as selective pharmacological inhibitors we quantified S phase entry by nuclear labeling with bromodeoxyuridine. Only in astroglial cells harvested from the marginal zone of the neocortex inhibition of phosphoinositide-3-kinases reduced the nuclear labeling with bromodeoxyuridine, indicating that neocortical astroglial cells differ in the regulation of proliferation. The two kinase isoforms p110 and p110were essential for S phase entry. p110 diminished the level of the p27Kip1 which inactivates the complex of cyclin E and CDK2 necessary for entry into the S phase. p110phosphorylated and inhibited glycogen synthase kinase-3which can prevent S-phase entry. Taken together, both isoforms mediated S phase in a subgroup of neocortical astroglial cells and acted via distinct pathways.

  12. Herpes simplex virus (HSV)-specific proliferative and cytotoxic T-cell responses in humans immunized with an HSF type 2 glycoprotein subunit vaccine

    Energy Technology Data Exchange (ETDEWEB)

    Zarling, J.M.; Moran, P.A.; Brewer, L.; Ashley, R.; Corey, L.

    1988-12-01

    Studies were undertaken to determine whether immunization of humans with a herpes simplex virus type 2 (HSV-2) glycoprotein-subunit vaccine would result in the priming of both HSV-specific proliferating cells and cytotoxic T cells. Peripheral blood lymphocytes (PBL) from all eight vaccinees studied responded by proliferating after stimulation with HSV-2, HSV-1, and glycoprotein gB-1. The PBL of five of these eight vaccinees proliferated following stimulation with gD-2, whereas stimulation with Gd-1 resulted in relatively low or no proliferative responses. T-cell clones were generated from HSV-2-stimulated PBL of three vaccinees who demonstrated strong proliferative responses to HSV-1 and HSV-2. Of 12 clones studied in lymphoproliferative assays, 9 were found to be cross-reactive for HSV-1 and HSV-2. Of the approximately 90 T-cell clones isolated, 14 demonstrated HSV-specific cytotoxic activity. Radioimmunoprecipitation-polyacrylamide gel electrophoresis analyses confirmed that the vaccinees had antibodies only to HSV glycoproteins, not to proteins which are absent in the subunit vaccine, indicating that these vaccinees had not become infected with HSV. Immunization of humans with an HSV-2 glycoprotein-subunit vaccine thus results in the priming of T cells that proliferate in response to stimulation with HSV and its glycoproteins and T cells that have cytotoxic activity against HSV-infected cells. Such HSV-specific memory T cells were detected as late as 2 years following the last boost with the subunit vaccine.

  13. Modulation of intracellular calcium and proliferative activity of invertebrate and vertebrate cells by ethylene

    Directory of Open Access Journals (Sweden)

    Müller Werner EG

    2001-05-01

    Full Text Available Abstract Background Ethylene is a widely distributed alkene product which is formed enzymatically (e.g., in plants or by photochemical reactions (e.g., in the upper oceanic layers from dissolved organic carbon. This gaseous compound was recently found to induce in cells from the marine sponge Suberites domuncula, an increase in intracellular Ca2+ level ([Ca2+]i and an upregulation of the expression of two genes, the potential ethylene-responsive gene, SDERR, and a Ca2+/calmodulin-dependent protein kinase. Results Here we describe for the first time, that besides sponge cells, mammalian cell lines (mouse NIH-3T3 and human HeLa and SaOS-2 cells respond to ethylene, generated by ethephon, with an immediate and strong, transient increase in [Ca2+]i level, as demonstrated using Fura-2 imaging method. A rise of [Ca2+]i level was also found following exposure to ethylene gas of cells kept under pressure (SaOS-2 cells. The upregulation of [Ca2+]i was associated with an increase in the level of the cell cycle-associated Ki-67 antigen. In addition, we show that the effect of ethephon addition to S. domuncula cells depends on the presence of calcium in the extracellular milieu. Conclusion The results presented in this paper indicate that ethylene, previously known to act as a mediator (hormone in plants only, deserves also attention as a potential signaling molecule in higher vertebrates. Further studies are necessary to clarify the specificity and physiological significance of the effects induced by ethylene in mammalian cells.

  14. Breast cancer proliferative activity: Is it the source of serum free DNA?

    African Journals Online (AJOL)

    Taha I. Hewala

    2013-04-13

    Apr 13, 2013 ... DNA concentration in lung cancer patients was 8-fold higher ... patients with invasive ductal carcinoma of clinical stages II and III,12 recently ... centrifuged for 20 min at 3500 rpm at 4 °C. The separated ser- um samples were ...

  15. Amine dependence of proliferative activity in two transplantable lines of mouse colonic carcinoma.

    Science.gov (United States)

    Tutton, P J; Barkla, D H

    1987-01-01

    Serotonin, histamine and their antagonists have previously been shown to influence both the cell proliferation rate and the volumetric growth rate of colonic tumours. Of these earlier studies, those on cell proliferation could not distinguish between direct effects on tumour cells and indirect effects on the host, whereas those on the volumetric growth rate of tumours, whilst suggesting an outcome related to the individual properties of the tumour rather than the host, could not distinguish between influences on cell gain, cell loss or stromal changes. In an attempt to distinguish between these possibilities the current experiments on the mitotic rate in two lines of transplantable mouse colonic carcinoma were undertaken. One line of tumour proved to be sensitive to inhibition by a histamine H2 receptor antagonist and a dopamine D2 antagonist but resistant to serotonin antagonists; the inhibition by histamine antagonists was surmountable by co-administration of histamine. The other line proved to be highly sensitive to the inhibitory effects of serotonin antagonist and less so to antagonists of the other two amines and in this case the effect of serotonin antagonists was surmountable by serotonin. These results suggest that the variations between different colonic tumours in the response to amine antagonists is due to differences in the extent of inhibition of cell proliferation rather than differences in cell loss or stromal effects. Thus it appears likely that amine antagonists are able to directly interfere with the proliferation of some colonic tumour cells.

  16. The prognostic relevance of estimates of proliferative activity in early breast cancer

    DEFF Research Database (Denmark)

    Offersen, B V; Sørensen, Flemming Brandt; Knoop, A

    2003-01-01

    clinicopathological parameters at diagnosis in early breast cancer patients.MATERIALS AND METHODS: Tumour specimens from 365 consecutively treated breast cancer patients were immunostained for MIB-1 and evaluated under the microscope using systematic random sampling accomplished by the CAST-grid system.......RESULTS: The systematic random sampling technique resulted in MIB-1 estimates with very high interobserver and intraobserver reproducibilities (P

  17. Changes in the proliferative activity of hippocampal neural stem cells from manganismus mice

    Institute of Scientific and Technical Information of China (English)

    Guohe Tan; Boning Yang; Guofu Tan; Bo Liang; Jiangu Gong; Xiaodong Ge; Songchao Guo

    2007-01-01

    BACKGROUND: Manganese neurotoxicity presents in the form of not only extracorticospinal tract injury of central nervous system (CNS), but also learning and memory ability damage. So, the mechanism of manganese neurotoxicity will be further studied from the angle ofhippocampus.OBJECTIVE: To observe the effects of manganism on learning and memory ability and the proliferation of neural stem cells (NSCs) in hippocampus of mouse brains, and analyze whether this effect has dose-dependence.DESIGN: Randomized controlled experiment.SETTING: Department of Human Anatomy, and Department of Industrial Hygiene and Occupational Diseases, Guangxi Medical University.MATERIALS: Twenty-eight male Kunming mice, aged 2 weeks, were involved in this experiment. The involved mice were randomized into 4 groups, with 7 in each: control group, low-dose manganism group,middle-dose manganism group and high-dose manganism group. Manganese chloride was purchased from Shantou Chemicals Factory.METHODS: This experiment was carried out in the Experimental Center for Preclinical Medicine, Guangxi Medical University from November 2005 to August 2006. Mice in the low-, middle- and high-dose manganism groups were intraperitoneally injected with 5, 20 and 50 mg/kg per day manganese chloride, once a day, for 2 weeks successively. Mice in the control group were injected with the same amount of stroke-physiological saline solution. Neurobehavioral detection of all the animals was performed in Morris water maze constantly from the 7th day after the first injection of manganese chloride solution. Learning ability was detected in the place navigation test. Mice were trained for 5 consecutive days with four trials per day. The time to find the platform was latency. Memory ability was detected in spatial probe test. Platform was withdrawn on the following day of place navigation. The mice were placed in the water from a random start in the edge of the pool. The number of times they traversed the plateform's region was recorded as the performance of spatial memory. At the final two days of the water maze tests, all the animals were daily intraperitoneally injected with 50 mg/kg BrdU three times successively, once every 4 hours. At 24 hours after the final BrdU injection, all the animals were sacrificed and perfused, and their brains were harvested, fixed and successively sliced at coronary plane on a freezing microtome. Distribution and number of BrdU-positive cells in the subgranular zone ofhippocampus of brains of experimental animas were detected respectively by immunohistochemistry for reflecting the proliferation of NSCs. Single-factor analysis of variance was used for comparing the difference of measurement data. Linear correlation analysis was used among the performance record in Morris water maze test, the number of BrdU-immunopositive cells and the dose of manganism.MAIN OUTCOME MEASURES: Learning and memory ability and the number of hippocampal NSCs of mice in each group.RESULTS: ①Performance of mice in Morris water maze: In the place navigation test, there was a significant retarded learning in mice of high-dose manganism group from the 3rd day as compared with control group (P < 0.01). Till the 5th day, escape latency of mice in each manganism group was prolonged,and learning performance was significantly decreased (P < 0.05), while swimming speed did not affect above results. In the spatial probe test, the average frequency of middle- and high-dose manganism groups was 1.17±1.60 and 0.80±1.10, respectively, and decreased remarkably than that of control group which was 4.86 ±1.35 (P < 0.01), indicating memory ability was decreased; while the average frequency of low-dose manganism group did not differ obviously from that of control group (P =0.066) although it was 2.67 ± 3.27.The difference of swimming speed in each group was still of no statistic significance (P > 0.05). ②Effect of manganism on the number of NSCs: After counting, the average number of BrdU- immunopositive cells of one side in the control group, low-, middle- and high-dose manganism groups was 69.20±4.48, 36.63 ±4.50,31.00 ±6.87, 26.76 ±4.83, individually (P < 0.01). ③Results of linear correlation analysis: The ability of spatial memory was significantly in positive correlation with the number of BrdU-labeled cells ( r =0.734,P < 0.01), and in negative correlation with the intensity of manganese poisoning (r =- 0.598, P <0.01).Meanwhile, there was a significant negative correlation between the number of BrdU-labeled cells and the intensity of manganese poisoning(r = - 0.666, P < 0.01).ONCLUSION: Manganese exposure in mice can affect the ability of learning and memory, which is probably caused by the inhibition of manganese to the neurogenesis of NSCs in hippocampus in dose-dependent manner.

  18. In vitro antioxidant and anti-proliferative activity of Ethiopian medicinal plant extracts

    Czech Academy of Sciences Publication Activity Database

    Tauchen, J.; Doskočil, I.; Caffi, C.; Lulekal, E.; Maršík, Petr; Havlík, J.; Van Damme, P.; Kokoška, L.

    2015-01-01

    Roč. 74, NOV 15 (2015), s. 671-679 ISSN 0926-6690 Institutional support: RVO:61389030 Keywords : Antioxidant * Anticarcinogenic * Plant extract Subject RIV: GM - Food Processing Impact factor: 3.449, year: 2015

  19. Peripheral blood T cell proliferative response to chlamydial organisms in gonococcal and non-gonococcal urethritis and presumed pelvic inflammatory disease

    Science.gov (United States)

    Shahmanesh, M.; Brunst, M.; Sukthankar, A.; Pearce, J. H.; Gaston, J. S.

    1999-01-01

    OBJECTIVE: To study peripheral blood mononuclear cell (PBMC) proliferative response to Chlamydia trachomatis elementary bodies in (a) controls, (b) various stages of gonococcal (c) and non-gonococcal urethritis, and (d) women with a clinical diagnosis of pelvic inflammatory disease (PID). METHODS: We categorised 102 men presenting to a GUM clinic with urethritis by organisms (C trachomatis (CT) or Neisseria gonorrhoeae (NG) (both by culture), and whether it was their first (urethritis naive) or subsequent (urethritis experienced) attack. 23 women presenting to the clinic with a clinical diagnosis of PID were also investigated. We measured PBMC proliferative responses to C trachomatis (DK20--an oculogenital strain, serovar E), lysate of McCoy cells (used to propagate chlamydiae), and the recall antigen PPD. Controls were 37 men and women without present or past history of urethritis or chlamydial infection. Results were expressed as the ratio of the stimulation index (SI) obtained with DK20 compared with McCoy cells (DK index), and the ratio of the SI obtained with DK20 compared with PPD (PPD index). RESULTS: The median SI to DK20 in the urethritis was 12.7 which was significantly higher than the controls (7.6, p urethritis patients (17.4) and the controls (22.4). All urethritis patient subgroups had a significantly higher DK index and PPD index than the controls. There was no difference in the PPD and DK index between urethritis naive and urethritis experienced patients and between the culture positive and culture negative urethritis subgroups. In PID patients only the PPD index was significantly higher than the controls. CONCLUSION: Men presenting with urethritis and women presenting with PID both have significantly greater peripheral blood mononuclear cell proliferative responses to the DK20 strain of C trachomatis than controls. A similar T cell proliferative response pattern in urethritis naive patients with either gonococcal or non-gonococcal urethritis could

  20. The anti-proliferative effect of cation channel blockers in T lymphocytes depends on the strength of mitogenic stimulation.

    Science.gov (United States)

    Petho, Zoltan; Balajthy, Andras; Bartok, Adam; Bene, Krisztian; Somodi, Sandor; Szilagyi, Orsolya; Rajnavolgyi, Eva; Panyi, Gyorgy; Varga, Zoltan

    2016-03-01

    Ion channels are crucially important for the activation and proliferation of T lymphocytes, and thus, for the function of the immune system. Previous studies on the effects of channel blockers on T cell proliferation reported variable effectiveness due to differing experimental systems. Therefore our aim was to investigate how the strength of the mitogenic stimulation influences the efficiency of cation channel blockers in inhibiting activation, cytokine secretion and proliferation of T cells under standardized conditions. Human peripheral blood lymphocytes were activated via monoclonal antibodies targeting the TCR-CD3 complex and the co-stimulator CD28. We applied the blockers of Kv1.3 (Anuroctoxin), KCa3.1 (TRAM-34) and CRAC (2-Apb) channels of T cells either alone or in combination with rapamycin, the inhibitor of the mammalian target of rapamycin (mTOR). Five days after the stimulation ELISA and flow cytometric measurements were performed to determine IL-10 and IFN-γ secretion, cellular viability and proliferation. Our results showed that ion channel blockers and rapamycin inhibit IL-10 and IFN-γ secretion and cell division in a dose-dependent manner. Simultaneous application of the blockers for each channel along with rapamycin was the most effective, indicating synergy among the various activation pathways. Upon increasing the extent of mitogenic stimulation the anti-proliferative effect of the ion channel blockers diminished. This phenomenon may be important in understanding the fine-tuning of T cell activation. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  1. DNA Polymerase α (swi7) and the Flap Endonuclease Fen1 (rad2) Act Together in the S-Phase Alkylation Damage Response in S. pombe

    Science.gov (United States)

    Koulintchenko, Milana; Vengrova, Sonya; Eydmann, Trevor; Arumugam, Prakash; Dalgaard, Jacob Z.

    2012-01-01

    Polymerase α is an essential enzyme mainly mediating Okazaki fragment synthesis during lagging strand replication. A specific point mutation in Schizosaccharomyces pombe polymerase α named swi7-1, abolishes imprinting required for mating-type switching. Here we investigate whether this mutation confers any genome-wide defects. We show that the swi7-1 mutation renders cells hypersensitive to the DNA damaging agents methyl methansulfonate (MMS), hydroxyurea (HU) and UV and incapacitates activation of the intra-S checkpoint in response to DNA damage. In addition we show that, in the swi7-1 background, cells are characterized by an elevated level of repair foci and recombination, indicative of increased genetic instability. Furthermore, we detect novel Swi1-, -Swi3- and Pol α- dependent alkylation damage repair intermediates with mobility on 2D-gel that suggests presence of single-stranded regions. Genetic interaction studies showed that the flap endonuclease Fen1 works in the same pathway as Pol α in terms of alkylation damage response. Fen1 was also required for formation of alkylation- damage specific repair intermediates. We propose a model to explain how Pol α, Swi1, Swi3 and Fen1 might act together to detect and repair alkylation damage during S-phase. PMID:23071723

  2. Long-term nonprogression and broad HIV-1-specific proliferative T-cell responses

    Directory of Open Access Journals (Sweden)

    Nesrina eImami

    2013-03-01

    Full Text Available Complex mechanisms underlying the maintenance of fully functional, proliferative, HIV-1-specific T-cell responses involve processes from early T-cell development through to the final stages of T-cell differentiation and antigen recognition. Virus-specific proliferative CD4 and CD8 T-cell responses, important for the control of infection, are observed in some HIV-1+ patients during early stages of disease, and are maintained in long-term nonprogressing subjects. In the vast majority of HIV-1+ patients, full immune functionality is lost when proliferative HIV-1-specific T-cell responses undergo a variable progressive decline throughout the course of chronic infection. This appears irreparable despite administration of potent combination antiretroviral therapy, which to date is non-curative, necessitating life-long administration and the development of effective, novel, therapeutic interventions. While a sterilising cure, involving clearance of virus from the host, remains a primary aim, a functional cure may be a more feasible goal with considerable impact on worldwide HIV-1 infection. Such an approach would enable long-term co-existence of host and virus in the absence of toxic and costly drugs. Effective immune homeostasis coupled with a balanced response appropriately targeting conserved viral antigens, in a manner that avoids hyperactivation and exhaustion, may prove to be the strongest correlate of durable viral control. This review describes novel concepts underlying full immune functionality in the context of HIV-1 infection, which may be utilised in future strategies designed to improve upon existing therapy. The aim will be to induce long-term nonprogressor or elite controller status in every infected host, through immune-mediated control of viraemia and reduction of viral reservoirs, leading to lower HIV-1 transmission rates.

  3. Cdc6 is a rate-limiting factor for proliferative capacity during HL60 cell differentiation

    International Nuclear Information System (INIS)

    Barkley, Laura R.; Hong, Hye Kyung; Kingsbury, Sarah R.; James, Michelle; Stoeber, Kai; Williams, Gareth H.

    2007-01-01

    The DNA replication (or origin) licensing pathway represents a critical step in cell proliferation control downstream of growth signalling pathways. Repression of origin licensing through down-regulation of the MCM licensing factors (Mcm2-7) is emerging as a ubiquitous route for lowering proliferative capacity as metazoan cells exit the cell division cycle into quiescent, terminally differentiated and senescent 'out-of-cycle' states. Using the HL60 monocyte/macrophage differentiation model system and a cell-free DNA replication assay, we have undertaken direct biochemical investigations of the coupling of origin licensing to the differentiation process. Our data show that down-regulation of the MCM loading factor Cdc6 acts as a molecular switch that triggers loss of proliferative capacity during early engagement of the somatic differentiation programme. Consequently, addition of recombinant Cdc6 protein to in vitro replication reactions restores DNA replication competence in nuclei prepared from differentiating cells. Differentiating HL60 cells over-expressing either wild-type Cdc6 or a CDK phosphorylation-resistant Cdc6 mutant protein (Cdc6A4) exhibit an extended period of cell proliferation compared to mock-infected cells. Notably, differentiating HL60 cells over-expressing the Cdc6A4 mutant fail to down-regulate Cdc6 protein levels, suggesting that CDK phosphorylation of Cdc6 is linked to its down-regulation during differentiation and the concomitant decrease in cell proliferation. In this experimental model, Cdc6 therefore plays a key role in the sequential molecular events leading to repression of origin licensing and loss of proliferative capacity during execution of the differentiation programme

  4. Cytomorphology of fibrocystic change, high-risk proliferative breast disease, and premalignant breast lesions.

    Science.gov (United States)

    Masood, Shahla

    2005-12-01

    In a prospective study using mammographically guided fine needle aspirates in 100 nonpalpable breast lesions, the author's group assessed the reliability of a cytological grading system to define the cytological features of proliferative and nonproliferative breast disease and to differentiate between benign, premalignant and malignant breast lesions. We developed a cytological grading system evaluating the aspirates for the cellular arrangement, the degrees of cellular pleomorphism and anisonucleosis, presence of myoepithelial cells and nucleoli and the status of the chromatin pattern. This grading system, now recognized as the Masood Cytology Index, is commonly used as a surrogate end point biomarker in chemoprevention trials.

  5. Proliferative myositis of the latissimus dorsi presenting in a 20-year-old male athlete

    LENUS (Irish Health Repository)

    Mc Hugh, N

    2017-08-01

    We describe the case of a 20-year-old rower presenting with an uncommon condition of Proliferative Myositis (PM) affecting the Latissimus Dorsi (LD). PM is a rare, benign tumour infrequently developing in the upper back. Its rapid growth and firm consistency may mistake it for sarcoma at presentation. Therefore, careful multidisciplinary work-up is crucial, and should involve appropriate radiological and histopathological investigations. Here, we propose the aetiology of LD PM to be persistent myotrauma induced by repetitive rowing motions. Symptoms and rate of progression ultimately determine the management which includes surveillance and\\/or conservative resection. There have been no documented cases of recurrence or malignant transformation.

  6. Surgical management of retinal diseases: proliferative diabetic retinopathy and traction retinal detachment.

    Science.gov (United States)

    Cruz-Iñigo, Yousef J; Acabá, Luis A; Berrocal, Maria H

    2014-01-01

    Current indications for pars plana vitrectomy in patients with proliferative diabetic retinopathy (PDR) include vitreous hemorrhage, tractional retinal detachment (TRD), combined tractional and rhegmatogenous retinal detachment (CTRRD), diabetic macular edema associated with posterior hyaloidal traction, and anterior segment neovascularization with media opacities. This chapter will review the indications, surgical objectives, adjunctive pharmacotherapy, microincision surgical techniques, and outcomes of diabetic vitrectomy for PDR, TRD, and CTRRD. With the availability of new microincision vitrectomy technology, wide-angle microscope viewing systems, and pharmacologic agents, vitrectomy can improve visual acuity and achieve long-term anatomic stability in eyes with severe complications from PDR. © 2014 S. Karger AG, Basel

  7. Methylthioadenosine phosphorylase compositions and methods of use in the diagnosis and treatment of proliferative disorders

    Science.gov (United States)

    Olopade, Olufunmilayo I.

    2005-03-22

    Disclosed are novel nucleic acid and peptide compositions comprising methythlioadenosine phosphorylase (MTAP) and methods of use for MTAP amino acid sequences and DNA segments comprising MTAP in the diagnosis of human cancers and development of MTAP-specific antibodies. Also disclosed are methods for the diagnosis and treatment of tumors and other proliferative cell disorders, and idenification tumor suppressor genes and gene products from the human 9p21-p22 chromosome region. Such methods are useful in the diagnosis of multiple tumor types such as bladder cancer, lung cancer, breast cancer, pancreatic cancer, brain tumors, lymphomas, gliomas, melanomas, and leukemias.

  8. Compositions and methods involving methyladenosine phosphorylase in the diagnosis and treatment of proliferative disorders

    Science.gov (United States)

    Olopade, Olufunmilayo I.

    2007-03-20

    Disclosed are novel nucleic acid and peptide compositions comprising methylthioadenosine phosphorylase (MTAP) and methods of use for MTAP amino acid sequences and DNA segments comprising MTAP in the diagnosis of human cancers and development of MTAP-specific antibodies. Also disclosed are methods for the diagnosis and treatment of tumors and other proliferative cell disorders, and identification of tumor suppressor genes and gene products from the human 9p21-p22 chromosome region. Such methods are useful in the diagnosis of multiple tumor types such as bladder cancer, lung cancer, breast cancer, pancreatic cancer, brain tumors, lymphomas, gliomas, melanomas, and leukemias.

  9. Proliferative, reparative, and reactive benign bone lesions that may be confused diagnostically with true osseous neoplasms.

    LENUS (Irish Health Repository)

    Wick, Mark R

    2014-01-01

    Diagnostic problems attending intraosseous and parosteal pseudoneoplastic lesions can be radiographic, or histological, or both. Proliferations in this category may contain cellular fibro-osseous or chondro-osseous tissues that are difficult to separate microscopically from those seen in various true neoplasms of the bones. This review considers the clinicopathologic features of fibrous dysplasia, benign fibro-osseous lesions of the jawbones, osteofibrous dysplasia, metaphyseal fibrous defect, giant-cell reparative granuloma, "brown tumor" of hyperparathyroidism, synovial chondrometaplasia, aneurysmal bone cyst, tumefactive chronic osteomyelitis, proliferative Paget disease, and polyvinylpyrrolidone storage disease of bone.

  10. Evaluation of a novel enzyme-linked immunosorbent assay for serological diagnosis of porcine proliferative enteropathy

    DEFF Research Database (Denmark)

    Boesen, Henriette Toft; Jensen, Tim Kåre; Møller, Kristian

    2005-01-01

    was a specific and sensitive method for detecting specific antibodies, and may be a good alternative to the existing serological tests for L intracellularis. It may be usable for diagnosis of proliferative enteropathy and for determination of a herd's epidemiologic status....... experimentally infected pigs and 62 serum samples from naturally infected pigs the sensitivity of the ELISA was calculated to 98.0%. The specificity of the test was 99.3%, calculated on the basis of 273 serum samples collected in six herds free of L. intracellularis after medicated eradication. The novel ELISA...

  11. Molecular mechanisms of celery seed extract induced apoptosis via s phase cell cycle arrest in the BGC-823 human stomach cancer cell line.

    Science.gov (United States)

    Gao, Lin-Lin; Feng, Lei; Yao, Shu-Tong; Jiao, Peng; Qin, Shu-Cun; Zhang, Wei; Zhang, Ya-Bin; Li, Fu-Rong

    2011-01-01

    Mechanisms of apoptosis in tumor cells is an important field of tumor therapy and cancer molecular biology. Loss of cell cycle control, leading to uncontrolled proliferation, is common in cancer. Therefore, the identification of potent and selective cyclin dependent kinase inhibitors is a priority for anti-cancer drug discovery. There are at least two major apoptotic pathways, initiated by caspase-8 and caspase-9, respectively, which can activate caspase cascades. Apoptosis triggered by activation of the mitochondrial-dependent caspase pathway represents the main programmed cell death mechanism. This is activated by various intracellular stresses that induce permeabilization of the mitochondrial membrane. Anti-tumor effects of celery seed extract (CSE) and related mechanisms regarding apoptosis were here investigated in human gastric cancer BGC-823 cells. CSE was produced by supercritical fluid extraction. Cell viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyl-tetrazolium bromide (MTT) assay and apoptosis by flow cytometry using Annexin/PI staining and DAPI staining and a laser scanning confocal microscope (LSCM). Cell cycling was evaluated using PI staining with flow cytometry and expression of cell cycle and apoptosis-related proteins cyclin A, CDK2, bcl-2 and bax was assessed by immunohistochemical staining. CSE had an anti-proliferation effect on human gastric cancer BGC-823 cells in a dose- and time-dependent manner. After treatment, the apoptotic rate significantly increased, with morphological changes typical of apoptosis observed with LSCM by DAPI staining. Cell cycle and apoptosis related proteins, such as cyclin A, CDK2 and bcl-2 were all down-regulated, whereas bax was up-regulated. The molecular determinants of inhibition of cell proliferation as well as apoptosis of CSE may be associated with cycle arrest in the S phase.

  12. Engineering amount of cell-cell contact demonstrates biphasic proliferative regulation through RhoA and the actin cytoskeleton

    International Nuclear Information System (INIS)

    Gray, Darren S.; Liu, Wendy F.; Shen, Colette J.; Bhadriraju, Kiran; Nelson, Celeste M.; Chen, Christopher S.

    2008-01-01

    Endothelial cell-cell contact via VE-cadherin plays an important role in regulating numerous cell functions, including proliferation. However, using different experimental approaches to manipulate cell-cell contact, investigators have observed both inhibition and stimulation of proliferation depending on the adhesive context. In this study, we used micropatterned wells combined with active positioning of cells by dielectrophoresis in order to investigate whether the number of contacting neighbors affected the proliferative response. Varying cell-cell contact resulted in a biphasic effect on proliferation; one contacting neighbor increased proliferation, while two or more neighboring cells partially inhibited this increase. We also observed that cell-cell contact increased the formation of actin stress fibers, and that expression of dominant negative RhoA (RhoN19) blocked the contact-mediated increase in stress fibers and proliferation. Furthermore, examination of heterotypic pairs of untreated cells in contact with RhoN19-expressing cells revealed that intracellular, but not intercellular, tension is required for the contact-mediated stimulation of proliferation. Moreover, engagement of VE-cadherin with cadherin-coated beads was sufficient to stimulate proliferation in the absence of actual cell-cell contact. In all, these results demonstrate that cell-cell contact signals through VE-cadherin, RhoA, and intracellular tension in the actin cytoskeleton to regulate proliferation

  13. Understanding Hematopoietic Stem Cell Development through Functional Correlation of Their Proliferative Status with the Intra-aortic Cluster Architecture.

    Science.gov (United States)

    Batsivari, Antoniana; Rybtsov, Stanislav; Souilhol, Celine; Binagui-Casas, Anahi; Hills, David; Zhao, Suling; Travers, Paul; Medvinsky, Alexander

    2017-06-06

    During development, hematopoietic stem cells (HSCs) emerge in the aorta-gonad-mesonephros (AGM) region through a process of multi-step maturation and expansion. While proliferation of adult HSCs is implicated in the balance between self-renewal and differentiation, very little is known about the proliferation status of nascent HSCs in the AGM region. Using Fucci reporter mice that enable in vivo visualization of cell-cycle status, we detect increased proliferation during pre-HSC expansion followed by a slowing down of cycling once cells start to acquire a definitive HSC state, similar to fetal liver HSCs. We observe time-specific changes in intra-aortic hematopoietic clusters corresponding to HSC maturation stages. The proliferative architecture of the clusters is maintained in an orderly anatomical manner with slowly cycling cells at the base and more actively proliferating cells at the more apical part of the cluster, which correlates with c-KIT expression levels, thus providing an anatomical basis for the role of SCF in HSC maturation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Understanding Hematopoietic Stem Cell Development through Functional Correlation of Their Proliferative Status with the Intra-aortic Cluster Architecture

    Directory of Open Access Journals (Sweden)

    Antoniana Batsivari

    2017-06-01

    Full Text Available During development, hematopoietic stem cells (HSCs emerge in the aorta-gonad-mesonephros (AGM region through a process of multi-step maturation and expansion. While proliferation of adult HSCs is implicated in the balance between self-renewal and differentiation, very little is known about the proliferation status of nascent HSCs in the AGM region. Using Fucci reporter mice that enable in vivo visualization of cell-cycle status, we detect increased proliferation during pre-HSC expansion followed by a slowing down of cycling once cells start to acquire a definitive HSC state, similar to fetal liver HSCs. We observe time-specific changes in intra-aortic hematopoietic clusters corresponding to HSC maturation stages. The proliferative architecture of the clusters is maintained in an orderly anatomical manner with slowly cycling cells at the base and more actively proliferating cells at the more apical part of the cluster, which correlates with c-KIT expression levels, thus providing an anatomical basis for the role of SCF in HSC maturation.

  15. Lymphocyte proliferative responses to mitogens in rats having an ancestry of a perinatal iodine-131 insult

    International Nuclear Information System (INIS)

    Stevens, R.H.; Cheng, H.F.

    1987-01-01

    The possible existence of a genealogical memory consisting of altered lymphocyte proliferative responses to a perinatal iodine-131 insult has been investigated in two generations of inbred Fischer F344 rat offspring. The studies which involved exposure to the radioiodine during late pregnancy with concentrations ranging from 1.85 MBq (50 μCi) to 7.4 MBq (200 μCi) revealed that only the peripheral blood T lymphocytes of the first generation male animals were significantly affected. These animals were found to possess T lymphocytes which exhibited increased proliferative responses expressed toward the mitogens concanavalin A and phytohemagglutin; however, no significant changes were noticeable in their B cell population following exposure to lipopolysaccharide. Neither the first generation females nor the male and female offspring of the second generation developed through sibling interbreeding seemed to be affected, this was unlike the cellular, humoral, and natural immunity which had previously been observed to be changed in both the second and third generation animals. These observations suggest that the effects of the radiation insult upon immunocompetency as measured by lymphocyte proliferation do not appear to be inherited

  16. Proliferative reactive gliosis is compatible with glial metabolic support and neuronal function

    Directory of Open Access Journals (Sweden)

    Fero Matthew

    2011-10-01

    Full Text Available Abstract Background The response of mammalian glial cells to chronic degeneration and trauma is hypothesized to be incompatible with support of neuronal function in the central nervous system (CNS and retina. To test this hypothesis, we developed an inducible model of proliferative reactive gliosis in the absence of degenerative stimuli by genetically inactivating the cyclin-dependent kinase inhibitor p27Kip1 (p27 or Cdkn1b in the adult mouse and determined the outcome on retinal structure and function. Results p27-deficient Müller glia reentered the cell cycle, underwent aberrant migration, and enhanced their expression of intermediate filament proteins, all of which are characteristics of Müller glia in a reactive state. Surprisingly, neuroglial interactions, retinal electrophysiology, and visual acuity were normal. Conclusion The benign outcome of proliferative reactive Müller gliosis suggests that reactive glia display context-dependent, graded and dynamic phenotypes and that reactivity in itself is not necessarily detrimental to neuronal function.

  17. Developmental control of transcriptional and proliferative potency during the evolutionary emergence of animals

    Science.gov (United States)

    Arenas-Mena, Cesar; Coffman, James A.

    2016-01-01

    Summary It is proposed that the evolution of complex animals required repressive genetic mechanisms for controlling the transcriptional and proliferative potency of cells. Unicellular organisms are transcriptionally potent, able to express their full genetic complement as the need arises through their life cycle, whereas differentiated cells of multicellular organisms can only express a fraction of their genomic potential. Likewise, whereas cell proliferation in unicellular organisms is primarily limited by nutrient availability, cell proliferation in multicellular organisms is developmentally regulated. Repressive genetic controls limiting the potency of cells at the end of ontogeny would have stabilized the gene expression states of differentiated cells and prevented disruptive proliferation, allowing the emergence of diverse cell types and functional shapes. We propose that distal cis-regulatory elements represent the primary innovations that set the stage for the evolution of developmental gene regulatory networks and the repressive control of key multipotency and cell-cycle control genes. The testable prediction of this model is that the genomes of extant animals, unlike those of our unicellular relatives, encode gene regulatory circuits dedicated to the developmental control of transcriptional and proliferative potency. PMID:26173445

  18. The effect of irradiation on function in self-renewing normal tissues with differing proliferative organisation

    International Nuclear Information System (INIS)

    Wheldon, T.E.; Michalowski, A.S.

    1982-01-01

    The primary effect of irradiation on self-renewing normal tissues is sterilisation of their proliferative cells, but how this translates into failure of tissue function depends on the mode of organisation of the tissue concerned. It has recently been suggested (Michalowski, 1981) that proliferative normal tissues may be classed as ''hierarchical'' (like haemopoietic tissues) or as ''flexible'' (like liver parenchyma) and that radiation injury to tissue function develops by different pathways in these tissues. Mathematical model studies confirm the different radiation responses of differently organized tissues. Tissues of the ''flexible'' or ''F-type'' category display a variety of novel radiobiological properties, different from those of the more familiar ''hierarchical'' or ''H-type'' tissues. The ''F-type'' responses are strongly influenced by radiation-sterilised (''doomed'') cells, and is is suggested that the role of ''doomed'' cells has been undervalued relative to that of clonogenic survivors. Since ''F-type'' tissues have characteristically low rates of cell renewal, it is possible that these tissues are preferentially responsible for late effects of irradiation in clinical radiotherapy. (author)

  19. Dashed line relaxing retinotomy in the management of retinal detachment with anterior proliferative vitreoretinopathy

    Directory of Open Access Journals (Sweden)

    Tsen CL

    2015-04-01

    Full Text Available Chui-Lien Tsen,1 Yu-Harn Horng,1 Shwu-Jiuan Sheu1,2 1Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; 2School of Medicine, National Yang-Ming University, Taipei, Taiwan Background: We describe the anatomical and functional outcomes of eyes that underwent a modified technique of relaxing retinotomy, dashed line relaxing retinotomy, in the management of retinal detachment with anterior proliferative vitreoretinopathy.Methods: We retrospectively reviewed 54 consecutive eyes in 52 patients who received pars plana vitrectomy with relaxing retinotomy during retinal detachment repair. Perfluorocarbon liquid (PFCL was used as a standard procedure to stabilize the retina during retinotomy to prevent slippage or inversion of the posterior flap. If PFCL was not available due to economic reasons, dashed line relaxing retinotomy was performed instead. Best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure measurement, lens status, and fundus examination were analyzed. We excluded patients who were followed up <4 months.Results: Regarding anatomical success rates and visual outcomes, we found no significant differences between patients treated with intraoperative PFCL and those treated with dashed line relaxing retinotomy without PFCL.Conclusion: Compared to the simple and efficient PFCL-assisted relaxing retinotomy, dashed relaxing retinotomy is not the first choice when PFCL is available. Based on our results, this modified technique may offer an alternative in patients with anterior proliferative vitreoretinopathy for whom PFCL is not available. Keywords: perfluorocarbon liquid, PFCL 

  20. Karyopherin alpha2 is essential for rRNA transcription and protein synthesis in proliferative keratinocytes.

    Directory of Open Access Journals (Sweden)

    Noriko Umegaki-Arao

    Full Text Available Karyopherin proteins mediate nucleocytoplasmic trafficking and are critical for protein and RNA subcellular localization. Recent studies suggest KPNA2 expression is induced in tumor cells and is strongly associated with prognosis, although the precise roles and mechanisms of KPNA2 overexpression in proliferative disorders have not been defined. We found that KPNA2 expression is induced in various proliferative disorders of the skin such as psoriasis, Bowen's disease, actinic keratosis, squamous cell carcinoma, Paget's disease, Merkel cell carcinoma, and mycosis fungoides. siRNA-mediated KPNA suppression revealed that KPNA2 is essential for significant suppression of HaCaT proliferation under starvation conditions. Ribosomal RNA transcription and protein synthesis were suppressed by starvation combined with knockdown of KPNA (including KPNA2 expression. KPNA2 localized to the nucleolus and interacted with proteins associated with mRNA processing, ribonucleoprotein complex biogenesis, chromatin modification, and transcription, as demonstrated by tandem affinity purification and mass spectrometry. KPNA2 may be an important promoter of ribosomal RNA and protein synthesis in tumor cells.

  1. The anti-proliferative and anti-angiogenic effect of the methanol extract from brittle star.

    Science.gov (United States)

    Baharara, Javad; Amini, Elaheh; Mousavi, Marzieh

    2015-04-01

    Anti-angiogenic therapy is a crucial step in cancer treatment. The discovery of new anti-angiogenic compounds from marine organisms has become an attractive concept in anti-cancer therapy. Because little data correlated to the pro- and anti-angiogenic efficacies of Ophiuroidea, which include brittle star, the current study was designed to explore the anti-angiogenic potential of brittle star methanol extract in vitro and in vivo. The anti-proliferative effect of brittle star extract on A2780cp cells was examined by MTT assays, and transcriptional expression of VEGF and b-FGF was evaluated by RT-PCR. In an in vivo model, 40 fertilized Ross eggs were divided into control and three experimental groups. The experimental groups were incubated with brittle star extract at concentrations of 25, 50 and 100 µg/ml, and photographed by photo-stereomicroscopy. Ultimately, numbers and lengths of vessels were measured by Image J software. Data were analyzed with SPSS software (pstar extract exerted a dose- and time-dependent anti-proliferative effect on A2780cp cancer cells. In addition, VEGF and b-FGF expression decreased with brittle star methanol extract treatment. Macroscopic evaluations revealed significant changes in the second and third experimental group compared to controls (pstar methanol extract in vitro and in vivo confer novel insight into the application of natural marine products in angiogenesis-related pathologies.

  2. Mutagenesis and lethality following S phase irradiation of xeroderma pigmentosum and normal human diploid fibroblasts with ultraviolet light

    International Nuclear Information System (INIS)

    Grosovsky, A.J.; Little, J.B.

    1983-01-01

    The mutagenic and lethal effects of u.v. light exposure in the DNA synthetic phase of the cell cycle were determined in xeroderma pigmentosum complementation group A (XP-A), hereditary adenomatosis of the colon and rectum (ACR), and a normal, foreskin derived cell strain (AG1522). For AG1522, an increased sensitivity to the cytotoxic effects of u.v. light was observed as compared to previous findings for confluent, non-proliferating cultures. XP-A fibroblasts were markedly hypersensitive and ACR fibroblasts exhibited an intermediate response. The mutagenic response of ACR fibroblasts, however, was similar to normal fibroblasts. A threshold of 1.5-2 J/m 2 was observed for u.v. induced mutagenesis in normal and ACR fibroblasts. XP fibroblasts, on the other hand, were strikingly hypermutable and demonstrated little or no threshold. When S phase mutagenesis was considered as a function of survival level rather than u.v. light dose, XP fibroblasts remained significantly hypermutable as compared with normal fibroblasts at all survival levels. Previous mutagenesis results with confluent, non-proliferating cultures of XP and normal fibroblasts were reanalyzed as a function of cytotoxicity; XP hypermutability at all survival levels was also observed. (author)

  3. Beyond Oncogenesis: The Role of S-Phase Kinase-Associated Protein-2 (SKP2 In Vascular Restenosis

    Directory of Open Access Journals (Sweden)

    Yih-Jer Wu

    2008-12-01

    Full Text Available The clinical benefits of percutaneous coronary intervention, the most prevalent procedure nowadays for the treatment of symptomatic coronary artery disease, are frequently offset by the occurrence of vascular restenosis. Although the introduction of drug-eluting stents has significantly reduced restenotic rates, the rare, but potentially fatal, delayed thrombosis remains a clinical threat. Further refinement of the drug-eluting stent based on a better understanding of cell cycle regulation between the vascular smooth muscle cell (VSMC and endothelial cell (EC is required. In this review, we discuss the role of S-phase kinase-associated protein-2 (Skp2, previously known as an oncoprotein, in the regulation of VSMC proliferation and its signaling axis. The currently available evidence suggests that the Rac1-Skp2-p27Kip1 signaling axis acts as a common final pathway for many factors that regulate VSMC proliferation, such as growth factors, extracellular matrices and cyclic nucleotides. Importantly, although EC proliferation is also shown to be regulated by the same axis, cAMP seems to regulate this axis differentially between VSMC and EC, rendering the underlying mechanism of this differential regulation a promising target for the development of a new generation of drug-eluting stent.

  4. Loss of heterozygosity in yeast can occur by ultraviolet irradiation during the S phase of the cell cycle

    Energy Technology Data Exchange (ETDEWEB)

    Daigaku, Yasukazu [Graduate School of Life Sciences, Tohoku University, Sendai 980-8577 (Japan); Mashiko, Satsuki [Graduate School of Life Sciences, Tohoku University, Sendai 980-8577 (Japan); Mishiba, Keiichiro [Iwate Biotechnology Research Center, Kitakami, Iwate 024-0003 (Japan); Yamamura, Saburo [Iwate Biotechnology Research Center, Kitakami, Iwate 024-0003 (Japan); Ui, Ayako [Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578 (Japan); Enomoto, Takemi [Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578 (Japan); Yamamoto, Kazuo [Graduate School of Life Sciences, Tohoku University, Sendai 980-8577 (Japan)]. E-mail: yamamot@mail.tains.tohoku.ac.jp

    2006-08-30

    A CAN1/can1{delta} heterozygous allele that determines loss of heterozygosity (LOH) was used to study recombination in Saccharomyces cerevisiae cells exposed to ultraviolet (UV) light at different points in the cell cycle. With this allele, recombination events can be detected as canavanine-resistant mutations after exposure of cells to UV radiation, since a significant fraction of LOH events appear to arise from recombination between homologous chromosomes. The radiation caused a higher level of LOH in cells that were in the S phase of the cell cycle relative to either cells at other points in the cell cycle or unsynchronized cells. In contrast, the inactivation of nucleotide excision repair abolished the cell cycle-specific induction by UV of LOH. We hypothesize that DNA lesions, if not repaired, were converted into double-strand breaks during stalled replication and these breaks could be repaired through recombination using a non-sister chromatid and probably also the sister chromatid. We argue that LOH may be an outcome used by yeast cells to recover from stalled replication at a lesion.

  5. Loss of heterozygosity in yeast can occur by ultraviolet irradiation during the S phase of the cell cycle.

    Science.gov (United States)

    Daigaku, Yasukazu; Mashiko, Satsuki; Mishiba, Keiichiro; Yamamura, Saburo; Ui, Ayako; Enomoto, Takemi; Yamamoto, Kazuo

    2006-08-30

    A CAN1/can1Delta heterozygous allele that determines loss of heterozygosity (LOH) was used to study recombination in Saccharomyces cerevisiae cells exposed to ultraviolet (UV) light at different points in the cell cycle. With this allele, recombination events can be detected as canavanine-resistant mutations after exposure of cells to UV radiation, since a significant fraction of LOH events appear to arise from recombination between homologous chromosomes. The radiation caused a higher level of LOH in cells that were in the S phase of the cell cycle relative to either cells at other points in the cell cycle or unsynchronized cells. In contrast, the inactivation of nucleotide excision repair abolished the cell cycle-specific induction by UV of LOH. We hypothesize that DNA lesions, if not repaired, were converted into double-strand breaks during stalled replication and these breaks could be repaired through recombination using a non-sister chromatid and probably also the sister chromatid. We argue that LOH may be an outcome used by yeast cells to recover from stalled replication at a lesion.

  6. H4 replication-dependent diacetylation and Hat1 promote S-phase chromatin assembly in vivo

    Science.gov (United States)

    Ejlassi-Lassallette, Aïda; Mocquard, Eloïse; Arnaud, Marie-Claire; Thiriet, Christophe

    2011-01-01

    While specific posttranslational modification patterns within the H3 and H4 tail domains are associated with the S-phase, their actual functions in replication-dependent chromatin assembly have not yet been defined. Here we used incorporation of trace amounts of recombinant proteins into naturally synchronous macroplasmodia of Physarum polycephalum to examine the function of H3 and H4 tail domains in replication-coupled chromatin assembly. We found that the H3/H4 complex lacking the H4 tail domain was not efficiently recovered in nuclei, whereas depletion of the H3 tail domain did not impede nuclear import but chromatin assembly failed. Furthermore, our results revealed that the proper pattern of acetylation on the H4 tail domain is required for nuclear import and chromatin assembly. This is most likely due to binding of Hat1, as coimmunoprecipitation experiments showed Hat1 associated with predeposition histones in the cytoplasm and with replicating chromatin. These results suggest that the type B histone acetyltransferase assists in shuttling the H3/H4 complex from cytoplasm to the replication forks. PMID:21118997

  7. Global profiling of DNA replication timing and efficiency reveals that efficient replication/firing occurs late during S-phase in S. pombe.

    Directory of Open Access Journals (Sweden)

    Majid Eshaghi

    Full Text Available BACKGROUND: During S. pombe S-phase, initiation of DNA replication occurs at multiple sites (origins that are enriched with AT-rich sequences, at various times. Current studies of genome-wide DNA replication profiles have focused on the DNA replication timing and origin location. However, the replication and/or firing efficiency of the individual origins on the genomic scale remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: Using the genome-wide ORF-specific DNA microarray analysis, we show that in S. pombe, individual origins fire with varying efficiencies and at different times during S-phase. The increase in DNA copy number plotted as a function of time is approximated to the near-sigmoidal model, when considering the replication start and end timings at individual loci in cells released from HU-arrest. Replication efficiencies differ from origin to origin, depending on the origin's firing efficiency. We have found that DNA replication is inefficient early in S-phase, due to inefficient firing at origins. Efficient replication occurs later, attributed to efficient but late-firing origins. Furthermore, profiles of replication timing in cds1Delta cells are abnormal, due to the failure in resuming replication at the collapsed forks. The majority of the inefficient origins, but not the efficient ones, are found to fire in cds1Delta cells after HU removal, owing to the firing at the remaining unused (inefficient origins during HU treatment. CONCLUSIONS/SIGNIFICANCE: Taken together, our results indicate that efficient DNA replication/firing occurs late in S-phase progression in cells after HU removal, due to efficient late-firing origins. Additionally, checkpoint kinase Cds1p is required for maintaining the efficient replication/firing late in S-phase. We further propose that efficient late-firing origins are essential for ensuring completion of DNA duplication by the end of S-phase.

  8. Characterisation of cell cycle arrest and terminal differentiation in a maximally proliferative human epithelial tissue: Lessons from the human hair follicle matrix.

    Science.gov (United States)

    Purba, Talveen S; Brunken, Lars; Peake, Michael; Shahmalak, Asim; Chaves, Asuncion; Poblet, Enrique; Ceballos, Laura; Gandarillas, Alberto; Paus, Ralf

    2017-09-01

    Human hair follicle (HF) growth and hair shaft formation require terminal differentiation-associated cell cycle arrest of highly proliferative matrix keratinocytes. However, the regulation of this complex event remains unknown. CIP/KIP family member proteins (p21 CIP1 , p27 KIP1 and p57 KIP2 ) regulate cell cycle progression/arrest, endoreplication, differentiation and apoptosis. Since they have not yet been adequately characterized in the human HF, we asked whether and where CIP/KIP proteins localise in the human hair matrix and pre-cortex in relation to cell cycle activity and HF-specific epithelial cell differentiation that is marked by keratin 85 (K85) protein expression. K85 expression coincided with loss or reduction in cell cycle activity markers, including in situ DNA synthesis (EdU incorporation), Ki-67, phospho-histone H3 and cyclins A and B1, affirming a post-mitotic state of pre-cortical HF keratinocytes. Expression of CIP/KIP proteins was found abundantly within the proliferative hair matrix, concomitant with a role in cell cycle checkpoint control. p21 CIP1 , p27 KIP1 and cyclin E persisted within post-mitotic keratinocytes of the pre-cortex, whereas p57 KIP2 protein decreased but became nuclear. These data imply a supportive role for CIP/KIP proteins in maintaining proliferative arrest, differentiation and anti-apoptotic pathways, promoting continuous hair bulb growth and hair shaft formation in anagen VI. Moreover, post-mitotic hair matrix regions contained cells with enlarged nuclei, and DNA in situ hybridisation showed cells that were >2N in the pre-cortex. This suggests that CIP/KIP proteins might counterbalance cyclin E to control further rounds of DNA replication in a cell population that has a propensity to become tetraploid. These data shed new light on the in situ-biography of human hair matrix keratinocytes on their path of active cell cycling, arrest and terminal differentiation, and showcase the human HF as an excellent, clinically

  9. Monitoring tumor proliferative response to radiotherapy using 18F-fluorothymidine in human head and neck cancer xenograft in comparison with Ki-67

    International Nuclear Information System (INIS)

    Fatema, Chowdhury Nusrat; Yu, Wenwen; Kitagawa, Yoshimasa; Zhao, Songji; Zhao, Yan; Murakami, Masahiro; Nishijima, Ken-ichi; Tamaki, Nagara; Kuge, Yuji

    2013-01-01

    Although radiotherapy is an important treatment strategy for head and neck cancers, it induces tumor repopulation which adversely affects therapeutic outcome. In this regard, fractionated radiotherapy is widely applied to prevent tumor repopulation. Evaluation of tumor proliferative activity using 18 F-fluorothymidine (FLT), a noninvasive marker of tumor proliferation, may be useful for determining the optimal timing of and dose in the repetitive irradiation. Thus, to assess the potentials of FLT, we evaluated the sequential changes in intratumoral proliferative activity in head and neck cancer xenografts (FaDu) using FLT. FaDu tumor xenografts were established in nude mice and assigned to control and two radiation-treated groups (10 and 20 Gy). Tumor volume was measured daily. 3 H-FLT was injected intravenously 2 h before killing. Mice were killed 6, 24, 48 h, and 7 days after the radiation treatment. Intratumoral 3 H-FLT level was visually and quantitatively assessed by autoradiography. Ki-67 immunohistochemistry (IHC) was performed. In radiation-treated mice, the tumor growth was significantly suppressed compared with the control group, but the tumor volume in these mice gradually increased with time. In the visual assessment, intratumoral 3 H-FLT level diffusely decreased 6 h after the radiation treatment and then gradually increased with time, whereas no apparent changes were observed in Ki-67 IHC. Six hours after the radiation treatment at 10 and 20 Gy, the intratumoral 3 H-FLT level markedly decreased to 45 and 40% of the control, respectively (P 3 H-FLT levels at 48 h and on day 7 were significantly higher than that at 6 h. The intratumoral 3 H-FLT levels in both treated groups were 68 and 60% at 24 h (P<0.001), 71 and 77% at 48 h (P<0.001), and 83 and 81% on day 7 (P=NS) compared with the control group. Intratumoral FLT uptake level markedly decreased at 6 h and then gradually increased with time. Sequential evaluation of intratumoral proliferative

  10. To report a case of unilateral proliferative retinopathy following noncerebral malaria with Plasmodium falciparum in Southern India

    Directory of Open Access Journals (Sweden)

    Aditya Verma

    2015-01-01

    Full Text Available The retinopathy in association with malaria fever described so far includes retinal hemorrhages, vessel changes, retinal discoloration/whitening and papilledema. Malaria retinopathy has been mostly described in severe cases, associated with Plasmodium falciparum, correlating the patho-physiology of retinal and cerebral manifestations. We report an unusual case of proliferative retinopathy as a manifestation of malaria fever, caused by P. falciparum with no cerebral involvement. The patient had features of unilateral retinal vascular occlusion with proliferative changes and vitreous hemorrhage. To the best of our knowledge, such a case has never been reported so far in the literature. This report highlights the possible occurrence of severe proliferative changes associated with malaria fever, which if diagnosed early can prevent possible blindness.

  11. History of Psychology Publish and Perish: Psychology's Most Prolific Authors Are Not Always the Ones We Remember.

    Science.gov (United States)

    Green, Christopher D

    2017-01-01

    What is the relationship between being highly prolific in the realm of publication and being remembered as a great psychologist of the past? In this study, the PsycINFO database was used to identify the historical figures who wrote the most journal articles during the half-century from 1890 to 1939. Although a number of the 10 most prolific authors are widely remembered for their influence on the discipline today-E. L. Thorndike, Karl Pearson, E. B. Titchener, Henri Pi6ron-the majority are mostly forgotten. The data were also separated into the 5 distinct decades. Once again, a mixture of eminent and obscure individuals made appearances. Most striking, perhaps, was the great increase in articles published over the course of the half-century-approximately doubling each decade-and the enormous turnover in who was most prolific, decade over decade. In total, 100 distinct individuals appeared across just 5 lists of about 25 names each.

  12. Mass Spectrometry Imaging Can Distinguish on a Proteomic Level Between Proliferative Nodules Within a Benign Congenital Nevus and Malignant Melanoma.

    Science.gov (United States)

    Lazova, Rossitza; Yang, Zhe; El Habr, Constantin; Lim, Young; Choate, Keith Adam; Seeley, Erin H; Caprioli, Richard M; Yangqun, Li

    2017-09-01

    Histopathological interpretation of proliferative nodules occurring in association with congenital melanocytic nevi can be very challenging due to their similarities with congenital malignant melanoma and malignant melanoma arising in association with congenital nevi. We hereby report a diagnostically challenging case of congenital melanocytic nevus with proliferative nodules and ulcerations, which was originally misdiagnosed as congenital malignant melanoma. Subsequent histopathological examination in consultation by one of the authors (R.L.) and mass spectrometry imaging analysis rendered a diagnosis of congenital melanocytic nevus with proliferative nodules. In this case, mass spectrometry imaging, a novel method capable of distinguishing benign from malignant melanocytic lesions on a proteomic level, was instrumental in making the diagnosis of a benign nevus. We emphasize the importance of this method as an ancillary tool in the diagnosis of difficult melanocytic lesions.

  13. Changes in the Proliferative Program Limit Astrocyte Homeostasis in the Aged Post-Traumatic Murine Cerebral Cortex.

    Science.gov (United States)

    Heimann, Gábor; Canhos, Luisa L; Frik, Jesica; Jäger, Gabriele; Lepko, Tjasa; Ninkovic, Jovica; Götz, Magdalena; Sirko, Swetlana

    2017-08-01

    Aging leads to adverse outcomes after traumatic brain injury. The mechanisms underlying these defects, however, are not yet clear. In this study, we found that astrocytes in the aged post-traumatic cerebral cortex develop a significantly reduced proliferative response, resulting in reduced astrocyte numbers in the penumbra. Moreover, experiments of reactive astrocytes in vitro reveal that their diminished proliferation is due to an age-related switch in the division mode with reduced cell-cycle re-entry rather than changes in cell-cycle length. Notably, reactive astrocytes in vivo and in vitro become refractory to stimuli increasing their proliferation during aging, such as Sonic hedgehog signaling. These data demonstrate for the first time that age-dependent, most likely intrinsic changes in the proliferative program of reactive astrocytes result in their severely hampered proliferative response to traumatic injury thereby affecting astrocyte homeostasis. © The Author 2017. Published by Oxford University Press.

  14. Inhibition of inflammatory and proliferative responses of human keratinocytes exposed to the sesquiterpene lactones dehydrocostuslactone and costunolide.

    Directory of Open Access Journals (Sweden)

    Claudia Scarponi

    Full Text Available The imbalance of the intracellular redox state and, in particular, of the glutathione (GSH/GSH disulfide couple homeostasis, is involved in the pathogenesis of a number of diseases. In many skin diseases, including psoriasis, oxidative stress plays an important role, as demonstrated by the observation that treatments leading to increase of the local levels of oxidant species ameliorate the disease. Recently, dehydrocostuslactone (DCE and costunolide (CS, two terpenes naturally occurring in many plants, have been found to exert various anti-inflammatory and pro-apoptotic effects on different human cell types. These compounds decrease the level of the intracellular GSH by direct interaction with it, and, therefore, can alter cellular redox state. DCE and CS can trigger S-glutathionylation of various substrates, including the transcription factor STAT3 and JAK1/2 proteins. In the present study, we investigated on the potential role of DCE and CS in regulating inflammatory and proliferative responses of human keratinocytes to cytokines. We demonstrated that DCE and CS decreased intracellular GSH levels in human keratinocytes, as well as inhibited STAT3 and STAT1 phosphorylation and activation triggered by IL-22 or IFN-γ, respectively. Consequently, DCE and CS decreased the IL-22- and IFN-γ-induced expression of inflammatory and regulatory genes in keratinocytes, including CCL2, CXCL10, ICAM-1 and SOCS3. DCE and CS also inhibited proliferation and cell-cycle progression-related gene expression, as well as they promoted cell cycle arrest and apoptosis. In parallel, DCE and CS activated the anti-inflammatory EGFR and ERK1/2 molecules in keratinocytes, and, thus, wound healing in an in vitro injury model. In light of our findings, we can hypothesize that the employment of DCE and CS in psoriasis could efficiently counteract the pro-inflammatory effects of IFN-γ and IL-22 on keratinocytes, revert the apoptosis-resistant phenotype, as well as inhibit

  15. Nucleolin down-regulation is involved in ADP-induced cell cycle arrest in S phase and cell apoptosis in vascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Wenmeng Wang

    Full Text Available High concentration of extracellular ADP has been reported to induce cell apoptosis, but the molecular mechanisms remain not fully elucidated. In this study, we found by serendipity that ADP treatment of human umbilical vein endothelial cells (HUVEC and human aortic endothelial cells (HAEC down-regulated the protein level of nucleolin in a dose- and time-dependent manner. ADP treatment did not decrease the transcript level of nucloelin, suggesting that ADP might induce nucleolin protein degradation. HUVEC and HAEC expressed ADP receptor P2Y13 receptor, but did not express P2Y1 or P2Y12 receptors. However, P2Y1, 12, 13 receptor antagonists MRS2179, PSB0739, MRS2211 did not inhibit ADP-induced down-regulation of nucleolin. Moreover, MRS2211 itself down-regulated nucleolin protein level. In addition, 2-MeSADP, an agonist for P2Y1, 12 and 13 receptors, did not down-regulate nucleolin protein. These results suggested that ADP-induced nucleolin down-regulation was not due to the activation of P2Y1, 12, or 13 receptors. We also found that ADP treatment induced cell cycle arrest in S phase, cell apoptosis and cell proliferation inhibition via nucleolin down-regulation. The over-expression of nucleolin by gene transfer partly reversed ADP-induced cell cycle arrest, cell apoptosis and cell proliferation inhibition. Furthermore, ADP sensitized HUVEC to cisplatin-induced cell death by the down-regulation of Bcl-2 expression. Taken together, we found, for the first time to our knowledge, a novel mechanism by which ADP regulates cell proliferation by induction of cell cycle arrest and cell apoptosis via targeting nucelolin.

  16. On the S-phase formation and the balanced plasma nitriding of austenitic-ferritic super duplex stainless steel

    Science.gov (United States)

    de Oliveira, Willian R.; Kurelo, Bruna C. E. S.; Ditzel, Dair G.; Serbena, Francisco C.; Foerster, Carlos E.; de Souza, Gelson B.

    2018-03-01

    The different physical responses of austenite (γ) and ferrite (α) iron structures upon nitriding result in technical challenges to the uniform modification of α-γ materials, as the super duplex stainless steel (SDSS). The effects of voltage (7-10 kV), frequency and pulse width on the nitrogen plasma immersion ion implantation of SDSS (α ∼ 56%, γ ∼ 44%) were investigated, correlated with structural, morphological and mechanical analyses. By controlling the treatment power, temperatures ranged from 292 °C to 401 °C. Despite the overall increase in hardness for any of the employed parameters (from ∼6 GPa to ∼15 GPa), the structure of individual grains was strikingly dissimilar at the same temperatures, depending on the energetic conditions of implantation. Modified-α grains containing iron nitrides (ε-Fe2-3N, γ‧ -Fe4N) presented intense brittleness, whereas the expanded phase γN (S-phase) laid principally in modified-γ grains, exhibiting ductile-like deformation features and thicker layers. The γN was the dominant phase in both α-γ grains at ∼401 °C, providing them with balanced structure and mechanical behavior. These phenomena corroborate with γN as mediator of the process, through a mechanism involving the nitrogen-promoted ferrite to austenite conversion and nitrides dissolution at high temperatures. An approximately linear correlation of the γN content with respect to the ion energy per pulse was demonstrated, which properly embodies limiting effects to the treatment. This can be a parameter for the α-γ steel surface modification, consisting in a better adjustment to obtain more precise control along with temperature.

  17. HIV-Infected Children Have Elevated Levels of PD-1+ Memory CD4 T Cells With Low Proliferative Capacity and High Inflammatory Cytokine Effector Functions.

    Science.gov (United States)

    Foldi, Julia; Kozhaya, Lina; McCarty, Bret; Mwamzuka, Mussa; Marshed, Fatma; Ilmet, Tiina; Kilberg, Max; Kravietz, Adam; Ahmed, Aabid; Borkowsky, William; Unutmaz, Derya; Khaitan, Alka

    2017-09-15

    During human immunodeficiency virus (HIV) disease, chronic immune activation leads to T-cell exhaustion. PD-1 identifies "exhausted" CD8 T cells with impaired HIV-specific effector functions, but its role on CD4 T cells and in HIV-infected children is poorly understood. In a Kenyan cohort of vertically HIV-infected children, we measured PD-1+ CD4 T-cell frequencies and phenotype by flow cytometry and their correlation with HIV disease progression and immune activation. Second, in vitro CD4 T-cell proliferative and cytokine responses to HIV-specific and -nonspecific stimuli were assessed with and without PD-1 blockade. HIV-infected children have increased frequencies of PD-1+ memory CD4 T cells that fail to normalize with antiretroviral treatment. These cells are comprised of central and effector memory subsets and correlate with HIV disease progression, measured by viral load, CD4 percentage, CD4:CD8 T-cell ratio, and immune activation. Last, PD-1+ CD4 T cells predict impaired proliferative potential yet preferentially secrete the Th1 and Th17 cytokines interferon-γ and interleukin 17A, and are unresponsive to in vitro PD-1 blockade. This study highlights differences in PD-1+ CD4 T-cell memory phenotype and response to blockade between HIV-infected children and adults, with implications for potential immune checkpoint therapies. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  18. Bilateral Proliferative Retinopathy as the Initial Presentation of Chronic Myeloid Leukemia

    Science.gov (United States)

    Macedo, Mafalda S. F.; Figueiredo, Ana R. M.; Ferreira, Natália N.; Barbosa, Irene M. A.; Furtado, Maria João F. B. S.; Correia, Nuno F. C. B. A.; Gomes, Miguel P.; Lume, Miguel R. B.; Menéres, Maria João S.; Santos, Marinho M. N.; Meireles S., M. Angelina C.

    2013-01-01

    The authors report a rare case of a 48-year-old male with chronic myeloid leukemia (CML) who initially presented with a bilateral proliferative retinopathy. The patient complained of recent visual loss and floaters in both eyes (BE). Ophthalmologic evaluation revealed a best corrected visual acuity (BCVA) of 20/50 in the right eye and 20/200 in the left eye (LE). Fundoscopy showed the presence of bilateral peripheral capillary dropout with multiple retinal sea fan neovascularisations, which were confirmed on fluorescein angiography. Full blood count revealed hyperleukocytosis, thrombocytosis, anemia, and hyperuricemia. Bone marrow aspiration and biopsy showed the reciprocal chromosomal translocation t (9;22), diagnostic of CML. The patient was started on hydroxyurea, allopurinol and imatinib mesylate. He received bilateral panretinal laser photocoagulation and a vitrectomy was performed in the LE. The patient has been in complete hematologic, cytogenetic, and major molecular remission while on imatinib and his BCVA is 20/25 in BE. PMID:24339689

  19. Hepatic progenitor cell resistance to TGF-β1's proliferative and apoptotic effects

    International Nuclear Information System (INIS)

    Clark, J. Brian; Rice, Lisa; Sadiq, Tim; Brittain, Evan; Song, Lujun; Wang Jian; Gerber, David A.

    2005-01-01

    The success of hepatocellular therapies using stem or progenitor cell populations is dependent upon multiple factors including the donor cell, microenvironment, and etiology of the liver injury. The following experiments investigated the impact of TGF-β1 on a previously described population of hepatic progenitor cells (HPC). The majority of the hepatic progenitor cells were resistant to endogenously produced TGF-β1's proapoptotic and anti-proliferative effects unlike more well-differentiated cellular populations (e.g., mature hepatocytes). Surprisingly, in vitro TGF-β1 supplementation significantly inhibited de novo hepatic progenitor cell colony formation possibly via an indirect mechanism(s). Therefore despite the HPC's direct resistance to supplemental TGF-β1, this cytokine's inhibitory effect on colony formation could have a potential negative impact on the use of these cells as a therapy for patients with liver disease

  20. Surgical management of fibrotic encapsulation of the fluocinolone acetonide implant in CAPN5-associated proliferative vitreoretinopathy.

    Science.gov (United States)

    Tlucek, Paul S; Folk, James C; Sobol, Warren M; Mahajan, Vinit B

    2013-01-01

    To review fibrosis of fluocinolone acetonide (FA) implants in subjects with CAPN5 autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV). A retrospective case series was assembled from ADNIV patients in which there was fibrotic encapsulation of a fluocinolone acetonide implant. CAPN5 genotypes and surgical repair techniques were reviewed. Two eyes of two ADNIV patients developed a fibrotic capsule over the fluocinolone acetonide implant. Both patients had Stage IV disease. Patient A had a c.731T > C mutation in the CAPN5 gene and patient B had a c.728G > T mutation. The fibrotic membrane was surgically excised and the implant function was restored. The exuberant fibrotic response in later stages of ADNIV may be resistant to local immunosuppression with steroids. Surgical excision of fibrotic membranes over FA implants can reestablish local steroid delivery in cases of severe proliferative vitreoretinopathy.

  1. Mitochondrial localization of the low level p53 protein in proliferative cells

    Energy Technology Data Exchange (ETDEWEB)

    Ferecatu, Ioana; Bergeaud, Marie; Rodriguez-Enfedaque, Aida; Le Floch, Nathalie [Laboratoire de Genetique et Biologie Cellulaire - CNRS UMR 8159, Universite de Versailles Saint-Quentin-en-Yvelines, Versailles, France and Laboratoire de Genetique Moleculaire et Physiologique, Ecole Pratique des Hautes Etudes, Versailles (France); Oliver, Lisa [INSERM U601, Universite de Nantes, Faculte de Medecine, Nantes Cedex (France); Rincheval, Vincent; Renaud, Flore [Laboratoire de Genetique et Biologie Cellulaire - CNRS UMR 8159, Universite de Versailles Saint-Quentin-en-Yvelines, Versailles, France and Laboratoire de Genetique Moleculaire et Physiologique, Ecole Pratique des Hautes Etudes, Versailles (France); Vallette, Francois M. [INSERM U601, Universite de Nantes, Faculte de Medecine, Nantes Cedex (France); Mignotte, Bernard [Laboratoire de Genetique et Biologie Cellulaire - CNRS UMR 8159, Universite de Versailles Saint-Quentin-en-Yvelines, Versailles, France and Laboratoire de Genetique Moleculaire et Physiologique, Ecole Pratique des Hautes Etudes, Versailles (France); Vayssiere, Jean-Luc, E-mail: jean-luc.vayssiere@uvsq.fr [Laboratoire de Genetique et Biologie Cellulaire - CNRS UMR 8159, Universite de Versailles Saint-Quentin-en-Yvelines, Versailles, France and Laboratoire de Genetique Moleculaire et Physiologique, Ecole Pratique des Hautes Etudes, Versailles (France)

    2009-10-02

    p53 protein plays a central role in suppressing tumorigenesis by inducing cell cycle arrest or apoptosis through transcription-dependent and -independent mechanisms. Emerging publications suggest that following stress, a fraction of p53 translocates to mitochondria to induce cytochrome c release and apoptosis. However, the localization of p53 under unstressed conditions remains largely unexplored. Here we show that p53 is localized at mitochondria in absence of apoptotic stimuli, when cells are proliferating, localization observed in various cell types (rodent and human). This is also supported by acellular assays in which p53 bind strongly to mitochondria isolated from rat liver. Furthermore, the mitochondria subfractionation study and the alkaline treatment of the mitochondrial p53 revealed that the majority of mitochondrial p53 is present in the membranous compartments. Finally, we identified VDAC, a protein of the mitochondrial outer-membrane, as a putative partner of p53 in unstressed/proliferative cells.

  2. Detection of Glutamate and γ-aminobutyric Acid in Vitreous of Patients with Proliferative Diabetic Retinopathy

    Institute of Scientific and Technical Information of China (English)

    Juan Deng; De-Zheng Wu; Rulong Gao

    2000-01-01

    Purpose: To study the levels of glutamate and γ-aminobutyric acid (GABA) in vitreous of patients with proliferative diabetic retinopathy(PDR) and to investigate their roles in retinal ischemia.Method: Vitreous samples were collected from 25 patients (27 eyes) with PDR and 14patients ( 14 eyes) with idiopathic macular hole. Glutamate and GABA detection were performed by high-performance liquid chromatography (HPLC).Results: Patients with PDR had significantly higher concentrations of glutamate and GABA than the control group. The glutamate level has a significantly positive correlation with GABA level.Conclusion: Detection of glutamate and GABA in vitreous provides biochemical support for the mechanism and treatment of ischemic retinal damage in patients with PDR.

  3. Structural Changes of the Macula on Optical Coherence Tomography after Vitrectomy for Proliferative Diabetic Retinopathy.

    Science.gov (United States)

    Im, Jong Chan; Kim, Jong Ho; Park, Dong Ho; Shin, Jae Pil

    2017-01-01

    This study aimed to evaluate the relationship between macular structural changes and visual prognosis after pars plana vitrectomy (PPV) for proliferative diabetic retinopathy. The study included 60 eyes that had undergone PPV. Macular optical coherence tomography (OCT) findings were classified into 5 groups preoperatively and 10 groups postoperatively. Best-corrected visual acuity (BCVA) were analyzed according to pre- and postoperative OCT. From the preoperative OCT, normal fovea with/without traction, normal fovea with preretinal hemorrhage, and tractional retinal detachment involving fovea showed an increase in BCVA after PPV (all p 20/50). Subfoveal fibrosis, macular hole, loss of foveal depression, and serous foveal detachment showed poor visual prognosis (BCVA <20/100). Macular structural changes were various after PPV, and visual prognosis correlated with these changes. © 2017 S. Karger AG, Basel.

  4. Mitochondrial localization of the low level p53 protein in proliferative cells

    International Nuclear Information System (INIS)

    Ferecatu, Ioana; Bergeaud, Marie; Rodriguez-Enfedaque, Aida; Le Floch, Nathalie; Oliver, Lisa; Rincheval, Vincent; Renaud, Flore; Vallette, Francois M.; Mignotte, Bernard; Vayssiere, Jean-Luc

    2009-01-01

    p53 protein plays a central role in suppressing tumorigenesis by inducing cell cycle arrest or apoptosis through transcription-dependent and -independent mechanisms. Emerging publications suggest that following stress, a fraction of p53 translocates to mitochondria to induce cytochrome c release and apoptosis. However, the localization of p53 under unstressed conditions remains largely unexplored. Here we show that p53 is localized at mitochondria in absence of apoptotic stimuli, when cells are proliferating, localization observed in various cell types (rodent and human). This is also supported by acellular assays in which p53 bind strongly to mitochondria isolated from rat liver. Furthermore, the mitochondria subfractionation study and the alkaline treatment of the mitochondrial p53 revealed that the majority of mitochondrial p53 is present in the membranous compartments. Finally, we identified VDAC, a protein of the mitochondrial outer-membrane, as a putative partner of p53 in unstressed/proliferative cells.

  5. [Heavy silicone oil (Densiron® 68) in proliferative vitreoretinopathy: 4 years of experience].

    Science.gov (United States)

    Macías-Murelaga, B; Ruiz, M; Bascarán, L; Gibelalde, A; Aldazabal, M; Irigoyen, C

    2013-11-01

    Prospective observational study including 10 patients (age range: 27-74 years) with recurrent retinal detachment (RD) and proliferative vitreoretinopathy (PVR) and 2.8 mean unsatisfactory previous surgeries. Densiron® was injected in all patients, with surgical retinectomy being required in 70% of them. Minimum follow-up time was 12 months. The mean length of time before Densiron® withdrawal was 4 months. Three patients (30%) presented with a new RD. The main complication detected was cataract development. No relationship was found between re-detachments and tamponade time, baseline disease or RD evolution time. Densiron® may be a good option in cases of recurrent RD in which previous treatment with scleral buckle, gas and/or 1,000/5,000 silicone oils has proven to be unsatisfactory. Copyright © 2012 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.

  6. CASE REPORT OF SEVERE PROLIFERATIVE RETINOPATHY IN A PATIENT WITH CONGENITAL LIPODYSTROPHY.

    Science.gov (United States)

    Rosin, Boris; Jaouni, Tareq

    2017-08-21

    A case report of a patient with severe proliferative retinopathy due to congenital lipodystrophy. We reviewed the medical history, imaging, and surgical procedures of a 25-year-old woman with a history of congenital lipodystrophy, presenting with bilateral combined tractional and exudative retinal detachment, poorly controlled diabetes mellitus, and extreme dislipidemia. The patient underwent retinal detachment repair surgery both eyes. On the last follow-up, both retinae were flat, and visual acuity had improved in the right eye to J3 for near and finger counting 3 m for distance. Surgery combining pars plana vitrectomy and scleral bucking successfully flattened both retinae and significantly improved visual acuity in one eye in this case of bilateral retinal detachment with combined tractional and exudative components in a patient with congenital lipodystrophy. Surgical control of retinal complications is thus possible, provided there is adequate control of the underlying risk factors.

  7. Retinitis pigmentosa reduces the risk of proliferative diabetic retinopathy: a nationwide population-based cohort study.

    Directory of Open Access Journals (Sweden)

    Yuh-Fang Chen

    Full Text Available PURPOSE: To study the association between retinitis pigmentosa (RP and the progression of diabetic retinopathy (DR. METHODS: Using the Longitudinal Health Insurance Database 2000 of Taiwan, we identified individuals with an initial diagnosis for RP during the period of 1997-2008. A non-RP comparison group, 10-fold frequency matched by sex, age, index year and the year of diabetes diagnosed, were randomly selected from the same database. The occurrence of DR was observed for all subjects until the end of 2009. The Kaplan-Meier curves were used to illustrate the cumulative probability of developing DR for the RP group and comparison groups. The hazard ratio (HR of DR for the RP group relative to the comparison group was estimated using Cox proportional hazards model after adjusting for potential confounders. RESULTS: The Kaplan-Meier curves were not statistically significant different between the RP group and the comparison group. However, the RP group had a higher cumulative probability of developing DR during the first six to seven years. The cumulative probability kept increasing and became higher in the comparison group but remained unchanged in the RP group. The HR for the RP patients comparing with the comparison group was 0.96 (95% confidence interval (CI = 0.43-2.14. Stratified by severity, RP was associated with a non-statistically significant reduced risk of proliferative DR (PDR (HR = 0.70, 95% CI = 0.16-3.14. The HR for non-proliferative DR (NPDR was 1.08 (95% CI = 0.40-2.86. CONCLUSION: In this study, RP was not statistically significant associated with the incidence of DR.

  8. Cranberry and Grape Seed Extracts Inhibit the Proliferative Phenotype of Oral Squamous Cell Carcinomas

    Directory of Open Access Journals (Sweden)

    Kourt Chatelain

    2011-01-01

    Full Text Available Proanthocyanidins, compounds highly concentrated in dietary fruits, such as cranberries and grapes, demonstrate significant cancer prevention potential against many types of cancer. The objective of this study was to evaluate cranberry and grape seed extracts to quantitate and compare their anti-proliferative effects on the most common type of oral cancer, oral squamous cell carcinoma. Using two well-characterized oral squamous cell carcinoma cell lines, CAL27 and SCC25, assays were performed to evaluate the effects of cranberry and grape seed extract on phenotypic behaviors of these oral cancers. The proliferation of both oral cancer cell lines was significantly inhibited by the administration of cranberry and grape seed extracts, in a dose-dependent manner. In addition, key regulators of apoptosis, caspase-2 and caspase-8, were concomitantly up-regulated by these treatments. However, cranberry and grape seed extracts elicited differential effects on cell adhesion, cell morphology, and cell cycle regulatory pathways. This study represents one of the first comparative investigations of cranberry and grape seed extracts and their anti-proliferative effects on oral cancers. Previous findings using purified proanthocyanidin from grape seed extract demonstrated more prominent growth inhibition, as well as apoptosis-inducing, properties on CAL27 cells. These observations provide evidence that cranberry and grape seed extracts not only inhibit oral cancer proliferation but also that the mechanism of this inhibition may function by triggering key apoptotic regulators in these cell lines. This information will be of benefit to researchers interested in elucidating which dietary components are central to mechanisms involved in the mediation of oral carcinogenesis and progression.

  9. ARTEMIS stabilizes the genome and modulates proliferative responses in multipotent mesenchymal cells

    Directory of Open Access Journals (Sweden)

    Tompkins Kathleen

    2010-10-01

    Full Text Available Abstract Background Unrepaired DNA double-stranded breaks (DSBs cause chromosomal rearrangements, loss of genetic information, neoplastic transformation or cell death. The nonhomologous end joining (NHEJ pathway, catalyzing sequence-independent direct rejoining of DSBs, is a crucial mechanism for repairing both stochastically occurring and developmentally programmed DSBs. In lymphocytes, NHEJ is critical for both development and genome stability. NHEJ defects lead to severe combined immunodeficiency (SCID and lymphoid cancer predisposition in both mice and humans. While NHEJ has been thoroughly investigated in lymphocytes, the importance of NHEJ in other cell types, especially with regard to tumor suppression, is less well documented. We previously reported evidence that the NHEJ pathway functions to suppress a range of nonlymphoid tumor types, including various classes of sarcomas, by unknown mechanisms. Results Here we investigate roles for the NHEJ factor ARTEMIS in multipotent mesenchymal stem/progenitor cells (MSCs, as putative sarcomagenic cells of origin. We demonstrate a key role for ARTEMIS in sarcoma suppression in a sensitized mouse tumor model. In this context, we found that ARTEMIS deficiency led to chromosomal damage but, paradoxically, enhanced resistance and proliferative potential in primary MSCs subjected to various stresses. Gene expression analysis revealed abnormally regulated stress response, cell proliferation, and signal transduction pathways in ARTEMIS-defective MSCs. Finally, we identified candidate regulatory genes that may, in part, mediate a stress-resistant, hyperproliferative phenotype in preneoplastic ARTEMIS-deficient MSCs. Conclusions Our discoveries suggest that Art prevents genome damage and restrains proliferation in MSCs exposed to various stress stimuli. We propose that deficiency leads to a preneoplastic state in primary MSCs and is associated with aberrant proliferative control and cellular stress

  10. Alteration of melatonin secretion in patients with type 2 diabetes and proliferative diabetic retinopathy

    Directory of Open Access Journals (Sweden)

    Hikichi T

    2011-05-01

    Full Text Available Taiichi Hikichi1, Naohiro Tateda2, Toshiaki Miura31Department of Ophthalmology, Ohtsuka Eye Hospital, Sapporo; 2Asahikawa National College of Technology, Asahikawa; 3Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, JapanBackground: The purpose of this study was to evaluate the dynamics of plasma melatonin secretion in patients with type 2 diabetes mellitus and diabetic retinopathy.Methods: Plasma melatonin levels were measured by high-performance liquid chromatography in 56 patients. Patients were divided into a diabetic group (30 patients and a nondiabetic group (26 patients. The diabetic group was divided further into a proliferative diabetic retinopathy (PDR group (n = 14 and a nonproliferative diabetic retinopathy (NPDR group (n = 16. Plasma melatonin levels obtained at midnight and 3 am were compared between the groups.Results: Nighttime melatonin levels were significantly lower in the diabetic group than in the nondiabetic group (P < 0.03 and lower in the PDR group than in the nondiabetic and NPDR groups (P < 0.01 and P < 0.03, respectively, but no significant difference was found between the nondiabetic and NPDR groups. The daytime melatonin level did not significantly differ between the nondiabetic and diabetic groups or between the nondiabetic, NPDR, and PDR groups.Conclusion: The nighttime melatonin level is altered in patients with diabetes and PDR but not in diabetic patients without PDR. Although patients with PDR may have various dysfunctions that affect melatonin secretion more severely, advanced dysfunction of retinal light perception may cause altered melatonin secretion. Alteration of melatonin secretion may accelerate further occurrence of complications in diabetic patients.Keywords: circadian rhythm, diabetes, proliferative diabetic retinopathy, melatonin

  11. Serum MiRNA Biomarkers serve as a Fingerprint for Proliferative Diabetic Retinopathy

    Directory of Open Access Journals (Sweden)

    Shao Qing

    2014-11-01

    Full Text Available Background: Diabetic retinopathy (DR is a retinopathy resulting from diabetes mellitus (DM which was classified into non-proliferative DR (NPDR and proliferative DR (PDR. Without an early screening and effective diagnosis, patients with PDR will develop serious complications. Therefore, we sought to identify special serum microRNAs (miRNAs that can serve as a novel non-invasive screening signature of PDR and test its specificity and sensitivity in the early diagnosis of PDR. Methods: In total, we obtained serum samples from 90 PDR cases, 90 matched NPDR patients and 20 controls. An initial screening of miRNA expression was performed through TaqMan Low Density Array (TLDA. The candidate miRNAs were validated by individual reverse transcription quantitative real-time PCR (RT-qPCR arranged in an initial and a two-stage validation sets. Moreover, additional double-blind testing was performed in 20 patients clinically suspected of having DR to evaluate the diagnostic value and accuracy of the serum miRNA profiling system in predicting PDR. Results: Three miRNAs were significantly increased in patients with PDR compared with NPDR after the multiple stages. The areas under the receiver operating characteristic (ROC curves of the validated three-serum miRNAs signature were 0.830, 0.803 and 0.873 in the initial and two validation sets, respectively. Combination of miR-21, miR-181c, and miR-1179 possessed a moderate ability to discrimination between PDR and NPDR with an area under ROC value of 0.89. The accuracy rate of the three-miRNA profile as PDR signature was 82.6%. Conclusions: These data provide evidence that serum miRNAs have the potential to be sensitive, cost-effective biomarkers for the early detection of PDR. These biomarkers could serve as a dynamic monitoring factor for detecting the progression of PDR from NPDR.

  12. Apoptotic Cell Death and the Proliferative Capacity of Human Breast Cancers

    Directory of Open Access Journals (Sweden)

    Gabriele A. Losa

    1998-01-01

    Full Text Available The proliferative capacity (%S‐phase fraction, DNA ploidy, apoptosis frequency (DNA fragmentation and steroid hormone receptor status (estrogen receptor, ER; progesterone receptor, PR of 110 samples of human breast tissues with ductal invasive carcinoma were measured using biochemical and cytofluorimetric procedures. The DNA fragmentation had a left‐skewed frequency distribution and an overall median value of 1.64%, whilst the median %S‐phase fraction was 8%. The median %DNA fragmentation and %S‐phase fraction were 1.96% and 16% in hyperdiploid tumours (n=29; DNA index >1.1 higher than in hypodiploid tumors (n=10; DNA index 0.96, 0.38% and 7.5%. DNA diploid tumours (n=71 had median %DNA fragmentation and %S‐phase values of 1.68% and 6%, consistently lower than the median values of DNA hyperdiploid tumours. The ER content of hypodiploid tumours was about one half (median: 5.9 fmol/mg the median values in hyperdiploid (10.6 fmol/mg and diploid tumours (14.6 fmol/mg. This may correlate with the lowest frequency of apoptosis in hypodiploid tumours, at least when measured by biochemical methods which only detect cells in the late phases of apoptosis. In contrast, the median PR was lowest in hyperdiploid tumours than in hypo and/or diploid tumours. The %S‐phase/%fragmented DNA ratio for the hypodiploid tumours was 19.7, significantly higher than the ratios for hyperdiploid (8.2 and diploid tumours (3.6. These findings indicated that there is an imbalance between proliferative capacity and cell death or growth arrest in human breast tumours. This imbalance may well be linked to a loss of steroid hormone control.

  13. Elevated Subclinical Double-Stranded DNA Antibodies and Future Proliferative Lupus Nephritis

    Science.gov (United States)

    Lee, Jessica J.; Prince, Lisa K.; Baker, Thomas P.; Papadopoulos, Patricia; Edison, Jess; Abbott, Kevin C.

    2013-01-01

    Summary Background and objectives Elevated anti–double-stranded DNA (dsDNA) antibody and C-reactive protein are associated with proliferative lupus nephritis (PLN). Progression of quantitative anti-dsDNA antibody in patients with PLN has not been compared with that in patients with systemic lupus erythematosus (SLE) without LN before diagnosis. The temporal relationship between anti-dsDNA antibody and C-reactive protein elevation has also not been evaluated. Design, setting, participants, & measurements This case-control Department of Defense Serum Repository (established in 1985) study compared longitudinal prediagnostic quantitative anti-dsDNA antibody and C-reactive protein levels in 23 patients with biopsy-proven PLN (Walter Reed Army Medical Center, 1993–2009) with levels in 21 controls with SLE but without LN matched for patient age, sex, race, and age of serum sample. The oldest (median, 2601 days; 25%, 1245 days, 75%, 3075 days), the second to last (368; 212, 635 days), and the last (180; 135, 477 days) serum sample before diagnosis were analyzed. Results More patients with PLN had an elevated anti-dsDNA antibody level than did the matched controls at any point (78% versus 5%; P4 years (33% versus 0%; P=0.04) before diagnosis. A rate of increase >1 IU/ml per year (70% versus 0%; P<0.001) was most specific for PLN. The anti-dsDNA antibody levels increased before C-reactive protein did in most patients with an antecedent elevation (92% versus 8%; P<0.001). Conclusions Elevated anti-dsDNA antibody usually precedes both clinical and subclinical evidence of proliferative LN, which suggests direct pathogenicity. Absolute anti-dsDNA antibody level and rate of increase could better establish risk of future PLN in patients with SLE. PMID:23833315

  14. Focal adhesion interactions with topographical structures: a novel method for immuno-SEM labelling of focal adhesions in S-phase cells.

    Science.gov (United States)

    Biggs, M J P; Richards, R G; Wilkinson, C D W; Dalby, M J

    2008-07-01

    Current understanding of the mechanisms involved in osseointegration following implantation of a biomaterial has led to adhesion quantification being implemented as an assay of cytocompatibility. Such measurement can be hindered by intra-sample variation owing to morphological changes associated with the cell cycle. Here we report on a new scanning electron microscopical method for the simultaneous immunogold labelling of cellular focal adhesions and S-phase nuclei identified by BrdU incorporation. Prior to labelling, cellular membranes are removed by tritonization and antigens of non-interest blocked by serum incubation. Adhesion plaque-associated vinculin and S-phase nuclei were both separately labelled with a 1.4 nm gold colloid and visualized by subsequent colloid enhancement via silver deposition. This study is specifically concerned with the effects microgroove topographies have on adhesion formation in S-phase osteoblasts. By combining backscattered electron (BSE) imaging with secondary electron (SE) imaging it was possible to visualize S-phase nuclei and the immunogold-labelled adhesion sites in one energy 'plane' and the underlying nanotopography in another. Osteoblast adhesion to these nanotopographies was ascertained by quantification of adhesion complex formation.

  15. Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A

    DEFF Research Database (Denmark)

    Sørensen, Claus Storgaard; Syljuåsen, Randi G; Falck, Jacob

    2003-01-01

    Chk1 kinase coordinates cell cycle progression and preserves genome integrity. Here, we show that chemical or genetic ablation of human Chk1 triggered supraphysiological accumulation of the S phase-promoting Cdc25A phosphatase, prevented ionizing radiation (IR)-induced degradation of Cdc25A...

  16. CXCR4 expression in feline mammary carcinoma cells: evidence of a proliferative role for the SDF-1/CXCR4 axis

    Directory of Open Access Journals (Sweden)

    Ferrari Angelo

    2012-03-01

    not show CXCR4 immunoreactivity. CXCR4 score was statistically significantly associated with the histological features of the samples, showing an increase accordingly with the degree of neoplastic transformation (from normal tissue to metastatic lesions. Finally, in the primary cultures obtained from 6 primary feline mammary carcinomas CXCR4 expression was detected in all cells and its activation by SDF-1 in vitro treatment caused a significant increase in the proliferation rate in 5 out of 6 tumours. Conclusions These results indicate that malignant feline mammary tumours commonly express CXCR4, with a higher level in malignant tumours, and, in most of the cases analysed, metastatic cells display stronger immunoreactivity for CXCR4 than the corresponding primary tumours. Moreover, CXCR4 activation in primary cultures of feline mammary carcinomas causes increase in the proliferative rate. Thus, SDF-1/CXCR4 system seems to play a tumorigenic in feline mammary gland malignancy and in vitro cultures from these tumour samples may represent an experimental model to investigate the biological and pharmacological role of this chemokinergic axis.

  17. miR-203 inhibits melanoma invasive and proliferative abilities by targeting the polycomb group gene BMI1

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Xiao [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Sun, Yong [Department of Burn and Plastic Surgery, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an 223300 (China); Han, Siqi [Department of Medical Oncology, Jinling Hospital, Nanjing 210002 (China); Zhu, Wei [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Zhang, Haiping, E-mail: zhanghaiping_2000@163.com [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Lian, Shi, E-mail: lianshi_2020@163.com [Department of Dermatology and Venereal Disease, Capital Medical University, Beijing