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Available online 3 March 2018 —
Vaginal anti-mycotics and the risk for spontaneous abortions
, MD, MPH, PhD, , , , MD, MPH, , , MD, FRCPC, FACMT, , , MD, MHA, , , , PhD, , , 1 Department of Public Health2 Department of Obstetrics and Gynecology3 Department of Faculty of Health Sciences, Ben-Gurion University of the Negev4 Department of Soroka Medical Center, Beer-Sheva, Israel5 Clalit Health Services (Southern District), Beer-Sheva, Israel6 The Motherisk Israel and Maccabi Health Services, Tel Aviv University, IsraelBackgroundSpontaneous abortions are the most common complication of pregnancy. Clotrimazole and miconazole are widely used vaginal-anti-mycotic agents used for the treatment of vulvovaginal candidiasis. A previous study has suggested an increased risk of miscarriage associated with these azoles, which may lead health professionals to refrain from their use even if clinically indicated. The aim of the current study was to assess the risk for spontaneous abortions following first trimester exposure to vaginal-anti-mycotics.MethodsA historical cohort study was conducted including all clinically apparent pregnancies which began between January 2003 and December 2009 and admitted for birth or spontaneous abortion at Soroka Medical Center, Clalit Health Services, Israel.A computerized database of medication dispensation was linked with two computerized databases containing information on births and spontaneous abortions. Time-varying COX regression models were constructed adjusting for mother&s age, diabetes mellitus, hypothyroidism, obesity, hypercoagulable or inflammatory conditions, recurrent miscarriages, intrauterine contraceptive device, ethnicity, tobacco use and the year of admission.ResultsA total of 65,457 pregnancies were included in the study: 58,949 (90.1%) ended with birth and 6,508 (9.9%) with a spontaneous abortion. Overall, 3,246 (5%) pregnancies were exposed to vaginal anti-mycotic medications until the 20th gestational week: 2,712 (4.2%) were exposed to clotrimazole and 633 (1%) to miconazole.Exposure to vaginal anti-mycotics was not associated with spontaneous abortions as a group (crude HR=1.11; 95% CI 0.96 to 1.29, adjusted HR=1.11; 95% CI 0.96 to 1.29) and specifically for clotrimazole (adjusted HR=1.05; 95% CI 0.89 to 1.25) and miconazole (adjusted HR=1.34; 95% CI 0.99 to 1.80). Furthermore, no association was found between categories of dosage of vaginal anti-mycotics and spontaneous abortions.CommentExposure to vaginal anti-mycotics was not associated with spontaneous abortions.Keywordsclotrimazole; miconazole; anti-mycotics; spontaneous abortions; miscarriage; pregnancy; drug safety; teratogens
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Obituary. Sally Diana Kaicher February 19, 1922-March 29, 1999
Lamprell, Kev., 1999: Obituary. Sally Diana Kaicher February 19, 1922-March 29, 1999. Australasian Shell News. D 104: 4
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Related referencesMicroRNA-29c-5p suppresses gallbladder carcinoma progression by directly targeting CPEB4 and inhibiting the MAPK pathway.
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):445-457. doi: 10.1038/cdd.. Epub
2017 Jan 6.MicroRNA-29c-5p suppresses gallbladder carcinoma progression by directly targeting CPEB4 and inhibiting the MAPK pathway.1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2, 1,2.1Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China.2Institute of Biliary Tract Disease, Shanghai Jiao Tong University School of Medicine, No. 1665 Kongjiang Road, Shanghai 200092, China.AbstractGallbladder cancer (GBC) is a leading cause of cancer-related deaths worldwide, and its prognosis remains poor, with a 5-year survival rate of ~5%. Given the crucial role of microRNAs (miRNAs) in cancer metastasis, we aimed to analyze the expression and function of the metastasis-associated miRNA miR-29c-5p in GBC.We validated that expression of miR-29c-5p was significantly downregulated in GBC and was closely associated with lymph node metastasis, overall survival and disease-free survival in 40 GBC patients who were followed clinically. Ectopic overexpression of miR-29c-5p dramatically repressed proliferation, metastasis, and colony formation and induced apoptosis in vitro, and it suppressed tumorigenicity in vivo through the MAPK pathway. Cytoplasmic polyadenylation element binding protein 4 (CPEB4) was identified as a critical effector target of miR-29c-5p. Enforced expression of miR-29c-5p significantly inhibited the expression of CPEB4, and restoration of CPEB4 expression reversed the inhibitory effects of miR-29c-5p on GBC cell proliferation and metastasis. Transforming growth factor-β (TGF-β) upregulated CPEB4 by downregulating miR-29c-5p, leading to MAPK pathway activation. In conclusion, the TGF-β/miR-29c-5p/CPEB4 axis has a pivotal role in the pathogenesis and poor prognosis of GBC, suggesting that miR-29c-5p is a tumor-suppressive miRNA that may serve as potential prognostic biomarker or therapeutic target for GBC.PMID:
[Indexed for MEDLINE] miR-29c-5p is frequently downregulated in GBC and is a promising prognostic biomarker for GBC. (a) A portion of the cluster analysis of the miRNA expression profiles of GBC tissues and NATs. (b) Expression of miR-29c-5p in 40 pairs of GBC tissues and their corresponding NATs. The expression levels of miR-29c-5p were determined by qRT-PCR and normalized to an endogenous control (U6 RNA). The data were analyzed using the formula 2-ΔCT. (c) Expression of miR-29c-3p in 40 pairs of GBC tissues and their corresponding NATs. (d) Box plot of miR-29c-5p expression with or without metastasis. (e) Receiver operating characteristic (ROC) curve analysis to predict lymph node metastasis. (f and g) The OS and DFS of patients with high or low miR-29c-5p expressionCell Death Differ. ):445-457.miR-29c-5p represses GBC cell proliferation, colony formation and cell-cycle progression in vitro and in vivo. (a) The expression of miR-29c-3p and -5p in five GBC cell lines (GBC-SD, SGC-996, NOZ, OCUG, and EH-GB-1) and a normal biliary epithelia cell line (HIBEC)was analyzed by qRT-PCR. (b) GBC-SD cells were transiently transfected with pre-miR-29c (10 nM or 20 nM) or pre-miR-NC for 48 h. The expression of miR-29c-3p and -5p was then analyzed.Growth curves (c), colony formation (d), and DNA replication (g) were assayed for GBC-SD cells and for NOZ cells infected with pre-miR-29c or negative control and with anti-miR-29c-5p or anti-NC. The number of colonies or the number of cells was counted and compared in the diagrams (*P&0.05, **P&0.01, and ***P&0.001). (e) Arrest at the G1/S cell-cycle transition induced by miR-29c-5p transfection. Protein expression levels of phospho-Chk1 (S345), phospho-Chk2 (T68), phospho-Rb (S780) and Cyclin D in the indicated cells were examined by western blotting. (f) Mice bearing NOZ subcutaneous xenografts were euthanized after 2 weeks of treatment with the miR-29c-5p agomir. The sizes of the tumors in the subcutaneous xenograft model were calculated and compared. (h) The expression of Ki-67, p-MEK, MEK, vimentin, and E-cadherin in local tumor tissues was determined by IHC stainingCell Death Differ. ):445-457.miR-29c-5p inhibits GBC cell migration and invasion in vitro and in vivo. (a) Transwell assays, with or without Matrigel, of GBC cells with miR-29c-5p overexpression or inhibition. The percentage of wound closure was calculated (b), or the number of cells that passed through the membrane was counted and compared in the diagrams (*P&0.05, **P&0.01, and ***P&0.001). (c and d) Protein expression levels of vimentin, E-cadherin, and β-catenin in the indicated cells were examined by western blotting and immunofluorescence analyses. Nuclei were counter stained with DAPI. (e) Representative images of lung metastases. The number of metastatic nodules in the lung was calculated and compared in the diagrams (***P&0.001).Scale bar, 100 μmCell Death Differ. ):445-457.miR-29c-5p exerts an antiapoptotic effect via the MAPK pathway. (a) Apoptosis was analyzed by flow cytometry. Cells stained with Annexin-V-APC were considered to be apoptotic. The apoptotic index was defined as the percentage of apoptotic cells. (b) Analysis of the mitochondrial membrane potential (ΔΨm). The indicated cells were stained with JC-1, and green fluorescence represents de-energized mitochondria. The images were taken with a fluorescence microscope. CCCP was used as a positive control. (c) Identification of potential pathways downstream of miR-29c-5p with the Agilent Whole Human Genome Microarray (4 × 44 K), as described in the Materials and Methods. (d) Phosphorylation of MAPK/ERK pathway-associated proteins was detected in the indicated cells by western blot analysis. β-actin was used as the loading control. (e) MEK phosphorylation is significantly inhibited in cells treated with 20 μM U0126 (MEK1/2 inhibitor). (f) 293T cells were co-transfected with pre-miR-29c (anti-miR-29c-5p) together with the pGL3-TP53/promoter and pRL-TK(pSV40-RL) plasmid. After 48 h, luciferase activity was measured. Three independent experiments were carried out, and the relative luciferase activity is indicated (**P&0.01, and ***P&0.001).Cell Death Differ. ):445-457.CPEB4 is a direct target of miR-29c-5p in GBC cells. (a) Potential miR-29c-5p targets predicted by two computational prediction programs. The overlap between themis listed (right). (b) Luciferase reporter plasmids were constructed as described in the materials and methods. The sequences of the predicted miR-29c-5p binding sites within the 3′ UTR of CPEB4 are shown, including the wild-type and mutant binding site. Relative luciferase activity was analyzed after co-transfection of the above reporter plasmids or a mock reporter plasmid into 293 T cells that were infected with pre-miR-29c (***P&0.001). (c) Western blot analysis of CPEB4 protein in GBC-SD and NOZ cells infected with anti-miR-29c-5p, anti-NC, pre-miR-NC, or pre-miR-29c. (d) CPEB4 mRNA levels in 40 pairs of GBC tissues and their corresponding NATs. (e and f) The correlation between the expression levels of miR-29c-5p and CPEB4 was determined using a linear regression analysis and a paired t-test with the same samples used in
(P&0.001, R=-0.571; Pearson's correlation). (g) Representative IHC micrographs showing CPEB4 protein expression in GBC tissues with high or low miR-29c-5p expression. Scale bar, 100 μm. (h) The OS of patients with positive or negative CPEB4 expression. (i) The OS rates of 40 GBC patients were compared between the high and low miR-29c-5p expression groups and the high and low CPEB4 expression groups by using Kaplan–Meier analysis. P-values were generated from all groups togetherCell Death Differ. ):445-457.Gain- and loss-of-function studies with a CPEB4 expression vector or with siCPEB4. To investigate whether CPEB4 expression may interfere with or mimic the function of miR-29c-5p, GBC cells were transfected with CPEB4 siRNA or a CPEB4 expression vector to inhibit or to restore, respectively, the expression of CPEB4. Cell growth curves (a), colony-formation (b), FCM analysis (c), and migration assays (d) were performed with the above cells. (e) Western blot for CPEB4 and its downstream proteins in GBC cells that were stably infected with CPEB4, siCPEB4, or reintroduced control vector (*P&0.05, **P&0.01, and ***P&0.001)Cell Death Differ. ):445-457.Reduced expression of miR-29c-5p is required for TGF-β-induced cell proliferation and metastasis. (a and b) Relative changes in miR-29c-5p and CPEB4 expression in GBC-SD and NOZ cells after 48 h of stimulation with TGF-β (*P&0.05, **P&0.01, and ***P&0.001). (c–e) GBC cells were treated with TGF-β (10 ng/ml) alone, TGF-β plus pre-miR-NC, or TGF-β plus pre-miR-29c for 48 h before cell growth curves, migration assays, and EMT-related gene expression were examined in the indicated cells (*P&0.05, **P&0.01, and ***P&0.001). (f) Schematic depiction of the function and potential mechanism of miR-29c-5p in GBCCell Death Differ. ):445-457.Publication typeMeSH termsSubstancesFull Text SourcesMedical
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External link. Please review our .Kid, a novel kinesin-like DNA binding protein, is localized to chromosomes and the mitotic spindle.
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1996 Feb 1;15(3):457-67.Kid, a novel kinesin-like DNA binding protein, is localized to chromosomes and the mitotic spindle.1, , , , , , .1The Institute of Medical Science, The University of Tokyo, Japan.AbstractMicrotubule-associated motor proteins are thought to be involved in spindle formation and chromosome movements in mitosis/meiosis. We have molecularly cloned cDNAs for a gene that codes for a novel member of the kinesin family of proteins. Nucleotide sequencing reveals that the predicted gene product is a 73 kDa protein and is related to some extent to the Drosophila node gene product, which is involved in chromosomal segregation during meiosis. A sequence similar to the microtubule binding motor domain of kinesin is present in the N-terminal half of the protein, and its ability to bind to microtubules is demonstrated. Furthermore we show that its C-terminal half contains a putative nuclear localization signal similar to that of Jun and is able to bind to DNA. Accordingly, the protein was termed Kid (kinesin-like DNA binding protein). Indirect immunofluorescence studies show that Kid colocalizes with mitotic chromosomes and that it is enriched in the kinetochore at anaphase. Thus, we propose that Kid might play a role(s) in regulating the chromosomal movement along microtubules during mitosis.PMID: 8599929 PMCID:
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External link. Please review our .14-3-3 proteins associate with phosphorylated simple epithelial keratins during cell cycle progression and act as a solubility cofactor.
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):345-57.14-3-3 proteins associate with phosphorylated simple epithelial keratins during cell cycle progression and act as a solubility cofactor.1, .1VA Palo Alto Health Care System, CA 94304, USA.Abstract14-3-3 is a ubiquitous protein family that interacts with several signal transduction kinases. We show that 14-3-3 proteins associate with keratin intermediate filament polypeptides 8 and 18 (K8/18) that are expressed in simple-type epithelia. The association is stoichiometrically significant (& or = one 14-3-3 molecule/keratin tetramer), occurs preferentially with K18, and is phosphorylation- and cell cycle-dependent in that it occurs during S/G2/M phases of the cell cycle when keratins become hyperphosphorylated. Binding of phospho-K8/18 to 14-3-3 can be reconstituted in vitro using recombinant 14-3-3 or using total cellular cytosol. Phosphatase treatment results in dissociation of 14-3-3, and dephosphorylation of phospho-K8/18 prevents reconstitution of the binding. Three cellular keratin subpopulations were analyzed that showed parallel gradients of keratin phosphorylation and 14-3-3 binding. Incubation of 14-3-3 with keratins during or after in vitro filament assembly results in sequestering of additional soluble keratin, only in cases when the keratins were hyperphosphorylated. Our results demonstrate a stoichiometrically significant cell cycle- and phosphorylation-regulated binding of 14-3-3 proteins to K18 and in vitro evidence of a simple epithelial keratin sequestering role for 14-3-3 proteins.PMID: 8609167 PMCID:
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