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  • 1
    Article
    Article
    Mitochondrial dynamics regulates migration and invasion of breast cancer cells
    2013
    ISSN: 0950-9232 
    Details
    Language: English
    In: Oncogene, 2013-10, Vol.32 (40), p.4814-4824
    Description: Mitochondria are highly dynamic and undergo constant fusion and fission that are essential for maintaining physiological functions of cells. Although dysfunction of mitochondria has been implicated in tumorigenesis, little is known about the roles of mitochondrial dynamics in metastasis, the major cause of cancer death. In the present study, we found a marked upregulation of mitochondrial fission protein dynamin-related protein 1 (Drp1) expression in human invasive breast carcinoma and metastases to lymph nodes. Compared with non-metastatic breast cancer cells, mitochondria also were more fragmented in metastatic breast cancer cells that express higher levels of total and active Drp1 and less mitochondrial fusion protein 1 (Mfn1). Silencing Drp1 or overexpression of Mfn1 resulted in mitochondria elongation or clusters, respectively, and significantly suppressed metastatic abilities of breast cancer cells. In contrast, silencing Mfn proteins led to mitochondrial fragmentation and enhanced metastatic abilities of breast cancer cells. Interestingly, these manipulations of mitochondrial dynamics altered the subcellular distribution of mitochondria in breast cancer cells. For example, silencing Drp1 or overexpression of Mfn1 inhibited lamellipodia formation, a key step for cancer metastasis, and suppressed chemoattractant-induced recruitment of mitochondria to lamellipodial regions. Conversely, silencing Mfn proteins resulted in more cell spreading and lamellipodia formation, causing accumulation of more mitochondria in lamellipodia regions. More importantly, treatment with a mitochondrial uncoupling agent or adenosine triphosphate synthesis inhibitor reduced lamellipodia formation and decreased breast cancer cell migration and invasion, suggesting a functional importance of mitochondria in breast cancer metastasis. Together, our findings show a new role and mechanism for regulation of cancer cell migration and invasion by mitochondrial dynamics. Thus targeting dysregulated Drp1-dependent mitochondrial fission may provide a novel strategy for suppressing breast cancer metastasis.
    Subject(s): ATP ; Breast cancer ; Breast carcinoma ; Breast Neoplasms - pathology ; Breast Neoplasms - physiopathology ; Cancer cells ; Cell adhesion & migration ; Cell Cycle ; Cell Line, Tumor ; Cell migration ; Cell spreading ; Cellular control mechanisms ; Cellular proteins ; Drp1 ; Dynamin ; Female ; fission and fusion ; Fusion protein ; Gene expression ; Gene Silencing ; GTP Phosphohydrolases - genetics ; GTP Phosphohydrolases - physiology ; Humans ; Invasiveness ; lamellipodia ; Lymph nodes ; Lymphatic Metastasis ; Membrane Potential, Mitochondrial ; Metastases ; Metastasis ; Microtubule-Associated Proteins - genetics ; Microtubule-Associated Proteins - physiology ; Mitochondria ; mitochondrial dynamics ; Mitochondrial Dynamics - physiology ; Mitochondrial Proteins - genetics ; Mitochondrial Proteins - physiology ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Physiological aspects ; Properties ; Proteins ; Pseudopodia ; Tumorigenesis
    ISSN: 0950-9232
    E-ISSN: 1476-5594
    DOI: 10.1038/onc.2012.494
    Source: Academic Search Ultimate
    Source: Nature Journals Online
    Source: Alma/SFX Local Collection
    URL: https://www.ncbi.nlm.nih.gov/pubmed/23128392$$D View this record in MEDLINE/PubMed
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  • 2
    Article
    Article
    Transforming growth factor (TGF)-β1-induced miR-133a inhibits myofibroblast differentiation and pulmonary fibrosis
    2019
    ISSN: 2041-4889 
    Details
    Language: English
    In: Cell death & disease, 2019-09-11, Vol.10 (9), p.670-17
    Description: Transforming growth factor (TGF)-β1, a main profibrogenic cytokine in the progression of idiopathic pulmonary fibrosis (IPF), induces differentiation of pulmonary fibroblasts to myofibroblasts that produce high levels of collagen, leading to concomitantly loss of lung elasticity and function. Recent studies implicate the importance of microRNAs (miRNAs) in IPF but their regulation and individual pathological roles remain largely unknown. We used both RNA sequencing and quantitative RT-PCR strategies to systematically study TGF-β1-induced alternations of miRNAs in human lung fibroblasts (HFL). Our data show that miR-133a was significantly upregulated by TGF-β1 in a time- and concentration-dependent manner. Surprisingly, miR-133a inhibits TGF-β1-induced myofibroblast differentiation whereas miR-133a inhibitor enhances TGF-β1-induced myofibroblast differentiation. Interestingly, quantitative proteomics analysis indicates that miR-133a attenuates myofibroblast differentiation via targeting multiple components of TGF-β1 profibrogenic pathways. Western blot analysis confirmed that miR-133a down-regulates TGF-β1-induced expression of classic myofibroblast differentiation markers such as ɑ-smooth muscle actin (ɑ-SMA), connective tissue growth factor (CTGF) and collagens. miRNA Target Searcher analysis and luciferase reporter assays indicate that TGF-β receptor 1, CTGF and collagen type 1-alpha1 (Col1a1) are direct targets of miR-133a. More importantly, miR-133a gene transferred into lung tissues ameliorated bleomycin-induced pulmonary fibrosis in mice. Together, our study identified TGF-β1-induced miR-133a as an anti-fibrotic factor. It functions as a feed-back negative regulator of TGF-β1 profibrogenic pathways. Thus, manipulations of miR-133a expression may provide a new therapeutic strategy to halt and perhaps even partially reverse the progression of IPF.
    Subject(s): Actin ; Actins - genetics ; Actins - metabolism ; Animals ; Bleomycin ; Bleomycin - toxicity ; Cell Differentiation - drug effects ; Cell Differentiation - genetics ; Cell signalling ; Collagen (type I) ; Collagen Type I - genetics ; Collagen Type I - metabolism ; Connective tissue growth factor ; Connective Tissue Growth Factor - genetics ; Connective Tissue Growth Factor - metabolism ; Connective tissues ; Female ; Fibroblasts ; Fibrosis ; Growth factors ; HEK293 Cells ; Humans ; Idiopathic Pulmonary Fibrosis - chemically induced ; Idiopathic Pulmonary Fibrosis - genetics ; Idiopathic Pulmonary Fibrosis - metabolism ; Idiopathic Pulmonary Fibrosis - pathology ; Lung diseases ; Mice ; Mice, Inbred C57BL ; MicroRNAs ; MicroRNAs - genetics ; MicroRNAs - metabolism ; miRNA ; Myofibroblasts - drug effects ; Myofibroblasts - metabolism ; NIH 3T3 Cells ; p38 Mitogen-Activated Protein Kinases - genetics ; p38 Mitogen-Activated Protein Kinases - metabolism ; Polymerase chain reaction ; Proteomics ; Pulmonary fibrosis ; Respiratory tract diseases ; Smad3 Protein - genetics ; Smad3 Protein - metabolism ; Smooth muscle ; Transforming Growth Factor beta1 - genetics ; Transforming Growth Factor beta1 - metabolism ; Transforming Growth Factor beta1 - pharmacology ; Transforming growth factor-a ; Transforming growth factor-b1
    ISSN: 2041-4889
    E-ISSN: 2041-4889
    DOI: 10.1038/s41419-019-1873-x
    Source: Nature Open Access
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    URL: https://www.ncbi.nlm.nih.gov/pubmed/31511493$$D View this record in MEDLINE/PubMed
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  • 3
    Article
    Article
    BI-01BLOOD SERUM AND C.S.F. ANALYTES SHOW POTENTIAL FOR USE AS A DIAGNOSTIC BIOMARKER FOR LOW AND HIGH GRADE GLIOMA
    2014
    ISSN: 1522-8517 
    Details
    Language: English
    In: Neuro-oncology (Charlottesville, Va.), 2014-11-01, Vol.16 (Suppl 5), p.v23-v23
    Description: INTRODUCTION: There is a need for a biomarker with high sensitivity and specificity to aid glioma diagnosis. Current methods of diagnosis are invasive with the diagnostic test requiring hospitalisation. A rapid diagnostic based upon blood serum and CSF samples would allow for a relatively non-invasive test and open up the possibility of screening for glioma as well as effective treatment monotoring and prediction of tumour recurrance. Analysis of the source of the proteins may reveal information regarding the mechanism of immunosuppression in these tumours. MATERIALS AND METHODS: Serum from 110 high grade and 44 low grade glioma patients, were analysed along with 33 control sera from non-cancerous patients. CSF was also analysed from 8 high grade glioma patients taken with lumbar puncture. The analysis was performed using a luminex immunoassay measuring 36 cancer-associated analytes simultaneously. Immunohistochemistry was also performed on tumour tissue from the same patients. RESULTS: There were significant differences in several analytes between sera and CSF of glioma patients of low and high grade and non-cancerous control patients. These were Angiopoietin, Follistatin, FGF, G-CSF, sHER2neu, HGF, sIL-6R, Leptin, PDGF-BB, PECAM-1, Prolactin and sVEGFR-1. CSF level differences confirmed and correlated with serum level differences in the majority of cases. Tumour tissue also revealed increased expression of several of the proteins. CONCLUSIONS: These results suggest that specific protein levels in different media can be used to detect and confirm a glioma diagnosis as well as to distinguish between low and high grade gliomas. These results may also be used to predict tumour recurrance and transformation between low and high grade gliomas. There was an interesting up-regulation of several receptor analytes that may have masked the presence of their associated ligand indicating that some potential biomarkers may be obscured. Modification of the capture antibody could reveal more potential biomarkers with greater clinical usefulness.
    Subject(s): Abstracts
    ISSN: 1522-8517
    E-ISSN: 1523-5866
    DOI: 10.1093/neuonc/nou239.1
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 4
    Article
    Article
    Up-regulated miR-133a orchestrates epithelial-mesenchymal transition of airway epithelial cells
    2018
    ISSN: 2045-2322 
    Details
    Language: English
    In: Scientific reports, 2018-10-19, Vol.8 (1), p.15543-11
    Description: Dysregulation of microRNAs (miRNAs) contributes to epithelial-mesenchymal transition (EMT) of cancer, but the pathological roles of miRNAs in airway EMT of lung diseases remains largely unknown. We performed sequencing and real-time PCR analysis of the miRNA expression profile of human airway epithelial cells undergoing EMT, and revealed miR-133a to be one of the most common up-regulated miRNAs. MiR-133a was previously reported to be persistently up-regulated in airway epithelial cells of smokers. We found that mice exposed to cigarette smoke (CS) showed airway hyper-responsiveness, a typical symptom occurring in CS-related lung diseases, up-regulation of miR-133a and EMT marker protein N-cadherin in airway epithelium. Importantly, miR-133a overexpression induces airway epithelial cells to undergo spontaneous EMT via down-regulation of grainyhead-like 2 (GRHL2), an epithelial specific transcriptional factor. Loss of GRHL2 causes down-regulation of epithelial splicing regulatory protein 1 (ESRP1), a central coordinator of alternative splicing processes that are critical in the regulation of EMT. Down-regulation of ESRP1 induces isoform switching of adherens junction-associated protein p120-catenin, and leads to the loss of E-cadherin. Our study is the first to demonstrate that up-regulated miR-133a orchestrates airway EMT via alternative splicing processes, which points to novel therapeutic possibilities for the treatment of CS-related lung disease.
    Subject(s): Alternative splicing ; Cancer ; Cigarette smoke ; E-cadherin ; Epithelial cells ; Epithelium ; Lung diseases ; Mesenchyme ; miRNA ; Mucous membrane ; N-Cadherin ; Proteins ; Respiratory tract ; Respiratory tract diseases
    ISSN: 2045-2322
    E-ISSN: 2045-2322
    DOI: 10.1038/s41598-018-33913-x
    Source: Nature Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    URL: https://www.ncbi.nlm.nih.gov/pubmed/30341388$$D View this record in MEDLINE/PubMed
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  • 5
    Article
    Article
    OP20BLOOD SERUM AND CSF ANALYTES SHOW POTENTIAL FOR USE AS A DIAGNOSTIC BIOMARKER FOR LOW AND HIGH GRADE GLIOMA
    2014
    ISSN: 1522-8517 
    Details
    Language: English
    In: Neuro-oncology (Charlottesville, Va.), 2014-10-01, Vol.16 (Suppl 6), p.vi19-vi20
    Description: INTRODUCTION: There is a need for a biomarker with high sensitivity and specificity to aid glioma diagnosis. Current methods of diagnosis are invasive with the diagnostic test requiring hospitalisation. A rapid diagnostic based upon blood serum and CSF samples would allow for a relatively non-invasive test and open up the possibility of screening for glioma METHOD: Serum from 110 high grade and 44 low grade glioma patients, were analysed along with 33 control sera from non-cancerous patients. CSF was also analysed from 8 high grade glioma patients taken with lumbar puncture. The analysis was performed using a luminex immunoassay measuring 36 cancer-associated analytes simultaneously. RESULTS: There were significant differences in several analytes between sera and CSF of glioma patients of low and high grade and non-cancerous control patients. These were Angiopoietin, Follistatin, FGF, G-CSF, sHER2neu, HGF, sIL-6R, Leptin, PDGF-BB, PECAM-1, Prolactin and sVEGFR-1. CSF level differences confirmed and correlated with serum level differences in the majority of cases. CONCLUSION: These results suggest that specific protein levels in different media can be used to detect and confirm a glioma diagnosis as well as to distinguish between low and high grade gliomas. There was an interesting up-regulation of several receptor analytes that may have masked the presence of their associated ligand indicating that a masking effect may be taking place for certain potential biomarkers.
    Subject(s): Abstracts
    ISSN: 1522-8517
    E-ISSN: 1523-5866
    DOI: 10.1093/neuonc/nou251.20
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 6
    Article
    Article
    Respiratory dysfunction progresses with age in Kcna1‐null mice, a model of sudden unexpected death in epilepsy
    2018
    ISSN: 0013-9580 
    Details
    Language: English
    In: Epilepsia (Copenhagen), 2018-02, Vol.59 (2), p.345-357
    Description: Summary Objective Increased breathing rate, apnea, and respiratory failure are associated with sudden unexpected death in epilepsy (SUDEP). We recently demonstrated the progressive nature of epilepsy and mortality in Kcna1−/− mice, a model of temporal lobe epilepsy and SUDEP. Here we tested the hypothesis that respiratory dysfunction progresses with age in Kcna1−/− mice, thereby increasing risk of respiratory failure and sudden death (SD). Methods Respiratory parameters were determined in conscious mice at baseline and following increasing doses of methacholine (MCh) using noninvasive airway mechanics (NAM) systems. Kcna1+/+, Kcna1+/−, and Kcna1−/− littermates were assessed during 3 age ranges when up to ~30%, ~55%, and ~90% of Kcna1−/− mice have succumbed to SUDEP: postnatal day (P) 32‐36, P40‐46, and P48‐56, respectively. Saturated arterial O2 (SaO2) was determined with pulse oximetry. Lung and brain tissues were isolated and Kcna1 gene and protein expression were evaluated by reverse transcriptase quantitative polymerase chain reaction (RT‐qPCR) and Western blot techniques. Airway smooth muscle responsiveness was assessed in isolated trachea exposed to MCh. Results Kcna1−/− mice experienced an increase in basal respiratory drive, chronic oxygen desaturation, frequent apnea‐hypopnea (A‐H), an atypical breathing sequence of A‐H‐tachypnea‐A‐H, increased tidal volume, and hyperventilation induced by MCh. The MCh‐provoked hyperventilation was dramatically attenuated with age. Of interest, only Kcna1−/− mice developed seizures following exposure to MCh. Seizures were provoked by lower concentrations of MCh as Kcna1−/− mice approached SD. MCh‐induced seizures experienced by a subset of younger Kcna1−/− mice triggered death. Respiratory parameters of these younger Kcna1−/− mice resembled older near‐SD Kcna1−/− mice. Kcna1 gene and protein were not expressed in Kcna1+/+ and Kcna1+/− lungs, and MCh‐mediated airway smooth muscle contractions exhibited similar half‐maximal effective concentration( EC50) in isolated Kcna1+/+ and Kcna1−/− trachea. Significance The Kcna1−/− model of SUDEP exhibits progressive respiratory dysfunction, which suggests a potential increased susceptibility for respiratory failure during severe seizures that may result in sudden death.
    Subject(s): Age ; Analysis ; Apnea ; Death ; DNA polymerases ; Epilepsy ; Hyperventilation ; hypopnea ; KCNA1 protein ; Kv1.1 knockout ; Methacholine ; Mice ; Mortality ; Polymerase chain reaction ; Respiration ; Respiratory tract ; Risk factors ; RNA-directed DNA polymerase ; Rodents ; Seizures ; Seizures (Medicine) ; Smooth muscle ; survival ; Temporal lobe ; Trachea
    ISSN: 0013-9580
    E-ISSN: 1528-1167
    DOI: 10.1111/epi.13971
    Source: Wiley Online Library All Backfiles
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    URL: https://www.ncbi.nlm.nih.gov/pubmed/29327348$$D View this record in MEDLINE/PubMed
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  • 7
    Article
    Article
    Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin
    2020
    ISSN: 0013-9580 
    Details
    Language: English
    In: Epilepsia (Copenhagen), 2020-03, Vol.61 (3), p.572-588
    Description: Objective Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic‐clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO2) in low‐risk and high‐risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high‐risk KO mice. Methods Heart rate and SaO2 were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100 mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry. Results Intermittent bradycardia was more prevalent in high‐risk KO mice, an effect that may be the result of increased parasympathetic drive. High‐risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild‐type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea‐apnea. Blocking orexin receptors prevented the methacholine (MCh)–induced increase in breathing frequency in KO mice and reduced MCh‐induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high‐risk KO mice increased longevity. Significance High‐risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.
    Subject(s): Apnea ; Bradycardia ; Cardiac arrhythmia ; Epilepsy ; Heart rate ; hypocretin ; Hypothalamus (lateral) ; Hypoxia ; Immunohistochemistry ; Kcna1 ; Longevity ; Methacholine ; Neuromodulation ; orexin ; Orexin receptors ; Orexins ; Parasympathetic nervous system ; Phenotypes ; Potassium channels (voltage-gated) ; Receptor mechanisms ; Respiration ; Rodents ; Seizures ; SUDEP ; Ventilation
    ISSN: 0013-9580
    E-ISSN: 1528-1167
    DOI: 10.1111/epi.16434
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    URL: https://www.ncbi.nlm.nih.gov/pubmed/32030748$$D View this record in MEDLINE/PubMed
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  • 8
    Article
    Article
    High-frequency oscillation ventilation for hypercapnic failure of conventional ventilation in pulmonary acute respiratory distress syndrome
    2015
    ISSN: 1364-8535 
    Details
    Language: English
    In: Critical care (London, England), 2015-05-01, Vol.19 (1), p.201-201
    Description: High-frequency oscillation ventilation (HFOV) is regarded as particularly lung protective. Recently, HFOV has been shown to be not beneficial for acute respiratory distress syndrome (ARDS) patients in general. Due to its special physical effects, it could be beneficial, however, in inhomogeneous ARDS. This study evaluates the effect of HFOV on PaCO2 removal in hypercapnic patients with ARDS of pulmonary origin. Between October 2010 and June 2014 patients with ARDS of pulmonary origin with PaO2/FiO2 ratio 〉60 mmHg, but respiratory acidosis (pH 〈7.26) under optimized protective ventilation were switched to HFOV, using moderate airway pressure (adopting the mean airway pressure of the prior ventilation). Data from these patients were analyzed retrospectively; PaCO2 and pH before, 1 h and 24 h after the start of HFOV were compared. Twenty-six patients with PaO2/FiO2 ratio 139 ± 49 and respiratory acidosis (PaCO2 68 ± 12 mmHg) were put on HFOV after 17 ± 22 h of conventional ventilation. Mean airway pressure was 19 cm H2O (15 to 28). PaCO2 decreased significantly: after 1 hour the mean difference was -14 ± 10 mmHg; P 〈0.01 and after 24 hours -17 ± 12 mmHg; P 〈0.01; n = 24. CO2 clearance improved in all but two patients; in those, extracorporeal lung support was initiated. Oxygenation remained unchanged after 1 h and slightly increased after 24 h. No complications related to HFOV were observed. Twenty-two patients improved and could be weaned from HFOV. Twenty patients (77%) were alive on day 30. HFOV could be a useful alternative in patients with ARDS of pulmonary origin with hypercapnic failure of lung-protective conventional ventilation.
    Subject(s): Acute respiratory distress syndrome ; Adults ; Aged ; Analysis ; Carbon dioxide ; Chronic obstructive pulmonary disease ; Clinical trials ; Comparative analysis ; Female ; High-Frequency Ventilation - methods ; High-Frequency Ventilation - utilization ; Humans ; Hypercapnia - diagnosis ; Hypercapnia - epidemiology ; Hypercapnia - therapy ; Intensive care ; Male ; Middle Aged ; Physiological aspects ; Physiology ; Respiration, Artificial - methods ; Respiration, Artificial - utilization ; Respiratory distress syndrome ; Respiratory Distress Syndrome, Adult - diagnosis ; Respiratory Distress Syndrome, Adult - epidemiology ; Respiratory Distress Syndrome, Adult - therapy ; Respiratory therapy ; Retrospective Studies ; Smoke inhalation ; Tomography ; Treatment Failure ; Ventilators
    ISSN: 1364-8535
    E-ISSN: 1466-609X
    DOI: 10.1186/s13054-015-0935-4
    Source: BioMedCentral Open Access
    Source: PubMed Central
    Source: Alma/SFX Local Collection
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
    URL: https://www.ncbi.nlm.nih.gov/pubmed/25929255$$D View this record in MEDLINE/PubMed
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  • 9
    Article
    Article
    Breast Cancer Migration and Invasion Depend on Proteasome Degradation of Regulator of G-Protein Signaling 4
    2009
    ISSN: 0008-5472 
    Details
    Language: English
    In: Cancer research (Chicago, Ill.), 2009, Vol.69 (14), p.5743-5751
    Description: Aberrant signaling through G-protein coupled receptors promotes metastasis, the major cause of breast cancer death. We identified regulator of G-protein signaling 4 (RGS4) as a novel suppressor of breast cancer migration and invasion, important steps of metastatic cascades. By blocking signals initiated through G(i)-coupled receptors, such as protease-activated receptor 1 and CXC chemokine receptor 4, RGS4 disrupted Rac1-dependent lamellipodia formation, a key step involved in cancer migration and invasion. RGS4 has GTPase-activating protein (GAP) activity, which inhibits G-protein coupled receptor signaling by deactivating G-proteins. An RGS4 GAP-deficient mutant failed to inhibit migration and invasion of breast cancer cells in both in vitro assays and a mouse xenograft model. Interestingly, both established breast cancer cell lines and human breast cancer specimens showed that the highest levels of RGS4 protein were expressed in normal breast epithelia and that RGS4 down-regulation by proteasome degradation is an index of breast cancer invasiveness. Proteasome blockade increased endogenous RGS4 protein to levels that markedly inhibit breast cancer cell migration and invasion, which was reversed by an RGS4-targeted short hairpin RNA. Our findings point to the existence of a mechanism for posttranslational regulation of RGS4 function, which may have important implications for the acquisition of a metastatic phenotype by breast cancer cells. Preventing degradation of RGS4 protein should attenuate aberrant signal inputs from multiple G(i)-coupled receptors, thereby retarding the spread of breast cancer cells and making them targets for surgery, radiation, and immune treatment.
    Subject(s): Animals ; Antineoplastic agents ; Biological and medical sciences ; Blotting, Western ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cell Line ; Cell Line, Tumor ; Cell Movement ; Female ; GTPase-Activating Proteins - genetics ; GTPase-Activating Proteins - metabolism ; Gynecology. Andrology. Obstetrics ; Humans ; Mammary gland diseases ; Mammary Neoplasms, Experimental - genetics ; Mammary Neoplasms, Experimental - metabolism ; Mammary Neoplasms, Experimental - pathology ; Medical sciences ; Mice ; Mice, Nude ; Mutation ; Neoplasm Invasiveness ; Pharmacology. Drug treatments ; Proteasome Endopeptidase Complex - metabolism ; rac1 GTP-Binding Protein - genetics ; rac1 GTP-Binding Protein - metabolism ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RGS Proteins - genetics ; RGS Proteins - metabolism ; RNA Interference ; Transplantation, Heterologous ; Tumor Burden ; Tumors
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    DOI: 10.1158/0008-5472.CAN-08-3564
    Source: HighWire Press (Free Journals)
    Source: Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
    URL: http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21884585$$DView record in Pascal Francis
    URL: https://www.ncbi.nlm.nih.gov/pubmed/19549919$$D View this record in MEDLINE/PubMed
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  • 10
    Article
    Article
    Treatment of severe neurological deficits with IgG depletion through immunoadsorption in patients with Escherichia coli O104:H4-associated haemolytic uraemic syndrome: a prospective trial
    2011
    ISSN: 0140-6736 
    Details
    Language: English
    In: The Lancet (British edition), 2011, Vol.378 (9797), p.1166-1173
    Description: Summary Background In May 2011, an outbreak of Shiga toxin-producing enterohaemorrhagic E coli O104:H4 in northern Germany led to a high proportion of patients developing post-enteritis haemolytic uraemic syndrome and thrombotic microangiopathy that were unresponsive to therapeutic plasma exchange or complement-blocking antibody (eculizumab). Some patients needed ventilatory support due to severe neurological complications, which arose 1 week after onset of enteritis, suggesting an antibody-mediated mechanism. Therefore, we aimed to assess immunoadsorption as rescue therapy. Methods In our prospective non-controlled trial, we enrolled patients with severe neurological symptoms and confirmed recent E coli O104:H4 infection without other acute bacterial infection or raised procalcitonin concentrations. We did IgG immunoadsorption processing of 12 L plasma volumes on 2 consecutive days, followed by IgG replacement (0·5 g/kg intravenous IgG). We calculated a composite neurological symptom score (lowest score was best) every day and assessed changes before and after immunoadsorption. Findings We enrolled 12 patients who initially presented with enteritis and subsequent renal failure; 10 (83%) of 12 patients needed renal replacement therapy by a median of 8·0 days (range 5–12). Neurological complications (delirium, stimulus sensitive myoclonus, aphasia, and epileptic seizures in 50% of patients) occurred at a median of 8·0 days (range 5–15) and mandated mechanical ventilation in nine patients. Composite neurological symptom scores increased in the 3 days before immunoadsorption to 3·0 (SD 1·1, p=0·038), and improved to 1·0 (1·2, p=0·0006) 3 days after immunoadsorption. In non-intubated patients, improvement was apparent during immunoadsorption (eg, disappearance of aphasia). Five patients who were intubated were weaned within 48 h, two within 4 days, and two patients needed continued ventilation for respiratory problems. All 12 patients survived and ten had complete neurological and renal function recovery. Interpretation Antibodies are probably involved in the pathogenesis of severe neurological symptoms in patients with E coli O104:H4-induced haemolytic uraemic syndrome. Immunoadsorption can safely be used to rapidly ameliorate these severe neurological complications. Funding Greifswald University and Hannover Medical School.
    Subject(s): Abridged Index Medicus ; Adult ; Aphasia ; Bacterial infections ; Biological and medical sciences ; Care and treatment ; Delirium ; Disease ; E coli ; Enterohemorrhagic Escherichia coli ; Escherichia coli ; Escherichia coli Infections - complications ; Female ; General aspects ; Hematologic and hematopoietic diseases ; Hemolytic-uremic syndrome ; Hemolytic-Uremic Syndrome - complications ; Humans ; Immunoadsorption ; Immunoglobulin G - blood ; Immunosorbent Techniques ; Internal Medicine ; Male ; Medical sciences ; Middle Aged ; Nephrology. Urinary tract diseases ; Nephropathies. Renovascular diseases. Renal failure ; Nervous system diseases ; Nervous System Diseases - microbiology ; Nervous System Diseases - therapy ; Plasma ; Platelet diseases and coagulopathies ; Renal failure ; Shiga-Toxigenic Escherichia coli ; Usage ; Ventilation
    ISSN: 0140-6736
    E-ISSN: 1474-547X
    DOI: 10.1016/S0140-6736(11)61253-1
    Source: Backfile Package - All of Back Files EBS [ALLOFBCKF]
    Source: Elsevier Journal Backfiles on ScienceDirect (DFG Nationallizenzen)
    URL: http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24558789$$DView record in Pascal Francis
    URL: https://www.ncbi.nlm.nih.gov/pubmed/21890192$$D View this record in MEDLINE/PubMed
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