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  • 1
    Keywords: EXPRESSION ; IN-VIVO ; DOWN-REGULATION ; QUALITY-CONTROL ; PLASMA-MEMBRANE ; EPITHELIAL-CELLS ; KERATIN INTERMEDIATE-FILAMENTS ; CYSTIC-FIBROSIS GENE ; TRANSMEMBRANE CONDUCTANCE REGULATOR ; CFTR ; PHARMACOLOGICAL RESCUE
    Abstract: We have previously reported an increased expression of cytokeratins 8/18 (K8/K18) in cells expressing the F508del mutation of cystic fibrosis transmembrane conductance regulator (CFTR). This is associated with increased colocalization of CFTR and K18 in the vicinity of the endoplasmic reticulum, although this is reversed by treating cells with curcumin, resulting in the rescue of F508del-CFTR. In the present work, we hypothesized that (i) the K8/K18 network may interact physically with CFTR, and that (ii) this interaction may modify CFTR function. CFTR was immunoprecipitated from HeLa cells transfected with either wild-type (WT) CFTR or F508del-CFTR. Precipitates were subjected to 2D-gel electrophoresis and differential spots identified by mass spectrometry. K8 and K18 were found significantly increased in F508del-CFTR precipitates. Using surface plasmon resonance, we demonstrate that K8, but not K18, binds directly and preferentially to the F508del over the WT human NBD1 (nucleotide-binding domain-1). In vivo K8 interaction with F508del-CFTR was confirmed by proximity ligation assay in HeLa cells and in primary cultures of human respiratory epithelial cells. Ablation of K8 expression by siRNA in F508del-expressing HeLa cells led to the recovery of CFTR-dependent iodide efflux. Moreover, F508del-expressing mice topically treated with K8-siRNA showed restored nasal potential difference, equivalent to that of WT mice. These results show that disruption of F508del-CFTR and K8 interaction leads to the correction of the F508del-CFTR processing defect, suggesting a novel potential therapeutic target in CF.
    Type of Publication: Journal article published
    PubMed ID: 22038833
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  66. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC); 20150607-20150610; Karlsruhe; DOCP 045 /20150602/
    Publication Date: 2015-06-03
    Keywords: Twist-1 ; Akirin-2 ; glioblastoma ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 3
    Keywords: PROTEIN ; IDENTIFICATION ; EPITHELIAL-CELLS ; RESCUE ; CYSTIC-FIBROSIS ; TRANSMEMBRANE CONDUCTANCE REGULATOR ; SMALL-MOLECULE CORRECTORS ; CFTR CHLORIDE CHANNEL ; TRAFFICKING DEFECT ; F508DEL-CFTR
    Abstract: The deletion of Phe508 (DeltaF508) in the first nucleotide binding domain (NBD1) of CFTR is the most common mutation associated with cystic fibrosis. The DeltaF508-CFTR mutant is recognized as improperly folded and targeted for proteasomal degradation. Based on molecular dynamics simulation results, we hypothesized that interaction between DeltaF508-NBD1 and housekeeping proteins prevents DeltaF508-CFTR delivery to the plasma membrane. Based on this assumption we applied structure-based virtual screening to identify new low-molecular-weight compounds that should bind to DeltaF508-NBD1 and act as protein-protein interaction inhibitors. Using different functional assays for CFTR activity, we demonstrated that in silico-selected compounds induced functional expression of DeltaF508-CFTR in transfected HeLa cells, human bronchial CF cells in primary culture, and in the nasal epithelium of homozygous DeltaF508-CFTR mice. The proposed compounds disrupt keratin8-DeltaF508-CFTR interaction in DeltaF508-CFTR HeLa cells. Structural analysis of DeltaF508-NBD1 in the presence of these compounds suggests their binding to NBD1. We conclude that our strategy leads to the discovery of new compounds that are among the most potent correctors of DeltaF508-CFTR trafficking defect known to date.
    Type of Publication: Journal article published
    PubMed ID: 23982976
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  • 4
    ISSN: 0898-6568
    Keywords: PKC ; Parathyroid hormone ; cAMP ; cGMP ; calcium current ; osteoblast ; vitamin D"3
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1420-9136
    Source: Springer Online Journal Archives 1860-2000
    Topics: Geosciences , Physics
    Notes: Abstract Observations of air flow in and around convective clouds are summarized and discussed in light of the requirements for parameterization of midlatitude convection. Both theory and observation indicate that a substantial portion of the compensating subsidence occurs as dry downdrafts in the immediate vicinity of convective clouds, which suggests that an additional physical mechanism is necessary in linking convection to the large scale. A conceptual three-dimensional model of midlatitude organized convection along with its implications for parameterization, particularly in mesoscale modeling, is presented. The effects of moist downdrafts are also considered and some differences between midlatitude and tropical convection are discussed.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-1424
    Keywords: K+ current ; Ca2+ current ; Arachidonic acid ; Osteoblast
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract We show that the voltage-gated K+ and Ca2+ currents of rat osteoblastic cells are strongly modulated by arachidonic acid (AA), and that these modulations are very sensitive to the AA concentration. At 2 or 3 μm, AA reduces the amplitude and accelerates the inactivation of the K+ current activated by depolarization; at higher concentrations (≥5 μm), AA still blocks this K+ current, but also induces a very large noninactivating K+ current. At 2 or 3 μm, AA enhances the T-type Ca2+ current, close to its threshold of activation, whereas at 10 μm, it blocks that current. AA (1–10 μm) also blocks the dihydropyridine-sensitive L-type Ca2+ current. Thus, the effect of AA on Ca2+ entry through voltage-gated Ca2+ channels can change qualitatively with the AA concentration: at 2 or 3 μm, AA will favor Ca2+ entry through T channels, both by lowering the voltage-gated K+ conductance and by increasing the T current, whereas at 10 μm, AA will prevent Ca2+ entry through voltage-gated Ca2+ channels, both by inducing a K+ conductance and by blocking Ca2+ channels.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-1424
    Keywords: Cl− current ; Hyperpolarization-activated ; Osmosensitivity ; Mechanosensitivity ; Osteoblast
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Abstract During whole-cell recording of rat osteoblastic cells with high-Cl− internal solutions, 10 sec hyperpolarizing jumps from 0 mV induce a slow inward current relaxation, which is shown to be carried by hyperpolarization-activated Cl− channels. This relaxation increases and becomes faster with stronger hyperpolarizations. It is insensitive to Cs+ ions but is blocked in a voltage-dependent manner by 4,4′-diisothiocyanatostilbene-2, 2′-disulfonic acid (DIDS) 1 mm and is reduced by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) 0.1 mm. Cd2+ ions are potent blockers of this current, blocking completely above 300 μm. The amplitude of the Cl− current activated by a given hyperpolarization increases during the first 10–20 min of whole-cell recording. This evolution and the fact that some recently cloned Cl− channels have been reported to be activated both by hyperpolarization and by external hyposmolarity led us to investigate the effects of external osmolarity. Reducing the external osmolarity induces a large Cl− current. However, this hyposmolarity-induced Cl− current and the hyperpolarization-activated Cl− current are shown to be distinct; 1,9-dideoxy forskolin selectively blocks the hyposmolarity-activated current. We show that the hyperpolarization-activated Cl− current is osmosensitive, but in an unusual way: it is reduced by external hyposmolarity and is increased by external hyperosmolarity. Furthermore, these modulations are more pronounced for small hyperpolarizations. The osmosensitivity of the hyperpolarization-activated Cl− current suggests a mechanosensitivity (activation by positive external pressure) that is likely to be physiologically important to bone cells.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1262
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Thirty-seven patients with rectal villous tumours were investigated by endorectal sonography to assess the integrity of the rectal muscularis propria at the tumour level. In four cases assessment of invasion was impossible. In 24 patients, endosonography revealed an ultrasonically superficial lesion not infiltrating the muscular layer. This was confirmed either, in the case of laser treatment, by the absence of malignant recurrence during the follow-up period or by histological examination after surgical resection. In nine patients, endosonography showed infiltration of the muscular layer. This was histologically confirmed in five operated patients. In the remaining four, laser destruction was performed: in two, a rectal adenocarcinoma was present 3 and 6 months later, respectively. These findings show that endosonography has a place in the management of rectal villous tumours, demonstrating invasive cancer in cases where other forms of assessment were wrongly reassuring.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-2218
    Keywords: Foreign body ; Common bile duct ; Endoscopy ; Sphincterotomy ; Endoprosthesis ; Ampullary adenocarcinoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We describe the application of a new two-stage endoscopic procedure for removal of a retained stent in the common bile duct (Type 1 foreign body in Ban's classification). The technique involves sphincterotomy and placement of the endoprosthesis.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1530-0358
    Keywords: Villous adenomas ; Colonic adenomas ; Laser ; Colonoscopy ; Polypectomy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The association of endoscopic resection with Nd:YAG laser photocoagulation was used to treat benign colorectal villous adenomas. Eighty-five patients were included: 49 with surgical contraindications, 35 for whom surgical resection appeared to be too hazardous, and 1 who refused surgery. Forty-five tumors had an axial extension between 1 and 3 cm, and 40 tumors had an axial extension of at least 4 cm. Diathermic snare resection was performed to remove large tumoral fragments prior to laser photocoagulation of the residual flat lesions. Treatments were repeated every 15 days until total tumor destruction was achieved. A carcinoma was detected in biopsy specimens obtained during endoscopic treatment of five patients. Two patients were lost to follow-up. Treatment results could be analyzed in 78 patients. Successful treatment was achieved in 67 patients. Tumor destruction was complete in 77 percent of patients who had lesions of at least 4 cm diameter and in 93 percent of patients with smaller lesions. The axial extension of the tumor was the main factor affecting the results of treatment. No major complications occurred. During the average 103-week follow-up period, 21 percent of the patients with total tumor destruction had a recurrence. The risk of recurrence was correlated with the number of initial treatment sessions and previous surgery treatment. It would appear that the treatment with endoscopic resection prior to Nd:YAG laser photocoagulation is a safe and effective method in the destruction of colorectal villous adenomas.
    Type of Medium: Electronic Resource
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