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Tittelbach-Helmrich, Klaus. "Digital DC blocker filters." Frequenz 75, no. 9-10 (February 18, 2021): 331–39. http://dx.doi.org/10.1515/freq-2020-0177.
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Abstract This paper mathematically investigates a special kind of digital infinite-impulse response (IIR) filters, suitable for filtering out very low frequencies near zero from digital signals. We investigate the transfer functions of such filters from 1st to 3rd order and provide formulas to calculate the filter coefficients from the desired cutoff frequency.
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Yates, R., and R. Lyons. "DC Blocker Algorithms[DSP Tips & Tricks]." IEEE Signal Processing Magazine 25, no. 2 (March 2008): 132–34. http://dx.doi.org/10.1109/msp.2007.914713.
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Nanda Kumar, N. S., Satish K. Singh, and Vazhaikkurichi M. Rajendran. "Mucosal potassium efflux mediated via Kcnn4 channels provides the driving force for electrogenic anion secretion in colon." American Journal of Physiology-Gastrointestinal and Liver Physiology 299, no. 3 (September 2010): G707—G714. http://dx.doi.org/10.1152/ajpgi.00101.2010.
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Intermediate conductance K+ (Kcnn4) channels are present in both mucosal and serosal membranes of colon. However, only serosal Kcnn4 channels have been shown to be essential for agonist-induced (cAMP and Ca2+) anion secretion. The present study sought to determine whether mucosal Kcnn4 channels also play a role in colonic anion secretion. Mucosal-to-serosal and serosal-to-mucosal unidirectional 86Rb (K+ surrogate) fluxes as well as short-circuit current ( Isc; a measure of anion secretion) were measured under voltage-clamp conditions in distal colon from rats fed either a standard or K+-free diet. 5,6-Dichloro-1-ethyl-1,3-dihydro-2H-benzimidazole-2-one (DC-EBIO) was used to activate Kcnn4 channels. Mucosal DC-EBIO both induced K+ secretion and enhanced anion secretion in normal rat distal colon. The DC-EBIO-induced K+ secretion was completely blocked by nonspecific (Ba2+) and Kcnn4-specific (TRAM-34) inhibitors, but was not blocked by the large-conductance K+ (iberiotoxin), small-conductance K+ (apamin), or KCNQ1 (chromanol 293B) specific blockers. Ba2+ and TRAM-34 also inhibited DC-EBIO-enhanced anion secretion. The DC-EBIO-enhanced anion secretion was completely inhibited by the nonspecific anion channel blocker 5-nitro-2-(3-phenylpropyl-amino)benzoic acid, whereas it was only partially inhibited by CFTR [CFTRinh-172, glibenclamide]- and CaCC (niflumic acid)-specific Cl− channel blockers. In contrast, mucosal DC-EBIO-enhanced K+ and anion secretion was not present in distal colon of dietary K-depleted rats, indicating absence of mucosal Kcnn4 channels. These observations indicate that mucosal Kcnn4 channels are capable of driving agonist-induced anion secretion mediated via CFTR and CaCC and likely contribute to stool K+ losses that accompany diarrheal illnesses.
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Nazir, Moazzam, Klaehn Burkes, and Johan H. Enslin. "Electrical Safety Considerations of Neutral Blocker Placements for Mitigating DC." IEEE Transactions on Industry Applications 57, no. 1 (January 2021): 1113–21. http://dx.doi.org/10.1109/tia.2020.3032081.
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Abdolhamidi, Mostafa, and Mahmoud Moahammad‐Taheri. "Theory and design of phase‐inverted balanced coupled‐line DC‐blocker." IET Microwaves, Antennas & Propagation 13, no. 8 (April 26, 2019): 1188–97. http://dx.doi.org/10.1049/iet-map.2018.5580.
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Wang, Lujun, Boyu Feng, Yu Wang, Tiezhou Wu, and Huipin Lin. "Bidirectional Short-Circuit Current Blocker for DC Microgrid Based on Solid-State Circuit Breaker." Electronics 9, no. 2 (February 10, 2020): 306. http://dx.doi.org/10.3390/electronics9020306.
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In order to solve the imminent problem in that the traditional protection strategy cannot meet time requirements, together with the fact that the rotational inertia of a DC microgrid is small and short-circuit fault develops rapidly, a bidirectional short-circuit current blocker (BSCCB) based on solid-state circuit breaker for a DC microgrid is proposed. Firstly, the bidirectional current blocking circuit structure is proposed based on the analysis of key components. Then, a top-level differential protection strategy is developed based on the aforementioned proposal. Finally, the performance of the blocking circuit is simulated and verified by experiments. The results show that the proposed method can block short-circuit current within 4 ms, and the response speed of the protection strategy is very fast compared with previous approaches. BSCCB also has reclosing, bidirectional blocking and energy releasing functions. The current blocker proposed in this paper can be reused multiple times and has a promising future in low-voltage DC microgrid application.
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Hae-Young, Lee. "A1364 Angiotensin II type 1 receptor blocker, fimasartan, reduces vascular smooth muscle cell senescence by inhibiting CYR61 signaling pathway." Journal of Hypertension 36 (October 2018): e14. http://dx.doi.org/10.1097/01.hjh.0000548042.95520.dc.
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Yu, Xiaobao, Ying Song, Zhihua Wang, and Baoyong Chi. "Self‐tuned SAW‐less GNSS receiver front end with blocker filtering and gain‐irrelevant DC offset cancellation." Electronics Letters 51, no. 8 (April 2015): 653–54. http://dx.doi.org/10.1049/el.2015.0170.
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Richter, Frank, Oskar Mikulik, Andrea Ebersberger, and Hans-Georg Schaible. "Noradrenergic Agonists and Antagonists Influence Migration of Cortical Spreading Depression in Rat—a Possible Mechanism of Migraine Prophylaxis and Prevention of Postischemic Neuronal Damage." Journal of Cerebral Blood Flow & Metabolism 25, no. 9 (April 13, 2005): 1225–35. http://dx.doi.org/10.1038/sj.jcbfm.9600120.
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Cortical spreading depression (CSD) is thought to be a neuronal mechanism that expands the penumbra zone after focal brain ischemia and that causes migraine aura. Both adrenergic agonists and antagonists significantly influence the size of the penumbra zone and decline the frequency of migraine. To study whether these compounds act by influencing CSD, we applied different drugs topically to an area of the exposed cortex of anesthetized adult rats and observed the migration of CSD-related DC potential deflections across the treated area. The adrenergic agonist norepinephrine (1 mmol/L) and the α2-agonist clonidine (0.56 mmol/L) blocked reversibly the migration of CSD. The β-blocker propranolol (250 μmol/L to 1 mmol/L) dose-dependently diminished migration velocity or even blocked migration of CSD. The CSD blockade by the α2-antagonist yohimbine (1.75 mmol/L) was because of its action on inhibitory 5-HT1A receptors. None of the substances in the concentrations used had influence on regional cerebral blood flow or on systemic arterial blood pressure. The data suggest that the interference of these compounds with CSD may contribute to their beneficial therapeutic effect. The effect of β-receptor antagonists in human migraine needs further exploration, since these drugs also work in migraine without aura.
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Richter, Frank, Sven Rupprecht, Alfred Lehmenkühler, and Hans-Georg Schaible. "Spreading Depression Can Be Elicited in Brain Stem of Immature But Not Adult Rats." Journal of Neurophysiology 90, no. 4 (October 2003): 2163–70. http://dx.doi.org/10.1152/jn.00388.2003.
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Spreading depression (SD), a neuronal mechanism involved in brain pathophysiology, occurs in brain areas with high neuronal density such as the cerebral cortex. By contrast, the brain stem is thought to be resistant to SD. Here we show that DC shifts resembling cortical SD can be elicited in rat brain stem by topical application of KCl but not by pricking the brain stem. However, this was only possible until postnatal day 13, and, in addition, susceptibility for SD had to be enhanced. The latter was achieved by superfusion of the brain stem for 45 min with a solution containing acetate instead of chloride ions. Transient asphyxia or hypoxia by 2 min breathing 6% O2 in N2 had a similar effect. Negative brain stem DC deflections were paralleled by an increase of extracellular potassium concentration ≤40 mM and were spreading, but unlike cortical SD they were not inducible by glutamate and N-methyl-d-aspartate (NMDA). Time course and slope of brain stem SD either resembled cortical SD or were long-lasting and sustained. The latter stopped normal breathing. Different from cortical SD, negative brain stem DC deflections were changed in their slope (mostly converted into sustained shape, peak time was significantly prolonged, decline-time and duration were prolonged), but not abolished by the NMDA receptor blocker MK-801. Thus we demonstrate that the immature brain stem has the capacity to generate negative DC shifts, which could be relevant as a risk factor in newborn brain stem function.
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Miura, Masami, Masatomo Yoshioka, Hiroyoshi Miyakawa, Hiroshi Kato, and Ken-Ichi Ito. "Properties of Calcium Spikes Revealed During GABAA Receptor Antagonism in Hippocampal CA1 Neurons From Guinea Pigs." Journal of Neurophysiology 78, no. 5 (November 1, 1997): 2269–79. http://dx.doi.org/10.1152/jn.1997.78.5.2269.
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Miura, Masami, Masatomo Yoshioka, Hiroyoshi Miyakawa, Hiroshi Kato, and Ken-Ichi Ito. Properties of calcium spikes revealed during GABAA receptor antagonism in hippocampal CA1 neurons from guinea pigs. J. Neurophysiol. 78: 2269–2279, 1997. Intracellular electrical responses and changes in intracellular calcium concentration ([Ca2+]i) in response to activation of synaptic inputs and to DC injections were recorded simultaneously from CA1 pyramidal neurons ( n = 42) in guinea pig hippocampal slices. In the presence of the γ-aminobutyric acid-A (GABAA) receptor antagonists, bicuculline (25 μM) and picrotoxin (10 μM), broad (>20 ms) all-or-none spikes were induced by activation of synaptic inputs (20 pulses, 30 Hz) and were accompanied by a simultaneous rapid and large rise in [Ca2+]i (34 of 34 cells). By contrast, direct depolarizing current (0.7 nA, 1 s) induced spikes having short duration, during which time the spike firing pattern was observed not to be significantly affected. When Na+ channels were blocked by QX-314 applied intracellularly through the recording microelectrode in the presence of GABAA receptor antagonists, broad spikes were frequently generated by activation of synaptic inputs (32 of 33 cells). These broad spikes were blocked by Cd2+ (200 μM) or in Ca2+-free medium (6 of 6 cells) but were resistant to either tetrodotoxin (TTX; 1 μM; 6 of 6 cells) or QX-314, whereas short-duration spikes were blocked by both TTX andQX-314. Based on these findings we conclude that broad and short-duration spikes are Ca2+ and Na+ spikes, respectively. To investigate the properties of the Ca2+ spikes, antagonists of a voltage-operated Ca2+ channel were applied to the evoked responses. Nifedipine (30 μM), a L-type Ca2+ channel blocker, suppressed the generation of Ca2+ spikes, whereas Ni2+ (100 μM), theT- and R-type Ca2+ channel blocker, and ω-agatoxin-IVA (ω-Aga-IVA, 60 nM), a P-type Ca2+ channel blocker, had little effect on the generation of Ca2+ spikes. Nifedipine suppressed the rise in [Ca2+]i induced by synaptic inputs up to 26% of the control in the soma and 18–32% in the dendrites ( n = 5), respectively, whereas Ni2+ suppressed the rise by 12–27% ( n = 5) in both soma and dendrites. ω-Aga-IVA showed little effect (less than a 10% change; n = 7). These results suggest that the GABAA inhibitory system tonically suppresses dendritic Ca2+ spikes, and the L-type Ca2+ channel plays a major role in the generation of Ca2+ spikes and in Ca2+ influx.
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Lee, Yongho, Shinil Chang, Jungah Kim, and Hyunchol Shin. "A CMOS RF Receiver with Improved Resilience to OFDM-Induced Second-Order Intermodulation Distortion for MedRadio Biomedical Devices and Sensors." Sensors 21, no. 16 (August 5, 2021): 5303. http://dx.doi.org/10.3390/s21165303.
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A MedRadio RF receiver integrated circuit for implanted and wearable biomedical devices must be resilient to the out-of-band (OOB) orthogonal frequency division modulation (OFDM) blocker. As the OFDM is widely adopted for various broadcasting and communication systems in the ultra-high frequency (UHF) band, the selectivity performance of the MedRadio RF receiver can severely deteriorate by the second-order intermodulation (IM2) distortion induced by the OOB OFDM blocker. An analytical investigation shows how the OFDM-induced IM2 distortion power can be translated to an equivalent two-tone-induced IM2 distortion power. It makes the OFDM-induced IM2 analysis and characterization process for a MedRadio RF receiver much simpler and more straightforward. A MedRadio RF receiver integrated circuit with a significantly improved resilience to the OOB IM2 distortion is designed in 65 nm complementary metal-oxide-semiconductor (CMOS). The designed RF receiver is based on low-IF architecture, comprising a low-noise amplifier, single-to-differential transconductance stage, quadrature passive mixer, trans-impedance amplifier (TIA), image-rejecting complex bandpass filter, and fractional phase-locked loop synthesizer. We describe design techniques for the IM2 calibration through the gate bias tuning at the mixer, and the dc offset calibration that overcomes the conflict with the preceding IM2 calibration through the body bias tuning at the TIA. Measured results show that the OOB carrier-to-interference ratio (CIR) performance is significantly improved by 4–11 dB through the proposed IM2 calibration. The measured maximum tolerable CIR is found to be between −40.2 and −71.2 dBc for the two-tone blocker condition and between −70 and −77 dBc for the single-tone blocker condition. The analytical and experimental results of this work will be essential to improve the selectivity performance of a MedRadio RF receiver against the OOB OFDM-blocker-induced IM2 distortion and, thus, improve the robustness of the biomedical devices in harsh wireless environments in the MedRadio and UHF bands.
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Zhang, Lu, Xing Ouyang, Xiaopeng Shao, and Jian Zhao. "Experimental demonstration of a real-time high-throughput digital DC blocker for compensating ADC imperfections in optical fast-OFDM receivers." Optics Express 24, no. 13 (June 15, 2016): 14215. http://dx.doi.org/10.1364/oe.24.014215.
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Gallemore, R. P., and R. H. Steinberg. "Light-evoked modulation of basolateral membrane Cl- conductance in chick retinal pigment epithelium: the light peak and fast oscillation." Journal of Neurophysiology 70, no. 4 (October 1, 1993): 1669–80. http://dx.doi.org/10.1152/jn.1993.70.4.1669.
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1. We studied the ionic mechanism of the light-peak voltage of the DC electroretinogram (DC ERG) in an in vitro preparation of chick neural retina-retinal pigment epithelium (RPE)-choroid. The light peak originates from a depolarization of the RPE basolateral (basal) membrane, associated with an increase in its conductance. Using conventional and Cl(-)-selective microelectrodes, we tested the hypothesis that the light-peak voltage is generated by an increase in Cl- conductance (gCl) of the basolateral (basal) membrane. 2. Perfusion of the RPE basal membrane with 4,4'-diisothiocyanostilbene-2,2'-disulfonate (DIDS), a known blocker of gCl in chick RPE, suppressed both the light-peak depolarization and the accompanying conductance increase of the basal membrane. 3. Using sustained transepithelial current to clamp the basal membrane potential at different levels, we estimated the reversal potential of the light peak. At membrane potentials above the equilibrium potential for Cl- (ECl = -40 +/- 10 mV mean +/- SE), light-peak polarity was reversed. Current-voltage (I-V) curves measured in the dark and at the peak of the light peak also gave a reversal potential in the same range as ECl. In addition, shifting ECl by changing intracellular Cl- (aCli) via passage of transepithelial current or perfusing the apical side of the RPE with the Cl- uptake blocker, furosemide, shifted the light-peak reversal potential in the same direction as the change in ECl. 4. The transference number for Cl-, TCl, was estimated from step decreases in basal Cl- and increased from 0.20 +/- 0.01 in the dark to 0.31 +/- 0.01 during the light peak. These results indicate an average increase of 55% in the relative conductance of the basal membrane for Cl-. 5. Light-evoked changes in aCli, measured with Cl(-)-selective microelectrodes, were too small to account for the change in basal membrane potential during the light peak. These data strongly support the hypothesis that the light peak originates from an increase in RPE basal membrane permeability to Cl-. 6. We also obtained support for the model of Joseph and Miller that the fast-oscillation trough of the DC ERG, generated by a delayed basal membrane hyperpolarization of the RPE, originates from light-evoked modulation of the Cl- transport pathway. Perfusing either the apical side of the RPE with furosemide or the basal side with DIDS suppressed the fast oscillation. The delayed basal hyperpolarization reversed polarity at membrane potentials positive to ECl.(ABSTRACT TRUNCATED AT 400 WORDS)
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Tapbergenov, S. O., B. S. Sovetov, A. T. Tapbergenov, and Elina Hahn. "Metabolic effects of combined introduction of adrenalin and blocker of methanoprolol beta-adrenophyleters." Biomeditsinskaya Khimiya 63, no. 2 (2017): 154–58. http://dx.doi.org/10.18097/pbmc20176302154.
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The effect of combined administration of adrenaline (0.4 mg/kg, i.p.) and b1-blocker metoprolol (25 mg/kg) on the activity of glutathione peroxidase (GPO), glutathione reductase (GR), catalase, adenosine deaminase (AD), AMP deaminase (AMPD), 5¢-nucleotidase (5¢N), on the level ofmalonic dialdehyde (MDA) and conjugated dienes (CD) was investigated. In blood adrenaline administration to animals caused an increase in the activity of AMPD, AD, 5¢N and GPO, and the increase the level of CD in the blood increases. Metoprolol caused a more pronounced increase in the activity of blood AMPD, AD, 5'N and the amount of CD. In contrast to adrenaline, metoprolol decreased the MDA level of, and decreased the activity of GPO and catalase. Combined administration of metoprolol and adrenaline to animals was accompanied by an increase in the activity of AD, AMPD, 5¢N, a decrease in the activity of GR, GPO, catalase, and a decrease in MDA in the blood. In the heart, adrenaline injection was accompanied by an increase in the MDA level, a decrease in 5¢N activity and an increase in the ratio of the activities of the enzymes AD+AMPD/5¢N. Metoprolol injection reduced MDA and CD levels and the activity of GR and GPO. The combined administration of metoprolol and adrenaline in the heart was accompanied by activation of AD, AMPD and 5¢N, and a decrease in the amount of MDA and CD, and a decrease in the activity of GR, GPO, and catalase. In the liver adrenaline caused an increase in MDA and DC levels, activation of catalase, AD, AMPD, and 5¢N. Metoprolol caused a decrease in MDA and CD levels and activity of catalase and GPO, an increase in the activity of AD and AMPD in the liver. Combined administration of adrenaline and metoprolol reduced manifestations of the heart and liver oxidative stress response as compared with administration of adrenaline alone.
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Hayashi, Mikio, Jing Wang, Susanne E. Hede, and Ivana Novak. "An intermediate-conductance Ca2+-activated K+ channel is important for secretion in pancreatic duct cells." American Journal of Physiology-Cell Physiology 303, no. 2 (July 15, 2012): C151—C159. http://dx.doi.org/10.1152/ajpcell.00089.2012.
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Potassium channels play a vital role in maintaining the membrane potential and the driving force for anion secretion in epithelia. In pancreatic ducts, which secrete bicarbonate-rich fluid, the identity of K+ channels has not been extensively investigated. In this study, we investigated the molecular basis of functional K+ channels in rodent and human pancreatic ducts (Capan-1, PANC-1, and CFPAC-1) using molecular and electrophysiological techniques. RT-PCR analysis revealed mRNAs for KCNQ1, KCNH2, KCNH5, KCNT1, and KCNT2, as well as KCNN4 coding for the following channels: KVLQT1; HERG; EAG2; Slack; Slick; and an intermediate-conductance Ca2+-activated K+ (IK) channel (KCa3.1). The following functional studies were focused on the IK channel. 5,6-Dichloro-1-ethyl-1,3-dihydro-2 H-benzimidazole-2-one (DC-EBIO), an activator of IK channel, increased equivalent short-circuit current ( Isc) in Capan-1 monolayer, consistent with a secretory response. Clotrimazole, a blocker of IK channel, inhibited Isc. IK channel blockers depolarized the membrane potential of cells in microperfused ducts dissected from rodent pancreas. Cell-attached patch-clamp single-channel recordings revealed IK channels with an average conductance of 80 pS in freshly isolated rodent duct cells. These results indicated that the IK channels may, at least in part, be involved in setting the resting membrane potential. Furthermore, the IK channels are involved in anion and potassium transport in stimulated pancreatic ducts.
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De Greve, Jacques, Teresa Moran, Marie-Pascale Graas, Daniella Galdermans, Peter Vuylsteke, Jean-Luc Canon, Vikram K. Chand, Yali Fu, Dan Massey, and Johan Vansteenkiste. "Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined non-small cell lung cancer (NSCLC) patients." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 8063. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.8063.
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8063 Background: EGFR mutation+ (M+) NSCLC pts have an improved response to EGFR TKIs vs non-M+ pts. Data on EGFR FISH+ (gene amplified) and HER2 M+ pts are, however, limited. Afatinib is an irreversible ErbB Family Blocker with efficacy in Ph II/III trials in EGFR M+ NSCLC. This exploratory, open-label trial assessed afatinib in 3 genotypically and demographically defined NSCLC groups. Methods: Never/ex-smokers with stage IIIB/IV lung adenocarcinoma with EGFR M+ tumors who had failed prior EGFR TKIs, HER2 M+ tumors independent of prior therapy, or EGFR FISH+ tumors who received ≤3 prior chemotherapies were enrolled. Afatinib 50 mg qd was administered until disease progression or intolerable adverse events. Tumor assessments (RECIST 1.0) were performed every 8 wks. Pts who progressed on afatinib but experienced clinical benefit could continue treatment with afatinib 40 mg qd + paclitaxel 80 mg/m² qw on days 1, 8 and 15 every 28-day cycle. Primary endpoint: Confirmed objective response. Results: 41 pts were treated: 63% female; median age 63 yrs; 68% never smokers; 32% ex-smokers. 33 pts received afatinib monotherapy only; 8 pts received afatinib followed by afatinib/paclitaxel combination therapy. 78% (n=32) of pts were EGFR M+, 5% (n=2) were EGFR FISH+ and 17% (n=7) were HER2 M+. For afatinib monotherapy, 1 confirmed partial response (PR) was observed (EGFR FISH+), stable disease (SD) was seen in 5/7 HER2 M+, 2/2 EGFR FISH+ and 17/32 EGFR M+ pts, and overall disease control (DC) rate was 59% (n=24); mean duration of DC was 26 wks.Median PFS was 16 wks (17 wks in HER2 M+ pts). Of 8 afatinib/paclitaxel-treated pts, 1 had a confirmed PR and 2 had SD; median PFS was 7 wks. Most frequently reported drug-related AEs in afatinib monotherapy pts were diarrhea (n=39; grade ≥3 n=13), rash/acne (n=33; grade ≥3 n=4) and stomatitis (n=19; grade ≥3 n=2). In the combination arm these were diarrhea (n=4; grade ≥3 n=1) and nausea (n=3; grade ≥3 n=0). Conclusions: Efficacy of afatinib in EGFR M+ NSCLC pts has been established in previous trials. Novel activity of afatinib in HER2 M+ and EGFR FISH+ NSCLC pts has been demonstrated here, with a manageable safety profile of afatinib in the overall population. Clinical trial information: NCT00730925.
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Rossi, Jean-Francois, Anne-Marie Conge, Catherine Barjot, Mohamed H. Zaki, Marian T. Nakada, Robert Corringham, and Bernard Klein. "Interterleukin-6 (IL-6) Produced by Monocyte Activation Reduces Dendritic Cell (DC) Differentiation in Patients with Multiple Myeloma (MM) and Malignant Lymphoma (ML): Role of CNTO 328, an Anti-IL-6 Monoclonal Antibody (Mab) and Possible Clinical Applications." Blood 104, no. 11 (November 16, 2004): 2662. http://dx.doi.org/10.1182/blood.v104.11.2662.2662.
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Abstract We developed a serum-free process in a closed system using culture cassettes and bags for large-scale and clinical-grade DC vaccination, accepted by the “Afssaps-French drug Agency” (Tarte K. et al. Leukemia2000; 14:2152 & patent). Intermediate mature DCs are generated from mononucleated cells obtained by mobilized leukapheresis, followed by Mo selection using adherence in specific cassettes (CLINIcell, Mabiol). Non-adherent cells are removed and Mo are cultured for 5 days (D) in X-VIVO15 medium (Cambrex) with 2% of human albumin, 100ng/ml of GM-CSF (Leukine, Berlex) and 25 ng/ml of IL-4 (CellGenix-Cellgen). At D5, immature DCs are harvested, pulsed with autologous tumor lysate (or peptides) for 4 h in X-VIVO15 medium + GM-CSF (100ng/ml) and maturation factors (TNF-α: 20ng/ml, CellGenix-CellGen, and PGE2: 100ng/ml; Prostine, Pharmacia). Maturation of DCs was allowed to proceed for 20 h with TNF-α and PGE2. Mo-conditioned media, or IL-6 as well as IL-1 are used for enhancing ex vivo DC maturation by different groups in spite of the fact that IL-6 has been described as a blocker of DC differentiation from CD34+ cells particularly in MM. We demonstrated that in our process, IL-6 is produced by activated Mo during their selection (mean= 378pg/mL, range 37–1219). The amount of the IL-6 released in the medium correlated with the % of CD14+ cells obtained at D5 (CD14<2.8%: mean IL-6=73.1 pg/mL; CD14>22.6%: mean IL-6=682.9 pg/mL), indicating that the intrinsic production of IL-6 is one major parameter of variability of the cellular product. By adding IL-6 from D1 to D5, the percentage of CD14+ cells at D5 was enhanced by a mean of 23-fold in samples from patients with MM (n=7) and 17-fold in ML (n=7). The modifications of other DCs markers including CD1a, CD 84 and CCR7 were modest. By using CNTO 328, an anti-IL-6 MAb (Centocor Inc) at 1–10μg/mL, we totally blocked the activity of added IL-6 and samples with high IL-6 intrinsic production, with a reduction of CD14+ cells at D5. In contrast, neither IL-6 nor CNTO 328 had any activity on terminal DC maturation after D5. IL-6 and CNTO328 are tested on DC functions. This means that in B-cell malignancies and other solid tumors with high levels of circulating IL-6: 1) anti-IL-6 treatment such as CNTO 328 may be associated with active immune therapy, including vaccinations; 2) mature and intermediate mature DCs are the only cells to be administered in vaccination programs because of a de-differentiation effect of immature DCs due to IL-6; 3) anti-IL-6 MAbs, particularly CNTO 328 could be added for ex vivo DC differentiation, instead of IL-6. mean % (range) of CD14+ cells at Day5 samples MM ML Control 2.9 (0.1–7.1) 12.2 (0–44.8) IL-6 (100ng/mL) 20 (6–35) 34.2 (0–71.4) IL-6+CNTO328 1μg/mL 2.8 (0.5–7.5) 15.7 (0–45.6) IL-6+CNTO328 10μg/mL 0.4 (0–0.8) 6.8 (0–20.3) CNTO328 1μg/mL 0.4 (0.1–0.7) 6.5 (0–19.5) CNTO328 10μg/mL 0.2 (0–0.4) 5.3 (0–15.3)
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RICHEZ, CHRISTOPHE, THOMAS BARNETCHE, LILIANE KHORYATI, PIERRE DUFFAU, MARIE KOSTINE, CÉCILE CONTIN-BORDES, PATRICK BLANCO, and THIERRY SCHAEVERBEKE. "Tocilizumab Treatment Decreases Circulating Myeloid Dendritic Cells and Monocytes, 2 Components of the Myeloid Lineage." Journal of Rheumatology 39, no. 6 (April 1, 2012): 1192–97. http://dx.doi.org/10.3899/jrheum.111439.
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Objective.Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) are proinflammatory cytokines involved in inflammatory response. Effective TNF-α blocker treatment is associated with an increase in circulating myeloid dendritic cells (mDC), suggesting their release from inflamed synovium. Currently, in vivo effects of IL-6 inhibition on DC are unknown. We monitored the changes in circulating mDC and plasmacytoid DC (pDC) during tocilizumab (TCZ) therapy in patients with rheumatoid arthritis (RA).Methods.DC subset levels were evaluated by flow cytometry in patients with RA (n = 43) and in healthy volunteers (n = 20). In patients with RA, these levels were measured before and during TCZ therapy (8 mg/kg every 4 weeks). Response to TCZ therapy was evaluated at 12 weeks. Statistical analysis was based on Mann-Whitney U tests or Wilcoxon signed-rank tests.Results.At baseline, patients with active RA were characterized by a significantly lower level of circulating mDC and pDC compared to healthy donors. However, this difference did not correlate with any disease activity score. TCZ-treated patients who met the European League Against Rheumatism (EULAR) improvement criteria at Week 12 had significant reductions in mDC and monocyte levels as compared with EULAR nonresponders. Levels of pDC, CD4+ T cells, and CD8+ T cells remained stable during the TCZ courses, regardless of treatment response.Conclusion.Our study reveals an unexpected reduction of circulating mDC and monocytes in patients with RA in response to TCZ therapy. In accord with reports on neutrophils and platelets decreasing during TCZ therapy, our data suggest an effect of IL-6 inhibition on cells from myeloid lineage.
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Heise, Nicole, Ekaterina Shumilina, Meerim K. Nurbaeva, Evi Schmid, Kalina Szteyn, Wenting Yang, Nguyen Thi Xuan, et al. "Effect of dexamethasone on Na+/Ca2+exchanger in dendritic cells." American Journal of Physiology-Cell Physiology 300, no. 6 (June 2011): C1306—C1313. http://dx.doi.org/10.1152/ajpcell.00396.2010.
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Ca+-dependent signaling regulates the function of dendritic cells (DCs), antigen-presenting cells linking innate and adaptive immunity. The activity of DCs is suppressed by glucocorticoids, potent immunosuppressive hormones. The present study explored whether the glucocorticoid dexamethasone influences the cytosolic Ca2+concentration ([Ca2+]i) in DCs. To this end, DCs were isolated from mouse bone marrow. According to fura-2 fluorescence, exposure of DCs to lipopolysaccharide (LPS, 100 ng/ml) increased [Ca2+]i, an effect significantly blunted by overnight incubation with 10 nM dexamethasone before LPS treatment. Dexamethasone did not affect the Ca2+content of intracellular stores, sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2 and SERCA3 expression, ryanodine receptor (RyR)1 expression, or Ca2+entry through store-operated Ca2+channels. In contrast, dexamethasone increased the transcript level and the membrane protein abundance of the Na+/Ca2+exchanger NCX3. The activity of Na+/Ca2+exchangers was assessed by removal of extracellular Na+in the presence of external Ca2+, a maneuver triggering the Ca2+influx mode. Indeed, Na+removal resulted in a rapid transient increase of [Ca2+]iand induced an outwardly directed current as measured in whole cell patch-clamp experiments. Dexamethasone significantly augmented the increase of [Ca2+]iand the outward current following removal of extracellular Na+. The NCX blocker KB-R7943 reversed the inhibitory effect of dexamethasone on LPS-induced increase in [Ca2+]i. Dexamethasone blunted LPS-induced stimulation of CD86 expression and TNF-α production, an effect significantly less pronounced in the presence of NCX blocker KB-R7943. In conclusion, our results show that glucocorticoid treatment blunts LPS-induced increase in [Ca2+]iin DCs by increasing expression and activity of Na+/Ca2+exchanger NCX3. The effect contributes to the inhibitory effect of the glucocorticoid on DC maturation.
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Valverde, P., T. Kawai, and M. A. Taubman. "Potassium Channel-blockers as Therapeutic Agents to Interfere with Bone Resorption of Periodontal Disease." Journal of Dental Research 84, no. 6 (June 2005): 488–99. http://dx.doi.org/10.1177/154405910508400603.
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Inflammatory lesions of periodontal disease contain all the cellular components, including abundant activated/memory T- and B-cells, necessary to control immunological interactive networks and to accelerate bone resorption by RANKL-dependent and -independent mechanisms. Blockade of RANKL function has been shown to ameliorate periodontal bone resorption and other osteopenic disorders without affecting inflammation. Development of therapies aimed at decreasing the expression of RANKL and pro-inflammatory cytokines by T-cells constitutes a promising strategy to ameliorate not only bone resorption, but also inflammation. Several reports have demonstrated that the potassium channels Kv1.3 and IKCa1, through the use of selective blockers, play important roles in T-cell-mediated events, including T-cell proliferation and the production of pro-inflammatory cytokines. More recently, a potassium channel-blocker for Kv1.3 has been shown to down-regulate bone resorption by decreasing the ratio of RANKL-to-OPG expression by memory-activated T-cells. In this article, we first summarize the mechanisms by which chronically activated/memory T-cells, in concert with B-cells and macrophages, trigger inflammatory bone resorption. Then, we describe the main structural and functional characteristics of potassium channels Kv1.3 and IKCa1 in some of the cells implicated in periodontal disease progression. Finally, this review elucidates some recent advances in the use of potassium channel-blockers of Kv1.3 and IKCa1 to ameliorate the clinical signs or side-effects of several immunological disorders and to decrease inflammatory bone resorption in periodontal disease. ABBREVIATIONS: AICD, activation-induced cell death; APC, antigen-presenting cells; B(K), large conductance; CRAC, calcium release-activated calcium channels; DC, dendritic cell; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IFN-γ, interferon-γ; IP3, inositol (1,4,5)-triphosphate; (K)ir, inward rectifier; JNK, c-Jun N-terminal kinase; I(K), intermediate conductance; LPS, lipopolysaccharide; L, ligand; MCSF, macrophage colony-stimulating factor; MHC, major histocompatibility complex; NFAT, nuclear factor of activated T-cells; RANK, receptor activator of nuclear factor-κB; TCM, central memory T-cells; TEM, effector memory T-cells; TNF, tumor necrosis factor; TRAIL, TNF-related apoptosis-inducing ligand; OPG, osteoprotegerin; Omp29, 29-kDa outer membrane protein; PKC, protein kinase C; PLC, phospholipase C; RT-PCR, reverse-transcriptase polymerase chain-reaction; S(K), small conductance; TCR, T-cell receptor; and (K)v, voltage-gated.
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Islam, S. M. Shamsul, Hae-Ok Byun, Bunsoon Choi, and Seonghyang Sohn. "Inhibition of CD83 Alleviates Systemic Inflammation in Herpes Simplex Virus Type 1-Induced Behçet’s Disease Model Mouse." Mediators of Inflammation 2019 (September 9, 2019): 1–15. http://dx.doi.org/10.1155/2019/5761392.
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Behçet’s disease (BD) is an autoinflammatory disease that can lead to life- and sight-threating complications. Dendritic cells (DCs) are the most potent antigen-presenting cells that can regulate multiple inflammatory pathways. The objective of this study was to investigate the association of the DC stimulatory molecule CD83 with BD. Frequencies of costimulatory molecules expressing DCs in peripheral blood leukocytes (PBL) were measured by flow cytometry (FACS). The severity of symptoms in HSV-1-induced BD symptomatic mice was also assessed. Frequencies of CD83-positive cells were significantly increased in mice exhibiting BD symptoms, compared to those in asymptomatic mice. Abatacept, a CD80/86 blocker, significantly decreased the frequencies of CD83-positive cells in a time- and dose-dependent manner. BD symptomatic mice treated with Abatacept showed gradual reduction in the severity score of symptoms. Intraperitoneal injection of CD83 siRNA significantly reduced the frequencies of CD83-positive cells in PBL and peritoneal macrophages. After CD83 siRNA injection, BD symptoms of mice were improved and disease severity was decreased. Discontinuation of CD83 siRNA deteriorated symptoms while readministration of CD83 siRNA again improved BD symptoms of mice. These results clearly indicate the involvement of CD83-expressing cells in the inflammatory symptoms of BD. Therefore, CD83 might be useful as a therapeutic target for BD.
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Ferrari, Davide, Paola Chiozzi, Simonetta Falzoni, Stefania Hanau, and Francesco Di Virgilio. "Purinergic Modulation of Interleukin-1β Release from Microglial Cells Stimulated with Bacterial Endotoxin." Journal of Experimental Medicine 185, no. 3 (February 3, 1997): 579–82. http://dx.doi.org/10.1084/jem.185.3.579.
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Microglial cells express a peculiar plasma membrane receptor for extracellular ATP, named P2Z/P2X7 purinergic receptor, that triggers massive transmembrane ion fluxes and a reversible permeabilization of the plasma membrane to hydrophylic molecules of up to 900 dalton molecule weight and eventual cell death (Di Virgilio, F. 1995. Immunol. Today. 16:524–528). The physiological role of this newly cloned (Surprenant, A., F. Rassendren, E. Kawashima, R.A. North and G. Buell. 1996. Science (Wash. DC). 272:735–737) cytolytic receptor is unknown. In vitro and in vivo activation of the macrophage and microglial cell P2Z/P2X7 receptor by exogenous ATP causes a large and rapid release of mature IL-1β. In the present report we investigated the role of microglial P2Z/P2X7 receptor in IL-1β release triggered by LPS. Our data suggest that LPS-dependent IL-1β release involves activation of this purinergic receptor as it is inhibited by the selective P2Z/P2X7 blocker oxidized ATP and modulated by ATP-hydrolyzing enzymes such as apyrase or hexokinase. Furthermore, microglial cells release ATP when stimulated with LPS. LPS-dependent release of ATP is also observed in monocyte-derived human macrophages. It is suggested that bacterial endotoxin activates an autocrine/paracrine loop that drives ATP-dependent IL-1β secretion.
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Newman, William J., Glen L. Xiong, and Amy V. Barnhorst. "Beta-Blockers." Psychopharm Review 48, no. 10 (October 2013): 73–80. http://dx.doi.org/10.1097/01.psyphr.0000436763.15959.dc.
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Salama, G., R. Lombardi, and J. Elson. "Maps of optical action potentials and NADH fluorescence in intact working hearts." American Journal of Physiology-Heart and Circulatory Physiology 252, no. 2 (February 1, 1987): H384—H394. http://dx.doi.org/10.1152/ajpheart.1987.252.2.h384.
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Voltage-sensitive dyes were used to stain intact perfused hearts and to simultaneously measure optical action potentials (APs) from 124 sites on the epicardium. Patterns of electrical depolarization (activation) and repolarization (recovery) along the surface of the heart were determined from the upstrokes and repolarization phases of optical APs. Standard surface extracellular techniques can detect electrical activation but not the recovery or the duration of APs. The optical recordings were previously shown to be equivalent to intracellular electrode measurements (Salama and Morad, Science Wash. DC 191: 485–487, 1976) and now reveal that AP durations are heterogeneous throughout the epicardium, with durations increasing from the base to the apex of the ventricles. In hearts beating under normal sinus rhythm, the direction and conduction velocity of the activation waves could be altered by electrical stimulation. The normal heterogeneities in AP durations became more pronounced in the presence of the Ca2+-entry blocker, verapamil. The local metabolic state of the tissue was also monitored optically through its intrinsic NADH fluorescence measured from 124 separate regions on the heart. The time course and extent of metabolic injury caused by general anoxia or by a local ischemia induced by a coronary ligation was monitored through maps of NADH fluorescence. The present technique makes it possible to correlate changes in the metabolic state of the muscle with detailed changes in patterns of electrical activity and thus provides a powerful new tool to study fundamental aspects of normal and abnormal cardiac rhythm.
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Bisenic, Vesna, Sasa Hinic, Mirjana Krotin, Branislav Milovanovic, Jelena Saric, and Goran Milasinovic. "Brugada syndrome: Case report." Srpski arhiv za celokupno lekarstvo 140, no. 1-2 (2012): 84–90. http://dx.doi.org/10.2298/sarh1202084b.
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Introduction. Brugada syndrome is an arrhythmogenic disease characterized by coved ST segment elevation and J point elevation of at least 2 mm in at least two of the right precordial ECG leads (V1-3) and ventricular arrhythmias, syncope, and sudden death. Risk stratifications of patients with Brugada electrocardiogram are being strongly debated. Case Outline. A 23-year-old man was admitted to the Coronary Care Unit of the Clinical Centre ?Bezanijska kosa? due to weakness, fatigue and chest discomfort. The patient suffered from fainting and palpitations. There was a family history of paternal sudden death at 36 years. Electrocardiogram showed a coved ST segment elevation of 4 mm in leads V1 and V2, recognised as spontaneous type 1 Brugada pattern. Laboratory investigations revealed normal serum cardiac troponin T and serum potassium, and absence of inflammation signs. Echocardiographic finding was normal, except for a mild enlargement of the right atrium and ventricle. The diagnosis of Brugada syndrome was made by Brugada-type 1 electrocardiogram and the family history of sudden death <45 years. The patient was considered as a high risk, because of pre-syncope and palpitations. He underwent ICD implantation (Medtronic MaximoVR7232Cx) using the standard procedure. After implantation, noninvasive electrophysiology study was done and demonstrated inducible VF that was interrupted with the second 35 J DC shock. The patient was discharged in stable condition with beta-blocker therapy. After a year of pacemaker check-ups, there were no either VT/ VF events or ICD therapy. Conclusion. Clinical presentation is the most important parameter in risk stratification of patients with Brugada electrocardiogram and Brugada syndrome.
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Nair, Jayakumar R., Louise M. Carlson, Noreen Ersing, Asher Alban Chanan-Khan, and Kelvin P. Lee. "Survival Signals, Growth Cytokines, Immunosuppressive Factors and Their Cellular Perpetrators in the Myeloma Tumor Microenvironment." Blood 112, no. 11 (November 16, 2008): 1664. http://dx.doi.org/10.1182/blood.v112.11.1664.1664.
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Abstract Multiple myeloma (MM) is an incurable neoplasia of terminally differentiated plasma cells in the bone marrow. Essential interactions of MM cells with host bone marrow stromal cells (BMSC) induce growth factors essential for MM progression and pathogenesis, as well as induce an immunosuppressive environment that inhibits endogenous and therapeutically-induced immune responses against the MM cells. However, despite their importance, little is known about the identity of these BMSC cells or the molecular basis of their interaction with myeloma cells. A potential MM surface protein that could be involved in these interactions is CD28, based on its known pro-survival role in T cells. Clinical studies have shown that expression of CD28 in multiple myeloma highly correlates (p=0.006) with myeloma disease progression. Moreover, CD28+ MM cells invariably express the CD28 ligand CD86. A survival role for MM-CD28 might involve interactions with cellular partners that express the B7 (CD80/CD86) ligands. Potential candidates would include CD86+ myeloma cells themselves or B7+ dendritic cells (DC) that are known to be closely associated with myeloma cells in the patient bone marrow. When myeloma-myeloma interactions were disrupted by using the high affinity CD80/CD86 blocker CTLA4Ig (Abatacept®), increased sensitivity to arsenic trioxide (ATO) and melphalan (MEL) was observed in all the three MM cell lines U266, RPMI8226 and MM1S. For U266 viability was 93% in media alone, 84% with CTLA4Ig (100 μg/ml) alone, 86% with 2 μM ATO alone and was significantly reduced to 36% with CTLA4Ig + ATO. Similar drops in viability were observed with 25 μM MEL in combination with CTLA4Ig (33% as opposed to 71–74 % with CTLA4Ig or MEL alone). Our data suggests that this does not involve the downregulation of anti-apoptotic proteins Bcl-2, Bcl-xL or Mcl-1, commonly associated with drug resistance in myeloma. In the second part of the study, we demonstrate that myeloma cell lines or primary CD138+ myeloma cells can enhance via direct contact the ability of human monocyte derived immature DC to produce the immunosuppressive tryptophan depleting enzyme indoleamine 2,3 dioxygenase (IDO, as estimated by kynurenine (Kyn) (a tryptophan catabolite) levels in the supernatant) and also the pro-plasma cell survival cytokine IL-6. In co-cultures of IFNg treated immature DCs with either MM cell lines or with primary CD138+ myeloma cells from patient BM aspirates, the activity of IDO was enhanced ~ 2–8 fold (81 mM kyn with U266 and 20–43mM with primary cells) over that observed in control IFNg-treated DCs (9.7 mM Kyn). Western analysis also demonstrated increased IDO expression relative to IFNg activated DC controls. Blocking MM-CD28 with (Fab)2 fragments of anti-hCD28 mAb 9.3 downregulated IDO activity (9.3 mM) close to that of control, demonstrating the involvement of MM-CD28 in these interactions. We also demonstrated a significant up-regulation of the pro-myeloma survival cytokine IL-6 when immature DCs were co-cultured with CD28+ MM1S (90–300 pg/ml), a 4–9 fold increase over that of DC only control (25 – 35 pg/ml). This was further enhanced when immature DCs cultured with IL-10 (+ GM-CSF + IL-4) was used in co-cultures with MM-1S (800 – 1300 pg/ml), or with primary CD138+ myeloma cells from patient bone marrow aspirates (128–1142 pg/ml). In conclusion, our data demonstrates that blocking myeloma-CD28 - myeloma-CD86 “autocrine” interaction can enhance drug cytotoxicity, while interactions with DCs produce the essential growth cytokines IL-6 and immunosuppressive enzyme IDO with potential implications in MM survival and immune escape. Use of clinically approved agents (e.g. Abatacept®) to block myeloma-CD28 binding to its B7 ligands (increase chemotherapeutic efficacy), 1-MT to inhibit IDO and targeting DCs in the microenvironment to disrupt the tumor microenvironment could be viable therapeutic strategies for the future treatment of multiple myeloma.
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Zhang, Si Yi, Donald Robertson, Graeme Yates, and Alan Everett. "Role of L-Type Ca2+ Channels in Transmitter Release From Mammalian Inner Hair Cells I. Gross Sound-Evoked Potentials." Journal of Neurophysiology 82, no. 6 (December 1, 1999): 3307–15. http://dx.doi.org/10.1152/jn.1999.82.6.3307.
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Intracochlear perfusion and gross potential recording of sound-evoked neural and hair cell responses were used to study the site of action of the L-type Ca2+ channel blocker nimodipine in the guinea pig inner ear. In agreement with previous work nimodipine (1–10 μM) caused changes in both the compound auditory nerve action potential (CAP) and the DC component of the hair cell receptor potential (summating potential, or SP) in normal cochleae. For 20-kHz stimulation, the effect of nimodipine on the CAP threshold was markedly greater than the effect on the threshold of the negative SP. This latter result was consistent with a dominant action of nimodipine at the final output stage of cochlear transduction: either the release of transmitter from inner hair cells (IHCs) or the postsynaptic spike generation process. In animals in which the outer hair cells (OHCs) had been destroyed by prior administration of kanamycin, nimodipine still caused a large change in the 20-kHz CAP threshold, but even less change was observed in the negative SP threshold than in normal cochleae. When any neural contamination of the SP recording in kanamycin-treated animals was removed by prior intracochlear perfusion with TTX, nimodipine caused no significant change in SP threshold. Some features of the data also suggest a separate involvement of nimodipine-sensitive channels in OHC function. Perfusion of the cochlea with solutions containing Ni2+ (100 μM) caused no measurable change in either CAP or SP. These results are consistent with, but do not prove, the notion that L-type channels are directly involved in controlling transmitter release from the IHCs and that T-type Ca2+channels are not involved at any stage of cochlear transduction.
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Ahn, Hee-Ran, and Bum-Man Kim. "Perfectly-Matched DC Blocks Terminated in Arbitrary Impedances." Journal of Korean Institute of Electromagnetic Engineering and Science 18, no. 8 (August 31, 2007): 895–903. http://dx.doi.org/10.5515/kjkiees.2007.18.8.895.
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Shumilina, Ekaterina, Meerim K. Nurbaeva, Wenting Yang, Evi Schmid, Kalina Szteyn, Antonella Russo, Nicole Heise, et al. "Altered regulation of cytosolic Ca2+ concentration in dendritic cells from klotho hypomorphic mice." American Journal of Physiology-Cell Physiology 305, no. 1 (July 1, 2013): C70—C77. http://dx.doi.org/10.1152/ajpcell.00355.2012.
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The function of dendritic cells (DCs), antigen-presenting cells regulating naïve T-cells, is regulated by cytosolic Ca2+ concentration ([Ca2+]i). [Ca2+]i is increased by store-operated Ca2+ entry and decreased by K+-independent (NCX) and K+-dependent (NCKX) Na+/Ca2+ exchangers. NCKX exchangers are stimulated by immunosuppressive 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the biologically active form of vitamin D. Formation of 1,25(OH)2D3 is inhibited by the antiaging protein Klotho. Thus 1,25(OH)2D3 plasma levels are excessive in Klotho-deficient mice ( klotho hm). The present study explored whether Klotho deficiency modifies [Ca2+]i regulation in DCs. DCs were isolated from the bone marrow of klotho hm mice and wild-type mice ( klotho+/+) and cultured for 7–9 days with granulocyte-macrophage colony-stimulating factor. According to major histocompatibility complex II (MHC II) and CD86 expression, differentiation and lipopolysaccharide (LPS)-induced maturation were similar in klotho hm DCs and klotho+/+ DCs. However, NCKX1 membrane abundance and NCX/NCKX-activity were significantly enhanced in klotho hm DCs. The [Ca2+]i increase upon acute application of LPS (1 μg/ml) was significantly lower in klotho hm DCs than in klotho+/+ DCs, a difference reversed by the NCKX blocker 3′,4′-dichlorobenzamyl (DBZ; 10 μM). CCL21-dependent migration was significantly less in klotho hm DCs than in klotho+/+ DCs but could be restored by DBZ. NCKX activity was enhanced by pretreatment of klotho+/+ DC precursors with 1,25(OH)2D3 the first 2 days after isolation from bone marrow. Feeding klotho hm mice a vitamin D-deficient diet decreased NCKX activity, augmented LPS-induced increase of [Ca2+]i, and enhanced migration of klotho hm DCs, thus dissipating the differences between klotho hm DCs and klotho+/+ DCs. In conclusion, Klotho deficiency upregulates NCKX1 membrane abundance and Na+/Ca2+-exchange activity, thus blunting the increase of [Ca2+]i following LPS exposure and CCL21-mediated migration. The effects are in large part due to excessive 1,25(OH)2D3 formation.
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Baribaud, Frédéric, Stefan Pöhlmann, George Leslie, Frank Mortari, and Robert W. Doms. "Quantitative Expression and Virus Transmission Analysis of DC-SIGN on Monocyte-Derived Dendritic Cells." Journal of Virology 76, no. 18 (September 15, 2002): 9135–42. http://dx.doi.org/10.1128/jvi.76.18.9135-9142.2002.
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ABSTRACT The C-type lectins DC-SIGN and DC-SIGNR efficiently bind human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) strains and can transmit bound virus to adjacent CD4-positive cells. DC-SIGN also binds efficiently to the Ebola virus glycoprotein, enhancing Ebola virus infection. DC-SIGN is thought to be responsible for the ability of dendritic cells (DCs) to capture HIV and transmit it to T cells, thus promoting HIV dissemination in vitro and perhaps in vivo as well. To investigate DC-SIGN function and expression levels on DCs, we characterized a panel of monoclonal antibodies (MAbs) directed against the carbohydrate recognition domain of DC-SIGN. Using quantitative fluorescence-activated cell sorter technology, we found that DC-SIGN is highly expressed on immature monocyte-derived DCs, with at least 100,000 copies and often in excess of 250,000 copies per DC. There was modest variation (three- to fourfold) in DC-SIGN expression levels between individuals and between DCs isolated from the same individual at different times. Several MAbs efficiently blocked virus binding to cell lines expressing human or rhesus DC-SIGN, preventing HIV and SIV transmission. Interactions with Ebola virus pseudotypes were also blocked efficiently. Despite their ability to block virus-DC-SIGN interactions on cell lines, these antibodies only inhibited transmission of virus from DCs by approximately 50% or less. These results indicate that factors other than DC-SIGN may play important roles in the ability of DCs to capture and transmit HIV.
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Uehori, Junji, Misako Matsumoto, Shoutaro Tsuji, Takashi Akazawa, Osamu Takeuchi, Shizuo Akira, Tsutomu Kawata, Ichiro Azuma, Kumao Toyoshima, and Tsukasa Seya. "Simultaneous Blocking of Human Toll-Like Receptors 2 and 4 Suppresses Myeloid Dendritic Cell Activation Induced by Mycobacterium bovis Bacillus Calmette-Guérin Peptidoglycan." Infection and Immunity 71, no. 8 (August 2003): 4238–49. http://dx.doi.org/10.1128/iai.71.8.4238-4249.2003.
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ABSTRACT The Mycobacterium bovis bacillus Calmette-Guérin (BCG) cell wall skeleton (CWS) consists of mycolic acids, arabinogalactan, and peptidoglycan (PGN) and activates Toll-like receptor 2 (TLR2) and TLR4. Here we investigated the ability of the essential portion of highly purified BCG CWS to support the TLR agonist function by using the following criteria: myeloid dendritic cell (DC) maturation, i.e., tumor necrosis factor alpha (TNF-α) production and CD83/CD86 up-regulation. The purified PGN region was sufficient to activate TLR2 and TLR4 in mouse DCs and macrophages; in TLR2 and TLR4 double-knockout cells the BCG PGN-mediated TNF-α production ability was completely impaired. Likewise, stimulation with BCG CWS of HEK293 cells expressing either human TLR2 or TLR4, MD-2, and CD14 resulted in NF-κB activation as determined by a reporter assay. Notably, specific blockers of extracellular human TLR2 (an original cocktail of monoclonal antibodies TLR2.45 and TH2.1) and TLR4 (E5531) inhibited BCG CWS-mediated NF-κB activation by 80%. Using this human TLR blocking system, we tested whether human myeloid DC maturation was TLR2 and TLR4 dependent. BCG PGN-mediated DC maturation was blocked by 70% by suppression of both TLR2 and TLR4 and by 30 to 40% by suppression of either of these TLRs. Similar but less profound suppression of BCG CWS-mediated DC maturation was observed. Hence, the presence of BCG PGN is a minimal requirement for activation of both TLR2 and TLR4 in human DCs, unlike the presence of PGNs of gram-positive bacteria, which activate only TLR2. Unexpectedly, however, BCG PGN, unlike BCG CWS, barely activated NF-κB in HEK293 cells coexpressing TLR2 plus TLR1, TLR2 plus TLR4, TLR2 plus TLR6, or TLR2 plus TLR10, suggesting that PGN receptors other than TLR2 and TLR4 present on human DCs but not on HEK293 cells are involved in TLR signaling for DC activation.
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Largo, Carlota, Geoffrey C. Tombaugh, Peter G. Aitken, Oscar Herreras, and George G. Somjen. "Heptanol But Not Fluoroacetate Prevents the Propagation of Spreading Depression in Rat Hippocampal Slices." Journal of Neurophysiology 77, no. 1 (January 1, 1997): 9–16. http://dx.doi.org/10.1152/jn.1997.77.1.9.
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Largo, Carlota, Geoffrey C. Tombaugh, Peter G. Aitken, Oscar Herreras, and George G. Somjen. Heptanol but not fluoroacetate prevents the propagation of spreading depression in rat hippocampal slices. J. Neurophysiol. 77: 9–16, 1997. We investigated whether heptanol and other long-chain alcohols that are known to block gap junctions interfere with the generation or the propagation of spreading depression (SD). Waves of SD were triggered by micro-injection of concentrated KCl solution in stratum (s.) radiatum of CA1 of rat hippocampal tissue slices. DC-coupled recordings of extracellular potential ( V o) were made at the injection and at a second site ∼1 mm distant in st. radiatum and sometimes also in st. pyramidale. Extracellular excitatory postsynaptic potentials (fEPSPs) were evoked by stimulation of the Schaffer collateral bundle; in some experiments, antidromic population spikes were evoked by stimulation of the alveus. Bath application of 3 mM heptanol or 5 mM hexanol completely and reversibly prevented the propagation of the SD-related potential shift (Δ V o) without abolishing the Δ V o at the injection site. Octanol (1 mM) had a similar but less reliably reversible effect. fEPSPs were depressed by ∼30% by heptanol and octanol, 65% by hexanol. Antidromic population spikes were depressed by 30%. In isolated, patch-clamped CA1 pyramidal neurons, heptanol partially and reversibly depressed voltage-dependent Na currents possibly explaining the slight depression of antidromic spikes and, by acting on presynaptic action potentials, also the depression of fEPSPs. Fluoroacetate (FAc), a putative selective blocker of glial metabolism, first induced multiple spike firing in response to single afferent volleys and then severely suppressed synaptic transmission (confirming earlier reports) without depressing the antidromic population spike. FAc did not inhibit SD propagation. The effect of alkyl alcohols is compatible with the idea that the opening of normally closed neuronal gap junctions is required for SD propagation. Alternative possible explanations include interference with the lipid phase of neuron membranes. The absence of SD inhibition by FAc confirms that synaptic transmission is not necessary for the propagation of SD, and it suggests that normally functioning glial cells are not essential for SD generation or propagation.
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Liu, Jifeng, Xiaoning Zhong, Zhiyi He, Jianquan Zhang, Jing Bai, Guangnan Liu, Yi Liang, Leilei Ya, and Xianglin Qin. "Erythromycin Suppresses the Cigarette Smoke Extract-Exposed Dendritic Cell-Mediated Polarization of CD4+ T Cells into Th17 Cells." Journal of Immunology Research 2020 (January 21, 2020): 1–9. http://dx.doi.org/10.1155/2020/1387952.
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Cigarette smoke is a major effector of chronic obstructive pulmonary disease (COPD), and Th17 cells and dendritic cells (DCs) involve in the pathogenesis of COPD. Previous studies have demonstrated the anti-inflammatory effects of macrolides. However, the effects of macrolides on the cigarette smoke extract- (CSE-) induced immune response are unclear. Accordingly, in this study, we evaluated the effects of erythromycin (EM) on CSE-exposed DCs polarizing naïve CD4+ T cells into Th17 cells. DCs were generated from bone marrow-derived mononuclear cells isolated from male BALB/c mice and divided into five groups: control DC group, CSE-exposed DC group, CD40-antibody-blocked CSE-exposed DC group, and EM-treated CSE-exposed DC group. The function of polarizing CD4+ T cells into Th17 cells induced by all four groups of DCs was assayed based on the mixed lymphocyte reaction (MLR) of naïve CD4+ T cells. CD40 expression in DCs in the CSE-exposed group increased significantly compared with that in the control group (P<0.05). The Th17 cells in the CSE-exposed DC/MLR group increased significantly compared with those in the control DC/MLR group (P<0.05). Moreover, Th17 cells in the CD40-blocked CSE-exposed DC/MLR group and EM-treated CSE-exposed DC/MLR group were reduced compared with those in the CSE-exposed DC/MLR group (P<0.05). Thus, these findings suggested that EM suppressed the CSE-exposed DC-mediated polarization of CD4+ T cells into Th17 cells and that this effect may be mediated through inhibition of the CD40/CD40L pathway.
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Green, J., and R. Jotte. "Interactions between T helper cells and dendritic cells during the rat mixed lymphocyte reaction." Journal of Experimental Medicine 162, no. 5 (November 1, 1985): 1546–60. http://dx.doi.org/10.1084/jem.162.5.1546.
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This paper describes the interactions between dendritic cells (DC) and T helper (Th) cells in the rat mixed lymphocyte reaction (MLR). Th blasts that are actively proliferating were generated in a 5 d primary MLR; resting Th memory cells were derived from a 10-12 d MLR. The DC were purified from thoracic duct lymph derived from rats whose mesenteric lymph nodes had been removed. The results show that DC are the major stimulators in the primary MLR and also for the restimulation of Th blasts and Th memory cells. Th blasts rapidly formed large clusters when cultured with DC but not with Ia+ macrophages or B cells. This interaction was not dependent on a major histocompatibility complex (MHC) difference between the T blasts and the DC. Con A-activated T and B blasts also formed clusters when cultured with DC. Th memory cells formed small clusters with DC, but, in a different assay in which clusters are dispersed, we detected an antigen-specific interaction between Th memory cells and DC. The monoclonal antibodies W3/25 (anti-rat CD4) and MRC OX-6 (anti-MHC class II) blocked proliferation in the primary MLR and also inhibited the restimulation of Th memory cells. However, the restimulation of Th blasts in a secondary MLR was only blocked by MRC OX-6. These results suggest that there are different requirements for the restimulation of T blasts than for the activation of primary or memory Th cells. W3/25 and MRC OX-6 did not affect the clustering of T blasts with DC but they both inhibited the antigen-specific binding of Th memory cells to DC. The data suggest that the CD4 (W3/25) antigen is involved in antigen-specific interactions between Th cells and DC.
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Galy, Anne, Indu Christopherson, Guido Ferlazzo, Guo Liu, Hergen Spits, and Katia Georgopoulos. "Distinct signals control the hematopoiesis of lymphoid-related dendritic cells." Blood 95, no. 1 (January 1, 2000): 128–37. http://dx.doi.org/10.1182/blood.v95.1.128.
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Abstract The molecular and cellular requirements for the development of different populations of human dendritic cells (DC) were studied. Conditions were defined that support DC production from lymphoid progenitors but that fail to induce DC formation from peripheral monocytes. The production of these lymphoid-related DC was severely blocked when hematopoietic progenitors overexpressed Ik7, a mutant dominant-negative Ikaros protein. In contrast, Ik7 did not block the formation of DC in conditions supporting the development of monocyte-derived DC. Furthermore, Ik7 did not block the formation of monocyte/macrophages and enhanced granulopoiesis. One of the molecular mechanisms mediated by Ik7 appears to be down-regulation of the flt3-receptor mRNA. Thus, distinct signals control the formation of DC demonstrating that some aspects of DC diversity are determined in part by distinct molecular cues at the hematopoietic level. (Blood. 2000;95:128-137)
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Galy, Anne, Indu Christopherson, Guido Ferlazzo, Guo Liu, Hergen Spits, and Katia Georgopoulos. "Distinct signals control the hematopoiesis of lymphoid-related dendritic cells." Blood 95, no. 1 (January 1, 2000): 128–37. http://dx.doi.org/10.1182/blood.v95.1.128.001k06_128_137.
Full textAbstract:
The molecular and cellular requirements for the development of different populations of human dendritic cells (DC) were studied. Conditions were defined that support DC production from lymphoid progenitors but that fail to induce DC formation from peripheral monocytes. The production of these lymphoid-related DC was severely blocked when hematopoietic progenitors overexpressed Ik7, a mutant dominant-negative Ikaros protein. In contrast, Ik7 did not block the formation of DC in conditions supporting the development of monocyte-derived DC. Furthermore, Ik7 did not block the formation of monocyte/macrophages and enhanced granulopoiesis. One of the molecular mechanisms mediated by Ik7 appears to be down-regulation of the flt3-receptor mRNA. Thus, distinct signals control the formation of DC demonstrating that some aspects of DC diversity are determined in part by distinct molecular cues at the hematopoietic level. (Blood. 2000;95:128-137)
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Gorji, A., D. Scheller, F. Tegtmeier, R. Köhling, H. Straub, and E.-J. Speckmann. "NiCl2 and Amiloride Induce Spreading Depression in Guinea Pig Hippocampal Slices." Cephalalgia 20, no. 8 (October 2000): 740–47. http://dx.doi.org/10.1111/j.1468-2982.2000.00124.x.
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Spreading depressions (SD) occur in association with ischaemia, epilepsy and migraine. Intracellular calcium oscillations have been suggested to be involved in the generation and propagation of SD. The present study was performed to study the mechanism of conditioning guinea pig hippocampal slices by the T-type calcium channel blockers NiCl2 and amiloride. SD-like fluctuations of DC potential were recorded by inserting microelectrodes into the CA1 and CA3 regions. The SD occurrence was significantly greater with 10 µmol/ l NiCl2 as well as with 25 and 50 µmol/ l amiloride than with other concentrations of these substances. The concentration response curve was inversely U-shaped with the maximum repetition rates of SDs being achieved at 10 µmol/ l NiCl2 as well as at 25 and 50 µmol/ l amiloride. SD occurrence could be completely blocked by the NMDA antagonist APV (10 µmol/ l) in all cases. These data demonstrate that modulation of the Ca2+ dynamics conditioned guinea pig hippocampal slices and increased their susceptibility to generate SD.
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Tassaneetrithep, Boonrat, Timothy H. Burgess, Angela Granelli-Piperno, Christine Trumpfheller, Jennifer Finke, Wellington Sun, Michael A. Eller, et al. "DC-SIGN (CD209) Mediates Dengue Virus Infection of Human Dendritic Cells." Journal of Experimental Medicine 197, no. 7 (April 7, 2003): 823–29. http://dx.doi.org/10.1084/jem.20021840.
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Dengue virus is a single-stranded, enveloped RNA virus that productively infects human dendritic cells (DCs) primarily at the immature stage of their differentiation. We now find that all four serotypes of dengue use DC-SIGN (CD209), a C-type lectin, to infect dendritic cells. THP-1 cells become susceptible to dengue infection after transfection of DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN), or its homologue L-SIGN, whereas the infection of dendritic cells is blocked by anti–DC-SIGN antibodies and not by antibodies to other molecules on these cells. Viruses produced by dendritic cells are infectious for DC-SIGN– and L-SIGN–bearing THP-1 cells and other permissive cell lines. Therefore, DC-SIGN may be considered as a new target for designing therapies that block dengue infection.
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Rasgado-Flores, Hector, Vamsi Krishna Mandava, Homayoun Siman, Willy Van Driessche, Joseph M. Pilewski, Scott H. Randell, and Robert J. Bridges. "Effect of apical hyperosmotic sodium challenge and amiloride on sodium transport in human bronchial epithelial cells from cystic fibrosis donors." American Journal of Physiology-Cell Physiology 305, no. 11 (December 1, 2013): C1114—C1122. http://dx.doi.org/10.1152/ajpcell.00166.2013.
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Hypertonic saline (HS) inhalation therapy benefits cystic fibrosis (CF) patients [Donaldson SH, Bennet WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. N Engl J Med 354: 241–250, 2006; Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, Belousova EG, Xuan W, Bye PT; the National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group. N Engl J Med 354: 229–240, 2006]. Surprisingly, these benefits are long-lasting and are diminished by the epithelial Na+ channel blocker amiloride (Donaldson SH, Bennet WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. N Engl J Med 354: 241–250, 2006). Our aim was to explain these effects. Human bronchial epithelial (hBE) cells from CF lungs were grown in inserts and were used in three experimental approaches: 1) Ussing chambers to measure amiloride-sensitive short-circuit currents ( INa); 2) continuous perfusion Ussing chambers; and 3) near “thin-film” conditions in which the airway surface of the inserts was exposed to a small volume (30 μl) of isosmotic or HS solution as the inserts were kept in their incubation tray and were subsequently used to measure INa under isosmotic conditions (near thin-film experiments; Tarran R, Boucher RC. Methods Mol Med 70: 479–492, 2002). HS solutions (660 mosmol/kgH2O) were prepared by adding additional NaCl to the isosmotic buffer. The transepithelial short-circuit current ( ISC), conductance ( GT), and capacitance ( CT) were measured by transepithelial impedance analysis (Danahay H, Atherton HC, Jackson AD, Kreindler JL, Poll CT, Bridges RJ. Am J Physiol Lung Cell Mol Physiol 290: L558–L569, 2006; Singh AK, Singh S, Devor DC, Frizzell RA, van Driessche W, Bridges RJ. Methods Mol Med 70: 129–142, 2002). Exposure to apical HS inhibited INa, GT, and CT. The INa inhibition required 60 min of reexposure to the isosmotic solution to recover 75%. The time of exposure to HS required to inhibit INa was <2.5 min. Under near thin-film conditions, apical exposure to HS inhibited INa, but as osmotically driven water moved to the apical surface, the aqueous apical volume increased, leading to an amiloride-insensitive decrease in its osmolality and to recovery of INa that lagged behind the osmotic recovery. Amiloride significantly accelerated the recovery of INa following exposure to HS. Our conclusions are that exposure to HS inhibits hBE INa and that amiloride diminishes this effect.
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Smit, Egbert F., Solange Peters, Rafal Dziadziuszko, Urania Dafni, Juergen Wolf, Bartosz Wasąg, Wojciech Biernat, et al. "A single-arm phase II trial of afatinib in pretreated patients with advanced NSCLC harboring a HER2 mutation: The ETOP NICHE trial." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 9070. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.9070.
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9070 Background: HER2mutations are identified in about 2% of lung adenocarcinomas and are critical for lung carcinogenesis. Afatinib is a selective and irreversible erbB family blocker with a manageable toxicity profile and promising results in small retrospective studies targeting HER2 in NSCLC. Methods: NICHE is a single-arm phase II trial exploring the potential of afatinib to control disease (complete or partial response or disease stabilization for ≥12 weeks) in pre-treated patients with advanced NSCLC harboring HER2 exon 20 mutations. Patients were treated with afatinib 40 mg/day p.o. until tumor progression or lack of tolerability. A Simon’s two stage phase II design was adopted, to explore whether afatinib can achieve a DCR of 75%, as opposed to a DCR of 50% under the current treatment options. For a 1-sided type I error of 10% and power of 80%, a total of 22 patients were needed. Results: As of 24 November 2016, 13 patients were recruited into the trial. Median age was 60 years, 69% female and 62% never smokers. The overall toxicity profile was in the expected range, with 5 patients experiencing serious adverse events (dyspnea, diarrhea, dehydration, epistaxis, pleural, pericardial and renal insufficiency). The median follow-up was 23 weeks (IQR 12 – 39). Three patients died and 10 were still on follow-up, among them five were still on treatment. Total of 7 patients (54%) achieved DC at 12-weeks, 3 patients had PD before and 3 at 12-weeks. The 12-week PFS was 51% (95% CI: 22 - 75) and the median PFS 13 weeks (95% CI 6 - NE). In the 1st stage analysis of the Simon’s design, with 9 patients included, the stopping boundary was crossed. Therefore and upon recommendations of the ETOP IDMC, recruitment into the trial was stopped prematurely in December 2016. Treatment and follow-up of the enrolled patients continues as planned. Conclusions: Based on the interim results, afatinib did not show the expected potential to control disease in this patient population. However in the full analysis set with 13 patients, clear signs of activity were seen. A comprehensive biomolecular analysis of the tumors is currently ongoing in order to identify a subgroup of patients who might still derive benefit from afatinib treatment. Clinical trial information: NCT02369484.
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Ayehunie, Seyoum, Eduardo A. Garcia-Zepeda, James A. Hoxie, Richard Horuk, Thomas S. Kupper, Andrew D. Luster, and Ruth M. Ruprecht. "Human Immunodeficiency Virus-1 Entry Into Purified Blood Dendritic Cells Through CC and CXC Chemokine Coreceptors." Blood 90, no. 4 (August 15, 1997): 1379–86. http://dx.doi.org/10.1182/blood.v90.4.1379.
Full textAbstract:
Abstract Blood dendritic cells (DC) are susceptible to both macrophage (M) and T-cell line (T) tropic human immunodeficiency virus type 1. The CC chemokines RANTES, macrophage inflammatory protein-1α (MIP-1α), MIP-1β, eotaxin, and, to a lesser extent, monocyte chemoattractant protein-1 (MCP-1) and MCP-4 blocked entry of M-tropic virus into blood DC. The CXC chemokine, SDF-1, a fusin (CXCR4 chemokine receptor) ligand, and an antifusin antibody inhibited DC entry by T-tropic virus. Purified blood DC contained CCR1, CCR2, CCR3, and CCR5 as well as the CXCR4 chemokine receptor RNA transcripts and high levels of fusin on the cell surface. The coexpression of multiple chemokine receptors offers a molecular mechanism to explain the permissiveness of DC for both M- and T-tropic viruses.
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Ayehunie, Seyoum, Eduardo A. Garcia-Zepeda, James A. Hoxie, Richard Horuk, Thomas S. Kupper, Andrew D. Luster, and Ruth M. Ruprecht. "Human Immunodeficiency Virus-1 Entry Into Purified Blood Dendritic Cells Through CC and CXC Chemokine Coreceptors." Blood 90, no. 4 (August 15, 1997): 1379–86. http://dx.doi.org/10.1182/blood.v90.4.1379.1379_1379_1386.
Full textAbstract:
Blood dendritic cells (DC) are susceptible to both macrophage (M) and T-cell line (T) tropic human immunodeficiency virus type 1. The CC chemokines RANTES, macrophage inflammatory protein-1α (MIP-1α), MIP-1β, eotaxin, and, to a lesser extent, monocyte chemoattractant protein-1 (MCP-1) and MCP-4 blocked entry of M-tropic virus into blood DC. The CXC chemokine, SDF-1, a fusin (CXCR4 chemokine receptor) ligand, and an antifusin antibody inhibited DC entry by T-tropic virus. Purified blood DC contained CCR1, CCR2, CCR3, and CCR5 as well as the CXCR4 chemokine receptor RNA transcripts and high levels of fusin on the cell surface. The coexpression of multiple chemokine receptors offers a molecular mechanism to explain the permissiveness of DC for both M- and T-tropic viruses.
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OSORIO, IVAN, and M. G. FREI. "SEIZURE ABATEMENT WITH SINGLE DC PULSES: IS PHASE RESETTING AT PLAY?" International Journal of Neural Systems 19, no. 03 (June 2009): 149–56. http://dx.doi.org/10.1142/s0129065709001926.
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Topological approaches for seizure abatement have received scarce attention. The ability to reset the phase of biological oscillations has been widely exploited in cardiology, as evidenced in part by the usefulness of implantable of defibrillators, but not in epileptology. The aim of this work is to investigate the feasibility of seizure blockage using single or brief monophasic (DC) pulse trains. Single DC or brief (0.1 s) pulse trains were delivered manually or automatically to generalized seizures, induced in rats with the convulsant 3-mercaptoprionic acid, a GABA inhibitor. Treatment outcome (blocked vs. not blocked seizures) was ascertained visually and correlated with the "rhythmicity index", an indirect estimate of neuronal synchrony level. Blockage using single or brief (0.1 s) DC pulses was consistently achieved for seizures with a rhythmicity index > 0.6, while seizures with levels <0.6 were not, although transient phase changes in their oscillations were effected. This work reveals that level of neuronal synchronization may be an important factor in determining the probability of seizure blockage. Seizure blockage using single or brief DC pulse trains and its effects on neural tissue merit further investigation. The clinical applicability of this therapeutic modality and means to enhance it are discussed.
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Hwang, Sung In, Jung-Kyun Lee, Dong Hoon Song, Dae Sik Choi, and Do-Kyeong Ko. "Enhancement of the Optical Image with a DC Blocked Spiral Holographic Pattern." Journal of the Korean Physical Society 58, no. 2 (February 15, 2011): 387–91. http://dx.doi.org/10.3938/jkps.58.387.
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Frankel, Sarah S., Ralph M. Steinman, Nelson L. Michael, Silvia Ratto Kim, Nina Bhardwaj, Melissa Pope, Mark K. Louder, et al. "Neutralizing Monoclonal Antibodies Block Human Immunodeficiency Virus Type 1 Infection of Dendritic Cells and Transmission to T Cells." Journal of Virology 72, no. 12 (December 1, 1998): 9788–94. http://dx.doi.org/10.1128/jvi.72.12.9788-9794.1998.
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ABSTRACT Prevention of the initial infection of mucosal dendritic cells (DC) and interruption of the subsequent transmission of HIV-1 from DC to T cells are likely to be important attributes of an effective human immunodeficiency virus type 1 (HIV-1) vaccine. While anti-HIV-1 neutralizing antibodies have been difficult to elicit by immunization, there are several human monoclonal antibodies (MAbs) that effectively neutralize virus infection of activated T cells. We investigated the ability of three well-characterized neutralizing MAbs (IgG1b12, 2F5, and 2G12) to block HIV-1 infection of human DC. DC were generated from CD14+ blood cells or obtained from cadaveric human skin. The MAbs prevented viral entry into purified DC and the ensuing productive infection in DC/T-cell cultures. When DC were first pulsed with HIV-1, MAbs blocked the subsequent transmission to unstimulated CD3+ T cells. Thus, neutralizing antibodies can block HIV-1 infection of DC and the cell-to-cell transmission of virus from infected DC to T cells. These data suggest that neutralizing antibodies could interrupt the initial events associated with mucosal transmission and regional spread of HIV-1.
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Santiago-Schwarz, F., DL Coppock, AA Hindenburg, and J. Kern. "Identification of a malignant counterpart of the monocyte-dendritic cell progenitor in an acute myeloid leukemia." Blood 84, no. 9 (November 1, 1994): 3054–62. http://dx.doi.org/10.1182/blood.v84.9.3054.3054.
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Abstract Myeloblasts derived from the peripheral blood of a patient with acute myelogenous leukemia (ORL47) were found to represent the malignant counterpart of the newly elucidated monocyte-dendritic cell colony- forming unit (mono-DC-CFU). The specific cytokine conditions require to achieve intermediate and terminal maturation of DCs and monocytes from these progenitors were defined. With tumor necrosis factor (TNF) + granulocyte-macrophage colony-stimulating factor (GM-CSF) + stem cell factor treatment numerous colony-like clusters developed. In contrast with normal DC development, further advancement of mono-DC-CFU and terminal DC maturation from the leukemic cells were dependent on the addition of interleukin-6. Functional and phenotypic analysis showed that the capacity to differentiate was maintained fully in the DC compartment, but only partially in the monocyte compartment, as judged by the lack of CD14 surface expression. Cells found at intermediate stages of DC development were potent stimulators of a mixed leukocyte reaction, a function usually attributed to mature DCs. As previously shown for normal DC development, antibodies to TNF alpha and GM-CSF blocked proliferative responses and DC growth. The importance of these observations in the classification of leukemias, normal DC development, and potential clinical strategies is discussed.
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Santiago-Schwarz, F., DL Coppock, AA Hindenburg, and J. Kern. "Identification of a malignant counterpart of the monocyte-dendritic cell progenitor in an acute myeloid leukemia." Blood 84, no. 9 (November 1, 1994): 3054–62. http://dx.doi.org/10.1182/blood.v84.9.3054.bloodjournal8493054.
Full textAbstract:
Myeloblasts derived from the peripheral blood of a patient with acute myelogenous leukemia (ORL47) were found to represent the malignant counterpart of the newly elucidated monocyte-dendritic cell colony- forming unit (mono-DC-CFU). The specific cytokine conditions require to achieve intermediate and terminal maturation of DCs and monocytes from these progenitors were defined. With tumor necrosis factor (TNF) + granulocyte-macrophage colony-stimulating factor (GM-CSF) + stem cell factor treatment numerous colony-like clusters developed. In contrast with normal DC development, further advancement of mono-DC-CFU and terminal DC maturation from the leukemic cells were dependent on the addition of interleukin-6. Functional and phenotypic analysis showed that the capacity to differentiate was maintained fully in the DC compartment, but only partially in the monocyte compartment, as judged by the lack of CD14 surface expression. Cells found at intermediate stages of DC development were potent stimulators of a mixed leukocyte reaction, a function usually attributed to mature DCs. As previously shown for normal DC development, antibodies to TNF alpha and GM-CSF blocked proliferative responses and DC growth. The importance of these observations in the classification of leukemias, normal DC development, and potential clinical strategies is discussed.
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Nonaka, Motohiro, Shogo Matsumoto, Bruce Yong Ma, Hiroshi Kido, Nana Kawasaki, Nobuko Kawasaki, and Toshisuke Kawasaki. "Glycan-Dependent and -Independent Dual Recognition between DC-SIGN and Type II Serine Protease MSPL/TMPRSS13 in Colorectal Cancer Cells." Applied Sciences 10, no. 8 (April 13, 2020): 2687. http://dx.doi.org/10.3390/app10082687.
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A class of glycoproteins such as carcinoembryonic antigen (CEA)/CEA-related cell adhesion molecule 1(CEACAM1), CD26 (DPPIV), and mac-2 binding protein (Mac-2BP) harbor tumor-associated glycans in colorectal cancer. In this study, we identified type II transmembrane mosaic serine protease large-form (MSPL) and its splice variant transmembrane protease serine 13 (TMPRSS13) as ligands of Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) on the colorectal cancer cells. DC-SIGN is a C-type lectin expressed on dendritic cells, serves as a pattern recognition receptor for numerous pathogens such as human immunodeficiency virus (HIV) and M. tuberculosis. DC-SIGN recognizes these glycoproteins in a Ca2+ dependent manner. Meanwhile, we found that MSPL proteolytically cleaves DC-SIGN in addition to the above glycan-mediated recognition. DC-SIGN was degraded more efficiently by MSPL when treated with ethylenediaminetetraacetic acid (EDTA), suggesting that glycan-dependent interaction of the two molecules partially blocked DC-SIGN degradation. Our findings uncovered a dual recognition system between DC-SIGN and MSPL/TMPRSS13, providing new insight into the mechanism underlying colorectal tumor microenvironment.
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Platzer, Barbara, Almut Jörgl, Sabine Taschner, Bernhard Höcher, and Herbert Strobl. "RelB regulates human dendritic cell subset development by promoting monocyte intermediates." Blood 104, no. 12 (December 1, 2004): 3655–63. http://dx.doi.org/10.1182/blood-2004-02-0412.
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In humans, epithelial Langerhans cells (LCs) and monocyte-derived/interstitial dendritic cells (DCs) constitute 2 myeloid DC sublineages. Molecular mechanisms involved in their development from common myeloid progenitors remain poorly defined. Here we demonstrate that the nuclear factor-κB (NF-κB) transcription factor RelB regulates the generation of monocytic CD14+CD11b+ precursors of interstitial DCs from human hematopoietic progenitors. RelB overexpression promoted, whereas endogenous RelB inhibition (by p100ΔN) blocked, precursor cell development along this DC subset pathway. RelB inhibition specifically arrested precursor progression from CD14loCD11b- to CD14+CD11b+ stages. Precursors were still capable of LC and granulocyte differentiation but were defective in macrophage–colony-stimulating factor (M-CSF)–dependent monocyte/macrophage differentiation. RelB inhibition markedly differed from classical NF-κB signaling inhibition because IκBα superrepressor (IκBα-SR), but not p100ΔN, impaired LC/DC differentiation, DC adhesion, and progenitor cell proliferation. Although RelB up-regulation and nuclear translocation are regarded as hallmarks of human myeloid DC maturation, ectopic RelB overexpression failed to promote DC maturation. Our results suggest that RelB regulates human monopoiesis and monocyte-derived DC subset development.