tbuckley/cabot-search huggingface dataset:
Ren1c Homozygous Null Mice Are Hypotensive and Polyuric, but Heterozygotes Are Indistinguishable from Wild-Type
Authors: Nobuyuki Takahashi, Maria Luisa S. Sequeira Lopez, John E. Cowhig, Melissa A. Taylor, Tomoko Hatada, Emily Riggs, Gene Lee, R. Ariel Gomez, Hyung-Suk Kim, Oliver Smithies
Journal: Journal of the American Society of Nephrology (2004)

Mice lacking <i>Ren1c</i> were generated using C57BL/6-derived embryonic stem cells. Mice homozygous for <i>Ren1c</i> disruption (<i>Ren1c</i>−/−) are born at the expected ratio, but approximately 80% die of dehydration within a few days. The surviving <i>Ren1c</i>−/− mice have no renin mRNA expression in the kidney, hydronephrosis, thickening of renal arterial walls, and fibrosis in the kidney. Plasma renin and angiotensins I and II are undetectable. Urinary aldosterone is 6% wild-type. They have low tail-cuff BP (84 ± 4 <i>versus</i> 116 ± 5 mmHg in +/+) and excrete large amounts of urine (5.2 ± 0.8 ml/d, 725 ± 34 mOsm <i>versus</i> 1.1 ± 0.1 ml/d, 2460 ± 170 mOsm in +/+). After 5 d of drinking 5% dextrose, desmopressin does not increase the osmolality of the urine in −/− mice (624 ± 19 to 656 ± 25 mOsm), whereas in +/+, it increases severalfold (583 ± 44 to 2630 ± 174 mOsm). Minipump infusion of angiotensin II to <i>Ren1c</i>−/− mice restores BP to wild-type level, but preexisting damage to the medulla prevents complete restoration of the ability of the kidney to concentrate urine. Heterozygous <i>Ren1c</i>+/− mice, in contrast, are indistinguishable from +/+ in BP, urine volume, and osmolality. Kidney renin mRNA, the number of kidney cells producing renin, and plasma renin concentration in the <i>Ren1c</i>+/− mice are also indistinguishable from +/+. These results demonstrate that renin is the only enzyme capable of maintaining plasma angiotensins and that renin expression in the kidney is very tightly regulated at the mRNA level.
Differentiation of the HaCaT keratinocyte cell line: modulation by adrenomedullin
Authors: O. Pleguezuelos, S. Kapas
Journal: British Journal of Dermatology (2006)

Adrenomedullin (AM) is a multifunctional peptide produced by a wide variety of cells, including keratinocytes. We, and others, have demonstrated that AM has a role as a growth regulatory factor of the skin and contributes as an antimicrobial agent in the integument's protective barrier. It is not known whether AM has a role in differentiating keratinocytes.To study the role of AM in keratinocyte differentiation, modulating the effects of calcium and in addition, to assess whether differentiated keratinocytes are still capable of initiating an inflammatory response.HaCaT cells were differentiated using CaCl2. Expression of transglutaminase type 1 (TG1) and E2F1 genes was used to monitor differentiation. AM secretion was measured by enzyme-linked immunosorbent assay (ELISA). NF-kappaB activity and interleukin (IL)-6 secretion in the cells were assessed after exposure to calcium and AM by electrophoretic mobility shift assay and ELISA, respectively.Secretion of AM by the keratinocyte cell line HaCaT was found to be increased during 1 mmol L(-1) CaCl2-induced cell differentiation but not 0.1 mmol L(-1) CaCl2. All treatments showed low levels of the cell proliferation marker, E2F1. Over time, cells incubated in the presence of 0.1 mmol L(-1) or 1 mmol L(-1) of CaCl2 showed an increase in TG1 expression, a marker of early differentiation. The addition of AM showed a decrease in TG1 expression when combined with 0.1 mmol L(-1) CaCl2, but not with 1 mmol L(-1) CaCl2. In addition, cells kept in 0.1 mmol L(-1) CaCl2 showed translocation of NF-kappaB after 48 h and 72 h of incubation, which was abolished when AM was added to the cells. Treatment with 1 mmol L(-1) CaCl2 led to earlier translocation of NF-kappaB at 24 h after treatment and addition of AM did not abolish the effect of 1 mmol L(-1) CaCl2 on NF-kappaB activation. Cells incubated in 0.1 mmol L(-1) CaCl2 showed increased secretion of IL-6 over time, consistent with NF-kappaB activation. The addition of AM to cells incubated with 0.1 mmol L(-1) CaCl2 showed a rapid decrease in IL-6 secretion after only 6 h. However, 1 mmol L(-1) CaCl2 did not induce secretion of IL-6 and the addition of AM did not affect the result.Our data indicate that AM can reverse calcium-induced differentiation when 0.1 mmol L(-1) CaCl2 is used but not 1 mmol L(-1) CaCl2. Cells differentiated with 0.1 mmol L(-1) CaCl2 are still capable of generating an inflammatory response, showing signs of late NF-kappaB activation and IL-6 secretion that can be inhibited by AM. However, cells differentiated with 1 mmol L(-1) CaCl2 lose their ability to secrete IL-6 but not AM, which could be acting as an antimicrobial peptide.
Elucidating endometrial function in the post-genomic era
Authors: L. C. Giudice
Journal: Human Reproduction Update (2003)

The post‐genomic era has now arrived, and science and biology are on the threshold of a transition from understanding functions of single molecules and pathways in cells, tissues and whole organisms to understanding integrative systems. The endometrium is a dynamic tissue that responds to multiple stimuli, depending on physiological and environmental conditions, including steroid hormones, an implanting conceptus, withdrawal of steroid hormones, contraceptive steroids, selective steroid hormone receptor modulators, infection, transient cell populations, and metaplastic and neoplastic agents. High throughput technologies with regard to DNA, RNA and proteins are well positioned to enable a thorough understanding of the dynamic changes and integrative systems involved in endometrial maturation, desquamation, receptivity to implantation, infertility, pregnancy maintenance and failure, inflammation and infection, and malignant transformation. This monograph reviews some of the salient features of the new technologies and summarizes current information on endometrial biology derived from these approaches.
Reduced seroprotection after pandemic H1N1 influenza adjuvant-free vaccination in patients with rheumatoid arthritis: implications for clinical practice
Authors: A. C. M. Ribeiro, L. K. N. Guedes, J. C. B. Moraes, C. G. S. Saad, N. E. Aikawa, A. L. Calich, I. L. A. Franca, J. F. Carvalho, P. D. Sampaio-Barros, C. R. Goncalves, E. F. Borba, M. d. C. S. Timenetsky, A. R. Precioso, A. Duarte, E. Bonfa, I. M. M. Laurindo
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> Reduced response to pandemic (2009) H1N1 (pH1N1) vaccine in patients with rheumatoid arthritis (RA) was recently reported. <h3>Objectives</h3> To evaluate the contribution of age, disease activity, medication and previous antibody levels to this reduced response. <h3>Methods</h3> 340 adult RA patients and 234 healthy controls were assessed before and 21 days after adjuvant-free influenza A/California/7/2009 (pH1N1) vaccine. Disease activity (DAS28), current treatment and pH1N1 antibody titres were collected. Seroprotection, seroconversion and factor increase in geometric mean titre (GMT) were calculated and adverse events registered. <h3>Results</h3> RA and controls showed similar (p&gt;0.05) prevaccination GMT (8.0 vs 9.3) and seroprotection (10.8% vs 11.5%). After vaccination a significant reduction (p&lt;0.001) was observed in all endpoints: GMT and factor increase in GMT, seroprotection and seroconversion rates. Disease activity did not preclude seroconversion or seroprotection and remained unchanged in 97.4% of patients. Methotrexate was the only disease-modifying antirheumatic drug associated with reduced responses (p=0.001). Vaccination was well tolerated. <h3>Conclusions</h3> The data confirmed both short-term anti-pH1N1 vaccine safety and, different from most studies with seasonal influenza, reduced seroprotection in RA patients, unrelated to disease activity and to most medications (except methotrexate). Extrapolation of immune responses from one vaccine to another may therefore not be possible and specific immunisation strategies (possibly booster) may be needed. Clinicaltrials.gov no NCT01151644.
Gene profiling reveals increased expression of uteroglobin and other anti-inflammatory genes in glucocorticoid-treated nasal polyps
Authors: Mikael Benson, Lena Carlsson, Mikael Adner, Margareta Jernås, Mats Rudemo, Anders Sjögren, Per Arne Svensson, Rolf Uddman, Lars Olaf Cardell
Journal: Journal of Allergy and Clinical Immunology (2004)
CFTR dysfunction induces vascular endothelial growth factor synthesis in airway epithelium
Authors: Clémence Martin, Nathalie Coolen, Yongzheng Wu, Guiti Thévenot, Lhousseine Touqui, Virginie Prulière-Escabasse, Jean-François Papon, André Coste, Estelle Escudier, Daniel J. Dusser, Isabelle Fajac, Pierre-Régis Burgel
Journal: European Respiratory Journal (2013)

Peribronchial angiogenesis may occur in cystic fibrosis and vascular endothelial growth factor (VEGF)-A regulates angiogenesis in airways. Peribronchial vascularity and VEGF-A expression were examined using immunocytochemistry and morphometric analysis in lung sections obtained in 10 cystic fibrosis patients at transplantation versus 10 control nonsmokers, and in two strains of Cftr-deficient mice versus wild-type littermates. Airway epithelial NCI-H292 cells and primary cultures of noncystic fibrosis human airway epithelial cells were treated with cystic fibrosis transmembrane conductance regulator (CFTR) inhibitors (CFTR-inh(172) or PPQ-102) or transfected with a CFTR small interfering (si)RNA with or without a selective epidermal growth factor receptor tyrosine kinase inhibitor. Concentrations of VEGF-A and phosphorylated epidermal growth factor receptor were measured by ELISA. Peribronchial vascularity was increased in cystic fibrosis patients, but not in Cftr-deficient mice. VEGF-A immunostaining was localised to airway epithelium and was increased in cystic fibrosis patients and in Cftr-deficient mice. In cultured airway epithelial cells, treatment with CFTR inhibitors or transfection with CFTR siRNA induced a twofold increase in VEGF-A production. CFTR inhibitors triggered epidermal growth factor receptor phosphorylation that was required for VEGF-A synthesis. Cystic fibrosis airways at transplantation showed increased peribronchial vascularity and epithelial VEGF-A expression. CFTR dysfunction triggered epithelial synthesis of VEGF-A, which may contribute to vascular remodelling.
Stim1 and Orai1 Mediate CRAC Currents and Store-Operated Calcium Entry Important for Endothelial Cell Proliferation
Authors: Iskandar F. Abdullaev, Jonathan M. Bisaillon, Marie Potier, Jose C. Gonzalez, Rajender K. Motiani, Mohamed Trebak
Journal: Circulation Research (2008)

Recent breakthroughs in the store-operated calcium (Ca 2+ ) entry (SOCE) pathway have identified Stim1 as the endoplasmic reticulum Ca 2+ sensor and Orai1 as the pore forming subunit of the highly Ca 2+ -selective CRAC channel expressed in hematopoietic cells. Previous studies, however, have suggested that endothelial cell (EC) SOCE is mediated by the nonselective canonical transient receptor potential channel (TRPC) family, TRPC1 or TRPC4. Here, we show that passive store depletion by thapsigargin or receptor activation by either thrombin or the vascular endothelial growth factor activates the same pathway in primary ECs with classical SOCE pharmacological features. ECs possess the archetypical Ca 2+ release-activated Ca 2+ current (I CRAC ), albeit of a very small amplitude. Using a maneuver that amplifies currents in divalent-free bath solutions, we show that EC CRAC has similar characteristics to that recorded from rat basophilic leukemia cells, namely a similar time course of activation, sensitivity to 2-aminoethoxydiphenyl borate, and low concentrations of lanthanides, and large Na + currents displaying the typical depotentiation. RNA silencing of either Stim1 or Orai1 essentially abolished SOCE and I CRAC in ECs, which were rescued by ectopic expression of either Stim1 or Orai1, respectively. Surprisingly, knockdown of either TRPC1 or TRPC4 proteins had no effect on SOCE and I CRAC . Ectopic expression of Stim1 in ECs increased their I CRAC to a size comparable to that in rat basophilic leukemia cells. Knockdown of Stim1, Stim2, or Orai1 inhibited EC proliferation and caused cell cycle arrest at S and G2/M phase, although Orai1 knockdown was more efficient than that of Stim proteins. These results are first to our knowledge to establish the requirement of Stim1/Orai1 in the endothelial SOCE pathway.
Individualised treatment in non-small cell lung cancer: precise tissue diagnosis for all?
Authors: R. Booton, F. Blackhall, K. Kerr
Journal: Thorax (2011)

A number of key advances in the therapeutic management of lung cancer have signposted the need for substantial changes in the diagnostic pathway and techniques for patients with suspected lung cancer. Cell-type-specific agents are available to treat lung cancer and, together with new molecular markers, they can improve outcomes through individualised treatment regimens. For example, a prospective phase III trial of platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC) demonstrated that the combination of cisplatin/pemetrexed improved outcomes for patients with non-squamous tumours, but that cisplatin/gemcitabine was better in patients with squamous histology.1 Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, plus chemotherapy is a standard of care in advanced NSCLC but is contraindicated in squamous cell subtypes due to the association with life-threatening haemoptysis.2 Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are indicated in first and second-line treatment of advanced NSCLC but are more effective in female, non-smokers with adenocarcinoma, an effect most likely mediated by the presence of sensitising EGFR gene mutations.3 4 Most recently, the National Institute for Health and Clinical Excellence (NICE) has approved the use of gefitinib (an EGFR TKI) in advanced NSCLC for patients demonstrating EGFR mutation positivity.5 In addition, EGFR gene copy number by fluorescence in-situ hybridisation may also help to predict favourable outcomes with EGFR TKI or cetuximab-containing therapy.6 EGFR mutation positivity may ‘trump’ the clinical phenotype as a predictor of response and improved survival following EGFR TKI, even in patients with a low performance score (PS 3, 4). A recent report describing first-line treatment with gefitinib in EGFR mutation-positive patients (50% with metastatic brain disease) demonstrated a response rate of 90% and a startling improvement in PS from 3, 4 to 0, 1 of 68% and 1-year survival of 63%.7 Taken together …
Targeting the oncogenic protein beta-catenin to enhance chemotherapy outcome against solid human cancers
Authors: Maher S Saifo, Donald R Rempinski, Youcef M Rustum, Rami G Azrak
Journal: Molecular Cancer (2010)

Abstract Background Beta-catenin is a multifunctional oncogenic protein that contributes fundamentally to cell development and biology. Elevation in expression and activity of β-catenin has been implicated in many cancers and associated with poor prognosis. Beta-catenin is degraded in the cytoplasm by glycogen synthase kinase 3 beta (GSK-3β) through phosphorylation. Cell growth and proliferation is associated with β-catenin translocation from the cytoplasm into the nucleus. This laboratory was the first to demonstrate that selenium-containing compounds can enhance the efficacy and cytotoxicity of anticancer drugs in several preclinical xenograft models. These data provided the basis to identify mechanism of selenium action focusing on β-catenin as a target. This study was designed to: (1) determine whether pharmacological doses of methylseleninic acid (MSeA) have inhibitory effects on the level and the oncogenic activity of β-catenin, (2) investigate the kinetics and the mechanism of β-catenin inhibition, and (3) confirm that inhibition of β-catenin would lead to enhanced cytotoxicity of standard chemotherapeutic drugs. Results In six human cancer cell lines, the inhibition of total and nuclear expression of β-catenin by MSeA was dose and time dependent. The involvement of GSK-3β in the degradation of β-catenin was cell type dependent (GSK-3β-dependent in HT-29, whereas GSK-3β-independent in HCT-8). However, the pronounced inhibition of β-catenin by MSeA was independent of various drug treatments and was not reversed after combination therapy. Knockout of β-catenin by ShRNA and its inhibition by MSeA yielded similar enhancement of cytotoxicity of anticancer drugs. Collectively, the generated data demonstrate that β-catenin is a target of MSeA and its inhibition resulted in enhanced cytotoxicity of chemotherapeutic drugs. Conclusions This study demonstrates that β-catenin, a molecule associated with drug resistance, is a target of selenium and its inhibition is associated with increased multiple drugs cytotoxicity in various human cancers. Further, degradation of β-catenin by GSK-3β is not a general mechanism but is cell type dependent.
Effects of Unilateral and Bilateral Carotid Baroreflex Stimulation on Cardiac and Neural Sympathetic Discharge Oscillatory Patterns
Authors: Raffaello Furlan, André Diedrich, Alexandra Rimoldi, Laura Palazzolo, Cesare Porta, Laura Diedrich, Paul A. Harris, Peter Sleight, Italo Biagioni, David Robertson, Luciano Bernardi
Journal: Circulation (2003)

Left and right carotid baroreflex afferents participate in generating the spontaneous variability of heart rate (HR), arterial pressure (AP), and muscle sympathetic nerve activity (MSNA), but the relative contribution of each side is unclear. Pathophysiological conditions unilaterally affecting carotid baroreceptor function might result in abnormal changes of HR, AP, and MSNA variability, thus markedly affecting prognosis. We tested the hypothesis that unilateral carotid baroreceptor perturbation might differentially affect HR, AP, and MSNA variability compared with stimulation of the opposite side.In 12 healthy volunteers, 4 sinusoidal neck suction procedures (0.1 Hz, from 0 to -50 mm Hg) were applied at the right, left, and combined right and left sides of the neck, in concordance or with phase opposition. Respiration was controlled at 0.25 Hz. Power spectrum analysis assessed the changes in the 0.1-Hz oscillatory component of the R-R interval, systolic AP (SAP), and MSNA variability induced by rhythmic baroreceptor stimulation. Mean R-R interval, SAP, and MSNA were unchanged during all procedures. The increase of the 0.1-Hz component of R-R and SAP variability during right and combined right and left carotid baroreceptor stimulation was greater than the changes induced by left-sided stimulation. The increase in the 0.1-Hz oscillatory component of MSNA variability was similar during all neck suction procedures.Right carotid baroreflex loading was as efficient as bilateral stimulation and more effective than left carotid suction in modulating R-R and SAP variability. There was no asymmetry in neural sympathetic discharge responses after single-sided carotid baroreceptor stimulation.
The European Respiratory Society, 1990-2010: a 20-year anniversary story of success
Authors: N. M. Siafakas
Journal: European Respiratory Journal (2009)

In 2010, the European Respiratory Society (ERS) celebrates its 20th anniversary. Since its foundation, the ERS has generated an impressive reputation and history of which our relatively young Society can be proud.

The “genesis” of the ERS was the merger of two European scientific societies: the Societas Europaea Physiologiae Clinicae Respoiratoriae (SEPCR), founded in 1966, and the European Society of Pneumology (SEP), founded in 1981. The merge took place in London in 1990 during the joint meeting of SEPCR and SEP; the late Stewart Clark was the President of the unified Society. This unification brought together the basic scientists of SEPCR with the clinicians of SEP in a harmonious relationship, and is considered the driving force behind the successful story of the ERS. The structure of the new Society was based on the scientific assemblies of SEPCR with the addition of a new, large clinical assembly from SEP. Those who envisioned and took part in the merge should not only be gratified by the ERS’s achievements over the last 20 years, they should also be extremely proud of its standing as one of the leading respiratory societies in the world.

In the initial years, the ERS leadership focused its efforts on building the structure of the Society, developing its missions and objectives, recruiting the appropriate staff, and establishing the ERS Headquarters. The first ERS office (in 1992) was a small flat in Paris (France) and was run by a few staff members. Within a few years, the office had moved to larger premises in Lausanne (Switzerland). Today, the ERS owns two beautiful buildings: the Headquarters, in Lausanne; and the Publications Office, in Sheffield (UK). In addition, the ERS runs an EU office in Brussels (Belgium).

Thanks to the efforts of the ERS’s inspired leadership, the Annual Congress became one of …
Suppression of the immune response in C3H/HeJ mice by protein-free lipopolysaccharides.
Authors: G P Haas, A G Johnson, A Nowotny
Journal: The Journal of Experimental Medicine (1978)

The experiments described herein demonstrate the plaque-forming cell response of C3H/HeJ mice can be suppressed by a Boivin type lipopolysaccharide (LPS) and a deproteinized glycolipid. Suppression was observed both in vivo and in vitro, and could be transferred to normal cells in coculture experiments. This newly discovered effect of LPS in C3H/HeJ mice indicates that the adjuvant and inhibitory action of LPS may be distinct phenomena which are under different genetic regulation. Thus, the C3H/HeJ strain provides a convenient animal model for study of immunosuppression independent of the adjuvant effect.
Role of Salvage Radical Prostatectomy for Recurrent Prostate Cancer After Radiation Therapy
Authors: Andrew J. Stephenson, James A. Eastham
Journal: Journal of Clinical Oncology (2005)

Patients with isolated local recurrence of prostate cancer after radiation therapy may potentially be cured of their disease by salvage radical prostatectomy (RP). The stage-specific 5-year cancer-control rates of salvage RP resemble those of standard RP. However, the ability to effectively administer salvage treatment to patients with radiorecurrent disease is compromised by the lack of diagnostic tests with sufficient sensitivity and specificity to detect local recurrence at an early stage while it is amenable to local salvage therapy. By the time biochemical recurrence is declared using the current American Society for Therapeutic Radiology and Oncology definition, the majority of patients have advanced local disease, precluding successful local salvage therapy. When salvage RP is performed at prostate-specific antigen levels of 10 ng/mL or less, an estimated 70% of patients are free of disease at 5 years. With better patient selection and technical modifications, the morbidity associated with salvage RP has improved substantially. Rates of urinary incontinence and anastomotic stricture are acceptable, although one third of patients will experience these complications. Salvage cryotherapy is a minimally invasive alternative to salvage RP, but cancer-control rates appear to be inferior and it does not provide a clear advantage over salvage RP in terms of reduced morbidity. Patients with local recurrence after radiation therapy are at increased risk of metastatic progression and cancer-specific mortality. Currently, salvage RP represents the only curative treatment option for these patients. Salvage RP may favorably alter the natural history of biochemical recurrence after radiation therapy, but it must be instituted early in the course of recurrent disease to be effective.