tbuckley/cabot-search huggingface dataset:
A2.20 ICOS-ICOSL interaction regulates lymphotoxin alpha expression and maturation of lymphoid-like stromal cells during inflammation
Authors: J Campos, S Nayar, M Chung, JR Hitchcock, DR Withers, AF Cunningham, G Carlesso, R Herbst, CD Buckley, F Barone
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and Objectives</h3> Costimulation Via ICOS-ICOSL Interaction is critical for germinal centre function in secondary lymphoid organs, enhancing T cell activation and maturation into cytokine-producing cells. In autoimmunity this signal has been extensively investigated and believed to contribute to the development of follicular T helper cells, autoimmune germinal centre B cells and abnormal autoantibody production. Blocking of ICOS-ICOSL interaction has been shown to amelliorate disease in animal models of systemic lupus erythematosus and rheumatoid arthritis. We used a novel model of ectopic lymphoneogenesis in adenoviral infected murine salivary glands to dissect the implications of ICOS-ICOSL interaction in T cell activation and consequent maturation of a subset of activated stromal cells in the formation of tertiary lymphoid organs (TLO). <h3>Methods</h3> The submandibular glands of wild-type (wt) and knockout (KO) mice were intra-ductally cannulated with luciferase-encoding replication deficient adenovirus to induce TLO formation. A combination of experiments in ICOSL KO mice or blocking experiments, bone marrow chimaeras and <i>in vitro</i> mixed co-culture were performed to address ICOS/ICOSL interaction in this model. <h3>Results</h3> We demonstrated that early post inflammatory insult ICOSL is significantly upregulated on a population of activated stromal cells that express gp38, adhesion molecules, TNFR1 and TNFR2. <i>In vivo</i> experiments in ICOSL knockout (KO) and blocking experiments, with an anti-ICOS blocking antibody, revealed a dramatic defect in TLO formation and reduced levels of ectopic lymphoid chemokines. We showed that engadgment of stromal derived ICOSL stimulates newly recruited effector T cells to produce lymphotoxin alpha (LTα) that in turn activates stromal cells via TNFR1 to produce lymphoid chemokines. These observations were further confirmed <i>in vitro</i>, in mixed co-cultures of lymphocytes, dendritic cells and stromal cells isolated from wt and ICOSL KO mice. Finally we validated this mechanism inducing TLO formation in ICOSL KO reconstituted with wt bone marrow. As predicted, ICOSLKO reconstituted with wt bone marrow showed a similar degree of impairment in the LTa/TNFR1 pathway as observed in the full KO. <h3>Discussion</h3> Collectively, these data demonstrate that ICOSL expression by stromal cells supports the up-regulation of LTα on T cells <i>in vivo</i> and provide a novel mechanism of action between ICOSL on stromal cells, ICOS on T cells and LTα pathways in the context of TLO formation. Importantly, our work shows that both genetic and therapeutic blockade of ICOS-ICOSL interaction impairs TLO formation, highlighting an important role for stroma-derived ICOSL and a possible therapeutic target in TLO associated diseases.
Fractional carbon monoxide uptake in an employed population
Authors: J. H. Stebbings
Journal: Thorax (1974)

<b>Stebbings, J. H. (1974).</b><i>Thorax</i>, <b>29</b>, 505-510. <b>Fractional carbon monoxide uptake in an employed population.</b> The fractional carbon monoxide uptake in 913 New York City transit workers was studied. A prediction equation for white males, based on nonsmokers, was obtained: fractional CO uptake = 0·58032 − 0·00204 × age + 0·0004 × weight (kilograms). Weight was the index of body size most strongly correlated with the fractional CO uptake. Decline in function with age by amount of tobacco smoked is described. A correction factor for respiration, based on results from 581 workers with two or more tests, was calculated: − 0·123654 × (standard tidal volume − observed tidal volume). Tidal volume was the most important contributor to individual variability of the fractional CO uptake, and minute volume or respiration rate do not add significantly to it. For epidemiological or screening uses, prediction equations are given for the fractional CO uptake corrected to 0·5 1. tidal volume. Respiration variables explain only 1·5% of individual variability, and individual variability over a mean period of 16·6 months was much larger (an individual standard error of 0·07) than the unexplained population variability (a population standard error of 0·01−0·02); thus the usefulness of the fractional CO uptake as a test of respiratory function is in doubt.
EGF Increases TRPM6 Activity and Surface Expression
Authors: Ste[Combining Acute Accent]phanie Thebault, R. Todd Alexander, Wouter M. Tiel Groenestege, Joost G. Hoenderop, Rene[Combining Acute Accent] J. Bindels
Journal: Journal of the American Society of Nephrology (2008)

Recent identification of a mutation in the EGF gene that causes isolated recessive hypomagnesemia led to the finding that EGF increases the activity of the epithelial magnesium (Mg2+) channel transient receptor potential M6 (TRPM6). To investigate the molecular mechanism mediating this effect, we performed whole-cell patch-clamp recordings of TRPM6 expressed in human embryonic kidney 293 (HEK293) cells. Stimulation of the EGF receptor increased current through TRPM6 but not TRPM7. The carboxy-terminal alpha-kinase domain of TRPM6 did not participate in the EGF receptor-mediated increase in channel activity. This activation relied on both the Src family of tyrosine kinases and the downstream effector Rac1. Activation of Rac1 increased the mobility of TRPM6, assessed by fluorescence recovery after photobleaching, and a constitutively active mutant of Rac1 mimicked the stimulatory effect of EGF on TRPM6 mobility and activity. Ultimately, TRPM6 activation resulted from increased cell surface abundance. In contrast, dominant negative Rac1 decreased TRPM6 mobility, abrogated current development, and prevented the EGF-mediated increase in channel activity. In summary, EGF-mediated stimulation of TRPM6 occurs via signaling through Src kinases and Rac1, thereby redistributing endomembrane TRPM6 to the plasma membrane. These results describe a regulatory mechanism for transepithelial Mg2+ transport and consequently whole-body Mg2+ homeostasis.
IL-12 Release by Engineered T Cells Expressing Chimeric Antigen Receptors Can Effectively Muster an Antigen-Independent Macrophage Response on Tumor Cells That Have Shut Down Tumor Antigen Expression
Authors: Markus Chmielewski, Caroline Kopecky, Andreas A. Hombach, Hinrich Abken
Journal: Cancer Research (2011)

During malignant progression cancer cells tend to lose cell surface expression of MHC and other immune antigens, making them invisible to cytotoxic T cells and therefore inaccessible to tumor antigen-directed immunotherapy. Moreover, cancer cell variants that have lost antigen expression frequently contribute to deadly tumor relapses that occur following treatments that had been initially effective. In an effort to destroy antigen-loss cancer cells in tumors, we created a strategy that combines a chimeric antigen receptor (CAR)-redirected T-cell attack with an engineered local release of the cytokine interleukin 12 (IL-12), which recruits and reinforces macrophage function. Cytotoxic T cells were engineered to release inducible IL-12 upon CAR engagement in the tumor lesion, resulting in destruction of antigen-loss cancer cells that would normally escape. Importantly, elimination of the antigen-loss cancer cells was accompanied by an accumulation of activated macrophages that was critical to the antitumor response, because removing the macrophages abolished the response and restoring them reengaged it. Neutralizing TNF-α also abrogated the elimination of antigen-loss cancer cells, implying this proinflammatory factor in the process. Taken together, our results show how IL-12 supplementation by CAR T cells can target otherwise inaccessible tumor lesions, in a manner associated with reduced systemic toxicity, by recruiting and activating innate immune cells for a proinflammatory response.
Systems Science Methods in Public Health: Dynamics, Networks, and Agents
Authors: Douglas A. Luke, Katherine A. Stamatakis
Journal: Annual Review of Public Health (2012)

Complex systems abound in public health. Complex systems are made up of heterogeneous elements that interact with one another, have emergent properties that are not explained by understanding the individual elements of the system, persist over time, and adapt to changing circumstances. Public health is starting to use results from systems science studies to shape practice and policy, for example in preparing for global pandemics. However, systems science study designs and analytic methods remain underutilized and are not widely featured in public health curricula or training. In this review we present an argument for the utility of systems science methods in public health, introduce three important systems science methods (system dynamics, network analysis, and agent-based modeling), and provide three case studies in which these methods have been used to answer important public health science questions in the areas of infectious disease, tobacco control, and obesity.
Increased d-dimer concentration in plasma of patients with severe acute urticaria
Authors: A. Kasperska-Zajac, Z. Brzoza
Journal: British Journal of Dermatology (2009)

Conflicts of interest: none declared. SIR, Acute urticaria (AU) is a skin disease frequently caused by different factors (drugs, infections, allergens, psychological stress), although the exact aetiology remains unidentified in many cases. The underlying pathophysiology of AU is mast cell activation.1 The cells release different factors, which exert profibrinolytic and antithrombotic effects.2, 3 Interestingly, it has been demonstrated that the coagulation cascade is activated in chronic urticaria4 and severe exacerbation of the disease is associated with elevated plasma d‐dimer concentration.5d‐dimer is a useful marker, reflecting a potential activation of both the coagulation and fibrinolytic cascade. Considering that changes in the haemostasis system may contribute to the pathogenesis of some types of urticaria, in the present study we measured plasma concentrations of d‐dimer in patients suffering from AU. The study group consisted of 17 consecutive symptomatic patients (10 women and seven men; the median age was 32 years, range 21–42) with AU. The patients were divided into two groups by disease severity according to the criteria defined by Asero et al.5 Ten patients with severe AU were virtually covered by wheals (grade 4, very severe). Seven patients with mild/moderate AU had 1–10 small (< 3 cm in diameter) wheals (grade 1, slight) to 10–50 small wheals or 1–10 large wheals (grade 2, moderate). Five patients suffered from AU caused by nonsteroidal anti‐inflammatory drugs; three patients had AU presumably in the course of acute respiratory tract infection; one suffered from AU and concomitant urinary tract infection treated with antibiotics (amoxicillin). In the remaining eight, the reasons for AU were unidentified. No patient had a history of chronic urticaria. The patients had not taken anti‐urticarial drugs. Blood for analysis was taken within 24 h from the onset of symptoms. The control group consisted of 30 healthy subjects (23 women and seven men; the median age was 31 years, range 19–40), also described previously.6
Does TEC explain the emergence of distal representations?
Authors: Mark Siebel
Journal: Behavioral and Brain Sciences (2004)

Hommel et al. (2001) try to explain the emergence of distal representations by an evolutionary account which includes their theory of event coding. A closer look at the way the terms “distal representations” and “representations of events” are defined reveals, however, that their hypothesis of a common code for perceived and to-be-produced events is in fact superfluous. Moreover, it shows that they mix up empirical facts with conceptual/definitional facts in the second assumption of their explanation.
Efficacy and safety of adalimumab for the treatment of peripheral arthritis in spondyloarthritis patients without ankylosing spondylitis or psoriatic arthritis
Authors: Jacqueline E Paramarta, Leen De Rycke, Tanja F Heijda, Carmen A Ambarus, Koen Vos, Huib J Dinant, Paul P Tak, Dominique L Baeten
Journal: Annals of the Rheumatic Diseases (2012)

To evaluate the efficacy and safety of adalimumab in patients with peripheral spondyloarthritis (SpA) not fulfilling the criteria for ankylosing spondylitis (AS) or psoriatic arthritis (PsA).40 patients with active peripheral SpA fulfilling the European Spondyloarthropathy Study Group or Amor criteria but not the criteria for AS or PsA were included in a randomised, double-blind, placebo-controlled clinical trial. Patients were treated 1 : 1 with adalimumab or placebo for 12 weeks, followed by an open label extension up to week 24. Safety and efficacy measurements were performed every 6 weeks, with the patient's global assessment of disease activity at week 12 as the primary endpoint.At week 12, the patient's and physician's global assessment of disease activity, swollen joint count, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS) and erythrocyte sedimentation rate improved significantly in the adalimumab group compared with the baseline values and compared with placebo. A similar improvement was seen upon adalimumab treatment from weeks 12 to 24 in the patients originally randomised to placebo, whereas the clinical response was maintained or even augmented at week 24 in the patients who received adalimumab from the start. ASDAS inactive disease and BASDAI50 responses were met in 42% of the adalimumab group versus 0%-5% in the placebo group at week 12 (p=0.001 and p=0.008, respectively), and were further increased at week 24. The number of adverse events was not different between the adalimumab and placebo groups.Adalimumab appears to be effective and well tolerated in SpA patients with peripheral arthritis, also in those patients not fulfilling the AS or PsA criteria.
Transforming Growth Factor-β/Smads Signaling Induces Transcription of the Cell Type–Restricted Ankyrin Repeat Protein CARP Gene Through CAGA Motif in Vascular Smooth Muscle Cells
Authors: Hiroyoshi Kanai, Toru Tanaka, Yasushi Aihara, Sin-ichi Takeda, Masahiro Kawabata, Kohei Miyazono, Ryozo Nagai, Masahiko Kurabayashi
Journal: Circulation Research (2001)

Abstract —Transforming growth factor (TGF)-β plays a major role in the development of vascular diseases. Despite the pleiotropic effects of TGF-β on vascular smooth muscle cells (VSMCs), only a few genes have been characterized as direct targets of TGF-β in VSMCs. Cardiac ankyrin repeat protein (CARP) has been thought to be expressed exclusively in the heart. In the present study, we showed that CARP is expressed in the vasculature after balloon injury and in cultured VSMCs in response to TGF-β. Analysis of a half-life of the cytoplasmic CARP mRNA levels and the transient transfection of the CARP promoter/luciferase gene indicates that the regulation of CARP expression is increased by TGF-β at the transcriptional level. Transfection of expression vectors encoding Smads significantly activated the CARP promoter/luciferase activity. Deletion analysis and site-specific mutagenesis of the CARP promoter indicate that TGF-β response element is localized to CAGA motif at −108 bp relative to the transcription start site. Electrophoretic mobility shift assays showed that the binding activity to the CAGA motif was increased in nuclear extracts of cultured VSMCs by TGF-β. Cells transfected with adenovirus vector expressing CARP showed a significant decrease in DNA synthesis. Overexpression of CARP enhanced the TGF-β–mediated inhibition of the DNA synthesis. These data indicate that CARP is a downstream target of TGF-β/Smad signaling in VSMCs and suggest a role of CARP in mediation of the inhibitory effects of TGF-β on the proliferation of VSMCs.
Frequent <i>hSNF5/INI1</i> Germline Mutations in Patients with Rhabdoid Tumor
Authors: Franck Bourdeaut, Delphine Lequin, Laurence Brugières, Stéphanie Reynaud, Christelle Dufour, François Doz, Nicolas André, Jean-Louis Stephan, Yves Pérel, Odile Oberlin, Daniel Orbach, Christophe Bergeron, Xavier Rialland, Paul Fréneaux, Dominique Ranchere, Dominique Figarella-Branger, Georges Audry, Stéphanie Puget, D. Gareth Evans, Joan Carles Ferreres Pinas, Valeria Capra, Véronique Mosseri, Isabelle Coupier, Marion Gauthier-Villars, Gaëlle Pierron, Olivier Delattre
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Germline hSNF5/INI1 mutations are responsible for hereditary cases of rhabdoid tumors (RT) that constitute the rhabdoid predisposition syndrome (RPS). Our study provides the first precise overview of the prevalence of RPS within a large cohort of RT. Experimental Design: hSNF5/INI1 coding exons were investigated by sequencing and by multiplex ligation-dependent probe amplification. Results: Seventy-four constitutional DNAs from 115 apparently sporadic RT were analyzed from 1999 to 2009. Germline mutations were found in 26 patients (35%). Data from 9 individuals from 5 RPS families (siblings) were also studied. The median age at diagnosis was much lower (6 months) in patients with germline mutation (P &amp;lt; 0.01) than in patients without (18 months). Nevertheless, 7 of 35 patients with germline mutation (20%) developed the disease after 2 years of age. The mutation could be detected in only 1 parent whereas germline blood DNA was wild type in the 20 other parent pairs, therefore indicating the very high proportion of germ-cell mosaicism or of de novo mutations in RPS. The former hypothesis could be clearly documented in 1 case in which prenatal diagnosis was positive in a new pregnancy. Finally, the 2 years' overall survival was 7% in mutated and 29% in wild-type patients, mainly due to the worse outcome of RT in younger patients. Conclusions: Our results show a high proportion of germline mutations in patients with RT that can be found at any age and up to 60% in the youngest patients. Genetic counseling is recommended given the low but actual risk of familial recurrence. Clin Cancer Res; 17(1); 31–8. ©2011 AACR.
Identification of CGA as a novel estrogen receptor-responsive gene in breast cancer: an outstanding candidate marker to predict the response to endocrine therapy.
Authors: Ivan Bieche, Béatrice Parfait, Vivianne Le Doussal, Martine Olivi, Marie-Christine Rio, Rosette Lidereau, Michel Vidaud
Journal: Cancer Research (2001)

The estrogen receptor (ER) status of breast tumors is used to identify patients who may respond to endocrine agents such as tamoxifen. However, ER status alone is not perfectly predictive, and there is a pressing need for more reliable markers of endocrine responsiveness. Here, we identified the well-known CGA gene (coding for the alpha subunit of glycoprotein hormones) as a new ERalpha-responsive gene in human breast cancer cells. We used a real-time quantitative reverse transcription-PCR assay to quantify CGA mRNA copy numbers in a large series of breast tumors. CGA overexpression (> 10 SD above the mean for normal breast tissues) was observed in 44 of 131 (33.6%) breast tumor RNAs, ranging from 20 to 16,500 times the level in normal breast tissues; the highest levels of CGA gene expression were close to those observed in placenta. Significant links were observed between CGA gene overexpression and Scarff-Bloom-Richardson histopathological grade I+II (P = 0.015), and progesterone (P = 0.0009) and estrogen (P < 10(-7)) receptor positivity, which suggested that CGA is a marker of low tumor aggressiveness. We observed CGA mRNA overexpression in 44 of 90 (48.9%) ERalpha-positive tumors and in none of the 41 ERalpha-negative tumors. Immunohistochemical studies demonstrated that human chorionic gonadotropin alpha protein was strictly limited to ERalpha-positive tumor cells. Overexpression of the CGA gene was not accompanied by overexpression of the CGB gene. Our results also suggest that CGA could be a more reliable marker than PS2 and PR for ERalpha functionality and, thus, for endocrine responsiveness. Moreover, the CGA marker has the added value of dichotomizing ERalpha-positive patients into two subgroups of similar size. Specific antibodies directed to secreted human chorionic gonadotropin alpha protein are commercially available, thus facilitating the future application of this marker to the clinical management of breast cancer.
Increased ectodomain shedding of lung epithelial cell adhesion molecule 1 as a cause of increased alveolar cell apoptosis in emphysema
Authors: Takahiro Mimae, Man Hagiyama, Takao Inoue, Azusa Yoneshige, Takashi Kato, Morihito Okada, Yoshinori Murakami, Akihiko Ito
Journal: Thorax (2013)

<h3>Rationale</h3> Alveolar epithelial cell apoptosis and protease/antiprotease imbalance based proteolysis play central roles in the pathogenesis of pulmonary emphysema but molecular mechanisms underlying these two events are not yet clearly understood. Cell adhesion molecule 1 (CADM1) is a lung epithelial cell adhesion molecule in the immunoglobulin superfamily. It generates two membrane associated C terminal fragments (CTFs), αCTF and βCTF, through protease mediated ectodomain shedding. <h3>Objective</h3> To explore the hypothesis that more CADM1-CTFs are generated in emphysematous lungs through enhanced ectodomain shedding, and cause increased apoptosis of alveolar epithelial cells. <h3>Methods and results</h3> Western blot analyses revealed that CADM1-CTFs increased in human emphysematous lungs in association with increased ectodomain shedding. Increased apoptosis of alveolar epithelial cells in emphysematous lungs was confirmed by terminal nucleotide nick end labelling (TUNEL) assays. NCI-H441 lung epithelial cells expressing mature CADM1 but not CTFs were induced to express αCTF both endogenously (by shedding inducers phorbol ester and trypsin) and exogenously (by transfection). Cell fractionation, immunofluorescence, mitochondrial membrane potentiometric JC-1 dye labelling and TUNEL assays revealed that CADM1-αCTF was localised to mitochondria where it decreased mitochondrial membrane potential and increased cell apoptosis. A mutation in the intracytoplasmic domain abrogated all three abilities of αCTF. <h3>Conclusions</h3> CADM1 ectodomain shedding appeared to cause alveolar cell apoptosis in emphysematous lungs by producing αCTF that accumulated in mitochondria. These data link proteolysis to apoptosis, which are two landmark events in emphysema.