tbuckley/cabot-search huggingface dataset:
Healthy but not RSV-infected lung epithelial cells profoundly inhibit T cell activation
Authors: H Wang, Z Su, J Schwarze
Journal: Thorax (2008)

<h3>Background:</h3> Respiratory viruses, including respiratory syncytial virus (RSV), can cause asthma exacerbations and bronchiolitis. Both conditions are associated with enhanced cognate immune responses and inflammation and reduced immune regulation. Lung epithelial cells (LECs) can contribute to antiviral and allergic immune responses while gut epithelial cells can inhibit effector T cell responses. A study was performed to determine whether healthy LECs regulate antigen-specific T cell responses and if this regulation is lost during RSV infection. <h3>Methods:</h3> LA4 cells, a murine LEC line, infected with RSV or primary murine LECs were co-cultured with ovalbumin-specific T cell receptor transgenic CD4+ T cells from DO11.10 mice and ovalbumin-pulsed bone marrow-derived dendritic cells (DC) to assess T cell proliferation by flow cytometry and cytokine production. <h3>Results:</h3> The presence of LECs abrogated DC-induced T cell proliferation and significantly reduced T cell cytokine release. These effects of LECs were predominantly contact-dependent, primarily affected T cells directly and were partly mediated by transforming growth factor β. Soluble factors and DC-mediated effects also contributed to T cell inhibition. RSV infection of LECs reduced their inhibitory capacity in an infection dose-dependent manner. This was independent of proinflammatory cytokines released by infected LECs, but in part due to Toll-like receptor activation and to infection-induced cell death. <h3>Conclusion:</h3> Healthy LECs are potent inhibitors of T cell activation, but this regulatory function is lost after RSV infection. These findings suggest a central role for LECs in maintaining the tolerogenic environment of healthy lungs. Loss of this regulatory capacity after viral infection may allow development of excessive cognate immune responses and pulmonary inflammation.
Biliary decompression promotes Kupffer cell recovery in obstructive jaundice.
Authors: W D Clements, M McCaigue, P Erwin, I Halliday, B J Rowlands
Journal: Gut (1996)

Jaundiced patients undergoing surgical procedures have an increased risk of Gram negative sepsis with potential morbidity and mortality. Depressed Kupffer cell clearance capacity (KCCC) predisposes jaundiced patients to endotoxaemia and its sequelae. Biliary decompression remains the main therapeutic strategy in obstructive jaundice.This study investigates the efficacy of internal (ID) and external biliary drainage (ED) on KCCC in an experimental model of extrahepatic biliary obstruction.Adult male Wistar rats (250-300 g) were assigned to one of six groups: sham operated, where the bile duct was mobilised but not divided; bile duct ligation (BDL) for three weeks, and sham operated or BDL for three weeks followed by a second laparotomy and further 21 days of ID or ED, by way of choledochoduodenostomy or choledochovesical fistula respectively. KCCC was measured using an isolated hepatic perfusion technique with FITC labelled latex particles (0.75 mu) as the test probe. Plasma was assayed for bilirubin, endotoxin, and anticore glycolipid antibody (ACGA) concentrations.Jaundiced rats had reduced KCCC (p < 0.001), increased concentrations of ACGA (p < 0.001), and endotoxin (p < 0.001) compared with controls. Biliary drainage for three weeks produced a recovery in KCCC and normalisation of endotoxin and ACGA concentrations, however, external drainage was less effective than ID (p < 0.01).These data support the hypothesis that endotoxaemia and its mediated effects are integral in the pathophysiology of jaundice. Furthermore, a short period of internal biliary drainage is a useful therapeutic strategy in restoring Kupffer cell function and negating systemic endotoxaemia and consequent complications in biliary obstruction.
Apolipoprotein D and Platelet-Derived Growth Factor-BB Synergism Mediates Vascular Smooth Muscle Cell Migration
Authors: Wesley C.Y. Leung, Allan Lawrie, Sandra Demaries, Hamid Massaeli, Andrea Burry, Shmuel Yablonsky, Jennifer M. Sarjeant, Euridiki Fera, Eric Rassart, J. Geoffrey Pickering, Marlene Rabinovitch
Journal: Circulation Research (2004)

We identified apolipoprotein (apo)D in a search for proteins upregulated in a posttranscriptional manner similar to fibronectin in motile smooth muscle cells (SMCs). To address the function of apoD in SMCs, we cloned a partial apoD cDNA from ovine aortic (Ao) SMCs using RT-PCR. We documented a 2.5-fold increase in apoD protein but no increase in apoD mRNA in Ao SMCs 48 hours after a multiwound migration assay (P<0.01). Confocal microscopy revealed prominent perinuclear and trailing edge expression of apoD in migrating SMCs but not in the confluent monolayer. Stimulation of Ao SMCs with 10 ng/mL platelet-derived growth factor (PDGF)-BB increased apoD protein expression (P<0.05). Moreover, PDGF-BB-stimulated migration of human pulmonary artery SMCs was suppressed by knock-down of apoD using RNAi. Stable overexpression of apoD in Ao SMCs cultured in 10% fetal bovine serum promoted random migration by 62% compared with vector-transfected cells (P<0.01). Overexpression of apoD or addition of exogenous apoD to a rat aortic SMC line (A10) stimulated their migration in response to a subthreshold dose of PDGF-BB (P<0.05). This was unrelated to increased phosphorylation of ERK1/2 or of phospholipase C-gamma1, but correlated with enhanced Rac1 activation. This study shows that apoD can be expressed or taken up by SMCs and can regulate their motility in response to growth factors.
Medical paternalism and expensive unsubsidised drugs
Authors: Michael Jefford, Julian Savulescu, Jacqui Thomson, Penelope Schofield, Linda Mileshkin, Emilia Agalianos, John Zalcberg
Journal: BMJ (2005)

When discussing treatment with patients, doctors may not mention newly licensed drugs that are not yet funded by healthcare schemes. Although their motives are good, the ethics are questionable 

The development of new drugs can be a lengthy process, requiring initial laboratory and animal testing and then a course of clinical studies.1 Clinical assessment involves phase I testing, which focuses on determination of side effects and an appropriate dose for later study; phase II studies, which assess efficacy in people with a particular condition; and phase III studies, which generally compare a new, experimental treatment with an existing standard treatment. Once a therapeutic benefit has been shown, the drug company can apply for approval from the relevant regulatory body. An extensive review follows, which may take many months or years. If the drug is approved, further delays may occur before funding arrangements permit the drug to be widely available. We consider some of the ethical dilemmas surrounding this process, using the example of drugs to treat people with cancer.

In Australia, the cost of most prescription medicines is subsidised by the government through the pharmaceutical benefits scheme. New drugs that have been approved by the Therapeutic Goods Administration are assessed for inclusion in the scheme by the Pharmaceutical Benefits Advisory Committee, an independent expert committee consisting of medical practitioners and pharmacists. The committee considers several issues before recommending a drug, including efficacy, safety, quality of life benefits, and cost effectiveness. The committee may apply restrictions on how drugs can be prescribed. Long delays can occur between the Therapeutic Goods Administration approving a new drug and listing on the pharmaceutical benefits scheme.

Similar delays between approval and subsidisation exists in other countries. In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) has been accused of considerable …
Effect of interleukin 17 on proteoglycan degradation in murine knee joints
Authors: J. Dudler
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVE</h3> To evaluate the effect of murine interleukin 17 (IL17) on cartilage catabolism and joint inflammation by direct intra-articular injection of the cytokine into murine knee joints. <h3>METHODS</h3> Knees of normal C57 Bl mice were injected once or repeatedly with recombinant IL17 or IL1β. Inflammation was estimated by technetium-99m pertechnetate (<sup>99</sup>Tc) uptake and histological scoring of tissue sections. Proteoglycan depletion was evaluated by histological scoring of safranin O stained sections. Effects on proteoglycan synthesis were studied by <sup>35</sup>SO<sub>4</sub>incorporation. <h3>RESULTS</h3> A single intra-articular injection of IL17 (10 ng/knee) produced effects very similar to those of IL1β (10 ng/knee). No inflammation was detected at six or 24 hours by <sup>99</sup>Tc uptake. However, safranin O staining showed depletion of proteoglycan at 48 hours. Repeated injections of IL17 induced joint inflammation and cartilage proteoglycan depletion as shown by histological scoring. Unlike IL1β, proteoglycan depletion induced by IL17 seemed to be the result of increased degradation only, as no suppression of<sup>35</sup>SO<sub>4</sub> incorporation was seen. <h3>CONCLUSION</h3> These findings confirm, in vivo, the catabolic effects of IL17 on cartilage. IL17 is thus the first T cell cytokine showing a direct catabolic effect on cartilage in addition to stimulatory effects on macrophages and synoviocytes, making it a potentially important cytokine in the pathogenesis of arthritis.
Immune regulation of in vitro murine megakaryocyte development. Role of T lymphocytes and Ia antigen expression.
Authors: M W Long, D N Shapiro
Journal: The Journal of Experimental Medicine (1985)

Mitogen-activated murine T lymphocytes or T cell hybridomas produce an activity (megakaryocyte [Mk] potentiator activity) that enhances the in vitro growth and development of Mk colonies. This activity was found in optimal concentrations (2.5%) in T cell hybridoma-conditioned medium, and was also produced by feeder layers of concanavalin A-activated T cells. A subpopulation of murine Mk progenitor cells (colony-forming units; CFU-Mk) bears the Ia antigen. Separate experiments indicated that T cell products stimulate CFU-Mk by increasing their basal levels of Ia expression as well as the frequency of cells actively synthesizing DNA. The hypothesis that the expression of this antigen was related to the cell cycle status of these progenitor cells was confirmed in studies that indicated that ablation of actively cycling cells in vivo abrogated the cytotoxic effects of anti-Ia monoclonal antibodies. The interdependence of T cell lymphokine regulation of both Ia expression and cell cycle status was also seen in in vitro experiments in which Ia+ progenitor cells were eliminated by complement-dependent cytotoxicity. The removal of Ia+ cells prevented 5-hydroxyurea-mediated inhibition of cells in S phase. We hypothesize that immune modulation of megakaryocytopoiesis occurs via soluble T cell products that augment Mk differentiation. Further, the mechanism of immune recognition/modulation may occur via Ia antigens present on the surface of these progenitor cells.
Plexin-A4–semaphorin 3A signaling is required for Toll-like receptor– and sepsis-induced cytokine storm
Authors: Haitao Wen, Yu Lei, So-Young Eun, Jenny P.-Y. Ting
Journal: The Journal of Experimental Medicine (2010)

Plexins and semaphorins are ligand–receptor pairs that serve as guidance molecules in the nervous system and play some roles in immunity. Plexins are similar to the Toll-like receptors (TLRs) in their evolutionary conservation from flies to mammals. By studying plexin-A4–deficient (Plxna4−/−) innate immune cells, in this study we show a novel influence of plexin-A4 on TLR signaling. Plxna4−/− cells exhibit defective inflammatory cytokine production upon activation by a spectrum of TLR agonists and bacteria. Plexin-A4 is required for TLR-induced activation of the small guanosine triphosphate hydrolase (GTPase) Rac1 (ras-related C3 botulinum toxin substrate 1). Rac1 activation is accompanied by JNK (c-Jun N-terminal kinase) and NF-κB activation, culminating in TLR-induced binding of NF-κB and AP-1 to the promoters of inflammatory cytokines. Plxna4−/− mice are remarkably resistant to TLR agonist–induced inflammation and polymicrobial peritonitis caused by cecal ligation and puncture. Administration of a ligand of plexin-A4, Sema3A (semaphorin 3A), exacerbates the cytokine storm caused by TLR agonists and bacterial sepsis. TLR engagement can induce Sema3A expression, thus completing an autocrine loop. These findings expand the role of plexins to TLR signaling and suggest plexin-A4 and Sema3A as new intervention points for treating sepsis.
A Randomized Trial of a Low-Carbohydrate Diet for Obesity
Authors: Gary D. Foster, Holly R. Wyatt, James O. Hill, Brian G. McGuckin, Carrie Brill, B. Selma Mohammed, Philippe O. Szapary, Daniel J. Rader, Joel S. Edman, Samuel Klein
Journal: New England Journal of Medicine (2003)

Despite the popularity of the low-carbohydrate, high-protein, high-fat (Atkins) diet, no randomized, controlled trials have evaluated its efficacy.
Definition of risk factors for death, end stage renal disease, and thromboembolic events in a monocentric cohort of 338 patients with systemic lupus erythematosus
Authors: K Manger
Journal: Annals of the Rheumatic Diseases (2002)

The survival rate in patients with systemic lupus erythematosus (SLE) has improved dramatically during the past four decades to 96.6% (five year) in the Erlangen cohort, but it is nearly three times as high as in an age and sex matched control population. Reasons for death are mainly cardiovascular diseases (37%) and infections (29%).To find risk factors existing at disease onset for a severe outcome in the Erlangen cohort.By using a database of 338 patients with SLE from a single centre, documented at least one to 15 years and including Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage score data and index (SDI) and an activity score (European Consensus Lupus Activity Measurement (ECLAM)), a retrospective search was made for risk factors for a severe outcome like death, end stage renal disease (ESRD), and thromboembolic events (TE) in SLE. For this purpose, multivariable Cox regression models were analysed using the statistical package SPSS 10.0 for Windows.The following were defined as risk factors for death at disease onset: male sex (p<0.001, relative risk (RR)=3.5), age >40 at disease onset (p<0.0001, RR=19.9), nephritis (p<0.05, RR=1.6), a reduction of creatinine clearance (p<0.001, RR=1.8), heart disease (p=0.05, RR=1.5), and central nervous system (CNS) disease (p=0.06, RR=1.6). An increase in the SDI of two or more points from the first to the third year of disease was the worst prognostic factor (p<0.0001, RR=7.7). The existence of Ro or nRNP antibodies, or both, was protective (p<0.05, RR =0.1). A low C3 (p<0.01 RR=3.0) and splenomegaly (p<0.01 RR=2.7) at disease onset turned out to be risk factors for ESRD besides a nephritis. In patients with hypertension (p<0.05) and/or high titres of dsDNA antibodies (>70 U/l) (p<0.01) and/or a mean ECLAM score of 4 (p<0.01) in the course of disease, a prevalence of ESRD was recorded in 9% (p<0.05) and 10% (p<0.01), and 8% (p<0.01) v 4% in the whole group. Analysis of risk factors at disease onset for TE identified positive lupus anticoagulant (p=0.17, RR=1.6), cryoglobulins (p<0.05, RR=1.8), and nephritis (p=0.05, RR=1.4), in addition to an age >40 at disease onset.A subgroup of patients in the Erlangen cohort with a typical clinical and serological phenotype at disease onset that is at high risk for a worse outcome was identified. Identification of these white patients at risk at disease onset will enable treatment to be intensified and thereby possibly prevent or better control late stage manifestations.
Getting More Out of Radiation Therapy in Glioblastoma
Authors: Brandyn A. Castro, Manish K. Aghi
Journal: Neuro-Oncology (2013)

While radiation therapy has been standard of care for newly diagnosed glioblastoma for several decades, it only delays but does not prevent recurrence of these aggressive tumors. Therefore, the identification and targeting of factors allowing glioblastoma cells to escape the deleterious effects of radiation is essential to allow this therapeutic modality to fulfill its potential. In an elegant study published in 2010, the Brown lab reported that irradiation induces recruitment of bone marrow-derived cells (BMDCs) into glioblastoma to form blood vessels de novo, a process defined as vasculogenesis, in contrast to angiogenesis which involves the remodeling of existing vessels in the tumor bed.1 In that study, pharmacologic inhibition of HIF-1 or of the interaction between the chemokine stromal derived factor-1 (SDF-1, CXCL12) and its receptor CXCR4 prevented the influx of BMDCs, primarily CD11b+ myelomonocytes, and the development of functional tumor vasculature after radiation, resulting in abrogation of tumor regrowth.1

Now, in a follow-up study entitled “Blockade of SDF-1 after irradiation inhibits tumor recurrences of autochthonous brain tumors in rats” published in this issue of Neuro-Oncology2, Liu and colleagues from that same group sought to improve upon limitations previously reported when they1 and others3 targeted the SDF-1/CXCR4 interaction using the small molecule CXCR4 inhibitor plerixafor (AMD3100). Specifically, the authors noted that endothelial cells in tumors like glioblastoma express high levels of CXCR7, the more recently discovered second receptor for SDF-1.4 Of note, besides its blockade of CXCR4, plerixafor is actually an allosteric agonist of CXCR7,5 which can signal through β-arrestin and may activate the endothelium leading to increased invasiveness of cancer cells.6

The authors therefore investigated combining radiation therapy with NOX-A12, 45 L-enantiomeric RNA nucleotides which form a structural scaffold that recognizes SDF-1 with high affinity and thus efficiently blocks the chemokine's interaction with CXCR4 and CXCR7 (Figure 1). They showed that NOX-A12 inhibits SDF-1 dependent chemotaxis of CXCR4 myelomonocytes and SDF-1 dependent CXCR7 internalization in endothelial cells. 






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Fig. 1.


Dual receptors lead to dual functions of SDF-1 (CXCL12) in glioblastoma vasculogenesis after radiation therapy. Irradiated tumor cells secrete SDF-1, which binds CXCR4 expressed by marrow-derived myelomonocytes and CXCR7 expressed by marrow-derived endothelial precursors, which together participate in vasculogenesis.
T Cell Surveillance of Oncogene-Induced Prostate Cancer Is Impeded by T Cell-Derived TGF-β1 Cytokine
Authors: Moses K. Donkor, Abira Sarkar, Peter A. Savage, Ruth A. Franklin, Linda K. Johnson, Achim A. Jungbluth, James P. Allison, Ming O. Li
Journal: Immunity (2011)
DNA-Mutation Inventory to Refine and Enhance Cancer Treatment (DIRECT): A Catalog of Clinically Relevant Cancer Mutations to Enable Genome-Directed Anticancer Therapy
Authors: Paul Yeh, Heidi Chen, Jenny Andrews, Riyad Naser, William Pao, Leora Horn
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Tumor gene mutation status is becoming increasingly important in the treatment of patients with cancer. A comprehensive catalog of tumor gene–response outcomes from individual patients is needed, especially for actionable mutations and rare variants. We created a proof-of-principle database [DNA-mutation Inventory to Refine and Enhance Cancer Treatment (DIRECT)], starting with lung cancer-associated EGF receptor (EGFR) mutations, to provide a resource for clinicians to prioritize treatment decisions based on a patient's tumor mutations at the point of care. Methods: A systematic search of literature published between June 2005 and May 2011 was conducted through PubMed to identify patient-level, mutation–drug response in patients with non–small cell lung cancer (NSCLC) with EGFR mutant tumors. Minimum inclusion criteria included patient's EGFR mutation, corresponding treatment, and an associated radiographic outcome. Results: A total of 1,021 patients with 1,070 separate EGFR tyrosine kinase inhibitor therapy responses from 116 different publications were included. About 188 unique EGFR mutations occurring in 207 different combinations were identified: 149 different mutation combinations were associated with disease control and 42 were associated with disease progression. Four secondary mutations, in 16 different combinations, were associated with acquired resistance. Conclusions: As tumor sequencing becomes more common in oncology, this comprehensive electronic catalog can enable genome-directed anticancer therapy. DIRECT will eventually encompass all tumor mutations associated with clinical outcomes on targeted therapies. Users can make specific queries at http://www.mycancergenome.org/about/direct to obtain clinically relevant data associated with various mutations. Clin Cancer Res; 19(7); 1894–901. ©2013 AACR.
Pulmonary arterial hypertension: Long term effects of oral ambrisentan on clinical status, exercise capacity and haemodynamics
Authors: Michele D'Alto, Emanuele Romeo, Paola Argiento, Anna Correra, Berardo Sarubbi, Antonello D'Andrea, Antonietta Caronna, Maria Pignatiello, Nicola Grimaldi, Raffaele Calabrò, Maria Giovanna Russo
Journal: European Respiratory Journal (2012)

Aim. To evaluate the efficacy and safety of oral ambrisentan in adult patients with pulmonary arterial hypertension (PAH) by assessing its long term effects on clinical status, exercise capacity and cardiopulmonary haemodynamics.  Methods. This was a single-centre, open-label, single-arm, prospective study. Clinical status, resting transcutaneous oxygen saturation (SpO2), 6-minute walk distance, serology and RHC were assessed at baseline (before starting ambrisentan therapy) and at one year follow-up.  Results. Twenty-seven consecutive adult patients (18 female, age 51±11y) with PAH (15 with idiopathic, 7 with congenital heart disease-related and 5 with connective tissue-related PAH) were enrolled. No patient treated with ambrisentan developed aminotransferase concentrations >3 times the upper limit of normal. After 12±4 months of therapy, an improvement in clinical status, 6-minute walk distance, pro-brain natriuretic peptide and haemodynamics was observed.  Conclusions. Long term ambrisentan therapy is safe and well tolerated at 12-month follow-up, resulting in a significant improvement in clinical status, exercise capacity and cardiopulmonary heamodynamics.