tbuckley/cabot-search huggingface dataset:
The Measurement of Pain from Metastatic Bone Disease: Capturing the Patient's Experience
Authors: Charles S. Cleeland
Journal: Clinical Cancer Research (2006)

Abstract Pain is prevalent for large numbers of patients with metastatic cancer, and this pain is often due to bone metastases. Despite the availability of effective pain treatments and various pain management guidelines, multiple studies document the undertreatment of pain in patients with cancer. The most frequently identified barriers to appropriate pain management are physician underestimation of the patient's pain, inadequate pain assessment, and patient reluctance to report pain. A first step toward reducing inadequate pain control in clinical practice is adequate assessment of cancer pain using validated pain measurement instruments. Using treatment for bone pain as an example, we discuss how patient satisfaction measures and self-report measures of pain and other symptoms, symptom interference with patient function, and related adverse effects can be combined with appropriate trial design to provide the information needed to choose the best possible treatment for bone pain. Symptom assessment needs to be done via standardized questionnaires, administered at appropriate times during the trial. The Brief Pain Inventory uses 11-point numerical rating scales to measure both pain severity and the resulting functional interference caused by pain. These severity and interference ratings can be further categorized as mild, moderate, or severe, as required to implement most pain management guidelines and define outcome expectations for clinical trials. Consistent pain measurement and standardized recording of analgesic use across clinical trials would enhance comparability and increase the chances that treatment decisions for management of bone pain could be evidence based. These and other considerations in the design of clinical trials are discussed.
Simultaneous Visualization of Protumorigenic Src and MT1-MMP Activities with Fluorescence Resonance Energy Transfer
Authors: Mingxing Ouyang, He Huang, Nathan C. Shaner, Albert G. Remacle, Sergey A. Shiryaev, Alex Y. Strongin, Roger Y. Tsien, Yingxiao Wang
Journal: Cancer Research (2010)

Abstract Both Src kinase and membrane type 1 matrix metalloproteinase (MT1-MMP) play critical roles in cancer invasion and metastasis. It is not clear, however, how the spatiotemporal activation of these two critical enzymes is coordinated in response to an oncogenic epithelial growth factor (EGF) stimulation. Here, we have visualized the activities of Src and MT1-MMP concurrently in a single live cell by combining two fluorescence resonance energy transfer (FRET) pairs with distinct spectra: (a) cyan fluorescent protein (CFP) and yellow FP (YFP), and (b) orange FP (mOrange2) and red FP (mCherry). The new FRET pair, mOrange2 and mCherry, was first characterized in vitro and in cultured mammalian cells. When integrated with the CFP/YFP pair, this new pair allowed the revelation of an immediate, rapid, and relatively dispersed Src activity. In contrast, the MT1-MMP activity displayed a slow increase at the cell periphery, although Src was shown to play a role upstream to MT1-MMP globally. This difference in the activation patterns of MT1-MMP and Src in response to EGF is further confirmed using an optimized MT1-MMP biosensor capable of being rapidly cleaved by MT1-MMP. The results indicate that although Src and MT1-MMP act globally in the same signaling pathway, their activations differ in space and time upon EGF stimulation, possibly mediated by different sets of intermediates at different subcellular locations. Our results also showed the potential of mOrange2/mCherry as a new FRET pair, together with the popular variants of CFP and YFP, for the simultaneous visualization of multiple molecular activities in a single live cell. Cancer Res; 70(6); 2204–12
Dust exposure: a missed environmental factor of Wegener's granulomatosis
Authors: B Granel
Journal: Annals of the Rheumatic Diseases (2002)

Infectious agents, genetic background, and environmental exposure as observed in this case report, are thought to play a part in Wegener's granulomatosis (WG).1

A 54 year old man consulted in 1999 for an eight year history of bilateral crusty and bloody rhinosinusitis. He had worked from 1965 to 1980 as a ship's carpenter. During this period he had constantly had nose pain, sore mucosal discomfort, frequent nasal bloody discharge, and chronic nasal obstruction when planing woods (iroko, oak, and ash), removing paint, and undertaking activities with dust exposure. He did not wear a mask. He had been a heavy smoker until the age of 40 and had never used cocaine. No nasal deformity was noted. Nasal fibroscopy disclosed erythematous and inflamed mucosa of the nasal …
How to teleconference effectively
Authors: H.C. Williams, J.R. Chalmers
Journal: British Journal of Dermatology (2015)

Teleconferencing, whereby a meeting is conducted over the telephone, is a convenient way of getting clinical, management or research business done for people residing in different locations, saving travelling time and costs, and reducing carbon emissions. Despite the convenience, teleconferences are often run poorly, due to inadequate planning or lack of understanding of the technology. Non-engaged participants typing emails, loud background noises and failure of the chair to bring in all participants and sum up are common problems. This Perspectives article seeks to offer some simple practical guidance to those hosting and participating in teleconferences in order to improve effective communication and efficient decision making.
Basic Mechanisms of Prostaglandin Action on Autonomic Neurotransmission
Authors: P Hedqvist
Journal: The Annual Review of Pharmacology and Toxicology (1977)

More than 40 years ago Euler (1) and Goldblatt (2) independently described the striking pharmacodynamic actions of human seminal plasma and extracts of sheep vesicular gland added to isolated organs or injected into the whole animal. Since the biological effects could not be accounted for by any known naturally occurring compound, the active substance(s) was named prostaglandin (3). Today prostaglan­ din (PG) is recognized, not as one, but rather a family of fatty acids of almost ubiquitous distribution in the mammalian organism. The principal biosynthetic pathways of the PGs and certain nonprostanoic compounds from their precursor, arachidonic acid, are shown in Figure 1. It should be recalled that PGs are formed from two other precursors as well, the only difference being the number of double bonds in the side chains, as indicated by the subscript numbers of the different PGs. Although the PG principle has been known for many years, it is only within the last decade that the pharmacology of the PGs has been systematically and exten­ sively investigated. These efforts, greatly aided by the availability of synthetic PGs and potent inhibitors of PG synthesis, have demonstrated that the PGs possess an impressive range of biological activities, which has given rise to many speculations concerning their physiological or pathophysiological significance. Admittedly, the PGs have distinct actions on most mammalian tissues, but few effects seem to be of the same widespread significance as those on autonomic nerves, since the auto­ nomic nervous system is such an essential regulator of the activities of a large number of organs and organ systems. There is a rapidly growing body of evidence indicating that PGs are released in the vicinity of autonomic neuroeffector junctions, both spontaneously and as a result of physical, chemical, and electrical stimuli; that PGs influence both transmitter release from nerve terminals and the response to the secreted transmitter; and that inhibitors of PG synthesis produce effects opposite to those of the POs. Taken
Enterocyte-specific A20 deficiency sensitizes to tumor necrosis factor–induced toxicity and experimental colitis
Authors: Lars Vereecke, Mozes Sze, Conor Mc Guire, Brecht Rogiers, Yuanyuan Chu, Marc Schmidt-Supprian, Manolis Pasparakis, Rudi Beyaert, Geert van Loo
Journal: The Journal of Experimental Medicine (2010)

A20 is a nuclear factor κB (NF-κB) target gene that encodes a ubiquitin-editing enzyme that is essential for the termination of NF-κB activation after tumor necrosis factor (TNF) or microbial product stimulation and for the prevention of TNF-induced apoptosis. Mice lacking A20 succumb to inflammation in several organs, including the intestine, and A20 mutations have been associated with Crohn’s disease. However, ablation of NF-κB activity, specifically in intestinal epithelial cells (IECs), promotes intestinal inflammation. As A20 deficiency sensitizes cells to TNF-induced apoptosis yet also promotes NF-κB activity, it is not clear if A20 deficiency in IECs would exacerbate or ameliorate intestinal inflammation. We generated mice lacking A20 specifically in IECs. These mice did not show spontaneous intestinal inflammation but exhibited increased susceptibility to experimental colitis, and their IECs were hypersensitive to TNF-induced apoptosis. The resulting TNF-driven breakdown of the intestinal barrier permitted commensal bacterial infiltration and led to systemic inflammation. These studies define A20 as a major antiapoptotic protein in the intestinal epithelium and further indicate that defects in A20 might contribute to inflammatory bowel disease in humans.
The TAO-Gen Algorithm for Identifying Gene Interaction Networks with Application to SOS Repair in <i>E. coli</i>
Authors: Takeharu Yamanaka, Hiroyoshi Toyoshiba, Hideko Sone, Frederick M. Parham, Christopher J. Portier
Journal: Environmental Health Perspectives (2004)

One major unresolved issue in the analysis of gene expression data is the identification and quantification of gene regulatory networks. Several methods have been proposed for identifying gene regulatory networks, but these methods predominantly focus on the use of multiple pairwise comparisons to identify the network structure. In this article, we describe a method for analyzing gene expression data to determine a regulatory structure consistent with an observed set of expression profiles. Unlike other methods this method goes beyond pairwise evaluations by using likelihood-based statistical methods to obtain the network that is most consistent with the complete data set. The proposed algorithm performs accurately for moderate-sized networks with most errors being minor additions of linkages. However, the analysis also indicates that sample sizes may need to be increased to uniquely identify even moderate-sized networks. The method is used to evaluate interactions between genes in the SOS signaling pathway in Escherichia coli using gene expression data where each gene in the network is over-expressed using plasmids inserts.
Suppressor cell regulation of cell-mediated immune responses in renal infection in vitro modulation of suppressor cell activity.
Authors: T Miller, E Marshall
Journal: Journal of Clinical Investigation (1980)

Infection-induced anergy is a frequent complication of bacterial, viral, and parsitic infection. A marked suppression of the thymus-derived (T) lymphocyte response to concanavalin A has been demonstrated in vitro during renal infection and the mechanisms by which suppression occurs have been investigated. In particular we have considered the possibility that suppression might result from the inhibitory effect of prostaglandins, secreted by activated macrophages with immunoregulatory potential. The experiments have shown that the T-lymphocyte effector status in experimentally-induced renal infection is determined by two suppressor cells, one infection-induced and the other naturally occurring. The inability to respond to mitogenic stimulation was reversible and restoration of immune responsiveness to splenic lymphocytes from infected animals could be achieved in two stepwise manipulations; differential centrifugation removed the infection-induced suppressor cells, and the suppressor activity of the naturally occurring suppressor cells could then be inhibited by indomethacin. Thus the two suppressor cells were distinguishable on the basis of their physical characteristics and their response to indomethacin. The dominant factor determining the immune responsiveness of splenic lymphocytes from the pyelonephritic animals was, however, the infection-induced suppressor cell. This cell has been characterized as a sedimentable cell (30 g) with suppressor activity demonstrable in co-culture experiments. Plastic-adherent cells from the sedimentable fraction of pyelonephritic animals' splenic cells were shown to have suppressor activity that was not inhibited by indomethacin. The infection-induced and naturally occurring suppressor cells can be viewed as prototypes for the equivalent cells in man and may be useful models for studying the role of these cells as determinants in the pathogenesis of infectious disease.
Adeno-associated virus-mediated aspartoacylase gene transfer to the brain of knockout mouse for canavan disease
Authors: Reuben Matalon, Sankar Surendran, Peter L Rady, Michael J Quast, Gerald A Campbell, Kimberlee M Matalon, Stephen K Tyring, Jingna Wei, Carmen S Peden, E.d L Ezell, Nicholas Muzyczka, Ronald J Mandel
Journal: Molecular Therapy (2003)

Canavan disease (CD) is an autosomal recessive leukodystrophy caused by deficiency of aspartoacylase (ASPA). Deficiency of ASPA leads to elevation of N-acetyl-l-aspartic acid (NAA) in the brain and urine. To explore the feasibility of gene transfer to replace ASPA in CD, we generated a knockout mouse and constructed an AAV vector that encodes human ASPA cDNA (hASPA) followed by green fluorescent protein (GFP) after an intraribosomal entry site. We injected CD mice with rAAV-hASPA-GFP in the striatum and thalamus or injected rAAV-GFP identically into control animals. Three to five months after the injection, we determined the presence of ASPA in the CD mouse brain by ASPA activity assay, GFP expression, and Western blot analysis. While rAAV-GFP-injected animals displayed undetectable levels of ASPA, all detection methods revealed significant ASPA levels in rAAV-hASPA-GFP-injected CD mice. We evaluated the functional effects of rAAV-hASPA-GFP-mediated ASPA expression by standard histological methods, magnetic resonance spectroscopy (MRS) for in vivo NAA levels, and magnetic resonance imaging of CD mice. rAAV-hASPA-injected animals displayed a remarkable lack of spongiform degeneration in the thalamus. However, pathology in sites unrelated to the injected areas showed no improvement in histopathology. The improvement in thalamic neuropathology was also detectable via in vivo MRI. MRS revealed that in vivo NAA levels were also reduced. These data indicate that rAAV-mediated ASPA delivery may be an interesting avenue for the treatment of CD.
Low-dose nebulized morphine does not improve exercise in interstitial lung disease.
Authors: A O Harris-Eze, G Sridhar, R E Clemens, T A Zintel, C G Gallagher, D D Marciniuk
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Recent reports have suggested that low-dose nebulized morphine may improve exercise tolerance in patients with interstitial lung disease (ILD) by acting on peripheral opioid-sensitive pulmonary receptors. We therefore examined whether the administration of low-dose nebulized morphine would influence dyspnea or the breathing pattern during exercise of subjects with ILD and improve their exercise performance. Each of six subjects with ILD underwent three maximal incremental cycle ergometer tests, each test separated from the last by at least 3 d. Each exercise test was similar except that 30 min before exercise, the subjects received nebulized saline (control), morphine 2.5 mg, or morphine 5.0 mg, respectively, in double-blinded fashion. No significant differences were noted in exercise duration, maximal workload, or sense of dyspnea at the end of exercise in the control test and the tests with either morphine 2.5 mg or morphine 5.0 mg. Nor were significant differences noted in resting, submaximal, or end-exercise measurements of oxygen uptake (VO2), carbon dioxide output (VCO2), end-tidal CO2 (PETCO2), oxygen saturation (SaO2), minute ventilation (VI), respiratory frequency (f), tidal volume (VT), or heart rate (HR) in the three tests. Low-dose nebulized morphine did not alter the subjects' breathing pattern or affect the relationship between dyspnea and ventilation during exercise. No significant side effects were noted. The administration of low-dose nebulized morphine to subjects with ILD neither relieves their dyspnea during exercise nor improves their maximal exercise performance.
Rheumatoid arthritis: correlation between rheumatoid factor levels and CA-125 tumour marker elevation
Authors: N. Tsavaris, C. P Mavragani, P. Dimitrios
Journal: Annals of the Rheumatic Diseases (2007)

Rheumatoid factors (RFs) are autoantibodies directed against the Fc portion of IgG. Tumour markers (eg, CA-125, CA-19-9) are tumour-expressed proteins that are usually measured in the serum by means of ELISA sandwich assays, in which murine monoclonal antibodies are used to capture the circulating antigen under investigation.1–3

Given the extensive homology between the Fc regions of murine and human IgG antibodies, it may not be unexpected that anecdotal reports have shown that tumour markers can be falsely increased in the presence of human antimouse antibodies or RFs.4–6 We systematically sought to determine whether patients with active RF-positive rheumatoid arthritis …
Vaccination With Cetuximab Mimotopes and Biological Properties of Induced Anti–Epidermal Growth Factor Receptor Antibodies
Authors: Angelika B. Riemer, Harald Kurz, Markus Klinger, Otto Scheiner, Christoph C. Zielinski, Erika Jensen-Jarolim
Journal: JNCI Journal of the National Cancer Institute (2005)

The monoclonal antibody cetuximab (IMC-225, Erbitux) inhibits epidermal growth factor receptor (EGFR) signaling and has been approved for metastatic colon cancer therapy. However, to achieve effective titers, passive antibody therapies must be repeatedly administered over long periods. To overcome this limitation, we aimed to generate a vaccine inducing continuously available "cetuximab-like" antibodies in vivo using the mimotope approach.We used the phage display technique to identify four peptides structurally mimicking the cetuximab epitope. We coupled two of these peptides to an immunogenic carrier protein, and we vaccinated four groups (n = 8) of BALB/c mice intraperitoneally with 10 microg of the mimotope conjugates, a control peptide conjugate, or the carrier protein alone. We assessed antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity mediated by the induced antibodies against EGFR-overexpressing human A431 carcinoma cells. We then tested receptor internalization capacity of the induced antibodies with fluorescently labeled EGFR, and we assayed their growth inhibitory potential toward A431 cells with a [3H]thymidine proliferation assay.Mimotope-induced antibodies recognized EGFR, and both types of antibody-mediated cytotoxic effects were elicited by these antibodies. In both cellular cytotoxicity assays, the mimotope-induced antibodies exhibited specific lysis of more than 50%. The induced antibodies caused internalization of the receptor from the cell surface into endocytic vesicles and inhibited growth of EGFR-expressing cells to a similar extent as cetuximab [67% (95% confidence interval {CI} = 55% to 79%) and 69% (95% CI = 55% to 84%), respectively].Epitope-specific immunization is feasible for active anti-EGFR immunotherapy. The in vitro biologic features of mimotope-induced antibodies are similar to those of the monoclonal antibody cetuximab.
Dysbiosis and Staphylococcus aureus Colonization Drives Inflammation in Atopic Dermatitis
Authors: Tetsuro Kobayashi, Martin Glatz, Keisuke Horiuchi, Hiroshi Kawasaki, Haruhiko Akiyama, Daniel H. Kaplan, Heidi H. Kong, Masayuki Amagai, Keisuke Nagao
Journal: Immunity (2015)
Origin and regulation of a disease-specific autoantibody response. Antigenic epitopes, spectrotype stability, and isotype restriction of anti-Jo-1 autoantibodies.
Authors: F W Miller, S A Twitty, T Biswas, P H Plotz
Journal: Journal of Clinical Investigation (1990)

Anti-Jo-1 antibodies (AJoA), which bind to and inhibit the activity of histidyl-transfer RNA synthetase (HRS), are found in a genetically and clinically distinct subset of myositis patients. This specificity suggests that understanding the antigenic epitopes and immunoregulation governing the production of AJoA may result in clues to disease pathogenesis. Limited digestion of human HRS by V8 protease resulted in four major antigenic polypeptides of 35, 34, 21, and 20 kD; digestion with subtilisin gave four fragments of the same sizes and two additional major antigenic polypeptides of 28 and 17 kD. Sera from 12 AJoA positive patients reacted indistinguishably with these proteolytic fragments by Western blotting, and AJoA elution studies suggested a common epitope(s) on all six. Isoelectric focusing showed a different polyclonal pattern of AJoA in each patient, although serial analyses in individual patients revealed stable AJoA spectrotypes over years of observation. Enzyme-linked immunosorbent assays showed that the AJoA response was mainly restricted to the IgG1 heavy chain isotype. The levels of IgG1 AJoA varied in proportion to disease activity over time but were independent of total IgG1 levels, and three patients became AJoA negative as their myositis remitted after treatment. These findings suggest that AJoA are induced by an antigen-driven mechanism, bind to a common epitope or epitopes on HRS, and are modulated by an immune response closely linked to that which is responsible for myositis in these patients.
Immune Infiltration of Spontaneous Mouse Astrocytomas Is Dominated by Immunosuppressive Cells from Early Stages of Tumor Development
Authors: Nhu Nam Tran Thang, Madiha Derouazi, Géraldine Philippin, Séverine Arcidiaco, Wilma Di Berardino-Besson, Frédérick Masson, Sabine Hoepner, Cristina Riccadonna, Karim Burkhardt, Abhijit Guha, Pierre-Yves Dietrich, Paul R. Walker
Journal: Cancer Research (2010)

Immune infiltration of advanced human gliomas has been shown, but it is doubtful whether these immune cells affect tumor progression. It could be hypothesized that this infiltrate reflects recently recruited immune cells that are immediately overwhelmed by a high tumor burden. Alternatively, if there is earlier immune detection and infiltration of the tumor, the question arises as to when antitumor competency is lost. To address these issues, we analyzed a transgenic mouse model of spontaneous astrocytoma (GFAP-V(12)HA-ras mice), which allows the study of immune interactions with developing glioma, even at early asymptomatic stages. T cells, including a significant proportion of Tregs, are already present in the brain before symptoms develop, followed later by macrophages, natural killer cells, and dendritic cells. The effector potential of CD8 T-cells is defective, with the absence of granzyme B expression and low expression of IFN-gamma, tumor necrosis factor, and interleukin 2. Overall, our results show an early defective endogenous immune response to gliomas, and local accumulation of immunosuppressive cells at the tumor site. Thus, the antiglioma response is not simply overwhelmed at advanced stages of tumor growth, but is counterbalanced by an inhibitory microenvironment from the outset. Nevertheless, we determined that effector molecule expression (granzyme B, IFN-gamma) by brain-infiltrating CD8 T-cells could be enhanced, despite this unfavorable milieu, by strong immune stimuli. This potential to modulate the strong imbalance in local antiglioma immunity is encouraging for the development and optimization of future glioma immunotherapies.