tbuckley/cabot-search huggingface dataset:
Acute lung injury: how the lung inflammatory response works
Authors: P A Ward
Journal: European Respiratory Journal (2003)

<h3>ABSTRACT</h3> Specialized epithelia produce apical matrices with distinctive topographies by enigmatic mechanisms. Here, we describe a holistic mechanism that integrates cortical actomyosin dynamics with apical matrix remodeling to pattern <i>C. elegans</i> cuticles. Therein, axial AFBs appear near the surface of lateral epidermal syncytia during an interval of transverse apical constriction (AC). AC gives rise to three temporary semi-circular cellular protrusions beneath a provisional matrix (sheath). In turn, sheath components pattern durable ridges along the midline of adult cuticles (alae). We propose that forces generated by AC are relayed via the sheath to sculpt the the acellular adult cuticle manifest several hours later. Furthermore, we provide evidence that circumferential actin filament bundles (CFBs) near the surface of the adjacent syncytia (hyp7) are largely dispensable for the propagation of annular cuticle structures from one larval stage to the next. Rather, the temporary CFBs extend from actin bundles overlying body wall muscles, which are situated between <i>Ce</i>. hemidesmosomes. Similar mechanisms may contribute to the morphogenesis of integumentary organs in higher metazoans.
CELLULAR MECHANISMS OF ANTIBACTERIAL DEFENSE IN LYMPH NODES
Authors: Ralph O. Smith, W. Barry Wood
Journal: The Journal of Experimental Medicine (1949)

The origin of the polymorphonuclear leucocytes found in the intermediary and subcapsular sinuses of the popliteal lymph node during acute bacterial lymphadenitis, and the effect of this leucocyte infiltration on the passage of bacteria through the lymph node have been investigated. It has been demonstrated that: 1. The polymorphonuclear leucocytes in the nodal sinuses originate both from blood vessels of the lymph node and from the primary inflammatory focus in the tissues. 2. Granulocytes invading the intermediary sinuses of the infected lymph node arise primarily from capillaries lining these sinuses. 3. Most of the polymorphonuclear leucocytes in the subcapsular sinus, on the other hand, originate from the inflammatory focus in the tissues and appear to traverse the node by way of this peripheral sinus. 4. The bacteremia following direct intralymphatic injection of pneumococci is suppressed by the presence of preformed inflammatory exudate in the nodal sinuses indicating that the filtering capacity of the node is thereby greatly increased.
Chronic lung diseases and the perception of breathlessness: a clinical perspective
Authors: JG Burdon, MC Pain, AR Rubinfeld, A Nana
Journal: European Respiratory Journal (1994)

Breathlessness is an extremely common symptom. Its genesis is incompletely understood but is known to be largely determined by many of the mechanical factors associated with the act of breathing. As with all subjective sensations various other factors including volition, behavioural style and other cortical and subcortical factors play a part in its genesis. The relief of breathlessness is primarily directed at the underlying disorder. In those conditions and situations where specific therapy has little to offer or little impact it is reasonable to consider ways of reducing the perception of breathlessness by pharmacological means. However, to date there is no convincing evidence that use of drugs in the pursuit of the relief of breathlessness has any specific effect in modifying the perception of this often distressing symptom. Any reduction in breathlessness achieved in this way can be adequately explained in terms of a reduction in ventilation and other indices of respiratory mechanics.
Thyrotoxicosis due to Ingestion of Excess Thyroid Hormone*
Authors: JOSEPH H. COHEN, SIDENEY H. INGBAR, LEWIS E. BRAVERMAN
Journal: Endocrine Reviews (1989)

THE TERM thyrotoxicosis factitia has been used to describe thyrotoxicosisinduced by ingestion of excess thyroid hormone (1). This entity has also been termed alimentary or exogenous thyrotoxicosis (2, 3), occult factitial thyrotoxicosis (4), and thyreoidismus medicamentosus (5). As they imply, these terms describe the various reasons why excess thyroid hormone is ingested. These include not only the ingestion of excess thyroid hormone by individuals with unstable psychiatric profiles, but also administration of excess thyroid hormone to volunteers including students (6) and prisoners (7) in an effort to produce thyrotoxicosis for research studies. The hormone has been ingested both intentionally (8–16) and unintentionally (5, 17) in diet pills and in ground beef contaminated with bovine thyroid tissue (18, 19). The accidental ingestion of large quantities of medication by children and, less frequently, by adults, is another cause of thyrotoxicosis factitia. The thyroid gland is unique among the endocrine glands because of its large store of preformed hormone. Furthermore, the peripheral turnover of the two major iodothyronines, T4 and T3, is relatively slow, 6.7 days and 1 day, respectively, due primarily to the tight binding of the hormones to circulating plasma proteins (20, 21).
Matrix metalloproteinase 17 is necessary for cartilage aggrecan degradation in an inflammatory environment
Authors: Kristen M Clements, Jo K Flannelly, Jonathan Tart, Sarah M V Brockbank, John Wardale, Jim Freeth, Andrew E Parker, Peter Newham
Journal: Annals of the Rheumatic Diseases (2011)

Aggrecan is a critical component of cartilage extracellular matrix. Several members of the 'a disintegrin and metalloproteinase with thrombospondin motifs' (ADAMTS) family have been characterised as aggrecanases by their ability to generate fragments containing the NITEGE neoepitope from aggrecan. Increased NITEGE fragments in synovial fluid and articular cartilage are a hallmark of osteoarthritis (OA) and it is hypothesised that the enhanced rate of aggrecan degradation is critical for cartilage destruction in OA. Recently, matrix metalloproteinase 17 (MMP17, also known as MT4-MMP) has been implicated in the activation of one of the key aggrecanases: ADAMTS4. In the present work, the hypothesis that MMP17 mediates the interleukin 1β (IL-1β) induced release of NITEGE neoepitope from human and murine articular cartilage is investigated.MMP17 was quantified at the protein and RNA level and NITEGE neoepitope generation by immunohistochemistry. Human postmortem articular cartilage explants were treated with recombinant MMP17, or IL-1β in the presence or absence of an MMP17 inhibitor. Glycosaminoglycan (GAG) loss into the media was quantified using the 1,9-dimethylmethylene blue (DMMB) assay. Intra-articular injection (IAI) of IL-1β or meniscotibial ligament transaction was carried out in MMP17 null mice.The data reveal an association between increased MMP17 protein and NITEGE staining in areas of OA cartilage damage. Ex vivo treatment of normal human cartilage with recombinant MMP17 protein increased NITEGE generation in the cartilage and GAG loss into the media. In addition, IL-1β mediated cartilage GAG loss, and increased NITEGE neoepitope expression, were attenuated with an MMP17 inhibitor. IAI of IL-1β into C57BL6/Jax mice resulted in increased MMP17 expression in articular cartilage and increased GAG content in the synovial fluid. MMP17 null mice were protected against this increase. However, aggrecan loss driven by mechanical stress following medial meniscotibial ligament transection was not dependent on MMP17.These data further implicate MMP17 in the control of articular cartilage extracellular matrix aggrecan integrity in an inflammatory environment.
Role of SRC-1 in the Promotion of Prostate Cancer Cell Growth and Tumor Progression
Authors: Irina U. Agoulnik, Ajula Vaid, William E. Bingman, Halime Erdeme, Anna Frolov, Carolyn L. Smith, Gustavo Ayala, Michael M. Ittmann, Nancy L. Weigel
Journal: Cancer Research (2005)

Prostate cancer is initially androgen dependent and there is evidence that androgen receptor continues to play a role in androgen-independent prostate cancer. Androgen receptor activity depends both on the level of androgens and on the level of coactivators that interact with androgen receptor. Our goal was to evaluate the role of the androgen receptor coactivator SRC-1 in prostate cancer progression. Using tissue arrays to measure SRC-1 protein levels, we found that increased SRC-1 expression in clinically localized, androgen-dependent cancer is associated with clinical and pathologic variables of increased tumor aggressiveness. Interestingly, there was variable expression of SRC-1 in normal prostate tissue which correlated with the staining intensity of the corresponding cancer tissue. To test the contribution of SRC-1, we examined its role in androgen-dependent LNCaP and androgen-independent C4-2 prostate cancer cell lines. Using small interfering RNA to reduce expression of androgen receptor, we found that androgen receptor was required both for cell growth and for basal expression of prostate-specific antigen in the androgen-independent C4-2 cell line. Thus, although the cells can grow in an androgen-depleted medium, they remained androgen receptor dependent. Reduction of SRC-1 expression significantly reduced growth and altered androgen receptor target gene regulation in both LNCaP and C4-2 cell lines whereas it had no effect on the growth of the androgen receptor-negative PC-3 and DU145 prostate cancer cell lines. Although the requirement for androgens and androgen receptor in the development of prostate cancer is well established, our study implicates enhanced androgen receptor activity through elevated expression of SRC-1 in the development of more aggressive disease in men with prostate cancer.
Safety of extended treatment with anakinra in patients with rheumatoid arthritis
Authors: R M Fleischmann
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objective:</b> To determine the safety profile of anakinra after extended exposure in a diverse clinical trial population of patients with rheumatoid arthritis. <b>Methods:</b> A six month, randomised, double blind phase comparing anakinra (100 mg/day) with placebo was followed by open label anakinra treatment for up to three years in patients with rheumatoid arthritis. Concomitant non-steroidal anti-inflammatory drugs, corticosteroids, and other disease modifying antirheumatic drugs were permitted. <b>Results:</b> In all 1346 patients with rheumatoid arthritis received anakinra for up to three years. Patients had varying levels of disease severity, concomitant drug use, and comorbid conditions. Cumulative, exposure adjusted event (EAE) rates for all adverse events (AEs), serious AEs, and deaths were similar during each year of anakinra treatment; the overall rate (0 to 3 years) was similar to that observed for controls during the blinded phase. The most frequent AEs were injection site reactions (122.26 events/100 patient-years), rheumatoid arthritis progression (67.80 events/100 patient-years), and upper respiratory infections (26.09 events/100 patient-years). The EAE rate of serious infections was higher for patients treated with anakinra for 0 to 3 years (5.37 events/100 patient-years) than for controls during the blinded phase (1.65 events/100 patient-years). However, if the patient was not receiving corticosteroid treatment at baseline, the serious infection rate was substantially lower (2.87 event/100 patient-years). The overall incidence of malignancies was consistent with expected rates reported by SEER. Neutralising antibodies developed in 25 patients, but appeared to be transient in 12; neutralising antibody status did not appear related to occurrence of malignancies or serious infections. There were no clinically significant trends in laboratory data related to anakinra. <b>Conclusion:</b> Anakinra is safe and well tolerated for up to three years of continuous use in a diverse population of patients with rheumatoid arthritis.
Aspirin sensitivity and eicosanoids
Authors: S. Farooque, T. H Lee
Journal: Thorax (2007)

Aspirin sensitive respiratory disease (ASRD) was first described in 1922 by the French physician Widal.1 It is characterised by asthma, chronic rhinosinusitis and nasal polyps on a background of aspirin sensitivity. The condition is a distinct, often aggressive, clinical syndrome, and it is rare in childhood with a peak age of onset in the early 30s.2 Rhinorrhoea and nasal congestion are typically the first symptoms with asthma usually manifesting 1–5 years after the onset of rhinitis.3 Once the disease is established, ingestion of aspirin induces the release of critical mediators that provoke an acute exacerbation of rhinosinusitis and asthma. It is estimated that 5–10% of all patients with asthma are aspirin sensitive.4 Often poorly responsive to treatment, patients with aspirin sensitivity are over-represented in the severe asthma group and 50% are steroid dependent.5

The aetiology of ASRD is complex, but most investigators are agreed that the reaction to aspirin is not mediated by allergic mechanisms. Most evidence points towards an abnormality of arachidonic acid (AA) metabolism. AA is a substrate for both the production of leucotrienes (via the 5-lipoxygenase (5-LO) pathway) and prostanoids (via the cyclooxygenase (COX) pathway).

ASRD is characterised by excessive cysteinyl leucotriene (CysLT) production both in the steady state and for several hours after aspirin challenge.6 Urinary leucotriene E4 (LTE4) levels, as a measure of total body production of CysLTs, are a mean sixfold higher in patients with ASRD, increasing fourfold higher still after aspirin challenge.7 To date, the question of whether ASRD is associated with a fundamental predetermined abnormality in the production of CysLT8 or whether …
Overcoming Glutathione <i>S</i>-Transferase P1–Related Cisplatin Resistance in Osteosarcoma
Authors: Michela Pasello, Francesca Michelacci, Isabella Scionti, Claudia Maria Hattinger, Monia Zuntini, Anna Maria Caccuri, Katia Scotlandi, Piero Picci, Massimo Serra
Journal: Cancer Research (2008)

Abstract Cisplatin (cis-diamminedichloroplatinum, CDDP) is one of the most used drugs for osteosarcoma chemotherapy. By using a series of CDDP-resistant variants, which were established from the U-2OS and Saos-2 human osteosarcoma cell lines, we found that CDDP resistance was mainly associated with the increase of both the intracellular level and enzymatic activity of glutathione S-transferase P1 (GSTP1). On the basis of these findings, we evaluated the clinical effect of GSTP1 in a series of 34 high-grade osteosarcoma patients and we found that the increased expression of GSTP1 gene was associated with a significantly higher relapse rate and a worse clinical outcome. These indications prompted us to assess the in vitro effectiveness of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), a promising new anticancer agent that is a highly efficient inhibitor of GSTP1. NBDHEX was tested on a panel of 10 human osteosarcoma cell lines and 20 variants of the U-2OS or Saos-2 cell lines that were resistant to CDDP, doxorubicin, or methotrexate. NBDHEX proved to be very active on the vast majority of these cell lines, including those with higher GSTP1 levels and enzymatic activity. Drug combination studies showed that NBDHEX can be used in association with CDDP and provided useful information about the best modality of their combined administration. In conclusion, our findings show that GSTP1 has a relevant effect for both CDDP resistance and clinical outcome of high-grade osteosarcoma and that targeting GSTP1 with NBDHEX may be considered a promising new therapeutic possibility for osteosarcoma patients who fail to respond to conventional chemotherapy. [Cancer Res 2008;68(16):6661–8]
CENSORING ISSUES IN SURVIVAL ANALYSIS
Authors: Kwan-Moon Leung, Robert M. Elashoff, Abdelmonem A. Afifi
Journal: Annual Review of Public Health (1997)

▪ Abstract A key characteristic that distinguishes survival analysis from other areas in statistics is that survival data are usually censored. Censoring occurs when incomplete information is available about the survival time of some individuals. We define censoring through some practical examples extracted from the literature in various fields of public health. With few exceptions, the censoring mechanisms in most observational studies are unknown and hence it is necessary to make assumptions about censoring when the common statistical methods are used to analyze censored data. In addition, we present situations in which censoring mechanisms can be ignored. The effects of the censoring assumptions are demonstrated through actual studies.
Lymphocyte recruitment into the aortic wall before and during development of atherosclerosis is partially L-selectin dependent
Authors: Elena Galkina, Alexandra Kadl, John Sanders, Danielle Varughese, Ian J. Sarembock, Klaus Ley
Journal: The Journal of Experimental Medicine (2006)

Atherosclerosis is an inflammatory disease of large arteries. Flow cytometry of aortic cell suspensions showed that B and T lymphocytes and some macrophages and dendritic cells are already present in the adventitia of normal/noninflamed mouse aortas. Adoptively transferred lymphocytes constitutively homed to the aorta and resided within the adventitia up to 7 d after transfer. Lymphocyte trafficking into normal/noninflamed or atherosclerosis-prone aortas was partially L-selectin dependent. Antigen-activated dendritic cells induced increased T lymphocyte proliferation within the aorta 72 h after adoptive transfer. During progression of atherosclerosis in apolipoprotein-E–deficient mice, the total number of macrophages, T cells, and dendritic cells, but not B cells, increased significantly. This alteration in immune cell composition was accompanied by the formation of tertiary lymphoid tissue in the adventitia of atherosclerotic aortas. These results demonstrate that lymphocytes already reside within the normal/noninflamed aorta before the onset atherosclerosis as a consequence of constitutive trafficking. Atherosclerosis induces the recruitment of macrophages and dendritic cells that support antigen presentation.
CD137 as a Biomarker for Tumor-Reactive T Cells: Finding Gold in the Desert
Authors: Yuwen Zhu, Lieping Chen
Journal: Clinical Cancer Research (2013)

Abstract Although human cancer is often surrounded by immune cells, only a small number are tumor-reactive T cells that recognize the tumor antigens and are able to eliminate the cancer cells. Ye and colleagues now found that many of these tumor-reactive T cells are marked by expressing CD137, a T-cell costimulatory receptor. Clin Cancer Res; 20(1); 3–5. ©2013 AACR.
Ischemic Preconditioning Prevents Endothelial Injury and Systemic Neutrophil Activation During Ischemia-Reperfusion in Humans In Vivo
Authors: Rajesh K. Kharbanda, Mark Peters, Benjamin Walton, Mia Kattenhorn, Michael Mullen, Nigel Klein, Patrick Vallance, John Deanfield, Raymond MacAllister
Journal: Circulation (2001)

Background —Endothelial dysfunction leading to neutrophil infiltration of tissues has been implicated in tissue injury caused by ischemia-reperfusion (IR). Tissue injury during IR can be reduced by prior ischemic preconditioning (IPC). In humans, it is unclear whether endothelial dysfunction occurs during IR or whether IPC offers protection against endothelial dysfunction and inflammatory cell activation. We studied the effects of experimental IR on endothelial and neutrophil function in the human forearm in vivo and examined the protection afforded by IPC. Method and Results —The forearm was made ischemic for 20 minutes by inflating a blood pressure cuff to 200 mm Hg. We assessed endothelial function of conduit (radial artery flow–mediated dilation) and resistance vessels (blood flow responses to intra-arterial infusion of the endothelium-dependent dilator acetylcholine) in healthy volunteers before and after IR. IR reduced flow-mediated dilation of the radial artery at 15 minutes of reperfusion (7.7±1.5% to 3.5±0.9%) and the dilator response of resistance vessels to acetylcholine at 15, 30, and 60 minutes of reperfusion. IR did not reduce the dilator response of the radial artery to glyceryltrinitrate and only caused a small reduction of glyceryltrinitrate-induced dilation of resistance vessels at 60 minutes of reperfusion. IR caused an increase in neutrophil CD11b expression and platelet-neutrophil complexes in the circulating blood. IPC (three 5-minute episodes of ischemia) before IR prevented endothelial dysfunction and neutrophil activation. Conclusions —A clinically relevant period of ischemia-reperfusion causes profound and sustained endothelial dysfunction and systemic neutrophil activation. IPC attenuates both of these effects in humans.
Validation of the Rockall risk scoring system in upper gastrointestinal bleeding
Authors: E M Vreeburg, C B Terwee, P Snel, E A J Rauws, J F W M Bartelsman, J H P vd Meulen, G N J Tytgat
Journal: Gut (1999)

Several scoring systems have been developed to predict the risk of rebleeding or death in patients with upper gastrointestinal bleeding (UGIB). These risk scoring systems have not been validated in a new patient population outside the clinical context of the original study.To assess internal and external validity of a simple risk scoring system recently developed by Rockall and coworkers.Calibration and discrimination were assessed as measures of validity of the scoring system. Internal validity was assessed using an independent, but similar patient sample studied by Rockall and coworkers, after developing the scoring system (Rockall's validation sample). External validity was assessed using patients admitted to several hospitals in Amsterdam (Vreeburg's validation sample). Calibration was evaluated by a chi2 goodness of fit test, and discrimination was evaluated by calculating the area under the receiver operating characteristic (ROC) curve.Calibration indicated a poor fit in both validation samples for the prediction of rebleeding (p<0.0001, Vreeburg; p=0.007, Rockall), but a better fit for the prediction of mortality in both validation samples (p=0.2, Vreeburg; p=0.3, Rockall). The areas under the ROC curves were rather low in both validation samples for the prediction of rebleeding (0.61, Vreeburg; 0.70, Rockall), but higher for the prediction of mortality (0.73, Vreeburg; 0.81, Rockall).The risk scoring system developed by Rockall and coworkers is a clinically useful scoring system for stratifying patients with acute UGIB into high and low risk categories for mortality. For the prediction of rebleeding, however, the performance of this scoring system was unsatisfactory.