tbuckley/cabot-search huggingface dataset:
A European framework for effective tuberculosis control
Authors: P.D.O. Davies
Journal: European Respiratory Journal (2002)

This edition of the Journal sees the publication of an important document in the control and elimination of tuberculosis in low-incidence countries 1. The authors start with the well-founded World Health Organization (WHO) document for control in high-prevalence countries but wisely do not attempt to adapt from it directly 2. Instead, the paper is an original and well-thought-out strategy for managing the disease in European countries in which it is relatively uncommon, but where ample resources should be available.

The steady decline of tuberculosis in many Western European countries for a century and a half, lead to complacency and neglect of all aspects of disease control. Existing frameworks were dismantled or fell into disuse. Health professionals neglected teaching clinical and epidemiological facts about tuberculosis with the result that the new generation of doctors, nurses and allied medical workers were largely ignorant of the basic skills needed in the diagnosis and management of the disease 3.

The combined expertize of the WHO, the International Union Against Tuberculosis and Lung Disease (IUATLD) and the Royal Netherlands Tuberculosis Association (KNCV) has provided much needed help by drawing up this original policy document, summarizing the essential elements of tuberculosis control in low-incidence countries. The paper provides particularly useful definitions, including what constitutes a definite case of tuberculosis and the various treatment outcomes that are achieved, which can now be agreed across all European countries.

As is the case with the WHO policy document for high-incidence countries, this document begins by stressing the need for government commitment to providing the basic infrastructure to succeed in tuberculosis control. Past experience shows that without constant reminders, …
Interstitial lung disease induced by exogenous agents: factors governing susceptibility
Authors: B Nemery, A Bast, J Behr, P J Borm, S J Bourke, P H Camus, P De Vuyst, H M Jansen, V L Kinnula, D Lison, O Pelkonen, C Saltini
Journal: European Respiratory Journal (2001)

The purpose of this review is to describe the present state of knowledge regarding host susceptibility factors that may determine the occurrence, development and severity of interstitial lung disease (ILD) caused by exogenous agents. First, host susceptibility may pertain to differences in the delivery and/or persistence of the noxious agent in the lung. The deposition and clearance of inhaled particles or fibres may vary depending on innate anatomical or physiological characteristics, and on acquired changes, such as nasal disease or smoking-induced alterations. Genetically- or environmentally-induced interindividual differences in the expression of pulmonary biotransformation enzymes may form the basis for, or contribute to the risk of, drug-induced interstitial lung disease. Secondly, there are genetic and acquired variations in various enzymatic and nonenzymatic defence systems that protect cells and tissues against oxidative stress, which is often involved in the pathogenesis of interstitial lung disease caused by particles, fibres, metals, organic agents and drugs. Thirdly, the occurrence of immunological sensitization is dependent on both genetic and environmental factors. This has been demonstrated in chronic beryllium lung disease and in hypersensitivity pneumonitis. Fourthly, the propensity of individuals to develop particular types of inflammation, such as granulomas, is probably under genetic control. The regulation and resolution of inflammation and fibrogenesis caused by dust particles are also partly determined by genetic factors, involving cytokine networks and growth factors. In conclusion, although the issue of genetics pervades the entire discussion of host susceptibility, genes are not the only determinants of health and disease. Environmental factors may be equally important in shaping host susceptibility. Therefore, research must be focused on both the genetic bases and the environmental determinants of interstitial lung disease, in order to provide mechanism-based prevention strategies, early detection of, and improved therapy for these conditions.
Osteopontin binds and modulates functions of eosinophil‐recruiting chemokines
Authors: A. Gela, G. Kasetty, M. Mörgelin, A. Bergqvist, J. S. Erjefält, J. E. Pease, A. Egesten
Journal: Allergy (2015)

Abstract Background Allergic asthma is characterized by eosinophilic inflammation and airway obstruction. There is also an increased risk of pulmonary infection caused by Streptococcus pneumoniae, in particular during severe asthma where high levels of the glycoprotein, osteopontin ( OPN ), are present in the airways. Eosinophils can be recruited by chemokines activating the receptor CCR 3 including eotaxin‐1/ CCL 11, eotaxin‐2/ CCL 24, eotaxin‐3/ CCL 26, RANTES / CCL 5, and MEC / CCL 28. In addition to inducing chemotaxis, several of these molecules have defensin‐like antibacterial properties. This study set out to elucidate the functional consequences of OPN binding to eosinophil‐recruiting chemokines. Methods Antibacterial activities of the chemokines were investigated using viable count assays and electron microscopy. Binding studies were performed by means of surface plasmon resonance. The potential interference of OPN with antibacterial, receptor‐activating, and lipopolysaccharide‐neutralizing abilities of these chemokines was investigated. Results We found that OPN bound all eosinophil‐recruiting chemokines with high affinity except for CCL 5. The eosinophil‐recruiting chemokines all displayed bactericidal activity against S. pneumoniae , but only CCL 26 and CCL 28 retained high antibacterial activity in the presence of sodium chloride at physiologic concentrations. Preincubation of the chemokines with OPN strongly inhibited their antibacterial activity against S. pneumoniae but did not affect their ability to activate CCR 3. All chemokines investigated showed LPS ‐neutralizing activity that was impaired by OPN only in the case of CCL 24. Conclusions The data suggest that OPN may impair host defense activities of the chemokines without affecting their eosinophil‐recruiting properties. This could be one mechanism explaining the increased vulnerability to acquire pneumococcal infection in parallel with sustained allergic inflammation in asthma.
Matrix metalloproteinase-9 in bronchiolitis obliterans syndrome after lung transplantation
Authors: R. H. Hübner, S. Meffert, U. Mundt, H. Böttcher, S. Freitag, N. E. El Mokhtari, T. Pufe, S. Hirt, U. R. Fölsch, B. Bewig
Journal: European Respiratory Journal (2005)

Bronchiolitis obliterans syndrome (BOS) is a severe complication after lung transplantation (LTX). In a retrospective cohort study 12 stable healthy recipients (non-BOS) and eight patients with BOS were enrolled after LTX and matrix metalloproteinases (MMP)-9, TIMP-1 and cell characteristics in bronchoalveolar lavage (BAL) samples (n = 145) were analysed. BALs from patients with BOS were further divided according to whether they were obtained before (pre-BOS) or after manifestation of BOS (BOS group). The MMP-9/TIMP-1 ratio was significantly increased in the BOS group compared with non-BOS or pre-BOS; furthermore, the ratio was negatively correlated with forced expiratory volume in one second. In zymography, the active form of MMP-9 was detected predominantly in the BOS group. In addition, zymography showed the banding pattern of neutrophil-derived MMP-9, indicating that polymorphonuclear neutrophils (PMNs) were the main source of MMP-9. According to that, MMP-9 was significantly correlated with the number of PMN. In immunocytochemistry, MMP-9 was also associated predominantly with PMN. This is the first study to evaluate the expression of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases-1 over time during manifestation of a fibroproliferative lung disease in patients. It demonstrates development of bronchiolitis obliterans syndrome after lung transplantation is associated with an imbalance of matrix metalloproteinases-9/tissue inhibitors of metalloproteinase-1 ratio.
Clarifying concussion in youth rugby: recognise and remove
Authors: L Hodgson, J Patricios
Journal: British Journal of Sports Medicine (2015)

In the April 2015 issue of BJSM, Kirkwood et al 1 drew attention to concussion in youth rugby, concluding with four recommendations, most of which are well founded.One would agree there is a lack of medical personnel at youth games, a need for increased awareness of concussion management and a requirement for generalised data collection.However, suggesting rugby alone should 'never be compulsory' is highlighting that it might perhaps be an unsafe sport to play.
Identification and Characterization of Novel Spliced Variants of Neuregulin 4 in Prostate Cancer
Authors: Nandini V.L. Hayes, Edith Blackburn, Laura V. Smart, Mary M. Boyle, Graham A. Russell, Teresa M. Frost, Byron J.T. Morgan, Anthony J. Baines, William J. Gullick
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The neuregulin (NRG) 1, 2, and 3 genes undergo extensive alternative mRNA splicing, which results in variants that show structural and functional diversity. The aims of this study were to establish whether the fourth member of this family, NRG4, is expressed in prostate cancer, if it is alternatively spliced and whether any functional differences between the variants could be observed. Experimental Design: The expression of NRG4 was determined using immunohistochemical staining of 40 cases of primary prostate cancer. Bioinformatic analysis and reverse transcription-PCR (RT-PCR) using NRG4 isotype-specific primers on a panel of normal and prostate cancer cell lines were used to identify alternatively spliced NRG4 variants. Expression of these variants was determined using isotype-specific antibodies. Transfection into Cos-7 cells of two of these green fluorescent protein-tagged variants allowed analysis of their subcellular location. Four of the variants were chemically synthesized and tested for their ability to activate the ErbB4 receptor. Results: NRG4 was variably expressed in the cytoplasm in the majority of prostate cancer cases, and in a subset of cases in the membrane, high levels were associated with advanced disease stage. Four novel NRG4 splice variants (NRGA2, NRG4 B1-3) were characterized, where each seemed to have a different subcellular location and were also expressed in the cytoplasm of the prostate tumors. NRG4 B3 was also present in endothelial cells. In transfected cells, the A type variant (NRG4 A1) was localized to the membrane, whereas the B type variant (NRG4 B1), which lacks the predicted transmembrane region, had an intracellular localization. Only the variants with an intact epidermal growth factor–like domain activated ErbB4 signaling. Conclusion: NRG4 overexpression is associated with advanced-stage prostate cancer. The alternative splice variants may have different roles in cell signaling, some acting as classic receptor ligands and some with as-yet unknown functions.
Survivin transcript variant 2 drives angiogenesis and malignant progression in proneural gliomas
Authors: T. Doucette, K. Latha, Y. Yang, G. N. Fuller, A. Rao, G. Rao
Journal: Neuro-Oncology (2014)

The influence of survivin isoforms on outcome in glioblastoma is poorly understood. We analyzed the dominant anti-apoptotic transcript variants of survivin using expression data and modeled them in vivo to determine their impact on glioma formation and progression. Using data from low- and high-grade glioma knowledge bases, we expressed the anti-apoptotic isoforms of survivin (transcript variants 1 and 2) in vivo using the RCAS/Ntv-a model of murine glioma. In low-grade gliomas, survivin RNA expression was increased in 22 of 167 (13.2%) of cases and was associated with shortened survival (P = .005). Survivin RNA was preferentially expressed in proneural (PN) relative to mesenchymal high-grade gliomas (P < .0001). In proneural gliomas, survivin was expressed in 94 of 141 (67%) of cases and was associated with shorter disease-free survival (P = .04). In a platelet-derived growth factor subunit B-dependent murine model of PN glioma, ectopic expression of variant 1 yielded tumors in 28 of 30 (93%) of mice, of which 25% were high-grade tumors, whereas ectopic expression of variant 2 yielded tumors in 27 of 28 (96%), of which 81% were high-grade tumors (P < .0001). Microvascular proliferation was significantly more prominent (P < .0001), and tumor-free survival was shorter in mice with variant 2 than variant 1-derived tumors (P = .01). Survivin expression in low-grade gliomas is associated with poor survival and is preferentially expressed in PN gliomas. Compared with variant 1, variant 2 was associated with poorer survival and promoted malignant progression, angiogenesis, and shorter tumor-free survival in the PN murine model. Inhibiting survivin transcript variant 2, rather than variant 1 (the common isoform), may be an effective treatment strategy for glioma.
Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance
Authors: Masatsugu Oh-hora, Megumi Yamashita, Patrick G Hogan, Sonia Sharma, Ed Lamperti, Woo Chung, Murali Prakriya, Stefan Feske, Anjana Rao
Journal: Nature Immunology (2008)
IL-8 Is an Angiogenic Factor in Human Coronary Atherectomy Tissue
Authors: Americo Simonini, Mauro Moscucci, David W. M. Muller, Eric R. Bates, Francis D. Pagani, Marie D. Burdick, Robert M. Strieter
Journal: Circulation (2000)

Background —Interleukin-8 (IL-8), a CXC chemokine that induces the migration and proliferation of endothelial cells and smooth muscle cells, is a potent angiogenic factor that may play a role in atherosclerosis. Previously, IL-8 has been reported in atherosclerotic lesions and circulating macrophages from patients with atherosclerosis. Therefore, we sought to determine whether IL-8 plays a role in mediating angiogenic activity in atherosclerosis. Methods and Results —Homogenates from 16 patients undergoing directional coronary atherectomy (DCA) and control samples from the internal mammary artery (IMA) of 7 patients undergoing bypass graft surgery were assessed for IL-8 content by specific ELISA, immunohistochemistry, and in situ hybridization for IL-8 mRNA. The contribution of IL-8 to net angiogenic activity was assessed using the rat cornea micropocket assay and cultured cells. IL-8 expression was significantly elevated in DCA samples compared with IMA samples (1.71±0.6 versus 0.05±0.03 ng/mg of total protein; P &lt;0.01). Positive immunolocalization of IL-8 was found exclusively in DCA tissue sections, and it correlated with the presence of factor VIII–related antigen. In situ reverse transcriptase polymerase chain reaction revealed the expression of IL-8 mRNA in DCA tissue. Corneal neovascular response, defined by ingrowth of capillary sprouts toward the implant, was markedly positive with DCA pellets, but no constitutive vessel ingrowth was seen with IMA specimens. Neutralizing IL-8 attenuated both the in vivo corneal neovascular response and the in vitro proliferation of cultured cells. Conclusions —The results suggest that, in human coronary atherosclerosis, IL-8 is an important mediator of angiogenesis and may contribute to plaque formation via its angiogenic properties.
<i>miR-21</i> Induces Myofibroblast Differentiation and Promotes the Malignant Progression of Breast Phyllodes Tumors
Authors: Chang Gong, Yan Nie, Shaohua Qu, Jian-You Liao, Xiuying Cui, Herui Yao, Yunjie Zeng, Fengxi Su, Erwei Song, Qiang Liu
Journal: Cancer Research (2014)

Phyllodes tumors of breast, even histologically diagnosed as benign, can recur locally and have metastatic potential. Histologic markers only have limited value in predicting the clinical behavior of phyllodes tumors. It remains unknown what drives the malignant progression of phyllodes tumors. We found that the expression of myofibroblast markers, α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), and stromal cell-derived factor-1 (SDF-1), is progressively increased in the malignant progression of phyllodes tumors. Microarray showed that miR-21 was one of the most significantly upregulated microRNAs in malignant phyllodes tumors compared with benign phyllodes tumors. In addition, increased miR-21 expression was primarily localized to α-SMA-positive myofibroblasts. More importantly, α-SMA and miR-21 are independent predictors of recurrence and metastasis, with their predictive value of recurrence better than histologic grading. Furthermore, miR-21 mimics promoted, whereas miR-21 antisense oligos inhibited, the expression of α-SMA, FAP, and SDF-1, as well as the proliferation and invasion of primary stromal cells of phyllodes tumors. The ability of miR-21 to induce myofibroblast differentiation was mediated by its regulation on Smad7 and PTEN, which regulate the migration and proliferation, respectively. In breast phyllodes tumor xenografts, miR-21 accelerated tumor growth, induced myofibroblast differentiation, and promoted metastasis. This study suggests an important role of myofibroblast differentiation in the malignant progression of phyllodes tumors that is driven by increased miR-21.
Durable Adoptive Immunotherapy for Leukemia Produced by Manipulation of Multiple Regulatory Pathways of CD8+ T-Cell Tolerance
Authors: Melissa M. Berrien-Elliott, Stephanie R. Jackson, Jennifer M. Meyer, Craig J. Rouskey, Thanh-Long M. Nguyen, Hideo Yagita, Philip D. Greenberg, Richard J. DiPaolo, Ryan M. Teague
Journal: Cancer Research (2012)

Abstract Tolerizing mechanisms within the host and tumor microenvironment inhibit T-cell effector functions that can control cancer. These mechanisms blunt adoptive immunotherapy with infused T-cells due to a complex array of signals that determine T-cell tolerance, survival, or deletion. Ligation of the negative regulatory receptors CTLA4, PD-1(PDCD1), or LAG3 on T-cells normally hinders their response to antigen through nonredundant biochemical processes that interfere with stimulatory pathways. In this study, we used an established mouse model of T-cell tolerance to define the roles of these inhibitory receptors in regulating CD8+ T-cell tolerance during adoptive immunotherapy to treat leukemia. Blocking CTLA4 and PD-1 in vivo combined to promote survival of transferred T-cells despite powerful deletional signals that mediate Bim (BCL2L11)–dependent apoptosis. However, this dual blockade was not optimal for stimulating effector function by responding T-cells, which required the additional blockade of LAG3 to induce full expansion and allow the acquisition of robust cytolytic activity. Thus, the cooperation of multiple distinct regulatory pathways was needed for the survival and effector differentiation of adoptively transferred tumor-reactive CD8+ T-cells. Our work defines the immune escape pathways in which simultaneous blockade could yield durable immunotherapeutic responses that can eradicate disseminated leukemia. Cancer Res; 73(2); 605–16. ©2012 AACR.
A 16 year study of injuries to professional boxers in the state of Victoria, Australia
Authors: T R Zazryn, C F Finch, P McCrory
Journal: British Journal of Sports Medicine (2003)

Objectives: Concerns about the significant injury risks in boxers have been well documented. To inform the continuing debate, updated information about the risk of injury for participants, and suitable means of modifying or preventing these risks, need to be identified. Methods: Data describing all professional boxing fight outcomes and injuries sustained during competition, from August 1985 to August 2001, were obtained from the Victorian Professional Boxing and Combat Sports Board. Results: A total of 107 injuries were recorded from 427 fight participations, corresponding to an injury rate of 250.6 injuries per 1000 fight participations. The most commonly injured body region was the head/neck/face (89.8%), followed by the upper extremities (7.4%). Specifically, injuries to the eye region (45.8%) and concussion (15.9%) were the most common. About three quarters of all injuries were lacerations/open wounds or superficial. No information was available on the mechanism of injury. Conclusions: Future research should collect information on the mechanism of injury, as this is crucial for the development and implementation of effective injury prevention strategies. A suggested boxing injury report form is provided to facilitate this.
An Oncolytic Adenovirus Enhanced for Toll-like Receptor 9 Stimulation Increases Antitumor Immune Responses and Tumor Clearance
Authors: Vincenzo Cerullo, Iulia Diaconu, Valentina Romano, Mari Hirvinen, Matteo Ugolini, Sophie Escutenaire, Sirkka-Liisa Holm, Anja Kipar, Anna Kanerva, Akseli Hemminki
Journal: Molecular Therapy (2012)

Oncolytic viruses represent a multifaceted tool for cancer treatment. In addition to specific killing of cancer cells (oncolysis), these agents also provide danger signals prompting the immune system to stimulate an antitumor immune response. To increase adenovirus adjuvancy, we engineered the genome of Ad5D24 by inserting 18 immunostimulatory islands (Ad5D24-CpG). The toxicity and immunogenicity profile of Ad5D24-CpG showed that the safety of the maternal virus was retained. The efficacy of the CpG-enriched virus was assessed in a xenograft model of lung cancer where a significant increase in antitumor effect was seen in comparison with controls. When the experiment was repeated in animal depleted of natural killer (NK) cells, Ad5D24-CpG lost its advantage. The same was seen when Toll-like receptor (TLR)9 was blocked systemically. In a syngeneic model of melanoma (B16-OVA), we observed a significant increase of OVA-specific T cells and a decrease of activation of myeloid-derived suppressor cells in Ad5D24-CpG–treated mice. In conclusion, we have generated the first genetically modified oncolytic adenovirus backbone able to enhance TLR9-stimulation for increased antitumor activity. Oncolytic viruses represent a multifaceted tool for cancer treatment. In addition to specific killing of cancer cells (oncolysis), these agents also provide danger signals prompting the immune system to stimulate an antitumor immune response. To increase adenovirus adjuvancy, we engineered the genome of Ad5D24 by inserting 18 immunostimulatory islands (Ad5D24-CpG). The toxicity and immunogenicity profile of Ad5D24-CpG showed that the safety of the maternal virus was retained. The efficacy of the CpG-enriched virus was assessed in a xenograft model of lung cancer where a significant increase in antitumor effect was seen in comparison with controls. When the experiment was repeated in animal depleted of natural killer (NK) cells, Ad5D24-CpG lost its advantage. The same was seen when Toll-like receptor (TLR)9 was blocked systemically. In a syngeneic model of melanoma (B16-OVA), we observed a significant increase of OVA-specific T cells and a decrease of activation of myeloid-derived suppressor cells in Ad5D24-CpG–treated mice. In conclusion, we have generated the first genetically modified oncolytic adenovirus backbone able to enhance TLR9-stimulation for increased antitumor activity.
Whole Blood Histamine Concentration Response To Omalizumab In Patients With Chronic Idiopathic/Spontaneous Urticaria: Post Hoc Analysis Of Asteria I, Asteria II and Glacial Studies
Authors: Sarbjit S. Saini, Karin Rosen, Hsin-Ju Hsieh, Patricia M. Sterba, John-Paul Courneya, Henry Hulter, Hubert Chen
Journal: Journal of Allergy and Clinical Immunology (2014)