tbuckley/cabot-search huggingface dataset:
Increasing Trial Generalizability
Authors: Carolyn C. Gotay
Journal: Journal of Clinical Oncology (2006)

The percentage of American cancer patients who enroll on clinical trials is only a small fraction of the total number of patients—as low as 1.7% according to a recent report of participation in clinical trials for the most common cancers. A Comments and Controversies article by Wright et al draws attention to this important issue and suggests that more complete information about the total patient pool and the proportions that are eligible and enrolled on trials would be useful in understanding barriers to accrual. This kind of data could be informative. However, it is only readily available in certain settings, where an institution or health care system has a defined cancer patient catchment population and a process to document all cancer care and decision-making about trials. It is perhaps not surprising that the only two examples that Wright et al found that met their recruitment reporting criteria were based in Japan and Sweden, two countries with a centralized approach to health care. In a decentralized health care system with multiple reimbursement options, such as that found in the United States, collecting such information is very challenging. In many communities, cancer patients are evaluated and enrolled on clinical trials across multiple locations. More than one hospital, clinic, and oncologist office often serves the same cancer patient population, and boundaries between the different institutions are porous. For example, patients may be diagnosed in one medical center and treated in another, seek second (and third opinions), and receive different modalities in different locations. Furthermore, patients may receive treatment in distant cities near family members or seek specialized care at tertiary referral centers. Discussions and evaluations for clinical trial participation can occur at any point or at multiple points along the treatment trajectory. This calculating the “denominator” (the number of patients potentially eligible and meeting eligibility criteria for a trial in a particular center) is very hard to do when there are multiple points of entry and exit within the health care system. It is possible that the increased use of standardized electronic medical records, and linkage among various sources of data may facilitate this process at some point in the future. Wright et al also raise another important concern that has received far too little attention— examining the extent to which clinical trials results can be used in the broader context of cancer care outside the trial itself. There are at least two approaches that can be taken to answer the question, “How can trial results be applied to patients in clinical practice?”
Glycosylphosphatidylinositols are potential targets for the development of novel inhibitors for aerolysin‐type of pore‐forming bacterial toxins
Authors: Qiuye Wu, Zhongwu Guo
Journal: Medicinal Research Reviews (2009)

Abstract Many bacteria produce toxins that cause damage through the formation of pores in the host cell membrane. Some of these toxins, such as aerolysin, use glycosylphosphatidylinositols (GPIs) as their binding receptors to assist the pore formation on the host cell surface and the subsequent insertion of the resultant pores into the cell membrane. GPIs are a class of complex glycolipids that anchor surface proteins and glycoproteins onto the cell membrane in eukaryotic species. This review has summarized the reported evidences supporting the GPI‐dependent pore‐forming mechanism for aerolysin‐type of toxins and analyzed the possibility of targeting this unique process for the design and development of novel GPI‐based inhibitors for these pore‐forming bacterial toxins. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 2, 258–269, 2010
A novel neutrophil-activating factor produced by human mononuclear phagocytes.
Authors: P Peveri, A Walz, B Dewald, M Baggiolini
Journal: The Journal of Experimental Medicine (1988)

The biological properties of a neutrophil-activating factor (NAF), which was recently identified as a novel peptide of approximately 6,000 mol wt, are described. NAF is produced de novo by human blood monocytes upon stimulation with LPS, PHA, and Con A. It induces two main responses in human neutrophils, i.e., exocytosis (release from specific granules in normal, and from specific and azurophil granules in cytochalasin B-treated cells) and the respiratory burst (formation of superoxide and hydrogen peroxide). The action of NAF appears to be mediated by a surface receptor as shown by the following observations. (a) NAF induces a rapid and transient rise in cytosolic free Ca2+; (b) interaction with NAF results in desensitization, since the cells do not respond to a second NAF challenge; and (c) the respiratory burst elicited by NAF is similar in onset, and time course to that induced by C5a or FMLP. The NAF receptor can be distinguished from the receptors of C5a, FMLP, platelet-activating factor, and leukotriene B4 by the lack of cross-desensitization. Unlike C5a, the other host-derived neutrophil-activating peptide, NAF is not inactivated by serum and thus presumably accumulates in inflamed tissue.
Risks and benefits in radiology.
Authors: J S Orr
Journal: BMJ (1987)

used in hair replacement (both for traumatic loss and for male pattern baldness), scar and tattoo removal, ear and nose reconstruction, facial reconstruction, and in treating syndactyly, port wine stains, and giant pigmented naevi.Expanders are even available for closing cleft palates as a primary procedure and for restoring an alveolar ridge in edentulous patients to allow dentures to be fitted.They can be used almost wherever there is a defect to be covered.
Relationship of aortic wall and baroreceptor properties during development in normotensive and spontaneously hypertensive rats.
Authors: M C Andresen, J M Krauhs, A M Brown
Journal: Circulation Research (1978)

We studied the relationship between aortic baroreceptor function and aortic wall properties in normotensive (NTR) and spontaneously hypertensive (SHR) rats 10-20 weeks old. Baroreceptor discharge, static pressure-volume (P-V), and pressure-radius relationships were measured in excised aortic segments. Histological studies of wall thickness and receptor numbers also were made. Circumferential wall stress and strain were calculated, as was the incremental elastic modulus (EINC). EINC in NTR's at 100 mm Hg was similar to values reported for in vivo human, dog, and rat aortas. At 10 weeks, SHR's had significantly elevated blood pressure, but SHR and NTR aortas had similar relationships among pressures, volumes, strains, and EINC's. Differences arose subsequently and, at 20 weeks, NTR aortas had larger volumes, larger strains, and smaller EINC's at equivalent pressures, whereas SHR aortas were unchanged. Thus the reduced distensibility of SHR relative to NTR aortas, rather than being due to retrogressive changes from normal, appeared to result from a failure to pass through a phase of increased distensibility. At 10 weeks, SHR baroreceptors showed resetting in both pressure-response and strain-response curves, and it was concluded that early hypertensive baroreceptor resetting was due to primary changes in the receptors. At 20 weeks, the order of the strain-response curves for NTR and SHR baroreceptors was reversed due to a reduction in strain sensitivity of NTR baroreceptors. Resetting of NTR baroreceptors during development may have important implications as a mechanism of blood pressure control in development.
Interleukin 34 expression is associated with synovitis severity in rheumatoid arthritis patients
Authors: M Chemel, B Le Goff, R Brion, C Cozic, M Berreur, J Amiaud, G Bougras, S Touchais, F Blanchard, M F Heymann, J M Berthelot, F Verrecchia, D Heymann
Journal: Annals of the Rheumatic Diseases (2011)

Objectives Interleukin (IL) 34 is a new cytokine implicated in macrophage differentiation and osteoclastogenesis. This study assessed IL-34 expression in the tissue of patients with rheumatoid arthritis (RA). Methods Immunohistochemistry was performed in synovial biopsies from patients with RA (n=20), osteoarthritis (n=3) or other inflammatory arthritis (n=4). IL-34 was detected in the synovial fluid by ELISA and its messenger RNA expression was studied by quantitative PCR in rheumatoid synovial fibroblasts after stimulation by tumour necrosis factor α (TNFα) and IL-1β. Wild-type, jnk1 −/− –jnk2 −/− and nemo −/− murine fibroblasts and pharmacological inhibition were used to determine the involvement of nuclear factor kappa B (NF-κB) and JNK in that effect. Results IL-34 was expressed in 24/27 biopsies, with three samples from RA patients being negative. A significant association was found between IL-34 expression and synovitis severity. Levels of IL-34 and the total leucocyte count in synovial fluid were correlated. TNFα and IL-1β stimulated IL-34 expression by synovial fibroblasts in a dose/time-dependent manner through the NF-κB and JNK pathway. Conclusion This work for the first time identifies IL-34 expression in the synovial tissue of patients with arthritis. This cytokine, as a downstream effector of TNFα and IL-1β, may contribute to inflammation and bone erosions in RA.
Major histocompatibility complex independent clonal T cell anergy by direct interaction of Staphylococcus aureus enterotoxin B with the T cell antigen receptor.
Authors: C R Hewitt, J R Lamb, J Hayball, M Hill, M J Owen, R E O'Hehir
Journal: The Journal of Experimental Medicine (1992)

The Staphylococcal enterotoxin superantigens stimulate vigorous responses in T cells bearing certain T cell antigen receptor (TCR) V beta regions. In addition to activation, these superantigens also impart negative signals to T cells resulting in a profound state of unresponsiveness or anergy. The Staphylococcus aureus enterotoxins (SE) B and C2 bind to a closely related site on major histocompatibility complex (MHC) human leukocyte antigen (HLA)-DR1 molecules. Only SEB, however, interacts with the TCR V beta 3 region of HA1.7, a human HLA-DR1 restricted T cell clone specific for influenza haemagglutinin. In competition experiments, we demonstrated that the induction of anergy in HA1.7 by SEB is unaffected by the presence of SEC2. These results suggest that SEB-induced anergy is MHC independent and involves a direct interaction between the TCR and SEB. To resolve definitively whether SEB binds directly to T cells in the absence of MHC class II molecules, the cDNAs encoding the HA1.7 TCR were transfected into an MHC class II-negative human T cell line. The addition of SEB to these transfectants resulted in the downregulation of cell surface TCR expression, an increase in the concentration of intracellular calcium ions, the production of lymphokines, and reduced responsiveness to a subsequent challenge with SEB. We conclude that SEB interacts directly with the TCR in the absence of cointeraction with MHC class II molecules, and that this interaction may induce anergy in HA1.7.
Diabetes and sleep apnoea: a hidden epidemic?
Authors: J Wilding
Journal: Thorax (2006)

<h3>ABSTRACT</h3> The research team has utilized privacy-protected mobile device location data, integrated with COVID-19 case data and census population data, to produce a COVID-19 impact analysis platform that can inform users about the effects of COVID-19 spread and government orders on mobility and social distancing. The platform is being updated daily, to continuously inform decision-makers about the impacts of COVID-19 on their communities using an interactive analytical tool. The research team has processed anonymized mobile device location data to identify trips and produced a set of variables including social distancing index, percentage of people staying at home, visits to work and non-work locations, out-of-town trips, and trip distance. The results are aggregated to county and state levels to protect privacy and scaled to the entire population of each county and state. The research team are making their data and findings, which are updated daily and go back to January 1, 2020, for benchmarking, available to the public in order to help public officials make informed decisions. This paper presents a summary of the platform and describes the methodology used to process data and produce the platform metrics.
S104 Double-blind Multi-centre Randomised Controlled Trial Of Vitamin D3 Supplementation In Copd (vidico)
Authors: A. Martineau, W. James, R. Hooper, N. Barnes, D. Jolliffe, A. Bhowmik, R. Rajakulasingam, A. Choudhury, D. Simcock, C. Corrigan, C. Hawrylowicz, C. Griffiths
Journal: Thorax (2014)

<h3>Introduction and objectives</h3> Inadequate vitamin D status is common in patients with COPD, and it associates with susceptibility to upper respiratory infection (URI) – a major precipitant of exacerbation. Multi-centre trials of vitamin D supplementation for prevention of exacerbation and URI in COPD are lacking. We therefore conducted a multi-centre double-blind randomised placebo-controlled trial of vitamin D supplementation for the prevention of moderate/severe exacerbation and URI in adults with COPD. <h3>Methods</h3> Two hundred and forty patients were allocated to receive a 2-monthly oral dose of 3 mg vitamin D<sub>3</sub> or placebo for one year. Co-primary outcomes were time to first moderate/severe exacerbation and time to first URI. Secondary outcomes included peak severity and area under the curve for exacerbation symptoms. A pre-specified sub-group analysis was conducted to determine whether effects of the intervention on co-primary outcomes were modified by baseline vitamin D status. This trial is registered with ClinicalTrials.gov (NCT00977873). <h3>Results</h3> 122 participants were allocated to the intervention arm of the trial, and 118 to the control arm. Vitamin D supplementation did not influence time to first exacerbation (HR 0.86, 95% CI 0.60–1.24, p = 0.42) or time to first URI (HR 0.95, 95% CI 0.69–1.31, p = 0.75) in the study population as a whole, but it did reduce peak severity (p = 0.042) and area under the curve (p = 0.032) for exacerbation symptoms. Pre-specified sub-group analysis revealed that vitamin D supplementation was protective against moderate/severe exacerbation among the 148 participants with baseline serum 25-hydroxyvitamin D (25[OH]D) concentration &lt; 50 nmol/L (aHR 0.57, 95% CI 0.35 to 0.92, p = 0.021), but not among the 92 participants with baseline serum 25(OH)D ≥ 50 nmol/L (aHR 1.45, 95% CI 0.81 to 2.62, p = 0.21; P for interaction = 0.021). Baseline vitamin D status did not modify the effect of vitamin D supplementation on risk of URI (P for interaction = 0.41). <h3>Conclusions</h3> Vitamin D supplementation protected against moderate/severe exacerbation, but not upper respiratory infection, in COPD patients with baseline 25(OH)D &lt; 50 nmol/L. It also modestly reduced peak severity and area under the curve for exacerbation symptom scores, irrespective of baseline vitamin D status.
Significance of physician judged chronic bronchitis versus emphysema
Authors: MeiLan Han, Manja Brose, Udo-Michael Goehring, Fernando Martinez
Journal: European Respiratory Journal (2012)

Background: Prior data suggest chronic bronchitic symptoms in COPD are associated with poorer outcomes, but symptoms of cough and sputum are difficult to quantify. The goal of this analysis is to determine the significance of physician judged chronic bronchitis versus emphysema.

Methods: Data from the placebo arms of two, one-year phase III studies of roflumilast (M2-111 & M2-112) in COPD were used to compare baseline characteristics between subjects with physician-judged emphysema vs either chronic bronchitis & combined chronic bronchitis and emphysema (CB). Cough and sputum were graded as 0 none, 1 mild, 2 moderate and 3 severe.

Results: Of 1,260 subjects, 413 (32.8%) had emphysema and 847 (67.2%) had CB. CB subjects had higher FEV1% predicted, 38.0 vs 34.6 (p<0.001)and more prevalent current smoking, 42.4% vs. 31.2% (p=0.0001). Baseline SGRQ total and symptom scores were similar between CB and emphysema patients, 49.5 vs. 48.7 (p=0.46) and 56.1 vs. 53.7 (p=0.06) respectively, but SGRQ activity and impacts scores were higher in CB subjects, 64.2 vs. 67.2 (p=0.01) and 39.0 vs. 36.2 (p=0.02) respectively. In adjusted analyses, CB was not associated with more frequent exacerbations, 1.12, p=0.26. Cough and sputum scores are outlined in Table 1.

View this table:

Table 1. Cough and Sputum Scores





Conclusions: Physicians distinguished between subjects with CB who despite better FEV1, had worse SGRQ activity and impacts scores than emphysema subjects. However, subjects with physician identified CB actually differed on baseline cough but not sputum scores.
The acinar regulator Gata6 suppresses<i>Kras<sup>G12V</sup></i>-driven pancreatic tumorigenesis in mice
Authors: Paola Martinelli, Francesc Madriles, Marta Cañamero, Enrique Carrillo-de Santa Pau, Natalia del Pozo, Carmen Guerra, Francisco X Real
Journal: Gut (2015)

<h3>Background and aims</h3> Gata6 is required to complete and maintain acinar differentiation in the mouse pancreas. Pancreas-specific Gata6 ablation during development causes extensive and persistent acinar-ductal metaplasia, which is considered an initial step of mutant <i>KRas</i>-driven carcinogenesis. Therefore, the <i>Gata6</i>-null pancreas might represent a tumour-prone environment. We investigated whether Gata6 plays a role during pancreatic tumorigenesis. <h3>Design</h3> We analysed genetically engineered mouse models and human pancreatic ductal adenocarcinoma (PDAC) cell lines, using a combination of histopathological studies, genome-wide expression and chromatin immunoprecipitation experiments to understand the role of Gata6 in the initiation and progression of <i>KRas<sup>G12V</sup></i>-driven tumours <h3>Results</h3> We show that Gata6 maintains the acinar differentiation programme, both directly and indirectly, and it concomitantly suppresses ectopic programmes in the pancreas. Gata6 ablation renders acinar cells more sensitive to <i>KRas<sup>G12V</sup></i>, thereby accelerating tumour development. Gata6 expression is spontaneously lost in a mouse model of <i>KRas<sup>G12V</sup></i>-driven PDAC, in association with altered cell differentiation. Using a combination of ChIP-Seq and RNA-Seq, we show that Gata6 exerts its tumour-suppressive effect through the promotion of cell differentiation, the suppression of inflammatory pathways, and the direct repression of cancer-related pathways. Among them is the epidermal growth factor receptor (EGFR) pathway, the activity of which is upregulated in the normal and preneoplastic <i>Gata6</i>-null pancreas. Accordingly, GATA6-silencing in human PDAC cells leads to an upregulation of EGFR. <h3>Conclusions</h3> We propose that, in the pancreas, Gata6 acts as a tumour suppressor by enforcing acinar cell differentiation, by directly and indirectly repressing ectopic differentiation programmes, and by regulating crucial cancer-related gene expression pathways.
Composite anatomical-clinical-molecular prognostic model in nonsmall cell lung cancer
Authors: A. López-Encuentra, F. López-Ríos, E. Conde, R. García-Luján, A. Suárez-Gauthier, N. Mañes, G. Renedo, J.L. Duque-Medina, E. García-Lagarto, R. Rami-Porta, G. González-Pont, J. Astudillo-Pombo, J.L. Maté-Sanz, J. Freixinet, T. Romero-Saavedra, M. Sánchez-Céspedes, A. Gómez de la Camara
Journal: European Respiratory Journal (2010)

The objective of the present study was to elaborate a survival model that integrates anatomic factors, according to the 2010 seventh edition of the tumour, node and metastasis (TNM) staging system, with clinical and molecular factors. Pathologic TNM descriptors (group A), clinical variables (group B), laboratory parameters (group C) and molecular markers (tissue microarrays; group D) were collected from 512 early-stage nonsmall cell lung cancer (NSCLC) patients with complete resection. A multivariate analysis stepped supervised learning classification algorithm was used. The prognostic performance by groups was: areas under the receiver operating characteristic curve (C-index): 0.67 (group A), 0.65 (Group B), 0.57 (group C) and 0.65 (group D). Considering all variables together selected for each of the four groups (integrated group) the C-index was 0.74 (95% CI 0.70–0.79), with statistically significant differences compared with each isolated group (from p = 0.006 to p&lt;0.001). Variables with the greatest prognostic discrimination were the presence of another ipsilobar nodule and tumour size &gt;3 cm, followed by other anatomical and clinical factors, and molecular expressions of phosphorylated mammalian target of rapamycin (phospho-mTOR), Ki67cell proliferation index and phosphorylated acetyl-coenzyme A carboxylase. This study on early-stage NSCLC shows the benefit from integrating pathological TNM, clinical and molecular factors into a composite prognostic model. The model of the integrated group classified patients with significantly higher accuracy compared to the TNM 2010 staging.
ER , ER , and gpER: novel aspects of oestrogen receptor signalling in atherosclerosis
Authors: M. R. Meyer, M. Barton
Journal: Cardiovascular Research (2009)

Cardiovascular disease represents the leading cause of morbidity and mortality in women. Epidemiological and experimental evidence indicates several atheroprotective effects of endogenous oestrogens, which interfere with atherosclerosis progression and inflammation. Nevertheless, oestrogen receptor function across different stages of atherosclerosis development remains poorly characterized. This viewpoint editorial discusses the current knowledge of oestrogen receptor function in physiology and within different stages of atherogenesis. Increasing our understanding of the molecular mechanisms determining oestrogen action in humans, with and without established atherosclerosis, may help to develop new strategies for the treatment of cardiovascular disease in women, and possibly also in men.

Despite substantial efforts to improve education and public awareness and despite the use of effective medications and life-style changes for controlling the associated risk factors—hypertension, tobacco use, hypercholesterolemia, obesity, and diabetes—cardiovascular disease remains the leading cause of death in women worldwide.1,2 In contrast to age-matched men, the incidence of clinical manifestations of coronary artery disease is considerably lower in premenopausal women; indeed, about 95% of women develop cardiovascular disease after menopause when endogenous oestrogen levels are low.3–5 Accordingly, endogenous oestrogen protects from accelerated atherogenesis due to obesity in female teenagers and young adults compared with their male counterparts.6 Cardiovascular risk increases after bilateral ovariectomy and in conditions associated with impaired ovarian function.3,7 Thus, ovarian dysfunction and either natural or surgical menopause have been recognized as a major risk factor for accelerated atherosclerotic vascular disease development. In addition, cardiovascular risk factors and certain polymorphisms in oestrogen receptor genes may also determine an earlier onset of menopause.8 Given that the number of postmenopausal women is expected to rise by 1 billion worldwide within the next 40 years,9 understanding the impact of menopause on women's cardiovascular health has become increasingly important.

In addition … 

*Corresponding author. Tel: +41 44 255 56 63; fax: +41 44 255 87 47. E-mail address : matthiasbarton{at}gmx.com