tbuckley/cabot-search huggingface dataset:
Dalteparin for prevention of catheter-related complications in cancer patients with central venous catheters: final results of a double-blind, placebo-controlled phase III trial
Authors: M. Karthaus, A. Kretzschmar, H. Kröning, M. Biakhov, D. Irwin, N. Marschner, C. Slabber, G. Fountzilas, A. Garin, N.G.F. Abecasis, W. Baronius, G.G. Steger, T. Südhoff, C. Giorgetti, P. Reichardt
Journal: Annals of Oncology (2005)
Intracellular calcium changes and tachycardia-induced contractile dysfunction in canine atrial myocytes
Authors: H Sun
Journal: Cardiovascular Research (2001)

Objectives: Indirect evidence suggests a role for Ca2+-overload in electrical and mechanical alterations caused by atrial tachycardia. The present study assessed the alterations in cellular [Ca2+] and contractile function caused by rapid atrial cellular activation. Methods: Intracellular Ca2+ transients (CaT) and cell shortening (CS) were measured by microfluorometry (Indo-1 AM) and video edge-detection in isolated, field-stimulated canine atrial myocytes (37°C). Results: Abrupt increases in frequency (0.3–3 Hz) caused rapid increases in diastolic [Ca2+]i (DCa) that were maintained during rapid-pacing for up to 50 min. When short-term (3-min) rapid-pacing was imposed, CaT and CS increased initially upon returning to 0.3 Hz, but then declined rapidly to 64±5 and 49±7%, respectively, of pre-tachycardia values, returning to control after ∼15 min. Post-tachycardia CaT and CS reductions were prevented by decreasing [Ca2+]o during tachycardia to prevent Ca2+-overload. CS reductions correlated with indices of Ca2+ loading during tachycardia. Restoration of CaT to normal during post-tachycardia contractile dysfunction (by increasing [Ca2+]o) returned CS to normal, indicating that reduced Ca2+ release, not reduced myofilament Ca2+-sensitivity, caused post-tachycardia contractile failure. Estimation of sarcoplasmic-reticulum Ca2+-stores (caffeine-induced Ca2+-release) confirmed tachycardia-induced Ca2+-loading and suggested that reduced Ca2+-stores decreased Ca2+-release post-tachycardia. Conclusions: Atrial tachycardia increases cellular Ca2+-loading, leading to post-tachycardia abnormalities in Ca2+-handling that produce contractile dysfunction. These findings are the first direct evidence for the frequently-postulated role of Ca2+-overload in tachycardia-induced abnormalities of atrial function.
Protease-Activated Drug Development
Authors: Ki Young Choi, Magdalena Swierczewska, Seulki Lee, Xiaoyuan Chen
Journal: Theranostics (2012)

In this extensive review, we elucidate the importance of proteases and their role in drug development in various diseases with an emphasis on cancer.First, key proteases are introduced along with their function in disease progression.Next, we link these proteases as targets for the development of prodrugs and provide clinical examples of protease-activatable prodrugs.Finally, we provide significant design considerations needed for the development of the next generation protease-targeted and protease-activatable prodrugs.
Effect of acute and chronic inflammatory stimuli on expression of protease-activated receptors 1 and 2 in alveolar macrophages
Authors: Nicolas Roche, Robert G. Stirling, Sam Lim, Brian G. Oliver, Tim Oates, Elen Jazrawi, Gaetano Caramori, K.Fan Chung
Journal: Journal of Allergy and Clinical Immunology (2003)
Docetaxel versus docetaxel alternating with gemcitabine as treatments of advanced breast cancer: final analysis of a randomised trial
Authors: H. Joensuu, L. Sailas, T. Alanko, K. Sunela, R. Huuhtanen, M. Utriainen, R. Kokko, P. Bono, T. Wigren, S. Pyrhönen, T. Turpeenniemi-Hujanen, R. Asola, M. Leinonen, M. Hahka-Kemppinen, P. Kellokumpu-Lehtinen
Journal: Annals of Oncology (2009)
LSC 2013 abstract - Cigarette smoke suppresses innate immunity of the upper-respiratory tract leading to enhanced colonization of the lung
Authors: Meike Voss, Jan Hellberg, Markus Bischoff, Christian Herr, Robert Bals, Christoph Beisswenger
Journal: European Respiratory Journal (2013)

Smoking promotes enhanced colonization of the upper and the lower respiratory tract with potential pathogens, which increases the susceptibility to pulmonary infections. Here, we examined whether smoke exposure favors colonization of the upper-respiratory tract with bacterial pathogens such as Streptococcus pneumoniae and translocation of bacteria into the lung. To investigate this, mice were exposed to cigarette smoke in a long-term-smoke model for 8 months and afterwards colonized with S. pneumoniae in the upper-respiratory tract. Smoked mice showed higher colonization levels of the upper-respiratory tract compared to non-smoke controls and were more susceptible to bacterial translocation into the lung. Furthermore, smoke exposure suppressed innate immune functions of the upper-respiratory tract and the lung. Release of inflammatory mediators in the upper-respiratory tract and in the lung, such as KC and IL-1β, in response to bacterial colonization was reduced in smoked mice compared to non-smoked controls. Our results show that smoke impacts innate immunity of the airways rendering the host susceptible for bacterial colonization and infection.

Colonization of the upper airways after Sp D39 colonization.

![Figure][1]  [1]: pending:yes
Much Ado About Mammography Variability
Authors: L. G. Kessler
Journal: JNCI Journal of the National Cancer Institute (2002)

Variability in quality of medical care is its Achilles’ heel, and one in great need of repair. But, how do we improve the quality of a procedure such as mammography and ensure that variability is minimized? This fundamental issue underlies the article by Elmore et al. in this issue of the Journal (1). For almost 10 years, Elmore and colleagues have examined the issue of variability of radiologists’ readings of mammograms (2–4). After reestablishing the well-known phenomenon of variability in radiologic reading in general (5,6), these authors have explored the factors that influence this variability, hoping they can find ways to reduce it (1). In their community-based study, they have found that false-positive rates ranged from 2.6% to 15.9%. They can account for half this range by controlling for patient, radiologist, and testing characteristics (e.g., year of mammographic examination or availability of previous mammographic examination for comparison), but that still leaves significant variability in this one indicator of mammography performance. These authors examined this variability question in a real-world setting rather than in a testing situation, which has been used to assess radiologists’ performance in other studies. Screening tests in the population require trade-offs. In the case of mammography, clinicians can judge many examinations abnormal (or positive) and spend a lot of their patients’ and their own time tracking down minor or low-level suspicious findings to minimize missed cancers. But the price of calling many examinations positive is a consequent increase in the false-positive proportion (that is, the specificity is low). This increase has considerable financial and psychological costs (3,7–10). It is important to find a screening strategy that is optimal from a population perspective. That is, women who receive a screening mammographic examination would like to know that their chance of having a cancer detected, if present, is very high (that is, the sensitivity of the test is very high). They would also like to know that any abnormalities detected have a relatively high chance of clinical significance (that is, the test has a high positive predictive value). In an ideal mammography system, women would know the sensitivity and specificity of mammographic tests performed by specific physicians or facilities. They could then choose to attend screening where they can get the most sensitive tests, with false-positive rates they consider acceptable. Indeed, women likely vary with respect to what they consider acceptable rates of false positives and, given the opportunity to make informed choices, would likely differ in their preferences for examinations in which they risk high rates of false positives for small increases in sensitivity. By making such choices, they would indicate their willingness to go through the anxiety and expense of extra tests to reduce their chance of a missed diagnosis.
Glasgow-supported self-management for patients with COPD
Authors: Morven E M Wilkie
Journal: Thorax (2012)

Respiratory infection Journal clubGlasgow-supported self-management for patients with COPD Supported self-management schemes have proven to be of benefit in some chronic conditions.This randomised control trial was aimed to determine if self-management could help reduce hospital readmissions in a population of patients discharged from hospital after an exacerbation of chronic obstructive pulmonary disease (COPD).The primary outcome measured was the time to first hospital readmission with exacerbation or death due to COPD over a 12-month follow-up.Secondary end-points were based on health-related quality-of-life tools including: change from baseline at 6 and 12 months in the St George's respiratory questionnaire, hospital anxiety and depression scale, COPD self-efficacy scale and EuroQol 5D.Subgroup analysis was made of the primary outcomes between groups characterised by baseline demographic features.Of 995 patients identified, 464 were randomised to the intervention group or control, characterised by age, sex, per cent predicted forced expiratory volume at one second, recent pulmonary rehabilitation, smoking status, deprivation status and previous COPD admissions.For the primary outcome, no difference was found between the two groups, and due to poor compliance with return of questionnaires, no values could be placed on secondary outcomes.Subgroup analysis did not identify any correlation between baseline demographics and primary outcomes.Analysis of the intervention group showed that younger patients, and those not living alone, responded better to self-management resulting in a statistically significant reduction in hospital readmission.This study benefited from a robust design and large patient cohort; however, low patient uptake and subsequent poor return of the questionnaires limited its interpretation.Though it demonstrates that self-management among the general COPD population is of limited value, it does raise the possibility that with careful patient identification it may have merit.
Mitochondrial Fusion is Essential for Organelle Function and Cardiac Homeostasis
Authors: Yun Chen, Yingqiu Liu, Gerald W. Dorn
Journal: Circulation Research (2011)

Mitochondria constitute 30% of myocardial mass. Mitochondrial fusion and fission appear essential for health of most tissues. Mitochondrial fission occurs in neonatal cardiomycyte and is implicated in cardiomyocyte death. Mitochondrial fusion has not been observed in postmitotic myocytes of adult hearts, and its occurrence and function in this context are controversial.Determine the consequences on organelle and organ function of disrupting cardiomyocyte mitochondrial fusion in vivo.The murine mfn1 and mfn2 genes, encoding mitofusins (Mfn) 1 and 2 that mediate mitochondrial tethering and outer mitochondrial membrane fusion, were interrupted by Cre-mediated excision of essential exons in neonatal (Nkx2.5-Cre) and adult (MYH6 modified estrogen receptor-Cre-modified estrogen receptor plus tamoxifen or Raloxifene) hearts. Embryonic combined Mfn1/Mfn2 ablation was lethal after e9.5. Conditional combined Mfn1/Mfn2 ablation in adult hearts induced mitochondrial fragmentation, cardiomyocyte and mitochondrial respiratory dysfunction, and rapidly progressive and lethal dilated cardiomyopathy. Before heart failure developed, cardiomyocyte shortening and calcium cycling were unaffected by absence of Mfn1 and Mfn2. Based on the time course over which fusion-defective mitochondrial size decreases, a mitochondrial fusion/fission cycle in adult mouse hearts occurs approximately every 16 days.Mitochondrial fusion in adult cardiac myocytes is necessary to maintain normal mitochondrial morphology and is essential for normal cardiac respiratory and contractile function. Interruption of mitochondrial fusion causes lethal cardiac failure at a time corresponding to 3 or 4 cycles of unopposed mitochondrial fission.
Mechanisms involved in increased plasma brain natriuretic peptide after heart transplantation
Authors: S. Talha, A. Charloux, I. Enache, F. Piquard, B. Geny
Journal: Cardiovascular Research (2010)

Increased brain natriuretic peptide (BNP), reflecting increased ventricular wall stress and pressure, is a well-known diagnostic and prognostic marker in patients with chronic heart failure. Heart transplantation (HT), the process of replacing the failing heart and restoring haemodynamics, should normalize cardiac endocrine function. Nevertheless, BNP levels remain raised after HT, likely because of increased secretion and/or decreased clearance of the cardiac hormone. Thus, BNP increases in proportion to the extent of left and right ventricular dysfunction after HT. Clinically complicated cardiac transplantation (cardiac systolic dysfunction, renal failure) is associated with the higher level of circulating BNP, and clinically successful cardiac transplantation (mild cardiac diastolic dysfunction) is associated with moderately increased BNP values. Surprisingly, however, increased BNP has also been found after HT in the absence of haemodynamic perturbations or allograft rejection, raising the hypothesis that even subtle modification in the immune system might influence BNP expression. In view of the potential interest in the cardiac hormone for subjects' risk stratification and therapy, a better knowledge of the mechanisms involved in the BNP increase after HT might be helpful for HT recipients' follow-up.
Development of a simple enzyme-linked immunosorbent assay for the detection of autoantibodies in anti-p200 pemphigoid
Authors: S. Groth, A. Recke, K. Vafia, R.J. Ludwig, T. Hashimoto, D. Zillikens, E. Schmidt
Journal: British Journal of Dermatology (2010)

Anti-p200 pemphigoid is a subepidermal blistering skin disease characterized by autoantibodies against a 200-kDa protein (p200) of the dermal-epidermal junction. The laminin γ1 chain has recently been identified as target antigen in this disease and the C-terminus was described as an immunodominant region of laminin γ1. Diagnosis of anti-p200 pemphigoid requires detection of serum IgG at the dermal side of 1 mol L(-1) salt-split skin by indirect immunofluorescence microscopy and labelling of a 200-kDa protein by Western blotting of dermal extract. However, preparation of dermal extract is not widely available, limiting the possibility of diagnosing this disease to a few laboratories.To develop a simple, sensitive and specific diagnostic tool for anti-p200 pemphigoid.Sera from patients with anti-p200 pemphigoid (n = 35), bullous pemphigoid (BP, n = 101), epidermolysis bullosa acquisita (EBA, n = 10), antilaminin 332 mucous membrane pemphigoid (MMP, n = 14), pemphigus vulgaris (PV, n = 51) and healthy volunteers (HV, n = 131) were tested by a novel enzyme-linked immunosorbent assay (ELISA) that employed a recombinant monomeric C-terminal fragment of human laminin γ1 (hLAMC1-cterm) expressed in Escherichia coli.Serum reactivity with hLAMC1-cterm was detected in sera from 24 of 35 (69%) patients with anti-p200 pemphigoid, two of 101 (2%) with BP, 0 of 10 with EBA, two of 14 (14%) with anti-laminin 332 MMP, 0 of 51 with PV, and 0 of 131 HV.This novel ELISA will facilitate the diagnosis of anti-p200 pemphigoid.
Fast and slow myosins as markers of muscle injury
Authors: Mario Guerrero, Marc Guiu- Comadevall, Joan Aureli Cadefau, Joan Parra, Ramón Balius, Assumpta Estruch, Gil Rodas, José Luis Bedini, Roser Cussó
Journal: British Journal of Sports Medicine (2007)

The diagnosis of muscular lesions suffered by athletes is usually made by clinical criteria combined with imaging of the lesion (ultrasonography and/or magnetic resonance) and blood tests to detect the presence of non-specific muscle markers. This study was undertaken to evaluate injury to fast and slow-twitch fibres using specific muscle markers for these fibres.Blood samples were obtained from 51 non-sports people and 38 sportsmen with skeletal muscle injury. Western blood analysis was performed to determine fast and slow myosin and creatine kinase (CK) levels. Skeletal muscle damage was diagnosed by physical examination, ultrasonography and magnetic resonance and biochemical markers.The imaging tests were found to be excellent for detecting and confirming grade II and III lesions. However, grade I lesions were often unconfirmed by these techniques. Grade I lesions have higher levels of fast myosin than slow myosin with a very small increase in CK levels. Grade II and III lesions have high values of both fast and slow myosin.The evaluation of fast and slow myosin in the blood 48 h after the lesion occurs is a useful aid for the detection of type I lesions in particular, since fast myosin is an exclusive skeletal muscle marker. The correct diagnosis of grade I lesions can prevent progression of the injury in athletes undergoing continual training sessions and competitions, thus aiding sports physicians in their decision making.
X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO in human T-cell development and/or survival
Authors: Ryuta Nishikomori, Hiroshi Akutagawa, Kyoko Maruyama, Mami Nakata-Hizume, Katsuyuki Ohmori, Kazunori Mizuno, Akihiro Yachie, Takahiro Yasumi, Takashi Kusunoki, Toshio Heike, Tatsutoshi Nakahata
Journal: Blood (2004)
Phenotypic characterisation of T-lymphocytes in COPD: abnormal CD4+CD25+ regulatory T-lymphocyte response to tobacco smoking
Authors: B. Barceló, J. Pons, J. M. Ferrer, J. Sauleda, A. Fuster, A. G. N. Agustí
Journal: European Respiratory Journal (2007)

Tobacco smoking induces an inflammatory response in the lungs of all smokers but, for reasons that are still poorly understood, only a proportion of them develop chronic obstructive pulmonary disease (COPD). Recent evidence indicates that this inflammatory response persists after smoking cessation, suggesting some type of auto-perpetuation mechanism similar to that described in autoimmune disorders. T-lymphocytes (CD4+ and CD8+) have been implicated in the pathogenesis of both COPD and several autoimmune processes. A subtype of regulatory CD4+ T-cells expressing CD25 (Tregs) plays a critical role in the maintenance of peripheral tolerance and the prevention of autoimmunity, but their potential role in COPD has not been explored. The present study sought to evaluate maturation (CD45RA/CD45R0) and activation markers (CD28) of T-lymphocytes and to explore potential Treg abnormalities in COPD. Flow cytometry was used to characterise T-lymphocytes obtained from blood and bronchoalveolar lavage fluid (BALF) in 23 patients with moderate COPD, 29 smokers with normal lung function and seven never-smokers. The main findings were that in BALF: patients with COPD showed higher CD8+CD45RA+ and lower CD8+CD45R0+ than smokers with normal lung function; and compared with never-smokers, smokers with preserved lung function showed a prominent upregulation of Tregs that was absent in patients with COPD. These observations indicate a final maturation-activation state of CD8+ T-lymphocytes in chronic obstructive pulmonary disease and, for the first time, identify a blunted regulatory T-cell response to tobacco smoking in these patients, further supporting a potential involvement of the acquired immune response in the pathogenesis of the disease.
Transgene Expression of <i>bcl-xL</i> Permits Anti-immunoglobulin (Ig)–induced Proliferation in <i>xid</i> B Cells
Authors: Nanette Solvason, Wei Wei Wu, Nisha Kabra, Fridjtof Lund-Johansen, Maria Grazia Roncarolo, Timothy W. Behrens, Didier A.M. Grillot, Gabriel Nunez, Emma Lees, Maureen Howard
Journal: The Journal of Experimental Medicine (1998)

Mutations in the tyrosine kinase, Btk, result in a mild immunodeficiency in mice (xid). While B lymphocytes from xid mice do not proliferate to anti-immunoglobulin (Ig), we show here induction of the complete complement of cell cycle regulatory molecules, though the level of induction is about half that detected in normal B cells. Cell cycle analysis reveals that anti-Ig stimulated xid B cells enter S phase, but fail to complete the cell cycle, exhibiting a high rate of apoptosis. This correlated with a decreased ability to induce the anti-apoptosis regulatory protein, Bcl-xL. Ectopic expression of Bcl-xL in xid B cells permitted anti-Ig induced cell cycle progression demonstrating dual requirements for induction of anti-apoptotic proteins plus cell cycle regulatory proteins during antigen receptor mediated proliferation. Furthermore, our results link one of the immunodeficient traits caused by mutant Btk with the failure to properly regulate Bcl-xL.
NFKB1 Is a Direct Target of the TAL1 Oncoprotein in Human T Leukemia Cells
Authors: Pei-Yun Chang, Kyle Draheim, Michelle A. Kelliher, Shigeki Miyamoto
Journal: Cancer Research (2006)

Abstract We recently showed that a subset of human T acute lymphoblastic leukemia (T-ALL) cell lines expresses low basal levels of p50, a nuclear factor-κB (NF-κB)/Rel family member, resulting in their capacity to activate the atypical p65:cRel complex rather than the classic p50:p65 dimer. Here, we show that the transcription factor TAL1 (also known as SCL) binds to the promoter of the NFKB1 gene that encodes p50 and represses its transcription to set up this unique response in T-ALL cells. When TAL1 expression is reduced in CEM T leukemia cells, basal NFKB1 expression is increased, and the levels of p65:cRel complex and transcription of its target gene, such as intercellular adhesion molecule-1 (ICAM-1), are reduced in response to etoposide treatment. Moreover, a significant negative correlation between NFKB1 and TAL1 or LMO1 was found in primary human TAL1/LMO1 double-positive T-ALL samples previously described by Ferrando et al. Thus, TAL1 modulates NFKB1 expression and an NF-κB-dependent transcriptional program in a subset of human T-cell leukemia cells. (Cancer Res 2006; 66(12): 6008-13)
CXorf6 is a causative gene for hypospadias
Authors: Maki Fukami, Yuka Wada, Kanako Miyabayashi, Ichizo Nishino, Tomonobu Hasegawa, Agneta Nordenskjöld, Giovanna Camerino, Christine Kretz, Anna Buj-Bello, Jocelyn Laporte, Gen Yamada, Ken-ichirou Morohashi, Tsutomu Ogata
Journal: Nature Genetics (2006)
Twitch potentiating effects of theophylline on rat diaphragm are enhanced by foreshortening
Authors: G Gayan-Ramirez, N Buts, M Decramer
Journal: European Respiratory Journal (1994)

In patients with chronic obstructive pulmonary disease (COPD) and acute respiratory failure, acute hyperinflation is likely to induce foreshortening of inspiratory muscles. Since no data are available on the effects of inotropic agents at lengths below the optimal length (Lo), we compared the effects of theophylline on forty rat diaphragm bundles placed at Lo and at 70% Lo. Twitches and tetanic stimulations were recorded before and after addition of theophylline, in concentrations of 20, 100, 200 or 400 mg.l-1. Compared with values obtained before theophylline, twitch tension (Pt) and maximal tetanic tension (Po) of the bundles placed at Lo slightly decreased at 20 and 100 mg.l-1 whereas a clear increase in Pt was obtained at 400 mg.l-1 (15 +/- 21% (mean +/- SD)). In contrast, Pt of the bundles placed at 70% Lo increased with all theophylline concentrations, and vastly more than at Lo (e.g. at 400 mg.l-1: 74 +/- 34%, p < 0.05); whereas Po slightly decreased, except at 400 mg.l-1. Moreover, the difference between the effects at Lo and at 70% Lo increased with increasing theophylline concentrations. We conclude that even at low, in vivo attainable serum levels, theophylline exerted greater positive inotropic effects on twitch tension (Pt) of rat diaphragm when foreshortened than when at optimal length.