tbuckley/cabot-search huggingface dataset:
Inferring the Origin of Metastases from Cancer Phylogenies
Authors: Woo Suk Hong, Max Shpak, Jeffrey P. Townsend
Journal: Cancer Research (2015)

Abstract Determining the evolutionary history of metastases is a key problem in cancer biology. Several recent studies have presented inferences regarding the origin of metastases based on phylogenies of cancer lineages. Many of these studies have concluded that the observed monophyly of metastatic subclones favored metastasis-to-metastasis spread (“a metastatic cascade” rather than parallel metastases from the primary tumor). In this article, we argue that identifying a monophyletic clade of metastatic subclones does not provide sufficient evidence to unequivocally establish a history of metastatic cascades. In the absence of a complete phylogeny of the subclones within the primary tumor, a scenario of parallel metastatic events from the primary tumor is an equally plausible interpretation. Future phylogenetic studies on the origin of metastases should obtain a complete phylogeny of subclones within the primary tumor. This complete phylogeny may be obtainable by ultra-deep sequencing and phasing of large sections or by targeted sequencing of many small, spatially heterogeneous sections, followed by phylogenetic reconstruction using well-established molecular evolutionary models. In addition to resolving the evolutionary history of metastases, a complete phylogeny of subclones within the primary tumor facilitates the identification of driver mutations by application of phylogeny-based tests of natural selection. Cancer Res; 75(19); 4021–5. ©2015 AACR.
NHS reforms create threat to patient confidentiality
Authors: A. O'Dowd
Journal: BMJ (2011)

The government’s planned reforms for the NHS will create a threat to patient confidentiality and could damage the doctor-patient relationship, it has been claimed.

The BMA has written to health minister Simon Burns to highlight serious concerns it has about flaws in the government’s Health and Social Care Bill, which is currently being scrutinised by MPs before its next stage towards becoming law later this year.

The letter outlines the BMA’s worries about certain wording in the bill dealing with the sharing of information.

As part of the NHS reforms, the bill proposes that a number of people/bodies—including the health secretary, the newly formed NHS Commissioning Board, and the NHS Information Centre—should be …
Interactive inhibitory effects of formoterol and montelukast on activated human neutrophils
Authors: C.M. Gravett, A.J. Theron, H.C. Steel, G.R. Tintinger, R. Cockeran, C. Feldman, R. Anderson
Journal: European Respiratory Journal (2010)

The research question addressed in the current study was: do formoterol (1 and 10 nM) and montelukast (2 μM) possess interactive inhibitory effects on activated human neutrophils, particularly in relation to alterations in cyclic AMP and cytosolic Ca 2+ fluxes? Isolated human blood neutrophils were activated with the chemoattractant N -formyl- l -methionyl- l -leucyl- l -phenylalanine (fMLP) (1 μM) in combination with cytochalasin B (CB; 3 μM). Fura-2-acetoxymethyl ester-based spectrofluorimetry, lucigenin-enhanced chemiluminescence, colorimetric and flow cytometric procedures were used to measure cytosolic Ca 2+ fluxes, production of superoxide, elastase release and beta-2 integrin (CR3) expression, respectively, while cyclic AMP and leukotriene (LT)B 4 were assayed using competitive binding ELISA procedures. Activation of the cells with fMLP/CB resulted in abrupt and sustained increases in cytosolic Ca 2+ , as well as release of elastase and production of superoxide and LTB 4 , and expression of CR3, all of which were attenuated by formoterol and montelukast individually, and especially by the combination of these agents. These anti-inflammatory effects of each agent, as well as the combination, were associated with significant increases in cyclic AMP. The findings of the current study may explain the efficacy of montelukast and formoterol when used in combination with inhaled corticosteroids in the treatment of severe asthma, possibly by controlling neutrophil-driven inflammation of the airways.
Contractile Responsiveness of Ventricular Myocytes to Isoproterenol Is Regulated by Induction of Nitric Oxide Synthase Activityin Cardiac Microvascular EndothelialCells in Heterotypic Primary Culture
Authors: Dan Ungureanu-Longrois, Jean-Luc Balligand, Ikutaro Okada, William W. Simmons, Lester Kobzik, Charles J. Lowenstein, Steven L. Kunkel, Thomas Michel, Ralph A. Kelly, Thomas W. Smith
Journal: Circulation Research (1995)

Abstract Unlike large-vessel endothelial cells in cell culture, cardiac microvascular endothelial cells (CMEC) isolated from adult rat ventricular muscle exhibit little detectable constitutive nitric oxide (NO) synthase activity after isolation in vitro but respond to specific combinations of inflammatory mediators with an increase in inducible NO synthase (iNOS; type 2 NO synthase) activity. CMEC iNOS is induced by soluble inflammatory mediators in lipopolysaccharide-activated rat alveolar macrophage–conditioned medium at 24 hours, and this induction can be partially prevented by either interleukin-1 (IL-1) receptor antagonist or a polyclonal anti–rat tumor necrosis factor-α (TNF-α) antiserum. Interferon-γ (IFN-γ), which by itself does not induce iNOS in CMEC, potentiates and accelerates iNOS induction by IL-1β. Transforming growth factor-β (TGF-β) decreases iNOS activity, protein content, and mRNA abundance in IL-1β– and IFN-γ–pretreated CMEC. To determine whether NO released by CMEC would affect myocyte contractile function in vitro, freshly isolated ARVM were allowed to settle onto confluent, serum-starved CMEC that had been pretreated for 24 hours with IL-1β, a cytokine that alone does not affect myocyte contractile function in vitro. Baseline contractile amplitude, at 2 Hz and 37°C, of myocytes in heterotypic culture with IL-1β–pretreated CMEC was not different from that of myocytes in control, homotypic myocyte cultures. However, cocultured myocytes exhibited decreased contractile responsiveness to 2 nmol/L isoproterenol compared with control cells, and this could be reversed by the addition of 1 mmol/L N G -monomethyl- l -arginine, an inhibitor of NOS. Thus, activation of endothelial cell iNOS by specific cytokines affects the contractile responsiveness to isoproterenol of adjacent cardiac myocytes in vitro. Reciprocal cell-cell signaling leading to TGF-β release and activation could act to limit the extent of endothelial cell iNOS induction in vivo.
VEGF-PET Imaging Is a Noninvasive Biomarker Showing Differential Changes in the Tumor during Sunitinib Treatment
Authors: Wouter B. Nagengast, Marjolijn N. Lub-de Hooge, Sjoukje F. Oosting, Wilfred F.A. den Dunnen, Frank-Jan Warnders, Adrienne H. Brouwers, Johan R. de Jong, Patricia M. Price, Harry Hollema, Geke A.P. Hospers, Philip H. Elsinga, Jan Willem Hesselink, Jourik A. Gietema, Elisabeth G.E. de Vries
Journal: Cancer Research (2010)

Non-invasive imaging of angiogenesis could ease the optimization of antiangiogenesis treatments for cancer. In this study, we evaluated the role of VEGF-PET as a biomarker of dynamic angiogenic changes in tumors following treatment with the kinase inhibitor sunitinib. The effects of sunitinib treatment and withdrawal on the tumor was investigated using the new VEGF-PET tracer (89)Zr-ranibizumab as well as (18)F-FDG PET, and (15)O-water PET in mouse xenograft models of human cancer. The obtained imaging results were compared with tumor growth, VEGF plasma levels and immunohistologic analyzes. In contrast to (18)F-FDG and (15)O-water PET, VEGF-PET demonstrated dynamic changes during sunitinib treatment within the tumor with a strong decline in signal in the tumor center and only minimal reduction in tumor rim, with a pronounced rebound after sunitinib discontinuation. VEGF-PET results corresponded with tumor growth and immunohistochemical vascular- and tumor- markers. Our findings highlight the strengths of VEGF-PET imaging to allow serial analysis of angiogenic changes in different areas within a tumor.
FUTSAL ATHLETES' ASSESSMENT: PRESEASON AND SIX MONTHS FOLLOW UP
Authors: C Bolling, M Leite, D Reis
Journal: British Journal of Sports Medicine (2014)

Background Futsal has high injury's incidence due to intensive training and reduced recovery time between games. Intrinsic factors, which predispose to injury could be investigated by preseason assessment. Objective To compare the preseason and 6 months follow up results of single leg hop test and seat and reach test in futsal athletes. Design This is an observational longitudinal and prospective study to compare preseason results and follow up in different categories futsal athletes. Setting Athletes from 7 competitive categories under 12, 13, 14, 15, 17, 18, 20 years old and professionals of a Brazilian sports club, competing in national level. Participants 75 male athletes, mean age of 14.71 years (±2.44), mean weight of 56.95 kg (±12.33) and average height of 166.44 cm (±10.47). Risk factor assessment The athletes were evaluated using single leg hop test and sit and reach test in February (preseason) and September of 2012. Main outcome measurements Two tests were analyzed (single leg hop test and seat and reach test) to compare preseason and 6 months follow up results. The paired t-test was used for statistical analysis by SPSS software, version 19.0. Results All categories except under 17 and 18 showed improvement in values of the single leg hop test (P&lt;.005) on both sides. No significant difference in single leg hop test symmetry were observed except in under 20 (P=.037). The seat and reach test values improved in all categories with a significant difference (P&lt;.005) in under 12, 14 and 15. Conclusions The changes between preseason and 6 months later were expected and could be associated with improvements in strenght, power and flexibility. The tests changes indicated a physical capacity enhancement revolving around injury prevention by intrinsic factors management.
A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea (TOMADO)
Authors: Timothy G Quinnell, Maxine Bennett, Jake Jordan, Abigail L Clutterbuck-James, Michael G Davies, Ian E Smith, Nicholas Oscroft, Marcus A Pittman, Malcolm Cameron, Rebecca Chadwick, Mary J Morrell, Matthew J Glover, Julia A Fox-Rushby, Linda D Sharples
Journal: Thorax (2014)

<h3>Rationale</h3> Mandibular advancement devices (MADs) are used to treat obstructive sleep apnoea-hypopnoea syndrome (OSAHS) but evidence is lacking regarding their clinical and cost-effectiveness in less severe disease. <h3>Objectives</h3> To compare clinical- and cost-effectiveness of a range of MADs against no treatment in mild to moderate OSAHS. <h3>Measurements and methods</h3> This open-label, randomised, controlled, crossover trial was undertaken at a UK sleep centre. Adults with Apnoea-Hypopnoea Index (AHI) 5–&lt;30/h and Epworth Sleepiness Scale (ESS) score ≥9 underwent 6 weeks of treatment with three non-adjustable MADs: self-moulded (SleepPro 1; SP1); semi-bespoke (SleepPro 2; SP2); fully-bespoke MAD (bMAD); and 4 weeks no treatment. Primary outcome was AHI scored by a polysomnographer blinded to treatment. Secondary outcomes included ESS, quality of life, resource use and cost. <h3>Main results</h3> 90 patients were randomised and 83 were analysed. All devices reduced AHI compared with no treatment by 26% (95% CI 11% to 38%, p=0.001) for SP1, 33% (95% CI 24% to 41%) for SP2 and 36% (95% CI 24% to 45%, p&lt;0.001) for bMAD. ESS was 1.51 (95% CI 0.73 to 2.29, p&lt;0.001, SP1) to 2.37 (95% CI 1.53 to 3.22, p&lt;0.001, bMAD) lower than no treatment (p&lt;0.001 for all). Compliance was lower for SP1, which was the least preferred treatment at trial exit. All devices were cost-effective compared with no treatment at a £20 000/quality-adjusted life year (QALY) threshold. SP2 was the most cost-effective up to £39 800/QALY. <h3>Conclusions</h3> Non-adjustable MADs achieve clinically important improvements in mild to moderate OSAHS and are cost-effective. Of those trialled, the semi-bespoke MAD is an appropriate first choice. <h3>Trial registration number</h3> ISRCTN02309506.
Changes in maximum expiratory flow-volume curve configuration after treatment with inhaled corticosteroids.
Authors: J Kraan, T W van der Mark, G H Koeter
Journal: Thorax (1989)

The present study reports the changes in configuration of maximal flow-volume curves after eight weeks' treatment with inhaled corticosteroids in 14 asthmatic patients. The configuration was compared with that seen after bronchodilatation following inhalation of a single dose of ipratropium bromide. After inhaled corticosteroids the shape of the flow-volume curves was less bowed toward the volume axis, whereas the shape of the flow-volume curves after inhalation of ipratropium bromide showed no significant change. A significant correlation was observed between the decrease in blood eosinophil cell count and the straightening of the flow-volume curves, quantitatively expressed as shape factor and slope ratio. It is concluded that these changes in flow-volume curve configuration reflect a decrease in inhomogeneously distributed inflammatory airway narrowing.
ZD6474, a Potent Inhibitor of Vascular Endothelial Growth Factor Signaling, Combined With Radiotherapy
Authors: Kaye J. Williams, Brian A. Telfer, Sandra Brave, Jane Kendrew, Lynsey Whittaker, Ian J. Stratford, Stephen R. Wedge
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis and acts as a radiation survival factor for endothelial cells. ZD6474 (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine) is a potent VEGF receptor 2 (KDR) tyrosine kinase inhibitor (TKI) that has additional activity versus the epidermal growth factor receptor. This study was designed to determine the efficacy of combining ZD6474 and radiotherapy in vivo. Experimental Design: The Calu-6 (non–small-cell lung cancer) tumor model was selected because it was found to be unresponsive to treatment with a selective epidermal growth factor receptor TKI but responds significantly to treatment with selective VEGF receptor TKIs. Tumor-bearing mice received either vehicle or ZD6474 (50 mg/kg, by mouth, once daily) for the duration of the experiment, with or without radiotherapy (3 × 2 Gy, days 1–3). Two combination schedules were examined: (a) ZD6474 given before each dose of radiation (concurrent schedule); and (b) ZD6474 given 30 minutes after the last dose of radiotherapy (sequential schedule). Results: The growth delay induced using the concurrent schedule was greater than that induced by ZD6474 or radiation treatment alone (22 ± 1 versus 9 ± 1 and 17 ± 2 days, respectively; P = 0.03 versus radiation alone). When administered sequentially, the growth delay was markedly enhanced (36 ± 1 days; P &amp;lt; 0.001 versus radiation alone or the concurrent schedule). Intravenous administration of Hoechst 33342 showed a trend toward reduced tumor perfusion after ZD6474 treatment, and a pairwise comparison (versus control) was significant after three doses of ZD6474 (P = 0.05 by one-tailed t test). Thus, impaired reoxygenation between fractions in the concurrent protocol may be the causal basis for the schedule dependency of the radiopotentiation observed. Conclusions: ZD6474 may be a successful adjuvant to clinical radiotherapy, and scheduling of the treatments could be important to ensure optimal efficacy.
Molecular Pathobiology of Human Cervical High-Grade Lesions: Paracrine STAT3 Activation in Tumor-Instructed Myeloid Cells Drives Local MMP-9 Expression
Authors: Nadine Schröer, Jennifer Pahne, Barbara Walch, Claudia Wickenhauser, Sigrun Smola
Journal: Cancer Research (2011)

Abstract In many tumors, the switch from precancerous lesions to malignancy critically relies on expression of the matrix-metalloprotease MMP-9, which is predominantly provided by infiltrating inflammatory cells. Our study defines a novel molecular cascade, how human neoplastic cells instruct tumor-associated myeloid cells to produce MMP-9. In biopsies of human papillomavirus–associated precancerous cervical intraepithelial neoplasia (CIN III lesions), we show broad activation of the transcription factor STAT3 and coexpression of MMP-9 in perivascular inflammatory cells. For the first time, we establish a causative link between tumor-mediated paracrine STAT3 activation and MMP-9 production by human tumor-instructed monocytes, whereas NF-κB activation is dispensable for this response. Our data provide evidence that STAT3 does not directly induce MMP-9 but first leads to a strong production of the monocyte chemoattractant protein-1 (CCL2) in the nanogram range. In a second phase, autocrine stimulation of the CCR2 receptor in the tumor-instructed monocytes amplifies MMP-9 expression via intracellular Ca2+ signaling. These findings elucidate a critical mechanism in the molecular pathobiology of cervical carcinogenesis at the switch to malignancy. Particularly in tumors, which are associated with infectious agents, STAT3-driven inflammation may be pivotal to promote carcinogenesis, while at the same time limit NF-κB–dependent immune responses and thus rejection of the infected preneoplastic cells. The molecular cascade defined in this study provides the basis for a rational design of future adjuvant therapies of cervical precancerous lesions. Cancer Res; 71(1); 87–97. ©2011 AACR. Cancer Res; 71(1); 87–97. ©2011 AACR.
Matrix Metalloproteinases (MMPs) Regulate Fibrin-invasive Activity via MT1-MMP–dependent and –independent Processes
Authors: Kevin B. Hotary, Ikuo Yana, Farideh Sabeh, Xiao-Yan Li, Kenn Holmbeck, Henning Birkedal-Hansen, Edward D. Allen, Nobuaki Hiraoka, Stephen J. Weiss
Journal: The Journal of Experimental Medicine (2002)

Cross-linked fibrin is deposited in tissues surrounding wounds, inflammatory sites, or tumors and serves not only as a supporting substratum for trafficking cells, but also as a structural barrier to invasion. While the plasminogen activator-plasminogen axis provides cells with a powerful fibrinolytic system, plasminogen-deleted animals use alternate proteolytic processes that allow fibrin invasion to proceed normally. Using fibroblasts recovered from wild-type or gene-deleted mice, invasion of three-dimensional fibrin gels proceeded in a matrix metalloproteinase (MMP)-dependent fashion. Consistent with earlier studies supporting a singular role for the membrane-anchored MMP, MT1-MMP, in fibrin-invasive events, fibroblasts from MT1-MMP–null mice displayed an early defect in invasion. However, MT1-MMP–deleted fibroblasts circumvented this early deficiency and exhibited compensatory fibrin-invasive activity. The MT1-MMP–independent process was sensitive to MMP inhibitors that target membrane-anchored MMPs, and further studies identified MT2-MMP and MT3-MMP, but not MT4-MMP, as alternate pro-invasive factors. Given the widespread distribution of MT1-, 2-, and 3-MMP in normal and neoplastic cells, these data identify a subset of membrane-anchored MMPs that operate in an autonomous fashion to drive fibrin-invasive activity.
Personality Pathology and Treatment Outcome in Major Depression: A Review
Authors: Roger T. Mulder
Journal: American Journal of Psychiatry (2002)

A longstanding belief among many clinicians is that patients with depression and comorbid personality pathology have a worse response to standard depression treatment. This presents potentially significant treatment implications, since personality pathology in depressed patients appears to be common.PsycINFO and MEDLINE were systematically searched for studies relating personality to treatment outcome. Over 50 studies were obtained and grouped according to the method used to assess personality pathology.High neuroticism scores generally predicted worse outcome, especially over long-term follow-up. Tridimensional Personality Questionnaire scores did not have a consistent relationship to treatment outcome despite some promising initial findings. Most studies involved patients with comorbid personality disorders; these studies produced conflicting results. Other measures of personality pathology produced an array of findings ranging from a moderately worse outcome to no difference.Whether or not personality pathology significantly worsens outcome in patients with major depression appears to depend on study design, since the rate of personality pathology varies markedly depending on how it is measured. In addition, depressed patients with personality pathology appear less likely to receive adequate treatment in uncontrolled studies. Finally, studies rarely control for depression characteristics (e.g., chronicity, severity) that may influence outcome and be related to personality pathology. Overall, the best-designed studies reported the least effect of personality pathology on depression treatment outcome. Clinically, this suggests that comorbid personality pathology should not be seen as an impediment to good treatment response.
STUDIES ON THE SENSITIZATION OF ANIMALS WITH SIMPLE CHEMICAL COMPOUNDS
Authors: K. Landsteiner, M. W. Chase
Journal: The Journal of Experimental Medicine (1940)

A method has been described by which sensitization to a simple chemical, picryl chloride (2:4:6 trinitrochlorobenzene), can be satisfactorily attained by means of intraperitoneal injection of the compound when killed tubercle bacilli suspended in paraffin oil were used as adjuvant. Sensitivity of the contact dermatitis type results therefrom. It follows that although skin sensitization of this type is most easily obtained by dermal application this route of administration is no necessary condition for such sensitivity.
Comparison of Cystic Fibrosis–Related Diabetes With Type 1 Diabetes Based on a German/Austrian Pediatric Diabetes Registry
Authors: Katja Konrad, Angelika Thon, Maria Fritsch, Elke Fröhlich-Reiterer, Eggert Lilienthal, Stefan A. Wudy, Reinhard W. Holl
Journal: Diabetes Care (2012)

OBJECTIVE The prevalence of cystic fibrosis–related diabetes (CFRD) has increased with improved life expectancy of patients. Clinical and care characteristics were compared with type 1 diabetes mellitus (T1DM) in a multicenter analysis of pediatric data. RESEARCH DESIGN AND METHODS Auxological and treatment data from 47,227 patients aged younger than 21 years with CFRD or T1DM in the German/Austrian Diabetes Prospective Documentation Initiative registry were analyzed by multivariable mixed regression modeling. RESULTS Diabetes onset (mean [interquartile range]) occurred later in individuals with CFRD (14.5 [11.8–16.3] years) than in individuals with T1DM (8.5 [4.9–11.8] years), with female preponderance in CFRD (59.1% vs. 47.5%; P &amp;lt; 0.01). CFRD patients had lower BMI standard deviation scores (−0.85 [−1.59 to −0.12] vs. +0.52 [−0.10 to +1.16]; P &amp;lt; 0.01) and lower HbA1c (6.87% vs. 7.97%; P &amp;lt; 0.01). Self-monitoring of blood glucose was more frequent in patients with T1DM (4.5 vs. 3.5; P &amp;lt; 0.01); 72% of CFRD patients received insulin. In insulin-treated patients, insulin dosage adjusted for age, sex, and diabetes duration differed significantly (T1DM: 0.79 IE per kilogram of body weight; CFRD: 0.83 IE per kilogram of body weight). Use of short-acting and long-acting insulin analogs was significantly more frequent in T1DM (47% vs. 39% and 37% vs. 28%; both P &amp;lt; 0.05). Metabolic control in CFRD patients without insulin was better compared with CFRD on insulin (HbA1c: 6.00 vs. 7.12; P &amp;lt; 0.01), but duration of disease was significantly shorter (0.8 years [0.1–2.4] compared with 2.4 years [0.6–4.6]). There was no significant difference for BMI standard deviations scores between CFRD patients with or without insulin treatment. CONCLUSIONS Pediatric patients with CFRD show clear auxological and metabolic differences from those with T1DM, with different treatment choices.