tbuckley/cabot-search huggingface dataset:
Epistasis and Pleiotropy Affect the Modularity of the Genotype–Phenotype Map of Cross-Resistance in HIV-1
Authors: Robert Polster, Christos J. Petropoulos, Sebastian Bonhoeffer, Frédéric Guillaume
Journal: Molecular Biology and Evolution (2016)

The genotype–phenotype (GP) map is a central concept in evolutionary biology as it describes the mapping of molecular genetic variation onto phenotypic trait variation. Our understanding of that mapping remains partial, especially when trying to link functional clustering of pleiotropic gene effects with patterns of phenotypic trait co-variation. Only on rare occasions have studies been able to fully explore that link and tend to show poor correspondence between modular structures within the GP map and among phenotypes. By dissecting the structure of the GP map of the replicative capacity of HIV-1 in 15 drug environments, we provide a detailed view of that mapping from mutational pleiotropic variation to phenotypic co-variation, including epistatic effects of a set of amino-acid substitutions in the reverse transcriptase and protease genes. We show that epistasis increases the pleiotropic degree of single mutations and provides modularity to the GP map of drug resistance in HIV-1. Moreover, modules of epistatic pleiotropic effects within the GP map match the phenotypic modules of correlated replicative capacity among drug classes. Epistasis thus increases the evolvability of cross-resistance in HIV by providing more drug- and class-specific pleiotropic profiles to the main effects of the mutations. We discuss the implications for the evolution of cross-resistance in HIV.
P123 Inhaled corticosteroid plus long-acting β2-agonist therapy is overused in the treatment of patients with chronic obstructive pulmonary disease: post hoc analyses of two 1-year studies: Abstract P123 Table 1
Authors: H Watz, GT Ferguson, L Grönke, F Voß, R Abrahams, R Buhl
Journal: Thorax (2015)

<h3>Rationale</h3> Inhaled corticosteroid (ICS) plus long-acting β<sub>2</sub>-agonist (LABA) therapy is indicated for different patient groups with chronic obstructive pulmonary disease (COPD) in the USA and Europe. In the previous version of the Global initiative for chronic Obstructive Lung Disease (GOLD) recommendations, the use of ICS plus LABA therapy was restricted to patients with severe and very severe lung-function impairment and frequent exacerbations, with overtreatment in milder patient populations well documented. The current GOLD document recommends the use of ICS plus LABA maintenance therapy for patients in categories C and D. <h3>Methods</h3> We present <i>post hoc</i> analyses from the two pivotal 1-year TONADO studies to assess the use of ICS plus LABA maintenance therapy in patients classified as GOLD A/B and C/D. As these studies were initiated before the update of the GOLD recommendations, no modified Medical Research Council Dyspnoea scale or COPD Assessment Test data were available to further classify these patients into categories A or B and C or D. Based on the reported COPD exacerbation history and lung-function measurements, 2259 patients were classified as GOLD A/B and 2903 as GOLD C/D. Baseline characteristics and concomitant medications at baseline are presented in Table 1. <h3>Results</h3> In the GOLD A/B subgroup, 7.3% of patients were receiving treatment with ICS alone and 31.3% were receiving treatment with ICS plus LABA at study baseline. In the GOLD C/D subgroup, the incidences of patients receiving treatment with ICS alone and ICS plus LABA at study baseline were 8.8% and 45.5%, respectively. <h3>Conclusions</h3> Almost 40% of patients classified as GOLD A/B are receiving treatment with ICS maintenance therapy, either alone, in free combination or as a fixed-dose combination therapy, despite GOLD recommendations for use only in patients with more severe lung-function impairment and frequent exacerbations. Our analyses confirm previous reports, highlighting that treatment regimens containing ICS therapy are being used early in the management of patients with COPD, which may not be appropriate based on current GOLD recommendations. <h3>Funding</h3> Boehringer Ingelheim.
Corticosteroids in IgA Nephropathy: Lessons from Recent Studies
Authors: Rosanna Coppo
Journal: Journal of the American Society of Nephrology (2016)

IgA nephropathy (IgAN) is a common chronic glomerular disease that, in most patients, slowly progresses to ESRD. The immune and autoimmune responses that characterize IgAN indicate a potential benefit for corticosteroids. The 2012 Kidney Disease Improving Global Outcome (KDIGO) guidelines suggest giving corticosteroids to patients with rather preserved renal function (GFR&gt;50 ml/min per 1.73 m 2 ) and persistent proteinuria &gt;1 g/d, despite 3–6 months of optimized supportive care with renin-angiotensin system blockers. However, the evidence supporting this guideline was considered of low quality. More recent results from large cohort studies and randomized, controlled trials have provided conflicting messages about the benefits of corticosteroid treatment over supportive care alone, mostly involving optimized renin-angiotensin system blockade, which might generate further uncertainty in the therapeutic choice. Overall, these results indicate that corticosteroids are a powerful tool for treating patients with IgAN; however, treatment success is not universal and mostly occurs in patients who are highly proteinuric with early CKD. In patients with advanced CKD, the side effects of corticosteroids increase, and the renal protection decreases. This brief review aimed at integrating the findings of these recently published reports to provide balanced advice for clinicians as well as suggestions for future trials.
BET protein bromodomain inhibitor-based combinations are highly active against post-myeloproliferative neoplasm secondary AML cells
Authors: D T Saenz, W Fiskus, T Manshouri, K Rajapakshe, S Krieger, B Sun, C P Mill, C DiNardo, N Pemmaraju, T Kadia, S Parmar, S Sharma, C Coarfa, P Qiu, S Verstovsek, K N Bhalla
Journal: Leukemia (2016)
Liver Microvascular Injury and Thrombocytopenia of Antibody–Calicheamicin Conjugates in Cynomolgus Monkeys—Mechanism and Monitoring
Authors: Magali Guffroy, Hadi Falahatpisheh, Kathleen Biddle, John Kreeger, Leslie Obert, Karen Walters, Richard Goldstein, Germaine Boucher, Timothy Coskran, William Reagan, Danielle Sullivan, Chunli Huang, Sharon Sokolowski, Richard Giovanelli, Hans-Peter Gerber, Martin Finkelstein, Nasir Khan
Journal: Clinical Cancer Research (2016)

Purpose: Adverse reactions reported in patients treated with antibody-calicheamicin conjugates such as gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin include thrombocytopenia and sinusoidal obstruction syndrome (SOS). The objective of this experimental work was to investigate the mechanism for thrombocytopenia, characterize the liver injury, and identify potential safety biomarkers.Experimental Design: Cynomolgus monkeys were dosed intravenously at 6 mg/m2/dose once every 3 weeks with a nonbinding antibody-calicheamicin conjugate (PF-0259) containing the same linker-payload as gemtuzumab ozogamicin and inotuzumab ozogamicin. Monkeys were necropsied 48 hours after the first administration (day 3) or 3 weeks after the third administration (day 63).Results: PF-0259 induced acute thrombocytopenia (up to 86% platelet reduction) with nadirs on days 3 to 4. There was no indication of effects on megakaryocytes in bone marrow or activation of platelets in peripheral blood. Microscopic evaluation of liver from animals necropsied on day 3 demonstrated midzonal degeneration and loss of sinusoidal endothelial cells (SECs) associated with marked platelet accumulation in sinusoids. Liver histopathology on day 63 showed variable endothelial recovery and progression to a combination of sinusoidal capillarization and sinusoidal dilation/hepatocellular atrophy, consistent with early SOS. Among biomarkers evaluated, there were early and sustained increases in serum hyaluronic acid (HA) that correlated well with serum aspartate aminotransferase and liver microscopic changes, suggesting that HA may be a sensitive diagnostic marker of the liver microvascular injury.Conclusions: These data support the conclusion that target-independent damage to liver SECs may be responsible for acute thrombocytopenia (through platelet sequestration in liver sinusoids) and development of SOS. Clin Cancer Res; 23(7); 1760-70. ©2016 AACR.
Engage - a Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study to Investigate the Efficacy and Safety of Eliglustat in Adults with Gaucher Disease Type 1: Results after 18 Months
Authors: Dominick J Amato, Majed Dasouki, Seymour Packman, Gregory M. Pastores, Sarit Assouline, Manisha Balwani, Pramod Mistry, Andres Ortega, Suma Shankar, Maria Helena Solano, Leorah H. Ross, Jennifer Angell, Judith Peterschmitt
Journal: Blood (2014)
Selinexor-Induced Thrombocytopenia Results from the Inhibition of Megakaryocyte Progenitor Cells in the Early Stage of Megakaryopoiesis
Authors: Kellie R Machlus, Stephen Wu, Robert Carlson, Sharon Friedlander, Trinayan Kashyap, Ori Kalid, Eran Shacham, Tami Rashal, Sharon Shacham, Joseph E Italiano, Yosef Landesman
Journal: Blood (2014)
Late treatment mortality and secondary cancers after autologous stem cell transplant for relapsed or refractory Hodgkin lymphoma (HL)
Authors: N. C. Dhani, T. Roberts, M. Pintilie, J. Kuruvilla, N. Franke, T. Nagy, R. Tsang, A. Keating, M. Crump
Journal: Journal of Clinical Oncology (2007)

8016 Background: Late treatment-related mortality and second cancers have an important influence on the long-term outcome of patients (pts) with HL. The incidence of treatment failure and causes of death were evaluated in pts with advanced HL receiving high-dose therapy and ASCT, to understand the impact of late events on overall survival (OS). Methods: From Dec 1986 to Nov 2005, 323 pts with relapsed/refractory HL after primary chemotherapy (plus radiation [RT]: 32%) received salvage chemotherapy to best response, followed by etoposide 60 mg/kg day -4 and melphalan 160–180 mg/m 2 day -3 supported by autologous bone marrow (46%), mobilized peripheral blood stem cells (49%) or both (5%)on day 0; 24% received involved field RT post-ASCT. Risk of treatment failure and second cancer was estimated using competing risks methods. Results: Patient Characteristics: male: 61%; median age 33 years (range16–67). Number of salvage regimens pre-ASCT: 1: 72%; 2: 25%. Disease status post-salvage chemotherapy: CR 28%, PR 66%. After a median follow-up of 4.7 years post-ASCT (range 1–17), 174 pts (54%) have experienced treatment failure (relapse or treatment related death) and 154 pts (48%) have died, 75% following relapse and 20% from toxicity without relapse. Of the 30 deaths without relapse, 30% occured &gt;5 years post-ASCT. Failure free survival at 3 and 10 years is 50% (95% CI, 44–55%) and 40% (33–46), and overall survival is 68% (63–73) and 39% (33- 46), respectively. There have been 29 second cancers (17 AML/MDS, 12 solid tumors) in pts alive without relapsed HL. The probability of a second cancer is 4.9% (2.8–7.8) at 3 years and 12% (8–17%) at 10 years. The hazard rates for second malignancy, leukemia and solid tumors for each 10-year age increment are 1.9 (p=0.0001), 1.9 (0.001) and 1.8 (0.03), respectively. Only 4 pts have relapsed beyond 5 years post- ASCT but the cumulative incidence of treatment-related death (from toxicity or second cancers) continues to increase from 9% (6–13) at 3 years to 15% (11–20) 10 yrs post-ASCT. Conclusions: In this single-institution series of uniformly treated patients with relapsed/refractory HL, late relapse of disease is uncommon, but late toxicities have a significant and ongoing impact on failure-free survival. No significant financial relationships to disclose.
Comparison of the clinical outcomes between antiviral-naïve patients treated with entecavir and lamivudine-resistant patients receiving adefovir add-on lamivudine combination treatment
Authors: Hong Joo Kim, Soo Kyung Park, Hyo Joon Yang, Yoon Suk Jung, Jung Ho Park, Dong Il Park, Yong Kyun Cho, Chong Il Sohn, Woo Kyu Jeon, Byung Ik Kim, Kyu Yong Choi
Journal: Clinical and Molecular Hepatology (2016)

Background/Aims To analyze the effects of preexisting lamivudine (LAM) resistance and applying antiviral treatment (adefovir [ADV] add-on LAM combination treatment) on long-term treatment outcomes, and comparing the clinical outcomes of antiviral-naÃ¯ve chronic hepatitis B patients receiving entecavir (ETV) monotherapy. Methods This study enrolled 73 antiviral-naÃ¯ve patients who received 0.5-mg ETV as an initial therapy and 54 patients who received ADV add-on LAM combination treatment as a rescue therapy from July 2006 to July 2010. Results During 24-month treatments, the decreases in serum log10HBV-DNA values (copies/mL) were significantly greater in the antiviral-naÃ¯ve patients treated with ETV than the patients receiving ADV add-on LAM combination treatment. The biochemical response rates for alanine aminotransferase normalization at 6 months (ETV) and 12 months (ADV add-on LAM) were 90.4% (66/73) and 77.8% (42/54), respectively (P=0.048). A Kaplan-Meier analysis indicated that the rates of serologic response, viral breakthrough, and emergence of genotypic resistance did not differ significantly between the two patient groups. There were also no significant intergroup differences in the rates of disease progression (PD) and new development of hepatocellular carcinoma (HCC). Conclusion The long-term clinical outcomes of antiviral-naÃ¯ve patients treated with ETV and LAM-resistant patients receiving ADV add-on LAM combination treatment were comparable in terms of the emergence of HCC and disease progression. Keywords: Entecavir; Adefovir; Chronic hepatitis B; Disease progression; Cirrhosis
L'importation de salade « roquette » partiellement responsable de l'augmentation de l'incidence de l'hépatite A en Suède, 2000-2001
Authors: K. Nygard, Y. Andersson, P. Lindkvist, C. Ancker, I. Asteberg, E. Dannetun, R. Eitrem, L. Hellström, M. Insulander, L. Skedebrant, K. Stenqvist, J. Giesecke
Journal: Eurosurveillance (2001)

L’augmentation de cas autochtones d’hepatite A sans qu’aucune source d’infection ne soit mise en evidence, associee a une flambee epidemique mineure vers la fin du printemps 2001, a conduit a mener une etude cas-temoins. La consommation de roquette importee a clairement ete associee a la maladie (odds ratio de 9,1, intervalle de confiance 95% de 1,5 a 69). L’importation de legumes d’une region ou l’hepatite A est endemique a une region qui en est depourvue continue de poser un probleme de sante publique.
Improving Research into Models of Maternity Care to Inform Decision Making
Authors: Ank de Jonge, Jane Sandall
Journal: PLoS Medicine (2016)

The key aim of health services research is to inform decisions made by service users, health care providers, and policy makers.Therefore, the evidence produced needs to be robust, and the limitations clearly described.Maternity care is one area of health services that needs strong evidence to underpin the way it is organised.There is a growing interest across the world in midwife-led continuity of care (MLCC) for childbearing women and their babies [1,2].In MLCC, one midwife or a small team of midwives lead the planning, organisation, and delivery of care, with some care delivered in consultation with obstetric staff in a timely and appropriate process [1].In a Cochrane systematic review of 15 trials involving 17,674 women, MLCC compared favourably with obstetrician-provided or family doctor-provided care or shared models of care [1].For example, women who had MLCC were less likely to have a preterm birth before 37 weeks (average risk ratio [RR] 0.76, 95% confidence interval [CI] 0.64-0.91),foetal loss/neonatal death before 24 weeks (average RR 0.81, 95% CI 0.67-0.98),regional analgesia (average RR 0.85, 95% CI 0.78-0.92),instrumental vaginal birth (average RR 0.90, 95% CI 0.83-0.97),and episiotomy (average RR 0.84, 95% CI 0.77-0.92).There were no significant differences in caesarean section, foetal loss or neonatal death at or after 24 weeks gestation, low Apgar scores, or rates of neonatal convulsions or admission to a neonatal intensive care unit.Overall, more women were satisfied with MLCC, and there was a trend towards a cost-saving effect compared to other models of care.Based on these positive results, MLCC has been advocated as an effective way to organise maternal and newborn care [2,3].
SAR131675, a new potent selective VEGFR-3-TK inhibitor: Effect on lymphangiogenic, tumor growth, and metastasis.
Authors: I. Blanc, A. Alam, O. Duclos, G. Gueguen, J. Bonnin, M.C. Laplace, P. Barron, F. Dol, P. Schaeffer, P. Savi, F. Bono
Journal: Journal of Clinical Oncology (2010)

e13623 Background: VEGFR-3 is a tyrosine kinase receptor recognized by VEGF-C and VEGF-D and plays a major role in lymphangiogenesis. A number of clinical and experimental studies have demonstrated that tumor lymphangiogenesis induced by VEGFR-3 promotes metastasis to regional lymph nodes. Methods: Here we describe the activity of SAR131675 in vitro on recombinant kinases and cellular assays and in vivo on tumor growth and metastasis. Results: SAR131675 inhibits VEGFR-3 tyrosine kinase activity with an IC50≈20nM and VEGFR-3 autophosphorylation in HEK cells with an IC50≈45nM. SAR131675 potently inhibits the proliferation of primary human lymphatic cells, induced by VEGF-C and VEGF-D (IC50≈ 20nM). It is highly selective for VEGFR- 3 compared to 107 receptors, enzymes and ion channels and to all a panel of 55 kinases. However, it exhibited a moderate activity on VEGFR-2 with a ratio VEGFR-3/VEGFR-2 of about 10. SAR131675 has no anti-proliferative activity on a panel of 30 cell lines, further demonstrating its high specificity and indicating that SAR131675 is not a cytotoxic or cytostatic agent. In the mice, SAR131675 was very well tolerated and significantly reduced the tumor volume of several tumor models with about 50% (mammary 4T1, Prostate, Rip1.Tag2…). Moreover, it significantly reduced lymph nodes (50%) and distant metastasis (30-50%) in the 4T1 model. Importantly, treatment of mice before (and only before) resection of 4T1 primary tumor was sufficient to prevent metastasis. Tumor-associated macrophages (TAMs) play an important role in tumor growth and have been described to express VEGFR-3. Immunohistological analysis on human cancer tissues confirmed the expression of VEGFR-3 on TAMs of all tumors analysed. F4/80 immunostaing staining of 4T1 mammary tumors revealed that at early stage, macrophages are located at tumor periphery and later they invade the tumor and form clusters. SAR13675 reduced not only the number of tumor infiltrating macrophages but also their aggregation. Conclusions: Altogether, we identified a highly specific VEGFR-3 inhibitor, endowed with anti-tumoral and anti-metastatic activities and which reduce the number of tumor associated macrophages. No significant financial relationships to disclose.
S79 The electronic Case-Based Discussion; a novel teaching method applied to smoking cessation: Abstract S79 Table 1
Authors: AJK Wilkinson
Journal: Thorax (2015)

<h3>Introduction</h3> Current smoking cessation training in U. K. medical schools fails to equip junior doctors with the skills necessary to effectively combat the leading preventable cause of death and disease.<sup>1</sup> Here I present a novel teaching method using an electronic Case-Based Discussion (eCBD) which streamlines the process of workplace-based assessments, facilitates high-quality learning and provides new insights into what students know about this critically important subject. <h3>Methods</h3> An electronic learning module was developed by the author based on existing NICE guidelines.<sup>2</sup> Candidates described a case of a smoker they had seen and were quizzed about the case by the learning module with some instant feedback, then deeper discussion with the author via e-mail. When the candidate was ready a CBD form was completed. Finally feedback was collected using an anonymous, online feedback form. <h3>Results</h3> Thirty students and junior doctors have completed the eCBD. The eCBD had excellent feedback with 94% rating the eCBD as “very useful” and 100% feeling more confident in giving smoking cessation advice. Ninety-four percent rated the eCBD as “easier” or “much easier” to arrange and 53% rated it “much better” at assessing knowledge than conventional CBDs. Analysis of responses revealed deficiencies in knowledge of medications to treat tobacco dependence; 97% knew of nicotine replacement therapy (NRT) but knowledge of some formulations was poor (none mentioned oral strips, 3% microtabs, 17% lozenges); 43% knew of varenicline and 40% bupropion. Only 37% thought that combination NRT was safe and effective and thematic analysis revealed widespread concerns about the risks of overdose. 57% would consider recommending e-cigarettes for selected patients although only 7% had already recommended them to patients. <h3>Conclusions</h3> The eCBD can be an effective method of encouraging learning in important and neglected subject areas. It also illustrates an often-wasted opportunity to collect data from online learning modules that could guide curriculum development and facilitate better training in future. <h3>References</h3> 1 Raupach T, Al-Harbi G, McNeill A, Bobak A, McEwen A. Smoking cessation education and training in U. <i>K. Medical schools: a national survey. Nicotine Tob Res</i>. 2015;<b>17</b>(3):372–375 2 National Institute for Health and Clinical Excellence. <i>Smoking cessation in secondary care: acute, maternity and mental health services.</i> PH48. London: NICE, 2013
Expression of CD49c and CD49d Chains of β1 Integrins Identifies B-CLL Subsets with Different Prognosis and Distinct Immunophenotypic Profiles.
Authors: Valter Gattei, Paolo Sonego, Riccardo Bomben, Michele Dal, Dania Benedetti, Eva Zaina, Paola Nanni, Giovanni Del Poeta, Massimo Degan, Antonella Zucchetto
Journal: Blood (2005)
Fusion between the apoptosis inhibitor gene AP12 and a novel 18q gene MLT , rearranged in the t(11,18)(q21;q21), marks half of the gastro-intestinal MALT type lymphomas without large cell proliferation
Authors: Thijs Baens, B Maes, Anja Steyls, Karel Geboes, C De Wolf-Peeters, Peter Marynen
Journal: Blood (1999)