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JOURNAL OF THROMBOSIS AND HAEMOSTASIS
2019 Refs: 20

b6dd8803-e681-4272-ae81-b3c8061533d8

Validity and reliability of the Colorado Adult Joint Assessment Scale in adults with moderate-severe hemophilia A.

Funk, Sharon M. (correspondence); Engelen, Sylvia; Benjamin, Katy; Moshkovich, Olga; Gentile, Brittany; Church, Nikki; Hong, Walter; Thornhill, Dianne; Manco-Johnson, Marilyn J.

no abstract available

CURRENT OPINION IN CHEMICAL BIOLOGY
2019 Refs: 37

deefdc41-e936-4e19-bdb2-495ce0d05cb6

Lipidated Stapled Peptides Targeting the Acyl Binding Protein UNC119.

Cromm, Philipp M.; Adihou, Helene; Kapoor, Shobhna; Vazquez-Chantada, Mercedes; Davey, Paul; Longmire, David; Hennes, Elisabeth; Hofer, Walter; Kuchler, Philipp; Chiarparin, Elisabetta; Waldmann, Herbert (correspondence); Grossmann, Tom N.

no abstract available

DRUG RESEARCH
2019 , Vol. 69, pp. S7-S8. Refs: 10

ea732939-6373-4613-8999-874fa268c432

Does everything get slower with age? Pharmacokinetics in the elderly.

Hochel, Joachim (correspondence)

no abstract available

CHEMICAL ENGINEERING
Chemical Engineering Research and Design (2019) , Volume 152, pp. 336-347, 30 refs.

b0fb6fcc-cbca-462e-87b5-0e2b0c6e69e6

Continuous viral filtration for the production of monoclonal antibodies

David Laura(1); Lobedann Martin(1); Niklas Jens(2); Budde Bastian(2); Schembecker Gerhard(3) Correspondence(s): David Laura(1)

no abstract available

JOURNAL OF HEPATOLOGY
2019

07082227-e955-490a-838a-a9d7dba7f997

Metabolic pathway analyses identify proline biosynthesis pathway as a promoter of liver tumorigenesis.

Ding Zhaobing; Ericksen Russell E; Escande-Beillard Nathalie; Lee Qian Yi; Loh Abigail; Denil Simon; Steckel Michael; Haegebarth Andrea; Wai Ho Timothy Shen; Chow Pierce; Toh Han Chong; Reversade Bruno; Gruenewald Sylvia; Han Weiping

BACKGROUND AIM Under the regulation of various oncogenic pathways, cancer cells undergo adaptive metabolic programming to maintain specific metabolic states that support their uncontrolled proliferation. As it has been difficult to directly and effectively inhibit oncogenic signaling cascades with pharmaceutical compounds, focusing on the downstream metabolic pathways that enable indefinite growth may provide therapeutic opportunities. Thus, we sought to characterize metabolic changes in hepatocellular carcinoma (HCC) development and identify metabolic targets required for tumorigenesis. METHODS We compared gene expression profiles of Morris Hepatoma (MH3924a) and DEN (Diethylnitrosamine)-induced HCC models to those of liver tissues from normal and rapidly regenerating liver models, and performed gain- and loss-of-function studies of the identified gene targets for their roles in cancer cell proliferation in vitro and in vivo. RESULTS The proline biosynthetic PYCR1 (Pyrroline-5-Carboxylate Reductase 1) was identified as a top up-regulated gene in the HCC models. Knockdown (KD) of PYCR1 potently reduced cell proliferation of multiple HCC cell lines in vitro and tumor growth in vivo. Conversely, overexpression of PYCR1 enhanced the proliferation of the HCC cell lines. Importantly, PYCR1 expression was not elevated in the regenerating liver, and KD or overexpression of PYCR1 had no effect on proliferation of non-cancerous cells. Besides PYCR1, we found that additional proline biosynthetic enzymes, such as ALDH18A1, were upregulated in HCC models and also regulated HCC cell proliferation. Clinical data demonstrated that PYCR1 expression was increased in HCC, correlated with tumor grade, and was an independent predictor of clinical outcome. CONCLUSION Enhanced expression of proline biosynthetic enzymes promotes HCC cell proliferation. Inhibition of PYCR1 or ALDH18A1 may be a novel therapeutic strategy to target HCC.

REGULATORY TOXICOLOGY AND PHARMACOLOGY
2019, Vol. 110,

9efdb22b-d423-4911-baa7-185f907a2741

A cross-sector call to improve carcinogenicity risk assessment through use of genomic methodologies.

Yauk Carole L; Harrill Alison H; Ellinger-Ziegelbauer Heidrun; van der Laan Jan Willem; Moggs Jonathan; Froetschl Roland; Sistare Frank; Pettit Syril

Robust genomic approaches are now available to realize improvements in efficiencies and translational relevance of cancer risk assessments for drugs and chemicals. Mechanistic and pathway data generated via genomics provide opportunities to advance beyond historical reliance on apical endpoints of uncertain human relevance. Published research and regulatory evaluations include many examples for which genomic data have been applied to address cancer risk assessment as a health protection endpoint. The alignment of mature, robust, reproducible, and affordable technologies with increasing demands for reduced animal testing sets the stage for this important transition. We present our shared vision for change from leading scientists from academic, government, nonprofit, and industrial sectors and chemical and pharmaceutical safety applications. This call to action builds upon a 2017 workshop on "Advances and Roadblocks for Use of Genomics in Cancer Risk Assessment." The authors propose a path for implementation of innovative cancer risk assessment including incorporating genomic signatures to assess mechanistic relevance of carcinogenicity and enhanced use of genomics in benchmark dose and point of departure evaluations. Novel opportunities for the chemical and pharmaceutical sectors to combine expertise, resources, and objectives to achieve a common goal of improved human health protection are identified.

NEW ENGLAND JOURNAL OF MEDICINE
2019

fb5b3fc9-5e52-4506-af9d-126854b548bf

A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement.

Dangas George D; Tijssen Jan G P; Wohrle Jochen; Sondergaard Lars; Gilard Martine; Mollmann Helge; Makkar Raj R; Herrmann Howard C; Giustino Gennaro; Baldus Stephan; De Backer Ole; Guimaraes Ana H C; Gullestad Lars; Kini Annapoorna; von Lewinski Dirk; Mack Michael; Moreno Raul; Schafer Ulrich; Seeger Julia; Tchetche Didier; Thomitzek Karen; Valgimigli Marco; Vranckx Pascal; Welsh Robert C; Wildgoose Peter; Volkl Albert A; Zazula Ana; van Amsterdam Ronald G M; Mehran Roxana; Windecker Stephan

BACKGROUND Whether the direct factor Xa inhibitor rivaroxaban can prevent thromboembolic events after transcatheter aortic-valve replacement (TAVR) is unclear. METHODS We randomly assigned 1644 patients without an established indication for oral anticoagulation after successful TAVR to receive rivaroxaban at a dose of 10 mg daily (with aspirin at a dose of 75 to 100 mg daily for the first 3 months) (rivaroxaban group) or aspirin at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) (antiplatelet group). The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated prematurely by the data and safety monitoring board because of safety concerns. RESULTS After a median of 17 months, death or a first thromboembolic event (intention-to-treat analysis) had occurred in 105 patients in the rivaroxaban group and in 78 patients in the antiplatelet group (incidence rates, 9.8 and 7.2 per 100 person-years, respectively; hazard ratio with rivaroxaban, 1.35; 95% confidence interval [CI], 1.01 to 1.81; P = 0.04). Major, disabling, or life-threatening bleeding (intention-to-treat analysis) had occurred in 46 and 31 patients, respectively (4.3 and 2.8 per 100 person-years; hazard ratio, 1.50; 95% CI, 0.95 to 2.37; P = 0.08). A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (5.8 and 3.4 per 100 person-years, respectively; hazard ratio, 1.69; 95% CI, 1.13 to 2.53). CONCLUSIONS In patients without an established indication for oral anticoagulation after successful TAVR, a treatment strategy including rivaroxaban at a dose of 10 mg daily was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy. (Funded by Bayer and Janssen Pharmaceuticals; GALILEO ClinicalTrials.gov number, NCT02556203.).

ONCOTARGET
2019, Vol. 10, No. 60, pp. 6494-6508.

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SNiPER: a novel hypermethylation biomarker panel for liquid biopsy based early breast cancer detection.

Mijnes Jolein; Tiedemann Janina; Eschenbruch Julian; Gasthaus Janina; Bringezu Sarah; Bauerschlag Dirk; Maass Nicolai; Arnold Norbert; Weimer Jorg; Anzeneder Tobias; Fasching Peter A; Rubner Matthias; Bruno Benjamin; Heindrichs Uwe; Freres Jennifer; Schulz Hanna; Hilgers Ralf-Dieter; Ortiz-Bruchle Nadina; von Serenyi Sonja; Knuchel Ruth; Kloten Vera; Dahl Edgar

Introduction Mammography is the gold standard for early breast cancer detection, but shows important limitations. Blood-based approaches on basis of cell-free DNA (cfDNA) provide minimally invasive screening tools to characterize epigenetic alterations of tumor suppressor genes and could serve as a liquid biopsy, complementing mammography. Methods 125). Results . Conclusions (SNiPER) provides a promising tool for blood-based breast cancer detection.

HAEMOPHILIA
Haemophilia : the official journal of the World Federation of Hemophilia,

9dd88c2e-e45c-45c3-b9cf-2d1c1149c312

PEGylated biologics in haemophilia treatment: Current understanding of their long-term safety.

Baumann Andreas

no abstract available

CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS
2019, Vol. 25, pp. 1076029619886022.

d84e3b36-df6a-41e4-9c1c-7306247b5bd9

Improved Benefit Risk Profile of Rivaroxaban in a Subpopulation of the MAGELLAN Study.

Spyropoulos Alex C; Lipardi Concetta; Xu Jianfeng; Lu Wentao; Suh Eunyoung; Yuan Zhong; Levitan Bennett; Sugarmann Chiara; De Sanctis Yoriko; Spiro Theodore E; Barnathan Elliot S; Raskob Gary E

Acutely ill medical patients are at risk of venous thromboembolism (VTE) and VTE-related mortality during hospitalization and posthospital discharge, but widespread adoption of extended thromboprophylaxis has not occurred. We analyzed a subpopulation within the MAGELLAN study of extended thromboprophylaxis with rivaroxaban to reevaluate the benefit risk profile. We identified 5 risk factors for major and fatal bleeding after a clinical analysis of the MAGELLAN study and analyzed efficacy and safety with these patients excluded (n = 1551). Risk factors included: active cancer, dual antiplatelet therapy at baseline, bronchiectasis/pulmonary cavitation, gastroduodenal ulcer, or bleeding within 3 months before randomization. We evaluated efficacy, safety, and benefit risk using clinically comparable endpoints in the subpopulation. At day 10, rivaroxaban was noninferior to enoxaparin (relative risk [RR] = 0.82, 95% confidence interval [CI] = 0.58-1.15) and at day 35 rivaroxaban was significantly better than enoxaparin/placebo (RR = 0.68, 95% CI = 0.53-0.88) in reducing VTE and VTE-related death. Major bleeding was reduced at day 10 (RR = 2.18, 95% CI = 1.07-4.44 vs 1.19, 95% CI = 0.54-2.65) and at day 35 (2.87, 95% CI = 1.60-5.15 vs 1.48, 95% CI = 0.77-2.84) for MAGELLAN versus this subpopulation, respectively. The benefit risk profile was favorable in this subpopulation treated for 35 days, with the number needed to treat ranging from 55 to 481 and number needed to harm from 455 to 1067 for all pairwise evaluations. Five exclusionary criteria defined a subpopulation of acutely ill medical patients with a positive benefit risk profile for in-hospital and extended thromboprophylaxis with rivaroxaban.

JOURNAL OF THE WORKING GROUPS ON CARDIAC PACING, ARRHYTHMIAS, AND CARDIAC CELLULAR ELECTROPHYSIOLOGY OF THE EUROPEAN SOCIETY OF CARDIOLOGY
2019

d1cb4f7d-d995-47c2-af69-2cae4c03693e

The association between patterns of atrial fibrillation, anticoagulation, and cardiovascular events.

Atar Dan; Berge Eivind; Le Heuzey Jean-Yves; Virdone Saverio; Camm A John; Steffel Jan; Gibbs Harry; Goldhaber Samuel Z; Goto Shinya; Kayani Gloria; Misselwitz Frank; Stepinska Janina; Turpie Alexander G G; Bassand Jean-Pierre; Kakkar Ajay K

AIMS Guidelines do not recommend to take pattern of atrial fibrillation (AF) into account for the indication of anticoagulation (AC). We assessed AF pattern and the risk of cardiovascular events during 2-years of follow-up. METHODS AND RESULTS We categorized AF as paroxysmal, persistent, or permanent in 29 181 patients enrolled (2010-15) in the Global Anticoagulant Registry In the FIELD of AF (GARFIELD-AF). We used multivariable Cox regression to assess the risks of stroke/systemic embolism (SE) and death across patterns of AF, and whether this changed with AC on outcomes. Atrial fibrillation pattern was paroxysmal in 14 344 (49.2%), persistent in 8064 (27.6%), and permanent 6773 (23.2%) patients. Median CHA2DS2-VASc, GARFIELD-AF, and HAS-BLED scores assessing the risk of stroke/SE and/or bleeding were similar across AF patterns, but the risk of death, as assessed by the GARFIELD-AF risk calculator, was higher in non-paroxysmal than in paroxysmal AF patterns. During 2-year follow-up, after adjustment, non-paroxysmal AF patterns were associated with significantly higher rates of all-cause death, stroke/SE, and new/worsening congestive heart failure (CHF) than paroxysmal AF in non-anticoagulated patients only. In anticoagulated patients, a significantly higher risk of death but not of stroke/SE and new/worsening CHF persisted in non-paroxysmal compared with paroxysmal AF patterns. CONCLUSION In non-anticoagulated patients, non-paroxysmal AF patterns were associated with higher risks of stroke/SE, new/worsening HF and death than paroxysmal AF. In anticoagulated patients, the risk of stroke/SE and new/worsening HF was similar across all AF patterns. Thus AF pattern is no longer prognostic for stroke/SE when patients are treated with anticoagulants. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

CLINICAL PHARMACOKINETICS
2019

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Favorable Pharmacokinetic Characteristics of Extended-Half-Life Recombinant Factor VIII BAY 94-9027 Enable Robust Individual Profiling Using a Population Pharmacokinetic Approach.

Solms Alexander; Iorio Alfonso; Ahsman Maurice J; Vis Peter; Shah Anita; Berntorp Erik; Garmann Dirk

BACKGROUND Prophylaxis with factor VIII (FVIII) should be individualized based on patient characteristics, including FVIII pharmacokinetics. Population pharmacokinetic (popPK) modeling simplifies pharmacokinetic studies by obviating the need for multiple samples. OBJECTIVE The objective of this study was to characterize the pharmacokinetics and inter-individual variability (IIV) of BAY 94-9027 in relation to patient characteristics in support of a popPK-tailored approach, including identifying the optimal number and timing of pharmacokinetic samples. METHODS Pharmacokinetic samples from 198 males (aged 2‒62 years) with severe hemophilia A, enrolled in BAY 94-9027 clinical trials, were analyzed. Baseline age, height, weight, body mass index, lean body weight (LBW), von Willebrand factor (VWF) level, and race were evaluated. A popPK model was developed and used to simulate pharmacokinetic endpoints difficult to observe from measured FVIII levels, including time to maintain FVIII levels above 1, 3, and 5 IU/dL after different BAY 94-9027 doses. RESULTS A one-compartment model adequately described BAY 94-9027 pharmacokinetics. Clearance and central volume of distribution were significantly associated with LBW; clearance was inversely correlated with VWF. Due to the monophasic pharmacokinetics and well-understood IIV sources, identification of patient pharmacokinetics was achievable with sparse blood sampling. Median predicted time to maintain FVIII levels > 1 IU/dL in patients aged ≥ 12 years ranged from 120.1 to 127.2 h after single BAY 94-9027 doses of 45‒60 IU/kg. CONCLUSIONS This analysis evaluated the pharmacokinetics of BAY 94-9027 and its sources of IIV. Using the model, determination of individual patient pharmacokinetics was possible with few FVIII samples, and a sparse sampling design to support pharmacokinetic-guided dosing was identified.

ACS MEDICINAL CHEMISTRY LETTERS
2019, Vol. 10, No. 11, pp.

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Optimization of PDE3A Modulators for SLFN12-Dependent Cancer Cell Killing.

Lewis Timothy A; de Waal Luc; Wu Xiaoyun; Youngsaye Willmen; Wengner Antje; Kopitz Charlotte; Lange Martin; Gradl Stefan; Ellermann Manuel; Lienau Philip; Schreiber Stuart L; Greulich Heidi; Meyerson Matthew

, was active in an SK-MEL-3 xenograft model of cancer.

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2019, pp.

184e2deb-7f08-4801-9578-b502ea7ae3ac

PKa (Plasma Kallikrein) Contributes to Coagulation in the Absence of FXI (Factor XI) by Activating FIX (Factor IX).

Visser Mayken; van Oerle Rene; Ten Cate Hugo; Laux Volker; Mackman Nigel; Heitmeier Stefan; Spronk Henri M H

OBJECTIVES mice treated with ellagic acid or long-chain polyphosphates compared with controls and this increase was significantly reduced by inhibition of PKa. CONCLUSIONS We demonstrated that activation of FXII leads to thrombin generation via FIX activation by PKa in the absence of FXI. These findings may, in part, explain the different phenotypes associated with FIX and FXI deficiencies.

SEXUAL MEDICINE
2019

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Testosterone Induces Relaxation of Human Corpus Cavernosum Tissue of Patients With Erectile Dysfunction.

Van den Broeck Thomas; Soebadi Mohammad Ayodhia; Falter Annelies; Raets Lore; Duponselle Jolien; Lootsma Joline; Heintz Alexander; Philtjens Uchelly; Hofkens Lien; Gonzalez-Viedma Arantxa; Driesen Karel; Sandner Peter; Albersen Maarten; Brone Bert; Van Renterghem Koenraad

INTRODUCTION Previous research in the field of cardiovascular diseases suggests a relaxing effect of testosterone (T) on smooth muscle cells. Therefore, it was hypothesized that T could play a significant role in erection development. AIM To investigate the relaxing effect of T and other molecules of the T signaling pathway on human corpus cavernosum (HCC) tissue. METHODS blocker, and flutamide (androgen receptor inhibitor). MAIN OUTCOME MEASURE The outcome was relaxation of the HCC tissue, normalized to a maximum precontraction achieved by phenylephrine. RESULTS channels, or the androgen receptor. CLINICAL IMPLICATIONS By understanding the underlying mechanisms of T-induced HCC relaxation, potential new therapeutic targets can be identified. STRENGTHS & LIMITATIONS The strength of the study is the use of fresh HCC tissues with reproducible results. The limitation is the need for supraphysiological T levels to induce the observed effect. CONCLUSION Rapid androgen-induced relaxation of HCC is likely to occur via nongenomic mechanisms. Previously suggested mechanisms of action by which T modulates HCC relaxation have been excluded. Van den Broeck T, Soebadi MA, Falter A, et al. Testosterone Induces Relaxation of Human Corpus Cavernosum Tissue of Patients With Erectile Dysfunction. J Sex Med 2019; XX:XXX-XXX.

Disclaimer: The Science in Spotlight@Bayer application automatically retrieves publications based on the affiliation of the author with Bayer. This may sporadically lead to cases where publications of authors who recently joined Bayer are referenced in Science in Spotlight@Bayer although the research work was conducted at the author´s previous institution or organization.

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