ScienceInSpotlight

Contact | Bayer Global

JOURNAL OF MEDICINAL CHEMISTRY
2019 Refs: 53

2eb256d7-2cb1-4384-8695-2b266973f2cb

Discovery and Characterization of the Potent and Selective P2X4 Inhibitor N-[4-(3-Chlorophenoxy)-3-sulfamoylphenyl]-2-phenylacetamide (BAY-1797) and Structure-Guided Amelioration of Its CYP3A4 Induction Profile.

Werner, Stefan (correspondence); Mesch, Stefanie; Hillig, Roman C.; Ter Laak, Antonius; Klint, Julie; Neagoe, Ioana; Laux-Biehlmann, Alexis; Dahllof, Henrik; Brauer, Nico; Puetter, Vera; Nubbemeyer, Reinhard; Schulz, Simone; Bairlein, Michaela; Zollner, Thomas M.; Steinmeyer, Andreas

ARCHIVES OF DISEASE IN CHILDHOOD
DEC 2019 , Vol. 104, No. 12, pp. 1167-+.

436fede8-9d20-4ebe-9ca2-59de10bf7d61

Development of a neonatal adverse event severity scale through a Delphi consensus approach

Salaets, Thomas; Turner, Mark A.; Short, Mary; Ward, Robert M.; Hokuto, Isamu; Ariagno, Ronald L.; Klein, Agnes; Beauman, Sandra; Wade, Kelly; Thomson, Merran; Roberts, Eve; Harrison, Judy; Quinn, Theresa; Baer, Gerri; Davis, Jonathan; Allegaert, Karel (Reprint); Allen, Marilee; Allen, Albert; Freimane, Dina Apele; Aschner, Judy; Ballard, Roberta; Belew, Yodit; Bax, Ralph; Bellflower, Bobby; Bhatt-Mehta, Varsha; Blum, Mike; Bonardi, Chiara; Bondurant, Patti; Boylan, Geraldine; Buracchio, Teresa; Burckart, Gilbert; Burnett, Amber; Burnham, Janelle; Carlson, Cheryl; Chen, Alice; Clay, Bob; Cohen, Alan; Connolly, Eamonn; Connor, Edward; Darsey, Edress; De Lisa, Roberto; Degl, Jennifer; Dempsey, Eugene; Diacovo, Tom; Dionne, Janis; Duchon, Jennifer; Eklund, Wakako; Fabbri, Laura; Fielder, Alistair; Freilich, Emily; Furst-Recktenwald, Sabine; Graham, Tamorah; Green, Dionna; Grogan, Cristal; Heiselman, Darell; Hellstrom, Ann; Herold, Ralf; Hibbs, Anna Maria; Hirschfeld, Steven; Brown, Mary Hise; Holberton, Jim; Iveli, Pablo; Jobe, Alan; Kayton, Allyson; Kenner, Carole; Kraft, Walter; Kusuda, Satoshi; Lacaze, Thierry; Lewis, Tamorah; Lui, Kei; Lutsar, Irja; Mangili, Alexandra; Mangum, Barry; McCune, Susan; McDonald, Karen; McGuire, Courtney; McPherson, Christopher; Miller, Thomas; Ming, Jeffrey; Mitzner, Alison; Modi, Neena; Morrison, Maya; Morsing, Eva; Mulugeta, Lily; Nakamura, Hide; Nelson, Skip; Noel, Gary; Olshansky, Miki; Oschman, Alex; Ozsahin, Hulya; Padula, Mike; Peiris, Vasum; Koplowitz, Luana Pesco; Pham, Josh; Pilon, Aprile; Portman, Ron; Pressler, Ronit; Rabe, Heike; Raju, Tonse; Roepke, Douglas Andrew; et. al.

INTERNATIONAL JOURNAL OF STROKE
2019, pp. 1747493019891516.

788ed4ca-66ec-4cfa-bf79-04e1c119783d

Prior stroke and transient ischemic attack as risk factors for subsequent stroke in atrial fibrillation patients: A report from the GARFIELD-AF registry.

Hacke Werner; Bassand Jean-Pierre; Virdone Saverio; Camm A John; Fitzmaurice David A; Fox Keith Aa; Goldhaber Samuel Z; Goto Shinya; Haas Sylvia; Kayani Gloria; Mantovani Lorenzo G; Misselwitz Frank; Pieper Karen S; Turpie Alexander Gg; van Eickels Martin; Verheugt Freek Wa; Kakkar Ajay K

NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
2019

06c4cc24-dfde-438d-a27e-067f33c204c0

cGMP: a unique 2nd messenger molecule - recent developments in cGMP research and development.

Friebe Andreas; Sandner Peter; Schmidtko Achim

CLINICAL PHARMACOKINETICS
2019

12c0f734-341f-4319-b336-2d60098e0c3a

A Physiologically Based Pharmacokinetic Model of Voriconazole Integrating Time-Dependent Inhibition of CYP3A4, Genetic Polymorphisms of CYP2C19 and Predictions of Drug-Drug Interactions.

Li Xia; Frechen Sebastian; Moj Daniel; Lehr Thorsten; Taubert Max; Hsin Chih-Hsuan; Mikus Gerd; Neuvonen Pertti J; Olkkola Klaus T; Saari Teijo I; Fuhr Uwe

THYROID
2019, Vol. 29, No. 12, pp. 1820-1827.

0dd8c284-7c3a-44d1-86ca-44371a1308b1

Body Composition in Patients with Radioactive Iodine-Refractory, Advanced Differentiated Thyroid Cancer Treated with Sorafenib or Placebo: A Retrospective Analysis of the Phase III DECISION Trial.

Huillard Olivier; Jouinot Anne; Tlemsani Camille; Brose Marcia S; Arrondeau Jennifer; Meinhardt Gerold; Fellous Marc; De Sanctis Yoriko; Schlumberger Martin; Goldwasser Francois

INFECTIOUS DISEASES
2019

b4ad6eee-6d43-4263-9b55-da3e503d71d5

Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial.

Niederman Michael S; Alder Jeff; Bassetti Matteo; Boateng Francis; Cao Bin; Corkery Kevin; Dhand Rajiv; Kaye Keith S; Lawatscheck Robert; McLeroth Patrick; Nicolau David P; Wang Chen; Wood G Christopher; Wunderink Richard G; Chastre Jean

AMERICAN JOURNAL OF HEMATOLOGY
2019

20a7c777-892d-4b84-91f5-75f61ecb68f1

Long-term safety and efficacy of the PI3K- inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study.

Dreyling Martin; Santoro Armando; Mollica Luigina; Leppa Sirpa; Follows George; Lenz Georg; Kim Won Seog; Nagler Arnon; Dimou Maria; Demeter Judit; Ozcan Muhit; Kosinova Marina; Bouabdallah Krimo; Morschhauser Franck; Stevens Don A; Trevarthen David; Munoz Javier; Rodrigues Liana; Hiemeyer Florian; Miriyala Ashok; Garcia-Vargas Jose; Childs Barrett H; Zinzani Pier Luigi

MOLECULES
2019, Vol. 25, No. 1.

d1298591-382c-4d1d-a45d-1d63c9fd1402

Modeling Physico-Chemical ADMET Endpoints with Multitask Graph Convolutional Networks.

Montanari Floriane; Kuhnke Lara; Ter Laak Antonius; Clevert Djork-Arne

ACADEMIC RADIOLOGY
2019

468ef17f-ebcb-4974-b275-ed3751eecd2c

Effect of Gadoxetic Acid Injection Duration on Tumor Enhancement in Arterial Phase Liver MRI.

Tsuboyama Takahiro; Jost Gregor; Pietsch Hubertus; Tomiyama Noriyuki

RATIONALE AND OBJECTIVES Rapid injection of gadoxetic acid has been shown not to increase tumor enhancement in arterial phase liver MRI for unknown reasons. This study aimed to investigate the effect of injection durations on peak contrast concentration in tumors and to correlate it with signal enhancement in gadoxetic acid-enhanced arterial phase MRI. MATERIALS AND METHODS Gadoxetic acid-enhanced arterial phase MRI was obtained using a bolus-tracking technique with injection durations of 1, 3, and 6s in six rabbits with VX2 liver tumors. The peak concentration of gadoxetic acid in the aorta and tumor was estimated by iopromide-enhanced time-resolved CT using the same injection volume and durations with those for MRI. Signal enhancement on MRI and peak enhancement on CT were compared and correlated. RESULTS There was no significant difference in MR signal enhancement of tumors among the 3 injection durations (p = 0.87). In CT, shorter injection durations significantly increased peak contrast concentration in the aorta (p < 0.01) but produced equivalent peak contrast concentration in tumors (p = 0.24). The longer injections resulted in the stronger correlation between peak contrast concentration in CT and MR signal enhancement in tumors (r = 0.31, 0.43, and 0.86 with 1s-, 3s-, and 6s-injection, respectively) with a statistical significance only found with 6s-injection (p = 0.03). CONCLUSION Estimation of contrast concentration by CT demonstrated that shorter injections did not increase peak contrast concentration in tumors despite increased peak concentration in the aorta. Furthermore, tumor signal enhancement in gadoxetic acid-enhanced arterial phase MRI was less correlated with the peak contrast concentration with shorter injections.

OPHTHALMOLOGY
2019

5cd590cf-b2df-4590-8d11-4cb4d936008c

Intravitreal Combined Aflibercept + Anti-Platelet-Derived Growth Factor Receptor Î² for Neovascular Age-Related Macular Degeneration: Results of the Phase 2 CAPELLA Trial.

Heier Jeffrey S; Wykoff Charles C; Waheed Nadia K; Kitchens John W; Patel Sunil S; Vitti Robert; Perlee Lorah; Chu Karen W; Leal Sergio; Asmus Friedrich; Son Vladimir; Schmelter Thomas; Brown David M

PURPOSE To compare the efficacy and safety of intravitreal aflibercept + anti-platelet-derived growth factor receptor β (PDGFRβ) combination with intravitreal aflibercept injection (IAI) monotherapy in patients with treatment-naïve neovascular age-related macular degeneration (nAMD). DESIGN Phase 2, randomized, double-masked study. PARTICIPANTS A total of 505 patients (eyes) with nAMD. METHODS Patients were randomized 1:2:2 to low-dose combination intravitreal anti-PDGFRβ 1 mg and aflibercept 2 mg (LD combo), high-dose combination intravitreal anti-PDGFRβ 3 mg and aflibercept 2 mg (HD combo), or IAI alone every 4 weeks through week 12. At week 12, patients in the HD combo and IAI groups were re-randomized to continue as assigned or switch to HD combo → IAI or IAI → HD combo and dosed every 4 weeks through week 28. During weeks 28 to 52, patients received treatment as needed per prespecified criteria. This report presents efficacy through week 28 and safety through week 52. MAIN OUTCOME MEASURES Mean best-corrected visual acuity (BCVA) change from baseline at week 12 (primary end point). RESULTS At week 12, mean BCVA gains from baseline were 5.8, 5.8, and 7.5 letters with LD combo, HD combo, and IAI, respectively (P = 0.21 for LD combo and P = 0.10 for HD combo vs. IAI). The corresponding proportions of eyes that gained ≥15 letters were 12%, 19%, and 22%, respectively. Mean reductions in central retinal thickness from baseline were 126.1, 127.1, and 126.9 μm, respectively. Proportions of eyes with complete resolution of fluid from baseline were 35%, 24%, and 42%, respectively. Vision and anatomic outcomes at week 28 were consistent with the week 12 results. Through week 52, the incidence of intraocular inflammation was 1.0%, 7.5%, 2.1%, 2.1%, and 0%, respectively. The incidence of Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events was 1.9%, 0.9%, 1.1%, 2.1%, and 1.9%, respectively. CONCLUSIONS Intravitreal aflibercept + anti-PDGFRβ did not improve BCVA over IAI alone. Anatomic outcomes evaluating complete fluid resolution favored IAI. Adverse events were consistent with the reported IAI safety profile, except for a higher frequency of intraocular inflammation in the HD combo group.

LIFE SCIENCE ALLIANCE
2019, Vol. 2, No. 6.

5feae7d2-3094-4623-bbae-501745c2059a

Evaluation of colorectal cancer subtypes and cell lines using deep learning.

Ronen Jonathan; Hayat Sikander; Akalin Altuna

Colorectal cancer (CRC) is a common cancer with a high mortality rate and a rising incidence rate in the developed world. Molecular profiling techniques have been used to better understand the variability between tumors and disease models such as cell lines. To maximize the translatability and clinical relevance of in vitro studies, the selection of optimal cancer models is imperative. We have developed a deep learning-based method to measure the similarity between CRC tumors and disease models such as cancer cell lines. Our method efficiently leverages multiomics data sets containing copy number alterations, gene expression, and point mutations and learns latent factors that describe data in lower dimensions. These latent factors represent the patterns that are clinically relevant and explain the variability of molecular profiles across tumors and cell lines. Using these, we propose refined CRC subtypes and provide best-matching cell lines to different subtypes. These findings are relevant to patient stratification and selection of cell lines for early-stage drug discovery pipelines, biomarker discovery, and target identification.

DALTON TRANSACTIONS
2019

12ea0714-8cce-4716-b817-ff04f107996f

Tuning a modular system - synthesis and characterisation of a boron-rich s-triazine-based carboxylic acid and amine bearing a galactopyranosyl moiety.

Kellert Martin; Hoppenz Paul; Lonnecke Peter; Worm Dennis J; Riedl Bernd; Koebberling Johannes; Beck-Sickinger Annette G; Hey-Hawkins Evamarie

Introduction of a bis(isopropylidene)-protected galactopyranosyl moiety in s-triazine-based boron-rich carboxylic acids and amines results in soluble and suitable coupling partners for tumour-selective biomolecules with applications as selective agents for boron neutron capture therapy (BNCT). Bearing either a carboxylic acid or primary amine as a functional group, these compounds are highly versatile and thus largely extend the possible coupling strategies with suitable biomolecules. Modification of the gastrin-releasing peptide receptor (GRPR) selective agonist [d-Phe6, β-Ala11, Ala13, Nle14]Bn(6-14) with the carboxylic acid derivative yielded a bioconjugate with an optimal receptor activation and internalisation profile. This demonstrates the great potential of this approach for the development of novel boron delivery agents.

SCIENTIFIC REPORTS
2019, Vol. 9, No. 1, pp. 18489.

402cd791-3a83-4daf-bc69-b970960508f6

Radiobiological effects of the alpha emitter Ra-223 on tumor cells.

Bannik Kristina; Madas Balazs; Jarzombek Marco; Sutter Andreas; Siemeister Gerhard; Mumberg Dominik; Zitzmann-Kolbe Sabine

/M phase, reduced cell survival to 11-20% and also increased DNA fragmentation measured by tail intensity (from 1.4 to 3.9) dose-dependently. The α-particle component of Ra-223 radiation caused most of the Ra-223 radiation-induced biological effects such as DNA DSBs, cell cycle arrest and micronuclei formation, leading ultimately to cell death. The variable effects of α-radiation onto the different tumor cells demonstrated that tumor cells show diverse sensitivity towards damage caused by α-radiation. If these differences are caused by genetic alterations and if the sensitivity could be modulated by the use of DNA damage repair inhibitors remains a wide field for further investigations.

EUROPEAN JOURNAL OF HEART FAILURE
2019

8d2d423f-3aa3-47a4-8688-a81b24548914

Baseline features of the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial.

Pieske Burkert; Patel Mahesh J; Westerhout Cynthia M; Anstrom Kevin J; Butler Javed; Ezekowitz Justin; Hernandez Adrian F; Koglin Joerg; Lam Carolyn S P; Ponikowski Piotr; Roessig Lothar; Voors Adriaan A; O'Connor Christopher M; Armstrong Paul W

AIM Describe the distinguishing features of heart failure (HF) patients with reduced ejection fraction (HFrEF) in the VICTORIA (Vericiguat Global Study in Patients with Heart Failure with Reduced Ejection Fraction) trial. METHODS AND RESULTS Key background characteristics were evaluated in 5050 patients randomized in VICTORIA and categorized into three cohorts reflecting their index worsening HF event. Differences within the VICTORIA population were assessed and compared with PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and COMMANDER HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure). VICTORIA patients had increased risk of mortality and rehospitalization: New York Heart Association class (40% class III), atrial fibrillation (45%), diabetes (47%), hypertension (79%) and mean estimated glomerular filtration rate of 61.5 mL/min/1.73 m2 . Baseline standard of HF care was very good: 60% received triple therapy. Their N-terminal pro-B-type natriuretic peptide was 3377 pg/mL [interquartile range (IQR) 1992-6380]. Natriuretic peptides were 30% higher level in the 67% patients with HF hospitalization <3 months, compared to those within 3-6 months of HF hospitalization and those randomized after recent outpatient intravenous diuretic therapy. Overall the median MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) risk score in VICTORIA was 23 (IQR 18-27) as compared to the MAGGIC risk score in PARADIGM-HF of 20 (IQR 16-24). CONCLUSIONS VICTORIA comprises a broadly generalizable high-risk population of three unique clinical strata of worsening chronic HFrEF despite very good HF therapy. VICTORIA will establish the role of vericiguat, a soluble guanylate cyclase stimulator, in HFrEF.

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.

Newsletter subscription