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Science in Spotlight is an internet platform listing scientific publications authored by Bayer employees to increase transparency and visibility of Bayer’s innovative research activities to the external scientific community.

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FRONTIERS IN PHARMACOLOGY
(2023) Vol. 14, pp. 1142534.

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Hurdles and signposts on the road to virtual control groups-A case study illustrating the influence of anesthesia protocols on electrolyte levels in rats.

Gurjanov A; Kreuchwig A; Steger-Hartmann T; Vaas L A I

Introduction: Virtual Control Groups (VCGs) represent the concept of using historical control data from legacy animal studies to replace concurrent control group (CCG) animals. Based on the data curation and sharing activities of the Innovative Medicine Initiatives project eTRANSAFE (enhancing TRANSlational SAFEty Assessment through Integrative Knowledge Management) the ViCoG working group was established with the objectives of i) collecting suitable historical control data sets from preclinical toxicity studies, ii) evaluating statistical methodologies for building adequate and regulatory acceptable VCGs from historical control data, and iii) sharing those control-group data across multiple pharmaceutical companies. During the qualification process of VCGs a particular focus was put on the identification of hidden confounders in the data sets, which might impair the adequate matching of VCGs with the CCG. Methods: During our analyses we identified such a hidden confounder, namely, the choice of the anesthetic procedure used in animal experiments before blood withdrawal. Anesthesia using CO(2) may elevate the levels of some electrolytes such as calcium in blood, while the use of isoflurane is known to lower these values. Identification of such hidden confounders is particularly important if the underlying experimental information (e.g., on the anesthetic procedure) is not routinely recorded in the standard raw data files, such as SEND (Standard for Exchange of Non-clinical Data). We therefore analyzed how the replacement of CCGs with VCGs would affect the reproducibility of treatment-related findings regarding electrolyte values (potassium, calcium, sodium, and phosphate). The analyses were performed using a legacy rat systemic toxicity study consisting of a control and three treatment groups conducted according to pertinent OECD guidelines. In the report of this study treatment-related hypercalcemia was reported. The rats in this study were anesthetized with isoflurane. Results: Replacing the CCGs with VCGs derived from studies comprising both anesthetics resulted in a shift of control electrolyte parameters. Instead of the originally reported hypercalcemia the use of VCG led to fallacious conclusions of no observed effect or hypocalcemia. Discussion: Our study highlights the importance of a rigorous statistical analysis including the detection and elimination of hidden confounders prior to the implementation of the VCG concept.

PEDIATRIC BLOOD & CANCER
(2023 May 02) pp. e30379.

53fe3249-d47f-4e33-a5b6-cae7a420ca45

TRK-inhibitor control of an NTRK-rearranged spindle cell tumor with malignant transformation in an adolescent.

Higuchi Naoko; Honda Yuko; Koga Yuhki; Asai Hiroshi; Ono Hiroaki; Kato Wakako; Nakashima Kentaro; Cuesta Esther De La; Tsujino Toshiaki; Yamamoto Hidetaka; Kusuhara Koichi; Hisaoka Masanori; Ohga Shouichi

PATIENT PREFERENCE AND ADHERENCE
(2023) Vol. 17, pp. 1181-1196.

d60e8b9b-23d6-48d3-99fd-582f94acdfbe

Patient Perspectives on the Burden of Heart Failure with Preserved Ejection Fraction in a US Commercially Insured and Medicare Advantage Population: A Survey Study.

Nguyen Chi; Bamber Luke; Willey Vincent J; Evers Thomas; Power Thomas P; Stephenson Judith J

BACKGROUND: Patient-reported health related quality of life (HRQOL) is not routinely assessed in clinical practice. Little is known about health status outcomes reported by patients with heart failure with preserved ejection fraction (HFpEF) in non-clinical trial settings. PURPOSE: To better understand patient burden of HFpEF in terms of HF-specific functional and symptom status, HRQOL, healthcare resource utilization (HCRU) and costs in a US-based commercial and Medicare Advantage insured population. PATIENTS AND METHODS: We conducted a cross-sectional survey of patients with HFpEF and linked their survey and administrative claims data. Consenting, eligible patients completed a survey that included the 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ-23) and the PROMIS Global Health-10 (GH-10) questionnaire, as well as clinical and demographic questions. HF medication use, HCRU and costs during the 12-month baseline period before the survey were determined from claims data. Generalized linear regression was used to assess the associations between baseline characteristics and the KCCQ-23 overall summary score. RESULTS: Of 598 survey respondents with survey and claims data, 54.7% were female with mean age 74.0 years. The KCCQ-23 overall summary and clinical summary scores were 64.8 and 63.0, respectively, and the GH-10 physical and mental health summary scores were 39.9 and 45.5. Factors related to lower KCCQ-23 overall summary scores were HF treatment and symptom changes during the past 4-weeks before the survey, hospital admission during the past year, low household income, high comorbidity index, and morbid obesity (BMI>40). Total all-cause healthcare costs were $38,243 during the year prior to the survey, of which 42% were HF-related. CONCLUSION: Patient-reported outcome measure scores indicated impairment due to HF symptoms and physical limitations in this real-world sample of patients with HFpEF, highlighting a need to assess patient-reported outcomes as well as the clinical and economic outcomes traditionally assessed by clinicians, health systems and payers.

METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.)
(2023) Vol. 2666, pp. 177-191.

52ce9182-59ab-4160-8ca0-0bf181cda242

In Vitro Reconstitution of Pseudouridylation Catalyzed by Human Box H/ACA Ribonucleoprotein Particles.

Adachi Hironori; Chen Jonathan L; Yin Qiangzong; Morais Pedro; Yu Yi-Tao

Pseudouridine (Psi) is the most common chemical modification in RNA. In eukaryotes and archaea, pseudouridine synthases, mainly guided by box H/ACA snoRNAs, convert uridine to Psi. Psi stabilizes RNA structure and alters RNA-RNA and RNA-protein interactions, conferring important roles in gene expression. Notably, several Psi-linked human diseases have been identified over the years. In addition, Psi has also been extensively used in developing mRNA vaccines. Furthermore, it has been shown that pseudouridylation can be site-specifically directed to modify specific nonsense codons, leading to nonsense suppression. All of these, together with a need to better understand the specific functions of Psis, have motivated the development of in vitro pseudouridylation assays using purified and reconstituted box H/ACA RNPs. Here, we describe an in vitro system for box H/ACA RNA-guided RNA pseudouridylation using human cell extracts. We show that a half guide RNA (only one hairpin) is just as functionally competent as the full-length guide RNA (two hairpins) in guiding site-specific pseudouridylation in the human cell extracts. This discovery offers the opportunity for direct delivery of a short guide RNA to human cells to promote site-specific nonsense suppression and therefore has potential clinical applications.

NPJ BREAST CANCER
(2023) Vol. 9, No. 1, pp. 38.

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Image analysis-based tumor infiltrating lymphocytes measurement predicts breast cancer pathologic complete response in SWOG S0800 neoadjuvant chemotherapy trial.

Fanucci Kristina A; Bai Yalai; Pelekanou Vasiliki; Nahleh Zeina A; Shafi Saba; Burela Sneha; Barlow William E; Sharma Priyanka; Thompson Alastair M; Godwin Andrew K; Rimm David L; Hortobagyi Gabriel N; Liu Yihan; Wang Leona; Wei Wei; Pusztai Lajos; Blenman Kim R M

We assessed the predictive value of an image analysis-based tumor-infiltrating lymphocytes (TILs) score for pathologic complete response (pCR) and event-free survival in breast cancer (BC). About 113 pretreatment samples were analyzed from patients with stage IIB-IIIC HER-2-negative BC randomized to neoadjuvant chemotherapy +/- bevacizumab. TILs quantification was performed on full sections using QuPath open-source software with a convolutional neural network cell classifier (CNN11). We used easTILs% as a digital metric of TILs score defined as [sum of lymphocytes area (mm(2))/stromal area(mm(2))] x 100. Pathologist-read stromal TILs score (sTILs%) was determined following published guidelines. Mean pretreatment easTILs% was significantly higher in cases with pCR compared to residual disease (median 36.1 vs.14.8%, p < 0.001). We observed a strong positive correlation (r = 0.606, p < 0.0001) between easTILs% and sTILs%. The area under the prediction curve (AUC) was higher for easTILs% than sTILs%, 0.709 and 0.627, respectively. Image analysis-based TILs quantification is predictive of pCR in BC and had better response discrimination than pathologist-read sTILs%.

THERAPEUTIC INNOVATION & REGULATORY SCIENCE
(2023)

55590aaf-ab2f-49e6-8106-70a6310dc3a9

Statistical Considerations on the Use of RWD/RWE for Oncology Drug Approvals: Overview and Lessons Learned.

Ro Sunhee K; Zhang Weidong; Jiang Qi; Li Xiaoyun Nicole; Liu Rong; Lu Chengxing Cindy; Marchenko Olga; Sun Linda; Zhao Jing

Despite increasing utilization of real-world data (RWD)/real-world evidence (RWE) in regulatory submissions, their application to oncology drug approvals has seen limited success. Real-world data is most commonly summarized as a benchmark control for a single arm study or used to augment the concurrent control in a randomized clinical trial (RCT). While there has been substantial research on usage of RWD/RWE, our goal is to provide a comprehensive overview of their use in oncology drug approval submissions to inform future RWD/RWE study design. We will review examples of applications and summarize the strengths and weaknesses of each example identified by regulatory agencies. A few noteworthy case studies will be reviewed in detail. Operational aspects of RWD/RWE study design/analysis will be also discussed.

CPT: PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
(2023)

ecf0f8ae-b5ee-48e0-9c1a-9b1fd595d43a

Physiologically Based Pharmacokinetic Modeling of Quinidine to Establish a CYP3A4, P-gp and CYP2D6 Drug-Drug-Gene Interaction Network.

Feick Denise; Rudesheim Simeon; Marok Fatima Zahra; Selzer Dominik; Loer Helena Leonie Hanae; Teutonico Donato; Frechen Sebastian; van der Lee Maaike; Moes Dirk Jan A R; Swen Jesse J; Schwab Matthias; Lehr Thorsten

The antiarrhythmic agent quinidine is a potent inhibitor of cytochrome P450 (CYP) 2D6 and P-glycoprotein (P-gp) and is therefore recommended for use in clinical drug-drug interaction (DDI) studies. However, as quinidine is also a substrate of CYP3A4 and P-gp, it is susceptible to DDIs involving these proteins. Physiologically-based pharmacokinetic (PBPK) modeling can help to mechanistically assess the absorption, distribution, metabolism, and excretion processes of a drug and has proven its usefulness in predicting even complex interaction scenarios. The objectives of the presented work were to develop a PBPK model of quinidine and to integrate the model into a comprehensive drug-drug(-gene) interaction (DD(G)I) network with a diverse set of CYP3A4 and P-gp perpetrators as well as CYP2D6 and P-gp victims. The quinidine parent-metabolite model including 3-hydroxyquinidine was developed using pharmacokinetic profiles from clinical studies after intravenous and oral administration covering a broad dosing range (0.1-600 mg). The model covers efflux transport via P-gp and metabolic transformation to either 3-hydroxyquinidine or unspecified metabolites via CYP3A4. The 3-hydroxyquinidine model includes further metabolism by CYP3A4 as well as an unspecific hepatic clearance. Model performance was assessed graphically and quantitatively with greater than 90% of predicted pharmacokinetic parameters within two-fold of corresponding observed values. The model was successfully used to simulate various DD(G)I scenarios with greater than 90% of predicted DD(G)I pharmacokinetic parameter ratios within two-fold prediction success limits. The presented network will be provided to the research community and can be extended to include further perpetrators, victims, and targets, to support investigations of DD(G)Is.

ACS CHEMICAL NEUROSCIENCE
(2023)

15caca89-e1d3-40a6-acac-90f93c049ccd

Gut Microbiome-Brain Alliance: A Landscape View into Mental and Gastrointestinal Health and Disorders.

Sasso Janet M; Ammar Ramy M; Tenchov Rumiana; Lemmel Steven; Kelber Olaf; Grieswelle Malte; Zhou Qiongqiong Angela

Gut microbiota includes a vast collection of microorganisms residing within the gastrointestinal tract. It is broadly recognized that the gut and brain are in constant bidirectional communication, of which gut microbiota and its metabolic production are a major component, and form the so-called gut microbiome-brain axis. Disturbances of microbiota homeostasis caused by imbalance in their functional composition and metabolic activities, known as dysbiosis, cause dysregulation of these pathways and trigger changes in the blood-brain barrier permeability, thereby causing pathological malfunctions, including neurological and functional gastrointestinal disorders. In turn, the brain can affect the structure and function of gut microbiota through the autonomic nervous system by regulating gut motility, intestinal transit and secretion, and gut permeability. Here, we examine data from the CAS Content Collection, the largest collection of published scientific information, and analyze the publication landscape of recent research. We review the advances in knowledge related to the human gut microbiome, its complexity and functionality, its communication with the central nervous system, and the effect of the gut microbiome-brain axis on mental and gut health. We discuss correlations between gut microbiota composition and various diseases, specifically gastrointestinal and mental disorders. We also explore gut microbiota metabolites with regard to their impact on the brain and gut function and associated diseases. Finally, we assess clinical applications of gut-microbiota-related substances and metabolites with their development pipelines. We hope this review can serve as a useful resource in understanding the current knowledge on this emerging field in an effort to further solving of the remaining challenges and fulfilling its potential.

PEST MANAGEMENT SCIENCE
(2023)

0a0def3b-baf1-41cd-99c4-89274df87f64

Recombinant glutathione transferases from flufenacet-resistant black-grass (Alopecurus myosuroides Huds.) form different flufenacet metabolites and differ in their interaction with pre- and post-emergence herbicides.

Parcharidou Evlampia; Ducker Rebecka; Zollner Peter; Ries Susanne; Orru Roberto; Beffa Roland

BACKGROUND: Black-grass (Alopecurus myosuroides Huds.) has become a problematic weed in cereals in Europe. Besides resistance to post-emergent herbicides becoming increasingly widespread, enhanced metabolism of inhibitors of the synthesis of very-long-chain fatty acids (VLCFAs), such as flufenacet, is evolving. Yet, cross-resistance patterns and evolution of this resistance remains poorly understood. RESULTS: The cDNA sequences of five glutathione transferases (GSTs) upregulated in flufenacet resistant black-grass were identified and used for recombinant protein expression. Moderate to slow detoxification of flufenacet was verified for all candidate GSTs expressed in E. coli, and the most active protein produced flufenacet-alcohol instead of a glutathione conjugate, in the presence of reduced glutathione (GSH). Moreover, cross-resistance to other VLCFA-inhibitors e.g., acetochlor and pyroxasulfone and the ACCase inhibitor fenoxaprop was verified in vitro. Various other herbicides of different modes of action including VLCFA-inhibitors were not detoxified by the candidate GSTs. CONCLUSIONS: As several in planta upregulated GSTs detoxified flufenacet in vitro, the shift in sensitivity observed in black-grass populations, is likely a result of an additive effect. The polygenic character and the relatively low turnover rate of the individual GSTs may explain the slow evolution of flufenacet resistance. In addition, flufenacet resistance was accompanied by cross-resistance with some, but not all, herbicides of the same mode of action, and furthermore to the ACCase inhibitor fenoxaprop-ethyl. Hence, not only the rotation of herbicide modes of action, but also of individual active ingredients is important for resistance management. (c) 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

FUTURE ONCOLOGY (LONDON, ENGLAND)
(2023)

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Larotrectinib versus historical standard of care in patients with infantile fibrosarcoma: protocol of EPI-VITRAKVI.

Carton Matthieu; Del Castillo Johanna Pena; Colin Jean-Baptiste; Kurtinecz Milena; Feuilly Marion; Pierron Gaelle; Arvis Pierre; Khadir Soumeya Khadidja; Sparber-Sauer Monika; Orbach Daniel

The EPI VITRAKVI study is a retrospective study designed to place the results of the single-arm Phase I/II larotrectinib SCOUT trial into context by comparison with external historical controls. Its primary objective is to compare the time to medical treatment failure between larotrectinib and the historical standard of care (chemotherapy) in patients with infantile fibrosarcoma. External historical cohorts have been selected by using objective criteria. The Inverse Probability of Treatment Weighting method will be used to adjust for potential confounding. The current publication illustrates how an external control arm study can complement data from a single-arm trial and addresses uncertainties encountered in the assessment of therapies targeting rare abnormalities where randomized controlled trials are considered not feasible. Clinical Trial Registration: NCT05236257 (ClinicalTrials.gov).

CHEMISTRY (WEINHEIM AN DER BERGSTRASSE, GERMANY)
(2023) pp. e202301420.

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Ruthenium-catalyzed Synthesis of Aryl and Alkenyl Halides from Fluorosulfonates.

Placais Clotilde; Kaldas Sherif J; Donnard Morgan; Panossian Armen; Bernier David; Pazenok Sergii; Leroux Frederic R

Aryl and alkenyl halides are widely used as key intermediates in organic synthesis, particularly for the formation of organometallic reagents or as radical precursors. They are also found in pharmaceutical and agrochemical ingredients. In this work, we report the synthesis of aryl and alkenyl halides from the corresponding fluorosulfonates using commercially available ruthenium catalysts. Notably, this is the first conversion of phenols to aryl halides that is efficient with chloride, bromide, and iodide. Fluorosulfonates are readily prepared using sulfuryl fluoride (SO2F2) and less expensive substitutes for triflates. Although aryl fluorosulfonates and their reactions are well known, this is the first report of an efficient coupling of alkenyl fluorosulfonates. To finish, we have demonstrated, by means of representative examples, that the reaction is possible in a one-pot process, starting directly from the phenol or aldehyde.

EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
(2023)

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Technical considerations for the implementation of the Multi-Attribute-Method by mass spectrometry in a Quality Control laboratory.

Pohl Thomas; Gervais Annick; Dirksen Eef; D'Alessio Valerio; Bechtold-Peters Karoline; Burkitt Will; Cao Li; Greven Simone; Lennard Andrew; Li Xue; Lossner Christopher; Niu Ben; Reusch Dietmar; O'Riordan Tomas; Shearer Justin; Spencer David; Xu Wei; Yi Linda

Multi-attribute methods employing mass spectrometry are applied throughout the biopharmaceutical industry for product and process characterization purposes but are not yet widely accepted as a method for batch release and stability testing under good manufacturing practice (GMP) due to limited experience and level of comfort with the technical, compliance and regulatory aspects of its implementation at quality control (QC) laboratories. Here, current literature related to the development and application of the multi-attribute method by peptide mapping liquid chromatography mass spectrometry (MAM) is compiled with the aim of providing guidance for the implementation of MAM in a QC laboratory. This article, focusing on technical considerations, is the first part of a two-tiered publication, whereby the second part will focus on GMP compliance and regulatory aspects. This publication has been prepared by a group of industry experts representing 14 globally acting major biotechnology companies under the umbrella of the European Federation of Pharmaceutical Industries and Associations (EFPIA) Manufacturing & Quality Expert Group (MQEG).

THE JOURNAL OF BIOLOGICAL CHEMISTRY
(2023) pp. 104768.

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Characterization of the cholesterol biosynthetic pathway in Dioscorea transversa.

Salisbury Lauren J; Fletcher Stephen J; Stok Jeanette E; Churchman Luke R; Blanchfield Joanne T; De Voss James J

Cholesterol is the precursor of bioactive plant metabolites such as steroidal saponins. An Australian plant, Dioscorea transversa, produces only two steroidal saponins: 1beta-hydroxyprotoneogracillin and protoneogracillin. Here, we used D. transversa as a model in which to elucidate the biosynthetic pathway to cholesterol, a precursor to these compounds. Preliminary transcriptomes of D. transversa rhizome and leaves were constructed, annotated, and analyzed. We identified a novel sterol side chain reductase (SSR) as a key initiator of cholesterol biosynthesis in this plant. By complementation in yeast, we determine that this SSR reduces Delta(24,28) double bonds required for phytosterol biogenesis, as well as Delta(24,25) double bonds. The latter function is believed to initiate cholesterogenesis by reducing cycloartenol to cycloartanol. Through heterologous expression, purification and enzymatic reconstitution we also demonstrate that the D. transversa sterol demethylase (CYP51) effectively demethylates obtusifoliol, an intermediate of phytosterol biosynthesis and 4-desmethyl-24,25-dihydrolanosterol, a postulated downstream intermediate of cholesterol biosynthesis. In summary, we investigated specific steps of the cholesterol biosynthetic pathway, providing further insight into the downstream production of bioactive steroidal saponin metabolites.

BRITISH JOURNAL OF PHARMACOLOGY
(2023)

e13b096e-d694-4c56-8419-7fd2158a8c04

Identification and characterization of the new generation sGC stimulator BAY 1165747 (BAY-747) designed for the treatment of resistant hypertension.

Wunder Frank; Stasch Johannes-Peter; Knorr Andreas; Mondritzki Thomas; Brockschnieder Damian; Becker-Pelster Eva-Maria; Sandner Peter; Tinel Hanna; Redlich Gorden; Hartung Ingo V; Vakalopoulos Alexandros; Follmann Markus

BACKGROUND AND PURPOSE: First-generation sGC stimulators have shown clinical benefit in pulmonary hypertension (riociguat), and chronic heart failure (vericiguat). However, given the broad therapeutic opportunities for sGC stimulators, tailored molecules for distinct indications are required. EXPERIMENTAL APPROACH: We report the high-throughput screening (HTS) -based discovery of a second-generation of sGC stimulators from a novel imidazo[1,2-a]pyridine lead series. An intense medicinal chemistry program resulted in the discovery of the sGC stimulator BAY-747. The pharmacokinetic profile of BAY-747 was determined in different species and BAY-747 was broadly characterized in pharmacological model systems relevant for vasodilatation and hypertension. KEY RESULTS: BAY-747 was characterized as a highly potent sGC stimulator in vitro. In addition, BAY-747 showed an excellent pharmacokinetic profile with long half-life and low peak-to-trough ratio. BAY-747 was investigated in experimental in vivo models of malignant and resistant hypertension (rHT). In spontaneously hypertensive (SH) rats, BAY-747 caused a dose-related and long-lasting decrease in mean arterial blood pressure (MAP). Oral treatment over 12 days resulted in a persistent MAP decrease. BAY-747 provided additional benefit when dosed on top of losartan, amlodipine, or spironolactone and even on top of triple combinations of frequently used antihypertensive drugs. In a new canine model of resistant hypertension BAY-747 caused a dose-related and long lasting (> 6 h) MAP decrease. CONCLUSION AND IMPLICATIONS: BAY-747 is a potent, orally available sGC stimulator. BAY-747 shows long-acting pharmacodynamic effects with a very low peak-to-trough ratio. BAY-747 could be a treatment alternative for patients with hypertension, especially those not responding to standard of care therapy.

MOLECULAR THERAPY - METHODS AND CLINICAL DEVELOPMENT
(2023) Vol. 29, pp. 286-302.

62a9109b-29f5-4002-abcb-f00df80c9e7b

Gene therapy for cross-correction of somatic organs and the CNS in mucopolysaccharidosis II in rodents and non-human primates.

Chen, Nancy; Ehmann, David E.; Crooker, Robert; Derakhchan, Katayoun; Fang, Xiaodong; Felice, Brian; Galbreath, Elizabeth J.; Glaus, Charles; Gu, Hongbo; Huang, Yan; Li, Christine; Li, Xing; Liu, Nan; Palmieri, Kathleen; Simic, Damir; Sypek, Joseph; Thompson, Susan; Winkelmann, Christopher T.; Choi, Vivian W.

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The Science in Spotlight platform 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 although the research work was conducted at the author´s previous institution or organization.
publications that are supported or sponsored by Bayer, but that are independently developed/written and/or do not include a Bayer author may not be referenced in Science in Spotlight.

Due to copyright reasons access to the full text of the publications depends on individual or journal access rights. Currently, Science in Spotlight references publications dating back to 2016.

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