WheyMet: The effects of 20 grams of whey protein on the metabolome and peptid hormones on 18-30 year old subjects versus 70-90 year old geriatric patients with presarcopenia or sarcopenia - WheyMet

开始日期2024-11-07

申办/合作机构

Klinikum der Universität München

DRKS00034150

/ RecruitingN/AIIT

Retrospective analysis of radiotherapy plans for patients with brain metastases

开始日期2024-10-01

申办/合作机构

Klinikum der Universität München

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4,437

项与 Klinikum der Universität München 相关的文献（医药）

2025-06-01·The Journal of Steroid Biochemistry and Molecular Biology

Continuous flow-through steady state system for in vitro characterization of CYP11B2 inhibitors–Impact on enzyme kinetics of steroidogenesis

Article

作者: Mir-Bashiri, Sanas ; Williams, Tracy Ann ; Bechmann, Nicole ; Constantinescu, Georgiana ; Schirbel, Andreas ; Dieterich, Peter ; Eisenhofer, Graeme ; Peitzsch, Mirko ; Hahner, Stefanie ; Fröbel, Dennis ; Heinze, Britta

BACKGROUNDThe homology of aldosterone- and cortisol-producing enzymes, aldosterone synthase (CYP11B2) and 11β-hydroxylase, complicates identification of selective CYP11B2 inhibitors required for antihypertensive treatment or for imaging approaches in patients with primary aldosteronism. To improve preclinical evaluation of novel CYP11B2-targeting compounds, we developed a flow-through cell culture system that provides insights into kinetics of steroidogenesis and inhibitory responses at CYP11B2 active sites.METHODSNCI-H295RA and HAC-15 cells were cultured in ibidi flow chambers under constant culture medium flow. Supernatants were collected hourly before and after treatment with (R)-1-[1-(4-iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinylamide (IMAZA), a non-selective CYP11B1/B2 inhibitor, or the potential CYP11B2 inhibitors ID-69 and ID-191. Steroid profiles were analyzed by liquid chromatography-tandem mass spectrometry. Steady state approximation in steroidogenesis allowed mathematical modeling-based calculation of metabolic fluxes and relative rate constants of biocatalytic steps.RESULTSAn optimized flow-through system is now available to characterize inhibitory responses at the three catalytic sites of CYP11B2 in two steroid-producing cell lines. IMAZA non-selectively inhibited CYP11B 11β-hydroxylase function, while ID-69 and ID-191 affected the CYP11B2-specific 18-hydroxylase active site with minor effects on catalytic activity of 11β-hydroxylase. ID-191 simultaneously impaired catalytic activity of cortisol production, whereas ID-69 was highly selective for CYP11B2 inhibition.CONCLUSIONOur flow-through system provides insights into inhibitor-induced alterations of metabolic fluxes and enzymatic rate constants, and thus represents an improved preclinical model sytem for complex characterization of CYP11B2 inhibitors.

2025-04-25·Cancer Research

Abstract CT112: Phase I open-label, multi-center study to evaluate the safety, tolerability, dosimetry, and preliminary activity of FXX489 ([177Lu]Lu-NNS309) in patients with pancreatic, lung, breast and colorectal cancers

作者: Razak, Albiruni ; Victoria Ruiz, Ivan Manuel ; Maccauro, Marco ; Filice, Angelina ; Kuboki, Yasutoshi ; McConathy, Jonathan ; Straub, Christopher ; Mancini, Brandon ; Ferrario, Cristiano ; Goldman, Jonathan ; Yang, Fang ; Al-Mansour, Laure ; Drzezga, Alexander ; Ferrandiz, Aitana Calvo ; Nienhuis, Hilde ; Iravani, Amir ; Heuschkel, Martin ; Ahnert, Jordi ; Deandreis, Desiree ; Geva, Ravit ; Couillebault, Xuan Mai ; Moradi, Farshad ; Schaefer, Niklaus ; Nagarajah, James ; Herrmann, Ken ; Eiber, Matthias ; Koessler, Thibaud ; Doger de Speville, Bernard ; Parent, Ephraim ; Origuchi, Shizuka ; Garayoa, Elisa Garcia ; Pectasides, Eirini ; Geoffrey, Johnson ; Juneau, Daniel ; Esfahani, Shadi Abdar ; Flamen, Patrick ; Hainzl, Dominik ; Roopa, Jayarama Naidu ; Chen, Xinyu

AbstractBackground:Fibroblast activation protein (FAP) is a type II integral membrane glycoprotein, highly expressed on the cell surface of cancer-associated fibroblasts (CAFs) present in the tumor microenvironment of most epithelial cancers and showing limited expression in normal tissues. Given this expression profile, FAP appears to be a promising target for radioligand therapy that has pan-cancer potential. [177Lu]Lu-NNS309 is a FAP-targeted radiopharmaceutical that shows improved tumor retention and demonstrates promising anti-tumor activity in translationally relevant preclinical models (e.g., PDAC, NSCLC) where FAP is expressed on CAFs.Methods:CFXX489A12101 (NCT06562192) is a first-in-human phase I, open-label, multi-center study of [177Lu]Lu-NNS309 in patients with pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), breast cancer (BC), and colorectal cancer (CRC). The study includes a dose escalation part followed by a dose expansion part. Key eligibility criteria include prior treatment for locally advanced unresectable or metastatic disease and having all measurable lesions (per RECIST 1.1) showing [68Ga]Ga-NNS309 uptake on positron emission tomography/computed tomography (PET/CT). Patients who are eligible for treatment receive one dose of [177Lu]Lu-NNS309 on day 1 of each cycle. A 6-week and a 4-week dosing schedule will be explored. Dosimetry data will be obtained from patients in the dose escalation part after the first dose and will be used to calculate the cumulative radiation exposure. Dose escalation will be guided by a Bayesian hierarchical logistic regression model with overdose control (EWOC) principle, and assessment of all relevant data available from all dose levels including safety, tolerability, clinical dosimetry, pharmacodynamics, and preliminary efficacy. Once the recommended dose(s) (RD) and schedule(s) of [177Lu]Lu-NNS309 are determined, the expansion part may open and will include patients with locally advanced or metastatic PDAC (n∼20), locally advanced or metastatic NSCLC (n∼20), HR+/HER2- ductal BC (n∼15), HR+/HER2- lobular BC (n∼15), and triple negative BC (; n∼24).The primary objectives of the study are to evaluate the safety and tolerability of [177Lu]Lu-NNS309 and to identify the RD(s) and regimen(s) of [177Lu]Lu-NNS309 for further clinical evaluation. Secondary objectives of the study are to evaluate the preliminary anti-tumor activity of [177Lu]Lu-NNS309, characterize the pharmacokinetics of [177Lu]Lu-NNS309 in blood and urine, the radiation dosimetry for organs and tumor lesions, and to evaluate the safety and imaging properties of [68Ga]Ga-NNS309.Conclusion:The study is currently enrolling in the dose escalation part.Citation Format:Ravit Geva, Daniel Juneau, Shadi Abdar Esfahani, Cristiano Ferrario, Farshad Moradi, Amir Iravani, Jordi Ahnert, Ivan Manuel Victoria Ruiz, Thibaud Koessler, Aitana Calvo Ferrandiz, Bernard Doger de Speville, Patrick Flamen, Albiruni Razak, Desiree Deandreis, Laure Al-Mansour, Niklaus Schaefer, James Nagarajah, Hilde Nienhuis, Marco Maccauro, Angelina Filice, Jonathan Goldman, Ken Herrmann, Matthias Eiber, Alexander Drzezga, Martin Heuschkel, Jonathan McConathy, Johnson Geoffrey, Ephraim Parent, Yasutoshi Kuboki, Shizuka Origuchi, Xuan Mai Couillebault, Elisa Garcia Garayoa, Jayarama Naidu Roopa, Christopher Straub, Dominik Hainzl, Xinyu Chen, Fang Yang, Eirini Pectasides, Brandon Mancini. Phase I open-label, multi-center study to evaluate the safety, tolerability, dosimetry, and preliminary activity of FXX489 ([177Lu]Lu-NNS309) in patients with pancreatic, lung, breast and colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT112.

2025-04-01·Circulation: Cardiovascular Imaging

3D Echocardiographic and CMR Imaging for the Assessment of Right Ventricular Function and Tricuspid Regurgitation Severity

Article

作者: Thiele, Holger ; Ennin, Cecilia ; Cavalcante, João L. ; Dinkel, Julien ; Hausleiter, Jörg ; Stolz, Lukas ; Doldi, Philipp M. ; Besler, Christian ; Lurz, Philipp ; Hahn, Rebecca T. ; Weckbach, Ludwig T. ; Fink, Nicola

BACKGROUND:Tricuspid regurgitation (TR) is associated with increased mortality and is often underdiagnosed due to limitations in imaging modalities. While routine 2-dimensional echocardiography (2DE) demonstrates frequent disagreement with cardiac magnetic resonance imaging (CMR) in classifying TR severity, the incremental value of 3-dimensional echocardiography (3DE) remains unknown also due to the lack of a generalizable grading scheme across imaging modalities. Therefore, this study provides an intermodality comparison of all 3 imaging modalities (2DE, 3DE, and CMR) in evaluating TR severity and proposes an adapted 5-class grading scheme for TR severity using CMR.METHODS:A total of 144 patients with symptomatic TR were analyzed across 2 cohorts: a derivation cohort (n=91) from the University Hospital of Munich and a validation cohort (n=53) from the Heart Center Leipzig. All patients underwent multimodality imaging, including transthoracic 2DE, transesophageal 3DE, and CMR. The adapted 5-class CMR-based grading scheme was proposed and externally validated.RESULTS: In the derivation cohort (median age 81 years, 66% female), TR severity grading by 3DE highly correlated with CMR (87% concordance within a 1-grade difference), significantly outperforming 2DE (68% concordance). While 3DE underestimated right ventricular dimensions compared with CMR ( P <0.001), it provided a comparable measure of TR severity and right ventricular function. 2DE achieved the lowest accuracy rates compared with CMR (34.5%; P =0.005) with frequent overestimation of TR severity. An overestimation of TR severity by 3DE compared with CMR was significantly less frequent than with 2DE (21% versus 56%; P <0.001). Cohen κ analysis confirmed a substantial and superior agreement between 3DE and CMR compared with 2DE (κ=0.63 versus 0.41; P =0.01). The results were externally validated, showing comparable results within the derivation and validation cohorts. CONCLUSIONS:3DE provides an accurate assessment of TR severity comparable to CMR. The proposed 5-class grading scheme for TR severity using CMR demonstrates high accuracy and external validity.

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