@article{LinzBrandsKertelsetal.2021,
  author    = {Linz, Christian and Brands, Roman C. and Kertels, Olivia and Dierks, Alexander and Brumberg, Joachim and Gerhard-Hartmann, Elena and Hartmann, Stefan and Schirbel, Andreas and Serfling, Sebastian and Zhi, Yingjun and Buck, Andreas K. and K{\"u}bler, Alexander and Hohm, Julian and Lapa, Constantin and Kircher, Malte},
  title     = {Targeting fibroblast activation protein in newly diagnosed squamous cell carcinoma of the oral cavity - initial experience and comparison to [18F]FDG PET/CT and MRI},
  series = {European Journal of Nuclear Medicine and Molecular Imaging},
  volume    = {48},
  journal   = {European Journal of Nuclear Medicine and Molecular Imaging},
  doi       = {10.1007/s00259-021-05422-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369331},
  pages     = {3951-3960},
  year      = {2021},
  abstract  = {Purpose While [18F]-fluorodeoxyglucose ([18F]FDG) is the standard for positron emission tomography/computed tomography (PET/CT) imaging of oral squamous cell carcinoma (OSCC), diagnostic specificity is hampered by uptake in inflammatory cells such as neutrophils or macrophages. Recently, molecular imaging probes targeting fibroblast activation protein α (FAP), which is overexpressed in a variety of cancer-associated fibroblasts, have become available and might constitute a feasible alternative to FDG PET/CT. Methods Ten consecutive, treatment-na{\"i}ve patients (8 males, 2 females; mean age, 62 ± 9 years) with biopsy-proven OSCC underwent both whole-body [18F]FDG and [68Ga]FAPI-04 (FAP-directed) PET/CT for primary staging prior to tumor resection and cervical lymph node dissection. Detection of the primary tumor, as well as the presence and number of lymph node and distant metastases was analysed. Intensity of tracer accumulation was assessed by means of maximum (SUVmax) and peak (SUVpeak) standardized uptake values. Histological work-up including immunohistochemical staining for FAP served as standard of reference. Results [18F]FDG and FAP-directed PET/CT detected all primary tumors with a SUVmax of 25.5 ± 13.2 (FDG) and 20.5 ± 6.4 (FAP-directed) and a SUVpeak of 16.1 ± 10.3 ([18F]FDG) and 13.8 ± 3.9 (FAP-directed), respectively. Regarding cervical lymph node metastases, FAP-directed PET/CT demonstrated comparable sensitivity (81.3\% vs. 87.5\%; P = 0.32) and specificity (93.3\% vs. 81.3\%; P = 0.16) to [18F]FDG PET/CT. FAP expression on the cell surface of cancer-associated fibroblasts in both primary lesions as well as lymph nodes metastases was confirmed in all samples. Conclusion FAP-directed PET/CT in OSCC seems feasible. Future research to investigate its potential to improve patient staging is highly warranted.},
  language  = {en}
}
@article{LinzBrandsHerterichetal.2021,
  author    = {Linz, Christian and Brands, Roman C. and Herterich, Theresia and Hartmann, Stefan and M{\"u}ller-Richter, Urs and K{\"u}bler, Alexander C. and Haug, Lukas and Kertels, Olivia and Bley, Thorsten A. and Dierks, Alexander and Buck, Andreas K. and Lapa, Constantin and Brumberg, Joachim},
  title     = {Accuracy of 18-F Fluorodeoxyglucose Positron Emission Tomographic/Computed Tomographic Imaging in Primary Staging of Squamous Cell Carcinoma of the Oral Cavity},
  series = {JAMA Network Open},
  volume    = {4},
  journal   = {JAMA Network Open},
  doi       = {10.1001/jamanetworkopen.2021.7083},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369313},
  year      = {2021},
  abstract  = {Importance Squamous cell carcinoma (SCC) of the oral cavity is one of the most common tumor entities worldwide. Precise initial staging is necessary to determine a diagnosis, treatment, and prognosis. Objective To examine the diagnostic accuracy of preoperative 18-F fluorodeoxyglucose (FDG) positron emission tomographic/computed tomographic (PET/CT) imaging in detecting cervical lymph node metastases. Design, Setting, and Participants This prospective diagnostic study was performed at a single tertiary reference center between June 1, 2013, and January 31, 2016. Data were analyzed from April 7, 2018, through May 31, 2019. Observers of the FDG PET/CT imaging were blinded to patients' tumor stage. A total of 150 treatment-naive patients with clinical suspicion of SCC of the oral cavity were enrolled. Exposures All patients underwent FDG PET/CT imaging before local tumor resection with selective or complete neck dissection. Main Outcomes and Measures The accuracy of FDG PET/CT in localizing primary tumor, lymph node, and distant metastases was tested. Histopathologic characteristics of the tissue samples served as the standard of reference. Results Of the 150 patients enrolled, 135 patients (74 [54.8\%] men) with a median age of 63 years (range, 23-88 years) met the inclusion criteria (histopathologically confirmed primary SCC of the oral cavity/level-based histopathologic assessment of the resected lymph nodes). Thirty-six patients (26.7\%) in the study cohort had neck metastases. Use of FDG PET/CT detected cervical lymph node metastasis with 83.3\% sensitivity (95\% CI, 71.2\%-95.5\%) and 84.8\% specificity (95\% CI, 77.8\%-91.9\%) and had a negative predictive value of 93.3\% (95\% CI, 88.2\%-98.5\%). The specificity was higher than for contrast-enhanced cervical CT imaging (67.0\%; 95\% CI, 57.4\%-76.7\%; P < .01) and cervical magnetic resonance imaging (62.6\%; 95\% CI, 52.7\%-72.6\%; P < .001). Ipsilateral lymph node metastasis in left- or right-sided primary tumor sites was detected with 78.6\% sensitivity (95\% CI, 63.4\%-93.8\%) and 83.1\% specificity (95\% CI, 75.1\%-91.2\%), and contralateral metastatic involvement was detected with 66.7\% sensitivity (95\% CI, 28.9\%-100.0\%) and 98.6\% specificity (95\% CI, 95.9\%-100.0\%). No distant metastases were observed. Conclusions and Relevance In this study, FDG PET/CT imaging had a high negative predictive value in detecting cervical lymph node metastasis in patients with newly diagnosed, treatment-naive SCC of the oral cavity. Routine clinical use of FDG PET/CT might lead to a substantial reduction of treatment-related morbidity in most patients.},
  language  = {en}
}
@article{LewisHabringerKircheretal.2021,
  author    = {Lewis, Richard and Habringer, Stefan and Kircher, Malte and Hefter, Maike and Peuker, Caroline Anna and Werner, Rudolf and Ademaj-Kospiri, Val{\"e}za and G{\"a}ble, Alexander and Weber, Wolfgang and Wester, Hans-J{\"u}rgen and Buck, Andreas and Herhaus, Peter and Lapa, Constantin and Keller, Ulrich},
  title     = {Investigation of spleen CXCR4 expression by [68Ga]Pentixafor PET in a cohort of 145 solid cancer patients},
  series = {EJNMMI Research},
  volume    = {11},
  journal   = {EJNMMI Research},
  doi       = {10.1186/s13550-021-00822-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-363820},
  year      = {2021},
  abstract  = {Background The chemokine receptor CXCR4 is frequently overexpressed and associated with adverse prognosis in most hematopoietic malignancies and solid cancers. Recently, CXCR4 molecular imaging using the CXCR4-specific positron emission tomography (PET) tracer Pentixafor ([68Ga]Pentixafor) has become a well-established method to non-invasively measure CXCR4 expression in vivo. In previous Pentixafor imaging studies, highly variable CXCR4 tracer uptake to the spleen was observed. Results We investigated the hypothesis that enhanced spleen [68Ga]Pentixafor uptake and thus CXCR4 expression in patients with solid tumors would indicate an activated spleen state and/or an association with clinical and prognostic features and survival parameters. In this retrospective study, [68Ga]Pentixafor-PET images and patient records of 145 solid tumor patients representing 27 cancer entities were investigated for an association of spleen [68Ga]Pentixafor uptake and clinical characteristics and outcome. Based on this assessment, we did not observe differences in clinical outcomes, measured by progression-free survival, overall survival and remission status neither within the entire cohort nor within subgroups of adrenal cancer, desmoplastic small round cell tumor, neuroendocrine tumors, non-small cell lung cancer, small cell lung cancer and pancreatic adenocarcinoma patients. No tumor entity showed especially high levels of spleen [68Ga]Pentixafor uptake compared to others or a control cohort. However, when investigating laboratory parameters, there was a positive correlation of high spleen [68Ga]Pentixafor uptake with leukocyte and/or platelet counts in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer. Conclusion Spleen [68Ga]Pentixafor uptake was not associated with stage of disease and clinical outcomes in solid tumor patients. We identified positively associated platelet and/or leukocyte counts with spleen [68Ga]Pentixafor uptake in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer, suggesting that splenic CXCR4 expression could possibly play a role in systemic immunity/inflammation in some types of solid tumors or a subgroup of patients within solid tumor entities.},
  language  = {en}
}
@article{AngayFriedrichPinneckeretal.2018,
  author    = {Angay, Oguzhan and Friedrich, Mike and Pinnecker, J{\"u}rgen and Hintzsche, Henning and Stopper, Helga and Hempel, Klaus and Heinze, Katrin G.},
  title     = {Image-based modeling and scoring of Howell-Jolly Bodies in human erythrocytes},
  series = {Cytometry Part A},
  volume    = {93},
  journal   = {Cytometry Part A},
  doi       = {10.1002/cyto.a.23123},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221140},
  pages     = {305-313},
  year      = {2018},
  abstract  = {The spleen selectively removes cells with intracellular inclusions, for example, detached nuclear fragments in circulating erythrocytes, called Howell-Jolly Bodies (HJBs). With absent or deficient splenic function HJBs appear in the peripheral blood and can be used as a simple and non-invasive risk-indicator for fulminant potentially life-threatening infection after spleenectomy. However, it is still under debate whether counting of the rare HJBs is a reliable measure of splenic function. Investigating HJBs in premature erythrocytes from patients during radioiodine therapy gives about 10 thousand times higher HJB counts than in blood smears. However, we show that there is still the risk of false-positive results by unspecific nuclear remnants in the prepared samples that do not originate from HJBs, but from cell debris residing above or below the cell. Therefore, we present a method to improve accuracy of image-based tests that can be performed even in non-specialized medical institutions. We show how to selectively label HJB-like clusters in human blood samples and how to only count those that are undoubtedly inside the cell. We found a "critical distance" dcrit referring to a relative HJB-Cell distance that true HJBs do not exceed. To rule out false-positive counts we present a simple inside-outside-rule based on dcrit—a robust threshold that can be easily assessed by combining conventional 2D imaging and straight-forward image analysis. Besides data based on fluorescence imaging, simulations of randomly distributed HJB-like objects on realistically modelled cell objects demonstrate the risk and impact of biased counting in conventional analysis. © 2017 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC.},
  language  = {en}
}
@article{SelcukTokluBeykanetal.2018,
  author    = {Selcuk, Nalan Alan and Toklu, Turkay and Beykan, Seval and Karaaslan, Serife Ipek},
  title     = {Evaluation of the dosimetry approaches in ablation treatment of thyroid cancer},
  series = {Journal of Applied Clinical Medical Physics},
  volume    = {19},
  journal   = {Journal of Applied Clinical Medical Physics},
  doi       = {10.1002/acm2.12350},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235882},
  pages     = {134-140},
  year      = {2018},
  abstract  = {In this study, we aimed to evaluate dosimetric approaches in ablation treatment of Differentiated Thyroid Carcinoma (DTC) without interrupting the clinical routine. Prior to therapy, 10.7 MBq 131I in average was orally given to 24 patients suffering from DTC. MIRD formalism was used for dosimetric calculations. For blood and bone marrow dosimetry, blood samples and whole-body counts were collected at 2, 24, 72, and 120 h after I-131 administration. For remnant tissue dosimetry, uptake measurements were performed at the same time intervals. To estimate the remnant volume, anterior and lateral planar gamma camera images were acquired with a reference source within the field of view at 24 h after I-131 administration. Ultrasound imaging was also performed. Treatment activities determined with the fixed activity method were administered to the patients. Secondary cancer risk relative to applied therapy was evaluated for dosimetric approaches. The average dose to blood and bone marrow were determined as 0.15 ± 0.04 and 0.11 ± 0.04 Gy/GBq, respectively. The average remnant tissue dose was 0.58 ± 0.52 Gy/MBq and the corresponding required activity to ablate the remnant was approximately 1.3 GBq of 131I. A strong correlation between 24th-hour uptake and time-integrated activity coefficient values was obtained. Compared to fixed activity method, approximately five times higher secondary cancer risk was determined in bone marrow dosimetry, while the risk was about three times lower in lesion-based dosimetry.},
  language  = {en}
}
@article{IsraelRiehlButtetal.2023,
  author    = {Israel, Ina and Riehl, Gabriele and Butt, Elke and Buck, Andreas K. and Samnick, Samuel},
  title     = {Gallium-68-labeled KISS1-54 peptide for mapping KISS1 receptor via PET: initial evaluation in human tumor cell lines and in tumor-bearing mice},
  series = {Pharmaceuticals},
  volume    = {17},
  journal   = {Pharmaceuticals},
  number    = {1},
  issn      = {1424-8247},
  doi       = {10.3390/ph17010044},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-355898},
  year      = {2023},
  abstract  = {Kisspeptins (KPs, KISS1) and their receptor (KISS1R) play a pivotal role as metastasis suppressor for many cancers. Low or lost KP expression is associated with higher tumor grade, increased metastatic potential, and poor prognosis. Therefore, KP expression has prognostic relevance and correlates with invasiveness in cancers. Furthermore, KISS1R represents a very promising target for molecular imaging and therapy for KISS1R-expressing tumors. The goal of this study was to evaluate the developed KISS1-54 derivative, [\(^{68}\)Ga]KISS1-54, as a PET-imaging probe for KISS1R-expressing tumors. The NODAGA-KISS1-54 peptide was labeled by Gallium-68, and the stability of the resulting [\(^{68}\)Ga]KISS1-54 evaluated in injection solution and human serum, followed by an examination in different KISS1R-expressing tumor cell lines, including HepG2, HeLa, MDA-MB-231, MCF7, LNCap, SK-BR-3, and HCT116. Finally, [\(^{68}\)Ga]KISS1-54 was tested in LNCap- and MDA-MB-231-bearing mice, using µ-PET, assessing its potential as an imaging probe for PET. [\(^{68}\)Ga]KISS1-54 was obtained in a 77 ± 7\% radiochemical yield and at a >99\% purity. The [\(^{68}\)Ga]KISS1-54 cell uptake amounted to 0.6-4.4\% per 100,000 cells. Moreover, the accumulation of [\(^{68}\)Ga]KISS1-54 was effectively inhibited by nonradioactive KISS1-54. In [\(^{68}\)Ga]KISS1-54-PET, KISS1R-positive LNCap-tumors were clearly visualized as compared to MDA-MB-231-tumor implant with predominantly intracellular KISS1R expression. Our first results suggest that [\(^{68}\)Ga]KISS1-54 is a promising candidate for a radiotracer for targeting KISS1R-expressing tumors via PET.},
  language  = {en}
}
@article{MichalskiSchloetelburgHartrampfetal.2023,
  author    = {Michalski, Kerstin and Schl{\"o}telburg, Wiebke and Hartrampf, Philipp E. and Kosmala, Aleksander and Buck, Andreas K. and Hahner, Stefanie and Schirbel, Andreas},
  title     = {Radiopharmaceuticals for treatment of adrenocortical carcinoma},
  series = {Pharmaceuticals},
  volume    = {17},
  journal   = {Pharmaceuticals},
  number    = {1},
  issn      = {1424-8247},
  doi       = {10.3390/ph17010025},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-355901},
  year      = {2023},
  abstract  = {Adrenocortical carcinoma (ACC) represents a rare tumor entity with limited treatment options and usually rapid tumor progression in case of metastatic disease. As further treatment options are needed and ACC metastases are sensitive to external beam radiation, novel theranostic approaches could complement established therapeutic concepts. Recent developments focus on targeting adrenal cortex-specific enzymes like the theranostic twin [\(^{123/131}\)I]IMAZA that shows a good image quality and a promising therapeutic effect in selected patients. But other established molecular targets in nuclear medicine such as the C-X-C motif chemokine receptor 4 (CXCR4) could possibly enhance the therapeutic regimen as well in a subgroup of patients. The aims of this review are to give an overview of innovative radiopharmaceuticals for the treatment of ACC and to present the different molecular targets, as well as to show future perspectives for further developments since a radiopharmaceutical with a broad application range is still warranted.},
  language  = {en}
}
@article{TranGiaDenisBacelarFerreiraetal.2023,
  author    = {Tran-Gia, Johannes and Denis-Bacelar, Ana M. and Ferreira, Kelley M. and Robinson, Andrew P. and Bobin, Christophe and Bonney, Lara M. and Calvert, Nicholas and Collins, Sean M. and Fenwick, Andrew J. and Finocchiaro, Domenico and Fioroni, Federica and Giannopoulou, Katerina and Grassi, Elisa and Heetun, Warda and Jewitt, Stephanie J. and Kotzasarlidou, Maria and Ljungberg, Michael and Louren{\c{c}}o, Val{\´e}rie and McGowan, Daniel R. and Mewburn-Crook, Jamie and Sabot, Benoit and Scuffham, James and Sj{\"o}green Gleisner, Katarina and Solc, Jaroslav and Thiam, Cheick and Tipping, Jill and Wevrett, Jill and Lassmann, Michael},
  title     = {On the use of solid 133Ba sources as surrogate for liquid 131I in SPECT/CT calibration: a European multi-centre evaluation},
  series = {EJNMMI Physics},
  volume    = {10},
  journal   = {EJNMMI Physics},
  organization    = {The MRT Dosimetry Collaboration},
  doi       = {10.1186/s40658-023-00582-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357740},
  year      = {2023},
  abstract  = {Introduction Commissioning, calibration, and quality control procedures for nuclear medicine imaging systems are typically performed using hollow containers filled with radionuclide solutions. This leads to multiple sources of uncertainty, many of which can be overcome by using traceable, sealed, long-lived surrogate sources containing a radionuclide of comparable energies and emission probabilities. This study presents the results of a quantitative SPECT/CT imaging comparison exercise performed within the MRTDosimetry consortium to assess the feasibility of using 133Ba as a surrogate for 131I imaging. Materials and methods Two sets of four traceable 133Ba sources were produced at two National Metrology Institutes and encapsulated in 3D-printed cylinders (volume range 1.68-107.4 mL). Corresponding hollow cylinders to be filled with liquid 131I and a mounting baseplate for repeatable positioning within a Jaszczak phantom were also produced. A quantitative SPECT/CT imaging comparison exercise was conducted between seven members of the consortium (eight SPECT/CT systems from two major vendors) based on a standardised protocol. Each site had to perform three measurements with the two sets of 133Ba sources and liquid 131I. Results As anticipated, the 131I pseudo-image calibration factors (cps/MBq) were higher than those for 133Ba for all reconstructions and systems. A site-specific cross-calibration reduced the performance differences between both radionuclides with respect to a cross-calibration based on the ratio of emission probabilities from a median of 12-1.5\%. The site-specific cross-calibration method also showed agreement between 133Ba and 131I for all cylinder volumes, which highlights the potential use of 133Ba sources to calculate recovery coefficients for partial volume correction. Conclusion This comparison exercise demonstrated that traceable solid 133Ba sources can be used as surrogate for liquid 131I imaging. The use of solid surrogate sources could solve the radiation protection problem inherent in the preparation of phantoms with 131I liquid activity solutions as well as reduce the measurement uncertainties in the activity. This is particularly relevant for stability measurements, which have to be carried out at regular intervals.},
  language  = {en}
}
@article{LisowskiHartrampfHasenaueretal.2023,
  author    = {Lisowski, Dominik and Hartrampf, Philipp E. and Hasenauer, Natalie and Nickl, Vera and Monoranu, Camelia-Maria and Tamihardja, J{\"o}rg},
  title     = {Complete loss of E-cadherin expression in a rare case of metastatic malignant meningioma: a case report},
  series = {BMC Neurology},
  volume    = {23},
  journal   = {BMC Neurology},
  doi       = {10.1186/s12883-023-03450-w},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357996},
  year      = {2023},
  abstract  = {Background Hematogenous tumor spread of malignant meningiomas occurs very rarely but is associated with very poor prognosis. Case presentation We report an unusual case of a patient with a malignant meningioma who developed multiple metastases in bones, lungs and liver after initial complete resection of the primary tumor. After partial hepatic resection, specimens were histologically analyzed, and a complete loss of E-cadherin adhesion molecules was found. No oncogenic target mutations were found. The patient received a combination of conventional radiotherapy and peptide receptor radionuclide therapy (PRRT). Due to aggressive tumor behavior and rapid spread of metastases, the patient deceased after initiation of treatment. Conclusions E-cadherin downregulation is associated with a higher probability of tumor invasion and distant metastasis formation in malignant meningioma. Up to now, the efficacy of systemic therapy, including PRRT, is very limited in malignant meningioma patients.},
  language  = {en}
}
@article{JanzWalzCirnuetal.2024,
  author    = {Janz, Anna and Walz, Katharina and Cirnu, Alexandra and Surjanto, Jessica and Urlaub, Daniela and Leskien, Miriam and Kohlhaas, Michael and Nickel, Alexander and Brand, Theresa and Nose, Naoko and W{\"o}rsd{\"o}rfer, Philipp and Wagner, Nicole and Higuchi, Takahiro and Maack, Christoph and Dudek, Jan and Lorenz, Kristina and Klopocki, Eva and Erg{\"u}n, S{\"u}leyman and Duff, Henry J. and Gerull, Brenda},
  title     = {Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes},
  series = {Molecular Metabolism},
  volume    = {79},
  journal   = {Molecular Metabolism},
  issn      = {2212-8778},
  doi       = {10.1016/j.molmet.2023.101859},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350393},
  year      = {2024},
  abstract  = {Highlights • Loss of DNAJC19's DnaJ domain disrupts cardiac mitochondrial structure, leading to abnormal cristae formation in iPSC-CMs. • Impaired mitochondrial structures lead to an increased mitochondrial respiration, ROS and an elevated membrane potential. • Mutant iPSC-CMs show sarcomere dysfunction and a trend to more arrhythmias, resembling DCMA-associated cardiomyopathy. Background Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy. Methods We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19 which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca\(^{2+}\) kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tv\(_{HeLa}\)). Results Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca\(^{2+}\) concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to β-adrenergic stimulation. Conclusions Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and leads to mitochondrial dysfunction, suggesting that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca\(^{2+}\) kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy.},
  language  = {en}
}